PMID- 11599963 TI - Synthesis and structural characterization of PHP[(C(5)Me(4))(2)], a monodentate chiral phosphine derived from intramolecular C-C coupling of tetramethylcyclopentadienyl groups: an evaluation of steric and electronic properties. AB - The chiral monodentate phosphine PhP[(C(5)Me(4))(2)] is readily obtained by oxidation of the lithium complex Li(2)[PhP(C(5)Me(4))(2)] with I(2), which couples the two cyclopentadienyl groups to form a five-membered heterocyclic ring. The steric and electronic properties of PhP[(C(5)Me(4))(2)] have been evaluated by X-ray diffraction and IR spectroscopic studies on a variety of derivatives, including Ph[(C(5)Me(4))(2)]PE (E = S, Se), Cp*MCl(4)[P[(C(5)Me(4))(2)]Ph] (M = Mo, Ta), Ir[P[(C(5)Me(4))(2)]Ph](2)(CO)Cl, and CpFe(CO)[PhP[(C(5)Me(4))(2)]]Me. For comparison purposes, derivatives of the related phospholane ligand PhP[Me(2)C(4)H(6)] have also been investigated, including Ph[Me(2)C(4)H(6)]PS, Ir[Ph[Me(2)C(4)H(6)]](2)(CO)Cl, Ir[Ph[Me(2)C(4)H(6)]](2)(CO)Me, Ir[PPh[Me(2)C(4)H(6)]](COD)(Cl), and Pd[P[Me(2)C(4)H(6)]Ph][eta(2)-C(6)H(4)C(H)(Me)NMe(2)]Cl. The steric and electronic properties of PhP[(C(5)Me(4))(2)] are determined to be intermediate between those of PPh(2)Me and PPh(3). Thus, the crystallographic cone angles increase in the sequence PPh(2)Me (134.5 degrees) < PhP[(C(5)Me(4))(2)] (140.2 degrees) < PPh(3) (148.2 degrees), while the electron donating abilities decrease in the sequence PPh(2)Me > PhP[(C(5)Me(4))(2)] > PPh(3). Finally, PhP[(C(5)Me(4))(2)] has a smaller cone angle and is less electron donating than the structurally similar phosphine, PhP[Me(2)C(4)H(6)]. PMID- 11599962 TI - New 10-membered inorganic heterocyclic diphosphanes, PhN(PX)(2)[( OC(6)H(2)((T)Bu)(2))(mu-S)(((t)Bu)(2)C(6)H(2)O-)] (x = cl, f). Synthesis and transition metal complexes (molybdenum(0), ruthenium(II), palladium(II), and platinum(II)) of heterocyclic diphosphanes. crystal and molecular structures of the chloro derivative, PhN(PCl)(2)[(-OC(6)H(2)((t)Bu)(2))(mu S)(((t)Bu)(2)C(6)H(2)O-)], and of a molybdenum(0) complex of the fluoro derivative, [Mo(CO)(3)[eta(3)-PhN(PF)(2)[(-OC(6)H(2)((t)Bu)(2))(mu S)(((t)Bu)(2)C(6)H(2)O-)]-kappa P,kappa P,kappa S]]. AB - Bis(dichlorophosphino)aniline, PhN(PCl(2))(2), reacts with stoichiometric amounts of 2,2'-thiobis(4,6-di-tert-butylphenol) to afford a 10-membered heterocycle, PhN(PCl)(2)[(-OC(6)H(2)((t)Bu)(2))(mu-S)(((t))Bu)(2)C(6)H(2)O-)] (1), in high yield. The structure of the heterocycle has been determined by a single-crystal X ray analysis. The 10-membered heterocycle 1 reacts with SbF(3) to afford the corresponding fluoro derivative 2 in good yield. The compounds 1 and 2 act as tridentate ligands with molybdenum carbonyl derivatives, forming complexes of the type [Mo(CO)(3)[eta(3)-PhN(PX)(2)[(-OC(6)H(2)((t)Bu)(2))(mu S)(((t)Bu)(2)C(6)H(2)O-)]-kappa P,kappa P,kappa S]] (3 X = Cl, 4 X = F). A crystal structure of the fluoro derivative 4 showed the facial tricarbonyl complex comprising a relatively strain-free tetracyclic structure with molybdenum in an octahedral environment; the two phosphorus and the sulfur centers were the donor atoms. Compound 2 readily reacts with Ru(II), Pd(II), and Pt(II) derivatives to form chelate complexes, demonstrating the eta(2) mode of coordination. PMID- 11599964 TI - Structural characterization and formation kinetics of sitting-atop (SAT) complexes of some porphyrins with copper(II) ion in aqueous acetonitrile relevant to porphyrin metalation mechanism. Structures of aquacopper(II) and cu(II)-SAT complexes as determined by XAFS spectroscopy. AB - The formation of the sitting-atop (SAT) complexes of 5,10,15,20 tetraphenylporphyrin (H(2)tpp), 5,10,15,20-tetrakis(4-chlorophenyl)porphyrin (H(2)t(4-Clp)p), 5,10,15,20-tetramesitylporphyrin (H(2)tmp), and 2,3,7,8,12,13,17,18-octaethylporphyrin (H(2)oep) with the Cu(II) ion was spectrophotometrically confirmed in aqueous acetonitrile (AN), and the formation rates were determined as a function of the water concentration (C(W)). The decrease in the conditional first-order rate constants with the increasing C(W) was reproduced by taking into consideration the contribution of [Cu(H(2)O)(an)(5)](2+) in addition to [Cu(an)(6)](2+) to form the Cu(II)-SAT complexes. The second-order rate constants for the reaction of [Cu(an)(6)](2+) and [Cu(H(2)O)(an)(5)](2+) at 298 K were respectively determined as follows: (4.1 +/- 0.2) x 10(5) and (3.6 +/- 0.2) x 10(4) M(-1) s(-1) for H(2)tpp, (1.15 +/- 0.06) x 10(5) M(-1) s(-1) and negligible for H(2)t(4-Clp)p, and (4.8 +/- 0.3) x 10(3) and (1.3 +/- 0.3) x 10(2) M(-1) s(-1) for H(2)tmp. Since the reaction of H(2)oep was too fast to observe the reaction trace due to the dead time of 2 ms for the present stopped-flow technique, the rate constant was estimated to be greater than 1.5 x 10(6) M(-1) s(-1). According to the structure of the Cu(II) SAT complexes determined by the fluorescent XAFS measurements, two pyrrolenine nitrogens of the meso-substituted porphyrins (H(2)tpp and H(2)tmp) bind to the Cu(II) ion with a Cu-N(pyr) distance of ca. 2.04 A, while those of the beta pyrrole-substituted porphyrin (H(2)oep) coordinate with the corresponding bond distance of 1.97 A. The shorter distance of H(2)oep is ascribed to the flexibility of the porphyrin ring, and the much greater rate for the formation of the Cu(II)-SAT complex of H(2)oep than those for the meso-substituted porphyrins is interpreted as due to a small energetic loss at the porphyrin deformation step during the formation of the Cu(II)-SAT complex. The overall formation constants, beta(n), of [Cu(H(2)O)(n)()(an)(6)(-)(n)](2+) for the water addition in aqueous AN were spectrophotometrically determined at 298 K as follows: log(beta(1)/M(-1)) = 1.19 +/- 0.18, log(beta(2)/M(-2)) = 1.86 +/- 0.35, and log(beta(3)/M(-3)) = 2.12 +/- 0.57. The structure parameters around the Cu(II) ion in [Cu(H(2)O)(n)(an)(6-n)](2+) were determined using XAFS spectroscopy. PMID- 11599965 TI - Carboxymethylated cage amines: coordination and lactamization. AB - Depending upon the position and degree of substitution, carboxymethyl derivatives of cage amines of the "sarcophagine" (3,6,10,13,16,19 hexaazabicyclo[6.6.6]icosane) type vary considerably in the stability of their lactamized forms. For 1,8-diamino-3-carboxymethylsarcophagine, L(1), only indirect evidence for some involvement of a lactamized form of its Ni(II) complex has been obtained. Crystal structure determinations for [Cu(H(2)L(1))](NO(3))(3.5)Cl(0.5) x 2.5H(2)O and [Ni(HL(1))]Cl(3) x 3H(2)O show distorted octahedral coordination of all six endocyclic N-donor atoms in both cases. For related diaminosarcophagine derivatives with either two (1,8; L(2)) or three (1,1,8; L(3)) carboxymethyl substituents on the exocyclic N atoms, crystallographic studies have shown a dilactam form for the ligands in their Ni(II) and Cu(II) complexes which is of almost identical conformation to that of the diprotonated "free" ligand in [H(2)L(3)][ZnCl(4)] x 6H(2)O. The lactamized ligands appear to strongly favor square planar four-coordination, and the Co(II) complex of L(2) shows a remarkable lack of reactivity toward oxygen. Kinetic studies indicate that the hydrolytic stability of the lactam rings is comparable to that of uncoordinated analogues. PMID- 11599966 TI - Valence tautomerism and metal-mediated catechol oxidation for complexes of copper prepared with 9,10-phenanthrenequinone. AB - Bis(pyridine)(9,10-phenanthrenequinone)(9,10-phenanthrenediolato)copper(II), Cu(py)(2)(PhenCat)(PhenBQ), has been prepared by treating copper metal with 9,10 phenanthrenequinone in pyridine solution. In dilute solution, both Cu(py)(2)(PhenCat)(PhenBQ) and the related complex Cu(tmeda)(PhenCat)(PhenBQ) lose PhenBQ to form Cu(II)L(2)(PhenCat), where L(2)= tmeda, 2 py. EPR spectra recorded at temperatures between 300 and 77 K reveal the presence of species with radical and metal localized spins together at equilibrium. Equilibria between Cu(II)L(2)(PhenCat) and Cu(I)L(2)(PhenSQ) redox isomers are solvent dependent, with a shift to higher temperature for polar solvents. Both complexes are oxygen sensitive, reacting with dioxygen to give complexes of diphenic acid. Structural characterization on products obtained with tmeda show that dioxygen insertion across the C-C bond within the chelate ring leads to dimeric products with adjacent Cu(II) ions bridged by diphenate ligands. The addition of O(2) to Cu(tmeda)(PhenCat) in acetonitrile solution at 0 degrees C appears to form a peroxo complex, tentatively identified as Cu(tmeda)(O(2))(PhenQ) on the basis of iodometric titration, as the precursor to the diphenate complex. PMID- 11599967 TI - (6,17-Dimethyl-8,15-diphenyldibenzo[b,i][1,4,8,11]-tetra aza[14]annulenato)nickel(II) in solids: two guest-free polymorphs and inclusion compounds with methylene chloride and fullerene (C(60))-carbon disulfide. AB - Two guest-free polymorphs and two inclusion compounds of the macrocyclic title complex [NiL] have been isolated and characterized with single-crystal and/or powder XRD, solid-state (13)C NMR, and other methods. The inclusion compound with methylene chloride, [NiL](CH(2)Cl(2)), is stable in air and thermally stable up to approximately 128 degrees C. Its crystal structure is consistent with van der Waals packing of the host [NiL] and guest CH(2)Cl(2) molecules. The host complex has square-planar coordination of the nickel(II) center with four nitrogen atoms of the macrocycle with an average Ni-N distance of 1.86 A. The molecule has a saddle-shaped conformation with the guest molecule located between one phenylene and two phenyl rings of the host molecule. Isostructural compounds with chloroform and 2-chloropropane form only as mixtures along with a guest-free host polymorph. The inclusion compound with C(60) has a composition 3[NiL]*(C(60))*2(CS(2)) and here also the crystal structure is consistent with a van der Waals type of packing. Three crystallographically inequivalent [NiL] molecules have geometries similar to that in the inclusion compound with methylene chloride. The concave surfaces of the complex molecules form a spherical cavity for the C(60) molecule. At -100 degrees C the C(60) molecule is disordered over two orientations centered at the same site. (13)C NMR studies at room temperature show that the C(60) molecule is undergoing rapid pseudo isotropic rotation. The stability and other properties of the title and related complexes are discussed. PMID- 11599968 TI - Triimidosulfonic acid and organometallic triimidosulfonates: S(+)-N(-) versus S=N bonding. AB - Sulfonic acids RSO(2)OH and their metal salts MO(3)SR are versatile catalysts in large-scale industrial cyclization and polymerization processes. Isoelectronic replacement of the oxygen atoms by NR imido groups gives triimidosulfonic acid and triimidosulfonates. The salts form nonaggregated soluble molecules rather than infinite solid-state lattices such as their oxo analogues. In this paper, we present the synthesis and structure of the basic starting material MeS(N(t)Bu)(3)H (1), the metal complexes [Me(2)Al(N(t)Bu)(3)SMe] (2) and [Zn[(N(t)Bu)(3)SMe](2)] (3), and the mixed metal adduct [(thf)Li[(N(t)Bu)(3)SMe].ZnMe(2)] (4). The chelating coordination, rather than the tripodal coordination, cannot be attributed to steric effects of the S-bonded methyl group, as the less demanding Ph-C triple bond C-alkynyl substituent at sulfur in [(thf)(2)Li[(N(t)Bu)(3)SCCPh]] (5) causes the same conformation. S-N bond shortening to the pendant imido group has to be attributed to closed-shell electrostatic attraction rather than to S-N double bonding by valence expansion at the central sulfur atom. Coordination to an additional N-->Zn dative bond in 4 widens the bond length to values normally interpreted as S-N single bonds. We take this fact as experimental evidence that S-N bonding is predominantly governed by electrostatic interaction rather than by valence expansion employing d-orbitals. This was predicted by theoreticians more than a decade ago. PMID- 11599969 TI - Stereoselective synthesis of chiral pinene[5,6]bipyridine ligands and their coordination chemistry. AB - The C(2)-symmetric chiral pinene[5,6]bipyridine V (Chart 1) was synthesized according to a procedure published by our group recently (Kolp, B.; Abeln, D.; Stoeckli-Evans, H.; Zelewsky, A. v. Eur. J. Inorg. Chem. 2001, 1207). A series of stereoselectively alkylated derivatives (Va-Vo) (Table 1) was prepared. The solid state structures of the compounds Vc and Vk were determined by single-crystal X ray diffraction, where both compounds show a transoid conformation of the bipyridine unit and proved to be alkylated stereoselectively from the sterically less hindered side of the pinene moiety. The X-ray structure of the cobalt complex 4 shows the metal ion to be tetrahedrally coordinated by one chiral bipyridine V and two chloride ligands. If 2 equiv of ligand V was used, 2:1 complexes were obtained with Cu(I), Ag(I), and Co(II) ions. PMID- 11599970 TI - Mixed-metal assemblies containing multiply bonded dirhenium species linked through thiocyanate- and cyanide-containing bridging units. AB - The lability of the terminal Re-Cl bond that is cis to the bridging CO ligand in the edge-sharing bioctahedral complexes Re(2)(mu-Cl)(mu-CO)(mu-PP)(2)Cl(3)(L), where PP = Ph(2)PC(=CH(2))PPh(2) (dppE) when L = CO (1) and PP = Ph(2)PCH(2)PPh(2) (dppm) when L = CO (2) or XyINC (3), has been exploited in the preparation of mixed-metal Re(4)Pd(2), Re(2)Ag, Re(2)W, Re(2)Pt, and Re(2)Rh assemblies, in which the dirhenium units are bound to the other metals through NCS or CN bridges. These complexes, which retain the Re=Re bonds of the parent dirhenium complexes, comprise the novel centrosymmetric complex [Re(2)Cl(3)(mu dppE)(2)(CO)(2)(mu-NCS)](2)Pd(2)(mu-SCN)(mu-NCS)Cl(2) (9), and the trimetallic complexes Re(2)Cl(3)(mu-dppE)(2)(CO)(2)[(mu-NC)Ag(CN)] (10), Re(2)Cl(3)(mu dppE)(2)(CO)(2)[(mu-NC)W(CO)(5)] (11), [Re(2)Cl(3)(mu-dppE)(2)(CO)(2)[(mu NC)Pt(CN)(CN-t-Bu)(2)]]PF(6) (12), [Re(2)Cl(3)(mu-dppE)(2)(CO)(2)[(mu N(CN)(2))Rh(CO)(PPh(3))(2)]]O(3)SCF(3) (13), and Re(2)Cl(3)(mu dppm)(2)(CO)(2)[(mu-NC)W(CO)(5)] (16). The identities of 9 and 16 have been established by X-ray crystallography, and all complexes characterized by IR and NMR spectroscopy and cyclic voltammetry. The reactions of the dicarbonyl complex 1, and the isomeric pair of complexes Re(2)Cl(4)(mu-dppm)(2)(CO)(CNXyl), which have edge-sharing bioctahedral (ESBO) (3) and open bioctahedral (OBO) (4) geometries, with Na[N(CN)(2)] and K[C(CN)(3)] have been used to prepare complexes in which the uncoordinated CN groups have the potential to coordinate other mono- or dimetal units to form extended arrays. The complexes which have been prepared and characterized are the monosubstituted species Re(2)Cl(3)(X)(mu dppE)(2)(CO)(2) (X = N(CN)(2) (14) or C(CN)(3) (15)) and Re(2)Cl(3)(X)(mu dppm)(2)(CO)(CNXyl) (X = N(CN)(2) (17) or C(CN)(3) (18) with ESBO structures; X = N(CN)(2) (19) or C(CN)(3) (20) with OBO structures), of which 15, 18, and 20 have been characterized by single-crystal X-ray structure determinations. The substitutional labilities of the Re-Cl bonds in the complexes Re(2)Cl(4)(mu dppm)(2)(CO) (5), Re(2)Cl(4)(mu-dppm)(2)(CNXyl) (6), and Re(2)Cl(4)(mu-dppm)(2) (7) toward Na[N(CN)(2)] and K[C(CN)(3)] have also been explored and the complexes Re(2)Cl(3)(X)(mu-dppm)(2)(CO) (X = N(CN)(2) (21) or C(CN)(3) (22)), Re(2)Cl(3)(X)(mu-dppm)(2)(CNXyl) (X = N(CN)(2) (23) or C(CN)(3) (24)), Re(2)Cl(2)(X)(2)(mu-dppm)(2)(CNXyl) (X = N(CN)(2) (25) or C(CN)(3) (26)), Re(2)[N(CN)(2)](4)(mu-dppm)(2) (27), and Re(2)[C(CN)(3)](4)(mu-dppm)(2) (28) isolated in good yield. Single-crystal X-ray structure determinations of 24, 26, and 27 have shown that the Re-Re triple bonds present in the starting materials 5 7 are retained in these products. PMID- 11599971 TI - A new three-dimensional inorganic-organic hybrid fluorinated-iron(III) arsenate: (C(6)H(14)N(2))[Fe(3)(HAsO(4))(2)(AsO(4))F(4)]0.5H(2)O. Hydrothermal synthesis, crystal structure, and spectroscopic and magnetic properties. PMID- 11599972 TI - Tuftsin receptor-binding peptide labeled with technetium: chemistry and preliminary in vitro receptor-binding study. PMID- 11599973 TI - Mononuclear hydroxamate five-coordinate nickel(II) complexes: structural and spectroscopic characterization. PMID- 11599975 TI - Electron transfer. 149. Reactions of hypervalent chromium with s(2) metal-ion reducing centers. PMID- 11599974 TI - EPR characteristics of the [(NC)(5)M(NO)](3-) ions (M = Fe, Ru, Os). Experimental and DFT study establishing NO* as a ligand. PMID- 11599976 TI - Convenient synthesis of tris-heteroleptic ruthenium(II) polypyridyl complexes. PMID- 11599977 TI - Mixed chloride/phosphine complexes of the dirhenium core. 8. Synthesis and crystal structure of the quadruply bonded dirhenium(III) anion [Re(2)Cl(7)(PMe(3))](-). PMID- 11599978 TI - Mild solvothermal synthesis and TEM investigation of unprotected nanoparticles of tin sulfide. PMID- 11599979 TI - Synthesis, X-ray structure, electrochemical, and EPR studies of a pentacoordinated mn(II) tetramethylcyclam complex. PMID- 11599980 TI - Redox isomerism for quinone complexes of chromium and chromium oxidation state assignment from X-ray absorption spectroscopy. PMID- 11599981 TI - Trans-disubstituted tetraarylporphyrin as a precursor to larger molecular architectures: an application of MacDonald "2 + 2" porphyrin synthesis in aqueous anionic surfactant. PMID- 11599982 TI - Determination of dithiocarbamate fungicide residues in food by a spectrophotometric method using a vertical disulfide reaction system. AB - Dithiocarbamates are a class of fungicides extensively used in many crops worldwide. The current residue definition of dithiocarbamates in food for compliance with maximum residue limits, at national and international levels, is total residues arising from the use of any or each dithiocarbamate fungicide, determined as CS(2). The analytical method most frequently used to analyze dithiocarbamate residues in food for monitoring purposes was proposed more than 30 years ago. In this method, total dithiocarbamates are decomposed to CS(2), which is purified and reacted with a cupric reagent. The yellow complex formed is quantified by spectrophotometry. In this paper, a new reaction system for the purification and complexation of CS(2) is proposed. The new system is less fragile than the traditional design, is easier to assemble, and allows for a higher sample throughput, in addition to being of low cost. Recovery of added mancozeb, thiram, or ziram (0.15-8.0 mg/kg) in rice, beans, apple, banana, orange, papaya, tomato, cucumber, and potato ranged from 82 to 120%, with relative standard deviations from 0 to 10% (n = 3 or 5). Analysis of apple, tomato, and papaya samples with field-incurred dithiocarbamate residues showed comparable results using both the traditional and the new reaction systems. PMID- 11599983 TI - Aloe exudate: characterization by reversed phase HPLC and headspace GC-MS. AB - From the leaves of aloe, a succulent plant, a dried exudate commonly called aloe can be obtained, which is used as a natural drug for its cathartic effect and is widely employed as a bittering agent in alcoholic beverages. This investigation provides a tentative characterization of several commercial aloe exudates carried out both by reversed phase HPLC and by headspace GC-MS analysis. By means of HPLC the derivatives were evaluated, and by GC-MS the volatile fraction was investigated. Qualitative and quantitative differences among the constituents in various samples of different origins were found. In particular, these were evident in the HPLC profile of Kenya aloe and an Aloe barbadensis sample, which exuded a high content of isoaloeresin D and aloins, whereas GC-MS analysis showed the presence of anisole exclusively in Kenya aloe samples. Moreover, the results obtained by means of the latter technique suggested a reason for the prevailing use of Mosselbay and Port Elizabeth aloes in bitter spirits formulation. PMID- 11599984 TI - Proteome analysis applied to meat science: characterizing postmortem changes in porcine muscle. AB - The aim of this work was to test the application of two-dimensional electrophoresis (2DE)-based proteome analysis in studying muscle tissues and meat of pork, and to use this technology to characterize as many of the changes that occur in pig muscle proteins during post mortem storage of the carcass as possible. For this purpose, 2DE proved to be a powerful tool, as it is far more sensitive and shows a higher resolving power than conventional SDS-PAGE, allowing for the precise and semiquantitative recognition of approximately 1000 individual muscle proteins in every 2DE display. In this study, we have chosen to analyze the subset of muscle proteins that have molecular masses of 5-200 kDa, and can be reproducibly separated in the pH span of 4-9. By comparing 2DE patterns of muscle samples taken immediately after slaughter (time 0), as well as those taken 4, 8, 24, and 48 h post mortem, we have estimated the relative changes of individual muscle proteins during the post mortem storage of the carcass. In this paper, of these changes we report the 15 most notable. PMID- 11599985 TI - Analysis of sweet diterpene glycosides from Stevia rebaudiana: improved HPLC method. AB - An improved analytical method was developed which may be applied to quality control of stevioside and rebaudioside A contents in dried leaves of Stevia rebaudiana before processing; in a selective sampling program searching for plants of higher yield in diterpene glycosides content; or when a large number of samples are sent to the laboratory for analysis. The procedure developed involves two steps: solvent extraction followed by an isocratic HPLC analysis. The sample, 1 g of dried leaves of S. rebaudiana, is ground and solvent-extracted with EtOH 70% (w/w) in Erlenmeyer flasks by shaking for 30 min in a 70 degrees C water bath. After the extract was cooled, it was filtered and analyzed by HPLC using an NH(2) column (250 x 4.6 mm) and a mixture of acetonitrile/water (80:20, v/v) as mobile phase, pH 5 adjusted with acetic acid. The detection was in the UV range at 210 nm (0.04 AUFS). Quantitation was performed by means of an external standard calibration curve for each analyte which had been obtained from standard solutions of pure stevioside and rebaudioside A. Working under these conditions there were no observed interference effects. The method saves time in sample preparation, and reduces sample handling and chromatographic analysis time, while having little loss of precision [coefficient of variation (CV%) between 1.8% and 3.0%] and recovery [between 98.5% and 100.5%]. The method was applied to 30 samples of S. rebaudiana from Misiones (Northeastern Argentina), and the stevioside content found ranged between 3.78 and 9.75% (weight) whereas Rebaudioside A content ranged between 1.62 and 7.27% (weight). PMID- 11599986 TI - Production, characterization, and cross-reactivity studies of monoclonal antibodies against the coccidiostat nicarbazin. AB - A cELISA was developed for the coccidiostat nicarbazin. On the basis of previous computer-assisted molecular modeling studies, p-nitrosuccinanilic acid (PNA-S) was selected as a hapten to produce antibodies to 4,4'-dinitrocarbanilide (DNC), the active component of the coccidiostat nicarbazin. Synthesis is described for the hapten [p-nitro-cis-1,2-cyclohexanedicarboxanilic acid (PNA-C)] used in a BSA conjugate as a plate coating antigen. Monoclonal antibodies (Mabs) were isolated that compete with nicarbazin, having IgM(kappa) isotype. Because of the lack of water solubility of nicarbazin, N,N-dimethylformamide (DMF) (3%, v/v) and acetonitrile (ACN) (10%, v/v) were added to the assay buffer to achieve solubility of nicarbazin and related compounds. The Nic 6 Mabs had an IC(35) value for nicarbazin of 0.92 nmol/mL, with a limit of detection of 0.33 nmol/mL. Nic 6 exhibited high cross-reactivity for PNA-S and PNA-C, and 3-nitrophenol, 4 nitrophenol, and 1-(4-chlorophenyl)-3-(4-nitrophenyl) urea. However, Nic 6 had little or no cross-reactivity with 15 other related compounds. PMID- 11599987 TI - Comparison of different electrophoretic separations of hen egg white proteins. AB - The hen egg white protein composition has not yet been fully defined. To improve the knowledge of this biological fluid, the most usual and recently developed electrophoretic methods have been used: SDS-PAGE, native-PAGE, isoelectric focusing (IEF), and 2-dimensional electrophoresis (2DE). Seven of the major known proteins were thus identified in at least one electrophoretic system. Isoforms of ovotransferrin, ovalbumin, and ovomucoid were visualized when pI was used for the separation. Two-dimensional electrophoresis allowed separation of a very large number of spots. In each of the four systems, some components were revealed but not identified, and unknown spots were particularly numerous with 2DE. With this technique, many spots corresponding to small acidic proteins were highlighted, among which was the Ch21 protein, whose presence in hen egg white was thus confirmed. This study thus constitutes, to our knowledge, the first proteomic investigation of hen egg white. PMID- 11599988 TI - Identification of flatfish (Pleuronectiforme) species using DNA-based techniques. AB - Identification of flatfish species using a DNA-based methodology was studied. The polymerase chain reaction was employed to obtain a 464 bp amplicon from mitochondrial cytochrome b gene. The sequences from this fragment belonging to 24 species were analyzed using a genetic distance method, and polymorphic sites were determined. The fragment was found to be highly polymorphic (231 sites), and this permitted the differentiation of most of the species. Phylogenetic tree construction was employed to allow the identification of flatfish species. As a result, each species was grouped in a well-differentiated clade, except for two pairs: Limanda ferruginea and L. limanda, and Solea impar and S. lascaris, which could not be differentiated. On the basis of the sequences obtained, restriction enzymes were selected to provide specific restriction profiles, which allow the differentiation of 21 species of flatfish in a faster and less expensive manner than sequencing. This polymerase chain reaction-restriction fragment length polymorphism methodology (PCR-RFLP) was tested using commercial samples. PMID- 11599989 TI - Inulin determination for food labeling. AB - Inulin and oligofructose exhibit valuable nutritional and functional attributes, so they are used as supplements as soluble fiber or as macronutrient substitutes. As classic analytical methods for dietary fiber measurement are not effective, several specific methods have been proposed. These methods measure total fructans and are based on one or more enzymatic sample treatments and determination of released sugars. To determine inulin for labeling purposes, we developed an easy and rapid anion-exchange high-performance liquid chromatography (HPLC) method following water extraction of inulin. HPLC conditions included an Aminex HPX- 87C column (Bio-Rad), deionized water at 85 degrees C as the mobile phase and a refractive index detector. The tested foods included tailor-made food products containing known amounts of inulin and commercial products (cookies, milk, ice creams, cheese, and cereal bars). The average recovery was 97%, and the coefficient of variation ranged from 1.1 to 5% in the food matrixes. The obtained results showed that this method provides an easier, faster and cheaper alternative than previous techniques for determining inulin with enough accuracy and precision for routine labeling purposes by direct determination of inulin by HPLC with refractive index detection. PMID- 11599990 TI - Analysis of swainsonine: extraction methods, detection, and measurement in populations of locoweeds (Oxytropis spp.). AB - An analytical method has been developed to measure the locoweed toxin, swainsonine, in locoweed plant material. Dry ground plant samples were extracted using a small-scale liquid/liquid extraction procedure followed by isolation of the swainsonine by solid phase extraction with a cation-exchange resin. Detection and quantitation of the swainsonine were accomplished using reversed phase high performance liquid chromatography coupled to atmospheric pressure chemical ionization tandem mass spectrometry (LC-MS(2)). The limit of quantitation was estimated to be 0.001% swainsonine by weight in dry plant material, which corresponds to the lower threshold for toxicity of locoweeds. The method of analysis was applied to the analysis of Oxytropis sericea (white locoweed) and Oxytropis lambertii (Lambert locoweed) plant samples to measure the variability of individual plant swainsonine levels within populations and within species. Individual plant variability was found to be highly significant for both O. sericea and O. lambertii populations. The combined three-year mean swainsonine values taken from three populations of O. sericea ranged from 0.046% in Utah to 0.097% in a New Mexico population. Sixteen individual populations of O. lambertii were sampled from eight different U.S. states. Swainsonine was detected at levels >0.001% in only 5 of the 16 collection sites. Those populations of O. lambertii found to contain higher swainsonine levels were restricted to the most southern and western portion of its distribution, and all were identified as belonging to var. bigelovii, whereas var. articulata and var. lambertii samples contained swainsonine at levels <0.001%. PMID- 11599991 TI - High-throughput analysis of total nitrogen content that replaces the classic Kjeldahl method. AB - A high-throughput method for determination of total nitrogen content has been developed. The method involves decomposition of samples, followed by trapping and quantitative colorimetric determination of the resulting ammonia. The present method is rapid, facile, and economical. Thus, it can replace the classic Kjeldahl method through its higher efficiency for determining multiple samples. Compared to the classic method, the present method is economical and environmentally friendly. Based on the present method, a novel reactor was constructed to realize routine high-throughput analyses of multiple samples such as those found for pharmaceutical materials, foods, and/or excrements. PMID- 11599992 TI - Influence of operating parameters on the use of the microwave-assisted process (MAP) for the extraction of azadirachtin-related limonoids from neem (Azadirachta indica) under atmospheric pressure conditions. AB - The use of the microwave-assisted process (MAP) for the extraction of azadirachtin-related limonoids (AZRL) from various parts of the neem tree was investigated under different operating conditions. The influence of microwave power, solvent, and irradiation time on the recovery of AZRL was studied. The efficiency of the microwave-assisted extraction (MAE) of the seed kernel, the seed shell, the leaf, and the leaf stem was compared to that of conventional extraction methods. The content of AZRL in the extracts was estimated with a vanillin-based colorimetric assay and a multivariate calibration technique. The results showed that the MAE technique can enhance the extraction of AZRL from different parts of neem possessing microstructures. Investigation of the influence of the solvent also indicted that the solvent used not only influences the efficiency but also affects the selectivity of the MAE. PMID- 11599993 TI - Analysis of pesticide residues in eggs by direct sample introduction/gas chromatography/tandem mass spectrometry. AB - Direct sample introduction (DSI) or "dirty sample injection" is a rapid, rugged, and inexpensive approach to large volume injection in gas chromatography (GC) for semivolatile analytes such as pesticides. DSI of complex samples such as eggs requires a very selective detection technique, such as tandem mass spectrometry (MS-MS), to determine the analytes among the many semivolatile matrix components that also appear. In DSI, the nonvolatile matrix components that normally would contaminate the GC system in traditional injection methods remain in a disposable microvial, which is removed after every injection. For example, 3 microg of nonvolatile residue typically remained in the microvial after an injection of egg extract using the DSI method. This analytical procedure involves the following: (i) weighing 10 g of egg in a centrifuge tube and adding 2 g of NaCl and 19.3 mL of acetonitrile (MeCN); (ii) blending for 1 min using a probe blender; (iii) centrifuging for 10 min; and (iv) analyzing 10 microL (5 mg of egg equivalent) of the extract using DSI/GC/MS-MS. No sample cleanup or solvent evaporation steps were required to achieve quantitative and confirmatory results with <10 ng/g detection limits for 25 of 43 tested pesticides from several chemical classes. The remaining pesticides gave higher detection limits due to poor fragmentation characteristics in electron impact ionization and/or degradation. Analysis of eggs incurred with chlorpyrifos-methyl showed a similar trend in the results as a more traditional approach. PMID- 11599994 TI - Method for determination of pentobarbital in dry dog food by gas chromatography/mass spectrometry. AB - A procedure has been developed and validated for measuring the concentration of pentobarbital residues in dry, extruded animal feed in the range of 3-200 ng/g (ppb) with an estimated limit of quantitation of 2 ppb. The method was developed for surveillance purposes: to measure the concentration of euthanizing agent which might be present in feeds incorporating rendered products which themselves might include some fraction of euthanized animals. A previously published qualitative procedure was modified by adding isotopically labelled pentobarbital as an internal standard. Dry feed was ground and extracted with methanol. The extract was loaded on a mixed-mode (C-18, anion exchange) solid-phase extraction cartridge designed for barbiturate residues. Pentobarbital was eluted and derivatized for gas chromatography/mass spectrometry in positive ion chemical ionization mode. Quantitation was based on the ratio of dimethyl-pentobarbital MH+ (m/z 255) vs dimethyl-pentobarbital-d(5) (m/z 260) in standards and extracts. Accuracy ranged from 112% at 3 ppb to 96% at 200 ppb, with relative standard deviations ranging from 4% at 3 ppb to 2% at 200 ppb. PMID- 11599995 TI - Quantitative determination of short-chain free fatty acids in milk using solid phase microextraction and gas chromatography. AB - The objective was to establish a rapid, precise, and accurate methodology for the quantification of short-chain free fatty acids (FFA) (C(4)-C(12)) in milk by solid-phase microextraction and gas chromatography. Sampling conditions such as fiber type, pH, salt addition, temperature, volume, and time were investigated. FFA extraction consisted of placing 40 mL of milk containing 28% NaCl at pH 1.5 in a sealed vial and equilibrating for 30 min at 70 degrees C. A polyacrylate fiber was exposed to the sample headspace for 60 min and desorbed for 5 min into the gas chromatograph. Calibration curves for FFA followed linear relationships with highly significant (p < 0.001) correlation coefficients (R(2) = 0.99). Coefficients of variation of less than 7.7% for FFA concentrations indicated that the technique was reproducible. The limits of quantification for C(4)-C(10) were in the low parts per million level, which were below the concentration range found in fresh pasteurized milk (0.48-2.52 ppm) or rancid milk (4.73-32.31 ppm). PMID- 11599996 TI - Supercritical fluid extraction of fat from ground beef: effects of water on gravimetric and GC-FAME fat determinations. AB - This study investigated the supercritical carbon dioxide (SC-CO(2)) extraction of fat from ground beef and the effects of several factors on the gravimetric determination of fat. The use of ethanol modifier with the SC-CO(2) was not necessary for efficient fat extraction; however, the ethanol did increase the coextraction of water. This coextraction of water caused a significant overestimation of gravimetric fat. Oven-drying ground beef samples prior to extraction inhibited the subsequent extraction of fat, whereas oven-drying the extract after collection decreased the subsequent gas chromatographic fatty acid methyl ester (GC-FAME) fat determination. None of the drying agents tested were able to completely prevent the coextraction of water, and silica gel and molecular sieves inhibited the complete extraction of fat. Measurements of collection vial mass indicated that CO(2) extraction/collection causes an initial increase in mass due to the density of CO(2) (relative to displaced air) followed by a decrease in vial mass due to the removal of adsorbed water from the collection vial. Microwave-drying of the empty collection vials removes approximately 3 mg of adsorbed water, approximately 15-20 min is required for readsorption of the displaced water. For collection vials containing collected fat, microwave-drying effectively removed coextracted water, and the vials reached equilibration after approximately 10-15 min. Silanizing collection vials did not significantly affect weight loss during microwave-drying. SC-CO(2) can be used to accurately determine fat gravimetrically for ground beef, and the presented method can also be followed by GC-FAME analysis to provide specific fatty acid information as well. PMID- 11599997 TI - Extraction and analysis of lead in sweeteners by flow-injection Donnan dialysis with flame atomic absorption spectroscopy. AB - Flow-injection Donnan dialysis is demonstrated for the extraction of lead in sweeteners using flame atomic absorption spectroscopy (FAAS). For spiked concentrations in the low microgram per gram range, recoveries were greater than 90%, and the relative standard deviation was typically less than 10% for a 15-min dialysis procedure. The method detection limit is 350 ng/g. Donnan dialysis is shown to be successful for the extraction of lead in sucrose, corn syrup, and honey but limited in performance for molasses and artificial syrup. This paper also includes a comparison to other procedures for the determination of lead in sweeteners and presents options for realizing improved method performance with Donnan dialysis. PMID- 11599998 TI - Development and validation of an improved oxygen radical absorbance capacity assay using fluorescein as the fluorescent probe. AB - An improved method of oxygen radical absorbance capacity (ORAC) assay has been developed and validated using fluorescein (3',6'-dihydroxyspiro[isobenzofuran 1[3H],9'[9H]-xanthen]-3-one) as the fluorescent probe. Our results demonstrate that fluorescein (FL) is superior to B-phycoerythrin. The oxidized FL products induced by peroxyl radical were identified by LC/MS, and the reaction mechanism was determined to follow a classic hydrogen atom transfer mechanism. In addition, methodological and mechanistic comparison of ORAC(FL) with other widely used methods was discussed. It is concluded that, unlike other popular methods, the improved ORAC(FL) assay provides a direct measure of hydrophilic chain-breaking antioxidant capacity against peroxyl radical. PMID- 11599999 TI - New flavanol derivatives from grape (Vitis vinifera) byproducts. Antioxidant aminoethylthio-flavan-3-ol conjugates from a polymeric waste fraction used as a source of flavanols. AB - A new family of antioxidants has been obtained from a residual fraction of polymeric polyphenols of grape origin. The integral exploitation of resources is important in any sustainable production scheme. Many byproducts and residues generated by the agroindustries contain polyphenols with potential application as preventative agents against cancer and cardiovascular diseases. Among these polyphenols oligomeric proanthocyanidins are particularly significant. The polymeric forms, considered of less interest because of their astringent properties, constitute the largest portion of the biologically active plant proanthocyanidins. The new compounds described here result from the breakdown of polymeric flavanols in the presence of cysteamine and bear an amino function, which facilitates their isolation from complex mixtures by cation-exchange gels or resins. In this way, valuable antioxidant molecules can be efficiently obtained from otherwise wasted polymers. The new molecules appear to be as effective as their underivatized counterparts (flavan-3-ols) as antioxidants. PMID- 11600000 TI - Identification of chemical components of corn kernel pericarp wax associated with resistance to Aspergillus flavus infection and aflatoxin production. AB - Kernel pericarp wax of the corn breeding population GT-MAS:gk has been associated with resistance to Aspergillus flavus infection and aflatoxin production. GT MAS:gk wax, previously compared to waxes of three susceptible genotypes, was presently compared to wax of a different, and more numerous, group of susceptible lines. Wax separation by TLC confirmed previous findings, demonstrating a unique GT-MAS:gk band and a unique "susceptible" band. Only GT-MAS:gk wax inhibited the growth of A. flavus; however, no association was established, as before, between kernel wax abundance and resistance. Gas chromatography-mass spectroscopy (GC-MS) analysis of kernel whole wax showed a higher percentage of phenol-like compounds in wax from GT-MAS:gk than in waxes from the susceptible lines. The GT-MAS:gk unique band contained phenol-like compounds and ethyl-hexadecanoate; butyl hexadecanoate was preeminent in most of the "susceptible bands". Alkylresorcinol (phenolic compounds) content was dramatically higher in GT-MAS:gk wax than in the wax of susceptible lines. An alkylresorcinol, 5-methylresorcinol, also inhibited in vitro growth of A. flavus. These and other phenolic compounds may contribute to kernel wax inhibition of A. flavus infection/aflatoxin production. Further investigation is needed to confirm a role for them in GT-MAS:gk resistance. PMID- 11600001 TI - Free radical scavenging active components from Cedrus deodara. AB - An activity-directed fractionation and purification process was used to identify the antioxidant components of Cedrus deodara. Dried heartwood powder of C. deodara was first defatted with petroleum ether and then extracted with chloroform. The chloroform extract showed strong antioxidant activity on 1,1 diphenyl-2-picrylhydrazyl (DPPH) free radical. This fraction was then subjected to separation and purification using silica gel column chromatography. Three compounds with potent antioxidant activity were isolated in significant yields and identified by spectroscopic methods ((1)H NMR, (13)C NMR, IR, and MS). They were identified as (-)-matairesinol, (-)-nortrachelogenin, and a dibenzylbutyrolactollignan (4,4',9-trihydroxy-3,3'-dimethoxy-9,9'-epoxylignan). This is the first report of the occurrence of these compounds in C. deodara. PMID- 11600002 TI - Identification and antioxidant activity of novel chlorogenic acid derivatives from bamboo (Phyllostachys edulis). AB - One known and two novel antioxidant compounds have been isolated from bamboo (Phyllostachys edulis). The butanol-soluble extract of the bamboo leaves was found to have a significant antioxidant activity, as measured by scavenging the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical and the superoxide anion radical (O(2)(-)) in the xanthine/xanthine oxidase assay system. Antioxidant activity-directed fractionation of the extract led to the isolation and characterization of three structural isomeric chlorogenic acid derivatives: 3-O (3'-methylcaffeoyl)quinic acid (1), 5-O-caffeoyl-4-methylquinic acid (2), and 3-O caffeoyl-1-methylquinic acid (3). Compounds 2 and 3 were isolated and characterized for the first time from the natural products. In the DPPH scavenging assay as well as in the iron-induced rat microsomal lipid peroxidation system, compounds 2 (IC(50) = 8.8 and 19.2 microM) and 3 (IC(50) = 6.9 and 14.6 microM) showed approximately 2-4 times higher antioxidant activity than did chlorogenic acid (IC(50) = 12.3 and 28.3 microM) and other related hydroxycinnamates such as caffeic acid (IC(50) =13.7 and 25.5 microM) and ferulic acid (IC(50) = 36.5 and 56.9 microM). Among the three compounds, compound 1 yielded the weakest antioxidant activity, and the DPPH scavenging and lipid peroxidation inhibitory activity (IC(50) = 16.0 and 29.8 microM) was lower than those of chlorogenic and caffeic acids. All three compounds exhibited both superoxide scavenging activities and inhibitory effects on xanthine oxidase. Their superoxide anion (O(2)(-)) scavenging activities (IC(50) = 1, 4.3 microM; 2, 2.8 microM; and 3, 1.2 microM) were markedly stronger than those of ascorbic acid (IC(50) = 56.0 microM), alpha-tocopherol (IC(50) > 100 microM), and other test compounds, although their inhibition effects on xanthine oxidase may contribute to the potent scavenging activity. alpha-Tocopherol exerted a significant inhibitory effect (65.5% of the control) on superoxide generation in 12-O-tetradecanoylphorbol-13-acetate-induced human promyelocytic leukemia HL-60 cells, and compound 3 showed moderate activity (36.0%). On the other hand, other compounds including 1, 2, chlorogenic acid, and other antioxidants were weakly active (24.8-10.1%) in the suppression of superoxide generation. PMID- 11600003 TI - Selective growth inhibitor toward human intestinal bacteria derived from Pulsatilla cernua root. AB - Among 21 medicinal plants, the growth-inhibiting activity of Pulsatilla cernua root-derived materials toward human intestinal bacteria was examined by using an impregnated paper disk method. The biologically active components of P. cernua roots were characterized as 4-hydroxy-3-methoxycinnamic acid and 3,4 dihydroxycinnamic acid by spectroscopic analysis. The activity was compared with that of six commercially available cinnamic acid derivatives trans cinnamaldehyde, trans-cinnamic acid, cinnamyl alcohol, 2-methoxycinnamic acid, 3 methoxycinnamic acid, and 4-methoxycinnamic acid. The growth responses varied with each bacterial strain tested. Two isolated compounds revealed a potent inhibition against Clostridium perfringens, and moderate to weak activity against Escherichia coli was exhibited by 4-hydroxy-3-methoxycinnamic acid. Weak or no inhibitory activity was obtained against the bifidobacteria or Lactobacillus acidophilus. The inhibitory effect was much more pronounced in C. perfringens and E. coli as compared to B. adolescentis, B. bifidum, B. fragilis, B. longum, or L. acidophilus. Cinnamaldehyde exhibited a strong growth-inhibiting activity, but no inhibition was observed from treatments with trans-cinnamic acid, cinnamyl alcohol, 2-methoxycinnamic acid, 3-methoxycinnamic acid, and 4-methoxycinnamic acid. These results may be an indication of at least one of the pharmacological actions of P. cernua root. PMID- 11600004 TI - Expression of a bacterial ice nucleation gene in a yeast Saccharomyces cerevisiae and its possible application in food freezing processes. AB - A 3.6 kb ice nucleation gene (ina) isolated from Erwinia herbicola was placed under control of the galactose-inducible promoter (GAL1) and introduced into Saccharomyces cerevisiae. Yeast transformants showed increased ice nucleation activity over untransformed controls. The freezing temperature of a small volume of water droplets containing yeast cells was increased from approximately -13 degrees C in the untransformed controls to -6 degrees C in ina-expressing (Ina(+)) transformants. Lower temperature growth of Ina(+) yeast at temperatures below 25 degrees C was required for the expression of ice nucleation activity. Shift of temperature to 5-20 degrees C could induce the ice nucleation activity of Ina(+) yeast when grown at 25 degrees C, and maximum ice nucleation activity was achieved after induction at 5 degrees C for approximately 12 h. The effects of Ina(+) yeast on freezing and texturization of several food materials was also demonstrated. PMID- 11600005 TI - Reactions of monosaccharides during heating of sugar-casein systems: building of a reaction network model. AB - The Maillard reaction is important during the heating and processing of foods for its contribution to food quality. To control a reaction as complex as the Maillard reaction, it is necessary to study the reactions of interest quantitatively. In this paper the main reaction products in monosaccharide-casein systems, which were heated at 120 degrees C and pH 6.7, were identified and quantified, and the reaction pathways were established. The main reaction routes were (i) sugar isomerization, (ii) degradation of the sugar into carboxylic acids, and (iii) the Maillard reaction itself, in which not only the sugar itself but also its reaction products react with the epsilon-amino group of lysine residues of the protein. Significant differences in reaction mechanism between aldose and ketose sugars were observed. Ketoses seemed to be more reactive in the sugar degradation reactions than their aldose isomers, and whereas the Amadori product was detected as a Maillard reaction intermediate in the aldose-casein system, no such intermediate could be found in the ketose-casein system. The reaction pathways found were put together into a model, which will be evaluated by kinetic modeling in a subsequent paper. PMID- 11600006 TI - Chemical reactions in cottonseed protein cross-linking by formaldehyde, glutaraldehyde, and glyoxal for the formation of protein films with enhanced mechanical properties. AB - Amino acids involved in cottonseed protein cross-linking by formaldehyde, glutaraldehyde, and glyoxal during protein film formation were identified by an original technique. The entire HPLC amino acid profile (after acid hydrolysis) was studied, along with variations in reactive lysine contents, in films cross linked or not with increasing quantities of formaldehyde, glutaraldehyde, and glyoxal. This strategy highlighted the formation of acid-resistant lysine derivatives that a simple reactive lysine determination would not have detected. The results-which agree with previously published data-enhance the overall understanding of cross-linking activities that occur in aqueous alkaline solutions during the formation of protein films made with cottonseed flour. Lysine was found to have a key role in protein cross-linking by dialdehydes, with the involvement of tyrosine in the presence of formaldehyde and of arginine in the presence of glyoxal. These results could provide valuable chemical tools for adjusting the mechanical properties of cottonseed protein films. PMID- 11600007 TI - The fluorescence of advanced Maillard products is a good indicator of lysine damage during the Maillard reaction. AB - The objective of this study was to determine whether in heat-treated milk resembling models or milk there is a lag phase, before lactulosyllysine (LL) is converted into advanced Maillard products (AMP), and if there is a step during the heat treatment where LL is actively degraded into AMP. For that purpose, a low temperature (60-85 degrees C) and a long heat treatment (15-90 h) were chosen. We observe that the heat treatment first induces a parallel increase in furosine and AMP fluorescence, confirming that AMP are produced very early during the heat treatment. At this step, both indicators are correlated with each other and precisely reflect the lysine damage. After a time, however, furosine reaches a steady-state concentration, whereas AMP fluorescence still increases, remaining correlated with the lysine blockage. Nevertheless, heat treatment applied to milk does not reach this step so that AMP fluorescence appears as a rapid alternative to furosine quantification. PMID- 11600008 TI - Influence of acyl chain lengths in mono- and diacyl-sn-glycerophosphatidylcholine on gelatinization and retrogradation of starch. AB - The influence of starch with 1- or 2-monoacyl-sn-glycerophosphatidylcholine (GPC) having various chain lengths of fatty acids on gelatinization and retrogradation of starch was studied by the measurement of starch-GPC complex formation, complexing index, and differential scanning calorimetry. The addition of GPC to the starch sample slightly increased the blue value and lambda(max) with increasing chain length of GPC but decreased the phosphorus content and complexing index. The gelatinization onset and peak temperatures of starch complexes increased significantly with increasing chain length, but the enthalpies were statistically lower, except for the treatment with 1,2-distearoyl sn-GPC when compared with that of the control. Among GPC (di and mono), 1- and 2 monomyristoyl-sn-GPC showed the highest complexing ability, whereas the complexing ability of the GPC decreased with the increasing chain length. According to the Avrami equation, the retrogradation rate (k, day(-1)) of starch was slower than that of the control, whereas the retrogradation rates of 1- and 2 monomyristoyl-sn-GPC were slowest among the GPCs. The positive linear relationship between k and the number of acyl groups of GPC suggests that a GPC with a shorter chain length could retard the retrogradation of starch during storage. PMID- 11600010 TI - Effect of different treatments on the evolution of polyamines during refrigerated storage of eggplants. AB - The applicability of a thermal treatment was compared with modified-atmosphere (MA) storage in relation to chilling injury (CI) and polyamines evolution in eggplants. Fruits underwent physiological disorders at 3 degrees C, evidenced by the appearance of surface injuries at the third day of storage, and, after moving the fruits to 20 degrees C, by increased respiratory activity and more intense ethylene production. Storage of fruits in sealed low-density polyethylene bags and a previous treatment with heated air (1 h at 35 degrees C) were both effective in retarding chilling injury, though the former was better. Two free polyamines were found in cv. Black Nite: putrescine, in greater proportion, and spermidine. Putrescine increased in control (untreated) fruits stored at 3 degrees C in parallel with the external appearance of chilling injury, whereas this increase was either not exhibited or retarded in treated or MA stored fruits. Spermidine did not change in control fruits at 3 degrees C, remaining almost constant over the whole storage period, whereas in heat- and MAP-treated fruits spermidine levels exhibited a decrease. PMID- 11600009 TI - Enzymatic oxidative treatments of wheat bran layers: effects on ferulic acid composition and mechanical properties. AB - Enzymatic treatments known to induce the gelation of feruloylated arabinoxylans solutions were applied to tissue strips isolated from peripheral layers of wheat grain to tentatively produce in situ arabinoxylan reticulation. The treatments by horseradish peroxidase (HRP) and manganese dependent peroxidase (MnP) induced a dimerization of ferulic acid (FA) in wheat bran with concomitant decrease of arabinoxylan solubility. Similar results were obtained, but to a lesser extent, by simple incubation of bran strips in water, suggesting the action of endogenous peroxidases. The fact that these treatments proved to be ineffective on the isolated aleurone layer and pericarp suggested that dimerization occurred mostly at the aleurone-pericarp interface. In addition, the MnP system generated a consumption of monomer and dimer of ferulic acid in the pericarp, perhaps due to their incorporation into lignin. Micro-mechanical tests using DMTA were performed on isolated tissue strips and showed that oxidation of wheat bran increased their mechanical strength (increase of stress and strain to rupture). PMID- 11600011 TI - Maillard reaction kinetics in model preservation systems in the vicinity of the glass transition: experiment and theory. AB - Rates of reactant consumption for the Maillard reaction between lysine and glucose were measured for a noncrystallizing trehalose-sucrose-water matrix in the glass transition region. At temperatures above the glass transition temperature (T(g)), the consumption rates showed Arrhenius temperature dependence with activation energies of 135 and 140 kJ mol(-1) for lysine and glucose, respectively. Finite reaction rates were observed for glassy samples that were faster than that of one of the nonglassy samples. A comparison of experimental results with predicted diffusion-controlled reaction rate constants indicated that the reaction was reaction-controlled at temperatures above T(g) and approached the diffusion-influenced regime in the glassy state. The needs for further research on reactant diffusivity, the theory of the orientation dependence of reactivity, and a detailed understanding of the reaction mechanism and kinetics were identified. PMID- 11600012 TI - Effect of roasting conditions on reduction of ochratoxin a in coffee. AB - A commercial lot of green coffee, naturally contaminated with ochratoxin A (OTA), was roasted under various conditions, and the effects on its final OTA content were determined. Precautions were taken in sampling the coffee to cope with OTA inhomogeneity. The roasting conditions were kept within the range of commercial practice. Roasting time was varied from 2.5 to 10 min, and the roast color varied from light medium to dark. The differences in OTA reduction between the different levels of roasting times and colors did not reach statistical significance. However, for all roasting conditions, the reduction was highly significant, 69% reduction over the combined results. In total, nine studies by various authors about OTA reduction during coffee roasting are now available. Seven out of these nine reported that the relevant range of OTA reductions was between 69 and 96%. Among these seven,are all four studies that reported using naturally contaminated beans, a sampling procedure adapted to mycotoxin inhomogeneity, and roasting conditions within the range of actual practice. Three different explanations are available for this reduction: physical removal of OTA with chaff, isomerization at the C-3 position into another diastereomer, and thermal degradation with possible involvement of moisture. All three explanations may play a partial role in the OTA reduction during coffee roasting. PMID- 11600013 TI - Structural changes in natural actomyosin and surimi from ling cod (Ophiodon elongatus) during frozen storage in the absence or presence of cryoprotectants. AB - Surimi and natural actomyosin (NAM) from ling cod (Ophiodon elongatus) were subjected to frozen storage in the absence or presence of cryoprotectants (sorbitol, sucrose, lactitol, and Litesse, either individually or in combination). Effects of frozen storage were studied for NAM frozen at -10 degrees C for 10 days and for surimi after eight freeze-thaw cycles. A commercial blend cryoprotectant (4% sucrose and 4% sorbitol), individual cryoprotectants at 8%, and optimal blends at 4, 5.5, 6, and 8%, were effective in maintaining the gel strength of surimi and NAM gels. Surimi or NAM frozen in the absence of cryoprotectants or with only 4% individual cryoprotectants, showed increased percent alpha-helical content by Raman analysis. Increased disulfide content was also observed in the treatment without cryoprotectants by the Raman SS stretching band and by chemical determination. Tyrosine residues were in a buried environment before and after freezing for all treatments, and surface hydrophobicity measured by 1-anilinonaphthalene-8-sulfonate decreased after frozen storage in the absence of cryoprotectants. PMID- 11600014 TI - Some furfural derivatives as nitrification inhibitors. AB - Three series of furfural derivatives, namely N-O-furfural oxime ethers, furfural Schiff bases (furfurylidene anilines), and furfural chalcones, have been synthesized and evaluated for nitrification inhibition activity in laboratory incubation studies in typic Ustocrept soil. Furfural oxime ethers and furfural Schiff bases showed potential activity, but furfural chalcones were only mildly active. N-O-ethyl furfural oxime among the oxime ethers, and furfurylidine-4 chloroaniline among the furfural Schiff bases, performed the best. These two compounds showed more than 50% nitrification inhibition on the 45th day at 5% dose as compared to 73% inhibition by nitrapyrin. Activity of furfural oxime ethers decreased with an increase in carbon atoms in the N-O-alkyl side chain. Introduction of a chlorine atom in the phenyl ring of furfurylidene anilines increased the persistence of their activity. N-O-Ethyl furfural oxime and furfurylidine-4-chloroaniline coated urea performed at par with their application in solution form. Ethyl and N-O-isopropyl oxime, as well as chloro- and nitro- substituted Schiff bases, did not reveal any phytotoxicity (adverse effect on germination) on chickpea seeds (Cicer arietinum) even at the highest dose (40 ppm, soil basis). PMID- 11600015 TI - Antifungal proteins and other mechanisms in the control of sorghum stalk rot and grain mold. AB - Research on antifungal proteins and other mechanisms that provide the biochemical basis for host-plant resistance to stalk rot and grain molds is reviewed in this paper. Stalk rot caused by Fusarium species leads to substantial yield loss due to poor grain filling and/or lodging. A transgenic sorghum expressing high levels of chitinase exhibited less stalk rot development when exposed to conidia of F. thapsinum. Grain mold of sorghum is associated with warm humid environments and results from colonization by several fungi (F. thapsinum, Curvularia lunata, and Alternaria alternata) of the developing caryopsis. The roles of several biochemical mechanisms (tannins, phenolic compounds, red pericarp, proteins, hard endosperm, and antifungal proteins) on grain mold resistance are discussed. Resistance mechanisms related to these compounds appear to be additive, and pyramiding of genes is a feasible approach to limit grain deterioration. Several experimental approaches are proposed to extend current findings. PMID- 11600016 TI - Multivariate methods for characterization and classification of espresso coffees from different botanical varieties and types of roast by foam, taste, and mouthfeel. AB - Three espresso coffee (EC) samples of different botanical varieties and types of roast were prepared in standard conditions using an experimental EC prototype: Arabica coffee, Robusta Natural blend, and Robusta Torrefacto blend (a special roast by adding sugar). The ECs were characterized with regard to the physical parameters, amount of total solids, total solids on filtrate, lipids, caffeine, trigonelline, and chlorogenic acids by HPLC, and sensory descriptive analysis related to foam appearance, taste, and mouthfeel. Principal component analysis (PCA) was applied to differentiate the EC samples. Arabica and Robusta samples were separated successfully by principal component 1 (55.3% of variance) including physicochemical and sensory parameters related to foam and taste of ECs. Torrefacto and Robusta Natural EC samples were separated by principal component 2 (20.7% of total variance) including mouthfeel and other attributes of color foam. Some interesting correlations among sensory and physicochemical variables were found. A very simple discriminate function was obtained by discriminate analysis allowing the classification of each EC sample into its respective group with a success rate of 100%. PMID- 11600017 TI - HPLC-DAD-ESIMS analysis of phenolic compounds in nectarines, peaches, and plums. AB - The phenolic compounds of 25 peach, nectarine, and plum cultivars were studied and quantified by HPLC-DAD-ESIMS. Hydroxycinnamates, procyanidins, flavonols, and anthocyanins were detected and quantified. White and yellow flesh nectarines and peaches, and yellow and red plums, were analyzed at two different maturity stages with consideration of both peel and flesh tissues. HPLC-MS analyses allowed the identification of procyanidin dimers of the B- and A-types, as well as the presence of procyanidin trimers in plums. As a general rule, the peel tissues contained higher amounts of phenolics, and anthocyanins and flavonols were almost exclusively located in this tissue. No clear differences in the phenolic content of nectarines and peaches were detected or between white flesh and yellow flesh cultivars. There was no clear trend in phenolic content with ripening of the different cultivars. Some cultivars, however, had a very high phenolic content. For example, the white flesh nectarine cultivar Brite Pearl (350-460 mg/kg hydroxycinnamates and 430-550 mg/kg procyanidins in flesh) and the yellow flesh cv. Red Jim (180-190 mg/kg hydroxycinnamates and 210-330 mg/kg procyanidins in flesh), contained 10 times more phenolics than cultivars such as Fire Pearl (38 50 mg/kg hydroxycinnamates and 23-30 mg/kg procyanidins in flesh). Among white flesh peaches, cultivars Snow King (300-320 mg/kg hydroxycinnamates and 660-695 mg/kg procyanidins in flesh) and Snow Giant (125-130 mg/kg hydroxycinnamates and 520-540 mg/kg procyanidins in flesh) showed the highest content. The plum cultivars Black Beaut and Angeleno were especially rich in phenolics. PMID- 11600018 TI - Interspecific variation in anthocyanins, phenolics, and antioxidant capacity among genotypes of highbush and lowbush blueberries (Vaccinium section cyanococcus spp.). AB - Recent interest in the possible protective effects of dietary antioxidant compounds against human degenerative disease has prompted investigation of foods such as blueberries (Vaccinium sp.), which have a high antioxidant capacity. Fruit obtained from genotypes of highbush blueberries (Vaccinium corymbosum L.) and lowbush blueberries (Vaccinium angustifolium Aiton) were analyzed for their antioxidant capacity, their content of anthocyanins, and total phenolic compounds, to evaluate the intraspecific and interspecific variation in these parameters. The method of extraction influenced the composition of fruit extracts; the highest anthocyanin and total phenolic contents and antioxidant capacity were found in extracts obtained using a solvent of acidified aqueous methanol. Regardless of the method, lowbush blueberries were consistently higher in anthocyanins, total phenolics, and antioxidant capacity, compared with highbush blueberries. There was no relationship between fruit size and anthocyanin content in either species. PMID- 11600019 TI - HPLC determination of chlorophyll and carotenoid pigments in processed green pea cultivars (Pisum sativum L.). AB - Chlorophyll and carotenoid pigments from six cultivars of processed green peas (Avola, Tristar, Rampart, Turon, Bella, and Greenshaft) were extracted with 100% acetone and analyzed by reversed-phase HPLC. A total of 17 pigments were identified in the pea cultivars including 8 xanthophylls ((all-E)-neoxanthin, (9'Z)-neoxanthin, (all-E)-violaxanthin, neochrome, (all-E)-lutein epoxide, (all E)-lutein, neolutein B, neolutein A), 4 chlorophyll b related compounds (chlorophyll b derivative, chlorophyll b, chlorophyll b', and pheophytin b), 4 chlorophyll a related compounds (chlorophyll a derivative, chlorophyll a, chlorophyll a', and pheophytin a), and (all-E)-beta-carotene. The efficiency of different extraction procedures using 100% acetone showed that initial extraction followed by three reextractions without holding time between gave a higher extraction yield than no reextraction and 30 or 60 min holding time. All six cultivars contained the same pigments, but the concentration of each pigment varied significantly. On average of the two years, the chlorophyll a concentration varied from 4800 to 7300 microg/100 g fresh weight, the chlorophyll b concentration from 2100 to 2800 microg/100 g fresh weight, the (all-E)-lutein concentration from 1200 to 1900 microg/100 g fresh weight, and the (all-E)-beta carotene concentration from 300 to 490 microg/100 g fresh weight in the processed pea cultivars. These differences in pigment concentration between the investigated cultivars are discussed in relation to maturity, product color and nutritional quality. PMID- 11600021 TI - New spirostanol saponins from Chinese chives (Allium tuberosum). AB - Three new spirostanol saponins have been isolated from the seeds of Allium tuberosum. On the basis of acid hydrolysis and comprehensive spectroscopic analysis, their structures were established as tuberoside J, (25R)-5alpha spirostan-2alpha,3beta,27-triol 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D glucopyranoside; tuberoside K, (25R)-5alpha-spirostan-2alpha,3beta,27-triol 3-O alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->4)]-beta-D glucopyranoside; and tuberoside L, 27-O-beta-D-glucopyranosyl-(25R)-5alpha spirostan-2alpha,3beta,27-triol 3-O-alpha-D-rhamnopyranosyl-(1-->2)-[alpha-L rhamnopyranosyl-(1-->4)]-beta-D-glucopyranoside. PMID- 11600020 TI - Differentiation of tea (Camellia sinensis) varieties and their geographical origin according to their metal content. AB - The metal content of 46 tea samples, including green, black, and instant teas, was analyzed. Al, Ba, Ca, Cu, Fe, K, Mg, Mn, Na, Sr, Ti, and Zn were determined by ICP-AES. Potassium, with an average content of 15145.4 mg kg(-1) was the metal with major content. Calcium, magnesium, and aluminum had average contents of 4252.4, 1978.2, and 1074.0 mg kg(-1), respectively. The average amount of manganese was 824.8 mg kg(-1). There were no clear differences between the metal contents of green and black teas. Pattern recognition methods such as principal component analysis (PCA), linear discriminant analysis (LDA), and artificial neural networks (ANN), were applied to differentiate the tea types. LDA and ANN provided the best results in the classification of tea varieties. These chemometric procedures were also useful for distinguishing between Asian and African teas and between the geographical origin of different Asian teas. PMID- 11600022 TI - Hydrophobicity of whey protein concentrates measured by fluorescence quenching and its relation with surface functional properties. AB - Surface hydrophobicity of whey protein concentrate (WPC) under heated (85 degrees C for 5, 10, 20, 30, 40, and 60 min) and unheated conditions was measured using cis-parinaric acid (CPA), 1-anilino-8-naphthalenesulfonate (ANS), and a fluorescence quenching method using acrylamide as a quencher. This last method evaluates the degree of exposure of tryptophanyl residues in proteins to the solvent. The initial slope of Stern-Volmer plots, K(app), was used as an index of protein hydrophobicity. Surface hydrophobicity of WPC exhibited good relation with surface functional properties such as emulsifying and foaming. Analysis of the data obtained in this work showed that the fluorescence quenching method gave results similar to those obtained using CPA and ANS. Therefore, this simple technique is satisfactory in effectively obtaining information about the hydrophobicity of whey proteins. PMID- 11600023 TI - Analysis of cooking oil fumes by ultraviolet spectrometry and gas chromatography mass spectrometry. AB - This paper investigated the components, especially aldehydes, in the fume condensates from four kinds of cooking oil using ultraviolet (UV) spectrometry and gas chromatography-mass spectrometry (GC-MS). It was observed that there was a great change of the UV absorption spectra from the results of the unheated oil to the results of the fume after heat treatment (190-200, 230-240, and 270-280 degrees C). There was a strong peak within the wavelength range of 260-270 nm in each condensate sample. From the GC-MS results, it was tentatively deduced that there were some 2,4-dialkylenaldehydes and other conjugated compounds in the condensates. The results showed there were large amounts of hexanal and 2 heptenal in the cooking oil fume and that the total aldehyde peak areas of the condensates from four kinds of oil were around 30-50% of the total peak area at 270-280 degrees C. PMID- 11600024 TI - Photochemical degradation of acifluorfen in aqueous solution. AB - To elucidate the photochemical behavior of diphenyl ether herbicides in superficial waters, the photodegradation of acifluorfen, 5-[2-chloro-4 (trifluoromethyl)phenoxy]-2-nitrobenzoic acid (CAS Registry No. 50594-66-6), was studied in water and acetonitrile. All experiments were carried out under laboratory conditions using a solar simulator (xenon arc) or jacket Pyrex reaction cell equipped with a 125 W high-pressure mercury lamp. The calculated polychromatic quantum efficiencies (Phi(solvent)) of acifluorfen in different solvents are as follows (units are degraded molecules photon(-1)): Phi(water) = 10(-4), Phi(acetonitrile) = 10(-4), Phi(methanol) = 10(-4), and Phi(hexane) = 10( 2). The results obtained in this work are in good agreement with the literature value of monochromatic quantum yield. HPLC-MS analysis (APCI and ESI in positive and negative modes) was used to identify acifluorfen photoproducts. These results suggest that the photodegradation of acifluorfen proceeds via a number of reaction pathways: (1) decarboxylation, (2) dehalogenation, (3) substitution of chlorine group by hydroxyl or hydrogen groups, and (4) cleavage of ether linkage, giving phenols. Photorearrangement products were studied by other investigators. No such products were observed. In addition, it was found that the trifluoro functional group on acifluorfen was not affected by any transformation, and no products of a nitro group reduction were found. PMID- 11600025 TI - Zeolites as pheromone dispensers. AB - Modification of the chemical and structural properties of zeolites has led to the preparation of an optimized zeolitic dispenser for insect attractants such as n decanol and trimedlure. The impact of zeolite variables such as the framework Si/Al ratio, nature of compensating cation, nature and strength of acid groups, and pore dimensions on the kinetics of emission has been studied, and the results are as follows. Zeolite pore dimensions and the presence or absence of acid sites have the greatest effect on the rate of release, decreasing with decreasing pore diameter and increasing acidity. Further tuning of the release characteristics is achieved by controlling the polarity and the polarizability of the framework by increasing the Si/Al ratio and nature of the compensating cations, i.e., the higher the polarizability and the lower the polarity, the slower the release of attractants. PMID- 11600026 TI - Reduction of the environmental impact of pesticides: waxy microspheres encapsulating the insecticide carbaryl. AB - A controlled-release system with reduced environmental impact was produced by encapsulating the pesticide carbaryl in the waxy lipophilic material Gelucire 54/02. The microspheres were prepared by a modified hydrophobic congealable disperse-phase method. The influence of experimental parameters, such as the reciprocal ratio between the amounts of pesticide and wax employed, on size, morphology, loading efficiency, and release behavior of the particles was evaluated. Microspheres were free-flowing and showed a nonporous scaly surface at SEM analysis. The mean particle size ranged from 15.8 to 19.8 microm and was independent of the amount of Gelucire used to prepare the microspheres. At a fixed Gelucire content, the increase in theoretical carbaryl content yielded up to 72% loading efficiency, whereas at a fixed carbaryl content the increase in Gelucire amount produced a 64% increase in encapsulation efficiency. These data were accounted for by the carbaryl leakage from molten Gelucire toward the dispersing aqueous phase. The release profiles of carbaryl from microspheres showed that the use of increasing amounts of waxy material decreased the carbaryl release rate, whereas at a fixed Gelucire content, the release was the slowest when carbaryl was not completely dissolved within the matrix. The possibility to achieve different burst effects by simply varying the formulation parameters offers an efficient tool to ensure the fast release of an active dose of insecticide. The lower vertical mobility of carbaryl encapsulated in waxy microspheres compared to the vertical mobility of the technical-grade product showed that the controlled-release system has a lower potential risk for groundwater contamination. PMID- 11600027 TI - Aromatic profile of aqueous banana essence and banana fruit by gas chromatography mass spectrometry (GC-MS) and gas chromatography-olfactometry (GC-O). AB - Gas chromatography-mass spectrometry (GC-MS) and gas chromatography-olfactometry (GC-O) were used to determine the aromatic composition and aroma active components of commercial banana essence and fresh banana fruit paste. Totals of 43 and 26 compounds were quantified in commercial banana essence and fresh banana fruit paste, respectively. Five new components in commercial banana essence were identified as methyl butyrate, 2,3-butanediol diacetate, 2-hydroxy-3 methylethylbutyrate, 1-methylbutyl isobutyrate, and ethyl 3-hydroxyhexanoate. A total of 42 components appear to contribute to the aromatic profile in banana. Isoamyl acetate, 2-pentanol acetate, 2-methyl-1-propanol, 3-methyl-1-butanol, 3 methylbutanal, acetal, isobutyl acetate, hexanal, ethyl butyrate, 2-heptanol, and butyl butyrate had high concentrations and were most detected by GC-O panelists in the commercial banana essence. Volatile components found only in fresh banana fruit paste that were detected by aroma panelists include E-2-hexenal, limonene, and eugenol. PMID- 11600028 TI - Quantitative gas chromatography-olfactometry carried out at different dilutions of an extract. Key differences in the odor profiles of four high-quality Spanish aged red wines. AB - Four Spanish aged red wines made in different wine-making areas have been extracted, and the extracts and their 1:5, 1:50, and 1:500 dilutions have been analyzed by a gas chromatography-olfactometry (GC-O) approach in which three judges evaluated odor intensity on a four-point scale. Sixty-nine different odor regions were detected in the GC-O profiles of wines, 63 of which could be identified. GC-O data have been processed to calculate averaged flavor dilution factors (FD). Different ANOVA strategies have been further applied on FD and on intensity data to check for significant differences among wines and to assess the effects of dilution and the judge. Data show that FD and the average intensity of the odorants are strongly correlated (r(2) = 0.892). However, the measurement of intensity represents a quantitative advantage in terms of detecting differences. For some odorants, dilution exerts a critical role in the detection of differences. Significant differences among wines have been found in 30 of the 69 odorants detected in the experiment. Most of these differences are introduced by grape compounds such as methyl benzoate and terpenols, by compounds released by the wood, such as furfural, (Z)-whiskey lactone, Furaneol, 4-propylguaiacol, eugenol, 4-ethylphenol, 2,6-dimethoxyphenol, isoeugenol, and ethyl vanillate, by compounds formed by lactic acid bacteria, such as 2,3-butanedione and acetoine, or by compounds formed during the oxidative storage of wines, such as methional, sotolon, o-aminoacetophenone, and phenylacetic acid. The most important differences from a quantitative point of view are due to 2-methyl-3 mercaptofuran, 4-propylguaiacol, 2,6-dimethoxyphenol, and isoeugenol. PMID- 11600029 TI - Aroma compounds of fresh milk from New Zealand cows fed different diets. AB - Volatile compounds were extracted from fresh milk produced by New Zealand cows using the newly developed solvent-assisted flavor evaporation (SAFE) technique. The two samples that were used came from cows that had been fed on different diets and represented the considerably different flavors of Northern hemisphere and New Zealand milk. Using gas chromatography-olfactometry (GC-O), 71 aroma compounds were found from the milk extracts, 66 of which were identified. Nearly all of the aroma compounds were common to both extracts, despite the two milk samples having quite different flavors. Only one compound, gamma-12:2 lactone, was significantly odor-active for the extract of milk from cows fed a supplement diet, but was not found for the extract of milk from cows fed a pasture diet. Thus, differences in milk flavor are primarily caused by concentration differences of a common set of flavor compounds, rather than by the occurrence of compounds uniquely associated with a particular feed. PMID- 11600030 TI - Formation of furfurylthiol exhibiting a strong coffee aroma during oak barrel fermentation from furfural released by toasted staves. AB - Furfurylthiol (FFT) is formed in white wines during alcoholic fermentation in the barrel from the furfural released by toasted staves. The quantity of furfural released into the must has a decisive effect on the quantity of FFT in the finished wine. Wines fermented in new barrels thus contain larger quantities of FFT than those fermented in used barrels. Fermentation conditions favorable to an excess production of H(2)S (hydrogen sulfide) by the yeast promote the formation of this volatile thiol. The presence of this volatile thiol in white wines is, therefore, closely related to the yeast's sulfur metabolism. PMID- 11600031 TI - Occurrence of anthocyanin-derived pigments in red wines. AB - Several anthocyanin-derived pigments that showed UV-visible spectra different from those of the original grape anthocyanins were detected by HPLC-DAD analysis in 1-year-old bottled Port wines from the Douro region. Among these, three malvidin 3-glucoside derived pigments were detected in large amounts, representing approximately 60% of the total anthocyanidin monoglucosides content. These pigments were isolated, purified, and identified by LSI-MS and NMR ((1)H, DQF-COSY, ROESY, HSQC, and HMBC) techniques. The major pigment is malvidin 3 glucoside pyruvic adduct, previously characterized, and the other two corresponded to its respective acetyl and coumaroyl glucoside derivatives. The latter is reported for the first time in red wines. PMID- 11600032 TI - Multivariate analysis of antioxidant power and polyphenolic composition in red wines. AB - It has been demonstrated that the dietary intake of compounds having antioxidant activity is very important, and various chemical, biological, and electrochemical methods have been proposed to evaluate the antioxidant power of compounds such as polyphenols. Wine, although nonessential, has a high polyphenol content up to 2-3 g/L in red wines obtained by traditional maceration. The polyphenol content of wines is usually evaluated by the Folin reagent, which provides an appropriate response to the requirements of wine manufacturers. Because the presence of individual polyphenols may be evaluated by HPLC, more or less selective methods toward the various chemical classes of polyphenols have been developed. An HPLC method set up recently was applied to evaluate how individual polyphenols contributed to the overall antioxidant power (AOP) of 60 Italian red wines, trying to identify the effect that individual compounds may have on the total AOP. Application of the multivariate analysis allowed us to detect some determining compounds such as gallic acid and some flavonols. On the basis of the correlation between two traditional chemical methods, namely the total polyphenol determination by the Folin reagent and the flavanol determination by the condensation reaction with p-(dimethylamino)-cinnamaldehyde, it was shown that the use of these two merely chemical methods is well correlated (r = 0.83 and 0.87) to an AOP evaluation of red wines. PMID- 11600033 TI - Kinetics and products of the degradation of chitosan by hydrogen peroxide. AB - Low concentrations of hydrogen peroxide induced random degradation of partially deacetylated chitin and chitosan. Average molecular weight decreased in accordance with first-order kinetics. The degradation rate was much faster than that of the ultrasonic degradation, and it was comparable to that of the enzymatic hydrolysis of chitosan. Chain-end scissions occurred after chitosan was degraded severely and produced significant amounts of oligosaccharides at temperatures > or =80 degrees C. Universal calibration moderated the change in molecular weight more closely than that calculated by the usual calibration using pullulan standards. Trace amounts of transition metal ions and the amino groups in chitosan were critical to the breakdown of the beta-1,4 glycosidic linkages. HPLC results of glucosamine and chito-oligosaccharides could be characterized by correlating the logarithmic values of retention time with the degrees of polymerization. The formation of glucosamine and chito-oligosaccharides depended on the concentration of H(2)O(2), temperature, and the physicochemical property of chitin/chitosan. PMID- 11600034 TI - Relationships between different hydration properties of commercial and laboratory soybean isolates. AB - Functional properties related to water protein interactions of soy protein isolates depend on the structural and aggregation characteristics of their major components (storage globulins 7S and 11S) that could be modified by the preparation procedure, thermal and/or chemical treatments, and drying methods. Commercial and laboratory isolates with different functionalities resulting from their structural modifications were compared. Isolates with high solubility or excessive thermally induced insolubilization or compact calcium-induced aggregates caused low water-imbibing capacity (WIC) values. The highest WIC results from the balance between intermediate solubility and the formation of aggregates with good hydration properties. The apparent viscosity of dispersions of commercial (spray dried) and laboratory (lyophilized) isolates depends on the WIC, the morphology and size of the particles, and the interaction of the hydrated particles. The hydration properties and viscosity of protein isolate suspensions were strongly determined by the amount and properties of the insoluble fraction. PMID- 11600035 TI - Composition of total, neutral, and phospholipids in Mapara (Hypophthalmus sp.) from the Brazilian Amazonian area. AB - Ten lots of mapara (Hypophthalmus sp.), captured from the Amazon River, Brazil, were analyzed for their lipid content and fatty acid composition. This knowledge would allow for the development of adequate processing methods and the formulation of therapeutic diets. Separation into neutral and phospholipids was accomplished by silica-gel column chromatography. Fat from the muscular tissue and from the orbital cavity of the mapara was analyzed by high-resolution gas chromatography-mass spectrometry in two different seasonal periods. There were high levels of saturated and monounsaturated fatty acids in the total and neutral lipid with the principal components 16:0, 18:1omega9, 18:0, 16:1omega7, 14:0, 18:3omega3, and 18:1omega7 in both seasons. In the phospholipids there was a high level of polyunsaturated fatty acids, including primarily 16:0, 18:1omega9, 18:0, 16:1omega7, 22:6omega3, 20:4omega6, 18:3omega3, and 20:5omega3. The ratio omega3/omega6 was the same in the muscular tissue and in the orbital cavity, in both seasonal periods. The muscle tissue could be used in diets that need high levels of polyunsaturated fatty acids, but use of the head to produce an omega3 fatty-acid-rich oil still requires greater study with respect to its economic viability. PMID- 11600036 TI - Structure-reactivity relationship in the oxidation of carotenoid pigments of the pepper (Capsicum annuum L.). AB - The relationship between the degradation rate and structure of each pigment of the pepper carotenoid profile was studied in mixtures of dehydrated fruit with lipid substrates of differing degrees of unsaturation and in different proportions (20 and 40%). The differences in structural nature of the carotenoids present in the pepper fruit produce a variable rate of oxidation, resulting in nonuniform degradation. The yellow xanthophylls and beta-carotene have the highest rates of oxidation, with the ketocarotenoids and violaxanthin degrading at lower rates. Autoxidation is greater or lesser depending on the functional groups, which stabilize the radical intermediaries of the reaction. The behavior of capsanthin and capsorubin is that expected of carotenoids having structures that include keto groups: a markedly greater stability to autoxidation processes. This increases their antioxidant capacity, adding to their beneficial impact by reducing the proliferation of radical processes, which are detrimental to health. PMID- 11600037 TI - Evidence for a tetrameric form of iceberg lettuce (Lactuca sativa L.) polyphenol oxidase: purification and characterization. AB - Polyphenol oxidase from iceberg lettuce (Lactuca sativa L.) chloroplasts was released from the thylakoid-membrane by sonication, and it was extensively purified to homogeneity as judged by SDS-PAGE. Purification was achieved by ammonium sulfate fractionation, gel-filtration chromatography, and ion-exchange chromatography. Two molecular forms were separated by gel-filtration chromatography with apparent molecular masses of 188 and 49 kDa. Both forms were characterized by sedimentation analysis with S(20,W) values of 10.2 and 4.1 S, respectively. For the high-molecular-weight form purified to homogeneity, denaturing SDS-PAGE indicated a molecular mass of 60 kDa. Thus, from these data we suggest that lettuce polyphenol oxidase is a tetramer of identical subunits. PMID- 11600038 TI - Cellular model for induction of drip loss in meat. AB - Drip loss from porcine muscle (M. longissimus dorsi) contained high concentrations of K(+) ( approximately 135 mM) and organic osmolytes, for example, taurine ( approximately 15 mM), as well as significant amounts of protein ( approximately 125 mg.mL(-1)). Thus, the drip reflects release of intramuscular components. To simulate events taking place at the time of slaughter and leading to release of osmolytes and subsequent formation of drip loss, C2C12 myotubes were exposed to anoxia and reduction in pH (from 7.4 to 6.0). Anoxia and acidification increased the cellular Ca(2+) concentration ([Ca(2+)](i)) at a rate of 22-32 nM.min(-)(1). The anoxia-induced increase in [Ca(2+)](i) was mainly due to influx via sarcolemmal Na(+) channels. As mammalian cells swell and release lysophospholipids during anoxia, C2C12 cells and primary porcine muscle cells were exposed to either hypotonic shock or lysophosphatidylcholine (LPC) and the release of taurine was followed. The swelling-induced taurine efflux was blocked in the presence of the anion channel blocker (DIDS), the 5-lipooxygenase inhibitors (ETH 615-139 and NDGA) but unaffected by the presence of vitamin E. In contrast, the LPC-induced taurine release was unaffected by DIDS but abolished by antioxidants (butylated hydroxytoluene and vitamin E). Thus, stress-induced taurine release from muscles may precede by two different mechanisms, one being 5-lipooxygenase dependent and the other involving generation of reactive oxygen species. A model for the cellular events, preceding formation of drip in meat, is presented. PMID- 11600039 TI - Hydroxycinnamic acids and ferulic acid dehydrodimers in barley and processed barley. AB - Hydroxycinnamic acid content and ferulic acid dehydrodimer content were determined in 11 barley varieties after alkaline hydrolysis. Ferulic acid (FA) was the most abundant hydroxycinnamate with concentrations ranging from 359 to 624 microg/g dry weight. p-Coumaric acid (PCA) levels ranged from 79 to 260 microg/g dry weight, and caffeic acid was present at concentrations of <19 microg/g dry weight. Among the ferulic acid dehydrodimers that were identified, 8 O-4'-diFA was the most abundant (73-118 microg/g dry weight), followed by 5,5' diFA (26-47 microg/g dry weight), the 8,5'-diFA benzofuran form (22-45 microg/g dry weight), and the 8,5'-diFA open form (10-23 microg/g dry weight). Significant variations (p < 0.05) among the different barley varieties were observed for all the compounds that were quantified. Barley grains were mechanically fractionated into three fractions: F1, fraction consisting mainly of the husk and outer layers; F2, intermediate fraction; and F3, fraction consisting mainly of the endosperm. Fraction F1 contained the highest concentration for ferulic acid (from 77.7 to 82.3% of the total amount in barley grain), p-coumaric acid (from 78.0 to 86.3%), and ferulic acid dehydrodimers (from 79.2 to 86.8%). Lower contents were found in fraction F2, whereas fraction F3 exhibited the lowest percentages (from 1.2 to 1.9% for ferulic acid, from 0.9 to 1.7% for p-coumaric acid, and <0.02% for ferulic acid dehydrodimers). The solid barley residue from the brewing process (brewer's spent grain) was approximately 5-fold richer in ferulic acid, p coumaric acid, and ferulic acid dehydrodimers than barley grains. PMID- 11600040 TI - Effects of pH and heat treatments on the structure and solubility of potato proteins in different preparations. AB - The soluble potato proteins are mainly composed of patatin and protease inhibitors. Using DSC and both far-UV and near-UV CD spectroscopy, it was shown that potato proteins unfold between 55 and 75 degrees C. Increasing the ionic strength from 15 to 200 mM generally caused an increase in denaturation temperature. It was concluded that either the dimeric protein patatin unfolds in its monomeric state or its monomers are loosely associated and unfold independently. Thermal unfolding of the protease inhibitors was correlated with a decrease in protease inhibitor activities and resulted in an ionic strength dependent loss of protein solubility. Potato proteins were soluble at neutral and strongly acidic pH values. The tertiary structure of patatin was irreversibly altered by precipitation at pH 5. At mildly acidic pH the overall potato protein solubility was dependent on ionic strength and the presence of unfolded patatin. PMID- 11600041 TI - Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus). AB - The antioxidant melatonin was recently identified in a variety of edible plants and seeds in high concentrations. In plants, as in animals, melatonin is believed to function as a free radical scavenger and possibly in photoperiodism. In this study, melatonin was detected and quantified in fresh-frozen Balaton and Montmorency tart cherries (Prunus cerasus) using high-performance liquid chromatography. Both cherry species contain high levels of melatonin compared to the melatonin concentrations in the blood of mammals. Montmorency cherries (13.46 +/- 1.10 ng/g) contain approximately 6 times more melatonin than do Balaton cherries (2.06 +/- 0.17 ng/g). Neither the orchard of origin nor the time of harvest influenced the amount of melatonin in fresh cherries. The implication of the current findings is that consuming cherries could be an important source of dietary melatonin inasmuch as melatonin is readily absorbed when taken orally. Also, previously published data and the results presented here show that melatonin is not only endogenously produced but also present in the diet. PMID- 11600042 TI - Study of metallopeptidase isozymes from malted barley (Hordeum vulgare cv. Morex). AB - It has been reported that germinated barley contains peptidases that are sensitive to metal-chelating agents; however, none of these enzymes have been isolated, nor have their roles in germinated barley been investigated. Anion exchange chromatography and chromatofocusing have been used to isolate a group of peptidases from barley (Hordeum vulgare cv. Morex) green malt that are sensitive to metal-chelating agents. Their activities were studied using one- and two dimensional polyacrylamide gel electrophoresis. When analyzed on two-dimensional PAGE gels that contained gelatin as substrate, the enzymes separated into three major and approximately six minor activity spots with acidic pI values. The enzymes were optimally active against the gelatin substrate at pH 8.0 and were completely inhibited by 1,10-phenanthroline and EDTA, indicating that they belonged to the metallopeptidase class (EC 3.4.24.x). After the enzymes were inhibited with EDTA, the activities were recovered in the presence of low concentrations of metal ions. The hydrolysis of gelatin substrate was also impaired by the presence of reducing agents. The metallopeptidases readily digested, in vitro, the barley prolamine D hordein, indicating that they may be involved in degrading storage proteins during barley germination. PMID- 11600043 TI - Impact of tween 20 hydroperoxides and iron on the oxidation of methyl linoleate and salmon oil dispersions. AB - To determine the role of surfactant hydroperoxides on the oxidative stability of fatty acids, the oxidation of methyl linoleate micelles and salmon oil-in-water emulsions was measured as a function of varying Tween 20 hydroperoxide concentrations. Increasing Tween 20 hydroperoxide concentrations from 3.5 to 14.7 micromol hydroperoxide/g Tween 20 decreased the lag phase of headspace hexanal formation but did not increase the total amount of hexanal formed in methyl linoleate/Tween 20 micelles. In the micelle system, Fe(2+) decreased the lag phase of hexanal formation but increased total hexanal concentrations only in micelles with the highest Tween 20 hydroperoxide concentrations (14.7 micromol hydroperoxide/g surfactant). Increasing Tween 20 surfactant hydroperoxide concentrations also increased the oxidation of salmon oil-in-water emulsions as determined by lipid hydroperoxides and headspace propanal. In both the micelle and emulsion systems, the prooxidant effect of Fe(2+) decreased with increasing Tween 20 hydroperoxide concentrations. These data show that surfactant hydroperoxides such as those in Tween 20 could decrease the oxidative stability of lipids in food emulsions. PMID- 11600044 TI - Tannin-protein complexes as radical scavengers and radical sinks. AB - The 2,2'-azinobis(3-ethylbenzothiazoline 6-sulfonic acid) radical cation (ABTS(*)(+)) decolorization assay has been used to determine the antioxidant activity of the polyphenol epicatechin(16) (4 --> 8) catechin (procyanidin, PC) alone or in complex with the model proteins bovine serum albumin (BSA) or gelatin. PC had a molar antioxidant capacity of approximately 54, 92, or 108 radicals at pH values of 3.0, 4.9, or 7.4, respectively. Radical scavenging occurred via a rapid step followed by a slow step. Interaction with gelatin reduced the rate of rapid scavenging by 50% (PC-BSA mixtures reduced by 15%). Inhibition paralleled formation of precipitable PC-protein complexes over a range of protein/PC ratios. However, inhibition was virtually overcome in 10 min. Reaction with ABTS(*)(+) converted the PC-protein complexes from a dissociable form to a form resistant to dissociation by strong denaturants such as SDS. This study demonstrates that PC is a potent ABTS(*)(+) scavenger even when bound to protein and that the complexes may act as a radical sink within the gastrointestinal tract. PMID- 11600045 TI - Degradation products of cyanidin glycosides from tart cherries and their bioactivities. AB - The bioactive anthocyanins present in tart cherries, Prunus cerasus L. (Rosaceae) cv. Balaton, are cyanidin 3-glucosylrutinoside (1), cyanidin 3-rutinoside (2), and cyanidin 3-glucoside (3). Cyanidin (4) is the major anthocyanidin in tart cherries. In our continued evaluation of the in vivo and in vitro efficacy of these anthocyanins to prevent inflammation and colon cancer, we have added these compounds to McCoy's 5A medium in an effort to identify their degradation products during in vitro cell culture studies. This resulted in the isolation and characterization of protocatechuic acid (5), the predominant degradation product. In addition, 2,4-dihydroxybenzoic acid (6) and 2,4,6-trihydroxybenzoic acid (7) were identified as degradation products. However, these degradation products were not quantified. Compounds 5-7 were also identified as degradation products when anthocyanins were subjected to varying pH and thermal conditions. In cyclooxygenase (COX)-I and -II enzyme inhibitory assays, compounds 5-7 did not show significant activities when compared to the NSAIDs Naproxen, Celebrex, and Vioxx, or Ibuprofen, at 50 microM concentrations. However, at a test concentration of 50 microM, the antioxidant activity of protocatechuic acid (5) was comparable to those of the commercial antioxidants tert-butylhydroquinone (TBHQ), butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA), and superior to that of vitamin E at 10 microM concentrations. PMID- 11600046 TI - Regulation of phenobarbital-mediated induction of CYP102 (cytochrome P450(BM-3)) in Bacillus megaterium by phytochemicals from soy and green tea. AB - Cytochrome P450 102 (CYP102 or Cytochrome P450(BM)(-)(3)) is induced in Bacillus megaterium by barbiturates, perioxisome proliferators, estrogen, and nonsteroidal antiinflammatory drugs. We have previously demonstrated that a CYP102 construct (BMC 143) coupled with a luciferase reporter gene can be used to identify the inducers of CYP102. We now describe the effect of added phytochemicals on the induction of CYP102 by phenobarbital (PB) in B. megaterium. The isoflavones genistein, biochanin A, coumestrol, and equol, the green tea flavanoid epicatechin, and the fungal toxin zearalenone inhibit the induction of CYP102 by PB in a dose-dependent manner. However, the isoflavone daidzein, the phytoalexin glyceollin, and catechin, an epimer of epicatechin, failed to exhibit a similar inhibitory effect on PB-mediated CYP102 induction. PMID- 11600047 TI - Sweetness and enzymatic activity of lysozyme. AB - Hen egg lysozyme elicits a sweet taste sensation for human beings. Effects of reduction of disulfide bonds, heat treatment, and chemical modification of hen egg lysozyme on both sweetness and hydrolytic activity were investigated. Both the sweetness and enzymatic activities were lost when the intradisulfide linkage in a lysozyme molecule was reduced and S-3-(trimethylated amino) propylated. The sweetness and enzymatic activity of lysozyme were lost on heating at 95 degrees C for 18 h. These facts suggest that tertiary structures of lysozyme are indispensable for eliciting a sweet taste as well as enzymatic activity. Although the modification of carboxyl residues in a lysozyme by glycine methylester or aminomethansulfonic acid resulted in the loss of enzymatic activity by blocking the catalytic residues, the sweetness was fully retained. These results indicate that the sweetness of lysozyme was independent of its enzymatic activity. The lysozyme purified from goose egg white similarly elicited a sweet taste, although goose (g-type) lysozyme is quite different from hen egg lysozyme (c-type) on the basis of structural, immunological, and enzymatic properties. These findings indicate that a specific protein property of lysozyme is required for sweetness elicitation and that the enzymatic activity and carbohydrates produced by enzymatic reaction are not related to the sweet taste. PMID- 11600048 TI - Evidence of the glycation and denaturation of LTP1 during the malting and brewing process. AB - The influence of malting and brewing processes on the chemical and structural modifications occurring on LTP1 was investigated by mass spectrometry and circular dichroism. Proteins were first purified from malt, and samples were collected at various steps of beer processing performed on two barley cultivars. The levels of LTP1 found in malt were not significantly different from the amounts in barley seed. However, in malt, both LTP1b, a post-translational form of LTP1, and a third isoform named LTP1c were isolated. Moreover, both of these proteins were found to be heterogeneously glycated but still exhibited an alpha helix structure. Both glycated LTP1 and LTP1b were recovered during mashing. It was also shown that glycated LTP1 was unfolded during heat treatment of wort boiling, which is in agreement with the denatured form previously isolated from beer. PMID- 11600049 TI - Effect of food reductones, 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) and hydroxyhydroquinone (HHQ), on lipid peroxidation and type IV and I allergy responses of mouse. AB - The effect of long-term supplementation of food reductones, 2,5-dimethyl-4 hydroxy-3(2H)-furanone (DMHF) (2%, w/w), detected in many foodstuffs including soy sauce, and hydroxyhydroquinone (1,2,4-benzenetriol) (HHQ) (1.2%, w/w), detected in coffee, on mouse lipid peroxidation and type IV and I allergy responses was investigated. The effect of supplementation of these reductones combined with NO(2) inhalation (5-6 ppm) was also investigated. Levels of thiobarbituric acid-reactive substances in lung were remarkably increased, and those in kidney and liver were slightly decreased by supplementation of DMHF or HHQ. The degree of 2,4-dinitrochlorobenzene (DNCB)-sensitized lymph node cell proliferation as assessed by lymph node assay was remarkably enhanced by supplementation of DMHF or HHQ. Both the DNCB-sensitized and the trimellitic anhydride-sensitized increases in IgE levels of mice were enhanced to greater extent by supplementation of DMHF or HHQ. In no cases were additive effects of NO(2) inhalation observable. Allergen-sensitized type IV and I allergy responses of mice may be enhanced by supplementation of food reductones, DMHF or HHQ. PMID- 11600050 TI - Antioxidant activities of dioscorin, the storage protein of yam (Dioscorea batatas Decne) tuber. AB - Dioscorin, the storage protein of yam (Dioscorea batatas Decne) tuber (which is different from dioscorine found in tubers of Dioscorea hirsuta), was purified to homogeneity after DE-52 ion exchange column according to the methods of Hou et al. (J. Agric. Food Chem. 1999, 47, 2168-2172). A single band of 32 kDa dioscorin was obtained on a sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel with 2-mercaptoethanol treatment. This purified dioscorin was shown by spectrophotometric method to have scavenging activity against 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical in a pH-dependent manner. There is a positive correlation between scavenging effects against DPPH (8-46%) and amounts of 32 kDa dioscorin (5.97-47.80 nmol) added in Tris-HCl buffer (pH 7.9), which are comparable to those of glutathione at the same concentrations. Using electron paramagnetic resonance (EPR) spectrometry for DPPH radical detection, it was found that the intensities of the EPR signal were decreased by 28.6 and 57 nmol of 32 kDa dioscorin in Tris-HCl buffer (pH 7.9) more than in distilled water compared to controls. EPR spectrometry was also used for hydroxyl radical detection. It was found that 32 kDa dioscorin could capture hydroxyl radical, and the intensities of the EPR signal were significantly decreased dose-dependently by 1.79-14.32 nmol of 32 kDa dioscorin (r = 0.975) compared to the control. It is suggested that 32 kDa dioscorin, the storage protein of yam tuber, may play a role as antioxidant in tubers and may be beneficial for health when people take it as a food additive or consume yam tubers. PMID- 11600051 TI - Improved method for the synthesis of trans-feruloyl-beta-sitostanol. AB - Phytosterols and phytostanols are known to lower low-density lipoprotein cholesterol (LDL-C) levels in humans by up to 15%, and at least two products, Benecol and Take Control, are now on the market as naturally derived fatty acid esters of phytostanols (stanol esters) and phytosterols (sterol esters), respectively. A synthetic process was developed to synthesize gram quantities of trans-feruloyl-beta-sitostanol from ferulic acid and beta-sitostanol, with high purity and yields of approximately 60%. The process involves (a) condensation of trans-4-O-acetylferulic acid with the appropriate phytostanol or phytostanol mixture in the presence of N,N-dicyclohexylcarbodiimide and 4 (dimethylamino)pyridine, (b) separation of the trans-4-O-acetylferuloyl products by preparative liquid chromatography, (c) selective deacetylation of the feruloyl acetate, and (d) chromatographic purification of the feruloylated phytostanols. The process was successfully applied to synthesize stanol trans-feruloyl esters from "Vegetable Stanols", a mixture of approximately 70:30 beta-sitostanol and beta-campestanol, in comparable purity and yield. PMID- 11600053 TI - beta-Lactoglobulin A with N-ethylmaleimide-modified sulfhydryl residue, polymerized through intermolecular disulfide bridge on heating in the presence of dithiothreitol. AB - Roles of sulfhydryl groups on thermal aggregation of beta-lactoglobulin A (betaLG A) at pH 7.5 were investigated. It is known that betaLG A modified at Cys(121) with N-ethylmaleimide (NEM-betaLG A) does not form an aggregate by heating and that dithiothreitol (DTT) reduces cystine residues and induces the intermolecular sulfhydryl/disulfide interchange reaction and/or oxidation. NEM-betaLG A was heated in the presence of DTT. The molecules were linked together with an intermolecular disulfide bridge, and the polymer formed increased with increase in DTT concentration. The largest portion of polymer was formed when DTT was added at around the same molar concentration as that of NEM-betaLG A. Then, polymer formation decreased with further increase in DTT concentration. The results suggest that sulfhydryl/disulfide residues other than Cys(121), generated from cysteine residues, can induce intermolecular sulfhydryl/disulfide interchange reactions to polymer and that thiol compounds, for example, added DTT, are capable of starting such reactions. PMID- 11600052 TI - Effects of water-soluble hemicellulose from soybean hull on serum antibody levels and activation of macrophages in rats. AB - Effects of soybean hull water-soluble hemicellulose (WSHC) on serum immunoglobulin (Ig) concentration and production of NO and IL-1beta from peritoneal macrophages were examined and compared with those of Agaricus blazei in the rat system. WSHC consisted of arabinose, galactose, xylose, glucose, and rhamnose, and the molecular weight was approximately 500000. Rats were ip administrated each sample at a dose of 0.67, 13.4, or 26.9 mg/kg/day for 14 days. The administration of WSHC resulted in significantly higher productions of IgM (p < 0.01 on day 6, p < 0.05 on day 14) and IgG (p < 0.05 on day 6) than those in other groups. When peritoneal macrophages were stimulated with various concentrations of sample (0.67, 13.4, or 26.9 mg/mL), WSHC significantly increased both NO and IL-1beta productions only at the concentration of 13.4 (mg/mL) compared with those of a saline group. These findings demonstrate that WSHC enhances humoral immunity and activation of macrophages, thereby leading to the augmentation of immune responses in rats. PMID- 11600054 TI - Effect of plant growth temperature on antioxidant capacity in strawberry. AB - The influence of four day/night growing temperature combinations (18/12, 25/12, 25/22, and 30/22 degrees C) on phenolic acid, flavonol, and anthocyanin content and their antioxidant activities against peroxyl radicals (ROO(*)), superoxide radicals (O(2)(*)(-)), hydrogen peroxide (H(2)O(2)), hydroxyl radicals (OH(*)), and singlet oxygen ((1)O(2)) in fruit juice of Earliglow and Kent strawberry (Fragaria x ananassa Duch.) cultivars was studied. Pelargonidin-based anthocyanins such as pelargonidin 3-glucoside (291.3-945.1 microg/g fresh wt.), pelargonidin 3-rutinoside (24.7-50.9 microg/g fresh wt.), and pelargonidin 3 glucoside-succinate (62.2-244.0 microg/g fresh wt.) were the predominant anthocyanins in strawberry fruit juice. The content of cyanidin-based anthocyanins, cyanidin 3-glucoside and cyanidin 3-glucoside-succinate, was much lower than that of pelargonidin-based anthocyanins. Strawberry growth in high temperature conditions significantly enhanced the content of p-coumaroylglucose, dihydroflavonol, quercetin 3-glucoside, quercetin 3-glucuronide, kaempferol 3 glucoside, kaempferol 3-glucuronide, cyanidin 3-glucoside, pelargonidin 3 glucoside, pelargonidin 3-rutinoside, cyanidin 3-glucoside-succinate, and pelargonidin 3-glucoside-succinate in strawberry juice. Plants grown in the cool day and cool night temperature (18/12 degrees C) generally had the lowest phenolic acid, flavonols, and anthocyanins. An increase in night temperature from 12 to 22 degrees C, with the day temperature kept constant at 25 degrees C, resulted in a significant increase in phenolic acid, flavonols, and anthocyanins. These conditions also resulted in a significant increase in antioxidant capacity. The highest day/night temperature (30/22 degrees C) yielded fruit with the most phenolic content as well as ROO(*), O(2)(*)(-), H(2)O(2), OH(*), and (1)O(2) radical absorbance capacity. Fruit of Kent cv. strawberry had higher values of phenolic acid, flavonols, anthocyanins, and antioxidant capacities than fruit of Earliglow cv. strawberry under all temperature regimes. PMID- 11600055 TI - Characterization of beta-conglycinin and glycinin soy protein fractions from four selected soybean genotypes. AB - The beta-conglycinin and glycinin fractions of soy protein were isolated from Macon, Ohio FG1, Enrei, and IL2 genotypes that were grown under the same environmental conditions. The soy protein fractions were evaluated to determine whether chemical composition and gel-forming properties were related. Amino acid analyses suggested that the hydrophobic residues may be the primary cause of differences in soy protein gel characteristics as the storage moduli increased with higher percentages of hydrophobic residues. Reversed-phase high-performance liquid chromatography profiles revealed variations in the composition of each fraction that corresponded to differences observed among the storage moduli. The gel-forming properties may be related to more than just protein content, such as the amount and type of amino acid in the fraction. PMID- 11600056 TI - Relationship between fatty acid profile and vitamin E content in maize hybrids (Zea mays L.). AB - The balance between the vitamin E (tocochromanols) and polyunsaturated fatty acid (PUFA) contents mainly determines the susceptibility to lipid peroxidation and the storage stability of corn oil. In 1997, field experiments were conducted at two different locations to evaluate a collection of 30 corn hybrids for fatty acid profiles and tocochromanol contents. Hybrids differed significantly (p < 0.01) for major fatty acids, as well as for tocochromanol contents and composition. The major fatty acids were palmitic, oleic, and linoleic acids, whose contents were in the ranges 9.2-12.1%, 19.5-30.5%, and 53.0-65.3%, respectively. The tocopherol contents ranged as follows: alpha-tocopherol, 67-276 mg (kg of oil)(-1); beta-tocopherol, 0-20 mg (kg of oil)(-1); gamma-tocopherol, 583-1048 mg (kg of oil)(-1); delta-tocopherol, 12-71 mg (kg of oil)(-1); total tocopherol, 767-1344 mg (kg of oil)(-1). gamma-Tocopherol was the predominant derivative among all tocopherols. The tocotrienol contents were in the ranges 46 89, 53-164, and 99-230 mg (kg of oil)(-1) for alpha-, gamma-, and total tocotrienol contents, respectively. The tocotrienol profile was not characterized by the predominance of any tocotrienol homologue. alpha-Tocopherol was positively correlated with PUFA (r = 0.41) and with the vitamin E equivalent (vit E equiv) (r = 0.84), and it was not correlated with gamma-tocopherol. gamma-Tocopherol was highly correlated with total tocopherol and tocochromanol contents (r = 0.93 and r = 0.90, respectively), indicating that the contribution of this vitamer to the total tocochromanol content is the most important among all tocochromanols. The high positive correlation found between the vit E/PUFA ratio and the vit E equiv, as well as the absence of correlation between this ratio and PUFA indicates that a higher vit E/PUFA ratio can be easier achieved be increasing the vitamin E content than by modifying fatty acid profile in corn oil. PMID- 11600057 TI - Oxytetracycline residues in giant freshwater prawn (Macrobrachium rosenbergii). AB - The distribution of oxytetracycline (OTC) in male and female Macrobrachium rosenbergii was examined after the prawns had been given medicated feed containing OTC at levels of 2.5 and 5.0 g/kg of feed for 1 week and nonmedicated feed thereafter. OTC levels in the heads of both male and female prawns were consistently higher than in the muscles. Batches of both male and female prawns treated with higher dosages had significantly higher OTC residues in both head and muscle tissues than the batches treated with lower dosages. During treatment, peak concentrations in the head and muscle from each group were reached within 4 6 days. After drug treatment ceased, 13 days for the head and 10 days for the muscle were required to reduce OTC residues to safe levels in all batches of both sexes and dosages. In practice, to account for variations in water temperature, drug dosage, duration of therapy, and other environmental conditions, a withdrawal period of 21 days is recommended. PMID- 11600058 TI - Contributions of major components to the antimutagenic effect of Hsian-tsao (Mesona procumbens Hemsl.). AB - Our aim was to determine the antimutagenic activity of various solvent extracts from an herb Mesona procumbens Hemsl, normally called Hsian-tsao in China. We also investigated the relationships between the special components in the water extract of Hsian-tsao (WEHT) and the antimutagenic activity. It was found that the extracts at 0-0.6 mg/plate from three solvents (water, methanol, and ethyl acetate) exhibited a dose-dependent antimutagenic effect against benzo[a]pyrene [B(a)P] and 2-amino-3-methylimidazo(4,5-f)quinoline (IQ), both are indirect mutagens in Salmonella tester strains TA98 and TA100. The WEHT from three different plantations revealed a similar inhibitory effect on the mutagenicity of IQ in TA 98 at 2.5-5.0 mg/plate. The inhibitory effect of WEHT on the mutagenicity of IQ correlates with their polyphenol and ascorbic acid contents but not with their chlorophyll contents. These findings suggest that the antimutagenicity activity of WEHT may be attributed mainly to their polyphenolic compounds and ascorbic acid. PMID- 11600059 TI - Emulsion properties of casein and whey protein hydrolysates and the relation with other hydrolysate characteristics. AB - Casein and whey protein were hydrolyzed using 11 different commercially available enzyme preparations. Emulsion-forming ability and emulsion stability of the digests were measured as well as biochemical properties with the objective to study the relations between hydrolysate characteristics and emulsion properties. All whey protein hydrolysates formed emulsions with bimodal droplet size distributions, signifying poor emulsion-forming ability. Emulsion-forming ability of some casein hydrolysates was comparable to that of intact casein. Emulsion instability was caused by creaming and coalescence. Creaming occurred mainly in whey hydrolysate emulsions and in casein hydrolysate emulsions containing large emulsion droplets. Coalescence was dominant in casein emulsions with a broad particle size distribution. Emulsion instability due to coalescence was related to apparent molecular weight distribution of hydrolysates; a relative high amount of peptides larger than 2 kDa positively influences emulsion stability. PMID- 11600060 TI - Synthesis and sweetness characteristics of L-aspartyl-D-alanine fenchyl esters. AB - Four isomers of the L-aspartyl-D-alanine fenchyl esters were prepared as potential peptide sweeteners. L-Aspartyl-D-alanine (+)-alpha-fenchyl ester and L aspartyl-D-alanine (-)-beta-fenchyl ester showed sweetness with potencies 250 and 160 times higher than that of sucrose, respectively. In contrast, L-aspartyl-D alanine (+)-beta-fenchyl ester and L-aspartyl-D-alanine (-)-alpha-fenchyl ester had the highest sweetness potencies at 5700 and 1100 times that of sucrose, respectively. In particular, L-aspartyl-D-alanine (-)-alpha-fenchyl ester had an excellent sweetness quality; but L-aspartyl-D-alanine (+)-beta-fenchyl ester did not have an excellent quality of sweetness because it displayed an aftertaste caused by the strong sweetness. PMID- 11600061 TI - Purification and characterization of a carboxypeptidase from squid hepatopancreas (Illex illecebrosus). AB - The hepatopancreas of squid (Illex illecebrosus) extract contains a wide range of carboxypeptidase (CP) activities based on hydrolysis of N-CBZ-dipeptide substrates. SDS-PAGE zymograms with N-CBZ-Phe-Leu substrate revealed three activity zones (CP-I, 23 kDa; CP-II, 29 kDa; CP-III, 42 kDa). CP-I was purified 225-fold with 86.20% recovery based on N-CBZ-Ala-Phe activity by chromatography on DEAE-cellulose, gel filtration, and chromatofocusing. The purified enzyme had broad specificity toward N-CBZ-dipeptides; however, it preferred substrates with a hydrophobic amino acid at the C terminus. CP-I had greatest activity with N-CBZ Ala-Phe (specific activity = 7104 units/mg of protein, K(m) = 0.40 mM, and physiological efficiency = 22863). CP-I had a pI of 3.4 and is a metalloprotease that is activated by Co(2+) and partially inhibited by Pefabloc, a serine protease inhibitor. With N-CBZ-Ala-Phe and Gly-Phe, it had optimum activity at pH 8 and 70 degrees C. The amino acid composition of squid CP-I is similar to that of CP A from other species. PMID- 11600063 TI - Maltodextrin-anionic surfactant interactions: isothermal titration calorimetry and surface tension study. AB - Interactions between maltodextrin (DE = 10) and an anionic surfactant (sodium dodecyl sulfate, SDS) were studied in a buffer solution (pH 7.0, 10 mM NaCl, 20 mM Trizma, 30.0 degrees C) using isothermal titration calorimetry (ITC), surface tension, differential scanning calorimetry (DSC), and turbidity techniques. ITC measurements indicated that the binding of SDS to maltodextrin was exothermic and that, on average, one SDS monomer bound per 24 glucose units of maltodextrin at saturation. Surface tension measurements indicated that there was a critical surfactant concentration ( approximately 0.05 mM SDS) below which surfactant and maltodextrin did not interact and that the amount of surfactant bound to the maltodextrin above this concentration increased with increasing maltodextrin concentration. Turbidity measurements indicated that the solutions remained transparent at all maltodextrin (0-1 wt %) and SDS (0-20 mM) concentrations studied, which suggested that phase separation did not occur. DSC measurements indicated that no phase transitions occurred between 10 and 110 degrees C for maltodextrin solutions (0.5 wt %) in the presence or absence of surfactant. A phase diagram was developed to describe the interactions between SDS and maltodextrin. PMID- 11600062 TI - Scavenging of free radicals, antimicrobial, and cytotoxic activities of the Maillard reaction products of beta-lactoglobulin glycated with several sugars. AB - The Maillard reaction occurs during many industrial and domestic thermal treatments of foods. It is widely used because of its role in creating colors, flavors, textures, and other functional properties in foodstuffs. Proteins glycated without the use of conventional chemical reagents have improved technofunctional properties such as heat stability, emulsifying, and foaming properties. The present study was carried out to determine the extent to which this reaction can convey antioxidant, antimicrobial, or cytotoxic activities to beta-lactoglobulin (BLG) and to its tryptic and peptic hydrolysates. BLG was modified with six different sugars in solution at 60 degrees C. Antiradical properties were estimated using a radical scavenging activity test. Antimicrobial activities against different bacterial strains were studied with a diffusion disk method. Cytotoxic tests were performed using two cell lines and the 3-(4,5 dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) rapid colorimetric assay. Glycation induced a radical scavenging activity to BLG, the intensity of which depended on the sugar used for modification. Proteins modified with ribose and arabinose showed the highest radical scavenging activities depicted by about 80 and 60% of 2,2-diphenyl-1-picrylhydrazyl (DPPH) absorption decrease at 515 nm. No antimicrobial effect of any glycated form of BLG against Escherichia coli, Bacillus subtilis, Listeria innocua, and Streptococcus mutans was observed. The MTT test showed no enhancement of cytotoxicity by modified proteins and peptides against COS-7 and HL-60 cells. Thus, glycated proteins could be used in formulated food as functional ingredients with a radical scavenging activity able to delay deterioration due to oxidation. This use could be even more advisable considering the lack of toxicity to eukaryotic and prokaryotic cell cultures demonstrated in this work. PMID- 11600064 TI - Developmental variation of sugars, carboxylic acids, purine alkaloids, fatty acids, and endoproteinase activity during maturation of Theobroma cacao L. seeds. AB - The changes of mono- and oligosaccharides, carboxylic acids, purine alkaloids, and fatty acid composition, and of aspartic endoproteinase activity, were analyzed during seed development in two varieties of cacao (Theobroma cacao). The majority of the components examined either decreased or accumulated steadily in concentration during the second half of bean development. Sucrose is the major sugar in the mature embryo, whereas fructose and glucose are at higher concentrations in the endosperm tissue. Considerable amounts of malate are found in the endosperm, whereas citrate is the dominant carboxylic acid in the embryo. A major change in the fatty acid composition occurs in the young embryo when the proportion of stearic acid increases rapidly at the expense of linoleic acid, which is reduced from about 18 to 3%. Theobromine is the dominant purine alkaloid (ca. 80%), and caffeine appears only toward the end of seed maturity. Aspartic endoproteinase activity increases rapidly during embryo expansion, reaching a maximal activity before final maturity. The results are discussed in conjunction with physiological changes in developing seeds, and the potential contributions of the compounds analyzed for cocoa quality. PMID- 11600065 TI - Postharvest induction modeling method using UV irradiation pulses for obtaining resveratrol-enriched table grapes: a new "functional" fruit? AB - A modeling method for the induction of resveratrol synthesis by UV irradiation pulses in Napoleon table grapes is proposed. The method is based on the combination of four main parameters: irradiation power (IW), irradiation time (IT), irradiation distance (ID), and number of elapsed days to achieve the highest resveratrol accumulation (D(m)). Maximum resveratrol content (11-fold higher than untreated grapes) was achieved using the combination: IW = 510 W, IT = 30 s, ID = 40 cm, and D(m) = 3 days. Sensory characteristics and main features of irradiated grapes (color, weight, firmness, flavor, size, ripening index and vitamin C content) remained unaltered after 1 week of storage. UV induction signal migrated to the hidden side of the grape skin with a delay of 3 days as compared to the directly irradiated side. Phenolic compounds were not detected in Napoleon grape flesh. Resveratrol content per standard serving (200 g) of irradiated grape was about 3 mg, an amount more than 10-fold higher than that of untreated Napoleon grapes. This means that a serving of irradiated grape (unpeeled) could supply the resveratrol content equivalent to 3 glasses of a red wine with high resveratrol content ( approximately 1 mg/glass). Therefore, controlled UV irradiation pulses are useful as a simple postharvest treatment (and alternative to genetic engineering) to obtain possible "functional" grapes (with enhanced health-promoting properties) as a dietary source of high resveratrol content. PMID- 11600066 TI - Evaluation of mushroom dietary fiber (nonstarch polysaccharides) from sclerotia of Pleurotus tuber-regium (Fries) singer as a potential antitumor agent. AB - Mushroom dietary fiber or nonstarch polysaccharides (NSPs) that were soluble in hot alkali and belonged to the beta-glucan type were isolated from the sclerotia of an edible mushroom, Pleurotus tuber-regium. The mushroom NSPs were further separated into a number of fractions [hot alkali extracts (HAEs)] with weight average molecular weights (M(w)) ranging from 1 x 10(4) to 42.2 x 10(4). The HAE fractions [with M(w) of (5.8-17.1) x 10(4)] administered intraperitoneally at a dose of 20 mg/kg of body weight to BALB/c mice implanted with solid tumor Sarcoma 180 were found to be effective in inhibiting tumor proliferation with an inhibition ratio of > or =50%. In vitro experiments using human tumor cell lines HL-60 and HepG2 had shown that HAE fractions with M(w) of (5.8-42.2) x 10(4) also had antiproliferative activity at three different concentrations (50, 100, and 200 microg/mL) toward the tumor cell lines tested. All HAE fractions did not inhibit the growth of a normal kidney cell line (Vero) from monkey. It is therefore postulated that the antitumoral effect of NSPs from the sclerotia of P. tuber-regium is probably host-mediated and cytocidal. PMID- 11600067 TI - Iron and zinc bioavailability in rats fed intrinsically labeled bean and bean rice infant weaning food products. AB - Beans are the core of the Latin American diet and contain iron and zinc. However, the bioavailability of these trace minerals from beans is low. The objective of this study was to determine if the bioavailability of iron and zinc could be improved with the use of fermentation and germination processing technologies. Black beans native to Costa Rica were grown hydroponically with either radioactive iron or zinc. The influence of fermentation and germination on iron and zinc bioavailability from intrinsically labeled infant weaning food products based on black beans and beans-rice was determined in rats. Mineral bioavailability was determined using whole-body (59)Fe retention for iron, and whole-body (65)Zn retention and incorporation of radiolabel into bone for zinc. Percent absorption of (59)Fe from fermented products ranged between 48.0 and 58.0. Percent absorption of (65)Zn ranged from 57.0 to 64.0. Fermentation did not increase iron bioavailability in rats fed fermented beans without rice. Fermentation of cooked beans significantly increased zinc retention. Germination significantly enhanced iron retention from cooked beans from 46 to 55% and from cooked beans-cooked rice from 34 to 48%. Germination significantly improved zinc absorption and retention from cooked beans without added rice. PMID- 11600068 TI - Protein digestibility-corrected amino acid scores for bean and bean-rice infant weaning food products. AB - Vegetable proteins are an integral part of infant weaning diets in Latin America. Protein quality in plant-based products, however, is constrained by amino acid composition and intrinsically present antinutritional factors. The goal of this study was to improve bean protein quality by utilizing fermentation and germination processing. The objectives were to determine if protein quality, as measured by Food and Agricultural Organization (FAO) approved True Protein Digestibility (TPD) and Protein Digestibility-Corrected Amino Acid Scores (PDCAAS), of formulated bean-based weaning products could be improved upon fermentation and germination and if protein quality could be further improved when processed beans were combined with cooked rice. Results showed that the highest TPD and PDCAAS values were obtained for cooked germinated beans combined with rice. The TPD values for products ranged from 80 to 91%, and the PDCAAS values were 0.38-0.51. There was no significant increase (P < 0.05) of either TPD or PDCAAS values upon fermentation. Germination increased TPD of cooked bean products; this increase was not, however, accompanied by an increase in PDCAAS. When combined with rice, the PDCAAS values for all bean products improved significantly, thus supporting the concept of cereal-legume complementation. In conclusion, this study showed the range of PDCAAS in processed black bean and bean-rice infant weaning food products. The potential for incorporation of these products into the diets of weaning age Latin American children would, however, be confirmed only after validation with growth or metabolic balance studies in human infants. PMID- 11600069 TI - Vicianin, prunasin, and beta-cyanoalanine in common vetch seed as sources of urinary thiocyanate in the rat. AB - When young rats were fed a diet containing common vetch seed for 1 month, they excreted in the urine approximately 7 times more thiocyanate than they had ingested. Vicianin, prunasin, and beta-cyanoalanine were identified as principal dietary sources of the excreted thiocyanate. Vicianin was isolated by chromatography and crystallization. Its structure was confirmed by mass spectrometry and by identification of its monosaccharides and aglycon. Prunasin was identified chromatographically by HPLC. The combined seed content of vicianin (0.68 micromol/g) and prunasin (0.16 micromol/g) corresponded to the cyanogen content of the seed (0.91 +/- 0.14 micromol/g; n = 7), determined as cyanide after autolysis. When vicianin was fed, the urinary thiocyanate output was 21% of the ingested amount of vicianin, whereas beta-cyanoalanine yielded a urinary thiocyanate output of < 0.2%. Calculations show that 73% of the thiocyanate can be derived from vicianin and prunasin, with 27% derived from beta-cyanoalanine. High urinary output of thiocyanate has been associated with endocrine and neurological disorders. PMID- 11600070 TI - Lumpidin, a novel biomarker of some ochratoxin a producing penicillia. AB - The novel compound lumpidin (1) has been isolated as a major compound from an isolate of Penicillium nordicum. Compound 1 is a diketopiperazine with a unique ring system likely to be a condensate of one mole each of L-tryptophan, L phenylalanine, and L-homo-proline. The fact that 1 has been detected from only three out of sixteen isolates of P. nordicum indicates that lumpidin-producing isolates might represent a separate and third ochratoxin A producing Penicillium species. PMID- 11600071 TI - Colour categorization by domestic chicks. AB - Spectral stimuli form a physical continuum, which humans divide into discrete non overlapping regions or categories that are designated by colour names. Little is known about whether non-verbal animals form categories on stimulus continua, but work in psychology and artificial intelligence provides models for stimulus generalization and categorization. We compare predictions of such models to the way poultry chicks (Gallus gallus) generalize to novel stimuli following appetitive training to either one or two colours. If the two training colours are (to human eyes) red and greenish-yellow or green and blue, chicks prefer intermediates, i.e. orange rather than red or yellow and turquoise rather than green or blue. The level of preference for intermediate colours implies that the chicks interpolate between the training stimuli. However, they do not extrapolate beyond the limits set by the training stimuli, at least for red and yellow training colours. Similarly, chicks trained to red and blue generalize to purple, but they do not generalize across grey after training to the complementary colours yellow and blue. These results are consistent with a modified version of a Bayesian model of generalization from multiple examples that was proposed by Shepard and show similarities to human colour categorization. PMID- 11600073 TI - Male mate choice, sexual conflict and strategic allocation of copulations in a lekking bird. AB - The males of lekking species are not expected to be choosy about mating because a reduced reproductive rate due to lost mating opportunities should outweigh any benefits of male choice. Females have traditionally not been expected to be competitive in this system since their reproduction has usually been assumed to be unconstrained by male availability. Here we show that, in contrast to these predictions, males are choosy and females may be competitive in the lekking great snipe Gallinago media. Males preferred by many females often refused to copulate with and even chased away females that the male had already copulated with, whereas females seemed to compete for repeated copulations. We conclude that choosiness may sometimes pay for popular males in those lekking species where females copulate repeatedly. Apparently, evolutionary conflicts of interest between individuals may cause a richer repertoire of behavioural adaptations than, to our knowledge, hitherto realized. PMID- 11600072 TI - The role of antigenic stimulation and cytotoxic T cell activity in regulating the long-term immunopathogenesis of HIV: mechanisms and clinical implications. AB - This paper develops a predictive mathematical model of cell infection, host immune response and viral replication that reproduces observed long-term trends in human immunodeficiency virus (HIV) pathogenesis. Cell activation induced by repeated exposure to many different antigens is proposed as the principal mechanism of providing target cells for HIV infection and, hence, of CD4+ T cell depletion, with regulation of the overall T cell pool size causing concomitant CD8 pool increases. The model correctly predicts the cross-patient variability in disease progression, the rate of which is found to depend on the efficacy of anti HIV cytotoxic T lymphocyte responses, overall viral pathogenicity and random effects. The model also predicts a variety of responses to anti-viral therapy, including episodic residual viral replication and discordant responses and we find that such effects can be suppressed by increasing the potency of treatment. PMID- 11600074 TI - Mate guarding in the Seychelles warbler is energetically costly and adjusted to paternity risk. AB - Males may increase their fitness through extra-pair copulations (copulations outside the pair bond) that result in extra-pair fertilizations, but also risk lost paternity when they leave their own mate unguarded. The fitness costs of cuckoldry for Seychelles warblers (Acrocephalus sechellensis) are considerable because warblers have a single-egg clutch and, given the short breeding season, no time for a successful replacement clutch. Neighbouring males are the primary threat to a male's genetic paternity. Males minimize their loss of paternity by guarding their mates to prevent them from having extra-pair copulations during their fertile period. Here, I provide experimental evidence that mate-guarding behaviour is energetically costly and that the expression of this trade-off is adjusted to paternity risk (local male density). Free-living males that were induced to reduce mate guarding spent significantly more time foraging and gained significantly better body condition than control males. The larger the reduction in mate guarding, the more pronounced was the increase in foraging and body condition (accounting for food availability). An experimental increase in paternity risk resulted in an increase in mate-guarding intensity and a decrease in foraging and body condition, and vice versa. This is examined using both cross sectional and longitudinal data. This study on the Seychelles warbler offers experimental evidence that mate guarding is energetically costly and adjusted to paternity risk. PMID- 11600075 TI - Molecular motors: thermodynamics and the random walk. AB - The biochemical cycle of a molecular motor provides the essential link between its thermodynamics and kinetics. The thermodynamics of the cycle determine the motor's ability to perform mechanical work, whilst the kinetics of the cycle govern its stochastic behaviour. We concentrate here on tightly coupled, processive molecular motors, such as kinesin and myosin V, which hydrolyse one molecule of ATP per forward step. Thermodynamics require that, when such a motor pulls against a constant load f, the ratio of the forward and backward products of the rate constants for its cycle is exp [-(DeltaG + u(0)f)/kT], where -DeltaG is the free energy available from ATP hydrolysis and u(0) is the motor's step size. A hypothetical one-state motor can therefore act as a chemically driven ratchet executing a biased random walk. Treating this random walk as a diffusion problem, we calculate the forward velocity v and the diffusion coefficient D and we find that its randomness parameter r is determined solely by thermodynamics. However, real molecular motors pass through several states at each attachment site. They satisfy a modified diffusion equation that follows directly from the rate equations for the biochemical cycle and their effective diffusion coefficient is reduced to D-v(2)tau, where tau is the time-constant for the motor to reach the steady state. Hence, the randomness of multistate motors is reduced compared with the one-state case and can be used for determining tau. Our analysis therefore demonstrates the intimate relationship between the biochemical cycle, the force-velocity relation and the random motion of molecular motors. PMID- 11600076 TI - Finding the tree of life: matching phylogenetic trees to the fossil record through the 20th century. AB - Phylogenies, or evolutionary trees, are fundamental to biology. Systematists have laboured since the time of Darwin to discover the tree of life. Recent developments in systematics, such as cladistics and molecular sequencing, have led practitioners to believe that their phylogenies are more testable now than equivalent efforts from the 1960s or earlier. Whole trees, and nodes within trees, may be assessed for their robustness. However, these quantitative approaches cannot be used to demonstrate that one tree is more likely to be correct than another. Congruence assessments may help. Comparison of a sample of 1000 published trees with an essentially independent standard (dates of origin of groups in geological time) shows that the order of branching has improved slightly, but the disparity between estimated times of origination from phylogeny and stratigraphy has, if anything, become worse. Controlled comparisons of phylogenies of four major groups (Agnatha, Sarcopterygii, Sauria and Mammalia) do not show uniform improvement, or decline, of fit to stratigraphy through the twentieth century. Nor do morphological or molecular trees differ uniformly in their performance. PMID- 11600077 TI - Plant lock and ant key: pairwise coevolution of an exclusion filter in an ant plant mutualism. AB - Although observations suggest pairwise coevolution in specific ant-plant symbioses, coevolutionary processes have rarely been demonstrated. We report on, what is to the authors' knowledge, the strongest evidence yet for reciprocal adaptation of morphological characters in a species-specific ant-plant mutualism. The plant character is the prostoma, which is a small unlignified organ at the apex of the domatia in which symbiotic ants excavate an entrance hole. Each myrmecophyte in the genus Leonardoxa has evolved a prostoma with a different shape. By performing precise measurements on the prostomata of three related myrmecophytes, on their specific associated ants and on the entrance holes excavated by symbiotic ants at the prostomata, we showed that correspondence of the plant and ant traits forms a morphological and behavioural filter. We have strong evidence for coevolution between the dimensions and shape of the symbiotic ants and the prostoma in one of the three ant-Leonardoxa associations. PMID- 11600078 TI - Skewed paternity and sex allocation in hermaphroditic plants and animals. AB - Models predict a reduced allocation to sperm when females preferentially use one of two males' sperm and the males do not know who is favoured. An analogous discounting occurs in plants when their paternity success is skewed by random, non-heritable factors such as location in the population and pollinator behaviour. We present a model that shows that skewed paternity can affect the sex allocation of hermaphrodites, that is it leads to a female-biased investment. The model highlights the close links between local mate competition and sperm competition. We use paternity data from Ficus in order to illustrate that skews in paternity success can lead to a high degree of sibling gamete competition in an apparently open breeding system. Since skews in paternity are ubiquitous in hermaphroditic plants and animals these findings should apply broadly. PMID- 11600079 TI - Precise tuning of barnacle leg length to coastal wave action. AB - Both spatial and temporal variation in environmental conditions can favour intraspecific plasticity in animal form. But how precise is such environmental modulation? Individual Balanus glandula Darwin, a common northeastern Pacific barnacle, produce longer feeding legs in still water than in moving water. We report here that, on the west coast of Vancouver Island, Canada, the magnitude and the precision of this phenotypic variation is impressive. First, the feeding legs of barnacles from protected bays were nearly twice as long (for the same body mass) as those from open ocean shores. Second, leg length varied surprisingly precisely with wave exposure: the average maximum velocities of breaking waves recorded in situ explained 95.6-99.5% of the variation in average leg length observed over a threefold range of wave exposure. The decline in leg length with increasing wave action was less than predicted due to simple scaling, perhaps due to changes in leg shape or material properties. Nonetheless, the precision of this relationship reveals a remarkably close coupling between growth environment and adult form, and suggests that between-population differences in barnacle leg length may be used for estimating differences in average wave exposure easily and accurately in studies of coastal ecology. PMID- 11600080 TI - Sexual selection at the protein level drives the extraordinary divergence of sex related genes during sympatric speciation. AB - An increasing number of molecular studies are indicating that, in a wide variety of species, genes directly related to fertilization evolve at extraordinarily high rates. We try to gain insight into the dynamics of this rapid evolution and its underlying mechanisms by means of a simple theoretical model. In the model, sexual selection and sympatric speciation act together in order to drive rapid divergence of gamete recognition proteins. In this process, intraspecific competition for fertilizations enlarges male gamete protein variation by means of evolutionary branching, which initiates sympatric speciation. In addition, avoidance of competition for fertilizations between the incipient species drives the rapid evolution of gamete recognition proteins. This mechanism can account for both strong stabilizing selection on gamete recognition proteins within species and rapid divergence between species. Moreover, it can explain the empirical finding that the rate of divergence of fertilization genes is not constant, but highest between closely related species. PMID- 11600081 TI - Postponed reproduction as an adaptation to winter conditions in Drosophila melanogaster: evidence for clinal variation under semi-natural conditions. AB - Patterns of climatic adaptation in drosophila and other insects have largely been inferred from laboratory comparisons of traits that vary clinally. Here, we extend this research to comparisons under semi-natural conditions. To test for clinal variation in reproductive patterns and survival over winter, Drosophila melanogaster populations were initiated from seven collection sites along the eastern coast of Australia, ranging from tropical to temperate regions. The fecundity and survival of these populations were monitored in field cages at a temperate location until all adults had died more than 5 months later. Total fecundity showed a curvilinear relationship with latitude, due to higher egg production by high- and low-latitude populations. Adults from temperate locations survived winter conditions better than those from subtropical populations but not tropical ones. There was a linear cline in the timing of egg production: temperate populations produced eggs later than populations from lower latitudes. This cline is likely to be adaptive because egg-to-adult viability experiments indicated that only eggs laid in spring developed successfully to the adult stage. There was no evidence for climatic adaptation in the immature stages. The adult mortality rate increased gradually over winter, and in some populations was also correlated with the minimum ambient temperature. These results indicate that adaptation to winter conditions in D. melanogaster has involved shifts in reproductive patterns. PMID- 11600082 TI - Experimental evidence for kin-biased helping in a cooperatively breeding vertebrate. AB - The widespread belief that kin selection is necessary for the evolution of cooperative breeding in vertebrates has recently been questioned. These doubts have primarily arisen because of the paucity of unequivocal evidence for kin preferences in cooperative behaviour. Using the cooperative breeding system of long-tailed tits (Aegithalos caudatus) in which kin and non-kin breed within each social unit and helpers are failed breeders, we investigated whether helpers preferentially direct their care towards kin following breeding failure. First, using observational data, we show that not all failed breeders actually become helpers, but that those that do help usually do so at the nest of a close relative. Second, we confirm the importance of kinship for helping in this species by conducting a choice experiment. We show that potential helpers do not become helpers in the absence of close kin and, when given a choice between helping equidistant broods belonging to kin and non-kin within the same social unit, virtually all helped at the nest of kin. This study provides strong evidence that kinship plays an essential role in the maintenance of cooperative breeding in this species. PMID- 11600083 TI - Increased reproductive effort results in male-biased offspring sex ratio: an experimental study in a species with reversed sexual size dimorphism. AB - Adaptive sex-ratio theory predicts that parents should overproduce the more beneficial offspring sex. Based on a recent experimental study of lesser black backed gulls, we tested this hypothesis with the great skua, Catharacta skua, a bird species closely related to gulls but where females are the larger sex. When in poor body condition, the gulls overproduced daughters, the smaller and more viable sex under those circumstances. To discriminate between a mandatory physiological overproduction of female (i.e. non-male) eggs versus the overproduction of the smaller and presumably more viable sex, we conducted an egg removal experiment with the great skua. Since the males are smaller, larger size and being male are separated. Through egg removal we induced females to increase egg production effort. Eggs were sexed using a DNA-based technique. Manipulated pairs produced a significant male bias at the end of the extended laying sequence, while the sex ratio in the control group did not differ from unity. Our results present an example of facultative sex-ratio manipulation and support the hypothesis that in sexually dimorphic birds parents overproduce the smaller sex under adverse conditions. PMID- 11600084 TI - Inter-current and nosocomial infections among visceral leishmaniasis patients in Ethiopia: an observational study. AB - From July 1989 up to September 1997, a total of 247 non-HIV associated visceral leishmaniasis (VL) patients were treated on outpatient basis in rural clinics (195 patients) and hospitalised in the Northern-Omo Regional Hospital (18 patients) and in Addis Ababa referral hospitals (34 patients). Patients treated in the rural clinics and in the Regional hospital originated from the same endemic area and had comparable baseline characteristics. Overall rates of complications (inter-current/concurrent infectious or non-infectious diseases or deaths) in the three categories were 10.7, 38.9 and 61.6%, while case fatality rates were 2.5, 5.6 and 11.7%, respectively. Nosocomial bacterial infections occurred in 16.6% of patients treated in the Regional hospital and 32.3% of patients treated in Addis Ababa referral hospitals, and these infections accounted for 42.8 and 52.4% of the complications seen in the respective categories. Among VL patients originating from the same endemic place and with comparable baseline clinical data, patients treated hospitalised had significantly higher rates of complications than patients treated on outpatient basis (P<0.001). Patients who had complications during the course of VL therapy had significantly lower pre-treatment haemoglobin levels. Considering the extra cost of hospitalisation and risk of nosocomial infections and petavalent antimonial therapy being fairly safe, we recommend that VL patients, unless with serious complications, should preferably be treated on ambulatory basis with follow-up to monitor response and inter-current infections if any. PMID- 11600085 TI - A high performance liquid chromatographic method for the estimation of diethylcarbamazine content in medicated salt samples. AB - A simple and reproducible method for the estimation of diethylcarbamazine citrate (DEC) by high performance liquid chromatography (HPLC) in DEC-medicated salt was developed. HPLC analysis was conducted with a mobile phase containing acetonitrile/phosphate buffer (20 mM KH(2)PO(4,) adjusted to pH 3.2 with 10% ortho-phosphoric acid) in the ratio of 1:9 and at a flow rate of 1.5 ml/min. A Phenomenex C8 column (15 cmx4.6 mm) of 5 microm particle size was used for the analysis. Analysis was done at UV 210 nm, 0.02 a.u.f. and 40 degrees C. The coefficient of variation was <10% in the range of 1-25 microg/ml and the minimum detectable level was 0.5 microg/ml. The quality of DEC-medicated salt prepared by two methods was analyzed by using the HPLC method. In spray drying method, 29 and 71% of the samples and in rotating drum method, 9 and 12% of samples were found to contain DEC at 0.15-0.25% and >0.25%, respectively. Thus, this quick and simple HPLC method for the estimation of DEC could play a vital role in checking the quality of the DEC medicated salt used for the control of filariasis. PMID- 11600087 TI - Hospital based clinical surveillance for dengue haemorrhagic fever in Bandung, Indonesia 1994-1995. AB - In Indonesia, by law dengue haemorrhagic fever (DHF) cases must be reported within 24 h to the district health authority. The objective of this study was to evaluate the adequacy, accuracy and reporting delay of this reporting system. In four major hospitals of the city of Bandung, medical records of hospitalised DHF cases admitted between April 1994 and March 1995 were reviewed. This list of DHF cases was compared with the list of reported cases to the Bandung Municipality Health Office. During the study period, 569 DHF cases and 81 dengue shock syndrome (DSS) cases were diagnosed. Only 199 (31%) of the 650 hospitalised cases with suspected DHF/DSS were reported to the Bandung Municipality Health Office. The percentage of fatal cases was significantly lower among all hospitalised cases 11/650 (1.7%) than among reported cases 5/199 (2.5%). In only 443 of the 583 hospitalised cases (76%) in which a dengue serological test was performed, was this test positive. Of the 199 reported DHF/DSS cases 151 (76%) had a positive haemagglutination inhibition test. This study shows that the surveillance system for DHF/DSS in Bandung should be strengthened. DHF/DSS cases should be reported on the basis of a diagnosis made during hospitalisation preferably after a serological confirmation is obtained. PMID- 11600086 TI - Spleen size determined by ultrasound in patients with sickle cell trait, HbAC trait and glucose-6-phosphate-dehydrogenase deficiency in a malaria hyperendemic area (Ashanti Region, Ghana). AB - The occurrence of enlarged spleens and its age distribution has long been used as a crude measure to estimate malaria endemicity in cross-sectional surveys. Spleen size, however, is influenced by several variables that should be considered if they are observed in a population under study. We hypothesized that spleen indices are dependent on distinct red blood cell polymorphisms. Accordingly, we expected a lower prevalence of splenomegaly among patients with the sickle-cell trait (HbAS), HbAC trait and G6PD deficiency than in patients without red cell disorders, possibly due to the lower incidence of malaria attacks in these individuals. In our survey, however, spleen rates and sizes did not differ significantly between HbAA-, HbAS- and HbAC-positive individuals. Furthermore, enlargement of spleens was found at similar frequencies in persons with and without glucose-6-phosphate-dehydrogenase (G6PD)-deficiency (G6PD-A(-)). PMID- 11600088 TI - Scope of infectious and tropical diseases in the Middle East. PMID- 11600089 TI - Immunization in the 21st century--the way forward. AB - Major changes will impact the way national immunization programmes and services are planned and implemented over the next decade and beyond. This paper presents the most significant health policy contexts, the relevant features of health systems development and new prospects for service delivery. It outlines ways of transforming a dedicated disease control programme, polio eradication, for a broader health agenda. Progress anticipated in research for new vaccines and technologies is described. Reaching the new targets being established will require strong partnerships and the recent creation of the Global Alliance for Vaccines and Immunizations is an important step in this direction. PMID- 11600090 TI - Poliomyelitis in Oman. I. The last outbreak? AB - Since 1988, the Sultanate of Oman has experienced three outbreaks of paralytic poliomyelitis. The last outbreak occurred in December 1993 and involved two children aged 10 months and 4 1/2 years. The children had received five and four doses, respectively, of trivalent oral polio vaccine (OPV) and lived in the same village. Serum neutralizing antibody tests suggested that paralytic polio in these children was due to poor antibody response to OPV. Wild poliovirus type 1 was isolated from both patients, as well as from seven of ten close contacts of the older child, and one of eight contacts of the younger child. All contacts had received three to six doses of OPV. Genomic sequence studies indicated that the virus isolates belonged to a genotypic group prevalent in southern and western Asia, but differed markedly from virus isolated during the 1988/89 outbreak, suggesting another importation of poliovirus. In response to the outbreak, supplementary immunization with OPV was given to children <6 years of age, initially in the affected district, and subsequently to children in the whole country. This study demonstrates that immunization with three to six doses of OPV did not prevent infection with wild poliovirus. In those children with sub optimal response to OPV, infection resulted in paralytic poliomyelitis. The outbreak remained localized in one village, indicating that the outbreak control measures were effective. PMID- 11600091 TI - Poliomyelitis in Oman. II. Toward eradication. AB - In the past decade, the Sultanate of Oman has experienced three outbreaks of paralytic poliomyelitis--a widespread polio type 1 epidemic in 1988/1989, four cases of polio type 3 in three different regions in 1991, and a localized type 1 outbreak in 1993. The lessons learnt from each of these epidemics have guided us to modify and improve our polio eradication activities. Currently, these activities include administration of five primary and three booster doses of trivalent oral polio vaccine, yearly national immunization campaigns (NIDs) since 1995 with coverage of >90%, localized immunization campaigns, acute flaccid paralysis (AFP) surveillance which involves reporting of all cases by facsimile to the Department of Surveillance within 24 h of detecting a case and weekly zero reporting from 22 sentinel sites, and virological testing of stool specimens of all AFP cases and their close contacts at the national, World Health Organization accredited laboratory. The cumulative success of these activities has resulted in Oman being free from polio for the past 6 years. However, the possibility of importation of wild poliovirus, particularly from southern and western Asia still exists. PMID- 11600092 TI - Effective control of hookworm infection in school children from Dhofar, Sultanate of Oman: a four-year experience with albendazole mass chemotherapy. AB - After 4 years of mass chemotherapy with a single annual dose of albendazole 400 mg, health education and promotion of environmental health, the prevalence of Necator americanus in Wilayat Tagah, Dhofar, Oman was reduced from 40 to 1.3% and from 6 to 0%, respectively, among rural and urban school children. Stool samples with egg load >1000 egg/gm were reduced from 28 to 0% after the first year of intervention and maintained as such in subsequent years. PMID- 11600093 TI - Occurrence of Cryptosporidium sp. oocysts in fecal and water samples in Austria. AB - Oocysts of Cryptosporidium spp. were detected and differentiated by a modular arranged gene amplification procedure in various samples, mostly human stool, feces of herpetotaxa, and water, in different locations of South and Eastern Austria. Cryptosporidium parvum was found in stool samples of immunocompromised persons, in reptile feces, and in water samples. The presence of Cryptosporidium in an area is probably associated with high human population densities since water from protected sources in sparsely inhabited areas is rarely contaminated. PMID- 11600094 TI - Efficacy of fluconazole and itraconazole in the treatment of oral candidiasis in HIV patients. AB - A total of 46 strains of Candida were collected from HIV infected patients, of which 25 strains were isolated from patients with oral candidiasis, and 21 strains were from mouthwash samples of asymptomatic carriers. The most common species isolated was Candida albicans (73.9%), followed by Candida tropicalis (21.7%). In vitro susceptibility of the strains to fluconazole and itraconazole was tested using minimum inhibitory concentration (MIC) studies by agar dilution technique. Out of the 18 strains of C. albicans isolated from mouthwash samples, four were resistant to fluconazole whereas only two were resistant to itraconazole. Out of 16 strains of C. albicans isolated from oral lesions, one was resistant to fluconazole where as all were sensitive to itraconazole. Among the other species of Candida tested, C. tropicalis gave higher MIC values to both drugs than other species such as Candida guillermondii and Candida krusei. In vitro MIC values correlated well with in vivo responses in patients. Hence, itraconazole may be used as an alternative in the treatment of candidiasis, which does not respond to fluconazole therapy. PMID- 11600095 TI - The spread of a mupirocin-resistant/methicillin-resistant Staphylococcus aureus clone in Kuwait hospitals. AB - High-level mupirocin- and methicillin-resistant Staphylococcus aureus (MRSA) isolated from five hospitals in Kuwait were studied by pulsed-field gel electrophoresis (PFGE) to determine their relatedness to one another and to high level mupirocin-resistant MRSA isolated previously in a Burns Unit. The genetic location of mupirocin resistance determinant was also determined. All of the isolates were resistant to gentamicin, kanamycin, streptomycin, tetracycline and cadmium, and contained plasmids of 38, 26 and 2.8 kb. Two isolates contained additional 4.4-kb plasmids. Transfer experiments demonstrated that the 38-kb plasmid encoded high-level mupirocin resistance and the 4.4-kb plasmid encoded chloramphenicol resistance. PFGE typing of representative isolates from the five hospitals demonstrated that the majority of them had identical or closely related pulsed-field patterns suggesting that they had a common origin. However, they differed from high-level mupirocin-resistant MRSA isolated previously in the Burns Unit in their resistance and pulsed-field patterns. Whereas the majority of the previous isolates were susceptible to ciprofloxacin and resistant to trimethoprim and chloramphenicol, the majority of the current isolates were susceptible to trimethoprim and chloramphenicol, and resistant to ciprofloxacin. Only one of the current isolates had identical pulsed-field pattern to the majority of isolates obtained previously in the Burns Unit. The results suggested that a previously dominant clone of high-level mupirocin-resistant MRSA has been replaced in the Burns Unit by a new clone, which also spread in four other hospitals. PMID- 11600096 TI - Tonsillar actinomycosis: a clinicopathological study. AB - Actinomycosis has been known to involve virtually every anatomic site in the body. Although actinomycosis has been identified in resected tonsils, its possible role in adeno-tonsillar disease has received little attention. A clinicopathological study of 302 patients who had adeno-tonsillar surgery is presented. Tonsillar actinomycosis was present in 86 (28.5%) patients. The statistical analysis revealed a significant association (P<0.0001) of actinomycosis and tonsillar hypertrophy (56.8%) compared to only 10.3% in the recurrent tonsillitis group. A statistically significant association (P<0.0001) of tonsillar actinomycosis and sickle cell anaemia, beta thalassaemia, bronchial asthma and beta haemolytic streptococcal infections was also seen. This data supports a predisposition of the above conditions to tonsillar actinomycosis and adeno-tonsillar hypertrophy and a possible etiopathologic role of this organism in adeno-tonsillar hypertrophy and disease. Although the clinical association of actinomycosis and tonsillar hypertrophy and beta haemolytic streptococcal infection has been described before the association of actinomycosis with sickle cell anaemia, beta thalassaemia and bronchial asthma is being observed for the first time in literature. PMID- 11600097 TI - Necrotizing fasciitis: a 10-year retrospective study of cases in a single university hospital in Oman. AB - OBJECTIVE: (1) To study the clinical profile of all cases of necrotizing fasciitis (NF) diagnosed in a university hospital in Oman. (2) To evolve a strategy for early diagnosis. PATIENTS AND METHODS: The inpatient records of the Sultan Qaboos University hospital from 1990-99 were searched for the words "fasciitis", "necrosis" or "gangrene" and cases of NF (defined as a soft tissue infection characterized by widespread necrosis of the subcutaneous tissues confirmed at surgery or pathology or both) were selected and analyzed. Cases with necrosis due to other obvious causes were excluded. RESULTS: Of the seven cases of NF (hospital incidence-8.4/10(5)), there were three post-operative, three spontaneous and one post-traumatic. Sites involved: upper limb (1), lower limb (2), abdomen (2), gluteal (1), and breasts (1). The median age was 50 years (range 21-85) and the male:female ratio was 4:3. All patients had local pain out of proportion to the signs and six had fever. Hypotension, liver or kidney dysfunction or coagulopathy were seen in four and a drop in haemoglobin was seen in six. In none was NF even considered by the referring or admitting physician, diagnosis being delayed by 2-10 days. In four cases a diagnostic incision under local anesthesia revealed the correct diagnosis. At surgery, extensive fascial and fat necrosis were seen in all, but only two had myonecrosis. The commonest isolate was beta-hemolytic group D streptococcus (4/7). Blood and tissue were positive for beta-hemolytic group A streptococci in one fatal case. Mean hospital stay was 54.5 days (11-134), mean surgical procedures were 2.3 per case, two required ICU admission with one death. CONCLUSION: NF is a rare but serious bacterial disease that is often incorrectly diagnosed. Unexplained severe local pain, deep tenderness without impressive local signs, fall in haemoglobin, organ system dysfunction and constitutional upsets were regular features. A high index of suspicion and immediate direct inspection of the fascia facilitates an early diagnosis. PMID- 11600098 TI - Acute fulminant fungal sinusitis: clinical presentation, radiological findings and treatment. AB - Acute fulminant fungal sinusitis is characterized by acute symptoms and rapid progress with a mortality rate of 60-80%. A large number of survivors have permanent neurological, visual and cosmetic disabilities. This clearly underscores the need of early recognition of this disease in at risk population in order to start urgent treatment. The at-risk population of diabetics, AIDS and other immunosuppressed is likely to increase, as will the incidence of acute fulminant fungal sinusitis. In the present study we have reviewed nine cases of acute fulminant fungal sinusitis to determine clinical presentation, related radiological picture and optimum treatment. Most common presenting features were fever, headache, facial swelling and proptosis. Many patients presented with blindness, facial paralysis and meningitis. Predisposing causes were uncontrolled diabetes with ketoacidosis in four out of six cases, post renal transplant immunosuppression and leukemia. All patients were treated with amphotericin B or liposomal amphotericin B (AmBisome). Diagnosis was confirmed by biopsy and culture of sinus mucosa, soft tissues of cheek, or orbit. Mucor (Zygomycetes) was identified on culture or histopathology in all cases. Surgical debridement was performed in seven cases. Six out of nine patients survived but morbidity was high: only two patients survived without any permanent disability. PMID- 11600099 TI - Abdominal tuberculosis--experience of a University hospital in Oman. AB - OBJECTIVE: To determine the clinical presentation and assess the usefulness of various diagnostic modalities and outcome of treatment of abdominal tuberculosis (TB). MATERIALS AND METHODS: The files of patients admitted to Sultan Qaboos University Hospital (SQUH) with a diagnosis of abdominal TB from January 91 to December 99 were studied retrospectively and data abstracted. RESULTS: Eighteen patients were diagnosed during this period, of which ten were males. The median age was 27 years (range 5-65). The common symptoms were fever, weight loss, anorexia, and abdominal pain. Abdominal signs were less frequent and included hepatomegaly and ascites. Eight patients had co-existent immunocompromised disorders; two of these had active pulmonary TB. Diagnostic investigations included gastrointestinal contrast studies in two, ultrasound (US) guided fine needle aspiration cytology (FNAC) in nine, and laparoscopy and/or laparotomy in seven. All patients underwent antituberculous therapy for 9-12 months, in addition to the treatment of associated disorders. The response to antituberculous therapy was good except in one patient with HIV. Four patients died from associated primary disorders. CONCLUSIONS: The clinical presentation was non-specific and nearly half of the patients had associated immunocompromised disorders; thus a high index of clinical suspicion is required. US guided FNAC and selective laparoscopy were the most useful diagnostic modalities. Antituberculous therapy was effective. PMID- 11600101 TI - Adverse events during a placebo phase for inpatients with chronic schizophrenia. AB - BACKGROUND: This report builds on a previous analysis examining the long-term effects of a placebo period on a group of inpatients with chronic schizophrenia. In the present analysis, outcome was evaluated through the use of the Psychiatric Adverse Events Rating Scale. METHODS: This retrospective analysis examined adverse events for 55 patients with chronic schizophrenia who were placed in a double-blind placebo study on the inpatient units of the National Institute of Mental Health Neuropsychiatric Research Hospital. The number and severity of adverse events experienced by these patients during baseline, placebo, and discharge periods were analyzed. RESULTS: The frequency and severity of adverse events for this group of patients were modest. Most patients did not experience a statistically significant increase in adverse events during their placebo phase; however, a subgroup of patients who were hospitalized for less than 2 months after antipsychotic medications were restored did experience a statistical elevation in adverse events, and that frequency remained statistically elevated at discharge. CONCLUSIONS: The results confirm the findings from our previous analysis. Regardless of whether outcome is measured by a behavioral rating scale or by an adverse event scale, given a sufficiently lengthy recovery period, patients with chronic schizophrenia who go through a placebo phase return to baseline. PMID- 11600100 TI - A comparison of symptom provocation procedures in psychiatry and other areas of medicine: implications for their ethical use in research. AB - BACKGROUND: Symptom provocation is used to study a wide variety of medical disorders. In contrast to other areas of medicine, the application of these procedures to the study of mental disease has generated significant scientific, political, and public debate. Purported differences include an overabundance of these procedures in psychiatry and a lack of diagnostic and therapeutic utility. Accurate appraisal of these research designs is needed to address scientific merit and ethical concerns. This article provides a general review of challenge studies in several areas of medical research, compares purposes and methods to those used in psychiatry, and ascertains whether fundamental differences exist. METHODS: In total, 655 challenge studies were identified using MEDLINE and PsychInfo Boolean key word searches. Information was collected from each study including the year of publication, whether subjects were healthy or patient volunteers, the disease being studied, and the study purpose (e.g., to study pathophysiology, test treatment efficacy, or diagnosis of a disorder). RESULTS: Differences in study design, purpose, and frequency of studies across time were similar for medical and psychiatric diseases. CONCLUSIONS: Given extensive similarity in purpose and procedures, why are psychiatric challenge studies being subjected to public criticism and special review and approval procedures? Several relevant issues are addressed including risk, scientific merit, and clinical application. PMID- 11600102 TI - Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice. AB - BACKGROUND: Abnormal sensory inhibition is observed in the majority of schizophrenic patients. DBA/2 mice spontaneously exhibit a similar deficit in sensory inhibition and thus provide a model for drug development targeted to this physiologic abnormality. The impaired sensory inhibition is characterized by diminished response of the hippocampal evoked potential to the second of closely paired auditory stimuli (500-m/sec interstimulus interval). Subnormal levels of hippocampal alpha7 nicotinic cholinergic receptors are associated with the deficient sensory inhibition in both DBA/2 mice and people with schizophrenia. METHODS: Our study examined the inhibition of the P20-N40 auditory evoked potential in DBA/2 mice after intragastric administration of DMXB-A (3-2,4 dimethoxybenzylidine anabaseine), an alpha7 nicotinic receptor partial agonist. After presentation of auditory stimuli, electroencephalographic responses were recorded and measured to monitor the effects of the DMXB-A, alone and in combination with selective nicotinic antagonists. RESULTS: Gastric administration of DMXB-A (10 mg/kg) improved sensory inhibition in DBA/2 mice. This improvement was blocked by alpha-bungarotoxin, but not mecamylamine, indicating that DMXB-A exerts its effects through the alpha7 nicotinic receptor. CONCLUSIONS: Intragastrically administered DMXB-A improves deficient sensory inhibition in DBA/2 mice through stimulation of alpha7 nicotinic receptors. These studies agree with results from previous studies with subcutaneously administered DMXB-A. PMID- 11600103 TI - Aberrant behavioral effects of a dopamine D1 receptor antagonist and agonist in monkeys: evidence of uncharted dopamine D1 receptor actions. AB - BACKGROUND: Basic research indicates a role for dopamine (DA) D1 antagonism in the treatment of schizophrenia. Clinical trials have not confirmed any role. Besides the defining second messenger (adenylyl cyclase [AC]), DA D1 receptors are linked to other effectors (e.g., phospholipase C [PLC]). Differing actions of DA D1 antagonists upon differing effectors could explain conflicting results between the lab/clinic. METHODS: In a monkey model in which behavioral effects of DA D1 antagonists/agonists have been well characterized we examined: 1) SKF 83959, biochemically, a DA D1 antagonist, behaviorally a DA D1 agonist, and 2) SKF 83822, biochemically, a DA D1 agonist, which, unlike all previously tested DA D1 agonists, does not also stimulate PLC. SKF 83959 and SKF 83822 were given alone and combined with DA D1 and D2 agonists, antagonists, and dextroamphetamine (AMP). RESULTS: SKF 83959 acted as a DA D1 agonist (induced oral dyskinesia given alone, counteracted DA D1 antagonist [NNC 756], induced dystonia, and did not inhibit AMP induced behaviors). SKF 83822, unlike previously studied DA D1 agonists, did not induce dyskinesia, but resulted in a state of extreme arousal and locomotor activation without stereotypy, effectively counteracted by NNC 756, but not by SKF 83959 nor raclopride (DA D2 antagonist). CONCLUSIONS: It is hypothesized that: 1) dyskinesia is linked to PLC stimulation; 2) DA D1 agonism can play a role in the induction of psychosis, via a mechanism linked neither to AC nor PLC, and 3) DA D1 antagonists differ in antipsychotic potential, possibly via this unidentified mechanism. PMID- 11600104 TI - Olanzapine activates the rat locus coeruleus: in vivo electrophysiology and c-Fos immunoreactivity. AB - BACKGROUND: Activation of central noradrenergic pathways by atypical antipsychotics has been hypothesized to play a role in their efficacy in treating the negative symptoms and cognitive impairment of schizophrenia. Because acute administration of the atypical antipsychotic olanzapine has been shown to increase extracellular levels of norepinephrine in the medial prefrontal cortex, we examined the effects of olanzapine on the noradrenergic cells of the locus coeruleus (LC). METHODS: The effects of olanzapine (0.25-16 mg kg(-1), IV) on the firing rates and patterns of LC neurons were determined by extracellular, single unit recordings in chloral hydrate-anaesthetized rats. The effects of olanzapine and clozapine on c-Fos expression in the LC, nucleus subcoeruleus part alpha (SubCA), and nucleus A5 (A5) were studied by immunohistochemistry. RESULTS: Olanzapine increased LC cell firing rates, de-regularized firing, and induced burst firing. Induction of c-Fos expression in the LC by olanzapine and clozapine was confirmed and was also found in the SubCA, but not in A5. CONCLUSIONS: Acute administration of olanzapine activates the noradrenergic neurons of the rat LC. This increased activity of LC neurons may play an important role in the efficacy of olanzapine and clozapine in treating both the negative symptoms and cognitive impairment observed in schizophrenic patients. PMID- 11600105 TI - Increased cortical kynurenate content in schizophrenia. AB - BACKGROUND: Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One of the key metabolites in this pathway, kynurenine, is either transaminated to form the glutamate receptor antagonist, kynurenate, or hydroxylated to 3 hydroxykynurenine, which in turn is further degraded to the excitotoxic N-methyl D-aspartate receptor agonist quinolinate. Because a hypoglutamatergic tone may be involved in the pathophysiology of schizophrenia, it is conceivable that alterations in kynurenine pathway metabolism may play a role in the disease. METHODS: The tissue levels of kynurenine, kynurenate, and 3-hydroxykynurenine were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites were determined in the same samples from three cortical brain regions (Brodmann areas 9, 10, and 19), obtained from 30 schizophrenic and 31 matched control subjects. RESULTS: Kynurenate levels were significantly increased in schizophrenic cases in Brodmann area 9 (2.9 +/- 2.2 vs. 1.9 +/- 1.3 pmol/mg protein, p <.05), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 +/- 28.0 vs. 22.4 +/- 14.3 pmol/mg protein; p <.05) and 19 (40.3 +/- 23.4 vs. 30.9 +/- 10.8; p <.05). No significant differences in 3-hydroxykynurenine content were observed between the two groups. In both groups, significant (p <.05) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p >.05). In rats, chronic (6-months) treatment with haloperidol did not cause an increase in kynurenate levels in the frontal cortex, indicating that the elevation observed in schizophrenia is not due to antipsychotic medication. CONCLUSIONS: The data demonstrate an impairment of brain kynurenine pathway metabolism in schizophrenia, resulting in elevated kynurenate levels and suggesting a possible concomitant reduction in glutamate receptor function. PMID- 11600106 TI - Selective bilateral hippocampal volume loss in chronic schizophrenia. AB - BACKGROUND: The hippocampus is implicated in the pathophysiology of schizophrenia; however, volumetric changes are subtle and have limited diagnostic specificity. It is possible that the shape of the hippocampus may be more characteristic of schizophrenia. METHODS: Forty-five patients with chronic schizophrenia and 139 healthy control subjects were scanned using magnetic resonance imaging. Hippocampi were traced manually, and two-dimensional shape information was analyzed. RESULTS: Two shape factors were found to be adequate to represent variance in the shape of the hippocampus. One of these factors, representing volume loss behind the head of the hippocampus, provided a degree of discrimination between patients with chronic schizophrenia and healthy control subjects; however, overall hippocampal volume following appropriate adjustment for brain volume showed a similar level of discrimination. Patients with chronic schizophrenia were best characterized using these two measures together, but diagnostic specificity was only moderate. CONCLUSIONS: This study identified that less of the hippocampus was distributed in its posterior two-thirds in patients with chronic schizophrenia, and specifically in the region just posterior to the hippocampal head. Group discrimination on the basis of hippocampal volume and shape measures was moderately good. A full three-dimensional analysis of hippocampal shape, based on large samples, would be a useful extension of the study. PMID- 11600107 TI - Cortical responsiveness during talking and listening in schizophrenia: an event related brain potential study. AB - BACKGROUND: Failures to recognize inner speech as self-generated may underlie positive symptoms of schizophrenia-like auditory hallucinations. This could result from a faulty comparison in auditory cortex between speech-related corollary discharge and reafferent discharges from thinking or speaking, with misattribution of internal thoughts to external sources. Although compelling, failures to monitor covert speech (thoughts) are not as amenable to investigation as failures to monitor overt speech (talking). METHODS: Effects of talking on auditory cortex responsiveness were assessed in 10 healthy adults and 12 patients with schizophrenia (DSM-IV) using N1 event-related potentials (ERPs) to acoustic and visual probes during talking aloud, listening to one's speech played back, and silent baseline. Trials contaminated by muscle artifact while talking were excluded. RESULTS: Talking and listening affected N1 to acoustic but not to visual probes, reflecting modality specificity of effects. Patterns of responses to acoustic probes differed between control subjects and patients. N1 to acoustic probes was reduced during talking compared with baseline in control subjects, but not in patients. Listening reduced N1 equivalently in both groups. CONCLUSIONS: Although the failure of N1 to be reduced during talking was not related to current hallucinations in patients, it may be related to the potential to hallucinate. PMID- 11600108 TI - Prefrontal N-acetylaspartate is strongly associated with memory performance in (abstinent) ecstasy users: preliminary report. AB - BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA or "Ecstasy") is known to damage brain serotonin neurons in animals and possibly humans. Because serotonergic damage may adversely affect memory, we compared verbal memory function between MDMA users and MDMA-naive control subjects and evaluated the relationship between verbal memory function and neuronal dysfunction in the MDMA users. METHODS: An auditory verbal memory task (Rey Auditory Verbal Learning Test) was used to study eight abstinent MDMA users and seven control subjects. In addition 1H-MRS was used in different brain regions of all MDMA users to measure N-acetylaspartate/creatine (NAA/Cr) ratios, a marker for neuronal viability. RESULTS: The MDMA users recalled significantly fewer words than control subjects on delayed (p =.03) but not immediate recall (p =.08). In MDMA users, delayed memory function was strongly associated with NAA/Cr only in the prefrontal cortex (R(2) =.76, p =.01). CONCLUSIONS: Greater decrements in memory function predicted lower NAA/Cr levels-and by inference greater neuronal dysfunction-in the prefrontal cortex of MDMA users. PMID- 11600111 TI - Intramedullary nailing. PMID- 11600110 TI - Comment on "Ketamine has equal affinity for NMDA receptors and the high-affinity state of the dopamine D(2) receptor". PMID- 11600112 TI - Intracranial pressure-alterations during controlled intramedullary reaming of femoral fractures: an animal study. AB - Reaming during intramedullary nailing increases the intramedullary pressure (IMP) and can cause fat intravasation and subsequently lead to pulmonary dysfunction, especially in polytraumatized patients with lung contusion as well as increases in intracranial pressure (ICP).ICP changes were measured in two groups consisting of 12 sheep each with either a fractured or intact femur. The animals were exposed to haemorrhagic shock and were resuscitated by autoinfusion. Transverse midshaft fractures were created bilaterally in one group before reaming of both femoral shafts. Controlled reaming was performed at 15 and 50 mm/s driving speed (DS) and at 150 and 450 revolutions per minute (RPM) with a reaming control system using AO-Reamers. Fat intravasation was measured by transoesophageal sonography (TES) and Gurd test. ICP monitoring was performed with a piezo electric epidural catheter. Haemodynamic and respiratory parameters, ICP, and cerebral perfusion pressure were measured continuously. High DS and low RPM caused higher IMP and ICP increases in both groups. Significantly higher microemboli were observed in TES in the fractured group as compared to the unfractured group with the same reaming parameters (P=0.021). However, the existence of a femoral fracture did not show a significant influence on changes in ICP (P-value=0.057). Reaming should be performed at a low DS and high RPM to minimize the risk of fat intravasation and the subsequent ICP increase. PMID- 11600113 TI - The assessment of cortical heat during intramedullary reaming of long bones. AB - BACKGROUND: This experimental study was designed to compare different in vitro methods of measuring the cortical temperature when reaming the medullary cavity. This was done to validate an approved mathematical model which can be used to determine the temperature gradient in cortical bone in the presence or absence of sensors. METHODS: Artificial bone was used with an intramedullary heat source instead of a reamer. Temperatures were measured with thermocouples placed radially and axially in the cortical wall. This method with these two measurement positions were compared and used to validate an approved mathematical model. This model was used to determine the temperature gradient in cortical bone in the absence of sensors. RESULTS: The measurement of the cortical temperature with the thermocouples in a radial position only reflects maximally 14% of the temperature of the reamer (calculated 55%). The measurement with the thermocouples in axial position reflects maximally 65% (calculated 70%) of the reamer temperature, which is similar to undisturbed bone. CONCLUSION: The measuring method with the thermocouples in a radial position cannot be recommended. It is likely that a much higher temperature is generated and conducted through reaming than has been assumed until now. PMID- 11600114 TI - Interface pressure produced by the traction post on a standard orthopaedic table. AB - Lower limb traction is applied with counter traction in the groin. The resultant tissue pressures can be high and may result in skin necrosis or nerve palsies. Volunteers were positioned on a fracture table and traction applied to the left leg. Perineal contact pressures were measured using pressure transducers connected to a laptop computer. Pressure readings and pain scores were recorded with different types of padding, whilst the leg was repositioned. Maximal pressures exceeded the 70 mmHg limit known to cause tissue damage. Larger (10 cm) padding devices significantly reduced the pressures. When employing the perineal traction post, care should be taken to pad this carefully to avoid the sequelae of high tissue pressure. PMID- 11600115 TI - Antegrade locked intramedullary nailing in humeral shaft fractures. AB - Thirty-three humeral nailings were carried out using the Russell-Taylor nail. Twenty-two acute fractures and one non-union united, gave an overall union rate of 70%. Eighteen patients (56%) experienced pain in the shoulder or at the fracture site. Thirteen patients (41%) had poor shoulder function. Only 17 (51%) of the patients were satisfied with the outcome. Fourteen patients (42%) needed further surgery. We conclude that antegrade intamedullary nailing of humeral shaft fractures leads to a substantial risk of non-union and impairment of shoulder function. There was no significant correlation between fracture comminution and fracture healing in our study. PMID- 11600116 TI - Retrograde fixation of fractures of the neck and shaft of the humerus with the 'Halder humeral nail'. AB - The Halder humeral nail is a new intramedullary device designed for displaced two part humeral neck and shaft fractures. It is inserted retrograde from the olecranon fossa and a unique trio wire is inserted through the nail to provide good proximal fixation. This avoids the use of proximal screws and damage to the rotator cuff thereby ensuring good rotator cuff function. The results of 100 cases are presented. At 6 weeks, 95 patients could perform the majority of daily tasks. There were four non-unions, one following a deep infection. PMID- 11600117 TI - Results of the long Gamma nail for complex proximal femoral fractures. AB - The results for a series of 35 patients with complex proximal femoral fractures treated with the long Gamma nail are presented. Fracture healing occurred in all surviving patients, but there were four technical problems associated with the implant. Two nails broke associated with delayed union of the fracture necessitating revision of the implant, one fracture of femur at the site of distal locking occurred during surgery and there was one later fracture at the tip of the nail. All but one failures of fixation were revised with another Gamma nail and healed uneventfully. Overall the number of fracture healing complications compares favourably to contemporary implants and improvements in the design and strength of the nail may further improve results. PMID- 11600118 TI - A new modular testing system for biomechanical evaluation of tibial intramedullary fixation devices. AB - This biomechanical study was performed to evaluate a new modular, tibial testing system developed for analysis of tibial nails and their locking screws.A new testing system, consisting of five modules, was designed to simulate a tibia. For this study one module was removed to simulate a 55-mm distal tibial defect inducing maximum loading on the distal portion of the implant and locking bolts. The tibial load offsets were 23 mm proximally and 10 mm distally medial to the centreline of the tibial shaft to simulate the location of the expected resultant load during the peak loading and inversion torque on the ankle during the gait cycle. Four solid tibial nails (STN, Stryker-Howmedica-Osteonics, Kiel, Germany) were tested to static failure and 15 nails were tested dynamically. Our results showed that the solid tibial nails fractured in the testing device in the same manner and location as they do in clinical series. Evaluation of the results showed the mean fatigue limit of the STN to be 1.4 kN for 500,000 cycles with a standard deviation (S.D.) of 0.33 kN. This biomechanical study establishes a standard technique for the biomechanical testing of tibial nails, in a clinically relevant manner, avoiding the inconsistency of cadaver bone tests. As it is a standardised test set-up this new modular testing system could serve as a standard by which small diameter tibial nails and other devices could be evaluated and compared with other systems currently in use. PMID- 11600119 TI - The AO distal locking aiming device: an evaluation of efficacy and learning curve. AB - OBJECTIVES: The AO nail mounted 'distal locking aiming device', developed to obtain radiation independent distal locking, has an unproven efficacy in a large clinical setting. This prospective study compares the efficacy and learning curve of the distal aiming device with the popular 'free hand technique'. MATERIALS AND METHODS: Distal locking in thirty cases of statically locked intramedullary femur nailing using the distal aiming device for rotationally stiff unslotted AO SUN nails was prospectively compared with the same number using the free-hand technique with regard to duration, radiation exposure, accuracy of screw placement, and learning curve. RESULTS AND DISCUSSION: For the free-hand technique and the distal aiming system respectively, the average distal locking time was 35.8+/-18.6 versus 19.3+/-9.8 minutes, and the average number of images taken to achieve distal locking was 11.5+/-3.4 versus 3.8+/-3.5. The decrease in average distal locking time by 46.1% and in radiation by 70.0% with the distal aiming system is statistically significant at P<0.001. There were three failures of the distal aiming device and these were converted to the free-hand technique. The learning curve for the distal aiming device was shorter and more predictable than that with the free hand technique. We also analyse the failures and associated pitfalls with the system. CONCLUSIONS: We found the AO distal locking aiming device to be an accurate, radiation-independent jig with a short and predictable learning curve. PMID- 11600120 TI - Extending fixation beyond the working length of an intramedullary nail with a linked intramedullary and extramedullary fixation in complex femoral fractures; a brief series. AB - We report the use of a fixed-angle side-plate device linked to an intramedullary nail in the femur with the interlocking screws applied through the plate. The 95 degrees device extends the effective length of the nail and increases the stability of the fixation. This technique is one of various adaptations that can be recommended to stabilise a complex combination of femoral fractures. This is a report of four such patients. PMID- 11600121 TI - Percutaneous removal of a bent intramedullary nail. PMID- 11600122 TI - Iatrogenic femoral neck fracture caused by mal-insertion of a curved intramedullary nail. PMID- 11600123 TI - Rare complication of segmental breakage of plastic medullary tube in closed intramedullary nailing. PMID- 11600124 TI - A new distal targeting device for closed interlocking nailing. AB - A new, image-intensifier mounted target device for closed interlocking nailing is described. The aim of locating the distal holes with the least radiation exposure is achieved. The proposed device has been designed to be mounted on the image intensifier, is absolutely stable, eliminates the need for a specialised X-ray technician and allows the surgeon to be away from the radiation beam (direct or scattered). It also permits image intensification in the anteroposterior view, without losing the target. The device has proved its reliability in the operating room during closed interlocking nailing procedures. PMID- 11600125 TI - Percutaneous intramedullary nailing of tibial shaft fractures: a new approach for prevention of anterior knee pain. PMID- 11600126 TI - The DeltauvrB mutations in the Ames strains of Salmonella span 15 to 119 genes. AB - The DeltauvrB mutations present in strains of Salmonella enterica Typhimurium used commonly in the Salmonella (Ames) mutagenicity assay were isolated independently for at least five different his mutants. These deletions all involved the galactose operon, biotin operon, nucleotide-excision-repair uvrB gene, and chlorate-resistance genes. Beyond this, the size of the deletions and the number and type of genes deleted have remained unknown for nearly 30 years. Here, we have used genomic hybridization to a Typhimurium microarray to characterize these five DeltauvrB deletions. The number of genes (and amount of DNA) deleted due to the DeltauvrB mutations are 15 (16kb) each in TA97 and TA104, 47 (50kb) in TA100, 87 (96kb) in TA1537, and 119 (125kb) in TA98, accounting for 0.3, 0.3, 1.0, 1.9, and 2.6% of the genome, respectively. In addition, TA97 and TA104 contain an identical three-gene deletion elsewhere in their genomes, and, most remarkably, TA104 contains a 282-gene amplification, representing 7% of the genome. Missing genes include mfdA and mdaA, encoding a multi-drug translocase and a major nitroreductase, respectively, both absent in TA98; dps, encoding a DNA-binding protein absent in TA1537 and TA98; and dinG, encoding a lexA regulated repair enzyme, absent in three DeltauvrB lineages. Genes involved in molybdenum cofactor biosynthesis and a number of ORFs of unknown functions are missing in all DeltauvrB strains investigated. Studies in DeltauvrB strains of Escherichia coli have found that the enhanced mutagenesis of some base analogues was due to the deletion of genes involved in molybdenum cofactor biosynthesis rather than to deletion of uvrB. These discoveries do not diminish the value of the data generated in the Ames strains. However, absence of genes other than uvrB may account for the enhanced mutagenicity of some compounds in DeltauvrB Ames strains. In general, microarrays will be useful for characterizing the extent and nature of deletion and amplification mutations. PMID- 11600127 TI - Elevated in vivo frequencies of mutant T cells with altered functional expression of the T-cell receptor or hypoxanthine phosphoribosyltransferase genes in p53 deficient mice. AB - We have studied the effects of a defect in the p53 gene on spontaneous and radiation-induced somatic mutation frequencies in vivo by measuring T-cell receptor (TCR) and hypoxanthine phosphoribosyltransferase (HPRT) mutant frequencies (MFs) in p53 deficient mice both before and after exposure to X irradiation. In the absence of irradiation, the TCR and HPRT mutant frequencies were roughly two-fold higher in p53 null (-/-) mice than in wild-type (+/+) mice. Unexpectedly, the TCR and HPRT MFs were slightly lower in heterozygote p53 (+/-) than in wild-type (+/+) mice, however. After 2 weeks 2Gy whole body irradiation the TCR and HPRT MFs were about two-fold higher in the p53 null (-/-) and p53 (+/ ) mice than in the wild-type. Taken together, these findings suggest that a defect in the p53 gene may lead to TCR and HPRT mutants being recovered at higher frequencies in both irradiated and unirradiated mice, but it should be emphasized that the effects we have observed are not particularly strong, albeit that they are statistically significant. Interestingly, several of the highest TCR MF values that we observed in the course of our experiments were recorded in p53 (-/ ) animals that had developed thymomas and hence appeared to be cancer prone. PMID- 11600128 TI - Identification of genetic alterations in the TGFbeta type II receptor gene promoter. AB - Modifications in the control sequences of tumor suppressor genes have been found to play a role in the activation or inactivation of these genes and may play an important role in tumorigenesis. For example, hypermethylation of CpG islands and promoter polymorphisms have been found to be involved in transcriptional repression. A decrease in the levels of expression of one such tumor suppressor gene, the TGFbeta type II receptor (TbetaR-II), has been associated with increased tumorigenicity in a number of human tumors. Genetic alterations have been described in several tumor types in the coding region of this gene. However, no comprehensive search for genetic alterations in the TbetaR-II promoter has been reported. Genetic alterations in the promoter of the TbetaR-II gene could inhibit binding of putative regulatory factors. For example, we have reported a A 364-G alteration in the TbetaR-II promoter, which results in decreased transcriptional activity. In this study, we analyzed the 1.0kb region upstream of the TbetaR-II transcriptional start site and found genetic alterations in 46% of the head and neck squamous cell carcinoma (SqCC) samples examined. The most frequent alteration was a G-875-A alteration, present in 41.6% of the samples. Analysis of normal healthy individuals showed a similar frequency of this alteration, suggesting that alterations within the TbetaR-II promoter are unlikely to account for the decreased expression of TbetaR-II in head and neck SqCC. PMID- 11600129 TI - The inhibition of DNA repair capacity by stilbene estrogen in Leydig cells: its implications in the induction of instability in the testicular genome. AB - In this study, we examined the effect of stilbene estrogen, diethylstilbestrol (DES), on the DNA repair capacity of mouse Leydig cells using the host cell reactivation assay. Cells transfected with UV-damaged plasmids, undamaged plasmids, or no plasmids (sham treatment) were grown in serum, serum-free, or DES plus serum-free medium. The serum-grown cells which have a shorter cell cycle time (16h) showed a 40% decrease in DNA repair capacity when compared to serum free cells with a longer cell cycle time (25h). A significant decrease in the DNA repair capacity of the Leydig cells exposed to DES was observed compared to untreated cells grown in a serum-free environment (P<0.05). The effect of DES on DNA repair in Leydig cells was dose dependent. We have recently shown that DES stimulates the growth of Leydig cells. Stimulatory growth of Leydig cells coupled with a decrease in DNA repair capacity by DES may allow the accumulation of mutagenic lesions in DNA. The mutagenic lesions may result from the attack of redox cycling products of DES and/or errors of replication. This, in turn, may produce alterations in the genome of Leydig cells resulting in genetically unstable cells that may serve as precursor cells for testicular carcinogenesis. PMID- 11600130 TI - Role of human cytochrome P450 (CYP) in the metabolic activation of N alkylnitrosamines: application of genetically engineered Salmonella typhimurium YG7108 expressing each form of CYP together with human NADPH-cytochrome P450 reductase. AB - The role of human cytochrome P450 (CYP) in the metabolic activation of N alkylnitrosamines was examined by Ames test using genetically engineered Salmonella typhimurium (S. typhimurium)YG7108 cells expressing each form of human CYP together with human NADPH-cytochrome P450 reductase (OR). The relationship between the structure of N-alkylnitrosamines and CYP form(s) involved in the activation was evaluated. Eleven strains of S. typhimurium YG7108 cells expressing each form of CYP (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 or CYP3A5) were employed. Eight N alkylnitrosamines including N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodipropylamine (NDPA), N-nitrosodibutylamine (NDBA), N nitrosomethylethylamine (NMEA), N-nitrosomethylpropylamine (NMPA), N nitrosomethylbutylamine (NMBA) and N-nitrosoethylbutylamine (NEBA) were examined. Minimal concentration (MC) value of a promutagen was defined as the concentration of a chemical giving a positive result. Mutagen-producing capacity of CYP, as indicated by induced revertants/nmol promutagen/pmol CYP, for an N alkylnitrosamine was determined for all forms of CYP. These N-alkylnitrosamines were mainly activated by CYP2E1, CYP2A6 and CYP1A1. N-alkylnitrosamines with relatively short alkyl chains such as NDMA and NMEA were primarily activated by CYP2E1 as judged by mutagen-producing capacity. With the increase of the number of the carbon atoms of the alkyl chains, the contribution of CYP2A6 increased. CYP2A6 played major roles in the activation of NDEA, NDPA, NMPA, NMBA and NEBA. Interestingly, CYP1A1 became a molecular form of CYP playing a major role in the metabolic activation of NDBA. PMID- 11600131 TI - High frequency of constitutive alkali-labile sites in mouse major satellite DNA, detected by DNA breakage detection-fluorescence in situ hybridization. AB - DNA breakage detection-fluorescence in situ hybridization (DBD-FISH) is a new procedure for detecting and quantifying DNA breaks and alkali-labile sites in single cells. Cells trapped within an agarose matrix are deproteinized and treated with an alkaline unwinding solution that transforms DNA breaks and alkali labile sites into single-strand DNA (ssDNA) motifs starting from the end of the break. These ssDNA motifs are susceptible to being hybridized with whole genome or specific DNA probes, and detected using current FISH procedures. As DNA breaks increase in a target region, more ssDNA is produced and more DNA probe hybridizes, thus increasing the FISH signal, which may be captured and analyzed using a digital image analysis system. This increase can be reflected in the surface area, mean and whole fluorescence intensity of the signal. When intact mouse splenocytes were processed with this technique using a whole genome probe, a very strong background signal was evident when compared with human blood leukocytes. In fact, when using 0.03M NaOH as the alkaline unwinding solution at 22 degrees C for 2.5min, the whole fluorescence intensity from mice cells was 50 times higher than that from human cells, thus suggesting the existence of a high frequency of constitutive alkali-labile sites in the DNA from mouse cells. Furthermore, when alkaline unwound mouse cells were simultaneously hybridized with the whole genome probe (FITC-revealed, green) and a major satellite DNA probe (Cy-3-labeled, red) both signals appeared co-localized. This result demonstrates that the high frequency of constitutive alkali-labile sites detected in the mouse genome is mainly located in the major satellite DNA sequences, resembling the findings from human 5bp classical satellite DNA sequences. PMID- 11600132 TI - Allergic contact dermatitis and its relationship to carcinogenicity. AB - The relationship between allergic contact dermatitis (ACD) and carcinogenicity was investigated using a recently developed and validated simulation approach. The analyses indicated that while there are electrophilic and non-electrophilic components to ACD, these were not identical to those operating in carcinogenicity. Accordingly, with respect to carcinogenicity prediction, the results of ACD do not improve the results based upon mutagenicity testing alone, the latter being a surrogate for potential electrophilicity. PMID- 11600133 TI - Protective effect of melatonin against in vitro iron ions and 7 mT 50 Hz magnetic field-induced DNA damage in rat lymphocytes. AB - We have previously shown that simultaneous exposure of rat lymphocytes to iron ions and 50Hz magnetic field (MF) caused an increase in the number of cells with DNA strand breaks. Although the mechanism of MF-induced DNA damage is not known, we suppose that it involves free radicals. In the present study, to confirm our hypothesis, we have examined the effect of melatonin, an established free radicals scavenger, on DNA damage in rat peripheral blood lymphocytes exposed in vitro to iron ions and 50Hz MF. The alkaline comet assay was chosen for the assessment of DNA damage. During pre-incubation, part of the cell samples were supplemented with melatonin (0.5 or 1.0mM). The experiments were performed on the cell samples incubated for 3h in Helmholtz coils at 7mT 50Hz MF. During MF exposure, some samples were treated with ferrous chloride (FeCl2, 10microg/ml), while the rest served as controls. A significant increase in the number of cells with DNA damage was found only after simultaneous exposure of lymphocytes to FeCl2 and 7mT 50Hz MF, compared to the control samples or those incubated with FeCl2 alone. However, when the cells were treated with melatonin and then exposed to iron ions and 50Hz MF, the number of damaged cells was significantly reduced, and the effect depended on the concentration of melatonin. The reduction reached about 50% at 0.5mM and about 100% at 1.0mM. Our results indicate that melatonin provides protection against DNA damage in rat lymphocytes exposed in vitro to iron ions and 50Hz MF (7mT). Therefore, it can be suggested that free radicals may be involved in 50Hz magnetic field and iron ions-induced DNA damage in rat blood lymphocytes. The future experimental studies, in vitro and in vivo, should provide an answer to the question concerning the role of melatonin in the free radical processes in the power frequency magnetic field. PMID- 11600134 TI - Lipid peroxidation end products-responded induction of a preneoplastic marker enzyme glutathione S-transferase P-form (GST-P) in rat liver on admistration via the portal vein. AB - The in vivo induction mechanism of a preneoplastic marker enzyme, glutathione S transferase P-form (GST-P), by a number of carcinogens and some noncarcinogens such as anti-oxidants [Proc. Natl. Acad. Sci. U.S.A. 85 (1984) 3964] has remained to be solved. Among the various administration routes tested, GST-P became immunohistochemically demonstrable in the liver centrilobular zone 3 after 24-48h on administration of prostaglandin J2's, 15-deoxy-Delta(12,14)-PGJ2, PGJ2 and Delta(12)-PGJ2 to male rats via the portal vein, whereby the animals had been pretreated with Soya oil intraperitoneally to exhaust fatty acid binding proteins. Unsaturated aldehydes, 4-hydroxynonenal, crotonaldehyde and acrolein, given by the same route induced putatively preneoplastic single cells positive for GST-P. As these lipid peroxidation end products are the substrates as well as inducers of the enzyme, its physiological function could be their detoxication. These results indicate that GST-P expression can be mediated through lipid peroxidation possibly accounting for induction observed with a wide variety of carcinogens. In addition, present method may also be of use as a direct, simple, rapid, and sensitive in vivo test in examination of other biological responses. PMID- 11600135 TI - Lifestyle factors and Ki-ras mutations in colon cancer tumors. AB - Heterogeneity in colon tumors implies that environmental, lifestyle, or genetic factors influence the type of mutations seen in tumors. In this study we evaluate the association between previously identified risk factors for colon cancer and Kirsten-ras (Ki-ras) mutations in tumors. The presence of Ki-ras mutations in codons 12 and 13 were determined in a population-based case-control study of colon cancer. Participants were between 30 and 79 years of age at time of diagnosis and include both men and women. Questionnaire data were used to obtain information on lifestyle factors. Valid study data and Ki-ras mutational status were available from 1428 cases of colon cancer, data from 2410 controls were available for comparative purposes. Participants with Ki-ras mutations were more likely to have proximal rather than distal tumors. Cigarette smoking, use of aspirin and/or NSAIDs, use of vitamin/mineral supplements, and consumption of caffeine were associated with both Ki-ras+ and Ki-ras- tumors; the associations were not confounded by dietary intake or other lifestyle factors. Among men, but not among women, those with low levels of physical activity were more likely to have a tumor with a Ki-ras mutation than one without a Ki-ras mutation. However, among women, those with a larger BMI were more likely to have a Ki-ras mutation in their tumor. Given the limited information available on what causes Ki-ras mutations, the information generated from this study indicates that these factors previously associated with colon cancer work through other disease pathways. PMID- 11600136 TI - TFIIH functions are altered by the P210BCR-ABL oncoprotein produced on the Philadelphia chromosome. AB - P210BCR-ABL counteracted against the complementary effect of XPB on DNA repair when ultraviolet (UV)-sensitive 27-1 cells were treated with UV or cisplatin but not with hydrogen peroxide. Wortmannin, an inhibitor of PI3 kinase did not affect its anti-repair effect. Enhanced recruitment of p44 with TFIIH after cisplatin treatment is inhibited by the expression of P210BCR-ABL in a kinase activity dependent manner. Although purified TFIIH from P210BCR-ABL expressor and non expressor showed almost no difference in molar ratio of each component, the in vitro activity of TFIIH was decreased by 5-10% in repair assay but was increased by more than two-fold in transcription assay. PMID- 11600137 TI - Mutation analysis of the acid beta-glucosidase gene in a patient with type 3 Gaucher disease and neutralizing antibody to alglucerase. AB - The beneficial effects of macrophage-targeted glucocerebrosidase (alglucerase, Ceredase) in patients with Gaucher disease are well established. A minority of recipients develop transient non-neutralizing antibodies to the exogenous enzyme. A 7-year-old patient with type 3 Gaucher disease, whose clinical course began to deteriorate while receiving alglucerase developed a progressively increasing titer of IgG antibody, that blocked the catalytic activity of alglucerase. We investigated the acid beta-glucosidase genotype in this patient. Direct sequencing of both cDNA and genomic PCR products was used to characterize the mutations underlying acid beta-glucosidase deficiency. The patient was shown to be a compound heterozygote for a previously reported missense mutation (G377S), and a novel single nucleotide deletion (g5255delT). The transcript originating from the latter allele was undetectable in RT-PCR experiments. We report the first characterization of a GBA genotype associated with the development of neutralizing antibody to alglucerase, in a patient affected with type 3 Gaucher disease. Our results may help to shed light on the mechanisms underlying this phenomenon which, in the rare instances where it occurs, hampers the efficacy of enzyme replacement therapy. PMID- 11600138 TI - The importance of distinct metabolites of N-nitrosodiethylamine for its in vivo mutagenic specificity. AB - Although N-nitrosodiethylamine (NDEA) is a potent carcinogen in rodents and a probable human carcinogen, little attempts were made to characterize its mutation spectrum in higher eukaryotes. We have compared forward mutation frequencies at multiple (700) loci with the mutational spectrum induced at the vermilion gene of Drosophila, after exposure of post- and pre-meiotic male germ cells to NDEA. Among 30 vermilion mutants collected from post-meiotic stages were 12 G:C-->A:T transitions (40%), 8 A:T-->T:A transversions (27%), and 4 structural rearrangements (13%). The remainder were three A:T-->G:C transitions, two G:C- >C:G transversions and one G:C-->T:A transversion. The results show that although NDEA induces predominantly transitions (40% G:C-->A:T and 10% A:T-->G:C), the frequencies of transversions (37%, of which 27% of A:T-->T:A transversions) and especially of rearrangements (13%) are remarkably high. This mutation spectrum differs significantly from that produced by the direct-ethylating agent N ethylnitrosourea (ENU), although the relative distribution of ethylated DNA adducts is similar for both carcinogens. These differences, in particular the occurrence of rearrangements, are most likely the result of the requirement of NDEA for bioactivation. Since all four rearrangements were collected from non metabolizing spermatozoa (or late spermatids), it is hypothesized that they derived from acetaldehyde, a stable metabolite of NDEA. Due to its cytotoxicity, attempts to isolate vermilion mutants from NDEA-exposed pre-meiotic cells were largely unsuccessful, because only two mutants (one A:T-->G:C transition and one 1bp insertion) were collected from those stages. Our results show that NDEA is capable of generating carcinogenic lesions other than base pair substitutions. PMID- 11600139 TI - DNA adducts, estrogenicity and rodent diets. PMID- 11600140 TI - Mouse uterine carcinogenicity of genistein: the currently most secure example of non-genotoxic rodent carcinogenicity? PMID- 11600141 TI - Plant cyclotides: circular, knotted peptide toxins. PMID- 11600142 TI - A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice. AB - This study compared the respective intramuscular (IM) safety margins of two preparations of botulinum toxin (BTX) serotype A and one preparation each of BTX serotypes B and F in mice. Mice received an IM injection (0-200 U kg(-1) body weight) of BTX-A (BOTOX or DYSPORT), an experimental preparation of BTX-B (WAKO Chemicals, Inc.), or an experimental preparation of BTX-F (WAKO). An observer who was masked to treatment scored muscle weakness using the Digit Abduction Scoring (DAS) assay. Peak DAS responses were plotted and IM ED(50) values calculated. The safety margin for each BTX preparation was calculated as a ratio of the IM median lethal dose after hind limb injection to the median effective dose in the DAS assay (IM LD(50)/IM ED(50)). Experiments were repeated 4-6-times for each preparation (10 mice/dose). Mean safety margin values were highest for BTX-F (WAKO; 16.7+/-3.9) and one of the BTX-A preparations (BOTOX; 13.9+/-1.7). Mean safety margins values for the other BTX-A preparation (DYSPORT) and BTX-B (WAKO) were significantly lower (7.6+/-0.9 and 4.8+/-1.1, respectively). Thus, the BTX preparations exhibited different safety margins in mice. These results support the hypothesis that the preparations are unique therapeutics and are not interchangeable based on a simple dose ratio. PMID- 11600143 TI - Pharmacokinetics of thrombin-like enzyme from venom of Agkistrodon halys ussuriensis Emelianov determined by ELISA in the rat. AB - A thrombin-like enzyme (TLE) was separated and purified from the venom of a northeast Chinese snake Agkistrodon halys ussuriensis Emelianov. Experiments were performed in rats to determine the pharmacokinetic parameters following an intravenous (i.v.) or a subcutaneous (s.c.) injection of the thrombin-like enzyme. The plasma levels of TLE were estimated by enzyme-linked immunosorbent assay. The method exhibited high reproducibility and accuracy in correlating optical densities with TLE concentrations (0.2-30 ng ml(-1), r=0.99). The plasma concentration-time course after i.v. administration of 50 microg kg(-1) TLE was well fitted by a two-compartment open model. The half-life of the alpha-phase was 18.0+/-3.2 min, and that of the beta-phase 3.9+/-0.7h. The apparent volume of distribution was 1.8+/-0.5l kg(-1), and clearance was 5.4+/-0.5 ml min(-1) kg( 1). When the TLE was injected s.c. at a dose of 0.75 mg kg(-1), the changes in plasma concentration were best described by a two-compartment model with a first order absorption. The maximal plasma level of 51+/-2.7 ng ml(-1) was reached at 5.2+/-0.5h. The absorption rate constant was 0.3+/-0.03 h(-1). The area under the plasma concentration-time curve (AUC) was 2.8+/-0.8 microg h(-1) ml(-1). PMID- 11600144 TI - Inhibition of human platelet aggregation by L-amino acid oxidase purified from Naja naja kaouthia venom. AB - L-Amino acid oxidase (LAO) widely exists in snake venoms. Purification of LAO from the Naja naja kaouthia (monocellate cobra) venom has been reported (Tan and Swaminathan, 1992), but its structural characterization and physiological function remained to be determined. The function of snake venom LAOs in hemostasis, especially their effect on platelet aggregation, has been controversial. We determined the N-terminal amino acid sequence of the N. n. kaouthia LAO named K-LAO to be DDRRSPLEECFQQNDYEEFLEIAKNGLKKTxNPKHVXxV (38 residues). The protein data base search revealed that the enzyme had high similarities with other snake venom LAOs. Further, platelet aggregation studies revealed that K-LAO functionally did not induce platelet aggregation in a platelet-rich plasma system, but that it inhibited platelet aggregation induced by agonists such as ADP, collagen and ristocetin in a dose-dependent manner. K LAO diminished platelet aggregation more intensely under low than high shear stress. This inhibitory activity of K-LAO on either ristocetin-induced or shear induced platelet aggregation was quenched by addition of catalase. These results indicate that K-LAO functions as an inhibitor to platelet aggregation through the formation of hydrogen peroxide. The enzyme may contribute to the development of a severe hematological disorder due to cobra envenomation. PMID- 11600145 TI - Effects of marine sponge extracts on mitogen-activated protein kinase (MAPK/ERK(1,2)) activity in SW-13 human adrenal carcinoma cells. AB - Some species of marine sponge have been shown to produce metabolites with endocrine-altering and cell growth regulatory properties. Since cell division and differentiation are controlled, in part, by the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK/ERK) cascade, we tested extracts (1.0mg/ml) from six shallow water marine species obtained in the Florida Keys for effects on MAPK/ERK(l,2) (sub-variant of EC 2.7.1.37) activity in incubations with SW-13 human adrenal carcinoma cells in culture. In these short-term incubations, extracts from two species, the purple bleeding sponge (Iotrochota birotulata) and the West Indian bath sponge (Spongia barbara), significantly inhibited MAPK/ERK(1,2) activity (to 51 and 44% of control levels, respectively) without altering cell survival. Western blots for phosphorylated and total ERK showed that ERK(2) predominated over ERK(1) by a factor of about 4:1 and that the phosphorylated forms of these isozymes were strongly suppressed by active extracts from both sponges. Another species, the green sponge (Haliclona veridis), whose extract has been shown previously to activate guanylate cyclase and to inhibit adenylate cyclase in a variety of mammalian tissues, was found not to affect MAPK/ERK(1,2) in human adrenal carcinoma cultures but did lyse and kill most of these cultured cells. Extracts from the sheepswool sponge (Hippospongia lachne) and the bleeding sponge (Oligoceras hemorrhages) did not significantly affect either MAPK/ERK(1,2) activity or the survival of attached cells. An extract from the fire sponge (Tedania ignis) did not alter MAPK/ERK(1,2) activity but did modestly decrease cell viability. These studies document for the first time species-specifc effects of marine sponge extracts on the MAPK/ERK(1,2) cascade and on the growth and survival of human adrenal carcinoma cells in culture. PMID- 11600147 TI - Ingestion of toxic Microcystis aeruginosa by dairy cattle and the implications for microcystin contamination of milk. AB - Microcystin (MCYST) toxins can be produced by the bloom-forming cyanobacterium Microcystis aeruginosa. They are chemically stable compounds and have both acute and chronic effects on the health of mammals, including cattle and humans. Cattle will drink water containing lethal cell concentrations of M. aeruginosa. When cattle consume sub-lethal doses of microcystins, the fate of those toxins is unknown. We provided drinking water containing 1 x 10(5) cells ml(-1) M. aeruginosa (strain MASH01-A19) to four lactating Holstein-Friesian dairy cattle for 21 days to determine if MCYST-LR produced by the cyanobacteria, could be detected in milk produced by the cattle. Cattle consumed up to 15 mg MCYST-LR at an ingestion rate of 1.21 microg kg (live weight) d(-1). Analysis by HPLC and ELISA indicated that no detectable amounts of microcystin from the cyanobacteria were present in the milk obtained from the treated animals. Based on the level of quantitation of the ELISA analyses, the maximum possible concentration in the milk was less than 2 ng l(-1). This is more than three orders of magnitude less that the concentration that could be considered problematic for milk of 0.86 microg l(-1) which we calculated using the World Health Organization derived tolerable daily intake for MCYST-LR and the per capita daily consumption of milk in Australia. PMID- 11600146 TI - The renal effects of Bothrops jararacussu venom and the role of PLA(2) and PAF blockers. AB - The most common complication in the lethal cases of ophidian bites in Brazil is acute renal failure, but its pathogenesis is obscure. The effects of Bothrops jararacussu venom (3, 10 and 30 microg/ml) were examined using the isolated perfused kidney from Wistar rats. Dexamethasone, and WEB 2086, a triazolobenzodiazepine substance, which is a platelet activating factor receptor antagonist, were tested for a possible blockade of the renal effects in the presence of 10 microg/ml of venom. The most intense effects of the venom were noticed at 120 min after using 30 microg/ml. We observed a decrease in the perfusion pressure and in the renal vascular resistance. However, the glomerular filtration rate (GFR) and the urinary flow (UF) increased significantly. The percent of sodium (%Na(tot)(+)) and potassium (%K(tot)(+)) tubular transport were also decreased. Dexamethasone was unable to block the effects of B. jararacussu in the kidney, while WEB 2086 blocked its effect in glomerular filtration rate, urinary flow and in the percentage of total tubular potassium reabsorption. We suggest that this venom promotes diuresis independently of perfusion pressure drop. The alterations in GFR, UF and %K(tot)(+) are probably mediated by platelet activating factor. Dexamethasone did not block the renal effects maybe because of the concentration used in this work or maybe the renal effects are promoted by the myotoxin, which does not have PLA(2) activity. PMID- 11600148 TI - Study of paralytic shellfish poisoning toxin profile in shellfish from the Mediterranean shore of Morocco. AB - Since 1992, a monitoring program for bivalve molluscs contaminated by algal toxins was established at different stations along the Mediterranean Moroccan shores. The monitored stations were tested every 2 weeks. The presence of toxicity was determined using the mouse bioassay method. Toxin profile was carried out by HPLC/FD in selected contaminated tissues. According to the outcomes of this surveillance from 1994 to 1999, reliable information on toxicity of shellfish was obtained. They indicate that PSP is a recurrent toxicity in molluscs along the Mediterranean shore of Morocco. It has been noted a difference of PSP accumulation among individual shellfish. The cockle (Achanthocardia tuberculatum) presents toxicity throughout the year, while other specimens from the same area such as clam (Callista chione), warty venus (Venus gallina) and marine beans (Donax trunculus) accumulate it seasonally from January to April, after which they depurate the toxin. Moreover, the study of toxin profiles among individual shellfish was undertaken. It was found that shellfish presented a complex profile pointing to contamination by Gymnodinium catenatum. PMID- 11600149 TI - Neutralization of proteases from Bothrops snake venoms by the aqueous extract from Casearia sylvestris (Flacourtiaceae). AB - Aqueous extract from Casearia sylvestris leaves, a typical plant from Brazilian open pastures, was able to neutralize the hemorrhagic activity caused by Bothrops asper, Bothrops jararacussu, Bothrops moojeni, Bothrops neuwiedi and Bothrops pirajai venoms. It also neutralized two hemorrhagic metalloproteinases from Bothrops asper venom. Proteolytic activity on casein induced by bothropic venoms and by isolated proteases, including Bn2 metalloproteinase from B. neuwiedi venom, was also inhibited by the C. sylvestris extract in different levels. The alpha-fibrinogen chain was partially protected against degradation caused by B. jararacussu venom, when this venom was incubated with C. sylvestris extract. We also observed that this extract partially increased the time of plasma coagulation caused by B. jararacussu, B. moojeni and B. neuwiedi venoms. C. sylvestris extract did not induce proteolysis in any substrate assayed. PMID- 11600150 TI - The facilitatory actions of snake venom phospholipase A(2) neurotoxins at the neuromuscular junction are not mediated through voltage-gated K(+) channels. AB - Electrophysiological investigations have previously suggested that phospholipase A(2) (PLA(2)) neurotoxins from snake venoms increase the release of acetylcholine (Ach) at the neuromuscular junction by blocking voltage-gated K(+) channels in motor nerve terminals. We have tested some of the most potent presynaptically acting neurotoxins from snake venoms, namely beta-bungarotoxin (BuTx), taipoxin, notexin, crotoxin, ammodytoxin C and A (Amotx C & A), for effects on several types of cloned voltage-gated K(+) channels (mKv1.1, rKv1.2, mKv1.3, hKv1.5 and mKv3.1) stably expressed in mammalian cell lines. By use of the whole-cell configuration of the patch clamp recording technique and concentrations of toxins greater than those required to affect acetylcholine release, these neurotoxins have been shown not to block any of these voltage-gated K(+) channels. In addition, internal perfusion of the neurotoxins (100 microg/ml) into mouse B82 fibroblast cells that expressed rKv1.2 channels also did not substantially depress K(+) currents. The results of this study suggest that the mechanism by which these neurotoxins increase the release of acetylcholine at the neuromuscular junction is not related to the direct blockage of voltage-activated Kv1.1, Kv1.2, Kv1.3, Kv1.5 and Kv3.1 K(+) channels. PMID- 11600151 TI - The C-terminal domain promotes the hemorrhagic damage caused by Vibrio vulnificus metalloprotease. AB - Vibrio vulnificus, an opportunistic human pathogen, produces a 45-kDa zinc metalloprotease (V. vulnificus protease; VVP) as an important virulence determinant. VVP injected intradermally into the dorsal skin causes the hemorrhagic damage through specific degradation of type IV collage in the vascular basement membrane. The N-terminal 35-kDa polypeptide (VVP-N), the catalytic domain, also evoked the hemorrhagic skin reaction within minutes. However, the hemorrhagic activity of VVP-N was one-third of that of VVP. Besides, the proteolytic activity of VVP-N toward the reconstituted basement membrane or type IV collagen was found to be about 50 % of VVP. VVP-N, like VVP, was quickly inactivated by an equimolar amount of alpha(2)-macroglobulin, a broad-spectrum plasma protease inhibitor. These findings indicate that the C-terminal 10-kDa polypeptide, the substrate-binding domain mediating the effective binding to protein substrates, functions to augment the hemorrhagic reaction of VVP. PMID- 11600152 TI - Cloning of cDNAs encoding C-type lectins from Elapidae snakes Bungarus fasciatus and Bungarus multicinctus. AB - A number of C-type lectins with various biological activities have been purified and characterized from Viperidae snake venoms. In contrast, only a few reports could be found in literature concerning the C-type lectins in Elapidae snake venoms. Based on the published cDNA sequences of C-type lectins from Viperidae snake venoms, oligonucleotide primers were designed and used to screen the cDNA libraries made from the venom glands of Bungarus fasciatus and Bungarus multicinctus. This allowed the cloning of three full length cDNAs encoding C-type lectins. The encoded proteins, named BFL-1, BFL-2 and BML, exhibit high degrees of sequence identities with Viperidae snake venom saccharide-binding lectins (around 60% with Trimeresurus stejnegeri venom lectin, Crotalus atrox venom lectin and Agkistrodon piscivorus venom lectin). They show much less identities with other venom C-type lectin-like proteins (around 30% with the platelet glycoprotein Ib-binding protein from Agkistrodon blomhoffi venom and the factor IX/X-binding protein from Trimeresurus flavoviridis venom). The cDNAs revealed that the precursors contain potential signal peptides characterized by a hydrophobic core. To our knowledge, these are the first cDNA cloning of group VII C-type lectins (Drickamer K. 1993. Prog. Nucleic Acid Res. Mol. Biol. 45, 207 232) from Elapidae snake venom glands. PMID- 11600154 TI - Venomous cone snails: molecular phylogeny and the generation of toxin diversity. AB - In order to investigate the generation of conotoxin diversity, delta-conotoxin sequences from nine Conus species were analyzed in the context of their phylogeny. Using a standard molecular marker, mitochondrial 16S RNA, we determined that the delta-conotoxins were derived from three distinct species clades based on the phylogenetic reconstruction of a large set (>80) of Conus species and other toxoglossate molluscs. Four different mechanisms appear to have contributed to the diversity of the delta-conotoxins analyzed: (1) Speciation: Delta-conotoxins in different species diverge from each other (the prepro regions of orthologous genes somewhat more slowly than the reference rRNA rate, the mature toxin regions significantly faster). (2) Duplication: Intraspecific delta conotoxin divergence is initiated by gene duplication events, some of which may have predated the species itself. (3) Recombination: A novel delta-conotoxin may arise through recombination of two parental delta-contoxin genes. (4) 'Focal hypermutation': This sudden, almost saltatory change in sequence is always restricted to the mature toxin region. The first three have been recognized previously as mechanisms important for the evolution of gene families in other phylogenetic systems; the last is a remarkable, mechanistically unexplained and specialized feature of Conus peptide diversification. PMID- 11600153 TI - Genes and peptides from the scorpion Centruroides sculpturatus Ewing, that recognize Na(+)-channels. AB - Sixteen different genes were cloned from the venomous glands of Centruroides sculpturatus Ewing using RNA extracted from scorpions collected in Tucson, Arizona. Based on the amino acid sequence similarities of the proteins coded by these genes, all together there are 22 different structural components in this venom, thought to be specific for Na(+)-channels. The genes reported contain signal peptides with 19 amino acid residues followed by mature peptides of 63-66 amino acid residues in length. One of them correspond to toxin I (CsEI), a known scorpion toxin specific for Na(+)-channels. Four different genes are almost identical to variant 1 (Csv1), presenting only one amino acid change from the original protein. For variant 2 (Csv2) four related genes were found, with only one amino acid change in their primary sequences. Another gene resembles to variant 3 (Csv3, the best known Centruroides sculpturatus toxin), with only three amino acid changes in their primary sequences. Additionally, two genes show variations only on the nucleotide sequence at level of the signal peptides, and several genes clearly show sequences that suggest post-transcriptional modifications, during the maturation process. A phylogenetic tree was generated with the primary structures available and three main divergent branches were found. PMID- 11600155 TI - Non-selective retention of PSP toxins by the mussel Mytilus galloprovincialis fed with the toxic dinoflagellate Alexandrium tamarense. AB - Mussels, Mytilus galloprovincialis, were contaminated by paralytic shellfish poisoning (PSP) toxins by being fed with the toxic dinoflagellate Alexandrium tamarense. Temporal variations in the toxin content and the profile of mussels during the feeding experiment were monitored by high-performance liquid chromatography (HPLC). The toxin profile of mussels was compared with that of A. tamarense to clarify the mechanism of uptake of toxins in mussels. The prominent toxins in mussels and A. tamarense were N-sulfocarbamoyl toxins (C1,2) and carbamate toxins, gonyautoxin-1,4 (GTX1,4). The toxin profiles of both mussels and A. tamarense were almost constant throughout the experimental period. There were no remarkable differences in the toxin proportion between mussel and A. tamarense. These results indicate that mussels do not selectively accumulate particular toxins. PMID- 11600156 TI - High grazer toxicity of [D-Asp(3),(E)-Dhb(7)]microcystin-RR of Planktothrix rubescens as compared to different microcystins. AB - Planktothrix rubescens, the dominant cyanobacterium in Lake Zurich, is generally considered to be toxic to zooplankton. The major toxin was determined by NMR spectroscopy and chemical analysis to be [D-Asp(3),(E)-Dhb(7)]microcystin-RR. The compound was isolated in high purity, and its 24-h acute grazer toxicity was compared with microcystin-LR, microcystin-RR, microcystin-YR, and nodularin using a Thamnocephalus platyurus bioassay. Based on LC(50) values [D-Asp(3),(E) Dhb(7)]microcystin-RR was the most toxic microcystin tested. Nodularin was slightly more toxic under the conditions of the assay. The large number of individuals available for the grazer bioassay allowed the determination of dose response curves of the different microcystins. These curves showed marked differences in their steepness. Microcystin-RR, which had nearly the same LC(50) as microcystin-LR and microcystin-YR, exhibited a very flat dose-response curve. This flat curve indicates that, for some individuals, lower concentrations of this microcystin are much more toxic than are the other two microcystins. Mortality of 100% requires much higher concentrations of microcystin-RR, indicating the resistance of some animals to the toxin. The purified [D Asp(3),(E)-Dhb(7)]microcystin-RR exhibited a higher molar absorption coefficient determined by quantitative amino acid analysis than the coefficients generally used for other microcystins. This observation has consequences for the risk assessment for microcystins and makes a structural determination of microcystins an absolute requirement. The presence of the dehydrobutyrine residue may be the reason for the higher specific toxicity of [D-Asp(3),(E)-Dhb(7)]microcystin-RR when compared to the N-methyldehydroalanine-containing microcystins. PMID- 11600157 TI - Isolation and identification of the toxic peptides from Lophyrotoma zonalis (Pergidae) sawfly larvae. AB - The broad-leaved paper bark tree Melaleuca quinquenervia (Cav) (Myrtaceae) was introduced into Florida (USA) early in this century it has proliferated to such an extent that urgent measures are now required to control it. The sawfly Lophyrotoma zonalis (Pergidae) has been introduced as a possible biological control agent due to its ability to defoliate M. quinquenervia. Because toxic D amino acid- containing peptides have been isolated from some sawfly species, L. zonalis larvae were processed using the previously reported method for the recovery of these compounds. The toxins lophyrotomin (as the free C-terminal acid) and a mixture of pergidin and Val (4)-pergidin were isolated at 0.36 and 0.43% yield of the dried larvae, respectively. Both compounds when dosed intraperitoneally to C57/Bl6 male mice were hepatotoxic with lowest lethal doses of 8 and 32 mg/kg, respectively. The pathology of the liver was different for each compound, with the lophyrotomin free acid causing a periportal haemorrhagic necrosis and the pergidin causing a periacinar coagulative necrosis. PMID- 11600158 TI - Preliminary characteristics of the prothrombin converting enzyme from venom of Stephen's banded snake (Hoplocephalus stephensii). AB - Stephen's banded snake (Hoplocephalus stephensii) is an infrequently encountered Australian elapid species. The crude venom contains coagulant activity and the component responsible is a prothrombin activator requiring factor V for activity. SDS-PAGE of the isolated native protein revealed two bands at 23 and 36 kDa. These findings indicate that the procoagulant is similar to that found in the Australian tiger snake (Notechis scutatus) and thus resembles factor Xa. PMID- 11600159 TI - Necrotic arachnidism in Australia. PMID- 11600166 TI - Cognitive behavioral therapy for chronic fatigue syndrome in a general hospital- feasible and effective. AB - Cognitive behavior therapy (CBT) has been shown to be effective in recent randomized controlled trials for chronic fatigue syndrome (CFS). We examined the effectiveness of CBT in a general hospital setting in a retrospective questionnaire follow-up study of 94 patients offered CBT by liaison psychiatry services. The questionnaire response rate was 61%. Eighteen percent had returned to normal functioning at follow-up. For the group as a whole, there was a significant improvement in the functional and social impairment and the number of frequently experienced symptoms. Those in work or study at follow-up was 53% (29% pretreatment), and 65% of patients mentioned occupational stress as a contributory factor in their illness. There was a significant reduction in the frequency of attendance at primary care in the year after the end of CBT. We conclude that cognitive behavioral therapy is an acceptable treatment for most patients and can be used in a general hospital outpatient setting by a variety of trained therapists. However, a proportion of patients do not benefit and remain significantly disabled by the condition. PMID- 11600165 TI - The Quality Improvement for Depression collaboration: general analytic strategies for a coordinated study of quality improvement in depression care. AB - It is difficult to evaluate the promise of primary care quality-improvement interventions for depression because published studies have evaluated diverse interventions by using different research designs in dissimilar populations. Preplanned meta-analysis provides an alternative to derive more precise and generalizable estimates of intervention effects; however, this approach requires the resolution of analytic challenges resulting from design differences that threaten internal and external validity. This paper describes the four-project Quality Improvement for Depression (QID) collaboration specifically designed for preplanned meta-analysis of intervention effects on outcomes. This paper summarizes the interventions the four projects tested, characterizes commonalities and heterogeneity in the research designs used to evaluate these interventions, and discusses the implications of this heterogeneity for preplanned meta-analysis. PMID- 11600167 TI - Changes in psychiatric consultations over ten years. AB - We report on the day-to-day functions of a consultation-liaison psychiatric service during a two-month period separated by ten years. As general hospitals transformed their delivery of services during the 1990s, we hypothesized that the day-to-day role of the consultation-liaison service would change in terms of the population served, timing of evaluations, and recommended interventions. Using a chart review, we retrospectively examined consultations referred to an adult consultation-liaison service at a university hospital during the same two-months in 1990 (N=75) and 2000 (N=90). Patients in 2000 were less educated, more likely to be divorced and more likely to be minorities. The 2000 patients appeared to have more severe psychiatric illness and to be more medically complicated. These findings have implications in the context of cost effective health care. PMID- 11600168 TI - Attempted suicide by drug overdose and by poison-ingestion methods seen at the main general hospital in the Fiji islands: a comparative study. AB - OBJECTIVE: This study examined the prevalence and the characteristics of deliberate self-poisoning patients seen at the main general hospital in the Fiji Islands. METHOD: Thirty-one consecutive patients with deliberate drug-overdose and 27 others with nonoverdosed self-poisoning were compared on sociodemographic and clinical variables. RESULTS: Deliberate self-poisoning cases represented 0.3% of the hospital admissions, and had a rate of 25.9 per 100,000 population. The overdose group was significantly older (P<.05), whereas the poison-ingestion group had significantly greater proportion of males (P<.03). The rate of psychiatric morbidity was significantly higher in the overdose group (P=.04), whereas the history of alcohol abuse was significantly higher in the other group (P=.04). Paracetamol (35.5%) and paraquat (29.7%) were the most commonly used agents. CONCLUSIONS: Age, gender, rate of psychiatric morbidity, or history of alcohol abuse could be predictive of whether drug overdose or poison ingestion would be used for deliberate self-poisoning. This information could be relevant in the formulation of suicide preventive strategies. PMID- 11600169 TI - Psychological intervention in cancer patients: a randomized study. AB - We examined the long-term effects of a behavioral intervention on the psychological distress of patients recently diagnosed with localized cancer, who were being treated at Hadassah University Hospital. All 116 patients who met the inclusion criteria (49 men and 67 women) were randomized into an intervention group and a control group on a 3:1 basis. The intervention chosen was Progressive Muscle Relaxation with Guided Imagery, which is intended to decrease psychological distress and increase the patient's sense of internal control. The Brief Symptom Inventory (BSI) and the Impact of Events Scale (IES) were used to assess psychological distress within 1 month of diagnosis, 3 months later (shortly before starting intervention), and 6 months after the end of the intervention. At the final assessment, the effect of the behavioral intervention on psychological distress was positive. The effect was relatively modest but statistically significant when assessed in terms of the Global Severity Index (GSI) (a decrease of 2.3 points in the GSI of the treatment group as compared to an increase of 1.2 points in the GSI of the control group P=.005). Despite these moderately positive findings, we suggest that the results might be more meaningful if cancer patients are first screened for psychological distress to exclude those with a low distress level that does not justify intervention, and only then randomized for participation in the study. PMID- 11600170 TI - Variables related to outcome following child psychiatric hospitalization. AB - Children (N = 110) hospitalized on a child psychiatric unit improved significantly in psychological functioning at discharge and 1- and 6-months follow-up relative to their functioning at admission. Children who were more impaired at admission made more progress during admission but were more impaired at follow-up than children who had milder symptoms at admission. Children without a behavior disorder had a better outcome than children with a behavior disorder. None of the other variables, alone or in combination, was significantly related to admission progress or follow-up outcome, including specific diagnoses, gender, race, age, IQ, family functioning, negative life events, parent education and employment, biological family history, length of hospitalization, parent involvement during admission and follow-up services. PMID- 11600171 TI - Asperger's disorder in the emergency psychiatric setting. AB - Asperger's syndrome (AS) is a pervasive developmental disorder that may be unrecognized, especially if signs of other psychiatric disorders coexist. The objectives of this paper are: 1) to ascertain the prevalence of AS in the emergency psychiatric setting; and 2) to describe features of AS which may help to differentiate these patients from patients with psychotic disorders. Among 2500 patients admitted to a psychiatric intensive care unit, 5 (0.2%) received a diagnosis of AS, for the first time. Besides impairment of social interaction, common features were the following: male gender, left handedness, obsessive compulsive symptoms, cognitive hyper-abilities, violent behavior, sense of humor, low WAIS total score, high WAIS verbal/performance score ratio, unusual, restricted interest and clumsiness. Comorbid schizophrenia is difficult to rule out in these patients. Psychotic symptoms should not be overvalued in making the diagnosis when specific features of AS are present. PMID- 11600172 TI - The impact of PTSD on treatment adherence in persons with HIV infection. PMID- 11600173 TI - Proceedings of the Second International Conference on Experimental and Clinical Reproductive Immunology. Amsterdam, The Netherlands, November 2000. PMID- 11600174 TI - Tryptophan catabolism prevents maternal T cells from activating lethal anti-fetal immune responses. AB - The murine conceptus is protected from maternal immunity by cells expressing indoleamine dioxygenase (IDO), which catabolizes tryptophan. Induction of lethal maternal anti-fetal immunity requires effective pharmacologic inhibition of IDO enzyme activity and the presence of maternal T cells, but not B cells and also depends on the degree of maternal-fetal tissue incompatibility. Based on these findings, we propose a model to explain the role of IDO in suppressing maternal immunity and the mechanism of fetal allograft rejection, when IDO activity is inhibited during gestation. This model incorporates observations that fetal allograft rejection is T cell dependent, antibody-independent and is accompanied by a novel type of inflammation involving extensive complement deposition at the maternal-fetal interface, when IDO activity is blocked during murine pregnancy. PMID- 11600175 TI - Cytokine cross-talk between mother and the embryo/placenta. AB - Cytokines are regulatory glycoproteins that can affect virtually every cell type in the body and have pleiotropic regulatory effects on hematopoietic, endocrine, nervous and immune systems. Chemokines, although considered as members of the cytokine superfamily, are establishing their own identity. Chemokines mediate leukocyte migration through specific G protein coupled receptors in various tissues. Recently, much evidence has suggested that cytokines and chemokines play a very important role in the reproduction, i.e. embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems. The close correlation between the embryo and endometrium and between the placenta and decidua are mediated by sex steroid hormones, cytokines and chemokines. As a result of this closely related cross-talk, pregnancy is successfully maintained. PMID- 11600176 TI - Defective production of LIF, M-CSF and Th2-type cytokines by T cells at fetomaternal interface is associated with pregnancy loss. AB - Development of CD4+ helper T (Th) cells into type 1 (Th1) or type 2 (Th2) effectors can be influenced by hormones enhanced during pregnancy. Progesterone, at concentrations comparable to those found at fetomaternal interface, promotes the production of IL-4 and IL-5, whereas relaxin promotes the production of IFN gamma by T cells. Furthermore, Th1-type cytokines promote allograft rejection and, therefore, may compromise pregnancy, whereas Th2-type cytokines, which inhibit Th1 responses, may allow allograft tolerance. In addition, T cell production of Leukemia Inhibitory Factor (LIF) and macrophage-stimulating factor (M-CSF), which are essential for embryo implantation and development, are up regulated by IL-4 and progesterone. Finally, a direct cause-and-effect relationship between the defective production of LIF, M-CSF and Th2-type cytokines by T cells present at feto maternal interface and the pregnancy loss has been observed. PMID- 11600177 TI - Immunobiology of papillomavirus infections. PMID- 11600178 TI - Induction of specific immune responses in the genital tract of women after oral or rectal immunization and rectal boosting with Salmonella typhi Ty 21a vaccine. AB - The purpose of this study was to determine the efficacy of intestinal tract immunization in the induction of specific antibodies in human female genital tract secretions. Live attenuated typhoid vaccine Ty 21a was administered to three groups of healthy female volunteers, who were not using hormonal contraceptives. Group 1 included 15 women vaccinated orally. Group 2 included seven of the same women, who were vaccinated rectally 6 months later. Group 3 included 11 volunteers, who were vaccinated rectally. Salmonella-specific antibodies of IgG and IgA were measured in vaginal lavage and cervical mucus after oral or rectal primary vaccination. Salmonella-specific antibodies measured 1 month after rectal booster vaccination demonstrated significant increases in vaginal fluids and cervical mucus and were dominated by IgA. These results indicate that specific antibodies in the human female genital tract induced by primary vaccination can be enhanced by subsequent rectal administration of vaccines. PMID- 11600179 TI - HLA relationships of pregnancy, microchimerism and autoimmune disease. AB - Recent studies have established that there is bi-directional cell traffic between mother and fetus during pregnancy. Suprisingly, fetal cells have been found to persist in the maternal circulation for years after pregnancy. Maternal cells can also persist into adult life in her progeny. When cells from one individual are present in the body of another the term chimerism is used and a low level of non host cells is referred to as microchimerism. Chronic graft-versus-host disease often occurs after stem cell transplantation, is a known condition of chimerism, and resembles spontaneously occurring autoimmune diseases including systemic sclerosis, Sjogren's syndrome, primary biliary cirrhosis and sometimes myositis and systemic lupus. Of central importance to the development of chronic graft versus-host disease is the HLA relationship of host and donor cells. Considering this constellation of observations together led to the hypothesis that microchimerism and HLA-relationships are involved in the pathogenesis of some autoimmune diseases. Although much additional work is needed, results of initial studies provide support to the concept that non-host cells could participate in the pathogenesis of some autoimmune diseases. PMID- 11600181 TI - Higher levels of activation markers and chemokine receptors on T lymphocytes in the cervix than peripheral blood of normal healthy women. AB - Heterosexual transmission of human immunodeficiency virus (HIV-1) is the predominant mode of infection world-wide. To better understand sexual transmission of HIV-1 in women we have analysed virus co-receptor and cellular activation marker expression on T lymphocyte subsets from the cervical epithelium and have made comparisons with peripheral blood T cells. Intraepithelial cervical T lymphocytes were obtained with a cytobrush, immunolabelled and analysed by flow cytometry. Activation markers (CD69, CD25 and HLA-DR) were found to be more highly expressed on cervical than on blood T lymphocytes. These higher levels of activation on cervical T lymphocyte subsets could facilitate HIV-1 infection. CXCR4 was expressed at marginally higher levels than CCR5 on T cells from the cervical epithelium and peripheral blood. Thus, the preferential transmission of macrophage tropic strains of HIV-1 following sexual contact cannot be explained solely on the expression of chemokine co-receptors by T lymphocyte subsets. PMID- 11600180 TI - Murine female reproductive tract intraepithelial lymphocytes display selection characteristics distinct from both peripheral and other mucosal T cells. AB - Despite immense effort, the development of vaccines effective at mucosal sites has proceeded at a faltering pace. Efforts concentrating on humoral immunity but neglecting cellular immunity may be misdirected by ignoring many viral mucosal pathogens. Improved understanding of the development and maintenance of lymphocytes populating the reproductive tract (rtIELs) may inform advances in vaccination strategies for sexually transmitted diseases. Recent studies highlight tissue-specific differences in the development of mucosal immunity and suggest that the local milieu may play a role in selection, maintenance and function of resident lymphocytes. Here, we describe MHC class I and thymus dependence of subpopulations of rtIELs. TCRalphabeta+ CD8alphabeta+ T cells in the periphery, intestine, and female reproductive tract are all developmentally dependent on classical class I MHC and the thymus. TCRalphabeta+ CD8alphaalpha+ are absent from the periphery and the rtIELs, but are present and classical MHC class I-independent, in the intestine. In contrast to intestinal TCRgammadelta+ cells, TCRgammadelta+ rtIELs are CD8 negative and thymus dependent. In contrast to peripheral TCRgammadelta+ cells, murine TCRgammadelta+ rtIELs express not a diverse array of Vdelta genes, but rather, a canonical Vdelta1. In summary, lymphocytes isolated from the murine female reproductive tract have characteristics distinct from both peripheral T cells and those found at other mucosal sites. Therefore, for the purpose of vaccination strategies, the female reproductive tract should be regarded neither as peripheral nor mucosal, but rather as a tissue with distinctive immunological characteristics. PMID- 11600182 TI - Interferon-gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol. AB - Gamma-interferon (IFN-gamma) plays an important role in the maintenance of immune homeostasis by regulating the functions of all key cells of the immune system. Pathologically, IFN-gamma has been implicated in several autoimmune diseases. Since estrogens affect autoimmunity, we investigated whether immunomodulatory estrogenic hormones affects IFN-gamma. Concanavalin-A-stimulated splenic lymphocytes from orchiectomized or ovariectomized C57BL/6 mice exposed to estrogen for 3-5 months secreted higher levels of IFN-gamma protein compared to controls. This increase is, in part, due to increased levels of IFN-gamma mRNA. Kinetic studies suggested that splenic lymphocytes from estrogen-treated gonadectomized mice had increased IFN-gamma mRNA and protein as early as 6-12 h of culture. Estrogen also increased the expression of co-stimulatory CD80 (B7-1) molecules on B cells. Since natural estrogen increases IFN-gamma, it became important to test whether diethylstilbestrol (DES, a synthetic estrogen which was given to millions of women) also alters IFN-gamma levels. Our initial investigatory studies show that prenatal mice exposed to DES had a normal ability to secrete IFN-gamma. However, a second exposure of these mice to DES (single dose of 1 microg/g.b.w), as late as 1-1.5 years of age, led to a pronounced increase in the number of IFN-gamma secreting cells and augmented secretion of IFN-gamma. Increased IFN-gamma secretion by splenic lymphocytes from these mice was noted even after stimulation with a submitogenic concentration of anti-CD3 antibodies with or without anti-CD28 antibodies. Cell mixing experiments suggested that the DES-induced increase in IFN-gamma secretion is due to hormonal effects on T cells but not on APC. Together our studies show that: (1) estrogens upregulate IFN-gamma secretion, a vital immunoregulatory cytokine, and (2) inappropriate exposure of developing fetus to DES may permanently alter the "cytokine programming" of lymphocytes. PMID- 11600184 TI - Haptoglobin polymorphism and schizophrenia: genetic variation on chromosome 16. AB - Recently, it was shown that schizophrenia is accompanied by an activation of the inflammatory response system with signs of an acute phase response, such as increased plasma haptoglobin (Hp) concentrations. Hp is characterized by a molecular variation with three known phenotypes, i.e. Hp 1-1, Hp 2-1 and Hp 2-2. The aim of the present study was to examine Hp phenotypic and genotypic frequencies in schizophrenic patients. Hp phenotyping was carried out in 98 Northwestern Italian schizophrenic patients and the phenotypic and genotypic distributions were compared with the distributions established in the Northwestern Italian population. Plasma Hp concentrations were determined by means of a laser nephelometric method. The allele frequency of the Hp phenotypes in schizophrenia, i.e. Hp 1-1 (9.2%), Hp 2-1 (38.8%) and Hp 2-2 (52.0%), was significantly different from that in the Northwestern Italian population, i.e. Hp 1-1 (17.0%), Hp 2-1 (51.3%) and Hp 2-2 (38.5%). The frequency of the Hp-2 gene was significantly higher in schizophrenic patients (71.7%) as compared with the observed frequency in the Northwestern Italian population (62.5%). The alterations in Hp phenotypic and genotypic distribution were more pronounced in the schizo-affective, disorganized, undifferentiated and residual schizophrenic patients than in paranoid schizophrenic patients. More than a third (35.7%) of the schizophrenic patients showed plasma Hp concentrations which were higher than the upper limits of normality. Schizophrenia is accompanied by an altered distribution of the Hp phenotypes and genotypes, suggesting that genetic variation on chromosome 16 may be associated with schizophrenia. PMID- 11600183 TI - Transcriptional control of MHC genes in fetal trophoblast cells. AB - Tight control of MHC expression is essential for the outcome of a successful pregnancy. The lack of MHC class II and class I mediated antigen presentation by fetal trophoblast cells is an important mechanism to evade maternal immune recognition. Interestingly, the deficient expression of MHC class II molecules (HLA-DR, -DQ and -DP) and of the classical MHC class I molecules HLA-A and HLA-B is also noted after IFN-gamma treatment in trophoblast-derived cell lines. Our studies show that in trophoblast cell lines the IFN-gamma induced transactivation of HLA-A and HLA-B promoters is repressed. Furthermore, it was found that trophoblast cells lacked IFN-gamma mediated induction of the class II transactivator (CIITA). This lack of CIITA expression in trophoblast cells is due to CIITA promoter hypermethylation. In addition to lack of CIITA expression, trophoblast cells also displayed a repressed expression of RFX5. Together, these observations reveal a silencing of multiple activation pathways that are critical to the transcriptional control of MHC class II and class I antigen presentation functions by trophoblast cells. PMID- 11600185 TI - Glial cell line-derived neurotrophic factor (GDNF) gene and schizophrenia: polymorphism screening and association analysis. AB - The glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic and potential differentiation factor for dopaminergic systems. Both the dopamine theory and the neurodevelopmental hypothesis of schizophrenia suggest that alterations of GDNF functions could be involved in the pathogenesis of schizophrenia. Using polymerase chain reaction and single strand conformational polymorphism analysis, we searched for polymorphisms in the GDNF gene in 50 patients with schizophrenia. No evidence was obtained, however, for the presence of polymorphisms in the DNA sequence encoding GDNF mature peptide in our patients. We then examined a trinucleotide repeat (AGG)(n) polymorphism in the 3'-UTR of the GDNF gene for allelic association in a Japanese sample of 99 schizophrenic patients and 98 control subjects. There was no significant difference in the overall distribution of the allele between the two groups. When each allele was examined separately, the allele (AGG)(10) was more common in schizophrenic patients than in control subjects, but this finding was not significant when multiple testing was taken into account in the analysis. Overall, we obtained no solid evidence for the involvement of the GDNF gene in the pathogenesis of schizophrenia, although further studies in larger numbers of subjects will be required to conclude whether the trinucleotide repeat polymorphism is associated with the development of schizophrenia. PMID- 11600186 TI - Alcoholism, ALDH2*2 allele and the A1 allele of the dopamine D2 receptor gene: an association study. AB - The inactive form of aldehyde dehydrogenase-2 (ALDH2) is regarded as a protective factor against the development of alcoholism, and alcoholics with inactive ALDH2 are considered to be relatively homogeneous. This examination of a possible allelic association of the dopamine D2 receptor (DRD2) gene TaqI A polymorphism failed to detect significant differences between 583 Japanese alcoholics and 295 unrelated Japanese controls, or between alcoholic subjects with different ALDH2 genotypes. Despite the significantly higher frequency of the DRD2 A1 allele in the 207 alcoholics with inactive ALDH2 than in the 376 alcoholics with active ALDH2, multiple logistic regression analysis (controlled for the ALDH2 genotype) revealed no association between the TaqI A polymorphism and alcoholism. Nor did the frequency of the DRD2 TaqI A polymorphism differ in alcoholic subjects grouped by several pertinent clinical characteristics, including severity of alcoholism. Although there remains a possibility that the DRD2 TaqI A polymorphism plays some role in modifying the phenotype of the disease, these results suggest that neither the A1 allele nor the homozygous A1 genotype is associated with alcoholism. PMID- 11600187 TI - Serotonin, testosterone and alcohol in the etiology of domestic violence. AB - In a previous study we administered the panicogenic agent sodium lactate to a select group of perpetrators of domestic violence and comparison groups. Results of that study showed that perpetrators exhibited exaggerated lactate-induced fear, panic and rage. In this current study, we compared the cerebral spinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and testosterone obtained from perpetrators of domestic violence and a group of healthy comparison subjects. All subjects were assessed for DSM-III-R diagnoses. Perpetrators with alcohol dependence (DV-ALC) (n=13), perpetrators without alcohol dependence (DV-NALC) (n=10) and healthy comparison subjects (HCS) (n=20) were clinically assessed using the Spielberger Trait Anxiety, Brown-Goodwin Aggression Scale, Buss Durkee Hostility Inventory and Straus Conflict Tactics. Following an overnight fast and bed rest, subjects received a lumbar puncture to obtain CSF concentrations of 5-HIAA and testosterone. Perpetrators scored significantly higher on measures of aggression than HCS. DV-NALC had significantly lower concentrations of CSF 5-HIAA and higher Straus Conflict Tactics (CT) physical violence scores than DV-ALC and HCS. DV-ALC had significantly higher concentrations of CSF testosterone than DV-NALC. DV-ALC also had significantly higher Straus CT physical violence scores than HCS. DV-NALC and DV-ALC differed on 5-HIAA concentrations, testosterone concentrations, Straus CT physical violence scores and alcohol dependence. These results suggest that DV NALC and DV-ALC groups could have different biological mechanisms mediating domestic violence. PMID- 11600188 TI - Urinary free cortisol excretion in elderly persons with minor and major depression. AB - Several studies have found that cortisol hypersecretion may occur in severely depressed patients, characterized by melancholic features. On the other hand, illness chronicity seems to be related to low, rather than high, cortisol levels. This study aims to trace factors associated with 24-h urinary free cortisol levels in a sample of 23 elderly persons with major or minor depression and 21 non-depressed control subjects. Depressive episodes were subdivided according to severity and chronicity (i.e. length and recurrence). None of the depressed persons showed unusually high 24-h cortisol levels, and cortisol excretion was not elevated as compared with that in the control group, regardless of subtype of depression. The results suggest, however, that hyposecretion of cortisol may be a feature of chronic depressive episodes, especially in males. PMID- 11600189 TI - Predictors of short-term deterioration and compliance in psychiatric emergency patients: a prospective study of 457 patients referred to the emergency room of a general hospital. AB - The aim of this study was to identify predictors of (1) short-term outcome and (2) short-term compliance with treatment (for non-hospitalized patients) in psychiatric emergency patients. Subjects comprised 457 patients referred to the emergency ward of a French general hospital and requiring examination by a psychiatrist. Clinical and therapeutic assessments were carried out at baseline, using DSM-IV diagnoses and overall psychopathological scoring scales [Brief Psychiatric Rating Scale (BPRS) and Symptom Checklist-90 Revised]. Clinical outcome and compliance were assessed 3 weeks after entry. For each of the two issues assessed, stepwise logistic regression analysis was performed following univariate comparisons. The three best predictors of deterioration at 3 weeks were lack of compliance to treatment, presence of a previous psychiatric history, and a low BPRS hebephrenic factor score. The best predictors of compliance in non hospitalized patients were a previous psychiatric history, marital status, a low BPRS hostility factor score, and older age. The main predictor of deterioration was non-compliance. Thus, we emphasize the importance of improving compliance, especially among young patients with no previous psychiatric history. PMID- 11600190 TI - P300 asymmetry in schizophrenia: a meta-analysis. AB - P300 event-related brain potential (ERP) amplitude is smaller in patients with schizophrenia compared to unaffected controls, but whether left temporal component amplitude is also smaller is debated. The present study employed meta analytical methods to quantitatively assess previous P300 schizophrenia asymmetry findings. All P300 articles on schizophrenia using an auditory oddball paradigm published before January 2000 were obtained by comprehensive literature searches and cross-referencing for related articles. A total of 19 original articles reporting complete midline electrode data and 11 articles reporting lateral asymmetry electrode data were reviewed, which included different independent conditions that yielded 50 independent data sets. P300 amplitude differences between patients with schizophrenia and control subjects from the midline electrodes yielded effect sizes that differed among recording sites, such that Fz was significantly smaller than Pz, with Cz effect sizes smaller than Pz but larger than Fz. Comparison of P300 amplitude from the lateral data for the T3 and T4 electrodes found no reliable effect size difference when these electrodes were analyzed separately. However, comparison of P300 amplitude effect sizes from the TCP1 was significantly larger than that from the TCP2 when these electrodes were analyzed separately. P300 amplitude is smaller overall in patients with schizophrenia compared to control subjects and differs in its effect size topography across the midline and temporal electrode sites, with the strongest effect sizes obtained for the Pz midline and TCP1 lateral electrodes. PMID- 11600191 TI - Shorter REM latency associated with more sleep cycles of a shorter duration in healthy humans. AB - A significant association between rapid eye movement (REM) sleep latency and the number of non-REM/REM sleep cycles was found 15 years ago in a large retrospective study. The present prospective study further explored this intra sleep relationship and analyzed the links between these two variables and the mean cycle duration. It was based on a carefully selected group of healthy control subjects whose sleep was polysomnographically recorded at home for 4 sequential nights. The latency of REM sleep was inversely correlated with the number of cycles and positively correlated with the mean cycle duration, both in individual nights and on means of 4 nights. The present study demonstrated that variations in the number of cycles or the mean cycle duration between the nights are far less important than the substantial differences observed between subjects. Present outcomes support the study of sleep cycle periods and frequencies in those psychiatric disorders where REM sleep latencies have been found to be shorter, and they suggest that these variables be included in sleep studies in which cycles are compared with each other. PMID- 11600192 TI - Basal activity of the hypothalamic-pituitary-adrenal axis in patients with depersonalization disorder. AB - Depersonalisation disorder may occur during severe anxiety or following a traumatic event, suggesting a possible role of stress hormones. This study investigated basal activity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with depersonalisation disorder. Salivary cortisol levels were measured at four time points over 12 h in patients with depersonalisation disorder (N=13), major depressive disorder (MDD, N=14) and healthy controls (N=13). Beck Depression Inventory scores were significantly higher in depersonalised subjects than controls, while MDD subjects demonstrated higher scores than both groups. Basal cortisol levels of depersonalised subjects were significantly lower than those of MDD subjects but not healthy controls. These results point to reduced basal activity of the HPA axis in depersonalisation disorder. This pilot study supports the distinction between depersonalisation disorder and major depressive disorder which should be examined in a larger sample. PMID- 11600193 TI - CD4 down modulation on T-cells: an 'immune' checkpoint for HIV. AB - Progressive decline of an efficient immune response during the asymptomatic phase of AIDS indicates a deletion of HIV-specific cells. The deletion of HIV-specific CD4(+) T cells may occur by direct or indirect cytopathic effects of productive infection. However, preceding cell death, several important cell surface molecules, such as MHC class I or CD4, are down modulated specifically in HIV infected cells. Down modulation of the CD4 molecule on CD4(+) HIV-specific cells would abrogate efficient help to the cytotoxic arm of the immune response. Therefore, CD4 down modulation may represent an important checkpoint in HIV biology, conferring 'immune' protection to the pool of infected cells. Furthermore, down regulation of CD4 generates a population of infected T cells that should be considered as a possible reservoir for viral replication at all stages of the infection. PMID- 11600195 TI - Dehydroepiandrosterone attenuates the spontaneous elevation of serum IgE level in NC/Nga mice. AB - Dehydroepiandrosterone (DHEA) and its sulfate derivatives are known to affect host immune function; however if such hormones influence the development of atopic dermatitis has not yet been clarified. In this study, we examined the effects of DHEA on the allergic process using NC/Nga mouse, a model animal of human atopic dermatitis. The administration of DHEA profoundly suppressed the spontaneous elevation of both serum IgE and interleukin-6 levels in NC/Nga mice during the observation period. These results indicate that DHEA promotes a shift in Thl/Th2 balance toward Th1-dominant immunity, and thus may be one of the effective alternatives in treating atopic dermatitis. PMID- 11600194 TI - High serum levels of additional IL-18 forms may be reciprocally correlated with IgE levels in patients with atopic dermatitis. AB - We established an ELISA system for determination of as yet unidentified species of interleukin 18 (IL-18), named IL-18 type 2, in human serum. Serum IL-18 levels and their effect on IgE levels were examined in 18 patients with atopic dermatitis (AD) with no other allergic symptoms. Three of these patients showed high IL-18 type 2 concentrations (25-100 ng/ml) in their blood serum, and this IL 18 type 2 was detectable only with our established ELISA system. In contrast, the level of the conventional form of IL-18 (type 1) was found to be 50-400 pg/ml in all patients by the commercially available ELISA. The levels of type 1 IL-18 showed no correlation with those of type 2 and approximately 2-fold higher in AD patients than in normal subjects. IL-12 p40 and IgE levels were correlated in the patients with no IL-18 type 2, and interestingly, relatively low IgE concentrations were detected in the three IL-18 type 2-positive patients. They showed considerable levels of IL-12 p40 unlike normal subjects. The IFNgamma inducing activity of IL-18 type 2 was >100-fold less potent by weight ratio than that of a recombinant 'active' IL-18 preparation, even after the treatment with Caspase 1. Although the relationship between AD and serum IgE levels is not clear cut, IL-18 type 2 appears to play some roles in the Th2-polarization involving IgE production in association with immune responses occurring in local inflammatory milieu such as atopic lesions. PMID- 11600196 TI - The adhesion molecules, l-selectin and sialyl lewis x, relate to the formation of the follicular dendritic cell-lymphocyte cluster in the mantle zone. AB - The follicular dendritic cell (FDC)-lymphocyte cluster is rich in the follicular light zone of the secondary lymphoid follicles (LFs). Although, the mantle zone (MZ) also has FDC-lymphocyte cluster, it has not known about what kind of adhesion molecules relates to cluster formation. In the present study, we investigated whether the adhesion molecules, L-selectin (CD62L) and sialyl Lewis x (CD15s) can mediate the formation of the cluster in human tonsillar LFs. The MZ only expressed both the adhesion molecules in the secondary LF. Isolated FDC lymphocyte clusters were composed of CD62L(+) lymphocytes and CD15s(+) FDCs. Stamper-Woodruff binding assay revealed that the binding of IgD(+) lymphocytes was significantly inhibited by pretreatment with anti-CD62L antibody or with anti CD15s antibody. These results indicate that CD62L on MZ lymphocytes and CD15s on FDCs may play a role of the cluster formation, unlike the clusters in the other parts of LFs. PMID- 11600198 TI - Comparison of phage pIII, pVIII and GST as carrier proteins for peptide immunisation in Balb/c mice. AB - Carrier proteins are important for improving the efficiency of synthetic peptide vaccines. Recently, genetically-based systems such as filamentous phage display or glutathione S-transferase (GST)-fusion proteins have been employed for immunisation. Whilst these carrier systems can facilitate the evaluation of a potential vaccine by reducing the time and cost of production, their relative efficacy and the kinetics of the immune response to each carrier has not been directly compared. In this study, we have displayed the epitopes of the anti-ErbB 2 Mabs N12 (C531-A586, EP531) and N28 (T216-C235, EP216) on phage minor coat protein pIII, major coat protein pVIII and GST. Balb/c H-2(d) mice were immunised with the constructs and the sera were tested after the initial, the 3rd, 5th and 6th immunisations for an anti-peptide, an anti-ErbB-2 and an anti-carrier response. The specificity of the antibody response was also mapped using synthetic peptides. It was found that GST was the best of the three carriers, both in terms of the magnitude and the kinetics of the induced anti-peptide and anti-ErbB-2 response. Multiple (five) administrations of the immunogens were necessary to obtain a high titre of antibodies specific for ErbB-2. It was further noted that whilst an anti-EP531 response was induced using all three carriers, EP216 was not immunogenic irrespective of the carrier used. The lack of immunogenicity of EP216 implies it does not contain a H-2(d) T cell recognition site. All three carriers provide a useful system for vaccination and consequently facilitate the identification of T-cell epitopes in Balb/c inbred mice. PMID- 11600197 TI - Early IFN-gamma production is related to the presence of interleukin (IL)-18 and the absence of IL-13 in experimental Trypanosoma cruzi infections. AB - Gamma-interferon (IFN-gamma) production, the hallmark of the Th1 immune response, has been shown to play a central role in the resistance to Trypanosoma cruzi infections, in particular when produced in the very early acute infection. BALB/c mice infected with T. cruzi, Tulahuen strain, reach high parasitemias during the acute phase, and their spleen cells release IFN-gamma in the second week of the infection, while those of the resistant C3H strain produce the cytokine earlier, at 2 days post-infection (pi). We studied in the spleen cells supernatants of infected BALB/c and C3H mice, the spontaneous production of cytokines involved in the induction, interleukin (IL)-18 and IL-12 p70, as well as in the downregulation, IL-13 and IL-10, of the Th1 immune response. We found that, at 2 days pi, only C3H mice produced IL-18, while IL-12 p70 was detected in both mouse strains. Moreover, at this time pi splenocytes from BALB/c mice spontaneously produced high amounts of IL-13. At 14 days pi, despite the increased levels of IL 13 and IL-10 detected in C3H mice, they still showed high concentrations of IL-18 and IL-12 p70. In contrast, spleen cells from BALB/c mice did not secrete IL-18, IL-12 p70 and IL-13 at this time pi, but produced higher amounts of IL-10 than C3H mice. Non of these cytokines was found increased in the cell supernatants of chronically infected mice. The addition of lipopolysaccharide (LPS) or Concanavalin A (Con A) to the cell cultures did not enhance the production of IL 18 and IL-12 at the time points tested. On the other hand, at 21 days pi, when parasitemia peaked, an inhibition of both the LPS induced IL-10 release and the IL-13 production upon Con A stimulation was observed in C3H, but not in BALB/c mice. We did not find an increase of IL-18, IL-10, or IL-12 p70 in the serum of the infected mice, despite the high seric IL-12 p40 concentrations reached during the infection. The data show that the different kinetics of the production of these cytokines in the spleen of both mouse strains could have a key role in the in vivo regulation of IFN-gamma production. In these experimental models, early IFN-gamma release and thus resistance to T. cruzi infection, could be related to the combined effect of both IL-18 and IL-12p70 in the absence of IL-13. PMID- 11600199 TI - Human HSP 60 peptide responsive T cell lines are similarly present in both Behcet's disease patients and healthy controls. AB - Heat shock protein (HSP, 60/65 kDa) is investigated as a candidate autoantigen in Behcet's disease (BD), a systemic vasculitis of unknown origin, and a prominent response to 'disease-specific epitopes' of mycobacterial and human HSP60/65 is described in BD patients. In this study, long-term T cell lines from peripheral blood of BD patients (n=6) and controls (n=7) were stimulated with mycobacterial recombinant HSP and purified protein derivate (PPD) and expanded with IL-2. In the BD group, 15 out 27 and in the controls, 25 out of 35 PPD specific T cell lines have responded to the synthetic peptides of the human HSP60. Out of the primarily HSP-specific T cell lines, 17/23 in patients and 8/8 in controls did recognize a peptide of human origin. T cell lines specifically reactive to 136 150, 179-197, 244-258 and 336-351 could be raised with similar frequency in both groups. In contrast to a previous report, T cells also reacted to peptide 425-441 frequently in both groups. The results demonstrate that the human proliferative response to mycobacterial HSP may also target the self-protein in both BD patients and controls. However, the responsive T cells may have different effects depending on their functional features such as cytokine secretions. PMID- 11600200 TI - Characterization of human monoclonal antibodies selected with a hypervariable loop-deleted recombinant HIV-1(IIIB) gp120. AB - Recombinant gp120 of the HIV-1(IIIB) isolate (BH10 clone) has been mutated to form the PR12 protein with the first 74 C-terminal amino acids and the V1, V2 and V3 hypervariable loops deleted. A variety of studies have shown that the CD4 binding domain (CD4bd) is very well exposed in PR12 in contrast to rgp120(LAI). Using PR12 for selection of human monoclonal antibodies (MAbs) from HIV-infected individuals, five MAbs were generated with specificities to the epitopes overlapping the CD4bd (1570A,1570C,1570D,1595 and 1599). The three MAbs, 1570A, C and D, generated from one HIV-infected individual, represent one MAb as determined by sequence analysis of the V(H)3 region. Since the epitopes overlapping the CD4bd exhibit variability among HIV-1 clades, the specificity of anti-CD4bd MAbs were distinguished by differing patterns of binding to recombinant envelope proteins derived from clade A, B, C, D and E viruses. The PR12-selected MAbs were also compared with a panel of gp120-selected anti-CD4bd MAbs and showed a different range of specificities. MAb 1599 is clade B specific, MAb 1595 reacts with the A, B and D clades, while MAb 1570 recognises the most conserved epitope, as it binds to all proteins. The results show that the exposure of different epitopes in the CD4bd of the PR12 protein allows this protein to serve as an immunogen and to induce anti-CD4bd antibodies. PMID- 11600201 TI - Enhanced IL-18 expression in common skin tumors. AB - Interleukin-18 (IL-18) has been found to have multiple effects upon various cells involved in inflammatory response. Recently we reported that B16 murine melanoma cells are able to produce IL-18, which is involved in the regulation of intracellular reactive oxygen intermediates (ROI) and Fas-ligand expression, indicating that IL-18 plays key role in the tumor activity of melanoma. In this study, we investigated the pattern of IL-18 expression in the human system. IL-18 production was tested by enzyme linked immunosorbent assay (ELISA) assay in various tumor cell lines, including Raji (Burkitt's lymphoma), IM-9 (B lymphoblast), Jurkat (acute T cell leukemia), SK-MES-1 (squamous cell carcinoma (SCC) cell line), SK-MEL-2, G-361, DM-4, and DX-3 (melanoma cell lines). ELISA tests showed that IL-18 was highly expressed in malignant skin tumors such as SK MES-1, SK-MEL-2, G-361, DM-4, and DX-3 cell lines, thus suggesting that IL-18 production may be associated with the malignancy of skin tumors. Here, we report that enhanced IL-18 expression is positively correlated with malignant skin tumors such as SCC and melanoma, suggesting the importance role of IL-18 in malignancy of skin tumors. Taken together, expression of IL-18 by tumor cells in human skin tissue may provide an important clue to understand the pathogenesis of malignant skin tumors. PMID- 11600202 TI - Activation of mouse macrophage by soluble endogenous murine leukemia virus (MuLV) envelope protein. AB - We identified recently an endogenous murine leukemia virus (MuLV) envelope protein as a new autoantigen reactive with autoimmune diabetic mouse sera and observed immunosuppressive activity of this envelope protein. In the present study, to elucidate the mechanism involved, we treated macrophages with the envelope protein and investigated activation of macrophage. We found enhancements of iNOS mRNA and nitrite in envelope protein-treated RAW264.7 cells and peritoneal macrophages. The stimulation was highly envelope protein-specific, and also time- and dose-dependent. The activation pattern was similar to that elicited by lipopolysaccharide (LPS) since the envelope protein showed a synergistic effect on macrophage activation in conjunction with interferon gamma (IFN-gamma). Furthermore, deacylated LPS as a competitive inhibitor of LPS showed inhibition of envelope protein-mediated macrophage activation. These data show that MuLV envelope protein can be a new macrophage activator and suggest that the retroviral envelope protein may elicit immunosuppressive activity through macrophage activation. PMID- 11600203 TI - Detection of Fcgamma binding protein antigen in human sera and its relation with autoimmune diseases. AB - Intestinal goblet cells of patients with ulcerative colitis and Crohn's disease highly express a binding protein of the Fc portion of IgG (FcgammaBP), which is entirely different from the Fcgamma receptors I,II, and III on neutrophils and macrophages. In this study, we proved the qualitative existence of FcgammaBP antigen in the sera of patients with rheumatoid arthritis and systemic lupus erythematosus, and, further, established a highly sensitive and quantitatively reproducible assay for FcgammaBP antigen in order to prevent the cross-reactivity of FcgammaBP with von Willebrand factor which has about 30% homology. This assay revealed a higher level of FcgammaBP antigen in the blood stream of patients with autoimmune diseases, especially progressive systemic sclerosis. This would suggest that abnormal production of autoantibodies reflects increased generation of FcgammaBP in goblet cells and its secretion into the circulation by an unknown mechanism. PMID- 11600204 TI - Parathyroid hormone-related protein and lung injury after pulmonary thromboendarterectomy. AB - Parathyroid hormone-related protein (PTHrP) is an autocrine growth and differentiation factor for alveolar type II epithelial cells. Type II cells secrete pulmonary surfactant and are pluripotent cells with a role in alveolar epithelial repair after lung injury. The goals of this study were to investigate whether the levels of PTHrP in bronchoalveolar lavage liquid (BAL) varied between patients who did and did not develop lung injury after pulmonary thromboendarterectomy (PTE). BAL was performed in 48 patients undergoing PTE for unresolved pulmonary emboli. Samples were obtained following induction of anesthesia, following separation from cardiopulmonary bypass, and 48 h postoperatively. PTHrP was measured by radioimmunoassay. Lung injury was diagnosed in 23 patients on the basis of hypoxemia (PaO(2)/FIO(2) < 300) and the presence of lung infiltrates in the absence of infection or atelectasis. Patients with lung injury had significantly lower preoperative BAL levels of PTHrP, 21 (21 30) pg/ml (median, interquartile gap), compared to patients without lung injury, 34 (21-41) pg/ml (P < 0.05). Preoperative BAL PTHrP levels < 32 pg/ml predicted lung injury with a positive predictive value of 60% and negative predictive value of 82%. The odds of developing lung injury for patients with preoperative PTHrP levels below this cutpoint were 6 times the odds for patients with higher levels. PMID- 11600205 TI - Gestational regulation of the gene expression of C-type natriuretic peptide in mouse reproductive and embryonic tissue. AB - C-Type natriuretic peptide (CNP) is a vasoactive hormone and the endothelial component of the natriuretic peptide system. We examined the expression of CNP in mouse reproductive organs and embryos at different stages of gestation. Pregnant mice were killed and embryos were dissected on gestational days 9.5, 12.5, 15.5, 18.5 postconceptionem (pc) and at term. Nonpregnant mice were used as controls. Total RNA was isolated from placenta, ovaries, myometrium and from head and trunk of embryos and neonates. CNP-mRNA was quantified by ribonuclease-protection assay (RPA). Uterine CNP-mRNA concentrations increase during pregnancy up to the sevenfold concentration, whereas in the ovaries these levels decrease to 10% compared to nonpregnant controls. In the placenta, a peak of CNP expression has been observed around day 15.5 pc, whereby placenta showed the strongest CNP signals. CNP-mRNA concentrations in embryos are gestational age-dependent with a high level at day 9.5 pc in head and trunk. These results indicate that CNP has a regulatory function in pregnancy and embryonic development. PMID- 11600207 TI - Accentuation of ANP secretion to endothelin-1 in hypertrophied atria. AB - To investigate modulation of ANP secretion by atrial hypertrophy, the secretion of ANP in response to stretch and endothelin-1 was studied using isolated perfused quiescent atria from rats treated with monocrotaline (MCT). Male Sprague Dawley rats were given a single subcutaneous injection of 50 mg/kg MCT or saline and were sacrificed at 6 weeks. Rats with right heart hypertrophy showed an increase in ANP mRNA and decrease in tissue concentration of ANP in hypertrophied atria and a marked increase in plasma concentration of ANP. In isolated perfused hypertrophied right atria from MCT rats, changes in atrial volume induced by increased atrial pressure caused proportional increases in mechanically stimulated extracellular fluid (ECF) translocation and stretch-activated ANP secretion. Changes in atrial volume and mechanically stimulated ECF translocation in hypertrophied right atria were not different from those in control right atria. The stretch-activated ANP secretion was suppressed without significant difference in basal ANP secretion, as compared to control right atria. Therefore, the stretch-activated ANP secretion from hypertrophied right atria into the atrial lumen in relation to the ECF translocation (ANP concentration in the interstitium) was lower than that from control atria. A positive correlation between the stretch-activated ANP secretion in relation to the ECF translocation and tissue ANP content was found in control atria but not in hypertrophied atria. Endothelin-1 caused increases in stretch-activated ANP secretion in a dose dependent manner, which were accentuated in hypertrophied right atria. Therefore, we suggest that atrial hypertrophy causes an attenuated response to stretch and accentuated response to endothelin-1 of ANP secretion. PMID- 11600206 TI - Characterisation of a new chimeric ligand for galanin receptors: galanin(1-13)-[D Trp(32)]-neuropeptide Y(25-36)amide. AB - In this work, we studied a novel chimeric peptide, M242, galanin(1-13)-[D Trp(32)]-neuropeptide Y(25-36)amide, and examined its properties in comparison with its parent peptide, M32, galanin(1-13)-neuropeptide Y(25-36)amide, a previously known high-affinity ligand for galanin receptors, and galanin itself. Binding assays performed in Bowes cells known to express human galanin receptor type 1 (hGalR1) and in Chinese hamster ovary cells overexpressing human galanin receptor type 2 (hGalR2) revealed that all three ligands had comparable affinities: at hGalR1<1 nM and at hGalR2<10 nM. However, in rat hippocampal membranes M242 had a 24-fold lower affinity than galanin (9.4 vs. 0.4 nM) and 134 fold lower affinity than M32 (9.4 vs. 0.07 nM). In the same tissue, we also examined the effects of these peptides on adenylate cyclase activity. M32 showed a weak antagonistic behaviour but M242 acted as a potent biphasic regulator of adenylate cyclase. In conclusion, we present and characterise a new peptide M242, which could be a useful tool in studies of galaninergic signalling. PMID- 11600208 TI - Endothelin-1 induces contraction of human and Australian possum gallbladder in vitro. AB - BACKGROUND: Endothelin-1 (ET-1) stimulates guinea pig gallbladder (GB) muscle strip contractility; however, the role and source of ET-1 in the GB remains to be elucidated. AIMS: To determine the effect of ET-1 on human and possum GB muscle strip contractility and evaluate whether ET-1 is present in GB tissue. METHODS: GB muscle strips were mounted in organ baths to measure isometric tension. ET-1 was added cumulatively with and without pretreatment with the neural blocker tetrodotoxin (TTX) or the ET receptor antagonists BQ-123, BQ-788, and tezosentan. Immunohistochemical localization of ET was performed on freshly fixed and cultured GBs. RESULTS: ET-1 induced concentration-dependent increases in tone in human and possum GB strips (p<0.05). This response was unaffected by BQ-123, BQ 788, and TTX but antagonized by BQ-123+BQ-788 in the human tissue only. Tezosentan (10(-4) mol/l) blocked the ET-1-induced response in human and possum GB strips (p<0.001). Although ET immunoreactivity was absent in freshly fixed possum GB, immunoreactivity was observed in the GB epithelium of freshly fixed human tissue and in both possum and human tissue following 24 h of organ culture. CONCLUSION: ET-1 acts directly on human and possum GB smooth muscle producing contractions, possibly via ET-B receptors. ET may be present under pathophysiological conditions altering GB function. PMID- 11600209 TI - Increased AT(1) receptors in adrenal gland of AT(2) receptor gene-disrupted mice. AB - Angiotensin II (Ang II) AT(2) receptor-gene disrupted mice have increased systemic blood pressure and response to exogenous Angiotensin II. To clarify the mechanism of these changes, we studied adrenal AT(1) receptor expression and mRNA by receptor autoradiography and in situ hybridization in female AT(2) receptor gene disrupted mice (agtr 2-/-) and wild-type controls (agtr 2+/+). We found high expression of AT(1) receptor binding and mRNA in adrenal zona glomerulosa of female wild-type mice. AT(2) receptors and mRNA were highly expressed in adrenal medulla of wild-type mice, but were not detected in zona glomerulosa. There was no AT(2) receptor binding or mRNA in adrenal glands of AT(2) receptor-gene disrupted mice. In these animals, AT(1) receptor binding and mRNA were increased in adrenal zona glomerulosa and AT(1) receptor mRNA was increased in the adrenal medulla when compared with wild-type animals.The present data support the hypothesis of an interaction or cross talk between AT(2) and AT(1) receptors in adrenal gland. The significant increase in AT(1) receptor expression in the absence of AT(2) receptor transcription may be partially responsible for the increased blood pressure and for the enhanced response to exogenously administered Angiotensin II in this model. PMID- 11600210 TI - Editorial. Anthropology and genetic markers. PMID- 11600211 TI - Letter from the ASHI president and council. PMID- 11600212 TI - Distinct mRNA microarray profiles of tolerogenic dendritic cells. AB - Dendritic cells are crucial to the activation as well as suppression of the immune response. Previous reports have illustrated that APC interacting with antigen-specific T suppressor cells become tolerogenic, inducing T helper anergy. To characterize the molecular changes occurring in tolerogenic APC, the mRNA profile of KG-1 dendritic cells exposed to allospecific T helper and T suppressor cells were analyzed. This study now provides evidence that immature dendritic cells stimulated by T suppressor cells differentiate into mature dendritic cells with a distinct phenotype. The identification of Ts induced pathways of dendritic cell differentiation is critical to the development of new therapeutic strategies. PMID- 11600213 TI - Differential expression of the efflux pumps P-glycoprotein and multidrug resistance-associated protein in human monocyte-derived dendritic cells. AB - P-glycoprotein (P-gp), an ATP-binding cassette (ABC) drug efflux pump, has been recently shown to play an important role in the physiology of Langherans cells, a subtype of dendritic cells (DC) found in the skin. The present study was designed to investigate expression and activity of P-gp and of multidrug resistance associated protein (MRP), another ABC efflux pump sharing numerous substrates with P-gp, in human monocyte-derived DC. Immunolabeling experiments and dye efflux assays indicated that such cells displayed elevated levels of MRP activity and expression when compared to those present in parental monocytes. Generation of DC from monocytes in the presence of the MRP inhibitor indomethacin did not, however, alter the capacity of DC to stimulate allogeneic T cells proliferation in mixed lymphocyte reaction. In addition, indomethacin did not inhibit the up regulation of the CD1a, a marker occurring during the differentiation of monocytes into DC. In contrast to that of MRP, functional expression of P-gp was not detected in monocyte-derived DC. Such antigen presenting cells that constitute a promising tool for antitumor vaccinal therapy therefore display differential expression of the efflux pumps P-gp and MRP. PMID- 11600214 TI - Expression of cathepsins B, L, S, and D by gastric epithelial cells implicates them as antigen presenting cells in local immune responses. AB - Helicobacter pylori infection is linked to chronic gastritis, peptic ulcer and gastric carcinoma. During H. pylori infection, class II MHC expression by the gastric epithelium increases, as does the number of local CD4(+) T cells, which appear to be important in the associated pathogenesis. These observations suggested that the epithelium might present antigens to T cells. Thus, we sought to determine whether gastric epithelial cells process antigens to establish their function as local antigen presenting cells (APC). We examined a panel of gastric epithelial cell lines for expression of the antigen processing cathepsins B (CB), L (CL), S (CS), and D (CD). The mRNA for these enzymes were detected by RT-PCR and the enzymes in the gastric epithelial cells were identified by various independent methods. We corroborated the expression of CB and CD on gastric epithelial cells from human biopsy samples. The functions of these proteases were confirmed by assessing their ability to digest ovalbumin, a conventional dietary antigen, and proteins from H. pylori. In summary, multiple lines of evidence suggest gastric epithelial cells process antigens for presentation to CD4(+) T cells. To our knowledge, these are the first studies to document the antigen processing capacity of human gastric epithelial cells. PMID- 11600215 TI - A new method for in vitro expansion of cytotoxic human CD3-CD56+ natural killer cells. AB - Adoptive transfer of immunocompetent cells may induce anti-tumor effects in vivo. However, a significant obstacle to the development of successful cellular immunotherapy has been the availability of appropriate cytotoxic cells. Among the immunologic effector cells that are considered mediators of anti-tumor effects, those with the highest per-cell cytotoxic capacity express a natural killer (NK) cell phenotype, i.e., CD56(+)CD3(-). However, such cells are normally present only in low numbers in peripheral blood mononuclear cells (PBMCs), lymphokine activated killer (LAK), and cytokine induced killer (CIK) cell preparations. To optimize the expansion of human NK cells, PBMCs were cultured in different serum free medium supplemented with monoclonal anti-CD3 antibodies and interleukin (IL) 2 at varying concentrations. By using Cellgro stem cell growth medium supplemented with 5% human serum and IL-2 (500 U/ml) cells expanded 193-fold (median, range 21-277) after 21 days, and contained 55% (median, range 7-92) CD3( )CD56(+) cells. The remaining cells were CD3(+) T cells, 22% (median, range 2-68) of which co-expressed CD56. The expanded cell population lysed 26 to 45% of K562 targets in a 1:1 effector to target ratio, signifying substantial cytotoxic efficacy. The described method is a simple and efficient way of expanding and enriching human NK cells. We have termed these high-yield CD3(-)CD56(+) cells cytokine-induced natural killer (CINK) cells. PMID- 11600216 TI - HLA-DQ8 transgenic and NOD mice recognize different epitopes within the cytoplasmic region of the tyrosine phosphatase-like molecule, IA-2. AB - Type 1 diabetes mellitus is strongly associated with HLA-DQ8 in humans and I A(g7) in the NOD mouse. The disease is characterized by loss of tolerance to auto antigens such as GAD, insulin, and the protein tyrosine phosphatase-like molecule, IA-2. We identified T cell epitopes on the intracytoplasmic region of IA-2 by immunizing DQ8/NOD, DQ8/B10, and NOD mice with overlapping 18 mer peptides in CFA. We identified four peptides presented both by DQ8 and NOD, five DQ8 specific peptides, and six NOD specific peptides. Both mouse lines failed to respond to ten peptides. We demonstrated MHC class II and CD4 restriction of proliferative responses using appropriate blocking antibodies. To understand the role of non-MHC genes in the generation of immune response to the islet auto antigen, we evaluated cytokine secretion following immunization of DQ8 transgenic mice with strongly immunogenic peptides. The NOD background resulted in increased secretion of cytokines. In conclusion, we have identified IA-2 peptides that induce lymphoproliferative responses in DQ8 transgenic and NOD mice and shown that these peptides stimulate production of Th1 and Th2 cytokines. PMID- 11600217 TI - Low prevalence of GAD and IA2 antibodies in schoolchildren from a village in the southwestern section of the Netherlands. AB - Glutamic acid decarboxylase (GAD) and insulinoma antigen 2 (IA2) antibodies are increasingly used as a tool to predict type I diabetes in children and as a differential diagnostic tool to distinguish type I and type II diabetes in adults. However, the background frequency of these antibodies in the general population has not been extensively studied and may differ between countries. The current study aims to establish the frequency of GAD and IA2 antibodies in an unselected population of schoolchildren and confirm the previously reported low prevalence of islet cell antibodies (ICA) in the general Dutch population. The study population consisted of 1403 unselected schoolchildren. All children were tested for GAD antibodies, and 1085 children were analyzed for IA2 antibodies by radiobinding assay. Development of diabetes was recorded during a 7-year follow up. Five children (0.4%) were positive for GAD antibodies, one child (0.1%) was positive for IA2 antibodies. Two children developed diabetes during follow-up, one was positive for GAD antibodies only, the second was positive for both GAD and IA2 antibodies. The frequency of GAD and IA2 antibodies in the southwestern part of The Netherlands is low. This observation is in concordance with earlier studies on ICA in Dutch schoolchildren. For future diabetes prediction and intervention trials it is important to establish the background frequencies and predictive power of antibody screening in different populations. PMID- 11600218 TI - Disappearance of clonally expanded T cells after allogeneic leukocyte immunotherapy in peripheral blood of patients with habitual abortion. AB - Allogeneic leukocyte immunotherapy is often used to improve fertility of patients with habitual abortion (HA), which probably acts through immune-mediated mechanisms. However, the involvement of T cells is not clear. This study examined the effect of allogeneic immunotherapy on T cells of patients with HA. Peripheral blood mononuclear cells were obtained from 5 healthy women and 14 women with HA. RNA was isolated from mononuclear blood cells. Reverse transcription-polymerase chain reaction (RT-PCR), followed by single-strand conformational polymorphism (SSCP) were used to analyze the gene segments of T-cell receptor beta chain (TCRbetaV) variable regions. Oligoclonal accumulation of T cells was identified in peripheral blood of nonpregnant patients with a history of HA. It was also revealed, however, that immunostimulation reduced the number of accumulating T cell clones (p = 0.0004). The results, together with the clinical effectiveness of immunotherapy, suggest that accumulation of T-cell clonotypes, which probably resulted from antigenic stimulation, is involved in the pathogenesis of HA. PMID- 11600219 TI - Anti-neutrophil cytoplasmic antibodies in echinococcus granulosus hydatid disease. AB - The authors studied the presence of ANCA, evaluated by indirect immunofluorescence (IIF) and ELISA for anti-lactoferrin (LF), and anti myeloperoxidase antibodies (anti-MPO), in sera of 69 patients with cystic echinococcosis (CE). According to Caremani's classification, 27 patients were considered to have active cysts and 42 patients were considered to have inactive cysts. ANCA were detected in 9 out of 27 patients (33.3%) with active cysts and in 3 out of 42 patients (7.1%) with inactive cysts. Differences between the two groups were statistically significant (P < 0.05). Anti-LF antibodies were found in seven patients (10.14%) and anti-MPO antibodies in ten patients (14.5%). PMID- 11600220 TI - Antigen, allele, and haplotype frequencies report of the ASHI minority antigens workshops: part 1, African-Americans. AB - HLA typing was performed on 977 African Americans residing throughout most of the United States. Class I and class II antigens and class II alleles were defined for all individuals and class I alleles were determined for a subset of individuals. The occurrence of 854 of the individuals in family groups permitted direct counting of allele and haplotype frequencies. The data were analyzed for antigen, allele, and haplotype frequencies; recombination frequencies; segregation distortion; distribution of haplotype frequencies; linkage disequilibria; and geographic distribution of DR antigens. Tables of the antigen, allele, the most common two and three point haplotypes, and 88 extended haplotypes that include class I and class II alleles are presented. Notable findings include a lower than expected frequency of recombination between the B and DR loci (theta= 0.0013), lower than expected frequency of inheritance (44.5% vs 54.5%) of the DRB1*1503; DQB1*0602 haplotype, lower than anticipated linkage disequilibrium values for DR; DQ haplotypes, and a skewed geographic distribution of DR antigens. PMID- 11600221 TI - Structural characterization of two CD1A allelic variants. AB - CD1 molecules are specialized in presenting lipidic antigens to T lymphocytes. They are structurally and evolutionary related to MHC molecules and show very limited polymorphism. We have previously described and partially characterized a new human CD1A allele differing from the wild type CD1A by a substitution of Cysteine by Tryptophan at position 52 in the alpha1 domain of the CD1A molecule. The frequency of this allele varies from 10% in individuals of Caucasian origin to 56% in Chinese people. The aim of the present work was to structurally characterize this CD1A allele. To do this we have cloned and sequenced the full length cDNA encoding the new CD1A allele. The cDNA sequence of this allele encodes a protein differing the wild type in two amino acids at positions 14 (Threonine versus Isoleucine) and 52 (Cysteine versus Tryptophan). The cDNAs encoding both wild type and mutant CD1A were cloned in the expression vector pSRalphaNeo and transfected into C1R and L721.221 cells. Cell surface expression of the protein products in transfected cell lines were analyzed by flow cytometry and immunoprecipitation using CD1a-specific monoclonal antibodies. Our results indicate that both allelic products are efficiently expressed on the cell surface. PMID- 11600222 TI - HLA-B*44 allele frequencies and haplotypic associations in Koreans. AB - We have investigated the frequencies of HLA-B*44 alleles and their haplotypic associations with HLA-A, -C, and -DRB1 loci in 450 healthy unrelated Koreans, including 213 parents from 107 families. All 79 samples (17.6%) typed as B44 by serology were analyzed for B*44 alleles using polymerase chain reaction (PCR) single-strand conformation polymorphism (SSCP) method. A total of three different B*44 alleles were detected: B*44031 (allele frequency 4.7%), B*44032 (3.1%), and B*4402 (1.3%). Three characteristic haplotypes revealing strong linkage disequilibrium were A*3303-Cw*1403-B*44031-DRB1*1302 (3.6%), A*3303-Cw*07-B*44032 DRB1*0701 (2.8%), and A*3201-Cw*05-B*4402-DRB1*0405 (0.4%). In addition, a strong association was observed for B*4402 with A*0301. The B*4403-bearing haplotypes of Koreans appear to be relatively common in Asian populations, whereas the B*4402 bearing haplotypes share some similarity to those of Caucasians. HLA-B44 alleles demonstrate a limited allelic diversity and comprise distinctive extended haplotypes in the Korean population. It is suggested that the frequencies of B44 subtype mismatches among ABDRB1-matched unrelated donor-recipient pairs would be low in this population. PMID- 11600223 TI - Tumor necrosis factor receptor 2 polymorphism in systemic lupus erythematosus: no association with disease. AB - Genetic factors and immune dysregulation play important roles in the development of systemic lupus erythematosus (SLE). Tumor necrosis factor receptor 2 (TNFR2) is suggested to be involved in the development of SLE because its genetic locus (1p36) encompasses one of the susceptible loci for SLE and its ligand (TNF) is associated with SLE. To investigate the role of TNFR2 in the pathogenesis of SLE, 139 Korean patients were genotyped with SLE, 137 healthy control subjects were genotyped for TNFR2 196 R/M polymorphism in exon 6 with PCR-SSCP, and the clinical characteristics of SLE were analyzed according to the genotypes. The genotype frequencies of 196 R/R, 196 R/M, and 196 M/M were 3.6%, 30.9%, and 65.5% in SLE patients and 4.4%, 26.3%, and 69.3% in healthy controls (p = 0.676). The allelic frequency of 196 R was 19.1% in SLE patients and 17.5% in healthy controls (p = 0.638, odds ratio = 1.109, and the 95% confidence interval = 0.720 1.708). The clinical characteristics were not different according to the genotypes. In conclusion, no skewed distribution of TNFR2 196 R/M polymorphism was found in Korean patients with SLE compared with healthy controls. Further studies in other populations will be needed to elucidate the role of the TNFR2 polymorphism in the development of SLE. PMID- 11600224 TI - Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer. AB - Human papillomaviruses type 16 and 18 are the major cause of cervical cancer. However, genetic factors contribute to the propensity of persistent HPV infection and cervical carcinoma. Allelic variants of the human leukocyte genes have shown to be associated with cervical neoplasia. The strongest associations have been found with the genes in the HLA class II region. The aim of this study was to analyze the association of two non-HLA class II markers with invasive cervical cancer. Microsatellite polymorphism of the TNFA gene located in the class III region and a short tandem repeat polymorphism of the MICA gene located in the centromeric end of the HLA class I region were analyzed. Eighty-five patients and 120 matched control individuals from a population-based cohort from Northern Sweden participated in this nested case-control study. MICA was not associated with cervical carcinoma. TNFa-11 frequency was increased in the HPV18 DNA positive patients (OR = 2.84, p = 0.0481, CI = 1.04-7.78, pc = NS). TNFa-11 was not associated with susceptibility to HPV16 infection, but it increased the risk for cervical cancer with the HLA DQ6 (DQA 1*0102-DQB 1*0602) haplotype. Our findings indicate that the association of TNFA with cervical cancer is different with CIN. The extended HLA DQ6-TNFa-11 haplotype is increasing the risk for development of cervical cancer significantly (OR = 3.08, p = 0.0104, CI = 1.30 7.31). PMID- 11600225 TI - Signal transduction events in human peripheral blood mononuclear cells stimulated by Schistosoma mansoni antigens. AB - Activation of protein tyrosine kinases (PTKs) is a common step of T cell stimulation. However, the relationship between PTKs and activation of peripheral blood mononuclear cells (PBMC) from intestinal chronic schistosomiasis patients has not been explored yet. In this study, we investigated the participation of Lck and ZAP-70 protein tyrosine kinases (PTKs), as well as PLC-gamma1 and Shc proteins in PBMC activation by Schistosoma mansoni antigens. PBMC were stimulated with SEA (soluble egg antigen) or SWAP (soluble worm preparation), lysed, precipitated with specific antibodies and the level of tyrosine phosphorylation evaluated. Our results show that Lck and Shc were phosphorylated upon stimulation of the cells with SWAP, as well as with SEA. However, the phosphorylation level was more pronounced in SWAP than in SEA-stimulated cells. Phosphorylation of ZAP 70 was observed only in SWAP stimulated cells. Additionally, PLC-gamma1 phosphorylation was not observed in PBMC stimulated with SEA. Together, these results indicate that SEA and SWAP induce PBMC proliferation through distinct intracellular signaling pathways. Moreover, the weaker response of PBMC to SEA compared to SWAP stimulation suggests down-regulation of cells from intestinal chronic schistosomiasis patients to SEA, which may occur during immunomodulation to S. mansoni response. PMID- 11600226 TI - Expression and function of TRAF-3 splice-variant isoforms in human lymphoma cell lines. AB - TRAF-3 gene products are signaling adaptor molecules required for lymphocytes to mediate T-dependent antibody responses in vivo. Previous work identified 8 splice variant TRAF-3 mRNA species by RT-PCR that have the potential to encode novel isoforms, seven of which induce NF-kappaB activation when over-expressed in 293 cells. Here, their expression was characterized by RNAse protection assay, which showed the T cell line Jurkat D1.1 and the B cell lines BJAB, Daudi, and Raji each expressed mRNA encoding TRAF-3 splice-variants in approximately the same rank order (from highest to lowest); TRAF-3 Delta103aa, Delta83aa, full-length, Delta25aa, Delta52aa, Delta56aa, Delta27aa, and Delta221aa mRNA. The TRAF-3 Delta130aa mRNA was not detectable in any of the cell lines examined. The functional effect of over-expressing each TRAF-3 splice-variant on NF-kappaB activation was studied in the TRAF-5-responsive B cell line, BJAB. Of the seven TRAF-3 splice-variant isoforms that induce NF-kappaB activation in 293 cells, only TRAF-3 Delta27aa, Delta103aa, or Delta130aa induce NF-kappaB activation in BJAB cells. Together, these data indicate that a number of TRAF-3 splice-variant mRNAs are expressed and function in B and T lymphoma lines, which suggests that certain TRAF-3 splice-variant isoforms may participate in mediating the known functions of the TRAF-3 gene in lymphocytes. PMID- 11600227 TI - A comparison of enzyme-linked immunoabsorbent assays and flow cytometry techniques for the detection of HLA specific antibodies. AB - LATM, Quikscreen (QS), and B-Screen (QSB) are ELISA-based tests for the detection of HLA specific antibodies. FlowPRA beads are microparticles coated with HLA antigens for the detection of HLA specific antibodies by flow cytometry. The aim of this study was to evaluate the sensitivity and specificity of the LATM, QS, QSB, and FlowPRA screening tests. One hundred sixty-three sera from renal transplant patients were tested using LATM, FlowPRA, QS, and QSB. Discrepant results were further investigated using complement dependent cytotoxicity, QuikID, and PRA-STAT. When QS was compared with LATMI and FlowPRAI for the detection of HLA class I specific antibodies the overall concordance was 82.8% with no particular specificity missed by any one test. Comparing QSB with LATMII and FlowPRAII, for the detection of HLA class II specific antibodies, there was 90.7% concordance. Although the overall concordance was better for class II specific antibodies, QSB failed to detect antibodies to HLA-DQ in a number of samples from different patients. Of the methods tested, flow cytometry using FlowPRA beads appeared to be the most sensitive and specific, missing the least number of specificities. However, the ELISA methods offer the advantage of being more suitable for testing large numbers of samples in a more time- and cost effective manner. PMID- 11600229 TI - Prodrug strategies in cancer therapy. AB - Systemic cytotoxic (anti-proliferative) anticancer drugs rely primarily for their therapeutic effect on cytokinetic differences between cancer and normal cells. One approach aimed at improving the selectivity of tumour cell killing by such compounds is the use of less toxic prodrug forms that can be selectively activated in tumour tissue (tumour-activated prodrugs; TAP). There are several mechanisms potentially exploitable for selective activation. Some utilise unique aspects of tumour physiology such as selective enzyme expression, hypoxia, and low extracellular pH. Others are based on tumour-specific delivery techniques, including activation of prodrugs by exogenous enzymes delivered to tumour cells via monoclonal antibodies (ADEPT), or generated in tumour cells from DNA constructs containing the corresponding gene (GDEPT). Because only a small proportion of the tumour cells may be competent to activate the prodrug, whichever activating mechanism is used, TAP need to be capable of killing activation-incompetent cells as well via a "bystander effect", in order to fully exploit these "activator" cells. A wide variety of chemistries have been explored for the selective activation of TAP. These include reduction of quinones, N oxides, nitroaromatics and metal complexes by endogenous enzymes or radiation, amide cleavage by endogenous peptidases, and metabolism by a variety of exogenous enzymes, including phosphatases, kinases, amidases and glycosidases. PMID- 11600230 TI - Novel inhibitors of the sodium-calcium exchanger: benzene ring analogues of N guanidino substituted amiloride derivatives. AB - A series of N-guanidino substituted 2,4-diamino-5-carbonylguanidine molecules related to amiloride were synthesised and evaluated for their ability to inhibit the sodium-calcium exchanger in rat insulinoma cells (RINm5F) and human platelets. Specific chemical pathways were used to prepare the benzene derivatives designed as bioisosteric analogues of the pyrazine derivatives of amiloride. Several so-called 'simplified analogues', where some substituents of amiloride were omitted or replaced, were also prepared and included in the biological evaluation. The inhibitory potency of the sodium-calcium exchanger was screened on both cell types by measuring their effect on 45Ca(2+) uptake. Among the most active compounds, N-(2-amino-5-chloro-4-nitrobenzoyl)-N'-(1 naphtylmethyl)guanidine (IC(50)=3.4 microM) was found more active than amiloride (IC(50)=690 microM) and 3,4-dichlorobenzamil (IC(50)=15.2 microM), the reference inhibitor. PMID- 11600231 TI - Synthesis and antibacterial screening of hydrazones, Schiff and Mannich bases of isatin derivatives. AB - Schiff bases and hydrazones of substituted isatins (1-28) were prepared by reacting isatin and aromatic primary amines/hydrazines. A new series of the corresponding N-Mannich base (29-35) was synthesised by reacting them with formaldehyde and diphenyl amine. The chemical structures were confirmed by means of 1H-NMR, IR spectral data and elemental analysis. The compounds were screened for antibacterial activity against seven Gram (+) and seven Gram (-) standard and pathological bacterial strains by the paper disc diffusion technique. The minimum inhibitory concentrations of the active compounds were determined. 1-Diphenyl amino-methyl-3-(4-bromo phenylimino)-1,3-dihydro-indol-3-one (30) and 3-(4-bromo phenylimino)-5-nitro-1,3-dihydro-indol-3-one (13) were found to be the most active compounds of the series. Mannich bases exhibited higher activity than the corresponding Schiff bases. PMID- 11600232 TI - Novel phthalazinone and benzoxazinone containing thiazolidinediones as antidiabetic and hypolipidemic agents. AB - We report here the synthesis of a series of 5-[4-[2-[substituted phthalazinones 2(or 4)yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and 5-[4-[2-[2,3 benzoxazine-4-one-2-yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and their plasma glucose and plasma triglyceride lowering activity in db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. In vitro and in vivo pharmacological studies showed that the phthalazinone analogue has better activity. PHT46 (compound 5a), the best compound in this series, showed better in vitro PPARgamma transactivation potential than troglitazone and pioglitazone. In insulin resistant db/db mice, PHT46 showed better plasma glucose and triglyceride lowering activity than the standard drugs. Pharmacokinetic study in Wistar rats showed good systemic exposure of PHT46. Subchronic toxicity study in Wistar rats did not show any treatment-related adverse effect. PMID- 11600234 TI - Synthesis of novel tetrahydroimidazole derivatives and studies for their biological properties. AB - Ethylenediamine was reacted with suitable aromatic aldehydes in order to prepare their respective diSchiff bases. These compounds were then reduced to give the corresponding tetrahydrodiSchiff bases, which were low melting in nature. Finally, these derivatives were condensed with different aromatic aldehydes to give the desired tetrahydroimidazoles. The structures of all these compounds were established on the basis of spectral data. These novel tetrahydroimidazoles showed promising anti-inflammatory and analgesic activity. The compounds were also screened for their anti-bacterial property against Staphylococcus aureus and Escherichia coli. PMID- 11600233 TI - New anti-inflammatory N-pyridinyl(alkyl)phthalimides acting as tumour necrosis factor-alpha production inhibitors. AB - This paper describes the synthesis of N-pyridinyl(alkyl)phthalimides related to N phenyl-4,5,6,7-tetrafluorophthalimides known to be inhibitors of tumour necrosis factor-alpha (TNFalpha) production. Pharmacomodulation at the phthalimidic nitrogen led to the selection of two pharmacophoric fragments (2,4-lutidinyl and beta-picolyl), allowing significant inhibition of TNFalpha production (compounds 12 and 17). Variation of the substituents linked to the homocycle of their phthalimide scaffold indicated that high (TNFalpha production) inhibitory potency could be achieved, notably by 5-fluoro, 4- or 5-nitro, 5-amino and especially tetrafluoro substitution. The most active compound, N-(pyridin-3-ylmethyl) 4,5,6,7-tetrafluorophthalimide (32) (84% inhibition at 10 microM), also produced an anti-oedematous effect in the PMA-induced mouse-ear swelling test. Although less active than dexamethasone, it exerted a marked reduction in ear thickness after oral administration (63% vs. 85% for dexamethasone at 0.2 mMkg(-1)) and remained efficient after topical application (46% vs. 96% for the dexamethasone). It also induced potent inhibition in the rat carrageenan foot oedema test with an ID(50) (0.14 microMkg(-1)) comparable with that of N-(2,6 diisopropylphenyl)phthalimide (4) (0.15 microMkg(-1)). PMID- 11600235 TI - Synthesis and steroid sulphatase inhibitory activity of C19- and C21-steroidal derivatives bearing a benzyl-inhibiting group. AB - Two series of compounds, benzyl alkylated at position 17alpha and 20 of androstane and pregnane, respectively, were synthesised and tested for steroid sulphatase inhibition. We compared the ability of the compounds to inhibit steroid sulphatase obtained from two different sources (homogenates of transfected HEK-293 cells and Jeg-3 cells) and with two types of substrate (DHEAS or E(1)S). The inhibitory activity of 17alpha-benzyl-5alpha-androstane 3beta,17beta-diol (7), 17alpha-benzyl-5-androstene-3beta,17beta-diol (9), 17alpha benzyl-4,17beta-dihydroxy-4-androsten-3-one (15) and 20-benzyl-5-pregnene 3beta,20alpha-diol (16) has proven to be superior to that of danazol, the first steroid sulphatase inhibitor to be reported, but still lower than that of the potent inhibitor estrone-3-O-sulphamate. The inhibitory activity of compound 7 was as potent as that of its previously reported estrane analogue, 17alpha-benzyl estradiol. Benzyl alkylated compounds with no OH group on the A-ring (with a 4 OCH(3), 4-Cl, or 4-H and their precursor epoxides), as well as a series of basic steroids without a benzyl group (ADT, epi-ADT, 3alpha-diol, 3beta-diol, DHEA, Delta(5)-diol, DHT, T, Preg and Prog), did not show steroid sulphatase inhibition. We have thus demonstrated that the steroid sulphatase inhibitory effect of a benzyl group, previously observed for an estrane nucleus, can be extended to certain androstane and pregnane nuclei bearing a 3beta-OH or a 4-OH group. Inhibitors 7, 9, 15 and 16 did not induce any proliferative effect on androgen-sensitive Shionogi cells. However, when tested on oestrogen-sensitive ZR 75-1 cells, a proliferative effect was observed for 7 and 9, but not for 15 and 16. PMID- 11600236 TI - Synthesis and olfactoric activity of side-chain modified beta-santalol analogues. AB - Three osmophoric points have been postulated to be necessary for the sandalwood scent of beta-santalol derivatives. One of these points, close to the hydroxyl group, is highly specific on the stereochemistry and, in particular, on the molecular shape. The role of the 2-methyl group in the side chain of beta santalol derivatives was studied by replacement through a hydrogen atom, an ethyl or an isopropyl group. It turns out that any change at the 2-methyl substituent leads to the complete loss of sandalwood odour. PMID- 11600237 TI - Synthesis of some triazolyl-antipyrine derivatives and investigation of analgesic activity. AB - The synthesis of some triazolyl-antipyrine derivatives starting from 4 chloroacetamidoantipyrine and 3-(aryloxyalkyl)-4-ethyl/phenyl-5-mercapto-1,2,4 triazoles is described. The chemical structures of the compounds were elucidated by IR, 1H-NMR and mass spectral studies. These compounds were tested for analgesic activity. PMID- 11600239 TI - Attentional modulation of blink startle at long, short, and very short lead intervals. AB - The present research investigated attentional blink startle modulation at lead intervals of 60, 240 and 3500 ms. Letters printed in Gothic or standard fonts, which differed in rated interest, but not valence, served as lead stimuli. Experiment 1 established that identifying letters as vowels/consonants took longer than reading the letters and that performance in both tasks was slower if letters were printed in Gothic font. In Experiment 2, acoustic blink eliciting stimuli were presented 60, 240 and 3500 ms after onset of the letters in Gothic and in standard font and during intertrial intervals. Half the participants (Group Task) were asked to identify the letters as vowels/consonants whereas the others (Group No-Task) did not perform a task. Relative to control responses, blinks during letters were facilitated at 60 and 3500 ms lead intervals and inhibited at the 240 ms lead interval for both conditions in Group Task. Differences in blink modulation across lead intervals were found in Group No-Task only during Gothic letters with blinks at the 3500 ms lead interval facilitated relative to control blinks. The present results confirm previous findings indicating that attentional processes can modulate startle at very short lead intervals. PMID- 11600240 TI - Cardiovascular recovery from stress predicts longitudinal changes in blood pressure. AB - Cardiovascular reactivity and recovery were examined as predictors of blood pressure changes over 3 years. Blood pressure and heart rate readings were obtained from 73 men and women aged 18-20 years during cold pressor, mental arithmetic, tourniquet ischemia, cycle exercise and step exercise tasks. Regression analyses indicated that after adjustment for initial blood pressure, initial age, initial body-mass index, sex, parental history of hypertension, and length of follow-up, heightened heart rate reactivity to mental arithmetic was associated with increased follow-up systolic blood pressure (DeltaR(2)=0.04, P<0.05). Systolic blood pressure recovery from cold pressor and tourniquet ischemia were also positively related to follow-up systolic blood pressure (DeltaR(2)=0.04 and 0.04, respectively, P<0.05) and remained so even after adjustment for the corresponding cardiovascular reactivity measures. These findings suggest that cardiovascular reactivity and recovery measures are modest predictors of longitudinal changes in blood pressure. PMID- 11600238 TI - Diesters of glycosylglycerols active in cancer chemoprevention. AB - Enzymatic transesterification, mediated by Pseudomonas cepacia lipase (lipase PS), led to the pure 1,6'-diacylderivatives of 2-O-beta-D-glucosyl-sn-glycerol and 2-O-beta-D-galactosyl-sn-glycerol, the acyl chains being derived from short medium length fatty acids. A study of the in vitro inhibitory effects of these diacylderivatives on Epstein-Barr virus early antigen activation induced by the tumour promoter 12-O-tetradecanoylphorbol-13-acetate revealed that maximum activity was reached for the hexanoyl chain and that the introduction of a second acyl chain did not significantly modify the inhibitory potential referring to the corresponding 1- or 6'-monoesters. PMID- 11600241 TI - Differences in autonomic physiological responses between good and poor inductive reasoners. AB - We investigated individual- and task-related differences in autonomic physiological responses induced by time limited figural and verbal inductive reasoning tasks. In a group of 52 participants, the percentage of correctly responded task items was evaluated together with nine different autonomic physiological response measures and respiration rate (RR). Weighted multidimensional scaling analyses of the physiological responses revealed three underlying dimensions, primarily characterized by RR, parasympathetic, and sympathetic activity. RR and sympathetic activity appeared to be relatively more important response dimensions for poor reasoners, whereas parasympathetic responsivity was relatively more important for good reasoners. These results suggest that poor reasoners showed higher levels of cognitive processing intensity than good reasoners. Furthermore, for the good reasoners, the dimension of sympathetic activity was relatively more important during the figural than during the verbal reasoning task, which was explained in terms of hemispheric lateralization in autonomic function. PMID- 11600242 TI - The influence of gender and the estrous cycle on learned helplessness in the rat. AB - Although the etiology of clinical depression is unknown, women are more likely to suffer from major depressive disorder than men. In addition, in some women, there is a clear association between depression and specific phases of the menstrual cycle. Surprisingly little research has examined gender differences and the influences of the estrous cycle in this and other animal behavioral models of clinical depression. Learned helplessness is a valid animal model of stress induced behavioral depression in which prior exposure to inescapable stress produces deficits in escape testing. Learned helplessness was studied in rats using an inescapable tail shock stress followed by a shuttle box test to determine escape latencies. Animals with mean escape latencies of >or=20 s after shuttle-box testing are defined as learned helpless. Males and normal cycling female rats in the estrus and diestrus II phases were studied. Female rats in the diestrus II phase had significantly higher escape latencies and exhibited a more helpless behavior than female rats in the estrus phase. Male rat escape latencies were intermediate between the two female phases. These results suggest a role for gonadal hormones in the development of stress-induced behavioral depression or 'learned helplessness.' PMID- 11600243 TI - Quadratic trend analysis and heartbeat detection. AB - In heartbeat detection tasks based on the Method of Constant Stimuli (MCS), subjects judge the simultaneity between their heartbeats and stimuli presented at six intervals ranging from 0 to 500 ms after the R-waves on an electrocardiogram. Because research suggests that subjects do not perceive stimuli at 0 or 500 ms as simultaneous, individual performance was indexed with quadratic trend analysis to test for distributions of simultaneity judgments across intervals that peak between 0 and 500 ms. Further, because some tasks use only two intervals, performance was also indexed using intervals of either 0 and 200 ms or 200 and 500 ms. Continuous performance scores from quadratic trend and two-interval analysis tended to correlate more highly with variables previously shown to correlate with heartbeat detection than scores from the commonly-used chi(2) analysis. These findings support the use of both quadratic trend analysis and two interval tasks for assessing heartbeat detection ability. PMID- 11600245 TI - Membrane and soluble forms of Fas (CD95) in peripheral blood lymphocytes and in serum from burns patients. AB - Burn trauma results in disorders of regulation of programmed cell death called apoptosis. Apoptosis of immunocytes is associated with the expression of Fas antigen. There are two major forms of Fas molecule, membranous Fas (mFas) and soluble Fas (sFas). The last form is generated by alternative splicing and differs from mFas by lacking 21 amino acid residues containing the transmembrane domain. We determined the expression of mCD3, mCD4, mCD8 and mFas in peripheral blood lymphocytes and the level of the soluble form of Fas in serum in patients with acute thermal trauma (n=32). As the control blood of healthy volunteers (n=25) was investigated. Compared to healthy volunteers, burn patients showed a remarkable reduction in number of CD3+ lymphocytes in the 24 h following injury, which was accompanied by a decrease in CD4+ but not CD8+ subsets by indirect immunofluorescence method. The decrease of expression of mFas in the patients with acute thermal trauma at all burn disease time was determined simultaneously. We established the decrease of level of sFas during the first (404+/-25 U/ml) and second (352+/-38 U/ml) postburn 10-day periods by the ELISA method. The contents of sFas in serum of healthy volunteers was 534+/-31.8 U/ml. There were no relations between the level of membrane Fas expression and contents of the soluble Fas in serum both in clinical manifestation and survival. We suppose that it is impossible to predict outcomes of burn disease by quantity of CD95+ cells and contents of sFas in serum. However, it is probable that significant deviations from the level of sFas may be attributes of non-revealed accompanying pathology. PMID- 11600246 TI - Susceptibility of thermally injured mice to cytomegalovirus infection. AB - Thermally injured patients are very susceptible to infection with cytomegaloviruses. In this study a role of burn-associated type 2 T cell responses on the cytomegalovirus infection was examined in a mouse model of thermal injury. A predominance of type 2 T cell responses in splenic lymphocytes of thermally injured mice has been previously demonstrated. SCID mice inoculated with splenic T cells from thermally injured mice were susceptible to infection with a small amount (5 PFU/mouse) of murine cytomegalovirus (MCMV). Conversely, SCID mice inoculated with splenic T cells from normal mice were resistant to the same infection. High levels of IL-4 and IL-10, but not IFN-gamma and IL-2, were detected in sera of thermally injured mice (TI-mice) infected with MCMV when those were compared with sera of normal mice infected with MCMV. IL-4 and IL-10 (type 2 cytokines) were produced by splenic T cells from MCMV-infected TI-mice, when they were stimulated in vitro with anti-CD3 mAb. Type 1 cytokines (IFN-gamma and IL-2), however, were not produced by these T cells after the same stimulation. In contrast, splenic T cells from MCMV-infected normal mice produced type 1 cytokines by the stimulation with anti-CD3 mAb. These results suggest that the susceptibility of mice to MCMV infection is markedly influenced by burn associated type 2 T cell responses. PMID- 11600247 TI - An outbreak of methicillin resistant Staphylococcus aureus on a burn unit: potential role of contaminated hydrotherapy equipment. AB - OBJECTIVE: To report a multi-institution outbreak caused by a single strain of methicillin-resistant Staphylococcus aureus (MRSA). OUTBREAK: Between September 19 and November 20, 1996 an index case and five secondary cases of nosocomial MRSA occurred on a 26 bed adult plastic surgery/burn unit (PSBU) at a tertiary care teaching hospital. Between November 11 and December 23, 1996, six additional cases were identified at a community hospital. One of the community hospital cases was transferred from the PSBU. All strains were identical by pulsed-field gel electrophoresis. MRSA may have contributed to skin graft breakdown in one case, and delayed wound healing in others. Patients required 2 to 226 isolation days. CONTROL MEASURES: A hand held shower and stretcher for showering in the hydrotherapy room of the PSBU were culture positive for the outbreak strain, and the presumed means of transmission. Replacement of stretcher showering with bedside sterile burn wound compresses terminated the outbreak. The PSBU was closed to new admissions and transfers out for 11 days during the investigation. Seven of 12 patients had effective decolonization therapy. CONCLUSION: Environmental contamination is a potential source of nosocomial MRSA transmission on a burn unit. Notification among institutions and community care providers of shared patients infected or colonized with an antimicrobial resistant microorganism is necessary. PMID- 11600248 TI - Cryopreserved cultured epidermal allografts achieved early closure of wounds and reduced scar formation in deep partial-thickness burn wounds (DDB) and split thickness skin donor sites of pediatric patients. AB - Burn treatment in children is associated with several difficulties, e.g. available skin replacement is small, donor area could expand, and subsequent hypertrophic scar and contracture could become larger along with their physical growth. In order to have better clinical results, the authors prepared cryopreserved cultured epidermal allografts from excess epidermal cells of other patients, and applied the epidermal allografts to 55 children, i.e. 43 cases of deep partial-thickness burn wounds (DDB) due to scald burn and 12 cases with split-thickness skin donor sites. In the 43 DDB patients, epithelialization was confirmed 9.1+/-3.6 days (mean+/-S.D.) after treatment. In 10 of the 43 patients, epithelialization was comparable between the area which received the epidermal allografts (grafted area) and the area which did not receive the epidermal allografts but was covered with usual wound dressing (non-grafted area). As a result, epithelialization day was 7.9+/-1.7 in grafted areas and 20.5+/-2.3 in non-grafted areas. In the 12 patients with split-thickness skin donor sites, epithelialization was confirmed 6.3+/-0.9 days after treatment. Epithelialization of the grafted and non-grafted areas was comparable in 8 of the 12 patients, and it was 6.5+/-1.1 days and 14.1+/-1.6 days, respectively. In these 10 DDB patients and 8 split-thickness skin donor site patients, redness and scar formation were also milder in the grafted area. The 55 patients have been followed up for 1-8 years (mean, 4.75 years), and scar formation was suppressed in both DDB and split thickness skin donor sites. These findings showed that cryopreserved cultured epidermal allografts achieve early closure of the wounds and good functional outcomes. PMID- 11600249 TI - Strategies to improve the take of commercially available collagen/glycosaminoglycan wound repair material investigated in an animal model. AB - Integra Artificial Skin is becoming widely used in burns and reconstructive surgery. However, poor take and loss due to infection remains a concern for some patients. This study describes how the successful bio-integration of Integra Artificial Skin was accomplished in isolated full-thickness wounds in the pig, by the use of sequential protocol modifications that more intimately opposed the material to the wound bed. Further improvement was achieved by measures to reduce bacterial colonisation including the use of topical anti-microbial agents. The level of histologically confirmed Integra 'take' improved from close to zero to a mean 96% of wound area (+/-11 S.D.). The efficacy of this dermal wound bed was confirmed by the histological analysis of wounds after the subsequent application of extremely thin (<130 microm) widely meshed autologous split-thickness skin grafts. The results of this animal study support the recommendation that the bio integration of Integra Artificial Skin is best achieved by the elimination of dead space below the material and by measures to hinder the penetration of microbes. The significant improvement in take achieved in this animal model using simple methodological refinements re-identifies priorities for the use of Integra Artificial Skin that can be applied in clinical management. PMID- 11600250 TI - Effect of trypsin-chymotrypsin (Chymoral Forte D.S.) preparation on the modulation of cytokine levels in burn patients. AB - The present study was carried out in burn patients administered with Trypsin Chymotrypsin (Chymoral Forte D.S.) preparation to observe if the acute-phase protein levels in the serum are modulated through the synthesis of IL-1beta and IL-6 and if the severity of the inflammatory phase could be regulated. The effects of Trypsin-Chymotrypsin preparation on the modulation of cytokine levels particularly, IL-6 and IL-1beta were analyzed in serum samples of 15 burn patients and compared with untreated controls. Significant differences in cytokine levels (P<0.05) were observed in untreated burn patients and Trypsin Chymotrypsin preparation treated patients. There were significant variations in serum IL-6 and IL-1beta on the day of admission and post burn day 10 in treated as well as untreated burn patients. Patients with a higher percentage of total body surface area and sepsis showed a significant increase in IL-1beta and IL-6 in the serum. An increase in serum levels of both cytokines was observed on post burn day 1 and a significant decrease was observed in Trypsin-Chymotrypsin preparation treated patients on days 7 and 10. The possible role of the inflammatory cytokines in the pathophysiology of burns is discussed. PMID- 11600251 TI - Nerve outgrowth and neuropeptide expression during the remodeling of human burn wound scars. A 7-month follow-up study of 22 patients. AB - Increasing data suggest that the skin nerve system is involved in wound healing. The objective of this study was to investigate the outgrowth of nerve fibers during the burn wound remodeling process and to analyze possible differences between normotrophic and hypertrophic burn wounds. In a prospective study, biopsies were taken from 22 patients with spontaneously healed partial-thickness burns at 1, 4 and 7-month post-burn. Nerve outgrowth and the expression of the neuropeptides substance P, neurokinin A, calcitonin gene-related peptide, vasoactive intestinal peptide and neuropeptide Y was monitored using immunohistochemistry. Our results showed that the number of nerve fibers gradually increased in both the dermis and the epidermis, but that they did not reach the levels of expression present in matched unburned skin of the same patient. A significantly higher number of nerve fibers were observed in normotrophic scars compared with hypertrophic scars. The number of neuropeptides containing nerves in normotrophic and hypertrophic scars were similar. IN CONCLUSION: 7 months after wound closure, burn wound scars contain less nerve fibers than unburned skin. The significantly higher number of nerve fibers in normotrophic, compared with hypertrophic scars suggests a regulatory role for the skin nerve system in the outcome of burn wound healing. PMID- 11600253 TI - Flame burn admissions and fire fatalities in Scotland with particular reference to the Strathclyde (Glasgow) region, and their prevention. AB - Scotland has the highest rate of fire fatalities in the UK. Nearly 50% of the population and fire deaths in Scotland are in the Strathclyde region. The data from the burns unit at Glasgow Royal Infirmary were studied to find the number of admissions due to flame burns and see how it compared with the fire deaths. During 1981-1993, amongst 2771 admissions to the burns unit, 1181 (43%) were due to flame burns and out of these flame burn victims, 69% were adults, 16% elderly and 15% children. The distribution of cases according to the total body surface area (TBSA) involvement was 866 (73%) with 1-15%, 165 (14%) with 16-30%, and 150 (13%) with > or =31% TBSA burns. The annual number of flame burn admissions declined during 1981-1993. In the Glasgow region 50% of the domestic fires leading to non-fatal burns or to death were started by misuse of smoking materials. Chip pan fires were responsible for 8% of admissions to the burns unit. The annual number of fire fatalities when reviewed for a longer period 1973 1995 also showed a decreasing trend. Further educational and legislative measures to prevent flame burns are discussed. PMID- 11600252 TI - Revised estimates of mortality from burns in the last 20 years at the Birmingham Burns Centre. AB - The Birmingham Burns Centre has been regularly presenting its mortality estimates since its pioneering work in 1949 on the use of probit analysis. The last of these estimates that showed a significant improvement in survival was presented in 1971. This improvement was attributed to the introduction of topical 0.5% silver nitrate against Pseudomonas aeruginosa. In the last 20 years, several changes in management of burns have taken place following a better knowledge of its pathophysiology. This study shows our experience from the last 20 years by comparing mortality estimates between two successive 10-year periods i.e., 1979 1988 and 1989-1998. We used probit analysis for deriving lethal area 50 (LA 50) for various age groups. The comparison showed that the mortality curves between the two periods were identical suggesting no improvement in the chances of survival. Since the mortalities were so similar the data were combined. The LA 50s derived from this combined data when compared with our earlier series from 1965 to 1970 also did not show a significant change in mortality. We conclude that in our experience the chances of dying for a given severity of injury have not changed significantly for more than 20 years. PMID- 11600254 TI - Treatment with cerium nitrate bathing modulate systemic leukocyte activation following burn injury: an experimental study in rat cremaster muscle flap. AB - It is suggested that burn toxin known as lipid protein complex (LPC) stimulates phagocytic cells that cause the release of a variety of inflammatory mediators which induce the activation of leukocytes. It is reported that cerium nitrate (CN) might fix LPC in eschar tissue and prevent LPC from entering the circulation. In this study, we tested the hypothesis that prevention or modulation of LPC initiated cell activation by fixing LPC in eschar tissue with CN treatment, would reduce the number of activated leukocytes, which is an important indicator of inflammation, in rat cremaster muscle flap model. Twenty eight animals were studied in four groups--group I (control), only cremaster muscle flap was dissected; group II (burn injury), burn injury was performed and flap was dissected; group III (saline); and group IV (CN), following burn injury rats treated with saline and CN, respectively, and than flaps were dissected. Blood vessels were observed in vivo under an intravital microscopy system and the number of rolling, sticking, and transmigrating leukocytes were measured in each group. Burn injury significantly increased the number of activated leukocytes (P<0.001). We observed that CN treatment significantly reduced the number of activated leukocytes following burn injury (P<0.001). In conclusion, we demonstrated that CN treatment significantly decreased the activation of leukocytes, which plays an important role in systemic inflammation. Decreased leukocyte activation is interpreted as prevention or modulation of systemic inflammatory response following burn injury. PMID- 11600255 TI - A new alcohol solution (N-duopropenide) for hygienic (or routine) hand disinfection is more useful than classic handwashing: in vitro and in vivo studies in burn and other intensive care units. AB - INTRODUCTION: Standard handwashing is a key measure for the prevention of crossed nosocomial infection, but this measure is not always observed. We study whether fast disinfection with an alcohol solution is better than handwashing and whether it can enhance observance. MATERIALS AND METHODS: The effects of several alcohol solutions on native and acquired microbiota are compared with classic handwashing in 'in vitro' and 'in vivo' (health volunteers) quantitative tests. A field assay was subsequently performed in severely ill patient intensive care units (ICUs) (Burn and other ICUs), using a semiquantitative method to compare the effects of disinfection with standard handwashing (n=102) with N-duopropenide alcohol application (n=264). RESULTS AND DISCUSSION: In both designs--health volunteers and hospital ward teams--we found significant differences between handwashing and N-duopropenide application. Handwashing barely modified the native or acquired microbiota (only 0.1 to <2 log10 reduction) and did not eliminate Staphylococcus aureus and Gram-negative bacteria (from 34 to 23%: P>0.05). However, N duopropenide reduced the acquired microbiota by 5 log (10) and the native hand microbiota by more than 2 log10, as well as significantly reducing S. aureus and Gram-negative bacteria (33-1.3%; P<0.01). PMID- 11600256 TI - Skin grafting of the naso-orbital region as a single aesthetic unit. AB - With improved acute care, a higher percentage of more severely injured facial burn patients are surviving their burns. When the full face needs resurfacing, total facial resurfacing should ideally be done with a single sheet of full thickness skin. Unfortunately, this type of single sheet total facial resurfacing is rarely possible or practical in the case of acute extensive burns. The nasoorbital region is a focal point of interpersonal communication and needs special emphasis. This report presents two patients with deep facial burns whose midface regions were resurfaced with thick split-thickness skin graft as a single aesthetic unit. Since there is no skin graft junction line on this region, a more homogeneous appearance and an aesthetically superior result could be achieved. PMID- 11600257 TI - A prospective controlled clinical study of skin donor sites treated with a 1-4,2 acetamide-deoxy-B-D-glucan polymer: a preliminary report. AB - The effect of Hyphecan (1-4,2-acetamide-deoxy-B-D-glucan) on skin donor site healing was compared with the standard skin donor site dressing Kaltostat (calcium sodium alginate) in 35 burn patients with 70 skin donor sites prospectively. The median time of wound healing for the Hyphecan group was 12 days with an average of 13.1+/-4.0 days (ranged from 9 to 28 days) while the Kaltostat group had a median healing time of 12 days (ranged from 8 to 28 days) with a mean of 13.0+/-4.1 days. The difference in healing time between these two groups was statistically insignificant with a P-value of 0.95. The infection rate was 2.9% for both Hyphecan and Kaltostat. These 35 patients had been followed up from 10 to 16 months and no difference in long-term donor site morbidity between Hyphecan and Kaltostat had been observed. This finding was encouraging because the cost of Hyphecan is less than 50% of Kaltostat and it may be worthwhile to explore the clinical application of Hyphecan in other area of burns treatment. PMID- 11600258 TI - Severe gastrointestinal haemorrhage and ischaemic necrosis of the small bowel in a child with 70% full-thickness burns: a case report. AB - Splanchnic ischaemia is an important problem in patients with large burns. This reports the case of an 11-year-old boy with 70% full-thickness TBSA burns who sustained multiple episodes of severe gastrointestinal haemorrhage due to both extensive ischaemic enterocolitis and severe gastric ulceration which required surgical intervention on several occasions. Causative mechanisms of splanchnic ischaemia in this patient including increased mesenteric vascular resistance, abdominal compartment syndrome and enteric feeding, are considered. PMID- 11600259 TI - Massive bleeding from a Dieulafoy-like lesion of the rectum in a burns patient. AB - Gastrointestinal haemorrhage is a rare but well-recognised complication of extensive burns, the site of haemorrhage usually being in the upper gastrointestinal tract. The case of an 18-year old female patient who developed sudden massive rectal bleeding 1 month after suffering 45% body surface area burns is presented. The source of the haemorrhage was a Dieulafoy-type lesion at the anorectal junction associated with mucosal ulceration, a cause of bleeding not previously described in a patient with major burns. Angiographic embolisation failed to control the haemorrhage and surgical arrest was required, following which the patient made a complete recovery with no recurrence of bleeding. Haemorrhage from the lower gastrointestinal tract is rarely associated with major burns but may be significant when it occurs. The aetiology is unclear but sepsis, mucosal ischaemia and ulceration may be implicated. PMID- 11600260 TI - Successful use of methadone in the treatment of chronic neuropathic pain arising from burn injuries: a case-study. AB - Methadone is used increasingly as a second-line opioid in the management of cancer pain refractory to conventional opioids. Recent case studies suggest that its use as an analgesic could be extended to non-cancer pain, especially neuropathic pain. The present case study reports, for the first time, the efficacy of methadone in a burn patient experiencing neuropathic pain in his healed wounds. The patient sustained extensive (55% total body surface area) chemical burns and developed chronic burning sensations, particularly in the lower limbs where skin grafting had been performed. Conventional pharmacotherapies against neuropathic pain were attempted to control pain for over 5 years. The agents used included long- and short-acting opioids, amitriptyline, clonazepam, and gabapentin, but they all failed to relieve the pain. When methadone (5 mg every 12 h) was introduced, it significantly alleviated the patient's pain within a few days of administration. The patient has now been taking methadone (15 mg every 12 h) for 10 months and reports that the opioid caused 70% pain relief and a 55% amelioration in his quality of life. Although these results are based on a case report, they suggest that a switch to methadone might be useful in some burn patients who have developed chronic neuropathic pain unrelieved by conventional pharmacotherapies. Methadone, however, needs to be titrated with vigilance and thus should be administered by a physician experienced with its use in the treatment of chronic pain. PMID- 11600261 TI - Fig leaf tanning lotion and sun-related burns: case reports. AB - A sun tan is considered a symbol of well-being in our society, but incorrect methods of sun exposure can create serious problems. We present two cases of severe sun-related burns caused by fig leaf decoction used as home-made tanning lotion. Twenty four-thirty six hours after application and sun exposure, patients developed a phytophotodermatitis characterised by erythema, and blister formation involving all the photoexposed areas (45-70% BSA). Their general conditions became rapidly critical and they were admitted to our Burn Centre. The patients were discharged after 11 and 26 days, respectively. Haemolytic anaemia and retinal haemorrhages presented as systemic complications due to the furocoumarins present in the fig leaf decoction. PMID- 11600262 TI - Garlic burns. AB - A patient with a second-degree burn of the forehead, induced by topical application of crushed garlic is reported. The literature on garlic burns is reviewed. PMID- 11600263 TI - Domestic aerosol and flash fire: warning from a fatal case. PMID- 11600264 TI - Characterization of monoclonal antibodies directed against the bovine herpesvirus 1 glycoprotein E and use for the differentiation between vaccinated and infected animals. AB - A panel of seven monoclonal antibodies (MAbs) directed against the bovine herpesvirus-1 (BHV-1) glycoprotein E (gE) was obtained. For that purpose, mice were either tolerized to BHV-1 gE-negative virus and then immunized with wild type BHV-1 or immunized with plasmid DNA expressing the gE and gI glycoproteins. The MAbs were characterized by their reactivity with the gE protein or the gE/gI complex and by competition experiments. Results showed that the MAbs were directed against three antigenic domains, two located on the gE glycoprotein and one on the gE/gI complex. Blocking experiments were performed with sera from experimentally vaccinated and infected cattle. A competition was observed between gE-positive bovine sera and six of the seven MAbs. The bovine sera thus recognized two of the three antigenic sites. Field sera were then tested in blocking enzyme-linked immunosorbent assay using one horseradish peroxidase conjugated MAb. A specificity of 98.2% and a sensitivity of 98.2% compared to the commercially available test were observed. PMID- 11600265 TI - Bovine respiratory syncytial virus can induce apoptosis in MDBK cultured cells. AB - Bovine respiratory syncytial virus (BRSV) is a major cause of respiratory disease in calves. BRSV infection is associated with epithelial cell death and inflammation. Over the past few years, a growing number of viruses have been found to induce apoptosis. In order to determine the ability of BRSV to induce apoptosis, we studied the effect of BRSV infection in cultured MDBK cells. We used ligation-mediated PCR assay to detect specific blunt-end cellular DNA fragments produced by cellular endonucleases cleaving the genomic DNA between the nucleosomes during apoptosis. We found that BRSV infection resulted in apoptosis in MDBK cells. This data demonstrates for the first time that BRSV can induce apoptosis. This data also may contribute to delineate the mechanisms that regulate tissue injury and potential lung repair following BRSV infection. PMID- 11600266 TI - Analysis of Korean strains of infectious laryngotracheitis virus by nucleotide sequences and restriction fragment length polymorphism. AB - Korean field strains of infectious laryngotracheitis virus (ILTV) were analyzed by comparison of nucleotide sequences of thymidine kinase (TK) and glycoprotein G (gG) genes and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) patterns. Main differences among TK gene sequence were found in both amino acid at 252 and mRNA polyadenylation signals. In virulent strains, amino acid 252 of TK gene was methionine but was threonine in low virulence and vaccine strains. The mRNA polyadenylation signals of TK gene were identified at 24bp downstream from the stop codon in virulent strains, but not in low virulence and vaccine strains. The gG gene of all virulent strains showed the same nucleotide sequence except for N87278 which had a gG gene sequence identical to that of vaccine strains. The virulent ILTV strains differed from low virulence and vaccine strains in PCR-RFLP patterns of TK and gG genes. The RFLP patterns of TK and gG genes of low virulence ILTV strains were identical to those of vaccine strains. In the case of N87278, the PCR-RFLP patterns of TK and gG genes were identical to those of virulent and vaccine strains of ILTV, respectively. From these results, ILTV field strains were classified into three groups according to sequences of TK and gG genes and PCR-RFLP, and the virulent ILTV strains could be discriminated from low virulence and vaccine strains by PCR-RFLP of TK gene. And it was suspected that N87278 might be produced by in vivo recombination between virulent and vaccine strains of ILTV. PMID- 11600267 TI - Expression and antigenic characterization of the major core protein VP7 of Chuzan virus, a member of the Palyam serogroup orbiviruses. AB - The Palyam serogroup-specific antigen, VP7, of Chuzan virus strain K-47 was expressed in insect cells by a recombinant baculovirus. The expressed protein appeared as a single band of 38kDa corresponding to the predicted molecular mass of Chuzan virus VP7 by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). In immunoprecipitation analysis, the recombinant VP7 was not only recognized by all polyclonal antibodies against the Palyam serogroup viruses (PALV) tested in this study, but also by antisera to bluetongue virus (BTV) serotype 1, epizootic haemorrhagic disease virus (EHDV) serotypes 1 and 2. However, in Western immunoblot assay, no positive signals were observed between this protein and these antisera, even in the homologous reaction using antiserum to Chuzan virus. These findings demonstrate that the common antigenic determinants on the VP7 proteins of Chuzan virus and the other PALV serotypes are mainly conformational and that the proteins share some epitopes with those of BTV and EHDV beyond the serogroup. No cross-reactivities were detected between Chuzan virus VP7 and antisera to BTV and EHDV in agar gel immunodiffusion (AGID) and indirect ELISA tests, indicating that the recombinant VP7 is useful as a diagnostic reagent for serological tests of congenital abnormalities of cattle caused by PALV. PMID- 11600268 TI - Presence of immune-complexes, and absence of antinuclear antibodies, in sera of dogs naturally and experimentally infected with Ehrlichia canis. AB - Antinuclear antibodies (ANA), immunoglobulin G (IgG) concentrations and circulating immune-complexes (CIC) were measured, over a period of 3 years, in 6 dogs experimentally infected with Ehrlichia canis, and in 10 dogs naturally infected with the rickettsia. No ANA were detected in any of the samples tested. The IgG concentrations were shown to be higher in the infected dogs when compared to the control dogs. CIC were detected in 2 of 10 naturally and 2 of 6 experimentally infected dogs, during both the acute and the subclinical phases of the disease. The results of this study suggest that ANA do not play a role in the pathogenesis of CME. It is however suggested that some manifestations in canine ehrlichiosis are immune-complex mediated. PMID- 11600269 TI - Calf survival from embryo transfer-induced twinning in dairy-beef cows and the effects of synchronised calving. AB - In each of 4 years, 94-116 mature cows had two 6-7-day-old embryos, produced by the in vitro fertilisation of oocytes, inserted non-surgically into one uterine horn of each cow. Starting 5 days before the expected date of calving, the cows were continuously observed and assistance at calving was provided when required. In year 1, perinatal calf survival was similar in twin-calving (TC) and single calving (SC) cows (98.1 versus 100% for calves born to TC and SC, respectively). There was a higher incidence of assistance at birth for TC (52%) than for SC (21%). In years 2 and 3, the calving of 30 SC and 33 TC was synchronised using an injection of Opticortinol (OP) 6-9 days before the injection of Estrumate and Dexol-5 (E+D). A further 34 SC calved naturally. Synchronised calving reduced the spread of calving from 16-25 to 8-9 days without reducing perinatal calf survival and had no significant effect on the incidence of assistance at birth in SC. The TC in years 2 and 3 had a high incidence of retained placenta at 48 h (70%) and a high incidence of assistance at birth (85%). In year 4, calving was synchronised in 16 SC and 21 TC with E+D and no pre-treatment with OP, while 15 SC were treated with both OP and E+D. There were no effects of the hormone treatment on perinatal calf survival and only small effects on the incidence of assisted births for SC. The incidence of retained placenta at 48 h was lower for SC pre treated with OP (40%) than for SC (88%) and TC (76%) not pre-treated with OP. Continuous supervision over calving produced perinatal calf survival rates for TC that were similar to SC, despite the higher incidence of assistance of TC at parturition. Hormonal synchronisation of calving can halve the time required for continuous supervision of calving, but the hormone treatments exacerbate the already high incidence of retained placenta in TC. PMID- 11600270 TI - Change in concentrations of luteinizing hormone subunit messenger ribonucleic acids in the estrous cycle of beef cattle. AB - Changes in the concentrations of LH subunit messenger ribonucleic acids (mRNAs) and in the LH content of the anterior pituitary of beef cattle were studied during the estrous cycle. Japanese beef cows were classified according to the expected day of the estrous cycle: stage I (early-luteal phase, days 1-4; day 1=day of ovulation), stage II (early-mid-luteal phase, days 5-10), stage III (late-mid-luteal phase, days 11-17) and stage IV (follicular phase, days 18-20), according to the morphology of the ovaries. The anterior pituitaries of the cows were collected and the levels of alpha and LHbeta subunit mRNAs were determined by slot-blot analyses. The LH content of the anterior pituitary was measured by radioimmunoassay. The level of alpha subunit mRNA in the pituitary of cows was highest in stage I and decreased significantly by stage II (P<0.05); thereafter it tended to increase. The level of LHbeta subunit mRNA did not change significantly during the estrous cycle. The LH content of the pituitary of cows was low in stage I and tended to increase by stage II, then to decrease from stage II to III, and to increase significantly from stage III to IV (P<0.05). These results suggest that the highest levels of gene expressions of alpha subunit in the anterior pituitary occur in the early-luteal phase of beef cows, while the LH content is increased most in the follicular phase. The enhanced gene expressions of common alpha subunit in the early-luteal phase could be important in replenishing the bovine anterior pituitary with LH, which is depleted of hormone by the LH surge or the enhanced pulsatile release. PMID- 11600271 TI - Influence of stage of maturation of bovine oocytes at time of vitrification on the incidence of diploid metaphase II at completion of maturation. AB - The present study was to verify the incidence of bovine diploid oocytes when vitrified at various maturation stages. Bovine cumulus-oocyte complexes were recovered from ovaries at a slaughterhouse and then divided into five groups: control group (unvitrified oocytes), 0 h group (composed of oocytes vitrified before the onset of maturation) and 8, 12, and 22 h groups (vitrified respectively at 8, 12 and 22 h after the onset of maturation). The oocytes remained vitrified for 24 h, and then were thawed. In all groups, the oocytes completed 24 h of maturation. Subsequently, the cumulus cells were removed, and the denuded oocytes fixed on slides and stained with aceto-orcein. No differences (P>0.05) in the incidence of diploid metaphase II oocytes were observed between the control, non-vitrified group (2.4%, 1/41) and oocytes vitrified at 12 h (6.9%, 3/43) or 22 h (2%, 1/50). However, significantly (P<0.05) more diploid oocytes were detected after vitrification at 0 h (28.5%, 10/35) or 8 h (35.4%, 11/31) of maturation. These results suggest that the nuclear stage at which bovine oocytes are vitrified may affect the incidence of diploid oocytes, especially in oocytes vitrified before maturation or 8 h after the onset of maturation. PMID- 11600272 TI - Effects of propylene glycol drenching on energy balance, plasma glucose, plasma insulin, ovarian function and conception in dairy cows. AB - We postulated that daily drenching of propylene glycol to cows in early lactation would increase plasma glucose and insulin concentrations and improve fertility in postpartum cows. Thirty-six Holstein cows were assigned to treatment or control groups. Each treatment cow was given 500 ml of propylene glycol by drenching daily from 7 to 42 days of lactation. Blood samples for glucose, insulin, nonesterified fatty acids (NEFA), and plasma urea N were collected at 0, 30, and 90 min postdrenching once weekly during 1-6 weeks. Blood samples were collected for progesterone analysis and cows were palpated three times per week until 11 weeks to assess ovarian status. Propylene glycol did not affect dry matter intake (DMI), milk yield or energy balance in treatment cows. After drenching, propylene glycol increased (P<0.01) plasma glucose and insulin and decreased (P<0.01) NEFA; plasma urea N of the treatment group tended (P=0.07) to be higher than that of the control group through 90 min. Days to first service, days open, and services per conception were not different between groups. Conception rates to first insemination were 33% in the control group and 57% in treated cows, but these were not significantly different. First ovulation of treatment cows occurred earlier than that of control cows (32.3 versus 44.5 days, P=0.06) and the length of the first luteal phase was longer in treated cows (13.1 versus 7.3 days, P<0.05). These data are consistent with the hypothesis that insulin is important for normal ovarian function. During negative energy balance, treatment with propylene glycol, which induced small increases in plasma concentrations of insulin, prevented the short luteal phase characteristic of the first estrous cycle in control cows. PMID- 11600273 TI - Endometrial mRNA expression of oestrogen receptor alpha, progesterone receptor and insulin-like growth factor-I (IGF-I) throughout the bovine oestrous cycle. AB - This study characterized endometrial expression of mRNAs of oestrogen and progesterone receptors (ER, PR) and insulin-like growth factor-I (IGF-I) during the oestrous cycle. Seven Holstein heifers that showed standing oestrus on the same day (day 0) were selected and blood samples for oestradiol (E2) and progesterone (P4) determinations by RIA were taken daily until day 23. Endometrial samples were taken by transcervical biopsies on days 0, 5, 12 and 19 for mRNA determination by solution hybridization. The highest endometrial mRNA levels of ERalpha and PR were observed at oestrus and a decline was observed already at day 5, which then decreased progressively at the end of the luteal phase. IGF-I mRNA levels were higher at day 0 and 5 than at day 12. At day 19, mRNA levels of ERalpha, PR and IGF-I were the lowest in heifers that were at the end of their luteal phase (n=4), but were high again in heifers which P4 levels were basal (n=3). The temporal changes in mRNA endometrial expression of ERalpha, PR and IGF-I and their relation to the changes in steroid concentrations during the bovine oestrus cycle are described. PMID- 11600274 TI - Changes in embryo production results and ovarian recrudescence during the acclimatisation to the semiarid tropics of embryo donor Holstein-Friesian cows raised in a temperate climate. AB - Pregnant Holstein-Friesian (HF) heifers were transported from central Europe (defined as temperate conditions) to north-eastern Brazil (defined as tropical, semiarid conditions). They were kept in open-sided pens with a hard floor, a roof for shade and sprinkled with water for 10 min every hour if ambient temperature exceeded 30 degrees C. Their diet was balanced to meet nutritional requirements and they were fed twice daily. Control animals were randomly chosen first and second lactation animals located on a farm 25 km away and receiving similar management. Imported animals were superovulated in 1996 (n=63) and 1997 (n=96), compared to 38 and 45 cows in the control herd. The variates recorded were: the interval post-partum to first oestrus; changes in ovarian size and activity; responses to superovulation; and, embryo quality. The average daily milk yields of the imported cows were 20.0 and 23.3 l in 1996 and 1997, respectively compared to 22.1 l throughout the experiment for cows in the control herd. The post-partum anoestrus interval in the imported cows were 112.1+/-30.5 days in 1996 compared to 55.0+/-18.0, 48.2+/-12.0 and 42.6+/-10.7 days in 1997 for control cows. The size and functionality of the ovaries was lowest for the imported animals in 1996 but did not differ between other group-year combinations. These animals also had a lower superovulatory response in 1996 than control cows in terms of the number of ovulations (6.4+/-4.3 versus 13.6+/-5.9, P<0.05) and good quality embryos (1.2+/-0.9 versus 4.4+/-2.1, P<0.05). The two groups of cows did not differ in respect of these characters in the second year of the study. The imported cows had lower reproductive efficiency and responses to superovulation in their first year in their new environment. A period of approximately 1.5 years is required for full adaptation. PMID- 11600275 TI - Effect of high progesterone concentrations during the early luteal phase on the length of the ovulatory cycle of goats. AB - The effect of exogenous progesterone exposure early in the oestrous cycle on the duration of the interovulatory interval was studied in dairy goats. A controlled intravaginal drug release (CIDR-G) device was inserted for 5 days starting at day 0 (D0 group, n=6) or day 3 (D3 group, n=5) postovulation. A third group was composed of untreated control goats (control group, n=7). Daily transrectal ultrasound was carried out during the interovulatory interval to assess the ovarian dynamics. Oestrous behaviour was checked twice a day and serum progesterone levels were assayed in daily jugular blood samples. Treated goats showed two different responses. In three D0 goats and one D3 goat, progesterone concentrations fell immediately after CIDR withdrawal and this was followed by oestrus and ovulation between days 8 and 11 (short cycles). In the other three D0 goats and in four D3 goats the treatment significantly reduced the interovulatory interval (18.3+/-0.3 and 18.5+/-0.3 days, respectively) (shortened cycles) compared with the control group (20.0+/-0.2 days; P<0.05), but the intervals with progesterone concentrations over 1 ng/ml were not different (15.7+/-0.3, 15.8+/ 0.7 and 16.0+/-0.5 days for D0, D3 and control goats, respectively). In all D0 goats with a short cycle response, the ovulatory follicle arose from the first follicular wave but in the D3 goat with a short cycle it arose from the second follicular wave. These results showed that premature progesterone exposure early in the ovulatory cycle of the goat affected its length inducing short or shortened cycles. The effect of progesterone could either affect luteotropic support of the corpus luteum (CL) and/or stimulate a premature release of the luteolysin. PMID- 11600276 TI - Effect of vulvomucosal injection of D-cloprostenol at weaning and at insemination on reproductive performance of sows during the low fertility summer season under field conditions. AB - The aim of this study was to evaluate the hypothesis that the intravulvar injection of a PGF2alpha analogue at weaning just prior to insemination may minimise the effects of summer infertility in pigs. From July to September 1999, two groups of 30 sows were randomly formed each month. The experimental group comprised sows receiving 37.5 microg of a PGF2alpha analogue, D-cloprostenol, in 0.5 ml injected into the vulvar lips at weaning and at insemination. Group 2 sows received 0.5 ml of saline solution injected into the vulvar lips and served as controls. The percentage of sows in oestrus within 7 days after weaning in treated sows was 27.93% higher than in controls (P<0.001). Fertility for treated sows was also significantly increased by the treatment (P<0.01). However, neither the percentage of inseminated sows that farrowed nor litter size was affected by treatment. PMID- 11600277 TI - Effect of co-culture of porcine sperm and oocytes with porcine oviductal epithelial cells on in vitro fertilization. AB - This study was designed to determine the effect of co-culture with porcine oviductal epithelial cell (POEC) monolayers on in vitro fertilization of pig oocytes. The in vitro penetrability of mature (experiment 1) or immature (experiment 2) oocytes was studied in presence or absence of POEC during IVF with fresh semen. In experiment 3, boar and POEC effects were analyzed but in this case with frozen-thawed spermatozoa. In experiment 4, the spermatozoa were pre incubated before IVF with or without POEC in order to assess their effect on IVF sperm-related parameters. In experiment 5, the effect of POEC was studied by co culturing them with oocytes before IVF to determine if monospermy was improved. The results showed that high sperm concentration and POEC increase oocyte penetrability (P<0.01) and decrease monospermy rate (P<0.01), in both mature and immature oocytes (P<0.01) with fresh semen and a 18 h culture time. With frozen semen was detected a boar and POEC effect (P<0.01) on penetration rate. The sperm pre-culture 2 h with POEC also resulted in an increase of sperm penetration in terms of number of sperm per oocyte (P<0.01) and this treatment did not increase monospermy when contact time between gametes was limited to 6 h although monospermy was higher when POEC were present during IVF. Finally, exposure of oocytes to POEC for 4 h before IVF facilitated monospermic penetration to over 70% (P<0.01). In conclusion, the use of POEC in porcine IVF systems provides the possibility of working with low sperm concentrations and the effect of POEC on monospermy depends on sperm concentration, boar and contact time between gametes. Moreover, the exposure of oocytes to POEC before IVF improves the rate of monospermy. PMID- 11600278 TI - The sow endometrium at different stages of the oestrous cycle: studies on the distribution of CD2, CD4, CD8 and MHC class II expressing cells. AB - The aim of this study was to investigate the distribution of CD2+, CD4+, CD8+ lymphocyte subpopulations and MHC class II expressing cells in the sow endometrium throughout the oestrous cycle. Fifteen crossbred multiparous sows (Swedish Landrace x Swedish Yorkshire), with an average parity number of 3.4+/ 0.7 (mean+/-S.D.) were used. Uterine samples from the mesometrial side of both horns, taken immediately after slaughter at late dioestrus (day 17, n=3), prooestrus (day 19, n=3), oestrus (day 1, n=3), early dioestrus (day 4, n=3) and dioestrus (days 11-12, n=3), were stored in a freezer at -70 degrees C until analysed by immunohistochemistry with an avidin-biotin peroxidase method using monoclonal antibodies to lymphocyte subpopulations and MHC class II molecules. The surface and glandular epithelium as well as connective tissue layers in subepithelial and glandular areas were examined by light microscopy. For the T lymphocyte subpopulations, all oestrous cycle stages and different tissue layers taken together, the most commonly observed cell type was CD2+ cells. The largest number of CD2+ cells within the surface and glandular epithelium were observed at oestrus and early dioestrus. In the surface epithelium, a larger number of CD8+ cells compared with CD4+ cells were observed and no CD4+ cells were found within the glandular epithelium at any stage of the oestrous cycle. In the subepithelial and glandular connective tissue layers, during the oestrus cycle stages, a larger number of CD4+ cells compared with CD8+ cells were found. Endothelial cells in the connective tissue generally expressed MHC class II. However, no obvious differences between oestrous cycle stages were observed. For other cells than endothelial cells, the result was as follows. In the surface epithelium, a large number of MHC class II expressing cells was observed at oestrus compared with the other stages. No MHC class II expressing cells were found at late dioestrus and dioestrus. MHC class II expressing cells were also found in the glandular epithelium, and in the subepithelial and glandular connective tissue layers during all oestrous cycle stages but with no significant differences between stages. In conclusion, the present study showed a variation in the distribution of T lymphocyte subpopulations (CD2+, CD4+ and CD8+) and MHC class II expressing cells in the sow endometrium during different stages of the oestrous cycle. Also a variation between different tissue layers was found. It is suggested that helper and cytotoxic function of the immune system have primary locations in different tissue layers of the endometrium. PMID- 11600279 TI - Development and expression of the green fluorescent protein in porcine embryos derived from nuclear transfer of transgenic granulosa-derived cells. AB - Nuclear transfer (NT) techniques have advanced in the last few years, and cloned animals have been produced from somatic cells in several species including pig. In this study we examined the feasibility of using granulosa-derived cells (GCs) as donor cells combined with a microinjection procedure to transfer those nuclei. In vitro matured oocytes were enucleated by aspirating the first polar body and adjacent cytoplasm. Mural GCs infected with an enhanced green fluorescence protein (EGFP) gene were serum-starved (0.5% serum, 7 days), injected directly into cytoplasm of enucleated oocytes and the oocytes were electrically activated. The reconstructed embryos were cultured for 7 days and stained with Hoechst 33342 to determine the number of nuclei. Non-manipulated oocytes were electrically activated and cultured as controls. At 9 h post-activation, the pronuclear formation rates were 78.7+/-3.7% in NT and 97.4+/-4.4% in controls at 9 h post activation. After 7 days culture, the cleavage rates were 24.5+/-7.2% in NT and 79.3+/-5.6% in controls. The blastocysts formation rates were 4.9+/-2.4% in NT and 26.8+/-3.8% in controls. To examine the effect of activation time on development of NT embryos, oocytes were activated at 0-0.5, 1-2, or 3-4 h post injection. At 18 h post-activation the pronuclear formation rates were higher (62.5+/-7.3%) in the 3-4 h group as compared to the 0-0.5 h (22.0+/-12.5%) or 1 2h (44.5+/-6.3%) groups (P<0.05). However, the cleavage rates (9.6+/-4.6 to 10.7+/-4.2%) and the blastocysts formation rates (1.2+/-2.4 to 4.9+/-3.7%) were not different among treatments (P>0.05). The mean cell number of blastocysts was 15.7+/-5.7 in NT and 25.3+/-24.7 in controls. Green fluorescence was observed in roughly half of the embryos from the one-cell to the blastocyst stage. These results indicate that granulosa-derived cell nuclei can be remodeled in the cytoplasm of porcine oocytes, and that the reconstructed embryos can develop to the blastocyst stage. In addition, EGFP can be used as a marker for gene expression of donor nuclei. PMID- 11600280 TI - Effects of canine oviduct epithelial cells on movement and capacitation of homologous spermatozoa in vitro. AB - In this study, the interaction between canine sperms and oviduct epithelial cells (OECs) was examined in vitro. The oviducts of eight bitches in the follicular (F ) phase and six bitches in the luteal (L-) phase were removed under halothane inhalation anesthesia. The entire oviduct was opened longitudinally, and the oviductal epithelium of bitches in the F- and L-phases was scraped with a scalpel into tissue culture medium (Eagle's MEM) containing 10% estrous bitch serum and 10% diestrous bitch serum, respectively. The OEC collected were preincubated for 24h and then coincubated with ejaculated canine sperms at 38 degrees C under an atmosphere of 5% CO2 in air. The percentages of sperms exhibiting active tail movement (% TM), hyperactivated sperms (% HA), and acrosome-reacted sperms (% AR) were investigated until 72 h after the start of coincubation. The percentage of sperms labeled with fluoresceinated Ca indicator (% Ca) was evaluated to assess the influx of Ca into sperms cytoplasm during capacitation. Canine sperms attached to both ciliated OEC and non-ciliated OEC. All of the mean % TM of the OEC-binding sperms in the F-OEC and L-OEC media after 24, 48, and 72 h of coincubation were significantly higher than the values of the freely swimming sperms (P< or =0.01). Conversely, the mean % AR and % Ca of the OEC-binding sperms were significantly lower (P<0.01). All of the mean % HA and % AR of the freely swimming sperms in the F-OEC medium after 24, 48, and 72 h of coincubation were significantly higher than the values of the sperms in the L-OEC medium (P< or =0.01). These results indicate that attachment of canine sperms to the OEC prolongs their viability and motility arid inhibits Ca influx into the sperms and sperm capacitation. These phenomena may be responsible for maintaining the active movement and the fertile life of canine sperms in homologous oviducts. PMID- 11600282 TI - Alternative high-performance liquid chromatographic assay for p-aminohippuric acid (PAH): effect of aging on PAH excretion in the isolated perfused rat kidney. AB - Para-aminohippuric acid (PAH), an indicator of renal plasma flow, is a commonly used marker of organic anion transport by the kidney. An analytical method for PAH using HPLC was developed. The method is simple, fast and requires a minimum amount of organic solvent. Sample preparation involved protein precipitation with zinc sulfate. Para-amino benzoic acid was utilized as an internal standard (IS). Chromatography was performed using a reversed-phase phenyl column with UV detection at a wavelength of 254 nm. Mobile phase consisted of 0.1 M acetic acid and acetonitrile (99:1) at a flow rate of 1 ml/min. The assay was validated over a standard concentration range from 1 to 25 microg/ml. Accuracy, precision, reproducibility and specificity of the method was established with coefficients of variation <10%. The method was sensitive and showed linear response in peak height ratio (analyte:IS) over the concentration range studied (r(2)>0.99). The assay was used to study the effect of aging on PAH excretion in the isolated perfused rat kidney model. Experiments were conducted in kidneys from young (2-3 months, n=6), adult (6-9 months, n=5) and aged (12-16 months, n=3) male Sprague Dawley rats at an initial drug concentration of 20 microg/ml. Significant differences in kidney function (e.g. glomerular filtration rate and glucose reabsorption) were observed in aged kidneys. Despite a 5-fold reduction in glomerular filtration rate, PAH renal clearance (kidney weight-corrected) decreased by only 2-fold in aged (2.2+/-0.42 ml/min per gram) compared to young (4.6+/-0.70 ml/min per gram, P<0.05) rats. Furthermore, renal excretion ratio was significantly higher in aged rats (27+/-8.0 vs. 15+/-5.0, P<0.05). These preliminary findings challenge the 'Whole Nephron Hypothesis' that assumes parallel reductions in renal filtration and secretory capacity secondary to disease or aging. PMID- 11600283 TI - In vitro metabolism studies of the prodrug, 2',3',5'-triacetyl-6-azauridine, utilizing an automated analytical system. AB - The purpose was to study in vitro metabolism of 2',3',5'-triacetyl-6-azauridine (1) by porcine liver esterase (PLE) and in human plasma using an automated analytical system developed previously. A gradient-LC method was developed to study the concentration-time course of 1 and its metabolites. A fast-LC assay was used to study the temperature effect on the metabolism of 1 by the PLE. 1 and all of its proposed possible metabolites were separated by the gradient-LC method in less than 10 min. Two simplified kinetic schemes were developed to describe the time course of 1, the intermediates and final metabolites with only five rate constants for the metabolisms of 1 by PLE and four rate constants in human plasma. Both enthalpy and entropy of activation in the in vitro metabolism of 1 by PLE were obtained. PMID- 11600284 TI - In vitro distribution of ketoprofen enantiomers in articular tissues of osteoarthritic patients. AB - The distribution of ketoprofen enantiomers in joint tissues was studied as a function of their relative tissular affinities using the multi-chamber distribution dialysis system described by Bickel et al. Selected off-cuts of synovial membrane, joint capsule, cartilage and ligament were obtained from ten patients suffering from osteoarthritis of the knee (n=3) or hip (n=7). Sorensen solution (4 ml) spiked with racemic ketoprofen (2 microg ml(-1)) was dialysed against 1 ml of the four solutions of tissue homogenates (0.4 g ml(-1)). Ketoprofen enantiomers were quantified in buffer and tissue solutions by high performance liquid chromatography. The distribution of ketoprofen enantiomers in the Bickel's multi-compartment model indicated that there was a non stereoselective affinity of ketoprofen enantiomers for their potential target tissues. Despite the interindividual variability in articular tissues, the concentrations (+/-S.D.) of R- and S-ketoprofen were significantly higher in synovial membrane (8.69 (4.76) microg g(-1) for S, 9.14 (5.57) microg g(-1) for R), joint capsule (5.71 (2.49) microg g(-1) for S, 5.49 (2.62) microg g(-1) for R) and ligament (6.28 (3.61) microg g(-1) for S, 6.40 (3.64) microg g(-1) for R) than in articular cartilage (3.67 (1.75) microg g(-1) for S, 3.70 (1.67) microg g(-1) for R). There were no significant differences in the distribution of R- and S-ketoprofen between the solutions of joint capsule, synovium and ligament tissues. These data may be related to differences in ketoprofen affinity for the different constituents of joints. This in vitro distribution profile is similar to that reported in vivo for other non-steroidal anti-inflammatory drugs. PMID- 11600285 TI - Demonstrative validation study employing a packed column pressurized fluid chromatography method that provides assay, achiral impurities, chiral impurity, and IR identity testing for a drug substance. AB - Assay development, assay validation, and documentation are reported here for a single packed column pressurized fluid chromatographic/ultraviolet (UV) method that provides: (1) simultaneous detection and quantification for the chiral drug, the chiral impurity and seven achiral impurities; and (2) a Fourier transform infrared (FT-IR) spectrometric identification test result for the Searle drug substance sample, xemilofiban. The separation is achieved in less than 30 min with three columns in tandem and a gradient of CO2-CH3OH. The post-column flow is split between UV (assay) and FT-IR (identification). Precision and accuracy are consistent within figures of merit obtained by liquid chromatographic-ultraviolet assays on analogous drug substances. The reported procedure combines three typical drug substance tests into one test (e.g. chiral impurities, achiral impurities, and infrared identification). PMID- 11600286 TI - Liquid chromatographic-tandem mass spectrometric urine assay for a highly metabolized cyclic ureidobenzenesulfonamide: issues concerning assay specificity and quality control preparation. AB - An LC-MS-MS method was validated for the quantitation of a beta(3) agonist (A) in human urine to support Phase I studies. A was designed to accelerate metabolism for weight reduction. During assay development a significant loss of A was apparent from frozen urine quality control samples. The addition of 0.75% bovine serum albumin (BSA) in urine (v/v) was required to maximize the recovery of A from urine. Urine samples were basified and extracted into methyl t-butyl ether isopropyl alcohol (90:10, v/v). The organic layer was washed, evaporated, reconstituted, and injected onto a 5 cm, C8 HPLC column prior to MS-MS analysis. The standard curve was linear from 5 to 500 ng/ml. Intraday precision for peak area ratios from BSA urine samples at seven separate concentrations over a range of 5-500 ng/ml (n=5) was <4.0% and calculated concentrations were within 91-115% of nominal concentrations. Interday precision for BSA urine quality control (QC) samples at four separate concentrations (n=10 of each) was <5.0% and individual calculated concentrations were within 90-111% of nominal concentrations. This work emphasizes that potential metabolites and quality control standards should be prepared and assayed as early as possible in method development, especially before the sample collection section of the clinical protocol is prepared. The methods described here have wide utility to other compounds containing basic benzene sulfonamides and to beta3 agonist candidates. PMID- 11600287 TI - Importance of injection solution composition for LC-MS-MS methods. AB - For the first time, the influence of the injection solution composition on the quality of LC-MS-MS methods, in terms of column efficiency and peak shape, was systematically investigated. Various types of compounds, including polar ionic acidic, polar ionic basic and non-polar neutral compounds, were prepared in different solutions ranging from 100% water to 100% acetonitrile. Different volumes of these solutions were injected onto either C18 or silica columns connected to tandem mass spectrometry. The mobile phases consisted of acetonitrile, water, and small amounts of volatile acid or buffer. On silica columns, the influence of injection solution on the peak shape and column efficiency was straightforward. The sharpest peaks and the highest column efficiency were obtained with 100% acetonitrile as the injection solvent. On C18 columns, this type of influence was less clear due to the dual retention mechanism of the bonded phase and of the residual silanol groups. On C18 column, retention due to residual silanol groups was significant even with a mobile phase containing less than 50% acetonitrile. Poor peak shape was observed when the injection solution had a stronger eluting strength than mobile phase, particularly for early eluting peaks. PMID- 11600288 TI - Derivative ratio spectra-zero crossing spectrophotometry and LC method applied to the quantitative determination of paracetamol, propyphenazone and caffeine in ternary mixtures. AB - Two methods were used to determine paracetamol, caffeine and propyphenazon in ternary mixtures and tablets. Derivative ratio spectra-zero crossing procedure was based on the simultaneous use of the first derivative of ratio spectra and measurements of derivative ratio analytical signals corresponding to the zero crossing points of wavelengths. By using propyphenazon as a divisor, the amounts of paracetamol and caffeine in the ternary mixture were determined by measuring the first derivative ratio amplitudes at 242.8 nm (zero-crossing point for caffeine) and 251.2 and 273.8 nm (zero-crossing point for paracetamol) respectively. Also by using paracetamol as a divisor, the contents of propyhenazon and caffeine in the same ternary mixture were determined by measuring the first derivative ratio amplitudes at 244.8 and 276.9 nm (zero crossing point for caffeine) and 250.6 and 274.0 nm (zero-crossing point for propyphenazon), respectively. For the HPLC procedure, a Nucleosil C18 column and a mobile phase consisted of water and methanol (20:80) were used to separate three compounds with cetrimide as an internal standard. The flow rate was 1.0 ml/min with an ultraviolet (UV) detection at 254 nm. Both methods were also applied to the determination of these three compounds in ternary mixtures and tablet formulation. The analytical results were quite good in all cases. PMID- 11600289 TI - Evaluation of the impurity profile of amino acids by means of CE. AB - The aim of this study was to develop a general approach for characterizing the impurity profile of amino acids at level 0.1% by means of capillary electrophoresis (CE). Checking a variety of labeling reagents revealed 9 fluorenylmethyl chloroformate to be favorable, due to the high stability of its derivatives and the fact that the reagent peaks do not interfere with the peaks of the impurities. After optimization, the method was sufficiently sensitive to evaluate impurities at a 0.1% level by UV detection. The method was representatively validated for phenylalanine (Phe) with regard to selectivity, precision, linearity and accuracy using model mixtures of potential impurities. The CE analyzes method was applied to Phe samples of different manufacturers and the capabilities of the strategy was also demonstrated by samples of tryptophan and serine. PMID- 11600290 TI - Isolation and identification of 8-hydroxypraziquantel as a metabolite of the antischistosomal drug praziquantel. AB - Praziquantel, a broad spectrum anthelmintic drug, is extensively metabolized in the liver, yielding mainly monohydroxylated and dihydroxylated phase-I metabolites. However, the exact chemical structure of most metabolites is still unknown. One of these unidentified phase-I metabolites was isolated from human urine by high performance liquid chromatography using an isocratic separation method. This metabolite was identified as 8-hydroxypraziquantel. For the structure elucidation, electrospray ionization-mass spectrometry, 1H and 13C NMR spectroscopy have been used. PMID- 11600291 TI - Non-aromatic naphthalane preparation; preliminary clinical study in the treatment of psoriasis vulgaris. AB - This study aimed to prove the similarity of the composition of non-aromatic Croatian naphthalane (NAN) with brown naphthalane (BN), which is used in the treatment of psoriasis vulgaris. The comparison of the compositions was performed by obtaining GC fingerprints, which were supported by GC-MS data. In spite of remarkable differences in general profiles of the GC chromatograms, lower and medium molecular weight components of NAN were found to be qualitatively the same as the saturated constituents of BN. Quantitatively, lower molecular weight components as well as all n-alkanes were comparatively lower in NAN. NAN, additionally, contained higher molecular weight components, among which there were saturated oligocyclic hydrocarbons (up to pentakishomohopanes), described as responsible for the curing effect of naphthalane. The composition characteristics of NAN including its non-aromatic character made it suitable for a clinical study. In the treatment, the efficacy was determined by means of comparison of Psoriasis Area Severity Indices, PASI, at the beginning and at the end of the therapy. Adult volunteer-patients, nine males and six females, applied NAN over the whole body, except the scalp, at the room temperature for 20 min and this was followed by the selective UVB radiation. After the 3-week therapy, all essential clinical manifestations as erythema, desquamation and infiltration were significantly reduced in 14 patients; in nine cases the improvement was 50-93%, while the state of five patients improved between 25 and 50%. In one case, there was no obvious change. No exacerbation occurred during the therapy period. No adverse effect on hematological or biochemical parameters was noticed. PMID- 11600292 TI - Interference in the Limulus amebocyte lysate assay for endotoxin determination in peritoneal dialysis fluids and concentrates for hemodialysis. AB - The interference of the saline concentration of fluids for peritoneal dialysis and concentrates for hemodialysis on the Limulus amebocyte lysate (LAL) assay for endotoxins was investigated. The experiments were carried out individually with each substance that compose fluids for hemodialysis, to determine the possible inhibition or enhancement effects that they could cause on the LAL assay. The compositions were also assayed to investigate the possibility of synergistic effect. They were assayed by the gel-clot method from two different suppliers, and the samples that showed inhibition effect were also assayed by the chromogenic method. The samples were analysed at successive dilutions, with different LAL sensitivities, to satisfy the endotoxin limits of 5 EU/ml for the concentrate and 0.25 EU/ml for the fluid for dialysis peritoneal. The results showed that the major interference on the gel-clot assay occurs in presence of acetic acid and in concentrates containing acid acetic, even the pH being adjusted between 6.5 and 7.5. However, the test, after an adequate dilution, could be validating for all samples. Chromogenic test can be used for peritoneal dialysis fluids considering a limit of 0.25 EU/ml and sample dilution of eight times, but it cannot be used for concentrates for hemodialysis without further dilution. Considering the results and that the chromogenic is a more time consuming method, endotoxins in fluids for hemodialysis can be satisfactorily assayed by the gel-clot method. PMID- 11600293 TI - Analysis of intracellular didanosine triphosphate at sub-ppb level using LC MS/MS. AB - An analytical procedure has been developed for the analysis of intracellular didanosine triphosphate (ddATP). An electrospray ionization tandem mass spectrometer (ESI-MS) was interfaced to liquid chromatography (LC) using a mobile phase CH3OH/H2O (25/75) containing 1% formic acid for the analysis of the 5' triphosphate metabolite of the antiviral didanosine. In this procedure, ddATP was extracted from CEM-T4 cells, isolated using an exchange anion solid phase extraction procedure, enzymatically dephosphorylated and then analyzed by LC MS/MS within a 1 min run time. The influence of several parameters (electrospray ionization interface, acidic modifiers of the mobile phase) has been studied. A calibration curve was generated and the linear regression analysis yielded a regression coefficient (r(2)) greater than 0.999. Using LC-MS/MS detection in single reaction monitoring mode (SRM), the limit of quantitation of ddA in CEM-T4 cells was 0.02 ng ml(-1). Furthermore, this procedure could be used to perform simultaneous detection of five nucleoside reverse transcriptase inhibitors, such as AZT, 3TC, ddA, ddC and d4T and make LC-MS/MS a method of choice for Therapeutic Drug Monitoring (TDM) in a clinical environment. PMID- 11600294 TI - A direct determination of thymidine triphosphate concentrations without dephosphorylation in peripheral blood mononuclear cells by LC/MS/MS. AB - A rapid, sensitive and specific analytical method with minimal sample preparation for the measurement of thymidine triphosphate (TTP) in peripheral blood mononuclear cells (PBMC) by LC/MS/MS has been developed. PBMC were separated from whole blood or buffy coat. The analyte and internal standard were extracted from PBMC with 70% methanol (pH 7.2). These extracts after centrifugation were directly injected onto LC/MS/MS without need for any further sample preparation. The calibration curve was linear over the range 0.8-800 ng/ml. Mean inter- and intra-assay coefficients of variation (CVs) over the range of the standard curve were less than 10%. The overall recovery of TTP was 103.5%. PMID- 11600295 TI - Determination of optical purity by nonenantioselective LC using CD detection. AB - The use of a circular dichroism (CD) based HPLC detection system was recently described by some authors and proposed for a nonenantioselective HPLC enantiomeric purity determination. Indeed the system, measuring both CD and UV signals simultaneously, allows the evaluation of the g anisotropy factor. In order to experimentally support such an analytical procedure as an alternative to the enantioselective chromatographic method currently found in some pharmacopoeial monographs, we have studied its application to the analysis of dexchlorpheniramine maleate, an active substance which exhibits a poor CD signal in the 250-270 nm spectral region with a g value of the order of 10(-4). The results reported indicate that the suitability of the studied procedure for the enantiomeric purity determination is obtained only when the CD-detector reaches high stability; indeed a certain time lag is systematically necessary to obtain stable responses, i.e. adequate precision. The enantioselective HPLC procedure seems to be more precise for enantiomeric purity values < or = 2% than the CD based detection system; such a disadvantage might be counterbalanced by the use of non chiral stationary phases. PMID- 11600296 TI - Analysis of three lupane type triterpenoids in Helicteres angustifolia by high performance liquid chromatography. AB - Kang-chih-ma is the dried roots and stems of Helicteres angustifolia (Sterculiaceae) and a commonly used folk herbal drug in Taiwan. It possesses antidotal, analgesic, anti-inflammatory and anti-bacterial effects and is also known as a kind of tumor inhibitory plant. To evaluate the quality of H. angustifolia, a simple, rapid and accurate high-performance liquid chromatographic (HPLC) method was developed for the assay of three lupane type triterpenes: 3beta-acetoxy-27-benzoyloxylup-20(29)-en-28-oic acid methyl ester (methyl helicterate), 3beta-acetoxy-27-benzoyloxylup-20(29)-en-28-oic acid, and 3beta-acetoxy-27-(p-hydroxyl) benzoyloxylup-20(29)-en-28-oic acid methyl ester. The present HPLC system used an Inertsil ODS-2 column by gradient elution with acetonitrile and water as the mobile phase and detected at UV 230 nm. Regression equations revealed good linear relationships (correlation coefficients: 0.9922 0.9997). The relative standard deviations of these three constituents ranged between 1.05-3.14% (intraday) and 2.12-4.38% (interday). The contents of these three constituents of the heartwood and the bark of the roots of H. angustifolia in five different samples have also been determined. PMID- 11600297 TI - LC method for the analysis of paracetamol, caffeine and codeine phosphate in pharmaceutical preparations. AB - An accurate, simple, reproducible and sensitive method for the determination of paracetamol, caffeine and codeine phosphate has been developed and validated. Paracetamol, caffeine and codeine phosphate were separated using a muBondapack C8 column by isocratic elution with flow rate 1.0 ml/min. The mobile phase composition was 420/20/30/30 (v/v/v/v) 0.01 M KH2PO4, methanol, acetonitrile, isopropyl alcohol and spectrophotometric detection was carried out at 215 nm. The linear range of detection for paracetamol, caffeine and codeine phosphate were between 0.400 and 1500 microg/ml; 0.075 and 90 microg/ml; 0.300 and 30 microg/ml, respectively. The method has been shown to be linear, reproducible, specific, sensitive and rugged. PMID- 11600298 TI - Simultaneous determination of tolperisone and lidocaine by high performance liquid chromatography. AB - A reversed phase high performance liquid chromatographic (RP-HPLC) method for the simultaneous determination of tolperisone (TP) and lidocaine (LD) has been developed. The drugs were separated on a column (4.60 x 250 mm(2)) Spherisorb ODS (5 microm) using 5.5% triethylamine in 70/30 v/v acetonitrile/water as mobile phase 0.7 ml min(-1)and UV detection at 254 nm. The detection limits for Tolperisone hydrochloride (TP-HCl) and lidocaine hydrochloride (LD-HCl) were 0.20 ng/20 microl and 100 ng/20 microl and the quantitation limits were 0.50 ng/20 microl and 250 ng/20 microl, respectively. Linear calibration curves over the ranges of 1-10, 10-100 and 150-500 microg ml(-1) for TP-HCl and 10-500 microg ml( 1) for LD-HCl were established. Different calibration slopes were found for TP probably owing to changes in refractive index due to increase in TP concentration. The average recoveries of the added TP in the samples (TP-HCl tablets and injection liquid). A solutions spiked with standard TP-HCl were 99.9 and 99.7% with the RSD (n=11) of 0.66 and 0.67%, respectively. The average recovery of the added LD in the sample (injection) spiked with standard LD-HCl was 98.9% with the RSD (n=11) of 0.59%. The proposed method has been applied to the determination of TP-HCl and LD-HCl in commercial products available in Thailand. Comparative determination of TP by UV spectrophotometry and LD by colorimetry were also carried out. The results obtained by both methods were in good agreement of those obtained by the proposed method verified by using t-test. The proposed RP-HPLC method is simple, accurate, reproducible and suitable for routine analysis. PMID- 11600299 TI - Electroanalysis of dapsone, an anti-leprotic drug. AB - The electrochemical oxidation and adsorption of dapsone, an anti-leprotic drug were studied in aqueous alcohol medium at a stationary glassy carbon electrode. Cyclic voltammetry studies showed one well-defined oxidation peak in the potential range 1.2-1.9 V at pH conditions 1.0, 4.0, 7.0, 9.2 and 13.0. The oxidation was irreversible and exhibited diffusion controlled adsorption. Controlled potential coulometry revealed one electron oxidation of the amino group in the molecule. A systematic study of the experimental parameters that affect the squarewave stripping response was carried out and the optimized experimental conditions were arrived at. A calibration plot was derived for the determination of the compound in solution. This method was used for the determination of dapsone in tablets and urine. The limits of determination was 0.0036 and 3.56 mg/ml and the relative standard deviation (n=10) was 4 ppt (0.4%) at a concentration level 0.100 mg/ml. PMID- 11600300 TI - Characterization of micellar solubilization of antibiotics using micellar electrokinetic chromatography. AB - Micellar electrokinetic chromatography (nMEKC) method was applied to the determination of the partition behaviour between water and micelle for a group of antibiotics using sodium dodecyl sulphate (SDS) as an anionic model surfactant. In the method, the running buffer contains both the micelles and the drug, and the injected solution contains the same concentration of the micelles as the running buffer but no drug. The mobility of the drug can be measured from a negative peak recorded in the chromatogram. The required parameters for the determination of the capacity factor were measured by the MEKC technique. Thermodynamic properties such as enthalpy and entropy changes of micellar solubilization were calculated from the temperature dependence of the partition coefficients. The critical micellar concentrations (CMC) of the SDS salt were determined in phosphate solutions at pH 7 at different temperatures using the MEKC. The method described in this article based on MEKC is efficient and very fast in order to determine parameters for characterizing micellar solubilization of drugs. PMID- 11600301 TI - The ICH guidance in practice: stress degradation studies on ornidazole and development of a validated stability-indicating assay. AB - The present study describes degradation of ornidazole under different ICH prescribed stress conditions (hydrolysis, oxidation and photolysis), and establishment of a stability-indicating reversed-phase HPLC assay. Degradation was found to occur in alkaline medium, under high acidic conditions, under oxidative stress, and also in the presence of light in acid conditions. Previously the drug is only known to decompose under alkaline conditions. Separation of drug and the degradation products under various conditions was successfully achieved on a C-18 column utilising water-acetonitrile in the ratio of 86:14. The detection wavelength was 310 nm. The method was validated with respect to linearity, precision, accuracy, selectivity, specificity and ruggedness. The response was linear in the drug concentration range of 5-500 microg ml(-1). The mean values (+/-RSD) of slope, intercept and correlation coefficient were 45251 (+/-1.59), 104418 (+/-2.49) and 0.9996 (+/-0.03), respectively. The RSD values for intra- and inter-day precision studies were <1 and <2.6%, respectively. The recovery of the drug ranged between 100-103% from a mixture of degradation products. The method was specific to drug and also selective to degradation products. PMID- 11600302 TI - Direct LC analysis of five benzodiazepines in human urine and plasma using an ADS restricted access extraction column. AB - An alkyl-diol-silica (ADS) precolumn was used for the direct and on-line extraction of several benzodiazepines from serum and urine. The protein component of the biological sample was flushed through the ADS column, while simultaneously extracting the benzodiazepine compounds in the pores of the ADS stationary phase. The role of hydrophobic interactions in the extraction mechanism was confirmed. Column switching was employed to elute the extracted analytes from the ADS column into a high-performance liquid chromatography reverse-phase C18 column for the isocratic separation and UV detection of the benzodiazepines. Sample preconcentration via large volume injections was possible, improving the limits of detection. The calculated clonazepam, oxazepam, temazepam, nordazepam and diazepam detection limits were 38.8, 24.2, 31.7, 31.3, 45.0 ng/ml in serum, respectively, and 48.4, 24.5, 31.7, 33.1, 52.9 ng/ml for urine, respectively. The method was linear over the range of 50-10000 ng/ml in both matrices with an average linear coefficient (R(2)) value of 0.9918. The injection repeatability and intra-assay precision of the method were evaluated over ten injections, resulting in a percent relative standard deviation <5%. The ADS extraction column was robust, providing many direct injections of biological fluids for the extraction and subsequent determination of benzodiazepines. PMID- 11600303 TI - Liposomes with tretinoin: a physical and chemical evaluation. AB - The comedolytic activity of tretinoin, incorporated in liposomes, is five to ten times higher compared to the conventional preparations and also the local tolerability is much better. This implies the big interest of a study on tretinoin in liposomes. First, the encapsulation capacity of tretinoin in the liposomes was determined. Therefore, a series of liposomes was prepared with different concentrations of tretinoin (1-6 mg/ml buffer) and lipids (100-300 mg/ml buffer) (egg phosphatidyl choline/cholesterol) with buffers pH=5 and 7. These series of liposomes were evaluated microscopically on the presence of tretinoin crystals outside the liposomes. The highest incorporation capacity was obtained using 2 mg of tretinoin and 300 mg of lipids per milliliter of buffer pH=5. The chemical stability of tretinoin in the liposomes, evaluated during 1 year, revealed no remarkable loss in tretinoin content, even when stored at 25 degrees C. The photo-degradation of tretinoin in the liposomes was about two times slower than in castor oil, but tretinoin degraded to approximately 25% of its initial content. The chemical evaluation of the lipid fraction showed no oxidative degradation of the polyunsaturated fatty acids in EPC because the determined concentration of conjugated dienes and hydroperoxides, two oxidative degradation products, was <1%, which is negligible. Finally, the in-vitro release of tretinoin from the liposomes, evaluated with a dialysis technique, was very low, but this is not a problem for topical use. PMID- 11600304 TI - High-performance liquid chromatographic separation and determination of the process related impurities of mebendazole, fenbendazole and albendazole in bulk drugs. AB - Simple, specific and rapid reversed-phase high-performance liquid chromatographic methods to separate and determine potential impurities of anthelmintic drugs viz., mebendazole, fenbendazole and albendazole are reported. These methods afforded efficient separation, good resolution and identification of all the impurities examined. The methods were successfully applied not only for quality assurance, but also process development of the select anthelmintic drugs. PMID- 11600305 TI - Simultaneous determination of melatonin and pyridoxine in tablets by gas chromatography-mass spectrometry. AB - A gas chromatographic-mass spectrometric (GC-MS) method for the qualitative and quantitative determination of melatonin plus pyridoxine commercial tablets is described. Melatonin and pyridoxine were simultaneously determined by GC-MS after extraction from ground tablets with methanol and derivatization with N-methyl-N-N trimethlylsilyltrifluoroacetamide (MSTFA). The mass chromatograms were generated using 232 m/z ion for melatonin and 280 m/z ion for pyridoxine, respectively. Splitless injection offers good reproducibility with a standard deviation of 2%. The developed method was applied to analyze the melatonin and pyridoxine content from two different tablet formulations. Also, recovery, detection and quantification limits are reported. PMID- 11600306 TI - A validated HPLC method for the determination of pyridostigmine bromide, acetaminophen, acetylsalicylic acid and caffeine in rat plasma and urine. AB - A method was developed for the separation and quantification of the anti-nerve agent pyridostigmine bromide (PB; 3-dimethylaminocarbonyloxy-N-methyl pyridinium bromide), the analgesic drugs acetaminophen and acetylsalicylic acid, and the stimulant caffeine (3,7-dihydro-1,3,7-trimethyl-1-H-purine-2,6-dione) in rat plasma and urine. The compounds were extracted using C(18) Sep-Pak(R) cartridges then analyzed by high performance liquid chromatography (HPLC) with reversed phase C18 column, and UV detection at 280 nm. The compounds were separated using gradient of 1-85% acetonitrile in water (pH 3.0) at a flow rate ranging between 1 and 1.5 ml/min in a period of 14 min. The retention times ranged from 8.8 to 11.5 min. The limits of detection were ranged between 100 and 200 ng/ml, while limits of quantitation were 150-200 ng/ml. Average percentage recovery of five spiked plasma samples were 70.9+/-9.5, 73.7+/-9.8, 88.6+/-9.3, 83.9+/-7.8, and from urine 69.1+/-8.5, 74.5+/-8.7, 85.9+/-9.8, 83.2+/-9.3, for pyridostigmine bromide, acetaminophen, acetylsalicylic acid and caffeine, respectively. The relationship between peak areas and concentration was linear over range between 100 and 1000 ng/ml. The resulting chromatograms showed no interfering peaks from endogenous plasma or urine components. This method was applied to analyze these compounds following oral administration in rats. PMID- 11600307 TI - Spectrophotometric multicomponent analysis of a mixture of metamizol, acetaminophen and caffeine in pharmaceutical formulations by two chemometric techniques. AB - Inverse least squares (ILS) and factor-based (principal component analysis (PCA)) techniques were proposed for the spectrophotometric multicomponent analysis of a ternary mixture consisting of metamizol, acetaminophen and caffeine, without prior separation. In these chemometric techniques, the measurements of the absorbance values were realized in the spectral range from 225 to 285 nm in the intervals of Deltalambda=5 nm at the 13 wavelengths in the zero-order spectra of the different ternary mixtures of these active ingredients in 0.1 M HCl. The prepared calibrations of both techniques using the absorbance data and concentration matrix data sets were used to predict the concentration of the unknown concentrations of metamizol acetaminophen and caffeine in their ternary mixture. The 'MAPLE V' software was used for the numerical calculations. Mean recoveries and relative standard deviations for ILS and PCA techniques were found to be 99.8 and 1.68%, 99.9 and 1.66% for caffeine, 99.8 and 1.84%, 100.4 and 2.85% for metamizol, and 99.7 and 1.04%, 99.6 and 1.34% for acetaminophen, respectively, for the first and second techniques. The techniques were successfully applied to two pharmaceutical formulations marketed in Turkey and results were compared with a new high-performance liquid chromatography method. PMID- 11600308 TI - Development of a simple, rapid and reproducible HPLC assay for the simultaneous determination of hypericins and stabilized hyperforin in commercial St. John's wort preparations. AB - A reversed-phase HPLC method was developed and validated for the simultaneous determination of hypericins and stabilized hyperforin in St. John's wort extract. The sample solution was prepared by extraction of the finely powdered extract with methanol-water (80:20, v/v) containing 5% HP-beta-cyclodextrin, and adjusted to pH 2.5 with orthophosphoric acid. Diluted extract solutions, maintained at 0 degrees C, were injected into a C18 column. The samples were eluted isocratically using a mobile phase consisting of acetonitrile and 0.3% v/v phosphoric acid (90:10, v/v) at a 1.5 ml/min flow rate with simultaneous fluorescence (315/590 nm, excitation/emission) and UV (273 nm) detection. Quantification of the marker compounds (hypericin, pseudohypericin, hyperforin) was achieved by use of standard curves generated by plotting peak heights versus concentrations. Validation studies demonstrated that this HPLC method is simple, rapid, reliable, and reproducible. The standard curves were linear over the concentration ranges, 0.5-2.5 microg/ml (hypericin), 0.35-1.6 microg/ml (pseudohypericin) and 5-50 microg/ml (hyperforin). The intra-day coefficients of variation obtained for hypericin, pseudohypericin and hyperforin were < or = 4.4%, < or = 5.4%, and < or = 2.8%, respectively; inter-day CVs were < or = 5.8%, < or = 4.9%, and < or = 2.5%, respectively. This method may be applied for the routine standardization of St. John's wort products against hyperforin and the hypericins, the putative antidepressant principles in the herbal. PMID- 11600309 TI - Identification and determination of nucleosides in rat brain microdialysates by liquid chromatography/electrospray tandem mass spectrometry. AB - A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed for the determination of brain basal nucleosides (inosine, guanosine and adenosine) in microdialysates from the striatum and cortex of freely moving rats. A microdialysis probe was surgically implanted into the striatum or cortex of individual rats and Ringer's solution was used as the perfusion medium at a flow rate of 0.3 or 0.5 microl/min. The samples were then analyzed off-line by LC/MS/MS experiments. The separation of inosine, guanosine and adenosine was carried out on a cyano column using a mobile phase of 10 mM ammonium acetate, 1% acetic acid and 8% methanol at a flow rate of 0.4 ml/min. Analytes were detected by electrospray ionization tandem mass spectrometry in the positive ion mode. The detection limit for inosine, guanosine and adenosine was 80, 80 and 40 pg on column, respectively. With this method, the intercellular basal inosine, guanosine and adenosine concentrations in striatum and cortex of rat were determined. PMID- 11600310 TI - Potential of on-line micro-LC immunochemical detection in the bioanalysis of cytokines. AB - An on-line liquid chromatography-immunochemical detection (LC-ICD) system for the quantification of cytokines in cell extracts has been developed using a post column continuous-flow reaction detection system using fluorescence labelled antibodies. Cytokines eluting from the micro-HPLC column react with antibodies to form fluorescent complexes. In a second step the excess of free antibody is trapped on a cytokine bound support prior to fluorescence detection. The concentration detection limit of the flow injection-ICD system was 50 pM (20 microl injection volume) for interleukin 4 (IL-4). An absolute detection limit of 1 fmol was obtained for IL-4. Similar to ICD systems for small non-protein analytes developed earlier, reaction times were in the order of 1 minute. The immobilised cytokine affinity columns can easily be regenerated and used for months. The present ICD system for interleukins 4, 6, 8 and 10 was coupled to ion exchange-, size exclusion- and reversed phase chromatography. Important parameters (reaction times, reaction conditions) were investigated to get a better understanding of post-column ICD systems for macromolecules. PMID- 11600311 TI - Voltammetric studies of 2-hydroxy-5-[(4-sulfophenyl)azo]benzoic acid as a novel prodrug of 5-aminosalicylic acid. AB - The electrochemical properties of a colon-targeted prodrug of 5-aminosalicylic acid (5-ASA), 2-hydroxy-5-[(4-sulfophenyl)azo]benzoic acid (SPSA), were investigated in aqueous solutions at glassy carbon electrodes using cyclic voltammetry and controlled potential electrolysis. The influence of the pH and experimental time domain on the reaction pathway has been studied. The electrochemical reduction of SPSA is identified as an ECE process always leading to the cleavage of azo bond. In an acidic media SPSA is reduced in a 4e(-)/4H(+) process yielding 5-ASA and sulfanilic acid. In neutral and weakly basic media SPSA is reduced in 2e(-)/2H(+) process resulting in the hydrazo intermediate that is stable enough to enable its reoxidation back to SPSA in the time scale of the cyclic voltammetry. PMID- 11600312 TI - Bioanalytical utility of sonovoltammetry. AB - Dopamine dissolved within egg homogenate was used as a model system to study the effects of electrode contamination and its subsequent reactivation through ultrasonically mediated in situ cleaning effects. The merits in conducting electroanalytical investigations under the influence of the ultrasonic field were also appraised. Maintaining the ultrasound field during oxidative measurements was found to yield hydrodynamic profiles that were linear over the concentration range 2-20 microM dopamine. The resulting sonolinear sweep voltammograms were compared with conventional rotating disk measurements, with the former found to provide significantly increased limiting currents that were attenuable through the manipulation of the field intensity. The problem of retaining selectivity in the presence of high concentrations of ascorbate was also assessed with the addition of cupric ion prior to commencing the measurements found to efficiently negate an otherwise substantive interference. PMID- 11600313 TI - LC determination of dinitrosopiperazine in simulated gastric juice. AB - A simple and specific reversed phase HPLC method for the determination of dinitrosopiperazine in simulated gastric juice using UV detection was reported. The chromatographic resolution of the analyte and the internal standard isosorbide dinitrate was performed without extraction from the gastric juice on a reversed phase ODS column. Isocratic elution was carried out with methanol-0.02 M sodium dihydrogen phosphate (60:40 v/v, pH 3.0) at a flow rate of 1.0 ml min(-1) with UV detection at 238 nm. The calibration graph was linear over the concentration range 0.072-2.88 microg ml(-1) of dinitrosopiperazine with minimum detectability (S/N=2) of 0.01 microg ml(-1) (8 x 10(-8) M). Inter-day and intra day precisions calculated as % RSD were in the range 0.32-0.38% and 0.19-0.25% respectively. Inter-day and intra-day accuracies calculated as % error were in the range 0.18-0.21 and 0.08-0.11% respectively. The proposed method was successfully applied to the study of the possible in-vivo production of DNPZ under the standard nitrosation conditions recommended by WHO. PMID- 11600314 TI - Voltammetric determination of vitamins in a pharmaceutical formulation. AB - Direct current polarography and differential pulse polarographic methods have been developed for the qualitative as well as quantitative analysis of vitamin B1, B2 and B6. Thiamin (vitamin B1) produced a well-defined wave in 0.1 M KCl at pH 5.2 with E(1/2)=-1.2 V and E(p)=-1.22 V versus saturated calomal electrode (SCE). Riboflavin (vitamin B2) gave two distinct waves in Britton Robinson buffer at pH 1.8 with E(1/2) values=-0.13 and -0.34 V versus SCE and at pH 6.5 with E(1/2)=-1.10 V and E(p)=-1.2 V versus SCE. Pyridoxin (vitamin B6) produced a well defined wave in Britton Robinson buffer at pH 6.5 with E(1/2)=-1.7 V and E(p)= 1.68 V versus SCE. All the three vitamins under study are reversibly reduced at the electrode surface. The number of electrons involved in the electrode process for vitamin B1 and B6 is one in each case where as for the two waves of B2 it is one and two, respectively. This has been confirmed by the measurement of E(3/4) E(1/4) values and also from the log plot slopes for the reduction waves. The wave height of polarogram was found to be proportional to the vitamin concentration. The developed methods have been standardised for the determination of these compounds in pharmaceutical formulation. The concentration of vitamin B1, B2 and B6 are found to be 9.96, 9.92 and 3.01 mg, respectively in 240 mg of capsule powder of a standard company (name has not been disclosed due to secrecy purpose). The results have been found to be in excellent agreement to that claimed by the manufacturer. The observed data has been subjected to statistical analysis, which revealed high reliability and precision. PMID- 11600316 TI - Medroxyprogesterone acetate alone or synergistic with chemotherapy suppresses colony formation and DNA synthesis in C6 glioma in vitro. AB - We have studied the effects of medroxyprogesterone acetate (MPA) on C6 glioma growth in vitro in order to prove the hypothesis that it could arrest growth and induce drug sensitisation in a glial tumour as it does in breast cancer cells. Plating, thymidine-labelling index, ultra-structure, and soft agar colony growth were determined after incubation with MPA, and/or cisplatin, procarbazine and methotrexate (MTX). MPA (microg/ml) reduced the thymidine-labelling index by 41 and 73% at 48 and 96 h, respectively, and decreased colony growth by 61%. Soft agar colony inhibition by MPA was almost as potent as MTX (0.3 microg/ml), but the latter drug showed very high cytotoxicity. Electron microscopy revealed that in medroxyprogesterone treated cells myeloid bodies developed, but MTX treatment caused mainly necrosis. Medroxyprogesterone increased procarbazine and cisplatin induced colony growth and S-phase inhibition, but reduced MTX-induced thymidine labelling inhibition. In conclusion, progesterone may inhibit growth and sensitize to drugs. PMID- 11600317 TI - Expression of glial cell line-derived neurotrophic factor (GDNF) in the developing human fetal brain. AB - GDNF expression was examined immunocytochemically in developing human fetal brains obtained from aborted fetuses ranging from 7 to 39 weeks in gestational age. At 7-8 weeks, strong immunoreactivity was noted within radial glial processes, glia limitans and choroid plexus of the telencephalic vesicle. By 10 weeks, ependymal cells, primitive matrix cells and early developing cortical plate neurons showed positive staining. By 15-16 weeks, migrating neurons in the subventricular and intermediate zones and in the cortical plate were strongly positive for GDNF. The glia limitans of the cerebral cortex and subependymal astrocytes remained positive at this time. As fetal age increased, GDNF expression shifted to neurons and glial cells in the deeper structures of the brain. The most prominent GDNF staining was observed in the cytoplasm and dendrites of Purkinje cells of the cerebellum by 25 weeks and thereafter. Pyramidal neurons of the CA1 region and granule cells of the dentate fascia of the hippocampus, neurons of the entorhinal cortex, and scattered neurons within the brain stem, medulla and spinal cord all showed strong GDNF staining by 25-35 weeks. Widespread GDNF expression in neuronal and non-neuronal cells with distinct developmental shifts suggests that GDNF may play a critical role in the survival, differentiation and maintenance of neurons at different stages of development in the developing human fetal brain. PMID- 11600318 TI - Cholinergic activity modulates the survival of retinal ganglion cells in culture: the role of M1 muscarinic receptors. AB - The control of natural cell death is mediated by neurotrophins released by target, afferent and glial cells. In the present work we show that treatment of retinal cells 'in vitro' for 48 h with 25 microM carbamylcholine induced a two fold increase in retinal ganglion cells survival. This effect was dose-dependent and mediated by M1 receptors since it could be blocked by 1 microM telenzepine (a M1 receptor antagonist) and mimicked by 200 microM oxotremorine (a M1 receptor agonist). The effect of carbamylcholine was abolished by 10 microM BAPTA-AM (an intracellular Ca2+ chelator), 30 microM dantrolene (an inhibitor of ryanodinic receptors), 500 nM H-89 (an inhibitor of PKA), 1.25 microM chelerythrine chloride (an inhibitor of PKC) and 50 microM PD-98059 (a MEK inhibitor). Treatment with 10 microM genistein (an inhibitor of tyrosine kinase), 25 microM LY-294002 (a PI-3 kinase blocker), 30 nM brefeldin-A (a blocker of polypeptides release), 50 nM K 252a (a Trk receptor inhibitor) and 20 microM fluorodeoxyuridine (an inhibitor of cell proliferation) totally inhibited the effect of carbamylcholine. Taken together our results indicate that muscarinic activity controls the survival of retinal ganglion cells through a mechanism involving the release of polypeptides and activation of Irk receptors. PMID- 11600320 TI - Reactive glia support and guide axon growth in the rat thalamus during the first postnatal week. A sharply timed transition from permissive to non-permissive stage. AB - The present study demonstrates a supportive and guiding effect of the reactive glia on the postlesional axon growth in vivo, and offers a model system to compare permissive and non-permissive forms of the glial reaction. After stab wounds in early postnatal (P2-P9) rats, the reactive glia and the nerve fibers were detected by the immunohistochemical staining of glial fibrillary acidic protein (GFAP) and neurofilament protein, respectively. In the thalamus of the animals lesioned at P5 or earlier, an extraordinary bundle of fibers immunoreactive to neurofilament protein was found, corresponding to the lesion track marked by reactive glia. This bundle persisted up to 2 months, as shown by electron microscopy. When the animals were lesioned at P7 or later, the lesion track was immunonegative to neurofilament protein. Following P6 lesions, an intermediate situation was found, the strip of immunoreactive neurofilament protein was missing, or short and weak. GFAP immunostaining demonstrated a typical reactive glia in every case. As a result of the same operation, reactive glia plus a deficiency of neurofilament protein immunostaining was found in every animal in the cortex and the corpus callosum, independently from the age at lesion. The results demonstrate that the permissive nature of the glial reaction depends on the lesioned area as well, and changes to a non-permissive effect in a short time interval. PMID- 11600319 TI - Brain-derived neurotrophic factor and TrkB tyrosine kinase receptor gene expression in zebrafish embryo and larva. AB - The genes that encode the neurotrophin family of secreted polypeptides and the Trk family of high affinity neurotrophin transmembrane protein tyrosine kinase receptors are induced at the time of neurogenesis in mammals and are known to play critical roles in nervous system development. We show here that in contrast to mammals, the genes encoding the neurotrophin brain-derived neurotrophic factor (BDNF) and the neurotrophin receptor TrkB are expressed throughout embryonic development in the zebrafish. At the embryonic stages preceding transcription of endogenous genes all cells contain BDNF transcripts and immunoreactive BDNF and the trkB transcripts lack the region that encodes a kinase domain. As development proceeds, progressively fewer cells contain BDNF transcripts and by the time of neurogenesis the trkB transcripts encode a kinase-domain. In the 4-day-old larva, a small subset of specialized sensory cells on the surface and cells in deeper structures including the gill arches, fin, and cloaca express the BDNF gene at high levels in a promoter-specific fashion. This progressive restriction of BDNF gene expression must involve an extinction of BDNF gene transcription in some and induction of high levels of transcription in a promoter-specific fashion in other cells. PMID- 11600321 TI - Evidence that the loss of Purkinje cells and deep cerebellar nuclei neurons in homozygous weaver is not related to neurogenetic patterns. AB - To determine whether the neurogenetic patterns of Purkinje cells and deep cerebellar nuclei neurons were normal in weaver homozygotes and whether the degeneration of those neuronal types was linked to their time of origin, [3H] thymidine autoradiography was applied on sections of homozygous weaver mice and normal controls on postnatal day 90. The experimental animals were the offspring of pregnant dams injected with [3H] thymidine on embryonic days 11-12, 12-13, 13 14 and 14-15. The results show that the onset of neurogenesis, its pattern of peaks and valleys, and its total span were similar between wild type and homozygous weaver in the cerebellar areas analyzed, indicating that the loss of Purkinje cells and deep cerebellar nuclei neurons is not related to neurogenetic patterns. In weaver homozygotes, the loss of Purkinje cells and deep cerebellar nuclei neurons followed a lateral to medial gradient of increasing severity. Thus, the vermis and the fastigial nucleus, which are medially located, presented the most important neuron loss, whereas in the lateral hemisphere and the dentate nucleus, neuron loss was spared. PMID- 11600322 TI - The Multiple Tasks Test: development and normal strategies. AB - Simultaneous challenge of posture and cognition ("dual tasks") may predict falls better than tests of isolated components of postural control. We describe a new balance test (the Multiple Tasks Test, MTT) which (1) is based upon simultaneous assessment of multiple (>2) postural components; (2) represents everyday situations; and (3) can be applied by clinicians. Relevant risk factors for falls and actual fall circumstances (identified from a prospective survey in Parkinson's disease) were used to design functional tests (or postural "components") that resembled everyday situations. We distinguished a "cognitive" component (answering serial questions) from largely "motor" components (standing up, sitting down, turning around, walking, avoiding obstacles, and touching the floor). Four additional components included carrying an empty or loaded tray, wearing shoes with slippery soles and reduced illumination. These components were combined to yield eight separate tasks of increasing complexity that were executed sequentially. The first and simplest task consisted of standing up, undisturbed walking, turning around and sitting down. For each of the next tasks, a new component was added to the earlier and otherwise identical task. All components within each task had to be performed simultaneously. Errors were defined as Hesitations (slowed performance) or Blocks (complete cessation), which were scored separately for execution of motor and cognitive components. Speed of performance was not stressed, but was measured for all tasks. The MTT was administered to 50 young healthy subjects (mean age 27.6 years) and 13 elderly subjects (mean age 62.0 years). To study learning effects, 20 different young subjects (mean age 21.0 years) received the MTT in order of gradually decreasing complexity. For subjects who received the MTT in order of increasing difficulty, 62% in both age groups performed all eight tasks without any Errors in the motor components. Among those making Errors, the proportion of subjects that made motor Errors increased significantly as the tasks became more complex (F(1,7)=2.66, P<0.05). This increase differed across the two groups (significant interaction of Group by Task; F(1,7)=3.07, P=0.01) because more elderly subjects produced motor Errors during the most complex tasks. Cognitive Errors increased even more than motor Errors with task complexity, and this increase was most pronounced in young subjects (significant interaction of Group by Error Type by Task; F(1,1,7)=3.85, P=0.001). Only eight young (16%) and four elderly subjects (30.8%) performed the MTT without any motor or cognitive Errors, again suggesting that more young subjects made cognitive Errors. Among subjects who received the MTT in reverse order, motor errors were more common than among subjects who received the MTT in order of increasing complexity (F(1,7)=5.90, P<0.05), particularly during the two most difficult tasks. The elderly performed all tasks slower than the young subjects. We conclude that the MTT is a new balance test based upon a multiple task design that resembles everyday situations. Performance by healthy subjects revealed interesting insights into normal postural strategies. For complex postural tasks, healthy subjects favour execution of motor components over execution of a cognitive component ("posture first" strategy). Young subjects were more inclined than elderly subjects to use this strategy. Motor learning influenced performance among subjects who received the MTT in order of increasing difficulty. Further studies must determine whether the MTT can be used to evaluate balance disorders. PMID- 11600323 TI - Attentional demands for postural control: the effects of aging and sensory reintegration. AB - The aim of this experiment was to examine if, with aging, the task of reintegrating sensory information perturbs balance and requires additional attentional demand. Young adults and the elderly were asked to maintain a stable upright posture while standing on a force platform. Visual and ankle proprioceptive information were removed or perturbed and suddenly reinserted. Subjects also had to respond vocally as quickly as possible to an unpredictable auditory stimulus presented before or following a sensory reintegration and in control conditions. Reaction times to the auditory stimuli were used as an index of the attentional demands necessary for calibrating the postural system. Reintegration of proprioception in absence of vision and under vision yielded a faster center of pressure velocity for both groups. This effect, however, was more important for the elderly than the young adults. An increased attentional demand was observed for both groups when proprioceptive information had to be reintegrated in absence of vision. Altogether, these results propose that, for the elderly persons, postural contexts requiring a reweighting of sensory inputs could lead to increased risk for loss of balance and falls if insufficient attentional resources are allocated to the postural task. PMID- 11600324 TI - Attention influences sensory integration for postural control in older adults. AB - This study investigated the influence of attention on the sensory integration component of postural control in young and older adults. Eighteen young and 18 older healthy subjects performed information-processing tasks during different postural challenge conditions. Postural conditions included seated, standing on a firm surface, standing on a sway-referenced floor, and standing on a sway referenced floor while viewing a sway-referenced scene. During each condition, reaction time (RT) was measured during two simple and one inhibitory RT tasks. For the inhibitory task, the time required to inhibit an action was derived, termed the inhibitory time (IT). Performing a RT task was associated with increased postural sway in older subjects, but not in young subjects. The greatest influence of RT task on sway of older subjects was found during the sway referenced floor/sway-referenced scene condition. Conversely, postural condition had an influence on RT task performance in both young and older subjects. The IT was increased in both young and older subjects only during the sway-referenced floor/scene condition. These results suggest that the sensory integration component of postural control in particular seems to require attention. Further, our data suggest that attentional processes related to inhibitory control are engaged when sensory integration requirements are high. PMID- 11600325 TI - Differential diagnosis of proprioceptive and vestibular deficits using dynamic support-surface posturography. AB - The objective of this study was to evaluate how effective dynamic support-surface posturography could be as a diagnostic tool in patients with balance disorders (proprioceptive or vestibular deficits). Specifically, we studied whether measures of trunk control and simple toe-up rotational perturbations, selected using statistical techniques, could provide a better diagnostic yield than either the analysis of lower-body movements or use of a "nulled" ankle input paradigm. The test subjects were 15 control subjects, five patients with bilateral peripheral vestibular loss (VL) and five patients with selective bilateral, lower leg proprioceptive loss (PL). Amplitudes and onset latencies of bursts of EMG activity in upper and lower-leg muscles, paraspinals and trapezius muscles, concurrent changes in ankle torque, and peak amplitudes of upper-leg, lower-leg, and trunk angular-velocities were measured. Stimuli included three different types of sudden movements of the support surface, a "nulled" ankle input paradigm, a simple toe-up rotation paradigm, and a combined toe-up rotation and backwards translation of the support surface. All stimuli were tested under eyes open and eyes-closed conditions. For each type of movement and condition the diagnostic classification accuracy (i.e. the overall sensitivity and specificity) was calculated based on those posturography measures providing the highest diagnostic separation between the three populations. Both patient groups showed increased trunk sway, changed support-surface reaction forces and muscle amplitudes compared with controls for toe-up and "nulled" test conditions. Measures providing the greatest diagnostic utility were the amplitude of trunk angular velocity (increased in VL subjects, less so in PL), the amplitude of balance-correcting paraspinal responses (increased in VL subjects, decreased in PL subjects), the amplitude of trapezius stabilising responses (increased in both patient groups) for simple toe-up rotations under eyes-closed conditions. We conclude, that diagnosis of balance disorders using dynamic posturography is best achieved using measures of trunk control following pure toe-up rotational perturbations tested under eyes-closed conditions. PMID- 11600326 TI - Trunk sway measures of postural stability during clinical balance tests: effects of a unilateral vestibular deficit. AB - This research evaluated whether quantified measures of trunk sway during clinical balance tasks are sensitive enough to identify a balance disorder and possibly specific enough to distinguish between different types of balance disorder. We used a light-weight, easy to attach, body-worn apparatus to measure trunk angular velocities in the roll and pitch planes during a number of stance and gait tasks similar to those of the Tinetti and CTSIB protocols. The tasks included standing on one or two legs both eyes-open and closed on a foam or firm support-surface, walking eight tandem steps, walking five steps while horizontally rotating or pitching the head, walking over low barriers, and up and down stairs. Tasks were sought, which when quantified might provide optimal screening for a balance pathology by comparing the test results of 15 patients with a well defined acute balance deficit (sudden unilateral vestibular loss (UVL)) with those of 26 patients with less severe chronic balance problems caused by a cerebellar-pontine angle-tumour (CPAT) prior to surgery, and with those of 88 age- and sex-matched healthy subjects. The UVL patients demonstrated significantly greater than normal trunk sway for all two-legged stance tasks especially those performed with eyes closed on a foam support surface. Sway was also greater for walking while rotating or pitching the head, and for walking eight tandem steps on a foam support surface. Interestingly, the patients could perform gait tasks such as walking over barriers almost normally, however took longer. CPAT patients had trunk sway values intermediate between those of UVL patients and normals. A combination of trunk sway amplitude measurements (roll angle and pitch velocity) from the stance tasks of standing on two legs eyes closed on a foam support, standing eyes open on a normal support surface, as well as from the gait tasks of walking five steps while rotating, or pitching the head, and walking eight tandem steps on foam permitted a 97% correct recognition of a normal subject and a 93% correct recognition of an acute vestibular loss patient. Just over 50% of CPAT patients could be classified into a group with intermediate balance deficits, the rest were classified as normal. Our results indicate that measuring trunk sway in the form of roll angle and pitch angular velocity during five simple clinical tests of equilibrium, four of which probe both stance and gait control under more difficult sensory conditions, can reliably and quantitatively distinguish patients with a well defined balance deficit from healthy controls. Further, refinement of these trunk sway measuring techniques may be required if functions such as preliminary diagnosis rather than screening are to be attempted. PMID- 11600327 TI - Fingertip touch improves postural stability in patients with peripheral neuropathy. AB - The purpose of this work was to determine whether fingertip touch on a stable surface could improve postural stability during stance in subjects with somatosensory loss in the feet from diabetic peripheral neuropathy. The contribution of fingertip touch to postural stability was determined by comparing postural sway in three touch conditions (light, heavy and none) in eight patients and eight healthy control subjects who stood on two surfaces (firm or foam) with eyes open or closed. In the light touch condition, fingertip touch provided only somatosensory information because subjects exerted less than 1 N of force with their fingertip to a force plate, mounted on a vertical support. In the heavy touch condition, mechanical support was available because subjects transmitted as much force to the force plate as they wished. In the no touch condition, subjects held the right forefinger above the force plate. Antero-posterior (AP) and medio lateral (ML) root mean square (RMS) of center of pressure (CoP) sway and trunk velocity were larger in subjects with somatosensory loss than in control subjects, especially when standing on the foam surface. The effects of light and heavy touch were similar in the somatosensory loss and control groups. Fingertip somatosensory input through light touch attenuated both AP and ML trunk velocity as much as heavy touch. Light touch also reduced CoP sway compared to no touch, although the decrease in CoP sway was less effective than with heavy touch, particularly on the foam surface. The forces that were applied to the touch plate during light touch preceded movements of the CoP, lending support to the suggestion of a feedforward mechanism in which fingertip inputs trigger the activation of postural muscles for controlling body sway. These results have clinical implications for understanding how patients with peripheral neuropathy may benefit from a cane for postural stability in stance. PMID- 11600328 TI - Postural control and cognitive task performance in healthy participants while balancing on different support-surface configurations. AB - Postural control during normal upright stance in humans is a well-learned task. Hence, it has often been argued that it requires very little attention. However, many studies have recently shown that postural control is modified when a cognitive task is executed simultaneously especially in the elderly and in the presence of pathology. This study examined postural control modifications when a cognitive task of varying difficulty levels is added. Postural stance difficulty was also varied. Results from this study suggest that a generalized capacity interference may occur due to the larger interference found with the addition of a cognitive task in the more novel and difficult postural task. Because the performance of the cognitive task was tapered by a speed-difficulty trade-off, it was not possible to determine whether a change in the level of difficulty of the cognitive task occurred and if it would produce larger dual-task interference. PMID- 11600329 TI - The translating platform paradigm: perturbation displacement waveform alters the postural response. AB - The translating platform paradigm is widely used to investigate the regulation of upright standing and locomotion. This study investigated how the displacement waveform characteristics underlying the translating platform perturbation are revealed in the resulting postural response. Eight participants experienced a series of backward-directed perturbations using a hydraulically driven forceplate. Two ranges of platform displacement (5 and 15 cm) in combination with two peak velocities (40 and 60 cm/s) were achieved using three distinct waveforms for platform displacement: (a) RAMP: ramp onset and ramp offset, (b) Ramp-to Parabola (R-P): ramp onset with parabolic offset and (c) SINE: sine-wave onset with sine wave offset. Our findings indicated that the unique and distinctive acceleration and deceleration characteristics that result from the three different platform displacement waveforms significantly altered the postural response to the perturbation. PMID- 11600330 TI - Effect of age on lower extremity joint moment contributions to gait speed. AB - We investigated the relationship of hip, knee and ankle function to gait speed in healthy elderly subjects. We hypothesized that the hip extension moment would make a significantly smaller contribution to propulsion power in the elderly than in healthy young subjects even when the elders were ambulating at speeds comparable to those of the young subjects. We analyzed the free speed gait of 16 young and 14 elderly subjects, and the fast gait of the elder subjects. In elderly subjects free speed gait linear power transfer from the leg to the upper body due to the hip and knee moments was decreased compared with young subjects walking at their normal gait speed. However, when asked to walk fast, elders significantly increase knee and hip moment contributions to hip linear power to levels comparable to those of young subjects at a similar speed. These results refute our hypothesis and support our earlier findings indicating that kinematic alterations at the hip are a cause of reduced gait speed in the elderly. PMID- 11600331 TI - Changes in muscle moment arms following split tendon transfer of tibialis anterior and tibialis posterior. AB - Moment arms of tibialis anterior (TA) and tibialis posterior (TP) about the subtalar and talocrural joint axes were measured in anatomic specimens both before and after split tendon transfers. These procedures are commonly performed to correct hindfoot varus, a gait deformity that is often seen in patients with cerebral palsy, stroke, and brain injury. Split tendon transfer significantly reduced the inversion moment arms of tibialis anterior and tibialis posterior at all subtalar joint angles except for the most everted position in the case of TA. Changes in subtalar joint moment arms produced by split tendon transfer, especially those seen in TA, were variable, suggesting that the procedure may be susceptible to technical errors, especially related to balancing tensions in the medial and lateral tendon halves. Talocrural joint moment arms of both muscles were preserved following split tendon transfer. This study presents the first measurements of the moment arms of split transferred muscles. These characterizations of the mechanics of split tendon transfer will aid in the planning and assessment of these procedures. PMID- 11600333 TI - Surgical pathology of the parietal pericardium: a study of 344 cases (1993-1999). AB - Among 344 cases with surgically resected parietal pericardium, ages ranged from 1 to 87 years (mean, 55), and 64% were male. Causes of pericardial disease included neoplastic (33%), idiopathic (30%), iatrogenic (23%), and others (14%). Pericardial constriction (Group 1) represented the largest group (143 cases, 76% male). Maximal pericardial thickness was 1-17 mm (mean, 4). Fibrotic thickening occurred in 96%. Chronic lymphoplasmacytic inflammation affected 73% (mild or moderate in 97%). Calcification was uncommon (gross in 28%, microscopic in 8%), and granulomas were rare (4%, none tubercular). Constriction was idiopathic in 49% and iatrogenic (postpericardiotomy or postirradiation) in 41%. Neoplasms and cysts (Group 2) represented the second largest group (96 cases). Among 43 cases with secondary pericardial involvement, carcinomas accounted for 53% and lymphomas 21%. Forty cases (Group 3) had pericardial effusions (75% chronic), which were idiopathic in 28% and postpericardiotomy in 23%. Thirty-three cases (Group 4) had acute or recurrent pericarditis clinically, which was idiopathic in 70%. Lastly, 32 cases (Group 5) had pericardial resection for conditions unrelated to primary pericardial disease. In conclusion, pericardial constriction tended to be nontubercular (100%), nongranulomatous (96%), idiopathic or iatrogenic (90%), and noncalcific (64%), and it could occur with normal pericardial thickness (4%). Because considerable overlap in the gross and microscopic features existed among cases with noncalcific pericardial constriction (Group 1), pericardial effusions (Group 3), and pericarditis (Group 4), clinical information was necessary to provide an accurate clinicopathologic interpretation. PMID- 11600334 TI - The role of myocardial gap junctions in electrical conduction and arrhythmogenesis. AB - Electrical activation of the heart requires cell-cell transfer of current via gap junctions, arrays of densely packed protein channels that permit intercellular passage of ions and small molecules. Because current transfer occurs only at gap junctions, the spatial distribution and biophysical properties of gap junction channels are important determinants of the conduction properties of cardiac muscle. Gap junction channels are composed of members of a multigene family of proteins called connexins. As a general rule, individual cells express multiple connexins, which creates the potential for considerable functional diversity in gap junction channels. Although gap junction channels are relatively nonselective in their permeability to ions and small molecules, cardiac myocytes actively adjust their level of coupling by multiple mechanisms including changes in connexin expression, regulation of connexin trafficking and turnover, and modulation of channel properties. In advanced stages of heart disease, connexin expression and intercellular coupling are diminished, and gap junction channels become redistributed. These changes have been strongly implicated in the pathogenesis of lethal ventricular arrhythmias. Ongoing studies in genetically engineered mice are revealing insights into the role of individual gap junction channel proteins in normal cardiac function and arrhythmogenesis. PMID- 11600335 TI - Structural evaluation of porcine heart valve prostheses with radiofrequency ultrasound. AB - BACKGROUND: Bioprosthetic heart valve use is limited by progressive degeneration. Early degenerative changes are often occult, making assessment of tissue integrity difficult. Ultrasound tissue characterization may detect alterations in tissue structure and allow early detection of leaflet degeneration. METHODS: Using a modified echocardiographic unit (Acuson), radiofrequency (RF) integrated backscatter amplitude (IBA) (integral/RF/dt) was measured in 38 leaflets from nine explanted and six control porcine valves. Regions of interest in each leaflet were studied using four ultrasound frequencies. Radiographic gray scale mean and leaflet thickness were measured at each region of interest. Percent collagen and mineral were calculated for each region of interest using color image processing of histologic sections and compared to IBA. RESULTS: IBA values for control vs. explanted leaflets were (mean value+/-standard deviation): 8.2+/ 4.69 dB vs. -4.7+/-4.64 dB at 7.0 MHz; -5.8+/-4.34 dB vs. -3.1+/-5.34 dB at 5.0 MHz; -3.8+/-3.38 dB vs. -2.1+/-3.18 dB at 3.5 MHz; and -9.0+/-4.58 dB vs. -7.1+/ 4.25 dB at 2.5 MHz. Collagen content was 27.7+/-8.50% vs. 33.2+/-10.90%, mineral content was 0.1+/-0.10% vs. 2.1+/-4.30%, and radiographic gray scale mean was 150.6+/-1.96 vs. 145.3+/-5.14 for control vs. explanted leaflets, respectively. For control and explanted leaflets IBA, collagen content, mineral content, and radiographic gray scale mean were different (control vs. explanted P<0.05). Leaflet thickness was also noted to be different between the two groups. IBA was different among explanted leaflets with low, medium, and high mineral content. CONCLUSION: IBA was found to be a useful technique to differentiate normal from explanted porcine prosthetic valves in vitro. This method may be useful in the serial assessment of bioprosthetic leaflet degenerative properties in vivo. PMID- 11600336 TI - Atheromas that cause fatal thrombosis are usually large and frequently accompanied by vessel enlargement. AB - Several lines of clinical evidence show that AMI frequently occurs at sites with mild to moderate degree of coronary stenosis. The degree of luminal stenosis depends on plaque deposition and degree of vessel remodeling, features poorly assessed by coronary angiography. This postmortem study tested the hypothesis that the size of coronary atheroma and the type of remodeling distinguish culprit lesion responsible for fatal AMI from equi-stenotic nonculprit lesion in the same coronary tree. The main coronary branches from 36 consecutive patients with fatal AMI were studied. The culprit lesion (Group 1) and an equi-stenotic nonculprit segment (Group 2) obtained in measurements of another coronary branch from the same patient were compared. Morphometry and plaque composition was assessed in both groups. Compared to Group 2, Group 1 had larger areas of: plaque 9.6 vs. 4.7 mm(2), vessel 12.7 vs. 7.4 mm(2) and lumen 1.7 vs. 1.2 mm(2); (P< .01). Positive remodeling was more frequent in Group 1 than Group 2: 21/30 (70%) vs. 8/26 (31%). Plaque area correlated positively with lipid core and macrophages and negatively with fibrosis and smooth muscle cells. Atherosclerotic plaques that cause fatal thrombosis are more frequently positively remodeled and tend to be larger than nonculprit plaques with the same degree of cross-sectional stenosis. We tested whether arterial remodeling and plaque size vary between segments containing a fatal thrombosed plaque versus an equi-stenotic nonculprit plaque. Culprit vessel segments had higher cross-sectional areas of intimal plaque and of vessel wall than equi-stenotic nonculprit plaques. The cross-sectional area of the vessel correlated positively with both the lipid core area and CD68(+) macrophage content, and negatively with fibrosis area and smooth muscle cell content. These results add elements explaining limitations of angiography in identifying plaques and provide new insights into the role of remodeling in plaque instability. PMID- 11600338 TI - Mechanisms of Douglas-fir resistance to western spruce budworm defoliation: bud burst phenology, photosynthetic compensation and growth rate. AB - We compared growth rates among mature interior Douglas-fir (Pseudotsuga menziesii var. glauca (Beissn.) Franco) trees showing resistance or susceptibility to defoliation caused by western spruce budworm (Choristoneura occidentalis Freeman), and among clones and half-sib seedling progeny of these trees in a greenhouse. We also investigated bud burst phenology and photosynthetic responses of clones to budworm defoliation in greenhouse experiments. Resistant mature trees had a higher radial growth rate than susceptible trees, especially during periods of budworm defoliation. Clones from resistant trees grew larger crowns than clones from susceptible trees, whereas stem base diameter at the ground line and height did not differ. Half-sib seedling progeny from resistant trees had larger stem diameter, height, and total biomass than progeny from susceptible trees. Mean 5-year radial growth increment of mature trees was more strongly correlated with growth of seedlings than with growth of clones. Clones from resistant trees had later bud burst than clones from susceptible trees, and budworm defoliation of clones depended on the degree of synchrony between bud burst phenology and budworm larval feeding. Clones of resistant and susceptible mature trees showed similar responses of net photosynthetic rate to 2 years of budworm defoliation. We conclude that phenotypic differences in crown condition of Douglas-fir trees following western spruce budworm defoliation are influenced by tree genotype and that high growth rate and late bud burst phenology promote tree resistance to budworm defoliation. PMID- 11600337 TI - Ventricular septal defect and multiple aneurysms. AB - A 41-year-old man with a small perimembranous ventricular septal defect (VSD) developed aneurysms and aortic elongation, tortuosity and dissecting aneurysm. The asymptomatic VSD, without pulmonary circulatory disturbance, was considered hemodynamically benign and too small to warrant surgical closure. However, prolonged strenuous sporting activities could have potentiated premature development of aortic sclerosis and the unusual vascular lesions secondary to the VSD, and an injury may have precipitated mural dissection in the vulnerable aortic wall. Clinicopathological analysis of the unusual complications associated with the VSD suggests that closure of the defect at an early age should be considered to possibly obviate premature degenerative, valvular and vascular changes in adulthood and also secondary endocardial infection. PMID- 11600339 TI - Genotypic variation in growth and physiological responses of Finnish hybrid aspen (Populus tremuloides x P. tremula) to elevated tropospheric ozone concentration. AB - Saplings of six Finnish hybrid aspen (Populus tremuloides Michx. x P. tremula L.) clones were exposed to 0, 50, 100 and 150 ppb ozone (O3) for 32 days in a chamber experiment to determine differences in O3 sensitivity among genotypes. Based on the chamber experiment, three clones with intermediate sensitivity to O3 were selected for a free-air O3 enrichment experiment in which plants were exposed for 2 months to either ambient air (control) or air containing 1.3 x the ambient O3 concentration. We measured stem height and radial growth, number of leaves, dry mass and relative growth rate of leaves, stem and roots, visible leaf injuries, net photosynthesis and stomatal conductance of the clones. There was high clonal variation in susceptibility to O3 in the chamber experiment, indicated by foliar injuries and differential reductions in growth and net photosynthesis. In the free-air O3 enrichment experiment, ozone caused a shift in resource allocation toward stem height growth, thereby altering the shoot to root balance. In both experiments, low O3 concentrations tended to stimulate growth of most clones, whereas 100 and 150 ppb O3 in the chamber experiment impaired growth of most clones. However, growth of the most O3-tolerant clone was not significantly affected by any O3 treatment. PMID- 11600340 TI - Stem growth and respiration in loblolly pine plantations differing in soil resource availability. AB - Stem respiration and growth in 10-year-old loblolly pine (Pinus taeda L.) plantations were measured monthly during the third year of fertilization and irrigation treatments to determine whether soil resource availability differentially altered growth and respiration in stem tissue. Fertilized trees had significantly greater stem biomass, stem nitrogen concentration ([N]) and growth rate than unfertilized trees. Stem respiration (Rt) was significantly greater in fertilized trees when expressed on a per unit surface area (Rt,a, micromol CO2 m-2 s-1), sapwood volume (Rt,v, micromol CO2 m-3 s-1), or mass (Rt,w, nmol CO2 g-1 s-1) basis; however, there was no difference between treatments when expressed as a function of stem N content (Rt,n, micromol CO2 (mol N)-1 s-1). Irrigation had no significant effect on Rt or annual stem growth. Daily total respiration (Rd, mol CO2 m-2 day-1) and stem diameter growth both had a seasonal bimodal pattern with peaks in early spring and midsummer. Stem [N] declined significantly during the growing season. Stem growth rate and [N] explained 75% of the seasonal variation in temperature-normalized Rt,a. The mature tissue method was used to partition total stem respiration (Rt) into maintenance (Rm) and growth (Rg) components. There was a linear correlation between winter Rt,v, a measure of basal Rm, and sapwood N content; however, Rt,v per unit N was greater in January before diameter growth started than in the following December after growth ceased, indicating that Rt,v declined as stem diameter increased. Consequently, estimates of annual maintenance respiration (RM) based on January data were 44% higher than estimates based on December data. Growth respiration was correlated with stem growth rate (r2 = 0.55). The growth respiration coefficient (rg)-the slope of the relationship between Rg and stem growth rate-was 0.24. Respiration accounted for 37% of annual stem carbon budget. Stem carbon-use efficiency (CUE)-the ratio of stem growth to stem growth plus respiration-averaged 0.63 and was unaffected by fertilization. PMID- 11600341 TI - Age-related changes in foliar morphology and physiology in red spruce and their influence on declining photosynthetic rates and productivity with tree age. AB - The contribution of changes in meristem behavior to age-related decline in forest productivity is poorly understood. We studied age-related trends in needle morphology and gas exchange in a population of red spruce (Picea rubens Sarg.) growing in a multi-cohort stand where trees ranged from first-year germinants to trees over 150 years old, as well as in grafted scions from these trees. In the field study, age-related trends in foliar morphology were determined in six cohorts ranging in age from 2 to 120 years, and differences in gas exchange characteristics were compared between 60- and 120-year age classes. In a common rootstock study, scions from trees representing 20-, 60-, and 120-year cohorts were grafted onto juvenile rootstock and maintained for three growing seasons, after which morphological and physiological foliar attributes were evaluated. The field study revealed significant age-related trends in foliar morphology, including decreasing specific leaf area, and increasing needle width, projected area, and width/length ratio. Similar trends were apparent in foliage from the grafted scions. Both in situ foliage and shoots of grafted scions from the oldest cohort showed significantly lower photosynthetic rates than their counterparts from younger trees; however, differences in stomatal conductance and internal CO(2) concentrations were not significant. These results suggest that: (1) foliage of red spruce exhibits age-related trends in both morphology and physiology; (2) age-related decreases in photosynthetic rates contribute to declining productivity in old red spruce; (3) declines in photosynthetic rates result from nonstomatal limitations; and (4) age-related changes in morphology and physiology are inherent in meristems and persist for at least 3 years in scions grafted to juvenile rootstock. PMID- 11600342 TI - Nitrogen availability modifies the ozone responses of Scots pine seedlings exposed in an open-field system. AB - Three-year-old Scots pine (Pinus sylvestris L.) seedlings were exposed to either ambient or elevated (1.5-1.6 x ambient) ozone concentration ([O3]) for three growing seasons in an open-field fumigation facility where they were irrigated during the growing season with a nutrient solution providing nitrogen (N) at 70 (LN treatment), 100 (control) or 150% (HN treatment) of the optimum supply rate. Treatment effects were most evident during the third year of exposure, when the ambient [O3] + HN treatment enhanced whole-plant biomass, root/shoot dry weight ratio, needle pigment concentrations and the number of chloroplast plastoglobuli in the mesophyll cells in current-year (C) needles, whereas it reduced starch accumulation in C needles and abscission of 2-year-old (C+2) needles. In the control fertilization, 3 years of exposure to elevated [O3] decreased stem-base diameter and increased K concentration and electron density of chloroplast stroma in C needles. Plants in the HN treatment exposed for 3 years to elevated [O3] had significantly lower heights, current-year main shoot length and root/shoot dry mass ratio than control plants, and increased abscission of C+2 needles. In contrast, O3-induced changes in the ultrastructure of mesophyll cells were most evident in seedlings grown for 3 years in the LN treatment. We conclude that, in Scots pine, a relatively O3-tolerant species, chronic O3 exposure leads to cumulative growth reduction, increased needle abscission and changes in carbon allocation that are strongly influenced by plant N availability. PMID- 11600343 TI - Responses of foliar delta13C, gas exchange and leaf morphology to reduced hydraulic conductivity in Pinus monticola branches. AB - We tested the hypothesis that branch hydraulic conductivity partly controls foliar stable carbon isotope ratio (delta13C) by its influence on stomatal conductance in Pinus monticola Dougl. Notching and phloem-girdling treatments were applied to reduce branch conductivity over the course of a growing season. Notching and phloem girdling reduced leaf-specific conductivity (LSC) by about 30 and 90%, respectively. The 90% reduction in LSC increased foliar delta13C by about 1 per thousand (P < 0.0001, n = 65), whereas the 30% reduction in LSC had no effect on foliar delta13C (P = 0.90, n = 65). Variation in the delta13C of dark respiration was similar to that of whole-tissues when compared among treatments. These isotopic measurements, in addition to instantaneous gas exchange measurements, suggested only minor adjustments in the ratio of intercellular to atmospheric CO2 partial pressures (ci/ca) in response to experimentally reduced hydraulic conductivity. A strong correlation was observed between stomatal conductance (gs) and photosynthetic demand over a tenfold range in gs. Although ci/ca and delta13C appeared to be relatively homeostatic, current year leaf area varied linearly as a function of branch hydraulic conductivity (r2 = 0.69, P < 0.0001, n = 18). These results suggest that, for Pinus monticola, adjustment of leaf area is a more important response to reduced branch conductivity than adjustment of ci/ca. PMID- 11600344 TI - Growth and annual ring structure of Larix sibirica grown at different carbon dioxide concentrations and nutrient supply rates. AB - We compared effects of ambient (360 vpm) and elevated (720 vpm) carbon dioxide concentration ([CO2]) and high and low nutrient supply rates on stem growth, annual ring structure and tracheid anatomy of Siberian larch (Larix sibirica Ledeb.) seedlings over two growing seasons. Elevated [CO2] had no significant effect on either stem height or diameter growth; however, both stem height and diameter growth were enhanced by the high nutrient supply rate, and these increases were stimulated by elevated [CO2]. Elevated [CO2] tended to increase the width of the annual xylem ring, the number of cells in a radial file spanning the ring, and tracheid lumen diameter, whereas it tended to reduce cell wall thickness, although there were no statistically significant CO2 effects on tracheid anatomy. Changes in tracheid cell morphology seemed to be dependent on changes in shoot elongation rates. PMID- 11600346 TI - Critical annotations to the use of azole antifungals for plant protection. PMID- 11600345 TI - Use of aminoglycosides in treatment of infections due to intracellular bacteria. PMID- 11600347 TI - Molecular analysis of antibiotic resistance gene clusters in vibrio cholerae O139 and O1 SXT constins. AB - Many recent Asian clinical Vibrio cholerae E1 Tor O1 and O139 isolates are resistant to the antibiotics sulfamethoxazole (Su), trimethoprim (Tm), chloramphenicol (Cm), and streptomycin (Sm). The corresponding resistance genes are located on large conjugative elements (SXT constins) that are integrated into prfC on the V. cholerae chromosome. We determined the DNA sequences of the antibiotic resistance genes in the SXT constin in MO10, an O139 isolate. In SXT(MO10), these genes are clustered within a composite transposon-like structure found near the element's 5' end. The genes conferring resistance to Cm (floR), Su (sulII), and Sm (strA and strB) correspond to previously described genes, whereas the gene conferring resistance to Tm, designated dfr18, is novel. In some other O139 isolates the antibiotic resistance gene cluster was found to be deleted from the SXT-related constin. The El Tor O1 SXT constin, SXT(ET), does not contain the same resistance genes as SXT(MO10). In this constin, the Tm resistance determinant was located nearly 70 kbp away from the other resistance genes and found in a novel type of integron that constitutes a fourth class of resistance integrons. These studies indicate that there is considerable flux in the antibiotic resistance genes found in the SXT family of constins and point to a model for the evolution of these related mobile elements. PMID- 11600348 TI - Effects of azithromycin and rifampin on Chlamydia trachomatis infection in vitro. AB - An in vitro cell culture model was used to investigate the long-term effects of azithromycin, rifampin, and the combination of azithromycin and rifampin on Chlamydia trachomatis infection. Although standard in vitro susceptibility testing indicated efficient inhibition by azithromycin, prolonged treatment did not reveal a clear elimination of chlamydia from host cells. Chlamydia were temporarily arrested in a persistent state, characterized by culture-negative, but viable, metabolically active chlamydia, as demonstrated by the presence of short-lived rRNA transcripts. Additionally, azithromycin induced generation of aberrant inclusions and an altered steady-state level of chlamydial antigens, with the predominance of Hsp60 protein compared to the level of the major outer membrane protein. Treatment with azithromycin finally resulted in suppression of rRNA synthesis. Chlamydial lipopolysaccharide and processed, functional rRNA were detectable throughout the entire incubation period. These in vitro data show a good correlation to those from some recent clinical investigations that have reported on the persistence of chlamydia, despite appropriate antibiotic treatment with azithromycin. Rifampin was highly active by in vitro susceptibility testing, but prolonged exposure to rifampin alone for up to 20 days resulted in the emergence of resistance. No development of resistance to rifampin was observed when chlamydia-infected cells were incubated with a combination of azithromycin and rifampin. This combination was shown to be more efficient than azithromycin alone, in that suppression of rRNA synthesis occurred earlier. Thus, such a combination may prove more useful than azithromycin alone. PMID- 11600349 TI - In vitro antimicrobial activities of bakuchiol against oral microorganisms. AB - Bakuchiol was isolated from the seeds of Psoralea corylifolia, a tree native to China with various uses in traditional medicine, followed by extraction with ether and column chromatography combined with silica gel and octyldecyl silane. In this study, the antimicrobial activities of bakuchiol against some oral microorganisms were evaluated in vitro. The cell growth of Streptococcus mutans was inhibited in a bakuchiol concentration-dependent manner, and growth of S. mutans was completely prevented by 20 microg of bakuchiol per ml. The bactericidal effect of bakuchiol on S. mutans was dependent on temperature and stable under the following conditions: sucrose, 0 to 10% (wt/vol); pH, 3.0 to 7.0; organic acids (3% [wt/vol] citric and malic acids). Bakuchiol showed bactericidal effects against all bacteria tested, including S. mutans, Streptococcus sanguis, Streptococcus salivarius, Streptococcus sobrinus, Enterococcus faecalis, Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Actinomyces viscosus, and Porphyromonas gingivalis, with MICs ranging from 1 to 4 microg/ml and the sterilizing concentration for 15 min ranging from 5 to 20 microg/ml. Furthermore, bakuchiol was also effective against adherent cells of S. mutans in water insoluble glucan in the presence of sucrose and inhibited the reduction of pH in the broth. Thus, bakuchiol would be a useful compound for development of antibacterial agents against oral pathogens and has great potential for use in food additives and mouthwash for preventing and treating dental caries. PMID- 11600350 TI - Family of class 1 integrons related to In4 from Tn1696. AB - The class 1 integron In28, found in the multidrug resistance transposon Tn1403, was found to be located in the res site of the backbone transposon and is flanked by a 5-bp direct duplication, indicating that it reached this position by transposition. In28 has a backbone structure related to that of In4, but has lost internal sequences, including the sul1 gene, due to an IS6100-mediated deletion. In28 also lacks the partial copy of IS6100 found in In4 and contains different gene cassettes, blaP1, cmlA1, and aadA1. In1, the class 1 integron found in the multidrug resistance plasmid R46, is also located in a putative res site and belongs to the In4 group. In1 has a shorter internal deletion than In28 and has also lost one end. Additional integrons with structures related to In4 were also found in databases, and most of them had also lost either one end or internal regions or both. Tn610 belongs to this group. PMID- 11600351 TI - DPC 681 and DPC 684: potent, selective inhibitors of human immunodeficiency virus protease active against clinically relevant mutant variants. AB - Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC(90)). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC(90)s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC(50) values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC(50) values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir). PMID- 11600352 TI - Development and validation of limited-sampling strategies for predicting amoxicillin pharmacokinetic and pharmacodynamic parameters. AB - Amoxicillin plasma concentrations (n = 1,152) obtained from 48 healthy subjects in two bioequivalence studies were used to develop limited-sampling strategy (LSS) models for estimating the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (C(max)), and the time interval of concentration above MIC susceptibility breakpoints in plasma (T>MIC). Each subject received 500-mg amoxicillin, as reference and test capsules or suspensions, and plasma concentrations were measured by a validated microbiological assay. Linear regression analysis and a "jack-knife" procedure revealed that three-point LSS models accurately estimated (R(2), 0.92; precision, <5.8%) the AUC from 0 h to infinity (AUC(0-infinity)) of amoxicillin for the four formulations tested. Validation tests indicated that a three-point LSS model (1, 2, and 5 h) developed for the reference capsule formulation predicts the following accurately (R(2), 0.94 to 0.99): (i) the individual AUC(0-infinity) for the test capsule formulation in the same subjects, (ii) the individual AUC(0 infinity) for both reference and test suspensions in 24 other subjects, and (iii) the average AUC(0-infinity) following single oral doses (250 to 1,000 mg) of various amoxicillin formulations in 11 previously published studies. A linear regression equation was derived, using the same sampling time points of the LSS model for the AUC(0-infinity), but using different coefficients and intercept, for estimating C(max). Bioequivalence assessments based on LSS-derived AUC(0 infinity)'s and C(max)'s provided results similar to those obtained using the original values for these parameters. Finally, two-point LSS models (R(2) = 0.86 to 0.95) were developed for T>MICs of 0.25 or 2.0 microg/ml, which are representative of microorganisms susceptible and resistant to amoxicillin. PMID- 11600353 TI - In vitro and in vivo effects of 14alpha-demethylase (ERG11) depletion in Candida glabrata. AB - Sterol 14alpha-demethylase (ERG11) is the target enzyme of azole antifungals that are widely used for the treatment of fungal infections. Candida glabrata is known to be less susceptible to fluconazole than most Candida albicans strains, and the incidence of C. glabrata infection has been increasing mostly in conjunction with the use of azole antifungals. Recently, it has been reported that C. glabrata can rescue the defect of ergosterol biosynthesis by incorporating cholesterol from serum. To explore the effect of inactivating Erg11p in C. glabrata, we generated mutant strains in which the ERG11 gene was placed under the control of tetracycline-regulatable promoters. In these mutants, expression of the ERG11 gene can be repressed by doxycycline (DOX). All mutants showed a growth defect in the presence of DOX. The numbers of CFU of the mutants were lowered by only 1/10 with DOX treatment. In these mutants, accumulation of 4,14-dimethylzymosterol, which differs from an accumulated abnormal sterol detected in C. albicans and Saccharomyces cerevisiae treated with fluconazole, was observed by DOX treatment. Although such phenotypes were also observed in serum-containing media by DOX treatment, they were alleviated. Furthermore, the mutant could grow in DOX treated mice without a severe reduction in the number of cells. Thus, depleting the expression of the ERG11 gene lowered the number of CFU by only 1/10 due to the accumulation of 4,14-demethylzymosterol in vitro, and it did not result in the defective growth of fungal cells in mice. These results suggested that Erg11p is not an ideal target molecule of antifungals for C. glabrata. PMID- 11600354 TI - Single ribosomal protein mutations in antibiotic-resistant bacteria analyzed by mass spectrometry. AB - Mutations in several ribosomal proteins are known to be related to antibiotic resistance. For several strains of Escherichia coli, the mutated protein is known but the amino acid actually altered has not been documented. Characterization of these determinants for antibiotic resistance in proteins will further the understanding of the precise mechanism of the antibiotic action as well as provide markers for resistance. Mass spectrometry can be used as a valuable tool to rapidly locate and characterize mutant proteins by using a small amount of material. We have used electrospray and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry to map out all 56 ribosomal proteins in E. coli based on intact molecular masses. We used this fingerprinting approach to locate variants of ribosomal proteins displaying a change in mass. In particular we have studied proteins responsible for streptomycin, erythromycin, and spectinomycin resistance in three strains of E. coli, and then we characterized each mutation responsible for resistance by analyzing tryptic peptides of these proteins by using MALDI-TOF and nanoelectrospray tandem mass spectrometry. The results provided markers for antibiotic resistance and demonstrated that mass spectrometry can be used to rapidly investigate changes in individual proteins from a complex with picomole amounts of protein. PMID- 11600355 TI - Rifampin resistance in Mycobacterium kansasii is associated with rpoB mutations. AB - Rifampin is the most potent drug used in the treatment of disease due to Mycobacterium kansasii. A 69-bp fragment of rpoB, the gene that encodes the beta subunit of the bacterial RNA polymerase, was sequenced and found to be identical in five rifampin-susceptible clinical isolates of M. kansasii. This sequence showed 87% homology with the Mycobacterium tuberculosis gene, with an identical deduced amino acid sequence. In contrast, missense mutations were detected in the same fragment amplified from five rifampin-resistant isolates. A rifampin resistant strain generated in vitro also harbored an rpoB gene missense mutation that was not present in the parent isolate. All mutations detected (in codons 513, 526, and 531) have previously been described in rifampin-resistant M. tuberculosis isolates. Rifampin MICs determined by E-test were <1 mg/liter for all rifampin-susceptible isolates and >256 mg/liter for all rifampin-resistant ones. In addition, four of the five rifampin-resistant isolates were also resistant to rifabutin. We have thus shown a strong association between rpoB gene missense mutations and rifampin resistance in M. kansasii. Although our results are derived from a small number of isolates and confirmation with larger numbers would be useful, they strongly suggest that mutations within rpoB form the molecular basis of rifampin resistance in this species. PMID- 11600356 TI - Clearance of infection with Mycobacterium bovis BCG in mice is enhanced by treatment with S28463 (R-848), and its efficiency depends on expression of wild type Nramp1 (resistance allele). AB - The mouse bcg host resistance gene is known to control the activation of host macrophages for killing of intracellular parasites like Leishmania donovani as well as intracellular bacteria, including Mycobacterium bovis BCG and Salmonella enterica serovar Typhimurium. The Nramp1 gene has been mapped to this locus and affects the efficiency of macrophage activation. It has been shown that imidazoquinoline compounds, including S28463, are able to improve the clearance of a number of intracellular pathogens such as herpes simplex virus 2, human papillomavirus, and Leishmania. The goal of this study was to determine whether S28463 is efficient against infection with another intracellular pathogen, M. bovis BCG, and to determine the molecular basis underlying this effect. To achieve this, B10A.Nramp1(r) and B10A.Nramp1(-/-) mice were infected with M. bovis BCG and treated with S28463. The bacterial content in the spleen from these mice was assayed by a colony-forming assay. In addition, in vitro experiments were performed using bone marrow-derived macrophage cell lines from these mice. These cells were treated with S28463 and/or gamma interferon (IFN-gamma), and nitric oxide (NO) production was measured. Our study was able to show that S28463 acts in synergy with IFN-gamma to increase the production of NO in vitro. We were also able to demonstrate that mice that carried the resistant allele of the Nramp1 gene and were infected with M. bovis BCG responded to treatment with S28463, resulting in a decreased bacterial load after 2 weeks of treatment. Mice that do not express the Nramp1 gene responded only to a very large dose of S28463, and the response was not as efficient as that observed in mice carrying a wild-type Nramp1 allele. Our data provide evidence for the potential of S28463 as an immunomodulator that may be helpful in designing efficient strategies to improve host defense against mycobacterial infection. PMID- 11600357 TI - Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. AB - The antifungal drug susceptibilities of two collections of Cryptococcus neoformans isolates obtained through active laboratory-based surveillance from 1992 to 1994 (368 isolates) and 1996 to 1998 (364 isolates) were determined. The MICs of fluconazole, itraconazole, and flucytosine were determined by the National Committee for Clinical Laboratory Standards broth microdilution method; amphotericin B MICs were determined by the E-test. Our results showed that the MIC ranges, the MICs at which 50% of isolates are inhibited (MIC(50)s), and the MIC(90)s of these four antifungal agents did not change from 1992 to 1998. In addition, very small numbers of isolates showed elevated MICs suggestive of in vitro resistance. The MICs of amphotericin B were elevated (>or=2 microg/ml) for 2 isolates, and the MICs of flucytosine were elevated (>or=32 microg/ml) for 14 isolates. Among the azoles, the fluconazole MIC was elevated (>or=64 microg/ml) for 8 isolates and the itraconazole MIC (>or=1 microg/ml) was elevated for 45 isolates. Analysis of 172 serial isolates from 71 patients showed little change in the fluconazole MIC over time. For isolates from 58 patients (82% of serial cases) there was either no change or a twofold change in the fluconazole MIC. In contrast, for isolates from seven patients (12% of serial cases) the increase in the MIC was at least fourfold. For isolates from another patient there was a 32 fold decrease in the fluconazole MIC over a 1-month period. We conclude that in vitro resistance to antifungal agents remains uncommon in C. neoformans and has not significantly changed with time during the past decade. PMID- 11600358 TI - Role of penicillin-binding protein 4 in expression of vancomycin resistance among clinical isolates of oxacillin-resistant Staphylococcus aureus. AB - It has been reported that penicillin-binding protein 4 (PBP4) activity decreases when a vancomycin-susceptible Staphylococcus aureus isolate is passaged in vitro to vancomycin resistance. We analyzed the PBP profiles of four vancomycin intermediately susceptible S. aureus (VISA) clinical isolates and found that PBP4 was undetectable in three isolates (HIP 5827, HIP 5836, and HIP 6297) and markedly reduced in a fourth (Mu50). PBP4 was readily visible in five vancomycin susceptible, oxacillin-resistant S. aureus (ORSA) isolates. The nucleotide sequences of the pbp4 structural gene and flanking sequences did not different between the VISA and vancomycin-susceptible isolates. Overproduction of PBP4 on a high-copy-number plasmid in the VISA isolates produced a two- to threefold decrease in vancomycin MICs. Inactivation of pbp4 by allelic replacement mutagenesis in three vancomycin-susceptible ORSA strains (COL, RN450M, and N315) led to a decrease in vancomycin susceptibility, an increase in highly vancomycin resistant subpopulations, and decreased cell wall cross-linking by high performance liquid chromatography analysis. Complementation of the COL mutant with plasmid-encoded pbp4 restored the vancomycin MIC and increased cell wall cross-linking. These data suggest that alterations in PBP4 expression are at least partially responsible for the VISA phenotype. PMID- 11600359 TI - Efficacies of moxifloxacin, ciprofloxacin, and vancomycin against experimental endocarditis due to methicillin-resistant Staphylococcus aureus expressing various degrees of ciprofloxacin resistance. AB - The new 8-methoxyquinolone moxifloxacin was tested against two ciprofloxacin susceptible Staphylococcus aureus strains (strains P8 and COL) and two ciprofloxacin-resistant derivatives of strain P8 carrying a single grlA mutation (strain P8-4) and double grlA and gyrA mutations (strain P8-128). All strains were resistant to methicillin. The MICs of ciprofloxacin and moxifloxacin were 0.5 and 0.125 mg/liter, respectively, for P8; 0.25 and 0.125 mg/liter, respectively, for COL; 8 and 0.25 mg/liter, respectively, for P8-4; and >or=128 and 2 mg/liter, respectively, for P8-128. In vitro, the rate of spontaneous resistance of P8 and COL was 10(-7) on agar plates containing ciprofloxacin at two times the MIC, whereas it was 0.1). Similarly, reduced susceptibility was more common in isolates responsible for hospital-acquired infections (30.9%) than in other adult inpatient (21.0%; P = 0.04) and outpatient (21.4%; P = 0.06) isolates. Isolates from pediatric patients were less likely to be resistant (1.3 versus 12.0%; P < 0.01) but were nearly as likely to have reduced susceptibility (17.7 versus 21.9%; P > 0.1) as nonpediatric isolates. There was an inverse relationship in the proportion of isolates that were resistant versus the proportion that had reduced susceptibility among isolates from individual hospitals (R = 0.031; P < 0.05). In an analysis of isolates from two hospitals, all 9 resistant strains possessed double point mutations in gyrA and all 19 strains with reduced susceptibility strains had single point mutations; no mutations were found among fully susceptible strains. Risk factors for resistance included underlying cancer (odds ratio [OR], 83; 95% confidence interval [CI(95)], 7.3 to 2,241; P < 0.001), exposure to a quinolone (OR, undefined; P = 0.02), and exposure to a nonquinolone antibiotic (OR, 20; CI(95), 2.2 to 482; P < 0.001); underlying cancer was the only independent risk factor (OR, 83; CI(95), 8.6 to 807; P < 0.001). There were no significant associations between any of these factors and reduced susceptibility. Whereas acute and chronic quinolone use in cancer patients is a major selective pressure for resistance, other undetermined but distinct selective pressures appear to be more responsible for reduced susceptibility to fluoroquinolones in E. coli. PMID- 11600361 TI - Pharmacodynamics and bactericidal activity of moxifloxacin in experimental Escherichia coli meningitis. AB - Moxifloxacin, an 8-methoxyquinolone with broad-spectrum activity in vitro, was studied in the rabbit model of Escherichia coli meningitis. The purposes of this study were to evaluate the bactericidal effectiveness and the pharmacodynamic profile of moxifloxacin in cerebrospinal fluid (CSF) and to compare the bactericidal activity with that of ceftriaxone and meropenem therapy. After induction of meningitis, animals were given single doses of 10, 20, and 40 mg/kg or divided-dose regimens of 5, 10, and 20 mg/kg twice, separated by 6 h. After single doses, the penetration of moxifloxacin into purulent CSF, measured as percentage of the area under the concentration-time curve (AUC) in CSF relative to the AUC in plasma, was approximately 50%. After single doses of 10, 20, and 40 mg/kg, the maximum CSF concentration (C(max)) values were 1.8, 4.2, and 4.9 microg/ml, respectively; the AUC values (total drug) were 13.4, 25.4, and 27.1 microg/ml x h, respectively, and the half-life values (t(1/2)) were 6.7, 6.6, and 4.7 h, respectively. The bacterial killing in CSF for moxifloxacin, calculated as the Deltalog(10) CFU per milliliter per hour, at 3, 6, and 12 h after single doses of 10, 20, and 40 mg/kg were -5.70, -6.62, and -7.02; -7.37, -7.37, and 6.87; and -6.62, -6.62, and -6.62, respectively, whereas those of ceftriaxone and meropenem were -4.18, -5.24, and -4.43, and -3.64, -3.59, and -4.12, respectively. The CSF pharmacodynamic indices of AUC/MBC and C(max)/MBC were interrelated (r = 0.81); there was less correlation with T > MBC (r = 0.74). In this model, therapy with moxifloxacin appears to be at least as effective as ceftriaxone and more effective than meropenem therapy in eradicating E. coli from CSF. PMID- 11600362 TI - BMS-284756 in experimental cephalosporin-resistant pneumococcal meningitis. AB - BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial activity, including Streptococcus pneumoniae. The purpose of this study was to evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae (CRSP). Meningitis was induced in rabbits by intracisternal inoculation of CRSP. BMS-284756 was given intravenously 16 h after intracisternal inoculation in single doses of 2.5 (n = 5 animals), 5 (n = 6), 10 (n = 6), 20 (n = 8), and 30 mg/kg (n = 6), in two doses of 10 mg/kg each separated by 5 h (n = 4), and as a 20-mg/kg dose followed 5 h later by 10 mg/kg (n = 5). The MICs and MBCs of BMS-284756, ceftriaxone, and vancomycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 microg/ml, respectively. After single doses of 10, 20, and 30 mg/kg, the maximum concentrations in cerebrospinal fluid (CSF) (mean +/- standard deviation) were 0.32 +/- 0.12, 0.81 +/- 0.38, and 1.08 +/- 0.43 microg/ml, respectively; the elimination half-life in CSF was 4.5 to 6.3 h. The CSF bacterial killing rates (BKR) at 5 h of the single-dose regimens of 10, 20 and 30 mg/kg were -0.84 +/- 0.48, -1.09 +/- 0.32, and -1.35 +/- 0.05 Deltalog(10) CFU/ml/h. The BKR(0-5) of the divided regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was -0.82 +/- 0.52 and -1.24 +/- 0.34 Deltalog(10) CFU/ml/h, respectively. The BKR(0-5) of the combined therapy with vancomycin and ceftriaxone was -1.09 +/- 0.39 Deltalog(10) CFU/ml/h. The penetration of BMS 284756 into purulent CSF relative to plasma was 14 to 25%. The bactericidal effect of BMS-284756 in CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or divided dose was as effective as standard therapy with vancomycin and ceftriaxone. PMID- 11600363 TI - Bronchopulmonary disposition of the ketolide telithromycin (HMR 3647). AB - Telithromycin (HMR 3647) is the first member of a new family of antimicrobials, the ketolides, developed specifically for the treatment of community-acquired respiratory tract infections. Telithromycin has proven in vitro activity against both common and atypical respiratory tract pathogens. The penetration of telithromycin into bronchopulmonary tissues and subsequent elimination from these sites were evaluated in four groups (groups A, B, C, and D) of six healthy male subjects who received telithromycin at 800 mg once daily for 5 days. Subjects in groups A, B, C, and D underwent fiberoptic bronchoscopy and bronchoalveolar lavage 2, 8, 24, and 48 h after receipt of the last dose, respectively. The concentration of telithromycin in the alveolar macrophages, epithelial lining fluid (ELF), and plasma was determined by the agar diffusion method with Bacillus subtilis ATCC 6633 as the test organism. The concentration of telithromycin in alveolar macrophages markedly exceeded that in plasma, reaching up to 146 times the concentration in plasma 8 h after dosing (median concentration, 81 mg/liter). Telithromycin was retained in alveolar macrophages 24 h after dosing (median concentration, 23 mg/liter), and it was still quantifiable 48 h after dosing (median concentration, 2.15 mg/liter). Telithromycin median concentrations in ELF also markedly exceeded concentrations in plasma (median concentration in ELF, 3.7 mg/liter 8 h after dosing). Telithromycin achieves high and sustained concentrations in ELF and in alveolar macrophages, while it maintains adequate levels in plasma, providing an ideal pharmacokinetic profile for effective treatment of community-acquired respiratory tract infections caused by either common or atypical, including intracellular, respiratory tract pathogens. PMID- 11600364 TI - Activities of new macrolides and fluoroquinolones against Mycobacterium ulcerans infection in mice. AB - Mice infected in the left hind footpad with 5 log(10) acid-fast bacilli of Mycobacterium ulcerans were divided into an untreated control group and 17 treatment groups that received one of the following regimens for 4 weeks (all doses in milligrams per kilogram): 100 mg of azithromycin (AZM), 100 mg of clarithromycin (CLR), or 50 mg of AZM for a duration of 5 days a week (daily), three times a week, or once weekly. In addition, the following regimens were administered daily: 100 mg of telithromycin (TLM), sparfloxacin (SPX), or moxifloxacin (MOX); 200 mg of levofloxacin (LVX); 100 mg of streptomycin (STR) or amikacin (AMK); 10 mg of rifampin (RIF); and the combination of 10 mg of RIF and 100 mg of AMK (RIF+AMK). After completion of treatment, mice were observed for 30 weeks. The effectiveness of treatment regimens was assessed in terms of the delay in median time to footpad swelling in treated mice compared with that in the untreated controls. Clear-cut bactericidal activity, i.e., an observed delay in footpad swelling that exceeded the period of treatment, was observed in the STR-, AMK-, and RIF+AMK-treated mice. However, all mice treated with either AMK or STR alone had swollen footpads before the end of the 30-week observation period, suggesting regrowth of M. ulcerans. In contrast, 50% of the mice treated with the RIF+AMK combination exhibited no lesion even after 30 weeks, suggesting cure. The remaining regimens could be assigned to one of three groups: (i) no activity (50 mg of AZM, 100 mg of AZM thrice weekly, TLM, and LVX); (ii) bacteriostatic activity, i.e., a delay in footpad swelling shorter than the 4-week treatment duration (100 mg of AZM daily or once weekly, CLR thrice or once weekly, and MOX); or (iii) weak bactericidal activity (CLR daily and SPX). The RIF+AMK combination and possibly RIF+STR warrant further study for the treatment of M. ulcerans infection in humans. PMID- 11600365 TI - Antibacterial activities and pharmacokinetics of E-4767 and E-5065, two new 8 chlorofluoroquinolones with a 7-azetidin ring substituent. AB - E-4767 [(-)-7-[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-8-chloro-1-cyclopropyl-1,4 dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid] and E-5065 [(-)-7-(3-amino-1 azetidinyl)-8-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3 quinolinecarboxylic acid] are two new chlorofluoroquinolones with an azetidine moiety at position 7. Their in vitro activities were evaluated in comparison with those of ciprofloxacin, ofloxacin, fleroxacin, and tosufloxacin, while ciprofloxacin was used as a reference for in vivo studies. Against gram-positive organisms, E-4767 and E-5065 were, in general, eight- and fourfold more active than tosufloxacin, which is the most potent of the reference compounds. E-4767 and E-5065 were also more potent than the reference compounds against all species of enteric bacteria tested. The MICs of E-4767 and E-5065 at which 90% of the isolates tested were inhibited (MIC(90)s) were 0.007 to 0.5 microg/ml and 0.03 to 2 microg/ml, respectively, for gram-positive organisms and 16 microg/ml). These azasordarin derivatives also showed significant activity against emerging fungal pathogens, which affect immunocompromised patients, such as Rhizopus arrhizus, Blastoschizomyces capitatus, and Geotrichum clavatum. Against these organisms, the MICs of GW 587270 ranged from 0.12 to 1 microg/ml, those of GW 479821 and GW 515716 ranged from 0.12 to 2 microg/ml, and those of GW 570009 ranged from 0.12 to 4 microg/ml. Against Fusarium oxysporum, Scedosporium apiospermum, Absidia corymbifera, Cunninghamella bertholletiae, and dermatophytes, GW 587270 was the most active compound, with MICs ranging from 4 to 16 microg/ml. Against Aspergillus spp., the MICs of the compounds tested were higher than 16 microg/ml. The in vitro selectivity of azasordarins was investigated by cytotoxicity studies performed with five cell lines and primary hepatocytes. Concentrations of compound required to achieve 50% inhibition of the parameter considered (Tox(50)s) of GW 570009, GW 587270, GW 479281, and GW 515716 in the cell lines ranged from 60 to 96, 49 to 62, 24 to 36, and 16 to 38 microg/ml, respectively. The cytotoxicity values of GW 471552 and GW 471558 were >100 microg/ml for all cell lines tested. Tox(50)s on hepatocytes were in the following order: GW 471558 > GW 471552 > GW 570009 > GW 587270 > GW 515716 > GW 479821, with values ranging from higher than 100 microg/ml to 23 microg/ml. The cytotoxicity results obtained with fully metabolizing rat hepatocytes were in total agreement with those obtained with cell lines. In summary, the in vitro activities against important pathogenic fungi and the selectivity demonstrated in mammalian cell lines justify additional studies to determine the clinical usefulness of azasordarins. PMID- 11600369 TI - Quinolone resistance mutations in Streptococcus pneumoniae GyrA and ParC proteins: mechanistic insights into quinolone action from enzymatic analysis, intracellular levels, and phenotypes of wild-type and mutant proteins. AB - Mutations in DNA gyrase and/or topoisomerase IV genes are frequently encountered in quinolone-resistant mutants of Streptococcus pneumoniae. To investigate the mechanism of their effects at the molecular and cellular levels, we have used an Escherichia coli system to overexpress S. pneumoniae gyrase gyrA and topoisomerase IV parC genes encoding respective Ser81Phe and Ser79Phe mutations, two changes widely associated with quinolone resistance. Nickel chelate chromatography yielded highly purified mutant His-tagged proteins that, in the presence of the corresponding GyrB and ParE subunits, reconstituted gyrase and topoisomerase IV complexes with wild-type specific activities. In enzyme inhibition or DNA cleavage assays, these mutant enzyme complexes were at least 8- to 16-fold less responsive to both sparfloxacin and ciprofloxacin. The ciprofloxacin-resistant (Cip(r)) phenotype was silent in a sparfloxacin-resistant (Spx(r)) S. pneumoniae gyrA (Ser81Phe) strain expressing a demonstrably wild-type topoisomerase IV, whereas Spx(r) was silent in a Cip(r) parC (Ser79Phe) strain. These epistatic effects provide strong support for a model in which quinolones kill S. pneumoniae by acting not as enzyme inhibitors but as cellular poisons, with sparfloxacin killing preferentially through gyrase and ciprofloxacin through topoisomerase IV. By immunoblotting using subunit-specific antisera, intracellular GyrA/GyrB levels were a modest threefold higher than those of ParC/ParE, most likely insufficient to allow selective drug action by counterbalancing the 20- to 40-fold preference for cleavable-complex formation through topoisomerase IV observed in vitro. To reconcile these results, we suggest that drug-dependent differences in the efficiency by which ternary complexes are formed, processed, or repaired in S. pneumoniae may be key factors determining the killing pathway. PMID- 11600370 TI - Pharmacokinetics of cefepime during continuous renal replacement therapy in critically ill patients. AB - The pharmacokinetics of cefepime were studied in 12 adult patients in intensive care units during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHDF) with a Multiflow60 AN69HF 0.60-m(2) polyacrylonitrile hollow-fiber membrane (Hospal Industrie, Meyzieu, France). Patients (mean age, 52.0 +/- 13.0 years [standard deviation]; mean weight, 96.7 +/- 18.4 kg) received 1 or 2 g of cefepime every 12 or 24 h (total daily doses of 1 to 4 g/day) by intravenous infusion over 15 to 30 min. Pre- and postmembrane blood (serum) samples and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, 8, and 12 or 24 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t(1/2)) of cefepime were 35.9 +/- 6.0 ml/min and 12.9 +/- 2.6 h during CVVH versus 46.8 +/- 12.4 ml/min and 8.6 +/- 1.4 h during CVVHDF, respectively. Cefepime clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 40 and 59% of CL(S), respectively. The results of this study confirm that continuous renal replacement therapy contributes substantially to total CL(S) of cefepime and that CVVHDF appears to remove cefepime more efficiently than CVVH. Cefepime doses of 2 g/day (either 2 g once daily or 1 g twice daily) appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC or=2 log(10)-enhanced killing at 24 h) was observed with GAT plus amikacin or a beta-lactam against 50 to 75% of strains, including strains nonsusceptible to one or both drugs. PMID- 11600385 TI - Indication of transposition of a mobile DNA element containing the vat(D) and erm(B) genes in Enterococcus faecium. AB - The vat(D) and erm(B) genes encoding streptogramin resistance in Enterococcus faecium transferred together, and a direct physical link between erm(B) and vat(D) was detected. Both the vat(D) and erm(B) probes hybridized to fragments of different sizes in the donor and transconjugants, which indicated a transposition event. PMID- 11600386 TI - Antimicrobial susceptibilities of 1,730 Haemophilus influenzae respiratory tract isolates in Spain in 1998-1999. AB - A beta-lactamase prevalence of 23% was found among 1,730 Haemophilus influenzae isolates. Ampicillin susceptibility was 70%, and 12% of beta-lactamase-negative strains presented diminished susceptibility to ampicillin (BLNAR phenotype). Susceptibility of 90% was found for cefaclor and clarithromycin, whereas it was nearly 100% for cefotaxime, cefixime, azithromycin, and cefuroxime. Ciprofloxacin resistant (0.1%) and beta-lactamase-positive amoxicillin/clavulanate-resistant (BLPACR) phenotypes (0.1%) are anecdotal so far. PMID- 11600387 TI - Efficacies of clarithromycin regimens against Mycobacterium xenopi in mice. AB - Mice were infected intravenously with 3.5 x 10(7) CFU of Mycobacterium xenopi and treated with various clarithromycin-containing regimens or left untreated for 4 weeks. All nine of the clarithromycin-containing regimens reduced the CFU counts to the levels below the pretreatment values, indicating that these regimens had a bactericidal effect on M. xenopi in mice. The rifampin-isoniazid-ethambutol regimen was significantly less bactericidal than clarithromycin alone or clarithromycin-containing combined regimens. PMID- 11600388 TI - Fungal phospholipase activity and susceptibility to lipid preparations of amphotericin B. AB - It has been postulated that phospholipases of fungal origin can affect in vitro susceptibility testing of amphotericin B lipid complex (ABLC). We used specific phospholipase-deficient mutants of Candida albicans and Cryptococcus neoformans in susceptibility testing and demonstrated that extracellular fungal phospholipase activity does not influence the in vitro susceptibilities of these two fungi to ABLC. PMID- 11600389 TI - In vitro and in vivo effects of quinupristin-dalfopristin against Pneumocystis carinii. AB - Quinupristin-dalfopristin (Q-D), which is active against bacteria and Toxoplasma gondii, was examined for its activity against Pneumocystis carinii. After 72 h of incubation with rat P. carinii in an ATP cytotoxicity assay, the 50% inhibitory concentration of Q-D was 10.6 microg/ml, a level that can be achieved in serum with high-dose administration. Q-D administered intraperitoneally at doses of 50 to 200 mg per kg of body weight per day in the treatment and 100 mg/kg/day three times per week in the prophylaxis of pneumocystosis in immunosuppressed mice reduced the organism burden up to 15- and 302-fold, respectively. We conclude that Q-D has activity against P. carinii in vitro and in vivo. PMID- 11600390 TI - Rifampin reduces concentrations of trimethoprim and sulfamethoxazole in serum in human immunodeficiency virus-infected patients. AB - To determine whether rifampin reduces concentrations of trimethoprim (TMP) and sulfamethoxazole (SMX) in serum of human immunodeficiency virus (HIV)-infected persons, levels of these agents were determined by high-performance liquid chromatography before and after more than 12 days of standard antituberculosis treatment for 10 patients who had been taking one double-strength tablet of co trimoxazole once daily for more than 1 month. Statistically significant, 47 and 23% decreases in TMP and SMX mean areas under the concentration-time curve from 0 to 24 h (AUC(0-24)), respectively, were observed after administration of rifampin. N-Acetyl-SMX profiles without and with rifampin were similar. The steady-state AUC(0-24) metabolite/parent drug ratio increased by 32% with rifampin administration. Our study shows that rifampin reduces profiles of TMP and SMX in serum of HIV-infected patients. PMID- 11600391 TI - Activities of a new fluoroketolide, HMR 3787, and its (des)-fluor derivative RU 64399 compared to those of telithromycin, erythromycin A, azithromycin, clarithromycin, and clindamycin against macrolide-susceptible or -resistant Streptococcus pneumoniae and S. pyogenes. AB - Activities of HMR 3787 and RU 64399 were compared to those of three macrolides, telithromycin, and clindamycin against 175 Streptococcus pneumoniae isolates and 121 Streptococcus pyogenes isolates. HMR3787 and telithromycin were the most active compounds tested against pneumococci. Telithromycin and RU 64399 were equally active against macrolide-susceptible (MICs, 0.008 to 0.06 microg/ml) and resistant S. pyogenes isolates, but HMR 3787 had lower MICs for ermB strains. PMID- 11600393 TI - In vivo efficacy of telithromycin (HMR3647) against Streptococcus pneumoniae and Haemophilus influenzae. AB - The in vivo activity of telithromycin against erythromycin A- and penicillin G resistant Streptococcus pneumoniae was superior to that of azithromycin, clarithromycin, cefdinir, and levofloxacin. In respiratory tract infections caused by erythromycin A-susceptible S. pneumoniae or Haemophilus influenzae in mice, telithromycin was more effective than clarithromycin and comparable to azithromycin. PMID- 11600392 TI - Novel tetracycline resistance gene, tet(32), in the Clostridium-related human colonic anaerobe K10 and its transmission in vitro to the rumen anaerobe Butyrivibrio fibrisolvens. AB - A novel tetracycline resistance gene, designated tet(32), which confers a high level of tetracycline resistance, was identified in the Clostridium-related human colonic anaerobe K10, which also carries tet(W). tet(32) was transmissible in vitro to the rumen anaerobe Butyrivibrio fibrisolvens 2221(R). The predicted gene product of tet(32) has 76% amino acid identity with Tet(O). PCR amplification indicated that tet(32) is widely distributed in the ovine rumen and in porcine feces. PMID- 11600394 TI - Susceptibilities of Eikenella corrodens, Prevotella intermedia, and Prevotella nigrescens clinical isolates to amoxicillin and tetracycline. AB - The AB Biodisk Etest showed that 106 (100%) and 98 (92%) isolates of Eikenella corrodens were susceptible to amoxicillin and tetracycline, respectively. Twenty three (68%) Prevotella intermedia isolates and 14 (67%) Prevotella nigrescens isolates were susceptible to amoxicillin. Seventy-nine percent of the P. intermedia isolates and 67% of the P. nigrescens isolates were susceptible to tetracycline. A higher percentage of beta-lactamase-producing isolates of P. intermedia and P. nigrescens were identified with selective agar containing amoxicillin than with nonselective agar. PMID- 11600395 TI - Congeners of SMAP29 kill ovine pathogens and induce ultrastructural damage in bacterial cells. AB - SMAP29, an ovine cathelicidin, was systematically altered to create a family of 23 related peptides for MIC and minimum bactericidal concentration determinations. SMAP28, SMAP29, and a derivative of SMAP29 called ovispirin were all antimicrobial. However, many congeners of SMAP29 and ovispirin were not as active as the parent molecules. With immunoelectron microscopy, SMAP29 was seen on membranes and within the cytoplasm of Pseudomonas aeruginosa PAO1. PMID- 11600396 TI - Eradication of biofilm-forming Staphylococcus epidermidis (RP62A) by a combination of sodium salicylate and vancomycin. AB - Staphylococcus epidermidis is a major cause of infections associated with indwelling medical devices. Biofilm production is an important virulence attribute in the pathogenesis of device-related infections. Therefore, elimination of these biofilms is an ideal treatment. Salicylate (5 mM) combined with 1 microg of vancomycin per ml inhibited biofilm formation by S. epidermidis (RP62A) by >or=99.9%. When biofilm-coated polystyrene beads were exposed to 5 mM sodium salicylate and 4 microg of vancomycin per ml (one-half the minimum biofilm eradication concentration), there was a >99.9% reduction in viable count. PMID- 11600397 TI - Aminoglycoside-streptothricin resistance gene cluster aadE-sat4-aphA-3 disseminated among multiresistant isolates of Enterococcus faecium. AB - Seventy-two Enterococcus faecium isolates of different origins highly resistant to nourseothricin and streptomycin were studied. Sequencing of a genomic fragment from two isolates identified a gene cluster, aadE-sat4-aphA-3, which has been isolated recently in staphylococci and Campylobacter coli. Patterns of digested PCR products of aadE-sat4-aphA-3 were identical for all isolates. PMID- 11600398 TI - In vitro and in vivo activities of sitafloxacin against Chlamydia spp. AB - The in vitro and in vivo antichlamydial activity of sitafloxacin was investigated. The MICs and minimal chlamydiacidal concentrations of sitafloxacin for various species of chlamydia ranged from 0.031 to 0.125 microg/ml. Sitafloxacin had an excellent therapeutic effect on experimental Chlamydia psittaci pneumonia and was more potent than tosufloxacin, ofloxacin, and ciproflxacin, although slightly less potent than sparfloxacin. PMID- 11600399 TI - Staphylococcus aureus mutants selected by BMS-284756. AB - BMS-284756, a novel des-fluoro(6)-quinolone, was used to select for in vitro mutants of Staphylococcus aureus ISP794. Step mutants were obtained, and the quinolone resistance-determining regions of four target genes, gyrA, gyrB, grlA, and grlB, were sequenced. The data suggest that DNA gyrase is the primary target for BMS-284756 in S. aureus. PMID- 11600401 TI - Ethics, revisited. PMID- 11600400 TI - In vitro susceptibility of Coxiella burnetii to linezolid in comparison with its susceptibilities to quinolones, doxycycline, and clarithromycin. AB - The in vitro susceptibility to linezolid shown by nine Greek isolates of Coxiella burnetii derived from patients with acute Q fever was investigated. MICs of linezolid were compared with those of pefloxacin, ciprofloxacin, ofloxacin, trovafloxacin, doxycycline, and clarithromycin using the shell vial assay. MICs of linezolid and clarithromycin ranged from 2 to 4 microg/ml; those of doxycycline, trovafloxacin, and ofloxacin ranged from 1 to 2 microg/ml; those of pefloxacin ranged from 1 to 4 microg/ml; and those of ciprofloxacin ranged from 4 to 8 microg/ml. Linezolid was effective in controlling intracellular parasites in cultures of Vero cells infected by C. burnetii. No bactericidal activity by linezolid was obtained against C. burnetii at 8 microg/ml. PMID- 11600402 TI - The promise of translational physiology. PMID- 11600403 TI - Hyperactive ENaC identifies hypertensive individuals amenable to amiloride therapy. AB - Pathophysiological features of both primary aldosteronism and pseudohyperaldosteronism are hyperactive amiloride-sensitive epithelial Na(+) channels (ENaC) and refractory hypertension. Peripheral blood lymphocytes express ENaC, which functions and is regulated similarly to ENaC expressed by renal principal cells. Thus it was hypothesized that individuals with either of these hypertensive etiologies could be identified by assessment of the function and regulation of peripheral blood lymphocyte ENaC, by whole cell patch clamp. We also tested the hypothesis that specific inhibition of hyperactive ENaC with amiloride could ameliorate the hypertension. To test these hypotheses, we solicited blood samples from normotensive, controlled hypertensive, and refractory hypertensive individuals. Lymphocytes were examined electrophysiologically to determine whether ENaC was hyperactive. All positive findings were from refractory hypertensive individuals. Nine refractory hypertensive patients had amiloride added to their hypertensive therapy. Amiloride normalized the blood pressure of four subjects. These individuals all had hyperactive ENaC. Amiloride had no effect on individuals with normal ENaC. These findings suggest that whole-cell patch clamp of peripheral blood lymphocytes can be used to identify accurately and rapidly hypertensive individuals who will respond to amiloride therapy. PMID- 11600404 TI - NHLBI workshop report: endothelial cell phenotypes in heart, lung, and blood diseases. AB - Endothelium critically regulates systemic and pulmonary vascular function, playing a central role in hemostasis, inflammation, vasoregulation, angiogenesis, and vascular growth. Indeed, the endothelium integrates signals originating in the circulation with those in the vessel wall to coordinate vascular function. This highly metabolic role differs significantly from the historic view of endothelium, in which it was considered to be merely an inert barrier. New lines of evidence may further change our understanding of endothelium, in regard to both its origin and function. Embryological studies suggest that the endothelium arises from different sites, including angiogenesis of endothelium from macrovascular segments and vasculogenesis of endothelium from microcirculatory segments. These findings suggest an inherent phenotypic distinction between endothelial populations based on their developmental origin. Similarly, diverse environmental cues influence endothelial cell phenotype, critical to not only normal function but also the function of a diseased vessel. Consequently, an improved understanding of site-specific endothelial cell function is essential, particularly with consideration to environmental stimuli present both in the healthy vessel and in development of vasculopathic disease states. The need to examine endothelial cell phenotypes in the context of vascular function served as the basis for a recent workshop sponsored by the National Heart, Lung, and Blood Institute (NHLBI). This report is a synopsis of pertinent topics that were discussed, and future goals and research opportunities identified by the participants of the workshop are presented. PMID- 11600405 TI - Oxygen sensitivity in the sheep adrenal medulla: role of SK channels. AB - The hypoxia-evoked secretion of catecholamines from the noninnervated fetal adrenal gland is essential for surviving intrauterine hypoxemia. The ion channels responsible for the initial depolarization that leads to catecholamine secretion have not been identified. Patch-clamp studies of adrenal chromaffin cells isolated from fetal and adult sheep revealed the presence of a Ca(2+)-dependent K(+) current that was reduced by hypoxia. Apamin, a blocker of small-conductance K(+) (SK) channels, reduced the Ca(2+)-dependent K(+) current, and the sensitivity of the channels to apamin indicated that the channels involved were of the SK2 subtype. In the presence of apamin, the hypoxia-evoked change in K(+) currents was largely eliminated. Both hypoxia and apamin blocked a K(+) current responsible for maintaining the resting potential of the cell, and the depolarization resulting from both led to an influx of Ca(2+). Simultaneous application of hypoxia and apamin did not potentiate the increase in cytosolic Ca(2+) concentration beyond that seen with either agent alone. Similar results were seen with curare, another blocker of SK channels. These results indicate that closure of SK2 channels would be the initiating event in the hypoxia-evoked catecholamine secretion in the adrenal medulla. PMID- 11600406 TI - Essential role of ICAM-1 in mediating monocyte adhesion to aortic endothelial cells. AB - Monocyte-endothelial cell interactions have been implicated in the pathogenesis of a number of vascular diseases that target arterial and aortic endothelium, including atherosclerosis. Many different adhesion molecules, such as intercellular adhesion molecule (ICAM)-1, are thought to mediate monocyte binding to endothelial cells during the development of these diseases. However, conflicting results have been reported regarding the specific role of ICAM-1 in these events. In this study, we used a genetic approach to determine the contribution of ICAM-1 in mediating monocyte adhesion to mouse aortic endothelial cells (MAEC) derived from both wild-type and ICAM-1(-/-) mice. Treatment of wild type MAEC with oxidized low-density lipoprotein significantly induced both WEHI 274.1 and whole blood monocyte adhesion, whereas similarly treated ICAM-1(-/-) MAEC showed a complete inhibition of monocyte binding. Dose-response treatment with tumor necrosis factor-alpha also increased monocyte adhesion to wild-type MAEC, but significant adhesion was only observed at higher doses for ICAM-1(-/-) MAEC. These data demonstrate a crucial role for ICAM-1-mediated monocyte endothelial cell interactions in response to specific stimuli involved in inflammatory vascular diseases. PMID- 11600408 TI - Upregulation of alpha(8)beta(1)-integrin in cardiac fibroblast by angiotensin II and transforming growth factor-beta1. AB - Using a novel pharmacological tool with (125)I-echistatin to detect integrins on the cell, we have observed that cardiac fibroblasts harbor five different RGD binding integrins: alpha(8)beta(1), alpha(3)beta(1), alpha(5)beta(1), alpha(v)beta(1), and alpha(v)beta(3). Stimulation of cardiac fibroblasts by angiotensin II (ANG II) or transforming growth factor-beta1 (TGF-beta1) resulted in an increase of protein and heightening by 50% of the receptor density of alpha(8)beta(1)-integrin. The effect of ANG II was blocked by an AT(1), but not an AT(2), receptor antagonist, or by an anti-TGF-beta1 antibody. ANG II and TGF beta1 increased fibronectin secretion, smooth muscle alpha-actin synthesis, and formation of actin stress fibers and enhanced attachment of fibroblasts to a fibronectin matrix. The alpha(8)- and beta(1)-subunits were colocalized by immunocytochemistry with vinculin or beta(3)-integrin at focal adhesion sites. These results indicate that alpha(8)beta(1)-integrin is an abundant integrin on rat cardiac fibroblasts. Its positive modulation by ANG II and TGF-beta1 in a myofibroblast-like phenotype suggests the involvement of alpha(8)beta(1)-integrin in extracellular matrix protein deposition and cardiac fibroblast adhesion. PMID- 11600407 TI - Role of PLCgamma and Ca(2+) in VEGF- and FGF-induced choroidal endothelial cell proliferation. AB - Although both vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors have been shown to be important in the regulation of vascular endothelial cell growth, the roles of phospholipase C (PLC)gamma and Ca(2+) in their downstream signaling cascades are still not clear. We have examined the effects of VEGF and FGF on PLCgamma phosphorylation and on changes in intracellular Ca(2+) levels in primary endothelial cells. VEGF stimulation leads to PLCgamma activation and increases in intracellular Ca(2+), which are correlated with mitogen-activated protein (MAP) kinase (MAPK) activation and cell growth. Inhibition of Ca(2+) increases by the Ca(2+) chelator 1,2-bis(2 aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA)-AM resulted in marked inhibition of MAPK activation, which was shown to be linked to regulation of cell growth in these cells. In contrast, FGF stimulation did not lead to PLCgamma activation or to changes in intracellular Ca(2+) levels, although MAPK phosphorylation and stimulation of cell proliferation were observed. Neither BAPTA-AM nor the PLC inhibitor U-73122 had an effect on these FGF-stimulated responses. These data demonstrate a direct role for PLCgamma and Ca(2+) in VEGF regulated endothelial cell growth, whereas this signaling pathway is not linked to FGF-mediated effects in primary endothelial cells. Thus endothelial cell specific factors regulate the ability of VEGF receptors and FGF receptors to couple to this signaling pathway. PMID- 11600409 TI - Actin depolymerization via the beta-adrenoceptor in airway smooth muscle cells: a novel PKA-independent pathway. AB - Actin is a major functional and structural cytoskeletal protein that mediates such diverse processes as motility, cytokinesis, contraction, and control of cell shape and polarity. While many extracellular signals are known to mediate actin filament polymerization, considerably less is known about signals that mediate depolymerization of the actin cytoskeleton. Human airway smooth muscle cells were briefly exposed to isoproterenol, forskolin, or the cAMP-dependent protein kinase A (PKA) agonist stimulatory diastereoisomer of adenosine 3',5'-cyclic monophosphate (Sp-cAMPS). Actin polymerization was measured by concomitant staining of filamentous actin with FITC-phalloidin and globular actin with Texas red DNase I. Isoproterenol, forskolin, or Sp-cAMPS induced actin depolymerization, indicated by a decrease in the intensity of filamentous/globular fluorescent staining. The PKA inhibitor Rp diastereomer of adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS) completely inhibited forskolin-stimulated depolymerization, whereas it only partially inhibited isoproterenol-induced depolymerization. The protein tyrosine kinase inhibitors genistein or tyrphostin A23 also partially inhibited isoproterenol-induced actin depolymerization. In contrast, the combination of Rp-cAMPS and either tyrosine kinase inhibitor had an additive effect at inhibiting isoproterenol-induced actin depolymerization. These results suggest that both PKA-dependent and -independent pathways mediate actin depolymerization in human airway smooth muscle cells. PMID- 11600410 TI - Evidence for functional role of epsilonPKC isozyme in the regulation of cardiac Na(+) channels. AB - Investigation of the role of individual protein kinase C (PKC) isozymes in the regulation of Na(+) channels has been largely limited by the lack of isozyme selective modulators. Here we used a novel peptide-specific activator (epsilonV1 7) of epsilonPKC and other peptide isozyme-specific inhibitors in addition to the general PKC activator phorbol 12-myristate 13-acetate (PMA) to dissect the role of individual PKCs in the regulation of the human cardiac Na(+) channel hH1, heterologously expressed in Xenopus oocytes. Peptides were injected individually or in combination into the oocyte. Whole cell Na(+) current (I(Na)) was recorded using two-electrode voltage clamp. epsilonV1-7 (100 nM) and PMA (100 nM) inhibited I(Na) by 31 +/- 5% and 44 +/- 8% (at -20 mV), respectively. These effects were not seen with the scrambled peptide for epsilonV1-7 (100 nM) or the PMA analog 4alpha-phorbol 12,13-didecanoate (100 nM). However, epsilonV1-7- and PMA-induced I(Na) inhibition was abolished by epsilonV1-2, a peptide-specific antagonist of epsilonPKC. Furthermore, PMA-induced I(Na) inhibition was not altered by 100 nM peptide-specific inhibitors for alpha-, beta-, delta-, or etaPKC. PMA and epsilonV1-7 induced translocation of epsilonPKC from soluble to particulate fraction in Xenopus oocytes. This translocation was antagonized by epsilonV1-2. In native rat ventricular myocytes, PMA and epsilonV1-7 also inhibited I(Na); this inhibition was antagonized by epsilonV1-2. In conclusion, the results provide evidence for selective regulation of cardiac Na(+) channels by epsilonPKC isozyme. PMID- 11600411 TI - Functional and molecular adaptations in skeletal muscle of myoglobin-mutant mice. AB - Myoglobin is a cytoplasmic hemoprotein that is restricted to cardiomyocytes and oxidative skeletal myofibers and facilitates oxygen delivery during periods of high metabolic demand. Myoglobin content in skeletal muscle increases in response to hypoxic conditions. However, we previously reported that myoglobin-null mice are viable and fertile. In the present study, we define important functional, cellular, and molecular compensatory adaptations in the absence of myoglobin. Mice without myoglobin manifest adaptations in skeletal muscle that include a fiber type transition (type I to type II in the soleus muscle), increased expression of the hypoxia-inducible transcription factors hypoxia-inducible factor (HIF)-1alpha and HIF-2 (endothelial PAS domain protein), stress proteins such as heat shock protein 27, and the angiogenic growth factor vascular endothelial growth factor (soleus muscle), as well as increased nitric oxide metabolism (extensor digitorum longus). The resulting changes in angiogenesis, nitric oxide metabolism, and vasomotor regulation are likely to account for preserved exercise capacity of animals lacking myoglobin. These results demonstrate that mammalian organisms are capable of a broad spectrum of adaptive responses that can compensate for a potentially serious defect in cellular oxygen transport. PMID- 11600412 TI - Endothelin-1 decreases glutamate uptake in primary cultured rat astrocytes. AB - Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is also known to induce a wide spectrum of biological responses in nonvascular tissue. In this study, we found that ET-1 (100 nM) inhibited the glutamate uptake in cultured astrocytes expressing the glutamate/aspartate transporter (GLAST); astrocytes did not express the glutamate transporter-1 (GLT-1). The V(max) and the K(m) of the glutamate uptake were reduced by 57% and 47%, respectively. Application of the ET(A) and ET(B) receptor antagonists BQ-123 and BQ-788 partly inhibited the ET-1 evoked decrease in the glutamate uptake, whereas the nonspecific ET receptor antagonist bosentan completely inhibited this decrease. Incubation of the cultures with pertussis toxin abolished the effect of ET-1 on the uptake. The ET 1-induced decrease in the glutamate uptake was independent of extracellular free Ca(2+) concentration, whereas the intracellular Ca(2+) antagonists thapsigargin and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester abolished the effect of ET-1 on the glutamate uptake. Incubation with the protein kinase C (PKC) antagonist staurosporine, but not with the fatty acid-binding protein bovine serum albumin, prevented the ET-1-induced decrease in the glutamate uptake. These results suggest that ET-1 impairs the high-affinity glutamate uptake in cultured astrocytes through a G protein-coupled mechanism, involving PKC and changes in intracellular Ca(2+). PMID- 11600413 TI - Airway surface liquid pH in well-differentiated airway epithelial cell cultures and mouse trachea. AB - Airway surface liquid (ASL) pH has been proposed to be important in the pathophysiology of cystic fibrosis, asthma, and cough. Ratio image analysis was used to measure pH in the ASL after staining with the fluorescent pH indicator 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-dextran. ASL pH in bovine airway cell cultures grown at an air-liquid interface was 6.98 +/- 0.06 in the absence and 6.81 +/- 0.04 in the presence of HCO/CO(2). Steady-state ASL pH changed in parallel to changes in bath pH and was acidified by Na(+) or Cl(-) replacement but was not affected by the inhibitors amiloride, glibenclamide, or 4,4'-dinitrostilbene-2,2'-disulfonic acid. In response to sudden acidification or alkalization of the ASL by approximately 0.4 pH units by HCl/NaOH, ASL pH recovered to its initial value at a rate of 0.035 pH units/min (-HCO) and 0.060 pH units/min (+HCO); the pH recovery rate was reduced by amiloride and H(2)DIDS. In anesthetized mice in which the trachea was surgically exposed for measurement of BCECF-dextran fluorescence through the translucent tracheal wall, ASL pH was 7.14 +/- 0.01. ASL pH was sensitive to changes in blood pH created by metabolic (HCl or NaHCO(3) infusion) or respiratory (hyperventilation, hypoventilation) mechanisms. ASL pH is thus primarily determined by basolateral fluid pH, and H(+)/OH(-) transport between the ASL and basolateral fluid involves amiloride sensitive Na(+)/H(+) exchange and stilbene-sensitive Cl(-)/HCO exchange. The rapid response of ASL pH to changes in systemic acid-base status may contribute to airway hypersensitivity in asthma and other airway diseases. PMID- 11600414 TI - Coupling strength between localized Ca(2+) transients and K(+) channels is regulated by protein kinase C. AB - Localized Ca(2+) transients resulting from inositol trisphosphate (IP(3)) dependent Ca(2+) release couple to spontaneous transient outward currents (STOCs) in murine colonic myocytes. Confocal microscopy and whole cell patch-clamp techniques were used to investigate coupling between localized Ca(2+) transients and STOCs. Colonic myocytes were loaded with fluo 3. Reduction in external Ca(2+) ([Ca(2+)](o)) reduced localized Ca(2+) transients but increased STOC amplitude and frequency. Simultaneous recordings of Ca(2+) transients and STOCs showed increased coupling strength between Ca(2+) transients and STOCs when [Ca(2+)](o) was reduced. Gd(3+) (10 microM) did not affect Ca(2+) transients but increased STOC amplitude and frequency. Similarly, an inhibitor of Ca(2+) influx, 1-2-(4 methoxyphenyl)-2-[3-(4-methoxyphenyl)propoxy]ethyl-1H-imidazole (SKF-96365), increased STOC amplitude and frequency. A protein kinase C (PKC) inhibitor, GF 109203X, also increased the amplitude and frequency of STOCs but had no effect on Ca(2+) transients. Phorbol 12-myristate 13-acetate (1 microM) reduced STOC amplitude and frequency but did not affect Ca(2+) transients. 4alpha-Phorbol (1 microM) had no effect on STOCs or Ca(2+) transients. Single channel studies indicated that large-conductance Ca(2+)-activated K(+) (BK) channels were inhibited by a Ca(2+)-dependent PKC. In summary 1) Ca(2+) release from IP(3) receptor-operated stores activates Ca(2+)-activated K(+) channels; 2) Ca(2+) influx through nonselective cation channels facilitates activation of PKC; and 3) PKC reduces the Ca(2+) sensitivity of BK channels, reducing the coupling strength between localized Ca(2+) transients and BK channels. PMID- 11600415 TI - Regulation of Cyr61 gene expression by mechanical stretch through multiple signaling pathways. AB - The cysteine-rich protein 61 (Cyr61) is a signaling molecule with functions in cell migration, adhesion, and proliferation. This protein is encoded by an immediate early gene whose expression is mainly induced by serum growth factors. Here we show that Cyr61 mRNA levels increase sharply in response to cyclic mechanical stretch applied to cultured bladder smooth muscle cells. Stretch induced changes of Cyr61 transcripts were transient and accompanied by an increase of the encoded protein that localized mainly to the cytoplasm and nucleus of the cells. With the use of pharmacological agents that interfere with known signaling pathways, we show that transduction mechanisms involving protein kinase C and phosphatidylinositol 3-kinase activation partly blocked stretch induced Cyr61 gene expression. Selective inhibition of Rho kinase pathways altered this stretch effect as well. Meanwhile, using inhibitors of the actin cytoskeleton, we show that Cyr61 gene expression is sensitive to mechanisms that sense actin dynamics. These results establish the regulation of Cyr61 gene by mechanical stretch and provide clues to the key signaling molecules involved in this process. PMID- 11600416 TI - NHE3-dependent cytoplasmic alkalinization is triggered by Na(+)-glucose cotransport in intestinal epithelia. AB - Cytoplasmic pH (pH(i)) was evaluated during Na(+)-glucose cotransport in Caco-2 intestinal epithelial cell monolayers. The pH(i) increased by 0.069 +/- 0.002 within 150 s after initiation of Na(+)-glucose cotransport. This increase occurred in parallel with glucose uptake and required expression of the intestinal Na(+)-glucose cotransporter SGLT1. S-3226, a preferential inhibitor of Na(+)/H(+) exchanger (NHE) isoform 3 (NHE3), prevented cytoplasmic alkalinization after initiation of Na(+)-glucose cotransport with an ED(50) of 0.35 microM, consistent with inhibition of NHE3, but not NHE1 or NHE2. In contrast, HOE-694, a poor NHE3 inhibitor, failed to significantly inhibit pH(i) increases at <500 microM. Na(+)-glucose cotransport was also associated with activation of p38 mitogen-activated protein (MAP) kinase, and the p38 MAP kinase inhibitors PD 169316 and SB-202190 prevented pH(i) increases by 100 +/- 0.1 and 86 +/- 0.1%, respectively. Conversely, activation of p38 MAP kinase with anisomycin induced NHE3-dependent cytoplasmic alkalinization in the absence of Na(+)-glucose cotransport. These data show that NHE3-dependent cytoplasmic alkalinization occurs after initiation of SGLT1-mediated Na(+)-glucose cotransport and that the mechanism of this NHE3 activation requires p38 MAP kinase activity. This coordinated regulation of glucose (SGLT1) and Na(+) (NHE3) absorptive processes may represent a functional activation of absorptive enterocytes by luminal nutrients. PMID- 11600417 TI - Differential MAP kinase activation and Na(+)/H(+) exchanger phosphorylation by H(2)O(2) in rat cardiac myocytes. AB - Bursts in reactive oxygen species production are important mediators of contractile dysfunction during ischemia-reperfusion injury. Cellular mechanisms that mediate reactive oxygen species-induced changes in cardiac myocyte function have not been fully characterized. In the present study, H(2)O(2) (50 microM) decreased contractility of adult rat ventricular myocytes. H(2)O(2) caused a concentration- and time-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and c-Jun NH(2)-terminal kinase (JNK) mitogen activated protein (MAP) kinases in adult rat ventricular myocytes. H(2)O(2) (50 microM) caused transient activation of ERK1/2 and p38 MAP kinase that was detected as early as 5 min, was maximal at 20 min (9.6 +/- 1.2- and 9.0 +/- 1.6 fold, respectively, vs. control), and returned to baseline at 60 min. JNK activation occurred more slowly (1.6 +/- 0.2-fold vs. control at 60 min) but was sustained at 3.5 h. The protein kinase C inhibitor chelerythrine completely blocked JNK activation and reduced ERK1/2 and p38 activation. The tyrosine kinase inhibitors genistein and PP-2 blocked JNK, but not ERK1/2 and p38, activation. H(2)O(2)-induced Na(+)/H(+) exchanger phosphorylation was blocked by the MAP kinase kinase inhibitor U-0126 (5 microM). These results demonstrate that H(2)O(2)-induced activation of MAP kinases may contribute to cardiac myocyte dysfunction during ischemia-reperfusion. PMID- 11600419 TI - Heterotypic gap junction channel formation between heteromeric and homomeric Cx40 and Cx43 connexons. AB - Recent evidence indicating formation of functional homomeric/heterotypic gap junction channels by connexin40 (Cx40) and connexin43 (Cx43) raises the question of whether data previously interpreted as support for heteromeric channel formation by these connexins might not instead reflect the activity of homomeric/heterotypic channels. To address this question and to further characterize the behavior of these channels, we used dual whole cell voltage clamp techniques to examine the junctions formed between cells that express only Cx40 (Rin40) or Cx43 (Rin43) and compared the results with those obtained when either of these cell types was paired with cells that naturally express both connexins (A7r5 cells). Rin40/Rin43 cell pairs formed functional gap junctions that displayed a strongly asymmetric voltage-dependent gating response. Single channel event amplitudes ranged between 34 and 150 pS, with 90- to 130-pS events predominating. A7r5/Rin43 and A7r5/Rin40 cell pairs had voltage-dependent gating responses that varied greatly, with most pairs demonstrating strong asymmetry. These cell pairs exhibited a variety of single-channel events that were not consistent with homomeric/homotypic Cx40 or Cx43 channels or homomeric/heterotypic Cx40/Cx43 channels. These data indicate that Cx40 and Cx43 form homomeric/heterotypic as well as heteromeric/heterotypic channels that display unique gating and conductance properties. PMID- 11600418 TI - Differential regulation of the expression of Na(+)/H(+) exchanger isoform NHE3 by PKC-alpha in Caco-2 cells. AB - Na(+)/H(+) exchange (NHE) activity has been shown to be regulated by various external signals and protein kinases in many tissues and cell types. A family of six NHE isoforms has been identified. Three isoforms, NHE1, NHE2, and NHE3, have been shown to be expressed in the human intestine. The present studies were designed to study regulation of these human NHE isoforms by the alpha-isoform of protein kinase C (PKC) in the Caco-2 cell line. The mRNA levels of the NHE isoforms in Caco-2 cells were initially measured by a semiquantitative RT-PCR technique in response to PKC downregulation by long-term exposure to 1 microM 12 O-tetradecanoylphorbol-13-acetate (TPA) for 24 h. PKC downregulation resulted in an approximately 60% increase in the mRNA level for NHE3, but not for NHE1 or NHE2. Utilizing dichlorobenzimidazole riboside, an agent to block the synthesis of new mRNA, we demonstrated that the increase in the NHE3 mRNA in response to downregulation of PKC was predominantly due to an increase in the rate of transcription, rather than a decrease in the NHE3 mRNA stability. Consistent with the mRNA results, our data showed that amiloride-sensitive (22)Na(+) uptake was increased after incubation of Caco-2 cells with 1 microM TPA for 24 h. To elucidate the role of PKC-alpha, an isoform downregulated by TPA, the relative abundance of NHE isoform mRNA levels and the apical NHE activity were assessed in Caco-2 cells over- and underexpressing PKC-alpha. Our results demonstrated that NHE3, but not NHE1 or NHE2, mRNA was downregulated by PKC-alpha and that apical NHE activity was higher in cells underexpressing PKC-alpha and lower in cells overexpressing PKC-alpha than in control cells. In conclusion, these data demonstrate a differential regulation of NHE3, but not NHE2 or NHE1, expression by PKC in Caco-2 cells, and this regulation appears to be predominantly due to PKC-alpha. PMID- 11600420 TI - Effects of IL-8, Gro-alpha, and LTB(4) on the adhesive kinetics of LFA-1 and Mac 1 on human neutrophils. AB - Firm adhesion of rolling neutrophils on inflamed endothelium is dependent on beta(2) (CD18)-integrins and activating stimuli. LFA-1 (CD11a/CD18) appears to be more important than Mac-1 (CD11b/CD18) in neutrophil emigration at inflammatory sites, but little is known of the relative binding characteristics of these two integrins under conditions thought to regulate firm adhesion. The present study examined the effect of chemoattractants on the kinetics of LFA-1 and Mac-1 adhesion in human neutrophils. We found that subnanomolar concentrations of interleukin-8, Gro-alpha, and leukotriene B(4) (LTB(4)) induced rapid and optimal rates of LFA-1-dependent adhesion of neutrophils to intercellular adhesion molecule (ICAM)-1-coated beads. These optimal rates of LFA-1 adhesion were transient and decayed within 1 min after chemoattractant stimulation. Mac-1 adhesion was equally rapid initially but continued to rise for >/=6 min after stimulation. A fourfold higher density of ICAM-1 on beads markedly increased the rate of binding to LFA-1 but did not change the early and narrow time window for the optimal rate of adhesion. Using well-characterized monoclonal antibodies, we showed that activation of LFA-1 and Mac-1 by Gro-alpha was completely blocked by anti-CXC chemokine receptor R2, but activation of these integrins by interleukin 8 was most effectively blocked by anti-CXC chemokine receptor R1. The topographical distribution of beads also reflected significant differences between LFA-1 and Mac-1. Beads bound to Mac-1 translocated to the cell uropod within 4 min, but beads bound to LFA-1 remained bound to the lamellipodial regions at the same time. These kinetic and topographical differences may indicate distinct functional contributions of LFA-1 and Mac-1 on neutrophils. PMID- 11600421 TI - Expression of the reduced folate carrier SLC19A1 in IEC-6 cells results in two distinct transport activities. AB - Intestinal absorption of folates has been characterized as a facilitative process with a low pH optimum. Studies with intestinal epithelial cells have suggested that this activity is mediated by the reduced folate carrier (RFC1). In this paper, we report on folate transport characteristics in an immortalized rat IEC-6 cell line that was found to exhibit the predominant influx activity for methotrexate (MTX) at pH 5.5 with a low level of activity at pH 7.4. Transfection of this cell line with an RFC1 construct resulted in clones exhibiting increased MTX uptake at both the pHs and high folic acid uptake only at the low pH. For the two clones with the highest level of transport activity, relative MTX influx at the two pHs was reversed. Moreover, the low pH MTX influx activity ([MTX](e) = 0.5 microM) was markedly inhibited by 20 microM folic acid while influx at neutral pH was not. Furthermore, in the presence and absence of glucose at low pH, MTX and folic acid influx activity was inhibited by azide, while MTX influx at pH 7.4 was stimulated by azide in the absence of glucose but was unchanged in the presence of glucose and azide. This was contrasted with the results of transfection of the same RFC1 construct into an L1210 murine leukemia cell line bearing a nonfunctional endogenous carrier. In this case, the activity expressed was only at pH 7.4. These data indicate that RFC1 can exhibit two distinct types of folate transport activities in intestinal cells that must depend on tissue specific modulators. PMID- 11600422 TI - Human endothelial cell response to gram-negative lipopolysaccharide assessed with cDNA microarrays. AB - To assess the feasibility of using cDNA microarrays to understand the response of endothelial cells to lipopolysaccharide (LPS) and to evaluate potentially beneficial agents in treatment of septic shock, human umbilical vein endothelial cells were exposed to Escherichia coli LPS for 1, 4, 7, 12, or 24 h. Total RNA was isolated and reverse-transcribed into (33)P-labeled cDNA probes that were hybridized to human GeneFilter microarrays containing approximately 4,000 genes. The mRNA levels of several genes known to respond to LPS changed after stimulation. In addition, a number of genes not previously implicated in the response of endothelial cells to LPS also appeared to be altered in expression. Nuclear factor-kappaB (NF-kappaB) was shown to play an important role in regulating genes identified from the microarray studies. Pretreatment of endothelial cells with a specific NF-kappaB translocation inhibitor eliminated most of the alterations in gene expression. Quantitative RT-PCR results independently confirmed the microarray results for monocyte chemotactic protein-1 and interleukin-8, and enzyme-linked immunosorbent assays demonstrated that augmented transcription was followed by translation and secretion. PMID- 11600424 TI - Opposing gates model for voltage gating of gap junction channels. AB - Gap junctions are intercellular channels that link the cytoplasm of neighboring cells. Because a gap junction channel is composed of two connexons docking head to-head with each other, the channel voltage-gating profile is symmetrical for homotypic channels made of two identical connexons (hemichannels) and asymmetric for the heterotypic channels made of two different connexons (i.e., different connexin composition). In this study we have developed a gating model that allows quantitative characterization of the voltage gating of homotypic and heterotypic channels. This model differs from the present model in use by integrating, rather than separating, the contributions of the voltage gates of the two member connexons. The gating profile can now be fitted over the entire voltage range, eliminating the previous need for data splicing and fusion of two hemichannel descriptions, which is problematic when dealing with heterotypic channels. This model also provides a practical formula to render quantitative several previously qualitative concepts, including a similarity principle for matching a voltage gate to its host connexon, assignment of gating polarity to a connexon, and the effect of docking interactions between two member connexons in an intact gap junction channel. PMID- 11600423 TI - Hypoxia induces apoptosis via two independent pathways in Jurkat cells: differential regulation by glucose. AB - Glucose uptake and metabolism inhibit hypoxia-induced apoptosis in a variety of cell types, but the underlying molecular mechanisms remain poorly understood. In the present study, we explore hypoxia-mediated cell death pathways in Jurkat cells in the presence and absence of extracellular glucose. In the absence of extracellular glucose, hypoxia caused cytochrome c release, caspase 3 and poly(ADP-ribose)polymerase cleavage, and DNA fragmentation; this apoptotic response was blocked by the caspase 9 inhibitor z-LEHD-FMK. The presence of extracellular glucose during hypoxia prevented cytochrome c release and activation of caspase 9 but did not prevent apoptosis in Jurkat cells. In these conditions, overexpression of the caspase 8 inhibitor v-FLIP prevented hypoxia mediated cell death. Thus hypoxia can stimulate two apoptotic pathways in Jurkat cells, one dependent on cytochrome c release from mitochondria that is prevented by glucose uptake and metabolism, and the other independent of cytochrome c release and resulting from activation of the death receptor pathway, which is accelerated by glucose uptake and metabolism. PMID- 11600426 TI - Skeletal muscle cell hypertrophy induced by inhibitors of metalloproteases; myostatin as a potential mediator. AB - Cell growth and differentiation are controlled in many tissues by paracrine factors, which often require proteolytic processing for activation. Metalloproteases of the metzincin family, such as matrix metalloproteases and ADAMs, recently have been shown to be involved in the shedding of growth factors, cytokines, and receptors. In the present study, we show that hydroxamate-based inhibitors of metalloproteases (HIMPs), such as TAPI and BB-3103, increase the fusion of C(2)C(12) myoblasts and provoke myotube hypertrophy. HIMPs did not seem to effect hypertrophy via proteins that have previously been shown to regulate muscle growth in vitro, such as insulin-like growth factor-I, calcineurin, and tumor necrosis factor-alpha. Instead, the proteolytic maturation of myostatin (growth differentiation factor-8) seemed to be reduced in C(2)C(12) cells treated with HIMPs, as suggested by the presence of nonprocessed myostatin precursor only in hypertrophic myotubes. Myostatin is a known negative regulator of skeletal muscle growth, belonging to the transforming growth factor-beta/bone morphogenetic protein superfamily. These results indicate that metalloproteases are involved in the regulation of skeletal muscle growth and differentiation, that the proteolytic maturation of myostatin in C(2)C(12) cells may be directly or indirectly linked to the activity of some unidentified HIMP-sensitive metalloproteases, and that the lack of myostatin processing on HIMP treatment may be a mediator of myotube hypertrophy in this in vitro model. PMID- 11600425 TI - PGE(2), Ca(2+), and cAMP mediate ATP activation of Cl(-) channels in pigmented ciliary epithelial cells. AB - Purines regulate intraocular pressure. Adenosine activates Cl(-) channels of nonpigmented ciliary epithelial cells facing the aqueous humor, enhancing secretion. Tamoxifen and ATP synergistically activate Cl(-) channels of pigmented ciliary epithelial (PE) cells facing the stroma, potentially reducing net secretion. The actions of nucleotides alone on Cl(-) channel activity of bovine PE cells were studied by electronic cell sorting, patch clamping, and luciferin/luciferase ATP assay. Cl(-) channels were activated by ATP > UTP, ADP, and UDP, but not by 2-methylthio-ATP, all at 100 microM. UTP triggered ATP release. The second messengers Ca(2+), prostaglandin (PG)E(2), and cAMP activated Cl(-) channels without enhancing effects of 100 microM ATP. Buffering intracellular Ca(2+) activity with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid or blocking PGE(2) formation with indomethacin inhibited ATP triggered channel activation. The Rp stereoisomer of 8-bromoadenosine 3',5' cyclic monophosphothioate inhibited protein kinase A activity but mimicked 8 bromoadenosine 3',5'-cyclic monophosphate. We conclude that nucleotides can act at >1 P2Y receptor to trigger a sequential cascade involving Ca(2+), PGE(2), and cAMP. cAMP acts directly on Cl(-) channels of PE cells, increasing stromal release and potentially reducing net aqueous humor formation and intraocular pressure. PMID- 11600427 TI - Flow-induced calcium oscillations in rat osteoblasts are age, loading frequency, and shear stress dependent. AB - Bone adaptation to mechanical loading is dependent on age and the frequency and magnitude of loading. It is believed that load-induced fluid flow in the porous spaces of bone is an important signal that influences bone cell metabolism and bone adaptation. We used fluid flow-induced shear stress as a mechanical stimulus to study intracellular calcium (Ca) signaling in rat osteoblastic cells (ROB) isolated from young, mature, and old animals. Fluid flow produced higher magnitude and more abundant [Ca(2+)](i) oscillations than spontaneous oscillations, suggesting that flow-induced Ca signaling encodes a different cellular message than spontaneous oscillations. ROB from old rats showed less basal [Ca(2+)](i) activity and were less responsive to fluid flow. Cells were more responsive to 0.2 Hz than to 1 or 2 Hz and to 2 Pa than to 1 Pa. These data suggest that the frequency and magnitude of mechanical loading may be encoded by the percentage of cells displaying [Ca(2+)](i) oscillations but that the ability to transduce this information may be altered with age. PMID- 11600428 TI - Bcl-2 protects lymphoma cells from apoptosis but not growth arrest promoted by cAMP and dexamethasone. AB - Glucocorticoids or increases in cellular cAMP promote apoptosis in many cell types, including murine S49 cells. We examined the impact of Bcl-2, an antiapoptotic protein, on S49 cell growth and death promoted by the glucocorticoid dexamethasone or agents that increase cAMP: isoproterenol (a beta adrenergic agonist) + 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor) and forskolin (diterpene). These agents promoted apoptosis (i.e., increased expression of annexin V) of wild-type (WT) S49 cells, but Bcl-2-overexpressing S49 cells were protected from this response. Bcl-2 overexpression did not protect cells from G(1) growth arrest but did allow cells to grow longer in culture and protected cells from culture-dependent necrosis. Commitment to and reversal from apoptosis vs. G(1) growth arrest by isoproterenol + 3-isobutyl-1-methylxanthine showed different kinetics. Although both processes required several hours to develop, removal of agonists readily reversed growth arrest, but not apoptosis. Thus commitment to apoptosis is less reversible than G(1) growth arrest. The findings also indicate that glucocorticoid- and cAMP-mediated G(1) growth arrest is unaffected by Bcl-2 overexpression, even though increased Bcl-2 allows these lymphoma cells to resist necrosis and apoptosis. PMID- 11600429 TI - Endogenous protein phosphatase 1 runs down gap junctional communication of rat ventricular myocytes. AB - Gap junctional channels are essential for normal cardiac impulse propagation. In ventricular myocytes of newborn rats, channel opening requires the presence of ATP to allow protein kinase activities; otherwise, channels are rapidly deactivated by the action of endogenous protein phosphatases (PPs). The lack of influence of Mg(2+) and of selective PP2B inhibition is not in favor of the involvements of Mg(2+)-dependent PP2C and PP2B, respectively, in the loss of channel activity. Okadaic acid (1 microM) and calyculin A (100 nM), both inhibitors of PP1 and PP2A activities, significantly retarded the loss of channel activity. However, a better preservation was obtained in the presence of selective PP1 inhibitors heparin (100 microg/ml) or protein phosphatase inhibitor 2 (I2; 100 nM). Conversely, the stimulation of endogenous PP1 activity by p nitrophenyl phosphate, in the presence of ATP, led to a progressive fading of junctional currents unless I2 was simultaneously added. Together, these results suggest that a basal phosphorylation-dephosphorylation turnover regulates gap junctional communication which is rapidly deactivated by PP1 activity when the phosphorylation pathway is hindered. PMID- 11600430 TI - Activation of G551D CFTR channel with MPB-91: regulation by ATPase activity and phosphorylation. AB - We have designed and synthesized benzo[c]quinolizinium derivatives and evaluated their effects on the activity of G551D cystic fibrosis transmembrane conductance regulator (CFTR) expressed in Chinese hamster ovary and Fisher rat thyroid cells. We demonstrated, using iodide efflux, whole cell patch clamp, and short-circuit recordings, that 5-butyl-6-hydroxy-10-chlorobenzo[c]quinolizinium chloride (MPB 91) restored the activity of G551D CFTR (EC(50) = 85 microM) and activated CFTR in Calu-3 cells (EC(50) = 47 microM). MPB-91 has no effect on the ATPase activity of wild-type and G551D NBD1/R/GST fusion proteins or on the ATPase, GTPase, and adenylate kinase activities of purified NBD2. The activation of CFTR by MPB-91 is independent of phosphorylation because 1) kinase inhibitors have no effect and 2) the compound still activated CFTR having 10 mutated protein kinase A sites (10SA CFTR). The new pharmacological agent MPB-91 may be an important candidate drug to ameliorate the ion transport defect associated with CF and to point out a new pathway to modulate CFTR activity. PMID- 11600431 TI - c-Src and HSP72 interact in ATP-depleted renal epithelial cells. AB - Disruption of cell contact sites during ischemia contributes to the loss of organ function in acute renal failure. Because prior heat stress protects cell contact sites in ATP-depleted renal epithelial cells in vitro, we hypothesized that heat shock protein 72 (HSP72), the major inducible cytoprotectant in mammalian cells, interacts with protein kinases that regulate cell-cell and cell-matrix interactions. ATP depletion increased the content of Tyr(416) Src, the activated form of this kinase. c-Src activation was associated with an increase in the tyrosine phosphorylation state of beta-catenin, paxillin, and vinculin, three c Src substrate proteins that localize to and regulate cell contact sites. Prior heat stress inhibited c-Src activation and decreased the degree of tyrosine phosphorylation of all three Src substrates during ATP depletion and/or early recovery. HSP72 coimmunoprecipitated with c-Src only in cells subjected to heat stress. ATP depletion markedly increased the interaction between HSP72 and c-Src, supporting the hypothesis that HSP72 regulates Src kinase activity. These results suggest that alterations in the tyrosine phosphorylation state of proteins located at the cell-cell and cell-matrix interface mediate, at least in part, the functional state of these structures during ATP depletion and may be modulated by interactions between HSP72 and c-Src. PMID- 11600432 TI - Ca(2+) channels activated by endothelin-1 in CHO cells expressing endothelin-A or endothelin-B receptors. AB - We compared the Ca(2+) channels activated by endothelin-1 (ET-1) in Chinese hamster ovary (CHO) cells stably expressing endothelin type A (ET(A)) or endothelin type B (ET(B)) receptors using the Ca(2+) channel blockers LOE-908 and SK&F-96365. In both CHO-ET(A) and CHO-ET(B), ET-1 at 0.1 nM activated the Ca(2+) permeable nonselective cation channel-1 (NSCC-1), which was sensitive to LOE-908 and resistant to SK&F-96365. ET-1 at 1 nM activated NSCC-2 in addition to NSCC-1; NSCC-2 was sensitive to both LOE-908 and SK&F-96365. ET-1 at 10 nM activated the same channels as 1 nM ET-1 in both cell types, but in CHO-ET(A), it additionally activated the store-operated Ca(2+) channel (SOCC), which was resistant to LOE 908 and sensitive to SK&F-96365. Up to 1 nM ET-1, the level of the formation of inositol phosphates (IPs) was low and similar in both cell types, but, at 10 nM ET-1, it was far greater in CHO-ET(A) than in CHO-ET(B). These results show that, in CHO-ET(A) and CHO-ET(B), ET-1 up to 10 nM activated the same Ca(2+) entry channels: 0.1 nM ET-1 activated NSCC-1, and ET-1 > or = 1 nM activated NSCC-1 and NSCC-2. Notably, in CHO-ET(A), 10 nM ET-1 activated SOCCs because of the higher formation of IPs. PMID- 11600433 TI - Influence of overload on phenotypic remodeling in regenerated skeletal muscle. AB - We studied the effects of 10 wk of functional overload on the expression of myosin heavy chain (MHC), sarcoplasmic reticulum Ca(2+)-ATPase isoforms (SERCA), and the activity of several metabolic enzymes in sham and regenerated plantaris muscles. Overload was accomplished by bilateral surgical ablation of its synergists 4 wk after right plantaris muscles regenerated after myotoxic infiltration. The overload-induced muscle enlargement was slightly less in regenerated than in sham muscles [28% (P < 0.005) and 43% (P < 0.001), respectively]. Overload led to an increase in type I MHC expression (P < 0.01) to a similar extent in sham and regenerated plantaris, while the expected shift from type IIb to type IIa MHC was less marked in regenerated than in sham plantaris. The overload-induced decrease in the expression of the fast SERCA isoform and in the activity of the M subunit of lactate dehydrogenase occurred to a similar extent in sham and regenerated plantaris [66% (P < 0.01) and 27% (P < 0.005), respectively]. In conclusion, the lesser responses of muscle mass and fast MHC composition of regenerated plantaris to mechanical overload suggest an alteration of the transcriptional, translational, and/or posttranslational control of gene expression in regenerated muscle. PMID- 11600434 TI - Phenotypic analysis of conditionally immortalized cells isolated from the BPK model of ARPKD. AB - To study the pathophysiology of autosomal recessive polycystic kidney disease (ARPKD), we sought to develop conditionally immortalized control and cystic murine collecting tubule (CT) cell lines. CT cells were isolated from intercross breedings between BPK mice (bpk(+/-)), a murine model of ARPKD, and the Immorto mice (H-2K(b)-ts-A58(+/+)). Second-generation outbred offspring (BPK x Immorto) homozygous for the BPK mutation (bpk(-/-); Im(+/+/-); cystic BPK/H-2K(b)-ts-A58), were phenotypically indistinguishable from inbred cystic BPK animals (bpk(-/-)). Cystic BPK/H-2K(b)-ts-A58 mice developed biliary ductal ectasia and massively enlarged kidneys, leading to renal failure and death by postnatal day 24. Principal cells (PC) were isolated from outbred cystic and noncystic BPK/H-2K(b) ts-A58 littermates at specific developmental stages. Epithelial monolayers were under nonpermissive conditions for markers of epithelial cell polarity and PC function. Cystic and noncystic cells displayed several properties characteristic of PCs in vivo, including amiloride-sensitive sodium transport and aquaporin 2 expression. Cystic cells exhibited apical epidermal growth factor receptor (EGFR) mislocalization but normal expression of ZO-1 and E-cadherin. Hence, these cell lines retain the requisite characteristics of PCs, and cystic BPK/H-2K(b)-ts-A58 PCs retained the abnormal EGFR membrane expression characteristic of ARPKD. These cell lines represent important new reagents for studying the pathogenesis of ARPKD. PMID- 11600435 TI - A muscle precursor cell-dependent pathway contributes to muscle growth after atrophy. AB - Slow-twitch skeletal muscle atrophies greatly in response to unloading conditions. The cellular mechanisms that contribute to the restoration of muscle mass after atrophy are largely unknown. Here, we show that atrophy of the mouse soleus is associated with a 36% decrease in myonuclear number after 2 wk of hindlimb suspension. Myonuclear number is restored to control values during the 2 wk recovery period in which muscle mass returns to normal, suggesting that muscle precursor cells proliferate and fuse with myofibers. Inhibition of muscle precursor cell proliferation by local gamma-irradiation of the hindlimb completely prevents this increase in myonuclear number. Muscle growth occurs normally during the first week in irradiated muscles, but growth during the second week is inhibited, leading to a 50% attenuation in the restoration of muscle mass. Thus early muscle growth occurs independently of an increase in myonuclear number, whereas later growth requires proliferating muscle precursor cells leading to myonuclear accretion. These results suggest that increasing the proliferative capacity of muscle precursor cells may enhance restoration of muscle mass after atrophy. PMID- 11600436 TI - Sustained hyposmotic stress induces cell death: apoptosis by defeat. AB - We describe sustained hyposmotic stress as a novel type of environmental condition enforcing apoptosis. In a dose- and time-dependent fashion, hyposmotic stress leads to a delayed type of apoptosis with considerable variations in constitutive sensitivity among different cell types. For example, after 48 h at 84 mosmol/l, the death rate ranged from 10.8 +/- 0.7% in AsPc1 human pancreatic carcinoma cells to 72.0 +/- 1.6% in HK-2 human kidney tubule cells. Caspase inhibitors rendered cells more resistant to hyposmolar stress; the caspase 3 inhibitor Ac-Asp-Glu-Val-aspartic acid aldehyde was the most efficient. After 24 h of stress, HT-29 colon carcinoma and HK-2 cells had increased their mitochondrial mass. This went along with an increase in mitochondrial membrane potential in HT-29 cells but with a decrease in HK-2 cells. Starting at 2 h of stress, we detected transient CD95L transcription followed by surface expression of CD95L in HT-29 but not in HK-2 cells. Inhibitory CD95L antibody partially inhibited specific death in HT-29 but not in HK-2 cells. Thus, as in other types of stress-induced apoptosis, the CD95/CD95L system is one of the different routes to suicide optionally used by hyposmotically stressed cells. Our findings may have clinical implications for the prevention and treatment of tissue damage caused by severe hyposmolar states. PMID- 11600437 TI - Expression of Ca(2+)-activated K(+) channels, SK3, in the interstitial cells of Cajal in the gastrointestinal tract. AB - A role for small-conductance Ca(2+)-activated K(+) (SK) channels on spontaneous motility of the gastrointestinal tract has been suggested. Although four subtypes of SK channels were identified in mammalian tissues, the subtypes of SK channel expressed in the gastrointestinal tract are still unknown. In this study, we investigated the expression and localization of SK channels in the gastrointestinal tract. RT-PCR analysis shows expression of SK3 and SK4 mRNA, but not SK1 or SK2 mRNA, in the rat intestine. SK3 immunoreactivity was detected in the myenteric plexus and muscular layers of the stomach, ileum, and colon. SK3 immunoreactive cells were stained with antibody for c-kit, a marker for the interstitial cells of Cajal (ICC), but not with that for glial fibrillary acidic protein in the ileum and stomach. Immunoelectron microscopic analysis indicates that SK3 channels are localized on processes of ICC that are located close to the myenteric plexus between the longitudinal and circular muscle layers and within the muscular layers. Because ICC have been identified as pacemaker cells and are known to play a major role in generating the regular motility of the gastrointestinal tract, these results suggest that SK3 channels, which are expressed specifically in ICC, play an important role in generating a rhythmic pacemaker current in the gastrointestinal tract. PMID- 11600439 TI - The stock market and science policy. PMID- 11600438 TI - Cell-based assay for high-throughput quantitative screening of CFTR chloride transport agonists. AB - Drug discovery by high-throughput screening is a promising approach to develop new therapies for the most common lethal genetic disease, cystic fibrosis. Because disease-causing mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) protein produce epithelial cells with reduced or absent Cl(-) permeability, the goal of screening is to identify compounds that restore cell Cl(-) transport. We have developed a rapid, quantitative screening procedure for analysis of CFTR-mediated halide transport in cells with the use of a conventional fluorescence plate reader. Doubly transfected cell lines were generated that express wild-type or mutant CFTR together with a yellow fluorescent protein (YFP)-based halide sensor. CFTR function was assayed from the time course of cell fluorescence in response to extracellular addition of 100 mM I(-) followed by forskolin, resulting in decreased YFP fluorescence due to CFTR mediated I(-) entry. Cell lines were chosen, and conditions were optimized to minimize basal halide transport to maximize assay sensitivity. In cells cultured on 96-well plastic dishes, the assay gave reproducible halide permeabilities from well to well and could reliably detect a 2% activation of CFTR-dependent halide transport produced by low concentrations of forskolin. Applications of the assay are shown, including comparative dose-dependent CFTR activation by genistein, apigenin, 8-cyclopentyl-1,3-dipropylxanthine, IBMX, 8-methoxypsoralen, and milrinone as well as activation of alternative Cl(-) channels. The fluorescence assay and cell lines should facilitate the screening of novel CFTR activators and the characterization of alternative Cl(-) channels and transporters. PMID- 11600440 TI - Comment on Frank Gannon's article "Searching for discrimination" in EMBO reports, August 2001. PMID- 11600441 TI - Comment on the interview with Ken-ichi Arai in EMBO reports, July 2001. PMID- 11600442 TI - Comment on Holger Breithaupt's article "Losing them is not an option" in EMBO reports, August 2001. PMID- 11600443 TI - Vaccines as instruments of foreign policy. The new vaccines for tropical infectious diseases may have unanticipated uses beyond fighting diseases. PMID- 11600444 TI - "How can we know the dancer from the dance?'--William B. Yeats. To solve problems in the new millennium, society needs more, not less science. PMID- 11600445 TI - In the name of science. The role of biologists in Nazi atrocities: lessons for today's scientists. PMID- 11600446 TI - Tackling the most difficult diseases. Genetics and genomics open new strategies to fight vector-borne diseases. PMID- 11600447 TI - Salt of the earth. Genetic engineering may help to reclaim agricultural land lost due to salinisation. PMID- 11600450 TI - Through the glass brightly. ELMI workshop on advanced light microscopy. PMID- 11600451 TI - From the cradle to the grave: molecular chaperones that may choose between folding and degradation. AB - Molecular chaperones are known to facilitate cellular protein folding. They bind non-native proteins and orchestrate the folding process in conjunction with regulatory cofactors that modulate the affinity of the chaperone for its substrate. However, not every attempt to fold a protein is successful and chaperones can direct misfolded proteins to the cellular degradation machinery for destruction. Protein quality control thus appears to involve close cooperation between molecular chaperones and energy-dependent proteases. Molecular mechanisms underlying this interplay have been largely enigmatic so far. Here we present a novel concept for the regulation of the eukaryotic Hsp70 and Hsp90 chaperone systems during protein folding and protein degradation. PMID- 11600452 TI - Genetic dangers in poly(A) signals. PMID- 11600453 TI - Irresistible IRES. Attracting the translation machinery to internal ribosome entry sites. AB - Studies on the control of eukaryotic translation initiation by a cap-independent recruitment of the 40S ribosomal subunit to internal messenger RNA sequences called internal ribosome entry sites (IRESs) have shown that these sequence elements are present in a growing list of viral and cellular RNAs. Here we discuss their prevalence, mechanisms whereby they may function and their uses in regulating gene expression. PMID- 11600454 TI - RNA and sex determination in Caenorhabditis elegans. Post-transcriptional regulation of the sex-determining tra-2 and fem-3 mRNAs in the Caenorhabditis elegans hermaphrodite. AB - The Caenorhabditis elegans hermaphrodite sequentially produces sperm and oocytes from a single pool of precursors. Therefore, the hermaphrodite's germ line is the site of two major cell fate decisions: a germ cell precursor first undergoes a mitosis/meiosis decision and then a sperm/oocyte decision. While the mitosis/meiosis decision is governed by Notch/GLP-1 signalling, the sperm/oocyte decision relies on post-transcriptional regulation of two key mRNAs, tra-2 and fem-3. This review focuses on factors that are required for the silencing of these mRNAs, which results in the sequential production of sperm and oocytes. Most factors that regulate the expression of tra-2 and fem-3 are homologous to proteins involved in RNA regulation in yeast, mammals or Drosophila, suggesting that at least some of the molecular mechanisms regulating the two worm mRNAs have been conserved throughout evolution. PMID- 11600456 TI - Life, death, and varices. PMID- 11600457 TI - Can endoscopic papillary balloon dilation really preserve sphincter of Oddi function? PMID- 11600455 TI - Non-pylori Helicobacter species in humans. PMID- 11600458 TI - Intravenous omeprazole after endoscopic treatment of bleeding peptic ulcers. PMID- 11600459 TI - Genomics at work: the global gene response to enteric bacteria. PMID- 11600460 TI - Protagonist: Should we eradicate Helicobacter pylori before long term antireflux therapy? PMID- 11600461 TI - Antagonist: Should we eradicate Helicobacter pylori before long term antireflux therapy? PMID- 11600462 TI - Expression of the p53 homologue p63alpha and DeltaNp63alpha in the neoplastic sequence of Barrett's oesophagus: correlation with morphology and p53 protein. AB - BACKGROUND: While loss of p53 function is a key oncogenic step in human tumorigenesis, mutations of p53 are generally viewed as late events in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett's oesophagus. Recent reports of a series of genes (p63, p73, and others) exhibiting close homology to p53 raise the possibility that abnormalities of these p53 family members may exert their influence earlier in the sequence. AIM: Following recent characterisation of expression of p63 and a major isoform DeltaNp63 by generation of an antiserum that recognises p63 isoforms, but not p53, our aim was a comparative study of expression of p63 protein and p53 protein in a morphologically well defined biopsy series representative of all stages of the metaplasia-dysplasia-carcinoma sequence in Barrett's oesophagus. METHODS: A series of 60 biopsy cases representing normal oesophagus through to invasive adenocarcinoma were stained, using immunohistochemistry, with antibodies to p63 and p53. All biopsies derived from patients with endoscopic and histopathological substantiation of a diagnosis of traditional/classical Barrett's oesophagus. RESULTS: There was exact concordance in p53 and p63 expression in more advanced forms of neoplasia, high grade dysplasia, and invasive adenocarcinoma, while p63, but not p53, was detected in the proliferative compartment of some non-neoplastic oesophageal tissue, in both squamous mucosa and in the non-neoplastic metaplastic glandular epithelium. CONCLUSIONS: In neoplastic Barrett's oesophagus there is upregulation of both p63 and p53 while p63 isoforms may well have an important role in epithelial biology in both non-metaplastic and metaplastic mucosa of the oesophagus. While abnormalities of p53 function represent an indisputable and critical element of neoplastic transformation, other closely linked genes and their proteins have a role in both the physiology and pathophysiology of the oesophageal mucosa. PMID- 11600463 TI - Duodenal fat intensifies the perception of heartburn. AB - BACKGROUND: Patients with gastro-oesophageal reflux disease (GORD) frequently report that meals high in fat worsen heartburn. Nevertheless, studies to determine whether high fat meals promote gastro-oesophageal reflux have produced conflicting and equivocal conclusions. PATIENTS AND METHODS: To determine, alternatively, whether fat in the small intestinal lumen intensifies the perception of heartburn, we studied 11 patients with typical heartburn from GORD. After being placed on omeprazole to suppress endogenous acid, these fasting subjects underwent oesophageal perfusions with graded doses of HCl at pH values of 1.0, 1.5, 2.0, and 2.5. Oesophageal perfusions were conducted while the duodenum was perfused with saline (control) and again with fat at 8 g/h. RESULTS: Time to onset, intensity, and severity of heartburn varied with dose of oesophageal acid (p<0.01). Time to onset was significantly (p<0.01) shorter, and intensity and severity of heartburn significantly (p<0.05) greater, during duodenal perfusion with fat. CONCLUSION: We conclude that duodenal fat intensifies the perception of heartburn. PMID- 11600464 TI - Analysis of iceA genotypes in South African Helicobacter pylori strains and relationship to clinically significant disease. AB - BACKGROUND: South African Helicobacter pylori isolates are characterised by the universal presence of cagA but have differences in vacuolating cytotoxin gene (vacA) alleles which correlate with clinically significant disease. However, the candidate virulence marker gene iceA has not been investigated. AIM: To characterise the genetic organisation and heterogeneity of iceA genotypes in different South African clinical isolates. PATIENTS AND METHODS: We studied H pylori strains isolated from 86 dyspeptic patients (30 with peptic ulcer disease (PUD), 19 with distal gastric adenocarcinoma (GC), and 37 with non-erosive gastritis) for the presence of iceA1 or iceA2 genes, and for differences in the genetic organisation of iceA2 by polymerase chain reaction, Southern hybridisation analysis, and sequencing. RESULTS: Genetic analysis of iceA1 demonstrated significant homology (92-95%) with the USA type strain 26695 and probably functions as a transcriptional regulator, while a novel variant (iceA2D') of iceA2 and marked differences in predicted protein secondary structure of the iceA2 protein were defined. iceA1 was detected in 68% and iceA2 in 80% of all clinical isolates. Although approximately 40% of patients had both strains, a higher prevalence (p< 0.01) of GC patients were infected with iceA1 isolates which were invariably vacA s1/iceA1 (p< 0.005 v gastritis). Isolates from PUD patients were distinguished by the structurally altered iceA2D variant (53%; p<0.03 v gastritis) while the iceA2C variant distinguished isolates from patients with gastritis alone (67%; p< 0.005 v PUD). CONCLUSION: In this study, an association between iceA1 and GC was noted while differences in variants of iceA2 differentiated between PUD and gastritis alone. Combination analyses of iceA genotypes and vacA alleles supported these associations. PMID- 11600465 TI - Interleukin 2 modulates ion secretion and cell proliferation in cultured human small intestinal enterocytes. AB - AIMS: To determine if interleukin 2 (IL-2) alters epithelial transport and barrier function in cultured human small intestinal enterocytes. METHODS: Confluent monolayers of small intestinal cells derived from duodenal biopsies were treated with IL-2 0.2-50 U/ml for 24 hours prior to study. Transport measurements were performed under short circuited conditions in Ussing chambers, with and without the secretagogues forskolin and 3-isobutyl-1-methyl xanthine (IBMX). Serosal to mucosal flux of 3[H] mannitol (permeability) and 3[H] thymidine uptake (proliferation) were measured. IL-2 receptor and cystic fibrosis transmembrane conductance regulator (CFTR) mRNA were identified using reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: IL-2 did not alter baseline electrical parameters but caused a significant increase in cAMP dependent chloride secretion. The effect was mediated by the IL-2 receptor and paralleled a rapid increase in tyrosine phosphorylation, janus kinase 1, and signal transducers and activators of transcription (STATs) 1, 3, and 5. IL-2 significantly increased proliferation but at a lower dose than observed for enhanced secretion but did not alter permeability. IL-2 receptor beta and gammac chains and CFTR mRNA were identified by RT-PCR. CONCLUSIONS: IL-2 treatment enhances cAMP stimulated chloride secretion and cellular proliferation in a human small intestinal cell line expressing a functional IL-2 receptor. PMID- 11600466 TI - Allelic variation at the interleukin 1beta gene is associated with decreased bone mass in patients with inflammatory bowel diseases. AB - BACKGROUND: Interleukin 1beta (IL-1beta) and its natural antagonist have been implicated in the pathogenesis of inflammatory bowel disease (IBD). Both cytokines influence bone formation. IL-1beta stimulates osteoclast activity while interleukin 1 receptor antagonist (IL-1ra) enhances bone formation. AIMS: To determine whether the decreased bone mass in IBD is related to gene polymorphisms coding for IL-1beta and IL-1ra, and thus identify patients with an increased risk. METHODS: Bone mineral densitometry was performed at the femoral neck, lumbar spine, and the distal third of the radius in 75 IBD patients (34 men/41 women; 40.3 (1.6) years) and in 58 healthy controls (HC; 28 men/30 women; 32.4 (1.2) years). Values were correlated with the TaqI and AvaI gene polymorphisms in the IL1B and the variable number of tandem repeats gene polymorphism in the IL1RN gene. RESULTS: In IBD patients, but not in HC, carriers of allele 2 at the AvaI gene polymorphism (IL1B-511*2) had significantly lower Z scores at the lumbar spine (-0.82 (0.13) v -0.29 (0.21) p=0.03) and the femoral neck (-0.59 (0.14) v 0.15 (0.19); p=0.003) than non-carriers. These patients also had a higher risk for osteopenia or osteoporosis at the femoral neck (odds ratio 3.63 (95% confidence interval 0.95-13.93)). No association was found between bone mass and the other gene polymorphisms analysed in IBD patients or in HC. CONCLUSIONS: Our results suggest that genetic variability may be a major determinant of bone loss in IBD. Carriers of IL1B-511*2, who are hypersecretors of IL-1beta, have a higher risk of presenting with low bone mass in IBD. Screening for this allele may contribute to determination of the risk of bone loss at the time of disease onset. PMID- 11600467 TI - Acute gastrointestinal permeability responses to different non-steroidal anti inflammatory drugs. AB - BACKGROUND AND AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage both in the upper and lower gastrointestinal tract. New anti-inflammatory drugs have been developed in an attempt to improve their gastrointestinal side effect profile. Our objective was to compare the effect on gastrointestinal permeability of acute equieffective doses of four different NSAIDs; three were designed to reduce gastrointestinal mucosal injury. MATERIALS: Healthy volunteers underwent sugar tests in a randomised fashion, 15 days apart, at: (1) baseline; (2) after two days of 75 mg slow release (microspheres) indomethacin; (3) after two days of 7.5 mg oral meloxicam which preferentially inhibits cyclooxygenase 2; and (4) after two days of 750 mg naproxen. A subgroup of subjects was tested after two days of 200 mg celecoxib. In each test, subjects ingested a solution containing sucrose, lactulose, and mannitol and sucralose, to evaluate gastroduodenal, intestinal, and colonic permeability, respectively. RESULTS: Gastric permeability was significantly affected by naproxen (p<0.05) but not by slow release indomethacin, meloxicam, or celecoxib. Intestinal permeability was significantly increased by the first three NSAIDs (p<0.05) but not by celecoxib. Abnormal lactulose/mannitol ratios were observed in 42% of meloxicam treatments, in 62% during indomethacin, and in 75% of subjects treated with naproxen. Finally, colonic permeability, as measured by sucralose, was not significantly increased by any of the four drugs. CONCLUSION: Our study provides evidence that the newly developed NSAIDs reduce gastric mucosal permeability significantly. However, most produced significant alteration of small intestinal permeability. In contrast, our results suggest that celecoxib seems to exhibit the most desirable gastrointestinal side effect profile. PMID- 11600468 TI - Leucopenia resulting from a drug interaction between azathioprine or 6 mercaptopurine and mesalamine, sulphasalazine, or balsalazide. AB - AIM: We evaluated the effect of coadministration of sulphasalazine, mesalamine, and balsalazide on the pharmacokinetics and pharmacodynamics of azathioprine and 6-mercaptopurine. METHODS: Thirty four patients with Crohn's disease receiving azathioprine or 6-mercaptopurine were enrolled in an eight week non-randomised parallel group drug interaction study and treated with mesalamine 4 g/day, sulphasalazine 4 g/day, or balsalazide 6.75 g/day. The primary outcome measure was the occurrence of clinically important leucopenia during the study, defined separately as total leucocyte counts < 3.0 x 10(9)/l and < or = 3.5 x 10(9)/l. Whole blood 6-thioguanine nucleotide concentrations were determined. RESULTS: Three patients could not be evaluated for the primary outcome measure. In the remaining 31 patients, the frequency of total leucocyte counts < 3.0 and < or = 3.5 were: 1/10 and 5/10 in the mesalamine group; 1/11 and 6/11 in the sulphasalazine group; and 0/10 and 2/10 in the balsalazide group. There were significant increases in mean whole blood 6-thioguanine nucleotide concentrations from baseline at most time points in the mesalamine and sulphasalazine groups but not in the balsalazide group. CONCLUSIONS: In patients with Crohn's disease receiving azathioprine or 6-mercaptopurine, coadministration of mesalamine, sulphasalazine, and possibly balsalazide results in an increase in whole blood 6 thioguanine nucleotide concentrations and a high frequency of leucopenia. PMID- 11600469 TI - Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease. AB - BACKGROUND: Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine. METHODS: We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6 thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease < 170, remission > or = 170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count. RESULTS: Mean (SD) inflammatory bowel disease questionnaire score was 176 (32). There was no correlation between inflammatory bowel disease questionnaire scores and 6-thioguanine nucleotide concentrations (r(s) = -0.09, p = 0.24). Median 6-thioguanine nucleotide concentrations in 56 patients with active disease and 114 patients in remission were similar (139 v 131 pmol/8 x 10(8) red blood cells; p = 0.26). There was no correlation between 6-thioguanine nucleotide concentrations and leucocyte counts. CONCLUSIONS: In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, 6-thioguanine nucleotide concentrations did not correlate with disease activity, as measured by the inflammatory bowel disease questionnaire, or leucocyte count. These findings are discrepant with most previous studies, possibly due to selection of responding patients who tolerated the medications. A prospective, randomised, dose optimisation trial using 6 thioguanine nucleotide concentrations is warranted. PMID- 11600470 TI - High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis. AB - BACKGROUND: The reported cumulative risk of developing pouchitis in ulcerative colitis (UC) patients undergoing ileal pouch-anal anastomosis (IPAA) approaches 50% after 10 years. To date, no preoperative serological predictor of pouchitis has been found. AIMS: To assess whether preoperative perinuclear antineutrophil cytoplasmic antibody (pANCA) expression was associated with acute and/or chronic pouchitis after IPAA. METHODS: Patients were prospectively assessed for the development of clinically and endoscopically proved pouchitis. Serum obtained at the time of colectomy in 95 UC patients undergoing IPAA was analysed for pANCA by ELISA and indirect immunofluorescence. pANCA+ patients were stratified into high level (>100 ELISA units (EU)/ml) (n=9), moderate level (40-100 EU/ml) (n=32), and low level (<40 EU/ml) (n=19) subgroups. RESULTS: Sixty of the 95 patients (63%) expressed pANCA. After a median follow up of 32 months (range 1-89), 32 patients (34%) developed either acute (n=14) or chronic (n=18) pouchitis. Pouchitis was seen in 42% of pANCA+ patients compared with 20% of pANCA- patients (p=0.09). There was no significant difference in the incidence of acute pouchitis between the three pANCA+ patient subgroups. The cumulative risk of developing chronic pouchitis among patients with high level pANCA (56%) before colectomy was significantly higher than in patients with medium level (22%), low level (16%), and those who were pANCA- (20%) (p=0.005). Multivariate analysis revealed that the sole parameter significantly associated with the development of chronic pouchitis after IPAA was the presence of high level pANCA before colectomy (p=0.005). CONCLUSION: High level pANCA before colectomy is significantly associated with the development of chronic pouchitis after IPAA. PMID- 11600471 TI - Risk of pancreatic cancer after cholecystectomy: a cohort study in Sweden. AB - BACKGROUND: Although some experimental studies have indicated that cholecystectomy may increase the risk of pancreatic cancer, data from epidemiological studies are conflicting. AIMS: We conducted a register based retrospective cohort study to explore the relationship between cholecystectomy and pancreatic cancer. SUBJECTS: The cohort included 87 263 men and 181 049 women with a documented cholecystectomy for cholelithiasis between 1965 and 1997. METHODS: By record linkage to the nationwide and virtually complete registers of Cancer, Emigration, and Causes of Death, the cohort was followed up until the occurrence of any cancer, emigration, death, or the end of follow up, 31 December 1997, whichever came first. Relative risk was estimated by standardised incidence ratio (SIR) using the Swedish nationwide sex, age, and calendar year specific cancer incidence rates as reference. RESULTS: During the period of observation, 1053 cases of pancreatic cancer were found, among which 231 (22%) occurred within 12 months after operation. After excluding cases and person years accrued during the first two years of follow up, we observed a non-significant 6% excess risk for pancreatic cancer (95% confidence interval (CI) -2 to 14%). The relative risk did not increase with increasing follow up duration, with a SIR equal to 0.98 (95% CI 0.79-1.20) 20 years or more after operation. Patients with a comorbidity of diabetes or chronic pancreatitis had higher relative risks (SIR=1.79, 95% CI 1.39-2.28; SIR=3.17, 95% CI 1.37-6.24, respectively). After excluding patients with recorded diabetes or chronic pancreatitis, the relative risk was close to unity (SIR=1.01, 95% CI 0.94-1.09). CONCLUSIONS: Our findings do not support the hypothesis that cholecystectomy increases the subsequent risk of pancreatic cancer. PMID- 11600472 TI - Improving prognosis following a first variceal haemorrhage over four decades. AB - BACKGROUND: Variceal bleeding is a frequent cause of death in patients with cirrhosis and portal hypertension. Over the past 40 years a number of new techniques have been introduced to control active variceal haemorrhage. Many randomised controlled trials were performed to evaluate these new therapies. While most have demonstrated efficacy in controlling haemorrhage few showed improved survival. AIM: The aim of this study was to investigate whether the prognosis for cirrhotic patients following a first variceal haemorrhage has improved over the past four decades. PATIENTS AND METHODS: A total of 1475 patients included in the control or untreated arms of randomised controlled prophylactic trials for the primary prevention of variceal haemorrhage between 1960 and 2000. Twenty eight eligible randomised controlled studies were included. Over the 40 year period of observation there was a reduction in bleeding related mortality over time from approximately 65% to approximately 40% (p=0.024). CONCLUSION: This study suggests that there has been a significant reduction in bleeding related mortality in patients with cirrhosis and portal hypertension over the past 40 years. PMID- 11600473 TI - Can endoscopic papillary balloon dilation really preserve sphincter of Oddi function? AB - BACKGROUND: Endoscopic papillary balloon dilation (EPBD) is assumed to preserve sphincter of Oddi function because it causes little trauma to the papilla. However, few studies have addressed this issue specifically. In this study, we investigated whether EPBD can preserve sphincter function, and evaluated whether or not such preservation has clinical significance. METHODS: Seventy patients with common bile duct (CBD) stones were randomly assigned to EPBD or endoscopic sphincterotomy (EST). Sphincter of Oddi (SO) function was measured by endoscopic manometry before, one week after, and one year after treatment. Incidence of pneumobilia and later complications were compared between the two groups at one year. Series manometric data were compared within each group and between the two groups. For a more detailed analysis of the cumulative incidence of later complications, retrospective cohorts were added to the study groups, giving a total number of 235 patients in the EPBD group and 126 in the EST group. RESULTS: Baseline characteristics did not differ significantly between the 35 EPBD and 35 EST patients. CBD stones were discharged successfully in all cases. CBD pressure, SO basal and peak pressures, and contraction frequency decreased significantly at one week in both groups. The damage was more severe in the EST group, and SO contraction completely disappeared in 23 patients in this group. The incidence of pneumobilia was significantly lower in the EPBD group than in the EST group (p<0.01) whereas CBD stones recurred and cholecystitis appeared at a similar rate in both groups at one year. A complete series of manometric data up to one year was obtained in 55 patients; 28 in the post-EPBD and 27 in post-EST groups. In the post-EPBD group, SO basal and peak pressures significantly recovered at one year compared with data at one week but these measures still remained significantly lower than those before EPBD (p< 0.01). In the post-EST group, SO contraction did not recover even after one year. A Kaplan-Meier analysis of 235 EPBD and 126 EST patients for a median follow up of 37 months revealed significantly lower incidences of biliary complications such as recurrent CBD stones and cholangitis, and cholecystitis in the EPBD group than in the EST group (p<0.05). The risk of pneumobilia was also significantly lower in the EPBD group (p<0.01). CONCLUSIONS: Preservation of papillary function after EPBD was not complete but remained somewhat reduced. However, preservation was more successful with EPBD than with EST. Such preservation may be clinically beneficial for the prevention of later complications. PMID- 11600474 TI - Inhibitory motor innervation of the gall bladder musculature by intrinsic neurones containing nitric oxide in the Australian brush-tailed possum (Trichosurus vulpecula). AB - BACKGROUND: Gall bladder functions are modulated by neurones intrinsic to the organ. Data are available on the neurochemical composition of intrinsic and extrinsic nerves innervating the gall bladder but are lacking on specific functional classes of gall bladder neurones. AIMS: To characterise the intrinsic motor neurones of the gall bladder and identify their roles using pharmacological techniques. METHODS: Retrograde tracing from the possum gall bladder muscle in vitro allowed identification of intrinsic motor neurones. Subsequently, their content of choline acetyltransferase and nitric oxide synthase, markers of acetylcholine and nitric oxide containing neurones, was established using immunohistochemical techniques. Organ bath pharmacology was used to evaluate neurotransmission by acetylcholine and nitric oxide in gall bladder muscle strips. RESULTS: Innervation of the gall bladder musculature by neurones of both the muscular and serosal plexuses was demonstrated. A large proportion (62%) of these motor neurones were immunoreactive for nitric oxide synthase. All gall bladder neurones showed immunoreactivity for choline acetyltransferase. Organ bath pharmacology confirmed the neuroanatomical data, showing acetylcholine and nitric oxide mediating neurotransmission to the gall bladder musculature. CONCLUSIONS: Neurones containing acetylcholine and nitric oxide, located within the muscular and serosal plexuses, provide excitatory and inhibitory motor innervation of the gall bladder, respectively. The large inhibitory innervation suggests active relaxation of the gall bladder during filling, mediated by intrinsic nerves. PMID- 11600475 TI - Interaction of human chagasic IgG with human colon muscarinic acetylcholine receptor: molecular and functional evidence. AB - BACKGROUND AND AIMS: Gastrointestinal disorders is one of the clinical manifestations of chronic Chagas' disease. The pathogenesis seems to be associated with autonomic dysfunction. Here, we consider the muscarinic cholinoceptor mediated alteration in distal colon function in chagasic megacolon. PATIENTS: Patients were divided into four groups: group I, chronic chagasic patients with megacolon; group II, chronic chagasic patients without megacolon; group III, non-chagasic patients with megacolon; and group IV, normal healthy volunteers (control). METHODS: Binding assay and immunoblot of cholinoceptors from human and rat colon and enzyme immunoassay (ELISA) using a synthetic 24mer peptide corresponding to the second extracellular loop of human M2 muscarinic acetylcholine receptors (mAChR) were used to detect the presence of serum antibodies. The effect of antibodies on basal tone and 3',5'-cyclic monophosphate (cAMP) production of human and rat distal colon strips were also tested. RESULTS: Group I but not the other groups had circulating antibodies capable of interacting with human colon activating M2 mAChR, as they competed with binding of specific radioligand to mAChR and interacted with the second extracellular loop of human M2 mAChR. Moreover, affinity purified anti-M2 peptide IgG from group I, in common with monoclonal antihuman M2 mAChR, recognised bands with a molecular weight corresponding to colon mAChR. This antibody also displayed an agonist-like activity, increasing basal tone and decreasing cAMP accumulation. Both effects were blunted by AF-DX 116 and neutralised by the synthetic peptide. CONCLUSIONS: In chagasic patients with megacolon there are antibodies that can recognise and activate M2 mAChR. The implications of these autoantibodies in the pathogenesis of chagasic megacolon is discussed. PMID- 11600476 TI - Cardiac autonomic function and oesophageal acid sensitivity in patients with non cardiac chest pain. AB - BACKGROUND: Acid reflux can elicit non-cardiac chest pain (NCCP), possibly through altered visceral sensory or autonomic function. The interactions between symptoms, autonomic function, and acid exposure are poorly understood. AIM: To examine autonomic function in NCCP patients during exposure to oesophageal acid infusion. SUBJECTS AND METHODS: Autonomic activity was assessed using power spectral analysis of heart rate variability (PSHRV), before and during oesophageal acidification (0.1 N HCl), in 28 NCCP patients (40.5 (10) years; 13 females) and in 10 matched healthy controls. Measured PSHRV indices included high frequency (HF) (0.15-0.5 Hz) and low frequency (LF) (0.06-0.15 Hz) power to assess vagal and sympathetic activity, respectively. RESULTS: A total of 19/28 patients had angina-like symptoms elicited by acid. There were no significant manometric changes observed in either acid sensitive or insensitive patients. Acid sensitive patients had a higher baseline heart rate (82.9 (3.1) v 66.7 (3.5) beats/min; p<0.005) and lower baseline vagal activity (HF normalised area: 31.1 (1.9)% v 38.9 (2.3)%; p< 0.03) than acid insensitive patients. During acid infusion, vagal cardiac outflow increased (p<0.03) in acid sensitive but not in acid insensitive patients. CONCLUSIONS: Patients with angina-like pain during acid infusion have decreased resting vagal activity. The symptoms elicited by perception of acid are further associated with a simultaneous increase in vagal activity in keeping with a vagally mediated pseudoaffective response. PMID- 11600477 TI - Regulation of E-box DNA binding during in vivo and in vitro activation of rat and human hepatic stellate cells. AB - BACKGROUND: Activation of hepatic stellate cells (HSCs) to a myofibroblastic phenotype is a key event in liver fibrosis. Identification of transcription factors with activities that are modulated during HSC activation will improve our understanding of the molecular events controlling HSC activation. AIMS: To determine if changes in E-box DNA binding activity occur during in vitro and in vivo activation of rat and human HSCs and to investigate mechanisms underlying any observed changes. METHODS: Nuclear extracts were prepared from rat HSCs isolated and cultured from normal and carbon tetrachloride injured rat livers and from HSCs isolated from human liver. EMSA analysis of E-box DNA binding activity was performed on nuclear extracts to determine changes during HSC activation. Western and northern blot analysis of MyoD and Id1 basic helix-loop-helix (bHLH) proteins was performed to confirm expression in HSC. RESULTS: HSC activation was associated with inducible expression of two low mobility E-box binding complexes that were immunoreactive with an anti-MyoD antibody. MyoD mRNA expression was found at similar levels in freshly isolated and activated HSCs; in contrast, MyoD protein expression was elevated in activated HSCs. Activation of rat HSCs was accompanied by reduced expression of the inhibitory bHLH protein Id1. CONCLUSIONS: In vitro and in vivo activation of rat and human HSCs is accompanied by induction of MyoD binding to E-box DNA sequences which appears to be mechanistically associated with elevated MyoD protein expression and reduced expression of the inhibitory Id1 protein. Clarification of the role of MyoD and Id1 proteins in HSC activation and liver fibrogenesis is now required. PMID- 11600478 TI - Extrahepatic portal vein thrombosis: aetiology and determinants of survival. AB - BACKGROUND: Malignancy, hypercoagulability, and conditions leading to decreased portal flow have been reported to contribute to the aetiology of extrahepatic portal vein thrombosis (EPVT). Mortality of patients with EPVT may be associated with these concurrent medical conditions or with manifestations of portal hypertension, such as variceal haemorrhage. PATIENTS AND METHODS: To determine which variables have prognostic significance with respect to survival, we performed a retrospective study of 172 adult EPVT patients who were followed over the period 1984-1997 in eight university hospitals. RESULTS: Mean follow up was 3.9 years (range 0.1-13.1). Overall survival was 70% (95% confidence interval (CI) 62-76%) at one year, 61% (95% CI, 52-67%) at five years, and 54% (95% CI, 45 62%) at 10 years. The one, five, and 10 year survival rates in the absence of cancer, cirrhosis, and mesenteric vein thrombosis were 95% (95% CI 87-98%), 89% (95% CI 78-94%), and 81% (95% CI 67-89%), respectively (n=83). Variables at diagnosis associated with reduced survival according to multivariate analysis were advanced age, malignancy, cirrhosis, mesenteric vein thrombosis, absence of abdominal inflammation, and serum levels of aminotransferase and albumin. The presence of variceal haemorrhage and myeloproliferative disorders did not influence survival. Only four patients died due to variceal haemorrhage and one due to complications of a portosystemic shunt procedure. CONCLUSION: We conclude that mortality among patients with EPVT is related primarily to concurrent disorders leading to EPVT and not to complications of portal hypertension. PMID- 11600479 TI - Treatment of intestinal Behcet's syndrome with chimeric tumour necrosis factor alpha antibody. AB - Few patients with Behcet's syndrome have gastrointestinal ulceration. Such patients are difficult to treat and have a higher mortality. Faced with refractory symptoms in two patients with intestinal Behcet's, we used the tumour necrosis factor alpha (TNF-alpha) monoclonal antibody infliximab to induce remission. Both women (one aged 27 years, the other 30 years) presented with orogenital ulceration, pustular rash, abdominal pain, bloody diarrhoea due to colonic ulceration, weight loss, and synovitis. One had thrombophlebitis, digital vasculitis, perianal fistula, and paracolic abscess; the other had conjunctivitis and an ulcer in the natal cleft. Treatment with prednisolone, methyl prednisolone, and thalidomide in one and prednisolone, colchicine, and cyclosporin in the other was ineffective. After full discussion, infliximab (3 mg/kg, dose reduced because of recent sepsis in one, and 5 mg/kg in the other) was administered. Within 10 days the ulcers healed, with resolution of bloody diarrhoea and all extraintestinal manifestations. A second infusion of infliximab was necessary eight weeks later in one case, followed by sustained (>15 months) remission on low dose thalidomide. Remission was initially sustained for 12 months in the other but thalidomide had to be stopped due to intolerance, and a good response to retreatment lasted only 12 weeks without immunosuppression, before a third infusion. The cause of Behcet's syndrome is unknown but peripheral blood CD45 gammadelta T cells in Behcet's produce >50-fold more TNF-alpha than controls when stimulated with phorbol myristate acetate and anti-CD3. Infliximab could have a role for inducing remission in Behcet's syndrome. PMID- 11600486 TI - The Harvard Twin Study of Substance Abuse: what we have learned. AB - The Harvard Twin Study of Substance Abuse was carried out with the members of the Vietnam Era Twin (VET) Registry. The VET Registry comprises over 8000 male twins who served in the United States military between 1965 and 1975 and were subsequently interviewed regarding their use of licit and illicit substances, as well as various types of psychopathology. Our research has demonstrated significant influences by genetic, shared environmental, and unique environmental factors on the abuse of illicit substances. Multivariate analyses have indicated that the co-occurrence of abuse of various types of illicit drugs reflects a common vulnerability, influenced by both genetic and environmental factors, that cuts across all categories of illicit drugs. We have also demonstrated that some drugs have unique determinants, both genetic and environmental, that are not shared with other drugs. In part, the genetic influence on marijuana abuse is mediated by genetic influence on subjective effects in response to the drug. The determinants of transitions from one stage of drug use to another differ depending on which drug or which transition is examined. We determined significant genetic influences on several aspects of nicotine and alcohol use separately, as well as genetic influences shared by both substances. We found that the co-occurrence of illicit drug abuse and major depression is due to unique environmental influences. The phenotypic association between symptoms of conduct disorder and alcohol and marijuana dependence is due largely to shared environmental influences. Our results, thus far, indicate a complex pattern of genetic and environmental influences on substance use and abuse. PMID- 11600480 TI - The hepatorenal syndrome. PMID- 11600488 TI - Developmental aspects of borderline personality disorder. AB - This study examined whether patients with borderline personality disorder and controls with other personality disorders remember their childhoods differently with respect to separation difficulties, evocative memory, temperamental factors such as frustration tolerance and mood reactivity, and onset of symptoms. Two hundred and ninety patients with borderline personality disorder and 72 with other personality disorders were assessed using an instrument to rate memories of separation difficulties, temperamental problems, and onset of symptoms before age 18. Patients with borderline personality disorder remembered more difficulties with separation between ages 6 and 17 years, more mood reactivity and poorer frustration tolerance between ages 6 and 17, and the onset of more symptoms (most prominently sadness, depression, anxiety, and suicidality) before age 18 than did patients with other personality disorders. The groups did not differ in reports of evocative memory before age 18. These results indicate that many of the features of adult patients with borderline personality disorder may initially appear during childhood and adolescence and that these features may be used to differentiate borderline from other personality disorders. PMID- 11600487 TI - Omega-3 fatty acids, homocysteine, and the increased risk of cardiovascular mortality in major depressive disorder. AB - Depression is associated with elevated rates of cardiovascular morbidity and mortality. This elevation seems to be due to a significantly increased risk of coronary artery disease and myocardial infarction and, once the ischemic heart disease is established, sudden cardiac death. Recent data suggest that the increased rates of cardiovascular disease in patients with depression may be the result of one or more still-unrecognized underlying physiological factors that predispose a patient to both depression and cardiovascular disease. Two possibly related factors that may have a causal relation with both depressive disorders and cardiovascular disease are an omega-3 fatty acid deficiency and elevated homocysteine levels. We present the available data connecting cardiovascular disease, depression, omega-3 fatty acids, and homocysteine. In addition, we suggest research strategies and some preliminary treatment recommendations that may reduce the increased risk of cardiovascular mortality in patients with major depressive disorder. PMID- 11600489 TI - Suicide, substances, and stories: treating a teenager in trouble. PMID- 11600490 TI - Sexuality in women. PMID- 11600491 TI - Is there a role for twin studies in the molecular genetics era? PMID- 11600492 TI - Metalloprotease-dependent protransforming growth factor-alpha ectodomain shedding in the absence of tumor necrosis factor-alpha-converting enzyme. AB - Zinc-dependent metalloproteases can mediate the shedding of the extracellular domain of many unrelated transmembrane proteins from the cell surface. In most instances, this process, also known as ectodomain shedding, is regulated via protein kinase C (PKC). The tumor necrosis factor alpha-converting enzyme (TACE) was the first protease involved in regulated protein ectodomain shedding identified. Although TACE belongs to the family of metalloprotease-disintegrins, few members of this family have been shown to participate in regulated ectodomain shedding. In fact, the phenotype of tace-/- cells and that of Chinese hamster ovary cell mutants defective in ectodomain shedding points to the existence of a common PKC-activated ectodomain shedding system, whose proteolytic component is TACE, that acts on a variety of transmembrane proteins. Examples of these proteins include the Alzheimer's disease-related protein beta-amyloid precursor protein (betaAPP) and the transmembrane growth factors protransforming growth factor-alpha (pro-TGF-alpha) and, as shown in this report, proheparin-binding epidermal growth factor-like growth factor (pro-HB-EGF). Here we show that the mercurial compound 4-aminophenylmercuric acetate (APMA), frequently used to activate in vitro recombinant matrix metalloproteases, is an activator of the shedding of betaAPP, pro-HB-EGF, and pro-TGF-alpha. Treatment of tace-/- cells or Chinese hamster ovary shedding-defective mutants with APMA activates the cleavage of pro-TGF-alpha but not that of pro-HB-EGF or betaAPP, indicating that APMA activates TACE and also a previously unacknowledged proteolytic activity specific for pro-TGF-alpha. Characterization of this proteolytic activity indicates that it acts on pro-TGF-alpha located at the cell surface and that it is a metalloprotease active in cells defective in furin activity. In summary, treatment of shedding-defective cell lines with APMA unveils the existence of a metalloprotease activity alternative to TACE with the ability to specifically shed the ectodomain of pro-TGF-alpha. PMID- 11600493 TI - Expression of Trp3 determines sensitivity of capacitative Ca2+ entry to nitric oxide and mitochondrial Ca2+ handling: evidence for a role of Trp3 as a subunit of capacitative Ca2+ entry channels. AB - The role of Trp3 in cellular regulation of Ca(2+) entry by NO was studied in human embryonic kidney (HEK) 293 cells. In vector-transfected HEK293 cells (controls), thapsigargin (TG)-induced (capacitative Ca(2+) entry (CCE)-mediated) intracellular Ca(2+) signals and Mn(2+) entry were markedly suppressed by the NO donor 2-(N,N-diethylamino)diazenolate-2-oxide sodium salt (3 microm) or by authentic NO (100 microm). In cells overexpressing Trp3 (T3-9), TG-induced intracellular Ca(2+) signals exhibited an amplitude similar to that of controls but lacked sensitivity to inhibition by NO. Consistently, NO inhibited TG-induced Mn(2+) entry in controls but not in T3-9 cells. Moreover, CCE-mediated Mn(2+) entry into T3-9 cells exhibited a striking sensitivity to inhibition by extracellular Ca(2+), which was not detectable in controls. Suppression of mitochondrial Ca(2+) handling with the uncouplers carbonyl cyanide m-chlorophenyl hydrazone (300 nm) or antimycin A(1) (-AA(1)) mimicked the inhibitory effect of NO on CCE in controls but barely affected CCE in T3-9 cells. T3-9 cells exhibited enhanced carbachol-stimulated Ca(2+) entry and clearly detectable cation currents through Trp3 cation channels. NO as well as carbonyl cyanide m-chlorophenyl hydrazone slightly promoted carbachol-induced Ca(2+) entry into T3-9 cells. Simultaneous measurement of cytoplasmic Ca(2+) and membrane currents revealed that Trp3 cation currents are inhibited during Ca(2+) entry-induced elevation of cytoplasmic Ca(2+), and that this negative feedback regulation is blunted by NO. Our results demonstrate that overexpression of Trp3 generates phospholipase C regulated cation channels, which exhibit regulatory properties different from those of endogenous CCE channels. Moreover, we show for the first time that Trp3 expression determines biophysical properties as well as regulation of CCE channels by NO and mitochondrial Ca(2+) handling. Thus, we propose Trp3 as a subunit of CCE channels. PMID- 11600494 TI - Determinants of the trans-dominant negative effect of truncated forms of the CCR5 chemokine receptor. AB - The human immunodeficiency virus, type 1 (HIV-1) entry process is triggered by interaction between the viral envelope and a seven membrane-spanning domain receptor at the cell surface, usually the CCR5 chemokine receptor. Different naturally occurring mutations in the CCR5 gene abolish receptor function, the most frequent being a 32-nucleotide deletion resulting in a truncated protein (Delta32) lacking the last three transmembrane domains (TM5-7). This mutant is retained in the endoplasmic reticulum and exerts a trans-dominant negative (TDN) effect on the wild type, preventing its exit from this compartment. This TDN effect is often considered as evidence for the oligomerization of CCR5 during transport to the cell surface. Here we use a genetic approach to define the structural determinants of the TDN effect of the Delta32 mutant. It was abolished by certain deletions and by mutations of cysteine residues preventing formation of a disulfide link between the first and second extracellular loops, suggesting that conformation of Delta32 is important for its interaction with CCR5. To circumvent this problem, we used chimeric forms of the Delta32 and wild type CCR5, consisting in substitutions with homologous domains from the mouse CCR5. All chimeric full-length receptors were expressed at the cell surface and were functional for interaction with HIV-1 or with a chemokine ligand, when assayed. The TDN effect was only observed if both the TM3 domain in CCR5 and the TM4 domain in Delta32 were from human origin, whereas the rest of the proteins could be from either origin. This suggests that the TDN effect involves some form of interaction between these transmembrane domains. Alternatively, but less likely to us, substitutions in TM4 could affect the conformation of CCR5 in the endoplasmic reticulum but not at the cell surface. However that may be, it seems that the TDN effect of the Delta32 mutant has no bearing to the issue of CCR5 dimerization and to its possible role in the processing of the receptor to the cell surface. PMID- 11600496 TI - Glycogen-targeting subunits and glucokinase differentially affect pathways of glycogen metabolism and their regulation in hepatocytes. AB - Overexpression of the glucose-phosphorylating enzyme glucokinase (GK) or members of the family of glycogen-targeting subunits of protein phosphatase-1 increases hepatic glucose disposal and glycogen synthesis. This study was undertaken to evaluate the functional properties of a novel, truncated glycogen-targeting subunit derived from the skeletal muscle isoform G(M)/R(Gl) and to compare pathways of glycogen metabolism and their regulation in cells with overexpressed targeting subunits and GK. When overexpressed in hepatocytes, truncated G(M)/R(Gl) (G(M)DeltaC) was approximately twice as potent as full-length G(M)/R(Gl) in stimulation of glycogen synthesis, but clearly less potent than GK or two other native glycogen-targeting subunits, G(L) and PTG. We also found that cells with overexpressed G(M)DeltaC are unique in that glycogen was efficiently degraded in response to lowering of media glucose concentrations, stimulation with forskolin, or a combination of both maneuvers, whereas cells with overexpressed G(L), PTG, or GK exhibited impairment in one or both of these glycogenolytic signaling pathways. (2)H NMR analysis of purified glycogen revealed that hepatocytes with overexpressed GK synthesized a larger portion of their glycogen from triose phosphates and a smaller portion from tricarboxylic acid cycle intermediates than cells with overexpressed glycogen-targeting subunits. Additional evidence for activation of distinct pathways of glycogen synthesis by GK and targeting subunits is provided by the additive effect of co overexpression of the two types of proteins upon glycogen synthesis and a much larger stimulation of glucose utilization, glucose transport, and lactate production elicited by GK. We conclude that overexpression of the novel targeting subunit G(M)DeltaC confers unique regulation of glycogen metabolism. Furthermore, targeting subunits and GK stimulate glycogen synthesis by distinct pathways. PMID- 11600495 TI - Expression of novel ING variants is regulated by thyroid hormone in the Xenopus laevis tadpole. AB - The candidate tumor suppressor gene, ING1, encodes several protein isoforms as a result of alternative splicing that may possess agonistic and antagonistic roles in the control of cell proliferation and apoptosis. Recently a related gene, ING2, was isolated in human whose expression is increased in adenocarcinomas. Little is known about the cellular function and regulation of these ING family members, but the fact that ING proteins contain a plant homeodomain finger suggests that these proteins may modulate transcription factor-mediated pathways. To elucidate how ING may interact in different tissues to modulate function, we used amphibian metamorphosis as a model system in which a single stimulus, thyroid hormone (TH), initiates tissue-specific proliferation, differentiation, and apoptosis. We have isolated the first Xenopus laevis ING2 and demonstrate that transcript levels increase in response to TH treatment. We provide evidence for the existence of splice variants that are differentially expressed in tissues with different TH-induced fates. Western blots using an antibody directed against the highly conserved C-terminal end of ING proteins reveal a tissue-specific pattern of ING isoform expression in adult Xenopus tissues. Analyses of premetamorphic tadpole tissues show a TH-induced accumulation of ING proteins in tail, whereas the levels in the leg are not affected. This TH-induced accumulation is also observed in serum-free tail organ cultures and is prevented by inhibitors of tail apoptosis. Therefore, this work presents the first link between ING expression and a hormonally regulated nuclear transcription factor mediated apoptotic response opening the possibility that ING family members may be involved in transducing the signal initiated by TH that determines cell fate. PMID- 11600498 TI - Transcription factor NF-kappa B is necessary for up-regulation of type 1 angiotensin II receptor mRNA in rat cardiac fibroblasts treated with tumor necrosis factor-alpha or interleukin-1 beta. AB - Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta up-regulate type 1 angiotensin II receptor (AT(1)) mRNA and protein in cultured neonatal rat cardiac fibroblasts. The use of pharmacologic inhibitors and a degradation-resistant mutant I kappa B-alpha demonstrated that the transcription factor nuclear factor kappa B (NF-kappa B) is necessary for cytokine-induced AT(1) up-regulation. The increase in AT(1) mRNA with TNF-alpha treatment is slow, reaching significance by 6-12 h and peaking by 24-48 h. Electrophoretic mobility shift assays revealed that NF-kappa B nuclear translocation was maintained for > or = 24 h with a single dose of TNF-alpha. Since prolonged NF-kappa B activation appeared necessary to maximize AT(1) up-regulation, the mechanism of persistent NF-kappa B activation was studied further. Stimulation with TNF-alpha induced a >10x increase in I kappa B kinase (IKK) activity that quickly diminished by 20 min. I kappa B-alpha and I kappa B-beta proteins were degraded during this time, and I kappa B-alpha was resynthesized subsequently by NF-kappa B-dependent transcription. However, I kappa B isoforms and IKK activity did not return completely to unstimulated values during a 12-h time course. These results suggest that low but persistent IKK activity and I kappa B degradation lead to prolonged NF-kappa B nuclear translocation and maximal AT(1) up-regulation in the continued presence of TNF-alpha. PMID- 11600499 TI - Mimetics of a T cell epitope based on poly-N-acylated amine backbone structures induce T cells in vitro and in vivo. AB - Peptidomimetics of the major histocompatibility complex (MHC) class I-restricted ovalbumin-derived T cell epitope SIINFEKL were generated by replacing parts of the peptide backbone by a poly-N-acylated amine (PAA) backbone with aromatic, heteroaromatic, and pseudoaromatic side chains that branch off of the main chain at the amine nitrogen. The structure of the PAAs was designed to position this side chain in the central epitope anchor pocket of the MHC molecule. A number of biologically active PAAs were found that induced cytolysis by the mouse cytotoxic T cell clone 4G3. Competition experiments with independent peptides that are known to bind to the restricting MHC molecule H-2K(b) suggest that the PAAs are bound by the MHC molecules at the same site as conventional peptide epitopes. The PAAs were active also in vivo and induced primary cytotoxic T cell responses in mice. PMID- 11600497 TI - Non-apoptotic signaling pathways activated by soluble Fas ligand in serum-starved human fibroblasts. Mitogen-activated protein kinases and NF-kappaB-dependent gene expression. AB - Many Fas-expressing cells do not undergo cell death upon Fas stimulation. In the normal human diploid cell line GM6112, the addition of soluble Fas ligand (sFasL) leads to morphological signs of cell death in less than 1% of cells. Treatment of serum-starved GM6112 fibroblasts with sFasL resulted in a rapid and transient phosphorylation of ERK1/2 without a significant increase in JNK and p38 activities. Unless co-treated with the protein synthesis inhibitor anisomycin, sFasL did not show gene-inducing activity in cells maintained in complete medium. However, when cells were serum-starved for 4 days, treatment with sFasL alone induced interleukin-6 gene expression and, less strongly, interleukin-8 gene expression. Sensitization of the gene-inducing activity by serum starvation correlated with NF-kappaB activation by sFasL. Furthermore, we found that the expression of FADD and caspase-8 was significantly reduced in serum-starved cells, whereas the level of cFLIP remained unchanged. Transfection of GM6112 cells with the antisense caspase-8 expression construct sensitized cells toward sFasL-induced NF-kappaB-dependent reporter activation. Our results support the notion that a change in the ratio of cFLIP and caspase-8 may be responsible for turning on the Fas-activated NF-kappaB pathway, which otherwise is supplanted by the death-inducing pathway. PMID- 11600500 TI - Melittin enables efficient vesicular escape and enhanced nuclear access of nonviral gene delivery vectors. AB - Entry of exogenously applied DNA into the cytoplasm and subsequent transport into the nucleus are major cellular barriers for nonviral gene delivery vectors. To overcome these barriers, we have covalently attached the cationic peptide melittin to poly(ethylenimine) (PEI). This conjugate condensed DNA into small, discrete particles (<100 nm in diameter), and the membrane lytic activity of melittin enabled efficient release of the DNA into the cytoplasm, as monitored by fluorescence microscopy and flow cytometry. Compared with PEI, the transfection activity was strongly increased within a broad range of cell lines and types tested, including different tumor cell lines but also primary hepatocytes and human umbilical vein endothelial cells. The early onset of gene expression (within 4 h, reaching maximal values after 12 h) and the high reporter gene expression achieved in slowly dividing or confluent cells suggested a further role of melittin after releasing the DNA into the cytoplasm. Intracytoplasmic microinjection of melittin-containing PEI.DNA complexes into fibroblasts produced 40% cellular frequency of reporter gene expression that was inhibitable by co injection of wheat germ agglutinin, whereas simple PEI.DNA complexes showed only 10%. These data suggest that melittin enables release of nonviral gene transfer particles into the cytoplasm and also enhances their transport into the nucleus, possibly via the cationic cluster KRKR near the C terminus of the peptide. PMID- 11600501 TI - Purification and biochemical characterization of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthases KasA and KasB. AB - Mycolic acids are vital components of the Mycobacterium tuberculosis cell wall, and enzymes involved in their formation represent attractive targets for the discovery of novel anti-tuberculosis agents. Biosynthesis of the fatty acyl chains of mycolic acids involves two fatty acid synthetic systems, the multifunctional polypeptide fatty acid synthase I (FASI), which performs de novo fatty acid synthesis, and the dissociated FASII system, which consists of monofunctional enzymes, and acyl carrier protein (ACP) and elongates FASI products to long chain mycolic acid precursors. In this study, we present the initial characterization of purified KasA and KasB, two beta-ketoacyl-ACP synthase (KAS) enzymes of the M. tuberculosis FASII system. KasA and KasB were expressed in E. coli and purified by affinity chromatography. Both enzymes showed activity typical of bacterial KASs, condensing an acyl-ACP with malonyl-ACP. Consistent with the proposed role of FASII in mycolic acid synthesis, analysis of various acyl-ACP substrates indicated KasA and KasB had higher specificity for long chain acyl-ACPs containing at least 16 carbons. Activity of KasA and KasB increased with use of M. tuberculosis AcpM, suggesting that structural differences between AcpM and E. coli ACP may affect their recognition by the enzymes. Both enzymes were sensitive to KAS inhibitors cerulenin and thiolactomycin. These results represent important steps in characterizing KasA and KasB as targets for antimycobacterial drug discovery. PMID- 11600502 TI - Identification of the GTP binding site of human glutamate dehydrogenase by cassette mutagenesis and photoaffinity labeling. AB - It has been reported that the hyperinsulinism-hyperammonemia syndrome is caused by mutations in glutamate dehydrogenase (GDH) gene that affects enzyme sensitivity to GTP-induced inhibition. To identify the GTP binding site(s) within human GDH, mutant GDHs at Tyr-266 or Lys-450 position were constructed by cassette mutagenesis. More than 90% of the initial activities were remained at the concentration of GTP up to 300 microm for the Lys-450 mutant GDHs regardless of their size, hydrophobicity, and ionization of the side chains, whereas the wild type GDH and the Tyr-266 mutant GDHs were completely inhibited by 30 microm GTP. The binding of GTP to the wild type GDH or the mutant GDHs was further examined by photoaffinity labeling with 8-[gamma-(32)P]azidoguanosine 5' triphosphate (8-N(3)-GTP). Saturation of photoinsertion with 8-N(3)-GTP occurred apparent K(d) values near 20 microm for the wild type GDH or the Tyr-266 mutant GDH, and the photoinsertion of 8-N(3)-[gamma-(32)P]GTP was significantly decreased in the presence of 300 microm GTP. Unlike the wild type GDH or the Tyr 266 mutant GDH, less than 10% of photoinsertion was detected in the Lys-450 mutant GDH, and the photoinsertion was not affected by the presence of 300 microm GTP. The results with cassette mutagenesis and photoaffinity labeling demonstrate selectivity of the photoprobe for the GTP binding site and suggest that Lys-450, but not Tyr-266, is required for efficient binding of GTP to GDH. Interestingly, studies of the steady-state velocity showed that both the wild type GDH and the Tyr-266 mutant GDHs were inhibited by ATP at concentrations between 10 and 100 microm, whereas less than 10% of the initial activities of the Lys-450 mutant GDHs were diminished by ATP. These results indicate that Lys-450, but not Tyr 266, may be also responsible for the ATP inhibition; therefore, ATP bound to the GTP site. PMID- 11600503 TI - Characterization of posttranslational formylglycine formation by luminal components of the endoplasmic reticulum. AB - C(alpha)-formylglycine is the key catalytic residue in the active site of sulfatases. In eukaryotes formylglycine is generated during or immediately after sulfatase translocation into the endoplasmic reticulum by oxidation of a specific cysteine residue. We established an in vitro assay that allowed us to measure formylglycine modification independent of protein translocation. The modifying enzyme was recovered in a microsomal detergent extract. As a substrate we used ribosome-associated nascent chain complexes comprising in vitro synthesized sulfatase fragments that were released from the ribosomes by puromycin. Formylglycine modification was highly efficient and did not require a signal sequence in the substrate polypeptide. Ribosome association helped to maintain the modification competence of nascent chains but only after their release efficient modification occurred. The modifying machinery consists of soluble components of the endoplasmic reticulum lumen, as shown by differential extraction of microsomes. The in vitro assay can be performed under kinetically controlled conditions. The activation energy for formylglycine formation is 61 kJ/mol, and the pH optimum is approximately 10. The activity is sensitive to the SH/SS equilibrium and is stimulated by Ca(2+). Formylglycine formation is efficiently inhibited by a synthetic sulfatase peptide representing the sequence directing formylglycine modification. The established assay system should make possible the biochemical identification of the modifying enzyme. PMID- 11600504 TI - Solution structure of the fibronectin type III domain from Bacillus circulans WL 12 chitinase A1. AB - Growing evidence suggests that horizontal gene transfer plays an integral role in the evolution of bacterial genomes. One of the debated examples of horizontal gene transfer from animal to prokaryote is the fibronectin type III domain (FnIIID). Certain extracellular proteins of soil bacteria contain an unusual cluster of FnIIIDs, which show sequence similarity to those of animals and are likely to have been acquired horizontally from animals. Here we report the solution structure of the FnIIID of chitinase A1 from Bacillus circulans WL-12. To the best of our knowledge, this is the first tertiary structure to be reported for an FnIIID from a bacterial protein. The structure of the domain shows significant similarity to FnIIIDs from animal proteins. Sequence comparisons with FnIIIDs from other soil bacteria proteins show that the core-forming residues are highly conserved and, thus, are under strong evolutionary pressure. Striking similarities in the tertiary structures of bacterial FnIIIDs and their mammalian counterparts may support the hypothesis that the evolution of the FnIIID in bacterial carbohydrases occurred horizontally. The total lack of surface-exposed aromatic residues also suggests that the role of this FnIIID is different from those of other bacterial beta-sandwich domains, which function as carbohydrate binding modules. PMID- 11600505 TI - Clinical review 136: Primary lymphoma of the pituitary: an emerging clinical entity. PMID- 11600506 TI - Clinical review 137: Sexual dimorphism in skeletal size, density, and strength. PMID- 11600507 TI - Subclinical hypothyroidism is mild thyroid failure and should be treated. PMID- 11600508 TI - The treatment of subclinical hypothyroidism is seldom necessary. PMID- 11600509 TI - A highly complex organization of the regulatory region of the human CYP19 (aromatase) gene revealed by the Human Genome Project. PMID- 11600510 TI - Extensive inflammatory pseudotumor of the pituitary. AB - A 40-yr-old female presented with an extensive lesion of the sellar area and the sphenoid sinus, spreading to the optic nerves and associated with pachymeningitis. Histological findings were consistent with an inflammatory pseudotumor, and steroid treatment allowed the disappearance of all the lesions. Inflammatory pseudotumors of the pituitary are very rare. This case appears unique with regard to the extension of the lesions and the dramatic response to medical treatment. The differential diagnosis of inflammatory lesions of the pituitary is difficult. It relies mainly on histological analysis and includes sarcoidosis, Wegener's granulomatosis, histiocytosis (Langerhans, Rosai-Dorfman, and Erdheim-Chester diseases) and lymphocytic hypophysitis. PMID- 11600511 TI - Report of National Institute on Aging Advisory Panel on Testosterone Replacement in Men. PMID- 11600512 TI - Limitations of the fasting glucose to insulin ratio as an index of insulin sensitivity. PMID- 11600513 TI - Fasting glucose insulin ratio: a useful measure of insulin resistance in girls with premature adrenarche. AB - The purpose of this study was to determine whether the fasting glucose/insulin ratio is a useful screening test for insulin resistance in prepubertal girls with premature adrenarche. The glucose/insulin ratio was compared with the insulin sensitivity index calculated from the frequently sampled iv glucose tolerance test with tolbutamide using the minimal model computer program. Thirty-three prepubertal girls (22 Caribbean Hispanic and 11 African American; mean age, 6.8 yr; bone age, 8 yr) were studied. All underwent a 60-min ACTH stimulation test. The fasting glucose/insulin ratio was also compared with IGF-binding protein-1 and ACTH-stimulated androgen levels. Insulin sensitivity correlated significantly with the glucose/insulin ratio (0.76; P < 0.001), fasting insulin (0.75; P < 0.001), and IGF-binding protein-1 (0.59; P < 0.005). Stepwise regression analysis with the insulin sensitivity index as the dependent variable showed that the fasting glucose/insulin ratio was significantly predictive of the insulin sensitivity index (P < 0.002). When viewed as a screening test, setting a value of the fasting glucose/insulin ratio of less than 7 as abnormal and of less than 5.7 x 10(-4) min/microU.ml for the insulin sensitivity index as evidence of insulin resistance (normal prepubertal insulin sensitivity index, >5.7 x 10(-4) min/microU.ml), the sensitivity of the fasting glucose/insulin ratio was 87%, and the specificity was 89%. Furthermore, those girls with a low glucose/insulin ratio (<7) had higher body mass index, fasting insulin, free T, and ACTH stimulated 17-hydroxypregnenolone and lower fasting IGF-binding protein-1 and SHBG than those girls with a glucose/insulin ratio greater than 7. The fasting glucose/insulin ratio is a useful screening test for insulin resistance in prepubertal Caribbean Hispanic and African American girls with premature adrenarche. PMID- 11600514 TI - The stimulatory G protein alpha-subunit gene: mutations and imprinting lead to complex phenotypes. PMID- 11600515 TI - Galphas transcripts are biallelically expressed in the human kidney cortex: implications for pseudohypoparathyroidism type 1b. AB - Pseudohypoparathyroid type 1b patients are characterized by renal resistance to PTH in the absence of Albright's hereditary osteodystrophy or other endocrine abnormalities. Kindred studies have suggested that the cause of this resistance is a specific decrease in Galphas activity in renal proximal tubules due to paternal imprinting of Galphas. To test this, allelic expression of Galphas was analyzed in human fetal kidney cortex samples by RT-PCR assays. The results showed that, in contrast to the parent-specific expression of exon 1A and XLalphas (paternal) or NESP (maternal) mRNAs, Galphas transcripts are biallelically expressed in human kidney cortex. These data implicate abnormal imprinting of alternative regions within the GNAS1 locus as a more likely cause of pseudohypoparathyroid type 1b. PMID- 11600516 TI - Analysis of the GNAS1 gene in Albright's hereditary osteodystrophy. AB - Albright's hereditary osteodystrophy (AHO) is characterized by phenotypic signs that typically include brachydactyly and sc calcifications occurring with or without hormone resistance toward PTH or other hormones such as thyroid hormone or gonadotropins. Different inactivating mutations of the gene GNAS1 encoding Gsalpha lead to a reduced Gsalpha protein activity in patients with AHO and pseudohypoparathyroidism type Ia or without resistance to PTH (pseudopseudohypoparathyroidism). We investigated 29 unrelated patients with AHO and pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism and their affected family members performing functional and molecular genetic analysis of Gsalpha. In vitro determination of Gsalpha protein activity in erythrocyte membranes was followed by the investigation of the whole coding region of the GNAS1 gene using PCR, nonisotopic single strand conformation analysis, and direct sequencing of the PCR products. All patients showed a reduced Gsalpha protein activity (mean 59% compared with healthy controls). In 21/29 (72%) patients, 15 different mutations in GNAS1 including 11 novel mutations were detected. In addition we add five unrelated patients with a previously described 4 bp deletion in exon 7 (Delta GACT, codon 189/190), confirming the presence of a hot spot for loss of function mutations in GNAS1. In eight patients, no molecular abnormality was found in the GNAS1 gene despite a functional defect of Gsalpha. We conclude that biochemical and molecular analysis of Gsalpha and its gene GNAS1 can be valuable tools to confirm the diagnosis of AHO. However, in some patients with reduced activity of Gsalpha, the molecular defect cannot be detected in the exons encoding the common form of Gsalpha. PMID- 11600517 TI - GH and cardiac failure. PMID- 11600518 TI - Six months of recombinant human GH therapy in patients with ischemic cardiac failure does not influence left ventricular function and mass. AB - Beneficial effects of recombinant human GH on cardiac function have been reported in humans with GH deficiency and in patients with idiopathic dilated cardiomyopathy. No randomized controlled trial has been performed on the effects of recombinant human GH on cardiac function in patients with ischemic cardiac failure. We therefore randomly assigned 22 patients with ischemic cardiac failure (left ventricular ejection fraction, <40%; 19 men and 3 women; mean age, 64 yr) to receive 6 months of unblinded therapy with recombinant human GH (2.0 IU/d) or no treatment. Primary end points were left ventricular ejection fraction and left ventricular mass. Left ventricular end-diastolic volume, left ventricular end systolic volume, and myocardial perfusion, both at rest and during exercise, were assessed as well. Cardiac imaging techniques were electrocardiographically gated single photon emission computer tomography and magnetic resonance imaging. In addition, biochemical and biometric measurements were performed. Nineteen patients completed the study (10 controls and 9 GH-treated subjects). IGF-I and IGF-binding protein-3 increased significantly after recombinant human GH treatment (+24% and +58%, respectively) compared with control values (-14% and +5%; P < 0.05). Left ventricular ejection fraction, left ventricular end diastolic volume, left ventricular end-systolic volume, left ventricular mass, and myocardial perfusion were not influenced by recombinant human GH therapy. We conclude that 6 months of recombinant human GH treatment in patients with ischemic cardiac failure had no beneficial effect on left ventricular function and mass. PMID- 11600519 TI - Accuracy of fine needle aspiration biopsy of thyroid nodules in detecting malignancy in childhood: comparison with conventional clinical, laboratory, and imaging approaches. AB - In childhood the traditional diagnostic approach to thyroid nodules consists of clinical, laboratory, and imaging evaluations. A safe and accurate procedure is needed to promptly identify patients who require surgery. In regard to the usefulness of fine needle aspiration biopsy, the data in the literature concerning children and adolescents are scanty. The aim of this study was to evaluate and compare the diagnostic accuracies of clinical, laboratory, and imaging data collected retrospectively in a group of pediatric patients with thyroid nodules submitted to fine needle aspiration biopsy. Forty-two patients who underwent surgery for thyroid nodules, recruited in 9 Italian pediatric endocrine units, were retrospectively studied. According to histological diagnosis, they were divided into 2 groups, 22 patients with benign lesions and 20 patients with malignant lesions. From clinical records we obtained data about 1) symptoms of neck compression; 2) cervical adenopathy; 3) thyroid function, calcitonin level, and antithyroid antibody titers; 4) ultrasonography; 5) (99m)Tc scintiscanning; and 6) cytology obtained with fine needle aspiration biopsy. Patients and nodule characteristics were analyzed statistically for associations with the presence of thyroid cancer. Among clinical findings, only adenopathy was significantly higher in the group with cancer (8 of 22 benign lesions vs. 16 of 20 malignant lesions; P = 0.006). Thyroid function and antibody titers were similar in the 2 groups, whereas the serum calcitonin level was elevated only in 1 patient with malignant lesions. Among ultrasonography findings, no significant statistical difference was found between the 2 groups with regard to number, dimensions, growth progression, or hypoechogenic pattern of the nodules. Regarding scintigraphic findings, no significant difference was found between the 2 groups. However, a positive correlation (r = 0.90; P < 0.0001) was found between fine needle aspiration biopsy cytological findings and histological diagnoses. The sensitivity, specificity, and accuracy of fine needle aspiration biopsy were 95%, 86.3%, and 90.4%, respectively. A multiple regression analysis showed that only fine needle aspiration biopsy (beta coefficient = 0.963; P < 0.0001) significantly contributed to detecting malignancy (multiple r = 0.973; P < 0.0001). This study provides strong evidence that fine needle aspiration biopsy is a safe technique even in childhood and adolescence, offering the best sensitivity, specificity, and accuracy in detecting malignancy compared with conventional approaches. PMID- 11600520 TI - Growth and adult height in GH-treated children with nonacquired GH deficiency and idiopathic short stature: the influence of pituitary magnetic resonance imaging findings. AB - We analyzed the final height of 146 short children with either nonacquired GH deficiency or idiopathic short stature. Our purpose was 1) to assess growth according to the pituitary magnetic resonance imaging findings in the 63 GH treated children with GH deficiency and 2) to compare the growth of the GH deficient patients with normal magnetic resonance imaging (n = 48) to that of 32 treated and 51 untreated children with idiopathic short stature (GH peak to provocative tests >10 microg/liter). The mean GH dose was 0.44 IU/kg.wk (0.15 mg/kg.wk), given for a mean duration of 4.6 yr. Among the GH-deficient children, 15 had hypothalamic-pituitary abnormalities (stalk agenesis), all with total GH deficiency (GH peak <5 microg/liter). They were significantly shorter and younger at the time of diagnosis than those with normal magnetic resonance imaging, had better catch-up growth (+2.7 +/- 0.9 vs. +1.3 +/- 0.8 SD score; P < 0.01), and reached greater final height (-1.1 +/- 1.0 vs. -1.7 +/- 1.0 SD score; P < 0.05). Among patients with normal magnetic resonance imaging, there was no difference in catch-up growth and final height between partial and total GH deficiencies. GH deficient subjects with normal magnetic resonance imaging and treated and untreated patients with idiopathic short stature had comparable auxological characteristics, age at evaluation, and target height. Although they had different catch-up growth (+1.3 +/- 0.8, +0.9 +/- 0.6, and +0.7 +/- 0.9 SD score, respectively; P < 0.01, by ANOVA), these patients reached a similar final height (-1.7 +/- 1.0, -2.1 +/- 0.8, and -2.1 +/- 1.0 SD score, respectively; P = 0.13). Pituitary magnetic resonance imaging findings show the heterogeneity within the group of nonacquired GH deficiency and help to predict the response to GH treatment in these patients. The similarities in growth between the GH-deficient children with normal magnetic resonance imaging and those with idiopathic short stature suggest that the short stature in the former subjects is at least partly due to factors other than GH deficiency. PMID- 11600521 TI - The effect of pubertal delay by GnRH agonist in GH-deficient children on final height. PMID- 11600522 TI - A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices. AB - GH replacement therapy has proved its efficacy and safety in short-term trials and in a few long-term trials with limited number of subjects. In this 1-center study, including 118 consecutive adults (70 men and 48 women; mean age, 49.3 yr; range, 22-74 yr) with adult-onset GH deficiency, the effects of 5 yr of GH replacement on body composition, bone mass, and metabolic indices were determined. The mean initial GH dose was 0.98 mg/d. The dose was gradually lowered, and after 5 yr the mean dose was 0.48 mg/d. The mean IGF-I SD score increased from -1.73 at baseline to 1.66 at study end. A sustained increase in lean body mass and a decrease in body fat were observed. The GH treatment increased total body bone mineral content as well as lumbar (L2-L4) and femur neck bone mineral contents. BMD in lumbar spine (L2-L4) and femur neck were increased and normalized at study end. Total cholesterol and low density lipoprotein cholesterol decreased, and high density lipoprotein cholesterol increased. At 5 yr, serum concentrations of triglycerides and hemoglobin A(1c) were reduced compared with baseline values. The treatment responses in IGF-I SD score, body fat as estimated by four- and five-compartment body composition models, total body protein and nitrogen, and lumbar bone mineral content and BMD were more marked in men than in women. One patient died during the period, four patients discontinued the study due to adverse events, and one dropped out due to lack of compliance. Four patients were lost to follow-up. However, all patients were retained in the statistical analysis according to the intention to treat approach used. In conclusion, 5 yr of GH substitution in GH-deficient adults is safe and well tolerated. The effects on body composition, bone mass, and metabolic indices were sustained. The effects on body composition and low density lipoprotein cholesterol were seen after 1 yr, whereas the effects on bone mass, triglycerides, and hemoglobin A(1c) were first observed after years of treatment. PMID- 11600523 TI - Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy. AB - Women with polycystic ovary syndrome who present with hyperandrogenemia, hyperinsulinemia, and insulin resistance appear to be at high risk of cardiovascular disease. Elevated levels of endothelin-1, a marker of vasculopathy, have been reported in insulin-resistant subjects with endothelial dysfunction. Male gender also seems to be an aggravating factor for cardiovascular disease. In this study we investigated endothelin-1 levels in women with polycystic ovary syndrome, and we evaluated the effect of an insulin sensitizer, metformin, on endothelin-1 levels. Plasma endothelin-1 levels were measured in 23 obese (mean age, 24.3 +/- 4.6 yr; body mass index, 35 +/- 5.6 kg/m(2)) and 20 nonobese women with polycystic ovary syndrome (24.1 +/- 3.6 yr; body mass index, 21.8 +/- 2.5 kg/m(2)) as well as in 7 obese and 10 nonobese healthy, normal cycling, age-matched women. Additionally, endothelin-1 levels were evaluated in a subgroup of women with polycystic ovary syndrome (10 obese and 10 nonobese) 6 months postmetformin administration (1700 mg daily). Our results showed that obese and nonobese women with polycystic ovary syndrome had higher levels of endothelin-1 compared with the controls [obese, 2.52 +/- 1.87 vs. 0.44 +/- 0.23 pmol/liter (by analysis of covariance, P < 0.02); nonobese, 1.95 +/- 1.6 vs. 0.43 +/- 0.65 pmol/liter (P < 0.009)]. All of the participating women with polycystic ovary syndrome (n = 43) when compared with the total group of controls (n = 17) demonstrated hyperinsulinemia (polycystic ovary syndrome, 24.5 +/- 19.6; controls, 11.2 +/- 3.4 U/liter; P < 0.03), lower glucose utilization (M40) during the hyperinsulinemic euglycemic clamps (3.4 +/- 2.4 vs. 5.6 +/- 1.75 mg/kg.min; P < 0.045, by one-tailed test), and higher levels of endothelin-1 (polycystic ovary syndrome, 2.52 +/- 1.87; controls, 0.44 +/- 0.23 pmol/liter; P < 0.02, analysis of covariance covariate for body mass index). A positive correlation of endothelin-1 with free T levels was also shown (r = 0.4, P = 0.002) as well as a negative correlation of endothelin-1 with glucose utilization (r = -0.3; P = 0.033) in the total studied population. Finally, after metformin therapy, endothelin-1 levels were significantly reduced in obese (endothelin-1 before, 3.25 +/- 2.2; endothelin-1 after, 1.1 +/- 0.9 pmol/liter; P < 0.003) and nonobese (endothelin-1 before, 2.7 +/- 2; endothelin-1 after, 0.7 +/ 0.4 pmol/liter; P < 0.01) women with polycystic ovary syndrome, with no change in body mass index. Moreover, after metformin therapy, hyperandrogenemia and hyperinsulinemia were normalized, and glucose utilization improved [obese before: total T, 0.9 +/- 0.15 ng/ml; fasting insulin, 22.2 +/- 12.1 U/liter; glucose utilization, 2.15 +/- 0.5 mg/kg.min; obese after: total T, 0.5 +/- 0.2 ng/ml; fasting insulin, 11.6 +/- 6 U/liter; glucose utilization, 4.7 +/- 1.4 mg/kg.min 9P < 0.003, P < 0.006, and P < 0.002, respectively); nonobese before: total T, 1 +/- 0.5 ng/ml; fasting insulin, 15.5 +/- 7.6 U/liter; glucose utilization, 3.4 +/ 0.7 mg/kg.min; nonobese after: total T, 0.8 +/- 0.5 ng/ml; fasting insulin, 9 +/ 3.8 U/liter; glucose utilization, 6 +/- 1.7 mg/kg.min (P < 0.04, P < 0.02, and P < 0.0008, respectively)]. In conclusion, our data clearly demonstrate that women with polycystic ovary syndrome, obese and nonobese, have elevated endothelin-1 levels compared with the age-matched control group. In addition, 6 months of metformin therapy reduces endothelin-1 levels and improves their hormonal and metabolic profile. PMID- 11600524 TI - The influence of intense ballet training on trabecular bone mass, hormone status, and gonadotropin structure in young women. AB - A cross-sectional study on young dancers and exdancers was performed to evaluate the effects of intense weight-bearing exercise and dietary restriction, started during puberty, on bone mineral density (BMD), menarche age, menstrual function, and gonadotropin structure. Twenty current dancers (group 1) and 9 exdancers (group 2) were compared with a control group of 30 age-matched, regularly cycling women. Body weight, body mass index, total daily caloric intake, and nutritional markers were significantly lower (P < 0.05) in groups 1 and 2 than in controls. Using Quantitative Computed Tomography for the BMD evaluation, 12 dancers and 5 exdancers had Z-scores less than 2.5 SD below the mean of the controls; whereas, in 6 dancers and in 2 exdancers, BMD was between 1 and 2.5 SD. Groups 1 and 2 had a delay of menarche, which correlated positively with years of dance before menarche (r = 0.8; P < 0.001). Dancers had low levels and altered structure of circulating gonadotropins, which improved after GnRH stimulation. In conclusion, ballet training performed by dancers during puberty, dietary restriction, and low body mass index can all be associated with reduction in BMD and altered gonadotropin isoforms, with subsequent delay of menarche, menstrual dysfunctions, and insufficient peak bone mass. A longitudinal study must be conducted to confirm the persistence of low lumbar spine bone density in adult age. PMID- 11600525 TI - Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory? AB - One of the main aims in the management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency is to achieve adequate suppression of the adrenal cortex with the smallest possible dose of glucocorticoid substitution. To evaluate the administration schedule of current replacement therapy regimens, we investigated the cortisol-17-hydroxyprogesterone interrelation in 36 patients (13 males and 23 females; median age, 12.3 yr; range, 6.1-18.8 yr) with salt-wasting congenital adrenal hyperplasia. As sufficient variation in 17-hydroxyprogesterone concentrations was required to allow analysis of the cortisol-17-hydroxyprogesterone interrelation, patients were divided into 2 groups depending on the adequacy of hypothalamic-pituitary adrenal axis suppression. The first group consisted of 17 patients with suppressed 17-hydroxyprogesterone concentrations (group 1), and the second group consisted of 19 patients with nonsuppressed 17-hydroxyprogesterone concentrations (group 2). We determined serum cortisol and 17-hydroxyprogesterone concentrations at 20-min intervals for a total of 24 h while patients were receiving their usual replacement treatment with hydrocortisone and 9alpha-fludrocortisone. We also determined the lowest dose of dexamethasone required to suppress the 0800 h serum ACTH concentrations when administered as a single dose (0.3 or 0.5 mg/m(2)) the night before. Mean 24-h cortisol and 17-hydroxyprogesterone concentrations were 3.9 microg/dl (SD = 2.1) and 66.2 ng/dl (SD = 92.7), respectively, in group 1 and 4.1 microg/dl (SD = 2.5) and 4865.7 ng/dl (SD = 6951) in group 2. The 24-h 17 hydroxyprogesterone concentrations demonstrated circadian variation, with peak values observed between 0400-0900 h. In group 2, 17-hydroxyprogesterone concentrations decreased gradually in response to the rise in cortisol concentrations during the day, but remained low during the night despite the almost undetectable cortisol concentrations between 1600-2000 h. Mean 0800 h androstenedione concentrations correlated strongly with integrated 17 hydroxyprogesterone concentrations (r = 0.81; P < 0.0001), but not with integrated cortisol concentrations. There was a significant negative correlation between cortisol and 17-hydroxyprogesterone at lag time 0 min (r = -0.187; P < 0.0001), peaking at lag time 60 min (r = -0.302; P < 0.0001), with cortisol leading 17-hydroxyprogesterone by these time intervals. Finally, 0800 h serum ACTH concentrations were sufficiently suppressed after a dexamethasone dose of 0.3 mg/m(2) in all but three patients. These findings indicate that in classic 21 hydroxylase deficiency, hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity, between 0400-1600 h, with the biggest dose given in the morning. Blood investigations performed as part of monitoring of congenital adrenal hyperplasia patients should include androstenedione and 17-hydroxyprogesterone concentrations determined in the morning before the administration of hydrocortisone. It should also be emphasized that blood investigations are only complementary to the overall assessment of these patients, which is primarily based on the evaluation of growth and pubertal progress. PMID- 11600527 TI - Baseline characteristics and the effects of five years of GH replacement therapy in adults with GH deficiency of childhood or adulthood onset: a comparative, prospective study. AB - The consequences of GH deficiency may differ if the disease is childhood onset or adulthood onset. In this single-center, prospective study, 21 consecutive adults with childhood onset GH deficiency and 21 adults with adulthood onset GH deficiency, matched for age, gender, body mass index, and number of anterior pituitary hormonal deficiencies, were included. Baseline differences and differences in the responses in body composition, muscle strength, bone mass, and metabolic indices during 5-yr GH replacement were determined. The duration of GH deficiency was longer and serum IGF-I level and body height were lower in the childhood onset patients than in the adulthood onset patients. Body fat (observed/predicted ratio) was increased, and lean mass and muscle strength were decreased, in the childhood onset patients. Total body and lumbar (L2-L4) bone mineral content and bone mineral density were lower in the childhood onset patients. Serum total cholesterol level was higher in the adulthood onset patients. The childhood onset and adulthood onset patients received a similar dose of GH. After adjustment for body weight, however, the dose of GH was higher in the childhood onset patients. The treatment responses were more marked in the childhood onset patients in lean mass, knee extensor strength, left-hand grip strength, and in total body and lumbar (L2-L4) bone mineral content and bone mineral density. The reduction in serum total cholesterol concentration was more marked in the adulthood onset patients. At study end, no differences remained between the two study groups after the correction for body height in the statistical analysis. In conclusion, the baseline analysis suggests more decreased lean mass, muscle strength, and bone mass in the childhood onset patients whereas the lipid profile was more disturbed in the adulthood onset patients. The 5-yr GH replacement eliminated all the anthropodometric and metabolic differences between the two groups. PMID- 11600526 TI - Dehydroepiandrosterone supplementation in healthy men with an age-related decline of dehydroepiandrosterone secretion. AB - Serum dehydroepiandrosterone declines with age. Whether this represents a harmful deficiency or an age-related adaptation is not known. Dehydroepiandrosterone replacement in adrenal insufficiency, a state of pathological loss of dehydroepiandrosterone production, improves well-being, mood, and sexuality. To determine the effects of dehydroepiandrosterone in healthy men with a physiological, age-related decline in serum dehydroepiandrosterone sulfate, we conducted a double blind cross-over study in 22 healthy male volunteers (age range, 50-69 yr) with endogenous dehydroepiandrosterone sulfate levels below 4.1 micromol/liter (1500 ng/ml) receiving 4 months of dehydroepiandrosterone (50 mg/d) and 4 months of placebo treatment in random order, with a 1-month washout period. Dehydroepiandrosterone treatment increased serum dehydroepiandrosterone and dehydroepiandrosterone sulfate to concentrations usually found in young men. Circulating androgen levels did not change; however, androgen metabolites increased, indicating enhanced peripheral androgen synthesis. At baseline, psychometric assessment revealed normal well-being and sexuality scores. After 4 months of dehydroepiandrosterone, no effect on sexuality was observed, whereas some mood scores improved slightly, but were not significantly different from scores after placebo. Compared with placebo, dehydroepiandrosterone had no effect on serum lipids, bone markers, body composition, or exercise capacity. Thus, in contrast to previous findings in adrenal insufficiency, we found no obvious benefit of 4 months of dehydroepiandrosterone supplementation in healthy men with a physiological decline of dehydroepiandrosterone production. PMID- 11600529 TI - Use of oral cholecystographic agents in the treatment of amiodarone-induced hyperthyroidism. AB - We describe here five cardiac patients with type II amiodarone-induced hyperthyroidism who were treated prospectively with a combination of an oral cholecystographic agent (sodium ipodate, Oragrafin, or sodium iopanoate, Telepaque) and a thionamide (propylthiouracil or methimazole); amiodarone was discontinued in all patients. All patients improved substantially clinically within a few days of treatment and became euthyroid or hypothyroid in 15-31 wk when treatment was discontinued. Four of the five became hypothyroid and required long-term treatment with L-T(4); the remaining patient was euthyroid, but died from cardiomyopathy and congestive heart failure at 29 wk, when he had been off oral cholecystographic agent and thionamide for 6 wk. We did not find any clinical or biochemical adverse effects of the treatment. Our study suggests that a combination of oral cholecystographic agent and thionamide is a safe and effective treatment of type II amiodarone-induced hyperthyroidism. Data also suggest that hypothyroidism is a common end result of type II amiodarone-induced hyperthyroidism. PMID- 11600528 TI - A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency. AB - Treatment of naive children with GH deficiency has relied upon long-term replacement therapy with daily injections of GH. The daily schedule may be inconvenient for patients and their caregivers, possibly promoting nonadherence with the treatment regimen or premature termination of treatment. We studied a new sustained release GH formulation, administered once or twice monthly, to determine its efficacy and safety in this population. Seventy-four prepubertal patients with documented GH deficiency were randomized to receive sustained release recombinant human GH at either 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by sc injection in a 6-month open-label study. Efficacy was determined by growth data from 69 patients completing 6 months and 56 patients completing 12 months in an extension study. Growth rates were significantly increased over baseline and were similar for the two dosage groups. The mean (+/-SD) annualized growth rate (pooled data) was 8.4 +/- 2.1 cm/yr at 6 months, and the growth rate was 7.8 +/- 1.8 at 12 months compared with 4.5 +/- 2.3 at baseline. Standardized height, bone age, and predicted adult height assessments demonstrated catch-up growth without excessive skeletal maturation. Injection site-related events (including pain, erythema, and nodules) were the most commonly reported adverse events; no serious adverse events related to treatment were reported. Laboratory studies documented no accumulation of trough GH or IGF-I levels during treatment, nor did glucose intolerance or persistent hyperinsulinism develop. Sustained release recombinant human GH is safe and effective for long-term GH replacement in children with GH deficiency. Patients achieved similar growth velocities when sustained release GH was given once or twice monthly. The enhanced convenience of this dosage form may result in greater long-term adherence to the treatment regimen. PMID- 11600530 TI - Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience. AB - We report 98 children who have reached final adult height in a long-term trial of LHRH agonist treatment. These children were 5.3 +/- 2.1 yr old at the start of treatment and were treated with either deslorelin (4 microg/kg.d sc) or histrelin (4-10 microg/kg.d) for an average of 6.1 +/- 2.5 yr. Final height averaged 159.8 +/- 7.6 cm in the 80 girls, which was significantly greater than pretreatment predicted height (149.3 +/- 9.6 cm) but still significantly less than midparental height (MPH) (163.7 +/- 5.6). Final height averaged 171.1 +/- 8.7 cm in the 18 boys, which was significantly greater than pretreatment predicted height (156.1 +/- 14.2 cm) but still significantly less than MPH (178.3 +/- 5.2 cm). However, the average adult height of the 54 children who had less than a 2-yr delay in the onset of treatment was not significantly different from their MPH, and 21 children exceeded MPH. Final height SD score correlated positively with duration of treatment (P < 0.01), midparental height (P < 0.001), predicted height at the start of treatment (P < 0.001), and growth velocity during the last year of treatment (P < 0.001) and correlated inversely with delay in the onset of treatment (P < 0.001), age at the start of treatment (P < 0.001), bone age at the start of treatment (P < 0.001), bone age at the end of treatment (P < 0.001), breast stage at the start of treatment (P = 0.02), and bone age minus chronological age at the start of treatment (P = 0.001). We conclude that LHRH agonist treatment improves the final height for children with rapidly progressing precocious puberty treated before the age of 8 yr for girls or 9 yr for boys. Less delay in the onset of treatment, longer duration of treatment, and lower chronological and bone age at the onset of treatment all lead to greater final height. All children with onset of pubertal symptoms before age 8 in girls and age 9 in boys should be evaluated for possible treatment. Treatment is appropriate in children with rapidly progressing puberty, accelerated bone maturation, and compromise of adult height prediction, regardless of bone age or chronological age at time of evaluation. However, once treatment is considered appropriate, it should be initiated quickly, because longer delays lead to shorter final height. In addition, the longer the treatment is continued, the greater is the final height outcome. PMID- 11600532 TI - Melatonin treatment for age-related insomnia. AB - Older people typically exhibit poor sleep efficiency and reduced nocturnal plasma melatonin levels. The daytime administration of oral melatonin to younger people, in doses that raise their plasma melatonin levels to the nocturnal range, can accelerate sleep onset. We examined the ability of similar, physiological doses to restore nighttime melatonin levels and sleep efficiency in insomniac subjects over 50 yr old. In a double-blind, placebo-controlled study, subjects who slept normally (n = 15) or exhibited actigraphically confirmed decreases in sleep efficiency (n = 15) received, in randomized order, a placebo and three melatonin doses (0.1, 0.3, and 3.0 mg) orally 30 min before bedtime for a week. Treatments were separated by 1-wk washout periods. Sleep data were obtained by polysomnography on the last three nights of each treatment period. The physiologic melatonin dose (0.3 mg) restored sleep efficiency (P < 0.0001), acting principally in the midthird of the night; it also elevated plasma melatonin levels (P < 0.0008) to normal. The pharmacologic dose (3.0 mg), like the lowest dose (0.1 mg), also improved sleep; however, it induced hypothermia and caused plasma melatonin to remain elevated into the daylight hours. Although control subjects, like insomniacs, had low melatonin levels, their sleep was unaffected by any melatonin dose. PMID- 11600531 TI - Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dose-finding studies. AB - Tibolone, a novel compound with tissue-specific effects, has been found to have antiresorptive properties in bone. To confirm the efficacy of tibolone and determine its minimum effective dose for prevention of bone loss in early postmenopausal women, two randomized, double-blind, placebo-controlled, dose finding studies were performed. Seven hundred seventy healthy women postmenopausal within 1-4 yr, with normal bone density for their age, were treated for 2 yr with 0.3, 0.625, 1.25, or 2.5 mg tibolone daily or placebo. All subjects took supplemental calcium carbonate (500 mg daily). Bone mineral density (BMD) of the lumbar spine and right proximal femur was measured by dual-energy x ray absorptiometry for up to 2 yr. At each dose level, except the lowest (0.3 mg), tibolone produced a progressive increase in lumbar spine and total hip BMD over the 2-yr treatment period; at 0.3 mg, total hip density was maintained. However, only the doses 1.25 mg and 2.5 mg produced a progressive increase in femoral neck BMD. The differences in mean percent change from baseline in spine and total hip density were significant (P < 0.05) for all tibolone dose groups compared with placebo at all time points. Tibolone was well tolerated, with a similar overall incidence of adverse events compared with placebo. Tibolone 1.25 mg per day is recommended because it shows a positive and statistically significant change in BMD of spine and femoral neck. PMID- 11600533 TI - Cytochrome c release is upstream to activation of caspase-9, caspase-8, and caspase-3 in the enhanced apoptosis of anaplastic thyroid cancer cells induced by manumycin and paclitaxel. AB - We previously demonstrated that the combination of a farnesyltransferase inhibitor, manumycin A, and paclitaxel had a synergistic antineoplastic effect on anaplastic thyroid cancer. In this study we investigated the apoptosis pathway involved. In ARO and KAT-4 cells, manumycin- plus paclitaxel-induced DNA fragmentation was blocked by the inhibitors of caspase-9, caspase-8, and caspase 3. The drug combination enhanced the activation of caspase-9, caspase-8, and caspase-3 and cytochrome c release into the cytosol. Cytochrome c release was not affected by the inhibitors of caspase-9, caspase-8 and caspase-3. In a cell-free reconstitution assay, DNA fragmentation occurred after incubating nuclei purified from untreated KAT-4 cells with deoxy-ATP, exogenous cytochrome c and S-100 extracts from control KAT-4 cells, and also after incubation of purified KAT-4 nuclei with S-100 extracts from KAT-4 cells treated with manumycin-plus paclitaxel. In both cases, the DNA fragmentation was blocked by the inhibitors of caspase-9, caspase-8 and caspase-3. We concluded that the cytochrome c release was upstream of the activation of caspase-9, caspase-8, and caspase-3 in the enhanced apoptosis of anaplastic thyroid cancer cells treated with manumycin plus paclitaxel, and that the interaction between manumycin and paclitaxel occurred at or upstream of cytochrome c in the apoptosis regulatory pathway in anaplastic thyroid cancer cells. PMID- 11600534 TI - Decreased expression of IGF-II and its binding protein, IGF-binding protein-2, in genital skin fibroblasts of patients with complete androgen insensitivity syndrome compared with normally virilized males. AB - The action of androgen by way of the AR is required for the development of male gonads and external genitalia. The interplay between androgens and the somatotropic axis, in particular the IGFs in sexual development, is currently under thorough investigation. The IGF system is thought to mediate the androgen action in androgen-responsive cells. To investigate the interaction of androgens with the IGF system, we compared the expression of IGFs and IGF-binding proteins in cultured genital skin fibroblasts from nine patients with the syndrome of complete androgen insensitivity with that in genital skin fibroblasts from 10 normally virilized males. Mutations in the AR gene and/or abnormalities of the AR protein in the immunoblot were detected in all complete androgen insensitivity genital skin fibroblast strains. They caused a complete failure of DHT binding. RIA and RT-PCR demonstrated that the genital skin fibroblast strains expressed IGF-II, IGF-binding protein-2, and IGF-binding protein-3, but no IGF-I. Most strikingly, complete androgen insensitivity genital skin fibroblast strains produced significantly lower IGF-II (P < 0.001; 42.2 +/- 9.7 vs. 106.9 +/- 11.8 ng/mg protein) and IGF-II mRNA (P < 0.01, by RT-PCR) than control genital skin fibroblast strains. The production of IGF-binding protein-2 was also decreased (P < 0.03) in complete androgen insensitivity genital skin fibroblasts, whereas that of IGF-binding protein-3 did not differ. Furthermore, high levels of IGF-binding protein-5 mRNA were detected in all genital skin fibroblast strains, whereby the 28-kDa band in the ligand blot, probably representing IGF-binding protein-5, was more abundant in complete androgen insensitivity genital skin fibroblasts. Exposure of the genital skin fibroblasts to T (5 x 10(-8) M) had only weak effects on the expression of IGFs and IGF-binding proteins. In conclusion, although the mechanism underlying these differences requires further study, it is conceivable that in addition to the endocrine actions of IGF-I, IGF-II and IGF binding protein-2, as local growth factors, are involved in the mediation of androgen action and growth of genital tissues. PMID- 11600535 TI - A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disorder characterized by hypoparathyroidism, adrenal failure, chronic mucocutaneous candidiasis, and ectodermal dystrophies and other organ-specific autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy is caused by mutations of the autoimmune regulator gene. We identified an Italian family with autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy and a pattern of inheritance suggestive of a dominant mechanism. Serological and clinical studies showed a high prevalence of hypothyroid autoimmune thyroiditis in affected members with classical autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Direct sequencing of the entire coding region of the autoimmune regulator gene revealed the presence in the proband of a novel missense (G228W) mutation in exon 6 in a heterozygous state. The same heterozygous mutation was identified in all family members with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and/or hypothyroid autoimmune thyroiditis. None of the unaffected family members and 50 unrelated Italian controls carried the mutation. In contrast with all other autoimmune regulator mutations reported in families, the novel G228W mutation acts in a dominant fashion in our family, as only one heterozygous mutation was found in the entire coding sequence of the autoimmune regulator gene in the proband. Moreover, analysis of the family tree showed direct transmission of the hypothyroid autoimmune thyroiditis/polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype to the offspring in each generation in the absence of consanguinity, further supporting a dominant inheritance. The G228W closely cosegregated with hypothyroid autoimmune thyroiditis in our family, whereas a low penetrance of the full autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype was observed. In conclusion, we report a novel mutation of the autoimmune regulator gene in a family with autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy, closely cosegregating with hypothyroid autoimmune thyroiditis. The G228W mutation acts in a dominant fashion and may shed light on the structure-function relationship of the autoimmune regulator protein. PMID- 11600536 TI - Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. AB - Ghrelin, an endogenous ligand for the GH secretagogue receptor, was isolated from rat stomach and is involved in a novel system for regulating GH release. Although previous studies in rodents suggest that ghrelin is also involved in energy homeostasis and that ghrelin secretion is influenced by feeding, little is known about plasma ghrelin in humans. To address this issue, we studied plasma ghrelin like immunoreactivity levels and elucidated the source of circulating ghrelin and the effects of feeding state on plasma ghrelin-like immunoreactivity levels in humans. The plasma ghrelin-like immunoreactivity concentration in normal humans measured by a specific RIA was 166.0 +/- 10.1 fmol/ml. Northern blot analysis of various human tissues identified ghrelin mRNA found most abundantly in the stomach and plasma ghrelin-like immunoreactivity levels in totally gastrectomized patients were reduced to 35% of those in normal controls. Plasma ghrelin-like immunoreactivity levels were increased by 31% after 12-h fasting and reduced by 22% immediately after habitual feeding. In patients with anorexia nervosa, plasma ghrelin-like immunoreactivity levels were markedly elevated compared with those in normal controls (401.2 +/- 58.4 vs. 192.8 +/- 19.4 fmol/ml) and were negatively correlated with body mass indexes. We conclude that the stomach is a major source of circulating ghrelin and that plasma ghrelin-like immunoreactivity levels reflect acute and chronic feeding states in humans. PMID- 11600537 TI - IL-1beta induction of RANTES (regulated upon activation, normal T cell expressed and secreted) chemokine gene expression in endometriotic stromal cells depends on a nuclear factor-kappaB site in the proximal promoter. AB - A complex network of cytokines mediates immunoregulatory responses in the pathogenesis of endometriosis. RANTES (regulated upon activation, normal T cell expressed and secreted) is a chemoattractant for monocytes and T cells. Endometriotic lesions express RANTES, and its concentration in peritoneal fluid correlates with the severity of endometriosis. We investigated the influence of IL-1beta, a potent macrophage cytokine, on RANTES production in endometriotic stromal cells and determined the region of the RANTES promoter responsible for IL 1beta action. RANTES mRNA was induced 5-fold in endometriotic stromal cells, and the conditioned medium RANTES protein concentrations were 12-fold higher in IL 1beta-treated endometriotic stromal cells vs. untreated controls (P < 0.05). IL 1beta activated the full-length (-940 bp) RANTES promoter as well as a truncated 456-bp 5'-flanking construct by 2-fold. Mutagenesis of a nuclear factor-kappaB response element at -30 bp abolished the IL-1beta effect, whereas mutation of a nearby TNF response element did not affect the IL-1beta induction. An IL-1beta time-course Western assay revealed a rapid diminution of IkappaB (endogenous inhibitor of nuclear factor-kappaB) in endometriotic stromal cells. Overexpression of IkappaB in endometriotic stromal cells inhibited the IL-1beta response of the RANTES gene promoter. Transcription of RANTES mRNA is up regulated by IL-1beta via a nuclear factor-kappaB response element in the proximal RANTES gene promoter. These results demonstrate a feed-forward regulatory loop in the pathogenesis of endometriosis by which IL-1beta produced from activated macrophages can lead to further macrophage recruitment via RANTES production in endometriotic stromal cells. PMID- 11600538 TI - GH is needed for the maturation of muscle mass and strength in adolescents. AB - The postpubertal period and the early years of adulthood may be of importance for continuing tissue maturation of importance in adulthood and aging. An example of this is the peak bone mass. This study has evaluated the importance of GH for lean mass and muscle strength in adolescents and young adults. GH treatment was discontinued in 40 adolescents aged 16-21 yr with GH deficiency of childhood onset. Measurements of isometric and isokinetic knee-extensor and flexor strength, handgrip strength, lean body mass, fat-free mass, and total body nitrogen were performed annually for 2 yr. Two hundred fifty healthy adolescents were randomly selected for prospective measurements of lean mass and handgrip strength between the ages of 17 and 21 yr. In the adolescents with continuing GH deficiency, lean body mass decreased, compared with the patients defined as having sufficient endogenous GH. The isometric strength in knee flexors increased in the sufficient endogenous GH group and was unchanged in the GH deficiency group during the 2 yr off GH treatment (between group, P < 0.05). The mean and peak handgrip strength increased on average by 9-15% in the group with sufficient endogenous GH and was unchanged in those with GH deficiency (P < 0.05). Lean body mass and handgrip strength (both, P < 0.001) increased in both the healthy boys and girls who were followed for 4 yr with a more marked increase in the boys. The mean increase in handgrip between the age of 17 and 21 yr was 7-9%. The increased lean mass and improved muscle performance seen in healthy adolescents did not occur in adolescents with GH deficiency. These findings suggest that GH is of importance for the maturation of lean mass and muscle strength in adolescents and young adults. PMID- 11600539 TI - Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation. AB - This study attempted an analysis of the mutational spectrum of 21-hydroxylase deficiency in 79 unrelated Austrian patients with classical and nonclassical forms of congenital adrenal hyperplasia and their respective 112 family members. Apparent large gene deletions/conversions were present in 31% of the 158 unrelated congenital adrenal hyperplasia alleles, whereas the most frequent point mutations were intron 2 splice (22.8%), I172N (15.8%), V281L (12%), and P30L (7.6%), in line with the frequencies reported for other countries. In 5 of the 12 congenital adrenal hyperplasia alleles carrying a P30L mutation the aberration is based on a single base substitution, whereas the remaining 7 represent part of a CYP21B conversion (1 allele) or CYP21B/21A hybrid gene (6 alleles), the latter characterized by a junction site before intron 2 as indicated by Southern blot, PCR, and sequence analyses. Previously described mutations were not present in 1.2% of unrelated congenital adrenal hyperplasia alleles, including one female patient presenting with severe genital virilization. Sequence analysis of the complete functional 21-hydroxylase gene revealed an as yet undescribed mutation in exon 10-Arg(426)His, which has not yet been described to represent a common pseudogene sequence. In vitro expression experiments showed the Arg(426)His mutant to exhibit only low enzyme activity toward the natural substrate 17 hydroxyprogesterone corresponding to the degree of disease manifestation in the patient in whom it was found. PMID- 11600540 TI - Incorporation of the fasting plasma FFA concentration into QUICKI improves its association with insulin sensitivity in nonobese individuals. AB - Insulin resistance plays a major role in the pathophysiology of diabetes and is associated with obesity and cardiovascular disease. Excellent methods exist for the assessment of insulin sensitivity in the laboratory setting, such as the glucose clamp. However, these methods are not suitable for large population studies, and, thus, surrogate estimates of insulin sensitivity based on measurements in a single blood sample have been developed. Recently an index based on the logarithm and the reciprocal of the insulin-glucose product (QUICKI) has been proposed. QUICKI correlated with insulin sensitivity across the entire spectrum of glucose tolerance, but its performance was less satisfactory in normal subjects. Aim of this study was to ascertain whether the inclusion of fasting plasma free fatty acids concentration into QUICKI improves its association with insulin sensitivity in nonobese subjects. To test this hypothesis, we performed a euglycemic hyperinsulinemic clamp [40 mU/(m(2).min)] in 57 young, healthy, nonobese individuals with (n = 17) or without (n = 40) first-degree relatives affected by type 2 diabetes (the former group being an in vivo model of mild insulin resistance). We then compared the clamp-based index of insulin sensitivity with both QUICKI and a revised QUICKI, the latter index including the contribution of fasting free fatty acid concentration as well. The revised QUICKI considerably improved the relationship with the clamp-based index of insulin sensitivity (r = 0.51, P < 0.0001) with respect to QUICKI (r = 0.27, P < 0.05). In addition, the revised QUICKI revealed a reduction of insulin sensitivity in the offspring of type 2 diabetes (10%; P < 0.006) that QUICKI was unable to detect (3%; P = 0.28). In conclusion, this study suggests that the incorporation of fasting free fatty acid level into QUICKI is useful to improve its correlation with the clamp-based index of insulin sensitivity and its discriminatory power in case of mild insulin resistance. Further investigation is needed to ascertain its applicability to patients with obesity and type 2 diabetes. PMID- 11600541 TI - The first signs of beta-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type 1 Diabetes Prediction and Prevention Study. AB - Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this population-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of beta-cell autoimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 genetically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant seroconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and antibodies to the protein tyrosine phosphatase-related IA-2 molecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate-risk genotype (1.2%; P = 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibodies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ-defined genetic risk of type 1 diabetes show signs of beta-cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specificity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of beta-cell autoimmunity suggests that infectious agents may play a role in the induction of such autoimmunity. PMID- 11600542 TI - Direct action of melatonin in human granulosa-luteal cells. AB - The direct involvement of melatonin in modulation of ovarian steroidogenesis, the high levels of melatonin found in human follicular fluid, and the presence of melatonin binding sites in the ovary led us to hypothesize that melatonin acts as a modulator of ovarian function. In contrast to the hypothalamus and pituitary, the mechanism of melatonin action at the level of the ovary is still poorly understood. In the present study, we investigated the gene expression of the two different forms of melatonin receptors in human granulosa-luteal cells, using RT PCR. PCR products corresponding to the expected sizes of the melatonin receptor subtypes, mt(1)-R and MT(2)-R, were obtained from granulosa-luteal cells, and the authenticity of the PCR products was confirmed by Southern blot hybridization with cDNA probes. Subsequent cloning and sequence analysis revealed that the ovarian mt(1)-R and MT(2)-R cDNAs are identical to their brain counterparts. Because gonadotropins and GnRH acting through specific receptors in the human ovary regulate cellular functions, we investigated the role of melatonin in the regulation of FSH receptor, LH receptor, GnRH, and GnRH receptor levels. Treatment with melatonin (10 pM-100 nM) significantly increased LH receptor mRNA levels without altering the expression of the FSH receptor gene. Both GnRH and GnRH receptor mRNA levels were significantly decreased, to 61% and 45% of control levels, respectively, after melatonin treatment. Melatonin treatment alone had no effect on basal progesterone production but enhanced the effects of human CG stimulated progesterone production. Because MAPKs are activated in response to a diverse array of extracellular stimuli leading to the regulation of cell growth, division, and differentiation, and because melatonin has been shown to modulate cellular proliferation and differentiation, in this study, we demonstrated that melatonin activated MAPK in a dose- and time-dependent manner. In summary, our studies demonstrate, for the first time, that melatonin can regulate progesterone production, LH receptor, GnRH, and GnRH receptor gene expression through melatonin receptors in human granulosa-luteal cells, which may be mediated via the MAPK pathway and activation of Elk-1. Our results support the notion that melatonin plays a direct role in regulating ovarian function. PMID- 11600543 TI - Effects of suckling on hypothalamic-pituitary-adrenal axis responses to psychosocial stress in postpartum lactating women. AB - In several studies lactation has been shown to be associated with a hypothalamic pituitary-adrenal axis hyporesponsiveness to physical and psychological stressors. As it is not known whether the marked blunting of endocrine stress reactivity in women can be ascribed to suckling as a short-term effect or to lactation in general, the acute effects of suckling on the hypothalamic-pituitary adrenal axis and the sympathetic-adrenal-medullary system responses to mental stress were investigated in lactating women. Forty-three lactating women were randomly assigned either to breast-feed or to hold their infants for a 15-min period with the onset 30 min before they were exposed to a brief psychosocial stressor (Trier Social Stress Test). Both breast-feeding and holding the infant yielded significant decreases in ACTH, total plasma cortisol, and salivary free cortisol (all P < 0.01). There were no significant differences in baseline hormone levels between the groups 1 min before the stress test. In response to stress exposure, ACTH, total plasma cortisol, salivary free cortisol, norepinephrine, and epinephrine were significantly increased in all lactating women (all P < 0.001). However, total cortisol and free cortisol responses to stress were attenuated in breast-feeding women (P = 0.001 and P = 0.067, respectively), who also showed significantly decreasing PRL levels during the stress test (P = 0.005). In addition, there was no change in plasma oxytocin or vasopressin in response to the stressor. Breast-feeding as well as holding led to decreased anxiety (P < 0.05), whereas, in contrast, stress exposure worsened mood, calmness, and anxiety in the total group (all P < 0.001). From these data we conclude that lactation in women, in contrast to that in rats, does not result in a general restraint of the hypothalamic-pituitary-adrenal axis response to a psychosocial stressor. Rather, suckling is suggested to exert a short-term suppression of the cortisol response to mental stress. PMID- 11600544 TI - Genetic study of patients with dexamethasone-suppressible aldosteronism without the chimeric CYP11B1/CYP11B2 gene. AB - Glucocorticoid-remediable aldosteronism is an inherited disorder caused by a chimeric gene duplication between the CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) genes. The disorder is characterized by hyperaldosteronism and high levels of 18-hydroxycortisol and 18-oxocortisol, which are under ACTH control. The diagnosis of glucocorticoid-remediable aldosteronism had been traditionally made using the dexamethasone suppression test; however, recent studies have shown that several patients with primary aldosteronism and a positive dexamethasone suppression test do not have the chimeric CYP11B1/CYP11B2 gene. The aim of this work was to evaluate whether other genetic alterations exist in CYP11B genes (gene conversion in the coding region of CYP11B1 or in the promoter of CYP11B2) that could explain a positive dexamethasone suppression test and to determine another genetic cause of glucocorticoid-remediable aldosteronism. We also evaluated the role of 18-hydroxycortisol as a specific biochemical marker of glucocorticoid-remediable aldosteronism. We studied eight patients with idiopathic hyperaldosteronism, a positive dexamethasone suppression test, and a negative genetic test for the chimeric gene. In all patients we amplified the CYP11B1 gene by PCR and sequenced exons 3-9 of CYP11B1 and a specific region (-138 to -284) of CYP11B2 promoter. We also measured the levels of 18-hydroxycortisol, and we compared the results with those found in four subjects with the chimeric gene. None of eight cases showed abnormalities in exons 3-9 of CYP11B1, disproving a gene conversion phenomenon. In all patients a fragment of 393 bp corresponding to a specific region of the promoter of CYP11B2 gene was amplified. The sequence of the fragment did not differ from that of the wild-type promoter of the CYP11B2 gene. The 18-hydroxycortisol levels in the eight idiopathic hyperaldosteronism patients and four controls with chimeric gene were 3.9 +/- 2.3 and 21.9 +/- 3.5 nmol/liter, respectively (P < 0.01). In summary, we did not find other genetic alterations or high levels of 18 hydroxycortisol that could explain a positive dexamethasone suppression test in idiopathic hyperaldosteronism. We suggest that the dexamethasone suppression test could lead to an incorrect diagnosis of glucocorticoid-remediable aldosteronism. PMID- 11600546 TI - Suppression of serum TSH by Graves' Ig: evidence for a functional pituitary TSH receptor. AB - Antithyroid treatment for Graves' hyperthyroidism restores euthyroidism clinically within 1-2 months, but it is well known that TSH levels can remain suppressed for many months despite normal free T(4) and T(3) levels. This has been attributed to a delayed recovery of the pituitary-thyroid axis. However, we recently showed that the pituitary contains a TSH receptor through which TSH secretion may be down-regulated via a paracrine feedback loop. In Graves' disease, TSH receptor autoantibodies may also bind this pituitary receptor, thus causing continued TSH suppression. This hypothesis was tested in a rat model. Rat thyroids were blocked by methimazole, and the animals were supplemented with L T(4). They were then injected with purified human IgG from Graves' disease patients at two different titers or with IgG from a healthy control (thyroid hormone binding inhibitory Ig, 591, 127, and < 5 U/liter). Despite similar T(4) and T(3) levels, TSH levels were indeed lower in the animals treated with high TSH receptor autoantibodies containing IgGs; the 48-h mean TSH concentration (mean +/- SEM; n = 8) was 11.6 +/- 1.3 ng/ml compared with 16.2 +/- 0.9 ng/ml in the controls (P < 0.01). The intermediate strength TSH receptor autoantibody treated animals had levels in between the other two groups (13.5 +/- 2.0 ng/ml). We conclude that TSH receptor autoantibodies can directly suppress TSH levels independently of circulating thyroid hormone levels, suggesting a functioning pituitary TSH receptor. PMID- 11600545 TI - Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis. AB - The hypothalamic peptides, orexin-A and orexin-B, have been implicated in the regulation of feeding behavior. In starved rats catabolic activity quickly predominates, reinforced by elevated corticosterone, independent of ACTH, implicating adrenal activity as a metabolic regulator. In view of these findings, we investigated whether orexin and orexin receptors are present in human adult adrenals and might therefore be implicated in hormonal regulation and energy homeostasis outside the central nervous system. RT-PCR, fluorescent in situ hybridization, immunoblotting, and immunostaining analysis confirmed the expression of the orexin type 2 receptor, but not of orexin type 1 receptor, in the adrenal cortex. Immunoblotting analysis also detected the presence of the prepro-orexin and its cleaved product orexin-A. Treatment of adult adrenal membranes with orexin-A increased the labeling of G(s), G(q), and, to a lesser degree, G(i), but not G(o). Stimulation with orexin-A induced cAMP and IP3 production in a dose-dependent manner. The data presented here provide conclusive evidence for the presence of orexin-A and orexin type 2 receptors in human adult adrenal glands. At the moment the functional relevance of this is uncertain. However, it is known that both orexin-A and orexin-B can induce corticosterone production in dispersed rat adrenocortical cells. Our data provide further evidence for a functional link between orexogenic signals and adrenal function. The concept that the peptide acting via these receptors in the adult adrenal is responsible for steroidogenesis and energy balance is attractive. PMID- 11600547 TI - Human pheochromocytomas express orexin receptor type 2 gene and display an in vitro secretory response to orexins A and B. AB - Orexins A and B are hypothalamic peptides, that act through two receptor subtypes, called OX1-R and OX2-R. OX1-R selectively binds orexin A, whereas OX2-R is nonselective for both orexins. High levels of OX1-R mRNA and low levels of OX2 R mRNA have been previously detected in the human adrenal cortex and medulla. Here we demonstrated by RT-PCR the expression of the OX2-R, but not the OX1-R, gene in 10 benign secreting pheochromocytomas. Both orexins A and B stimulated catecholamine secretion from pheochromocytoma slices; the maximal effective concentration was 10(-8) mol/liter. Orexins A and B (10(-8) mol/liter) increased IP3, but not cAMP production, by tumor slices, and the effect was blocked by the PLC inhibitor U-73122. The catecholamine response to 10(-8) mol/liter orexins A and B was abolished by either U-73122 or the PKC antagonist calphostin C and was unaffected by the adenylate cyclase inhibitor SQ-22536 and the PKA inhibitor H 89. Collectively, these findings suggest that orexins stimulate catecholamine secretion from human pheochromocytomas, acting through OX2-R coupled to the PLC PKC signaling pathway. PMID- 11600548 TI - The prevalent Gly1057Asp polymorphism in the insulin receptor substrate-2 gene is not associated with impaired insulin secretion. AB - Disruption of the insulin receptor substrate-2 was shown to cause type 2 diabetes in mice. This could be largely attributed to abnormal beta-cell development. In humans, a prevalent polymorphism in insulin receptor substrate-2 (Gly1057Asp) was not found be associated with type 2 diabetes in linkage and association studies. We tested the hypothesis that an extreme challenge of the beta cell might reveal subtle abnormalities in carriers of this polymorphism undetected by conventional insulin secretion tests. Therefore, in addition to assessing beta-cell function by oral glucose tolerance testing (n = 318, normal glucose tolerance), we measured the secretory response to maximal stimulation by hyperglycemia (10 mM), glucagon-like peptide-1, and arginine administered in an additive fashion (n = 77, nondiabetic). The allelic frequency of the Asp allele was approximately 37%. Neither the beta-cell function indices from the oral glucose tolerance test nor the secretory response during the hyperglycemic clamp differed measurably between carriers and controls. Moreover, maximal plasma C-peptide concentrations in response to the combined glucose, glucagon-like peptide-1, and arginine stimulus was not different between Gly/Gly (10,745 +/- 1,186 pmol/liter) and X/Asp (10,800 +/- 490 pmol/liter, P = 0.99). In conclusion, our findings strongly suggest that the Gly1057Asp polymorphism in insulin receptor substrate-2 is not associated with beta-cell dysfunction. The normal maximal insulin secretory response makes it unlikely that this common polymorphism results in abnormal beta-cell development. PMID- 11600549 TI - Prevalence, characteristics and diabetes risk associated with transient maternally acquired islet antibodies and persistent islet antibodies in offspring of parents with type 1 diabetes. AB - Accurate assessment of type 1 diabetes risk in young children requires discrimination between antibodies that are produced by the child and antibodies acquired through the placenta from an islet antibody-positive mother. We studied 682 offspring from mothers with type 1 diabetes and 329 offspring from fathers with type 1 diabetes and nondiabetic mothers for insulin (auto)antibodies, glutamic acid decarboxylase antibodies, and tyrosine phosphatase IA-2 antibodies before age 1 yr and again at age 2 yr to ascertain transience or persistence. Antibodies were detected at age 9 months in 5 (1.5%) offspring from fathers with type 1 diabetes; all were insulin (auto)antibodies only, all persisted and developed multiple antibodies, and 1 developed type 1 diabetes. In contrast, 31 (4.5%) offspring from mothers with type 1 diabetes had antibodies at 9 months; 12 (1.8%) persisted at age 2 yr, and 19 (2.8%) did not persist, suggestive of transient residual maternal antibodies. Multiple antibodies at 9 months were usually persistent (3 of 4 offspring), as were single insulin (auto)antibodies in offspring from mothers with type 1 diabetes (8 of 13 offspring), whereas persistent glutamic acid decarboxylase antibodies (1 of 12) and tyrosine phosphatase IA-2 antibodies (0 of 2) were rare. Offspring with persistent antibodies at age 9 months had a high type 1 diabetes risk (100% by age 5 yr for those with multiple antibodies and 27% for single antibodies at 9 months), whereas offspring with transient antibodies had 0% type 1 diabetes risk (P < 0.01). Transience was associated with very high antibody levels at birth. For insulin (auto)antibodies, the measurement of subclass was also informative. Residual maternal antibody was indicated by similar insulin (auto)antibodies subclasses at 9 months and at birth, whereas different subclasses were indicative of nonmaternal antibody. Moreover, the presence of IgG1-insulin (auto)antibodies was associated with antibody persistence and type 1 diabetes risk. These strategies are helpful in discriminating high and low risk antibodies before age 1 yr and should be important for prognosis and reducing unnecessary parent anxiety. PMID- 11600550 TI - Complementary DNA expression array analysis suggests a lower expression of signal transduction proteins and receptors in cold and hot thyroid nodules. AB - Autonomously functioning thyroid nodules are characterized by an increased proliferation and function, which is predominantly caused by constitutively activating TSH receptor mutations leading to an activation of cAMP. In contrast to autonomously functioning thyroid nodules, cold thyroid nodules are functionally inactive and less differentiated. Their molecular cause is still unknown. To further investigate the pathophysiological aspects of autonomously functioning thyroid nodules and to elucidate the molecular etiology of cold thyroid nodules, it is essential to identify genes with differential expression in autonomously functioning thyroid nodules and cold thyroid nodules and to compare this expression to that in normal surrounding tissue. The list of possible candidates for differential regulation ranges from growth factors and their receptors to transcription factors or oncogenes. Therefore, we evaluated the potential of cDNA arrays and studied the expression of 588 known genes from 6 different classes of proteins in thyroid nodules characterized for their function. Forty-seven genes showed a differential expression between nodular and surrounding tissue identified by the expression arrays. The differential expression of 15 transcripts was verified by real-time PCR. About 25% of the transcripts determined by LightCycler PCR are considered false positives because data from PCR and array analysis did not agree. This indicates the reliability of cDNA expression arrays to identify differentially expressed genes in thyroid nodules compared with their surrounding tissue. The 15 selected genes were additionally quantified by real-time PCR in 7 additional cold thyroid nodules, autonomously functioning thyroid nodules, and their surrounding tissues. The highest number of differentially expressed genes was in the group of signal transduction proteins (4 of 38 detectable genes) and extracellular cell signaling and communication proteins (2 of 62 detectable genes). In contrast, transcripts of other classes of proteins were unchanged (e.g. DNA-binding molecules and stress responses). Most of the transcripts were down-regulated in autonomously functioning thyroid nodule and cold thyroid nodule compared with the respective surrounding tissue. This finding could be the result of a dominant activation of a signal transduction pathway, with the cAMP pathway being the likely candidate for autonomously functioning thyroid nodules. The qualitatively similar pattern of changes in this limited number of genes in autonomously functioning thyroid nodules and cold thyroid nodules could suggest a similar dominant activation of a specific signaling cascade in cold thyroid nodules as the constitutively activating mutations in autonomously functioning thyroid nodules. PMID- 11600552 TI - Cerebrospinal fluid and plasma concentrations of leptin, NPY, and alpha-MSH in obese women and their relationship to negative energy balance. AB - Leptin and its principal mediators, NPY and alpha-MSH are postulated to play a pivotal role in energy balance. To determine the possibility of the disturbance in neuropeptides in human obesity and their consequent changes in response to negative energy balance, we evaluated plasma and cerebrospinal fluid (CSF) leptin, NPY, and alpha-MSH levels in obese women before and after weight loss in comparison with normal control women. Subjects included 16 obese women [mean body mass index (BMI), 35.6 kg/m(2)] before and after weight loss induced by a 2-wk very low caloric diet (800 kcal/d) and 14 normal weight women (mean BMI, 20.4 kg/m(2)). The CSF to plasma leptin ratio in normal weight subjects was 2.3-fold higher than that in obese subjects. After weight loss in obese subjects, plasma leptin levels decreased by 40% and CSF levels decreased by 51%. There was a positive linear correlation between CSF and plasma leptin levels at baseline in obese subjects (r = 0.74, P < 0.05) and a positive logarithmic correlation in normal weight subjects (r = 0.89, P < 0.05) and in obese subjects after weight loss (r = 0.64, P < 0.05). The BMI was negatively correlated with the CSF to plasma leptin ratio (r = -0.86, P < 0.05) in all subjects. Neither the baseline plasma levels nor the baseline CSF levels of NPY were different between normal weight subjects and obese subjects. After weight loss, the CSF NPY level decreased significantly compared with baseline values in obese subjects. The alpha-MSH levels in plasma and CSF did not differ significantly from controls in obese subjects at baseline or after weight loss. Baseline CSF leptin level correlated with neither the baseline CSF NPY level nor the baseline CSF alpha-MSH level. In conclusion, this study demonstrated that the efficiency of brain leptin delivery is reduced in human obesity and central nervous system leptin uptake involves a combination of a saturable and an unsaturable mechanism. CSF NPY and alpha-MSH did not differ from controls in human obesity, and the CSF NPY level decreased significantly whereas alpha-MSH did not differ after weight loss in obese subjects compared with baseline. There was no significant correlation between CSF leptin and CSF NPY or alpha-MSH. This could be the result of leptin resistance present in human obesity and/or the more complex mechanisms involved in modulating appetite and regulating energy balance in human obesity. PMID- 11600551 TI - Goiter and hypothyroidism in two siblings due to impaired Ca(+2)/NAD(P)H dependent H(2)O(2)-generating activity. AB - We report herein the study of two siblings (DESM and DSM) with hypothyroidism, goiter, and positive perchlorate discharge tests (50% and 70%) in a family (M) with no history of consanguinity. Thyroid gland histology showed a predominance of hyperactive follicles, with high epithelial cells and variable colloid content. Thyroid peroxidase iodide oxidation (DESM, 1034; DSM, 1064 U/g protein) and albumin iodination (DESM, 16; DSM, 8 nmol I/mg protein) activities were within the normal range. Tg content was normal in both glands compared with that in diffuse toxic goiter (DESM, 28; DSM, 17; diffuse toxic goiter, 19 mg/g tissue), and Tg could be normally iodinated by thyroid peroxidase in vitro (DESM, 3.4; DSM, 4.3; diffuse toxic goiter, 6.3 nmol I/mg Tg). Thyroid cytochrome c reductase activities in these goiters were higher than that in paranodular tissues (DESM, 473; DSM, 567; paranodular tissues, 78 nmol NADP(+)/h/mg protein). However, thyroid NADPH oxidase activities were very low both in the particulate 3,000 x g (DESM, 4.8; DSM, 44; paranodular tissues, 224 nmol H(2)O(2)/h/mg protein) and in the particulate 100,000 x g fractions (DESM, 40; DSM, 47; paranodular tissues, 200 nmol H(2)O(2)/h/mg protein). Thus, a decreased Ca(2+)/NAD(P)H-dependent H(2)O(2) generation is the probable cause of the organification defect in these goiters. PMID- 11600553 TI - Relationships between placental GH concentration and maternal smoking, newborn gender, and maternal leptin: possible implications for birth weight. AB - The control of fetal growth depends on multiple hormones, including both IGF-I and placental GH (PGH) in the mother, and IGF-I rather than pituitary GH (pitGH) in the fetus. Leptin, which is produced by adipocytes and syncitiotrophoblast cells, has also been thought to influence fetal growth by an as yet unknown mechanism. This study assessed the relationships between the GH-IGF-I axis in mothers and newborns, and maternal smoking, neonate gender, and maternal and fetal leptin. We collected blood in 87 mothers at the onset of labor and cord blood immediately after birth in their 87 healthy full-term newborns. GH concentrations were log(10) transformed, and data were expressed as the geometric mean (-1, +1 tolerance factor). PGH was lower in the 30 smoking mothers, as compared with the 57 nonsmoking mothers [18.2 (11.5; 28.6) vs. 27.0 (15.1; 48.2) microg/liter, P < 0.01]. Cord blood IGF-I was lower in neonates from smoking mothers (90 +/- 44 vs. 135 +/- 65 microg/liter, mean +/- SD, P < 0.01), consistent with their lower birth weight percentile (P < 0.01). A gender effect was observed for PGH, which was higher when the newborn was female, and for newborn pitGH and newborn leptin, which were, respectively, lower and higher in females, even after adjustment for birth weight and maternal smoking category (P < 0.05 for all comparisons). Multiple regression analyses identified maternal leptin as a negative predictor of PGH (P < 0.05) and newborn leptin as a positive predictor of newborn IGF-I (P < 0.05). Maternal smoking is associated to decreased maternal PGH and cord blood IGF-I concentrations. A sexual dimorphism for PGH, newborn pitGH, and newborn leptin exists at the time of birth, but its physiological significance remains to be studied. The relationships between maternal leptin and PGH and between cord blood leptin and IGF-I are consistent with the hypothesis that leptin could contribute to the control of fetal growth. PMID- 11600554 TI - TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). AB - This study evaluated the effect of physiological, TSH-guided, L-thyroxine treatment on serum lipids and clinical symptoms in patients with subclinical hypothyroidism. Sixty-six women with proven subclinical hypothyroidism (TSH, 11.7 +/- 0.8 mIU/liter) were randomly assigned to receive L-thyroxine or placebo for 48 wk. Individual L-thyroxine replacement (mean dose, 85.5 +/- 4.3 microg/d) was performed based on blinded TSH monitoring, resulting in euthyroid TSH levels (3.1 +/- 0.3 mIU/liter). Lipid concentrations and clinical scores were measured before and after treatment. Sixty-three of 66 patients completed the study. In the L thyroxine group (n = 31) total cholesterol and low density lipoprotein cholesterol were significantly reduced [-0.24 mmol/liter, 3.8% (P = 0.015) and 0.33 mmol/liter, 8.2% (P = 0.004), respectively]. Low density lipoprotein cholesterol decrease was more pronounced in patients with TSH levels greater than 12 mIU/liter or elevated low density lipoprotein cholesterol levels at baseline. A significant decrease in apolipoprotein B-100 concentrations was observed (P = 0.037), whereas high density lipoprotein cholesterol, triglycerides, apolipoprotein AI, and lipoprotein(a) levels remained unchanged. Two clinical scores assessing symptoms and signs of hypothyroidism (Billewicz and Zulewski scores) improved significantly (P = 0.02). This is the first double blind study to show that physiological L-thyroxine replacement in patients with subclinical hypothyroidism has a beneficial effect on low density lipoprotein cholesterol levels and clinical symptoms of hypothyroidism. An important risk reduction of cardiovascular mortality of 9-31% can be estimated from the observed improvement in low density lipoprotein cholesterol. PMID- 11600555 TI - The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity. AB - Genomic effects of T are exerted via the AR. The length of the polymorphic CAG repeat sequence in the AR gene is inversely correlated with the transcriptional regulation of target genes by T. In 110 healthy men (20-50 yr), we investigated the interactions among this polymorphism, serum levels of sex hormones, cardiovascular risk factors, and flow-mediated and nitrate-induced vasodilatation of the brachial artery. The number of CAG repeat had no significant correlations with serum concentrations of total or free T. Stepwise multiple regression analysis revealed positive correlations of the number of CAG repeat with serum levels of high density lipoprotein cholesterol (partial r = 0.44; P < 0.001) and flow-mediated vasodilatation (partial r = 0.37; P < 0.001). The association of CAG repeat with high density lipoprotein (HDL) cholesterol was independent of body fat content and serum levels of free T, which both had significant negative correlations with HDL cholesterol. The association of CAG repeat with flow mediated vasodilatation was independent of cigarette smoking and serum levels of free T and low density lipoprotein cholesterol, which also were correlated with flow-mediated vasodilatation. We conclude that a low number of CAG repeat in the AR gene implies a greater chance for low levels of HDL cholesterol and reduced endothelial response to ischemia, which are both important risk factors for coronary heart disease. PMID- 11600556 TI - Effects of timing of administration and meal composition on the pharmacokinetic and pharmacodynamic characteristics of the short-acting oral hypoglycemic agent nateglinide in healthy subjects. AB - These studies examined the influence of timing of administration of nateglinide on the glucose profile and beta-cell secretory response to a standardized test meal and the effect of meal composition on the pharmacokinetic and pharmacodynamic profile. In study 1, nateglinide (60 mg) or placebo was given orally at -10, -1, or +10 min to healthy subjects (n = 12), in relation to a standardized test meal (500 kcal) that commenced at 0 min. In study 2, also in healthy subjects (n = 12), a single oral dose (60 mg) of nateglinide was given either 10 min before or 10 min after the start of each of three different test meals (i.e. high in carbohydrate, fat, or protein). In both studies, the postmeal observation period was a minimum of 240 min. In the first study premeal (-10,-1 min), administration of nateglinide led to earlier and higher peak plasma nateglinide concentrations, compared with postprandial dosing (+10 min). A significantly lower maximum postprandial glucose concentration was seen with preprandial dosing compared with either placebo (P < 0.01) or nateglinide given postprandially (P < 0.01). The impact on the glucose profile was consistent with the enhanced insulin profiles after nateglinide, resulting in higher peak plasma insulin concentrations compared with placebo (P < 0.01). Study 2 confirmed the greater impact of pre- vs. postprandial dosing on the glucose and insulin profiles, irrespective of meal type. Nateglinide administration, before a meal, resulted in a more rapid rise and higher peak nateglinide plasma concentrations, irrespective of meal composition. Preprandial administration of nateglinide was more effective in reducing prandial glucose excursions, compared with postmeal dosing (+10 min), a consequence of the earlier insulin response. PMID- 11600557 TI - Dihydrotestosterone treatment in adolescents with delayed puberty: does it explain insulin resistance of puberty? AB - Puberty is characterized by temporary insulin resistance, which subsides with the completion of pubertal development. This insulin resistance is manifested by lower rates of insulin-stimulated glucose metabolism and compensatory hyperinsulinemia in pubertal compared with prepubertal children. Whether or not pubertal insulin resistance is the result of sex steroids or GH or a combination of both has been investigated in our laboratory. Previously, we demonstrated that T treatment in adolescents with delayed puberty was not associated with the deterioration of insulin action. The present investigation evaluated the effects of 4 months of dihydrotestosterone administration (50 mg im every 2 wk) on body composition, glucose, fat, and protein metabolism, and insulin sensitivity. Ten adolescents with delayed puberty were evaluated before and after 4 months of DHT administration. Body composition was assessed by dual energy x-ray absorptiometry. Insulin-stimulated glucose metabolism was measured during a 3-h hyperinsulinemic (40 mU/m(2).min)-euglycemic clamp procedure. Lipolysis and proteolysis were evaluated by stable isotopes of [(2)H(5)]glycerol and [1 (13)C]leucine. After 4 months of dihydrotestosterone treatment, height, weight, and fat free mass increased and percentage of body fat decreased. IGF-I and nocturnal GH levels did not change. There was no significant change in insulin stimulated glucose metabolism (57.2 +/- 3.9 vs. 58.3 +/- 3.9 micromol/kg.min). Total body proteolysis and lipolysis did not change. In summary, based on the present and past studies, we conclude that during puberty insulin resistance/hyperinsulinemia is not attributable to gonadal sex steroids in boys. PMID- 11600558 TI - Inhibition of P450 aromatase enhances gonadotropin secretion in early and midpubertal boys: evidence for a pituitary site of action of endogenous E. AB - In early pubertal boys, E concentrations are very low. We studied the role and site of action of endogenous E in the regulation of gonadotropin secretion in early and midpubertal boys by inhibiting the action of E with a potent and specific P450 aromatase inhibitor, letrozole. A total of 35 boys who were referred to us because of suspicion of delayed puberty were included in the study. The boys were in either early or midpuberty, and they composed 3 groups: 10 boys did not receive any treatment, 12 boys received T alone, and 13 boys received T and letrozole. In the untreated group during the 5-month follow-up, no changes were observed in 17beta-E2, T, basal gonadotropin, or inhibin B concentrations or in the GnRH-induced gonadotropin responses. In the T-treated group during the 5-month treatment, the T concentration increased by 55% (P < 0.05), and the 17beta-E2 concentration increased by 130% (P < 0.02). Concurrently, basal gonadotropin concentrations were suppressed, but the GnRH induced gonadotropin responses and the inhibin B concentration remained unchanged. In the T- plus letrozole-treated group during the 5-month treatment, an increase in T concentration of 606% was observed (P < 0.001), but the 17beta E2 concentration remained unchanged. The changes in the 17beta-E2 concentration within 5 months in the untreated and the T- plus letrozole-treated groups were different (P < 0.02), indicating significant inhibition of endogenous E synthesis during letrozole treatment. During the T plus letrozole treatment, basal gonadotropin concentration, the GnRH-induced LH response, and inhibin B concentration increased, and the GnRH-induced FSH response did not change significantly. Serum nocturnal gonadotropin pulses were determined in 5 boys treated with T and in 5 boys treated with T plus letrozole. In the T- plus letrozole-treated group, the nocturnal LH pulse amplitude increased, and the LH pulse frequency and interpulse interval remained unchanged. In conclusion, in early and midpubertal boys, suppression of the action of E by the P450 aromatase inhibitor increased LH concentration, LH pulse amplitude, and the GnRH-induced LH response, which indicates that in boys during early and midpuberty, endogenous E regulates LH secretion at the site of the pituitary. PMID- 11600559 TI - Plasma leptin concentrations during extended fasting and graded glucose infusions: relationships with changes in glucose, insulin, and FFA. AB - Despite numerous studies, the in vivo regulation of plasma leptin levels in response to nutritional factors continues to remain unclear. We investigated temporal and dose-response relationships of plasma leptin in response to physiological changes in insulin/glucose. After an overnight fast of 10 h, lean, healthy subjects were investigated for an additional 16 h of either extended fasting or one of three levels of glycemia/insulinemia induced by stepwise increasing iv glucose infusions. During extended fasting, plasma leptin values declined steadily and significantly. Plasma leptin levels remained constant at glucose concentrations between 5.8-6.5 mmol/liter, which maintained normoinsulinemia at 41.5-45.4 pmol/liter and FFA at 106-123 mg/liter, but leptin concentrations were increased at higher rates of glucose infusion (with plasma glucose rising to 8.7 mmol/liter). Concentrations of serum leptin were inversely related to FFA levels during extended fasting and at all levels of glycemia. Our data indicate that in lean healthy subjects, physiological changes in glycemia and insulinemia significantly alter plasma FFA and leptin concentrations. The increases in leptin concentrations demonstrate dose-dependent relationships that appear to relate to changes in FFA levels as well as to changes in glycemia/insulinemia. PMID- 11600561 TI - Serum dehydroepiandrosterone sulfate concentration as an indicator of adrenocortical suppression in asthmatic children treated with inhaled steroids. AB - ACTH regulates adrenal androgen production, which may thus be reduced during glucocorticosteroid therapy. Dehydroepiandrosterone sulfate is the most abundant androgen secreted by the adrenals. We wished to evaluate whether serum levels of dehydroepiandrosterone sulfate can be used as an indicator of adrenal suppression during inhaled steroid treatment in children. Sixty school-aged children with newly diagnosed asthma were randomly divided into budesonide (n = 30) and fluticasone propionate (n = 30) groups. Fifteen cromone-treated children served as a control group. The budesonide dose was 800 microg/d during the first 2 months and 400 microg/d thereafter. The respective fluticasone propionate doses were 500 and 200 microg/d. Serum dehydroepiandrosterone sulfate concentrations were measured before and after 2 and 4 months of treatment. In the budesonide group, serum dehydroepiandrosterone sulfate decreased from the baseline by a mean of 21% (95% confidence interval, 13-29%; P < 0.001) after 2 months of high dose treatment and by 16% (95% confidence interval, 8-25%; P < 0.001) after 4 months of treatment. In the fluticasone propionate group, the respective figures were 10% (95% confidence interval, 4-16%; P < 0.01) and 6% (95% confidence interval, 16% decrease-3% increase; P = NS). A low dose ACTH test indicated adrenocortical suppression at 4 months in 14 (23%) steroid-treated children. In these children, dehydroepiandrosterone sulfate decreased by a mean of 21% (95% confidence interval, 14-28%), whereas in those 46 steroid-treated children with normal ACTH test results, dehydroepiandrosterone sulfate decreased by 8% (95% confidence interval, 0-16%; P < 0.05 between these groups). In the control group, dehydroepiandrosterone sulfate levels tended to increase (by a mean of 26%), reflecting the normal physiological change at this age. In conclusion, inhaled steroid treatment suppresses dehydroepiandrosterone sulfate production in a dose dependent manner. Monitoring of serum dehydroepiandrosterone sulfate concentrations can be used as a practical method to follow adrenocortical function and to detect its suppression during inhaled steroid treatment in children. PMID- 11600560 TI - Glucose-induced insulin hypersecretion in lipid-infused healthy subjects is associated with a decrease in plasma norepinephrine concentration and urinary excretion. AB - We investigated the effect of a 48 h triglyceride infusion on the subsequent insulin secretion in response to glucose in healthy men. We measured the variations in plasma concentration and urinary excretion of catecholamines as an indirect estimation of sympathetic tone. For 48 h, 20 volunteers received a triglyceride/heparin or a saline solution, separated by a 1-month interval. At time 48 h, insulin secretion in response to glucose was investigated by a single iv glucose injection (0.5 g/kg(-1)) followed by an hyperglycemic clamp (10 mg.kg( 1).min(-1), during 50 min). The triglyceride infusion resulted in a 3-fold elevation in plasma free fatty acids and an increase in insulin and C-peptide plasma concentrations (1.5- and 2.5-fold, respectively, P < 0.05), compared with saline. At time 48 h of lipid infusion, plasma norepinephrine (NE) concentration and urinary excretion levels were lowered compared with saline (plasma NE: 0.65 +/- 0.08 vs. 0.42 +/- 0.06 ng/ml, P < 0.05; urinary excretion: 800 +/- 70 vs. 620 +/- 25 nmol/24 h, P < 0.05). In response to glucose loading, insulin and C peptide plasma concentrations were higher in lipid compared with saline infusion (plasma insulin: 600 +/- 98 vs. 310 +/- 45 pM, P < 0.05; plasma C-peptide 3.5 +/- 0.2 vs. 1.7 +/- 0.2 nM, P < 0.05). In conclusion, in healthy subjects, a 48-h lipid infusion induces basal hyperinsulinemia and exaggerated insulin secretion in response to glucose which may be partly related to a decrease in sympathetic tone. PMID- 11600562 TI - Hypoglycemia, but not insulin, acutely decreases LH and T secretion in men. AB - Hypoandrogenemia is frequently associated with hyperinsulinemia in men with the metabolic syndrome. We questioned whether insulin or changes in blood glucose levels influence pituitary gonadotropin secretion or testicular steroidogenesis in healthy men. Also, the relationship between hypoglycemia-induced activation of the hypothalamus-pituitary-adrenal axis and altered steroidogenesis was examined. Euglycemic and hypoglycemic clamp experiments were performed in 30 healthy men over a period of 6 h. Half of the men were infused with insulin at a rate of 1.5 mU/min.kg; the other half were infused at a rate of 15.0 mU/min.kg. Plasma glucose was held constant during a euglycemic clamp session and was decreased stepwise in a hypoglycemic clamp session. LH and total/free T concentrations decreased under hypoglycemic conditions regardless of the rate of insulin infusion. With euglycemic conditions, LH and T levels remained unchanged. Dehydroepiandrosterone concentrations increased during hypoglycemia, but not during the euglycemic conditions. The FSH concentration was not affected by insulin or glycemic clamps. Hypoglycemia acutely suppresses T secretion, and this effect is apparently mediated by pituitary LH. Insulin is ineffective. As counterregulation to hypoglycemia begins at normoglycemic ranges in poorly controlled type 2 diabetes and probably also in patients with long-term perturbed glucose regulation in the metabolic syndrome, control of glucose-responsive neurons in the brain may contribute to hypoandrogenemia. Apart from down regulation of hypothalamic release of GnRH, concurrent activation of the pituitary-adrenal axis (i.e. increased release of dehydroepiandrosterone) may add to the suppressive effect of hypoglycemia on gonadal steroidogenesis. PMID- 11600563 TI - Defective mitochondrial ATP synthesis in oxyphilic thyroid tumors. AB - Oxyphilic tumors (oncocytomas or Hurthle cell tumors) form a rare subgroup of thyroid tumors characterized by cells containing abundant mitochondria. The relationship between the mitochondrial proliferation and the pathogenesis of these tumors is unknown. We have assessed the expression of the mitochondrial ND2 and ND5 (subunits of the nicotinamide adenine dinucleotide dehydrogenase complex) genes and the nuclear UCP2 (uncoupling protein 2) gene in 22 oxyphilic thyroid tumors and matched controls. The consumption of oxygen in mitochondria from tumors was determined by polarography. ATP assays were used to explore the mitochondrial respiratory chain activity and the oxidative phosphorylation coupling in seven fresh thyroid tumors and controls. Adenosine triphosphate synthesis was significantly lower in all the tumors, compared with controls, suggesting that a coupling defect in oxidative phosphorylation may be a cause of mitochondrial hyperplasia in oxyphilic thyroid tumors. PMID- 11600564 TI - Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol. AB - The aims of this study were to examine the presence of mutations in the low density lipoprotein receptor gene among subjects clinically diagnosed with familial hypercholesterolemia and to analyze whether the molecular diagnosis helps to predict the response to simvastatin treatment in our familial hypercholesterolemia population. Fifty-five probands and 128 related subjects with familial hypercholesterolemia were studied. Genetic diagnosis was carried out following a three-step protocol based on Southern blot and PCR-single strand conformational polymorphism analysis. A randomized clinical trial with simvastatin was conducted in 42 genetically diagnosed subjects with familial hypercholesterolemia classified as carriers of null mutations (n = 22) and of defective mutations (n = 20). A mutation-causing familial hypercholesterolemia was identified in 46 probands (84%). In 41 of them (89%), a total of 28 point mutations were detected, 13 of which have not been previously described. The remaining five probands (11%) were carriers of large rearrangements. Familial hypercholesterolemia with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of plasma total and low-density lipoprotein cholesterol levels in these subjects were significantly lower (24.8 +/- 10.3 vs. 34.8 +/- 10.9, P = 0.04 and 30.0 +/- 39.8 vs. 46.1 +/- 18.2, P = 0.02, respectively) than in subjects with defective mutations. Baseline and posttreatment high-density lipoprotein cholesterol plasma values were significantly lower in subjects with familial hypercholesterolemia with null mutations (P < 0.001). In an outbreed Caucasian population, a three-step protocol for genetic screening detected a mutation in the low-density lipoprotein receptor gene in a high percentage (84%) of subjects with familial hypercholesterolemia. Subjects with familial hypercholesterolemia with null mutations (class I) showed lower plasma high-density lipoprotein cholesterol values and a poor low-density lipoprotein cholesterol response to simvastatin treatment. PMID- 11600565 TI - IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. AB - Clinical observations indicate that some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, frequently remit during pregnancy but exacerbate, or have their onset, in the postpartum period. The immune basis for these phenomena is poorly understood. Recently, excessive production of IL-12 and TNF-alpha was causally linked to rheumatoid arthritis and multiple sclerosis. We studied 18 women with normal pregnancies in their third trimester and during the early postpartum period. We report that during the third trimester pregnancy, ex vivo monocytic IL-12 production was about 3-fold and TNF-alpha production was approximately 40% lower than postpartum values. At the same time, urinary cortisol and norepinephrine excretion and serum levels of 1,25-dihydroxyvitamin were 2- to 3-fold higher than postpartum values. As shown previously, these hormones can directly suppress IL-12 and TNF-alpha production by monocytes/macrophages in vitro. We suggest that a cortisol-, norepinephrine-, and 1,25-dihydroxyvitamin-induced inhibition and subsequent rebound of IL-12 and TNF alpha production may represent a major mechanism by which pregnancy and postpartum alter the course of or susceptibility to various autoimmune disorders. PMID- 11600566 TI - The effect of type 1 diabetes mellitus on vascular responses to endothelin-1 in pregnant women. AB - Diabetes is associated with vascular dysfunction, which may be due in part to altered vascular responses to endogenous peptides such as endothelin-1. These altered responses may also contribute to the decreased maternal peripheral resistance in pregnancy. The aim of this study was to examine the effect of diabetes on the vasoconstrictor response to endothelin-1 in pregnant women. Small arteries were isolated from nine healthy pregnant, seven type 1 diabetic pregnant women, and five healthy nonpregnant women. Contraction curves were performed on a wire myograph for noradrenaline (1 nM to 30 microM) and endothelin-1 (1 pM to 0.3 microM). Maximum responses and sensitivity were compared by t test. No differences in maximum response to noradrenaline or potassium were seen among the three groups. The maximum response to endothelin-1 was significantly increased in pregnancy (P < 0.05), whereas endothelin-1 sensitivity was reduced in the diabetic compared with the nondiabetic pregnant women (P < 0.05). Pregnant women have an increased maximum vasoconstriction response to endothelin-1 compared with nonpregnant women, whereas diabetic pregnant women demonstrate reduced sensitivity to endothelin-1. These observations suggest that endothelin-1 may play a role in maintaining peripheral vascular tone in normal pregnancy, and the decreased sensitivity seen in pregnant women with diabetes may reflect abnormal vascular reactivity. PMID- 11600567 TI - Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding. AB - The N-terminal domain is conserved in all members of the IGF-binding protein superfamily. Most recently, studies have demonstrated the importance of an IGF binding protein N-terminal hydrophobic pocket for IGF binding. To examine more critically the amino acids important for IGF binding within the full-length IGF binding protein-3 protein while minimizing changes in the tertiary structure, we targeted residues I56, L80, and L81 within the proposed hydrophobic pocket for mutation. With a single change at these sites to the nonconserved glycine there was a notable decrease in binding. A greater reduction was seen when both L80 and L81 were substituted with glycine, and complete loss of affinity for IGF-I and IGF-II occurred when all three targeted amino acids were changed to glycine. Furthermore, the ability of the IGF-binding protein-3 mutants to inhibit IGF-I stimulated phosphorylation of its receptor was a reflection of their affinity for IGF, with the lowest affinity mutants having the least inhibitory effect. These studies, thus, support the hypothesis that an N-terminal hydrophobic pocket is the primary site of high affinity binding of IGF to IGF-binding protein-3. The mutants provide a tool for future studies directed at IGF-dependent and IGF independent actions of IGF-binding protein-3. PMID- 11600568 TI - Efficient fat storage in premenopausal women and in early pregnancy: a role for estrogen. AB - There is a sexual dimorphism in body fat in humans. Adipose tissue increases with puberty and early pregnancy in women, suggesting gonadal steroids can influence body fat. Previously, we have observed that oral estrogen, compared with transdermal estrogen, reduced postprandial lipid oxidation and increased body fat, possibly due to suppressed hepatic lipid oxidation. If estrogen effects lipid oxidation, we predicted that subjects with significantly different endogenous estrogen production would oxidize lipids at different rates. The aim of this study was to compare energy metabolism in 12 pregnant (19 wk gestation, 29 +/- 1 yr, 1.66 +/- 0.02 m, 73.5 +/- 2.4 kg), 11 nonpregnant premenopausal (29 +/- 2 yr, 1.68 +/- 0.02 m, 63.1 +/- 1.8 kg), and 28 postmenopausal (58 +/- 1 yr, 1.62 +/- 0.01 m, 69.9 +/- 1.0 kg) women who were not receiving estrogen, and to relate these findings to endogenous estrogen concentrations. All women underwent indirect calorimetry under identical situations in the basal and postprandial state following a standard mixed meal. Basal (5998 +/- 184 vs. 5712 +/- 184 vs. 5800 +/- 121 kJ.24 h, respectively) and postprandial energy expenditure (7172 +/- 239 vs. 6964 +/- 210 vs. 6955 +/- 147 kJ.24 h) was similar among groups. However, basal lipid oxidation was reduced in pregnant (45.3 +/- 6.1 mg/min, P < 0.05) and nonpregnant women (44.5 +/- 6.3 mg/min, P < 0.05) compared with postmenopausal women (58.4 +/- 2.9 mg/min). Postprandial lipid oxidation differed among groups, being least in pregnant women (8.8 +/- 6.2 mg/min) compared with nonpregnant (28.9 +/- 6.4 mg/min, P < 0.04) and postmenopausal (48.1 +/- 4.0 mg/min, P = 0.0001) women. There was a significant reciprocal increase in postprandial carbohydrate oxidation. Mean postprandial glucose levels were slightly but nonsignificantly higher in pregnant women. Insulin levels were significantly higher in postmenopausal compared nonpregnant, but not pregnant, women. In a multiple regression analysis, serum estradiol (log transformed) correlated negatively with postprandial lipid oxidation (r = -0.66, P = 0.0001) and positively with postprandial nonesterified free fatty acid levels, whereas no correlation was found with postprandial insulin, glucose, fat free mass, and fat mass. In summary, postprandial lipid oxidation is reduced in pregnancy compared with that in healthy nonpregnant women, who in turn have lower postprandial lipid oxidation than postmenopausal women. This implies that the premenopausal years and early pregnancy are states of efficient fat storage, possibly mediated through reduced lipid oxidation due to estrogen, therefore increasing body fat for reproduction, thus supporting the notion that fat mass can be regulated. PMID- 11600569 TI - Autoantibodies and human leucocyte antigen class II in first-degree family members of Mexican-American type 1 diabetic patients. AB - As part of a genetic study of type 1 diabetes in Mexican-Americans, 360 first degree relatives of 108 type 1 diabetic probands were studied. Islet cell antibody (ICA), insulin autoantibody, glutamic acid decarboxylase (GAD(65)), and protein tyrosine phosphatase autoantibodies were measured and human leucocyte antigen (HLA) class II alleles DRB1 and DQB1 genotyping was performed. ICA was positive in 37% of the probands and 5.8% of the relatives. A subgroup of 26 probands (12 ICA+, 14 ICA-) was tested for GAD(65) and was found positive. 4/14 ICA+ first-degree relatives were GAD(65) positive. Four relatives, positive for two antibodies, subsequently developed type 1 diabetes. Life-Table analysis of first-degree relatives with autoantibodies indicated an 80% disease-free survival at 3.5 yr. HLA-DRB1 was found to be associated with the presence of ICA in both probands and relatives, whereas HLA-DPB1 was associated with autoantibody in relatives of type 1 diabetic probands. These results suggest that autoimmunity occurs in type 1 diabetes families of Mexican descent in similar frequencies to that of non-Hispanic, Caucasian families. The presence of autoantibodies appears to be regulated in part by HLA class II genes, even in the absence of overt diabetes. PMID- 11600570 TI - Effect of spontaneous GH secretion and the GH sampling period on the accuracy of models for predicting growth responses to GH treatment. PMID- 11600571 TI - Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination. AB - Recent studies suggest that immunization with autologeous dendritic cells (DCs) pulsed with tumor antigen result in protective immunity and rejection of established tumors in various human malignancies. The objective of this study was to develop a DC vaccination therapy in patients with metastasized medullary thyroid carcinoma (MTC). Mature DCs were generated from peripheral blood monocytes in the presence of granulocyte macrophage colony-stimulating factor, IL 4, and TNFalpha. After loading with calcitonin and carcinoembryonic antigen (CEA) peptide, 2-5 x 10(6) DCs were repeatedly delivered by sc injections. During follow-up (mean, 13.1 months) all patients developed a strong delayed-type hypersensitivity skin reaction caused by perivascular and epidermal infiltration with CD4+ memory T cells and CD8+ cytotoxic T cells. Clinical responses with a decrease of serum calcitonin and CEA were initially documented in three of seven patients. One of these patients had a complete regression of detectable liver metastases and a significant reduction of pulmonary lesions. T-cell response in this patient revealed a calcitonin- and CEA-specific immunreactivity. Our data indicate that vaccination with calcitonin and/or CEA peptide-pulsed DC results in the induction of a cellular, antigen-specific immune response in patients with MTC, leading to clinical response in some patients. Our approach may represent the basis for the development of new therapeutic strategies not only in MTC but also in other endocrine malignancies. PMID- 11600572 TI - An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors. AB - Mutations of the p53 tumor suppressor gene are the single most common genetic alterations in human cancers. Recently, a distinct nucleotide substitution was identified in exon 10 of the p53 gene, leading to an Arg337His mutation in 97% of children with adrenocortical tumors from Southern Brazil. In the present study, we investigated the presence of this mutation in a larger series of 55 patients (37 adults and 18 children) with benign and malignant sporadic adrenocortical tumors. None of the patients had family cancer histories that conformed to the criteria for Li-Fraumeni syndrome. Twenty-one asymptomatic close relatives of patients with p53 mutations and 60 normal unrelated individuals were also studied. The missense Arg337His mutation was identified in 19 patients (14 children and 5 adults), and 8 of 11 cases studied had LOH. Among the 19 patients with the Arg337His mutation, only one boy and three adults showed fatal evolution or recurrent metastases. This mutation was also identified in heterozygous state in asymptomatic first-degree relatives of the patients, indicating that Arg337His mutation was inherited in most cases. In contrast, this mutation was not found in 120 alleles of normal unrelated controls. In conclusion, the germ line Arg337His mutation of p53 protein is present at a high frequency (77.7%) in children with benign or malignant sporadic adrenocortical tumors, but it is not restricted to the pediatric group, since 13.5% of adults with adrenocortical tumors also had this mutation. The presence of this mutation was related to unfavorable prognosis in most of the adults, but not in the children with adrenocortical tumors. PMID- 11600573 TI - Th2 cytokines have a partial, direct protective effect on the function and survival of isolated human islets exposed to combined proinflammatory and Th1 cytokines. AB - Studies in rodents have suggested that Th2 and Th3 cytokines can be effective in reducing proinflammatory and Th1 cytokine-induced islet damage. Whether this is the case with human islets and might be due to a direct action of Th2 and Th3 cytokines is not known. In the present study, we evaluated whether Th2 (500 U/ml IL-4 plus 100 U/ml IL-10) or Th3 (5 ng/ml TGF-1beta) cytokines may prevent the derangements induced on isolated human islets by prolonged (12 or 72 h) exposure to combined proinflammatory (50 U/ml IL-1beta, 1000 U/ml TNF alpha) and Th1 (1000 U/ml interferon gamma) cytokines. Compared with control islets, cells preincubated for 12 or 72 h with proinflammatory and Th1 cytokines showed a significant decrease of glucose-stimulated insulin secretion and a significant increase of nitrites production. The addition of IL-4 plus IL-10 or TGF-1beta in the medium prevented these cytostatic effects in the 12-h incubation experiments, but not after the 72-h exposure period. IL-1beta, interferon gamma, and TNF alpha caused no major change in either islet cell survival or Bcl-2 and Bax mRNA expression after a 12-h incubation; however, a marked increase in the amount of dead cells, with a major decrease of Bcl-2 mRNA expression, was observed after 72 h. The presence of Th2, but not of Th3, cytokines significantly reduced beta-cell death, without any major effect on Bcl-2 and Bax mRNA expression. These results suggest that Th2 and (at lower extent) Th3 cytokines may have a partial, direct protective effect on isolated human islets exposed to the cytostatic and cytotoxic action of proinflammatory and Th1 cytokines. PMID- 11600574 TI - Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. AB - 11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) inactivates cortisol to cortisone. In the placenta 11beta-HSD2 activity is thought to protect the fetus from the deleterious effects of maternal glucocorticoids. Patients with apparent mineralocorticoid excess owing to mutations in the 11beta-HSD2 gene invariably have reduced birth weight, and we have recently shown reduced placental 11beta HSD2 activity in pregnancies complicated by intrauterine growth restriction. This is reflected in the literature by evidence of hypercortisolemia in the fetal circulation of small babies. In this study we have determined the levels of placental 11beta-HSD2 mRNA expression across normal gestation (n = 86 placentae) and in pregnancies complicated by intrauterine growth restriction (n = 19) and evaluated the underlying mechanism for any aberrant 11beta-HSD2 mRNA expression in intrauterine growth restriction. 11beta-HSD2 mRNA expression increased more than 50-fold across gestation, peaking at term. Placental 11beta-HSD2 mRNA levels were significantly decreased in intrauterine growth restriction pregnancies when compared with gestationally matched, appropriately grown placentae [e.g. at term DeltaCt (11beta-hydroxysteroid dehydrogenase type 2/18S) 12.8 +/- 0.8 (mean +/- SE) vs. 10.2 +/- 0.2, respectively, P < 0.001]. These differences were not attributable to changes in trophoblast mass in intrauterine growth restriction placentae, as assessed by parallel analyses of cytokeratin-8 mRNA expression. No mutations were found in the 11beta-HSD2 gene in the intrauterine growth restriction cohort, and imprinting analysis revealed that the 11beta-HSD2 gene was not imprinted. Although the underlying cause is unknown, 11beta-HSD2 gene expression is reduced in intrauterine growth restriction pregnancies. These data highlight the important role of 11beta-HSD2 in regulating fetal growth, a known factor in determining fetal morbidity but also the subsequent development of cardiovascular disease in adulthood. PMID- 11600575 TI - Substantial production of ghrelin by a human medullary thyroid carcinoma cell line. AB - Ghrelin, an endogenous ligand for the GH secretagogue receptor, is a novel acylated peptide produced in the gastrointestinal endocrine cells as well as neuroendocrine cells in the hypothalamus. The Ser(3) residue of ghrelin is modified by n-octanoic acid, a modification necessary for hormonal activity. Human medullary thyroid carcinoma is known to produce a variety of gastrointestinal and neuroendocrine peptides. In the present study we investigated ghrelin production in the thyroid gland, especially in human medullary thyroid carcinoma. PCR amplification demonstrated prepro-ghrelin gene transcripts in normal human thyroid tissue and two medullary thyroid carcinoma cell lines (human TT cells and rat 6-23 cells), but not in a rat thyroid follicular cell line. TT cells showed the expression of prepro-ghrelin mRNA of about 0.6 kb by Northern blot analysis. Furthermore, production of ghrelin in TT cells was demonstrated by RIA and immunocytochemistry. Accumulation of des-n octanoyl ghrelin in the cultured medium of the cells was confirmed. Finally, human medullary thyroid carcinoma surgical specimens showed significantly higher des-n-octanoyl ghrelin contents than normal thyroid tissues. In conclusion, we revealed that ghrelin was produced by the human thyroid parafollicular carcinoma cell line, TT cells. These findings suggest that ghrelin is produced in the thyroid C cells as well as in medullary thyroid carcinoma and may provide opportunities to investigate its physiological role in the thyroid gland. PMID- 11600576 TI - Osteopontin and its receptor alphavbeta(3) integrin are coexpressed in the human endometrium during the menstrual cycle but regulated differentially. AB - Osteopontin is an arginine-glycine-aspartic acid-containing acidic glycoprotein component of the extracellular matrix that is postulated to bind to integrin receptors at the cell surface to mediate cellular adhesion and migration during embryo implantation. The primary aim of this study was to examine the uterine expression of osteopontin throughout the menstrual cycle in normal fertile controls sampled prospectively based on urinary LH surge detection. Expression of osteopontin was documented using Northern blot analysis, in situ hybridization, and immunohistochemistry. Furthermore, the temporal pattern of osteopontin expression was compared with that of its receptor, the alphavbeta3 integrin. Using Ishikawa cells, a well differentiated endometrial adenocarcinoma cell line, the in vitro regulation of osteopontin and its receptor alphavbeta3 integrin was studied. By Northern blot analysis, osteopontin mRNA appears during the early secretory phase, with maximal expression occurring in mid to late secretory-phase endometrium. The in situ hybridization analyses showed that osteopontin mRNA specifically localized in epithelial cells within the endometrium. Immunostaining of osteopontin was detected in the glandular secretions and on the apical portions of surface (luminal) epithelium. The patterns of expression of osteopontin by Northern blotting, in situ hybridization, and immunohistochemistry are remarkably similar to the pattern for the alphavbeta3 integrin. Despite these similarities in distribution, in vitro studies demonstrate that osteopontin and beta3 integrin subunit expression are differentially regulated. The expression of osteopontin was primarily induced in response to progesterone, whereas the beta3 integrin subunit was up-regulated by epidermal growth factor or heparin-binding epidermal growth factor. The differential regulation of these two endometrial proteins suggests the existence of two separate pathways regulating epithelial gene expression in human endometrium during the window of implantation. In adhesion assays using Ishikawa cells, alphavbeta3 but not alphavbeta5 or beta1 integrins appear to be the primary receptors for osteopontin. These findings may better define the factors that favor the development of a receptive endometrium. PMID- 11600577 TI - Production and metabolism of serotonin (5-HT) by the human adrenal cortex: paracrine stimulation of aldosterone secretion by 5-HT. AB - In the human adrenal cortex, serotonin (5-HT) is contained in mast-like cells, and we have shown that 5-HT stimulates aldosterone secretion, suggesting that 5 HT may control glomerulosa cells through a paracrine mechanism. Concurrently, the presence of 5-hydroxyindolacetic acid in human adrenocortical extracts indicates that 5-HT may be metabolized after local release by mast cells. The aim of the present study was to investigate in vitro the production and metabolism of 5-HT by the human adrenal cortex. Perifused adrenal slices released spontaneously detectable amounts of 5-HT (0.74 +/- 0.38 fmol/mg wet tissue.min). The mast cell depleting drug compound 48/80 induced a burst of 5-HT secretion followed by a gradual increase in aldosterone production. Administration of the specific 5 HT(4) receptor antagonist GR 113808 (10(-6) M) did not affect compound 48/80 induced 5-HT release but abolished the stimulatory effect of compound 48/80 on aldosterone secretion, indicating that 5-HT released locally is responsible for a paracrine control of steroidogenesis. Incubation of cells from the human adrenal cortex with 5-HT (10(-5) M) provoked the formation of the 5-HT metabolite 5 hydroxytryptophol. The type A monoamine oxidase (MAO) inhibitor clorgyline (10( 6) M) suppressed the metabolism of 5-HT into 5-hydroxytryptophol. Immunocytochemical staining of cultured cells revealed the presence of a subpopulation of MAO-A-positive cells. Double labeling with an antiserum against chromogranin A showed that MAO-A was actually contained in chromaffin cells. Similarly, immunohistochemical staining of adrenal slices showed that MAO-A was expressed in chromaffin cells located both in the medulla and in intracortical rays. In conclusion, the present study shows that, in the human adrenal cortex, 5 HT, released by mast-cells, may stimulate aldosterone secretion in a paracrine manner. Our data also indicate that 5-HT is metabolized by MAO-A located in intracortical chromaffin cells. PMID- 11600578 TI - Thyrocytes from autoimmune thyroid disorders produce the chemokines IP-10 and Mig and attract CXCR3+ lymphocytes. AB - To better understand the selective migration of lymphocytes in autoimmune thyroid disorders (AITDs), we analyzed thyroid samples and demonstrated an enhanced expression of the chemokines interferon (IFN)-inducible protein (Ip)-10 and regulated on activation normal T lymphocyte expressed and secreted (RANTES) in thyroids from AITD patients. Ip-10 and monokine induced by IFN-gamma (Mig) were expressed in vivo in thyroid follicular cells (TFCs) from AITD thyroids. Interestingly, Ip-10 mRNA, although not basally detected in cultured TFCs, was strongly induced by IFN-gamma and synergistically increased by TNF-alpha addition. Furthermore, high levels of Ip-10 protein were detected in the supernatants of IFN-gamma-stimulated TFCs. Likewise, Mig protein was strongly induced in TFCs by the same stimuli as Ip-10. Unlike Ip-10 and Mig, the expression of RANTES was induced mainly by TNF-alpha. In addition, intrathyroidal lymphocytes from AITD patients showed higher expression of CXCR3, CCR2, and CCR5 chemokine receptors than autologous peripheral blood lymphocytes. T lymphoblasts expressing CXCR3 showed an increased migration to supernatants from stimulated TFCs, which was abolished by specific antibodies to the chemokines Ip-10 and Mig, as well as to their receptor CXCR3. Taken together, these data suggest a potential role of TFCs, through the production of the chemokines Ip-10, Mig and RANTES, in regulating the recruitment of specific subsets of activated lymphocytes in AITDs. PMID- 11600579 TI - PPARgamma/RXRalpha heterodimers control human trophoblast invasion. AB - The ligand-dependent nuclear receptors PPARgamma and RXRalpha/beta were recently determined to be essential for murine placental development and trophoblast differentiation. In the current study we examined the expression and role of the PPARgamma/RXRalpha heterodimers in human invasive trophoblasts. We first report that in human first trimester placenta, PPARgamma and RXRalpha are highly expressed in cytotrophoblasts at the feto-maternal interface, especially in the extravillous cytotrophoblasts involved in uterus invasion. The coexpression of PPARgamma and RXRalpha genes in extravillous cytotrophoblast nuclei were then confirmed by immunocytochemistry, immunoblot, and real-time quantitative PCR using cultured purified primary extravillous cytotrophoblasts. We next examined, using the extravillous cytotrophoblast culture model, the biological role of PPARgamma/RXRalpha heterodimers in vitro, and we showed that both synthetic (rosiglitazone) and natural [15-deoxy-delta-(12,14)PGJ(2)] PPARgamma agonists inhibit extravillous cytotrophoblast invasion in a concentration-dependent manner and synergize with pan-RXR agonists. Conversely, PPARgamma or pan-RXR antagonists promoted extravillous cytotrophoblast invasion. Furthermore, the pan-RXR antagonist abolished the inhibitory effect of the PPARgamma agonists. Together these data underscore an important function of PPARgamma/RXRalpha heterodimers in the modulation of trophoblast invasion. PMID- 11600580 TI - Transforming events in thyroid tumorigenesis and their association with follicular lesions. AB - Thyroid tumors comprise a broad spectrum of neoplastic phenotypes, and distinct molecular events have been implicated in their pathogenesis. Pituitary tumor transforming gene, originally isolated from GH(4) pituitary cells, is tumorigenic in vivo, regulates basic fibroblast growth factor secretion, and is homologous to a securin inhibitor of chromatid separation. Pituitary tumor transforming gene 1 is expressed at low levels in several normal human tissues and is abundantly expressed in neoplasms, including colorectal carcinoma, where pituitary tumor transforming gene expression correlated highly with tumor invasiveness. As pituitary tumor transforming gene is regulated by E and as thyroid cancer shows a strong female preponderance, we examined pituitary tumor transforming gene 1 expression and action in human thyroid tumors and in normal human and rat thyroid cells. Increased pituitary tumor transforming gene 1 expression was evident early in thyroid tumors and was most abundantly expressed in a subset of thyroid hyperplasia, follicular adenomas, and follicular carcinomas (1.8-fold; P < 0.0001). Pituitary tumor transforming gene 1 overexpression in rat FRTL5 thyroid cells and in primary human thyroid cell cultures causes in vitro transformation and produces a dedifferentiated neoplastic phenotype. As pituitary tumor transforming gene 1 was abundantly overexpressed in follicular adenoma and follicular carcinoma, we propose that pituitary tumor transforming gene overexpression may play a role in the early molecular events leading to divergent development of follicular and papillary carcinoma. PMID- 11600581 TI - Identification of heme oxygenase in human endometrium. AB - The aim of the present study was to investigate the presence of heme oxygenase (HO)-1 and HO-2 in human endometrium at various stages of the menstrual cycle using RT-PCR, Western blotting, and immunohistochemistry. RT-PCR detected mRNA for HO-1 and HO-2 in human endometrium at all stages of the menstrual cycle. Western blotting also revealed the expression of the two distinct HO proteins throughout the menstrual cycle. HO-1 was constitutively expressed, whereas HO-2 expression was apparently greater in the secretory phase than in the menstrual and proliferative phases. Immunohistochemistry showed that distribution of the two HO isoforms had distinct topographic patterns: HO-1 was observed in endometrial epithelial cells and macrophages, whereas HO-2 was found in endothelial cells and smooth muscle cells of blood vessels in the endometrium. The detection of mRNA and protein for HO-1 and HO-2 in normal human endometrium suggests that the carbon monoxide/HO system may play a role in the local control of endometrial function. PMID- 11600582 TI - Three novel mutations causing complete T(4)-binding globulin deficiency. AB - Inherited T(4)-binding globulin deficiency is caused by mutations in the T(4) binding globulin gene located on the X chromosome. We describe herein three novel mutations in three different families producing complete T(4)-binding globulin deficiency. The proposita of a family from Harwichport is a female with XO Turner's syndrome who expressed only the mutant T(4)-binding globulin allele. Her T(4)-binding globulin sequence has a 19-nucleotide deletion in the distal portion of exon 4. This causes a frameshift and a premature stop at codon 384 of the mature protein. Structure analysis with the Swiss PDB-Viewer revealed that this mutation removes beta-strand s5B from the core of the T(4)-binding globulin molecule, leading to a severe folding defect that is likely to prevent synthesis and secretion. The propositi of complete T(4)-binding globulin deficiency 7 and 8 were 7-month-old and 3-wk-old male infants who were identified because of low serum T(4) levels detected during neonatal screening. Sequencing of complete T(4) binding globulin deficiency 7 revealed a single nucleotide deletion, a G at position 2690 in exon 3. This leads to an alteration of the amino acid sequence starting at codon 283 and a premature stop at codon 301. Complete T(4)-binding globulin deficiency 8 also has a deletion of the first nucleotide of exon 4, a G at position 3358. This leads to a frameshift and a premature stop at codon 374. As in the case of complete T(4)-binding globulin deficiency J, which has also a nucleotide deletion but downstream (position 3421) and a stop at codon 374, these two T(4)-binding globulin mutants undoubtedly have a defect in intracellular transport and therefore fail to be secreted. This explains the lack of T(4) binding globulin in the hemizygous affected subjects. PMID- 11600583 TI - The effects of androgens and estrogens on preadipocyte proliferation in human adipose tissue: influence of gender and site. AB - The gender-specific differences in body fat distribution suggest that sex steroids play an important role in regulating body fat distribution. Sex steroids may regulate adipose tissue mass by altering adipocyte number and size. The effects of various sex steroids on in vitro proliferation of preadipocytes from both sc and omental fat depots was investigated in men and women. Abdominal sc and omental preadipocytes from men (n = 14) and women (8 premenopausal and 7 postmenopausal) were cultured in the presence of 17beta-E2 (10(-7)-10(-9) M), estrone (10(-7)-10(-9) M), or dehydrotestosterone (DHT) (10(-7)-10(-9) M), and the rate of proliferation was measured over time (1-96 h) by DNA accumulation assays (micromoles per microg) and [(3)H]thymidine incorporation (disintegrations per min). In sc preadipocytes the rate of proliferation was increased between 24 48 h with E2 (10(-7) M) in both men (P = 0.028) and women (P = 0.017). Subcutaneous preadipocytes from women were more responsive to E2 in stimulating proliferation than those from men (women vs. men, DNA assay, 24 h, P = 0.014). In omental preadipocytes the increase in the rate of proliferation occurred at 24 h with E2 (10(-7) M) in women (P = 0.034) and at 48 h in men (P = 0.031). Gender appeared to influence the rate of proliferation by E2 in omental preadipocytes, with maximal stimulation of proliferation at 48 h in preadipocytes from women treated with E2 (10(-7) M; p = 0.007) compared with 72 h in preadipocyte cells from men (P = 0.048), as shown by DNA assay. Both estrone and the androgen DHT had no significant gender- or site-specific effect on the rate of proliferation at any time point. All DNA content data were further validated by thymidine incorporation analysis. In summary, E2 stimulates the rate of proliferation of preadipocytes in a dose-dependent manner, with significant gender- and site specific differences. Neither estrone nor DHT affected adipocyte mass through proliferation of preadipocytes in this study. In conclusion, E2 may act as an important local factor influencing the proliferation of preadipocytes that may affect fat cell number in a depot- and gender-specific pattern in human abdominal sc and omental adipose tissue. PMID- 11600584 TI - Ghrelin-producing endocrine tumors of the stomach and intestine. AB - Ghrelin is a novel gastrointestinal hormone produced by about 20% of the rat and human gastric neuroendocrine cell population, which possesses strong GH-releasing activity, but also plays other central and peripheral roles, including influence on food intake, gastric motility, and acid secretion. The aim of the present study was to determine whether gastrointestinal endocrine hyperplastic and neoplastic lesions produce ghrelin, at both protein (immunohistochemistry) and mRNA (in situ hybridization and/or RT-PCR) levels, and express the GH secretagogue receptor mRNA by RT-PCR. Sixteen gastric and 20 intestinal carcinoids as well as normal gastrointestinal mucosa and atrophic gastritis associated neuroendocrine cell hyperplasia were studied. The majority (12 of 16, 75%) of gastric carcinoids and only 5 of 18 (27%) of intestinal endocrine tumors were immunoreactive for ghrelin. In situ hybridization confirmed the immunohistochemical data, but also showed ghrelin mRNA in 1 gastric and 8 intestinal additional tumors. RT-PCR showed ghrelin mRNA in 14 of 14 cases, indicating a low level of ghrelin gene expression in all gastrointestinal endocrine tumors tested. Gastric neuroendocrine hyperplastic cells were also strongly positive for ghrelin. GH secretagogue receptor mRNA was absent in 3 gastric, but present in 7 of 11 intestinal carcinoids studied by RT-PCR. These findings demonstrate that most gastric carcinoids (and related neuroendocrine cell hyperplasias) and some intestinal carcinoids produce ghrelin. These hyperplastic/neoplastic conditions could represent the clinical model to clarify the existence and impact of ghrelin hypersecretion on endocrine and nonendocrine functions. PMID- 11600585 TI - The postmenopausal ovary is not a major androgen-producing gland. AB - It is currently believed that the postmenopausal ovary remains a gonadotropin driven, androgen-producing gland. However, the adrenal contribution to circulating androgen levels may explain some conflicting results previously reported. In addition, the steroidogenic potential and gonadotropin responsiveness of the postmenopausal ovary have not been recently reassessed. Plasma T, bioavailable T, free T, androstenedione (Adione), and dehydroepiandrosterone sulfate levels were measured in postmenopausal or ovariectomized women with complete adrenal insufficiency, compared with women with intact adrenals. A stimulation human chorionic gonadotropin test (on d 0, 3, and 6) was performed in postmenopausal women with adrenal insufficiency. Dexamethasone was administered for 4 d in postmenopausal women with intact adrenals. Intraovarian T and androstenedione were also measured in homogenates of ovarian tissue from postmenopausal women. Immunocytochemistry was performed on postmenopausal ovaries and premenopausal controls to detect the presence of steroidogenic enzymes (P-450 aromatase, P-450 SCC, 3beta HSD, and P-450 C17) and gonadotropin receptors. Plasma androgen levels were below or close to the limit of the assay in all women with adrenal insufficiency. They were similar in postmenopausal and oophorectomized women with normal adrenals. No hormonal changes were observed after human chorionic gonadotropin injections in women with adrenal insufficiency. In contrast, a dramatic decrease of all steroids was observed after dexamethasone administration in postmenopausal women with intact adrenals. Intraovarian T and androstenedione levels were negligible in postmenopausal ovarian tissue. P-450 aromatase was absent from the 17 ovaries studied, and the enzymes for androgen biosynthesis were either absent (n = 13) or present in very low amounts (n = 4). In all the postmenopausal ovaries, FSH and LH receptors were completely absent. In the absence of adrenal steroids, postmenopausal women have no circulating androgens. This result is consistent with the immunocytochemical studies showing the almost constantly absent steroidogenic enzymes and LH receptors in the postmenopausal ovary. Thus, the climacteric ovary is not a critical source of androgens. The arrest of androgen secretion after menopause may impact significantly on women's health. PMID- 11600586 TI - Skeletal muscle PGF(2)(alpha) and PGE(2) in response to eccentric resistance exercise: influence of ibuprofen acetaminophen. AB - PGs have been shown to modulate skeletal muscle protein metabolism as well as inflammation and pain. In nonskeletal muscle tissues, the over the counter analgesic drugs ibuprofen and acetaminophen function through suppression of PG synthesis. We previously reported that ibuprofen and acetaminophen inhibit the normal increase in skeletal muscle protein synthesis after high intensity eccentric resistance exercise. The current study examined skeletal muscle PG levels in the same subjects to further investigate the mechanisms of action of these drugs in exercised skeletal muscle. Twenty-four males (25 +/- 3 yr) were assigned to 3 groups that received the maximal over the counter dose of ibuprofen (1200 mg/d), acetaminophen (4000 mg/d), or a placebo after 10-14 sets of 10 eccentric repetitions at 120% of concentric 1 repetition maximum using the knee extensors. Preexercise and 24 h postexercise biopsies of the vastus lateralis revealed that the exercise-induced change in PGF(2alpha) in the placebo group (77%) was significantly different (P < 0.05) from those in the ibuprofen (-1%) and acetaminophen (-14%) groups. However, the exercise-induced change in PGE(2) in the placebo group (64%) was only significantly different (P < 0.05) from that in the acetaminophen group (-16%). The exercise-induced changes in PGF(2alpha) and PGE(2) were not different between the ibuprofen and acetaminophen groups. These results suggest that ibuprofen and acetaminophen have a comparable effect on suppressing the normal increase in PGF(2alpha) in human skeletal muscle after eccentric resistance exercise, which may profoundly influence the anabolic response of muscle to this form of exercise. PMID- 11600587 TI - The glucocorticoid receptor is specifically expressed in the stromal compartment of the human endometrium. AB - The human endometrium is a classical target tissue for steroid hormones. While the expression pattern and functional roles of both the estrogen receptor (ER) and the progesterone receptor (PR) are well defined, expression of the glucocorticoid receptor (GR) in this tissue has not been described so far. In the present study, we used immunohistochemistry to analyze the expression of GR in the normal human endometrium throughout the menstrual cycle. The expression of GR was compared to that of ER and PR, which were analyzed in parallel. We show that GR is expressed in the human endometrium with a pattern that markedly differs from the expression patterns of ER and PR. ER and PR are expressed in the nuclei of endometrial glands, whereas GR is completely absent from these structures. However, GR is strongly expressed in the stromal compartment of the endometrium throughout the cycle. Both stromal fibroblasts and lymphocytes are GR-positive. In addition GR expression is also observed in the endothelium of small endometrial blood vessels, which are ER- and PR-negative. Western blot analysis performed on endometrial tumor cell lines of glandular (HEC-1B) and mesodermal (SKUT-1B) origin, respectively, showed GR expression only in the latter. In summary, we demonstrate that GR is expressed in fibroblasts, lymphocytes and endothelial cells of the human endometrial stroma, while it is absent from the glandular compartment. The specific expression pattern of GR within the human endometrium points to a possible functional role of glucocorticoids in the process of decidualization which occurs primarily in the stromal compartment. PMID- 11600588 TI - Expression and antiproliferative effect of a second form of gonadotropin releasing hormone in normal and neoplastic ovarian surface epithelial cells. AB - Epithelial ovarian carcinomas are the most common cause of death from gynecological malignancies and appear to arise from ovarian surface epithelium (OSE), but the exact mechanism of ovarian tumorigenesis has not been elucidated. Recent cloning of a second form of gonadotropin-releasing hormone (GnRH-II) has been reported in various human tissues including the ovary. However, the expression and role of GnRH-II in human OSE and ovarian carcinomas is not known. In the present study, we demonstrated that in addition to the GnRH receptor (GnRH R), GnRH-II mRNA is expressed in normal OSE, immortalized OSE (IOSE) cells, primary cultures of ovarian tumors and ovarian cancer cell lines. Treatments with increasing doses (10(-9)-10(-7) M) of GnRH-I and -II resulted in a growth inhibition in both non-tumorigenic IOSE-29 and tumorigenic IOSE-29EC cells. These results indicate for the first time the expression and potential anti proliferative effect of GnRH-II, suggesting that GnRH-II, similar to GnRH-I, may have a growth-regulatory effect in normal and neoplastic OSE cells. PMID- 11600589 TI - Alteration of the adrenomedullin receptor components gene expression associated with the blood pressure in pregnancy-induced hypertension. AB - Adrenomedullin (AM) is a potent vasodilator. Pregnancy-induced hypertension (PIH) is a common cause of maternal or fetal mortality. We measured the changes of adrenomedullin receptor components gene expression, receptor activity-modifying protein 2 (RAMP2) and calcitonin receptor-like receptor (CRLR), at feto-maternal tissues in human normotensive pregnant women and pregnancy-induced hypertensive women by Northern blot analysis. Samples of the placenta, uterine muscle, umbilical artery, and fetal membranes were obtained from each patient under informed consent. RAMP2 mRNA significantly decreased in the umbilical artery (54%, P < 0.01) and uterus (53%, P < 0.01) of the patients with PIH. CRLR mRNA also significantly decreased in both tissues of the patients with PIH. On the other hand, the RAMP2 mRNA was significantly increased in the fetal membrane of the patients with PIH. In addition, there was a significant negative correlation between the RAMP2 mRNA levels in the umbilical artery (systolic; r = -0.623, P < 0.01, diastolic; r = -0.552, P < 0.01) and uterine muscle (systolic; r = -0.563, P < 0.01, diastolic; r = -0.553, P< 0.01) and blood pressure. However, there was no correlation between the mRNA level and blood pressure in fetal membrane and placenta, suggesting that there is no close relationship to the pathogenesis in PIH. These findings suggested that the reduced expression of adrenomedullin receptor component in umbilical artery and uterus may have some role in PIH. PMID- 11600590 TI - Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. AB - Ghrelin, a 28 amino acid gastric hormone is a natural ligand of the GH Secretagogue (GHS) receptor (GHS-R) and strongly stimulates GH secretion though, like synthetic GHS, it shows other endocrine and non-endocrine activities. Aim of the present study was to clarify whether ghrelin administration influences insulin and glucose levels in humans. To this goal, we compared the effects of ghrelin, hexarelin, a synthetic GHS, or placebo on insulin and glucose as well as on GH levels in 11 normal young volunteers (age [mean +/- SEM]: 28.5 +/- 3.1 yr; BMI: 22.2 +/- 0.9 Kg/m(2)). Ghrelin induced very marked increase in GH secretion (DeltaAUC(0-180): 5777.1 +/- 812.6 microg/l/h; p < 0.01) which was not modified by placebo. Placebo administration did not modify insulin and glucose levels. On the other hand, ghrelin administration induced a prompt increase in glucose levels (DeltaAUC(0-180): 1343.1 +/- 443.5 mg/dl/h; p < 0.01 vs. saline). Absolute glucose levels at +15' were already higher than those at baseline (93.9 +/- 7.1 mg/dl; p < 0.01) and persisted elevated up to 165' (90.3 +/- 5.8 mg/dl; p < 0.01 vs. 0'). Ghrelin administration was also followed by a decrease in serum insulin levels (DeltaAUC(0-180): -207.1 +/- 70.5 mU/l/h; p < 0.05 vs. saline). Absolute insulin levels were significantly reduced from 30' (11.4 +/- 0.9 mU/l, p < 0.1 vs. 0'), showed the nadir at +45' (10.0 +/- 0.6 mU/l, p < 0.01 vs. 0') and then persisted lower (p < 0.01) than baseline up to +105'. Hexarelin administration did not modify glucose and insulin levels despite its marked GH-releasing effect (DeltaAUC(0-180): 4156.8 +/- 1180.3 microg/l/h; p < 0.01 vs. saline) that was slightly lower (p < 0.05) than that of ghrelin. In conclusion, these findings show that, besides stimulating GH secretion, ghrelin is a gastric hormone possessing metabolic actions such as hyperglycemic effect and lowering effect on insulin secretion in humans, at least after acute administration. PMID- 11600591 TI - What is the significance of IGF-binding protein-3 proteolysis in the circulation? PMID- 11600594 TI - Expression of TR isoforms in failing human heart. PMID- 11600596 TI - Troglitazone use in polycystic ovary syndrome. PMID- 11600598 TI - Comment on "Clinical review 122: Parathyroid carcinoma". PMID- 11600597 TI - Comment on "Editorial: The role of androgens in women". PMID- 11600599 TI - Endocrine-related resources from the National Institutes of Health. PMID- 11600600 TI - Neoadjuvant MVAC: the long and winding road is getting shorter and straighter. PMID- 11600601 TI - Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. AB - PURPOSE: We conducted a phase III trial to investigate the timing of chemotherapy with respect to surgery for patients with resectable but high-risk urothelial cancer. The trial was also designed to evaluate the accuracy of clinical staging in patients with locally advanced cancer and the prognostic significance of chemotherapy-induced downstaging. PATIENTS AND METHODS: A total of 140 uniformly evaluated patients with locally advanced urothelial cancer were studied. Planned treatment was five cycles of chemotherapy (M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin) plus radical cystectomy and pelvic lymph node dissection. Patients were randomly assigned to receive either two courses of neoadjuvant M-VAC followed by surgery plus three additional cycles of chemotherapy, or, alternatively, to have initial cystectomy followed by five cycles of adjuvant chemotherapy. RESULTS: There were no significant differences in outcome between the two groups. By intent-to-treat, 81 patients (58%) remain disease-free, with median follow-up of 6.8 years. We confirmed a high rate of clinical understaging in this cohort, especially among patients showing lymphovascular invasion on biopsy. Patients with no residual muscle-invasive disease at cystectomy after neoadjuvant chemotherapy were likely to be cured. CONCLUSION: These results lend further support to the impression from small randomized trials that, in a high-risk cohort, there is an improved cure fraction by the combination of multiagent chemotherapy and surgery, although we found no preferred sequence. Importantly, it is possible to select appropriate patients for such therapy on the basis of clinical staging information. These results establish a benchmark of outcome for this cohort. PMID- 11600602 TI - Brief-duration high-intensity chemotherapy for patients with small noncleaved cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. AB - PURPOSE: To define the activity and feasibility of brief-duration high-intensity chemotherapy for adults with small noncleaved, non-Hodgkin's lymphoma (SNC) and the L3 variant of acute lymphocytic leukemia (L3 ALL). PATIENTS AND METHODS: Seventy-five adults with either SNC or L3 ALL (median age, 44 years) were treated with an aggressive regimen that consisted of one cycle of cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide; high-dose methotrexate, vincristine, dexamethasone, and either doxorubicin or etoposide/cytarabine; or intrathecal triple therapy with prophylactic CNS irradiation. RESULTS: All 24 patients with L3 ALL and the 30 of 51 patients with SNC confirmed by central histologic review were included in this analysis. Forty three of 54 patients achieved complete response (CR) (18 of 24 with ALL and 25 of 30 with SNC), and 28 are alive and in continuous CR with a median follow-up of 5.1 years. Hematologic toxicity was profound, and nonhematologic toxicity was notable, with 10 of 75 patients treated developing significant neurologic toxicity consisting of transverse myelitis in five patients, CNS toxicity in three, and severe peripheral neuropathy in two. All patients who did not achieve CR died of the disease, and all recurrences occurred within 16 months of the end of treatment. Responses and toxicities were similar in the patients with both lymphoma and leukemia. CONCLUSION: Aggressively delivered chemotherapy is potentially curative in as many as half of patients with SNC and the L3 ALL variant. This treatment regimen had considerable neurologic toxicity and has been modified. PMID- 11600603 TI - Extramedullary involvement at relapse in acute promyelocytic leukemia patients treated or not with all-trans retinoic acid: a report by the Gruppo Italiano Malattie Ematologiche dell'Adulto. AB - PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy. PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell'Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA). RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse. CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone. PMID- 11600604 TI - T1-T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy. AB - PURPOSE: The end results after radiation therapy for T1-T2N0 glottic carcinoma vary considerably. We analyze patient-related and treatment-related parameters that may influence the likelihood of cure. PATIENTS AND METHODS: Five hundred nineteen patients were treated with radiation therapy and had follow-up for >or= 2 years. Three patients who were disease-free were lost to follow-up at 7 months, 21 months, and 10.5 years. No other patients were lost to follow-up. RESULTS: Local control rates at 5 years after radiation therapy were as follows: T1A, 94%; T1B, 93%; T2A, 80%; and T2B, 72%. Multivariate analysis of local control revealed that the following parameters significantly influenced this end point: overall treatment time (P < .0001), T stage (P = .0003), and histologic differentiation (P = .013). Patients with poorly differentiated cancers fared less well than those with better differentiated lesions. Rates of local control with laryngeal preservation at 5 years were as follows: T1A and T1B, 95%; T2A, 82%; and T2B, 76%. Cause-specific survival rates at 5 years were as follows: T1A and T1B, 98%; T2A, 95%; and T2B, 90%. One patient with a T1N0 cancer and three patients with T2N0 lesions experienced severe late radiation complications. CONCLUSION: Radiation therapy cures a high percentage of patients with T1-T2N0 glottic carcinomas and has a low rate of severe complications. The major treatment related parameter that influences the likelihood of cure is overall treatment time. PMID- 11600605 TI - Neurobehavioral status and health-related quality of life in newly diagnosed high grade glioma patients. AB - PURPOSE: To evaluate the health-related quality of life (HRQOL) and cognitive functioning of high-grade glioma patients in the postneurosurgical period. PATIENTS AND METHODS: The HRQOL, as assessed by the Short-Form Health Survey-36, tumor-specific symptoms, and objective and subjective neuropsychologic functioning, of 68 newly diagnosed glioma patients were compared with that of 50 patients with non-small-cell lung cancer (NSCLC) and to age- and sex-matched healthy controls. The association between tumor lateralization, extent of resection, and use of medication, and the HRQOL outcomes was also investigated. RESULTS: The HRQOL of the two patient groups was similar but significantly lower than that of the healthy controls. Glioma patients reported significantly more neurologic symptoms and poorer objective and subjective neuropsychologic functioning than the NSCLC patients. Using healthy controls as the reference group, cognitive impairment assessed at the individual patient level was observed in all glioma patients and 52% of the NSCLC patients. Poor performance on timed tasks in the glioma group could be attributed, in large part, to visual and motor deficits. Tumor lateralization was found to affect neuropsychologic functioning in a predictable manner. The extent of resection was not related significantly to neuropsychologic functioning. Corticosteroid use was associated with better recognition memory, whereas antiepileptic drug use was correlated negatively with working memory capacity. CONCLUSION: The general HRQOL of glioma patients is similar to that of patients with NSCLC. However, they suffer from a number of condition-specific neurologic and neuropsychologic problems that have a significant impact on their daily lives in the postsurgical period, before treatment with radiotherapy. PMID- 11600606 TI - Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. AB - PURPOSE: To evaluate the efficacy of carboplatin plus paclitaxel in primarily advanced or recurrent endometrial cancers. PATIENTS AND METHODS: Four distinct patient groups received carboplatin (area under the curve, 5 to 7) plus paclitaxel 175 mg/m(2) for 3 hours at 4-week intervals: group 1 (n = 21), patients with primarily advanced, nonpapillary serous cancers; group 2 (n = 20), the same as group 1 but with papillary serous cancers; group 3 (n = 18), recurrent, nonpapillary serous cancers; and group 4 (n = 4), recurrent, papillary serous cancers. Involved-field irradiation was used in groups 1 and 2 for those with radioencompassable disease. RESULTS: Sixty-three patients were treated. Response rates to chemotherapy in the assessable patients in the four groups were 78% (95% confidence interval [CI], 51% to 100%); 60% (95% CI, 35% to 85%), 56% (95% CI, 34% to 78%), and 50%, respectively. Nineteen patients (90%) in group 1 also were irradiated, and the median failure-free survival time for all 21 patients was 23 months, with a 62% 3-year overall survival rate. Eleven patients (55%) in group 2 were irradiated, and the median failure-free survival time for all 18 patients was 18 months, with a 39% 3-year overall survival rate. The median failure-free interval in the patients in group 3 was 6 months, with a 15 month median overall survival time. Toxicity was manageable, reversible, and predominantly hematologic. Two patients developed neutropenic fever, and three patients, including these two, were hospitalized for complications. CONCLUSION: Carboplatin-paclitaxel is an efficacious, low-toxicity regimen for managing primarily advanced or recurrent endometrial cancers. PMID- 11600607 TI - Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels. AB - PURPOSE: To determine an accurate definition for progression of ovarian cancer in patients with a persistently elevated serum CA-125. PATIENTS AND METHODS: A retrospective analysis was performed on 300 patients with epithelial ovarian carcinoma with at least one measurement of CA-125. The date of progression according to clinical or radiologic criteria was ascertained in the 88 patients with persistently elevated CA-125 levels (> 23 U/mL). This was compared with the date of progression according to CA-125, defined as the date on which the CA-125 level first increased to >or= twice its nadir level, confirmed by a second sample also >or= twice the nadir. RESULTS: Eighty of the 88 patients had evidence of progression by both standard and CA-125 criteria, giving a sensitivity of 94%. In six of these patients, no sample was taken to confirm CA-125 doubling. In 13 patients, CA-125 doubling occurred after the date of clinical progression. Only one patient had a false-positive prediction of progression according to CA-125; the patient died as a result of a myocardial infarct before evidence of clinical progression. CONCLUSION: In patients whose CA-125 level decreases to normal after chemotherapy, a doubling from the upper limit of normal has been shown to predict progression. In those with persistently elevated levels, doubling of CA-125 from its nadir level has now been shown to accurately define progression. If confirmed, these CA-125 criteria should be used as additional end points in clinical trials. PMID- 11600608 TI - Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group. AB - PURPOSE: To identify which patients with rhabdomyosarcoma and microscopic residual disease (group II) are likely to not respond to therapy. PATIENTS AND METHODS: Six hundred ninety-five patients with group II tumors received chemotherapy and 90% received radiation therapy on Intergroup Rhabdomyosarcoma Study (IRS)-I to IRS-IV (1972 to 1997). Tumors were subgrouped depending on the presence of microscopic residual disease only (subgroup IIa), resected positive regional lymph nodes, (subgroup IIb), or microscopic residual disease and resected positive regional lymph nodes (subgroup IIc). RESULTS: Overall, the 5 year failure-free survival rate (FFSR) was 73%, and patients with embryonal rhabdomyosarcoma treated on IRS-IV fared especially well (5-year FFSR, 93%; n = 90). Five-year FFSRs differed significantly by subgroup (IIa, 75% and n = 506; IIb, 74% and n = 101; IIc, 58% and n = 88; P = .0037) and treatment (IRS-I, 68%; IRS-II, 67%; IRS-III, 75%; IRS-IV, 87%; P < .001). Multivariate analysis revealed positive associations between primary site (favorable), histology (embryonal), subgroup IIa or IIb, treatment (IRS-III/IV), and better FFSRs. Patterns of treatment failure revealed local failure to be 8%, regional failure, 4%, and distant failure, 14%. The relapse pattern noted over the course of IRS-I to IRS IV shows a decrease in the systemic relapse rates, particularly for patients with embryonal histology, suggesting that improvement in FFSRs is primarily a result of improved chemotherapy. CONCLUSION: Group II rhabdomyosarcoma has an excellent prognosis with contemporary therapy as used in IRS-III/IV, and those less likely to respond can be identified using prognostic factors: histology, subgroup, and primary site. Patients with embryonal rhabdomyosarcoma are generally cured, although patients with alveolar rhabdomyosarcoma or undifferentiated sarcoma, particularly subgroup IIc at unfavorable sites, continue to need better therapy. PMID- 11600609 TI - Mechanism-based pharmacokinetic model for paclitaxel. AB - PURPOSE: To create a model based on known mechanisms of paclitaxel distribution that could describe the pharmacokinetics (PK) of total and unbound plasma concentrations, as well as blood concentrations. In addition, to investigate the relationship between exposure, based on unbound and total concentrations, and neutropenia. PATIENTS AND METHODS: Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions. Seven of the patients received combination therapy with doxorubicin or cisplatin. The population PK model was built to fit three types of data simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrophil survival fraction from 19 patients (29 courses in total) to exposure based on unbound and total plasma concentration, respectively. RESULTS: The PK model included a linear three-compartment model for unbound concentration, binding directly proportional to CrEL, linear and nonlinear binding to plasma proteins, and linear and nonlinear binding to blood cells. The threshold model best described the PK/pharmacodynamic (PD) relationship for total concentration. No distinction could be made between the models for unbound drug. CONCLUSION: Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations. PMID- 11600610 TI - MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. AB - PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations. PATIENTS AND METHODS: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives. RESULTS: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant. CONCLUSION: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered. PMID- 11600611 TI - Phase I clinical and pharmacogenetic trial of irinotecan and raltitrexed administered every 21 days to patients with cancer. AB - PURPOSE: Irinotecan and raltitrexed display schedule-dependent synergy in vitro, which supports the clinical investigation of the combination. Functional polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene result in intracellular redistribution of folate derivatives, which may affect raltitrexed associated cytotoxicity. PATIENTS AND METHODS: Patients with a range of solid cancers and good performance status received irinotecan as a 90-minute infusion on day 1 and raltitrexed as a 15-minute infusion on day 2, repeated every 21 days. Samples were collected for MTHFR C677T genotyping and fasting plasma homocysteine during the first cycle. RESULTS: Thirty-nine assessable patients received 127 cycles of therapy. Irinotecan doses ranged from 100 to 350 mg/m(2), and raltitrexed, 1.0 to 4.0 mg/m(2). Raltitrexed doses of more than 3.0 mg/m(2) were not tolerated and were associated with dose-limiting asthenia, diarrhea, and AST/ALT elevation. Irinotecan/raltitrexed doses of 350/3.0 mg/m(2) were well tolerated; principal toxicities included neutropenia, diarrhea, and fatigue. Two partial responses were observed in patients with pretreated gastroesophageal cancers. Homozygotes with the MTHFR 677 TT polymorphism incurred significantly less raltitrexed-associated toxicity than those with either wild-type or heterozygous genotypes (P = .05). No significant differences were noted in plasma homocysteine values between the genotypic subtypes, and plasma homocysteine levels did not predict the risk of toxicity. CONCLUSION: Irinotecan and raltitrexed doses of 350 and 3.0 mg/m(2) are recommended for further study on a day 1, 2 schedule every 21 days. Efficacy results suggest that trials in upper and lower gastrointestinal malignancies are warranted. MTHFR C677T genotypes may be predictive of clinical raltitrexed toxicity. PMID- 11600612 TI - Diagnostic and therapeutic quandaries in a patient with a germ cell tumor. PMID- 11600613 TI - Treatment of inoperable and/or metastatic biliary tree carcinomas with single agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. PMID- 11600614 TI - Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: sobering results. PMID- 11600616 TI - Correction: Meningeal carcinomatosis from breast carcinoma responsive to trastuzumab. PMID- 11600617 TI - Age-related changes and condition-dependent modifications in distribution of limb movements during embryonic motility. AB - It has long been known that the chick initiates spontaneous motility early in embryogenesis, that the distribution of this activity is episodic, and that it varies both quantitatively and qualitatively with age. It is also well established that embryonic motility is controlled by spinal circuits and features of motility at early stages of development are likely the product of immature network properties. Over the course of embryonic development, however, the episodic distribution of motility becomes more variable. Because we are interested in determining whether movement experience in ovo is fundamental to the establishment of adaptive posthatching behaviors, this study examines the normal within-subject variability of episodic activity in embryos across ages under control and several experimental conditions. The distribution of activity, pause, and episode duration was obtained from video recordings of embryos prepared for electromyographic (EMG) and/or kinematic studies of motility in ovo at select ages (E9, E10, E12, E15, E18) under control conditions (control), acute reduction in buoyancy (ARB), ankle restraint (AR), thoracic spinal transection (spinal). Both control and ARB embryos exhibited significant age-related changes in the distribution of motility. Activity duration progressively increased with age and largely accounted for age-related increases in the variability of episodic behavior. Pause duration decreased markedly between E9 and E12 and did not appear to be a critical parameter in accounting for age-related changes in motility distribution. Activity duration was significantly lengthened in ARB embryos and decreased in spinal embryos. Pause duration was selectively lengthened in AR embryos. Collectively, age-related changes and selective effects of experimental preparations suggest that activity and pause duration are controlled by different mechanisms that operate independent of one another by E12. The results also suggest that the spinal network controlling motility becomes increasingly dependent on excitatory drive from supraspinal centers between E9 and E18. It is proposed that age-related increases in activity duration variability and condition-dependent effects on the distribution of activity are indicative of changing inputs weights for descending and sensory pathways and that they significantly impact spinal control of motility as the embryo's movement and posture are increasingly constrained by the fixed volume of the egg. PMID- 11600619 TI - Central positional nystagmus simulated by a mathematical ocular motor model of otolith-dependent modification of Listing's plane. AB - To find an explanation of the mechanisms of central positional nystagmus in neurological patients with posterior fossa lesions, we developed a three dimensional (3-D) mathematical model to simulate head position-dependent changes in eye position control relative to gravity. This required a model implementation of saccadic burst generation, of the neural velocity to eye position integrator, which includes the experimentally demonstrated leakage in the torsional component, and of otolith-dependent neural control of Listing's plane. The validity of the model was first tested by simulating saccadic eye movements in different head positions. Then the model was used to simulate central positional nystagmus in off-vertical head positions. The model simulated lesions of assumed otolith inputs to the burst generator or the neural integrator, both of which resulted in different types of torsional-vertical nystagmus that only occurred during head tilt in roll plane. The model data qualitatively fit clinical observations of central positional nystagmus. Quantitative comparison with patient data were not possible, since no 3-D analyses of eye movements in various head positions have been reported in the literature on patients with positional nystagmus. The present model, prompted by an open clinical question, proposes a new hypothesis about the generation of pathological nystagmus and about neural control of Listing's plane. PMID- 11600618 TI - Model of gamma frequency burst discharge generated by conditional backpropagation. AB - Pyramidal cells of the electrosensory lateral line lobe (ELL) of the weakly electric fish Apteronotus leptorhynchus have been shown to produce oscillatory burst discharge in the gamma-frequency range (20-80 Hz) in response to constant depolarizing stimuli. Previous in vitro studies have shown that these bursts arise through a recurring spike backpropagation from soma to apical dendrites that is conditional on the frequency of action potential discharge ("conditional backpropagation"). Spike bursts are characterized by a progressive decrease in inter-spike intervals (ISIs), and an increase of dendritic spike duration and the amplitude of a somatic depolarizing afterpotential (DAP). The bursts are terminated when a high-frequency somatic spike doublet exceeds the dendritic spike refractory period, preventing spike backpropagation. We present a detailed multi-compartmental model of an ELL basilar pyramidal cell to simulate somatic and dendritic spike discharge and test the conditions necessary to produce a burst output. The model ionic channels are described by modified Hodgkin-Huxley equations and distributed over both soma and dendrites under the constraint of available immunocytochemical and electrophysiological data. The currents modeled are somatic and dendritic sodium and potassium involved in action potential generation, somatic and proximal apical dendritic persistent sodium, and K(V)3.3 and fast transient A-like potassium channels distributed over the entire model cell. The core model produces realistic somatic and dendritic spikes, differential spike refractory periods, and a somatic DAP. However, the core model does not produce oscillatory spike bursts with constant depolarizing stimuli. We find that a cumulative inactivation of potassium channels underlying dendritic spike repolarization is a necessary condition for the model to produce a sustained gamma-frequency burst pattern matching experimental results. This cumulative inactivation accounts for a frequency-dependent broadening of dendritic spikes and results in a conditional failure of backpropagation when the intraburst ISI exceeds dendritic spike refractory period, terminating the burst. These findings implicate ion channels involved in repolarizing dendritic spikes as being central to the process of conditional backpropagation and oscillatory burst discharge in this principal sensory output neuron of the ELL. PMID- 11600620 TI - Reorganization in awake rat auditory cortex by local microstimulation and its effect on frequency-discrimination behavior. AB - In common with other sensory cortices, the mammalian primary auditory cortex (AI) demonstrates the capacity for large-scale reorganization following many experimental situations. For example, training animals in frequency discrimination tasks has been shown to result in an increase in cortical frequency representation. Such central changes-most commonly, an increase in central representation of specific stimulus parameters-have been hypothesized to underlie the improvements in perceptual acuity (perceptual learning) seen in many learning situations. The actual behavioral relevance of central reorganizations, however, remains speculative. Here, we directly examine this issue. We first show that stimulating the AI cortex of the awake rat with a weak electric current (intracortical microstimulation or ICMS) has the effect of inducing central reorganizations similar to those accompanying the traditional plasticity experiments (a result previously noted only in anesthetized preparations). Depending on the site of AI stimulation, ICMS enlarged the cortical representation of certain frequencies. Next we examined the direct perceptual consequences of ICMS-induced AI reorganization for the rat's ability to discriminate frequencies. Over the course of the experiment, we also detailed, and made comparisons between, the frequency-response characteristics of rat AI cortex in the awake and ketamine-anesthetized animal. AI cells that responded to pure tones were divided into two categories--strongly and weakly responsive- based on the strength of their evoked discharge. Individual cells maintained their respective response strengths in both awake and anesthetized conditions. Strongly responsive cells showed at least four different temporal responses and tended to be narrowly tuned. Their responses were stable over the long term. In general frequency-response characteristics were qualitatively similar in the anesthetized and awake animal; bandwidths tended to be broader in awake animals. Although both strong and weak cell populations respond to tones, only the strongly responsive cells fit into a tonotopically organized scheme. By contrast, weakly responsive cells did not exhibit a frequency mapping and may represent a more diffuse input to AI than that underlying strongly responsive cells. In general, the overall frequency organization of AI was found to be equally well expressed in both the awake and anesthetized rat. ICMS reorganization of AI did not alter frequency-discrimination behavior in the rat--either signal detectability or response bias--suggesting that an increase in central representation, by itself, is insufficient to account for perceptual learning. It is likely that cortical reorganizations that accompany perceptual learning are strongly keyed to specific behavioral contexts. PMID- 11600621 TI - Investigation into non-monosynaptic corticospinal excitation of macaque upper limb single motor units. AB - There has been considerable recent debate as to relative importance, in the primate, of propriospinal transmission of corticospinal excitation to upper limb motoneurons. Previous studies in the anesthetized macaque monkey suggested that, compared with the cat, the transmission of such excitation via a system of C3-C4 propriospinal neurons may be relatively weak. However, it is possible that in the anesthetized preparation, propriospinal transmission of cortical inputs to motoneurons may be depressed. To address this issue, the current study investigated the responses of single motor units (SMUs) to corticospinal inputs in either awake (n = 1) or lightly sedated (n = 3) macaque monkeys. Recordings in the awake state were made during performance of a precision grip task. The responses of spontaneously discharging SMUs to electrical stimulation of the pyramidal tract (PT) via chronically implanted electrodes were examined for evidence of non-monosynaptic, presumed propriospinal, effects. Single PT stimuli (up to 250 microA; duration, 0.2 ms, 2 Hz) were delivered during steady discharge of the SMU (10-30 imp/s). SMUs were recorded from muscles acting on the thumb (adductor pollicis and abductor pollicis brevis, n = 18), wrist (extensor carpi radialis, n = 29) and elbow (biceps, n = 9). In all SMUs, the poststimulus time histograms to PT stimulation consisted of a single peak at a fixed latency and with a brief duration [0.74 +/- 0.25 (SD) ms, n = 56], consistent with the responses being mediated by monosynaptic action of cortico-motoneuronal (CM) impulses. Later peaks, indicating non-monosynaptic action, were not present even when the probability of the initial peak response was low and when there was no evidence for suppression of ongoing SMU activity following this peak (n = 20 SMUs). Even when repetitive (double-pulse) PT stimuli were used to facilitate transmission through oligosynaptic linkages, no later peaks were observed (16 SMUs). In some thumb muscle SMUs (n = 8), responses to PT stimulation were compared with those evoked by transcranial magnetic stimulation, using a figure eight coil held over the motor cortex. Responses varied according the orientation of the coil: in the latero-medial position, single peak responses similar to those from the PT were obtained; their latencies confirmed direct excitation of CM cells, and there were no later peaks. In the posterio-anterior orientation, responses had longer latencies and consisted of two to three subpeaks. At least under the conditions that we have tested, the results provide no positive evidence for transmission of cortical excitation to upper limb motoneurons by non monosynaptic pathways in the macaque monkey. PMID- 11600622 TI - Excitatory synaptic currents in lumbosacral parasympathetic preganglionic neurons elicited from the lateral funiculus. AB - Excitatory postsynaptic currents (EPSCs) in parasympathetic preganglionic neurons (PGNs) were examined using the whole cell patch-clamp recording technique in L6 and S1 spinal cord slices from neonatal rats (6-16 days old). PGNs were identified by labeling with retrograde axonal transport of a fluorescent dye (Fast Blue) injected into the intraperitoneal space 3-7 days before the experiment. Synaptic responses were evoked in PGNs by field stimulation of the lateral funiculus (LF) in the presence of bicuculline methiodide (10 microM) and strychnine (1 microM). In approximately 40% of the cells (total, 100), single shock electrical stimulation of the LF elicited short, relatively constant latency [3.0 +/- 0.1 (SE) ms] fast EPSCs consistent with a monosynaptic pathway. The remainder of the cells did not respond to stimulation. At low intensities of stimulation, the EPSCs often occurred in an all-or-none manner, indicating that they were mediated by a single axonal input. Most cells (n = 33) exhibited only fast EPSCs (type 1), but some cells (n = 8) had fast EPSCs with longer, more variable latency polysynaptic EPSCs superimposed on a slow inward current (type 2). Type 1 fast synaptic EPSCs were pharmacologically dissected into two components: a transient component that was blocked by 6-cyano-7-nitroquinoxaline 2,3-dione (CNQX, 5 microM), a non-NMDA glutamatergic antagonist, and a slow decaying component that was blocked by 2-amino-5-phosphonovalerate (APV, 50 microM), a NMDA antagonist. Type 2 polysynaptic currents were reduced by 5 microM CNQX and completely blocked by combined application of 5 microM CNQX and 50 microM APV. The fast monosynaptic component of type 1 EPSCs had a linear current voltage relationship and reversed at a membrane potential of 5.0 +/- 5.9 mV (n = 5), whereas the slow component exhibited a negative slope conductance at holding potentials greater than -20 mV. The type 1, fast synaptic EPSCs had a time to peak of 1.4 +/- 0.1 ms and exhibited a biexponential decay (time constants, 5.7 +/- 0.6 and 38.8 +/- 4.0 ms). In the majority of PGNs (n = 11 of 15 cells), EPSCs evoked by electrical stimulation of LF exhibited paired-pulse inhibition (range; 25-33% depression) at interstimulus intervals ranging from 50 to 120 ms. These results indicate that PGNs receive monosynaptic and polysynaptic glutamatergic excitatory inputs from axons in the lateral funiculus. PMID- 11600623 TI - Horizontal vestibuloocular reflex evoked by high-acceleration rotations in the squirrel monkey. IV. Responses after spectacle-induced adaptation. AB - The horizontal angular vestibuloocular reflex (VOR) evoked by sinusoidal rotations from 0.5 to 15 Hz and acceleration steps up to 3,000 degrees /s(2) to 150 degrees /s was studied in six squirrel monkeys following adaptation with x2.2 magnifying and x0.45 minimizing spectacles. For sinusoidal rotations with peak velocities of 20 degrees /s, there were significant changes in gain at all frequencies; however, the greatest gain changes occurred at the lower frequencies. The frequency- and velocity-dependent gain enhancement seen in normal monkeys was accentuated following adaptation to magnifying spectacles and diminished with adaptation to minimizing spectacles. A differential increase in gain for the steps of acceleration was noted after adaptation to the magnifying spectacles. The gain during the acceleration portion, G(A), of a step of acceleration (3,000 degrees /s(2) to 150 degrees /s) increased from preadaptation values of 1.05 +/- 0.08 to 1.96 +/- 0.16, while the gain during the velocity plateau, G(V), only increased from 0.93 +/- 0.04 to 1.36 +/- 0.08. Polynomial fits to the trajectory of the response during the acceleration step revealed a greater increase in the cubic than the linear term following adaptation with the magnifying lenses. Following adaptation to the minimizing lenses, the value of G(A) decreased to 0.61 +/- 0.08, and the value of G(V) decreased to 0.59 +/- 0.09 for the 3,000 degrees /s(2) steps of acceleration. Polynomial fits to the trajectory of the response during the acceleration step revealed that there was a significantly greater reduction in the cubic term than in the linear term following adaptation with the minimizing lenses. These findings indicate that there is greater modification of the nonlinear as compared with the linear component of the VOR with spectacle-induced adaptation. In addition, the latency to the onset of the adapted response varied with the dynamics of the stimulus. The findings were modeled with a bilateral model of the VOR containing linear and nonlinear pathways that describe the normal behavior and adaptive processes. Adaptation for the linear pathway is described by a transfer function that shows the dependence of adaptation on the frequency of the head movement. The adaptive process for the nonlinear pathway is a gain enhancement element that provides for the accentuated gain with rising head velocity and the increased cubic component of the responses to steps of acceleration. While this model is substantially different from earlier models of VOR adaptation, it accounts for the data in the present experiments and also predicts the findings observed in the earlier studies. PMID- 11600624 TI - Function of NMDA receptors and persistent sodium channels in a feedback pathway of the electrosensory system. AB - Voltage-dependent amplification of ionotropic glutamatergic excitatory postsynaptic potentials (EPSPs) can, in many vertebrate neurons, be due either to the intrinsic voltage dependence of N-methyl-D-aspartate (NMDA) receptors, or voltage-dependent persistent sodium channels expressed on postsynaptic dendrites or somata. In the electrosensory lateral line lobe (ELL) of the gymnotiform fish Apteronotus leptorhynchus, glutamatergic inputs onto pyramidal cell apical dendrites provide a system where both amplification mechanisms are possible. We have now examined the roles for both NMDA receptors and sodium channels in the control of EPSP amplitude at these synapses. An antibody specific for the A. leptorhynchus NR1 subunit reacted strongly with ELL pyramidal cells and were particularly abundant in the spines of pyramidal cell apical dendrites. We have also shown that NMDA receptors contributed strongly to the late phase of EPSPs evoked by stimulation of the feedback fibers terminating on the apical dendritic spines; further, these EPSPs were voltage dependent. Blockade of NMDA receptors did not, however, eliminate the voltage dependence of these EPSPs. Blockade of somatic sodium channels by local somatic ejection of tetrodotoxin (TTX), or inclusion of QX314 (an intracellular sodium channel blocker) in the recording pipette, reduced the evoked EPSPs and completely eliminated their voltage dependence. We therefore conclude that, in the subthreshold range, persistent sodium currents are the main contributor to voltage-dependent boosting of EPSPs, even when they have a large NMDA receptor component. PMID- 11600625 TI - Effect of the group I metabotropic glutamate agonist DHPG on the visual cortex. AB - Metabotropic glutamate receptors have a variety of effects in visual cortex that depend on the age of the animal, the layer of the cortex, and the group of the receptor. Here we describe these effects for group I receptors, using both in vivo and in vitro preparations. The metabotropic group I glutamate receptor agonist 3,5 dihydroxyphenylglycine (DHPG) potentiates the responses to N-methyl-D aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in slices of rat visual cortex. It also increases, initially, the visual response in the cat visual cortex. Both these effects are largest at 3-4 wk of age and decline to insignificance by 10 wk of age. Both are also largest in lower layers of cortex, which explains why the facilitatory effects found with the general metabotropic glutamate agonist 1S,3R aminocyclopentane-1,3-dicarboxylic acid (ACPD) are observed only in lower layers. Prolonged application of DHPG in the cat visual cortex, after the initial excitatory effect, produces depression. We also found that DHPG facilitates the NMDA response in fast-spiking cells, which are inhibitory, providing a partial explanation for this. Thus there are multiple effects of group I metabotropic glutamate receptors, which vary with layer and age in visual cortex. PMID- 11600626 TI - Characterization of the spontaneous synaptic activity of amacrine cells in the mouse retina. AB - Amacrine cells are a heterogeneous class of interneurons that modulate the transfer of the light signals through the retina. In addition to ionotropic glutamate receptors, amacrine cells express two types of inhibitory receptors, GABA(A) receptors (GABA(A)Rs) and glycine receptors (GlyRs). To characterize the functional contribution of these different receptors, spontaneous postsynaptic currents (sPSCs) were recorded with the whole cell configuration of the patch clamp technique in acutely isolated slices of the adult mouse retina. All amacrine cells investigated (n = 47) showed spontaneous synaptic activity. In six amacrine cells, spontaneous excitatory postsynaptic currents could be identified by their sensitivity to kynurenic acid. They were characterized by small amplitudes [mean: -13.7 +/- 1.5 (SE) pA] and rapid decay kinetics (mean tau: 1.35 +/- 0.16 ms). In contrast, the reversal potential of sPSCs characterized by slow decay kinetics (amplitude-weighted time constant, tau(w), >4 ms) was dependent on the intracellular Cl(-) concentration (n = 7), indicating that they were spontaneous inhibitory postsynaptic currents (sIPSCs). In 14 of 34 amacrine cells sIPSCs were blocked by bicuculline (10 microM), indicating that they were mediated by GABA(A)Rs. Only four amacrine cells showed glycinergic sIPSCs that were inhibited by strychnine (1 microM). In one amacrine cell, sIPSCs mediated by GABA(A)Rs and GlyRs were found simultaneously. GABAergic sIPSCs could be subdivided into one group best fit by a monoexponential decay function and another biexponentially decaying group. The mean amplitude of GABAergic sIPSCs ( 42.1 +/- 5.8 pA) was not significantly different from that of glycinergic sIPSCs (-28.0 +/- 8.5 pA). However, GlyRs (mean T10/90: 2.4 +/- 0.08 ms) activated significantly slower than GABA(A)Rs (mean T10/90: 1.2 +/- 0.03 ms). In addition, the decay kinetics of monoexponentially decaying GABA(A)Rs (mean tau(w): 20.3 +/- 0.50), biexponentially decaying GABA(A)Rs (mean tau(w): 30.7 +/- 0.95), and GlyRs (mean tau(w) = 25.3 +/- 1.94) were significantly different. These differences in the activation and decay kinetics of sIPSCs indicate that amacrine cells of the mouse retina express at least three types of functionally different inhibitory receptors: GlyRs and possibly two subtypes of GABA(A)Rs. PMID- 11600627 TI - NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons. AB - We have previously shown that presynaptic N-methyl-D-aspartate receptors (NMDARs) can facilitate glutamate release onto principal neurons in the entorhinal cortex (EC). In the present study, we have investigated the subunit composition of these presynaptic NMDARs. We recorded miniature alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (mEPSCs), from visually identified neurons in layers II and V of the EC in vitro. In both layers, bath application of the NR2A/B subunit-selective agonist, homoquinolinic acid (HQA), resulted in a marked facilitation of mEPSC frequency. Blockade of presynaptic Ca(2+) entry through either NMDARs or voltage-gated Ca(2+) channels with Co(2+) prevented the effects of HQA, confirming that Ca(2+) entry to the terminal was required for facilitation. When the NR2B-selective antagonist, ifenprodil, was applied prior to HQA, the increase in mEPSC frequency was greatly reduced. In addition, we found that an NMDAR antagonist blocked frequency-dependent facilitation of evoked release and reduced mEPSC frequency in layer V. Thus we have demonstrated that NMDA autoreceptors in layer V of the EC bear the NR2B subunit, and that NMDARs are also present at terminals onto superficial neurons. PMID- 11600629 TI - Functional overlap of finger representations in human SI and SII cortices. AB - We aimed to find out to what extent functional representations of different fingers of the two hands overlap at the human primary and secondary somatosensory cortices SI and SII. Somatosensory evoked fields (SEFs) were recorded with a 306 channel neuromagnetometer from 8 subjects. Tactile stimuli, produced by diaphragms driven by compressed air, were delivered to the fingertips in three different conditions. First, the right index finger was stimulated once every 2 s. Then two other stimuli were interspersed, in different sessions, to right- or left-hand fingers (thumb, middle finger, or ring finger) between the successive right index finger stimuli. Strengths of the responses to right index finger stimuli were evaluated in each condition. Responses to right index finger stimuli were modeled by three current dipoles, located at the contralateral SI and the SII cortices of both hemispheres. The earliest SI responses, peaking around 65 ms, were suppressed by 18% (P < 0.05) when the intervening stimuli were presented to the same hand; intervening stimuli to the other hand had no effect. The SII responses were bilaterally suppressed by intervening stimuli presented to either hand: in the left SII, the suppression was 39 and 42% (P < 0.01) and in the right SII 67 and 72% (P < 0.001) during left- and right-sided intervening stimuli, respectively. Left- and right-sided intervening stimuli affected similarly the SII responses and had no effect on the response latencies. The results indicate a strong and symmetric overlap of finger representations for both hands in the human SII cortices, and a weaker functional overlap for fingers of the same hand in the SI cortex. PMID- 11600628 TI - Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms. AB - Zinc and copper are highly concentrated in several mammalian brain regions, including the olfactory bulb and hippocampus. Whole cell electrophysiological recordings were made from rat olfactory bulb neurons in primary culture to compare the effects of zinc and copper on synaptic transmission and voltage-gated ion channels. Application of either zinc or copper eliminated GABA-mediated spontaneous inhibitory postsynaptic potentials. However, in contrast to the similarity of their effects on inhibitory transmission, spontaneous glutamate mediated excitatory synaptic activity was completely blocked by copper but only inhibited by zinc. Among voltage-gated ion channels, zinc or copper inhibited TTX sensitive sodium channels and delayed rectifier-type potassium channels but did not prevent the firing of evoked single action potentials or dramatically alter their kinetics. Zinc and copper had distinct effects on transient A-type potassium currents. Whereas copper only inhibited the A-type current, zinc modulation of A-type currents resulted in either potentiation or inhibition of the current depending on the membrane potential. The effects of zinc and copper on potassium channels likely underlie their effects on repetitive firing in response to long-duration step depolarizations. Copper reduced repetitive firing independent of the initial membrane voltage. In contrast, whereas zinc reduced repetitive firing at membrane potentials associated with zinc-mediated enhancement of the A-type current (-50 mV), in a significant proportion of neurons, zinc increased repetitive firing at membrane potentials associated with zinc-mediated inhibition of the A-type current (-90 mV). Application of zinc or copper also inhibited voltage-gated Ca(2+) channels, suggesting a possible role for presynaptic modulation of neurotransmitter release. Despite similarities between the effects of zinc and copper on some ligand- and voltage-gated ion channels, these data suggest that their net effects likely contribute to differential modulation of neuronal excitability. PMID- 11600630 TI - Forward versus backward walking: transfer of podokinetic adaptation. AB - We asked whether podokinetic adaptation to walking on a circular treadmill transfers to different forms of locomotion. Subjects were blindfolded and asked to walk straight across the floor, in the forward and backward directions, following podokinetic (PK) stimulation that consisted of 30 min of forward walking-in-place on the perimeter of a disk rotating in the clockwise direction. During both forward and backward walking following forward-walking PK stimulation, subjects involuntarily walked along curved trajectories at angular velocities well above vestibular threshold, although they perceived that they were walking along straight paths. The curved paths of forward and backward walking were indistinguishable from one another. Transfer of PK adaptations acquired during forward walking on the turntable to backward walking trials suggests that the PK system controls general locomotor trajectory. Adaptation of the system thus influences forms of locomotion other than that used during acquisition of the adaptation. This transfer also supports the concept that forward and backward walking are controlled by neural networks that share common elements. An interesting feature of the transfer of PK adaptation is that for both forward and backward walking, subjects turned in a counterclockwise direction. As such, the direction of relative rotation between the trunk and feet was maintained for both forward and backward walking. However, the relationship of the lower extremities to the center of rotation was not preserved. The left limb was the inner leg during PK stimulation and forward walking after adaptation, but the left leg was the outer leg during backward walking. These results suggest that PK adaptation affects general locomotor trajectory via a remodeling of the rotational relationship between the trunk and the feet. PMID- 11600631 TI - Voltage-gated sodium channels shape subthreshold EPSPs in layer 5 pyramidal neurons from rat prefrontal cortex. AB - The role of voltage-dependent channels in shaping subthreshold excitatory postsynaptic potentials (EPSPs) in neocortical layer 5 pyramidal neurons from rat medial prefrontal cortex (PFC) was investigated using patch-clamp recordings from visually identified neurons in brain slices. Small-amplitude EPSPs evoked by stimulation of superficial layers were not affected by the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonopentanoic acid but were abolished by the AMPA receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione, suggesting that they were primarily mediated by AMPA receptors. AMPA receptor-mediated EPSPs (AMPA-EPSPs) evoked in the apical dendrites were markedly enhanced, or increased in peak and duration, at depolarized holding potentials. Enhancement of AMPA EPSPs was reduced by loading the cells with lidocaine N-ethylbromide (QX-314) and by local application of the Na(+) channel blocker tetrodotoxin (TTX) to the soma but not to the middle/proximal apical dendrite. In contrast, blockade of Ca(2+) channels by co-application of Cd(2+) and Ni(2+) to the soma or apical dendrite did not affect the AMPA-EPSPs. Like single EPSPs, EPSP trains were shaped by Na(+) but not Ca(2+) channels. EPSPs simulated by injecting synaptic-like current into proximal/middle apical dendrite (simEPSPs) were enhanced at depolarized holding potentials similarly to AMPA-EPSPs. Extensive blockade of Ca(2+) channels by bath application of the Cd(2+) and Ni(2+) mixture had no effects on simEPSPs, whereas bath-applied TTX removed the depolarization-dependent EPSP amplification. Inhibition of K(+) currents by 4-aminopyridine (4-AP) and TEA increased the TTX sensitive EPSP amplification. Moreover, strong inhibition of K(+) currents by high concentrations of 4-AP and TEA revealed a contribution of Ca(2+) channels to EPSPs that, however, seemed to be dependent on Na(+) channel activation. Our results indicate that in layer 5 pyramidal neurons from PFC, Na(+), and K(+) voltage-gated channels shape EPSPs within the voltage range that is subthreshold for somatic action potentials. PMID- 11600632 TI - Grasp with hand and mouth: a kinematic study on healthy subjects. AB - Neurons involved in grasp preparation with hand and mouth were previously recorded in the premotor cortex of monkey. The aim of the present kinematic study was to determine whether a unique planning underlies the act of grasping with hand and mouth in humans as well. In a set of four experiments, healthy subjects reached and grasped with the hand an object of different size while opening the mouth (experiments 1 and 3), or extending the other forearm (experiment 4), or the fingers of the other hand (experiment 5). In a subsequent set of three experiments, subjects grasped an object of different size with the mouth, while opening the fingers of the right hand (experiments 6-8). The initial kinematics of mouth and finger opening, but not of forearm extension, was affected by the size of the grasped object congruently with the size effect on initial grasp kinematics. This effect was due neither to visual presentation of the object, without the successive grasp motor act (experiment 2) nor to synchronism between finger and mouth opening (experiments 3, 7, and 8). In experiment 9 subjects grasped with the right hand an object of different size while pronouncing a syllable printed on the target. Mouth opening and sound production were affected by the grasped object size. The results of the present study are discussed according to the notion that in an action each motor act is prepared before the beginning of the motor sequence. Double grasp preparation can be used for successive motor acts on the same object as, for example, grasping food with the hand and ingesting it after bringing it to the mouth. We speculate that the circuits involved in double grasp preparation might have been the neural substrate where hand motor patterns used as primitive communication signs were transferred to mouth articulation system. This is in accordance with the hypothesis that Broca's area derives phylogenetically from the monkey premotor area where hand movements are controlled. PMID- 11600633 TI - Excess synchrony in motor cortical neurons provides redundant direction information with that from coarse temporal measures. AB - Previous studies have shown that measures of fine temporal correlation, such as synchronous spikes, across responses of motor cortical neurons carries more directional information than that predicted from statistically independent neurons. It is also known, however, that the coarse temporal measures of responses, such as spike count, are not independent. We therefore examined whether the information carried by coincident firing was related to that of coarsely defined spike counts and their correlation. Synchronous spikes were counted in the responses from 94 pairs of simultaneously recorded neurons in primary motor cortex (MI) while monkeys performed arm movement tasks. Direct measurement of the movement-related information indicated that the coincident spikes (1- to 5-ms precision) carry approximately 10% of the information carried by a code of the two spike counts. Inclusion of the numbers of synchronous spikes did not add information to that available from the spike counts and their coarse temporal correlation. To assess the significance of the numbers of coincident spikes, we extended the stochastic spike count matched (SCM) model to include correlations between spike counts of the individual neural responses and slow temporal dependencies within neural responses (approximately 30 Hz bandwidth). The extended SCM model underestimated the numbers of synchronous spikes. Therefore as with previous studies, we found that there were more synchronous spikes in the neural data than could be accounted for by this stochastic model. However, the SCM model accounts for most (R(2) = 0.93 +/- 0.05, mean +/- SE) of the differences in the observed number of synchronous spikes to different directions of arm movement, indicating that synchronous spiking is directly related to spike counts and their broad correlation. Further, this model supports the information theoretic analysis that the synchronous spikes do not provide directional information beyond that available from the firing rates of the same pool of directionally tuned MI neurons. These results show that detection of precisely timed spike patterns above chance levels does not imply that those spike patterns carry information unavailable from coarser population codes but leaves open the possibility that excess synchrony carries other forms of information or serves other roles in cortical information processing not studied here. PMID- 11600634 TI - Neck muscles in the rhesus monkey. I. Muscle morphometry and histochemistry. AB - Morphometric methods were used to describe the musculotendinous lengths, fascicle lengths, pennation angles, and cross-sectional areas of neck muscles in adult Macaca mulatta monkeys. Additionally, muscles were frozen, sectioned, and stained for ATPase activity to determine fiber-type composition. Individual rhesus muscles were found to vary widely in their degree of similarity to feline and human muscles studied previously. Suboccipital muscles and muscles supplied by the spinal accessory nerve were most similar to human homologs, whereas most other muscles exhibited architectural specializations. Many neck muscles were architecturally complex, with multiple attachments and internal aponeuroses or tendinous inscriptions that affected the determination of their cross-sectional areas. All muscles were composed of a mixture of type I, IIa, and IIb fiber types the relative proportions of which varied. Typically, head-turning muscles had lower proportions of type II (fast) fibers than homologous feline muscles, whereas extensor muscles contained higher proportions of type II fibers. The physical and histochemical specializations described here are known to have a direct bearing on functional properties, such as force-developing capacity and fatigue-resistance. These specializations must be recognized if muscles are to be modeled accurately or studied electrophysiologically. PMID- 11600635 TI - Neck muscles in the rhesus monkey. II. Electromyographic patterns of activation underlying postures and movements. AB - Electromyographic (EMG) activity was recorded in < or = 12 neck muscles in four alert monkeys whose heads were unrestrained to describe the spatial and temporal patterns of neck muscle activation accompanying a large range of head postures and movements. Some head postures and movements were elicited by training animals to generate gaze shifts to visual targets. Other spontaneous head movements were made during orienting, tracking, feeding, expressive, and head-shaking behaviors. These latter movements exhibited a wider range of kinematic patterns. Stable postures and small head movements of only a few degrees were associated with activation of a small number of muscles in a reproducible synergy. Additional muscles were recruited for more eccentric postures and larger movements. For head movements during trained gaze shifts, movement amplitude, velocity, and acceleration were correlated linearly and agonist muscles were recruited without antagonist muscles. Complex sequences of reciprocal bursts in agonist and antagonist muscles were observed during very brisk movements. Turning movements of similar amplitudes that began from different initial head positions were associated with systematic variations in the activities of different muscles and in the relative timings of these activities. Unique recruitment synergies were observed during feeding and head-shaking behaviors. Our results emphasize that the recruitment of a given muscle was generally ordered and consistent but that strategies for coordination among various neck muscles were often complex and appeared to depend on the specifics of musculoskeletal architecture, posture, and movement kinematics that differ substantially among species. PMID- 11600636 TI - Change in neuronal firing patterns in the process of motor command generation for the ocular following response. AB - To explore the process of motor command generation for the ocular following response, we recorded the activity of single neurons in the medial superior temporal (MST) area of the cortex, the dorsolateral pontine nucleus (DLPN), and the ventral paraflocculus (VPFL) of the cerebellum of alert monkeys during ocular following elicited by sudden movements of a large-field pattern. Using second order linear-regression models, we analyzed the quantitative relationships between neuronal firing frequency patterns and eye movements or retinal errors specified by three parameters (position, velocity, and acceleration). We first attempted to reconstruct the temporal waveform of each neuronal response to each visual stimulus and computed the coefficients for each parameter using the least square error method for each stimulus condition. The temporal firing patterns were generally well reconstructed [coefficient of determination index (CD) > 0.7] from either the retinal error or the associated ocular following response. In the MST and DLPN datasets, however, the fit with the retinal error model was generally better than with the eye-movement model, and the estimated coefficients of acceleration and velocity ranged widely, indicating that temporal patterns in these regions showed considerable diversity. The acceleration component is greater in MST and DLPN than in VPFL, suggesting that an integration occurs in this pathway. When we determined how well the temporal patterns of the neuronal responses of a given cell could be reconstructed for all visual stimuli using a single set of coefficients, good fits were found only for Purkinje cells (P- cells) in the VPFL using the eye-movement model. In these cases, the coefficients of acceleration and velocity for each cell were similar, and the mean ratio of the acceleration and velocity coefficients was close to that of motor neurons. These results indicate that individual MST and DLPN neurons are each encoding some selective aspects of the sensory stimulus (visual motion), whereas the P cells in VPFL are encoding the complete dynamic command signals for the associated motor response (ocular following). We conclude that the sensory-to motor transformation for the ocular following response occurs at the P-cells in VPFL. PMID- 11600637 TI - Greater movement-related cortical potential during human eccentric versus concentric muscle contractions. AB - Despite abundant evidence that different nervous system control strategies may exist for human concentric and eccentric muscle contractions, no data are available to indicate that the brain signal differs for eccentric versus concentric muscle actions. The purpose of this study was to evaluate electroencephalography (EEG)-derived movement-related cortical potential (MRCP) and to determine whether the level of MRCP-measured cortical activation differs between the two types of muscle activities. Eight healthy subjects performed 50 voluntary eccentric and 50 voluntary concentric elbow flexor contractions against a load equal to 10% body weight. Surface EEG signals from four scalp locations overlying sensorimotor-related cortical areas in the frontal and parietal lobes were measured along with kinetic and kinematic information from the muscle and joint. MRCP was derived from the EEG signals of the eccentric and concentric muscle contractions. Although the elbow flexor muscle activation (EMG) was lower during eccentric than concentric actions, the amplitude of two major MRCP components-one related to movement planning and execution and the other associated with feedback signals from the peripheral systems-was significantly greater for eccentric than for concentric actions. The MRCP onset time for the eccentric task occurred earlier than that for the concentric task. The greater cortical signal for eccentric muscle actions suggests that the brain probably plans and programs eccentric movements differently from concentric muscle tasks. PMID- 11600638 TI - Dorsal root ganglion neurons express multiple nicotinic acetylcholine receptor subtypes. AB - Although nicotinic agonists can modulate sensory transmission, particularly nociceptive signaling, remarkably little is known about the functional expression of nicotinic acetylcholine receptors (nAChRs) on primary sensory neurons. We have utilized molecular and electrophysiological techniques to characterize the functional diversity of nAChR expression on mammalian dorsal root ganglion (DRG) neurons. RT-PCR analysis of subunit mRNA in DRG tissue revealed the presence of nAChR subunits alpha2-7 and beta2-beta4. Using whole cell patch-clamp recording and rapid application of nicotinic agonists, four pharmacologically distinct categories of nicotinic responses were identified in cultured DRG neurons. Capacitance measurements were used to divide neurons into populations of large and small cells, and the prevalence of nicotinic responses was compared between groups. Category I (alpha7-like) responses were seen in 77% of large neurons and 32% of small neurons and were antagonized by 10 nM methyllycaconitine citrate (MLA) or or 50 nM alpha-bungarotoxin (alpha-BTX). Category II (alpha3beta4-like) responses were seen in 16% of large neurons and 9% of small neurons and were antagonized by 20 microM mecamylamine but not 10 nM MLA or 1 microM DHbetaE. Category II responses had a higher sensitivity to cytisine than nicotine. Two other types of responses were identified in a much smaller percentage of neurons and were classified as either category III (alpha4beta2-like) or category IV (subtype unknown) responses. Both the alpha7-like and alpha3beta4-like responses could be desensitized by prolonged applications of the analgesic epibatidine. PMID- 11600639 TI - Spinal NMDA receptors contribute to neuronal processing of acute noxious and nonnoxious colorectal stimulation in the rat. AB - The present study investigated the role of NMDA receptors in the spinal processing of acute noxious and nonnoxious colorectal stimulation using extracellular single-unit recording in the rat. Fifty-three neurons in the L6-S2 dorsal horn of the spinal cord were studied. Neurons were identified using touch and light pinch of the ipsilateral perianal/scrotal area and colorectal distention (CRD). All neurons had excitatory responses to CRD. Thirty neurons were studied using a search stimulus of 80-mmHg CRD. The effects of a systemically administered N-methyl-D-aspartate (NMDA) receptor channel blocker, dizocilpine maleate (MK-801) (0.1, 0.5, 1.0, and 5.0 mg/kg), were tested on the CRD-evoked responses of 13 neurons. The lowest dose had no effect on the neuronal responses to CRD, while greater doses lowered the CRD-evoked responses at all distention pressures tested (20, 40, 60, and 80 mmHg). Similarly, spinal application of MK-801 (20, 50, 100, and 200 nmol) attenuated CRD-evoked activity (n = 9). In addition, a spinally administered competitive NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV) (30, 60, 120, and 240 nmol), dose-dependently attenuated the CRD-evoked response at all distention pressures (n = 5). Systemically administered APV did not affect neuronal responses to CRD (n = 3). Twenty-three neurons were studied in animals that never received distention pressures exceeding 30 mmHg; the search stimulus ranged between 20- and 30-mmHg CRD. These neurons were tested using 20-mmHg CRD. Systemically administered MK-801 facilitated the response to 20-mmHg CRD in three neurons and inhibited the response in five neurons, and the response of five neurons was not affected. Spinally administered MK-801 had no effect on neuronal responses to 20 mmHg CRD in six neurons. However, spinally administered APV dose-dependently decreased the response to 20-mmHg CRD in four neurons. These results are consistent with our previous observations that used Fos expression as the index, suggesting that spinal NMDA receptors contribute to processing of both noxious and nonnoxious CRD. PMID- 11600640 TI - Differences in time course of ACh and GABA modulation of excitatory synaptic potentials in slices of rat hippocampus. AB - Activation of muscarinic receptors and GABA(B) receptors causes presynaptic inhibition of glutamatergic synaptic potentials at excitatory feedback connections in cortical structures. These effects may regulate dynamics in cortical structures, with presynaptic inhibition allowing extrinsic afferent input to dominate during encoding, while the absence of presynaptic inhibition allows stronger excitatory feedback during retrieval or consolidation. However, proposals for a functional role of such modulatory effects strongly depend on the time course of these modulatory effects; how rapidly can they turn off and on? In brain slice preparations of hippocampal region CA1, we have explored the time course of suppression of extracellularly recorded synaptic potentials after pressure pulse application of acetylcholine and GABA. Acetylcholine causes suppression of extracellular potentials with onset time constants between 1 and 2 s, and decay constants ranging between 10 and 20 s, even with very brief injection pulses. GABA causes suppression of extracellular potentials with onset time constants between 0.2 and 0.7 s, and decay time constants that decrease to values shorter than 2 s for very brief injection pulses. These techniques do not give an exact measure of the physiological time course in vivo, but they give a notion of the relative time course of the two modulators. The slow changes due to activation of muscarinic acetylcholine receptors may alter the dynamics of cortical circuits over longer intervals (e.g., between different stages of waking and sleep), setting dynamics appropriate for encoding versus consolidation processes. The faster changes in synaptic potentials caused by GABA could cause changes within each cycle of the theta rhythm, rapidly switching between encoding and retrieval dynamics during exploration. PMID- 11600641 TI - Local correlation-based circuitry can account for responses to multi-grating stimuli in a model of cat V1. AB - In cortical simple cells of cat striate cortex, the response to a visual stimulus of the preferred orientation is partially suppressed by simultaneous presentation of a stimulus at the orthogonal orientation, an effect known as "cross orientation inhibition." It has been argued that this is due to the presence of inhibitory connections between cells tuned for different orientations, but intracellular studies suggest that simple cells receive inhibitory input primarily from cells with similar orientation tuning. Furthermore, response suppression can be elicited by a variety of nonpreferred stimuli at all orientations. Here we study a model circuit that was presented previously to address many aspects of simple cell orientation tuning, which is based on local intracortical connectivity between cells of similar orientation tuning. We show that this model circuit can account for many aspects of cross-orientation inhibition and, more generally, of response suppression by nonpreferred stimuli and of other nonlinear properties of responses to stimulation with multiple gratings. PMID- 11600642 TI - Excitatory postsynaptic potentials trigger a plateau potential in rat subthalamic neurons at hyperpolarized states. AB - The subthalamic nucleus (STN) directly innervates the output structures of the basal ganglia, playing a key role in basal ganglia function. It is therefore important to understand the regulatory mechanisms for the activity of STN neurons. In the present study, we aimed to investigate how the intrinsic membrane properties of STN neurons interact with their synaptic inputs, focusing on their generation and the properties of the long-lasting, plateau potential. Whole cell recordings were obtained from STN neurons in slices prepared from postnatal day 14 (P14) to P20 rats. We found that activation of glutamate receptor-mediated excitatory synaptic potentials (EPSPs) evoked a plateau potential in a subpopulation of STN neurons (n = 13/22), in a voltage-dependent manner. Plateau potentials could be induced only when the cell was hyperpolarized to more negative than about -75 mV. Plateau potentials, evoked with a depolarizing current pulse, again only from a hyperpolarized state, were observed in about half of STN neurons tested (n = 162/327). Only in neurons in which a plateau potential could be evoked by current injection did EPSPs evoke plateau potentials. L-type Ca(2+) channels, Ca(2+)-dependent K(+) channels, and TEA sensitive K(+) channels were found to be involved in the generation of the potential. The stability of the plateau potential, tested by the injection of a negative pulse current during the plateau phase, was found to be robust at the early phase of the potential, but decreased toward the end. As a result the early part of the plateau potential was resistant to membrane potential perturbations and would be able to support a train of action potentials. We conclude that excitatory postsynaptic potentials, evoked in a subpopulation of STN neurons at a hyperpolarized state, activate L-type Ca(2+) and other channels, leading to the generation of a plateau potential. Thus about half of STN neurons can transform short-lasting synaptic excitation into a long train of output spikes by voltage dependent generation of a plateau potential. PMID- 11600644 TI - Aging and learning-specific changes in single-neuron activity in CA1 hippocampus during rabbit trace eyeblink conditioning. AB - Rabbit trace eyeblink conditioning is a hippocampus-dependent task in which the auditory conditioned stimulus (CS) is separated from the corneal airpuff unconditioned stimulus (US) by a 500-ms empty trace interval. Young rabbits are able to associate the CS and US and acquire trace eyeblink conditioned responses (CRs); however, a subset of aged rabbits show poor learning on this task. Several studies have shown that CA1-hippocampal activity is altered by aging; however, it is unknown how aging affects the interaction of CA1 single neurons within local ensembles during learning. The present study examined the extracellular activity of CA1 pyramidal neurons within local ensembles in aged (29-34 mo) and young (3-6 mo) rabbits during 10 daily sessions (80 trials/session) of trace eyeblink conditioning. A single surgically implanted nonmovable stereotrode was used to record ensembles ranging in size from 2 to 12 separated single neurons. A total of six young and four aged rabbits acquired significant levels of CRs, whereas five aged rabbits showed very few CRs similar to a group of five young pseudoconditioned rabbits. Pyramidal cells (2,159 total) were recorded from these four groups during training. Increases in CA1 pyramidal cell firing to the CS and US were diminished in the aged nonlearners. Local ensembles from all groups contained heterogeneous types of pyramidal cell responses. Some cells showed increases while others showed decreases in firing during the trace eyeblink trial. Hierarchical clustering was used to isolate seven different classes of single-neuron responses that showed unique firing patterns during the trace conditioning trial. The proportion of cells in each group was similar for six of seven response classes. Unlike the excitatory modeling patterns reported in previous studies, three of seven response types (67% of recorded cells) exhibited some type of inhibitory decrease to the CS, US, or both. The single-neuron response classes showed different patterns of learning-related activity across training. Several of the single-neuron types from the aged nonlearners showed unique alterations in response magnitude to the CS and US. Cross-correlation analyses suggest that specific single-neuron types provide more correlated single neuron activity to the ensemble processing of information. However, aged nonlearners showed a significantly lower level of coincident pyramidal cell firing for all cell types within local ensembles in CA1. PMID- 11600643 TI - Indirectly gated Cl(-)-dependent Cl(-) channels sense physiological changes of extracellular chloride in the leech. AB - The maintenance of ion homeostasis requires adequate ion sensors. In leeches, 34 nephridial nerve cells (NNCs) monitor the Cl(-) concentration of the blood. After a blood meal, the Cl(-) concentration of leech blood triples and is gradually restored to its normal value within 48 h after feeding. As previously shown in voltage-clamp experiments, the Cl(-) sensitivity of the NNCs relies on a persistent depolarizing Cl(-) current that is turned off by an increase of the extracellular Cl(-) concentration. The activation of this Cl(-)-dependent Cl(-) current is independent of voltage and of extra- and intracellular Ca(2+). The transduction mechanism is now characterized on the single-channel level. The NNC's sensitivity to Cl(-) is mediated by a slowly gating Cl(-)-dependent Cl(-) channel with a mean conductance of 50 pS in the cell-attached configuration. Gating of the Cl(-) channel is independent of voltage, and channel activity is independent of extra- and intracellular Ca(2+). Channel activity and the macroscopic current are reversibly blocked by bumetanide. In outside-out patches, changes of the extracellular Cl(-) concentration do not affect channel activity, indicating that channel gating is not via direct interaction of extracellular Cl( ) with the channel. As shown by recordings in the cell-attached configuration, the activity of the channels under the patch is instead governed by the Cl(-) concentration sensed by the rest of the cell. We postulate a membrane-bound Cl(-) sensing receptor, which-on the increase of the extracellular Cl(-) concentration closes the Cl(-) channel via a yet unidentified signaling pathway. PMID- 11600645 TI - Characterization of reliability of spike timing in spinal interneurons during oscillating inputs. AB - The spike timing in rhythmically active interneurons in the mammalian spinal locomotor network varies from cycle to cycle. We tested the contribution from passive membrane properties to this variable firing pattern, by measuring the reliability of spike timing, P, in interneurons in the isolated neonatal rat spinal cord, using intracellular injection of sinusoidal command currents of different frequencies (0.325-31.25 Hz). P is a measure of the precision of spike timing. In general, P was low at low frequencies and amplitudes (P = 0-0.6; 0 1.875 Hz; 0-30 pA), and high at high frequencies and amplitudes (P = 0.8-1; 3.125 31.25 Hz; 30-200 pA). The exact relationship between P and amplitude was difficult to describe because of the well-known low-pass properties of the membrane, which resulted in amplitude attenuation of high-frequency compared with low-frequency command currents. To formalize the analysis we used a leaky integrate and fire (LIF) model with a noise term added. The LIF model was able to reproduce the experimentally observed properties of P as well as the low-pass properties of the membrane. The LIF model enabled us to use the mathematical theory of nonlinear oscillators to analyze the relationship between amplitude, frequency, and P. This was done by systematically calculating the rotational number, N, defined as the number of spikes divided by the number of periods of the command current, for a large number of frequencies and amplitudes. These calculations led to a phase portrait based on the amplitude of the command current versus the frequency-containing areas [Arnold tongues (ATs)] with the same rotational number. The largest ATs in the phase portrait were those where N was a whole integer, and the largest areas in the ATs were seen for middle to high (>3 Hz) frequencies and middle to high amplitudes (50-120 pA). This corresponded to the amplitude- and frequency-evoked increase in P. The model predicted that P would be high when a cell responded with an integer and constant N. This prediction was confirmed by comparing N and P in real experiments. Fitting the result of the LIF model to the experimental data enabled us to estimate the standard deviation of the internal neuronal noise and to use these data to simulate the relationship between N and P in the model. This simulation demonstrated a good correspondence between the theoretical and experimental values. Our data demonstrate that interneurons can respond with a high reliability of spike timing, but only by combining fast and slow oscillations is it possible to obtain a high reliability of firing during rhythmic locomotor movements. Theoretical analysis of the rotation number provided new insights into the mechanism for obtaining reliable spike timing. PMID- 11600646 TI - Electrophysiological evidence for a chemotopy of biologically relevant odors in the olfactory bulb of the channel catfish. AB - Extracellular electrophysiological recordings from single olfactory bulb (OB) neurons in the channel catfish, Ictalurus punctatus, indicated that the OB is divided into different functional zones, each processing a specific class of biologically relevant odor. Different OB regions responded preferentially at slightly above threshold to either a mixture of 1) bile salts (10(-7) to 10(-5) M Na(+) salts of taurocholic, lithocholic, and taurolithocholic acids), 2) nucleotides [10(-6) to 10(-4) M adenosine-5'-triphosphate (ATP), inosine-5' monophosphate (IMP), and inosine-5'-triphosphate (ITP)], or 3) amino acids (10( 6) to 10(-4)M L-alanine, L-methionine, L-arginine, and L-glutamate). Excitatory responses to bile salts were observed primarily in a thin, medial strip in both the dorsal (100-450 microm) and ventral (900-1,200 microm) OB. Excitatory responses to nucleotides were obtained primarily from dorsal, caudolateral OB, whereas excitatory responses to amino acids occurred more rostrally in the dorsolateral OB, but continued more medially in the ventral OB. The chemotopy within the channel catfish OB is more comparable to that previously described by optical imaging studies in zebrafish than by field potential studies in salmonids. The present results are consistent with recent studies, suggesting that the specific spatial organization of output neurons in the OB is necessary for the quality coding/decoding of olfactory information. PMID- 11600647 TI - Neural and mechanical factors in eye control. AB - Soft tissue "pulleys" in the orbit alter the paths of the eye muscles in a way that may simplify the brain's work in implementing Listing's law, i.e., in holding ocular torsion at zero. But Listing's law does not apply to some oculomotor systems, such as the vestibuloocular reflex (VOR), which shows a different kinematic pattern. To explain this different pattern, some authors have assumed that the pulleys must adopt a different configuration, retracting along their muscles when the eye switches from Listing's law to VOR mode. The proposed retraction has not so far been observed, although the pulleys do move in other ways. We show that the hypothetical retraction of the pulleys would not in fact explain the full kinematic pattern seen in the VOR. But this pattern can be explained entirely on the basis of pulley positions and motions that have actually been observed. If one takes into account the neural processing within the VOR, specifically the fact that the reflex is weak in the torsional dimension, then a single mode of pulley action can serve both vestibuloocular kinematics and Listing's law. PMID- 11600648 TI - Focal synchronization of ripples (80-200 Hz) in neocortex and their neuronal correlates. AB - Field potentials from different neocortical areas and intracellular recordings from areas 5 and 7 in acutely prepared cats under ketamine-xylazine anesthesia and during natural states of vigilance in chronic experiments, revealed the presence of fast oscillations (80-200 Hz), termed ripples. During anesthesia and slow-wave sleep, these oscillations were selectively related to the depth negative (depolarizing) component of the field slow oscillation (0.5-1 Hz) and could be synchronized over ~10 mm. The dependence of ripples on neuronal depolarization was also shown by their increased amplitude in field potentials in parallel with progressively more depolarized values of the membrane potential of neurons. The origin of ripples was intracortical as they were also detected in small isolated slabs from the suprasylvian gyrus. Of all types of electrophysiologically identified neocortical neurons, fast-rhythmic-bursting and fast-spiking cells displayed the highest firing rates during ripples. Although linked with neuronal excitation, ripples also comprised an important inhibitory component. Indeed, when regular-spiking neurons were recorded with chloride filled pipettes, their firing rates increased and their phase relation with ripples was modified. Thus besides excitatory connections, inhibitory processes probably play a major role in the generation of ripples. During natural states of vigilance, ripples were generally more prominent during the depolarizing component of the slow oscillation in slow-wave sleep than during the states of waking and rapid-eye movement (REM) sleep. The mechanisms of generation and synchronization, and the possible functions of neocortical ripples in plasticity processes are discussed. PMID- 11600649 TI - Electrophysiology of interneurons in the glomerular layer of the rat olfactory bulb. AB - In the mammalian olfactory bulb, glomeruli are surrounded by a heterogeneous population of interneurons called juxtaglomerular neurons. As they receive direct input from olfactory receptor neurons and connect with mitral cells, they are involved in the initial stages of olfactory information processing, but little is known about their detailed physiological properties. Using whole cell patch-clamp techniques, we recorded from juxtaglomerular neurons in rat olfactory bulb slices. Based on their response to depolarizing pulses, juxtaglomerular neurons could be divided into two physiological classes: bursting and standard firing. When depolarized, the standard firing neurons exhibited a range of responses: accommodating, nonaccommodating, irregular firing, and delayed to firing patterns of action potentials. Although the firing pattern was not rigorously predictive of a particular neuronal morphology, most short axon cells fired accommodating trains of action potentials, while most delayed to firing cells were external tufted cells. In contrast to the standard firing neurons, bursting neurons produced a calcium-channel-dependent low-threshold spike when depolarized either by current injection or by spontaneous or evoked postsynaptic potentials. Bursting neurons also could oscillate spontaneously. Most bursting cells were either periglomerular cells or external tufted cells. Based on their mode of firing and placement in the bulb circuit, these bursting cells are well situated to drive synchronous oscillations in the olfactory bulb. PMID- 11600650 TI - The motor inhibitory system operating during active sleep is tonically suppressed by GABAergic mechanisms during other states. AB - The present study was undertaken to explore the neuronal mechanisms responsible for muscle atonia that occurs after the microinjection of bicuculline into the nucleus pontis oralis (NPO). Specifically, we wished to test the hypothesis that motoneurons are postsynaptically inhibited after the microinjection of bicuculline into the NPO and determine whether the inhibitory mechanisms are the same as those that are utilized during naturally occurring active (rapid eye movement) sleep. Accordingly, intracellular records were obtained from lumbar motoneurons in cats anesthetized with alpha-chloralose before and during bicuculline-induced motor inhibition. The microinjection of bicuculline into the NPO resulted in a sustained reduction in the amplitude of the spinal cord Ia monosynaptic reflex. In addition, lumbar motoneurons exhibited significant changes in their electrophysiological properties [i.e., a decrease in input resistance and membrane time constant, a reduction in the amplitude of the action potential's afterhyperpolarization (AHP) and an increase in rheobase]. Discrete, large-amplitude inhibitory postsynaptic potentials (IPSPs) were also observed in high-gain recordings from lumbar motoneurons. These potentials were comparable to those that are only present during the state of naturally occurring active sleep. Furthermore, stimulation of the medullary nucleus reticularis gigantocellularis evoked a large-amplitude IPSP in lumbar motoneurons after, but never prior to, the injection of bicuculline; this reflects the pattern of motor responses that occur in conjunction with the phenomenon of "reticular response-reversal." The preceding changes in the electrophysiological properties of motoneurons, as well as the development of active sleep-specific IPSPs, indicate that lumbar motoneurons are postsynaptically inhibited following the intrapontine administration of bicuculline in a manner that is comparable to that which occurs spontaneously during the atonia of active sleep. The present results support the conclusion that the brain stem-spinal cord inhibitory system, which is responsible for motor inhibition during active sleep, can be activated by the injection of bicuculline into the NPO. These data suggest that the active sleep dependent motor inhibitory system is under constant GABAergic inhibitory control, which is centered in the NPO. Thus during wakefulness and quiet sleep, the glycinergically mediated postsynaptic inhibition of motoneurons is prevented from occurring due to GABAergic mechanisms. PMID- 11600651 TI - Neural basis of a perceptual decision in the parietal cortex (area LIP) of the rhesus monkey. AB - We recorded the activity of single neurons in the posterior parietal cortex (area LIP) of two rhesus monkeys while they discriminated the direction of motion in random-dot visual stimuli. The visual task was similar to a motion discrimination task that has been used in previous investigations of motion-sensitive regions of the extrastriate cortex. The monkeys were trained to decide whether the direction of motion was toward one of two choice targets that appeared on either side of the random-dot stimulus. At the end of the trial, the monkeys reported their direction judgment by making an eye movement to the appropriate target. We studied neurons in LIP that exhibited spatially selective persistent activity during delayed saccadic eye movement tasks. These neurons are thought to carry high-level signals appropriate for identifying salient visual targets and for guiding saccadic eye movements. We arranged the motion discrimination task so that one of the choice targets was in the LIP neuron's response field (RF) while the other target was positioned well away from the RF. During motion viewing, neurons in LIP altered their firing rate in a manner that predicted the saccadic eye movement that the monkey would make at the end of the trial. The activity thus predicted the monkey's judgment of motion direction. This predictive activity began early in the motion-viewing period and became increasingly reliable as the monkey viewed the random-dot motion. The neural activity predicted the monkey's direction judgment on both easy and difficult trials (strong and weak motion), whether or not the judgment was correct. In addition, the timing and magnitude of the response was affected by the strength of the motion signal in the stimulus. When the direction of motion was toward the RF, stronger motion led to larger neural responses earlier in the motion-viewing period. When motion was away from the RF, stronger motion led to greater suppression of ongoing activity. Thus the activity of single neurons in area LIP reflects both the direction of an impending gaze shift and the quality of the sensory information that instructs such a response. The time course of the neural response suggests that LIP accumulates sensory signals relevant to the selection of a target for an eye movement. PMID- 11600652 TI - Effects of optic flow in motor cortex and area 7a. AB - Moving visual stimuli were presented to behaving monkeys who fixated their eyes and did not move their arm. The stimuli consisted of random dots moving coherently in eight different kinds of motion (right, left, up, downward, expansion, contraction, clockwise, and counterclockwise) and were presented in 25 square patches on a liquid crystal display projection screen. Neuronal activity in the arm area of the motor cortex and area 7a was significantly influenced by the visual stimulation, as assessed using an ANOVA. The percentage of cells with a statistically significant effect of visual stimulation was 3 times greater in area 7a (370/587, 63%) than in motor cortex (148/693, 21.4%). With respect to stimulus properties, its location and kind of motion had differential effects on cell activity in the two areas. Specifically, the percentage of cells with a significant stimulus location effect was approximately 2.5 times higher in area 7a (311/370, 84%) than in motor cortex (48/148, 32.4%), whereas the percentage of cells with a significant stimulus motion effect was approximately 2 times higher in the motor cortex (79/148, 53.4%) than in area 7a (102/370, 27.6%). We also assessed the selectivity of responses to particular stimulus motions using a Poisson train analysis and determined the percentage of cells that showed activation in only one stimulus condition. This percentage was 2 times higher in the motor cortex (73.7%) than in area 7a (37.7%). Of all kinds of stimulus motion tested, responses to expanding optic flow were the strongest in both cortical areas. Finally, we compared the activation of motor cortical cells during visual stimulation to that observed during force exertion in a center --> out task. Of 514 cells analyzed for both the motor and visual tasks, 388 (75.5%) showed a significant relation to either or both tasks, as follows: 284/388 (73.2%) cells showed a significant relation only to the motor task, 27/388 (7%) cells showed a significant relation only to the visual task, whereas the remaining 77/388 (19.8%) cells showed significant relations to both tasks. Therefore a total of 361/514 (70.2%) cells were related to the motor task and 104/514 (20.2%) were related to the visual task. Finally, with respect to receptive fields (RFs), there was no clear visual receptive field structure in the motor cortical neuronal responses, in contrast to area 7a where RFs were present and could be modulated by the type of optic flow stimulus. PMID- 11600653 TI - Plateau potentials in sacrocaudal motoneurons of chronic spinal rats, recorded in vitro. AB - Intracellular recordings were made from sacrocaudal tail motoneurons of acute and chronic spinal rats to examine whether plateau potentials contribute to spasticity associated with chronic injury. The spinal cord was transected at the S2 level, causing, over time, exaggerated long-lasting reflexes (hyperreflexia) associated with a general spasticity syndrome in the tail muscles of chronic spinal rats (1-5 mo postinjury). The whole sacrocaudal spinal cord of chronic or acute spinal rats was removed and maintained in vitro in normal artificial cerebral spinal fluid (ACSF). Hyperreflexia in chronic spinal rats was verified by recording the long-lasting ventral root responses to dorsal root stimulation in vitro. The intrinsic properties of sacrocaudal motoneurons were studied using intracellular injections of slow triangular current ramps or graded current pulses. In chronic spinal rats, the current injection triggered sustained firing and an associated sustained depolarization (plateau potential; 34/35 cells; mean, 5.5 mV; duration >5 s; normal ACSF). The threshold for plateau initiation was low and usually corresponded to an acceleration in the membrane potential just before recruitment. After recruitment and plateau activation, the firing rate changed linearly with current during the slow ramps [63% of cells had a linear frequency current (F-I) relation] despite the presence of the plateau. The persistent inward current (I(PIC)) producing the plateau and sustained firing was estimated to be on average 0.8 nA as determined by the reduction in injected current needed to stop the sustained firing [DeltaI = -0.8 +/- 0.6 (SD) nA], compared with the current needed to start firing (I = 1.7 +/- 1.5 nA; 47% reduction). In motoneurons of acute spinal rats, plateaus were rarely seen (3/22), although they could be made to occur with bath application of serotonin. In motoneurons of chronic spinal rats there were no significant changes in the mean passive input resistance, rheobase or amplitude of the spike afterhyperpolarization (AHP) as compared with acute spinal rats. However, there were significant increases in AHP duration and initial firing rate at recruitment and decreases in minimum firing rate and F-I slope. We suggest that the higher initial firing rate resulted from the plateau activation at recruitment and the lower F-I slope resulted from an increase in active conductance during firing, due to I(PIC). Brief dorsal root stimulation also triggered a plateau and sustained discharge (long-lasting reflexes; 2-5 s) in motoneurons of chronic (but not acute) spinal rats. When the plateau was eliminated by a hyperpolarizing current bias, the reflex response was significantly shortened (to 1 s). Thus plateaus contributed substantially to the long-lasting reflexes in vitro and therefore should contribute significantly to the corresponding exaggerated reflexes and spasticity in awake chronic spinal rats. PMID- 11600654 TI - Evidence for plateau potentials in tail motoneurons of awake chronic spinal rats with spasticity. AB - Motor units of segmental tail muscles were recorded in awake rats following acute (1-2 days) and chronic (>30 days) sacral spinal cord transection to determine whether plateau potentials contributed to sustained motor-unit discharges after injury. This study was motivated by a companion in vitro study that indicated that after chronic spinal cord injury, the tail motoneurons of the sacrocaudal spinal cord exhibit persistent inward currents (I(PIC)) that cause intrinsically sustained depolarizations (plateau potentials) and firing (self-sustained firing). Importantly, in this companion study, the plateaus were fully activated at recruitment and subsequently helped sustain the firing without causing abrupt nonlinearities in firing. That is, after recruitment and plateau activation, the firing rate was modulated relatively linearly with injected current and therefore provided a good approximation of the input to the motoneuron despite the plateau. Thus in the present study, pairs of motor units were recorded simultaneously from the same muscle, and the firing rate (F) of the lowest-threshold unit (control unit) was used as an estimate of the synaptic input to both units. We then examined whether firing of the higher-threshold unit (test unit) was intrinsically maintained by a plateau, by determining whether more synaptic input was required to recruit the test unit than to maintain its firing. The difference in the estimated synaptic input at recruitment and de-recruitment of the test unit (i.e., change in control unit rate, DeltaF) was taken as an estimate of the plateau current (I(PIC)) that intrinsically sustained the firing. Slowly graded manual skin stimulation was used to recruit and then de-recruit the units. The test unit was recruited when the control unit rate was on average 17.8 and 18.9 Hz in acute and chronic spinal rats, respectively. In chronic spinal rats, the test unit was de-recruited when the control unit rate (re: estimated synaptic input) was significantly reduced, compared with at recruitment (DeltaF = -5.5 Hz), and thus a plateau participated in maintaining the firing. In the lowest threshold motor units, even a brief stimulation triggered very long-lasting firing (seconds to hours; self-sustained firing). Higher-threshold units required continuous stimulation (or a spontaneous spasm) to cause firing, but again more synaptic input was needed to recruit the unit than to maintain its firing (i.e., plateau present). In contrast, in acute spinal rats, the stimulation did not usually trigger sustained motor-unit firing that could be attributed to plateaus because DeltaF was not significantly different from zero. These results indicate that plateaus play an important role in sustaining motor-unit firing in awake chronic spinal rats and thus contribute to the hyperreflexia and hypertonus associated with chronic injury. PMID- 11600655 TI - Synchronization of neuronal activity in the human primary motor cortex by transcranial magnetic stimulation: an EEG study. AB - Using multichannel electroencephalography (EEG), we investigated temporal dynamics of the cortical response to transcranial magnetic stimulation (TMS). TMS was applied over the left primary motor cortex (M1) of healthy volunteers, intermixing single suprathreshold pulses with pairs of sub- and suprathreshold pulses and simultaneously recording EEG from 60 scalp electrodes. Averaging of EEG data time locked to the onset of TMS pulses yielded a waveform consisting of a positive peak (30 ms after the pulse P30), followed by two negative peaks [at 45 (N45) and 100 ms]. Peak-to-peak amplitude of the P30-N45 waveform was high, ranging from 12 to 70 microV; in most subjects, the N45 potential could be identified in single EEG traces. Spectral analysis revealed that single-pulse TMS induced a brief period of synchronized activity in the beta range (15-30 Hz) in the vicinity of the stimulation site; again, this oscillatory response was apparent not only in the EEG averages but also in single traces. Both the N45 and the oscillatory response were lower in amplitude in the 12-ms (but not 3-ms) paired-pulse trials, compared with the single-pulse trials. These findings are consistent with the possibility that TMS applied to M1 induces transient synchronization of spontaneous activity of cortical neurons within the 15- to 30 Hz frequency range. As such, they corroborate previous studies of cortical oscillations in the motor cortex and point to the potential of the combined TMS/EEG approach for further investigations of cortical rhythms in the human brain. PMID- 11600656 TI - Distinguishing subregions of the human MT+ complex using visual fields and pursuit eye movements. AB - In humans, functional imaging studies have demonstrated a homologue of the macaque motion complex, MT+ [suggested to contain both middle temporal (MT) and medial superior temporal (MST)], in the ascending limb of the inferior temporal sulcus. In the macaque monkey, motion-sensitive areas MT and MST are adjacent in the superior temporal sulcus. Electrophysiological research has demonstrated that while MT receptive fields primarily encode the contralateral visual field, MST dorsal (MSTd) receptive fields extend well into the ipsilateral visual field. Additionally, macaque MST has been shown to receive extraretinal smooth-pursuit eye-movement signals, whereas MT does not. We used functional magnetic resonance imaging (fMRI) and the neural properties that had been observed in monkeys to distinguish putative human areas MT from MST. Optic flow stimuli placed in the full field, or contralateral field only, produced a large cluster of functional activation in our subjects consistent with previous reports of human area MT+. Ipsilateral optic flow stimuli limited to the peripheral retina produced activation only in an anterior subsection of the MT+ complex, likely corresponding to putative MSTd. During visual pursuit of a single target, a large portion of the MT+ complex was activated. However, during nonvisual pursuit, only the anterolateral portion of the MT+ complex was activated. This subsection of the MT+ cluster could correspond to putative MSTl (lateral). In summary, we observed three distinct subregions of the human MT+ complex that were arranged in a manner similar to that seen in the monkey. PMID- 11600657 TI - Responses to task-irrelevant visual features by primate prefrontal neurons. AB - The primate brain is equipped with prefrontal circuits for interpreting visual information, but how these circuits deal with competing stimulus-response (S-R) associations remains unknown. Here we show different types of responses to task irrelevant visual features in three functionally dissociated groups of primate prefrontal neurons. Two Japanese macaques participated in a go/no-go task in which they had to discriminate either the color or the motion direction of a visual target to make a correct manual response. Prior to the experiment, the monkeys had been trained extensively so that they acquired fixed associations between visual features and required responses (e.g., "green = go"; "downward motion = no-go"). In this design, the monkey was confronted with a visual target from which it had to extract relevant information (e.g., color in the color discrimination condition) while ignoring irrelevant information (e.g., motion direction in the color-discrimination condition). We recorded from 436 task related prefrontal neurons while the monkey performed the multidimensional go/no go task: 139 (32%) neurons showed go/no-go discrimination based on color as well as motion direction ("integration cells"); 192 neurons (44%) showed go/no-go discrimination only based on color ("color-feature cells"); and 105 neurons (24%) showed go/no-go discrimination only based on motion direction ("motion-feature cells"). Overall, however, 162 neurons (37%) were influenced by irrelevant information: 53 neurons (38%) among integration cells, 71 neurons (37%) among color-feature cells, and 38 neurons (36%) among motion-feature cells. Across all types of neurons, the response to an irrelevant feature was positively correlated with the response to the same feature when it was relevant, indicating that the influence from irrelevant information is a residual from S-R associations that are relevant in a different context. Temporal and anatomical differences among integration, color-feature and motion-feature cells suggested a sequential mode of information processing in prefrontal cortex, with integration cells situated toward the output of the decision-making process. In these cells, the response to irrelevant information appears as a congruency effect, with better go/no-go discrimination when both the relevant and irrelevant feature are associated with the same response than when they are associated with different responses. This congruency effect could be the result of the combined input from color- and motion-feature cells. Thus these data suggest that irrelevant features lead to partial activation of neurons even toward the output of the decision-making process in primate prefrontal cortex. PMID- 11600658 TI - Surround suppression in primate V1. AB - We investigated the spatial organization of surround suppression in primate primary visual cortex (V1). We utilized drifting stimuli, configured to extend either from within the classical receptive field (CRF) to surrounding visual space, or from surrounding visual space into the CRF or subdivided to generate direction contrast, to make a detailed examination of the strength, spatial organization, direction dependence, mechanisms, and laminar distribution of surround suppression. Most cells (99/105, 94%) through all cortical layers, exhibited suppression (mean reduction 67%) to uniform stimuli exceeding the CRF, and 43% exhibited a more than 70% reduction. Testing with an annulus revealed two different patterns of surround influence. Some cells (37% of cells), classical surround suppression (CSS) cells exhibited responses to an annulus encroaching on the CRF that were less than the plateau in the spatial summation curve. The majority (63%), center-gated surround suppression (CGSS) cells, showed responses to annuli that equaled or exceeded the plateau in the spatial summation curve. Analysis suggested the CSS mechanism was implemented in all cells while the CGSS mechanism was implemented in varying strength across the sample with the extreme reflected in cells that gave larger responses to annuli than to a center stimulus. Reversing the direction of motion of the portion of the stimulus surrounding the CRF revealed four different patterns of effect: no reduction in the degree of suppression (22% of cells), a reduction in surround suppression (41%), a facilitation of the response above the level to the inner stimulus alone (37%), and a facilitation of the response above that to the inner stimulus alone that also exceeded the values associated with an optimal inner stimulus. The facilitatory effects were only seen for reverse direction interfaces between the central and surrounding stimulus at diameters equal to or more than the CRF size. The zones driving the suppressive influences and the direction contrast facilitation were often spatially heterogeneous and for a number of cells bore strong comparison with the class of behavior reported for surround mechanisms in MT. This suggests a potential role, for example, in extracting information about motion contrast in the representation of the three dimensional structure of moving objects. PMID- 11600660 TI - Prefrontal cortical representation of visuospatial working memory in monkeys examined by local inactivation with muscimol. AB - In primates, dorsolateral areas of the prefrontal cortex (PFC) play a major role in visuospatial working memory. To examine the functional organization of the PFC for representing visuospatial working memory, we produced reversible local inactivation, with the local injection of muscimol (5 microg, 1 microl), at various sites (n = 100) in the dorsolateral PFC of monkeys and observed the behavioral consequences in an oculomotor delayed-response task that required memory-guided saccades for locations throughout both visual fields. At 82 sites, the local injection of muscimol induced deficits in memory-guided saccades to a few specific, usually contralateral, target locations that varied with the location of the injection site. Such deficits depended on the delay length, and longer delays were associated with larger deficits in memory-guided saccades. The injection sites and affected spatial locations of the target showed a gross topographical relationship. No deficits appeared for a control task in which the subject was required to make a visually guided saccade to a visible target. These findings suggest that a specific site in the dorsolateral PFC is responsible for the working memory process for a specific visuospatial coordinate to guide goal directed behavior. Further, memoranda for specific visuospatial coordinates appear to be represented in a topographical memory map within the dorsolateral PFC to represent visuospatial working memory processes. PMID- 11600659 TI - A comparison of the firing properties of putative excitatory and inhibitory neurons from CA1 and the entorhinal cortex. AB - The superficial layers of the entorhinal cortex (EC) provide the majority of the neocortical input to the hippocampus, and the deep layers of the EC receive the majority of neocortically bound hippocampal outputs. To characterize information transmission through the hippocampal and EC circuitry, we recorded simultaneously from neurons in the superficial EC, the CA1 region of hippocampus, and the deep EC while rodents ran for food reward in two environments. Spike waveform analysis allowed us to classify units as fast-spiking (FS) putative inhibitory cells or putative excitatory (PE) cells. PE and FS units' firing were often strongly correlated at short time scales, suggesting the presence a monosynaptic connection from the PE to FS units. EC PE units, unlike those found in CA1, showed little or no tendency to fire in bursts. We also found that the firing of FS and PE units from all regions was modulated by the approximately 8 Hz theta rhythm, although the firing of deep EC FS units tended to be less strongly modulated than that of the other types of units. When we examined the spatial specificity of FS units, we determined that FS units in all three regions showed low specificity. At the same time, retrospective coding, in which firing rates were related to past position, was present in FS units from all three regions and deep EC FS units often fired in a "path equivalent" manner in that they were active in physically different, but behaviorally related positions both within and across environments. Our results suggest that while the firing of FS units from CA1 and the EC show similarly low levels of position specificity, FS units from each region differ from one another in that they mirrored the associated PE units in terms of their tendency to show more complex positional firing properties like retrospective coding and path equivalence. PMID- 11600661 TI - Human cortical activity correlates with stereoscopic depth perception. AB - Stereoscopic depth perception is based on binocular disparities. Although neurons in primary visual cortex (V1) are selective for binocular disparity, their responses do not explicitly code perceived depth. The stereoscopic pathway must therefore include additional processing beyond V1. We used functional magnetic resonance imaging (fMRI) to examine stereo processing in V1 and other areas of visual cortex. We created stereoscopic stimuli that portrayed two planes of dots in depth, placed symmetrically about the plane of fixation, or else asymmetrically with both planes either nearer or farther than fixation. The interplane disparity was varied parametrically to determine the stereoacuity threshold (the smallest detectable disparity) and the upper depth limit (largest detectable disparity). fMRI was then used to quantify cortical activity across the entire range of detectable interplane disparities. Measured cortical activity covaried with psychophysical measures of stereoscopic depth perception. Activity increased as the interplane disparity increased above the stereoacuity threshold and dropped as interplane disparity approached the upper depth limit. From the fMRI data and an assumption that V1 encodes absolute retinal disparity, we predicted that the mean response of V1 neurons should be a bimodal function of disparity. A post hoc analysis of electrophysiological recordings of single neurons in macaques revealed that, although the average firing rate was a bimodal function of disparity (as predicted), the precise shape of the function cannot fully explain the fMRI data. Although there was widespread activity within the extrastriate cortex (consistent with electrophysiological recordings of single neurons), area V3A showed remarkable sensitivity to stereoscopic stimuli, suggesting that neurons in V3A may play a special role in the stereo pathway. PMID- 11600662 TI - Neural correlates for roughness choice in monkey second somatosensory cortex (SII). AB - This experiment explored the relationship between neural firing patterns in second somatosensory cortex (SII) and decisions about roughness of tactile gratings. Neural and behavioral data were acquired while monkeys made dichotomous roughness classifications of pairs of gratings that differed in groove width (1.07 vs. 1.90 and 1.42 vs. 2.53 mm). A computer-controlled device delivered the gratings to a single immobilized finger pad. In one set of experiments, three levels of contact force (30, 60, and 90 g) were assigned to these gratings at random. In another set of experiments, three levels of scanning speed (40, 80, and 120 mm/s) were assigned to these gratings at random. Groove width was the intended variable for roughness. Force variation disrupted the monkeys' groove width (roughness) classifications more than did speed variation. A sample of 32 SII cells showed correlated changes in firing (positive or negative effects of both variables) when groove width and force increased. While these cells were recorded, the monkeys made roughness classification errors, confusing wide groove width gratings at low force with narrow groove-width gratings at high force. Three-dimensional plots show how some combinations of groove width and force perturbed the monkeys' trial-wise classifications of grating roughness. Psychometric functions show that errors occurred when firing rates failed to distinguish gratings. A possible interpretation is that when asked to classify grating roughness, the monkeys based classifications on the firing rates of a subset of roughness-sensitive cells in SII. Results support human psychophysical data and extend the roughness range of a model of the effects of groove width and force on roughness. One monkey's SII neural sample (21 cells) showed significant correlation between firing rate response functions for groove width and speed (both correlations either positive or negative). Only that monkey showed a statistically significant interaction between groove width and speed on roughness classification performance. This additional finding adds weight to the argument that SII cell firing rates influenced monkey roughness classifications. PMID- 11600663 TI - Transplants of NGF-secreting fibroblasts restore stimulus-evoked activity in barrel cortex of basal-forebrain-lesioned rats. AB - Cholinergic nuclei in the basal forebrain supply the cerebral cortex with acetylcholine (ACh). Depletion of cholinergic fibers following basal forebrain lesion results in reduced stimulus-evoked functional activity in rat barrel cortex in response to whisker stimulation. We showed previously that exogenous delivery of nerve growth factor (NGF) to the lateral ventricle restores reduced functional activity toward normal despite persistent reductions in cortical cholinergic activity. Gene transfer of therapeutic peptides using genetically engineered cells allows for localized and biological delivery of compounds to the CNS, circumventing systemic administration or repetitive invasive surgery. In this study, we grafted genetically engineered fibroblasts that secrete NGF (NGF+) into three CNS loci of rats with unilateral basal forebrain lesions, along with control fibroblasts (NGF-) that did not secrete NGF. Only NGF+ fibroblasts grafted into ACh-depleted somatosensory cortex resulted in improvement of functional activity following cholinergic depletion. NGF+ fibroblast transplants into the lateral ventricle or basal forebrain did not improve functional activity nor did NGF- fibroblasts in any site. Similar to our previous experiments using intraventricular NGF injections, despite improvements in functional activity, the affected barrel cortex remained depleted of acetylcholinesterase-stained fibers following insertion of NGF+ fibroblasts. These data support the idea that NGF can act directly on the cerebral cortex following reductions in cholinergic innervation. The mechanism of NGF action is elusive, however, since the presence of its high-affinity receptor, trkA, in the cerebral cortex is controversial. PMID- 11600664 TI - Wavelets of excitability in sensory neurons. AB - We have investigated variations in the excitability of mammalian cutaneous mechanoreceptor neurons. We focused on the phase dynamics of an action potential relative to a periodic stimulus, showing that the excitability of these sensory neurons has interesting nonstationary oscillations. Using a wavelet analysis, these oscillations were characterized through the depiction of their period as a function of time. It was determined that the induced oscillations are weakly dependent on the stimulus frequency, and that lower temperatures significantly reduce the frequency of the phase response. Our results reveal novel excitability properties in sensory neurons, and, more generally, could prove significant in the deduction of mechanistic attributes underlying the nonstationary excitability in neuronal systems. Since peripheral neurons feed information to the CNS, variable responses observed in higher regions may be generated in part at the site of sensory detection. PMID- 11600665 TI - Neural activity in primary motor cortex related to mechanical loads applied to the shoulder and elbow during a postural task. AB - Whole-arm motor tasks performed by nonhuman primates have become a popular paradigm to examine neural activity during motor action, but such studies have traditionally related cell discharge to hand-based variables. We have developed a new robotic device that allows the mechanics of the shoulder and elbow joints to be manipulated independently. This device was used in the present study to examine neural activity in primary motor cortex (MI) in monkeys (Macaca mulatta) actively maintaining their hand at a central target as they compensated for loads applied to the shoulder and/or elbow. Roughly equal numbers of neurons were sensitive to mechanical loads only at the shoulder, only at the elbow, or loads at both joints. Neurons possessed two important properties. First, cell activity during multi-joint loads could be predicted from its activity during single-joint loads as a vector sum in a space defined by orthogonal axes for the shoulder and elbow. Second, most neurons were related to flexor torque at one joint coupled with extensor torque at the other, a distribution that paralleled the observed activity of forelimb muscles. These results illustrate that while MI activity may be described by independent axes representing each mechanical degree-of-freedom, neural activity is also strongly influenced by the specific motor patterns used to perform a given task. PMID- 11600666 TI - Asymmetric propagation of spreading depression along the anteroposterior axis of the cerebral cortex in mice. AB - The purpose of this study was to ascertain whether or not spreading depression (CSD) propagates symmetrically along the anteroposterior axis of the cortex of mice, and to determine where CSD should be elicited to achieve a uniform exposure of the cortex to this phenomenon. Experiments were performed in halothane anesthetized mice, with three different locations aligned 1.5 mm from the midline used for either KCl elicitation of CSD or the recording of its propagation. Our results demonstrated that, at least in the mouse cortex, CSD propagated much more effectively from posterior to anterior regions than in the opposite direction. This feature was due to a different efficacy of propagation in the two opposite directions, and not to a reduced susceptibility of occipital regions to CSD elicitation. Heterogeneous CSD propagation constitutes a potential pitfall for neurochemical studies of post-CSD changes in mice, as brain tissue samples collected for this purpose should be uniformly exposed to CSD. Occipital sites for CSD induction are clearly optimal for this purpose. If CSD propagation is confirmed to be more effective from posterior to anterior regions in other species, this may be relevant to the pathophysiology of classical migraine because the most frequent aura symptoms (i.e., visual disturbances) originate in the occipital cortex. PMID- 11600667 TI - Implications of ocular kinematics for the internal updating of visual space. AB - Recent studies have suggested that during saccades cortical and subcortical representations of visual targets are represented and remapped in retinal coordinates. If this is correct, then the remapping processes must incorporate the noncommutativity of rotations. For example, our three-dimensional (3-D) simulations of the commutative vector-subtraction model of retinocentric remapping predicted centripetal errors in saccade trajectories between "remembered" eccentric targets, whereas our noncommutative model predicted accurate saccades. We tested between these two models in five head-fixed human subjects. Typically, a central fixation light appeared and two peripheral targets were flashed. With all targets extinguished, subjects were required to saccade to the remembered location of one of the peripheral targets and saccade between their remembered locations. Subjects showed minor misestimations of the spatial locations of targets, but failed to show the cumulative pattern of errors predicted by the commutative model. This experiment indicates that if targets are remapped in a retinal frame, then the remapping process also takes the noncommutativity of 3-D eye rotations into account. Unlike other noncommutative aspects of eye rotations that may have mechanical explanations, the noncommutative aspects of this process must be entirely internal. PMID- 11600668 TI - Neural readaptation to Earth's gravity following return from space. AB - The consequence of exposure to microgravity on the otolith organs was studied by recording the responses of vestibular nerve afferents supplying the utricular otolith organ to inertial accelerations in four toadfish, Opsanus tau, sequentially for 5 days following two National Aeronautics and Space Administration shuttle orbital flights. Within the first day postflight, the magnitude of response to an applied translation was on average three times greater than for controls. The reduced gravitational acceleration in orbit apparently resulted in an upregulation of the sensitivity of utricular afferents. By 30 h postflight, responses were statistically similar to control. The time course of return to normal afferent sensitivity parallels the reported decrease in vestibular disorientation in astronauts following return from space. PMID- 11600670 TI - Calcium signalling through nucleotide receptor P2X1 in rat portal vein myocytes. AB - 1. ATP-mediated Ca2+ signalling was studied in freshly isolated rat portal vein myocytes by means of a laser confocal microscope and the patch-clamp technique. 2. In vascular myocytes held at -60 mV, ATP induced a large inward current that was supported mainly by activation of P2X1 receptors, although other P2X receptor subtypes (P2X3, P2X4 and P2X5) were revealed by reverse transcription-polymerase chain reaction. 3. Confocal Ca2+ measurements revealed that ATP-mediated Ca2+ responses started at initiation sites where spontaneous or triggered Ca2+ sparks were not detected, whereas membrane depolarizations triggered Ca2+ waves by repetitive activation of Ca2+ sparks from a single initiation site. 4. ATP mediated Ca2+ responses depended on Ca2+ influx through non-selective cation channels that activated, in turn, Ca2+ release from the intracellular store via ryanodine receptors (RYRs). Using specific antibodies directed against the RYR subtypes, we show that ATP-mediated Ca2+ release requires, at least, RYR2, but not RYR3. 5. Our results suggest that, in vascular myocytes, Ca2+ influx through P2X1 receptors may trigger Ca2+-induced Ca2+ release at intracellular sites where RYRs are not clustered. PMID- 11600669 TI - Muscle-derived interleukin-6: possible biological effects. AB - Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the increase in plasma IL-6 during exercise. The production of IL-6 during exercise is related to the intensity and duration of the exercise, and low muscle glycogen content stimulates the production. Muscle-derived IL-6 is released into the circulation during exercise in high amounts and is likely to work in a hormone-like fashion, exerting an effect on the liver and adipose tissue, thereby contributing to the maintenance of glucose homeostasis during exercise and mediating exercise-induced lipolysis. Muscle-derived IL-6 may also work to inhibit the effects of pro-inflammatory cytokines such as tumour necrosis factor alpha. The latter cytokine is produced by adipose tissue and inflammatory cells and appears to play a pathogenetic role in insulin resistance and atherogenesis. PMID- 11600671 TI - Calcium waves induced by hypertonic solutions in intact frog skeletal muscle fibres. AB - 1. Regenerative Ca2+ waves and oscillations indicative of calcium-induced calcium release (CICR) activity were induced in fully polarized, fluo-3-loaded, intact frog skeletal muscle fibres by exposure to hypertonic Ringer solutions. 2. The calcium waves persisted in fibres exposed to EGTA-containing solutions, during sustained depolarization of the membrane potential or following treatment with the dihydropyridine receptor (DHPR)-blocker nifedipine. 3. The waves were blocked by the ryanodine receptor (RyR)-specific agents ryanodine and tetracaine, and potentiated by caffeine. 4. In addition to these pharmacological properties, the amplitudes, frequency and velocity of such hypertonicity-induced waves closely resembled those of Ca2+ waves previously described in dyspedic skeletal myocytes expressing the cardiac RyR-2. 5. Quantitative transmission and freeze-fracture electronmicroscopy demonstrated a reversible cell shrinkage, transverse (T) tubular luminal swelling and decreased T-sarcoplasmic reticular (SR) junctional gaps in fibres maintained in and then fixed using hypertonic solutions. 6. The findings are consistent with a hypothesis in which RyR-Ca2+ release channels can be partially liberated from their normal control by T-tubular DHPR-voltage sensors in hypertonic solutions, thereby permitting CICR to operate even in such fully polarized skeletal muscle fibres. PMID- 11600672 TI - Attenuation of G protein-mediated inhibition of N-type calcium currents by expression of caveolins in mammalian NG108-15 cells. AB - 1. Caveolins are integral proteins of glycolipid/cholesterol-rich plasmalemmal caveolae domains, where, they may function as a plasma membrane scaffold onto which many classes of signalling molecules, including receptors and heterotrimeric G proteins, can assemble. To ascertain whether caveolins influence G protein-mediated signal transduction, we stably expressed caveolin-1 and -3 isoforms in the neuroblastoma x glioma NG108-15 hybrid cell line, lacking endogenous caveolins. Subsequently, using whole-cell voltage clamp methods, we examined whether the modulation of N-type voltage-gated Ca2+ channels by G(o) protein-coupled, delta-type opioid receptors might be affected by recombinant caveolin expression. 2. In transfected NG108-15 cells, caveolins localized at the plasma membrane and, upon subcellular fractionation on sucrose density gradients, they co-localized in Triton-resistant, low buoyancy fractions, with endogenous G(o) protein alpha-subunits. 3. The voltage-dependent inhibition of omega conotoxin GVIA-sensitive Ba2+ currents following either activation of delta opioid receptors by the agonist [o-pen2,o-pen5]-enkephalin (DPDPE), or direct stimulation of G proteins with guanosine 5'-O-(thiotriphosphate) (GTPgammaS) was significantly attenuated in caveolin-expressing cells. The kinetics of Ca2+ channel inhibition were also modified by caveolins. 4. Overall, these results suggest that caveolins may negatively affect G protein-dependent regulation of voltage-gated N-type Ca2+ channels, presumably by causing a reduction of the available pool of activated G proteins. PMID- 11600673 TI - cAMP-regulated guanine nucleotide exchange factor II (Epac2) mediates Ca2+ induced Ca2+ release in INS-1 pancreatic beta-cells. AB - 1. The signal transduction pathway responsible for cAMP-dependent Ca2+-induced Ca2+ release (CICR) from endoplasmic reticulum Ca2+ stores was assessed in the insulin-secreting cell line INS-1. 2. CICR was triggered by the GLP-1 receptor agonist exendin-4, an effect mimicked by caffeine, Sp-cAMPS or forskolin. CICR required influx of Ca2+ through L-type voltage-dependent Ca2+ channels, and was blocked by treatment with nimodipine, thapsigargin, or ryanodine, but not by the IP3 receptor antagonist xestospongin C. 3. Treatment with the cAMP antagonist 8 Br-Rp-cAMPS blocked CICR in response to exendin-4, whereas the PKA inhibitor H-89 was ineffective when tested at a concentration demonstrated to inhibit PKA dependent gene expression. 4. RT-PCR of INS-1 cells demonstrated expression of mRNA coding for the type-II isoform of cAMP-regulated guanine nucleotide exchange factor (cAMP-GEF-II, Epac2). 5. CICR in response to forskolin was blocked by transient transfection and expression of a dominant negative mutant isoform of cAMP-GEF-II in which inactivating mutations were introduced into the exchange factor's two cAMP-binding domains. 6. It is concluded that CICR in INS-1 cells results from GLP-1 receptor-mediated sensitization of the intracellular Ca2+ release mechanism, a signal transduction pathway independent of PKA, but which requires cAMP-GEF-II. PMID- 11600675 TI - Small-conductance calcium-activated potassium currents in mouse hyperexcitable denervated skeletal muscle. AB - 1. Hyperexcitability in denervated skeletal muscle is associated with the expression of SK3, a small-conductance Ca2+-activated K+ channel (SK channel). SK currents were examined in dissociated fibres from flexor digitorum brevis (FDB) muscle using the whole-cell patch clamp configuration. 2. Depolarization activated a K+-selective, apamin-sensitive and iberiotoxin-insensitive current, detected as a tail current upon repolarization, in fibres from denervated but not innervated muscle. Dialysis of the fibres with 20 mM EGTA in the patch pipette solution eliminated the tail current, consistent with this current reflecting Ca2+-activated SK channels expressed only in denervated muscle. 3. Activation of SK tail currents depended on the duration of the depolarizing pulse, consistent with a rise in intracellular Ca2+ due to release from the sarcoplasmic reticulum (SR) and influx through voltage-gated Ca2+ channels. 4. The envelope of SK tail currents was diminished by 10 microM ryanodine for all pulse durations, whereas 2 mM cobalt reduced the SK tail current for pulses greater than 80 ms, demonstrating that Ca2+ release from the SR during short pulses primarily activated SK channels. 5. In current clamp mode with the resting membrane potential set at -70 mV, denervation decreased the action potential threshold by approximately 8 mV. Application of apamin increased the action potential threshold in denervated fibres to that measured in innervated fibres, suggesting that SK channel activity modulates the apparent action potential threshold. 6. These results are consistent with a model in which SK channel activity in the T tubules of denervated skeletal muscle causes a local increase in K+ concentration that results in hyperexcitability. PMID- 11600674 TI - Mitochondria regulate inactivation of L-type Ca2+ channels in rat heart. AB - 1. L-type Ca2+ channels play an important role in vital cell functions such as muscle contraction and hormone secretion. Both a voltage-dependent and a Ca2+ dependent process inactivate these channels. Here we present evidence that inhibition of the mitochondrial Ca2+ import mechanism in rat (Sprague-Dawley) ventricular myocytes by ruthenium red (RR), by Ru360 or by carbonyl cyanide m chlorophenylhydrazone (CCCP) decreases the magnitude of electrically evoked transient elevations of cytosolic Ca2+ concentration ([Ca2+]c). These agents were most effective at stimulus rates greater than 1 Hz. 2. RR and CCCP also caused a significant delay in the recovery from inactivation of L-type Ca2+ currents (I(Ca)). This suggests that sequestration of cytosolic Ca2+, probably near the mouth of L-type Ca2+ channels, into mitochondria during cardiac contractile cycles, helps to remove the Ca2+-dependent inactivation of L-type Ca2+ channels. 3. We conclude that impairment of mitochondrial Ca2+ transport has no impact on either L-type Ca2+ currents or SR Ca2+ release at low stimulation frequencies (e.g. 0.1 Hz); however, it causes a depression of cytosolic Ca2+ transients attributable to an impaired recovery of L-type Ca2+ currents from inactivation at high stimulation frequencies (e.g. 3 Hz). The impairment of mitochondrial Ca2+ uptake and subsequent effects on Ca2+ transients at high frequencies at room temperature could be physiologically relevant since the normal heart rate of rat is around 5 Hz at body temperature. The role of mitochondria in clearing Ca2+ in the micro-domain near L-type Ca2+ channels could be impaired during high frequencies of heart beats such as in ventricular tachycardia, explaining, at least in part, the reduction of muscle contractility. PMID- 11600676 TI - The effect of external divalent cations on spontaneous non-selective cation channel currents in rabbit portal vein myocytes. AB - 1. The effects of external divalent cations on spontaneous single non-selective cation channel currents were studied in outside-out patches from rabbit portal vein smooth muscle cells in K+-free conditions. 2. In an external medium containing 1.5 mM Ca2+ (Ca2+o) the majority of spontaneous channel currents had a unitary conductance of 23 pS, reversal potential (Vr) of +10 mV and a low open probability (Po) at negative patch potentials. Some channels opened to a lower conductance state of about 13 pS suggesting that the cation channels have two conductance states. Open time and burst duration distributions could both be described by two exponentials with time constants of about of 1 ms and 7 ms for open times and 3 ms and 16 ms for burst durations. 3. In 0 Ca2+o the majority of spontaneous cation channels had a unitary conductance of 13 pS and Vr was shifted to +4 mV. Moreover the longer open time and longer burst duration time constants were both reduced to approximately half the values in 1.5 mM Ca2+o. 4. Compared to 0 Ca2+o the single channel currents in 3 microM and 100 microM Ca2+o had a 5- to 6-fold increase in Po which was accompanied by increases in both open times and burst durations. In 3 microM and 100 microM Ca2+o the unitary conductance of the single channel currents was between 22 and 26 pS. 5. At positive membrane potentials the single channel currents had an increased Po compared to negative potentials which was associated with increased open times and burst durations but these values were similar in 3 microM, 100 microM and 1.5 mM Ca2+o. 6. In 1.5 mM Sr2+o and 1.5 mM Ba2+o channels opened to the higher conductance state of about 22-25 pS and had a 3- to 7-fold greater Po than in 0 Ca2+o. 7. In conclusion, external divalent cations have marked effects on the unitary conductance and kinetic behaviour of non-selective cation channels in rabbit portal vein smooth muscle cells. PMID- 11600677 TI - Evidence for involvement of A-kinase anchoring protein in activation of rat arterial K(ATP) channels by protein kinase A. AB - 1. We have investigated the possible role of A-kinase anchoring proteins (AKAPs) in protein kinase A (PKA) signalling to ATP-sensitive K+ (K(ATP)) channels of rat isolated mesenteric arterial smooth muscle cells using whole-cell patch clamp and peptides that inhibit PKA-AKAP binding. 2. Intracellular Ht31 peptide (20 microM), which inhibits the PKA-AKAP interaction, blocked K(ATP) current activation by either dibutyryl cAMP or calcitonin gene-related peptide. Ht31 proline (20 microM), which does not inhibit PKA binding to AKAP, did not block K(ATP) current activation. 3. Ht31 reduced K(ATP) current activated by pinacidil and also prevented its inhibition by Rp-cAMPS, effects consistent with Ht31 blocking steady-state K(ATP) channel activation by PKA. However, Ht31 did not prevent K(ATP) current activation by the catalytic subunit of PKA. 4. An antibody to the RII subunit of PKA showed localization of PKA near to the cell membrane. Our results provide evidence that both steady-state and receptor-driven activation of K(ATP) channels by PKA involve the localization of PKA by an AKAP. PMID- 11600678 TI - GABA-mediated Ca2+ signalling in developing rat cerebellar Purkinje neurones. AB - 1. Cellular responses to GABA(A) receptor activation were studied in developing cerebellar Purkinje neurones (PNs) in brain slices obtained from 2- to 22-day-old rats. Two-photon fluorescence imaging of fura-2-loaded cells and perforated-patch recordings were used to monitor intracellular Ca2+ transients and to estimate the reversal potential of GABA-induced currents, respectively. 2. During the 1st postnatal week, focal application of GABA or the GABA(A) receptor agonist muscimol evoked transient increases in [Ca2+]i in immature PNs. These Ca2+ transients were reversibly abolished by the GABA(A) receptor antagonist bicuculline and by Ni2+, a blocker of voltage-activated Ca2+ channels. 3. Perforated-patch recordings were used to measure the reversal potential of GABA evoked currents (E(GABA)) at different stages of development. It was found that E(GABA) was about -44 mV at postnatal day 3 (P3), it shifted to gradually more negative values during the 1st week and finally equilibrated at -87 mV at around the end of the 2nd postnatal week. This transition was well described by a sigmoidal function. The largest change in E(GABA) was -7 mV x day(-1), which occurred at around P6. 4. The transition in GABA-mediated signalling occurs during a period in which striking changes in PN morphology and synaptic connectivity are known to take place. Since such changes were shown to be Ca2+ dependent, we propose that GABA-evoked Ca2+ signalling is one of the critical determinants for the normal development of cerebellar PNs. PMID- 11600679 TI - Gradient of sodium current across the left ventricular wall of adult rat hearts. AB - 1. Gradients of ion channels across the left ventricular (LV) wall have been well characterized and it has been shown that disruption of such gradients leads to altered rates of repolarization across the wall, which is associated with the generation of arrhythmias. 2. We have hypothesized that a transmural gradient of I(Na) is present and have directly measured this current in adult rat myocytes isolated from both the epicardial and endocardial layers of the left ventricle. Currents were also recorded in right ventricular (RV) myocytes for comparison. 3. Peak inward I(Na) currents, at -30 mV, were -49.7 +/- 2.5 pA pF(-1) (n = 22), 32.9 +/- 3.2 pA pF(-1) (n = 16) and -49.7 +/- 3.7 pA pF(-1) (n = 24) for RV, LV epicardial and LV endocardial myocytes, respectively. No differences in the voltage dependence of inactivation, the voltage dependence of steady-state inactivation, or reactivation were reported. 4. Our results demonstrate that a gradient of sodium current density is present across the LV wall of adult rat hearts. PMID- 11600680 TI - Sodium currents in vagotomized primary afferent neurones of the rat. AB - 1. Nodose ganglion neurones (NGNs) become less excitable following section of the vagus nerve. To determine the role of sodium currents (I(Na)) in these changes, standard patch-clamp recording techniques were used to measure I(Na) in rat NGNs maintained in vivo for 5-6 days following vagotomy, and then in vitro for 2-9 h. 2. Total I(Na) and I(Na) density in vagotomized NGNs were similar to control values. However, steady-state I(Na) inactivation in vagotomized NGNs was shifted 9 mV relative to control values (V(1/2), -74 +/- 2 vs. -65 +/- 2 mV, P < 0.01) and I(Na) activation was shifted by -7 mV (V(1/2), -21 +/- 2 vs. -14 +/- 2 mV, P < 0.006). I(Na) recovery from inactivation was also slower in vagotomized NGNs (fast time constant, 2.8 +/- 0.4 vs. 1.6 +/- 0.3 ms, P < 0.02). 3. The fraction of I(Na) resistant to 1 microM tetrodotoxin (TTX-R) was halved in vagotomized NGNs (21 +/- 8 vs. 56 +/- 8 % of total I(Na), P < 0.05). This change from TTX-R I(Na) to TTX-sensitive (TTX-S) I(Na) may explain altered I(Na) activation, inactivation and repriming in vagotomized NGNs. 4. The contribution of alterations in I(Na) to NGN firing patterns was assessed by measuring I(Na) evoked by a series of action potential (AP) waveforms. In general, control NGNs produced large, repetitive TTX-R I(Na) while vagotomized NGNs produced smaller TTX-S I(Na) that rapidly inactivated during AP discharge. We conclude that TTX-R I(Na) is important for sustained AP discharge in NGNs, and that its diminution underlies the decreased AP discharge of vagotomized NGNs. PMID- 11600681 TI - A cluster of negative charges at the amino terminal tail of CFTR regulates ATP dependent channel gating. AB - 1. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is activated by protein kinase A (PKA) phosphorylation of its R domain and by ATP binding at its nucleotide-binding domains (NBDs). Here we investigated the functional role of a cluster of acidic residues in the amino terminal tail (N tail) that also modulate CFTR channel gating by an unknown mechanism. 2. A disease-associated mutant that lacks one of these acidic residues (D58N CFTR) exhibited lower macroscopic currents in Xenopus oocytes and faster deactivation following washout of a cAMP -activating cocktail than wild-type CFTR. 3. In excised membrane patches D58N CFTR exhibited a two-fold reduction in single channel open probability due primarily to shortened open channel bursts. 4. Replacing this and two nearby acidic residues with alanines (D47A, E54A, D58A) also reduced channel activity, but had negligible effects on bulk PKA phosphorylation or on the ATP dependence of channel activation. 5. Conversely, the N-tail triple mutant exhibited a markedly inhibited response to AMP-PNP, a poorly hydrolysable ATP analogue that can nearly lock open the wild-type channel. The N-tail mutant had both a slower response to AMP-PNP (activation half-time of 140 +/- 20 s vs. 21 +/- 4 s for wild type) and a lower steady-state open probability following AMP-PNP addition (0.68 +/- 0.08 vs. 0.92 +/- 0.03 for wild type). 6. Introducing the N-tail mutations into K1250A CFTR, an NBD2 hydrolysis mutant that normally exhibits very long open channel bursts, destabilized the activity of this mutant as evidenced by decreased macroscopic currents and shortened open channel bursts. 7. We propose that this cluster of acidic residues modulates the stability of CFTR channel openings at a step that is downstream of ATP binding and upstream of ATP hydrolysis, probably at NBD2. PMID- 11600682 TI - Positive allosteric modulation by ultraviolet irradiation on GABA(A), but not GABA(C), receptors expressed in Xenopus oocytes. AB - 1. Recombinant rat GABA(A) (alpha1beta2, alpha1beta2gamma2, beta2gamma2) and human GABA(C) (rho1) receptors were expressed in Xenopus oocytes to examine the effect of ultraviolet (UV) light on receptor function. 2. GABA-induced currents in individual oocytes expressing GABA receptors were tested by two-electrode voltage clamp before, and immediately after, 312 nm UV irradiation. 3. UV irradiation significantly potentiated 10 microM GABA-induced currents in alpha1beta2gamma2 GABA receptors. The modulation was irradiation dose dependent, with a maximum potentiation of more than 3-fold. 4. The potentiation was partially reversible and decayed exponentially with a time constant of 8.2 +/- 1.2 min toward a steady-state level which was still significantly elevated (2.7 +/- 0.3-fold) compared to the control level. 5. The effect of UV irradiation on GABA(A) receptors varied with receptor subunit composition. UV irradiation decreased the EC50 of the alpha1beta2, alpha1beta2gamma2 and beta2gamma2 GABA(A) receptors, but exhibited no significant effect on the rho1 GABA(C) receptor. 6. UV irradiation also significantly increased the maximum current 2-fold in alpha1beta2 GABA(A) receptors with little effect on the maximum of alpha1beta2gamma2 (1.1-fold) or beta2gamma2 (1.1-fold) GABA(A) receptors. 7. The effect of UV irradiation on GABA(A) receptors did not overlap the effect of the GABA receptor- allosteric modulator, diazepam. 8. The UV effect on GABA(A) receptors was not prevented by the treatment of the oocytes before and during UV irradiation with one of the following free-radical scavengers: 40 mM D-mannitol, 40 mM imidazole or 40 mM sodium azide. In addition, the effect was not mimicked by the free-radical generator, H2O2. 9. Potential significance and mechanism(s) of the UV effect on GABA receptors are discussed. PMID- 11600684 TI - Bidirectional electrogenic transport of peptides by the proton-coupled carrier PEPT1 in Xenopus laevis oocytes: its asymmetry and symmetry. AB - 1. The giant patch clamp technique in the inside-out configuration and the two electrode voltage clamp technique were used to characterize the bidirectional transport properties of the proton-coupled peptide carrier PEPT1 expressed in Xenopus laevis oocytes. 2. The addition of the neutral dipeptide Gly-L-Gln to the cytoplasmic solution induced a net outward transport current in a membrane potential range between -80 and +60 mV, even in the absence of a pH gradient. 3. The concentration dependency of the outwardly directed transport currents followed Michaelis-Menten-type kinetics, with an apparent K0.5 of 3.28 mM (at pH 7.5 and +60 mV membrane potential). This apparent affinity is around fivefold lower than the apparent affinity measured for the inward transport mode (K0.5 of 0.70 mM (at pH 7.5 and -60 mV) under identical experimental conditions). 4. Apparent K0.5 values were strongly pH and potential dependent only on the external face for inward transport. The transport currents were potential dependent, but essentially pH independent for inward transport and only modestly altered by pH in the reverse direction. In addition to the membrane potential, the transmembrane substrate gradient acts as a driving force and contributes significantly to total transport currents. 5. The differences in apparent substrate affinity under identical experimental conditions suggest major differences in the conformation of the substrate binding pocket of PEPT1 when exposed to the external versus the internal face of the membrane. The lower affinity on the internal face allows the substrate to be released into the cytosolic compartment even in the absence of a proton-motive force. 6. Our study demonstrates for the first time that PEPT1 can transport dipeptides bidirectionally in an electrogenic and proton-coupled symport mode. When substrates are present on both sides of the membrane in sufficiently high concentrations, the direction and rate of transport are solely dependent on the membrane potential, and transport occurs symmetrically. PMID- 11600683 TI - Mutation K448E in the external loop 5 of rat GABA transporter rGAT1 induces pH sensitivity and alters substrate interactions. AB - 1. The effect of the mutation K448E in the rat GABA transporter rGAT1 was studied using heterologous expression in Xenopus oocytes and voltage clamp. 2. At neutral pH, the transport-associated current vs. voltage (I-V) relationship of the mutated transporter was different from wild-type, and the pre-steady-state currents were shifted towards more positive potentials. The mutated transporter showed an increased apparent affinity for Na+ (e.g. 62 vs. 152 mM at -60 mV), while the opposite was true for GABA (e.g. 20 vs. 13 microM at -60 mV). 3. In both isoforms changes in [Na+]o shifted the voltage dependence of the pre-steady state and of the transport-associated currents by similar amounts. 4. In the K448E form, the moved charge and the relaxation time constant were shifted by increasing pH towards positive potentials. The transport-associated current of the mutated transporter was strongly reduced by alkalinization, while acidification slightly decreased and distorted the shape of the I-V curve. Accordingly, uptake of [3H]GABA was strongly reduced in K448E at pH 9.0. The GABA apparent affinity of the mutated transporter was reduced by alkalinization, while acidification had the opposite result. 5. These observations suggest that protonation of negatively charged residues may regulate the Na+ concentration in the proximity of the transporter. Calculation of the unidirectional rate constants for charge movement shows that, in the K448E form, the inward rate constant is increased at alkaline pH, while the outward rate constant does not change, in agreement with an effect due to mass action law. 6. A possible explanation for the complex effect of pH on the transport-associated current may be found by combining changes in local [Na+]o with a direct action of pH on GABA concentration or affinity. Our results support the idea that the extracellular loop 5 may participate to form a vestibule to which sodium ions must have access before proceeding to the steps involving charge movement. PMID- 11600685 TI - Developmental changes in P2X purinoceptors on glycinergic presynaptic nerve terminals projecting to rat substantia gelatinosa neurones. AB - 1. In mechanically dissociated rat spinal cord substantia gelatinosa (SG) neurones attached with native presynaptic nerve endings, glycinergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded using nystatin perforated patch recording mode under voltage-clamp conditions. Under these conditions, it was tested whether the changes in P2X receptor subtype on the glycinergic presynaptic nerve terminals occur during postnatal development. 2. ATP facilitated glycinergic mIPSC frequency in a concentration-dependent manner through all developmental stages tested, whereas alphabeta-methylene-ATP (alphabeta-me-ATP) was only effective at later developmental stages. 3. alphabeta me-ATP-elicited mIPSC frequency facilitation was completely occluded in the Ca2+ free external solution, but it was not affected by adding 10(-4) M Cd2+. 4. alphabeta-me-ATP still facilitated mIPSC frequency even in the presence of 10(-6) M thapsigargin, a Ca2+ pump blocker. 5. In later developmental stages, ATP elicited presynaptic or postsynaptic responses were reversibly blocked by 10(-5) M pyridoxal-5-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), but only partially blocked by 10(-7) M 2',3'-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP). However, alphabeta-me-ATP-elicited presynaptic or postsynaptic responses were completely and reversibly blocked by either 10(-5) M PPADS or 10(-7) M TNP-ATP. 6. alphabeta-me-ATP significantly reduced the evoked glycinergic IPSC amplitude in postnatal 28-30 day neurones, whereas it had no effect in 10-12 day neurones. 7. It was concluded that alphabeta-me-ATP-sensitive P2X receptors were functionally expressed on the glycinergic presynaptic nerve terminals projecting to SG neurones in later developmental stages. Such developmental changes of presynaptic P2X receptor subtypes might contribute to synaptic plasticity such as the regulation of neuronal excitability and the fine controlling of the pain signal in spinal dorsal horn neurones. PMID- 11600687 TI - Drainage of plasma proteins from the renal medullary interstitium in rats. AB - 1. Lymph vessels are scarce or lacking in the renal inner medulla, raising the question of whether plasma proteins entering the medullary interstitium are removed by diffusion through the interstitium to lymphatics in the outer medulla or cortex, or by convection into the vasa recta. 2. Using micropipettes, we infused 125I-albumin into the papilla of anaesthetized rats and watched its disappearance from the injection site as well as the uptake in the thoracic duct and plasma. 3. Tracer infused into the renal cortex appeared almost immediately in the thoracic duct lymph, and rose to a sevenfold higher concentration than in plasma, whereas tracer infused into the papilla appeared first and increased more sharply in plasma than in the lymph. No spread from the papillary injection site was observed. Tracer injected in renal hilar lymphatics was quantitatively recovered in the thoracic duct. 4. The plasma concentration pattern following papillary infusion was similar to that obtained by intravenous injection, indicating uptake in blood and subsequent distribution to extracellular fluid and lymph from all organs. 5. We conclude that plasma proteins normally diffusing out from the vasa recta are brought back through water flux (1) from the collecting ducts due to the high sodium chloride concentration in the papillary interstitium and (2) from the interstitium into the vasa recta driven by plasma protein osmotic pressure. Accordingly, there is no need for lymph vessels in the inner medulla. PMID- 11600686 TI - Neuronal mechanisms of the anoxia-induced network oscillations in the rat hippocampus in vitro. AB - 1. A spindle of fast network oscillations precedes the ischaemia-induced rapid depolarisation in the rat hippocampus in vivo. However, this oscillatory pattern could not be reproduced in slices and the underlying mechanisms remain poorly understood. We have found that anoxia-induced network oscillations (ANOs, 20-40 Hz, lasting for 1-2 min) can be reproduced in the intact hippocampi of postnatal day P7-10 rats in vitro, and we have examined the underlying mechanisms using whole-cell and extracellular field potential recordings in a CA3 pyramidal layer. 2. ANOs were generated at the beginning of the anoxic depolarisation, when pyramidal cells depolarised to subthreshold values. Maximal power of the ANOs was attained when pyramidal cells depolarised to -56 mV; depolarisation above -47 mV resulted in a depolarisation block of pyramidal cells and a waning of ANOs. 3. A multiple unit activity in extracellular field recordings was phase locked to the negative and ascending phases of ANOs. Pyramidal cells recorded in current-clamp mode generated action potentials with an average probability of about 0.05 per cycle. The AMPA receptor-mediated EPSCs and the GABA receptor-mediated IPSCs in CA3 pyramidal cells were also phase locked with ANOs. 4. ANOs were prevented by tetrodotoxin and glutamate receptor antagonists CNQX and APV, and were slowed down by the allosteric GABA(A) receptor modulator diazepam. In the presence of the GABA(A) receptor antagonist bicuculline, ANOs were transformed to epileptiform discharges. 5. In the presence of the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the anoxia induced an epileptiform activity and no ANOs were observed. 6. In normoxic conditions, a rise of extracellular potassium to 10 mM induced an epileptiform activity. Increasing extracellular potassium in conjunction with a bath application of the adenosine A1 receptor agonist cyclopentyladenosine induced oscillations similar to ANOs. 7. Multisite recordings along the septo-temporal hippocampal axis revealed that ANOs and anoxic depolarisation originate in the temporal part, and propagate towards the septal pole at a speed of 1.9 mm x min(-1). 8. ANOs were observed starting from P7, i.e. at a developmental stage when the effects of GABA change from depolarisation to hyperpolarisation. 9. These results suggest that the synchronisation of anoxia-induced oscillations relies on synaptic mechanisms; that the inhibition by GABA and adenosine sets the tune for a generation of oscillations and prevents an epileptiform activity; and that a synchronous GABAergic inhibition is instrumental in a phase locking neuronal activity similarly to other types of oscillatory activities in the gamma frequency range. PMID- 11600688 TI - Evidence of amiloride-sensitive fluid absorption in rat descending colonic crypts from fluorescence recovery of FITC-labelled dextran after photobleaching. AB - 1. Fluorescence recovery after photobleaching (FRAP) of fluorescein isothiocyanate (FITC)-labelled 10 and 250 kDa dextran (FITC dextran) in isolated rat descending colonic crypts was measured at 35 degrees C using laser scanning confocal microscopy. 2. FRAP of either 10 or 250 kDa FITC dextran in crypt lumens was almost complete within 2-3 min. 3. In the presence of amiloride (0.1 mM), or in the absence of Na+, the rate of FITC dextran uptake into the crypt lumens was reduced by 70-80 %. 4. The rate of fluid uptake into the crypt lumen, as estimated from the rate of total FITC dextran uptake into the crypt lumen and its adjacent pericryptal region after FRAP, was between 1.3 x 10(-3) and 1.7 x 10(-3) cm x s(-1). 5. Convective flow during FRAP was also determined from the initial rate of FITC dextran advance along the crypt lumen. This effect was almost completely blocked by amiloride (0.1 mM). 6. The permeability of 10 kDa FITC dextran across the descending colonic crypt wall was found to be higher than that of 250 kDa FITC dextran (3.7 (+/- 0.6) x 10(-5) and 1.8 (+/- 0.3) x 10(-6) cm x s(-1), respectively; n = 3 for both, P < 0.01). The permeability of the caecal crypt wall to 10 kDa dextran was higher than that of the descending crypt wall (2.03 (+/- 0.21) x 10(-5) cm x s(-1); n = 3, P < 0.025). 7. Simulation of the flow of Na+, water and FITC dextran into the crypt lumen and across the crypt wall and pericryptal sheath corroborates the observed parameters of water and Na+ flows. PMID- 11600689 TI - Loss of interstitial cells of Cajal and development of electrical dysfunction in murine small bowel obstruction. AB - 1. Partial obstruction of the murine ileum led to changes in the gross morphology and ultrastructure of the tunica muscularis. Populations of interstitial cells of Cajal (ICC) decreased oral, but not aboral, to the site of obstruction. Since ICC generate and propagate electrical slow waves in gastrointestinal muscles, we investigated whether the loss of ICC leads to loss of function in partial bowel obstruction. 2. Changes in ICC networks and electrical activity were monitored in the obstructed murine intestine using immunohistochemistry, electron microscopy and intracellular electrophysiological techniques. 3. Two weeks following the onset of a partial obstruction, the bowel increased in diameter and hypertrophy of the tunica muscularis was observed oral to the obstruction site. ICC networks were disrupted oral to the obstruction, and this disruption was accompanied by the loss of electrical slow waves and responses to enteric nerve stimulation. These defects were not observed aboral to the obstruction. 4. Ultrastructural analysis revealed no evidence of cell death in regions where the lesion in ICC networks was developing. Cells with a morphology intermediate between smooth muscle cells and fibroblasts were found in locations that are typically populated by ICC. These cells may have been the redifferentiated remnants of ICC networks. 5. Removal of the obstruction led to the redevelopment of ICC networks and recovery of slow wave activity within 30 days. Neural responses were partially restored in 30 days. 6. These data describe the plasticity of ICC networks in response to partial obstruction. After obstruction the ICC phenotype was lost, but these cells regenerated when the obstruction was removed. This model may be an important tool for evaluating the cellular/molecular factors responsible for the regulation and maintenance of the ICC phenotype. PMID- 11600690 TI - Altered cross-bridge characteristics following haemodynamic overload in rabbit hearts expressing V3 myosin. AB - 1. Our goal in this study was to evaluate the effect of haemodynamic overload on cross-bridge (XBr) kinetics in the rabbit heart independently of myosin heavy chain (MHC) isoforms, which are known to modulate kinetics in small mammals. We applied a myothermal-mechanical protocol to isometrically contracting papillary muscles from two rabbit heart populations: (1) surgically induced right ventricular pressure overload (PO), and (2) sustained treatment with propylthiouracil (PTU). Both treatments resulted in a 100 % V3 MHC profile. 2. XBr force-time integral (FTI), evaluated during the peak of the twitch from muscle FTI and tension-dependent heat, was greater in the PO hearts (0.80 +/- 0.10 versus 0.45 +/- 0.05 pN s, means +/- S.E.M., P = 0.01). 3. Within the framework of a two-state XBr model, the PO XBr developed more force while attached (5.8 +/- 0.9 versus 2.7 +/- 0.3 pN), with a lower cycling rate (0.89 +/- 0.10 versus 1.50 +/- 0.14 s(-1)) and duty cycle (0.14 +/- 0.03 versus 0.24 +/- 0.02). 4. Only the ventricular isoforms of myosin light chain 1 and 2 and cardiac troponin I (cTnI) were expressed, with no difference in cTnI phosphorylation between the PO and PTU samples. The troponin T (TnT) isoform compositions in the PO and PTU samples were significantly different (P = 0.001), with TnT2 comprising 2.29 +/- 0.03 % in PO hearts versus 0.98 +/- 0.01 % in PTU hearts of total TnT. 5. This study demonstrates that MHC does not mediate dramatic alterations in XBr function induced by haemodynamic overload. Our findings support the likelihood that differences among other thick and thin filament proteins underlie these XBr alterations. PMID- 11600691 TI - Cardiac troponin T mutations: correlation between the type of mutation and the nature of myofilament dysfunction in transgenic mice. AB - 1. The heterogenic nature of familial hypertrophic cardiomyopathy (FHC) in humans suggests a link between the type of mutation and the nature of patho physiological alterations in cardiac myocytes. Exactly how FHC-associated mutations in cardiac troponin T (cTnT) lead to impaired cardiac function is unclear. 2. We measured steady-state isometric force and ATPase activity in detergent-skinned cardiac fibre bundles from three transgenic (TG) mouse hearts in which 50, 92 and 6 % of the native cTnT was replaced by the wild type (WT) cTnT, R92Q mutant cTnT (R92Q) and the C-terminal deletion mutant of cTnT (cTnT(DEL)), respectively. 3. Normalized pCa-tension relationships of R92Q and cTnT(DEL) fibres demonstrated a significant increase in sensitivity to Ca2+ at short (2.0 microm) and long (2.3 microm) sarcomere lengths (SL). At short SL, the pCa50 values, representing the midpoint of the pCa-tension relationship, were 5.69 +/- 0.01, 5.96 +/- 0.01 and 5.81 +/- 0.01 for WT, R92Q and cTnT(DEL) fibres, respectively. At long SL, the pCa50 values were 5.81 +/- 0.01, 6.08 +/- 0.01 and 5.95 +/- 0.01 for WT, R92Q and cTnT(DEL) fibres, respectively. 4. The difference in pCa required for half-maximal activation (DeltapCa50) at short and long SL was 0.12 +/- 0.01 for the R92Q (92 %) TG fibres, which is significantly less than the previously reported DeltapCa50 value of 0.29 +/- 0.02 for R92Q (67 %) TG fibres. 5. At short SL, Ca2+-activated maximal tension in both R92Q and cTnT(DEL) fibres decreased significantly (24 and 21 %, respectively; P < 0.005), with no corresponding decrease in Ca2+-activated maximal ATPase activity. Therefore, at short SL, the tension cost in R92Q and cTnT(DEL) fibres increased by 35 and 29 %, respectively (P < 0.001). 6. The fibre bundles reconstituted with the recombinant mutant cTnT(DEL) protein developed only 37 % of the Ca2+-activated maximal force developed by recombinant WT cTnT reconstituted fibre bundles, with no apparent changes in Ca2+ sensitivity. 7. Our data indicate that an important mutation linked effect on cardiac function is the result of an inefficient use of ATP at the myofilament level. Furthermore, the extent of the mutation-induced dysfunction depends not only on the nature of the mutation, but also on the concentration of the mutant protein in the sarcomere. PMID- 11600692 TI - The effect of systemic hypoxia on interstitial and blood adenosine, AMP, ADP and ATP in dog skeletal muscle. AB - 1. We investigated the effect of moderate systemic hypoxia on the arterial, venous and interstitial concentration of adenosine and adenine nucleotides in the neurally and vascularly isolated, constant-flow perfused gracilis muscles of anaesthetized dogs. 2. Systemic hypoxia reduced arterial PO2 from 129 to 28 mmHg, venous PO2 from 63 to 23 mmHg, arterial pH from 7.43 to 7.36 and venous pH from 7.38 to 7.32. Neither arterial nor venous PCO2 were changed. Arterial perfusion pressure remained at 109 +/- 8 mmHg for the first 5 min of hypoxia, then increased to 131 +/- 11 mmHg by 9 min, and then decreased again throughout the rest of the hypoxic period. 3. Arterial adenosine (427 +/- 98 nM) did not change during hypoxia, but venous adenosine increased from 350 +/- 52 to 518 +/- 107 nM. Interstitial adenosine concentration did not increase (339 +/- 154 nM in normoxia and 262 +/- 97 nM in hypoxia). Neither arterial nor venous nor interstitial concentrations of adenine nucleotides changed significantly in hypoxia. 4. Interstitial adenosine, AMP, ADP and ATP increased from 194 +/- 40, 351 +/- 19, 52 +/- 7 and 113 +/- 36 to 764 +/- 140, 793 +/- 119, 403 +/- 67 and 574 +/- 122 nM, respectively, during 2 Hz muscle contractions. 5. Adenosine, AMP, ADP and ATP infused into the arterial blood did not elevate the interstitial concentration until the arterial concentration exceeded 10 microM. 6. We conclude that the increased adenosine in skeletal muscle during systemic hypoxia is formed by the vascular tissue or the blood cells, and that adenosine is formed intracellularly by these tissues. On the other hand, adenosine formation takes place extracellularly in the interstitial space during muscle contractions. PMID- 11600694 TI - Absence of arterial baroreflex modulation of skin sympathetic activity and sweat rate during whole-body heating in humans. AB - 1. Prior findings suggest that baroreflexes are capable of modulating skin blood flow, but the effects of baroreceptor loading/unloading on sweating are less clear. Therefore, this project tested the hypothesis that pharmacologically induced alterations in arterial blood pressure in heated humans would lead to baroreflex-mediated changes in both skin sympathetic nerve activity (SSNA) and sweat rate. 2. In seven subjects mean arterial blood pressure was lowered (approximately 8 mmHg) and then raised (approximately 13 mmHg) by bolus injections of sodium nitroprusside and phenylephrine, respectively. Moreover, in a separate protocol, arterial blood pressure was reduced via steady-state administration of sodium nitroprusside. In both normothermia and heat-stress conditions the following responses were monitored: sublingual and mean skin temperatures, heart rate, beat-by-beat blood pressure, skin blood flow (laser Doppler flowmetry), local sweat rate and SSNA (microneurography from peroneal nerve). 3. Whole-body heating increased skin and sublingual temperatures, heart rate, cutaneous blood flow, sweat rate and SSNA, but did not change arterial blood pressure. Heart rate was significantly elevated (from 74 +/- 3 to 92 +/- 4 beats x min(-1); P < 0.001) during bolus sodium nitroprusside-induced reductions in blood pressure, and significantly reduced (from 92 +/- 4 to 68 +/- 4 beats x min(-1); P < 0.001) during bolus phenylephrine-induced elevations in blood pressure, thereby demonstrating normal baroreflex function in these subjects. 4. Neither SSNA nor sweat rate was altered by rapid (bolus infusion) or sustained (steady-state infusion) changes in blood pressure regardless of the thermal condition. 5. These data suggest that SSNA and sweat rate are not modulated by arterial baroreflexes in normothermic or moderately heated individuals. PMID- 11600693 TI - Parallel nociceptive reflex pathways with negative and positive feedback functions to foot extensors in the cat. AB - 1. Nociceptive reflex pathways to foot extensors were investigated with particular attention given to those not following a flexor reflex (FRA) or withdrawal pattern. 2. In anaemically decapitated, high spinal paralysed cats nociceptive afferents of the foot pad were activated by noxious radiant heat (48 60 degrees C), while for comparison non-nociceptive afferents were activated by weak mechanical stimulation of the skin or graded electrical nerve stimulation. The reflex action of the afferents on hindlimb motoneurones, innervating plantaris and intrinsic foot extensors (tibial nerve), was investigated by intracellular recording, by monosynaptic reflex testing and by recording of neurograms during fictive locomotion. A possible descending control of the nociceptive and non-nociceptive pathways was tested by application of opioidergic and monoaminergic compounds. 3. Beside the typical FRA pattern evoked in the majority of hindlimb motoneurone pools by nociceptive afferents from different skin areas of the foot, the results revealed parallel excitatory and inhibitory nociceptive reflex pathways from the central pad and partly from the toe pads to foot extensors. The excitatory pathways, which did not follow the FRA pattern, were predominantly to plantaris and intrinsic foot extensors. They were distinctly less depressed by opioids and monoaminergic compounds than FRA pathways. 4. While the nociceptive FRA pathways have a general nocifensive withdrawal function, the nociceptive excitatory non-FRA pathway to the foot extensors causes a movement of the affected area towards the stimulus or at least a resistance against the stimulus, i.e. it mediates a positive feedback. PMID- 11600695 TI - Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. AB - 1. We investigated the effect of oral creatine supplementation during leg immobilization and rehabilitation on muscle volume and function, and on myogenic transcription factor expression in human subjects. 2. A double-blind trial was performed in young healthy volunteers (n = 22). A cast was used to immobilize the right leg for 2 weeks. Thereafter the subjects participated in a knee-extension rehabilitation programme (3 sessions x week(-1), 10 weeks). Half of the subjects received creatine monohydrate (CR; from 20 g down to 5 g daily), whilst the others ingested placebo (P; maltodextrin). 3. Before and after immobilization, and after 3 and 10 weeks of rehabilitation training, the cross-sectional area (CSA) of the quadriceps muscle was assessed by NMR imaging. In addition, an isokinetic dynamometer was used to measure maximal knee-extension power (Wmax), and needle biopsy samples taken from the vastus lateralis muscle were examined to asses expression of the myogenic transcription factors MyoD, myogenin, Myf5, and MRF4, and muscle fibre diameters. 4. Immobilization decreased quadriceps muscle CSA (approximately 10 %) and Wmax (approximately 25 %) by the same magnitude in both groups. During rehabilitation, CSA and Wmax recovered at a faster rate in CR than in P (P < 0.05 for both parameters). Immobilization changed myogenic factor protein expression in neither P nor CR. However, after rehabilitation myogenin protein expression was increased in P but not in CR (P < 0.05), whilst MRF4 protein expression was increased in CR but not in P (P < 0.05). In addition, the change in MRF4 expression was correlated with the change in mean muscle fibre diameter (r = 0.73, P < 0.05). 5. It is concluded that oral creatine supplementation stimulates muscle hypertrophy during rehabilitative strength training. This effect may be mediated by a creatine-induced change in MRF4 and myogenin expression. PMID- 11600696 TI - Directional tuning of human forearm muscle afferents during voluntary wrist movements. AB - 1. Single unit activity was recorded with the microneurography technique from sixteen spindle afferents and one Golgi tendon organ afferent originating from the forearm extensor muscles. Impulse rates were studied while subjects performed unobstructed aiming movements at the wrist in eight different directions 45 deg apart. In addition, similar imposed movements were performed while the subject was instructed to remain relaxed. Movement amplitudes were about 5 deg and the speed 10-30 deg x s(-1). Joint movements were translated to movements of a cursor on a monitor to provide visual feedback. 2. Individual spindle afferents modulated their activity over a number of targets, i.e. were broadly tuned, during these aiming movements. The preferred direction for a spindle afferent was the same during both passive and active movements, indicating that the fusimotor effects associated with active contractions had little or no effect on the direction of tuning. 3. The direction of tuning of individual spindle afferents could be predicted from the biomechanically inferred length changes of the parent muscle. Thus spindle afferents responded as stretch receptors, i.e. impulse rates increased with lengthening and decreased with shortening, in active as well as passive movements. 4. Spindles from muscles, which continuously counteracted gravity exhibited a stretch response and directional tuning during the phase of movement alone whereas their position sensitivity was poor. In contrast, spindle afferents from the muscles that had no or minimal antigravity role were directionally tuned during both the dynamic and the static phase of the aiming task and their position sensitivity was substantially higher. 5. In spite of the limited data base from three extensor muscles it could be demonstrated that wrist joint position was remarkably well encoded in the ensemble muscle spindle data. In some cases the ensemble muscle spindle data encoded the instantaneous trajectory of movement as well. PMID- 11600697 TI - Effects of different duration isometric contractions on tendon elasticity in human quadriceps muscles. AB - 1. The present study aimed to investigate the influence of isometric training protocols with long- and short-duration contractions on the elasticity of human tendon structures in vivo. The elasticity was assessed through in vivo determination of the elongation (L) of the tendons and aponeuroses using ultrasonography, while the subjects performed ramp isometric exercise up to maximum voluntary contraction (MVC). 2. Eight young males completed 12 weeks (4 days per week) of a unilateral isometric training programme on knee extensors, which consisted of two different combinations of contraction and relaxation times at 70 % MVC: one leg was trained using a short-duration protocol (3 sets of 50 repetitions of contraction for 1 s and relaxation for 2 s), and the other leg was trained using a long-duration protocol (4 sets of a combination of contraction for 20 s and relaxation for 1 min). The training volume per session, expressed as the integrated torque, was the same for the two protocols. 3. Both protocols resulted in a significant increase in MVC: 31.8 +/- 17.2 % for the short-duration protocol and 33.9 +/- 14.4 % for the long-duration protocol. Moreover, the training produced significant increases in the muscle volume of the constituents of the quadriceps femoris, with similar relative gains for the two protocols: 7.4 +/- 3.9 % for the short-duration protocol and 7.6 +/- 4.3 % for the long-duration protocol. 4. The short-duration protocol produced no significant change in L values at any of the force production levels. For the long-duration protocol, however, the L values above 550 N were significantly shorter after training. Analysis revealed that the group x test time interaction effect on tendon stiffness was significant. Stiffness increased significantly for the long duration protocol, but not for the short-duration protocol. 5. The present study demonstrates a greater increase in stiffness of human tendon structures following isometric training using longer duration contractions compared to shorter contractions. This suggests that the changes in the elasticity of the tendon structures after resistance training may be affected by the duration of muscle contraction. PMID- 11600698 TI - A novel class of plant-specific zinc-dependent DNA-binding protein that binds to A/T-rich DNA sequences. AB - Complementary DNA encoding a DNA-binding protein, designated PLATZ1 (plant AT rich sequence- and zinc-binding protein 1), was isolated from peas. The amino acid sequence of the protein is similar to those of other uncharacterized proteins predicted from the genome sequences of higher plants. However, no paralogous sequences have been found outside the plant kingdom. Multiple alignments among these paralogous proteins show that several cysteine and histidine residues are invariant, suggesting that these proteins are a novel class of zinc-dependent DNA-binding proteins with two distantly located regions, C-x(2)-H-x(11)-C-x(2)-C-x((4-5))-C-x(2)-C-x((3-7))-H-x(2)-H and C-x(2)-C-x((10 11))-C-x(3)-C. In an electrophoretic mobility shift assay, the zinc chelator 1,10 o-phenanthroline inhibited DNA binding, and two distant zinc-binding regions were required for DNA binding. A protein blot with (65)ZnCl(2) showed that both regions are required for zinc-binding activity. The PLATZ1 protein non specifically binds to A/T-rich sequences, including the upstream region of the pea GTPase pra2 and plastocyanin petE genes. Expression of the PLATZ1 repressed those of the reporter constructs containing the coding sequence of luciferase gene driven by the cauliflower mosaic virus (CaMV) 35S90 promoter fused to the tandem repeat of the A/T-rich sequences. These results indicate that PLATZ1 is a novel class of plant-specific zinc-dependent DNA-binding protein responsible for A/T-rich sequence-mediated transcriptional repression. PMID- 11600699 TI - Pyret, a Ty3/Gypsy retrotransposon in Magnaporthe grisea contains an extra domain between the nucleocapsid and protease domains. AB - A novel Ty3/Gypsy retrotransposon, named Pyret, was identified in the plant pathogenic fungus Magnaporthe grisea (anamorph Pyricularia oryzae). Pyret-related elements were distributed in a wide range of Pyricularia isolates from various gramineous plants. The Pyret element is 7250 bp in length with a 475 bp LTR and one conceptual ORF. The ORF contains seven nonsense mutations in the reading frame, indicating that the Pyret clone is lightly degenerate. Comparative domain analysis among retroelements revealed that Pyret exhibits an extra domain (WCCH domain) beyond the basic components of LTR retrotransposons. The WCCH domain consists of approximately 300 amino acids and is located downstream of the nucleocapsid domain. The WCCH domain is so named because it contains two repeats of a characteristic amino acid sequence, W-X(2)-C-X(4)-C-X(2)-H-X(3)-K. A WCCH motif-like sequence is found in the precoat protein of some geminiviruses, viral RNA-dependent RNA polymerase and also in an Arabidopsis protein of unknown function. Interestingly, detailed sequence analysis of the gag protein revealed that Pyret, as well as some other chromodomain-containing LTR retrotransposons, displays significant sequence homology with members of the gammaretroviruses (MLV related retroviruses) in the capsid and nucleocapsid domains. This suggests that chromodomain-containing LTR retrotransposons and gammaretroviruses may share a common ancestor with the gag protein. PMID- 11600700 TI - The role of acetylation in rDNA transcription. AB - Treatment of NIH 3T3 cells with trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), resulted in a dose-dependent increase in transcription from a rDNA reporter and from endogenous rRNA genes. Chromatin immunoprecipitation using anti-acetyl-histone H4 antibodies demonstrated a direct effect of TSA on the acetylation state of the ribosomal chromatin. TSA did not reverse inhibition of transcription from the rDNA reporter by retinoblastoma (Rb) protein, suggesting that the main mechanism by which Rb blocks rDNA transcription may not involve recruitment of deacetylases to rDNA chromatin. Overexpression of histone transacetylases p300, CBP and PCAF stimulated transcription in transfected NIH 3T3 cells. Recombinant p300, but not PCAF, stimulated rDNA transcription in vitro in the absence of nucleosomes, suggesting that the stimulation of rDNA transcription by TSA might have a chromatin-independent component. We found that the rDNA transcription factor UBF was acetylated in vivo. Finally, we also demonstrated the nucleolar localization of CBP. Our results suggest that the organization of ribosomal chromatin of higher eukaryotes is not static and that acetylation may be involved in affecting these dynamic changes directly through histone acetylation and/or through acetylation of UBF or one of the other components of rDNA transcription. PMID- 11600701 TI - Species-specific differences in the operational RNA code for aminoacylation of tRNA(Trp). AB - Identity elements play essential roles in the recognition of tRNAs by their cognate aminoacyl-tRNA synthetase. An operational RNA code relates amino acids to specific sequences and structural features of tRNA acceptor stems. In this study, a series of tRNA(Trp) variants was prepared by in vitro transcription and their efficiencies of aminoacylation by tryptophan (k(cat)/K(m)) were measured with the aid of Bacillus subtilis and human tryptophanyl-tRNA synthetases (TrpRS). The identity elements in the operational RNA code of human tRNA(Trp) were found to be: major element, discriminator base A73; minor elements, G1/C72 and U5/G68. From the cross-species aminoacylation assays, we conclude that the identity elements in tRNA(Trp) from B.subtilis and human all contribute to species specific aminoacylation by TrpRS. Analyses of 22 TrpRS sequences covering three taxonomic domains (bacteria, eukarya and archaea) reveal that the sequences are divided into two evolutionarily distant groups. The same partition is also observed in the analyses of tRNA(Trp) acceptor stem sequences. Our data suggest that the two TrpRS groups may reflect co-adaptations needed to accommodate changes in the operational RNA code for tryptophan. PMID- 11600702 TI - Efficient repair of large DNA loops in Saccharomyces cerevisiae. AB - Small looped mispairs are efficiently corrected by mismatch repair. The situation with larger loops is less clear. Repair activity on large loops has been reported as anywhere from very low to quite efficient. There is also uncertainty about how many loop repair activities exist and whether any are conserved. To help address these issues, we studied large loop repair in Saccharomyces cerevisiae using in vivo and in vitro assays. Transformation of heteroduplexes containing 1, 16 or 38 nt loops led to >90% repair for all three substrates. Repair of the 38 base loop occurred independently of mutations in key genes for mismatch repair (MR) and nucleotide excision repair (NER), unlike other reported loop repair functions in yeast. Correction of the 16 base loop was mostly independent of MR, indicating that large loop repair predominates for this size heterology. Similarities between mammalian and yeast large loop repair were suggested by the inhibitory effects of loop secondary structure and by the role of defined nicks on the relative proportions of loop removal and loop retention products. These observations indicate a robust large loop repair pathway in yeast, distinct from MR and NER, and conserved in mammals. PMID- 11600703 TI - The 1.19 A X-ray structure of 2'-O-Me(CGCGCG)(2) duplex shows dehydrated RNA with 2-methyl-2,4-pentanediol in the minor groove. AB - The crystal and molecular structure of 2'-O-Me(CGCGCG)(2) has been determined at 1.19 A resolution, at 100 K, using synchrotron radiation. The structure in space group P3(2)12 is a half-turn right-handed helix that includes two 2-methyl-2,4 pentanediol (MPD) molecules bound in the minor groove. The structure deviates from A-form RNA. The duplex is overwound with an average value of 9.7 bp per turn, characterised as having a C3'-endo sugar pucker, very low base pair rise and high helical twist and inclination angles. The structure includes 65 ordered water molecules. Only a single row of water molecules is observed in the minor groove due to the presence of hydrophobic 2'-O-methyl groups. As many as five magnesium ions are located in the structure. Two are in the major groove and interact with O(6) and N(7) of guanosine and N(4) of cytidine residues through their hydration spheres. This work provides the first example of molecular interactions of nucleic acids with MPD, which was used as a precipitant, cryo solvent and resolution enhancing agent. The two MPD molecules intrude into the hydration network in the minor groove, each forming hydrogen bonds between their secondary hydroxyl group and exo-amino functions of guanosine residues. Comparison of the 2'-O-Me(CGCGCG)(2) structure in the P3(2)12 and P6(1)22 crystals delineates stability of the water network within the minor groove to dehydration by MPD and is of interest for evaluating factors governing small molecule binding to RNA. Intrusion of MPD into the minor groove of 2'-O Me(CGCGCG)(2) is discussed with respect to RNA dehydration, a prerequisite of Z RNA formation. PMID- 11600704 TI - Highly conserved amino acids in Pax and Ets proteins are required for DNA binding and ternary complex assembly. AB - Combinatorial association of DNA-binding proteins on composite binding sites enhances their nucleotide sequence specificity and functional synergy. As a paradigm for these interactions, Pax-5 (BSAP) assembles ternary complexes with Ets proteins on the B cell-specific mb-1 promoter through interactions between their respective DNA-binding domains. Pax-5 recruits Ets-1 to bind the promoter, but not the closely related Ets protein SAP1a. Here we show that, while several different mutations increase binding of SAP1a to an optimized Ets binding site, only conversion of Val68 to an acidic amino acid facilitates ternary complex assembly with Pax-5 on the mb-1 promoter. This suggests that enhanced DNA binding by SAP1a is not sufficient for recruitment by Pax-5, but instead involves protein protein interactions mediated by the acidic side chain. Recruitment of Ets proteins by Pax-5 requires Gln22 within the N-terminal beta-hairpin motif of its paired domain. The beta-hairpin also participates in recognition of a subset of Pax-5-binding sites. Thus, Pax-5 incorporates protein-protein interaction and DNA recognition functions in a single motif. The Caenorhabditis elegans Pax protein EGL-38 also binds specifically to the mb-1 promoter and recruits murine Ets-1 or the C.elegans Ets protein T08H4.3, but not the related LIN-1 protein. Together, our results define specific amino acid requirements for Pax-Ets ternary complex assembly and show that the mechanism is conserved between evolutionarily related proteins of diverse animal species. Moreover, the data suggest that interactions between Pax and Ets proteins are an important mechanism that regulates fundamental biological processes in worms and humans. PMID- 11600705 TI - UP element-dependent transcription at the Escherichia coli rrnB P1 promoter: positional requirements and role of the RNA polymerase alpha subunit linker. AB - The UP element stimulates transcription from the rrnB P1 promoter through a direct interaction with the C-terminal domain of the RNA polymerase alpha subunit (alphaCTD). We investigated the effect on transcription from rrnB P1 of varying both the location of the UP element and the length of the alpha subunit interdomain linker, separately and in combination. Displacement of the UP element by a single turn of the DNA helix resulted in a large decrease in transcription from rrnB P1, while displacement by half a turn or two turns totally abolished UP element-dependent transcription. Deletions of six or more amino acids from within the alpha subunit linker resulted in a decrease in UP element-dependent stimulation, which correlated with decreased binding of alphaCTD to the UP element. Increasing the alpha linker length was less deleterious to RNA polymerase function at rrnB P1 but did not compensate for the decrease in activation that resulted from displacing the UP element. Our results suggest that the location of the UP element at rrnB P1 is crucial to its function and that the natural length of the alpha subunit linker is optimal for utilisation of the UP element at this promoter. PMID- 11600706 TI - SUMO modification of Rad22, the Schizosaccharomyces pombe homologue of the recombination protein Rad52. AB - The Schizosaccharomyces pombe rad31 and hus5 genes are required for the DNA damage response, as mutants defective in these genes are sensitive to DNA damaging agents, such as UV and ionising radiation and to the DNA synthesis inhibitor hydroxyurea (HU). Sequence analysis has suggested that rad31 and hus5 encode components of the Pmt3 (SUMO) modification process in S.pombe. We show here that the rad31 null and hus5.62 mutants display reduced levels of Pmt3 modification. We have initiated a search for proteins required for the DNA damage response, which may be modified by Pmt3 and have identified Rad22, the fission yeast homologue of the recombination protein Rad52. Purification of myc + His tagged Rad22 protein from cells expressing HA-tagged Pmt3 identifies an 83 kDa species which cross-reacts with anti-HA antisera. We show here that Rad22 interacts with Rhp51 and Rpa70 (the fission yeast homologues of Rad51 and the large subunit of RPA, respectively), but that neither of these proteins appears to be responsible for the 83 kDa species. The 83 kDa species is observed when extracts are prepared under both native and denaturing conditions, and is also observed when myc + His-tagged Rad22 and Pmt3 are expressed at wild type levels, suggesting that Rad22 is modified by Pmt3 in vivo. We have established an S.pombe in vitro Pmt3 modification system and have shown that Rad22 and Rhp51 are modified in vitro, but that Rpa70 is not. PMID- 11600707 TI - Improved hybridisation potential of oligonucleotides comprising O-methylated anhydrohexitol nucleoside congeners. AB - The hybridising potential of anhydrohexitol nucleoside analogues (HNAs) is well documented, but tedious synthesis of the monomers hampers their development. In a search for better analogues, the synthesis of two new methylated anhydrohexitol congeners 1 and 2 was accomplished and the physico-chemical properties of their respective oligomers were evaluated. Generally, oligonucleotides (ONs) containing the 3'-O-methyl derivative 1 showed a small increase in thermal stability towards complementary sequences as compared to HNA. Compared to the altritol modification, 3'-O-methylation seems to cause a small decrease in thermal stability of duplexes, especially when targeting RNA. These results suggest the possibility of derivatisation of the 3'-hydroxyl group of altritol-containing congeners without significantly affecting the thermal stability of the duplexes. The methyl glycosidic analogues 2 likewise increased the affinity for RNA in comparison with well-known HNA, while at the same time being economically more favorable monomers. However, homopolymers of 2 displayed self-pairing, but not so homopolymers of 1. Upon incorporation of the hexitols within RNA sequences in an effort to induce a beneficial pre-organised structure, the positive effect of the 3'-O-methyl derivative 1 proved larger than that of 2. PMID- 11600709 TI - Arg660Ser mutation in Thermus aquaticus DNA polymerase I suppresses T-->C transitions: implication of wobble base pair formation at the nucleotide incorporation step. AB - We examined the replication fidelity of an Arg660Ser (R660S) mutant of Thermus aquaticus DNA polymerase I (Taq pol I). In a forward mutation assay, R660S showed a marked reduction in T-->C transitions, one of the most frequent errors made by the wild-type enzyme. Steady-state kinetics showed that R660S discriminates against dGTP incorporation at a template T 13-fold better than the wild-type. R660S was also 3.2-fold less efficient than the wild-type at extending a T:dG mismatch. These results indicate that R660S has enhanced fidelity during incorporation and extension, which reduces its T-->C transition frequency. Interestingly, R660S also discriminated correct from incorrect nucleotides at the incorporation step of C:dATP, A:dATP, G:dATP and C:8-OH-dGTP mispairs 28-, 6.0-, 4.1- and 6.8-fold better, respectively, than the wild-type, although it may not always be as accurate as the wild-type at the extension step. A structural model suggests that Arg660 may participate in two interactions that influence fidelity; the guanidinium group of Arg660 might interact with the incoming guanine base at the major groove and it might compete for forming another interaction with the primer terminus. Substituting Arg with Ser may eliminate or alter these interactions and destabilize the closed complex with incorrect substrates. Our data also suggest that T:dGTP and C:dATP base pairs form 'wobble' structures at the incorporation step of Taq pol I. PMID- 11600708 TI - Families of restriction enzymes: an analysis prompted by molecular and genetic data for type ID restriction and modification systems. AB - Current genetic and molecular evidence places all the known type I restriction and modification systems of Escherichia coli and Salmonella enterica into one of four discrete families: type IA, IB, IC or ID. StySBLI is the founder member of the ID family. Similarities of coding sequences have identified restriction systems in E.coli and Klebsiella pneumoniae as probable members of the type ID family. We present complementation tests that confirm the allocation of EcoR9I and KpnAI to the ID family. An alignment of the amino acid sequences of the HsdS subunits of StySBLI and EcoR9I identify two variable regions, each predicted to be a target recognition domain (TRD). Consistent with two TRDs, StySBLI was shown to recognise a bipartite target sequence, but one in which the adenine residues that are the substrates for methylation are separated by only 6 bp. Implications of family relationships are discussed and evidence is presented that extends the family affiliations identified in enteric bacteria to a wide range of other genera. PMID- 11600710 TI - Degeneration of a homing endonuclease and its target sequence in a wild yeast strain. AB - Mobile introns and inteins self-propagate by 'homing', a gene conversion process initiated by site-specific homing endonucleases. The VMA intein, which encodes the PI-SceI endonuclease in Saccharomyces cerevisiae, is present in several different yeast strains. Surprisingly, a wild wine yeast (DH1-1A) contains not only the intein(+) allele, but also an inteinless allele that has not undergone gene conversion. To elucidate how these two alleles co-exist, we characterized the endonuclease encoded by the DH1-1A intein(+) allele and the target site in the intein(-) allele. Sequence analysis reveals seven mutations in the 31 bp recognition sequence, none of which occurs at positions that are individually critical for activity. However, binding and cleavage of the sequence by PI-SceI is reduced 10-fold compared to the S.cerevisiae target. The PI-SceI analog encoded by the DH1-1A intein(+) allele contains 11 mutations at residues in the endonuclease and protein splicing domains. None affects protein splicing, but one, a R417Q substitution, accounts for most of the decrease in DNA cleavage and DNA binding activity of the DH1-1A protein. Loss of activity in the DH1-1A endonuclease and target site provides one explanation for co-existence of the intein(+) and intein(-) alleles. PMID- 11600711 TI - The topoisomerase II poison clerocidin alkylates non-paired guanines of DNA: implications for irreversible stimulation of DNA cleavage. AB - Clerocidin, a diterpenoid with antibacterial and antitumor activity, stimulates in vitro DNA cleavage mediated by mammalian and bacterial topoisomerase (topo) II. Different from the classical topoisomerase poisons, clerocidin-stimulated breaks at guanines immediately preceding the sites of DNA cleavage are not resealed upon heat or salt treatment. To understand the mechanism of irreversible trapping of the topo II-cleavable complex, we have investigated the reactivity of clerocidin per se towards DNA. We show here that the drug is able to nick negatively supercoiled plasmids. DNA cleavage by clerocidin in enzyme-free medium is due to the ability of the drug to form covalent adducts with guanines. Indeed, clerocidin was able to specifically react with short oligonucleotides when the guanines were unpaired and exposed as in bulges or in the single-strand form. The clerocidin epoxy group attacks the nitrogen at position 7 of guanines, leading to strand scission at the modified site. Our findings also demonstrate that trapping of topoisomerases by clerocidin is specific for type II enzymes. The guanine alkylating ability of clerocidin suggests an unprecedented mechanism of topo II poisoning, according to which the enzyme renders the drug reactive toward DNA by distorting the double-helical structure of the nucleic acid at the cleavage site. PMID- 11600712 TI - Proton exchange and local stability in a DNA triple helix containing a G.TA triad. AB - Recognition of a thymine-adenine base pair in DNA by triplex-forming oligonucleotides can be achieved by a guanine through the formation of a G.TA triad within the parallel triple helix motif. In the present work, we provide the first characterization of the stability of individual base pairs and base triads in a DNA triple helix containing a G.TA triad. The DNA investigated is the intramolecular triple helix formed by the 32mer d(AGATAGAACCCCTTCTATCTTATATCTGTCTT). The exchange rates of imino protons in this triple helix have been measured by nuclear magnetic resonance spectroscopy using magnetization transfer from water and real-time exchange. The exchange rates are compared with those in a homologous DNA triple helix in which the G.TA triad is replaced by a canonical C(+).GC triad. The results indicate that, in the G.TA triad, the stability of the Watson-Crick TA base pair is comparable with that of AT base pairs in canonical T.AT triads. However, the presence of the G.TA triad destabilizes neighboring triads by 0.6-1.8 kcal/mol at 1 degrees C. These effects extend to triads that are two positions removed from the site of the G.TA triad. Therefore, the lower stability of DNA triple helices containing G.TA triads originates, in large part, from the energetic effects of the G.TA triad upon the stability of canonical triads located in its vicinity. PMID- 11600714 TI - DNA exhibits multi-stranded binding recognition on glass microarrays. AB - In the course of exploring the hybridization properties of glass DNA microarrays, multi-stranded DNA structures were observed that could not be accounted for by classical Watson-Crick base pairing. Non-denatured double-stranded DNA array elements were shown to hybridize to single-stranded (ss)DNA probes. Similarly, ssDNA array elements were shown to bind duplex DNA probes. This led to a series of experiments demonstrating the formation of multi-stranded DNA structures on the surface of microarrays. These structures were observed with a number of heterogeneous sequences, including both purine and pyrimidine bases, with shared sequence identity between the ssDNA and one of the duplex strands. Furthermore, we observed a strong binding preference near the ends of duplexes containing a 3' homologous strand. We suggest that such binding interactions on cationic solid surfaces could serve as a model for a number of biological processes mediated through multi-stranded DNA. PMID- 11600713 TI - In vivo gene repair of point and frameshift mutations directed by chimeric RNA/DNA oligonucleotides and modified single-stranded oligonucleotides. AB - Synthetic oligonucleotides have been used to direct base exchange and gene repair in a variety of organisms. Among the most promising vectors is chimeric oligonucleotide (CO), a double-stranded, RNA-DNA hybrid molecule folded into a double hairpin conformation: by using the cell's DNA repair machinery, the CO directs nucleotide exchange as episomal and chromosomal DNA. Systematic dissection of the CO revealed that the region of contiguous DNA bases was the active component in the repair process, especially when the single-stranded ends were protected against nuclease attack. Here, the utility of this vector is expanded into Saccharomyces cerevisiae. An episome containing a mutated fusion gene encoding hygromycin resistance and eGFP expression was used as the target for repair. Substitution, deletion and insertion mutations were corrected with different frequencies by the same modified single-stranded vector as judged by growth in the presence of hygromycin and eGFP expression. A substitution mutation was repaired the most efficiently followed by insertion and finally deletion mutants. A strand bias for gene repair was also observed; vectors designed to direct the repair of nucleotide on the non-transcribed (non-template) strand displayed a 5-10-fold higher level of activity. Expanding the length of the oligo vector from 25 to 100 nucleotides increases targeting frequency up to a maximal level and then it decreases. These results, obtained in a genetically tractable organism, contribute to the elucidation of the mechanism of targeted gene repair. PMID- 11600715 TI - Duplex Scorpion primers in SNP analysis and FRET applications. AB - Scorpions are fluorogenic PCR primers with a probe element attached at the 5'-end via a PCR stopper. They are used in real-time amplicon-specific detection of PCR products in homogeneous solution. Two different formats are possible, the 'stem loop' format and the 'duplex' format. In both cases the probing mechanism is intramolecular. We have shown that duplex Scorpions are efficient probes in real time PCR. They give a greater fluorescent signal than stem-loop Scorpions due to the vastly increased separation between fluorophore and quencher in the active form. We have demonstrated their use in allelic discrimination at the W1282X locus of the ABCC7 gene and shown that they can be used in assays where fluorescence resonance energy transfer is required. PMID- 11600716 TI - Random multi-recombinant PCR for the construction of combinatorial protein libraries. AB - Development of a new methodology to create protein libraries, which enable the exploration of global protein space, is an exciting challenge. In this study we have developed random multi-recombinant PCR (RM-PCR), which permits the shuffling of several DNA fragments without homologous sequences. In order to evaluate this methodology, we applied it to create two different combinatorial DNA libraries. For the construction of a 'random shuffling library', RM-PCR was used to shuffle six DNA fragments each encoding 25 amino acids; this affords many different fragment sequences whose every position has an equal probability to encode any of the six blocks. For the construction of the 'alternative splicing library', RM PCR was used to perform different alternative splicings at the DNA level, which also yields different block sequences. DNA sequencing of the RM-PCR products in both libraries revealed that most of the sequences were quite different, and had a long open reading frame without a frame shift or stop codon. Furthermore, no distinct bias among blocks was observed. Here we describe how to use RM-PCR for the construction of combinatorial DNA libraries, which encode protein libraries that would be suitable for selection experiments in the global protein space. PMID- 11600717 TI - Expression and purification of recombinant human c-Fos/c-Jun that is highly active in DNA binding and transcriptional activation in vitro. AB - c-Fos and c-Jun are members of the AP-1 family of transcriptional activators that regulate the expression of genes during cell proliferation. To facilitate in vitro studies of mechanisms of transcriptional activation by c-Jun and c-Fos we developed a method for obtaining recombinant c-Fos/c-Jun that is highly active in DNA binding and transcriptional activation in vitro. Full-length human c-Fos and c-Jun were expressed in Escherichia coli. The expression of c-Fos was dependent on a helper plasmid that encodes rare (Arg)tRNAs. Both over-expressed c-Fos and c Jun were recovered from inclusion bodies. A c-Fos/c-Jun complex was generated by co-renaturation and purified via a His-tag on the full-length human c-Fos. The resulting c-Fos/c-Jun bound DNA with high affinity and specificity, and activated transcription in a reconstituted human RNA polymerase II transcription system. The availability of active recombinant human c-Fos/c-Jun will allow future biochemical studies of these important transcriptional activators. PMID- 11600718 TI - A novel yeast system for in vivo selection of recognition sequences: defining an optimal c-Myb-responsive element. AB - Yeast (Saccharomyces cerevisiae) has proved to be a highly valuable tool in a range of screening methods. We present in this work the design and use of a novel yeast effector-reporter system for selection of sequences recognised by DNA binding proteins in vivo. A dual HIS3-lacZ reporter under the control of a single randomised response element facilitates both positive growth selection of binding sequences and subsequent quantification of the strength of the selected sequence. A galactose-inducible effector allows discrimination between reporter activation caused by the protein under study and activation due to endogenous factors. The system mimics the physiological gene dosage relationship between transcription factor and target genes in vivo by using a low copy effector plasmid and a high copy reporter plasmid, favouring sequence selectivity. The utility of the novel yeast screening system was demonstrated by using it to refine the definition of an optimal recognition element for the c-Myb transcription factor (MRE). We present screening data supporting an extended MRE consensus closely mimicking known strong response elements and where a sequence of 11 nt influences activity. Novel features include a more strict sequence requirement in the second half-site of the MRE where a T-rich sequence is preferred in vivo. PMID- 11600719 TI - Genetic synthetic lethality screen at the single gene level in cultured human cells. AB - Recently, we demonstrated the feasibility of a chemical synthetic lethality screen in cultured human cells. We now demonstrate the principles for a genetic synthetic lethality screen. The technology employs both an immortalized human cell line deficient in the gene of interest, which is complemented by an episomal survival plasmid expressing the wild-type cDNA for the gene of interest, and the use of a novel GFP-based double-label fluorescence system. Dominant negative genetic suppressor elements (GSEs) are selected from an episomal library expressing short truncated sense and antisense cDNAs for a gene likely to be synthetic lethal with the gene of interest. Expression of these GSEs prevents spontaneous loss of the GFP-marked episomal survival plasmid, thus allowing FACS enrichment for cells retaining the survival plasmid (and the GSEs). The dominant negative nature of the GSEs was validated by the decreased resident enzymatic activity present in cells harboring the GSEs. Also, cells mutated in the gene of interest exhibit reduced survival upon GSE expression. The identification of synthetic lethal genes described here can shed light on functional genetic interactions between genes involved in normal cell metabolism and in disease. PMID- 11600721 TI - Adverse health effects after low level exposure to organophosphates. PMID- 11600720 TI - Evaluation of phosphodiesterase I-based protocols for the detection of multiply damaged sites in DNA: the detection of abasic, oxidative and alkylative tandem damage in DNA oligonucleotides. AB - It has been proposed that DNA multiply damaged sites (MDS), where more than one moiety in a local region ( approximately 1 helical turn, 10 bp) of the DNA is damaged, are lesions of enhanced biological significance. However, other than indirect measures, there are few analytical techniques that allow direct detection of MDS in DNA. In the present study we demonstrate the potential of protocols incorporating an exonucleolytic snake venom phosphodiesterase (SVPD) digestion stage to permit the direct detection of certain tandem damage, in which two lesions are immediately adjacent to each other on the same DNA strand. A series of prepared oligonucleotides containing either single or pairs of tetrahydrofuran moieties (F), thymine glycol lesions (T(g)) or methylphosphotriester adducts (Me-PTE) were digested with SVPD and the digests examined by either (32)P-end-labelling or electrospray mass spectrometry. The unambiguous observation of SVPD-resistant 'trimer' species in the digests of oligonucleotides containing adjacent F, T(g) and Me-PTE demonstrates that the SVPD digestion strategy is capable of allowing direct detection of certain tandem damage. Furthermore, in studies to determine the specificity of SVPD in dealing with pairs of lesions on the same strand, it was found mandatory to have the two lesions immediately adjacent to each other in order to generate the trimer species; pairs of lesions separated by as few as one or two normal nucleotides behave principally as single lesions towards SVPD. PMID- 11600722 TI - Monitoring trends in occupational illness. PMID- 11600724 TI - Estimation of cumulative exposure to organophosphate sheep dips in a study of chronic neurological health effects among United Kingdom sheep dippers. AB - OBJECTIVES: To derive a method for retrospectively estimating cumulative exposure to organophosphate (OP) pesticides among a cross section of United Kingdom sheep dippers, as part of a wider epidemiological study of neurological abnormality within this group of workers. METHODS: A hygiene study of dipping sessions at 20 farms using diazinon based dips was carried out by two experienced occupational hygienists. Observations on the exposure of people to concentrate and dilute dip were recorded throughout each dipping session, together with the other relevant factors including the use and condition of protective clothing. Concentrations of urinary metabolites of diazinon were used to measure actual exposure to OPs. To estimate exposure in the subsequent epidemiological study, an occupational exposure history questionnaire was developed using results from the hygiene study and an empirical exposure model. RESULTS: In the hygiene study, increased urinary metabolites were associated with the handling of concentrate dip and exposure to dilute dip wash through splashing. Very few dippers wore the recommended protective clothing. The handling of concentrate dip was the principal source of exposure to OPs. Dipping task was used as a surrogate for splashing of dilute dip in retrospective exposure estimation. In the epidemiological study, cumulative exposure to OP sheep dips was highly correlated with the total number of dipping days, but not with age. CONCLUSIONS: Sheep dip concentrate is the most important source of OP exposure among sheep dippers and estimates of exposure to OPs during routine dipping should take due account of exposure to concentrate dip as well as to the dilute dip wash. The observed use of recommended protective clothing by most subjects was insufficient to allow a proper empirical assessment of its effectiveness. PMID- 11600725 TI - An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers. AB - OBJECTIVES: To investigate the hypothesis that chronic low level exposure to organophosphates (OPs) in sheep dips is related to clinically detectable measures of polyneuropathy. METHODS: The design was a cross sectional exposure-response study of sheep dippers and other non-exposed groups. The study group consisted of 612 sheep dipping farmers, 53 farmers with no sheep dipping experience, and 107 ceramics workers. Retrospective exposure information was obtained by questionnaire based on stable and easily identifiable features of sheep dipping found during the first phase of the study; in particular, estimates of handling concentrate and splashing with dilute dip. Neurological assessments were based on a standard neuropathy symptoms questionnaire, and thermal and vibration quantitative sensory tests. RESULTS: Adjusted for confounders there was a weak positive association between cumulative exposure to OPs and neurological symptoms, the significance of which was dependent on the inclusion of a few individual workers with extremely high exposure. There was no evidence of an association between cumulative exposure and the thermal or vibration sensory thresholds. However, separating the effects of exposure intensity and duration showed a higher prevalence of symptoms, primarily of a sensory type, among sheep dippers who handled the OP concentrate. There was also evidence that sensory and vibration thresholds were higher among concentrate handlers, the highest exposed group of dippers. CONCLUSIONS: The findings showed a strong association between exposure to OP concentrate and neurological symptoms, but a less consistent association with sensory thresholds. There was only weak evidence of a chronic effect of low dose cumulative exposure to OPs. It is suggested that long term health effects may occur in at least some sheep dippers exposed to OPs over a working life, although the mechanisms are unclear. PMID- 11600726 TI - Mortality experience among employees at a hydrometallurgical nickel refinery and fertiliser complex in Fort Saskatchewan, Alberta (1954-95). AB - OBJECTIVE: To study the mortality experience of workers at a hydrometallurgical nickel refinery and fertiliser complex in Fort Saskatchewan, Alberta, Canada. METHODS: A total of 1649 male employees of Sherritt International who worked for at least 12 continuous months during the years 1954 to 1978 at the Fort Saskatchewan, Alberta hydrometallurgical nickel refinery and fertiliser complex were followed up for an additional 17 years. Mortality was ascertained from the Canadian mortality data base maintained by Statistics Canada and covered the years 1954-95. Statistics were analysed with Monson's computer program. RESULTS: Total mortality, when compared with the Canadian population, was significantly below expectation. Fewer deaths were found for circulatory disease, ischaemic heart disease, respiratory disease, neoplasms, digestive cancer, and accidents, poisonings, and violence. Among the 718 men in the group exposed to nickel, there were no deaths due to nasal cavity or paranasal sinus cancer. Fewer deaths were found for all causes, circulatory disease, ischaemic heart disease, neoplasms and digestive cancer. Lower death rates were observed than expected for respiratory malignancies and cancer of the bronchus and lung. CONCLUSION: No association was found in this study between exposure to nickel concentrate or metallic nickel in the hydrometallurgical refining process and the subsequent development of respiratory cancer. PMID- 11600727 TI - Urinary 1-hydroxypyrene in coke oven workers relative to exposure, alcohol consumption, and metabolic enzymes. AB - OBJECTIVES: To investigate the influence of personal lifestyle--such as smoking and alcohol consumption-on urinary 1-hydroxypyrene (1-OHP) concentrations in coke oven workers exposed to polycyclic aromatic hydrocarbons (PAHs) and to evaluate the association of 1-OHP concentrations with the genetic polymorphism of several metabolic enzymes including cytochrome P-450 (CYP) 1A1 and glutathione S tranferases (GSTs). METHODS: The study population contained 162 coke oven workers and 58 controls employed at the largest iron and steel factory in China. Personal data were collected at the interview. 1-OHP in urine was measured with high performance liquid chromatography with fluorescence detection. Genetic polymorphisms were identified by the polymerase chain reaction (PCR) method. RESULTS: A positive association between excretion of urinary 1-OHP and the levels of exposure to PAHs was confirmed. Those people who consumed >or=50 g/day ethanol had significantly higher 1-OHP excretion than did other coke oven workers (p<0.01). No significant difference in urinary 1-OHP was found between smokers and non-smokers, in both controls and exposed subjects. The variant homozygotes at exon 7 of the CYP1A1 gene had significantly higher urinary 1-OHP concentrations than other CYP1A1 genotypes among the exposed workers (p=0.03). There was less association between the concentrations of 1-OHP and the GSTM1, GSTP1, or GSTT1 polymorphism. CONCLUSIONS: The present study confirmed that urinary 1-OHP is a good biomarker for exposure to PAHs. Alcohol consumption affected urinary 1-OHP excretion. The variant genotypes of the CYP1A1 gene may result in the enhancement of PAH metabolites. It is helpful to understand the role of individual susceptibility on metabolism of carcinogens. These findings suggest that the modulating effect of individual lifestyle factors or genetic nature should be considered in future studies on occupational exposure to PAHs and in evaluating the health risk from harmful chemicals. PMID- 11600728 TI - Are occupational, hobby, or lifestyle exposures associated with Philadelphia chromosome positive chronic myeloid leukaemia? AB - OBJECTIVES: To investigate a broad range of occupational, hobby, and lifestyle exposures, suggested as risk factors for Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML). METHODS: A case-control study, comprising 255 Ph+CML patients from southern Sweden and matched controls, was conducted. Individual data on work tasks, hobbies, and lifestyle exposures were obtained by telephone interviews. Occupational hygienists assessed occupational and hobby exposures for each subject individually. Also, occupational titles were obtained from national registries, and group level exposure-that is, the exposure proportion for each occupational title-was assessed with a job exposure matrix. The effects of 11 exposures using individual data and two exposures using group data (organic solvents and animal dust) were estimated. RESULTS: For the individual data on organic solvents, an effect was found for moderate or high intensity of exposure (odds ratio (OR) 3.4, 95% confidence interval (95% CI) 1.1 to 11) and for long duration (15-20 years) of exposure (OR 2.1, 95% CI 1.1 to 4.0). By contrast, the group data showed no association (OR 0.69, 95% CI 0.27 to 1.8; moderate or high intensity versus no exposure). For extremely low frequency electromagnetic fields (EMFs), only individual data were available. An association with long occupational exposure to EMFs was found (OR 2.3, 95% CI 1.2 to 4.5). However, no effect of EMF intensity was indicated. No significant effects of benzene, gasoline or diesel, or tobacco smoking were found. OR estimates below unity were suggested for personal use of hair dye and for agricultural exposures. CONCLUSIONS: Associations between exposure to organic solvents and EMFs, and Ph+CML were indicated but were not entirely consistent. PMID- 11600729 TI - Work correlates of back problems and activity restriction due to musculoskeletal disorders in the Canadian national population health survey (NPHS) 1994-5 data. AB - OBJECTIVES: To describe the prevalence of musculoskeletal problems in the Canadian working population and to determine cross sectional associations between such problems and work factors, particularly job strain and physical demand variables. METHODS: The Canadian 1994 national population health survey (NPHS) sampled 4230 working men and 4043 working women (ages 18-64) who answered an abbreviated version of the job content questionnaire. Workers were classified into four strain categories: high, passive, active, and low. Outcomes were restricted activity due to musculoskeletal disorders and the diagnosis of a back problem (both yes or no). Survey weights were incorporated to allow for different probabilities of selection. Logistic regression analyses were carried out separately for women and men, controlling for sociodemographic factors. RESULTS: Prevalence of chronic back problems diagnosed by a health practitioner was 14.5% among men and 12.5% among women. Men had a 6.6% prevalence of restricted activity due to musculoskeletal disorders, whereas the corresponding figure for women was 5.3%. Women, but not men, in high strain jobs were more likely to report both back problems (odds ratio (OR) 1.60, 95% confidence interval (95% CI) 1.14 to 2.28) and restricted activity (OR 1.98, 95% CI 1.16 to 3.48) compared with those in low strain jobs. High physical exertion was an independent predictor of back problems in both sexes. For both men and women, low social support at work and high job insecurity were independent predictors of restricted activity due to musculoskeletal disorders. Conversely, chronic back problems contributed to explanation of high job strain among women (OR 1.76, 95% CI 1.30 to 2.39) and high physical exertion among men (OR 1.39, 95% CI 1.09 to 1.77), whereas restricted activity due to musculoskeletal disorders contributed to explanation of high job insecurity in both sexes. CONCLUSIONS: Associations of interest between work stressors and musculoskeletal problems in this cross sectional study provide evidence for physical and psychosocial factors both affecting disability and being affected by disability in a working population. PMID- 11600731 TI - Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. AB - OBJECTIVES: To explore how metabolic risk factors for cardiovascular disease (CVD) differ between shift workers and day workers in a defined population. Shift work has been associated with an increased risk of CVD. Risk factors and causal pathways for this association are only partly known. METHODS: A working population of 27,485 people from the Vasterbotten intervention program (VIP) has been analysed. Cross sectional data, including blood sampling and questionnaires were collected in a health survey. RESULTS: Obesity was more prevalent among shift workers in all age strata of women, but only in two out of four age groups in men. Increased triglycerides (>1.7 mmol/l) were more common among two age groups of shift working women but not among men. Low concentrations of high density lipoprotein (HDL) cholesterol (men<0.9 and women<1.0 mmol/l) were present in the youngest age group of shift workers in both men and women. Impaired glucose tolerance was more often found among 60 year old women shift workers. Obesity and high triglycerides persisted as risk factors in shift working men and women after adjusting for age and socioeconomic factors, with an OR of 1.4 for obesity and 1.1 for high triglyceride concentrations. The relative risks for women working shifts versus days with one, two, and three metabolic variables were 1.06, 1.20, and 1.71, respectively. The corresponding relative risks for men were 0.99, 1.30, and 1.63, respectively. CONCLUSIONS: In this study, obesity, high triglycerides, and low concentrations of HDL cholesterol seem to cluster together more often in shift workers than in day workers, which might indicate an association between shift work and the metabolic syndrome. PMID- 11600733 TI - A review of the evidence for a "Gulf War syndrome". PMID- 11600730 TI - The role of cumulative physical work load in lumbar spine disease: risk factors for lumbar osteochondrosis and spondylosis associated with chronic complaints. AB - OBJECTIVES: To investigate the relation with a case-control study between symptomatic osteochondrosis or spondylosis of the lumbar spine and cumulative occupational exposure to lifting or carrying and to working postures with extreme forward bending. METHODS: From two practices and four clinics were recruited 229 male patients with radiographically confirmed osteochondrosis or spondylosis of the lumbar spine associated with chronic complaints. Of these 135 had additionally had acute lumbar disc herniation. A total of 197 control subjects was recruited: 107 subjects with anamnestic exclusion of lumbar spine disease were drawn as a random population control group and 90 patients admitted to hospital for urolithiasis who had no osteochondrosis or spondylosis of the lumbar spine radiographically were recruited as a hospital based control group. Data were gathered in a structured personal interview and analysed using logistic regression to control for age, region, nationality, and other diseases affecting the lumbar spine. To calculate cumulative forces to the lumbar spine over the entire working life, the Mainz-Dortmund dose model (MDD), which is based on an overproportional weighting of the lumbar disc compression force relative to the respective duration of the lifting process was applied with modifications: any objects weighing >or=5 kg were included in the calculation and no minimum daily exposure limits were established. Calculation of forces to the lumbar spine was based on self reported estimates of occupational lifting, trunk flexion, and duration. RESULTS: For a lumbar spine dose >9 x 10(6) Nh (Newton x hours), the risk of having radiographically confirmed osteochondrosis or spondylosis of the lumbar spine as measured by the odds ratio (OR) was 8.5 (95% confidence interval (95% CI) 4.1 to 17.5) compared with subjects with a load of 0 Nh. To avoid differential bias, forces to the lumbar spine were also calculated on the basis of an internal job exposure matrix based on the control subjects' exposure assessments for their respective job groups. Although ORs were lower with this approach, they remained significant. CONCLUSIONS: The calculation of the sum of forces to the lumbar spine is a useful tool for risk assessment for symptomatic osteochondrosis or spondylosis of the lumbar spine. The results suggest that cumulative occupational exposure to lifting or carrying and extreme forward bending increases the risk for developing symptomatic osteochondrosis or spondylosis of the lumbar spine. PMID- 11600734 TI - The development of three-dimensional range of motion measurement systems for clinical practice. PMID- 11600735 TI - Outcome measures in Sjogren's syndrome. PMID- 11600737 TI - Investigation of cutaneous microvascular activity and flare response in patients with fibromyalgia syndrome. AB - OBJECTIVES: To assess microvascular activity in the skin of patients with fibromyalgia syndrome (FMS) as compared with normal controls. METHODS: Fifteen patients, who fulfilled the American College of Rheumatology criteria for FMS, and 15 age- and sex-matched healthy controls, were studied. The microvascular activity of the skin overlying the trapezius muscle was quantified using iontophoresis of acetylcholine as an endothelial-dependent vasodilator and sodium nitroprusside as an endothelial-independent vasodilator. We also studied the flare response by iontophoresing acetylcholine continuously for 10 min to stimulate a ring of nociceptor c-fibre endings in the skin. RESULTS: There was no significant difference in cutaneous vascular responses to short-duration iontophoresis of acetylcholine and sodium nitroprusside at the three different doses used. The area under the curve (AUC) (mean+/-s.e.m.) for acetylcholine baseline, 20, 40, and 80 s were 6+/-0.7, 23+/-6, 45+/-7 and 66+/-10 AU for patients and 11+/-4, 24+/-3, 49+/-7 and 62+/-12 AU for controls, respectively (P=0.2, 0.9, 0.7, 0.8, respectively). The corresponding figures for sodium nitroprusside were 5+/-1, 18+/-7, 51+/-14 and 68+/-14 AU for patients and 8+/-3, 13+/-2, 39+/-5 and 61+/-9 AU for controls, respectively (P=0.2, 0.5, 0.4, 0.7, respectively). There was also no significant difference in the flare response in patients with FMS as compared with control subjects (119+/-15 and 131+/-13 AU, respectively; P=0.57). CONCLUSION: There are no significant differences in cutaneous microvascular reactivity between patients with FMS and control subjects. PMID- 11600736 TI - Low levels of nitric oxide (NO) in systemic sclerosis: inducible NO synthase production is decreased in cultured peripheral blood monocyte/macrophage cells. AB - OBJECTIVE: To investigate nitric oxide (NO) production and inducible NO synthase expression by cultured peripheral blood mononuclear cells (PBMC) in patients with systemic sclerosis (SSc). METHODS: Eighteen patients with SSc were compared with two control groups: 16 patients with rheumatoid arthritis (RA) and 23 patients with mechanical sciatica. Nitrate was determined by fluorimetry in plasma and by spectrophotometry in supernatants. Inducible NO synthase (iNOS) was detected in cultured PBMC by immunofluorescence, immunoblotting and flow cytometry with or without treatment of the cells with interleukin (IL) 1beta+ tumour necrosis factor alpha (TNF-alpha), IL-4 or interferon gamma (IFN-gamma) from day 1 to day 5. RESULTS: NO metabolite concentrations were lower in SSc patients (mean+/ s.e.m. 34.3+/-2.63 micromol/l) than in RA (48.3+/-2.82 micromol/l; P<0.02) and sciatica (43.3+/-5.24 micromol/l; P<0.03) patients. iNOS was detected in cultured monocytes in all three groups but induction occurred on day 1 in RA, day 2 in sciatica and only on day 3 in SSc, whatever the stimulus. CONCLUSIONS: The concentrations of NO metabolites are decreased in SSc patients and the metabolism of these compounds in PBMC is altered. Low levels of NO, a vasodilator, may be involved in vasospasm, which is critical in SSc. This may have therapeutic implications. PMID- 11600739 TI - The role of technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography (SPECT) in the detection of cardiovascular involvement in systemic lupus erythematosus patients with non-specific chest complaints. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) can affect multiple organs. Coronary artery disease has received increasing recognition as a major cause of morbidity and mortality in SLE in recent years. The purpose of this study was to evaluate the utility of technetium-99m sestamibi single-photon emission computed tomography ((99m)Tc-sestamibi SPECT) in the detection of cardiovascular involvement in SLE patients with non-specific clinical chest symptoms such as chest discomfort and/or dyspnoea and/or occasional palpitation. METHODS: Thirty three SLE female patients (age range: 22-45 yr) with non-specific complaints such as chest discomfort and/or dyspnoea and/or occasional palpitation were investigated using a (99m)Tc-sestamibi myocardial perfusion SPECT scan at rest and after dipyridamole infusion in a stress study. The age- and sex-matched healthy group (24 cases) and SLE patients without any cardiovascular symptoms/signs (28 cases) were also included as controls in this study. The results of the uptake pattern of (99m)Tc-sestamibi were classified into four types including normal, persistent perfusion defect, reversible perfusion defect and reverse redistribution. RESULTS: Perfusion abnormalities were detected in 27 cases (seven patients had persistent perfusion defects, 15 patients had reversible perfusion defects, one patient had both persistent and reversible perfusion defects, two patients showed a reverse redistribution pattern and two patients had both reversible perfusion defects and a reverse redistribution pattern). The results of the SPECT in the healthy group were all normal. However, perfusion abnormalities were detected in 12 cases in the group of asymptomatic SLE patients. CONCLUSIONS: (99m)Tc-sestamibi myocardial perfusion SPECT is a useful non-invasive imaging modality to detect cardiovascular involvement in SLE patients with non-specific clinical complaints of heart disease. PMID- 11600738 TI - Ankle brachial pressure index in systemic sclerosis: influence of disease subtype and anticentromere antibody. AB - OBJECTIVE: To test the hypothesis that patients with limited cutaneous systemic sclerosis (SSc) have a higher incidence of lower limb large vessel disease than patients with diffuse cutaneous disease, and that anticentromere antibody is a risk factor for lower limb large vessel disease. METHODS: Clinical and laboratory data from 119 patients with SSc (91 patients with limited cutaneous disease, 28 patients with diffuse cutaneous disease) who had bilateral ankle brachial pressure indices (ABPI) measured between March 1997 and January 2000 were reviewed retrospectively. RESULTS: There was no evidence of reduced ABPI in limited cutaneous disease (P=0.65), average reduction 0.01 [95% confidence interval (CI) -0.04 to +0.07]. There was some suggestion of reduced ABPI in anticentromere-positive patients (P=0.12), average reduction 0.04 (95% CI -0.01 to +0.09). CONCLUSIONS: The severity of large vessel macrovascular disease, as assessed by ABPI, is not dependent on disease subtype. Anticentromere antibody may be weakly associated with a reduction in ABPI. PMID- 11600740 TI - The validity of the Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire. AB - OBJECTIVE: To examine further the usefulness of a 30-item disease-specific quality of life (QoL) questionnaire in patients with rheumatoid arthritis (RA). METHODS: The Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire was applied to two groups consisting of 210 and 300 patients with RA, one group with increasing difficulty in performing activities of daily living and one group with stable disease. The associations between the RAQoL and measures of utility, QoL, functional status and disease activity were evaluated. Factor analysis was carried out to investigate if one or more QoL dimensions could be distinguished within this questionnaire. RESULTS: Similar results regarding the association between the RAQoL and different sets of outcome measures were found in the two groups of patients. Regression analysis showed that about 75% of the variance of the RAQoL could be explained with variables of QoL, functional status and disease activity. Physical contact could be distinguished as a separate dimension within the RAQoL, in addition to the dimensions mobility/energy, self-care and mood/emotion. CONCLUSION: The RAQoL is a valid instrument for measuring QoL in different populations of patients with RA. Physical contact, a dimension that is not covered by other common instruments in RA, could be distinguished as a separate dimension within the questionnaire. PMID- 11600741 TI - T-cell responses to viral, bacterial and protozoan antigens in rheumatoid inflammation. Selective migration of T cells to synovial tissue. AB - OBJECTIVE: To identify any preferential or selective migration of T-cell specificities to inflamed tissues of rheumatoid arthritis (RA) patients. METHODS: Lymphocytes from peripheral blood (PB) and synovial tissue (ST) were isolated from RA patients and stimulated with a panel of crude antigen preparations from 18 bacterial, protozoan and viral sources. Proliferative responses of the T lymphocytes to each antigen and group of antigens were compared in PB and ST. Antigen-specific T-cell clones were developed and their migratory capacities towards synovial chemokines were compared. RESULTS: ST-derived T cells showed a small but significantly higher stimulation index (SI) to the group of intestinal bacteria compared with PB T cells. Conversely, responses of ST-derived T cells to Acanthamoeba polyphaga (AP) were both profoundly and significantly lower compared with PB-derived T cells. The viral antigens as a whole gave comparable reactivities in blood and ST. The migratory capacity of AP-specific T-cell clones towards chemokines produced by ST was profoundly poorer compared with Campylobacter jejuni- and herpes simplex virus-specific T-cell clones. CONCLUSIONS: The results indicate a selective migration of T cells of given specificities to the inflamed rheumatoid synovium. PMID- 11600742 TI - Autoantibodies to the 27 C-terminal amino acids of calpastatin are detected in a restricted set of connective tissue diseases and may be useful for diagnosis of rheumatoid arthritis in community cases of very early arthritis. AB - BACKGROUND: Calpastatin is the natural inhibitor of calpains, a protease that is overexpressed in rheumatoid synovial tissue and plays a key role in cartilage destruction. Autoantibodies to calpastatin (ACAST) were recently detected in rheumatoid arthritis (RA). Our aim was to determine their prevalence and their clinical significance. METHODS: ACAST were detected in a solid-phase enzyme linked immunosorbent assay (ELISA) using a synthetic peptide corresponding to the 27 C-terminal amino acids of calpastatin (CAST-C27) as the antigen. All sera reacting with this peptide also bound to purified erythrocyte calpastatin in an ELISA and/or an immunoblot assay. The frequencies and clinical significance of ACAST-C27 were assessed in sera from a well-documented population of 102 community-recruited patients (76 females; mean age 50 yr) with RA that had been evolving for <5 yr (median 2 yr) (group 1), 109 healthy blood donors, 289 patients with non-RA rheumatic disease and 88 community cases of very early (median 4 months) arthritis, i.e. 58 RA and 30 non-RA patients (group 2). RESULTS: The sensitivity of ACAST-C27 for RA was 19.5% (20/102) in group 1 and 10.3% (6/58) in group 2. These antibodies were also found in patients with anti double-stranded DNA-positive systemic lupus erythematosus (SLE) (15.5%) and patients with anti-Ro-positive Sjogren's syndrome (18.5%). However, they were not detected in cases of rheumatism resembling early RA, i.e. peripheral spondylarthropathies. ACAST-C27 were not detected in the 30 non-RA patients of group 2. They were predominantly of immunoglobulin isotype G3 and exclusively expressed lambda chains. Among ACAST-C27-positive sera, eight out of 20 (group 1) and four out of six (group 2) were negative for rheumatoid factor and anti keratin antibodies/antiperinuclear factor. No relationship was found between ACAST-C27 and clinical, biological or radiological findings. CONCLUSION: ACAST C27 are detected only in a restricted set of connective tissue diseases and therefore appear to be specific for RA when antibodies that are usually associated with SLE or primary Sjogren's syndrome are negative. Because of their presence in community cases of very early RA, particularly in some seronegative forms, ACAST-C27 may be useful in discriminating recent-onset RA from the more common non-RA rheumatic diseases, such as spondylarthropathies. PMID- 11600743 TI - Clinical significance of anti-topoisomerase I antibody levels determined by ELISA in systemic sclerosis. AB - OBJECTIVE: To determine the clinical associations of the levels of anti topoisomerase I (topo I) antibody in patients with systemic sclerosis (SSc). METHODS: Anti-topo I antibody levels were determined by enzyme-linked immunosorbent assay. In a longitudinal study, 125 sera from 21 patients were analysed during a follow-up period of 0.2-4.7 yr. RESULTS: Anti-topo I antibody levels were correlated positively with skin thickness score and renal vascular resistance, and inversely with percentage vital capacity. In the longitudinal study, five patients with a low anti-topo I antibody level at their first visit exhibited a stable antibody level or a small decrease in the level during the follow-up period, and their skin sclerosis was stable. Of 16 patients with a high anti-topo I antibody level at their first visit, seven showed a stable level, four had an increasing level and five had a decreasing level. The decreasing levels were accompanied mainly by atrophic skin change during the follow-up period, whereas the increasing levels were associated with new onset or worsening of organ involvement. CONCLUSIONS: These results suggest the potential clinical significance of anti-topo I antibody levels in evaluating disease severity and the prognosis in SSc. PMID- 11600744 TI - Radiographic joint space in rheumatoid elbow joints. A 15-year prospective follow up study in 74 patients. AB - OBJECTIVE: To evaluate radiographically the humeroulnar (HU) and humeroradial (HR) joint spaces in patients with long-term rheumatoid arthritis (RA). METHODS: An inception cohort of 74 patients with RA were followed for 15 yr. At the end point, 148 elbows were radiographed by a standard method. The HU and HR joint spaces were examined from the anteroposterior radiographs by measuring the shortest tangential distance in the middle of the joints. Destruction of the elbow joints, assessed with the Larsen method on a scale of 0-5, was studied in relation to the joint-space measurements. RESULTS: Mean (s.d.) HU joint space (n=148) in RA patients was 2.5 (1.1) mm, range 0-4 mm [2.9 (0.8) mm in men and 2.4 (1.1) mm in women]. Mean (s.d.) HR joint space (n=140) was 2.3 (0.9) mm, range 0-4 mm [2.5 (0.8) mm in men and 2.3 (1.0) mm in women]. HU and HR spaces of the affected joints (Larsen grades 2-5) [1.9 (s.d. 1.1) and 1.8 (0.9) mm respectively] were notably narrower than those of the unaffected (Larsen grades 0 1) joints [3.1 (0.7) and 2.9 (0.6) mm]. All the joints graded as Larsen 4 or 5 (n=13) had a value of 0 mm for both joint spaces. Both the HU and the HR joint space narrowing was associated with increasing destruction (Larsen grading) of the joint. [r= -0.69 (95% CI -0.77 to -0.60) and r= -0.70 (-0.78 to -0.60)]. The monotonic narrowing was significantly increasing from unaffected (Larsen 0, 1), slightly (2), moderately (3) to severely (4, 5) affected joints (P<0.001). A step in this process occurred between Larsen grades 3 and 4, when the mean joint space diminished from 1.4 and 1.5 respectively to 0 mm. CONCLUSIONS: Joint-space narrowing is a frequent consequence of rheumatoid affection of the elbow joint. HR joint space decreases together with HU joint space; however, the HR joint space is already slightly narrower at the start. The narrowing is a rather late phenomenon, occurring only after erosive destruction. This should be borne in mind when using the Larsen method to evaluate changes in the elbow joint. PMID- 11600746 TI - Anti-fibrillarin antibodies in systemic sclerosis. AB - OBJECTIVES: To investigate the nature and extent of organ involvement in anti fibrillarin antibody (AFA)-positive patients within a UK systemic sclerosis (SSc) population. METHODS: We investigated 1026 consecutive patients with SSc. AFA was identified by the characteristic clumpy nucleolar and coilin body pattern of staining in interphase cells and staining of fibrillarin in metaphase cells by indirect immunofluorescence using HEp-2 cells. Identity of the 34-kDa fibrillarin protein was confirmed by immunoprecipitation from [(35)S]methionine-labelled HeLa cell extract. RESULTS: AFA was detected in 42 patients (4.1%) with early disease onset (mean age 36 yr). Sixteen (38%) patients had limited cutaneous (lcSSc) and 26 (62%) diffuse cutaneous SSc (dcSSc). All eight Afro-Caribbean patients with AFA had dcSSc whereas the Caucasians were equally divided between dcSSc and lcSSc. Within the dcSSc subgroup, 54% had myositis, 35% had pulmonary hypertension, 15% had cardiac involvement and 23% had renal involvement. CONCLUSIONS: AFA identifies young SSc patients with frequent internal organ involvement, especially pulmonary hypertension, myositis and renal disease. In contrast to previous reports, AFA was not restricted to dcSSc patients in Caucasians. PMID- 11600745 TI - Chondrocyte phenotype and cell survival are regulated by culture conditions and by specific cytokines through the expression of Sox-9 transcription factor. AB - OBJECTIVE: To investigate the effects of culture conditions, serum and specific cytokines such as insulin-like growth factor (IGF) 1 and interleukin (IL) 1alpha on phenotype and cell survival in cultures of Syrian hamster embryonic chondrocyte-like cells (DES4(+).2). METHODS: Proteins and RNA extracted from subconfluent and confluent early- and late-passage DES4(+).2 cells cultured in the presence or absence of serum and IL-1alpha or IGF-1 or both cytokines together were analysed for the expression of chondrocyte-specific genes and for the chondrogenic transcription factor Sox-9 by Western and Northern blotting. Apoptosis was assessed by agarose gel electrophoresis of labelled low-molecular weight DNA extracted from DES4(+).2 cells and another Syrian hamster embryonic chondrocyte-like cell line, 10W(+).1, cultured under the different conditions and treatments. RESULTS: Early passage DES4(+).2 cells expressed chondrocyte-specific molecules such as collagen types alpha1(II) and alpha1(IX), aggrecan, biglycan and link protein and collagen types alpha1(I) and alpha1(X) mRNAs, suggesting a prehypertrophic chondrocyte-like phenotype. The expression of all genes investigated was cell density- and serum-dependent and was low to undetectable in cell populations from later passages. Early-passage DES4(+).2 and 10W(+).1 cells survived when cultured at low cell density, but died by apoptosis when cultured at high cell density in the absence of serum or IGF-1. IGF-1 and IL-1alpha had opposite and antagonistic effects on the chondrocyte phenotype and survival. Whereas IL-1alpha acting alone suppressed cartilage-specific gene expression without significantly affecting cell survival, IGF-1 increased the steady-state mRNA levels and relieved the IL-1alpha-induced suppression of all the chondrocyte specific genes investigated; it also enhanced chondrocyte survival. Suppression of the chondrocyte phenotype by the inflammatory cytokine IL-1alpha correlated with marked down-regulation of the transcription factor Sox-9, which was relieved by IGF-1. The expression of the Sox9 gene was closely correlated with the expression of the chondrocyte-specific genes under all conditions and treatments. CONCLUSIONS: The results suggest that the effects of cartilage anabolic and catabolic cytokines IGF-1 and IL-1alpha on the expression of the chondrocyte phenotype are mediated by Sox-9. As Sox-9 appears to be essential for matrix production, the potent effect of IL-1alpha in suppressing Sox-9 expression may limit the ability of cartilage to repair during inflammatory joint diseases. PMID- 11600747 TI - Involvement of bone morphogenic protein-2 (BMP-2) in the pathological ossification process of the spinal ligament. AB - OBJECTIVE: To investigate the function of bone morphogenic protein-2 (BMP-2) in the ossification of the spinal ligament (OSL). METHODS: Total RNA was prepared from the cultured spinal ligament cells from patients with OSL and analysed by reverse transcription-polymerase chain reaction using specific primers for BMP-2. BMP-2 mRNA expression in ligament tissues was examined by in situ hybridization. Spinal ligament cells from patients without OSL were treated with BMP-2 and examined for alkaline phosphatase activity. RESULTS: Expression of the BMP-2 gene was detected in cultured spinal ligament cells. In ligament tissues, BMP-2 mRNA was present in the chondrocyte-like cells in the fibrocartilage zone. Exogenous BMP-2 increased alkaline phosphatase activity in spinal ligament cells from patients without OSL. CONCLUSION: The BMP-2 gene is expressed in the spinal ligaments of OSL patients, and exogenous BMP-2 stimulates osteogenic differentiation of spinal ligament cells. The expression of BMP-2 in the spinal ligaments could be a clue in elucidating how heterotrophic osteogenesis develops in ligament tissue. PMID- 11600748 TI - Characteristics of handicap for patients with recent onset rheumatoid arthritis: the validity of the Disease Repercussion Profile. AB - OBJECTIVES: To investigate the applicability of the Disease Repercussion Profile (DRP) in the assessment of people with recently diagnosed rheumatoid arthritis. Previous research using this instrument has been confined to chronic samples. METHODS: Fifty-three patients with recent onset rheumatoid arthritis completed the DRP and other commonly used clinical outcome measures. RESULTS: The life areas of the DRP were highly interrelated, with the exception of finance. The total DRP score was associated with joint function, disability, subjective pain and coping, but was most highly associated with emotional disturbance, particularly depressive symptoms. No associations were found between measures of disease or demographic variables and DRP subscales. Activity was the area most often affected, with social life, emotions and appearance all more strongly endorsed than finances and relationships. However, whenever any of the areas was endorsed as affected, its impact was inevitably rated as very important. The pattern of self-perceived handicap was different from that reported in people with chronic arthritis. CONCLUSIONS: These results offer evidence that the DRP provides a valid measure of handicap for patients with early illness even with relatively low levels of disability. However, handicap in early rheumatoid arthritis may be more highly associated with psychological distress than in later stages of the illness. PMID- 11600749 TI - A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. AB - OBJECTIVE: Whether food intake can modify the course of rheumatoid arthritis (RA) is an issue of continued scientific and public interest. However, data from controlled clinical trials are sparse. We thus decided to study the clinical effects of a vegan diet free of gluten in RA and to quantify the levels of antibodies to key food antigens not present in the vegan diet. METHODS: Sixty-six patients with active RA were randomized to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 yr. All patients were instructed and followed-up in the same manner. They were analysed at baseline and after 3, 6 and 12 months, according to the response criteria of the American College of Rheumatology (ACR). Furthermore, levels of antibodies against gliadin and beta-lactoglobulin were assessed and radiographs of the hands and feet were performed. RESULTS: Twenty-two patients in the vegan group and 25 patients in the non-vegan diet group completed 9 months or more on the diet regimens. Of these diet completers, 40.5% (nine patients) in the vegan group fulfilled the ACR20 improvement criteria compared with 4% (one patient) in the non-vegan group. Corresponding figures for the intention to treat populations were 34.3 and 3.8%, respectively. The immunoglobulin G (IgG) antibody levels against gliadin and beta-lactoglobulin decreased in the responder subgroup in the vegan diet-treated patients, but not in the other analysed groups. No retardation of radiological destruction was apparent in any of the groups. CONCLUSION: The data provide evidence that dietary modification may be of clinical benefit for certain RA patients, and that this benefit may be related to a reduction in immunoreactivity to food antigens eliminated by the change in diet. PMID- 11600750 TI - Revisiting Sjogren's syndrome in the new millennium: perspectives on assessment and outcome measures. Report of a workshop held on 23 March 2000 at Oxford, UK. PMID- 11600751 TI - Alfred Baring Garrod (1819-1907). PMID- 11600752 TI - Post-partum septic sacroiliitis. PMID- 11600753 TI - Anti-thymocyte globulin in scleroderma. PMID- 11600754 TI - Metabolic abnormalities associated with microalbuminuria in systemic lupus erythematosus. PMID- 11600756 TI - Combined central retinal artery and vein occlusion in a patient with systemic lupus erythematosus. PMID- 11600755 TI - Giant cell arteritis is more prevalent in urban than in rural populations. PMID- 11600757 TI - Sjogren's syndrome: a potential new aetiology of mild cobalamin deficiency. PMID- 11600758 TI - Robin goodfellow. PMID- 11600759 TI - Alkaline metal oxoantimonates(III), A3[SbO3] (A = K or Cs). AB - The two title trialkaline trioxoantimonates(III), tripotassium trioxoantimonate(III), K(3)[SbO(3)], (I), and tricaesium trioxoantimonate(III), Cs(3)[SbO(3)], (II), crystallize in the cubic Na(3)[AsS(3)] structure type in space group P2(1)3. The structures show discrete Psi-tetrahedral [SbO(3)](3-) anions with C(3v) point-group symmetry. The Sb-O distances are 1.923 (4) A in (I) and 1.928 (2) A in (II), and the O-Sb-O bond angles are 99.5 (2) degrees in (I) and 100.4 (1) degrees in (II). PMID- 11600760 TI - A new crystalline phase of nitric acid dihydrate. AB - The crystal structure of a new high-temperature phase of nitric acid dihydrate, HNO(3).2H(2)O, has been determined at 225 K by single-crystal X-ray diffraction. The H atom of the nitric acid is delocalized to one water molecule, leading to an association of equimolar NO(3)(-) and H(5)O(2)(+) ionic groups. The asymmetric unit contains two molecules of HNO(3).2H(2)O. The two independent molecules are related by a pseudo-twofold c axis, by a translation of 0.54 (approximately (1/2)) along b, with a mean atomic distance difference of 0.3 A, except for one H atom of the water molecules (1.5 A), because of their different orientations in the two molecules. The two independent molecules, linked by strong hydrogen bonds, are arranged in layers. These layers are linked by weaker hydrogen bonds oriented approximately along the c axis. A three-dimensional hydrogen-bond network is observed. PMID- 11600761 TI - Bis(diethylenetriamine-kappa3N)nickel(II) 5-amino-1,3,4-thiadiazole-2 sulfonamidate chloride monohydrate. AB - In the X-ray crystal structure of the title complex, [Ni(C(4)H(13)N(3))(2)](C(2)H(3)N(4)O(2)S(2))Cl.H(2)O, the coordination polyhedron is composed of non-centrosymmetric [Ni(diethylenetriamine)(2)](2+) cations in which the triamine ligands coordinate to the metal centre as tridentate ligands in a facial position. The Ni(II) ions are linked to six N atoms in an octahedral arrangement, slightly compressed in one extreme. The sulfonamide behaves as a counter-ion instead of as a ligand. Important information about the deprotonated sulfonamide group conformation has been obtained. PMID- 11600762 TI - Tricarbonyl[1,1',1"-ethylidynetris(pyrazole-kappaN2)]rhenium(I) bromide and tricarbonyl[methylidynetris(pyrazole-kappaN2)]rhenium(I) iodide ethanol hemisolvate. AB - The two title compounds, [Re(C(10)H(10)N(6))(CO)(3)]Br and [Re(C(11)H(12)N(6))(CO)(3)]I.0.5C(2)H(6)O, have slightly distorted octahedral geometries about the rhenium centers. The distortions result from the constraints of the eta(3)-coordinated tris(pyrazol-1-yl)methane ligands in each case which reduce the N-Re-N bond angles well below the preferred value of 90 degrees for facially disposed ligands at a six-coordinate metal center. PMID- 11600763 TI - Transition metal complexes with thiosemicarbazide-based ligands. XLII. Bis(S methylisothiosemicarbazido-N1, N4)bis(pyrazole-N2)-nickel(II) diiodide. AB - In the title compound, [Ni(C(2)H(7)N(3)S)(2)(C(3)H(4)N(2))(2)]I(2), the Ni(II) ion assumes a centrosymmetric distorted octahedral geometry. The two molecules of S-methylisothiosemicarbazide are coordinated as bidentate ligands via the terminal N atoms, forming five-membered chelate rings. The I atoms are approximately in the equatorial plane of the chelate rings at a similar distance from both. The five-membered chelate rings are almost planar and exhibit flattened envelope conformations. There is a weak intermolecular interaction between the lone pair of electrons of the S atom and the center of the pyrazole ring. PMID- 11600764 TI - Pyridinium tetrakis(nitrato-kappa2O,O')(2,2':6',2"-terpyridine kappa3N)cerate(III) pyridine solvate and bis(methanol-kappaO)tris(nitrato kappa2O,O')(2,2':6',2"-terpyridine-kappa3N)cerium(III). AB - The title complexes, (C(5)H(6)N)[Ce(NO(3))(4)(C(15)H(11)N(3))].C(5)H(5)N or (Hpy)[Ce(NO(3))(4)(terpy)].py, (I) (py is pyridine, C(5)H(5)N, and terpy is terpyridine, C(15)H(11)N(3)), and [Ce(NO(3))(3)(C(15)H(11)N(3))(CH(4)O)(2)] or [Ce(NO(3))(3)(terpy)(OHCH(3))(2)], (II), are 11-coordinate. The coordination polyhedron of the Ce atom in (I) is irregular, while that in (II) can be described as an icosahedron with two vertices replaced by one. PMID- 11600765 TI - X-ray powder structure of a new two-dimensional nickel(II) coordination polymer with pyrazine-2,3,5,6-tetracarboxylic acid. AB - The new nickel(II) coordination polymer poly[diaquanickel(II)-mu-(pyrazine 2,3,5,6-tetracarboxylato)-tetraaquanickel(II)], [[[Ni(C(8)N(2)O(8))(H(2)O)(2)]Ni(H(2)O)(4)]](n), has been synthesized and characterized both spectroscopically and crystallographically, by X-ray powder diffraction analysis. In this two-dimensional coordination polymer, Ni(II) ions are bridged by pyrazine-2,3,5,6-tetracarboxylic acid, coordinating in a bis bidentate manner, so forming one-dimensional polymeric chains. The chains are linked by a second Ni(II) ion, via an O atom of the coordinated carboxylate group, resulting in the formation of a two-dimensional layer-like polymer. The remaining coordination sites of the two independent octahedral Ni(II) ions are occupied by water molecules. The layers are connected via hydrogen bonds involving all six coordinated water molecules. PMID- 11600766 TI - A potassium-18-crown-6 salt of a cyclic myo-inositol phosphate. AB - The six-membered phosphorinane ring in (1,4,7,10,13,16 hexaoxacyclooctadecane)potassium 2-O-benzoyl-1,3,5-O-methylidyne-myo-inositol 4,6 cyclophosphate trihydrate, [K(C(12)H(24)O(6))](C(14)H(12)O(9)P).3H(2)O, has a boat rather than a chair conformation. The K(+) ion is eight-coordinate and is connected to one of the phosphate O atoms, one of the O atoms of the myo-inositol residue and the six O atoms of the crown ether. PMID- 11600767 TI - Glycine sodium nitrate. AB - The glycine molecule in the title compound, Na(NO(3)).C(2)H(5)NO(2), exists in the zwitterionic form. The Na atom exhibits eightfold coordination and the polyhedron may be visualized as a distorted hexagonal bipyramid. The glycine molecules are linked through head-to-tail hydrogen bonds and are found 'sandwiched' between the Na(NO(3)) layers. PMID- 11600768 TI - Tetrachlorobis(N1-phenylacetamidino-kappaN2)rhenium(IV) at 11 K by X-ray diffraction and at 20 K by neutron diffraction. AB - The crystal structure of the title compound, [ReCl(4)(C(8)H(10)N(2))(2)], has been determined by X-ray diffraction at 11 K and by neutron diffraction at 20 K. The accurate and extensive data sets lead to more precise determinations than are available from earlier work. The agreement in atomic positional and displacement parameters at these very low temperatures is good. The results will facilitate re examination of the magnetic structure of the complex. The Re atom lies on a special position and the molecule has twofold crystallographic symmetry. PMID- 11600769 TI - The first pyridyl N,N'-coordinated di-2-pyridyl ketone oxime, fac tricarbonylchloro(di-2-pyridyl ketone oxime)rhenium(I) dimethyl sulfoxide solvate. AB - The structure of the first metal compound of pyridyl N,N'-coordinated di-2 pyridyl ketone oxime (dpk-o), fac-tricarbonylchloro(di-2-pyridyl-kappaN ketone oxime)rhenium(I) dimethyl sulfoxide solvate, [ReCl(C(11)H(9)N(2)O)(CO)(3)].C(2)H(6)OS, (I), is reported. The coordinated atoms (two N atoms from the pyridyl rings, three C atoms from the carbonyl groups and one Cl atom) are in a distorted octahedral arrangement, with the major distortion being due to the constraints associated with the binding of dpk-o. The packing of the molecules shows antiparallel tapes of (I), with a network of classical (O...H O) and non-classical (O...H-C) hydrogen bonds between the dimethyl sulfoxide solvate molecule and the complexed metal moiety. PMID- 11600770 TI - Bis[1-hydroxypyridine-2(1H)-thionato-S,O]copper(II). AB - The crystal structure of the widely used title fungicidal material, [Cu(C(5)H(4)NOS)(2)], has been determined at 150 (2) K from a microcrystalline fragment using synchrotron radiation. The molecule adopts a trans-square-planar configuration, with the Cu atom sited at a crystallographic centre of inversion. PMID- 11600771 TI - Mu-peroxo-bis[trans-chloro(1,4,8,11-tetraazacyclotetradecane)cobalt(III)] bis(tetraphenylborate) diacetone solvate. AB - The title complex, [Co(2)Cl(2)(mu-O(2))(cyclam)(2)](C(24)H(20)B)(2).2Me(2)CO, was obtained when [Co(cyclam)Cl(2)](BPh(4))(2) was crystallized from acetone in air; cyclam is 1,4,8,11-tetraazacyclotetradecane, C(10)H(24)N(4). The peroxo O-O moiety straddles a crystallographic centre of inversion (the two octahedral Co atoms are symmetrically bridged by the O(2) moiety), hence only half of the complex cation is in the asymmetric unit. A comparison of the O-O [1.483 (3) A], Co-Cl [2.2647 (8) A] and Co-O [1.894 (2) A] bond lengths with similar bonds in previously determined structures indicates the oxidation of Co(II) to Co(III) during the crystallization process. In the crystal lattice, cation dimers are encapsulated by six [BPh(4)](-) anions, with C-H...pi hydrogen bonds between the cyclam methylene groups and the phenyl rings of the anion. PMID- 11600772 TI - Complexes of Ag1 with cationic ligands: bis[(pyridylmethyl)ammonio]silver(I) salts. AB - Bis[(2-pyridylmethyl)ammonio]silver(I) trinitrate, [Ag(C(6)H(9)N(2))(2)](NO(3))(3), (I), and bis[bis[(4 pyridylmethyl)ammonio]silver(I)] hexakis(perchlorate) dihydrate, [Ag(C(6)H(9)N(2))(2)](2)(ClO(4))(6).2H(2)O, (II), are rare examples of complexes with cationic ligands. In (I), the Ag(+) cation has a T-shaped [2+1] coordination involving the pyridine N atoms and a nitrate O atom, while in (II) there are three independent two-coordinate Ag complex cations (two with the Ag atoms on independent inversion centres) and disordered ClO(4)(-) ions. The crystal structures reveal the role of hydrogen bonding in stabilizing these complexes. PMID- 11600773 TI - Bis(N-octylsalicylideniminato-N,O)copper(II). AB - In the title compound, [Cu(C(15)H(22)NO)(2)], the Cu(II) cation lies on a centre of symmetry. The coordination geometry about the Cu(II) ion is a parallelogram, formed by the N(2)O(2) donor set of the two bidentate long alkane chain Schiff base imine-phenol ligands. The Cu-N and Cu-O distances are 2.009 (3) and 1.888 (3) A, respectively. PMID- 11600774 TI - Diaquabis(ethylenediamine)copper(II) bis[tris(ethylenediamine)nickel(II)] tris(naphthalene-2,6-disulfonate) tetrahydrate. AB - The title mixed-metal compound, [Cu(C(2)H(8)N(2))(2)(H(2)O)(2)][Ni(C(2)H(8)N(2))(3)](2)(C(10)H(6)O(6)S(2))(3).4H( )O, was obtained during investigations of the porous frameworks constructed by amino-coordinated metal complex cations and large organic anions. All three naphthalene-2,6-disulfonate anions and the [Cu(en)(2)(H(2)O)(2)](2+) cation are located on crystallographic inversion centers and assemble into an extended two dimensional network through intermolecular hydrogen bonds, creating cavities in which the [Ni(en)(3)](2+) cations and water molecules are included. PMID- 11600775 TI - [N,N'-(4-Methyl-4-azaheptane-1,7-diyl-kappaN)bis(4-methoxysalicylideniminato kappa4O,N,N',O')]cobalt(II) ethanol hemisolvate. AB - The title compound, [Co(C(23)H(29)N(3)O(4))].0.5C(2)H(6)O or [Co(II)[(4-MeO sal)(2)Medpt]].0.5CH(3)CH(2)OH [(4-MeO-sal)(2)Medpt is N,N'-(4-methyl-4 azaheptane-1,7-diyl)bis(4-methoxysalicylideniminate)], obtained through the reaction of H(2)[(4-MeO-sal)(2)Medpt] and Co(CH(3)COO)(2) in refluxing ethanol under an atmosphere of ultrapure nitrogen, has the usual pseudo-trigonal bipyramidal coordination arrangement previously found for this class of (sal)(2)Rdpt compounds. The O-Co-O bond angle [120.4 (1) degrees] is significantly smaller than the corresponding values previously found for most non O(2)-bound [Co(II)[(sal)(2)Medpt]]-type molecules (observed range 126.9-138.6 degrees), whereas the equatorial Co-N bond [2.185 (3) A] is relatively long. PMID- 11600776 TI - Short intramolecular S...O interactions in S-substituted 2-mercaptoacetophenones. AB - The non-bonded S...O intramolecular interactions in the title compounds 2 (phenylthio)acetophenone [IUPAC: 2-[2-(phenylsulfanyl)phenyl]ethanone], C(14)H(12)OS, and 2-(benzylthio)acetophenone [IUPAC: 2-[2 (benzylsulfanyl)phenyl]ethanone], C(15)H(14)OS, are unusually short, indicating the contribution of heterocyclic oxathiole-type resonance structures to the overall bonding. PMID- 11600777 TI - Conformational comparison of five follicular fluid meiosis-activating sterol related active and inactive compounds. AB - The crystal structures of five follicular fluid meiosis-activating sterol-related Delta(8,14)-sterol compounds are presented. These are 4,4-dimethyl-23-phenyl-24 nor-5alpha-chola-8,14-dien-3beta-ol, C(31)H(44)O, 4,4-dimethyl-22-phenyl-23,24 dinor-5alpha-chola-8,14-dien-3beta-ol, C(30)H(42)O, (20R)-4,4-dimethyl-22-oxa 5alpha,20-cholesta-8,14,24-trien-3beta-ol, C(28)H(44)O(2), 4,4-dimethyl-23-phenyl 22-oxa-24-nor-5alpha-chola-8,14-dien-3beta-ol-water (4/1), 4C(30)H(42)O(2).H(2)O, and 4,4-dimethyl-5alpha-cholesta-8,14-dien-3-one, C(29)H(46)O. Two of the derivatives are inactive and three are active as agonists. Preliminary structure activity relationship studies showed that the positions of the double bonds in the skeleton and the structures of the side chains are important determinants for activity. The conformations of the skeletons were compared with double-bond isomers retrieved from the Cambridge Structural Database [Allen & Kennard (1993). Chem. Des. Autom. News, 8, 1, 31-37]; no significant differences were found. Thus, conformational changes induced by the double bonds are not discriminative with respect to the activity of the compounds. Comparisons of the side-chain conformations of active and inactive structures revealed that the crystal structures were not conclusive as far as correlation of conformation and activity of the side chains were concerned. PMID- 11600778 TI - Anti-inflammatory drugs. X. Hydrated pyrrolidinium [2-[(2,6 dichlorophenyl)amino]phenyl]acetate(HP.D.H2O). AB - In the solid-state structure of the title compound, C(4)H(10)N(+).C(14)H(10)Cl(2)NO(2)(-).H(2)O, the asymmetric unit contains one cation, one anion and a water molecule. There is a network of hydrogen bonds which is similar to that found in the hydrated diethylammonium diclofenac salt. A comparison is made of the molecular conformation of the anions in the two related structures. PMID- 11600779 TI - Hydrogen bonding in the inner-salt zwitterion and in two different charged forms of 5,6-bis(2-pyridyl)pyrazine-2,3-dicarboxylic acid. AB - 5,6-Bis(2-pyridyl)pyrazine-2,3-dicarboxylic acid exists as an inner-salt zwitterion, 3-carboxy-5-(2-pyridinio)-6-(2-pyridyl)pyrazine-2-carboxylate, (Ia), C(16)H(10)N(4)O(4). The adjacent pyridine and pyridinium rings are almost coplanar due to the presence of an intramolecular hydrogen bond involving the pyridine N atom and the NH H atom of the pyridinium group. In the crystal of (Ia), symmetry-related molecules are hydrogen bonded via the carboxylic acid OH group and one of the carboxylate O atoms to form a polymer, which exhibits a channel-type structure. In the HCl, HClO(4) and HPF(6) salts, 6-carboxy-5 carboxylatopyrazine-2,3-diyldi-2-pyridinium chloride 2.25-hydrate, (II), C(16)H(11)N(4)O(4)(+).Cl(-).2.25H(2)O, 6-carboxy-5-carboxylatopyrazine-2,3-diyldi 2-pyridinium perchlorate trihydrate, (IIIa), C(16)H(11)N(4)O(4)(+).ClO(4)( ).3H(2)O, and 6-carboxy-5-carboxylatopyrazine-2,3-diyldi-2-pyridinium hexafluorophosphate trihydrate, (IIIb), C(16)H(11)N(4)O(4)(+).PF(6)(-).3H(2)O, both pyridine rings are protonated. In the perchlorate form, and in the isomorphous hexafluorophosphate form, the molecule possesses C(2) symmetry, with has a symmetrical intramolecular hydrogen bond involving the adjacent carboxylate and carboxylic acid substituents. In the crystals of the chloride and perchlorate (or hexafluorophosphate) salts, hydrogen-bonded polymers are formed which are three-dimensional and one-dimensional, respectively. PMID- 11600780 TI - Azole. 47. Uber 3-thiomorpholino- und 3-(4-methylpiperazino)-5-nitroindazole. AB - The structures of 5-nitro-3-thiomorpholino-1H-indazole, C(11)H(12)N(4)O(2)S, (IIa), and 3-(4-methylpiperazino)-5-nitro-1H-indazole-methanol-water (2/1/1), 2C(12)H(15)N(5)O(2).CH(3)OH.H(2)O, (IIIa), are described. In the crystal lattice of (IIa), the molecules are linked into dimers by N-H...N hydrogen bonds. The asymmetric unit of (IIIa) contains two independent molecules of the indazole moiety, one molecule of methanol and one of water. The three components of (IIIa) are linked by hydrogen bonds to form double chains running along the x axis. pi Stacking involving the indazole moieties occurs in both compounds. PMID- 11600781 TI - 1-Amino-2-nitraminoethane. AB - The molecule of title compound, C(2)H(7)N(3)O(2), has a zwitterionic structure. All non-H atoms, apart from the terminal N atom of the NH(3) group, lie in the same plane, with a maximum deviation of 0.056 (1) A for the amine N atom of the nitramine group, whereas the deviation of the terminal N atom of the NH(3) group from the same plane is 1.222 (2) A. Intermolecular hydrogen bonds within the crystal form a three-dimensional network. PMID- 11600782 TI - Hexahydroxybenzene-2,2'-bipyridine (1/2). AB - 2,2'-Bipyridine (2BPY) and hexahydroxybenzene (HHB) crystallize in a 2:1 ratio as a neutral molecular adduct, C(6)H(6)O(6).2C(10)H(8)N(2), in space group P1 with Z = 1 and with the HHB molecule lying on an inversion centre. HHB, of which this is the first single-crystal X-ray structure determination, forms O-H...O hydrogen bonded chains parallel to the a axis, with O...O distances of 2.761 (1) and 2.782 (1) A. O-H...N hydrogen bonds to the 2BPY molecules crosslink these chains, with O...N distances of 2.707 (1) and 2.735 (1) A. PMID- 11600783 TI - Interpenetrating supramolecular lattices in 4,4'-bipyridine-2,3,5,6-tetrahydroxy 1,4-benzoquinone (3/2). AB - 4,4'-Bipyridine (BPY) and 2,3,5,6-tetrahydroxy-1,4-benzoquinone (THBQ) crystallize in a 3:2 ratio as a neutral molecular adduct, 3C(10)H(8)N(2).2C(6)H(4)O(6), in space group P1. There are two independent and centrosymmetric THBQ molecules and two different BPY molecules in the asymmetric unit, one of which lies about an inversion centre. The molecules link together through O-H...O and O-H...N hydrogen bonds to form three interpenetrating networks which create a 'superlattice' of three times the volume of the primitive cell. PMID- 11600785 TI - 2-Amino-5-methyl-1,3,4-thiadiazole and 2-amino-5-ethyl-1,3,4-thiadiazole. AB - The structures of 2-amino-5-methyl-1,3,4-thiadiazole, C(3)H(5)N(3)S, and 2-amino 5-ethyl-1,3,4-thiadiazole, C(4)H(7)N(3)S, have been determined for comparison with unsubstituted 2-amino-1,3,4-thiadiazole. Despite their different space groups (P2(1)/n and Pbca, respectively), the packing modes of the methyl and ethyl derivatives are similar, with comparable three-dimensional hydrogen-bonding associations. This is in contrast to the hydrogen-bonding network in 2-amino 1,3,4-thiadiazole, which is one-dimensional and has denser packing. It is shown that both packing forms are different polymorphs of a specific subunit of each array. PMID- 11600784 TI - Cinnamoyl shikonin. AB - The title compound, 1-(5,8-dihydro-1,4-dihydroxy-5,8-dioxo-2-naphthyl)-4 methylpent-3-en-1-yl cinnamate, C(25)H(22)O(6), crystallizes in space group P2(1). The phenyl ring of the cinnamate is anti to the carbonyl group of the same moiety [C-C-C-C = -175.6 (2) degrees] and is nearly parallel to the naphthyl ring system. Two six-membered rings formed by intramolecular hydrogen bonds, with O H...O distances of 2.587 (2) and 2.589 (2) A, occur on either side of the fused ring system, creating a tetracyclic pyrene-shaped system. The phenyl ring forms an intermolecular stack with the benzoquinone ring, as a result of aromatic pi-pi interactions. PMID- 11600786 TI - 4-Nitro-2-(1H-tetrazol-1-yl)phenol. AB - There are two symmetry-independent molecules in the unit cell of the title compound, C(7)H(5)N(5)O(3). The tetrazole and phenyl rings are essentially planar and are not coplanar in either molecule [dihedral angles 30.2 (1) and 7.0 (1) degrees]. In the structure, four molecules are connected by O-H...N bridges, forming four-membered molecular aggregates which are linked together by a complex three-dimensional hydrogen-bond network. PMID- 11600787 TI - Hydrogen bonding in C-methylated nitroanilines: a room-temperature monoclinic polymorph of 4-methyl-3-nitroaniline with Z' = 2. AB - The title compound, C(7)H(8)N(2)O(2), is monoclinic (space group P2(1)/n) at 295 (2) K with Z' = 2. The two types of molecule form independent C(7) chains, and the structure is related to that of the low-temperature triclinic polymorph, where Z' = 4 in P1, by a simple displacive transformation. PMID- 11600788 TI - Hydrogen bonding in nitroaniline analogues: a three-dimensional framework in 2 amino-6-nitro-1,3-benzothiazole. AB - In the title compound, C(7)H(5)N(3)O(2)S, the molecules are linked into a three dimensional framework by a combination of a three-centre N-H...(O)(2) hydrogen bond, and two-centre N-H...N and C-H...O hydrogen bonds. PMID- 11600789 TI - 4-Iodo-2-methyl-5-nitroaniline exhibits neither strong hydrogen bonding nor intermolecular I...nitro interactions. AB - In the title compound, C(7)H(7)IN(2)O(2), the O atoms of the nitro group are disordered over two sets of sites and there is evidence that the intramolecular I...nitro interaction is repulsive. In the crystal structure, there are neither strong hydrogen bonds, nor intermolecular I...nitro interactions, nor aromatic pi pi-stacking interactions. PMID- 11600790 TI - Bis(beta-alaninium) biphenyl-4,4'-disulfonate. AB - In the crystal structure of the title compound, 2C(3)H(8)NO(2)(+).C(12)H(8)O(6)S(2)(2-), N-H...O hydrogen bonds formed between the amino H atoms and the sulfonate O atoms give rise to the assembly of cationic beta-alaninium dimers and centrosymmetric biphenyl-4,4'-disulfonate anions into an extended two-dimensional layer. The resulting hydrogen-bonded ribbons can be described as C(2)(2)(6)R(4)(4)(12) according to graph-set notation. C-H...O hydrogen bonds between adjacent sheets further extend the structure into a three dimensional arrangement. PMID- 11600791 TI - The methanol hemisolvate of amiloride hydrochloride. AB - In the asymmetric unit of N-(3,5-diamino-6-chloropyrazin-2-ylcarbonyl)-N (diaminomethylene)ammonium chloride methanol hemisolvate, C(6)H(9)ClN(7)O(+).Cl( ).0.5CH(4)O, there are two crystallographically different amiloride molecules. Crystallographically identical amiloride molecules are stacked one above the other, alternately rotated by 180 degrees. These stacks are arranged parallel to each other, forming layer A. The least-squares plane of the non-H atoms of the other molecules lying in layer B is tilted against the corresponding plane of the molecules in layer A by an angle of 79.89 (3) degrees. The methanol molecules and Cl(-) anions are located between these layers, although the methanol molecules are closer to layer A. PMID- 11600793 TI - 2-[1-(Hydroxyimino)ethyl]-2,5,5-trimethylperhydropyrimidine-butane-2,3-dione monooxime (1/1). AB - The title compound, C(9)H(19)N(3)O.C(4)H(7)NO(2), displays strong intramolecular O-H...N [O...N 2.6743 (13) A] and N-H...N [N...N 2.6791 (15) A] hydrogen bonds, and strong intermolecular O-H...N [O...N 2.7949 (15) A] and N-H...O [N...O 3.0924 (16) A] hydrogen bonds. This creates chains of perhydropyrimidine molecules, linked by hydrogen bonds. Each chain is linked to a partner chain, through hydrogen bonds to two butane-2,3-dione monooxime molecules, in a structure reminiscent of a ladder. PMID- 11600792 TI - Design of peptides with alpha,beta-dehydro residues: a dipeptide with a branched beta-carbon dehydro residue at the (i+1) position, methyl N-(benzyloxycarbonyl) alpha,beta-didehydrovalyl-L-tryptophanate. AB - The structure of the title peptide, C(25)H(27)N(3)O(5), has been determined and its conformation analysed. Values of the standard peptide torsion angles are phi(1) = -44.2 (3) degrees, psi(1) = 135.9 (2) degrees, phi(2) = -141.6 (2) degrees and psi(2)(T) = 168.0 (2) degrees. The crystal structure is stabilized by an intermolecular hydrogen bond, with an N...O distance of 2.919 (3) A, which is formed between screw-axis-related NH and CO groups of dehydrovaline residues. PMID- 11600794 TI - 4,5-Dihydro-7,8-dimethoxy-1-phenyl-3H-2,3-benzodiazepin-4-one. AB - The title compound, C(17)H(16)N(2)O(3), is an antagonist for AMPA/kainate receptors. The molecule has its seven-membered oxadiazole ring in a boat conformation. Asymmetry of the two methoxy bond angles is evident, with (Me)O-C-C angles of 115.45 (12) and 124.78 (13) degrees, and 114.67 (12) and 125.31 (12) degrees. A centrosymmetric dimer involving the HN-CO moieties, with an N...O distance of 2.876 (2) A, graph set R(2)(2)(8), is further linked into chains through methoxy Csp(3)-H...N hydrogen bonds, with a C...N distance of 3.418 (2) A. PMID- 11600795 TI - trans-2,4,4,6,8,8-Hexamorpholino-2,6-bis(n-propylamino)cyclo 2lambda5,4lambda5,6lambda5,8lambda5-tetraphosphazatetraene. AB - The title compound, C(30)H(64)N(12)O(6)P(4), consists of a centrosymmetric chair shaped cyclic tetrameric phosphazene ring with six bulky morpholino and two n propylamino side groups. The two n-propylamino side groups are in trans positions. The bulky substituents mainly determine the eight-membered-ring conformation. The endocyclic N-P-N angles around the P atoms having different substituents are not the same as the P-N-P angles of the macrocyclic ring. PMID- 11600796 TI - The biology of the future and the future of biology. PMID- 11600797 TI - The presence and influence of religion in American bioethics. AB - From the inception of the relatively short history of American bioethics in the mid-to-late 1960s, the place of religion in this field has been complex and controversial. It has also been a subject of more than casual interest and concern to bioethicists, and to an array of medical and non-medical groups in U.S. society for whom the activities and issues in which bioethics is engaged have ongoing import. The questions and the tensions linked to the status and influence of religion in the sphere of bioethics have ramifications that extend beyond bioethics and biomedicine into matters involving the relationship of religion to the institutional structure of American society--most particularly its political, legal foundations, and realm of public affairs--and to its cultural attributes and tradition. It is within this larger perspective that we will consider the association between American bioethics and religion. Our analysis includes two case studies: (1) how, in the early years of bioethics, a pioneering organization in the field dealt with the "redefinition of death" in its discussions and in a major medical journal publication; and (2) the way in which the most recently appointed federal bioethics commission, the National Bioethics Advisory Commission, involved religion in its work on cloning and stem cell research. PMID- 11600798 TI - Genetic conflict and apoptosis. AB - The benefits of apoptosis in the removal of unnecessary, damaged, or dangerous cells are dependent on the altruism resulting from the absence of genetic conflict between genes in cells. However, this altruism can be exploited by self promoting or ultra-selfish genes. These self-promoting genes can be endogenous, as with neoplasia or germ cell mutations, or exogenous, as with cellular pathogens. The fundamental flaw of apoptosis is that its development and maintenance as a system is constantly opposed by the emergence of self-promoting genes. Since apoptotically impaired cells cannot be relied on to kill themselves, apoptotic input from other cells is required for controlling self-promoting genes. Certain unique features of germ cell development, such as linkage by cytoplasmic bridges and the requirement for granulosa or Sertoli cells, appear to serve this requirement for control of self-promoting genes. PMID- 11600799 TI - Hans Berger: from psychic energy to the EEG. PMID- 11600800 TI - The origin of radiophobias. PMID- 11600801 TI - Evolution of knowledge encapsulated in scientific definitions. PMID- 11600802 TI - Muscle dysmorphia: a critical review of the proposed criteria. AB - While body-image related disorders such as anorexia nervosa have focused on thinness, only recently have clinical criteria for a disorder that centers around muscularity--muscle dysmorphia--been proposed. An individual affected by muscle dysmorphia is overly concerned with his or her degree of muscularity. This preoccupation is manifested in the individual's behavior (excessive weight lifting, excessive attention to diet, social impairment). This article examines the historical aspects and proposed criteria for muscle dysmorphia and contrasts them with those of anorexia nervosa. While the authors of the proposed criteria have suggested that muscle dysmorphia be classified as a subcategory of body dysmorphic disorder, both the historical and clinical aspects of this syndrome are more consistent with its classification as an obsessive-compulsive disorder. PMID- 11600803 TI - A normative construction of Gulf War syndrome. AB - In early 1992, U.S. troops returning from the Gulf War began reporting a variety of nonspecific symptoms such as fatigue, skin rash, headache, muscle and joint pain, and loss of memory. These reports marked the beginning of what was to be identified as the Gulf War Syndrome (GWS). In the years since the war, as many as 100,000 troops have claimed they suffer from this mysterious disease. In our culture, the existence of disease as a specific entity is fundamental to ensuring the validity of that disease. The legitimacy of GWS has been repeatedly called into question because no specific physiological etiology has been confirmed, and it is becoming more and more likely that the origin of GWS will never be clearly delineated. The purpose of this paper is to illustrate the complicated process of defining GWS as a legitimate illness in the absence of etiological evidence and to suggest a method of treatment for individuals who still suffer from its sequelae. PMID- 11600804 TI - Patient autonomy naturalized. AB - Traditional informed consent often promotes passive acquiescence rather than active exercise of autonomy. A more natural biologically based model of autonomy is needed, a model that both recognizes the biological roots and therapeutic benefits of active confident choices among real alternatives, and offers substantive guidelines for promoting patient autonomy. A biological model of patient autonomy explains the value of information to patients, outlines the circumstances under which patients make effective choices, and suggests complementary roles for patients and professional caregivers. PMID- 11600805 TI - More on Merde. AB - Whereas food has always received much attention in conversation, commerce, and the literature, the subject of feces has been comparatively neglected. To fill this lacuna, a small book on comparative coprology was recently published (Lewin 1999). The present article aims to supplement this book with a review of overlooked or new items relating to biological and medical aspects of coprology, notably chemical and microbial components of human and animal feces, their uses as fertilizers, and a few other sociological impacts. PMID- 11600806 TI - [Hereditary colorectal carcinomas - reflection on preventive surgery]. AB - Nonpolyposis Colorectal Cancer (HNPCC) accounts for about 5% of all colorectal cancers and is the most frequent familial form; familial adenomatous polyposis coli accounts for about 1%. Prerequisitive for individually tailored surveillance is the identification of the pathogenic germline mutation. In classical FAP, surgical standard is a restorative proctocolectomy while in HNPCC there is no surgical standard other than standard oncological resection due to missing evidence. In HNPCC, prophylactic colectomy before the onset of the first colorectal cancer is not recommended. Main arguments for the extension of the resection in the case of the first colorectal carcinoma in HNPCC are the rate of metachronous colorectal carcinomas of 40-45% in a 10-year interval and rapid tumor progression. In HNPCC, in the case of first colon cancer a subtotal colectomy seems to be indicated. A proctocolectomy or, if indicated, a restorative proctocolectomy may be considered in the case of carcinomas in the lower rectum. These considerations should be evaluated in a prospective clinical trial. Counselling, molecular diagnosis and surgery in patients with hereditary colorectal cancers should only be performed in interdisciplinary centers. PMID- 11600807 TI - [New developments in chemotherapy of gastrointestinal carcinomas]. PMID- 11600808 TI - [Rehabilitation in integrative treatment of cancer patients]. PMID- 11600809 TI - [Quality of life in oncological studies]. AB - During the past 20 years many efforts were made in oncology to establish quality of-life research within clinical trials. The first step was to introduce research questions regarding the quality of life (QoL) of patients into the clinical oncological study context. Particularly after publication of the QLQ C 30 questionnaire by the EORTC Quality of Life Study Group a valid and reliable standard instrument for QoL evaluation was available, and many study groups started to include research questions on QoL in their trial protocols. However, it became obvious during the last years that the necessary integration of these methods into the treatment-oriented study protocols was only in part successful. Although QoL is mentioned more and more as a primary or secondary endpoint, the number of investigations that actually employ QoL for answering clinically relevant questions is still very limited. Moreover, under the growing economic pressure in health care during the last years, a shift occurred towards the development of 'general health measures' and towards the economic evaluation of treatment outcome. These developments are very closely linked to quality control and quality assurance issues in regard to the structures of medical decision making. The implications of these developments for QoL research in oncology are addressed. PMID- 11600810 TI - [Coping and quality of life, the psychosomatic gynecological point of view]. PMID- 11600811 TI - [Locally ablative therapies of hepatocellular carcinoma]. AB - Locally Ablative Therapies of Hepatocellular Carcinoma Delayed diagnosis of hepatocellular carcinomas (HCC) leads to a poor prognosis with a median survival time of less than 10 months. Surgical resection of small HCCs is the treatment of choice in patients with good residual liver function. The recurrence-free 5-year survival rate after curative resection is 33%. Resectability of HCC is often limited by the low hepatic functional reserve. Only 20% of all HCC are resectable in spite of novel diagnostic tools, an intensified screening, and advances in surgical technique. Local methods for tumor ablation are promising extensions of tumor therapy, especially in patients with limited liver function, nonresectable tumors, or multifocal tumors. Vis-a-vis a change of therapeutic options, local methods of tumor ablation in combination with tumor resection promise a yet unknown improvement of the prognosis for patients with HCC. Controlled randomized studies comparing and validating these methods of local tumor ablation are eagerly awaited. In the following article different methods of tumor ablation are described. Percutaneous interventions can be distinguished into vascular regional (TAE = transarterial embolization and TACE = transarterial catheter embolization) and local ablative approaches like PEI (percutaneous ethanol instillation), LITT (laser-induced thermotherapy), Cryo (cryotherapy), and RFA (radio frequency ablation). PMID- 11600813 TI - [The search for therapeutic gain in radiation oncology]. AB - The Search for Therapeutic Gain in Radiation Oncology Novel strategies in radiation oncology aim at increasing the therapeutic gain, i.e., to decrease side effects while maintaining cure rates, or to increase cure rates at the same level of complications. Over the years, physical and biological strategies have been developed to achieve this goal. The physical development led to the possibility of precise, computer-controlled beam application by using modern imaging techniques and three-dimensional treatment planning. Improved patient immobilization methods allow minimal safety distances, resulting in steep dose gradients when used together with isocentric multi-field techniques. These predominantly stereotactic irradiation techniques yield therapeutic gain towards the tumor surrounding normal tissue. A critical issue that determines the tolerance of radiation therapy are structures at risk within the target volume. Fractionation is a reliable method to exploit the differential potential for recovery of radiation-induced DNA damage in normal tissues. Radiogenetic strategies aim at the sensibilization of tumor cells by targeting specific characteristics like mutations of p53. The reverse idea, gene-therapeutic radioprotection of normal tissue, is under investigation. PMID- 11600812 TI - [Ldr brachytherapy, a minimally invasive alternative in the treatment of organ confined prostate cancer]. AB - LDR Brachytherapy, a Minimally Invasive Alternative in the Treatment of Organ Confined Prostate Cancer In den letzten Jahren erlebte die Brachytherapie mit permanenten Implantaten beim organbegrenzten Prostatakarzinom besonders in den USA, wo im Jahre 1999 mehr als 40 000 Implantationen durchgefuhrt wurden, eine Renaissance. Mit einer gewissen Verzogerung nimmt die Popularitat dieser Methode auch in Europa immer mehr zu. Dies, obwohl die Brachytherapie keine absolut neue Methode in der Behandlung des Prostatakarzinoms ist, sie hat im Gegenteil eine lange Tradition. PMID- 11600814 TI - [Tumor-specific therapy strategies in oncology]. PMID- 11600815 TI - [Gene therapy of pancreatic cancer with microencapsulated CYP2B1-expressing cells]. PMID- 11600816 TI - [Selective inhibition of tyrosine kinases - a new therapeutic principle in oncology]. AB - Tyrosine kinases are enzymes that regulate mitosis, differentiation, migration, neovascularization, and apoptosis. Their spectrum and association with specific malignancies offer multiple targets for therapeutic intervention. Chronic myelogenous leukemia (CML) represents an ideal target for a therapy using a selective inhibitor of the BCR-ABL tyrosine kinase. The 2-phenylpyrimidine derivative STI571 was rationally designed to inhibit ABL and BCR-ABL tyrosine kinase activities through competitive ATP-binding pocket interactions. Phase II data demonstrate hematologic and cytogenetic responses in interferon refractory chronic-phase, accelerated-phase and blast crisis patients. However, long-term observation is needed to confirm that response data result in prolongation of survival. STI571 is being studied in other malignancies, including leukemias characterized by expression of alternate molecular forms of BCR-ABL and those expressing protein tyrosine kinases with ATP-binding pockets structurally similar to ABL, e.g. c-kit and PDGF-R. Gastrointestinal stromal tumor (GIST) cells overexpress the stem cell factor receptor CD117, the product of the proto oncogene c-kit. Inhibition of c-kit in vivo results in an immediate metabolic change of the tumor cells, detectable by positron emission tomography. Since c kit overexpression is inhibited in small-cell lung cancer cell lines, a study with STI571 as second-line therapy of c-kit-positive small-cell lung cancer is in progress. Clinical studies are ongoing in malignancies associated with an enhanced activity of the PDGF-R, such as highgrade glioma, prostate cancer and leukemias with rearrangements of PDGF-R. The development of selective tyrosine kinase inhibitors is considered a promising approach for the design of new drugs. Clinical responses to STI571 in various malignancies may stimulate greater interest in the clinical use of tyrosine kinase inhibitors. PMID- 11600817 TI - [Immunobiology of the non-small-cell lung carcinoma: new aspects]. PMID- 11600818 TI - [Angiogenesis in patients with hematologic malignancies]. AB - Angiogenesis in Patients with Hematologic Malignancies The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. Emerging data suggest an involvement of angiogenesis in the pathophysiology of hematologic malignancies as well. Recently, we and others have reported increased angiogenesis in the bone marrow of patients with acute myeloid leukemia (AML) and normalization of bone marrow microvessel density when patients achieved a complete remission (CR) after induction chemotherapy. Tumor angiogenesis depends on the expression of specific mediators that initiate a cascade of events leading to the formation of new microvessels. Among these, VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor) and angiopoietins play a pivotal role in the induction of neovascularization in solid tumors. These cytokines stimulate migration and proliferation of endothelial cells and induce angiogenesis in vivo. Recent data suggest an important role for these mediators in hematologic malignancies as well. Isolated AML blasts overexpress VEGF and VEGF receptor 2. Thus, the VEGF/VEGFR-2 pathway can promote the growth of leukemic blasts in an autocrine and paracrine manner. Therefore, neovascularization and angiogenic mediators/receptors may be promising targets for anti-angiogenic and anti-leukemic treatment strategies. The immunomodulatory drug thalidomide inhibits angiogenesis in animal models. Moreover, it has significant activity in refractory multiple myeloma. In a current phase II study for patients with primary refractory or relapsed multiple myeloma using a combination of thalidomide with hyperfractionated cyclophosphamide and dexamethasone (Hyper-CDT), we observed a partial remission in 12 of 14 evaluable patients (86%). Thus, this combination seems to be very potent. Furthermore, we evaluated the safety and efficacy of thalidomide in patients with AML not qualifying for intensive cytotoxic chemotherapy. 20 patients aged 58-85 (median 69) years were recruited to this phase I/II study and were treated with a dose of 200-400 mg per os daily for a duration of 1-40 (median 6) weeks, dependent on the individual tolerability of the drug. In 4 patients we observed a partial response (PR - defined as more than 50% reduction in leukemic blast infiltration in the bone marrow). This was accompanied by an increase in platelet counts and hemoglobin values. One additional patient showed a significant improvement of peripheral blood counts without fulfilling the criteria of a PR. In parallel, we observed a significant decrease in microvessel density in these 5 patients during treatment with thalidomide. In conclusion, thalidomide seems to have anti angiogenic as well as anti-leukemic activity in AML. The VEGF/VEGFR-2 pathway seems to play an important role in AML. Therefore, receptor tyrosine kinase inhibitors like SU5416 or SU6668 are currently evaluated in the context of phase II studies in AML. We could recently induce a stable remission in a patient with second relapse of her AML refractory towards chemotherapy by administration of SU5416 (compassionate use), a tyrosine kinase inhibitor of VEGFR-2 and ckit. Current and future studies will clarify the role of anti-angiogenic treatment strategies in AML and other hematologic malignancies. PMID- 11600819 TI - Clinical perspectives on HIV-associated lipodystrophy syndrome: an update. PMID- 11600820 TI - Production of HIV-1 by resting memory T lymphocytes. AB - BACKGROUND: The persistence of HIV-1 within resting memory CD4 T cells constitutes a major obstacle in the control of HIV-1 infection. OBJECTIVE: To examine the expression of HIV-1 in resting memory CD4 T cells, using an in-vitro model. DESIGN AND METHODS: Phytohaemagglutinin-activated peripheral blood mononuclear cells were challenged with T cell-tropic and macrophage-tropic HIV-1 clones, and with a replication-incompetent and non-cytotoxic HIV-1-derived vector (HDV) pseudotyped by the vesicular stomatitis virus glycoprotein G. To obtain resting memory CD4 T cells containing HIV-1 provirus, residual CD25(+), CD69(+) and HLA-DR(+) cells were immunodepleted after a 3 week cultivation period. RESULTS: In spite of the resting phenotype, the majority of provirus-harbouring T cells expressed HIV-1 genomes and produced infectious virus into cell-free supernatant. The expression of HDV dropped by only 30% during the return of activated HDV-challenged cells into the quiescent phase. Although resting memory T cells generated in vitro expressed HIV-1 and HDV genome when infected during the course of the preceding T cell activation, they were resistant to HIV-1 and HDV challenge de novo. The infected culture of resting memory T cells showed a higher resistance to the cytotoxic effects of HIV-1 in comparison with the same cultures after reactivation by phytohaemagglutinin. CONCLUSION: The majority of resting memory T cells infected during the course of a preceding cell activation produces virus persistently, without establishing a true HIV-1 latency. The described system could be used as a model for testing new drugs able to control residual HIV-1 replication in resting memory T cells. PMID- 11600821 TI - CCR5 and CXCR4 expression correlated with X4 and R5 HIV-1 infection yet not sustained replication in Th1 and Th2 cells. AB - OBJECTIVE: To investigate the infectivity of T-helper (Th)1 and Th2 cells (derived from ccr5 wild-type and homozygous ccr5 Delta 32) to R5 and X4 HIV-1. DESIGN: It remains unclear whether infection of Th1 and Th2 CD4 cells by R5 and X4 viruses mirrors their co-receptor expression profile as no direct quantitation of coreceptor levels and infection has been performed. In addition, it is unknown whether the lack of CCR5 expression affects the degree of Th1/Th2 polarization. METHODS: Surface expression of CCR5 and CXCR4 was determined by quantitative fluorescence activated cell sorter analysis on in vitro differentiated Th1 and Th2 cells. R5 (Ba-L) and X4 (IIIB) HIV-1 isolates were used for infection studies and the efficiency of viral entry was determined by quantitative real time polymerase chain reaction detection of reverse transcribed proviral DNA. RESULTS: Cell surface density of CCR5 molecules was eight-fold higher in Th1 versus Th2 subsets (P = 0.005) whereas CXCR4 surface density was four-fold higher in Th2 versus Th1 subsets (P = 0.006). Preferential infection and entry of Th1 cells by R5 HIV-1 was not associated with preferential replication, as eventually the R5 virus replicated to a higher level in Th2 cells in spite of lower initial viral infection/entry. By contrast, Th2 cells preferentially supported X4-virus infection and replication. High beta chemokine secretion by Th1 cells was associated with a lower R5 replication rate. CONCLUSIONS: Th1 and Th2 cells differ in their infection efficiency for R5 and X4 HIV-1. ccr5 Delta 32 homozygous individuals maintain the ability for Th1/Th2 polarization, i.e., the expression of CCR5 is not required for Th1/Th2 polarization. PMID- 11600822 TI - Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AB - OBJECTIVE: To examine the emergence and fading of NVP resistance (NVP(R)) mutations in HIV-1-infected Ugandan women and infants who received single dose NVP to prevent HIV-1 vertical transmission. DESIGN: We examined NVP(R) in women and infants who received NVP in the HIVNET 012 clinical trial, including 41 out of 48 women with infected infants, 70 randomly-selected women with uninfected infants, and 33 out of 49 infected infants. METHODS: Plasma HIV-1 was analyzed using the Applied Biosystems ViroSeq HIV-1 Genotyping System. RESULTS: NVP(R) mutations were detected in 21 out of 111 (19%) women tested 6-8 weeks after delivery. The rate of NVP(R) was similar among women whose infants were or were not HIV-1 infected. K103N was the most common mutation detected. NVP(R) mutations faded from detection within 12-24 months in all 11 evaluable women. High baseline viral load and low baseline CD4 cell count were associated with development of NVP(R). NVP(R) mutations were detected in 11 out of 24 (46%) evaluable infants who were infected by 6-8 weeks of age. The most common NVP(R) mutation detected in infants was Y181C. Those mutations faded from detection by 12 months of age in all seven evaluable infants. Of nine evaluable infants with late HIV-1 infection, only one had evidence of NVP(R). CONCLUSIONS: NVP(R) was detected more frequently in infants than women following NVP prophylaxis, and different patterns of NVP(R) mutations were detected in women versus infants. NVP(R) was detected infrequently in infants with late HIV-1 infection. NVP-resistant HIV-1 faded from detection in women and infants over time. PMID- 11600824 TI - Persistence of HIV-1 resistance in lymph node mononuclear cell RNA despite effective HAART. AB - OBJECTIVE: To analyse the presence of genotypic and phenotypic resistance in lymph node mononuclear cells from patients with sustained undetectable plasma HIV 1 RNA with highly active antiretroviral therapy. DESIGN: Cross-sectional study on 27 HIV-infected patients receiving triple therapy for a mean period of 232.8 +/- 22.1 weeks. METHODS: HIV-1 RNA was measured in plasma and lymph node cells using PCR. Reverse transcriptase and protease genes were sequenced from HIV-1 RNA obtained from lymph node cells and from peripheral blood mononuclear cell proviral DNA using a commercially available kit (TruGene). Phenotypic resistance was assessed by using a recombinant virus assay (AntiVirogram). RESULTS: Mutations were not found in lymph node mononuclear cell RNA in six out of nine patients on first-line regimens although they were detected in 15 out of 18 who received prior suboptimal combinations. Phenotypic resistance was confirmed in most of these cases. These patterns of resistance were closely related to patients' history of antiretroviral therapy and genotypic analysis of plasma HIV 1 RNA taken just before initiation of the current regimen. In half the patients analysed, resistance mutations found in lymph nodes were not always detected in archival proviral DNA from blood cells. Mean levels of HIV-1 RNA in lymph node cells were not different in patients exhibiting resistance compared with those harbouring wild-type viruses. CONCLUSION: These data demonstrate that resistant HIV-1 is produced in lymphoid tissues for prolonged periods despite effective therapy. The mechanism could represent a release from previously infected cells rather than new cycles of cellular infection. PMID- 11600823 TI - Viral phenotype affects the thymic production of new T cells in HIV-1-infected children. AB - OBJECTIVE: To determine whether viral phenotype has any effect on thymic production of new T cells in HIV-1-infected children. DESIGN: Differences in CD4+ T-cell counts and a marker of thymic output [T-cell antigen receptor (TCR) rearrangement excision circles (TRECs)], between HIV-1-infected children with non syncytium-inducing (NSI) and syncytium-inducing (SI) viral strains were determined. PATIENTS AND METHODS: A cross-sectional study in 90 samples from vertically HIV-1-infected-children (median age 4.9 years) treated with combination therapy, and a longitudinal study in three children that underwent a change from NSI to SI phenotype were carried out. Viral load, viral phenotype, CD4+ T-cell counts, and quantification of TRECs values were determined. RESULTS: Children with SI virus showed significant lower levels of CD4+ T cells and a lower thymic production of new T cells than children with NSI. These reductions were independent of the treatment and the age of the children. However, there were no differences in viral load with the phenotype between those groups. In children with both NSI and SI viral phenotype, there was a significant correlation between CD4+ T-cell counts and TRECs values. CONCLUSION: The decrease of CD4+ T cells in presence of T-tropic viruses would be mainly due to a lower production of new CD4+ T cells as consequence of the inhibitory effect of these T tropic strains on thymic function. This effect is not due either to the amount of circulating virus or to the replication kinetics of those strains, but rather depends on the ability of T-tropic viruses to infect T-cell precursors using CXCR4 receptors, which are highly expressed in immature thymocytes. PMID- 11600825 TI - Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511). AB - OBJECTIVE: To evaluate the safety and antiretroviral activity of nelfinavir mesylate at two doses as part of a combination regimen in HIV-infected, antiretroviral-naive patients. DESIGN: Phase III, multicenter, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Two-hundred and ninety-seven patients were randomized to one of three treatment groups: nelfinavir 750 mg three times daily (tid), nelfinavir 500 mg tid, or matching placebo, each in combination with open-label zidovudine (ZDV) 200 mg tid and lamivudine (3TC) 150 mg twice daily (bid). Data were analyzed on an intent-to-treat basis. RESULTS: Sixty-seven percent of patients receiving nelfinavir 750 mg tid, and 50% receiving nelfinavir 500 mg tid in combination with ZDV/3TC achieved HIV RNA < 400 copies/ml compared to 7% receiving ZDV/3TC plus placebo (P < 0.001); 55% and 30% of patients in the nelfinavir-containing arms achieved HIV RNA < 50 copies/ml at week 24. This compared with 4% in the placebo-containing arm. For patients continuing nelfinavir treatment (750 mg or 500 mg tid as treated) for a further 6 months, the proportions achieving < 400 copies/ml at week 48 were 75% and 54% (P = 0.001) and < 50 copies/ml 61% and 37%, respectively (P = 0.004). The mean increases from baseline in CD4 cell counts were also durable in patients receiving the triple combination nelfinavir therapy. The range and incidence of adverse events was similar for the two nelfinavir-containing arms, with diarrhea being the most common adverse event. CONCLUSIONS: Nelfinavir plus ZDV/3TC was superior to ZDV/3TC/placebo. In addition, the 750 mg tid nelfinavir dose was better than the 500 mg tid dose. Virologic responses were sustained over 12 months. PMID- 11600826 TI - HIV-protease inhibitors alter retinoic acid synthesis. AB - BACKGROUND: An increasing rate of highly-active antiretroviral therapy (HAART) associated metabolic and morphological abnormalities has been reported in HIV infected persons. Some of them resemble retinoid-related adverse events, indicating alteration(s) of retinol metabolism or of retinoic acid-mediated signalling. OBJECTIVE: To evaluate retinol levels in patients with or without HAART and to assess the effect of antiretroviral agents on retinal dehydrogenase (RALDH), a key enzyme involved in retinoic acid synthesis. DESIGN: Plasma retinol levels, measured in six patients receiving HAART and in five others with no antiretroviral therapy, were correlated with levels of serum retinol-binding proteins. We then studied the effects of seven antiretroviral agents on RALDH activity and gene expression in a kidney-derived cell line (LLCPK). RESULTS: Plasma retinol levels in patients receiving HAART were decreased in comparison with those not receiving antiretroviral drugs (51 +/- 5 versus 66 +/- 11 microg/dl; P = 0.03), whereas retinol-binding protein levels were increased (68 +/- 18 versus 45 +/- 10 mg/l; P = 0.04). RALDH activity was heightened by ritonavir (24%), indinavir (17%), saquinavir (17%), zalcitabine (14%), delavirdine (12%) and nelfinavir (10%) and decreased (22%) by DMP-450. RALDH gene expression was induced only by indinavir. CONCLUSIONS: These data indicate that certain retinoid-like adverse effects in HAART-receiving patients are not due to higher retinol levels. Enhanced RALDH activity or/and gene expression by some protease inhibitors could increase retinoic acid concentrations. Elevated retinoic acid levels might be responsible for retinoid-like or other adverse effects due to alterations in the expression of retinoic acid-responsive genes. PMID- 11600827 TI - Long-term quality of life outcomes in three antiretroviral treatment strategies for HIV-1 infection. AB - OBJECTIVE: To compare changes in quality of life (QoL) over 96 weeks in patients enrolled in a triple-therapy protocol, a treatment-intensification protocol, or an induction-maintenance therapy protocol, and to compare QoL between patients who continued and discontinued their antiretroviral regimen. PATIENTS: Naive patients enrolled in a triple-therapy protocol (zidovudine/lamivudine or stavudine/didanosine or stavudine/lamivudine supplemented with protease inhibitor therapy of choice) (n = 35), a protocol of treatment intensification (ritonavir/saquinavir or ritonavir/saquinavir/stavudine) (n = 74) in which therapy was intensified with nucleoside analogue(s) in cases of insufficient viral suppression, and a protocol of induction (saquinavir/nelfinavir/lamivudine/ stavudine) maintenance (saquinavir/nelfinavir or stavudine/nelfinavir) therapy (n = 50). MAIN OUTCOME MEASURE: Changes from baseline in QoL assessed by the Medical Outcomes Study HIV Health Survey at weeks 0, 12, 24, 36, 48, 72 and 96. RESULTS: Patients in the triple-therapy and treatment-intensification protocols showed more favourable changes in physical function, social function, mental health, energy/fatigue, health distress and overall QoL compared to patients in the induction-maintenance protocol, with patients in the first two protocols showing improvements in QoL and those in the induction-maintenance protocol showing declining or unchanged QoL. Patients who discontinued study medication due to insufficient efficacy, toxicities or at their own request showed less favourable changes in QoL compared with patients who continued their regimen. The highest proportion of discontinuations was within the induction-maintenance protocol. CONCLUSION: Antiretroviral treatment strategies that are effective and tolerable have the potential to improve patients' QoL over 96 weeks. PMID- 11600828 TI - Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome. AB - OBJECTIVE: To examine the relationships between protease inhibitor (PI) therapy, body fat distribution and metabolic disturbances in the HIV lipodystrophy syndrome. DESIGN: Cross-sectional study. SETTING: HIV primary care practices. PATIENTS: PI-treated patients with lipodystrophy (n= 14) and PI-treated (n= 13) and PI-naive (n= 5) patients without lipodystrophy. MAIN OUTCOME MEASURES: Body composition was assessed by physical examination, dual-energy X-ray absorptiometry and computed tomography. Insulin sensitivity (SI) was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. Lipid profiles, other metabolic parameters, duration of HIV infection, CD4 lymphocyte counts, HIV-1 RNA load and resting energy expenditure (REE) were also assessed. RESULTS: PI-treated patients with lipodystrophy were significantly less insulin sensitive than PI-treated patients and PI-naive patients without any changes in fat distribution (SI(22) x 10(-4) (min(-1)/microU/ml) versus 3.2 x 10( 4) and 4.6 x 10(-4) (min(-1)/microU/ml), respectively; P < 0.001). Visceral adipose tissue area and other measures of central adiposity correlated strongly with metabolic disturbances as did the percent of total body fat present in the extremities; visceral adipose tissue was an independent predictor of insulin sensitivity and high density lipoprotein cholesterol levels. REE per kg lean body mass was significantly higher in the group with lipodystrophy compared to the groups without lipodystrophy (36.9 versus 31.5 and 29.4 kcal/kg lean body mass; P < 0.001), and SI was strongly correlated with and was an independent predictor of REE in this population. CONCLUSIONS: Body fat distribution and metabolic disturbances are strongly correlated in the HIV lipodystrophy syndrome and REE is increased. PMID- 11600829 TI - Elevated blood pressure in subjects with lipodystrophy. AB - OBJECTIVES: To assess the prevalence of elevated blood pressure in patients with lipodystrophy. DESIGN: Case-control study. PARTICIPANTS: Forty-two patients with abnormal body fat (100%) and serum lipids (86%) (HIV-positive cohort) were matched by age and sex to 42 HIV-positive controls without previously diagnosed lipodystrophy and to 13 HIV-negative controls. SETTING: Tertiary care, university based, fully dedicated HIV clinic. MAIN OUTCOME MEASURES: Frequency and magnitude of elevated blood pressure during highly active antiretroviral therapy. RESULTS: There were 23 +/- 16 and 22 +/- 12 blood pressure measurements recorded per subject over 21 +/- 11 and 22 +/- 11 months for the HIV-positive cohort and HIV positive controls, respectively. Three or more elevated readings occurred in 74% of the cohort and in 48% of the HIV-positive controls (P = 0.01) and accounted for 38 +/- 25% versus 22 +/- 26% (P = 0.01) of the total readings, respectively. The average of the three highest systolic readings (153 +/- 17 versus 144 +/- 15 mmHg; P = 0.01) and diastolic readings (92 +/- 10 versus 87 +/- 9 mmHg; P = 0.01) was greater for the cohort than for the HIV-positive controls. Family history of hypertension was more common in the cohort than in the controls but accounted for only 13% of the log odds ratio value for elevated blood pressure in the cohort. Systolic blood pressure was correlated with waist-to-hip ratios in the cohort (r = 0.45; P = 0.003) but not in the HIV controls (r = 0.06; P = 0.68) and tended to be related to fasting triglycerides (r = 0.34; P = 0.052) in subjects with HIV. CONCLUSIONS: Elevated blood pressure may be linked to the metabolic disorders occurring in patients with HIV, as in the dysmetabolic syndrome. PMID- 11600830 TI - Impact of early-untreated HIV infection on chronic hepatitis C in intravenous drug users: a case-control study. AB - OBJECTIVE: The impact of early-untreated HIV infection on chronic hepatitis C was determined in a case-control study, aimed at limiting factors associated with the progression of immunodeficiency. METHODS: HIV-infected patients attending for a medical examination during 1995-1996 were systematically screened for: previous intravenous drug use without other HIV or Hepatitis C virus (HCV) risk factor, CD4 cell count > 200/microl, no AIDS, no antiretroviral treatment, positive anti HCV antibody, negative hepatitis B surface antigen, abnormal aminotransferase activity. Thirty-eight consecutive eligible HIV-infected patients (cases) were included. Thirty-eight HCV-infected patients without HIV infection whose unique risk factor was intravenous drug use (controls) were paired to cases according to age, sex, and duration of HCV infection. RESULTS: Cases and controls had similar ages, sex ratios, duration of HCV infection, and alcohol intake. They were infected predominantly by genotypes 1 and 3. Viraemia was higher in cases than in controls. METAVIR histological scores of activity and fibrosis in cases versus controls were 2.2 +/- 0.8 versus 1.6 +/- 0.7 (P = 0.0008) and 1.8 +/- 1 versus 1.5 +/- 0.8 (P = 0.06), respectively. The percentage of cirrhosis was higher in cases, without reaching statistical difference. The progression rate of fibrosis was higher in cases. Age at contamination and METAVIR activity score were significantly associated with the progression of fibrosis in cases. CONCLUSION: Early-untreated HIV infection is associated with higher HCV viraemia and more severe liver injury in intravenous drug users with chronic hepatitis C. PMID- 11600831 TI - The impact of HIV/AIDS on mortality and household mobility in rural Tanzania. AB - OBJECTIVE: To assess the impact of the AIDS epidemic on mortality and household mobility before and after death. DESIGN: Open community cohort study with a demographic surveillance system and two sero-epidemiological surveys. METHODS: Ten rounds of demographic surveillance were completed during 1994-1998 in the study area, which has a population of about 20 000 people in a rural ward in north-west Tanzania. Households with deaths were visited for a detailed interview, including a verbal autopsy. Data on HIV status were collected in two surveys of all residents aged 15-44 years. RESULTS: Mortality rates among HIV infected adults were 15 times higher than those among HIV-negative adults and HIV/AIDS was associated with nearly half of deaths at ages 15-44 years. Verbal autopsies without HIV test results considerably underestimated the proportion of deaths associated with HIV/AIDS. The mortality probability between 15 and 60 years was 49% for men and 46% for women and life expectancy was 43 years for men and 44 years for women. By their second birthday nearly one-quarter of the newborns of HIV-infected mothers had died, which was 2.5 times higher than among children of HIV-negative mothers. Mobility of household members before and after death was high. In 44% of households in which the head died all members moved out of the household. CONCLUSIONS: In this rural population with HIV prevalence close to 7% among adults aged 15-44 years during the mid-1990s, HIV/AIDS is having substantial impact on adult mortality. A common response to death of a head of household in this community is household dissolution, which has implications for measurement of the demographic and socio-economic impact of AIDS. PMID- 11600832 TI - The development of the HIV epidemic in Karonga District, Malawi. AB - OBJECTIVE: To investigate the prevalence and sociodemographic risk factors for HIV infection, during the early stages of the epidemic, in a rural area of northern Malawi. METHODS: As part of a community-based study of mycobacteria, socioeconomic data and HIV results are available on approximately 30,000 individuals from random population samples in 1981-1984 and 1987-1989 from a rural area of Malawi. These have been analysed to characterize the early stages of the HIV epidemic. RESULTS: The earliest HIV-positive specimens were collected in 1982. HIV prevalence in individuals aged 15-49 years was 0.1% in the early 1980s and 2.0% in the late 1980s. In the early 1980s, eight out of 11 HIV positive individuals were new immigrants to the district or had recently returned there. In the late 1980s, immigration and having spent time outside the district continued to be major risk factors for HIV. HIV infection was more common in those with occupations other than subsistence farming, in those with more schooling, and in those in the best housing. The association with schooling was seen at all ages for both men and women. CONCLUSION: Immigration and travel were important in the repeated introduction and establishment of the HIV epidemic. The association with schooling is similar to that found elsewhere in Africa. PMID- 11600833 TI - Cost-effectiveness of HIV screening of patients attending clinics for sexually transmitted diseases in Amsterdam. AB - OBJECTIVE: To estimate the cost-effectiveness of universal HIV screening of patients attending a clinic for sexually transmitted diseases (STD) in Amsterdam. DESIGN: Cost effectiveness analysis. METHODS: A Bernoulli model for the secondary transmission of HIV was linked with epidemiological data on infection with HIV and other STD in patients attending a STD clinic in Amsterdam from 1991 to 1997. This gave estimates of the number of secondary HIV infections caused by attenders of the STD clinic. Combined with data on the health and monetary benefits of averting HIV infection and costs of HIV screening, we assessed the cost effectiveness of HIV-screening of attenders of the STD clinic. RESULTS: Increased risk for HIV infection was found in STD clinic attendees infected with other STD. (odds ratio, 2.07). The risk differed for specific STD: the highest odds ratios were found for syphilis and gonorrhoea. Screening of all attendees was estimated at net costs of 82,552 Euro per secondary infection averted. The cost effectiveness ranges between 680 Euro and 9335 Euro per life-year gained, depending on the value of key parameters used in the model. CONCLUSION: Compared to other interventions in infectious diseases control in the Netherlands, screening of STD clinic attendees for HIV has an acceptable cost-effectiveness. PMID- 11600834 TI - Getting to the HAART of insulin resistance. PMID- 11600835 TI - Elevated substance P levels in HIV-infected men. AB - The neuropeptide, substance P, is a potent modulator of neuroimmunoregulation. Substance P and its receptor modulate HIV infection. HIV-seropositive men had significantly higher plasma substance P levels compared with uninfected controls, which were associated with decreased CD16 and CD56 natural killer (NK) cell populations. The changes in plasma substance P levels and decreases in NK subsets did not correlate with CD4 cell levels, but a diurnal pattern was suggested for substance P. The balance between substance P expression and functions of immune cells may be important in the immunopathogenesis of HIV infection. PMID- 11600837 TI - Short-term exercise training improves body composition and hyperlipidaemia in HIV positive individuals with lipodystrophy. AB - Exercise/physical activity is increasingly being advocated as a positive addition to the treatment regimen of HIV-positive individuals. We investigated the effects of 10 weeks' aerobic and resistance training on individuals with HIV-related lipodystrophy. These individuals demonstrated an improvement in exercise tolerance, body composition and blood lipid profiles. Potentially, such changes may contribute to an amelioration of some of the adverse metabolic effects associated with highly active antiretroviral therapy. PMID- 11600836 TI - A single-nucleotide polymorphism in the sterol-regulatory element-binding protein 1c gene is predictive of HIV-related hyperlipoproteinaemia. AB - A single-nucleotide polymorphism (3'322C/G) was identified in the gene encoding a key cholesterol/triglyceride regulator, sterol-regulatory element-binding protein 1c (SREBP-1c). Although it did not alter the amino acid sequence, SREBP-1c 3'322C/G was predictive of highly active antiretroviral therapy-related hyperlipoproteinaemia. Increases in cholesterol were less frequently associated with homozygous SREBP-1c-3'322G (genotype 22) than with heterozygous/homozygous SREBP-1c-3'322C (genotypes 11/12) and correlated with leptin and insulin increases, particularly in genotype 11/12 carriers. A functional mutation linked to SREBP-1c-3'322C/G or messenger RNA conformation differences may explain our findings. PMID- 11600838 TI - Penetration of efavirenz into the male genital tract: drug concentrations and antiviral activity in semen and blood of HIV-1-infected men. AB - Efavirenz is a potent non-nucleoside reverse transcriptase inhibitor, licensed for the treatment of HIV-1. Data on sanctuary site penetration are limited. Therefore, we measured efavirenz concentrations in the blood and semen of 19 HIV 1-positive men and found concentrations in seminal plasma averaged 10% of those in blood plasma. Furthermore, seminal plasma viral loads were suppressed by 24 weeks of therapy in all patients. These data suggest that efavirenz-containing regimens have antiviral activity within the male genital tract. PMID- 11600840 TI - Rapid disease progression and the rate of spread of the HIV epidemic. AB - Traditional HIV epidemic models suggest that rapid disease progression may lead to reduced transmission because of a decreased time for the spread of the virus. We present a transmission model structured by age and duration of infection, and propose that rapid disease progression may lead to higher viraemia at a younger age, when individuals are more sexually active. We suggest that rapid disease progression should be considered as a factor in the scale of the HIV epidemic in Africa. PMID- 11600839 TI - Co-infection with HTLV-1 is associated with a shorter survival time for HIV-1 infected patients in Bahia, Brazil. AB - Co-infection with HTLV-1 reaches 20% among patients infected by HIV-1 in Bahia, Brazil. To evaluate its impact on survival, we conducted a retrospective, case control study involving 198 patients (63 cases). Co-infection was associated with parenteral exposure (P = 0.0001) and female sex (P = 0.02). Co-infected patients had a shorter mean survival (1849 days) than controls (2430 days, P = 0.001), regardless of sex or baseline CD4 cell count. In Bahia, Brazil, co-infection with HIV-1 and HTLV-1 is associated with a shorter survival time. PMID- 11600841 TI - Prevalence and correlates of anal sex with men among young adult women in an inner city minority neighborhood. AB - In a population-representative sample of 202 18-24-year-old women in a neighborhood with widespread injection of drugs and HIV, 14% reported unprotected anal sex with men in the past year. Independent significant predictors were illegal drug use, having a main partner who takes the lead in deciding what to do during sex, and less self-deception. Having ever had anal sex was associated with having ever been infected with hepatitis B. PMID- 11600842 TI - Efficacy of cidofovir on human herpesvirus 8 viraemia and Kaposi's sarcoma progression in two patients with AIDS. PMID- 11600843 TI - Acute hepatitis B by sexual transmission after interruption of lamivudine containing antiretroviral regimen. PMID- 11600844 TI - Diverse BF recombinants have spread widely since the introduction of HIV-1 into South America. AB - OBJECTIVE: To describe the genetic diversity of HIV-1 in South America by full genome sequencing and analysis. METHODS: Purified peripheral blood mononuclear cell DNA from HIV-infected individuals in Argentina, Uruguay and Bolivia was used to amplify full HIV-1 genomes. These were sequenced using the ABI 3100 automated sequencer and phylogenetically analysed. RESULTS: Twenty-one HIV-1 strains from three South American countries, 17 of which were pre-screened by envelope heteroduplex mobility assay (HMA), were studied. Ten out of 10 HMA subtype F and four out of seven HMA subtype B strains were actually BF recombinants upon full genome analysis. Two BF recombinants from Argentina and two from Uruguay had the same structure, representing a new circulating recombinant form termed CRF12_BF(ARMA159). Twelve other BF recombinants had structures related to CRF12 but with additional segments of subtype B; each was unique. BF recombinants were temporally and geographically widespread, found as early as 1986-1987 in vertically infected Argentinian children and in Argentina, Uruguay, and Bolivia. PMID- 11600847 TI - Alternative and complementary medicine: an overview. PMID- 11600848 TI - Alternative therapies of morning sickness. PMID- 11600849 TI - Traditional Native American practices in obstetrics. PMID- 11600850 TI - Home birth. PMID- 11600851 TI - Complementary and alternative medicine in the labor and delivery suite. PMID- 11600853 TI - Alternative therapies for the management of pain in labor and delivery. PMID- 11600852 TI - Doulas: an alternative yet complementary addition to care during childbirth. PMID- 11600854 TI - Use of water in labor and birth. PMID- 11600855 TI - Varieties of alternative experience: complementary care in the neonatal intensive care unit. PMID- 11600857 TI - Alternative medicine in gynecology. Foreword. PMID- 11600858 TI - Overview of complementary, alternative, and integrative medicine. PMID- 11600859 TI - Regulation of dietary supplements in the United States: understanding the dietary supplement health and education act. PMID- 11600860 TI - Industry self-regulation in the manufacture of dietary supplements and botanical medicines. PMID- 11600861 TI - Traditional Chinese medicine. PMID- 11600862 TI - Botanicals in cardiovascular health. PMID- 11600863 TI - Herbs affecting the central nervous system: gingko, kava, St. John's wort, and valerian. PMID- 11600864 TI - Clinical effects of phytoestrogens. PMID- 11600865 TI - Soy phytoestrogens: research on benefits and risks. PMID- 11600866 TI - Botanicals: medicines and menopause. PMID- 11600867 TI - Unconventional estrogens: estriol, biest, and triest. PMID- 11600868 TI - Potential therapeutic effects of prescribed and over-the-counter androgens in women. PMID- 11600869 TI - Use of growth hormone and growth hormone secretagogues in aging: help or harm. PMID- 11600870 TI - Integrating complementary and alternative medicine into clinical practice. PMID- 11600873 TI - Biology of cancer: some questions to answer. AB - Though great advances in cancer biology have taken place through these years, some fundamental questions are still to be explained. Some observations in this regard are discussed in the present paper. In the course of experimental studies on hormonal stimulation of target cells, it was observed that goat granulosa cells showed differential proliferative response to sustained stimulation by oLH and hCG in culture. oLH caused cells to proliferate whereas hCG failed to stimulate the cells though both the gonadotropins have common receptors on the target cell. Further studies might throw some light on the mechanism of signal transduction in cell biology and neoplasia. A question is also posed as to how to interpret thermodynamically the sustained growth of cancer vis-a-vis the host. PMID- 11600874 TI - Clinical study: epileptic seizures may modify cytokine secretion in patients suffering from epilepsy and in experimental animals. PMID- 11600875 TI - Gut neuroendocrine cells: relationship to the proliferative activity and apoptosis of mucous epitheliocytes in aging. AB - OBJECTIVES: Diffuse neuroendocrine system (DNES) cells regulate homeostasis via neurocrine, endocrine and paracrine mechanisms. Extensive effects of peptide hormones and biogenic amines necessitate studying of DNES cell biology in aging. In this connection, the functional morphology of gut neuroendocrine cells (NEC), proliferative activity and apoptosis of mucous epithelial cells in aging have been studied. MATERIAL AND METHODS: The study was performed on BALB/c-nu mice of 4, 21 and 34 months of age. NEC, proliferative activity and apoptosis of mucous epitheliocytes in stomach and duodenum have been studied by histochemical, immunohistochemical and morphometrical methods. RESULTS: The total number of NEC shows an increasing trend with advancing age. However, the different types of NEC elicit differential patterns. The total number of epithelial cell nuclei does not show any statistically significant difference during aging. The proliferative activity of mucous epitheliocytes also shows no difference among the three animal groups studied. On the contrary, the apoptotic index increases with advancing age. CONCLUSIONS: The results demonstrate that various gut NEC show differential behavior with age and their time-courses are dependent on the site of location (stomach or duodenum). The picture seems quite complex to allow a comprehensive interpretation, nonetheless it gives us some useful indications for further investigation. In fact, since the gut does not show evident gross age-related physiological changes, modifications with age in specific biological parameters can suggest the key mechanisms of compensative regulatory processes possibly acting during aging. PMID- 11600876 TI - Anti-tumoral action of octreotide and bromocriptine on the experimental rat prolactinoma: anti-proliferative and pro-apoptotic effects. AB - OBJECTIVES: The purpose of the study was to compare the effects of bromocriptine (BC) - D-2 receptor agonist and octreotide (OCT) - somatostatin analog on the tumor weight, prolactin (PRL) secretion, cell proliferation and apoptosis in the diethylstilboestrol (DES)-induced rat prolactinoma. MATERIAL AND METHODS: Male four-week Fisher 344 rats were used in the experiment. The animals were implanted subcutaneously (s.c.) with capsules containing DES. Six weeks after the implantation the rats were given OCT (2 x 25 microg/animal/24 h s.c.) or BC (3 mg/kg b.w./24 h s.c.) for 10 days. The incorporation of bromodeoxyuridine (BrDU) into the tumor cell nuclei was used as an index of cell proliferation (labeling index - LI). The labeling of nuclear DNA fragmentation according to the TUNEL method was considered as an index of apoptosis (AI). PRL was measured by radioimmunoassay (RIA). RESULTS: It has been found that OCT and BC significantly decreased the tumor weight and LI of tumor cells to the same extent. Both OCT and BC suppressed the PRL levels, but the inhibitory effect of BC was stronger than that of OCT. BC and OCT significantly enhanced the number of apoptotic cells in the tumor, but the pro-apoptotic effect of BC was more pronounced. The joint treatment exerted additive effects on tumor mass reduction, PRL secretion and cell proliferation, but OCT attenuated the pro-apoptotic effect of BC. CONCLUSIONS: Summing up, both OCT and BC inhibit PRL secretion and cell proliferation. The anti-tumoral action of BC, and to some extent the action of OCT, is also connected with induction of apoptosis. PMID- 11600877 TI - The relationship between neuropeptides and hormones in starvation. AB - OBJECTIVES: Some hormonal disturbances were demonstrated in starvation. Leptin, NPY and galanin play an important role in the control of appetite and in the mechanism of hormone release. METHODS: In order to evaluate the effect of starvation on the relationship between leptin, neuropeptide Y (NPY) galanin and pituitary and gonadal hormones release, plasma leptin, NPY and galanin as well as serum LH, FSH, prolactin (PRL), estradiol, progesterone levels in non-starved female rats (in diestrus) and after 72 hrs of starvation were measured with RIA methods. Effects of leptin, NPY and galanin administration on pituitary and gonadal hormones were investigated in vivo and in vitro experiments. RESULTS: Plasma leptin, NPY and galanin as well as serum estradiol and progesterone concentrations were significantly lower in starved rats as compared with non starved rats. However serum prolactin level was significantly higher in starved rats. Opposite effects after leptin and NPY administration on hormone release in vivo and in vitro experiments were observed in non-starved rats. However, in starved rats we did not find changes in pituitary and gonadal hormones release after leptin, NPY and galanin injection or the hormonal response was blunted. CONCLUSIONS: 1) The disturbances in neuropeptides activity and in hormones release were observed in starvation. 2) Leptin, NPY and galanin have direct and indirect effects on pituitary and gonadal hormones release. 3) In starvation the hormonal response to leptin, NPY and galanin is impaired. PMID- 11600878 TI - Plasma leptin, neuropeptide Y (NPY) and galanin concentrations in bulimia nervosa and in anorexia nervosa. AB - OBJECTIVES: It has been reported that leptin and neuropeptide Y (NPY) play a role in the control of appetite and in the regulation of hormonal secretion. METHODS: Plasma leptin, neuropeptide Y (NPY) and galanin concentrations were estimated in 13 women with bulimia nervosa (BN) 19 women with anorexia nervosa (AN) and in 19 healthy women of the control group (CG). RESULTS: Plasma leptin concentration in BN was significantly higher than that in AN and it was lower as compared with the control group, despite the same BMI (body mass index) in both the groups. Plasma leptin level in AN was significantly lower as compared with the controls. Plasma galanin concentrations in AN and BN did not differ significantly from the control group. Plasma NPY concentration in AN was lower than that in the control group. However, plasma NPY level in BN was significantly higher as compared with AN and with the control group (CG). The observed increase of NPY in BN was independent of BMI because BMI in bulimia nervosa was normal. CONCLUSIONS: The data may suggest that other factors than body weight changes may be involved in the modulation of leptin and NPY release in BN. The pathological behaviour of patients with bulimia nervosa may result from disturbed NPY release which is the strongest orexigenic factor. PMID- 11600879 TI - Essays on chronomics spawned by transdisciplinary chronobiology. Witness in time: Earl Elmer Bakken. PMID- 11600881 TI - Human pheromones: integrating neuroendocrinology and ethology. AB - The effect of sensory input on hormones is essential to any explanation of mammalian behavior, including aspects of physical attraction. The chemical signals we send have direct and developmental effects on hormone levels in other people. Since we don t know either if, or how, visual cues might have direct and developmental effects on hormone levels in other people, the biological basis for the development of visually perceived human physical attraction is currently somewhat questionable. In contrast, the biological basis for the development of physical attraction based on chemical signals is well detailed. PMID- 11600882 TI - Increased urinary 6-sulfatoxymelatonin excretion in women with non-classical steroid 21-hydroxylase deficiency. AB - OBJECTIVES: To determine melatonin production in hyperandrogenic women. MATERIAL AND METHODS: Seventeen women with late onset adrenal hyperplasia due to 21 hydroxylase deficiency (LOCAH) and 15 control women were studied in early follicular phase of the menstrual cycle. Fasting serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E(2)), testosterone, dihydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP) as well as the peak 17-OHP response to ACTH (250 microg IV) and 24h urinary 6 sulfatoxymelatonin (aMT6s) were determined in all participants. RESULTS: All 17 hyperandrogenic women were carrying mutations of the CYP21 gene. Women with LOCAH had significantly higher serum testosterone, DHEA-S, 17-OHP and ACTH stimulated 17-OHP values compared with controls. Their aMT6s values (44.6+/-20.3 microg/24h) were significantly higher than the values in control women (31.5+/-20.3) (p<0.03). The urinary aMT6s values were positively correlated with testosterone (p<0.04), DHEA-S (p<0.02) and peak 17-OHP (p<0.04). CONCLUSIONS: Women with LOCAH have increased melatonin production. There is a relationship between adrenal androgens and melatonin in these women. PMID- 11600883 TI - Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. AB - Isolated strabismus affects 1-5% of the general population. Most forms of strabismus are multifactorial in origin; although there is probably an inherited component, the genetics of these disorders remain unclear. The congenital fibrosis syndromes (CFS) represent a subset of monogenic isolated strabismic disorders that are characterized by restrictive ophthalmoplegia, and include congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DURS). Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2), but no genes have been identified. Here, we report three mutations in ARIX (also known as PHOX2A) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription factor protein previously shown to be required for nIII/nIV development in mouse and zebrafish. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain. These findings confirm the hypothesis that CFEOM2 results from the abnormal development of nIII/nIV (ref. 7) and emphasize a critical role for ARIX in the development of these midbrain motor nuclei. PMID- 11600884 TI - Mutant protein in Huntington disease is resistant to proteolysis in affected brain. AB - The cause of Huntington disease pathophysiology is unknown, but a major hypothesis suggests that toxicity arises from the cleavage and accumulation of amino-terminal fragments containing an expanded polyglutamine region. In evaluating huntingtin protein (HD) from human brain, transgenic animals and cells, we observed, unexpectedly, that mutant HD is more resistant to proteolysis than normal HD. The N-terminal cleavage fragments we observed arise from the processing of normal HD and are sequestered by full-length mutant HD. Our results support a model in which inhibition of proteolysis of mutant HD leads to aggregation and toxicity through the sequestering of important targets, including normal HD. PMID- 11600885 TI - Replication validity of genetic association studies. AB - The rapid growth of human genetics creates countless opportunities for studies of disease association. Given the number of potentially identifiable genetic markers and the multitude of clinical outcomes to which these may be linked, the testing and validation of statistical hypotheses in genetic epidemiology is a task of unprecedented scale. Meta-analysis provides a quantitative approach for combining the results of various studies on the same topic, and for estimating and explaining their diversity. Here, we have evaluated by meta-analysis 370 studies addressing 36 genetic associations for various outcomes of disease. We show that significant between-study heterogeneity (diversity) is frequent, and that the results of the first study correlate only modestly with subsequent research on the same association. The first study often suggests a stronger genetic effect than is found by subsequent studies. Both bias and genuine population diversity might explain why early association studies tend to overestimate the disease protection or predisposition conferred by a genetic polymorphism. We conclude that a systematic meta-analytic approach may assist in estimating population-wide effects of genetic risk factors in human disease. PMID- 11600886 TI - Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. AB - Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. Here we identified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range of tissue-specific antigens. We found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output. It may facilitate tolerance induction to self antigens that would otherwise be temporally or spatially secluded from the immune system. However, the array of promiscuously expressed self-antigens appeared random rather than selected and was not confined to secluded self-antigens. PMID- 11600887 TI - IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice. AB - Immunity to infection with intracellular pathogens is regulated by interleukin 12 (IL-12), which mediates protective T helper type 1 (TH1) responses, or IL-4, which induces TH2 cells and susceptibility. Paradoxically, we show here that when present during the initial activation of dendritic cells (DCs) by infectious agents, IL-4 instructed DCs to produce IL-12 and promote TH1 development. This TH1 response established resistance to Leishmania major in susceptible BALB/c mice. When present later, during the period of T cell priming, IL-4 induced TH2 differentiation and progressive leishmaniasis in resistant mice. Because immune responses developed via the consecutive activation of DCs and then T cells, the contrasting effects of IL-4 on DC development and T cell differentiation led to immune responses that had opposing functional phenotypes. PMID- 11600888 TI - TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. AB - Here we used mice lacking tumor necrosis factor-alpha (TNF alpha) and its associated receptors to study a model of demyelination and remyelination in which these events could be carefully controlled using a toxin, cuprizone. Unexpectedly, the lack of TNF alpha led to a significant delay in remyelination as assessed by histology, immunohistochemistry for myelin proteins and electron microscopy coupled with morphometric analysis. Failure of repair correlated with a reduction in the pool of proliferating oligodendrocyte progenitors (bromodeoxyuridine-labeled NG2(+) cells) followed by a reduction in the number of mature oligodendrocytes. Analysis of mice lacking TNF receptor 1 (TNFR1) or TNFR2 indicated that TNFR2, not TNFR1, is critical to oligodendrocyte regeneration. This unexpected reparative role for TNF alpha in the CNS is important for understanding oligodendrocyte regeneration/proliferation, nerve remyelination and the design of new therapeutics for demyelinating diseases. PMID- 11600889 TI - Consolidation of human memory over decades revealed by functional magnetic resonance imaging. AB - Medial temporal lobe (MTL) lesions typically produce retrograde amnesia characterized by the disproportionate loss of recently acquired memories. Temporally graded memory loss is interpreted traditionally as evidence for a consolidation process guided by the MTL. Here, using functional magnetic resonance imaging (fMRI), we show temporally graded changes in MTL activity in healthy older adults taking a famous faces remote memory test. Evidence for temporally graded change in the hippocampal formation was mixed, suggesting it may participate only in consolidation processes lasting a few years. Entorhinal cortex was associated with temporally graded changes extending up to 20 years. These findings support the basic tenets of consolidation theory and suggest that the entorhinal cortex, rather than the hippocampal formation, participates in memory consolidation over decades. PMID- 11600890 TI - A candidate gene for human neurodegenerative disorders: a rat PKC gamma mutation causes a Parkinsonian syndrome. PMID- 11600891 TI - Interactions with identified muscle cells break motoneuron equivalence in embryonic zebrafish. AB - Two zebrafish motoneurons, CaP and VaP, are initially developmentally equivalent; later, CaP innervates ventral muscle, whereas VaP dies. Current models suggest that vertebrate motoneuron death results from failure to compete for limited, target-derived trophic support. In contrast, we provide evidence that zebrafish ventral muscle can support both CaP and VaP survival. However, VaP's growth cone is prevented from extending into ventral muscle by CaP-dependent interactions with identified muscle fibers, the muscle pioneers; this interaction breaks the initial equivalence of CaP and VaP. Thus, the processes mediating VaP death are more complex than failure to compete for trophic support, and may be important for correct spatial patterning. PMID- 11600896 TI - Cell swelling and ion redistribution assessed with intrinsic optical signals. AB - Cell volume changes are associated with alterations of intrinsic optical signals (IOS). In submerged brain slices in vitro, afferent stimulation induces an increase in light transmission. As assessed by measurement of the largely membrane impermeant ion tetramethylammonium (TMA) in the extracellular space, these IOS correlate with the extent and time course of the change of the extracellular space size. They have a high signal to noise ratio and allow measurements of IOS changes in the order of a few percent. Under conditions of reduced net KCl uptake (low Cl solution) a directed spatial buffer mechanism (K syphoning) can be demonstrated in the neocortex with widening of the extracellular space in superficial layers associated with a reduced light transmission and an increase of extracellular K concentration. The nature of the IOS under pathophysiological conditions is less clear. Spreading depressions first cause an increase of light transmission, then a decrease. Such a decrease has also been observed following application of NMDA where it was associated with structural damage. Pharmacological analyses suggest that under physiological conditions changes of extracellular space size are mainly caused by astrocytic volume changes while with strong stimuli and under pathophysiological conditions also neuronal swelling occurs. With reflected light usually signals opposite to those observed with transmitted light are seen. Recording of IOS from interface slices gives very complex signals since under these conditions an increase of light transmission has been reported to be superimposed by a decrease of the signal due to mechanical lensing effects of the slice surface. Depending on the method of measurement and the exact conditions, several mechanisms may contribute to IOS. Under well defined conditions IOS are a useful supplementary tool to monitor changes of extracellular volume both in space and time. PMID- 11600897 TI - Wave onset in central gray matter - its intrinsic optical signal and phase transitions in extracellular polymers. AB - The brain is an excitable media in which excitation waves propagate at several scales of time and space. "One-dimensional" action potentials (millisecond scale) along the axon membrane, and spreading depression waves (seconds to minutes) at the three dimensions of the gray matter neuropil (complex of interacting membranes) are examples of excitation waves. In the retina, excitation waves have a prominent intrinsic optical signal (IOS). This optical signal is created by light scatter and has different components at the red and blue end of the spectrum. We could observe the wave onset in the retina, and measure the optical changes at the critical transition from quiescence to propagating wave. The results demonstrated the presence of fluctuations preceding propagation and suggested a phase transition. We have interpreted these results based on an extrapolation from Tasaki's experiments with action potentials and volume phase transitions of polymers. Thus, the scatter of red light appeared to be a volume phase transition in the extracellular matrix that was caused by the interactions between the cellular membrane cell coat and the extracellular sugar and protein complexes. If this hypothesis were correct, then forcing extracellular current flow should create a similar signal in another tissue, provided that this tissue was also transparent to light and with a similarly narrow extracellular space. This control tissue exists and it is the crystalline lens. We performed the experiments and confirmed the optical changes. Phase transitions in the extracellular polymers could be an important part of the long-range correlations found during wave propagation in central nervous tissue. PMID- 11600898 TI - Genome engineering via homologous recombination in mouse embryonic stem (ES) cells: an amazingly versatile tool for the study of mammalian biology. AB - The ability to introduce genetic modifications in the germ line of complex organisms has been a long-standing goal of those who study developmental biology. In this regard, the mouse, a favorite model for the study of the mammals, is unique: indeed not only is it possible since the late seventies, to add genes to the mouse genome like in several other complex organisms but also to perform gene replacement and modification. This has been made possible via two technological breakthroughs: 1) the isolation and culture of embryonic stem cells (ES), which have the unique ability to colonize all the tissues of an host embryo including its germ line; 2) the development of methods allowing homologous recombination between an incoming DNA and its cognate chromosomal sequence (gene "targeting"). As a result, it has become possible to create mice bearing null mutations in any cloned gene (knock-out mice). Such a possibility has revolutionized the genetic approach of almost all aspects of the biology of the mouse. In recent years, the scope of gene targeting has been widened even more, due to the refinement of the knock-out technology: other types of genetic modifications may now be created, including subtle mutations (point mutations, micro deletions or insertions, etc.) and chromosomal rearrangements such as large deletions, duplications and translocations. Finally, methods have been devised which permit the creation of conditional mutations, allowing the study of gene function throughout the life of an animal, when gene inactivation entails embryonic lethality. In this paper, we present an overview of the methods and scenarios used for the programmed modification of mouse genome, and we underline their enormous interest for the study of mammalian biology. PMID- 11600899 TI - Evolution and development: some insights from evolutionary theory. AB - Developmental biology and evolutionary biology are both mature integrative disciplines which started in the 19th century and then followed parallel and independent scientific pathways. Recently, a genetical component has stepped into both disciplines (developmental genetics and evolutionary genetics) pointing out the need for future convergent maturation. Indeed, the Evo-Devo approach is becoming popular among developmental biologists, based on the facts that distant groups share a common ancestry, that precise phylogenies can be worked out and that homologous genes often play similar roles during the development of very different organisms. In this essay, I try to show that the real future of Evo Devo thinking is still broader. The evolutionary theory is a set of diverse concepts which can and should be used in any biological field. Evolutionary thinking trains to ask << why >> questions and to provide logical and plausible answers. It can shed some light on a diversity of general problems such as how to distinguish homologies from analogies, the costs and benefits of multicellularity, the origin of novel structures (e.g. the head), or the evolution of sexual reproduction. In the next decade, we may expect a progressive convergence between developmental genetics and quantitative genetics. PMID- 11600904 TI - [Sera levels of anti-Trypanosoma cruzi IgG in the course of chronic chagasic cardiopathy in 10 years]. AB - In order to investigate the relationship between T. cruzi specific antibodies (IgG) levels and the clinical course of chronic chagasic cardiopathy, the authors analyzed sera from 140 non-treated patients with specific drugs from Virgem da Lapa, Minas Gerais, during 10 years. Of these patients, 92 were women and 48 men, varying from 10 to 70 years old (mean = 38 +/-13.5 years). Antibody levels were estimated by the mean of titers obtained by an indirect immunofluorescence test, indirect hemagglutination assay and by the mean reactivity indexes (OD/cut-off) obtained by ELISA tests using a conventional antigens and recombinant proteins (CRA+FRA). During the study period, the course of the disease was as follows: 49 did not present cardiac alterations, 29 coursed to cardiopathy, 33 maintained initial cardiopathy, 25 evolved with aggravation of the cardiopathy and 4 with normalization of the electrocardiogram. Statistical analysis showed a significant increase in antibody levels among patients in the group with progressive cardiopathy, as well as in patients with age interval of 20 to 59 years, independent of sex. These findings indicated a direct association between T. cruzi specific antibodies (IgG) levels and the clinical course of chronic chagasic cardiopathy. PMID- 11600905 TI - [Identification of Vibrio spp bacteria on skin lesions of fisherman in the county of Raposa-MA]. AB - The study was undertaken aiming at identifying bacteria from the county of Raposa in the state of Maranhao. The clinical sample was collected by using a swab and held in a Cary-Blair transport medium. Enrichment in alkaline peptone water, isolation in TCBS selective indicator medium and biochemical coding of species were used for laboratory processing. Fifty fisherman with age varying from 12-65 years took part on the study. Vibrio bacteria isolated in 21 subjects had been identified. There was a predominance of V. alginolyticus (66.6%) followed by V. parahaemolyticus (42.8%), and V. cholerae non-O1 (9.5%). Lesions predominated on lower limbs, presenting hyperhemia, swelling, secretion, and pain. Some species of gram-negative bacteria of the Serratia, Proteus, Escherichia, Citrobacter, Enterobacter associated to the vibrios were isolated, as well as other non fermenting bacteria (30.9) and gram-positive bacteria of the genos Staphylococcus. PMID- 11600906 TI - [Cardiac attacks in patients with acute Chagas disease in a family micro outbreak, in Abaetetuba, Brazilian Amazon]. AB - The authors describe the main clinical findings relative to cardiac involvement, in patients with acute Chagas' disease (CD) in yet another familial micro epidemic episode of CD in Amazon region. Thirteen patients were studied with acute Chagas' disease, resident in the city of Abaetetuba in Para state; they were submitted to clinical and heart evaluation, with electrocardiograph and echocardiograph exams. Ventricular extrasystole occurred in 38.5% of the cases. Right bundle branch block and 1st and 2nd degree atrioventricular block were found in 30.8% of the patients. Attention is called to two findings in the Doppler echocardiography: pericardiac involvement and an image suggestive of aneurismatic formation in two patients. The findings reveal acute heart disease, with evidence of cardiomyopathy and alterations in the conduction system of the heart, bearing similarity with the description of the disease in endemic areas. PMID- 11600907 TI - [Sludge anaerobic treatment and its efficiency in reducing the viability of helminth eggs]. AB - This study evaluates the prevalence and viability of helminth eggs and protozoan cysts in sludge obtained by anaerobic treatment in four treatment stations in Curitiba, Parana State, Brazil. The parasites observed were helminths: Ascaris sp (85%), Toxocara sp (5.5%), Trichuris sp (4.5%), Hymenolepis diminuta (3.7%), H. nana (1%) and Taenia sp (0.4%), protozoan: Isospora sp, Entamoeba coli, Entamoeba histolytica, Giardia lamblia, Endolimax nana. In biological treatment based on the anaerobic digestion the effectiveness depends on the duration and temperature. The treatment showed efficiency for pathogen reduction of between 59.7 to 93%. However, the number of helminth eggs found in treatment stations was still high and new higher performance treatment is necessary for land application or for other objectives, seeking to reduce the risks for human and animal health. PMID- 11600908 TI - [Survival and infectious processes in pacients with AIDS: analysis based on initial serum vitamin A levels]. AB - Patients with Aids (n = 39) were followed up for a maximum period of 36 weeks, after which the types and topographies of infectious complications presented and patient survival were analyzed and correlated with the vitamin A levels presented by the patients at the beginning of clinical follow-up. Twenty-one (53,8%) patients presented serum retinol levels below 1.6 micromol/L, 12 (57%) of whom had values lower than 1.05 micromol/L. There was no correlation between low serum vitamin A levels and the types or topographies of the infectious complications that occurred during the follow-up period. Although mean survival at the end of the 36 months follow-up period was similar for the two groups, patients with retinol deficiency presented a lower probability of survival during the first 24 months of follow-up compared to patients without hypovitaminosis A (8.44 x 1.42 months; p = 0.003). PMID- 11600909 TI - [Triatoma infestans in area under entomological surveillance for Chagas' disease in Sao Paulo State, Brazil]. AB - In response to notification of the capture of a winged triatomine bug by local inhabitants, an epidemiological investigation was investigated in the rural area of the Municipality of Paulinia, Sao Paulo State (Brazil). This led to the collection of 109 specimens of Triatoma infestans from peridomiciliary breeding sites. Local conditions favored colonization by triatomine bugs: many abandoned outbuildings were inhabited by pigeons and sparrows, which meant abundant feed for these bugs. Thus, surveillance is mandatory as long as conditions for triatomine breeding persist. Nevertheless, entomological and serological indicators ruled out immediate concern over vectorial transmission of Chagas' disease in this municipality. All domiciliary units of the region were sprayed with residual-effect insecticides and the triatomine breeding sites were destroyed by the use of mechanical control of bird nests. The importance of reporting the occurrence of triatomine bugs, particularly Triatoma infestans, in this region, is emphasized. PMID- 11600910 TI - [Leishmania (Leishmania) chagasi infection in children from an endemic area of visceral leishmaniasis in the Sao Luis Island-MA, Brazil]. AB - A prospective study was undertaken in 648 children with less than 6 years of age in the municipality of Raposa, Maranhao, Brazil, from June 1997 to June 1998, to evaluate the characteristics of the infection by L.(L.)chagasi and verify if there is an association between malnutrition and asymptomatic infection. A standardized questionnaire was used containing socioeconomic, environmental and behavioral data. Montenegro skin reaction (IDRM) with L. amazonensis and Enzyme Linked Immunosorbent Assay (ELISA) test to detect infection, and anthropometric examination were performed. Initial and final prevalence and incidence of infection were 18.6%, 20.6% and 10.8% as measured by IDRM and 13.5%, 34.4% and 28% according to ELISA. The prevalence of chronic malnutrition was 26%. No association was detected between malnutrition and asymptomatic infection by L. (L.) chagasi. More effective control measures are needed in these areas since asymptomatic infection seems to be on the increase. PMID- 11600911 TI - Seroprevalence of human Trypanosoma cruzi infection in diferent geografic zones of Chiapas, Mexico. AB - A serologic survey was carried out in four different geographic zones of Chiapas, Mexico. A total of 1,333 samples were collected from residents of thirteen communities located on the Coast, Central Mountain, Lacandon Forest and a zone called Mesochiapas. One hundred and fifty one seropositive individuals (11.3%) were identified. Human Trypanosoma cruzi infection was influenced by geography. In the Lacandon Forest and Central Mountains there was a higher seroprevalence 32.1 and 13.8% respectively, than on the coast (1.2%). In Mesochiapas there were no seropositive individuals among the 137 persons tested. An active transmission is probably continuing because seropositive cases (13.8%) were detected in children under 10 years of age. The vector recognized on the Coast was Triatoma dimidiata while in the Lacandon Forest it was Rhodnius prolixus. PMID- 11600912 TI - [Chagas' disease in a urban population of the health district of Rio Verde, Mato Grosso do Sul State, Brazil]. AB - In order to evaluate some aspects of the Chagas' disease on urban population of the 12 municipalities of the sanitarian district of Rio Verde, Mato Grosso do Sul state, on 1998 we carried out a serological survey investigating anti-T. cruzi IgG by indirect immunofluorescence on blood samples collected on filter paper of 14,709 resident persons, confirmed by indirect hemagglutination and ELISA in serum. The parasitaemia was evaluated by indirect xenodiagnosis on 134 chagasic patients and the morbidity evaluated by anamnesis, physical exam and electrocardiogram in 191 pairs of chagasic/non-chagasic patients. The seropositivity was 1.83% (0.93% in autochtonous, 5.01% in alochtonous), xenodiagnosis was positive in 17.2% of the individuals (12.3% in autochtonous, 20.8% in alochtonous) and 24.6% of the seropositive patients presented chronic chagasic cardiopathy (19.1% in autochtonous, 27.8 in alochtonous). The analysis of the dates showed that alochtonous population is the main responsible for presence of the infection and morbidity of Chagas disease in the studied area. PMID- 11600913 TI - Entamoeba histolytica and Entamoeba dispar infections as detected by monoclonal antibody in an urban slum in Fortaleza, Northeastern Brazil. AB - In this study the authors used the Elisa-based antigen detection tests that distinguish E. histolytica from E. dispar to examine the prevalence of E. histolytica infection in individuals from an urban slum in Fortaleza, Northeastern, Brazil. This test has a sensitivity and specificity that is comparable to PCR and isoenzyme analysis, which is the gold standard. Single stools samples were obtained from 735 individuals. The prevalence of E. histolytica infection was 14.9% (110/735) and 25.4%(187/735) for E. dispar-E. histolytica complex. The most affected age group for E. histolytica /E. histolytica-E. dispar infection was the 1-5 year olds but there was no remarkable decrease with age. There was no significant difference in colonization rates between males and females. The results from this survey demonstrate that E. histolytica is highly prevalent in the Community studied. Furthermore, it offers promise for the antigen detection test as a sensitive and technically simple tool for detecting E. histolytica infection in the field. PMID- 11600914 TI - [Decline and social inequalities of infant mortality caused by diarrhea]. AB - This ecological study describes the temporal trend from 1977 to 1998, and spatial patterns of infant mortality from diarrhea in the city of Salvador, Bahia State, Brazil. The annual proportional of infant mortality and specific-cause mortality rate were estimated. Spatial units of geographical zones within the city's urban area were utilized for administrative purposes, which were aggregated according to quartile of living conditions indicators. Over the study period, the diarrhea induced infant mortality rate decreased 91.9%. The mortality risk from diarrhea in the lowest living condition strata was 90% greater than in the highest conditions. Also, infant mortality due to diarrhea increases proportionally as living conditions worsen, which necessitates a review of the control policies concerning this important public health problem. Although the infant mortality rate declined during the study period, social inequalities related to infant mortality due to diarrhea persist, reflecting a continuing poor social development. PMID- 11600915 TI - [Detection of transmissible forms of enteroparasites in water and vegetables consumed at schools in Sorocaba, Sao Paulo state, Brazil]. AB - Water and raw vegetables consumed in ten nursery schools were evaluated for the presence of transmissible forms of enteroparasites. The water was submitted to filtration through membranes. The washed membrane water was submitted to the Faust method. The in natura and washed vegetables were washed and the water analyzed by the sedimentation method. Contamination was not detected in one school; in two schools, all the materials were contaminated; in four schools, two items were contaminated and in three, one material presented contamination. The water presented a contamination index of 0.7% contamination (Hymenolepis diminuta, Strongyloides stercoralis and Ancylostomatidae); the vegetables in natura, 3.9% (Strongyloides stercoralis, Ancylostomatidae, Ascaris lumbricoides and Giardia lamblia) and the washed samples 1.3% (Strongyloides stercoralis, Ascaris lumbricoides and Giardia lamblia). The water and vegetables are enteroparasites vehicles. The larval form predominated. The vegetables in natura presented higher contamination than those that were washed. Elimination of these forms in vegetables was not guaranteed by washing. PMID- 11600916 TI - [Outbreak of histoplasmosis in Pedro Leopoldo, Minas Gerais, Brazil]. AB - An outbreak of histoplasmosis was spotted in Pedro Leopoldo, a city in Minas Gerais State, Brazil, in 1997, where four individuals had been in contact with a bat-inhabited cave. Acute pulmonary histoplasmosis diagnosis was made by the use of clinical, serologic, radiographic and epidemiological criteria. An antifungal treatment with ketoconazole (400mg daily for 30 days) was administered resulting in symptons' remission in a few days. PMID- 11600917 TI - [Toxoplasmosis of the central nervous system in a patient without immunosupression: case report]. AB - The clinical manifestations of acquired toxoplasmosis in the immunocompetent patient rarely include localized neurological signs, which are frequent in the immunosuppressed patient (Aids). The objective of this paper is to report the case of a woman with Toxoplasma gondii brain abscess, without an identified cause of immunosuppression. PMID- 11600918 TI - [Panstrongylus megistus in artificial ecotopes on islands of the Parana River]. AB - In response to complaints of triatomines on islands of the Alto Parana River, an investigation to determine the presence of triatomines was conducted in 145 artificial ecotopes and 4 (2.8%) were infested, comprising a residence, a sports and leisure club, a former school and a woodpile. Of the 35 P. megistus collected, 17 were analyzed and 12 (70.6%) were found to be infected with Trypanosoma cruzi. Birds and rodents were the most common food sources. All serologic examinations (56 human, 18 dogs and 10 cats) were negative. PMID- 11600919 TI - [Program for the control of visceral leishmaniasis]. PMID- 11600920 TI - [Priority research on Chagas' disease in the Amazonia Region: a short-medium term agenda]. PMID- 11600922 TI - [The experience of public service users with group psychotherapy: a qualitative study]. AB - OBJECTIVE: To assess the experience of public service users in a time-limited psychotherapeutic group dynamic intervention. METHODS: Eleven patients were randomly selected from a group of 52 who had participated in an efficacy study and were interviewed in-depth. Their account was submitted to content analysis, according to the Grounded Theory methodology. RESULTS: In general, patients accepted well and positively evaluated the psychotherapy intervention. The main findings were the importance of patient's interaction with the group participants, and their therapeutic course after the intervention, when most of them carried on with psychotherapy. CONCLUSIONS: The psychotherapeutic intervention was well accepted among the patients, had a favorable outcome and stimulated them to proceed with psychotherapy. PMID- 11600921 TI - [Epidemiological research in Brazil]. AB - The current epidemiological research in Brazil is described. Secondary data sources were consulted, such as the year 2000 database of the Brazilian Directory of Research Groups and the National Board of Scientific and Technological Development (CNPq). The criterion to identify a group as a research one relies on the existence of at least one research line in the field of epidemiology, as defined by the group leader. After identifying the defined universe of epidemiological research, which included 176 groups and 320 different research lines, the following issues were presented and discussed: the relationships between research financing and health research, focusing on CAPES (Coordination Center for the Advance of University Professionals) graduation programs, public health research and epidemiological research, geographic and institutional distribution and outreach of the current epidemiological research, the researchers and students directly participating in epidemiological research, research topics and patterns of disseminating research findings; the journals where papers in its fullness were published; the financial support of the epidemiological research focusing on the 23 officially recognized graduate programs in public health field. PMID- 11600923 TI - [Self-perception of oral health status by the elderly]. AB - OBJECTIVE: To assess the self-perception of oral health status of the elderly and to analize the clinics, subjectives and sociodemographic factors that interfer in this perception. METHODS: Results are based on interviews and clinical assessment of 201 subjects aged 60 years and over, who were dentate, functionally independents and used to go to a health care center in the town of Araraquara, SP, Brazil. A questionnaire with questions about social characteristics of the sampled population, their oral health status self-perception and the Geriatric Oral Health Assessment Index (GOHAI) was applied. All subject underwent a clinical examination to determine the prevalence of the main oral diseases. Statistical analyses were performed to determine the association between social and clinic variables, and the GOHAI index with their oral health self perceptions. In addition, analyses were made to identify self-assessment predictors. RESULTS: The clinical examination revealed that dental caries and periodontal disease had a significant prevalence, though 42.7% of the sample assessed their oral health status as regular. Social class, the GOHAI index, and the decayed and missing teeth were all associated with the self-assessment. The multivariate analysis showed that the self-assessment predictors were the GOHAI index, missing teeth and Community Periodontal Index and Treatment Needs index. These predictors accounted for 30% of the self-assessment variability. CONCLUSIONS: As the oral health self-perception had minor influence on the clinical conditions, developing educational and preventive actions for the elderly population are recommended. PMID- 11600925 TI - Cancer incidence in eighteen cities of the State of Sao Paulo, Brazil. AB - OBJECTIVE: As in Brazil cancer registries are mostly based on large cities, there are no estimates per state or per region and information on the disease incidence in the vast in-land areas is very scarce. An incidence survey was conducted in 18 major cities of the state of Sao Paulo, excluding the capital, aiming to collect information about cancer incidence in the state of Sao Paulo. METHODS: Of the 18 cities in state of Sao Paulo included in the survey, all had available resources for cancer management. Data from the year of 1991 were collected by the personnel of the Instituto Brasileiro de Geografia e Estatistica (Brazilian Institute of Statistics), who were especially trained by the study coordinators at the Fundacao Oncocentro de Sao Paulo (Cancer Center of Sao Paulo). The collected data were processed and analyzed at the Oncocentro. Data collection, processing, and analyses were performed according to the recommendations of the International Agency for Research on Cancer. RESULTS: Although some discrepancies were observed in cancer incidence rates between the cities, results obtained for all 18 cities combined were remarkably close to those recently found for the city of Sao Paulo in the year 1993. One remarkable finding was the relatively high cancer incidence rates in both sexes in the city of Santos. CONCLUSIONS: The very similar all sites cancer incidence rates found in the year 1991, when compared to those for the city of Sao Paulo in the year 1993, are suggestive that all regions have common cancer-related factors. Nevertheless, other explanations, such as the inclusion in the study of prevalent cases, as well as of non-residents, may have occurred in both studies, biasing the results. There is a need of further studies to confirm the high cancer incidence in Santos. PMID- 11600924 TI - Evaluation of a program to reduce back pain in nursing personnel. AB - OBJECTIVE: To evaluate the effectiveness of a program designed to reduce back pain in nursing aides. METHODS: Female nursing aides from a university hospital who had suffered episodes of back pain for at least six months were included in the study. Participants were randomly divided into a control group and an intervention group. The intervention program involved a set of exercises and an educational component stressing the ergonomic aspect, administered twice a week during working hours for four months. All subjects answered a structured questionnaire and the intensity of pain was assessed before and after the program using a visual analogue scale (VAS). Student's t-test or the Wilcoxon Rank Sum Test for independent samples, and Chi-square test or the Exact Fisher test for categorical analysis, were used. The McNemar test and the Wilcoxon matched pairs test were used to compare the periods before and after the program. RESULTS: There was a statistically significant decrease in the frequency of cervical pain in the last two months and in the last seven days in the intervention group. There was also a reduction in cervical pain intensity in the two periods (2 months, 7 days) and lumbar pain intensity in the last 7 days. CONCLUSIONS: The results suggest that a program of regular exercise with an emphasis on ergonomics can reduce musculoskeletal symptoms in nursing personnel. PMID- 11600926 TI - [Exhumations procedures for investigating the genetic link in bones]. AB - OBJECTIVE: To identify technical problems in exhumations performed for DNA detection in bones and to propose solutions through a protocol. METHODS: A prospective and qualitative study of exhumations was carried out according to the methods proposed in the medical legal literature. From 1995 to 1998, were performed 10 exhumations to collect human remains for DNA extraction. Of them, seven cases were of civil interest and three of criminal. Alternatives were sought to overcome technical difficulties found during the execution of these procedures. RESULTS: For all cases, there was scarcity of useful information to identify the human remains. In half of them, identification was based on the individual's morphological characteristics, given by their relatives. Individual morphological characteristics contributed to identification in 50% of cases. In three cases, it was possible to determine only the sex, and in one of them, only the age. Lack of infrastructure and police security in the cemeteries impaired the examination. CONCLUSIONS: To assure the reliability of the DNA molecular examination, it is necessary to identify the individual to whom the exhumed mortal remains belonged. To an efficacious investigation, it is paramount to have a working protocol that will cover, among other issues, those concerning identification, infrastructure and staff safety at the site of examination. PMID- 11600927 TI - Isolation and serological identification of enteropathogenic Escherichia coli in pasteurized milk in Brazil. AB - OBJECTIVE: To evaluate the microbiological quality of pasteurized milk commercialized in Rio de Janeiro, Brazil, and determine serologically enteropathogenic Escherichia coli (EPEC) strains in E. coli isolates obtained from milk samples. METHODS: Ninety samples of pasteurized milk - types B and C - of three different commercial brands, purchased in supermarkets and bakeries in Rio de Janeiro, were examined. The amount of total and fecal coliform bacteria was estimated using the Most Probable Number technique. Mesophilic, psychrotrophic, and thermoduric microorganism counts were determined by the Standard Plate Count technique. Isolation and identification of E. coli were carried out using conventional physiological tests. Commercial antisera were used for serological characterization of EPEC. RESULTS: The three milk brands analyzed revealed bacterial counts above the regulated values of the Brazilian government. It was found that among 208 strains of E. coli isolated, 46 (22.1%) were serologically classified as EPEC. The most common EPEC serogroup was O55 (15.2%). CONCLUSIONS: Though recent studies on virulence factors indicate that not all strains serologically classified as EPEC are able to attaching/effacing lesion, it is believed that the isolation of EPEC serogroups from pasteurized milk represent a potential risk for children, as well as an indicative of the presence of other enteropathogens. PMID- 11600928 TI - [Identification and typing of Yersinia enterocolitica biotypes and serotypes isolated]. AB - OBJECTIVE: To assess the presence of Yersinia enterocolitica in otherwise healthy pigs slaughtered for human consumption. METHODS: One hundred pharyngeal tonsils were sampled in a slaughterhouse in the state of Mexico. The minimum sample size (n=100) was calculated based on a preliminary sample of 20 cases, which had 20% positive cases. The collected tonsil samples were inoculated in Rappaport broth, and Salmonella-Shigella and McConkey media. The biotyping identification process was based on biochemical and serological tests using O:3, O:8 and O:9 antisera. RESULTS: Twenty-two isolates were obtained. Most were biotype 1 (8 cases of O:3 and 8 cases of O:9), but 6 cases could not be serotyped. None of the isolates were of O:8 group. CONCLUSIONS: This was the first time that Y. enterocolitica serotypes were isolated from pig tonsils in Mexico. Its importance rely on the fact that the isolated serotypes are the most commonly found in public health problems. PMID- 11600929 TI - [Frequency of Aedes aegypti and Aedes albopictus larvae and pupae in traps, Brazil]. AB - OBJECTIVE: To evaluate the monthly frequency of larvae and pupae of Aedes albopictus, Aedes aegypti and other mosquitoe species in tires, and the influence of environmental factors on that. METHODS: The immature stages of mosquitoes were collected monthly from four tires in the municipality of Nova Iguacu, Brazil, from November 1997 to October 1998. The following variables were measured: rainfall, temperature, water volume, water pH. The tires were arranged in a pyramid, one at the base (tire 1) and 3 others (2,3 e 4) laying over it. RESULTS: Were collected 10,310 larvae and 612 pupae. Aedes albopictus was the most common species in both the larval and pupal stages. Aedes aegypti and Aedes albopictus were collected throughout the year but were more frequent during in the rainy season. The number of Aedes aegypti was significantly correlated with the temperature, rainfall and water volume of the tires. The correlation between water pH and number of larvae was not significant. Aedes albopictus larvae were more frequent in tires left in the shade. CONCLUSIONS: Aedes albopictus was more abundant in tires than Aedes aegypti. Discarded tires seem to be an important source of both Aedes species throughout the year. The favored environmental conditions of the tires, such as water volume and exposure to sunlight differ for Aedes albopictus and Aedes aegypti. PMID- 11600930 TI - [Ecology of mosquitoes in areas of the National Park of "Serra da Bocaina", Brazil: II - Monthly frequency and climatic factors]. AB - OBJECTIVE: To establish the influence of climatic factors on the monthly frequency of mosquito fauna in areas of the National Park of Serra da Bocaina, Brazil. METHODS: Human bait collections were conducted once a month, in diurnal and nocturnal hours, throughout 24 months, from January 1991 to December 1992. RESULTS: A total of 11,808 adult mosquitoes belonging to 28 different species were collected. Anopheles cruzii, Runchomyia reversa, and Ru. frontosa were the most commonly found species each month. An. cruzii was found mostly from October to February; Ru. reversa and Ru. frontosa predominated in September. An. lutzi, Chagasia fajardoi, Coquillettidia chrysonotum, Aedes serratus, Trichoprosopon simile, Wyeomyia theobaldi, Ru. humboldti, and Ru. theobaldi are the second most prevalent species and they were found mostly throughout the hottest, rainiest and most humid months. Temperature and rainfall have positively influenced the incidence of the majority of the species. CONCLUSIONS: The exuberant and well preserved tropical forest of Mata Atlantica, rainfalls, and temperatures had a direct and significant contribution to the mosquito fauna in the park. In the months with greater rainfalls, temperatures and humidity, there was an increase in the density and diversity of mosquito species. The period from September to March was the most favorable for their proliferation. In the colder and drier period, from April to August, about 70% of the species showed a significant decline in number, and they were hardly found during these months. PMID- 11600931 TI - [Influence of temperature and humidity on the nymphal development of Rhodnius robustus]. AB - OBJECTIVE: To assess the significant differences in the nymphal development of the Rhodnius robustus Larrousse, 1927 under different temperatures and humidity conditions. This is a species found in the northern region of Brazil (states of Acre, Amazonas, and Para), Colombia, Equator, Peru and Venezuela. METHODS: Three groups of triatominae were kept under the following laboratory conditions: 33/40 (33+1 degree C and 40+/-5% of relative humidity - RH), 33/70 (33+/-1 degree C and 70+/-5% RH), and 28/70 (28+/-1 degree C and 70+/-5% RH). The incubation period of the eggs, developmental time of each stage, mortality percentage, number of bloodmeals, and the total amount of time from the egg hatching to adult ecdysis were observed. RESULTS: The shortest average time of nymphal development was observed in the 28/70 group, with following averages: 14.4, 17.3, 20.3, 22.8, and 40. Significant differences were observed in the embryonic development between the groups (p<0.01). For all groups, the number of bloodmeals had a gradual increase near the adult phase, except for the 3rd instar of the 33/70 group. The smallest mortality percentages were seen in the 28/70 group. CONCLUSIONS: High temperatures, regardless of the humidity, can accelerate the biological development cycle of R. robustus. However, these temperatures can impair the colonies' survival, preventing their maintenance in the laboratory. PMID- 11600932 TI - [Finding of anophelines, subgenus Nyssorhynchus, in artificial containers, Brazil]. AB - Larvae and a pupa of anophelines were found in deactivated artificial containers. Anopheles argyritarsis larvae were found in an abandoned water container in Pedregulho, district of Ponta Negra, and a Anopheles aquasalis pupa was found in a container left outdoors as part of an experiment, in the district of Itaipuacu. Three cases of malaria were reported in this same district in 1997. Both findings of anophelines took place in a town of the state of Rio de Janeiro, Brazil. PMID- 11600933 TI - Expression of type XII collagen and hemidesmosome-associated proteins in keratoconus corneas. AB - PURPOSE: Keratoconus is a disease characterized by thinning of the central and paracentral cornea and scarring in advanced cases. This study was performed to examine the expression of type XII collagen, proteins associated with hemidesmosomes, and beta1 integrin in keratoconus corneas. METHODS: Corneal buttons were collected from normal subjects and patients with keratoconus and other corneal diseases. Immunofluorescence staining was performed on frozen sections for type XII collagen, bullous pemphigoid antigen (BP180), and integrin subunits alpha6, beta4, and beta1. RESULTS: To varying degrees, all proteins examined were expressed in normal human corneas. The staining intensity of type XII collagen was diminished in keratoconus corneas in the epithelial basement membrane zone and the stromal matrix. No significant variation was found in either the staining patterns or intensities for BP180, or integrins alpha6, beta4, and beta1. CONCLUSIONS: The level of type XII collagen was reduced in the epithelial basement membrane zone and stromal matrices in keratoconus corneas. These alterations may affect critical interactions of the corneal epithelium with the under-lying basement membrane, and cell-matrix interactions and matrix organization in the stroma. PMID- 11600935 TI - Immunohistochemical localization of NAD(P)H:quinone oxidoreductase in conjunctival melanomas and primary acquired melanosis. AB - PURPOSE: Mitomycin C has been used in the treatment of primary acquired melanosis and melanomas of the conjunctiva. Because there is increasing evidence that NAD(P)H:quinone oxidoreductase (EC 1.6.99.2, NQO1) or DT-diaphorase plays an important role in the bioactivation of mitomycin C, we examined pathologic specimens of these tumors for NQO1 by immunohistochemistry. METHODS: Formalin fixed, paraffin-embedded sections with histologic diagnoses of primary acquired melanosis or conjunctival melanomas were obtained from the Eye Pathology Laboratory, University of Colorado Health Sciences Center. Detection of NQO1 in tissues was performed using standard immunohistochemical techniques with monoclonal antibodies against NQO1 and immunoperoxidase staining. Samples were examined by two independent reviewers and NQO1 staining was graded from 0 (no staining) to 3+ (intense staining). RESULTS: Eleven of 11 melanomas (95% confidence interval, 72% to 100%) and three of three lesions with primary acquired melanosis with atypia stained positively for NQO1. In the melanomas, staining was relatively uniform, while in primary acquired melanosis there was cell-to-cell variability in the staining. CONCLUSIONS: NQO1 was detected by immunohistochemistry in every examined section of primary acquired melanosis and melanoma of the conjunctiva, suggesting that NQO1 may play a role in the bioactivation of mitomycin C in these tumors. PMID- 11600934 TI - Interleukin-6 (IL-6) production by cytokine-stimulated human Muller cells. AB - PURPOSE: To investigate whether or not human Muller cells synthesize interleukin (IL)-6. METHODS: Using RT-PCR, we first confirmed whether cultured human Muller cells express IL-6 mRNA. Then, to determine Muller cell IL-6 production after stimulation, cultured Muller cells were exposed to various concentrations of IL 1beta (0.2 ng/ml, 2 ng/ml, 20 ng/ml) or lipopolysaccharide (LPS) (0.001 microg/ml, 0.1 microg/ml, 10 microg/ml) in 24 hr assays. In addition, to determine Muller cell time-dependent induction of IL-6 production, cultured Muller cells were exposed to IL-1beta (0.02 ng/ml, 2 ng/ml) or LPS (10 microg/ml) for 6, 12, 24, 36 hr. IL-6 production in supernatants was quantified by ELISA: RESULTS: IL-6 mRNA was expressed in cultured human Muller cells, which produced IL-6 after stimulation with either IL-1beta or LPS for 24 hours. IL-1beta was a significantly more potent stimulator of IL-6 production than was LPS. Exposure of cultured human Muller cells to either IL-1beta or LPS stimulated IL-6 production in a time-dependent fashion. CONCLUSIONS: Our findings indicate that human Muller cells can produce IL-6 when stimulated by IL-1beta or LPS. Muller cell IL-6 production may have an important role in various conditions involving ocular inflammation PMID- 11600936 TI - Laminin-5 is a component of preserved amniotic membrane. AB - PURPOSE: To determine if laminin-5 is retained in the matrix of cryopreserved human amniotic membrane tissue prepared for ocular surgeries. METHODS: Amniotic membrane was solubilized in urea/SDS buffer. Constituent proteins were resolved by SDS-PAGE and laminin-5 content was determined by Western blot analysis using a panel of antibodies directed against the alpha3, beta3 or gamma2 chains of the molecule. Human corneal epithelial cells were seeded on amniotic membrane and cultured in the presence or absence of EGF. The cell-membrane construct was examined for laminin-5 content using Western blot analysis and immunofluorescence microscopy. RESULTS: In preserved amniotic membrane the laminin-5 alpha3 chain is present in both the unprocessed (190-kDa) and processed (160-kDa) forms. The beta3 chain is found in the 145-kDa form. The gamma2 chain appears to be predominantly in the processed (105-kDa) form. Very little of the unprocessed form of the gamma2 chain (155-kDa) could be detected using immunoblot analysis. A similar distribution of laminin-5 was also present in extracts of corneal epithelial cells cultured on amniotic membrane. Immunofluorescence analysis of cells cultured on the membrane demonstrated polarization of laminin-5 at the cell membrane interface. CONCLUSIONS: The presence of both the unprocessed and processed forms of laminin-5 alpha3 and gamma2 chains in preserved human amniotic membrane suggests that when used as a substrate in ocular surgeries, this membrane may be capable of promoting corneal epithelial cell motility and adhesion. Regulation of the motile or adhesive function may lie with factors secreted by the corneal epithelium that populates the membrane following surgery. PMID- 11600937 TI - Central imidazoline (I(1)) receptors modulate aqueous hydrodynamics. AB - The purpose of this work is to determine the relative contributions of central imidazoline (I(1)) receptors to the ocular hydrodynamic action of moxonidine. Moxonidine (MOX), an alpha(2) and I(1) receptor agonist, and efaroxan (EFA), a relatively selective I(1) antagonist, were utilized to study alterations in intraocular pressure (IOP) and aqueous flow in New Zealand white rabbits subjected to intracerebroventricular (i.c.v.) cannulation and sympathectomy. Intracerebroventricular administration of MOX (0.033, 0.33 and 3.33 microg) to normal rabbits produced dose-dependent, bilateral IOP decreases of 3, 6, and 8 mmHg, respectively. The ocular hypotensive response to MOX was immediate (10 min. post drug), lasted for one hour, and was inhibited by prior administration of efaroxan (3.33 microg i.c.v.). In unilaterally sympathectomized (SX) rabbits, the ocular hypotensive response induced by i.c.v MOX in the denervated eye was attenuated approximately 50%, but the duration of ocular hypotension in the surgically altered eye was longer than that of the normal eye. MOX (0.33 microg i.c.v.), caused a statistically significant decrease (2.24 to 1.59 ml/min.) in aqueous flow in normal eyes. In SX eyes, there was no change in aqueous flow by MOX, suggesting that IOP effect in i.c.v. MOX observed in the SX eye might be mediated by changes in outflow resistance. Sedation was observed in all the rabbits treated with MOX (i.c.v.) and was dose-dependent. These in vivo data support the suggestion that centrally located I(1) receptors modulate the early contralateral response to topically administered MOX and are involved in lowering of IOP and aqueous flow in rabbit. In addition, expression of the full ocular hypotensive effect of centrally applied MOX depends on intact sympathetic innervation. Ocular hypotension induced by MOX in the SX eye may involve an effect on uveoscleral outflow. PMID- 11600938 TI - Synthetic bile acid derivatives induce nonapoptotic death of human retinal pigment epithelial cells. AB - PURPOSE: To study whether the synthetic ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) derivatives, which we have synthesized and have reported their apoptosis-inducing effect, have the effect on the proliferation of retinal pigment epithelial cells. METHODS: UDCA, CDCA, and their synthetic derivatives were administered in culture to the human retinal pigment cell line, ARPE-19. The effect on cell viability and growth was assessed by trypan blue dye exclusion. In order to evaluate the type of cell death, mitochondrial membrane potential assay, DNA electrophoresis, TUNEL assay, nuclear staining and Western blotting for caspase-3 and poly(ADP-ribose) polymerase (PARP) activities were conducted. RESULTS: Unlike UDCA and CDCA, which did not exhibit a significant effect on viability, their synthetic derivatives decreased the viability of ARPE 19 cells in a concentration-dependent manner. The cells treated with the synthetic derivatives did not demonstrate the characteristic findings of apoptosis, such as DNA ladder, DNA fragmentation, nuclear condensation or fragmentation, and caspase-3 and PARP activation. The reduction of mitochondrial membrane potential was shown. In electron microscopical study nuclear condensation was not shown. CONCLUSIONS: The synthetic UDCA and CDCA derivatives induced nonapoptotic death of ARPE-19 cells. PMID- 11600939 TI - Development of T cell lineages in rat lacrimal glands. AB - PURPOSE: The purpose of this study was to examine T cell development in rat lacrimal glands, determine whether the thymus is the source of immature T cells in this tissue and compare lacrimal gland T lymphocytes with other T cell subpopulations. METHODS: Mononuclear cells were isolated from lacrimal glands of normal or thymectomized female Fischer 344 rats and stained for flow cytometric analysis. RESULTS: The lacrimal gland T lymphocyte population included large percentages of cells with an activated phenotype and also subpopulations of immature, naive and memory T cells. The numbers of immature (Thy-1(+)) lacrimal gland T cells were unchanged following short-term adult thymectomy. In comparison, spleen had large percentages of naive T cells, only a small subpopulation of activated T cells, and similar percentages of immature (Thy 1(+)) T cells, which were nearly eliminated after thymectomy. Lacrimal gland T cells had small subpopulations of TCRgammadelta(+) and CD8alphaalpha( +) T cells, a large subpopulation of NKT cells and many integrin alphaEbeta7( +) T cells. CONCLUSIONS: Lacrimal gland T cells are composed of a variety of subpopulations whose composition is distinct from splenocytes. The marked reduction of immature splenic T cell percentages eleven days after adult thymectomy indicates that these cells were mostly derived from thymic precursors. In contrast, the unchanged percentages of immature lacrimal gland T cells following thymectomy indicate that they may have an extrathymic source. These studies provide a foundation for further investigation into the cellular basis of lacrimal gland immunobiology. PMID- 11600940 TI - Hydrogels as potential probes for investigating the mechanism of lenticular presbyopia. AB - PURPOSE: To synthesize and characterize hydrogels with viscoelastic properties comparable to those of the natural lens. METHODS: Hydrogels were synthesized in water by free-radical polymerization of the monomer poly(ethyleneglycol) monomethacrylate. Three different molecular weights of poly(ethyleneglycol) dimethacrylates were used as crosslinkers. For each crosslinker used, five different monomer-to-crosslinker weight ratios were utilized while the total mass of the reactants was kept constant. In another series, the concentration of the reactants was varied while the weight ratio of monomer to crosslinker was kept constant at 95 : 5. The percent optical transmission, equilibrium water content, moduli (elastic, shear, storage, and loss), and retardation time constant of the hydrogels were determined. In addition, endocapsular polymerization was performed in the capsular bag of porcine eyes. RESULTS: The hydrogels examined exhibited the following ranges for viscoelastic properties: elastic modulus, 1.33-2.37 x 10(4) Pa; shear modulus, 3.35-6.72 x 10(3) Pa; storage modulus, 1.65-6.24 x 10(4) Pa. For any given hydrogel, raising its crosslinker's weight ratio increased its moduli and decreased its equilibrium water content and optical transmission. For any given monomer-to-crosslinker weight ratio, increasing the molecular weight of the crosslinker reversed these trends. Reactant concentrations increased the elastic modulus and decreased the equilibrium water content. The hydrogels formed ex vivo (in the evacuated capsular bag of porcine eyes) allowed for the clear and undistorted viewing of objects. CONCLUSIONS: Hydrogels that exhibit physical and mechanical properties comparable to those of the natural lens were successfully identified, synthesized, and characterized, and the feasibility of endocapsular polymerization was demonstrated. PMID- 11600941 TI - The effect of mechanical strain on matrix metalloproteinase production by bovine trabecular meshwork cells. AB - PURPOSE: To evaluate the effects of mechanical stretching of trabecular meshwork cells on matrix metalloproteinase activity. METHODS: Cultured bovine trabecular meshwork cells grown on collagen-coated elastomer were subjected to 10% biaxial mechanical stretching. After various time intervals, culture medium was collected from stretched and non-stretched control cells. Matrix metalloproteinase activity was studied by zymography and levels of inhibitors were determined by immunoblotting or immunoassay of the collected medium. RESULTS: Trabecular meshwork cells subjected to mechanical strain showed increased stromelysin and gelatinase A activity at 24 to 72 hours after initial stretching compared to control cells. By 72 hours of strain, stromelysin activity increased to up to 73% (p < 0.01) whereas gelatinase A activity increased by 31% (p < 0.05). The increased metalloproteinase activity was reversible with relaxation of mechanical stretch. Levels of tissue inhibitor of matrix metalloproteinase-1 and -2 remained unchanged during 72 hours of stretch. CONCLUSIONS: Changes in mechanical strain on the trabecular meshwork, which may occur in vivo during changes in intraocular pressure, induce changes in matrix metalloproteinase activity. The resultant alterations in the extracellular matrix may affect outflow resistance through the trabecular meshwork in response to alterations in intraocular pressure. PMID- 11600943 TI - [The Architecture of the Fibrous Complex between the Palmar Aponeurosis and the Flexor Retinaculum]. AB - Summary. During cadaver dissections of 34 adult human hands (fixed in formaldehyd solution), we examined a fibrous complex at the distal end of the flexor retinaculum. This fibrous complex was first mentioned by Legueu and Juvara (1892). It is located always ulno-dorsally to the attachment of the palmaris longus tendon into the palmar aponeurosis. Measurements of this special connective tissue show a mean length of 18.6 mm, a mean height of 4.3 mm and a mean width of 3.1 mm.Also, we looked for the fibrous complex in six adult plastinated transverse sections and in 12 fetal hands where it occurred in a constant way. We also found a very close topographic relationship between these oblique criss-crossed fibers and the palmar cutaneous branch of the median nerve. This nerve regularly gives some ulnar branches to the fibrous complex. The clinical relevance of the fibrous complex is discussed in relationship to a carpal tunnel syndrome. The described transverse fibers of the connective tissue complex are in danger as well as the ulnar branches of the palmar cutaneous nerve when releasing the flexor retinaculum during operation. PMID- 11600944 TI - [Morphological and functional interface between palmar plates of metacarpophalangeal joints and intrinsic muscles of the hand]. AB - Summary. After a ten-year period of intensively dealing with the hand as a Medical Artist, it became quite obvious that the palmar section of MP joints is described in the literature partly different from what we found in our cadaver studies. This especially applies to the proximal continuation and fixation of palmar plates and the deep transverse metacarpal ligament. Thus we tried to understand and explain the complex character of interaction between locomotion apparatus and structures of the hand's "connective-tissue body". METHOD AND MATERIAL: Cadaveric operation microscope-assisted dissection of the palmar ligament (plate), deep transverse metacarpal ligament, interosseous muscles as well as mechanically stable sections of the "connective tissue body" and fascia allowed a clear view of morphology, interaction, and character of these structures during passive finger motion. RESULTS: 1. Proximally, the palmar ligament (plate) of a metacarpophalangeal joint ranges to the tendinous sheets of origin of the interosseous muscles and in extension of these it is attached to the palmar carpal ligaments. In the following, these tendinous structures will be referred to as "deep longitudinal metacarpal fibres". This highly sophisticated proximal attachment is formed bilaterally from each palmar plate in several cascades. Thus, a widely ranging distribution of forces implied by MP-extension is guaranteed. The deep transverse metacarpal ligament executes the function of a "force dissipating center": Extension strain is passed on from the fingers via the "lateral digital sheet" and the "spiral ligament" to the palmar fascia and further on into a proximal and "deep" direction by the vertical sheets (Legueu and Juvara 1892/1974). On the next central level, a similar flow of forces reaches the palmar carpal ligaments from the osseous phalangeal base via the phalangoglenoidal ligaments and the palmar plate. Junction of these forces is the "soft tissue confluence" (Zancolli 1992), whereas the described "deep longitudinal metacarpal fibres" can be understood as a final common route. Overstretching forces at the index finger are transferred to the palmar carpal ligaments by a ligamentous "Arcus adductorius".2. Contrary to published reports, the palmar ligament (plate) does not have a determined and constant length but does adapt its extension in longitudinal direction to the joints' excursions, more than doubling in length in extended position compared to its minimal length in a maximally flexed MP joint. This is performed by criss-crossing fibers throughout the palmar ligament.3. Distally, the palmar ligament is attached to the base of the proximal phalanx on both sides with no mechanically relevant fixation in the middle. This predominant lateral attachment is additionally stabilized by the proximal section of the phalangoglenoidal ligaments, thus extending the area of osseous fixation. CONCLUSION: The biomechanical principle of restraining extension in the MP joints can be compared to the architecture of Gothic cathedrals or modern bridges. Here too, simple algorithms create complex systems. One major force (extension of MP joint) is split up into many single components to spread out the strain over a wide area. This allows high endurance with minimal expension of materials and simultaneously a well-distinguished mobility of the fingers. Operative treatment in this area (Zancolli's capsuloplasty for treatment of paralytic claw fingers) could be modified by considering these functional and morphological criteria, thus lowering frequency of relapse in palmar plate surgery. PMID- 11600945 TI - [The Extensor Pollicis et Indicis: An Accessory or Rudimentary Deep Extensor Tendon to the Thumb? Variants - Frequency - Clinical Relevance]. AB - PURPOSE/BACKGROUND: Are the supernumerary deep extensor tendons to the thumb in man of accessory or rudimentary origin? METHOD AND CLINICAL MATERIAL: Two findings of extensor pollicis et indicis (EPI) were classified referring to the literature of comparative anatomy. RESULTS: Extensor pollicis longus (EPL) and extensor indicis (EI) developed phylogenetically from EPI. A common origin and proximal muscle belly of EPL and EI is a frequent manifestation of incomplete rudimentary EPI. A complete rudimentary EPI with absent EPL and EI has not yet been found in man. The accessory EPI coexisting with EPL and EI occurs in about 2 % of humans. CONCLUSION: During the EI-tendon transposition to EPL, the tendons must be identified very carefully because of the numerous variants of the deep extensors. Transposition of extensor digitorum communis of the index or just one tendon of a double-tendoned EI to EPL by mistake, will make separate extension of the thumb impossible postoperatively. PMID- 11600946 TI - [Coincidence of Lipoma and Liposarcoma of the Right Hand in an 84-Year-Old Patient: A Case Report]. AB - Summary. We report the case of an 84-year-old patient presenting with a painless tumor between the thumb and the index finger. MRI showed a clearly defined tumor of the thenar eminence with a centrally localized more solid structure. There was a signal enhancement after intravenous administration of contrast medium. We performed a local resection of the tumor. Histologically, we found a lipoma with a centrally localized liposarcoma. We discuss the rare case of malignant transformation of a lipoma. In long-standing large lipomas we suggest regular controls by MR imaging. PMID- 11600949 TI - [Melorheostosis of the hand. A case report]. AB - Summary. Melorheostosis is a sclerosing disease commonly affecting the bone, rarely soft tissue. Etiology is unknown. It causes uncharacteristic symptoms such as pain, joint stiffness, soft tissue contractures, and limb deformities. Standard radiology reveals the diagnosis. Until now there is no standard therapy. Melorheostosis is a rare bone dysplasia and important as a differential diagnosis for tumorous changes in the limb or in painful joints. PMID- 11600947 TI - [Comment on the contribution by W. Baer, P. Schaller and S. Ruf--Coincidence of lipoma and liposarcoma of the right hand in an 84-year-old patient: a case report]. PMID- 11600950 TI - [High-pressure injection injuries of the hand. Pathogenesis, problems and therapy]. AB - Summary.High-pressure injection injuries are rare and the extent of tissue damage is often underestimated. They usually have devastating effects on tissues and result in poor functional outcome of the involved hand. The severity of these injuries is related to the nature, pressure, volume and toxicity of the injected substance. The major problem of this injury is a toxic edema followed by ischemia, causing a gangrene of the involved finger, which may require amputation. The pathogenesis is characterized by different, but often synchronous onsets, leading to an apparent chain of events that occur once the material has been injected. Increase of pressure within the closed space leads to tamponade, intravascular thrombosis and spasm of vessels create circulatory embarrassment, a chemical irritation provokes an acute inflammation. Three stages of progress are described. Timing is an important factor influencing the results. An early, wide decompression and aggressive debridement with complete removal of foreign substances and necrosectomy is recommended in the acute stage and will improve prognosis and outcome. Open wound treatment and second-look operations during the intermediate stage are followed by secondary wound closure with local or free flaps, if necessary. We emphasize the role of early active motion during this time. Reconstructive surgery is reserved for the late stage.43 patients were treated surgically in our department over the last 28 years (1972 to 2000). 12 of them (28 %) required amputation at different levels of the involved finger. Only nine patients healed without any functional loss. Most frequent injuries were of the paint or paint-solvent and grease-gun type. PMID- 11600951 TI - [Electrophysiological methods for diagnosis of entrapment syndromes of peripheral nerves]. AB - Summary. Apart from clinical findings, the diagnosis of compression syndromes of peripheral nerves is based on electrophysiological investigations. This includes the determination of nerve conduction velocities, distal motor latency and electromyography, which gives a qualitative indication of the condition of nerves and their related muscles. In the 1980s, new methods were developed for quantifying the diagnoses of nerve lesions and their recovery. Due to the development of new software, we can now carry out these investigations with commercial equipment. The macro-EMG and the motor-unit-estimation give information about the size and number of activated motor units of muscles. One needs a special needle which derives single-fibre- and macro-potentials for recording of the macro-EMG. The single-fibre-potential is used for triggering. The motor-unit-estimation represents a non-invasive method to determine the approximate number of motor units. Multiple point stimulation of the nerve is used to determine action potentials which are registered by surface electrodes. Afterwards, the medians of amplitudes and areas of motor unit action potential are defined and must be divided by the corresponding value of maximal compound muscle action potential for estimating motor units. In this way, the extent of nerve damage can be determined exactly. Additionally, a post-operative follow-up is possible. Furthermore, these methods give information about regeneration processes after nerve damage and their recovery after reconstruction and transplantation. From our point of view, these methods should be included in investigation routinely. PMID- 11600952 TI - [Hyperextension instability of the thumb metacarpophalangeal joint treated by sesamoid arthrodesis]. AB - Summary. Inadequate treatment of hyperextension trauma of the metacarpophalangeal joint of the thumb can cause chronic instability with pain and weakness of pinch. Between January 1995 and December 1998, nine patients (seven posttraumatic and two associated with CMC joint arthrosis) were treated with an arthrodesis of the radial sesamoid. The bones were fused in seven cases by intraosseous sutures and in two cases with small screws. Kirschner wire temporary fixation of the MP joint and cast immobilization for six weeks was our standard procedure. The follow-up time ranged from six to forty-seven months (average 26 months). One patient had screw loosening after a second injury. Another one had pain because of posttraumatic arthrosis in the MP joint. The remaining seven patients reported a significant improvement in their condition, they were satisfied and free of pain. Palmar stability was restored. A little flexion restriction in the MP joint was found. An arthrodesis of the radial sesamoid of the MP joint of the thumb is a simple technique to treat palmar instabilities. This operation should not be performed if additional collateral ligament injury or arthrosis exist. PMID- 11600953 TI - [Treatment costs in initially underestimated infections of the hand]. AB - Summary. Infections that develop as a complication of minor injuries to the hand, frequently are underestimated by the patient or by the physician initially consulted. Between 1990 and 2000, we have treated 172 in-patients as a result of this underestimation. In a retrospective study we have tried to evaluate the economic consequences. According to our results, treatment costs of 210,000 D Mark could have been saved, if adequate treatment had been initiated on time. PMID- 11600954 TI - [After suicide]. PMID- 11600955 TI - [Suicide! "Is Satan among us?"]. PMID- 11600956 TI - [The consequences of a suicide for the bereaved - current knowledge, unresolved questions and tasks of future research]. AB - Since the publication of Cain's landmark book Survivors of Suicide in 1972, the consequences of a suicide for the bereaved have been scientifically investigated. Mclntosh (1996) issued the most current bibliography of literature on the aftermath of suicide, including publications issued between 1986 and 1995. Mclntosh came to the conclusion that several unresolved issues still exist in this field of suicidology. OBJECTIVE: This paper aims at giving an overview on current knowledge of the aftermath of suicide. lt shall be investigated which questions and unresolved issues in this field still remain. This leads to a description of future tasks and challenges for researchers investigating the after effects of suicide. METHODS: At first, an overview on the most important aspects of current knowledge on the aftermath of suicide will be given. This will be done with reference to the unresolved issues and unanswered questions presented by McIntosh. How many of these issues and questions have come to a resolution after the publication of Mclntosh's bibliography shall be investigated. RESULTS: Upon examination of publications issued after 1995 it was found that several basic questions regarding the after effects of a suicide have not yet been answered in a satisfactory manner. To name a few, the term suicide survivor has not yet been clearly determined and reliable numbers as to how many people are bereaved by suicide do not exist. Moreover, a comprehensive theory regarding the consequences of a suicide for survivors is still lacking. CONCLUSIONS: Resolving these basic questions among a number of others can be seen as the main task of future research in this field. Additionally, it is pointed out that more affention should be given to the implementation of suicide postvention measures in order to alleviate the negative aftereffects of suicides. PMID- 11600957 TI - [How and to what extent is suicide postvention part of the routine of health care professionals in psychiatric hospitals after inpatient suicide?]. AB - OBJECTIVE: To elucidate how and to what extent suicide postvention is part of the routine of health care professionals in psychiatric hospitals after inpatient suicide was aim of the study. METHODS: In 11 South German psychiatric hospitals the head of the nursing team of the ward, the therapist and the medical assistant director were asked how suicide postvention after the last suicide was handled. RESULTS: Suicide postvention is part of the routine in these hospitals and discussion on the issue is rather open. The members of the team confronted with suicide feel mostly sufficiently supported. (2/3) of both therapists and heads of nursing teams considered the procedere to be adequate. CONCLUSION: Mainly for the nursing team there seems to be a need to further improve procedures for suicide postvention to gain more team satisfaction with regard to how the situation is managed. PMID- 11600958 TI - [Did suicidal behavior have relevance for prison suicide?]. AB - OBJECTIVE: Suicides in correctional institutions occur more frequently than in the general population. Inmate suicide rates have been increasing in many countries during the last decades, possibly reflecting a selection of highly endangered individuals with a high prevalence of mental disorders. This study investigates all suicides in all correctional institutions of Austria during the last 25 years. METHODS: All available personal files of inmates who had committed suicide in the 29 Austrian prisons between January 1st, 1975, and December 31st, 1999, were analysed. Beside personal characteristics and circumstances of custody, information concerning psychiatric disorders and the inmate's history of suicidal behavior was included. RESULTS: 220 personal files of 250 suicides were available and included. Half of all suicides had a history of attempted suicide and 37 % had expressed suicidality. Referral to psychiatric consultants was known in 48.6 % and about 37 % received psychopharmacological treatment. Based on these frequent signs of psychiatric illness and vulnerability, possible implications of these results for psychiatric services of the correctional system to improve suicide prevention are discussed. CONCLUSIONS: Obvious signs of suicidality play an important role in vulnerability profiles for jail and prison suicides. Any signs of suicidality (st. p. attempted suicide, verbal suicide threat, self-harm) should have the consequence of further psychiatric care. PMID- 11600959 TI - [Suicides in psychiatric in-patient treatment]. AB - OBJECTIVE: The aim of this study was to evaluate characteristics and predictors for in-patient suicides. METHOD: All in-patient suicides registered by the psychiatric basic documentation for the period 1989 - 1999 were described and analysed by the means of chi(2)-tests and multivariate logistic regression. RESULTS: A total of 30 in-patient suicides were found among 39 372 cases, corresponding to a mean annual suicide rate of 76 per 100 000 admissions. All suicides were committed using violent methods and took place outside the hospital in more than 75 % of the cases. Nearly 85 % of the patients were on leave or an outing. According to the logistic regression the risk of hospital suicides is significantly increased for patients with schizophrenia, a higher cumulative length of stay and a previous suicide attempt, but not suicidality or suicide attempt before index admission. CONCLUSION: Schizophrenic patients represent the high risk group for suicide in psychiatric hospital. An especially focussed prevention on this group could reduce in-patient suicide rates. PMID- 11600960 TI - [Patient suicide in a psychiatric hospital : an inquiry]. PMID- 11600961 TI - [The development of suicide rates in the Bezirkskrankenhaus Bayreuth 1976 - (including) 2000]. AB - Newer publications about psychiatric in-patient suicide discuss the so-called "increase hypothesis" of suicide of mentally ill in-patients controversially. In our study of in-patient suicides of the Bezirkskrankenhaus Bayreuth, a state mental hospital for adult psychiatry, the number of suicides and suicide rate over 25 years 1979 - 2000 did not show any increase. During the last 4 - 5 years we observe a trend toward a decrease. PMID- 11600962 TI - [The aftermath of suicide of a psychiatric inpatient - experiences in psychiatric hospitals with relatives as suicide survivors]. AB - OBJECTIVE: In a first part we describe the situation of suicide survivors after the suicide of a family member in USA and Germany by reviewing the literature. In a second part we try to elucidate typical patterns of reactions and coping of relatives. METHODS: On the basis of either own experience or from supervision cases, we try to elaborate reaction types of relatives of inpatients who committed suicide. RESULTS: Relatives as suicide survivors show reactions from shock, disbelief, grief, guilt, self-doubt, anger and relief to accusation and threat of lawsuit toward therapists. An attempt is made to subsummarize these reactions in three preliminary categories. CONCLUSIONS: Generally, relatives should be offered the opportunity of more than one common talk with the health care professionals. Postvention is preventive work, that aims at avoiding that the suicide survivors becomes a patient himself. PMID- 11600963 TI - [Tabooisation of a family suicide - possible consequences for relatives]. AB - We introduce the history of a 27 year old woman who lost her mother by suicide at the age of one year. Grown up in the fathers family she came to know the mothers suicide with 14 years. In the same time she had the first contact with the two half-brothers from the mother's side. In this "new" family they discussed open about the suicide, what she perceived as a relief and important for her personal development. The consequences of the rarely studied tabooisation of the family suicide could have impact for the intercourse with the relatives of suicide victims in the clinical work. PMID- 11600964 TI - [Survivors of suicide victims searching for answers and ways out of the crisis]. PMID- 11600965 TI - [Bright spot on the horizon - self-help group for suicide survivors]. PMID- 11600966 TI - [Experiences and deliberations of a psychiatrist as suicide survivor--on suicide in psychiatric families]. PMID- 11600967 TI - Congenial public, contrary press, and biased estimates of the climate of opinion. AB - This field experiment focused on perceived public opinion about the use of primates in laboratory research. We used this contentious issue to examine the simultaneous effects of three hypothetical ideas-the hostile media perception, the persuasive press inference, and the projection bias-on partisan perceptions of public opinion. Our data supported the projection hypothesis but also confirmed that partisans on each side of the issue judged news articles to be biased in a disagreeable direction relative to judgments of those on the other side. The perception of relatively disagreeable media bias, in turn, influenced perceptions of public opinion. Results supported the hypothesis that people make inferences about the climate of opinion based on their reading of the news, especially the perceived slant of that news. PMID- 11600968 TI - Performance and race in evaluating minority mayors. AB - This research compares a performance model to a racial model in explaining approval of a black mayor. The performance model emphasizes citizen evaluations of conditions in the city and the mayor's perceived effectiveness in dealing with urban problems. The racial model stipulates that approval of a black mayor is based primarily on racial identification or racism. A model of mayoral approval is tested with two surveys over different years of citizens in a city that has had 20 years' experience with black mayors. Findings indicate that performance matters when evaluating black mayors, indicating that the national performance models of presidential approval are generalizable to local settings with black executives. Implications for black officeholders are discussed. However, the racial model is alive and well, as indicated by its impact on approval and the finding that, in this context, performance matters more to white voters than to black voters. A final, highly tentative conclusion is offered that context conditions the relative power of these models. The performance model may explain more variation in approval of the black mayor than the racial model in a context of rapidly changing city conditions that focuses citizen attention on performance, but during a period of relative stability the two models are evenly matched. PMID- 11600970 TI - The polls-trends: devolution and confidence in government. PMID- 11600969 TI - Liability of commercial and social hosts for alcohol-related injuries: a national survey of accountability norms and judgments. AB - Legal standards for liability of commercial sellers and social providers of alcoholic beverages are affected by social norms concerning accountability and responsibility. Using a nationwide probability sample telephone survey of 7,021 U.S. residents, we conducted a randomized experiment in which each subject was asked to respond to multiple vignettes. The vignettes told stories of drinking situations, systematically varying dimensions concerning age of drinker, commercial versus social settings, amount of alcohol consumed, history of previous behavior, and seriousness of damage or injury following drinking. Analyses involved linear mixed (i.e., random effects) model regressions, using responses to vignettes as the outcome variable, controlling for a series of sociodemographic, behavioral, and attitudinal measures. Results showed that age of drinker (young), setting (bar), and previous behavior (history of irresponsibility) were most strongly associated with harsher judgments of civil liability. Citizens' multiple standards for assigning legal liability and implications for public policy are discussed. PMID- 11600971 TI - Assessing poll performance in the 2000 campaign. PMID- 11600972 TI - Histologic analysis of the tibial bone tunnel after anterior cruciate ligament reconstruction using solvent-dried and gamma-irradiated fascia lata allograft. AB - Anterior cruciate ligament (ACL) reconstruction using free tendon graft requires biologic fixation in the bone tunnel. This report describes the intratunnel histology retrieved from a 47-year-old woman who underwent high tibial osteotomy 17 months after ACL reconstruction using a hybrid graft (a solvent-dried and gamma-irradiated fascia lata allograft as a core wrapped with iliotibial autograft). The patient underwent revision because of pain resulting from osteoarthrotic change, and the graft appeared to be taut and healthy on second look arthroscopy. The sample was taken from the site of the metaphyseal osteotomy site. Histologic examination of the samples was performed with a light microscope (H&E and Masson trichrome stain). Biologic fixation of the graft to the bone was evident from observation of collagen fiber continuities, resembling Sharpey fibers. Integration of the autograft and allograft seemed to have occurred; the junction between the allograft and the autograft could not be determined. However, there was a difference in ligamentization depending on location. In the peripheral region of the graft (the autograft region), the collagen fibers showed a distinct crimped pattern; the fibroblasts were arranged regularly along the major axis of the collagen fiber bundle. In the central part of the graft (the allograft region), remodeling seemed to be delayed. There were acellular, bubbly or myxoid degeneration areas in which the fiber bundles were less oriented and there was increased vascularity. PMID- 11600973 TI - One-portal technique of endoscopic fasciotomy: Chronic compartment syndrome of the lower leg. AB - Many athletes complain of exercise-induced pain in the lower leg that can be caused by inflammatory diseases, peripheral nervous system disease, fatigue fracture, shin splint, and chronic compartment syndrome (CCS). CCS is the most typical exercise-induced condition and it often requires surgical decompression of the several compartments. There are already many techniques reported in the literature. Recently, an endoscopic technique for CCS was reported with which excellent results were achieved. We have modified it and developed a new technique for treating CCS of the lower leg. We report a case of CCS of the lower leg treated with 1-portal endoscopic fasciotomy. The technique helps to decrease damage to soft tissue and patients will immediately return to normal activities of daily living. PMID- 11600974 TI - Chondral injury from bioabsorbable screws after meniscal repair. AB - A case of chondral injury after medial meniscal repair with a headless bioabsorbable screw is reported. As these implants can take a long time to be absorbed, all arthroscopic surgeons should be aware of possibility of this complication during this period. PMID- 11600975 TI - Quadrupled semitendinosus anterior cruciate ligament reconstruction: 5-year results in patients without meniscus loss. AB - PURPOSE: The purpose of this study was to determine the mid-term (minimum 5-year) results of isolated primary anterior cruciate ligament (ACL) reconstructions with intact or repaired menisci. TYPE OF STUDY: Case series. METHODS: Of 184 ACL reconstructions from April 1990 to February 1992, 33 initially met the inclusion criteria of primary reconstruction with quadrupled semitendinosus tendon and without extra-articular reconstruction or meniscus removal. Patients with known traumatic rerupture of the graft with revision (1 case) or subsequent meniscectomy (1 case) were excluded from the study. Twenty of the remaining 31 patients were available for follow-up at an average of 5.7 years after surgery. At follow-up, a comprehensive knee examination, KT-1000 arthrometry, radiography, functional testing, and isokinetic strength testing were performed. A subjective questionnaire, Tegner scale, and IKDC evaluation were administered as well. Four patients who were unable to come in for follow-up returned a knee-assessment questionnaire. RESULTS: Arthrometric anterior tibial translation was reduced from a preoperative average of 6.3 +/- 2.8 mm (manual maximum side-to-side difference) to an average of 0.0 +/- 1.3 mm (range, -2.5 to 2 mm). Radiographically, 1 patient experienced mild narrowing in the lateral compartment. Tegner activity level was maintained at the preinjury level in nearly half the patients. Isokinetic strength deficits were less than 10%; 17 (85%) of the patients had a normal or nearly normal result as graded by the IKDC scoring system. CONCLUSIONS: The above data show minimal morbidity, a low reoperation rate, and excellent clinical outcome. Because the stability of the knee persists beyond 5 years after ACL reconstruction, patients are able to maintain preinjury activity levels without reinjury. PMID- 11600977 TI - Semitendinosus muscle in anterior cruciate ligament surgery: Morphology and function. AB - PURPOSE: To evaluate the fate of the hamstring muscles in general and the semitendinosus muscle in particular, after anterior cruciate ligament (ACL) reconstruction with an autologous semitendinosus tendon graft from the ipsilateral side. TYPE OF STUDY: Prospective consecutive case series investigation. METHODS: Included were 16 consecutive patients, 14 male and 2 female, with a mean age of 26 years. The inclusion criterion was chronic unilateral ACL insufficiency with no concomitant knee ligament injuries. ACL reconstruction was performed with a quadruple semitendinosus tendon graft using the EndoButton technique (Acufex, Mansfield, MA). Intraoperatively, muscle specimens were taken from the semitendinosus muscle on the harvested side. Follow up at a minimum of 6 months included clinical examination, isokinetic strength performance, magnetic resonance imaging (MRI) of the thigh and knee, and ultrasound-guided muscle biopsy procurement from the semitendinosus muscle for histochemical and enzymatic analyses. RESULTS: Of the patients, 75% showed regeneration of their semitendinosus tendons. The neotendons all inserted below the knee joint where they had fused with the gracilis tendon to a conjoined tendon inserting in the pes anserinus. The semitendinosus muscle had a smaller cross-sectional area on the operated side but none showed total atrophy. Less atrophy was present in the patients with a regenerated semitendinosus neotendon compared with those without regeneration (P =.029). In the latter group the semimembranosus muscle seemed to compensate for this with hypertrophy (P =.019). Cross-sectional muscle fiber areas, the relative number of each fiber type and oxidative potential as estimated by citrate synthase activity, showed no significant differences between the operated and nonoperated legs. The isokinetic strength of the hamstrings and quadriceps was significantly lower in the operated leg than in the nonoperated leg. CONCLUSIONS: With this surgical technique, the semitendinosus muscle can recover and the tendon has, according to the MRI images, a great potential to regenerate after its removal. PMID- 11600976 TI - Single- versus bi-socket anterior cruciate ligament reconstruction using autogenous multiple-stranded hamstring tendons with endoButton femoral fixation: A prospective study. AB - PURPOSE: This prospective study was conducted to compare the single-socket and the bi-socket anterior cruciate ligament (ACL) reconstruction techniques in terms of outcome. TYPE OF STUDY: Nonrandomized control trial. METHODS: There were 160 consecutive patients with unilateral chronic ACL insufficiency who underwent endoscopic single- or bi-socket ACL reconstruction alternately using multiple stranded medial hamstring tendon and EndoButton (Smith & Nephew, Andover, MD) femoral fixation. All patients underwent the same postoperative rehabilitation protocol. Of them, 106 patients (57 single, 49 bi) were available for 2-year follow-up. RESULTS: According to the IKDC Knee Ligament Evaluation Form, 23 patients (40%) of the single-socket group were subjectively graded as normal, 30 (53%) as nearly normal, and 4 (7%) as abnormal. Twenty-six patients (53%) of the bi-socket group were graded as normal, 21 (43%) as nearly normal, and 2 (4%) as abnormal (P =.19). The mean side-to-side anterior laxity difference (KT-1000 manual maximum force) was 0.9 +/- 1.8 mm for the single-socket group and 0.7 +/- 1.2 mm for the bi-socket group (P =.44). Fifty-three of 57 patients (93%) in the single-socket group and all patients in the bi-socket group showed anterior laxity differences of +/-3 mm or less (P =.12). There were no differences in thigh muscle strength between the groups. CONCLUSIONS: Both single- and bi-socket ACL reconstruction using autogenous multiple-stranded hamstring tendons with EndoButton fixation provided satisfactory anterior stability, and there were no statistically significant differences in subjective results or measured restored stability between the 2 groups. PMID- 11600978 TI - Anterior cruciate ligament reconstruction in patients with or without accompanying injuries: A re-examination of subjects 5 to 9 years after reconstruction. AB - PURPOSE: The purpose of this study was to compare the clinical and radiologic results of an anterior cruciate ligament (ACL) reconstruction in patients with an isolated ACL tear and patients with an ACL tear and accompanying injuries. TYPE OF STUDY: A retrospective investigation. METHODS: Seventy-two patients who did not have previous knee surgery or surgery of the contralateral knee were re examined 5 to 9 years after the primary ACL reconstruction. The clinical assessment was made using the International Knee Documentation Committee (IKDC) evaluation system, and the Lysholm and the Marshall knee scores. Also, radiographic evaluation and isokinetic strength testing were performed. There were 34 patients (25 men and 9 women) with an isolated ACL tear (group A), and 38 patients (23 men and 15 women) with an ACL tear and accompanying injuries (group B). The mean age was 29 years (SD 9; range, 15 to 49 years) in group A, and 34 years (SD 12; range, 15 to 61 years) in group B. Bone-patellar tendon-bone autograft with mini-arthrotomy technique and screw fixation was used in all patients. Postoperative rehabilitation was also similar in both groups. In group B, 10 medial and 12 lateral (partial or subtotal) arthroscopic meniscectomies were performed at the same time as the ACL reconstruction. Also, 18 of the 19 medial collateral ligament ruptures, the 2 lateral collateral ligament ruptures, and the 1 posterior cruciate ligament rupture were treated surgically at this operation. RESULTS: Subjectively (overall assessment, pain, swelling, and giving way of the knee) and objectively (range of motion, stability, crepitation, isokinetic strength testing, and radiological changes of the knee), the groups did not have any significant differences in the 5- to 9-year results. Also, the final evaluation results using the IKDC and the Lysholm and the Marshall knee scores were similar in both groups. However, there were significantly more subsequent knee surgeries in the injured knee in group B than in group A. CONCLUSIONS: Our results show no large differences between patients with an isolated ACL tear and those with an ACL tear with accompanying injuries 5 to 9 years after an ACL reconstruction with a bone-patellar tendon-bone autograft. Tibiofemoral osteoarthritis was quite rare, and this may be partly attributable to the fact that the ACL reconstructions were successful, so that all the knees were stable at the re-examination. However, the future will show the final outcome for the patients. PMID- 11600979 TI - Arthroscopically assisted osteosynthesis of tibial plateau fractures in patients older than 55 years. AB - PURPOSE: To evaluate the end results of arthroscopically assisted osteosynthesis of tibial plateau fractures in patients older than 55 years of age. TYPE OF STUDY: Case series. METHODS: Over a 5-year period, 201 consecutive patients presented with tibial plateau fracture; 131 of these patients were treated with arthroscopically assisted osteosynthesis of the tibial plateau. Inclusion in the retrospective analysis was limited to those patients older than 55 years at the time of injury and those who were available for follow-up at the time of the study. Thirty patients met these criteria. RESULTS: Secondary displacement occurred in 9 patients (30%) within 12 weeks after surgery. After a median follow up of 3 years, 24 of 30 patients (80%) had an excellent or good clinical result according to the modified Rasmussen criteria. There was no difference in clinical outcome between the patients with or without secondary displacement of the fracture. CONCLUSIONS: Given the good clinical results, arthroscopically assisted osteosynthesis has been shown to be highly efficient in the treatment of tibial plateau fractures in the elderly. PMID- 11600980 TI - Arthroscopic osteochondral transplantation: Histologic results. AB - PURPOSE: Localized, full-thickness articular cartilage defects of the femoral condyle are challenging. This report presents the histology of clinical cases obtained at intervals from 2 to 12 months after arthroscopic osteochondral transplantation. TYPE OF STUDY: Longitudinal cohort study. METHODS: Patients found at arthroscopy to have full-thickness femoral condyle defects between 1 and 3.5 cm in diameter underwent arthroscopic osteochondral transplantation. Exclusion criteria were associated tibial defects, patellar defects, or generalized arthritic change. The grafts taken from the superior and lateral intercondylar femoral notch were press-fit into holes drilled into the defect starting adjacent to the articular cartilage margin. Cancellous bone bridges were maintained between grafts. At various time intervals from 2 to 12 months after the osteochondral transplantation, arthroscopic biopsy specimens of the recipient sites were obtained. RESULTS: Ten patients (5 male, 5 female) enrolled at 2 centers were evaluated arthroscopically at various intervals up to 13 months after osteochondral transplantation. The average patient age was 40 years (range, 17 to 65 years). One to 3 plugs had been harvested and inserted. Seven patients underwent biopsy at intervals ranging up to 12 months postoperatively. All showed maintenance of the integrity of the grafts with living chondrocytes and osteocytes. Donor sites filled without grafting and were covered with fibrocartilagenous scar. No complications occurred in this group. CONCLUSIONS: These histologic results suggest that arthroscopic osteochondral transplantation is a viable alternative for treating full-thickness chondral defects, with the grafts retaining their integrity and living chondrocytes and osteocytes observed in the grafts for up to 12 months after implantation. PMID- 11600981 TI - Arthroscopic diagnosis of tibiofibular syndesmosis disruption. AB - PURPOSE: We have been able to diagnose tibiofibular syndesmosis injury by ankle arthroscopy, and in the present study we compare these results with the results from plain radiographs. TYPE OF STUDY: Case series. METHODS: Thirty-eight type-B (Weber system) distal fibular fractures in 38 patients were diagnosed to determine whether tibiofibular syndesmosis disruption was present. According to the Lauge-Hansen system, 16 patients had supination-external rotation fractures and 22 had pronation-abduction fractures. Standard non-weight-bearing anteroposterior radiographs and mortise radiographs were evaluated. Furthermore, ankle arthroscopy was performed on all patients. RESULTS: Tibiofibular syndesmosis disruptions were diagnosed in 16 of the 38 patients (42%) by anteroposterior radiography, 21 of 38 patients (55%) by mortise radiography, and 33 of 38 patients (87%) by ankle arthroscopy. All of the patients who were diagnosed with tibiofibular syndesmosis disruption by anteroposterior radiography and mortise radiography were also confirmed by ankle arthroscopy to have injured their tibiofibular syndesmosis. In 12 patients, ankle arthroscopy was the only method used to diagnose the tibiofibular syndesmosis disruption. CONCLUSIONS: Ankle arthroscopy excels in term of the diagnosis ratio for tibiofibular syndesmosis disruption compared with both anteroposterior and mortise radiography. Therefore, we conclude that ankle arthroscopy is necessary for the correct diagnosis of tibiofibular syndesmosis disruption. PMID- 11600982 TI - Two-year outcome of arthroscopic bankart repair and electrothermal-assisted capsulorrhaphy for recurrent traumatic anterior shoulder instability. AB - PURPOSE: Arthroscopic treatment of chronic anterior shoulder instability in active athletes is reportedly less successful than open techniques. We performed arthroscopic stabilization for confirmed capsulolabral avulsions and followed-up patients prospectively for a minimum of 24 months. TYPE OF STUDY: Prospective nonrandomized study. METHODS: We studied 42 patients (mean age, 26 years) with recurrent traumatic anterior dislocations. They reported an average of 9 dislocations preoperatively. An average of 69 months elapsed from initial dislocation to surgery. The shoulders underwent arthroscopic capsulolabral repair with either a suture anchor and horizontal mattress suture, or an absorbable tack. Each shoulder also was treated with a monopolar radiofrequency probe for thermal shrinkage of the middle, anteroinferior, and posteroinferior glenohumeral ligaments. Patients were evaluated prospectively for pain, motion, stability, and function using the modified Rowe score. RESULTS: At a mean of 28 months postoperatively, 38 patients had returned to their preinjury sports. Three patients (7%) had a traumatic redislocation. Using the modified Rowe score, statistically significant improvements were noted for pain, stability, and function. There was no significant change in motion. The overall modified Rowe score improved from 38 points preoperatively to 89 points at final evaluation (P <.001). CONCLUSIONS: These results indicate that arthroscopic treatment of patients with recurrent traumatic anterior instability yields results comparable to open procedures, including athletes involved in high-level contact and collision sports. We believe that addressing capsular laxity surgically is critical, particularly when dealing with chronic instability. This procedure allows the surgeon to reliably correct the labral detachment and the capsular redundancy while preserving motion and minimizing morbidity. PMID- 11600983 TI - Significance of the internal locking mechanism for loop security enhancement in the arthroscopic knot. AB - PURPOSE: Secure tissue fixation of an arthroscopic knot depends on the security of the initial loop and additional locking half-hitches. The purpose of this report is to evaluate the loop and knot security relative to the internal locking mechanism of arthroscopic slip knot. TYPE OF STUDY: This is an experimental study designed for knot and loop security on a material testing system. The measurements were carried out in a blinded fashion in which the tester was not aware of the type of knot being tested. METHODS: Five configurations of arthroscopic knots (overhand throw, Duncan loop, Revo knot, Tennessee slider, and SMC knot) were created around a 5-mm diameter metal bar using a No. 2 braided suture. For each knot configuration, 10 knots were tested for displacement at cyclic loading, load to clinical failure (3-mm displacement), ultimate failure load, and mode of failure on the servo-hydraulic material testing system (MTS 858 MiniBionix test system; MTS, Minneapolis, MN). A 1-way analysis of variance was used to determine the statistical difference in displacement at cyclic loading, load to clinical failure, and ultimate failure load between each knot configuration. RESULTS: In the cyclic loading test, the average displacement of all knots was clinically insignificant, with the average being less than 0.24 mm. The overhand throw had the worst characteristic in the load to failure test. The other 4 knots had an optimal load to failure. The SMC knot, which has an internal locking mechanism, had good loop and knot security in the load to clinical failure and ultimate failure load (P <.05). The SMC and the Revo knots failed by knot breakage (material failure) whereas the other knots failed by knot slippage (loop failure). CONCLUSIONS: The internal locking mechanism flips the post strand to convert the loop strand into a new post strand while rerouting the original post strand around a new post. An arthroscopic knot with an internal locking mechanism can enhance loop security. PMID- 11600985 TI - Electromyographic activity of the biceps brachii muscle in shoulders with anterior instability. AB - PURPOSE: The purpose of this study was to evaluate the activity of the biceps muscle in the vulnerable abduction and external rotation position of the shoulder in patients with anterior instability. TYPE OF STUDY: This experimental study included a prospective analysis of the electromyographic (EMG) data on a group of patients with traumatic unilateral anterior instability of the shoulder. The EMG data of the unstable shoulders was compared with those of the opposite shoulders as control. The optimal sample size for the case-control study was calculated using an nQuery Advisor program (nQuery Advisor 3.0, Statistical Solutions, Cork, Ireland). METHODS: The EMG analyses were conducted in 76 shoulders in 38 patients who had a traumatic anterior instability in 1 shoulder. The EMG records were obtained at different positions of the shoulder, which included 0 degrees, 45 degrees, 90 degrees, and 120 degrees of shoulder abduction. In each angle of shoulder abduction, the arms were placed in an external rotation as tolerated by the anterior apprehension. The paired-sample t test was used to compare the difference of the root mean square (RMS) voltages between the stable and unstable shoulders in each degree of arm position. RESULTS: The RMS voltage of the biceps muscle was significantly greater in the unstable shoulder than the opposite stable shoulder in all positions of the arm (P =.00). The RMS voltage of the biceps was maximal at 90 degrees and 120 degrees of external rotation in the unstable shoulder (P <.05). The RMS voltage of the supraspinatus muscle revealed no differences in any of the test conditions (P =.904,.506,.119, and.781 in 0 degrees, 45 degrees, 90 degrees, and 120 degrees, respectively). CONCLUSIONS: In the vulnerable abduction and externally rotated position, the biceps muscle plays an active compensatory role in the unstable shoulder but not in the stable shoulder. PMID- 11600984 TI - A morphologic, biochemical, and biomechanical assessment of short-term effects of osteochondral autograft plug transfer in an animal model. AB - PURPOSE: The objective of this study was to assess the short-term changes that occur after an osteochondral autograft plug transfer from the femoral trochlea to the medial femoral condyle in a goat model. TYPE OF STUDY: Articular cartilage repair animal study. METHODS: Six adult male goats were used in this study. Two 4.5-mm osteochondral plugs were transferred from the superolateral femoral trochlea to 2 recipient sites in the central portion of the medial femoral condyle for a survival period of 12 weeks. Postmortem, the global effects of the procedure were assessed by gross morphologic inspection and by analyzing the synovial DNA for inflammatory response. The recipient sites were also evaluated histologically and biomechanically. Metabolic activity was determined by (35)SO(4) uptake, and viability was assessed using a live/dead stain and by confocal laser microscopy. RESULTS: There was no evidence of significant gross morphologic or histologic changes in the operative knee as a result of the osteochondral donor or recipient sites. The patella, tibial plateau, and medial meniscus did not show any increased degenerative changes as a result of articulating against the donor or recipient sites of the osteochondral autografts. Analysis of synovial DNA revealed no inflammatory response. Biomechanically, 6- to 7-fold greater stiffness was noted in the cartilage of the transferred plugs compared with the control medial femoral condyle. Furthermore, on histologic examination, the healing subchondral bone interface at the recipient site had increased density. Glycosaminoglycan synthesis as determined by (35)SO(4) uptake was upregulated in the transplanted cartilage plug relative to the contralateral control, showing a repair response at the site of implantation. And finally, confocal microscopy showed 95% viability of the transferred plugs in the medial femoral condyle region. CONCLUSIONS: Our findings demonstrate the ability to successfully transfer an osteochondral autograft plug with maintenance of chondrocyte cellular viability. The transferred cartilage is stiffer than the control medial femoral condyle cartilage, and there is concern regarding the increased trabecular mass in the healing subchondral plate, but these do not result in increased degenerative changes of the opposing articular surfaces in the short term. PMID- 11600986 TI - Arthroscopic diagnosis and management of ochronotic arthropathy of the knee. AB - Ochronotic arthropathy is a progressive joint disorder resulting from the deposition of a derivative of homogentisic acid into connective tissues, especially meniscal and articular cartilage. Patients may present with symptoms, physical examination results, and radiographic changes consistent with degenerative joint disease. We present a case in which an operative arthroscopy of the knee was highly suggestive of ochronotic arthropathy. The definitive diagnosis of ochronosis was subsequently confirmed by laboratory and pathologic evaluation. PMID- 11600987 TI - Open reduction of a lateral femoral notch associated with an acute anterior cruciate ligament tear. AB - The lateral notch is a radiographic sign that describes a depression in the lateral femoral condyle near the terminal sulcus. The sign was first described in association with chronic instability in an anterior cruciate ligament-deficient knee. Recently, the senior author, after a prospective study, reported that these lateral notches might occur acutely at the time of anterior cruciate ligament injury. We report such a case in which the lateral femoral condylar depression fracture resulted in symptoms of lateral compartment incongruity. Open reduction and internal fixation were required. Anterior cruciate ligament reconstruction was performed as a staged procedure 2 months after fracture reduction. The postoperative result has been excellent for over 5 years. This case is an example that lateral femoral notches may be acute and a source of symptoms. In some cases, reduction and fixation of significant depressions in association with ligament reconstruction can alleviate these symptoms and may improve the patient's long-term result. PMID- 11600988 TI - Infection following knee arthroscopy. AB - Arthroscopy of the knee is not a risk-free procedure. Although rare, numerous complications have been reported in the literature. Fortunately, infection is a rare complication following arthroscopy, which, when treated, usually results in a benign outcome. We present the first reported case of Candida albicans infection following routine arthroscopy of the knee, which eventually resulted in a knee fusion. A review of infections that can occur after knee arthroscopy and their treatment is also presented. This and other potential complications should be considered when performing knee arthroscopy. PMID- 11600989 TI - Office-based arthroscopic synovectomy of the wrist in rheumatoid arthritis. AB - We present an office-based technique for performing arthroscopic synovectomy of the wrist in patients with rheumatoid arthritis. Intra-articular anesthesia as well as subcutaneous portal anesthesia are used. Standard portals are used in the radial carpal and midcarpal joints. Standard instrumentation is used and the synovectomy is accomplished using a motorized shaver. We performed 30 procedures in 21 patients: 15 complete synovectomies, 3 radioulnar carpal synovectomies because of only limited disease, and 12 limited synovectomies because these patients were participants in a clinical trial and required only limited synovectomy for investigational purposes. There were no complications. Office based arthroscopic synovectomy of the wrist in patients with refractory rheumatoid arthritis can be performed safety and effectively. This technique is useful in both a clinical as well as a research setting. PMID- 11600990 TI - The accessory posterior portal for shoulder arthroscopy: Description of technique and cadaveric study. AB - As the indications for shoulder arthroscopy continue to expand, so too does the need for complete access to the glenohumeral joint. Specific regions of the joint, including the axillary recess, are often times difficult to access using traditionally described posterior and anterior portals. In this article, we describe a technique for the placement of an accessory posterior portal into the inferior hemisphere of the glenohumeral joint, effectively in the 8 o'clock or 4 o'clock position. To demonstrate the safety and effectiveness of this portal, 6 cadaveric specimens were dissected after the placement of a standard and accessory posterior portal. The proximity of the posterior portals to the axillary and suprascapular nerves was analyzed. Measurements were made in simulated beach-chair and lateral decubitus positions. The authors show that the accessory posterior portal is safe to use and may prove useful to the surgeon who wishes to gain access to the inferior recesses of the glenohumeral joint. PMID- 11600991 TI - Arthroscopic-assisted simultaneous reconstruction of the posterior cruciate ligament and the lateral collateral ligament using hamstrings and absorbable screws. AB - Arthroscopic-assisted simultaneous reconstruction of the posterior cruciate ligament (PCL) and the lateral collateral ligament (LCL) using hamstring tendon grafts is described. The femoral tunnel is drilled through an incision over the medial femoral condyle and the tibial tunnel through the same skin incision used for harvesting the tendon graft. PCL reconstruction is performed using a 4-strand hamstring tendon graft and absorbable screw fixation. The tendon of the semitendinosus muscle of the uninvolved knee is used as a lateral loop for LCL reconstruction. After pulling the transplant through the fibular head, femoral fixation of the loop is made with an absorbable screw. PMID- 11600994 TI - Regarding the article "A Comparison of Outcomes at 2 to 6 Years After Acute and Chronic Anterior Cruciate Ligament Reconstructions Using Hamstring Tendon Grafts" by Vipool K. Goradia and William A. Grana (Arthroscopy2001;17:383-392). PMID- 11600995 TI - Decisions at end of life. PMID- 11600996 TI - Eosinophilic bronchitis. PMID- 11600998 TI - [Antisense oligonucleotides inhibit c-myc and PCNA expression in the vascular smooth muscle cells]. AB - OBJECTIVE: To study the methods for prevention and treatment of vascular restenosis. METHODS: We used two factors which result in hyperplasia of vascular smooth muscle cells (VSMCs) and applied antisense c-myc, PCNA oligonucleotides to attenuate the expression of their related gene. The sense, antisense, and mismatched oligomers for c-myc or PCNA were designed and synthesized. They were individually delivered to the cultured VSMCs after the oligomers were stable in culture medium for 5 days and could cross the plasma membranes into the cells. Using RT-PCR and the image analysis system, we observed the changes of both c-myc and PCNA gene expression in the VSMCs. RESULTS: Antisense c-myc and PCNA at a concentration of 10 mumol/L were able to inhibit the expression of c-myc and PCNA gene in VSMCs (P < 0.05), whereas the sense and the mismatched ones couldn't inhibit the expression (P > 0.05). CONCLUSION: The antisense technique is an effective method for the inhibition of VSMCs proliferation. PMID- 11600999 TI - [The relation-ship between apoptosis, apoptosis related-gene expression and proliferative activity in smooth muscle cell after autogenous vein grafting]. AB - OBJECTIVE: To study the mechanism of graft vein stenosis. METHODS: A rat experimental model of autogenous vein graft was established by transplanting the right external jungular vein into the infrarenal abdominal aorta in 100 Wister rats. Electric microscope, TUNEL and immunohistochemical S-P technique were used to detect the apoptosis, the expression of apoptosis related-gene bcl-2 and bax and proliferation cell nuclear antigen (PCNA) of smooth muscle cells(SMCs) in vein graft. RESULTS: From 1 to 8 weeks after replacement, the expression of apoptosis and PCNA of SMCs was continuously higher than the control group (P < 0.01). From 1 to 2 weeks, the expression of TUNEL and PCNA showed peak value. From 1 to 2 weeks, the positive rate of apoptosis was lower than that of PCNA, but from 4 to 8 weeks, the positive rate of TUNEL was higher than that of PCNA. There was obvious positive correlation between the expression of TUNEL and PCNA (r = 0.813 P < 0.05). One to 2 weeks after vein grafting, bcl-2 positive rate increased and was more different than the control group and the group of 4 to 8 weeks after vein grafting (P < 0.010). CONCLUSIONS: The imbalance of proliferation and apoptosis may be related to the vessel remodeling and vein graft stenosis, and bcl-2 and bax protein may involve in the regulation of apoptosis of VSMC. Adopting the mixed strategy to regulate the balance between proliferation and apoptosis may be useful to prevent vein graft stenosis. PMID- 11601000 TI - [Soft extravascular model (SEM) with beta-radioactive ray inhibits smooth muscle cell proliferation and intimal hyperplasia in autogenous vein graft]. AB - OBJECTIVE: To investigate the effects of the soft extravascular model (SEM) with 32P on intimal hyperplasia and smooth muscle cell preliferation in autogenous vein grafts. METHODS: We transplanted the femoral veins to the co-lateral femoral arteries in rabbits. The animals were divided into three groups of Aspirin group, 32P group and control group. We observed the expression density of endothelin type A receptor cDNA (ETAcDNA) and intimal relative thickness by using in situ molecular hybridization of ETAcDNA by computerized image analysis technology. RESULTS: SEM with beta-ray obviously inhibited SMC preliferation from 1 W to 12 W postoperation, and notably restrained intimal hyperplasia at early to middle stage of graft. Aspirin could not inhibit SMC proliferation and intimal hyperplasia under the condition of this experiment. PMID- 11601001 TI - [A molecular epidemiology study on risk factors and mechanism of HBV intrauterine transmission]. AB - OBJECTIVE: To clarify the risk factors and mechanism of HBV intrauterine infection by molecular epidemiology method. METHODS: We performed a case-control study. 402 HBsAg-positive pregnant women and their infants were collected as subjects. 15 infants infected by HBV intrauterine transmission were selected as case group and others as controls. Besides, HBsAg titer in 182 maternal sera and HBV DNA concentration in 185 maternal sera were determined. To identify the HBV infection in the placentas, immunohistochemistry stain and HBV DNA hybridization in situ were conducted. The data from both laboratory and epidemiological fields were analysed. RESULTS: The findings indicated that the positiveness of HBeAg in mother's sera (OR = 17.07) and the history of threatened premature labour (OR = 5.44) were the main risk factors. Intrauterine transmission was significantly related to HBsAg titers and HBV DNA concentration in mother's sera (P = 0.01). The results of immunochemistry stain and HBV DNA situ in hybridization in the placentas from 101 full-term pregnancy women showed that HBV infection rates had a decreasing trend (P = 0.0009) from mother's side to fetus's in placenta and there was a significant association between HBV intrauterine transmission and HBV infection in villous capillary endothelial cells in placenta (OR = 18.46, P = 0.0002). CONCLUSION: There might be a "cellular transfer" of HBV infection in the placenta. With regard to the mechanism of HBV intrauterine transmission; there are two transmission routes, namely, hemagenous route and cellular route. PMID- 11601002 TI - [Relationship of polymorphism of LMP2 gene to insulin-dependent diabetes mellitus and DR3 gene]. AB - OBJECTIVE: To investigate the relationship of polymorphism of large multifunctional protease (LMP) 2 genes to insulin-dependent diabetes mellitus (IDDM) and DR3 gene. METHODS: The polymorphism of LMP2 genes was identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 68 IDDM patients and 71 healthy controls. IDDM patients and healthy controls were respectively divided into 2 groups according to DR3 genotyping. One group included subjects with DR3 gene, and another group subjects without DR3 gene. RESULTS: In the subjects with DR3 gene, the frequencies of LMP2-R/H, LMP2-R/R, LMP2-H/H were 47%, 47% and 6% in the IDDM patients, 13%, 87%, 0% in the controls. Compared with the Controls, the IDDM patients had a higher frequency of LMP2-R/H (P < 0.05) and a lower frequency of LMP2-R/R (P < 0.05). In the subjects without DR3 gene, the frequencies of LMP2-R/H, LMP2-R/R, LMP2-H/H were 58%, 39%, 2.8% respectively in the IDDM patients, and 32%, 54%, 14% respectively in the controls. Compared with the controls, the IDDM patients had a higher frequency of LMP2-R/H (P < 0.05), the frequency of LMP2-R/R in the IDDM patients did not have a significant difference from that in the controls (P > 0.05). CONCLUSIONS: There may be a significant association of LMP2-R/H and LMP2-R/R with the susceptibility to IDDM. The LMP2-R/H is a susceptible gene. The people with LMP2-R/H have a higher risk of suffering from IDDM. The LMP2-R/R is a protective gene. The people with LMP2-R/R have a decreased risk of suffering from IDDM. The effects of LMP2 on ID-DM are not affected by DR3 gene. PMID- 11601003 TI - [The significance of antiendothelial cell antibodies in patients with lupus nephritis: a clinical and renal pathological study]. AB - OBJECTIVE: To investigate the prevalence and possible role of antiendothelial cell antibodies (AECA) in the pathogenesis of lupus nephritis. METHODS: Sera from 58 patients with lupus nephritis were studied. Cellular ELISA were used to detect AECA, and immunoblotting was performed to determine specific endothelial target. RESULTS: 36% of the patients with lupus nephritis had elevated IgG-AECA. IgG-AECA was correlated with the higher incidence of thrombocytopenia, higher serum immuoglobulin G levels, lower serum C3(13 +/- 7) g/L and higher titers of antibodies against nucli and dsDNA. AECA consisted of a group of heterogeneous antibodies and reacted with different endothelial cell antigens ranging from 12,000 to 90,000 in molecular size. A correlation was demonstrated between heavy proteinuria (> 3.5 g/24 hr) and the existence of antibodies simultaneously against the 27,000, 29,000 endothelial cell antigens (34% vs 4%), we also found an association between the presence of glomerular capillary thrombi and antibody against the 29,000 endothelial cell antigen (60% vs 14%). CONCLUSION: These results suggested that lupus nephritis patients with AECA showed a complex autoimmune disorder and provided an indirect evidence that AECA might contribute to the pathogenesis of lupus nephritis. PMID- 11601004 TI - [Chromosomal abnormalities in 38 CML cases of various phases]. AB - OBJECTIVE: To study the genomic abnormality underlying the blast crisis of chronic myeloid leukemia(CML). METHODS: 15 CML patients in blast crisis (BC), 3 in accelerated phase (AP) and 20 in chronic phase (CP) were analyzed by conventional cytogentics, comparative genomic hybridization (CGH) and dual color chromosomal painting. RESULTS: Philadelphia (Ph) chromosome was identified in every case studied. Only 5 among 20 CP patients had additional abnormalities while 12 out of 14 patients with disease progression (BC + AP) showed extra numerical and/or structural chromosmal aberrations. Cytogenetically, the most common chromosome gains during BC and AP were double or triple Ph chromosome(5/14), trisomy 8(5/14), trisomy 7(1/14) and 17 (1/14). Three cases showed the same region being involved in translocations t(1;17)(q12-21;q10), t(1;10) (q12-21;q26) and t(1;11)(q12-21;p15). CGH analysis detected genetic imbalances in 8 cases. In one case, a very complex chromosmal translocation del(3), del(6)(q13-21), der(6)t(17;3;6), der(17)t(6;17) was characterized by chromosomal painting. CONCLUSION: We find that the combined use of CGH, chromosomal painting, and classic cytogenetic analysis allows a better evaluation of the genomic aberration involved in CML blastic transformation, and offers new directions for its further molecular investigation. PMID- 11601006 TI - [Vascular surgery in China: current status and future tasks]. PMID- 11601005 TI - [A surveillance study on penicillin-resistant Streptococcus pneumoniae in China]. AB - OBJECTIVES: To find out if there are penicillin-resistant Streptococcus pneumoniae and the resistance rate in China. METHODS: 989 pediatric patients with respiratory tract infections aged from 6 months to 3 years from two pediatric units were enrolled. Perthroat swabs were immediately streaked onto blood agar plates and incubated overnight. Pneumococci were identified and isolated. Antibiotic susceptibility was assessed by the disk diffusion method and MIC determination according to Protocol and NCCLS. RESULTS: Of the 51 Streptococcus pneumoniae isolates, 5 strains had zones > or = 20 mm. Two of the 5 strains had penicillin MICs > or = 0.1 mg/L (2 and 4 mg/L) and considered to be fully resistant to penicillin(4%). The resistance rate to ceftriaxone and cefotaxime was 0 and 4% respectively. For the other 10 antimicrobial agents, the resistance rates were as follows: ampicillin 12%, piperacillin 26%, furbenicillin 14%, cefuroxime 6%, erythromycin 54%, clarithromycin 52%, meleumycin 64%, roxithromycin 52%, chloramphenicol 32%, and tetracycline 100%. CONCLUSIONS: The study suggested that penicillin resistant Streptococcus Pneumoniae strains also exist, and the cross-resistance is a significant phenomenon in China. PMID- 11601007 TI - [Biological properties of reconstructed mouse hematopoiesis with hematopoietic stem cells transfected by bcl-2 gene]. AB - OBJECTIVE: To observe resistance to radiochemical agents in the mice reconstructed hematopoiesis with hematopoietic stem cells transfected by bcl-2 gene. METHODS: The plasmid containing bcl-2 cDNA retrovirus vector was transfected to PA317 cells with Lipofecaine kite. A PA317 cell clone(D3) with high virus titer was obtained through G418 selection. The virus supernatant of D3 clone cells was used to transfect mouse embryo-liver hematopoietic stem cells. Hematopoiesis in the mice treated with lethal dose irradiation was reconstructed by hematopoietic stem cells transfected with bcl-2 gene. The resistance to radiochemical agents in the mice with reconstructed hematopoiesis was evaluated according to the number of WBC of periphereal blood and mononuclear cells of bone marrow, CFU-S and CFU-S regeneration. RESULTS: The expression of bcl-2 protein was increased in the hematopoietic cells transfected by bcl-2 gene. The mice reconstructed hematopoiesis by stem cells transfected bcl-2 gene can tolerate high dose combined with chemotherapy and radiation of middle dose. The mice reconstructed hematopoiesis with stem cells transfected bcl-2 gene survived over one year, no tumors were found. CONCLUSION: The mice with reconstructed hematopoiesis by stem cells carried bcl-2 gene possess the ability of resistance to radiochemical agents, even only part of hematopoietic stem cells were transfected with bcl-2 gene. PMID- 11601008 TI - [Gene diagnosis of X linked retinitis pigmentosa by linkage analysis]. AB - OBJECTIVE: To establish a gene diagnosis method for X linked retinitis pigmentosa (XLRP). METHODS: Ten microsatellite markers were selected from the region where the RP2 and RP3 gene may be located at Xp21.1-p11.23. Haplotype analysis for XLRP pedigrees was used to determine the chromosome region which is RP related and whether this region was carried by the individuals we want to detect. RESULTS: The young female who is the RP carrier or the young boy who is the pre-symptom RP patient could be determined this way in 4 XLRP family. CONCLUSION: Haplotype analysis for XLRP Pedigrees is useful. PMID- 11601009 TI - [Specific point-mutate p53 mini-gene transfectimg effects on biological behaviors of a human cancer cell line PG derived from human pulmonary giant carcinoma]. AB - OBJECTIVES: To explore the suppressive effects of a murine genomic p53 minigene containing an Arg-->Leu substitution at its encoding amino acid 172 on biological behaviors of human carcinoma cell and evaluate its potential application in cancer gene therapy. METHODS: By LipofectaMINE and electraporation methods, this mutant p53 gene which lacked of exon 1 and intron 1 expression vector driven by CMV promoter was co-transfected with PCMVneo into PG cell in which dominant negative p53 pre-exists. A wild-type and another kind of genomic mutate-type p53 gene expression vector were transfected. The latter p53 gene encoding protein contained an Arg-->His substitution at the same position, and pBLuscript plasmid was used as control. All transfectants were screened by 500 micrograms/ml geneticin and identified by mouse specific p53 mRNA RT-PCR and Northern blot analysis. After transfection, the biological behavior changes were studied by colony formation and TUNEL test together with in-situ clone regression for chemosensitivity of anti-cancer drugs. RESULTS: The transfecting effects of this unusual p53 gene were surprisingly strong. They were more significant than those of the wild-type p53 and could suppress the formation of transgenic colonies and passage. The transgenic colonies were sensitive to be treated in adromycin and 5 Fu, and the gene transient expression could result in cell apoptosis. CONCLUSION: Codon 172 mutant (Arg-->Leu) p53 genomic DNA exhibited a strong suppressive transfecting effects on carcinoma cell, so it is a possible candidate to be used in cancer gene therapy. PMID- 11601010 TI - [Analysis of the protein of Haemophilus influenzae]. AB - OBJECTIVE: To understand Haemophilus influenzae special protein and to help for preparing Haemophilus influenzae Vaccine. METHODS: Proteins from isolates of Haemophilus influenzae were examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). RESULTS: 23 isolates were from nasopharyngeal secretions of children with pneumonia and 33 from pharyx swab of healthy children. Conventional tests showed that 79% of fifty-six strains of Haemophilus influenzae were non-serotypable and all belonged to one of eight biotypes. The common biotypes were II (48%). All strains contained more than 10 proteins with molecular weights of 96,000, 86,000, 55,000, 51,000, 46,000, 40,000, 39,000, 31,000, 29,000, 25,000, and 16,000. Among them, three were major proteins (31,000, 51,000 and 96,000) and different proteins were mainly between peptide 31,000 and 51,000. A possible association between biotype and protein was unclear. CONCLUSION: Analysis of protein of Haemophilus influenzae is helpful for epidemiological study of non-serotypable Haemophilus influenzae and making Haemophilus influenzae vaccine. PMID- 11601011 TI - [Some issues of the development of medical sciences in the 21st century]. PMID- 11601012 TI - [Progress in the study of mechanism of endotoxin-induced signal transduction of endothelial cells]. PMID- 11601013 TI - [Vascular endothelial growth factor in non-small cell lung carcinoma expression and its significance]. AB - OBJECTIVE: To clarify the relationship between the expression of vascular endothelial growth factor (VEGF) and the angiogenesis, invasion, prognostic value in non-small cell lung cancer. METHODS: Immunohistochemistry. RESULTS: 53 patients with NSCLC after radical resection were evaluated. A significantly higher microvessel density (MVD) was observed in the tumors with high expression of VEGF compared with that of the low expression (P < 0.001). 29 patients (80%, 29/33) with the high expression of VEGF showed lymph node metastasis and 4 patients (27%, 4/15) unlymph node metastasis (P < 0.001). By Cox's proportional hazard model analysis, the expression of VEGF was considered an independent predictor for the prognosis of NSCLC. CONCLUSIONS: The expression of VEGF has a significant correlation among MVD, growth, invasion, and lymph node metastasis. The patient with the tumor of the higher expression of VEGF and MVD may have poor prognosis. VEGF may be an independent predictor of prognosis. PMID- 11601014 TI - [Diagnosis of sex chromosome abnormality by fluorescence in-situ hybridization]. AB - OBJECTIVE: To evaluate the diagnostic value of fluorescence in-situ hybridization (FISH) in sex chromosome abnormality. METHOD: alpha-satellits DNA probes of X, Y chromosomes were used to FISH with blood samples from 19 patients with primary anemia or of gonad dysplasia. Five infertile men who were detected abnormal by G banding analysis during metaphase and interphase. Samples from healthy men and women were used as positive controls and reactions with hybridization fluid without probes as negative controls. RESULTS: The karyotypes, 45, X; 45, X/46, XX/47, XXX; 45, X/46, XY; 47, XXY; 45, X/46, XXX were detected by FISH. Others were not detected by G banding such as 45, X/46, X,r? 46, X,r? but were found to be 45, X/46, X,r(X), 46, X, r(X), by FISH technique, confirming to be X ring chromosome. A female patient whose karyotype was 45, X/46, X, mar. by G banding. But G banding technique could not analyze the property of the marker and FISH revealed the marker was dici(yq), that is dicentric chromosome Y with two long arms of equal length. The real karyotype was 45, X/46, X, dici(yq) mosaicism. It belonged to Y chromosome abnormal and gonadal dysplasia syndrome. CONCLUSION: FISH can help to detect those chromosome abnormalities which can not be confirmed by traditional cytogenetics. It is of value in studying the complex chromosome mutation such as sex chromosome abnormality, unknown little marker, ring chromosome, mosaiciasm and translocation. PMID- 11601015 TI - [Cells culture of human lumbar disc and its morphological observation]. AB - OBJECTIVE: To observe the continuous changes of disc cells, and explore the degeneration influenced by the cell effects. METHODS: Three discs were obtained from three human embryos and one was from a healthy adult. They were dissected and were digested with trypsin and collagenase. The isolated cells were cultured in HAM F-12 medium and 10% fetal bovine serum. The cultured cells were refrigerated and revived for observation under light microscope and TEM. RESULTS: The biological characteristics of the primary and the second generation of the disc cells were similar to those of the cells in vivo. After subculture, notochordal cells and chondrocytes were shown the characteristics of dedifferentiation. The metabolism of the revived cells after refrigeration was normal. The structures of the organellae in disc cells varied with the changes of cell biological characteristics. CONCLUSION: This successful model is useful for the study of biology and pharmacology of human disc cells. PMID- 11601016 TI - [Protective effect of exogenous pulmonary surfactant on pulmonary function during cardiopulmonary bypass in children]. AB - OBJECTIVE: To study the protective effect of exogenous pulmonary surfactant (PS) on respiratory insufficiency after cardiopulmonary bypass in children. METHODS: 24 children of VSD associated with pulmonary hypertension undergoing heart surgery with cardiopulmonary bypass(CPB) were randomly divided into two groups: control group and PS group. In the PS group, exogenous natural porcine PS 150 mg/kg was dropped into the intracheal tube before opening the chest and removing the aortic clamp. Equal amount of normal saline was given in the control group. Lung dynamic compliance and oxygenate index were measured before and after operation. The plasma molondialdehyde(MDA) concentration of the lung was analysed perioperatively with ELISA methods. The intubation time of the two groups and ultrastructure of the lung also was measured. RESULTS: The dynamic compliance of the PS group was higher than that of the control group (P < 0.05), and the oxygenate index was significantly lower than that of the control group (P < 0.01) after CPB. Compared to the control group, the exogenous PS was able to markedly reduce the generation of MDA(P < 0.01). The intubation time of the PS group was 8.9 hours, much shorter than 13.8 hours of the control group(P < 0.001). The histological examination confirmed that the degree of pulmonary damage was significantly ameliorated in the PS group. CONCLUSION: Exogenous natural PS has protective effect on respiratory insufficiency after CPB in children with VSD associated with pulmonary hypertension. PMID- 11601017 TI - [Surgical treatment of frontal lobe epilepsy--40 cases]. AB - OBJECTIVE: To compare the methods and outcome of the treatment of frontal lobe epilepsy (FLE). METHODS: We combined such techniques, as intraoperative electrocorticography (ECoG), corpus callostomy(CCS), and multiple subpial transection(MST) to improve the surgical results. When preoperative semiology suggested the involvement of the bilateral frontal lobe or ECoG detected bilaterally synchronized epileptic discharged, anterior corpus callosotomy was performed before the main surgical procedure. MST was applied to the unresectable motor or involved speech zone. This technique was also useful for the treatment of widely disseminated epileptic zone. Satisfactory results were obtained in surgical treatment of FLE. RESULTS: One month after operation, most patients were free from seizure. No severe complications and operative death occurred. Follow up lasted for 0.5 to 3 years(mean 2.5 years). Seizure free was noted in 19 patients(47.5%), seizure attack less than 3 times per year or no real attack in 11(27.5%), significant reduction of seizure attack in 6(15%); and no change in 4 (10%). The total effective rate was 90%. CONCLUSION: Indicated by ECoG, combined resection with corpus callosotomy or multiple subpial transection is an effective method for FLE. PMID- 11601018 TI - [Retroviral transfer of a human beta-globin gene linked to beta locus control region hypersensitive site 2 into murine hematopoietic stem cells]. AB - OBJECTIVE: To examine the in vivo properties of retroviral recombinants carrying partially deleted human beta-globin gene (delta beta) and truncated erythroid enhancer (292 bp and 341 bp of 5'HS2) at the mRNA levels following short- and long-term reconstitution in mice with infected marrow cells. METHODS: First ecotropic virus producer cell lines with higher virus titers were isolated using "ping-pong" procedures. Then the human beta-globin gene was transferred into murine hematopoietic progenitor cells and the integration and expression of transferred gene were analyzed by southern blot and RNase protection assay or RT PCR. RESULTS: The virus titers of both recombinants increased obviously after "ping-pong" procedures. The transferred human beta-globin gene was detected in murine CFU-S12 and the expression level was about 0.5%-5% of endogenous mouse alpha-globin gene. In 3 of 14 mice surviving long-term transplanted with bone marrow cells transduced with high-titer virus, bone marrow, spleen and thymus from two mice and bone marrow and spleen from another mouse contained the intact proviral genome. Long-term expression of the transferred gene was seen in one mouse at level of 7% of endogenous murine alpha-globin gene. CONCLUSIONS: The transferred human beta-globin gene can stably integrate into murine hematopoietic stem cells mediated by retroviral vectors and express in an erythroid-specific manner. PMID- 11601019 TI - [Bilirubin induced apoptosis of cerebellar granule neurons]. AB - OBJECTIVE: To investigate the mechanism of bilirubin-induced neurotoxicity from cellular and molecular level. METHODS: Bilirubin was exposed to primary cultured rat cerebellar granule and cortical neurons and its neurotoxicity was observed DNA staining and agars gel electrophores were used to identify the biochemical and morphological features of bilirubin-induced neurotoxicity in cultured cerebellar granule and cortical neurons. RESULTS: Bilirubin selectively induced death of cerebellar granule neurons in a concentration- and time-dependent manner. Neuronal death displayed biochemical and morphological features of apoptotic nuclei: condensation of nuclear chromatin and DNA fragmentation. RNA and protein synthesis inhibitors blocked the neurotoxicity induced by bilirubin. However, the cortical neurons displayed a relative insensitivity to bilirubin. CONCLUSIONS: Bilirubin induced neuron death is an active process, requiring de novo synthesis of RNA and protein. Bilirubin may selectively induce apoptosis of cerebellar granule neurons. PMID- 11601020 TI - [Vascular endothelial growth factor gene therapy for peripheral artery disease: experimental study]. AB - OBJECTIVE: To Study experimentally VEGF gene for treatment of peripheral artery disease. METHODS: The human VEGF cDNA was cloned into the eukaryotic expression vector pcD2. Using gene suture, the recombinant plasmid was transferred into the hindlimbs' adductor of Rhesus monkey, of which the distal end of the external iliac arteries were ligated and the femoral arteries were completely excised. With angiography, the biological effect of VEGF gene in experimental animals was investigated. Safety tests were analyzed by transferring of VEGF into mouse, rat, and Rhesus monkey, evaluated by biochemistry analysis, histopathological examination, PCR, and indirect ELISA. RESULTS: The transfer of VEGF gene stimulated the formation of focal microvessels, established collateral circulation, and augmented blood perfusion. The system had no adverse effect and remarkable pathological change in mouse, rat, and Rhesus monkey. CONCLUSION: The experimental studies indicated that VEGF would be effective and safe for clinical trial after approval. PMID- 11601021 TI - [Inhibition of mesangial cell proliferation and mesangial matrix expansion by antisense oligodeoxynucleotide targeting preproendothelin-1 mRNA in vivo]. AB - OBJECTIVE: To investigate the effect of endothelin-1 (ET-1) on mesangial cells(MC) proliferation and mesangial matrix expansion in vivo. METHODS: Antisense oligodeoxynucleotide(As-ODN) and its control sequences, sense oligodeoxynucleotide(Se-ODN) and mismatch oligodeoxynucleotide(Mis-ODN), targeting pre-proendothelin-1 mRNA (ppET-1) were delivered into the kidney of rats with mesangioproliferative glomerulonephritis (MsPGN) model respectively at day 2 by lipofectin-mediated gene transfer method. The efficiency of transfer of ODNs into MC was examined with biotinylated As-ODN staining. Four days after the rats were sacrificed, the influence of ODNs on ET-1 production by glomeruli was tested with radioimmunoassay(RIA). The action of ODNs on MC proliferation and mesangial matrix expansion was evaluated with quantitative pathologic analysis. RESULTS: ODNs were transferred into MC in vivo. The glomerular ET-1 production was decreased by As-ODN [(32 +/- 19) ng/g, P < 0.05] with reduction of mesangial cell proliferation [(0.82 +/- 0.04)/100 micron 2, P < 0.05] and mesangial matrix expansion[(12.8 +/- 1.6)%, P < 0.05], where Se-ODN and Mis-ODN did not show any effect on all of these. CONCLUSIONS: Specific inhibition of ET-1 gene expression leads to reduction of proliferation of mesangial cell and expansion of mesangial matrix in rats with MsPGN model. ET-1 is one of the important inflammatory mediators which can stimulate MC proliferation and mesangial matrix expansion in vivo. PMID- 11601022 TI - [Pathogenetic effect of platelet activating factor on enterogenic endotoxemia after burn]. AB - OBJECTIVE: To investigate the effects of platelet activating factor (PAF) on the occurrence of enterogenic endotoxemia after burn. METHODS: The relationship between changes of PAF and enterogenic endotoxima was observed on a model of rats with 30% TBSA III degree burn. RESULTS: The intestinal permeability and plasma endotoxin were significantly elevated and were positively correlated with the increase of PAF in the intestinal tissue and blood. PAF antagonist treatment significantly decreased the intestinal permeability and the levels of plasma endotoxin. After intravenous injection of enogenous PAF to healthy rats, the intestinal permeability and plasma endotoxin were also markedly increased, which was significantly depended on the dose of PAF. CONCLUSION: PAF is one of the important factors for the occurrence of postburn enterogenic endotoximia. PMID- 11601023 TI - [Expression of recombinant inserting mutants of HBsAg in vitro and its antigenic analysis]. AB - OBJECTIVE: To study the immunological characteristics of two inserting variants of HBsAg as further to elucidate the role of inserting mutants in the development of HBsAg-negative chronic hepatitis B. METHODS: The inserting mutants of HBsAg were constructed by PCR-mediated mutagenesis in vitro. Epstein-Barr virus vector pCEP4 and retrovirus vector PXT1 carrying the mutant genes of HBsAg were transfected into mammalian cells. The affinity of polyclonal and monoclonal antibodies against HBsAg for mutant antigens were studied by ELISA and western blot. RESULTS: Two insertions were introduced into s gene, and a six nucleotide insertion introduced two aminoacids (Arg and Ala) between codons 122 and 123 of the s polypeptide, whereas a nine nucleotide insertion introduced three aminoacids(Arg, Gly and Ala) between codons 123 and 124. These s genes were subcloned into two eukaryotic expression vectors (pCEP4 and PXT1), and the recombinant eukaryotic expression plasmids had been constructed, which could express s polypeptide in mammalian cells. Cell lines expressing wild-type or mutant-type HBsAg stably were obtained after transfection of these vectors into mammalian cells. Two two inserting variants failed to react with polyclonal and monoclonal antibodies against HBsAg by ELISA and Western blot. CONCLUSION: The insertions may result in a conformational change of the s protein, and affect its antigenicities, suggesting that the inserting mutations may be critical for immunoescape of HBV and in part responsible for chronicity of HBsAg-negative patients. PMID- 11601024 TI - [Effects of calcium overload in the conversion of acute edematous pancreatitis to necrotizing pancreatitis in rats]. AB - OBJECTIVE: To investigate the potential of pancreatic acinar cell calcium overload in the conversion of acute edematous pancreatitis (AEP) to necrotizing pancreatitis (ANP). METHODS: Ninety-six Sprague-Dawley rats were randomized in three experimental groups. Sham-operated control (Group I) AEP (Group II) was induced by pancreatic duct ligation and intravenous injection of bombesin (100 micrograms/kg) and secretin (10 micrograms/kg). ANP (Group III) was induced same as group II but with a large dose of dextran 110,000(500 mg/kg) intravenously. Pancreatic acinar cell Ca2+ overload was studied using fluorescent probe Fura2. Cytosolic free Ca2+ concentration ([Ca2+]i) in isolated pancreatic acinar cells and Ca(2+)-ATPase activity in pancreatic cell plasma membranes were determined 1, 3, 6, 9 h respectively after treatment. RESULTS: The results showed that pancreatic acinar cell [Ca2+]i was elevated at 1 h[(213 +/- 19) nmol/L, P < 0.05] and increased to (464 +/- 29) nmol/L at 6 h(P < 0.05) in rats with ANP, pancreatic cell plasma membrane Ca(2+)-ATPase activity decreased significantly from (29.8 +/- 0.4) nmol.min-1.mgp-1 at 1 h to (18.6 +/- 0.5) nmol.min-1.mgp-1 at 9 h in rats with ANP (P < 0.05). CONCLUSIONS: In ischemia-induced conversion of AEP to ANP, there exists Ca2+ overload in the pancreatic acinar cells. The decreased pancreatic cell plasma membrane Ca(2+)-ATPase activity may be an important reason for acinar cell Ca2+ overload in the development of acute pancreatitis. PMID- 11601025 TI - [Advances in the study of Alzheimer's disease associated genes]. PMID- 11601026 TI - [Research design and quality of clinical studies]. PMID- 11601027 TI - [To improve the quality of research of clinical medicine in China]. PMID- 11601028 TI - [Conference on research design of clinical medicine in China]. PMID- 11601029 TI - [Likelihood ratio and ROC curve in evaluation of iron parameters for diagnosing iron deficiency]. AB - OBJECTIVE: To evaluate the value of iron parameters in diagnosing iron deficiency (ID). METHODS: Cross-sectional study was performed for diagnostic tests. Ninety consecutive patients with anemia including iron deficiency anemia without chronic diseases (36 cases), chronic diseases (54) were divided into chronic diseases without ID(ACD) (23 cases) and chronic diseases with ID(CDID) (31) by bone marrow iron staining. The exclusion criteria included hemolytic anemia, deficiency of Vitamin B12 or folic acid, blood transfusion, taking iron preparations within one month and hematological malignancies. By using absence of bone marrow iron as gold standard of ID, we compared the diagnostic powers in the diagnosis of iron deficiency for sTfR, serum iron, total iron binding capacity, serum ferritin (SF), transferrin saturation and the presence of hypochromic red cells by analyzing the likelihood ratio, the area under ROC(AUCROC). RESULTS: AUCROC for sTfR in determining ID in groups IDA + CDID vs. ACD, IDA vs. ACD and CDID vs. ACD were 0.9 (95% CI: 0.82-0.98), 0.96(0.9-0.99) and 0.84 (0.72-0.96) respectively, AUCROC for SF in above groups 0.87 (95% CI: 0.77-0.87), 0.94(0.86-0.99) and 0.77(0.63-0.91) respectively. AUCROC for other iron parameters in determining iron deficiency in chronic diseases was lower than 70%. CONCLUSION: ROC and LR are useful tools for evaluating iron parameters in diagnosing iron deficiency. TfR is a best parameter in determining iron deficiency in chronic diseases than SF and other iron parameters. PMID- 11601030 TI - [Research of dendritic cells and their relation to the prevention and treatment of diseases]. PMID- 11601031 TI - [The endocytic routes of exogenous antigen in murine dendritic cells and macrophages]. AB - OBJECTIVE: To compare the endocytic routes of exogenous antigen in murine dendritic cells (DC) and macrophages. METHODS: Murine bone marrow-derived DC and peritoneal macrophages were pulsed with HRP-5 nm colloidal gold for 10 minutes and chased for 0-120 minutes in culture medium. Intracellular distribution of 5 nm colloidal gold was explored by means of cellular enzymatic-chemistry of acidic phosphatase and MHC II cellular immunochemistry under electron microscope. RESULTS: After 10 minutes pulse with HRP-5 nm colloidal gold and then 30 minutes of chase, most of HRP-5 nm colloidal gold internalized by DC entered into MHC II positive MIICs, but a little entered into acidic phosphatase-positive lysosomes. In contrast to DC, most of lysosomes of macrophages were accessed by HRP-5 nm colloidal gold, and a small portion of HRP-5 nm colloidal gold entered into MIICs. After 60 minutes of chase, 5 nm colloidal gold could hardly be seen within macrophages, whereas most of 5 nm colloidal gold retained in DC. CONCLUSION: The endocytic route of exogenous antigen in DC apparently differs from that in macrophages. Most of antigens taken by macrophages enter into lysosomes within 30 minutes. In the case of DC, most of internalized antigens enter into MIICs, which may be related to their unique antigen-presenting function. In addition, macrophages seem to have more powerful capacity of scavenging exogenous antigen than DC. PMID- 11601032 TI - [Enhanced antitumor effects induced by lymphotactin gene-modified dendritic cells after pulsed with tumor antigen peptide]. AB - OBJECTIVE: To evaluate the potent effects of lymphotactin on tumor immunogene therapy and to improve the therapeutic efficacy of dendritic cells (DCs)-based vaccine, the protective and therapeutic effects of tumor antigen peptide-pulsed lymphotactin gene-modified dendritic cells were investigated. METHODS: In the tumor model of 3LL Lewis lung carcinoma, mouse bone marrow DCs transduced with mouse lymphotactin gene by adenovirus vector (Ltn-DC) were pulsed with MHC-I restricted, 3LL cell-specific tumor peptide Mut 1 (FEQNTAQP), and used to vaccinate syngeneic mice or to treat the preestablished tumor-bearing mice with spontaneous pulmonary metastases. RESULTS: Immunization with Mut 1 peptide-pulsed Ltn-DC induced specific CTL against 3LL cells and induced protective antitumor immunity, which rendered the immunized mice resistant completely to 3LL tumor challenge. In vivo depletion of immune cell subsets with mAbs demonstrated that the protective immunity induced by Mut1 peptide-pulsed Ltn-DC in the induction phase was dependent on both CD4+ T cells and CD8+ T cells rather than NK cells, and in the effector phase on CD8+ T cells rather than CD4+ T cells or NK cells. CD28/CTLA4 pathway of T cell costimulation and IFN-gamma were also necessary for induction of antitumor immunity by Ltn-DC pulsed with Mut1 peptide. Treatment with Mut1 peptide-pulsed Ltn-DC significantly inhibited the 3LL spontaneous pulmonary metastases of the preestablished tumor-bearing mice and exhibited obvious therapeutic effects. CONCLUSIONS: Our data suggest that Ltn gene modified DCs are more potent in the induction of protective and therapeutic antitumor immunity through the preferential chemotaxis of DCs on T cells. Vaccination with tumor antigen-pulsed Ltn-DC may be a novel approach to immunotherapy of cancer. PMID- 11601033 TI - [In vivo migration and survival of donor-derived dendritic cell progenitors genetically modified using an adenoviral vector encoding cDNA for TGF beta 1]. AB - OBJECTIVE: To investigate the migration and survival of B10 mouse bone marrow (BM)-derived DCs in C3H mice and if genetic modification of these DCs to overexpress TGF beta 1 may potentiate their tolerogenicity. METHOD: B10 mouse BM derived DCs were propagated in GM-CSF and TGF beta(DC1), transduced DC1 with replication-deficient Ad vectors encoding genes for LacZ (DC2) or TGF beta 1(DC3). Cells of different groups were injected into one footpad of C3H mice. The mice were sacrificed on days 1, 2, 7, and 14, and spleens, thymuses, popliteal and mesenteric lymph nodes removed and stained with anti-IAb mAb. The incidences of B10 DC were determined by the mean number of IAb positive cells with dendriform morphology per low power field (x 100). RESULTS: Transduction with Ad LacZ or Ad-TGF beta 1 did not affect DC migration or distribution in C3H recipients, i.e. IAb+ cells were first observed under the capsule of popliteal LN (peak at d1), then migrated into the marginal T dependent area of spleens (peak at d7), and were found occasionally in the thymus. Transduction of Ad-LacZ reduced the numbers of IAb+ cells identified in both LN and spleens at all time points post injection, compared with injection of unmodified control DC, suggesting that Ad transduction itself can affect DC life span in allogeneic recipients. Overexpression of TGF beta 1 by transduction of Ad-TGF beta 1 not only fully reversed the reduction of DC numbers induced by Ad transduction, but also prolonged the life span of DC in spleen, as shown by the 2-fold increase in number of IAb+ cells in spleen at d14 compared with control DCs. CONCLUSION: Mouse BM-derived TGF beta DCs can be transduced to express TGF beta 1 using an adenoviral vector, and exhibit the same migration characteristics as unmodified DC. The survival of TGF beta gene transduced DCs appears to be enhanced compared with unmodified or LacZ gene-transduced DCs. PMID- 11601034 TI - [Transforming growth factor-beta 1 inhibits the generation of dendritic cells from murine hematopoietic progenitor cells in vitro]. AB - OBJECTIVE: To investigate the regulatory effect of transforming growth factor beta 1 (TGF-beta 1) on the generation of dendritic cells (DCs) from hematopoietic progenitor cells (HPCs) and its cellular and molecular mechanisms. METHODS: Murine bone marrow derived-Lin c-kit+ HPCs were isolated by a cell sorter and cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM CSF), stem cell factor (SCF), tumor necrosis factor alpha(TNF alpha) and TGF-beta 1. The generation of DC precursors and mature DCs and their phenotypes were analyzed by a cell sorter, reverse transcription-polymerase chain reaction (RT PCR), and allogenic mixed lymphocyte reaction (MLR). RESULTS: TGF-beta 1 could significantly inhibit the generation of DC precursors at day 6 and mature DCs at day 12 from murine Lin- c-kit+ HPCs stimulated with GM-CSF + SCF + TNF alpha or GM-CSF + SCF. Moreover, TGF-beta 1 markedly suppressed the expression of antigen peresenting molecule Ia and co-stimulatory molecule CD86 on the surface of cultured Lin- c-kit+ HPCs. Examination of RT-PCR showed that TGF-beta 1 could also inhibit the expression of MHC class II trans-activator (CTIIA) mRNA, which encodes a transcriptional factor to strictly control the expression of MHC class II antigens in the cultured cells. CONCLUSION: Our results suggest that TGF-beta 1 is an inhibitory cytokine for the generation of DC precursors and maturation of DC from HPCs, which may account for the cellular mechanisms of TGF-beta 1 mediated immuno-suppressive functions in vivo and in vitro. PMID- 11601035 TI - [A single strand comformation polymorphism of vacuolating cytotoxin gene in H. pylori]. AB - OBJECTIVE: To use PCR/SSCP analysis of the vacuolating cytotoxin gene (vacA) of H. pylori for differentiation of various strains of H. pylori. METHODS: PCR was performed using the primers amplifing vacA gene of the bacteria embeded in the gastric mucosa of 159 patients with various gastric duodenal diseases. The products of PCR were further processed for SSCP analysis and southern blot hybridization. In the meantime, vacA genes of three different SSCP-patterns from three patients with duodenal ulcers were sequenced. RESULTS: The rate of detection of H. pylori with the method was 100%. vacA1 and vacA2, the two subtypes of vacA, were 76.5% (114/149) and 23.5%(35/149), respectively. Eight different SSCP-patterns were distributed in various gastroduodenal diseases, and that 80% of duodenal ulcers was predominated with B pattern. Sequencing of DNA indicated a diversity of vacA gene structure. CONCLUSION: PCR/SSCP can be used in the differentiation of different strains of H. pylori in epidemology, and in the follow up study after H. pylori eradication, especially in the differentiation between H. pylori recrudescence and reinfection. PMID- 11601036 TI - [Correlation between apoptosis and proliferation in gastric pre-carcinoam]. AB - OBJECTIVE: To clarify the correlation between apoptosis/proliferation and the expressions of oncogene bcl-2 and P53 in the changes from superficial gastritis, intestinal metaplasia, dysplasia, gastric cancer in early stage to advanced gastric cancer. METHODS: TUNEL method was used to detected apoptosis. Immunohistochemical analysis was used to detect the expressions of proliferating cellular nuclear antigen(PCNA), bcl-2 protein and P53 protein. Results In the patients of superficial gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, early gastric cancer and advanced gastric cancer and advanced gastric cancer, apoptotic indexes were: (6.4 +/- 1.9)%, (14.1 +/- 4.1)%, (23.3 +/- 6.1)%, (17.4 +/- 2.6)%, (11.3 +/- 3.7)%, (6.3 +/- 2.0)% respectively. PCNA indexes were: (11.3 +/- 2.2)%, (18.9 +/- 6.5)%, (20.3 +/- 7.3)%, (40.0 +/- 10.6)%, (53.1 +/- 10.9)% and (72.4 +/- 18.4)% respectively; the expression rates of bcl-2 were 10.0%, 23.3%, 40.0%, 56.7%, 85.7% and 46.7%. The expression rates of P53 were: 0%, 0%, 0%, 4.3%, 14.3% and 53.3%. The difference in the majority of observed indexes were significant (P < 0.05-0.01). CONCLUSION: During the changes of gastric cancer, the apoptotic and proliferating indexes incerased simultaneously in superficial gastritis, atrophic gastritis and intestinal metaplasia. However, PCNA indexes further increased but apoptotic indexes decreased in dysplasia, early gastric cancer and advanced gastric cancer and advanced gastric cancer. The former may be the phenomenon in early gastric cancer and advanced gastric cancer and advanced gastic cancer. The former may be the phenomenon in ear early gastric cancer the latter may be the phenomenon in advanced gastric cancer. PMID- 11601038 TI - [Reduction of mitochondrial transmembrane potential constitutes an early event of peripheral blood monocytes apoptosis in hemodialysis patients]. AB - OBJECTIVE: To investigate the relationship between monocyte apoptosis and mitochondria function in hemodialysis (HD) patients. METHODS: Fluorescein labeled Annexin-V was used to detect the phosphatidyserine (PS) of apoptosis cells, and mitochondrial transmembrane potential was studied by 3,3'-dihexyloxacarbocyanine iodide, Di0C6(3), and analyzed by flow cytometry. Swelling of mitochondrial permeability transition (PT) was recorded by spectrophotometer. RESULTS: Spontaneous apoptosis of cultured monocytes increased at 24, 72 hours in HD patients (41.4 +/- 12.2)%, (22.0 +/- 3.0)% as compared with controls (20.6 +/- 8.8)%, (9.8 +/- 2.1)%. Freshly isolated monocytes in HD patients had little apoptosis, but mitochondrial transmembrane potential was reduced to half of disruption (43 +/- 9)%. As to swelling of PT, those freshly isolated monocytes mitochondria in HD patients experienced overwhelming opening of PT, (80 +/- 5.6)%. CONCLUSION: Swelling of PT and breakdown of mitochondrial transmembrane potential constitute the early events of monocytes apoptosis in HD patients, which could contribute to the impaired monocytes function. PMID- 11601037 TI - [Fentanyl reduces the MAC of sevoflurane]. AB - OBJECTIVE: To determine the interaction between fentanyl and sevoflurane following a bolus injection of fentanyl after induction iwth sevoflurane inhalation only. METHODS: Sixty children aged 5-10 years who were diagnosed as having VSD or ASD were randomly allocated into three groups. The first group received sevoflurane in oxygen without any other drugs. The second group received sevoflurane in oxygen with fentanyl 3 ng/kg, and the third group received sevoflurane in oxygen with fentanyl 6 ng/kg. MAC determination, in response to the stimulus of skin incision, was made using the "up-down" method. RESULTS: The MAC of sevoflurane in oxygen was (2.72 +/- 0.08)%. Fentanyl 3 ng/kg bolus injection produced a fentanyl plasma concentration of (0.64 +/- 0.13) microgram/L at skin incision and resulted in a MAC for sevoflurane of (1.03 +/- 0.07)%. Fentanyl 6 ng/kg bolus injection produced a fentanyl plasma concentration of (1.51 +/- 0.18) micrograms/L at skin incision and resulted in a MAC for sevoflurane of (0.64 +/- 0.01)%. By the stimulation of skin incision, the Hr, MAP of group I increased 39%, 29%, compared with group II 14%, 15%, group III 20%, 14%, respectively. These results were significantly different (P < 0.01). CONCLUSION: The MAC of sevoflurane is significantly reduced 20 minutes after a single dose of 3 ng/kg of fentanyl and that increasing the fentanyl dose to 6 ng/kg produces a little further decrease in MAC of sevoflurane. PMID- 11601039 TI - [Investigation of serum immunosuppresive acidic protein levels in gynecological tumor]. AB - OBJECTIVE: To study the clinical significance for measureing serum immunosuppresive acidic protein (IAP) levels to diagnoze and follow up survey patients with the gynecological tumor. METHODS: Serum IAP levels were determined by IAP-single radial immunodiffusion test in 235 patients with gynecological tumor, 38 patients had benign ovary tumor, 41 were malignant ovary tumor, 66 hysteromyoma, 34 cervical carcinoma, 16 endometrial carcinoma, 27 received chemotherapy, and 13 had tumor recurrence. The control group consisted of 50 health women. RESULTS: The serum IAP level was (889 +/- 208) mg/L in malignant ovary tumor, and higher than that of the health women and benign ovary tumor, (P < 0.01). In patients with cervical carcinoma and endometrial carcinoma, the IAP level was (741 +/- 213) and (763 +/- 209) mg/L respectively, and higher than that of the health women and benign ovary tumor (P < 0.01). After chemotherapy, the serum IAP level of malignant ovary tumor was decreased. In patients with recurrence of ovary tumor, the IAP levels was increased to compare with the health women (P < 0.01), the incidence of the abnormal value was 100%. CONCLUSION: Detecting IAP level of the gynecological tumor may be an auxiliary index for monitoring gynecological tumor and identifying whether it is benign or malignant. PMID- 11601040 TI - [Multivariate analysis of clinical factors in restenosis after coronary interventional treatment]. AB - OBJECTIVE: To found the independent predictors for restenosis after coronary interventional treatment. METHODS: Quantitative angiography was performed in 103 patients(128 successfully dilated lesions) at angioplasty and at 6-month follow up, and then univariate analysis and multivariate logistic regression analysis were performed to identify correlates of restenosis with clinical factors. RESULTS: The total restenosis rate was 39.8% (51 of 128 lesions). According to univariate analysis, the patients who had undergone coronary tenting > or = 3.5 mm had a lower rate of restenosis(3/29 and 6/30) and the others with the ACC/AHA lesion type B and C(46/51 and 51/77), collateral circulation to the obstruction set(17/51 and 2/77), high percentage diameter stenosis before PTCA(86 +/- 14)% and (79 +/- 15)%, and high maximal inflation pressure(8.3 +/- 2.1) kPa and (7.4 +/- 1.7) kPa had a higher rate of restenosis (P < 0.01). Stable angina showed a low restenosis rate (3/29 and 6/30). The less minimal lumen diameter before(0.43 +/- 0.41) mm and (0.66 +/- 0.43) mm and after PTCA(2.56 +/- 0.55) mm and (2.85 +/ 0.59) mm, had the higher the restenosis rate (P < 0.05). Multivariate logistic regression analysis showed that coronary stenting had a low rate of restenosis, and that lesion type B and C, high percentage diameter stenosis before PTCA, high maximal inflation pressure, and male had a high rate of restenosis. CONCLUSION: Coronary stent, percentage diameter stenosis before PTCA, lesion type, maximal inflation pressure, and sex were independent predictors for restenosis. PMID- 11601041 TI - [Pathogenicity in mice infected with three different strains H. pylori]. AB - OBJECTIVE: To observe the differences of colonization and histopathology between CagA+ strains and lacking CagA by three different strains infecting C57BL/C mice. METHODS: CYP3401 wild type strain (CagA+), CYP3401(the isogenic CagA) knockout mutant CagA-, Sydney strain (CagA+) were used. The mice were administered orally with 0.5 ml, 10(9) CFU/ml of the above bacterial suspensions, respectively. Serum IgG antibodies were measured by ELISA. All the mice were sacrificed at 8 weeks after inoculation and their stomaches were removed for histopathologic study. RESULTS: The colonization of the bacteria was evident in Sydney strain and mild type strain, but characterized by wild to moderate infiltration by nutrophils and momocytes histologically. Only a small number of organisms were observed in the CagA- strains group. The levels of serum IgG antibodies were the highest in Sydney and wild strains group as compared with the control group (P < 0.01). There was no significant difference between the CagA-group and the control group. CONCLUSION: A strong correlation was observed between CagA+, bacterial colonization, gastric mucosa inflammation, and serum IgG antibodies. The study of C57BL/C mice helps understand the pathogenicity with CagA+ strains in human body and study H. pylori infection and associated diseases. PMID- 11601042 TI - [Human breast myoepithelial cell blocks estrogen receptor-negative breast carcinoma cell invasion]. AB - OBJECTIVE: To investigate the effect of mammary myoepithelial cell on breast cancer cell infiltration. METHODS: By immunohistochemistry, Western Blot, Northern Blot and Matrigel invasion experiments, we detected the maspin in breast cancer cell and myoepithelial cell, and studied the machanism of breast cancer cell invasion inhibition by myoepithelial cell. RESULTS: Histologically, ducts and ductal carcinoma in situ (DCIS) were surrounded by an intact circumferential layer of myoepithelial cells. In invasive carcinoma, the myoepithelial cell layer appeared disrupted. In matrigel invasion experiments, myoepithel cell and its condition medium could block the ER-negative breast carcinoma cell line MDA-MB 231 cell invasion. The proteinase inhibitor most dramatically up-regulated in myoepithelial cells was the tumor suppressor maspin which was only highly expressed in myoepithelial cells, not in breast cancer cells. CONCLUSION: Mammary myoepithelial cells could inhibit tumor cell invasion, suggesting that myoepithelial cell might have antitumor effect in the regulation of breast cancer development and progression in vivo. PMID- 11601043 TI - [Role of neuronal nitric oxide synthase in dynorphin spinal neurotoxicity and analgesia in rats]. AB - OBJECTIVE: To investigate the different role of neuronal constitutive nitric oxide synthase (nc-NOS) in dynorphin (Dyn) A(1-17) spinal neurotoxicity and analgesia. METHODS: The cNOS activity in ventral and dorsal spinal cord in rats was measured with H-L-arginine conversion, and ncNOS immunoreactivity(IR) was observed with strepavidin-peroxidase immunohisto-chemistry. RESULTS: Intrathecal administration of Dyn A(1-17) produced dose-dependent paralysis of hindlimbs and tail as well as inhibition of tail flick (TF) and foot flinch (FF) reflexes. Dyn A(1-17) 10 nmol induced only transient paralysis and apparently reduced the ncNOS IR in the superficial dorsal horn but did not induce any change of ncNOS-IR in the ventral horn cells as compared with saline control. Dyn A(1-17) 20 nmol produced permanent paraplegia with irreversible spinal cord damage, characterized by central and progressive necrosis. Dyn A(1-17) 20 nmol remarkedly induced the expression of ncNOS-IR in the ventral horn cells whereas inhibited ncNOS-IR in the superficial dorsal horn. Dyn A(1-17) 20 nmol also significantly increased the activities of cNOS in the ventral spinal cord but did not affect cNOS activities in the dorsal spinal cord. Intrathecal pretreatment with 7-nitroindazole (7-NI) 1 mumol, a selective ncNOS inhibitor 10 min prior to i.t. Dyn A(1-17) 20 nmol significantly ameliorated Dyn-induced neurological outcome, but TF and FF remained inhibited. 7-nitroindazole also significantly antagonized the increases of cNOS activities and ncNOS-IR in the ventral spinal cord at 4 h after i.t. Dyn A(1-17) 20 nmol, but did not affect or even potentiated Dyn-induced inhibition of cNOS activity and ncNOS-IR in the dorsal spinal cord. CONCLUSIONS: Over expression or over-activation of ncNOS in the ventral spinal cord may be involved in Dyn spinal neurotoxicity, whereas as the reduction of ncNOS activities in the dorsal spinal cord might reflect Dyn spinal analgeisia or pain modulation. PMID- 11601044 TI - [High-level expression of 6B11 ovarian carcinoma anti-idiotypic antibody scFv genes in E. Coli]. AB - OBJECTIVE: To express high-level 6B11 ovarian carcinoma anti-idiotypic antibody single chain Fv (scFv) genes in E. Coli. METHODS: Using PCR cloning technique, We cloned 6B11scFv genes into bacterial expression vector pKPL-3a. Recombinant plasmid vector pL-6B11scFv was transformed into E. Coli pop2136 with temperature control to produce proteins. Renaturated proteins were purified on DEAE-Sepharose Fast Flow ion exchange column with salt gradient elution. Immunoactivity was determined with ELISA and inhibition ELISA tests respectively. RESULTS: 6B11scFv genes were expressed as inclusion bodies in the cytoplasm. The purity of 6B11scFv turned out by SDS-PAGE was more than 95%. The expressed proteins after purification specifically reacted with anti-ovarian carcinoma monoclonal antibody COC166-9 and efficiently inhibited the reaction between primary ovarian carcinoma antigen OC166-9 and COC166-9. CONCLUSION: We successfully expressed high-level 6B11scFv genes in E. Coli. Expressed proteins showed pretty good immunoactivity. PMID- 11601045 TI - [In vitro reversal effect of cyclosporin A in combination with cytokines on multidrug resistant cell line K562/A02]. AB - OBJECTIVE: To explore the reversal effect of cyclosporin A(CsA) in combination with cytokines on multidrug resistant cell line K562/A02. METHOD: The cytotoxicities of daunorubicin(DNR) were assayed by MTT method. Intracellular rhodamine(Rh123) concentration was measured by flow cytometry. P-glycoprotein(p gp) expression was analyzed for staining with monoclonal JSB-1. Mdr1 mRNA expression was detected by RT-PCR. RESULTS: The cytotoxicities of DNR to K562/A02 were enhanced by 1 mumol/L CsA, 500 U/ml IFN-alpha and 200 U/ml, IL-2 respectively, and their IC50 was (3.78 +/- 0.03), (13.77 +/- 0.38) mu/ml, (18.5 +/- 0.60) micrograms/ml. Their reversal effect was 6.70, 1.84 and 1.37 times than that of K562/A02. But IC50 of combined CsA and IFN-alpha was (1.71 +/- 0.19) micrograms/ml; its reverse effect increased in 14.8 times. The combination could increase intracellular Rh123 accumulation significantly as compared with either of them alone, but p-gp and mdr1 mRNA expression were not decreased obviously. CsA in combination with IL-2 didn't show a synergistic effect. CONCLUSION: Mdr could be partially reversed by cytokines or low doses CsA(1 mumol/L), but the combination of CsA and IFN-alpha showed a greater synergistic reversal interaction. PMID- 11601046 TI - [Use of the Internet in medicine and pharmacy]. PMID- 11601047 TI - [Post-bone-marrow transplantation infection in China]. PMID- 11601048 TI - [The 3rd State Conference on immunodeficiency and infection in China]. PMID- 11601049 TI - [Condition and mechanism of host antiinfect capacity induced by bypass-activated complement: experimental study]. AB - OBJECTIVE: To verify host antiinfect capacity induced by bypass-activated complement. METHODS: A monolayer culture of human PMNs and rats kupffer cells (KCs) were added with zymosan-activated human serum (ZAHS) and 3 parameters were measured. ZAHS had been neutralized in tube with antiserum against human C3 and C5. RESULTS: In 0.07-0.09 ml ZAHS and 1-3 h, intracellular bactericidal activity (ICBA) showed a peak but significant top value at 2nd hour. The value dropped markedly with time and significantly in 4-6 h. Superoxide ions (O2-) dynamics was similar to ICBA. Acid phosphatase (ACP) curve distinguished from the former's with monotonous decrease (1-6 h) and more deep. With 0.11 ml ZAHS after 4 h, about 80% of KCs were fallen off. Three parameters of PMNs were decreased and reached the lowest point in the 6th hour after the adding 0.05-0.09 ml of ZAHS. After blocking test with antihuman C3 and C5 serum, the values of ICBA, O2- and ACP surpassed those in the experimental group. CONCLUSION: The possible mechanism of the origination of the harmful effects of ZAHS is suggested. Before KCs and PMNs undertake phagocytosis, they release the bactericidal and inflamagenic (O2- and ACP) so the intracellular bactericidal activity of KCs and PMNs are decreased. The accumulation of KCs and PMNs in tissues can damage themselves and the adjacent tissues barrier, which will lead to the occurrence of infection. PMID- 11601050 TI - [Antimicrobial resistance in Streptococcus pneumoniae in Beijing and molecular typing of penicillin-resistant strains]. AB - OBJECTIVE: To investigate antimicrobial resistance of Streptococcus pneumoniae in Beijing and molecular epidemiology of penicillin-resistant pneumococci strains. METHODS: The resistance to beta-lactam and non-beta-lactam antibiotics of 244 nasopharyngeal isolates of Streptococcus pneumoniae collected from September to November 1997 in 8 day-care centers in Beijing was studied by Etest and agar dilution method. Serotyping was done by "capsular swelling" technique. BOX-PCR technique was used to detect the DNA of resistant strains. RESULTS: 24.8% (244/985) of the children carried Streptococcus pneumoniae. The agreement between the MICs obtained by Etest and agar dilution for penicillin and ceftriaxone was > 93.7%. By Etest, 3/244 (1.3%) strains were resistant to penicillin(MICs, 3 micrograms/ml) and 32/244(13.1%) strains in termedinte (MICs, 0.094-0.25 microgram/ml). Penicillin-susceptible strains were also susceptible to the other 4 tested beta-lactams. In penicillin non-susceptible strains, 11.4% (4/35) isolates were resistant to the other beta-lactams. The resistant rates of erythromycin, tetracycline, chloramphenicol and trimethoprim-sulfamethoxazole (TMP-SMZ) were 74.0%, 87.6%, 47.8%, 63.3%, respectively. All of the strains were susceptible to vancomycin and rifampin. 119/244(48.7%) strains isolated were multiresistant to tetracycline, erythromycin and TMP/SMZ. Serotype 6A(33.6%), 19F(16.8%), 23F(15.1%), 15(11.2%), 6B(4.3%) were most common. 57.1% (20/35) penicillin non-susceptible strains were of serotype 23F and had similar or identical multiresistance and BOX patterns. CONCLUSION: In Beijing, the prevalence of penicillin-resistant pneumococci was obviously lower than that of neighboring countries, but resistant rate to non-beta-lactams was high. The epidemic multiresistant 23F clone found in day-care centers was different from the Spanish clone. PMID- 11601051 TI - [Immune activation genes expression in CD28-costimulated lymphocytes and its application as a diagnostic tool in kidney transplantation]. AB - OBJECTIVE: To investigate the detection of immune activation genes expression as an indicator for the diagnosis of immunological rejection in renal transplantation. METHODS: In 61 renal allograft recipients, the immune activation genes expression of CD28-costimulated peripheral blood mononuclear cells (PBMC) was studied by RT-PCR. RESULTS: The mRNA expression positive rate of IL-10, CD40L, Fas, Perforin, IL-2, IFN-gamma, FasL, bcl-xL, Granzyme B (GB), TGF-beta 1 and IL-4 was 91.8%, 70.5%, 88.5%, 96.7%, 41%, 54.1%, 60.7%, 67.2%, 67.2%, 54.1% and 32.8% respectively. IL-2, IFN-gamma, FasL and Granzyme B were screened out as indicators for the diagnosis of allograft rejection. Any three or more of IL-2, IFN-gamma, FasL, and Granzyme B genes expression could be used as a diagnostic tool for rejection with much favorable sensitivity (93%) and specificity (75%). CONCLUSION: The detection of IL-2, IFN-gamma, FasL and Granzyme B genes expression is beneficial for the evaluation of immunological state in renal allograft recipients. This non-invasive method can be used for clinical diagnosis of allograft rejection. PMID- 11601052 TI - [The relationship between ophthalmic nerve lesion in glaucoma and ocular and systemic haemodynamic disturbance]. AB - OBJECTIVE: To explore the relationship between the optic nerve lesion in glaucoma and ocular and systemic haemodynamic disturbance. METHODS: The color Doppler imaging was used to study blood velocity in the ophthalmic, the central retinal and the short posterior ciliary arteries in 34 patients with primary open angle glaucoma, 31 patients with low tension glaucoma and 90 healthy controls. The peak systolic velocity(PSV), the end diastolic velocity (EDV) and resistive index (RI) in each artery were measured, moreover the nailfold microcirculation and blood viscosity in each patient were examined. RESULTS: Compared with the control group, the PSV and EDV of the central retinal arteries were significantly lower while the RI of the central retinal arteries was significantly higher in both POAG and LTG patients. The RI of the short posterior ciliary arteries however was significantly higher in POAG. Nailfold microcirculation shows that some important parameters, including flow pattern, loop surrounding, morphological weighted value, total weighted value and capillary deformity rate in the two glaucoma groups were higher, whereas the flow velocity was lower than in the control group. The plasm viscosity and the whole blood viscosity (low spear) were higher than normal. According to our measurements, the nailfold microcirculation and blood viscosity was worse at the end stage of glaucoma than at early stage. The correlative analysis between measurement results of color doppler imaging and microcirculation and heamorrheology showed that nailfold microcirculation morphological weighted value was negatively correlated with the EDV of the central retinal artery and positively correlated with the RI of the central retinal artery in LTG patients. CONCLUSIONS: The abnormity of ocular haemodynamics and systemic microcirculation and blood viscosity is one important factor of optic nerve damage in glaucoma. PMID- 11601053 TI - [Gene expression of beta-adrenoceptor signal transmitters in heart failure]. AB - OBJECTIVE: To investigate the alteration in steady-state levels of messenger RNA(mRNA) of beta-adrenoceptor signal transmitters in heart failure. METHODS: The reverse transcription polymerase chain reaction (RT-PCR) was used to assess gene expression in small quantity of circulatory lymphocytes. With selected oligonucleotide primers, we used quantitative RT-PCR to amplify mRNAs encoding beta 2-adrenergic receptor(beta 2-AR), adenylate cyclase (AC), beta 2-adrenergic receptor kinase(beta-ARK), and beta-arrestin and cAMP response element binding protein (CREB) in 16 healthy subjects and 30 heart-failing patients. RESULTS: The alteration of gene expression in heart failure appeared to be selective, the steady-state levels of mRNA increased significantly involving AC and the transcription factor, CREB; decreased significantly involving membrane receptor, beta 2-AR; unchanged significantly involving phosphorylating factors of beta-AR uncoupling, beta-ARK and beta-arrestin. CONCLUSION: The aberrant gene expression of beta-adrenergic receptor might play an important role in the pathogenesis of heart failure. PMID- 11601054 TI - [The association between signal-regulatory protein alpha and hepatocellular carcinoma]. AB - OBJECTIVE: To study the roles of signal-regulatory protein alpha (SIRP alpha) in the development of hepatocellular carcinoma (HCC). METHODS: 42 pairs of HCC and the surrounding noncancerous hepatic tissues were used. The expression of SIRP alpha in various tissues was determined by Northern blot analysis and immunohistochemistry assay, by which together with the pathologic characteristics of each sample, the role of SIRP alpha was investigated. RESULTS: The expression of SIRP alpha significantly decreased in 21 cases of samples (50.0%) to the 3.9 kb transcript and 27 cases of samples (64.3%) to the 2.5 kb transcript respectively. The SIRP alpha decreasing rate in large HCC(> 5 cm in diameter) was higher than in small HCC (< or = 5 cm in diameter), and in HCC with cancer embolus was higher than that of without cancer embolus. No association was found between the SIRP alpha expression and the patient's age, tumor grade, tumor capsule, serum AFP level, and HBV infection. Immunohistochemistry showed that all the normal hepatocytes, cholangioepithelial cells, Ito cells, regenerated hepatocytes, new generated cholangioepithelial cells and part of HCC cells were positive. The HCC tissues in which SIRP alpha was down-regulated showed positive particles becoming weaker and less, and some tumor cells and area were completely negative. CONCLUSION: The expression of SIRP alpha especially 2.5 kb transcript is down-regulated in HCC, which is closely related with the tumor growth and invasiveness. SIRP alpha may be an important negative regulator of HCC. PMID- 11601056 TI - [The effect of bactericidal/permeability-increasing protein on lipopolysaccharide binding protein and lipopolysaccharide receptor CD14 mRNA expression in rats after thermal injury]. AB - OBJECTIVE: To elucidate the possible mechanisms underlying beneficial effect of recombinant bactericidal/permeability-increasing protein (rBPI) on multiple organ damage secondary to major burns. METHODS: Wistar rats were subjected to a 35% full-thickness scald injury, and randomly divided into 3 groups: normal controls (n = 8), thermal injury (n = 21), and rBPI21 treatment (n = 12). In thermal injury and rBPI21 treatment groups, animals were sacrificed at 12 and 24 hours after burn, respectively. Tissue samples from liver, kidneys, lungs and intestine were collected to measure lipopolysaccharide-binding protein (LBP)/lipopolysaccharide receptor CD14 and tumor necrosis factor-alpha (TNF alpha) mRNA expression. In addition, blood samples were obtained for measurement of organ function parameters. RESULTS: Treatment with rBPI21 could significantly decrease tissue LBP and CD14 mRNA expression in various organs (P < 0.05-0.01). Also, TNF-alpha mRNA expression in liver, kidneys and lungs were markedly inhibited by rBPI21 secondary to acute insults (P < 0.05-0.01). Moreover, in the rBPI21 treatment group, significant reduction in serum GPT levels and elevation in intestinal DAO activities were found compared to those in the thermal injury group (P < 0.05-0.01). CONCLUSIONS: Treatment with rBPI21 is effective in attenuating multiple organ damage resulted from gut origin endotoxin translocation after thermal injury, which might be associated with down regulation effect of tissue LBP and CD14 gene expression by use of rBPI21. PMID- 11601055 TI - [The sarcoplasmic reticulum Ca2+ handling protein and left ventricular hypertrophy in SHR]. AB - OBJECTIVE: To elucidate the role of myocardial angiotensin II and sarcoplasmic reticulum (SR) Ca2+ handling protein (ryanodine receptor and Ca2+ ATPase) in the process of left ventricular hypertrophy. METHODS: The myocardial angiotensin II level, Bmax and Kd value of ryanodine receptor and calcium ATPase activity in SR were determined among 3 groups: spontaneously hypertensive rats (SHR), SHR treated with perindopril and WKY. RESULTS: The blood pressure (BP) of the SHR group, the ratio of left ventricular weight to body weight (LVW/BW) and the myocardial angiotensin II level were higher than those of the WKY group (P < 0.01), Perindopril decreased the BP(P < 0.01) and the myocardial angiotensin II level, and reversed the LVW/BW of the SHR group (P < 0.05). Compared to the WKY group, the Bmax value of cardiac ryanodine receptor in the SHR group was increased (232 +/- 27) fmol.mg-1 vs (173 +/- 18) fmol.mg-1, (P < 0.01), but there was no difference in Kd value (P > 0.05). The SR calcium ATPase activity was also decreased in the SHR group [(0.52 +/- 0.11) mumol.g-1.min-1 vs (1.03 +/- 0.22) mumol.g-1.min-1, P < 0.01]. In the SHR perindopril treatment group, the Bmax of ryanodine receptor was decreased [(191 +/- 23) fmol.mg-1, P < 0.05]. There was no difference in Kd value. The calcium ATPase activity was increased [(0.82 +/- 0.28) mumol.g-1.min-1, P < 0.05)]. CONCLUSION: The left ventricular hypertrophy is closely related to the myocardial angiotensin II and the SR calcium handling protein. PMID- 11601057 TI - [The effects of 6A8 cDNA transfection on biological behavior of tumor cells]. AB - OBJECTIVE: To investigate the effects of antisense 6A8 cDNA on the malignant behavior of tumor. METHODS: Highly metastatic clonal variant CNE-2L2 from nasopharygeal carcinoma cell line(CNE-2Z) was transfected with antisense 6A8 cDNA or mock plasmid. Their adhesion, locomotion, proteolytic ability, in vitro invasion, in vivo growth and metastasis were comparatively studied with the wild CNE-2L2 cells. RESULTS: Antisense 6A8 cDNA transfected CNE-2L2 showed less adhesion to FN and LN, weakened locomotive ability and proteolytic ability, retarded in vivo growth and much less metastasis. CONCLUSION: Transfection of antisense 6A8 cDNA obviously decreased the malignant behavior of tumor cells. PMID- 11601059 TI - [Cisplatin-induced apoptosis in laryngeal squamous cell carcinoma strain and the influence on cell cycle]. AB - OBJECTIVE: To find more effective chemotherapeutic agents and treatment regimens, we studied the cytotoxicity of cisplatin to human laryngeal squamous cell carcinoma strain Hep2. METHODS: Using flow cytometry, fluorescence microscopy, and DNA agarose gel electrophoresis technique, we investigated in vitro Hep2 cells in different conditions. RESULTS: Hep2 was adherent cells in normal survival condition. Cisplatin affected Hep2 cell growth apparently. Under fluorescence microscope, necrotic cells were red, apoptotic cells were blue with condensed and fragmented nuclei, and normal cells were evenly blue. Adherent cells were 86%-96% viable. But nonadherent cells were 6%-13% viable. Death cells increased with the increase of drug concentration and time elapsing. Death cells were mainly apoptotic cells. The latter appeared to be time- and dose-dependent. DNA "ladder" was observed for nonadherent cells in agarose gel electrophoresis, but adherent cells were not. "Sub-G1" phase peak occurred in flow cytometry. After cisplatin treatment, the volume of adherent cells increased with dose- and time dependence. Cisplatin could cause Hep2 cell cycle to change. At first, G1 phase cell percentage reduced, while S phase increased. With time elapsing, G2/M phase increased. Cells experienced a slow-down in S-phase followed by a G2 block. CONCLUSION: Apoptosis is a major way of Hep2 cell death after cisplatin treatment and appeared to be time- and dose-dependent. In clinical chemotherapy, cisplatin should be used in high concentration. Inducing apoptosis is one of the characteristics of chemotherapeutic agents. Cisplatin should be taken a combination regimen with cell cycle-special agents. PMID- 11601058 TI - [Reversion of the malignant phenotype of gastric cancer by c-erbB-2 specific ribozyme]. AB - OBJECTIVE: To probe the effect of c-erbB-2 specific ribozyme to the malignant phenotype of gastric cancer. METHODS: The eucaryotic expression vector of c-erbB 2 specific ribozyme RZ1 was designed by computer and named pDOR-RZ1. The transfection of the gastric cancer cell line SGC-7901 was mediated by Lipofect AMINE. Flow cytometry was used to analyse the expression of the c-erbB-2 product P185. In vivo study of tumorogenecity of the transfected cells was performed in nude mice. RESULTS: pDOR-RZ1 was successfully transfected into the gastric cancer cell line SGC-7901 and then the single clones were selected by G418 and named SGC/RZ1. Flow cytometry analysis showed that the expression of P185 was suppressed by 62.7%. The growth rate of SGC/RZ1 was inhibited by 55%. The tumor forming time in SGC/RZ1 in nude mice was delayed remarkably and the tumor size was also much smaller than that in the control group, indicating the inhibition of the tumorogenecity of SGC/RZ1 in nude mice. CONCLUSION: c-erbB-2 specific ribozyme is very efficient in reversing the malignant phenotype of gastric cancer. This might provide a new approach for gene therapy of gastric cancer. PMID- 11601060 TI - [Defense mechanism of viral immunologic escape and its preventive measurements]. PMID- 11601061 TI - [Current status and prospects of the study on the repair of soft tissue injuries in China]. PMID- 11601062 TI - Price survey. IOL prices stable as uses grow. PMID- 11601063 TI - Grounded: logistics crunch averted in wake of tragedy. PMID- 11601064 TI - On Wisconsin: conversion nets big bucks. PMID- 11601065 TI - Antitrust. Law specifically exempts 'joint purchasing'. PMID- 11601066 TI - [Advanced glycosylation end products or glycotoxins: under-evaluated components of diet?]. PMID- 11601067 TI - [Jamot and the myth of Sisyphus]. PMID- 11601068 TI - [Epidemiology of uterine cancers]. AB - Uterine cancers comprise 2 distinct pathological entities: cancer of the cervix and cancer of the corpus. They differ both in descriptive and etiologic epidemiology. Cervical cancer is more frequent in the developing world, is decreasing in terms of incidence and even more mortality in many countries and has essentially a viral etiology, being linked to human papilloma viruses. Cancer of the uterine corpus is more frequent in the developed world, is rather stable in terms of incidence and mostly has a hormonal etiology. PMID- 11601069 TI - [Viruses and cervical cancers]. AB - Currently it is evident that human papillomaviruses are involved in the development of cervical cancer. The mechanisms of cancer initiation are in relation with certain types of papillomavirus. But the discrepancy between the high prevalence of papillomavirus infection and the low frequency of cancer in infected women, gives evidence of the importance of healing process in relation with the host's immune response and the activation of other carcinogenic factors. The understanding of the role of papillomavirus in cervical cancer, gives prospects to prophylactic and therapeutic strategies in relation with antiviral treatments or papillomavirus-specific vaccines. PMID- 11601070 TI - [Histology and cytology of cervical cancers]. AB - Squamous cell and glandular carcinomas are the two usual forms of cervical cancer. Precancerous and preinvasive lesions must be detected by cervical cancer screening by Pap smears. The Bethesda system is recommended in order to facilitate correlation between cytological and histological diagnosis and to perform the best management of these lesions. Carcinoma in situ and early invasive carcinoma are well known in this situation because of their easy observation. The growing awareness of the role of human papillomavirus with the peculiar cellular modification called koilocytosis, in the carcinogenesis of cervical cancer introduced new possibilities of molecular biology applications. PMID- 11601071 TI - [Screening and diagnosis of cervical cancer]. AB - The screening of cervical cancer is ideal. Performing its screening allows discovering early stage of invasive cancer but above all to diagnose numerous precursor lesions: their treatment carry out the prevention of invasive cancer. Without an organised screening in France, there is a spontaneous screening. Nevertheless the incidence of invasive cancer decreased twofold since twenty years. It remains unfortunately frequent. With a well organised mass screening its rate will probably decrease significantly. PMID- 11601073 TI - [Diagnosis of endometrial cancer]. AB - Endometrial cancer, a hormone-related disease with unopposal hyperestrogenemia as one of its major risk factor is usually diagnosed during post menopausal bleeding. Pathologic examination after endometrial biopsy or curettage is mandatory for the diagnosis before any treatment. The 2 first line procedures in the work up are transvaginal ultrasound with colour Doppler and hysteroscopy. Currently, there is not any cost-effective screening test for the early detection of endometrial cancer. PMID- 11601072 TI - [Evaluation and treatment of cervical cancer]. AB - Tumour stage, tumour size and nodal status are the most important prognostic factors in cervical cancer. Treatment of invasive cervical carcinoma consists of radio-surgical combination, exclusive radiation therapy or exclusive surgery in favourable cases. Radical hysterectomy with lymphadenectomy (pelvic +/- para aortic) is the reference technical surgery in stage IB and II cervical carcinoma. Conservative surgery can be discussed in young patients with stage IB1 disease. Radiotherapeutic treatment is based on a combination of external irradiation and brachytherapy, with concomitant chemotherapy when bad prognostic factors are present. This treatment represents the reference treatment in advanced stages. Total dose, overall treatment time are important prognostic factors of survival and local control. Pelvic exenteration with reconstructive surgery could be discussed in young patients with centro-pelvic recurrence of a cervical carcinoma. PMID- 11601074 TI - [Evaluation and treatment of endometrial cancer]. AB - Endometrial cancer is the most common gynaecologic cancer and its incidence increases with age. Prognosis is good because in over 80% of cases the cancer is discovered early. Preoperative work-up should include definition of the operability of such patients, who are often elderly with frequent co-morbidity. Preoperative evaluation and operative findings allow guiding the treatment and evaluating the prognosis. Main determinants are local extension, penetration into the myometrium, histologic stage of the tumour and involvement of lymph modes or peritoneum. Surgery is the first approach since it establishes the evaluation and comprises the first step of treatment. When necessary, subsequent treatment uses irradiation. Treatment with hormones or antimitotic drugs is less effective and is used for forms that are locally advanced, metastatic or recurrent after initial treatment. PMID- 11601075 TI - [Laparoscopy in the management of uterine cancers]. AB - There are two places for laparoscopic surgery in the management of uterine cancer. For the patients who have to be submitted to primary surgery the laparoscope enables us to select the ones who can be operated without laparotomy (no lymph nodes involvement after laparoscopic lymphadenectomy) and to make easier the "minimal access surgery" (laparoscopically assisted vaginal hysterectomy and radical hysterectomy). For the patients who have to be submitted to radiotherapy (and concomitant chemotherapy), the laparoscope enables us to select the ones for whom an extended field radiotherapy is useless (no aortic lymph nodes involved after laparoscopic lymphadenectomy) and to perform an ovarian transposition which protects the ovarian function of young patients. PMID- 11601076 TI - [Diuretics. Principles and rules of use]. PMID- 11601077 TI - [Small cell bronchial cancers: epidemiology, pathologic anatomy, etiology, diagnosis, course, treatment]. PMID- 11601078 TI - [Duchenne's muscular dystrophy: epidemiology, genetics, diagnosis]. PMID- 11601079 TI - [Fragile X syndrome: epidemiology, genetics, diagnosis]. PMID- 11601081 TI - [Perinatal mortality. Epidemiology]. PMID- 11601080 TI - [Prenatal protection. Regulations]. PMID- 11601082 TI - [Heparins, antivitamins K. Principles and rules of use. Posology of non fractionated heparins]. PMID- 11601084 TI - [Guidelines in heart failure. Too little adherence by the family practitioner?]. PMID- 11601083 TI - [Hip pain. Diagnostic orientation]. PMID- 11601085 TI - [Vertigo--fatigue--vision disorders. Is moldy living area to blame? (interview by Dr. Brigitte Moreano)]. PMID- 11601086 TI - [Voice disorders, dyspnea, aspiration. A laryngeal injury can be the cause]. AB - Injuries to the larynx may have extracorporeal (external), or endolaryngeal (internal), causes and are here classified on the basis of traumatic mechanisms. External trauma may be due to the action of blunt force or sharp objects--also including ruptures. Internal injuries may occur as a result of endotracheal intubation (also for anesthesia), long-term intubation and mechanical ventilation, ingestion of foreign bodies, surgical or nonsurgical interventions. In some cases, laryngeal injuries may be difficult to diagnose and evaluate. If the patient survives the primary traumatic event and his vital functions are preserved and stable, a careful laryngoscopic exploration--where indicated also such imaging procedure as high-resolution CT, direct microlaryngoscopy and laryngometry--should be applied to establish the diagnosis and decide on appropriate treatment. PMID- 11601087 TI - [Conservative therapy of hoarseness. What can be accomplished with voice therapy?]. PMID- 11601088 TI - [Organic changes of the vocal cords. Phonosurgery helps here]. AB - Surgical interventions aimed at preserving, improving or restoring vocal function define the term phonosurgery. Options include endolaryngeal microscopic techniques and extralaryngeal approaches for the treatment of vocal cord polyps, Reinke's edema, nodules and cysts, treatment of injuries to the larynx, and partial resection of malignant tumors. Further indications are deficits in vocal cord closure resulting from impaired laryngeal nerve function. Of particular importance in this connection are augmentation and medialization of the vocal cords. Additional possibilities are modification (higher/lower) of the pitch of the voice to improve the quality of life of transsexuals. Provided the indications are carefully established and concomitent voice training is offered, phonosurgical interventions may be a good means of ameliorating morphological and functional deficits of the larynx. Patient information on the possibilities of phonosurgery, careful selection of the appropriate surgical technique, adequate experience on the part of the surgeon, and good anesthesiological management, all impact on the outcome of this form of treatment. PMID- 11601089 TI - [Voice rehabilitation after laryngectomy. How your patient learns to speak again]. PMID- 11601090 TI - [Emergencies in general practice. Acute bronchial asthma]. PMID- 11601091 TI - [New European guidelines for heart failure. Proper treatment]. PMID- 11601092 TI - [Hypertension in the elderly. Do the same limit values apply?]. PMID- 11601093 TI - [Protracted jaundice, hemolytic anemia, acute renal failure. Hepatitis A almost has a fatal outcome]. PMID- 11601094 TI - [Without warning. Weight loss with dyspnea. Pleural mesothelioma]. PMID- 11601095 TI - [Recommended by patients. MOSES: patient education program for epilepsy patients]. PMID- 11601096 TI - [Controlled evaluation study of MOSES: effective and popular!]. PMID- 11601097 TI - [Antibiotic therapy. Avoiding resistance]. PMID- 11601099 TI - [Better blood glucose control. Extending metformin dosage]. PMID- 11601098 TI - [Double blockade should protect the stomach. New approach to rheumatism]. PMID- 11601100 TI - [Patients with heart failure need exercise. Is swimming allowed?]. PMID- 11601101 TI - [Drug therapy of heart failure. Take the chance!]. PMID- 11601102 TI - Clinical aspects of reptile behavior. AB - At first glance, the abstract world of reptile ethology may seem remote to clinicians dealing with the health and disease of captive animals. By delving a little deeper, however, veterinarians can learn to appreciate the reasons for certain behaviors and actually use these behaviors as indicators of various biologic states. Close scrutiny of subtle changes in behavior can further help assess reptile well-being and judge captive welfare. In the future, it is hoped that improved ethologic understanding will result in behavioral enrichment for reptiles, as is already promoted for many nondomestic mammals and birds. PMID- 11601103 TI - Behavioral aspects of captive birds of prey. AB - This article describes concepts of raptor behavior in captive birds of prey with inferences from the behavior of their wild counterparts that will assist the veterinarian in understanding the causes of managing abnormal behaviors. PMID- 11601104 TI - Psittacine restraint in the examination room. AB - This article suggests that there is a high probability of connections between emotional and physical health in animals. Many avian veterinarians are putting these ideas into practice. Recently, several veterinary schools have invited speakers to address their students about these ideas, suggesting a positive change in attitude (Irene Pepperburg, personal communication, 2000). There has been substantial progress in the avian veterinary community's attitude towards the psychological health of these exceptionally intelligent animals. In fact, over the last 5 years, there has been a substantial increase in avian medicine's interest in the work lay parrot behaviorists are doing regarding the psychology of these fascinating birds. More significant progress in the coming years is expected. PMID- 11601105 TI - Biting and screaming behavior in parrots. AB - Biting and excessive screaming in companion parrots are common problems, but they are also correctable. Through clear and unaggressive training and the consistent use of commands, controls, and limits on their behaviour, parrots can learn how to successfully share the human habitat. PMID- 11601106 TI - Feather picking and self-mutilation in psittacine birds. AB - Feather-picking and self-mutilation behaviors are common in psittacine birds. These behaviors are best defined as stereotypic behaviors or obsessive compulsive disorders. There is likely a genetic predisposition for these behaviors as reflected in the overrepresentation of a number of species of psittacines. Stereotypies most often result from a high level of arousal and the inability to respond with the appropriate natural behaviors. More specifically, conflict may be induced by the absence of releasing stimuli or target objects. On a chemical level, stereotypic behavior appears to be related to an increased dopaminergic activity and an increased dopamine turnover. Feather-picking and self-mutilation patients are challenging to treat and are most likely to respond to treatment at an early stage of development. The best results are obtained by identifying and removing the cause of conflict, enhancing the environment, using appropriate drugs when indicated, and employing counter-conditioning. PMID- 11601107 TI - Rabbit behavior. AB - Rabbit behavior is complex and closely related to wild rabbit behavior. The rabbit as a prey species, the rabbit's environment and natural social structure, and the rabbit as an herbivore all play significant roles in rabbit behavior. Stress, especially the stress related to predation, crowding, heat, and inappropriate caging, may affect the behavior of the pet rabbit and its success as a medical or surgical patient. The veterinarian treating the pet rabbit will have a higher level of success if these stresses and the rabbit's behaviors and physiologic responses related to them are taken into consideration. PMID- 11601108 TI - Normal behavior and the clinical implications of abnormal behavior in guinea pigs. AB - Cavies are becoming more popular as pets because they are relatively easy to care for and provide never-ending love and entertainment with their curious but gentle nature. As with other species, the best way to learn about guinea pig behavior is to own guinea pigs. Understanding normal behavior provides the practitioner with the ability to more easily recognize pathology and abnormal behavior. This allows the veterinarian to provide necessary supportive care and pain management more quickly while performing diagnostics and determining the need for therapeutics. Understanding the behavior of cavies allows the clinician to better educate guinea pig-owning clients and to better and more quickly serve the needs of their guinea pig patients. PMID- 11601109 TI - Behavior of Mustela putorius furo (the domestic ferret). AB - Behavior patterns exhibited by the domestic ferret, although similar to its wild cousins, are distinctly domestic in nature. Domestic ferrets use many different types of behaviors, including body posturing, animations, vocalizations, and scent markings. These behaviors may differ somewhat from ferret to ferret. The domestic ferret is best understood by observation and recognition of its behavior patterns and interactions as it plays and communicates with both humans and animals within its home environment. As with all other species of animals kept as pets, the clinician will be greatly benefited by urging the pet owner to regularly note typical behavior patterns for their individual pet. Following is a brief summary of behavioral changes noted in domestic ferrets that may aid the owner or keeper in the detection of potential illness or injury: A normally active ferret suddenly becoming quiet or vice-versa Any sudden increase or decrease in daily food and water intake Routine behaviors performed out of context or order, especially in older animals Any sudden increase or decrease in the speed at which routine behaviors are performed (such as urination, defecation, grooming, food, or water intake) Any sudden increase in the effort required to perform normal or routine behaviors Any sudden changes in personality or attitude toward other ferrets or toward other animals or people. The previous information was gathered over the last 15 years from personal observations, experiences, and studies of ferrets in the shelter, home, and animal hospital environments. This information regarding ferret behavior can assist the veterinarian in differentiating between normal and abnormal behaviors in domestic ferrets. This increased understanding of ferret behavior can aid in the diagnosis of injury and disease and assist the veterinarian in educating clients regarding ferret behavior, care, and recognition of potential disease. PMID- 11601110 TI - Behavior of miniature pet pigs. AB - Pigs are clean, intelligent, and entertaining animals. Because they are domesticated animals, they are not even as unusual a pet as a hedgehog or snake. The animal lover that buys a pig on impulse, however, is likely to have a disappointing experience. Those who acquire a pet pig with the most common preconceived but inaccurate notions are even more likely to be quickly disenchanted with their "exotic pet." Many pet owners will complain of the size that their pig attains; but if the pig were more manageable and better behaved, its ultimate size would probably be of less concern. Given the proper environment, diet and veterinary care, the miniature pig can be a terrific pet. PMID- 11601111 TI - [Anticoagulant therapy]. PMID- 11601112 TI - [Inhibition of the renin-angiotensin system in type 2 diabetes. New significant results concerning type 2 diabetes and renal disease]. PMID- 11601113 TI - [Mesenchymal stem cells. Potential use in cell and gene therapy of bone loss caused by aging and osteoporosis]. AB - Mesenchymal stem cells (MSC) originate from bone marrow and give rise to various cell types, including osteoblasts, chondrocytes, adipocytes, and myocytes. Lineage-specific differentiation is dependent on activation of specific transcription factors. MSCs play an important role in bone modelling and remodelling where they give rise to the osteoblasts necessary for bone formation. Human studies have shown that the number and differentiation potential of MSC are unchanged with age and osteoporosis. In recent years, there has been an increasing interest in the clinical use of MSCs. These have been used to augment healing of bone fractures. Some animal studies have shown that MSCs infused intravenously target bone and possibly participate in bone formation. These studies represent the beginning of a new era, where transplantation with autologous MSCs or genetically-modified MSCs expanded in vitro is a potential treatment strategy to augment bone formation in patients with diverse metabolic and genetic bone diseases, including osteoporosis. PMID- 11601115 TI - [Osteoporosis and Colles' fracture]. AB - We describe the connection between osteoporosis and Colles' fractures of the distal radius from an epidemiological and aetiological point of view. In addition, the value of these fractures as markers of osteoporosis and future risk of fracture is assessed. Several studies have clearly shown an epidemiological association between osteoporosis and fractures of the distal radius, with the association strongest for women up to 65 years of age and for osteoporosis located in the forearm. The association weakens for other locations and for older women. Osteoporosis may have some aetiologic significance for the development of Colles' fractures, but several extraskeletal factors are of equal or further importance. The occurrence of a Colles' fracture in the first 10-15 years after the postmenopause indicates an increased relative risk of sustaining another fracture in the future. However the relative risk approaches one after a few years and, because of the comparatively low absolute risk in this age-group, Colles' fracture as a risk factor contributes little to an assessment of the lifetime fracture risk. In a few longitudinal studies, Colles' fractures could not predict the long-term risk of osteoporosis. The presence of a Colles' fracture should lead to considerations concerning the skeletal and extraskeletal causes of the fracture for the purpose of initiating preventive and therapeutic measures. PMID- 11601114 TI - [The importance of osteoporosis in the treatment of fractures and orthopedic surgical possibilities]. AB - The treatment of osteoporosis-related fractures can be difficult, when secure fixation and stable osteosynthesis is obtained in frail trabecular and cortical bone. In the case of defects, bone grafting and substitutes may be needed to reinforce osteosynthesis and promote fracture healing, which may be delayed. The structural grafts may be biologically inert or osteoconductive, but also osteoinductive, and various osteoinductive growth factors and hormones could be a supplement to treatment. Several types of osteosyntheses have improved the clinical outcome, among them: sliding hip screw, neck screws, intramedullary nails with neck screw, retrograde intramedullary nails, external fixation, cannulated screws, various plates, tension band wiring, threaded K-pins, and to some extent arthroplasties and reconstructive spine instrumentation. The goal in the treatment of osteoporosis-related fractures is to restore functional abilities as soon as possible, and the prevention of subsequent fractures is indicated. PMID- 11601116 TI - [Pool exercise therapy of rheumatoid arthritis]. AB - Aquatic therapy is a subgroup of balneotherapy and consists of exercises in a hot water pool. It uses the physical properties of water to achieve better mobility for patients whose pain, lack of muscle strength, and joint deformities are inhibiting factors when exercising on land. Pool therapy shows positive effects as part of the treatment of rheumatoid arthritis patients, but too few studies with an acceptable design and a well-defined patient group have been carried out. The documentation available on aquatic therapy indicates that more large clinical, controlled, and randomised studies must be conducted. PMID- 11601117 TI - [Effect of losartan on renal and cardiovascular complications of patients with type 2 diabetes and nephropathy]. AB - INTRODUCTION: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in type 1 diabetic patients, but similar data are not available for type 2, the most common form of diabetes. We assessed the role of the angiotensin II receptor antagonist, losartan, in type 2 diabetic patients with nephropathy. MATERIAL AND METHODS: One thousand five hundred and thirteen patients were enrolled in this randomised, placebo-controlled study of losartan (50 to 100 mg, once daily) or placebo, in addition to conventional antihypertensive treatment (calcium antagonists, diuretics, alpha- and beta-blockers, centrally acting agents) for a mean of 3.4 years. The primary outcome was the composite of doubling of baseline serum creatinine, end-stage renal disease, or death. Secondary end points included a composite of cardiovascular morbidity and mortality, proteinuria, and the progression rate of renal disease. RESULTS: Baseline demographics in the two groups were similar. Three hundred and twenty seven patients receiving losartan reached the primary end point, as compared with 359 on placebo (risk reduction = 16 per cent, p = 0.02). Losartan reduced the incidence of doubling of serum creatinine (risk reduction = 25 per cent, p = 0.006) and end-stage renal disease (risk reduction = 28 per cent, p = 0.002), but had no effect on death. Benefits exceeded that attributable to changes in blood pressure. The composite of cardiovascular morbidity and mortality was similar in the two groups, except hospitalisation for heart failure, which was reduced with losartan (risk reduction = 32 per cent, p = 0.005). Proteinuria declined by 35 per cent with losartan (p < 0.001). DISCUSSION: Losartan conferred significant renal benefits in type 2 diabetic patients with nephropathy and was generally well tolerated. PMID- 11601118 TI - [Effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes]. AB - INTRODUCTION: Microalbuminuria and hypertension are risk factors for the development of diabetic nephropathy. Blockade of the renin-angiotensin system reduces progression to diabetic nephropathy in type 1 diabetic patients, whereas similar data are lacking for hypertensive type 2 diabetic subjects. We evaluated the renoprotective effect of an angiotensin II receptor antagonist, irbesartan, in hypertensive type 2 diabetic patients with microalbuminuria. MATERIAL AND METHODS: Five hundred and ninety hypertensive type 2 diabetic patients with microalbuminuria were enrolled in this multinational, randomised, double-blind, placebo-controlled study of irbesartan 150 mg/daily or 300 mg/daily or matching placebo for two years. The primary outcome was time to progression to diabetic nephropathy, defined as a persistent overnight albuminuria > 200 micrograms/min and at least a 30 per cent increase from baseline. RESULTS: Baseline characteristics in the three groups were similar. Ten patients (5.2 per cent) receiving irbesartan 300 mg and 19 patients (9.7 per cent) receiving irbesartan 150 mg daily reached the primary end point, as compared to 30 (14.9 per cent) patients on placebo (hazard ratio 0.30 [95 per cent confidence interval 0.14 to 0.61], p < 0.001 and 0.61 [95 per cent confidence interval 0.34 to 1.08] p = 0.08), respectively). The average blood pressure throughout the study was 144/83, 143/83, and 141/81 mmHg in the placebo, irbesartan 150 mg and 300 mg group, respectively (p = 0.004 for systolic blood pressure). Serious adverse events were less frequent in the patients treated with irbesartan (p = 0.02). DISCUSSIONS: Irbesartan is renoprotective independently of its blood pressure lowering effect in type 2 diabetic subjects with microalbuminuria. It is safe and well tolerated. PMID- 11601119 TI - [Preimplantation genetic diagnosis. The first experiences in Denmark]. AB - INTRODUCTION: Preimplantation genetic diagnosis (PGD) is a possible alternative to prenatal diagnosis, whereby families with serious inherited diseases can avoid having children with the disease. The genetic diagnosis is performed on embryos before implantation and therefore implies IVF. Hence, PGD offers the possibility of transferring embryos without disease, thereby avoiding termination of pregnancy owing to an affected fetus. MATERIAL AND METHODS: Activities at the Centre for Preimplantation Genetic Diagnosis at Aarhus University Hospital since its opening in February 1999 are described. The fluorescent in situ hybridisation (FISH) technique was used for sex selection (hemophilia A and Duchenne's muscular dystrophy) and translocations. The polymerase chain reaction (PCR) was used for cystic fibrosis. RESULTS: Of 20 PGD cycles started, 15 were successful in terms of transference of healthy or carrier embryos. A positive pregnancy test was found after six of 15 embryo transfers (40%) with two subsequent clinical pregnancies. CONCLUSIONS: The present pregnancy rates with PGD are comparable to those following IVF; the clinical pregnancy rate may seem low, but the cycle numbers are small. Preimplantation genetic diagnosis seems to be a realistic alternative for selected genetic diseases, in cases where the couple find abortion unacceptable. PMID- 11601120 TI - [The significance of a reminder and physician's motivation for the response rate of a questionnaire survey in general practice]. AB - The use of a mailed reminder to improve the response rate in a questionnaire survey was analysed in a general practice multicentre survey in Denmark, Norway, and the Netherlands. In total 14 general practitioners (GP's) handed out the questionnaire to 650 adult patients. A randomized sample of the patients who did not respond after three weeks received a reminder including a new questionnaire. In the group that received a reminder the response rate was significantly higher compared with the group that did not (79% vs. 62%). In Denmark, two of the four participating GP's were specially motivated. The response rate for these GP's was significantly higher compared to the normally motivated GP's (91% vs. 71%). Specially motivated GP's can increase the response rate and thereby minimise the effect of the reminder. PMID- 11601121 TI - [Tobacco smoking and risk of hip fracture in men and women. Results from the Hovedstadens Center for Prospective Population Studies]. AB - INTRODUCTION: In the present population-based cohort study, we prospectively determined the influence of current, previous, and cumulative smoking history on the risk of hip fracture in men and women and addressed the issue of possible gender difference in susceptibility to tobacco smoking. MATERIAL: A total of 13,393 women and 17,379 men, initially examined between 1964 and 1992, were followed up until 1997 for their first admission because of hip fracture. RESULTS: During follow-up, a total of 1169 hip fractures were identified. After adjustment for potential confounders, female current smokers had a relative risk of hip fracture of 1.36 (1.12-1.65) and male smoked 1.59 (1.04-2.43) relative to those who have never smoked. In both sexes, the relative risk of hip fracture gradually increased with current and accumulated tobacco consumption. A test for interaction between gender and smoking habits was insignificant. Men who stopped smoking for more than five years had a lower risk of hip fracture than men who currently smoked, whereas no such risk reduction was seen in female ex-smokers. CONCLUSION: Tobacco smoking is an independent risk factor for hip fracture in men and women, and there appears to be no gender differences in the smoking-related risk. Men who stopped smoking for more than five years had lower risk of hip fracture than men who currently smoked, whereas no such risk reduction was seen in female ex-smokers. PMID- 11601122 TI - [Exchange of paraclinical information between the primary and secondary health sectors]. AB - INTRODUCTION: The purpose of the study was to investigate the extent to which, biochemical test results obtained in the primary health sector could be regarded as valid information in the clinical assessment of patients admitted to hospital. METHODS: The study was based on a questionnaire, which was designed to assess the value of historical biochemical data in the initial diagnostic process. The data was transferred from the laboratory of Copenhagen general practitioners (KPLL) database to a computer terminal in the emergency medical ward at H:S Bispebjerg Hospital. RESULTS: It was possible to assess historical KPLL data on close to 80% of all hospitalised patients. In 50% of these patients, doctors indicated that the data always (96%) contributed to the diagnosis. In 70%, the data further contributed to the subsequent planning of diagnostic strategy. With regard to the initial diagnosis, comparison of KPLL data with data obtained on admission always resulted in a further classification of at least one condition. The comparison of KPLL data with admission data always led to a more precise plan for further diagnostic strategy. CONCLUSION: The comparison of KPLL data with admission data, significantly contributes to differentiate the initial diagnostic strategy. In turn, this seems to have a significant bearing on the planning of further diagnostic strategy. It is postulated that a computer-based information system, through which the primary and secondary health sectors can exchange patient related clinical data, would lead to a more focused use of resources, and hold significant advantages for the patient. PMID- 11601123 TI - [Hemorrhagic diarrhea with competing etiologies]. AB - A case history of a 41-year-old woman with bloody diarrhoea is described. A right sided hemicolectomy was performed and histological findings showed pseudomembranous colitis. The woman was infected with verotoxin-producing E. coli O103:H2. She had taken an overdose of ergotamine and was using a contraceptive containing oestrogen. Each of these have previously been described as being the cause of bloody diarrhoea, but we suggest the combination as the aetiology in the present case. PMID- 11601125 TI - [Gastroesophageal reflux--surgical or medical treatment?]. PMID- 11601124 TI - [Cataract--an initial symptom of diabetes mellitus in a 14-year old girl]. AB - A 14-year-old girl presented with cataract as an initial sign of IDDM. Before the diagnosis of DM, she showed no acute symptoms, including ketoacidosis. Retrospectively, there had been faint signs of polyuria, polydipsia, and nycturia. Diabetic cataract is a rare complication in young diabetics and is usually associated with long-standing DM and poor metabolic control. Previous cases have a striking resemblance to our patient, thus suggesting that a small group of young diabetics have weak symptoms, but are nevertheless at great risk of developing diabetic complications. PMID- 11601126 TI - [When physicians prepare drugs]. PMID- 11601127 TI - [Nordic toasts]. PMID- 11601128 TI - Digital diagnoses in an analog world. PMID- 11601129 TI - Morphometry confirms the presence of considerable nuclear size overlap between "small cells" and "large cells" in high-grade pulmonary neuroendocrine neoplasms. AB - We morphometrically evaluated 5-micron H&E-stained sections from 28 surgically resected high-grade pulmonary neuroendocrine neoplasms, including 16 small cell lung carcinomas (SCLCs) and 12 large cell neuroendocrine carcinomas (LCNECs). For each case, 200 tumor nuclei and 20 to 100 normal lymphocytes were measured. The frequency distributions of tumor cell/lymphocyte (TC/L) size ratios were plotted in bins ranging from 1 to 6, classified into 6 histogram types with TC/L size ratio peaks ranging from 2 to 6 (A-E) and a histogram with a wide distribution (F). SCLCs fit histograms A through E; LCNECs, A through F. Morphometry demonstrated considerable nuclear size overlap in high-grade neoplasms. Approximately one third of SCLCs exhibited considerable numbers of neoplastic cells that were larger than 3 normal lymphocytes, while 4 of 12 LCNECs had a predominant number of small cells. Ten tumors exhibited a B histogram with a "borderline" peak TC/L of 3. The rule that a TC/L size ratio larger than 3 helps distinguish "large" from "small" neoplastic cells was confirmed in only 9 of 28 cases. The use of more generic terminology such as "high-grade neuroendocrine carcinoma" or "grade III neuroendocrine carcinoma" for SCLC and LCNEC is discussed. PMID- 11601130 TI - Consultative (expert) second opinions in soft tissue pathology. Analysis of problem-prone diagnostic situations. AB - We reviewed 500 consecutive soft tissue lesions referred for expert consultation to determine types of lesions and/or situations in which major discrepancies occur. Of 266 cases (53.2%) accompanied by a diagnosis, essential agreement with the second opinion was noted in 68%, minor discrepancy in 7%, and major discrepancy in 25%. The 65 major discrepancies were distributed proportionally to the referring sources and could be divided into 4 groups: benign mesenchymal lesions diagnosed as sarcomas (45%), sarcomas diagnosed as benign tumors (23%), nonmesenchymal lesions diagnosed as sarcoma (20%), and major grading discrepancies (12%). Relatively few lesions accounted for a major proportion of major discrepancies. Problematic lesions were lipoma and fasciitis and their variants and desmoplastic-neurotropic melanoma. Needle biopsy specimens were somewhat more likely to be associated with a discrepant opinion. With the exception of nonmesenchymal lesions, the diagnosis for all major discrepant cases could be made on the basis of the H&E-stained slides, suggesting that failure to perform immunostains did not account for discrepancies. Lack of familiarity with rare or unusual lesions is probably more significant in explaining diagnostic discrepancies than is the increasing use of needle biopsy or the failure to perform immunohistochemical analysis. PMID- 11601131 TI - Accuracy of thyroid fine-needle aspiration using receiver operator characteristic curves. AB - Although many large series demonstrate the effectiveness of thyroid fine-needle aspiration (FNA), measuring its accuracy has been suboptimal owing to inappropriate statistical methods. All thyroid fine-needle aspirates were correlated with corresponding histologic and cytologic follow-up for a 4-year period, and the accuracy was determined using receiver operator characteristic curves, which allow inclusion of nondiagnostic and indeterminate cases. There were 1,085 cases, 291 with follow-up. The overall accuracy was 0.90 +/- 0.02 for a single aspiration session. A nondiagnostic aspirate was associated with a significant risk of malignancy (16%). However, 70% of patients who underwent reaspiration had adequate and negative results, and reaspiration significantly increased overall accuracy. Subcategorizing the nondiagnostic category did not affect accuracy, but did define categories with a significantly different change of a negative diagnosis on repeated aspiration. Although subcategories of papillary carcinoma were associated with significantly different risks of carcinoma (40% vs 81%), they did not significantly improve overall accuracy. Receiver operator characteristic curves can be used to define the accuracy of thyroid FNA. This method demonstrates significantly increased accuracy with repeated aspiration of nondiagnostic cases and demonstrates that subcategorization does not improve the overall accuracy of the test. PMID- 11601132 TI - The value of thyroid transcription factor-1 in cytologic preparations as a marker for metastatic adenocarcinoma of lung origin. AB - In tissue sections, thyroid transcription factor-1 (TTF-1) is a sensitive marker for adenocarcinomas of lung and thyroid origin. This immunohistochemical study evaluates the effectiveness of TTF-1 as a marker for pulmonary adenocarcinomas in paraffin sections of cell block preparations derived from effusion and fine needle aspiration specimens. We evaluated 122 cell blocks including 8 primary and 39 metastatic pulmonary adenocarcinomas, 11 pulmonary neoplasms of other types, 50 specimens with nonpulmonary metastatic tumors, and 14 mesotheliomas. TTF-1 was reactive in 42 (89%) of 47 pulmonary adenocarcinomas. Only 1 of 4 pulmonary small cell/neuroendocrine tumors was TTF-1 positive, while 1 of 7 squamous cell carcinomas was weakly reactive. Of 50 metastatic tumors of nonpulmonary origin, focal weak reactivity was noted only for 1 metastatic ovarian carcinoma. All mesotheliomas were nonreactive. In cytologic preparations, TTF-1 is a highly selective marker for pulmonary adenocarcinoma and also can have a role in the distinction between pulmonary adenocarcinoma and mesothelioma. PMID- 11601133 TI - Molecular characterization and sequence analysis of polyomavirus strains isolated from needle biopsy specimens of kidney allograft recipients. AB - We retrospectively examined 29 renal allograft biopsy specimens from 42 kidney transplant recipients by means of molecular biologic techniques (nested polymerase chain reaction), immunohistochemical analysis (anti-SV40 antibody), and histologic examination to evaluate the presence of polyomaviruses (PVs), viral genotypes, genomic mutations, and their pathologic significance. PV genomes were found in six cases (21%); restriction fragment length polymorphism analysis characterized 4 as JC virus (JCV) and 2 as BK virus (BKV). The latter also were positively stained immunohistochemically and showed histologically typical intranuclear viral inclusions; JCV cases were negative. DNA sequence analysis revealed only minor changes in the 4 JCV cases (3 archetypes and 1 JCV type 3, not associated with a known pathogenic genotype) but identified 2 specific variants in the BKV isolates (AS and WW strains). Given the different histologic findings (mixed inflammatory infiltration in the AS and no inflammation in the WW strain), we speculate that different BKV strains may cause differential damage in transplanted kidneys. Finally, the negative histologic and immunohistochemical JCV results, as well as the absence of viral mutations, indicate that JCV renal infection is latent in transplant recipients. PMID- 11601134 TI - Assessment of HER-2/neu status in breast cancer. Automated Cellular Imaging System (ACIS)-assisted quantitation of immunohistochemical assay achieves high accuracy in comparison with fluorescence in situ hybridization assay as the standard. AB - This retrospective study of formalin-fixed infiltrating breast cancer specimens compared manual immunohistochemical assay with a new image analyzer-assisted immunohistochemical quantitation method, using fluorescence in situ hybridization assay (FISH) as the standard. Following the manual immunohistochemical assay, 189 cases, including most manual immunohistochemically positive and some random negative cases, were analyzed by FISH assay for Her-2/neu gene amplification and by the Automated Cellular Imaging System (ACIS) for immunohistochemical staining. Using the FISH standard, the ACIS immunohistochemical assay attained a higher concordance rate and sensitivity than the manual immunohistochemical assay (91.0% and 88% vs 85.7% and 71%, respectively), with only a slight decrease in specificity (93% vs 96%, respectively). In particular, the ACIS immunohistochemical assay resulted in a higher correlation with the FISH assay in the manual immunohistochemical assay 2+ cases. The ACIS immunohistochemical assay achieved higher accuracy than the manual method according to receiver operating characteristic curve analysis. The ACIS method represents a substantial improvement over the manual method for objective evaluation of the HER-2/neu status. PMID- 11601135 TI - The tumor cells in nodular lymphocyte-predominant Hodgkin disease are clonally related to the large cell lymphoma occurring in the same individual. Direct demonstration by single cell analysis. AB - Large cell lymphoma (LCL) sometimes occurs concurrently or subsequently in patients with nodular lymphocyte-predominant Hodgkin disease (NLPHD). Although there is evidence of a clonal relationship between LCL and NLPHD, there has been no direct demonstration that the lymphocytic and histiocytic (L&H) cells in NLPHD are related to the tumor cells in LCL. We identified 2 cases of NLPHD with an associated LCL. Single L&H cells, the Reed-Sternberg cell variants in NLPHD, were isolated from immunostained tissue sections by micromanipulation, and the immunoglobulin heavy chain gene (IgH) complementarity determining region (CDR) III of the cells was amplified by the polymerase chain reaction (PCR). The products were compared with those obtained from microdissected LCL cells using polyacrylamide gel electrophoresis and nucleotide sequencing. The IgH CDRIII sequences from the L&H cells were related to each other, but also showed nucleotide substitutions, consistent with a germinal center origin. The sequences from the L&H cells also were related to those from the corresponding LCL cells. We have provided direct evidence through sequence analysis of the IgH CDRIII that the L&H cells are clonally related to the corresponding LCL arising in 2 cases of NLPHD. PMID- 11601136 TI - Immunophenotypic analysis of peripheral T-cell neoplasms. A multiparameter flow cytometric approach. AB - We retrospectively reviewed multiparameter flow cytometric analyses in 50 peripheral T-cell neoplasms (PTCNs). Results were interpreted within the context of a large cohort of nonneoplastic T-cell populations. All PTCN diagnoses were confirmed with morphologic and/or molecular analysis. Aberrant populations were defined as discrete immunophenotypic clusters exhibiting loss of or increased or diminished expression of T-cell antigens relative to internal immunophenotypically normal T-cell populations. An antigenic pattern was considered abnormal if it exceeded ranges for T-cell subsets in specific anatomic sites or was not normally encountered. Forty-six of 50 and 41 of 50 demonstrated 1 or more and 2 or more aberrations, respectively. The most common abnormally expressed antigen was CD3, followed by CD7, CD5, and CD2. Except for CD7, abnormally dim or bright antigen expression was more common than deletion. Only 3 cases were abnormal solely based on expansion of an otherwise immunophenotypically normal population; the remainder had patterns of antigen expression not seen in nonneoplastic populations. These data indicate that most PTCNs are aberrant by multiparameter flow analysis. However, results must be interpreted within the context of thorough knowledge of the immunophenotypic spectrum of nonneoplastic T cells. PMID- 11601137 TI - Detection of clonal T-cell receptor-gamma gene rearrangement by PCR/temporal temperature gradient gel electrophoresis. AB - Limited combinatorial and junctional diversity in TCR-gamma gene rearrangement can result in amplification products that are difficult to interpret when analyzed by conventional gel electrophoresis methods that separate DNA based on size (polymerase chain reaction [PCR]/polyacrylamide gel electrophoresis [PAGE]). We describe a simple approach to the detection of clonal TCR-gamma gene rearrangement using temporal temperature gradient gel electrophoresis (TTGE) that uses a gradual and uniform increase in the temperature of a constant denaturing gel to resolve different DNA molecules based on base pair composition. We tested 42 clinical specimens (30 blood specimens and 12 formalin-fixed paraffin-embedded tissues) for T-cell clonality by PCR/PAGE and PCR/TTGE. Concordant results were obtained in only 22 specimens (52%). Of the 20 discordant cases, 18 samples were positive by TTGE and negative by PAGE. For all of the discordant cases, the TTGE yielded results that correlated better with the clinical data than did the PAGE method. We conclude that PCR/TTGE is more accurate and easier to perform than current methods for detecting clonal populations of T cells. PMID- 11601138 TI - Cyclin D1 overexpression in multiple myeloma. A morphologic, immunohistochemical, and in situ hybridization study of 71 paraffin-embedded bone marrow biopsy specimens. AB - Cyclin D1 expression was evaluated by immunohistochemical analysis and biotin labeled in situ hybridization (ISH) in a series of 71 decalcified, paraffin embedded bone marrow biopsy specimens from patients with multiple myeloma (MM). Cyclin D1 messenger RNA (mRNA) overexpression was detected by ISH in 23 (32%) of 71 cases, whereas cyclin D1 protein was identified by immunohistochemical analysis in 17 (24%) of 71 specimens. All cases that were positive by immunohistochemical analysis also were positive by ISH. Statistically significant associations were found between cyclin D1 overexpression and grade of plasma cell differentiation and between cyclin D1 overexpression and extent of bone marrow infiltration. Our findings demonstrate the following: (1) ISH for cyclin D1 mRNA is a sensitive method for the evaluation of cyclin D1 overexpression in paraffin embedded bone marrow biopsy specimens with MM. (2) ISH is more sensitive than immunohistochemical analysis in the assessment of cyclin D1 expression. (3) Cyclin D1 overexpression in MM is correlated positively with higher histologic grade and stage. PMID- 11601139 TI - Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course. AB - We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM). Each LPL/WM case was classified as lymphoplasmacytoid (n = 18), lymphoplasmacytic (n = 10), or polymorphous (n = 9) using the Kiel criteria. Of 12 cases with chromosomal abnormalities, a single numeric abnormality was present in 4 and a complex karyotype in 8. The most common numeric abnormalities were and -8 in 3 cases each; the most common structural abnormality was del(6q) in 6 cases. Cytogenetic abnormalities were significantly less common in the lymphoplasmacytic and lymphoplasmacytoid groups (5/28 [18%]) compared with the polymorphous group (7/9 [78%]). Clinical follow-up was available for 28 patients for a median of 36 months. Six (67%) of 9 patients with aneuploid tumors, including 4 with polymorphous subtype, subsequently had clinical progression or developed high-grade lymphoma. In contrast, 4 (21%) of 19 patients with diploid tumors, including 1 of polymorphous type, developed clinical progression or high-grade lymphoma. We conclude that abnormal cytogenetic findings in LPL/WM correlate with the polymorphous subtype and poor prognosis. PMID- 11601140 TI - Hyperplasia of mantle/marginal zone B cells with clear cytoplasm in peripheral lymph nodes. A clinicopathologic study of 35 cases. AB - We describe 35 peripheral lymph nodes classified as mantle cell/marginal zone B cell hyperplasia with clear cells using morphologic and immunologic findings. For the purpose of this study, we obtained clinical follow-up information and performed immunoglobulin gene rearrangement studies on paraffin sections by polymerase chain reaction. Architecturally, the nodes were suggestive of a benign process: no pericapsular infiltration, sinuses readily identified, scattered reactive follicles present, and paracortical nodular hyperplasia present. No monocytoid B cells were present. Focally, small lymphoid cells with round nuclei and clear cytoplasm (clear cells) formed monomorphic nodular, inverse follicular, and/or marginal zone patterns. Flow cytometry and immunohistochemical analysis revealed neither light chain restriction nor an aberrant B-cell phenotype. Immunoglobulin gene rearrangement studies showed a clonal band in 1 of 26 cases in which DNA was amplified. To ascertain the clinical relevance of this positive case, follow-up information was obtained 30 months after the initial biopsy; the 83-year-old woman was alive without treatment but had splenomegaly and bone marrow involvement by marginal zone B-cell lymphoma. The morphologic and immunologic criteria used for diagnosis of mantle cell/marginal zone B-cell hyperplasia with clear cytoplasm are valid; however, to rule out the possibility of occult lymphoma, immunoglobulin gene rearrangement studies and clinical follow up are necessary. PMID- 11601141 TI - HIV transmissions from a window-period platelet donation. AB - Recently, blood centers began investigational testing for HIV RNA by pooled nucleic acid testing (NAT). A 35-year-old frequent platelet donor tested HIV p24 antigen positive, antibody negative before implementation of NAT. He made 2 platelet donations (day -4 and -11) immediately before testing positive for HIV. The donor's HIV seroconversion was monitored, and stored samples were tested retrospectively for HIV RNA. Platelet recipients were tested for HIV infection. The day -4 sample tested positive for HIV RNA by pooled and individual sample NAT. The day -11 sample tested negative for HIV RNA by both NAT tests. The 2 recipients of the day -4 platelets tested HIV RNA and p24 antigen positive. The recipient of the day -11 platelets could not be tested because he had died. HIV NAT would have prevented transmission of HIV had it been available at the time of this donor's HIV seroconversion. PMID- 11601142 TI - Quantification and facilitated comparison of von Willebrand factor multimer patterns by densitometry. AB - The analysis of von Willebrand factor (vWF) multimers is an important laboratory tool for distinguishing among the numerous subtypes of von Willebrand disease (vWD). Comparability and reproducibility of this method are insufficient; standardization and external references are pending. Interlaboratory comparison of results therefore may be difficult. We applied densitometry to obtain a reproducible quantification of vWF multimer patterns in healthy donors, patients with vWD variants, and factor VIII/vWF concentrates to improve the reproducibility and comparability of vWF multimer analysis. Multimers were separated and visualized luminographically on x-ray films. Films were scanned and evaluated by densitometry. The variation inherent in vWF multimer analysis and the range of the normal could be quantified. In vWD variants and factor VIII/vWF concentrates, densitometry could quantify and visualize alterations of vWF multimer patterns and facilitate their comparison. Densitometry permits a precise quantitative comparison of sample patterns to a reference plasma. It could be a valuable tool offering reproducible quantification and additional visualization of normal and pathologic vWF multimer patterns, facilitating their comparison and contributing to a standardization of vWF multimer analysis. PMID- 11601143 TI - Plasma total transcobalamin I. Ethnic/racial patterns and comparison with lactoferrin. AB - Plasma total transcobalamin (TC) I levels were measured in 434 healthy volunteers by radioimmunoassay (RIA). The results were analyzed for demographic patterns and were compared with lactoferrin, cobalamin, homocysteine, and chemistry panel results. Plasma TC I was higher in blacks than in other ethnic/racial groups and higher in women than in men. TC I levels did not correlate with lactoferrin levels. Lactoferrin showed significant ethnic differences also, but, unlike TC I, its levels were highest in whites. TC I levels correlated with cobalamin but not homocysteine levels. Neither TC I nor lactoferrin correlated with chemistry panel results, including creatinine, total protein, albumin, lactate dehydrogenase, and alkaline phosphatase levels. The demonstration with an RIA that directly measures total TC I that plasma levels are significantly higher in blacks than in other groups may explain the well-known higher cobalamin levels in blacks. Surprisingly, plasma lactoferrin, which has the same cellular sources as TC I, does not correlate with plasma TC I levels and shows dissimilar demographic patterns; lactoferrin levels are highest in whites. These findings suggest that regulation and/or secretion of these 2 proteins differ even though their localization and expression patterns in myeloid precursors are similar. PMID- 11601145 TI - Fas (CD95)-mediated apoptosis in celiac disease. PMID- 11601144 TI - Neutrophil-rich anaplastic large cell lymphoma. PMID- 11601146 TI - [Calcium ions and the nervous system plasticity]. AB - The nervous system is different from all other systems of the organism by extreme flexibility of the structural and functional properties of its elements. This unique feature of the nervous system can be best described as plasticity in a broad sense of the word. All forms of plastic changes in the nervous system functioning have common basic mechanisms, the changes at the free Ca2+ cytosol ions being the most important one. These "calcium signals" trigger an extremely complicated intracellular machinery capable of controlling the structural and functional properties of the nervous system during the whole life span. This review summarises data on the intracellular Ca2+ ions mechanisms controlling the developmental plasticity of neuronal elements, synaptic plasticity of the mature nervous system, and the decline of plastic capabilities with ageing. PMID- 11601147 TI - [Structure of glutamate receptor ion channels and mechanisms of their blockade by organic cations]. AB - Structural determinants of blocking the glutamate receptors of AMPA and NMDA subtypes, were studied. Close location of hydrophobic and ammonium groups is necessary for affective blocking of the NMDA receptor channels, whereas blockers of the AMPA receptor channels have a distance of about 10 angstroms between these two groups. Models of the channels meeting these topographic data have been devised using a molecular mechanics approach. The accomplished studies revealed molecular basis of channel blockade of the NMDA and AMPA receptors. This may allow designing predictable new blocking compounds with a desired selectivity. PMID- 11601148 TI - [A cognitive set and top-down processes in the functional organization of visual recognition]. AB - A top-down processing model and the role of frontal and prefrontal cortex in the neural mechanisms of recognition of verbal and non-verbal visual stimuli, are discussed. Stimulus recognition is considered to be a result of integration of the bottom-up and top-down streams. The cognitive set phenomenon can be used for studying the downward control in the neurocognitive visual system and in functional organisation of stimuli recognition. PMID- 11601149 TI - [The visual cortex alpha-scanning: EEG and magnetic resonance tomography data]. AB - Exact localization of equivalent current dipoles (ECD) was obtained by combining the EEG and the MRI mapping allowing to trace the ECG displacement over the cortex. The data obtained corroborate localization of the alpha-rhythm ECD in the Gyrus Calcarina: the human primary visual cortex. Successive shifts of the ECD over this area during generation of each alpha-wave, were revealed. The data are discussed in the light of the "scanning hypothesis" that predicted a certain functional meaning of the alpha-wave spreading for cortical processing of sensory information. PMID- 11601150 TI - [Immunity and stress]. AB - Changes occurring in stress response in the immune system and their effect upon resistance against infectious diseases, were studied. The main mechanisms of the stress induction involve: enhancement of the corticotropin-releasing factor and/or adrenocorticotropic hormone synthesis under the effect of interleukin-1; induced by an infection synthesis of the adrenocorticotropic hormone by lymphocytes, enhancement of the corticotropin-releasing factor synthesis under the effect of a psycho-emotional tension. The main reasons of decline in the immune-competence in stress, are discussed. Significance of stress-response as one of the mechanisms of the organism physiological response to extreme circumstances, is considered. PMID- 11601151 TI - [Endothelial dysfunction in the development of vascular complications in diabetes mellitus]. AB - Patients with type 1 diabetes, aged 18 to 42 years, were compared to those aged 11 to 22 years. Activities of endothelial vasoactive factors and endothelial and leukocyte adhesion molecules were studied at different stages of development diabetes complications: nephropathy and retinopathy. The findings reveal role of the vasoactive factors in microangiopathy course. PMID- 11601152 TI - [Functional and structural basis of presynaptic inhibition in primary afferents of the spinal cord in vertebrates]. PMID- 11601153 TI - [Increase of water permeability and recovery of water impermeability of the frog urinary bladder]. AB - The experiments carried out on the urinary bladder of the frog Rana temporaria L. have shown that the period of recovery of water impermeability after an increase of osmotic water permeability induced by arginine-vasotocin, desmopressin, or cAMP depends on the degree of increase of the osmotic permeability but not on the nature of the substance stimulating the increase of osmotic water permeability. The removal of the hormone in the absence of autacoids fails to recover the water impermeability. After cessation of the vasotocin action the water permeability decrease is delayed if phospholipase A2 and cyclooxygenase are inhibited by qiunacrine and voltaren, respectively. An agonist of V1-receptors has no effect on dynamics of the recovery of water impermeability. This recovery has been shown to depend on PGE2 concentration in the serosal solution after the hormone removal. The obtained results indicate that decrease of water permeability depends not only on removal of vasotocin or cAMP but also on involvement of autacoids. PMID- 11601154 TI - [The role of protein kinase C in insulin signal transduction via adenylyl cyclase signaling mechanism]. AB - Activation of proteinkinase C with diacylglycerol or phorbol-12-myristate-13 acetate in the rat muscle membrane or Anodonta cygnea mollusc blocks the insulin stimulating signal to adenylyl cyclase via tyrosinekinase type receptor. The same occurs with stimulating effect of biogenic amines to adenylyl cyclase via serpentine type receptor. Transduction of the inhibitory signal induced with isoproterenol to adenylyl cyclase remained unchanged in case of the proteinkinase C activation. The findings suggest that phorbol-sensitive proteinkinase C realizes a negative regulation of insulin-sensitive adenylyl cyclase signalling system. This negative regulation might prove a universal mechanism of the adenylyl cyclase system desensitisation. PMID- 11601155 TI - [Hyperbaric oxygen inhibits neutrophil infiltration and reduces postischemic brain injury in rats]. AB - Reversible occlusion of the middle cerebral artery (MCA) was used to test hypothesis that hyperbaric oxygen inhibits the neutrophile infiltration into the ischemic brain thus reducing the brain injury. Treatment with hyperbaric oxygen prior to ischemia or during MCA occlusion significantly reduced neutrophile infiltration, motor disorders, and cerebral infarction volume. PMID- 11601156 TI - [Effects of pre-exposure to an experimental chamber on memory trace retrieval in aggressive and submissive mice during extinction of conditioning]. AB - Mice with a submissive stereotype of behaviour developed a fast habituation to novelty of environment. A subsequent training revealed a deficit of passive avoidance learning and prolongation of the memory trace extinction. Aggressive mice are characterised by a delay of the habituation and absence of any significant changes in the memory trace retrieval. The findings suggest that responses to environmental novelty and use of its estimation in learning and retention of memory traces are essentially predetermined by the basic strategy of behaviour. PMID- 11601157 TI - [Evaluation of the tonic and phasic effects of endogenous adenosine on the transmitter secretion in the neuromuscular junction]. AB - Exogenous adenosine reduced the amplitude of multiquantal end-plate currents due to a depressant action on transmitter release. Theophylline did not change the amplitude of end-plate currents under low-rate motor nerve stimulation. The findings suggest a possibility of both tonic and phasic inhibitory actions of endogenous adenosine on transmitter release when utilization of this purine in synaptic cleft is inactivated. PMID- 11601158 TI - Annual review hospital visits for patients with cystic fibrosis. PMID- 11601159 TI - Mucolytic therapy in cystic fibrosis. PMID- 11601160 TI - Barriers and good practice in transition from paediatric to adult care. PMID- 11601161 TI - The child with cystic fibrosis who fails to gain weight. PMID- 11601162 TI - Smoking and cystic fibrosis. PMID- 11601163 TI - Drug-induced fever and bone marrow suppression in a 12-year-old girl with cystic fibrosis. PMID- 11601164 TI - Transition from paediatric to adult care: psychological principles. PMID- 11601165 TI - Transition from paediatric to adult care: problems that arise in the adult cystic fibrosis clinic. PMID- 11601166 TI - Terror weapons. The next threat? PMID- 11601168 TI - Follow-up care: nuts, bolts, carrots, and sticks. PMID- 11601167 TI - Make the most of the new tax law. PMID- 11601170 TI - Get a life--go flextime. PMID- 11601169 TI - Handshake partnerships: tick ... tick ... tick.... PMID- 11601171 TI - Diagnostic tools you can't afford to ignore. PMID- 11601172 TI - Earnings. Time to call a code? PMID- 11601173 TI - "It's time to quit". PMID- 11601174 TI - Paying for your partners' mistakes. PMID- 11601175 TI - [Pathologic diagnosis of pancreatic cancer--facts, pitfalls, challenges]. AB - Discrimination between the well differentiated pancreatic carcinoma and the chronic fibrotizing pancreatitis is one of the most difficult diagnostic problems in the field of pancreatology, and it is also a challenge for the pathologist. The author outlines those objective facts that might lead to diagnostic errors. The two diseases may coexist; on the one hand, malignant tumor can be developed as a complication of a long-standing chronic pancreatitis, while on the other hand, pancreatic carcinoma is frequently accompanied by chronic inflammation. The majority of adenocarcinomas induce a striking desmoplastic stromal reaction, but the chronic pancreatitis is also characterized by a vigorous fibroblast proliferation leading to the possibility of macroscopical misdiagnosis. Microscopically, the pancreatitis can be mistaken for carcinoma, because the actively growing connective tissue irregularly separates the ducts and in addition, the continuous regenerative activity may lead to regressive atypia. For that reason, cytopathologist must evaluate several criteria together, because the nuclear alterations by themselves can be misleading. Although there are some promising new differential diagnostic techniques (apomucins, CAM 17.1, telomerase activity, loss of chromosome Y), so far the most reliable method has been the meticulous evaluation of the cellular and histological findings by the well trained pathologist. To date, molecular pathological methods have shown no advantage in the differential diagnosis. PMID- 11601176 TI - [Epidemiology of hypertension in adolescence and factors influencing blood pressure]. AB - The authors summarize the determining and influencing factors of adolescent hypertension. An overview of the definition and prevalence of hypertension in adolescence is given and the predictive role of the adolescent hypertension on the incidence of adult cardiovascular diseases is pointed out. According to the previous literature data, adult hypertension is more frequent in those people who have had hypertension in their adolescence. There are no widely used, population based nomograms of adolescent hypertensives available. According to the opinion of the authors, a population-based hypertension screening program would help in delineating the factors influencing adolescent blood pressure, and the most frequent risk factors for hypertension in Hungary. With the follow-up and appropriate treatment of the hypertensives the reduction of target-organ damages may be possible. PMID- 11601177 TI - [Gastrointestinal side effects of non-steroidal anti-inflammatory drugs in high risk patients--role of selective cyclooxygenase inhibitors]. AB - Non-steroidal anti-inflammatory drugs (NSAID) are the most widely used drugs in the world. Gastrointestinal (GI) side effects of NSAID have a significant economical impact (3-4% clinical GI event, and 1.5% serious/life threatening GI event/year). Selective cyclooxigenase-2 inhibitors (coxibs) are equally effective as non-selective NSAID with about 50% reduction of serious/life threatening GI events. Serious GI events are significantly less in high-risk patients (history of peptic ulcer disease, age over 65 years, treatment with anticoagulants), therefore the use of coxibs is cost-effective in these population. Most of patients with long-term NSAID therapy also require co-therapy with acid suppression or prostaglandin analogue, but coxibs may replace both. The treatment with coxibs in long-term NSAID users thus is cheaper then non-selective NSAID + co-therapy. Patients with GI adverse events during coxib therapy require co therapy with acid suppression or prostaglandin analogue. PMID- 11601178 TI - [Experience with surgical treatment of prosthetic valve endocarditis]. AB - Prosthetic valve endocarditis (PVE) is a rare but dangerous complication that may occur after the implantation. The authors retrospectively summarize their 11-year experience in treating PVE. 2357 prosthetic valve (PV) implantations were performed over 11 years at the Department of Cardiovascular Surgery, Semmelweis University, Budapest, PVE was found to be the indication for operation in 1.8% of the cases (43/2357). 43 surgical interventions were carried out on 38 patients (mean age: 52.5 yrs, male/female ratio: 25/13). Blood cultures were positive in 86% and negative in 14% of the cases. The infected PV-s were replaced emergently (14%), urgently (79%) or electively (7%). The explanted valves were aortic in 55% and mitral 45% of the cases, 63% were mechanical and 37% biological. PVE followed the primary PV implantation in less than a year in 39.5%. Infected environment during the primary PV implantation was found to be a predisposing factor for the late endocarditis episodes. The mean age of the infected and explanted aortic bioprosthetic valves was significantly higher than that of explanted mechanical valves (p < 0.05). No such difference could be found at the mitral valves. The explanted valves were replaced by mechanical (75.5%) or biological (22.5%) devices. Homograft was implanted once. Early postoperative mortality of the primary PV replacements was 10.5%) devices. Homograft was implanted once. Early postoperative mortality of the primary PV replacements was 10.5%. Endocarditis reoccurred in 20% of the cases. Means follow-up duration was 45.5 months. Two-, five- an 10-year survival were 75%, 64% and 51% respectively. In conclusion in the surgical treatment of PVE, bioprosthetic and mechanical valves are suitable alternatives as opposed to homografts and freestyle stentless valves. PMID- 11601179 TI - [Kennedy disease in a patient with progressive speech disorder]. AB - Kennedy disease is an adult onset neuromuscular disease characterized by slowly progressive proximal and bulbar muscle weakness. The disease associates with gynecomastia, adult onset infertility and sensory neuropathy, and caused by pathologic expansion of CAG repeats at the N-terminal region of the androgen receptor gene at Xq11-q12. We report on a patient presenting with slowly progressive muscle weakness of the lower extremities, progressive dysartry and swallowing difficulties. The clinical symptoms were not fully specific for the disease. Moreover the family history was suggestive for an autosomal dominant trait meaning a diagnostic pitfall at the original examination. Finally the firm diagnosis of the Kennedy disease was established by a polimerase chain reaction based method. PMID- 11601180 TI - Age prediction based on skeletal morphology. AB - Treatment plan for a child requires a complete diagnosis with monitoring of the skeleto-dental morphological changes during active period of growth. Growth modifications are done while the forces of growth are still at the peak of activity in a developing child. This study was undertaken on lateral cephalograms of 100 North Indian samples in the age group of 9-12 years consisting of 50 males and 50 females divided into normal occlusion and malocclusion groups, to predict and assess age by evaluating the skeleto-dental morphology in developing normal children having flush terminal plane molar relationship and children with developing class II pattern. It was concluded that based on measurements used in the study of dentofacial morphology, the age of a child could be statistically determined. PMID- 11601181 TI - Oto-mandibulo-facial dysostosis: a case report. AB - The case presented here is a 6 year old male child with oto-mandibulo-facial dysostosis syndrome. Oto-mandibulo-facial dysostosis is a term used for a unilateral congenital birth defect in which abnormalities can range from minor unilateral ear anomalies or preauricular tags to severe ones involving anotia and mandibular hypoplasia. PMID- 11601183 TI - Management of an infant with cleft lip and palate with phocomelia in dental practice. AB - Cleft lip and palate is a severe birth defect occurring approximately one in 800 1000 newborn infants. The incidence varies widely among races. Cleft lip and palate together account for approximately 50% of all cases whereas isolated cleft lip and isolated cleft palate occur in about 25% of cases. Many of these congenital anomalies appear to be genetically determined though the majority are of unknown causes or teratogenic influences. Presented here is a 3 day old infant with bilateral cleft lip and palate and phocomelia for whom a feeding obturator was made and delivered to facilitate feeding. PMID- 11601182 TI - Effect of black tea on teeth. AB - Dental caries is the prime cause of premature loss of teeth in children. Tea contains high percentage of fluoride along with polyphenolic constituents which act on GTF of S. mutans in plaque synthesis. Combination of fluoride and polyphenolic constituents inhibit caries activity. PMID- 11601184 TI - Mesiodens: a retrospective study of fifty teeth. AB - A retrospective study of 30 cases of mesiodens is presented. male preponderance of 1.5:1. was 64% mesiodens were impacted and 36% erupted. Inverted impacted mesiodens was seen in 62.5% of the impacted mesiodens. 66.6% cases had 2 mesiodens per case. The harmful effects on the dentition were mostly crowding, rotation, diastema and impacted permanent incisor. PMID- 11601185 TI - A clinical profile to assess the potential risk factors for cleft lip and palate. AB - Cleft lip and palate is one of the most common malformations in man. Although the subject of a great deal of investigation, etiologic factors contributing to these congenital deformities remain largely unknown. Various factors like race, sex, parental age at the time of conception etc. have been listed as the exogenous factors. This article strives to project any significant relationship of these factors to cleft lip and cleft palate. PMID- 11601186 TI - Talon cusp in the deciduous dentition: a case report. AB - Talon cusp is a type of developmental anomaly affecting coronal portion of tooth in cingulum region, rarely found in the deciduous dentition. PMID- 11601187 TI - Effects of variation in the timing of palatal repair on sagittal craniofacial morphology in complete cleft lip and palate children. AB - The complete cleft lip and palate children, ranging from 6-14 years of age were studied to evaluate the effect of variation in the timing of palatal repair on craniofacial morphology and compared to the noncleft children. It was observed that all the groups early (8 to < or = 24 months), medium (> 24 to < or = 36 months) and late repair (> 36 to < or = 78 months) had significantly larger cranial base, retruded maxillomandibular relations, skeletodental and incisal relationships compared to the noncleft children. However, intercomparison among the cleft groups showed insignificant difference amongst them suggesting that the timing of palatal repairs does not effect the anterioposterior (sagittal) relationship. PMID- 11601189 TI - Three-dimensional ultrasonic images of normal fetus. AB - BACKGROUND: The purpose of this study was to assess the usefulness and feasibility of 3-dimensional (3D) ultrasound for routine fetal observation. METHODS: Eighty-five normal pregnancies with gestational ages of 20-36 weeks were studied. A conventional ultrasound scanner with a specially designed operation unit, frame memory, and 3D probe was the apparatus used in this study. The unit has a circuit board consisting of digital integrated circuit chips designed to make calculations of volume ray tracings for volume rendering in real time. For each fetus, scanning was performed with different levels of opacity in the equation for volume rendering. In areas where there was an inadequate amniotic fluid pocket to perform an adequate examination, the pregnant woman was asked to push the fetus to the opposite side by gently pressing on her abdomen. RESULTS: Face, limbs, and fingers which are difficult to visualize on conventional ultrasonography could be seen clearly. Extremely satisfactory images were obtained at between 24 and 34 weeks of gestation that produced sonographic pictures easily recognized even by laypersons. Beyond 34 weeks of gestation due to the relative decrease in the size of amniotic fluid pockets, and before 24 weeks of gestation due to frequent fetal movement, the soft tissue of fetuses is thin and its acoustic impedance is virtually the same as that of water, so surface-rendered images are less satisfactory. In addition, the anterior wall placenta, multiple pregnancies, and oligohydramnios made viewing even more difficult. CONCLUSION: Between 24 and 34 weeks of gestation, 3D ultrasound is a feasible and useful procedure for routine antenatal examination. PMID- 11601188 TI - Cryogen spray cooling in conjunction with pulse dye laser treatment of port wine stains of the head and neck. AB - BACKGROUND: When a cryogen spurt is applied to the skin surface for an appropriately short period of time, the spatial distribution of cooling remains localized in the normal overlying epidermis, while leaving the temperature of deeper port wine stain (PWS) blood vessels unchanged. Furthermore, cooling continues after pulsed laser exposure as cryogen remaining on the surface evaporates and removes heat deposited by light absorption in epidermal melanin. The objective of this study was to evaluate the efficacy and advantages of cryogen spray cooling plus flashlamp-pumping in conjunction with dye laser treatment (CSC-LT) of PWS. METHODS: From 1996 to 2000, a retrospective study was conducted on 63 patients, consisting of 43 women and 20 men, between the ages of 8 and 62 years treated with pulsed dye laser (lambda = 585 nm, tau p = 450 microseconds) over a 4-year period. The duration of cryogen spurts and the delay period between cryogen delivery and laser illumination were controlled. An infrared focal plane array thermodetector measured changes of lesion surface temperature which were recorded. The subject was asked to score discomfort during treatment using a pain scale. The primary efficacy measure was the quantitative assessment of a blanching response score. RESULTS: The ambient skin surface temperature of PWS was 33.31 +/- 1.55 degrees C. The mean pain score for uncooled sites was 39.85 +/- 0.23 compared to 20.18 +/- 0.15 for cooled sites. There was a statistically significant difference in pain elimination between cooled and uncooled sites (p = 0.001). The mean blanching response score of CSC-LT was 3.70. A significant blanching response of PWS when receiving CSC-LT was noted. CONCLUSION: Our clinical studies demonstrate the feasibility of selective epidermal cooling while achieving photothermolysis of blood vessels during pulsed dye laser treatment of PWS. PMID- 11601191 TI - The health status of rural and urban ambulatory elderly in Taipei County. AB - BACKGROUND: To study the differences in the health status of rural and urban ambulatory elderly in Taipei County. METHOD: Non-compulsory general health check up for elderly people over 65 years old in rural and urban areas. The content of the health examination included past medical history, health behavior, physical examination, laboratory examination, electrocardiogram and x-ray. Chi square test, t-test and logistic regression were applied for analysis. Risk factors relating to the cardiovascular system were included in the study. Gender differences affecting the prevalence of diseases and health behavior were also considered in the analysis. RESULTS: Significantly higher proportions of the rural elderly men smoked, drank alcohol, and had hypertension and impaired renal function. On the other hand, higher proportions of rural elderly women were obese and had diabetes, hypertension and renal impairment. The mean plasma glucose level of newly-diagnosed diabetic patients in the rural area was significantly higher than that in the urban area (p < 0.05). Diabetes, obesity, hypercholesterolemia and smoking were significantly associated with hypertension. The odds ratio for hypertension between rural and urban areas was 1.45 (p < 0.0001). The cardiovascular risk-rating score of rural elderly was statistically higher than that of urban elderly (p < 0.001). CONCLUSION: There were some minor differences in health status between urban and rural elderly. Health promotion should be varied according to the needs of various communities and various risk groups. Further studies should concentrate on prospective cohort research with well-defined determinants to evaluate whether cost-effective biopsychosocial intervention is necessary. PMID- 11601190 TI - Ocular ischemic syndrome. AB - BACKGROUND: The purpose of this study was to investigate the clinical features and management of ocular ischemic syndrome (OIS) and factors influencing its development. METHODS: Ten patients (12 eyes) with OIS underwent detailed medical and ocular histories, complete ophthalmic evaluation including fluorescein angiography, internal carotid artery evaluation by duplex ultrasonography, and management. The following outcome measures were considered: visual acuity, anterior segment neovascularization, lens status, retinal and choroidal changes, and carotid artery stenosis or occlusion. RESULTS: The mean age of the patients was 63 +/- 8 years. Presenting visual symptoms included gradual (82.5%) or sudden (17.5%) onset of vision loss. At initial visit, eyes with OIS had visual acuity less than or equal to counting fingers in 50%, iris neovascularization in 58%, and neovascular glaucoma in 42%. Initially associated systemic diseases in these patients included arterial hypertension (60%), diabetes mellitus (40%), coronary artery disease (20%), previous stroke (30%) and hemodialysis (10%). Complete occlusion or severe occlusion (70-99%) of the internal carotid artery was seen in 75% on the side of OIS. Panretinal photocoagulation did not prevent OIS from progressing but vitreous hemorrhage and rubeosis iris regressed. Carotid endarterectomy had some benefit in stabilizing or improving vision in patients with OIS. CONCLUSION: OIS has a poor visual prognosis. It is imperative that the clinician be aware of the signs and symptoms of carotid disease in order to facilitate prompt diagnosis and appropriate referral, because OIS may be the presenting sign of serious ischemic cerebrovascular and ischemic heart disease. PMID- 11601192 TI - Choroidal masses: a fourteen-year analysis. AB - BACKGROUND: Choroidal masses present much diversification in clinical features and incidence. The purpose of this study is to investigate the epidemiological and clinicopathological manifestations of different choroidal tumors in order to tabulate appropriate diagnostic approaches. METHODS: A retrospective analysis of patients with choroidal masses was conducted, the analysis being based upon the review of our medical records from January 1986 to December 1999 inclusively. A definite diagnosis of choroidal mass was confirmed by at least two experienced ophthalmologists. For patients who were enrolled in this study, an ophthalmic examination was conducted and medical history was recorded. Some ancillary tests, such as indirect ophthalmoscopy, ultrasonography, fluorescein angiography, computed tomography, and magnetic resonance imaging, were used to support the accuracy of our diagnoses. RESULTS: A total of 149 patients were enrolled in this study, of which 103 cases were excluded due to a loss of follow-up or incomplete medical records. Forty-six patients (51 eyes) included 12 cases (26%) of malignant metastases, 10 cases (22%) of hemangiomas, 2 cases (4%) of osteomas, 5 cases (11%) of melanocytomas, 8 cases (17%) of melanomas, and 9 cases (20%) of other melanocytic lesions. The male to female ratio was 21:25. The average length of follow-up was 20.5 months, and the average age of these patients was 42.8 years. Presenting with varied clinical incidence and pictures, each category of choroidal mass was investigated thoroughly. CONCLUSION: With more clinical experience and a better understanding of choroidal masses, we are able to propose an early differential diagnosis and therapeutic approach to the effective management of them in order to minimize ocular morbidity and improve patients' survival and quality of life. PMID- 11601193 TI - Groove pancreatitis: case report and literature review. AB - Groove pancreatitis is a form of chronic pancreatitis affecting the groove between the head of the pancreas, the duodenum and the common bile duct. It was first described by Becker in 1973. Differentiation between groove pancreatitis and pancreatic head carcinoma is often difficult. Herein, we report a 24-year-old man with groove pancreatitis presenting with epigastralgia, jaundice, fever and vomiting. The diagnosis was confirmed by computed tomography of the abdomen, endoscopic retrograde cholangiopancreatography and surgical exploration. The operative procedures involved were pancreatic biopsy and choledochotomy with T tube drainage. The patient had an uneventful postoperative course. PMID- 11601194 TI - Pulmonary valvular stenosis complicated by cerebrovascular accident and congestive heart failure in a young child. AB - Pulmonary valvular stenosis (PS) with intact ventricular septum is a common congenital heart disease. In general, mild PS has a benign clinical course. However, in severe PS and some cases of moderate stenosis, increasing severity of the lesion may occur. The manifestations of either cerebrovascular accident (CVA) or congestive heart failure (CHF) are rarely reported in pediatric patients with PS. In this report, we describe a girl with severe PS complicated by seizures and sudden onset of hemiparesis at 13 months of age who developed CHF when 16 months old. CHF was cured after successful balloon valvuloplasty. She remained well without residual hemiparesis or recurrent seizures during the 1-year follow-up. Early balloon valvuloplasty should be emphasized in patients with severe PS, even if there are no significant clinical symptoms. With prompt balloon valvuloplasty, these complications can be effectively prevented. PMID- 11601195 TI - Neuroleptic malignant syndrome associated with long-term clozapine treatment: report of a case and results of a clozapine rechallenge. AB - Clozapine has recently been found to be associated with neuroleptic malignant syndrome (NMS) after long-term treatment. Here, I report on a 34-year-old Taiwanese woman who had been diagnosed with schizophrenic disorder 17 years previously. She had received clozapine 250 mg/day monotherapy for 7 years. She had sudden onset of NMS signs with high fever, profuse diaphoresis, severe muscular rigidity, elevated creatine phosphokinase level and consciousness disturbance. Brain computed tomography, blood culture and cerebral spinal fluid studies were negative. She had no muscle rigidity and fever after treatment with normal saline 1500 ml/day and diazepam 30 mg/day for 8 days. On day 15, a rechallenge with clozapine was done with caution because the patient was experiencing auditory hallucinations and delusions of persecution. The dose was slowly increased to 250 mg/day over 18 days. She had no active psychotic symptoms or NMS again in the following year. I reported this case to remind readers of the possibility of induced NMS with long-term use of clozapine and successful clozapine rechallenge. PMID- 11601196 TI - Minilaparotomy for internal drainage of a symptomatic lymphocele after renal transplantation. AB - Development of a lymphocele after renal transplantation is a well-described complication that occurs with relative frequency. Management options include simple aspiration with sclerotherapy and operative marsupialization of the lymphoceles into the peritoneal cavity. Laparoscopic internal drainage has been favored in recent reports. Still, the laparoscopic procedure is associated with a number of potential problems, including difficulty in localizing lymphoceles if laparoscopic ultrasound is unavailable. In addition, lobulated lymphoceles are more difficult to completely dissect with laparoscopy, and lymphoceles always occur on the anterior and medial aspects of the graft which are easily approached directly from the anterior skin. We tried to resolve these complications by modifying traditional laparotomy and proved that laparoscopy is a progressive, popular procedure, and that fenestration with finger dissection of the lobulated lymphoceles through minilaparotomy is still a reliable, effective procedure. PMID- 11601197 TI - A rapid and successful treatment for airbag-related traumatic macular hole. AB - A 28-year-old female was diagnosed as having an airbag-related traumatic macular hole in the right eye 9 days subsequent to a traffic accident. Four weeks after the trauma, the patient's visual acuity was deteriorating to 20/600. Following vitrectomy, membrane peeling, use of autologous serum and intraocular gas tamponade, the hole healed within 12 days, more rapidly than the expected interval for the treatment of a traumatic macular hole. The visual acuities at the 3-month and 1-year follow-up examinations were 20/50, much better than the conventional surgical treatment of idiopathic macular hole and comparable to previous reports of the treatment of traumatic macular hole. Vitrectomy procedure has been proved to be effective for the treatment of traumatic macular hole. Vitrectomy combined with membrane peeling, autologous serum and intraocular gas tamponade can heal the traumatic macular hole more rapidly than the conventional treatment with vitrectomy only. PMID- 11601198 TI - [Advances in the study of acute lymphocytic leukemia treated by large dosage of methotrexate]. PMID- 11601199 TI - [Study of TEL-AML1 fusion gene in childhood B-lineage acute lymphoblastic leukemia]. AB - OBJECTIVE: To determine the incidence of TEL-AML1 fusion gene and its role in clinical diagnosis and prognosis of childhood B-lineage acute lymphoblastic leukemia (B-ALL), and to compare the two techniques: nested RT-PCR and dual-color fluorescence in situ hybridization (FISH). METHODS: Nested RT-PCR and dual-color FISH techniques were used to detect TEL-AML1 fusion gene. RESULTS AND CONCLUSION: TEL-AML1 fusion transcript was found in 22.5%(9/40) of patients with B-ALL by RT PCR. The prognosis of these TEL-AML1 positive patients was relatively good and the complete remission rate was 100%. Both RT-PCR and FISH techniques were proved to be useful for detecting TEL-AML1 fusion gene and suitable for clinical diagnosis and prognosis evaluation. PMID- 11601200 TI - [Refractory anemia and preleukemia: an analysis of 92 cases]. AB - OBJECTIVE: To investigate the relationship between MDS-RA (refractory anemia subtype of myelodysplastic syndromes) and preleukemia (PL). METHODS: Hematological parameters of 86 RA and 6 PL patients were retrospectively analyzed. RESULTS: Thirty-four RA cases (39.53%) transformed into acute leukemia (AL), RA with excess blasts (RAEB), or RAEB in transformation (RAEB-t). As compared with 52 non-transformed RA cases, the transformed cases showed the following hematological features: 1. higher frequencies of immature granulocytes (P < 0.005), erythroblasts (P < 0.05) and megaloerythrocytes (P < 0.05), and higher granulocyte nuclear lobulation (P < 0.001) in peripheral blood; 2. higher percentages of early erythroid and granulocytic lineages (P < 0.05), and higher frequencies of erythroblasts with multiple nuclei (P < 0.05), pseudo Pelger-Huet abnormality (P < 0.05), and micromegakaryocytes (P < 0.005) in bone marrow. CONCLUSION: There is a higher overlap between RA and PL; the above hematological features may be useful for predicting the transformation of RA patients. Based on those findings, a score system for predicting the transformation of RA was proposed. PMID- 11601201 TI - [WT1 gene expression in leukemia patients and its correlation with prognosis and multidrug resistance]. AB - OBJECTIVE: To evaluate the value of expression of WT1 gene in predicting the prognosis of leukemia patients, and explore the relationship between WT1 gene expression and multidrug resistance and cell apoptosis. METHODS: Expressions of WT1, MRP and mdr1 were measured in 68 leukemia patients by RT-PCR method. Expression of bcl-2 was measured in 32 AML patients by immunofluorescence flow cytometry. RESULTS: Expression of WT1 was revealed in 36 of 68 leukemia patients and none of 23 normal controls. Complete remission rate (59.46%) was lower in WT1 positive patients than that (87.10%, P = 0.011) in WT1 negative patients. The rate of MRP expression was also higher in patients with WT1 expression (58.33%), than in those without WT1 expression (32.26%, P = 0.033). Thirty-two AML patients were divided into high-, intermediate-, and low-risk groups according to the expression of WT1 and bcl-2. CR rates were significantly different among these 3 groups (33.33% for high-, 47.37% for intermediate-, and 100% for low-risk group, P < 0.05). CONCLUSION: The expression of WT1 can predict the treatment outcome and the prognosis for leukemia patients. Expression of WT1 is the most important risk factor, and the coexpression of WT1 and bcl-2 predicts poor prognosis of AML patients. PMID- 11601202 TI - [Clinical and experimental study of 9 cases of adult T cell leukemia]. AB - OBJECTIVE: In order to clarify the clinical and laboratory features of adult T cell leukemia (ATL): morphology, immunology, cytogenetics, serology and molecular biology. METHODS: Indirect immunofluorescence assay and ELISA were used to detect serum HTLV-I antibody. The HTLV-I provirus sequence were amplified by PCR and confirmed by liquid hybridization. RESULTS AND CONCLUSION: Nine cases of ATL were diagnosed. The major clinical manifestation was lymph node enlargement found in all patients. Skin involvement and osteolysis were not frequent. The characteristic finding was leukemic cells with highly indented or lobulated flower-like nuclei in peripheral blood and bone marrow. ATL cells were CD2, CD3, CD4, CD25 positive and CD8 negative. No specific chromosome abnormality or HLA type was found. Seven of 8 patients examined had HTLV-I antibody. The HTLV-I provirus genome sequence integrated into host cell DNA was amplified by PCR and confirmed by liquid hybridization. All of these results showed that HTLV-I was also the etiological agent of ATL in China. One of the 9 cases of ATL was classified as lymphoma type, one as chronic-type, and the rest as acute type. PMID- 11601203 TI - [Study on the expression of myeloid markers and CD34 antigen in adult acute lymphoblastic leukemia]. AB - OBJECTIVE: To analyse the expression of myeloid markers and CD34 antigen on lymphoblasts in adult ALL and its relationship with prognosis. METHOD: Immunophenotypes were examined using indirect immunofluorescence method in 102 de novo ALL. RESULTS: The incidence of myeloid antigen expression in adult ALL was 21.6% and the commonest one was CD33 (15.7%). There was a higher incidence of myeloid antigens expression in ALL-L2 than in ALL-L1 (25.6% vs 5.3%, P = 0.05). CD34 was expressed in lymphoblasts from 30 of 56 patients (53.6%). Incidence of CD34 expression in B-ALL was higher than that in T-ALL (61.7% vs 11.1%, P < 0.01). No relationship between CD34, myeloid antigens and cell maturity was found within B-ALL. There was no relation between expression of myeloid antigens and CD34. The CR rate in My(+)-ALL was lower than that in My(-)-ALL (52.6% vs 80.0%, P < 0.025), and was no relation with CD34 expression. In addition, Ph chromosome and/or bcr/abl fusion gene was positive in 35.9% of the patients, and CR rate of Ph positive patients was higher than that in Ph negative patients. CONCLUSION: Expression of myeloid antigens was related to FAB subtype and cell maturity in adult ALL. There was no relationship between myeloid antigen expression and CR rate. A higher incidence of CD34 expression was found in Pro-B-ALL than in common ALL and Pre-B-ALL. Expression of CD34 had no relation with CR rate. PMID- 11601204 TI - [Clinical significance of human calcitonin and gene-related peptide in the serum of myelodysplastic syndromes patients]. AB - OBJECTIVE: To find out indications for predicting MDS transforming into AML. METHODS: Serum levels of human calcitonin (hCT) and calcitonin gene-related peptide (CGRP) were measured in 45 patients with myelodysplastic syndromes (MDS), 40 with acute myeloid leukemia (AML) and 50 controls by radioimmunoassay (RIA). Some patients in RA or RAEB stages were followed up to study changes in serum hCT and CGRP levels during clinical evolution. RESULTS: hCT and CGRP were of high level in the sera of patients with MDS and de novo AML, which were significantly different from those of the controls (P < 0.01), and were higher in RAEB group than in RA group. hCT and CGRP levels increased gradually as RA was evoling into RAEB or RAEB was evolving into AML. CONCLUSION: The serum levels of hCT and CGRP can be used as indices for the early prediction of MDS evolving into AML. PMID- 11601205 TI - [Study on electrochemical behavior of HL-60 cells during the etoposide-inducing apoptosis]. AB - OBJECTIVE: To study the electrochemical behavior of apoptotic HL-60 cells induced with etoposide. METHODS: Electrochemical cytosensor was used to monitor HL-60 cells treated with etoposide. RESULTS: The peak current and electron transfer rate decreased as etoposide dosage increased. The decrease appeared at 2 micrograms/ml etoposide treatment and was remarkable at 20 micrograms/ml, which occurred before the typical changes of cell morphology and DNA contents for apoptosis. FCM-DNA analysis showed that the apoptotic cells were of 10.5%-20% while the peak current decreased from 1.8 microA to 0.4 microA after 2.3 and 4 hours treatment with 200 micrograms/ml etoposide, and the peak current after 4 hours treatment was 5 times lower than that before induction. CONCLUSION: The changes of electrochemical behavior during the early stage of apoptosis occurred earlier and could be accumulated. PMID- 11601207 TI - [Immunophenotype and P-glycoprotein expression in CD7 positive adult acute myeloid leukemia]. AB - OBJECTIVE: To study the immunophenotype and P-glycoprotein expression in CD7 positive adult acute myeloid leukemia (CD7+ AML). METHODS: Morphology, P glycoprotein, cytogenetics and immunophenotype were examined in 30 previously untreated CD7+ AML patients. RESULTS: The CD7 positive rate was 11.4% in 262 AML patients. CD7+ AML patients had a significantly higher incidence of peripheral leukocytosis and blasts and FAB M1 subtype and were associated with CD34 and P glycoprotein expression. 42.3% of CD7+ AML achieved complete remission with a median remission duration of 4 months, and a median time to CR of 48 days. CONCLUSION: Patients with CD7+ AML are usually CD34 and P-glycoprotein positive. These patients had a lower CR rate and a shorter remission duration. PMID- 11601206 TI - [Study of the role of cyclin-dependent kinases (CDKs) in retinoic acid (RA) inducing HL-60 cell differentiation]. AB - OBJECTIVE: To investigate the role of CDKs in the RA inducing HL-60 cell differentiation. METHODS: The effects of all-trans retinoic acid (ATRA) and arotinoid ethylester(AE) at the dosage of 5 x 10(-6) mol/L on the proliferation and differentiation of HL-60 cells were examined by NBT reduction test and cytometry analysis. Meanwhile, histone H1 kinase assay was used to observe the changes of CDK2 activities in HL-60 cells treatment with ATRA and AE. The amounts of both cyclin E/CDK2 and cyclin D1/CDK4 complexes were observed with immunoprecipitates. RESULTS: Both ATRA and AE inhibited the growth of HL-60 cells, arrested cells in G1/G0 phase, and induced cells to differentiation. The activities of cyclin E/CDK2 and the amounts of cyclin D1/CDK4 complexes were decreased in ATRA- or AE-treated HL-60 cells. CONCLUSION: The effects of RA on the proliferation and differentiation of HL-60 cells may be associated with significant decreases in the activities of CDKs. PMID- 11601208 TI - [Experimental study of cord blood plasma enhancing the anti-leukemia effect of Ara-C]. AB - OBJECTIVE: To study the in vitro effect of cord blood plasma(CBP) on the sensitivity of acute myeloid leukemia(AML) cells to cytosine arabinoside (Ara-C). METHODS: Cytotoxicity of Ara-C was detected by MTT assay in twenty-eight patients. RESULTS AND CONCLUSION: The sensitivity of AML cells to Ara-C was heterogeneous, but CBP could significantly enhanced the cytotoxic activity of Ara C to drug resistant AML cells. PMID- 11601209 TI - [Serum levels of soluble intercellular adhesion molecule 1 in malignant lymphoproliferative disorders]. AB - OBJECTIVE: To investigate the correlation of serum levels of soluble intercellular adhesion molecule 1 (sICAM-1) with clinical situation and treatment outcome in lymphoproliferative disorders. METHODS: Serum sICAM-1 levels were measured by immunoenzymatic assay. RESULTS: Pre-treatment serum sICAM-1 levels were above normal in 41% (9/22) of multiple myeloma (MM), 53% (17/32) of non Hodgkin's lymphoma (NHL) and 63% (12/19) of acute lymphocytic leukemia (ALL) patients. Serum sICAM-1 levels in MM were positively correlated with Bataille stages, but were not related to Durie stage. Meanwhile, sICAM-1 levels in NHL were associated with the category of pathology, Ann Arbor stage and B symptom, but were not related to serum LDH levels. sICAM-1 levels were significantly higher in ALL patients complicated with central nervous system leukemia (CNSL) than in those without CNSL. Patients with elevated serum sICAM-1 levels had poorer treatment outcomes. Serum sICAM-1 levels were returned to normal at remission. CONCLUSION: Measurement of serum sICAM-1 levels in lymphoproliferative disorders patients is helpful for judging the clinical status and treatment outcome. PMID- 11601210 TI - [Function of B7/CD28 in anti-myeloma immunoreaction through activating T cells]. AB - OBJECTIVE: To explore the role of B7/CD28 molecule in priming the anti-myeloma effect of T lymphocyte and the mechanism by which CD28 promoted the immunogenicity of myeloma cells. METHODS: Human B7-1 gene was transducted into XG s cells. CD28 agonist monoclonal antibody was primed. Primary allogeneic MLR, immunophenotypic analysis and quantitative measurement of IL-2 were performed. RESULTS: XG cells were successfully transfected with B7-1 cDNA. The expressions of CD54, CD58, CD11a/CD18, CD40, CD40L, CD56, B7-2(CD86), HLA-I and HLA-II molecules were not affected by the transfection. The transduction of B7 gene dramatically increased the immunogenicity of tumor cells. In allo-MLR, the B7-1 expressing XG cell could more effectively mediate the activation, proliferation and IL-2 secretion of alloantigenic CD8+ T cells than XG cells did. Like B7-1 molecules, anti-CD28 agonistic McAb could induce the MLR of allo-T cell. CONCLUSION: Human multiple myeloma cells failed to induce antitumor immunoreaction because of the weak expression of B7 molecules. The transfection of B7-1 or CD28 agonist antibody could stimulate and proliferate T lymphocytes and increase the immunogenicity of myeloma cells. CD28 agonist antibody might be promising for clinical application. PMID- 11601212 TI - [Transfection of Fas(CD95) gene into HL-60 cell and its role in rhG-CSF-induced apoptosis]. AB - OBJECTIVE: To explore the role of Fas gene in rhG-CSF-induced apoptosis. METHODS: Mediated by lipofection (DOTAP), Fas cDNA was transferred into HL-60 cells. In situ hybridization, Western blotting and FCM analysis were used to demonstrate the successful transfection. The apoptosis percentages of HL-60 and Fas transfected HL-60 cells were compared after coculturing with rhG-CSF at the same final concentration. RESULTS: After cocultured with rhG-CSF (10 ng/ml) for 96 hours, the apoptosis percentage of Fas transferred HL-60 cells was significantly higher than that of HL-60 cells, and the Fas expressions could be up-regulated by rhG-CSF. CONCLUSIONS: Fas is an apoptosis-induction oncogene, and rhG-CSF induces apoptosis of HL-60 cells through Fas signalling pathway. PMID- 11601211 TI - [A clinicopathological study of nodular lymphocyte predominance Hodgkin's disease]. AB - OBJECTIVE: To investigate the clinicopathological characteristics of nodular lymphocyte predominance Hodgkin's disease. METHODS: Eleven samples of paraffin embedded lymph node and one of frozen lymph node from nodular lymphocyte predominance Hodgkin's disease patients were studied. HE staining, immunohistochemistry for CD3, CD19, CD20, CD30, CD45RB, kappa and lambda light chain and single L&H cell polymerase chain reaction (PCR) were performed. RESULTS: The diagnosis of nodular lymphocyte predominance Hodgkin's disease was established by the identification of characteristic L&H cells in the nodular small lymphocytes and histiocytes background. L&H cells expressed CD19(10/12), CD20(12/12), CD45RB(12/12) and kappa light chain (11/12). IgH and V kappa 4 family gene rearrangements were detected in the single L&H cell. Eight of the patients survived more than 5 years. CONCLUSION: Nodular lymphocyte predominance Hodgkin's disease has a very slow disease course and a better prognosis. It is a malignant lymphoma derived from B cells. PMID- 11601213 TI - [Estimation and clinical significance of serum soluble tumor necrosis factor receptors in patients with acute leukemia]. AB - OBJECTIVE: To explore the levels of serum soluble tumor necrosis factor receptors (sTNFRs) and the relationships with clinical situation, chemotherapeutic effects and TNF alpha level in acute leukemia (AL) patients. METHODS: Serum levels of sTNFRs and TNF alpha were measured by ELISA. Six parameters which might influence therapeutic effects were analyzed by logistic regression. RESULTS: 1. Serum levels of sTNFR I and sTNFR II in 31 untreated AL patients were significantly higher than those in controls(P < 0.001 and < 0.005, respectively) and in bone marrow remission (BMR) AL patients (P < 0.005 and < 0.05, respectively). The levels of sTNFR I and sTNFR II in 11 relapsed/refractory AL patients were significantly higher than those in controls(P < 0.001 and < 0.05, respectively), but were not different from those in untreated AL patients. 2. Serum levels of sTNFR I in untreated ALL patients were significantly higher than those in ANLL patients (P < 0.05). 3. High levels of serum sTNFR I were more common in patients with high leukocyte count(> or = 100 x 10(9)/L) and high levels of serum sTNFR II were more common in patients with splenomegaly. Levels of the two sTNFRs positively correlated with blasts in peripheral blood (P < 0.001 and < 0.05, respectively). 4. The level of TNF alpha in 31 untreated AL patients significantly correlated with the level of sTNFR I (r = 0.440, P < 0.05). 5. The BMR rate was higher in those serum sTNFR I level < 2.0 micrograms/L than in those > or = 2.0 micrograms/L(P < 0.05). 6. Of the six parameters which might influence AL therapeutic effects, only sTNFR I < 2.0 micrograms/L was predictive. CONCLUSION: High levels of serum sTNFRs in AL patients might be derived from leukemic cells and predicted an adverse prognosis. PMID- 11601214 TI - [Expressions of cellular M-CSF and M-CSFR in hematopoietic cells]. AB - OBJECTIVE: To study the distribution of cellular M-CSF and its receptor in abnormal hematopoiesis. METHODS: Six hematopoietic cell lines, 144 bone marrow (BM) and 160 peripheral blood (PB) samples were investigated with ABC immunoperoxidase assay. RESULTS: Cellular M-CSF and/or M-CSFR were positive in all the 6 hematopoietic cell lines, a few normal BM(4 cases) and PB (32 cases) samples, hematological malignancies and a few benign hematological disorder samples. M-CSF and M-CSFR were found mainly in granulocytic lineage cells, seldom in erythroid and megakaryocytic lineage cells and never in lymphocytes. M-CSF and M-CSFR usually presented in cytoplasma and membrane and in some cases in nuclei. CONCLUSION: Cellular M-CSF and M-CSFR is widely distributed in abnormal hematopoiesis, and is especially high in myeloid leukemias. PMID- 11601215 TI - [Leukocyte glucocorticoid receptor and its mRNA levels in leukemia patients]. AB - OBJECTIVE: To explore factors for differentiating non-Hodgkin's lymphoma cell leukemia (NHLCL) and acute lymphoblastic leukemia (ALL). METHODS: Leukocyte glucocorticoid receptor (GR) and GR mRNA levels were measured in 22 NHLCL, 18 ALL, 10 chronic lymphocytic leukemia (CLL) patients and 6 healthy subjects by using radio-ligand binding assay and molecular hybridization using GR cDNA as the probe. RESULTS AND CONCLUSIONS: The leukocyte GR and GR mRNA levels were significantly different between NHLCL and ALL(P < 0.01), and could be used as parameters for differential diagnosis of these two types of leukemia. PMID- 11601216 TI - [Identification of beta-FBG-455G/A polymorphisms in 210 samples of Guangdong population and the relationship with plasma fibrinogen level]. AB - OBJECTIVE: To analyze the frequency of beta-fibrinogen (beta-FBG) gene G/A-455 polymorphisms in Guangdong Chinese population and the relationship between genotype and plasma fibrinogen levels. METHODS: DNA of 210 samples were analyzed by using PCR-RFLP. Turbidimetric method for the levels of plasma fibrinogen was performed in 92 samples. RESULTS: The frequency of beta-FBG G/A-455 genotype A/A was 0.038; G/G was 0.514 and G/A was 0.448. The frequency of the A-allele was 0.262. The average plasma fibrinogen level in 46 samples of genotype G/A was (2.18 +/- 0.24) g/L and in 42 samples of G/G genotype was (2.03 +/- 0.25) g/L. There was significant difference between genotype and plasma fibrinogen (P < 0.01). CONCLUSION: The frequency of beta-FBG G/A-455 A-allele in Guangdong Chinese population is higher than that in European. The plasma fibrinogen level in G/A genotype is higher than that in G/G genotype. It suggested that the beta FBG gene expression might be associated with the genotype. PMID- 11601217 TI - [Regulation of arsenic trioxide-inducing apoptosis]. AB - OBJECTIVE: To explore the relationship among intercellular -SH, caspase, retinoic acid (RA) and arsenic trioxide(As2O3)-induced apoptosis. METHODS: The in vitro effect of different thiols compounds, RA and caspase inhibitors on As2O3-induced apoptosis in NB4 and HL-60 cells was studied. RESULTS: 1. NAC completely blocked, BSO potentiated while MTG, BAL had no effect on As2O3-induced apoptosis. 2. Z VAD.fmk blocked while Y-VAD.fmk had no effect on As2O3-induced apoptosis. 3. RA and As2O3 showed synergism in HL-60 cells, while showed antagonism in NB4 cell. CONCLUSIONS: 1. As2O3 binds with intracellular -SH, changes signal transduction, selectively activates caspase and causes apoptosis. 2. The regulating effect of RA on As2O3-induced apoptosis depends on cell types. PMID- 11601218 TI - [Cellular origin of multiple myeloma]. PMID- 11601219 TI - [Signal transduction mechanism of induced proliferation and differentiation of K562 cells]. PMID- 11601220 TI - [To promote the collaboration in clinical study of aplastic anemia]. PMID- 11601222 TI - [Study on the effect of ligustrazine on adherent molecule expression of bone marrow cells in immune-mediated aplastic anemia mice]. AB - OBJECTIVE: To explore the effect of ligustrazine on the expression of adherent molecule of bone marrow cells in immune-mediated aplastic anemia(AA) mice. METHODS: Each immune-mediated AA mouse was intraperitoneally injected with 5 mg ligustrazine twice a day. On the 14th day, expressions of CD49d and CD49c in bone marrow mononuclear cells(MNC) were detected by flow cytometry, and VCAM-1 on stromal cells by immunohistochemistry SABC. RESULTS: Expressions of CD49d, CD49e and VCAM-1 were significantly lower in AA group than in normal group(t = 11.96, 17.18 and 7.09 respectively, P < 0.001), and were much higher in ligustrazine treated group than in non-treated group(t = 9.05, 14.61 and 6.91 respctively, P < 0.001). Expressions of CD49d and VCAM-1 were in the normal range in ligustrazine group. CONCLUSIONS: Ligustrazine can increase the expression of adherent molecule of bone marrow cells in immune-mediated AA mice, thus promote the growth of hematopoietic cells. PMID- 11601221 TI - [Antilymphocyte globulin combining with cyclosporine A in the treatment of severe aplastic anemia]. AB - OBJECTIVE: To explore more effective regimen for severe aplastic anemia (SAA). METHODS: A prospective, randomized clinical trial was conducted to determine whether the outcome of SAA patients treated with the combination of antilymphocyte globulin(ALG) and cyclosporine A(CsA) (intensive immunosuppressive therapy, IIST) was better than that with ALG alone (non-intensive immunosuppressive therapy, NIIST). RESULTS: The response rate of IIST group(83.7%) was significantly higher than that of NIIST group(57.6%), with a lower risk of early mortality and a shorter time to red cell transfusion independence. Furthermore, the recovery of bone marrow BFU-E and CFU-GM of the responding patients was more complete in IIST group than in NIIST group. CONCLUSIONS: The treatment outcome was better with IIST than with NIIST for SAA. PMID- 11601223 TI - [The value of 99mTc-sulfer colloid bone marrow scintigraphy in differential diagnosis of aplastic anemia]. AB - OBJECTIVE: To diagnose equivocal aplastic anemia(AA) patients by the combination of clinical data and bone marrow scintigraphy. METHODS: Bone marrow scintigraphy using 99mTc-sulfer colloid 370-550 MBq was analysed in 47 patients, including 28 cases of AA, 12 of myelodysplastic syndromes(10 MDS-RA and 2 MDS-RAEB) and 7 of AA-PNH syndrome. RESULTS: Pancytopenia, hypercellular bone marrow associated with uneven disappearance of marrow image or focal hematopoiesis were found in 28 AA and 2 of 30 MDS-RA cases. Marrow imaging showed uneven low accumulation of radioactivity in 12 and focal patterns in 18 patients. Normal or high activity and expanded periphery of bone marrow was found in MDS patients (8 RA and 2 RAEB cases). Changes of activity and distribution of bone marrow during the transforming course were noticed in 4 AA-PNH syndrome patients. CONCLUSIONS: Patch distribution and focal hemopoiesis is the outstanding features of AA marrow. The imaging features as well as expanded manner and increased activity of bone marrow are helpful to the differential diagnosis, evaluation of clinical status and explanation of marrow aspirate results. PMID- 11601224 TI - [Remnant abnormal clonal hematopoiesis in patients with paroxysmal nocturnal hemoglobinuria of clinical remission]. AB - OBJECTIVE: To observe the abnormal clonal hematopoiesis status in patients with paroxysmal nocturnal hemoglobinuria(PNH) attained complete clinical remission(CCR). METHODS: Immunofluorescence labeling and flow cytometry were used to detect the expression of CD59 in bone marrow mononuclear cells and peripheral red blood cell and the number of bone marrow CD34+ hematopoietic stem/progenitor cells. RESULTS: In two patients in CCR, the coexistence of normal and abnormal hematopoiesis could still be found. However, the percentage of normal cells with CD59+ phenotype in peripheral red blood cells, bone marrow mononuclear cells and CD34+ hematopoietic stem/progenitor cells were significantly higher as compared with those in patients without remission, indicating that the normal hematopoiesis gradually regained dominance over the abnormal one when the disease approached remission. CONCLUSIONS: In PNH patients in CCR, remnant abnormal (CD59 ) cells could still be found in peripheral blood and bone marrow. It seems not necessary to climinate thoroughly all abnormal clones to achieve CCR in patients with PNH, and the dominance of abnormal hematopoicsis could vanish under some presently unknown mechanism. PMID- 11601225 TI - [CD59-blocked erythrocytes and hemolysis tests of paroxysmal nocturnal hemoglobinuria]. AB - OBJECTIVE: To investigate the relationship between CD59 and traditional hemolysis tests for paroxysmal nocturnal hemoglobinuria. METHODS: To make different concentrations of CD59-blocked erythrocytes by mixing with normal erythrocytes, and investigate the relationship between quantitative abnormalities of CD59 and hemolysis tests. RESULTS: The hemolysis rate was positively related to the percentage of CD59-blocked erythrocytes. The greatest hemolysis of CD59-blocked erythrocytes was found in the CoF-initiated hemolysis test when the CD59-defects less than 16%, and the greater in Ham's test. When the CD59 defects were more than 16%, CD59-blocked erythrocytes hemolyzed to a greater extent in Ham's test than in the others. CONCLUSIONS: Quantitative differences of CD59 underlies the variability in hemolysis tests, and the CoF-initiated hemolysis test is the most sensitive in detection of small CD59-defects. PMID- 11601226 TI - [Detection of three common G6PD gene point mutations in Guangdong province by using ARMS]. AB - OBJECTIVE: To detect three common G6PD gene point mutations, G1388A, G1376T and A95G, in Guangdong province and to estimate the approximate frequencies. METHODS: Using the amplification refractory mutation system(ARMS) method to detect G1388A and G1376T and the newly developed ARMS to identify A95G mutation. RESULTS: Ninety cases of G6PD deficient male were examined, and 42 of them were identified to be G1388A(46.7%), 14 G1376T(15.6%), and 12 A95G(13.3%). Totally 68 out of the 90 cases(75.6%) were of the three common mutations. The rest belong to rare or undefined mutations. CONCLUSION: ARMS method can be used in detecting common mutations of G6PD gene with the benefits of simple, fast, economic, and accurate. PMID- 11601227 TI - [Identification of three common G6PD gene mutations in Yi minority in Yunnan province]. AB - OBJECTIVE: To identify three common G6PD gene mutations in Yi minority in Yunnan province. METHODS: G6PD gene mutation of 28 samples from G6PD deficient patients was detected by using amplification refractory mutation system(ARMS). Samples were collected from Yi minority in Yunnan province. RESULTS: In 28 cases, 22 were identified to be three known mutations, including 12 of 1388(G-->A), 9 of 1376(G- >T) and 1 of 95(A-->G). The remaining 6 cases were undefined. CONCLUSIONS: This is the first report of G6PD gene G1376T and A95G mutations in Yi minority. The three common mutations account for 78.6% of the 28 cases. PMID- 11601228 TI - [Studies on a G6PD polymorphic site, cDNA C1311T]. AB - OBJECTIVE: To use amplification refractory mutation system(ARMS) method to detect the G6PD cDNA C1311T mutation, estimate its frequency in a normal south Chinese population, and investigate whether IVS-11 C93T mutation is the cause of certain G6PD deficient cases. METHODS: DNA sequencing was used to confirm the C1311T and the IVS-11 C93T mutations. ARMS was set up to detect the C1311T and to estimate its frequency. RESULTS: Three cases of C1311T mutation were found in 40 G6PD deficient samples. The optimal condition for ARMS was established. Using this method, 19 cases of C1311T were detected in 103 normal men, and the frequency of this polymorphic mutation was estimated to be 18.4% in southern Chinese population. Four cases with G6PD deficiency were demonstrated to be C at the IVS 11 93 position. At the same time, a case of IVS-11 93 C-->T was found in a normal man. CONCLUSIONS: ARMS is a simple, time-saving, and reliable method for detecting known G6PD gene point mutation. The frequency of C1311T in a normal south Chinese population is 18.4%. IVS-11 C93T might be another polymorphic site of the G6PD gene, and it is not the cause of enzyme deficiency in certain G6PD deficient cases. PMID- 11601230 TI - [Analysis of prenatal diagnosis for 120 cases of beta-thalassemia]. AB - OBJECTIVE: To analyse the results of prenatal gene diagnosis of beta-thalassemia. METHODS: By using the reverse dot blot method with an allele specific oligonucleotide probe(ASO/DRB). RESULTS: In 120 cases of prenatal gene diagnosis, there are 30 of normal fetal; 63 of beta-thalassemia heterozygotes; 26 of beta thalassemia homozygotes or dual heterozygotes; one of no diagnosis because the beta mutated gene can not be detected in one side of the parent. CONCLUSIONS: Acording to the follow-up studies, the babies unconcordance with prenatal diagnosis have not been found, the accuracy rate being 100%. Amniotic fluid specimen of the middle stage of pregnancy is the best for detection. PMID- 11601229 TI - [Direct genotyping of an hereditary persistence of fetal hemoglobin deletion and rapid prenatal diagnosis of the fetus at-risk for compound heterozygote of this defect with beta-thalassemia in a Chinese family]. AB - OBJECTIVE: To investigate the relationship between genotype and phenotype of a deletional hereditary persistence of fetal hemoglobin(HPFH) found in a Chinese family and explore an approach to rapid prenatal diagnosis for compound heterozygote of HPFH defects with beta-thalassemia. METHODS: By using the PCR based method with three primers bridging a HPFH breakpoint and reverse dot blot (RDB) for detecting beta-thalassemia mutations, a Chinese family who had a propositus of six years old with intermediate thalassemia and requested prenatal diagnosis for the second pregnancy were screened. RESULTS: The propositus carried the HPFH deletion determinant inherited from her mother, and a codons 14-15 (+G) frameshift mutation causing beta-thalassemia from her father. Of six members in this family screened for this type of HPFH deletion, four were positive. Prenatal diagnosis of the fetus showed the same results as that of the propositus. An advice of termination of pregnancy was given and the result of prenatal diagnosis was confirmed in the DNA samples obtained after abortion. CONCLUSIONS: This is the first time to have performed prenatal diagnosis of Chinese family at-risk for compound heterozygotes for beta-thalassemia and HPFH in mainland China. The PCR assay for directly detecting the HPFH deletion is rapid and inexpensive and can be used as a routine in HPFH carrier screening and prenatal diagnosis. PMID- 11601231 TI - [Detection of alpha-thalassemia 1 gene among 142 beta-thalassemia gene carriers]. AB - OBJECTIVE: To investigate the coincidental rate of double heterozygous state of beta-thalassemia and alpha-thalassemia 1 in Guangdong area. METHODS: One handred and forty-two DNA samples with beta-thalassemia trait were amplified by polymerase chain reaction(PCR) to detect alpha-thalassemia 1 gene. The positive cases were further detected by mutant primer PCR or by reverse dot blot hybridization (ASO/RDB) to confirm their beta-thalassmia mutations. RESULTS: Thirteen cases (9.15%) were identified to combine with alpha-thalassemia 1 gene. The mutant loci of beta-globin gene in these cases were that 5 were in CD 41-42 ( TCTT), 3 in IVS-2-654(C-->T), 2 in CD 17 (A-->T) and 3 in CD 71-72 (+A), CD 43(G- >T) and -28 (A-->G), respectively. CONCLUSIONS: The occurrence of this dual heterozygotes among beta-thalassemia trait is relatively frequent and it should be paid much attention to in genetic counselling and prenatal diagnosis of thalassemia in this area. PMID- 11601232 TI - [Current status of the epidemiologic study of aplastic anemia]. PMID- 11601233 TI - [Current status of the study of pyruvate kinase deficiency]. PMID- 11601234 TI - [Mutation (Ala737-->Glu) in type 2A von Willebrand disease]. AB - OBJECTIVE: To identify mechanism of molecular pathogenesis and relationship between phenotype and genotype of von Willebrand disease (vWD). METHODS: Two patients from a family were studied. They were diagnosed as type 2A vWD showing prolonged bleeding time, markedly decreased vWF: Ag and FVIII: C Ag and absence of high and intermediate molecular weight form of von Willebrand factor multimers in plasma. The 28th exon of authenticity vWF gene was obtained by polymerase chain reaction and PAGE and then screened by denaturing gradient electrophoresis (DGGE). The abnormal bands were sequenced. RESULTS: A heterozygous C-->A transition was identified, resulting in an ala737glu mutation in the A2 domain of the mature vWF subunit. CONCLUSION: The new mutation will be a tool for the study of the structure and function of vWF. PMID- 11601235 TI - [Study of thrombopoietin and its receptor C-mpl in acute leukemia]. AB - OBJECTIVE: To study the expression of C-mpl gene in acute leukemia (AL) and its implication and investigate the effect of recombinant human thrombopoietin (rhTpo) on acute leukemic cells as well as its relation to C-mpl expression. METHODS: C-mpl expression was detected in 43 AL patients by using semi quantitative reverse transcription polymerase chain reaction and the effect of rhTpo on acute leukemia cells by MTT assay. RESULTS: C-mpl was expressed in 22 of 35 patients with acute myeloblastic leukemia (AML), but did not in 8 patients with ALL. The percentage of C-mpl expression (16/22, 72.7%) was significantly higher in CD34 positive AML patients than in CD34 negative group (4/12, 33.3%, P = 0.031), and was higher in patients with M2b, M3 and M4EO than in those with other AML subtypes (40.0% vs 80.0%, P = 0.019). The complete remission rate in C mpl positive AML patients was lower than that in negative patients (70.0% vs 81.8%, P = 0.394), although the difference was not significant. In 9 of 28 cases of AML, the in vitro treatment with rhTpo induced proliferation of leukemia cells. Among these 28 patients, leukemic cells from 8 of 17 (47.0%) patients expressing C-mpl responded to rhTpo, but only the cells from one of 11 (9.1%) non expressing patients did. The rhTpo induced proliferation of AML cells was enhanced when combined with IL-3, GM-CSF or SCF. CONCLUSIONS: C-mpl was expressed in some AML, but did not in ALL. Tpo could induce AML cells to proliferate and the effect was augmented when combined with other hematopoietic growth factors. PMID- 11601236 TI - [Study on the pathogenesis of acquired pure amegakaryocytic thrombocytopenic purpura]. AB - OBJECTIVE: To investigate the possible pathogenesis of acquired pure amegakaryocytic thrombocytopenic purpura(APATP). METHODS: Twenty eight patients with APATP were studied. Bone marrow mononuclear cells(MNCs) from these patients were plated into methyl cellulose cultures for CFU-GM, CFU-E and CFU-MK assay. The influence of depleting T cells or adherent cells from patients' marrow cells on CFU-MK growth was observed. The humoral inhibitory effect on CFU-MK was determined by co-incubation of patients' sera or IgG with normal or autologous MNCs prior to cultures. The serum MK-CSA was also assessed. RESULTS: Fifteen cases (53.6%) of APATP was resulted from intrinsic defect of CFU-MK. The megakaryocyte colony formation was augmented significantly in 3 T lymphocytes depleted and 2 mono-macrophages depleted patients. Sera from 6 patients(21.4%) were inhibitor to CFU-MK. The inhibitor originated from IgG and selectively directed against the megakaryocyte. In the remaining 2 cases, the pathogenesis was not ascertained. CONCLUSION: The intrinsic defect of megakaryocyte progenitor cell is considered to be a primary pathogenesis of APATP. In some patients the disease can result from abnormal immune mechanisms. The decompensation of MK-CSA production could also be an important cause for APATP. PMID- 11601237 TI - [Alterations of platelet membrane glycoproteins in patients with diabetes mellitus and their clinical significance]. AB - OBJECTIVE: To investigate changes of platelet glycoproteins in patients with diabetes mellitus(DM) type II and their clinical significance. METHODS: Seventy DM patients and 28 normal individuals entered in this study. The platelet glycoproteins Ib, IIb, IIIa and P-selectin were analyzed by flow cytometry (FCM). Platelet surface P-selectin was measured by Immunoradiometric analysis (IRMA), and plasma P-selectin concentration by ELISA. RESULTS: On FCM, the P-selectin expression on platelets of patients with vascular diseases [(10.28 +/- 4.86)%] was higher than that of normal subjects [(3.75 +/- 1.83)%] (P < 0.01) and patients without vascular diseases [(4.25 +/- 2.29)%] (P < 0.01). Similar results were obtained using IRMA. Plasma P-selectin concentration in patients with vascular diseases [(6.18 +/- 3.20) ng/ml] was higher than that of control group [(3.43 +/- 1.56) ng/ml](P < 0.05) and that of patients without vascular diseases [(3.71 +/- 2.12) ng/ml] (P < 0.05). On the contrary, the platelet surface GP Ib expression in patients with vascular diseases [(86.35 +/- 11.00)%] was remarkably lower than that of normal subjects [(92.63 +/- 7.55)%] (P < 0.05), while platelet GP IIb and IIIa were not changed in any cases. CONCLUSION: The P-selectin levels in plasma and on platelet surface were increased while platelet membrane GP Ib was decreased in DM type II patients with vascular events. PMID- 11601238 TI - [The effect of thrombin on tissue factor activity in cultured bovine aortic endothelial cells and its correlation with PKC pathway]. AB - OBJECTIVE: To study the stimulating effect of thrombin on the expression of tissue factor (TF) activity in cultured bovine aortic endothelial cells (BAEC) and to elucidate if it is associated with the PKC system. METHODS: The BAECs were cultured after the Schwartz's method and one stage clotting time assay was used to measure TF activity in BAEC lysates. The TF activity was identified by EDGR VIIa and a monoclonal antibody against TF. RESULTS: Thrombin enhanced the expression of TF activity in cultured BAEC and the effect was dose- (r = 0.78, P < 0.05, n = 8) and time-dependent (r = 0.88, P < 0.05, n = 8). PMA, a PKC activator, also induced the expression of TF activity in BAEC. H7, a protein kinase C inhibitor, inhibited the inductive effects of PMA and thrombin on TF in BAEC. CONCLUSION: Thrombin can induce the expression of TF activity in cultured BAEC and the effect depends on PKC pathway. PMID- 11601239 TI - [The relationship between the expression of transferrin receptors (TfR) on leukemia cells and the cell proliferation and iron metabolism status in childhood acute leukemias]. AB - OBJECTIVE: To explore the relationship between transferrin receptor (TfR) expression and cell proliferation capacity and iron metabolism status. METHODS: The binding site numbers and dissociation constant (Kd) of TfR of leukemic cells were assayed by radio-ligand binding assay. RESULTS AND CONCLUSION: The binding site numbers of TfR were (7.826 +/- 6.054) x 10(4) sites/cell in ALL group and (20.406 +/- 17.876) x 10(4) sites/cell in AML group, and the Kds of TfR were (6.468 +/- 4.777) nmol/L and (8.683 +/- 4.890) nmol/L, respectively. The binding sites of TfR were significantly less in complete remission group than in relapsed or dead groups. There was a positive relationship between the TfR binding sites and the 3H-TdR incorporation in the leukemic cells (AML and ALL) and in the phytohemagglutinin stimulated peripheral mononuclear cells. In both ALL and AML group, the SF, CF were higher and Tf, TIBC were lower than those in control group. TfR binding sites were positively correlated with SF and CF, and negatively with Tf. PMID- 11601240 TI - [Cytogenetic analysis and bcr/abl mRNA detection in chronic myeloid leukemia]. AB - OBJECTIVE: To define the relationship between Ph chromosome and BCR/ABL mRNA expression in chronic myeloid leukemia (CML) patients, and compare cytogenetic analysis and PCR method. METHODS: Marrow or peripheral blood samples from 33 CML patients were analyzed by R banding technique and PCR method. Eleven patients who received allogeneic BMT or alpha-IFN + low dose HU were followed up. RESULTS: In 33 patients, 29 were Ph(+), 30 expressed BCR/ABL mRNA. In 6 patients who received BMT, 4 were Ph(-), 2 were Ph(+). However, 2 patients were (-), 4 were (+) by PCR method. In 5 patients who received alpha-IFN, the percentage of Ph(+) cells reduced after 6 and 12 months treatment than before treatment in 2 cases respectively. In 41 samples, 34 cases were consistent by 2 methods. CONCLUSION: Each method, Cytogenetic analysis or PCR has its advantage and defect. The better method are integration of 2 methods in diagnosis and treatment monitoring of CML patients, so that provide real and beneficial information for clinic. PMID- 11601241 TI - [In vitro study on the transduction of mutant human dihydrofolate reductase cDNA into human umbilical cord blood CD34+ cells]. AB - OBJECTIVE: To explore whether human umbilical cord blood hematopoietic progenitor cells transduced with mutant dihydrofolate reductase(mDHFR) gene increase resistance to metrotrexate(MTX). METHODS: Cord blood CD34+ cells were enriched with a high-gradient magnetic cell sorting system(MACS), and then transfected with supernatant of retrovirus containing human mDHFR cDNA. Hematopoietic progenitor clonogenic assay was used to evaluate mDHFR-conferred resistance to MTX. RESULTS: The purity of cord blood CD34+ cells was approximately 90% and recovery rate was 71.1%. The transduced and mock-transduced CD34+ cells were cultured in mediums containing 20 nmol/L MTX for 14 days. The percentages of progenitor colonies of transduced and mock-transduced CD34+ cells were higher than that of non-transduced (P < 0.01), obviously. The resistance of the former to MTX is nearly twofold of the latter. CONCLUSION: Transduction of mDHFR gene could confer the resistance of human hematopoietic progenitor cells to MTX toxicity. PMID- 11601242 TI - [The effect of human cytomegalovirus on human marrow granulocyte/macrophage progenitor]. AB - OBJECTIVE: To investigate whether the suppression of CFU-GM is caused directly by human cytomegalovirus(HCMV). METHODS: The effect of HCMV AD 169 strain on CFU-GM growth was assayed in vitro and HCMV AD 169 DNA in CFU-GM was detected by in situ PCR(ISPCR). RESULTS: Significant inhibition of CFU-GM was observed when HCMV AD 169 containing fluid was diluted to 2 x 10(5) pfu/ml and 2 x 10(6) pfu/ml (P < 0.01). The suppression was in a dose-dependent fashion. HCMV AD 169-DNA was detected by ISPCR on the nuclear of CFU-GM. CONCLUSION: HCMV might cause suppression of CFU-GM growth by direct infection. PMID- 11601243 TI - [In vitro study on cellular and molecular mechanism of tripterine treating leukemic mast cells]. AB - OBJECTIVE: To explore the effect of tripterine on leukemic mast cells. METHODS: The human leukemic mast cell line (HMC-1) was used as target cells for the tripterine's effect. RESULTS: 1. Apoptosis of HMC-1 cells could be efficiently induced by tripterine (0.125-1.0 mumol/L), showing the apoptotic changes in morphology, DNA ladder on argarose gel electrophoresis and apoptotic peak before G1 phase of cell cycle on flowcytometry. 2. The magnitude of apoptosis increased with the augmentation of tripterine concentration and duration of exposure; 3. With G1 phase cells decreasing, S phase cells were increased, and then apoptotic cells increased with a diminution of S phase cells. They bored significant negative relation (P < 0.01); 4. Tripterine could upregulate Bax, c-myc expression and downregulate bcl-2 expression at protein level. CONCLUSION: Tripterine can efficiently induce HMC-1 cell apoptosis, occurring mainly in S phase, which is correlated with upregulating Bax, c-myc expression and downregulating bcl-2 expression. PMID- 11601244 TI - [Fibrinogen and thrombosis]. PMID- 11601245 TI - [Hereditary sideroblastic anemia: causative gene and gene therapy]. PMID- 11601246 TI - Five types of glycophorin variants found in southern China. AB - PURPOSE: To summarize the results of gene analysis for five types of glycophorin (GP) variants found in a screening survey conducted in several regions of Southern China. DATA SOURCES: Papers cited in Chinese biochemical and biomedical literatures with a bibliographic review of articles relevant to hematology and biochemistry. STUDY SELECTION: All GP variant reports of our research group published during 1991-1997 were included. DATA EXTRACTION: Data concerning 5 types of GP variants found in Southern China were briefly abstracted. GP variant frequencies with their phenotypes among 3 districts and those among Han, Li, Buyi and Yao ethnic groups were calculated. RESULTS: Five phenotypes of GP variants [Sta, Mi III, Mi V (J.L.), Mi VI and a novel case] were identified from 180 unrelated healthy individuals (Hunan, Hainan) and 222 residents of a tertian malaria hyperendemic area (Guizhou), using immunoblotting techniques, Southen hybridization and PCR-direct sequencing. CONCLUSIONS: These five types of GP variants were first reported in China. There were some differences in the geographical distribution of GP variants among Hunan, Hainan and Guizhou districts. Mi III GP was commonly found in national minorities of Li and Buyi, while the frequency of Sta GP occurrence was considerably higher in Han ethnic group. The frequency of GP variants in a malaria hyperendemic area of Guizhou Province does not depend upon the severity of tertian malaria morbidity. PMID- 11601247 TI - 40 years' review of intestinal atresia. AB - OBJECTIVE: To analyze the 40 years' experience of intestinal atresia and to introduce a new design of long-oblique anastomosis for disproportional loops of the intestine. METHODS: A total of 449 cases of congenital atresia of the small intestine were classified into three groups according to the embryopathology: high group (145 cases), including duodenal and high jejunal atresia; middle group (288), including ileo-jejunal atresia; and low group (16), including terminal ileal atresia. To analyze the survival rate and mode of treatment, we assigned the cases into 3 groups according to the year of admission: 1) 1956-1969 (173 cases), under the general pediatric surgical care; 2) 1970-1985 (147), under the specialty neonatal surgical care; and 3) 1986-1996 (129), with additional use of total parenteral nutrition. RESULTS: The ileojejunal atresia group (middle group) had the highest mortality rate (47.6%). The overall mortality rate decreased as the time went by, dropping from 64.7% in the early years down to 18.6% in the recent years, and no hospital death occurred in the recent couple of years. CONCLUSION: Besides the improvement of neonatal surgical techniques, selecting a proper surgical procedure according to the embryopathology is essential to the reduction of mortality. The long-oblique anastomosis is particularly acceptable in China at present for marked disproportional loops. PMID- 11601248 TI - Hyperhomocysteinemia and hyperlipidemia in coronary heart disease. AB - OBJECTIVE: To examine the relationship between coronary heart disease (CHD) and serum lipid, plasma homocysteine (HCY) as well as the factors related to HCY metabolisms. METHODS: The mutation of the 677C-->T transition of 5, 10 methylenetetrahydrofolate reductase (MTHFR) was determined by PCR-based assay. Whole-blood and plasma folate and plasma vitamin B12, as cofactors of MTHFR, were determined by radio-immunologic assay. Plasma HCY was determined by HPLC. RESULTS: Patients with CHD had elevated plasma HCY concentrations (17.38 +/- 1.94 mumol/L vs 10.25 +/- 1.57 mumol/L, P < 0.01). In patients with myocardial infarction (MI) and family history (FH) of CHD, plasma HCY were elevated even higher (P < 0.05). Plasma HCY concentrations had significant non-linear inverse correlation with plasma folate and B12 concentrations, i.e. the lower the serum folate or B12 concentrations, the higher the plasma HCY concentrations (P < 0.01). Patients with homozygous mutants had higher plasma HCY concentrations. Patients with CHD had increased serum Chol and LDL-C and Apo-B levels (P < 0.01, P < 0.05 and P < 0.05 respectively). But plasma HCY concentrations had no correlation with serum lipid levels. 24.1% of the patients had high lipid and high HCY level, 25.9% had high lipid level and normal HCY level, 20.4% had normal lipid and high HCY level, and 29.6% had normal lipid and HCY level. CONCLUSIONS: HCY may have strong association with the genesis of CHD. Low plasma folate and B12 concentrations may induce Hyperhomocysteinemia [HH(e)]. Plasma HCY concentrations have no correlation with serum lipid levels, so HCY may be an independent risk factor. CHD may be induced by different mechanisms and can be classified into hyperlipidemia, HH (e) and normolipidemia, and normohomocysteinemia. PMID- 11601249 TI - An analysis of factors influencing electrocardiogram stress test for detecting coronary heart disease. AB - OBJECTIVE: To evaluate factors influencing electrocardiogram (ECG) stress test. METHODS: The treadmill stress test and coronary angiogram (CAG) records were reviewed retrospectively in 435 consecutive patients with chest pain between 1991 and 1997. There were 44 cases with normal CAG but positive exercise stress test results (false-positive, Group A), and 33 cases with both negative CAG and negative exercise test (true-negative, Group B). The baseline ECG, echocardiogram, abnormal systolic blood pressure response and history of diabetes mellitus and hypertension in the two groups were compared. RESULTS: There was no significant difference between the two groups with respect to age, gender, and antianginal medication. More patients in Group A had hypertension (52.3% vs 27.3%, P < 0.05) and diabetes mellitus (15.9% vs 0%, P < 0.05). Left ventricular (LV) hypertrophy in baseline ECG and by echocardiogram was more often present in Group A (25.0% vs 3.0%, P < 0.05; 36.4% vs 12.1%, P < 0.05). There were no significant differences between the two groups with respect to maximal heart rate, maximal systolic blood pressure (BP), metabolic equivalents, postexercise systolic BP, termination for exercise test, baseline ECG with bundle branch block and ST depression. CONCLUSION: Our results suggest that LV hypertrophy and a history of hypertension or diabetes mellitus are the main factors influencing ECG stress test for detecting coronary heart disease. PMID- 11601250 TI - Relationship between remodeling and function of left ventricle and angiotensin II AT1 receptor expression after myocardial infarction in rats. AB - OBJECTIVE: To determine the relationship between remodeling and dysfunction of left ventricle (LV) and the expression of the angiotensin II AT1 receptor mRNA after myocardial infarction (MI) in rats. METHODS: Nine MI rats (Group A) and 8 sham-operated rats (Group B) were studied by both Doppler echocardiography and Dot blot using Digoxingenin-labelled cDNA probes. RESULTS: Compared with Group B, Group A showed the increase in LV internal diastolic diameter (0.87 +/- 0.06 mm vs 0.66 +/- 0.03 mm, respectively, P < 0.01) and volume (0.73 +/- 0.09 ml vs 0.51 +/- 0.05 ml, P < 0.01). In addition, thinning of anterior wall, thickening of posterior wall, increasing of peak early filling velocity (peak E), decreasing of late filling velocity (peak A) and increasing of the E/A were demonstrated in MI rats 7 weeks after MI. The levels of the cardiac angiotensin II AT1 receptor mRNA in Group A were higher than those of Group B (2.2-fold). CONCLUSIONS: Seven weeks after MI in rats, character of LV remodeling and dysfunction were developed and the expression of cardiac angiotensin II AT1 receptor mRNA was increased. PMID- 11601251 TI - The significance of anti-endothelial cell antibodies in patients with lupus nephritis and immunoblotting analysis of the target components. AB - OBJECTIVE: To investigate the prevalence of anti-endothelial cell antibodies and its possible role in the pathogenesis in lupus nephritis. METHODS: Sera from 58 patients with lupus nephritis were studied. Cellular enzyme linked immunoabsaborbent assay was used to detect anti-endothelial cell antibodies, and immunoblotting technique was performed to determine its specific endothelial target antigens. RESULTS: 36.2% of the patients with lupus nephritis had elevated IgG isotype anti-endothelial cell antibodies. The association was revealed between the presence of anti-endothelial cell antibodies (AECA) and some laboratory and renal biopsy features, such as thrombocytopenia, higher serum IgG level, lower serum C3 level, higher erythrocyte sedimentation rate (ESR), presence of anti-nuclear antibody (ANA), anti-dsDNA antibodies and glomerular thrombosis. Anti-endothelial cell antibodies were consisted of a group of heterogeneous antibodies, and reacted with different endothelial cell antigens which ranged from 12-90 kD in molecular size in immunoblot. A correlation was demonstrated between heavy proteinuria (> 3.5 g/24 hr) and the existence of antibodies against both 27 and 29 kD endothelial cell antigens, an association between the presence of glomerular capillary thrombi and antibody against the 29 kD endothelial cell antigen was also found. CONCLUSIONS: Lupus nephritis patients with anti-endothelial cell antibodies showed a complex autoimmune disorder and clinical disease activity, and the results also provided an indirect evidence that anti-endothelial cell antibodies might contribute to the pathogenesis of lupus nephritis. PMID- 11601252 TI - Is endothelin-1 an aggravating factor in the development of acute pancreatitis? AB - OBJECTIVE: We have reported previously that cerulein-induced edematous pancreatitis would transform into hemorrhagic pancreatitis by administration of endothelin-1 in rats. In the present study, we tried to protect rat model from developing into hemorrhagic pancreatitis with BQ123 (an ETA receptor antagonist). METHODS: The rat model was made by 5-hour restraint water-immersion stress and two intraperitoneal injections of cerulein (40 micrograms/kg) at hourly interval. BQ123 (3 or 6 mg/kg) was administered intravenously 30 minutes before and 2 hours after the first cerulein injection. RESULTS: Acute hemorrhagic pancreatitis was induced in all rats treated with cerulin + stress. The score for pancreatic hemorrhage was 2.4 +/- 0.2 in this group. In the rats pretreated with BQ123, the score was reduced to 1.0 +/- 0.0, pancreas wet weight and serum amylase activity were significantly reduced, and histologic alterations in the pancreas lightened, also the local pancreatic blood flow improved without affecting the systemic blood pressure. CONCLUSIONS: These results suggest that endothelin-1 should play a role in aggravating the development of acute hemorrhagic pancreatitis, through its action on the pancreatic microcirculation. PMID- 11601253 TI - Altered expression of bcl-2 mRNA and Bax in hippocampus with focal cerebral ischemia model in rats. AB - OBJECTIVE: Ischemia and reperfusion insults may induce anti-injury response in the sick brain cells, in which regulative genes involved in programmed cell death (PCD) may be activated at the same time. It is attempted to obtain more solid evidence to support the above hypothesis even though the mechanism and pathway of PCD in brain cells after cerebral ischemia has not been identified yet. METHODS: Focal ischemic model in rats and dot plot hybridization were used to make an observation on the level of bcl-2 mRNA and Bax mRNA expression in the hippocampus cells after a focal ischemic injury, compared to the controls in a pseudo operation. RESULTS: Bcl-2 mRNA was remarkably overexpressed in hippocampus area on the ischemic side after 2 hours' ischemia and then 24 hours' reperfusion, but the expression of Bax mRNA was increased without statistically significance. The findings suggested that there was an obvious increase of the expression of the bcl-2 mRNA in the vulnerable area of the brain after a focal ischemia. CONCLUSION: Bcl-2 may promote the survival of neuron but Bax may induce apoptosis of the cells in hippocampus area of this model. It is also suggested the biologic therapeutic studies, e.g., up-regulation of the expression of the bcl-2 mRNA or down-regulation of expression of the Bax mRNA should be further performed, which may induce the tolerance of the brain cells to the ischemic insult. PMID- 11601254 TI - Relationship between diabetes mellitus, impaired glucose tolerance and age, menopause, pregnancy: a survey of 5153 women in Shenzhen. AB - OBJECTIVE: To investigate the relationship between diabetes mellitus (DM) including impaired glucose tolerance (IGT) and the factors of age, menopause, and pregnancy. METHODS: A systemic epidemiological survey was conducted in 5153 women, aged 20 years and above. RESULTS: The prevalence of DM was 4.58%, and IGT 12.83%. In those subjects with DM less than 59 years old and those with IGT less than the age of 49, the prevalence was parallel to the increase of age. Ten years might lead the IGT subjects into DM. Moreover, the prevalence of DM and IGT after menopause were significantly high. It was found that the prevalence of DM and IGT in mothers who had conceived giant baby was significantly higher than that of the others. CONCLUSIONS: Therapeutic emphasis should be laid on the population of women in the age between 50 and 59, while the management of IGT women is equally important. The early intervention of IGT subjects in the age between 40 and 49 is essential in decreasing the prevalence of DM. Disorders of the endocrine system during climacteric might play an important role in the development of DM and IGT. Moreover, the mothers who have conceived giant babies are at great risk for DM, and thus, this population should be closely monitored. PMID- 11601255 TI - Very long survival in pediatric cancer between 1944 and 1993. AB - OBJECTIVE: To identify factors associated with very long survival among all cancer cases diagnosed at age 19 years or younger registered by the Cancer Data Service at the University of Kansas Medical Center in Kansas City, Kansas, U.S.A. in the 40-year period between 1944 and 1983, with follow-up to 1993. METHODS: There were 2720 pediatric patients with 2750 cancers who were studied. Forty-four types of cancer were grouped into 11 diagnostic categories. Diagnosis years spanned four eras: 1944-1953, 1954-1963, 1964-1973, and 1974-1983. Cases were compared using specific characteristics and were divided into short-term and long term survivors with the division generously set at seven years. The proportions of the long-term survivors were compared by specific characteristics. RESULTS: Among the diagnostic categories, leukemias were the most common (29.8%), followed by CNS tumors (15.2%), and Hodgkin's disease (9.0%). Male to female ratio was 4:3; average age at diagnosis was 8.83 +/- 6.08 years. Long-term survivors totaled 1148 (41.7%). Prognosis was better in cases diagnosed in earlier stages and in later eras. Proportion of long-term survivors increased from 18.7% in era I to 52.6% in era IV. Improvement of survival was statistically significant in most diagnostic categories. CONCLUSIONS: This study shows continuing improvement of survival during four consecutive eras for childhood and adolescent cancer. Early diagnosis was associated with better survival. Unstaged cases decreased over time reflecting progress in diagnostic techniques. Many patients died before seven years after diagnosis. Those who survived more than seven years had excellent survival. Pediatricians can expect to participate in the care of these patients long after the original dianosis and treatment. PMID- 11601256 TI - Application of recombinant human granulocyte colony stimulating factor in children with acute myeloid leukemia. AB - OBJECTIVE: To evaluate the effect of recombinant human granulocyte colony stimulating factor (rhG-CSF) on accelerating neutrophil recovery and decrease fatal infections for childhood acute myeloid leukemia (AML). METHODS: From November 1992 to March 1997, 45 patients were enrolled into our study and 15 were newly diagnosed. All were treated with high dose chemotherapy combined with rhG CSF. RESULTS: Of 15 newly diagnosed patients, 13 achieved complete remission (CR) after one course of therapy and 2 achieved CR after two courses of therapy. For newly diagnosed patients, the durations of absolute neutrophil counts (ANC) < 0.5 x 10(9)/L were 5 days and 10 days in rhG-CSF group and control group respectively (P < 0.05). The incidences of infection of these two groups were 40% and 60% respectively (P < 0.05). As for patients who received intensive therapy, the durations of ANC < 0.5 x 10(9)/L were 5 days and 8 days in rhG-CSF group and control group, respectively (P < 0.05), and the incidences of infection were 25% and 44.4% respectively (P < 0.05). CONCLUSIONS: The application of rhG-CSF in children with AML after chemotherapy may hasten the hematopoietic recovery. The duration of neutropenia was shortened by 3-4 days, and the incidence of fatal infection was reduced. rhG-CSF does not stimulate AML growth in vivo. PMID- 11601257 TI - Evaluation of cardiac beta-adrenergic receptor function in children by dobutamine stress echocardiography. AB - OBJECTIVE: To investigate the role of dobutamine stress echocardiography in evaluating cardiac beta-adrenergic receptor (beta-AR) function and responsiveness in children. METHODS: Left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular end systolic volume index (ESVI), the ratio of systolic blood pressure and ESVI (SP/ESVI) were measured by dobutamine stress echocardiography (DSE) in 30 children with beta-AR hypersensitivity, 15 children with dilated cardiomyopathy and 30 normal children respectively. RESULTS: Before pharmacological stress, EF and FS were 0.72 and 0.39 respectively in beta-AR hypersensitivity group versus 0.70 and 0.35 respectively in control group. There was no difference of the indices between the two groups (P > 0.05). SP/ESVI was 0.76, higher than the value of 0.66 in control group (P < 0.05); EF, FS and SP/ESVI were 0.41, 0.15 and 0.10 respectively, which were significantly lower than those in control group. After dobutamine stress of 5 micrograms.kg-1.min-1 and 10 micrograms.kg-1.min-1, EF, FS and SP/ESVI were significantly increased in patients with beta-AR hypersensitivity and there were no changes in children with dilated cardiomyopathy compared with values of baseline. CONCLUSION: Cardiac beta AR function and responsiveness can be evaluated by dobutamine stress echocardiography. PMID- 11601258 TI - Portal hemodynamics in cirrhotics with portal hypertension using color Doppler velocity profile. AB - OBJECTIVE: To investigate portal hemodynamics and its correlation with esophageal variceal bleeding (EVB) in cirrhotics with portal hypertension by using a newly developed technique, color Doppler velocity profile (CDVP). METHODS: Hemodynamics of portal trunk (PT), right anterior branch (RAB) and splenic vein (SV) were evaluated in 48 cirrhotics with portal hypertension and 35 normal volunteers by CDVP. The parameters included maximum cross-sectional velocity (CS-Vmax), flow volume, congestion index (CI), profile parameter N and pattern of flow curve. Stepwise logistic regression model was employed to determine EVB-relating factors in cirrhotics. RESULTS: CS-Vmax in PT and RAB was significantly lower in cirrhotic group than that of normal group, being 14.91 +/- 3.08 cm/s, 9.44 +/- 2.70 cm/s vs 30.52 +/- 6.75 cm/s, 12.82 +/- 2.69 cm/s, respectively (P < 0.01 for both). Flow volume of PT and SV was significantly higher in cirrhotic group compared with that of normal group, being 25.16 +/- 10.48 ml.min-1.kg-1, 15.83 +/ 9.18 ml.min-1.kg-1 vs 20.43 +/- 5.57 ml.min-1.kg-1, 5.81 +/- 2.04 ml.min-1.kg-1, respectively (P < 0.01 for both). CI of PT, RAB and SV was significantly higher in cirrhotic group than in normal group, being 0.142 +/- 0.0654, 0.105 +/- 0.0496, 0.0884 +/- 0.0431 vs 0.0326 +/- 0.0142, 0.0757 +/- 0.0342, 0.0483 +/- 0.0230, respectively (P < 0.01 for all). In dynamic variation of flow volume over time, RAB and SV in cirrhotic group increasingly presented flat pattern and periodically changed pattern, respectively (P < 0.01 for both). Between cirrhotic subgroups without and with EVB history, there were significant differences in flow volume, CI and N value of SV, splenic size, degree of esophageal varices (EV) and portal hypertensive gastropathy (PHG), and stepwise logistic regression revealed that N value of SV, splenic size, degree of EV and PHG were four independent factors in relation to EVB. EVB scores calculated from the regression equation had a close correlation with EVB. In patients with EVB score > 0, 88.9% of them had EVB, and in those with EVB < 0, 76.9% of them had no history of EVB. CONCLUSION: In cirrhotics with portal hypertension, portal venous system has the features of elevated vascular resistance and hyperdynamics, and the latter mainly results from increased blood flow in SV. EVB score may become a valuable parameter in predicting occurrence of EVB. PMID- 11601259 TI - Toxicology of intrahepatic arterial administration of interventional phosphorus 32 glass microspheres to domestic pigs. AB - OBJECTIVE: To evaluate the toxic response to intrahepatic arterial administration of radioactive phosphorus-32 glass microspheres (32P-GMS) in domestic pigs. METHODS: Through selective catheterization of hepatic artery, 32P-GMS was infused to 5 healthy domestic pigs in a dosage equivalent to the therapeutic dose for human being, and 31P-GMS was infused to other 5 healthy domestic pigs. Two pigs served as the whole course blank controls. One pig from each group was surrendered to euthanasia at week 1, 2, 4, 8 and 16, respectively, and liver biopsies were performed on the rest of pigs at the corresponding time points. Liver tissues from different sites were taken for light and electron microscopy. The ultrastructural histopathological changes were evaluated semiquantitatively. RESULTS: The accumulative amount of 32P-GMS in the target tissue attained more than 90% of the total dose administrated. Histologically, abnormal hepatocytes were easily found at week 1 or 2. At week 4 they were less than at week 1 or 2, and endothelium of the sinuses were damaged prominently. At week 8 they were scarcely seen, and liver tissue recovered gradually. The histological features of liver tissue restored to normal at week 16. Semiquantitative analysis of ultrastructural morphology in the experimental group showed no statistical difference (P > 0.50) between the nuclear abnormality (Nabn) and mitochrondrial variability (Mvar) at week 1 or 2, but revealed prominent difference (P < 0.01, P < 0.001) as compared with those in other groups. In the experimental group the Nabn in tissues showed no significant difference (P > 0.20) between week 8 and week 16. CONCLUSION: 32P-GMS internal irradiation at the dosage equivalent to human therapeutic dosage exerts reversible injury to domestic pig liver tissue, and it takes more than 8 weeks for the injured liver tissue to recover. PMID- 11601260 TI - Congenital choledochal cyst with pancreatitis. AB - OBJECTIVE: To understand the relationship among congenital choledochal cyst, anomalous junction of pancreaticobiliary duct (AJPBD) and pancreatitis. METHODS: 25 children with choledochal cyst treated in our hospital were included in this study. Their ages ranged from 2 months to 14 years. Intraoperative cholangiography was performed in 24 children. Pancreatic samples obtained from the head and body of the pancreas at operation were observed under light and electron microscope. Serum amylase was analyzed one week before and after operation respectively. Bile amylase in the cyst and gallbladder was measured at operation. RESULTS: The incidence of AJPBD was 70%. Inflammatory cell infiltration and fibrous hyperplasia were seen in the pancreatic specimens of 5 children, of whom 4 had AJPBD. No ultrastructural changes were found in 2 children without AJPBD, while different changes were seen in 6 with AJPBD, including those showing no pathological changes under light microscope. All the changes became more severe as the age of the patient increased. The bile and serum amylase levels were higher in children with AJPBD than those without AJPBD (P < 0.05). CONCLUSION: Congenital choledochal cyst has a close relationship with AJPBD and pancreatitis. Pancreatic pathological changes have a long and chronic course from ultrastructural changes to macroscopic changes for the developing of pancreatitis. PMID- 11601261 TI - Cross-sectional survey of intralymphocytic and serum elements in hypertensive patients. AB - OBJECTIVE: To investigate the distribution characteristics of some common and trace elements in both serum and lymphocyte in patients with essential hypertension and to analyse their possible role in the pathogenesis of hypertension. METHODS: A cross-sectional study was carried out in 102 hypertensive patients matched with equal number of normotensive subjects by sex, age, and hypertensive family history; all of them were randomly selected from the same community. Both intralymphocytic and serum concentrations of some relevant elements including Na+, K+, Ca2+, Mg2+, Zn2+, Cu2+ and P were measured for all studied subjects, using the inductively coupled plasma spectrometry (ICPS). RESULTS: 1. Both intralymphocytic and serum concentrations of Na+ (P = 0.009, 0.004 respectively), and Ca2+ (P = 0.001, 0.049 respectively) in hypertensive group were significantly higher than those in the normotensives. 2. Stepwise regression analysis disclosed that systolic and diastolic blood pressure had significant correlation with age, serum Na+/K+ ratio and intralymphocytic Ca2+, Mg2+ concentrations (P < 0.001 for both). 3. According to hypertensive family history, the method of multiple variance analysis had been employed for 4 subgroups and the results revealed that the concentrations of serum Ca2+ and lymphocytic Na+ were significantly higher in hypertensives with or without family history than in normotensives without family history. Furthermore, intralymphocytic Na+ concentration was significantly higher in normotensives with positive family history than that in normotensives without family history. CONCLUSION: The serum and intralymphocytic distribution characteristics of elements in hypertensive patients compared with normotensive controls suggested that there might exist certain defects of the ion-transporting system on cell membrane which might be genetically linked. PMID- 11601262 TI - MRI evaluation of bone marrow of normal lumbar vertebra in the Chinese: normal patterns and preliminary quantitative study. AB - OBJECTIVES: To establish the normal patterns of lumbar vertebral marrow in normal Chinese, to determine its normal value of relaxation times (T1 and T2), and to investigate the relationship between relaxation time and age or sex. METHODS: 320 of 1000 cases (sampled randomly) received MR imaging. According to the MRI findings of sagittal T1WI, marrow patterns were established. 268 cases were studied quantitatively (T1 and T2 measurements). RESULTS: The normal bone marrow patterns of lumbar vertebra were divided into four main patterns (six subgroups). The normal values of relaxation times (T1 and T2) were measured. T1 or T2 value decreased with aging. No significant difference in T1 value between two sexes (< 40 years old: u = 0.4307, P > 0.50; > or = 40 years old: u = 0.554, P > 0.05). No significant difference was seen in T2 value between two sexes before 40 years old (u = 1.3628, P > 0.10), but significant difference after 40 years old (u = 2.1498, P < 0.05). CONCLUSIONS: To establish the normal patterns of lumbar vertebral marrow and determine its normal values of relaxation times have important clinical value in the diagnosis of bone marrow diseases. PMID- 11601263 TI - Immunological characteristics of natural resistance in Microtus fortis to infection with Schistosoma japonicum. AB - OBJECTIVE: To explore the immunological characteristics of natural resistance to Schistosoma japonicum infection in Microtus fortis (MF) living in the Dongting Lake area. METHODS: Passive transfer of sera from uninfected laboratory bred MF (BMF) to albinao mice (AM) was performed to observe the acquired protection. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme linked immunoblotting (ELIB) methods were used to recognize 4 different life cycle stage antigens of S. japonicum by sera from wild MF (WMF), BMF, BMF13 and BMF19. Tests were also performed on in vitro killing effect of sera and/or lymphocytes from BMF and WMF to schistosomulae; quantitative determination of C3 and C4 by immunoturbidometry, and interleukin-4 (IL-4) and antibodies to the 4 stage antigens in sera from WMF, BMF and infected BMF by ELISA. RESULTS: Compared with the control group, stool eggs per gram (EPG) of AM in the test group was significantly reduced by 81.54%, miracidium hatching rate, by 50.67%, liver egg counts, by 72.07%, the diameter of hepatic egg granuloma, by 70.39 microns. Western blotting probed with the 4 MF sera all revealed 7 specific bands for SSA, 3 for AWA and SEA, but none for CA antigens. The sera and/or lymphocytes from WMF and BMF gave obvious killing effects on schistosomulae with an adjusted death rate of 64.12%-78.83%. The levels of "natural antibodies" produced by MF to S. japonicum were in the following order: anti-SSA > anti-AWA > anti-SEA > anti-CA, all of which increased significantly after the infection. Serum levels of C3, C4 and IL-4 in uninfected BMF were significantly higher than those in AM. After infection, levels of C3 and C4 were further increased respectively by 72.83% and 295.49% in the 4th week and IL-4 by 303.83% in the 9th day. CONCLUSIONS: Immunological characteristics of innate resistance in M. fortis to S. japonicum infection were existed with no significant difference between WMF and BMF. PMID- 11601264 TI - A surveillance study on penicillin-resistant streptococcus pneumoniae in China. AB - OBJECTIVES: To find out whether there are also penicillin-resistant streptococcus pneumoniae and the resistant rate in China. METHODS: A surveillance study which is a part of the international surveillance on pneumococci resistance to penicillin and other antimicrobial agents was conducted in Beijing, China. More than 900 pediatric patients with respiratory tract infections aged from six months to three years selected from two pediatric units were enrolled in the study. Perthroat swabs were immediately streaked onto blood agar plates. Isolates were identified as pneumococci by their typical appearance, gram stain, confirmation tests. Antibiotic susceptibility was assessed by the disk diffusion method and minimal inhibition concentration (MIC) determination according to Protocol and National Committee for Clinical Laboratory Standards (NCCLS). RESULTS: Of the 51 streptococcus pneumoniae isolates, 5 strains had zones of inhibition indicative of penicillin resistance, of which two had penicillin MICs > or = 0.1 mg/L and were considered to be relatively or fully resistant to penicillin. The MICs of two penicillin resistant strains were 2 mg/L and 4 mg/L. Resistant rates to ceftriaxone and cefotaxime were 0% and 10% respectively. For the other ten antimicrobial agents, the resistant rates were as follows: ampicillin 12%, piperacillin 26%, furbenicillin 14%, cefuroxime 6%, erythromycin 54%, clarithromycin 52%, meleumycin 64%, roxithromycin 52%, chloramphenicol 35%, tetracycline 100%. CONCLUSIONS: The study suggested that penicillin resistant streptococcus pneumoniae strains existed in China and were also resistant to ampicillin, piperacillin, furbenicillin and cefuroxime. Moreover, the resistant rates of penicillin resistant streptococcus pneumoniae to macrolides and tetracycline were high. PMID- 11601265 TI - Correlation of cell proliferation inhibition and apoptosis induction with expression of human beta 5 integrin on hematopoietic cells. AB - OBJECTIVE: To investigate the function of the alpha v beta 5 integrin in hematopoietic cells. METHODS: Tissue culture, integrin expression vectors, gene transfer, polymerase chain reaction (PCR), apoptosis analyses and cytometic analysis were made on hematopoietic cells. RESULTS: The beta 5 integrin cDNA was not expressed in hematopoietic cells following exposure to the beta 5 integrin retrovirus vector pG beta 5CHT. Unbalanced expression of the alpha v beta 3 and alpha v beta 5 integrins occurred during apoptosis induced by serum depletion and upon differentiation. The treatment of hematopoietic cells with anti-alpha v beta 5 monoclonal antibody inhibited apoptosis induced by serum depletion. Inducible expression of the beta 5 integrin cDNA in the hematopoietic cell line K562 caused cellular proliferation inhibition. CONCLUSION: The alpha v beta 5 integrin cDNA in hematopoietic cells can inhibit the proliferation of the hematopoietic cell, cause the differentiation of the hematopoietic cells and induce the apoptosis of the hematopoietic cells. PMID- 11601266 TI - Use of infrared emission detection thermometer in Chinese neonates. AB - OBJECTIVE: To evaluate the reproducibility of Thermoscan, an infrared emission detection ear thermometer, and to establish the normal reference range of ear temperature in Chinese neonates. METHODS: Neonates were recruited from the inpatients population with exclusion of those suffering from infections. RESULTS: Forty-nine neonates were recruited with 1,115 temperature taking sessions. Mean left ear temperature was 36.64 degrees C +/- 0.35 degree C. Mean right ear temperature was 36.64 degrees C +/- 0.37 degree C. Clinical repeatability for left and right ear was 0.17 degree C and 0.17 degree C, respectively. CONCLUSION: Thermoscan produced reproducible results in Chinese neonates. The normal range of ear temperature for Chinese neonates is 35 degrees C to 37 degrees C. Ear temperature > 37.8 degrees C should be regarded as fever. PMID- 11601267 TI - Pulmonary sequestration: diagnosis by magnetic resonance angiography and computed tomography. PMID- 11601268 TI - Surgical treatment of single coronary artery anomaly complicated with atherosclerotic coronary artery disease. PMID- 11601269 TI - The present status and prospect of tropical medicine in China. PMID- 11601270 TI - DNA vaccine pCD-Sj32 and its efficacy of protective immunity against infection of Schistosoma japonicum. AB - OBJECTIVE: To study protective immunity afforded by murine immunization with DNA vaccine of Schistosoma japonicum (S. japonicum) as measured by reduction in worm burden and host antibody, cytokines. METHODS: DNA vaccine pCD-Sj32 was constructed, identified and expressed. pCD-Sj32 could induce substantial protective immunity against infection of S. japonicum in BALB/c mice. The best efficacy can be produced with one injection of 100 micrograms DNA into the quadriceps muscle, combined with challenge for 8 weeks after immunization. T lymphocyte subsets of CD8+, IL-2. TNF and IFN-gamma of experimental animal could play important roles in regulating immune functions of schistosomiasis. RESULTS: High titre of specific antibody IgG could be induced by vaccinated with pCD-Sj32, and antibody can mediate macrophage to produce ADCC effects in vitro. CONCLUSION: pCD-Sj32 may represent a new approach to developing subunit vaccine. PMID- 11601271 TI - Modulation of in vivo granuloma formation related to regulation of in vitro IFN gamma and IL-4 expressions in experimental schistosomiasis japonica. AB - OBJECTIVE: To find out relationship between the in vitro schistosome egg antigen (SEA) stimulated IFN-gamma and IL-4 mRNA expressions and the in vivo SEA elicited granulomatous responses, the transcriptions of IFN-gamma and IL-4 gene were investigated in the spleen of BALB/c mice infected with Schistosoma japonicum (S. japonicum). METHODS: Spleens were removed at 0, 3, 5, 8, and 10 and 12 weeks after infection and the spleen cells were incubated in the presence of SEA. The extracted RNA was analyzed for IFN-gamma and IL-4 mRNA by reverse transcription PCR (RT-PCR). Newly-formed liver granulomas were measured. RESULTS: The study revealed that no detectable IFN-gamma and IL-4 mRNA RT-PCR products were found in SEA treated spleen cells from uninfected, or 3-week infected mice, whereas IL-4 mRNA was found to be expressed in 5- and 8-week infected mice, and an appreciable enhanced expression of IL-4 mRNA was observed in SEA stimulated spleen cells at 8 week infection than at 5-week infections. However, SEA could not induce IFN-gamma and IL-4 mRNA transcription in 10- and 12-week infected mice, indicating the modulated expression of IFN-gamma and IL-4 mRNA. CONCLUSION: The significant changes of IL-4 mRNA expression in SEA stimulated spleen cells during S. japonicum infection were coincident with SEA elicited granuloma formation and modulation in vivo. PMID- 11601272 TI - Effects of the configuration of a multi-epitope chimeric malaria DNA vaccine on its antigenicity to mice. AB - OBJECTIVE: Four B and Th cell epitopes were selected from conservative domain of Plasmodium falciparum antigens to construct two groups of chimeric malaria DNA vaccines with different configurations and their antigenicities were studied. METHODS: The partially synthesized oligonucleotide was annealed, PCR amplified and cloned into a mammalian cell expression vector. By using a pair of isocaudamers on the vector, different single copies of B epitopes were multiplied and were tenderly stringed into two groups of chimeric DNA vaccine with different configurations. BALB/c mice were immunized with these DNA plasmids by either intramuscular or intradermal injections. RESULTS: The antisera from the immunized mice tested by ELISA showed that only the configuration which had a single copy of universal T helper cell epitope, CS. T3, located at the C terminal of the multi-copy B cell epitopes induced a high antibody response. The T helper cell epitope at any other position of the peptide, or the double T helper cell epitopes configured with the B cell epitopes did not enhance antibody response, and some configurations even decreased the humoral response to a B cell epitope. CONCLUSION: This study demonstrated that both combination and configuration of the epitope may affect the antigenicity of a chimeric multiple antigen. PMID- 11601273 TI - A recombinant multi-epitope, multi-stage malaria vaccine candidate expressed in Escherichia coli. AB - OBJECTIVE: To construct and evaluate a recombinant multi-epitope, multistage malaria vaccine candidate expressed in Escherichia coli (E. coli). METHODS: A hybrid gene (HGF) encoding several putative immunodominant T or T/B epitopes from MSP-1, MSP-2, Pf155/RESA of Plasmodium falciparum (P. falciparum) and two immune stimulating epitopes from interleukin-1 and tetanus toxin was synthesized. Two copies of HGF and a copy of gene encoding Pattaroyo's Spf66 were connected together to construct a sandwich hybrid gene HGFSP. The gene was cloned into an expression vector pWR450-I for production of a fusion protein with beta galactosidase. Efficacy of this vaccine candidate in inducing specific immunity against malaria parasites was evaluated. RESULTS: Immunization of different species of animals with purified recombinant peptide showed that the peptide was able to induce remarkable antibody response to the immunized peptide as well as falciparum malaria parasites. The epitopes included in the construct could induce antibodies against the intact parasite proteins as demonstrated by western blotting, indicating the epitopes retained their antigenicity in the new peptide construct. Antibodies from animals immunized with recombinant HGFSP peptide exhibited good ability in inhibition of the in vitro growth of malaria parasites, augmentation of phagocytosis of the parasites or infected RBC by phagocytes, and facilitation of antibody dependent cell mediated cytotoxicity to the cultured malaria parasites. CONCLUSION: The recombinant peptide seems to be a potential candidate which is valuable for further investigation. PMID- 11601274 TI - Cloning and sequence analysis of an amastin coding gene from Leishmania major Abdou. AB - OBJECTIVE: To clone a surface protein encoding gene from Leishmania major Abdou parasites. METHODS: Using Trypanosotidae cruzi (T. cruzi) amastin DNA sequence as a reference, computer search was done on Genbank and dbEST data bases with BLASTN path. A Leishmania major Abdou DNA library has been established and screened by in situ colony hybridization. RESULTS: No homology sequence to T. cruzi amastin was found in Genbank, but a 309 nt DNA fragment from Leishmania major (L. major) existed in bEST. Leishmania major Abdou DNA library was screened using specific probes synthesized according to 309 nt DNA sequence of T. cruzi amastin gene, and full-length coding sequence for Leishmania major Abdou amastin was cloned. The coding sequence consisted of 552 nt, and translated into 183 amino acid residues. The homology is 23.5% at amino acid sequence level between Leishmania major Abdou and T. cruzi amastins. CONCLUSION: We have cloned the full length amastin coding DNA for Leishmania major Abdou. PMID- 11601275 TI - Angiotensin I-converting enzyme gene polymorphism in Chinese patients with obstructive sleep apnea syndrome. AB - OBJECTIVE: To investigate the relationship of an insertion/deletion (I/D) polymorphism of the angiotension-converting enzyme (ACE) gene to obstructive sleep apnea syndrome (OSAS) patients and the control subjects. METHODS: Genomic DNA was extracted from blood samples and amplified by polymerase chain reaction (PCR). PCR primers flanked the polymorphic region in intro 16 of the ACE gene. RESULTS: OSAS patients had significantly higher frequencies of I/I genotype and insertion allele of the ACE gene as compared with the control subjects in Chinese population. The OSAS patients with I/I genotype had significantly longer apnea time, lower minimum SaO2 and greater AHI than the OSAS patients with I/D genotype. CONCLUSION: These results indicate that the I/I genotype and I allele are a risk factor for OSAS in Chinese. PMID- 11601276 TI - Effect of WT1 gene expression on cell growth and proliferation in myeloid leukemia cell lines. AB - OBJECTIVE: To investigate the effects and mechanism of Wilms' tumor (WT1) antisense oligonucleotides (AS-oligomers) on proliferation and apoptosis in myeloid leukemia cell lines. METHODS: K562 and HL-60 cells were cultured in presence of WT1 oligomers. Both cell lines express WT1 gene with no p53 protein expression. Cells growth, apoptosis and expression of WT1, bcl-2 genes were analysed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylmetrazolium bromide (MTT) colorimetric assay, flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR) methods. RESULTS: WT1 antisense oligonucleotides inhibited cellular proliferation of K562 cells and the effect was concentration-dependent. When cultured at concentration of 200 micrograms/ml oligomers, growth inhibition was 46.2% for antisense oligonucleotide cultivated group and 28.1% for sense oligonucleotide cultured group (P = 0.008) respectively. WT1 antisense oligonucleotide can induce apoptosis of K562 and HL-60 cells. Percentages of apoptotic cells in antisense oligonucleotide and sense oligonucleotide treated groups were 30.88% versus 13.62% for K562 cells and 40.15% versus 4.23% for HL-60 cells. However the growth of HL-60 cells and expression of bcl-2 gene were unaffected. CONCLUSIONS: The WT1 gene is related with proliferation and apoptosis of leukemic cells. Effect of anti-apoptosis may be independent of the cellular p53 status and bcl-2 expression. WT1 gene may play an important role in leukemogenesis. PMID- 11601277 TI - Effect of benzene, toluene, xylene on the semen quality of exposed workers. AB - OBJECTIVE: To examine the effects on semen and sperm quality of workers after a short and long term exposure to benzene, toluene, and xylene. METHODS: The semen and blood of 24 married workers exposed to benzene, toluene, and xylene from shoemaking, spray painting, or paint manufacturing factories were collected. The concentration of benzene, toluene, and xylene in the blood and semen was determined by using headspace chromatographic method. Routine sperm test was carried out and acrosin activity detected. RESULTS: The results showed that benzene, toluene, and xylene were found in the blood and semen of some ex-workers in a working environment where the air concentration of benzene, toluene, and xylene exceeded the maximum allowable concentration (MAC). This result was not found in workers of the control group. There were also some effects on the quality of semen in the exposed workers. For example, the percentage of semen with liquefaction time exceeding 30 minutes increased. The sperm vitality, motility and acrosin activity decreased. At the same time, there were a positive correlation between liquefaction time and the level of toluene in semen, and a negative correlation between sperm vitality, sperm activity or acrosin activity and working history. CONCLUSIONS: The results suggested that the mixture could affect the quality of semen and sperm, which might be the main reason of the abnormal pregnancy outcome among the wives of workers exposed to benzene, toluene, and xylene. Further studies are, however, required to confirm these findings. PMID- 11601278 TI - Surgical treatment of DeBakey type I aortic dissection using the "elephant trunk technique". AB - OBJECTIVES: To review the indications, operative methods and postoperative management of the "elephant trunk technique", and to report two cases of DeBakey type I aortic dissection treated with the "elephant trunk technique". METHODS: Two cases of DeBakey type I aortic dissection were operated with selective cerebral perfusion via the right subclavian artery. At the first stage, a tubular dangling aortic graft prosthesis ("elephant trunk") was inserted into the distal aorta while replacing the ascending aorta and aortic arch. The distal elephant trunk prosthesis was then used at the second stage involving the replacement of the sections of the distal aorta via a left-sided thoracotomy. RESULTS: The two operations were successful. Ultrafast computed tomograph (UFCT) showed that the two patients were cured after the first stage operation, and the second stage procedure could have been avoided. CONCLUSIONS: The "elephant trunk technique" is a multiple stage approach in the treatment of extensive aneurysmal diseases of the aorta. The procedure is indicated for patients who have combined diseases of both ascending aorta plus aortic arch segments and descending aortic aneurysm. It can also be used for patients with DeBakey type I aortic dissection. Some patients can be cured after the first stage operation. PMID- 11601279 TI - External valvuloplasty technique in deep venous valve insufficiency of the lower limbs. AB - OBJECTIVE: To evaluate the therapeutic effects of external valvuloplasty technique in deep venous valve insufficiency of the lower limbs. METHODS: External valvuloplasty of the femoral vein valve was performed in 30 patients(41 limbs) with deep venous valve insufficiency of the lower limbs. The patients ranged in age from 16 to 69 years (mean +/- s, 50.8 +/- 9.2). External valvuloplasty of the first pair of superficial femoral vein valve was carried out in all limbs. External valvuloplasty of the second pair of superficial femoral vein valve was added in 7 limbs and valvuloplasty of the common femoral vein valve in 6 limbs. RESULTS: Venous claudication, swelling, aching disappeared in 78.0% limbs (32), obvious improvement was seen in 22.0% (9), and varicosis disappeared in all limbs. Ulcer healing was observed in 80% (8/10) limbs. Deep venous valve sufficiency was shown in 90.2% limbs, and reflux I degree-II degree in 4 by color Doppler. CONCLUSION: External valvuloplasty is an effective method to treat deep venous valve insufficiency of the lower limbs. PMID- 11601280 TI - Effect of burn healing liquid on keratinocyte and fibroblast proliferation and on collagen lattice contraction. AB - OBJECTIVES: To investigate the effect of Burn Healing Liquid (BHL) on the proliferation of keratinocytes and fibroblasts and to explore the potential effect of BHL on fibroblast contraction. METHODS: Human keratinocytes and dermal fibroblasts were cultured in media containing serial dilutions of BHL followed by cell proliferation determination assessed with MTT (3-[4, 5-dimehtylthiazol-2-yl] 2, 5-diphenyl tetrazolium bromide) assay at different time intervals. The in vitro collagen lattice contraction model was utilized for determining the contractility of fibroblasts cultured in BHL containing medium. RESULTS: The 1:10(7) dilution of BHL enhanced the growth of both keratinocytes and fibroblasts whereas the 1:10 dilution increased the growth of keratinocytes only. Collagen lattice contraction was inhibited dose-dependently by BHL and such an inhibition could be reversed by switching BHL containing medium to normal medium containing 10% fetal calf serum. CONCLUSION: BHL enhances the growth of both keratinocytes and fibroblasts and reversibly inhibits the fibroblast contraction in collagen lattice. PMID- 11601281 TI - Neuronavigation for the resection of cavernous angiomas. AB - OBJECTIVE: To introduce the use of the StealthStation neuronavigator combined with preoperative computerized tomography (CT) in resection of intracranial cavernous angiomas (CAs). METHODS: The StealthStation neuronavigator was used to provide a realtime correlation of the operating field and the computerized images in 6 patients with CAs. All patients suffered from epileptic seizures. Four patients underwent keyhole surgery and 2 underwent small skin-flap craniotomy. The mean follow-up was 4.5 months. RESULTS: With the guidance of neuronavigator, lesionectomy associated with removal of hemosiderin deposition, gliosis and calcification was performed precisely. The mean fiducial error was from 1.65 mm to 4.53 mm, the predicted accuracy at 10 cm was between 1.82 mm and 3.28 mm, and the sustained accuracy ranged from 0.50 mm to 3.45 mm. CONCLUSION: The StealthStation neuronavigator is reliable and accurate in the resection of CAs. PMID- 11601283 TI - Effects of rhidosin on expression of fibroblast growth factor on olfactory bulb in rats and its relation with senile hyposmia. AB - OBJECTIVES: To determine the expression of fibroblast growth factor (FGF) on olfactory bulb in rats and its relation with senile hyposmia, and to discuss the effects of rhidosin on expression of FGF on olfactory bulb in senile rats and its significance. METHODS: Four groups of rats, i.e., young group, senile group, rhidosin group, and physiological saline control group were used in this study. After the removal of the heads of these rats, olfactory mucosa and olfactory bulbs were immediately fixed with neutral formalin, followed with paraffin embedding, serial sectioning, immunohistochemical staining and light microscopic observation. RESULTS: The positive expression rate of FGF on olfactory bulb in young group was significantly higher than that in senile group (P < 0.01). The positive expression rate of FGF on olfactory bulb in rhidosin group was significantly higher than that in physiological saline control group (P < 0.01). No positive expression of FGF on olfactory mucosa was observed in these four groups. CONCLUSION: These results suggest that the expression of FGF on olfactory bulb gradually decline with aging. The decrease of expression of FGF on olfactory bulb may play a key role in the occurrence of senile hyposmia. Rhidosin can increase the expression of FGF on olfactory bulbs in senile rats and this may be one of the mechanisms by which rhidosin promotes the growth of olfactory cells and inhibits aging effects on the olfactory system. PMID- 11601282 TI - Discernment of the sensitized inner ear by peripheral immunocompetent lymphocytes. AB - OBJECTIVE: To investigate the role of peripheral immunocompetent lymphocytes during the immune response in the inner ear. METHODS: Sensitized lymphocytes from peripheral blood, neck lymph nodes and spleen of three groups of donor animals, i.e., group A immunized intradermally with keyhole limpet hemocyanine (KLH) and both inner ears challenged with KLH, group B received only KLH intradermally without inner ear challenge, and group C used as control, were isolated and labelled with 51Cr. The labelled lymphocytes were injected intravenously into the recipients. They were immunized intradermally with right inner ears challenged with KLH. Twenty to 24 h later, the radioactivities in the temporal bones of the recipients were assayed to detect the infiltration of labelled cells. RESULTS: In groups A and B, the radioactivity in the right temporal bones was higher than that in the left temporal bones (P < 0.05). The highest labelling radioactivity was detected in the right temporal bones of group A. The lowest migration of 51Cr labelled cells to the inner ear was found in group C. The ratio of radioactivity between right (challenged) and left (unchallenged) inner ears was higher in group A than in groups B and C, with the difference being significant (P < 0.05). CONCLUSION: The immune reaction in response to antigenic stimulation in the inner ear is immunologically modulated by the peripheral systemic circulation. PMID- 11601284 TI - Classification and digital subtraction angiography evaluation of carotid cavernous fistulas. AB - OBJECTIVE: To investigate the role of digital subtraction angiography (DSA) in evaluation of carotid cavernous fistulas, and to initiate a new classification for carotid cavernous fistula. METHODS: Cerebral angiography and selective external and internal carotid angiography were carried out in 56 patients who were classified into 5 types according to their hemodynamic features. RESULTS: The types were A (38 patients), B (4), C (10), D (2), and E (2). One of the 38 direct fistulas was located at C1 of the cavernous segment. Fistulas at C2 were observed in 10 patients, at C3 in 4, at C4 in 10 and at C5 in 5. The anterior communicating arteries were patent and well compensated in 33 of the 56 patients. The posterior communicating arteries were patent and well compensated in 39 patients. Both communicating arteries were well compensated in 31 patients. Fifty of the 56 patients were drained by ophthalmic veins, 47 by inferior petrous sinuses, 18 by cortical veins, and 8 to the posterior fossa region. CONCLUSIONS: Digital subtraction angiography was helpful in localization of the rents in carotid cavernous fistulas, in evaluation of function of Willis circles and provided valuable information for treatment of carotid cavernous fistulas. Carotid cavernous fistulas were divided into 5 categories: type A, B, C, D and E, among which type E was not previously described elsewhere. PMID- 11601285 TI - Three-dimensional electron beam CT angiography in the diagnosis of intracranial aneurysms. AB - OBJECTIVE: To assess the accuracy of three-dimensional electron beam CT angiography (3D-EBCTA) in the detection of intracranial aneurysms. METHODS: 31 patients with suspected cerebral aneurysms (including 3 post-operative patients) were examined by 3D-EBCTA. Those receiving angiography or surgery acted as controls. Maximum intensity projection (MIP) and shaded surface display (SSD) reconstruction ways were selected. RESULTS: 24 aneurysms were found in 23 patients. Of the 31 patients, false positive was noted in 1 patient, and false negative in 2 on 3D-EBCTA. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 92.0%, 88.9%, 91.2%, 95.8% and 80.0% respectively. CONCLUSION: 3D-EBCTA is an noninvasive, rapid, valuable method in diagnosis and screening of patients with suspected aneurysms. The reconstruction modes such as MIP and SSD should be used together to optimise the visualization. PMID- 11601286 TI - Combined effect of alpha-fetoprotein antisense oligodeoxy-nucleotides and 5 fluorouracil on human hepatoma cell growth. AB - OBJECTIVE: To investigate the effect of alpha-fetoprotein (AFP) antisense phosphorothioate oligodeoxynucleotides in combination with 5-fluorouracil (5-FU) on the growth of BEL-7404 human hepatoma cells in vitro. METHODS: Phosphorothioate oligodeoxynucleotides were synthesized by beta-cyanoethyl phosphoramidite chemistry. AFP gene expression in human hepatoma cells was determined by avidin-biotin-peroxidase complex (ABC) immunocytochemical method. Cell growth in the presence or absence of experimental agents was measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-dipheny ltetrazolium (MTT) microculture tetrazolium assay. RESULTS: AFP antisense oligomers markedly suppressed the growth of BEL-7404 human hepatoma cells in vitro by sequence-specific blocking of the AFP gene expression in the cells (P < 0.05). 5-FU also inhibited the hepatoma cell growth in a dose-dependent manner when used alone (P < 0.05). The combined treatment with AFP antisense oligomers and 5-FU showed significantly enhanced hepatoma cell growth inhibition than either AFP antisense or 5-FU treated cells alone (P < 0.05). CONCLUSION: Combined use of AFP antisense oligomers and 5-FU could more effectively inhibit the growth of BEL-7404 human hepatoma cells in vitro. PMID- 11601287 TI - cDNA cloning and sequence analysis of hepatitis G virus genome isolated from a Chinese blood donor. AB - OBJECTIVE: To obtain full-length sequence of a Chinese hepatitis G virus (HGV) strain (HGVch) and investigate the genetic characteristic of HGVch and its identity to other isolates. METHODS: Reverse transcription (RT) and nested-PCR were used to screen HGV RNA positive serum and amplify cDNA fragments. A positive serum without known hepatitis virus markers was selected for isolating HGV RNA template. The HGV genome was divided into 12 overlapping fragments and directly cloned into pGEM-T vector. Sequences were determined by dideoxy terminus-end method of DNA sequencing and then analyzed by computer. RESULTS: The twelve fragments of HGVch cover 9213 nucleotides in length, containing a large open reading frame (ORF) encoding 2873 animo acids polyprotein that began with a methonine residue and ended at termination codon. HGVch is about 86.5%-89.5% identical to other known HGV isolates at the nucleotide level and about 93.9% 96.2% at the deduced animo acid level. CONCLUSION: HGV is a non-A-E hepatitis causal agent, proved to be related with posttransfusion hepatitis in all over the world. Chinese HGV isolate has very close relationship to other isolates from Africa, Europe, Japan, without significant difference across the entire genome. It is suggested that the sequences of HGV isolates are very conservative and the evolution is very slow. PMID- 11601288 TI - Selection and determination of specific and protective antigens of Mycobacterium tuberculosis. AB - OBJECTIVE: To select and identify the specific and protective antigens of Mycobacterium tuberculosis (M. tuberculosis) for searching a new approach to diagnose and treat tuberculosis. METHODS: Extract and culture filtrates of M. tuberculosis were obtained by ultrasonic treatment and millipore membrane filtration, respectively. The protein samples were tested with monoclonal antibody (MAb) and patient sera. The proteins showing positive reaction were sequenced on Beckman/LF 3200/peptide amino acid sequencer. RESULTS: Proteins of M. tuberculosis with molecular weight of 31 ku and 30 ku showed positive results when reacted with anti-M. tuberculosis MAb and sera of tuberculosis patients, but not with normal mouse serum and healthy human sera. N-terminal sequences of the 31 ku and 30 ku antigen were Ala Glu Val Asp Trp Leu Val Phe Ala Val and Phe Ser Arg Pro Gly Leu Pro Val Glu Try respectively. CONCLUSION: 31 ku and 30 ku proteins of M. tuberculosis are immune protective proteins. They play important or dominant roles in determination of immunorecognization. PMID- 11601289 TI - Maternal serum screening for Down syndrome in a teaching hospital in Hong Kong. AB - OBJECTIVE: To study prospectively the use of maternal serum alpha-fetoprotein (AFP) and total beta-human chorionic gonadotropin (hCG) concentrations for screening of Down syndrome in Hong Kong. METHODS: AFP and total beta-hCG were measured in serum samples from 1638 singleton Chinese pregnancies at 14-22 weeks of gestation, recruited over a twelve-month period. Gestational ages were determined by ultrasonographic parameters measured at the same visit as the test for all cases. The gestational-age-specific and weight-adjusted medians for serum AFP and total beta-hCG were calculated. Risk for fetal Down syndrome (FDS) was derived by mathematical modeling of the medians together with maternal age. Amniocenteses were offered to women with a calculated FDS risk of 1:270 or greater. RESULTS: The gestational-age-specific and weight-adjusted medians for maternal serum AFP were similar to previous studies while that of total beta-hCG were higher. A total of 101 patients (6.1%) were classified as being high risk for FDS, including 3.4% (48/1394) of those younger than 35 years of age and 21.7% (53/244) of those who were 35 or above. There were 4 cases of Down syndrome, 1 case of Tumer syndrome and 1 of Edward syndrome. Three out of the four cases of Down syndrome were screened positive, corresponding to a detection rate of FDS of 75%. A case of Tumer syndrome was also screened positive. A case of trisomy 18 was found to have very low levels of AFP [0.262 multiple of median (MoM)] and total beta-hCG (0.115 MoM). CONCLUSIONS: Maternal serum screening using double biochemical markers (AFP and total beta-hCG) in combination with gestational dating by ultrasonography is effective in the detection of fetal Down syndrome and possibly other chromosomal disorders in Chinese pregnant women. PMID- 11601291 TI - Clinical analysis of 69 patients with familial benign chronic pemphigus. AB - OBJECTIVE: To analyze the clinical feature, efficacy of treatment and prognosis in familial benign chronic pemphigus (FBCP). METHODS: Sixty-nine cases of FBCP were retrospectively analyzed. RESULTS: The ratio of male to female is 3.93:1 in 69 patients (55 males, 14 females). The mean age at the onset was 29.09 years (3 60 years). There was familial history in 27 families in all of the cases. The lesion usually involved in genital area, neck, axillae and popliteal fossa. Erythemas and vesicles on the soles were seen only in 1 case. Histopathologically 44 cases had special features of FBCP, and immunopathologically 8 cases were direct immunofluorescence (DIF) negative, in which one case had C3 linear deposition along dermoepidermal junction. The combined regimen was more effective. The low-dose X-ray could improve the effect. CONCLUSION: The disease is transmitted as an irregular autosomal dominant trait. The condition in males is more frequent than that in females, probably owing to the different level of female hormone in both sexes. Our patients have the same clinical features as those reported in the literature, but the erythema, vesicle lesions on sole have not been documented in the literature. The combined therapy should be adopted in this condition. PMID- 11601290 TI - Rapid expression of vascular endothelial growth factor in early acute myocardial ischemia in rats. AB - OBJECTIVE: To study the expression of vascular endothelial growth factor (VEGF) in different parts of heart during early acute myocardial ischemia. METHODS: The expression of VEGF in control and study group in rats was performed with the Strept Avidin-Biotin-Peroxidase Complex (SABC) method. RESULTS: A rapid expression of VEGF in ischemic areas was observed 1 hour after the ligation of rat left anterior descending (LAD) coronary artery, and in peri-ischemic and non ischemic areas 3 hours after ischemia. The grade of expression of VEGF increased with the continuation of myocardial ischemia, the positive myocytes of SABC-VEGF staining mainly localized in peri-ischemic areas 5 hours after ischemia. No expression of VEGF in control group was found. CONCLUSION: The expression of VEGF may be up-regulated in rapid and continuous manner with characteristic spatial and temporal kinetic during early acute myocardial ischemia. PMID- 11601292 TI - Hyperplastic callus in osteogenesis imperfecta. PMID- 11601293 TI - The proceedings of the 4th International and the 2nd Chinese National Meeting of Tropical Medicine and Parasitology. PMID- 11601295 TI - [Pharmacognosy of hog nail of Sus scrofa domestica Brisson]. AB - This paper reports the characteristics of microscopic and physicochemical identifications, as well as the determination of amino acids and inorganic elements in Unguis Suillus of the crude drug Hog Nail of Sus scrofa domestica. The results show that the protein content of Unguis Suillus amounts to 80.65%. The amino acids in the drug consist of 7 essential amino acids and 9 nonessential amino acids. The main inorganic elements are Na, Mg, Al, Si, P, S, Cl, K, Ca, Fe and Zn. PMID- 11601294 TI - [Differentiation of original plants of xihuangcao by using random amplified polymorphic DNA (RAPD) markers]. AB - Four original plants of Xihuangcao have been differentiated from each other by random amplified polymorphic DNA polymorphism. The results show that RAPD technique is an effective method for identification and quality study of Chinese medicinal materials. PMID- 11601296 TI - [Analysis gastrodin in various types of Gastrodia elata Bl]. AB - This paper analyzes the gastrodin in various types of Gastrodia elata quantitatively and qualitatively by means of TLC and HPLC. The TLC result shows the various types of G. elata to be almost the same. The HPLC result reveals that the peak number and retention times of these various types are similar, but the peak areas or peak heights are different. PMID- 11601297 TI - [Effects of processing on toxicity and pharmacological action of flos Genkwa]. AB - Daphne genkwa can not be taken unless the toxicity is removed. The study on the effect of processing on the toxicity and pharmacological action of Flos Genkwa has shown that the toxicity of vinegar-processed Flos Genkwa is lower than that of the rude drug, but the pharmacological action is better. Both genkwanin and its vinegar-processed imitation have antitussive and expectorant actions without marked difference in efficacy. Both yuanhuacine and its vinegar-processed imitation could cause contraction of the extracorporeal womb and the intestinal canal, and the efficacy is almost similar in the concentration of 1:10(-5)-10( 6). The gestational womb was observed more sensitive than the normal one. PMID- 11601298 TI - [Experimental studies on the quality of ostracean powder]. AB - In this paper, the contents of astragaloside IV, calcium carbonate, amino acids and trace elements in Ostraacean Powder have been measured. These studies present a scientific evaluation on the quality of Ostracean Powder. PMID- 11601299 TI - [Chemical constituents in aerial part of Ampelopsis grossedentata(Hand.-Mazz.) W.T. Wang]. AB - Five compounds were isolated from the aerial part of Ampelopsis grossedentata and identified as ampelopsin, ambrein, beta-sitosterol, myricetin and myricitrin by means of UV, IR, 1HNMR and MS spectral analysis. They were isolated from this plant for the first time. PMID- 11601300 TI - [Isolation and identification of triterpenoids from Rubus alceaefolius Poir]. AB - Five triterpenoid compounds were isolated from Rubus alceaefollius. On the basis of the chemical and spectral analysis the compounds were identified as corosolic acid, tormentic acid, niga-inchigoside F1, trachelosperoside E-1 and suavissimoside R1, were obtained from the plant for the first time. PMID- 11601301 TI - [Chemical constituents of Phyllanthus urinaria L. and its antiviral activity against hepatitis B virus]. AB - Studies on the chemical constituents of Phyllanthus urinaria and its antiviral activity against hepatitis B virus were completed. Eleven compounds have been isolated. Two of them are new compounds methyl ester dehydrochebulic acid and methyl brevifolin carboxylate. Antiviral experiments on HBsAg in vitro and liver damage caused by CCl4 have shown that. Phyllanthus urinaria possesses antiviral activities against HBV. PMID- 11601302 TI - [Quantitative analysis of salidroside and lotaustralin in Rhodiola by gas chromatography]. AB - The contents of salidroside and lotaustralin in 10 species of Rhodiola genus were determined by GC method with propionylated mannitol as internal standard compound under the condition of silylation with hexamethyl disilazane:trimethyl chlorosiland (2:1). The recoveries are 100.05% (salidroside) and 97.85% (lotaustralin). PMID- 11601303 TI - [Determination of content of radix Paeoniae Rubar(Chishao)801 in rabbit's plasma by HPLC]. AB - A HPLC method was used to determine the content of Radix Paeoniae Rubar (Chishao)801 in rabbit's plasma, using Nucleosil C18 column, methanol, water and glacial acetic acid (48:50:2) as mobile phase ethye 4-hydroxybenzoate as internal standard, and UV-detector(lambda max: 275 nm, AUFS: 0.02). The average recovery was 96.70%(C: 2.5 micrograms/ml) and 98.86%(C: 5 micrograms/ml) respectively. The lowest determination limit was 0.1 microgram/ml. The method is simple, accurate, sensitive and reliable. PMID- 11601304 TI - [Effect of xueling on relating substances of renal hypertension in rats]. AB - Xueling(p.o.) obviously reduces the aldosterone content of renal hypertension rats, but not affecting markedly the endothelin, atrial natriuretic factor, calcitonin gene-related peptide, thromboxane B2 and 6-keto-prostaglandin F1 alpha. The content reduction of aldosterone is one of the mechanisms to lower blood pressure. PMID- 11601305 TI - [Protective effect of Astragalus membranaceus (Fisch.) Bge. and Hedysarum polybotrys Hand.-Mazz. on experimental model of cerebral ischemia in rats]. AB - The experimental model of middle cerebral artery embolism in rats was made by inserting nylon thread. It was discovered that Astragalus membranaceus decoction(both 4.26 g.kg-1 and 7.1 g.kg-1) could reduce the capillary hyperpermeability and alleviate the dyskinesia caused by cerebral ischemia in rats. Purified Hedysarum polybotrys decoction (waste substances removed with alcohol after decocting with water) (12.5 g.kg-1) could reduce the water content in brain caused by occlusion of bilateral carotids in rats. Purified Hedysarum polybotrys decoction showed a tendency to reduce the water content in brain, but without statistical significance. PMID- 11601306 TI - [Observation on inhibitory effect of Coptis alone and its combination with Scutellaria and Liquorice on the growth of Staphylococcus aureus]. AB - Using MIC as relative index, an observation was made on the growth inhibition of Staphylococcus aureus by Coptis alone or in combination with Scutellaria and or liquorice. The result shows that when Coptis is combined with Scutellaria, the bacteriostatic effect gets weaker for Scutellaria, but remains unchanged for Coptis, and when Scutellaria takes greater percentages in the combination, the effect of Coptis seems to be stronger. When Coptis is combined with liquorice, whatever the respective percentages may be, the effect tends to get weaker. When the three drugs are used in combination, the effect remains unchanged or even gets stronger for Coptis or liquorice, but tends to decrease for Scutellaria. Coptis used singly or in combination with Scutellaria or liquorice is inferior in bacteriostatic effect to the combination of the three drugs. The mechanism is yet to be further studied. PMID- 11601307 TI - [Identification of 12 species of hailong and haima by HPCE]. AB - Twelve species of Hailong and Haima were analyzed by HPCE(high performance capillary electrophoresis) and significant differences among the species were found. The method is rapid, highly efficient and reproducible, thus providing experimental criteria for the qualitative identification of these two crude drugs. PMID- 11601308 TI - [Identification of mineral drug limonitum]. AB - Two kinds of Chinese mineral drug Limonitum (a special ore of Limonitum in egg type and a general ore of Limonitum) were identified. The results showed that the main chemical components and optical characters of the two drugs were similar, but there were considerable differences in properties, element contents and IR spectra. PMID- 11601309 TI - [Infrared spectra of Caulis Mahoniae and 6 species of medicinal plants of the same genus]. AB - Based on the IR spectra of the petroleum ether extract, ethyl ether extract and water extract of Caulis Mahoniae and six species of medicinal plants of the same genus, it has been found out that the differences of chemical constituents among the samples can be reflected by the changes of IR spectra. This method can be used as a rapid and exact means to search unknown species with same chemical constituents in the same genus and family. PMID- 11601310 TI - [Cell clone technique for Taxus cuspidata Sieb. et Zuicc]. AB - The cell clone technique was studied for Taxus cuspidata with needle-derived calli cells. The plating efficiency(PE) of the third generation of suspension culture cells was found to be the highest one and the PE of the medium solidified with phytagel was found to be almost the same as that of the medium solidified with low melting agarose gel. Solid-solid double layer culture was found to promote the PE of Taxus cuspidata cells moderately. A large number of stable cell lines with high growth rate were obtained and the browning problem of cells was completely solved via plate culture of the cell clones of T. cuspidata. The growth rate of the best cell line reached 0.4 g.FW/g.FW.d. PMID- 11601311 TI - [Seasonal and sexual variety of Ginkgo flavonol glycosides in the leaves of Ginkgo biloba L]. AB - HPLC methods have been developed for the determination of Ginkgo flavonol glycosides in the Ginkgo biloba leaves obtained from May to November in the fallen leaves and in the leaves obtained from female and male trees. The method includes hydrolysis of the leaves and subsequent quantitative chromatographic assay of the aglycones, followed by calculation of Ginkgo flavonol glycosides content. The result shows that the leaves obtained in May have the highest content of 0.96%, and then the content decreases from May to August, and from August to November remains almost the same, that is 0.5% also. Fallen leaves have the lowest content of 0.44%. The content range is 0.96% to 0.44%. Male trees have higher content of glycosides than female trees. PMID- 11601312 TI - [Influence of processing on effective components in rhizoma chuanxiong]. AB - The contents of the essential oil ferulic acid in different processed products of Rhizoma Chuanxiong were determined, and the changes of constituents in the essential oil before and after processing were compared. The results have provided a scientific basis for processing Rhizoma Chuanxiong. PMID- 11601313 TI - [Determination of quercetin in changyanning tablets by RP-HPLC]. AB - The quercetin in Changyannning Tablets was determined by reverse phase HPLC on Shim-Pack CLC-ODS column(150 mm x 4.6 mm) with UV detector and methanol-water phosphoric acid(55:44.6:0.4) as mobile phase (1.0 ml/min). The average recovery relative standard deviation were 99.7% and 1.01% respectively. PMID- 11601314 TI - [A research on chemical dynamic changes and drug efficacy of shengmaisan compound prescription: chemical researches on shengmaisan prescription(II)]. AB - The content changes of 5-hydroxymethyl-2-furaldehyde(5-HMF), a new compound reported in the previous paper, in eight prescriptions of different composition were further determined by HPLC with a view to find the chemical dynamic changes and compatibility of medicines. The contents of 5-HMF in different combinations of Radix Ophiopogonis and Fructus Schisandrae, different boiling times and boiling frequency were examined. The results indicated that 5-HMF was produced in the boiling process of Radix Ophiopogonis and Fructus Schisandra combined. The contents of 5-HMF would increase with the increase of Radix Ophiopogonis amount, reaching the highest value after 1.5 h boiling and two times of boiling. PMID- 11601315 TI - [Chemical constituents of Conyza blinii Levl]. AB - Five compounds were isolated from the aerial part of Conyza blinii. On the basis of physicochemical properties and spectroscopic analysis, they were identified as alpha-spinasterol, 5, 8-dihydroxy-7, 3', 4'-trimethoxyflavone, caffeic acid, quercetin and syringic acid. All these compounds were isolated from the plant of C. blinii for the first time. PMID- 11601317 TI - [The effect of Codonopsis pilosula (Franch.) Nannf. on gastric acid, serum gastrin and plasma somatostatin concentration in dogs]. AB - The results were obtained by oral administration of the decoction of Codonopsis pilosula in three different doses(10 g, 20 g, 40 g) to 5 dogs with Heidenhain pouch. No significant changes occurred in the acidity output of Heidenhain pouch and plasma somatostatin concentration out of the oral administration (P > 0.05). A significant increase occurred in serum gastrin concentration (P < 0.05 or P < 0.01) 150 min after a dose of 10 g, 90 min and 150 min after doses of 20 g, and 30 min, 60 min, and 150 min after doses of 40 g. PMID- 11601316 TI - [Analysis of constituents of essential oils from flos Magnoliae]. AB - The constituents of essential oils from Magnolia biondii, M. denudata and M. sprengeri were analysed by GC-MS qualitatively and GC quantitatively. Ninety-one compounds of M. biondii, seventy-one compounds of M. denudata and eighty-eight compounds of M. sprengeri were identified at rates of 97.37%, 97.66% and 95.68% respectively. PMID- 11601318 TI - [Effect of rotundine on gastric acid and pepsin activity in rats]. AB - A test was made on the effect of rotundine on the secretion of gastric acid and pepsin activity in rats. Compared with the control group, rotundine(> or = 17.1 mg/kg) inhibited gastric acid and decreased secretion of gastric juice(P < 0.01), but had no influence on pepsin activity. There was a negative relationship between total acidity and pH of gastric juice (r = -0.9818). PMID- 11601319 TI - [An experimental study on antitumor activity of psoralen on mammary cancer cell line EMT6 in vitro and in vivo]. AB - To investigate the antitumor activity of psoralen on mammary cancer cells of EMT6 line, the cytotoxity of the drug against EMT6 cells was tested by MTT assay; an experimental therapy was carried out in 15 nude mice that were subcutaneously injected with EMT6 cells; the morphological changes of tumor tissues were observed under electron microscope; and the DNA content was measured and analysed with a computerized MPV-microspectrophotometer. The result shows that psoralen has a strong antitumor effect on mammary cancer EMT6 cells both in vivo and in vitro, with an IC50 value of 2.23 micrograms/ml. The antitumor effect might be related to the relative decrease of cell DNA content and the degeneration and cavitation of cellular mitochondriums. Therefore psoralen may be an effective agent for the treatment of mammary cancer. PMID- 11601320 TI - [A review of the researches on the cultivation of medicinal plants in past years]. PMID- 11601321 TI - The Fifth Asian Dermatological Congress and the development of dermatology in China. PMID- 11601322 TI - In vitro activities of five antifungal agents against pathogenic Exophiala species. AB - OBJECTIVES: To examine the in vitro activities of five antifungal agents against common pathogenic Exophiala species; to detect the minimum inhibitory concentration (MIC) discrepancies among different drugs and different species; to evaluate the role of the influence factors in MIC determination; and to establish a standard method for the antifungal susceptibility testing of Exophiala spp. METHODS: MICs of itraconazole (ICZ), fluconazole, ketoconazole, amphotericin B (AmB) and 5-flucytosine against 5 species (57 strains) of Exophiala spp were determined by modified NCCLS M27-A broth microdilution method. Two inoculum sizes (0.5 x 10(3)-2.5 x 10(3) CFU/ml and 0.5 x 10(4)-2.5 x 10(4) CFU/ml) and three incubation times (4, 7 and 10 days) were evaluated. The minimum fungicidal concentrations (MFC) of itraconazole against 20 Exophiala strains were also detected. RESULTS: All the tested Exophiala species were sensitive to AmB and ICZ. MICs varied among different species and drugs. Resistant strains to different drugs existed in this genus. The proper inoculum density was about 0.5 x 10(3) CFU/ml to 2.5 x 10(3) CFU/ml, and the 4-day incubation time was suitable for more than 90% of the strains. CONCLUSIONS: AmB or ICZ may serve as the first choice in treatment of phaeohyphomycosis. A standard microdilution procedure for MIC detection of Exophiala species is established in this experiment. The inoculum size and incubation time are the essential factors in the standardization of antifungal susceptibility testing of filamentous fungi. We hope this experiment may correlate well with the clinical treatment of phaeohyphomycosis caused by Exophiala species. PMID- 11601324 TI - Significant reduction of T-cell chemotaxis to MCP-1 in patients with primary and metastatic melanoma. AB - OBJECTIVE: To address whether circulating T-cells from the patients with primary and metastatic malignant melanoma show altered chemotaxis to monocyte-chemotactic protein 1 (MCP-1) and its relation to tumor infiltrating lymphocyte (TIL) and metastasis. METHODS: Chemotactic response of T-cells towards MCP-1 and immuno histochemistry study of TIL and tumor-associated-macrophages (TAM) were investigated in patients with primary and metastatic melanoma compared to patients with basal cell carcinoma and healthy persons. RESULTS: T-cells from patients with primary and metastatic melanoma showed a significantly decreased chemotactic migration towards MCP-1 and T-cells from patients with basal cell carcinoma showed normal chemotactic response. Immuno-histochemistry study showed that there was no correlation between the number of TIL and the decreased chemotaxis of circulating T-cells to MCP-1 in patients with primary melanoma. CONCLUSIONS: Circulating T-cells from patients with primary and metastatic melanoma showed a MCP-1-specific decrease in chemotactic migration. This may be due to abnormal expression or modulation of MCP-1-receptor expression on these cells. PMID- 11601323 TI - Isolation and identification of Mycoplasma genitalium from high risk populations of sexually transmitted diseases in China. AB - OBJECTIVE: To investigate Mycoplasma genitalium (Mg) infection in high risk populations of sexually transmitted diseases (STDs) in China by means of culture, Mg-DNA detection, observation under an electron microscope (EM) and an atomic force microscope (AFM). METHODS: 227 urogenital specimens taken from both patients in clinics and high risk populations of STDs in Beijing, Nanjing and Shanghai areas were cultured in SP-4 medium for isolation of Mg. Suspicious positive strains were identified first by PCR technique which could amplify the special DNA fragments of Mg adhesion protein (Mg-Pa) and 16S-rRNA sequences. The morphologic features of Mg were observed under EM and AFM. RESULTS: Eight strains were isolated from the 227 specimens, the total positive rate was 3.52%. The isolated strains met the criteria of growth and metabolic conditions required by Mg. Specific fragments of Mg-DNA (374 bp based on Mg-Pa and 402 bp on 16S-rRNA primers, respectively) could be amplified from both the isolates and the genital secretions. Under EM and AFM, Mg showed different shapes, including flask, pear, spindle and globe shape. The typical shape of Mg was flask or pear shape with projecting neck portion and broadened terminal structure under EM and with constrictive ring between the neck and body under AFM. CONCLUSION: Mg infection exists in high risk populations of STDs in China. We highly suggest the use of AFM in dermatological study. PMID- 11601325 TI - Allele loss on chromosome 9q22.2-22.3 in sporadic basal cell carcinoma in Chinese. AB - OBJECTIVE: To investigate the role of allele loss on chromosome 9 in the pathogenesis of basal cell carcinoma (BCC) by examining the loss of heterozygosity in sporadic basal cell carcinoma and other cutaneous tumors. METHODS: DNA samples were isolated from the tumors, the matched adjacent normal skin and the blood of patients with sporadic basal cell carcinoma (14), squamous cell carcinoma (25) and Bowen's disease (5) by phenol-chloroform extraction. In our study, we used two microsatellite markers on chromosome 9, one was locus D9S319 (9p21), and the other was D9S299 (9q22.2-22.3). After PCR was performed, the samples were electrophoresed through 5% denatured polyacrylamide gels which were dried and exposed to Fuji XR films. RESULTS: Loss of heterozygosity with D9S319 (9p21) marker was not observed in the 10 informative cases of sporadic basal cell carcinoma, 19 squamous cell carcinoma and 4 Bowen's disease. Allelic deletion of D9S299 was not seen in the 21 informative cases of squamous cell carcinoma and 4 Bowen's disease. D9S299 (9q22.2-22.3) allele loss occurred in 2 of the 10 informative cases of sporadic basal cell carcinoma, indicating that there might be a susceptible tumor suppressor gene on chromosome 9, and loss of this allele might play an important role in the development of basal cell carcinoma. Inactivation of Drosophila patch (PTCH) (MSSE gene ESS1) in BCC might be necessary, if not sufficient, for BCC carcinogenesis. CONCLUSION: Chromosome 9q22.2-22.3 may contain a putative tumor suppressor gene, and the loss of this gene may play an important role in the development of sporadic basal cell carcinoma. PMID- 11601326 TI - Quantitative in vitro assessment of drug phototoxicity by a chemiluminescence method. AB - OBJECTIVE: To establish a test model for phototoxic agents using the method of chemiluminescence. METHODS: The phototoxicity of pipemidic acid, doxycycline, griseofuvin and chlorpromazine was detected. These agents and distilled water were irradiated with ultraviolet A (UVA) in the presence of nicotinamide adenine dinucleotide reduced (NADH), and the duplicated samples were incubated in the dark as dark controls. Then luminol was added to the test samples, and the chemiluminescent value was counted and calculated. RESULTS: Chemiluminescent values of pipemidic acid, doxycycline and griseofuvin were significantly higher than those in controls. The result of linear regression analysis showed that phototoxic intensity was linear correlated with UVA dosage. The regression coefficient for distilled water was 0.56, indicating that the luminescent value (LV) rose slightly after UVA irradiation. For pipemidic acid, griseofuvin and doxycycline, the regression coefficients reached 76.96, 254.33 and 92.61 respectively, significantly increased in comparison with those of negative controls (P < 0.01). CONCLUSION: Phototoxicity of pipemidic acid, doxycycline and griseofuvin can be detected with the method of chemiluminescence. PMID- 11601327 TI - Experimental studies on topoisomerase inhibitor camptothecin as an antipsoriatic agent. AB - OBJECTIVES: To elucidate the therapeutic mechanism of topical camptothecin (CPT) in treating psoriasis and to detect the effects of CPT on keratinocyte proliferation, differentiation and apoptosis. METHODS: Mitotic numbers in mouse vaginal epithelium at estrus and numbers of scale with granular layer per 100 scales in mouse tail epidermis were determined in vivo. Experiments on cultured normal human keratinocytes were performed using the methods of crystal violet staining, absorbance-cell number converting, cell counting and quantitation of morphologic changes during differentiation, transglutaminase assay and nucleosomal enrichment assay. RESULTS: Inhibition of cell proliferation and promotion of cell differentiation by camptothecin were showed in animal models and were reconfirmed in cultured keratinocytes. Apoptosis was induced by camptothecin and was showed by activation of "tissue" transglutaminase and increase in nucleosomes. The endonuclease activity was reduced by an endonuclease inhibitor aurintricarboxylic acid. CONCLUSION: The therapeutic effects of camptothecin on psoriasis can at least partly be explained by its multiple effects on DNA as a topoisomerase inhibitor. PMID- 11601328 TI - Effects of ultraviolet-irradiated urocanic acid on IL-10 secreted by T lymphocytes. AB - OBJECTIVE: To further investigate the effects of ultraviolet (UV)-irradiated urocanic acid (UCA) on T lymphocytes, the effects of cis-UCA on T lymphocyte IL 10 secretion was studied. METHODS: Four groups of normal lymphocytes were cultured in RPMI-1640 containing 15% fetal calf serum. Besides negative and phytohemagglutinin (PHA) positive control, the cis-UCA and trans-UCA groups were set. The number of lymphocytes was 1.5 x 10(6). PHA was 0.05 mg/ml in each group. Both cis-UCA and trans-UCA were detected by 1.00, 0.75, 0.50 and 0.20 mmol/L respective concentrations. IL-10 was detected by ELISA method after 48 hours' culture. IL-10 mRNA expression level was assayed by RT-PCR. RESULTS: The results indicated cis-UCA could reduce IL-10 secreted by T lymphocytes much more than trans-UCA (t = 2.91, P < 0.05) could. It was also found that the concentrations of cis-UCA were negatively correlated with IL-10 levels (r = -0.99, tr = 9.23, P < 0.01). The IL-10 mRNA expression of T lymphoctytes was inhibited by cis-UCA. CONCLUSION: Our investigations revealed that cis-UCA, a major UV receptor in the stratum comeum of epidermis, could inhibit T lymphoctes secreting IL-10 by suppressing IL-10 mRNA expression, finally affects the humoral immune response. PMID- 11601329 TI - SSA/Ro antigen expressed on membrane of UVB-induced apoptotic keratinocytes is pathogenic but not detectable in supernatant of cell culture. AB - OBJECTIVES: To better understand the potential effect of ultraviolet light on the photosensitivity of patients with lupus erythematosus (LE), to elucidate the mechanisms of SSA/Ro antibody formation after UV exposure, and to investigate the role of this autoantibody in the pathogenesis of skin lesions. METHODS: Primary human keratinocytes were cultured in Medium-154. After ultraviolet-B light (UVB) irradiation, the keratinocytes were treated with affinity-purified anti-SSA/Ro sera and stained with FITC-labeled goat-anti-human IgG and propidium iodide (PI), followed by enzyme digestion with RNase, RNase-free DNase or RNase plus DNase. As target cells, the irradiated keratinocytes were incubated with affinity-purified anti-SSA/Ro sera, with or without fresh human sera as complement. The supernatants of irradiated keratinocytes were analyzed with ELISA method for SSA/Ro antigens. RESULTS: UVB irradiation induced apoptotic blebs on the cell surface. The blebs were composed of ribonucleoproteins and contained SSA/Ro antigens. SSA/Ro antigens expressed on UVB irradiated keratinocytes bound to affinity-purified anti-SSA/Ro sera, leading to complement-dependent cytotoxicity. However, no SSA/Ro antigens were detected in the supernatants. CONCLUSIONS: SSA/Ro, a ribonucleoprotein antigen expressed on UVB irradiated keratinocytes, may be recognized and presented to immune cells by a direct cell-cell contact other than be eliminated into the circulation. PMID- 11601330 TI - Effects of nitric oxide inhibitor on prostacyclin biosynthesis in portal hypertensive rats. AB - OBJECTIVE: To evaluate the effects of nitric oxide inhibitor on prostacyclin (PGI2) biosynthesis and the role of PGI2 in hyperhemodynamics of portal hypertension. METHODS: Sprague Dawley rats were divided into four groups: intrahepatic portal hypertension (IHPH) by injection of CCl4, prehepatic portal hypertension (PHPH) by stenosis of the portal vein, end-to-side portacaval shunt (PCS), and sham-operated controls (SO). Animals of each group were subdivided into 2 groups: systemic administration of nitric oxide inhibitor L-NMMA and vehicle. The radioactive microsphere method was used for hemodynamic study. The level of plasma PGI2 (6-keto-PGF1 alpha) was measured by radioimmunoassay. RESULTS: The characteristics of hyperdynamic circulatory state including increased cardiac output and splanchnic blood flow, decreased mean arterial blood pressure, total peripheral vascular resistance, and splanchnic vascular resistance were observed in IHPH, PHPH and PCS rats. The magnitude of hyperhemodynamics was in the order of PCS > PHPH > IHPH rats. The hyperdynamic circulatory state in IHPH, PHPH and PCS rats could be effectively reversed by L NMMA to the baseline values of hemodynamics in SO rats. The baseline concentrations of plasma 6-keto-PGF1 alpha (ng/ml) in PHPH, IHPH, PCS, and SO rats were 6.93 +/- 2.43, 5.09 +/- 2.27, 2.36 +/- 1.01 and 1.56 +/- 0.61, respectively. The concentrations of plasma 6-Keto-PGF1 alpha in PHPH, IHPH and PCS rats were significantly higher than those in SO rats. Moreover, the concentrations were significantly higher in PHPH and IHPH rats than in PCS rats (P < 0.05). After administration of L-NMMA, the concentrations of plasma 6-Keto PGF1 alpha (ng/ml) in PHPH, IHPH, PCS and SO rats were 7.69 +/- 2.98, 5.68 +/- 2.66, 5.50 +/- 0.79, 5.02 +/- 2.86, respectively. As compared to the baseline value, the concentrations of 6-keto-PGF1 alpha rats were slightly increased in IHPH, PHPH rats (P > 0.05), but significantly increased in PCS and SO rats (P < 0.05). CONCLUSIONS: In this study, the hyperdynamic circulatory state in portal hypertensive rats and portacaval shunt rats was completely reversed by L-NNMA to normal, but the level of 6-keto-PGF1 alpha was still elevated. The results indicate that PGI2 is not involved in hyperhemodynamics of portal hypertension. PMID- 11601331 TI - Molecular mechanisms of drug resistance in Mycobacterium tuberculosis clinical isolates. AB - OBJECTIVE: To study the molecular mechanisms of drug resistance in Mycobacterium (M). tuberculosis, to evaluate the value of the beta subunit of RNA polymerase (rpoB), the ribosomal siz protein (rpsL), 16Sr RNA (rrs), catalase-peroxidase gene (katG) genes, and inhA regulatory sequence as genetic markers for rifampin (RFP), streptomycin (SM), isoniazid (INH) resistance, and to develop new methods for detecting the drug resistance. METHOD: The rpoB, rpsL, rrs, katG genes, and inhA regulatory sequence in 85 M. tuberculosis isolates were analyzed with polymerase chain reaction (PCR), PCR-single-stranded conformation polymorphism analyses (SSCP), PCR-nucleotide sequence analyses (NS) and PCR-restriction fragment length polymorphism (RFLP). RESULTS: The sensitivity of amplifying the drug-resistant genes with PCR was 1-10 pg DNA. Twenty-eight drug-sensitive strains had no alterations in the rpoB, rpsL, rrs, katG genes, and inhA regulatory sequences. 93.3% of 45 M. tuberculosis RFP-resistant (RFPr) isolates had rpoB mutations. Codon 531 and 526 of the rpoB are the most common sites of nucleotide substitutions. 72.5% of 40 SM-resistant (SMr) isolates had an identical mutation at codon 43 of the rpsL gene. No isolates had a mutation at codon 88 of the rpsL. Only 7.5% of these SMr isolates had A-to-C transversions at position 513 of the rrs gene. Of 34 INH-resistant (INHr) isolates, 11.8% had complete katG deletions, 55.9% had mutations in the selected region of katG. Only 8.8% had alterations in the inhA regulatory sequences. 60.9% of RFPr, INHr, and SMr isolates had mutations in genetic markers for these drug resistance. CONCLUSIONS: Most drug resistance in M. tuberculosis was due to simple mutations occurring in chromosomally encoded genes. Alterations in rpoB, rpsL and katG gene may be the important mechanism of M. tuberculosis resistance to RFP, SM, and INH. PCR, PCR-SSCP, PCR-NS, and PCR-RFLP are going to become the simple, rapid and reliable diagnostic tests for drug resistance in M. tuberculosis. PMID- 11601332 TI - Preliminary studies on tin miners' lung cancer tissue related genes by differential display mRNA. AB - OBJECTIVE: To study the genes related to tin miners' lung cancer tissue. METHOD: Differential display mRNA. RESULTS: Thirty cDNA fragments which differentially expressed in lung cancer tissues and the same patient's normal lung tissues were discovered. Among these, 16 expressed in lung cancer tissues, not in normal lung tissues; fourteen expressed on the contrary. Six cDNA fragment sequence was determined. Five sequences CG2, CG7, CG8, CA5 and CC6 had less than 75% homology with known sequences in GenBank BLAST, so they were believed to be new sequences which we have recorded in Genbank. Only one fragment coded CG3 had homology up to 95% with human ribosome protein L27a gene. CONCLUSIONS: mRNA differential display provides a unique and powerful experimental system to study differential gene expression in tin miners' lung cancer tissues and the same patient's normal lung tissues. Using the system, differential expression of 30 cDNA fragments was observed. Six of them may be used to study the molecular mechanism of miners' radon-associated lung cancer. PMID- 11601333 TI - Lack of human papillomavirus types 16 and 18 DNA in esophageal squamous carcinoma cell lines. AB - OBJECTIVE: To assess the role of human papillomavirus (HPV) in the carcinogenesis of the esophageal carcinomas in a high-incidence geographical area in Northern China. METHODS: The presence of HPV types 16 and 18 DNA in the three esophageal carcinoma cell lines was examined by type-specific polymerase chain reaction (PCR). RESULTS: No HPV type 16 and 18 DNA was found in any of the three esophageal carcinoma cell lines. CONCLUSION: The results suggest that the role of HPV in human esophageal carcinogenesis in a high-incidence geographical area remains to be elucidated. PMID- 11601334 TI - cDNA representational difference analysis of differentially expressed cDNA sequences in human nasopharyngeal carcinoma. AB - OBJECTIVE: To search differentially expressed sequences correlated with pathogenesis of human nasopharyngeal carcinoma (NPC), including the candidates of tumor suppressor genes. METHODS: Representational difference analysis (RDA) was performed to isolate differentially expressed sequences between cDNA from normal human primary cultures of nasopharyngeal epithelial cells and cDNA from NPC cell line HNE1. The source of differentially expressed products were proved by Southern blot, Northern blot and in situ hybridization. The fragments were cloned with pGEM-T easy kit and sequenced by the chain termination reaction. RESULTS: Four differentially expressed cDNA fragments were isolated in the fourth subtractive hybridization using cDNA from normal human nasopharyngeal epithelial cells as tester amplicon and cDNA from NPC cell line HNE1 as driver amplicon by cDNA RDA. These differential cDNA fragments revealed that they really came from the tester amplicon and were not expressed or down-regulated in the NPC HNE1 cells. Some of the genes were expressed only in human nasopharyngeal epithelial cells but deleted or down-regulated in the biopsies of NPC. Of these obtained clones, some were the sequences of the human known genes including house-keeping genes, the others represented novel gene sequences. CONCLUSION: The differentially expressed products including the candidates of tumor-suppressor genes may be associated with the initiation of the NPC. PMID- 11601336 TI - Epidermal growth factor receptor participates in growth hormone signaling pathway in cardiac myocytes of neonatal rat. AB - OBJECTIVE: To examine whether growth hormone (GH) promotes the phosphorylation of epidermal growth factor (EGF) receptor and to elucidate the mechanisms by which EGF receptors were transactivated by GH stimulation. METHODS: Cultured cardiac myocytes were stimulated by GH directly or pretreated with inhibitors before GH stimulation. The phosphorylations of EGF receptor and JAK2 were examined with immunoprecipitation followed by Western blotting using anti-phosphotyrosine antibody (4G10). The activities of extracellular signal-regulated kinases (ERKs) were assayed with the method of MBP-containing gel. RESULTS: GH stimulated phosphorylation of EGF receptor in a time-dependent manner. Tyrphostin AG1478, a selective inhibitor of EGF receptor, strongly suppressed GH-induced ERK activation, while tyrphostin AG1295, a selective inhibitor of PDGF receptor, had no effects on the activation of ERKs stimulated by GH in cardiac myocytes. In addition, GH induced tyrosine phosphorylation of JAK2, a cytoplasmic protein tyrosine kinase, in cardiac myocytes. Moreover, tyrphostin B42, an inhibitor of JAK2 suppressed GH-induced phosphorylation of EGF receptor as well as GH-induced activation of ERKs in cardiac myocytes. CONCLUSIONS: GH evokes the phosphorylation of EGF receptor in cardiac myocytes through activating JAK2. Phosphorylated EGF receptor plays a critical role in GH signaling pathway leading to ERK activation in cardiac myocytes. PMID- 11601335 TI - Very low and intermediate density lipoprotein fractions from apolipoprotein E gene-knockout mice induce cholesteryl ester accumulation in J774 macrophages. AB - OBJECTIVE: To investigate the atherogenic role of very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) fraction isolated from plasma of apolipoprotein E (apoE)-knockout mice. METHODS: Containing both VLDL and IDL (apoEko-VLDL/IDL), lipoprotein fraction was isolated from plasma of apoE-knockout mice by ultracentrifugation, and its interaction with J774 macrophages was examined together with its physicochemical properties including lipid content, electrophoresis mobility and apolipoprotein components. RESULTS: ApoEko-VLDL/IDL could be actively taken up by J774 macrophages, resulting in marked cholesterol ester accumulation in the cells (55 +/- 9 nmol/mg cell protein), which was a 7 fold increase over the corresponding lever induced by low density lipoprotein and significantly higher than non-loaded group (P < 0.01). CONCLUSION: ApoEko VLDL/IDL induced significant cholesterol ester accumulation through an apoE independent pathway. This pathway may explain, partly the mechanism of cholesterol deposition in arterial wall in apoE-knockout mice. PMID- 11601337 TI - Regulatory roles of IL-12, IL-4 and IFN-gamma on IgE synthesis in atopic patients. AB - OBJECTIVE: To investigate the mechanism of cytokine regulation in atopy by analyzing the effects of three major cytokines, IL-4, IL-12 and IFN-gamma on in vitro IgE synthesis of human peripheral blood mononuclear cell (PBMC) from normal individuals and atopic patients. METHODS: We investigated 5 normal individuals and 22 atopic patients including 12 allergic asthma, 8 allergic rhinitis and 2 atopic dermatitis. Human PBMCs were separated and incubated in 96-wells culture plates with different cytokines. Cultured for 7 days, the supernatant was collected and the contents of IgE synthesized in vitro were detected. RESULTS: There was no IgE synthesis in vitro of PBMC from all the normal individuals and 7 patients, however, other 15 patients' PBMC could produce IgE in vitro. We found that rhIL-4 could induce in vitro IgE synthesis of PBMC from all the normal individuals and 22 patients. rhIL-12 could inhibit IgE synthesis induced by rhIL 4. Further investigation of cytokine effects on IgE synthesis was conducted in 15 patients whose PBMCs did produce IgE in vitro (average level was 714 +/- 1105 ng/L). The following effects were observed: (1) 10 micrograms/L rhIL-4 could augment in vitro IgE synthesis from 714 +/- 1105 ng/L to higher level of 1483 +/- 1396 ng/L; (2) 20 micrograms/L rhIL-12 could inhibit in vitro IgE synthesis from 714 +/- 1105 ng/L to lower level of 452 +/- 969 ng/L; (3) rhIL-12 could block IgE synthesis induced by rhIL-4 to the level of 583 +/- 1084 ng/L; (4) 50 micrograms/L IFN-gamma could inhibit in vitro IgE synthesis from 714 +/- 1105 ng/L to the level of 461 +/- 1063 ng/L. CONCLUSIONS: rhIL-4 could induce in vitro IgE synthesis, rhIFN-gamma could inhibit the in vitro IgE synthesis and rhIL-12 could antagonize rhIL-4 effect on in vitro IgE synthesis of PBMC from atopic patients. PMID- 11601338 TI - Diagnostic role of antibodies to glutamic acid decarboxylase in latent autoimmune diabetes mellitus in adults. AB - OBJECTIVE: To investigate the diagnostic role of antibodies to glutamic acid decarboxylase (GAD65-Ab) in latent autoimmune diabetes of adults (LADA) and the frequency of GAD-Ab in Chinese patients initially diagnosed as non-insulin dependent diabetes mellitus (NIDDM). METHODS: Forty-five control subjects and 195 consecutive inpatients initially classified as NIDDM with > or = 35 years of age at onset and nonketotic history for > 6 months after diagnosis, were recruited. In vitro transcripted and translated recombinant human 35S-GAD65 was used in radioligand assay of GAD-Ab. RESULTS: The overall prevalence of GAD65-Ab was 14.8% (29/195) in NIDDM patients and 2.2% (1/45) in control subjects, respectively. Of the 29 GAD65-Ab positive patients, 17 (58.6%) were insulin deficient while 12 (41.4%) were non-insulin-deficient. The prevalence of GAD65-Ab in NIDDM group with age of < 40 years at diabetes onset, ketotic history, body mass index (BMI) < 21 kg/m2, were significantly higher than that of corresponding control diabetic subgroups (2.5, 4.1 and 3.2 times, respectively). The sex, duration, symptoms of polyphagia, polydipsia, polyuria and weight loss at onset of the disease were not related to the prevalence of GAD65-Ab positivity. CONCLUSIONS: In China, patients initially diagnosed as NIDDM may in many cases suffer from LADA. Testing by GAD65-Ab may be of assistance to identifying LADA at the earliest stage of disease. PMID- 11601339 TI - Effect of lithium on growth of bone marrow stromal cells. AB - OBJECTIVE: To investigate the effect of lithium on the growth of bone marrow stromal cells. METHODS: We compared the different effects of lithium with the concentration of 0.1-12 mmol/L on the growth of murine fibroblast colony forming unit (mCFU-F), human fibroblast colony forming unit (hCFU-F) and their intercolonial cells. Pure murine bone marrow stromal cell assay was used to investigate the mechanism. RESULTS: Cultures with 1-4 mmol/L lithium resulted in significant increase in the number of hCFU-F, but distinct decrease in the number of mCFU-F. Furthermore, there were much more endothelial cells between mCFU-Fs than those between hCFU-Fs. The direct effect of 1-4 mmol/L lithium on the growth of pure murine fibroblasts and endothelial cells was stimulatory. Serum-free endothelial cell conditioned medium (EC-CM) could inhibit the growth of mCFU-F. CONCLUSIONS: 1-4 mmol/L lithium has stimulatory effect on the growth of pure murine fibroblasts and endothelial cells. The inhibitory effect of lithium on mCFU-F formation may result from the effect of increased endothelial cells. PMID- 11601340 TI - The relationship between apoptosis and spontaneous hypertension. AB - OBJECTIVE: To explore the relationship between apoptosis and spontaneous hypertension, and the effect of angiotensin converting enzyme (ACE) inhibitor on apoptosis. METHODS: Male spontaneously hypertensive rats (SHR) and normotensive control rats (WKY) at different ages were used, meanwhile, the treatment of SHR with ramipril, an inhibitor of ACE was administered orally (1 mg.kg-1.d-1) to SHR from 3 to 10 or from 5 to 10 weeks of age. Apoptosis in cardiomyocytes of SHR was quantified by a maximal labeling (Lmax) method and the characteristic features of apoptosis were identified by electron microscopy (EM), in situ labeling of DNA strand breaks with terminal deoxynucleotidyl transferase mediated dUTP end labeling (TUNEL) and autoradiographic analysis of DNA fragments. RESULTS: The results of a quantitative method showed an age-dependent increase in apoptosis in the cardiac tissues of SHR. A significant increase in DNA breaks occurred as early as 4 weeks and continued to increase up to a plateau at 16 weeks in the cardiac tissue of SHR whereas there was no significant change in apoptosis in WKY up to 64 weeks. Moreover, after the treatment of SHR with ramipril, an inhibitor of angiotensin converting enzyme (ACE), from 3 to 10 or from 5 to 10 weeks of age, the DNA fragmentation as well as blood pressure (BP) was reduced significantly compared with that of untreated SHR (P < 0.01), and similar to that of the control WKY. CONCLUSION: There is a significant increase in the apoptosis of SHR cardiac tissues with increasing age, and ramipril can significantly prevent the increase of apoptosis and in blood pressure, which demonstrates that apoptosis may be involved in the pathogenesis of genetic hypertension. The inhibition of apoptosis as well as hypertension by ACE inhibitors may open a new avenue for developing therapeutic approach for hypertension. PMID- 11601341 TI - Development of paediatric nephrology in Hong Kong. PMID- 11601342 TI - Serum 1,5-anhydro-D-glucitol as a new clinical marker for glucose metabolism in type 2 diabetics. PMID- 11601343 TI - Primary aldosteronism in pregnancy: review of cases. PMID- 11601344 TI - [Diagnostic significance of cuticular patterns on corolla surface from Pueraria spp]. AB - OBJECTIVE: To provide reference materials for the classification and identification of Pueraria spp. by studying the cuticular patterns on corolla surface. METHOD: The cuticular patterns of corolla were observed under SEM (scanning electron microscope). RESULT: The species of the genus Pueraria are defferent from each other in cuticular patterns. CONCLUSION: The diagnostic characters of the cuticular patterns on corolla surface can be used for the classification and identification of Pueraria spp. PMID- 11601345 TI - [Species and distribution of Ainsliaea medicinal plants in Guizhou]. AB - OBJECTIVE: To gain a clear idea of the medicinal plant Ainsliaea in Guizhou Province. METHOD: Collecting data and conducting spot investigation. RESULT: The distribution, growing environment and medicinal parts of 16 species and 1 variety of Ainsliaea have been clarified, and an index for their identification is presented. CONCLUSION: The investigation has been proved ture and useful in further studying the medicinal plant Ainsliaea. PMID- 11601346 TI - [Identification of commercial Chinese medicine ziwan]. AB - OBJECTIVE: Commercial samples of Ziwan have been investigated and identified to find out the original species in circulation. METHOD: Comparative histological and morphological identification. RESULT: The main original plant species are Aster tataricus, Ligularia fischeri, L. hodgsonii, L. intermedia, L. wilsoniana, L. sibirica var. araneosa, L. veitchiana and L. caloxantha. CONCLUSION: The root and rhizome of A. tataricus are used as Ziwan in most areas of China; but those of Ligularia species are used as Ziwan(named Shanziwan) in southwest, and part of northwest and northeast areas of China. PMID- 11601347 TI - [Effect of different nitrogen concentrations on the growth and contents of berberine in rhizome of Coptis chinensis Franch]. AB - OBJECTIVE: Selecting the best N concentrations for the growth of the Chinese goldthread(Coptis chinensis). METHOD: Employing sand culture procedures. RESULT: The symptoms of shortage of nitrogen were reduced in low N(1/5 N) solution, but the new roots and aerial parts were adversely affected in over nitrogen solution(2 N); the activity of NR in leaves and the content of berberine in rhizome were also low in 2 N solution; the range of optimum N concentrations for growth and high contents of effective components is 1/2 N to 1 N. CONCLUSION: The consumption of nitrogen by Coptis chinensis is lower in the period of maximum contents of effective components in rhizome than in the period of luxuriant growing of the plant. PMID- 11601348 TI - [HPLC determination of two flavonoids in pollen Typhae (puhuang) and its different processed products]. AB - OBJECTIVE: To study the changes of chemical constituents in Pollen Typhae(Puhuang) after processing. METHOD: The contents of two flavonoids, typhaneoside(I) and isorhamnetin-3-O-neohesperidoside(II), in Pollen Typhae (Puhuang) and its different processed products were determined by HPLC. RESULT: Compared with the crude drug, the contents of I and II decreased by 40.22% and 49.87% respectively in the stir-fried product. I and II were not detected in the carbonized product. CONCLUSION: The decrease of contents of I and II after processing shows that the chemical constituents in Pollen Typhae (Puhuang) have changed after processing. PMID- 11601349 TI - [Chemical constituents of Rheum wittrochii Lundstr(I)]. AB - OBJECTIVE: To study the chemical constituents in the root of Rheum wittrochii. METHOD: Chromatography and spectroscopic analysis were used to isolate and elucidate the chemical constituents in the plant. RESULT: Six compounds, namely chrysophanol, physcion, emodin, chrysophanol-8-O-beta-D-glucopyranoside, physcion 8-O-beta-D-glucopyranoside and beta-sitosterol, have been isolated from petroleum ether and ethyl acetate fractions. CONCLUSION: All the above-cited compounds were isolated from the title plant for the first time, and anthraquinone compounds are some of the major constituents of R. wittrochii. PMID- 11601350 TI - [Chemical constituents of essential oil from roots and rhizomes of Valeriana alernifolia Bunge]. AB - OBJECTIVE: To study the chemical constituents of essential oil from the root and rhizome of Valeriana alternifolia. METHOD: The essential oil was extracted by steam distillation. The components were separated and identified by gas chromatography-mass spectrometry and elucidated on the standard mass spectral data and the percentages were determined by gas chromatographic area normalization method. RESULT: Twenty-eight constituents were identified, which make up 64.05% of the oil. CONCLUSION: Bornyl acetate is the main constituent, and other constituents include borneol, terpinyl acetate, alpha-curcumene, camphene, isovaleric acid, trans-beta-farnesene, beta-bisabolene, etc. PMID- 11601351 TI - [Chemical constituents of Tetrastigma hemsleyanum Diels. et Gilg]. AB - OBJECTIVE: To investigate the chemical constituents of Tetrastigma hemsleyanum. METHOD: Compounds were separated by rechromatography on silica gel from the chloroform solubles of its ethanol extracts, and the structures were determined by spectral analysis and chemical evidence. RESULT: Three compounds were isolated and elucidated as 6'-O-benzoyldaucosterol, daucosterol and beta-sitosterol. CONCLUSION: All the three compounds were isolated from this plant for the first time, of which 6'-O-benzoyldaucosterol is a new natural product. PMID- 11601352 TI - [Chemical constituents of the root of Pimpinella thellungiana Wolff]. AB - OBJECTIVE: To search for new effective hypotensive components from the Chinese folk drug, the root of Pimpinella thellungiana. METHOD: A new compound was isolated from etheral extract of the drug by chromatographic method and identified by physical, chemical and spectroscopic methods. RESULT: The compound has been identified as 2-(1',2'-dihydroxy)propyl-4-methoxy phenol. CONCLUSION: The compound was obtained from the root of P. thellungiana for the first time. PMID- 11601353 TI - [Chemical constituents of the leaves of Crataegus scabrifolia (Franch.) Rehd]. AB - OBJECTIVE: To explore the medicinal resources of Crataegus and seek compounds with pharmaceutical effects. METHOD: Column chromatography was employed for the isolation and purification of constituents and the structures were elucidated by spectral analysis and chemical evidence. RESULT: Six compounds were obtained and identified as rutin, hyperoside, vitexin, ursolic acid, daucosterol, and nonacosanol. CONCLUSION: The main constituents of the leaves of Crataegus scabrifolia are flavonoids. PMID- 11601355 TI - [Reversal effect of Ys-96, a bisbenzylisoquinoline, on adriamycin or vincristine resistance in human cancer cells in vitro]. AB - OBJECTIVE: Reversal effect of Ys-96, a bisbenzylisoquinoline, on the resistance of human cancer cells to adriamycin or vincristine was studied in vitro. METHOD: In an in vitro culture system of human cancer cells MCF-7 and its adriamycin resistant line MCF-7/Ad or KB and its vincristine-resistant line KBv200, the sensitivity(IC50) of the resistant cell lines to adriamycin or vincristine was evaluated with a MTT assay. RESULT: IC50 value of adriamycin or vincristine in combination with Ys-96 at a concentration of 1.00 mumol/L against MCF-7/Ad or KBv200 was found to be close to that of adriamycin alone or vincristine alone against the sensitive cell line MCF-7 or KB. CONCLUSION: The drug resistance of MCF-7/Ad or KBv200 could be essentially reversed by Ys-96 at a concentration of 1.00 mumol/L. PMID- 11601354 TI - [Inhibitory effect of methanol extract of Boschniakia rossica Fedtsch. et Flerov on rat hepatic preneoplastic lesions induced by diethylnitrosamine]. AB - OBJECTIVE: To investigate the inhibitory effect of Boschniakia rossica(BR) on hepatocarcinogenesis in rats. METHOD: Based on immunohistochemistry techniques, the expression of placental form glutathione S-transferase(GST-P), mutant p53 and p21 protein were investigated in hepatic preneoplastic lesions induced by Solt Farber protocol in the liver of rats that had been treated with the above method, administered with BR extract and of control group. RESULT: The extract of BR(500 mg/kg) has inhibitory effect on the formation of diethylnitrosamine-induced GST-P positive foci in F344 rat and the expression of mutant p53 and p21 protein was lower than that of hepatic preneoplastic lesions, and the increasing gamma glutamyltranspeptidase(gamma-GT) activity in rat liver treated with Solt-Farber protocol was decreased by the extract of BR. CONCLUSION: These results indicate that BR has inhibitory effect on DEN induced hepatic preneoplastic lesions in F344 rat. PMID- 11601356 TI - [Effect of yuanhua on isolated uterine strips in unpregnant rats]. AB - OBJECTIVE: To explore the mechanism on the effect of Yuanhua on the contractile activity of isolated uterine strips in rats under artificial oestrum. METHOD: Isolated strips were suspended in a tissue chamber in which Yuanhua was added with some antagonists of inhibitors or without. RESULT: Yuanhua could excite the uterine smooth muscle strips in a dose-dependent manner, but atropine, phentolamine, hexamethonium and diphenhydramine could not inhibit this exciting action. This exciting effect could be inhibited completely by verapamil and decreased by indomethacin(inhibitor of prostaglandin synthase). CONCLUSION: The exciting effect of Yuanhua on un-pregnant rats in vitro might be related to an action on the cell membrane Ca2+ channel as well as to a partial stimulation of synthesis and release of PG. PMID- 11601358 TI - Clean up your English. Avoiding superfluous words in scientific reporting. PMID- 11601357 TI - [Chemical changes of compatibility for shaoyao decoction]. AB - OBJECTIVE: To probe the regular patterns of interactions among chemical components in Chinese medicinal complex prescriptions. METHOD: The active components of Rhubarb, Coptis root and Baikal skullcap root in different patterns of compatibility were determined by TLC-scanner. RESULT: The berberine content in Coptis root can be decreased obviously by Rhubarb, Baikai skullcap root and Licorice root, especially by Rhubarb. Coptis root can also decrease the contents of acid components. CONCLUSION: The acid components can affect each other, thus reducing the contents of effective components. PMID- 11601359 TI - Evaluation of pollution-related stress factors for forest ecosystems in central Europe. AB - Since the early eighties air pollution by SO2 and Pb and, to a lesser degree by NOx and NH3, have been significantly reduced in Europe. This was done in part for the protection of forest ecosystems. The reductions are reflected in the pollutant impacts and inputs and have been verified through the bioindicator Norway spruce. In contrast, ozone concentrations increased at most of the evaluated measuring locations and trends were calculated based on the results of about 100 stations in Austria and Germany. Despite reduced emissions, large parts of the forest ecosystems are still affected by air-pollution impacts. Negative effects can be assessed using different legal standards and Critical Levels and Critical Loads, respectively: The legal standard for the evaluation of SO2 impact, as used in Austria, is well suited. The provisional European Critical Level for ozone, the AOT40 must, in order to be a meaningful criterion for field applications, be further refined. Continuing the Critical Load concept, the spatial risk of acid depositions in areas of high geomorphic variability were evaluated using the new parameter of 'critical soil depth'. With the help of the newly defined 'lead accumulation index', the accumulation of Pb from air pollution could be evaluated. Air-pollution inputs and the spatial acidification risk is directly related to altitude. Up to altitudes of 1000 m and 1100 m, SO2 impact and acid depositions, respectively were indicated and elevated ozone doses and Pb inputs were observed in the sensitive sub-alpine areas. These results underline the necessity for increased protection of mountain forest ecosystems, among others through a further reduction of emissions or forest-related strategies. PMID- 11601360 TI - Natural attenuation/phytoremediation in the vadose zone of a former industrial sludge basin. AB - The natural attenuation of polyaromatic hydrocarbons (PAHs) in the vadose zone of a naturally revegetated former industrial sludge basin (0.45 ha) was examined. This was accomplished by comparing the concentration of 16 PAH contaminants present in sludge collected below the root zone of plants with contaminants present at 3 shallower depths within the root zone. Chemical analysis of 240 samples from 60 cores showed the average concentration of total and individual PAHs in the 0-30 cm, 30-60 cm, and bottom of the root zone strata were approximately 10, 20, and 50%, respectively, of the 16, 800 ppm average total PAH concentration in deep non-rooted sludge. Statistically significant differences in average PAH concentrations were observed between each strata studied and the non rooted sludge except for the concentrations of acenaphthene and chrysene present at the bottom of the root zone in comparison to sludge values. The rooting depth of the vegetation growing in the basin was dependent on both vegetation type and plant age. Average rooting depths for trees, forbs (herbaceous non-grasses), and grasses were 90, 60, and 50 cm, respectively. The deepest root systems observed (100-120 cm) were associated with the oldest (12-14 year-old) mulberry trees. Examination of root systems and PAH concentrations at numerous locations and depths within the basin indicated that plant roots and their microbially active rhizospheres fostered PAH disappearance; including water insoluble, low volatility compounds, i.e. benzo(a)pyrene and benzo(ghi)perylene. The reduced concentration of PAHs in the upper strata of this revegetated former sludge basin indicated that natural attenuation had occurred. This observation supports the concept that through appropriate planting and management practices (phytoremediation) it will be possible to accelerate, maximize, and sustain natural processes, whereby even the most recalcitrant PAH contaminants (i.e. benzo(a)pyrene) can be remediated over time. PMID- 11601361 TI - Accuracy and traceability concepts applied to environmental speciation analysis. AB - Traceability issues are of increasing concern in all fields where chemical measurements form the basis for decisions. The concepts of accuracy and traceability as applied to environmental analysis are, however, still prone to misunderstandings, which has been recently illustrated by controversial discussions among the analytical community with respect to accuracy and traceability issues in the area of speciation analysis. Analytical techniques used for the determination of chemical species (speciation analysis) are generally based on a succession of steps (e.g. extraction derivatisation, separation, detection) which are all prone to various sources of systematic errors. Many speciation measurement techniques have been studied within the last decade through interlaboratory studies and certification of reference materials. These collaborative efforts have been understood as being directed towards strive for accuracy (trueness and precision). It has been recognised recently that the achievements actually enabled mostly to establish reference points (e.g. certified values in reference materials) which does not necessarily correspond to 'true values' but rather offer a mean for laboratories to compare their data internationally and, hence, achieve traceability. This ambiguity still generates confusion and misunderstandings among the scientific community. This communication discusses this issue, focusing on analytical measurements only. Extending discussions on general traceability issues would imply an examination of steps prior to laboratory work (sampling, storage, etc.) which is beyond the scope of this contribution. PMID- 11601363 TI - Trace metal levels in freshwater fish, sediment and water. AB - The trace metal concentrations in water, sediment and aquatic organisms, such as fish, could indicate the level and tendency of the pollution. This is important not only for the protection of the environment, but for evaluation of the quality of fish meat either captured from natural waters or cultured in fishponds. The total trace metal concentrations in samples of fish from different regions of Hungary and from different species have been determined by using an X-ray fluorescence technique (EDXRF). Water, sediment and fish samples from fishpond systems with different feeding and stocking has also been analyzed. In the case of zinc contents, differences have been traced between the cultured and wild common carp. In the case of common carp reared under different feeding conditions, differences were also observed in the zinc concentration. The retention of the trace metals in the fish has been studied by measuring the levels in sediment, water and feed. The different retention can be explained by the different availability of zinc in the applied feeds, which can be related to the presence of different metal species in the feeds. PMID- 11601362 TI - Environmental toxicity monitoring using electrochemical biosensing systems. AB - Environmental monitoring faces the challenge of measuring an increasing number of analytes at ever decreasing concentrations. Since not all species of a given analyte have the same detrimental impact on the environment, new analytical devices and techniques are required to distinguish between the different species of a pollutant or different groups of pollutants. This paper describes analytical techniques based on biomaterials that are toxically sensitive to pollutants. This approach permits the biomonitoring of certain compounds by looking at their toxic properties. Although these techniques are based on a sound analytical strategy, their applications are limited because most of the interactions between the biological material and the analyte are irreversible. Additionally, the immobilised biological material has a limited stability. Several biomonitoring strategies based on electrochemical biosensing are discussed here and how to recover the bioactivity of biosensing system, both in discrete and automated procedures, is also reviewed. PMID- 11601364 TI - Speciation of heavy metals in estuarine sediments in the northeast of Brazil. AB - An analytical procedure involving a three-step sequential extraction was used to determine the chemical association of heavy metals (Zn, Cr, Mn and Fe) with the major phases (exchangable, reducible and oxidizable) in samples from a fishpond of estuarine sediments. The pond is located in the Capibaribe River estuary, within the boundaries of the city of Recife, in the State of Pernambuco in the northeast of Brazil. The total metal content was determined as well. All metals were extracted from the residual fraction at a percentage greater than 50%. PMID- 11601365 TI - Total and methylmercury levels of a coastal human population and of fish from the Brazilian northeast. AB - A descriptive exposure survey was conduced at Santa Cruz Channel, Pernambuco, Brazil, to assess the possible risk of mercury contamination to which a coastal human population could be exposed through fish consumption. The area was formerly known to be contaminated due to a chlor-alkali plant installed along one of the tributaries of the channel. The values for total and methylmercury were measured in human hair from inhabitants of Itapissuma (1.9 +/- 1.6 ng THg/mg and 1.2 +/- 1.0 ng MHg/mg--mean values), a coastal fishing village, and fish (Mugil sp.) catch in the area (26.9 +/- 26.1 ng THg/g and 19.6 +/- 16.0 ng MHg/g--mean values). Both human hair and fish muscle presented relatively low values for total and methylmercury concentrations. These were found to be well within the average when compared to other Brazilian coastal environments. PMID- 11601366 TI - H2O2 formation from photocatalytic processes at the ZnO/water interface. AB - The paper focuses on the production of H2O2 by photocatalysis over ZnO in an aerated aqueous phase. The presence of different reductants that increase the H2O2 production in the aqueous phase is analysed; particular attention is paid to nitrite, which has been shown to be the reductant that produces the most significant increments in the H2O2 production. The photocatalytic anodic decomposition of ZnO in the presence of the different reductants is also investigated. From the results obtained, the relevance of the ZnO photocatalysis in the formation of environmental hydrogen peroxide is estimated. PMID- 11601367 TI - Environmental education and research in Greece. PMID- 11601368 TI - The second wave. Physicians brace for the coming siege on body and mind. PMID- 11601369 TI - From lost to dead. PMID- 11601370 TI - A time for parenting. PMID- 11601371 TI - The day the Web was a lifeline. PMID- 11601372 TI - Security officers as first responders: one med center's experience. PMID- 11601373 TI - How new NFPA code can affect security department responsibilities. AB - The latest edition of the "101 Life Safety Code" published by the National Fire Protection Association (NFPA) provides significant options for hospitals and other healthcare facilities during renovation and new construction projects in jurisdictions adopting the latest code and pertinent chapter. Changes in the healthcare chapters of the code effective February 11, 2000 stipulate conditions for the first time under which smoking may be approved, according to Tom Bulow, a Tucson, AZ, healthcare consultant and current chairman of the codes and standards review committee for the healthcare section of NFPA. Bulow also advises hospital officials "to expect a significant change in equipment and devices required in a hospital setting" as a result of an upcoming vote on a revision of the "NFPA 99 Health Care Facilities Code," an operational code. PMID- 11601374 TI - Experts warn of violence potential from recent layoffs. PMID- 11601375 TI - Dealing with problem number one--budget cuts: can you do more with less? AB - To cope with current budget restraints and cutbacks, hospital security departments are increasingly integrating their manpower with technology in the form of access control, CCTV cameras, and alarm systems to supplement their services as well as becoming more dependent on computerized information technology systems and IT departments to track hospital activities and incidents. Security directors contacted for this report also emphasize that they are doing more with less by providing value-added services both to expand activities and to demonstrate the importance of their departments to top management. PMID- 11601376 TI - New electronic device powers hospital employee background checks. AB - Ohio has a new electronic system for performing criminal background checks on potential employees. The Internet-based computer program, called WebCheck, was developed through the cooperation of Ohio's Bureau of Criminal Identification and Investigation and Cogent Systems, Inc., South Pasadena, CA. BCI&I initiated the development of WebCheck in response to Ohio law, which requires background checks on anyone applying for a job involving children and the elderly. PMID- 11601377 TI - IgA monoclonal and polyclonal proteins as regulatory factors of the NK cytotoxic activity. AB - The presence of receptors for IgA (IgAR) on natural killer (NK) cells was only indirectly suggested yet. To elucidate the presence of IgAR on NK cells and its possible role in modulation of the NK activity, was initiated a preliminary study carried out in a homologous system, using human non adherent lymphocytes (NAL) and human seric or secretory IgA. A proportion of over 20% NK cells (CD16+ CD56+) was determined by flow-cytometry in the NAL-cells population. Dose-dependent IgA binding to NAL cells was determined, showing a limitation of the IgA+ NAL proportion for a cell population of 32% and a ligand concentration of 4 mg/ml/10(7) cells. The binding parameters of the IgA/IgAR system, calculated by Scatchard procedure, revealed values of the affinity constant (K) and of the maximum number of ligand molecules bound/cell (n) depending on the aggregation degree of the ligands: K-values of 1.0 and 0.4 x 10(7) M-1 for dimeric and respectively, monomeric IgA, and n-values of 0.8 and 1.7 molecules/cell, respectively. A proportion of 3% IgA molecules endowed with cytophilic property was also calculated. The turnover rate of secretory IgA (sIgA) on the NAL cells surface showed values of the ligand half time (T 1/2) of 1 h. The effect of polyclonal IgA, (sIgA and normal seric IgA) and of monoclonal IgA myeloma (monomeric and dimeric IgA) on the NK cytotoxicity target K562 cell line was of inhibition, depended on the ligand doses and varied with the IgA type. The possible relevance of immunoglobulins A and of the activity of natural killer cells in processing of some mechanisms of the antiviral protection was discussed. PMID- 11601378 TI - Optimization of immunochemical methods for intracellular protein detection. AB - Given the possibility that cell kinetics and p53 status may be important determinants of chemotherapeutical efficacy, the aim of the present study was to determine the optimal methods and conditions for qualitative and quantitative intracellular proteins detection. Bradford assay is the better choice for protein concentration detection because it is more sensitive and more rapid than Sheffield assay despite the fact that it utilizes a higher amount of samples. The direct staining method for flow-cytometrical detection of intracellular proteins is more rapid as compared to the indirect staining one, also providing information about protein expression during cell cycle phases, but it is low sensitive for protein expression estimation and is prohibitive for masked intracellular proteins like PCNA. More than that, it can be performed with both fixed and freshly isolated cells as compared to the indirect staining method, but the last one provides advantages by signal amplification and by its availability of using it for a large number of intracellular proteins detection. PMID- 11601379 TI - Dynamics of the HIV-1 variability in adults from Bucharest, 1992-1998. AB - Variability is a hallmark of HIV viruses both at the genetic and the phenotypic level. Viral sequencing and phylogenetic analysis of many isolates revealed specific distribution of HIV-1 subtypes according to the geographic location and route of transmission. In Romania, the currently available data coming from the study of pediatric HIV infection suggest the predominance of subtype F. However, there are few data concerning the distribution of HIV-1 subtypes among adults. We investigated the changes in the distribution of different HIV-1 subtypes among HIV-1 infected adult patients from Bucharest over a 6 years period (1992-1998) by means of V3 binding assays. The analysis of the relative incidence of different HIV-1 serotypes revealed the steady predominance of serotype F (50-75%) among the adults from Bucharest and a small but constant increase of the number of samples with serotype B- from 5% in 1994 to 14% in 1998. In contrast, the serotype E is either absent or weakly represented (4%) during the period of the study. All over the years there was a relatively high proportion (6-30%) of non-reactive samples. This could be an indication for the possible emergence of new or recombinant HIV 1 subtypes. PMID- 11601380 TI - Romanian HIV-AIDS epidemic after a decade of evolution. AB - Situated in Southeastern Europe, with a surface of 237,500 km2 and a population of over 22 million, Romania was a special case in the evolution of global AIDS crisis. After the first reported case in a homosexual male in 1985, five years elapsed till the epidemiological investigations done in the Institute of Virology, Bucharest (1-4) provided strong evidence for what may represent the world's largest iatrogenic transmission of blood-borne pathogens in children. On the basis of Epidemiological Fact Sheet concerning Romania provided by UNAIDS/WHO Working Group on Global HIV/AIDS and STD Surveillance we offer a couple of graphics which are considered important for informed decision-making and planning at national and regional levels. We emphasize the lack of availability of many specific data both on epidemiological and socio-behavioral indicators. Structural collapse in Eastern Europe sets the scene for the rapid spread of HIV/AIDS among young people and the lack of information may contribute to an unexpected rebound of the epidemic. PMID- 11601381 TI - Evidence of TNF system activation and high expression of TNF alpha messenger transcripts in necrotizing enterocolitis of HIV-infected children. AB - TNF alpha contributes to the necrotizing enterocolitis (NEC) pathogenesis. To date, this clinical entity of neonates was never described in HIV-infected children. In 15 HIV-positive children with histological evidence of various intestinal lesions resembling NEC, we have studied serum TNF alpha and soluble TNF receptor concentrations by ELISAs, and archived paraffin embedded intestinal tissues by in situ hybridization with DIG-labeled RNA probes for TNF alpha messenger transcripts. We found increased levels of TNF alpha and soluble receptors, proving TNF alpha system activation. We detected TNF alpha messenger transcripts in all cases, regardless of the presence of microbial pathogens at intestinal level. Since HIV can infect many cells of the gastrointestinal tract, also triggering the secretion of TNF alpha, we concluded that factors contributing to NEC pathogenesis in HIV-infected children are complex. At least the nutritional and immunological status are involved, other viral co-infections, opportunistic microbes (such as mycobacteria), and pathogenic activities of HIV. All together enhance both circulating TNF alpha system and its cytotoxic effects at intestinal level. PMID- 11601382 TI - Experimental study of possible involvement of some apoptosis mechanisms in pathogenesis of the HIV infection: 2. The CD4+ T lymphocytes depletion in the HIV infection occurs through activation-induced apoptosis. AB - The present work is a part of a complex experimental study aimed at the demonstration of the two previously published hypotheses regarding the involvement of apoptosis in general in the viral infection and especially in HIV infection (1). Our researches have shown that the significant lowering of the number of peripheral CD4+ T lymphocytes in HIV-infected children is associated with a marked increase of the soluble interleukin 2-receptor (sIL2-R)# concentration, in comparison with HIV-negative, healthy or acute infections exhibiting controls. As sIL-2R is a circulating marker of cell activation, we investigated the role of monocytes (antigen-presenting cells) in the viability of peripheral lymphocytes isolated from HIV-infected children in comparison with the controls. Lymphocytes cultivation in the absence and in the presence of autologous monocytes led to the following conclusions: 1) freshly isolated lymphocytes from HIV-positive individuals undergo an accelerated spontaneous apoptosis in comparison with that of lymphocytes isolated from HIV-negative individuals: 2) the normal antiapoptotic effect of monocytes on lymphocytes diminishes gradually in the HIV infection, changing into a proapoptotic effect, corresponding to the sIL-2R augmentation to increasingly higher values. Our results show that peripheral CD4+ T-lymphocyte depletion in HIV infection occurs through apoptosis and the activation-induced cell death is one of the possible apoptosis mechanisms. PMID- 11601383 TI - Virological and immunological aspects in the juvenile laryngeal papillomatosis. AB - The juvenile laryngeal papillomatosis, a disease which in the absence of an adequate monitoring may have an invalidating character, represented for a long time a problem as regards both its treatment and its possible etiology. The use of monoclonal antibodies, as well as of molecular biology techniques, permitted to elucidate some aspects, such as the viral origin of the infection. Twenty five juvenile laryngeal papillomas, removed intra-operatively, were investigated immunohistochemically, a significant increase of the epidermal growth factor (EGF) receptor being found. Ten samples were also analyzed with the PCR technique, for the purpose of detecting the presence of the corresponding DNA sequences of human papillomaviruses (HPV): all were positive. The HPV genotyping showed the presence of only the HPV6 and 11 genotypes. PMID- 11601384 TI - Is the human papillomavirus DNA present in penile warts? AB - Infection with human papillomavirus (HPV) has been established to be a sexually transmitted disease, with a potential risk of intraepithelial neoplasia and invasive cancer, function of the genotype involved. Scraped cells from lesions of 27 men establishing various types of penile warts were investigated by PCR for HPV DNA detection. Twenty patients (76.9%) were found to have an HPV infection. By RFLP genotyping of only 13 samples, 4 HPV16. 2 HPV6 and 7 HPV ND infections were determined. Comments about these cases, in correlation with other factors are presented. The findings in this study confirmed the HPV involvement in penile warts. PMID- 11601386 TI - [Ultrastructural and morphometrical analysis of apoptosis stages in cardiomyocytes of MDX mice]. AB - Our previous study of apoptosis in mdx mouse myocardium cells demonstrated the presence of middle-sized DNA fragments (60-65 kbp) in extracts of myocardium DNA, and irregular shape of membrane enveloped nuclei in cardiomyocytes. The DNA fragmentation (DNA laddering) was observed after biomechanical stress (5 min sweeming) only. Based on these results we concluded that the majority of cardiomyocytes were at the first stage of apoptosis. The purpose of this work was to provide some morphometrical quantitive characteristics of ultrastructural properties of the nuclei and mitochondria, and to determine morphological patterns of apoptosis in cardiomyocytes of mdx and C57B1 mice. To resolve the task, we made a morphometrical analysis of the electron microscope images of nuclei and mitochondria. First of all, we divided all nuclear images into three categories: normal, semi-pathological, and pathological forms according to the extent of nuclear membrane invaginations and that of condensed chromatin spreading. The most part of C57B1 cardiomyocyte nuclei belonged to the normal form (88.9 +/- 4.3%), while the smaller part (11.1 +/- 4.3%) was regarded as semi pathological forms. Just a reverse was observed in mdx mice: the largest part of cardiomyocytes fell into category of semi-pathological (54.6 +/- 4.4%) and pathological (31.5 +/- 4.1%) forms while, the smallest part belonged to the normal form (13.8 +/- 3.0%). 24 h after biodynamic stress, the quantity of normal nuclei of C57B1 cardiomyocytes decreased to 61 +/- 5%, the number of semi pathological nuclei increased to 39.0 +/- 4.4% (P < 0.05). The number of pathological nuclei of mdx, cardiomyocytes fell to 15.4 +/- 3.0% (P < 0.05). It means that mdx cardiomyocytes with pathological form of their nuclei disappear because of emerging the second, destructive stage of apoptosis. To estimate the degree of ultrastructural changes in the nuclei of all three forms of cardiomyocytes we counted the square/perimeter ratio in each nucleus (circle shape factor; CSF). The value of CSF for normal nuclei of all the forms of cardiomyocytes varied between 0.65 +/- 0.02 and 0.71 +/- 0.04. In semi pathological and pathological nuclei a significant decrease in CSF to 0.56 +/- 0.02 and 0.56 +/- 0.03 was observed, respectively (P < 0.05). The biodynamical stress did not reduce the CSF value below this level. We also counted the ratio of the square to the product of a long and a short axes (ellipse shape factor; ESF). The ESF value for normal nuclei of all forms of cardiomyocytes varied between 0.97 +/- 0.01 and 0.99 +/- 0.01. In the case of mdx mice the biodynamical stress reduced ESF to 0.95 +/- 0.01 (P < 0.05) for pathological form of nuclei. The specific density of mitochondria in mdx cardiomyocytes (0.274 +/- 0.016) was less than that in C57B1 cardiomyocytes (0.329 +/- 0.018). At the destructive stage of apoptosis, the nuclei of cardiomyocytes were round in shape, the nuclear chromatin being hypercondensed, and mitochondria swollen. The cardiomyocyte morphology was in agreement with the definition of the final stage of apoptosis as secondary necrosis. Morphometrical results show that as many as 86-90% of nuclei of mdx cardiomyocytes have abnormal structure that confirms our conclusion that mdx cardiomyocytes were at the first stage of apoptosis. The final stage of apoptosis is rarely observed by biochemical or morphological methods. It suggests the presence of some inner mechanisms regulating the initiation of the final (destructive) stage of mdx cardiomyocyte apoptosis. PMID- 11601385 TI - An outbreak of aseptic meningitis due to ECHO 30 virus in Romania during the 1999 summer. AB - Between April-September 1999 an unusually high number of acute aseptic meningitis was reported in six North Eastern counties of Romania. At the end of 1999 summer the epidemic area extended in South Romania including the Capital City Bucharest. The total number of cases surpassed 5500. The majority of confirmed cases were young children under 15 years of age. More than 1800 cases were registered in the same interval in the neighboring Republic of Moldavia. We report the isolation of ECHO 30 virus from 12 CSF samples of 52 tested on RD and human diploid cells. A small case control study identified high seroneutralization titers confirming a recent ECHO 30 infection in 74% of patient's samples and in 54% of samples from control children tested. The time spent outdoors and poor hygiene practices were prominent risk factors for transmission. PMID- 11601388 TI - [Polar filaments of Myxobolus pseudodispar spores]. AB - Spores of Myxobolus pseudodispar from plasmodia occurring in the roach muscles (Rutilus rutilus) were studied by light, transmission and scanning electron microscopy, before and after discharge of their polar filaments. Scanning microscopy reveals that discharged polar filaments bear no spines and their walls are slightly folded. Polar filaments of M. pseudodispar have been compared with stinging threads of the parasitic cnidarium Polypodium hydriforme. PMID- 11601387 TI - [Structural changes of the nucleolar organizing regions in rhabdomyosarcoma RA-23 tumor cells induced by okadaic acid]. AB - It has been recently shown that okadaic acid (OA), an inhibitor of dephosphorilation, is capable of inducing changes in the nucleolar organizer regions (AgNORs) of some mammalian cells. Our work was focused on studying the structural changes in AgNORs of tumour cells of rat rhabdomyosarcoma RA-23 by their exposure to 100 nM OA. A standard silver staining procedure of interphase AgNORs in tumour cells was used. We measured no less than 100 tumour cells in each clone. In the examined tumour cell populations, the index of interphase AgNORs varied from 1.54 to 4.35. A clear structure and form of AgNORs was not observed in 30% okadaic acid-treated tumour cells, as opposed to 10% of the control ones. AgNORs in these cells looked like a mixture of thin threads encompassing some dark dots lying, mostly, separately. Additional procedures of tumour cell staining with Giemsa and fluorescent dye Hoechst 33,258, respectively, revealed that such structures were not chromosomes. Meanwhile, the frequency of cells at the stage of prophase exceeded 3%, as opposed to the control, where the frequency of cells at this stage was less than 0.5%. Thus, we can conclude that we have detected specific changes in AgNORs and chromatin structure of okadaic acid-treated tumour cells. PMID- 11601389 TI - [Dimethyl suberimidate as a specific inductor of apoptosis in transformed cells]. AB - A modification of protein-protein interactions can be considered to be a way to regulate cell death. Chemical cross-linking agents have been traditionally used for protein complexing. This study has been undertaken to test a possibility to induce and(or) to modify cell death by a homobifunctional cross-linker dimethyl suberimidate (DMS). It was shown that the protein cross-linking by DMS resulted in a death of transformed cells by apoptosis. DMS-induced apoptosis was accompanied by cell cycle perturbations and down-regulation of p21/Waf1 mRNA expression. The RT-PCR analysis of bcl-2 family genes revealed the engagement of mitochondria in DMS-induced cytotoxicity. Then, the influence of DMS treatment on TNF-dependent and Fas-mediated apoptosis was investigated. Cell pre-incubation with DMS resulted in their increasing sensitivity for the TNF cytotoxic effect, though activities of anti-Fas cytotoxic antibodies were inhibited. The effects observed are probably due to cross-linking of TNF-receptors. Thus, this study first demonstrated that a chemical cross-linker DMS in capable of inducing apoptosis in transformed cells and modifying TNF-dependent and Fas-mediated apoptosis. PMID- 11601390 TI - [Comparative evaluation of the efficiency of the effect of very high frequency electromagnetic waves on platelet functional activity]. AB - A comparative analysis was made of the effect of two kinds of EMI MMD-radiation: EMI MMD-waves, generated by a vehicle "Jav-1 M" (42.2 and 53.5 HHz), and EMI MMD waves exerting influence with frequencies of molecular spectrum of radiation and nitric oxide absorption (150.176-150.644 HHz), obtained with a specially created generator, with respect to their influence on the functional ability of platelets of unstable angina pectoris patients. It was shown that in vitro EMI MMD fluctuations with frequencies of molecular spectrum of radiation and nitric oxide absorption exert a stronger inhibiting influence on the functional activity of platelets of unstable angina pectoris patients. Features of the action of various kinds of EMI MMD-effect on the activative-high-speed characteristics of platelet aggregation are shown. PMID- 11601391 TI - [The effect of electromagnetic waves of very high frequency of molecular spectra of radiation and absorption of nitric oxide on the functional activity of platelets]. AB - A study was made of the effect of electromagnetic EMI MMD-fluctuation on the frequencies of molecular spectra of radiation, and nitric oxide absorption under in vitro conditions on the functional activity of platelets in patients with unstable angina pectoris, with the help of a specially created generator. At amplitude-modulated and continuous modes of EMI MMD-irradiation of platelet-rich plasma for 5, 15 and 30 min the platelet functional activity decreases, which was shown up in reduction of their activation and fall of aggregative ability. The degree, to which platelet functional activity was inhibited, depended on the mode of irradiation and on duration of EMI MMD effect. The most obvious changes in platelet activation and in their readiness to aggregative response were observed at a continuous mode of irradiation within a 15 min interval. PMID- 11601392 TI - [In vitro modelling of the interactions between the promoter and enhancer complexes]. AB - The aim of this work is to study in vitro mechanisms of interactions between the promoter and enhancer complexes of the transcriptional apparatus. We used retardation assay for the labeled TATA-box containing oligonucleotide with an unfractionated nuclear extract and with a second unlabeled oligonucleotide carrying an enhancer sequence. As an enhancer sequence we have chosen e5 element that is known to interact with members of Pax family transcription factors. We showed that the presence of unlabeled e5 element led to a significant decrease in the mobility of TATA-box associated complex. E5 element with a mutated homeodomen binding site does not produce such an effect, while a mutation in the paired binding site does not change the ability of e5 element to influence the formation of promoter-associated complex. We observed the same complex using crude nuclear extracts from cells that express chimeric protein Pax7-FKHR with higher molecular weight. The fact that the increase in the size of the transcription factor does not influence the size of the TATA-box associated complex led us to conclude that this complex did not result from association of original promoter and enhancer components, but rather the role of enhancer may be to stabilize the slowly migrating complex on the TATA-box via short-term interactions inducing conformational changes in the included proteins. PMID- 11601393 TI - [The methylation peculiarities of pericentromeric heterochromatin of chromosomes 1,9 and 16 in human embryo]. AB - By means of in situ nick-translation technique, methylation patterns of pericentric heterochromatin of chromosomes 1, 9 and 16 in extraembryonic (chorion) and embryonic cells of 5-8 week old human fetuses with normal karyotype (5), and in one specimen with trisomy for chromosome 16 were studied. Fixed metaphase chromosomes from direct chromosome preparations were digested with either endonuclease Msp I or its isoshizomer Hpa II recognizing and restricting the same sDNA sequence C decreases CGC with Hpa II, but not Msp I sensitive to methylation state of internal cytosin. According to our results, heterochromatin of extraembryonic, but not embryonic cells is hypomethylated. An obvious difference was registered in signal strength between homologous regions in iq12 of both parental chromosomes 1 in early (5-6 week old), but not in more advanced fetuses. Methylation pattern difference was detected in pericentric chromatin of triple copies of chromosome 16 in extraembryonic tissues of the 47,XY, + 16 fetus. These results are in line with a hypothesis of intraheterochromatin location of "early" genes governing initial stages of embryonic development in humans. PMID- 11601394 TI - [Immunoelectron study of RNA polymerase II distribution in human oocyte nuclei]. AB - The intranuclear distribution of two (unphosphorylated and hyperphosphorylated) forms of RNA polymerase II (Pol II) was studied in human oocytes from antral follicles using immunogold labeling/electron microscopy. The distribution of Pol II was as well as to the distribution of two splicing factors (snRNPs and SC-35) in the intranuclear entities, namely, interchromatin granule clusters (IGCs), nucleolus-like bodies (NLBs), and perichromatin fibrils (PFs). The results have shown that 1) antibodies directed against two forms of Pol II have a similar pattern of intranuclear distribution 2) both Pol II and splicing factors progressively accumulate in IGCs with a decrease in the transcriptional activity of the oocyte nucleus, 3) both Pol II and splicing factors are located on PFs, and 4) Pol II is present in the NLBs at all transcriptional states of the oocyte nucleus. The accumulation of Pol II and splicing factors in IGCs, concomitant with a decrease in the transcriptional activity, suggests a coordinated mechanism for the movement of both Pol II and splicing factors from the sites of action to the sites of storage. PMID- 11601395 TI - [Visualization of ribosomal genes transcription in SPEV culture cells using bromouridine triphosphate]. AB - We applied a sensitive and specific method for detection of run-on rDNA transcription in cultured mammalian cells. This technique is based on the capability of RNA polymerase I to maintain transcriptional activity following cell fixation with methanol, and on the use of BrUTP as a precursor of rRNA synthesis. The results obtained have shown that in cultured pig cells (PK cells) the ribosomal genes are transcribed during interphase to become repressed at the end of mitotic prophase. The rDNAs are not transcribed at the prometaphase, metaphase and anaphase stages. The ribosomal genes become derepressed at early telophase. At early telophase, the number of BrUTP-incorporated sites is equal to that of the nucleolus organizing regions (NORs), but it is augmented during telophase progression. A similar dynamics of ribosomal gene reactivation is also revealed following spatial separation of NO-chromosomes between individual micronuclei caused by hypotonic chock. This indicates that the spatial integration of chromosomal NORs is not a prerequisite for ribosomal gene reactivation at mitosis. PMID- 11601396 TI - [Phospholipase C negatively regulates tyrosine phosphorylation of EGF receptor in A-431 cells]. AB - It is known that EGF induces tyrosine phosphorylation and internalization of the EGF receptor in A-431 cells. U73122, an inhibitor of phospholipase C, induces tyrosine phosphorylation of the EGF receptor and its association with phospholipase C still in nonstimulated cells. In U73122 treated cells EGF exerted no effect on these processes. Receptor-mediated endocytosis was not observed in A 431 cells treated with U73122. The reorganization of actin cytoskeleton was detected in U73122 cells. PMID- 11601397 TI - [Cytogenetic effects of separate and combined action of 232Th and Cd nitrates on Allum cepa root meristem cells]. AB - Effects of separate and combined action of 232Th and Cd on Allium cepa root tip cells were investigated. It has been shown that cytogenetic effects of 232Th results mainly from its ability to induce genome damages. Cadmium in the examined concentration does not induce chromosomal vagrants, and this effect is not intensified by the combined action of 232Th and Cd (with 232Th). Cd induced increased aberrations of chromosome type frequency (1.5 times more than in control group), and fragment frequence, while mitotic index was significantly decreased. While taking into consideration the frequency of anaphase--telophase damages, and the number of aberrations per cell, the combined effects of 232Th and Cd may be considered as synergic. The aberration type ratio, frequencies of bridges and fragments, and also the level of proliferative activity of 232Th and Cd in the presence of both ions were similar with the corresponding parameters obtained when Cd acted alone. Possible mechanisms of formation of 232Th and Cd synergic effects are discussed. PMID- 11601398 TI - [Adaptive significance and possible origin of B-chromosomes in Picea Glauca (moench.) voss = P.canadensis B.S.P]. AB - The karyotype (2n = 24 + 1B) was detected in 8 trees of Picea glauca (Moench.) Voss. = P. canadensis B.S.P., and the karyotype (2n = 24) was detected in 2 trees of spruce from the same stand in the centre of Voronezh. The majority of seeds, collected from these trees, were empty. From 150 selected seeds, which were full, four plantlets were obtained. One of them died, another one had no mitotic figures, and the third and fourth plantlets had karyotypes (2n = 24 + 1B, and 2n = 24, respectively). A possible mechanism of formation of B-chromosomes and their adaptive role are discussed. PMID- 11601399 TI - Electrophoretic karyotypes of some species of the genus Leptomonas (kinetoplastida, trypanosomatidae), homoxenous trypanosomatids parasites of insects. AB - Electrophoretic karyotypes of homoxenous trypanosomatids Leptomonas peterhoffi, L. mycophilus, L. nabiculae and Leptomonas sp. have been studied by transverse alternating-field electrophoresis under varying electrophoretic conditions. From 12 to 17 chromosomal DNA bands, ranging from 370 to more than 1500 kb were detected in the karyograms of the species compared. In each pattern, some intensely stained bands could represent more than one chromosome. Taking into account the number of intensely stained bands, the karyotype of L. peterhoffi was estimated to contain at least 18 chromosomes, the karyotypes of L. mycophilus and L. nabiculae, at least 21 chromosome each, and the karyotype of Leptomonas sp. up to 20 chromosomes. Interclonal variations of electrophoretic karyotypes of 10 clones of Leptomonas sp. (cfmI-cfmX) were studied. Seven of ten clones had identical electrophoretic patterns. In the karyograms of three clones (cfmI, cfmVI, cfmVII), additional chromosomal DNA bands were observed. The obtained results suggest, that electrophoretic karyotypes cannot be used as reliable markers of species of homoxenous trypanosomatids, since intraspecies variability does occur in these parasites. PMID- 11601400 TI - [In vitro interaction between persisting oocysts of Cryptosporidium parvum and murine resident peritoneal macrophages. I. Effect of parasite on macrophage capability for oxidative burst]. AB - Cryptosporidiosis in an opportunistic infection which poses a significant threat to the immunodeficient patients (including people with AIDS). The aim of the present work was to study whether oxidative burst, known as a nonspecific immune response of macrophages, may be modulated in vitro by persisting oocysts of a coccidian pathogen Cryptosporidium parvum. Live oocysts of C. parvum engulfed by murine perithoneal macrophages may persist within the phagosomes and retain their initial morphology for about 7 days following oocyst injection into macrophage monolayer. A short-term interaction of adherent macrophages with C. parvum oocyst suspension for 5-15 min caused oxidative burst in these macrophages. After a while, the intensity of this oxidative burst smoothly decreased to vanish within the following 2-6 h oocyst-macrophage cultivation. Dead oocysts caused no oxidative burst in macrophages. Co-cultivation of macrophages with oocysts for 1.0-1.5 days led to the appearance of macrophages, which had oocysts both contacting the cell surface and existing inside the phagosomes. In these macrophages the oxidative burst in response to the addition of a chemotactic peptide (fMLP) was considerably higher than in uninfected control cells. During a 1-4 day co-cultivation, the degree of oxidative burst caused by fMLP in macrophages containing only phagocytosed oocysts did not differ from that in the non-infected (oocyst-free) control. The data obtained enable us to propose that the products of oxidative burst in macrophages, formed in response to the interaction with C. parvum oocysts, do not kill the oocysts. These can survive for a long time in the phagosomes of macrophages. Such a long persistence of oocysts in phagosomes does not affect the capability of macrophages for oxidative burst in response to the action of fMLP. PMID- 11601401 TI - [The spine functional capability]. PMID- 11601402 TI - [Medical examination in the Naval Air Force personnel]. PMID- 11601403 TI - My billiant career--finance. Making it count. Interview by Lyn Whitfield. PMID- 11601404 TI - Initial messages. PMID- 11601405 TI - Dose of fun aids JCAHO preparation. PMID- 11601406 TI - Frequent questions on safe harbors. PMID- 11601407 TI - Quality improvement will require a major commitment. PMID- 11601408 TI - Aramark profile. Monique Begin. Interview by Cynthia Martin. PMID- 11601409 TI - The universe of ADHD drugs--more drugs to treat hyperactivity. PMID- 11601410 TI - International AIDS and health fund. PMID- 11601411 TI - UN agencies launch new plan to halve mortality of measles. PMID- 11601412 TI - MS specialist nursing in North America. PMID- 11601413 TI - Mental health resources in the world: initial results of Project ATLAS. PMID- 11601414 TI - The "24-hour" question. PMID- 11601415 TI - Your lawyer, your advocate. PMID- 11601416 TI - The wisdom for them of giving to us. PMID- 11601417 TI - "Pipeline" of veterinarians drying up. PMID- 11601418 TI - The entorhinal cortex in Alzheimer's disease. PMID- 11601419 TI - Neuropsychological effects of pallidotomy in patients with Parkinson's disease. PMID- 11601420 TI - Response to botulinum toxin in a case of rigid spine syndrome. PMID- 11601422 TI - Impact of EU clinical trial directive. PMID- 11601421 TI - "Hot cross bun" sign in a patient with parkinsonism secondary to presumed vasculitis. PMID- 11601423 TI - Why the EU matters in cancer. PMID- 11601425 TI - Cost-effectiveness of colonoscopy in screening for colorectal cancer; cost effectiveness of screening colorectal cancer in the general population. PMID- 11601426 TI - Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis. PMID- 11601427 TI - The dynamics of reconstitution of microtubules around the cell center after cooling. AB - In interphase PE cells, after cooling (2 h at 0 degree C), some microtubules are retained in the cytoplasm. After the transfer of the cells to a thermostat (37 degrees C), the reconstitution of the microtubule network begins near the cell center. At this time in most of the cells around the center one can see the electron-dense foci of convergence of microtubules which then disappear. The number of microtubules diverging radially from the mother centriole reaches a maximum after 15 to 16 min, that of microtubules growing from the daughter centriole 12 min after the cells are placed at 37 degrees C. 45 min after the heating started the number of radially diverging microtubules somewhat exceeds the control level. These data show that microtubules are associated with the centers only during their growth. The mature microtubule is separated from the center and may be replaced by a new one. Thus, most, of not all, microtubules originate from the cell center, but at any moment only some of the microtubules are associated with it. PMID- 11601430 TI - Interventional neurophysiology for pain control: duration of pain relief following repetitive transcranial magnetic stimulation of the motor cortex. AB - The chronic electrical stimulation of a motor cortical area corresponding to a painful region of the body, by means of surgically-implanted epidural electrodes is a validated therapeutical strategy to control medication-resistant neurogenic pain. Repetitive transcranial magnetic stimulation (rTMS) permits to stimulate non-invasively and precisely the motor cortex. We applied a 20-min session of rTMS of the motor cortex at 10 Hz using a 'real' or a 'sham' coil in a series of 14 patients with intractable pain due to thalamic stroke or trigeminal neuropathy. We studied the effects of rTMS on pain level assessed on a 0-10 visual analogue scale from day 1 to day 12 following the rTMS session. A significant pain decrease was observed up to 8 days after the 'real' rTMS session. This study shows that a transient pain relief can be induced in patients suffering from chronic neurogenic pain during about the week that follows a 20 min session of 10 Hz-rTMS applied over the motor cortex. PMID- 11601431 TI - Arterial dissection and stroke in children. AB - OBJECTIVE: To describe the clinical characteristics of dissections of cerebral arteries in children. METHODS: Searches of MEDLINE (1966-2000) and bibliographies were systematically performed for English-language publications that described patients <18 years old with anterior circulation arterial dissections (ACAD) or posterior circulation arterial dissections (PCAD). RESULTS: A total of 2,027 studies were reviewed; 118 patients were identified in 79 studies. Seventy-four percent of patients with ACAD (n = 73) and 87% with PCAD (n = 47) were male (p < 0.0001). When patients with preceding trauma were excluded, this male predominance persisted. All patients had evidence of cerebral ischemia at the time of diagnosis. Headache was reported in approximately half of patients. Sixty percent of ACAD were intracranial. ACAD with no preceding trauma were more commonly intracranial than those preceded by significant trauma (86 vs 25%, p = 0.002). The most common location for PCAD was the vertebral artery at the level of the C1-C2 vertebral bodies (53%). Recurrent ischemic events after the diagnosis of dissection were reported in 15% of PCAD and 5% of ACAD cases. None of the PCAD group and 10% of the ACAD group had recurrent dissections. CONCLUSIONS: There is a marked male predominance among children with cerebral arterial dissections that is not explained by trauma. Unlike adult ACAD, childhood ACAD are most commonly intracranial. Spontaneous ACAD, in particular, tend to be intracranial, while post-traumatic ACAD are more often extracranial. The vertebral artery segment most susceptible to dissection is similar between children and adults. PMID- 11601432 TI - [Cerebral aneurysm and HIV]. PMID- 11601433 TI - Pediatric gastroenterology in Chile--a personal perspective. PMID- 11601434 TI - Clinical quiz. An ileocolonic intussusception associated with C. difficile infection. PMID- 11601435 TI - More questions about growth hormone in Crohn disease. PMID- 11601436 TI - Soleus H-reflex changes during loading and unloading of the spine and their relation to the diagnosis of lumbosacral radiculopathy in mechanical back pain. PMID- 11601437 TI - Seizures and epileptiform EEG abnormalities in FRAXE syndrome. PMID- 11601438 TI - Effect of subliminally perceived stimulus differences or of superliminally perceived order differences. PMID- 11601439 TI - Mechanical properties of abdominal aortic aneurysm wall. AB - There is a need to understand why and where the abdominal aortic aneurysm may rupture. Our goal therefore is to investigate whether the mechanical properties are different in different regions of the aneurysm. Aorta samples from five freshly excised whole aneurysms, > or = 5 cm in diameter, from five patients, average age 71 +/- 10 years, were subjected to uniaxial testing. We report the wall thickness, yield stress and strain, and parameters that describe nonlinear stress-strain curves for the anterior, lateral and posterior regions of the aneurysm. The posterior region was thicker than the anterior region (2.73 +/- 0.46 mm versus 2.09 +/- 0.51 mm). The stress-strain curves were described by sigma = a epsilon(b), where sigma is true stress and epsilon is engineering strain. In the circumferential direction, the wall stiffness increased from posterior to anterior to lateral. In the longitudinal direction, the lateral and anterior regions showed greater wall stiffness than the posterior region. The wall stiffness was greater in the circumferential than longitudinal direction. The anterior region was the weakest, especially in the longitudinal direction (yield stress sigmaY = 0.38 +/- 0.18 N mm(-2)). For a less complex model the aneurysmal wall could be considered orthotropic with sigma = 12.89epsilon(2.92) and 4.95epsilon(2.84) in the circumferential and longitudinal directions. For the isotropic model, sigma =7.89epsilon(2.88). In conclusion, different regions of the aneurysm have different yield stress, yield strains, and other mechanical properties, and this must be considered in understanding where the rupture might occur. PMID- 11601440 TI - Implementation of a microcontroller-based semi-automatic coagulator. AB - The coagulator is an instrument used in hospitals to detect clot formation as a function of time. Generally, these coagulators are very expensive and therefore not affordable by a doctors' office and small clinics. The objective of this project is to design and implement a low cost semi-automatic coagulator (SAC) prototype. The SAC is capable of assaying up to 12 samples and can perform the following tests: prothrombin time (PT), activated partial thromboplastin time (APTT), and PT/APTT combination. The prototype has been tested successfully. PMID- 11601441 TI - Fuzzy oxygen control system for the indirect calorimeter of premature infants. AB - The indirect calorimetric system of measuring O2 consumption and CO2 production has been developed for energy expenditure estimation of premature infants. This apparatus requires an input room air mixing with pure oxygen to obtain a stable gas with definite oxygen concentration flowing into the hood for neonatal breath or supplemental oxygen treatments. In this paper, we propose an oxygen control system based on fuzzy control logic to automatically adjust the mixing ratio of room air to pure oxygen gas from the hospital's supply system, designed for premature infants. It is designed to reduce the risks of oxygenic toxicity and retinopathy of prematurity by lowering the overshoot of oxygen concentration. Its performance was evaluated and optimal membership functions were obtained. As a result, the system is quite robust with little effect caused by disturbance and has little or no overshoot when step changing the level of oxygen concentration in the mixed gas. PMID- 11601442 TI - Adaptive fuzzy logic restriction rules for error correction and safe stimulation patterns during functional electrical stimulation. AB - Adaptive restriction rules based on fuzzy logic have been developed to eliminate errors and to increase stimulation safety in the foot-drop correction application, specifically when using adaptive logic networks to provide a stimulation control signal based on neural activity recorded from peripheral sensory nerve branches. The fuzzy rules were designed to increase flexibility and offer easier customization, compared to earlier versions of restriction rules. The rules developed quantified the duration of swing and stance phases into states of accepting or rejecting new transitions, based on the cyclic nature of gait and statistics on the current gait patterns. The rules were easy to custom design for a specific application, using linguistic terms to model the actions of the rules. The rules were tested using pre-recorded gait data processed through a gait event detector and proved to reduce detection delay and the number of errors, compared to conventional rules. PMID- 11601444 TI - Fixed bending current for Elekta SL25 linear accelerators. AB - In a medical linear accelerator a bending magnet is used to bend the electron beam produced by the accelerator tube, in the treatment direction. For each electron energy the strength of the magnetic field has to be set to a specific level. Changing the magnetic field strength is done by changing the electric current through the bending magnet. When electron energy and magnetic field strength are not matched, performance of the linac can be affected. As electron energy, magneticfield strength and electrical current through the bending magnet are related to each other, it is reasonable to assume that for each electron energy the correct bending current can be predetermined. This calculated bending current reduces the number of variable parameters used to set up a treatment beam. Predetermining a variable simplifies the tuning procedures. It also prevents a deviation of the electron beam energy being compensated by variation of the bending current. Preventing false machine settings can contribute to increase linac performance and reduce down time and cost of ownership. PMID- 11601443 TI - Transthoracic defibrillation with chopping-modulated biphasic waveforms. AB - The superiority of different biphasic pulses for transthoracic defibrillation was proven by several studies. These efficient waveforms were implemented in some commercially available defibrillators. Recently we have devised and evaluated a biphasic waveform with a specially balanced ratio of the first-to-second phase voltages and with 5 kHz frequency 1:1 on-off chopping. It used less than half the energy for successful defibrillation in comparison with the 'classic' monophasic damped sinusoidal wave and showed considerably less post-shock negative effects. This experience led us to try several laws of chopping modulation. A pulse-width modulation, combining low energy with gradual upslope of the modelled transmembrane potential, proved to have better performance than the standard damped sinusoid wave and the non-chopped biphasic truncated exponential pulse. This waveform was tested in a series of animal experiments in comparison with other modulated pulses, with the non-modulated waveform and the standard damped sinusoid wave. The experiments demonstrated the superiority of the modulated waveform, assessed by combining the parameters of threshold defibrillation energy and of post-shock disturbances reduction. PMID- 11601445 TI - A methodology for evaluation of boundary detection algorithms on breast ultrasound images. AB - Image segmentation is the partition of an image into a set of non-overlapping regions that comprise the entire image. The image is decomposed into meaningful parts, which are uniform with respect to certain characteristics, such as grey level or texture. This study presents a novel methodology to evaluate ultrasound image segmentation algorithms. The sonographic features can differentiate between various sized malignant and benign breast tumours. The clinical experiment can determine whether a tumour is benign or not, based on contour, shape, echogenicity and echo texture. Further study of the standardized sonographic features, especially the tumour contour and shape, will improve the positive predictive value and accuracy rate in breast tumour detection. The effectiveness of using this methodology is illustrated by evaluating image segmentation on breast ultrasound images. Via definite segmentation, the appreciated tumour shape and contour can be ascertained. Furthermore, this method can enhance the ability of ultrasound to distinguish between benign and malignant breast lesions. PMID- 11601446 TI - A microvolt calibrator for EMG systems. AB - Non-evoked electromyographic signals range from several hundred microvolts for voluntary contractions to less than a microvolt far resting activity. Calibration of EMG recording equipment at such low levels may prove problematic. We have designed a useful battery operated calibrator for low level EMG recording in areas such as bio-feedback and stress management. PMID- 11601447 TI - Pesticide residue analysis (1999-2000): a review. AB - The literature of pesticide residue analysis is reviewed selectively for the period 1999-2000. Analyses of a wide range of pesticide classes and sample types, as well as some related organic pollutants, are covered. Studies of exposure and monitoring as well as pesticide degradation, persistance, leaching, mobility, and metabolism studies are included. PMID- 11601448 TI - Supercritical fluid extraction of halogenated monoterpenes from the red alga Plocamium cartilagineum. AB - Supercritical fluid extraction (SFE) of the marine red alga Plocamium cartilagineum, which is known to contain complex mixtures of halogenated monoterpenes, was investigated. P. cartilagineum samples were extracted by SFE with carbon dioxide and modified carbon dioxide containing up to 10% methanol at different pressure and temperature conditions to establish the optimum conditions for extraction. These conditions were then used in the extraction of halogenated monoterpenes from 2 different samples of P. cartilagineum: one from Davenport, CA, and the other from Casa Beach (San Diego, CA). Several halogenated monoterpenes isolated by conventional solvent extraction with methanol and purified by column chromatography were used as the reference compounds for the determination of the extraction efficiency in the SFE experients. Plocamium cartilagineum belongs to the red alga family--Plocamiaceae, and has been found to contain a large number of halogenated monoterpenes, whose structures typically contain 1-6 bromine and/or chlorine atoms. P. cartilagineum grows along the Pacific coast from Washington to Chile, the British Isles, Australia, and Spain. Interestingly, P. cartilagineum collected from different geographical areas in the world are all reported to produce halogenated monoterpenes, but of different structural types and halogen substitution patterns. Most of these halogenated monoterpenes have been found to exhibit varied biological activities, including antifungal, antimicrobial, and molluscicidal activity. PMID- 11601449 TI - Performance of a proposed determinative method for p-TSA in rainbow trout fillet tissue and bridging the proposed method with a method for total chloramine-T residues in rainbow trout fillet tissue. AB - Chloramine-T is an effective drug for controlling fish mortality caused by bacterial gill disease. As part of the data required for approval of chloramine-T use in aquaculture, depletion of the chloramine-T marker residue (para toluenesulfonamide; p-TSA) from edible fillet tissue of fish must be characterized. Declaration of p-TSA as the marker residue for chloramine-T in rainbow trout was based on total residue depletion studies using a method that used time consuming and cumbersome techniques. A simple and robust method recently developed is being proposed as a determinative method for p-TSA in fish fillet tissue. The proposed determinative method was evaluated by comparing accuracy and precision data with U.S. Food and Drug Administration criteria and by bridging the method to the former method for chloramine-T residues. The method accuracy and precision fulfilled the criteria for determinative methods; accuracy was 92.6, 93.4, and 94.6% with samples fortified at 0.5X, 1X, and 2X the expected 1000 ng/g tolerance limit for p-TSA, respectively. Method precision with tissue containing incurred p-TSA at a nominal concentration of 1000 ng/g ranged from 0.80 to 8.4%. The proposed determinative method was successfully bridged with the former method. The concentrations of p-TSA developed with the proposed method were not statistically different at p < 0.05 from p-TSA concentrations developed with the former method. PMID- 11601450 TI - Determination of clopidol residues in chicken tissues by liquid chromatography: part I. Optimization of analytical conditions and comparison with AOAC gas chromatography method. AB - A simple and specific liquid chromatographic method was developed for determination of clopidol in chicken tissues. Samples were extracted with acetonitrile. The extracts were cleaned up on an alumina column and an anion exchange column. The clopidol was separated on a column (30 cm x 3.9 mm) of microBondapak C18 (10 microm) by using acetonitrile-water (20 + 80, v/v) as mobile phase, and determined quantitatively at 270 nm. Recoveries were 86.0 97.6%, with relative standard deviations of 2.14-9.42% at 0.010-2.0 mg/kg from 4 spiked matrixes of chicken muscle, egg, liver, and kidney. The limit of detection was 0.005 mg/kg. Compared with the modified AOAC gas chromatographic method, the present method is simple and fast to operate. Its results are accurate and reliable, making it favorable for environmental protection and meeting requirements for human safety. Thus, it is suitable for routine analysis of large quantities of samples. PMID- 11601451 TI - Determination of clopidol residues in chicken tissues by liquid chromatography: part II. Distribution and depletion of clopidol in chicken tissues. AB - A study was made of the distribution and depletion of clopidol residues at different tissue locations in chickens fed with feeds incurred with clopidol. Experiments showed that the residue levels were not identical at 5 different tissue locations in each chicken. The sequence of residue levels from high to low was livers, kidneys, upper breast, lower breast, and leg meat. The maximum residue values after suspension of the drug for 8 h were (mg/kg): livers, 4.600; kidneys, 3.619; upper breast, 1.742; lower breast, 1.641; leg meat, 1.525. The averages were taken after values for 10 chickens were determined. After suspension of the drug for 3 days, >80% residue clopidol was depleted, and the depletion was nearly completed within 7 days. The speed of depletion varied at different tissue locations in each chicken, with the sequence from fast to slow being equivalent to that of the residue levels. Analytical results of 350 samples during 7 days showed that the proposed method is specific for determination of clopidol in chickens. PMID- 11601452 TI - Determination of clopidol residues in chicken tissues by liquid chromatography: part III. Quality control analysis of export chickens. AB - A summary is presented of the liquid chromatographic (LC) determination of clopidol residues in export chickens from 1992 to 1999. Over the past 8 years, we analyzed >7000 chicken samples. A total of 0.66% of samples contained clopidol residues, ranging from 0.005 to 0.79 mg/kg; however, none exceeded 3 mg/kg, the Chinese maximum residue limit. In comparison with 1992, the number of samples multiplied 70-fold, and the frequency of clopidol found in samples decreased 148 fold in 1999. The chickens inspected were exported to foreign countries; all were cleared by the buyers with no disputes. This report also introduces the critical control points of the proposed LC method as well as identification of false positive procedures by both experience and LC/mass spectrometric confirmation. Our experiences over the past 8 years have demonstrated that the ruggedness of the proposed LC method is quite good. PMID- 11601453 TI - Validation of a UV spectrophotometric method for the determination of melatonine in solid dosage forms. AB - The aim of the work described in this paper was to provide a fast, easy, inexpensive, precise, and accurate method for the determination of melatonine in solid pharmaceutical dosage forms. The developed method is based on a UV first derivative spectrophotometric determination, which exhibits excellent linearity in aqueous solutions (r2 = 0.996) for analyte concentrations of 1.5-4.5 mg/dL within a pH range of 5-9. Neither excipients present in the formulation nor indole adulterants, such as tryptophan (up to 5%), interfere with the assay. A study of variation parameters showed that sonication temperature was the main factor for successful determination. At temperatures of <45 degrees C, the sample dissolved completely, and accurate spectrophotometric measurements were obtained. A study was conducted of all the parameters established by the United States Pharmacopeia, 23rd Rev., to validate an analytical method for a solid pharmaceutical form, i.e., linearity, range, accuracy, precision, and specificity. All the parameters were in accordance with the acceptance criteria of the Comite de Guias Oficiales de Validacion de la Direccion General de Control de Insumos para la Salud de Mejico. In addition, robustness and content uniformity tests were performed to substantiate the usefulness of the method. PMID- 11601455 TI - Determination of salicylate in blood serum by flow injection with immobilized salicylate hydroxylase. AB - A flow injection (FI) enzymatic system, based on the use of immobilized salicylate hydroxylase in glass beads, was developed for the determination of salicylate. Salicylate hydroxylase and nicotinamide adenine dinucleotide (NADH) are used to convert salicylate to catechol. The reaction of catechol with 4 aminophenol at high pH yields a colored product which is detected spectrophotometrically at 565 nm. Ten samples of human serum containing from 5.0 x 10(-4) to 5.0 x 10(-3) mol/L added salicylate were analyzed and the recovery was determined. Eight additional serum samples containing salicylate were analyzed by the Trinder test and the proposed method. The results obtained with the 2 methods showed good agreement by the statistical Student's t-test. The relative precision of the method is about 3.4% (RSD of the mean recovery). Considering the lowest concentration analyzed, the quantitative limit of detection is about 0.2 x 10(-5) mol/L (3 x SD). The volume of the sample used was 150 microL. The proposed method was also used to analyze medicines containing acetylsalicylic acid. The results were statistically compared with those obtained through the U.S. Pharmacopoeia procedure and showed excellent agreement. PMID- 11601454 TI - Simultaneous determination of emamectin and ivermectin residues in Atlantic salmon muscle by liquid chromatography with fluorescence detection. AB - A liquid chromatographic (LC) method for determining residues of the antiparasitic drugs emamectin (EMA) and ivermectin (IVR) in fish tissues has been developed. EMA and IVR residues are extracted with acetonitrile and cleaned up on a C18 solid-phase extraction column. Extracts are derivatized with 1 methylimidazole and trifluoroacetic anhydride and the components are determined by LC on a C18 reversed-phase column with fluorescence detection (excitation: 365 nm, emission: 470 nm). The mobile phase is 94% acetonitrile-water run isocratically. Calibration curves were linear between 1 and 32 ng injected for both EMA and IVR. The limit of detection for both analytes was 0.5 ng/g, with a limit of quantitation of 1.5 ng/g. Recoveries of EMA and IVR added to salmon muscle averaged 96 +/- 9% and 86 +/- 6%, respectively, at levels between 5 and 80 ng/g. The percent relative standard deviation for the described method was less than 7% over the range of concentrations studied. The operational errors, interferences, and recoveries for fortified samples compare favorably with an established IVR method. The recommended method is simple, rapid, and specific for monitoring residues of EMA and IVR in Atlantic salmon muscle. PMID- 11601456 TI - Bioavailable organochlorine pesticides in a semi-arid region of eastern Oregon, USA, as determined by gas chromatography with electron-capture detection. AB - A group of dissolved-bioavailable organochlorine (OC) pesticides and inorganic anions in water and total OC pesticides in sediments were measured in the Malheur Watershed, a semi-arid region in the western United States, over a 2-year period. OC pesticide levels were compared with those from a 1990 study of the lower section of the river, the most recent data available. After calculating the dissolved fraction from the 1990, study it seems that DDD and dieldrin levels have decreased in the water by 50-70%, while DDE and DDT have changed little. Although banned nearly 30 years ago, DDT is still persistent throughout the Malheur River basin/watershed because it was found in all water samples tested. All of the OC pesticides tested during the 2-year study are well below the criterion continuous concentration for aquatic community exposure as defined by the U.S. Environmental Protection Agency (EPA). OC pesticides appear to be decreasing, however, at lower Ontario there remains a human health risk (EPA Human Health Risk Water Quality Criteria) for DDT, because this criteria includes daily consumption of water and fish from the river. Overall, although the upper forest watershed sites have lower OC pesticide concentrations, they represent an important contribution to the total DDT load to this watershed, a source not previously acknowledged. The large increase in DDT and sigmaDDT between the Ontario sites may indicate a possible historical point source of contamination or historical preferential deposition of contamination. Normalized sediment (sigmaDDT/organic carbon) strongly correlates with dissolved water sigmaDDT. PMID- 11601457 TI - Development and validation of a method using on-line solid-phase extraction and liquid chromatography with ultraviolet detection for the determination of bisphenol A, octylphenol, and nonylphenol in groundwater. AB - Alkylphenols are nonbiodegradable metabolites arising from various pathways of aerobic and anaerobic degradation of the nonionic surfactants alkylphenol ethoxylates. A method based on the use of on-line solid-phase extraction (SPE) and liquid chromatography (LC) with UV detection was developed to determine bisphenol A, octylphenol, and nonylphenol at trace levels in water. The on-line coupled SPE procedure automatically enables an approximately 300-fold preconcentration of analytes, which can be further enhanced by an increase in applied sample volume. By using C18 cartridges, recoveries of >90% were obtained for all the analytes. A validation procedure was carried out with a groundwater sample to ensure the quality of the results; performance criteria such as detection limits (LODs), quantitation limits (LOQs), linearity, and precision were evaluated. LODs and LOQs in the range of 0.17-0.36 and 0.35-1.88 microg/L, respectively, were found; for all the analytes, linearity was established over 2 orders of magnitude (r2 >0.997, n = 54). The intraday repeatability values expressed as relative standard deviations were <5.3%; a nested analysis of variance was performed to verify the influence of 3 different factors, i.e., different days, extraction procedure, and LC replicate injection, on data precision. PMID- 11601458 TI - Environmental monitoring of pesticides by immunoanalytical techniques: validation, current status, and future perspectives. AB - Reliable monitoring technology is an essential component of effective regulation and risk management of environmental contaminants such as pesticides. Most environmental monitoring and analysis is currently conducted using instrumental techniques such as gas-liquid chromatography (GLC) and liquid chromatography (LC). Immunoanalysis provides powerful monitoring techniques that have emerged in the last 3 decades. This paper shows they can deliver rapid, accurate, and relatively inexpensive analysis with high throughput and that have the capability to be field oriented. The technique is versatile in application and can be formatted to suit different purposes such as quantitative analysis or simple "yes/no" tests that are field-portable. While there is a range of opinion on the merits of immunoassays as an analytical tool for pesticides, we suggest that this technology is best considered as complementary to GLC and LC, extending the range of capability for field monitoring. Supporting this view, an increasing number of successful applications of immunoassays to monitoring have been reported in recent years. We also report here the implications of recent developments in the field of immunodiagnostics and their application to monitoring of environmental contaminants. We emphasise that, together with adequate validation by instrumental techniques, immunoassays provide monitoring services yielding realistic and comprehensive data for risk management, allowing decisions on appropriate action by various authorities to be made. PMID- 11601459 TI - Liquid chromatographic/mass spectrometric determination of desmedipham and phenmedipham and their metabolites in soil. AB - A simple method is described for the simultaneous determination of residues of 2 carbamate herbicides (phenmedipham and desmedipham) and related metabolites (m aminophenol, aniline, and m-toluidine) in soil. The analytes are extracted from spiked soils with methanol. The solvent/soil suspension is centrifuged, and the supernatant is directly injected, without any further cleanup, into a reversed phase liquid chromatography/mass spectrometry apparatus equipped with a TurbolonSpray interface. The method was tested on 5 soils having different physicochemical properties. Recoveries from the soil types, spiked over the range of 50-200 ppb, were essentially quantitative for each analyte. The detection limits of the method are < or = 25 ng/g. PMID- 11601460 TI - Determination of N-nitrosodimethylamine in environmental aqueous samples by isotope-dilution GC/MS-SIM. AB - An analytical method for the determination of N-nitrosodimethylamine (N-NDMA) in environmental aqueous samples has been developed using isotope dilution gas chromatography/mass spectrometry in the selected ion monitoring mode (GC/MS-SIM). After deuterated N-nitrosodimethylamine (d6-N-NDMA) as surrogate standard was added to the samples, the analytes were extracted with methylene chloride, dried with anhydrous sodium sulfate, and concentrated in a rotary evaporator. The concentrated extracts were analyzed by GC/MS-SIM after adding N nitrosodiethylamine as an internal standard. The method detection limit for N NDMA was 0.003 pg/microL and was validated by an analysis of a fortified water sample. The method was applied to real samples. PMID- 11601461 TI - Multiresidue determination of pesticides in drinking and related waters by gas chromatography/mass spectrometry after solid-phase extraction: interlaboratory study. AB - As part of a project funded by the European Commission (EC) for the development and evaluation of multiresidue methods for analysis of drinking and related waters, 15 European laboratories evaluated a method using styrene-divinylbenzene co-polymer solid-phase extraction followed by gas chromatography/mass spectrometry. The main aim of the study was to evaluate whether the method meets the requirements of EC Directive 98/83 in terms of accuracy, precision, and detection limit for 22 pesticides according to the following requirements: limit of detection, < or = 0.025 microg/L; accuracy, expressed as recovery between 75 and 125%; and precision, expressed as repeatability relative standard deviation of the method of < 12.5% and as reproducibility relative standard deviation of the method of < 25%. Analyses for unknown concentrations were performed with fortified commercial bottled and tap waters. All laboratories were able to achieve detection limits of 0.01 microg/L for all pesticides except dimethoate and desisopropylatrazine (0.02 microg/L). The criteria for repeatability were met for all compounds except trifluralin, dimethoate, and lindane in bottled water and chlorpyrifos, dimethoate, and lindane in tap water. The criteria for reproducibility were met for all compounds except trifluralin, dimethoate, and lindane in bottled water and pendimethalin, chlorpyrifos, dimethoate, terbutryn, and lindane in tap water. In terms of accuracy, the method meets the requirements for all pesticides in both matrixes, except for lindane in bottled water and lindane and chlorpyrifos in tap water. PMID- 11601462 TI - Petrifilm rapid S. aureus Count Plate method for rapid enumeration of Staphylococcus aureus in selected foods: collaborative study. AB - A rehydratable dry-film plating method for Staphylococcus aureus in foods, the 3M Petrifilm Rapid S. aureus Count Plate method, was compared with AOAC Official Method 975.55 (Staphylococcus aureus in Foods). Nine foods-instant nonfat dried milk, dry seasoned vegetable coating, frozen hash browns, frozen cooked chicken patty, frozen ground raw pork, shredded cheddar cheese, fresh green beans, pasta filled with beef and cheese, and egg custard-were analyzed for S. aureus by 13 collaborating laboratories. For each food tested, the collaborators received 8 blind test samples consisting of a control sample and 3 levels of inoculated test sample, each in duplicate. The mean log counts for the methods were comparable for pasta filled with beef and cheese; frozen hash browns; cooked chicken patty; egg custard; frozen ground raw pork; and instant nonfat dried milk. The repeatability and reproducibility variances of the Petrifilm Rapid S. aureus Count Plate method were similar to those of the standard method. PMID- 11601463 TI - Determination of ochratoxin A in baby food by immunoaffinity column cleanup with liquid chromatography: interlaboratory study. AB - An interlaboratory study funded by the European Commission, Standards, Measurement and Testing Programme (4th Framework Programme) was performed to evaluate the effectiveness of an immunoaffinity column cleanup liquid chromatographic (LC) method for the determination of ochratoxin A in baby food at a possible future European regulatory limit (0.1 ng/g). The test portion is extracted in a blender with tert-butyl methyl ether (chosen to avoid use of chloroform but shown to give equivalent extraction efficiency) after addition of 0.5 mol/L phosphoric acid-2 mol/L sodium chloride solution. The extract is centrifuged and redissolved in a mixture of phosphate buffered saline solution and methanol. After removal of lypophilic substances with hexane, the extract is applied to an immunoaffinity column containing antibodies specific to ochratoxin A. The column is washed with water to remove the interfering compounds and the purified ochratoxin A is eluted with methanol. The separation and determination of ochratoxin A is performed by reversed-phase LC and detected by fluorescence after postcolumn derivatization (PCD) with ammonia. Test materials (baby food infant formulae), both spiked and naturally contaminated with ochratoxin A, were sent to 13 laboratories in 8 different European countries. Test portions were spiked at a level of 0.085 ng/g ochratoxin A. The average recovery for the spiked blank baby food was 108%. Based on results for spiked samples (blind pairs at 0.085 ng/g) as well as naturally contaminated samples (blind pairs at levels between 0.05 and 0.22 ng/g) the relative standard deviation for repeatability (RSDr) ranged from 18-36%. The relative standard deviation for reproducibility (RSDR) ranged from 29-63% and HORRAT values of between 0.4 and 0.9 were obtained. PMID- 11601464 TI - Determination of zearalenone content in cereals and feedstuffs by immunoaffinity column coupled with liquid chromatography. AB - The zearalenone content of maize, wheat, barley, swine feed, and poultry feed samples was determined by immunoaffinity column cleanup followed by liquid chromatography (IAC-LC). Samples were extracted in methanol-water (8 + 2, v/v) solution. The filtered extract was diluted with distilled water and applied to immunoaffinity columns. Zearalenone was eluted with methanol, dried by evaporation, and dissolved in acetonitrile-water (3 + 7, v/v). Zearalenone was separated by isocratic elution of acetonitrile-water (50 + 50, v/v) on reversed phase C18 column. The quantitative analysis was performed by fluorescence detector and confirmation was based on the UV spectrum obtained by a diode array detector. The mean recovery rate of zearalenone was 82-97% (RSD, 1.4-4.1%) on the original (single-use) immunoaffinity columns. The limit of detection of zearalenone by fluorescence was 10 ng/g at a signal-to-noise ratio of 10:1 and 30 ng/g by spectral confirmation in UV. A good correlation was found (R2 = 0.89) between the results obtained by IAC-LC and by the official AOAC-LC method. The specificity of the method was increased by using fluorescence detection in parallel with UV detection. This method was applicable to the determination of zearalenone content in cereals and other kinds of feedstuffs. Reusability of immunoaffinity columns was examined by washing with water after sample elution and allowing columns to stand for 24 h at room temperature. The zearalenone recovery rate of the regenerated columns varied between 79 and 95% (RSD, 3.2 6.3%). Columns can be regenerated at least 3 times without altering their performance and without affecting the results of repeated determinations. PMID- 11601465 TI - Detection of preformed type A botulinal toxin in hash brown potatoes by using the mouse bioasssay and a modified ELISA test. AB - A foodborne illness caused by type A toxin-producing Clostridium botulinum was investigated by using the standard mouse bioassay and a rapid invitro test for toxin detection. The patient, who consumed improperly stored hash brown potatoes that contained the preformed toxin, was diagnosed with type A botulism. C. botulinum type A toxin was detected in the hash brown potatoes as well as in the tryptone-peptone-glucose-yeast extract (TPGY) medium subcultures of this food using the mouse bioassay and an amplified ELISA technique. The mouse bioassay revealed preformed toxin at 10,000 minimum lethal dose (MLD)/g uncooked product and the amplified ELISA an equivalent 50,000 MLD/g. The cultural toxin from the uncooked product killed mice at the 10(6) dilution and a modification of the ELISA procedure was positive at the 10(3) dilution. Cooked food obtained from the consumer's waste can contained 100 MLD/g and the ELISA was also positive at the same dilution of the product. The culture of the cooked product obtained from the waste can was lethal for mice at the 10(7) dilution and positive using the modified ELISA at the 10(4) dilution. The unmodified amplified ELISA method indicated a toxin level of approximately 1 ng/mL (equivalent to 5 x 10(5) MLD/mL) in diluted culture fluid from the uncooked food and the culture of cooked food obtained from the waste can. The hash brown potatoes were negative for types B, E, and F preformed and cultural botulinal toxins using both assays. PMID- 11601466 TI - Enzyme immunoassay for aflatoxin B1-lysine adduct and its validation. AB - A simple procedure was developed for in vitro synthesis and characterization of aflatoxin B1-lysine adduct using aflatoxin B1, N-alpha-acetyl lysine and m chloroperbenzoic acid (MCPBA). At a molar ratio of 1:16 (aflatoxin B1:N-alpha cetyl lysine), the recovery of adduct was 62%. Analysis of the adduct by thin layer chromatography showed a single spot (Rf = 0). Absorption spectra of the adduct showed 2 peaks at 275 and 335 nm. Liquid chromatographic (LC) analysis of the AFB1-lysine adduct showed a relative retention time of 2.1 min. Using the same epoxidation procedure, BSA-AFB1 adduct and ovalbumin-AFB1 adduct were synthesized for production of antibodies and as coating antigen, respectively. Control rat serum, spiked with AFB1-lysine adduct and subjected to LC analysis showed a retention time of 2.1 min, which is similar to that of AFB1-lysine reference standard, synthesized. Further, enzymatically hydrolyzed, control rat serum spiked with BSA-AFB1 adduct showed 2 peaks with retention times of 2.1 and 2.7 min. Based on the LC analysis, recovery of BSA-AFB1 in terms of AFB1-lysine adducts was 67 +/- 5%. The major peak (2.1 min) accounted for 72% of the adduct; the second minor peak (2.7 min) accounted for 28% of the total AFB1-lysine adducts formed. Stability studies on the AFB1-lysine adduct synthesized, indicated that it was stable for 1 month. Antibody capture assay showed an absorbance of 0.9 to 1.0 at a dilution of 1:50,000 when ovalbumin-AFB1 was used as a coating antigen. Indirect competitive ELISA showed 50% displacement (IC50) of the antibodies at a concentration of 13 ng AFB1-lysine, whereas the IC50 for AFB1 was 7 ng. The recovery of AFB1-lysine adduct spiked to control rat serum followed by enzymatic hydrolysis and immunoanalysis (indirect ELISA) was 93 +/- 6%. The enzyme immunoassay was validated by a rodent model, in which the animals were exposed to aflatoxin B1 (20 microg AFB1/kg body mass/day). The level of AFB1 lysine adduct in the rat serum was 27.3 +/- 4.37 microg/mg albumin. PMID- 11601467 TI - Fluorometric determination of ethanol in liquor samples by flow-injection analysis using an immobilized enzyme-reactor column with packing prepared by coupling alcohol oxidase and peroxidase onto chitosan beads. AB - A flow-injection system was developed for the determination of ethanol with an immobilized enzyme-reactor column. This system, which consisted of hand-made reactor columns packed with alcohol oxidase and horseradish peroxidase immobilized onto chitosan beads, and a fluorometric detector, was applied to the determination of ethanol in liquor samples. Under the recommended conditions, the ethanol, which was present in the pretreated samples, was converted to hydrogen peroxide when it was passed through the immobilized alcohol oxidase (AOD) column with 0.1 mol/dm3 phosphate buffer (pH 7.0). A sample can be analyzed with this system in <10 min. The calibration curve for ethanol was linear from 2.0 to 0.1 mg/dm3. The determination limit, which was defined by the difference between the sample peak and blank peak, was estimated to be 50 microg/dm3 for ethanol. Interferences from some substances present in actual liquor samples decreased the analytical response and activity of the immobilized AOD-reactor column, but they were removed by dilution and pretreatment with an octyldecylsilane cartridge. PMID- 11601468 TI - Development of a rapid method for the detection of cocoa butter equivalents in mixtures with cocoa butter. AB - A simple and rapid gas chromatographic (GC) method was developed for the detection of cocoa butter equivalents (CBEs) in cocoa buffer (CB). It is based on the use of a 5 m nonpolar capillary column for the separation of the main triglycerides of CB according to their acyl/carbon numbers. The GC procedure was optimized to avoid thermal degradation of the triglycerides. By computing the ratio C54/C50 and (C54/C50) x C52 and by 2-dimensional plotting of these values, authentic CB samples were clearly distinguished from samples containing various CBEs. The detection of little as 1% CBE in CB (corresponding to about 0.3% CBE in chocolate) in a model system was shown to be possible. Under real conditions, for a wide range of CBs, about 2.5% CBEs in CB were detected. With this method, quantitation was possible at a concentration of 5% CBEs in CB mixtures, which corresponds to around 1% in chocolate; this value is far below the maximum level of 5% CBEs allowed to be added to chocolate. PMID- 11601469 TI - Determination of trans octadecenoic acids by silver-ion chromatography-gas liquid chromatography: an intercomparison of methods. AB - Several silver-ion chromatography-gas liquid chromatography (GLC) techniques for the determination of trans octadecenoic acids in partially hydrogenated vegetable fats were collaboratively evaluated. Twelve laboratories participated in the study. All collaborators used high polarity fused silica capillary columns for the separation of fatty acid methyl esters by GLC; 7 collaborators isolated trans monoenes by silver-ion liquid chromatography (Ag-LC) and the remainder used silver-ion thin-layer chromatography (Ag-TLC). Eight artificially prepared materials [soybean oil spiked with either methyl elaidate, trielaidin, or trans octadecenoates isolated from partially hydrogenated sunflower oil (PHSO)] and 2 matrix materials (PHSO and a blend of PHSO and palm oil) served as test samples. Ag-TLC and Ag-LC proved to be equivalent techniques for the prefractionation of trans monoenes. Recovery of methyl elaidate, trielaidin, or trans octadecenoates isolated from PHSO varied between 97.9-103.7% over a concentration range of 1 to 30 g trans fatty acids/100 g. Reproducibility relative standard deviation (RSDR) for the spiked samples were in the range of 3.1-8.6% for 30-1% trans monoene content. For the 2 matrix samples (mean 3.75 and 19.08% trans monoene content) RSDR was 13.2 and 3.6%. The hyphenated techniques tested proved to be highly accurate and sufficiently precise methods for the determination of trans monoenes in partially hydrogenated vegetable fats. Procedural variations of the silver-ion chromatography prefractionation step (separation mode, mobile phase, and detection systems) did not significantly influence the results of the test. Therefore, silver-ion chromatography is a robust method, which does not need rigorous standardization to achieve high precision of test results. A further benefit of the hyphenated technique is that any type of efficient polar capillary column can be used. PMID- 11601470 TI - Determination of fat in raw and processed milks by the Gerber method: collaborative study. AB - The Gerber method is used worldwide as a simple and rapid method for determining fat in raw and processed milks. However, the volume of the test portion used in the method has not been internationally agreed upon. A collaborative study was conducted to evaluate performance of the Gerber method using either a weighed test portion (11.13 g) or by a 10.77 mL test portion delivered by pipet. For each method, laboratories received 10 test samples: 5 raw and 5 pasteurized homogenized milks, 2 of which were blind duplicate pairs. Eleven and 10 laboratories participated in the evaluation of aliquot addition by weight and pipet, respectively. Mojonnier ether extraction (Method 989.05) was used as the reference method. Interlaboratory study statistics were similar between methods of test portion addition and between raw and processed materials; therefore, summary interlaboratory study statistics were pooled. The fat content of milk samples ranged from 0.96 to 5.48%. Absolute reproducibility and repeatability were not affected by fat level, and pooled statistical performance (invalid and outlier data removed) was (g fat/100 g milk) s(r) = 0.026, s(R) = 0.047, r = 0.074, and R = 0.132. Relative standard deviations increased with decreasing fat content, and were summarized by fat level: 1-2% fat milk, mean = 1.437, RSD(r) = 1.809%, RSD(R) = 3.271%; 2-6% fat milk, mean = 4.156, RSD(r) = 0.626%, RSD(R) = 1.131%. Compared with ether extraction, test results by the Gerber method were slightly lower (0.02% fat) using a weighed test portion and significantly lower (0.06% fat) using a 10.77 mL volume addition by pipet. A trend toward underestimating fat content at lower fat concentrations (1-2% fat) was observed with the weighed test portion but not when a pipet was used. The Associate Referee recommends that the Gerber method using a weighed test portion be adopted as First Action with applicability limited to whole milk. PMID- 11601471 TI - Detection of added beet or cane sugar in maple syrup by the site-specific deuterium nuclear magnetic resonance (SNIF-NMR) method: collaborative study. AB - Results of a collaborative study are reported for the detection of added beet or cane sugar in maple syrup by the site-specific natural isotope fractionation nuclear magnetic resonance (SNIF-NMR) method. The method is based on the fact that the deuterium content at specific positions of the sugar molecules is different in maple syrup from that in beet or cane sugar. The syrup is diluted with pure water and fermented; the alcohol is distilled with a quantitative yield and analyzed with a high-field NMR spectrometer fitted with a deuterium probe and fluorine lock. The proportion of ethanol molecules monodeuterated at the methyl site is recorded. This parameter (D/H)I is decreased when beet sugar is added and increased when cane sugar is added to the maple syrup. The precision of the method for measuring (D/H)I was found to be in good agreement with the values already published for the application of this method to fruit juice concentrates (AOAC Official Method 995.17). An excellent correlation was found between the percentage of added beet sugar and the (D/H)I isotopic ratio measured in this collaborative study. Consequently, all samples in which exogenous sugars were added were found to have a (D/H)I isotopic ratio significantly different from the normal value for an authentic maple syrup. By extension of what is known about plants having the C4 cycle, the method can be applied to corn sweeteners as well as to cane sugar. One limitation of the method is its reduced sensitivity when applied to specific blends of beet and cane sugars or corn sweeteners. In such case, the C13 ratio measurement (see AOAC Official Method 984.23, Corn Syrup and Cane Sugar in Maple Syrup) may be used in conjunction. PMID- 11601472 TI - Determination of fat in dairy products using pressurized solvent extraction. AB - Gravimetric fat data were obtained for a wide range of dairy products with fat contents ranging from 0.5 to 83% using pressurized solvent extraction at elevated temperatures and pressure (80-120 degrees C; 10.3 MPa). Extraction performance was sensitive to solvent composition, temperature, and sample matrix. By optimizing solvent mixtures, sample-solvent contact times of 8-10 min were sufficient for high recoveries from all products tested. The most successful solvents with regard to speed of extraction, selectivity, and recovery (average recovery, %) were various mixtures of hexane (or petroleum ether)-dichloromethane methanol for dried cream (99.8%), dried whole milk (99.6%), dried buttermilk (98.2%), dried skim milk (97.0%), dried whey protein concentrate (97.5%), casein (95.0%), and caseinate (102.1%); petroleum ether-acetone-ethanol or petroleum ether-acetone-isopropanol for cheddar-type cheese (99.4%); petroleum ether acetone for butter (99.9%); petroleum ether-acetone-isopropanol for cream (100.3%); and petroleum ether-isopropanol for liquid milks (99.0%). Relative standard deviations for repeatability were obtained for dried whole milk (0.2%), dried whey protein concentrate (0.7%), cheese (0.3%), butter (0.1%), and ultraheat treated (UHT) milk (0.7%). Solvent removal and drying of extracts with a heated block evaporator saved time compared with conventional drying ovens. Estimated savings in labor (50-75%) and solvents (80%) were substantial compared with the manual Mojonnier methods. PMID- 11601473 TI - Detection of hazelnut oil in virgin olive oil by assessment of free sterols and triacylglycerols. AB - Free sterols were evaluated as factors for discriminating between genuine virgin olive oil and hazelnut-mixed virgin olive oil. Numeric analyses of the results amplified the differences between groups. The application of this method to virgin olive oil samples and their mixtures with 10% hazelnut oil distinguished between genuine and nongenuine virgin olive oil with statistical certainty. Triacylglycerol analysis was tested for the same purpose by using parameter deltaECN42, but although it possessed a discriminating capacity, it alone could not distinguish the aforementioned groups with sufficient certainty. Free delta7 sterols data were combined with deltaECN42 data into a single discriminating function to improve differentiation and bring more ruggedness, and for detection of low amounts (10%) of hazelnut oil in virgin olive oil. In fact, the values obtained by addition of delta7-sterol data and deltaECN42 data showed a higher discriminating capacity than single parameters. In a single operation the method produced all the oil fractions necessary for analysis of free sterols and triacylglycerols with ECN42. Solid-phase extraction was applied in substitution of traditional chromatography on a silica column. PMID- 11601474 TI - Simultaneous determination of six triazolic pesticide residues in apple and pear pulps by liquid chromatography with ultraviolet diode array detection. AB - A method is described for the simultaneous determination of diclobutrazol, flusilazole, flutriafol, hexaconazole, paclobutrazol, and tetraconazole in apple and pear pulps used in baby food at a limit of 0.01 mg/kg. Apple and pear pulp samples are subjected to selective solid-phase microdispersion (SPMD) with SPE-ED Matrix-38 and acetone-cyclohexane, and the extracts are cleaned up on a Florisil cartridge with hexane-cyclohexane-acetone. The extracts are then analyzed by liquid chromatography with ultraviolet detection, using an octadecylsilane column with a gradient-programmed acetonitrile-water mobile phase. Recoveries were determined by spiking apple and pear pulps with the 6 pesticides under investigation at 0.1, 0.05, 0.03, and 0.01 mg/kg. Six determinations were performed at each level for each pesticide. Recoveries were > or = 70% at the 0.01 mg/kg level. PMID- 11601475 TI - Ultrasound treatment acceleration of solvent extraction for fumigant residues from wheat. AB - Concerns about consumer and worker safety and the fate of fumigants have fuelled strong efforts to determine their residues in foodstuffs. Fumigants are usually extracted from commodities with solvent at room temperature (25 degrees C). In this paper, solvent extraction of methyl bromide, phosphine, carbonyl sulfide, and carbon disulfide using ultrasonic acceleration or heating was evaluated. Wheat samples plus solvent, in gas-tight bottles, were placed in an ultrasonic chamber or an oven (50 degrees C), and fumigants were released into the headspace over the solvent. Completeness of extraction was demonstrated within 2 h for ultrasonic extraction, 7-20 h for 50 degrees C heating, and 8-35 h for room temperature extraction. The rapidity of extraction was mainly due to ultrasonic vibration rather than increased temperature. PMID- 11601476 TI - On-line complexation/preconcentration system for the determination of lead in wine by inductively coupled plasma-atomic emission spectrometry with ultrasonic nebulization. AB - An on-line lead preconcentration and determination system implemented with inductively coupled plasma-atomic emission spectrometry (ICP-AES) with ultrasonic nebulization (USN) in association with flow injection was studied. For the preconcentration of lead, a Pb-quinolin-8-ol complex was formed on-line at pH 6.8 and retained on Amberlite XAD-16 resin. The lead was removed from the microcolumn by countercurrent elution with nitric acid. A total enhancement factor of 225 was obtained with respect to ICP-AES with pneumatic nebulization (15.0 for USN and 15.0 for the column). The detection limit for Pb for the preconcentration of a 10 mL wine sample was 0.15 microg/L. The precision for 10 replicate determinations at a Pb level of 25 microg/L was a relative standard deviation of 2.5%, calculated from the peak heights obtained. The calibration graph obtained by using the preconcentration system for lead was linear with a correlation coefficient of 0.9995 for levels near the detection limit up to > or = 1000 microg/L. The method was successfully applied to the determination of lead in wine samples. PMID- 11601477 TI - Multiresidue determination of organochlorine pesticides and polychlorinated biphenyls in milk by gas chromatography with electron-capture detection after extraction by matrix solid-phase dispersion. AB - A multiresidue analytical method based on matrix solid-phase dispersion was developed to analyze liquid milk for 22 organochlorine pesticides (OCPs) and 6 polychlorinated biphenyls (PCBs). Initial extraction is performed by loading 3 mL milk onto a 2.0 g octadecyl (C18)-bonded silica cartridge with n-hexane as the eluant. Neutral alumina column chromatography with sodium sulfate as the drying agent is used for further cleanup. The eluate is concentrated to 0.5 mL, and target analytes are determined by capillary gas chromatography with electron capture detection. The optimized method was validated by determining accuracy (recovery percentages), precision (repeatability and reproducibility), and sensitivity (detection and quantitation limits) from analyses of milk samples fortified at 10 and 1 microg/L levels. Average recoveries were between 74 and 106% for all residues except beta-HCH, beta-endosulfan, and endosulfan sulfate. Both repeatability and reproducibility relative standard deviation values were < 22% for all residues. Detection limits ranged from 0.02 to 0.12 microg/L and quantitation limits were between 0.02 and 0.62 microg/L. The proposed analytical method may be used as a fast and simple procedure in routine determinations of OCPs and PCBs in milk. PMID- 11601478 TI - Estimation of measurement uncertainty in pesticide residue analysis. AB - Proficiency test results from 5 countries involving 61 separate interlaboratory proficiency tests for pesticide residues were examined in this study. A total of 24 different matrixes and 869 relative standard deviations of the mean (or median) pesticide residue concentration were statistically evaluated in relation to the Horwitz function. The aim was to determine whether or not the concentration-dependent relationship described by Horwitz would hold for the much narrower range of chemicals and concentrations covered in routine pesticide residue analysis. Although for fatty (animal-derived) matrixes the variability increased as the concentration decreased in line with the Horwitz equation, the between-laboratories relative standard deviations for nonfatty matrixes (fruit, vegetables, and grain) remained at 25% over the entire concentration range of 1 microg/kg to 10 mg/kg for the pesticides studied. Given these findings, the Horwitz equation remains valid for calculating uncertainties involving pesticide residues in fatty matrixes. However, for pesticide residue analyses involving nonfatty matrixes, a constant relative standard deviation of 25% is more appropriate for calculating uncertainties, particularly when a reported result is assessed against a regulatory limit. PMID- 11601479 TI - Recognition of the bouquet of Chinese spirits by artificial neural network analysis. AB - Forty-six samples of Chinese spirits, whose bouquets were determined by sensory evaluations, and 17 compounds characteristic of the flavors determined by gas chromatography/gas chromatography-mass spectrometry (GC/GC-MS), were subjected to neural network analysis and their corresponding factor scores developed. To make the bouquet recognition more efficient, an improved artificial back-propagation neural network (BPNN) was applied. In each kind of data, the BPNN was trained repeatedly until the error rate was less than the predetermined threshold error; then the trained network was applied to the test set that was not involved in the training process to establish the validity of the network, and a correct prediction rate of 100% was obtained. The BPNN provided a correlation between the data offered from sensory evaluations and the data of chemical compositions determined by instrumental analysis. The BPNN approach is feasible regardless of whether the crude data or the factor scores are used; however, recognition results were better with the latter than with the former. In a comparison of all the results obtained by BPNN, cluster analysis, and discriminant analysis, the method of artificial neural network analysis appeared to be the optimal technique for recognizing the bouquet of Chinese spirits. PMID- 11601480 TI - Enzyme immunoassay of staphylococcal enterotoxins in dairy products with cleanup and concentration by immunoaffinity column. AB - Two different immunoaffinity columns (IACs) were prepared for detection of staphylococcal enterotoxins (SETs) from dairy products. First, a specific IAC for staphylococcal enterotoxin A (SEA), IAC-1, was prepared by coupling monoclonal antibody (mAb) directed against SEA; second, a polyspecific IAC for SEA, staphylococcal enterotoxin B (SEB), staphylococcal enterotoxin C (SECs), and staphylococcal enterotoxin D (SED), IAC-2, was prepared by coupling a mixture of mAbs against SEA, SECs, and SED, and rabbit IgG against SEB. These columns were applied for detection of SETs in dairy products, after extraction, immunoaffinity chromatography, and enzyme immunosorbent assay (EIA). Overall recoveries from dairy products spiked with 1 ng SEA/25 g averaged 81.2% (range, 76-85%) on IAC-1. The repeated use of IAC-1 was then determined with good efficiency of 91.5%, in more than 10 runs. On the other hand, a recovery yield of 77% of SETs (SEA, SEB, SEC, and SED) from dairy products spiked with 2.5 ng of each enterotoxin per 25 g, was obtained with IAC-2. IAC-2 was also successfully subjected to the chromatography of naturally contaminated foods implicated in staphylococcal food poisoning outbreaks. This new extraction-concentration-immunoaffinity chromatography method (ECIC) is very useful for improving staphylococcal enterotoxin detection and eliminating matrix effect in EIA of dairy products. PMID- 11601481 TI - Liquid chromatographic analysis of vitamin B6 in soy-based infant formula. AB - A liquid chromatographic (LC) method is described for determination of total vitamin B6 in soy-based infant formula. Total vitamin B6 is quantitated by using ion-pair LC after precolumn transformation of phosphorylated and free vitamers into pyridoxol. The limit of detection is 0.3 ng and the limit of quantitation is 1.0 ng on-column (injection volume = 100 microL). Linear response ranged from 39 to 616 ng/mL (r2 = 0.99986). Analysis of a soy-based infant formula control fortified at 6 different concentration levels gave recoveries that averaged 104%. Assay of SRM 1846 gave results within the certified range (8.6 +/- 0.086 mg/kg versus the certified value of 8.4 +/- 1.0 mg/kg). The method provides a rapid and specific assay for the analysis of total vitamin B6 in fortified soy-based infant formula. PMID- 11601482 TI - Identification of commercial fish species belonging to the orders pleuronectiformes and gadiformes: library of isoelectric focusing patterns. AB - Isoelectric focusing in polyacrylamide gel was used to establish an identification archive of fish species belonging to the orders Pleuronectiformes, or flat fish, and Gadiformes, or gadoid fish. The 2 orders include species of different commercial value and interest that are frequently requested in European fish markets, but are susceptible to substitution either because they are morphologically similar or because they arrive on the markets already filleted or sliced. The sarcoplasmic protein profiles are species-specific and reproducible. The use of densitometry and image analysis coupled with a simple computer program overcomes the subjective evaluation of the patterns, making it possible to identify species correctly. PMID- 11601483 TI - Application of a mixed-mode solid-phase extraction and cleanup procedure for LC/MS determination of thiabendazole and carbendazim in apple juice. AB - Recently, a mixed-mode solid-phase extraction (SPE) procedure was developed for rapid extraction and cleanup for determination of the fungicides thiabendazole and carbendazim in various fruit juices. This paper reports the application of that sample preparation procedure to the liquid chromatographic/mass spectrometric determination of these fungicides in apple juice with detection by positive electrospray ionization mass spectrometry (ESI/MS). Response was linear for sample concentrations from 2 to 500 microg/L (ppb). Recoveries averaged 74% (9% RSD) for carbendazim and 93% (9% RSD) for thiabendazole. After SPE cleanup, no matrix supression was observed for the ESI+ response for either compound studied. The method was applied to the analysis of incurred residues in 4 store bought apple juices; carbendazim levels ranged from 10 to 70 microg/L and thiabendazole levels ranged from less than 2 to 130 microg/L. PMID- 11601484 TI - Review and assessment of in vitro detection methods for algal toxins. AB - Algal toxins produced by marine and freshwater microalgae present a significant analytical challenge because of their complex structures and frequent occurrence as mixtures of structural congeners, which differ in toxic potencies and are present at varying proportions in contaminated samples. Rapid, sensitive in vitro detection methods specific for each class of algal toxins have been developed over the past decade, including immunoassays, enzyme inhibition assays, receptor assays, and cell assays. This review discusses the conceptual approaches to assay development and provides a detailed assessment of the use of in vitro detection methods for marine and freshwater algal toxins. PMID- 11601485 TI - Analysis of cyanobacterial toxins by physicochemical and biochemical methods. AB - Cyanobacteria (blue-green algae) produce a wide range of low molecular weight metabolites that include potent neurotoxins, hepatotoxins, and cytotoxins. The accumulation of such toxins in freshwaters, and in brackish and marine waters presents hazards to human and animal health by a range of exposure routes. A review is presented of developments in the detection and analysis of cyanobacterial toxins, other than bioassays, including application of physicochemical, immunoassays, and enzyme-based methods. Analytical requirements are considered with reference to recently derived guideline levels for the protection of health and to the availability, or otherwise, of purified, quantitative cyanobacterial toxin standards. PMID- 11601486 TI - Trace analysis of microcystins in environmental samples. AB - Microcystins, the cyclic heptapeptide toxins produced by cyanobacteria such as Microcystis sp., show potent hepatotoxicity and tumor-promoting activity through inhibition of protein phosphatases 1 and 2A. A toxic incident resulting in the death of 50 people in Brazil in 1996 was due to microcystins in water used for hemodialysis. Microcystins are now threatening human health and life, but many problems associated with microcystins remain unsolved. This report describes how to analyze trace amounts of microcystins in complicated matrixes such as liver tissue, lake water, and sediments. PMID- 11601487 TI - Integrated enzyme-linked immunosorbent assay screening system for amnesic, neurotoxic, diarrhetic, and paralytic shellfish poisoning toxins found in New Zealand. AB - Enzyme-linked immunosorbent assays (ELISAs) were developed for amnesic, neurotoxic, and diarrhetic shellfish poisoning (ASP, NSP, and DSP) toxins and for yessotoxin. These assays, along with a commercially available paralytic shellfish poisoning (PSP) ELISA, were used to test the feasibility of an ELISA-based screening system. It was concluded that such a system to identify suspect shellfish samples, for subsequent analysis by methods approved by international regulatory authorities, is feasible. The assays had sufficient sensitivity and can be used on simple shellfish extracts. Alcohol extraction gave good recovery of all toxin groups. The ease of ELISAs permits the ready expansion of the system to screen for other toxins, as new ELISAs become available. PMID- 11601488 TI - Immunoassay methods for paralytic shellfish poisoning toxins. AB - The current status of immunochemical techniques for analysis of paralytic shellfish poisoning (PSP) toxins is summarized. Important aspects regarding production of the biological reagents necessary for immunochemical methods, the characteristics of polyclonal and monoclonal antibodies against saxitoxin and neosaxitoxin, and the importance of test sensitivity and specificity are discussed. Applications of immunochemical techniques for PSP toxins include microtiter plate enzyme immunoasays and enzyme-linked immunofiltration assays for toxin detection, and immunoaffinity chromatography (IAC) for sample extract cleanup. A major advantage of enzyme immunoassay (EIA) is simplicity and rapidity of the test procedure, and higher sensitivity than other methods. However, quantitative agreement between EIA and mouse bioassay is dependent on antibody specificity and the toxin profile in the shellfish; thus, both over- and underestimation of total toxicity may occur. For screening purposes, however, EIAs offer major advantages over the mouse bioassay, which is criticized in Europe because of animal welfare. A major application of antibodies against PSP toxins is their use for extract cleanup by IAC, which gives highly purified extracts, thereby enhancing determination of PSP toxins by conventional physicochemical methods such as liquid chromatography. IAC can also be used to isolate PSP toxins for preparation of analytical standard solutions. PMID- 11601489 TI - Determination and confirmation of the amnesic shellfish poisoning toxin, domoic acid, in shellfish from Scotland by liquid chromatography and mass spectrometry. AB - During 1998 and early 1999, shellfish samples from sites in Scotland were found to contain the amnesic shellfish poisoning toxin, domoic acid (DA). Two different techniques, liquid chromatography (LC) with UV diode-array detection and LC with mass spectrometric (MS) detection, were used to detect and confirm DA in shellfish extracts. The LC/UV method was validated for routine monitoring by recovery experiments on spiked mussel and scallop tissues with a certified mussel tissue used as reference material. Crude extracts of selected samples as well as extracts cleaned with strong anion exchange (SAX) were analyzed by both LC/UV and LC/MS. Good correlation (linear regression r2 = 0.996, slope = 0.93) between the 2 methods was found for cleaned extracts. Analyses of crude extracts by LC/UV produced false-positive results in 2 crab samples, whereas LC/MS analyses gave accurate results. It was concluded that LC/UV is a valid approach for routine monitoring of DA in shellfish when cleanup is performed with a SAX cartridge to prevent false positives. A variety of shellfish species were surveyed for DA content, including Pecten maximus (king scallops), Chlamys opercularis (queen scallop), Mytilus edulis (blue mussels), Cancer pugaris (crab), and Ensis ensis (razor fish). The highest concentration of DA was 105 microg/g in Pecten maximus. PMID- 11601490 TI - Development of reference materials for paralytic shellfish poisoning toxins. AB - A project was undertaken to develop mussel reference materials that were certified for their mass fractions of saxitoxin and decarbamoyl-saxitoxin. Fifteen laboratories from various European countries participated. Three of these had major responsibility for substantial parts of the work and overall coordination of the project. The project involved 4 main activities: (1) procurement and characterization of calibrants; (2) improvement of analytical methodology; (3) preparation of reference materials, including homogeneity and stability studies; (4) 2 interlaboratory studies and a certification exercise. The joint activities resulted in 3 homogeneous and stable reference materials: 2 lyophilized mussel materials with and without naturally incurred paralytic shellfish poisoning (PSP) toxins, and a saxitoxin enrichment solution. The reference materials were certified with respect to their saxitoxin and decarbamoyl-saxitoxin content. The lyophilized mussel material with PSP toxins (CRM 542) contained <0.07 mg saxitoxin x 2HCl/kg and 1.59 +/- 0.20 mg decarbamoyl saxitoxin x 2HCl/kg. The lyophilized mussel material without PSP toxins (CRM 543) contained <0.07 mg saxitoxin x 2HCl/kg and <0.04 mg decarbamoyl-saxitoxin x 2HCl/kg. The certified value of the saxitoxin mass fraction in the saxitoxin enrichment solution (CRM 663) was 9.8 +/- 1.2 microg/g. PMID- 11601491 TI - How healthy are soy burgers? New AOAC method determines isoflavone content in today's soy foods. PMID- 11601492 TI - Endogenous retroviruses and multiple sclerosis. PMID- 11601493 TI - Matrix metalloproteinases in multiple sclerosis: is it time for a treatment trial? PMID- 11601494 TI - Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. AB - Human endogenous retroviruses (HERVs) have been implicated as causative agents in diseases characterized by inflammation and macrophage activation, such as multiple sclerosis. Because monocyte activation and differentiation influence retroviral transcription and replication, we investigated the contribution of these processes to the expression of four HERV families (HERV-W, HERV-K, HERV-E, and HERV-H) in human monocytes, and autopsied brain tissue from patients with brain diseases associated with increased macrophage activity. Reverse transcriptase-polymerase chain reaction analysis of primary macrophages and U937 monocytoid cells stimulated with phorbol-12-myristate-13-acetate or lipopolysaccharide revealed three- to ninefold increases in HERV-W, HERV-K, and HERV-H RNA levels. In addition, elevated reverse transcriptase activity and HERV RNA were detectable in supernatants from PMA-stimulated U937 cultures, properties that could be attenuated with the inhibitor of monocyte differentiation threonine lysine-proline. In contrast, stimulation of monocytes decreased or had no effect on HERV-E expression. Compared with controls, HERV-W and HERV-K expression was increased in brain tissue from patients with multiple sclerosis or human immunodeficiency virus infection or AIDS, with concomitant elevated tumor necrosis factor-alpha levels. Similarly, elevated HERV-W levels were detected in patients with Alzheimer's dementia only when tumor necrosis factor-alpha expression was also evident (2 of 6 cases). The detection of several HERVs in inflammatory brain diseases and the capacity to augment HERV expression in monocytes with compounds that influence cellular activity suggest that increased expression of these viruses is a consequence of increased immune activity rather than causative of distinct diseases. PMID- 11601495 TI - Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary progressive multiple sclerosis patients. AB - Matrix metalloproteinases (MMPs) have recently been implicated in the pathogenesis of multiple sclerosis. Their suggested role includes the disruption of the blood-brain barrier, immune cell transmigration into the central nervous system, and myelin degradation. The present study characterized the mRNA level of a wide spectrum of MMPs and tissue inhibitors of metalloproteinases (TIMPs) expressed by peripheral blood leukocytes from relapsing-remitting (n = 16) and secondary-progressive (n = 12) multiple sclerosis patients. The expression of the same MMPs and TIMPs was evaluated also in a prospective 12-month follow-up of 6 patients randomly chosen from each of the 2 groups during interferon beta-1a treatment. Reverse transcription-polymerase chain reaction assessment demonstrated elevated levels of MT1-MMP and MMP-7 mRNA levels in both groups of patients, and no significant differences in MMP-9 levels, compared with healthy controls. Divergent expression of MMP-2 between relapsing-remitting and secondary progressive patients compared with controls was observed. Interferon-beta treatment was associated with significant suppression of MMP-9 and MMP-7 mRNA in relapsing-remitting patients, though no significant changes were observed in the secondary-progressive group. These results contribute to the understanding of the IFN-beta-mediated immunomodulatory and therapeutic effects in multiple sclerosis patients and also support evidence for distinct immune mechanism(s) underlying relapsing-remitting versus secondary-progressive multiple sclerosis. The study also suggests that MMPs may be considered as potential biomarkers for response to treatment as well as targets for immunotherapy in multiple sclerosis. PMID- 11601496 TI - Hereditary motor and sensory neuropathy-russe: new autosomal recessive neuropathy in Balkan Gypsies. AB - A novel peripheral neuropathy of autosomal recessive inheritance has been identified in Balkan Gypsies and termed hereditary motor and sensory neuropathy Russe (HMSN-R). We investigated 21 affected individuals from 10 families. Distal lower limb weakness began between the ages of 8 and 16 years, upper limb involvement beginning between 10 and 43 years, with an average of 22 years. This progressive disorder led to severe weakness of the lower limbs, generalized in the oldest subject (aged 57 years), and marked distal upper limb weakness. Prominent distal sensory loss involved all modalities, resulting in neuropathic joint degeneration in two instances. All patients showed foot deformity, and most showed hand deformity. Motor nerve conduction velocity was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent. There was loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve. HMSN-R is a new form of autosomal recessive inherited HMSN caused by a single founder mutation in a 1 Mb interval on chromosome 10q. PMID- 11601497 TI - Are certain diuretics also anticonvulsants? AB - A history of diuretic use has been shown to be protective for first unprovoked seizure in adult patients. Recent animal studies suggest that certain diuretics have anticonvulsant activity. We evaluated the potential for the anticonvulsant activity of current diuretic use in a population-based, case-control study in older adults. We also tested chlorthiazide and furosemide for seizure protection in animal models of epilepsy. Concurrent medical prescription of any diuretic was protective for the development of epilepsy [odds ratio (OR) = 0.62, 95% confidence interval (CI) = 0.39-0.99]. A protective effect for current thiazide use was observed (OR = 0.53, CI = 0.31-0.90), and a protective effect for furosemide was suggested (OR = 0.44, CI = 0.1-1.9). In mice, both chlorthiazide and furosemide suppressed the occurrence of maximal electroshock-induced seizures in a dose-dependent manner. Chlorthiazide's toxic dose for 50% of animals tested (TD50) could not be achieved even with dosing as high as 1,500 mg/kg for furosemide; TD50 was 549 mg/kg. Results were similar in rats. Furosemide and chlorthiazide are protective for unprovoked seizures in an epidemiological study and in animal models. Given the potential therapeutic value for seizure control, low toxicity, and low cost, therapeutic efficacy should be explored in clinical studies. PMID- 11601498 TI - Individual blood-brain barrier phenylalanine transport determines clinical outcome in phenylketonuria. AB - Different clinical outcomes in spite of comparable dietary controls are well known in patients with phenylketonuria. Currently, reasons for this phenomenon are unknown. Kinetic investigations in 15 patients with classic phenylketonuria were performed using in vivo nuclear magnetic resonance spectroscopy before and after an oral phenylalanine load (100 mg/kg body weight). Patients' brain phenylalanine concentrations were quite different in spite of similar blood phenylalanine levels. Interindividual variations of the apparent transport Michaelis constant, K(t,app), covered a range from 0.10 to 1.03 mmol/L. The ratio of the maximal transport velocity, Tmax, over the intracerebral consumption rate, Vmet, varied between 2.61 and 14.0. Both parameters as well as the preload brain phenylalanine levels correlated significantly with the degree of cerebral white matter abnormalities on magnetic resonance images. Correlations of K(t,app), Tmax/Vmet, and the preload brain phenylalanine levels with patients' intelligence scores approached significance. In conclusion, blood-brain barrier phenylalanine transport characteristics and the resultant brain phenylalanine levels seem to be causative factors for the individual clinical outcome in phenylketonuria. This observation may lead to individual dietary recommendations in the future. PMID- 11601499 TI - Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain. AB - The human apolipoprotein E4 (ApoE4) isoform is associated with genetic risk for Alzheimer's disease. To assess the effects of different ApoE isoforms on amyloid plaque formation, human ApoE3 and ApoE4 were expressed in the brains of transgenic mice under the control of the human transferrin promoter. Mice were crossed with transgenic mice expressing human amyloid precursor protein containing the Swedish mutation (APPsw), which facilitates amyloid beta peptide (A beta) production. The following progeny were selected for characterization: APPsw+/- x ApoE3+/- and APPsw+/-, APPsw+/- x ApoE4+/- and APPsw+/- littermates. All mice analyzed were wild type for the endogenous mouse APP and ApoE genes. Mice expressing ApoE4 in combination with APPsw have accelerated A beta deposition in the brain as assessed by enzyme immunoassay for A beta40 and A beta42 extractable in 70% formic acid, by assessment of amyloid plaque formation using thioflavin-S staining, and by immunohistochemical staining with antibodies specific for A beta40 or A beta42 and the 4G8 monoclonal or 162 polyclonal antibody. No difference in the rate of A beta deposition in the brain was seen in mice expressing ApoE3 in combination with APPsw. Thus, our data are consistent with the observation in Alzheimer's disease that ApoE4 is associated with increased accumulation of A beta in the brain relative to ApoE3. PMID- 11601500 TI - Relationship of the extended tau haplotype to tau biochemistry and neuropathology in progressive supranuclear palsy. AB - Two extended haplotypes of the tau gene (H1 and H2) have been described. The frequency of H1 haplotype is increased in progressive supranuclear palsy (PSP). PSP is associated with filamentous tau lesions in neurons and glia, which are reportedly composed exclusively of tau isoforms with four repeats in the microtubule-binding domain (4R tau). To determine the influence of the tau haplotype on tau isoform composition and neuropathology, we studied 25 PSP cases and 6 Alzheimer's disease patients matched for age, sex, and postmortem delay. In the basal ganglia, tau and amyloid burdens were determined to see if there was an effect of concurrent Alzheimer-type pathology, and the ratio of 4R to 3R tau was measured in detergent-insoluble tau fractions. Insoluble tau from PSP was not composed exclusively of 4R tau. All brains had a mixture of 4R and 3R tau, but the ratio was different in Alzheimer's disease and PSP. In Alzheimer's disease there was less 4R than 3R tau, whereas the ratio was reversed in PSP. In PSP cases with concurrent Alzheimer-type pathology, the ratio of 4R to 3R was intermediate between Alzheimer's disease and PSP. The H1 haplotype had no effect on the 4R to 3R ratio or on tau and amyloid burdens. In summary, the H1 haplotype does not have a major influence on the pathological or biochemical phenotype of PSP. PMID- 11601501 TI - Pick's disease associated with the novel Tau gene mutation K369I. AB - Exonic and intronic mutations in Tau cause neurodegenerative syndromes characterized by frontotemporal dementia and filamentous tau protein deposits. We describe a K369I missense mutation in exon 12 of Tau in a patient with a pathology typical of sporadic Pick's disease. The proband presented with severe personality changes, followed by loss of cognitive function. Detailed postmortem examination of the brain showed atrophy, which was most pronounced in the temporal lobes; and numerous tau-immunoreactive Pick bodies and Pick cells in the neocortex and the hippocampal formation, as well as in subcortical brain regions. Their appearance and staining characteristics were indistinguishable from those of sporadic Pick's disease. However, immunoblot analysis of sarkosyl-insoluble tau showed three major bands of 60, 64, and 68 kDa, consistent with the presence of 3- and 4-repeat tau isoforms, as in Alzheimer's disease. Isolated tau filaments were irregularly twisted ribbons, with a small number of Alzheimer-type paired helical filaments. In the presence of heparin, tau proteins with the K369I mutation formed short, slender filaments. Biochemically, recombinant tau proteins with the K369I mutation showed reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation by providing a pool of aberrant tau for filament assembly. Taken together, results indicate that the K369I mutation in Tau can cause a dementing disease with a neuropathology like that of Pick's disease. PMID- 11601502 TI - Metabolic changes following subthalamotomy for advanced Parkinson's disease. AB - We studied 6 advanced-stage Parkinson's disease patients with [18F] fluorodeoxyglucose/positron emission tomography before and 3 months after unilateral ablation of the subthalamic nucleus performed with microelectrode mapping. Operative changes in glucose metabolism were assessed by comparing baseline and postoperative scans. We also quantified operative changes in the activity of an abnormal Parkinson's disease-related metabolic network that we had identified in previous [18F] fluorodeoxyglucose/positron emission tomography studies. Following unilateral subthalamic nucleus ablation, a highly significant reduction in glucose utilization was present in the midbrain ipsilateral to the lesion site, most pronounced in the vicinity of the substantia nigra pars reticularis. Significant metabolic reductions were also present in the ipsilateral internal globus pallidus, ventral thalamus, and pons. Operative changes in Parkinson's disease network activity differed significantly for the lesioned and unlesioned hemispheres. In the lesioned hemisphere, network activity declined significantly following surgery, but was unaltered in the contralateral, unlesioned hemisphere. These results suggest that subthalamotomy reduces basal ganglia output through internal globus pallidus/substantia nigra pars reticularis and also influences downstream neural activity in the pons and ventral thalamus. This procedure also reduces the activity of abnormal Parkinson's disease-related metabolic brain networks, suggesting a widespread modulation of motor circuitry. PMID- 11601503 TI - Human brain mapping in dystonia reveals both endophenotypic traits and adaptive reorganization. AB - Dystonia has a wide clinical spectrum from early-onset generalized to late-onset sporadic, task-specific forms. The genetic origin of the former has been clearly established. A critical role of repetitive skilled motor tasks has been put forward for the latter, while underlying vulnerability traits are still being searched for. Using magnetoencephalography, we looked for structural abnormalities reflecting a preexisting dysfunction. We studied finger representations of both hands in the primary sensory cortex, as compared in 23 patients with unilateral task-specific dystonia and 20 control subjects. A dramatic disorganization of the nondystonic hand representation was found in all patients, and its amount paralleled the severity of the dystonic limb motor impairment. Abnormalities were also observed in the cortex coding the dystonic limb representation, but they were important only in the most severely affected patients. The abnormal cortical finger representations from the nondystonic limb appear to be endophenotypic traits of dystonia. That finger representations from the dystonic limb were almost normal for the less severely affected patients may be due to intrinsic beneficial remapping in reaction against the primary disorder. PMID- 11601504 TI - Neuronal activity in the globus pallidus in chorea caused by striatal lacunar infarction. AB - Pallidotomy was performed in a patient with hemichorea caused by lacunar infarction in the striatum. Chorea in the lower limb was reduced after a neurosurgical lesion in the medial portion of the sensorimotor territory of the internal segment of the globus pallidus, and chorea in the upper limb disappeared after an additional lesion in the lateral portion of that same area. Intraoperative neuronal recording revealed that mean firing rates were low, and that firing was irregular in the globus pallidus compared with off-state parkinsonian patients. These results suggest that chorea with striatal infarction is driven by phasic neuronal activity with a low firing rate in the globus pallidus and that the neural pathway of chorea has a functional somatotopical organization in the globus pallidus. PMID- 11601505 TI - Myelinopathia centralis diffusa (vanishing white matter disease): evidence of apoptotic oligodendrocyte degeneration in early lesion development. AB - We describe histopathological changes in a 2-year-old boy who died from myelinopathia centralis diffusa. Despite extensive white matter destruction, surprisingly high numbers of oligodendrocytes expressing proteolipid protein mRNA were detected. In an active demyelinating lesion in the brainstem, oligodendrocytes showed typical signs of apoptosis. We suggest that death of mature oligodendrocytes is the critical event in the disease. PMID- 11601506 TI - A novel deafness/dystonia peptide gene mutation that causes dystonia in female carriers of Mohr-Tranebjaerg syndrome. AB - Sex-linked male deafness and dystonia (Mohr-Tranebjaerg syndrome) arises from mutation of the deafness/dystonia peptide (DDP) gene. We describe a novel guanine deletion at nucleotide 108 of the DDP gene in a family with Mohr-Tranebjaerg syndrome, which terminates this 97-amino acid protein at codon 25. Unlike previously reported kindreds, carrier females in this family also manifest dystonias, including torticollis and writer's cramp. A family history of male deafness should alert clinicians to the possibility of DDP mutation in women with focal dystonias. PMID- 11601507 TI - Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene. AB - Mitochondrial cytochrome b mutations have been reported to have a homogenous phenotype of pure exercise intolerance. We describe a novel mutation in the cytochrome b gene of mitochondrial DNA (A15579G) associated with a selective decrease of muscle complex III activity in a patient who, besides severe exercise intolerance, also has multisystem manifestations (deafness, mental retardation, retinitis pigmentosa, cataract, growth retardation, epilepsy). The point mutation is heteroplasmic in muscle (88%) and leukocytes (15%), and changes a highly conserved tyrosine to cysteine at amino acid position 278. PMID- 11601508 TI - Dextran reduces embolic signals after carotid endarterectomy. AB - One hundred fifty patients undergoing carotid endarterectomy were randomly assigned to receive intravenous 10% dextran 40 or placebo. Transcranial Doppler monitoring of the ipsilateral middle cerebral artery 0 to 1 hour postoperatively detected embolic signals in 57% of placebo and 42% of dextran patients, with overall embolic signal counts 46% less for dextran (p = 0.052). Two to 3 hours postoperatively, embolic signals were present in 45% of placebo and 27% of dextran patients, with embolic signal counts 64% less for dextran (p = 0.040). We conclude that dextran reduces embolic signals within 3 hours of CEA. PMID- 11601509 TI - Mutation of the doublecortin gene in male patients with double cortex syndrome: somatic mosaicism detected by hair root analysis. AB - The molecular basis of double cortex syndrome was investigated in 2 male patients. Magnetic resonance imaging of the patients' heads showed diffuse subcortical band heterotopia, as is seen in female patients. We found a heterozygous mutation for Asp50Lys or Arg39Stop in both patients. Microsatellite polymorphism analysis revealed that both patients had inherited a single X chromosome from their mothers. Restriction enzyme analysis using DNA extracted from the hair roots of each patient showed four different patterns in the combination of cells carrying wild and mutant alleles, which strongly suggest somatic mosaicism. We conclude that somatic mosaic mutations in the doublecortin gene in male patients can cause subcortical band heterotopia, and that molecular analysis using hair roots is a useful method for detecting somatic mosaicism. PMID- 11601510 TI - Conjugal multiple sclerosis. PMID- 11601511 TI - Compound heterozygosity and variable penetrance in SOD1 amyotrophic lateral sclerosis pedigrees. PMID- 11601513 TI - FMD: chief scientist sets out his views on vaccination. PMID- 11601512 TI - Electroencephalographic and clinical correlation of hyponatremia induced during transurethral resection of the prostate. PMID- 11601514 TI - Factors associated with the introduction of classical swine fever virus into pig herds in the central area of the 1997/98 epidemic in The Netherlands. AB - A matched case-control study of 135 infected and 99 uninfected pig herds from the central area of the 1997 to 1998 epidemic of classical swine fever (CSF) in The Netherlands was undertaken to identify factors associated with the introduction of the virus. The herds were matched on the basis of herd type and the shortest geographical distance between pairs of herds. Data on management, hygienic measures, experiences during the depopulation of an infected nearest neighbour, and the frequency of contact with professionals and other agencies were collected by means of a questionnaire taken by personal interview. There were no significant differences between the infected and uninfected herds in the median total number of contacts per year with professionals and other agencies either with or without contact with the pigs. On the basis of a multivariable analysis, five variables were found to be significantly associated with an increased risk of infection: (1) the presence of commercial poultry on the premises; (2) visitors entering the pig units without wearing an overcoat or overalls and boots supplied by the farm; (3) the driver of the lorry transporting pigs for the Pig Welfare Disposal Scheme (PWDS) using his own boots instead of boots supplied by the farm; (4) herds of moderate size (500 to 1,000 animals) and very large herds (>7,000 animals) were at greater risk than small herds (<500 animals); and (5) an aerosol, produced during high-pressure cleaning of the electrocution equipment used to kill the pigs on a neighbouring infected herd less than 250 m away was carried by the wind on to the premises. Two variables were significantly associated with a decreased risk of CSFV-infection: (1) more than 30 years of experience in pig farming; and (2) additional cleaning of the lorries used to transport pigs for the PWDS before they were allowed on to the premises. In the opinion of the cooperating farmers, airborne transmission of the virus and its transmission during the depopulation of an infected neighbour were among the most important routes of infection. PMID- 11601515 TI - Fertility parameters of dairy cows with cystic ovarian disease after treatment with gonadotrophin-releasing hormone. AB - Fertility data were collected every four weeks for 10 years from 40 herds of Holstein-Friesian dairy cattle. The data collected during 925 lactations from cows with cystic ovarian disease which were treated with 500 microg gonadorelin were compared with data from a control group of 13,869 normal lactations. The intervals between parturition and first insemination and between parturition and conception were significantly shorter (P<0.001) in the normal cows, but the interval between first insemination and conception was not. The overall conception rate tended to be higher (P<0.10) in the normal cows, but the conception rate after the first insemination was significantly higher (P<0.001) and the number of services per conception was significantly lower (P=0.008) in the normal cows. PMID- 11601516 TI - Disseminated eosinophilic disease resembling idiopathic hypereosinophilic syndrome in a dog. AB - True idiopathic hypereosinophilic syndrome has been described in human beings and cats, but not in dogs. The syndrome is characterised by prolonged unexplained peripheral mature eosinophilia, the infiltration of many organs by eosinophils, organ dysfunction and a fatal outcome. This paper describes an idiopathic disseminated eosinophilic disease in a dog involving various organs, manly the heart and the lungs, accompanied by a leukemoid eosinophilic response, and a fatal outcome. The histopathological findings included the infiltration of the myocardium, lung parenchyma, liver, spleen, lymph nodes and skeletal muscles with eosiniphils. PMID- 11601517 TI - Experimental Ehrlichia phagocytophila infection in red deer (Cervus elaphus). PMID- 11601518 TI - B cell lymphoma in the brain of a sheep. PMID- 11601519 TI - Parapoxvirus infection in Norwegian semi-domesticated reindeer (Rangifer tarandus tarandus). PMID- 11601520 TI - Pesticide poisoning in a free-ranging lappet-faced vulture (Torgos tracheliotus). PMID- 11601521 TI - Caseous lymphadenitis in sheep in the United Kingdom. PMID- 11601522 TI - Mouth ulcers in horses. PMID- 11601523 TI - Training in international animal health. PMID- 11601524 TI - Welfare movement licensing. PMID- 11601525 TI - Welfare movement licensing. PMID- 11601526 TI - Veterinary nurses and vaccination certificates. PMID- 11601527 TI - Ocean storage of nuclear wastes? Experiences from the Russian Arctic. AB - An international demonstration (RD&D) project for ocean storage of radioactive wastes should be proposed, to study the feasibility of the concept of ocean storage of nuclear waste. This international project should utilize the scientific, engineering and technical capabilities of selected universities, oceanographic institutions, NGOs and industries. This project would need to be an independent (non-governmental) study, utilizing the capabilities of selected universities, oceanographic institutions, environmental NGOs (Non-Governmental Organizations) and industries. Scientists and engineers first need to conduct an engineering, environmental, and economic feasibility study of the concept. The goal of the project would be to determine if ocean-based storage reduced the risks to the environment and public health to a greater degree than land-based storage. This would require comparing the risks and factors involved and making the data and information available to anyone, anywhere, anytime on the internet. The mere presence of an investigation of the ocean storage option could facilitate scientific and engineering competition between the two options, could subsequently reduce environmental and public risks and provide better protection and cost benefits in the system utilized. One of the primary concerns of the scientific community would be related to the sensitivity and precision of the monitoring of individaul containers on the ocean bottom. An advantage of the land based option is that if there is a release, its presence could be detected at very low levels and be contained in the storage facility. On the ocean bottom, a release from a container might not be easily detected due to dispersion. Therefore the containment system would have to be a system within a system with monitoring between the two providing greater protection. Ocean storage may have greater technical and political hurdles than land-based options, but it may provide greater protection over time, because it negates the threat of terrorism, it therefore merit further study. In the future if the use of nuclear energy and nuclear wastes increases, the global society could benefit from this international project, because it could reduce environmental and public health risks and promote energy independence. PMID- 11601528 TI - Sorption of radioactive contaminants by sediment from the Kara Sea. AB - The purpose of this study is to quantify some of the parameters needed to perform near-field modelling of sites in the Kara Sea that were impacted by the disposal of radioactive waste. The parameters of interest are: the distribution coefficients (Kd) for several important radionuclides, the mineralogy of the sediment, and the relationship of Kd to liquid-to-solid ratio. Sediment from the Kara Sea (location: 73 degrees 00'N, 58 degrees 00'E) was sampled from a depth of 287 m on August 23/24, 1992. Analysis of the material included mineralogy, grain size and total organic carbon (TOC). Uptake kinetics were determined for 85Sr, 137Cs, 241Am, 99Tc, 1251, 232U and 210Pb and distribution coefficients (Kd) were determined for these radionuclides using batch type experiments. Sorption isotherms, developed for 137Cs, 85Sr and 99Tc, were linear in each case. Increasing the liquid-to-solid ratio strongly increased uptake of 137Cs and moderately increased uptake of 99Tc. Analysis for anthropogenic radionuclides indicated the presence only of 239/240Pu in the sediment with the highest activity (at the top section of the core) being 0.420 Bq kg(-1). Other anthropogenic radionuclides were below detection limits. PMID- 11601529 TI - Modeling the potential radionuclide transport by the Ob and Yenisey Rivers to the Kara Sea. AB - A major portion of the former Soviet Union (FSU) nuclear program is located in the West Siberian Basin. Among the many nuclear facilities are three production reactors and the spent nuclear fuel reprocessing sites, Mayak, Tomsk-7, and Krasnoyarsk-26, which together are probably responsible for the majority of the radioactive contamination found in the Ob and Yenisey River systems that feed into the Arctic Ocean through the Kara Sea. This manuscript describes ongoing research to estimate radionuclide fluxes to the Kara Sea from these river systems. Our approach is to apply a hierarchy of simple models that use existing and forthcoming data to quantify the transport and fate of radionuclide contaminants via various environmental pathways. We present an initial quantification of the contaminant inventory, hydrology, meteorology, and sedimentology of the Ob River system and preliminary conclusions from portions of the Ob River model. PMID- 11601530 TI - Organochlorine compounds and aliphatic hydrocarbons in Pacific walrus blubber. AB - Blubber samples were collected from 8 male and 19 female Pacific walrus (Odobenus rosmarus divergens) taken during a 1991 joint USA/USSR cruise traveling widely through the Bering Sea. Dieldrin was found at a level similar to that reported 10 years earlier; oxychlordane was found at a slightly higher concentration than reported previously (Taylor et aL, 1989). Heptachlor epoxide was detected for the first time and found at a low concentration. An initial testing for alpha-, beta- and gamma-HCH detected concentrations similar to those in other Bering Sea pinnipeds. Mean summation of PCB was 0.45 microg g(-1) wet weight in males and 0.16 microg g(-1) in females; only one sample was > 1 microg g(-1). Traces of aliphatic hydrocarbons were detected in all sampled animals, only pristane (x = 0.48 microg g(-1)) was found in concentrations > 1 microg g(-1). Small sample sizes, a lack of samples from immature animals, and uniformly low concentrations of contaminants precluded meaningful analysis of age-related effects and regional differences. PMID- 11601531 TI - Spatial differences in persistent organochlorine pollutant concentrations between the Bering and Chukchi Seas (1993). AB - During August-September 1993, a joint Russian-United States expedition to the Bering and Chukchi Seas took place. Surface water samples were collected from 21 sites and separated into dissolved (duplicates) and suspended solids; 19 sediment and 6 air samples were also collected. These samples were analysed for 19 organochlorine pesticides, 11 chlorobenzenes and 113 PCB congeners. The report provides data on selected compounds which occured in > or = 75% of the water samples. Highest water concentrations were observed for HCH in open waters north and south of the Bering Strait, both regions being similar (alpha-HCH; 2.2 ng/L and lindane: 0.35 ng/L). Air levels observed were also constant (alpha-HCH; 0.041 ng/m3, lindane: 0.0093 ng/m3). Suspended solids and air particulares contributed little to the concentrations in their respective media, an observation common to all analytes except for the PCBs and the DDT residues. The sum of PCB concentrations in water were higher in the Bering Sea area compared to the Chukchi Sea (1.0 vrs 0.67 ng/L) and lower for air (0.46 vrs 0.23 ng/m3). Sum of DDT in water was higher in the Bering Sea than in the Chukchi Sea (0.23 vrs 0.15 ng/L) while in sediments and air, the Bering Sea concentrations were lower (0.95 vrs 1.6 ng/g and 36 vrs 56 pg/m3, respectively). Other organochlorine compounds for which data are presented include: pp'-DDE, pp'-DDT, dieldrin, HCB, 3 chlorobenzenes and 3 PCB congeners. Fluxes of all these chemicals through the Berin Strait are estimated; they ranged from 57 t/a (alpha-HCH) through 26 t/a (for sum of PCBs) to 0.2 t/a (pp'-DDE, dieldrin and 1,2,3-trichlorobenzene). Fugacity ratios for the HCHs and PCBs indicate the alpha-HCH is degassing in both the Bering and Chukchi Seas and that the gamma-isomer is degassing in the Bering Sea and is close to equilibrium (weakly absorbing) in the Chuchi Sea; the sum of PCBs are strongly absorbing in both areas. PMID- 11601532 TI - Environment and biology of the Kara Sea: a general view for contamination studies. AB - The recent revelation that over the past 30 years there has been a history of dumping waste including high-level radioactive wastes in the shallow Kara Sea has caused wide-spread concern. The potential impact of these contaminants and other non-nuclear pollutants in the Arctic ecosystem and on human health need to be assessed and, thus, a better insight gained on radioecological processes in cold waters. The present paper proposes a general view on the biology and the environment of the Kara Sea, as a basic tool for the experimental and modelling assessments of the impact of these contaminants. PMID- 11601533 TI - Northern ocean inventories of organochlorine and heavy metal contamination. PMID- 11601534 TI - Two regimes of the Arctic's circulation from ocean models with ice and contaminants. AB - A two-dimensional barotropic, coupled, ocean-ice model with a space resolution of 55.5 km and driven by atmospheric forces, river run-off, and sea-level slope between the Pacific and the Arctic Oceans, has been used to simulate the vertically averaged currents and ice drift in the Arctic Ocean. Results from 43 years of numerical simulations of water and ice motions demonstrate that two wind driven circulation regimes are possible in the Arctic, a cyclonic and an anti cyclonic circulation. These two regimes appear to alternate at 5-7 year intervals with the 10-15 year period. It is important to pollution studies to understand which circulation regime prevails at any time. It is anticipated that 1995 is a year with a cyclonic regime, and during this cyclonic phase and possibly during past cyclonic regimes as well, pollutants may reach the Alaskan shelf. The regime shifts demonstrated in this paper are fundamentally important to understanding the Arctic's general circulation and particularly important for estimating pollution transport. PMID- 11601535 TI - Organochlorine pesticide and trace metal monitoring of Russian rivers flowing to the Arctic Ocean: 1990-1996. AB - Information is presented on the concentrations of organochlorine pesticides (HCHs and DDT residues) and trace metals (Fe, Cu, Zn and Ni) in waters of 15 large Russian rivers flowing to the Arctic Ocean during 1990-1996. Estimates of the corresponding annual fluxes are made. Other contaminants (Hg, Pb, Cr, Mn, beta HCH and dihydroheptachlor) were examined briefly. Concentration data are presented as averaged annual means for each of the seven years with the ranges, standard deviations and numbers of samples. Also given are data on locations, the methods of analysis and limited quality assurance data. Data on discharges to the Northern Seas for the more frequently monitored contaminants are given for rivers accounting for >70% of the total northerly flows. Scaled-up fluxes to account for unmonitored rivers as well are given for each sea; totals over the period were: Fe, 1452; Cu, 15; Zn, 59 (x 10(3) t yr(-1)); alpha-HCH, 25; gamma-HCH, 44 (t yr( 1)). Ni was monitored at too few rivers to estimate its total Russian flux. The fluxes for the HCHs considerably exceed previous estimates and indicate that the Arctic Ocean is not in balance as much as was previously believed. PMID- 11601536 TI - Radioactive waste disposal in seas adjacent to the territory of the Russian Federation. AB - The former USSR illegally dumped into the ocean liquid and solid radioactive wastes (RW) originating from nuclear-powered vessels and ships. The Russian President created a special Commission to analyse both the scale and consequences of this activity. According to documentary data and expert estimates at the Commission's disposal, the maximum activity of RW that entered the seas adjacent to Russian territory could have been as much as 2,500 kCi at the time of disposal. The greatest radio-ecological hazard comes from reactors from nuclear submarines and core plates of the nuclear icebreaker 'Lenin', which had spent nuclear fuel in place and which were dumped in shallow water in the Kara Sea near Novaya Zemlya. Editor's note: This article extracts material from a Commission which published a report produced in Russia in 1993. Numerous sources in many Ministries and other government agencies, noted in the text, formed the basis for the final draft. The authors of the draft report were A. Yablokov, V. Karasev, V. Rumyantsev, M. Kokeev, O. Petrov, V. Lystsov, A. Yemelyanenkov and P. Rubtsov. After approving the draft report, the Commission submitted the report to the President of the Russian Federation in February 1993. By Presidential decision, this report (after several technical corrections) was open to the public: it is known variously as 'the Yablokov Commission report, or more simply the 'Yablokov Report', the 'White Book' or 'Yablokov White Paper'. During April-May 1993, 500 copies were distributed among governmental agencies inside Russia, and abroad through a net of Russian Embassies. This article was later sent to Dr Mike Champ as part of the ongoing collections of papers on the Arctic published in this journal (edited by Champ et al.: 1997 'Contaminants in the Arctic', Marine Pollution Bulletin 35, pp. 203-385 and in Marine Pollution Bulletin 2000, vol. 40, pp. 801-868, and continued with the present collection). PMID- 11601537 TI - Potential for photoenhanced toxicity of spilled oil in Prince William Sound and Gulf of Alaska waters. AB - Photoenhanced toxicity is the increase in the toxicity of a chemical in the presence of ultraviolet light (UV) compared to a standard laboratory test conducted with fluorescent lighting (minimal UV). Oil products, weathered oil, and specific polycyclic aromatic compounds present in oil are 2 to greater than 1000 times more toxic in the presence of UV. The photoenhanced toxicity of oil to fish and aquatic invertebrates appears to occur through a process of photosensitization, rather than photomodification of the aqueous phase oil. In photosensitization, the bioaccumulated chemical transfers light energy to other molecules causing toxicity through tissue damage rather than a narcosis mechanism. The available evidence indicates that phototoxic components of oil are specific 3-5 ring polycyclic aromatic hydrocarbons (PAHs) and heterocycles. Determinants of photoenhanced toxicity include the extent of oil bioaccumulation in aquatic organisms and the spectra and intensity of UV exposure. No studies have specifically investigated the photoenhanced toxicity of spilled oil in Alaska waters. Although there are substantial uncertainties, the results of this evaluation indicate there is potential for photoenhanced toxicity of spilled oil in Prince William Sound and the Gulf of Alaska. The potential hazard of photoenhanced toxicity may be greatest for embryo and larval stages of aquatic organisms that are relatively translucent to UV and inhabit the photic zone of the water column and intertidal areas. Photoenhanced toxicity should be considered in oil spill response because the spatial and temporal extent of injury to aquatic organisms may be underestimated if based on standard laboratory bioassays and existing toxicity databases. Additionally, the choice of counter measures and oil removal operations may influence the degree of photoenhanced toxicity. PMID- 11601538 TI - Persistent organic pollutants (POPs) in a small, herbivorous, arctic marine zooplankton (Calanus hyperboreus): trends from April to July and the influence of lipids and trophic transfer. AB - Samples of Calanus hyperboreus, a herbivorous copepod, were collected (n = 20) between April and July 1998, and water samples (n = 6) were collected in May 1998, in the Northwater Polynya (NOW) to examine persistent organic pollutants (POPs) in a high Arctic marine zooplankton. Lipid content (dry weight) doubled, water content (r2 = 0.88) and delta15N (r2 = 0.54) significantly decreased, and delta13C significantly increased (r2 = 0.30) in the C. hyperboreus over the collection period allowing an examination of the role of these variables in POP dynamics in this small pelagic zooplankton. The rank and concentrations of POP groups in C. hyperboreus over the entire sampling was sum of PCB (30.1 +/- 4.03 ng/g, dry weight) > sum of HCH (11.8 +/- 3.23) > sum of DDT (4.74 +/- 0.74), sum of CHLOR (4.44 +/- 1.0) > sum of CIBz (2.42 +/- 0.18), although these rankings varied considerably over the summer. The alpha- and gamma-HCH and lower chlorinated PCB congeners were the most common POPs in C. hyperboreus. The relationship between bioconcentration factor (BCF) and octanol-water partition coefficient (Kow) observed for the C. hyperboreus was linear and near 1:1 (slope = 0.72) for POPs with a log Kow between 3 and 6 but curvilinear when hydrophobic POPs (log Kow > 6) were included. Concentrations of sum of HCH. Sum of CHLOR and sum of CIBz increased over the sampling period, but no change in sum of PCB or sum of DDT was observed. After removing the effects of time, the variables lipid content, water content, delta15N and delta13C did not describe POP concentrations in C. hyperboreus. These results suggest that hydrophobic POP (log Kow = 3.86.0) concentrations in zooplankton are likely to reflect water concentrations and that POPs do not biomagnify in C. hyperboreus or likely in other small, herbivorous zooplankton. PMID- 11601539 TI - Nutrient cycling in a tropical seasonal rain forest of Xishuangbanna, Southwest China. Part 1: tree species: nutrient distribution and uptake. AB - Tropical rain forests are characterized by large numbers of the species with diverse growth habits. The objective of the present study was to determine the distribution of nutrient content in the major trees of the tropical rain forests in Xishuangbanna. This will improve the understanding of the nutrient losses from such sites that result from harvesting and flow of nutrients within the ecosystem and lead to the development of effective and rational forest management strategies. Based on the results in this study, the distribution of nutrients among biomass components of trees varied: The ordering of major elements concentrations was K > N > Mg > Ca > P in branch, stem and root tissues but was N > K > Mg > Ca > P in leaves. The maximum amount of all nutrients per ha occurred in the stems followed by branches, roots and leaves. Of the total uptake of 6167.7 kg ha(-1) of all nutrients, the contribution of various nutrients was found to be N (2010.6 t ha(-1)), P (196.3 t ha(-1)), K (2123.8 kg ha(-1)), Ca (832 kg ha(-1)) and Mg (1005 kg ha(-1)). However, comparing the nutrient uptake of other tropical and sub tropical forests, the results indicated that rates for the Xishuangbanna forests were 20-35% lower than previously reported values. PMID- 11601540 TI - Clostridium lentocellum SG6--a potential organism for fermentation of cellulose to acetic acid. AB - A cellulolytic, acetic acid producing anaerobic bacterial isolate, Gram negative, rod-shaped, motile, terminal oval shaped endospore forming bacterium identified as Clostridium lentocellum SG6 based on physiological and biochemical characteristics. It produced acetic acid as a major end product from cellulose fermentation at 37 degrees C and pH 7.2. Acetic acid production was 0.67 g/g cellulose substrate utilized in cellulose mineral salt (CMS) medium. Yeast extract (0.4%) was the best nitrogen source among the various nitrogenous nutrients tested in production medium containing 0.8% cellulose as substrate. No additional vitamins or trace elemental solution were required for acetic acid fermentation. This is the highest acetic acid fermentation yield in monoculture fermentation for direct conversion of cellulose to acetic acid. PMID- 11601541 TI - Biotransformation of nitrophenols in upflow anaerobic sludge blanket reactors. AB - Four identical bench-scale upflow anaerobic sludge blanket (UASB) reactors, R1, R2, R3 and R4, were used to assess nitrophenols degradation at four different hydraulic retention times (HRT). Reactor R1 was used as control, whereas R2, R3, and R4 were fed with 2-nitrophenol (2-NP), 4-nitrophenol (4-NP), and 2,4 dinitrophenol (2,4-DNP), respectively. The concentration of each nitrophenol was gradually varied from 2 to 30 mg/l during acclimation. After acclimation reactors were operated under steady-state conditions at four different HRTs--30, 24, 18, and 12 h, to study its effect on the removal of nitrophenols. Overall removal of 2-NP and 4-NP was always more than 99% but 2,4-DNP removal decreased from 96% to 89.7% as HRT was lowered from 30 to 12 h. 2-Aminophenol (2-AP), 4-aminophenol (4 AP) and 2-amino,4-nitrophenol (2-A,4-NP) were found to be the major intermediates during the degradation of 2-NP, 4-NP and 2,4-DNP, respectively. Out of the total input of nitrophenolic concentration (30 mg/l), on molar basis, about 41.248.4% of 2-NP, 59.4-68% of 4-NP, 30-26.6% of 2,4-DNP was recovered in the form of their respective amino derivatives at 30-12 h HRT. COD removal was 98-89%, 97-56%, 97 52%, and 94-46% at 30-12 h HRT for R1, R2, R3 and R4, respectively. Average cell growth was observed to be 0.15 g volatile suspended solid (VSS) per g COD consumed. Methanogenic inhibition was observed at lower HRTs (18 and 12 h), however denitrification was always more than 99% with non-detectable level of nitrite. The granules developed inside the reactors were black in color and their average size varied between 1.9 and 2.1 mm. PMID- 11601542 TI - Solute adsorption and enzyme immobilization on chitosan beads prepared from shrimp shell wastes. AB - The equilibrium and kinetics of adsorption of reactive dye RR222 and Cu2+, and the activity of immobilization of acid phosphatase, on highly swollen chitosan beads were examined at 30 degrees C. The chitosan was prepared from shrimp shell wastes and was cross-linked with different dosages of glutaraldehyde or glyoxal (100-80,000 mg/l). It was shown that the amounts of solute adsorption and the immobilization capacity of acid phosphatase on cross-linked chitosan beads were substantially affected by their degree of cross-linking. The cross-linking rate of chitosan with glutaraldehyde could be described by a pseudo-second-order equation and the cross-linking equilibrium by the Freundlich equation. This provided an experimental method to control the degree of cross-linking of chitosan beads. Finally, the activity and lifetime of the immobilized enzyme were measured to evaluate the application potential. PMID- 11601543 TI - Investigation on molar mass, solubility and enzymatic fragmentation of xylans by multi-detected SEC chromatography. AB - Four xylan samples from different origin were investigated, using a multi detector, size exclusion, chromatographic system with two chromatographic column sets and mobile phases differing in the DMSO:water ratio. Molar mass distribution could be analysed best using a mobile phase of DMSO:water (90:10) with addition of 0.05 M LiBr, a system offering good solubilisation of the polymers and a proper chromatographic separation. SEC analysis in aqueous systems provided information on solubility and aggregation of xylans. A comparison of UV- and RI signals in different systems gave further information on lignin impurities, which in some cases were involved in aggregation phenomena. Both analytical systems were applied to study the enzymatic fragmentation of xylans. Combining the information derived from the two systems can differentiate between the enzymatic degradation of the well-dissolved and the associated polymer fractions. PMID- 11601544 TI - Cellulolytic activity in leachate during leach-bed anaerobic digestion of municipal solid waste. AB - The degradation of municipal solid waste (MSW) under mesophilic conditions can be enhanced by exchanging leachate between fresh waste and stabilised waste. The optimum point in time when leachate from an anaerobically digesting waste bed can be used to initiate degradation of another waste bed might occur when the leachate of the digesting waste bed is highly active with cellulolytic and methanogenic bacteria. In this study, the cellulolytic activity of the leachate was measured using the cellulose-azure assay. As products of hydrolysis are soluble compounds, the rate of generation of these compounds was estimated based on a soluble chemical oxygen demand (SCOD) balance around the fresh waste bed. It was found that once the readily soluble material present in MSW was washed out there was very little generation of SCOD without the production of methane, indicating that flushing leachate from a stabilised waste bed resulted in a balanced inoculation of the fresh waste bed. With the onset of sustained methanogenesis, the rate of SCOD generation equalled the SCOD released from the digester as methane. The experimental findings also showed that cellulolytic activities of the leachate samples closely followed the trend of SCOD generation. reserved. PMID- 11601545 TI - Comparative studies on metal biosorption by two strains of Cladosporium cladosporioides. AB - Two strains of a fungus, Cladosporium cladosporioides 1 and C. cladosporioides 2 showed different metal biosorption properties. Strain 1 showed preferential sorption of gold and silver, while strain 2 could bind metals such as copper and cadmium in addition to gold and silver. Strain 1 had a cell-wall hexosamine content of 0.1%. X-ray photoelectron spectroscopy (XPS) and Fourier transform infra-red spectroscopy (FTIR) analyses indicated that nitrogen was not involved in metal biosorption by the strain. In strain 2 the cell-wall hexosamine content was 150 times that of strain 1. These results indicated that hexosamine was responsible for non-specific metal binding while cell-wall polymers other than hexosamines had a role in conferring selectivity in precious-metal binding. PMID- 11601546 TI - Microbial characterization during composting of municipal solid waste. AB - This study investigates the prevailing physico-chemical conditions and microbial community; mesophilic bacteria, yeasts and filamentous fungi, bacterial spores, Salmonella and Shigella as well as faecal indicator bacteria: total coliforms, faecal coliforms and faecal Streptococci, present in a compost of municipal solid waste. Investigations were conducted in a semi-industrial pilot plant using a moderate aeration during the composting process. Our results showed that: (i) auto-sterilization induced by relatively high temperatures (60-55 degrees C) caused a significant change in bacterial communities. For instance, Escherichia coli and faecal Streptococci populations decreased, respectively, from 2 x 10(7) to 3.1 x 10(3) and 10(7) to 1.5 x 10(3) cells/g waste dry weight (WDW); yeasts and filamentous fungi decreased from 4.5 x 10(6) to 2.6 x 10(3) cells/g WDW and mesophilic bacteria were reduced from 5.8 x 10(9) to 1.8 x 10(7) bacteria/g WDW. On the other hand, the number of bacterial spores increased at the beginning of the composting process, but after the third week their number decreased notably; (ii) Salmonella disappeared completely from compost by the 25th day as soon as the temperature reached 60 degrees C; and (iii) the bacterial population increased gradually during the cooling phase. While Staphylococci seemed to be the dominant bacteria during the mesophilic phase and at the beginning of the thermophilic phase, bacilli predominated during the remainder of the composting cycle. The appearance of gram-negative rods (opportunistic pathogens) during the cooling phase may represent a serious risk for the sanitary quality of the finished product intended for agronomic reuse. Compost sonication for about 3 min induced the inactivation of delicate bacteria, in particular gram-negatives. By contrast, gram-positive bacteria, especially micrococcus, spores of bacilli, and fungal propagules survived, and reached high concentrations in the compost. PMID- 11601547 TI - Effect of iron concentration on hydrogen fermentation. AB - The effect of the iron concentration in the external environment on hydrogen production was studied using sucrose solution and the mixed microorganisms from a soybean-meal silo. The iron concentration ranged from 0 to 4,000 mg FeCl2 l(-1). The temperature was maintained at 37 degrees C. The maximum specific hydrogen production rate was found to be 24.0 ml g(-1) VSS h(-1) at 4,000 mg FeCl2 l(-1). The specific production rate of butyrate increased with increasing iron concentration from 0 to 20 mg FeCl2 l(-1) and decreased with increasing iron concentration from 20 to 4,000 mg FeCl2 l(-1). The maximum specific production rates of ethanol (682 mg g(-1) VSS h(-1)) and butanol (47.0 mg g(-1) VSS h(-1)) were obtained at iron concentrations of 5 and 3 mg FeCl2 l(-1), respectively. The maximum hydrogen production yield of 131.9 ml g(-1) sucrose was obtained at the iron concentration of 800 mg FeCl2 l(-1). The maximum yields of acetate (389.3 mg g(-1) sucrose), propionate (37.8 mg g(-1) sucrose), and butyrate (196.5 mg g(-1) sucros) were obtained at iron concentrations of 3, 200 and 200 mg FeCl2 l(-1), respectively. The sucrose degradation efficiencies were close to 1.0 when iron concentrations were between 200 and 800 mg FeCl2 l(-1). The maximum biomass production yield was 0.283 g VSS g(-1) sucrose at an iron concentration of 3,000 mg FeCl2 l(-1). PMID- 11601548 TI - Carbon from Cassava peel, an agricultural waste, as an adsorbent in the removal of dyes and metal ions from aqueous solution. AB - Cassava (Manihot esculenta) is a short lived erect perennial shrub, planted vegetatively from hard wood stem cuttings. It is an important crop across a wide range of tropical environments and is a significant component of cropping systems. Cassava peel is an agricultural waste from the food processing industry. Activated carbons prepared from waste cassava peel employing physical and chemical methods were tested for their efficiency in the removal of dyes and metal ions from aqueous solution. While both of these were efficient as adsorbents for dyes and metal ions, the material impregnated with H3PO4 showed higher efficiency than the heat treated materials. PMID- 11601549 TI - Surgical instrument restraint in weightlessness. AB - BACKGROUND: Performing a surgical procedure during spaceflight will become more likely in the future as the duration of missions becomes longer. Only minimal surgical capability was available on previous missions since the definitive medical care time was short and the likelihood of a surgical event too low to justify carrying surgical hardware onboard. Early demonstrations of surgical procedures in the microgravity environment of parabolic flight indicated the need for careful logistical planning and restraint of surgical hardware. Human ergonomics also has more effect in microgravity than in the conventional 1-G environment. METHODS: Three methods of surgical instrument restraint--a Minor Surgical Kit (MSK), a Surgical Restraint Scrub Suit (SRSS), and a Surgical Tray (ST)--were evaluated in parabolic flight surgical procedures. RESULTS: The MSK was easily stored, easily deployed, and demonstrated the best ability to facilitate a surgical procedure in microgravity. CONCLUSION: Important factors in a surgical restraint system for microgravity include excellent organization of supplies, ability to maintain sterility, accessibility while providing secure restraint, ability to dispose of sharp items and biological trash, and ergonomic efficiency. PMID- 11601550 TI - Human sensorimotor coordination during spaceflight: an analysis of pointing and tracking responses during the "Neurolab" Space Shuttle mission. AB - BACKGROUND: It has been shown that pointing movements are slowed during microgravity, however there is a paucity of corresponding data for other movement types. METHODS: In our study, subjects pointed at visual targets without seeing their hand, and tracked targets moving around a circular path with and without hand vision, with and without a secondary reaction-time task. RESULTS: Pointing responses were slowed distinctly in microgravity, but the speed of tracking movements was not affected. The secondary task had comparable effects on tracking performance in space and on Earth. CONCLUSIONS: Response slowing in space is not due to an increased dependence on visual feedback, since it persists without hand vision. Differential effects of microgravity on pointing and tracking could be due to subjects' strategic decisions. PMID- 11601551 TI - Immune responses and latent herpesvirus reactivation in spaceflight. AB - BACKGROUND: Increased frequency and severity of herpesvirus infections are common in individuals with impaired cellular immunity, a phenomenon observed in both the elderly and astronauts alike. This study investigated immune responses and latent herpesvirus reactivation during a 9-d spaceflight. In addition, adrenocortical and immune responses of an elderly astronaut (payload specialist-2, PS2; age 77) who flew on this mission were compared with that of younger crewmembers. HYPOTHESIS: Spaceflight and associated stresses will decrease cellular immunity and reactivate latent herpesviruses. METHODS: Blood and urine samples, collected from the seven crewmembers who flew on the Space Shuttle Discovery (STS-95), were analyzed for levels of neuroendocrine hormones, leukocyte and lymphocyte subsets, and evidence of herpes-virus reactivation. RESULTS: Prior to flight, increased antibody titers to latent Epstein-Barr virus were found. During flight, acute changes in dehydroepiandrosterone sulfate (DHEAS) and cortisol resulted in a pronounced decrease in the DHEAS/cortisol ratio by the end of the mission for PS2 and a younger crewmember. Shedding of cytomegalovirus (CMV) in urine and increased CMV antibody titers also occurred inflight. At landing, the percent increases in adrenocorticotropic hormone and cortisol were greatest for PS2 as compared with the other six crewmembers. A significant neutrophilia also was observed in all crewmembers. Notably, PS2 had large increases in monocytes and natural killer cells at landing while other crewmembers showed little change or a decrease. CONCLUSIONS: These findings indicate that spaceflight and associated stresses reactivate latent herpesviruses and suggest that acute changes in neuroendocrine hormones mediate these changes in part by downregulating cellular immunity. Moreover, the similarities between aging and spaceflight suggest that the study of the immune system in elderly subjects may be useful as a predictive model for astronauts enduring long-term spaceflights. PMID- 11601553 TI - Effect of vitamin E supplementation on hypoxia-induced oxidative damage in male albino rats. AB - BACKGROUND: There is growing evidence that free radicals mediated oxidative injury due to inadequate oxygen availability is an important factor in various pathologies at high altitude. Since vitamin E is known to protect the cells from oxidative damage due to its potent antioxidant properties, the present study was carried out to explore the effect of vitamin E supplementation on various hematological and biochemical parameters in hypoxia-induced oxidative stress in albino rats. METHODS: The experiments were conducted on male albino rats by intermittently exposing them to a simulated altitude of 7,576 m (25,000 ft), daily for 6 h for 15 d at 32 +/- 2 degrees C. The control group was fed vehicle only (1% Tween 80) and the experimental group was given vitamin E (40 mg per rat x d(-1)) orally, 5 d prior to and during the period of hypoxic exposure. The variables studied include: hemoglobin, hematocrit, RBC deformability index, alpha tocopherol level, malondialdehyde (MDA), reduced glutathione (GSH), oxidized glutathione (GSSG), lactate dehydrogenase (LDH) and protein level in blood/plasma and various tissues. RESULTS: Significant increase in hematocrit and hemoglobin and decrease in RBC deformability index was observed on exposure to hypoxia while vitamin E supplementation maintained them at the normal level. Hypoxia led to the decrease in plasma vitamin E and blood glutathione (GSH) level and two-fold increase in the plasma malondialdehyde (MDA) level. Vitamin E supplementation, on the other hand, resulted in less of an increase in MDA and increased the GSH concentration significantly. LDH activity, which was elevated on exposure to hypoxia, was arrested on vitamin E supplementation. CONCLUSION: The results indicate that vitamin E supplementation results in preventing oxidative damage due to high altitude stress. PMID- 11601552 TI - Blood pressure changes during orthostatic stress: evidence of gender differences in neuroeffector distribution. AB - BACKGROUND: Research has demonstrated that exogenous adrenergic agonists produce dose-related vasoconstriction in men but not women. This suggests that the distribution of adrenergic receptor sites differ with gender. Women may have a higher density of receptor sites in the arterioles (fast acting with low gain) while men may have higher density in the larger vessels (slow acting with high gain). METHODS: To partially test this hypothesis, the time course in beat-to beat responses in systolic and diastolic BP, and heart rate was compared between six men and six women during the transition from a supine to an upright posture and during prolonged standing. RESULTS: The transient change in systolic and diastolic BP was very rapid in women, but completed within 15 to 30 s after assuming an upright position. Men increased BP at a much slower rate, but continued to produce higher BPs over the complete testing session (up to 15 min). The rate of change for men (15 mm Hg systolic and 10 mm Hg diastolic) was approximately half that for women (30 mm Hg systolic and 15 mm Hg diastolic) during the first 30 s of upright posture. However, after 60 s of standing, absolute change in systolic BP for the men exceeded that of the women by approximately 5 mm Hg for both systolic and diastolic BP. While men's heart rate remained relatively constant during standing, women compensated for the lower change in BP by a continual increase in heart rate throughout the duration of the test. Although both men and women demonstrated increases in norepinephrine at 5 and 15 min during standing, no difference between genders was observed. Similarly, there were no differences in dominant periodicity of heart rate during standing, although women demonstrated slightly higher beat-to-beat variation (RMS) than men. CONCLUSION: The results support the hypothesis of distributional differences in neuroeffector responses between men and women and have implications for how men and women respond to orthostatic stress across a variety of environmental conditions. PMID- 11601554 TI - Oxygen uptake response during maximal cycling in hyperoxia, normoxia and hypoxia. AB - BACKGROUND: Oxygen uptake (VO2) on-kinetics is decelerated in acute hypoxia and accelerated in hyperoxia in comparison with normoxia during submaximal exercise. However, the effects of fraction of oxygen in inspired air (FIO2) on VO2 kinetics during maximal exercise are unknown. HYPOTHESIS: The effects of FIO2 on VO2 on kinetics during maximal exercise are similar to submaximal exercise. METHODS: There were 11 endurance athletes who were studied during maximal 7-min cycle ergometer exercise in hyperoxia (FIO2 0.325), hypoxia (FIO2 0.166) and normoxia (FIO2 0.209). The individual VO2 data were fit to a curve by using a three exponential model. RESULTS: In hypoxia, VO2 on-response amplitude during Phase 2 (approximately 20-100 s from the beginning of exercise) was lower (p < 0.05) when compared with hyperoxia; time constant of VO2 Phase 3 (beyond approximately 100 s after beginning of exercise) was shorter (p < 0.05) when compared with hyperoxia; and mean response time (MRT, O-63%) for VO2peak was shorter (p < 0.05) when compared with normoxia and hyperoxia. VO2peak was higher in hyperoxia (4.80 +/- 0.48 L x min(-1), p < 0.05) and lower in hypoxia (4.03 +/- 0.46 L x min(-1), p < 0.05) than in normoxia (4.36 +/- 0.44 L x min(-1)). CONCLUSIONS: Moderate hypoxia or hyperoxia do not affect VO2 time constants at the onset of maximal exercise. However, MRT for VO2peak is shortened in hypoxia. It is suggested that the differences in VO2peak and power output during the latter half of the test and the point that FIO2 was modified only moderately might explain most of the discrepancy with the previous studies. PMID- 11601555 TI - Breath-holding ability of offshore workers inadequate to ensure escape from ditched helicopters. AB - BACKGROUND: Following a helicopter ditching in water, the survival rate of individuals not mortally injured by the impact ranges from 50-85%. One possible cause for this low survival rate is that the crew and passengers cannot hold their breath underwater long enough to make the often difficult escape from an inverted and submerged helicopter. METHODS: We investigated pulmonary function, breath-holding times in air (BHTa) and water (BHTw) of 228 students enrolled in offshore survival courses required to work in either the offshore petroleum industry or in military marine aviation. Comparisons were performed based on occupation, SCUBA experience, and smoking. RESULTS: In 25 degrees C pool water, the overall BHTw ranged from 5.4 to 120 s with a median of 37 s. Of the 228 subjects, 34% had a BHTw less than the 28 s required for the complete evacuation of a Super Puma helicopter under ideal conditions. No significant differences in BHTw were observed based on either smoking history (Non-Smoker, 41.5 +/- 21.6 s; Smoker, 37.2 +/- 20.2 s) or occupation (Novice, 37.5 +/- 21.1 s; Offshore, 40.5 +/- 21.1 s; Military, 45.2 +/- 20.9 s). However, SCUBA-trained individuals had a significantly longer BHT, (47.4 +/- 21.6 s) than non-SCUBA (37.6 +/- 20.6 s), as well as a greater force vital capacity (FVC), BHTa, and subjective comfort in water. CONCLUSIONS: It is concluded that the inability to breath-hold in emergency situations is a major contributor to the low survival rates of marine helicopter ditchings. Therefore, efforts must be made to both decrease escape times and to increase survival time underwater. PMID- 11601556 TI - In-flight psychiatric emergencies. AB - BACKGROUND: Although studies have been published regarding airline in-flight medical emergencies, there is a lack of any specific studies about in-flight psychiatric emergencies. This study seeks to ascertain the incidence of in-flight psychiatric emergencies, their associated factors, and outcomes. METHODS: All in flight calls for physician consultation to MedAire, a leading medical resource for airlines, during 1997 were reviewed for psychiatric symptomatology. RESULTS: Of 1375 consultations, 3.5% were characterized as psychiatric, with a large majority (90%) of these cases presenting primarily as acute anxiety. Most of the psychiatric cases (69%) required arrangements for the passenger to be evaluated on arrival, and three cases required emergency flight diversion and landing. CONCLUSIONS: This study suggests that an anxiolytic agent with a rapid onset may be indicated for the on-board medical kit. PMID- 11601557 TI - An aviator with cardiomyopathy and genetic susceptibility to hereditary hemochromatosis: a case report. AB - A 44-yr-old male pilot was diagnosed with non-ischemic cardiomyopathy, possibly as a complication of hereditary hemochromatosis, 8 yr after an acquired left bundle branch block was discovered on a routine ECG. Biochemical testing returned high levels of iron and percentage transferrin saturation, and genetic testing for hemochromatosis was remarkable for a heterozygous H63D mutation in the HFE gene on chromosome 6. Hereditary hemochromatosis should be considered in the differential diagnosis when a patient presents with cardiomyopathy and genetic testing for HFE gene variants influencing iron overload is now available as a clinical adjunct for diagnosis and patient management issues. Cardiomyopathy and symptomatic hemochromatosis are aeromedically disqualifying conditions in the U.S. Air Force; however, early identification of hereditary hemochromatosis susceptibility with biochemical or genetic diagnostic tests, followed by education in primary and secondary prevention, will prevent a significant proportion of the possible sequelae. PMID- 11601558 TI - Modeling cardiac sensitization potential of humans exposed to Halon 1301 or Halon 1211 aboard aircraft. AB - BACKGROUND: Halon 1301 and Halon 1211 are being replaced because they contribute to the depletion of ozone. Many of the potential candidate chemicals for replacing them are, like them, halogenated hydrocarbons. These chemicals have the potential to cause cardiac sensitization at high enough exposure concentrations. METHODS: A physiologically based pharmacokinetic model, which mathematically describes the uptake, distribution, metabolism, and elimination of chemicals, was used to relate exposure to these chemicals with arterial blood concentrations resulting from the exposure. This information was then used to evaluate the potential for the occurrence of a cardiac-sensitizing event. The model was used to analyze the exposures to Halon 1301 and Halon 1211 in three aircraft (Navy E 2B, Cessna-421B, and Cessna-210C). RESULTS: Halon 1301 exposures were shown to be safe, but Halon 1211 resulted in arterial concentrations in exposed individuals that reached levels that could potentially cause cardiac sensitization. CONCLUSIONS: Use of the model for evaluating the risk from exposure to Halon 1301 and Halon 1211 is a moot point since both chemicals are being replaced. However, demonstration of the validity of the approach provides a tool for the evaluation of the health safety of replacement candidates. The National Fire Protection Association has approved use of this model for assessing times for safe egress from situations where agents are used to flood an area to extinguish a fire. PMID- 11601559 TI - The number of steps taken by flight attendants during international long-haul flights. AB - BACKGROUND: Previous studies have revealed that female cabin attendants on long flights are most likely to have health problems. Since health problems can be related to workload and work stress and since the number of steps taken by an employee during a work shift can be an objective measure of the work load of cabin attendants, it is necessary to evaluate the predictors of the number of steps. METHODS: We used pedometers worn by 118 female flight attendants to study the number of steps during flights and its predictors during long international flights. RESULTS: The mean number of steps during 636.53 (SD = 129.11 )-minute flights was 10,742.85 (SD = 3,547.17). The crude number of steps per minute was 16.88, and the adjusted number of steps per minute was 14.04. Flight length and the number of sleeping hours worked (i.e., between midnight and 6:00 am) were significant predictors of the number of steps. CONCLUSION: Although it is implied that flight duration and night flight increase the work load of flight attendants, we need to consider psychological aspects to evaluate the overall effects of their jobs on work stress and health. PMID- 11601560 TI - A brief overview of the development of aerospace medicine in the United States. AB - Aerospace medicine has evolved into a legitimate specialty through a long process of historical observation and technical achievement. However, most public literature on the topic has only covered information written through the late 1960s. This paper seeks to give a brief overview of the development of aerospace medicine and includes information about early advances in the field as well as more recent data. A MEDLINE search using "history," "aerospace medicine," and several other search terms as subject headings was the first step in gathering data. Also, personnel from the U.S. Air Force School of Aerospace Medicine library at Brooks AFB, TX, were consulted for current literature on the subject. From the earliest descriptions of mountain sickness, to the first manned balloon flight, and on to the invention of the airplane with man's forays into space, aerospace medicine has had a rich history. A great part of this rich history was contributed by pioneers, both past and present, of the U.S. Air Force. PMID- 11601561 TI - Medical guidelines for space passengers. Aerospace Medical Association Task Force on Space Travel. AB - In the foreseeable future, private companies will manufacture space vehicles with a capacity of transporting tourists into low Earth orbit. Because of the stresses of spaceflight, the effects of microgravity, and limited medical care capability, a system of medical clearance is highly recommended for these space tourists. It is our purpose to establish guidelines for use by private businesses, medical providers, and those planning on being a space tourist. Consequently, a Task Force was organized by the Aerospace Medical Association (AsMA) for the purpose of facilitating safety of passengers, fellow passengers, crew, and flight operations. The guidelines are meant to serve only as a template with the full expectation that exceptions might be made with appropriate rationale. PMID- 11601562 TI - Can dietary treatment of non-anemic iron deficiency improve iron status? AB - OBJECTIVE: To investigate the efficacy of, first, a dietary regimen involving increased consumption of iron-rich foods and enhancers of iron absorption and decreased consumption of inhibitors of iron absorption and, second, a low dose iron chelate iron supplement, for increasing iron stores in young adult New Zealand women with mild iron deficiency (MID). METHODS: The study was a 16 week randomized placebo-controlled intervention. Seventy-five women aged 18 to 40 years with MID (serum ferritin < 20 microg/L and hemoglobin > or = 120 g/L) were assigned to one of three groups: Placebo, Supplement (50 mg iron/day as amino acid chelate) or Diet. Participants in the Diet Group were given individual dietary counseling to increase the intake and bioavailability of dietary iron. Dietary changes were monitored by a previously validated computer-administered iron food frequency questionnaire. RESULTS: Diet Group members significantly increased their intake of flesh foods, heme iron, vitamin C and foods cooked using cast-iron cookware and significantly decreased their phytate and calcium intakes. Serum ferritin increased in the Supplement and Diet Groups by 59% (p=0.001) and 26% (p=0.068), respectively, in comparison to the Placebo Group. The serum transferrin receptor:serum ferritin ratio decreased by 51% in the Supplement Group (p=0.001), and there was a non-significant decrease of 22% (p=0.1232) in the Diet Group. CONCLUSIONS: This study is the first, to our knowledge, to demonstrate that an intensive dietary program has the potential to improve the iron status of women with iron deficiency. PMID- 11601563 TI - Oral stimulation influences postprandial triacylglycerol concentrations in humans: nutrient specificity. AB - OBJECTIVE: To determined whether the nature of the lipid in an oral stimulus modifies postprandial triacylglycerolemia. METHODS: Sixteen healthy adults (eight male, eight female) participated in six test sessions conducted weekly. The test sessions were administered randomly after overnight fasts and included: ingestion of 50 grams of butter in capsules (to avoid oral stimulation with lipids) and 500 mL of water in 15 minutes followed by oral stimulation with one of the following foods on a cracker: butter, unsaturated fatty acid (UFA) margarine, jelly, UFA margarine + jelly, cracker alone or no oral stimulation. Sensory stimulation entailed masticating and expectorating approximately 5.0 g samples of each stimulus every three minutes for 110 minutes. Blood was drawn immediately after preload ingestion and at minutes 35, 85, 200, 320, and 440 post loading and analyzed for serum triacylglycerol (TAG), insulin and glucose concentrations. RESULTS: Only the oral samples containing the UFA margarine led to significant elevations of serum TAG concentration compared to baseline (p < 0.05). Maximum change of TAG concentrations were greater following orosensory stimulation with UFA margarine compared to orosensory stimulation with butter, jelly or UFA margarine + jelly. No differences were observed relative to vehicle alone or no orosensory stimulation, but this is due to lower nadir values for these treatments. Insulin and glucose concentrations were not different between treatments. CONCLUSION: Oral exposure specifically to an unsaturated dietary lipid augments the postprandial rise of TAG, compared to baseline. PMID- 11601564 TI - Effects of long versus short bout exercise on fitness and weight loss in overweight females. AB - OBJECTIVE: The specific aim of this study was to determine if three 10 minute bouts of exercise per day (3 x 10) and two 15 minute bouts per day (2 x 15) were as effective as one 30 minute bout per day (1 x 30) for improving VO2 max and weight loss. METHODS: Overweight, female college students (body mass index > or = 28 kg/m2) were recruited and assessed at baseline and post-treatment for aerobic fitness (Astrand maximal cycle test), weight, skinfold thickness (7-site), and circumference measures (4-site). Following measurement of resting energy expenditure (REE), subjects were asked to follow a self-monitored calorie restricted diet (80% of REE) for the twelve week duration of the study and were assigned (non-random) to one of four treatment groups: 1) a nonexercising control group (control, n = 8), 2) a 30 minutes continuous exercise group (1 x 30, n = 12), 3) a 30 minutes accumulated exercise group (2 x 15, n = 10) and 4) a second 30 minutes accumulated exercise group (3 x 10, n = 8). The exercising subjects participated in aerobic exercise training at 75% of heart rate reserve three to five days per week with all exercise monitored. RESULTS: VO2 max increased significantly while weight, body mass index, sum of skinfolds, and sum of circumferences decreased significantly from baseline to post-treatment in the 1 x 30, 2 x 15 and the 3 x 10 groups, but not in the control group. A tertiary finding was that exercise participation did not differ among the exercising groups with regard to the average number of days per week. CONCLUSIONS: These results support the hypothesis that exercise accumulated in several short bouts has similar effects as one continuous bout with regard to aerobic fitness and weight loss during caloric restriction in overweight, young women. PMID- 11601565 TI - Self-reported calcium intake and bone mineral content in children and adolescents. AB - OBJECTIVE: We examined the relationship between self-reported calcium (Ca) intake and bone mineral content (BMC) in children and adolescents. We hypothesized that an expression of Ca adjusted for energy intake (EI), i.e., Ca density, would be a better predictor of BMC than unadjusted Ca because of underreporting of EI. METHODS: Data were obtained on dietary intakes (repeated 24-hour recalls) and BMC (by DEXA) in a cross-section of 227 children aged 8 to 17 years. Bivariate and multivariate analyses were used to examine the relationship between Ca. Ca density, and the dependent variables total body BMC and lumbar spine BMC. Covariates included were height, weight, bone area. maturity age, activity score and EI. RESULTS: Reported EI compared to estimated basal metabolic rate suggested underreporting of EI. Total body and lumbar spine BMC were significantly associated with EI, but not Ca or Ca density, in bivariate analyses. After controlling for size and maturity, multiple linear regression analysis revealed unadjusted Ca to be a predictor of BMC in males in the total body (p = 0.08) and lumbar spine (p = 0.01)). Unadjusted Ca was not a predictor of BMC at either site in females. Ca density was not a better predictor of BMC at either site in males or females. CONCLUSIONS: The relationship observed in male adolescents in this study between Ca intake and BMC is similar to that seen in clinical trials. Ca density did not enable us to see a relationship between Ca intake and BMC in females, which may reflect systematic reporting errors or that diet is not a limiting factor in this group of healthy adolescents. PMID- 11601566 TI - Alcohol drinkers overreport their energy intake in the BIRNH study: evaluation by 24-hour urinary excretion of cations. Belgian Interuniversity Research on Nutrition and Health. AB - OBJECTIVE: Alcohol drinkers are generally considered to underreport their alcohol intake, but little is known about whether they correctly report their energy intake (EI). We assessed the validity of the reported energy intake of alcohol drinkers using the 24-hour urinary (U) excretion of potassium (K) and sodium (Na) as biomarkers. METHODS: A total of 2,124 men and 1,998 women 25 to 74 years of age with a 24-hour urine collection, a random sample of the Belgian Interuniversity Research on Nutrition and Health (BIRNH). were studied. Dietary intake (D), including alcohol consumption, was assessed by a one-day food record. Basal metabolic rate (BMR) was predicted from age, gender and weight. As a measure for the degree of reporting error, D-K/U-K, D-Na/U-Na, EI/U-K, Non alcohol EI/U-Na (NAEI/U-Na), EI/U-Na, EI/U-creatinine and EI/BMR ratios were calculated and compared among non-, moderate and heavy drinkers in both genders. RESULTS: EI, NAEI and all seven ratios examined generally increased with the level of alcohol intake in both genders. After adjustment for age, body mass index, smoking and educational level, most ratios were significantly higher in moderate drinkers (p < 0.02 to p < 0.0001) and in heavy drinkers (all p < 0.0001) than in non-drinkers. These differences were most significant in male heavy drinkers. The exceptions were D-K/U-K, D-Na/U-Na and NAEI/U-Na in moderate and female heavy drinkers and EI/U-K in male moderate drinkers. The estimated amount of the overreporting of EI by heavy drinkers was 27.8% in men and 13.7% in women. CONCLUSIONS: This study provides evidence that EI and NAEI obtained from the BIRNH study was overreported among alcohol drinkers, especially among male heavy drinkers. It also indicates that EI from alcohol replaced EI from food. PMID- 11601568 TI - Effects of dietary fat and endurance exercise on plasma cortisol, prostaglandin E2, interferon-gamma and lipid peroxides in runners. AB - OBJECTIVE: Exercise and the neuroendocrine and oxidative stress it elicits on immune function is modulated by dietary fat intake. The effects of increasing dietary fat on endurance exercise-induced alterations 80% of VO2max for 2 hours) in the plasma levels of cortisol and prostaglandin E2 (PGE2), interferon-gamma (IFN-gamma) and lipid peroxides were investigated. As higher levels of cortisol, PGE2 and lipid peroxides could be immunosuppressive, the effects of different levels of dietary fat on these measures in runners were determined. METHODS: Healthy trained runners (males and females) consumed serially 15% fat diet (of daily energy), 30% fat diet and 40% fat diets for four weeks each. In the last week of each diet period the subjects ran to exhaustion at 80% of their VO2max and blood was drawn pre- and post-run. Cortisol, IFN-gamma, PGE2 and lipid peroxides were determined using standard techniques. RESULTS: Pre-exercise levels of plasma cortisol were elevated, IFN-gamma was unchanged and PGE2 and lipid peroxides decreased on the 40%F diet compared to 30%F and 15%F. Post-exercise levels of plasma cortisol (p < 0.004), PGE2 (p < 0.0057) and lipid peroxide levels increased (p < 0.0001) after endurance exercise on all diets. The rates of increase of plasma cortisol levels during exercise were similar on all three diets. Although absolute cortisol levels were higher in the high fat group, the rate of increase of plasma cortisol level during exercise was similar on each diet. The dietary fat levels did not affect IFN-gamma, however, PGE2 and lipid peroxides decreased with increasing fat at baseline at 40%F level (p < 0.01; 30%F vs. 40% F: p < 0.002; 15%F vs. 40%F: p < 0.007). CONCLUSIONS: Data from the present study suggest that higher levels of fat in the diet, up to 40%, increase endurance running time without adverse effects on plasma cortisol, IFN-gamma, and lipid peroxide levels. PMID- 11601567 TI - Endocrine and lipid responses to chronic androstenediol-herbal supplementation in 30 to 58 year old men. AB - OBJECTIVE: The effectiveness of an androgenic nutritional supplement designed to enhance serum testosterone concentrations and prevent the formation of dihydrotestosterone and estrogen was investigated in healthy 3 to 58 year old men. DESIGN: Subjects were randomly assigned to consume a nutritional supplement (AND-HB) containing 300-mg androstenediol, 480-mg saw palmetto, 450-mg indole-3 carbinol, 300-mg chrysin, 1,500 mg gamma-linolenic acid and 1.350-mg Tribulus terrestris per day (n = 28), or placebo (n = 27) for 28 days. Subjects were stratified into age groups to represent the fourth (30 year olds, n = 20), fifth (40 year olds, n = 20) and sixth (50 year olds, n = 16) decades of life. MEASUREMENTS: Serum free testosterone, total testosterone, androstenedione, dihydrotestosterone, estradiol, prostate specific antigen and lipid concentrations were measured before supplementation and weekly for four weeks. RESULTS: Basal serum total testosterone, estradiol, and prostate specific antigen (PSA) concentrations were not different between age groups. Basal serum free testosterone concentrations were higher (p < 0.05) in the 30- (70.5 +/- 3.6 pmol/L) than in the 50 year olds (50.8 +/- 4.5 pmol/L). Basal serum androstenedione and dihydrotestosterone (DHT) concentrations were significantly higher in the 30- (for androstenedione and DHT, respectively, 10.4 +/- 0.6 nmol/L and 2198.2 +/- 166.5 pmol/L) than in the 40- (6.8 +/- 0.5 nmol/L and 1736.8 +/- 152.0 pmol/L) or 50 year olds (6.0 +/- 0.7 nmol/L and 1983.7 +/- 147.8 pmol/L). Basal serum hormone concentrations did not differ between the treatment groups. Serum concentrations of total testosterone and PSA were unchanged by supplementation. Ingestion of AND-HB resulted in increased (p < 0.05) serum androstenedione (174%), free testosterone (37%), DHT (57%) and estradiol (86%) throughout the four weeks. There was no relationship between the increases in serum free testosterone, androstenedione, DHT, or estradiol and age (r2 = 0.08, 0.03, 0.05 and 0.02, respectively). Serum HDL-C concentrations were reduced (p < 0.05) by 0.14 mmol/L in AND-HB. CONCLUSIONS: These data indicate that ingestion of androstenediol combined with herbal products does not prevent the formation of estradiol and dihydrotestosterone. PMID- 11601569 TI - Capsular contracture after cosmetic breast implant surgery in Denmark. AB - The authors investigated the association between the occurrence of capsular contracture and implant and patient characteristics. All women with breast implants from 1977 to 1997 were identified from the files of two private plastic surgery clinics in Denmark. Information on implant and patient characteristics, surgical procedure, and complications was obtained through medical records and self-administered questionnaires. Of 754 women (1,572 implants), average age at implantation was 32 years. Implant types were silicone double lumen, textured, 31.2%; silicone single lumen, textured, 27.8%; silicone single lumen, smooth, 24.5%; silicone double lumen, smooth, 0.8%; and other or missing, 15.7%. Placement was submuscular for more than 90% of implants. Capsular contracture occurred in 7.9% of implanted breasts, on an average of 621 days postoperatively, with 51.6% being bilateral. Overall, 66.1% of capsular contractures were recorded within the first 12 months postoperatively, and 79.0% were recorded within 24 months. Double-lumen implants were associated with a significantly (p < 0.01) reduced occurrence of capsular contracture. In summary, capsular contracture typically occurs within the first 2 years of implantation. Host factors may be important because more than half the capsular contractures in the current study were bilateral. Occurrence of capsular contracture did not appear to be associated with implant surface or placement, occurrence of local complications, or patient characteristics, although these findings should be interpreted cautiously. PMID- 11601570 TI - MRI for detecting silicone breast implant rupture: meta-analysis and implications. AB - The objective of this study was to assess the accuracy of magnetic resonance imaging (MRI) in detecting silicone breast implant rupture, and to explore implications of the use of MRI for screening and estimating the prevalence of rupture among asymptomatic women. The study consisted of a meta-analysis of published studies with the calculation of sensitivity and specificity as independent parameters, the summary receiver operating characteristic (ROC) curve, and other clinically important values such as positive predictive value (PPV) and negative predictive value. Participants included women with breast implants who underwent both MRI and subsequent implant removal. Eighteen studies, performed primarily in academic settings, with approximately 1,039 women and 2,036 implants met entry criteria. Most studies involved women with symptomatic implants. Assuming that sensitivity and specificity were independent parameters, the summary sensitivity was 78% (95% confidence interval [CI], 71-83) and the summary specificity was 91% (95% CI, 86-94). Using ROC meta-analysis methodology, the odds ratio describing the overall accuracy of the test was 40.1 (range, 18.8 85.4). There was substantial heterogeneity across studies. Studies using breast coils, those with convenience samples, larger studies, and studies of lower report quality tended to report higher levels of accuracy. The quality of study reports was generally poor. Among symptomatic women, PPV was fairly high. Among lower prevalence populations, PPV appeared to be insufficient to warrant use as a screening tool. MRI is moderately accurate in detecting silicone breast implant rupture. However, MRI should remain a confirmatory diagnostic test and should not be used to screen asymptomatic women. PMID- 11601571 TI - Patterns of oculomotor nerve distribution to the levator palpebrae superioris muscle, and correlation to temporary ptosis after blepharoplasty. AB - Transient diplopia, blepharoptosis, or both conditions are rare postoperative complications of blepharoplasty performed with the patient under local anesthesia. It has been hypothesized that some cases of postoperative diplopia and blepharoptosis could be attributed to the myotoxic effects of local anesthetics to the extraocular muscles and the levator muscle or to the neurotoxic effects of lidocaine. In 30 cadavers, the superior division of the oculomotor nerve was severed en bloc 1.5 cm anterior to the annulus of Zinn with the levator palpebrae superioris (LPS) and the superior rectus muscles. These muscles were detached from their origins, and their attachments to the scleral and tarsal plates were divided respectively. The specimens were treated in guanidine-hydrochloride and Alizarin Red solution, and were dissected under an operating microscope. The nerve branches of the superior division of the oculomotor nerve innervated the proximal third (type I) in 2 of 30 LPS muscles (6.7%), in 8 of 30 muscles (26.7%) extended to the middle third (type II), and reached the distal third (type III) in 20 of 30 muscles (66.7%). The terminal branches ran through the medial third (type IIIa) in 6 of 20 type III LPS muscles (30%), the central third (type IIIb) in 8 muscles(40%), and the lateral third (type IIIc) in 6 muscles (30%). The oculomotor nerve ends that extend forward to the distal third of the LPS muscle (type III) are exposed and vulnerable to local anesthetics and may be numbed during blepharoplasty. If this is so, postoperative blepharoptosis may be caused by transient paralysis of the LPS muscle, and great care should be taken during the injection of local anesthetics near the LPS. PMID- 11601572 TI - Simplifying microvascular head and neck reconstruction: a rational approach to donor site selection. AB - The purpose of this study was to review the authors' 13-year experience with free tissue transfer for head and neck oncology patients. This study was a retrospective review of 728 free flaps performed in 698 patients. Recipient sites were subdivided by region into the mandible (N = 253), mid face/orbit (N = 190), hypopharynx (N = 134), oral cavity (N = 104), skull base (N = 36), and scalp (N = 11). The overall free flap success rate was 98.6%. Seventy-nine flaps (10.9%) were reexplored for vascular compromise. Ten flaps (1.4%) were lost in their entirety. The overall complication rate was 17.5%. Four donor sites (forearm, fibula, rectus, and jejunum) were used for 92% of the patients. The results of the study confirm the efficacy of free tissue transfer in the reconstruction of oncological head and neck defects. In this series the free forearm, fibula, rectus, and jejunum flaps have become the workhorse donor sites for the vast majority of defects. PMID- 11601573 TI - Supercharged gastric tube pull-up procedure for total esophageal reconstruction. AB - Total esophageal reconstruction using a gastric tube is complicated because it sometimes causes postoperative complications such as anastomotic leakage, stenosis, or fistula formation resulting from insufficient blood flow at the distal end. To overcome this problem, during the past 5 years the authors performed seven additional microvascular anastomoses using the short gastric vessels of the gastric tube. No postoperative complications occurred except partial tracheal necrosis in 1 patient. Postoperative radiographic examination showed no reflux or stasis in all patients, and no evidence of necrosis at the anastomotic site of the pulled-up gastric tube was observed by postoperative endoscopy. This technique reduces risk and may contribute to the successful reconstruction of the digestive tract after total esophagectomy. PMID- 11601574 TI - Management of radiated reoperative wounds of the cervicothoracic spine: the role of the trapezius turnover flap. AB - Reoperation for malignant disease of the cervicothoracic spine can lead to compromised wound healing secondary to poor tissue quality from previous operations, heavily irradiated beds, and concomitant steroid therapy. Other complicating factors include exposed dura and spinal implants. Introducing well vascularized soft tissue to obliterate dead space is critical to reliable wound healing. The purpose of this study was to determine the efficacy of the trapezius turnover flap in the management of these complex wounds. This study is a retrospective review of all patients undergoing trapezius muscle turnover flaps for closure of complex cervicothoracic wounds after spinal operations for metastatic or primary tumors. Six patients (3 male/3 female) were operated over an 18-month period (mean patient age, 43 years). Primary pathologies included radiation-induced peripheral nerve sheath tumor (N = 2), chondrosarcoma (N = 1), nonsmall-cell lung cancer (N = 1), paraganglioma (N = 1), and spindle cell sarcoma (N = 1). Trapezius muscle turnover flaps were unilateral and based on the transverse cervical artery in every patient. Indication for flap closure included inability to perform primary layered closure (N = 3), open wound with infection (N = 2), and exposed hardware (N = 1). All patients had previous operations of the cervicothoracic spine (mean, 5.8 months; range 2-9 months) for malignant disease and prior radiation therapy. Exposed dura was present in all patients, and 2 patients had dural repairs with bovine pericardial patches. Spinal stabilization hardware was present in 4 patients. All patients underwent perioperative treatment with systemic corticosteroids. All flaps survived, and primary wound healing was achieved in each patient. The only wound complication was a malignant pleural effusion communicating with the back wound, which was controlled with a closed suction drain. All wounds remained healed during the follow-up period. Four patients died from progression of disease within 10 months of surgery. The trapezius turnover flap has been used successfully when local tissue conditions prevent primary closure, or in the setting of open, infected wounds with exposed dura and hardware. The ease of flap elevation and minimal donor site morbidity make it a useful, single-stage reconstructive option in these difficult wounds. PMID- 11601575 TI - Tattoo removal by grafting enzymatically separated epidermis. AB - A novel method of tattoo removal in which the enzymatically separated epidermis of an excised tattoo was grafted in situ was applied to 3 patients. Unlike the conventional skin-grafting procedure, this method resulted in the complete obliteration of the tattoos without donor site scars. In 1990, Hosokawa and colleagues first reported a technique similar to the one described, but the enzymatic process required surgery to be performed over two consecutive days and, thus, it did not become an established procedure. A modification of Hosokawa's method enabled the authors to reduce the enzymatic processing time to an hour using Dispase. The thinning of the tattooed skin using a Paget's-type dermatome before its exposure to an enzymatic solution facilitated the enzyme's infiltration of the basal layer of the epidermis. Hence, the time taken for the epidermis to separate from the tattooed skin was markedly shortened. Although laser removal continues to be the optimal treatment method, skin grafting or other abrasive procedures, including dermabrasion and cryosurgery, are still necessary for those patients who want complete tattoo obliteration over a shorter time frame and at less expense. In these patients the authors recommend that their procedure be offered as an alternative treatment to laser removal. PMID- 11601576 TI - Hair removal by long-pulse alexandrite laser in oriental patients. AB - The laser depilation system, cleared by the Food and Drug Administration since 1995, is evolving rapidly. However, the parameters in the hair removal function of these devices emphasize use for white people with fair skin (Fitzpatrick types I, II, or III). The characteristics of oriental skin and hair are black, coarse hairs in darker skin (Fitzpatrick types IV or V). As seen, the higher the skin melanin content, the more difficult to remove hair by laser. The authors report 146 oriental patients (156 body sites) who underwent treatment with the long pulse alexandrite laser (wavelength, 755 nm) depilation system since November 1997. Percentage of hair removal (clearance rate) was assessed, and the histological change from laser pulse damage was observed. After two treatments, the clearance rates in the axillae and the leg were 61% and 62% respectively in the 15 to 20-J group (N = 47), and were 66% and 67% respectively in 21 to 25-J group (N = 64). After five treatments, 59 patients (37 axillae and 22 legs, all of which received 21-25 J per square centimeter of laser energy treatment during the course) had an average clearance rate of 91% (axillae) and 86% (leg), and the clearance rates have been maintained near 90% after long-term follow-up (average follow-up, 17 months). Minimal and transient complications are noted. In conclusion, using a combination of longer wavelength (but still in the optimal window of 630-870 nm), long pulse duration (10-40 msec), high fluence (but limited up to 25 J per square centimeter), multiple treatments, and concomitant direct cooling applied to the skin of oriental patients (Fitzpatrick types IV and V) with black, moderately coarse hair shafts achieves satisfying long-term hair removal results. PMID- 11601577 TI - The effect of gradually increased blood flow on ischemia-reperfusion injury. AB - Even with excellent operative techniques, prolonged ischemic periods may cause unwanted results because of a complex mechanism called reperfusion injury. Various pharmacological and immunological agents have been used to prevent this type of injury. Another known way to diminish reperfusion injury is the gradual reperfusion of the ischemic tissues. In this study, the effect of a gradual increase in blood flow on ischemia-reperfusion injury of the skeletal muscle was investigated. The right hind limbs of 15 rats were partially amputated, leaving the femoral vessels intact. Preischemic femoral arterial blood flow was measured by using a transonic small-animal blood flowmeter (T106) in all animals. The rats were divided into three groups: Group I consisted of control rats; no ischemia was induced. Group II was the conventional clamp release group. Clamps were applied to the femoral vessels to induce 150 minutes of ischemia. The clamps were then released immediately and postischemic blood flow was measured. Group III was the gradual clamp release group. After 150 minutes of ischemia, clamps were released gradually at a rate so that the blood flow velocity would reach one fourth the mean preischemic value at 30 seconds, one half at 60 seconds, three fourths at 90 seconds, and would reach its preischemic value at 120 seconds. Total clamp release was allowed when blood flow was less than 1.5 fold of the preischemic values. Postoperatively the soleus muscles were evaluated histopathologically, and malonyldialdehyde and myeloperoxidase levels were measured. The mean preischemic blood flow was 13.6 +/- 2.24 ml per kilogram per minute in all groups. In the conventional release group, postischemic flow reached four to five fold its preischemic values (61.06 ml per kilogram per minute). Histopathology revealed more tissue damage in the conventional release group. Malondialdehyde and myeloperoxidase levels were also significantly lower in the gradual release group. Depending on histological and biochemical findings, a gradual increase in blood flow was demonstrated to reduce the intensity of ischemia-reperfusion injury in the soleus muscle of this animal model. PMID- 11601578 TI - The ontogeny of scarless healing II: EGF and PDGF-B gene expression in fetal rat skin and fibroblasts as a function of gestational age. AB - Twenty years ago, surgeons noted the ability of early-gestation fetal skin to heal in a scarless manner. Since that time, numerous investigators have attempted to elucidate the mechanisms behind this phenomenon. As a result of this effort, it is now well established that many animals undergo a transition late in development from scarless cutaneous healing to a scar-forming, adultlike phenotype. The authors have been interested in the role played by cytokines known to be involved in the adult wound-healing process and how they relate to scarless repair. They therefore asked the following question: Are genes for epidermal growth factor (EGF) and platelet-derived growth factor-B (PDGF-B) expressed differentially as a function of gestational age in fetal rat skin and dermal fibroblasts? To answer this question, skin from fetal Sprague-Dawley rats (N = 56) at time points that represented both the scarless and scar-forming periods of rat gestation was harvested. In addition, fibroblasts derived from fetal rat skin were cultured in vitro at similar times. These cells were expanded in culture and, when confluent, total ribonucleic acid from both fibroblasts and whole skin was extracted and subjected to Northern blot analysis with probes for EGF and PDGF-B. Results demonstrated that neither EGF nor PDGF-B gene expression changed markedly as a function of gestational age in fetal fibroblasts alone. In whole skin, however, both EGF and PDGF-B demonstrated a marked decrease in gene expression with increasing gestational age. Furthermore, the most striking decrease in gene expression for both cytokines came between 16 and 18 days of gestation-the transition point between scarless and scar-forming repair in the fetal rat. These data suggest that EGF and PDGF may play a role in the mechanism of scarless cutaneous repair. Moreover, it appears that fetal fibroblasts are not the cell type responsible for this differential gene expression. These results raise questions about the unique cytokine milieu likely to be present during the time of scarless healing and the cells that ultimately guide the mechanisms leading to skin regeneration. PMID- 11601579 TI - Molecular response to ischemia-reperfusion of rat skin: study of expression of p53, p21WAF-1, and Bax proteins, and apoptosis. AB - The authors investigated the expression of p53, p21WAF-1, and Bax proteins, and apoptosis to elucidate the cellular response to ischemia-reperfusion of the skin. The rat left lower limb was dissected at the inguinal region retaining the bone and femoral vessels, and the vessels were clamped to produce an ischemic condition. After 6 hours the clamps were removed, and the plantar skin was resected at various times up to 72 hours after reperfusion. Five skin specimens were obtained at each time point from 5 rats. When a rat died during the study, additional rats were used until five specimens could be obtained from 5 rats at each time point. The expression of the three proteins was detected by Western blot analysis. The apoptotic cells were detected using the terminal deoxytransferase-mediated dUDP nick-end labeling assay. After reperfusion, the levels of p53 and p21WAF-1 were significantly higher in the ischemia-reperfusion rats compared with the sham-operated rats. However, the levels of Bax protein did not show a noticeable increase at any period. The apoptotic cells in both the epidermis and dermis were not evident compared with the sham skin, which were similar to those in the nontreated, normal skin. These results demonstrate that p53 and p21WAF-1 proteins accumulate after 6 hours of ischemia of the skin during reperfusion. Moreover, it is speculated that accumulation of these proteins plays an important role in the survival of the skin by inducing growth arrest of the cells, but not apoptosis. PMID- 11601580 TI - A case study of a patient with closed avulsion rupture of a single slip of the flexor digitorum superficialis tendon. AB - A case of a closed rupture of a single slip of flexor digitorum superficialis to the little finger is described. Closed rupture injuries of the flexor digitorum profundus tendon are quite common, but closed injuries to the superficialis tendon have been rarely reported. A single slip avulsion rupture of this tendon would seem to be very uncommon. The clinical presentation is reviewed. PMID- 11601581 TI - Preexisting gastric carcinoid in a gastro-omental free flap. AB - The authors present a 72-year-old man with an extensive medical history including stage III squamous cell carcinoma of the right pyriform sinus diagnosed approximately 10 years before this report. They were asked to evaluate the patient for esophageal reconstruction after local radiation had led to benign stricture of his esophagus and subsequent development of a large, draining esophagocutaneous fistula. A gastro-omental free flap reconstruction of the esophagus and overlying skin defect was complicated by the intraoperative diagnosis of gastric carcinoid obtained from several polyps noticed on the gastric mucosa on routine inspection. This case report signifies the importance of close inspection of all free tissue transfers before interposition. Failure to do so could result in disastrous outcomes. PMID- 11601582 TI - Primary one-stage reconstruction of cheek defect after a shotgun blast to the face: use of the latissimus dorsi musculocutaneous free flap for soft-tissue repair and facial reanimation. AB - The authors describe a case of a shotgun blast injury to the face in which early definitive repair of both facial soft tissues and facial reanimation was accomplished in one stage using a free flap. The trauma occurred 2 days before presentation via a hunting rifle fired at a short range. On examination, a 8 x 5 cm cheek defect was evident, involving the full thickness of the perioral facial mimetic muscles as well. A free latissimus dorsi musculocutaneous flap was transferred to the defect, with the thoracodorsal nerve coapted to an ipsilateral, severed buccal branch of the facial nerve. Postoperatively, the flap survived completely, with its skin paddle excised subsequently in two stages. Good muscle movement was obtained, providing resting symmetry and a pleasant smile. Other than soft-tissue and bony defects resulting from shotgun injuries, ablation of the facial nerve or facial mimetic muscles may be an important component of the defect that needs further consideration. The authors conclude that the current technique of one-stage, early definitive repair of soft tissues and facial reanimation in such cases of facial shotgun blast injury offers the advantages of achieving both goals with one flap and accomplishing the procedure primarily in one stage. PMID- 11601583 TI - A new contralateral split-breast flap for breast reconstruction and its salvage after complication: an alternative for select patients. AB - Different approaches to breast reconstruction have been described and nowadays nearly optimized. One major aim in further developments is to reduce donor site morbidity as low as possible. Theoretically, the lowest donor site morbidity could be achieved by using tissue that would be normally discarded during an operation necessary for a different reason. The authors present a new method of breast reconstruction in a mastectomy patient who needed a reduction mammaplasty on the remaining side in addition to the reconstruction. A single-stage split breast flap from the reduced contralateral side pedicled on its internal mammary perforators was used, thus lowering donor site morbidity by using otherwise discarded tissue. The technical details, patient selection, advantages, possible pitfalls, management of complications, and the risk factors for contralateral malignancy are discussed. PMID- 11601584 TI - Cephalic vein-pedicled arterialized anteromedial arm venous flap for head and neck reconstruction. AB - The authors describe a case of transfer of an arterialized cephalic venous flap from the anteromedial arm region to the neck with the cranial limb of the cephalic vein serving as the drainage vein and a pedicle. The burn scar contracture of a 45-year-old man was released and repaired with a venous flap based on the cephalic vein in the anteromedial arm. After dissection of the cranial end of the cephalic vein as a drainage vein in the deltopectoral groove, until the flap could be transposed easily to the neck defect pedicled on the dissected cranial limb of the cephalic vein, the flap was arterialized by anastomosing the caudal end of the cephalic vein to a recipient artery in the neck The donor defect was skin grafted and the flap survived completely. The neck contracture improved substantially. PMID- 11601585 TI - Possibility of venous return through bone marrow in the free fibular osteocutaneous flap. AB - The authors report a case of a free fibular graft that was successful as a result of venous return delivered through the bone marrow. A 26-year-old man underwent reconstruction of the left tibia and a soft-tissue defect of the lower leg. A free vascularized fibular bone and skin flap was elevated. The fibular vessels were anastomosed to the dorsalis pedis vessels. The elevated fibular bone was fixed to the tibia. The next day, reanastomosis was necessary because of venous thrombosis. However, the fibular vein rethrombosed, but blood flow was ascertained by Doppler flowmetry, with darker blood flow being recognized from the edge of the flap. Four days after surgery, the skin color gradually improved, and the flap had almost completely taken. On retrospective evaluation, the authors concluded that this flap succeeded because venous return was routed through the bone marrow in the free fibular graft. PMID- 11601586 TI - Coverage of a thumb wound and correction of a first web space contracture using a longitudinally split reverse radial forearm flap. AB - The authors describe a new design for a reverse-flow radial forearm flap. A total thumb amputation by severe avulsion was salvaged by microsurgical replantation and a reverse-flow radial forearm flap with a modified design to allow repair of two separate hand defects concomitantly. This newly described flap design for the reverse radial forearm flap offers a refined technique for simultaneous reconstruction of multiple defects in the hand. PMID- 11601587 TI - A modified technique of using the tongue tip for closure of large anterior palatal fistula. AB - Anteriorly based dorsal tongue flaps are the most commonly used flaps for closure of difficult palatal fistulae. The author presents a patient in whom the palatal defect was thought to be too big to be closed by the standard tongue flap. The tongue tip was divided into equal dorsal and ventral flaps, and both flaps were used to reconstruct the palatal defect. Technical considerations, and advantages and disadvantages of the procedure are discussed. PMID- 11601588 TI - Sensate sole-to-sole reconstruction using the combined medial plantar and medialis pedis free flap. AB - The coverage of soft-tissue defects of the sole needs special consideration because of the forces of weight bearing on the reconstruction. A variety of free tissue transfers have been advocated for soft-tissue replacement of the weight bearing portions. However, there is no doubt that the ideal tissue for resurfacing the sole is the plantar tissue itself. The authors present a case of reconstructing the sole with the combined medial plantar and medialis pedis free flap that involves approximately 70% of the weight-bearing portion. This contralateral, combined fasciocutaneous free flap based on the posterior tibial medial plantar vascular system is a good alternative in covering extensive sole injuries. PMID- 11601589 TI - Severe wrist contracture in a child with linear scleroderma. AB - Linear scleroderma is an unusual disorder characterized by linear streaks of fibrotic skin involvement, which can lead to severe limb deformities and contractures. The authors present a case of severe wrist contracture in a child with linear scleroderma treated by release of the contracture with coverage of the exposed carpus with an abductor digiti minimi flap and skin graft. Reports of successful treatment of extremity deformities are rare. At 1 year this correction appears to have been successful. PMID- 11601590 TI - A new method of conveying the pedicle through a subcutaneous tunnel in free flap surgery. PMID- 11601591 TI - A new swing of the atasoy volar V-Y flap. PMID- 11601592 TI - Correction of cryptotia using full-thickness skin grafts. PMID- 11601593 TI - Double auricle? PMID- 11601594 TI - The Trauma Symptom Checklist for Young Children (TSCYC): reliability and association with abuse exposure in a multi-site study. AB - OBJECTIVE: The Trauma Symptom Checklist for Young Children (TSCYC) is a 90-item caretaker-report measure of children's trauma- and abuse-related symptomatology. It contains two reporter validity scales and eight clinical scales [Post traumatic Stress-Intrusion (PTS-I), Post-traumatic Stress-Avoidance (PTS-AV), Post-traumatic Stress-Arousal (PTS-AR), Post-traumatic Stress-Total (PTS-TOT), Sexual Concerns (SC), Dissociation (DIS), Anxiety (ANX), Depression (DEP), and Anger/Aggression (ANG)], as well as an item assessing hours per week of caretaker contact with the child. This paper introduces the TSCYC and describes its psychometric properties in a multisite validity study. METHOD: A total of 219 TSCYCs administered by six clinician/researchers across the United States were analyzed for scale reliability and association with several types of childhood maltreatment. RESULTS: The TSCYC clinical scales have good reliability and are associated with exposure to childhood sexual abuse, physical abuse, and witnessing domestic violence. The PTS-I, PTS-AV, PTS-AR, and PTS-TOT scales were most predictive, followed by SC in the case of sexual abuse and DIS in the case of physical abuse. There were a small number of age, sex, and race effects on TSCYC scores. CONCLUSIONS: The TSCYC appears to have reasonable psychometric characteristics, and correlates as expected with various types of trauma exposure. Subject to continued validation and the development of general population norms, its use as a clinical measure is supported. PMID- 11601595 TI - Evaluations, attributions, affect, and disciplinary choices in mothers at high and low risk for child physical abuse. AB - OBJECTIVE: The present study investigated several components of a social information-processing model of child physical abuse. The main objective was to examine the extent to which high-risk, relative to low-risk, mothers differed in their evaluations, attributions, negative affect, and disciplinary choices for children's behavior, and to explore whether these differences may be expressed in interactions between risk status and mitigating information. METHOD: Nineteen high- and 19 matched low-risk mothers' evaluations of children transgressions, attributions, affect, and choices of disciplinary techniques were examined using six vignettes depicting a child engaging in moral, conventional, and personal transgressions. One-half of the vignettes contained mitigating information and one-half did not. High- and low-risk mothers were chosen based on their potential for physical child abuse. A three-factor (2 x 3 x 2) design was used to assess the dependent variables. RESULTS: As expected, high-risk, relative to low-risk, mothers reported more hostile intent, stable and global attributions, aversiveness, annoyance, and use of power-assertion discipline. A risk group by type of transgression interaction was found for evaluation and indifference and a risk group by mitigating information interaction was found for evaluation of wrongness, internal attributions, and aversiveness. A risk by type of transgression by mitigating information interaction was found for global/specific attributions, aversiveness, and indifference toward child transgressions. CONCLUSIONS: Results support a social information processing model of child physical abuse, which suggests that high-risk, compared to low-risk, mothers process child-related information differently and use more power-assertive disciplinary techniques. PMID- 11601596 TI - Gender differences in the risk for delinquency among youth exposed to family violence. AB - OBJECTIVE: The purpose of this research was to illuminate gender differences in adolescent delinquency against a backdrop of childhood exposure to both marital violence and physical child abuse. Specifically, analyses were performed to trace the unique effects of exposure to either form of family violence (marital or child) on the violent and nonviolent delinquency of boys and girls. METHOD: This is a prospective study of 299 children who were interviewed with their mothers in 1991 about forms of abuse in the family. Approximately 5 years later a search of juvenile court records was performed for these same children. Details on the nature of the crimes were collected. Outcome variables included: (1) whether there was ever an arrest; and (2) whether there was ever an arrest for a violent crime. RESULTS: Preliminary analyses indicated no gender differences in overall referral rates to juvenile court, although boys were more likely than girls to be referred for property, felony, and violent offenses. Exposure to marital violence in childhood predicted referral to juvenile court. Girls with a history of physical child abuse were arrested for violent offenses more than boys with similar histories, but the context of violent offenses differed dramatically by gender: Nearly all referrals for a violent offense for girls were for domestic violence. CONCLUSIONS: Although boys and girls share similar family risk factors for delinquency, girls are more likely than boys to be arrested for violent offenses in the aftermath of child physical abuse. These findings suggest that it takes more severe abuse to prompt violence in girls than is necessary to explain boys' violent offending. PMID- 11601597 TI - Stability of retrospective self-reports of child abuse and neglect before and after therapy for child abuse issues. AB - OBJECTIVE: This study is a follow-up to a previously reported outcome study evaluating the efficacy of an emotionally focused therapy for adult survivors of childhood abuse. The present purpose was to evaluate the stability of self reports of child maltreatment in the context of reduced psychopathology after therapy. The Childhood Trauma Questionnaire (CTQ; Bernstein et al., 1994) was used to measure the extent of child abuse and neglect. METHOD: The CTQ and measures of symptomatology, abuse resolution, and self-esteem were administered at pretreatment to 44 clients and after 6 months of therapy to 33 therapy completers. Post-treatment interviews also assessed changes in clients' perceptions of self and abusive and neglectful others. Analyses examined change on dependent measures, in interviews, and on the CTQ, as well as the test-retest and alpha reliabilities of CTQ factor scales, and the relationship of CTQ factor scales with pretreatment measures of distress. RESULTS: Analyses revealed significant reductions in psychopathology on all dependent measures and reduced self-blame, negatively biased memories, avoidance, and minimization of the abuse after therapy. Reports of abuse and physical neglect on the CTQ remained stable from pre- to post-therapy. All CTQ dimensions demonstrated good internal consistency and convergent validity with trauma-specific measures of distress. CONCLUSIONS: The stability of the CTQ in the context of significantly reduced psychopathology contributes to evidence supporting the accuracy of retrospective self-reports of childhood abuse. PMID- 11601598 TI - Childhood victimization and alcohol symptoms in females: causal inferences and hypothesized mediators. AB - OBJECTIVE: Previous research has reported a relationship between childhood victimization experiences and alcohol problems in females. This paper has two distinct goals: (1) to determine whether it is appropriate to make a causal inference regarding the association between early child abuse and neglect and alcohol symptoms in females; and (2) to examine five potential mechanisms (depression, worthlessness, social isolation/loneliness, low self esteem, and using alcohol and/or drugs to cope) that may mediate the relationship between child abuse and neglect and alcohol symptomatology. METHOD: Substantiated cases of child abuse and neglect from 1967 to 1971 were matched on sex, age, race, and approximate social class with nonabused and non-neglected children and followed prospectively into young adulthood. Subjects were administered a 2-h in-person interview, including the NIMH Diagnostic Interview Schedule (DIS-III-R) to assess alcohol use and abuse. Analyses are restricted to females in the sample (N = 582). RESULTS: Structural equation modeling provides support for the inference that childhood victimization plays a causal role in the development of alcohol symptoms in women. There also is support for the hypothesized mediating role of two mechanisms (depression and using alcohol/drugs to cope), but not for the other mediators. CONCLUSIONS: Evidence from this prospective study suggests that childhood victimization may be one of the causal factors in the development of alcohol problems in females. Interventions should bedirected at abused and neglected females of all ages to help them to deal with depression and to develop coping strategies to prevent the development of serious alcohol problems. PMID- 11601599 TI - Maltreatment perpetrators: a 54-month analysis of recidivism. AB - OBJECTIVE: This study compared recidivism rates for alleged maltreatment perpetrators whose initial report was substantiated and those whose initial report was not substantiated, to determine whether they returned to the child welfare system at differing rates. METHOD: Statewide administrative child welfare services data over a period of 4 1/2 years was analyzed. The sample included 31,531 perpetrators of intrafamilial maltreatment. Separate analyses were conducted for each type of maltreatment (sexual abuse, physical abuse, and neglect). RESULTS: Bivariate relationships (substantiation status and recidivism) were analyzed using survival curves, and the study found that recidivism patterns differed by type of maltreatment and by substantiation status at the index event. Multivariate analyses using Cox Proportional Hazards models found that bivariate relationships held true even when controlling for neighborhood mean income, ethnicity, and gender. CONCLUSIONS: The study's finding that perpetrators whose index event was not substantiated return to the child welfare system at a high rate suggests the need to learn how to discriminate those unsubstantiated alleged perpetrators who are most at risk for recidivism. The finding of frequent cross type recidivism indicates that intervention should focus on common themes across maltreatment types. PMID- 11601600 TI - The relationship between the transverse hymenal orifice diameter by the separation technique and other possible markers of sexual abuse. AB - OBJECTIVE: To evaluate the relationship between the transverse hymenal orifice diameter as measured by separation technique (THODST), using a method that maximized the diameter of the hymenal orifice, and other possible markers of sexual abuse in girls from 3 through 12 years old. METHODS: Over a 10-year period, clinical information was recorded on girls referred to the WakeMed Child Sexual Abuse Team in Raleigh, NC at the time of examination. The study population comprised 1975 girls of the 2058 evaluated for sexual abuse. The girls were interviewed, examined, and tested for sexually transmitted diseases. Information from referral sources, accompanying guardians, and previous recent physical examinations was recorded. The girls were assigned to three groups based upon their risk of being sexually abused. Linear regression was performed to evaluate how well the THODST distinguished between the risk groups, as well as how it was correlated with individual established markers of sexual abuse. RESULTS: The size of the THODST did not distinguish between the three risk groups, nor did it correlate with any potential or established markers of sexual abuse other than three potential markers of hymenal trauma: narrowing of the posterior hymenal rim, hymenal tears and lacerations, and hymenal clefts between 5 and 7 o'clock in the supine position. CONCLUSION: Thus, we found the THODST as we measured it to have no value for answering the question, "Was this child sexually abused?" PMID- 11601601 TI - Confirmed, unconfirmed, and false allegations of abuse made by adults with mental retardation who are members of a class action lawsuit. AB - OBJECTIVE: The purpose is to explore differences in confirmed, unconfirmed, and false allegations of abuse made by consumers with mental retardation in regards to type of abuse and perpetrator. METHOD: Interviews were conducted with 1,220 people with mental retardation who were part of a class action lawsuit in North Carolina. A content analysis of abuse allegations was performed. Frequencies of responses and subgroup differences are reported for type of abuse allegation and perpetrator. RESULTS: Unconfirmed claims are the most frequent. Females made more allegations of abuse than males in general, and more allegations of rape. There are no significant differences among the subgroups (confirmed, unconfirmed, and false allegations) by type of abuse allegation. There are significant differences among the subgroups in regard to the alleged perpetrator. Other consumers with mental retardation are most frequently accused of confirmed assaults. Staff members are most frequently accused in false allegations. CONCLUSION: Ability of the alleged victim to report information and timing of the investigation are important factors in substantiating abuse. Awareness of consumer-to-consumer violence and prevalence of false accusations against staff necessitates increased safeguards for both consumers and staff. PMID- 11601602 TI - Chronic pain: the next frontier in child maltreatment research. PMID- 11601603 TI - The use of micro-organisms for L-ascorbic acid production: current status and future perspectives. AB - L-Ascorbic acid (L-AA) has been industrially produced for around 60 years in a primarily chemical process utilising D-glucose (D-glc) as starting material. Current world production is estimated at approximately 80,000 tonnes per annum with a worldwide market in excess of U.S. $600 million. We present a brief overview of research geared to exploiting micro-organisms for the industrial production of vitamin C, with emphasis on recent approaches using genetically engineered bacterial strains. We also discuss the potential for direct production of L-AA exploiting novel biochemical pathways with particular reference to yeast fermentations. The potential advantages of these novel approaches over current chemical and biotechnological processes are outlined. PMID- 11601604 TI - The potential of genetic engineering for improving brewing, wine-making and baking yeasts. AB - The end of the twentieth century was marked by major advances in life technology, particularly in areas related to genetics and more recently genomics. Considerable progress was made in the development of genetically improved yeast strains for the wine, brewing and baking industries. In the last decade, recombinant DNA technology widened the possibilities for introducing new properties. The most remarkable advances, which are discussed in this Mini Review, are improved process performance, off-flavor elimination, increased formation of by-products, improved hygienic properties or extension of substrate utilization. Although the introduction of this technology into traditional industries is currently limited by public perception, the number of potential applications of genetically modified industrial yeast is likely to increase in the coming years, as our knowledge derived from genomic analyses increases. PMID- 11601605 TI - Mating-type genes for classical strain improvements of ascomycetes. AB - The ability to mate fungi in the laboratory is a valuable tool for genetic analysis and for classical strain improvement. In ascomycetous fungi, mating typically occurs between morphologically identical partners that are distinguished by their mating type. In most cases, the single mating-type locus conferring mating behavior consists of dissimilar DNA sequences (idiomorphs) in the mating partners. All ascomycete mating-type idiomorphs encode proteins with confirmed or putative DNA-binding motifs. These proteins control, as master regulatory transcription factors, pathways of cell speciation and sexual morphogenesis. Mating-type organization of four of the six classes of ascomycetes has been studied at the molecular level over the past 20 years. This review gives a short overview of the structural organization of the mating-type loci of yeasts and filamentous ascomycetes. In addition, this review describes how the availability of mating-type sequences allows the investigation of key issues concerning genetic and phylogenetic analyses of fungal species. PMID- 11601606 TI - Mating-type genes for basidiomycete strain improvement in mushroom farming. AB - Mushroom production is dependent on the quality of the spawn used to inoculate the cultures. In order to produce high-quality spawn, breeding programs for strains resistant to certain diseases and able to form high-quality fruit bodies under standard growth conditions are necessary. The investigation of the molecular basis for mating provides access to the use of mating-type genes in order to facilitate breeding. For research purposes, two mushroom-forming homobasidiomycetes have been used due to their easy cultivation and sexual propagation on defined minimal media: Schizophyllum commune and Coprinus cinereus. The mating-type genes control formation of the dikaryon from two haploid strains. Only the dikaryon is fertile and able to form mushrooms under the right environmental conditions. These genes are now used in mating-type assisted breeding programs for economically important mushrooms, especially the white button mushroom, Agaricus bisporus, and the oyster mushroom, Pleurotus ostreatus, aiming at high-yield and high-quality standard mushroom production. Most mushroom species posses two mating-type loci that control their breeding. The genes encoded in the A loci lead to the formation of transcription factors that belong to the class of homeodomain proteins. Active transcription factors are formed by heterodimerization of two proteins of different allelic specificities. In nature, this is only the case if two cells of different mating type have fused to combine the different proteins in one cytoplasm. While fusion in homobasidiomycetes is found irrespectively of mating type, exchange of nuclei between mating mycelia is dependent on the products of the B mating-type loci. The B genes form a pheromone and receptor system that enables the fungi to initiate nuclear migration. The molecular details of the two genetic systems controlling breeding in basidiomycetes are presented in this review. PMID- 11601607 TI - A system of categorizing enzyme-cell wall associations in Agaricus bisporus, using operational criteria. AB - Enzymes were investigated for their occurrence in the cell wall fraction (4,000 g sediment of the homogenate) of Agaricus bisporus sporocarps. Besides the markers malate dehydrogenase (MalDH), hexokinase (HK) and ATPase, the range of entities studied included gamma-glutamyl transferase (gamma-GT), mannitol dehydrogenase (MDH), phenoloxidase, chitin and beta-1,3-glucan synthases (ChS, beta-GS), chitinase, beta-N-acetylhexosaminidase (HexNAc'ase) and beta-glucanase. Using the extractability in dilute buffer, digitonin and NaCl at high ionic strength as the operational criteria, four categories (I-IV) of enzyme-wall associations could be discerned: category I encompasses enzymes which are artefactually present (i.e. contaminants); category II, enzymes that are hydrophobically bound (which may or may not be genuinely wall-associated), III includes enzymes that are ionically bound and IV, enzymes whose bonding to the wall is in all probability covalent. The same enzyme entity may have representatives in more than one category, e.g. ChS and beta-GS (I, II, IV), phenolase (I, II, III, IV), beta-glucanase, chitinase and HexNAc'ase (I, IV). It is thought that the categorization presented could be of general applicability in fungi as well as in higher plants to specify enzyme-wall associations in a straightforward, comparable manner, thus avoiding some of the ambiguous terms prevailing in the literature, such as "weakly", "strongly" or "tightly" wall bound. The results are discussed in more detail for several of the more economically important enzymes studied. PMID- 11601608 TI - Mass production of entomopathogenic nematodes for plant protection. AB - Entomopathogenic nematodes of the genera Heterorhabditis and Steinernema are commercially used to control pest insects. They are symbiotically associated with bacteria of the genera Photorhabdus and Xenorhabdus, respectively, which are the major food source for the nematodes. The biology of the nematode-bacterium complex is described, a historical review of the development of in vitro cultivation techniques is given and the current use in agriculture is summarised. Cultures of the complex are pre-incubated with the symbiotic bacteria before the nematodes are inoculated. Whereas the inoculum preparation and preservation of bacterial stocks follow standard rules, nematodes need special treatment. Media development is mainly directed towards cost reduction, as the bacteria are able to metabolise a variety of protein sources to provide optimal conditions for nematode reproduction. The process technology is described, discussing the influence of bioreactor design and process parameters required to obtain high nematode yields. As two organisms are grown in one vessel and one of them is a multicellular organism, the population dynamics and symbiotic interactions need to be understood in order to improve process management. Major problems can originate from the delayed or slow development of the nematode inoculum and from phase variants of the symbiotic bacteria that have negative effects on nematode development and reproduction. Recent scientific progress has helped to understand the biological and technical parameters that influence the process, thus enabling transfer to an industrial scale. As a consequence, costs for nematode-based products could be significantly reduced. PMID- 11601610 TI - Biodegradation and bioremediation of hydrocarbons in extreme environments. AB - Many hydrocarbon-contaminated environments are characterized by low or elevated temperatures, acidic or alkaline pH, high salt concentrations, or high pressure, Hydrocarbon-degrading microorganisms, adapted to grow and thrive in these environments, play an important role in the biological treatment of polluted extreme habitats. The biodegradation (transformation or mineralization) of a wide range of hydrocarbons, including aliphatic, aromatic, halogenated and nitrated compounds, has been shown to occur in various extreme habitats. The biodegradation of many components of petroleum hydrocarbons has been reported in a variety of terrestrial and marine cold ecosystems. Cold-adapted hydrocarbon degraders are also useful for wastewater treatment. The use of thermophiles for biodegradation of hydrocarbons with low water solubility is of interest, as solubility and thus bioavailability, are enhanced at elevated temperatures. Thermophiles, predominantly bacilli, possess a substantial potential for the degradation of environmental pollutants, including all major classes. Indigenous thermophilic hydrocarbon degraders are of special significance for the bioremediation of oil-polluted desert soil. Some studies have investigated composting as a bioremediation process. Hydrocarbon biodegradation in the presence of high salt concentrations is of interest for the bioremediation of oil polluted salt marshes and industrial wastewaters, contaminated with aromatic hydrocarbons or with chlorinated hydrocarbons. Our knowledge of the biodegradation potential of acidophilic, alkaliphilic, or barophilic microorganisms is limited. PMID- 11601609 TI - The cellulosome and cellulose degradation by anaerobic bacteria. AB - Despite its simple chemical composition, cellulose exists in a number of crystalline and amorphous topologies. Its insolubility and heterogeneity makes native cellulose a recalcitrant substrate for enzymatic hydrolysis. Microorganisms meet this challenge with the aid of a multi-enzyme system. Aerobic bacteria produce numerous individual, extra-cellular enzymes with binding modules for different cellulose conformations. Specific enzymes act in synergy to elicit effective hydrolysis. In contrast, anaerobic bacteria possess a unique extracellular multi-enzyme complex, called cellulosome. Up to 11 different enzymes are aligned on the non-catalytic scaffolding protein and thus ensure a high local concentration, together with the correct ratio and order of the components. These multi-enzyme complexes attach both to the cell envelope and to the substrate, mediating the proximity of the cells to the cellulose. Binding to the scaffolding stimulates the activity of each individual component towards the crystalline substrate. The most complex and best investigated cellulosome is that of the thermophilic bacterium Clostridium thermocellum, but a scheme for the cellulosomes of the mesophilic clostridia and the ruminococci emerges. Many crucial details of cellulose hydrolysis are still to be uncovered. Yet, a mechanistic model for the action of enzyme complexes on the surface of insoluble substrates becomes apparent and the application of enzymatic hydrolysis of cellulosic biomass can now be addressed. PMID- 11601611 TI - Production of polyhydroxyalkanoates from intact triacylglycerols by genetically engineered Pseudomonas. AB - Pseudomonas putida and P oleovorans have been extensively studied for their production of medium-chain-length (mcl)-polyhydroxyalkanoates (PHA). These bacteria are incapable of metabolizing triacylglycerols (TAGs). We have constructed recombinant P. putida and P. oleovorans that can utilize TAGs as substrates for growth and mcl-PHA synthesis. A recombinant plasmid, pCN51lip-1, carrying Pseudomonas lipase genes was used to electrotransform these organisms. The transformants expressed TAG-hydrolyzing activity as shown by a rhodamine B fluorescence plate assay. The genetically modified organisms grew in TAG containing medium to a cell dry weight of 2-4 g/l. The recombinant P. putida produced mcl-PHA at a crude yield of 0.9-1.6 g/l with lard or coconut oil (Co) as substrate. While P. oleovorans transformant did not produce mcl-PHA, a mixed culture fermentation approach with the wild-type and recombinant strains afforded polymer production from Co at a crude yield of 0.5 g/l. Compositional analysis by gas chromatography/mass spectrometry showed that beta-hydroxyoctanoate (31-45 mol %) and beta-hydroxydecanoate (28-35 mol %) were the dominant repeat units of the TAG-based PHA. The number-average and weight-average molecular masses of the PHAs as determined by gel permeation chromatography were 82-170 x 10(3) g/mol and 464 693 x 10(3) g/mol, respectively. The recombinant approach can greatly increase the number of organisms that can be used to produce PHA from fat and oil substrates. PMID- 11601612 TI - Effect of exogenous lysine on the expression of early cephamycin C biosynthetic genes and antibiotic production in Nocardia lactamdurans MA4213. AB - In beta-lactam producing microorganisms, the first step in the biosynthesis of the beta-lactam ring is the condensation of three amino acid precursors: alpha aminoadipate, L-cysteine and D-valine. In Nocardia lactamdurans and other cephamycin-producing actinomycetes, alpha-aminoadipate is generated from L-lysine by two sequential enzymatic steps. The first step involves a lysine-6 aminotransferase activity (LAT), considered to be one of the rate-limiting steps for antibiotic biosynthesis. Here, we report the effect of exogenous lysine on antibiotic production by N. lactamdurans MA4213. Lysine-supplemented cultures showed higher titers of cephamycin C, an effect that was more significant at early fermentation times. The increase in cephamycin C production was not quantitatively correlated with specific LAT activity in lysine-supplemented cultures. Observation of a positive effect of lysine on cephamycin C production by N. lactamdurans was dependent on carbon source availability in the culture media. Supplementation of the culture media with exogenous lysine did not affect the mRNA levels of the early biosynthetic genes controlled by the bidirectional promoter. These results indicate that L-lysine is required not only for antibiotic biosynthesis, but particularly as carbon or nitrogen source. PMID- 11601613 TI - Propionic acid production in an in situ cell retention bioreactor. AB - Continuous fermentations were conducted with in situ cell retention using spin filters (pore size 5 microm and 10 microm) for propionic acid production by Propionibacterium acidipropionici. Continuous fermentation with a 5-microm pore size spin filter resulted in 50% cell retention. Propionic acid productivity was enhanced (0.9 g l(-1) h(-1)) by approximately four-fold compared to conventional batch fermentation (0.25 g l(-1) h(-1)). The in situ cell retention (5-microm pore size spin filter) bioreactor was operated continuously and smoothly for 8 days at a dilution rate of D=0.05 h(-1). PMID- 11601614 TI - Spacer-mediated display of active lipase on the yeast cell surface. AB - We have constructed a Saccharomyces cerevisiae strain displaying an active lipase on the cell surface by cell surface engineering. The gene encoding Rhizopus oryzae lipase (ROL) was fused with the genes encoding the pre-alpha-factor leader sequence and the C-terminal half of alpha-agglutinin including the glycosylphosphatidylinositol-anchor attachment signal. The constructed gene was overexpressed under the control of the glyceraldehyde-3-phosphate dehydrogenase promoter. Linker peptides (spacers) consisting of the Gly/Ser repeat sequence were inserted at the C-terminal portion of ROL to enhance lipase activity by preserving the conformation of the active site near the C-terminal portion. Localization of the expressed ROL on the cell surface was confirmed by immunofluorescence microscopy. The ROL displayed on the yeast cell wall exhibited activity toward soluble 2,3-dimercaptopropan-1-ol tributyl ester (BALB) and insoluble triolein. The insertion of linker peptides effected the activity towards BALB, thereby demonstrating that the optimal length of linker peptides was present. The activity towards triolein was higher in lipases with longer linker peptides. ROL displayed on the cell wall exhibited a comparable and/or higher activity towards triolein than the secreted form of the enzyme. This is the first report of an active lipase displayed on the cell surface. Furthermore, insertion of a linker peptide of the appropriate length as a spacer may be an improved method to effectively display enzymes, especially those having the active region at the C-terminal portion, on the cell surface. PMID- 11601615 TI - Pressure measurement to evaluate ethanol or lactic acid production during glucose fermentation by yeast or heterofermentative bacteria in pure and mixed culture. AB - A rapid and simple technique to follow CO2 release during fermentation of glucose by heterofermentative bacteria or yeasts was used in order to evaluate ethanol and lactate production in pure and mixed cultures of yeast and bacteria. In pure cultures, good correlations were found between gas pressure variations (deltaP) and ethanol or lactate production by yeasts or heterofermentative bacteria, and ratios between deltaP and ethanol or lactate produced could be established. In mixed cultures, ratios between maximal deltaP and total amount of glucose consumed were determined. It was thus possible to evaluate the amount of glucose that was consumed by each strain and then deduce the bacterial lactate production. Good results were obtained for mixed cultures of yeast and homofermentative bacteria. This technique may be useful to evaluate the activity of strains in mixed cultures of yeast and lactic acid bacteria. PMID- 11601616 TI - An improved procedure for characterization of spatial and temporal evolution of immobilized cells in gel membranes. AB - An improved procedure that allows the simple and reproducible characterization of spatial and temporal distribution of immobilized biomass in gel membranes was developed. This procedure involves three main steps in the preparation of membrane samples, the use of a standard microtome to obtain membrane slices, and the measurement of cell concentration by spectrophotometry. The key improvement in this procedure is to prepare the membrane samples by clamping them between two glass plates and storing them in a -80 degrees C freezer for a specified period of time depending on the membrane thickness. With this simple pre-treatment, the membrane samples were frozen in an ideal physical state to be cut into flat, consistent, slices using a commercial freezing sledge microtome, thus providing accurate and reproducible results. As a validation case study, a gel membrane bioreactor was constructed in which an alginate gel membrane with immobilized Lactobacillus rhamnosus cells was flanked by two well-mixed chambers with identical fermentation media. The improved procedure was employed to experimentally determine the intra-membrane cell distribution in the alginate membranes during fermentation. The experimental results showed a heterogeneous "U shape" biomass distribution across the membrane, with the highest cell concentration at the membrane-solution interface. High reproducibility and accuracy were verified by a low average standard deviation (<5%) and a high biomass recovery ratio (>90%), respectively. PMID- 11601617 TI - Thioglucosidase activity from Sphingobacterium sp. strain OTG1. AB - Screening for novel thioglucoside hydrolase activity resulted in the isolation of Sphingobacterium sp. strain OTG1 from enrichment cultures containing octylthioglucoside (OTG). OTG was hydrolysed into octanethiol and glucose by cell free extracts. Besides thioglucoside hydrolysis, several other glucoside hydrolase activities were detected in the Sphingobacterium sp. strain OTG1 cell free extract. By adding beta-glucosidase inhibitors it was possible to discriminate between these different activities. Ascorbic acid and D-gluconic acid lactone inhibited the hydrolysis of p-nitrophenyl beta-glucoside, but did not affect octyl- and octylthioglucoside hydrolase activity. Besides OTG, various other thioglucosides were hydrolysed by the novel thioglucosidase, with almost the same activities regardless of the nature of the aglycone, including the myrosinase model substrate sinigrin (a glucosinolate). Sinigrin could also be used as a growth substrate by Sphingobacterium sp. strain OTG1, although at concentrations exceeding 0.15 mM degradation was not complete. PMID- 11601618 TI - Stable transformation of Pleurotus ostreatus to hygromycin B resistance using Lentinus edodes GPD expression signals. AB - It was reported that Pleurotus ostreatus was transformed unstably using recombinant plasmids containing a hygromycin B phosphotransferase gene (hph) under the control of Aspergillus nidulans expression signals, and that the plasmids were maintained extrachromosomally in the transformants. Here we report a stable and integrative transformation of the fungus to hygromycin B resistance, using a recombinant hph fused with Lentinus edodes glyceraldehyde-3-phosphate dehydrogenase expression signals. Restriction-enzyme-mediated integration (REMI) was also tried and increased the transformation efficiency about ten-fold. PMID- 11601619 TI - Effect of transketolase modifications on carbon flow to the purine-nucleotide pathway in Corynebacterium ammoniagenes. AB - Transketolase, one of the enzymes in the nonoxidative branch of the pentose phosphate pathway, operates to shuttle ribose 5-phosphate and glycolytic intermediates together with transaldolase, and might be involved in the availability of ribose 5-phosphate, a precursor of nucleotide biosynthesis. The tkt and tal genes encoding transketolase and transaldolase, respectively, were cloned from the typical nucleotide- and nucleoside-producing organism Corynebacterium ammoniagenes by a PCR approach using oligonucleotide primers derived from conserved regions of each amino acid sequence from other organisms. Enzymatic and molecular analyses revealed that the two genes were clustered on the genome together with the glucose 6-phosphate dehydrogenase gene (zwf). The effect of transketolase modifications on the production of inosine and 5' xanthylic acid was investigated in industrial strains of C. ammoniagenes. Multiple copies of plasmid-borne tkt caused about tenfold increases in transketolase activity and resulted in 10-20% decreased yields of products relative to the parents. In contrast, site-specific disruption of tkt enabled both producers to accumulate 10-30% more products concurrently with a complete loss of transketolase activity and the expected phenotype of shikimate auxotrophy. These results indicate that transketolase normally shunts ribose 5 phosphate back into glycolysis in these biosynthetic processes and interception of this shunt allows cells to redirect carbon flux through the oxidative pentose pathway from the intermediate towards the purine-nucleotide pathway. PMID- 11601620 TI - Production of selenomethionine-labelled proteins using simplified culture conditions and generally applicable host/vector systems. AB - The amino acid analogue selenomethionine (SeMet) is shown to be efficiently incorporated into recombinant proteins expressed in Escherichia coli grown in a simple minimal medium without the addition of synthetic amino acids. Furthermore, satisfactory SeMet incorporation is obtained with a methionine-prototrophic strain transformed with commonly used vector systems. As examples, purified tryparedoxin 1 from Crithidia fasciculata, alkylhydroperoxide reductase (AhpC) from Mycobacterium marinum and the 16-kDa antigen from M. tuberculosis are shown to be efficiently labelled with SeMet, using the culture conditions and the host/vector systems described here. Enzymatic analysis reveals no differences between native and SeMet-labelled tryparedoxin 1 enzyme. Both proteins yield crystals under similar conditions. The culture conditions and host vector systems described greatly facilitate selenium-labelling of proteins for 3-D structure determination. PMID- 11601621 TI - Characterization of the eugenol hydroxylase genes (ehyA/ehyB) from the new eugenol-degrading Pseudomonas sp. strain OPS1. AB - During the screening for bacteria capable of converting eugenol to vanillin, strain OPS1 was isolated, which was identified as a new Pseudomonas species by 16 s rDNA sequence analysis. When this bacterium was grown on eugenol, the intermediates, coniferyl alcohol, ferulic acid, vanillic acid, and protocatechuic acid, were identified in the culture supernatant. The genes encoding the eugenol hydroxylase (ehyA, ehyB), which catalyzes the first step of this biotransformation, were identified in a genomic library of Pseudomonas sp. strain OPS1 by complementation of the eugenol-negative mutant SK6165 of Pseudomonas sp. strain HR199. EhyA and EhyB exhibited 57% and 85% amino acid identity to the eugenol hydroxylase subunits of Pseudomonas sp. strain HR199 and up to 34% and 54% identity to the corresponding subunits of p-cresol methylhydroxylase from P. putida. Moreover, the amino-terminal sequences of the alpha- and beta-subunits reported recently for an eugenol dehydrogenase of P fluorescens E118 corresponded well with the appropriate regions of EhyA and EhyB. Downstream of ehyB, an open reading frame was identified, whose deduced amino acid sequence exhibited up to 71% identity to azurins, representing most probably the gene (azu) of the physiological electron acceptor of the eugenol hydroxylase. The eugenol hydroxylase genes were amplified by PCR, cloned, and functionally expressed in Escherichia coli. PMID- 11601622 TI - Characterization of the lipA gene encoding the major lipase from Pseudomonas aeruginosa strain IGB83. AB - The lipases produced by Pseudomonas have a wide range of potential biotechnological applications. Pseudomonas aeruginosa IGB83 was isolated as a highly lipolytic strain which produced a thermotolerant and alkaline lipase. In the present work, we have characterized the P. aeruginosa IGB83 gene (lipA) encoding this enzyme. We describe the construction of a lipA mutant and report on the effect of two carbon sources on lipase expression. PMID- 11601623 TI - The meroperon of a mercury-resistant Pseudoalteromonas haloplanktis strain isolated from Minamata Bay, Japan. AB - A mer operon of mercury-resistant Pseudoalteromonas haloplanktis strain M1, isolated from sea water of Minamata Bay, was cloned and analyzed. The mer genes were located in the chromosome and organized as merR-merT-merP-merC-merA-merD, the same order as that in Tn21. However, the orientation of the merR gene is the same as that of other mer genes (opposite direction to Tn21), and merR was cotranscribed with other mer genes, a pattern that has not been previously seen with mer determinants from other Gram-negative bacteria. Furthermore, the amino acid similarities of the corresponding mer gene products between those from strain M1 and Tn21 were unusually low. PMID- 11601624 TI - Investigation of sequential behavior of carboxyl protease and cysteine protease activities in virus-infected Sf-9 insect cell culture by inhibition assay. AB - Proteases produced during the culture of Spodoptera frugiperda Sf-9 cells infected with Autographa californica nuclear polyhedrosis virus (AcNPV) were assayed with various protease inhibitors. This inhibitory analysis revealed that: (1) carboxyl and cysteine proteases were predominantly produced by the insect cells infected with recombinant AcNPV, the gene of which encoded a variant of green fluorescent protein in a portion of the polyhedrin gene of the baculovirus, and (2) the protease activity was almost completely blocked by pepstatin A (carboxyl protease inhibitor) and E64 (cysteine protease inhibitor) in an additive manner in the presence of EDTA. Utilizing the additive property of the inhibitors, the inhibition-based protease assay discriminated between the two protease activities and elucidated the sequential behavior of the carboxyl and cysteine proteases produced in the virus-infected Sf-9 cell culture. The carboxyl protease(s) existed in the virus-infected cells all the time and their level in the medium continuously increased. Uninfected cells also contained a carboxyl protease activity, the level of which was similar to that of the virus-infected cells. At a certain time after virus infection, the cysteine protease activity was largely increased in the virus-infected cells and a significant amount of the protease(s) was released into the medium, due to the cell membranes losing their integrity. The behavior of intracellular and extracellular cysteine protease activities coincided with that of a recombinant protein whose expression was under the control of the viral polyhedrin promoter. Similar examinations with wt AcNPV-infected and uninfected insect cells showed that the inhibition-based protease assay was useful for analyzing the carboxyl protease and cysteine protease activities emerging in the insect cell (Sf-9)/baculovirus expression system. PMID- 11601625 TI - Carotenoid accumulation in the psychrotrophic bacterium Arthrobacter agilis in response to thermal and salt stress. AB - A psychrotrophic strain of Arthrobacter agilis, isolated from Antarctic sea ice, grows from 5 degrees C to 40 degrees C and in culture media containing 0-10% (w/v) NaCl. Maximum growth rate occurred at 30-35 degrees C with a drastic decline as the cultivation temperatures diverged. Adaptation to extremes of low temperature may be partially attributed to the production of the C-50 carotenoid bacterioruberin, and its glycosylated derivatives. Lowering of the cultivation temperature resulted in a concomitant increase in carotenoid production, which may contribute to membrane stabilisation at low temperature. Maximum biomass accumulation occurred at 5-30 degrees C with a tenfold reduction at 40 degrees C. Changes in growth rates were minimal in culture media containing 0-2% (w/v) NaCl at 10 degrees C while a gradual decrease in growth rates occurred at higher salinity. Biomass accumulation at different salinity followed a trend similar to that observed with different cultivation temperatures. Maximum biomass accumulation was observed in culture media containing 0-5% (w/v) NaCl with a tenfold reduction at 10% (w/v) NaCl. Carotenoid production also decreased as salinity increased. PMID- 11601626 TI - Bioconversion of nitriles by Candida guilliermondii CCT 7207 cells immobilized in barium alginate. AB - Nitrile degradation by Candida guilliermondii CCT 7207 using free and immobilized cell systems was compared. Different specific growth rates were observed for immobilized (mumax=0.021 h(-1)) and the free cells (mumax=0.029 h(-1)). The maximum specific rate of acetic acid formation was 0.387 h(-1) and 0.266 h(-1) for free and immobilized cells, respectively. Cell adhesion to the support materials was confirmed by scanning electron microscopy. When immobilized, the yeast was able to use high nitrile and amide concentrations (aliphatic and aromatic) as nitrogen sources. The results suggest that C. guilliermondii CCT 7207 presents a physiological pattern potentially useful for the bioremediation of polluted environments or for the bioproduction of amides and organic acid of high commercial value. PMID- 11601627 TI - Xylanase from a newly isolated Fusarium verticillioides capable of utilizing corn fiber xylan. AB - A fungus, Fusarium verticillioides (NRRL 26518), was isolated by screening soil samples using corn fiber xylan as carbon source. The extracellular xylanase from this fungal strain was purified to apparent homogeneity from the culture supernatant by ultrafiltration using a 30,000 cut-off membrane, octyl-Sepharose chromatography and Bio gel A-0.5 m gel filtration. The purified xylanase (specific activity 492 U/mg protein; MW 24,000; pI 8.6) displayed an optimum temperature at 50 degrees C and optimum pH at 5.5, a pH stability range from 4.0 to 9.5 and thermal stability up to 50 degrees C. It hydrolyzed a variety of xylan substrates mainly to xylobiose and higher short-chain xylooligosaccharides. No xylose was formed. The enzyme did not require metal ions for activity and stability. PMID- 11601628 TI - Redirection of pyruvate catabolism in Lactococcus lactis by selection of mutants with additional growth requirements. AB - Based on requirements for acetate or lipoic acid for aerobic (but not anaerobic) growth, Lactococcus lactis subsp. lactis mutants with impaired pyruvate catabolism were isolated following classical mutagenesis. Strains with defects in one or two of the enzymes, pyruvate formate-lyase (PFL), lactate dehydrogenase (LDH) and the pyruvate dehydrogenase complex (PDHC) were obtained. Growth and product formation of these strains were characterized. A PFL-defective strain (requiring acetate for anaerobic growth) displayed a two-fold increase in specific lactate production compared with the corresponding wild-type strain when grown anaerobically. LDH defective strains directed 91-96% of the pyruvate towards alpha-acetolactate, acetoin and diacetyl production when grown aerobically in the presence of acetate and absence of lipoic acid (a similar characteristic was observed in an LDH and PDHC defective strain in the presence of both acetate and lipoic acid) and more than 65% towards formate, acetate and ethanol production under anaerobic conditions. Another strain with defective PFL and LDH was strictly aerobic. However, a variant with strongly enhanced diacetyl reductase activities (NADH/NAD+ dependent diacetyl reductase, acetoin reductase and butanediol dehydrogenase activities) was selected from this strain under anaerobic conditions by supplementing the medium with acetoin. This strain is strictly aerobic, unless supplied with acetoin. PMID- 11601629 TI - Quantification of intracellular amino acids in batch cultures of Saccharomyces cerevisiae. AB - The dynamics of intracellular amino acid pools were determined in batch cultures of Saccharomyces cerevisiae. Immediate termination of metabolic activity was found to be necessary for accurate quantification of in vivo concentrations of intracellular amino acids, due to significant changes in most intracellular amino acid pools observed during extraction without an instantaneous stop of the metabolism. The method applied to batch-cultures of S. cerevisiae on glucose revealed complex dynamics in intracellular amino acid pools. The most drastic changes were observed during the diauxic shift and at the entry into the stationary phase. Even during phases of exponential growth on glucose and ethanol, cells showed significant variations in intracellular amino acid concentrations. The method presented can be used to investigate the physiology of yeast cultures, including industrially relevant batch and fed-batch processes. PMID- 11601630 TI - Biomonitoring of continuous microbial community adaptation towards more efficient phenol-degradation in a fed-batch bioreactor. AB - The anaerobic degradation of phenol was studied in a fed-batch culture. Nitrate was added as electron acceptor and phenol was provided three times, to a final concentration of 200 mg/l. Randomly amplified polymorphic DNA (RAPD) and terminal fraction fragment length polymorphism (T-RFLP) were used and compared in order to monitor the microbial succession in the reactor. Phenol degradation started after an initial lag phase of 14 days and was then completed within a few days. In addition, the duration of the lag phase was shortened and the degradation rate was increased after each phenol amendment. Nitrate reduction correlated with microbial growth and phenol depletion, confirming that the degradation was carried out anaerobically. Results from the DNA analysis showed that the structure of the microbial community changed after each phenol amendment. This study confirms the potential for anaerobic degradation of environmental pollutants and also confirms that microbial acclimation towards faster degradation rates occurred upon repeated substrate amendments. Furthermore, both of the DNA-based techniques described the phenol degradation-linked community shifts with similar general results. RAPD is a faster, simpler technique that gives a higher resolution and consequently reflects the shifts in the microbial community structure better, whereas T-RFLP is more suitable for phylogenetic studies. PMID- 11601632 TI - Microbial degradation of phenanthrene and pyrene in a two-liquid phase partitioning bioreactor. AB - A study was conducted to determine the potential of two-liquid phase-bioreactors for the treatment of (polycyclic aromatic hydrocarbons) PAHs. Phenanthrene and pyrene were supplied two times at a concentration of 100 mg/l of reactor broth, either as crystals or dissolved in silicone oil. Complete phenanthrene biodegradation was achieved within 3 days after each addition to the biphasic inoculated reactor. Its concentration in the monophasic reactors dropped by 93% within 4 days, but remained incomplete for the duration of the experiment. Pyrene removal occurred to a limited extent only in the presence of phenanthrene. Significant pollutant losses were recorded in the monophasic reactors, most likely caused by volatilization. Pollutant degradation was improved upon repeated phenanthrene amendment to the biphasic system. Biphasic reactors allow the fast and complete degradation of PAHs and prevent their hazardous disappearance. The use of biphasic reactors for the degradation of poorly soluble pollutants should become more beneficial when the substrate-interface uptake mechanism is operating. Thus, biphasic reactors should be integrated into the microbial enrichment procedure. PMID- 11601631 TI - Preliminary examinations for applying a carbazole-degrader, Pseudomonas sp. strain CA10, to dioxin-contaminated soil remediation. AB - A method for bioremediation of chlorinated dibenzo-p-dioxins (CDDs) and dibenzofurans (CDFs) by a carbazole-utilizing bacterium, Pseudomonas sp. strain CA10, was developed. CA10 cells transferred to carbon- and nitrogen-free mineral medium supplemented with 1 mg carbazole (CAR)/ml grew rapidly during the first 2 days; and the cells at the end of this rapid growth period showed the highest 2,3 dichlorodibenzo-p-dioxin (2,3-Cl2DD)-degrading activity. The CA10 cells pregrown for 2 days efficiently degraded 2,3-Cl2DD in aqueous solution at either 1 ppm or 10 ppm. The effect of inoculum density on the efficiency of 2,3-Cl2DD degradation was investigated in a soil slurry microcosm [ratio of soil:water = 1:5 (w/v)]. The results showed that a single inoculation with CA10 cells at densities of 10(7) CFU/g soil and 10(9) CFU/g soil degraded 46% and 80% of 2,3-Cl2DD, respectively, during the 7-day incubation. The rate of degradation of each CDD congener, 2-ClDD, 2,3-Cl2DD, and 1,2,3-Cl3DD (1 ppm each) by strain CA10 in the soil slurry system was not significantly influenced by the coexistence of the other congeners. Using this soil slurry system, we tried an experimental bioremediation of the actual dioxin-contaminated soil, which contained mainly tetra- to octochlorinated dioxins. Although the degradation rate of total CDD and CDF congeners by a single inoculation with CA10 cells was 8.3% after a 7-day incubation, it was shown that strain CA10 had a potential to degrade tetra- to hepta-chlorinated congeners including the most toxic compound, 2,3,7,8 tetrachlorinated dibenzo-p-dioxin. PMID- 11601633 TI - Pyrene degradation by two fungi in a freshwater sediment and evaluation of fungal biomass by ergosterol content. AB - Mucor racemosus var. sphaerosporus and Phialophora alba were investigated for their abilities to degrade pyrene in a freshwater sediment, with or without glucose supply as nutrient or carbon source, during 90 days. The ergosterol contents in sediment were quantified to estimate fungal biomass and to assess the correlation between fungal activity and biodegradation of pyrene. Results showed that, in an heterogeneous environment, these fungi presented different abilities to degrade pyrene. P. alba increased the degree of pyrene degradation by 9%, compared to the native micro-organisms, but a supply of glucose acted as an inhibitor to pyrene disappearance. M. racemosus var. sphaerosporus was not efficient at sediment bioremediation (with or without glucose added), because it reduced the rate of pyrene degradation by the native microflora. In any case, there was no increase of ergosterol in boxes during bioremediation experiments. In our experimental conditions, ergosterol content could not be correlated to pyrene degradation. PMID- 11601634 TI - Development of a rapid pH-based biosensor to monitor and control the hygienic quality of reclaimed domestic wastewater. AB - The re-use of treated domestic wastewater necessitates a rigorous control and rapid monitoring of the hygienic quality of the reclaimed water. For this purpose, a new pH-based biosensor was developed. The essence of the methodology of the sensor is the monitoring of the acidification due to bacterial metabolism of added glucose. To improve the sensitivity, the alkalinity of the water sample is reduced prior to monitoring the acidification. This is done by stripping CO2 at a neutral or acidic pH value. The hygienic aspect of the sensor lies in the applied temperature (37 degrees C) and the use of N2 as decarbonizing gas, thus creating conditions favorable for enteric bacteria. The developed sensor could be used onsite at an advanced stage of treatment, as an endpoint or intake quality control device. For both applications, a useful correlation was obtained between log total plate count and lag time or acidification rate, respectively. Absolute detection limits lay in the ranges of either 10(3) colony-forming units (CFU)/ml in 6 h (endpoint quality control), or less than 10(5) CFU/ml in 1 h (intake quality control). PMID- 11601635 TI - A PCR test to identify bacillus subtilis and closely related species and its application to the monitoring of wastewater biotreatment. AB - A PCR test based on the 16S rRNA gene was set up that could identify any of the five species of the 'Bacillus subtilis group' (B. subtilis, B. pumilus, B. atrophaeus, B. lichenijormis and B. amyloliquefaciens). The test was directly applicable to single colonies and showed excellent specificity. In the mixed population context of wastewater analysis, direct detection of the target Bacillus species by PCR on either crude or purified DNA extracts had poor sensitivity. When assayed on cell suspensions derived from enriched wastewater samples, sensitivity was increased. Using a simple calibration method, it was possible to estimate the proportion of the target organisms. This method was found suitable for easy monitoring of a wastewater bioaugmentation experiment carried out with a mixture of sporulated Bacillus strains. PMID- 11601636 TI - Aerobic treatment of a concentrated urea wastewater with simultaneous stripping of ammonia. AB - An industrial wastewater containing a total Kjeldahl nitrogen (TKN) of 12.80 g l( 1) was treated in a continuously fed activated sludge reactor. The main contaminant was urea (21.52 g l(-1)), together with minor amounts of the nitrification inhibitor dicyandiamide (0.46 g l(-1)) and free ammonia (0.56 g l( 1)). The wastewater was diluted 1:1 with water and treated under alkaline conditions (pH 9.4), enabling the simultaneous hydrolysis of urea and stripping of free ammonia in one aerobic reactor. Experiments were conducted to eliminate the remaining ammonia in a separate treatment unit by nitrification/denitrification. An adapted nitrifying bacterial population was isolated which was able to nitrify at a rate of 0.1 g nitrogen l(-1) day(-1) at a dicyandiamide concentration of 0.22 g l(-1). However, this was found to be too slow for an industrial-scale operation. Therefore, separate stripping with air or steam after pH adjustment to > or =10.5 is proposed. The diluted wastewater was treated with a hydraulic retention time of 6 days, corresponding to a volumetric nitrogen loading rate of 1.1 g nitrogen l(-1) day(-1) with an overall TKN reduction of 78.0%. PMID- 11601637 TI - Investigations into the application of a process for the determination of microbial activity in biofilms. AB - The formation of biofilms in a waste paper medium was studied in a pilot plant by analysing the redox potential in the biofilm. Miniaturised redox electrodes were applied at the reactor wall/biofilm phase boundary. With this measurement set-up, it was possible to demonstrate the effectiveness of biocides and thus to avoid under- and over-doses with these agents. The redox signals measured were correlated with reference methods, such as colony-forming units and dehydrogenase activity. PMID- 11601639 TI - Synthesis and biological evaluation of some differently substituted 9,10 anthracenediones. AB - 9,10-Anthracenedione derivatives are known to exhibit a quite potent anticancer activity. It has also been reported that these compounds can be effectively employed in both antibacterial and antitrypanosomal therapy. Anthraquinones also exhibit some undesirable side effects, like cardiotoxicity. So many interactions seem to demonstrate that 9,10-anthracenediones strongly interact with a number of biological sites. In this paper we wish to report on the synthesis and the pharmaceutical activity of some newly synthesised derivatives containing the anthraquinone pharmacophore. PMID- 11601638 TI - Pegylated enzyme entrapped in poly(vinyl alcohol) hydrogel for biocatalytic application. AB - A procedure for enzyme entrapment into matrices suitable for biocatalytic applications is reported. The method, which takes advantage of the stable formation of polyvinyl alcohol (PVA) hydrogels by freezing and thawing PVA aqueous solutions, was assayed using lipase as model enzyme. The leakage of lipase was minimised by using high molecular weight PVA and by previous conjugation of the enzyme to PEG. The immobilised PEG enzyme maintained its catalytic activity in organic solvents also, thus allowing enzymatic activity towards water insoluble substrates. The activity was largely increased reducing the diffusional constrain by cutting the matrices into slices of micron size. Matrix-entrapped lipase-PEG, when used in the hydrolysis of acetoxycoumarins, showed a conversion rate of about 10 times lower than the enzyme-PEG in the free form, and maintained regioselectivity when a diacetylated product was used as substrate. PMID- 11601640 TI - Synthesis of N-terminal substituted anthranilic acid dimer derivatives for evaluation on CCK receptors. AB - A series of new N-substituted anthranilic acid dimer derivatives having a C terminal Phe residue was synthesized and evaluated for their affinity for CCK receptors. These compounds resulted from a blended approach based firstly on the use of an alternative substructure embedded within asperlicin and secondly on the derivatization of this template with substituents chosen considering the C terminal primary structure of the endogenous ligand. Although these compounds exhibited a regnylogical-type organization similar to that of CCK-4, they are characterized by about 1000-fold greater affinity for CCK-A receptor than the C terminal tetrapeptide. PMID- 11601641 TI - Synthesis of some halogen-containing 1,2,4-triazolo-1,3,4-thiadiazines and their antibacterial and anticancer screening studies--part I. AB - A series of 7-arylidene-6-(2,4-dichloro-5-fluorophenyl)-3-substituted-1,2,4 triazolo[3,4-b]-1,3,4-thiadiazines (3) were prepared by the condensation of 4 amino-5-mercapto-3-substituted-1,2,4-triazoles (1) and 3-aryl-1-(2,4-dichloro-5 fluorophenyl)-2-bromo-2-propen-1-one (2). An alternative route for the synthesis of the title compound 3 has been described. The newly synthesised compounds were characterised on the basis of N-analyses, IR, 1H NMR and mass spectral data. Some of the newly synthesised compounds were tested for their antibacterial activities against Gram + ve and Gram - ve bacteria. Among the tested compounds 3n showed the highest degree of antibacterial activity against S. aureus and evaluation of the LD50 value of this compound was carried out. Some of the newly synthesised compounds were also screened for their anticancer activities. Among these, compounds 3b, 3g, 3n and 3p are found to be active against NCI-H460 (lung), MCF7 (breast), SF 268 (CNS) in the preliminary anticancer screening studies. Further, 60-cell-line anticancer studies of these compounds were carried out. The results of such studies are discussed in this paper. PMID- 11601643 TI - Application of potassium dichromate and iron-thiocyanate in the spectrophotometric investigations of phenothiazines. AB - A spectrophotometric procedure for the determination of phenothiazines in pure form and in a number of their pharmaceutical preparations has been developed that offers the advantages of simplicity, accuracy, precision and sensitivity over many other methods. The method is based on the oxidation of phenothiazines by a known excess amount of potassium dichromate followed by the estimation of unreacted amount of dichromate by reacting with excess of iron(II) and measuring the iron(III) formed by complexing with thiocyanate. The reacted oxidant corresponds to the drug content. Different variables affecting the reaction between drugs and dichromate were studied and optimized. At the maximum absorption of 480 nm, Beer's law is obeyed in the range 2.5-29.75 microg/ml. The molar absorptivity and Sandell sensitivity of the procedure were calculated in addition to detection limit. Statistical treatment of the experimental results indicates that the procedure is precise and accurate. Excipients used as additives in pharmaceutical formulations did not interfere in the proposed procedure. The reliability of the method was established by parallel determination against the official BP methods. The procedure described was successfully applied to the determination of the bulk drugs and in pharmaceutical formulations. PMID- 11601642 TI - Synthesis and in vitro anticancer and anti-HIV evaluation of new 2 mercaptobenzenesulfonamides. AB - The reactions of 6-chloro-3-methylthio-1,4,2-benzodithiazine 1,1-dioxide derivatives with appropriate diamines were investigated. Depending on the reaction conditions 2-mercaptobenzenesulfonamide derivatives or their oxidation product disulfides were obtained. All the compounds were tested at the US National Cancer Institute (Bethesda) for their in vitro anticancer and anti-HIV activities. The highest sensibility against leukemia cell lines was found for bis[2-(6-chloro-4-phenyl-3,4-dihydroquinazolin-2-yl)aminosulfonyl-5-chloro-4-(4 R2-phenylcarbamoyl)phenyl]disulfides (R2 = H or Cl). The results of anti-HIV tests displayed moderate activity of N-(pirydo[3,2-d]imidazol-2-yl)-2 mercaptobenzenesulfonamide. PMID- 11601644 TI - Synthesis and antimycobacterial activity of [5-(pyridin-2-yl)-1,3,4-thiadiazol-2 ylthio]acetic acid arylidene-hydrazide derivatives. AB - [5-(Pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid arylidene-hydrazide derivatives were synthesized and tested for their in vitro antimycobacterial activity. Some compounds showed a feable activity against a strain of Mycobacterium tuberculosis and a strain of Mycobacterium avium. PMID- 11601645 TI - Synthesis and antimycobacterial activity of 5-aryl-1-isonicotinoyl-3-(pyridin-2 yl)-4, 5-dihydro-1H-pyrazole derivatives. AB - 5-Aryl-1-isonicotinoyl-3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazole derivatives were synthesized and tested for their in vitro antimycobacterial activity. The compounds showed an interesting activity against a strain of Mycobacterium tuberculosis and a human strain of M. tuberculosis H4. PMID- 11601646 TI - Flow-injection spectrophotometric determination of certain cephalosporins based on the formation of dyes. AB - A flow-injection spectrophotometric method is described for the determination of cefadroxil (I) and cefotaxime (II). The method is based on the hydrolysis of the cephalosporin with sodium hydroxide whereby the sulfide ion is produced. The latter is allowed to react with N,N-diethyl-p-phenylenediamine sulfate (N,N-DPPD) and Fe (III), and the blue color produced is measured at 670 nm (method A). Linear calibration graphs are obtained in the range 36.34-109.2 and 95.48-477.4 microgml(-1) for I and II, respectively. The experimental limits of detection (three times the noise signal) are 0.036 and 0.048 microgml(-1) for I and II, respectively. The total flow-rate is 5.3 ml min(-1) for both drugs. Alternately, the sulfide ion produced is allowed to react with p-phenylenediamine dihydrochloride (PPDD) and Fe (III), and the violet color produced is measured at 597 nm (method B). Linear calibration graphs are obtained in the range 0.5-400 and 0.5-450 microg ml(-1) for I and II, respectively. The limits of detection are 0.4 and 0.2 microg ml(-1) for I and II, respectively. The total flow-rate is 3 ml min(-1) for both drugs. The methods have been successfully applied to the analysis of some pharmaceutical formulations, particularly of the injection and capsule types. The relative standard deviation (RSD) (n = 10) at the 50 and 100 microg ml(-1) levels of I and II were 0.83-0.77 and 0.9-0.8% with N,N-DPPD and PPDD as reagents, respectively. Recoveries were quantitative; the results obtained agreed with those obtained by other reported methods. PMID- 11601647 TI - Synthesis and preliminary biological evaluation at the glycineB site of (+)- and (-)-3-oxetanylglycine, novel non-proteinogenic amino acids. AB - Two novel non-proteinogenic amino acids, (+)- and (-)-3-oxetanylglycine were synthesized and evaluated for their ability to diplace [3H]-glycine from the glycine site of the NMDA receptor complex. The lack of activity of these compounds at concentrations up to 100 microM may help in understanding the topological requirements of the glycine site of the NMDA receptor complex. PMID- 11601648 TI - Spectrophotometric methods for the determination of ritodrine hydrochloride and its application to pharmaceutical preparations. AB - Two simple and sensitive spectrophotometric methods are described for the determination of ritodrine hydrochloride (RTH) in both pure and dosage forms. The methods are based on the interaction of diazotised p-nitroaniline (DPNA) and sulphanilic acid (DSNA) with RTH in an alkaline medium. The resulting azo dyes are measured at 480 nm (for the DPNA method) and at 440 nm (for the DSNA method) and are stable for more than 1 h. The optimum reaction conditions and other analytical parameters are evaluated. A study of the effect of commonly associated excipients and additives do not interfere with the determinations. Statistical analysis of results indicates that the methods are precise and accurate. PMID- 11601649 TI - Antituberculosis agents II. Evaluation of in vitro antituberculosis activity and cytotoxicity of some 2-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole derivatives. AB - Using the radiometric BACTEC 460-TB methodology, the minimum inhibitory concentration (MIC) of a series of 2-(1-methyl-5-nitro-2-imidazolyl-1,3,4 thiadiazole-5-alkylsulfides, alkylsulfoxides and alkylsulfones which had been reported previously as antifungal agents, were determined. Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line. The results indicate that compounds bearing a primary alkylthio substitution displayed good antituberculosis activity (MIC = 3.13-6.25 microg/ml). Oxidation to sulfone abolished the antituberculosis activity in methyl and propyl derivatives while the ethylsulfonyl analogue was active (MIC = 1.56 microg/ml). The cytotoxic effects indicate that 2-(1-methyl-5-nitro-2-imidazolyl)-5 methylthio-1,3,4-thiadiazole was the least toxic compound (IC50 > 10 microg/ml). Generally, all compounds showed a low selectivity index. PMID- 11601650 TI - Synthesis of new N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H-thieno[2,3-h] 1-benzopyran-2-ones. AB - The synthesis of some N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H thieno[2,3-h]-1-benzopyran-2-ones (4a-f), by reaction of phenylchloroketene with a series of N,N-disubstituted (E)-5-aminomethylene-6,7-dihydrobenzo[b]thiophen 4(5)-ones, followed by dehydrochlorination in situ of the primary adducts with DBN, is described. A moderate local anaesthetic activity was observed in the title compounds, particularly in 4e. PMID- 11601651 TI - Improvement of the synthesis of diphenylmethyl 7beta-(o-hydroxy)benzylideneamino 3-hydroxymethyl-3-cephem-4-carboxylate. AB - The title product (I) is synthesized currently from 7-aminocephalosporanic acid, and diphenyldiazomethane (DDM) is used as a protective reagent of the acid function for further reactions. When DDM was prepared from benzophenone hydrazone by reaction with chloramine T, it was resulted impure by p-toluenesulfonamide, formed as side product, which cannot be removed during the final purification step carried out according to the literature procedure. Two simple methods are proposed here to obtain I with the suitable degree of purity necessary for a drug. PMID- 11601652 TI - Direct reception of light by chromatophores of lower vertebrates. AB - Rapid color changes of lower vertebrates are caused by the motile activities of pigment cells (chromatophores) present in the skin tissue. Chromatophore motility is generally regulated by neural and/or by endocrine systems. However, in some cases, light also induces pigment aggregation or dispersion directly, which suggests the existence of visual pigments in chromatophores. In fact, some opsins, including melanopsin, have been identified. This article reviews light sensitive chromatophores of lower vertebrates. Photoreceptive molecules (visual pigments) and signal transduction of light via a GTP-binding protein (G protein) are also discussed. PMID- 11601653 TI - The dilute locus and Griscelli syndrome: gateways towards a better understanding of melanosome transport. AB - In this review an overview of recent advances in the understanding of melanosome movement within epidermal melanocytes is given. Exploration of the molecular events involved in and determining the process of melanosome transport, as an essential part of human pigmentation, could lead to the identification of agents that augment, or down-regulate the transfer of melanosomes to surrounding keratinocytes. This would present a major breakthrough in the possibilities to influence pigmentation and related disorders, of great concern to some patients. Moreover, melanosome transport offers a good model to study mammalian organelle trafficking and its key players in general. PMID- 11601654 TI - BMP-2 stimulates tyrosinase gene expression and melanogenesis in differentiated melanocytes. AB - Cells of the vertebrate neural crest (crest cells) differentiate in vitro to melanocytes and sympathoadrenal (SA) progenitor cells. We have shown previously, using primary J. quail neural crest cultures, the combinatorial effect of bone morphogenetic protein-2 (BMP-2) and cAMP signaling on SA cell development. Herein, we report that in primary J. quail neural crest cultures, BMP-2 and cAMP signaling similarly exert a combinatorial effect on melanocyte development. We demonstrate that BMP-2 treatment of neural crest cells increases melanogenesis by promoting the synthesis of melanin. This increased melanin synthesis by BMP-2 is effected by the selective increase in the transcription of the tyrosinase gene, encoding the rate-limiting enzyme of the melanin biosynthetic pathway. By contrast, BMP-2 exerts no effect on the expression of the tyrosine-related proteins 1 and 2 (Tyrpl and Dct), also involved in the melanin biosynthetic process, or on the expression of microphalmia (Mitf) gene, supporting the fact that BMP-2 does not affect melanocyte differentiation. Employing transient transfection analysis of tyrosinase-reporter constructs in B16 melanoma cells, we demonstrate that the BMP-2 response-element is localized between 900 and 1,100 bp upstream from the tyrosinase transcriptional start site. These studies support a role for BMP-2 in melanogenesis by selectively targeting the expression of the tyrosinase gene involved in melanin biosynthesis. PMID- 11601655 TI - Variation in melanin content and composition in type V and VI photoexposed and photoprotected human skin: the dominant role of DHI. AB - A combination of techniques, including high-performance liquid chromatography (HPLC), spectrophotometric measurements, and a novel method for quantifying melanosome morphology, were applied to the analysis of melanin content and composition in highly pigmented (Fitzpatrick type V and VI) human skin. We found that total epidermal melanin content is significantly elevated in photoexposed type V and VI skin (approximately 1.6 x), while analysis of individual melanin components suggests that pheomelanin content increases only slightly, whereas 5,6 dihydroxyindole-2-carboxylic acid (DHICA)-eumelanin and to a greater extent 5,6 dihydroxyindole (DHI)-eumelanin content are both markedly elevated. Analysis of the relative composition of epidermal melanin in these subjects revealed that DHI eumelanin is the largest single component (approximately 60-70%), followed by DHICA-eumelanin (25-35%), with pheomelanin being a relatively minor component (2 8%). Moreover, there was a comparative enrichment of DHI-eumelanin at photoexposed sites, with a corresponding decline in the relative contributions from DHICA-eumelanin and pheomelanin. There was also a good correlation and close agreement between the concentration of spheroidal melanosomes determined by morphological image analysis and the concentration of pheomelanin determined by a combination of HPLC and spectrophotometric analysis (r = 0.89, P < 0.02). This study demonstrates the usefulness of melanosome morphology analysis as a sensitive new method for the quantification of melanin composition in human skin. The data also suggest that DHI-eumelanin formation is the dominant pathway for melanin synthesis in heavily pigmented (Fitzpatrick V and VI) skin types in vivo, and is the favoured pathway when melanin production is increased in chronically photoexposed skin. PMID- 11601656 TI - Distinct melanogenic response of human melanocytes in mono-culture, in co-culture with keratinocytes and in reconstructed epidermis, to UV exposure. AB - Striking differences are observed in the melanogenic response of normal human melanocytes to UVA and UVB irradiation depending on culture conditions and the presence of keratinocytes. Exposure of melanocytes co-cultured with keratinocytes to UVB irradiation triggered, already at low doses (5 mJ/cm2), an increase in melanin synthesis whereas in melanocyte mono-cultures, UVB doses up to 50 mJ/cm2 had no melanogenic effect. Unlike UVB, UVA exposure caused the same melanogenic response in both mono- and co-cultures. Removing certain keratinocyte growth factors from the co-culture medium abolished the melanogenic response to UVB, but not to UVA exposure. When integrated into the basal layer of a reconstructed human epidermis, human melanocytes similarly reacted to UVA and UVB irradiation as in vivo by increasing their production and transfer of melanin to the neighboring keratinocytes which resulted in a noticeable tanning of the reconstructed epidermis. The presence of a dense stratum corneum, known to scatter and absorb UV light, is responsible for higher minimal UVB and UVA doses required to trigger a melanogenic response in the reconstructed epidermis compared to keratinocyte-melanocyte co-cultures. Furthermore, an immediate tanning response was observed in the pigmented epidermis following UVA irradiation. From these results we conclude that: (i) keratinocytes play an important role in mediating UVB-induced pigmentation, (ii) UVA-induced pigmentation is the result of a rather direct effect on melanocytes and (iii) reconstructed pigmented epidermis is the most appropriate model to study UV induced pigmentation in vitro. PMID- 11601657 TI - Norepinephrine induces apoptosis in skin melanophores by attenuating cAMP-PKA signals via alpha2-adrenoceptors in the medaka, Oryzias latipes. AB - The density of skin melanophores in many teleost fish decreases during long-term adaptation to a white background. Using the medaka, Oryzias latipes, we previously reported that apoptosis is responsible for the decrease in melanophores, and that a sympathetic neurotransmitter, norepinephrine (NE), induces their apoptosis in skin tissue cultures. In this study, we show that NE induced apoptosis of melanophores is mediated by the activation of alpha2 adrenoceptors. Clonidine, an alpha2-adrenoceptor agonist, induced apoptotic melanophore death in skin organ culture, while phenylephrine, an alpha1 adrenoceptor agonist, had no effect. NE-induced apoptosis was diminished by an alpha2-adrenoceptor antagonist, yohimbine, but an alpha1-adrenoceptor antagonist, prazosin, did not abrogate the effect of NE. Furthermore, forskolin inhibited NE induced apoptosis, while an inhibitor of PKA, H-89, mimicked the effect of NE. These results suggest that NE induces apoptosis in melanophores by attenuating cAMP-PKA signaling via alpha2-adrenoceptors. PMID- 11601659 TI - The value and influence of Pharmacotherapy to the advancement of clinical pharmacology and pharmacotherapy. PMID- 11601658 TI - Inverse correlation between pink-eyed dilution protein expression and induction of melanogenesis by bafilomycin A1. AB - The pink-eyed dilution protein (p) plays a pivotal role in the synthesis of eumelanin. In its absence, critical melanosomal proteins fail to traffic to the melanosome. Pink-eyed dilution gene (P) mutations are the most common cause of tyrosinase-positive oculocutaneous albinism worldwide. Thus, reports that bafilomycin A1 was able to induce synthesis of melanin in tyrosinase-positive melanomas led us to test the drug on p-null murine melanocytes. We found that in melanocytes lacking p, bafilomycin A1 was able to induce melanin synthesis. These cells, once transfected with an expression vector encoding an epitope-tagged p transcript, failed to respond to the drug. The increase in melanin synthesis is accompanied by a reduction in tyrosinase protein cleavage and secretion with subsequent accumulation within the melanocyte. Bafilomycin A1 has also been reported to induce pigmentation of normal Caucasian melanocytes. Based on these data we hypothesize that p may serve as a key control point at which ethnic skin color variation is determined. PMID- 11601660 TI - Effect of triplicate prescription policy on benzodiazepine administration in nursing home residents. AB - OBJECTIVE: To estimate the effect of a triplicate prescription policy on administration of benzodiazepines and possible substitute drugs in nursing home residents during 1994-1995. DESIGN: Retrospective cross-sectional study SETTING: Medicare- and Medicaid-certified nursing homes in five states: New York, which has a policy requiring triplicate prescription forms for certain drugs, and four states without such a policy. SUBJECTS: A total of 211,177 nursing home residents. MEASUREMENTS AND MAIN RESULTS: Data were collected using the Minimum Data Set; logistic regression provided an estimated effect of the policy on prescribing benzodiazepines. We also estimated possible substitute drugs for benzodiazepines (e.g., barbiturates, antidepressants, antipsychotics, and miscellaneous sedative-hypnotics) while adjusting simultaneously for potential confounders. New York nursing home residents were less likely to be receiving benzodiazepine therapy than those in nonpolicy states (odds ratio 0.42; 95% confidence interval 0.41-0.44). No increases occurred in administration of benzodiazepine substitute drugs in New York versus states without a triplicate prescription policy. CONCLUSION: Policy did affect prescription and administration of benzodiazepines in nursing homes in states with versus without a triplicate prescription policy Lack of substitution with other drugs makes it unclear whether overprescribing occurred in states without a policy, or undertreatment occurred in the state with a policy. PMID- 11601661 TI - An institution-specific heparin titration nomogram: development, validation, and assessment of compliance. AB - STUDY OBJECTIVE: To develop, validate, and assess compliance with a heparin titration nomogram. DESIGN: Prospective, open-label trial. SETTING: University teaching hospital. SUBJECTS: Patients admitted with heart failure who required therapy with intravenous unfractionated heparin. Intervention. An in vitro concentration-response was determined by measuring activated partial thromboplastin times (aPTTs) on normal pooled plasma containing known concentrations of heparin. The therapeutic aPTT range was determined from the concentration-response by using the therapeutic heparin concentration range of 0.2-0.4 U/ml (protamine neutralization). Patients were consecutively enrolled, and therapy was managed by using the heparin titration nomogram. Paired aPTT heparin concentrations were obtained, and nomogram validation was performed by comparing the in vitro and the ex vivo concentration-responses with use of linear regression. Nomogram compliance also was assessed. MEASUREMENTS AND MAIN RESULTS: The therapeutic aPTT ranges based on in vitro and ex vivo data were determined to be 45-72 seconds and 47-61 seconds, respectively. The ranges were significantly different (p<0.001). Overall compliance with the nomogram was 88%. CONCLUSION: These results confirm that, even in a relatively homogeneous disease-state patient population, in vitro data do not accurately predict ex vivo data. If in vitro data are used to develop an institution-specific nomogram, a validation procedure should be used to ensure accuracy. Although 100% compliance to a nomogram may not be attainable, it should be expected. Therefore, a compliance rate of 88% is concerning and suggests a need for increased nursing and physician education. PMID- 11601662 TI - Impact of age and gender on the pharmacokinetics of gemtuzumab ozogamicin. AB - STUDY OBJECTIVE: To determine the pharmacokinetic parameters of the components of gemtuzumab ozogamicin and to assess the possible influence of age and gender on the values. DESIGN: Phase II, multicenter, open-label, nonrandomized, parallel study SETTING: Hospitals and outpatient oncology clinics. PATIENTS: Fifty-eight patients with acute myeloid leukemia in first relapse participated. Demographic data included 29 men and 29 women; 34 were younger than 60 years of age (mean age 53+/-16 yrs). INTERVENTION: Patients received gemtuzumab ozogamicin as a single 2 hour infusion of 9 mg/m2. Serial plasma samples were collected over 10 days after the beginning of the infusion. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of components of gemtuzumab ozogamicin (hP67.6 antibody, total and unconjugated calicheamicin derivatives) were measured by validated enzyme-linked immunosorbent assays. Pharmacokinetic parameters were determined by noncompartmental methods and comparisons between groups were made by analysis of variance. No significant differences were seen between men and women or between those over 60 and those less than 60 years of age in maximum concentration, time to maximum concentration, area under the curve, clearance, or volume of distribution for components of gemtuzumab ozogamicin. CONCLUSION: No differences occur in the pharmacokinetics of the components of gemtuzumab ozogamicin (hP67.6 or calicheamicin) based on gender or age. PMID- 11601663 TI - Efficacy of metoclopramide in postoperative ileus after exploratory laparotomy. AB - STUDY OBJECTIVE: To assess the efficacy of metoclopramide for treatment of postoperative ileus in patients who underwent exploratory laparatomy. DESIGN: Prospective observational study SETTING: Surgical intensive care unit (SICU). PATIENTS: Thirty-two patients who underwent exploratory laparatomy INTERVENTION: Sixteen patients received metoclopramide, and 16 did not. The primary outcome was time to first postoperative bowel movement. Secondary end points were length of stay (LOS) in the SICU and total hospital LOS. MEASUREMENTS AND MAIN RESULTS: The mean number of days to first bowel movement was nearly identical for both the treatment group and control group (4.8 vs 4.7 days, respectively, p=0.93). Length of stay in the SICU was 8.3 days for the treatment group and 8.6 days for the control group (p=0.89), and total LOS was 18.0 and 20.1 days, respectively (p=0.63). CONCLUSION: The time to first bowel movement was not significantly different between the treatment and control groups. Also, metoclopramide did not decrease LOS. Metoclopramide does not have a role in the treatment of postoperative ileus. PMID- 11601664 TI - Hematologic and chemical changes observed during and after cardiac arrest in a canine model--a pilot study. AB - STUDY OBJECTIVE: To evaluate the effect of cardiac arrest and cardiopulmonary resuscitation (CPR) on blood chemistry in a canine model. DESIGN: Evaluative canine animal study. SETTING: Animal laboratory accredited by the Association for Assessment and Accreditation of Laboratory Animals. SUBJECTS: Twenty-six adult mongrel dogs. INTERVENTION: The dogs underwent an episode of induced fibrillatory cardiac arrest for 3 minutes followed by 10 minutes of standard CPR. Blood samples were taken at baseline (before cardiac arrest), after 10 minutes of ventricular fibrillation, and 10 minutes after successful resuscitation for determination of blood chemistries and hematologic parameters. MEASUREMENTS AND MAIN RESULTS: Glucose, blood urea nitrogen, serum creatinine, sodium, potassium, chloride, calcium, phosphorus, uric acid, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, protein, albumin, cholesterol, triglycerides, iron, white blood cell count, red blood cell count, and hematocrit were measured. Significant changes (p<0.05) in values obtained during CPR versus baseline values were noted for all laboratory parameters except blood urea nitrogen, chloride, and alkaline phosphatase. Eighteen dogs achieved return of spontaneous circulation (ROSC); their laboratory values were obtained after CPR. Significant changes (p<0.05) after ROSC compared with baseline were noted for all laboratory values except chloride, blood urea nitrogen, uric acid, alkaline phosphatase, glucose, potassium, calcium, triglycerides, iron, red blood cell count, and hematocrit. CONCLUSION: Results indicate that significant changes in blood chemistries and hematologic parameters occur during and after CPR. Clinicians should note these normal laboratory parameter changes when interpreting laboratory data in patients who experience cardiac arrest. PMID- 11601665 TI - Effects of metronidazole on hepatic CYP3A4 activity. AB - STUDY OBJECTIVE: To evaluate the effect of a short course of oral metronidazole, commonly used for bowel-preparation regimens, on hepatic cytochrome P450 (CYP) 3A4 activity, as measured by the [14C N-methyl]-erythromycin breath test (ERMBT) in healthy volunteers. DESIGN: Prospective, nonrandomized, interventional study SETTING: University-affiliated, community, teaching hospital. SUBJECTS: Five healthy male volunteers. INTERVENTION: Subjects underwent a baseline ERMBT in the morning before receiving three oral doses of metronidazole 500 mg administered at 3 P.M., 7 P.M., and 11 P.M. Repeat ERMBTs were performed at 24, 72, and 96 hours after the initial ERMBT. Changes in ERMBT values were compared with baseline results using Freidman's repeated-measures analysis of variance on ranks. MEASUREMENTS AND MAIN RESULTS: The ERMBT values did not change significantly compared with baseline (p=0.82). Median (range) ERMBT values expressed as a percentage of baseline at 24, 72, and 96 hours were 110.3 (96.2-136.9), 101.3 (99.3-115.0), and 101.8 (95.5-116.3), respectively CONCLUSION: A short course of oral metronidazole does not result in a significant change in hepatic CYP3A4 activity as measured by the ERMBT. PMID- 11601666 TI - Assessment of a community pharmacy-based program for patients with asthma. AB - STUDY OBJECTIVE: To implement and assess a community-based pharmaceutical care program for patients with asthma. DESIGN: Prospective, randomized, controlled trial. SETTING: Community pharmacies (11 control, 11 intervention) in Malta. PATIENTS: Community-dwelling patients with asthma. INTERVENTIONS: A comprehensive asthma education and monitoring program was implemented. Intervention patients received verbal counseling, an educational video, an information leaflet, and subsequent monitoring with reinforcement; control patients received routine dispensing services. MEASUREMENTS AND MAIN RESULTS: Parameters assessed at baseline and at 4, 8, and 12 months were health-related quality of life, peak expiratory flow (PEF), inhaler technique, compliance with therapy, hospitalization rates, days lost from work, asthma symptoms, and patient satisfaction. Health-related quality of life of the intervention patients improved at 12 months (p=0.044). In the same time period, PEF significantly decreased in control patients compared with intervention patients (p=0.009) whereas inhaler technique improved in the intervention group (p=0.021). There were significantly fewer self-reported hospitalizations in intervention patients. CONCLUSIONS: A community-based pharmaceutical care program was appreciated by the participants and had a positive impact on the vitality of patients with asthma, inhaler technique, and PEE. PMID- 11601667 TI - Telithromycin: an oral ketolide for respiratory infections. AB - The ketolides represent a new subclass of antibiotics among the macrolide lincosamide-streptogramin group. Telithromycin, the first ketolide to be awarded approvable status for clinical use, demonstrates in vitro activity against community-acquired respiratory pathogens including penicillin- and erythromycin resistant Streptococcus pneumoniae. An extended half-life permits once-daily oral administration. Telithromycin is a substrate for cytochrome P450 (CYP) 3A4 and also inhibits drugs metabolized by CYP3A4. A relatively high frequency of mild-to moderate gastrointestinal adverse effects has been reported. Similar clinical and microbiologic efficacy has been demonstrated with oral dosing in comparative clinical trials for community-acquired pneumonia, acute sinusitis, acute exacerbations of chronic bronchitis, and pharyngitis. Although limited data on penicillin-resistant S. pneumoniae and erythromycin-resistant Streptococcus pyogenes are available from clinical trials, this drug appears promising for respiratory infections caused by these pathogens. PMID- 11601668 TI - Clinical implications of drug interactions with coxibs. AB - Nonsteroidal antiinflammatory drugs (NSAIDs) often are prescribed to patients who are taking concomitant drugs. Cyclooxygenase (COX)-2 inhibitors (coxibs) rofecoxib and celecoxib are highly selective inhibitors of COX-2, differentiating them from nonselective NSAIDs, which substantially inhibit both COX-1 and COX-2. Like nonselective NSAIDs, coxibs are hepatically metabolized: rofecoxib primarily by reduction by cytosolic enzymes and celecoxib by the cytochrome P450 (CYP) enzyme system. Because rofecoxib is not significantly metabolized by CYP, it has fewer confirmed or potential drug interactions than celecoxib. However, potent inducers of CYP, such as rifampin, may decrease rofecoxib concentrations because of induction of general hepatic metabolic activity. Celecoxib is metabolized by CYP2C9 and may be increased or decreased by CYP2C9 modifiers. It also inhibits CYP2D6 and may affect concentrations of CYP2D6 substrates. Similar to NSAIDs, many pharmacodynamic interactions involving coxibs are related to inhibition of production of renal prostaglandins. However, coxibs have no antiplatelet activity and may be preferred to NSAIDs in patients receiving antithrombotic therapy. Nonetheless, when a potential for an interaction exists, standard monitoring is recommended when starting or discontinuing a coxib. Due to lack of data to support these interactions, which are primarily theoretical, additional studies are necessary to establish the drug interaction profiles of coxibs. PMID- 11601669 TI - Biopsy-proved acute tubulointerstitial nephritis and toxic epidermal necrolysis associated with vancomycin. AB - A 70-year-old man receiving vancomycin for a methicillin-resistant Staphylococcus aureus (MRSA) abscess developed a drug-induced hypersensitivity reaction with rash, eosinophilia, and acute renal failure requiring dialysis. Renal biopsy revealed diffuse and marked interstitial and tubular infiltration by mononuclear cells and eosinophils; acute tubulointerstitial nephritis (TIN) was diagnosed. The rash progressed to erythema multiforme major after rechallenge with vancomycin in the setting of MRSA peritoneal catheter-related peritonitis and then to fatal toxic epidermal necrolysis in the setting of steroid taper and persistent serum vancomycin levels. This case further implicates vancomycin as a drug that infrequently can cause severe acute TIN and exfoliative dermatitis. When a renally excreted drug such as vancomycin is administered, serum drug levels should be serially monitored and high-dosage steroids be maintained or tapered slowly until serum drug levels become undetectable. PMID- 11601670 TI - Difficulties in anticoagulation management during coadministration of warfarin and rifampin. AB - The clinical significance of rifampin's induction of warfarin metabolism is well documented, but no published studies or case reports have quantified this interaction with respect to the international normalized ratio (INR). A patient receiving concomitant rifampin and warfarin to treat a mycobacterial infection and intraventricular thrombus, respectively, underwent routine INR testing at a pharmacist-managed anticoagulation clinic to assess his anticoagulation regimen. A 233% increase in warfarin dosage over 4 months proved insufficient to attain a therapeutic INR during long-term rifampin therapy More aggressive titration of the warfarin dosage was needed. In addition, a gradual 70% reduction in warfarin dosage over 4-5 weeks was necessary to maintain a therapeutic INR after rifampin discontinuation, demonstrating the clinically significant offset of this drug interaction. Extensive changes in warfarin dosage are required to attain and maintain a therapeutic INR during the initiation, maintenance, and discontinuation of rifampin. PMID- 11601671 TI - Quantifying the interaction between angiotensin-converting enzyme inhibitors and aspirin: are we using the right method? AB - Angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients with heart failure and coronary artery disease. Recently, there has been growing concern about the possible interaction between ACE inhibitors and aspirin. Numerous investigators have addressed this issue; however, results are equivocal. Most researchers used a statistical test of interaction, but the use of this method has been criticized. To assess the interaction between ACE inhibitors and aspirin properly, an additive model-more specifically, the Rothman Synergy Index should be used. Further investigation with this model, however, is needed. PMID- 11601672 TI - The "superiority" of enoxaparin for treatment of acute coronary syndromes. PMID- 11601673 TI - Routine differential diagnosis of proteinurias by capillary electrophoresis. AB - Capillary electrophoresis is a relatively new analytical technique that begins to have an impact on both routine and research in clinical laboratories. Recently, a fully automated system has become commercially available (Paragon CZE 2000, Beckman, USA) for the analysis of human serum proteins. Urine protein analysis, on the other hand, is currently accomplished by electrophoresis of concentrated urine specimens. The method is used to distinguish the glomerular from the tubular proteinuria and for the identification of Bence-Jones proteins. The procedure is labor-intensive and technically demanding. We developed a technique for the serum capillary electrophoresis instrument that can also be applied routinely to the differential diagnosis of proteinurias. Overriding the programmed dilution step of the instrument, we were able to distinguish different types of proteinurias without concentration of specimens with a total protein content of 150-200 mg/l as determined by sulfosalicylic acid. The different electrophoretic patterns obtained by the capillary electrophoresis system for various specimens correlated well with established techniques (Hydragel Proteinurie Kit, Sebia, France). The method is applicable for routine analysis of urinary proteins. It is reliable, less expensive and faster than the conventional methods (electrophoretic or immunonephelometric) used today for the differentiation of proteinurias, and it can be used as a quick screening test. PMID- 11601674 TI - Diagnostic testing in Epstein-Barr virus infection. AB - Laboratory diagnosis of Epstein-Barr virus (EBV) infection is improving with the development of new technologies. Quantification of the virus by real-time polymerase chain reaction (PCR) and evaluation of EBV-specific T cells, especially by tetrameric human leukocyte antigens, are noteworthy candidates for monitoring procedures in clinical laboratories involved in the management of transplant recipients. Standardization of PCR is essential for improving the quality of these monitoring procedures. PMID- 11601675 TI - Establishing a reference system in clinical enzymology. AB - The goal of standardization for measurements of catalytic concentrations of enzymes is to achieve comparable results in human samples, independent of the reagent kits, instruments and laboratory where the procedure is carried out. To pursue this objective, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) has launched a project to establish a reference system in clinical enzymology. This system is based on three hinges: a) extensively evaluated and carefully described reference procedures, b) certified reference materials and c) a network of reference laboratories operating in a highly controlled manner. The original IFCC-recommended procedures for alanine aminotransferase, aspartate aminotransferase, creatine kinase, gamma glutamyltransferase, lactate dehydrogenase and alpha-amylase have been slightly modified to optimize them at 37 degrees C, with the definition of detailed operating procedures. A group of laboratories perform these procedures manually, with self-made reagents on carefully calibrated instruments. Partially purified and stabilized materials, prepared in the past by the Community Bureau of Reference, have been re-certified by these laboratories for alanine aminotransferase, creatine kinase, gamma-glutamyltransferase and lactate dehydrogenase activities. Using these materials and the manufacturer's standing procedures, industry can assign traceable values to commercial calibrators. Thus, clinical laboratories, which will use routine procedures with these validated calibrators to measure human specimens, can finally obtain values which are traceable to reference procedures. PMID- 11601676 TI - Prediction of the development of pregnancy-induced hypertensive disorders in high risk pregnant women by artificial neural networks. AB - Pregnancy-induced hypertensive disorders (PIHD) are common complications of pregnancy and are associated with increased maternal and fetal morbidity. In this study, artificial neural networks (aNN) and multivariate logistic regression (MLR) were applied to a set of clinical and laboratory data (urea, creatinine, uric acid, total proteins, hematocrit, iron and ferritin) collected at 16 and 20 weeks of gestation. The efficacy of the two approaches in predicting the development of PIHD in 303 consecutive normotensive pregnant women at high risk of pre-eclampsia and intrauterine fetal growth retardation was then compared. The aNN were trained with a randomly selected set of 187 patient records and evaluated on the remainder (n=116). MLR analysis was done with the same 116 patients. The performance of each model was assessed using receiver operator characteristic (ROC) curves. Pregnancies had a normal physiological course in 227 cases, whereas 76 (25.1%) women developed PIHD during the third trimester. The best aNN at 20 weeks yielded an area under the ROC curve of 0.952, the sensitivity of 86.2%, the specificity of 95.4%, the positive predictive value of 86.2% and the negative predictive value of 95.5% for PIHD. The corresponding values for the MLR at 20 weeks were 0.962, 79.3%, 97.7%, 92% and 93.4%, respectively. The computer-aided integrated use of these conventional tests seems to provide a useful means for and early prediction of PIHD development. PMID- 11601677 TI - Fast homogeneous assay for plasma procarboxypeptidase U. AB - Carboxypeptidase U (EC 3.4.17.20, CPU, TAFIa) is a novel determinant of the fibrinolytic rate. It circulates as an inactive zymogen, procarboxypeptidase U, which becomes active during the process of coagulation. We developed a high throughput method on microtiter plates for the determination of the procarboxypeptidase U concentration in human plasma samples. Following activation of procarboxypeptidase U by thrombin-thrombomodulin, the resulting enzyme activity cleaves p-OH-Hip-Arg and the generated p-OH-hippuric acid is converted by hippuricase to p-hydroxybenzoic acid and glycine. Finally, oxidative coupling of p-hydroxybenzoic acid with 4-aminoantipyrine by NaIO4 forms the quinoneimine dye. The absorbance of the latter dye is determined at 506 nm in a microtiter plate reader. A mean value of 620 U/l was found, with a CV of 3.0% within-run and 4.3% between-run. The assay showed a good correlation with the activities observed using a HPLC assay as reference method (n = 25, r = 0.979). The presented method enables the routine analysis of large sample pools in clinical setting. PMID- 11601678 TI - Detection and quantification of small numbers of circulating tumour cells in peripheral blood using laser scanning cytometer (LSC). AB - The detection of circulating tumour cells disseminated from solid tumours requires extremely sensitive methods. Molecular genetic methods, which are most sensitive, are not applicable to solid tumours because no tumour-specific genetic markers are available. Detection of disseminated tumour cells by immunocytochemistry is time-consuming, whereas fluorimetry is fast and quantitative. The laser scanning cytometer (LSC) provides an automated microscopic procedure for screening up to 5x10(4) cells in suitable time. Using this system together with an enrichment procedure which allows up to ten thousand fold enrichment, we have quantified minimal numbers of tumour cells. In a model system, breast cancer cell line cells diluted into peripheral blood mimicked seeding of tumour cells into the periphery. After staining with fluorochrome conjugated anti-epithelial antibody, slides were screened for positive events directly or after enrichment with antibody-coated magnetic beads. One positive cell was unequivocally detectable in 10(4) cells and 50 out of 60 tumour cells were reliably recovered from a 20 ml blood volume, equal to 1-2 cells per 10(7), after magnetic bead enrichment. This method allows quantitation of tumour cells in peripheral blood and bone marrow in reasonable time and will, for the first time, enable extensive investigation of the seeding behaviour of tumours. PMID- 11601679 TI - Monotherapy with metformin: does it improve hypoxia in type 2 diabetic patients? AB - Metformin reduces blood glucose levels predominantly by inhibiting hepatic gluconeogenesis, although it also may enhance insulin receptor number or activity. The full effects of metformin are still poorly understood. In this study the effects of metformin on plasma xanthine oxidase (XO) activity, thiobarbituric acid-reactive substance (TBARS), lactate and fructosamine concentration as well as erythrocyte antioxidant enzyme activities were investigated in 46 patients with type 2 diabetes mellitus. All parameters were measured simultaneously just before metformin therapy (T0), 1 month (T1) and 2 months (T2) later. Results were compared with placebo and control group. We noted significant decrease in XO activity and in TBARS concentration (p<0.001) during monotherapy with metformin vs. placebo and T0 group. A significant correlation was observed between the activity of XO and the concentration of fructosamine (p<0.001). Erythrocyte glutathione peroxidase showed significantly lower activity in T2 group in comparison with T0 group (p<0.01). It is known that diabetic patients produce more TBARS as a result of enhanced free radical generation the source of which may also be the large amounts of XO produced following the conversion of xanthine dehydrogenase in hypoxic diabetic tissues. Thus, our results indirectly suggest that metformin can reduce toxic tissue damage through the inhibition on XO activity. PMID- 11601681 TI - The effect of corticosteroids on serum and cerebrospinal fluid nitric oxide levels in multiple sclerosis. AB - Multiple sclerosis is a disease characterized by perivascular infiltrates and demyelination of the white matter in the central nervous system. In this study, we compared the serum and cerebrospinal fluid nitric oxide levels before and after methylprednisolone therapy, and during remission period, and investigated the relationship of nitric oxide to the activity of multiple sclerosis. Cerebrospinal fluid and serum nitric oxide levels were measured blind as nitrite plus nitrate, using the nitrate reductase and Griess reaction method in 20 patients with multiple sclerosis before and after corticosteroid therapy, and during remission period, and in 20 control subjects. Mean cerebrospinal fluid and serum nitric oxide levels were highest in the pretreatment group and lowest in the control group. There was no correlation with nitric oxide levels in these two groups. Although corticosteroid therapy did not have any great effect on Expanded Disability Status Scales, it led to a decrease in nitric oxide levels. The possible cause of this might be the inhibition of nitric oxide synthesis by methylprednisolone, or a decrease in multiple sclerosis activity. We conclude that serum or cerebrospinal fluid nitric oxide levels do not reflect the activity in multiple sclerosis. PMID- 11601680 TI - Cigarette smoking and hypertension influence nitric oxide release and plasma levels of adhesion molecules. AB - Progression of atherosclerosis is currently believed to involve interactions between leukocytes and vascular endothelium. Epidemiological risk factors for atherosclerosis such as hypertension and smoking are known to cause endothelial dysfunction, which is an early event in the atherosclerotic process; they also may be considered in the light of their effects on adhesion molecule expression and release. Little is known about the additive effect between these two risk factors on endothelial adhesion molecule expression and nitric oxide release. Soluble adhesion molecules and the nitric oxide were quantified in smoking hypertensive patients in comparison to those from patients with hypertension alone. Cotinine, a stable metabolite of nicotine, has been used to identify smokers. One hundred and three hypertensive patients were selected: 51 smokers (plasma cotinine levels >25 ng/ml) and 52 non-smokers. Plasma concentrations of soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble endothelial leukocyte adhesion molecule-1 (sELAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-I) were quantified with ELISA methods. Plasma concentration of nitric oxide metabolites was measured by HPLC, whilst plasma concentration of cotinine was measured by RIA. Significant increases of sICAM-1 and sVCAM-1 were demonstrated in smokers (p<0.001 and p<0.05, respectively). In the same patients, a positive significant correlation between sVCAM-1 and plasma cotinine levels was observed (p<0.002). Nitric oxide metabolites were reduced significantly (p<0.04) in smokers. In conclusion, our data show that the two risk factors, smoking and hypertension, are additive risk factors in generating endothelial dysfunction and vascular damage, which plays a key role in atherogenesis. PMID- 11601682 TI - Glutathione transferase P1 polymorphism in neuroblastoma studied by endonuclease restriction mapping. AB - Several members of the different glutathione transferase (GST) gene classes are polymorphic. Particular interest has been focused on the GSTP class because this gene class is up-regulated during the early stage of oncogenesis and is significantly overexpressed in many human tumors. It has also been shown that high levels of GSTP1 expression are associated directly with tumor drug resistance and with poor patient survival. Our aim was to understand the possible association between GSTP1 polymorphism and cellular response to chemotherapeutic drugs in neuroblastoma. In fact, several antineoplastic drugs used in the neuroblastoma high-risk chemotherapeutic protocol are potential substrates of GSTP1-1 (etoposide, adriamycin and carboplatin). The GSTP1 genotype homozygote *A/*A was identified in 11 patients independent of their response to the chemotherapeutic treatment. Only four patients had a heterozygote genotype A*/B*. Therefore, based on our preliminary data, we were not able to conclude that GSTP1 polymorphism had an impact on patient response to treatment in neuroblastoma. PMID- 11601683 TI - Biological variation of interleukin-1beta, interleukin-8 and tumor necrosis factor-alpha in serum of healthy individuals. AB - Components of biological variation can be used to assess the usefulness of reference values, to evaluate the significance of changes in serial results from an individual and to define objective analytical goals. The aim of the study was to assess, in 15 healthy subjects studied at regular monthly intervals over a period of 6 consecutive months, the biological variation of interleukin-1beta (IL 1beta), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha). Biological variation data (within-subject and between-subject coefficient of variation (CV)) were determined using a simple nested analysis of variance. Derived parameters (index of individuality, reliability coefficient and critical diferences) were calculated from within-subject and between-subject CV. The mean and standard deviation (SD), within-subject CV, between-subject CV, index of individuality and reliability coefficient were as follows: for IL-1beta, 0.67 (0.32) pg/ml, 30%, 36%, 0.85, and 0.76; for IL-8, 3.68 (1.45) pg/ml, 24%, 31%, 0.85 and 0.75; and for TNF-alpha, 3.14 (1.87) pg/ml, 43%, 29%, 1.56 and 0.50, respectively. We conclude that between-subject variation and within-subject variation are quite similar for IL-1beta and IL-8 and are relatively high for the three cytokines studied. Index of individuality is less than 1.4 for IL-1beta and IL-8, and thus reference intervals based on population studies are of limited value. On the contrary, the index of individuality for TNF-alpha is greater than 1.4 and reference values can be used for diagnosis. Quality goals for imprecision are easily achieved for the three cytokines with current methodology. PMID- 11601684 TI - Reference intervals and variation for urinary epinephrine, norepinephrine and cortisol in healthy men and women in Denmark. AB - Reference intervals for urinary epinephrine, norepinephrine and cortisol in 120 healthy individuals performing their routine work were established according to the International Union of Pure and Applied Chemistry (IUPAC) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) for use in the risk assessment of exposure to occupational stress. Reference intervals were established for three different times of the day: in morning samples (05.45-07.15) the limit of detection (LOD) was 2.10 micromol epinephrine/mol creatinine (82 women) and 2.86 micromol epinephrine/mol creatinine (37 men), and the reference interval was 3.6-29.1 micromol norepinephrine/mol creatinine and 2.3-52.8 micromol cortisol/mol creatinine (119 women and men); in afternoon samples (15.30-18.30) the reference interval was 0.64-10.8 micromol epinephrine/mol creatinine (82 women), 1.20-11.2 micromol/epinephrine/mol creatinine (36 men), 11.0-54.1 micromol/ norepinephrine/mol creatinine and LOD was 42.4 micromol cortisol/mol creatinine (117 women and men); in evening samples (21.45-23.45) LOD was 8.66 micromol epinephrine/mol creatinine (81 women) and 7.99 micromol/epinephrine/mol creatinine (36 men), the reference interval was 11.0-54.1 micromol norepinephrine/mol creatinine, and LOD was 42.4 micromol cortisol/mol creatinine (117 women and men). A variance component model for describing the effects of age, body mass index (BMI), diurnal variation, gender, days of sick leave during past year and smoking habits was established. Women showed a higher morning value but excreted lower amounts of epinephrine during the day as compared to men. No gender differences could be demonstrated for the excretion of norepinephrine and cortisol. Excretion of epinephrine and norepinephrine increased with smoking and decreased with increased BMI. No effects were observed in the excretion of cortisol. PMID- 11601685 TI - Determination of serum cystatin C: biological variation and reference values. AB - Human cystatin C is a low molecular weight protein which has been proposed as a better marker of glomerular filtration rate than creatinine. To be able to interpret results obtained in different patient populations it is necessary to define cystatin C reference values. We measured serum concentration of cystatin C in 1223 subjects using a particle-enhanced nephelometric assay. Subjects were aged 4 to 79 years and were selected among apparently healthy individuals who came to the Centre for Preventive Medicine in Vandoeuvre-Les-Nancy, France. We observed a Gaussian distribution of cystatin C concentration in serum. We did not find any effect of age or gender in children, hormonal status in women (puberty, menopause, oral contraceptives or hormone replacement therapy) or alcohol intake. Cystatin C concentration was slightly lower in female than in male adults below the age of 60 years. Cystatin C levels significantly increased above the age of 60 in both males and females, probably due to physiological aging of renal function. No other significant differences were observed between males and females. Using multiple regression analysis, moderate correlations were observed between body mass index and cystatin C, and between smoking and cystatin C, but these were not biologically significant. According to the literature, only methylprednisolone and cyclosporin A increased and decreased cystatin C levels, respectively. The reference values for cystatin C obtained in a carefully selected population were 0.75+/-0.089 mg/l for children aged 4-19 years, 0.74+/ 0.100 mg/l for males and 0.65+/-0.085 mg/l for females (aged 20-59 years), and 0.83+/-0.103 mg/l for older individuals (> or =60 years). PMID- 11601686 TI - Certification of the mass concentration of creatine kinase isoenzyme 2 (CK-MB) in the reference material BCR 608. AB - We describe the certification of a mass concentration value in the already prepared creatine kinase-2 reference material (BCR 608). Creatine kinase-2 was purified from human heart. The purified enzyme was diluted in order to measure its protein concentration by the Doetsch method. A protein concentration value of 124.30+/-13.17 mg/l was assigned to the stock solution of purified creatine kinase-2. This stock solution was diluted in 25 mmol/l piperazine-N,N'-bis[2 ethanesulfonic acid] (PIPES) pH 7.2, containing 2 mmol/l ADP, 5 mmol/l 2 mercaptoethanol, 154 mmol/l sodium chloride and 50 g/l human albumin to obtain a stable liquid standard of known creatine kinase-2 mass concentration (80.36 microg/l). This standard was then used to recalculate the creatine kinase-2 mass concentration measured in the BCR 608 material by immunoassay. The mass concentration of creatine kinase-2 in samples of reconstituted BCR 608 was certified to be 93.30+/-9.65 microg/l. PMID- 11601687 TI - Carbohydrate-deficient transferrin (CDT) determination by nephelometry using a commercial kit. Analytical and diagnostic aspects. AB - Carbohydrate-deficient transferrin (CDT) has been proposed as the most efficient marker of alcohol abuse. Absolute and relative concentrations of CDT were measured with a commercial assay (%CDTTIA from AXIS-Shield, Oslo, Norway) using rate nephelometry for transferrin determination. One hundred eighty-eight alcoholic patients (154 males, 34 females) and 132 control patients (113 males, 19 females) were included in the study. Within-run and day-to-day imprecision were 3.15% and 9.77%, respectively. The calibration curve was stable for more than 4 months with a shift below 5%. The commercial assay lacked sensitivity (Se = 0.48), but was highly specific (Sp = 0.98). Lowering the cut-off from 6% to 4.6% raised the sensitivity of the %CDTTIA test to 0.76 with a specificity of 0.90. We conclude that this adaptation to the Array Protein System (Beckman Coulter) is suitable for routine use and offers precise results. It, however, requires an adaptation of the cut-off value for patients and of the target value for kit controls. PMID- 11601688 TI - Higher CK-MB mass values in heparin plasma than in serum measured with the Abbott AxSYM system. PMID- 11601689 TI - Clinical case material for teaching clinical chemistry and laboratory medicine. PMID- 11601690 TI - Comparison of sample preparation methods for recovering Salmonella from raw fruits, vegetables, and herbs. AB - Methods for preparing raw fruits, vegetables, and herbs for enrichment or direct plating to determine the presence and populations of pathogenic bacteria vary greatly. A study was done to compare three sample processing methods (washing in 0.1% peptone, stomaching, and homogenizing) for their influence on recovery of Salmonella inoculated onto 26 types of raw produce. The mean numbers of Salmonella recovered from 10 fruits, 11 vegetables, and 5 herbs using all three processing methods were 7.17, 7.40, and 7.27 log10 CFU/sample, respectively. Considering all 26 types of produce and all processing methods, the number of Salmonella recovered ranged from 7.24 to 7.29 log10 CFU/sample, with no significant differences attributable to a particular sample processing method. Mean percent recoveries of Salmonella from washed, stomached, and homogenized produce were 39.4, 44.7, and 42.4%, respectively. Mean percent recoveries from fruits, vegetables, and herbs, regardless of sample preparation method, were 41.7, 50.1, and 25.9%, respectively. The number of Salmonella recovered from stomached and homogenized produce, but not washed produce, with pH < or = 4.53 was significantly less than the number recovered from produce with pH from 5.53 to 5.99, suggesting that the acidic environment in stomachates and homogenates was lethal to a portion of Salmonella. Reduced percent recoveries from herbs (pH 5.94 to 6.34) is attributed, in part, to antimicrobials released from plant cells during sample preparation. Overall, the type of processing method did not substantially affect the number of Salmonella recovered from the 26 types of raw produce representing a wide range of structural and morphological characteristics, composition, and pH. The influence of sample size, diluent composition, and processing time on efficiency of recovery of Salmonella and other pathogens needs to be evaluated before a method(s) for processing samples of raw produce can be recommended. PMID- 11601691 TI - Validation of methods used to recover Escherichia coli O157:H7 and Salmonella spp. subjected to stress conditionst. AB - Escherichia coli O157:H7, Salmonella spp., and Salmonella Typhimurium DT104 were stressed with lactic acid and cell-free supernatants from lactic acid bacteria and plated on three different media to determine if injured cells were recovered. A comparison of the susceptibility and recovery of antibiotic-resistant strains of the pathogens and nonresistant strains was also made. Acid stress conditions were created by adjusting the pH of a cocktail mixture (two to four strains) of the pathogen to 3.50 with lactic acid and holding for 18 h. The pathogen cocktail was also stressed with a cell-free supernatant of Lactobacillus lactis (pH 3.90) in a 4:6 ratio. Both nonstressed and stressed cocktail cultures were plated on Trypticase soy agar (TSA) and violet red bile agar (VRBA) for E. coli and xylose lysine tergitol4 (XLT4) for Salmonella. Repair of injured cells was evaluated by pour plating the stressed cells on a 5-ml thin layer of TSA and allowing a 2-h room temperature incubation followed by overlaying with VRBA or XLT4. There were significant reductions in the populations of both pathogens under both stress conditions when plating was done on nonselective media. Injured E. coli O157:H7 was not recovered on recovery or selective media compared with TSA. Numbers of cells of supernatant-stressed Salmonella spp. plated on selective and recovery media were similar to those on TSA. Acid-stressed cells for all Salmonella spp. were not recovered on TSA, selective, or recovery media at levels comparable to recovery on TSA. Antibiotic-resistant strains showed similar recovery patterns on all media evaluated. However, the antibiotic-resistant strains were less sensitive to both stress conditions. The use of antibiotic-resistant strains resulted in a greater recovery of stressed pathogens than the use of recovery media. PMID- 11601692 TI - Improving recovery of Salmonella enterica serovar typhimurium DT104 cells injured by heating at different water activity values. AB - This study describes the evaluation of potentially more sensitive methods for the recovery of Salmonella cells injured by heating (54 to 60 degrees C) at different water activity values (0.65 to 0.90, reduced using equal portions of glucose and fructose). These methods included gradual rehydration, the use of diluting media with added solutes or blood, the addition of blood to plating agar, and the use of different incubation temperatures and times. Gradual rehydration of cells that had been challenged at low water activity (0.65 and 0.70) and high temperature markedly improved recovery, measured as a >50% increase in the time to obtain a 3 log10 reduction in cell numbers, compared to dilution into media with a high water activity. Adding sucrose, glycerol, or blood to the diluting media (maximal recovery diluent) did not improve recovery, but a plating agar containing blood recovered approximately 38% more cells than nutrient agar. Prolonged incubation of agar plates allowed recovery of injured Salmonella cells that presumably had extended lag periods, with significantly higher recovery rates after 48 h incubation at 37 degrees C than after 24 h (P = 0.05). This work highlights that by recovering Salmonella using a method specific to the nature of the injury, a better prediction of food safety and the success of food processing can be made. PMID- 11601693 TI - Efficacy and reproducibility of a produce wash in killing Salmonella on the surface of tomatoes assessed with a proposed standard method for produce sanitizers. AB - The reproducibility of a method developed to evaluate point-of-use sanitizers for fresh produce was tested at three different laboratories. Mixtures of five Salmonella serotypes were inoculated on the surface of ripe tomatoes. After the inoculum was dry, tomatoes were placed inside a plastic bag and sprayed with sterile USP water, Dey and Engley (D/E) neutralizer broth, or a prototype Fit produce wash (PW), an alkaline solution comprised of generally recognized as safe ingredients (water, oleic acid, glycerol, ethanol, potassium hydroxide, sodium bicarbonate, citric acid, and distilled grapefruit oil), and rubbed for 30 s. The tomatoes were rinsed 10 s with 195 ml of D/E neutralizer broth (rinse solution), then combined with 20 ml of D/E neutralizer (residual wash solution) and rubbed by hand to remove residual Salmonella. Populations of Salmonella were determined for each tomato in the rinse solution and residual wash solution. Treatment with PW resulted in reductions in the number of Salmonella 2 to 4 logs greater than those achieved with the sterile water or D/E neutralizer broth controls. Consistent results were obtained across the three study sites, indicating reproducible results were obtained using the test method. The method used to determine the efficacy of killing or removing Salmonella from tomatoes in this study is suggested as a standard method for measuring the efficacy of sanitizers on tomatoes and other similar fruits and vegetables with rigid, smooth surfaces. PMID- 11601694 TI - Survival of Salmonella spp. and Escherichia coli O157:H7 on fresh and frozen strawberries. AB - For maximum shelf life, fresh strawberries are harvested directly without washing into retail containers. Frozen berries are usually hulled in the field and washed prior to freezing, sometimes with the addition of sucrose. To determine survival of potential bacterial contaminants, cut or intact surfaces of fresh strawberries were spot inoculated with five- or six-strain cocktails of Salmonella or Escherichia coli O157:H7 (log 7.0 CFU/sample). Inoculated strawberries were dried for 1 h at 24 degrees C and were stored in closed containers at 5 or 24 degrees C. Sliced strawberries with or without added 20% sucrose were inoculated with one of two strains of E. coli O157:H7 and frozen at -20 degrees C. An initial population reduction of approximately 0.5-log cycles was observed on intact but not cut berries after the 1-h drying period. During storage at 24 degrees C for up to 48 h, populations of Salmonella and E. coli O157:H7 did not decline further. When strawberries were stored at 5 degrees C for up to 7 days, populations of both pathogens remained constant on cut surfaces but decreased by 1 - to 2-log cycles on intact surfaces. After 30 days of frozen storage, the population of E. coli O157:H7 had declined by 0.7- to 2.2-log cycles (with and without sucrose, respectively). Results of this study indicate that E. coli O157:H7 and Salmonella are capable of survival but not growth on the surface of fresh strawberries throughout the expected shelf life of the fruit and can survive in frozen strawberries for periods of greater than 1 month. PMID- 11601695 TI - Efficacy of chemical treatments in eliminating Salmonella and Escherichia coli O157:H7 on scarified and polished alfalfa seeds. AB - Alfalfa seeds are sometimes subjected to a scarification treatment to enhance water uptake, which results in more rapid and uniform germination during sprout production. It has been hypothesized that this mechanical abrasion treatment diminishes the efficacy of chemical treatments used to kill or remove pathogenic bacteria from seeds. A study was done to compare the effectiveness of chlorine (20,000 ppm), H2O, (8%), Ca(OH)2 (1%), Ca(OH)2 (1%) plus Tween 80 (1%), and Ca(OH)2 (1%) plus Span 20 (1%) treatments in killing Salmonella and Escherichia coli O157:H7 inoculated onto control, scarified, and polished alfalfa seeds obtained from two suppliers. The influence of the presence of organic material in the inoculum carrier on the efficacy of sanitizers was investigated. Overall, treatment with 1% Ca(OH)2 was the most effective in reducing populations of the pathogens. Reduction in populations of pathogens on seeds obtained from supplier I indicate that chemical treatments are less efficacious in eliminating the pathogens on scarified seeds compared to control seeds. However, the effectiveness of chemical treatment in removing Salmonella and E. coli O157:H7 from seeds obtained from supplier 2 was not markedly affected by scarification or polishing. The presence of organic material in the inoculum carrier did not have a marked influence on the efficacy of chemicals in reducing populations of test pathogens. Additional lots of control, scarified, and polished alfalfa seeds of additional varieties need to be tested before conclusions can be drawn concerning the impact of mechanical abrasion on the efficacy of chemical treatment in removing or killing Salmonella and E. coli O157:H7. PMID- 11601696 TI - Prevalence of antimicrobial resistance in Salmonellae isolated from market-age swine. AB - Antimicrobial resistance levels were examined for 365 Salmonella isolates recovered from the lymph nodes (n = 224) and cecal contents (n = 141) of market age swine at slaughter. Antimicrobial resistance testing was performed by disk diffusion using 13 antibiotics common in the treatment of disease in human and veterinary medicine. Although none of the antibiotics tested were used subtherapeutically within the last 5 years on the farms sampled, resistance to chlortetracycline, penicillin G, streptomycin, and sulfisoxazole was common. Penicillin G resistance was significantly more frequent (P = 0.03) and sulfisoxazole resistance was significantly less frequent (P < 0.01) in lymph node versus cecal isolates. Multidrug resistance was observed among 94.7% of the lymph node isolates and 93.5% of the cecal isolates. The most frequent multidrug resistance pattern included three antibiotics-penicillin G, streptomycin, and chlortetracycline. Isolates in somatic serogroup B, and more specifically, Salmonella Agona and Salmonella Schwarzengrund isolates, were often resistant to a greater number of antibiotics than were isolates in the other serogroups. Streptomycin, sulfisoxazole, ampicillin (lymph node isolates), and nitrofurantoin (cecal isolates) resistance levels differed significantly between somatic serogroups. The prevalence of penicillin G-, streptomycin-, and sulfisoxazole resistant isolates differed significantly between serovars for both lymph node and cecal isolates. Results of this study suggest that a correlation exists between the somatic serogroup or serovar of a Salmonella isolate and its antimicrobial resistance status, which is specific to the antibiotic of interest and the source of the isolate (lymph node versus cecal contents). PMID- 11601697 TI - Chicken mim-1 protein, P33, is a heterophil chemotactic factor present in Salmonella enteritidis immune lymphokine. AB - Lymphokine (ILK) secreted from concanavalin A-stimulated T cells from Salmonella Enteritidis-immune chickens is an undefined mixture of proteins that confers protection against Salmonella infectivity when administered to day-old chicks. It has previously been shown that polyclonal antibodies raised against human granulocyte colony-stimulating factor (GCSF) can neutralize the heterophil activation that is responsible for ILK's protective effect. Western blot analysis of ILK probed with anti-GCSF antibodies detects a prominent protein of mass 33 kDa. We have sequenced the first 20 amino acids of this protein and found it to be identical to residues 24 to 43 of P33, a 326-amino acid protein of unknown function encoded by the chicken mim-1 gene. The primary structure of P33 consists of two 140-residue imperfect repeats that are each homologous to a mammalian neutrophil chemotactic factor termed leukocyte cell-derived chemotaxin 2 (LECT2). We have expressed mim-1 in Escherichia coli and demonstrated in vitro that recombinant P33 is chemotactic for heterophils, the avian equivalent of mammalian neutrophils. We have also constructed a derivative of P33 that consists of residues 33 to 165 (P33[33-165]), the first repeat sequence of P33 that is homologous to LECT2. P33(33-165) is chemotactic for heterophils both in vitro and in vivo, inducing an influx of heterophils into the peritoneum in a response similar to that observed with ILK. These results suggest that P33 functions as a chemotactic factor in chickens and that it plays an active role in ILK-mediated protection against Salmonella infection. PMID- 11601698 TI - Combined effect of water activity and pH on the inhibition of Escherichia coli by nisin. AB - The Doehlert design and surface response methodology were used to study the influence of pH and water activity (aw) on Escherichia coli inhibition by nisin. Combining stress factors at levels where they are not inhibitory by themselves, a reduction of E. coli survival fraction can be achieved with lower nisin doses than in a single nisin treatment. For all the pH values assayed, a synergistic effect of aw and nisin concentration was detected, and the isoresponse lines showed the existence of an area of maximum inhibition. Factors that reduced viable cell counts by 4 to 5 log cycles were 1,000 to 1,400 IU of nisin per ml at pH 5.5 to 6.5 and a water activity of 0.97 and 0.98. The addition of different ionic and nonionic solutes to control aw suggested that the effect of aw in the inhibitory action of nisin on E. coli cells was not solute-specific. The use of the Doehlert experimental design was effective to determine the optimal combination of stress factors, as well as to point out the most important variables that affected E. coli inhibition. PMID- 11601699 TI - Effect of sampling method on the representative recovery of microorganisms from the surfaces of aquacultured finfish. AB - The objective of this study was to determine if a gentle rinse procedure was equivalent to the combination of excision and homogenization with a stomacher for the relative removal of various microorganisms from finfish fillets. Fillets of hybrid striped bass and rainbow trout were obtained from local markets and sampled using three methods: rinse (R), excision followed by homogenization in a stomacher (S), and homogenization of fillets following a rinse (RS). Microorganisms were enumerated on selective and nonselective media, and randomly selected colonies from aerobic plate counts were identified using MIDI Sherlock and BIOLOG microbial identification systems. Enrichments and selective media were used for the isolation of Listeria monocytogenes, Salmonella spp., and Yersinia enterocolitica. This study confirms previous reports that stomaching is superior to rinsing for enumerating total microbial populations from fish fillets. Rinsing was more effective for rainbow trout than for striped bass. Sampling method did not affect the relative magnitude of plate counts on media selective for aeromonads, pseudomonads, Shewanella, lactic acid bacteria, enterics, and gram positive cocci. In the compositional analysis of random isolates, R recovered significantly lower fractions of aeromonads than did S or RS, but sampling method did not affect the percent recovery of lactic acid bacteria, pseudomonads, Shewanella, Moraxellaceae, or Cytophaga/Flavobacterium. However, observations suggest that with increased replication, differences among Moraxellaceae, Pseudomonas, and gram positives might be significant. Only one L. monocytogenes colony was isolated, and no Salmonella or Y. enterocolitica, so the effect of sampling method could not be determined for these organisms. Differences in predominant bacterial populations were seen between fish species. PMID- 11601700 TI - Comparative evaluation of culture- and BAX polymerase chain reaction-based detection methods for Listeria spp. and Listeria monocytogenes in environmental and raw fish samples. AB - Two commercial polymerase chain reaction (PCR)-based Listeria detection systems, the BAX for Screening/Listeria monocytogenes and the BAX for Screening/Genus Listeria, and a culture-based detection system, the Biosynth L. monocytogenes Detection System (LMDS), were evaluated for their ability to detect L. monocytogenes and Listeria spp. in raw ingredients and the processing environment. For detection of L. monocytogenes from raw fish, enrichment was performed in Listeria enrichment broth (LEB), followed by plating on both Oxford agar and LMDS L. monocytogenes plating medium (LMPM). Detection of Listeria and L. monocytogenes from environmental samples was performed using LMDS enrichment medium, followed by plating on both Oxford agar and LMPM. A total of 512 environmental samples and 315 raw fish were taken from two smoked fish processing facilities and screened using these molecular and cultural Listeria detection methods. The BAX for Screening/L monocytogenes was used to screen raw fish and was 84.8% sensitive and 100% specific. The BAX for Screening/Genus Listeria was evaluated on environmental samples and had 94.7% sensitivity and 97.4% specificity. In conjunction with enrichment in LEB, LMPM had a sensitivity and specificity for detection of L. monocytogenes from raw fish of 97.8 and 100%, respectively. Use of LMDS enrichment medium followed by plating on LMPM allowed for sensitivity and specificity rates of 94.8 and 100%, respectively, for detection of L. monocytogenes from environmental samples. We conclude that both the BAX systems and the use of LMPM allow for reliable and rapid detection of Listeria spp. and L. monocytogenes. While the BAX systems provide screening results in about 3 days, the use of LMPM allows for L. monocytogenes isolation in 4 to 5 days. PMID- 11601701 TI - Heat treatment adaptations in Clostridium perfringens vegetative cells. AB - Vegetative cells of Clostridium perfringens enterotoxigenic strains NCTC 8679, NCTC 8238. and H6 were grown at 37 degrees C followed by a 60-min exposure to 28 degrees C or 46 degrees C. D10-values, as a measure of thermal resistance at 60 degrees C, were significantly lower for 28 degrees C exposures as compared with cultures given 37 and 46 degrees C exposures. Following refrigeration at 4 degrees C for 24 h, D10-values for the 37 and 46 degrees C samples could not be differentiated from 28 degrees C samples. Western immunoblot analyses of lysates from heat-adapted cells also detected the increased expression of proteins reacting with antiserum directed against the molecular chaperonins from Escherichia coli; GroEL, DnaJ, and the small acid soluble protein from Bacillus subtilis, SspC. Differential scanning calorimetry (DSC) identified thermal transitions corresponding to ribosomal protein denaturations at 72.1 +/- 0.5 degrees C. Any cellular heat adaptations in the DSC profiles were lost following refrigeration for several days to simulate minimally processed food storage conditions. Further analyses of high-speed pellets from crude cell extract fractions using two-dimensional gel electrophoresis detected the differential gene expression of at least four major proteins in heat-adapted vegetative cells of C. perfringens. N-terminal amino acid analyses identified two of the proteins as glyceraldehyde 3-phosphate dehydrogenase and rubrerythrin. Both appear to have roles in this anaerobe under stressful conditions. PMID- 11601702 TI - Effect of Bacillus cereus exocellular factors on human intestinal epithelial cells. AB - To gain insight on the biological effects of the exocellular factors produced by Bacillus cereus, culture filtrate supernatants of different strains were coincubated with differentiated Caco-2 cells. Exocellular factors were able to detach enterocyte-like cells from the substratum after 1 h of incubation. In addition, microvilli effacing and dramatic changes on the cellular surface of enterocytes were found after incubation periods as short as 20 min. Since cell detachment was not inhibited by fetal calf serum, thiol activated cholesterol binding cytolysin, cereolysin O, does not seem to be involved. Also, translocation of phosphatidylserine from the inner to the outer leaflets of the plasma membrane was demonstrated by using fluorescein isothiocyanate (FITC) Annexin V. In contrast to the high capability of detaching Caco-2 cells shown by all the strains under study, the mitochondrial dehydrogenase activity was lowered by culture filtrate supernatants in a strain-dependent manner. For strain M2, the decrease in dehydrogenase activity was already evident after 30 min of incubation. Production of biologically active factors depends on the growth phase, and maximal activity was found in late exponential-early stationary phases. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of concentrated exocellular factors showed a very complex scenery supporting the multifactorial character of the biological activity of B. cereus. PMID- 11601703 TI - Efficacy of chitosan, carvacrol, and a hydrogen peroxide-based biocide against foodborne microorganisms in suspension and adhered to stainless steel. AB - The ability of natural compounds to inactivate foodborne organisms adhered to surfaces was investigated with the ultimate aim of replacing synthetic biocides by more environmentally friendly, natural alternatives. The antimicrobial efficacy of 0.5, 1.0, and 2.0% chitosan and Spor-Klenz RTU (a commercial biocide based on hydrogen peroxide and peroxyacetic acid) and 0.5, 1.25, and 2.0 mM carvacrol was determined at 20 degrees C against Listeria monocytogenes, Salmonella enterica serovar Typhimurium, Staphylococcus aureus, and Saccharomyces cerevisiae adhered to stainless steel disks. Treatment with up to 2.0% chitosan reduced the viable cell count in the microbial films of the four test organisms by 2.4, 1.8, 2.3, and 0.9 log CFU/test surface (t.s.), respectively. By contrast, planktonic counts of the same organisms were reduced by 0.8 to 1.7 log CFU/ml at 2.0% chitosan. Treatment with 2 mM carvacrol reduced the viable counts of adhered listeriae, salmonellae, and yeasts by 2 to 3 log CFU/t.s. but S. aureus counts were reduced by only 0.9 log CFU/t.s. The efficacy of any single compound was species specific. In the case of microbial films prepared using listeriae and salmonellae, Spor-Klenz RTU was most biocidal, followed by carvacrol and then chitosan. However, dried films of S. aureus were most sensitive to chitosan and relatively resistant to carvacrol and Spor-Klenz RTU. By contrast, yeast films were most sensitive to carvacrol and least sensitive to chitosan. It was concluded that carvacrol and chitosan may have potential for use as natural biocides although optimization of conditions would be necessary. PMID- 11601705 TI - Identification of bacteria crucial to histamine accumulation in pacific mackerel during storage. AB - Bacterial growth and histamine formation in Pacific mackerel during storage at 0, 4, 15, and 25 degrees C were monitored. To identify bacterial species contributing to histamine formation, several groups of bacteria were isolated by using selective media under temperatures corresponding to the various storage conditions. Initially, low counts of bacteria were found in the gill, skin, and intestine of fresh fish, and only weak histamine formers were found in the gill. Histamine was found in the muscle when fish were stored above 4 degrees C, and aerobic plate counts reached 10(6) CFU/g. When fish became unsuitable for human consumption by abusive storage, toxicological levels of histamine were always found. The highest level of histamine formed was 283 mg/100 g in 2 days. The optimum temperature for supporting growth of prolific histamine formers was 25 degrees C. The most prolific and prevalent histamine former was Morganella morganii, followed by Proteus vulgaris, both of which were isolated on violet red bile glucose (VRBG) agar. At 15 degrees C, a significant level of histamine was still produced in fish muscle, although prolific histamine formers were less frequently detected than at 25 degrees C. The isolates on thiosulfate citrate bile salts sucrose (TCBS) agar were weak histamine formers and identified as Vibrio parahaemolyticus and Vibrio alginolyticus. At 4 degrees C, less than 57.4 mg/100 g of histamine was found in fish stored for 14 days. Most isolates were natural bacterial flora in the marine environment and identified as weak histamine formers. At 0 degrees C, neither histamine former nor histamine production was detected up to 14 days of storage. PMID- 11601704 TI - Process lethality and product yield for chicken patties processed in a pilot scale air-steam impingement oven. AB - Chicken breast patties were processed in a pilot-scale air-steam impingement oven to a patty center temperature of 55 to 80 degrees C. Thermal processing was conducted at an air temperature of 149 degrees C, an air velocity of 7 to 13 m3/min, and a wet bulb temperature of 39 to 98 degrees C. From thermal histories, the total process lethality of the patties was calculated for Salmonella spp. and Listeria innocua using the previously published z-values. The effect of product temperature, wet bulb temperature, and air velocity on process lethality was analyzed using a regression model. The process lethality of Salmonella spp. and L. innocua in the cooked chicken patties was correlated to the patty center temperatures and cooking conditions. The process lethality was strongly correlated to product temperature and was affected by cooking conditions. Process lethality started to increase rapidly at the product temperature around 67 degrees C. Regression analysis was used to correlate the product yield with cooking conditions. Depending on air velocity, product yield decreased 10 to 14% with increasing endpoint temperature from 55 to 80 degrees C and increased 2 to 9% with increasing wet bulb temperature from 39 to 98 degrees C. The effect of air velocity on the yield interacted with product temperature and wet bulb temperature. PMID- 11601706 TI - A rapid assay for detecting sulfonamides in tissues of slaughtered animals. AB - Governments regulate antimicrobial residues in slaughtered animals with surveillance programs for detecting drugs in food-producing animals. Although initial screening bioassay systems are recognized for their sensitivities to antimicrobial drug groups, none are sensitive to sulfonamides at or near the maximum residue levels (MRLs) in the Codex Alimentarious. We have developed a sulfonamide-sensitive rapid assay using Bacillus stearothermophilus inoculated PM indicator agar containing bromcresol purple and trimethoprim, where the end point is a combination of color change in the agar and zone of microbial growth inhibition around the sampling disk. Five sulfonamides, plus 16 other antimicrobial drugs were tested in standard concentrations in water, bovine kidney, and ground beef. Sulfonamides were detected at concentrations near the MRLs, and they were presumptively identified using para-aminobenzoic acid. The rapid assay was extremely sensitive to beta-lactams that were presumptively identified using penase. The system also was sensitive to tetracyclines, aminoglycosides, and macrolides, of which tetracyclines and gentamicin were identified using enzyme-linked immunosorbent assay (ELISA). In trials on slaughterhouse tissues submitted for testing in Ontario's meat surveillance program, the rapid assay identified twofold the number of positive kidneys and threefold the number of positive diaphragm samples compared to a standard microbiological inhibition test (MIT) currently approved. Fifty-three of 471 carcasses were sulfonamide positive with the rapid assay, while no sulfonamides were detected with the MIT. ELISA and thin-layer chromatography were used on selected samples to confirm the rapid assay sulfonamide presumptive results. PMID- 11601707 TI - Quality of irradiated alfalfa sproutst. AB - Alfalfa (Medicago sativa L.) sprouts were irradiated with gamma rays at doses of 0, 0.85, 1.71, and 2.57 kGy at 5 degrees C. then stored at 6 degrees C for 14 days. Antioxidant power, total ascorbic acid (TAA) (ascorbic acid plus dehydroascorbic acid), carotenoid, chlorophyll, and color were measured at 1, 7, and 14 days of storage. Antioxidant power increased linearly with radiation dose at both 1 and 7 days of storage. Irradiation had minimal effect on TAA content when compared with the decrease in TAA content during storage. Carotenoid content of sprouts irradiated at 1.71 and 2.57 kGy was higher than that of control at 7 days of storage. Irradiation did not have a consistent effect on chlorophyll content or color. PMID- 11601708 TI - Heated scallop-shell powder slurry treatment of shredded cabbage. AB - The main component of scallop-shell powder is calcium carbonate (CaCO3). Through heat treatment, CaCO3 in the shell is converted to CaO, which exhibits antibacterial activity. The disinfecting effect of heated scallop-shell powder on shredded cabbage was investigated for various powder concentrations (0.1 to 1.0 g dm(-3)) and treatment temperatures (10 to 40 degrees C). Scallop-shell powder treatment was found to reduce the aerobic bacteria count in cabbage, with increasing effectiveness at higher powder concentrations and treatment temperatures. Coliforms were completely eliminated within 5 min with as little as 0.1 g dm(-3) powder treatment. During storage at 4 degrees C, aerobic bacterial counts did not increase after powder treatment, whereas counts increased with water-washing or sodium hypochlorite treatment at 200 microg dm(-3). The inactivation pattern of bacterial cells in shredded cabbage involved an accelerated decline followed by an extended tail at powder concentrations of 0.1 and 0.5 g dm(-3). We postulate that a fraction of bacterial cells in the initial population becomes tolerant to the shell powder. A proposed model accurately predicts the reducing bacterial counts on shredded cabbage by scallop-shell powder treatment. The decrease in the L-ascorbic acid content of shredded cabbage was approximately 20 to 30% for scallop-shell powder treatment at 0.1 and 0.5 g dm(-3) (20 degrees C), which is almost identical to that by sodium hypochlorite treatment at 200 micorg dm(-3). PMID- 11601709 TI - Effects of storage temperature and preservative treatment on shelf life of the pond-raised freshwater fish, silver perch (Bidyanus bidyanus). AB - Sensory and microbiological characteristics of pond-raised freshwater silver perch (Bidyanus bidyanus) fish, during cold storage over a period of 25 days were evaluated. Whole fish (averaging 400 g each) were stored in cold storage rooms at either 0 to 2 degrees C, 5 degrees C, or 5 degrees C + potassium sorbate as a preservative. The organoleptic and hypoxanthine test results show that the treatment of potassium sorbate can slow the process of spoilage by about 5 days. Yet, the most important factor affecting the shelf life of these fish is the storage temperature. Keeping the fish at 0 to 2 degrees C can prolong the storage prior to spoilage by 10 days compared with those kept at 5 degrees C. These results obtained through organoleptic tests are corroborated by both the chemical (hypoxanthine and total volatile basic nitrogen) and to some extent by the physical (cosmos) tests. The initial total bacteriological counts were 5 x 10(2) CFU/cm2 for fish surface and <10(2) CFU/g for fish flesh, and these counts rose continuously, reaching about 106 CFU/g (0 to 2 degrees C) and 10(7) CFU/g (5 degrees C) in flesh and 10(7) to 10(8) CFU/cm2 on the surface by the end of the storage period. The addition of potassium sorbate led to a smaller increase in bacterial numbers, especially during the first 15 days. Bacterial composition fluctuated during storage. The initial load on the fish surface was predominantly mesophilic and gram positive and consisted mostly (80%) of Micrococci, Bacillus, and Corynebacterium. During the next 10 days, these bacteria were practically replaced by gram-negative flora comprised mostly of Pseudomonas fluorescens that rapidly increased with storage time and accounted for 95% after 15 days. PMID- 11601710 TI - Comparison of culture media, simplate, and petrifilm for enumeration of yeasts and molds in food. AB - The efficacy of three culture media, dichloran rose bengal chloramphenicol (DRBC), dichloran 18% glycerol agar (DG18), and potato dextrose agar (PDA) supplemented with two antibiotics, were compared with the Simplate and Petrifilm techniques for mold and yeast enumeration. The following foods were analyzed: corn meal, wheat flour, cassava flour, bread crumbs, whole meal, sliced bread, ground peanuts, mozzarella cheese, grated parmesan cheese, cheese rolls, orange juice, pineapple pulp, pineapple cake, and mushroom in conserve. Correlation coefficients of DRBC versus PDA and DG18 for recovering total mold and yeast counts from the composite of 14 foods indicated that the three media were generally equivalent. Correlation coefficients for Petrifilm versus culture media were acceptable, although not as good as between culture media. Correlation coefficients of Simplate versus DRBC, DG18, PDA, and Petrifilm for recovering total yeasts and molds from a composite of 11 foods demonstrated that there was no equivalence between the counts obtained by Simplate and other culture media and Petrifilm, with significant differences observed for the most foods analyzed. PMID- 11601711 TI - Development of a flow-through enzyme immunoassay and application in screening green coffee samples for ochratoxin A with confirmation by high-performance liquid chromatography. AB - A flow-through enzyme immunoassay has been developed for the screening of green coffee bean samples for ochratoxin A (OA) and was later used in a survey on OA in green coffee from different countries. The test has a sensitivity of 8 ng/g, and calculated recoveries ranged from 70 to 89% and from 86 to 95% for spiked and naturally contaminated samples, respectively. There were no significant differences in within-day and between-day assay performance (P > 0.05). Green coffee samples (15 Arabica and 7 Robusta) received from an international coffee trader were analyzed for intrinsic fungal contamination, screened for OA, and subsequently confirmed by high-performance liquid chromatography (HPLC). All 22 samples were contaminated by fungal species of the genus Aspergillus, while Penicillium species were isolated from a mere 13.6% of the total number of samples. Isolates were tested for their ability to produce OA, and only 3.9% were positive. There was no correlation between occurrence of OA-producing isolates and levels of OA in contaminated samples. Results of the screening procedure showed that 4 of the 22 samples were contaminated with 8 ng/g or higher. The HPLC method confirmed that the OA levels ranged from 27 to 168 ng/g. A fifth sample, which was shown to be negative during screening, had an OA concentration of 4 ng/g. There were no false negatives or positives recorded, and the flow-through enzyme immunoassay results correlated with those obtained by HPLC. PMID- 11601712 TI - Detection of trichothecenes in animal feeds and foodstuffs during the years 1997 to 2000 in Saudi Arabia. AB - A total of 843 commercial animal feed and foodstuff samples (465 samples of agricultural commodities and 378 samples of animal feeds) from all over the Kingdom of Saudi Arabia were collected during the years 1997 to 2000 and analyzed for type A and type B trichothecenes (diacetoxyscirpenol, neosolaniol, HT-2 toxin, T-2 toxin, nivalenol, fusarenon-x, deoxynivalenol). Levels of mycotoxins detected ranged from <2 to 4,000 microg/kg deoxynivalenol, 3.25 to 500 microg/kg fusarenon-x, 3.13 to 600 microg/kg nivalenol, 3.13 to 50 microg/kg diacetoxyscirpenol, 6.25 to 200 microg/kg neosolaniol, 3.13 to 18.75 microg/kg HT 2 toxin, and 6.25 microg/kg T-2 toxin. The study reflected the need for routine surveillance of agricultural commodities to minimize potential hazards to human health. PMID- 11601713 TI - Chlorine inactivation of Escherichia coli O157:H7 in water. AB - Six human isolates of Escherichia coli O157:H7 and E. coli (ATCC 11229) were used to determine the concentrations of free chlorine and exposure times required for inactivation. Free chlorine concentrations of 0.25, 0.5, 1.0, and 2.0 ppm at 23 degrees C were evaluated, with sampling times at 0, 0.5, 1.0, and 2.0 min. Results revealed that five of six E. coli O157:H7 isolates and the E. coli control strain were highly susceptible to chlorine, with >7 log10 CFU/ml reduction of each of these strains by 0.25 ppm free chlorine within 1 min. However, comparatively, one of the seven strains was unusually tolerant to chlorine at 23 degrees C for 1 min, with a 4-, 5.5-, 5.8-, and >5.8-log CFU/ml reduction at free chlorine concentrations (ppm) of 0.25, 0.5, 1.0, and 2.0. respectively. Based on these studies most isolates of E. coli O157:H7 have no unusual tolerance to chlorine; however, one strain was exceptional in being recovered after 1-min of exposure of 10(7) CFU/ml to 2.0 ppm of free chlorine. This isolate may be a useful reference strain for future studies on chlorine tolerance of E. coli O157:H7. PMID- 11601714 TI - Screening bovine carcass sponge samples for Escherichia coli O157 using a short enrichment coupled with immunomagnetic separation and a polymerase chain reaction based (BAX) detection stept. AB - A bovine carcass sponge sample screening protocol for detecting Escherichia coli O157:H7 was composed of a short selective enrichment followed by an immunomagnetic separation (IMS) and target detection using the BAX E. coli O157 polymerase chain reaction assay. This screening protocol was compared to a culture-based method for detection of the organism in carcass sponge samples. Enriched samples were subjected to IMS; the bead suspension was divided and plated on selected media or stored at -20 degrees C, then subjected to BAX analysis. The results showed a high degree of agreement between the plating method and the BAX system. Fifty-two of the 59 culture-positive samples were also positive using the BAX system (88.1% sensitivity). Of the 76 samples that appeared negative for the presence of E. coli O157:H7 by the culture method, 66 were determined as negative using the BAX system (86.8% specificity). Four of the 10 samples found negative by the initial culture method and positive by the BAX method were subsequently found to be culture positive upon reanalysis. Based on these data, the BAX system combined with a short, selective enrichment and IMS may be a rapid, reliable, and simple method to screen for E. coli O157:H7 in carcass sponge samples. Our data indicate that optimization and subsequent testing of this protocol for use as a carcass screening tool are warranted. PMID- 11601715 TI - Shiga toxin-producing Escherichia coli in beef heifers grazing an irrigated pasture. AB - Shiga toxin-producing Escherichia coli (STEC) produce toxins that have been associated with several human illnesses. E. coli O157:H7 is the most well-studied STEC and was first associated with consumption of improperly cooked ground beef in 1982. E. coli O157:H7 is not the only foodborne STEC because other STEC serotypes are also associated with human illnesses. The objective of this study was to assess prevalence of STEC in 23 yearling beef (Angus) heifers grazing an irrigated grass pasture in spring (April), summer (July), fall (October), and winter (December) of 1999. A total of 86 fecal samples were rectally collected and were subjected to microbiological testing for the presence of STEC. Nine E. coli isolates from five heifers (one in spring and fall and three in winter) were toxic to Vero cells. Of these isolates, four were E. coli O157:H7, two belonged to the serogroup O6, one O39:NM, one O113:H-, and the final isolate was untypable. The STEC prevalence rate in our herd ranged from 4% (spring) to 15% (winter). Based on detecting both O157:H7 and non-O157:H7 STEC in our heifers, it is clear that screening fecal samples should not be limited to E. coli O157:H7. Identification of STEC-positive cattle prior to slaughter should help in reducing the risk of beef contamination with such foodborne pathogens if pre- and/or postharvest control measures are applied to such animals. PMID- 11601716 TI - Automated ribotyping differentiates vibrio parahaemolyticus O3:K6 strains associated with a Texas outbreak from other clinical strains. AB - Automated ribotyping with a Qualicon Riboprinter was used to determine whether clinical isolates of Vibrio parahaemolyticus O3:K6 recovered during two U.S. outbreaks of oyster-associated gastroenteritis in 1998 were related to each other and to a previously identified highly virulent Asian clone of this serotype. The patterns produced using the restriction enzymes Eco RI and Pst I suggest that the outbreak in the Northeastern United States was caused by a single strain closely related to the Asian clone. In contrast, it appears that multiple strains were involved in the Texas outbreak and that the predominant type was genetically distinct from the Northeastern and Asian clone. PMID- 11601717 TI - Effect of chlorine, sodium chloride, trisodium phosphate, and ultraviolet radiation on the reduction of Yersinia enterocolitica and mesophilic aerobic bacteria from eggshell surface. AB - Eggshell sanitizing practices are necessary to improve microbiological safety of fresh hen eggs and their products. In this work, the effects of 100 mg/liter free chlorine (chl), 3% sodium chloride (NaCl), 1, 5, and 12% trisodium phosphate (TSP) in wash solutions, and UVR (ultraviolet radiation; 4.573 microW/cm2) were studied at different times on uninoculated and Yersinia enterocolitica-inoculated eggs. On uninoculated eggs, the best results were obtained with 100 mg/liter chlorine and UV exposure for >25 min, with reductions of 1.28 and 1.60 log cycles, respectively, compared to the average bacterial count (4.55 log CFU/egg) on the control (untreated eggs). On Y. enterocolitica-inoculated eggs, highest reductions of the average bacterial count (7.35 log CFU/egg) were obtained with 5 and 12% TSP and 100 mg/liter chl. The decrease obtained with 12% TSP (3.74-log reduction) was significantly higher (P < 0.05) than those obtained with the remaining treatments. Y. enterocolitica was more resistant to UVR than the eggshell natural mesophilic aerobic microflora, except when low inoculum (4.39 log CFU/egg) was assayed. Changes in eggshell microstructure were measured by the blue lake staining method. The presence of Yersinia and Salmonella in eggshell natural flora was also investigated. PMID- 11601718 TI - Effect of irradiation temperature on inactivation of Escherichia coli O157:H7 and Staphylococcus aureus. AB - The resistance of Escherichia coli O157:H7 and Staphylococcus aureus in ground beef to gamma radiation was significantly (P < 0.05) higher at subfreezing temperatures than above freezing. Ground beef was inoculated (ca. 2 x 10(8) CFU/g) with five isolates of either E. coli O157:H7 or S. aureus and subdivided into 25-g samples, vacuum packaged in barrier pouches, and tempered to 20, 12, 4, 0, -4, -12, -20, -30, -40, or -76 degrees C before gamma irradiation. The studies were repeated twice. The D10-values for both of these pathogens increased significantly at subfreezing temperatures, reaching maxima at approximately -20 degrees C. The D10-values for E. coli O157:H7 at 4 and -20 degrees C were 0.39 +/ 0.04 and 0.98 +/- 0.23 kGy, respectively. The D10-values for S. aureus at 0 and 20 degrees C were 0.51 degrees 0.02 and 0.88 +/- 0.05 kGy, respectively. PMID- 11601719 TI - Efficacy of trisodium phosphate solutions in reducing Listeria monocytogenes populations on chicken skin during refrigerated storage. AB - Chicken skin inoculated with l0(8) CFU/ml of Listeria monocytogenes was dipped for 15 min in sterile water (control) and in 8, 10, or 12% trisodium phosphate (TSP) solutions. Skin samples were stored at 2 degrees C for 5 days, with microbial monitoring on days 0, 1, 3, and 5 after treatment. Compared to the water dip, all TSP treatments significantly (P < 0.05) reduced L monocytogenes populations on chicken skin. The concentration of the TSP was a significant factor in reducing the populations of the bacteria at days 0, 1, 3, and 5 of refrigerated storage. For all sampling times, the best outcomes were attained with the highest TSP concentration studied (12%). Bacterial reductions in counts during the first day of storage were between 1.52 and 2.70 log10 cycles for 8 and 12% TSP-treated samples, respectively. Significantly greater reductions were observed from the third day of refrigerated storage onward. This occurred largely because populations of L. monocytogenes on control samples increased somewhat, but on TSP-treated samples the pathogen remained practically constant. Differences between L monocytogenes counts in skin samples immersed in water and those treated with TSP ranged from 2.10 (8% TSP-treated samples) and 3.63 (12% TSP-treated samples) log10 cycles on day 5 of storage. These results indicated that TSP is effective against L. monocytogenes in chicken meat, especially after several days of refrigerated storage. PMID- 11601720 TI - Modeling the combined effect of pH and temperature on the heat resistance of Bacillus stearothermophilus spores heated in a multicomponent food extract. AB - The combined effect of pH and temperature on the heat resistance of Bacillus stearothermophilus spores heated in an extract of complex food was studied. The results showed that, in general, reducing the pH reduced the heat resistance of the spores. Similarly, the value for the D parameter in the nonacidified extract was between 30 and 70% lower than the one obtained with double-distilled water. This result once again shows the importance of the substrate in inactivation studies of microorganisms. The experimental data were used to carry out a comparison of two predictive mathematical models of inactivation, one based on a multiparametric regression obtained in this study and the other obtained from the bibliography and based on a linear-Bigelow equation. Both models predict reasonably well, although the multiparametric model presented a slightly better accuracy factor (1.11) than the one obtained with the linear-Bigelow equation (1.13). PMID- 11601721 TI - Dynamic optimization of human walking. AB - A three-dimensional, neuromusculoskeletal model of the body was combined with dynamic optimization theory to simulate normal walking on level ground. The body was modeled as a 23 degree-of-freedom mechanical linkage, actuated by 54 muscles. The dynamic optimization problem was to calculate the muscle excitation histories, muscle forces, and limb motions subject to minimum metabolic energy expenditure per unit distance traveled. Muscle metabolic energy was calculated by slimming five terms: the basal or resting heat, activation heat, maintenance heat, shortening heat, and the mechanical work done by all the muscles in the model. The gait cycle was assumed to be symmetric; that is, the muscle excitations for the right and left legs and the initial and terminal states in the model were assumed to be equal. Importantly, a tracking problem was not solved. Rather only a set of terminal constraints was placed on the states of the model to enforce repeatability of the gait cycle. Quantitative comparisons of the model predictions with patterns of body-segmental displacements, ground-reaction forces, and muscle activations obtained from experiment show that the simulation reproduces the salient features of normal gait. The simulation results suggest that minimum metabolic energy per unit distance traveled is a valid measure of walking performance. PMID- 11601722 TI - Experimental and finite element comparison of various fixation designs in combined loads. AB - The short- and long-term successes of tibial cementless implants depend on the initial fixation stability often provided by posts and screws. In this work, a metallic plate was fixed to a polyurethane block with either two bone screws, two smooth-surfaced posts, or two novel smooth-surfaced posts with adjustable inclinations. For this last case, inclinations of 0, 1.5, and 3 deg were considered following insertion. A load of 1031 N was eccentrically applied on the plate at an angle of approximately 14 deg, which resulted in a 1000 N axial compressive force and a 250 N shear force. The response was measured under static and repetitive loading up to 4000 cycles at 1 Hz. The measured results demonstrate subsidence under load, lift-off on the unloaded side, and horizontal translation of the plate specially at the loaded side. Fatigue loading increased the displacements, primarily during the first 100 cycles. Comparison of various fixation systems indicated that the plate with screw fixation was the stiffest with the least subsidence and liftoff. The increase in post inclination from 0 to 3 deg stiffened the plate by diminishing the liftoff. All fixation systems demonstrated deterioration under repetitive loads. In general, the finite element predictions of the experimental fixation systems were in agreement with measurements. The finite element analyses showed that porous coated posts (modeled with nonlinear interface friction with and without coupling) generated slightly less resistance to liftoff than smooth-surfaced posts. In the presence of porous coated posts, Coulomb friction greatly overestimated the rigidity by reducing the liftoff and subsidence to levels even smaller than those predicted for the design with screw fixation. The sequence of combined load application also influenced the predicted response. Finally, the finite element model incorporating measured interface friction and pull-out responses can be used for the analysis of cementless total joint replacement systems during the post operation period. PMID- 11601723 TI - Design optimization of cementless femoral hip prostheses using finite element analysis. AB - Implant separation from bone tissue, resulting in the necessity for revision surgery, is a serious drawback of cementless total joint replacement. Unnatural stress distribution around the implant is considered the main reason for the failure. Optimization of the implant properties, especially its geometric parameters, is believed to be the right way to improve reliability of joint prosthetics. An efficient numerical model of thefemur-implant system is presented in the paper, including the finite element formulation featuring computation of sensitivity gradients, parametric mesh generator, and a gradient-based optimization scheme. Numerical examples show results of shape optimization of an implant for two sets of design parameters and for the initial stability criterion taken as the optimization goal. The optimum shape appears to be relatively long and proximally porous-coated on about half of its length. The method can be flexibly adjusted to various implant types, stress- and displacement-based optimum criteria, and geometric design parameters. PMID- 11601724 TI - Trabecular surface remodeling simulation for cancellous bone using microstructural voxel finite element models. AB - A computational simulation method for three-dimensional trabecular surface remodeling was proposed, using voxel finite element models of cancellous bone, and was applied to the experimental data. In the simulation, the trabecular microstructure was modeled based on digital images, and its morphological changes due to surface movement at the trabecular level were directly expressed by removing/adding the voxel elements from/to the trabecular surface. A remodeling simulation at the single trabecular level under uniaxial compressive loading demonstrated smooth morphological changes even though the trabeculae were modeled with discrete voxel elements. Moreover, the trabecular axis rotated toward the loading direction with increasing stiffness, simulating functional adaptation to the applied load. In the remodeling simulation at the trabecular structural level, a cancellous bone cube was modeled using a digital image obtained by microcomputed tomography (microCT), and was uniaxially compressed. As a result, the apparent stiffness against the applied load increased by remodeling, in which the trabeculae reoriented to the loading direction. In addition, changes in the structural indices of the trabecular architecture coincided qualitatively with previously published experimental observations. Through these studies, it was demonstrated that the newly proposed voxel simulation technique enables us to simulate the trabecular surface remodeling and to compare the results obtained using this technique with the in vivo experimental data in the investigation of the adaptive bone remodeling phenomenon. PMID- 11601725 TI - The role of flow-independent viscoelasticity in the biphasic tensile and compressive responses of articular cartilage. AB - A long-standing challenge in the biomechanics of connective tissues (e.g., articular cartilage, ligament, tendon) has been the reported disparities between their tensile and compressive properties. In general, the intrinsic tensile properties of the solid matrices of these tissues are dictated by the collagen content and microstructural architecture, and the intrinsic compressive properties are dictated by their proteoglycan content and molecular organization as well as water content. These distinct materials give rise to a pronounced and experimentally well-documented nonlinear tension-compression stress-strain responses, as well as biphasic or intrinsic extracellular matrix viscoelastic responses. While many constitutive models of articular cartilage have captured one or more of these experimental responses, no single constitutive law has successfully described the uniaxial tensile and compressive responses of cartilage within the same framework. The objective of this study was to combine two previously proposed extensions of the biphasic theory of Mow et al. [1980, ASME J. Biomech. Eng., 102, pp. 73-84] to incorporate tension-compression nonlinearity as well as intrinsic viscoelasticity of the solid matrix of cartilage. The biphasic-conewise linear elastic model proposed by Soltz and Ateshian [2000, ASME J. Biomech. Eng., 122, pp. 576-586] and based on the bimodular stress-strain constitutive law introduced by Curnier et al. [1995, J. Elasticity, 37, pp. 1-38], as well as the biphasic poroviscoelastic model of Mak [1986, ASME J. Biomech. Eng., 108, pp. 123-130], which employs the quasi-linear viscoelastic model of Fung [1981, Biomechanics: Mechanical Properties of Living Tissues, Springer-Verlag, New York], were combined in a single model to analyze the response of cartilage to standard testing configurations. Results were compared to experimental data from the literature and it was found that a simultaneous prediction of compression and tension experiments of articular cartilage, under stress-relaxation and dynamic loading, can be achieved when properly taking into account both flow-dependent and flow-independent viscoelasticity effects, as well as tension-compression nonlinearity. PMID- 11601726 TI - A linear viscoelastic biphasic model for soft tissues based on the Theory of Porous Media. AB - Based on the Theory of Porous Media (mixture theories extended by the concept of volume fractions), a model describing the mechanical behavior of hydrated soft tissues such as articular cartilage is presented. As usual, the tissue will be modeled as a materially incompressible binary medium of one linear viscoelastic porous solid skeleton saturated by a single viscous pore-fluid. The contribution of this paper is to combine a descriptive representation of the linear viscoelasticity law for the organic solid matrix with an efficient numerical treatment of the strongly coupled solid-fluid problem. Furthermore, deformation dependent permeability effects are considered. Within the finite element method (FEM), the weak forms of the governing model equations are set up in a system of differential algebraic equations (DAE) in time. Thus, appropriate embedded error controlled time integration methods can be applied that allow for a reliable and efficient numerical treatment of complex initial boundary-value problems. The applicability and the efficiency of the presented model are demonstrated within canonical, numerical examples, which reveal the influence of the intrinsic dissipation on the general behavior of hydrated soft tissues, exemplarily on articular cartilage. PMID- 11601727 TI - Total strain fields of the antero-inferior shoulder capsule under subluxation: a stereoradiogrammetric study. AB - The antero-inferior capsule (AIC) is the primary restraint to antero-inferior glenohumeral dislocation. This study utilizes a biomechanical model to determine the total strain field of the AIC in a subluxed shoulder. Strains were calculated from two capsule states: a nominal strain state set by inflation and a strained state set by subluxation. Marker coordinates on the AIC were reconstructed from stereoradiographs and strain fields calculated. Peak strain on the glenoid side of the AIC was significantly greater than the humeral side and strain fields were highly variable. This study reports an accurate method for measuring planar strains in a three-dimensional membrane. PMID- 11601728 TI - The influence of surface padding properties on head and neck injury risk. AB - A validated computational head-neck model was used to understand the mechanical relationships between surface padding characteristics and injury risk during impacts near the head vertex. The study demonstrated that injury risk can be decreased by maximizing the energy-dissipating ability of the pad, choosing a pad stiffness that maximizes pad deformation without bottoming out, maximizing pad thickness, and minimizing surface friction. That increasing pad thickness protected the head without increasing neck loads suggests that the increased cervical spine injury incidence previously observed in cadaveric impacts to padded surfaces relative to lubricated rigid surfaces was due to increased surface friction rather than pocketing of the head in the pad. PMID- 11601729 TI - An analytically solvable model for biomechanical response of the cornea to refractive surgery. AB - An analttically solvable model that considers the elasticity of the cornea is developed for use in the current and novel corneal refractive surgery procedures. The model assumes that the cornea is a thin spheroid shell with an elastic response to intraocular pressure. The value of the Young's modulus of the post operative cornea and its dependence on the geometric parameters of the ablation zone are estimated employing "best-fit" approach to nomograms currently used in corneal refractive surgery. These elasticity parameters are applied for quantitative modeling of different types of refractive surgery for myopia. PMID- 11601730 TI - The surface-tension-driven flow of blood from a droplet into a capillary tube. AB - In tissue, medical, or dental engineering, when blood comes into contact with a new artificial material, the flow may be influenced by surface tension between the blood and the surface of the material. The effect of surface tension on the flow of blood is significant, especially in microscale. The leading edge of the flowing blood is the triple point where the blood, the material surface, and a stationary gas orfluid meet. The movement of the triple point, i.e., the advancing front of the flow, is driven by surface tension, resisted by viscous shear stress, and balanced by the inertial force (-mass x acceleration). In this article, the dynamics is illustrated in detail in the case of blood flowing into a capillary tube by contact. The capillar, tube draws the blood into it. It is shown theoretically that initially the flow of blood in the capillary has a large acceleration, followed by a relatively large deceleration over the next short period of time, then the acceleration becomes small and oscillatory. The velocity history appears impulsive at first, then slows down. The history of the length of blood column appears smooth after integration. Existing solutions of the Navier Stokes equation permit the analysis of simpler cases. Further fluid mechanics development is needed to meet the practical needs of bioengineering. The importance of experimental study of surface tension and contact angle over a biological surface or a man-made material as a future direction of research is pointed out. PMID- 11601731 TI - Analysis of temporal shear stress gradients during the onset phase of flow over a backward-facing step. AB - Endothelial cells in blood vessels are exposed to bloodflow and thus fluid shear stress. In arterial bifurcations and stenoses, disturbed flow causes zones of recirculation and stagnation, which are associated with both spatial and temporal gradients of shear stress. Such gradients have been linked to the generation of atherosclerotic plaques. For in-vitro studies of endothelial cell responses, the sudden-expansion flow chamber has been widely used and described. A two dimensional numerical simulation of the onset phase of flow through the chamber was performed. The wall shear stress action on the bottom plate was computed as a function of time and distance from the sudden expansion. The results showed that depending on the time for the flow to be established, significant temporal gradients occurred close to the second stagnation point of flow. Slowly ramping the flow over 15 s instead of 200 ms reduces the temporal gradients by a factor of 300, while spatial gradients are reduced by 23 percent. Thus, the effects of spatial and temporal gradients can be observed separately. In experiments on endothelial cells, disturbed flow stimulated cell proliferation only when flow onset was sudden. The spatial patterns of proliferation rate match the exposure to temporal gradients. This study provides information on the dynamics of spatial and temporal gradients to which the cells are exposed in a sudden-expansion flow chamber and relates them to changes in the onset phase of flow. PMID- 11601732 TI - Intimal hyperplasia and wall shear in arterial bypass graft distal anastomoses: an in vivo model study. AB - The observation of intimal hyperplasia at bypass graft anastomoses has suggested a potential interaction between local hemodynamics and vascular wall response. Wall shear has been particularly implicated because of its known effects upon the endothelium of normal vessels and, thus, was examined as to its possible role in the development of intimal hyperplasia in arterial bypass graft distal anastomoses. Tapered (4-7 mm I.D.) e-PTFE synthetic grafts 6 cm long were placed as bilateral carotid artery bypasses in six adult, mongrel dogs weighing between 25 and 30 kg with distal anastomotic graft-to-artery diameter ratios (DR) of either 1.0 or 1.5. Immediately following implantation, simultaneous axial velocity measurements were made in the toe and artery floor regions in the plane of the anastomosis at radial increments of 0.35 mm, 0.70 mm, and 1.05 mm using a specially designed 20 MHz triple crystal ultrasonic wall shear rate transducer Mean, peak, and pulse amplitude wall shear rates (WSRs), their absolute values, the spatial and temporal wall shear stress gradients (WSSG), and the oscillatory shear index (OSI) were computed from these velocity measurements. All grafts were harvested after 12 weeks implantation and measurements of the degree of intimal hyperplasia (IH) were made along the toe region and the artery floor of the host artery in 1 mm increments. While some IH occurred along the toe region (8.35+/ 23.1 microm) and was significantly different between DR groups (p<0.003), the greatest amount occurred along the artery floor (81.6+/-106.5 microm, mean +/- S.D.) (p < 0.001) although no significant differences were found between DR groups. Linear regressions were performed on the paired IH and mean, peak, and pulse amplitude WSR data as well as the absolute mean, peak, and pulse amplitude WSR data from all grafts. The mean and absolute mean WSRs showed a modest correlation with IH (r = -0.406 and -0.370, respectively) with further improvements seen (r = -0.482 and -0.445, respectively) when using an exponential relationship. The overall best correlation was seen against an exponential function of the OSI (r = 0.600). Although these correlation coefficients were not high, they were found to be statistically significant as evidenced by the large F statistic obtained. Finally, it was observed that over 75 percent of the IH occurred at or below a mean WSR value of 100 s(-1) while approximately 92 percent of the IH occurred at or below a mean WSR equal to one-half that of the native artery. Therefore, while not being the only factor involved, wall shear (and in particular, oscillators wall shear) appears to provide a stimulus for the development of anastomotic intimal hyperplasia. PMID- 11601733 TI - Blood flow in abdominal aortic aneurysms: pulsatile flow hemodynamics. AB - Numerical predictions of blood flow patterns and hemodynamic stresses in Abdominal Aortic Aneurysms (AAAs) are performed in a two-aneurysm, axisymmetric, rigid wall model using the spectral element method. Physiologically realistic aortic blood flow is simulated under pulsatile conditions for the range of time averaged Reynolds numbers 50< or =Re(m)< or =300, corresponding to a range of peak Reynolds numbers 262.5< or =Re(peak) < or = 1575. The vortex dynamics induced by pulsatile flow in AAAs is characterized by a sequence of five different flow phases in one period of the flow cycle. Hemodynamic disturbance is evaluated for a modified set of indicator functions, which include wall pressure (p(w)), wall shear stress (tau(w)), and Wall Shear Stress Gradient (WSSG). At peak flow, the highest shear stress and WSSG levels are obtained downstream of both aneurysms, in a pattern similar to that of steady flow. Maximum values of wall shear stresses and wall shear stress gradients obtained at peak flow are evaluated as a function of the time-average Reynolds number resulting in a fourth order polynomial correlation. A comparison between predictions for steady and pulsatile flow is presented, illustrating the importance of considering time dependent flow for the evaluation of hemodynamic indicators. PMID- 11601734 TI - Steady-state pleural fluid flow and pressure and the effects of lung buoyancy. AB - Both theoretical and experimental studies of pleural fluid dynamics and lung buoyancy during steady-state, apneic conditions are presented. The theory shows that steady-state, top-to-bottom pleural-liquid flow creates a pressure distribution that opposes lung buoyancy. These two forces may balance, permitting dynamic lung floating, but when they do not, pleural-pleural contact is required. The animal experiments examine pleural-liquid pressure distributions in response to simulated reduced gravity, achieved by lung inflation with perfluorocarbon liquid as compared to air. The resulting decrease in lung buoyancy modifies the force balance in the pleural fluid, which is reflected in its vertical pressure gradient. The data and model show that the decrease in buoyancy with perfluorocarbon inflation causes the vertical pressure gradient to approach hydrostatic. In the microgravity analogue, the pleural pressures would be toward a more uniform distribution, consistent with ventilation studies during space flight. The pleural liquid turnover predicted by the model is computed and found to be comparable to experimental values from the literature. The model provides the flow field, which can be used to develop a full transport theory for molecular and cellular constituents that are found in pleural fluid. PMID- 11601735 TI - Laser-Doppler measurements of velocities just downstream of a collapsible tube during flow-induced oscillations. AB - The flow field less than one diameter downstream of the end of a collapsible tube executing self excited oscillations was examined using a two-component fiber optic laser-Doppler anemometer. The time-averaged Reynolds number of the flow was 11,000. With the tube oscillating periodically, results obtained during many cycles of oscillation were combined to yield surface plots of the axial component over the cross section at 16 phases of the cycle. By combining measurements obtained with the laser probe in two different orientations, secondary flow vectors over the cross section were likewise constructed for 16 phases. The measurements showed strongly phasic turbulence intensity, with the phase of high intensity coinciding with the time of maximal tube collapse. Reverse flow occurred during much of the cycle, at places in the cross section that agree with our previous observations of laminar and turbulent steady flow through a rigid simulated collapsed tube. PMID- 11601736 TI - Pulsatile blood flow effects on temperature distribution and heat transfer in rigid vessels. AB - The effect of blood velocity pulsations on bioheat transfer is studied. A simple model of a straight rigid blood vessel with unsteady periodic flow is considered. A numerical solution that considers the fully coupled Navier-Stokes and energy equations is used for the simulations. The influence of the pulsation rate on the temperature distribution and energy transport is studied for four typical vessel sizes: aorta, large arteries, terminal arterial branches, and arterioles. The results show that: the pulsating axial velocity produces a pulsating temperature distribution; reversal of flow occurs in the aorta and in large vessels, which produces significant time variation in the temperature profile. Change of the pulsation rate yields a change of the energy transport between the vessel wall and fluid for the large vessels. For the thermally important terminal arteries (0.04-1 mm), velocity pulsations have a small influence on temperature distribution and on the energy transport out of the vessels (8 percent for the Womersley number corresponding to a normal heart rate). Given that there is a small difference between the time-averaged unsteady heat flux due to a pulsating blood velocity and an assumed nonpulsating blood velocity, it is reasonable to assume a nonpulsating blood velocity for the purposes of estimating bioheat transfer. PMID- 11601737 TI - Virus transmission through compromised synthetic barriers: part I--effect of unsteady driving pressures. AB - Although synthetic membranes such as gloves, condoms, and instrument sheaths are used in environments with highly time-varying stresses, their effectiveness as barriers to virus transmission is almost always tested under static conditions. In this paper it is shown how a previously developed mathematical model can be used to transform information from static barrier tests into predictions for more realistic use conditions. Using a rate constant measured for herpes adsorption to latex in saline, and an oscillatory trans-membrane pressure representative of coitus, the amount of virus transmitted through a hole (2 microm diameter) in a condom is computed. Just beyond the exit orifice of the pore, transport is dominated by the rapidly dissipating viscous jet of virus suspension, which results in an accumulation of viruses roughly 20 pore radii from the barrier surface during each cycle. Due to virus adsorption to the barrier surfaces, the simulations reveal a gradual decrease in virus flow with increasing number of cycles, and thus a slow divergence from predictions based upon steady-state conditions. Still, over the 500 cycles simulated, steady-state predictions approximate the net number of viruses transmitted to within 25 percent error. PMID- 11601738 TI - Virus transmission through compromised synthetic barriers: part II--influence of pore geometry. AB - When stressed during normal use, synthetic barriers such as gloves and condoms can develop tears that are undetectable by the user. It is of considerable public health importance to estimate the quantity of virus transmitted through the tear, in the event of viral contamination of the fluid medium. A mathematical model that accounts for virus adsorption to the barrier material was used to compute the quantity of virus transmitted through defects of various geometries. Slits were modeled as cylinders of elliptic cross section, and upper and lower bounds for the transmission rate of HIV and Hepatitis B virus (HBV) were calculated for barrier-use scenarios such as coitus and gripping of surgical instruments. For a 1-microm high slit, HIV transmission was found to be negligible for all likely use scenarios. HIV transmission became potentially significant for a 5-microm slit. Due to its high titer, HBV transmitted at potentially important levels even through the 1-microm slit. The dependence of the transmission rate upon pore aspect ratio was determined and found to be very strong for high-adsorption situations and near-circular pores. Numerical predictions of virus transport through a laser-drilled hole in a condom matched experimental measurements well, even when the tapered nature of the geometry is ignored. PMID- 11601739 TI - The asymmetry of transient response in compression versus release for cartilage in unconfined compression. AB - Observations in compression tests of articular cartilage have revealed unequal load increments for compression and release of the same amplitude applied to a disk with an identical previously imposed compression (in equilibrium). The mechanism of this asymmetric transient response is investigated here using a nonlinear fibril-reinforced model. It is found that the asymmetry is predominantly produced by the fibril stiffening with its tensile strain. In addition, allowing the hydraulic permeability to decrease significantly with compressive dilatation of cartilage increases the transient fibril strain, resulting in a stronger asymmetry. Large deformation also enhances the asymmetry as a consequence of stronger fibril stiffening. PMID- 11601740 TI - Regulated exocytosis in immune function: are SNARE-proteins involved? PMID- 11601741 TI - Computer program supporting the diagnostic accuracy of cellular BALF analysis: a new release. AB - Recently we developed a validated computer program based on polychotomous logistic regression analysis using bronchoalveolar avage fluid (BALF) results to distinguish between the three most common interstitial lung diseases (ILD): sarcoidosis, idiopathic pulmonary fibrosis (IPF) and extrinsic allergic alveolitis (EAA) or drug-induced pneumonitis. One of the limitations of this program was that it was not useful in discriminating between infectious disorders and non-infectious disorders. Therefore, we added BALF samples obtained from patients with a confirmed bacterial pulmonary infection based on culture results > or = 10(4) cfum l(-1) (group I: n=31) to the study population mentioned above (group II: n=272). Notably, just one variable, i.e. the percentage of polymorphonuclear neutrophils, allowed us to distinguish between infectious and non-infectious disorders. The agreement of predicted with the actual diagnostic group membership was 99.67% (groups I and II). Additionally, 91.2% of the cases with ILD were correctly classified. In conclusion, this updated Windows version 2000 of the validated computer program provides a very reliable prediction of the correct diagnosis for an arbitrary patient with suspected pneumonia or with ILD given information obtained from BALF analysis results, and is thought to improve the diagnostic power of BALF analysis. PMID- 11601742 TI - Epstein-Barr virus and wild p53 in idiopathic pulmonary fibrosis. AB - Both Epstein-Barr virus (EBV) and p53 have independently been associated with idiopathic pulmonary fibrosis (IPF). This study explores further whether a relationship potentially exists between EBV and p53 in IPF, thereby providing a possible mechanism for the role of EBV in the disease progression of IPF. Lung tissue from open lung biopsies of 14 IPF patients was compared with a control group of 19 patients. EBV status was determined using both immunohistochemistry and PCR, while p53 expression was assessed with immunohistochemistry Seven of 14 IPF patients expressed p53 compared to one of 19 control subjects (P = 0.011). Eight IPF patients and no controls were positive for EBV (P < 0.01). Four IPF patients demonstrated both EBVand p53 expression compared with no controls, (P = 0.05). This study suggests that a relationship between EBV and p53 may exist in patients with IPF. PMID- 11601743 TI - Macrophages, neutrophils and tumour necrosis factor-alpha expression in bronchiectatic airways in vivo. AB - Bronchiectasis is increasingly being recognized as an inflammatory condition of the airways in which pathological permanent dilation occurs. We have obtained endobronchial biopsies in 14 patients with stable bronchiectasis and 15 control subjects. Airway neutrophils, macrophages and tumour necrosis factor-alpha (TNFalpha)-positive cells were stained with monoclonal antibodies and the densities of positive cells in the lamina propria were determined by using a computer image analyser. There was significantly higher neutrophil, macrophage and TNFalpha-positive cell densities in the lamina propria of bronchiectatic than control airways (P < 0.001, P < 0.001 and P=0.0002, respectively). Airway neutrophil density in bronchiectasis but not in controls, correlated with TNFalpha-positive cell density (r=0.71, P=0.004). A significant correlation between airway macrophage and TNFalpha-positive cell densities was demonstrated in both control and bronchiectatic airways (r=0.63, P=0.016 and r=0.60, P=0.02 respectively). Neutrophil density negatively correlated with per cent forced vital capacity (FVC%) predicted among patients with bronchiectasis (r=-0.53, P=0.04). Bronchiectasis patients who were regular sputum producers had a significantly higher macrophage, but not neutrophil density than their counterparts (P=0.02 and P=0.48 respectively). Our original findings suggest that airway macrophages could contribute to neutrophil influx into airway walls through their production of TNFalpha and therefore play an important role in the pathogenesis of bronchiectasis. PMID- 11601744 TI - Sputum eosinophilia in Churg-Strauss syndrome. AB - Sputum induction (IS) can be used to study airway inflammation in asthmatics and other lung diseases. However, no data are available for patients with Churg Strauss syndrome (CSS). A study was carried out to evaluate eosinophil counts and eosinophil cationic protein (ECP) levels in induced sputum during the follow-up of three patients with CSS. Induced sputum was carried out in 10 patients with corticosteroid-dependent asthma (used as a control group). Patients with CSS had significantly higher eosinophils percentages and ECP levels in sputum than those with stable corticosteroid-dependent asthma. During the follow-up, patients with CSS presented increased ECP levels sputum and eosinophils in sputum as well as increased blood eosinophils, despite their oral corticosteroid and immunosuppressive treatment. Eosinophil percentage in sputum and the total number of eosinophils in peripheral blood were more predictive of exacerbations of CSS than sputum ECP. PMID- 11601745 TI - Delays in the diagnosis and treatment of hospitalized patients with smear positive pulmonary tuberculosis. AB - The aim of present study was to investigate whether there was any delay in the diagnosis and treatment of inpatients with smear-positive pulmonary tuberculosis followed-up in our centre. We reviewed clinical records in February 1999 and identified 134 hospitalized patients with smear-positive pulmonary tuberculosis. Clinical files of the patients were analysed and a questionnaire was completed. Several intervals and delays were calculated. Median application interval was 17.5 days [95% confidence interval (CI) 21.3-32.4 days], median referral interval was 3.5 days (95% CI 6.8-11.4 days), median diagnosis interval was 3 days (95% CI 3.3-4.5 days) and median initiation of treatment interval was 1 day (95% CI 1.1 1.6 days). Patients delay was present in 28.4% of cases. The referral interval was longer than 2 days in 82 patients (institutional delay). Ninety-three patients (69.4%) had delays in the diagnosis and 34 patients (25.4%) had delays in the treatment. There was a doctor's delay in 119 of 134 patients (88.8%) and clinic's delay in 98 patients (73.2%). Our results have suggested that hospitalized patients with smear-positive pulmonary tuberculosis experience several delays. These delays may result in increased risk for transmission of infection. Decrease in the risk of infection for community and medical personal may only be obtained by preventing these delays. PMID- 11601746 TI - Increased level of bronchial responsiveness in inactive children with asthma. AB - We estimated the association between bronchial responsiveness and hours of exercise per week in children with and without asthma. A random sample of school children (n = 2188), 6-16 years old, was enrolled in a cross-sectional study of asthma in Oslo using the ISAAC questionnaire. Lung function and bronchial responsiveness (BR) using methacholine was measured in a random sample of 80 children with asthma, wheeze and no asthma/no wheeze. The relation between hours of exercise per week and BR [log (DRS)] was estimated by linear regression. Sex and age were included as covariates. Hours of exercise were categorized in: none, 30 min, 1 h, 2-3 h, 4-6 h and 7 h or more. The mean values of log (DRS) were different in the low and high exercise groups for children with asthma (P = 0.02), whereas there was no effect of exercise on BR for children without asthma. BR increased with decreasing hours of exercise per week in children with asthma. The bronchial responsiveness decreased with 0.11 (95% CI -0.20, -0.01) pr unit in scale. This pattern was not present in children without asthma. The results suggest that there is a relation between hours of exercise per week and bronchial responsiveness in children with asthma. PMID- 11601747 TI - Chlamydia pneumoniae infection and acute exacerbation of chronic obstructive pulmonary disease (COPD). AB - The objective of the study was to investigate the possible association of Chlamydia pneumoniae (Cpn) in acute exacerbations of chronic obstructive pulmonary disease (COPD) patients. Thirty-eight acutely exacerbated COPD patients and 17 healthy smokers were enrolled in the study, as the study and control groups respectively. Nasopharyngeal swabs and paired serum samples for antibody testing of Cpn (microimmunofluorescence--MIF) were obtained from all subjects. Sputum cultures of COPD patients were also performed. No pathogenic bacteria were isolated from nasopharyngeal swabs in any subject. Serologic evidence of recent Cpn infection was observed in 13 (34%) COPD patients and in one (5%) control subject. The prevalence of Cpn IgG and IgM antibodies representing acute infection were significantly higher in COPD patients than in control subjects (P < 0.05 and P < 0.01 respectively). Prevalence of IgA antibodies and IgG pre existing antibodies did not show any difference (P > 0.05). Microbiologic culture of the sputa yielded potentially pathogenic micro-organisms in 23 of 38 (60%) COPD patients. Alpha-haemolytic streptococcus (35%), Niesseria spp. (31%) and Candida spp. (9.5%) were most prominent micro-organisms in positive cultures. Although a high prevalence of IgG antibodies against Cpn was detected, it was the sole causative agent in only four (10%) patients. We conclude that a remarkable number of COPD patients (34%) are acutely infected with Cpn and it may either be the sole causative agent or frequently a co-agent in acute exacerbations. PMID- 11601748 TI - Rapid onset of bronchodilation in COPD: a placebo-controlled study comparing formoterol (Foradil Aerolizer) with salbutamol (Ventodisk). AB - Formoterol fumarate is a beta2-agonist bronchodilator that combines a fast onset of action with a long duration of action. Its fast onset of action is well documented in asthma but has not been directly compared with that of salbutamol in patients with chronic obstructive pulmonary disease (COPD). This randomized, double-blind, placebo-controlled study was conducted to assess the bronchodilatory effects over the first 3 h after inhalation of single doses of formoterol 24 microg delivered via the Aerolizer dry powder inhaler device (double-blind), or salbutamol 400 microg delivered by a Diskhaler dry powder inhaler (single-blind) in patients with COPD. A total of 24 patients with COPD were randomized [mean age 61.6 +/- 7.8 years, mean forced expiratory volume in 1 sec (FEV1) 1.38 +/- 0.32 l and 45.8 +/- 9.6% of predicted]. Inhalation of formoterol or salbutamol resulted in similar increases in FEV from 0 to 3 h post dose. Both drugs produced similar bronchodilation by 5 min, which became almost maximal by 30 min. The primary efficacy variable, the area under the curve (AUC) of the FEV increase above predose baseline from 0 to 30 min (AUC(0-30 min)), demonstrated significant effects for formoterol (mean 5.89 +/- 4.67 l min(-1)), and salbutamol (mean 6.06 +/- 4.34 l min(-1)), which were not statistically different from each other but statistically significantly higher (P<0.0001) than that observed with placebo (-0.32 +/- 2.59 l min(-1)). In addition, both formoterol and salbutamol produced similar and rapid increases in forced vital capacity (FVC). In summary, this study confirms the rapid onset of action of formoterol and indicates that the onset of action of formoterol and salbutamol are similar in patients with COPD. PMID- 11601749 TI - Induced sputum in the diagnosis of peripheral lung cancer not visible endoscopically. AB - The diagnosis of small peripheral lung cancer is difficult to achieve by non invasive methods. We hypothesized that in these patients induced sputum might ncrease the diagnostic yield over spontaneous sputum, representing a good diagnostic alternative in selected patients. We prospectively evaluated 60 patients with peripheral lung lesions and normal bronchoscopic evaluation. Six samples of sputum (three spontaneous and three induced with nebulization of hypertonic saline) before bronchoscopy and six samples of sputum after bronchoscopy (three spontaneous and three induced) were obtained in each subject. Forty-two out of the 60 patients included were finally diagnosed with lung cancer. Eighteen patients were diagnosed with different benign conditions of the lung. Overall, malignant cells in sputum were observed in 21 patients and in all but one, the final diagnosis of lung cancer was achieved. Only one patient with a pseudoinflammatory tumour of the lung had a false-positive result in one spontaneous sputum sample. The diagnosis of lung cancer was obtained in 18 patients with the induced sputum (43%) and in 14 patients with spontaneous sputum (31%) (P=NS). Samples of induced sputum were more adequate for cytological analysis than samples of spontaneous sputum (P < 0.001). Of 13 patients with peripheral lung neoplasms of 2 cm or less in diameter, five were diagnosed using induced sputum (38%) and only one using spontaneous sputum (8%) (P<0.05). In conclusion, induced sputum is a valuable technique for the diagnosis of peripheral lung cancer. Induced sputum gives better quality specimens and better diagnostic yield in small lesions than the spontaneous sputum and may be indicated in selected patients with disseminated disease, inoperability or severe co-morbities. PMID- 11601750 TI - Prognostic factors in diffuse malignant pleural mesothelioma: effects of pretreatment clinical and laboratory characteristics. AB - The aim of this study was to investigate the effects of various pretreatment clinical and laboratory characteristics on the survival of patients with diffuse malignant pleural mesothelioma (DMPM). One hundred histopathologically confirmed DMPM patients were evaluated. Fifty-nine were treated with chemoimmunotherapy while 41 who had refused chemoimmunotherapy received supportive therapy alone. The following pretreatment characteristics were evaluated in both univariate and multivariate Cox regression analyses: age, gender, Karnofsky performance score (KPS), histology asbestos exposure, presence of chest pain, dyspnoea, weight loss, symptom duration, smoking history, disease location, platelet count, haemoglobin, white blood cell (WBC) count, serum lactate dehydrogenase (LDH) and extent of disease (stage). Univariate analysis showed that patients with age > or = 75 years, male gender, smoking history advanced stages above stage I disease, KPS < 70, WBC count > or = 8450 and LDH level > or = 500 IU l(-1) have a worse prognosis. With multivariate Cox regression analyses, age > or = 75 years, advanced stages above stage I disease, KPS < 70 and LDH level > or = 500 IU l(-1) were found to be indicators of a poorer prognosis. In conclusion, in our study each of low performance status, older age, advanced stage disease, high LDH level and prognosis were found to be related. PMID- 11601751 TI - Delayed referral reduces the success of video-assisted thoracoscopic debridement for post-pneumonic empyema. AB - The aim of this study was to evaluate the effect of preoperative delay on the efficacy of video-assisted thoracoscopic surgery (VATS) for post-pneumonic pleural empyema (PPE). This was a prospective study of 39 consecutive patients with PPE who were treated by VATS with curative intent over a 4-year period. Failure to obtain full lung re-expansion resulted in conversion to thoracotomy. Pre- and post-operative variables were correlated with surgical outcome. VATS debridement was successful in 16 (41%) patients while conversion to open decortication was needed in 23 patients (21 immediate, two delayed), There was no difference in the age/sex distribution of the two groups. In the failed VATS group the delay from hospital admission to operation was longer: 24 (2.1) vs. 16.6 (2.7) days (P = 0.03, 95% CI 0.53-14.3 days); operating time was longer: 128.2 (7.9) vs. 86.2 (10.4) min (P = 0.003, 95% CI 15.2-68.5 min) and post operative stay was longer: 8.4 (0.8) vs. 5.2 (0.6) days (P = 0.03, 95% CI 1.1-5.3 days). VATS can be used successfully to treat PPE with a faster post-operative recovery when successful than open surgery. Delayed surgical intervention decreases the success of VATS thus earlier referral for surgical intervention in PPE (ideally within 21 days) is advocated to gain its full benefits. PMID- 11601752 TI - Multi-focal tuberculosis with multiple intracranial tuberculomas in a non immunocompromised patient. PMID- 11601753 TI - Glaucoma associated with metered-dose bronchodilator therapy. PMID- 11601754 TI - Gene therapy for cystic fibrosis. AB - Cystic fibrosis (CF) is associated with significant morbidity and mortality, despite significant advances in conventional treatment. The field of gene therapy has progressed rapidly since the cystic fibrosis transmembrane conductance regulator (CFTR) gene was cloned. In this review we discuss current knowledge on the underlying molecular defect in CF, and the progress in gene transfer studies from the early in vitro work through to clinical trials, including the development of endpoints to assess efficacy. We highlight the problems encountered, and likely future directions of the field. PMID- 11601755 TI - Genetic reshuffling reconstitutes functional expression cassettes in retroviral vectors. AB - BACKGROUND: A major prerequisite for the design of retroviral vectors encoding cell toxic or harmful genes is the possibility to tightly control gene expression, thus limiting activity to the relevant target cells and protecting the packaging cell used for production of recombinant viral particles. METHODS: In the present study a system was developed in which genetic reshuffling during the retroviral life cycle is exploited, allowing reconstitution of functional expression cassettes from separate elements exclusively in transduced target cells. For construction of these murine leukaemia virus (MLV)-based reconstituting viral vectors (ReCon), a promoterless inverted enhanced green fluorescent protein (EGFP) reporter gene cassette was inserted in place of the U3 region of the 3' LTR. Subsequently, the human ubiquitin promoter was inserted in the inverse orientation into the R/U5 border of the 5' LTR of the vector. RESULTS: PA317 packaging cells stably transfected with ReCon vectors were established and EGFP expression was analysed by fluorescence-activated cell sorting (FACS). After detection of low-level background expression, an additional polyadenylation signal was introduced in antisense orientation into the 3' LTR at the R/U5 border to prevent accidental read-through transcription from neighbouring cellular promoters. Virus-containing cell culture supernatants were then used to infect NIH3T3 target cells. EGFP expression, recloning and sequencing of integrated proviruses demonstrated the correct reassembly of the transduced ubiquitin/EGFP transcription unit in these infected cells. CONCLUSIONS: This facile and convenient system should allow production of retroviral vectors encoding potentially toxic proteins, cell cycle inhibitors or inducers of apoptosis, all of which would interfere with vector production if expressed in the retroviral packaging cell. PMID- 11601756 TI - Optimization of retroviral vector generation for clinical application. AB - BACKGROUND: For many inherited and acquired diseases of the blood system, gene transfer into hematopoietic cells is a promising strategy to alleviate disease related symptoms or even correct genetic alterations. In clinical gene therapy applications, low transduction efficiencies have been a major limitation mainly because of insufficient effective titers of the retroviral supernatants used. Thus, optimization of clinical-grade vector production under current 'Good Manufacturing Practice' (GMP) conditions is a prerequisite for successful gene therapy trials. METHODS: We established stable retroviral producer clones with single integrations of a retroviral vector encoding for the multidrug-resistance gene 1 (MDR1). Optimization of vector production in multi-tray cell factories (MTCFs) was studied with particular regard to harvest medium, cell density and harvest time point. RESULTS: We demonstrated that high-titer vector stocks could be produced in serum-free medium. By reducing the volume of harvest medium, titers could be increased up to four-fold. Plating optimal cell densities of 1 x 10(4) cells/cm2, repetitive harvests of vector supernatant were feasible over four consecutive days. Combining the most advantageous culture and harvest parameters tested, we were able to produce large quantities of serum-free vector supernatant in 40-tray MTCFs. Highly efficient gene transfer into primary human CD34+ progenitor cells demonstrated the quality of these vector stocks. CONCLUSION: The large-scale vector-production protocol in MTCFs described here is easy to handle, is applicable to a wide range of adherent producer cell lines and, most importantly, complies with current GMP guidelines. PMID- 11601757 TI - Non-invasive observation of repeated adenoviral GFP gene delivery to the anterior segment of the monkey eye in vivo. AB - BACKGROUND: Glaucoma is a group of chronic eye diseases often associated with an elevated intraocular pressure (IOP). If not controlled, the condition leads to blindness. The eye tissue responsible for maintaining aqueous humor resistance and thus normal IOP is the trabecular meshwork (TM). Adenoviral vectors are capable of transducing the TM in several rodent species. Because of the relevance of the non-human primate model in the study of glaucoma, gene transfer to the eyes of cynomolgus monkeys was investigated. METHODS: Four cynomolgus monkeys were injected with AdenoGFP into the anterior chamber: two monkeys received 10(9) pfu and the other two 10(7) pfu. One monkey received four consecutive injections into the same eye (10(7) pfu in each injection) over a 7-month period. In vivo gene transfer (fluorescence) and IOP were evaluated by standard clinical ophthalmic instruments (slit lamp biomicroscopy, gonioscopy and tonometry). Histopathology and cellular distribution were assessed postmortem. RESULTS: The first injection of the lower viral dose resulted in marked TM-preferred gene transfer visible non-invasively by in vivo gonioscopy. The expression of the transgene lasted for 3-4 weeks with little or no signs of clinical inflammation. Gene transfer was achieved on three sequential occasions (3-4 weeks each) but failed and induced substantial, albeit reversible, corneal abnormalities on the fourth occasion. CONCLUSIONS: Gene transfer to the TM and cornea can be monitored non-invasively in non-human primates, allowing correlation of gene transfer with physiological parameters. Because of ocular immune privilege, repeated anterior chamber administrations of adenoviral vectors expressing appropriate genes may have therapeutic potential for glaucoma. PMID- 11601758 TI - Protection from experimental endotoxemia by a recombinant adeno-associated virus encoding interleukin 10. AB - BACKGROUND: Interleukin 10 (IL-10) is a homodimeric cytokine that shows considerable clinical promise. Adeno-associated virus (AAV) vectors appear increasingly useful for in vivo gene-transfer applications. METHODS: A recombinant AAV type 2 vector encoding human IL-10 (rAAVhIL10) was constructed by using an adenoviral-free, three-plasmid co-transfection. Cytokine production was measured by using an enzyme-linked immunosorbent assay. Endotoxic shock was induced by lipopolysaccharide (LPS) injection. RESULTS: As media from rAAVhIL10 infected COS cells caused a dose-dependent blockade of IL-12 secretion from spleen cells of IL-10 knockout (KO) mice challenged with Brucella abortus, it was clear that vector-derived hIL-10 was biologically active in vitro. Intravenous or intramuscular administration of relatively modest levels of rAAVhIL10 (10(10) genomes) to IL-10 KO mice resulted in hIL-10 secretion into the bloodstream, which, at 8 weeks, gave median serum levels of 0.9 and 0.45 pg/ml, respectively. Acute endotoxic shock led to a 33% mortality rate, and severe morbidity, in control IL-10 KO mice, whereas no mortality and little morbidity were seen in IL 10 KO mice given rAAVhIL10 7 weeks earlier. CONCLUSIONS: The findings demonstrate that a modest dose of rAAVhIL10 administered in vivo provides long-term protection against LPS-induced endotoxic shock in a murine model. Thus, this vector may be useful for clinical applications requiring sustained IL-10 expression, for example in the treatment of several autoimmune diseases. PMID- 11601759 TI - Preclinical safety testing of DISC-hGMCSF to support phase I clinical trials in cancer patients. AB - BACKGROUND: DISC-hGMCSF is a gH-deleted HSV-2 based vector expressing human GM CSF that is being developed for cancer immunotherapy. To support first clinical use, a range of preclinical safety studies were performed using DISC-hGMCSF in addition to DISC-murine-GMCSF and the backbone vector, TA-HSV. METHODS: The toxicity of the DISC vectors was assessed by repeated dose, neurovirulence and neuroinvasiveness studies in mice, and by safety studies in rabbits, guinea pigs and athymic nude mice. Studies were also conducted to determine whether the vector could establish latency in local ganglia in mice following intradermal injection, and whether it could reactivate from the latent state. The vector biodistribution following intravenous administration was also investigated in mice, using PCR to detect vector DNA. RESULTS: The DISC vectors were essentially non-toxic in all the systems studied. No adverse reactions were seen in mice receiving four intravenous doses of DISC-mGMCSF and the results from studies of neurovirulence, neuroinvasiveness, local tolerance in rabbit, general safety in mice and guinea pigs and safety in athymic nude mice were consistent with DISC being unable to replicate and cause disease. The vector could establish latency in local ganglia in mice, but at low efficiency, and could not reactivate infectious virions. Following intravenous administration, vector DNA was widely distributed up to Day 28, but by Day 56 had disappeared from gonads and brain and was only found in blood and liver. CONCLUSION: The panel of safety studies provided evidence that DISC-hGMCSF will be unable to replicate and cause disease, and has low toxicity in man. These data were presented to the Medicines Control Agency and the Gene Therapy Advisory Committee as part of the regulatory submissions for a clinical trial in melanoma patients. These submissions have been approved, and DISC-hGMCSF has now entered a phase I clinical trial in the UK by direct intratumoural injection. PMID- 11601760 TI - Replication-deficient vaccinia virus gene therpay vector: evaluation of exogenous gene expression mediated by PUV-inactivated virus in glioma cells. AB - BACKGROUND: Mild psoralen and UV (PUV) treatments inactivate viral DNA replication, but the virus retains its ability to infect cells. Thus, PUV treatment of vaccinia virus (VV) vectors may increase the safety of gene delivery and extend the duration of gene expression. Although the first studies on PUV inactivated VV (PUV-VV) for the delivery of suicide or cytokine genes to cancer cells were promising, the efficiency and kinetics of exogenous gene expression have not been fully evaluated. Furthermore, these studies should be extended to other gene therapy strategies, e.g. tumor suppressor genes. METHODS: We constructed VV recombinants carrying the luciferase (luc) gene, or the tumor suppressor p53 gene, to analyze exogenous gene expression after PUV treatment. Apoptosis induction and antitumor effects were examined in glioma cell culture and in an animal model, respectively. RESULTS: PUV-VV induced efficient PE/L driven expression of luc and p53 exogenous genes in infected cells. A surprising prolonged p53 protein production was measured in glioma cells infected with PUV VV expressing p53 (VV-TK-53) on Days 5-7 post-infection, reaching a maximal level of 9 microg/ml. VV-TK-53 induced apoptosis in 88% and 77.6% of infected C6 and 9L glioma cells, respectively. In contrast, 80% of cells infected with the PUV inactivated control virus remained viable. Finally, ex vivo infection of C6 glioma cells with PUV-inactivated VV-TK-53 significantly reduced subsequent tumor growth in nude mice. CONCLUSIONS: Replication-deficient PUV-VV is safe and very efficient in prolonged foreign gene expression. Therefore PUV-VVs are recommended as vectors for applications in cancer gene therapy and recombinant vaccine development. PMID- 11601761 TI - Sterically stabilized BGTC-based lipoplexes: structural features and gene transfection into the mouse airways in vivo. AB - BACKGROUND: Colloidal stability of lipid/DNA aggregates is a major requirement for cationic lipid-mediated transfection which is particularly difficult to fulfil at the high DNA concentrations used for in vivo gene delivery. Thus, we have investigated the potential of poly(ethyleneglycol) (PEG) conjugates for steric stabilization of lipoplexes formed by bis(guanidinium)-tren cholesterol/dioleoyl phosphatidylethanolamine (BGTC/DOPE) liposomes, a class of cationic liposomes we have developed over the past few years. METHODS AND RESULTS: We demonstrate that adequate lipophilic PEG derivatives can stabilize BGTC/DOPE lipoplexes formed at high DNA concentration. We also report the results of cryotransmission electron microscopy studies indicating that PEG-stabilized lipoplexes form DNA-coated structures which assemble into clusters exhibiting various complex morphologies. Finally, we report data from in vivo transfection experiments suggesting that PEG-mediated colloidal stabilization of concentrated lipoplex solutions may allow enhanced transfection of the mouse airways via intranasal administration. CONCLUSION: Our results represent an important step towards the design of multimodular BGTC-based systems for improved in vivo gene transfection. PMID- 11601762 TI - Non-viral, integrin-mediated gene transfer into fibroblasts from patients with lysosomal storage diseases. AB - BACKGROUND: Non-viral vectors consisting of Lipofectin/integrin-targeting peptide/DNA (LID) complexes have great potential for gene therapy, as they are safe, simple, and able to package large DNA molecules. In this study, these vectors were evaluated in vitro for the therapy of lysosomal storage disorders. METHODS: Non-viral vectors were designed to deliver therapeutic genes by integrin mediated uptake into fibroblasts from patients with the lysosomal storage disorders fucosidosis and Fabry disease, which result from deficiencies of alpha L-fucosidase and alpha-galactosidase A, respectively. The vectors consisted of a complex (LID) of Lipofectin and a peptide containing an integrin-targeting domain and a poly-lysine domain to which was bound plasmid DNA, containing alpha-L fucosidase (LID-alpha-Fuc) or alpha-galactosidase A (LID-alpha-Gal). RESULTS: Patients' fibroblasts transfected with LID-alpha-Fuc and LID-alpha-Gal produced the corresponding enzyme at levels which were 10-40% of the total activity in cultures of normal fibroblasts. However, 95-98% of this activity was secreted. Transfection of endothelial cells, the main target cells in Fabry disease, with an LID-alpha-Gal produced a total alpha-galactosidase activity 65% higher than that in untransfected cultures after 6 days, 67% of the activity being secreted. Although transfection of fibroblasts with LID complexes also caused small changes in the distribution of endogenous lysosomal enzymes, it did not appear to affect the viability of the cells. CONCLUSIONS: The integrin-mediated transfer of genes encoding lysosomal enzymes into cells results in the secretion of large amounts of normal enzyme that could be taken up by other cells. This could be a useful strategy for enzyme-replacement therapy. PMID- 11601763 TI - Oxygen tension and a pharmacological switch in the regulation of transgene expression for gene therapy. AB - BACKGROUND: The combination of physiologically and pharmacologically controlled elements may provide a means to ensure both the regulation and the safety of transgene expression--two major goals in gene therapy. METHODS: A two-gene modulation system was developed that uses the following three levels of control: (i) the hypoxia-responsive element directing the transcription of the tetracycline-controlled transactivator (tTA); (ii) part of the oxygen-degradation domain limiting the production of tTA in normoxia; and (iii) the tetracycline switch of the transactivator activity (the tet-off system). RESULTS: This triple control system allowed high expression of the gene of interest (luciferase or erythropoietin) by transfected cells upon hypoxia and low expression under normoxia or in the presence of tetracycline. This control of transgene expression was also obtained in mouse tumors. CONCLUSIONS: This multiple-control system is of interest for spatially restricting transgene expression into hypoxic tumors, and for finely adjusting the expression level of a therapeutic protein to the oxygen supply in medical applications such as neoangiogenesis or the erythropoietin-mediated treatment of anemia. PMID- 11601764 TI - Efficient ablation by immunotoxin-mediated cell targeting of the cell types that express human interleukin-2 receptor depending on the internal ribosome entry site. AB - BACKGROUND: Immunotoxin-mediated cell targeting (IMCT) is a technique for conditional genetic ablation of specific cell types. IMCT provides a useful approach for generating animal models for human neurodegenerative disorders. The strategy of IMCT depends on the cytotoxic activity of antiTac-based recombinant immunotoxins that selectively target cells expressing the human interleukin-2 receptor alpha-subunit (IL-2Ralpha). Transgenic mice were generated that express the IL-2Ralpha under the control of an appropriate tissue-specific gene promoter, and they were treated with the recombinant immunotoxins resulting in the ablation of the target cell types. To restrict the expression of IL-2Ralpha transgene in the cell types of interest, it is useful to knock-in the IL-2Ralpha expression cassette into the specific marker gene locus with gene targeting. Moreover, the knock-in of the IL-2Ralpha cassette located downstream of an internal ribosome entry site (IRES) into the 3'-untranslated region of the marker gene enables IL 2Ralpha expression in the restricted cell types while preserving the intact marker gene expression. However, there is a possibility that IRES-dependent expression of the receptor may be less efficient than cap-dependent expression. METHODS AND RESULTS: The efficiency of IRES-dependent IL-2Ralpha expression and immunotoxin responsiveness of the cells expressing the receptor were examined. The IL-2Ralpha gene fused to green fluorescence protein (GFP) (IL-2R/ GFP) was used as the target receptor. Embryonic stem cell clones were isolated that carry two types of bicistronic vectors in which the IL-2R/GFP fusion gene or the chloramphenicol acetyltransferase gene was connected upstream or downstream of IRES. The expression level of IL-2R/GFP protein in the cell clones was evaluated by GFP fluorescence detection and Western blot analysis. The IRES-dependent expression produced the same level of receptor protein as cap-dependent expression. The immunotoxin responsiveness of the cloned cells was evaluated by measuring the colony-forming efficiency in medium containing various amounts of a recombinant immunotoxin. The colony-forming efficiency of the cells expressing IL 2R/ GFP through IRES-dependent expression was reduced together with increasing immunotoxin concentration in a similar dose-dependent manner to the cells expressing the receptor through cap-dependent expression. CONCLUSIONS: The present results indicate that it is possible to effectively use the IRES dependent expression system for IMCT. The system permits expression of the target receptor in selective cell types by introducing the IRES-driven expression cassette into the 3'-untranslated region of the marker gene locus. PMID- 11601765 TI - Microleakage in endodontically treated teeth: influence of calcium hydroxide dressing following bleaching. AB - AIM: The purpose of the present study was to evaluate microleakage of a fourth generation dentine-bonding agent and composite restoration during a walking bleach treatment. METHODOLOGY: Thirty extracted non-carious incisors were selected and conventional root canal treatment was performed. Teeth were randomly divided into 3 groups (n = 10): group A (control), access cavities were restored with a fourth generation dentine-bonding agent, and incrementally restored with composite resin; group B, a paste composed of sodium perborate and hydrogen peroxide was placed into the pulp chamber and sealed with glass ionomer cement for 7 days, teeth were then restored in the same manner as group A; group C, a paste of sodium perborate and hydrogen peroxide was placed in the pulp chamber for 7 days and then after removal of the bleaching mixture, pulp chambers were filled with a calcium hydroxide paste and cavities sealed with glass ionomer for 1 week. The cavities were then restored with bonded restorations as in groups A and B. Teeth were subjected to thermal cycling and immersed in methylene blue for 8 h. Teeth were sectioned from buccal to lingual, through the centre of the restoration, using a diamond disk. Leakage was assessed using a standard scheme, under magnification (x20). Data were submitted to statistical analysis using nonparametric Kruskal-Wallis test. RESULTS: Groups A and C exhibited similar leakage patterns, and both demonstrated less leakage values than group B (P < 0.05). CONCLUSIONS: It was concluded that bleaching with sodium perborate and hydrogen peroxide increases microleakage; short-term use of a calcium hydroxide medicament did not increase microleakage. PMID- 11601766 TI - An audit of root canal treatment performed by undergraduate students. AB - AIM: The objective of this study was to audit the quality of root canal treatment performed by undergraduate students on adult patients. METHODOLOGY: All root canal treatment completed by first and second clinical year undergraduates over a 12-month period were included in the study. The availability and readability of pretreatment, diagnostic length, try-in point and postoperative radiographs were noted for each case. All readable postoperative radiographs of primary treatments were examined for quality of the root filling, categorized as complete, incomplete apical, incomplete apical and lateral or not assessable. The distance from the radiographic apex of the root to the apical extent of each root filling was measured to 0.1 mm precision. RESULTS: Undergraduates performed primary treatment on 157 teeth. A postoperative radiograph was available in 97% of cases. A try-in point radiograph was unavailable in one-fifth of cases. Twenty-seven teeth (13%) were categorized as satisfactory in terms of both radiographic quality and distance of the root filling from the radiographic apex. CONCLUSIONS: Overall, the technical quality of root canal treatment completed by undergraduate students was poor. PMID- 11601767 TI - Periapical lesion progression and cytokine expression in an LPS hyporesponsive model. AB - AIM: The purpose of this study was to compare periapical lesion progression and the expression of the bone modulating cytokines IL-1alpha, TNF-alpha, IL-4, IL-6 and IL-11 in periapical lesions of normal and C3H/HeJ (LPS hyporesponsive) mice. METHODOLOGY: Pulps of both mandibular first molars from C3H/HeJ and BALB/c (normal) mice were exposed and inoculated with normal mouse oral microorganisms for 2, 4, 6, and 8 weeks. After euthanasia, specimens were prepared for histological examination. A quantitative evaluation of the lesional area and immunohistochemical stain counts was performed. RESULTS: There were no statistically significant differences in progression of periapical lesions for both mouse strains with time (two-factor ANOVA, P > 0.05). The immunohistochemical staining revealed no overall differences between the two strains in levels of expression of the cytokines (P > 0.05). IL-11 expression did not change from control levels in BALB/c mice, but correlated with the expression of IL-6 and IL-4 in C3H/HeJ mice. CONCLUSION: Responsiveness to LPS may not be significant in the pathogenesis of periapical lesions and in cytokine expression within the lesions, when the lesions are induced by non-specific oral flora. PMID- 11601769 TI - Periradicular surgery of molars: a prospective clinical study with a one-year follow-up. AB - AIM: The purpose of this prospective clinical study was to evaluate the outcome of periradicular surgery of molars after one year. METHODOLOGY: The material consisted of 25 molars with 39 roots demonstrating periradicular lesions of endodontic origin. Surgical treatment included root-end resection, root-end preparation with sonic microtips, and root-end filling with Super-EBA cement. At the one-year follow-up examination, healing was evaluated clinically and radiographically. Healing was assigned to three categories: (i) success (ii) improvement, and (iii) failure using well defined criteria. RESULTS: Eighty-eight per cent of the surgically treated molars showed successful healing. In 8%, the healing was rated as improved and only 4% were failures. CONCLUSIONS: The outcome of the present study and data of recently published studies show that periradicular surgery may result in a predictable treatment outcome in molars with persistent periradicular lesions. PMID- 11601768 TI - Quantec SC rotary instruments versus hand files for gutta-percha removal in root canal retreatment. AB - AIM: The purpose of this study was to compare Quantec SC rotary instruments and hand files for removal of gutta-percha during retreatment. METHODOLOGY: Twenty maxillary central incisors with a single straight canal were selected. The canals were instrumented and filled before the teeth were randomly divided into two groups of 10 specimens each. In group 1 Quantec SC rotary instruments were used for filling removal and in group 2, hand files and solvent. The following factors were evaluated: time taken to reach working length, time for gutta-percha removal, total time, apically extruded material during filling removal and number of fractured instruments. Radiographs were taken and the teeth were grooved longitudinally and split. The canal walls of each half and the radiographs were evaluated visually for cleanliness. They were then digitized using a scanner and the residual debris assessed. The analysis was carried out in the cervical, middle and apical thirds separately as well for the whole canal. RESULTS: The time for root filling removal was significantly less when Quantec SC was used (P < 0.05). The amount of apically extruded material was not significantly different between the groups (P > 0.05). Direct evaluation of the canal walls revealed that hand files and solvent demonstrated better cleanliness in the cervical third and in whole canal (P < 0.05). Radiographic analysis demonstrated that hand files performed significantly better when viewed in a mesiodistal direction (P < 0.05). CONCLUSIONS: Although Quantec SC instruments took less time, hand instruments and solvent cleaned canals more effectively. PMID- 11601770 TI - Pattern of transmission of laser light through carious molar teeth. AB - AIMS: The aims of this study were to investigate the pattern of transmission of laser light through carious human molar teeth, and to examine the effect on light transmission of reactions to caries in the dentine. METHODOLOGY: Sectioned carious human molars were examined whilst illuminated from their external surfaces by a helium-neon laser probe of 0.5 mm diameter. The pattern of light transmission was observed and selected specimens were photographed. The passage of light through the surrounding dentine toward the pulp space was investigated by confocal microscopy. Further carious and restored teeth were illuminated from three buccal and three lingual sites to establish the probability of light being able to reach the coronal pulp space. RESULTS: For all 31 teeth examined, it was possible to illuminate the pulp space from a position on the buccal side. The presence of intracoronal restorations did not necessarily prevent light transmission to the pulp. Confocal microscopy demonstrated conduction of light within dystrophic deposits of irregular secondary dentine. CONCLUSIONS: The presence of carious lesions or restorations in molar teeth does not necessarily interfere with transmission of laser light to the pulp space. Light is conducted within irregular secondary dentine. With appropriate probe placement, assessments of pulp health in diseased posterior teeth may be possible using laser Doppler flowmetry. PMID- 11601771 TI - The effectiveness of manual and rotary techniques in the cleaning of root canals: a scanning electron microscopy study. AB - AIM: The purpose of this scanning electron microscope (SEM) study was to compare the cleanliness of the root canal walls following either a manual or a rotary technique of canal instrumentation. The hypothesis was that a rotary technique would produce a cleaner root canal. METHODOLOGY: Manual filing was performed on 10 extracted teeth using stainless steel S-files (Sjodings, Sendoline, Sweden). Powered instrumentation was carried out on a further 10 extracted teeth, using ProFile rotary nickel-titanium files in a handpiece (250 r.p.m.) according to the manufacturer's instructions. A solution of 0.5% sodium hypochlorite was used for irrigation. The roots were cut longitudinally and the canal walls were examined for debris and smear layer at the apical, middle and coronal level. RESULTS: Significantly less debris was found in the apical region using the manual filing technique (P < 0.05); no significant differences could be found at the other levels. Overall, significantly less debris was found on the root canal walls using the manual technique when the data from the three levels were compared (P = < 0.05). CONCLUSIONS: The manual technique employed in this study produced cleaner root canal walls than the rotary ProFile technique. PMID- 11601772 TI - A comparative study of root canal preparation with HERO 642 and Quantec SC rotary Ni-Ti instruments. AB - AIM: The purpose of this study was to compare several parameters of root canal preparation using two different rotary nickel-titanium instruments: HERO 642 (Micro-Mega, Besancon, France) and Quantec SC (Tycom, Irvine, CA, USA). METHODOLOGY: Fifty extracted mandibular molars with root canal curvatures between 20 micro and 40 micro were imbedded into a muffle system. All root canals were prepared to size 45 (Quantec SC), or 40 (HERO 642), respectively. The following parameters were evaluated: straightening of curved root canals, postoperative root canal diameter, safety issues (file fractures, perforations, apical blockages, loss of working length), cleaning ability, and working time. RESULTS: Both Ni-Ti-systems maintained curvature well; the mean degree of straightening was 2.3 degrees for Quantec SC and 1.6 degrees for HERO 642. Most procedural incidents occurred with Quantec SC instruments (five fractures, three apical blockages, eight cases of loss of working length), HERO 642 preparation resulted in three blockages and one perforation. Following preparation with HERO 642, 63% of the root canals showed a round, 24% an oval, and 17% an irregular diameter; Quantec SC preparations resulted in a round diameter in 24% of the cases, oval shape in 29%, and irregular cross-section in 47% of the cases. Mean working time was shorter for HERO 642 (52 s) than for Quantec (117 s). Cleanliness of the root canal walls was investigated under the SEM using a five-score system for debris and smear layer. For debris HERO 642 achieved better results (80% scores 1 and 2) than Quantec SC (76%). The results for smear layer were similar: cleaner root canal walls were found after preparation with HERO 642 (53% scores 1 and 2), followed by Quantec SC (41%). CONCLUSIONS: Both systems respected original root canal curvature well and showed good cleaning ability; Quantec SC showed deficiencies in terms of safety. PMID- 11601773 TI - A new in vitro model for the study of microbial microleakage around dental restorations: a preliminary qualitative evaluation. AB - AIM: The aim of this study was to develop an in vitro model to replicate microbial microleakage at a tooth/ restoration interface using a constant depth film fermentor (CDFF). METHODOLOGY: Amalgam restorations were placed in machined bovine dentine cylinders and sealed externally with varnish, leaving a 1-mm perimeter exposed around the tooth/restoration interface. The dentine cylinders were housed in a CDFF and 300-microm thick microcosm dental plaques were grown over their exposed surfaces. The biofilms were maintained with a mucin-containing artificial saliva for up to 8 weeks. Cylinders were aseptically removed from the CDFF (at 1, 2, 4, & 8 weeks) and surface-decontaminated with validated protocols prior to splitting and sampling of apposing amalgam and dentine surfaces. Scanning electron microscopy (SEM) was used to ascertain the position and structure of the bacterial aggregates. Bacterial viability was determined by vital staining of the bacteria in situ. RESULTS: At all sampling times, SEM showed cocci, rods and filaments on both amalgam and dentine surfaces; some originated as cascades from the surface biofilm and extended into the tooth/restoration microspace. Vital staining showed the majority of bacteria from both dentine and amalgam surfaces to be viable. CONCLUSION: This preliminary investigation showed that the CDFF may be a valuable tool for the in vitro study of the dynamics of microbial microleakage around dental restorations. PMID- 11601774 TI - Effect of occlusal trauma on healing of periapical pathoses: report of two cases. AB - AIM: To present two clinical cases and demonstrate that occlusal trauma may affect healing of periapical pathoses. SUMMARY: Two teeth with periradicular disease did not respond successfully to conventional root canal treatment or endodontic surgery. Occlusal adjustment was finally performed on both cases. After occlusal adjustment, uncomplicated healing and periapical repair occurred in both cases. The findings in these two cases suggest that occlusal trauma may play a role in the healing of periapical pathoses. KEY LEARNING POINTS: Occlusal trauma is positively correlated with changes in periodontal tissues. Although experiments in animals have shown that application of forces to teeth will not induce further periodontal destruction, we believe that some failures of root canal treatment may be due to the presence of occlusal trauma modulating the responses of inflamed periapical tissues or apical pathoses with persistent infection. PMID- 11601775 TI - An unusual swelling following endodontic and prosthodontic treatment of a mandibular molar due to a foreign body reaction. AB - AIM: The purpose of this case report is to stress the importance of taking a proper history and the appropriate evaluation of diagnostic tests in order to prevent incorrect diagnosis and treatment. Moreover, the management of postoperative problems in a healthcare system in which specialists take on specific parts of the treatment is discussed. SUMMARY: This article describes the diagnosis and treatment of an unsuspected flare-up 1 week after root canal treatment. The swelling and pain appeared to be associated with an accidentally embedded piece of impression material. General practitioners and specialists should be aware of alternate treatment plans and treatment procedures and take these into consideration whenever there is a postoperative problem to be solved. KEY LEARNING POINTS: Impression materials can cause a foreign body reaction when embedded in the soft tissues. History taking and evaluation of diagnostic tests are of paramount importance in order to prevent incorrect diagnosis and treatment. Both general practitioners and specialists have the responsibility to evaluate patients with a broad vision. PMID- 11601776 TI - Animal health groups issue resolution on livestock and wildlife diseases. PMID- 11601777 TI - Disagrees with one aspect of the euthanasia panel report. PMID- 11601778 TI - Thinks AMA should concentrate on human antibiotic resistance. PMID- 11601779 TI - Thoughts on the value of veterinarians. PMID- 11601780 TI - Thoughts on the value of veterinarians. PMID- 11601781 TI - Sees no scientific evidence in rebuttal for raw dog foods. PMID- 11601782 TI - Doesn't agree with response document. PMID- 11601783 TI - An alternative look at separation anxiety. PMID- 11601784 TI - What is your diagnosis? Bilateral osteosarcoma of the radius. PMID- 11601785 TI - What is your neurologic diagnosis? Osteochondroma of the dorsal process of T4. PMID- 11601786 TI - Liability for horse injury--extending the assumption of risk doctrine. PMID- 11601787 TI - Survey of veterinary technical and professional skills in students and recent graduates of a veterinary college. AB - OBJECTIVES: To determine perceptions of veterinary technical and professional skills among veterinary students and recent graduates. DESIGN: Cross-sectional study. SAMPLE POPULATION: 281 students and 142 recent graduates from the Ontario Veterinary College. PROCEDURE: A survey was designed and administered to first- through fourth-year students and veterinarians who had graduated either 1 or 6 years before survey administration. RESULTS: Overall response rate was 70%. Learning about technical and professional skills was highly valued. Most participants felt they had not received instruction about professional skills, but those who had felt more competent about them. Perceptions of competence increased slightly with increased comfort discussing emotional veterinary issues with instructors. Neither gender nor increased age was related to increased feelings of competence. Almost all fourth-year students felt competent and comfortable about examining an animal with the client present, assessing suffering, diagnosing parvovirus infection, performing surgery, and working as group members. However, many did not feel competent or comfortable about delivering bad news, setting time limits yet providing quality service, helping clients with limited funds make treatment decisions, dealing with demanding people, and euthanasia. Feelings of competence and comfort were closely related but were not identical. CONCLUSIONS AND CLINICAL RELEVANCE: In the interests of best preparing entry-level veterinarians, technical and professional skills need to be emphasized in a learning environment where students feel comfortable discussing emotional veterinary issues. A professional skills curriculum addressing underlying self-awareness, communication, and interpersonal issues, as well as procedural matters, would likely increase the proportion of fourth-year students who feel competent and comfortable about professional skills by the end of their undergraduate training. PMID- 11601788 TI - Assessment of claims of short- and long-term complications associated with onychectomy in cats. PMID- 11601790 TI - Seroprevalence of antibodies against equine arteritis virus in horses residing in the United States and imported horses. AB - OBJECTIVE: To compare seroprevalence of antibodies against equine arteritis virus (EAV) in horses residing in the United States with that of imported horses. DESIGN: Serologic survey. SAMPLE POPULATION: Serum samples from 364 horses on 44 equine operations in California and 226 horses imported from various countries. PROCEDURE: Serum samples were collected from each imported horse and from up to 20 horses on each operation. For resident horses, the number of sampled horses on each operation was determined on the basis of the number of horses on the operation. Samples were tested for antibodies against EAV by use of a serum neutralization test. RESULTS: 1.9% of resident horses and 18.6% of imported horses were seropositive to EAV, including 16.1% of imported stallions. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that the EAV seroprevalence of horses residing in California is considerably lower than that of imported horses, including imported stallions. PMID- 11601789 TI - Prolonged anesthesia with desflurane and fentanyl in dogs during conventional and laparoscopic surgery. AB - OBJECTIVE: To determine the effects of prolonged anesthesia with desflurane in dogs undergoing laparotomy or abdominal laparoscopy. DESIGN: Randomized prospective study. ANIMALS: 20 adult mixed-breed dogs. PROCEDURE: Dogs were randomly assigned to 1 of 2 groups with 10 dogs/group. Anesthesia was induced with propofol and maintained with desflurane and fentanyl, and pyloroplasty was performed. In 10 dogs, a ventral midline laparotomy was performed; in the other 10, abdominal laparoscopy was performed. Dogs were monitored for cardiovascular and respiratory responses (ECG, oxygen saturation [SpO2], arterial blood pressure, rectal temperature, end-tidal partial pressure of carbon dioxide [PETCO2], and expired desflurane concentration). Recovery times were recorded. RESULTS: Mean +/- SD duration of anesthesia was 201 +/- 25 minutes for dogs undergoing laparotomy and 287 +/- 15 minutes for dogs undergoing laparoscopy. Anesthesia was accompanied by hypotension that was less severe in dogs undergoing laparoscopy. Heart rate did not vary significantly during anesthesia. The SpO2 was > 97% in all dogs at all times, and PETCO2 remained within reference limits. Recovery times for dogs that underwent laparotomy were not significantly different from those for dogs that underwent laparoscopy. Mean +/- SD time to standing was 13.6 +/- 2.4 minutes for dogs that underwent laparotomy and 12.5 +/- 2.9 minutes for dogs that underwent laparoscopy. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that induction of anesthesia with propofol and maintenance with desflurane and fentanyl is safe in dogs undergoing abdominal surgery. PMID- 11601791 TI - Severe complication after administration of formalin for treatment of progressive ethmoidal hematoma in a horse. AB - Formalin was injected into an ethmoidal hematoma in an 18-year-old Arabian gelding. Abnormal neurologic signs were observed within minutes of the injection. The horse did not respond favorably to medical treatment of the neurologic signs and was euthanatized. Postmortem examination revealed erosion and necrosis of the ventral cribriform plate, which appeared to have allowed the injected formalin to reach the rostral portion of the frontal lobe of the brain. Endoscopy and radiography had been performed prior to euthanasia, but neither delineated the cribriform lesion. Before treating large progressive ethmoidal hematomas with formalin, it may be beneficial to perform computed tomography to assess the extent of damage caused by the lesion. PMID- 11601792 TI - Umbilical evagination of the urinary bladder in a neonatal filly. AB - An 8-hour-old Standardbred filly was evaluated because of an enlarging umbilical mass and stranguria. It was suspected that the mass was the urinary bladder; this was confirmed on surgical exploration of the abdomen. Despite a normal umbilical ring, the bladder had descended and partially everted through its urachal communication with the umbilical stalk. Partial cystectomy and umbilical resection were performed and resulted in an excellent clinical outcome. Evagination of the urinary bladder via the umbilicus has rarely been described in human infants, and, to our knowledge, it has not been reported in the veterinary literature. PMID- 11601793 TI - Failure of holmium:yttrium-aluminum-garnet laser lithotripsy in two horses with calculi in the urinary bladder. AB - Holmium:yttrium-aluminum-garnet (Ho:YAG) laser lithotripsy was attempted in a mare and a gelding with calculi in the urinary bladder. The procedure was unsuccessful in producing adequate fragmentation of the calculi. In the gelding, pulsed dye laser lithotripsy was subsequently used to fragment the urolith. Manual removal of the urolith via the urethra was performed in the mare. PMID- 11601794 TI - Endoscopic assessment of airway function as a predictor of racing performance in Thoroughbred yearlings: 427 cases (1997-2000). AB - OBJECTIVE: To compare endoscopic findings of the upper portion of the respiratory tract in Thoroughbred yearlings with their subsequent race records to determine whether subjective assessment of airway function may be used as a predictor of future racing performance. DESIGN: Retrospective study. ANIMALS: 427 Thoroughbred yearlings. PROCEDURES: Endoscopic examination findings were obtained from the medical records and the videoendoscopic repository of the Keeneland 1996 September yearling sales. Racing records were requested for the yearlings through the end of their 4-year-old racing season (1997-2000). Twenty-nine measures of racing performance were correlated with endoscopic findings. Subjective arytenoid cartilage movement grades were determined, using a 4-point grading scale (grade 1 = symmetrical synchronous abduction of the arytenoid cartilages; grade 4 = no substantial movement of the left arytenoid cartilage). RESULTS: Of the 427 Thoroughbred yearlings included in this study, 364 established race records, and 63 did not. Opinions regarding suitability for purchase, meeting conditions of the sale, and the presence of epiglottic abnormalities had no significant association with racing performance. Arytenoid cartilage movement grades were significantly associated with many of the dependent variables. However, palatine abnormalities were not predictive of inferior racing performance. CONCLUSIONS AND CLINICAL RELEVANCE: Thoroughbred yearlings with grade-1 and -2 arytenoid cartilage movements had significantly better racing performance as adults, compared with yearlings with grade-3 arytenoid cartilage movements. In contrast, epiglottic and palatine abnormalities were not predictive of inferior racing performance. Therefore, evaluation of laryngeal function, but not epiglottic or palatine abnormalities, using the 4-point grading system, should be the major factor in developing recommendations for prospective buyers. PMID- 11601795 TI - Effect of calfhood vaccination on transmission of bovine viral diarrhea virus under typical drylot dairy conditions. AB - OBJECTIVE: To estimate transmission of bovine viral diarrhea virus (BVDV) and crude morbidity and mortality ratios in BVDV-vaccinated and unvaccinated dairy heifer calves managed under typical dairy drylot conditions. DESIGN: Randomized clinical trial. ANIMALS: 106 female Holstein calves. PROCEDURE: Seroconversion rates for BVDV types I and II and proportional morbidity and mortality ratios were compared between calves given a killed BVDV type-I vaccine at 15 days of age and a modified-live BVDV type-I vaccine at 40 to 45 days of age (n = 53) and calves given no BVDV vaccines (53). Sera were collected at 45-day intervals as calves moved from individual hutches to corrals holding increasingly larger numbers of calves. Seroconversion was used as evidence of exposure to BVDV. RESULTS: Crude proportional morbidity (0.16) and mortality (0.17) ratios for control calves did not differ significantly from those of vaccinated calves (0.28 and 0.12, respectively). The proportion of control calves that seroconverted to BVDV type I through 9 months of age (0.629) was significantly higher than that of vaccinated calves that seroconverted, unrelated to vaccination, during the same period (0.536). Estimated overall protective effect of vaccination against BVDV type I through 4 to 9 months of age was 48%. The proportion of control calves that seroconverted to BVDV type II (0.356) was not different from that of vaccinated calves (0.470). CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggest that calfhood vaccination may be an appropriate strategy to help reduce short term transmission of some but not necessarily all strains of BVDV. PMID- 11601796 TI - Bacteremia associated with naturally occuring acute coliform mastitis in dairy cows. AB - OBJECTIVE: To determine the incidence of bacteremia in dairy cows with naturally occurring acute coliform mastitis (ACM) with a wide range of disease severity. DESIGN: Cohort study. ANIMALS: 144 dairy cows with ACM from 6 herds. PROCEDURE: Cows were examined at time of identification of ACM (time 0) and classified as having mild, moderate, or severe mastitis on the basis of rectal temperature, hydration status, rumen contraction rate, and attitude. Cows were reexamined at 24 or 48 hours. Bacteriologic culturing of milk and blood (30 ml), CBC, and serum biochemical analysis were performed at each time point. Appropriate samples were obtained at a single point from herdmates without mastitis (controls) that were closely matched for lactation number and days since parturition. Blood culture results were compared among severity groups and controls by use of chi2 tests, as was outcome of an ACM episode for cows grouped by blood bacterial isolates. RESULTS: Bacteria were isolated from 52 blood samples from 46 of 144 (32%) cows with ACM, which was significantly more than control cows (11/156; 7.1%). Group-1 isolates (Escherichia coli, Pasteurella multocida, Mannheimia haemolytica, Klebsiella pneumoniae, Enterobacter agglomerans, and Salmonella enterica serotype Typhimurium) were identified in 20 of 144 (14%) cows with ACM and 0 of 156 control cows. Group-1 isolates were identified in 4.3, 9.1, and 42% of cows classified as having mild, moderate, and severe ACM, respectively. Escherichia coli and K pneumoniae milk and blood isolates obtained from the same cow were of the same genotype. Bacillus spp were identified in 21 of 144 (15%) cows with ACM, which was significantly more than control cows (3/156; 1.9%). Thirty-five percent of cows with a group-1 isolate died during the mastitis episode. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that bacteremia develops in a substantial proportion of cows with ACM. Classification of severity of disease is important for establishment of effective treatment protocols; parenteral antimicrobial treatment may be indicated in cows with ACM. PMID- 11601797 TI - Cultural controversies on child abuse. PMID- 11601798 TI - Fever without source in infants and young children--a hot potato? PMID- 11601799 TI - Managing pain at the end of life. PMID- 11601800 TI - Overview of refractive surgery. AB - Patients with myopia, hyperopia and astigmatism can now reduce or eliminate their dependence on contact lenses and eyeglasses through refractive surgery that includes radial keratotomy (RK), photorefractive keratectomy (PRK), laser assisted in situ keratomileusis (LASIK), laser thermal keratoplasty (LTK) and intrastromal corneal rings (ICR). Since the approval of the excimer laser in 1995, the popularity of RK has declined because of the superior outcomes from PRK and LASIK. In patients with low-to-moderate myopia, PRK produces stable and predictable results with an excellent safety profile. LASIK is also efficacious, predictable and safe, with the additional advantages of rapid vision recovery and minimal pain. LASIK has rapidly become the most widely performed refractive surgery, with high patient and surgeon satisfaction. Noncontact Holium: YAG LTK provides satisfactory correction in patients with low hyperopia. ICR offers patients with low myopia the potential advantage of removal if the vision outcome is unsatisfactory. Despite the current widespread advertising and media attention about laser refractive surgery, not all patients are good candidates for this surgery. Family physicians should be familiar with the different refractive surgeries and their potential complications. PMID- 11601801 TI - Information from your family doctor. What should I know about refractive surgery? PMID- 11601802 TI - Interstitial cystitis: urgency and frequency syndrome. AB - Interstitial cystitis is a chronic, severely debilitating disease of the urinary bladder. Excessive urgency and frequency of urination, suprapubic pain, dyspareunia, chronic pelvic pain and negative urine cultures are characteristic of interstitial cystitis. The course of the disease is usually marked by flare ups and remissions. Other conditions that should be ruled out include bacterial cystitis, urethritis, neoplasia, vaginitis and vulvar vestibulitis. Interstitial cystitis is diagnosed by cystoscopy and hydrodistention of the bladder. Glomerulations or Hunner's ulcers found at cystoscopy are diagnostic. Oral treatments of interstitial cystitis include pentosan polysulfate, tricyclic antidepressants and antihistamines. Intravesicular therapies include hydrodistention, dimethyl sulfoxide and heparin, or a combination of agents. Referral to a support group should be offered to all patients with interstitial cystitis. PMID- 11601803 TI - Information from your family doctor. Interstitial cystitis: a bladder problem. PMID- 11601804 TI - Evaluation and management of infants and young children with fever. AB - A practice guideline for the management of febrile infants and children younger than three years of age sparked controversy when it was published in 1993. Surveys indicate that many office-based physicians do not agree with recommendations for venipuncture and bladder catheterization in nontoxic febrile children, and that many employ watchful waiting rather than empiric antibiotic therapy. Surveys of parents note a preference for less testing and treatment. More aggressive management may be appropriate in febrile infants younger than three months old; however, criteria have been proposed to identify infants older than one month who are at low risk for serious bacterial infection. Because of widespread vaccination against Haemophilus influenzae infection, Streptococcus pneumoniae has become the cause of most cases of bacteremia. The risk of serious bacterial infection is greater in younger children and in those with higher temperatures and white blood cell counts. Controversy persists regarding the age, temperature and white blood cell count values that serve as indications for further evaluation or empiric antibiotic therapy. PMID- 11601805 TI - Challenges in pain management at the end of life. AB - Effective pain management in the terminally ill patient requires an understanding of pain control strategies. Ongoing assessment of pain is crucial and can be accomplished using various forms and scales. It is also important to determine if the pain is nociceptive (somatic or visceral pain) or neuropathic (continuous dysesthesias or chronic lancinating or paroxysmal pain). Nociceptive pain can usually be controlled with nonsteroidal antiinflammatory drugs or corticosteroids, whereas neuropathic pain responds to tricyclic antidepressants or anticonvulsants. Relief of breakthrough pain requires the administration of an immediate-release analgesic medication. If a significant amount of medication for breakthrough pain is already being given, the baseline dose of sustained-release analgesic medication should be increased. If pain does not respond to one analgesic medication, physicians should use an equianalgesic dose chart when changing the medication or route of administration. Opioid rotation can be used if pain can no longer be controlled on a specific regimen. The impact of unresolved psychosocial or spiritual issues on pain management may need to be addressed. PMID- 11601806 TI - Photo quiz. A widened mediastinum. PMID- 11601807 TI - What is the best way to treat trichomoniasis in women? PMID- 11601808 TI - ACIP releases guidelines on the prevention and control of influenza. Advisory Committee on Immunization Practices. PMID- 11601809 TI - Confronted by an unexpected laboratory result. PMID- 11601810 TI - An investigation of psychological distress in patients who have been treated for head and neck cancer. AB - There is now ample evidence that psychological distress is common in patients with head and neck cancer and that psychology has a role in reducing this distress. In this study, the prevalence, nature, and correlates of distress were investigated, in 18 patients who were no longer being actively treated but were attending a follow-up clinic or support group (n= 9 each). Four of the patients had appreciable psychological distress and four each had anxiety or depression of at least borderline importance. The degree of depression and distress decreased with increasing age and there were trends for depression to decrease with time after the onset of the illness and to be slightly less common among those attending the support group (2/9 compared to 4/9). Numerous psychosocial difficulties were reported and perceptions of support available from friends and family were mixed. There are implications for services, and in particular, patients need to be given clear information about the resources available to give them psychosocial support. PMID- 11601811 TI - Functional status of patients with oral cancer and its relation to style of coping, social support and psychological status. AB - Sixty-eight patients were evaluated 6 months to 6 years after treatment for oral cancer using standardized questionnaires to explore the influence of age, sex, site and stage of tumour, and primary treatment on their functional status measured by the University of Washington Quality of Life Questionnaire (UW-QoL), and the association between functional status and psychological outcome measured by the Hospital Anxiety and Depression Scale (HADS), style of coping measured by the Mental Adjustment to Cancer Questionnaire (MAC-Q), and social support measured by the Short-Form Social Support Questionnaire (SSQ-6). Young patients, women, patients with advanced tumours, those with oropharyngeal tumours and those who had been treated with both surgery and radiotherapy reported worse function. The worse the functional domain, the more likely it was to be associated with anxiety, depression and ineffective coping style, and better functional scores were weakly associated with fighting spirit, level of social support and satisfaction with that support. We have identified patients at need and highlighted their problems. Dealing with these problems may ultimately improve the perception of function after treatment of oral cancer. PMID- 11601812 TI - Reflections on: psychology and head and neck cancer. PMID- 11601813 TI - Reflections on coping with head and neck cancer. PMID- 11601814 TI - Clinical and radiological evidence to support superficial parotidectomy as the treatment of choice for chronic parotid sialadenitis: a retrospective study. AB - We present a retrospective series of 23 consecutive parotidectomies, over a 10 year period (1989-1999) for 22 patients with chronic sialadenitis unresponsive to conservative measures. There were 10 male and 12 female patients. Mean age was 52 years (range 12-72), and mean duration of symptoms 4.5 years (range 8 months-30 years). All patients had preoperative sialography and 2 had computed tomography to exclude a neoplasm. A complete superficial parotidectomy with preservation of the main duct was done in all cases. Fifteen patients developed temporary facial nerve weakness postoperatively and 7 developed Frey's syndrome. There were no cases of permanent facial nerve palsy. Nineteen patients reported complete resolution of their symptoms and 3 patients had mild persisting symptoms that did not necessitate any further treatment. Histologically there was evidence of sialadenosis in one case and benign lymphoepithelial lesion in another; the others showed evidence of chronic sialadenitis of varying degrees of severity. Fifteen patients had postoperative sialograms, of which 11 showed evidence of some filling of residual parotid gland parenchyma and in 8 patients there was filling of a normal-looking accessory lobe. In this series, superficial parotidectomy with preservation of the main duct was safe and effective, with minimal long-term complications, for most patients with chronic parotid sialadenitis that was unresponsive to conservative measures and, in some patients, it allowed some preservation of function. The potential damage to the facial nerve and the cosmetic problems associated with a total or near-total parotidectomy were avoided. PMID- 11601815 TI - A new device for microincremental automatic distraction osteogenesis. AB - We have invented a distraction device that can be placed intraorally and provides autodistraction. The device consists of two units: an implantable component that is applied directly on the bone, and an external component that is distant from the surgical site. The external component is mounted on a standard, battery driven portable syringe driver or infusion pump. A fine flexible non-compressible tube connects the two. The compression of the bellows in the external component causes fluid to be forced through the connecting tube into the distraction component. The combination of the sealed system and incompressible fluid guarantees expansion of the bellows of the distraction component and gradually separates the bone segments. PMID- 11601816 TI - Segmental mandibular reconstruction by microincremental automatic distraction osteogenesis: an animal study. AB - We investigated the reconstruction of a surgically created critical size mandibular defect in sheep using a newly developed automatic distraction device. The device has an implantable component, which is fixed to the mandible to allow the transfer of the transport disc across the created defect, and an external component which is mounted on the activation pump and secured away from the site of bone distraction. Compression of the bellows in the external component causes fluid to be forced through the connecting tube into the distraction component. Distraction at a rate of 1 mm over 24 h was achieved in six sheep. New bone generated at the site of the created defects both anterior (compression side) and posterior (tension side) to the transport disc and had similar radiodensity to the adjacent mandibular bone eight weeks after the completion of distraction. PMID- 11601817 TI - Aprotinin reduces blood loss and the need for transfusion in orthognathic surgery. AB - A randomized, placebo-controlled, double-blind trial (n= 15 in each group) showed that patients given aprotinin intravenously (200 ml, [2000000 kallikrein inactivator units] before the operation and then 50 ml per h until the end of the operation) during simultaneous maxillary Le Fort 1 and mandibular sagittal split osteotomies, lost 52% less blood than controls (calculated by subtracting the volume of saline irrigant used from the volume of blood collected in the aspirator bottle and surgical drains). Patients given aprotinin lost a mean (SD) of 473 (190) ml compared with 986 (356) ml in controls. They also required significantly less transfused blood (1 was given 2 units in the aprotinin group compared with 9 given a mean of 1.5 units (range 1-4) in the control group). There were no complications attributable to this drug. PMID- 11601818 TI - A new modified endaural approach for access to the temporomandibular joint. AB - We present a new modification of an endaural incision for access to the temporomandibular joint. This gives excellent posterior, anterior, lateral and inferior exposure, avoids important anatomical structures and provides an almost invisible scar. PMID- 11601819 TI - Pseudoankylosis of the mandible as a result of methyl methacrylate-induced inflammatory cicatricial contracture of the temporal muscle after cranioplasty. AB - Pseudoankylosis of the mandible after intracranial surgical procedure has been widely reported, and is usually caused by fibrosis of the temporal muscle as a result of injury during the operation. We present an unusual case of mandibular pseudoankylosis as a result of methyl methacrylate-induced aseptic inflammatory cicatricial contracture of the temporal muscle after cranioplasty. PMID- 11601820 TI - Experimental model of invasion and metastasis by orthotopic transplantation of oral squamous and adenoid cystic carcinomas into the tongue of nude mice. AB - Three squamous cell carcinoma (SCC) cell lines established from oral cancer, seven specimens of SCC and three of adenoid cystic carcinomas taken from the oral cavity during operations were transplanted into the tongues of nude mice. Metastases to the regional lymph nodes and the lungs were examined histologically. We were able to transplant every cell line or specimen of tissue into the tongue of nude mice, and found that cancer transplanted in the tongue invaded diffusely to the surrounding tissues without forming a capsule, and that the mode of invasion of the transplanted SCC was similar to that of the biopsy specimen of the patient from whom the material had been obtained. We also found that all three of the SCC cell lines, 3 of the 7 SCC specimens and 2 of the 3 adenoid cystic carcinoma tissues metastasized to the regional lymph node. SCC did not metastasize to the lung, but in two of the three adenoid cystic carcinomas we did see micrometastases to the lung. The study indicates that this method can be used as a model of metastasis in oral squamous cell carcinoma and adenoid cystic carcinoma to show the stages of metastasis in cancer. PMID- 11601821 TI - Microstructural investigations of strain-related collagen mineralization. AB - Distraction osteogenesis in rabbit mandibles after osteotomy can be used as an experimental model to study the microstructural features of mineralization of callus under defined mechanical loads. Our aim was to study the relation between the micromotions in the gap and the resulting features of mineralization of the matrix. We found that assembly of collagen and formation of crystals depended on the magnitude of the mechanical stress applied. At physiological bone strains (2000 microstrains), the callus had collagen type I in a mature bone-like extracellular arrangement, whereas at 20000 microstrains bundles were orientated predominantly towards the tension vector. Maximum loads (200000 microstrains) resulted in disorganized assembly of the collagen. Quantitative energy-dispersive analysis by X-rays confirmed that high strains were associated with substantially lower concentrations of calcium and phosphate. In contrast to bone-like apatitic formation of crystals at physiological strains, significantly fewer but larger crystals were detected by electron diffraction analysis in samples exposed to high strains. We suggest that mechanical stress regulates the assembly and mineralization of collagen during distraction osteogenesis. PMID- 11601822 TI - Pleomorphic adenoma of the lacrimal gland: case report. AB - Lacrimal gland tumours are rare. We present a case of a lacrimal gland pleomorphic adenoma in a 19-year-old man. The tumour was removed and he has made an uncomplicated recovery, with no sign of recurrence after nine months of follow up. We will keep him under long-term review. PMID- 11601823 TI - Alveolar soft-part sarcoma of the cheek. AB - Alveolar soft-part sarcoma is a rare malignant tumour of uncertain histogenesis, the two main sites of which are the lower extremities in adults and the head and neck in children. We know of only three case reports of intraoral locations without tongue involvement. Here, we describe the first case of an alveolar soft part sarcoma of the cheek which presented in a patient over 30 years old and had an extremely rapid and eventually fatal evolution. We have also reviewed hypotheses about its aetiology. PMID- 11601824 TI - Interdental wiring in jaw fractures: effects on teeth and surrounding tissues after a one-year follow-up. AB - Several authors have suggested that interdental wiring may have an adverse effect on the teeth and surrounding tissues. In the present study we examined 250 teeth that had been subjected to wiring and 142 adjacent teeth that had not been wired (controls). During the wiring period, and after a minimum of 1 year following treatment of the jaw fracture, the teeth and periodontal tissues were examined by periodontal probing, percussion sound test, mobility test, sensitivity test, and radiography. One tooth showed temporary increased mobility. Periodontal health was clinically and radiologically fully restored after a year in all teeth. Progressive caries was seen in 2 patients and was treated. Loss of sensitivity was seen in 3 teeth adjacent to the fracture site and in one tooth adjacent to a titanium cortical screw. However, these pulpal changes either recovered spontaneously or were treated endodontically. There were few late problems in the teeth and surrounding tissues. In 243 teeth (97%), completely healthy conditions were found in pulp and periodontium. There was no evidence of root resorption or dentoalveolar ankylosis. We conclude that late deleterious effects on the teeth and periodontal tissues from interdental wiring in the treatment of jaw fractures were uncommon 1 year after the removal of the interdental wiring. PMID- 11601826 TI - Osteoid osteoma of the eminence of the temporomandibular joint. AB - We describe an osteoid osteoma in the articular eminence of the left temporomandibular joint of a 24-year-old woman. This is an uncommon tumour of the jaws, and has not previously been reported in this location. The mass was removed, she made a good recovery, and there are not signs of recurrence four years later. PMID- 11601825 TI - Primary tuberculosis of the tongue: report of three cases. AB - Tuberculosis of the oral cavity is uncommon and poses a diagnostic challenge. We report three patients with primary tuberculosis of the tongue, all of whom responded well to treatment and were cured. PMID- 11601830 TI - Partnership in cardiovascular medicine. A key to success not only for professional organizations. PMID- 11601831 TI - Platelet aggregability in syndrome X: a role for adenosine. PMID- 11601832 TI - Residual myocardial ischaemia as a contributor to electrical instability after myocardial infarction. PMID- 11601833 TI - A monk's prayer: O Lord what is the answer to in-stent restenosis? Commentary on the TRAPIST Study. PMID- 11601834 TI - The endothelin-type-A receptor in dilated cardiomyopathy: another key player? PMID- 11601835 TI - ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. PMID- 11601836 TI - Platelet aggregability in cardiac syndrome X. AB - AIMS: To assess platelet aggregability at rest and in response to exercise in patients with cardiac syndrome X (anginal chest pain, ST-segment depression on exercise, angiographically normal coronary arteries). METHODS AND RESULTS: We performed a symptom/sign-limited exercise test in 31 patients with syndrome X, 25 patients with coronary artery disease and 29 healthy subjects. Platelet aggregability was measured in flowing whole blood at baseline, at peak exercise, and after 30 and 120 min, as the time to occlude a collagen/adenosine diphosphate coated ring (aggregation time). Resting aggregation time was shorter in syndrome X patients (83.2+/-12 s), compared to patients with coronary disease (94.0+/-18 s, P<0.01) and to healthy subjects (96.4+/-21 s, P<0.01). With exercise, aggregation time did not change in healthy controls, decreased in patients with coronary disease (-13.8 s at peak; 95% CI, -10.2, -17.3 s;P<0.001), but increased in syndrome X (+17.4 s 30 min after exercise; 95% CI, +10.4, +24.4 s;P<0.0001). The intravenous administration of an adenosine antagonist (theophylline) prevented the exercise-induced prolongation of aggregation time in syndrome X patients (n=11), but had no effect in healthy controls (n=11). CONCLUSION: Platelet aggregability at rest was increased in syndrome X patients, compared to patients with coronary artery disease and healthy subjects. In contrast to patients with coronary disease, however, platelet aggregability was reduced by exercise. This response was prevented by theophylline, strongly suggesting the involvement of adenosine. PMID- 11601837 TI - Influence of residual myocardial ischaemia on induced ventricular arrhythmias following a first acute myocardial infarction. AB - OBJECTIVES: The purpose of this study was to assess the possible effect of residual myocardial ischaemia on induced ventricular arrhythmia during programmed ventricular stimulation in survivors of a first acute myocardial infarction. BACKGROUND: Most deaths after hospital discharge for acute myocardial infarction are sudden and presumably arrhythmic. Sudden cardiac death results from a dynamic interaction of structural abnormalities and transient triggering factors. The role of myocardial ischaemia as a trigger for ventricular arrhythmias remains unclear. We hypothesized that residual myocardial ischaemia after a first acute myocardial infarction is a potent trigger for sustained ventricular tachyarrhythmias, particularly in the presence of an abnormal myocardium. METHODS AND RESULTS: In this prospective study, programmed electrical stimulation, coronary angiography and dipyridamole-thallium-201 scintigraphy single-photon emission computed tomography were performed in 90 consecutive survivors of a first acute myocardial infarction. Patients, divided in two groups - group 1 with induced ventricular tachyarrhythmia (n=24) and group 2 without induced ventricular tachyarrhythmia (n=66) - were compared regarding residual myocardial ischaemia. The two groups were comparable in terms of mean left ventricular ejection fraction, infarct size and location, gender ratio, peak creatine kinase value, and extent of coronary disease. Residual myocardial ischaemia was detected in 32 patients: 15 (42.5%) belonged to group 1 and 17 (25.7%) to group 2. There was a statistically significant difference between the two groups regarding the presence and the extent of residual myocardial ischaemia (P<0.05). CONCLUSION: Residual myocardial ischaemia, revealed by dipyridamole-thallium-201 scintigraphy following a first acute myocardial infarction, might contribute to electrical instability evaluated by programmed ventricular stimulation. PMID- 11601838 TI - The TRAPIST Study. A multicentre randomized placebo controlled clinical trial of trapidil for prevention of restenosis after coronary stenting, measured by 3-D intravascular ultrasound. AB - BACKGROUND: Studies have reported benefit of oral therapy with the phosphodiesterase inhibitor, trapidil, in reducing restenosis after coronary angioplasty. Coronary stenting is associated with improved late outcome compared with balloon angioplasty, but significant neointimal hyperplasia still occurs in a considerable proportion of patients. The aim of this study was to investigate the safety and efficacy of trapidil 200 mg in preventing in-stent restenosis. METHODS: Patients with a single native coronary lesion requiring revascularization were randomized to placebo or trapidil at least 1 h before, and continuing for 6 months after, successful implantation of a coronary Wallstent. The primary end-point was in-stent neointimal volume measured by three dimensional reconstruction of intravascular ultrasound images recorded at the 6 month follow-up catheterization. RESULTS: Of 312 patients randomized at 21 centres in nine countries, 303 (148 trapidil, 155 placebo) underwent successful Wallstent implantation, and 139 patients (90%) in the placebo group and 130 (88%) in the trapidil group had repeat catheterization at 26+/-2 weeks. There was no significant difference between trapidil and placebo-treated patients regarding in stent neointimal volume (108.6+/- 95.6 mm(3)vs 93.3+/-79.1 mm(3);P=0.16) or % obstruction volume (38+/-18% vs 36+/-21%;P=0.32), in angiographic minimal luminal diameter at follow-up (1.63+/-0.61 mm vs 1.74+/-0.69 mm;P=0.17), restenosis rate (31% vs 24%;P=0.24), cumulative incidence of major adverse cardiac events at 7 months (22% vs 20%;P=0.71) or anginal complaints (30% vs 24%;P=0.29). CONCLUSION: Oral trapidil 600 mg daily for 6 months did not reduce in-stent hyperplasia or improve clinical outcome after successful Wallstent implantation and is not indicated for this purpose. PMID- 11601839 TI - A polymorphism in the endothelin-A receptor gene predicts survival in patients with idiopathic dilated cardiomyopathy. AB - AIMS: The endothelin system plays a role in the complex pathophysiology of idiopathic dilated cardiomyopathy. We investigated whether genetic polymorphisms of the endothelin system might be associated with dilated cardiomyopathy-related cardiac phenotypes and differences in disease outcome. METHODS: One hundred and twenty-five unrelated dilated cardiomyopathy patients of a well characterized dilated cardiomyopathy cohort were genotyped for six common polymorphisms of the endothelin-1, endothelin-A (ETA) and endothelin-B (ETB) receptor genes using hybridization with allele-specific oligonucleotides. RESULTS: The H323H (C/T) polymorphism in exon 6 of the ETA receptor gene was significantly associated with a shorter survival time after diagnosis. The odds ratio for carriers of the less frequent ET(A)T allele to die within 2 years after diagnosis was 5.5 (95% confidence interval, 1.4 to 21.0, P=0.013) compared to non-carriers. Kaplan-Meier analysis revealed a significantly different survival time for T allele carriers as compared to non-carriers as tested by logrank (P=0.0196), Breslow (P=0.0195), and Tarone tests (P=0.020). The influence of the ETA H323H polymorphism on survival remained significant when known predictors of prognosis such as left ventricular ejection fraction, left ventricular end-diastolic diameter, age and NYHA functional classification were entered in a Cox proportional hazards analysis. In this model, end-diastolic diameter showed a trend to influence survival (P=0.07) but only the ETA H323H polymorphism (P=0.0029) was a significant independent predictor of survival. CONCLUSIONS: Our results suggest that genetic variation in the ETA receptor predicts survival in dilated cardiomyopathy patients, which might have important consequences for the identification of high-risk individuals. PMID- 11601840 TI - Management of atrial fibrillation: discrepancy between guideline recommendations and actual practice exposes patients to risk for complications. AB - AIMS: To assess compliance to guidelines in the management of patients with atrial fibrillation. METHODS AND RESULTS: A total of 728 questionnaires were mailed to physicians with the intention of studying 'theoretical' compliance to practice guidelines. A retrospective evaluation of 200 records from consecutive patients hospitalized with atrial fibrillation was performed in order to verify 'actual' compliance to guidelines. The response rate to the questionnaires was 68%. More than 94% of the physicians stated that patients with risk factors for thromboembolic complications and chronic atrial fibrillation should receive long term warfarin treatment. Of evaluated records, 108 patients were in chronic atrial fibrillation with at least one risk factor for stroke, and with no known contraindication to warfarin. In this group, only 40% received warfarin. Moreover, several other discrepancies were detected as regards the use of antiarrhythmic therapy. CONCLUSION: This study reveals a clear discrepancy between recommendations in guidelines and actual practice in patients with atrial fibrillation. The most important finding was a significant under use of thromboembolic prophylaxis in patients at high risk for such events. Implementation and the study of adherence to management guidelines on atrial fibrillation need to be carefully reviewed by surveys of actual clinical practice in order to establish reasonable therapeutic quality. PMID- 11601842 TI - MicF: an antisense RNA gene involved in response of Escherichia coli to global stress factors. AB - The micF gene is a stress response gene found in Escherichia coli and related bacteria that post-transcriptionally controls expression of the outer membrane porin gene ompF. The micF gene encodes a non-translated 93 nt antisense RNA that binds its target ompF mRNA and regulates ompF expression by inhibiting translation and inducing degradation of the message. In addition, other factors, such as the RNA chaperone protein StpA also play a role in this regulatory system. Expression of micF is controlled by both environmental and internal stress factors. Four transcriptional regulators are known to bind the micF promoter region and activate micF expression. The crystal structure of one these transcriptional activators, Rob, complexed with the micF promoter has been reported. Here, we review new developments in the micF regulatory network. PMID- 11601843 TI - The two mitochondrial heat shock proteins 70, Ssc1 and Ssq1, compete for the cochaperone Mge1. AB - Two members of the heat shock protein 70 kDa (Hsp70) family, Ssc1 and Ssq1, perform important functions in the mitochondrial matrix. The essential Ssc1 is an abundant ATP-binding protein required for both import and folding of mitochondrial proteins. The function of Ssc1 is supported by an interaction with the preprotein translocase subunit Tim44, the cochaperone Mdj1, and the nucleotide exchange factor Mge1. In contrast, only limited information is available on Ssq1. So far, a basic characterization of Ssq1 has demonstrated its involvement in the maintenance of mitochondrial DNA, the maturation of the yeast frataxin (Yfh1) after import, and assembly of the mitochondrial Fe/S cluster. Here, we analyzed the biochemical properties and the interaction partners of Ssq1 in detail. Ssq1 showed typical chaperone properties by binding to unfolded substrate proteins in an ATP-regulated manner. Ssq1 was able to form a specific complex with the nucleotide exchange factor Mge1. In particular, complex formation in organello was enhanced significantly when Ssc1 was inactivated selectively. However, even under these conditions, no interaction of Ssq1 with the two other mitochondrial Hsp70-cochaperones, Tim44 and Mdj1, was observed. The Ssq1-Mge1 interaction showed a lower overall stability but the same characteristic nucleotide-dependence as the Ssc1-Mge1 interaction. A quantitative analysis of the interaction properties indicated a competition of Ssq1 with Ssc1 for binding to Mge1. Perturbation of Mge1 function or amounts resulted in direct effects on Ssq1 activity in intact mitochondria. We conclude that mitochondria represent the unique case where two Hsp70s compete for the interaction with one nucleotide exchange factor. PMID- 11601844 TI - Quantification of DNaseI-sensitivity by real-time PCR: quantitative analysis of DNaseI-hypersensitivity of the mouse beta-globin LCR. AB - We employ real-time PCR to allow us to quantify the sensitivity of chromatin to digestion by DNaseI. This approach has three clear advantages over the more conventional use of the Southern hybridization assay: the accuracy of quantification is improved; the resolution of the assay is enhanced, by designing primers to amplify small amplicons it is possible to analyze sequences both co incident and proximal to sites of DNaseI-hypersensitivity; less material is needed, as little as 5 ng of treated genomic DNA. We applied this method in an analysis of the chromatin structure of the previously described mouse beta-globin locus control region (LCR) using fetal liver cells. The four hypersensitive sites of the canonical mouse LCR, HS1 to HS4, are shown to have kinetics of digestion consistent with these sequences being nucleosome-free in vivo. A different pattern was seen for HS6, a recently described "weak" hypersensitive site. The site was also rapidly lost but more of the sites proved resistant, we interpreted this to show that this hypersensitive was only forming in a portion of the erythroid cells. This finding implies that in vivo the LCR is structurally heterogeneous. Sequences proximal to the hypersensitive sites show a third pattern of intermediate sensitivity, consistent with the chromatin being unfolded but the sites still bound by a continual nucleosomal array. Our results demonstrate that this method has the potential to achieve accurate and detailed mapping of chromatin structure from small amounts of tissue samples. PMID- 11601845 TI - Central domain assembly: thermodynamics and kinetics of S6 and S18 binding to an S15-RNA complex. AB - The 30 S ribosomal subunit assembles in vitro through the hierarchical binding of 21 ribosomal proteins to 16 S rRNA. The central domain of 16 S rRNA becomes the platform of the 30 S subunit upon binding of ribosomal proteins S6, S8, S11, S15, S18 and S21. The assembly of the platform is nucleated by binding of S15 to 16 S rRNA, followed by the cooperative binding of S6 and S18. The prior binding of S6 and S18 is required for binding of S11 and S21. We have studied the mechanism of the cooperative binding of S6 and S18 to the S15-rRNA complex by isothermal titration calorimetry and gel mobility shift assays with rRNA and proteins from the hyperthermophilic bacterium Aquifex aeolicus. S6 and S18 form a stable heterodimer in solution with an apparent dissociation constant of 8.7 nM at 40 degrees C. The S6:S18 heterodimer binds to the S15-rRNA complex with an equilibrium dissociation constant of 2.7 nM at 40 degrees C. Consistent with previous studies using rRNA and proteins from Escherichia coli, we observed no binding of S6 or S18 in the absence of the other protein or S15. The presence of S15 increases the affinity of S6:S18 for the RNA by at least four orders of magnitude. The kinetics of S6:S18 binding to the S15-rRNA complex are slow, with an apparent bimolecular rate constant of 8.0 x 10(4) M(-1) s(-1) and an apparent unimolecular dissociation rate of 1.6 x 10(-4) s(-1). These results, which are consistent with a model in which S6 and S18 bind as a heterodimer to the S15-rRNA complex, provide a mechanistic framework to describe the previously observed S15 mediated cooperative binding of S6 and S18 in the ordered assembly of a multi protein ribonucleoprotein complex. PMID- 11601846 TI - Quasi-equivalence in site-specific recombinase structure and function: crystal structure and activity of trimeric Cre recombinase bound to a three-way Lox DNA junction. AB - The crystal structure of a novel Cre-Lox synapse was solved using phases from multiple isomorphous replacement and anomalous scattering, and refined to 2.05 A resolution. In this complex, a symmetric protein trimer is bound to a Y-shaped three-way DNA junction, a marked departure from the pseudo-4-fold symmetrical tetramer associated with Cre-mediated LoxP recombination. The three-way DNA junction was accommodated by a simple kink without significant distortion of the adjoining DNA duplexes. Although the mean angle between DNA arms in the Y and X structures was similar, adjacent Cre trimer subunits rotated 29 degrees relative to those in the tetramers. This rotation was accommodated at the protein-protein and DNA-DNA interfaces by interactions that are "quasi-equivalent" to those in the tetramer, analogous to packing differences of chemically identical viral subunits at non-equivalent positions in icosahedral capsids. This structural quasi-equivalence extends to function as Cre can bind to, cleave and perform strand transfer with a three-way Lox substrate. The structure explains the dual recognition of three and four-way junctions by site-specific recombinases as being due to shared structural features between the differently branched substrates and plasticity of the protein-protein interfaces. To our knowledge, this is the first direct demonstration of quasi-equivalence in both the assembly and function of an oligomeric enzyme. PMID- 11601847 TI - Structure of c-phycocyanin from the thermophilic cyanobacterium Synechococcus vulcanus at 2.5 A: structural implications for thermal stability in phycobilisome assembly. AB - The crystal structure of the light-harvesting phycobiliprotein, c-phycocyanin from the thermophilic cyanobacterium Synechochoccus vulcanus has been determined by molecular replacement to 2.5 A resolution. The crystal belongs to space group R32 with cell parameters a=b=188.43 A, c=61.28 A, alpha=beta=90 degrees, gamma=120 degrees, with one (alphabeta) monomer in the asymmetric unit. The structure has been refined to a crystallographic R factor of 20.2 % (R-free factor is 24.4 %), for all data to 2.5 A. The crystals were grown from phycocyanin (alphabeta)(3) trimers that form (alphabeta)(6) hexamers in the crystals, in a fashion similar to other phycocyanins. Comparison of the primary, tertiary and quaternary structures of the S. vulcanus phycocyanin structure with phycocyanins from both the mesophilic Fremyella diplsiphon and the thermophilic Mastigocladus laminosus were performed. We show that each level of assembly of oligomeric phycocyanin, which leads to the formation of the phycobilisome structure, can be stabilized in thermophilic organisms by amino acid residue substitutions. Each substitution can form additional ionic interactions at critical positions of each association interface. In addition, a significant shift in the position of ring D of the B155 phycocyanobilin cofactor in the S. vulcanus phycocyanin, enables the formation of important polar interactions at both the (alphabeta) monomer and (alphabeta)(6) hexamer association interfaces. PMID- 11601848 TI - The 1.85 A resolution crystal structures of tissue factor in complex with humanized Fab D3h44 and of free humanized Fab D3h44: revisiting the solvation of antigen combining sites. AB - The outstanding importance of the antigen-antibody recognition process for the survival and defence strategy of higher organisms is in sharp contrast to the limited high resolution structural data available on antibody-antigen pairs with antigenic proteins. The limitation is the most severe for structural data not restricted to the antigen-antibody complex but extending to the uncomplexed antigen and antibody. We report the crystal structure of the complex between tissue factor (TF) and the humanized Fab fragment D3h44 at a resolution of 1.85 A together with the structure of uncomplexed D3h44 at the same resolution. In conjunction with the previously reported 1.7 A crystal structure of uncomplexed TF, a unique opportunity is generated to explore details of the recognition process. The TF.D3h44 interface is characterised by a high number of polar interactions, including as may as 46 solvent molecules. Conformational changes upon complex formation are very small and almost exclusively limited to the reorientation of side-chains. The binding epitope is in complete agreement with earlier mutagenesis experiments. A revaluation of two other antibody-antigen pairs reported at similar resolutions, shows that all these complexes are very similar with respect to the solvation of the interface, the number of solvent positions conserved in the uncomplexed and complexed proteins and the number of water molecules expelled from the surface and replaced by hydrophilic atoms from the binding partner upon complex formation. A strategy is proposed on how to exploit this high resolution structural data to guide the affinity maturation of humanised antibodies. PMID- 11601849 TI - Structure of a variant of lac repressor with increased thermostability and decreased affinity for operator. AB - A single amino acid substitution, K84L, in the Escherichia coli lac repressor produces a protein that has substantially increased stability compared to wild type. However, despite the increased stability, this altered tetrameric repressor has a tenfold reduced affinity for operator and greatly decreased rate-constants of inducer binding as well as a reduced phenotypic response to inducer in vivo. To understand the dramatic increase in stability and altered functional properties, we have determined the X-ray crystal structures of a dimeric repressor with and without the K84L substitution at resolutions of 1.7 and 3.0 A, respectively. In the wild-type dimer, K84-11, Lys84 forms electrostatic interactions at the monomer-monomer interface and is partially exposed to solvent. In the K84L-11 substituted protein there is reorientation of the N subdomains, which allows the leucine to become deeply buried at the monomer monomer interface. This reorientation of the N-subdomains, in turn, results in an alteration of hydrogen bonding, ion pairing, and van der Waals interactions at the monomer-monomer interface. The lysine residue at position 84 appears to exert its key effects by destabilizing the "optimal" conformation of the repressor, effectively loosening the dimer interface and allowing the repressor to adopt the conformations necessary to function as a molecular switch. PMID- 11601850 TI - The 1.2 A structure of a novel quorum-sensing protein, Bacillus subtilis LuxS. AB - In bacteria, the regulation of gene expression in response to changes in cell density is called quorum sensing. The autoinducer-2 production protein LuxS, is involved in a novel quorum-sensing system and is thought to catalyse the degradation of S-ribosylhomocysteine to homocysteine and the autoinducer molecule 4,5-dihydroxy-2,3-pentadione. The crystal structure of Bacillus subtilis LuxS has been determined at 1.2 A resolution, together with the binary complexes of LuxS with S-ribosylhomocysteine and homocysteine to 2.2 and 2.3 A resolution, respectively. These structures show that LuxS is a homodimer with an apparently novel fold based on an eight-stranded beta-barrel, flanked by six alpha-helices. Each active site contains a zinc ion coordinated by the conserved residues His54, His58 and Cys126, and includes residues from both subunits. S-ribosylhomocysteine binds in a deep pocket with the ribose moiety adjacent to the enzyme-bound zinc ion. Access to the active site appears to be restricted and possibly requires conformational changes in the protein involving the movement of residues 125-129 and those at the N terminus. The structure contains an oxidised cysteine residue in the active site whose role in the biological process of LuxS has not been determined. The autoinducer-2 signalling pathway has been linked to aspects of bacterial virulence and pathogenicity. The structural data on LuxS will provide opportunities for targeting this enzyme for the rational design of new antibiotics. PMID- 11601851 TI - The crystal structure of bar-headed goose hemoglobin in deoxy form: the allosteric mechanism of a hemoglobin species with high oxygen affinity. AB - The crystal structure of a high oxygen affinity species of hemoglobin, bar-headed goose hemoglobin in deoxy form, has been determined to a resolution of 2.8 A. The R and R(free) factor of the model are 0.197 and 0.243, respectively. The structure reported here is a special deoxy state of hemoglobin and indicates the differences in allosteric mechanisms between the goose and human hemoglobins. The quaternary structure of the goose deoxy hemoglobin shows obvious differences from that of human deoxy hemoglobin. The rotation angle of one alphabeta dimer relative to its partner in a tetramer molecule from the goose oxy to deoxy hemoglobin is only 4.6 degrees, and the translation is only 0.3 A, which are much smaller than those in human hemoglobin. In the alpha(1)beta(2) switch region of the goose deoxy hemoglobin, the imidazole ring of His beta(2)97 does not span the side-chain of Thr alpha(1)41 relative to the oxy hemoglobin as in human hemoglobin. And the tertiary structure changes of heme pocket and FG corner are also smaller than that in human hemoglobin. A unique mutation among avian and mammalian Hbs of alpha119 from proline to alanine at the alpha(1)beta(1 )interface in bar-headed goose hemoglobin brings a gap between Ala alpha119 and Leu beta55, the minimum distance between the two residues is 4.66 A. At the entrance to the central cavity around the molecular dyad, some residues of two beta chains form a positively charged groove where the inositol pentaphosphate binds to the hemoglobin. The His beta146 is at the inositol pentaphosphate binding site and the salt-bridge between His beta146 and Asp beta94 does not exist in the deoxy hemoglobin, which brings the weak chloride-independent Bohr effect to bar-headed goose hemoglobin. PMID- 11601852 TI - Crystal structures of penicillin acylase enzyme-substrate complexes: structural insights into the catalytic mechanism. AB - The crystal structure of penicillin G acylase from Escherichia coli has been determined to a resolution of 1.3 A from a crystal form grown in the presence of ethylene glycol. To study aspects of the substrate specificity and catalytic mechanism of this key biotechnological enzyme, mutants were made to generate inactive protein useful for producing enzyme-substrate complexes. Owing to the intimate association of enzyme activity and precursor processing in this protein family (the Ntn hydrolases), most attempts to alter active-site residues lead to processing defects. Mutation of the invariant residue Arg B263 results in the accumulation of a protein precursor form. However, the mutation of Asn B241, a residue implicated in stabilisation of the tetrahedral intermediate during catalysis, inactivates the enzyme but does not prevent autocatalytic processing or the ability to bind substrates. The crystal structure of the Asn B241 Ala oxyanion hole mutant enzyme has been determined in its native form and in complex with penicillin G and penicillin G sulphoxide. We show that Asn B241 has an important role in maintaining the active site geometry and in productive substrate binding, hence the structure of the mutant protein is a poor model for the Michaelis complex. For this reason, we subsequently solved the structure of the wild-type protein in complex with the slowly processed substrate penicillin G sulphoxide. Analysis of this structure suggests that the reaction mechanism proceeds via direct nucleophilic attack of Ser B1 on the scissile amide and not as previously proposed via a tightly H-bonded water molecule acting as a "virtual" base. PMID- 11601853 TI - Beta-hairpin folding simulations in atomistic detail using an implicit solvent model. AB - We have used distributed computing techniques and a supercluster of thousands of computer processors to study folding of the C-terminal beta-hairpin from protein G in atomistic detail using the GB/SA implicit solvent model at 300 K. We have simulated a total of nearly 38 micros of folding time and obtained eight complete and independent folding trajectories. Starting from an extended state, we observe relaxation to an unfolded state characterized by non-specific, temporary hydrogen bonding. This is followed by the appearance of interactions between hydrophobic residues that stabilize a bent intermediate. Final formation of the complete hydrophobic core occurs cooperatively at the same time that the final hydrogen bonding pattern appears. The folded hairpin structures we observe all contain a closely packed hydrophobic core and proper beta-sheet backbone dihedral angles, but they differ in backbone hydrogen bonding pattern. We show that this is consistent with the existing experimental data on the hairpin alone in solution. Our analysis also reveals short-lived semi-helical intermediates which define a thermodynamic trap. Our results are consistent with a three-state mechanism with a single rate-limiting step in which a varying final hydrogen bond pattern is apparent, and semi-helical off-pathway intermediates may appear early in the folding process. We include details of the ensemble dynamics methodology and a discussion of our achievements using this new computational device for studying dynamics at the atomic level. PMID- 11601854 TI - Roles of native topology and chain-length scaling in protein folding: a simulation study with a Go-like model. AB - We perform folding simulations on 18 small proteins with using a simple Go-like protein model and analyze the folding rate constants, characteristics of the transition state ensemble, and those of the denatured states in terms of native topology and chain length. Near the folding transition temperature, the folding rate k(F) scales as k(F) approximately exp(-c RCO N(0.6)) where RCO and N are the relative contact order and number of residues, respectively. Here the topology RCO dependence of the rates is close to that found experimentally (k(F) approximately exp(-c RCO)), while the chain length N dependence is in harmony with the predicted scaling property (k(F) approximately exp(-c N(2/3))). Thus, this may provides a unified scaling law in folding rates at the transition temperature, k(F) approximately exp(-c RCO N(2/3)). The degree of residual structure in the denatured state is highly correlated with RCO, namely, proteins with smaller RCO tend to have more ordered structure in the denatured state. This is consistent with the observation that many helical proteins such as myoglobin and protein A, have partial helices, in the denatured states. The characteristics of the transition state ensemble calculated by the current model, which uses native topology but not sequence specific information, are consistent with experimental phi-value data for about half of proteins. PMID- 11601855 TI - Genetic selection for and molecular dynamic modeling of a protein transmembrane domain multimerization motif from a random Escherichia coli genomic library. AB - In order to identify new transmembrane helix packing motifs in naturally occurring proteins, we have selected transmembrane domains from a library of random Escherichia coli genomic DNA fragments and screened them for homomultimerization via their abilities to dimerize the bacteriophage lambda cI repressor DNA-binding domain. Sequences were isolated using a modified lambda cI headpiece dimerization assay system, which was shown previously to measure transmembrane helix-helix association in the E. coli inner membrane. Screening resulted in the identification of several novel sequences that appear to mediate helix-helix interactions. One sequence, representing the predicted sixth transmembrane domain (TM6) of the E. coli protein YjiO, was chosen for further analysis. Using site-directed mutagenesis and molecular dynamics, a small set of models for YjiO TM6 multimerization interface interactions were generated. This work demonstrates the utility of combining in vivo genetic tools with computational systems for understanding membrane protein structure and assembly. PMID- 11601856 TI - A fragment library based on Gaussian mixtures predicting favorable molecular interactions. AB - Here, a protein atom-ligand fragment interaction library is described. The library is based on experimentally solved structures of protein-ligand and protein-protein complexes deposited in the Protein Data Bank (PDB) and it is able to characterize binding sites given a ligand structure suitable for a protein. A set of 30 ligand fragment types were defined to include three or more atoms in order to unambiguously define a frame of reference for interactions of ligand atoms with their receptor proteins. Interactions between ligand fragments and 24 classes of protein target atoms plus a water oxygen atom were collected and segregated according to type. The spatial distributions of individual fragment - target atom pairs were visually inspected in order to obtain rough-grained constraints on the interaction volumes. Data fulfilling these constraints were given as input to an iterative expectation-maximization algorithm that produces as output maximum likelihood estimates of the parameters of the finite Gaussian mixture models. Concepts of statistical pattern recognition and the resulting mixture model densities are used (i) to predict the detailed interactions between Chlorella virus DNA ligase and the adenine ring of its ligand and (ii) to evaluate the "error" in prediction for both the training and validation sets of protein-ligand interaction found in the PDB. These analyses demonstrate that this approach can successfully narrow down the possibilities for both the interacting protein atom type and its location relative to a ligand fragment. PMID- 11601857 TI - Anatomy of Escherichia coli ribosome binding sites. AB - During translational initiation in prokaryotes, the 3' end of the 16S rRNA binds to a region just upstream of the initiation codon. The relationship between this Shine-Dalgarno (SD) region and the binding of ribosomes to translation start points has been well studied, but a unified mathematical connection between the SD, the initiation codon and the spacing between them has been lacking. Using information theory, we constructed a model that treats these three components uniformly by assigning to the SD and the initiation region (IR) conservations in bits of information, and by assigning to the spacing an uncertainty, also in bits. To build the model, we first aligned the SD region by maximizing the information content there. The ease of this process confirmed the existence of the SD pattern within a set of 4122 reviewed and revised Escherichia coli gene starts. This large data set allowed us to show graphically, by sequence logos, that the spacing between the SD and the initiation region affects both the SD site conservation and its pattern. We used the aligned SD, the spacing, and the initiation region to model ribosome binding and to identify gene starts that do not conform to the ribosome binding site model. A total of 569 experimentally proven starts are more conserved (have higher information content) than the full set of revised starts, which probably reflects an experimental bias against the detection of gene products that have inefficient ribosome binding sites. Models were refined cyclically by removing non-conforming weak sites. After this procedure, models derived from either the original or the revised gene start annotation were similar. Therefore, this information theory-based technique provides a method for easily constructing biologically sensible ribosome binding site models. Such models should be useful for refining gene-start predictions of any sequenced bacterial genome. PMID- 11601858 TI - A standard reference frame for the description of nucleic acid base-pair geometry. PMID- 11601859 TI - Biophysical vision model and learning paradigms about vision: review. AB - A learning paradigm of a new biophysical vision model (BVM) is presented. It incorporates anatomical and physiological evidence from micro- and macroscopic research on vision as reported in the literature during the past five years. Anatomical and physiological vision research tends to drift away from the technological foundations of encoding and reproducing size-defined images of real ongoing life scenarios. White and color light waves reflecting life scenarios are converted by the retina to encoded electrical train pulses with attached real information to be decoded by cortical vision neurons. The BVM paradigm is based on the ideas that: (1) cinema technology reproduces real-life scenes just as the human eye sees them; (2) virtual reality and robotics are computerized replications of categorized human vision faculties in operation. We believe that vision-related technology may extend our knowledge about vision and direct vision research into new horizons. The biophysical vision model has three prerequisites: (1) The faculties of human vision must be categorized. (2) Logic circuits of the 'hardware' of neuronal vision must be present. (3) Vision faculties are operated by self-induced 'software'. Vision research may be enhanced with devices constructed according to BVM that would enable biophysical vision experiments in both humans and animals. PMID- 11601860 TI - AIDS possibly caused by HIV and latent malaria coinfection. AB - The presented hypothesis suggests that chronic latent malaria infection prepares the niche where the otherwise feeble HIV coinfection can thrive and cause AIDS. It is suggested that the roots of the HIV outbreak and AIDS pandemic lay in the urbanization processes in Africa that resulted in the eradication of the Anopheles vector from previously endemic areas, which changed the immunological status of the inhabitants there as they lost their natural immunity to malaria. Since malarial parasites may persist in the lymphatic network for a lifetime and reduce T cell proliferation while adhering to immature dendritic cells, the loss of this natural immunity made the African population, which was chronically affected with scanty parasitemia, vulnerable to opportunistic infections, HIV among them. The specific transmission modes of latent malaria infection elucidate why AIDS flares up in Africa and spreads there evenly in the population, while in the West it expands rather slowly and is restricted mainly to homosexuals and blood recipients. PMID- 11601861 TI - Circadian variation in portal pressure: appropriate use of non-selective beta blockers in the prevention of variceal bleed. AB - The circadian variation in some biologic functions may have clinical, fiscal and therapeutic implications. The authors discuss circadian variation in portal pressure in cirrhotic patients and nocturnal occurrence of bleeding from varices in these patients. The pathogenesis of the diurnal variation in portal pressure is presented. The authors submit the hypothesis that an optimal dosing regimen for non-selective beta blocker therapy in the prevention of variceal bleed must include an evening dose of beta blocker medication. In studies reporting comparative efficacy of beta blocker therapy with other modalities in the prevention of variceal bleeding, the optimal dosing schedule for beta blocker therapy must be emphasized. PMID- 11601862 TI - Chronic infection, inflammation, and epithelial ovarian cancer. AB - At the present time, the etiology of epithelial ovarian cancer is poorly understood. It has recently been recognized that certain chronic infectious agents may contribute to carcinogenesis by inducing a state of persistent inflammation. Since the female upper genital tract is a frequent site of chronic infections, we propose various strategies that may be useful for determining the potential role of chronic infection and persistent inflammation in the pathogenesis of epithelial ovarian cancer. PMID- 11601863 TI - Dysfunctional mitochondria, not oxygen insufficiency, cause cancer cells to produce inordinate amounts of lactic acid: the impact of this on the treatment of cancer. AB - It has been known for decades that cancer cells produce excessive amounts of lactic acid. The fact that most cancers have poor vascular systems has led cancer scientists to assume that such cells are deprived of a normal supply of oxygen. Researchers believe that without sufficient oxygen, cancer cells must revert to fermentation for their energy supply and this is what causes them to produce excessive lactic acid. I challenge this traditional assumption and suggest instead that cancer cells have dysfunctional mitochondria, which prevent their use of the citric acid or Krebs cycle. Consequently, pyruvic acid, the end product of glycolysis, which normally would enter the mitochondria for its total combustion into energy, is instead converted to lactic acid. Evidence exists to support this hypothesis which, when acknowledged, could dynamically impact both cancer research and the treatment of all forms of cancer. PMID- 11601864 TI - Melatonin: a significant contributor to the pathogenesis of migraine. AB - It is generally accepted that migraine is caused by a primary biochemical disorder of the central nervous system involving neurotransmitters, specifically serotonin. The pathogenetic mechanism triggered by external and internal stimuli is not well explained or understood. This article points to the possibility that the pineal gland, a primary source of central serotonin and melatonin, contributes significantly to migraine attacks. PMID- 11601865 TI - Asymptomatic Borrelia burgdorferi infection. AB - Little is known about the natural history of asymptomatic Borrelia burgdorferi infection. Our analysis of the asymptomatic infections diagnosed serologically in a recent OspA vaccine trial conducted in the United States (N Engl J Med 1998;339: 209-215), suggests that the natural history of this event is more benign than that reported for untreated patients with erythema migrans (Ann Intern Med 1987;107: 725-731). We hypothesize that this is due either to incorrect diagnosis since the specificity of the serologic criteria used to diagnose asymptomatic infection in the vaccine study is unknown, or to infection with non-pathogenic strains of B. burgdorferi. Increasing evidence indicates that the invasive potential of strains of B. burgdorferi varies according to the specific subtype. Theoretically, a serologic testing method could be devised which would distinguish infection with invasive versus non-invasive strains of B. burgdorferi, and allow testing of the second hypothesis. PMID- 11601866 TI - Dynamics of neural networks: a proposed mechanism to account for changes in clinical symptomatology through time in patients with psychotic diseases. AB - The classical Kraepelinean dichotomy between manic depressive insanity and the schizophrenias has been recently challenged from clinical and neurobiological quarters. It is not so infrequent to see patients shift from a manic to a schizophrenic symptomatology and vice versa. This paper proposes neurobiological mechanisms as to how these changes may occur, based on recent data on the functioning of neural networks at different modes. PMID- 11601867 TI - Atherosclerosis, and Newton, Poiseuille, Reynolds and Prandtl. AB - Atherosclerotic fibrous plaques typically manifest at inlets of branches and in expansions etc. of large elastic arteries. A resting man with a surface area of 1.78 m(2)produces energy at a rate of 100 W (86 kcal/h), mainly by core organs. Core blood heat is convected to arterial walls and conducted through tissues to be lost from body surfaces. High losses are compensated by an increase in the basal metabolic rate, and vice versa. In laminar flow, the fluid-tube wall heat transfer coefficient is higher close to tube inlets than downstream. Unless lipoprotein etc. suspects are exceptions from the rule that an increase in temperature speeds up chemical reactions, transfer of core heat may contribute to plaque localization. In laminar flow, heat transfer is little influenced by viscosity. Hence correlations between blood viscosity and cardiovascular disease (CVD) may reside in other mechanisms: viscosity limits flow relatively more in small than in large arteries, and viscosity-linked thixotropic properties of blood increase resistance to flow in capillaries and postcapillary venules (exchange vessels). The exchange vessels of large arteries belong to the vasa vasorum, in which reduction of flow induces diffuse parent artery wall changes found also in plaques. Correlations between blood viscosity and peripheral symptoms of CVD may be explained by reduced flow in vascular loops of symptomatic organs, even if maximum flow is limited by upstream plaques. Physiological differences in the type of blood flow and in blood-tissue exchange between vessels of different size may shed light on apparent paradoxes in research on CVD. PMID- 11601868 TI - 'Sensitivity syndromes' related to radiation exposures. AB - The primary health effects of radiation are traditionally believed to result from cellular genetic damage. These effects are believed to result in a statistically detectable increase in the induction of cancer in exposed populations. A significant number of residents of areas affected by the Chernobyl disaster and workers involved in the clean-up ('liquidators') have reported debilitating physical illnesses that cannot be easily explained by a genetic effect. This paper presents results of a literature search that strongly suggests that a previously unrecognized neural pathway may be responsible for the induction of these debilities. In addition, a common link between radiation and chemical sensitivity syndromes may now be identified. PMID- 11601869 TI - Tertiary gain and disability syndromes. AB - Since the introduction of the concept of tertiary gain by Dansak in 1973, there has been little further publication or research on this topic. Yet, tertiary gain is often the subject of debate amongst physicians, therapists, insurers, the media, and even at times the general public. Much of the controversy of disability syndromes and the health and economic burden they present has focused on secondary gain and illness behaviour. The role of tertiary gain in illness behaviour is likely also relevant, and a model of tertiary gain is needed to begin further understanding the implications of this phenomenon for patients and those who treat them. This article introduces a phraseology for tertiary gain, and models the effects of tertiary gain on illness behaviour and the interactions of secondary and tertiary gain in the setting of disability syndromes. PMID- 11601870 TI - A simplified approach to the statistical incidence of myeloid and erythroid leukemias in humans. AB - Using order parameters from field theory, the paper rationalizes the statistics of myeloid and erythroid leukemias more satisfactorily than the random mutation hypothesis. Adapted to B- and plasma cell lineages, the same arguments conceptualize the statistics of related malignancies congruently to clinical findings. PMID- 11601871 TI - Selective serotonin-reuptake inhibitor antidepressants increase the risk of falls and hip fractures in elderly people by inhibiting cardiovascular ion channels. AB - Surprising results from recently published retrospective studies show that the use of new selective serotonin-reuptake inhibitor antidepressants (SSRIs), similarly to the older tricyclic antidepressants (TCAs), increases the risk of falls and hip fractures among elderly people.The mechanism whereby antidepressants increase this risk is complex and may include orthostatic hypotension, arrhythmias, sedation and confusion. The increased risk of falls and hip fractures with the use of TCAs is not surprising considering their well-known cardiovascular, anticholinergic and antihistaminergic side-effects. But the increased risk of falls with SSRIs is highly unexpected since these drugs are believed to be free from the disadvantages of TCAs. We hypothesized that the new SSRI antidepressants may also have cardiovascular effects similarly to the older TCA compounds, which may be an explanation for the increased rate of falls and hip fractures. The experimental and clinical evidence in support of this hypothesis are discussed. PMID- 11601872 TI - Prophylaxis of climbers for prevention of embolic accidents. AB - The development of deep venous thrombosis and the ensuing secondary complications of pulmonary embolism, disseminated intravascular coagulation, and stroke may be produced in high altitude climbers as a result of acclimatization to altitude. To prevent these serious disorders, investigation for predisposing risk factors and consideration of anticoagulative therapy should be considered. PMID- 11601873 TI - Iron supplementation during human immunodeficiency virus infection: a double edged sword? AB - Although iron supplementation is considered beneficial for groups at risk for anemia, concern has been raised that it could be harmful during human immunodeficiency virus (HIV) infection. Studies suggest: (1) faster HIV disease progression in thalassemia major patients receiving inadequate doses of iron chelating drug; (2) higher mortality among patients receiving iron supplementation with dapsone compared with aerosolized pentamidine for prophylaxis against Pneumocytis carinii pneumonia; (3) higher iron stores and mortality among patients with haptoglobin Hp 2-2 phenotype; and (4) shorter survival among patients with high bone marrow iron deposition. These studies largely involved men in developed countries. Among HIV-infected pregnant women in Africa with a high prevalence of iron deficiency, no relationship was found between indicators of iron status and HIV disease severity. The available data do not contraindicate the current practice of iron supplementation in developing countries where there is a high prevalence of both HIV infection and iron deficiency. PMID- 11601874 TI - Role of thyroid hormones in the effects of selenium on mood, behavior, and cognitive function. AB - Changes in thyroid function may affect mood, behavior, and cognitive function. Selenium is required for appropriate thyroid hormone synthesis, activation, and metabolism. Selenium status influences thyroid function. Selenium status also affects psychological condition and cognitive function. The author suggests that the effects of selenium status on mood, behavior, and cognition may be partly mediated by changes induced by selenium deficiency or selenium supplementation in thyroid function. Selenium deficiency decreases immunocompetence and promotes viral infections. The author proposes that patients who have a combination of depression, hypothyroidism, and increased susceptibility to viral infections, could reasonably be assessed for selenium deficiency, especially if they live in an area where the soil is low in selenium. PMID- 11601875 TI - Control of skin infections by a combined action of ultraviolet A (from sun or UVA lamp) and hydrogen peroxide (HUVA therapy), with special emphasis on leprosy. AB - Despite its abundance and certain therapeutic value, the importance of sunlight in the treatment of infectious skin diseases has not been fully exploited. One reason is that a sufficient amount of the damaging components of sunlight (UVC and most UVB) cannot reach us and the band of UV that can reach (UVA) is a poor inactivator of living cells. UVA, however, can be deleterious to cells in the presence of sensitizers and a number of biological and chemical sensitizers have been identified which can inactivate microbes in the presence of UVA. Of several known agents, I have selected hydrogen peroxide (H(2)O(2)) as a UVA sensitizer and propose that a combined action of H(2)O(2)and UVA (HUVA therapy) can be utilized in controlling skin infections of various types. Of particular interest is infection by Mycobacterium leprae, which is known to affect many millions of humans globally. H(2)O(2)being relatively cheap (and UVA from the sun being free) the cost of application, particularly in third-world countries where leprosy is more common, would be low and therefore the treatment can be employed on a wide scale. A further reason for proposing the use of H(2)O(2)is that, out of several agents we have tested, this was found to be the most potent; it is also easily able to reach target sites, very cheap, relatively safe and there is no known microbial resistance to HUVA. PMID- 11601876 TI - Electrocardiographic diagnosis of left ventricular hypertrophy: is the method obsolete or should the hypothesis be reconsidered? AB - The current ECG diagnosis of LVH is based on QRS voltage criteria and aims to estimate left ventricular mass. Its underlying hypothesis includes unstated assumptions about the non-spatial determinants of QRS voltage;that the electrical properties of hypertrophied myocardium do not differ from those healthy myocardium, and that they are not changed in the course of developing LVH. Since these two assumptions are not true, the performance of the voltage criteria is limited and is reflected in the high number of so-called false negative ECG results, as well as their low sensitivity. The reconsidered hypothesis is based on a more complex understanding of LVH and on the analysis of information provided by electrocardiography. It considers false negative results for LVH diagnosis as a relative voltage deficit, and introduces a new parameter for its quantification: the specific potential (the relative QRS voltage).The relative voltage deficit is related to changes of active and passive electrical properties (electrophysiological remodelling) of the hypertrophied myocardium. This new hypothesis also takes into account changes of the relative QRS voltage in different stages of LVH. The potential of this concept is its usefulness as a parameter in the frame of diagnostics of LVH, of diffuse changes of myocardium, in cardiovascular risk assessment, and well as for evaluation of the effects of therapy. PMID- 11601877 TI - Compactotomy in Huntington's chorea. AB - Advances in neuroradiological and neurosurgical techniques have lead to a growing interest in functional neurosurgical interventions for medically intractable movement disorders. The majority of these procedures are performed in patients with hypokinetic movement disorders, especially Parkinson's disease. However, relatively few interventions were done in hyperkinetic disorders such as Huntington's disease (HD), mainly owing to the lack of an adequate target nucleus. We have recently described the case of a reversible chorea in a genetically confirmed HD patient. We subsequently identified a marked bilateral degeneration of the substantia nigra as the probable reason for choreatic cessation. We therefore suggest that primary striatal atrophy causing hyperkinesia and secondary substantia nigra atrophy favouring hypokinesia were balanced in this patient, thus resulting in a close-to-physiologic GABAergic basal ganglia output. We postulate that deep brain stimulation of the substantia nigra pars compacta may ameliorate hyperkinesia in choreatic movement disorders, thus representing the first effective therapy in Huntington's chorea. Several lines of evidence in recent neurophysiological research support our hypothesis and are discussed below. PMID- 11601878 TI - The role of nitric oxide in the formation of keloid and hypertrophic lesions. AB - Keloid and hypertrophic scars are a type of scarring pathology which is characterised by excess collagen deposition produced during the wound healing process. The mechanism by which this occurs is not understood and although hypertrophic scars can regress spontaneously, keloids do not, and currently no effective treatment exists. In this paper we hypothesise that nitric oxide, a free radical molecule synthesised by numerous mammalian cells, is involved in the formation of these scars. We suggest that the excess collagen production in keloid lesions can be attributed to higher than normal levels of nitric oxide, as the free radical is a known stimulus for fibroblast collagen synthesis. Furthermore, we propose that the basal epidermis is a source of this additional nitric oxide and we discuss this in relation to known histological characteristics of keloid and hypertrophic lesions. PMID- 11601879 TI - Nonsteroidal anti-inflammatory drugs for treatment of advanced gastric cancer: cyclooxygenase-2 is involved in hepatocyte growth factor mediated tumor development and progression. AB - Surgical treatment of gastric cancer patients is dismal because advanced tumor is often noted at diagnosis. In order to obtain better adjuvant therapy for gastric cancer patients after operation, it is important to understand the mechanism of invasion and metastasis. It is well known that binding of hepatocyte growth factor (HGF) to its receptor (c-Met) regulates gastric cancer progression and metastasis. Recently, HGF was found to up-regulate the expression of cyclooxygenase-2 (COX-2) gene and increase prostaglandin (PG)synthesis in gastric mucosa cells. Over-expression of COX-2 and increased PG secretion have also been found to be involved in the growth and metastasis of gastric cancer. These results together suggest that the signaling pathway of HGF and c-Met may be mediated through ERK2 activation, up-regulation of COX-2 and increased production of PGE(2)in gastric cancer cells. In view of the fact that c-Met is over expressed in the majority of gastric cancer patients with poor prognosis, COX-2 specific inhibitors may provide beneficial effects in these patients. PMID- 11601880 TI - On the physiological function of lithium from a psychiatric view point. AB - Lithium is a naturally occurring alkali metal, which living organisms ingest from dietary sources and which is also present in trace amounts in the human body. In much higher concentrations, lithium is effective as a medication for mania and mood swings including manic depressive disorders. Many studies have shown that a deficiency in 'endogenous' lithium, i.e. lithium in food and drinking water, can lead to defects in growth and development in animals and to grave psychopathological problems in humans. It is therefore conceivable that lithium has an essential function in the physiological regulation of mood and that a subgroup of pathological mood disorders cause a bodily requirement for drastically higher concentrations of lithium in compartments. Taking lithium long term could have a prophylactic effect on this kind of change in bodily requirements. PMID- 11601881 TI - Is milk responsible for male reproductive disorders? AB - The role of environmental compounds with estrogenic activity in the development of male reproductive disorders has been a source of great concern. Among the routes of human exposure to estrogens, we are particularly concerned about cows' milk, which contains considerable amounts of estrogens. The major sources of animal-derived estrogens in the human diet are milk and dairy products, which account for 60-70% of the estrogens consumed. Humans consume milk obtained from heifers in the latter half of pregnancy, when the estrogen levels in cows are markedly elevated. The milk that we now consume may be quite unlike that consumed 100 years ago. Modern genetically-improved dairy cows, such as the Holstein, are usually fed a combination of grass and concentrates (grain/protein mixes and various by-products), allowing them to lactate during the latter half of pregnancy, even at 220 days of gestation. We hypothesize that milk is responsible, at least in part, for some male reproductive disorders. PMID- 11601882 TI - Noninvasive cardiac absolute pressure sensing: a fundamentally new approach. AB - Noninvasive cardiac pressure sensing using an imaging modality to ascertain changes in absolute pressure would be of immense benefit as a replacement for the Swan-Ganz catheter in current use. However, very little research has been published in this area. This paper reviews the small number of relevant studies to date, points out the many gaps in the research record, and discusses possible new avenues of approach in solving the problem. PMID- 11601883 TI - Identification of butyrylcholinesterase adducts after inhibition with isomalathion using mass spectrometry: difference in mechanism between (1R)- and (1S)-stereoisomers. AB - Previous kinetic studies found that butyrylcholinesterase (BChE) inhibited by (1R)-isomalathions readily reactivated, while enzyme inactivated by (1S)-isomers did not. This study tested the hypothesis that (1R)- and (1S)-isomers inhibit BChE by different mechanisms, yielding distinct adducts identifiable by peptide mass mapping with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Equine BChE (EBChE) was inhibited to <10% of control activity with each isomer of isomalathion and the reference compound isoparathion methyl. Control and treated enzyme was digested with trypsin, and peptides were fractionated with HPLC. Separated and unseparated peptides were analyzed with MALDI-TOF-MS. Identity of an organophosphorus peptide adduct was confirmed by fragmentation using postsource decay analysis. EBChE inhibited by (1R) isomalathions or (S)-isoparathion methyl readily reactivated after oxime treatment with 30-40% activity recovered. Enzyme inactivated by (1S) isomalathions or (R)-isoparathion methyl recovered <2% and <5% activity, respectively, after oxime treatment. MALDI-TOF-MS analysis revealed that inhibition of EBChE by (1R)-isomalathions and (R)- or (S)-isoparathion methyl yielded O,S-dimethyl phosphate adducts. Enzyme inactivated by (1S)-isomalathions produced only O-methyl phosphate adduct. EBChE modified by (1R)-isomalathions or either enantiomer of isoparathion methyl yielded an O-methyl phosphate adduct as well. The results indicate that EBChE inhibition by (1R)-isomalathions proceeds with loss of diethyl thiosuccinate, but inactivation by (1S)-isomers occurs with loss of thiomethyl as the primary leaving group followed by rapid expulsion of diethyl thiosuccinate to yield an aged enzyme. Furthermore, the data suggest that aging of the O,S-dimethyl phosphate adduct occurs via an S(N)2 process with loss of thiomethyl. PMID- 11601884 TI - A physiologically based pharmacokinetic model for inhalation and intravenous administration of naphthalene in rats and mice. AB - A diffusion limited physiologically based pharmacokinetic model for rats and mice was developed to characterize the absorption, distribution, metabolism, and elimination of naphthalene after inhalation exposure. This model includes compartments for arterial and venous blood, lung, liver, kidney, fat, and other organs. Primary sites for naphthalene metabolism to naphthalene oxide are the lung and the liver. The data used to create this model were generated from National Toxicology Program inhalation and iv studies on naphthalene and consisted of blood time-course data of the parent compound in both rats and mice. To examine the basis for possible interspecies differences in response to naphthalene, the model was extended to describe the distribution and metabolism of naphthalene oxide and the depletion and resynthesis of glutathione. After testing several alternative models, the one presented in this paper shows the best fit to the data with the fewest assumptions possible. The model indicates that tissue dosimetry of the parent compound alone does not explain why this chemical was carcinogenic to the female mouse lung but not to the rat lung. The species difference may be due to a combination of higher levels of naphthalene oxide in the mouse lung and a greater susceptibility of the mouse lung to epoxide induced carcinogenesis. However, conclusions regarding which metabolite(s) may be responsible for the lung toxicity could not be reached. PMID- 11601885 TI - Aroclor 1254 inhibits the mitochondrial permeability transition and release of cytochrome c: a possible mechanism for its in vivo toxicity. AB - The mitochondrial permeability transition (MPT) occurs in several forms of necrotic cell death induced by various insults, including oxidative stress, ischemia/reperfusion injury Ca(2+)-ionophore toxicity, and apoptosis. In fact, the release of an apoptogenic factor such as cytochrome c is often associated with the opening of the transition pore. The present study shows that Aroclor 1254, a mixture of polychlorinated biphenyls that was banned in the U.S. in 1977 but is still present in the environment, inhibits the MPT in a dose-dependent manner in a concentration range of 1 to 25 nmol/mg protein. The compound prevents key phenomena associated with the MPT, including colloid-osmotic swelling, the collapse of membrane potential, nonspecific bidirectional traffic of solutes through the transition pore, and the oxidation of pyridine nucleotides. In contrast, Aroclor 1254 does not inhibit uptake of Ca(2+) or P(i). The effects of Aroclor 1254 are evident both in sucrose-based media and in saline and are observed when the compound is added before the opening of the pore. Aroclor 1254 prevents MPT induction provoked by a variety of agents, including phosphate, menadione, tert-butylhydroperoxide, and atractyloside. Aroclor 1254 also inhibits the specific release of cytochrome c, a correlate of MPT induction. These effects reveal a possible toxicological mechanism of action of this compound. The possibility that its effect on mitochondrial function is linked to its action as a tumor promoter is discussed. PMID- 11601886 TI - Novel effects of minocycline on Ca(2+)-dependent Cl(-) secretion in human airway epithelial Calu-3 cells. AB - The present study concerns previously unreported effects of the antibiotic minocycline on the transepithelial Cl(-) transport in Calu-3 cells, which display electrophysiological properties consistent with human airway serous cells. Basolateral 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS, 200 microM) augmented Cl(-) secretion, which was detected as a 5-nitro-2-(3 phenylpropylamino)-benzoate (NPPB, 100 microM, a Cl(-) channel blocker)-sensitive short-circuit current (I(sc)). The DIDS-induced I(sc) was composed of Ca(2+) activated K(+) (K(Ca)) channel-dependent and -independent components. The former was selectively inhibited by 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA/AM, 10 microM), charybdotoxin (ChTx, 100 nM), clotrimazole (10 microM), basolateral Ca(2+) removal, and basolateral minocycline (IC(50) = 20 microM). The latter was attenuated by basolateral BaCl (5 mM). In contrast, forskolin (10 microM)-induced I(sc), which is insensitive to BAPTA/AM and ChTx, was unaffected by minocycline (100 microM). ATP-induced I(sc) was partially inhibited by basolateral but not by apical minocycline. I(sc) due to basolateral application of ionomycin (1 microM) was markedly suppressed by NPPB and basolateral Ca(2+) removal. These inhibitory effects were mimicked by minocycline applied only from the basolateral side of the monolayer. In the basolateral absence of Ca(2+), 1-ethyl-2-benzimdazolinone (500 microM), a K(Ca) channel opener, generated a sustained I(sc) sensitive to ChTx. Minocycline had no significant effect on the ChTx-sensitive component of the I(sc). It is concluded that minocycline inhibits K(Ca) channel-dependent Cl(-) secretion via a blockade of Ca(2+) influx across the basolateral membrane from the extracellular side. PMID- 11601887 TI - Inhibition of UVB-induced oxidative stress-mediated phosphorylation of mitogen activated protein kinase signaling pathways in cultured human epidermal keratinocytes by green tea polyphenol (-)-epigallocatechin-3-gallate. AB - Exposure of normal human epidermal keratinocytes (NHEK) to UVB radiation induces intracellular release of hydrogen peroxide (oxidative stress) and phosphorylation of mitogen-activated protein kinase cell signaling pathways. Here, we demonstrate that pretreatment of NHEK with (-)-epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, inhibits UVB-induced hydrogen peroxide (H(2)O(2)) production and H(2)O(2)-mediated phosphorylation of MAPK signaling pathways. We found that treatment of EGCG (20 microg/ml of media) to NHEK before UVB (30 mJ/cm(2)) exposure inhibited UVB-induced H(2)O(2) production (66-80%) concomitant with the inhibition of UVB-induced phosphorylation of ERK1/2 (57-80%), JNK (53 83%), and p38 (50-77%) proteins. To demonstrate whether UVB-induced phosphorylation of MAPK occurs via UVB-induced H(2)O(2) (oxidative stress) production, NHEK were treated with the oxidant H(2)O(2). Treatment of H(2)O(2) to NHEK resulted in phosphorylation of ERK1/2, JNK, and p38. Using the same in vitro system, when these cells were pretreated with EGCG or with the known antioxidant ascorbic acid (as positive control), H(2)O(2)-induced phosphorylation of ERK1/2, JNK, and p38 was found to be significantly inhibited. These findings demonstrate that EGCG has the potential to inhibit UVB-induced oxidative stress-mediated phosphorylation of MAPK signaling pathways, suggesting that EGCG could be useful in attenuation of oxidative stress-mediated and MAPK-caused skin disorders in humans. PMID- 11601889 TI - The cellular metabolism and systemic toxicity of arsenic. AB - Although it has been known for decades that humans and many other species convert inorganic arsenic to mono- and dimethylated metabolites, relatively little attention has been given to the biological effects of these methylated products. It has been widely held that inorganic arsenicals were the species that accounted for the toxic and carcinogenic effects of this metalloid and that methylation was properly regarded as a mechanism for detoxification of arsenic. Elucidation of the metabolic pathway for arsenic has changed our understanding of the significance of methylation. Both methylated and dimethylated arsenicals that contain arsenic in the trivalent oxidation state have been identified as intermediates in the metabolic pathway. These compounds have been detected in human cells cultured in the presence of inorganic arsenic and in urine of individuals who were chronically exposed to inorganic arsenic. Methylated and dimethylated arsenicals that contain arsenic in the trivalent oxidation state are more cytotoxic, more genotoxic, and more potent inhibitors of the activities of some enzymes than are inorganic arsenicals that contain arsenic in the trivalent oxidation state. Hence, it is reasonable to describe the methylation of arsenic as a pathway for its activation, not as a mode of detoxification. This review summarizes the current knowledge of the processes that control the formation and fate of the methylated metabolites of arsenic and of the biological effects of these compounds. Given the considerable interest in the dose-response relationships for arsenic as a toxin and a carcinogen, understanding the metabolism of arsenic may be critical to assessing the risk associated with chronic exposure to this element. PMID- 11601888 TI - Fumonisin B(1) induces apoptosis in LLC-PK(1) renal epithelial cells via a sphinganine- and calmodulin-dependent pathway. AB - Fumonisins are a family of mycotoxins produced by Fusarium moniliforme, which is the most common mold found on corn throughout the world. These compounds are both toxic and carcinogenic for animals, and perhaps humans, with the kidney being the most sensitive organ to fumonisin toxicity. The molecular mechanism of fumonisin toxicity appears to involve disruption of de novo biosynthesis of sphingolipids and accumulation of sphinganine. The goals of this study were to determine whether fumonisin B(1) kills LLC-PK(1) renal kidney epithelial cells by inducing apoptosis and to identify genes affected by sphinganine that mediate fumonisin B(1)-induced cell death. Fumonisin B(1) produced morphological changes (i.e., cell shrinkage, membrane blebbing) and time-dependent increases in DNA fragmentation demonstrating that the toxin induces apoptosis. Simultaneously, fumonisin B(1) blocked sphingolipid biosynthesis and caused accumulation of sphinganine. To further investigate the role of sphinganine in fumonisin B(1) induced apoptosis, beta-fluoroalanine (betaFA) was used to inhibit serine palmitoyltransferase, which catalyzes an earlier step in the sphingolipid biosynthetic pathway. betaFA blocked sphinganine accumulation and prevented fumonisin B(1)-induced DNA fragmentation, confirming that apoptosis induced by fumonisin B(1) is dependent upon accumulation of sphinganine. To examine gene expression, differential display reverse transcriptase polymerase chain reaction (DDRT-PCR) was applied to RNA isolated after 16 h of exposure to fumonisin B(1). Differential expression in response to fumonisin B(1) of a gene identified as calmodulin has been verified by Northern analysis. Sphinganine appears to mediate the effect because betaFA reduces induction of calmodulin mRNA by fumonisin B(1). Fumonisin B(1) also increases calmodulin protein in a concentration-dependent manner and the calmodulin antagonist W7 blocks fumonisin B(1)-induced DNA fragmentation, supporting a role for calmodulin in fumonisin B(1)-induced apoptosis. In contrast, fumonisin B(1) had no effect on expression of bcl-2 family genes (bax, bcl-2, and bcl-x). These findings demonstrate that fumonisin B(1) kills LLC-PK(1) kidney cells by inducing apoptosis. Further, the results establish a sequence of events for fumonisin B(1)-induced apoptosis involving initial disruption of sphingolipid metabolism and accumulation of sphinganine (or a metabolite), which, in turn, induces expression of calmodulin. PMID- 11601890 TI - Antibody neutralization epitopes and integrin binding sites on nonenveloped viruses. PMID- 11601893 TI - Further identification and characterization of novel intermediate and mature cleavage products released from the ORF 1b region of the avian coronavirus infectious bronchitis virus 1a/1b polyprotein. AB - The coronavirus 3C-like proteinase is one of the viral proteinases responsible for processing of the 1a and 1a/1b polyproteins to multiple mature products. In cells infected with avian coronavirus infectious bronchitis virus (IBV), three proteins of 100, 39, and 35 kDa, respectively, were previously identified as mature cleavage products released from the 1b region of the 1a/1b polyprotein by the 3C-like proteinase. In this report, we show the identification of two more cleavage products of 68 and 58 kDa released from the same region of the polyprotein. In addition, two stable intermediate cleavage products with molecular masses of 160 and 132 kDa, respectively, were identified in IBV infected cells. The 160-kDa protein was shown to be an intermediate cleavage product covering the 100- and 68-kDa proteins, and the 132-kDa protein to be an intermediate cleavage product covering the 58-, 39-, and 35-kDa proteins. Immunofluorescent staining of IBV-infected cells and cells expressing individual cleavage products showed that the 100-, 68-, and 58-kDa proteins were associated with the membranes of the endoplasmic reticulum, and the 39- and 35-kDa proteins displayed diffuse distribution patterns. PMID- 11601892 TI - Identification and characterization of the neutralization epitope(s) of the hepatitis E virus. AB - The neutralization epitope(s) of the hepatitis E virus (HEV) was studied by an in vitro neutralization assay using antibodies obtained by immunization of mice with 51 overlapping 30-mer synthetic peptides spanning the region 221-660 amino acids (aa) of the HEV open reading frame 2 encoded protein (pORF2) and 31 overlapping recombinant proteins of different sizes derived from the entire pORF2 of the HEV Burma strain. Antibodies against synthetic peptides and short recombinant proteins of approximately 100 aa did not neutralize HEV, suggesting the HEV neutralization epitope(s) is conformation-dependent. However, one recombinant protein of approximately 400 aa in length comprising the pORF2 sequence at position 274-660 aa as well as all truncated derivatives of this protein containing region 452-617 aa elicited antibodies, demonstrating HEV neutralizing activity. These findings establish for the first time that the minimal size fragment, designated pB166, that can efficiently model the neutralization epitope(s) is 166 aa in length and is located at position 452-617 aa of the HEV pORF2. Additionally, antibodies against pB166 were found to cross-neutralize three different HEV genotypes, suggesting that a common neutralization epitope(s) may exist within the different HEV genotypes. Thus, recombinant proteins constructed in this study may be considered as potential candidates for the development of an HEV subunit vaccine as well as for the development of highly sensitive and specific diagnostic tests. PMID- 11601891 TI - Foot-and-mouth disease virus lacking the VP1 G-H loop: the mutant spectrum uncovers interactions among antigenic sites for fitness gain. AB - The Arg-Gly-Asp (RGD) triplet found in the G-H loop of capsid protein VP1 of foot and-mouth disease virus (FMDV) is critically involved in the interaction of FMDV with integrin receptors and with neutralizing antibodies. Multiplication of FMDV C-S8c1 in baby hamster kidney 21 (BHK-21) cells selected variant viruses exploiting alternative mechanisms of cell recognition that rendered the RGD integrin-binding triplet dispensable for infectivity. By constructing chimeric viruses, we show that dispensability of the RGD in these variant FMDVs can be extended to surrounding amino acid residues. Replacement of eight amino acid residues within the G-H loop of VP1 by an unrelated FLAG marker yielded infectious virus. Evolution of FLAG-containing viruses in BHK-21 cells generated complex quasispecies in which individual mutants included amino acid replacements at other antigenic sites of FMDV. Inclusion of such replacements in the parental FLAG clone resulted in an increase of relative fitness of the viruses. These results suggest structural or functional connections between antigenic sites of FMDV and underscore the value of mutant spectrum analysis for the identification of fitness-promoting genetic modifications in viral populations. The possibility of producing viable viruses lacking antigenic site A may find application in the design of new anti-FMD vaccines. PMID- 11601894 TI - Growth transformation of primary epithelial cells with a NPC-derived Epstein-Barr virus strain. AB - The Epstein-Barr virus (EBV) is associated with two major human epithelial malignancies, where it is likely to play a role in the malignant phenotype: undifferentiated nasopharyngeal carcinoma (100% of cases) and gastric carcinomas (about 10% of cases). We and others have obtained growth transformation of monkey kidney primary epithelial cells by transfection of viral DNA, especially with the BARF1 gene of EBV (Wei et al., 1997). We now report that the same type of primary epithelial cells can be growth-transformed using EBV particles derived from a nasopharyngeal carcinoma tumor line. Not only can these EBV-infected cells grow over 100 passages, escaping senescence, in contrast to their noninfected counterparts, but they can also survive and proliferate at very low cell density. Several subclones were characterized in terms of viral gene expression. All these clones gave a similar pattern, with detection of EBNA1 and BARF1 proteins but absence of LMP1. CD21, which is the main EBV receptor on B lymphocytes, was not expressed on parental monkey kidney epithelial cells nor on EBV-infected cell clones. This model of epithelial cell transformation will be useful for a better investigation of EBV functions critical for oncogenesis of epithelial cells. PMID- 11601895 TI - Generation of a high-capacity hybrid vector: packaging of recombinant adenoassociated virus replicative intermediates in adenovirus capsids overcomes the limited cloning capacity of adenoassociated virus vectors. AB - Gene therapy aims to complement or, ideally, correct defective genes. The broad clinical application of this emerging technology requires the development of safe high-capacity gene delivery vehicles that combine efficient transduction of dividing as well as quiescent cells with sustained transgene expression. Here we present a new hybrid vector system that unites favorable attributes of adenoassociated virus (AAV) and adenovirus (Ad) vectors in a single particle. This was achieved by inclusion of Ad packaging elements in different sized recombinant AAV genomes. In the presence of AAV replicative functions and a recombinant helper Ad, AAV/Ad hybrid particles were generated via encapsidation of AAV-dependent replicative intermediates into Ad capsids. In stringent in vitro models based on transduction of proliferating cells we show that AAV/Ad hybrid vectors are superior to Ad vectors in establishing prolonged transgene expression and can be used to deliver DNA fragments of at least 27 kb. PMID- 11601896 TI - Sequence diversity and virulence in Zea mays of Maize streak virus isolates. AB - Full genomic sequences were determined for 12 Maize streak virus (MSV) isolates obtained from Zea mays and wild grass species. These and 10 other publicly available full-length sequences were used to classify a total of 66 additional MSV isolates that had been characterized by PCR-restriction fragment length polymorphism and/or partial nucleotide sequence analysis. A description is given of the host and geographical distribution of the MSV strain and subtype groupings identified. The relationship between the genotypes of 21 fully sequenced virus isolates and their virulence in differentially MSV-resistant Z. mays genotypes was examined. Within the only MSV strain grouping that produced severe symptoms in maize, highly virulent and widely distributed genotypes were identified that are likely to pose the most serious threat to maize production in Africa. Evidence is presented that certain of the isolates investigated may be the products of either intra- or interspecific recombination. PMID- 11601897 TI - Comparison of different forms of herpes simplex replication-defective mutant viruses as vaccines in a mouse model of HSV-2 genital infection. AB - Some subunit vaccines composed of herpes simplex virus (HSV) glycoproteins have been shown to protect guinea pigs against primary and recurrent genital infection by HSV-2. However, these vaccines were ineffective or only marginally effective in clinical trials. To attempt to define an animal model that would better discriminate the protective capacity of different vaccine formulations, we have examined the requirements for vaccine-induced protection against HSV-2 infection and disease in a mouse genital model. Unlike the guinea pig model where inactivated viral vaccines can protect nearly as well as live viral vaccines, inactivated viral vaccine afforded little protection in this mouse model. Using replication-defective mutant viruses as a form of live viral vaccine, we found that the extent of protection conferred by live vaccine was proportional to the amount of replication-defective mutant virus inoculated, over doses from 10(4) to 10(6) PFU. Furthermore, the mouse genital model showed quantitative differences in the degree of protection induced by various viral vaccine constructs. An HSV-2 replication-defective mutant virus protected better than an HSV-1 replication defective mutant that expressed HSV-2 glycoprotein D, which in turn protected better than an HSV-2 replication-defective mutant virus. We conclude that this mouse genital model can rank different vaccine constructs for their capacity to induce protective immunity. Thus, genital infection of the mouse with HSV-2 may provide a stringent animal model that can predict the relative capacity of viral vaccines to stimulate protective immunity against HSV-2. PMID- 11601898 TI - Bovine adenovirus type 3 E1B(small) protein is essential for growth in bovine fibroblast cells. AB - In order to study the function of bovine adenovirus type 3 (BAV-3) E1A and E1B(small) proteins, we constructed two mutants: (a) BAV102A carries an in-frame deletion in the coding region for the E1A protein (nt 831-1080); (b) BAV102B carries an insertion of triple stop codons in the E1B region (nt 1654, 178 bp downstream of the E1B(small) start codon), which stops the translation of the E1B(small) gene. BAV102A virus could grow to the wild-type BAV-3 titer in transformed cell line VIDO R2 (HAV-5 E1 transformed) cells, but no progeny virus could be found in fetal bovine retina cells (FBRC). RT-PCR and Western blot analysis showed that neither mRNA transcripts nor protein expression of early genes [E1B(small) and DNA binding protein (DBP)] could be detected in BAV102A infected FBRC. The BAV102B grew 1.5 log less than wild-type BAV-3 in FBRC; however, no BAV102B progeny virus could be observed in bovine fibroblast (BFB) cells. No appreciable difference was observed in DBP transcript synthesis between wild-type BAV-3- or BAV102B-infected FBRC. However, compared to wild-type BAV-3, BAV102B viral DNA synthesis and fiber gene expression were found to be slightly reduced in FBRC. In contrast, compared to wild-type BAV-3, DBP transcripts and viral DNA synthesis were drastically reduced in BAV102B-infected BFB cells. In addition, no fiber gene expression could be detected in BAV102B-infected BFB cells. These results suggest that BAV-3 E1A is essential for virus replication and is required for activating the transcription of other BAV-3 early genes. However, the requirement for E1B(small) protein for BAV-3 replication appears to be cell type-dependent. PMID- 11601900 TI - Construction of chimeric arteriviruses reveals that the ectodomain of the major glycoprotein is not the main determinant of equine arteritis virus tropism in cell culture. AB - The recent development of arterivirus full-length cDNA clones makes possible the construction of chimeric arteriviruses for fundamental and applied studies. Using an equine arteritis virus (EAV) infectious cDNA clone, we have engineered chimeras in which the ectodomains of the two major envelope proteins, the glycoprotein GP(5) and the membrane protein M, were replaced by sequences from envelope proteins of related and unrelated RNA viruses. Using immunofluorescence microscopy, we monitored the transport of the hybrid GP(5) and M proteins to the Golgi complex, which depends on their heterodimerization and is a prerequisite for virus assembly. The only viable chimeras were those containing the GP(5) ectodomain from the porcine (PRRSV) or mouse (LDV) arteriviruses, which are both considerably smaller than the corresponding sequence of EAV. Although the two viable GP(5) chimeras were attenuated, they were still able to infect baby hamster kidney (BHK-21) and rabbit kidney (RK-13) cells. These cells can be infected by EAV, but not by either PRRSV or LDV. This implies that the ectodomain of the major glycoprotein GP(5), which has been postulated to be involved in receptor recognition, is not the main determinant of EAV tropism in cell culture. PMID- 11601899 TI - Intranuclear localization of the transcription coadaptor CBP/p300 and the transcription factor RBP-Jk in relation to EBNA-2 and -5 in B lymphocytes. AB - We have studied the expression and the localization of the cellular proteins CBP/p300 and RBP-Jk in in vitro EBV-infected human B lymphocytes in relation to the EBNA-2 and EBNA-5 proteins. We found that the level of CBP/p300 was elevated drastically by EBV infection and also after activation by CD40 ligation. Thus the increase in CBP/p300 expression in the EBV-infected cells is related to the virus induced activation and proliferation of the cells. EBNA-2 and RBP-Jk colocalized in the nucleoplasm, which is in accordance with their functional interaction. We confirmed earlier reports about the presence and colocalization of EBNA-5 and CBP in the nuclear POD bodies. On the other hand, neither EBNA-2 nor p300 was detected in the PODs. The expression of these two proteins overlapped in some distinct dots of the nucleoplasm. Taken together, the different patterns of CBP and p300 expression and their different localization in relation to the PML bodies and two EBV-encoded proteins in the B cells may provide some clue to their distinct functional roles. PMID- 11601901 TI - Synergistic effects of gene-end signal mutations and the M2-1 protein on transcription termination by respiratory syncytial virus. AB - Individual mononegavirus genes terminate with a short cis-acting element, the gene-end (GE) signal, that directs polyadenylation and termination and might also influence the efficiency of reinitiation at the next downstream gene. The 12-13 nucleotide (nt) GE signals of human respiratory syncytial virus (RSV) consist of a conserved pentanucleotide (3'-UCAAU, negative sense), followed by a 3-nt middle region that is AU-rich but otherwise not conserved, followed by a 4- or 5-nt poly(U) region that is thought to generate the poly(A) tail of the encoded mRNA by reiterative copying. Most of the naturally occurring differences in the GE signals of the various RSV genes occur in the "middle" and "poly(U)" regions. We mutated a copy of the fusion protein (F) GE signal that was positioned at the end of the promoter-proximal gene of a tricistronic minigenome and evaluated the effect of these mutations on RSV transcription in a plasmid-initiated, intracellular assay. Mutations confirmed the importance of the middle region's AU rich nature and 3-nt length, and the poly(U) tract's 4-nt minimum functional length, with maximal termination efficiency observed at five U residues. Nt assignments other than U at position 13 also affected the efficiency of termination, showing that this position is part of the functional 13-nt GE signal. These results indicate that differences in nt assignments in the middle and poly(U) regions of the GE signal, which occur frequently in nature, affect the efficiency of termination. Unexpectedly, the ability of certain mutations to inhibit termination was completely dependent on coexpression of the M2-1 protein, and in many other cases the inhibitory effect of the mutation was greatly enhanced in the presence of M2-1. Thus, M2-1 appears to have the effect of altering the polymerase such that it ignores suboptimal GE signals. Interestingly, certain mutations that greatly decreased the efficiency of termination in the absence of M2-1 did not have much effect on the expression of the second gene, implying that correct termination and/or polyadenylation at the upstream gene is not obligatory for reinitiation at the next downstream gene. PMID- 11601902 TI - Cleavage of vesicular stomatitis virus matrix protein prevents self-association and leads to crystallization. AB - The matrix protein (M) of vesicular stomatitis virus is responsible for the budding of newly formed virions out of host cells. In vitro, it has been shown to self-associate, a property that may be related to the role of M in virus assembly but also prevents crystallization. Using limited proteolysis by thermolysin, we have isolated and characterized two soluble fragments of the protein that remain noncovalently associated. The digestion product does not self-associate nor is it recruited in aggregates formed by intact M molecules. These results identify a peptide, located at the surface of the protein and disorganized by thermolysin cleavage, responsible for M self-association. The thermolysin-resistant core of M has been crystallized and the crystals diffract to 2-A resolution. PMID- 11601903 TI - In vivo and in vitro characterization of an RNA replication enhancer in a satellite RNA associated with turnip crinkle virus. AB - RNA replication enhancers are cis-acting elements that can stimulate replication or transcription of RNA viruses. Turnip crinkle virus (TCV) and satC, a parasitic RNA associated with TCV infections, contain stem-loop structures that are RNA replication enhancers (P. Nagy, J. Pogany, and A. E. Simon, EMBO J. 1999, 18, 5653-5665). We have found that replacement of 28 nt of the satC enhancer, termed the motif1-hairpin, with 28 randomized bases reduced satC accumulation 8- to 13 fold in Arabidopsis thaliana protoplasts. Deletion of single-stranded flanking sequences at either side of the hairpin also affected RNA accumulation with combined alterations at both sides of the hairpin showing the most detrimental effect in protoplasts. In vitro analysis with a partially purified TCV RdRp preparation demonstrated that the motif1-hairpin in its minus-sense orientation was able to stimulate RNA synthesis from the satC hairpin promoter (located at the 3' end of plus strands) by almost twofold. This level of RNA synthesis stimulation is approximately fivefold lower than that observed with a linear promoter, suggesting that a highly stable hairpin promoter is less responsive to the presence of the motif1-hairpin enhancer than a linear promoter. The motif1 hairpin in its plus-sense orientation was only 60% as active in enhancing transcription from the hairpin promoter. Since the motif1-hairpin is a hotspot for RNA recombination during plus-strand synthesis and since satC promoters located on the minus-strand are all short linear sequences, these findings support the hypothesis that the motif1-hairpin is primarily involved in enhancing plus-strand synthesis. PMID- 11601904 TI - Comparative genomics reveals close genetic relationships between phages from dairy bacteria and pathogenic Streptococci: evolutionary implications for prophage-host interactions. AB - The genome of the highly pathogenic M1 serotype Streptococcus pyogenes isolate SF370 contains eight prophage elements. Only prophage SF370.1 could be induced by mitomycin C treatment. Prophage SF370.3 showed a 33.5-kb-long genome that closely resembled the genome organization of the cos-site temperate Siphovirus r1t infecting the dairy bacterium Lactococcus lactis. The two-phage genomes shared between 60 and 70% nucleotide sequence identity over the DNA packaging, head and tail genes. Analysis of the SF370.3 genome revealed mutations in the replisome organizer gene that may prevent the induction of the prophage. The mutated phage replication gene was closely related to a virulence marker identified in recently emerged M3 serotype S. pyogenes strains in Japan. This observation suggests that prophage genes confer selective advantage to the lysogenic host. SF370.3 encodes a hyaluronidase and a DNase that may facilitate the spreading of S. pyogenes through tissue planes of its human host. Prophage SF370.2 showed a 43-kb-long genome that closely resembled the genome organization of pac-site temperate Siphoviridae infecting the dairy bacteria S. thermophilus and L. lactis. Over part of the structural genes, the similarity between SF370.2 and S. thermophilus phage O1205 extended to the nucleotide sequence level. SF370.2 showed two probable inactivating mutations: one in the replisome organizer gene and another in the gene encoding the portal protein. Prophage SF370.2 also encodes a hyaluronidase and in addition two very likely virulence factors: prophage-encoded toxins acting as superantigens that may contribute to the immune deregulation observed during invasive streptococcal infections. The superantigens are encoded between the phage lysin and the right attachment site of the prophage genome. The genes were nearly sequence identical with a DNA segment in S. equi, suggesting horizontal gene transfer. The trend for prophage genome inactivation was even more evident for the remaining five prophage sequences that showed massive losses of prophage DNA. In these prophage remnants only 13-0.3 kb of putative prophage DNA was detected. We discuss the genomics data from S. pyogenes strain SF370 within the framework of Darwinian coevolution of prophages and lysogenic bacteria and suggest elements of genetic cooperation and elements of an arms race in this host-parasite relationship. PMID- 11601905 TI - A single amino acid substitution in the viral polymerase creates a temperature sensitive and attenuated recombinant bovine parainfluenza virus type 3. AB - Bovine parainfluenza virus type 3 (bPIV3) is under development as a live virus vaccine vector. The RNA genome of a recombinant bPIV3 harbored four nucleotide changes, one of which resulted in a mutation of the viral polymerase (A. A. Haller et al., 2000, J. Virol. 74, 11626-11635). The contribution of this conservative amino acid substitution (I1103V) in the polymerase to the temperature-sensitive and attenuation phenotypes of r-bPIV3 was investigated by creating a new virus, r-bPIV3(I), that expressed the wild-type polymerase. r bPIV3(I) was not temperature-sensitive for growth in vitro and the replication of r-bPIV3(I) was no longer restricted in hamsters. The effect of the amino acid substitution in the polymerase was also studied in a chimeric bovine/human PIV3, a virus that displayed temperature-sensitive and attenuated phenotypes (A. A. Haller et al., 2000, J. Virol. 74, 11626-11635). It was not clear whether these defects were due to the impaired polymerase or the replacement of the bPIV3 surface glycoproteins with those of hPIV3. The results showed that the altered polymerase was indeed responsible for the temperature-sensitive phenotype of bovine/human PIV3 but did not appear to play a role in the attenuation phenotype. PMID- 11601906 TI - Inactivation of frog virus 3 and channel catfish virus by esculentin-2P and ranatuerin-2P, two antimicrobial peptides isolated from frog skin. AB - While it is clear that some amphibian populations have recently experienced precipitous declines, the causes of those die-offs are complex and likely involve multiple variables. One theory suggests that environmental factors may trigger events that result in depressed immune function and increased susceptibility to infectious disease. Here we examine one aspect of innate immunity in amphibians and show that esculentin-2P (E2P) and ranatuerin-2P (R2P), two antimicrobial peptides isolated from Rana pipiens, inactivate frog virus 3, a potentially pathogenic iridovirus infecting anurans, and channel catfish herpesvirus. In contrast to mammalian antimicrobial peptides, E2P and R2P act within minutes, at temperatures as low as 0 degrees C, to inhibit viral infectivity. Moreover, these compounds appear to inactivate the virus directly and do not act by inhibiting replication in infected cells. This is the first report linking amphibian antimicrobial peptides with protection from an amphibian viral pathogen and suggests that these compounds may play a role in maintaining amphibian health. PMID- 11601907 TI - Heterogeneous distribution of TT virus of distinct genotypes in multiple tissues from infected humans. AB - TT virus (TTV) DNA was quantitated in the serum and nine autopsy tissues (bone marrow, lymph node, muscle, thyroid gland, lung, liver, spleen, pancreas, and kidney) obtained from each of three TTV-infected subjects by real-time polymerase chain reaction (PCR), which can detect all TTV genotypes. TTV DNA was detected in all examined tissues, with the viral load being equal to or up to 300 times higher than that in the corresponding serum (2.1 x 10(5) to 5.3 x 10(7) copies/g vs 1.2-3.9 x 10(5) copies/ml). Generally, the TTV viral load was higher in the bone marrow, lung, spleen, and liver than in the other tissues, although it varied by individual. Restriction fragment length polymorphism (RFLP) analysis of the PCR-amplified TTV DNA of 3.3 kilobases (kb) revealed considerable differences among the TTVs in the serum and tissue specimens from each subject. Further, the 3.3-kb amplicons from the serum and tissue specimens from one subject were molecularly cloned, and 30 clones each from the serum and each tissue specimen were subjected to RFLP and sequence analysis (total, 300 clones): the TTV clones were classified into six genotypes including four novel genotypes. The genotypic variability was remarkable: each specimen had one to five TTV genotypes at different frequencies. TTV DNA in replicative intermediate forms and TTV mRNA were detectable in all tissues tested. These results indicate the broad, uneven distribution of TTV genotypes in tissues and suggest that viral replication takes place in multiple tissues at distinct levels in infected individuals. PMID- 11601908 TI - KSHV-K5 inhibits phosphorylation of the major histocompatibility complex class I cytoplasmic tail. AB - The carboxy-terminal region of major histocompatibility complex class I (MHC I) molecules is required for the rapid internalization mediated by Kaposi's sarcoma associated herpesvirus (KSHV) proteins K3 and K5. The cytoplasmic tail of MHC I contains highly conserved serine phosphorylation sites that have been implicated in intracellular trafficking. Indeed, in vivo labeling experiments reveal a lack of MHC I phosphorylation in K5-transfected HeLa cells. Phosphorylation of the MHC I tail was restored upon mutation of the PHD/LAP domain of K5. However, deletion and mutation studies of the MHC I tail show that both K3 and K5 are able to downregulate MHC I lacking the conserved phosphorylation site. This result suggests that inhibition of phosphorylation reflects, but does not cause, MHC I internalization. Interestingly, K3 and K5 differ from each other, as well as from human immunodeficiency virus nef, with respect to the minimal MHC I tail sequences required for MHC downregulation. These data support the notion that K3 and K5 downregulate MHC I molecules by a distinct molecular mechanism that is different from other viral immune evasion molecules. PMID- 11601909 TI - Hepatitis C virus core protein modulates the interferon-induced transacting factors of Jak/Stat signaling pathway but does not affect the activation of downstream IRF-1 or 561 gene. AB - Hepatitis C virus (HCV) has a propensity to cause chronic infection, with a low proportion of patients exhibiting a sustained response to interferon-alpha (IFNalpha) therapy. An earlier report suggested that HCV inhibits IFNalpha induced signal transduction through the Jak/Stat pathway by preventing the formation of the transacting factor ISGF3 complex, although the effect on downstream pathway and the specific viral protein responsible for inhibition of IFNalpha-mediated signal transduction were not elucidated. HCV core protein displays a number of intriguing functional properties and has been implicated in virus-mediated pathogenesis. In this study, we have analyzed the effect of core protein upon IFNalpha- or IFNgamma-induced regulation of the Jak/Stat signaling pathway. HCV core protein expression exhibited a reduced Stat1 expression in IFN treated mammalian cells. A gel retardation assay suggested a reduced level of formation of the transacting factors, GAF and ISGF3, in IFN-treated cells. Further studies from protein expression and RNase protection assay revealed that the reduced level of GAF or ISGF3 formation could be attributed to modulation of Stat1 protein expression, an important player for innate immunity in host defense mechanism. However, these modulatory effects did not interfere with the activation of the downstream effector genes, IRF-1 and 561, in IFN-treated cells. Stable transfectants of cells after introduction of a plasmid DNA encoding both the structural and the nonstructural proteins of HCV also exhibited a similar effect. Taken together, these results suggest that although expression of the core protein alone or with other HCV proteins modulate transacting factors of Jak/Stat signaling pathway, expression of the downstream effector genes IRF-1 and 561 remains unaffected upon IFN treatment and may contribute to host defense mechanism. PMID- 11601910 TI - Umbravirus-encoded proteins both stabilize heterologous viral RNA and mediate its systemic movement in some plant species. AB - The proteins encoded by open reading frame 3 (ORF3) of the umbraviruses pea enation mosaic virus-2 and tobacco mottle virus, like that of groundnut rosette virus, mediated the movement of viral RNA through the phloem of infected Nicotiana benthamiana or N. clevelandii plants when they were expressed from chimeric tobacco mosaic virus in place of the coat protein. However, these chimeras did not move systemically in N. tabacum. In lysates of N. benthamiana or N. tabacum protoplasts, the chimeric RNAs were more stable than was RNA of tobacco mosaic virus lacking the coat protein gene. The chimeric viruses also protected the latter in trans, suggesting that the ORF3 proteins can increase the stability of heterologous viral RNA. Umbraviral ORF3 proteins contain a conserved arginine-rich domain, and the possible roles of this motif in the functions of the proteins are discussed. PMID- 11601911 TI - Virus targeting of the tumor necrosis factor superfamily. AB - Herpesviruses appear to peacefully coexist with their natural hosts, with infection typically manifested as a benign, but lifelong process. However, coexistence depends on active resistance by innate and specific immune defenses as revealed in the striking virulence of herpesviruses when immunity fails. This pattern of infection is characteristic of a viral pathogen, such as cytomegalovirus, that has evolved efficient strategies targeted at host defense systems. Targeting members of the tumor necrosis factor (TNF)/lymphotoxin (LT) superfamily of cytokines is a strategy found in all herpesviruses, which suggests the existence of an intimate evolutionary link in their host-parasite relationship. Here we examine some of the strategies used by herpesvirus that target members of the TNF superfamily and discuss a recent study that revealed a novel mechanism that links LT-related ligands and interferons (IFN) to the establishment of coexistence between herpesvirus and its host cell. PMID- 11601912 TI - A lethal disease model for hantavirus pulmonary syndrome. AB - Hantaviruses are associated with two human diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Development of vaccines and therapies to prevent and treat HFRS and HPS have been hampered by the absence of a practical animal model. Here we report that Andes virus (ANDV), a South American hantavirus, is highly lethal in adult Syrian hamsters. The characteristics of the disease in hamsters, including the incubation period, symptoms of rapidly progressing respiratory distress, and pathologic findings of pulmonary edema and pleural effusion, closely resemble HPS in humans. This is the first report of a lethal disease model for hantaviruses that causes HPS. PMID- 11601913 TI - The apoptotic capability of coxsackievirus B3 is influenced by the efficient interaction between the capsid protein VP2 and the proapoptotic host protein Siva. AB - Infections with coxsackievirus B3 (CVB3) are common causes of myocarditis in humans. One detail of CVB3-induced pathogenesis is apoptosis. The interaction between the capsid protein VP2 of the myocardial virus variant CVB3H3 and the proapoptotic host cell protein Siva has recently been observed. In order to characterize the interaction between both proteins more precisely, the binding activity of the CVB3H3 VP2 to Siva was compared to that of the mutant virus CVB3H310A1 VP2. We found that the asparagine at position 165 in VP2 is essential for a stable interaction with Siva influencing also the induction of apoptosis, viral spread, and inflammatory responses in vivo. Furthermore, the specific binding site of Siva to VP2 is located at amino acid positions 118-136. Together, these results show that the interaction between VP2 of CVB3H3 and Siva is a highly specific process involving distinct amino acids on both proteins that most likely influence the outcome of CVB3-caused disease. PMID- 11601914 TI - Differentiation-dependent redistribution of heparan sulfate in epithelial intestinal Caco-2 cells leads to basolateral entry of cytomegalovirus. AB - Human cytomegalovirus (HCMV) causes a broad spectrum of clinical manifestations in immunocompromised patients, including infection of the gastrointestinal tract. To investigate the role of epithelial cells in the gastrointestinal HCMV disease, we used the intestinal epithelial cell line Caco-2, which is permissive for HCMV replication. In differentiated Caco-2 cells, we showed previously that HCMV infection proceeds preferentially from the basolateral membrane, suggesting that receptors for HCMV may be contained predominantly in the basolateral membrane (A. Esclatine et al., 2000, J. Virol. 74, 513-517). Therefore, we examined expression and localization in Caco-2 cells of heparan sulfate (HS) proteoglycan and annexin II, previously implicated in initial events of HCMV infection. We observed that annexin II is expressed in Caco-2 cells, but is not essential for entry of HCMV. We showed that, during the differentiation process, HS, initially present on the entire surface of the membrane of undifferentiated cells, ultimately became sequestered at the basolateral cell surface of fully differentiated cells. We established by biochemical assays that membrane-associated HS proteoglycan mediates both viral attachment to, and subsequent infection of, Caco-2 cells, regardless of the cell differentiation state. Thus, the redistribution of HS is implicated in the basolateral entry of HCMV into differentiated Caco-2 cells. PMID- 11601915 TI - The crystal structure of the influenza matrix protein M1 at neutral pH: M1-M1 protein interfaces can rotate in the oligomeric structures of M1. AB - The influenza matrix protein (M1) forms a protein layer under the viral membrane and is essential for viral stability and integrity. M1 mediates the encapsidation of the viral RNPs into the viral membrane by its membrane and RNP-binding activities. In order to understand the roles of M1-M1 protein interactions in forming the M1 layer, X-ray crystallographic studies of a M1 fragment (1-162) were carried out at neutral pH and compared with an acidic pH structure. At neutral pH the asymmetric unit was a stacked dimer of M1. A long molecular ribbon of neutral stacked dimers was formed by translation as dictated by the P1 space group. The elongated ribbon had a positively charged stripe on one side of the ribbon. A similar M1-M1 stacking interface was also found in the acidic asymmetric unit. However, within the acidic stacked dimer the molecules were not straight, but rotated in relation to each other by slightly changing the M1-M1 stacking interface. The acidic structure possessed an additional M1-M1 twofold interface. Protein docking confirmed that the M1-M1 stacking and M1-M1 twofold interfaces could be used to form a double ribbon of M1 molecules. By iterative repetition of the rotated relationship among the M1 molecules, a helix of M1 was generated. These studies suggest that M1 has the ability to form straight or bent elongated ribbons and helices. These oligomers are consistent with previous electron microscopic studies of M1, which demonstrated that isolated M1 formed elongated and flexible ribbons when isolated from what appeared to be a helical shell of M1 in the influenza virus. PMID- 11601916 TI - Functional formation of domain V of the poliovirus noncoding region: significance of unpaired bases. AB - Previously we have shown that polioviruses with mutations that disrupt the predicted secondary structure of the 5' noncoding region of domain V are temperature sensitive for growth. Non-temperature-sensitive revertant viruses had mutations that re-formed secondary structure by a direct back mutation of changes in the opposite strand. We mutated unpaired regions and selected revertants of viruses with single base deletions, where no obvious back mutation was available in order to gain information on secondary structure. Results indicated that conservation of length of a three base loop between two double-stranded stems was essential for a functional domain V to form. The requirement for the unpaired "hinge" base at 484 which is implicated in the attenuation of Sabin 2 was also confirmed. Results also underline the necessity for functional folding over local secondary structure stability. PMID- 11601917 TI - Green fluorescent protein expression from recombinant lettuce infectious yellows virus-defective RNAs originating from RNA 2. AB - Lettuce infectious yellows virus (LIYV) RNA 2 defective RNAs (D RNAs) were compared in protoplasts for their ability to replicate and to express the green fluorescent protein (GFP) from recombinant D RNA constructs. Initially four LIYV D RNAs of different genetic composition were compared, but only two (LIYV D RNA M5 and M18) replicated to high levels. Both of these contained at least two complete ORFs, one being the 3'-terminal ORF encoding P26. Northern hybridization analysis using probes corresponding to 3' regions of LIYV RNA 2 detected the P26 subgenomic RNA from protoplasts infected with LIYV RNAs 1 and 2 or protoplasts inoculated only with RNA 1 plus either the LIYV D RNA M5 or M18, suggesting that these LIYV D RNAs served as templates to generate the P26 subgenomic RNA. The GFP coding region was inserted as an in-frame insertion into the P26 coding region of the LIYV M5 and M18 D RNAs, yielding M5gfp and M18gfp. When transcripts of M5gfp and M18gfp were used to inoculate protoplasts, bright fluorescence was seen only when they were co-inoculated with LIYV RNA 1. The percentage of fluorescent protoplasts ranged from experiment to experiment, but was as high as 5.8%. Time course analyses showed that fluorescence was not detected before 48 h pi, and this correlated with the timing of LIYV RNA 2 and RNA 2 D RNA accumulation, but not with that of LIYV RNA 1. PMID- 11601919 TI - Hemagglutinin residues of recent human A(H3N2) influenza viruses that contribute to the inability to agglutinate chicken erythrocytes. AB - To identify the molecular determinants contributing to the inability of recent human influenza A(H3N2) viruses to agglutinate chicken erythrocytes, phenotypic revertants were selected upon passage in eggs or MDCK cells. The Leu194Ile or Val226Ile substitutions were detected in their hemagglutinin (HA) sequence concomitantly with the phenotypic reversion. Remarkably, as little as 3.5% of variants bearing a Val226Ile substitution was found to confer the ability to agglutinate chicken erythrocytes to the virus population. Hemadsorption assays following transient expression of mutated HA proteins showed that the successive Gln226 --> Leu --> Ile --> Val changes observed on natural isolates resulted in a progressive loss of the ability of the HA to bind chicken erythrocytes. The Val226Ile change maintained the preference of the HA for SAalpha2,6Gal over SAalpha2,3Gal and enhanced binding of the HA to alpha2,6Gal receptors present on chicken erythrocytes. In contrast, simultaneous Ser193Arg and Leu194Ile substitutions that were found to confer the ability to agglutinate sheep erythrocytes increased the affinity of the HA for SAalpha2,3Gal. PMID- 11601918 TI - Rubella virus DI RNAs and replicons: requirement for nonstructural proteins acting in cis for amplification by helper virus. AB - A rubella virus (RUB) replicon was constructed by replacing the 3' proximal structural protein ORF (SP-ORF) in Robo402, a RUB infectious cDNA clone, with a reporter gene, green fluorescent protein (GFP). This replicon, RUBrep/GFP, mimics naturally occurring RUB defective-interfering (DI) RNAs generated during serial undiluted passage that maintain the 5' proximal nonstructural protein ORF (NS ORF) but contain deletions in the SP-ORF. Following transfection of Vero cells with in vitro RNA transcripts from RUBrep/GFP, replicon replication occurred and the replicon was amplified and spread to other cells in the presence of standard helper virus. GFP expression was a much more sensitive indicator of replicon replication than was Northern analysis to detect replicon-specific RNAs. Most of a series of RUBrep/GFP constructs with deletions in the NS-ORF not only were incapable of self-replication, but were not amplified by standard helper virus. The only exception was a construct with an in-frame deletion between two NotI sites that removed nucleotides 1685-2192 of the genome; this construct did not express GFP by itself, but did express GFP in the presence of standard helper RUB and was spread to other cells. Thus, with the exception of this region, the NS ORF is required in cis for amplification of RUB replicons by standard helper virus, explaining the selection of DI RNAs that maintain the NS-ORF. Surprisingly, when the NotI deletion was introduced into Robo402, a viable virus resulted that replicated only threefold less efficiently than did Robo402 virus. Thus, the NotI region of the NS-ORF is not necessary for virus replication. This deletion covers a region of the NS-ORF without predicted function, which therefore may function as a spacer or hinge between functional domains. Nevertheless, it was an unexpected finding that a small virus such as RUB could dispense with approximately 10% of its genome. PMID- 11601920 TI - The fusion protein of Peste des petits ruminants virus mediates biological fusion in the absence of hemagglutinin-neuraminidase protein. AB - To study the process of membrane fusion in Morbilliviruses, the fusion (F) glycoproteins of Peste des petits ruminants virus (PPRV) and Rinderpest virus (RPV) were expressed transiently in mammalian cells. The recombinant F proteins were found to be localized at the surface of transfected cells. The fusion activity, as evident from cell fusion assays and lysis of chicken erythrocytes, documented that transiently expressed PPRV F glycoprotein induces cell fusion in the absence of homotypic hemagglutinin-neuraminidase (HN) attachment glycoprotein. The coexpression of homotypic HN increased the extent of fusion by twofold, while the efficiency of fusion was found to be substantially enhanced. In contrast, in RPV F-expressing cells, fusion was detected only when homotypic hemagglutinin (H) or heterotypic HN protein was coexpressed. This differs from the strict type-specific requirement for the attachment protein as in the fusion process of most of the paramyxoviruses. Further, we demonstrate by fluorescence transfer experiments that while PPRV F brings about both hemifusion and complete fusion on its own, RPV F induces only hemifusion while it brings about complete fusion in the presence of homotypic or heterotypic attachment protein. PMID- 11601921 TI - Association of L* protein of Theiler's murine encephalomyelitis virus with microtubules in infected cells. AB - We used an antibody raised against a synthetic peptide corresponding to amino acid residues 70-88 for characterizing the L* protein of Theiler's murine encephalomyelitis virus (TMEV), which is only synthesized in DA subgroup strains from an alternative AUG and is out of frame with the viral polyprotein; evidence suggests that L* protein is critical to viral persistence, demyelination, and growth in murine macrophage cell lines. It was synthesized with kinetics similar to that of other viral proteins, although less in amount. After synthesis, it remained stable in the cytoplasm and was not incorporated into virions. Immunofluorescent staining and immunoblotting of microtubule preparations demonstrated that it is associated with microtubules. Expression of L* protein also demonstrated that the 5' one third of the coding region may be responsible for the association. The association of L* protein with microtubules may be important in the disease-inducing and in vitro characters of L* protein. PMID- 11601922 TI - Extensively deleted simian immunodeficiency virus (SIV) DNA in macaques inoculated with supercoiled plasmid DNA encoding full-length SIVmac239. AB - Using long-distance DNA PCR, we prospectively followed rhesus monkeys that had been inoculated intramuscularly with supercoiled plasmid DNA encoding intact simian immunodeficiency virus (SIV). From 4 to 10 weeks postinoculation onward, we detected extensively deleted proviral genomes along with full-length viral genomes in peripheral blood mononuclear cells (PBMC) in adult macaques. During their chronic asymptomatic phase of infection, the frequency of deleted proviral genomes was similar in PBMC and lymph nodes. The latter, however, harbored significantly more full-length proviral DNA than PBMC, consistent with the lack of effective antiviral cytotoxic T-cell activity in lymph nodes described by others during human immunodeficiency virus infection. After the macaques progressed to AIDS, full-length proviral DNA became equally abundant in lymph nodes and in PBMC. We have demonstrated that although a single molecular species of proviral DNA was inoculated, genomic diversity was detected within a short time, thus confirming the genetic instability of the SIV genome in vivo. PMID- 11601924 TI - Mutations in the NS3 gene and 3'-NCR of Japanese encephalitis virus isolated from an unconventional ecosystem and implications for natural attenuation of the virus. AB - The T1P1 strain of Japanese encephalitis (JE) virus was recently isolated from paddy-free Liu-Chiu Islet in which natural JE antibody has been prevalent. In mouse neuroblastoma-derived Neuro-2a cells, T1P1 appeared significantly lower in virus productivity than another local isolate, CH1392. It implied that this new isolate possesses a characteristic viral replication pattern other than that of CH1392. T1P1 has also shown lower neurovirulence, which was reflected by a significantly higher LD(50) (2.44 x 10(6) PFU) than CH1392 (2.87 x 10(2) PFU). In comparison of the full-length RNA sequences between T1P1 and CH1392, a total of 7 nucleotides, including 1 in preM/M and 2 each in NS3, NS5, and the 3'-end noncoding region (NCR), appeared different. Of them, only the changes in NS3 (position 325, T for CH1392, A for T1P1; and position 364, G for CH1392 and A for T1P1) resulted in substitutions of deduced amino acids. There were two additional nucleotide changes appearing in the 3'-NCR. The amino acids 109 Phe and 122 Glu in NS3 of CH1392 were substituted by Ile and Lys, respectively, in T1P1. The unique growth properties and low virulence of T1P1 presented in this report were likely related to abnormal enzymatic activity due to mutations of the NS3 gene (especially position 364) and possibly to the mutations in the 3'-NCR. The natural attenuation of T1P1 that has been circulating in paddy-free Liu-Chiu Islet may account for the absence of clinical JE cases in past years. PMID- 11601923 TI - Identification and analysis of a new hepadnavirus in white storks. AB - We identified, cloned, and functionally characterized a new avian hepadnavirus infecting storks (STHBV). STHBV has the largest DNA genome of all avian hepadnaviruses and, based on sequence and phylogenetic analysis, is most closely related to, but distinct from, heron hepatitis B virus (HHBV). Unique for STHBV among the other avian hepadnaviruses is a potential HNF1 binding site in the preS promoter. In common only with HHBV, STHBV has a myristylation signal on the S and not the preS protein, two C terminally located glycosylation sites on the precore/core proteins and lacks the phosphorylation site essential for the transcriptional transactivation activity of duck-HBV preS protein. The cloned STHBV genomes were competent in gene expression, replication, and viral particle secretion. STHBV infected primary duck hepatocytes very inefficiently suggesting a restricted host range, similar to other hepadnaviruses. This discovery of stork infections unravels novel evolutionary aspects of hepadnaviruses and provides new opportunities for hepadnavirus research. PMID- 11601925 TI - Studies on functional interaction between brome mosaic virus replicase proteins during RNA recombination, using combined mutants in vivo and in vitro. AB - Two viral proteins, 1a and 2a, direct replication of brome mosaic bromovirus (BMV) RNAs as well as they participate in BMV RNA recombination. To study the relationship between replication and recombination, double BMV variants that carried mutations in 1a and 2a genes were tested. The observed effects revealed that the 1a helicase and 2a N-terminal or core domains were functionally linked during both processes in vivo. The use of a series of mutant BMV replicase (RdRp) preparations demonstrated in vitro the participation of the 1a and 2a domains in BMV RNA copying and in template switching during minus-strand synthesis. The observed effects support previous observations that the characteristics of homologous and nonhomologous recombination can be modified separately by mutations at different sites on BMV replicase proteins. PMID- 11601926 TI - Quasispecies heterogeneity of the carboxy-terminal part of the E2 gene including the PePHD and sensitivity of hepatitis C virus 1b isolates to antiviral therapy. AB - Two regions within the HCV genome, hypervariable region 1 (HVR1) within the envelope (E)2 region and the PKR-binding domain (PKRbD) comprising the interferon sensitivity determining region (ISDR) within the nonstructural (NS)5A protein, have been reported to correlate with the outcome of antiviral treatment. Recently, a PKR/eIF2alpha phosphorylation homology domain (PePHD) within the E2 protein of HCV-1 isolates was described to inhibit PKR in vitro. PePHD deleted HCV-1 mutants remain capable of binding PKR to some extent while inhibition of PKR was found to be abolished by carboxy-terminal truncated E2 protein. The importance of mutations and quasispecies heterogeneity within the carboxy terminal part of the E2 protein comprising the PePHD of HCV-1b is unknown. Therefore, the carboxy-terminal part of the HCV E2 gene (codons 618-746) including the PePHD was analyzed by sequencing of PCR products and individual clones of 41 HCV-1b-infected patients with sustained (SR, n = 12), end-of treatment (ETR, n = 10), or no virological (NR, n = 19) response to antiviral therapy. Two highly conserved regions (codons 658-673 comprising the PePHD and codons 675-704) and one variable region (codons 705-720) were detected within the carboxy-terminal part of E2. No significant correlation of specific mutations or number of mutations with treatment response was observed for the PePHD and the carboxy-terminal part of the E2 protein. Phylogenetic and conformational analyses showed no specific clusters related to treatment outcome. Calculation of genetic complexity and diversity based on nucleotide sequence analyses of 20 individual clones per patient showed no differences between matched SR, ETR, and NR patients. However, calculation of genetic complexity and diversity on the basis of amino acid sequences showed significantly lower normalized Shannon entropy as well as mean Hamming distances for SR patients than in ETR and NR patients (P = 0.029 and P = 0.027, respectively). This indicates that patients achieving a sustained virological response to interferon-alpha-based antiviral therapy may elicit more effective immunological pressure, resulting in continuous clearing of individual variants of HCV quasispecies. PMID- 11601927 TI - Effect of case management on unmet needs and utilization of medical care and medications among HIV-infected persons. AB - BACKGROUND: Although case management has been advocated as a method for improving the care of chronically ill persons, its effectiveness is poorly understood. OBJECTIVE: To assess the effect of case managers on unmet need for supportive services and utilization of medical care and medications among HIV-infected persons. DESIGN: Baseline and follow-up interview of a national probability sample. SETTING: Inpatient and outpatient medical facilities in the United States. PARTICIPANTS: 2437 HIV-infected adults representing 217 081 patients receiving medical care. MEASUREMENTS: Outcomes measured at follow-up were unmet need for supportive services, medical care utilization (ambulatory visits, emergency department visits, and hospitalizations), and use of HIV medication (receipt of antiretroviral therapy and prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis). RESULTS: At baseline, 56.5% of the sample had contact with a case manager in the previous 6 months. In multiple logistic regression analyses that adjusted for potential confounders, contact with a case manager at baseline was associated with decreased unmet need for income assistance (odds ratio [OR], 0.57 [95% CI, 0.36 to 0.91]), health insurance (OR, 0.54 [CI, 0.33 to 0.89]), home health care (OR, 0.29 [CI, 0.15 to 0.56]), and emotional counseling (OR, 0.62 [CI, 0.41 to 0.94]) at follow-up. Contact with case managers was not significantly associated with utilization of ambulatory care (OR, 0.77 [CI, 0.57 to 1.04]), hospitalization (OR, 1.13 [CI, 0.84 to 1.54]), or emergency department visits (OR, 1.30 [CI, 0.97 to 1.73]) but was associated with higher utilization of two-drug (OR, 1.58 [CI, 1.23 to 2.03]) and three-drug (OR, 1.34 [CI, 1.00 to 1.80]) antiretroviral regimens and of treatment with protease inhibitors or non-nucleoside reverse transcriptase inhibitors (OR, 1.29 [CI, 1.02 to 1.64]) at follow-up. CONCLUSIONS: Case management appears to be associated with fewer unmet needs and higher use of HIV medications in patients receiving HIV treatment. PMID- 11601928 TI - Bethesda guidelines: relation to microsatellite instability and MLH1 promoter methylation in patients with colorectal cancer. AB - BACKGROUND: Microsatellite instability is a hallmark of mismatch repair deficiency in hereditary nonpolyposis colorectal cancer and results from mutations in the mismatch repair genes MLH1 or MSH2 or from gene inactivation associated with DNA methylation. The Bethesda guidelines were established to identify patients with colorectal cancer who should be tested for microsatellite instability. OBJECTIVE: To assess the Bethesda guidelines for detection of microsatellite instability and to determine the role of MLH1 promoter methylation in colorectal cancer. DESIGN: Prospective cohort study. SETTING: Tertiary care referral center in Frankfurt, Germany. PATIENTS: 125 consecutive patients with colorectal cancer. MEASUREMENTS: Patients were assessed according to the Bethesda guidelines, and tumor specimens were analyzed for microsatellite instability. Patients with microsatellite instability were tested for MLH1 promoter methylation and MLH1 and MSH2 germline mutations. RESULTS: Microsatellite instability was detected in 17 of 58 patients who fulfilled and 5 of 67 patients who did not fulfill criteria of the Bethesda guidelines. In 11 of 17 patients with microsatellite instability who fulfilled Bethesda guidelines, an MLH1 (n = 3), MSH2 (n = 7), or combined MLH1 and MSH2 (n = 1) mutation was found. Among the patients with microsatellite instability who did not fulfill Bethesda guidelines, no mutations were observed; MLH1 promoter methylation was observed in 6 of 11 patients with an MLH1 or MSH2 mutation and 5 of 11 patients without an MLH1 or MSH2 mutation. CONCLUSIONS: The Bethesda guidelines are useful for selecting patients for microsatellite instability testing. MLH1 and MSH2 testing should be recommended in all patients with colorectal cancer and microsatellite instability who fulfill at least one Bethesda criterion. MLH1 promoter methylation may accompany rather than initiate carcinogenesis in patients with colorectal cancer who have mismatch repair gene defects. PMID- 11601929 TI - Cost-effectiveness of microsatellite instability screening as a method for detecting hereditary nonpolyposis colorectal cancer. AB - BACKGROUND: The National Cancer Institute has published consensus guidelines for universal screening for hereditary nonpolyposis colorectal cancer (HNPCC) in patients with newly diagnosed colorectal cancer. OBJECTIVE: To determine the cost effectiveness of screening compared with standard care in eligible patients with colorectal cancer and their siblings and children. DESIGN: Cost-effectiveness analysis. DATA SOURCES: National colorectal cancer registry data, the Creighton International Hereditary Colorectal Cancer Registry, Medicare claims records, and published literature. TARGET POPULATION: Patients with newly diagnosed colorectal cancer and their siblings and children. TIME HORIZON: Lifetime (varies depending on age at screening). PERSPECTIVE: Societal. INTERVENTIONS: Initial office-based screening to determine eligibility (based on personal and family cancer history), followed by tumor testing for microsatellite instability. Those with microsatellite instability were offered genetic testing for HNPCC. Siblings and children of patients with cancer and the HNPCC mutation were offered genetic testing, and those who were found to carry the mutation received lifelong colorectal cancer screening. MEASUREMENTS: Life-years gained. RESULTS OF BASE CASE ANALYSIS: When only the patients with cancer were considered, cost effectiveness of screening was $42 210 per life-year gained. When patients with cancer and their siblings and children were considered together, cost effectiveness increased to $7556 per life-year gained. RESULTS OF SENSITIVITY ANALYSIS: The model was most sensitive to the estimated survival gain from screening siblings and children, to the prevalence of HNPCC mutations among patients with newly diagnosed cancer, and to the discount rate. In probabilistic analysis, the 90% CI for the cost-effectiveness of screening patients with cancer plus their relatives was $4874 to $21 576 per life-year gained. CONCLUSION: Screening patients with newly diagnosed colorectal cancer for HNPCC is cost effective, especially if the benefits to their immediate relatives are considered. PMID- 11601931 TI - Herbal medicines today and the roots of modern pharmacology. AB - The transformation of digitalis from a folk medicine, foxglove, to a modern drug, digoxin, illustrates principles of modern pharmacology that have helped make drugs safer and more effective. Digitalis was improved because its preparation was standardized, first by bioassay and then by chemical methods; however, few of today's herbs are standardized by methods that can ensure a consistent product and, hence, consistent safety and efficacy profiles. Many herbs have been evaluated in randomized, controlled trials, and several-St. John's wort and ginkgo, for example-are apparently effective. Yet, many trials of herbs have limited value because of poor design, small samples, and, above all, use of products of uncertain composition and consistency. The uncertain composition of many herbal products raises questions about their safety, as does evidence indicating that herbs may have harmful interactions with prescription drugs. Such adverse effects of herbs are probably underreported. Meanwhile, systematic studies, such as those identifying adverse reactions to drugs, are hindered because herbal preparations are not standardized-one brand of St. John's wort, for example, will differ chemically from another-and, unlike for prescription drugs, there are no databases linking herb consumption to later medical problems. Since herbal medicines are regulated as dietary supplements, they are not subject to the premarketing regulatory clearance required for drugs. The burden of proof is on the U.S. Food and Drug Administration to show a dietary supplement is unsafe, unlike for drugs, which cannot be approved until the manufacturer has demonstrated safety and effectiveness. PMID- 11601930 TI - Venous limb gangrene during warfarin treatment of cancer-associated deep venous thrombosis. AB - BACKGROUND: The cause of cancer-associated venous limb gangrene is unknown but could paradoxically be due to warfarin. OBJECTIVE: To determine the pathogenesis of venous gangrene in a patient with cancer. DESIGN: Case report. SETTING: University hospital in Ontario, Canada. PATIENT: 66-year-old woman with metastatic lung cancer and deep venous thrombosis. MEASUREMENTS: Levels of vitamin K-dependent factors, additional coagulation factors, and thrombin antithrombin complexes (marker of thrombin generation). RESULTS: During warfarin use, venous limb gangrene developed when the international normalized ratio (INR) reached 6.0 (therapeutic range, 2.0 to 3.0); at this time, the level of protein C (a vitamin K-dependent natural anticoagulant) was severely reduced, but thrombin antithrombin complexes remained markedly elevated. The supratherapeutic INR was explained by the greatly reduced levels of factor VII, which correlated closely with protein C levels; therefore, the high INR was a surrogate marker for severely reduced protein C activity. CONCLUSION: Warfarin may contribute to the pathogenesis of cancer-associated venous limb gangrene by leading to severe depletion of protein C while at the same time failing to reduce thrombin generation. PMID- 11601932 TI - Update in endocrinology. PMID- 11601933 TI - Twenty years into the HIV epidemic, do we CARE enough to manage it well? PMID- 11601934 TI - Glass houses and the glory of the climb. PMID- 11601935 TI - Guidelines for the management of patients with chronic stable angina: treatment. AB - The dual aims of treating patients with chronic stable angina are 1) to reduce morbidity and mortality and 2) to eliminate angina with minimal adverse effects and allow the patient to return to normal activities. In the absence of contraindications, beta-blockers are recommended as initial therapy. All beta blockers seem to be equally effective. If the patient has serious contraindications to beta-blockers, unacceptable side effects, or persistent angina, calcium antagonists should be administered. Long-acting dihydropyridine and nondihydropyridine agents are generally as effective as beta-blockers in relieving angina. Long-acting nitrates are considered third-line therapy because a nitrate-free interval is required to avoid developing tolerance. All long acting nitrates seem to be equally effective. Patients with angina should take 75 to 325 mg of aspirin daily unless they have contraindications. Such risk factors as smoking, elevated low-density lipoprotein cholesterol level, diabetes, and hypertension should be treated appropriately. Coronary revascularization has not been shown to improve survival for most patients with chronic angina but may be required to control symptoms. However, coronary artery bypass grafting (CABG) is often indicated for symptomatic patients with left-main disease, three-vessel disease, or two-vessel disease including proximal stenosis of the left anterior descending coronary artery; it improves their survival. Percutaneous transluminal coronary angioplasty is an alternative to CABG for patients with normal left ventricular function and favorable angiographic features. Coronary artery bypass grafting is initially more effective in relieving angina than medical therapy, but the two procedures yield similar results after 5 to 10 years. Eighty percent of patients who undergo CABG remain angina-free 5 years after surgery. In low risk patients, percutaneous transluminal coronary angioplasty seems to control angina better than medical therapy, but recurrent angina and repeated procedures are more likely than with CABG. Patient education is an important component of management. Long-term follow-up should be individualized to ascertain clinical stability at regular intervals and to reassess prognosis when warranted. PMID- 11601937 TI - Videotape-based decision aid for colon cancer screening. PMID- 11601939 TI - Reforming the core clerkship in internal medicine. PMID- 11601941 TI - Recurrent necrotizing fasciitis in complement C4 deficiency. PMID- 11601944 TI - Disease prediction models aim to guide medical decision making. PMID- 11601945 TI - How and why we should move our geriatric cheese. PMID- 11601946 TI - Assessing care of vulnerable elders: ACOVE project overview. PMID- 11601947 TI - Assessing care of vulnerable elders: methods for developing quality indicators. PMID- 11601948 TI - Acove quality indicators. PMID- 11601949 TI - Quality indicators for dementia in vulnerable community-dwelling and hospitalized elders. PMID- 11601950 TI - Quality indicators for end-of-life care in vulnerable elders. PMID- 11601951 TI - Quality indicators for the management and prevention of falls and mobility problems in vulnerable elders. PMID- 11601952 TI - Quality indicators for the management of heart failure in vulnerable elders. PMID- 11601953 TI - Quality indicators for appropriate medication use in vulnerable elders. PMID- 11601954 TI - Quality indicators for the management of osteoarthritis in vulnerable elders. PMID- 11601955 TI - Quality indicators for the management of osteoporosis in vulnerable elders. PMID- 11601956 TI - Quality indicators for pain management in vulnerable elders. PMID- 11601957 TI - Quality indicators for the management of pneumonia in vulnerable elders. PMID- 11601958 TI - Quality indicators for prevention and management of pressure ulcers in vulnerable elders. PMID- 11601959 TI - Quality indicators for the management of urinary incontinence in vulnerable community-dwelling elders. PMID- 11601960 TI - Supramolecular arrays based on dimetal building units. AB - Supramolecular chemistry is today a major thrust area, a significant part of which is based on the use of metal atoms or ions as key elements in promoting the assembly of and dictating the main structural features of the supramolecular products. Most of the work has been done with single metal atoms or ions in this role, but considerable success has already been achieved by employing M-M bonded dimetal entities instead. We review here the work done in our laboratory. Metal metal bonded cationic complexes of the [M(2)(DAniF)(n)(MeCN)(8-2n)]((4-n)+) type, where M = Mo or Rh and DAniF is an N,N'-di-p-anisylformamidinate anion, have been used as subunit precursors and then linked by various equatorial and axial bridging groups such as polycarboxylate anions, polypyridyls, and polynitriles. Characterization of the products by single-crystal X-ray diffraction, CV, DPV, NMR, and other spectroscopic techniques has revealed the presence of discrete tetranuclear (pairs or loops), hexanuclear (triangles), octanuclear (squares), and dodecanuclear (cages) species and one-, two-, or three-dimensional molecular nanotubes. These compounds display a rich electrochemical behavior which is affected by the nature of the linkers. PMID- 11601961 TI - A mimicking enzyme analogue for chemical sensors. AB - An artificial enzyme analogue of Nafion/lead-ruthenium oxide pyrochlore (Py) chemically modified electrode (NPyCME) is synthesized by in situ precipitation through blocking of Nafion's hydrophilic zones. The catalytically active Py sites covered with a hydrophobic core of Nafion resemble an enzymatic structure. Moreover, the NPyCME obeys the Michaelis-Menten mechanism for the oxidation of many organic and biological molecules. This Account highlights aspects of the preparation, characterization, and application of the NPyCME. PMID- 11601962 TI - Time reversal and molecular properties. AB - Chemists regularly exploit point group symmetry in their analyses of molecular structure and properties but they rarely utilize time reversal symmetry. The time reversal operator T reverses the momenta and spins of all particles in a system and distinguishes properties which are even under T, such as the electric dipole moment, from those that are odd, such as the magnetic dipole moment. We review the role of T in quantum mechanics and discuss its application to the properties of molecules in electric and magnetic fields. Among the properties considered are natural and magnetic optical activity, magneto-chiral effects, antisymmetric Raman scattering, optical NMR and ESR, chirality, and absolute enantioselection. PMID- 11601964 TI - Advances in metal chemistry of quinonoid compounds: new types of interactions between metals and aromatics. AB - This Account presents an overview of current research activities that focus on novel types of interactions between cationic transition metal complexes and arene systems and on unprecedented quinonoid complexes which result from such interactions. When a negatively charged phenoxy group is present in a position para to the metal in a high oxidation state, intramolecular charge transfer occurs, giving the corresponding metallaquinones or quinone methide complexes. In addition, two types of interactions involving low-valent metal compounds have been observed: methylene arenium complexes which result from positive charge transfer to the aromatic ring and sigma-bonded C-H and C-C agostic complexes of cationic metals. These sigma-complexes are proposed as intermediates in metal based bond activation processes. PMID- 11601963 TI - Follow the protons: a low-barrier hydrogen bond unifies the mechanisms of the aspartic proteases. AB - Seven proton transfers in five steps participate in a catalytic turnover of an aspartic protease. The Rosetta Stone for elucidating their role is a low-barrier hydrogen bond that holds the two aspartic carboxyls in a coplanar conformation. The proton of this bond shuttles between oxygens during chemical steps via hydrogen tunneling, unlike in previous proposals where it was transferred to substrate. After the release of products, both carboxyls are protonated and the bond is missing. Re-forming the bond is a significant step within a kinetic isomechanism. The bond also explains-at long last-the extremely low pK in pH profiles. PMID- 11601965 TI - Using resonance Raman spectroscopy to examine vibrational barriers to electron transfer and electronic delocalization. AB - A time-dependent approach to the interpretation of resonance Raman scattering intensities has been used to obtain quantitative vibrational mode displacement information from scattering intensities associated with charge-transfer excitation. The displacements and associated frequencies are the key parameters needed to understand Franck-Condon effects in electron-transfer kinetics, and to delineate in a mode-specific way the composition of vibrational reorganization energies. Application of the approach to a number of types of electron-transfer reactions is described, including symmetrical and unsymmetrical intervalence electron transfers in inorganic and organic redox systems, metal-to-ligand charge transfer reactions, and interfacial electron-transfer reactions. Also described is how the approach can be used to elucidate mechanisms for valence delocalization in strongly interacting redox systems. PMID- 11601966 TI - Investigations of the roles of the distal heme environment and the proximal heme iron ligand in peroxide activation by heme enzymes via molecular engineering of myoglobin. AB - To pursue structure-function relationships of heme enzymes in the activation of peroxides, we have chosen to use myoglobin as the framework for our molecular engineering studies. Comparison of the crystal structures of myoglobin and peroxidases reveals differences in the arrangement of amino acid residues in heme active sites. On the basis of these structural differences and the reaction mechanisms of peroxidases, we have converted myoglobin into a peroxidase-like enzyme by alternation of the heme distal pocket via site-directed mutagenesis. The replacement of the proximal histidine with cysteine and the exogenous substituted imidazoles slightly accelerates the peroxide O-O bond cleavage due to the electron donor characteristics. However, we have not observed an enhancement in the activation of peroxide by the proximal mutant with tyrosine, the exogenous phenolate, and benzoate. A clear understanding of the absolute role of the proximal ligand remains elusive. PMID- 11601967 TI - Solid-phase syntheses of beta-turn analogues to mimic or disrupt protein-protein interactions. AB - Protein-protein interactions are difficult targets in medicinal chemistry, but they will become increasingly important as data from The Human Genome Project is interpreted. Our work focuses on beta-turn mimics that are designed to mimic or disrupt some of these interactions. Solid-phase syntheses and preferred conformations of beta-turn mimics that incorporate dipeptide units are discussed. The activity of one illustrative compound that potentiates the interaction of the nerve growth factor with its transmembrane tyrosine kinase receptor TrkA is outlined. Finally, the importance of dimeric turn mimics and some new approaches to these are described. PMID- 11601968 TI - Targeting RNA with small-molecule drugs: therapeutic promise and chemical challenges. AB - Researchers' increasing awareness of the essential role played by RNA in many biological processes and in the progression of disease makes the discovery of new RNA targets an emerging field in drug discovery. Since most existing pharmacologically active compounds bind proteins, RNA provides nearly untapped opportunities for pharmacological development. The elucidation of the structure of the ribosome and other cellular and viral RNA motifs creates the opportunity for discovering new drug-like compounds that inhibit RNA function. However, further advances in understanding the chemistry and structure of RNA recognition are needed before these promises are fulfilled. PMID- 11601969 TI - Evidence for DNA charge transport in the nucleus. AB - Oxidative damage to DNA bases in isolated HeLa nuclei occurs upon treatment with rhodium intercalators and photoactivation. Oxidation occurs preferentially at the 5'-guanine of 5'-GG-3' sites, indicative of base damage by DNA-mediated charge transfer chemistry. Moreover, oxidative damage occurs at protein-bound sites which are inaccessible to rhodium. Thus, on transcriptionally active DNA within the cell nucleus, DNA-mediated charge transport leads to base damage from a distance, and direct interaction of an oxidant is not necessary to generate a base lesion at a specific site. These observations require consideration in designing new chemotherapeutics and in understanding cellular mechanisms for DNA damage and repair. PMID- 11601970 TI - Probing the dark state tertiary structure in the cytoplasmic domain of rhodopsin: proximities between amino acids deduced from spontaneous disulfide bond formation between Cys316 and engineered cysteines in cytoplasmic loop 1. AB - A dark state tertiary structure in the cytoplasmic domain of rhodopsin is presumed to be the key to the restriction of binding of transducin and rhodopsin kinase to rhodopsin. Upon light-activation, this tertiary structure undergoes a conformational change to form a new structure, which is recognized by the above proteins and signal transduction is initiated. In this and the following paper in this issue [Cai, K., Klein-Seetharaman, J., Altenbach, C., Hubbell, W. L., and Khorana, H. G. (2001) Biochemistry 40, 12479-12485], we probe the dark state cytoplasmic domain structure in rhodopsin by investigating proximity between amino acids in different regions of the cytoplasmic face. The approach uses engineered pairs of cysteines at predetermined positions, which are tested for spontaneous formation of disulfide bonds between them, indicative of proximity between the original amino acids. Focusing here on proximity between the native cysteine at position 316 and engineered cysteines at amino acid positions 55-75 in the cytoplasmic sequence connecting helices I-II, disulfide bond formation was studied under strictly defined conditions and plotted as a function of the position of the variable cysteines. An absolute maximum was observed for position 65 with two additional relative maxima for cysteines at positions 61 and 68. The observed disulfide bond formation rates correlate well with proximity of these residues found in the crystal structure of rhodopsin in the dark. Modeling of the engineered cysteines in the crystal structure indicates that small but significant motions are required for productive disulfide bond formation. During these motions, secondary structure elements are retained as indicated by the lack of disulfide bond formation in cysteines that do not face toward Cys316 in the crystal structure model. Such motions may be important in light-induced conformational changes. PMID- 11601971 TI - Probing the dark state tertiary structure in the cytoplasmic domain of rhodopsin: proximities between amino acids deduced from spontaneous disulfide bond formation between cysteine pairs engineered in cytoplasmic loops 1, 3, and 4. AB - To probe proximities between amino acids in the cytoplasmic domain by using mutants containing engineered cysteine pairs, three sets of rhodopsin mutants have been prepared. In the first two sets, a cysteine was placed, one at a time, at positions 311-314 in helix VIII, while the second cysteine was fixed at position 246 (set I) and at position 250 (set II) at the cytoplasmic end of helix VI. In the third set, one cysteine was fixed at position 65 while the second cysteine was varied between amino acid positions 306 and 321 located at the cytoplasmic end of helix VII and throughout in helix VIII. Rapid disulfide bond formation in the dark was found between the cysteine pairs in mutants A246C/Q312C,A246C/K311C and in mutants H65C/C316, H65C/315C and H65C/312C. Disulfide bond formation at much lower rates was found in mutants A246C/F313C, V250C/Q312C, H65C/N310C, H65C/K311C, H65C/F313C, and H65C/R314C; the remaining mutants showed no significant disulfide bond formation. Comparisons of the results from disulfide bond formation in solution with the distances observed in the rhodopsin crystal structure showed that the rates of disulfide bond formation in most cases were consistent with the amino acid proximities as revealed in crystal structure. However, deviations were also found, in particular, in the set containing fixed cysteine at position Cys246 and cysteines at positions 311-314. The results implicate significant effects of structural dynamics on disulfide bond formation in solution. PMID- 11601973 TI - Dehydration is catalyzed by glutamate-136 and aspartic acid-135 active site residues in Escherichia coli dTDP-glucose 4,6-dehydratase. AB - The dTDP-glucose 4,6-dehydratase catalyzed conversion of dTDP-glucose to dTDP-4 keto-6-deoxyglucose occurs in three sequential chemical steps: dehydrogenation, dehydration, and rereduction. The enzyme contains the tightly bound coenzyme NAD(+), which mediates the dehydrogenation and rereduction steps of the reaction mechanism. In this study, we have determined that Asp135 and Glu136 are the acid and base catalysts, respectively, of the dehydration step. Identification of the acid catalyst was performed using an alternative substrate, dTDP-6-fluoro-6 deoxyglucose (dTDP-6FGlc), which undergoes fluoride ion elimination instead of dehydration, and thus does not require protonation of the leaving group. The steady-state rate of conversion of dTDP-6FGlc to dTDP-4-keto-6-deoxyglucose by each Asp135 variant was identical to that of wt, in contrast to turnover using dTDP-glucose where differences in rates of up to 2 orders of magnitude were observed. These results demonstrate Asp135's role in protonating the glucosyl C6(OH) during dehydration. The base catalyst was identified using a previously uncharacterized, enzyme-catalyzed glucosyl-C5 hydrogen-solvent exchange reaction of product, dTDP-4-keto-6-deoxyglucose. Base catalysis of this exchange reaction is analogous to that occurring at C5 during the dehydration step of net catalysis. Thus, the decrease in the rate of catalysis ( approximately 2 orders of magnitude) of the exchange reaction observed with Glu136 variants demonstrates this residue's importance in base catalysis of dehydration. PMID- 11601972 TI - Monomeric solution structure of the prototypical 'C' chemokine lymphotactin. AB - Lymphotactin, the sole identified member of the C class of chemokines, specifically attracts T lymphocytes and natural killer cells. This 93-residue protein lacks 2 of the 4 conserved cysteine residues characteristic of the other 3 classes of chemokines and possesses an extended carboxyl terminus, which is required for chemotactic activity. We have determined the three-dimensional solution structure of recombinant human lymphotactin by NMR spectroscopy. Under the conditions used for the structure determination, lymphotactin was predominantly monomeric; however, pulsed field gradient NMR self-diffusion measurements and analytical ultracentrifugation revealed evidence of dimer formation. Sequence-specific chemical shift assignments were determined through analysis of two- and three-dimensional NMR spectra of (15)N- and (13)C/(15)N enriched protein samples. Input for the torsion angle dynamics calculations used in determining the structure included 1258 unique NOE-derived distance constraints and 60 dihedral angle constraints obtained from chemical-shift-based searching of a protein conformational database. The ensemble of 20 structures chosen to represent the structure had backbone and heavy atom rms deviations of 0.46 +/- 0.11 and 1.02 +/- 0.14 A, respectively. The results revealed that human lymphotactin adopts the conserved chemokine fold, which is characterized by a three-stranded antiparallel beta-sheet and a C-terminal alpha-helix. Two regions are dynamically disordered as evidenced by (1)H and (13)C chemical shifts and [(15)N]-(1)H NOEs: residues 1-9 of the amino terminus and residues 69-93 of the C terminal extension. A functional role for the C-terminal extension, which is unique to lymphotactin, remains to be elucidated. PMID- 11601974 TI - Proximity of transmembrane segments M3 and M1 of the alpha subunit of Na+,K+ ATPase revealed by specific oxidative cleavage mediated by a complex of Cu2+ ions and 4,7-diphenyl-1,10-phenanthroline. AB - This paper describes a novel approach to specific oxidative cleavage of Na(+),K(+)-ATPase, mediated by Cu(2+) ions and a hydrophobic phenanthroline, 4,7 diphenyl-1,10-phenanthroline (DPP), in the presence of ascorbate and H(2)O(2). The cleavage produces two major fragments of the alpha subunit, with apparent molecular masses of 96.5 and 76 kDa, and N-termini near the cytoplasmic entrance of transmembrane segments M1 and M3, respectively, The kinetics indicate that both cleavages are mediated by a single Cu(2+)-DPP complex. We infer that M3 and M1 are in proximity near the cytoplasmic surface. The yields of 96.5 and 76 kDa fragments are not significantly affected by ligands that stabilize different E(1) and E(2) conformations. In E(2)(K) and E(2)P conformations, a minor 5.5 kDa fragment with its N-terminus in M10 is also observed. The 96.5 and 76 kDa fragments are indistinguishable from two fragments near M3 and M1 produced by Fe(2+)-catalyzed cleavage described previously [Goldshleger, R., and Karlish, S. J. D. (1999) J. Biol. Chem. 274, 16213-16221], whereas other Fe(2+)-catalyzed cleavage fragments in the cytoplasmic P and A domains are not observed with the Cu(2+)-DPP complex. These findings provide experimental support for the concept of two separate Fe(2+) sites. A homology model, with Na(+),K(+)-ATPase residues within transmembrane segments and connecting loops substituted into the crystal structure of Ca(2+)-ATPase, shows the proximity between the sequences HFIH in M3 and EVWK in M1, near the cytoplasmic surface. Thus, the model strongly supports the conclusions based on cleavages mediated by the Cu(2+)-DPP complex (or Fe(2+) at site 2). As a corollary, the cleavages provide evidence for similar packing of M1 and M3 of Na(+),K(+)-ATPase and Ca(2+)-ATPase. PMID- 11601975 TI - Crystal structure of native chicken fibrinogen at 2.7 A resolution. AB - The crystal structure of native chicken fibrinogen (320 kDa) complexed with two synthetic peptides has been determined at a resolution of 2.7 A. The structure provides the first atomic-resolution view of the polypeptide chain arrangement in the central domain where the two halves of the molecule are joined, as well as of a putative thrombin-binding site. The amino-terminal segments of the alpha and beta chains, including fibrinopeptides A and B, are not visible in electron density maps, however, and must be highly disordered. The alphaC domain is also very disordered. A residue by residue analysis of the coiled coils with regard to temperature factor shows a strong correlation between mobility and plasmin attack sites. It is concluded that structural flexibility is an inherent feature of fibrinogen that plays a key role in both its conversion to fibrin and its subsequent destruction by plasmin. PMID- 11601976 TI - Structural basis for the substrate specificity of the feruloyl esterase domain of the cellulosomal xylanase Z from Clostridium thermocellum. AB - Feruloyl esterases function in the cleavage of ferulic acid's bonds to arabinoxylan and pectin where the ferulic acid moieties cross-link the layers of polysaccharide chains within hemicellulose. This work presents the crystal structure of FAE_XynZ, the domain of Clostridium thermocellum's cellulosomal xylanase Z that displays feruloyl esterase activity. The structure was obtained via multiple isomorphous replacement with anomalous scattering (MIRAS) using three heavy atom derivatives and refined against X-ray diffraction data of up to 1.75 A resolution. The R-value of the final model was 0.187 (R(free) = 0.21). FAE_XynZ displays an eight-stranded alpha/beta-fold with the characteristic "catalytic triad" at the heart of the active site. To define the substrate specificity determinants of the enzyme, the crystal structures of FAE_XynZ and the inactive FAE_XynZ(S172A) mutant were determined in complexes with the feruloyl-arabinoxylans FAXX and FAX(3), respectively. In the complex crystals, the ferulic acid moieties are clearly recognizable and allowed identification of the hydrophobic binding pocket. The carbohydrate part of both substrates is not visible in either structure. The location of the putative carbohydrate binding pocket was inferred based on the location and orientation of the adjacent ferulic acid molecule. Five of the six residues lining the pocket were found to be conserved in FAE A from Orpinomyces sp., which further supports the proposed role of these amino acids. PMID- 11601977 TI - The N-terminus of retinol dehydrogenase type 1 signals cytosolic orientation in the microsomal membrane. AB - We determined the orientation of the SDR (short-chain dehydrogenase/reductase) rat RoDH1 (retinol dehydrogenase type 1) in the endoplasmic reticulum to provide insight into its function in retinol metabolism, and to resolve whether retinoid metabolizing SDRs differ from several other SDRs by requiring a C-terminal segment for the membrane orientation. In contrast to several soluble SDRs, the membrane-associated RoDH1 has hydrophobic extensions N- and C-terminal to the SDR core. Confocal microscopy and/or proteinase K protection assays of RoDH1, RoDH1 mutants, and RoDH1-green fluorescent protein fusion proteins showed that the N terminal segment anchors RoDH1 to the endoplasmic reticulum membrane facing the cytosol. The C-terminal hydrophobic segment increases the relative proportion of RoDH1 associated with the endoplasmic reticulum, but has no affect on orientation. Deletion of either or both extensions causes nearly total loss of enzyme activity, possibly through altering the nature of RoDH1 association with membranes, or destabilizing the enzyme, but does not alter the expression of RoDH1 or convert it into a soluble protein. The latter suggests that the SDR core of RoDH1 has marked external hydrophobicity that causes nonspecific membrane association. PMID- 11601978 TI - Temperature dependence of dynamics and thermodynamics of the regulatory domain of human cardiac troponin C. AB - Binding of Ca(2+) to the regulatory domain of troponin C (TnC) in cardiac muscle initiates a series of protein conformational changes and modified protein-protein interactions that initiate contraction. Cardiac TnC contains two Ca(2+) binding sites, with one site being naturally defunct. Previously, binding of Ca(2+) to the functional site in the regulatory domain of TnC was shown to lead to a decrease in conformational entropy (TDeltaS) of 2 and 0.5 kcal mol(-1) for the functional and nonfunctional sites, respectively, using (15)N nuclear magnetic resonance (NMR) relaxation studies [Spyracopoulos, L., et al. (1998) Biochemistry 37, 18032-18044]. In this study, backbone dynamics of the Ca(2+)-free regulatory domain are investigated by backbone amide (15)N relaxation measurements at eight temperatures from 5 to 45 degrees C. Analysis of the relaxation measurements yields an order parameter (S(2)) indicating the degree of spatial restriction for a backbone amide H-N vector. The temperature dependence of S(2) allows estimation of the contribution to protein heat capacity from pico- to nanosecond time scale conformational fluctuations on a per residue basis. The average heat capacity contribution (C(p,j)) from backbone conformational fluctuations for regions of secondary structure for the regulatory domain of cardiac apo-TnC is 6 cal mol(-1) K(-1). The average heat capacity for Ca(2+) binding site 1 is larger than that for site 2 by 1.3 +/- 0.8 cal mol(-1) K(-1), and likely represents a mechanism where differences in affinity between Ca(2+) binding sites for EF hand proteins can be modulated. PMID- 11601979 TI - Time-resolved fluorescence analysis of the photosystem II antenna proteins in detergent micelles and liposomes. AB - We have studied the time-resolved fluorescence properties of the light-harvesting complexes (Lhc) of photosystem II (Lhcb) in order to obtain information on the mechanism of energy dissipation (non-photochemical quenching) which is correlated to the conversion of violaxanthin to zeaxanthin in excess light conditions. The chlorophyll fluorescence decay of Lhcb proteins LHCII, CP29, CP26, and CP24 in detergent solution is mostly determined by two lifetime components of 1.2-1.5 and 3.6-4 ns while the contribution of the faster component is higher in CP29, CP26, and CP24 with respect to LHCII. The xanthophyll composition of Lhc proteins affects the ratio of the lifetime components: when zeaxanthin is bound into the site L2 of LHCII, the relative amplitude of the faster component is increased and, consequently, the chlorophyll fluorescence quenching is enhanced. Analysis of quenching in mutants of Arabidopsis thaliana, which incorporate either violaxanthin or zeaxanthin in their Lhc proteins, shows that the extent of quenching is enhanced in the presence of zeaxanthin. The origin of the two fluorescence lifetimes was analyzed by their temperature dependence: since lifetime heterogeneity was not affected by cooling to 77 K, it is concluded that each lifetime component corresponds to a distinct conformation of the Lhc proteins. Upon incorporation of Lhc proteins into liposomes, a quenching of chlorophyll fluorescence was observed due to shortening of all their lifetime components: this indicates that the equilibrium between the two conformations of Lhcb proteins is displaced toward the quenched conformation in lipid membranes or thylakoids with respect to detergent solution. By increasing the protein density in the liposomes, and therefore the probability of protein-protein interactions, a further decrease of fluorescence lifetimes takes place down to values typical of quenched leaves. We conclude that at least two major factors determine the quenching of chlorophyll fluorescence in Lhcb proteins, i.e., intrasubunit conformational change and intersubunit interactions within the lipid membranes, and that these processes are both important in the photoprotection mechanism of nonphotochemical quenching in vivo. PMID- 11601980 TI - Tyr275 and Lys279 stabilize NADPH within the catalytic site of NADPH:protochlorophyllide oxidoreductase and are involved in the formation of the enzyme photoactive state. AB - Fluorescence spectroscopic and kinetic analysis of photochemical activity, cofactor and substrate binding, and enzyme denaturation studies were performed with highly purified, recombinant pea NADPH:protochlorophyllide oxidoreductase (POR) heterologously expressed in Escherichia coli. The results obtained with an individual stereoisomer of the substrate [C8-ethyl-C13(2)-(R) protochlorophyllide] demonstrate that the enzyme photoactive state possesses a characteristic fluorescence maximum at 646 nm that is due to the presence of specific charged amino acids in the enzyme catalytic site. The photoactive state is converted directly into an intermediate having fluorescence at 685 nm in a reaction involving direct hydrogen transfer from the cofactor (NADPH). Site directed mutagenesis of the highly conserved Tyr275 (Y275F) and Lys279 (K279I and K279R) residues in the enzyme catalytic pocket demonstrated that the presence of these two amino acids in the wild-type POR considerably increases the probability of photoactive state formation following cofactor and substrate binding by the enzyme. At the same time, the presence of these two amino acids destabilizes POR and increases the rate of enzyme denaturation. Neither Tyr275 nor Lys279 plays a crucial role in the binding of the substrate or cofactor by the enzyme. In addition, the presence of Tyr275 is absolutely necessary for the second step of the protochlorophyllide reduction reaction, "dark" conversion of the 685 nm fluorescence intermediate and the formation of the final product, chlorophyllide. We propose that Tyr275 and Lys279 participate in the proper coordination of NADPH and PChlide in the enzyme catalytic site and thereby control the efficiency of the formation of the POR photoactive state. PMID- 11601981 TI - Solution NMR characterization of the thermodynamics of the disulfide bond orientational isomerism and its effect of cluster electronic properties for the hyperthermostable three-iron cluster ferredoxin from the archaeon Pyrococcus furiosus. AB - The thermodynamics and dynamics of the Cys21-Cys48 disulfide "S" if "R" conformational isomerism in the three-iron, single cubane cluster ferredoxin (Fd) from the hyperthermophilic archaeon Pyrococcus furiosus (Pf) have been characterized by (1)H NMR spectroscopy in both water and water/methanol mixed solvents. The mean interconversion rate at 25 degrees C is 3 x 10(3) s(-1) and DeltaG(298) = -0.2 kcal/mol [DeltaH = 4.0 kcal/mol; DeltaS = 14 cal/(mol.K)], with the S orientation as the more stable form at low temperature (< 0 degrees C) but the R orientation predominating at >100 degrees C, where the organism thrives. The distinct pattern of ligated Cys beta-proton contact shifts for the resolved signals and their characteristic temperature behavior for the forms of the 3Fe Fd with alternate disulfide orientations have been analyzed to determine the influences of disulfide orientation and methanol cosolvent on the topology of the inter-iron spin coupling in the 3Fe cluster. The Cys21-Cys48 disulfide orientation influences primarily the spin couplings involving the iron ligated to Cys17, whose carbonyl oxygen is a hydrogen bond acceptor to the Cys21 peptide proton. Comparison of the Cys beta-proton contact shift pattern for the alternate disulfide orientations with the pattern exhibited upon cleaving the disulfide bridge confirms an earlier [Wang, P.-L., Calzolai, L., Bren, K. L., Teng, Q., Jenney, F. E., Jr., Brereton, P. S., Howard, J. B., Adams, M. W. W., and La Mar, G. N. (1999) Biochemistry 38, 8167-8178] proposal that the structure of the same Fd with the R disulfide orientation resembles that of the Fd upon cleaving the disulfide bond. PMID- 11601982 TI - The electric field generated by photosynthetic reaction center induces rapid reversed electron transfer in the bc1 complex. AB - The cytochrome bc(1) complex is the central enzyme of respiratory and photosynthetic electron-transfer chains. It couples the redox work of quinol oxidation and cytochrome reduction to the generation of a proton gradient needed for ATP synthesis. When the quinone processing Q(i)- and Q(o)-sites of the complex are inhibited by both antimycin and myxothiazol, the flash-induced kinetics of the b-heme chain, which transfers electrons between these sites, are also expected to be inhibited. However, we have observed in Rhodobacter sphaeroides chromatophores, that when a fraction of heme b(H) is reduced, flash excitation induces fast (half-time approximately 0.1 ms) oxidation of heme b(H), even in the presence of antimycin and myxothiazol. The sensitivity of this oxidation to ionophores and uncouplers, and the absence of any delay in the onset of this reaction, indicates that it is due to a reversal of electron transfer between b(L) and b(H) hemes, driven by the electrical field generated by the photosynthetic reaction center. In the presence of antimycin A, but absence of myxothiazol, the second and following flashes induce a similar ( approximately 0.1 ms) transient oxidation of approximately 10% of the cytochrome b(H) reduced on the first flash. From the observed amplitude of the field-induced oxidation of heme b(H), we estimate that the equilibrium constant for sharing one electron between hemes b(L) and b(H) is 10-15 at pH 7. The small value of this equilibrium constant modifies our understanding of the thermodynamics of the Q-cycle, especially in the context of a dimeric structure of bc(1) complex. PMID- 11601983 TI - Effect of multiple aliphatic amino acids substitutions on the structure, function, and mode of action of diastereomeric membrane active peptides. AB - The initial stages leading to the binding and functioning of membrane-active polypeptides including hormones, signal sequences, and lytic peptides are mainly governed by electrostatic attraction and hydrophobic partitioning between water and lipid bilayers. Antimicrobial peptides serve as an important model for studying the details of these initial steps. However, a systematic analysis of the contribution of multiple hydrophobic amino acids to these steps have been hindered by the propensity of many peptides to aggregate and become inactivated in solution. To this end, we synthesized a series of model amphipathic all L amino acid peptides and their diastereomers with the sequence KX(3)KWX(2)KX(2)K, where X = Gly, Ala, Val, Ile, or Leu. The effect of the aliphatic amino acids on the biological activity, binding, structure, membrane localization, and mode of action of these peptides was investigated. Most of the L-amino acid peptides oligomerized and adopted distinct structures in solution and in a membrane mimetic environment. Among this group only the Leu containing peptide was hemolytic and highly active on most bacteria tested. The Val- and Leu-containing peptides were hemolytic but inactive toward most bacteria tested. In contrast, the diastereomeric peptides were monomeric and unstructured in solution, but they adopted distinct structures upon membrane binding. While hemolytic activity was drastically reduced, the spectrum of antibacterial activity was preserved or increased. Importantly, we found a direct correlation with the diastereomers between hydrophobicity and propensity to form a helical/distorted-helix and activity (induced membrane leakage and antibacterial activity), despite the fact that they contained 30% D-amino acids. Furthermore, efficient increase in membrane permeability can proceed through different mechanisms. Specifically, the Leu-containing diastereomeric peptide micellized vesicles and possibly bacterial membranes while the Ile-containing diastereomeric peptide fused model membranes and irregularly disrupted bacterial membranes. PMID- 11601984 TI - Interaction of chicken liver basic fatty acid-binding protein with fatty acids: a 13C NMR and fluorescence study. AB - Two different groups of liver fatty acid-binding proteins (L-FABPs) are known: the mammalian type and the basic type. Very few members of this second group of L FABPs have been characterized and studied, whereas most of the past studies were concerned with the mammalian type. The interactions of chicken liver basic fatty acid-binding protein (Lb-FABP) with 1-(13)C-enriched palmitic acid (PA) and oleic acid (OA) were investigated by (13)C NMR spectroscopy. Samples containing fatty acids (FA) and Lb-FABP at different molar ratios exhibited only a single carboxylate resonance corresponding to bound FA, and showed a binding stoichiometry of 1:1 both for PA and for OA. Fluorescence spectroscopy measurements yielded the same binding stoichiometry for the interaction with cis parinaric acid [K(d) = 0.38(4) microM]. Competition studies between cis-parinaric acid and the natural ligands indicated a decreasing affinity of chicken Lb-FABP for PA, OA, and retinoic acid (RA). (13)C NMR proved that pH and ionic strength affect complex stability. The carboxyl signal intensity reversibly decreased upon lowering the pH up to 5. The pH dependence of the bound carboxyl chemical shift yielded an apparent pK(a) of 4.8. A decrease of the integrated intensity of the bound carboxylic signal in the NMR spectra was observed while increasing the chloride ion concentration up to 200 mM. This body of evidence indicates that the bound FA is completely ionized at pH 7.4, that its polar head is positioned in a solvent-accessible region, that a FA-protein strong ionic bond is not present, and that high ionic strength causes the release of the bound FA. The reported results show that, insofar as the number of bound ligands and its relative affinity for different FAs are concerned, chicken Lb-FABP is remarkably different from the mammalian liver FABPs, and, within its subfamily, that it is more similar to catfish Lb-FABP while it behaves quite differently from shark or axolotl Lb-FABPs. PMID- 11601985 TI - Evidence for simultaneous binding of dissimilar substrates by the Escherichia coli multidrug transporter MdfA. AB - The mechanism by which multidrug transporters interact with structurally unrelated substrates remains enigmatic. Based on transport competition experiments, photoaffinity labeling, and effects on enzymatic activities, it was proposed in the past that multidrug transporters can interact simultaneously with a number of dissimilar substrate molecules. To study this phenomenon, we applied a direct binding approach and transport assays using the Escherichia coli multidrug transporter MdfA, which exports both positively charged (e.g., tetraphenylphosphonium, TPP(+)), zwitterionic (e.g., ciprofloxacin), and neutral (e.g., chloramphenicol) drugs. The interaction of MdfA with various substrates was examined by direct binding assays with the purified transporter. The immobilized MdfA binds TPP(+) in a specific manner, and all the tested positively charged substrates inhibit TPP(+) binding. Surprisingly, although TPP(+) binding is not affected by zwitterionic substrates, the neutral substrate chloramphenicol stimulates TPP(+) binding by enhancing its affinity to MdfA. In contrast, transport competition assays show inhibition of TPP(+) transport by chloramphenicol. We suggest that MdfA binds TPP(+) and chloramphenicol simultaneously to distinct but interacting binding sites, and the interaction between these two substrates during transport is discussed. PMID- 11601986 TI - Phosphorylation of the regulator of G protein signaling RGS9-1 by protein kinase A is a potential mechanism of light- and Ca2+-mediated regulation of G protein function in photoreceptors. AB - In vertebrate photoreceptors, photoexcited rhodopsin interacts with the G protein transducin, causing it to bind GTP and stimulate the enzyme cGMP phosphodiesterase. The rapid termination of the active state of this pathway is dependent upon a photoreceptor-specific regulator of G protein signaling RGS9-1 that serves as a GTPase activating protein (GAP) for transducin. Here, we show that, in preparations of photoreceptor outer segments (OS), RGS9-1 is readily phosphorylated by an endogenous Ser/Thr protein kinase. Protein kinase C and MAP kinase inhibitors reduced labeling by about 30%, while CDK5 and CaMK II inhibitors had no effect. cAMP-dependent protein kinase (PKA) inhibitor H89 reduced RGS9-1 labeling by more than 90%, while dibutyryl-cAMP stimulated it 3 fold, implicating PKA as the major kinase responsible for RGS9-1 phosphorylation in OS. RGS9-1 belongs to an RGS subfamily also including RGS6, RGS7, and RGS11, which exist as heterodimers with the G protein beta subunit Gbeta5. Phosphorylated RGS9-1 remains associated with Gbeta5L, a photoreceptor-specific splice form, which itself was not phosphorylated. RGS9-1 immunoprecipitated from OS was in vitro phosphorylated by exogenous PKA. The PKA catalytic subunit could also phosphorylate recombinant RGS9-1, and mutational analysis localized phosphorylation sites to Ser(427) and Ser(428). Substitution of these residues for Glu, to mimic phosphorylation, resulted in a reduction of the GAP activity of RGS9-1. In OS, RGS9-1 phosphorylation required the presence of free Ca(2+) ions and was inhibited by light, suggesting that RGS9-1 phosphorylation could be one of the mechanisms mediating a stronger photoresponse in dark-adapted cells. PMID- 11601988 TI - Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair. AB - To understand the mechanism involved in the coordination of the sequential repair reactions that lead to long-patch BER, we have investigated interactions between proteins involved in this pathway. We find that human AP endonuclease 1 (APE1) physically interacts with flap endonuclease 1 (FEN1) and with proliferating cell nuclear antigen. An oligonucleotide substrate containing a reduced abasic site, which was pre-incised with APE1, was employed to reconstitute the excision step of long-patch BER with purified human DNA polymerase beta and FEN1. We demonstrate that addition of APE1 to the excision reaction mixture slightly (1.5 2-fold) stimulates the removal of the displaced flap by FEN1. These results suggest the possibility that long-patch BER is coordinated and directed by protein-protein interactions. PMID- 11601987 TI - Allosteric interaction of minor groove binding ligands with UL9-DNA complexes. AB - The herpes simplex virus type 1 origin binding protein (UL9) is a sequence specific DNA binding protein. Several studies have demonstrated that UL9 binds to the 11-base pair sequence 5'-CGTTCGCACTT-3' primarily, or solely, through interaction with the major groove. Minor groove binding ligands, such as distamycin, netropsin, and GLX, an indole-linked dimer of netropsin, can effectively disrupt the UL9-DNA complex only when their DNA binding sites are coincident with the right side of the DNA binding site of the protein and overlap with the protein binding site by two (TT) base pairs. These results suggest that the right side of the UL9-DNA complex has a unique structure that is sensitive to minor groove ligand binding. In addition, a biphasic displacement curve was observed with GLX, which suggests two modes of ligand binding which have different effects on UL9-DNA complexes. Using a fluorescence-based hybridization stabilization assay, we determined that GLX can bind to its binding site as an overlapping dimer (i.e., 2:1 stoichiometry). Footprinting of UL9-DNA complexes with the minor groove directed chemical nuclease 1,10-phenanthroline copper confirms that the DNA conformation at the position of the right-side ligand binding site of GLX is altered and has a widened minor groove. In contrast, it is well established that at 1:1 stoichiometries, AT sequence specific ligands, such as netropsin, distamycin, and GLX, prefer uniform, narrow minor grooves. The opposing conformational requirements of UL9 and lower concentrations of GLX at the ligand binding A-tract overlapping the right side of the protein binding site indicate that allosteric inhibition, rather than direct steric competition, contributes to ligand-induced protein displacement. At higher GLX concentrations, giving 2:1 binding in a widened minor groove, co-binding with UL9 is allowed. A model is presented that is consistent with these observations, and implications for targeted regulation of gene transcription are discussed. PMID- 11601989 TI - A role for aromatic amino acids in the binding of Xenopus ribosomal protein L5 to 5S rRNA. AB - The formation of the Xenopus L5-5S rRNA complex depends on nonelectrostatic interactions. Fluorescence assays with 1-anilino-8-naphthalenesulfonate demonstrate that a hydrophobic region on L5 becomes exposed upon removal of bound 5S rRNA by treatment with ribonucleases. Several conserved aromatic amino acids, mostly tyrosines, were identified by comparative sequence analysis and changed individually to alanine. Substitution with alanine at any of three positions, Y86, Y99, or Y226, essentially abolishes RNA-binding activity, whereas those made at Y95 and Y207 have more modest effects. Replacement with phenylalanine at Y86 and Y226 does not change binding affinity, indicating that the aromatic ring of the side chain, not the hydroxyl group, is the critical functionality for binding. Alternatively, the phenolic hydroxyls at Y99 and Y207 do contribute to binding. The structural integrity of the mutant proteins was assessed using thermal denaturation and limited digestion with proteases. The T(m) of Y99A is 10 degrees C lower than that of the wild-type protein, and there are some differences in the protease digestion patterns that together indicate the structure of this mutant has been significantly perturbed. The structures of the other variants are not detectably different from the wild-type protein. These results provide evidence that intermolecular stacking interactions involving at least two tyrosine residues, Y86 and Y226, are necessary for formation of the L5 5S rRNA complex and can account, at least in part, for the contribution nonelectrostatic interactions make to the free energy of binding. PMID- 11601990 TI - Isolation and structural determination of novel sulfated hexasaccharides from squid cartilage chondroitin sulfate E that exhibits neuroregulatory activities. AB - Squid cartilage chondroitin sulfate E (CS-E) exhibits various biological activities, including anticoagulant activities, lymphoid regulatory activities, and neuroregulatory activities [Ueoka, C., Kaneda, N., Okazaki, I., Nadanaka, S., Muramatsu, T., and Sugahara, K. (2000) J. Biol. Chem. 275, 37407-37413]. These activities are expressed through molecular interactions with specific proteins, including heparin cofactor II, selectins, CD44, chemokines, and the heparin binding growth factor midkine. Hence, the sugar sequence information is essential for a better understanding of the CS-E functions. Previously, several novel tetrasaccharides containing the unreported 3-O-sulfated glucuronic acid (GlcA) were isolated after digestion of squid cartilage CS-E with testicular hyaluronidase. In this study, hexasaccharides were isolated to obtain more detailed sequence information, especially around the GlcA(3-O-sulfate) residue, and were characterized by fast atom bombardment mass spectrometry and 500 or 600 MHz (1)H NMR spectroscopy. The findings demonstrate one tetrasulfated and five pentasulfated hexasaccharide sequences, five of them being novel. They were composed of three disaccharide building units of either A [GlcA(beta1-3)GalNAc(4 O-sulfate)], E [GlcA(beta1-3)GalNAc(4,6-O-disulfate)], K [GlcA(3-O-sulfate)(beta1 3)GalNAc(4-O-sulfate)], L [GlcA(3-O-sulfate)(beta1-3)GalNAc(6-O-sulfate)], or M [GlcA(3-O-sulfate)(beta1-3)GalNAc(4,6-O-disulfate)], forming E-A-A, M-A-A, K-L-A, E-E-A, K-K-A, and A-M-A hexasaccharide sequences. The K-L tetrasaccharide sequence is to date unreported. The isolated sequences appear to indicate the occurrence of an unreported GlcA 3-O-sulfotransferase specific for chondroitin sulfate. The obtained sequence information will be useful for investigating the structure-function relationship and biosynthesis of CS-E. PMID- 11601991 TI - Biosynthesis of sialylated lipooligosaccharides in Haemophilus ducreyi is dependent on exogenous sialic acid and not mannosamine. Incorporation studies using N-acylmannosamine analogues, N-glycolylneuraminic acid, and 13C-labeled N acetylneuraminic acid. AB - Haemophilus ducreyi is a Gram-negative bacterium that causes chancroid, a sexually transmitted disease. Cell surface lipooligosaccharides (LOS) of H. ducreyi are thought to play important biological roles in host infection. The vast majority of H. ducreyi strains contain high levels of sialic acid (N acetylneuraminic acid, NeuAc) in their LOS. Here we investigate the biosynthetic origin of H. ducreyi sialosides by metabolic incorporation studies using a panel of N-acylmannosamine and sialic acid analogues. Incorporation of sialosides into LOS was assessed by matrix-assisted laser desorption and electrospray ionization mass spectrometry. A Fourier transform ion cyclotron resonance mass spectrometer provided accurate mass measurements, and a quadrupole time-of-flight instrument was used to obtain characteristic fragment ions and partial carbohydrate sequences. Exogenously supplied N-acetylmannosamine analogues were not converted to LOS-associated sialosides at a detectable level. In contrast, exogenous (13)C labeled N-acetylneuraminic acid ([(13)C]NeuAc) and N-glycolylneuraminic acid (NeuGc) were efficiently incorporated into LOS in a dose-dependent fashion. Moreover, approximately 1.3 microM total exogenous sialic acid was sufficient to obtain about 50% of the maximum production of sialic acid-containing glycoforms observed under in vitro growth conditions. Together, these data suggest that the expressed levels of sialylated LOS glycoforms observed in H. ducreyi are in large part controlled by the exogenous concentrations of sialic acid and at levels one might expect in vivo. Moreover, these studies show that to properly exploit the sialic acid biosynthetic pathway for metabolic oligosaccharide engineering in H. ducreyi and possibly other prokaryotes that share similar pathways, precursors based on sialic acid and not mannosamine must be used. PMID- 11601993 TI - Contributions of valine-292 in the nicotinamide binding site of liver alcohol dehydrogenase and dynamics to catalysis. AB - The participation of Val-292 in catalysis by alcohol dehydrogenase and the involvement of dynamics were investigated. Val-292 interacts with the nicotinamide ring of the bound coenzyme and may facilitate hydride transfer. The substitution of Val-292 with Ser (V292S) increases the dissociation constants for the coenzymes (NAD(+) by 50-fold, NADH by 75-fold) and the turnover numbers by 3 7-fold. The V292S enzyme crystallized in the presence of NAD(+) and 2,3,4,5,6 pentafluorobenzyl alcohol has an open conformation similar to the structure of the wild-type apo-enzyme, rather than the closed conformation observed for ternary complexes with wild-type enzyme. The V292S substitution perturbs the conformational equilibrium of the enzyme and decreases the kinetic complexity, which permits study of the hydride transfer step with steady-state kinetics. Eyring plots show that the DeltaH for the oxidation (V(1)) of the protio and deuterio benzyl alcohols is 13 kcal/mol and that the kinetic isotope effect of 4.1 is essentially temperature-independent. Eyring plots for the catalytic efficiency for reduction of benzaldehyde (V(2)/K(p)) with NADH or NADD are distinctly convex, being temperature-dependent from 5 to 25 degrees C and temperature-independent from 25 to 50 degrees C; the kinetic isotope effect of 3.2 for V(2)/K(p) is essentially independent of the temperature. The temperature dependencies and isotope effects for V(1) and V(2)/K(p) are not adequately explained by semiclassical transition state theory and are better explained by hydride transfer occurring through vibrationally assisted tunneling. PMID- 11601992 TI - Nonlinear free energy relationship in the general-acid-catalyzed acylation of rat kidney gamma-glutamyl transpeptidase by a series of gamma-glutamyl anilide substrate analogues. AB - The gamma-glutamyl transpeptidase (GGT) purified from rat kidney reacts with a series of eight parasubstituted L-glutamyl gamma-anilides, in the presence of Gly Gly, catalyzing the formation of gamma-Glu-Gly-Gly (pH 8.0, 37 degrees C). The transpeptidation reaction was followed through the discontinuous colorimetric determination of the concentration of released parasubstituted aniline. Steady state kinetic studies were performed to measure k(cat) and K(M) values for each anilide substrate. A Hammett plot constructed by the correlation of log(k(cat)) and the sigma(-) parameter for each anilide substrate displays statistically significant upward curvature, consistent with a general-acid-catalyzed acylation mechanism in which the geometry of the transition state changes with the nature of the para substituent. Kinetic isotope effects were measured and are consistent with a reaction involving a proton in flight at the rate-limiting transition state. The pH-rate profiles measured over pH 7.0-9.5 are bell-shaped with kinetic pK(a) values that may be attributed to the active site nucleophile (or its general-base catalytic partner) and the active-site general acid. The variation of the latter pK(a) value as a function of temperature is consistent with an enthalpy of ionization expected for an ammonium ion acting as a general acid. Examination of the variation of k(cat) as a function of temperature gave values for the enthalpy and entropy of activation that are similar to those determined for the general-acid-catalyzed breakdown of the tetrahedral intermediate formed during acylation of chymotrypsin by similar amide substrates. PMID- 11601994 TI - Saccharomyces cerevisiae leukotriene A4 hydrolase: formation of leukotriene B4 and identification of catalytic residues. AB - Leukotriene A(4) hydrolase in mammals is a bifunctional zinc metalloenzyme that catalyzes the hydrolysis of leukotriene A(4) into the proinflammatory mediator leukotriene B(4), and also possesses an aminopeptidase activity. Recently we cloned and characterized an leukotriene A(4) hydrolase from Saccharomyces cerevisiae as a leucyl aminopeptidase with an epoxide hydrolase activity. Here we show that S. cerevisiae leukotriene A(4) hydrolase is a metalloenzyme containing one zinc atom complexed to His-340, His-344, and Glu-363. Mutagenetic analysis indicates that the aminopeptidase activity follows a general base mechanism with Glu-341 and Tyr-429 as the base and proton donor, respectively. Furthermore, the yeast enzyme hydrolyzes leukotriene A(4) into three compounds, viz., 5S,6S dihydroxy-7,9-trans-11,14-cis-eicosatetraenoic acid, leukotriene B(4), and Delta(6)-trans-Delta(8)-cis-leukotriene B(4), with a relative formation of 1:0.2:0.1. In addition, exposure of S. cerevisiae leukotriene A(4) hydrolase to leukotriene A(4) selectively inactivates the epoxide hydrolase activity with a simultaneous stimulation of the aminopeptidase activity. Moreover, kinetic analyses of wild-type and mutated S. cerevisiae leukotriene A(4) hydrolase suggest that leukotriene A(4) binds in one catalytic mode and one tight-binding, regulatory mode. Exchange of a Phe-424 in S. cerevisiae leukotriene A(4) hydrolase for a Tyr, the corresponding residue in human leukotriene A(4) hydrolase, results in a protein that converts leukotriene A(4) into leukotriene B(4) with an improved efficiency and specificity. Hence, by a single point mutation, we could make the active site better suited to bind and turn over the substrate leukotriene A(4), thus mimicking a distinct step in the molecular evolution of S. cerevisiae leukotriene A(4) hydrolase toward its mammalian counterparts. PMID- 11601995 TI - MDP-1 is a new and distinct member of the haloacid dehalogenase family of aspartate-dependent phosphohydrolases. AB - MDP-1 is a eukaryotic magnesium-dependent acid phosphatase with little sequence homology to previously characterized phosphatases. The presence of a conserved motif (Asp-X-Asp-X-Thr) in the N terminus of MDP-1 suggested a relationship to the haloacid dehalogenase (HAD) superfamily, which contains a number of magnesium dependent acid phosphatases. These phosphatases utilize an aspartate nucleophile and contain a number of conserved active-site residues and hydrophobic patches, which can be plausibly aligned with conserved residues in MDP-1. Seven site specific point mutants of MDP-1 were produced by modifying the catalytic aspartate, serine, and lysine residues to asparagine or glutamate, alanine, and arginine, respectively. The activity of these mutants confirms the assignment of MDP-1 as a member of the HAD superfamily. Detailed comparison of the sequence of the 15 MDP-1 sequences from various organisms with other HAD superfamily sequences suggests that MDP-1 is not closely related to any particular member of the superfamily. The crystal structures of several HAD family enzymes identify a domain proximal to the active site responsible for important interactions with low molecular weight substrates. The absence of this domain or any other that might perform the same function in MDP-1 suggests an "open" active site capable of interactions with large substrates such as proteins. This suggestion was experimentally confirmed by demonstration that MDP-1 is competent to catalyze the dephosphorylation of tyrosine-phosphorylated proteins. PMID- 11601996 TI - Elementary steps in the acquisition of Mn2+ by the fosfomycin resistance protein (FosA). AB - The fosfomycin resistance protein, FosA, catalyzes the Mn(2+)-dependent addition of glutathione to the antibiotic fosfomycin, (1R,2S)-epoxypropylphosphonic acid, rendering the antibiotic inactive. The enzyme is a homodimer of 16 kDa subunits, each of which contains a single mononuclear metal site. Stopped-flow absorbance/fluorescence spectrometry provides evidence suggesting a complex kinetic mechanism for the acquisition of Mn(2+) by apoFosA. The binding of Mn(H(2)O)(6)(2+) to apoFosA alters the UV absorption and intrinsic fluorescence characteristics of the protein sufficiently to provide sensitive spectroscopic probes of metal binding. The acquisition of metal is shown to be a multistep process involving rapid preequilibrium formation of an initial complex with release of approximately two protons (k(obsd) > or = 800 s(-1)). The initial complex either rapidly dissociates or forms an intermediate coordination complex (k > 300 s(-1)) with rapid isomerization (k > or = 20 s(-1)) to a set of tight protein-metal complexes. The observed bimolecular rate constant for formation of the intermediate coordination complex is 3 x 10(5) M(-1) s(-1). The release of Mn(2+) from the protein is slow (k approximately 10(-2) s(-1)). The kinetic results suggest a more complex chelate effect than is typically observed for metal binding to simple multidentate ligands. Although the addition of the substrate, fosfomycin, has no appreciable effect on the association kinetics of enzyme and metal, it significantly decreases the dissociation rate, suggesting that the substrate interacts directly with the metal center. PMID- 11601997 TI - Long-range effects on calcium binding and conformational change in the N-domain of calmodulin. AB - Proteins within the EF-hand protein family exhibit different conformational responses to Ca(2+) binding. Calmodulin and other members of the EF-hand protein family undergo major changes in conformation upon binding Ca(2+). However, some EF-hand proteins, such as calbindin D9k (Clb), bind Ca(2+) without a significant change in conformation. Here, we investigate the effects of replacement of a leucine at position 39 of the N-terminal domain of calmodulin (N-Cam) with a phenylalanine derived from Clb. This variant is studied alone and in the context of other mutations that affect the conformational properties of N-Cam. Strikingly, the introduction of Phe39, which is distant from the calcium binding sites, leads to a significant enhancement of Ca(2+) binding affinity, even in the context of other mutations which trap the protein in the closed form. The results yield novel insights into the evolution of EF-hand proteins as calcium sensors versus calcium buffers. PMID- 11601999 TI - C5-(1-propynyl)-2'-deoxy-pyrimidines enhance mismatch penalties of DNA:RNA duplex formation. AB - UV melting experiments show that C5-(1-propynyl)ation of seven pyrimidines to give a fully propynylated oligodeoxynucleotide (PrODN) heptamer increases the thermodynamic stability of six Watson-Crick paired DNA:RNA duplexes by 8.2 kcal/mol, on average, at 37 degrees C. About 2.5 kcal/mol of this enhancement is due to long-range cooperativity between the propynylated pyrimidines, Y(p)'s. On average, penalties for dU(p):rG, dC(p):rA, dU(p):rC, and dC(p):rC mismatches are enhanced by 2.9 kcal/mol in PrODN:RNA duplexes over those in unmodified duplexes. This results in penalties as large as 10 kcal/mol for a single mismatch. Removing a single propyne two base pairs away from a mismatch in a PrODN:RNA duplex eliminates the enhancement in specificity. Evidently, enhanced specificity is directly linked to long-range cooperativity between Y(p)'s. In most cases, the enhanced specificity is larger for internal than for terminal mismatches. PrODN:RNA duplexes are destabilized by full phosphorothioate backbone substitution to give S-PrODN:RNA duplexes. The S-PrODN:RNA duplexes retain enhanced mismatch penalties, however. These results provide insight for utilizing long-range cooperativity and enhanced specificity to improve nucleic acid based probe and drug design. PMID- 11601998 TI - Kinetic resolution of a conformational transition and the ATP hydrolysis step using relaxation methods with a Dictyostelium myosin II mutant containing a single tryptophan residue. AB - The fluorescence emission intensity from a conserved tryptophan residue (W501) located in the relay loop (F466 to L516) of the Dicytostelium discoideum myosin II motor domain is sensitive to ATP binding and hydrolysis. The initial binding process is accompanied by a small quench in fluorescence, and this is followed by a large enhancement that appears coincident with the hydrolysis step. Using temperature and pressure jump methods, we show that the enhancement process is kinetically distinct from but coupled to the hydrolysis step. The fluorescence enhancement corresponds to the open-closed transition (k(obs) approximately 1000 s(-1) at 20 degrees C). From the overall steady-state fluorescence signal and the presence or absence of a relaxation transient, we conclude that the ADP state is largely in the open state, while the ADP.AlF(4) state is largely closed. At 20 degrees C the open-closed equilibria for the AMP.PNP and ADP.BeF(x) complexes are close to unity and are readily perturbed by temperature and pressure. In the case of ATP, the equilibrium of this step slightly favors the open state, but coupling to the subsequent hydrolysis step gives rise to a predominantly closed state in the steady state. Pressure jump during steady-state ATP turnover reveals the distinct transients for the rapid open-closed transition and the slower hydrolysis step. PMID- 11602001 TI - Calcitonin gene-related peptide (CGRP) and the pathophysiology of headache: therapeutic implications. AB - Cerebral blood vessels are innervated by sensory nerves that store several neurotransmitters. In primary headaches, there is a clear association between head pain and the release of the neuropeptide calcitonin gene-related peptide (CGRP). Furthermore, when triptan antimigraine agents are administered, headache subsides and the neuropeptide release normalises, in part via a presynaptic effect. The central role of CGRP in primary headaches has led to the search for suitable antagonists of the receptors for this neuropeptide, which it is hoped will have less cardiovascular adverse effects than the triptans. Recently, the initial pharmacological profile of such a group of compounds has been disclosed. These compounds are small molecules with high selectivity for human CGRP receptors. Hypothetically, these agents will be efficacious in the relief of migraine headaches via blockade of the effects of CGRP. PMID- 11602002 TI - Design of clinical trials of antidepressants: should a placebo control arm be included? AB - There is no doubt that available antidepressants are efficacious and effective. Nevertheless, more effective drugs with improved tolerability are needed. With this need in mind, some protagonists claim that future antidepressants should be proved superior to, or at least as effective as, established antidepressants, making placebo control methodologically dispensable in clinical trials. Moreover, the use of placebo control is criticised as unethical because it might result in effective treatment being withheld. There are, however, a number of methodological reasons why placebo control is indispensable for the proof of efficacy of antidepressants. Comparing investigational antidepressants only with standard antidepressants and not placebo yields ambiguous results that are difficult to interpret, be it in superiority or equivalence testing, and this method of assessment requires larger sample sizes than those required with the use of placebo control. Experimental methodology not adhering to the optimal study design is ethically questionable. Restricting the testing of investigational antidepressants only to superiority over standard antidepressants is an obstacle to therapeutic progress in terms of tolerability and the detection of innovative mechanisms of action from which certain subgroups of future patients might benefit. The use of a methodology that requires larger samples for testing of superiority or equivalence is also ethically questionable. In view of the high placebo response rates in trials of antidepressants, placebo treatment does not mean withholding effective treatment. Accepting the necessity of the clinical evaluation of new, potentially ineffective antidepressants implicitly means accepting placebo control as ethically justified. Three- or multi-arm comparisons including placebo and an active reference represent the optimal study design. PMID- 11602003 TI - Severe depression: is there a best approach? AB - A major depressive episode can be categorised as severe based on depressive symptoms, scores on depression rating scales, the need for hospitalisation, depressive subtypes, functional capacity, level of suicidality and the impact that the depression has on the patient. Several biological, psychological and social factors, and the presence of comorbid psychiatric or medical illnesses, impact on depression severity. A number of factors are reported to influence outcome in severe depression, including duration of illness before treatment, severity of the index episode, treatment modality used, and dosage and duration of and compliance with treatment. Potential complications of untreated severe depression include suicide, self-mutilation and refusal to eat, and treatment resistance. Several antidepressants have been studied in the treatment of severe depression. These include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline (norepinephrine) reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin 5 HT(2) receptor antagonists, monoamine oxidase inhibitors, and amfebutamone (bupropion). More recently, atypical antipsychotics have shown some utility in the management of severe and resistant depression. Data on the differential efficacy of TCAs versus SSRIs and the newer antidepressants in severe depression are mixed. Some studies have reported that TCAs are more efficacious than SSRIs; however, more recent studies have shown that TCAs and SSRIs have equivalent efficacy. There are reports that some of the newer antidepressants may be more effective than SSRIs in the treatment of severe depression, although the sample sizes in some of these studies were small. Combination therapy has been reported to be effective. The use of an SSRI-TCA combination, while somewhat controversial, may rapidly reduce depressive symptoms in some patients with severe depression. The combination of an antidepressant and an antipsychotic drug is promising and may be considered for severe depression with psychotic features. Although the role of cognitive behaviour therapy (CBT) in severe depression has not been adequately studied, a trial of CBT may be considered in severely depressed patients whose symptoms respond poorly to an adequate antidepressant trial, who are intolerant of antidepressants, have contraindications to pharmacotherapy, and who refuse medication or other somatic therapy. A combination of CBT and antidepressants may also be beneficial in some patients. Electroconvulsive therapy (ECT) may be indicated in severe psychotic depression, severe melancholic depression, resistant depression, and in patients intolerant of antidepressant medications and those with medical illnesses which contraindicate the use of antidepressants (e.g. renal, cardiac or hepatic disease). PMID- 11602006 TI - A self-correcting method for improving the precision of beam blocks. AB - A technique for manufacturing precise custom blocks is described. Using the tracing stylus of the mold making machine, reference markers are cut into the lateral borders of the polystyrene mold after the cavities for the blocks have been made. These markers are aligned with the central ray cross hair of the shadow tray when the blocks are mounted on the tray. The ability of the technique to enhance precision has been verified in laboratory tests by intentionally introducing small imperfections into a mold making machine and checking the positional accuracy of the mounted blocks. The clinical performance has been tested by evaluating 47 check films of blocks for 16 randomly selected patients. The average positional error of individual blocks, projected to the isocenter, was less than one mm. The average time needed to cut the reference markers was 25 seconds. Implementing the technique required only minor modifications of a commercial mold making machine. PMID- 11602007 TI - Comparison of two planning systems for HDR brachytherapy gynecological application. AB - PURPOSE: This report compares the Nucletron NPS and PLATO planning system for patients treated for cervix cancer. MATERIALS AND METHODS: This study compares calculations generated using the older NPS (version 11.43) planning system and the more recent PLATO (version 14.1) system for two cases: 1) a single dwell position and 2) an actual patient application using a tandem and ovoid. RESULTS: For one dwell position: for NPS planning the dose for points along the source axis forward of the cable was 9.85% more than for symmetrically placed points in the cable direction. For PLATO, the same test gave rise to a difference of 10.2%. Comparing the two systems, NPS calculated doses for points in the forward direction 14% greater than those calculated by PLATO. The entry of points using the digitizer accounted for less than 1% of any difference. For the patient case: the dose difference between NPS and PLATO planning for all patient reference points entered from films ranged from 1 to 4%. The difference in dose between optimized and nonoptimized planning was approximately 0.5% for prescription points (points A), while for the bladder and rectum the differences were 6% and 20%, respectively with NPS, and with PLATO, 8% and 22%, respectively. CONCLUSION: This study highlighted the effects of the differences in the calculational algorithm between the older and newer planning systems from Nucletron. While the differences were minimal on the perpendicular bisector of the source, along the axis they become considerable. In a practical gynecological case, these differences mostly affect the dose to the rectum, since that organ receives the greatest proportion of its dose from rays near the same axis. Overall, the PLATO system plan required about 2.5% less integrated reference air kerma than the NPS plan for the same dose to point A. For either planning system, optimization is crucial in decreasing dose to bladder and rectal points. PMID- 11602008 TI - Commissioning of a mobile electron accelerator for intraoperative radiotherapy. AB - Radiation performance characteristics of a dedicated intraoperative accelerator were determined to prepare the unit for clinical use. The linear accelerator uses standing wave X-band technology (wavelength approximately 3 centimeters) in order to minimize the mass of the accelerator. The injector design, smaller accelerator components, and low electron beam currents minimize radiation leakage. The unit may be used in a standard operating room without additional shielding. The mass of the accelerator gantry is 1250 Kg (weight approximately 2750 lbs) and the unit is transportable between operating rooms. Nominal electron energies are 4, 6, 9, and 12 MeV, and operate at selectable dose rates of 2.5 or 10 Gray per minute. D(max) depths in water for a 10 cm applicator are 0.7, 1.3, 1.7, and 2.0 for these energies, respectively. The depths of 80% dose are 1.2, 2.1, 3.1, and 3.9 cm, respectively. Absolute calibration using the American Association of Physicists in Medicine TG-51 protocol was performed for all electron energies using the 10 cm applicator. Applicator sizes ranged from 3 to 10 cm diameter for flat applicators, and 3 to 6 cm diameter for 30 degrees beveled applicators. Output factors were determined for all energies relative to the 10 cm flat applicator. Central axis depth dose profiles and isodose plots were determined for every applicator and energy combination. A quality assurance protocol, performed each day before patient treatment, was developed for output and energy constancy. PMID- 11602005 TI - Role of estrogen in the aetiology and treatment of mood disorders. AB - Worldwide, the prevalence of depression in women is significantly greater than in men. Available data suggest that estrogen, or its absence, is strongly implicated in the regulation of mood and behaviour, as well as in the pathobiology of mood disorders. The multiple effects of estrogens and their complex interactions with the CNS and endocrine system have been well documented, although the specific, multifaceted role of estrogen in each dysphoric state has yet to be elucidated. Several facts suggest that estrogen plays a vital role in the precipitation and course of mood disorders in women. Gender differences in the prevalence of depression first appear after menarche, continue through reproductive age, and dissipate after perimenopause. Periods of hormonal fluctuations or estrogen instability (i.e. premenstrually, postpartum, perimenopausally) have been associated with increased vulnerability to depression among susceptible women. It is plausible that the phenotype of these depressions is distinguishable from those that are not associated with reproductive events or that occur in men. Based on current knowledge, estrogen treatment for affective disorders may be efficacious in two situations: (i) to stabilise and restore disrupted homeostasis - as occurs in premenstrual, postpartum or perimenopausal conditions; and (ii) to act as a psychomodulator during periods of decreased estrogen levels and increased vulnerability to dysphoric mood, as occurs in postmenopausal women. There is growing evidence suggesting that estrogen may be efficacious as a sole antidepressant for depressed perimenopausal women. It is still unclear whether estrogen is efficacious as an adjunct to selective serotonin reuptake inhibitors or as one of the paradigms to manage treatment-resistance depression in menopausal women, but such efficacy is plausible. PMID- 11602004 TI - Sleep disturbances in patients with Alzheimer's disease: epidemiology, pathophysiology and treatment. AB - Older adults represent an ever-growing proportion of the population of the industrialised nations, with a corresponding increase in the numbers of patients with dementing disorders. A common complaint in both normal aging and the dementias is that of significant sleep disturbance. The major causes of sleep disruption in aging and dementia include: (i) physiological changes that arise as part of normal, 'nonpathological' aging; (ii) sleep problems due to one of many physical or mental health conditions and their treatments; (iii) primary sleep disorders; (iv) poor 'sleep hygiene', that is, sleep-related practices and habits; and (v) some combination of these factors. Disrupted sleep in patients with dementia is a significant cause of stress for caregivers and frequently leads to institutionalisation of patients. It should be a target of clinical management when the goal is sustained home care, and when it is associated with disturbances of mood or behaviour. While the neuropathology of dementia can directly disrupt sleep, sleep disturbances in patients with dementia often have multiple causes that require systematic evaluation. Thorough assessment of associated psychopathology, day-time behaviour, medical disorders, medications, pain and environmental conditions is needed for optimal management. Differential diagnosis of a sleep problem in dementia is the basis of rational pharmacotherapy. However, patients with dementia are likely to be more sensitive than elderly persons without dementia to adverse cognitive and motor effects of drugs prescribed for sleep. Clinicians need to: (i) evaluate sleep outcomes when treating medical, psychiatric and behavioural disorders in older adults; (ii) be alert to emerging behavioural and environmental approaches to treatment; (iii) combine nonpharmacological strategies with drug therapies, when required, for added value; and (iv) avoid use of multiple psychotropic medications unless they prove essential to the adequate management of sleep disturbances. PMID- 11602009 TI - Reproducibility of interactive registration of 3D CT and MR pediatric treatment planning head images. AB - The reproducibility of an interactive image registration technique used as part of the radiotherapy treatment planning process was investigated for 3D CT and MR pediatric head images. Over a nine month period, 85 CT/MR image registrations, required for treatment planning, were repeated, 52 by the same operator and 33 by a different operator. All were performing image registrations for normal clinical care and the first registration was used clinically. Inter- and intra-operator reproducibility of the translation and rotation were calculated separately. The standard deviation of the average total translation and rotation was 0.39 mm and 1.7 degrees, and 0.58 mm and 2.8 degrees, respectively. The maximum difference between registrations was 1.1 mm and 4.1 degrees when repeated by the same operator, and 1.4 mm and 5.8 degrees when repeated by another operator. The variation for the lowest resolution parameters, out of plane translation and rotations, was 2 to 3 times larger than for in-plane movements. A registration took between 5 minutes and over half an hour for difficult cases, with a mean of 14.3 minutes. One to two millimeter reproducibility was not achieved and interactive registration was relatively time consuming. There is a clear image resolution effect on registration reproducibility, suggesting that reducing slice thickness could considerably improve registration reproducibility. PMID- 11602010 TI - The overshoot phenomenon in step-and-shoot IMRT delivery. AB - The control loop in the Varian DMLC system (V4.8) requires approximately 65 msec to monitor and halt the irradiation of a segment, causing an "overshoot" effect: the segment ends on a fractional monitor unit larger than that planned. As a result, the actual MU delivered may differ from that planned. In general, for step-and-shoot treatments, the first segment receives more, the last receives less, and intermediate segments vary. The overshoot for each segment (DeltaMU) is small, approximately 0.6 MU at 600 MU/min. Our IMRT planning system (Corvus) produces plans often having more than 20% of the segments with less than 1 MU/segment. Such segments may be skipped if the DeltaMU exceeds the segments' planned MU. Furthermore, QA filming often requires reducing the total MU by a factor of 4-6, increasing the potential for dosimetric error. This study measured DeltaMU over a range of MU/min and MU/segment. At >5 MU/segment, the DeltaMU was stable, corresponding to a delay of 62 msec. DeltaMU became larger and more variable at <1 MU/segment. The behavior was modeled in a computer program that predicted the change in delivered MU/segment and total change in delivered MU to each beamlet. Beams were analyzed for patients receiving 5 field prostate or 9 field head and neck treatments. At 400 MU/min, 28% and 16%, respectively, of the planned segments were skipped. For QA filming, up to 75% of the segments were skipped. The cumulative error averaged <0.1 MU/beamlet, but individual beamlets had errors exceeding 200%. The effect is most significant for low dose regions. Recommendations are given for deciding when to treat or do QA studies with lower MU/min. In general, treatments are not significantly affected, but QA films taken at reduced MU may be improved if irradiated at lowered MU/min. PMID- 11602011 TI - Verification of the accuracy of 3D calculations of breast dose during tangential irradiation: measurements in a breast phantom. AB - This report specifically describes the use of a unique anthropomorphic breast phantom to validate the accuracy of three-dimensional dose calculations performed by a commercial treatment-planning system for intact-breast tangential irradiation. The accuracy of monitor-unit calculations has been corroborated using ionization chamber measurements made in this phantom. Measured doses have been compared to those calculated from a variety of treatment plans. The treatment plans utilized a 6-MV x-ray beam and incorporated a variety of field configurations and wedge combinations. Dose measurements at several clinically relevant points within the breast phantom have confirmed the accuracy of calculated doses generated from the variety of treatment plans. Overall agreement between measurements and calculations averaged 0.998+/-0.009. These results indicate that the dose per monitor-unit calculations performed by the treatment planning system can be confidently utilized in the fulfillment of clinical dose prescriptions. PMID- 11602012 TI - Radiation therapy vault shielding calculational methods when IMRT and TBI procedures contribute. AB - The additional intensity modulated radiation therapy (IMRT) and total body irradiation (TBI) to conventional treatment clinical treatment procedures can significantly increase the contribution of accelerator head leakage radiation. Previously recommended procedures by the National Council on Radiation Protection and Measurements (NCRP) for vault design, specifically calculations of primary and secondary barrier thicknesses, are not valid when leakage radiation significantly exceeds direct radiation. Use factor distributions are also influenced by IMRT and TBI procedures. Methods are proposed to extend the NCRP barrier design formulas to resolve these problems. The medical accelerator (weekly) workload is separately determined for the direct, leakage, and scatter radiation components. Applications of the formulas to the calculation of primary and secondary barriers are discussed. The addition of IMRT to the shielding design is explored as a function of the fraction patients receiving IMRT and the MU to dose ratio. Secondary barrier thicknesses could be increased by as much as 1 TVL. PMID- 11602013 TI - Shielding assessment of a mobile electron accelerator for intraoperative radiotherapy. AB - A new approach to intraoperative radiotherapy makes use of a mobile electron linear accelerator delivering therapeutic radiation doses in an operating room suite. This unconventional technology has raised questions concerning protection for personnel and the necessity of shielding the adjoining areas. In this study, the leakage and scatter radiation from the mobile electron accelerator is measured and characterized in a series of spherical projections. An analysis is performed to determine the need for shielding or, alternatively, patient-based load restrictions in the operating room. This investigation provides a resource to assess shielding and/or patient load restrictions for any facility performing intraoperative radiotherapy with a similar unit. The data presented indicates that the mobile electron accelerator may be operated in an area with little or no shielding under nominal patient load expectations. PMID- 11602014 TI - Radiation safety issues regarding the cremation of the body of an I-125 prostate implant patient. AB - Radiation exposure to the public is estimated if the body of an I-125 prostate implant patient is cremated. Precautions regarding the handling of cremated remains are suggested. Cremation can be performed safely at any time. PMID- 11602015 TI - b matrix errors in echo planar diffusion tensor imaging. AB - Diffusion-weighted magnetic resonance imaging (DW-MRI) is a recognized tool for early detection of infarction of the human brain. DW-MRI uses the signal loss associated with the random thermal motion of water molecules in the presence of magnetic field gradients to derive parameters that reflect the translational mobility of the water molecules in tissues. If diffusion-weighted images with different values of b matrix are acquired during one individual investigation, it is possible to calculate apparent diffusion coefficient maps that are the elements of the diffusion tensor. The diffusion tensor elements represent the apparent diffusion coefficient of protons of water molecules in each pixel in the corresponding sample. The relation between signal intensity in the diffusion weighted images, diffusion tensor, and b matrix is derived from the Bloch equations. Our goal is to establish the magnitude of the error made in the calculation of the elements of the diffusion tensor when the imaging gradients are ignored. PMID- 11602016 TI - Fluorescence of fungi in superficial and deep fungal infections. AB - BACKGROUND: Fluorescence of many fungi is noted when H&E stained sections are examined under a fluorescent microscope. In theory, this phenomenon could aid in the diagnosis of cutaneous and disseminated fungal infections without the delay associated with special stains. Seventy-six cases of superficial and deep fungal infections and 3 cases of protothecosis were studied to determine the clinical usefulness of this technique. RESULTS: In most cases, fluorescence was noted, but was not intense. Fluorescence of fungi did not correlate with the age of the specimen. In most cases, organisms in H&E stained sections were more easily identified with routine light microscopy than with fluorescent microscopy. CONCLUSION: This report suggests that in H&E stained skin specimens, fluorescent microscopy is of little benefit in the identification of fungal organisms. PMID- 11602017 TI - Small-scale analysis of exopolysaccharides from Streptococcus thermophilus grown in a semi-defined medium. AB - BACKGROUND: Exopolysaccharides (EPSs) produced by lactic acid bacteria are important for the texture of fermented foods and have received a great deal of interest recently. However, the low production levels of EPSs in combination with the complex media used for growth of the bacteria have caused problems in the accurate analysis of the EPS. The purpose of this study was to find a growth medium for physiological studies of the lactic acid bacterium Streptococcus thermophilus, and to develop a simple method for qualitative and quantitative analysis of EPSs produced in this medium. RESULTS: A semi-defined polysaccharide medium was developed and evaluated on six strains of Streptococcus thermophilus. The EPSs were analysed using a novel protocol incorporating ultracentrifugation for the removal of interfering sugars, hydrolysis and analysis of the monomer composition by High Performance Anion-Exchange Chromatography with pulsed amperometric detection. The medium and analysis method allowed accurate quantification and monomer analysis of 0.5 ml samples of EPSs from tube cultures. CONCLUSIONS: The presented medium should be useful for physiological studies of S. thermophilus, and, in combination with the method of analysis of EPS, will allow downscaling of physiological studies and screening for EPSs. PMID- 11602018 TI - The paired availability design for historical controls. AB - BACKGROUND: Although a randomized trial represents the most rigorous method of evaluating a medical intervention, some interventions would be extremely difficult to evaluate using this study design. One alternative, an observational cohort study, can give biased results if it is not possible to adjust for all relevant risk factors. METHODS: A recently developed and less well-known alternative is the paired availability design for historical controls. The paired availability design requires at least 10 hospitals or medical centers in which there is a change in the availability of the medical intervention. The statistical analysis involves a weighted average of a simple "before" versus "after" comparison from each hospital or medical center that adjusts for the change in availability. RESULTS: We expanded requirements for the paired availability design to yield valid inference. (1) The hospitals or medical centers serve a stable population. (2) Other aspects of patient management remain constant over time. (3) Criteria for outcome evaluation are constant over time. (4) Patient preferences for the medical intervention are constant over time. (5) For hospitals where the intervention was available in the "before" group, a change in availability in the "after group" does not change the effect of the intervention on outcome. CONCLUSION: The paired availability design has promise for evaluating medical versus surgical interventions, in which it is difficult to recruit patients to a randomized trial. PMID- 11602019 TI - Bacteremia in hospitalized patients with human immunodeficiency virus: A prospective, cohort study. AB - BACKGROUND: Bacterial infections complicate the course of patients with human immunodeficiency virus infection. The purpose of this study was to describe the bacterial pathogens causing blood stream infection, identify the risk factors for the development of blood stream infection and determine the impact of blood stream infection on the outcome of patients infected with human immunodeficiency virus. METHODS: The incidence, etiology, risk factors and outcome of bacterial blood stream infection were prospectively determined in 1,225 consecutive hospitalizations of adults with human immunodeficiency virus infection. RESULTS: Blood stream infection occurred in 88 hospitalizations (7%); 73 of 89 infections (82%) were community acquired. The most commonly isolated gram-positive organism was Streptococcus pneumoniae (21); gram-negative, Escherichia coli (14). Blood stream infection was detected in 8% of African Americans and 22% of Hispanics compared with 2% of whites (P = 0.0013). Patients with blood stream infection had higher white blood cell counts (median, 6.5 vs. 4.9 x 109/L; P = 0.0002) and mortality (18% vs. 4%; P < 0.0001) than patients without infection. CONCLUSIONS: In patients with human immunodeficiency virus, blood stream infection is associated with an increased mortality rate. Recognition of the incidence, etiology, and risk factors of blood stream infection in patients with human immunodeficiency virus infection could lead to measures that reduce the increased mortality. PMID- 11602020 TI - Blood and alveolar lymphocyte subsets in pulmonary cytomegalovirus infection after lung transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) pneumonitis has been shown to be associated with lymphocytic alveolitis after lung transplantation. In the present study, we investigated a series of bronchoalveolar (BAL) and blood samples, collected in the absence of rejection or acute infectious episodes. in order -1: to evaluate intra-alveolar cell population changes concomitant with CMV replication and -2: to reappraise the value of cell population analysis in the management of patients after lung transplantation. METHODS: We used flow cytometry to investigate modifications of lymphocyte subpopulations related to pulmonary cytomegalovirus infections in blood and BAL samples from a series of 13 lung transplant recipients. After exclusion of samples obtained during pulmonary rejection, bronchiolitis obliterans or acute bacterial infection, 48 blood and BAL samples were retained for analysis: 17 were CMV positive by shell-vial assay and 31 were CMV negative in blood and BAL. RESULTS: Our results demonstrate that pulmonary CMV infection is associated with a significant increase in the total lymphocyte population in BAL samples, but with minor modifications of the various lymphocyte subpopulations and a significantly higher absolute number of B lymphocytes in blood samples. CONCLUSIONS: Cytomegalovirus pulmonary infection is accompanied by only minor changes in BAL lymphocyte subpopulations. The study of BAL lymphocyte subpopulations therefore appears to be of limited clinical value in the diagnosis of pulmonary CMV infection. However, increased blood B-lymphocytes seems to be a clinical feature associated with CMV infection. PMID- 11602021 TI - Cellulose acetate phthalate, a common pharmaceutical excipient, inactivates HIV-1 and blocks the coreceptor binding site on the virus envelope glycoprotein gp120. AB - BACKGROUND: Cellulose acetate phthalate (CAP), a pharmaceutical excipient used for enteric film coating of capsules and tablets, was shown to inhibit infection by the human immunodeficiency virus type 1 (HIV-1) and several herpesviruses. CAP formulations inactivated HIV-1, herpesvirus types 1 (HSV-1) and 2 (HSV-2) and the major nonviral sexually transmitted disease (STD) pathogens and were effective in animal models for vaginal infection by HSV-2 and simian immunodeficiency virus. METHODS: Enzyme-linked immunoassays and flow cytometry were used to demonstrate CAP binding to HIV-1 and to define the binding site on the virus envelope. RESULTS: 1) CAP binds to HIV-1 virus particles and to the envelope glycoprotein gp120; 2) this leads to blockade of the gp120 V3 loop and other gp120 sites resulting in diminished reactivity with HIV-1 coreceptors CXCR4 and CCR5; 3) CAP binding to HIV-1 virions impairs their infectivity; 4) these findings apply to both HIV-1 IIIB, an X4 virus, and HIV-1 BaL, an R5 virus. CONCLUSIONS: These results provide support for consideration of CAP as a topical microbicide of choice for prevention of STDs, including HIV-1 infection. PMID- 11602022 TI - Voluntary self-poisoning as a cause of admission to a tertiary hospital internal medicine clinic in Piraeus, Greece within a year. AB - BACKGROUND: Out of 1705 patients hospitalised for various reasons in the 3rd Internal Medicine Department of the Regional General Hospital of Nikaea, in Piraeus, 146(8,5%) persons were admitted for drug intoxication between November 1999 and November 2000. METHODS: On average, these persons [male 50(34,2%)- female 96(65,8%)] were admitted to the hospital within 3.7 hours after taking the drug. RESULTS: The drugs that were more frequently taken, alone or in combination with other drugs, were sedatives (67.1%), aspirins and analgesics (mainly paracetamol) (43.5%). 38.3% of patients had a mental illness history, 31.5% were in need of psychiatric help and 45.2% had made a previous suicide attempt. No death occurred during the above period and the outcome of the patients' health was normal. After mental state examination, the mental illnesses diagnosed were depression (20.96%), psychosis (15.32%), dysthymic disorder (16,2%), anxiety disorder (22.58%) and personality disorder (8.87%). CONCLUSIONS: Self-poisoning remains a crucial problem. The use of paracetamol and sedatives are particularly important in the population studied. Interpersonal psychiatric therapy may be a valuable treatment after people tried to poison themselves. PMID- 11602023 TI - Mycobacterial and nonbacterial pulmonary complications in hospitalized patients with human immunodeficiency virus infection: a prospective, cohort study. AB - BACKGROUND: A prospective observational study was done to describe nonbacterial pulmonary complications in hospitalized patients with human immunodeficiency virus (HIV) infection. METHODS: The study included 1,225 consecutive hospital admissions of 599 HIV-infected patients treated from April 1995 through March 1998. Data included demographics, risk factors for HIV infection, Acute Physiology and Chronic Health Evaluation (APACHE) II score, pulmonary complications, CD4+ lymphocyte count, hospital stay and case-fatality rate. RESULTS: Patient age (mean +/- SD) was 38.2 +/- 8.9 years, 62% were men, and 84% were African American. The median APACHE II score was 14, and median CD4+ lymphocyte count was 60/microL. Pulmonary complications were Pneumocystis carinii pneumonia (85) in 78 patients, Mycobacterium avium complex (51) in 38, Mycobacterium tuberculosis (40) in 35, Mycobacterium gordonae (11) in 11, Mycobacterium kansasii (10) in 9, Cytomegalovirus (10) in 10, Nocardia asteroides (3) in 3, fungus ball (2) in 2, respiratory syncytial virus (1), herpes simplex virus (1), Histoplasma capsulatum (1), lymphoma (3) in 3, bronchogenic carcinoma (2) in 2, and Kaposi sarcoma (1). The case-fatality rate of patients was 11% with Pneumocystis carinii pneumonia; 5%, Mycobacterium tuberculosis; 6%, Mycobacterium avium complex; and 7%, noninfectious pulmonary complications. CONCLUSION: Most pulmonary complications in hospitalized patients with HIV are from Pneumocystis and mycobacterial infection. PMID- 11602024 TI - A surrogate-based approach for post-genomic partner identification. AB - BACKGROUND: Modern drug discovery is concerned with identification and validation of novel protein targets from among the 30,000 genes or more postulated to be present in the human genome. While protein-protein interactions may be central to many disease indications, it has been difficult to identify new chemical entities capable of regulating these interactions as either agonists or antagonists. RESULTS: In this paper, we show that peptide complements (or surrogates) derived from highly diverse random phage display libraries can be used for the identification of the expected natural biological partners for protein and non protein targets. Our examples include surrogates isolated against both an extracellular secreted protein (TNFbeta) and intracellular disease related mRNAs. In each case, surrogates binding to these targets were obtained and found to contain partner information embedded in their amino acid sequences. Furthermore, this information was able to identify the correct biological partners from large human genome databases by rapid and integrated computer based searches. CONCLUSIONS: Modified versions of these surrogates should provide agents capable of modifying the activity of these targets and enable one to study their involvement in specific biological processes as a means of target validation for downstream drug discovery. PMID- 11602026 TI - Fibromyalgia syndrome improved using a mostly raw vegetarian diet: an observational study. AB - BACKGROUND: Fibromyalgia engulfs patients in a downward, reinforcing cycle of unrestorative sleep, chronic pain, fatigue, inactivity, and depression. In this study we tested whether a mostly raw vegetarian diet would significantly improve fibromyalgia symptoms. METHODS: Thirty people participated in a dietary intervention using a mostly raw, pure vegetarian diet. The diet consisted of raw fruits, salads, carrot juice, tubers, grain products, nuts, seeds, and a dehydrated barley grass juice product. Outcomes measured were dietary intake, the fibromyalgia impact questionnaire (FIQ), SF-36 health survey, a quality of life survey (QOLS), and physical performance measurements. RESULTS: Twenty-six subjects returned dietary surveys at 2 months; 20 subjects returned surveys at the beginning, end, and at either 2 or 4 months of intervention; 3 subjects were lost to follow-up. The mean FIQ score (n = 20) was reduced 46% from 51 to 28. Seven of the 8 SF-36 subscales, bodily pain being the exception, showed significant improvement (n = 20, all P for trend < 0.01). The QOLS, scaled from 0 to 7, rose from 3.9 initially to 4.9 at 7 months (n = 20, P for trend 0.000001). Significant improvements (n = 18, P < 0.03, paired t-test) were seen in shoulder pain at rest and after motion, abduction range of motion of shoulder, flexibility, chair test, and 6-minute walk. 19 of 30 subjects were classified as responders, with significant improvement on all measured outcomes, compared to no improvement among non-responders. At 7 months responders' SF-36 scores for all scales except bodily pain were no longer statistically different from norms for women ages 45-54. CONCLUSION: This dietary intervention shows that many fibromyalgia subjects can be helped by a mostly raw vegetarian diet. PMID- 11602025 TI - Insight to structural subsite recognition in plant thiol protease-inhibitor complexes : understanding the basis of differential inhibition and the role of water. AB - BACKGROUND: This work represents an extensive MD simulation / water-dynamics studies on a series of complexes of inhibitors (leupeptin, E-64, E-64-C, ZPACK) and plant cysteine proteases (actinidin, caricain, chymopapain, calotropin DI) of papain family to understand the various interactions, water binding mode, factors influencing it and the structural basis of differential inhibition. RESULTS: The tertiary structure of the enzyme-inhibitor complexes were built by visual interactive modeling and energy minimization followed by dynamic simulation of 120 ps in water environment. DASA study with and without the inhibitor revealed the potential subsite residues involved in inhibition. Though the interaction involving main chain atoms are similar, critical inspection of the complexes reveal significant differences in the side chain interactions in S2-P2 and S3-P3 pairs due to sequence differences in the equivalent positions of respective subsites leading to differential inhibition. CONCLUSION: The key finding of the study is a conserved site of a water molecule near oxyanion hole of the enzyme active site, which is found in all the modeled complexes and in most crystal structures of papain family either native or complexed. Conserved water molecules at the ligand binding sites of these homologous proteins suggest the structural importance of the water, which changes the conventional definition of chemical geometry of inhibitor binding domain, its shape and complimentarity. The water mediated recognition of inhibitor to enzyme subsites (Pn.H2O.Sn) of leupeptin acetyl oxygen to caricain, chymopapain and calotropinDI is an additional information and offer valuable insight to potent inhibitor design. PMID- 11602027 TI - Prenatal low-level exposure to CO alters postnatal development of hippocampal nitric oxide synthase and haem-oxygenase activities in rats. AB - The effects of prenatal CO exposure (150 ppm from days 0 to 20 of pregnancy) on the postnatal development of hippocampal neuronal NO synthase (nNOS) and haem oxygenase (HO-2) isoform activities in 15-, 30- and 90-d-old rats were investigated. Unlike HO-2, hippocampal nNOS activity increased from postnatal days 15-90 in controls. Prenatal CO produced a long-lasting decrease in either nNOS or HO-2. The results suggest that the altered developmental profile of hippocampal nNOS and HO-2 activities could be involved in cognitive deficits and long-term potentiation dysfunction exhibited by rats prenatally exposed to CO levels resulting in carboxyhaemoglobin (HbCO) levels equivalent to those observed in human cigarette smokers. PMID- 11602028 TI - Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease. AB - In-vivo metabolic measures with positron emission tomography using (18)F fluorodeoxyglucose (FDG-PET) have demonstrated hypometabolism in temporal, frontal, and hippocampal areas during the early stages of Alzheimer's disease (AD). Progression of the dementia in AD involves compromised cholinergic functioning. Cholinesterase inhibitors have demonstrated efficacy in improving cognition and behaviour in AD. In this study, we demonstrate the usefulness of FDG-PET in measuring the progression of untreated AD and its modification by treatment with rivastigmine (Exelon, Novartis Pharmaceuticals, East Hanover, New Jersey, USA), a centrally selective cholinesterase inhibitor of the carbamate type. Patients with mild to moderate probable AD (Mini-Mental Status Exam scores of 10-26, inclusive) were enrolled in a double-blind, placebo controlled comparison of three fixed daily doses of rivastigmine (3, 6, or 9 mg/d) or placebo for 26 wk. FDG-PET scans were obtained on 27 patients at baseline and following 26 wk of treatment using the Snodgrass Picture Naming activation task. A total of 71.4% of the patients treated with placebo deteriorated clinically compared to only 25.0% of the patients treated with rivastigmine (chi2 = 4.8; p & 0.03). Rivastigmine-responders (i.e. those who clinically improved or remained clinically stable as measured by the Clinicianaposs Interview-Based Impression of Change-plus) showed a marked increase in brain metabolism (p <0.01) involving, but not limited to, structures comprising the memory-related cortices and the prefrontal system. These metabolic changes were not observed in the placebo treated patients or the rivastigmine non-responders. Of note is that responders increased hippocampal metabolism by 32.5% (p < 0.03) compared to a non significant decrease in the non-responders (6.4%) and placebo-treated patients (4.1%). These results are consistent with the literature suggesting that FDG-PET can sensitively measure the progression of AD and its improvement with cholinesterase inhibitors. Rivastigmine prevented the expected deterioration in clinical status and dramatically increased brain metabolic activity in a majority of patients. PMID- 11602030 TI - Catatonia: an open prospective series with carbamazepine. AB - In view of reports in the literature that catatonia responds well to benzodiazepines, and the possible association between catatonia and seizure disorders, an open prospective study was conducted to explore the possibility that catatonia may be successfully treated with carbamazepine. Patients meeting DSM-IV criteria for catatonia were challenged with lorazepam IMI and their response assessed. Non-responders, partial responders and patients who had a recurrence of symptoms were put on a trial of carbamazepine and their response assessed. Nine patients were assessed at our unit. Six of the 9 had a complete, but transient response to lorazepam. All of the patients were given a trial of carbamazepine: 4 had a complete resolution of catatonic symptoms, 1 had a partial resolution and 4 patients did not show a significant improvement. Carbamazepine seems to be an effective treatment, both in the acute phase, and as maintenance in a subgroup of retarded catatonic patients. PMID- 11602029 TI - Taijin kyofusho: a form of social anxiety disorder that responds to serotonin reuptake inhibitors? AB - Taijin kyofusho (TKS) has been categorized as a "culture-bound" illness that is unique to the East, although an alternative view holds that some TKS patients are best conceptualized as having a form of social anxiety disorder (SAD). However, pharmacotherapeutic interventions for TKS have not yet been rigorously investigated. A review was undertaken of 48 TKS patients initially treated with serotonin reuptake inhibitors (SRIs) in an outpatient setting of a Japanese hospital. Psychiatric diagnoses were determined according to DSM-IV, and a set of TKS diagnostic criteria based on a modification of DSM-IV SAD criteria. In addition, response to SRIs (clomipramine and fluvoxamine) was evaluated retrospectively using the Clinical Global Impressions (CGI) scale. All 48 patients met SAD-based TKS diagnostic criteria. In the pretreatment assessment, DSM-IV Axis I diagnoses included SAD (38%), major depressive episode (27%), and delusional disorder somatic type (15%). Sixteen (48%) of 33 patients treated with clomipramine or fluvoxamine for at least 6 months were categorized as responders (CGI = 1 or 2). Compared to responders, non-responders were significantly less likely to have pretreatment major depression, and significantly more likely to have comorbid cluster A personality disorders and to have received augmentation with antipsychotic drugs. Although TKS may be a heterogeneous condition with various comorbidities, patients invariably fulfilled diagnostic criteria for TKS based on SAD criteria. SRIs may be effective for a substantial number of TKS patients. Prospective controlled trials are necessary to confirm these findings and to delineate the pharmacotherapeutic profile of TKS. PMID- 11602031 TI - Analysis of neurosteroid levels in attention deficit hyperactivity disorder. AB - Neurosteroids are important neuroactive substrates with demonstrated involvement in several neurophysiological and disease processes. Attention deficit hyperactivity disorder (ADHD) has been associated with dysregulation of the catecholaminergic and serotonergic systems, however its relationship to irregularities or changes in neurosteroid levels remains unknown. We examined the relationship between blood levels of dehydroepiandrosterone (DHEA), its principal precursor pregnenolone and its principal metabolite dehydroepiandrosterone sulphate (DHEAS) in 29 young male subjects aged 7-15 years with DSM-IV criteria of ADHD. Subjects were evaluated by a specially designed scale, following which patients were divided into two groups according to severity of symptomatology. Results indicated significant inverse correlations between clinical symptomatology and levels of DHEA and pregnenolone in the total group. These inverse correlations were particularly evident in the less severe group of subjects. Levels of DHEA and DHEAS were inversely correlated with the hyperactivity subscale. Furthermore, using median blood levels as a cut-off indicator, higher blood levels of DHEA and DHEAS were associated with fewer ADHD symptoms, in particular hyperactivity symptomatology. Our findings suggest a possible protective effect of various neurosteroids on the expression of ADHD symptomatology. PMID- 11602032 TI - Effect of electroconvulsive therapy in repetitive transcranial magnetic stimulation non-responder MDD patients: a preliminary study. AB - The aim of this study was to measure the effectiveness of ECT in-patients who had failed to respond to a course of repetitive transcranial magnetic stimulation (rTMS) treatment. Seventeen patients with severe MDD who had not responded to a course of rTMS were switched to receive ECT treatments. All the patients were assessed with the Hamilton Rating Scale for Depression, the Global Assessment Functioning Scale, the Global Depression Scale, and the Pittsburgh Sleep Quality Index. Response to the treatment was defined as a 50% decrease in HDRS final score and a final GAS higher than 60. Seven out of 17 patients responded to ECT. Three out of 5 non-psychotics and 4 out of 12 psychotic patients responded. ECT seems to be an effective treatment for 40% of patients who failed to respond to rTMS treatment. Whether this is a result of reduced responsiveness to ECT in rTMS resistant patients or a consequence of small sample size requires further study. PMID- 11602033 TI - Association study of the serotonin transporter gene polymorphism in obsessive compulsive disorder. AB - The hypothesis implicating the serotonergic system in the pathophysiology of obsessive-compulsive disorder (OCD) is supported by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). Since SSRIs act on the serotonin transporter (5-HTT), it has been suggested that the 5-HTT gene (SCL6A4) could be a good candidate for OCD. The SCL6A4 gene has a 44-bp insertion/deletion polymorphism in its promoter region (5-HTTLPR). Previous studies have revealed an association between OCD and the l allele. We analysed the 5-HTTLPR polymorphic system in 115 Mexican OCD patients and 136 controls. No significant association was found between l allele and OCD (chi2 = 1.54, d.f. = 1, p = 0.21). Furthermore, we assessed alternative methods that employ family-based designs in a sample of 43 trios. Haplotype-based haplotype relative risk and transmission disequilibrium analysis did not show a preferential transmission of l allele to OCD probands. Our results indicate the need to analyse larger samples using family-based methods. PMID- 11602034 TI - Lack of association between GABRA3 and unipolar affective disorder: a multicentre study. AB - Available data on gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in the brain GABAergic system activity contributes to vulnerability to affective disorders (AD), including bipolar disorder (BPAD) and unipolar disorder (UPAD). The localization of the alpha3 subunit GABA receptor (GABRA3) gene in Xq28, a region of interest for BPAD suggests that GABRA3 may be a relevant candidate gene. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentre UPAD case control sample [UPAD (n = 106), controls (n = 212)]. Our negative results suggest that GABRA3 does not confer susceptibility nor is it in linkage disequilibrium with another close gene involved in the genetic aetiology of UPAD. PMID- 11602035 TI - Social anxiety disorder in review: two decades of progress. AB - Social anxiety disorder (SAD) is among the most common of all psychiatric disorders. It presents with a lifetime prevalence rate of up to 16% in the general population and, like other anxiety disorders, is more frequent in women. Patients with SAD suffer from considerable psychiatric comorbidity that is often preceded by social anxiety. Social anxiety affects people early in life and provokes a great deal of impairment and cost, much being related to the under recognition and/or under-treatment of this disorder, which occurs frequently with GPs and others specialists. There is a clear need among GPs for training and awareness about the existence of this disorder, its assessment, differential diagnosis and available treatments. In this paper we review the development of the concept of SAD and its epidemiology, and discuss the available information regarding cost and how SAD presents in primary-care settings. Potential aetiologies and studies concerning possible neurobiological mechanisms are also reviewed. Pharmacological and psychosocial treatments for SAD are examined and effect sizes calculated for placebo-controlled pharmacological studies of five medication categories. PMID- 11602036 TI - The pharmacology of human working memory. AB - Experimental studies conducted primarily on non-human primates have begun to address the anatomical and neurochemical correlates of working memory. There is an associated growing body of experimental literature investigating whether modulating key neurotransmitters can facilitate working memory in humans. This paper reviews evidence that acute modulation of dopamine in particular, but also noradrenaline, acetylcholine and serotonin may influence working-memory performance in humans. Differences in neurochemical specificity with regard to stages of working memory, type of working memory (spatial or non-spatial) and cortical effects are also discussed. This evidence has contributed to neuropharmacological understanding of working memory in humans. The important therapeutic consequences of a better understanding of facilitation of working memory is discussed in reference to schizophrenia, Parkinson's disease and Alzheimer's disease. PMID- 11602037 TI - Electroconvulsive therapy in the era of modern psychopharmacology. AB - Fifty years of advances in the pharmacotherapy of major depression (MDE), mania, schizophrenia, and other severe and persistent psychiatric disorders have neither made ECT obsolete nor unnecessary. However, advances in pharmacotherapy have radically changed the practice of ECT. ECT is rarely a first-line treatment of mental disorder, unless the clinical situation is desperate. Otherwise, ECT is most often offered to persons who have failed to respond to pharmacotherapy, thus defining a relatively treatment-refractory population for ECT. The physician who refers patients for ECT, as well as the ECT provider, must be able to judge at what point a patient is deemed "medication resistant", implying expertise in pharmacotherapy for both the referring physician and the ECT provider. Authoritative sources from 20 years ago quoted antidepressant response rates > or = 90% for ECT, but the antidepressant response rate in medication-resistant MDE may be only 60%. Improvements in the safety of ECT have resulted in the referral of large numbers of older persons for ECT. High relapse rates after ECT are perhaps the biggest problem presently facing patients and providers. High relapse rates are not surprising given that (i) most patients are medication resistant, and (ii) ECT is usually withdrawn at the moment it becomes effective. Although continuation/maintenance ECT is an option in preventing relapse, it may not be a practical solution for persons still in their productive years, and it is resource-intensive. Still, continuation/maintenance ECT is the only method to prevent relapse and recurrence of severe psychiatric disorder for some persons. PMID- 11602040 TI - Thrush and fever as markers of immune competence in the era of highly active antiretroviral therapy. AB - The presence of clinical manifestations of HIV-1 infection is one measure of immune function failure. We examined the occurrence of clinical manifestations of HIV-1 infection, in particular fever and oral thrush, before and after the initiation of highly active antiretroviral therapy (HAART). Using data collected from 645 participants in the Multicenter AIDS Cohort Study (MACS) who used HAART, 7517 person-visits from January 1992 through March 2000 were stratified by time relative to HAART initiation (> or =1 year preinitiation, <1 year preinitiation, >1 year postinitiation, and > or =1 year postinitiation) and CD4+ T cell count (< or =100, 101-200, 201-350, and >350 cells/microl). Multivariate logistic regression was used to assess the relationship between HAART, CD4+ T cell count, and each self-reported symptom (oral hairy leukoplakia, diarrhea, fever, and oral thrush). After initiation of HAART, clinical manifestations of HIV-1 infection continued to occur and, similar to patterns seen before HAART, were more likely at lower CD4+ T cell counts than at higher (p < 0.001). Except for diarrhea, symptoms did not occur more frequently after HAART. Rather, beyond 1 year after initiation of HAART, there was less oral thrush even at the same CD4+ T cell count. These results provide evidence that increases in CD4+ T cell count due to HAART represent a reconstitution of immune function. PMID- 11602041 TI - HIV type 1 non-B subtype prevalence in Spain, 1997-1998. AB - We have evaluated the prevalence of HIV-1 non-B subtypes in Spain by means of an enzyme immunoassay (EIA) for discrimination between B and non-B subtypes. Samples were obtained from newly diagnosed patients attended at internal medicine outpatient clinics between October 1997 and October 1998. Discrimination between HIV-1 B and non-B subtypes was carried out by means of the EIA, with V3 synthetic peptides specific to the different subtypes. Non-B-serotyped samples were genetically analyzed in the gp41 region from the original sera. During the study period, 909 samples were collected from 21 medical units located in various Spanish geographical regions. Serotyping was possible in 885 cases, of which 791 were assigned as B serotype (89.38%), 70 showed no reactivity to any of the peptides (7.91%), and the remaining samples displayed other reaction patterns (2.72%). Of the 94 non-B-assigned samples, 65 were genetically characterized in the gp41 region of the env gene: 55 were B subtype, 5 were A subtype (4 clustered with CRF02AG reference strains), 3 were C subtype, and 2 were G subtype. The prevalence rate for non-B subtypes in Spain was established at 1.13% (95% CI, 0.59-2.21). Although the B subtype is predominant in the Spanish population, other subtypes have been detected. PMID- 11602042 TI - Emergence of drug resistance mutations in a group of HIV-infected children taking nelfinavir-containing regimens. AB - HIV-1-infected children are often treated with therapy regimens including protease inhibitors (PIs). We monitored the virologic response in a small group of pediatric patients undergoing therapy with regimens including the PI nelfinavir and determined whether new drug resistance mutations were present immediately after virologic failure. Seventeen reverse transcriptase inhibitor (RTI)-experienced children starting nelfinavir-containing therapy regimens were studied. After virologic failure, HIV-1 protease (PR) and RT sequences were examined for drug resistance mutations. Viral load levels decreased to <400 HIV RNA copies/ml in six patients and remained at <400 HIV RNA copies/ml in four patients. Three patients did not respond virologically; all three had mutations specific for one or more of their regimen drugs either before or soon after nelfinavir initiation. The virologic response was transient in eight patients whose viral loads did not decrease to <400 HIV RNA copies/ml. Genotypic data from seven of the eight patients revealed mutations specific for one or more of their regimen drugs after virologic rebound. PI resistance mutations occurred in eight patients: D30N in six, and L90M in three. In three patients, the only new mutation after failure was the RT mutation M184V. Despite virologic failure, sustained increases in CD4+ lymphocyte counts were noted in eight patients. We conclude that in this small group of pediatric patients, virologic failure occurred in all patients whose viral loads did not become undetectable after the switch to a nelfinavir-containing regimen. After failure, new drug resistance mutations were found in either PR or RT. Studies of larger cohorts are warranted to determine whether HIV-1 genotypic data can help in the formulation of effective salvage therapies in children. PMID- 11602043 TI - Expression of P-glycoprotein and multidrug resistance-associated protein in healthy volunteers and HIV-infected patients. AB - Increased expression of the multidrug efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) has been suggested as a potential mechanism for decreased drug availability at certain intracellular sites that provide sanctuary for HIV. Here we investigate the expression of these transporters in peripheral blood mononuclear cells (PBMCs) of HIV-infected patients and healthy volunteers. Venous blood (30 ml) was taken from healthy volunteers (n = 21) and HIV-infected patients (n = 21; 4 antiretroviral drug naive, 17 antiretroviral drug experienced). PBMCs were isolated and fixed. To assess P-gp expression, PBMCs were incubated with an isotype control antibody or an antibody directed to an external epitope of P-gp (UIC2). To assess MRP expression, cells were permeabilized before incubation with either a control antibody or an antibody directed to an internal epitope of MRP (MRPm5). After washing, a secondary phycoerythrin-bound antibody was incubated. After additional wash steps, samples were fixed and analyzed by flow cytometry. The median fluorescence intensity of 5000 events was recorded. Results are expressed as fold increase between isotype control and UIC2/MRPm5 samples. Expression of P-gp in HIV-infected patients (1.42 +/- 0.36) was significantly lower (p = 0.0021; 95% CI, -0.633 to -0.164) than in healthy volunteers (1.82 +/- 0.55). However, MRP expression was similar in HIV-infected patients (1.37 +/- 0.34) and healthy volunteers (1.37 +/- 0.21; p = 0.91; 95% CI, -0.148941 to 0.165191). We conclude that in HIV infection, P-gp expression in total PBMCs is reduced whereas MRP expression appears to be unaltered. PMID- 11602045 TI - Stepwise deletion of the HIV type 1 glycoprotein 41 N terminus leads to an increasing export of microvesicles containing uncleaved Env glycoprotein. AB - Deletion of two or more amino acid residues from the N terminus of HIV-1 gp41 leads to an increasing loss of cleavability of the envelope (Env) precursor on introduction of an env-expressing vector into HeLa-T4+ cells. In protein analysis, this is paralleled by the appearance of a second form of uncleaved Env precursor that is terminally sialylated. Cell-derived microvesicles that preferentially incorporate this form of Env precursor were found in the culture medium. The same applies to a mutant with a nonfunctional cleavage site, indicating that a pathway by which uncleaved Env glycoprotein leaves the cell exists. The amount of exported glycoprotein is augmented as compared with wild type Env. Transfection with a wild-type Env-expressing vector leads to the presence of extracellular microvesicles that contain only the transmembrane domain of HIV-1 Env. Microvesicles derived from wild-type Env and mutant Env contain sialylated glycoproteins that are resistant to exo- and endoglycosidase treatment unless the particles have been previously lysed by detergent. This raises the possibility that the C-terminal domains of the glycoproteins are exposed on the surface of the exported microvesicles. PMID- 11602044 TI - Immunologic and virologic analyses of an acutely HIV type 1-infected patient with extremely rapid disease progression. AB - The immunologic and virologic factors that impact on the rate of disease progression after acute infection with human immunodeficiency virus (HIV) type 1 are poorly understood. A patient with an extraordinarily rapid disease course leading to AIDS-associated death within 6 months of infection was studied intensively for the presence of anti-HIV immune reactivities as well as changes in the genetic and biologic properties of virus isolates. Although altered humoral responses were evident, the most distinctive immunologic feature was a nearly complete absence of detectable HIV-specific CTL responses. In addition to a rapid decline in CD3+CD4+ cells, elevated percentages of CD8+CD45RA+ and CD8+CD57+ cells and diminished CD8+CD45R0+ and CD8+CD28+ cells were evident. Primary viral isolates recovered throughout the course of infection exhibited limited sequence diversity. Cloned viral envelopes were found to have unusually broad patterns of coreceptor usage for cell-cell fusion, although infectivity studies yielded no evidence of infection via these alternative receptors. The infectivity studies demonstrated that these isolates and their envelopes maintained an R5 phenotype throughout the course of disease. The absence of demonstrable anti-HIV CTL reactivities, coupled with a protracted course of seroconversion, highlights the importance of robust HIV-specific immune responses in the control of disease progression. PMID- 11602046 TI - Gammadelta T cell activation by chronic HIV infection may contribute to intrahepatic vdelta1 compartmentalization and hepatitis C virus disease progression independent of highly active antiretroviral therapy. AB - HIV and hepatis C virus (HCV) coinfection is frequently associated with rapid progression of HCV-related disease, resulting in a higher risk of cirrhosis. Data suggest that natural T cells expressing the Vdelta1 T cell receptor rearrangement are recruited in the liver of chronically HCV-infected patients and are increased in the peripheral blood of HIV-infected persons. We studied gammadelta T cell distribution in the peripheral blood and liver of HCV-infected and HIV/HCV coinfected patients in the presence and absence of antiretroviral therapy. We observed that Vdelta1+ T cells releasing helper T cell type 1 cytokines are compartmentalized not only in the liver of HCV+ patients, but also of HIV/HCV coinfected persons. HIV/HCV patients showed an increased frequency of both peripheral and intrahepatic Vdelta1 natural T lymphocytes, resulting in a higher degree of hepatic inflammation when compared with patients with other liver diseases. Finally, highly active antiretroviral therapy (HAART) was unable to restore Vdelta1T cell circulation to normal levels in chronically HIV-infected persons. We conclude that gammadelta T lymphocytes released from tissue to the bloodstream circulation under the influence of chronic HIV infection may contribute to intrahepatic Vdelta1 compartmentalization and progression of liver disease, independently of HAART. PMID- 11602047 TI - Downregulation of major histocompatibility class I on human dendritic cells by HIV Nef impairs antigen presentation to HIV-specific CD8+ T lymphocytes. AB - The HIV early regulatory Nef protein downregulates surface expression of major histocompatibility class I (MHC I) molecules on various immortalized cell lines and on T lymphocytes. MHC I-restricted presentation induces CD8+ T cell responses, which have a major role in limiting HIV infection. Induction of primary immune responses requires dendritic cells, which are major candidates as the first cells that can internalize the virus and present it to T cells in mucosal contamination. To test the effect of Nef on MHC I-restricted antigen presentation by dendritic cells, we used recombinant vaccinia viruses. Flow cytometric analysis of double labeling for a vaccinia protein and MHC I showed that HIV-1 Lai Nef indeed downregulated MHC I surface expression on dendritic cells. MHC I-restricted presentation to a Nef-specific CD8+ cell clone from an infected patient was decreased in an interferon gamma ELISpot assay. Presentation of a reverse transcriptase epitopic peptide on sorted Nef-infected cells was decreased in a peptide concentration-dependent way, confirming the role of MHC I downregulation in the impairment of the CD8+ cell-specific response. Therefore, Nef downregulates MHC I surface expression on human dendritic cells, impairing presentation to HIV-specific CD8+ cells. This action of Nef probably induces a deleterious delay in the early CD8+ responses during the first days of infection and at the onset of new viral mutants. PMID- 11602048 TI - [Construction of a dicistronic expression plasmid vector containing double-valent hepatitis B surface gene]. AB - OBJECTIVE: In order to enhance vaccine response, we constructed a dicistronic expression plasmid containing double HBsAg immunogenes. METHODS: At first, pcDNA3.1 plasmid vector was digested with NheI and EcoRI to get the coding sequence of the small (S) surface protein of HBV, then cloned into pCI-neo vector and named it pCI-S. By PCR amplification, the product of IRES-S was digested with SalI & BamHI, and cloned into pBluescript IIK+S to generate pBKS-IRES-S vector, then subcloned to the pCI-S plasmid to generate pCI-S-IRES-S, which is a dicistronic plasmid of double value HBsAg genes. RESULTS: Two plasmids we constructed were digested with related restriction nucleic enzymes. Sequence analysis of HBsAg and IRES-S gene did not reveal any mutation. CONCLUSIONS: The construction of dicistronic plasmid of divalue HBsAg immunogenes has been well cloned, which is convenient for further research on cell expression and gene immunization in animals. PMID- 11602049 TI - [Experimental study on the effect of combination therapy with lamivudine and famciclovir against duck hepatitis B virus in vivo]. AB - OBJECTIVE: To study the antiviral effect of combination therapy with the nucleoside analog lamivudine and famciclovir on duck hepatitis virus (DHBV) in vivo. METHODS: The Chongqing duck hepatitis B model was treated with lamivudine and famciclovir by intragastric administration for 4 weeks. DHBV DNA and DHBsAg in serum were observed by serum dot-blot hybridization and ELISA. ALT and AST in serum were also detected. Histological observation on the duck liver was done simultaneously. The trial was contrasted with a single acyclovir (ACV), famciclovir (FCV), or Lamivudine (3TC). RESULTS: Combination therapy with Lamivudine and famciclovir could significantly reduce the serum DHBV DNA level. After stopping the treatment for 1 week, serum DHBV DNA level did not return significantly. The change of DHBsAg was similar to DHBV DNA. The level of ALT, AST, and the features of liver histopathology in combination-treated ducks were not different from those in control ducks. CONCLUSIONS: The study confirms that combination therapy is superior to single antiviral agent in vivo for ducks with chronic DHBV carrier. PMID- 11602050 TI - [Treatment of severe hepatitis with artificial liver support system and liver transplantation]. AB - OBJECTIVE: To observe and investigate the efficacy of the hybrid artificial liver support system plus liver transplantation in the treatments of patients with severe viral hepatitis. METHODS: Eight severe viral hepatitis patients with metaphase and advanced stage liver failure received the artificial liver support using a self-command extracorporeal hybrid artificial liver support system and orthotopic liver transplantation after the artificial support for 3-14 days. RESULTS: The liver failure of the 8 patients was controlled by the hybrid artificial liver support effectively. All patients were successfully bridged to orthotopic liver transplantation. Four out of the eight patients survived after transplantation. Four patients died of pulmonary infection or hepatorenal syndrome. CONCLUSIONS: Artificial liver support system combined with liver transplantation can be regarded as an efficient measure for the treatment of metaphase and advanced stage patients of severe viral hepatitis. PMID- 11602051 TI - [HCV core protein activates expression of vascular endothelial growth factor in HepG(2) cells]. AB - OBJECTIVE: To explore the effect of HCV core protein on vascular endothelial growth factor (VEGF) in HepG(2) cells. METHODS: The HCV core gene cDNA was recoverd by PCR, and cloned into PBK-CMV. The recombinant plasmid (PBK-HCVc) and the vector-alone were transfected into HepG(2) cells with liposome. After being selected with G418,resistant colonies were obtained. The reverse transcription PCR and Western blot was analyzed to show HCV core protein expression. VEGF was analyzed by immunohistochemical and Western blot; VEGF mRNA was analyzed by in situ hybridization and reverse transcription PCR. RESULTS: The results suggest that the recombinant plasmid could express HCV core protein efficiently under the control of vector's promoter. The VEGF of HepG(2)-C cells was higher than that of HepG(2)-CMV. CONCLUSIONS: HCV C protein can activates the expression of VEGF in HepG(2) cells and may contributes to viral carcinogenesis. PMID- 11602052 TI - [Screening and characterization of human phage antibody to hepatitis C core antigen]. AB - OBJECTIVE: To screen and characterize human phage antibody (ScFv) against hepatitis C core antigen. METHODS: The recombinant phages were panned by core antigen that was coated in a microtiter plate. After three rounds of biopanning, 48 clones were determined specific to core antigen. The specificity of each ScFv colone was determined by ELISA. The coding gene for HCV protein ScFv has been sequenced. RESULTS: Phage antibody for HCV core protein had a specific combination character with core antigen of hepatitis C virus. The DNA sequence data showed that the ScFv gene included 774 bp. CONCLUSIONS: Human single chain antibody to hepatitis C core antigen has been identified by means of the phage display technology. PMID- 11602053 TI - [Genetic variation of the core and E1 region of hepatitis C virus in serum collected from patients with chronic hepatitis]. AB - OBJECTIVE: To study the association of the core and E1 region variation of hepatitis C virus (HCV) with the chronicity of HCV infection. METHODS: Acute phase plasma samples from two drug-injection users who acquired HCV infection during six-month follow-up and ten patients with chronic hepatitis C were obtained. A 1-kb fragment containing the 3' half of core, completed E2 and 3' half of E2 were amplified by nested reverse transcription polymerase chain reaction (RT-PCR). For each 30 cloned cDNAs were examined by a method that combined heteroduplex (HD) analysis and a single-stranded conformational polymorphism (SSCP) assay to assess quasispecies complexity and optimize selection of clones with unique gel shift patterns for sequenceing. Amino acid sequences were analyzed for signature patterns and glycosylation signals. RESULTS: There was obvious difference between the SSCP bands of cloned cDNAs representing core-E1 region, but not obvious distance between heteroduplexes and the homoduplex. There was no change in the sequence of each clonotype from acutely HCV-infected subjects, whereas the rate of nonsynonymous substitution was 1.32% in amino acid sequence of E1 from persistently HCV-infected subjects with except for functional patterns. CONCLUSIONS: The variation of the E1 gene of HCV is in the presence of quasispecies population but might not related with its immunologic escape. PMID- 11602054 TI - [Studies on mimotopes of hepatitis C virus E1 protein]. AB - OBJECTIVE: To study the B-cell epitope of E1 protein of hepatitis C virus. METHODS: By induction of IPTG, the E.coli M15 strains harboring the pQE30-HCVe118 expressed truncated C-terminal HCV E1 protein (Pte1). The proteins were purified with preparative electrophoreses system, which captured anti-E1 IgG in HCV (+) sera. By applying the antibodies as selective molecular 12 mers random peptide libraries were panned, and positive clones were obtained by ELISA. Amino acid sequences of display peptide were compared with that of HCV E1 protein. RESULTS: The purified HCV E1 proteins could react specifically with partly anti-HCV sera by ELISA. Among 10 phage display peptides, 6, 6, 2 were the most homologous to HCV E1 protein at position 320-336aa, 251-263aa, 225-248, respectively. CONCLUSIONS: There exist multiple B-cell epitopes in HCV E1 protein. At least one preponderant epitope is mapped at residues 320-336 of HCV E1 protein. PMID- 11602055 TI - [Expression of neural cell adhesion molecule in murine livers with experimental autoimmune hepatitis]. AB - OBJECTIVE: To investigate the expression of neural cell adhesion molecule (NCAM) in murine livers with experimental autoimmune hepatitis (EAH) and its relationship with histological grades. METHODS: To induce the EAH model, the syngeneic S-100 antigen emulsified in complete Freud's adjuvant was injected intraperitoneally to C57Bl/6 at day 1 and day 7. The mice were sacrificed at day 7, 14, and 21 after the first immunization. The expression of NCAM was observed using histoimmunochemistry and RT-PCR. RESULTS: The expression of NCAM increased gradually with aggravation of lymphocyte infiltration and hepatocyte injury. The administration of prednisolone decreased the histological grade, and inhibited the expression of NCAM. There was a correlation between the expression of NCAM and histological grade (r=0.71, P<0.01). CONCLUSIONS: NCAM provides a traffic signal for infiltration of lymphocytes in the liver, hence induces the injury of hepatocytes. PMID- 11602056 TI - [Adenovirus-mediated transfer of human wild-type p53, GM-CSF, and B7-1 genes efficiently produces growth suppression and apoptosis of hepatocellular cells in vitro]. AB - OBJECTIVE: To investigate the tumor suppressor activity of recombinant adenovirus vector expressing the human wild-type p53, GM-CSF, and B7-1 proteins (designated as BB-102) in human hepatocellular carcinoma cells (HCC) in vitro. METHODS: The wild-type p53 BEL-7402, mutant p53 HLE, and HuH-7 HCC cell lines were infected with BB-102 at MOI of 50 in vitro. Immunohistochemical assay was used to determine p53 expressed by BB-102. Tumor suppressor activity of the expressed p53 was identified by terminal deoxynucleotidy I transferase (TdT) assay in BB-102 infected HCC cell lines. RESULTS: p53 protein was found to express in a dose dependent manner in BB-102-infected HCC cell lines. The proliferation of HCC cell lines were suppressed significantly at the average rates of 58.5%, 81.5%, and 71.1% for BEL-7402, HLE, and HuH-7 respectively from 4 to 10 days, accompanying inducing apoptosis in BB-102-infected HCC cell lines. CONCLUSIONS: Besides the expression of B7-1 and GM-CSF, BB-102 is able to express p53 protein in independent manner and exerts its anti-tumor activity, which suggests that BB-102 may be useful for gene therapy against HCC in vivo. PMID- 11602057 TI - [Effects of nitric oxide and prostaglandin on gastric mucosal perfusion in rats with portal hypertensive gastropathy]. AB - OBJECTIVE: To observe the effects of nitric oxide (NO) and prostaglandin on gastric mucosal perfusion in rats with portal hypertensive gastropathy (PHG). METHODS: Two weeks after partial portal vein ligation, gastric mucosal blood flow (GMBF) was measured with the neutral red clearance method and the changes of portal venous pressure (PVP) were observed. RESULTS: GMBF and PVP were significantly higher in rats with PHG than in sham operated rats (P<0.01). Low dose inhibitor of NO synthesis N(-nitro-L-arginine methyl ester (L-NAME 1mg/kg, 4mg/kg) caused a significant and dose dependent reduction in GMBF in PHG rats, but had no effect on sham operated rats. High dose L-NAME (12 mg/kg) significantly decreased GMBF in both PHG and sham operated rats. The inhibition of prostaglandin synthesis with indomethacin significantly decreased GMBF in rats with PHG, but had no effect in sham operated rats. In sham operated rats pretreated with indomethacin, GMBF was not modified after and before injection of low dose L-NAME (4mg/kg); likewise, high dose of L-NAME (12mg/kg) did not alter the significant reduction in GMBF as compared with pretreatment without indomethacin. In PHG rats the significant dose dependent reduction in GMBF induced by L-NAME (4mg/kg, 12mg/kg) was not significantly different between pretreatment with and without indomethacin. CONCLUSIONS: NO and prostaglandins play an important role in the regulation of GMBF in rats with PHG, but no synergistic interactions between them. PMID- 11602058 TI - [Effects of emodin on hepatic fibrosis in rats]. AB - OBJECTIVE: To investigate the effect of emodin on hepatic fibrosis in rats and study its possible mechanism. METHODS: The rat hepatic fibrotic model was induced by the subcutaneous injection of 40% CCl(4) (twice a week for 6 weeks). The fibrotic rats were treated with low-dose, mediate-dose and high-dose emodin (20, 40 and 80 mg/kg body weight, once a day for 42 days). Liver function, serum hyaluronic acid, laminin, and liver hydroxyproline were determined, Histopathological changes were examined by optical microscopy. The expression of alpha-smooth muscle actin (alpha-SMA) in liver tissue were detected by immunohistochemical techniques. RESULTS: Compared with model group, it revealed that in emodin-treated rats: (1) Liver functions was improved, alanine transaminase (ALT) and alkaline phosphatase (AKP) obviously reduced (P<0.05 or <0.01), total protein (TP) and albumin (ALB) significantly increased (P<0.05 or <0.01). (2) Serum hyaluronic acid and laminin markedly reduced (P<0.05 or <0.01). (3) Liver hydroxyproline were significantly decreased (P<0.05 or <0.01). (4) The degrees of fibrosis were reduced (P<0.05). (5) The expression of alpha-SMA in liver tissue were ameliorated. CONCLUSIONS: Emodin has an effect on hepatic fibrosis in rats. The effect may be related to slowing hepatocyte injury and inhibiting liver alpha-SMA expressions. PMID- 11602059 TI - [The effect of p53 gene on p-glycoprotein expression and chemotherapeutic cytotoxicity of hepatocellular carcinoma]. AB - OBJECTIVE: To test the hypothesis that wild-type p53 regulates the expression of p-glycoprotein. METHODS: Hep3B cells which lack the expression of both p53 and retinoblastoma tumor suppressor genes because of deletions, were transfected with a wild-type (wt) p53 cDNA and control vector by a liposome method. RESULTS: After G418 selection, stable wt-p53 transformants and control vector transformants (pNeo) were obtained. Northern and Western blot analysis determined the expression of p53 mRNA and protein in wt-p53 transformants, respectively. In wt p53 transformants, induction of transcriptionally active p53 was confirmed by the increase of P21(waf1/cip1) protein. Levels of P-gp reduced in the cells expressing wild-type p53 were linked to wt-p53 activity. Cytotoxicity assays revealed that the wt-p53 transfectants were more sensitive to doxorubicin and mitomycin compared with the pNeo transformants. Flow cytometry showed that the accumulation of doxorubicin in wt-p53 transfectants was as 13 times as that of the pNeo transformants. CONCLUSIONS: Restoration of wt-p53 activity in Hep3B leads to sensitiveness to chemotherapeutic agents because of the decrease of p glycoprotein expression. PMID- 11602061 TI - Nutritional interventions to reduce cardiovascular disease: individual versus population perspectives. PMID- 11602060 TI - [Quantitative assay of metabolic rate of para-aminobenzoic acid combining glycine for the assessment of rabbit liver function]. AB - OBJECTIVE: To evaluate liver function by the assessment of the capacity of glycine combining para-aminobenzoic acid (PABA) to form hippuric acid in rabbits with acute liver injury. METHODS: Thirty rabbits were randomly divided into two groups: experiment group (n=20) received D-galactosamine to be subject to acute liver necrosis, and control group (n=10) received saline as placebo. Serum concentrations of PABA, para-aminohippuric acid (PAHA), para-acetamidobenzoic acid (PAABA), and para-acetamidohippuric acid (PAAHA) were measured by high pressure liquid chromatography (HPLC). RESULTS: Compared with control group, the serum concentrations of PAHA and PAAHA were significantly reduced in experimental group, which were correlated with the degree of liver injury. CONCLUSIONS: The metabolic rate of glycine combining PABA is a sensitive index for quantitative test of liver function and assessment of acute liver necrosis. PMID- 11602062 TI - Antioxidants blunt high-density lipoprotein response to statin plus niacin therapy. PMID- 11602063 TI - Mediterranean diets and cardiovascular disease. AB - Coronary heart disease remains the leading cause of death in the Western world. Among these countries, however, there is a marked discrepancy in the prevalence of heart disease in spite of similar traditional risk factor profiles. This is undoubtedly due to differences in lifestyle, the most important of which are diet and exercise. Both epidemiologic data and clinical trials suggest that the beneficial impact of specific dietary and lifestyle changes on cardiac event rates could be greater than that achieved by any of the drug or revascularization trials to date. PMID- 11602064 TI - Effect of diet on vascular reactivity: an emerging marker for vascular risk. AB - New technology for studying vascular activity in vivo has shown that the endothelium plays a critical role in the development of atherosclerosis. The healthy endothelium is a metabolically active tissue that exquisitely regulates vascular tone via release of the powerful vasodilator, nitric oxide. Endothelial integrity reduces cell adhesion, lipid deposition, and other early steps in atherogenesis. There is compelling evidence that endothelial function can be altered within hours of eating certain foods, further affirming the role of dietary factors in the prevention and progression of cardiovascular disease. This article reviews recent work on dietary factors (fatty acids, L-arginine, antioxidants, polyphenols, and folic acid) that alter vascular tone, and critically evaluates two noninvasive measures (flow-mediated dilation and total peripheral resistance) for use in dietary intervention trials. PMID- 11602065 TI - Effects of the glycemic index of foods on serum concentrations of high-density lipoprotein cholesterol and triglycerides. AB - The role of carbohydrates in cardiovascular disease prevention has garnered increasing attention due to accumulating evidence showing deleterious effects of low-fat, high-carbohydrate diets on serum triglycerides and high-density lipoprotein (HDL) cholesterol. Researchers argue that classifying carbohydrates based on their capacity for increasing blood glucose (termed the glycemic index ) is a useful tool for elucidating the effects of carbohydrate-rich foods on glucose and lipid metabolism. Several epidemiologic reports show that lower dietary GI is associated with lower serum triglycerides and higher HDL cholesterol. Results from intervention studies show that substituting low-GI for high-GI foods in a low-fat, high- carbohydrate diet lowers serum triglycerides by 15% to 25%. The available evidence to date suggests that the glycemic index of foods will be an important factor in future dietary prevention research. PMID- 11602066 TI - Recent findings in the study of postprandial lipemia. AB - The study of postprandial metabolism is in the early stages compared with other areas of atherosclerosis research. Recent advances in postprandial research have included improvements in methodology and the investigation of factors that modulate the lipemic response to a meal. Enough studies have now been performed that normal ranges have been identified for blood triacylglycerol (TAG) concentrations that occur after a healthy patient consumes a standardized-mixed meal or a high-fat shake designed to elicit lipemia. Typical postprandial concentrations of other metabolites, such as apolipoproteins B48 and B100 or gastrointestinal hormones (eg, cholecystokinin), have not been studied sufficiently to be able to qualify what represents a standard postprandial response. The method of data analysis is also a key point to consider. Data from children are now becoming available, and the specific effects of ethnicity have just begun to be explored. New areas of study include the effects of different fatty acids (monosaturates or polyunsaturates), the sources of chylomicron lipids (dietary TAG and cholesterol versus that newly synthesized in the body), and the effects of alcoholic beverages consumed with the meal. Variables that can also affect the results of a meal test are under investigation. These include the type of food that is consumed the day before the meal test, the time of day the test is performed, and the palatability of the food. Given solid evidence that delayed postprandial lipemia is an independent risk factor for coronary heart disease, future scientific investigation in the area of postprandial metabolism is likely to yield discoveries that will significantly contribute to advancements in disease treatment. PMID- 11602067 TI - Effects of dietary animal and soy protein on cardiovascular disease risk factors. AB - A growing body of research offers insight into the influence of dietary protein on cardiovascular disease (CVD) risk. Early studies in rabbits indicated that animal protein was atherogenic; however, this has not been demonstrated in other animals species (pig, primate) or humans. More recent studies have found that low fat animal protein can effectively improve some CVD risk factors. Soy protein has received much attention in recent years due to its seemingly marked effect on plasma cholesterol levels. However, further research has shown the hypocholesterolemic effect of soy protein to be most pronounced in cases of moderate to severe elevations in plasma lipids. Still, animal and soy protein sources contain a variety of bioactive components that may offer protection above and beyond cholesterol reduction. This review provides evidence that as part of a low-saturated fat diet, animal and/or soy protein intake at or above the recommended intake level of 15% of total calories lowers plasma cholesterol levels, reduces blood pressure, and potentially facilitates healthy weight management. PMID- 11602068 TI - Cardiovascular disease risk factors and atherosclerosis in children and adolescents. AB - As more is learned about the natural history of the development of atherosclerosis, it is clear that the process that results in morbidity and mortality in adults has its origins in childhood and adolescence. It is also clear that the traditional risk factors, such as hypertension and dyslipidemia, are important in the early stages of the process. It appears that the prevalence and severity of obesity are increasing in children and adolescents in the United States. This trend is associated with increasing blood pressure and the occurrence of type 2 diabetes mellitus in young individuals. These trends may result in increased cardiovascular morbidity and mortality as these overweight pediatric patients become obese adults. Intervention and prevention strategies should be directed at the pediatric population as a whole, as well as at higher risk individuals. For the latter, it will be necessary to identify those at highest risk. Both nonpharmacologic and pharmacologic approaches may be necessary for treatment of pediatric patients with hyperlipidemia and hypertension. Studies are needed that evaluate the longer-term impact of intervention on cardiovascular risk factors in young patients. PMID- 11602070 TI - Innovative approaches to comprehensive cardiovascular disease risk reduction in clinical and community-based settings. AB - We have developed, tested, and successfully implemented an affordable, evidence based, comprehensive cardiovascular disease risk-reduction program for use in primary and secondary prevention settings. The program is administered at hospitals, physician practices, cardiac rehabilitation programs, work sites, shopping malls, and health clubs. The program is also delivered from a call center using the telephone and the Internet. Program staff are guided by a computerized participant management and tracking system. Lifestyle management interventions are based on several behavior change models, primarily social learning theory, the stages of change model, and single concept learning theory. Typically, the program is administered entirely by non-physician healthcare professionals whose services are integrated with the care provided by the participants' physicians. Outcome data have documented the clinical effectiveness of this innovative approach. PMID- 11602071 TI - Diet and drug therapy: a dynamic duo for reducing coronary heart disease risk. AB - A large proportion of the United States population requires aggressive low density lipoprotein (LDL) cholesterol- lowering therapy to meet the new treatment guidelines established by the National Cholesterol Education Program Adult Treatment Panel III. This has further widened the gap between the number of people being treated compared with those who should be treated. Moreover, many people being treated do not meet their LDL cholesterol goal. Diet and healthy lifestyle practices remain the cornerstone of treatment to lower LDL cholesterol. Pharmacologic therapy has assumed an increasingly important role in reaching LDL cholesterol goals. Diet and healthy-lifestyle interventions have been shown to augment the benefits of cholesterol-lowering drugs. Together, this dynamic duo provides the most effective clinical means identified to date for maximally lowering LDL cholesterol levels. PMID- 11602072 TI - The 10 most important advances in cardiovascular medicine during the past 50 years, with apologies to David Letterman. PMID- 11602069 TI - Prevention and treatment of childhood obesity. AB - Obesity has reached epidemic proportions among children and youth in the United States. Surveys indicate that the number of overweight children aged 6 to 17 years has doubled within three decades. In the decade between the late 1970s and the late 1980s, the prevalence of overweight increased from 7.6% to 10.9% for children aged 6 to 11 years, and from 5.7% to 10.8% for adolescents aged 12 to 19 years. Data for 1999 indicates that the epidemic is continuing to increase, so that 13% of 6- to 11-year-old children and 14% of 12- to 19-year- old children are currently overweight (body mass index > or = 95th percentile for age/gender). This article reviews newer concepts related to etiologic factors, comorbidities, and strategies for prevention and treatment. PMID- 11602074 TI - Should all implantable cardioverter defibrillators for ventricular arrhythmias be dual-chamber devices? AB - The advantages of a dual-chamber implantable cardioverter defibrillator (ICD) over a single-chamber ICD include physiologic pacing capability, atrial electrogram storage, enhanced arrhythmia discrimination algorithms, and a potential to treat atrial arrhythmia by pacing or defibrillation. Current evidence supports the supposition that dual-chamber ICDs are definitely indicated in patients who have a concomitant indication for physiologic pacing, such as bradycardia or bradycardia-dependent ventricular tachyarrhythmias. Refined dual chamber arrhythmia discrimination algorithms and enhanced atrial therapies are probably required for patients with frequent supraventricular arrhythmias. Furthermore, in patients with systolic heart failure, low ejection fraction, and intraventricular conduction delay, triple-chamber ICDs with biventricular pacing may improve their functional status and prevent sudden arrhythmic death. Careful patient selection is required to optimize the cost-effectiveness of these sophisticated technologies. PMID- 11602075 TI - Transthoracic epicardial catheter ablation to treat recurrent ventricular tachycardia. AB - Nonsurgical epicardial transthoracic catheter ablation is a minimally invasive procedure that has proven to be efficacious for the treatment of ventricular tachycardia (VT). The usefulness of this technique depends on the prevalence of epicardial circuits, which seem more frequent in Chagasic than post-myocardial infarction VT. This approach is limited by concern regarding the potential adverse effects of radiofrequency (RF) ablation on the coronary arteries. However, the effects of RF ablation delivered in the vicinity of a major coronary artery are limited to the medial artery. Severe intimal hyperplasia and intravascular thrombosis may occur only when RF ablation is delivered above the artery. Moreover, susceptibility to damage is inversely proportional to the vessel size. Coronary artery injury is an uncommon (< 1%) complication that could be prevented by a coronary angiogram prior to ablation. Hemopericardium, another predictable complication occurring in 10% of patients, can be easily controlled in the electrophysiology laboratory. PMID- 11602077 TI - Algorithms for better arrhythmia discrimination in implantable cardioverter defibrillators. AB - The discrimination of concomitant atrial tachyarrhythmias and sinus tachycardias in patients with malignant ventricular tachyarrhythmias is a major challenge for new defibrillator devices. Different algorithms have now been established to distinguish between atrial and ventricular tachyarrhythmias. Furthermore, new dual-chamber implantable defibrillators are capable of tiered atrial therapies for both regular and irregular atrial and ventricular tachyarrhythmias. The increasingly complex and subtle dual-chamber detection algorithms have proven to be safe and effective for the detection of ventricular tachycardia, and also in terms of an increase in specificity and a reduction in inappropriate ventricular therapies for supraventricular tachyarrhythmias. Stable electrode position, and a continuous and correct atrial signal quality, are prerequisites for atrial therapies and algorithms for arrhythmia discrimination. PMID- 11602076 TI - Are drugs and catheter ablation effective for treating ventricular arrhythmias in populations that cannot afford implantable cardioverter defibrillators? AB - Despite recent advances, ventricular arrhythmias continue to pose a therapeutic challenge, especially to the clinician in the developing world. Although the implantable cardioverter defibrillator (ICD) has improved survival in both primary and secondary prevention trials, it still remains a costly modality for the developing world. Even though certain subgroups stand to benefit unequivocally in survival from the ICD, there are others in whom this therapy may not offer a survival benefit over empiric antiarrhythmic drug therapy with amiodarone. The utility of optimized drug therapy (including either amiodarone or sotalol, b-blockers, and angiotensin-converting enzyme inhibitors) needs to be compared with the ICD in a randomized manner in these lower-risk patients with ventricular arrhythmias. The role of conventional catheter ablation techniques is mostly adjunctive to drugs and ICDs, although the newer mapping and ablation techniques may offer greater promise in the future. PMID- 11602079 TI - An evidence-based approach to diagnosing renovascular hypertension. AB - Making the diagnosis of potentially reversible renovascular hypertension can be problematic. Although there are a number of noninvasive screening tests available, no one study is appropriate for every patient. In general, the available tests can be divided into those that identify the functional consequences of a renal artery obstruction (angiotensin-converting enzyme inhibitor-augmented renography) and those that identify the anatomic presence of stenosis (duplex ultrasonography, magnetic resonance angiography, and contrast tomography angiography). The most appropriate diagnostic approach is based largely on the clinical index of suspicion, the potential etiology of the renal artery lesion (fibromuscular dysplasia or atherosclerosis), and the individual patient's physiology and presentation. A potential treatment algorithm is presented. PMID- 11602081 TI - Treatment of coexisting diabetes and hypertension. AB - The rapidly growing number of patients with coexisting diabetes and hypertension must be intensively treated to protect them from their very high risk for premature cardiovascular morbidity and mortality. After careful ascertainment of their out-of-the-office blood pressure, and testing for postural hypotension, therapy should consist of both lifestyle modifications and antihypertensive drugs. Usually, two or more such drugs are needed to bring blood pressure below the 130/85 mm Hg level. In addition, control of hyperglycemia and dyslipidemia is usually required. Despite the costs and difficulties of achieving adequate control of these diseases, such patients can be protected from the debilities of diabetes and hypertension. PMID- 11602080 TI - Diastolic function in hypertension. AB - Diastolic dysfunction in patients with hypertension may present as asymptomatic findings on noninvasive testing, or as fulminant pulmonary edema, despite normal left ventricular systolic function. Up to 40% of hypertensive patients presenting with clinical signs of congestive heart failure have normal systolic left ventricular function. In this article we review the pathophysiologic factors affecting diastolic function in individuals with diastolic function, current and emerging tools for measuring diastolic function, and current concepts regarding the treatment of patients with diastolic congestive heart failure. PMID- 11602082 TI - Implications of recent heart failure trials for patients with hypertension. AB - There are two major reasons why hypertension is an important risk factor for heart failure. The first is that an elevated blood pressure increases the wall stress in the left ventricle. The second is that hypertension, in a complex manner, contributes to the development of atheromatous vascular disease. Among the more common causes of heart failure are the sequelae of coronary heart disease. The treatment of hypertension modifies the progression to heart failure and the occurrence of coronary events. In patients who have heart failure, hypotension rather than hypertension is a predictor of a poor outcome, likely because low blood pressure is a consequence of damage to the myocardium. The clinical message is that hypertension should be treated aggressively. Where heart failure is a likely outcome, or where hypertension occurs in the presence of heart failure, there is a strong case for using drugs that have been shown to be beneficial in the treatment of both hypertension and heart failure. PMID- 11602084 TI - [Impact of meta-analysis in clinical practice: the example of psychiatry]. AB - BACKGROUND: To analyze the features of the studies on meta-analysis in psychiatry and assess the effect of these papers on the psychiatric reference textbooks. METHODS: Two researchers reviewed electronic databases Medline and Embase during the period 1977-98, using the key words: clinical trial, randomized observational trial, metaanalysis, systematic review. To confirm the validity of the searching strategy inter and intra-raters reliability was studied with satisfactory kappa figures. RESULTS: Psychiatry is the medical specialty in which more studies on meta-analysis have been carried out (N= 179, 11,79% out of the total), followed by cardiology and oncology. The increase in this kind of research during 1977-98 has been very high in all medical fields and, specifically, in psychiatry. There is no correlation between impact factor of a scientifical journal and number of meta-analysis published in it. Only 0.002% of the references of one of the most important textbook in psychiatry (Kaplan) are related to meta-analysis. There is no studies on meta-analysis developed by Spanish researchers. CONCLUSIONS: Studies on meta-analysis are not referred by psychiatric reference textbooks. As a consequence, their impact on clinical practice is scarce. PMID- 11602083 TI - The role of angiotensin-converting enzyme inhibitors in the treatment of hypertension. AB - Angiotensin-converting enzyme (ACE) inhibitors continue to find new uses. The Heart Outcomes Prevention Evaluation study has demonstrated their wide application as a preventive measure for patients at high risk of cardiovascular disease, but the available clinical trials in hypertensive subjects do not so far suggest any clear superiority over conventional treatment. The available trials may have been underpowered to detect non-blood pressure-related benefits on smooth muscle growth, endothelial function, left ventricular hypertrophy, and plaque rupture, when used in relatively low-risk subjects with uncomplicated hypertension. Clinical trials have also shown that two or more drugs are needed to lower blood pressure even to 140/90. Few patients have uncomplicated hypertension, so the choice of their drugs will be powerfully influenced by their other clinical problems. Nevertheless, there is a strong case for an attack on the renin-angiotensin system. Whether this will be by ACE inhibition, angiotensin II receptor blockade, or both, is the subject of current clinical trials. PMID- 11602085 TI - [Treatment with sildenafil and satisfaction with life in depressive patients with erectile dysfunction]. AB - INTRODUCTION: To evaluate the effectiveness of Sildenafil in the treatment of erectile dysfunction (ED) in patients with depression; and the satisfaction with differents aspects of life. METHODS: A multicenter, observational, prospective and non-comparative study conducted in primary care units. Effectiveness was measured by the questionnarie International Index of Erectile Function (IIEF), satisfaction with life by the Life Satisfaction Check-List (LSCL), and partner's satisfaction by Satisfaction with treatment of erectile dysfunction (EDITS). The study enrolled 330 patients with ED and Depression, treated with 50 mg (adjusted to 25/100 mg according to response) of Sildenafil for at least 10 weeks. RESULTS: The erections improved for the 84.2%. At the initial visit a 58.2% had a severe dysfunction, and at the post-treatment visit for the 41.2% of the sample, the dysfunction was light. The most important increase in the LSCL was sexual activity and partner relationship. CONCLUSIONS: Significant increases were observed in the LSCL was sexual activity and partner relationship. PMID- 11602086 TI - [Prevalence of polydipsia and water intoxication in psychiatric inpatients]. AB - INTRODUCTION: The prevalence of polydipsia and water intoxication among psychiatric inpatients has been described in different countries, however few studies have been conducted in Europe. The present study was aimed at evaluating the prevalence of polydipsia and water intoxication in an European Psychiatric Hospital. METHODS: SPGU (Specific Gravity of Urine) and Normalised Diurnal Weight Gain (NDWG) were evaluated among 201 inpatients. RESULTS: Risk of polydipsia and water intoxication were found among 51% of all patients. Risk of primary polydipsia was present in 25% of patients, and primary polydipsia and risk of water intoxication among 25% of all patients. CONCLUSIONS: This is one of the unique studies of polydipsia and water intoxication in psychiatric inpatients in Europe, and the first one conducted in Spain. The development of specific preventative and clinical programmes in psychiatric patients is suggested due to the clinical relevance and high prevalence of this pathology. PMID- 11602087 TI - [Clinical characteristics of 104 patients with obsessive compulsive disorder]. AB - INTRODUCTION: Obsessive compulsive disorder is a common disorder, but research on its clinical features is scarce. The goal of this study is to describe the clinical characteristics and demographic features of a large sample of patients with Obsessive compulsive disorder. METHOD: The characteristics of 104 patients who sought psychiatric treatment and who were diagnosed as having Obsessive compulsive disorder were assessed by means of a structured questionnaire. RESULTS: The mean age of onset was 20 years and the mean time before soliciting treatment was 4 years. Most of the patients reported an insidious onset and related the onset to an stressful event. The most frequent obsessions were doubt, aggressiveness and contamination. Checking, need to ask and mental rituals were the most frequent compulsions. Cleaning and repetition compulsions were most frequent in women. DISCUSSION: Our results regarding age at onset of illness, way of onset or prevalence of certain obsessions and compulsions are similar to previous research. No agreement was obtained with previous research regarding the link between stress and illness onset, the course of the disorder or the time before treatment was sought. The differences with respect to previous studies could be accounted for the use of different instruments or criteria. The need for the development of instruments allowing to shed light on these discrepancies is stressed. PMID- 11602088 TI - [Diagnostic validity of Zung's self-rating depression scale on primary care patients]. AB - INTRODUCTION: Although the Spanish version of the Zung's Self-Rating Depression Scale (SDS) is widely used, there are no studies about its validity as a diagnostic test in primary health care patients. METHODS: In a first phase, a sample of 350 consecutive primary care patients was assessed with the SDS. In a second phase, a subsample composed by all the positive test results and 1/3 of the negatives selected at random, was assessed with the modules of current Major Depressive Episode and Dysthymia of the Structured Clinical Interview for DSM-IV. Specific methods to avoid verification bias were used. Prevalence, sensitivity and specificity, predictive values, Receiver Operating Characteristic (ROC) curve, and Stratum Specific Likelihood Ratios (SSLR) were calculated. RESULTS: Prevalence estimations of major depression and dysthymia were 14,7% (IC95%: 10,7 18,7%) and 4,6% (IC95%: 2,4%-6,8%) respectively. Sensitivity and specificity to detect both diagnoses were 0,95 (IC95%: 0.87-1) and 0,74 (IC95%: 0,68-0,79). Area under ROC curve was 0,93. SSLR for scoring < 50 led to a post-test probability of 0.01. In the stratum with scoring > 69 the SSLR generated a post-test probability of 0.96. Less conclusive results were obtained by intermediate strata. CONCLUSIONS: The SDS is effective in primary care patients and shows operating characteristics comparable to other depression assessment scales. SSLR provides practical information to estimate the probability of suffer a depressive disorder in individual patients. PMID- 11602089 TI - [Dysthymia and depressive personality: clinical differentiation]. AB - INTRODUCTION: Personality and depressive disorders are frequently associated in clinical samples. If these are chronical or have residual symptoms, it is more difficult their differentiation from personality traits. An example of this is the present polemic about dysthymia and depressive personality disorder. The aim of this study is to differentiate them clinically. METHOD: A outpatient sample of patients in a MHC with nonpsychotic affective disorders is randomized and recruited. Two groups are made, with dysthymia or depressive personality disorder. They are differentiated according clinical variables and personality disorders comorbidity. RESULTS: Patients with depressive personality disorder are more associated with group C and schizoid personality disorder and dysthymic patients with group B personality disorder (axis II-DSM-IV). There is also some dimensional differentiation between them. CONCLUSIONS: Depressive personality disorder and dysthymia are different constructs, though there is overlapping with several traits. It is necessary a longitudinal study in order to see clearly clinical and comorbidity differences. PMID- 11602090 TI - [Clinical predictors of long-term outcome of lithium prophylaxis in bipolar disorder]. AB - INTRODUCTION: In spite of the frequent prophylactic use of lithium salts in affective disorders, few papers have been published about clinical outcome predictors in long-term follow-up. OBJECTIVE: To identify clinical predictors of long-term outcome in a sample of bipolar outpatients on lithium treatment. METHODS: An intervention study was conducted in a case series of all patients treated, at least for two years, at two Affective Disorders ambulatory Units. It was examined the association between two dependent outcome variables (presence vs absence of relapses and number of relapses/person/year) and the rest of clinical variables. RESULTS: 139 outpatients diagnosed of bipolar disorder were included in the sample. In each case, therapeutic lithium dosages were administered. Delay time to start treatment since the disorder has begun was the only variable useful to predict weakly outcome. The time spent without treatment and the association with other mood stabilizers or neuroleptics correlates with bad outcome. CONCLUSION: Whichever clinical characteristics of the sample may be, patients should be treated as soon as possible with lithium to get better outcome. PMID- 11602091 TI - [Safety in melatonin use]. AB - INTRODUCTION: The interest on melatonin (MLT) as a psychiatric treatment has increased a lot in the last decade. This is mainly due to MLT safety and its lack of serious adverse reactions. The aim of this paper consists of reviewing the adverse effects to MLT consumption in humans. METHOD: A 35-year (1966-2000) bibliographic search using the Medline database was carried out. The intersection of the key word melatonin with the group of words adverse effects or side effects or adverse reactions or toxicity was the strategy of the search. RESULTS: 307 articles were elicited and 9 were related to MLT adverse effects. The range of MLT dose involved in the adverse reactions oscillated between 1 mg and 36 mg. The adverse reactions were: one patient with autoimmune hepatitis, one case of confusion due to MLT overdose, one case of optic neuropathy, four subjects with fragmented sleep, one psychotic episode, one case of nistagmus, four cases of seizures, one case of headache and two cases of skin eruptions. CONCLUSIONS: Attention should be paid on the necessity of enquiring about the drugs that patients are taking, because this product is not harmless for health. PMID- 11602092 TI - [Alexithymia and verbal intelligence: a psychometric study]. AB - INTRODUCTION: Alexithymia is a concept that describes the unability to put emotions into words ant that has been associated with somatization and psychosomatic disorders. METHODS: A sample of 124 outpatients attending the Psychosomatic Unit of a General Hospital was studied in order to test the hypothesis that alexithymic patients have a significantly lower verbal intelligence than nonalexithymics. Alexithymia was assessed by the Toronto Alexithymia Scale (TAS), and verbal, nonverbal and general intelligence were measured by the WAIS. RESULTS: TAS scores were not related to medical and psychiatric diagnoses, and alexithymic patients (n: 53) showed not only significantly lower scores in verbal intelligence than undifferentiated subjects (n: 37) and nonalexithymics (n: 34) but also significantly lower scores in nonverbal and general intelligence. CONCLUSION: The results do not confirm our hypothesis and are discussed in relation to theories that consider alexithymia as a consequence of cerebral asymmetry and interhemispheric dysfunctions. PMID- 11602093 TI - [Heroin prescribing: Is there scientific evidence of its efficacy for the treatment of its dependence?]. AB - It is in the United Kingdom where medical prescription of opiates has been more widely used. Although these practice had been increasing until the sixties, several factors caused a decreased since then, so that it is currently 1.6% of all maintenance programmes, becoming methadone prescription more important. Mainly through studies conducted in Switzerland, the debate over the appropriateness of this practice. In such studies, it appears that heroin prescription supports important improvements in the patients outcome, as it is associated with better retention rates, a reduction in abuse of illicit substances, and improvements in patients health and social aspects. However, methodological limitations of these studies and ambiguous results of studies carried out in other countries, make it difficult to determine the effectiveness or efficacy of this pharmacotherapy, so that more studies are needed to scientifically justify this practice. PMID- 11602094 TI - [Mania, parkinson disease and risperidone. Case report]. AB - Risperidone is an atypical antipsychotic with a low prevalence of extrapyramidal side-effects. The use of this antipsychotic in Parkinson's disease is still controversial. We describe a 59 year-old bipolar patient with Parkinson's disease non-responding to conventional antimanic drugs successfully treated with risperidone. PMID- 11602097 TI - [Research foundations in primary care: health care, teaching... or research?]. PMID- 11602095 TI - [Esquizofreniform psychosis after epilepsy surgery. A case of forced normalization fenomena]. AB - The present case report is about the development of a eschizophreniform psychosis after epilepsy surgery (anterior temporal lobectomy). This adverse event was the novo, in a patient without a history of previous psychosis. This case have been studied pre and post-surgery, and have been used the DSM IV diagnosis criteria. The patient developed a subacute alucinatory-delusion syndrome, while seizures disappeared. This inverse relationship is an example of alternative psychosis or forced normalization after surgery treatment. This clinic example may us think about the controversial relationship between temporal epilepsy and psychosis. PMID- 11602098 TI - [Evaluation of the organisation of care for patients without appointment]. AB - OBJECTIVES: To calculate the improvement achieved in organising care for patients without appointments after introducing corrective measures. Second, to study the reasons for consultation, the duration of the symptoms because of which consultations without appointment take place, and the assessment by health personnel of the relevance of the emergency. DESIGN: Before-and-after study.Setting. Health Area 9, urban health centre, Leganes, Madrid. PATIENTS: All the patients attending consecutively without appointment in the study periods (assessment: November 1998; reassessment: November-December 1999). MAIN RESULTS: 588 patients were included in the assessment and 562 in the reassessment. They belonged to general practice and paediatrics. 5 quality criteria were set: recording of basic details; recording of reason for consultation; assessment in under ten minutes; attempt at prior appointment; and record in the clinical notes. As there were no references in the bibliography, they were agreed by the team. After corrective measures were taken, all criteria except the fourth improved significantly. Nonetheless, the previously set norm was only achieved in the second. The professionals thought 27% of the consultations without appointment in paediatrics were urgent, and 30% in general medicine. Mean duration of symptoms in non-urgent pathologies was 1.5 days in paediatrics and 13.4 in general medicine. The most common reasons for consultation were prescriptions (20%) in general medicine and digestive pathology (20.4%) in paediatrics. CONCLUSIONS: Setting up an improvement cycle at our health centre managed to raise the quality of care given to patients without appointment, although there are still some facets that could be improved so as to reach, at least, the standards set. PMID- 11602099 TI - [Diagnosis and monitoring of hypertension in Catalonia. The DISEHTAC study]. AB - OBJECTIVES: To evaluate the diagnosis, monitoring and control of hypertension in reformed primary care centres in Catalonia, on the basis of the evaluation indicators proposed in the primary care hypertension guidelines. DESIGN: Multi centre cross-sectional descriptive study.Setting. Primary care.Participants. 31 reformed PCC in Catalonia. Randomised sampling of centres and hypertense patients (n = 2240). External audit. MEASUREMENTS AND MAIN RESULTS: a) Diagnosis indicator: in 19.4% of cases a triple double-take of blood pressure showed an average of = 140/90 mmHg. b) Monitoring indicator: 77.9% of patients had been seen for blood pressure in the previous 6 months. c) Indicator of degree of control of blood pressure: 38.8% of patients had pressure below the figures then recommended ((3/4) 65 < 140/90 mmHg, and > 65, < 160/95 mmHg). 25.7% of cases were found to have blood pressure figures < 140/90 mmHg. CONCLUSIONS: There was high compliance on the monitoring indicator. The degree of control of hypertense patients treated at reformed PCCs is still low. PMID- 11602100 TI - [Consumption of medicinal herbs and medicines]. AB - OBJECTIVE: Given the possibility of adverse side-effects, interactions with medicines and poisoning by contaminants among herbal medicine consumers (HM), we aimed to describe the consumption of HM by health centre users being treated with medicines. DESIGN: Cross-sectional, observational study.Setting. Thirteen health centres in the Community of Valencia. PATIENTS AND OTHER PARTICIPANTS: Users of either sex, over 14, chosen for a study of use of medicines to find differences between the sexes. MEASUREMENTS AND MAIN RESULTS: The study variables, age, gender, education, consumption of medicines and use of HM, were gathered from the clinical records, the long-treatment card and an ad hoc structured survey. 801 out of 812 users took medicines. 159 took HM (19.6%; 95% CI, 16.9-22.3); average age 55.8 (SD, 16.5); women 58.5% (95% CI, 50.8-66.1). They took 226 HM (mean of 1.42; 95% CI, 1.32-1.52). Men consumed more HM (p < 0.05). There were no differences in consumption of HM for age, educational background or number of medicines taken. 42.8% (95% CI, 35.1-50.2) of those who took HM attended for consultation over 10 times in the previous year. 96.9% (95% CI, 93.7-98.4) of HM were taken by self-medication. They were consumed: <> by 36.7% (95% CI, 30.4-43.0); stomach problems, 19.5% (95% CI, 14.3-24.6); nerves/depression, 12.8% (95% CI, 8.5-17.2); intestinal disorders, 10.6% (95% CI, 6.6-14.6); insomnia 5.8% (95% CI, 3.1-9.6). 49.1% (95% CI, 42.6-52.6) were manufactured HM. CONCLUSIONS: One of every five patients being treated with medicines is also taking HM by self-medication. The health authorities and doctors should advise of the risks to health and of the counter-indications of these products. PMID- 11602101 TI - [Cardiovascular morbidity and its relationship to left ventricular hypertrophy in a cohort of hypertensive patients: the Gotic study]. AB - BACKGROUND: To describe cardiovascular morbidity of a hypertensive patients cohort and relate it to the presence of left ventricular hypertrophy (LVH), LVH geometric patterns, other cardiovascular risk factors (CRF), previous pathology (PP) and a range of variables. DESIGN: Prospective study of the cohort visited in a from 1993 to 1998. Place. Downtown primary care center. PATIENTS: A random sample of 267 hypertensive patients under 80 years old was used. Method and procedures. The presence of universals of CRF, PP and a range of variables such as age, sex, systolic and diastolic blood pressure (SBP and DBP), heart rate, body mass index (BMI), left ventricular mass index (LVMI) and Cornell and Sokolov Lyon electrocardiographic criteria were registered. Also cardiovascular events (CE) were recorded: heart failure (HF), coronary heart disease (CHD), stroke, arrythmia and peripheral vascular disease (PVD). Then the association between these variaables and CE appearance was studied. MEASURES AND RESULTS: The total amount of CE was 60, with an accumulated incidence of 22.5% (confidence interval 95% from 19.4 to 25.7%).HF was more frequent among patients with a higher BMI (p = 0.05). The patients with HF showed a stronger smoking habit as CRF and a higher PAS (p = 0.05). The PVD was more common among hypertensive patients with smoking habit as CRF (p = 0.05).EC was highly observed in those patients either with LVH or CRF, especially in those cases such as HF (90% had LVH), stroke (87.5%) and arrythmias (83.3%). However, it was less observed in those ones with PVD (66.7%) and HF (60%). No relation was found between the patterns of LVH and EC. CONCLUSIONS: The HF was more frequent among the hypertensive patients with a higher LVMI, the HF among the smokers and a higher PAS and PVD among the smokers. The LVH is strongly related to the HF, stroke and arrythmias. The differences among the populations with cardiovascular epidemiology as well as the short span of follow-up may have contributed to obtaining such results. PMID- 11602102 TI - [Clinicopathological correlation in 370 cases of skin minor surgery carried out by family physicians]. AB - OBJECTIVE: To analyse the concordance between presurgical diagnosis and anatomical pathology diagnosis in 370 cutaneous lesions in primary care centres. DESIGN: Descriptive study.Setting. Primary care centres and hospital pathology service, Medina del Campo. MEASUREMENTS AND MAIN RESULTS: The prior diagnosis was compared with the anatomical pathology for simple agreement. There were 370 lesions. Complete date were obtained for 345 lesions of 298 patients (156 male and 142 female, aged between 6 and 98). Most problems diagnosed were nevocellular nevi (99 cases), fibroepithelial papiloma (72 cases), epidermoid cyst and viral wart (44). There was 63.1% global agreement between the laboratory report and doctor's diagnosis. Concordance and misdiagnosis were described in each type of lesion, mostly in skin cancer. CONCLUSIONS: Performing minor surgery in primary care is feasible and effective. There is a high concordance between clinical diagnosis and anatomical pathology diagnosis. PMID- 11602104 TI - [Changes in antidepressants consumption in the health area of Zamora from 1996 to 1999]. AB - OBJECTIVE: To describe the evolution of antidepressants outside hospital consumption (therapeutic subgroup N06A) in the health area of Zamora since 1996 to 1999, and also to rate the impact of the most recently marketed drugs introduction. DESIGN: Retrospective observational study. SETTING: Primary care. METHODOLOGY: All antidepressants containers dispensed in Zamora with prescription of the Seguridad Social in the 1996-1999 period are obtained from SIFAR (Pharmacy Management Informatic System), computing defined daily doses per 1000 inhabitants day (DHD) for each drug. RESULTS: An increase of 47% in antidepressants whole consumption is observed, progressively since 1996 to 1999: 18.91 DHD (1996); 22.09 DHD (1997); 24.67 DHD (1998); 27.85 DHD (1999).ISRS (88%) and heterocyclics (56%) increase in this period, whereas IMAO (71%) and tricyclic antidepressants (14%) decrease. CONCLUSION: Antidepressant whole consumption experiments an outstanding increase in the area of Zamora. Recently marketed drugs utilisation increases as well, superseding classical antidepressants. The five most used drugs in 1999 were, in decreasing order, paroxetine, fluoxetine, sertraline, citalopram and venlafaxine. These last three ones got the most outstanding rise in the reviewed period. PMID- 11602103 TI - [Unnecessary attendance at a hospital emergency service and linked factors]. AB - OBJECTIVES: To adapt to our environment a protocol that assesses the adequacy of attendance at a hospital emergency service (HES), in order to calculate the frequency of unnecessary attendance and to analyse possible linked factors. DESIGN AND SETTING: Qualitative study using retrospective cross-sectional analysis of 269 records of patients attended at a third-level HES in Granada. METHODS: A heterogeneous group of experts (4 HES doctors and 4 PC doctors) agreed a scale for identifying unnecessary attendance at HES, which was then applied to a randomised sample of records of patients seen in the preceding year. An analysis was made of the proportion of unnecessary attendance and various associated factors: demographic variables, accessibility and variables involving the reason for consultation. The statistical techniques used were: confidence intervals to calculate percentage of unnecessary attendance, kappa index for agreement among observers on using the scale, and multiple logistic regression to analyse the association between unnecessary attendance and the factors studied. RESULTS: Inter-observer concordance for 73% of the scale. 35% of visits unnecessary (95% CI, 29-41%). Unnecessary use of the HES was more by women (OR, 1.94, p = 0.023), patients from unreformed health areas (OR, 2.02, p = 0.028), those coming from home without having seen their general practitioner (OR, 2.54, p = 0.08), those who had had for longer the condition occasioning the attendance, and medical-type emergencies (OR, 1.52, p = 0.022). CONCLUSIONS: More studies to test the reliability of the scale need to be performed. The apparent deduction is that a special reverence for emergency hospital care still exists and that this is sometimes used to side-step waiting-lists. PMID- 11602105 TI - [Impact and applicability of the system of reference prices]. PMID- 11602106 TI - [Health questionnaires in Spain and their use in primary care]. PMID- 11602107 TI - [Ten minutes, the least! A paradigm of the reason explaining why we are where we are]. PMID- 11602109 TI - [Local infiltrations with corticoids in primary care]. PMID- 11602110 TI - [Emergency service saturation in winter]. PMID- 11602111 TI - [What are we, pediatricians, doing in primary care?]. PMID- 11602114 TI - [Family medicine, next station?]. PMID- 11602116 TI - [Control of blood pressure in a population of patients with hypertension and in a subgroup with hypertension and diabetes: relationship with characteristics of the health care center and the community]. AB - AIMS: To evaluate how well blood pressure (BP) is controlled in the population of persons with hypertension alone and with diabetes, and to evaluate the influence of characteristics of the health care center on the degree of control of BP. Design. Descriptive, cross-sectional, multicenter, retrospective study. SETTING: 31 health centers in Catalonia (Northeastern Spain). Participants. Random sample of 2240 clinical records of patients with hypertension who were seen at 31 different primary care centers in Catalonia between January and December 1996. MAIN OUTCOME MEASURES: Audit of clinical records. We recorded the two most recent BP measurements, and annotations regarding screening for and diagnosis of other cardiovascular risk factors. We also recorded health center and physician characteristics. RESULTS: 495 patients (22.1%) had diabetes in addition to hypertension. 61.2% were women. Mean age was 64.9 years (95% CI, 64.4-65.4 years). In 25.7% of the patients, BP was below 140/90 mmHg (95% CI, 23.9-27.5%), but among patients with diabetes only 6.7% had BP below 130/85 mmHg (95% CI, 4.5 8.9%). Mean systolic and diastolic BP at the end of the study period were higher at teaching centers. Diastolic BP was significantly higher at urban centers and in patients younger than 65 years. Diastolic BP was also higher in patients with at least one associated cardiovascular risk factor, and at centers less than 6 years old, although these differences were not statistically significant. We found no differences according to physician characteristics. CONCLUSIONS: Blood pressure was adequately controlled in few patients with hypertension and diabetes in Catalonia. Associated cardiovascular risk factors, age less than 65 years, and being a patient at a teaching center or an urban center, were associated with a worse degree of BP control. PMID- 11602117 TI - [Analysis of a programme of direct referral between primary and specialist care in potential surgery patients]. AB - OBJECTIVE: To describe the results of a programme of direct referral of potential surgery patients between primary and specialist care, designed to lessen waiting times.Design. Prospective, longitudinal and descriptive study. SETTING: Health Area N. masculine 19 (Valencian Health Service): Surgery Service of Elche Hospital and 6 Health Centres. PARTICIPANTS: Patients with pathologies that do not need special techniques for diagnosis except examination and who have a clear irrefutable indication of surgery without risk factors (ASA I-II).Intervention. The referral protocol consists of: a) diagnosis of pathology and pre-operative study in primary care (PC); b) appointment made by phone for the surgery clinic at the hospital, where diagnosis and pre-operative study are confirmed; c) referral and operation in the unit of non-hospital major surgery (UCMA); d) monitoring post-operation by the home hospitalisation unit (HHU) or preferably by the health centre, and e) check-up at the surgery clinic. Main measurements. The degree of agreement between PC and the specialist, assessment of the pre operative study, and waiting time. RESULTS: 86 patients were referred (average age, 35; 76% male) by 28 doctors. The most common pathologies were hernia (36%), pilonidal sinus (23.2%) and miscellaneous (32.5%). There was general agreement in diagnosis in 90.7% of cases. 89.5% of patients brought the proper pre-operative study. Mean waiting time between the primary care consultation in the different procedures and the first hospital consultation was 19 days; with 44 more days elapsing till the surgical operation. CONCLUSIONS: This new programme is effective and economic, in that there is <> of patients, waiting time is reduced by over 7 months for pilonidal sinus and by over 2 years for hernia pathology, and the procedure can be used for a large number of patients, as the pathologies involved are very common. PMID- 11602118 TI - [Do patients understand their prescribed antibiotic treatments?]. AB - OBJECTIVE: To assess to what degree patients who had been prescribed an antibiotic understand the dose and duration of the prescription. DESIGN: Descriptive, cross-sectional. SETTING: Primary care in Toledo. PARTICIPANTS: People over 18 who attended 10 pharmacies in Toledo with an antibiotic prescription in April and May 2000. MAIN MEASUREMENTS: The prescriptions were dispensed by a pharmacist in charge at each establishment. After receipt of the prescription, the patient was asked about the dose of the drug prescribed. This was then compared with the instructions on the drug. RESULTS: 155 women and 163 men made up the sample, with an average age of 46.42 (SD, 17.2). The most commonly prescribed antibiotics were: a) amoxycillin (24.2%), 2) amoxycillin clavulanic acid (18.2%), and c) ciprofloxacin (10.6%). 63.2% of those interviewed remembered correctly the dosage prescribed without having to consult any kind of instruction, whereas 17.6% did need to consult instructions. 33% brought instructions written by the doctor. The average age of those who answered incorrectly was 52.8; and of those who answered correctly, 44.9 (p < 0.01). There were no significant differences between men and women. CONCLUSIONS: There is an important number of patients, especially older ones, who have not received or have not understood the instructions received from their doctor. PMID- 11602119 TI - [Validity of the clinical diagnosis of the basal cell carcinoma in primary health care]. AB - OBJECTIVE: To measure the validity of the clinical diagnosis of the basal cell carcinoma (BCC) in primary care. DESIGN: Cross-sectional study. SETTING: Primary health care Area 8 in Madrid. PATIENTS AND ITNERVENTIONS: A study was carried out on a group of patients that had been histopathologically diagnosed of BCC and on another that had received any of the most frequent differential diagnoses. A sample estimate was made with the most unfavourable situation of a sensitivity and a specificity of 50%, a precision of 5%, a confidence of 95% and losses of 20%. It was estimated that 962 cases were necessary. MEASUREMENTS: The histopathological diagnosis (gold standard) were compared to the clinical diagnosis. Sensitivity, specificity, predictive values, likelihood ratios and global value were estimated. RESULTS: 963 patients were included of which 7.6% were lost 890 cases were studied, 491 with BCC and 399 with differential diagnoses. The most frequent location of BCC was the face (65.8%). Sensitivity was 27.5% (95% CI, 23.531.5%), specificity 90.5% (95% CI, 87.5-93.5%), the global value of 55.7% (95% CI, 52.7-58.7%), positive predictive value, 78.0% (95% CI, 72.084.0%) and negative predictive value 50,3% (95% CI, 46.354.3%). CONCLUSIONS: Validity was moderate with low sensitivity and very low positive predictive value, the latter estimated for its expected prevalence. The clinical diagnosis of BCC in primary health care must be complemented with other diagnostic tests. PMID- 11602120 TI - [Food safety: mad cow disease and other paradigms]. PMID- 11602122 TI - [Postgraduate education in family education: what do we know about residents?]. PMID- 11602121 TI - [Therapeutic innovations in the treatment of asthma]. PMID- 11602123 TI - [Use of antibiotics in exacerbated chronic obstructive pulmonary disease]. PMID- 11602124 TI - [EuroQol-5D: a simple alternative for measuring health-related quality of life in primary care]. PMID- 11602125 TI - [Effectiveness of a multifactorial intervention to prevent falls among elderly people in a community]. AB - INTRODUCTION: The falls of old people are a common problem that will increase as the population ages and which are accompanied by high morbidity and mortality. Multifactorial intervention has proved effective in reducing the number of falls. OBJECTIVE: To reduce the number of falls and their complications in the population >= 70 years old of a health district through a multifactorial community intervention programme. METHOD: Multi-centred community intervention quasi-experimental study with no randomised allocation. It will be run in two communities, viz Salt and Girona-4, both of which are health districts in the province of Girona. In both an initial study will seek to establish the prevalence of falls and their consequences in people >= 70 years old. Data will be obtained from several randomised samples, using a questionnaire drawn up for the purpose. A multifactorial community intervention lasting two years (intervention group) will be made in the Salt Health District. There will be no specific intervention in the other community (control group). Later, effectiveness will be evaluated through randomised samples given the same questionnaire. DISCUSSION: Possible limitations of the study are the effect of contamination between the two communities, the existence of factors external to the intervention programme, losses due to people moving and deaths, and difficulty in assessing community activity. This programme can be applied to other communities as part of care and health education activities undertaken by primary care teams. PMID- 11602126 TI - [Quality of the contents of the home care physician's medicine case]. PMID- 11602127 TI - [Rhabdomyolysis induced by cerivastatin]. PMID- 11602128 TI - [Cerivastatin and gemfibrozil: a dangerous combination]. PMID- 11602129 TI - [Utopian or naive?]. PMID- 11602132 TI - [PSA and population screening for prostate cancer in primary care]. PMID- 11602131 TI - [Family physician, adults physician, or health center physician? Childhood, a competency to be recovered]. PMID- 11602133 TI - [Burnout among primary care physicians]. PMID- 11602135 TI - [Usefulness of pharmaco-kinetics in antimicrobial treatments]. PMID- 11602136 TI - [Compliance of antituberculosis therapy among ex-inmates in the Madrid area]. AB - BACKGROUND: The inmate population is not a tight compartment without communication with the community but there is a flow of persons and thus of health problems. The high incidence of tuberculosis among inmates is therefore of concern for the Public Health System. METHODS: The outcomes of antituberculosis treatment among ex-inmates released from prison in 1987 in the Madrid Area were evaluated and compared with those who remained in jail on treatment. Individuals who met the case definition of tuberculosis were included in the study. The outcome was defined as the individual status one year after the beginning of therapy. To determine the association between the study variables with outcome, odds ratios (OR) with their 95% confidence intervals were used. The Chi2 test was used to determine the statistical significance. RESULTS: Differences between outcomes of individuals in the two groups were observed: 69.7% of inmates had completed their therapy compared with 20.5% of ex-inmates. Treatment had to be prolonged in 15.2% of inmates compared with 46.2% in ex-inmates. The only predictor associated with therapy completion one year after the beginning was imprisonment, as OR for not having completed therapy for ex-inmates was almost 13 times higher (OR=12.94; 95% IC, 3.38-13.10) than those in jail. CONCLUSIONS: Special strategies should be developed that assure clinical cure of persons with factors related to non-compliance. PMID- 11602137 TI - [Nasal carriers of methicillin-resistant Staphylococcus aureus among cuban children attending day-care centers]. AB - BACKGROUND: Recent but scarce reports of methicillin-resistant Staphylococcus aureus strains (MRSA) among children without risk factors associated with its acquisition prompted us to investigate its presence in the community. PATIENTS AND METHODS: During the September and October months in 1997, nasal and pharyngeal swabs were obtained from 358 children aged less than five years who attended three day-care centers in the Marianao Area, La Habana City, Cuba. The isolated S. aureus strains were characterized for antimicrobial sensitivity using the Kirby-Bauer method. Methicillin resistance was confirmed by te Oxacillin Salt Agar Screening-Plate method recommended by the National Committee for Clinical Laboratory Standards. RESULTS: 18.7% of children were carriers of S. aureus in the upper respiratory tract; 2.2% of children carried MRSA strains. The highest resistance levels corresponded to erythromycin (50.74%) and tetracycline (29.9%). All tested strains were sensitive to ciprofloxacin. CONCLUSIONS: Our results provide evidence on the recovery of MRSA strains among healthy children attending day-care centers and are suggestive of a rapid colonization and spread of these microorganisms in the community. PMID- 11602138 TI - [Invassive infections caused by Group A streptococci: clinical characteristics and microbiological analyses in 31 cases]. AB - BACKGROUND: In the last two decades an increase in the incidence of invassive Streptococcus pyogenes infections has been reported in several countries. The objective of this study was to determine the clinical features of these infections in our hospital. METHODS: Retrospective study (1995-1998) of patients admitted at Son Dureta Hospital, Palma de Mallorca, Spain, who had S. pyogenes recovered from blood, sterile fluids or soft tissues. Patients clinical records were reviewed and bacterial isolates characterized. RESULTS: A total of 31 patients with invassive infections caused by S. pyogenes were identified. The annual incidence rates (number of episodes/1,000 admissions) were: 0.13 (1995), 0.20 (1996), 0.27 (1997), and 0.23 (1998). The mean age of patients was 41 years. Seventy four percent of patients had some underlying disease, and the most relevant conditions included: diabetes mellitus (5), parenteral drug abuse (4), chronic alcoholism (3), chronic liver disease (3) and infection with the human immunodeficiency virus (3). The most common portal of entry was the skin (78%). The initial clinical presenting form was cellulitis (39%). Necrotizing fasciitis, septic shock, and streptococcal toxic shock syndrome (STSS) were observed in 9.6%, 12.9%, and 6.4% of patients, respectively. The mortality rate was 16.1%. The phenotypic characterization of S. pyogenes isolates indicated that most isolates were of mucoid type and identified 11 different M serotypes, M1 being the most common. CONCLUSIONS: A steady increase in the incidence of invassive infections caused by S. pyogenes was observed since 1995 to 1997 in our hospital. Patients with certain underlying conditions are more susceptible to acquire these infections. The worst outcome of these infections corresponded to elderly patients, those with septic shock or STSS. Most strains responsible for these infections were encapsulated and the M1 serotype predominated. PMID- 11602139 TI - [Treatment of opportunistic infections among adult and adolescent patients infected with the human immunodeficiency virus in the era of highly active anti retroviral therapy]. PMID- 11602140 TI - [Problems and current solutions for the treatment of infections caused by gram positive microorganisms]. PMID- 11602141 TI - [Fungal-protozoal sinusitis]. PMID- 11602143 TI - [External otitis due to fly larvas]. PMID- 11602142 TI - [Pyomyositis in a patient undergoing bone marrow transplantation]. PMID- 11602144 TI - [Usefulness of Rose Bengal, Coombs and counter-immunoelectrophoresis for the diagnosis of human brucellosis cases with negative seroagglutination]. PMID- 11602145 TI - [Detection of methicillin-resistant Staphylococcus aureus strains by means of a latex agglutination test]. PMID- 11602146 TI - [Spleen infarction associated with the presence of lupic inhibitor in a patient with AIDS]. PMID- 11602147 TI - [Evaluation of a capture enzyme-immunoassay (ELISA) for the diagnosis of measles virus infection]. PMID- 11602148 TI - [Enterobius vermicularis and enuresis]. PMID- 11602149 TI - [Severe pulmonary hypertension treated with low dose carvedilol in a patient infected with the human immunodeficiency virus]. PMID- 11602150 TI - [Septic shock with adult respiratory distress syndrome and Alcaligenes xylosoxidans]. PMID- 11602151 TI - [Septic arthritis due to Staphylococcus lugdunensis]. PMID- 11602152 TI - [Diagnosis and etiology of pneumonia associated with mechanical ventilation]. PMID- 11602153 TI - [Survival and prognostic factors for gastric cancer. Analysis of 2,334 patients]. AB - BACKGROUND: The analysis of the survival of patients diagnosed with gastricadenocarcinoma and the factors which modify prognosis. PATIENTS AND METHOD: Retrospective cohort study of overall patients diagnosed with gastric adenocarcinoma treated in the Xeral-Calde and Juan Canelejo hospitals of Lugo and La Coruna (Spain) between 1975 and 1993. The following variables were studied: age, sex, the year of diagnosis, place of residence, delayed diagnosis, localisation of the primitive tumour, the TNM classification, the Lauren histological type and the type of surgical resection when conducted. The Kaplan Meier statistical method was employed to determine the probability of survival. Cox regression was used to determine prognosis factors. RESULTS: The diagnosis was established on 2,334 patients: 63,2% were males;the average overall age was 66.5 (11,9 SD) years, the median delayed diagnostic was 3,19 months, the lower third was the most common localisation (46,3%), 30,2% of the cases were diagnosed in the IV stage, and curative surgery was conducted in 46,4% of the cases. The probability of survival for overall numbers was 26% and curative surgery, was conducted in 45% of cases. The most advanced states in the TNM classification and the absence of curative surgery were factors associated with the poorest prognosis. CONCLUSIONS: Survival after gastric cancer is low. Initial stage and radical surgical treatment are the main factors for prognosis. PMID- 11602154 TI - [Abdominal fat assessment by magnetic resonance: comparison with biometric profiles and cardiovascular risk markers]. AB - BACKGROUND: Obesity is associated with numerous metabolic complications and cardiovascular disease. Magnetic Resonance (MR) imaging provides fair resolution of fat distribution, its quantification by semiautomatic methods being feasible. Our purpose was to analyze abdominal fat deposition by MR imaging and quantify its relative distribution in 50 obese patients. RESULTS were then related to anthropometric measures and cardiovascular risk markers. PATIENTS AND METHOD: Six axial T1-weighted abdominal images were obtained from each patient and transferred to a PC. A software (ASYMED 3.0; Valencia) was used to analyze the images and quantify relative fat deposition. Comparison of MR results with several cardiovascular risk markers was performed using unpaired data Student t test. Significance level was defined as a P < 0.05. RESULTS: 12% of patients showed predominant intra-abdominal fat deposition.Significant differences were found with regard to age, waist-hip ratio and average serum levels of total cholesterol, LDL, VLDL,triglycerides and apoprotein B between intra-abdominal deposition versus subcutaneous fat deposition. CONCLUSION: MR imaging allows estimation of abdominal fat deposition and its relative distribution. There is a significant relationship between a predominant intra-abdominal fat deposition and an atherogeniclipid profile. PMID- 11602155 TI - [Relationship between dyspnea and quality of life with body mass index and pulmonary function in patients with chronic obstructive airways disease and emphysema]. AB - BACKGROUND: We aimed to evaluate the differences in pulmonary function, quality of life (CVRS) and dyspnea in patients with chronic obstructive pulmonary disese (COPD) and emphysema according to the body mass index (BMI). Moreover, we analyzed the relation between BMI, pulmonary function, CVRS and dyspnea. PATIENTS AND METHOD: This was a prospective, 12-months study including 20 patients with COPD and emphysema. They were classified in group A (BMI < 21 kg/m(2) group B (BMI >= 21 kg/m(2)). We performed pulmonary function tests and determined the levels of dyspnea and CVRS according to a scale of dyspnea and a CVRS questionnaire. RESULTS: Seven patients had a BMI < 21 kg/m(2) and it was >=21 kg/m(2) in 13 patients. DLCO in group A patients was lower than in group B. After a multiple regression analysis, the FVC accounted for 52% of dyspnea variability. Both PEM and dyspnea were the parameters that better predicted the CVRS. CONCLUSIONS: Patients with COPD and emphysema with a VMI < 21 kg/m(2) have a lower DLCO than patients with a BMI >= 21 kg/m(2). In our patients, dyspnea sensation depended on the FVC. In addition,the CVRS depended on dyspnea sensation and PEM. PMID- 11602157 TI - [Hypereosinophilic syndrome]. PMID- 11602156 TI - [Seasonal blood pressure changes in mild hypertension]. AB - BACKGROUND: Our goal was to evaluate seasonal blood pressure (BP) changes in patients with mild hypertension. PATIENTS AND METHOD: Forty-three hypertensive subjects underwent two clinical examinations in different seasons (summer and winter), separated by a 6 month-interval.Each examination included a 24 h ambulatory BP monitoring. RESULTS: Ambulatory diurnal BP was higher in winter that it was in summer(p < 0.01). Seasonal changes were inversely correlated to the body mass index (r = -0.44; p < 0.05, for systolic BP). CONCLUSIONS: Ambulatory diurnal BP is subjected to seasonal influences. Seasonal variations of BP habe implications for the clinical management of hypertension. PMID- 11602158 TI - [What is a confounding variable?]. PMID- 11602159 TI - [Practical considerations for the diagnosis of Helicobacter pylori infection]. PMID- 11602160 TI - [Xenotransplantation: limitations and perspectives]. PMID- 11602161 TI - [Positional sleep apnea: report of a case with upper airway resistance syndrome in lateral decubitus position]. PMID- 11602162 TI - [Methanol poisonig. Is it another source of donors?]. PMID- 11602164 TI - [Autologous stem cell transplantation in a patient with rheumatoid arthritis]. PMID- 11602163 TI - [Mediastinal adenopathies and pulmonary cavitated mass as onset form of Hodgkin's disease]. PMID- 11602167 TI - [Efficiency of multidisciplinary treatment of chronic pain with locomotor disability]. AB - BACKGROUND AND OBJECTIVE: Disabling chronic pain is especially devastating among working population and, in many cases, it does not respond to conventional therapies. In chronic pain, the importance of psychosocial and occupational factors, in addition to biological ones, has prompted the development of successful multidisciplinary treatment programmes in various countries. We assessed the outcome of a multidisciplinary therapeutic program for work-disabled selected patients with chronic pain refractory to conventional treatment. PATIENTS AND METHOD: The study included 70 patients (58 women, mean age [SD]: 42 [9]years) with chronic pain and sick leave (mean [SD]: 7 [4] months of work disability) diagnosed with fibromyalgia (51%), chronic low back pain (16%), regional myofascial pain (15%), cervicocraneal syndrome (3%), anquilosing spondylitis (3%), and other conditions(12%). All patients had received previous pharmacological treatment,physical therapy and/or other measures (surgery in 12% cases)without improvement. All patients underwent an intensive multidisciplinary treatment of 4 weeks' duration including medical techniques for pain control, cognitive-behavioural therapy, physical therapy,and occupational therapy. Average follow-up was 10 (4) months(1-24 months) post-discharge. RESULTS: Significant improvements were observed with regard to all relevant variables, as reflected in pre and post-discharge measures: pain(Visual-Analogue Scale 1-10 cm): 7.4 (1.5) versus 3.2 (2) (p <0.01); anxiety (HARS), 19 (7) versus 14 (8) (p < 0.01); depression(BDI), 16 (8) versus 10 (8) (p < 0.01); functional ability(HAQ), 1.6 (0.4) versus 0.6 (0.5) (p < 0.001). At discharge,73% of patients returned to work. In addition, 69% of treated patients maintained the acquired improvement and their employment status at the end of follow-up. CONCLUSION: Multidisciplinary treatment of chronic pain with special attention to work return is useful for selected patients with a disabling chronic pain syndrome refractory to conventional treatment. PMID- 11602168 TI - [Incidence of infection acquired at a health center]. AB - BACKGROUND: Nosocomial infections in geriatric patients have specific features in geriatric health care facilities and services. The incidence of nosocomial infection in a long-term care hospital is described. PATIENTS AND METHOD: The study was carried in L'AlianCa from Barcelona, a long-term care hospital of 138 beds of geriatric rehabilitation or convalescence. All nosocomial infections occurred in 1999 were recorded. The criteria of nosocomial infection were those of McGeer, adapted to make them suitable to a long-term care hospital. The statistical methods employed were the Student'st test to compare means and chi2 to compare proportions. RESULTS: The incidence of nosocomial infections was 2.8 per 1,000 resident care days, showing a statistically significant increase in the group aged over 75 (p = 0.009). Infected patients had longer hospital stay and greater physical dependence. Lower respiratory tract infections were the most common type of infection accounting for the 39.7% of the cases. The mortality rate was greater in the infected group (RR: 2.61; CI 95%, 1.60-4.25). CONCLUSIONS: Elderly patients are at greater risk of contracting nosocomial infections. It is necessary to develop infection control programs useful for the long-term care hospital. PMID- 11602169 TI - [Influenza vaccination of human immunodeficiency virus-infected patients with severe immunodepression. Impact on CD4 lymphocytes and plasma viral load]. AB - BACKGROUND: The aim of this study was to assess the effect of influenza vaccination on plasma HIV viral load and CD4 T-lymphocytes in patients with advanced HIV disease. PATIENTS AND METHOD: Observational study carried out in HIV infected patients with a CD4 cell count < 200 X 10(6)on highly active antiretroviral therapy(HAART). Influenza vaccine was voluntarily offered and plasma viral load and CD4 cell counts were measured at baseline, 4 weeks and 12 weeks in vaccinated and control subjects. RESULTS: Sixteen patients were analysed, 10 of them being immunized with the influenza vaccine. A significant decline in CD4 cell counts at 4 and 12 weeks and an increasing trend of viral load were seen in all immunized patients who had a high viral load at the time of vaccination (n = 6), but not in those with an undetectable viral load. The mean decrease of CD4 T-lymphocytes in these 6 patients was 49.8%. Three patients showed a huge drop of the CD4 cell count (over 60% of baseline). CONCLUSIONS: Influenza vaccination of severely immunocompromised HIV-infected patients who are failing to HAART might be associated with an immunological impairment. PMID- 11602170 TI - [Hospital-acquired infections in elderly patients]. PMID- 11602171 TI - [Decreasing susceptibility to vancomycin in isogenic Staphylococcus aureus strains isolated from a single patient]. AB - BACKGROUND: We aimed at evaluating the microbiological characteristics and clinical implication of 7 isogenic strains of Staphylococcus aureus with decreased susceptibility to vancomycin. SUBJECT AND METHOD: A patient with nosocomial trival vularendocarditis due to methicillin-resistant S. aureus had positive blood cultures for 8 weeks despite antimicrobial therapy with vancomycin (normal serum levels) and rifampicin. The patient rejected surgical treatment but the process cured with antimicrobial therapy. The epidemiological relationship of strains was evaluated by pulsed field gel electrophoresis. The susceptibility to vancomycin was evaluated by microdilution and E-test using two different in ocula. The activity of oxacillin, ampicillin and cephalotin was evaluated in Mueller Hinton (MH) agar containing different concentrations of vancomycin (0.06 to 4 mg/l). Heteroresistant subpopulations were determined in both MH and brain heart infussion agar containing vancomycin (0.5 to 512 mg/l). All seven strains belonged to the same clone. Vancomycin MIC ranged from 1 mg/l (isolates 1 to 5) to 4 mg/l (isolates 6 and 7). Isolates 6 and 7 displayed differences in pigmentation and slower growth rates. The susceptibility of these isolates to betalactams inMH containing different concentrations of vancomycin was greater than that in controls. Subpopulations heteroresistant to vancomycin were not detected. CONCLUSION: The decreased susceptibility of the isogenic S. aureus strains evaluated in this study was not due to heteroresistance and did not cause therapeutic failure. PMID- 11602172 TI - [Patients' capacity for decision making]. PMID- 11602173 TI - [New concepts on the treatment of atrial fibrillation]. PMID- 11602174 TI - [Gastrointestinal bleeding caused by rofecoxib]. PMID- 11602175 TI - [Selective immunoglobulin A deficiency associated with chronic autoimmune hepatitis]. PMID- 11602176 TI - [Alternative medicine vs. scientific medicine in a basic health area. An emergent phenomenon?]. PMID- 11602178 TI - Beta-Arrestins: new roles in regulating heptahelical receptors' functions. AB - The last few years have seen a marked expansion in appreciation of the diversity of roles played by the betaArrestins in regulating GPCR functions. Originally discovered as molecules that desensitize such receptors, the roles of betaArrestins have expanded to include acting as signalling adapters or intermediates that recruit other key molecules to the GPCRs in an agonist regulated fashion. For example, interactions with components of the endocytic machinery, such as clathrin, the adapter protein AP-2 and the N-ethylmaleimide sensitive fusion protein (NSF), demonstrate the ability of betaArrestins to act as adapters to facilitate the clathrin-mediated endocytosis of certain members of the GPCR family. BetaArrestins have also been shown to serve as signalling molecules. The Ras-dependent activation of ERK1/2 may involve the betaArrestin dependent recruitment of c-Src to the beta2-adrenergic receptor (beta2-AR). More recently, betaArrestins have been shown to act as molecular scaffolds that coordinate the assembly of certain MAP kinase complexes that lead to the stimulation of either ERK1/2 or JNK3. Finally, long-term accumulation of arrestin rhodopsin complexes, in photoreceptor cells has been shown to trigger apoptosis. PMID- 11602179 TI - Regulation of phospholipase C gamma isoforms in haematopoietic cells: why one, not the other? AB - Phospholipase C gamma (PLCgamma) isoforms are critical for the generation of calcium signals in haematopoietic systems in response to the stimulation of immune receptors. PLCgamma is unique amongst phospholipases in that it is tightly regulated by the action of a number of tyrosine kinases. It is itself directly phosphorylated on a number of tyrosines and contains several domains through which it can interact with other signalling proteins and lipid products such as phosphatidylinositol 3,4,5-trisphosphate. Through this network of interactions, PLCgamma is activated and recruited to its substrate, phosphatidylinositol 4,5 bisphosphate, at the membrane. Both isoforms of PLCgamma, PLCgamma1 and PLCgamma2, are present in haematopoietic cells. The signalling cascade involved in the regulation of these two isoforms varies between cells, though the systems are similar for both PLCgamma1 and PLCgamma2. We will compare these cascades for both PLCgamma1 and PLCgamma2 and discuss possible reasons as to why one form of PLCgamma and not the other is required for signalling in specific haematopoietic cells, including T lymphocytes, B lymphocytes, platelets, and mast cells. PMID- 11602180 TI - Testosterone- and phorbol ester-stimulated proliferation in human cultured prostatic stromal cells. AB - Prostatic stromal proliferation may be commonly associated with the development of benign prostatic hyperplasia. In this study, we investigate the role of testosterone and protein kinase C in stimulating cultured stromal cell proliferation. Testosterone increased the uptake of [(3)H]-thymidine into the human cultured prostatic stromal cells, this was reduced by the protein kinase C inhibitors, bisindolylymaleimide (10 nM) and myristoylated protein kinase C inhibitor (mPKCi, 20 microM), but not by Go 6983 (1 microM) or Go 6976 (1 microM). Cells responded to the addition of the PKC activators phorbol 12,13 dibutyrate (PDB), phorbol 12,13 diacetate (PDA), 12-deoxyphorbol 13-acetate (DPA) and 12-deoxyphorbol 13-tetradecanoate (DPT) with proliferation (order of potency DPT> or =PDB>>PDA=DPA). The DPT-stimulated proliferative response was inhibited after cells were electroporated with PKCalpha antisense, but not mismatch oligonucleotides (8 microM). These results indicate that PKCalpha is involved in the proliferative response of human cultured prostatic stromal cells. PMID- 11602181 TI - Maitotoxin-induced calcium entry in human lymphocytes: modulation by yessotoxin, Ca(2+) channel blockers and kinases. AB - We have studied the effect of the ciguatera-related toxin maitotoxin (MTX) on the cytosolic free calcium concentration ([Ca(2+)]i) of human peripheral blood lymphocytes loaded with the fluorescent probe Fura2 and the regulation of MTX action by different drugs known to interfere in cellular Ca(2+) signalling mechanisms and by the marine phycotoxin yessotoxin (YTX). MTX produced a concentration-dependent elevation of [Ca(2+)]i in a Ca(2+)-containing medium. This effect was stimulated by pretreatment with YTX 1 microM and NiCl(2) 15 microM. The voltage-independent Ca(2+) channel antagonist 1-[beta-[3-(4 methoxyphenyl)propoxyl]-4-methoxyphenyl]-1H-imidazole hydrochloride (SKF96365) blocked the MTX-induced [Ca(2+)]i elevation, while the L-type channel blocker nifedipine had no effect. Pretreatment with NiCl(2) or nifedipine did not modify YTX-induced potentiation of MTX effect, and SKF96365-induced inhibition was reduced in the presence of YTX, which suggest different pathways to act on [Ca(2+)]i. Preincubation with N-[2-(p-bromocinnamylamino)ethyl]-5 isoquinolinesulfonamide.2HCl (H-89) or genistein (10 microM) also had no effect on the MTX-induced [Ca(2+)]i increment. In contrast, the PKC inhibitor bisindolilmaleimide I (GF109203X 1 microM) potentiated the MTX effect, whereas phosphatidylinositol (PI) 3-kinase inhibition with wortmannin (10 nM) reduced the MTX-elicited Ca(2+) entry. In summary, MTX produced Ca(2+) influx into human lymphocytes through a SKF96365-sensitive, nifedipine-insensitive pathway. The MTX induced [Ca(2+)]i elevation was stimulated by the marine toxin YTX through a mechanism insensitive to SKF96365, nifedipine or NiCl(2). It was also stimulated by the divalent cation Ni(2+) and PKC inhibition and was partially inhibited by PI 3-kinase inhibition. PMID- 11602182 TI - The somatostatin analogue TT-232 induces apoptosis in A431 cells: sustained activation of stress-activated kinases and inhibition of signalling to extracellular signal-regulated kinases. AB - TT-232 is a somatostatin analogue containing a five-residue ring structure. The present report describes TT-232-induced signalling events in A431 cells, where a 4-h preincubation with the peptide irreversibly induced a cell death program, which involves DNA-laddering and the appearance of shrunken nuclei, but is unrelated to somatostatin signalling. Early intracellular signals of TT-232 include a transient two-fold activation of the extracellular signal-regulated kinase (ERK2) and a strong and sustained activation of the stress-activated protein kinases c-Jun NH(2)-terminal kinase (JNK)/SAPK and p38MAPK. Blocking the signalling to ERK or p38MAPK activation had no effect on the TT-232-induced cell killing. At the commitment time for inducing cell death, TT-232 decreased EGFR tyrosine phosphorylation and prevented epidermial growth factor (EGF)-induced events like cRaf-1 and ERK2 activation. Signalling to ERK activation by FCS, phorbol 12-myristate 13-acetate (PMA) and platelet-derived growth factor (PDGF) was similarly blocked. Our data suggest that TT-232 triggers an apoptotic type of cell death, concomitant with a strong activation of JNK and a blockade of cellular ERK2 activation pathways. PMID- 11602184 TI - The gamma subunit of the rod photoreceptor cGMP phosphodiesterase can modulate the proteolysis of two cGMP binding cGMP-specific phosphodiesterases (PDE6 and PDE5) by caspase-3. AB - We have investigated whether the proteolysis of members of the cGMP binding phosphodiesterases (PDE6, PDE5A1, and PDE10A2) by caspase-3 is modulated by the gamma inhibitor subunit of PDE6. We show here that purified caspase-3 proteolyses PDE6, an enzyme composed of two nonidentical catalytic subunits (termed alpha and beta) with molecular mass of 88 and 84 kDa. The proteolysis of PDE6 produced a single fragment with a molecular mass of 78 kDa. This corresponds to the possible cleavage of the caspase-3 consensus DFVD site (amino acids: 164-168) in the alpha subunit and leads to a 50% decrease in the cGMP hydrolysing activity of the enzyme. The addition of rod PDEgamma to the incubation completely blocked the cleavage of PDE6 by caspase-3. In contrast, rod PDEgamma converted PDE5A1 (molecular mass of 98 kDa) to a better substrate for caspase-3. This resulted in the formation of four major fragments with molecular mass of 82-83, 67, 43, and 34 kDa. In addition, caspase-3 induced an approximately 80% reduction in the activity of a partially purified preparation of PDE5A1 in the presence of rod PDEgamma. Caspase-3 also cleaved PDE10A2 (molecular mass of 95 kDa) to a single 48-kDa fragment. This was consistent with cleavage of the DLFD site (amino acids: 312-315) in PDE10A2. In contrast with both PDE6 and PDE5A1, rod PDEgamma was without effect on this enzyme. These data show that rod PDEgamma interacts with at least two members of the cGMP binding PDE family (PDE5A1 and PDE6) and can exert differential effects on the cleavage of these enzymes by caspase-3. PMID- 11602183 TI - p73 is a growth-regulated protein in vascular smooth muscle cells and is present at high levels in human atherosclerotic plaque. AB - p73 is a newly described homologue of the tumour suppressor p53 that was cloned serendipitously and subsequently shown to possess considerable homology in the most evolutionarily conserved p53 domains. Yet despite the fact that p53 and p73 have extensive structural similarities, their functions are proving to be quite different. We now show that p73 is a growth-regulated protein in the vasculature, being markedly increased in cultured vascular smooth muscle (VSM) cells stimulated with 10% serum, with no significant change in p73 mRNA levels. Stability of p73 is increased after serum stimulation and, probably contributing to this increase in p73 stability, the c-Abl oncogene protein displays a higher molecular weight species and is probably phosphorylated and activated in serum stimulated VSM cells. The serum-mediated induction of p73 is not altered when the cells are incubated with inhibitors of the MAP/ERK pathway or tyrosine kinases, and is not stimulated by PDGF-BB, demonstrating that the mechanism of the increase in p73 does not involve this classical receptor tyrosine kinase growth factor signalling cascade. p73 is markedly increased in plaque tissue taken from atherosclerotic human carotid arteries, but not in comparable intimal scrapings from normal human arteries. Our data indicate that the tumour suppressor homologue p73 probably plays a role in VSM cell cycle progression, being mediated by a specific, as yet unidentified, serum component, and identifies a new function for this protein as being important in the pathogenesis of human atherosclerosis as well as other vascular diseases. PMID- 11602186 TI - Nitric oxide inhibition of cAMP synthesis in parotid acini: regulation of type 5/6 adenylyl cyclase. AB - The nitric oxide (NO) donor, GEA 3162, inhibited isoproterenol-induced cyclic AMP (cAMP) accumulation in a concentration- and time-dependent manner in mouse parotid acini; SIN-1 mimicked these effects. Inhibition of stimulated cAMP accumulation was independent of phosphodiesterase activity. GEA 3162 also inhibited forskolin-induced cAMP accumulation. Removal of extracellular Ca(2+), addition of La(3+), or the calmodulin (CaM) inhibitor, calmidazolium, did not prevent the NO-mediated response, and addition of the soluble guanylyl inhibitor, ODQ, did not reverse GEA 3162-induced inhibition of cAMP accumulation. GEA 3162 also inhibited adenylyl cyclase in vitro independently of Ca(2+)/CaM. Further studies revealed that the NO synthase (NOS) inhibitor, 7-nitroindazole (7-NI), reduced significantly thapsigargin-induced Ca(2+) release and capacitative Ca(2+) entry and reversed thapsigargin inhibition of the AC Type 5/6 isoform (AC5/6). Data suggest that NO produced endogenously has dual effects on cAMP accumulation in mouse parotid acini, an inhibitory effect on AC activity and a modulatory effect on capacitative Ca(2+) entry resulting in AC5/6 inhibition. PMID- 11602185 TI - Activation of Raf/ERK1/2 MAP kinase pathway is involved in GM-CSF-induced proliferation and survival but not in erythropoietin-induced differentiation of TF-1 cells. AB - The involvement of MAPK pathways in differentiation, proliferation and survival was investigated by comparing Epo and GM-CSF signalling in human factor-dependent myeloerythroid TF-1 cells with abnormal Epo-R. GM-CSF withdrawal induced cell cycle arrest and apoptosis accompanied by increased caspase-3 activity, DNA degradation and reduced expression of the antiapoptotic Bcl-2 and Bcl-xl proteins. Readministration of GM-CSF but not Epo reversed these processes and induced proliferation. The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA binding. In contrast, Epo failed to activate the Raf-1/ERK1/2 MAPK pathway or to induce Egr-1 and/or c-Fos expression, while it induced erythroid differentiation in GM-CSF-deprived cells. In addition, the Epo-induced haemoglobin production was inhibited in the presence of GM-CSF. These results demonstrate that the activation of MAPK cascade is not necessary for Epo-induced haemoglobin production in TF-1 cells and suggest a negative cross-talk between the signalling of GM-CSF-stimulated cell proliferation and Epo-induced erythroid differentiation. PMID- 11602187 TI - Biochemical mechanisms that interact with membrane-associated IL-1 RII (60-kDa decoy) receptors in populations of adherent macrophages and vascular endothelium. AB - The aim of this investigation was to identify the potential biochemical mechanisms that alter the integrity of membrane-associated IL-1 RII (decoy) receptor complexes expressed by populations of adherent macrophages and vascular endothelium. The initial research strategy utilized to achieve this objective involved delineating the ability of macrophage activation or exposure of macrophages and vascular endothelium to a spectrum of enzyme proteases to influence the expression of membrane-associated IL-1 RII (decoy) or generate soluble fragments of this receptor complex. Results from these investigations revealed that stimulated macrophages displayed proportional increases in both the expression of membrane-associated IL-1 RII (decoy) and release of soluble receptor fragments. Exposure of macrophages and vascular endothelium to the reference proteases discovered the ability of cathepsin-D to biochemically deplete membrane-associated IL-1 RII (decoy) in addition to generating soluble fragments of this receptor complex. Complementary investigations isolated a carboxyl/aspartate protease from activated macrophages utilizing pepstatin-A affinity chromatography. Exposure of vascular endothelium to pepstatin-A binding proteins resulted in a detectable depletion of membrane-associated IL-1 RII (decoy) and generation of soluble receptor fragments. Evaluation of pepstatin-A binding proteins by SDS-PAGE identified a primary protein fraction with a molecular mass of 47-52 kDa that closely correlates with the known molecular size of leukocyte cathepsin-D fractions. Macrophage pepstatin-A binding protein fractions evaluated by nondenaturing haemoglobin-substrate PAGE (Hb-PAGE) analysis detected a lucent proteolytic band at 47-52 kDa. Macrophage pepstatin-A binding proteins also hydrolyzed a synthetic enzyme-specific substrate that selectively recognizes cathepsin-D biochemical activity. In conclusion, the leukocyte carboxyl/aspartate protease cathepsin-D can biochemically alter the integrity and generate soluble fragments of membrane-associated IL-1 RII (60-kDa decoy) receptor complexes expressed by macrophages and vascular endothelium. PMID- 11602189 TI - Evolution of effectors and receptors of innate immunity. AB - The bony fishes are derived from one of the earliest divergent vertebrate lineages to have both innate and acquired immune systems. They are considered by some to be an ideal model to study the underpinnings of immune systems precisely because of their phylogenetic position and the fact that their adaptive immune systems have not been elaborated to the extent seen in mammals. By the same token, examination of innate immune systems in invertebrates and early chordates can provide insight into how homologous systems operate in fish and higher vertebrates. Herein, we provide an overview of the molecular evidence that we hope helps clarify the evolutionary relationships of innate immune molecules identified in bony fishes. The innate immune systems being considered include select chemokines (CC and CXC chemokines and their receptors), cytokines (IL-1, IL-8, interferons, TGF-beta, TNF-alpha), acute phase proteins (SAA, SAP, CRP, alpha2M, and the complement components--C3-C9, MASP, MBL, Bf), NK cell receptors, and molecules upstream and downstream of the Toll signaling pathways. PMID- 11602190 TI - The relationship between major histocompatibility receptors and innate immunity in teleost fish. AB - Studies of the innate immune system have recently shown that, in addition to its role in producing the primary response that slows down pathogens, it may also play an important role in initiating and directing the type of response that the adaptive immune system makes. These discoveries have shown a complex web of control containing new roles for the innate immune system in organizing responses of T-cell to antigens being presented by major histocompatibility receptors, as well as new roles for those receptors in innate immune responses. Both of these activities are managed through feedback networks involving elements of both the innate and adaptive immune system. This paper will discuss these newly discovered interactions and how they are influencing current theories regarding the initiation of adaptive immune responses. In particular, it will highlight the recent progress that is being made towards understanding these relationships in the immune systems of teleost fish. PMID- 11602191 TI - The non-specific cytotoxic cell receptor (NCCRP-1): molecular organization and signaling properties. AB - The evolutionary precursor to mammalian natural killer cells in teleost fish is called non-specific cytotoxic cells (NCC). NCC collaborate with other non specific effector mechanisms to provide innate resistance during acute stress responses. The NCC receptor protein (NCCRP-1) contains 238 amino acid residues and is believed to be a type III membrane protein with three distinct functional domains. The antigen-binding domain has been mapped to amino acids nos. 104-119. The intracellular C-terminus contains a high concentration of potential phosphorylation sites (Y, S, T). Indeed, we have shown that activation of NCC by crosslinking of NCCRP-1 leads to receptor tyrosine and serine phosphorylation. The N-terminus of the molecule is also inside the cells and has as well signature amino acids, proline-rich motifs (PRM), that are indicative of functional relevance. The cytokine/hormone receptor-like PRMs are known docking sites for JAK kinases. We have evidence that following activation, NCCRP-1 comes in contact with JAK kinase and as a result of this interaction, STAT 6 is translocated into the nucleus. These results suggest that NCCRP-1 may play a dual role in the activation of NCC: first, as an antigen recognition molecule necessary for target cell lysis, and second, as an initiator of cytokine release from NCC. Both of these processes are required for a competent innate immune response. PMID- 11602192 TI - Cytokines and innate immunity of fish. PMID- 11602193 TI - The acute phase response and innate immunity of fish. AB - Tissue trauma or invasion by pathogens or parasites induce changes in the quantities of several macromolecules in animal body fluids. These changes comprise one aspect of the acute phase response (APR), which in toto involves metabolic changes in several organ systems. One clear indication of the response is the increase in synthesis and secretion by the liver of several plasma proteins, with simultaneous decreases in others. These acute phase proteins (APP) function in a variety of defense-related activities such as limiting the dispersal of infectious agents, repair of tissue damage, inactivation of proteases, killing of microbes and other potential pathogens, and restoration of the healthy state. Some APP are directly harmful to microbes, while others modify targets thus marking them for cell responses. Some work alone while others contribute to cascades. Proteins that are APP in mammals, and that have been identified in both teleosts and elasmobranchs include C-reactive protein, serum amyloid P, and several components of the Complement system. Others reported in teleosts include transferrin and thrombin. Of these, only CRP has been reported to increase in acute phase plasma. In trout, a precerebellin-like protein is an APP with unknown functions. A cDNA library enriched in fragments of transcripts that were more abundant in livers from fish undergoing an APR recently yielded sequences resembling 12 additional known APP, and as many others either not known to be APP, or not similar to others yet in public databases. It appears that, as in mammals, hepatocytes are the prime source of APP in fish, and that pro inflammatory cytokines induce transcription of their genes. PMID- 11602194 TI - Phylogenetic aspects of the complement system. AB - During evolution two general systems of immunity have emerged: innate or, natural immunity and adaptive (acquired), or specific immunity. The innate system is phylogenetically older and is found in some form in all multicellular organisms, whereas the adaptive system appeared about 450 million years ago and is found in all vertebrates except jawless fish. The complement system in higher vertebrates plays an important role as an effector of both the innate and the acquired immune response, and also participates in various immunoregulatory processes. In lower vertebrates complement is activated by the alternative and lectin pathways and is primarily involved in the opsonization of foreign material. The Agnatha (the most primitive vertebrate species) possess the alternative and lectin pathways while cartilaginous fish are the first species in which the classical pathway appears following the emergence of immunoglobulins. The rest of the poikilothermic species, ranging from teleosts to reptilians, appear to contain a well-developed complement system resembling that of the homeothermic vertebrates. It seems that most of the complement components have appeared after the duplication of primordial genes encoding C3/C4/C5, fB/C2, C1s/C1r/MASP-1/MASP-2, and C6/C7/C8/C9 molecules, in a process that led to the formation of distinct activation pathways. However, unlike homeotherms, several species of poikilotherms (e.g. trout) have recently been shown to possess multiple forms of complement components (C3, factor B) that are structurally and functionally more diverse than those of higher vertebrates. We hypothesize that this remarkable diversity has allowed these animals to expand their innate capacity for immune recognition and response. Recent studies have also indicated the possible presence of complement receptors in protochordates and lower vertebrates. In conclusion, there is considerable evidence suggesting that the complement system is present in the entire lineage of deuterostomes, and regulatory complement components have been identified in all species beyond the protochordates, indicating that the mechanisms of complement activation and regulation have developed in parallel. PMID- 11602195 TI - Transcriptional regulation of hemopoiesis. AB - The regulation of blood cell formation, or hemopoiesis, is central to the replenishment of mature effector cells of innate and acquired immune responses. These cells fulfil specific roles in the host defense against invading pathogens, and in the maintenance of homeostasis. The development of hemopoietic cells is under stringent control from extracellular and intracellular stimuli that result in the activation of specific downstream signaling cascades. Ultimately, all signal transduction pathways converge at the level of gene expression where positive and negative modulators of transcription interact to delineate the pattern of gene expression and the overall cellular hemopoietic response. Transcription factors, therefore, represent a nodal point of hemopoietic control through the integration of the various signaling pathways and subsequent modulation of the transcriptional machinery. Transcription factors can act both positively and negatively to regulate the expression of a wide range of hemopoiesis-relevant genes including growth factors and their receptors, other transcription factors, as well as various molecules important for the function of developing cells. The expression of these genes is dependent on the complex interactions between transcription factors, co-regulatory molecules, and specific binding sequences on the DNA. Recent advances in various vertebrate and invertebrate systems emphasize the importance of transcription factors for hemopoiesis control and the evolutionary conservation of several of such mechanisms. In this review we outline some of the key issues frequently identified in studies of the transcriptional regulation of hemopoietic gene expression. In teleosts, we expect that the characterization of several of these transcription factors and their regulatory mechanisms will complement recent advances in a number of fish systems where identification of cytokine and other hemopoiesis-relevant factors are currently under investigation. PMID- 11602196 TI - Nonspecific cytotoxic cells and innate immunity: regulation by programmed cell death. AB - Although programmed cell death (PCD) and the cellular pathology of apoptosis have been extensively studied in mammals and invertebrates, little is known regarding these important regulatory processes in cold blooded vertebrates, especially teleost fish. In the present review, select immunoregulatory properties of PCD/apoptosis in nonspecific cytotoxic cells (NCC) from catfish and tilapia were identified. The techniques used to define the characteristics of PCD in NCC were DNA ploidy, Annexin-V binding and cellular morphology. Using these procedures, we determined that the biochemical/genetic changes that NCC undergo during PCD are similar to those described in mammalian cells. We hypothesize that one immediate response of NCC to acute stress in teleost fish is the release of apoptosis regulatory factors (ARF) or stress activated serum factors (SASF) into the peripheral blood. These cytokine-like factors activate NCC by protecting them from initiation of: "activation induced cell death" (AICD); from "receptor induced apoptosis"; and from initiation of dexamethasone induced DNA hypoploidy. We predict that the mechanism of these actions is enhanced NCC recycling capacity and initiation of migration of NCC into sites of inflammation. In this review, studies were also summarized regarding the expression and release of "death and survival proteins" by NCC. Although the survey was not exhaustive, we showed that tilapia NCC that were activated in vitro with SASF contained increased levels of two adaptor proteins (i.e. CAS, FADD) and soluble FasL. At present the relevance of expression of the adaptor proteins by NCC is not known, however, additional evidence for the role of FasL in NCC innate immune responses was presented. Interestingly, NCC contained constitutive cytosolic FasL, and activation with tumor cells caused a significant decrease in the cytoplasmic levels of this "death protein". This indicated that FasL in NCC may function as a secretory cytokine-like molecule. Unlike mammalian NK cells and T-cells, activated NCC do not express membrane FasL. A level of phosphatase regulation of NCC apoptosis was indicated by demonstrating a reduced camptothecin induce DNA hypoploidy by pretreatment of NCC with the tyrosine phosphatase inhibitor sodium orthovanadate. This review emphasized the important regulatory functions of PCD/apoptosis for NCC in innate immune responses. PMID- 11602197 TI - Antimicrobial mechanisms of fish phagocytes and their role in host defense. AB - Phagocytosis is a primitive defense mechanism in all multicellular animals. Phagocytes such as macrophages and neutrophils play an important role in limiting the dissemination of infectious agents, and are responsible for the eventual destruction of phagocytosed pathogens. These cells have evolved elaborate killing mechanisms for destroying pathogens. In addition to their repertoire of degradative enzymes and antimicrobial peptides, macrophages and neutrophils can be activated to produce a number of highly toxic molecules. Production of reactive oxygen and nitrogen intermediates by these cells are potent cytotoxic mechanisms against bacteria and protozoan pathogens. Studies in fish suggest that the biological basis of these inducible killing mechanisms is similar to those described in mammals. More recent work suggest novel roles for regulating these killing responses in fish. In this review, we describe the biological basis of these killing mechanisms and how they are regulated in fish. PMID- 11602198 TI - Innate host defense mechanisms of fish against viruses and bacteria. AB - The integumental defenses provide a physical and chemical barrier to the attachment and penetration of microbes. Besides the entrapping and sloughing of microbes in the mucus, the latter contains many antibacterial substances including anti-bacterial peptides, lysozyme, lectins and proteases. The gastro intestinal tract is a hostile environment of acids, bile salts and enzymes able to inactivate and digest many viruses and bacteria. In most cases the integumental defenses are sufficient to protect against even quite virulent organisms which often only produce disease when the integument has been physically damaged. If a microbe gains access to the tissues of the fish, it is met with an array of soluble and cellular defenses. The complement system, present in the blood plasma, plays a central role in recognising bacteria and its activated products may lyse the bacterial cells, initiate inflammation, induce the influx of phagocytes and enhance their phagocytic activity. Complement can be activated directly by bacterial products and constituents and also indirectly by other factors, principally C-reactive protein and lectins, which can also bind to the bacterial surface. Plasma also contains a number of factors which inhibit bacterial growth(e.g. transferrin and anti-proteases) or which are bactericidal e.g. lysozyme. Following the infection of fish with virus pathogens, infected cells produce interferon. This induces antiviral defenses in neighbouring cells which are then protected from becoming infected. Anti-viral cytotoxic cells are able to lyse virally infected cells and thus reduce the rate of multiplication of virus within them. Innate defenses thus provide a pre-existing and fast-acting system of protection which is non-specific and relatively temperature-independent and thus has several advantages over the slow-acting and temperature-dependent specific immune responses. PMID- 11602199 TI - The occurrence and mechanisms of innate immunity against parasites in fish. AB - Parasitic infections in teleost fish are limited by constitutive innate defence mechanisms that render the host refractory or reduce the severity of infection. Controlled challenge trials using naive animals provide indirect evidence of innate immunity as well as identifying the host range or specificity of a parasite, often when specific details of defence mechanism(s) are lacking. Examples of parasites for which innate immunity may be inferred from cross infectivity studies include Gyrodactylus spp., Lepeophtheirus salmonis, Cryptobia spp., Trypanosoma spp., Ceratomyxa shasta, Myxobolus cerebralis and Kudoa thyrsites. Recent studies however, have begun to clarify the relative roles of innate and acquired immunity against parasitic infection in teleosts by recognizing the presence and significance of specific innate effector mechanisms. The physico-chemical characeristics of skin mucus, the presence of bioactive substances including lysozyme, complement, C-reactive protein, haemolysins and lectins and the epidermal migration of inflammatory cells and their secretions may affect the establishment and proliferation of ectoparasitic copepods, ciliates or monogenea. Similarly in refractory species, haematozoic parasites are lysed via the alternative complement pathway and in susceptible and refractory hosts, protease inhibitors associated with the plasma neutralize proteolytic virulence factors. Detailed knowledge of innate resistance mechanisms against histiozoic parasites are lacking although non-specific cytotoxic lymphoid cells and macrophages probably play a role. The demonstration in certain disease models that innate resistance traits are under genetic control and may be inherited in a simple Mendelian fashion suggests opportunities for selective breeding for resistance against parasitic disease. Beyond a small number of well-described models however, research programs focussing on innate immunity against parasites in fish are lacking. Given the relative importance of innate immunity in fish, particularly as disease losses continue to have an economic impact in aquaculture, this area deserves considerable attention. PMID- 11602200 TI - Ecotoxicology and innate immunity in fish. AB - This review summarizes the scattered literature on the effects of toxicants on the external and internal innate immunity of fish. Insecticides, heavy metals and surfactants have been the most frequently examined toxicants, whereas dioxins, furans and polychlorinated biphenyls have been tested less frequently. Studies to date have been conducted at the levels of cells in vitro, of fish in the laboratory and microcosms, and also of fish in the field. Among innate immune parameters, phagocyte respiratory burst appears especially sensitive to toxicants. Toxicant-induced alterations in external mucous production have also been observed repeatedly. Field studies have occasionally examined changes to melano-macrophage centers, but the meaning of such changes is not clear. Advances in basic knowledge of fish innate immunity should lead to improvements in monitoring fish health and predicting the impact of toxicants on fish populations, which is a fundamental ecotoxicological goal. PMID- 11602202 TI - Aging research in Switzerland. AB - The present review on aging research in Switzerland describes ongoing gerontological and geriatric research in the field of both basic science and clinical research. Although Switzerland is situated at the rear end of the scale in regard of size or number of inhabitants, the number of high quality research groups per inhabitant positions it amongst the leading countries in the Western world. Being a small country Switzerland counts only five universities with clinical affiliations. Aging research in Switzerland therefore does not cover all areas of this rapidly developing discipline but some of the scientific contributions are mirrored in highest scored journals or others focus on topics that clearly bridge geriatric research and research on cellular and molecular mechanisms of aging. PMID- 11602201 TI - Biological ageing research in the Netherlands. AB - After an introduction on the development of biological ageing research in the Netherlands during the past decades, 606 papers on aging published by Dutch institutes in the period 1991-2000, collected from PubMed, were analysed for their relevance to research into biological ageing. For the period 1996-2000, the total number of research papers on biological ageing amounted to 142, which accounts for 23% of all publications on ageing in that period. The number of publications per year did not change. On the basis of these papers and additional information provided by research groups a comprehensive overview of biological ageing research in the Netherlands is presented, together with an extensive literature list. Ageing of the central nervous system (CNS), of the endocrinological system and of the cardiovascular system are the topics most studied. It is concluded that general biological ageing research has not increased in the Netherlands over the last ten years, and that the infrastructure for basic biological ageing research in the Netherlands is weak. PMID- 11602203 TI - The human melanocyte: a model system to study the complexity of cellular aging and transformation in non-fibroblastic cells. AB - The melanocyte is a neural crest-derived cell that localizes in humans to several organs including the epidermis, eye, inner ear and leptomeninges. In the skin, melanocytes synthesize and transfer melanin pigments to surrounding keratinocytes, leading to skin pigmentation and protection against solar exposure. We have investigated the process of replicative senescence and accompanying irreversible cell cycle arrest, in melanocytes in culture. As was found in other cell types, progressive telomere shortening appears to trigger replicative senescence in normal melanocytes. In addition, senescence is associated with increased binding of the cyclin-dependent kinase inhibitor (CDK I) p16(INK4a) to CDK4, down-regulation of cyclin E protein levels (and consequent loss of cyclin E/CDK2 activity), underphosphorylation of the retinoblastoma protein RB and subsequent increased levels of E2F4-RB repressive complexes. In contrast to fibroblasts, however, the CDK-Is p21(Waf-1) and p27(Kip-1) are also down-regulated. These changes appear to be important for replicative senescence because they do not occur in melanocytes that overexpress the catalytic subunit of the enzyme telomerase (hTERT), or in melanomas, which are tumors that originate from melanocytes or melanoblasts. In contrast to unmodified melanocytes, hTERT overexpressing (telomerized) melanocytes displayed telomerase activity, stable telomere lengths and an extended replicative life span. However, telomerized melanocytes show changes in cell cycle regulatory proteins, including increased levels of cyclin E, p21(Waf-1) and p27(Kip-1). Cyclin E, p21(Waf-1) and p27(Kip-1) are also elevated in many primary melanomas, whereas p16(INK4a) is mutated or deleted in many invasive and metastatic melanomas. Thus, the molecular mechanisms leading to melanocyte senescence and transformation differ significantly from fibroblasts. This suggests that different cell types may use different strategies to halt the cell cycle in response to telomere attrition and thus prevent replicative immortality. PMID- 11602205 TI - Identification of the gene immediately downstream of the murine INK4a/ARF locus. AB - The tumor suppressor gene ARF is formed by three exons, namely exons 1 beta, 2 and 3. Here, we show that embryo fibroblasts from mice genetically deficient in exons 2 and 3 (Delta 2,3) express a transcript formed by exon 1 beta followed by the 3'-terminal exon of the gene immediately downstream of the INK4a/ARF locus, which we have called NTp16 (Next-To-p16). The chimeric ARF-NTp16 transcript is not detectable in wild-type fibroblasts but its expression level in Delta 2,3 fibroblasts is 30% compared to the level of the normal ARF transcript in wild type cells. Expression of the ARF-NTp16 transcript in Delta 2,3 cells is subject to normal regulatory features, such as upregulation by the accumulation of cell doublings, and by the presence of oncogenic Ras or E1a. The chimeric ARF-NTp16 transcript has the potential to encode a 17kDa peptide; however, this peptide is not accumulated in cells at detectable levels, probably reflecting poor codon usage or protein instability. We conclude that Delta 2,3 cells do not retain ARF functionality, at least to a significant extent. Interestingly, the expression pattern of the full-length NTp16 gene is altered in several tissues by the presence of the Delta 2,3 mutation. Finally, these data identify the gene immediately downstream of the INK4a/ARF locus, a region that has been previously proposed to contain another tumor suppressor different from the INK4a/ARF genes. PMID- 11602204 TI - Mathematical modeling of the aging processes and the mechanisms of mortality: paramount role of heterogeneity. AB - Main problems of modeling the link between aging processes and mechanisms of mortality are addressed. Various applications of Gompertz's law, which allowed to formulate some fruitful hypotheses on the field, are reviewed. Some pitfalls occurring in its applications are also discussed using a model built on purpose to overcome these difficulties. The role played by heterogeneity emerges as the common cause of some relevant failure in using Gompertz's law and the necessary key ingredient of any model aimed to interpret the link between aging and mortality correctly. Though a number of problems are related to inter-individual variability, the search for their solution can lead to an intriguing approach to the study of aging and mortality. Living beings can be considered as complex systems and their age-related changes can be described at the light of complex system theory. PMID- 11602206 TI - Variations of cardiovascular disease associated genes exhibit sex-dependent influence on human longevity. AB - This article investigates the relationship between the polymorphic variations in genes associated with cardiovascular disease and longevity in the Danish population. A new procedure that combines both demographic and the individual genetic information in determining the relative risks of the observed genetic variations is applied. The sex-dependent influences can be found by introducing sex-specific population survival and incorporating the risk of gene-sex interaction. Three genetic polymorphisms, angiotensinogen M/T235, blood coagulation factor VII (FVII) R/Q353 and FVII-323ins10, manifest significant influences on survival in males, with reduced hazards of death for carriers of the angiotensinogen M235 allele, the F VII Q353 allele, and the FVII-323P10 allele. The results show that some of these genotypes associated with lower risk of CVD could also reduce the carrier's death rate and contribute to longevity. However, the presence of sex-dependent effects and the fact that major CVD associated genes failed to impose detrimental influence on longevity lead us to concur that the aging process is highly complicated. PMID- 11602207 TI - Up-regulation of S100C in normal human fibroblasts in the process of aging in vitro. AB - S100 proteins belonging to the EF-hand Ca(2+)-binding protein family regulate a variety of cellular processes via interaction with different target proteins. Several diseases, including cancer and Alzheimer's disease, are related to a disorder of multifunctional S100 proteins, which are expressed in cell- and tissue-specific manners. We previously demonstrated that S100C could move to and accumulate in the nuclei of normal human fibroblasts but not in the nuclei of immortalized and neoplastic cells. In addition, we found that its nuclear accumulation resulted in suppression of DNA synthesis in normal cells at a confluent stage. In the present study, we investigated whether S100C was associated with cellular senescence in vitro. We found that S100C expression increased in normal human fibroblasts in the process of aging in culture and was accompanied by accumulation of its protein in the nuclei of senescent fibroblasts. In addition, the nuclear accumulation of S100C increased expression of a cyclin-dependent kinase inhibitor p21(Sdi1), a strong inhibitor of cell growth. These findings suggest that an increase in the cells having nuclear accumulation of S100C is closely related to the process of cellular senescence of normal human fibroblasts. PMID- 11602208 TI - Replicative senescence of human endothelial cells in vitro involves G1 arrest, polyploidization and senescence-associated apoptosis. AB - Human ageing is characterized by a progressive loss of physiological functions, increased tissue damage and defects in various tissue renewal systems. Age related decreases of the cellular replicative capacity can be reproduced by in vitro assays of cellular ageing. When diploid human fibroblasts reach their finite lifespan, they enter an irreversible G1 growth arrest status referred to as replicative senescence. While deregulation of programmed cell death (apoptosis) is a key feature of age-related pathology in several tissues, this is not reflected in the standard in vitro senescence model of human fibroblasts, and the role of apoptosis during cellular ageing remains unclear. We have analyzed replicative senescence of human umbilical vein endothelial cells (HUVEC) in vitro and found that senescent HUVEC also arrest in the G1 phase of the cell cycle but, unlike fibroblasts, accumulate with a 4N DNA content, indicative of polyploidization. In contrast to human fibroblasts, senescent endothelial cells display a considerable increase in spontaneous apoptosis. The data imply that age dependent apoptosis is a regular feature of human endothelial cells and suggest cell type specific differences in human ageing. PMID- 11602209 TI - A cost of reproduction: oxidative stress susceptibility is associated with increased egg production in Drosophila melanogaster. AB - The present study tests the hypothesis that reproduction is correlated with decreased oxidative stress resistance. In numerous species, it has been observed that longevity is negatively correlated with reproduction but the physiological basis of this cost is not well understood. In the present study, female egg production was stimulated by adding live yeast to the surface of Drosophila food. After females were held on yeast-supplemented and unmodified medium for 6-12 days, susceptibility to oxidative stress was measured by exposure to methyl viologen. Added yeast was associated with stress susceptibility of fertile females but not of sterile females. The results of the present study suggest that oxidative stress susceptibility is a physiological cost of reproduction. PMID- 11602210 TI - Age-related increase in mitochondrial superoxide generation in the testosterone producing cells of Brown Norway rat testes: relationship to reduced steroidogenic function? AB - Aging in Brown Norway rats is accompanied by the reduced production of testosterone by the Leydig cells, the testicular cells responsible for synthesizing and secreting this essential steroid. As yet, the mechanism by which Leydig cell steroidogenesis is reduced is unknown. Herein we assess the production of mitochondrial reactive oxygen species by intact Leydig cells isolated from the testes of young and old rats. To this end, Leydig cells were incubated with lucigenin (bis-N-methylacridinium nitrate), a probe that enters cells, localizes to mitochondria, and yields a significant chemiluminescent response following its reaction with intramitochondrial superoxide. Leydig cells from old rats elicited significantly greater lucigenin-derived chemiluminescence (LDCL) than those from young rats. Electron microscopic stereological analysis revealed that the absolute volume of mitochondria in the old cells was reduced from that in the young. These results, taken together, suggest that there are age related changes in the production of reactive oxygen species by the mitochondria of Leydig cells, with those of old Leydig cells producing significantly greater levels than those of young Leydig cells. The results are consistent with the proposal that mitochondrial-derived reactive oxygen may play a role in the irreversible decline in the ability of old Leydig cells to produce testosterone. PMID- 11602211 TI - Levels of 8-hydroxy-2'-deoxyguanosine in cellular DNA from 12 tissues of young and old Sprague-Dawley rats. AB - The age dependent increase of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) reported in DNA of organs of old rats appears to vary with the strain, age and sex of the animals used for the investigation. Here we report on 8-OH-dG concentrations in the cellular DNA of 12 tissues of male Sprague-Dawley rats aged 5 or 30 months and kept under standard conditions throughout their lives until being killed. DNA from frozen organs was isolated using a Qiagen DNA purification kit. Following digestion (nuclease P1, alkaline nuclease) hydrolysed DNA was applied onto a HPLC column; native nucleosides were monitored at 254 nm and 8-OH-dG by electrochemical detection. 8-OH-dG levels in organs of young rats ranged between 10 and 90 micromol/mol deoxyguanosine (dG). Highest levels (micromol 8-OH-dG /mol dG) were detected in the oesophagus (90), muscle (61), brain (65), liver (59), spleen (57), and testicles (63). 8-OH-dG in DNA from kidney, lung, heart, small and large intestine ranged between 28 and 38 micromol/mol dG. Lowest amounts were found in the glandular stomach (10). DNA of old rats generally contained higher 8 OH-dG levels with significant increases in liver (186%) and kidney (372%); other organs showed no significant decreases (spleen, brain, testicles) or increases up to 69% (heart). These findings are discussed in the context with previously published data on 8-OH-dG levels in organs from young and old rats. PMID- 11602212 TI - Aging promotes a different phosphatidic acid utilization in cytosolic and microsomal fractions from brain and liver. AB - Among the morphological and biochemical changes taking place in the membranes of aged tissues, we reported in previous studies on alterations in phospholipid synthesis and phospholipid-specific fatty acid composition. Phosphatidic acid (PA) and diacylglycerol (DAG) are central intermediates in phosphoglyceride and neutral lipid biosynthetic pathways and have also recently been implicated in signal transduction. The present paper shows the effect of aging on phosphatidate phosphohydrolase (PAPase) activiy, which operates on phosphatidic acid to synthesize diacylglycerol. Two forms of mammalian PAPase can be indentified on the basis of subcellular localization and enzyme properties, one involved predominantly in lipid synthesis (PAP 1) and the other in signal transduction (PAP 2). Microsomal and cytosolic fractions of brain and liver from 3.5-month-old (adult) and 28.5-month-old (aged) rats were used. PAPase isoform activities were differentiated on the basis of N-ethylmaleimide (NEM) sensitivity and Mg(2+) dependency. Our results demonstrate that aging caused PAP 2 to increase in brain microsomal fractions but did not affect PAP 1, whereas in brain cytosolic fractions, it caused a strong decrease in PAP 1 (57%). The distribution of enzymes between microsomes and cytosol changed in aged rats with respect to adult rats, showing a translocation of PAP 1 from cytosol to microsomes. In addition, an increase in the production of monoacylglycerol (MAG) was observed in microsomes from aged brain. PAP 2 activity in liver microsomal fractions from aged rats showed no changes with respect to adult rats whereas PAP 1 activity increased 228% in microsomal fractions and 76% in cytosolic fractions in this tissue. The distribution of PAP 1 activity between microsomal and cytosolic fractions in liver tissue was also affected in aged rats, indicating a translocation of this form of the enzyme from cytosolic to microsomal fractions. The production of monoacylglycerol in liver microsomes also increased, whereas there was a decrease in MAG formation from cytosolic fraction. The changes observed in the two PAPase forms in brain and liver of aged rats with respect to adult rats suggest that PA is differently utilized by the PAPase isoforms, probably generating aging-related DAGs different to those present in adults and required for specific cellular functions. The changes observed in liver PAP 1 from aged with respect to adult rats suggest that such changes could be related with modifications in lipid homeostasis induced by age-altered hormonal balance. However, PA-modified utilization during aging through PAP 2 activity could be related to alterations in neural signal transduction mechanisms. PMID- 11602213 TI - Activin A serum levels and aging of the pituitary-gonadal axis: a cross-sectional study in middle-aged and elderly healthy subjects. AB - Aim of the study was to investigate activin A serum concentration in healthy adult males and post-menopausal females over a wide age-range and its correlation to gonadotropins, inhibin B and testosterone concentrations. The study included 73 males (aged 30-101 years) and 42 postmenopausal females (aged 50-104 years). Blood samples were collected after an overnight fast to measure serum activin A, inhibin B, LH, FSH, and gonadal steroid levels. A significant increase in serum activin A levels over age in both genders, especially in the oldest age-groups, was observed. Serum inhibin B and testosterone concentrations showed a sharp decrease in male subjects, reflecting the age-related decrease of testicular function and by consequence serum FSH and LH significantly increased. In female subjects LH and FSH levels were very high in subjects in their 50s and showed a continuous decline due to pituitary aging. Simple and multivariable regression analyses demonstrated the lack of correlation between activin A and FSH in both males and females. In conclusion, a steep increase in activin A levels is present during aging in both genders, especially in the last decades of life. The physiologic role and site of production of activin A in old subjects remain to be clarified. PMID- 11602214 TI - Caloric restriction lowers plasma lipoprotein (a) in male but not female rhesus monkeys. AB - Many age-associated pathophysiological changes are retarded by caloric restriction (CR). The present study has investigated the effect of CR on plasma lipoprotein (a) [Lp(a)], an independent risk factor for the age-associated process of atherosclerosis. Rhesus monkeys were fed a control diet (n=19 males, 12 females) or subjected to CR (n=20 males, 11 females fed 30% less calories) for >2 years. All female animals were premenopausal. Plasma Lp(a) levels in control animals were almost two fold higher for males than females (47+/-9 vs 25+/-5mg/dl mean+/-SEM, p=0.05). CR resulted in a reduction in circulating Lp(a) in males to levels similar to those measured in calorie-restricted females, (27+/-5 vs 24+/-4 mg/dl mean+/-SEM). For all animals, plasma Lp(a) was correlated with total cholesterol (r=0.27, p=0.03) and LDL cholesterol (r=0.50, p=0.0001) whether unadjusted or after adjustment for treatment, gender or group. These studies introduce a new mechanism whereby CR may have a beneficial effect on risk factors for the development of atherosclerosis in primates. PMID- 11602215 TI - Psychological risk factors in heart disease: what Type D personality is (not) about. PMID- 11602216 TI - Feelings of being disabled as a predictor of mortality in men 10 years after percutaneous coronary transluminal angioplasty. AB - OBJECTIVE: To examine the independent prognostic value of the four subscales of the Heart Patients Psychological Questionnaire (HPPQ) on mortality in male and female patients 10 years following percutaneous transluminal coronary angioplasty (PTCA). METHODS: The HPPQ, which measures well-being, feelings of being disabled, despondency, and social inhibition, was administered to 356 patients (23% women) post-PTCA. The patients were followed for a median of 10 years. Clinical and demographic variables were sampled from medical records. RESULTS: During the follow-up period, 104 patients (29%) had died. Women scored significantly worse on all psychological subscales compared with men. Fifty-nine (72%) women and 92 (34%) men had a score indicating at least mild to moderate feelings of being disabled. Men scoring high on feelings of being disabled were at increased risk of mortality compared with men having a low score, adjusted for other cardiac risk factors (chi(2)=7; P=.008). No differences were found between women with low or high scores on feelings of being disabled (relative risk (RR): 1.2; 95% confidence interval (CI): 0.5-3.3). None of the other HPPQ subscales were related to mortality. CONCLUSION: Feelings of being disabled measured at least 1 year after hospital discharge is a significant predictor of mortality in men 10 years post-PTCA, but not in women. This finding adds to the increasing knowledge that psychosocial variables influence morbidity and mortality in cardiac patients. PMID- 11602217 TI - Experimentally induced anger, cardiovascular reactivity, and pain sensitivity. AB - It was investigated whether an angry state, induced by a computer task with harassing comments, would lead to a decrease in cold pressor pain threshold and tolerance in comparison to a neutral situation. It was hypothesized that an increase in cardiovascular activity might partially mediate effects of anger. Furthermore, it was examined whether subjects given the opportunity to express anger would show reduced cardiovascular activity and pain report compared to subjects not given this opportunity. Finally, trait measures for anger expression style and hostility were included. The results show an increase instead of the expected decrease in pain tolerance for subjects in the harassment condition compared to those in the neutral condition. While cardiovascular reactivity was positively related to pain threshold and tolerance, increased anger was associated with increased pain report. It is suggested that anger and cardiovascular reactivity may have important but sometimes opposing influences on pain. PMID- 11602218 TI - Alexithymia following myocardial infarction: psychometric properties and correlates of the Toronto Alexithymia Scale. AB - OBJECTIVE: The purpose was to explore the psychometrics and correlates of the Toronto Alexithymia Scale (TAS-20) after myocardial infarction (MI). METHODS: The TAS-20 and other self-report measures were administered 3-6 months after discharge to 1443 patients. RESULTS: Good internal reliability was confirmed for the total TAS-20 and two subscales (F1 and F2). The F3 showed low internal consistency linked to negatively keyed items. The prevalence of alexithymia was 30.2% at the first interview. Alexithymics were older, less educated, more likely to have previous MIs and had higher scores on all measures of negative emotions. Six-month test-retest reliability was.47 (n=167). Residual change score analysis showed patients with more education and a first MI had greater decreases in alexithymia than expected. CONCLUSIONS: The TAS-20 has adequate internal consistency in post-MI patients, and its correlates are similar to other reports. Low temporal stability suggests that secondary alexithymia is important after MI. PMID- 11602220 TI - Anger, negative emotions, and cardiovascular reactivity during interpersonal conflict in women. AB - OBJECTIVE: In order to evaluate the relationship between women's subjective emotional discomfort with anger and cardiovascular responses to stress, cardiovascular and affective responses were examined during two anger-provoking conditions: one in which anger would be in self-defense, and one in which anger would be in defense of a significant other. METHODS: A total of 42 healthy, normotensive women aged 18-35 years recruited a close female friend to participate in the study with them, and were randomly assigned to one of two harassment conditions: (i) Self-Harass, where women were harassed while performing a math task; (ii) Friend-Harass, where women witnessed a close female friend being harassed while their friend performed a math task. RESULTS: Self Harass and Friend-Harass women reported feeling equally angry, annoyed, and irritated (all P's<.01) during their respective anger-provocation conditions. However, Self-Harass women reported experiencing significantly greater increases in feelings of depression and guilt during anger provocation (P's<.05) relative to Friend-Harass women. Interestingly, it was also the Self-Harass women who exhibited significantly greater elevations in heart rate (HR), cardiac output (CO), systolic blood pressure (SBP), forearm blood flow (FBF), and significant reductions in forearm vascular resistance (FVR; P's<.001) relative to Friend Harass women during anger provocation. CONCLUSIONS: Results suggest that women may experience other negative emotions (e.g., guilt, depression) when anger is in self-defense relative to when it is in defense of others, and that these emotions may play a more important role than anger in moderating cardiovascular reactivity (CVR) during interpersonal conflict. PMID- 11602219 TI - Predictors of attendance at cardiac rehabilitation after myocardial infarction. AB - OBJECTIVE: The purpose of this study was to determine predictors of attendance at cardiac rehabilitation after myocardial infarction (MI). METHODS: Various demographic, behavioural, and clinical variables were measured during hospitalisation in 288 MI patients. Of these, 263 were available to attend outpatient-based cardiac rehabilitation: 108 actually attended. RESULTS: Multiple logistic regression analyses indicated that nonattenders lived in more deprived areas and were less likely to have paid employment. Nonattenders also registered more symptoms of depression and anxiety and exercised less frequently prior to their MI, although only the last of these variables were predicted in a multivariate model. In terms of clinical status, whether patients had been thrombolysed or not was the strongest predictor of attendance. CONCLUSIONS: Attendance at cardiac rehabilitation is not an arbitrary matter. Strategies should be developed for encouraging greater attendance among those not in paid employment, those from deprived areas, and those who exercise infrequently. PMID- 11602222 TI - Social relationships and mortality in patients with congestive heart failure. AB - The present study was undertaken to evaluate the possible effects of social relationships (perceived social support, and perceived social isolation) upon mortality risk among patients with congestive heart failure (CHF). Proportional hazard models were used to evaluate the effects of different social factors on mortality among 119 clinically stable patients (71.4% men; mean age 65.7+/-9.6 years) with symptomatic heart failure, recruited from an outpatient cardiology practice. Twenty deaths were registered during the 24-month period of data collection, all from cardiac causes. Results indicated that social isolation was a significant predictor of mortality (relative risk, 1.50, confidence interval (CI), 1.00 to 2.19; P<.038), controlling for depressive symptoms, heart failure severity, and functional status and age. Perceived intimate network support was marginally significantly associated with increased risk of mortality in this population of CHF patients (relative risk, 0.60, CI, 0.35-1.02; P<.06). However, the sample is small and caution in drawing conclusions should be exercised. Further research is required in order to either deny or confirm these findings, and to illuminate the mechanisms behind the relationships between social isolation and mortality. PMID- 11602223 TI - Comparison of headache parameters using headache type and emotional status. AB - OBJECTIVE: The literature on the impact of headache has traditionally focused on the relationship of subject variables to specific headache types. Recently, increasing attention is being paid to the impact on disease of emotional distress. The current study was designed to determine whether differences in subject variables arose when comparing them by headache type vs. empirically derived emotional distress clusters. METHOD: A review of responses to measures of headache impact (e.g., duration, medication use) and emotional distress (Brief Symptom Inventory, BSI) completed by 292 patients attending a headache clinic was conducted. Patient responses were analyzed by headache type and emotional distress cluster. RESULTS: Comparison by headache type revealed that combined headaches were of longer duration, used more medications, and were more likely to have seen a chiropractor. Comparison by distress cluster revealed high-distress patients to have missed more days of work, have legal involvement, have sought psychological services, and to be male. CONCLUSION: The results suggest that clinically useful information can be obtained by using both headache diagnosis and emotional status. In addition, this information may be useful by providing additional knowledge that may lead to different clinical protocols in headache management. PMID- 11602221 TI - The influence of Type A behavior pattern on the response to the panicogenic agent CCK-4. AB - OBJECTIVES: Review of the literature equivocally suggests that subjects with Type A behavioral pattern (TABP) compared to subjects with Type B behavioral pattern display an increased sympathetic activity, a condition associated with sudden cardiac death. The objective of this study was to determine whether healthy subjects classified as Type A or Type B differed in their reactivity to the beta 1 and beta 2 receptor agonist isoproterenol and to the panicogenic agent cholecystokinin-tetrapeptide (CCK-4). By comparing reactivity to CCK-4 after pretreatment with placebo or propranolol, a beta 1 and beta 2 receptor antagonist, the role of the beta adrenergic system in the hypothesized increased response of Type A subjects to CCK-4 was also assessed. METHODS: The study used a randomized, double-blind, placebo-controlled design. Twenty-seven Type A or B subjects were included in the study. The reactivity to isoproterenol was assessed with the CD25 of isoproterenol (i.e., the intravenous dose of isoproterenol necessary to increase the heart rate of 25 bpm). The panic symptom response and the cardiovascular response to bolus injection of 50 microg of CCK-4 was assessed in subjects pretreated with either propranolol or placebo infusions prior to the CCK-4 challenge. An additional group of subjects was recruited and these subjects received a placebo infusion pretreatment before an injection of placebo. RESULTS: The CD25 was significantly greater in Type A subjects than in Type B subjects. No difference was found among the groups on behavioral sensitivity to the CCK-4 challenge. However, CCK-4-induced maximum increase in heart rate was greater in Type A subjects. CONCLUSION: Our finding that Type A subjects exhibited greater CD25 of isoproterenol and greater increases in heart rate following CCK-4 administration compared to Type B subjects suggests that peripheral beta-receptor sensitivity may be increased in individuals with TABP. PMID- 11602224 TI - Psychological features of subjects with idiopathic environmental intolerance. AB - OBJECTIVES: Idiopathic environmental intolerance (IEI) is associated with unexplained symptoms attributed to non-noxious levels of environmental substances. Clinically, some of the symptoms of IEI overlap with those of panic disorder (PD). We have recently reported a link between IEI and panic responses to a single inhalation of 35% carbon dioxide (CO(2)), a reliable panic induction challenge. This study assessed depression, stress, anxiety, and agoraphobic symptoms among IEI subjects from our previous study versus healthy controls. METHODS: Thirty-six IEI and 37 control subjects with no preexisting psychiatric history were compared on self-report psychological questionnaires. RESULTS: IEI subjects scored significantly higher than controls on the Agoraphobic Cognitions Questionnaire (ACQ), Depression Anxiety Stress Scales (DASS), and Mobility Inventory for Agoraphobia (MI) (Student's t, P<.05). CONCLUSIONS: IEI subjects represent a group with morbidity significantly higher than a control population but less than what would be expected for a clinical psychiatric population. PMID- 11602225 TI - Cellular relations between mu-opioid receptive, GABAergic and reticulospinal neurons in the rostral ventrolateral medulla. AB - Physiological studies have suggested that mu-opioid receptor (MOR) activation can both excite and inhibit reticulospinal neurons in the rostral ventrolateral medulla (RVL), possibly via influences on GABAergic neurons. Thus, to determine the cellular relationships of MORs to GABAergic neurons in the RVL, two experimental approaches were used. First, single sections through the RVL were labeled for MOR using immunoperoxidase detection and for GABA using immunogold detection and examined by electron microscopy. These studies revealed that MOR immunoreactive (IR) terminals were smaller on average than GABA-IR terminals and formed both asymmetric and symmetric synapses, whereas GABA-IR terminals formed exclusively symmetric synapses. MOR and GABA immunoreactivities rarely co localized. Interactions between axons and terminals containing MOR or GABA immunoreactivity were primarily: (1) direct appositions with each other; or (2) convergence onto a common dendritic target that sometimes contained either MOR or GABA immunoreactivity. Since the identity of these target dendrites mostly was unknown, a second study was designed to determine if they might be reticulospinal neurons. For this study, reticulospinal neurons were identified with a retrograde tracer and both MOR and GABA were localized in the same sections of the RVL. These studies revealed that numerous GABA-IR terminals formed symmetric synapses on the perikarya and proximal dendrites of reticulospinal neurons. In contrast, few MOR-IR terminals contacted reticulospinal perikarya and large dendrites although they were often found nearby. These results provide anatomical evidence that MOR activation by endogenous or exogenous agonists may indirectly alter GABAergic neurotransmission in the RVL either through presynaptic interactions between cells or through competing influences on postsynaptic targets. PMID- 11602226 TI - The effect of adrenalectomy on cocaine and amphetamine-regulated transcript (CART) expression in the hypothalamic nuclei of the rat. AB - CART peptide is a neurotransmitter involved in various physiological processes including feeding, sensory processing, development, addiction, and stress. Substantial amounts of CART mRNA and CART peptide expression have been demonstrated in the hypothalamic periventricular area, the paraventricular nucleus of hypothalamus, the anterior lobe of the pituitary gland and the adrenal gland in addition to many other brain areas. This localization defines the HPA axis, responsible for the stress response. The aim of the present study was to assess the possible mediation of the CART peptides in the stress response by testing for changes in CART in adrenalectomized animals. Three groups of male Sprague-Dawley rats were used for the study: sham operated, adrenalectomized (ADX), and ADX+hormone replacement (corticosterone, 30 microg/ml in drinking water/5 days). All rats were perfused 7 days after the surgery, brains were removed and serial coronal sections were prepared. Immunohistochemistry was used to assess CART peptide expression in paraventricular and supraoptic cells. ADX lowered both the number and percentage of CART-positive cells compared to the sham-operated group, and hormone replacement partially restored the decrease in the CART cell numbers in ADX animals. There were no significant changes in the supraoptic nucleus. Our results suggest a role for CART peptides in the stress response. PMID- 11602227 TI - Comparison of excitotoxic profiles of ATPA, AMPA, KA and NMDA in organotypic hippocampal slice cultures. AB - The excitotoxic profiles of (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4 yl)propionic acid (ATPA), (RS)-2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainic acid (KA) and N-methyl-D-aspartate (NMDA) were evaluated using cellular uptake of propidium iodide (PI) as a measure for induced, concentration-dependent neuronal damage in hippocampal slice cultures. ATPA is in low concentrations a new selective agonist of the glutamate receptor subunit GluR5 confined to KA receptors and also in high concentrations an AMPA receptor agonist. The following rank order of estimated EC(50) values was found after 2 days of exposure: AMPA (3.7 mM)>NMDA (11 mM)=KA (13 mM)>ATPA (33 mM). Exposed to 30 microM ATPA, 3 microM AMPA and 10 microM NMDA, CA1 was the most susceptible subfield followed by fascia dentata and CA3. Using 8 microM KA, CA3 was the most susceptible subfield, followed by fascia dentata and CA1. In 100 microM concentrations, all four agonists induced the same, maximal PI uptake in all hippocampal subfields, corresponding to total neuronal degeneration. Using glutamate receptor antagonists, like GYKI 52466, NBQX and MK-801, inhibition data revealed that AMPA excitotoxicity was mediated primarily via AMPA receptors. Similar results were found for a high concentration of ATPA (30 microM). In low GluR5 selective concentrations (0.3-3 microM), ATPA did not induce an increase in PI uptake or a reduction in glutamic acid decarboxylase (GAD) activity of hippocampal interneurons. For KA, the excitotoxicity appeared to be mediated via both KA and AMPA receptors. NMDA receptors were not involved in AMPA-, ATPA- and KA-induced excitotoxicity, nor did NMDA-induced excitotoxicity require activation of AMPA and KA receptors. We conclude that hippocampal slice cultures constitute a feasible test system for evaluation of excitotoxic effects and mechanisms of new (ATPA) and classic (AMPA, KA and NMDA) glutamate receptor agonists. Comparison of concentration-response curves with calculation of EC(50) values for glutamate receptor agonists are possible, as well as comparison of inhibition data for glutamate receptor antagonists. The observation that the slice cultures respond with more in vivo-like patterns of excitotoxicity than primary neuronal cultures, suggests that slice cultures are the best model of choice for a number of glutamate agonist and antagonist studies. PMID- 11602228 TI - Neuronal injury and loss after traumatic brain injury: time course and regional variability. AB - We have examined regional neuronal injury after traumatic brain injury using Fluoro-Jade, an acidic dye that exhibits a marked affinity for both the degenerating neuronal cell body and its processes and have determined the extent to which early injury corresponds to regional patterns of neuronal loss. Rats (n=45) were subjected to lateral fluid percussion brain injury and euthanized at 3 h to 28 days post injury. Complementary Fluoro-Jade, silver impregnation methods and TUNEL were used to assess neuronal injury. Neuronal loss was evaluated in sections immunostained for NeuN, a neuronal specific nuclear protein. Overt neuronal cell loss was evident by 7 days post injury in the cortex, hippocampus and thalamus. Injured neurons were apparent in the ipsilateral cortex bordering the impact site, hippocampus (CA1 and dentate), thalamus, and vermis of the cerebellum as early as 3 h post injury. Degenerating neurons were maximal by 1 and 3 days in the cortex and hippocampus, by 3 and 7 days in the cerebellum, and by 7 days in the thalamus. The regional distribution of Fluoro-Jade-labeled neurons corresponded to a similar pattern of silver and TUNEL staining. Together, these findings demonstrate a regionally specific temporal pattern of neuronal injury that results in overt neuronal cell loss within both cortical and subcortical regions. PMID- 11602229 TI - Responses of ectostriatal neurons during delayed matching-to-sample behavior in pigeons (Columba livia). AB - We recorded from 71 neurons in the ectostriatum of awake behaving pigeons performing the delayed matching-to-sample task. The ectostriatum is considered to be equivalent to the primate extrastriate cortex. Many of the neurons (n=56, 78.9%) were visually responsive to either or both the red and green stimuli. In addition, a large number of neurons (n=51, 71.8%) exhibited delay activity, that is, a change in activity during the delay period when memory was required compared to the baseline intertrial interval period when memory was not required. We were more likely to encounter a delay neuron when the subjects performed well (>75% correct) compared to when the subjects performed poorly (<75% correct), suggesting that delay activity may carry some functional significance. Finally, the magnitude of the delay activity did not vary across the delay period but remained at a constant elevated or depressed level. Overall, our findings in pigeons are very similar to those reported for primates, and suggest that the pigeon may be an excellent model in which to study the neural mechanisms of visual information processing. PMID- 11602230 TI - Light and electron microscopic observations of a direct projection from mesencephalic trigeminal nucleus neurons to hypoglossal motoneurons in the rat. AB - A direct projection from rat mesencephalic trigeminal nucleus (Vme) neurons to the hypoglossal nucleus (XII) motoneurons was studied using a double labeling method of anterogradely biotinylated dextran amine (BDA) tracing combined with retrogradely horseradish peroxidase (HRP) transport at both light and electron microscopic levels. BDA was iontophoresed unilaterally into the caudal Vme, and 7 days later HRP was injected into the ipsilateral tongue to label hypoglossal motoneurons. The BDA-labeled fibers were seen descended along Probst' tract and were traced to the caudal medulla. In this course, the fibers gave off axon collaterals bearing varicosities in the trigeminal motor nucleus (Vmo), the parvicellular reticular formation (PCRt), the dorsomedial portions of the subnuclei of oralis (Vodm) and interpolaris (Vidm) and in the XII ipsilaterally. The labeling of terminals was most dense in the PCRt at the levels of caudal pons and rostral medulla, which displayed a "dumbbell-shaped" form in the transverse planes. In the XII, labeled terminals were distributed mainly in the dorsal compartment of the nucleus. One hundred sixty-eight appositions made by BDA labeled terminals on HRP-labeled motoneurons were seen in the dorsal compartment (71%) and in the lateral subcompartment (24%) of the ventral XII. Under electron microscopy BDA-labeled boutons containing clear, spherical synaptic vesicles were found to form synaptic contacts with the somata and dendrites of hypoglossal motoneurons with asymmetric specializations. The present study provides new evidence that the trigeminal proprioceptive afferent neurons terminate in the XII and make synaptic contacts with their motoneurons. PMID- 11602231 TI - Differences in the laminar origin of projections from the medial prefrontal cortex to the nucleus accumbens shell and core regions in the rat. AB - The medial prefrontal cortex (mPFC) projects to the nucleus accumbens shell, core and rostral pole. In this retrograde tract-tracing study of rat mPFC to nucleus accumbens projection neurons, the advantages of Neurobiotin are utilised in order to reveal the detailed morphology of labelled projection cells, and to permit an examination of the laminar projections to shell and core compartments The retrogradely transported Neurobiotin was found in somata, proximal and distal dendrites of neurons that project from the mPFC to the nucleus accumbens. The morphology of these projection neurons was revealed in great detail and confirmed that the projection arises wholly from pyramidal cells. Interestingly, it was also found that retrogradely labelled neurons were exclusively located in prelimbic and infralimbic regions in layers V and VI, after shell injections, but also in layer II following core sites. This observation may reflect possibly different roles for cortical laminae on the nucleus accumbens. PMID- 11602232 TI - Epileptic-like activity induces multiple forms of plasticity in hippocampal area CA1. AB - Mesial temporal lobe epilepsy is a relatively common form of epilepsy that afflicts many thousands of people. It has been suggested that the development of primary and secondary foci may involve mechanisms similar to long-term potentiation (LTP). In vitro seizure models typically involve an increase in spontaneous asynchronous bursting activity (epileptiform activity) induced either by increasing excitation or decreasing inhibition. Previous experiments have indicated that these models often generate bursting activity that closely resembles epileptic activity. LTP is often observed following epileptiform activity. In area CA1 of the hippocampus two forms of LTP that are dependent on the activation of either the L-type voltage dependent calcium channel (vdccLTP) or the N-methyl-D-aspartate receptor/channel (nmdaLTP) have been described. It is unclear from previous experiments which type of LTP results from epileptiform activity. Recent evidence indicates that nmdaLTP is most likely a short-term type of plasticity while vdccLTP may be a long-lasting form of synaptic plasticity. Given the characteristics of vdccLTP it is a likely candidate mechanism to underlie the development and formation of secondary seizure foci. We have therefore tested the ability of epileptiform activity induced by elevated potassium chloride to induce multiple forms of LTP in area CA1 of the rat hippocampus. Elevation of extracellular potassium chloride resulted in spontaneous asynchronous bursting. The net result of the spontaneous asynchronous bursting was to induce a compoundLTP consisting of nmdaLTP and vdccLTP components. PMID- 11602233 TI - Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients. AB - For determining whether both the spinal cord motor neurons and glial cells are exposed to increased oxidative stress in amyotrophic lateral sclerosis (ALS), we performed an immunohistochemical investigation of end products of lipid peroxidation and protein glycoxidation in spinal cords from seven sporadic ALS patients and seven age-matched control individuals. In the ALS spinal cords, immunoreactivities for adducts of 4-hydroxy-2-nonenal-histidine and crotonaldehyde-lysine as markers of lipid peroxidation, N(epsilon) (carboxymethyl)lysine as a marker of lipid peroxidation or protein glycoxidation, and pentosidine as a marker of protein glycoxidation were localized in the gray matter neuropil and almost all of the motor neurons, reactive astrocytes and microglia/macrophages, whereas none of the immunoreactivities for N(epsilon) (carboxyethyl)lysine or argpyrimidine as markers of protein glycoxidation or enzymatic glycolysis, or pyrraline or imidazolone as markers of nonoxidative protein glycation were detectable. The control spinal cords displayed no significant immunoreactivities for any of these examined products. Our results indicate that in sporadic ALS, both lipid peroxidation and protein glycoxidation are enhanced in the spinal cord motor neurons and glial cells, and suggest that the formation of certain products in these abnormal reactions is implicated in motor neuron degeneration. PMID- 11602234 TI - The relationship between circadian rhythmicity and vasoactive intestinal polypeptide in the suprachiasmatic nucleus of congenitally anophthalmic mice. AB - To date, the search for the clock component that is both necessary and sufficient for generation of circadian rhythms has relied primarily on experimental interventions such as lesions and transplantation of fetal SCN. While these approaches have been fruitful, lesions disrupt adjacent host tissue and fiber pathways, and donor tissue is likewise subject to trauma during harvest and transplantation. The current investigation has used congenitally anophthalmic (eyeless) mice to ask whether VIP-IR SCN neurons are necessary and sufficient for generation of circadian rhythms. In this animal model, arrhythmic mice occur naturally, together with their rhythmic littermates. We have combined recording of wheel-running activity with light microscopic immunocytochemistry for vasoactive intestinal polypeptide (VIP) and cytoarchitectural analysis of the suprachiasmatic nuclei (SCN) in rhythmic and arrhythmic anophthalmic mice. Our data provide the first definitive evidence that the presence of VIP neurons in the SCN is not sufficient for generation of circadian locomotor rhythms. PMID- 11602235 TI - Changes in the cochlear dopaminergic system of the aged rat. AB - The levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) have been quantified in cochleae of male and female rats aged 3, 6, 9, 12, 19 and 24 months. Animals were exposed for 1 h, under general anesthesia, to: (1) silence (basal conditions) or (2) white noise at 90 dB SPL. Afterwards, the concentrations of DA, DOPAC and HVA were determined by HPLC with electrochemical detection in homogenates of individual cochleae. In basal conditions, the cochlear concentrations of DA, DOPAC and HVA in aged females were higher than in adult ones. The concentrations of DA and DOPAC were also higher in aged males with respect to adult ones. A decrease in DA and an increase in DOPAC and HVA concentrations, with respect to silence, were detected when adult animals were exposed to noise. Meanwhile, aged animals showed either a noise-induced increase or no modification of DA and DOPAC with respect to basal levels. Present results suggest age-related failures in DA release and metabolizing mechanisms within the cochlea, together with a compensatory DA synthesis increase. However, the possibility of an initial damage in the primary auditory neurons which could also stimulate the synthesis of DA must not be excluded. Present age-related changes could indicate that the cochlear dopaminergic innervation is affected during the aging process. Since this innervation plays an important role in both the modulation and the protection of the primary auditory neurons, its metabolic alteration could profoundly modify the auditory process. PMID- 11602236 TI - The role of the habenular complex in the elevation of dorsal raphe nucleus serotonin and the changes in the behavioral responses produced by uncontrollable stress. AB - Previous research indicates that the serotonergic neurons of the caudal dorsal raphe nucleus (DRN) are activated to a greater degree by inescapable shock (IS) as compared to escapable shock (ES), causing a greater release of serotonin (5 HT) in the DRN and in target regions. This differential activation is necessary for the behavioral changes that occur after exposure to IS, but not to ES (i.e. learned helplessness/behavioral depression). Although the critical role of the DRN in learned helplessness is clear, the neural inputs to the caudal DRN which result in this selective activation are unknown. One structure that may be involved in the activation of the DRN and the induction of learned helplessness/behavioral depression is the habenular complex. In experiment 1, habenula lesions eliminated the differential rise in DRN extracellular 5-HT levels in response to IS and ES exposure by severely attenuating the rise in 5-HT for both groups. In experiment 2, sham operated and habenula lesioned rats were exposed to either ES, IS or no stress (home cage control; HCC). Twenty-four hours later, sham rats previously exposed to IS exhibited longer escape latencies as compared to both ES and HCC rats (i.e. learned helplessness). The habenular lesion eliminated the differences in escape latency between groups, thus eliminating the induction of learned helplessness/behavioral depression. These results suggest that the habenula is necessary for the differential activation of the DRN and the escape deficits produced by IS. PMID- 11602237 TI - Effects of isatin on rotational behavior and DA levels in caudate putamen in Parkinsonian rats. AB - Isatin was a potent endogenous monoamine oxidase (MAO) inhibitor that is more active against MAO-B than MAO-A. The acute effects of isatin on apomorphine (APO) induced rotations were evaluated in Parkinsonian rats induced by 6 hydroxydopamine (6-OHDA) lesion. Furthermore, the effects of isatin on DA release in caudate putamen (CPu) of model and normal rats were monitored using fast cyclic voltammetry (FCV). The contents of monoamine transmitters and their metabolites in CPu of model and normal rats were also analyzed by high performance liquid chromatography with electrochemical detection after administration of isatin. Here we show that isatin (100 mg/kg, i.p.) apparently inhibited APO-induced rotations of Parkinsonian rats to 39.1+/-3.7% of the control (n=12), while it had no apparent effects on electrical stimuli-induced DA release either in normal rats or in model rats. In addition, the content of 5 hydroxytryptamine but not DA was increased in both normal rats and model rats after isatin (100 mg/kg, i.p.) was administered (P<0.01, n=6). The content of 5 hydroxyindole acetic acid was not changed. These results suggest that isatin cannot increase DA levels in rat CPu. Therefore, the effects of isatin on APO induced rotations of our Parkinsonian rats could not attribute to its inhibition of DA catabolism as a MAO inhibitor. PMID- 11602238 TI - An inhibitory effect of cytokine-induced neutrophil chemoattractant on corticotropin-releasing factor-induced increase in locomotor activity. AB - To investigate whether cytokine-induced neutrophil chemoattractant (CINC) has an influence on corticotropin-releasing factor (CRF) in the central nervous system, the effects of intracerebroventricular (i.c.v.) injection of CINC on CRF-induced behavior were examined. Intracerebroventricular CRF injection produced an increase in locomotor activity, which was significantly reduced by i.c.v. injection of CINC. The intravenous injection of CINC did not alter CRF-induced locomotor hyperactivity. These results suggested that CINC has a functional antagonistic action on the response to CRF and may attenuate stress responses. PMID- 11602239 TI - How carcinogens (or telomere dysfunction) induce genetic instability: associated selection model. AB - Carcinogens induce carcinogen-specific genetic instability (defects in DNA repair). According to the 'direct-selection' model, defects in DNA repair per se provide an immediate growth advantage. According to the 'associated-selection' model, carcinogens merely select for cells with adaptive mutations. Like any mutations, adaptive mutations occur predominantly in genetically unstable cells. The 'associated-selection' model predicts that carcinogen-driven selection minimizes cytotoxic but maximizes mutagenic effects of carcinogens. A purely mutagenic (neither cytotoxic, nor cytostatic) environment will favor effective DNA repair, whereas any growth-limiting conditions (telomerase deficiency, anticancer drugs) will select for genetically unstable cells. Genetic instability is a postmark of selective pressure rather than a hallmark of cancer per se. Once selected, genetic instability facilitates the development of resistance to any other growth-limiting conditions. As an example, a putative link between prior exposure to carcinogens and the ability to develop a telomerase-independent growth is discussed. PMID- 11602240 TI - Specificity in pleckstrin homology (PH) domain membrane targeting: a role for a phosphoinositide-protein co-operative mechanism. AB - Pleckstrin homology (PH) domains are protein modules found in proteins involved in many cellular processes. The majority of PH domain-containing proteins require membrane association for their function. It has been shown that most PH domains interact directly with the cell membrane by binding to phosphoinositides with a broad range of specificity and affinity. While a highly specific binding of the PH domain to a phosphoinositide can be necessary and sufficient for the correct recruitment of the host protein to the membrane, a weaker and less specific interaction may be necessary but not sufficient, thus probably requiring alternative, co-operative mechanisms. PMID- 11602241 TI - High-pressure NMR study of the complex of a GTPase Rap1A with its effector RalGDS. A conformational switch in RalGDS revealed from non-linear pressure shifts. AB - Unusually large non-linear 1H and 15N nuclear magnetic resonance chemical shifts against pressure have been detected for individual amide groups of the Ras binding domain of Ral guanine dissociation stimulator (GDS). The non-linear response is largest in the region of the protein remote from the Rap1A-binding site, which increases by about two-fold by the complex formation with its effector protein Rap1A. The unusual non-linearity is explained by the increasing population of another conformer (N'), lying energetically above the basic native conformer (N), at higher pressure. It is considered likely that the conformational change from N to N' in the Ras-binding domain of RalGDS works as a switch to transmit the effector signal further to molecules of different RalGDS dependent signaling pathways. PMID- 11602242 TI - Nitric oxide production in living neurons is modulated by sphingosine: a fluorescence microscopy study. AB - An investigation was carried out into the possible effect of sphingosine (Sph) on nitric oxide (NO) production in living neurons. Differentiated granule cells were used in a dynamic videoimaging analysis of single cells labeled, simultaneously, with FURA-2 and the NO indicator 4,5-diaminofluorescein. The results demonstrate that Sph exerts a potent inhibitory effect on the Ca2+-dependent production of NO, without modifying the [Ca2+]i. The effect appears to be specific as neither ceramide nor Sph-1-phosphate had any effect on the NO and [Ca2+]i levels. The data demonstrate that Ca2+-dependent NO production is a specific Sph target in living granule cells, suggesting that this bioactive sphingoid plays a relevant role in neuronal NO signaling. PMID- 11602243 TI - An amino acid residue whose change by mutation affects drug binding to the HERG channel. AB - We did the experiments to search for amino acids that affect quinidine binding to the HERG channel, and have identified an amino acid whose change by mutation affects the binding of various drugs. The residue is located at position 647 in the S6 and is not involved in the recently identified methanesulfonanilide binding pocket. The homology model of the HERG channel indicated that the residue faces toward the outside of the channel pore. We conclude that the residue at position 647 does not interact directly with drug molecules but plays an important role in keeping the binding site's high affinity for drugs. PMID- 11602245 TI - Tetrameric dipeptidyl peptidase I directs substrate specificity by use of the residual pro-part domain. AB - The crystal structure of mature dipeptidyl peptidase I reveals insight into the unique tetrameric structure, substrate binding and activation of this atypical papain family peptidase. Each subunit is composed of three peptides. The heavy and light chains form the catalytic domain, which adopts the papain fold. The residual pro-part forms a beta-barrel with the carboxylate group of Asp1 pointing towards the substrate amino-terminus. The tetrameric structure appears to stabilize the association of the two domains and encloses a 12700 A3 spherical cavity. The tetramer contains six chloride ions, one buried in each S2 pocket and two at subunit interfaces. PMID- 11602244 TI - The AP-1 repressor, JDP2, is a bona fide substrate for the c-Jun N-terminal kinase. AB - The Jun dimerization protein 2 (JDP2) is a novel member of the basic leucine zipper family of transcription factors. JDP2 binds DNA as a homodimer and heterodimer with ATF2 and Jun proteins but not with c-Fos proteins. JDP2 overexpression represses activating protein 1 transcription activity. Whereas JDP2 mRNA and protein levels are stable following different cell stimuli, JDP2 is rapidly phosphorylated upon UV irradiation, oxidative stress and low levels of translation inhibitor. The c-Jun N-terminal kinase phosphorylates JDP2 both in vitro and in vivo. JDP2 contains a putative consensus JNK docking-site and a corresponding phosphoacceptor site. Substitution of threonine 148 to an alanine residue blocks JNK-dependent JDP2 phosphorylation. Our data indicate that JDP2 is a bona fide substrate for the c-Jun N-terminal kinase. The precise role of JDP2 phosphorylation on its function is not yet known. PMID- 11602246 TI - Signalling of GPI-anchored CD157 via focal adhesion kinase in MCA102 fibroblasts. AB - CD157, a glycosylphosphatidylinositol-anchored protein, has previously been shown to mediate tyrosine phosphorylation of a 130 kDa protein (p130) in several cell lines. In this study, we have identified the p130 protein to be focal adhesion kinase (FAK or pp125(FAK)). FAK undergoes phosphorylation at Tyr-397 and Tyr-861 in intact MCA102 cells stably transfected with CD157 (MCA/CD157). MCA/CD157 cells, which displayed a rounded and compact cell morphology, exhibited a dispersed distribution, in contrast to a more closely associated and elongated spindle cell shape in the vector-transfected cells. MCA/CD157 cells proliferated at a rate 20-25% slower than the control cells. Our results demonstrate, for the first time, that FAK is a downstream signalling molecule of CD157. PMID- 11602247 TI - Biliary excretion of a stretched bilirubin in UGT1A1-deficient (Gunn) and Mrp2 deficient (TR-) rats. AB - The metabolism and biliary excretion of a stretched bilirubin analog with a p xylyl group replacing the central CH2 hinge were investigated in normal rats, Gunn rats deficient in bilirubin conjugation, and TR- rats deficient in bilirubin glucuronide hepatobiliary transport. Unlike bilirubin, the analog was excreted rapidly in bile unchanged in all three rat strains after intravenous administration. In TR- rats biliary excretion of the analog was diminished, but still substantial, demonstrating that the ATP-binding cassette transporter Mrp2 is not required for its hepatic efflux. These effects are attributable to differences in the preferred conformations of bilirubin and the analog. PMID- 11602248 TI - Involvement of protein dynamics in enzyme stability. The case of glucose oxidase. AB - Dynamics of glucose oxidase immobilized and in solution were compared through their tryptophan fluorescence spectra, decay times and quenching by acrylamide. Energy barrier for thermal inactivation and melting temperature of both soluble and immobilized enzyme were also measured. Data show that the fluctuation amplitude is at the origin of protein instability. PMID- 11602249 TI - Effects of Fe(III) binding to the nucleotide-independent site of F1-ATPase: enzyme thermostability and response to activating anions. AB - Mitochondrial F1-ATPase was induced in different conformations by binding of specific ligands, such as nucleotides. Then, Fourier transform infrared spectroscopy (FT-IR) and kinetic analyses were run to evaluate the structural and functional effects of Fe(III) binding to the nucleotide-independent site. Binding of one equivalent of Fe(III) induced a localised stabilising effect on the F1 ATPase structure destabilised by a high concentration of NaCl, through rearrangements of the ionic network essential for the maintenance of enzyme tertiary and/or quaternary structure. Concomitantly, a lower response of ATPase activity to activating anions was observed. Both FT-IR and kinetic data were in accordance with the hypothesis of the Fe(III) site location near one of the catalytic sites, i.e. at the alpha/beta subunit interface. PMID- 11602251 TI - Disruption of Thermus thermophilus genes by homologous recombination using a thermostable kanamycin-resistant marker. AB - Genes of an extremely thermophilic bacterium, Thermus thermophilus, were disrupted by homologous recombination using a recently developed, thermostable kanamycin-resistant marker. First, the trpE gene was disrupted with various constructions of DNA. The transformation efficiency was exponentially increased as the length of the homologous regions flanking the marker gene increased above the minimum length (200-300 bp). We then disrupted five genes of the nucleotide excision repair system and examined their phenotypes. The convenience and high reliability of this method should prompt its application to the high-throughput systematic disruption of the genes of this thermophilic bacterium. PMID- 11602250 TI - A plant steroid, diosgenin, induces apoptosis, cell cycle arrest and COX activity in osteosarcoma cells. AB - Cyclooxygenases (COXs) are key enzymes in the conversion of arachidonic acid into prostanoids which are involved in apoptosis and inflammation. Two distinct COXs have been identified: COX-1 which is constitutively expressed and COX-2 which is induced by different products such as tumor promoters or growth factors. Previously, we demonstrated that a plant steroid, diosgenin, was a new megakaryocytic differentiation inducer of human erythroleukemia cells. In our study, we investigated the effect of diosgenin on the proliferation rate, cell cycle distribution and apoptosis in the human osteosarcoma 1547 cell line. The effects of this compound were also tested on COX expression and COX activities. Diosgenin treatment caused an inhibition of 1547 cell growth with a cycle arrest in G1 phase and apoptosis induction. Moreover, we found a correlation between p53, p21 mRNA expression and nuclear factor-kappaB activation and we observed a time-dependent increase in PGE2 synthesis after diosgenin treatment. PMID- 11602252 TI - In vitro transactivation of Bacillus subtilis RNase P RNA. AB - Deletion of the 'signature' PL5.1 stem-loop structure of a Type II RNase P RNA diminished its catalytic activity. Addition of PL5.1 in trans increased catalytic efficiency (kcat/KM) rather than kcat. Transactivation was due to the binding of a single PL5.1 species per ribozyme with an apparent Kd near 600 nM. The results are consistent with the role of PL5.1 being to position the substrate near the active site of the ribozyme, and with the hypothesis that ribozymes can evolve by accretion of preformed smaller structures. PMID- 11602253 TI - Molecular interactions between poly(ADP-ribose) polymerase (PARP I) and topoisomerase I (Topo I): identification of topology of binding. AB - The molecular interactions of poly(ADP-ribose) polymerase I (PARP I) and topoisomerase I (Topo I) have been determined by the analysis of physical binding of the two proteins and some of their polypeptide components and by the effect of PARP I on the enzymatic catalysis of Topo I. Direct association of Topo I and PARP I as well as the binding of two Topo I polypeptides to PARP I are demonstrated. The effect of PARP I on the 'global' Topo I reaction (scission and religation), and the activation of Topo I by the 36 kDa polypeptide of PARP I and catalytic modifications by poly(ADP-ribosyl)ation are also shown. The covalent binding of Topo I to circular DNA is activated by PARP I similar to the degree of activation of the 'global' Topo I reaction, whereas the religation of DNA is unaffected by PARP I. The geometry of PARP I-Topo I interaction compared to automodified PARP I was reconstructed from direct binding assays between glutathione S-transferase fusion polypeptides of Topo I and PARP I demonstrating highly selective binding, which was correlated with amino acid sequences and with the 'C clamp' model derived from X-ray crystallography. PMID- 11602254 TI - Membrane-anchored cyclin A2 triggers Cdc2 activation in Xenopus oocyte. AB - In Xenopus oocyte, the formation of complexes between neosynthesized cyclins and Cdc2 contributes to Cdc2 kinase activation that triggers meiotic divisions. It has been proposed that cytoplasmic membranes could be involved in this process. To investigate this possibility, we have injected in the oocyte two undegradable human cyclin A2 mutants anchored to the endoplasmic reticulum (ER) membrane. They encode fusion proteins between the truncated cyclin A2-Delta152 and a viral or cellular ER-targeting domain. We show that both mutants are fully functional as mitotic cyclins when expressed in Xenopus oocytes, bind Cdc2 and activate M-phase promoting factor. PMID- 11602255 TI - A possible regulatory role for the metal-binding domain of CadA, the Listeria monocytogenes Cd2+-ATPase. AB - Using the baculovirus/Sf9 expression system, we produced CadA and DeltaMBD, a metal-binding domain, truncated CadA. Both proteins had the expected properties of P-type ATPases: ATP-induced Cd2+ accumulation, Cd2+-sensitive ATP and Pi phosphorylation and ATPase activity. DeltaMBD displayed lower initial transport velocity as well as lower maximal ATPase activity than CadA. MBD truncation flattened the Cd2+ dependence of the ATPase activity and increased apparent Cd2+ affinity, suggesting a positive cooperativity between MBD and membranous transport sites. We propose that occupancy of MBD by Cd2+ modulates CadA activity. PMID- 11602256 TI - Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. AB - In human embryonic kidney cells over-expressing the human vanilloid receptor type 1 (VR1), palmitoylethanolamide (PEA, 0.5-10 microM) enhanced the effect of arachidonoylethanolamide (AEA, 50 nM) on the VR1-mediated increase of the intracellular Ca2+ concentration. PEA (5 microM) decreased the AEA half-maximal concentration for this effect from 0.44 to 0.22 microM. The PEA effect was not due to inhibition of AEA hydrolysis or adhesion to non-specific sites, since bovine serum albumin (0.01-0.25%) potently inhibited AEA activity, and PEA also enhanced the effect of low concentrations of the VR1 agonists resiniferatoxin and capsaicin. PEA (5 microM) enhanced the affinity of AEA for VR1 receptors as assessed in specific binding assays. These data suggest that PEA might be an endogenous enhancer of VR1-mediated AEA actions. PMID- 11602257 TI - A vesicle transport system inside chloroplasts. AB - Intracellular transport via membrane vesicle traffic is a well known feature of eukaryotic cells. Yet, no vesicle transport system has been described for prokaryotes or organelles of prokaryotic origin, such as chloroplasts and mitochondria. Here we show that chloroplasts possess a vesicle transport system with features similar to vesicle traffic in homotypic membrane fusion. Vesicle formation and fusion is affected by specific inhibitors, e.g. nucleotide analogues, protein phosphatase inhibitors and Ca2+ antagonists. This vesicle transfer is an ongoing process in mature chloroplasts indicating that it represents an important new pathway in the formation and maintenance of the thylakoid membranes. PMID- 11602258 TI - Elements from the cAMP signaling pathway are involved in the control of expression of the yeast gluconeogenic gene FBP1. AB - cAMP represses the transcription of some Saccharomyces cerevisiae genes sensitive to catabolite repression. The effect of cAMP on the expression of FBP1, encoding fructose-1,6-bisphosphatase (FbPase), has been further investigated. In yeast cells shifted to a derepressing medium, synthesis of FbPase was delayed if the strong decrease in intracellular cAMP, which occurs during the shift, was prevented. A similar delay occurred in a RAS2val19 strain, while in a tpk1w strain, with weak protein kinase A activity, induction of FbPase occurred earlier than in a TPK1 strain. In the tpk1w strain, proteins which bind the UAS1 element of FBP1 were present during growth on glucose but they were only weakly operative. Expression of CAT8 and SIP4, encoding proteins which bind the UAS2 element, was blocked by a high concentration of cAMP, but catabolite repression of these genes was not much relieved in a tpk1w strain. We conclude that in S. cerevisiae, as reported for Schizosaccharomyces pombe, control of FBP1 requires both cAMP-dependent and independent pathways; however, the mechanisms operating in the two yeasts are different. PMID- 11602259 TI - TAK1 activation of the mouse JunB promoter is mediated through a CCAAT box and NF Y. AB - The JunB gene is activated by many stimuli including transforming growth factor beta (TGFbeta) family members and interleukin-6 (IL-6). Here the effect of TGFbeta activated kinase 1 (TAK1), a mitogen activated protein kinase kinase kinase (MAPKKK) implicated in TGFbeta, bone morphogenetic protein (BMP) and interleukin-1 (IL-1) signaling, on JunB promoter activity was investigated. Promoter analysis led to the identification of a CCAAT motif in the JunB gene, essential for activation by TAK1. Transfer of this CCAAT element to a heterologous minimal promoter conferred TAK1-responsiveness. The CCAAT-binding transcription factor, nuclear factor Y (NF-Y), activated the JunB promoter and a dominant negative NF-YA construct inhibited TAK1 activation of JunB. Our results demonstrate that JunB gene activation by TAK1 is mediated by the CCAAT-binding factor NF-Y. PMID- 11602260 TI - Function of nucleophosmin/B23, a nucleolar acidic protein, as a histone chaperone. AB - We previously identified and purified a nucleolar phosphoprotein, nucleophosmin/B23, as a stimulatory factor for replication from the adenovirus chromatin. We show here that nucleophosmin/B23 functions as a histone chaperone protein such as nucleoplasmin, TAF-I, and NAP-I. Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to mediate formation of nucleosome, and to decondense sperm chromatin. These activities of B23 were dependent on its acidic regions as other histone chaperones, suggesting that B23/nucleophosmin is a member of histone chaperone proteins. PMID- 11602261 TI - The yeast cyclins Pc16p and Pc17p are involved in the control of glycogen storage by the cyclin-dependent protein kinase Pho85p. AB - Pho85p is a yeast cyclin-dependent protein kinase (Cdk) that can interact with 10 cyclins (Pcls) to form multiple protein kinases. The functions of most of the Pcls, including Pc16p and Pc17p, are poorly defined. We report here that Pc16p and Pc17p are involved in the metabolism of the branched storage polysaccharide glycogen under certain conditions and deletion of PCL6 and PCL7 restores glycogen accumulation to a snf1 pcl8 pcl10 triple mutant, paradoxically activating both glycogen synthase and phosphorylase. Pho85p thus affects glycogen accumulation through multiple Cdks composed of different cyclin partners. PMID- 11602262 TI - Structural basis for the emission of violet bioluminescence from a W92F obelin mutant. AB - Mutation of the Trp92 that is known to lie within the active site of the photoprotein obelin from Obelia longissima, results in a shift of the bioluminescence color from blue (lambda(max)=485 nm) to violet. The corrected spectrum shows a new band with lambda(max)=410 nm now contributing equally to the one at longer wavelength. The crystal structure of this W92F obelin determined at 1.72 A resolution shows that there is no significant change in the dimensions of the active site between WT obelin (recombinant Ca2+-regulated photoprotein from Obelia longissima) and the mutant. It is proposed that the bioluminescence spectral shift results from removal of a hydrogen bond from the indole of W92 nearby a hydroxyl belonging to the 6-phenyl substituent of the substrate coelenterazine. Propagation of this change through a conjugated bond system in the excited state of the product coelenteramide affects the coupling of the N1 position and the hydrogen-bonded Y138. PMID- 11602263 TI - Identification of an Arabidopsis cDNA encoding a lipoyltransferase located in plastids. AB - In plant cells, the pyruvate dehydrogenase (PDH) complex that requires lipoic acid as an essential coenzyme is located in plastids and mitochondria. The enzyme complex has to be lipoylated in both organelles. However, the lipoyltransferase located in plastids has not been reported. In this study, an Arabidopsis thaliana LIP2p cDNA for a lipoyltransferase located in plastids has been identified. We have shown that this cDNA encodes a lipoyltransferase by demonstrating its ability to complement an Escherichia coli mutant lacking lipoyltransferase activity, and that LIP2p is targeted into chloroplasts. These findings suggest that LIP2p is located in plastids and responsible for lipoylation of the plastidial PDH complex. PMID- 11602264 TI - Arabidopsis thaliana ferrochelatase-I and -II are not imported into Arabidopsis mitochondria. AB - Using in vitro import assays into purified mitochondria and chloroplasts we found that Arabidopsis ferrochelatase-I and ferrochelatase-II were not imported into mitochondria purified from Arabidopsis (or several other plants) but were imported into pea leaf chloroplasts. Other dual targeted proteins could be imported into purified mitochondria from Arabidopsis. As only two ferrochelatase genes are present in the completed Arabidopsis genome, the presence of ferrochelatase activity in plant mitochondria needs to be re-evaluated. Previous reports of Arabidopsis ferrochelatase-I import into pea mitochondria are due to the fact that pea leaf (and root) mitochondria appear to import a variety, but not all chloroplast proteins. Thus pea mitochondria are not a suitable system to either study dual targeting, or to distinguish between isozymes present in mitochondria and chloroplasts. PMID- 11602266 TI - Effects of the implementation of the Resident Assessment Instrument on gaps between perceived needs and nursing care supply for nursing home residents in the Netherlands. AB - This study evaluated the effects of the implementation of the Resident Assessment Instrument (RAI) on gaps perceived between residents' needs and nursing care received in Dutch nursing homes. In a controlled group design residents were interviewed before and after the implementation. Most gaps were perceived in the psycho-social area rather than physical or needs with aids and facilities. In general, perceived gaps decreased more strongly in the experimental group. The results give an indication that assessment using RAI leads to a better meeting of the residents' perceived needs. More research is needed to investigate the quality of the assessment using RAI in more detail. PMID- 11602267 TI - The health behaviours of Chinese people with chronic illness. AB - This study was undertaken to elucidate the type and range of health-promoting behaviours that Chinese people with chronic illness perform to enhance their health. Eight people with a diagnosed chronic illness were interviewed using a semi-structured interview schedule. From the perspectives of these subjects, health behaviour comprises three dimensions: physical, psychosocial and spiritual. The results of this study clarify health behaviours amongst Chinese people with a chronic illness and illustrate the important influence that culture has upon such activity. Additionally, exploring the health behaviours of these Chinese people can be used to inform and enable nurses to adjust their practices to relate more appropriately to patients' perspectives. PMID- 11602268 TI - Vital signs in hospital patients: a systematic review. AB - OBJECTIVES: This review was initiated to identify the best available evidence on vital sign measurements in hospital patients. METHOD: Inclusion Criteria--Studies that evaluated some aspect of vital signs. Search--Covered all major databases and the references of identified studies. Data Analysis--Because of the nature of identified studies, data were summarised using narrative rather than statistical methods. RESULTS: A total of 737 papers of which 69 met the inclusion criteria. CONCLUSION: This review has highlighted a need for further investigation of issues related to the role, nature and optimal practice of monitoring patient vital signs. PMID- 11602269 TI - Patients' experiences of 'feeling on their own' following a diagnosis of colorectal cancer: a phenomenological approach. AB - The aim of this paper is to describe a Hermeneutical phenomenological study of the experience of being diagnosed with colorectal cancer. The research objective was to understand this particular lived experience and uncover the meanings and structures within it. Eight patients who had been diagnosed with colorectal cancer in the preceding four weeks were purposively sampled to describe their experiences. Data was generated using semi-structured, in-depth, face-to-face interviews. The data was analysed using the method described by Benner. Six themes were identified as the main components of this experience for these patients. An overview of the participants' experiences is presented followed by a more detailed discussion of one of the most poignant themes, which is entitled 'Feeling 'on your own". PMID- 11602270 TI - Privacy: a review of the literature. AB - The concept of privacy is used in many disciplines and is recognised as one of the important concepts also in nursing. In this review, a description about the perspectives and dimensions of the concept will be made and empirical studies in the area will be analysed. Perspectives include units experiencing privacy, desired-achieved state, and reactiveness. Dimensions are divided into physical, psychological, social and informational. In the empirical studies, the concept of the privacy has mainly been studied in hospital organisations using the physical dimension. The concept needs further clarification in future. PMID- 11602271 TI - Quality of life for patients with diabetes in Korea--I: the meaning of health related quality of life. AB - This study describes the impact of diabetes and the meaning of health-related quality of life (HRQOL) for 22 male and female patients in Korea. Open-ended interviews yielded six HRQOL themes: health, overall well-being, harmonious relationships and family responsibilities, a rewarding life, spiritual life, and material support. The physical impact of diabetes included decreased energy, limitations, and physical suffering; while its psychological/spiritual impact extended to general stress, helplessness, fear, depression, anger, and relationship with God. Like Americans, Koreans valued health, psychological well being and interpersonal support. In addition, the Koreans valued smooth, harmonious interpersonal relationships, overall well-being pertaining to living a comfortable and honorable life. PMID- 11602273 TI - Alpha-latrotoxin: from structure to some functions. PMID- 11602274 TI - Venom from the ectoparasitic wasp Nasonia vitripennis increases Na+ influx and activates phospholipase C and phospholipase A2 dependent signal transduction pathways in cultured insect cells. AB - The mode of action of venom from the ectoparasitic wasp Nasonia vitripennis in eliciting cell death was examined using an in vitro approach with BTI-TN-5B1-4 cells, and the cell responses were compared to those evoked by the extensively studied wasp toxin mastoparan. Wasp venom increased plasma membrane permeability to Na+, resulting in cellular swelling and death due to oncosis. When ouabain was used to disable Na+, K+-ATPases, the effects of venom were enhanced. Measurements of intracellular calcium using fluo-4 AM revealed a rearrangement and an increase in cytosolic [Ca+2]i within 30 min after exposure of BTI-TN-5B1-4 cells to venom. This venom-mediated increase in Ca+2 was apparently due to mobilization of intracellular stores since the changes occurred in the absence of extracellular Ca+2. Phospholipase C (PLC) inhibitors, neomycin and U-73122, blocked the venom induced death temporarily (<3h), but by 24h, all venom-treated cells swelled and lysed. Pre-treatment of cells with caffeine or theophylline but not ryanodine attenuated the induction of oncosis by wasp venom. Anti-inflammatory peptide 1 (antiflammin 1) but not bromophenacyl bromide, agents that block phospholipase A2 (PLA2) activity, abolished the responsiveness of BTI-TN-5B1-4 cells to venom. These results suggest that venom initiates cell death by inducing Ca+2 release from intracellular stores probably via phospholipase C and IP3. A possible mode of action for venom from N. vitripennis requiring dual activation of PLC and PLA2 is discussed and compared to the pathways known to be activated by mastoparan. PMID- 11602275 TI - SCORPION, a molecular database of scorpion toxins. AB - Increasing interest in the studies of toxins and the requirements for better structural and functional annotations have created a need for improved data management in the field of toxins. The molecular database, SCORPION, contains more than 200 entries of fully referenced scorpion toxin data including primary sequences, three-dimensional structures, structural and functional annotations of scorpion toxins along with relevant literature references. SCORPION has a set of search tools that allow users to extract data and perform specific queries. These entries have been compiled from public databases and literature, cleaned of errors and enriched with additional structural and functional information. The grouping of scorpion toxins provides a basis for extending and clarifying the existing structural and functional classifications. The bioinformatics modules in SCORPION facilitate analyses aimed at classification of scorpion toxins and identification of sequence patterns associated with specific structural or functional properties of scorpion toxins. The SCORPION database is accessible via the Internet at sdmc.krdl.org.sg:8080/scorpion. PMID- 11602276 TI - Esterification of DSP toxins by Portuguese bivalves from the Northwest coast determined by LC-MS--a widespread phenomenon. AB - Okadaic acid (OA) and dinophysistoxin-2 (DTX2) were confirmed by liquid chromatography with mass spectrometry detection both in extracts of digestive glands and edible parts of Portuguese shellfish. No dinophysistoxin-1 was found even in highly contaminated samples examined. However, only in blue mussel (Mytilus edulis) were these two parent toxins commonly found in a free form. Usually they were found largely esterified in all remaining shellfish species common cockle (Cerastoderma edule), peppery furrow shell (Scrobicularia plana), carpet shell (Venerupis pullastra), oyster (Crassostrea japonica), razor clam (Ensisspp.), and clam (Ruditapes decussata). Oysters were the least toxic. In mussels esterified OA did not surpass 50% of the total OA found in edible parts, while DTX2 esterification rates were usually much lower. In remaining shellfish species usually more than 95% of the total OA was found esterified, while free DTX2 was rarely found. Also ratios of total DTX2/total OA were higher in mussels than in the remaining species examined. From all these species commercially exploited at the northern coast, mussels and cockles contained the highest levels of DSP toxins, thus representing the highest theoretical health risk. The previous association of DTX2 with the dinoflagellate Dinophysis acuta was confirmed with selective MS detection; while OA was the only parent diarrhoeic toxin found associated with Dinophysis acuminata. PMID- 11602277 TI - Analysis of fatty acids released by crotoxin in rat brain synaptosomes. AB - Crotoxin, the main toxin of Crotalus durissus terrificus venom, exerts its lethal effect by blocking neurotransmission at the neuromuscular junction level through a triphasic mechanism. This effect seems to depend on its phospholipasic activity, suggesting that the mechanism of neurotransmission blockage may be related to fatty acids release in specific sites of the nervous terminal. In this work, we purified the fatty acids released by crotoxin's activity and this outline was compared with other phospholipases A(2), including CB, a subunit of crotoxin. Our results show a higher release of palmitate and arachidonate by crotoxin when compared to other phospholipases A(2). Since palmitate has a role in protein acylation processes and arachidonate participates in signal transduction events, these mechanisms may be related to the neurotoxic actions of crotoxin. PMID- 11602278 TI - Biochemical characterization of fibrinogenolytic serine proteinases from Vipera lebetina snake venom. AB - Two glycosylated serine fibrinogenases isolated from Vipera lebetina venom have homologous N-terminal sequences and antigenic determinants but can be clearly differentiated according to substrate specificity, glycosylation levels, molecular mass and fibrinogen degradation. alpha-Fibrinogenase has no homolog among known serine proteinases. It has N-terminal similarity with snake venom arginine esterases but does not hydrolyze the esters of arginine, lysine and tyrosine. The enzyme has strong proteolytic activity and degrades alpha-chain of fibrinogen altering its clottability by thrombin. beta-Fibrinogenase is a typical arginine esterase which hydrolyzes esters and amides of arginine and attacks the beta-chain of fibrinogen. PMID- 11602279 TI - Purification and characterisation of two hemorrhagic metalloproteinases from the venom of the long-nosed viper, Vipera ammodytes ammodytes. AB - Two hemorrhagic proteins, VaH1 and VaH2, have been purified from Vipera ammodytes ammodytes venom. They are monomeric glycoproteins of an apparent molecular mass of 70kDa and multiple isoelectric points around pH 5.5. Both molecules are proteolytically active against azocasein as substrate. VaH1, which was characterised in detail, showed maximum activity at pH 7.5. Ethylenediaminetetraacetic acid eliminated the proteolytic as well as the hemorrhagic activity of VaH1 while iodoacetamide, phenylmethylsulfonyl fluoride and pepstatin A, inhibitors of cysteine, serine and aspartic proteinases respectively, had no effect. VaH1 is therefore a metalloproteinase whose hemorrhagic activity is very likely the result of its proteolytic activity. VaH1 is a fibrinogenase, hydrolysing exclusively the Aalpha-chain of fibrinogen. In the B-chain of insulin it cleaved with a high preference the bond between Ala(14) and Leu(15). Based on its molecular mass, VaH1 (as well as VaH2) is a Class P-III metalloproteinase. Partial amino acid sequences of its CNBr fragments demonstrated a high level of identity with the reprolysin subfamily of zinc metalloproteinases. PMID- 11602280 TI - Neutralization of a snake venom hemorrhagic metalloproteinase prevents coagulopathy after subcutaneous injection of Bothrops jararaca venom in rats. AB - Coagulopathy is one of the major complications following envenomations by crotalid and viperid snakes. The present study was undertaken to examine the effect of a hemorrhagic metalloproteinase in Bothrops jararaca venom, jararafibrase I (JF I), on the development of coagulopathy using rat snakebite model. Coagulation parameters were monitored after subcutaneous injection of B. jararaca crude venom, JF I-neutralized venom and purified JF I in rats. Crude venom induced unclottable blood and fibrinogen consumption, while JF I neutralized venom and purified JF I did not induce coagulopathy. Plasma venom antigen level of rats given JF I-neutralized venom was lower than that of rats given crude venom. We conclude that venom hemorrhagic metalloproteinases play an important role in the development of coagulopathy through rapid spreading of venom coagulation components from the injected area into systemic circulation. PMID- 11602281 TI - An electrophysiological study on the effects of Pa-1G (a phospholipase A(2)) from the venom of king brown snake, Pseudechis australis, on neuromuscular function. AB - The effects of Pa-1G, a phospholipase A(2) (PLA(2)) from the venom of the Australian king brown snake (Pseudechis australis) were determined on the release of acetylcholine, muscle resting membrane potential and motor nerve terminal action potential at mouse neuromuscular junction. Intracellular recording from endplate regions of mouse triangularis sterni nerve-muscle preparations revealed that Pa-1G (800 nM) significantly reduced the amplitude of endplate potentials within 10 min exposure. The quantal content of endplate potentials was decreased to 58+/-6% of control after 30 min exposure to 800 nM Pa-1G. The toxin also caused a partial depolarisation of mouse muscle fibres within 60 min exposure. Extracellular recording of action potentials at motor nerve terminals showed that Pa-1G reduced the waveforms associated with both sodium and potassium conductances. To investigate whether this was a direct or indirect effect of the toxin on these ionic currents, whole cell patch clamp experiments were performed using human neuroblastoma (SK-N-SH) cells and B82 mouse fibroblasts stably transfected with rKv1.2. Patch clamp recording experiments confirmed that potassium currents sensitive to alpha-dendrotoxin recorded from B82 cells and sodium currents in SK-N-SH cells were not affected by the toxin. Since neither facilitation of acetylcholine release at mouse neuromuscular junction nor depression of potassium currents in B82 cells has been observed, the apparent blockade of potassium currents at mouse motor nerve endings induced by the toxin is unlikely to be due to a selective block of potassium channels. PMID- 11602282 TI - Comparison of oral and intraperitoneal toxicity of yessotoxin towards mice. AB - Currently, yessotoxin is regulated among the toxins in the diarrhetic shellfish poisoning (DSP) complex. Yessotoxin is equally acutely toxic towards mice upon intraperitoneal injections as those algal toxins giving diarrhea, but is not diarrheagenic. Its presence in mussels may therefore lead to overestimation of risk of DSP in consumers when the standard mouse bioassay is used. Arguments are presented for the use of analytical methods instead of the mouse bioassay for the diarrheagenic DSP toxins and yessotoxin. Yessotoxin was found to be more than ten times less toxic to mice via the oral route, compared with intraperitoneal injections. Even at 10mg/kg body weight, the highest dose ever tested orally, yessotoxin did not kill the mice. By means of light microscopy of several organs, moderate changes were only observed in the heart. Ultrastructural studies revealed swelling of heart muscle cells leading to separation of the organelles. Effects were most pronounced close to the capillaries. The pathological changes were clearly dose dependent, and the lowest oral dose where any effects were seen was 2.5mg yessotoxin per kg. PMID- 11602283 TI - Hamamelitannin from Hamamelis virginiana inhibits the tumour necrosis factor alpha (TNF)-induced endothelial cell death in vitro. AB - The tumour necrosis factor-alpha (TNF) inhibitory activity of hamamelitannin from Hamamelis virginiana was investigated by assessing the TNF-mediated EAhy926 endothelial cell death and adhesiveness to monocytes. Treatment of the cells by TNF (25 ng/ml) and actinomycin D (0.1ng/ml) resulted in significant DNA fragmentation (34+/-0.6, n=4) and cytotoxicity (97+/-4.5%, n=6) following treatment for 8 and 24h, respectively. One to 100 microM concentrations of hamamelitannin inhibited the TNF-mediated endothelial cell death and DNA fragmentation in a dose-dependent manner. One hundred % protection against TNF induced DNA fragmentation and cytotoxicity was obtained for hamamelitannin concentrations higher than 10 microM. The protective effect of hamamelitannin was comparable with that of a related compound epigallocatechin gallate while gallic acid was a weak protective agent (<40% protection). EAhy926 endothelial cells upregulated (by 4- to 7-fold) the surface expression of intercellular adhesion molecule-1 (ICAM-1) and adhesiveness to monocytic U937 cells after treatment with TNF (0.5ng/ml) for 6 or 24h. Concentrations (1-100 microM) of hamamelitannin that inhibited the TNF-mediated cell death and DNA fragmentation, however, failed to inhibit the TNF-induced ICAM-1 expression and EAhy926 cell adhesiveness to U937 cells. Thus, hamamelitannin inhibits the TNF-mediated endothelial cell death without altering the TNF-induced upregulation of endothelial adhesiveness. The observed anti-TNF activity of hamamelitannin may explain the antihamorrhaegic use of H. virginiana in traditional medicine and its claimed use as a protective agent for UV radiation. PMID- 11602284 TI - Induction of neutralizing antibodies against Tityus serrulatus scorpion toxins by immunization with a mixture of defined synthetic epitopes. AB - We have used the Spot method of multiple peptide synthesis to prepare sets of immobilized overlapping peptides of uniform size (15 mer), covering the complete amino acid sequences of TsNTxP a non-toxic and immunogenic protein and TsIV, an alpha-type toxin that is the major lethal component of the venom of scorpion Tityus serrulatus. Anti-TsNTxP antibodies binding to peptides, revealed three antigenic regions, one in the N-terminal, the second in the central part and the other in the C-terminal part of TsNTxP. One peptide epitope in the C-terminal part of TsIV was identified with anti-TsIV neutralizing rabbit antibodies. Anti peptide antibodies were raised against these four peptides all together covalently coupled to keyhole limpet hemocyanin (KLH) and found to neutralize in vitro the toxic effects of the T. serrulatus venom. Quantities of venom equivalent to 13.5 LD(50) were effectively neutralized by 1ml of the anti-peptide serum. The antigenic specificities of the anti-peptides were compared by an indirect enzyme-linked immunosorbent assay (ELISA) using synthetic peptides and crude venoms from T. serrulatus, T. bahiensis, T. cambridgei, T. stigmurus, Androctonus autralis Hector and Centruroides sculpturatus to coat the microtitration plates. The anti-peptide antibodies had a comparable high reactivity with the crude venom of T. serrulatus, moderate binding to T. bahiensis, T. cambridgei, T. stigmurus and Centruroides sculpturatus venoms but were unable to recognize the venom of Androctonus autralis Hector. These results show that by using peptides derived from the sequence of scorpion toxins, the generation of anti-peptide antibodies able to neutralize the cognate venom appears to be an alternative strategy for the easy preparation of antivenoms. PMID- 11602285 TI - Purification of microcystins by DEAE and C(18) cartridge chromatography. AB - Microcystins (MCs) were purified by DEAE and C(18) cartridge chromatography. Addition of EtOH to the eluents (20%) in DEAE chromatography gave higher resolution than no addition of EtOH. The chromatogram showed three peaks: MC-LR; MC-LY and MC-LF; MC-LW. MC-LR and MC-LW were obtained by one step chromatography with purity of 96 and 88%, respectively. The separation of MC-LF and MC-LW with DEAE chromatography was better than that with reversed-phase chromatography. MC LY and MC-LF were separated with C(18) cartridge. On the chromatogram, there were three peaks consisting of MC-LY (81% purity), MC-LF (86%), and an unknown compound which was considered as a MC variant judging from the results in HPLC/PDA, FAB-MS, and 1H NMR analyses, but the structure could not be determined. It is concluded that the combination of DEAE and C(18) cartridge chromatography would be a practical approach for the purification of various MCs. PMID- 11602286 TI - Localization of tetrodotoxin in the skin of a brackishwater puffer Tetraodon steindachneri on the basis of immunohistological study. AB - A monoclonal antibody-based immunoassay for localization of tetrodotoxin (TTX) in the skin of a brackishwater puffer Tetraodon steindachneri is described in this paper. TTX was recognized in the undifferentiated basal cells and succiform cells in the skin under light microscope. Malpighian cells of the skin did not exhibit any TTX antigen. Neither gland nor enclosed gland-like apparatus possessing TTX was apparent in the skin. PMID- 11602287 TI - Acres of antibodies: the future of recombinant biomolecule production? AB - The Cambridge Healthtech Institute's second international conference entitled "Recombinant Therapeutics: Antibodies and Biomolecules" was held in Baltimore, MD, USA, 30 May-1 June 2001. PMID- 11602288 TI - All aboard the chip! AB - The Cambridge Healthtech Institute's Microarrays and Microchips conference was held in Tokyo, Japan, 4-5 June 2001. PMID- 11602289 TI - Biocontrol agents in the age of molecular biology. AB - The NATO Advanced Research Workshop "Enhancing Biocontrol Agents and Handling Risks" was held in Florence, Italy, 9-15 June 2001. PMID- 11602290 TI - Biosensors in the livestock industry: an automated ovulation prediction system for dairy cows. AB - Biosensor technology can offer the livestock industry new types of monitoring and measuring devices of which the specificity, sensitivity, reproducibility, speed and ease of use exceed the current technology. Biosensors can be applied to the detection and identification of infectious diseases in livestock, contaminants and toxins in feed, therapeutic drug residues in animal husbandry and oestrus detection. Our team is applying biosensor technology to the livestock industry by developing a fully automated ovulation prediction system for dairy cows. The results from field-tests show that the progesterone biosensor can characterize the ovulation cycles of cows and detect pregnancy. PMID- 11602307 TI - The bioseparation needs for tomorrow. AB - Will we replace oil with wheat or corn as a feedstock for producing natural plastic? The success of biotechnology for bulk product manufacturing will heavily depend on engineering solutions in the downstream processes in which separation and purification have a crucial role with respect to commercial development. Development of efficient bioseparation methods is important for a broad range of business areas including pharmaceuticals, nutrition and health products, bio based materials and crop protection chemicals. Depending on the value of the end product and the scale of production, the processing required varies significantly. Key factors that have an impact on the choice of separation strategy include process throughput, particle size of the product and impurities and the desired end-product concentration. The development of efficient, economical and selective separation methods will be required for successful commercialization of bioprocesses. Despite this well-recognized need, there are relatively few available methods for commercial implementations. Development of novel mechanical systems for selective separation of solid and liquid mixtures must become a top priority for current research investment to reduce the reliance on expensive chromatographic and thermal separation methods. PMID- 11602308 TI - The development of new methods for the recycling of chiral catalysts. AB - This article discusses different methods for the recycling of chiral catalysts, including heterogenization of the soluble catalyst on an insoluble inorganic or organic support, membrane filtration of homogeneously soluble catalysts, precipitation, and two-phase systems. In principle, all the methods presented enable the repeated use of a chiral catalyst without loss of activity and/or enantioselectivity. Examples will be given from laboratory and industrial processes, incuding hydrogenations, ketone reductions, epoxidations, dihydroxylations, diethylzinc additions and Diels-Alder reactions catalyzed by chemocatalysts or biocatalysts. Different approaches for cyanation, hydrogenation and epoxidation are compared. Data from industrial processes include the production of metalochlor, the production of (-)-menthol and the production of L tert-leucine. PMID- 11602309 TI - Altering the glycosylation pattern of bioactive compounds. AB - Many bioactive natural products are glycosylated compounds in which the sugars are important or essential for biological activity. The isolation of several sugar biosynthesis gene clusters and glycosyltransferases from different antibiotic-producing organisms, and the increasing knowledge about these biosynthetic pathways opens up the possibility of generating novel bioactive compounds through combinatorial biosynthesis in the near future. Recent advances in this area indicate that antibiotic glycosyltransferases show some substrate flexibility that might allow us to alter the types of sugar transferred to the different aglycons or, less frequently, to change the position of its attachment. PMID- 11602310 TI - Two-phase partitioning bioreactors: a new technology platform for destroying xenobiotics. AB - Toxic organic compounds (xenobiotics) pose serious environmental and health risks worldwide. Biological treatment of these materials is severely constrained by their toxic and inhibitory nature and great care is required with respect to the rate at which they are provided to cells. The use of a second, distinct, organic phase in a bioreactor has been shown to provide a virtually foolproof means of feeding substrate to cells because this process concept relies only on thermodynamic equilibrium and the cells' own rate of metabolism. This technology can be applied to stockpiled xenobiotics as well as contamination of air, water and soil environments. PMID- 11602311 TI - Microarrays: handling the deluge of data and extracting reliable information. AB - Application of powerful, high-throughput genomics technologies is becoming more common and these technologies are evolving at a rapid pace. Genomics facilities are being established in major research institutions to produce inexpensive, customized cDNA microarrays that are accessible to researchers in a broad range of fields. These high-throughput platforms have generated a massive onslaught of data, which threatens to overwhelm researchers. Although microarrays show great promise, the technology has not matured to the point of consistently generating robust and reliable data when used in the average laboratory. This article addresses several aspects related to the handling of the deluge of microarray data and extracting reliable information from these data. We review the essential elements of data acquisition, data processing and data analysis, and briefly discuss issues related to the quality, validation and storage of data. Our goal is to point out some of the problems that must be overcome before this promising technology can achieve its full potential. PMID- 11602312 TI - Manipulating redox systems: application to nanotechnology. AB - Redox proteins and enzymes are attractive targets for nanobiotechnology. The theoretical framework of biological electron transfer is increasingly well understood, and several properties make redox centres good systems for exploitation: many can be detected both electrochemically and optically; they can perform specific reactions; they are capable of self-assembly; and their dimensions are in the nanoscale. Great progress has been made with the two main approaches of protein engineering: rational design and combinatorial synthesis. Rational design has put our understanding of the structure-function relationship to the test, whereas combinatorial synthesis has generated new molecules of interest. This article provides selected examples of novel approaches where redox proteins are "wired up" in efficient electron-transfer chains, are "assembled" in artificial multidomain structures (molecular Lego), are "linked" to surfaces in nanodevices for biosensing and nanobiotechnological applications. PMID- 11602314 TI - Introducing the review series on emerging technologies. PMID- 11602315 TI - Protein-protein interactions in hematology and phage display. AB - Phage display, which exploits fundamental tools and principles of immune repertoire diversity, antigen-antibody interactions, and clonal and immunologic selection, is used increasingly to advance experimental and clinical hematology. Phage display is based on the ability of bacteriophage to present engineered proteins on their surface coat. Diverse libraries of proteins such as peptides, antibody fragments, and protein domains corresponding to gene fragments or cDNAs may be displayed. Interactions between phage-displayed proteins and target antigens can be identified rapidly and characterized using high throughput methodologies. Peptide and gene fragment libraries are particularly useful to characterize binding interactions between proteins, such as ligand-receptor interactions. This approach allows rapid generation of human antibodies, often against nonimmunogenic, conserved proteins. Phage antibodies against surface and intracellular antigens are used as reagents for flow cytometry, in vivo imaging, and therapeutic targeting. Phage-derived antibodies also facilitate analyses of the humoral antibody response. Finally, cellular delivery of phage-displayed peptides and gene fragments can be used to modulate functional pathways and molecules in vitro and in vivo. The combinatorial power of phage display enables identification of candidate epitopes without knowledge of the protein interaction, a priori. Overall, these capabilities provide a versatile, high throughput approach to develop tools and reagents useful for a plethora of experimental hematology applications. This paper focuses on current and future applications of antibody and epitope phage display technology in hematology. PMID- 11602316 TI - Portofino International Conference on Chronic Myeloid Leukemia. PMID- 11602317 TI - The biology of natural killer cells in cancer, infection, and pregnancy. AB - OBJECTIVE: NK cells are important cells of the immune system. They are ultimately derived from pluripotent hematopoietic stem cells. NK cell cytotoxicity and other functions are tightly regulated by numerous activating and inhibitory receptors including newly discovered receptors that selectively recognize major histocompatibility complex class I alleles. Based on their defining function of spontaneous cytotoxicity without prior immunization, NK cells have been thought to play a critical role in immune surveillance and cancer therapy. However, new insights into NK cell biology have suggested major roles for NK cells in infection control and uterine function. The purpose of this review is to provide an update on NK cell function, ontogeny, and biology in order to better understand the role of NK cells in health and disease. DATA SOURCES: In the Medline database, the major subject heading "Natural Killer Cells" was introduced in 1983, identifying 16,848 citations as of December 31, 2000. Since 1986, there have been approximately 1000 citations per year under this subject heading. In this database, 68% of manuscripts are limited to human NK cells; 40% of citations cross with the major sub-heading of cytotoxicity, 40% with cytokines, 36% with neoplasm, 5% with antibody-dependent cellular cytotoxicity, 2.8% with pregnancy, and 1.3% with infection. Of references from the year 2000-2001, 46 were selected to combine with contributions from earlier literature. CONCLUSIONS: NK cells should no longer be thought of as direct cytotoxic killers alone as they clearly serve a critical role in cytokine production which may be important to control cancer, infection, and fetal implantation. Understanding mechanisms of NK cell functions may lead to novel therapeutic strategies for the treatment of human disease. PMID- 11602318 TI - Functional analyses of cord blood natural killer cells and T cells: a distinctive interleukin-18 response. AB - OBJECTIVE: To search for the functional property of cord blood (CB) cells, the effects of interleukin-18 (IL-18) on interferon-gamma (IFN-gamma) production of T cells or natural killer (NK) cells were compared between CB and adult peripheral blood (PB). MATERIALS AND METHODS: T cells, CD45RA(+) T cells, and NK cells were purified from CB and adult PB mononuclear cells using magnetic beads or a cell sorter. After stimulation with or without IL-18 in the presence of IL-12 for 48 hours (NK cells) or 72 hours (T cells or CD45RA(+) T cells), IFN-gamma concentration was measured in each subset. Although IL-18 induced significant IFN gamma production from both CB and adult PB T cells in the presence of IL-12, the IFN-gamma levels from CB T cells were lower than those from adult PB T cells. However, CD45RA(+) T cells from CB and from adult PB produced similar levels of IFN-gamma after stimulation with IL-18 + IL-12. On the other hand, CB NK cells exhibited higher IFN-gamma production and CD69 expression than adult PB NK cells after stimulation with IL-18 + IL-12. Cytolytic activity of CB NK cells increased to a level comparable to that of adult PB NK cells after the same IL-18/IL-12 stimulation. CONCLUSIONS: These results suggest that a low response of CB T cells to IL-18 is due to a higher proportion of naive (CD45RA(+)) T cells in CB, which may be one of the factors responsible for the neonatal immaturity of the immune system as well as the low incidence of graft-vs-host disease in patients receiving CB stem cell transplantation. On the other hand, a high response of CB NK cells to IL-18 may contribute to the host defense during the neonatal period and antitumor effects in CB stem cell transplantation. PMID- 11602319 TI - Promegapoietin, a family of chimeric growth factors, supports megakaryocyte development through activation of IL-3 and c-Mpl ligand signaling pathways. AB - OBJECTIVE: The signaling pathways induced by promegapoietin (PMP), a family of chimeric growth factors that activate the human IL-3 and c-Mpl receptors, were investigated. METHODS: The biological activity of PMP was examined by receptor binding, cell proliferation, ex vivo expansion of hematopoietic progenitor cells, and in vivo production of platelets. The activation of signaling pathways was examined by Western blot and Northern blot analyses. RESULTS: Two PMP molecules, PMP-1 and PMP-1a, induced proliferation of cells expressing the IL-3 receptor, c Mpl, or both receptors and bound to the IL-3 receptor and c-Mpl with high affinity. Ex vivo expansion assays using human bone marrow CD34(+) cells suggested that PMP-1 induced greater total cellular expansion as well as expansion of CD41(+) megakaryocytic precursor cells than IL-3 or c-Mpl ligand alone. Subcutaneous administration of 50 microg/kg of PMP-1 for 10 days to rhesus monkeys resulted in increased platelet production in vivo from a baseline of 357 +/- 45 x 10(3) cells/mL to 1376 +/- 151 x 10(3) cell/mL. PMP-1 induced phosphorylation of the beta(c) subunit of IL-3 receptor and c-Mpl, JAK2, and STAT5b, but not STAT3. PMP-1 induced greater expression of Pim-1, c-Myc, and cyclin D2 than did either an IL-3 receptor agonist or c-Mpl receptor agonist alone. The magnitude of induction of early response genes was similar for PMP and the coaddition of IL-3 receptor agonist and c-Mpl receptor agonist. CONCLUSION: PMP combines the biological activities of IL-3 and c-Mpl ligand in a single molecule that can simultaneously activate signaling pathways induced by both these ligands. PMID- 11602320 TI - Flt3 ligand and granulocyte-macrophage colony-stimulating factor preferentially expand and stimulate different dendritic and T-cell subsets. AB - OBJECTIVE: Mechanisms of T-cell stimulation by Flt3 ligand (Flt3L) and granulocyte-macrophage colony-stimulating factor (GM-CSF) remain unclear. Herein, we compared the effects of Flt3L and GM-CSF on the expansion of dendritic cells (DC) and T-cell subsets and cytokine expression. METHODS: Naive and effector/memory T cells were analyzed by flow cytometry (FC). CD4(+) and CD8(+) T cells and CD11c(+)CD11b(dull/-)(DC1) and CD11c(+)CD11b(+) (DC2) subsets were isolated and the frequency of IFN-gamma-, IL-12- (type 1) and IL-4-, IL-10 (type 2)-producing cells and cytokine mRNA expression evaluated. RESULTS: Flt3L expanded both DC1 and DC2 subsets with a significantly higher percentage and number of DC1 than DC2, while GM-CSF preferentially expanded the DC2 subset. Isolated DC1 from Flt3L-injected mice had significantly higher levels of IL-12 (p40) than IL-10, while the converse occurred with DC2. The numbers of naive and memory T cells were elevated in mice that received Flt3L or GM-CSF. However, the number of memory CD4(+) and CD8(+) T cells was significantly increased in Flt3L as compared to GM-CSF cohorts. While GM-CSF increased the frequency of both type 1 and type 2 cytokine-producing cells, Flt3L significantly augmented the frequency of type 1 T cells. CONCLUSIONS: In contrast to GM-CSF, Flt3L preferentially induces the expansion of type 1 T cells. The mechanism of Flt3L induced T-cell stimulation is associated with the expansion of the IL-12 (p40) producing DC1 and memory T cells. PMID- 11602322 TI - Novel erythropoiesis stimulating protein (darbepoetin alfa) alleviates anemia associated with chronic inflammatory disease in a rodent model. AB - OBJECTIVE: We developed a rodent model of noninfectious systemic inflammation to examine the pathogenesis of the associated anemia of chronic disorders (ACD), to evaluate the similarity of this ACD model to human ACD, and to evaluate the potential efficacy of novel erythropoiesis stimulating protein (darbepoetin alfa) as an ACD therapy. METHODS: Lewis rats were immunized with peptidoglycan polysaccharide polymers (PG-APS), the chronic inflammation and associated ACD were characterized, and the effects of darbepoetin alfa treatment on complete blood counts (CBC), red blood cell (RBC) indices, and iron metabolism were analyzed weekly. RESULTS: Acutely inflamed rats had reduced peripheral blood (PB) RBC counts and hemoglobin (Hb) concentrations and increased reticulocyte counts. PB RBC numbers normalized during chronic inflammation, but RBC remained hypochromic and microcytic. Consequently, the rats remained chronically anemic. Anemic rats had fluctuating serum erythropoietin (EPO) concentrations, but mean EPO concentrations never varied significantly from baseline control levels. Histology of anemic rat spleen sections revealed reticuloendothelial siderosis. Total serum iron concentrations were chronically low. Peritoneal exudate cells (PEC) isolated from anemic rats and stimulated with PG-APS in vitro produced more interleukin (IL)-1alpha and interferon (IFN)-gamma, and significantly more tumor necrosis factor (TNF)-alpha and IL-10 than control cultures. Darbepoetin alfa restored Hb concentrations to baseline levels within 2 to 7 weeks, depending on dosage. A refined treatment strategy restored Hb to baseline and maintained those levels with reduced dosing. CONCLUSION: ACD in this rodent model closely replicates human ACD. Darbepoetin alfa treatment reversed ACD in this model by increasing RBC production and RBC hemoglobinization while reducing siderosis and hypoferremia. PMID- 11602321 TI - Erythroid involvement in CD36 deficiency. AB - OBJECTIVE: The CD36 molecule is expressed in platelets, monocytes, erythroblasts, and other different tissues. The two types of platelet CD36 deficiency, types I and II, are associated with the absence and presence of CD36 on monocytes, respectively. To clarify the involvement of the erythroid lineage in CD36 deficiency, we investigated the phenotype and RNA expression of CD36. MATERIALS AND METHODS: CD36 expression was examined in 296 patients with several cardiovascular diseases in our outpatient clinic. There were 12 patients with type I deficiency and 16 with type II CD36 deficiency. A bone marrow sample was examined in five type I and four type II patients. Expression of CD36 mRNA was examined in burst-forming unit-erythroid (BFU-E). The sequences of reverse transcriptase polymerase chain reaction (RT-PCR) products of the CD36 mRNA from monocytes were examined. RESULTS: As expected, CD36 was deficient in erythroblasts from all five patients with type I deficiency. CD36 was present in erythroblasts from three of the four with type II deficiency, suggesting that their abnormality is restricted to platelets (type IIa). CD36 was unexpectedly absent from erythroblasts of a single type II patient (type IIb). CD36-specific mRNA was identified in BFU-E from each of two normals, six type I, and six type II patients, including type IIb. The sequences of RT-PCR products of the CD36 mRNA in a patient with type IIa and another with type IIb showed homozygous wild alleles. CONCLUSION: The findings provide evidence for further heterogeneity among CD36-deficient individuals and the existence of a basic principle mechanism of type II, such as glycosylation abnormality. PMID- 11602323 TI - Efficient lentiviral transduction of human cord blood CD34(+) cells followed by their expansion and differentiation into dendritic cells. AB - OBJECTIVE: To support immune reconstitution after cord blood transplantation, immunotherapy using gene-modified dendritic cells (DCs), the most potent antigen presenting cells, can be a powerful strategy for preventing infection and recurrence. To investigate the applicability of lentiviral vector-transduced DCs compared to retroviral vectors, we transduced umbilical cord blood (CB) CD34(+) cells, then expanded and differentiated them into DCs. MATERIALS AND METHODS: We transduced CB CD34(+) cells by vesicular stomatitis virus G-protein pseudotyped self-inactivating lentiviral vector or retroviral vectors carrying the enhanced green fluorescent protein gene. The cells were expanded in the stroma-dependent culture system and transferred to the culture condition for developing DCs. The efficiency of transduction and expression of the transgene in severe combined immunodeficiency (SCID) mice-repopulating cells (SRCs) and DCs were compared between lentiviral vector and retroviral vectors. Induced DCs were cocultured with allogeneic or autologous T cells to test the ability to present antigens. RESULTS: CB CD34(+) cells transduced by lentiviral vector and expanded ex vivo sustained stable transgene expression and multipotentiality by assessing SRCs assay and clonogenic assay of bone marrow cells from the transplanted mice. DCs derived from these cells expressed green fluorescent protein and surface markers CD1a, CD80, and HLA-DR and showed potent allo-stimulatory activity as well as nontransduced DCs did. On the other hand, we did not detect transgene expression in SRCs and DCs transduced by retroviral vectors. CONCLUSION: Gene-modified DCs derived from ex vivo expanded CB CD34(+) cells transduced by lentiviral vector will be useful in future immunotherapy protocols. PMID- 11602324 TI - A model of chronic lymphocytic leukemia with Ritcher's transformation in severe combined immunodeficiency mice. AB - OBJECTIVE: The major aim of the study was to establish a murine model of chronic lymphocytic leukemia with B-1 cells derived from a New Zealand white mouse. MATERIAL AND METHODS: Malignant B-1 cells (named CLL-RT cells) derived from a New Zealand white mouse were injected into the peritoneal cavity of severe combined immunodeficiency mice. Upon follow-up of recipient mice, the lymphomas showed characteristics similar to chronic lymphocytic leukemia (CLL) with Ritcher's transformation. RESULTS: Blood samples from the recipient mice showed that CLL-RT cells increased rapidly in peripheral blood after 5 weeks. Serum interleukin-10 also increased significantly in recipient mice, as in human chronic lymphocytic leukemia patients. These CLL-RT cells showed a high nucleus-to-cytoplasm ratio. These cells could metastasize via circulation in the recipients and form diffuse lymphomas in various tissues. These aggressive and diffuse lymphomas were similar to Ritcher's transformation of human CLL. The cell surface antigens of the spleen and peritoneal resident cells were analyzed by flow cytometry. The CLL-RT cells constantly expressed surface immunoglobulins M and G, and CD5, CD19, B220, and CD40 molecules. They did not express any CD11b, CD3, MAC-3, CD23, NK1.1, or H 2K(d) molecules. CONCLUSIONS: The characteristics of our animal model are very similar to human CLL. This animal system could be an ideal model for the human disease. We believe the animal model would be valuable in therapeutic studies and aid in the identification of the specific genetic alleles associated with the disease. PMID- 11602325 TI - Ribozyme-mediated cleavage of wt1 transcripts suppresses growth of leukemia cells. AB - OBJECTIVE: The Wilms' tumor gene product (WT1) was identified as a tumor suppressor in pediatric kidney tumors. Conversely, acute leukemias express WT1 at a high frequency, and leukemias with high levels of WT1 expressed by leukemic blast cells have a significantly worse prognosis, suggesting an oncogenic function of WT1 in leukemic cells. To address this issue, we developed five hammerhead ribozymes (RZ1-RZ5) designed to cleave various wt1-mRNA GUC recognition sites and thus suppress wt1 expression. METHODS: Using in vitro transcribed ribozymes and truncated wt1 target RNAs as substrates, we performed in vitro cleavage assays. The sequence of two ribozymes was then cloned into the pCDNA3 expression vector containing a self-processing ribozyme cassette. Downregulation of wt1 due to ribozyme expression was analyzed in the human 293 embryonic kidney and the K562 chronic myeloid leukemia cell line by Western blotting and RT-PCR. Growth of stable transfected K562 cells was determined by proliferation analysis and 3H-thymidine incorporation. RESULTS: In vitro, the anti-wt1 ribozymes were able to recognize and cleave the target RNA in a highly sequence-specific and time-dependent manner. The ribozymes showed different catalytic activity. Coexpression of wt1 and the self-processing ribozymes pRZ3 and pRZ5, respectively, resulted in a significantly downregulated WT1 protein level when transiently transfected in 293 cells. Furthermore, stable transfection of pRZ3 and pRZ5 resulted in considerably reduced expression of endogenous wt1 in K562 cells, correlating with the inhibition of cell proliferation and the induction of cell death. CONCLUSION: Our data suggest that anti-wt1 ribozymes are a potent inhibitor of wt1 expression with possible implications for the inhibition of cell proliferation in leukemic cells. PMID- 11602327 TI - Different times of withdrawal from cocaine administration cause changes in muscarinic and dopaminergic receptors in rat premotor cortex. AB - The present work studied neurochemical changes in rat premotor cortex 30 min, 1 and 5 days after withdrawal from cocaine repeated administration (20 and 30 mg/kg, intraperitoneally, daily for 7 days). Binding assays were performed in 10% homogenates, and ligands used were [(3)H]-N-methylscopolamine, [(3)H]-SCH 23390, and [(3)H]-spiroperidol for muscarinic, D(1)- and D(2)-like receptors, respectively. Levels of cyclic AMP (cAMP) and cyclic guanosine monophosphate (cGMP) were determined using a commercial kit. Scatchard analyses of muscarinic receptors showed an upregulation after 1 and 5 days withdrawal. While D(2)-like receptors were upregulated at all withdrawal periods, D(1)-like receptors were upregulated only at the 30 min withdrawal, and returned to normal levels after 1 day of the last injection. In relation to cAMP levels, the repeated cocaine administration, 1 day after the last injection produced a decrease (around 26%) with both doses, while a 67% increase was seen in cGMP levels with the 30 mg/kg dose. These findings indicate lasting neurochemical changes in premotor cortex caused by cocaine which remained after different withdrawal periods. PMID- 11602326 TI - Alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway. AB - Substantial evidence suggests that the accumulation of beta-amyloid (Abeta) derived peptides contributes to the aetiology of Alzheimer's disease (AD) by stimulating formation of free radicals. Thus, the antioxidant alpha-lipoate, which is able to cross the blood-brain barrier, would seem an ideal substance in the treatment of AD. We have investigated the potential effectiveness of alpha lipoic acid (LA) against cytotoxicity induced by Abeta peptide (31-35) (30 microM) and hydrogen peroxide (H(2)O(2)) (100 microM) with the cellular 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction and fluorescence dye propidium iodide assays in primary neurons of rat cerebral cortex. We found that treatment with LA protected cortical neurons against cytotoxicity induced by Abeta or H(2)O(2). In addition, LA-induced increase in the level of Akt in the neurons was observed by Western blot. The LA-induced neuroprotection and Akt increase were attenuated by pre-treatment with the phosphatidylinositol 3-kinase inhibitor, LY294002 (50 microM). Our data suggest that the neuroprotective effects of the antioxidant LA are partly mediated through activation of the PKB/Akt signaling pathway. PMID- 11602328 TI - Histological demonstration of voltage dependent calcium channels on calcitonin gene-related peptide-immunoreactive nerve fibres in the mouse knee joint. AB - The afferent (excitability) and efferent functions (release of neuropeptides) of primary afferent nerve fibres are based on Ca(2+)-influx. The aim of the present study was to examine the presence of L- and N-type Ca(2+)-channels at sensory nerve fibres in the mouse knee joint capsule. Specific fluorescent labelled channel blockers and antisera against these channel subtypes were combined with an immunohistochemical staining for calcitonin gene-related peptide (CGRP), a neuropeptide that is widely distributed in primary afferents. There was a nearly complete colocalisation of CGRP immunoreactivity and the binding of omega conotoxin GVIA (toxin VIA of Conus geographus or BODIPY-verapamil (BODIPY(R) FL verapamil, hydrochloride) demonstrating the presence of N-type and L-type Ca(2+) channels, respectively. These data were further confirmed by identical results obtained after an immunohistochemical demonstration of the two channel subtypes at the peptidergic nerve fibres. PMID- 11602329 TI - Kainate receptors in primary afferents to the rat gracile nucleus. AB - In a previous work, we demonstrated that under weak paraformaldehyde fixation, kainate receptors (KR) (GluR5/6/7) are expressed in primary afferent terminals in superficial dorsal horn. We extended our study to primary afferents to the gracile nucleus; immunostaining for GluR5/6/7 in weakly fixed sections was in puncta of variable size. In double-stained sections, the majority of immunostained puncta colocalized with synaptophysin. Because of their large size and relations with smaller puncta, single-stained for synaptophysin, these terminals were presumed to be of dorsal column primary afferents. This was confirmed by anterograde labeling with cholera toxin B and with electron microscopy, which showed that GluR5/6/7 was present in terminals with morphology of primary afferents. These observations demonstrate that expression of presynaptic KR is a general feature of primary afferents with different functional properties. PMID- 11602330 TI - Phosphorylation of tau by glycogen synthase kinase 3beta in intact mammalian cells influences the stability of microtubules. AB - Tau is a neuronal microtubule-associated protein found predominantly in axons. Hyperphosphorylation of tau reduces the stability of microtubules, which may be a pathogenic mechanism in Alzheimer's disease. To understand the different effects between tau and glycogen synthase kinase 3beta (GSK-3beta) phosphorylated tau on the organization and stability of microtubules, we performed transfection studies on 3T3 cells using EGFP-tau (Enhanced Green Fluorescence Protein-tau) and GSK 3beta to quantify the stability of microtubules. Laser confocal microscope observation revealed that thick and thin microtubule bundles could be induced by tau and GSK-3beta phosphorylated tau. The bundles appeared either to be relatively straight or to form a ring around the circumference of the cell. Both the thick and thin microtubule bundles were resistant to colchicine-induced dissociation, with thick bundles more resistant than thin bundles. The bundles induced by GSK-3beta phosphorylated tau were sensitive to colchicine, and could be reversed by the addition of LiCl, an inhibitor of GSK-3beta. PMID- 11602331 TI - The retinal input to calbindin-D28k-defined subdivisions in macaque inferior pulvinar. AB - Several studies have provided evidence for direct retinal input to the pulvinar of macaques monkeys, but there is no general agreement regarding the extent of this projection. Moreover, it is not known how retinal input correlates with chemoarchitectonic subdivisions recently recognized within the large, classical divisions of the pulvinar. The potential implications of this correlation have become more evident after reports that chemoarchitectonic subdivisions of the inferior pulvinar (PI) have specific patterns of connections with cortical visual areas. We have therefore re-examined the retino-PI projection using intraocular injections of horseradish peroxides, and correlated it with pulvinar subdivisions revealed using an antibody for calbindin-D28k. Retinal projections were found preferentially within the medial subdivision of the PI, with some involvement of the posterior and central calbindin-D28k defined subdivisions. PMID- 11602332 TI - Event-related beta desynchronization indicates timing of response selection in a delayed-response paradigm in humans. AB - Voluntary movements are preceded by event-related desynchronization (ERD) of alpha and beta activity. The present study used magnetoencephalography to investigate the relationship between motor preparation and the time course of beta ERD in a delayed response paradigm. Depending on the task, the required response (left or right finger lifting) was cued either spatially by the lateralization of a sound at trial onset, or verbally by the content of a midline auditory event. Beta ERD appeared over sensorimotor regions contralaterally to the response side about 200 ms earlier for the spatial than the verbal cue task. This suggests a close relationship between the latency of beta ERD onset and the duration of cognitive processes involved in selecting a motor response. PMID- 11602333 TI - Meta-analysis of functional outcome in Parkinson patients treated with unilateral pallidotomy. AB - Parkinson's disease (PD) profoundly affects activities of daily living (ADL) and quality of human life. Although unilateral pallidotomy has become a common surgical treatment for persons with advanced PD, functional outcome data from previous reports have failed to uniformly support this procedure. In the present investigation, results from 12 studies meeting specific inclusion criteria were subjected to meta-analysis. Only reports featuring unilateral pallidotomy as the exclusive surgery, a sample size of at least five patients, explicit assessment of ADL, and sufficient quantitative data were subjected to analysis. Type of research design was not a factor in the selection process. The results of our analysis suggest that unilateral pallidotomy successfully enhances functional outcome in patients with clinically advanced PD. PMID- 11602335 TI - Characterization of the functional subunit combination of nicotinic acetylcholine receptors in bovine adrenal chromaffin cells. AB - The combination of nicotinic acetylcholine receptors (nAChRs) subunits connecting with the secretion of catecholamines in bovine adrenal chromaffin cells was pharmacologically investigated using selective agonists and antagonists for their nAChRs. The EC(50) values (microM) for the agonists that stimulate the catecholamine secretion and the rank order were as follows: nicotine (3.3)> or =1,1-dimethyl-4-phenylpiperazinium (3.5) > (E)-N-methyl-4-(3-pyridinyl)-3-butene 1-amine (14) > cytisine (23) > or =acetylcholine (25). However, because both the rank order and the EC(50) values differed considerably from those in the various subunits' combinations expressed in Xenopus oocytes or mammalian cells (e.g. alpha2beta2, alpha3beta4, alpha4beta4, etc.), we could not compare them. On the other hand, the IC(50) values (microM) for the antagonists that inhibit the secretion and the rank order were mecamylamine (0.08) > alpha-conotoxin-MII (alpha-CTX-MII) (0.71) > dihydro-beta-erythroidine (DHbetaE) (48) > alpha bungarotoxin (alpha-BTX) (no effect). Mecamylamine is a highly selective antagonist for alpha3beta4 nAChRs, and alpha-CTX-MII and alpha-BTX are specific antagonists for alpha3beta2 and alpha7 nAChRs, respectively. DHbetaE is a selective antagonist for the alpha4beta2. It has already been shown that the mRNAs for alpha3, alpha5, alpha7 and beta4 subunits are expressed in the chromaffin cells. Therefore, the subunit combination of nAChRs associated with the catecholamine secretion from bovine adrenal chromaffin cells is suggested to be at least alpha3beta4 or alpha3beta4alpha5. Further, the results indicate that the utilization of the nicotinic agonists as selective ligands for the subunit combination of nAChRs may be not suitable for the characterization of nAChRs. PMID- 11602334 TI - A new splicing variant for human tyrosine hydroxylase in the adrenal medulla. AB - It has been reported that several mRNA isoforms of tyrosine 3-monooxygenase (tyrosine hydroxylase; TH) occur only in primates. New TH isoforms produced by skipping of exon 3 in the adrenal medulla of patients with progressive supranuclear palsy (PSP) have recently been reported, J. Neurochem. 67 (1996) 19. Here, we looked for the presence of new TH isoforms in control brains and adrenal medulla and in brains from patients with PSP. We found a novel type of TH mRNA in the adrenal medulla from one of the control subjects. The mRNA lacked exon 4, resulting in a premature stop codon at amino acid 147. This result suggests the importance of alternative splicing in the regulation of TH activity. PMID- 11602336 TI - Marked reduction of the Cu/Zn superoxide dismutase polypeptide in a case of familial amyotrophic lateral sclerosis with the homozygous mutation. AB - We identified a missense mutation of the Cu/Zn superoxide dismutase (SOD) gene (Leu126Ser) in a Japanese family with ALS that included a patient with the homozygous mutation. The content of the Cu/Zn SOD polypeptide in erythrocytes was markedly reduced in the case with the homozygous mutation compared to those with the heterozygous mutation. We speculated that this reduction of the mutant Cu/Zn SOD molecule might be related to the severe clinical phenotype of the case. PMID- 11602337 TI - Modulation of dopamine uptake in rat nucleus accumbens: effect of specific dopamine receptor antagonists and sigma ligands. AB - The ability of dopamine (DA) antagonists and sigma receptor ligands to alter [(3)H]-DA uptake was examined using synaptosomes prepared from the nucleus accumbens of female rats. Pre-incubation with compounds having a high affinity for sigma (rimcazole, haloperidol, and spiperone) receptors produced dose dependent inhibition of (3)H-DA uptake. Sulpiride, a pure DA D(2) antagonist had no effect. In contrast, DA uptake was potentiated in response to (+)-3-(3 hydroxyphenyl)-N-(1-propyl)piperidine, a mixed sigma receptor antagonist and DA D(2) receptor agonist. Similarly, SKF-10,047, a selective sigma receptor agonist, and progesterone, a putative endogenous ligand for the sigma receptor, produced significant increases in (3)[H]-DA uptake. These data suggest a potential role for sigma and DA ligands in the regulation of DA uptake in the nucleus accumbens. PMID- 11602338 TI - Migration, integration, and differentiation of hippocampus-derived neurosphere cells after transplantation into injured rat spinal cord. AB - Hippocampus-derived neurospheres were prepared from transgenic rat fetuses expressing green fluorescent protein (GFP), and transplanted into an alginate filled lesion of young rat spinal cord. One, two and four weeks after transplantation, a large number of grafted cells survived, many of which expressed immunoreactivity for glial fibrillary acidic protein, and a few expressed immunoreactivity for beta-tubulin III. The grafted cells closely attached to the host tissue including astrocytes at the border of the lesion. It was notable that numerous GFP-positive cells had migrated within host spinal cord tissue up to 2 mm away from the implanted site 4 weeks postoperation. These results demonstrate that rat fetal hippocampus-derived neurosphere cells could survive, differentiate, extensively migrate, and integrate well into the host spinal cord tissue. PMID- 11602339 TI - Reduction in asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in the cerebrospinal fluid during aging and in patients with Alzheimer's disease. AB - To investigate the significance of nitric oxide (NO) -mediated neuron death in aging and Alzheimer's disease (AD), the concentration of asymmetrical dimethylarginine (ADMA), an endogenous NO synthase inhibitor, in the cerebrospinal fluid was determined in neurologically normal controls and patients with AD. The ADMA concentration significantly decreased with age, whereas the arginine concentration was unaltered. In patients with AD, the ADMA concentration was significantly decreased, compared with controls of a similar age (-48%, P=0.0001), and it significantly decreased with decreasing cognitive functions (r(s)=0.58, P<0.05), whereas the arginine concentration did not change. These findings suggest that ADMA may play an important role in regulating NO synthesis in brain aging and AD. PMID- 11602341 TI - Function and regulation of the transcription factors of the Myc/Max/Mad network. AB - The members of the Myc/Max/Mad network function as transcriptional regulators. Substantial evidence has been accumulated over the last years that support the model that Myc/Max/Mad proteins affect different aspects of cell behavior, including proliferation, differentiation, and apoptosis, by modulating distinct target genes. The unbalanced expression of these genes, e.g. in response to deregulated Myc expression, is most likely an important aspect of Myc's ability to stimulate tumor formation. Myc and Mad proteins affect target gene expression by recruiting chromatin remodeling activities. In particular Myc interacts with a SWI/SNF-like complex that may contain ATPase activity. In addition Myc binds to TRRAP complexes that possess histone acetyl transferase activity. Mad proteins, that antagonize Myc function, recruit an mSin3 repressor complex with histone deacetylase activity. Thus the antagonism of Myc and Mad proteins is explained at the molecular level by the recruitment of opposing chromatin remodeling activities. PMID- 11602340 TI - Surface markers expressed by multipotent human and mouse neural progenitor cells include tetraspanins and non-protein epitopes. AB - Surface molecules play important roles in a wide range of cellular functions, yet little has been reported regarding the expression of such markers by neural stem cells. Here, multipotent human neural progenitor cells (hNPCs) were expanded as a monolayer in the presence of fibroblast/epidermal growth factor, harvested, labeled with monoclonal antibodies, and analyzed by flow cytometry. Positive markers included CD9, CD15, CD81, CD95 (Fas), GD(2) ganglioside, and major histocompatibility complex class I and beta2 microglobulin, as well as low levels of the hematopoietic stem cell marker CD34. Of these, mouse NPCs were positive for CD9, CD15, CD81, and GD(2) ganglioside. The markers reported here have been implicated in a wide range of cellular functions including proliferation, migration, differentiation, apoptosis, and immune recognition. PMID- 11602342 TI - The effects of wild-type p53 tumor suppressor activity and mutant p53 gain-of function on cell growth. AB - The tumor suppressor p53 plays a central role in the protection against DNA damage and other forms of physiological stress primarily by inducing cell cycle arrest or apoptosis. Mutation of p53, which is the most frequent genetic alteration detected in human cancers, inactivates these growth regulatory functions and causes a loss of tumor suppressor activity. In some cases, mutation also confers tumor-promoting functions, such as the transcriptional activation of genes involved in cell proliferation, cell survival and angiogenesis. Consequently, cells expressing some forms of mutant p53 show enhanced tumorigenic potential with increased resistance to chemotherapy and radiation. Our current understanding of these activities is summarized in this review. By dissecting out mechanistic differences between wild-type and mutant p53 activities, it may be possible to develop therapeutics that restore tumor suppressor function to mutant p53 or that selectively inactivate mutant p53 tumor-promoting functions. PMID- 11602343 TI - Co-transcriptional splicing of pre-messenger RNAs: considerations for the mechanism of alternative splicing. AB - Nascent transcripts are the true substrates for many splicing events in mammalian cells. In this review we discuss transcription, splicing, and alternative splicing in the context of co-transcriptional processing of pre-mRNA. The realization that splicing occurs co-transcriptionally requires two important considerations: First, the cis-acting elements in the splicing substrate are synthesized at different times in a 5' to 3' direction. This dynamic view of the substrate implies that in a 100 kb intron the 5' splice site will be synthesized as much as an hour before the 3' splice site. Second, the transcription machinery and the splicing machinery, which are both complex and very large, are working in close proximity to each other. It is therefore likely that these two macromolecular machines interact, and recent data supporting this notion is discussed. We propose a model for co-transcriptional pre-mRNA processing that incorporates the concepts of splice site-tethering and dynamic exon definition. Also, we present a dynamic view of the alternative splicing of FGF-R2 and suggest that this view could be generally applicable to many regulated splicing events. PMID- 11602344 TI - Human pigmentation genes: identification, structure and consequences of polymorphic variation. AB - The synthesis of the visible pigment melanin by the melanocyte cell is the basis of the human pigmentary system, those genes directing the formation, transport and distribution of the specialised melanosome organelle in which melanin accumulates can legitimately be called pigmentation genes. The genes involved in this process have been identified through comparative genomic studies of mouse coat colour mutations and by the molecular characterisation of human hypopigmentary genetic diseases such as OCA1 and OCA2. The melanocyte responds to the peptide hormones alpha-MSH or ACTH through the MC1R G-protein coupled receptor to stimulate melanin production through induced maturation or switching of melanin type. The pheomelanosome, containing the key enzyme of the pathway tyrosinase, produces light red/yellowish melanin, whereas the eumelanosome produces darker melanins via induction of additional TYRP1, TYRP2, SILV enzymes, and the P-protein. Intramelanosomal pH governed by the P-protein may act as a critical determinant of tyrosinase enzyme activity to control the initial step in melanin synthesis or TYRP complex formation to facilitate melanogenesis and melanosomal maturation. The search for genetic variation in these candidate human pigmentation genes in various human populations has revealed high levels of polymorphism in the MC1R locus, with over 30 variant alleles so far identified. Functional correlation of MC1R alleles with skin and hair colour provides evidence that this receptor molecule is a principle component underlying normal human pigment variation. PMID- 11602345 TI - Molecular biology of HMGA proteins: hubs of nuclear function. AB - Members of the HMGA (a.k.a. HMGI/Y) family of 'high mobility group' (HMG) proteins participate in a wide variety of nuclear processes ranging from chromosome and chromatin mechanics to acting as architectural transcription factors that regulate the expression of numerous genes in vivo. As a consequence, they function in the cell as highly connected 'nodes' of protein-DNA and protein protein interactions that influence a diverse array of normal biological processes including growth, proliferation, differentiation and death. The HMGA proteins, likewise, participate in pathological processes by, for example, acting as regulators of viral gene transcription and by serving as host-supplied proteins that facilitate retroviral integration. HMGA genes are bona fide proto oncogenes that promote tumor progression and metastasis when overexpressed in cells. High constitutive HMGA protein levels are among the most consistent feature observed in all types of cancers with increasing concentrations being correlated with increasing malignancy. The intrinsic attributes that endow the HMGA proteins with these remarkable abilities are a combination of structural, biochemical and biological characteristics that are unique to these proteins. HMGA proteins have little, if any, secondary structure while free in solution but undergo disordered-to-ordered structural transitions when bound to substrates such as DNA or other proteins. Each protein contains three copies of a conserved DNA-binding peptide motif called the 'AT-hook' that preferentially binds to the minor groove of stretches of AT-rich sequence. In vivo HMGA proteins specifically interact with a large number of other proteins, most of which are transcription factors. They are also subject to many types of in vivo biochemical modifications that markedly influence their ability to interact with DNA substrates, other proteins and chromatin. And, most importantly, both the transcription of HMGA genes and the biochemical modifications of HMGA proteins are direct downstream targets of numerous signal transduction pathways making them exquisitely responsive to various environmental influences. This review covers recent advances that have contributed to our understanding of how this constellation of structural and biological features allows the HMGA proteins to serve as central 'hubs' of nuclear function. PMID- 11602346 TI - Epithelial biology: lessons from Caenorhabditis elegans. AB - Epithelial cells are essential and abundant in all multicellular animals where their dynamic cell shape changes orchestrate morphogenesis of the embryo and individual organs. Genetic analysis in the simple nematode Caenorhabditis elegans provides some clues to the mechanisms that are involved in specifying epithelial cell fates and in controlling specific epithelial processes such as junction assembly, trafficking or cell fusion and cell adhesion. Here we review recent findings concerning C. elegans epithelial cells, focusing in particular on epithelial polarity, and transcriptional control. PMID- 11602347 TI - Identification and analyses of the Xenopus TERT gene that encodes the catalytic subunit of telomerase. AB - The Xenopus telomerase catalytic component gene, xTERT (Xenopus telomerase reverse transcriptase), has been cloned. The production of xTERT recombinant protein together with the proposed Xenopus telomerase RNA (xTR) (Chen et al., 2000. Cell 100, 503-514) in a rabbit reticulocyte lysate system led to the reconstitution of active telomerase, indicating that both products are functional telomerase components. Both xTERT expression and telomerase activity are high from the early to the late blastula stage. However, they are decreased at the gastrula stage and thereafter, suggesting that the xTERT expression level is the primary mechanism for regulating telomerase activity in Xenopus development. This is the first report of a non-mammalian vertebrate TERT gene. Sequence comparison of xTERT with human and mouse TERTs has uncovered four regions conserved in the amino-terminal halves of vertebrate TERT proteins, the functions of which will be discussed herein. PMID- 11602348 TI - The histone acetyltransferase activity of PCAF cooperates with the brahma/SWI2 related protein BRG-1 in the activation of the enhancer A of the MHC class I promoter. AB - Major histocompatibility complex (MHC) class I proteins are an essential component of the immune system allowing the organism to protect from viral infections and neoplastic transformation. Expression of the MHC class I genes is regulated by a variety of cis-regulatory promoter elements among which the enhancer A is of particular importance. This enhancer is synergistically activated through AP-1/ATF and NF-kappa B transcription factors. NF-kappa B recruits the histone acetyltransferase (HAT) p300/CREB-binding protein (CBP) to the multiprotein complex bound to the enhancer A. Here we present evidence that acetylation and deacetylation processes are involved in the activation of the enhancer A. The p300/CBP associated factor PCAF, but not p300/CBP, counteracts the repression of the enhancer A mediated by the histone deacetylase HDAC1. Furthermore, overexpression of PCAF results in an increase in the acetylation of histone H4 bound to the enhancer A and HDAC1 counteracts the PCAF-mediated H4 acetylation. The activation function of PCAF requires the p300/CBP binding motif indicating that PCAF might be recruited to the enhancer A through an association with p300/CBP. Moreover, PCAF and the Brahma/SWI2-related protein BRG-1, which is a key factor of the human ATP-dependent chromatin remodelling complex SWI/SNF, synergistically up-regulate the enhancer A. Synergistic activation requires the HAT domain of PCAF. Taken together our data suggest that members of two different groups of chromatin modifying complexes are involved in the activation of the enhancer A of the MHC class I promoter. PMID- 11602350 TI - Structural characterization and chromosomal localization of the MAGE-E1 gene. AB - Genes of the melanoma-associated antigen (MAGE) family are characterized by the expression of tumor antigens on a malignant melanoma recognized by autologous cytolytic T lymphocytes. We have previously identified novel members of the MAGE gene family expressed in human glioma and named them MAGE-E1a-c. In the present study, we have revealed the genomic structure of MAGE-E1 by sequence analysis of a human chromosome bacterial artificial chromosome clone containing the MAGE-E1 gene. The MAGE-E1 gene is composed of 13 exons, and three of these (exon 2, exon 3 and exon 12) are alternatively spliced in each variant (E1a-c). The open reading frame encoding the MAGE-E1 peptides initiates in exon 2 and ends in exon 13. We have also demonstrated that the MAGE-E1 gene is located in Xp11 through the analysis of radiation hybrid panels. The genomic structure of MAGE-E1 is markedly similar to that of MAGE-D and its chromosomal locus is also identical to that of MAGE-D, but these features contrast with those of other MAGEs. These results suggest that MAGE-D and -E1 may be evolutionarily distant from other members of the MAGE family, and the two may be ancestral genes for the others. PMID- 11602349 TI - HNF-1 regulates the liver-specific transcription of the chipmunk HP-20 gene. AB - The chipmunk hibernation-specific protein HP-20 is a component of the 140 kDa complex that drastically decreases in the blood during hibernation, and its gene is expressed specifically in the liver. To reveal molecular mechanisms underlying the liver-specific transcription of the HP-20 gene, we isolated chipmunk HP-20 genomic clones. The HP-20 gene spans approximately 6 kb, and consists of three exons. The transcription start site, as determined by 5' RACE-PCR analysis, was found to be 160 bp upstream of the translation initiation codon. Transient transfection studies in HepG2 cells revealed that the 57 bp 5' flanking sequence was sufficient for the liver-specific promoter activity. A database search revealed that this region contains a potential binding site for hepatocyte nuclear factor-1 (HNF-1). In a gel retardation assay, in vitro-synthesized HNF-1 bound to the 5' flanking sequence from -52 to -26. A similar shifted band was also observed with HepG2 nuclear extracts, and this complex was super-shifted by an anti-(HNF-1) Ig. When transfected into COS-7 cells, HNF-1 transactivated transcription from the HP-20 gene promoter, and this activity was abolished by a mutation of the HNF-1 binding site, indicating that HNF-1 plays an important role in HP-20 gene expression. PMID- 11602351 TI - Identification and characterization of a silkgland-related matrix association region in Bombyx mori. AB - From DNA fragments in vivo attached to the nuclear matrix in silkglands of Bombyx mori 5th instar larvae, we have screened a matrix association region (MAR), termed BmMAR1, by means of in vitro binding assay. BmMAR1 was identified to be specifically in vivo attached to the nuclear matrix only in the silkglands, neither in other tissues nor in the silkworm cell line Bm5, indicating its silkgland-relatedness. This 1983-bp DNA fragment contains a 1.1-kb core necessary for the effective in vitro binding although it is of relatively lower A/T composition (61%) compared to the 5' and 3' flanking regions (73 and 69%, respectively). Two degenerate sequences derived from Bm1 and L1Bm repetitive elements are located in the core region. BmMAR1 shares the widely considered typical MAR's features, DNA unwinding motif, A-box, T-box, H-box, replication origin, MAR recognition signature (MRS), the 90%AT box and Drosophila topoisomerase II consensus sequence. Furthermore we compared the occurrences of these patterns in BmMAR1 and some MARs from other organisms. PMID- 11602352 TI - Multiple alternative splicing forms of human RAD17 and their differential response to ionizing radiation. AB - In this study, we have identified four alternatively spliced RAD17 RNAs, FM1, FM2, FM3, and FM4, which are produced through alternative splicing within the first 300 base-pairs of the coding region. FM3 and FM4 are two novel forms that have not been reported before. All four alternatively spliced RAD17 RNAs were detected in the tissues we examined. However, the levels of these forms varied from tissue to tissue. The expression of these four forms was also found to differ in different phases of the cell cycle and following exposure to X irradiation. FM2, FM1, FM4, and FM3 encode putative polypeptides consisting of 681, 670, 596, and 516 amino acids, respectively. To determine if these polypeptides were expressed in cells, we generated a polyclonal antibody using a synthetic peptide. A major band around 71 kDa and two minor bands around 73 and 62 kDa were detected in human normal fibroblasts on Western blots. These three bands appear to represent the proteins encoded by FM2 (the 73 kDa band), FM1 (the 71 kDa band), and FM4 (the 62 kDa band) since the apparent molecular weights are close to their theoretical weights of the predicted amino acid sequences. The abundance of the 71 kDa protein was not significantly affected by X-irradiation, while the abundance of the 73 and the 62 kDa proteins was increased at least 5 fold 14 h postirradiation. The differential expression of these four alternatively spliced forms in different tissues, in different phases of the cell cycle, and their differential response to X-irradiation suggest that they may perform different functions in cell-cycle regulation and in the response to irradiation. PMID- 11602354 TI - An expressed GNRP-like gene shares a bi-directional promoter with SF3A2 (SAP62) immediately upstream of AMH. AB - A region of homology, containing the contiguous SF3A2 (formerly called SAP62) and AMH genes, exists between human chromosome 19 (HSA19p) and mouse chromosome 10 (MMU10). In a previous study it was shown that SF3A2/Sf3a2 is very highly conserved between the two species and that AMH/Amh is somewhat less conserved although both human and mouse genes encode a protein (AMH) playing the same critical role during early male sex differentiation. The close association between SF3a2/Sf3a2 and AMH/Amh was thought to maintain open chromatin in the AMH/Amh promoter region, thus facilitating the necessary precise timing of AMH/Amh expression following that of SRY/Sry at the onset of testis differentiation. Further investigation of DNA upstream of Amh has revealed that there is another gene, in close association (about 400 bp) with Sf3a2, which has significant similarities to the N-terminus of a known guanine nucleotide releasing protein (GNRP) and consequently is provisionally named GNRPx/Gnrpx. The Gnrpx-Sf3a2-Amh (GSA) locus of the mouse (MMU10) is conserved in the human (HSA19p). Mapping the Sf3a2 transcription start site eventually led us to locate and characterize its promoter. We found that Sf3a2 and Gnrpx share a bi directional promoter, with the latter being transcribed in an antisense direction. It has now been shown by RT-PCR analysis that both Sf3a2 and Gnrpx are widely expressed and therefore are likely to be 'housekeeping' genes. GNRPx/Gnrpx messenger RNA codes for a C-terminally truncated protein (149/164 aa), which contains an as yet uncharacterized domain common to GNRPs (and related proteins) and which may therefore act as a specific antagonist of a complete GNRP protein (>1200 aa) involved in the regulation of the GTPase (G-protein/Ras) cycle. PMID- 11602353 TI - Murine cysteine dioxygenase gene: structural organization, tissue-specific expression and promoter identification. AB - The murine gene encoding cysteine dioxygenase (CDO; EC 1.13.11.20), a key enzyme of L-cysteine metabolism, was isolated and characterized, and the proximal promoter was identified. A bacterial artificial chromosome mouse library was screened and a single clone containing the entire CDO gene was isolated. The murine CDO gene contains five exons and spans about 15 kb. The open reading frame is encoded within all five exons. All intron/exon splice junctions and all intron sizes are conserved with the rat CDO gene and are very similar to those of the human CDO gene. The primary transcriptional initiation site is located 213 bp upstream of the initiation ATG codon. The nucleotide sequence of the 5'-promoter region is highly conserved between the mouse and rat genes and contains a TATA box-like sequence and GC boxes. A variety of consensus cis-acting elements were also identified in the 5'-flanking region. These included HNF-3 beta, HFH-1, HFH 2, HFH-3, C/EBP, and C/EBP beta, all of which are consistent with the tissue specific expression profiles of the gene. Gene reporter studies of the CDO 5' region indicated the presence of an active promoter within the first 223 bp upstream of the transcriptional initiation site and the possible presence of repressor elements upstream of bp -223. Northern blot analyses indicated that the CDO gene displays tissue-specific expression, with the highest mRNA level present in liver and with detectable levels found in kidney, lung, brain and small intestine. Western blot analyses indicated that CDO protein levels parallel mRNA levels. These results are consistent with the known function of CDO in whole-body cysteine homeostasis. PMID- 11602355 TI - Sequence analysis of a fish vitellogenin cDNA with a large phosvitin domain. AB - Vitellogenins (Vtg) are egg-yolk precursor proteins crucial for reproductive success in oviparous animals. We have cloned the first complete cichlid Vtg cDNA from the tilapia fish, Oreochromis aureus. This cDNA has the largest phosvitin (PV) domain amongst piscine Vtgs, being comparable to those of lamprey, Xenopus, and chicken. Thus, the size of PV is independent of the evolutionary advancement of a species. The closer interspecific relationship between O. aureus Vtg1 and Fundulus VtgII than the intraspecific relationship between Fundulus VtgI and II isoforms suggests that teleost ancestors had at least two Vtg isoforms. Contrary to the results of previous phylogenetic inference using Vtgs which indicate that insect lineage is most diverged and nematodes are closer to vertebrate lineage, our results show that nematodes and hexapods form two monophyletic sister groups. Another arthropod taxon, represented by a malacostracan crustacean, Penaeus japonicus, appears to be more closely related to the vertebrates than the hexapods. PMID- 11602356 TI - Regulated expression of myosin II heavy chain and RacB using an inducible tRNA suppressor gene. AB - An inducible expression system that indirectly regulates gene expression through the use of an inducible suppressor tRNA has been used to express both endogenous and exogenous genes in Dictyostelium. The tetracycline repressor and tRNA suppressor (Glu) are expressed from a single G418 selectable vector, while a gene engineered to contain a stop codon is expressed from a separate hygromycin selectable vector. beta-Galactosidase could be induced over 300 fold with this system, and the extent of induction could be varied depending upon the amount of tetracycline added. It took 3 days to fully induce expression, and about 3 days for expression to decrease to baseline after removal of the tetracycline. Dictyostelium myosin II heavy chain could also be expressed in an inducible manner, although the induction ratio was not as high as beta-galactosidase and the maximum expression level was not as high as wild-type levels. A significant accumulation of the truncated peptide indicates that complete suppression of the stop codon was not achieved. Partial phenotypic reversion was observed in null mutants inducibly expressing myosin II. RacB could also be inducibly expressed, whereas the protein could not be expressed from a constitutive promoter, presumably because expression at high levels is lethal. Therefore, the inducible tRNA system can be used to control expression of endogenous Dictyostelium genes. PMID- 11602357 TI - Cloning, sequence and structure of a gene encoding an antifungal glucan 1,3-beta glucosidase from Trichoderma atroviride (T. harzianum). AB - A gene (gluc78) encoding an antifungal glucan 1,3-beta-glucosidase was cloned from strain P1 of the biocontrol fungus Trichoderma atroviride (formerly T. harzianum). A putative regulatory sequence upstream from the coding region was cloned using single-strand extension from a primer in the known portion of the gene, circularized with T4 ligase, and then reamplified with PCR to generate double-stranded DNA. The entire genomic DNA sequence consisted of 3440 bp, with 559 and 579 bp, respectively, in 5' and 3' untranslated regions. The transcription unit contains a single intron, positioned in the 5' untranslated region. The gene encodes for a protein of 770 aa, including a 40 aa signal peptide. Symmetry between the first and second halves of the mature protein was found. The gene is present as a single copy in T. atroviride and a similar gene also is present in T. harzianum and T. virens. The encoded protein has similarity to a small group of sequences from filamentous fungi and no significant similarity to 1,3-beta-glucanases or glucosidases from other organisms. Northern analysis indicates that the gene is repressed in the presence of 3% glucose and expressed in media containing 0.1% of the sugar. Laminarin (0.1%) enhances expression after 18 h and other polymers such as scleroglucan and pustulan may enhance expression after 40 h of growth. PMID- 11602358 TI - Characterization of steroidogenic factor 1 during sexual differentiation in a marsupial. AB - In eutherian mammals, such as mice and humans, steroidogenic factor 1 (SF1) plays important roles in the development of the gonad and in its steroidogenic activity. Marsupial and eutherian mammals have been evolving independently for at least 100 million years and so we were interested in comparing SF1 of a marsupial with that of eutherians. To this end, we have cloned SF1 from an Australian marsupial, the tammar wallaby. Although the amino acid sequence of SF1 is highly conserved among vertebrate species, tammar SF1 appears to have diverged less from the ancestral SF1 than have eutherian SF1 proteins. Tammar SF1 is expressed by both ovaries and testes on the day of birth, just prior to the onset of testicular differentiation, until at least 8 days after birth by which time the ovary also has begun to sexually differentiate. SF1 transcripts are localized predominantly to the pre-granulosa and Sertoli cells of the ovary and testis, respectively. In the testis SF1 transcripts are also present in the interstitial cells, although at a lower level than that which is observed in the Sertoli cells. SF1 is also transcribed in adult testis and ovary. In the adult ovary SF1 is expressed in the interstitial gland, and in the granulosa cells and theca interna of small to medium-sized antral follicles, but is not expressed in large antral follicles. Thus, although the structure of tammar SF1 is divergent from that of eutherians, its expression profile is similar, supporting a conserved role in gonadal development and steroidogenesis. PMID- 11602359 TI - A Streptomyces rimosus aphVIII gene coding for a new type phosphotransferase provides stable antibiotic resistance to Chlamydomonas reinhardtii. AB - Although Chlamydomonas reinhardtii serves as the most popular algal model system, no efficient enzymatic selection marker for the nuclear transformation of wild type cells is available. We sequenced an aminoglycoside 3'-phosphotransferase gene (aph) from Streptomyces rimosus. Though the derived protein sequence is homologous to members of APH type V, it constitutes a new type, named APHVIII. Since the aphVIII gene has a codon bias similar to that of the nuclear genome of green algae, the aphVIII coding sequence was fused to the 5'- and 3'-untranslated regions of the C. reinhardtii rbcS2 gene. C. reinhardtii transformants were capable of inactivating the antibiotics paromomycin, kanamycin, and neomycin, to which wild-type cells are sensitive. After addition of the 5'-region of hsp70A as a second promoter and insertion of the rbcS2 intron I, the transformation rate increased to two transformants per 1 x 10(5) cells, which is close to the efficiency of transforming auxotrophic strains with the homologous marker arg7. Transformation with the promoter-less aphVIII led to random gene fusion at high frequency. In an aphVIII-based reporter gene assay we have found a so far unknown promoter activity of the 3'-untranslated region of rbcS2, that may promote antisense RNA synthesis from the rbcS2 gene in vivo. We conclude that the aphVIII gene is a useful marker for nuclear transformation and promoter tagging of C. reinhardtii wild-type and probably other green algae. PMID- 11602360 TI - The gene structure and minimal promoter of the human agouti related protein. AB - The murine agouti related protein (mAGRP) is upregulated in obese and diabetic mice and stimulates hyperphagia when administered intracerebroventricularly (i.c.v.) or when overexpressed in transgenic mice. The human ortholog, hAGRP, has been isolated and has similar molecular and physiological properties. Here, we report the complete gene structure of the human AGRP gene and upstream regions with differential promoter activity. A polymorphism, A67T, in the third exon was identified but was not associated with obesity- or type 2 diabetes-related phenotypes. Putative binding sites for transcription factors were identified in the promoter of the gene including recognition sites for the signal transducers and activators of transcription (STATs) that may potentially mediate leptin's action in the hypothalamus. The upstream non-coding exon had significant promoter activity in a periphery- but not so in a hypothalamus-derived cell line, suggesting that it might contain the minimal promoter required for expression of the short transcript of hAGRP in the periphery. PMID- 11602363 TI - Domains of consultation research in primary care. AB - The consultation is increasingly viewed as a crucial aspect of general practice medicine, but a variety of methods of conceptualising, describing and modifying its structure and content have been described. This article describes the historical background to the current interest in the consultation, and describes four qualitatively distinct approaches (or 'domains') to understanding the consultation: the psychodynamic; clinical-observational; social-psychological; and sociological. Four key dimensions along which the domains can be differentiated are described. These concern whether the critique of medical practice inherent in the domain is internal or external to the discipline of general practice; whether the focus of the domain is on the consultation participants' identities or activities; whether the key research methodology is quantitative or qualitative in character; and the degree to which the objective of research within the domain is to describe current practice or prescribe ways of conducting the consultation. Methods of encouraging work across domains are discussed. PMID- 11602361 TI - Role of the LIM domains in DNA recognition by the Lhx3 neuroendocrine transcription factor. AB - LIM homeodomain transcription factors regulate many aspects of development in multicellular organisms. Such factors contain two LIM domains in their amino terminus and a DNA-binding homeodomain. To better understand the mechanism of gene regulation by these proteins, we studied the role of the LIM domains in DNA interaction by Lhx3, a protein that is essential for pituitary development and motor neuron specification in mammals. By site selection, we demonstrate that Lhx3 binds at high affinity to an AT-rich consensus DNA sequence that is similar to sequences located within the promoters of some pituitary hormone genes. The LIM domains reduce the affinity of DNA binding by Lhx3, but do not affect the specificity. Lhx3 preferentially binds to the consensus site as a monomer with minor groove contacts. The Lhx3 binding consensus site confers Lhx3-dependent transcriptional activation to heterologous promoters. Further, DNA molecules containing the consensus Lhx3 binding site are bent to similar angles in complexes containing either wild type Lhx3 or Lhx3 lacking LIM domains. These data are consistent with Lhx3 having the properties of an architectural transcription factor. We also propose that there are distinct classes of LIM homeodomain transcription factors in which the LIM domains play different roles in modulating interactions with DNA sites in target genes. PMID- 11602364 TI - Becoming a doctor: fostering humane caregivers through creative writing. AB - We qualitatively examined themes covered in a creative writing elective designed to enhance pre-clinical medical students' writing, observation, and reflection skills relative to experiences in their medical education. Qualitative analysis of writings' themes was carried out via iterative consensus building process and validated through member checks and literature review. Fourteen students completed the elective, seven for each year it was given. Students submitted 86 written pieces. Qualitative analysis demonstrated the presence of nine themes: students' role confusion, developing a professional identity, medicine as a calling, physician privilege and power, humanizing the teacher, the limits of medicine, death and dying, anticipating future challenges, and identification with the patient. Students evaluated this creative writing course favorably, indicating value in writing and reflection. Themes covered are of concern to second-year medical students as well as other trainees and practicing physicians. Writing may aid in the professional development of physicians. PMID- 11602365 TI - The SEGUE Framework for teaching and assessing communication skills. AB - This article examines uses and characteristics of the SEGUE Framework, a research based checklist of medical communication tasks. A recent survey of US and Canadian medical schools indicates that the SEGUE Framework is the most widely used structure for communication skills teaching and assessment in North America. Student and faculty response to the SEGUE Framework as a teaching tool has been positive. Data drawn from clinical skills assessments with standardized patients provide evidence of concurrent and construct validity. Analysis of visits between general internists and their patients reinforces validity of the SEGUE Framework in an actual practice setting. Interrater reliability is high when standardized patients are recording student performance immediately after a live encounter, and when coders are evaluating videotaped or audiotaped encounters; intrarater reliability is strong as well. The SEGUE Framework has a high degree of acceptability, can be used reliably, has evidence of validity, and is applicable to a variety of contexts. Studies of predictive validity are needed. PMID- 11602366 TI - Assessment of medical students' communicative behaviour and attitudes: estimating the reliability of the use of the Amsterdam attitudes and communication scale through generalisability coefficients. AB - It is widely accepted that adequate attitudes and communicative skills are among the essential objectives in medical education. The Amsterdam attitude and communication scale (AACS) was developed to assess communicative skills and professional attitudes of medical students. More specifically, it was designed to evaluate the clinical behaviour of clerks to establish their suitability for the medical profession. The AACS covers nine dimensions. Moreover, an overall judgement of the student's performance is included. The present paper reports first results on the reliability of the use of the AACS. Data were collected in the course of an AACS training programme for future judges: senior medical and nursing staff members (N=98). Participants judged three videotapes of clerks interviewing patients at the bedside. For the assessment of videotapes, the first four dimensions of the AACS and the overall judgement are relevant. By applying Generalisability Theory to the training data we can forecast the reliability of the AACS in practice and gain insight in the number of raters that is needed to achieve sufficient reliability in clinical practice. If clerk behaviour is rated by six judges, summative assessment is sufficiently precise, i.e. <0.25. When using the full AACS, covering 10 items, the same number of judges is needed. Scores on individual AACS items are not sufficiently reliable. In conclusion, the results indicate that students' behaviour can be evaluated in a reliable manner using the AACS as long as enough judges and items are involved. PMID- 11602367 TI - Community voices: views on the training of future doctors in Birmingham, UK. AB - The United Kingdom (UK) population is diverse with nearly 6% minority ethnic communities. Both patients and doctors experience difficulties when dealing with someone from a different ethnic group. Medical education has failed to keep pace with the changing needs of the diverse population. We report a project in which 12 established (religious/cultural and specific interest) community groups expressed their views on what future doctors should learn about serving diverse populations. Data were obtained by group discussion and through the media using a structured format. Fifteen themes emerged which were grouped under three broad themes: firstly, the identification by group members of their perception of the 'differences' in social and cultural beliefs and behaviours of their individual community; secondly, the identification of characteristics of a culturally sensitive doctor; and lastly, recommendations for changes in medical training. New teaching has been introduced to the medical curriculum that incorporates the themes raised by the communities and which reflects consciousness raising and communication issues. PMID- 11602368 TI - Pudor, honor, and autoridad: the evolving patient-physician relationship in Spain. AB - The expression of emotion and the sharing of information are determined by cultural factors, consultation time, and the structure of the health care system. Two emblematic situations in Spain - the expression of aggression in the patient physician encounter, and the withholding of diagnostic information from the patient - have not been well-described in their sociocultural context. To explore these, the authors observed and participated in clinical practice and teaching in several settings throughout Spain and analyzed field notes using qualitative methods. In this paper, we explore three central constructs - modesty (pudor), dignity (honor), and authority (autoridad) - and their expressions in patient physician encounters. We define two types of emotions in clinical settings - public, extroverted expressions of anger and exuberance; and private, deeply held feelings of fear and grief that tend to be expressed through the arts and religion. Premature reassurance and withholding of information are interpreted as attempts to reconstruct the honor and pudor of the patient. Physician authority and perceived loyalty to the government-run health care system generate conflict and aggression in the patient-physician relationship. These clinical behaviors are contextualized within cultural definitions of effective communication, an ideal patient-physician relationship, the role of the family, and ethical behavior. Despite agreement on the goals of medicine, the behavioral manifestations of empathy and caring in Spain contrast substantially with northern European and North American cultures. PMID- 11602369 TI - Client communication behaviors with health care providers in Indonesia. AB - Patient participation in health care consultations can improve the quality of decision making and increase patients' commitment to the treatment plan. This study examines client participation, operationally defined as client active communication, during family planning consultations in Indonesia. Data were collected on 1203 consultations in the provinces of East Java and Lampung. Sessions were audiotaped and the conversation coded using an adaptation of the roter interaction analysis system (RIAS). Culturally acceptable ways for Indonesian clients to participate in consultations include asking questions, requesting clarification, stating opinions, and expressing concerns. Factors significantly associated with client active communication were, in order of importance, providers' information giving, providers' facilitative communication, providers' expressions of negative emotion, client educational level, and province. The latter suggests the influence of culture on client participation. The results suggest that a combination of provider training and client education on key communication skills could increase client participation in health care consultations. PMID- 11602370 TI - From nurse-centered health counseling to empowermental health counseling. AB - The main goals of this study were to examine aspects of the delivery and reception of advice and questions in interaction between nurses and patients and to describe linguistic features that constructed nurse-centered and empowermental health counseling. The research data, 38 health counseling sessions, were videotaped, transcribed verbatim, and analyzed by using an adaptation of conversational analysis. During nurse-centered discussions, the nurses' advice did not correspond to the patients' need for information. These counseling sessions began with check-up questions about the patients' condition and continued with factual questions about their illnesses and health care measures. During empowering health counseling, the nurses made use of the patients' knowledge of their circumstances and supported the patients' ability to reflect on their health behavior. Questioning and advising strategies were found to be crucial for building up empowermental conversation and enhancing the impact of health counseling. PMID- 11602373 TI - Cancer burden in the year 2000. The global picture. PMID- 11602374 TI - Environmental causes of human cancers. AB - Epidemiological studies have clearly shown a causal association between tobacco exposure and various human cancers, hepatitis B and C infection and hepatocellular carcinoma, human papilloma viruses and cervical cancer, and the occupational origin of certain human cancers is well established. The identification of the environmental causes of human cancers has been a long and difficult process. Much remains to be understood about the role of specific components of the diet and the interaction of different risk factors in the aetiology of human cancers. Withstanding the progress made on the understanding of the cancer process and their potential impact in the therapy of cancer, primary prevention remains, in developed and developing countries, the most effective measure to reduce cancer mortality. PMID- 11602375 TI - Genetics and the common cancers. AB - Rare highly penetrant genes cannot account for much of the familial risk for most common cancers, and there is increasing evidence that a high proportion of cancers arise in a susceptible minority who carry low-penetrance genes or gene combinations. The evidence for the existence of such genes and the prospects for identifying them are reviewed. PMID- 11602376 TI - Cell biology of precancer. AB - This article explores the possibilities of understanding the natural history of human cancers. In particular it attempts to understand precancer in cell biological or molecular rather than clinical or pathological terms. The questions discussed on the relevance of precancer in the neoplastic development are: are all cancers preceded by precancer? Is a precancer in the cell lineage characterised by hypermutability? Is there a direct DNA lineage from precancer to cancer? How many mutations have been added as a function of a number of DNA generations in the process to neoplastic transformation? Is precancer reversible? Can analysis of precancer provide a short cut to assessment of carcinogenic risk? The present data addressing these questions are discussed and the still unexplained phenomena are highlighted. PMID- 11602377 TI - The mechanisms of neoplastic transformation. PMID- 11602378 TI - Primary and secondary prevention in the reduction of cancer morbidity and mortality. AB - Overall, cancer is a highly preventable disease. Indeed, modifiable external factors, discovered by epidemiological studies during the last 50 years, account for a majority of all cancer deaths. In this review, we discuss briefly these factors and their contribution to the current burden of cancer with an emphasis on the developed countries. Needless to say, tobacco smoking remains the largest contributor to the cancer landscape, whilst the contribution of poor diet and obesity may be equally important, but much more difficult to quantify. Our main goal was to assess what prevention of cancer has accomplished and might accomplish in the next two decades. Based on (necessarily crude) estimates, age adjusted mortality rates from cancer in year 2000 had been reduced by approximately 13% due to primary prevention and an additional 6% due to the combined effect of early diagnosis and screening (secondary prevention). According to a realistic goal for the year 2020, a further 29% reduction might be achieved by primary, and 4% by secondary prevention. The main contribution to such accomplishments would be a reduction in tobacco smoking, improvements in diet--including reduced alcohol intake--and arrest of the obesity epidemic, in part through increased physical exercise. Rather than being granted, these goals require great effort and major commitment from all those who share responsibility for public health. PMID- 11602379 TI - Perspectives in cancer chemotherapy. PMID- 11602380 TI - Between the body and the mind: the involvement of psychological factors in the development of multifactorial diseases. AB - A possible aetiological role for psychological factors has been propounded in particular in relation to diseases of which the causes are only partially known and which are in most cases multifactorial, such as cancer. The long period between a possible first event and the point of no return, gives appeal to the belief that life events other than "material" causes may play a role in cancer. The evidence that the immune and the nervous system may produce the same substances has opened the way to a new area of research. However, a lack of standardised instruments and the difficulty of conducting systematic and adequate analyses of potential confounding variables have discouraged most qualified scientists from devoting time and effort to investigating the possible role of psychological factors in the aetiology of human diseases. A few studies have reported a positive association between severe life events and breast cancer, but the prevailing view of the medical establishment is that there is no true association between stress and the onset of breast cancer. Although many criticisms of the studies reporting a positive association are definitely based on solid arguments, at least some of the criticisms cling to the requirement for absolute certainty in establishing a cause-effect relationship, which epidemiological studies can rarely, if ever, provide. A challenge for the future of research will be to investigate and better understand the role of subjective factors on the course and outcome of various pathologies, and in modulating the risk of developing a pathology. PMID- 11602381 TI - Palliative care research. AB - Most of the research in palliative medicine is of a descriptive nature. Clinical practice is based upon clinical experience rather than upon research. The level of appropriate research reduces the chance for improvement of palliative care. Ethical and methodological obstacles seem to be prominent in palliative care research. The Declaration of Helsinki is generally accepted as an ethical code of practice for clinical research and it also applies to palliative care. In order to obtain reliable data, standardisation of data collection is needed. Improvement of quality of life is the primary endpoint in most studies in palliative care. The existing validated quality of life instruments such as the European Organization for Research and Treatment of Cancer (EORTC) quality of life (QLQ)-C30 can be used until the patient is too sick to complete the questionnaire. New approaches are needed and must be developed for the dying patients. Palliative care research needs proper funding; specific programmes supporting research on a European level are needed. The European Association for Palliative Care (EAPC) is capable of conducting and coordinating collaborative research in palliative care on a European level. PMID- 11602384 TI - [Clinical usefulness of global assays of the anticoagulant pathway of protein C]. AB - Abnormalities of the protein C anticoagulant pathway i.e. protein C and protein S deficiencies and factor V Leiden-related activated protein C resistance are among the most frequent risk factors for thrombosis in the Caucasian population. Until now, their screening is based upon the use of individual assays for each component. However, normal results are found in more than 70% of the tested patients. So, there was a rational behind the development of global assays to evaluate the functionality of the protein C pathway, as this would rationalize the use of costly specific assays. Such global assays are based on the ability of endogenous activated protein C generated by activation of protein C by a snake venom extract to prolong a clotting time. Up to now, two assays are commercially available, the ProC Global assay (Dade Behring) and the Protein C Pathway Test (Gradipore). Both were found to be highly sensitive for the factor V Leiden and for protein C deficiency, as confirmed by different studies in patients with a history of venous thrombosis. However, sensitivity of both global assays for protein S deficiency was found to be only moderate and highly variable depending of the cut-off level used. So, these global assays can be validly used for the screening of the factor V Leiden-related APC resistance and for protein C deficiency, but protein S have to be measured in all the cases. The overall sensitivity of these assays for abnormalities of the protein C pathway was dramatically different, since 40% of the patients without any known abnormality have a decreased response to the ProC Global assay versus less than 13% for the Protein C Pathway Test. These characteristics suggest that the clinical usefulness of these two global assays might be different. PMID- 11602383 TI - [Apoptosis during spermatogenesis and in ejaculated spermatozoa: importance for fertilization]. AB - It has become clear in recent years that programmed cell death occurs spontaneously in the cycle of the seminiferous epithelium. Induced germ cell apoptosis occurs at specific stages of the spermatogenic cycle and the existence of supracellular control of germ cell death during spermatogenesis has been documented. If apoptosis is a key phenomenon in the control of sperm production, the existence and role of apoptosis in ejaculated sperm cells remain controversial. Apoptosis - as determined by DNA fragmentation (Tunel) and ultrastructural analysis - is abnormally frequent in the sperm cells of the ejaculate of sterile men. In this review, we discuss the possible origins of DNA damage in ejaculated human spermatozoa and the consequences of these DNA damage if the apoptotic spermatozoa is used for ICSI. Percentages of DNA fragmentation in human ejaculated sperm correlated with fertilization rates after FIV or ICSI assay. Detection of DNA fragmentation in human sperm could provide additional information about the biochemical integrity of sperm and may be used in future studies for fertilization failures not explained by conventional sperm parameters. However, the analysis of other molecular markers of apoptosis (Fas, Annexine V.) is now necessary to assess the role of apoptosis in human ejaculated sperm cells. PMID- 11602385 TI - [Contribution of the complete blood cell count to the efficiency of fragmentation haemolytic anaemia diagnosis]. AB - Schistocytes result from red cell fragmentation. The identification of the schistocytes is critical for decisions on appropriate management of the patients. Detection of schistocytes on a peripheral blood smear is an abnormal finding, which raises the occurrence of a microangiopathy. The avaibility of effective treatment prompted the urgency to establish this crucial diagnosis. Nevertheless, schistocytes can be observed in a broader spectrum of disorders than thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, or might be delayed even absent. PMID- 11602386 TI - [Optimisation of the measurement of nitrite and nitrate in serum by the Griess reaction]. AB - Nitrite (NO2-) and nitrate (NO3-) concentrations are usually measured as a marker of NO metabolism. Indeed, this radical plays an important role in a lot of pathological processes. The aim of this study was to validate and standardize a method for the quantification of these two metabolites in serum. The most commonly method involved to determine nitrite and nitrate is the Griess reaction. From the different methods which are reported in literature, we tested several parameters to define operating conditions: the samples were deproteinized with zinc sulfate and reduced with cadmium granules. Analytical recovery of NO3- added to serum samples after reduction was 99.6% +/- 3.2% (n = 4). Within-run precision was 6.1% (n = 17) and between-day precision was 6.6% (n = 12). Usual values were determined from healthy fasted subjects: the mean concentration of NO2- and NO3- was 47.8 muM +/- 15.7 muM (n = 25). The detection limit of the assay was 1.3 muM and the quantitation limit was 2.5 muM. We tested also an HPLC method. However, it was not possible to use it from a biological matrice. PMID- 11602387 TI - [Monoclonal IgM autoantibody activity vis-a-vis glycoconjugates of peripheral nerves: apropos of 112 cases]. AB - Serum IgM and IgG autoantibodies against carbohydrate epitopes on glycolipids and glycoproteins have been determined in a series of 112 neuropathies associated with monoclonal IgM (M-IgM) by different immunological techniques. The M-IgM anti myelin sheath antibodies were determined by indirect immunofluorescence microscopy, the M-IgM anti-myelin associated glycoprotein (MAG) antibodies by western-blot analysis, the M-IgM anti-SGPG and SGLPG antibodies by immunodetection on thin-layer chromatography, the M-IgM anti-ganglioside GM3, GM2, GD3, GM1, GD1a, GD1b, GT1b, GQ1b and anti-sulfatide antibodies by immunodot blot assay on membrane. Among the 112 M-IgM, 81 had autoantibody activity against nerve glycolipid antigens concentrated in peripheral nerve (72%). M-IgM bound strongly to myelin sheath in 34,5% of cases, to MAG in 38% of cases, to SGPG/SGLPG in 52% of cases, to gangliosides in 21.5% of cases and to sulfatide in 26 % of cases. Six M-IgM autoantibody activity profiles have been described in correlation with distinct clinical syndromes: - the M-IgM autoantibody activity profile against the carbohydrate epitope common to the glycolipids SGPG and SGLPG and myelin associated glycoprotein (MAG) in chronic demyelinating sensitive and sensorimotor peripheral neuropathies (58 patients, 52%); - the M-IgM autoantibody activity profile against immunodominant GM1 in demyelinating pure motor neuropathies (9 patients, 8%); - the M-IgM autoantibody activity profile against immunodominant disialosylgangliosides in chronic demyelinating sensitive ataxic neuropathies (8 patients, 7%); - the M-IgM autoantibody activity profile against immunodominant GM2 in demyelinating motor polyneuropathies (3 patients, 2.5%); - the M-IgM autoantibody activity profile against immunodominant GD1a in pure motor polyneuropathies (2 patients, 2%); - the M-IgM autoantibody activity profile against immunodominant GT1b and polysialosylgangliosides in one acute polyradiculoneuropathy (1%). The M-IgM recognized all gangliosides except GM1 and GM2. The neuropathies associated with IgM monoclonal gammopathy with autoreactive specificity form distinct syndromes. In 27.5% of cases, M-IgM had no identifiable activity autoantibodies. PMID- 11602389 TI - [Emerging new risks of food-borne infections]. PMID- 11602388 TI - [Influence of oral anticoagulant treatment on D-dimers levels]. AB - The usefulness of D-dimers determination for the exclusion of deep vein thrombosis (DVT) has been extensively studied. The persistence of high levels of D-dimers has also been suggested as a marker of hypercoagulability in rare studies and might be used to identify patients at risk for recurrent DVT. We have studied the influence of oral anticoagulant treatment in 149 patients, 17 to 84 year-old, with a history of venous thromboembolism; 81 received oral anticoagulant treatment, 68 did not. Patients with known reasons for high level of D-dimers such as cancer were excluded. Thrombophilia was found in 84 patients. D-dimers measurements were performed by ELFA technique using Vidas (bioMerieux, France) analyzer. A significantly lower level of D-dimers was observed in patients under oral anticoagulant compared to patients without this treatment, 197 +/- 134 mug/L versus 399 +/- 239 mug/L, respectively (p < 0.001). A level upper the normal value (500 mug/L) was found in only 3 patients out of 81 receiving an oral anticoagulant treatment as compared with 21 of the 68 patients without treatment. This decrease of D-dimers in patients receiving oral anticoagulants was the same in the different age populations. There was no correlation between INR and D-dimers levels in this study. The clinician should be informed of the decrease of D-dimers in patients treated with anticoagulants. The decrease of D-dimers plasma level during oral anticoagulant treatment suggest that D-dimers concentration in plasma is an indirect marker of reduced clotting activity in vivo. PMID- 11602390 TI - [Infections caused by Bartonella spp]. PMID- 11602392 TI - [Etiologic diagnosis of malnutrition in pediatrics: reflections about a case]. PMID- 11602393 TI - [Plasma vitamin B12 assay on ACS180 Bayer diagnostics. Comparison with a radioligand binding assay]. PMID- 11602391 TI - [Toxicological analysis in the dawn of the third millenium]. PMID- 11602394 TI - [Analytical evaluation of Rapidpoint 400 blood gas analyser]. PMID- 11602395 TI - [Interference by a contrast medium with total protein determination by the biuret reaction: evidence in synovial fluid and proposed solutions]. PMID- 11602396 TI - [Laboratory study of a new marker of iron deficiency diagnosis: the soluble transferrin receptor]. PMID- 11602397 TI - [Comparative values of blood renin and aldosterone levels in Ivorian and French young adults]. PMID- 11602398 TI - [Comparison of three methods for the detection of anti-SCL70 autoantibodies]. PMID- 11602400 TI - [Evaluation of the BD QuikHeel device for capillary blood sampling in neonates]. PMID- 11602399 TI - [Stability of estradiol, progesterone, LH and FSH concentrations in whole blood stored 3 days at room temperature]. PMID- 11602401 TI - [Skin necrosis induced by heparin: apropos of 2 cases]. PMID- 11602402 TI - [A case of ethylene glycol intoxication: interference with blood lactate determination?]. PMID- 11602403 TI - [Diagnosis of Glanzmann thrombastenia in a 66-year-old patient]. PMID- 11602405 TI - Langerhans' cell histiocytosis: is there a role for genetics? PMID- 11602406 TI - Impact factor and electronic versions of biomedical scientific journals. AB - BACKGROUND AND OBJECTIVES: The development of electronic editions of scientific journals and the rapid spread of scientific information might modify the pattern the bibliographic citations, and thus the impact factor and quality of journals. We assessed changes in the impact factor over years of a number of journals and whether the presence of an electronic version of the journal was associated with the impact factor score. DESIGN AND METHODS: This is a retrospective longitudinal study. The availability of journals (table of contents (TOC), abstracts, full text and free full text) on Internet, in years 1995-2000, was assessed between December 2000 and January 2001. The first 20 top-journals from 8 subject categories were included. Changes in impact factor over time and association with Internet availability were modeled. RESULTS: Overall, 118/139 journals (85%) had their TOC on the Internet, of these 107 (77%) had abstracts, 97 (70%) had full text and 33 (24%) free full text. The median impact factor for all journals was 1.65, 2.08, 2.10, 2.21 and 2.35 for the years from 1995 to 1999, respectively. This increase was statistically significant, with differences among subject categories. The presence of TOC, abstracts and full text on the Internet was also significantly associated with higher impact factor, after accounting for time and subject category. INTERPRETATION AND CONCLUSIONS: The impact factor has been used for assessing the quality of journals. We identified a new limitation of this indicator: the impact factor seems to be related to the amount of circulation of information through Internet. This could be a temporary limitation, associated with diffusion of journals on, and spread of Internet. PMID- 11602407 TI - Engraftment potential into NOD/SCID mice of CD34+ cells derived from human fetal liver as compared to fetal bone marrow. AB - BACKGROUND AND OBJECTIVES: We hypothesized that qualitative or quantitative differences in hematopoietic stem cells from fetal liver (FL) and fetal bone marrow (FBM) may be the cause of their organ specificity. DESIGN AND METHODS: To analyze possible differences in vivo, we compared the engraftment potential of equal numbers of CD34+ cells isolated from human FL or FBM into immunodeficient NOD/SCID mice. RESULTS: Mice showing engraftment following transplantation of CD34+ cells from FL demonstrated 14% (range 2-76%) CD45+ cells of human origin in the bone marrow compared to significantly lower levels of engraftment (4%, range 2-20%, p < 0.04) of FBM CD34+ cells. Likewise, the percentage of CD34+ CD38- cells in FBM was 4 times lower than the percentage in FL (1.4+/-0.9% and 5.6+/ 0.7%, respectively). Similar organ distribution of engrafted human cells was found. Subset analysis of human cells in bone marrow of engrafted mice revealed identical distribution of the lymphoid, myeloid and erythroid lineages after transplantation of CD34+ cells from FL or FBM. INTERPRETATION AND CONCLUSIONS: The FL CD34+ cells showed a four-fold higher content of the CD34+ CD38- subset coinciding with a four-fold higher engraftment of CD34+ cells into NOD/SCID mice. Since the organ distribution and differentiation potential of the cells engrafted were similar, we concluded that CD34+ hematopoietic cells derived from FL and FBM have quantitatively different, but qualitatively the same potential for engraftment into NOD/SCID mice. PMID- 11602408 TI - Enhanced lytic activity of cytokine-induced killer cells against multiple myeloma cells after co-culture with idiotype-pulsed dendritic cells. AB - BACKGROUND AND OBJECTIVES: There are numerous reports of in vitro and in vivo usage of dendritic cells (DC) pulsed with idiotype, the tumor-specific antigen of multiple myeloma (MM), for immunotherapy of MM. Data suggest that not only T cells, but also the innate immune system reacts against MM. Here, we examined the cytotoxic activity of cytokine-induced killer (CIK) cells against myeloma cells. This heterogeneous effector population consists of T-, NK- and NKT-cells. DESIGN AND METHODS: CIK cells generated from buffy coats or blood from patients with MM were co-cultured with autologous idiotype-pulsed DC. The cytotoxic activity was investigated in lactate dehydrogenase release assays against cell lines or autologous CD138 positive cells from bone marrow. RESULTS: CIK cells were able to lyse MM cells at low effector to target ratios. This effect was significantly enhanced by co-culturing with specifically pulsed DC (83.8% lysis at an effector to target ratio of 16:1). Using an interferon-g secreting MACS separation assay, the cytotoxic activity of CIK cells was enhanced to maximal lysis at the lower effector to target ratio of 5:1. High cytotoxic activity was also shown in a completely autologous setting against enriched CD138+ cells from a patient with MM (54.4% lysis at an effector to target ratio of 6:1). Interestingly, there was no cytotoxic activity against the CD138- fraction of the bone-marrow. INTERPRETATION AND CONCLUSIONS: Using a heterogeneous population of effector cells, we were able to activate the innate and the adoptive immune-system against myeloma cells. CIK cells showed high lytic activity against MM cells, which could be enhanced by co-culturing with antigen-specific pulsed DC. PMID- 11602409 TI - Assessment of stromal function, and its potential contribution to deregulation of hematopoiesis in the myelodysplastic syndromes. AB - BACKGROUND AND OBJECTIVES: The regulation of hematopoiesis by marrow stroma in vitro, has been shown to be abnormal in some patients with myelodysplastic syndromes (MDS). This study was performed to assess whether a range of mechanisms may be altered within the MDS microenvironment. DESIGN AND METHODS: The effects of diffusible factors produced by normal or MDS stromal layers on hematopoietic cells were studied by comparing the ability of media conditioned (CM) by normal or MDS stroma to regulate migration of target normal marrow CD34+ cells across 5 microm transmembranes. The ability of CM to stimulate hematopoietic cells was also assessed: changes in membrane polarity of KG-1a cells on exposure to stroma CM were compared. Subsequently, contact-mediated interactions between normal marrow CD34+ cells and normal and MDS stroma were studied: survival of allogeneic normal marrow CD34+ cells on live and glutaraldehyde-fixed normal and myelodysplastic stroma after 24h of co-culture was measured using 7 aminoactinomycin D staining. To determine whether hematopoietic cell survival on normal and MDS stroma was related to oxidative stress within the stromal microenvironment, intracellular superoxide levels, both constitutively and induced by tumor necrosis factor-a were measured within live stromal cells by FACScan analysis of ethidium bromide stained cells. RESULTS: The ability of CM from normal and MDS stroma to regulate short-term migration and activation of hematopoietic cells was similar. The mean percentage of apoptotic CD34+ cells (13+/-11%) adherent to glutaraldehyde-fixed myelodysplastic stroma was higher than on paired fixed normal stroma (11+/-10%) (n=6, p=0.056). Constitutive mean levels of superoxide in myelodysplastic cultures (9.5+/-2.1) were greater than in normal stromal cultures (4.9+/-0.6; n=6). However, following treatment with tumor necrosis factor-a, the mean value for superoxide in myelodysplastic stromal cultures was unchanged (fractional change=0.99+/-0.56), compared with an increase in normal stroma (fractional change=1.6+/-0.1, p<0.05). No correlation was observed between superoxide levels, proportion of apoptotic CD34+ cells and percentage of CD14+ stromal cells [mean 8%, range 0-37% (myelodysplastic); mean 1.3%, range 0-5% (normal)]. INTERPRETATION AND CONCLUSIONS: Abnormalities of stromal function in myelodysplastic syndromes are likely to be heterogeneous in origin: altered matrix molecules and changes in superoxide within stromal cells may contribute to abnormal survival and development of hematopoietic cells within the myelodysplastic marrow microenvironment PMID- 11602410 TI - Efficacy of anti-CD20 monoclonal antibodies (Mabthera) in patients with progressed hairy cell leukemia. AB - BACKGROUND AND OBJECTIVES: Recently, a chimeric monoclonal antibody (MoAb) directed against the CD20 antigen (rituximab) has been successfully introduced in the treatment of several CD20-positive B-cell neoplasias and particularly of follicular lymphomas. Based on these premises we evaluated the efficacy and the toxicity of chimeric anti-CD20 monoclonal antibody (MoAb) in relapsed/progressed hairy cell leukemia (HCL). DESIGN AND METHODS: Ten patients with relapsed/progressed HCL entered the study. Eight patients were males and two females with a median age of 55 years (range 41-78) and all of them had been previously treated with 2-chlorodeoxyadenosine and/or deoxycoformycin and a interferon. Two out of 10 patients were anemic (Hb < 10 g/dL), 4 thrombocytopenic (Plt < 100 x 10(9)/L), 3 had fewer than 1.0 x 10(9)/L neutrophils and 3 had circulating hairy cells (HC). All patients received 375 mg/m2 i.v. of anti-CD20 MoAb once a week for 4 doses. RESULTS: All patients were evaluable for response, one patient showing a complete remission and 4 a partial response. Adverse reactions, such as fever, chills, bone pain, hypotension and thrombocytopenia, were transient and mild (grade 1-2) and occurred only during the first course of treatment. One month after the last infusion, patients who had had anemia, neutropenia or thrombocytopenia, recovered normal peripheral blood values. Circulating HC also disappeared within one month. Immunostained bone marrow biopsies were checked 1, 3 and 6 months after the end of therapy and in 5 out of 10 patients a >50% reduction of bone marrow HC infiltration was recorded. INTERPRETATION AND CONCLUSIONS: On the basis of these preliminary results observed in 10 patients with progressed HCL, it appears that treatment with anti CD20 MoAb is safe and effective in at least 50% of patients, particularly in those with a less evident bone marrow infiltration (50%) and in those previously splenectomized. PMID- 11602411 TI - High dose of idarubicin-based regimen for diffuse large cell AIDS-related non Hodgkin's lymphoma patients: a pilot study. AB - BACKGROUND AND OBJECTIVES: Intensive chemotherapy (CHT) in AIDS-related non Hodgkin's lymphoma (AIDS-NHL patients) is a vexing problem. Our purpose was to evaluate the feasibility of a high dose idarubicin (HD-IDA)-based regimen in diffuse large cell (DLC) AIDS-NHL patients. DESIGN AND METHODS: Fourteen stage I IV untreated DLC AIDS-NHL patients with a performance status <3 and no prior AIDS related diseases received CIOD: cyclophosphamide, HD-IDA (25 mg/m2 in 8 patients, 20 mg/m2 in 6 patients) vincristine and dexamethasone plus granulocyte colony stimulating factor (G-CSF) and prophylaxis against infections. The outcomes measured were: rate of response, disease-free survival (DFS), overall survival (OS) and the impact of chemotherapy on immunologic and virological parameters. RESULTS: Complete response was achieved in 13/14 cases (response rate: 93%). The median time of response and survival was 33 (range 5-79) and 35.5 (range 6-84) months, respectively. At 60 months the DFS and OS were 71% and 44%, respectively. CIOD with idarubicin 20 mg/m2 was better tolerated than that with 25 mg/m2 and was administered with a higher mean average-relative-dose-intensity (95.38+/-7% vs 83.35+/-15.59%, p=0.0001). Opportunistic infections were more frequent in patients with a baseline CD4 <100 than those with >100 cells/microL (4/5 vs 1/9: p=0.0229). After 3 CIOD courses the mean CD4 cells/microL was significantly lower (p=0.001) and the mean HIV.1 RNA load was significantly higher (p=0.045) than at baseline. INTERPRETATION AND CONCLUSIONS: The proposed chemotherapeutic regimen for AIDS-related non-Hodgkin's lymphoma is feasible in an outpatient setting in selected patients with relatively well-preserved immune function. PMID- 11602412 TI - Effect of computer-aided management on the quality of treatment in anticoagulated patients: a prospective, randomized, multicenter trial of APROAT (Automated PRogram for Oral Anticoagulant Treatment). AB - BACKGROUND AND OBJECTIVES: We carried out a prospective, randomized trial to test whether a computer-based decision support system to initiate and maintain oral anticoagulant (OA) treatment can improve the laboratory quality of therapy. DESIGN AND METHODS: Two separate sets of patients on oral anticoagulants, in five Italian anticoagulant clinics, were studied: 335 patients in the first three months of treatment (stabilization phase), 916 patients (775 patient-years) beyond the third month of treatment (maintenance phase). Patients were randomized to a computerized system, which included algorithms able to suggest OA dosing and to schedule appointments (computer-aided dosing) or to an arm in which OA were prescribed by the same teams of expert physicians without such algorithms (control group). Primary outcomes were: A) the percentage of patients reaching a stable state of anticoagulation during each of the first three months of treatment; B) the percentage of time individuals spent within the aimed therapeutic range (maintenance phase). RESULTS: Patients in the computer-aided dosing group achieved a stable state significantly faster (p<0.01) and they spent more time within the therapeutic range during maintenance (p<0.001) than controls. The favorable effect of computer-aided dosing was mainly due to a reduction of the time spent below the therapeutic range and was associated with an increase of mean INR value, of anticoagulant drug dosage, and with a reduction of the number of appointments per patient (all changes significant: p<0.001). INTERPRETATION AND CONCLUSIONS: The computer decision-aided support improves the laboratory quality of anticoagulant treatment, both during long-term maintenance and in the early, highly unstable phase of treatment, and it also significantly reduces the number of scheduled laboratory controls. PMID- 11602413 TI - Early full donor myeloid chimerism after reduced-intensity stem cell transplantation using a combination of fludarabine and busulfan. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate lineage-specific chimerism reconstitution after reduced-intensity allogeneic stem cell transplantation (RIST) using a combination of fludarabine (30 mg/m2 for 6 days) and busulfan (4 mg/kg for 2 days). DESIGN AND METHODS: We prospectively enrolled 8 consecutive patients with hematologic malignancies who were not candidates for conventional transplantation because of either high age or organ dysfunction. Host-donor chimerism was evaluated using polymerase chain reaction-based amplification of a polymorphic short tandem repeat region. RESULTS: All of our patients achieved engraftment within a median of 11 days after transplantation. On day 30, full donor myeloid cell chimerism (>90%) was achieved in 7 patients whereas full donor T-cell chimerism was achieved in only one patient. Thus, in contrast to other reported results, full donor chimerism was achieved earlier in the myeloid lineage than the T-cell lineage. On day 60, however, T-cell chimerism caught up with myeloid chimerism. Two patients developed grade II-IV acute graft versus-host disease (GVHD) before the detection of full donor T-cell chimerism. INTERPRETATION AND CONCLUSIONS: Our findings suggest that the kinetics of lineage specific chimerism depend on the agents used in the conditioning regimen, and may provide insight into the chimerism kinetics and pathogenesis of GVHD. Thus, the strategy for controlling immunosuppression after RIST should be modified according to the type of conditioning regimen applied. PMID- 11602414 TI - Severe infections after allogeneic peripheral blood stem cell transplantation: a matched-pair comparison of unmanipulated and CD34+ cell-selected transplantation. AB - BACKGROUND AND OBJECTIVES: T-cell depletion of the graft delays immune recovery following allogeneic peripheral blood stem cell transplantation (PBSCT), but it is not clear whether it actually increases the risk of severe infections after the transplant. DESIGN AND METHODS: We have compared the occurrence of severe infections following 162 CD34+ cell-selected allogeneic PBSCT and 162 unmanipulated PBSCT (CD34+ and UM groups, respectively) from HLA-identical siblings. RESULTS: The probability of infection-related mortality (IRM) was 22% in the UM group and 31% in the CD34+ group (log-rank, p=0.2). In multivariate analyses only the use of fluconazole prophylaxis showed a protective effect on IRM in the whole set of patients, while in both transplant groups the most significant factor was the development of moderate-to-severe graft-versus-host disease (GVHD). The probability of developing cytomegalovirus (CMV) infection was 42% in the UM group and 59% in the CD34+ group (p=0.002), with no differences in CMV disease (10% and 9%, respectively). Multivariate analysis of CMV infection identified three variables associated with a higher risk in the whole set of patients: CMV positive serostatus, CD34+ transplant group and recipient age above 40 years. The development of moderate-to-severe GVHD was a significant factor only in the UM group. Disseminated varicella-zoster virus infection was more common in the CD34+ group (19% and 12%, p=0.05), as were early (< 30 days post transplant) severe bacterial infections (28% vs 14%, p=0.002). Invasive fungal infections and pneumonias of unknown origin did not differ between groups. INTERPRETATION AND CONCLUSIONS: Our results do not show a significant increase in the risk of dying from an opportunistic infection with CD34+-PBSCT, but the risk of CMV infection is increased, with no differences in CMV disease or mortality attributable to CMV. There is an additive effect on IRM of developing moderate-to severe GVHD (acute or chronic) following CD34+-PBSCT, and in this subset of patients maximum efforts for the prevention and early treatment of opportunistic infections should be pursued. PMID- 11602415 TI - Comparative cost analysis of autologous peripheral blood progenitor cell and bone marrow transplantation in pediatric patients with malignancies. AB - BACKGROUND AND OBJECTIVES: This study was conducted in order to compare and analyze clinical and economic outcomes of autologous transplantation using bone marrow or peripheral blood as the source of hematopoietic progenitor cells in pediatric patients with malignancies. DESIGN AND METHODS: We collected clinical information and resource utilization from 131 consecutive autologous transplantations (102 peripheral blood progenitor cell (PBPC) and 29 bone marrow (BM) transplants) at a single institution between January 1989 and December 1998 in children with a variety of malignancies. Multivariable linear regression was used to evaluate the associations between pre-transplantation variables, post infusion events and overall costs. A cost-effectiveness analysis of transplantation for acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) patients was also performed. RESULTS: Hematopoietic recovery was faster in the PBPCT group (days to neutrophil and platelet engraftment: 9 and 13, respectively, versus 14 and 21 for BMT, p<0.0001). There were less transfusion, antibiotic and parenteral nutrition requirements and hospital stay was shorter (median 17 days; range 8-38) in the PBPCT group than in the BMT one (median 28 days; range 11-65) (p<0.0001) resulting in a median lower overall cost for PBPCT (US$ 7895) compared to BMT (US$ 11820)(p<0.0001). Major determinants of overall costs for both groups were total body irradiation (TBI)-based conditioning regimen, days of hospitalization and number of transfused platelets. In PBPCT patients, a graft containing > or = 5 x 10(6)/kg CD34+ cells decreased the total cost of transplantation by 27%. Cost-effectiveness was higher for PBPCT than BMT for pediatric AML patients (p<0.0001) whereas in ALL patients the cost effectiveness of the two transplant strategies was not significantly different. INTERPRETATIONS AND CONCLUSIONS: We conclude that, compared to BMT, autologous PBPCT in children is associated not only with clinical benefits but also economic advantages. PMID- 11602416 TI - Lentiviral vectors show dramatically increased efficiency of transduction of human leukemic cell lines. PMID- 11602417 TI - Origin and spread of Hb G-San Jose in Southern Italy. PMID- 11602418 TI - Isolation of human mesenchymal stem cells: bone marrow versus umbilical cord blood. PMID- 11602419 TI - Delayed cytogenetic response with prolonged interferon-alpha treatment in chronic myeloid leukemia patients: quantification of BCR-ABL transcript by competitive reverse transcription-polymerase chain reaction. PMID- 11602420 TI - Rituximab with peripheral blood stem cell transplantation in CD20 lymphoproliferative disorders. PMID- 11602421 TI - Systemic mast cell disease associated with B-chronic lymphocytic leukemia. PMID- 11602422 TI - Thalidomide and thrombosis in patients with multiple myeloma. PMID- 11602423 TI - Combined hemophilia A and type 2 von Willebrand's disease: defect of both factor VIII level and factor VIII binding capacity of von Willebrand factor. PMID- 11602425 TI - Allogeneic non-myeloablative stem cell transplantation for the patients with heavily pre-treated refractory lymphoma. PMID- 11602424 TI - Thrombophilia in thalassemia major patients: analysis of genetic predisposing factors. PMID- 11602426 TI - High prevalence of non-virus/non-alcohol-related alanine-aminotransferase increase in blood donors. PMID- 11602427 TI - The irreplaceable image: Leptomeningeal leukemia masquerading as cauda equina syndrome: appraisal by magnetic resonance imaging. PMID- 11602429 TI - The irreplaceable image: B-cell lymphoma of the gallbladder. PMID- 11602428 TI - The irreplaceable image: IgA multiple myeloma with multiple cutaneous plasmacytomas. PMID- 11602430 TI - Rhe irreplaceable image: Superficial thrombosis of a varicose vein of the abdominal wall as the first sign of an otherwise occult locally-advanced ovarian cancer. PMID- 11602431 TI - A young woman with microcytic anemia and hypertransaminasemia. PMID- 11602432 TI - Successful allogeneic bone marrow transplantation for hepatosplenic gammadelta T cell lymphoma. PMID- 11602433 TI - DMSO and non DMSO clonogenic assays from thawed cord blood. PMID- 11602434 TI - Reactive polyclonal T-cell lymphocytosis mimicking Sezary syndrome in a patient with hairy cell leukemia. PMID- 11602435 TI - Diagnosis of deep venous thrombosis in the elderly: a higher D-dimer cut-off value is better? PMID- 11602436 TI - Saliphagia: a new form of an old symptom. PMID- 11602437 TI - Myelodysplastic syndrome/acute myelogenous leukaemia after adjuvant chemotherapy with pyrimidine anti-metabolites in three patients. PMID- 11602438 TI - Extramedullary relapse following allogeneic stem cell transplantation in acute promyelocytic leukemia: the role of ATRA. PMID- 11602440 TI - SIMPLIFICATION, NOT DEMYSTIFICATION NOR TRIVIALIZATION OF STEM CELL TRANSPLANTATION. PMID- 11602439 TI - Recurrent pyoderma gangrenosum and myelodysplasia. PMID- 11602441 TI - Growing up in an affluent family: unique psychosocial issues for the adolescent. AB - Most people would agree that it is preferable to grow up in a wealthy family than in one that is impoverished. However, adolescents who live in affluent families are in danger of developing a sense of entitlement that may impede future vocational and social success. Parental presence may be minimal, with discipline and child-rearing delegated to paid caretakers. The pressure to achieve in school may overwhelm the less than gifted adolescent. Excessive parental participation in school affairs may deter the adolescent from developing a sense of independence and competency. Eating disorders are more likely to develop in affluent youth. Participation in delinquent behaviors may be due to boredom with the affluent lifestyle, and such behavior may not be punished since youth from affluent families are often shielded from proper discipline by law enforcement authorities. Because of their social standing in the community and as a consequence of their wealth, affluent youth are in unique positions to become leaders and to participate in altruistic endeavors. Health care providers taking care of adolescents in wealthy families should be aware of these issues and should discuss them with adolescents and their families. PMID- 11602443 TI - Adolescent health in a globalised world: a picture of health inequalities. AB - More than half of the world's population of 6 billion people is under age 25 years. Of the estimated 1.2 billion adolescents worldwide (1 in every 5 people is an adolescent), about 85% live in developing countries and the remainder in the industrialised world. Changing social, political, and economic realities are having a major and dramatic impact on young people and their families. In this context, however, the health of young people in developing countries has been largely ignored. Of particular concern are the implications of poverty, health inequality, gender discrimination, economic instability, and political unrest. These troubling dimensions create scenarios that challenge paediatricians and other health workers to become more active and courageous as advocates for the health rights and health care of young people. In this chapter, we outline and describe some of the key issues involved, recognise a number of initiatives being undertaken, and propose additional measures for consideration. PMID- 11602442 TI - Consumerism: its impact on the health of adolescents. AB - Marketplace practices are integral to the larger economic and social context of adolescent health risk behaviors. To corporations and marketers, adolescents represent a gold mine of current and future profits. Adolescent incomes increased by almost a third in the 1990s. The annual spending of the U.S. adolescent population is estimated now to have reached 155 billion US dollars. The sheer size of the adolescent population and its spending power are of keen interest to corporations and marketers. This chapter presents a brief history of youth targeted marketing and examines the major avenues in the media and inside schools that marketers and corporations use today to reach adolescents with their messages and products. It outlines the impact of consumerism and marketing on adolescent health using five case examples: tobacco, alcohol, cosmetic surgery, laxatives, and diet pills. It then concludes with a discussion of resistance efforts, led by health advocates, policy makers, parents, and youth themselves to restrict sales of harmful products to youth and curtail advertisers' access to adolescents in schools. A critical role for adolescent health researchers and advocates is to contribute a public health perspective into ongoing debates over regulating business practices that negatively affect the health of young people. PMID- 11602444 TI - The changing ethnic makeup of America's adolescents: implications for health. AB - As the percentage of minority adolescents in society increases, behaviors that affect the health of these adolescents will become increasingly important. Both mental and physical health as well as substance abuse and violence need to be addressed, and the ethnicity and culture of the adolescent patient may guide specific approaches and considerations. Many of the health problems affecting adolescents are preventable, and health care providers should aim significant resources at these issues. Gaps in adolescent health care, and especially barriers to entry for some ethnic groups, deserve greater attention to ensure that all groups can enjoy access to quality health care. Options available to health care practitioners for reducing these barriers are offered in the final portion of the article. PMID- 11602445 TI - Volunteering and community service in adolescence. AB - Since the 1980s, volunteering has been studied as an avenue for positive development in adolescents. Reviews in the early 1990s were mixed regarding the benefits of volunteering, questioning the ability to transfer volunteer skills to other aspects of life as well as the true reduction in risky behaviors the adolescent will go on to undertake. This article addresses the gaps in the prior reviews and looks more closely at the benefits of volunteering. The author suggests that adolescent volunteers develop fewer problem behaviors in their later teens, enjoy a sense of connection to their community, maintain a better work ethic, and show a greater concern for the welfare of others. There are innumerable options for integrating volunteering into the life of an adolescent. This article offers many options, reviews some of the most popular, and suggests conditions that may increase the success of a volunteering program. PMID- 11602446 TI - High schools and development of healthy young people. AB - While high schools were designed to teach and guide adolescents, institutions today often fail and even harm their students. Low-income and minority youth are the most affected by this trend because poor quality schools are most often found in urban settings, and poorer students are the least able to call upon other resources to make up for the inadequacies in the school. Furthermore, today's high school paradigm is the least helpful to the student who will enter the job market immediately after high school, carrying few marketable skills and little understanding of his or her place in the community. Several effective school models do exist, and these often meet the needs of the minority students as traditional high schools do not. Physicians in the adolescent health field can and must help in this arena. Getting a teen out of a poor school and offering alternative schools where appropriate will contribute to the health of each individual, and hopefully will encourage change in schools generally. PMID- 11602447 TI - The health of youth in the juvenile justice systems. AB - A substantial number of adolescents are imprisoned each year in the United States. Many of them come to detention with significant medical and mental health problems which, in many cases, have been neglected. The time of detention provides an opportunity to address these problems, thereby benefiting both the juvenile and society. The medical department has a vital role in giving individual care and ensuring that the detention facility provides a safe, positive environment in which delinquents can be rehabilitated. There are substantial barriers impeding the care of detainees that can be overcome using a variety of collaborations in the local and national communities. Involving teaching institutions brings outside oversight as well as new ideas into these closed institutions. Research in areas that will benefit inmates can improve our ability to provide appropriate care. Adolescent medicine and pediatric training programs have a duty to expose physician trainees to detention medicine so that an adequate number of appropriately trained physicians are available to work in juvenile correctional facilities. Juvenile detention medicine should be fully integrated into mainstream medical care and seen as a valuable career. PMID- 11602448 TI - Adolescent children of drug-abusing parents. AB - The effects of a substance-abusing parent on a child are wide-spread, and unfortunately they follow that child well into adolescence and adulthood. Cognitive difficulty, poor judgment, and conduct problems are but a few of the sequelae, and similar results are seen whether the drug is alcohol or cocaine or another illicit substance. In addition to affecting the biology of the adolescent from the perinatal period, parental substance abuse often causes a disrupted, chaotic home, financial insecurity, and exposure of the teen to illegal substances and violence. The emotional toll on the adolescent is steep, and the overall cost to the health care system is enormous. Ultimately, many of these adolescents progress to substance abuse themselves. Health care providers need to be sensitive to the possibility of substance abuse in the home, and should aggressively pursue early treatment/therapy options for those teens at risk. PMID- 11602449 TI - The impact of parental divorce for adolescents: a consideration of intervention beyond the crisis. AB - The effects of divorce on children and adolescents remain a major public health issue. Over the last three decades, there has been ongoing debate among researchers and mental health and legal professionals who counsel divorcing families as to whether the effects are acute but time-limited or more enduring. This chapter looks at the tasks of normal adolescent psychosocial development and how divorce complicates those tasks. It suggests ways that pediatricians and other health professionals can intervene effectively with divorcing families within the context of their role. Divorce-specific resources and services are explained. PMID- 11602450 TI - Body and spirit: Religion, spirituality, and health among adolescents. AB - Religion and spirituality are important in the lives of many adolescents. This article traces patterns of adolescent religious/spiritual belief and practice and summarizes theories about religious development as they pertain to this age group. Data are provided that explore possible relationships between religion and health-related behavior among adolescents. Much of this data shows that greater religiosity/spirituality may be associated with less involvement in high-risk behaviors and more involvement in health-promoting behaviors. Implications of these data are discussed as well as possible negative roles that religion may play in youths' lives. The doctor's role in approaching religion and spirituality with patients is controversial. Health care professionals should be prepared to discuss these issues with adolescents for whom they are important, especially with patients who are hospitalized. Yet, doctors should be sensitive to those adolescents who may not want to delve into spiritual/religious issues in a health care setting. PMID- 11602451 TI - Adolescence and poverty. AB - Adolescents living in America suffer the triple burden of a disproportionate representation among the poor, a major conflict of developmental challenges and poverty-related challenges, and, frequently, additional challenges accompanying a minority heritage. At the same time, these individuals and the communities in which they live enjoy many strengths. This chapter reviews these and related issues. PMID- 11602452 TI - Adolescents and the workplace. AB - Adolescents have always played a major role in the workplace, whether using employment to add to the family's income needs or to provide the adolescent with "extra" spending money. Although employment affords many positive aspects to today's youths (including improved self-esteem and practical, real-world skills), there are many potential risks faced by the working adolescent. Workplaces create physical risks for disability, and adolescents who work long hours do so to the detriment of their social and educational obligations. Physicians should be aware that teens are working in record numbers, they should take careful occupational histories, and they should be aware of the pitfalls common to employment in their area (farm hazards in rural communities versus homicide and personal injury risks in an urban area, for example). Physicians should join with other authority figures in communities to push for the safest working environments possible for their adolescent patients. PMID- 11602455 TI - Setting the stage. AB - Intradialytic hypotension (IDH) occurs during 25% to 50% of end-stage renal disease (ESRD) hemodialysis (HD) treatments. The development of IDH signals both technology- and patient-dependent limitations expressed across a broad range of symptoms, from nausea and muscle cramps to ischemic injury. While traditional thinking has emphasized the link between hypertension and cardio-cerebrovascular injury, more recent studies of ESRD patients have stimulated significant interest in hypotension and poor outcomes. Theoretically, hypotension can contribute to the increased relative risk of death in ESRD by several mechanisms, which include acute coronary syndrome, autoregulation dysfunction, ischemia, and arrhythmogenicity. Endothelial abnormalities (increased procoagulation, thrombogenecity risk, and alterations in coronary flow reserve) and altered vascular distribution within the myocardium provide an environment for vascular injury. The current symposia will examine the pathophysiology of IDH, the specific HD prescription modifications to prevent IDH, and newer pharmacologic interventions to treat IDH and will highlight the approach to several clinical cases based on the information presented. It is becoming increasingly important to identify patients at "high risk" for IDH, to customize the HD prescription to the individual patient, to use drug therapy to prevent IDH events, and to track the prevalence of chronic hypotension and the incidence of IDH complications in the dialysis unit. PMID- 11602456 TI - Pathophysiology of dialysis hypotension: an update. AB - Dialysis hypotension occurs because a large volume of blood water and solutes are removed over a short period of time, overwhelming normal compensatory mechanisms, including plasma refilling and reduction of venous capacity, due to reduction of pressure transmission to veins. In some patients, seemingly paradoxical and inappropriate reduction of sympathetic tone may occur, causing reduction of arteriolar resistance, increased transmission of pressure to veins, and corresponding increase in venous capacity. Increased sequestration of blood in veins under conditions of hypovolemia reduces cardiac filling, cardiac output, and, ultimately, blood pressure. Adenosine release due to tissue ischemia may participate in reducing norepinephrine release locally, and activation of the Bezold-Jarisch reflex, perhaps in patients with certain but as yet undefined cardiac pathology, may be responsible for sudden dialysis hypotension. Patients with diastolic dysfunction may be more sensitive to the effects of reduced cardiac filling. The ultimate solution is reducing the ultrafiltration rate by use of longer dialysis sessions, more frequent dialysis, or reduction in salt intake. Increasing dialysis solution sodium chloride levels helps maintain blood volume and refilling but ultimately increases thirst and interdialytic weight gain, with a possible adverse effect on hypertension. Blood volume monitoring with ultrafiltration or dialysis solution sodium feedback loops are promising new strategies. Maintaining tissue oxygenation via an adequate blood hemoglobin level seems to be important. Use of adenosine antagonists remains experimental. Given the importance of sympathetic withdrawal, the use of pharmacologic sympathetic agonists is theoretically an attractive therapeutic strategy. PMID- 11602457 TI - Modifying the dialysis prescription to reduce intradialytic hypotension. AB - The dialysis prescription can have a substantial impact on the frequency of intradialytic hypotension (IDH). Plasma volume will decline to a greater extent when the ultrafiltration (UF) rate is rapid (high interdialytic weight gains and/or short treatment time), favoring IDH. The relationship of the target weight to the euvolemic weight determines the size of the interstitial fluid compartment, which is a major determinant of the rate of plasma refilling during UF. The higher the dialysate sodium, the smaller the decline in plasma volume for any given amount of UF. Use of a dialysate temperature that prevents a positive thermal balance during dialysis will allow peripheral vascular resistance to be maintained and minimize IDH. A higher ionized calcium during treatment facilitates an increase in cardiac output, a benefit that may be particularly notable in patients with depressed cardiac ejection fraction. Low dialysate magnesium, potassium, and bicarbonate may all favor IDH, although insufficient data are available for definitive conclusions. The choice of antihypertensive medication and the treatment schedule must be carefully considered in patients with IDH. The future integration of technology to monitor blood pressure, plasma volume, and thermal and sodium balance into a computer-based biofeedback system will very likely go a long way toward reducing the frequency of IDH. PMID- 11602458 TI - Pharmacologic options available to treat symptomatic intradialytic hypotension. AB - Treatment of symptomatic intradialytic hypotension (IDH) is a difficult task for the practicing nephrologist. Minimizing patient factors that precipitate IDH as well as dialysis procedure-related components that lower blood pressure are the initial approaches to this problem. However, despite these maneuvers, hypotension often persists in a group of high-risk patients. Pharmacologic interventions are often used to reduce IDH. Unfortunately, many of the available therapies are marginally effective and/or poorly tolerated. A few therapies appear to be efficacious and well tolerated-carnitine, sertraline, and midodrine. This article reviews the various pharmacologic therapies used for IDH and makes recommendations for treatment of this difficult problem. PMID- 11602459 TI - Clinical case-based approach to understanding intradialytic hypotension. AB - The approach to end-stage renal disease (ESRD) patients who develop intradialytic hypotension (IDH) encompasses an understanding of the pathophysiology, appropriate dialysis prescription modification, application of newer pharmacologic therapies, and development of strategies for prevention. Patients should have a "minimal data set" as part of their predialysis assessment. This information is critical to prescription modifications that may help decrease the risk for IDH. Individuals at "high risk" for IDH should be kept to a "safe zone" for dialysis ultrafiltration (35% or >45% relative post-Gd enhancement, synovial membrane volumes were estimated at each time point. At 4.25 minutes post-Gd, volumes were also determined by a more accurate but time consuming "manual method". RESULTS: The initially observed synovium-effusion borderline remained clearly visible, and on the same location, within at least the initial 11 minutes post-Gd (that is, within the normal time frame of post-Gd imaging in RA) but started blurring and moving centripetally thereafter. Compared with volumes at all other time points, synovial membrane volumes at 0.75 and 2.50 minutes post-Gd were significantly lower (Wilcoxon Pratt), suggesting that some synovial membrane areas had not yet exceeded the enhancement threshold. Thereafter, the measured volumes remained practically unchanged. CONCLUSION: This study suggests that MR image acquisition in arthritic knee joints should be performed within the initial approximately 10 minutes after gadolinium contrast injection to achieve the most accurate distinction between synovium and joint fluid but that small time variations are not of major importance to the measured synovial membrane volumes. PMID- 11602478 TI - Low incidence of reactive arthritis in children following a salmonella outbreak. AB - OBJECTIVES: To assess the incidence of reactive arthritis (ReA) in an outbreak of salmonella infection in a large cohort of children in Germany. METHODS: A few days after the salmonella outbreak all parents of affected children and all paediatricians and general practitioners in the region were provided with detailed information about the possibility of ReA. Six weeks after the outbreak a telephone call was made to all general practitioners and paediatricians to identify patients with ReA. Ten weeks after the outbreak a questionnaire assessing symptoms of ReA was mailed to all parents, and after a period of 4 months paediatricians and general practitioners were contacted again to search for additional unreported cases of ReA. RESULTS: Of the 286 children (age range 11 months to 9 years) with diarrhoea and stool cultures positive for Salmonella enteritidis lysotype 8/7, not a single case of arthritis was reported over the 4 month period. However, six children (2%) had arthralgia of various duration (1 day to 6 weeks) with a single recurrence in one child. The joint pattern was oligoarticular and lower limb joints (knee/ankle) were affected exclusively. CONCLUSION: The incidence of ReA after salmonella infection in children appears to be very low which may be related to differences in the immune response between children and adults. PMID- 11602479 TI - Subclinical vasculitis in polymyalgia rheumatica. PMID- 11602480 TI - Musculoskeletal manifestations in polymyalgia rheumatica and temporal arteritis. AB - OBJECTIVE: To evaluate the incidence and characteristics of musculoskeletal manifestations in polymyalgia rheumatica (PMR) and temporal arteritis (TA). METHODS: The records of 163 cases of PMR or TA diagnosed over a 15 year period in one area of Spain were reviewed for the presence and type of musculoskeletal manifestations. RESULTS: Of 163 patients, 90 had isolated PMR and 73 had TA. Eighteen of the 90 patients (20%) with isolated PMR developed distal peripheral arthritis either at diagnosis or during the course of the disease. When it occurred, synovitis was mild, monoarticular or pauci-articular, asymmetrical, transient, and not destructive. Other distal manifestations observed in these patients were carpal tunnel syndrome and distal extremity swelling with pitting oedema. In all cases these manifestations occurred in conjunction with active PMR. As expected, PMR was the most frequent musculoskeletal manifestation in patients with TA, occurring in 56% of cases. On the contrary, only 11% of patients with TA developed peripheral arthritis. An important finding was that peripheral arthritis in these patients appears to be linked only temporally to the presence of simultaneous PMR and is not observed in its absence. Distal extremity swelling or defined polyarthritis were not observed. CONCLUSION: The spectrum of distal musculoskeletal manifestations of PMR in our series is similar to that reported in other populations. By contrast, distal musculoskeletal symptoms are uncommon in TA. The almost complete absence of distal musculoskeletal manifestations in patients with pure TA suggests different mechanisms of disease in PMR and TA, supporting the view of two separate conditions or one common disease in which host susceptibility influences the clinical expression. PMID- 11602481 TI - Efficacy of extracorporeal shock wave treatment in calcaneal enthesophytosis. AB - OBJECTIVE: To evaluate the efficacy of extracorporeal shock wave treatment (ESWT) in calcaneal enthesophytosis. METHODS: 60 patients (43 women, 17 men) were examined who had talalgia associated with heel spur. A single blind randomised study was performed in which 30 patients underwent a regular treatment (group 1) and 30 a simulated one (shocks of 0 mJ/mm(2) energy were applied) (group 2). Variations in symptoms were evaluated by visual analogue scale (VAS). Variations in the dimension of enthesophytosis were evaluated by x ray examination. Variations in the grade of enthesitis were evaluated by sonography. RESULTS: A significant decrease of VAS was seen in group 1. Examination by x ray showed morphological modifications (reduction of the larger diameter >1 mm) of the enthesophytosis in nine (30%) patients. Sonography did not show significant changes in the grade of enthesitis just after the end of the treatment, but a significant reduction was seen after one month. In the control group no significant decrease of VAS was seen. No modification was observed by x ray examination or sonography. CONCLUSION: ESWT is safe and improves the symptoms of most patients with a painful heel, it can also structurally modify enthesophytosis, and reduce inflammatory oedema. PMID- 11602482 TI - Polyarteritis nodosa and mixed cryoglobulinaemia related to hepatitis B and C virus coinfection. AB - OBJECTIVE: To determine the responsibility of hepatitis B virus (HBV) and hepatitis C virus (HCV) and therapeutic implications in a patient who developed systemic vasculitis. CASE REPORT: The case of a 38 year old woman who had a past history of addiction to intravenous drugs and developed systemic vasculitis after infection by HBV and HCV is described. The clinical and laboratory findings substantiated not only the diagnosis of polyarteritis nodosa (PAN) but also that of mixed cryoglobulinaemia with a monoclonal IgMkappa component. CONCLUSION: Because cryoglobulins are rarely found in HBV related PAN but often associated with HCV infection, and in light of the histological findings, cryoglobulinaemia was interpreted as being secondary to HCV infection. This example of a highly complex situation emphasises the need to gather all relevant clinical, biological, histological, and complementary data so that the best treatment for overlapping of distinct vasculitides can be selected. PMID- 11602483 TI - Vascular endothelial growth factor in articular cartilage of healthy and osteoarthritic human knee joints. AB - OBJECTIVE: To determine the levels of vascular endothelial growth factor (VEGF) mRNA and protein expression in normal and osteoarthritic (OA) human articular cartilage, and whether VEGF expression alters during the progression of OA. METHODS: Sections from normal and OA human knee cartilage were immunotained with a polyclonal antibody recognising VEGF. In addition, total RNA was isolated from normal and osteoarthritic human knee cartilage and analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) for VEGF mRNA expression. RESULTS: VEGF was found to be present in normal and OA human knee cartilage in all cartilage layers. A significant increase of VEGF immunopositive chondrocytes to up to approximately 82% was detected in severe OA cartilage compared with normal articular cartilage (approximately 56% of immunopositive chondrocytes). RT PCR analysis showed the expression of VEGF also on the mRNA level. CONCLUSIONS: VEGF is expressed by articular chondrocytes in normal and OA human knee cartilage. The percentage of VEGF immunopositive chondrocytes significantly increases in late stages of the disease. The VEGF transcript levels encoding all four isoforms shows a big variability in samples from different donors, suggesting a distinct regulation of the expression of the four VEGF isoforms in normal and OA cartilage. PMID- 11602484 TI - Papulopustular skin lesions are seen more frequently in patients with Behcet's syndrome who have arthritis: a controlled and masked study. AB - OBJECTIVE: To determine the prevalence of acneiform skin lesions (comedones, papules, and pustules) in patients with Behcet's syndrome (BS) with arthritis. METHODS: Study groups included 44 patients with BS with arthritis (32 men, 12 women, mean (SD) age 37.8 (8.9)), 42 patients with BS without arthritis (31 men, 11 women, mean age 35.5 (6.4)), 21 patients with active rheumatoid arthritis (five men, 16 women, mean age 48.8 (14)), and 33 healthy volunteers (28 men, five women, mean age 40.1 (8.1)). All probands and controls were examined by a rheumatologist and a dermatologist, in a prospective and masked protocol. An ophthalmological evaluation was performed if necessary. Skin lesions, including comedones, papules, and pustules, were counted and scored as 0: absent, 1: 1-5, 2: 6-10, 3: 11-15, 4: 16-20, and 5: >20. RESULTS: Although there was no significant difference between the four groups in the prevalence of comedones, the number of papules and pustules was significantly higher in patients with BS with arthritis (p=0.0037 for papules and p<0.0001 for pustules) than in the remaining three groups. CONCLUSION: Acneiform skin lesions (papules and pustules) seem to be more frequent in patients with BS with arthritis. This suggest that the arthritis seen in BS may possibly be related to acne associated arthritis. PMID- 11602485 TI - Atherosclerosis, autoimmunity, and systemic lupus erythematosus. PMID- 11602486 TI - Matrix metalloproteinase hypothesis of plaque rupture: players keep piling up but questions remain. PMID- 11602488 TI - Central hypotensive action of clonidine requires nitric oxide. AB - Background- Clonidine has an antihypertensive effect by its action in the brain and, because we observed that the tonic production of nitric oxide (NO) in the brain is required to maintain blood pressure at its low, normotensive level, the current study was designed to determine whether the hypotensive action of clonidine resulted from its stimulation of excess NO in the brain. Methods and Results- Porphyritic microsensors were used to quantify NO concentration in the nucleus tractus solitarius (NTS) in vitro in brain slices and in vivo in the anesthetized rat. In both preparations, the basal production of NO in the NTS was 15+/-3 nmol/L. In vitro stimulation of the NTS with clonidine (50 nmol/L) resulted in an increase in the NO concentration to 84+/-7 nmol/L. In vivo, the intracerebroventricular (ICV) infusion of clonidine (0.03 microgram) caused an increase in NO concentration in the NTS to 128+/-17 nmol/L. This ICV injection of clonidine caused a fall in mean arterial pressure of -22+/-1 mm Hg and a decrease of heart rate of -18+/-2%. The blockade of NO production with N(G)-nitro-L arginine-methyl ester (2 micromol; delivered ICV, 30 minutes before the clonidine) reduced responses to clonidine for both mean arterial pressure and heart rate (-3+/-1 mm Hg and -2+/-1% change, respectively). Conclusion- The stimulation of the release of NO in the brain by clonidine contributes to its central antihypertensive action. PMID- 11602489 TI - Risk factors for cardiovascular disease in systemic lupus erythematosus. AB - BACKGROUND: Cardiovascular disease (CVD) is overrepresented in patients with systemic lupus erythematosus (SLE). We determined the prevalence of traditional and nontraditional risk factors for CVD in SLE patients with and without CVD compared with controls. METHODS AND RESULTS: Twenty-six women (aged 52+/-8.2 years) with SLE and a history of CVD (SLE cases) were compared with 26 age matched women with SLE but without manifest CVD (SLE controls) and 26 age-matched population-based control women (population controls). Common carotid intima-media thickness (IMT) was measured by B-mode ultrasound as a surrogate measure of atherosclerosis. SLE cases had increased IMT compared with SLE controls (P=0.03) and population controls (P=0.001), whereas IMT of SLE controls did not differ from population controls. SLE cases had raised plasma concentrations of circulating oxidized LDL (OxLDL; P=0.03), as measured by the monoclonal antibody EO6, and autoantibodies to epitopes of OxLDL (P<0.001); dyslipidemia with raised triglycerides (P<0.001) and lipoprotein(a) (P=0.002) and decreased HDL cholesterol concentrations (P=0.03); raised alpha-1-antitrypsin (P=0.002), lupus anticoagulant (P=0.007), and homocysteine levels (P=0.03); more frequent osteoporosis (P=0.03); and a higher cumulative prednisolone dose (P=0.05) compared with SLE controls. Disease duration, smoking, blood pressure, body mass index, and diabetes mellitus did not differ significantly between the groups. CONCLUSIONS: alpha set of distinct CVD risk factors separate SLE cases from SLE controls and population controls. If confirmed in a prospective study, they could be used to identify SLE patients at high risk for CVD in order to optimize treatment. PMID- 11602490 TI - Selective serotonin reuptake inhibitors and myocardial infarction. AB - BACKGROUND: Depression is an independent risk factor for myocardial infarction (MI). Selective serotonin reuptake inhibitors (SSRIs) may reduce this risk through attenuation of serotonin-mediated platelet activation in addition to treatment of depression itself. METHODS AND RESULTS: case-control study of first MI in smokers 30 to 65 years of age was conducted among all 68 hospitals in an 8 county area during a 28-month period. Cases were patients hospitalized with a first MI. Approximately 4 community control subjects per case were randomly selected from the same geographic area using random digit dialing. Detailed information regarding use of antidepressant medication as well as other clinical and demographic data were obtained by telephone interview. A total of 653 cases of first MI and 2990 control subjects participated. After adjustment, using multivariable logistic regression, for age, sex, race, education, exercise, quantity smoked per day, body mass index, aspirin use, family history of MI, number of physician encounters, and history of coronary disease, diabetes, hypertension, or hypercholesterolemia, the odds ratio for MI among current SSRI users compared with nonusers was 0.35 (95% CI 0.18, 0.68; P<0.01). Non-SSRI antidepressant users had a nonsignificant reduction in MI risk with wide confidence intervals (adjusted odds ratio 0.48, CI 0.17, 1.32; P=0.15). However, analysis of this group was limited by the small number of exposed subjects. CONCLUSIONS: The use of SSRIs may confer a protective effect against MI. This could be attributable to the inhibitory effect SSRIs have on serotonin-mediated platelet activation or possibly amelioration of other factors associated with increased risk for MI in depression. PMID- 11602487 TI - Cholesterol in vascular and valvular calcification. PMID- 11602491 TI - Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. AB - BACKGROUND: Loss of interstitial collagen, particularly type I collagen, the major load-bearing molecule of atherosclerotic plaques, renders atheroma prone to rupture. Initiation of collagen breakdown requires interstitial collagenases, a matrix metalloproteinase (MMP) subfamily consisting of MMP-1, MMP-8, and MMP-13. Previous work demonstrated the overexpression of MMP-1 and MMP-13 in human atheroma. However, no study has yet evaluated the expression of MMP-8, known as "neutrophil collagenase," the enzyme that preferentially degrades type I collagen, because granulocytes do not localize in plaques. METHODS AND RESULTS: Transcriptional profiling and reverse transcription-polymerase chain reaction analysis revealed inducible expression of MMP-8 transcripts in CD40 ligand stimulated mononuclear phagocytes. Western blot analysis demonstrated that 3 atheroma-associated cell types, namely, endothelial cells, smooth muscle cells, and mononuclear phagocytes, expressed MMP-8 in vitro upon stimulation with proinflammatory cytokines such as interleukin-1beta, tumor necrosis factor-alpha, or CD40 ligand. MMP-8 protein elaborated from these atheroma-associated cell types migrated as 2 immunoreactive bands, corresponding to the molecular weights of the zymogen and the active molecule. Extracts from atherosclerotic, but not nondiseased arterial tissue, contained similar immunoreactive bands. Moreover, all 3 cell types expressed MMP-8 mRNA and protein in human atheroma in situ. Notably, MMP-8 colocalized with cleaved but not intact type I collagen within the shoulder region of the plaque, a frequent site of rupture. CONCLUSIONS: These data point to MMP-8 as a previously unsuspected participant in collagen breakdown, an important determinant of the vulnerability of human atheroma. PMID- 11602492 TI - Dysfunctional endothelial nitric oxide biosynthesis in healthy smokers with impaired endothelium-dependent vasodilatation. AB - BACKGROUND: The mechanisms involved in the dysfunction of both endothelium dependent vasodilatation (EDV) and NO biosynthesis related to smoking are unclear. In this study, EDV was assessed in healthy smokers and nonsmokers in vivo and, using serum from the same individuals, was related to the NO biosynthetic pathway in vitro. METHODS AND RESULTS: Flow-mediated EDV of the brachial artery was measured in 23 male patients (8 nonsmokers and 15 smokers). Serum was collected, added to confluent ( approximately 85%) monolayers of human umbilical vein endothelial cells (HUVECs), and incubated for 12 hours. Basal and substance P-stimulated NO production was measured. The HUVECs used for measuring basal NO production were lysed, and both endothelial NO synthase (eNOS) protein expression and eNOS activity were determined. EDV was lower in smokers compared with nonsmokers (P<0.001). HUVECs treated with serum from smokers compared with nonsmokers showed significantly lower basal (P<0.0001) and stimulated (P<0.02) NO production, higher eNOS expression (P<0.0001), but lower eNOS activity (P<0.004). There was a significant positive correlation between in vivo EDV and in vitro substance P-stimulated NO production (rho=0.57, P<0.01) and between basal NO production and eNOS activity (r=0.54, P<0.008) and a negative correlation between basal NO production and eNOS protein expression (r=-0.60, P<0.003). CONCLUIONS: This is the first study to combine an in vivo model with a near-physiological in vitro model to demonstrate an association between decreased NO production and reduced EDV. Cigarette smoking was associated with reduced EDV, NO generation, and eNOS activity in the presence of increased eNOS protein expression. PMID- 11602493 TI - Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. AB - BACKGROUND: An attenuated heart rate recovery after exercise has been shown to be predictive of mortality. In prior studies, recovery heart rates were measured while patients were exercising lightly, that is, during a cool-down period. It is not known whether heart rate recovery predicts mortality when measured in the absence of a cool-down period or after accounting for left ventricular systolic function. METHODS AND RESULTS: We followed 5438 consecutive patients without a history of heart failure or valvular disease referred for exercise echocardiography for 3 years. Heart rate recovery was defined as the difference in heart rate between peak exercise and 1 minute later; a value /=0.94 or 16 atm was achieved. IVUS was then performed. FFR was measured with a coronary pressure wire with intracoronary adenosine to induce hyperemia. The diagnostic characteristics of an FFR <0.94 to predict suboptimal stent expansion by IVUS, defined in both absolute and relative terms, were calculated. Over a range of IVUS criteria, the highest sensitivity, specificity, and predictive accuracy of FFR were 80%, 30%, and 42%, respectively. Receiver operator characteristic analysis defined an optimal FFR cut point at >/=0.96; at this threshold, the sensitivity, specificity, and predictive accuracy of FFR were 75%, 58%, and 62%, respectively (P=0.03 for comparison of predictive accuracy, P=0.01 for concordance between FFR and IVUS). The negative predictive value was 88%. Significantly better diagnostic performance was achieved in a subgroup that received higher doses (>30 microgram) of intracoronary adenosine during pressure measurements, suggesting that FFR might be overestimated in the other group. CONCLUSIONS: A fractional flow reserve <0.96, measured after stent deployment, predicts a suboptimal result based on validated intravascular ultrasound criteria; however, an FFR >/=0.96 does not reliably predict an optimal stent result. Higher doses of intracoronary adenosine than previously used to measure FFR improve these results. PMID- 11602495 TI - Treatment of isolated systolic hypertension is most effective in older patients with high-risk profile. AB - BACKGROUND: Although present guidelines suggest that treatment of hypertension is more effective in patients with multiple risk factors and higher risk of cardiovascular events, this hypothesis was never verified in older patients with systolic hypertension. METHODS AND RESULTS: Using data from the Systolic Hypertension in the Elderly Program, we calculated the global cardiovascular risk score according to the American Heart Association Multiple Risk Factor Assessment Equation in 4,189 participants free of cardiovascular disease (CVD) and in 264 participants with CVD at baseline. In the placebo group, rates of cardiovascular events over 4.5 years were progressively higher according to higher quartiles of CVD risk. The protection conferred by treatment was similar across quartiles of risk. However, the numbers needed to treat (NNTs) to prevent one cardiovascular event were progressively smaller according to higher cardiovascular risk quartiles. In participants with baseline CVD, the NNTs to prevent one cardiovascular event were similar to those estimated for CVD-free participants in the highest-risk quartile. CONCLUSIONS: Treatment of systolic hypertension is most effective in older patients who, because of additional risk factors or prevalent CVD, are at higher risk of developing a cardiovascular event. These patients are prime candidates for antihypertensive treatment. PMID- 11602496 TI - Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. AB - BACKGROUND: Recent studies demonstrated an influence of atherosclerotic risk factors on the progression of aortic valve stenosis. The extent of aortic valve calcification (AVC) was also found to be a strong predictor of stenosis progression. We investigated the influence of the LDL cholesterol level (LDL), other standard cardiovascular risk factors, and the extent of coronary calcification (CC) on the progression of AVC quantified by electron beam tomography (EBT). METHODS AND RESULTS: In 104 patients (64.7+/-8 years, 89 male) with an EBT scan positive for AVC, CC and AVC were quantified using a volumetric score. EBT was repeated at a mean interval of 15 months (10 to 36 months), and the progression of AVC and CC was determined. Patients were divided into 2 groups according to LDL: group 1, LDL3.36 mmol/L (130 mg/dL), 47 patients. Mean values for CC were 546+/-932 mm(3) in scan 1 and 665+/-1085 mm(3) in scan 2 for AVC 324+/-796 mm(3) and 404+/-1076 mm(3), respectively. The mean progression of CC was 27+/-37% (group 1, 16+/-22%; group 2, 39+/-46%, P80% at E13.5. The most apparent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM(+/-) mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production. CONCLUSIONS: AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production. PMID- 11602504 TI - High-density lipoproteins and endothelial function. AB - Elevated plasma levels of HDL cholesterol or apolipoprotein A-I, the major protein moiety of HDL particles, are protective against coronary artery disease. HDL particles remove cholesterol from peripheral cells and transfer it to the liver for bile acid synthesis. The interaction between lipoproteins is not mediated through simple contact between 2 phospholipid membranes but involves specific protein-receptor interactions, charged phospholipid-phospholipid contact, and activation of cellular signaling pathways. These lead to regulation of genes or the modification of proteins involved in vasomotor function, platelet activation, thrombosis and thrombolysis, cell adhesion, apoptosis and cell proliferation, and cellular cholesterol homeostasis. PMID- 11602505 TI - Ischemic pain in aortic regurgitation. PMID- 11602506 TI - Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. PMID- 11602507 TI - Coil embolization of a periprosthetic mitral valve leak associated with severe hemolytic anemia. PMID- 11602508 TI - Cardiovascular news. US uninsured rate at 14%, but Bush administration prepares for many to lose insurance. PMID- 11602509 TI - Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. AB - The in vitro inhibitory effects of gemfibrozil on cytochrome P450 (CYP) 1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2C19 (S-mephenytoin 4'-hydroxylation), CYP2D6 (dextromethorphan O-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (midazolam 1'-hydroxylation) activities were examined using pooled human liver microsomes. The in vivo drug interactions of gemfibrozil were predicted in vitro using the [I]/([I] + K(i)) values. Gemfibrozil strongly and competitively inhibited CYP2C9 activity, with a K(i) (IC(50)) value of 5.8 (9.6) microM. In addition, gemfibrozil exhibited somewhat smaller inhibitory effects on CYP2C19 and CYP1A2 activities, with K(i) (IC(50)) values of 24 (47) microM and 82 (136) microM, respectively. With concentrations up to 250 microM, gemfibrozil showed no appreciable effect on CYP2A6, CYP2D6, CYP2E1, and CYP3A4 activities. Based on [I]/([I] + K(i)) values calculated using peak total (or unbound) plasma concentration of gemfibrozil, 96% (56%), 86% (24%), and 64% (8%) inhibition of the clearance of CYP2C9, CYP2C19, and CYP1A2 substrates could be expected, respectively. In conclusion, gemfibrozil inhibits the activity of CYP2C9 at clinically relevant concentrations, and this is the likely mechanism by which gemfibrozil interacts with CYP2C9 substrate drugs, such as warfarin and glyburide. Gemfibrozil may also impair clearance of CYP2C19 and CYP1A2 substrates, but inhibition of other CYP isoforms is unlikely. PMID- 11602510 TI - Characterization of dextromethorphan O- and N-demethylation catalyzed by highly purified recombinant human CYP2D6. AB - The O-demethylation of dextromethorphan to dextrorphan in humans is catalyzed primarily by cytochrome P450 2D6 (CYP2D6). However, contrary to conventional wisdom, preparations of recombinant cytochrome P450 (P450) expressed from CYP2D6*1 cDNA also appear to produce significant amounts of 3-methoxymorphinan, the N-demethylated metabolite of dextromethorphan, when assayed in vitro. We hypothesized that both pathways were intrinsic to 2D6 and here further examine the kinetics of formation using a highly purified preparation of CYP2D6 in a reconstituted lipid system. Purified CYP2D6 protein with a measured molecular weight of 55772.0 (55769.6 Da predicted) was reconstituted into an active, lipid vesicle environment with purified rat cytochrome P450 reductase before the addition of substrate and NADPH. Reaction kinetics were followed, and apparent Michaelis-Menten constants were determined for the appearance of each metabolite by high-pressure liquid chromatography, using both UV and fluorescence detection. In a 2-min assay, purified 2D6 catalyzed the formation of dextrorphan with an apparent K(m) value of 1.9 +/- 0.2 microM and a V(max) value of 8.5 +/- 0.2 nmol/nmol of P450/min and measured simultaneously the formation of 3 methoxymorphinan with an apparent K(m) value of 5000 +/- 700 microM and V(max) value of 176 +/- 12 nmol (nmol of P450)(-1) min(-1). These results indicate that at least two distinct binding orientations exist for dextromethorphan within the active site of CYP2D6. PMID- 11602512 TI - Importance of amine pKa and distribution coefficient in the metabolism of fluorinated propranolol derivatives. Preparation, identification of metabolite regioisomers, and metabolism by CYP2D6. AB - A series of 1"-mono-, di-, and trifluorinated analogs of propranolol and related steric congeners was prepared, and their metabolism was examined in recombinant expressed CYP2D6. The structural changes in this series of compounds, principally added fluorines and methyl groups in the 1"-position of the N-isopropyl group, provided compounds that varied in pK(a) by more than 5 log units and also varied in lipophilicity and in steric size. Products of both aromatic hydroxylation and N-dealkylation were observed in the metabolic experiments. The regiochemistry of aromatic hydroxylation at the 4'- and 5'-positions was assigned based on high pressure liquid chromatography, fluorescence, and mass spectral characteristics of the products and standards. Correlations of the metabolic kinetic parameters K(m) and catalytic efficiency (k(cat)/K(m)) with substituent parameters of the added groups showed that increased basicity (higher pK(a) values) was associated with increased enzyme affinity (low K(m) values) and increased catalytic efficiency. More basic methyl-substituted compounds showed higher affinities for CYP2D6 than the structurally analogous less basic fluorinated congeners, indicating the decrease in affinity of the fluorinated compounds was not due to the size of the N-alkyl substituent. Correlations with log D reflected the degree of ionization and showed that the less lipophilic substrates (more basic compounds) had higher affinity for CYP2D6. These results are consistent with the proposal in the literature that ion pairing of the protonated amine of the substrate with Asp301 in the active site of CYP2D6 is very important to substrate affinity. PMID- 11602511 TI - Cytochromes P450 and flavin monooxygenases--targets and sources of nitric oxide. AB - This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 01 meeting in Orlando, FL. The presentations addressed the mechanisms of inhibition and regulation of cytochrome P450 and flavin monooxygenase enzymes by nitric oxide. They also highlighted the consequences of these effects on metabolism of drugs and volatile amines as well as on important physiological parameters, such as control of blood pressure, renal ion transport, and steroidogenesis. This is achieved via regulation of P450-dependent prostacyclin, hydroxyeicosatetraenoic acid, and epoxyeicosatrienoic acid formation. Conversely, the mechanisms and relative importance of nitric oxide synthases and P450 enzymes in NO production from endogenous and synthetic substrates were also addressed. PMID- 11602513 TI - Importance of amine pKa and distribution coefficient in the metabolism of fluorinated propranolol analogs: metabolism by CYP1A2. AB - A series of 1"-mono-, di-, and trifluorinated analogs of propranolol and related steric congeners was prepared, and their metabolism was examined with recombinant expressed CYP1A2. The structural changes in this series of compounds, principally added fluorines and methyl groups in the 1"-position of the N-isopropyl group, provided compounds that varied in pK(a) by more than 5 log units, in log D by 3 log units, and in size of the added substituents. N-Dealkylation and aromatic hydroxylation (formation of the 4'- and 5'-regioisomers) were catalyzed by CYP1A2. Correlations of the metabolic kinetic parameters K(m) and catalytic efficiency (k(cat)/K(m)) with physicochemical properties pK(a) and log D showed that increased lipophilicity (higher log D values) was associated with increased affinity (lower K(m)) and increased catalytic efficiency for CYP1A2. Comparison of log K(m) and log k(cat)/K(m) with pK(a) showed that the less basic analogs had higher affinities and increased catalytic efficiencies. The changes associated with pK(a) reflect increased lipid partitioning of substrate (increased log D) caused by an increase in the proportion of nonionized substrate. Increased steric bulk in the N-substituent alone did not decrease substrate affinity for CYP1A2 but did increase the amount of aromatic hydroxylation versus N-dealkylation. Removal of the hydroxyl group from the propanolamine side chain of propranolol resulted in a similar change in regioselectivity of metabolism. PMID- 11602514 TI - Differential metabolism of 1,1-dichloroethylene in livers of A/J, CD-1, and C57BL/6 mice. AB - 1,1-Dichloroethylene (DCE) causes hepatocellular necrosis that preferentially affects centrilobular hepatocytes. The cytotoxic lesion has been attributed to DCE oxidation mediated mainly by CYP2E1, resulting in formation of reactive intermediates including the DCE epoxide. Here, we have tested the hypothesis that differing levels of hepatic CYP2E1 in A/J, CD-1, and C57BL/6 (B6) mice lead to differences in magnitudes of DCE metabolism and severities of hepatotoxicity. Our results showed that amounts of the CYP2E1 protein were higher in A/J mice than in B6 and CD-1 mice. Covalent binding of DCE to liver proteins was variable in the three strains of mice and was higher in A/J than in B6 mice; intermediate levels were found in CD-1 mice. Levels of a DCE epoxide-derived glutathione conjugate detected in liver cytosol correlated with those present in bile extracts and were significantly higher in A/J than in CD-1 and B6 mice. Immunohistochemical studies showed that formation of DCE epoxide-cysteine protein adducts was enhanced in the livers of A/J mice, compared with those produced in the livers of CD-1 and B6 mice. Similarly, centrilobular necrosis was more severe in the livers of A/J mice than in those in either CD-1 or B6 mice. Levels of glutathione were similar in the three strains of untreated mice and were diminished at comparable levels in all mice. These results indicated that high expression of hepatic CYP2E1 in A/J mice coincided with increased DCE metabolism and enhanced severity of hepatotoxicity, relative to those in CD-1 and B6 mice. PMID- 11602515 TI - Pharmacokinetics and metabolism of a cysteinyl leukotriene-1 receptor antagonist from the heterocyclic chromanol series in rats: in vitro-in vivo correlation, gender-related differences, isoform identification, and comparison with metabolism in human hepatic tissue. AB - CP-199,331 is a potent antagonist of the cysteinyl leukotriene-1 (LT(1)) receptor, targeted for the treatment of asthma. The pharmacokinetic/metabolism properties of CP-199,331 were studied in rats and compared with those in human liver microsomes/hepatocytes. In vitro biotransformation of CP-199,331 in rat and human hepatocytes was similar, consisting primarily of CP-199,331 O demethylation. Marked sex-related differences in plasma clearance (CL(p)) of CP 199,331 were observed in rats: 51 and 1.2 ml/min/kg in males and females, respectively. This difference in CL(p) was attributed to gender differences in metabolizing capacity because V(max) and K(m) values for CP-199,331 metabolism were 30-fold higher and 8-fold lower, respectively, in male rat liver microsomes compared with female microsomes. Scale-up of the in vitro microsomal data predicted hepatic clearance (CL(h)) of 64 and 2.5 ml/min/kg in male and female rats, respectively. These values were in close agreement with the in vivo CL(p), suggesting that CP-199,331 CL(p) in male and female rats was entirely due to hepatic metabolism. Studies with rat recombinant cytochromes P450 and anti-rat cytochrome P450 (CYP) antibodies revealed the involvement of male rat-specific CYP2C11 in the metabolism of CP-199,331. In contrast, CP-199,331 metabolism in human liver microsomes was principally mediated by CYP3A4. The projected human clearance in liver microsomes and hepatocytes varied 6-fold from low to moderate, depending on CYP3A4 activity. Considering that O-demethylation is the major route of elimination in humans, the in vivo clearance of CP-199,331 may exhibit moderate variability, depending on CYP3A4 abundance in the human population. PMID- 11602517 TI - Absorption, distribution, metabolism, and excretion considerations in selection of orally active indole-containing endothelin antagonist. AB - A series of potent indole-containing endothelin antagonists were evaluated in rat pharmacokinetic studies as part of a rational drug design program. Early compounds in this series were found to show poor gastrointestinal absorption, limiting their utility as oral agents. Structural modifications and pharmacokinetic studies indicated that reducing the overall H-bonding potential, through a reduction in the number of H-bond donors and acceptors, could increase absorption of the molecules. There was a correlation between calculated H-bonding capacity and rate of permeability across Caco-2 monolayers for this series of compounds. Caco-2 permeability was also shown to be indicative of the estimated extent of absorption in rats. Balancing the requirements of absorption and systemic clearance lead to the selection of an alcohol-containing compound, compound 7a (single enantiomer of compound 7) that was moderately absorbed after oral administration and converted to an active acid metabolite, which itself was of low intrinsic clearance. Species differences were observed between the absorption of compound 7a in rat and dog and also in the extent of conversion to the acid metabolite. Absorption was estimated at 30% in rat and 100% in dog. Approximately 30% of the absorbed drug was converted to systemically available acid metabolite in rat, compared with only 3% in dog. PMID- 11602518 TI - Caffeic acid, chlorogenic acid, and dihydrocaffeic acid metabolism: glutathione conjugate formation. AB - The antioxidant properties of the dietary dihydroxycinnamic acids [caffeic (CA), dihydrocaffeic (DHCA), and chlorogenic (CGA) acids] have been well studied but little is known about their metabolism. In this article, evidence is presented showing that CA, DHCA, and CGA form quinoids and hydroxylated products when oxidized by peroxidase/H(2)O(2) or tyrosinase/O(2). Mass spectrometry analyses of the metabolites formed with peroxidase/H(2)O(2)/glutathione (GSH) revealed that mono- and bi-glutathione conjugates were formed for all three compounds except CGA, which formed a bi-glutathione conjugate only when GSH was present. In contrast, the metabolism of the dihydroxycinnamic acids by tyrosinase/O(2)/GSH resulted in the formation of only mono-glutathione conjugates. In the absence of GSH, hydroxylated products and p-quinones of CA or CGA were formed by peroxidase/H(2)O(2). DHCA formed a hydroxylated adduct (even though GSH was present), as well as the corresponding p-quinone and dihydroesculetin, an intramolecular cyclization product. NADPH also supported rat liver microsomal catalyzed CA-, CGA-, and DHCA-glutathione conjugate formation, which was prevented by benzylimidazole, a cytochrome P450 inhibitor. Furthermore, the cytotoxicity of CA, CGA, and DHCA toward isolated rat hepatocytes was markedly enhanced by hydrogen peroxide or cumene hydroperoxide-supported cytochrome P450 and was prevented by benzylimidazole. Cytotoxicity was also markedly enhanced by dicumarol, an NADPH/oxidoreductase inhibitor. These results suggest that dihydroxycinnamic acids were metabolically activated by P450 peroxidase activity to form cytotoxic quinoid metabolites. PMID- 11602519 TI - Identification of new derivatives of sinigrin and glucotropaeolin produced by the human digestive microflora using 1H NMR spectroscopy analysis of in vitro incubations. AB - One- and two-dimensional (1)H NMR spectroscopy were used to study the biotransformation of two dietary glucosinolates, sinigrin (SIN), and glucotropaeolin (GTL) by the human digestive microflora in vitro. The molecular structures of the new metabolites issued from the aglycone moiety of the glucosinolate were identified, and the modulation of carbon metabolism was studied by quantifying bacterial metabolites issued from the xenobiotic incubation in the presence or absence of a source of free glucose. Unambiguously and for the first time, it was shown that SIN and GTL were transformed quantitatively into allylamine and benzylamine, respectively. The comparison of the kinetics of transformation of SIN and GTL with and without glucose clearly showed that the presence of glucose did not modify either the nature of the metabolites or the rate of transformation of the glucosinolates (complete degradation within 30 h). The main end products of the glucose moiety of glucosinolates were characteristic of anaerobic carbon metabolism in the digestive tract (acetate, lactate, ethanol, propionate, formate, and butyrate) and similar to those released from free glucose. This work represents the first application of (1)H NMR spectroscopy to the study of xenobiotic metabolism by the human digestive microflora, demonstrating allyl- and benzylamine production from glucosinolates. Whether these amines are produced in vivo from dietary glucosinolates remains to be established. This would reduce the availability of other glucosinolate metabolites, notably cancer-protective isothiocyanates. PMID- 11602516 TI - Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19. AB - Hybridomas were isolated that produce 13 monoclonal antibodies (mAbs) that are specific and highly inhibitory to members of the human P450 2C subfamily, 2C8, 2C9, 2C9*2, and 2C19. Many of the mAbs to P450 2C8, 2C9, and 2C19 are specific and exhibit potent inhibitory activity (85-95%). mAb 281-1-1 specifically binds, immunoblots, and strongly inhibits the activity of P450 2C8. mAb 763-15-5 specifically binds and strongly inhibits the activity of P450 2C9. mAb 1-7-4-8 specifically binds and strongly inhibits the activity of P450 2C19. The other mAbs bind and inhibit sets and subsets of the P450 2C family. The single and the combinatorial use of the mAbs can "reaction phenotype", i.e., determine the metabolic contribution and interindividual variation of a P450 isoform for the metabolism of a drug or nondrug xenobiotic in human liver microsomes. The utility of the mAb-based analytic system was examined with the model substrates Taxol (paclitaxel), diazepam, tolbutamide, diclofenac, mephenytoin, and imipramine. The mAb system can identify drugs metabolized by a common P450 or several P450s and polymorphic P450s. The mAb system identifies drugs or drug metabolic pathways that are catalyzed by a single P450 and thus may be used for in vivo phenotyping. The mAb system can identify whether a particular drug is metabolized by a single P450 that may exhibit polymorphic expression in humans. The mAb system offers large potential for studies of cytochrome P450 function useful in drug discovery and reduces the possibility of adverse drug reactions due to polymorphisms and drug interactions. PMID- 11602520 TI - Induction of CYP3A4 by 1 alpha,25-dihydroxyvitamin D3 is human cell line-specific and is unlikely to involve pregnane X receptor. AB - Under certain culture conditions, exposure of the human colon adenocarcinoma cell line Caco-2 to 1,25-(OH)(2)-D(3) induces expression of CYP3A4 to levels comparable to that in human small intestinal epithelium. To determine whether 1,25-(OH)(2)-D(3) could be used to restore CYP3A expression in other culture models, we examined several cell lines derived from malignancies of human tissues known to express CYP3A enzymes: Hep G2 (liver), LS180 (colon), HPAC (pancreas), Hs746T (stomach). Primary cultures of human hepatocytes from two donors were also examined. 1,25-(OH)(2)-D(3) increased CYP3A catalytic activity in LS180 (15 fold), HPAC (6-fold), and hepatocytes (2- to 3-fold); this was accompanied by induction of CYP3A4 mRNA and CYP3A immunoreactive protein. However, 1,25-(OH)(2) D(3) had no effect on CYP3A expression in Hs746T or Hep G2. Known ligands for pregnane X receptor (PXR) (rifampin, dexamethasone, and dexamethasone t-butyl acetate) markedly induced CYP3A4 expression in human hepatocytes. In contrast, these ligands had little or no effect on CYP3A4 expression in Caco-2 cells, even at concentrations 1 to 2 orders of magnitude greater than effective concentrations of 1,25-(OH)(2)-D(3) or two other vitamin D receptor (VDR) ligands (25-OH-D(3) and 1-OH-D(3)). The retinoic acid receptor ligand all-trans-retinoic acid augmented the 1,25-(OH)(2)-D(3)-mediated induction of CYP3A4 catalytic activity up to 2-fold in Caco-2 cells, while having no demonstrable effect on levels of CYP3A4 mRNA or protein. The retinoid X receptor ligand 9-cis-retinoic acid appeared to slightly reduce CYP3A4 catalytic activity. We conclude that 1,25 (OH)(2)-D(3) can be used to increase CYP3A4 expression in some, but not all, human cell lines derived from tissues known to express CYP3A enzymes. The mechanisms involved in this induction are unlikely to involve PXR and may involve VDR. PMID- 11602521 TI - Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. AB - Between 45 and 60% of all drugs currently used are metabolized by the CYP3A4 protein. CYP3A4 expression in liver varies up to 60-fold in the general population, which can lead to ineffective drug therapy (high CYP3A4) or, on the other hand, to harmful drug reactions (low CYP3A4). Most of this variability has been attributed to genetic factors, but to date their identity remains unknown. Recently, it was shown that CYP3A expression is largely controlled by the pregnane X receptor (PXR). We, therefore, hypothesized that polymorphisms in PXR may contribute to CYP3A4 variability. The presence of PXR variants was investigated in two ethnic groups, Caucasians and Africans. Six missense mutations leading to variant PXR proteins were identified, and their consequences on CYP3A4 expression were analyzed. Expressed in LS174T cells, three protein variants, V140M, D163G, and A370T, exhibited altered basal and/or induced transactivation of CYP3A promoter reporter genes. Thus, these natural PXR protein variants may play a role in the observed interindividual variability of CYP3A4 expression and may be involved in rare, atypical responses to drugs or altered sensitivities to carcinogens. PMID- 11602522 TI - Blood thiols following amifostine and mesna infusions, a pediatric oncology group study. AB - The Pediatric Oncology Group study for metastatic Ewing's sarcoma used amifostine and mesna with the alkylating agents. To determine the fate of combined drug thiols, we measured thiol levels in plasma, red blood cells (RBC), and peripheral blood mononuclear cells (PBMC) of four patients. We also conducted analogous measurements on two patients who received mesna alone and a volunteer's blood following in vitro treatment. Thiols were labeled with monobromobimane, separated on high-pressure liquid chromatography, and detected by fluorescence. Incubation of a volunteer's blood with mesna, WR-1065, or both revealed that cellular uptake of total reducible drug was approximately 10% of plasma level for mesna but approximately 60% for WR-1065. Cellular drugs were mainly the thiol form, whereas half of the plasma drugs were disulfides. Combined incubation with both thiols did not change the extent or form of uptake. WR-1065 and mesna prevented glutathione depletion by 4-hydroperoxycyclophosphamide. Results from patients were similar. WR-1065 and mesna appeared in the cells by the end of the drug infusions, although WR-1065 uptake was more efficient than mesna. The concentration-time profiles of mesna in RBC paralleled those in plasma. Amifostine administration during mesna infusion caused transient increase in mesna levels. Both agents increased blood cysteine and decreased total reducible cysteine. Mesna alone and mesna plus amifostine prevented cellular glutathione depletion. In conclusion, mesna is imported by RBC and PBMC, but less efficiently than WR-1065. When present at equal levels, these thiols do not influence each other's uptake. Adequate dosing of either drug is necessary for protecting the cells from toxic effects of alkylating agents. PMID- 11602523 TI - Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor. AB - Identification and characterization of the pregnane X receptor (PXR) as a key regulator of cytochrome P450 3A (CYP3A) gene expression has led to an increased understanding of the molecular basis of many drug-drug interactions. Mice lacking PXR (PXR-KO) were used in the present study to delineate the role of PXR in regulating hepatomegaly and regulating the activity of CYP3A, organic anion transporting polypeptide-2 (Oatp2), and Cyp7a1 (cholesterol 7alpha-hydroxylase) gene products in vivo. Pregnenolone-16alpha-carbonitrile (PCN) produced hepatomegaly in the wild-type mice but not in the PXR-KO mice. PCN increased both the number of proliferating cell nuclear antigen immuno-positive nuclei and apparent cell size in the wild-type mice but not in the PXR-KO mice. To determine the role PXR plays in regulating CYP3A activity, 6beta-hydroxylation of testosterone and the duration of the loss of righting reflex following administration of the muscle-relaxant zoxazolamine were measured. PCN increased the level of testosterone 6beta-hydroxylation and decreased the duration of the loss of righting-reflex time following zoxazolamine administration in wild-type mice, but did not effect either of these parameters in PXR-KO mice. PCN increased the hepatic uptake of [(3)H]digoxin, an Oatp2 substrate, in wild-type mice but not in the PXR-KO mice. Similarly, PCN decreased bile acid excretion in wild-type mice but not in the PXR-KO mice. Taken together, these data demonstrate a pivotal role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo. PMID- 11602524 TI - Testosterone, 7-benzyloxyquinoline, and 7-benzyloxy-4-trifluoromethyl-coumarin bind to different domains within the active site of cytochrome P450 3A4. AB - Testosterone, 7-benzyloxyquinoline, and 7-benzyloxy-4-trifluoromethyl-coumarin, marker substrates for cytochrome P450 3A4 are commonly used within the pharmaceutical industry to screen new chemical entities as inhibitors of CYP3A4 in a high-throughput manner to predict the potential for drug-drug interactions. However, it has been observed that inhibition data obtained with a given CYP3A4 probe substrate may not correlate well with results from a different probe. As a consequence, the choice of the probe compound becomes an important consideration in such screens. In the present study, kinetic interactions between either two of the above three substrates were evaluated, and three-dimensional nonlinear regression analysis was performed to understand the kinetic mechanisms of drug interaction. Our results demonstrate that the kinetic interaction between each pair of substrates does not appear to be competitive and that the interactions are characterized by an unchanged or a decrease in both apparent K(m) (a = 0.21 0.72, a change of K(m) in the absence of the effector) and V(max) (alpha and beta = 0.09-0.75, changes of V(max) in the absence of the effector). These data suggest that 1) the three substrates bind to different domains; 2) at least two substrates can coexist in the active site of CYP3A4; and 3) the two bound substrates interact kinetically with each other (e.g., through steric hindrance), thereby leading to a change in both apparent kinetic parameters and partial inhibition. Selection of multiple substrates, which are shown not to be competitive, is necessary to accurately predict CYP3A4 inhibition and the potential for drug-drug interaction. PMID- 11602525 TI - CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's disease, as revealed from experiments with recombinant enzymes. AB - In view of conflicting data in the literature regarding the enzyme(s) responsible for metabolism of selegiline, a drug used in the treatment of Parkinson's disease, investigations were carried out in vitro using the human cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 recombinantly expressed in yeast to elucidate the enzyme specificity in selegiline metabolism. In the yeast microsomes used, desmethylselegiline and levomethamphetamine were formed from selegiline at significant rates. The highest contribution to the hepatic clearance of selegiline was calculated to be exerted by CYP2B6 (124 l/h) CYP2C19 (82 l/h), whereas CYP3A4 (27 l/h) and CYP1A2 (21 l/h) were of less importance. Antibodies against CYP2B6 inhibited metabolism of selegiline in microsomes containing CYP2B6 but not in microsomes without significant amounts of the enzyme. In contrast to previous reports, we could not find any role for CYP2D6 in the metabolism of selegiline. The data strongly indicate that the high extent of interindividual variation seen in vivo for selegiline clearance is caused by the metabolism of the compound by the highly polymorphic CYP2B6 and CYP2C19. PMID- 11602526 TI - Oxidation mechanism of 7-hydroxy-delta 8-tetrahydrocannabinol and 8-hydroxy-delta 9-tetrahydrocannabinol to the corresponding ketones by CYP3A11. AB - A cDNA isolated from a C57BL/6 mouse liver cDNA library had the identical nucleotide sequence in coding region with the mouse CYP3A11, and the NH(2) terminal sequence was also identical to that of cytochrome P450 (P450) MDX-B, a microsomal alcohol oxygenase. The COS-7 cells transfected with the CYP3A11 expression vector formed 7-oxo-Delta(8)-tetrahydrocannabinol (7-oxo-Delta(8)-THC) from 7alpha- and 7beta-hydroxy-Delta(8)-THC. An immunologically related protein with P450 MDX-B was expressed in the COS-7 cell microsomes. The cell microsomes expressed CYP3A11; COS-3A11 catalyzed the oxidation of 7-hydroxy-Delta(8)-THC and 8-hydroxy-Delta(9)-THC to 7-oxo-Delta(8)-THC and 8-oxo-Delta(9)-THC, respectively, in a reconstituted system. (18)O derived from atmospheric oxygen was incorporated into about 30% of the corresponding ketones formed from 7alpha hydroxy-Delta(8)-THC and 8beta-hydroxy-Delta(9)-THC by mouse hepatic microsomes, P450 MDX-B, and COS-3A11, although incorporation of the stable isotope into the oxidized metabolites from 7beta-hydroxy-Delta(8)-THC and 8alpha-hydroxy-Delta(9) THC was negligible. (18)O, however, was not incorporated into 7-oxo-Delta(8)-THC formed from 7alpha-hydroxy-Delta(8)-THC by using cumene hydroperoxide instead of NADPH under (18)O(2). When (18)O-labeled 7alpha-hydroxy-Delta(8)-THC and 8beta hydroxy-Delta(9)-THC were incubated with above enzymes under air, about 30% of the ketones formed released (18)O from a hydroxy group at the 7 and 8 positions in the course of the oxidation. These results suggest that 7alpha-hydroxy Delta(8)-THC and 8beta-hydroxy-Delta(9)-THC may be oxidized to the corresponding ketones by CYP3A11 via a gem-diol pathway. 7beta-Hydroxy-Delta(8)-THC and 8alpha hydroxy-Delta(9)-THC may be also converted to the ketones through a stereoselective dehydration of an enzyme-bound gem-diol rather than through a direct hydrogen extraction as a peroxy form of the enzyme. PMID- 11602527 TI - Pharmacokinetics and metabolism of hydroxytyrosol, a natural antioxidant from olive oil. AB - 3,4-Dihydroxyphenylethanol (DOPET) is the major o-diphenol detectable in extra virgin olive oil, either in free or esterified form. Despite its relevant biological effects, mainly related to its antioxidant properties, little data have been reported so far on its toxicity and metabolism. The aim of the present work is to evaluate DOPET toxicity and to investigate its molecular pharmacokinetics by using the (14)C-labeled diphenol. When orally administered to rats, the molecule does not show appreciable toxicity up to 2 g/kg b.wt. To identify and quantify its metabolites, [(14)C]DOPET has been synthesized and intravenously injected in rats. The pharmacokinetic analysis indicates a fast and extensive uptake of the molecule by the organs and tissues investigated, with a preferential renal uptake. Moreover, 90% of the administered radioactivity is excreted in urine collected up to 5 h after injection, and about 5% is detectable in feces and gastrointestinal content. The characterization of the labeled metabolites, extracted from the organs and urine, has been performed by high pressure liquid chromatography analysis. In all the investigated tissues, DOPET is enzymatically converted in four oxidized and/or methylated derivatives. Moreover, a significant fraction of total radioactivity is associated with the sulfo-conjugated forms, which also represent the major urinary excretion products. On the basis of the reported results, an intracellular metabolic pathway of exogenously administered DOPET, implying the involvement of catechol-O methyltransferase, alcohol dehydrogenase, aldehyde dehydrogenase, and phenolsulfotransferase, has been proposed. PMID- 11602528 TI - Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers. AB - Regulation of the CYP3A4 gene has been studied using an in vitro reporter gene assay. The effect of 17 xenobiotics on approximately 1 kilobase of the CYP3A4 proximal promoter, upstream of a secretory placental alkaline phosphatase reporter gene was investigated following transfection into the HepG2 cell line. Transfections were carried out either in the basal system or with cotransfection of expression plasmids for the human pregnane X receptor (hPXR) and the human glucocorticoid receptor (hGR), two important receptors in the regulation of CYP3A4 gene expression. Compounds were tested at four concentrations, and the resulting data were used to calculate maximal induction (I(max)) and EC(50) values. An "overall inductive ability" (IA) was derived by dividing I(max) by EC(50). Of the compounds tested seven were established transcriptional inducers, all of which were positive in the in vitro assay. The remaining 10 compounds represented a group with preliminary evidence for CYP3A transcriptional activation. Nine of these compounds produced statistically significant inductions in vitro, with only pravastatin failing to activate the reporter gene. This is of potential interest in light of the high IA values observed with the other structurally and functionally similar statins tested. We conclude that a four concentration-point, in vitro model is capable of identifying CYP3A4 transcriptional inducers and yields an IA value allowing the ranking of compounds for their overall ability to induce CYP3A4 transcription. In addition, the majority of the compounds tested showed increased IA values in the hPXR/hGR cotransfected system, underpinning the importance of these receptors in CYP3A4 gene transcriptional regulation. PMID- 11602529 TI - A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4. AB - Irinotecan (CPT-11) is an anticancer prodrug. It is converted by carboxylesterase to yield an active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), which acts as a topoisomerase I inhibitor. Several oxidative metabolites of CPT-11 have been identified in humans, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1 piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1 piperidino)carbonyloxycamptothecin (NPC), generated by cytochrome P-450 3A4 (CYP3A4). Other minor metabolites in which metabolic pathways and biologic activities have not been identified also exist. To further investigate the metabolism of CPT-11 in human liver, we analyzed metabolites of CPT-11 in human hepatic microsomes using a high-performance liquid chromatography/mass spectrometry (HPLC/MS) system and detected a new metabolite that was the major one produced in the microsomal system. HPLC-tandem mass spectrometry (HPLC/MS/MS) analysis indicated that this compound was an oxidation product formed by the loss of two hydrogen atoms from the terminal piperidine ring. Kinetic analyses indicated that a single enzyme generated the metabolite, and we have identified this enzyme in two in vitro systems. The formation of the new metabolite was significantly inhibited by SKF525A, ketoconazole, and an anti-CYP3A4 antibody and catalyzed specifically by CYP3A4 expressed in insect microsomes. A significant correlation was observed between the generation of this metabolite and the CYP3A4 content in individual human hepatic microsomes. These findings indicate that this newly detected metabolite is a CYP3A4-generated product that may be produced in hepatic microsomes of patients treated with CPT-11. PMID- 11602530 TI - Comparative contribution to dextromethorphan metabolism by cytochrome P450 isoforms in vitro: can dextromethorphan be used as a dual probe for both CTP2D6 and CYP3A activities? AB - Dextromethorphan (DXM) is a widely used probe drug for human CYP2D6 activity both in vitro and in vivo. In humans, DXM is metabolized to dextrorphan (DXO), as well as 3-methoxymorphinan (MEM) and 3-hydroxymorphinan (HYM). The formation of MEM has been attributed primarily to CYP3A4, and the use of DXM has been debated as a simultaneous probe for CYP3A4 and CYP2D6 activities. Recently, we found that highly purified CYP2D6 has significant DXM N-demethylase activity in addition to its well known DXM O-demethylase activity. Therefore, we desired to further compare the contribution to DXM metabolism by individual human cDNA-expressed cytochromes P450, including 2C8, 2C9, 2C18, 2C19, 2D6, 2B6, and 3A4. Metabolites were quantified following separation by high-pressure liquid chromatography and apparent Michaelis-Menten constants determined for the appearance of DXO and MEM. Intrinsic clearance values were estimated for each P450 and normalized using the average percentage content and relative activity factor approaches for comparison. Simplified kinetic models (when [S] << K(m), V(max)/K(m) = V(o)/[S]) were used at fixed DXM concentrations of 20 (for DXM N-demethylation) and 0.2 microM (for DXM O-demethylation), as well as 2 microM to mimic plasma DXM concentrations in human extensive metabolizers. The results confirm that CYP2D6 contributes at least 80% to the formation of DXO, and CYP3A4 contributes more than 90% to the formation of MEM. All of our in vitro results are consistent and indicate that DXM as a marker for monitoring both CYP2D6 and CYP3A activities is practical in an average human or human liver microsomal preparation. PMID- 11602531 TI - Can cardiomyocytes divide? PMID- 11602532 TI - Coronary angiography cannot be used to assess myocardial perfusion in patients undergoing reperfusion for acute myocardial infarction. PMID- 11602533 TI - Angiographic assessment of myocardial perfusion: TIMI myocardial perfusion (TMP) grading system. PMID- 11602534 TI - Ambulances. PMID- 11602535 TI - Torsade de pointes tachycardia as a rare manifestation of acute enteroviral myocarditis. AB - A patient with cardiac arrest and documented torsade de pointes ventricular tachycardia is presented in whom acute coxsackievirus B2 myocarditis was identified as the most likely underlying cardiac condition. This case shows that torsade de pointes may occur as a rare manifestation of viral myocarditis. Serial serological tests and endomyocardial biopsies may be helpful in establishing a diagnosis in such patients. PMID- 11602536 TI - Gene therapy for coronary restenosis: is the enthusiasm justified? PMID- 11602538 TI - Aortico-atrial fistula secondary to bacterial endocarditis. PMID- 11602537 TI - Poor prognosis of patients presenting with symptomatic myocardial infarction but without chest pain. AB - OBJECTIVE: To describe the clinical features, prognosis, and treatment of patients presenting with atypical forms of acute myocardial infarction. DESIGN: Consecutive cases of possible acute myocardial infarction were sought from coronary care registers, biochemistry records, and hospital management systems. Case notes were reviewed and predefined epidemiological and clinical variables were abstracted. SETTING: 20 adjacent hospitals in the former Yorkshire region. PATIENTS: 3684 consecutive cases of possible acute myocardial infarction admitted in a three month period were identified, of whom 2096 had a first episode of confirmed acute myocardial infarction. RESULTS: 20.2% of all patients admitted with an eventual diagnosis of acute myocardial infarction presented with symptoms other than chest pain. Compared with the group presenting with chest pain, these patients were older (76.6 v 69.1 years, p < 0.001), were more often women (54.6% v 35.3%, p < 0.001), and were more likely to have a history of heart failure (18.6% v 6.9%, p < 0.001). They had a higher 30 and 365 day mortality (49.2% and 61.0%, respectively) compared with patients presenting with chest pain (17.9% and 26.2%). In a Cox regression analysis the hazard ratio for presentation without chest pain was 1.60 (95% confidence interval 1.30 to 1.97) (p < 0.001) adjusted for age, heart rate, blood pressure, left ventricular impairment, and infarction with ST segment elevation as covariates. Importantly, they were also less likely to receive treatments with a proven ability to improve prognosis. CONCLUSIONS: Atypical presentation of myocardial infarction without chest pain is common and associated with increased mortality. This may result in part from a failure to use beneficial treatment strategies. PMID- 11602540 TI - Large coiled right ventricular outflow tract thrombus resolved after thrombolytic treatment. PMID- 11602539 TI - Is the prevalence of coronary heart disease falling in British men? AB - OBJECTIVE: To assess whether long term trends over time in acute coronary heart disease (CHD) event rates have influenced the burden of prevalent CHD in British men. DESIGN: Longitudinal cohort study. PARTICIPANTS: 7735 men, aged 40-59 at entry (1978-80), selected from 24 British towns. METHODS: The prevalences of current angina symptoms and history of diagnosed CHD were ascertained by questionnaire in 1978-80, 1983-85, 1992, and 1996. New major CHD events (fatal and non-fatal) were ascertained throughout the study from National Health Service central registers and general practice record reviews. Age adjusted trends in CHD prevalence were compared with trends in major CHD event rates. RESULTS: From 1978 1996 there was a clear decline in the prevalence of current angina symptoms: the age adjusted annual percentage change in odds was -1.8% (95% confidence interval (CI) -2.8% to -0.8%). However, there was no evidence of a trend in the prevalence of history of diagnosed CHD (annual change in odds 0.1%, 95% CI -1.0% to 1.2%). Over the same period, the CHD mortality rate fell substantially (annual change 4.1%, 95% CI -6.5% to -1.6%); rates of non-fatal myocardial infarction, all major CHD events, and first major CHD event fell by -1.7% (95% CI -3.9% to 0.5%), -2.5% (95% CI -4.1% to -0.8%), and -2.4% (95% CI% -4.3 to -0.4%), respectively. CONCLUSIONS: These results suggest that middle aged British men are less likely to experience symptoms of angina than in previous decades but are just as likely to have a history of diagnosed CHD. Despite falling rates of new major events and falling symptom prevalence, the need for secondary prevention among middle aged men with established CHD is as great as ever. PMID- 11602541 TI - Ischaemic heart disease and Cag A strains of Helicobacter pylori in the Caerphilly heart disease study. AB - OBJECTIVE: To look for the presence of the more virulent strains of Helicobacter pylori (H pylori) in men who developed ischaemic heart disease over a 10 year period and in controls. DESIGN: The Caerphilly prospective heart disease study recruited 2512 men aged 45-59 years during 1979-83. Western blot analysis or enzyme linked immunosorbent assay (ELISA) was performed on serum taken from those who subsequently died of ischaemic heart disease, or developed non-fatal myocardial infarction, to determine H pylori and Cag A status. Similar information was available on age matched controls. RESULTS: During the first decade of the study, 312 men died of ischaemic heart disease or developed non fatal myocardial infarction. Serum was available from 172 of these (55%). There was no evidence of an association between Cag A seropositivity and incident ischaemic heart disease or ischaemic heart disease mortality, either before or after adjustment for potential confounders (adjusted odds ratios 1.18 (95% confidence interval (CI) 0.76 to 1.85) and 1.13 (95% CI 0.61 to 2.07), respectively). Further, the odds ratios for ischaemic heart disease incidence and ischaemic heart disease mortality by H pylori seropositivity did not appear to depend on the presence or absence of Cag A strains (p = 0.76 and 0.77, respectively). CONCLUSIONS: In this cohort of middle aged men, followed over a 10 year period, there is little evidence of an association between Cag A seropositivity and either incident ischaemic heart disease or ischaemic heart disease mortality. PMID- 11602542 TI - Dobutamine stress echocardiography versus quantitative technetium-99m sestamibi SPECT for detecting residual stenosis and multivessel disease after myocardial infarction. AB - OBJECTIVE: To compare the relative accuracy of dobutamine stress echocardiography (DSE) and quantitative technetium-99m sestamibi single photon emission computed tomography (mibi SPECT) for detecting infarct related artery stenosis and multivessel disease early after acute myocardial infarction. DESIGN: Prospective study. SETTING: University hospital. METHODS: 75 patients underwent simultaneous DSE and mibi SPECT at (mean (SD)) 5 (2) days after a first acute myocardial infarct. Quantitative coronary angiography was performed in all patients after imaging studies. RESULTS: Significant stenosis (> 50%) of the infarct related artery was detected in 69 patients. Residual ischaemia was identified by DSE in 55 patients and by quantitative mibi SPECT in 49. The sensitivity of DSE and mibi SPECT for detecting significant infarct related artery stenosis was 78% and 70%, respectively, with a specificity of 83% for both tests. The combination of DSE and mibi SPECT did not change the specificity (83%) but increased the sensitivity to 94%. Mibi SPECT was more sensitive than DSE for detecting mild stenosis (73% v 9%; p = 0.008). The sensitivity of DSE for detecting moderate or severe stenosis was greater than mibi SPECT (97% v 74%; p = 0.007). Wall motion abnormalities with DSE and transient perfusion defects with mibi SPECT outside the infarction zone were sensitive (80% v 67%; NS) and highly specific (95% v 93%; NS) for multivessel disease. CONCLUSIONS: DSE and mibi SPECT have equivalent accuracy for detecting residual infarct related artery stenosis of >/= 50% and multivessel disease early after acute myocardial infarction. DSE is more predictive of moderate or severe infarct related artery stenosis. Combined imaging only improves the detection of mild stenosis. PMID- 11602543 TI - Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study. AB - OBJECTIVES: Though atrial fibrillation (AF) is an important cause of cardiovascular morbidity, there are few large epidemiological studies of its prevalence, incidence, and risk factors. The epidemiological features of AF are described in one of the largest population cohorts ever studied. METHODS: The prevalence and incidence of AF were studied in the Renfrew/Paisley population cohort of 15 406 men and women aged 45-64 years living in the west of Scotland. This cohort was initially screened between 1972 and 1976 and again between 1977 and 1979. Incident hospitalisations with AF in the 20 year period following initial screening were also studied. RESULTS: The population prevalence of AF in this cohort was 6.5 cases/1000 examinations. Prevalence was higher in men and older subjects. In those who were rescreened, the four year incidence of AF was 0.54 cases/1000 person years. Radiological cardiomegaly was the most powerful predictor of new AF (adjusted odds ratio 14.0). During 20 year follow up, 3.5% of this cohort was discharged from hospital with a diagnosis of AF; the rate of incident hospitalisation for AF was 1.9 cases/1000 person years. Radiological cardiomegaly (adjusted odds ratio 1.46) and systolic blood pressure (adjusted odds ratio 2.1 for >/= 169 mm Hg) were independent predictors of this outcome. CONCLUSIONS: Data from one of the largest epidemiological studies ever undertaken confirm that AF has a large population prevalence and incidence, even in middle aged people. More important, it was shown that the long term incidence of hospitalisation related to AF is high and that two simple clinical measurements are highly predictive of incident AF. These findings have important implications for the prevention of AF. PMID- 11602545 TI - Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data. AB - BACKGROUND: Atrial fibrillation is the most common supraventricular arrhythmia in patients with acute myocardial infarction. Recent advances in pharmacological treatment of myocardial infarction may have changed the impact of this arrhythmia. OBJECTIVE: To assess the incidence and prognosis of atrial fibrillation complicating myocardial infarction in a large population of patients receiving optimal treatment, including angiotensin converting enzyme (ACE) inhibitors. METHODS: Data were derived from the GISSI-3 trial, which included 17 944 patients within the first 24 hours after acute myocardial infarction. Atrial fibrillation was recorded during the hospital stay, and follow up visits were planned at six weeks and six months. Survival of the patients at four years was assessed through census offices. RESULTS: The incidence of in-hospital atrial fibrillation or flutter was 7.8%. Atrial fibrillation was associated with indicators of a worse prognosis (age > 70 years, female sex, higher Killip class, previous myocardial infarction, treated hypertension, high systolic blood pressure at entry, insulin dependent diabetes, signs or symptoms of heart failure) and with some adverse clinical events (reinfarction, sustained ventricular tachycardia, ventricular fibrillation). After adjustment for other prognostic factors, atrial fibrillation remained an independent predictor of increased in-hospital mortality: 12.6% v 5%, adjusted relative risk (RR) 1.98, 95% confidence interval (CI) 1.67 to 2.34. Data on long term mortality (four years after acute myocardial infarction) confirmed the persistent negative influence of atrial fibrillation (RR 1.78, 95% CI 1.60 to 1.99). CONCLUSIONS: Atrial fibrillation is an indicator of worse prognosis after acute myocardial infarction, both in the short term and in the long term, even in an unselected population. PMID- 11602544 TI - Effects of intravenous dofetilide on induction of atrioventricular re-entrant tachycardia. AB - OBJECTIVE: To assess the efficacy and safety of intravenous dofetilide in preventing induction of atrioventricular re-entrant tachycardia. DESIGN: A multicentre, open, dose ranging trial. Fifty one patients with electrically inducible atrioventricular re-entrant tachycardia were allocated to one of five doses of dofetilide (1.5, 3, 6, 9, and 15 microgram/kg), two thirds of the dofetilide dose being given over a 15 minute loading period and the remainder over a 45 minute maintenance period. MAIN OUTCOME MEASURE: Responders were defined as patients in whom dofetilide prevented reinduction of atrioventricular re-entrant tachycardia at the end of the infusion. RESULTS: Intravenous dofetilide had no effect on tachycardia inducibility at the two lower doses (1.5 and 3 microgram/kg) but prevented the reinduction of tachycardia at the three higher doses (6, 9, and 15 microgram/kg) at a rate of 36% (11/31). There was a clear relation between plasma dofetilide concentrations and efficacy (p = 0.009). In non-responders, dofetilide increased the cycle length of induced atrioventricular re-entrant tachycardia. Dofetilide increased the atrial and ventricular effective refractory periods, as well as the antegrade and retrograde effective refractory period of the accessory pathway. Treatment related side effects were reported in four patients, one with a new sustained incessant supraventricular tachycardia. CONCLUSIONS: Dofetilide shows promise as an agent for the prevention of atrioventricular re-entrant tachycardia in patients without structural heart disease. PMID- 11602546 TI - Pravastatin and endothelium dependent vasomotion after coronary angioplasty: the PREFACE trial. AB - OBJECTIVE: To test the hypothesis that the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor pravastatin ameliorates endothelium mediated responses of dilated coronary segments: the PREFACE (pravastatin related effects following angioplasty on coronary endothelium) trial. DESIGN: A double blind, randomised, placebo controlled, multicentre study. SETTING: Four hospitals in the Netherlands. PATIENTS: 63 non-smoking, non-hypercholesterolaemic patients scheduled for elective balloon angioplasty (pravastatin 34, placebo 29). INTERVENTIONS: The effects of three months of pravastatin treatment (40 mg daily) on endothelium dependent vasomotor function were studied. Balloon angioplasty was undertaken one month after randomisation, and coronary vasomotor function tests using acetylcholine were performed two months after balloon angioplasty. The angiograms were analysed quantitatively. MAIN OUTCOME MEASURES: The efficacy measure was the acetylcholine induced change in mean arterial diameter, determined in the dilated segment and in an angiographically normal segment of an adjacent non-manipulated coronary artery. RESULTS: Increasing acetylcholine doses produced vasoconstriction in the dilated segments (p = 0.004) but not in the normal segments. Pravastatin did not affect the vascular response to acetylcholine in either the dilated segments (p = 0.09) or the non-dilated sites. Endothelium dependent vasomotion in normal segments was correlated with that in dilated segments (r = 0.47, p < 0.001). There were fewer procedure related events in the pravastatin group than in the placebo group (p < 0.05). CONCLUSIONS: Endothelium dependent vasomotion in normal segments is correlated with that in dilated segments. A significant beneficial effect of pravastatin on endothelial function could not be shown, but in the dilated segments there was a trend towards a beneficial treatment effect in the pravastatin group. PMID- 11602547 TI - Coronary sinus diverticulum containing posteroseptal accessory pathway. PMID- 11602548 TI - Washout collaterometry: a new method of assessing collaterals using angiographic contrast clearance during coronary occlusion. AB - OBJECTIVE: To investigate the hypothesis that the time to washout of radiographic contrast medium trapped distal to an occluded collateral receiving vessel is inversely related to collateral flow, and that this provides an accurate method for characterising coronary collaterals. METHODS: An intracoronary pressure derived collateral flow index was determined in 54 patients undergoing percutaneous transluminal coronary balloon angioplasty (PTCA). The study group was subdivided according to whether the collateral vessels were sufficient (n = 17) or insufficient (n = 37) to prevent ECG signs of myocardial ischaemia during PTCA. Washout collaterometry-an angiographic washout method-was carried out simultaneously; after injection of radiographic contrast medium into the collateral receiving vessel followed immediately by vascular occlusion, the number of heart beats was counted until approximately half the length of the epicardial vessel was cleared of contrast. RESULTS: The collateral flow index was higher (0.28 (0.09) v 0.12 (0.07); p < 0.0001) and the contrast washout time shorter (8.0 (2.9) v 17.5 (6.7) heart beats; p < 0.0001) in patients with sufficient versus insufficient collaterals. There was an inverse correlation between contrast washout time and collateral flow index (r = 0.72, p < 0.0001). Washout of contrast distal to the occluded vessel within 11 heart beats correctly determined sufficient and insufficient collaterals with 88% sensitivity and 81% specificity. CONCLUSIONS: Washout collaterometry is a new radiographic contrast washout method based on the inverse relation between collateral flow and the time to clearance of radiographic dye injected into the ipsilateral vessel during PTCA. It appears to be an accurate method of characterising coronary collateral vessels. PMID- 11602549 TI - Acute type A aortic dissection in an adult patient with Turner's syndrome. PMID- 11602550 TI - Value of fractional flow reserve in making decisions about bypass surgery for equivocal left main coronary artery disease. AB - OBJECTIVE: To investigate the value of coronary pressure derived fractional flow reserve (FFR) measurements in supporting decisions about medical or surgical treatment in patients with angiographically equivocal left main coronary artery stenosis. DESIGN: A two centre prospective single cohort follow up study. INTERVENTIONS: FFR of the left main coronary artery was determined in 54 consecutive patients with angiographically equivocal left main coronary artery disease. If FFR was >/= 0.75, medical treatment was chosen; if FFR was < 0.75, surgical treatment was chosen. MAIN OUTCOME MEASURES: Freedom from death, myocardial infarction, or any coronary revascularisation procedure. RESULTS: In 24 patients (44%), FFR was >/= 0.75 and medical treatment was chosen (medical group). In the remaining 30 patients (56%), FFR was < 0.75 and bypass surgery was performed (surgical group). Mean (SD) follow up was 29 (15) months (range 12-65 months). Survival among patients at three years of follow up was 100% in the medical group and 97% in the surgical group. Event-free survival was 76% in the medical group and 83% in the surgical group. CONCLUSIONS: FFR supports decision making in equivocal left main coronary artery disease. If FFR is below 0.75, the decision for bypass surgery is supported. If FFR is above 0.75, a conservative approach is justified. PMID- 11602552 TI - Unusual multiple spasm during coronary angioplasty. PMID- 11602551 TI - Residual pulmonary vasoreactivity to inhaled nitric oxide in patients with severe obstructive pulmonary hypertension and Eisenmenger syndrome. AB - OBJECTIVE: To determine whether inhaled NO (iNO) can reduce pulmonary vascular resistance in adults with congenital heart disease and obstructive pulmonary hypertension or Eisenmenger syndrome. DESIGN: 23 patients received graded doses of iNO. Pulmonary and systemic haemodynamic variables and circulating cyclic guanosine monophosphate (cGMP) concentrations were measured at baseline and after 20 and 80 ppm iNO. Patients were considered responders when total pulmonary resistance was reduced by at least 20%, and rebound was defined as a greater than 10% increase in total pulmonary resistance upon withdrawal from iNO. RESULTS: In response to 20 ppm iNO, total pulmonary resistance decreased in four patients (18%, 95% confidence interval (CI), 2% to 34%), while in response to 80 ppm iNO it decreased in six patients (29%, 95% CI 10% to 38%). Systemic blood pressure did not change. Withdrawal resulted in rebound in three patients (16%, 95% CI 0% to 32%) after cessation of 20 ppm iNO, and in six patients (35%, 95% CI 12% to 58%) after cessation of 80 ppm iNO. Patients with predominant right to left shunting did not respond. In all patients cGMP increased from (mean (SD)) 28 (13) micromol/l at baseline to 55 (30) and 78 (44) micromol/l after 20 and 80 ppm iNO (p < 0.05 v baseline). CONCLUSIONS: NO inhalation is safe and is associated with a dose dependent increase in circulating cGMP concentrations. Pulmonary vasodilatation in response to iNO was observed in 29% of patients and was influenced by baseline pulmonary haemodynamics. Responsiveness to acute iNO may identify patients with advanced obstructive pulmonary hypertension and Eisenmenger syndrome who could benefit from sustained vasodilator treatment. PMID- 11602554 TI - A novel approach to temporary stenting: degradable cardiovascular stents produced from corrodible metal-results 6-18 months after implantation into New Zealand white rabbits. AB - OBJECTIVE: To determine whether corrodible materials may be safely used as biodegradable cardiovascular implants. DESIGN: Corrodible iron stents (> 99.8% iron) were produced from pure iron and laser cut with a stent design similar to a commercially available permanent stent (PUVA-AS16). A total of 16 NOR-I stents were implanted into the native descending aorta of 16 New Zealand white rabbits (mean luminal diameter at the implantation site 3.4 mm, balloon diameter to vessel diameter ratio 1.13). RESULTS: No thromboembolic complications and no adverse events occurred during the follow up of 6-18 months. All stents were patent at repeat angiography after 6 (n = 9), 12 (n = 5), and 18 months (n = 2) with no significant neointimal proliferation, no pronounced inflammatory response, and no systemic toxicity. CONCLUSIONS: This initial in vivo experience suggests that degradable iron stents can be safely implanted without significant obstruction of the stented vessel caused by inflammation, neointimal proliferation, or thrombotic events. PMID- 11602553 TI - Molecular enhancement of porcine cardiac chronotropy. AB - OBJECTIVE: To test the potential of gene transfer approaches to enhance cardiac chronotropy in a porcine system as a model of the human heart. METHODS: Plasmids encoding either the human beta(2) adrenergic receptor or control constructs were injected into the right atria of native Yorkshire pig hearts. Percutaneous electrophysiological recording catheters equipped with 33 gauge circular injection needles were positioned in the mid-lateral right atrium. At the site of the earliest atrial potential the circular injection needles were rotated into the myocardium and the beta(2) adrenergic receptor (n = 6) or control plasmid constructs (n = 5) were injected. RESULTS: Injection of the beta(2) adrenergic receptor construct significantly enhanced chronotropy compared with control injections. The average (SD) heart rate of the pigs was 108 (16) beats/min before injection. Two days after injection with control plasmids the heart rate was 127 (25) beats/min (NS compared with preinjection rates). After injection with plasmid encoding the beta(2) adrenergic receptor the heart rate increased by 50% to 163 (33) beats/min (p < 0.05 compared with preinjection and postinjection control rates). CONCLUSIONS: The present studies showed in a large animal model that local targeting of gene expression may be a feasible modality to regulate cardiac pacemaking activity. In addition, these investigations provide an experimental basis for developing future clinical gene transfer approaches to upregulate heart rate and modulate cardiac conduction. PMID- 11602555 TI - Heart transplantation in children with mitochondrial cardiomyopathy. PMID- 11602556 TI - Effect of circadian rhythm on response to carotid sinus massage. PMID- 11602557 TI - Role of conscious sedation for external cardioversion. PMID- 11602558 TI - Sedation by physician with diazepam for DC cardioversion of atrial arrhythmias. PMID- 11602559 TI - Heart failure: What causes the symptoms of heart failure? PMID- 11602560 TI - Electrophysiology: Ventricular tachycardia: diagnosis of broad QRS complex tachycardia. PMID- 11602561 TI - Imaging techniques: Transoesophageal Echo-Doppler in cardiology. PMID- 11602562 TI - Transseptal left heart catheterisation guided by intracardiac echocardiography. AB - OBJECTIVE: To develop a novel approach of transseptal puncture guided by intracardiac echocardiography and to assess its efficacy. METHODS: Transcatheter intracardiac echocardiography with a 9 MHz rotating transducer was performed to guide transseptal puncture in 12 patients (mean age 43.1 years, range 31-68) who underwent radiofrequency catheter ablation of left sided accessory pathways. Initially, the echocardiography and transseptal catheters were placed adjacent to each other in the superior vena cava and were withdrawn to the level of the fossa ovalis. RESULTS: The successful puncture site was associated with visualisation of the fossa ovalis (12 patients, 100%) and the aorta (12 patients, 100%), tenting of the fossa (six patients, 50%), penetration of the needle visualised by the ultrasound catheter (12 patients, 100 %), and echocardiographic contrast material applied in the left atrium (12 patients, 100%). The characteristic jump of the needle onto the fossa ovalis was observed simultaneously with fluoroscopy and intracardiac ultrasound (12 patients, 100%). All procedures were successful. There were no complications associated with the transseptal procedure. CONCLUSIONS: Intracardiac echocardiography is feasible to guide transseptal puncture. The optimal puncture site can be assessed by simultaneous detection of the characteristic downward jump of the transseptal needle onto the fossa ovalis by intracardiac ultrasound and fluoroscopy. PMID- 11602563 TI - Delayed post-traumatic tamponade together with rupture of the tricuspid valve in a 15 year old boy. AB - With the increase in the number of high speed motor vehicle accidents, blunt, non penetrating trauma to the heart has become an important health problem. An unusual case is reported of a 15 year old boy urgently referred with cardiac tamponade and a new systolic murmur four months after a car accident. The problems of the diagnosis and possible causes of late cardiac tamponade and tricuspid regurgitation following this type of accident are discussed. PMID- 11602564 TI - Infected cardiac hydatid cyst. AB - A 24 year old woman presented with chest pain and palpitation. The presence of a semisolid mass-an echinococcal cyst or tumour-in the left ventricular apex was diagnosed by echocardiography, computed tomography, and magnetic resonance imaging. The infected cyst was seen at surgery. The cyst was removed successfully by using cardiopulmonary bypass with cross clamp. PMID- 11602565 TI - Long term follow up of long QT syndrome treated by overdrive pacing. AB - Long term follow up of a patient with idiopathic long QT syndrome is described. A 5 year old girl was admitted with attacks of unconsciousness. Epilepsy was diagnosed and the patient was treated with anticonvulsants. During other episodes, ECG study showed torsades de pointes. The patient was treated with beta blockers, stellectomy without success, and later with overdrive pacing. The young woman is now 43 years old and in good health. It is suggested that early overdrive pacing be implanted in young people with symptomatic long QT syndrome. PMID- 11602566 TI - Coronary stent deployment in situs inversus. AB - Situs inversus with dextrocardia occurs in approximately one in 10 000 patients. Successful stent deployment for the treatment of unstable angina and situs inversus is presented. Three technical challenges associated with the procedure are highlighted. Firstly, the successful choice of diagnostic and interventional catheters is based on an understanding of the orientation of the aortic arch. With a right sided aorta Judkins catheters should be successful. Secondly, image reversal is not necessarily required for image interpretation. Thirdly, successful coronary engagement with catheters requires rotation in a direction opposite to that normally used. PMID- 11602567 TI - Fulminant thrombosis of mechanical mitral valve prosthesis. AB - In patients with prosthetic heart valves non-cardiac surgery may require temporary discontinuation of oral anticoagulation. Although the risk of valve related thromboembolic complications may generally be only slightly increased during the short perioperative period, in the presence of certain risk factors, replacement of oral anticoagulation with heparin is recommended. In the presented patient, unusually fulminant and finally fatal thrombosis of a mechanical mitral valve prosthesis developed within only 48 hours after non-cardiac surgery despite heparin treatment. The thrombosis was triggered by clinical conditions favouring a hypercoagulable state. This report dramatically shows that despite improvements in prosthetic heart valve design and in the management of anticoagulation, thrombosis remains one of the most dangerous complications after valve replacement with a mechanical prosthesis. PMID- 11602568 TI - Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. AB - Ribavirin is administered in combination with interferon-alpha for treatment of hepatitis C virus (HCV) infection. Recently, we demonstrated that the antiviral activity of ribavirin can result from the ability of a viral RNA polymerase to utilize ribavirin triphosphate and to incorporate this nucleotide with reduced specificity, thereby mutagenizing the genome and decreasing the yield of infectious virus (Crotty, S., Maag, D., Arnold, J. J., Zhong, W., Lau, J. Y., Hong, Z., Andino, R., and Cameron, C. E. (2000) Nat. Med. 6, 1375-1379). In this study, we performed a quantitative analysis of a novel HCV RNA polymerase derivative that is capable of utilizing stably annealed primer-template substrates and exploited this derivative to evaluate whether lethal mutagenesis of the HCV genome is a possible mechanism for the anti-HCV activity of ribavirin. These studies demonstrate HCV RNA polymerase-catalyzed incorporation of ribavirin opposite cytidine and uridine. In addition, we demonstrate that templates containing ribavirin support CMP and UMP incorporation with equivalent efficiency. Surprisingly, templates containing ribavirin can also cause a significant block to RNA elongation. Together, these data suggest that ribavirin can exert a direct effect on HCV replication, which is mediated by the HCV RNA polymerase. We discuss the implications of this work on the development of nucleoside analogs for treatment of HCV infection. PMID- 11602569 TI - The Phe-X-Glu DNA binding motif of MutS. The role of hydrogen bonding in mismatch recognition. AB - The crystal structures of MutS protein from Thermus aquaticus and Escherichia coli in a complex with a mismatch-containing DNA duplex reveal that the Glu residue in a conserved Phe-X-Glu motif participates in a hydrogen-bonded contact with either an unpaired thymidine or the thymidine of a G-T base-base mismatch. Here, the role of hydrogen bonding in mismatch recognition by MutS is assessed. The relative affinities of MutS for DNA duplexes containing nonpolar shape mimics of A and T, 4-methylbenzimidazole (Z), and difluorotoluene (F), respectively, that lack hydrogen bonding donors and acceptors, are determined in gel mobility shift assays. The results provide support for an induced fit mode of mismatch binding in which duplexes destabilized by mismatches are preferred substrates for kinking by MutS. Hydrogen bonding between the O epsilon 2 group of Glu and the mismatched base contributes only marginally to mismatch recognition and is significantly less important than the aromatic ring stack with the conserved Phe residue. A MutS protein in which Ala is substituted for Glu(38) is shown to be defective for mismatch repair in vivo. DNA binding studies reveal a novel role for the conserved Glu residue in the establishment of mismatch discrimination by MutS. PMID- 11602570 TI - PYK2 as a mediator of endothelin-1/G alpha 11 signaling to GLUT4 glucose transporters. AB - Endothelin-1 (ET-1) signaling through G alpha(q/11) stimulates translocation of intracellular GLUT4 glucose transporters to the plasma membrane of 3T3-L1 adipocytes by an unknown mechanism that requires protein tyrosine phosphorylation and ADP-ribosylation factor 6 (ARF6) but is independent of phosphatidylinositol 3 (PI3)-kinase. In contrast, insulin action on this process requires PI3-kinase but not ARF6. Here we report the identification of two proteins selectively tyrosine phosphorylated in response to ET-1 but not insulin: the Ca(2+)-activated tyrosine kinase PYK2 and its physiological substrate, the adhesion scaffold protein paxillin. Endogenous paxillin as well as expressed Myc-tagged PYK2 or a Myc tagged kinase-deficient PYK2 protein were acutely directed to F-actin-rich adhesion sites from the adipocyte cytoplasm in response to ET-1 but not insulin. CADTK-related non-kinase (CRNK) is a dominant negative form of PYK2 containing the C-terminal portion of the protein, which binds paxillin but lacks the PYK2 autophosphorylation site (Tyr(402)). CRNK expression in 3T3-L1 adipocytes inhibited ET-1-mediated F-actin polymerization and translocation of Myc-tagged GLUT4-enhanced green fluorescent protein (EGFP) to the plasma membrane without disrupting insulin action on these processes. These data reveal the tyrosine kinase PYK2 as a required signaling element in the regulation of GLUT4 recycling in 3T3-L1 adipocytes by ET-1, whereas insulin signaling is directed through a different pathway. PMID- 11602571 TI - Structural basis for helper T-cell and antibody epitope immunodominance in bacteriophage T4 Hsp10. Role of disordered loops. AB - Antigen three-dimensional structure potentially limits the access of endoproteolytic processing enzymes to cleavage sites and of class II major histocompatibility antigen-presenting proteins to helper T-cell epitopes. Helper T-cell epitopes in bacteriophage T4 Hsp10 have been mapped by restimulation of splenocytes from CBA/J and C57BL/6J mice immunized in conjunction with mutant (R192G) heat-labile enterotoxin from Escherichia coli. Promiscuously immunogenic sequences were associated with unstable loops in the three-dimensional structure of T4 Hsp10. The immunodominant sequence lies on the N-terminal flank of the 22 residue mobile loop, which is sensitive to proteolysis in divergent Hsp10s. Several mobile loop deletions that inhibited proteolysis in vitro caused global changes in the helper T-cell epitope map. A mobile loop deletion that strongly stabilized the protein dramatically reduced the immunogenicity of the flanking immunodominant helper T-cell epitope, although the protein retained good overall immunogenicity. Antisera against the mobile loop deletion variants exhibited increased cross-reactivity, most especially the antisera against the strongly stabilized variant. The results support the hypothesis that unstable loops promote the presentation of flanking epitopes and suggest that loop deletion could be a general strategy to increase the breadth and strength of an immune response. PMID- 11602572 TI - Interaction with BRCA2 suggests a role for filamin-1 (hsFLNa) in DNA damage response. AB - The BRCA2 tumor suppressor plays significant roles in DNA damage response. The human actin binding protein filamin-1 (hsFLNa, also known as ABP-280) participates in orthogonal actin network, cellular stress responses, signal transduction, and cell migration. Through a yeast two-hybrid system, an in vitro binding assay, and in vivo co-immunoprecipitations, we identified an interaction between BRCA2 and hsFLNa. The hsFLNa binding domain of BRCA2 was mapped to an internal conserved region, and the BRCA2-interacting domain of hsFLNa was mapped to its C terminus. Although hsFLNa is known for its cytoplasmic functions in cell migration and signal transduction, some hsFLNa resides in the nucleus, raising the possibility that it participates in DNA damage response through a nuclear interaction with BRCA2. Lack of hsFLNa renders a human melanoma cell line (M2) more sensitive to several genotoxic agents including gamma irradiation, bleomycin, and ultraviolet-c light. These results suggest that BRCA2/hsFLNa interaction may serve to connect cytoskeletal signal transduction to DNA damage response pathways. PMID- 11602573 TI - Down-modulation of type 1 interferon responses by receptor cross-competition for a shared Jak kinase. AB - In contrast to the large number of class I and II cytokine receptors, only four Janus kinase (Jak) proteins are expressed in mammalian cells, implying the shared use of these kinases by many different receptor complexes. Consequently, if receptor numbers exceed the amount of available Jak, cross-interference patterns can be expected. We have engineered two model cellular systems expressing two different exogenous Tyk2-interacting receptors. A receptor chimera was generated wherein the extracellular part of the interferon type 1 receptor (Ifnar1) component of the interferon-alpha/beta receptor is replaced by the equivalent domain of the erythropoietin receptor. Despite Tyk2 activation, erythropoietin treatment of cells expressing this erythropoietin receptor/Ifnar1 chimera did not evoke any detectable IFN-type response. However, a dose-dependent interference with signal transduction via the endogenous Ifnar complex was found for STAT1, STAT2, STAT3, Tyk2, and Jak1 activation, for gene induction, and for antiviral activity. In a similar approach, cells expressing the beta1 chain of the interleukin-12 receptor showed a reduced transcriptional response to IFN-alpha as well as reduced STAT and kinase activation. In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference. PMID- 11602574 TI - Effect of glutathione depletion on antitumor drug toxicity (apoptosis and necrosis) in U-937 human promonocytic cells. The role of intracellular oxidation. AB - Treatment with the DNA topoisomerase inhibitors etoposide, doxorubicin, and camptothecin, and with the alkylating agents cisplatin and melphalan, caused peroxide accumulation and apoptosis in U-937 human promonocytic cells. Preincubation with the reduced glutathione (GSH) synthesis inhibitor l-buthionine (S,R)-sulfoximine (BSO) always potentiated peroxide accumulation. However, although GSH depletion potentiated the toxicity of cisplatin and melphalan, occasionally switching the mode of death from apoptosis to necrosis, it did not affect the toxicity of the other antitumor drugs. Hypoxia or preincubation with antioxidant agents attenuated death induction, apoptotic and necrotic, by alkylating drugs. The generation of necrosis by cisplatin could not be mimicked by addition of exogenous H(2)O(2) instead of BSO and was not adequately explained by caspase inactivation nor by a selective fall in ATP content. Treatment with cisplatin and melphalan caused a late decrease in mitochondrial transmembrane potential (DeltaPsim), which was much greater during necrosis than during apoptosis. The administration of the antioxidant agents N-acetyl-l-cysteine and butylated hydroxyanisole after pulse treatment with cisplatin or melphalan did not affect apoptosis but attenuated necrosis. Under these conditions, both antioxidants attenuated the necrosis-associated DeltaPsim decrease. These results indicate that oxidation-mediated alterations in mitochondrial function regulate the selection between apoptosis and necrosis in alkylating drug-treated human promonocytic cells. PMID- 11602575 TI - Role of interfacial hydrophobic residues in the stabilization of the leucine zipper structures of the transcription factors c-Fos and c-Jun. AB - This study documents a new and versatile experimental approach to study the relative stabilization energetics of recombinant polypeptide and protein mutants. In particular, the effect of temperature change over the range of T = 278-338 K on the thermodynamics of interaction of several leucine zipper coiled-coil polypeptides related to the transcription factors, c-Fos and c-Jun, following binding to immobilized n-octyl ligands has been determined. Plots of the change in heat capacity, DeltaC(p)0, versus T, in combination with the corresponding van't Hoff plots, allow the energetics of the interaction of polypeptides with n octyl ligands to be rationalized and the respective mid-point transition temperatures, T(m) values, determined for the melting of their supramolecular structures. The derived experimental data correlated well with information available from other procedures, confirming that this new approach provides complementary insight into the interaction thermodynamics and the molecular nature of the thermal stability of recombinant polypeptides in non-polar or other types of chemical environments. PMID- 11602576 TI - In vivo mutagenesis by Escherichia coli DNA polymerase I. Ile(709) in motif A functions in base selection. AB - The fidelity of DNA replication by Escherichia coli DNA polymerase I (pol I) was assessed in vivo using a reporter plasmid bearing a ColE1-type origin and an ochre codon in the beta-lactamase gene. We screened 53 single mutants within the region Val(700)-Arg(712) in the polymerase active-site motif A. Only replacement of Ile(709) yielded mutator polymerases, with substitution of Met, Asn, Phe, or Ala increasing the beta-lactamase reversion frequency 5-23-fold. Steady-state kinetic analysis of the I709F polymerase revealed reductions in apparent K(m) values for both insertion of non-complementary nucleotides and extension of mispaired primer termini. Abolishment of the 3'-5' exonuclease activity of wild type pol I increased mutation frequency 4-fold, whereas the combination of I709F and lack of the 3'-5' exonuclease yielded a 400-fold increase. We conclude that accurate discrimination of the incoming nucleotide at the polymerase domain is more critical than exonucleolytic proofreading for the fidelity of pol I in vivo. Surprisingly, the I709F polymerase enhanced mutagenesis in chromosomal DNA, although the increase was 10-fold less than in plasmid DNA. Our findings indicate the feasibility of obtaining desired mutations by replicating a target gene at a specific locus in a plasmid under continuous selection pressure. PMID- 11602577 TI - Differential regulation of two alternatively spliced isoforms of hypoxia inducible factor-1 alpha in activated T lymphocytes. AB - Cell adaptation to hypoxia is partially accomplished by hypoxia-inducible transcription factor-1 (HIF-1). Here we report the hypoxia-independent up regulation of HIF-1 alpha subunit in antigen receptor-activated T cells. This is explained by a selective up-regulation of alternatively spliced mRNA isoform I.1 that encodes the HIF-1 alpha protein without the first 12 N-terminal amino acids. We show that both short (I.1) and long (I.2) HIF-1 alpha isoforms display similar DNA binding and transcriptional activities. Major differences were observed between these two HIF-1 alpha isoforms in their expression patterns with respect to the resting and activated T lymphocytes in hypoxic and normoxic conditions. The T cell antigen receptor (TCR)-triggered activation of normal ex vivo T cells and differentiated T cells results in up-regulation of expression of I.1 isoform of HIF-1 alpha mRNA without an effect on constitutive I.2 HIF-1 alpha mRNA expression. The accumulation of I.1 HIF-1 alpha mRNA isoform in T lymphocytes is also demonstrated during cytokine-mediated inflammation in vivo, suggesting a physiological role of short HIF-1 alpha isoform in activated lymphocytes. The TCR triggered, protein kinase C and Ca(2+)/calcineurin-mediated HIF-1 alpha I.1 mRNA induction is protein synthesis-independent, suggesting that the HIF-1 alpha I.1 gene is expressed as an immediate early response gene. Therefore, these data predict a different physiological role of short and long isoforms of HIF-1 alpha in resting and activated cells. PMID- 11602578 TI - HIV-1 nucleocapsid protein and the secondary structure of the binary complex formed between tRNA(Lys.3) and viral RNA template play different roles during initiation of (-) strand DNA reverse transcription. AB - In human immunodeficiency virus type 1 (HIV-1), the tRNA(Lys.3) primer and viral RNA template can form a specific complex that is characterized by extensive inter and intramolecular interactions. Initiation of reverse transcription from this complex has been shown to be distinguished from subsequent elongation by early pausing events, such as at the +1 and +3 nucleotide positions. One major concern regarding the biological relevance of these results is that most kinetic studies of HIV-1 reverse transcription have been performed using tRNA(Lys.3)-viral (v) RNA complexes that were formed by heat annealing. In contrast, tRNA(Lys.3) in viruses is placed onto the primer binding site by nucleocapsid (NC) sequences of the Gag protein. In this study, we have further characterized the initiation features of reverse transcription in the presence of HIV-1 NC protein. In contrast to results obtained with a heat-annealed tRNA(Lys.3).vRNA complex, we found that polymerization reactions catalyzed by HIV-1 reverse transcriptase did not commonly pause at the +1 nucleotide position when a NC-annealed RNA complex was used, and that this was true regardless whether NC was actually still present during reverse transcription. This activity of NC required both zinc finger motifs, as demonstrated by experiments that employed zinc finger-mutated forms of NC protein (H23C NC and ddNC), supporting the involvement of the zinc fingers in the RNA chaperone activity of NC. However, NC was not able to help reverse transcriptase to escape the +3 pausing event. Mutagenesis of a stem structure within the tRNA(Lys.3). vRNA complex led to disappearance of the +3 pausing event as well as to significantly reduced rates of reverse transcription. Thus, this stem structure is essential for optimal reverse transcription, despite its role in promotion of the +3 pausing event. PMID- 11602579 TI - Molecular events in transmembrane signaling via E-selectin. SHP2 association, adaptor protein complex formation and ERK1/2 activation. AB - E-selectin is a cytokine-inducible adhesion molecule that is expressed by activated endothelial cells at sites of inflammation. In addition to supporting rolling and stable arrest of leukocytes, there is increasing evidence that E selectin functions in transmembrane signaling into endothelial cells during these adhesive interactions. We have previously shown that adhesion of HL-60 cells (which express ligands for E-selectin), or antibody-mediated cross-linking of E selectin, results in formation of a Ras/Raf-1/phospho-MEK macrocomplex, extracellular signal-regulated protein kinase (ERK1/2) activation, and c-fos up regulation. All of these downstream signaling events appear to require an intact cytoplasmic domain of E-selectin. Here we demonstrate that tyrosine 603 in the cytoplasmic domain of E-selectin is required for the E-selectin-dependent ERK1/2 activation. Tyrosine 603 plays an important role in mediating the association of E-selectin with SHP2, and the catalytic domain of SHP2 is, in turn, critical for E-selectin-dependent ERK1/2 activation. An adapter protein complex consisting of Shc.Grb2.Sos bridges between SHP2 and the Ras.Raf.phospho-MEK macrocomplex. These molecular events thus outline a mechanism by which cross-linking of E-selectin by engagement of ligands on adherent leukocytes can initiate a multifunctional signaling pathway in the activated endothelial cell at sites of inflammation. PMID- 11602580 TI - Differential effects of HIV-1 protease inhibitors on dendritic cell immunophenotype and function. AB - Recent findings show that human immunodeficiency virus (HIV)-1 protease inhibitors designed to specifically inhibit the aspartic protease of HIV-1 nonetheless exert various effects on immune cell function in vitro and in vivo. Dendritic cells (DC), central players of the immune system, express several aspartic proteases that are important for DC function. In the present study, we demonstrate that all of the HIV-1 protease inhibitors tested affect DC maturation. In addition, saquinavir had a strong inhibitory effect on the T-cell stimulatory capacity of mature DC. In contrast, indinavir had only a slight effect on DC induced T-cell proliferation and allowed efficient transduction of DC with a replication-incompetent HIV-1 vector designed for DC-based immunotherapy. HIV-1 protease inhibitors that have little or no effect on DC function may be preferable for combination with immunotherapy for HIV/AIDS. PMID- 11602581 TI - Histone deacetylase 1 phosphorylation promotes enzymatic activity and complex formation. AB - Accessibility of the genome to DNA-binding transcription factors is regulated by proteins that control the acetylation of amino-terminal lysine residues on nucleosomal histones. Specifically, histone deacetylase (HDAC) proteins repress transcription by deacetylating histones. To date, the only known regulatory mechanism of HDAC1 function is via interaction with associated proteins. Although the control of HDAC1 function by protein interaction and recruitment is well precedented, we were interested in exploring HDAC1 regulation by post translational modification. Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1. Deletion of the highly charged carboxyl-terminal region of HDAC1 also decreased its deacetylase activity and protein associations, revealing its requirement in maintaining HDAC1 function. Our results reinforce the importance of protein associations in modulating HDAC1 function and provide the first step toward characterizing the role of post-translational modifications in regulating HDAC activity in vivo. PMID- 11602582 TI - Exchange of the actin-bound nucleotide in intact arterial smooth muscle. AB - The actin-bound ADP was separated from cytoplasmic nucleotides by treatment of intact arterial smooth muscle with 50% ethanol. In (32)P-labeled smooth muscle the actin-bound ADP and phosphate readily exchanged with the cytoplasmic [gamma,beta-(32)P]ATP; the specific radioactivity of actin-bound ADP was equal to that of the beta-phosphate of cytoplasmic ATP and the specific radioactivity of actin-bound phosphate was equal to that of the gamma-phosphate of cytoplasmic ATP. In contrast, the exchange of the actin-bound ADP in skeletal muscle was very slow. The presence of cytoplasmic ATP was required for the exchange of the actin bound ADP and phosphate; if ATP synthesis was inhibited the exchange was also inhibited. The extent of exchange was reduced in muscles contracted by histamine or K(+), as compared with resting muscles. The exchange was also shown in other mammalian smooth muscles, uterus, urinary bladder, and stomach. The data indicate a dynamic state of actin in smooth muscle. The data also suggest that polymerization-depolymerization of actin is part of the contraction-relaxation cycle of smooth muscle. PMID- 11602583 TI - The N-terminal globular domain and the first class A amphipathic helix of apolipoprotein A-I are important for lecithin:cholesterol acyltransferase activation and the maturation of high density lipoprotein in vivo. AB - To investigate the role of the N terminus of apolipoprotein A-I (apoA-I) in the maturation of high density lipoproteins (HDL), two N-terminal mutants with deletions of residues 1-43 and 1-65 (referred to as Delta 1-43 and Delta 1-65 apoA-I) were studied. In vitro, these deletions had little effect on cellular cholesterol efflux from macrophages but LCAT activation was reduced by 50 and 70% for the Delta 1-43 and Delta 1-65 apoA-I mutants, respectively, relative to wild type (Wt) apoA-I. To further define the role of the N terminus of apoA-I in HDL maturation, we constructed recombinant adenoviruses containing Wt apoA-I and two similar mutants with deletions of residues 7-43 and 7-65 (referred to as Delta 7 43 and Delta 7-65 apoA-I, respectively). Residues 1-6 were not removed in these mutants to allow proper cleavage of the pro-sequence in vivo. Following injection of these adenoviruses into apoA-I-deficient mice, plasma concentrations of both Delta 7-43 and Delta 7-65 apoA-I were reduced 4-fold relative to Wt apoA-I. The N terminal deletion mutants, in particular Delta 7-65 apoA-I, were associated with greater proportions of pre beta-HDL and accumulated fewer HDL cholesteryl esters relative to Wt apoA-I. Wt and Delta 7-43 apoA-I formed predominantly alpha migrating and spherical HDL, whereas Delta 7-65 apoA-I formed only pre beta-HDL of discoidal morphology. This demonstrates that deletion of the first class A amphipathic alpha-helix has a profound additive effect in vivo over the deletion of the globular domain alone (amino acids 1-43) indicating its important role in the production of mature alpha-migrating HDL. In summary, the combined in vitro and in vivo studies demonstrate a role for the N terminus of apoA-I in lecithin:cholesterol acyltransferase activation and the requirement of the first class A amphipathic alpha-helix for the maturation of HDL in vivo. PMID- 11602584 TI - Saccharomyces cerevisiae multidrug resistance gene expression inversely correlates with the status of the F(0) component of the mitochondrial ATPase. AB - Loss of the mitochondrial genome (rho(0) cell) or elimination of the mitochondrial inner membrane protein Oxa1p causes a dramatic increase in expression of the ATP binding cassette transporter-encoding gene PDR5 in the yeast Saccharomyces cerevisiae. This increase in gene expression occurs via activation of the function of the Cys(6)-Zn(II)(2) cluster transcription factor Pdr3p, which in turn autoregulates expression of its structural gene. Surprisingly, the acquisition of PDR5-dependent multidrug resistance occurs at a very high frequency, consistent with the appearance of rho(-) cells in a fermentatively growing culture (approximately 2%). The degree of activation of Pdr3p target genes was found to vary considerably and to be influenced by the presence of the homologous protein, Pdr1p. Mutagenesis and overexpression studies provided evidence that the control of Pdr3p expression was the major control point of this transcription factor by mitochondrial retrograde signaling. Because both rho(0) and oxa1 mutant cells have multiple defects including loss of normal respiratory chain function and oxidative phosphorylation, a series of mutant strains with more selective defects in mitochondrial function was employed to identify the molecular signal that triggers PDR5 transcriptional activation. Only mutations that influenced the functional status of the F(0) subunit of the mitochondrial ATPase were found to lead to activation of PDR5 expression. PMID- 11602585 TI - Partial phosphorylation of the N-formyl peptide receptor inhibits G protein association independent of arrestin binding. AB - It is now well accepted that G protein-coupled receptors activated by agonist binding become targets for phosphorylation, leading to desensitization of the receptor. Using a series of phosphorylation deficient mutants of the N-formyl peptide receptor (FPR), we have explored the role of phosphorylation on the ability of the receptor to interact with G proteins and arrestins. Using a fluorometric assay in conjunction with solubilized receptors, we demonstrate that phosphorylation of the wild type FPR lowers its affinity for G protein, whereas mutant receptors lacking four potential phosphorylation sites retain their ability to couple to G protein. Phosphorylated mutant receptors lacking only two potential phosphorylation sites are again unable to couple to G protein. Furthermore, whereas stimulated wild type FPR in whole cells colocalizes with arrestin-2, and the solubilized, phosphorylated FPR binds arrestin-2, the stimulated receptors lacking four potential phosphorylation sites display no interaction with arrestin-2. However, the mutant receptors lacking only two potential phosphorylation sites are restored in their ability to bind and colocalize with arrestin-2. Thus, there is a submaximal threshold of FPR phosphorylation that simultaneously results in an inhibition of G protein binding and an induction of arrestin binding. These results are the first to demonstrate that less than maximal levels of receptor phosphorylation can block G protein binding, independent of arrestin binding. We therefore propose that phosphorylation alone may be sufficient to desensitize the FPR in vivo, raising the possibility that for certain G protein-coupled receptors, desensitization may not be the primary function of arrestin. PMID- 11602586 TI - Mitochondrial creatine kinase and mitochondrial outer membrane porin show a direct interaction that is modulated by calcium. AB - Mitochondrial creatine kinase (MtCK) co-localizes with mitochondrial porin (voltage-dependent anion channel) and adenine nucleotide translocator in mitochondrial contact sites. A specific, direct protein-protein interaction between MtCK and mitochondrial porin was demonstrated using surface plasmon resonance spectroscopy. This interaction was independent of the immobilized binding partner (porin reconstituted in liposomes or MtCK) or the analyzed isoform (chicken sarcomeric MtCK or human ubiquitous MtCK, human recombinant porin, or purified bovine porin). Increased ionic strength reduced the binding of MtCK to porin, suggesting predominantly ionic interactions. By contrast, micromolar concentrations of Ca(2+) increased the amount of bound MtCK, indicating a physiological regulation of complex formation. No interaction of MtCK with reconstituted adenine nucleotide translocator was detectable in our experimental setup. The relevance of these findings for structure and function of mitochondrial contact sites is discussed. PMID- 11602587 TI - Recruitment of activated G protein-coupled receptors to pre-existing clathrin coated pits in living cells. AB - The process of clathrin-mediated endocytosis tightly regulates signaling of the superfamily of seven-transmembrane G protein-coupled receptors (GPCRs). A fundamental question in the cell biology of membrane receptor endocytosis is whether activated receptors can initiate the formation of clathrin-coated pits (CPs) or whether they are simply mobilized to pre-existing CPs. Here, using various approaches, including a dynamic assay to monitor the distribution of CPs and GPCR-beta-arrestin complexes in live HeLa cells, we demonstrate for the first time that activated GPCRs do not initiate the de novo formation of CPs but instead are targeted to pre-existing CPs. PMID- 11602588 TI - N-terminal cleavage of the salivary MUC5B mucin. Analogy with the Van Willebrand propolypeptide? AB - Sequence similarities between the oligomeric mucins (MUC2, MUC5AC, MUC5B) and the von Willebrand factor suggest that they may be assembled in a similar way. After oligomerization, a fragment corresponding to the D1 and D2 domains is released from the von Willebrand factor. This cleavage does not appear to occur in pig submaxillary mucin, the only mammalian mucin in which this cleavage has been examined thus far, but whether other oligomeric mucins undergo N terminus proteolysis is not known. Antibodies recognizing the D1, D2, D3, and the first Cys domains in MUC5B were established and used to investigate to what extent proteolytic cleavage occurs within the N-terminal part of salivary MUC5B. The antibodies against the D1 and D2 domains identified a polypeptide corresponding in size to a MUC5B fragment generated by cleavage within the D' domain analogously with the von Willebrand factor propolypeptide. The antibodies did not recognize the main mucin population, suggesting that the major part of salivary MUC5B is subjected to this cleavage. An antibody recognizing the D3 domain was used to reveal a second cleavage site in the "soluble" but not in the "insoluble" MUC5B fraction: the first structural difference observed between soluble and insoluble salivary MUC5B. The identification of these cleavage events shows that the N-terminal sites for MUC5B oligomerization are present in the D3 domain and/or in domains located C-terminal to this part of the molecule. PMID- 11602589 TI - c-Jun N-terminal kinase specifically phosphorylates p66ShcA at serine 36 in response to ultraviolet irradiation. AB - Mice lacking expression of the p66 isoform of the ShcA adaptor protein (p66(ShcA)) are less susceptible to oxidative stress and have an extended life span. Specifically, phosphorylation of p66(ShcA) at serine 36 is critical for the cell death response elicited by oxidative damage. We sought to identify the kinase(s) responsible for this phosphorylation. Utilizing the SH-SY5Y human neuroblastoma cell model, it is demonstrated that p66(ShcA) is phosphorylated on serine/threonine residues in response to UV irradiation. Both c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinases are activated by UV irradiation, and we show that both are capable of phosphorylating serine 36 of p66(ShcA) in vitro. However, treatment of cells with a multiple lineage kinase inhibitor, CEP-1347, that blocks UV-induced JNK activation, but not p38, phosphatidylinositol 3-kinase, or MEK1 inhibitors, prevented p66(ShcA) phosphorylation in SH-SY5Y cells. Consistent with this finding, transfected activated JNK1, but not the kinase-dead JNK1, leads to phosphorylation of serine 36 of p66(ShcA) in Chinese hamster ovary cells. In conclusion, JNKs are the kinases that phosphorylate serine 36 of p66(ShcA) in response to UV irradiation in SH-SY5Y cells, and blocking p66(ShcA) phosphorylation by intervening in the JNK pathway may prevent cellular damage due to light-induced oxidative stress. PMID- 11602590 TI - Lipopolysaccharide-induced expression of interferon-beta mediates the timing of inducible nitric-oxide synthase induction in RAW 264.7 macrophages. AB - The production of nitric oxide by macrophages has been implicated as a host defense mechanism against microbial pathogens and tumor cells. Recent reports have implicated interferon-alpha/beta (IFN-alpha/beta) as an autocrine/paracrine signal critical for the induction of murine iNOS. In this report we have systematically investigated the role of IFN-beta in the induction of iNOS in the murine macrophage cell line, RAW 264.7. First, we demonstrate that IFN-beta expression is highly up-regulated, and is secreted in response to lipopolysaccharide (LPS). Treatment of RAW macrophages with LPS results in a time dependent phosphorylation of STAT-1 on both tyrosine residue 701 (Tyr-701) and serine residue 727 (Ser-727) that is consistent with the timing of endogenous IFN beta expression. LPS also induces interferon regulatory factor-1 expression with similar kinetics. We further demonstrate that exogenous IFN-beta accelerates the induction of iNOS by LPS. The acceleration of iNOS induction is observed at the levels of transcription, protein expression, and NO formation. Accordingly, we propose that the cytokine environment of macrophages may determine the rate and magnitude of nitric oxide production, thereby regulating the cytotoxic response to pathogen challenge. PMID- 11602591 TI - Redox centers of 4-hydroxybenzoyl-CoA reductase, a member of the xanthine oxidase family of molybdenum-containing enzymes. AB - 4-Hydroxybenzoyl-CoA reductase (4-HBCR) is a key enzyme in the anaerobic metabolism of phenolic compounds. It catalyzes the reductive removal of the hydroxyl group from the aromatic ring yielding benzoyl-CoA and water. The subunit architecture, amino acid sequence, and the cofactor/metal content indicate that it belongs to the xanthine oxidase (XO) family of molybdenum cofactor-containing enzymes. 4-HBCR is an unusual XO family member as it catalyzes the irreversible reduction of a CoA-thioester substrate. A radical mechanism has been proposed for the enzymatic removal of phenolic hydroxyl groups. In this work we studied the spectroscopic and electrochemical properties of 4-HBCR by EPR and Mossbauer spectroscopy and identified the pterin cofactor as molybdopterin mononucleotide. In addition to two different [2Fe-2S] clusters, one FAD and one molybdenum species per monomer, we also identified a [4Fe-4S] cluster/monomer, which is unique among members of the XO family. The reduced [4Fe-4S] cluster interacted magnetically with the Mo(V) species, suggesting that the centers are in close proximity, (<15 A apart). Additionally, reduction of the [4Fe-4S] cluster resulted in a loss of the EPR signals of the [2Fe-2S] clusters probably because of magnetic interactions between the Fe-S clusters as evidenced in power saturation studies. The Mo(V) EPR signals of 4-HBCR were typical for XO family members. Under steady-state conditions of substrate reduction, in the presence of excess dithionite, the [4Fe-4S] clusters were in the fully oxidized state while the [2Fe-2S] clusters remained reduced. The redox potentials of the redox cofactors were determined to be: [2Fe-2S](+1/+2) I, -205 mV; [2Fe-2S] (+1/+2) II, -255 mV; FAD/FADH( small middle dot)/FADH, -250 mV/-470 mV; [4Fe-4S](+1/+2), -465 mV and Mo(VI)/(V)/(VI), -380 mV/-500 mV. A catalytic cycle is proposed that takes into account the common properties of molybdenum cofactor enzymes and the special one-electron chemistry of dehydroxylation of phenolic compounds. PMID- 11602592 TI - Electron transfer kinetics between hemoglobin subunits. AB - The kinetics for electron transfer have been measured for samples of hemoglobin valency hybrids with initially one type of subunit, alpha or beta, in the oxidized state. Incubation of these samples under anaerobic conditions tends to randomize the type of subunit that is oxidized. With a time coefficient of a few hours at pH 7, 25 degrees C, the Hb solution (0.1 mm heme) approaches a form with about 60% of beta chains reduced, indicating a faster transfer rate in the direction alpha to beta. There was no observable electron transfer for samples saturated with oxygen. The electron transfer occurs predominantly between deoxy and aquo-met subunits, both high spin species. Furthermore, electron transfer does not depend on the quaternary state of hemoglobin. Incubation of oxidized cross-linked tetramer Hb A with deoxy Hb S also displayed electron transfer, implying a mechanism via inter-tetramer collisions. A dependence on the overall Hb concentration confirms this mechanism, although a small contribution of transfer between subunits of the same tetramer cannot be ruled out. These results suggest that in vivo collisions between the Hb tetramers will be involved in the relative distribution of the methemoglobin between subunits in association with the reductase system present in the erythrocyte. PMID- 11602593 TI - Three oligopeptide-binding proteins are involved in the oligopeptide transport of Streptococcus thermophilus. AB - The functions necessary for bacterial growth strongly depend on the features of the bacteria and the components of the growth media. Our objective was to identify the functions essential to the optimum growth of Streptococcus thermophilus in milk. Using random insertional mutagenesis on a S. thermophilus strain chosen for its ability to grow rapidly in milk, we obtained several mutants incapable of rapid growth in milk. We isolated and characterized one of these mutants in which an amiA1 gene encoding an oligopeptide-binding protein (OBP) was interrupted. This gene was a part of an operon containing all the components of an ATP binding cassette transporter. Three highly homologous amiA genes encoding OBPs work with the same components of the ATP transport system. Their simultaneous inactivation led to a drastic diminution in the growth rate in milk and the absence of growth in chemically defined medium containing peptides as the nitrogen source. We constructed single and multiple negative mutants for AmiAs and cell wall proteinase (PrtS), the only proteinase capable of hydrolyzing casein oligopeptides outside the cell. Growth experiments in chemically defined medium containing peptides indicated that AmiA1, AmiA2, and AmiA3 exhibited overlapping substrate specificities, and that the whole system allows the transport of peptides containing from 3 to 23 residues. PMID- 11602594 TI - Gbetagamma affinity for bovine rhodopsin is determined by the carboxyl-terminal sequences of the gamma subunit. AB - Two native betagamma dimers, beta(1)gamma(1) and beta(1)gamma(2), display very different affinities for receptors. Since these gamma subunits differ in both primary structure and isoprenoid modification, we examined the relative contributions of each to Gbetagamma interaction with receptors. We constructed baculoviruses encoding gamma(1) and gamma(2) subunits with altered CAAX (where A is an aliphatic amino acid) motifs to direct alternate or no prenylation of the gamma chains and a set of gamma(1) and gamma(2) chimeras with the gamma(2) CAAX motif at the carboxyl terminus. All the gamma constructs coexpressed with beta(1) in Sf9 cells yielded beta(1)gamma dimers, which were purified to near homogeneity, and their affinities for receptors and Galpha were quantitatively determined. Whereas alteration of the isoprenoid of gamma(1) from farnesyl to geranylgeranyl and of gamma(2) from geranylgeranyl to farnesyl had no impact on the affinities of beta(1)gamma dimers for Galpha(t), the non-prenylated beta(1)gamma(2) dimer had significantly diminished affinity. Altered prenylation resulted in a <2-fold decrease in affinity of the beta(1)gamma(2) dimer for rhodopsin and a <3-fold change for the beta(1)gamma(1) dimer. In each case with identical isoprenylation, the beta(1)gamma(2) dimer displayed significantly greater affinity for rhodopsin compared with the beta(1)gamma(1) dimer. Furthermore, dimers containing chimeric Ggamma chains with identical geranylgeranyl modification displayed rhodopsin affinities largely determined by the carboxyl-terminal one-third of the protein. These results indicate that isoprenoid modification of the Ggamma subunit is essential for binding to both Galpha and receptors. The isoprenoid type influences the binding affinity for receptors, but not for Galpha. Finally, the primary structure of the Ggamma subunit provides a major contribution to receptor binding of Gbetagamma, with the carboxyl-terminal sequence conferring receptor selectivity. PMID- 11602595 TI - Cell cycle-dependent proteolysis and phosphorylation of human Mcm10. AB - Mcm10 (Dna43) is an essential protein for chromosomal DNA replication in Saccharomyces cerevisiae. Recently, we identified a human Mcm10 homolog that interacts with the mammalian Orc2 and Mcm2-7 complex. We additionally demonstrated that human Mcm10 binds nuclease-resistant nuclear structures during S phase and dissociates from them in G(2) phase. In this study, we have further characterized the subcellular localization, modification, and expression levels of human Mcm10 protein throughout the cell cycle. Human Mcm10 protein decreased in late M phase, remained low during G(1) phase, started to accumulate, and bound chromatin at the onset of S phase. Proteasome inhibitors stabilized Mcm10 levels, suggesting that proteolysis is involved in the down-regulation of the protein in late M/G(1) phase. Dissociation of Mcm10 from chromatin in G(2)/M phase was concomitant with alterations in the electrophoretic mobility of the protein. Treatment with lambda phosphatase revealed that mobility shifts were due to hyperphosphorylation. These results indicate that human Mcm10 is regulated by proteolysis and phosphorylation in a cell cycle-dependent manner. It is further suggested that mammalian Mcm10 is involved in S phase progression, and not the formation of a prereplicative complex, as previously proposed from data on the S. cerevisiae protein. PMID- 11602596 TI - Type-specific regulation of adenylyl cyclase. Selective pharmacological stimulation and inhibition of adenylyl cyclase isoforms. AB - Crystallographic studies have elucidated the binding mechanism of forskolin and P site inhibitors to adenylyl cyclase. Accordingly, computer-assisted drug design has enabled us to identify isoform-selective regulators of adenylyl cyclase. After examining more than 200 newly synthesized derivatives of forskolin, we found that the modification at the positions of C6 and C7, in general, enhances isoform selectivity. The 6-(3-dimethylaminopropionyl) modification led to an enhanced selectivity for type V, whereas 6-[N-(2-isothiocyanatoethyl) aminocarbonyl] and 6-(4-acrylbutyryl) modification led to an enhanced selectivity for type II. In contrast, 2'-deoxyadenosine 3'-monophosphate, a classical and 3' phosphate-substituted P-site inhibitor, demonstrated a 27-fold selectivity for inhibiting type V relative to type II, whereas 9-(tetrahydro-2-furyl) adenine, a ribose-substituted P-site ligand, showed a markedly increased, 130-fold selectivity for inhibiting type V. Consequently, on the basis of the pharmacophore analysis of 9-(tetrahydro-2-furyl) adenine and adenylyl cyclase, a novel non-nucleoside inhibitor, 2-amino-7-(2-furanyl)-7,8-dihydro-5(6H) quinazolinone (NKY80), was identified after virtual screening of more than 850,000 compounds. NKY80 demonstrated a 210-fold selectivity for inhibiting type V relative to type II. More importantly, the combination of a type III-selective forskolin derivative and 9-(tetrahydro-2-furyl) adenine or NKY80 demonstrated a further enhanced selectivity for type III stimulation over other isoforms. Our data suggest the feasibility of adenylyl cyclase isoform-targeted regulation of cyclic AMP signaling by pharmacological reagents, either alone or in combination. PMID- 11602597 TI - A self-restricted CD38-connexin 43 cross-talk affects NAD+ and cyclic ADP-ribose metabolism and regulates intracellular calcium in 3T3 fibroblasts. AB - Connexin 43 (Cx43) hexameric hemichannels, recently demonstrated to mediate NAD(+) transport, functionally interact in the plasma membrane of several cells with the ectoenzyme CD38 that converts NAD(+) to the universal calcium mobilizer cyclic ADP-ribose (cADPR). Here we demonstrate that functional uncoupling between CD38 and Cx43 in CD38-transfected 3T3 murine fibroblasts is paralleled by decreased [Ca(2+)](i) levels as a result of reduced intracellular conversion of NAD(+) to cADPR. A sharp inverse correlation emerged between [Ca(2+)](i) levels and NAD(+) transport (measured as influx into cells and as efflux therefrom), both in the CD38(+) cells (high [Ca(2+)](i), low transport) and in the CD38(-) fibroblasts (low [Ca(2+)](i), high transport). These differences were correlated with distinctive extents of Cx43 phosphorylation in the two cell populations, a lower phosphorylation with high NAD(+) transport (CD38(-) cells) and vice versa (CD38(+) cells). Conversion of NAD(+)-permeable Cx43 to the phosphorylated, NAD(+)-impermeable form occurs via Ca(2+)-stimulated protein kinase C (PKC). Thus, a self-regulatory loop emerged in CD38(+) fibroblasts whereby high [Ca(2+)](i) restricts further Ca(2+) mobilization by cADPR via PKC-mediated disruption of the Cx43-CD38 cross-talk. This mechanism may avoid: (i) leakage of NAD(+) from cells; (ii) depletion of intracellular NAD(+) by CD38; (iii) overproduction of intracellular cADPR resulting in potentially cytotoxic [Ca(2+)](i). PMID- 11602598 TI - Pilt, a novel peripheral membrane protein at tight junctions in epithelial cells. AB - Tight junctions (TJs) serve as a barrier that prevents solutes and water from passing through the paracellular pathway, and as a fence between the apical and basolateral plasma membranes in epithelial cells. TJs consist of transmembrane proteins (claudin, occludin, and JAM) and many peripheral membrane proteins, including actin filament (F-actin)-binding scaffold proteins (ZO-1, -2, and -3), non-F-actin-binding scaffold proteins (MAGI-1), and cell polarity molecules (ASIP/PAR-3 and PAR-6). We identified here a novel peripheral membrane protein at TJs from a human cDNA library and named it Pilt (for protein incorporated later into TJs), because it was incorporated into TJs later after the claudin-based junctional strands were formed. Pilt consists of 547 amino acids with a calculated M(r) of 60,704. Pilt has a proline-rich domain. In cadherin-deficient L cells stably expressing claudin or JAM, Pilt was not recruited to claudin-based or JAM-based cell-cell contact sites, suggesting that Pilt does not directly interact with claudin or JAM. The present results indicate that Pilt is a novel component of TJs. PMID- 11602600 TI - Prolactin negatively regulates caveolin-1 gene expression in the mammary gland during lactation, via a Ras-dependent mechanism. AB - Caveolin-1 is a 22-kDa integral membrane protein that has been suggested to function as a negative regulator of mitogen-stimulated proliferation in a variety of cell types, including mammary epithelial cells. Because much of our insight into caveolin-1 function has come from the study of human breast tumor-derived cell lines in culture, the normal physiological regulators of caveolin-1 expression in the mammary gland remain unknown. Here, we examine caveolin-1 expression in mice at different stages of mammary gland development. We show that caveolin-1 expression is significantly down-regulated during late pregnancy and lactation. Upon weaning, mammary gland expression of caveolin-1 rapidly returns to non-pregnant "steady-state" levels. Injection of virgin mice with a battery of hormones normally up-regulated during lactation demonstrates that prolactin is the main mediator of caveolin-1 down-regulation. Virtually identical results were obtained with human mammary epithelial cells (hTERT-HME1) in culture. In addition, we demonstrate that prolactin-mediated down-regulation of caveolin-1 expression occurs at the level of transcriptional control and via a Ras-dependent mechanism. Interestingly, in the mammary gland, both mammary epithelial cells and the surrounding mammary adipocytes show prolactin-mediated down-regulation of caveolin-1. This hormone-dependent regulation of caveolin-1 expression is specific to the mammary fat pad. Finally, we employed HC11 cells, a well established model of mammary epithelial cell differentiation, to study the possible functional effects of caveolin-1 expression. In the presence of lactogenic hormones, recombinant expression of caveolin-1 in HC11 cells dramatically suppresses the induction of the promoter activity and the synthesis of beta-casein, an established reporter of lactogenic differentiation and milk production. These findings may explain why caveolin-1 levels are normally down regulated during lactation. This report is the first demonstration that caveolin 1 levels are down-regulated during a normal physiological event in vivo, i.e. lactation, because previous reports have only documented that down-regulation of caveolin-1 occurs during cell transformation and tumorigenesis. PMID- 11602599 TI - Oncostatin M regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor alpha, and oncostatin M receptor beta by distinct mechanisms. AB - The cytokine receptor subunits gp130, leukemia inhibitory factor receptor alpha (LIFRalpha), and oncostatin M receptor beta (OSMRbeta) transduce OSM signals that regulate gene expression and cell proliferation. After ligand binding and activation of the Janus protein-tyrosine kinase/STAT and mitogen-activated protein kinase signal transduction pathways, negative feedback processes are recruited. These processes attenuate receptor action by suppression of cytokine signaling and by down-regulation of receptor protein expression. This study demonstrates that in human fibroblasts or epithelial cells, OSM first decreases the level of gp130, LIFRalpha, and OSMRbeta by ligand-induced receptor degradation and then increases the level of the receptors by enhanced synthesis. The transcriptional induction of gp130 gene by OSM involves STAT3. Various cell lines expressing receptor subunits to the different interleukin-6 class cytokines revealed that only LIFRalpha degradation is promoted by activated ERK and that degradation of gp130, OSMRbeta, and a fraction of LIFRalpha involves mechanisms that are separate from signal transduction. These mechanisms include ligand mediated dimerization, internalization, and endosomal/lysosomal degradation. Proteosomal degradation appears to involve a fraction of receptor subunit proteins that are ubiquitinated independently of ligand binding. PMID- 11602602 TI - Structural basis for Ni(2+) transport and assembly of the urease active site by the metallochaperone UreE from Bacillus pasteurii. AB - Bacillus pasteurii UreE (BpUreE) is a putative chaperone assisting the insertion of Ni(2+) ions in the active site of urease. The x-ray structure of the protein has been determined for two crystal forms, at 1.7 and 1.85 A resolution, using SIRAS phases derived from a Hg(2+)-derivative. BpUreE is composed of distinct N- and C-terminal domains, connected by a short flexible linker. The structure reveals the topology of an elongated homodimer, formed by interaction of the two C-terminal domains through hydrophobic interactions. A single Zn(2+) ion bound to four conserved His-100 residues, one from each monomer, connects two dimers resulting in a tetrameric BpUreE known to be formed in concentrated solutions. The Zn(2+) ion can be replaced by Ni(2+) as shown by anomalous difference maps obtained on a crystal of BpUreE soaked in a solution containing NiCl(2). A large hydrophobic patch surrounding the metal ion site is surface-exposed in the biologically relevant dimer. The BpUreE structure represents the first for this class of proteins and suggests a possible role for UreE in the urease nickel center assembly. PMID- 11602601 TI - Residue 457 controls sugar binding and transport in the Na(+)/glucose cotransporter. AB - The Na(+)/glucose cotransporter (SGLT1) is highly selective for its natural substrates, d-glucose and d-galactose. We have investigated the structural basis of this sugar selectivity on the human isoform of SGLT1, single site mutants of hSGLT1, and the pig SGLT3 isoform, expressed in Xenopus oocytes using electrophysiological methods and the effects of cysteine-specific reagents. Kinetics of transport of glucose analogues, each modified at one position of the pyranose ring, were determined for each transporter. Correlation of kinetics with amino acid sequences indicates that residue Gln-457 sequentially interacts with O1 of the pyranose in the binding site, and with O5 in the translocation pathway. Furthermore, correlation of the selectivity characteristics of the SGLT isoforms (SGLT1 transports both glucose and galactose, but SGLT2 and SGLT3 transport only glucose) with amino acid sequence differences, suggests that residue 460 (threonine in SGLT1, and serine in SGLT2 and SGLT3) are involved in hydrogen bonding to O4 of the pyranose. In addition, the results show that substrate specificity of binding is not correlated to substrate specificity of transport, suggesting there are at least two steps in the sugar translocation process. PMID- 11602603 TI - Human tryptase epsilon (PRSS22), a new member of the chromosome 16p13.3 family of human serine proteases expressed in airway epithelial cells. AB - Probing of the GenBank expressed sequence tag (EST) data base with varied human tryptase cDNAs identified two truncated ESTs that subsequently were found to encode overlapping portions of a novel human serine protease (designated tryptase epsilon or protease, serine S1 family member 22 (PRSS22)). The tryptase epsilon gene resides on chromosome 16p13.3 within a 2.5-Mb complex of serine protease genes. Although at least 7 of the 14 genes in this complex encode enzymatically active proteases, only one tryptase epsilon-like gene was identified. The trachea and esophagus were found to contain the highest steady-state levels of the tryptase epsilon transcript in adult humans. Although the tryptase epsilon transcript was scarce in adult human lung, it was present in abundance in fetal lung. Thus, the tryptase epsilon gene is expressed in the airways in a developmentally regulated manner that is different from that of other human tryptase genes. At the cellular level, tryptase epsilon is a major product of normal pulmonary epithelial cells, as well as varied transformed epithelial cell lines. Enzymatically active tryptase epsilon is also constitutively secreted from these cells. The amino acid sequence of human tryptase epsilon is 38-44% identical to those of human tryptase alpha, tryptase beta I, tryptase beta II, tryptase beta III, transmembrane tryptase/tryptase gamma, marapsin, and Esp 1/testisin. Nevertheless, comparative protein structure modeling and functional studies using recombinant material revealed that tryptase epsilon has a substrate preference distinct from that of its other family members. These data indicate that the products of the chromosome 16p13.3 complex of tryptase genes evolved to carry out varied functions in humans. PMID- 11602604 TI - RGS16 function is regulated by epidermal growth factor receptor-mediated tyrosine phosphorylation. AB - Galpha(i)-coupled receptor stimulation results in epidermal growth factor receptor (EGFR) phosphorylation and MAPK activation. Regulators of G protein signaling (RGS proteins) inhibit G protein-dependent signal transduction by accelerating Galpha(i) GTP hydrolysis, shortening the duration of G protein effector stimulation. RGS16 contains two conserved tyrosine residues in the RGS box, Tyr(168) and Tyr(177), which are predicted sites of phosphorylation. RGS16 underwent phosphorylation in response to m2 muscarinic receptor or EGFR stimulation in HEK 293T or COS-7 cells, which required EGFR kinase activity. Mutational analysis suggested that RGS16 was phosphorylated on both tyrosine residues (Tyr(168) Tyr(177)) after EGF stimulation. RGS16 co-immunoprecipitated with EGFR, and the interaction did not require EGFR activation. Purified EGFR phosphorylated only recombinant RGS16 wild-type or Y177F in vitro, implying that EGFR-mediated phosphorylation depended on residue Tyr(168). Phosphorylated RGS16 demonstrated enhanced GTPase accelerating (GAP) activity on Galpha(i). Mutation of Tyr(168) to phenylalanine resulted in a 30% diminution in RGS16 GAP activity but completely eliminated its ability to regulate G(i)-mediated MAPK activation or adenylyl cyclase inhibition in HEK 293T cells. In contrast, mutation of Tyr(177) to phenylalanine had no effect on RGS16 GAP activity but also abolished its regulation of G(i)-mediated signal transduction in these cells. These data suggest that tyrosine phosphorylation regulates RGS16 function and that EGFR may potentially inhibit Galpha(i)-dependent MAPK activation in a feedback loop by enhancing RGS16 activity through tyrosine phosphorylation. PMID- 11602605 TI - Reduced cell migration and disruption of the actin cytoskeleton in calpain deficient embryonic fibroblasts. AB - The physiological functions and substrates of the calcium-dependent protease calpain remain only partly understood. The mu- and m-calpains consist of a mu- or m-80-kDa large subunit (genes Capn1 and Capn2), and a common 28-kDa small subunit (Capn4). To assess the role of calpain in migration, we used fibroblasts obtained from Capn4(-/-) mouse embryos. The cells lacked calpain activity on casein zymography and did not generate the characteristic calpain-generated spectrin breakdown product that is observed in wild-type cells. Capn4(-/-) cells had decreased migration rates and abnormal organization of the actin cytoskeleton with a loss of central stress fibers. Interestingly, these cells extended numerous thin projections and displayed delayed retraction of membrane protrusions and filopodia. The number of focal adhesions was decreased in Capn4( /-) cells, but the cells had prominent vinculin-containing focal complexes at the cell periphery. The levels of the focal adhesion proteins, alpha-actinin, focal adhesion kinase (FAK), spectrin, talin, and vinculin, were the same in Capn4(+/+) and Capn4(-/-) cells. FAK, alpha-actinin, and vinculin were not cleaved in either cell type plated on fibronectin. However, proteolysis of the focal complex component, talin, was detected in the wild-type cells but not in the Capn4(-/-) cells, suggesting that calpain cleavage of talin is important during cell migration. Moreover, talin cleavage was again observed when calpain activity was partially restored in Capn4(-/-) embryonic fibroblasts by stable transfection with a vector expressing the rat 28-kDa calpain small subunit. The results demonstrate unequivocally that calpain is a critical regulator of cell migration and of the organization of the actin cytoskeleton and focal adhesions. PMID- 11602607 TI - Phosphatidylethanolamine has an essential role in Saccharomyces cerevisiae that is independent of its ability to form hexagonal phase structures. AB - Two yeast enzymes, Psd1p and Psd2p, catalyze the decarboxylation of phosphatidylserine to produce phosphatidylethanolamine (PtdEtn). Mitochondrial Psd1p provides approximately 90% of total cellular phosphatidylserine decarboxylase activity. When the PSD1 gene is deleted, the resultant strain (psd1Delta) grows normally at 30 degrees C in glucose and in the absence of exogenous choline or ethanolamine. However, at elevated temperature (37 degrees C) or on the nonfermentable carbon source lactate, the growth of psd1Delta strains is minimal without ethanolamine supplementation. The reduced growth and viability correlate with a PtdEtn content below 4% of total phospholipid. These results suggest that there is a critical level of PtdEtn required to support growth. This theory is supported by growth data revealing that a psd1Delta psd2Delta dpl1Delta strain can only grow in the presence of ethanolamine. In contrast, a psd1Delta psd2Delta strain, which makes low levels of PtdEtn from sphingolipid breakdown, can be rescued by ethanolamine, choline, or the ethanolamine analogue propanolamine. psd1Delta psd2Delta cells grown in 2 mm propanolamine accumulate a novel lipid, which was determined by mass spectrometry to be phosphatidylpropanolamine (PtdPrn). PtdPrn can comprise up to 40% of the total phospholipid content in supplemented cells at the expense of phosphatidylcholine and PtdEtn. The absolute level of PtdEtn required for growth when PtdPrn is present appears to be 1% of the total phospholipid content. The essential function of the PtdEtn in the presence of propanolamine does not appear to be the formation of hexagonal phase lipid, insofar as PtdPrn readily forms hexagonal phase structures detectable by (31)P NMR. PMID- 11602606 TI - Manganese superoxide dismutase in Saccharomyces cerevisiae acquires its metal co factor through a pathway involving the Nramp metal transporter, Smf2p. AB - Eukaryotes express both copper/zinc (SOD1)- and manganese (SOD2)-requiring superoxide dismutase enzymes that guard against oxidative damage. Although SOD1 acquires its copper through a specific copper trafficking pathway, nothing is known regarding the intracellular manganese trafficking pathway for SOD2. We demonstrate here that in Saccharomyces cerevisiae cells delivery of manganese to SOD2 in the mitochondria requires the Nramp metal transporter, Smf2p. SOD2 activity is greatly diminished in smf2Delta mutants, even though the mature SOD2 polypeptide accumulates to normal levels in mitochondria. Treating smf2Delta cells with manganese supplements corrected the SOD2 defect, as did elevating intracellular manganese through mutations in PMR1. Hence, manganese appears to be inaccessible to mitochondrial SOD2 in smf2 mutants. Cells lacking SMF2 also exhibited defects in manganese-dependent steps in protein glycosylation and showed an overall decrease in steady-state levels of accumulated manganese. By comparison, mutations in the cell surface Nramp transporter, Smf1p, had very little impact on manganese accumulation and trafficking. Smf2p resides in intracellular vesicles and shows no evidence of plasma membrane localization, even in an end4 mutant blocked for endocytosis. We propose a model in which Smf2p containing vesicles play a central role in manganese trafficking to the mitochondria and other cellular sites as well. PMID- 11602608 TI - Ligand exchange of major histocompatibility complex class II proteins is triggered by H-bond donor groups of small molecules. AB - Hydrogen bonds (H-bonds) are crucial for the stability of the peptide-major histocompatibility complex (MHC) complex. In particular, the H-bonds formed between the peptide ligand and the MHC class II binding site appear to have a great influence on the half-life of the complex. Here we show that functional groups with the capacity to disrupt hydrogen bonds (e.g. -OH) can efficiently catalyze ligand exchange reactions on HLA-DR molecules. In conjunction with simple carrier molecules (such as propyl or benzyl residues), they trigger the release of low affinity ligands, which permits the rapid binding of peptides with higher affinity. Similar to HLA-DM, these compounds are able to influence the MHC class II ligand repertoire. In contrast to HLA-DM, however, these simple small molecules are still active at neutral pH. Under physiological conditions, they increase the number of "peptide-receptive" MHC class II molecules and facilitate exogenous peptide loading of dendritic cells. The drastic acceleration of the ligand exchange on these antigen presenting cells suggests that, in general, availability of H-bond donors in the extracellular milieu controls the rate of MHC class II ligand exchange reactions on the cell surface. These molecules may therefore be extremely useful for the loading of antigens onto dendritic cells for therapeutic purposes. PMID- 11602609 TI - Sequential roles for phosphatidylinositol 3-phosphate and Rab5 in tethering and fusion of early endosomes via their interaction with EEA1. AB - Early endosome antigen 1 (EEA1) is a 170-kDa polypeptide required for endosome fusion in mammalian cells. The COOH terminus of EEA1 contains a FYVE domain that interacts specifically with phosphatidylinositol 3-phosphate (PtdIns-3-P) and a Rab5 GTPase binding region adjacent to the FYVE domain. The dual interaction of EEA1 with both PtdIns-3-P and Rab5 has been hypothesized to provide the specificity required to target EEA1 to early endosomes. To test this hypothesis, we generated truncated (amino acids 1277--1411) and full-length EEA1 constructs containing point mutations in the COOH terminus that impair Rab5 but not PtdIns-3 P binding. These constructs localized to endosomes in intact cells as efficiently as their wild-type counterparts. Furthermore, overexpression of the truncated constructs, both wild-type and mutated, impaired the function of endogenous EEA1 resulting in the accumulation of small, untethered endosomes. These results suggest that association with Rab5 is not necessary for the initial binding and tethering functions of EEA1. A role for Rab5 binding was revealed, however, upon comparison of endosomes in cells expressing full-length wild-type or mutated EEA1. The mutant full-length EEA1 caused the accumulation of endosome clusters and suppressed the enlargement of endosomes caused by a persistently active form of Rab5 (Rab5Q79L). In contrast, expression of wild-type EEA1 with Rab5Q79L enhanced this enlargement. Thus, endosome tethering depends on the interaction of EEA1 with PtdIns-3-P, and its interaction with Rab5 appears to regulate subsequent fusion. PMID- 11602610 TI - HuA and tristetraprolin are induced following T cell activation and display distinct but overlapping RNA binding specificities. AB - AU-rich elements found in the 3'-untranslated regions of cytokine and proto oncogene transcripts regulate mRNA degradation and function as binding sites for the mRNA-stabilizing protein HuA and the mRNA-destabilizing protein tristetraprolin. Experiments were performed to evaluate the expression of HuA and tristetraprolin in purified human T lymphocytes and to evaluate the ability of these proteins to recognize specific AU-rich sequences. HuA is a predominantly nuclear protein that can also be found in the cytoplasm of resting T lymphocytes. Within 1 h after stimulation of T lymphocytes with anti-T cell receptor antibodies or a combination of a phorbol myristate acetate and ionomycin, an increase in cytoplasmic HuA RNA-binding activity was observed. Although absent in resting cells, cytoplasmic tristetraprolin protein was detected 3-6 h following activation. HuA recognized specific AU-rich sequences found in c-jun or c-myc mRNA that were poorly recognized by tristetraprolin. In contrast, tristetraprolin recognized an AU-rich sequence in interleukin-2 mRNA that was poorly recognized by HuA. Both HuA and tristetraprolin, however, recognized AU-rich sequences from c-fos, interleukin-3, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor mRNA. HuA may transiently stabilize a subset of AU-rich element-containing transcripts following T lymphocyte activation, and tristetraprolin may subsequently mediate their degradation. PMID- 11602611 TI - Structure-function investigation of the interaction of 1- and 2-substituted 3 hydroxypyridin-4-ones with 5-lipoxygenase and ribonucleotide reductase. AB - The structural and physiochemical properties of 3-hydroxypyridin-4-one chelators (HPOs) which influence inhibition of the iron-containing metalloenzymes ribonucleotide reductase (RR) and 5-lipoxygenase (5-LO) have been investigated. HPOs with substituents at the 1- and 2-positions of the pyridinone ring have been synthesized, and their inhibitory properties compared with those of desferrioxamine (DFO). Varying the alkyl substituents does not affect the affinity constant of these ligands for iron(III), but permits a systematic investigation of the effect of hydrophobicity and molecular shape on inhibitory properties. The inhibition of RR was monitored, indirectly by measuring tritiated thymidine incorporation into DNA and directly by the quantification of the EPR signal of the enzyme tyrosyl radical. 5-LO inhibition was examined spectrophotometrically, measuring the rate of linoleic hydroperoxide formation by soybean lipoxygenase. The results indicate that the substituent size introduced at the 2-position of the HPO ring is critical for determining inhibition of both enzymes. Large substituents on the 2-position, introduce a steric factor which interferes with accessibility to the iron centers. These studies have identified chelators such as 1,6-dimethyl-2-(N-4',N-propylsuccinamido)methyl-3 hydroxypyridin-4-one (CP358), which causes only a 10% inhibition of 5-LO after 24 h of incubation at 110 microm IBE (iron-binding equivalents) in comparison to simple dialkyl HPOs such as Deferiprone (CP20) which cause up to 70% inhibition. Using EPR spectroscopy, CP358 inhibits RR at a slower rate than CP20, while chelating intracellular iron(III) at a similar rate, a finding consistent with an indirect inhibition of the tyrosyl radical. However, hepatocellular iron is mobilized at a faster rate by CP358 (P < 0.001). These findings demonstrate that it is possible to design bidentate HPOs which access intracellular iron pools rapidly while inhibiting non-heme iron-containing enzymes relatively slowly, at rates comparable to DFO. It is anticipated that such compounds will possess a superior therapeutic safety margin to currently available bidentate HPOs. PMID- 11602612 TI - The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. AB - The inhibitor-of-apoptosis proteins (IAPs) play a critical role in the regulation of apoptosis by binding and inhibiting caspases. Reaper family proteins and Smac/DIABLO use a conserved amino-terminal sequence to bind to IAPs in flies and mammals, respectively, blocking their ability to inhibit caspases and thus promoting apoptosis. Here we have identified the serine protease Omi/HtrA2 as a second mammalian XIAP-binding protein with a Reaper-like motif. This protease autoprocesses to form a protein with amino-terminal homology to Smac/DIABLO and Reaper family proteins. Full-length Omi/HtrA2 is localized to mitochondria but fails to interact with XIAP. Mitochondria also contain processed Omi/HtrA2, which, following apoptotic insult, translocates to the cytosol, where it interacts with XIAP. Overexpression of Omi/HtrA2 sensitizes cells to apoptosis, and its removal by RNA interference reduces cell death. Omi/HtrA2 thus extends the set of mammalian proteins with Reaper-like function that are released from the mitochondria during apoptosis. PMID- 11602614 TI - Autoimmune diseases: are markers ready for prediction? PMID- 11602613 TI - Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B independent, caspase-3-dependent pathway. AB - Agonistic antibodies against the Fas receptor, when administered to mice in vivo, cause significant apoptosis in the liver. In this study we show that anti-Fas antibody not only causes apoptosis of liver cells but also provokes hepatic inflammation. Two hours after injection of anti-Fas, when mice displayed evidence of caspase-3 activation and apoptosis, we found significant hepatic induction of the CXC chemokines macrophage inflammatory protein-2 and KC. Coincident with the chemokine induction was infiltration of the hepatic parenchyma by neutrophils. Neutralization experiments identified that chemokines were the cause of Fas induced hepatic inflammation, with KC having the predominant effect. Chemokine induction in the livers of anti-Fas-treated mice was not associated with activation of NF-kappa B. Instead, it coincided with nuclear translocation of activator protein-1 (AP-1). AP-1 activation in liver was detected 1-2 h after anti-Fas treatment, suggesting a connection to the onset of apoptosis. When apoptosis was prevented by pretreating mice with a caspase-3 inhibitor, AP-1 activation and hepatic chemokine production were both significantly reduced. Hepatic inflammation was also reduced by 70%. Taken together, these findings indicate that Fas ligation can induce inflammation in the liver in vivo. Inflammation does not arise from Fas-mediated signaling through NF-kappa B; rather, it represents an indirect effect, requiring activation of caspase-3 and nuclear translocation of AP-1. PMID- 11602615 TI - Mechanisms for the induction of autoimmunity by infectious agents. PMID- 11602616 TI - The blooming of the French lilac. PMID- 11602617 TI - Linking a serotonin transporter polymorphism to vascular smooth muscle proliferation in patients with primary pulmonary hypertension. PMID- 11602618 TI - Selective deletion of leptin receptor in neurons leads to obesity. AB - Animals with mutations in the leptin receptor (ObR) exhibit an obese phenotype that is indistinguishable from that of leptin deficient ob/ob mice. ObR is expressed in many tissues, including brain, and the relative importance of leptin's effects on central versus peripheral sites has not been resolved. To address this, we generated mice with neuron-specific (ObR(SynI)KO) and hepatocyte specific (ObR(Alb)KO) disruption of ObR. Among the ObR(SynI)KO mice, the extent of obesity was negatively correlated with the level of ObR in hypothalamus and those animals with the lowest levels of ObR exhibited an obese phenotype. The obese mice with low levels of hypothalamic ObR also show elevated plasma levels of leptin, glucose, insulin, and corticosterone. The hypothalamic levels of agouti-related protein and neuropeptide Y RNA are increased in these mice. These data indicate that leptin has direct effects on neurons and that a significant proportion, or perhaps the majority, of its weight-reducing effects are the result of its actions on brain. To explore possible direct effects of leptin on a peripheral tissue, we also characterized ObR(Alb)KO mice. These mice weigh the same as controls and have no alterations in body composition. Moreover, while db/db mice and ObR(SynI)KO mice have enlarged fatty livers, ObR(Alb)KO mice do not. In summary, these data suggest that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain. PMID- 11602619 TI - Retinoic acid prevents experimental Cushing syndrome. AB - Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome. PMID- 11602620 TI - Requirement for endocytic antigen processing and influence of invariant chain and H-2M deficiencies in CNS autoimmunity. AB - The role of processing in antigen (Ag) presentation and T cell activation in experimental allergic encephalomyelitis (EAE) was evaluated in wild-type mice, mice that selectively express either Ii p31 or p41, and mice completely deficient in Ii or H-2M. We demonstrate that processing of myelin oligodendrocyte glycoprotein (MOG) is required for presentation of the dominant encephalitogenic MOG epitope, p35-55. Ii p31- and p41-expressing mice developed EAE with similar incidence to wild-type mice, although p41 mice had a more severe course. Ag presenting cells (APCs) from Ii- or H-2M-deficient mice could present p35-55, but not MOG, demonstrating that these APCs could not process native MOG. Ii- and H-2M deficient mice were not susceptible to EAE by immunization with p35-55 or MOG or by adoptive transfer of encephalitogenic T cells. However, CD4+ T cells from p35 55-immunized H-2M-deficient mice proliferated, secreted IFN-gamma, and transferred EAE to wild-type, but not H-2M-deficient, mice. Thus, EAE resistance in H-2M-deficient mice is not due to an inability of APCs to present p35-55, or an intrinsic defect in the encephalitogenic T cell repertoire, but reflects a defect in APC function. Our results indicate that processing is required for initial Ag presentation and CNS T cell activation and suggest that autopathogenic peptides of CNS autoantigen may not be readily available for presentation without processing. PMID- 11602621 TI - Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. AB - Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we found that PA-SMCs from patients with PPH grow faster than PA-SMCs from controls when stimulated by serotonin or serum and that these effects are due to increased expression of the serotonin transporter (5-HTT), which mediates internalization of indoleamine. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no longer observed. As compared with controls, the expression of 5-HTT was increased in cultured PA-SMCs as well as in platelets and lungs from patients with PPH where it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, which is associated with 5-HTT overexpression and increased PA-SMC growth, was present in homozygous form in 65% of patients but in only 27% of controls. We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibility to PPH. PMID- 11602622 TI - Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. AB - Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein BP180. Passive transfer of antibodies to the murine BP180 (mBP180) ectodomain triggers a blistering skin disease in mice that depends on complement activation and neutrophil infiltration and closely mimics human BP. In the present study, we show that mast cells (MCs) play a crucial role in experimental BP. Wild-type mice injected intradermally with pathogenic anti-mBP180 IgG exhibited extensive MC degranulation in skin, which preceded neutrophil infiltration and subsequent subepidermal blistering. In contrast, mice genetically deficient in MCs or MC sufficient mice pretreated with an inhibitor of MC degranulation failed to develop BP. Further, MC-deficient mice reconstituted in skin with MCs became susceptible to experimental BP. Despite the activation of complement to yield C3a and C5a, in the absence of MCs, accumulation of neutrophils at the injection site was blunted. The lack of response due to MC deficiency was overcome by intradermal administration of a neutrophil chemoattractant, IL-8, or by reconstitution of the injection sites with neutrophils. These findings provide the first direct evidence to our knowledge that MCs play an essential role in neutrophil recruitment during subepidermal blister formation in experimental BP. PMID- 11602623 TI - Corticotropin-releasing hormone regulates IL-6 expression during inflammation. AB - Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by proinflammatory cytokines results in increased release of glucocorticoid that restrains further development of the inflammatory process. IL-6 has been suggested to stimulate the HPA axis during immune activation independent of the input of hypothalamic corticotropin-releasing hormone (CRH). We used the corticotropin-releasing hormone-deficient (Crh(-/-)) mouse to elucidate the effect of CRH deficiency on IL-6 expression and IL-6-induced HPA axis activation during turpentine-induced inflammation. We demonstrate that during inflammation CRH is required for a normal adrenocorticotropin hormone (ACTH) increase but not for adrenal corticosterone rise. The paradoxical increase of plasma IL-6 associated with CRH deficiency suggests that IL-6 release during inflammation is CRH-dependent. We also demonstrate that adrenal IL-6 expression is CRH-dependent, as its basal and inflammation-induced expression is blocked by CRH deficiency. Our findings suggest that during inflammation, IL-6 most likely compensates for the effects of CRH deficiency on food intake. Finally, we confirm that the HPA axis response is defective in Crh(-/-)/IL-6(-/-) mice. These findings, along with the regulation of IL-6 by CRH, support the importance of the interaction between the immune system and the HPA axis in the pathophysiology of inflammatory diseases. PMID- 11602624 TI - Role of AMP-activated protein kinase in mechanism of metformin action. AB - Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders. PMID- 11602625 TI - Antigenicity and immunogenicity of allogeneic retinal transplants. AB - The transplantation of neuronal cells and tissues represents a promising approach for the treatment of incurable neurodegenerative diseases. Indeed, it has been reported recently that retinal transplantation can rescue photoreceptor cells and delay age-related changes in various retinal layers in rodents. However, retinal grafts deteriorate progressively after placement in recipients' eyes. Here we investigated whether a host's immune response elicited toward the graft contributes to its deterioration. Using an ELISA spot assay, we measured T cell responses to retinal tissues placed in the vitreous cavity of syngeneic and allogeneic mice. We found that allogeneic retinas induced potent alloimmune responses mediated by T cells secreting type 1 cytokines (IFN-gamma and IL-2). No response was found in mice engrafted with syngeneic retinas. In addition, all syngeneic retinal grafts displayed no signs of tissue damage (at 55 days), while the majority of allogeneic retinas deteriorated as early as 12 days after placement. Next, we showed that anti-donor responses occurred within two phenotypically and functionally distinct T cell subsets: CD4+ T cells secreting IL-2 and CD8+ T cells producing IFN-gamma. Importantly, CD4+ T cells were necessary and sufficient to cause graft deterioration, while CD8+ T cells did not contribute to this process. PMID- 11602626 TI - CD4+CD28- costimulation-independent T cells in multiple sclerosis. AB - Multiple lines of evidence suggest that CD4+ lymphocytes initiate autoimmune responses against myelin antigens in multiple sclerosis (MS). The increased frequency of activated myelin-specific cells in MS patients indicates that the activation of autoreactive cells represents a central event in the pathogenesis of the disease. We identified a CD4+ subpopulation that is characterized phenotypically by the persistent absence of surface CD28 expression and functionally by CD28-independent activation and Th1 cytokine secretion. Owing to their costimulation-independent activation and their expression of a full agonist signaling activation pattern, CD4+CD28- cells have the potential to initiate autoimmune responses in the central nervous system, a compartment devoid of professional antigen presenting cells. Long-term memory CD4+CD28- cells produce high amounts of IFN-gamma and maximally upregulate IFN-gamma and IL-12Rbeta2 chain expression in the absence of costimulation. They exhibit prominent growth characteristics and increased survival after activation, likely related to their persistent lack of CTLA-4 surface expression. The CD4+CD28- population is expanded in a subgroup of MS patients. Myelin basic protein-specific cells detected in this cell subset may play an important role in the inflammatory response within the central nervous system. PMID- 11602627 TI - Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development. AB - We examined the kenetics of p15 methylation and expression during myeloid development. We treated human cord blood CD34+ cells with either GM-CSF alone or in combination with stem cell factor and followed methylation at this locus using bisulfite genomic sequencing. CD34+ cells were found to be either fully methylated or completely unmethylated at 27 CpG dinucleotide sites in exon 1 and at 18 CpG sites in the promoter region of the p15 gene. A time-course study showed that the percentage of the allelic methylation of p15 CpG island increased to approximately 50% to 60% until 7 days after cytokine stimulation, then decreased to less than 10% after 21 days. The methylation was also observed in bone marrow CD34+ cells exposed to GM-CSF. p15 expression varied inversely with methylation. Expression was negligible or at low levels until 14 days, after which it increased substantially. The frequency of myeloid colony-forming cells in the progeny decreased and myeloid-specific markers increased in the later stages. Based on our observations on cells grown with GM-CSF and 5-aza-2' deoxycytidine, DNA methylation of the p15 promoter region CpG island appears to be associated with proliferation rather than differentiation of normal human myeloid progenitors. PMID- 11602628 TI - Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. AB - Although insulin regulates metabolism in both brown and white adipocytes, the role of these tissues in energy storage and utilization is quite different. Recombination technology using the Cre-loxP approach allows inactivation of the insulin receptor in a tissue-specific manner. Mice lacking insulin receptors in brown adipocytes show an age-dependent loss of interscapular brown fat but increased expression of uncoupling protein-1 and -2. In parallel, these mice develop an insulin-secretion defect resulting in a progressive glucose intolerance, without insulin resistance. This model provides direct evidence for not only a role for the insulin receptors in brown fat adipogenesis, the data also suggest a novel role of brown adipose tissue in the regulation of insulin secretion and glucose homeostasis. PMID- 11602629 TI - Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. AB - Hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and absent or markedly reduced circulating concentrations of parathyroid hormone. The transcription factor GCMB is predominantly, if not exclusively, expressed in parathyroid cells and is critical for development of the parathyroid glands in mice. Thus, in the present study we examined the GCMB gene, mapped to 6p23-24, as a candidate for isolated hypoparathyroidism. We defined the boundaries of the five exons of the human GCMB gene and then identified a large intragenic mutation in the GCMB genes of the proband of an extensive kindred with isolated hypoparathyroidism. Her parents and several other unaffected relatives were heterozygous for the mutation. Despite an absence of any history of consanguinity, microsatellite analysis showed shared genotypes that flanked the GCMB gene over a span of 5 cM, suggesting that both of the proband's GCMB alleles had been derived from a single common ancestor. Analysis of additional, unrelated cases did not disclose the same mutation. We conclude that homozygous loss of function of the GCMB gene impairs normal parathyroid gland embryology and is responsible for isolated hypoparathyroidism in a subset of patients with this disease. PMID- 11602630 TI - A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunction and apoptosis. AB - Infection with Helicobacter pylori causes chronic gastritis, which is characterized by a dense mucosal infiltration by inflammatory cells such as monocytes/macrophages. H. pylori-induced inflammation is a risk factor for the development of gastric adenocarcinoma, but the mechanisms involved in H. pylori associated carcinogenesis are poorly understood. A cecropin-like H. pylori peptide, Hp(2-20), was found to be a monocyte chemoattractant and activated the monocyte NADPH-oxidase to produce oxygen radicals. The receptors mediating monocyte activation were identified as FPRL1 and the monocyte-specific orphan receptor FPRL2. Hp(2-20)-activated monocytes inhibited lymphocytes with antitumor properties, such as CD56+ natural killer (NK) cells and CD3epsilon+ T cells. The changes observed in NK cells and T cells--a reduced antitumor cytotoxicity, downregulation of CD3zeta expression, and apoptosis--were mediated by Hp(2-20) induced oxygen radicals. Histamine, a gastric mucosal constituent, rescued NK cells and T cells from inhibition and apoptosis by suppressing Hp(2-20)-induced oxygen radical formation. We conclude that H. pylori expression of this monocyte activating peptide contributes to its ability to attract and activate monocytes and reduces the function and viability of antineoplastic lymphocytes. These novel mechanisms may be subject to local, histaminergic regulation in the gastric mucosa. PMID- 11602633 TI - c-Rel regulates interleukin 12 p70 expression in CD8(+) dendritic cells by specifically inducing p35 gene transcription. AB - Interleukin 12 (IL-12) is a 70-kD proinflammatory cytokine produced by antigen presenting cells that is essential for the induction of T helper type 1 development. It comprises 35-kD (p35) and 40-kD (p40) polypeptides encoded by separate genes that are induced by a range of stimuli that include lipopolysaccharide (LPS), DNA, and CD40 ligand. To date, the regulation of IL-12 expression at the transcriptional level has mainly been examined in macrophages and restricted almost exclusively to the p40 gene. Here we show that in CD8(+) dendritic cells, major producers of IL-12 p70, the Rel/nuclear factor (NF)-kappaB signaling pathway is necessary for the induction of IL-12 in response to microbial stimuli. In contrast to macrophages which require c-Rel for p40 transcription, in CD8(+) dendritic cells, the induced expression of p35 rather than p40 by inactivated Staphylococcus aureus, DNA, or LPS is c-Rel dependent and regulated directly by c-Rel complexes binding to the p35 promoter. This data establishes the IL-12 p35 gene as a new target of c-Rel and shows that the regulation of IL-12 p70 expression at the transcriptional level by Rel/NF-kappaB is controlled through both the p35 and p40 genes in a cell type-specific fashion. PMID- 11602631 TI - Receptors for prostaglandin E(2) that regulate cellular immune responses in the mouse. AB - Production of prostaglandin E(2) (PGE(2)) is enhanced during inflammation, and this lipid mediator can dramatically modulate immune responses. There are four receptors for PGE(2) (EP1-EP4) with unique patterns of expression and different coupling to intracellular signaling pathways. To identify the EP receptors that regulate cellular immune responses, we used mouse lines in which the genes encoding each of the four EP receptors were disrupted by gene targeting. Using the mixed lymphocyte response (MLR) as a model cellular immune response, we confirmed that PGE(2) has potent antiproliferative effects on wild-type responder cells. The absence of either the EP1 or EP3 receptors did not alter the inhibitory response to PGE(2) in the MLR. In contrast, when responder cells lacked the EP2 receptor, PGE(2) had little effect on proliferation. Modest resistance to PGE(2) was also observed in EP4-/- responder cells. Reconstitution experiments suggest that EP2 receptors primarily inhibit the MLR through direct actions on T cells. Furthermore, PGE(2) modulates macrophage function by activating the EP4 receptor and thereby inhibiting cytokine release. Thus, PGE(2) regulates cellular immune responses through distinct EP receptors on different immune cell populations: EP2 receptors directly inhibit T cell proliferation while EP2 and EP4 receptors regulate antigen presenting cells functions. PMID- 11602634 TI - Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte binding to lymphatic endothelium. AB - Continuous lymphocyte recirculation between blood and lymphoid tissues forms a basis for the function of the immune system. Lymphocyte entrance from the blood into the tissues has been thoroughly characterized, but mechanisms controlling lymphocyte exit from the lymphoid tissues via efferent lymphatics have remained virtually unknown. In this work we have identified mannose receptor (MR) on human lymphatic endothelium and demonstrate its involvement in binding of lymphocytes to lymphatic vessels. We also show that the binding requires L-selectin, and L selectin and MR form a receptor-ligand pair. On the other hand, L-selectin binds to peripheral lymph node addressins (PNAds) on high endothelial venules (HEVs) that are sites where lymphocytes enter the lymphatic organs. Interestingly, MR is absent from HEVs and PNAds from lymphatic endothelium. Thus, lymphocyte L selectin uses distinct ligand molecules to mediate binding at sites of lymphocyte entrance and exit within lymph nodes. Taken together, interaction between L selectin and MR is the first molecularly defined mechanism mediating lymphocyte binding to lymphatic endothelium. PMID- 11602635 TI - CD8(-) T cell transfectants that express a high affinity T cell receptor exhibit enhanced peptide-dependent activation. AB - T cells are activated by binding of the T cell receptor (TCR) to a peptide-major histocompatibility complex (MHC) complex (pMHC) expressed on the surface of antigen presenting cells. Various models have predicted that activation is limited to a narrow window of affinities (or dissociation rates) for the TCR-pMHC interaction and that above or below this window, T cells will fail to undergo activation. However, to date there have not been TCRs with sufficiently high affinities in order to test this hypothesis. In this report we examined the activity of a CD8-negative T cell line transfected with a high affinity mutant TCR (K(D) = 10 nM) derived from cytotoxic T lymphocyte clone 2C by in vitro engineering. The results show that despite a 300-fold higher affinity and a 45 fold longer off-rate compared with the wild-type TCR, T cells that expressed the mutant TCRs were activated by peptide. In fact, activation could be detected at significantly lower peptide concentrations than with T cells that expressed the wild-type TCR. Furthermore, binding and functional analyses of a panel of peptide variants suggested that pMHC stability could account for apparent discrepancies between TCR affinity and T cell activity observed in several prior studies. PMID- 11602637 TI - In vivo priming of CD4 T cells that produce interleukin (IL)-2 but not IL-4 or interferon (IFN)-gamma, and can subsequently differentiate into IL-4- or IFN gamma-secreting cells. AB - The differentiation of antigen-stimulated naive CD4 T cells into T helper (Th)1 or Th2 effector cells can be prevented in vitro by transforming growth factor (TGF)-beta and anti-interferon (IFN)-gamma. These cells proliferate and synthesize interleukin (IL)-2 but not IFN-gamma or IL-4, and can differentiate into either Th1 or Th2 cells. We have now used two-color Elispots to reveal substantial numbers of primed cells producing IL-2 but not IL-4 or IFN-gamma during the Th1- or Th2-biased immune responses induced by soluble proteins or with adjuvants. These cells were CD4(+)CD44(high) and were present during immediate and long-term immune responses of normal mice. Naive T cell receptor for antigen (TCR) transgenic (DO11.10) T cells were primed in vivo after adoptive transfer into normal hosts and FACS((R)) cloned under conditions that did not allow further differentiation. After clonal proliferation, aliquots of each clone were cultured in Th1- or Th2-inducing conditions. Many in vivo-primed cells were uncommitted, secreting IL-2 but not IL-4 or IFN-gamma at the first cloning step, but secreting either IL-4 or IFN-gamma after differentiation in the appropriate conditions. These in vivo-primed, uncommitted, IL-2-producing cells may constitute an expanded pool of antigen-specific cells that provide extra flexibility for immune responses by differentiating into Th1 or Th2 phenotypes later during the same or subsequent immune responses. PMID- 11602636 TI - Processing of a multiple membrane spanning Epstein-Barr virus protein for CD8(+) T cell recognition reveals a proteasome-dependent, transporter associated with antigen processing-independent pathway. AB - Epstein-Barr virus (EBV) latent membrane protein (LMP)2 is a multiple membrane spanning molecule which lacks ectodomains projecting into the lumen of the endoplasmic reticulum (ER). Human CD8(+) cytotoxic T lymphocytes (CTL)s recognize a number of epitopes within LMP2. Assays with epitope-specific CTLs in two different cell backgrounds lacking the transporter associated with antigen processing (TAP) consistently show that some, but not all, LMP2 epitopes are presented in a TAP-independent manner. However, unlike published examples of TAP independent processing from endogenously expressed antigens, presentation of TAP independent LMP2 epitopes was abrogated by inhibition of proteasomal activity. We found a clear correlation between hydrophobicity of the LMP2 epitope sequence and TAP independence, and experiments with vaccinia minigene constructs expressing cytosolic epitope peptides confirmed that these more hydrophobic peptides were selectively able to access the HLA class I pathway in TAP-negative cells. Furthermore, the TAP-independent phenotype of particular epitope sequences did not require membrane location of the source antigen since (i) TAP-independent LMP2 epitopes inserted into an EBV nuclear antigen and (ii) hydrophobic epitope sequences native to EBV nuclear antigens were both presented in TAP-negative cells. We infer that there is a proteasome-dependent, TAP-independent pathway of antigen presentation which hydrophobic epitopes can selectively access. PMID- 11602638 TI - Legionella pneumophila is internalized by a macropinocytotic uptake pathway controlled by the Dot/Icm system and the mouse Lgn1 locus. AB - The products of the Legionella pneumophila dot/icm genes enable the bacterium to replicate within a macrophage vacuole. This study demonstrates that the Dot/Icm machinery promotes macropinocytotic uptake of L. pneumophila into mouse macrophages. In mouse strains harboring a permissive Lgn1 allele, L. pneumophila promoted formation of vacuoles that were morphologically similar to macropinosomes and dependent on the presence of an intact Dot/Icm system. Macropinosome formation appeared to occur during, rather than after, the closure of the plasma membrane about the bacterium, since a fluid-phase marker preloaded into the macrophage endocytic path failed to label the bacterium-laden macropinosome. The resulting macropinosomes were rich in GM1 gangliosides and glycosylphosphatidylinositol-linked proteins. The Lgn1 allele restrictive for L. pneumophila intracellular replication prevented dot/icm-dependent macropinocytosis, with the result that phagosomes bearing the microorganism were targeted into the endocytic network. Analysis of macrophages from recombinant inbred mouse strains support the model that macropinocytotic uptake is controlled by the Lgn1 locus. These results indicate that the products of the dot/icm genes and Lgn1 are involved in controlling an internalization route initiated at the time of bacterial contact with the plasma membrane. PMID- 11602639 TI - Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein mediated p53 phosphorylation. AB - Syncytia arising from the fusion of cells expressing a lymphotropic human immunodeficiency virus (HIV)-1-encoded envelope glycoprotein complex (Env) gene with cells expressing the CD4/CXCR4 complex undergo apoptosis through a mitochondrion-controlled pathway initiated by the upregulation of Bax. In syncytial apoptosis, phosphorylation of p53 on serine 15 (p53S15) precedes Bax upregulation, the apoptosis-linked conformational change of Bax, the insertion of Bax in mitochondrial membranes, subsequent release of cytochrome c, caspase activation, and apoptosis. p53S15 phosphorylation also occurs in vivo, in HIV 1(+) donors, where it can be detected in preapoptotic and apoptotic syncytia in lymph nodes, as well as in peripheral blood mononuclear cells, correlating with viral load. Syncytium-induced p53S15 phosphorylation is mediated by the upregulation/activation of mammalian target of rapamycin (mTOR), also called FKBP12-rapamycin-associated protein (FRAP), which coimmunoprecipitates with p53. Inhibition of mTOR/FRAP by rapamycin reduces apoptosis in several paradigms of syncytium-dependent death, including in primary CD4(+) lymphoblasts infected by HIV-1. Concomitantly, rapamycin inhibits p53S15 phosphorylation, mitochondrial translocation of Bax, loss of the mitochondrial transmembrane potential, mitochondrial release of cytochrome c, and nuclear chromatin condensation. Transfection with dominant negative p53 has a similar antiapoptotic action as rapamycin, upstream of the Bax upregulation/translocation. In summary, we demonstrate that phosphorylation of p53S15 by mTOR/FRAP plays a critical role in syncytial apoptosis driven by HIV-1 Env. PMID- 11602640 TI - A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. AB - Gene targeting of the adaptor molecule DAP12 in mice caused abnormal distribution and impaired antigen presentation capacity of dendritic cells (DCs). However, the DAP12-associated receptors expressed on DCs and their functions have not been identified yet. Here we show that the triggering receptor expressed on myeloid cells-2 (TREM-2) is a cell surface receptor on human monocyte-derived DCs, which is associated with DAP12. TREM-2/DAP12 promotes upregulation of CC chemokine receptor 7, partial DC maturation, and DC survival through activation of protein tyrosine kinases and extracellular signal-regulated kinase. In contrast to Toll like receptor-mediated signaling, TREM2/DAP12 stimulation is independent of nuclear factor-kappaB and p38 stress-activated protein kinase. This novel DC activation pathway may regulate DC homeostasis and amplify DC responses to pathogens, explaining the phenotype observed in DAP12-deficient mice. PMID- 11602642 TI - Arrested B lymphopoiesis and persistence of activated B cells in adult interleukin 7(-/)- mice. AB - Interleukin 7 is a crucial factor for the development of murine T and B lymphocytes. We now report that, in the absence of interleukin 7, B lymphocyte production takes place exclusively during fetal and perinatal life, ceasing after 7 wk of age. In peripheral organs, however, the pool of B lymphocytes is stable throughout adult life and consists only of cells that belong to the B1 and marginal zone (MZ) compartments. This is accompanied by a 50-fold increase in the frequency of immunoglobulin (Ig)M- and IgG-secreting cells, and the concentration of serum immunoglobulins is increased three- to fivefold. Both the MZ phenotype and the increase in serum IgM are T cell independent. These findings reveal a previously undescribed pathway of B lymphopoiesis that is active in early life and is interleukin 7 independent. This pathway generates B1 cells and a normal sized MZ B lymphocyte compartment. PMID- 11602641 TI - Reprogramming of the macrophage transcriptome in response to interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase. AB - Macrophage activation determines the outcome of infection by Mycobacterium tuberculosis (Mtb). Interferon-gamma (IFN-gamma) activates macrophages by driving Janus tyrosine kinase (JAK)/signal transducer and activator of transcription dependent induction of transcription and PKR-dependent suppression of translation. Microarray-based experiments reported here enlarge this picture. Exposure to IFN-gamma and/or Mtb led to altered expression of 25% of the monitored genome in macrophages. The number of genes suppressed by IFN-gamma exceeded the number of genes induced, and much of the suppression was transcriptional. Five times as many genes related to immunity and inflammation were induced than suppressed. Mtb mimicked or synergized with IFN-gamma more than antagonized its actions. Phagocytosis of nonviable Mtb or polystyrene beads affected many genes, but the transcriptional signature of macrophages infected with viable Mtb was distinct. Studies involving macrophages deficient in inducible nitric oxide synthase and/or phagocyte oxidase revealed that these two antimicrobial enzymes help orchestrate the profound transcriptional remodeling that underlies macrophage activation. PMID- 11602643 TI - Homeostasis of peripheral B cells in the absence of B cell influx from the bone marrow. AB - To study homeostasis of peripheral B lymphocytes in the absence of B cell influx from the bone marrow, we generated a mouse mutant in which the recombination activating gene (RAG)-2 can be inducibly deleted. When RAG-2 was deleted at the age of 8-10 wk, splenic naive follicular B cells were gradually lost over a year of observation, with a half-life of approximately 4.5 mo. By contrast, the pool of marginal zone B cells in the spleen and of B-1 cells in the peritoneal cavity were kept at normal level. In lymph nodes, approximately 90% of the B cells were lost within 4 mo, and B cell numbers remained constant thereafter. Mice in which RAG-2 was deleted at birth maintained a small population of activated B cells with an increased proportion of marginal zone B cells. Additionally, an increase of the pool of IgM secreting cells and B-1a cells was observed. PMID- 11602644 TI - Deamidation of asparagine in a major histocompatibility complex-bound peptide affects T cell recognition but does not explain type B reactivity. AB - We have analyzed a panel of T cell hybridomas specific for the chemically dominant epitope of hen egg-white lysozyme 48-61 which has asparagine 59 as an important T cell receptor contact residue. A number of T cells recognize 48-61 with asparagine at position 59, but not the aspartic acid or isoaspartic acid derivatives. Conversely, we find T cells that specifically recognize 48-61 bearing an isoaspartic acid at residue 59, but not asparagine. For other T cells, asparagine, aspartic acid, or isoaspartic acid at residue 59 is irrelevant. We present evidence that our previous distinction between type A and type B T cells is not explained by asparagine deamidation at residue 59. PMID- 11602645 TI - CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. AB - Human plasmacytoid dendritic cells (pDCs) are major producers of IFNalpha, are activated by CpG motifs, and are believed to enter lymph nodes (LNs) via L selectin dependent extravasation across high endothelial venules. To identify a similar murine DC type, CD11c(+) cells in the LNs of L-selectin-deficient and control BALB/c mice were compared, revealing a population of CD11c(+)CD11b(-) cells that is reduced 85% in the LNs of L-selectin-deficient mice. These cells are Gr-1(+)B220(+)CD19(-), either CD4(+) or CD8(+), and localize within T cell zones of LNs. Freshly isolated CD11c(+)Gr-1(+) cells express major histocompatibility complex class II at low levels, display a plasmacytoid morphology, and survive poorly in culture. Their survival is increased and they develop a DC-like morphology in interleukin 3 and CpG. Like human pDCs, CD11c(+)Gr-1(+) cells stimulate T cell proliferation after activation with CpG and produce IFNalpha after stimulation with influenza virus. These cells also display a strain-specific variation in frequency, being fivefold increased in the LNs of BALB/c relative to C57BL/6 mice. These CD11c(+)CD11b(-)B220(+)Gr-1(+) cells appear to be the murine equivalent of human pDCs. PMID- 11602646 TI - Dendritic cell maturation overrules H-2D-mediated natural killer T (NKT) cell inhibition: critical role for B7 in CD1d-dependent NKT cell interferon gamma production. AB - Given the broad expression of H-2 class Ib molecules on hematopoietic cells, antigen presentation pathways among CD1d expressing cells might tightly regulate CD1d-restricted natural killer T (NKT) cells. Bone marrow-derived dendritic cells (BM-DCs) and not adherent splenocytes become capable of triggering NK1.1(+)/T cell receptor (TCR)(int) hepatic NKT cell activation when (a) immature BM-DCs lack H-2D(b)-/- molecules or (b) BM-DCs undergo a stress signal of activation. In such conditions, BM-DCs promote T helper type 1 predominant CD1d-restricted NKT cell stimulation. H-2 class Ia-mediated inhibition involves more the direct H 2D(b) presentation than the indirect Qa-1(b) pathway. Such inhibition can be overruled by B7/CD28 interactions and marginally by CD40/CD40L or interleukin 12. These data point to a unique regulatory role of DCs in NKT cell innate immune responses and suggest that H-2 class Ia and Ib pathways differentially control NKT cell recognition of DC antigens. PMID- 11602648 TI - Regulation of adult neurogenesis by psychotropic drugs and stress. AB - Proliferation and maturation of neurons has been demonstrated to occur at a significant rate in discrete regions of adult brain, including the hippocampus and subventricular zone. Moreover, adult neurogenesis is an extremely dynamic process that is regulated in both a positive and negative manner by neuronal activity and environmental factors. It has been suggested to play a role in several important neuronal functions, including learning, memory, and response to novelty. In addition, exposure to psychotropic drugs or stress regulates the rate of neurogenesis in adult brain, suggesting a possible role for neurogenesis in the pathophysiology and treatment of neurobiological illnesses such as depression, post-traumatic stress disorder, and drug abuse. As the mechanisms that control adult neurogenesis continue to be identified, the exciting prospect of developing pharmacological agents that specifically regulate the proliferation and maturation of neurons in the adult brain could be fulfilled. PMID- 11602647 TI - T cell-independent interleukin 15Ralpha signals are required for bystander proliferation. AB - Cytokine driven or "bystander" proliferation of T cells occurs in vivo independently of major histocompatibility complex-T cell receptor interactions. This process may be important for supporting T cell homeostasis and facilitating T cell responses to microbial antigens, and may involve the cytokine interleukin (IL)-15. In this study, we find that IL-15Ralpha-deficient (IL-15Ralpha(-/-)) mice fail to undergo poly I:C or IL-15 driven bystander proliferation of CD8(+) T cells. Surprisingly, IL-15Ralpha(-/-) CD8(+) T cells proliferate in response to poly I:C when adoptively transferred into normal mice, and normal CD8(+) T cells fail to proliferate in IL-15Ralpha(-/-) mice. Normal mice reconstituted with IL 15Ralpha(-/-) bone marrow cells also fail to exhibit bystander responses. Thus, CD8(+) T cell independent IL-15Ralpha signals from radiation sensitive hematopoietic cells are likely required for bystander responses. Moreover, normal CD8(+) T cells proliferate in IL-15Ralpha(-/-) mice after treatment with IL-15. Therefore, IL-15Ralpha signals may mediate a positive feedback loop involving the further physiological production of IL-15. These findings provide new insights into how IL-15Ralpha supports memory phenotype CD8(+) T cell proliferation, and suggest novel mechanisms by which memory CD8(+) T cells are maintained in vivo. PMID- 11602649 TI - Estrogenic actions in the brain: estrogen, phytoestrogens, and rapid intracellular signaling mechanisms. AB - The endogenous gonadal steroid 17beta-estradiol (E2) plays an important role in the development, maturation, and function of a wide variety of reproductive and nonreproductive tissues, including those of the nervous system. The actions of E2 at target tissues can be divided into 1) long-term "genomic" actions that are mediated by intracellular estrogen receptor-induced changes in gene expression and 2) rapid actions that modulate a diverse array of intracellular signal transduction cascades. Environmental estrogens are compounds present in the environment that can mimic, and in some cases antagonize, the effects of endogenous estrogens. As a result of these actions, there is currently much interest within the scientific community regarding the relative benefits or threats associated with exposure to different environmental estrogens. Within the general public there is considerable acceptance of the benefits associated with increased use of "natural" estrogens as a component of a healthy diet and in postmenopausal women as an alternative to estrogen replacement therapies. First, this review will focus attention on the role of estrogens in the central nervous system by briefly discussing some of the known mechanisms through which estrogen's effects are mediated, focusing on rapid intracellular signaling mechanisms during neurodevelopment. Second, with the hope of bringing attention to an area of study that until recently has received little consideration, we will briefly discuss phytoestrogens and suggest that these compounds have the potential to influence rapid E2-induced mechanisms in the nervous system in ways that may result in modified brain functions. PMID- 11602650 TI - Prodigiosin blocks T cell activation by inhibiting interleukin-2Ralpha expression and delays progression of autoimmune diabetes and collagen-induced arthritis. AB - Prodigiosin (PDG) was previously reported to be a T cell-specific immunosuppressant. Here we describe the mechanism of action of PDG in T cells and the effect of PDG on autoimmune diseases. PDG selectively suppresses concanavalin A (Con A)-induced T cell proliferation, but has little effect on lipopolysaccharide-induced proliferation of B cells and nitric oxide production of macrophages. Although PDG does not block interleukin (IL)-2 production, it efficiently inhibits interleukin-2 receptor alpha-chain (IL-2Ralpha) expression, and this results in a disruption of the IL-2/IL-2R signaling pathway, on which a great part of the regulation of T cell activation depends. PDG blocks T cell differentiation into effector helper T cells secreting interferon-gamma and IL-4 as well as into effector cytotoxic T lymphocytes expressing perforin, which is at least in part resulting from inhibition of the IL-2/IL-2R signaling. PDG indirectly blocks signal transducer and activator of transcription activation by inhibiting cytokine signalings in Con A-activated T cells, although it does not inhibit the activation of nuclear factor-kappaB, nuclear factor of activated T cells, and activator protein-1. As direct evidence of immunosuppression in vivo, we show that PDG markedly reduced blood glucose levels and cellular infiltration into the pancreatic islets in nonobese diabetic mice, and that it also delays the onset of collagen-induced arthritis in DBA/1 mice. In conclusion, our results demonstrate that PDG has a unique mode of action, namely, that it blocks T cell activation by inhibiting primarily IL-2Ralpha expression in the IL-2/IL-2R signaling, and show that this compound represents a promising immunosuppressant candidate for the treatment of autoimmune diseases. PMID- 11602651 TI - Nontoxic doses of suramin enhance activity of doxorubicin in prostate tumors. AB - We recently reported that acidic and basic fibroblast growth factors (aFGF and bFGF) confer a broad-spectrum chemoresistance in solid tumors, and that inhibitors of these proteins enhanced the antitumor activity of several anticancer drugs. The present study investigated the effect of FGF inhibitors on doxorubicin activity in human prostate PC3 tumors. In in vitro studies, conditioned medium (CM) obtained from histocultures of rat MAT-LyLu lung metastases and different combinations of recombinant FGF induced a 7- to 15-fold doxorubicin resistance. Suramin had no effect on the doxorubicin activity in the absence of CM or FGF, but reversed the CM- and FGF-induced resistance by > or =90% at concentrations that had no cytotoxicity (i.e., 1-17 microM suramin). In the in vivo study, immunodeficient mice bearing well established, subcutaneous PC3 tumors (approximately 100 mg in size) were treated intravenously with doxorubicin (5 mg/kg) and suramin (10 mg/kg), administered twice weekly for 3 weeks. The suramin dose, selected to yield plasma concentration of below 50 microM, had neither antitumor activity nor toxicity. Doxorubicin alone reduced tumor growth rate by approximately 60%, reduced the density of nonapoptotic tumor cells by approximately 60%, enhanced the apoptotic cell fraction by 4-fold, and reduced the body weight by approximately 15% (p < 0.05 compared with control). Addition of suramin to doxorubicin therapy did not increase weight loss but significantly enhanced the antitumor effect, resulting in complete inhibition of tumor growth, an additional 3-fold reduction in the density of nonapoptotic tumor cells, and an additional 2-fold enhancement of the apoptotic tumor cell fraction (p < 0.05 compared with all other groups). These data indicate significant enhancement of the effectiveness of doxorubicin in prostate tumors by nontoxic and subtherapeutic doses of suramin. PMID- 11602652 TI - cDNA microarray analysis of multidrug resistance: doxorubicin selection produces multiple defects in apoptosis signaling pathways. AB - Doxorubicin plays an important role in the treatment of leukemias, lymphomas, and a variety of carcinomas. Tumor cell resistance to doxorubicin is often associated with expression of the multidrug resistance gene MDR1, which codes for the drug efflux pump P-glycoprotein, and a multidrug-resistant phenotype. Evidence from multiple sources suggests, however, that additional genes besides MDR1 are involved in development of multidrug resistance. To identify genes involved in the multidrug resistance phenotype, we created a 5760-gene cDNA microarray to search for differentially expressed genes between the human multiple myeloma cell line RPMI 8226 and its doxorubicin-selected sublines 8226/Dox6 and 8226/Dox40, both of which express MDR1 and are multidrug-resistant. The cDNA microarray results identified a set of differentially expressed genes, which included MDR1 as expected. Thirty Northern analyses were used to confirm the results of the cDNA microarrays; comparison with the microarray results showed a 90% agreement between the two techniques. Within the set of differentially expressed genes identified by the cDNA microarrays, 29 were of particular interest as they can participate in apoptotic signaling, particularly as mediated by ceramide and the mitochondrial permeability transition. The functional importance of these changes in gene expression is supported by their explanation of the 8226/Dox cell lines' cross-resistance to substances that are not P-glycoprotein substrates, such as Fas/CD95 ligand and staurosporine. We conclude that doxorubicin selection led to changes in gene expression that reduce the apoptotic response to death-inducing stimuli and thus contribute to the multidrug resistance phenotype. PMID- 11602653 TI - Preventing gut leakiness by oats supplementation ameliorates alcohol-induced liver damage in rats. AB - Only 30% of alcoholics develop liver disease (ALD) suggesting that additional factors are needed. Endotoxin is one such factor, but its etiology is unclear. Since the gut is the main source of endotoxin, we sought to determine whether an increase in intestinal permeability (leaky gut) is required for alcohol-induced endotoxemia and liver injury and whether the gut leakiness is preventable. For 10 weeks, rats received by gavage increasing alcohol doses (to 8 g/kg/day) and either oats (10 g/kg) or chow b.i.d. Intestinal permeability was then assessed by urinary excretion of lactulose and mannitol. Liver injury was evaluated histologically, biochemically (liver fat content), and by serum aminotransferase. Alcohol caused gut leakiness that was associated with both endotoxemia and liver injury. Oats prevented these changes. We conclude that chronic gavage of alcohol in rats is a simple experimental model that mimics key aspects of ALD, including endotoxemia and liver injury, and can be useful to study possible mechanisms of endotoxemia in ALD. Since preventing the gut leakiness by oats also prevented the endotoxemia and ameliorated liver damage in rat, our results suggest that alcohol induced gut leakiness 1) may cause alcohol-induced endotoxemia and liver injury and 2) may be the critical cofactor in the 30% of alcoholics who develop ALD. Further studies are needed to determine whether ALD in humans can be prevented by preventing alcohol-induced gut leakiness, studies that should lead to the development of useful therapeutic agents for the prevention of ALD. PMID- 11602654 TI - Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function. AB - The present study investigated the effects of the selective neurokinin-2 (NK2) receptor antagonist SR48968 in behavioral, electrophysiological, and biochemical tests sensitive to the action of prototypical antidepressants (fluoxetine, imipramine) or to corticotropin-releasing factor (CRF) receptor antagonists, which have been proposed recently as potential antidepressants. Results showed that SR48968 (0.3-10 mg/kg i.p.) produced antidepressant-like activity because it reduced immobility in the forced swimming test in both mice and rats, and decreased the amount of maternal separation-induced vocalizations in guinea pig pups. This latter effect appears to involve a reduction of stress-induced substance P release because SR48968 reduced the separation-induced increase in the number of neurons displaying neurokinin-1 receptor internalization in the amygdala. Furthermore, SR48968 increased the expression of the cAMP response element binding protein mRNA in the rat hippocampus after repeated (1 mg/kg i.p., 21 days), but not acute administration. Finally, neuronal firing of the locus coeruleus (LC) and noradrenergic (NE) release in the prefrontal cortex both elicited by an uncontrollable stressor or an intraventricular administration of CRF were reduced by SR48968 (0.3-1 mg/kg i.p.). The finding that SR48968 (1 mg/kg i.p.) blocked the cortical release of NE induced by an intra-LC infusion of the preferential NK2 receptor agonist neurokinin A suggested the presence of NK2 receptors in this latter region. Importantly, SR48965 (1-10 mg/kg i.p.), the optical antipode of SR48968, which is devoid of affinity for the NK2 receptor, was inactive in all the models used. These data suggest that NK2 receptor blockade may constitute a novel mechanism in the treatment of depression and CRF related disorders. PMID- 11602655 TI - Characterization of novel kidney-specific delivery system using an alkylglucoside vector. AB - The alkylglucoside vector has been demonstrated to be a kidney-specific drug delivery system via cell surface-specific binding sites. In the present study, we examined the targeting efficiency of this vector derivatized with several types of ligand to determine the efficacy and limitations of this system. The tissue uptake clearance in the kidney (CL(uptake, kidney)) of alkylglucoside-acylated poly-L-lysine conjugates (Glc-S-C8-APL) with a mol. wt. of 4,500, 17,000, or 41,000 was greater than that accounted for by glomerular filtration and was reduced by coadministration of n-octyl-thioglucoside, which has an affinity for alkylglycoside binding sites. The mol. wt. distribution, assessed by gel filtration high-performance liquid chromatography, of the radioactivity associated with the kidney after intravenous administration of Glc-S-C8-APL41000 was shifted to a lower mol. wt. range compared with the authentic compound. The CL(uptake, kidney) and specific binding of Glc-S-C8-APL, fractionated based on mol. wt., to kidney membrane fractions was reduced as the mol. wt. of the fractionated Glc-S-C8-APL increased. These results suggest that the target efficiency of this vector depends on the size of the ligand that it delivers. Both the CL(uptake, kidney) and specific binding to kidney membranes of an alkylglucoside-tyrosine conjugate (Glc-S-C8-Tyr) with an acidic charge was much lower than that of Glc-S-C8-Tyr with cationic and neutral charges, suggesting that the anionic moiety could reduce the renal targeting efficiency. Thus, the targeting efficacy of the alkylglucoside vector seems to depend on, at least, the size and charge of the ligand that it delivers. PMID- 11602656 TI - Functional characterization of cyclooxygenase-2 polymorphisms. AB - Cyclooxygenases (COX)-1 and -2 are the key enzymes in the conversion of arachidonic acid to prostaglandins. COX-2 appears to play an emerging role in inflammation and carcinogenesis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used for the treatment of numerous diseases and reduce the risk of developing colorectal cancer. Polymorphisms in the COX-2 gene could alter enzyme expression, function, and/or the response to NSAIDs. Therefore, they could modify individual risks for developing cancer and other diseases or the occurrence of side effects or sensitivity toward selective or nonselective COX inhibitors. We sequenced the COX-2 gene of 72 individuals and identified rare polymorphisms in the promoter and the coding region. A COX-2 molecular model was used to locate the coding region polymorphisms relative to functional sites in the protein, and the COX-2 V511A polymorphism was very near to the active site. This variant protein was expressed, and function was evaluated, but no difference was detected in metabolism of the COX-2 substrates, arachidonic acid, linoleic acid, and 2 arachidonyl glycerol, compared with the wild type. The Km values for arachidonic acid showed no differences between the COX-2 wild type and V511A mutant. Inhibition with selective or nonselective COX inhibitors was essentially the same for the two enzymes. The absence of functionally important polymorphisms in the COX-2 gene may suggest that there has been selective pressure against those single nucleotide polymorphisms because of the critical role of this enzyme in maintenance of homeostasis. PMID- 11602657 TI - Dependence of delta1-opioid receptor-induced cardioprotection on a tyrosine kinase-dependent but not a Src-dependent pathway. AB - We investigated the possibility that opioids activate a tyrosine kinase (TK) that mediates cardioprotection in an in vivo rat model of myocardial infarction. All animals underwent 30 min of regional ischemia and 2 h of reperfusion. Infarct size was expressed as a percentage of the area at risk (IS/AAR). Control animals had an IS/AAR of 58.2 +/- 0.6. Cardioprotection was induced with the delta1- or delta1/delta2-selective opioid agonists, TAN-67, or D-Ala D-Leu enkephalin (DADLE). Both significantly reduced IS/AAR (28.8 +/- 3.6 and 34.8 +/- 3.8, respectively). The general TK inhibitor, genistein, abolished cardioprotection produced by TAN-67 or DADLE (59.1 +/- 3.2 and 61.5 +/- 3.4, respectively), whereas the structural analog, daidzein, lacking TK inhibitory activity, did not. Interestingly, the selective Src/epidermal growth factor (EGF) receptor TK inhibitor, lavendustin A, did not abolish TAN-67-induced cardioprotection (22.1 +/- 6.8). Similarly, the Src-selective TK antagonist, PP2, had no effect on DADLE induced cardioprotection (31.1 +/- 7.3). These unexpected findings suggest that Src and EGF receptor TKs are not important in the genesis of cardioprotection produced by TAN-67. Finally, we demonstrate that genistein did not affect protein kinase C (PKC) translocation induced by TAN-67. These data suggest that a TK, but most likely not an Src/EGF receptor TK, is important in cardioprotection via opioid receptor stimulation and that the pathway for TK activation is downstream from or parallel to PKC activation in the in situ rat heart since genistein could not affect PKC translocation of selective isoforms induced by TAN-67 and assessed by immunohistochemistry. PMID- 11602658 TI - Mechanism of pluronic effect on P-glycoprotein efflux system in blood-brain barrier: contributions of energy depletion and membrane fluidization. AB - Pluronic block copolymer, P85, inhibits the P-glycoprotein (Pgp) drug efflux system and increases the permeability of a broad spectrum of drugs in the blood brain barrier (BBB). This study examines the mechanisms by which P85 inhibits Pgp using bovine brain microvessel endothelial cells (BBMEC) as an in vitro model of the BBB. The hypothesis was that simultaneous alterations in intracellular ATP levels and membrane fluidization in BBMEC monolayers by P85 results in inhibition of the drug efflux system. The methods included the use of 1) standard Pgp substrate rhodamine 123 to assay the Pgp efflux system in BBMEC, 2) luciferin/luciferase assay for ATP intracellular levels, and 3) 1,6-diphenyl 1,3,5-hexatriene for membrane microviscosity. Using 3H-labeled P85 and fluorescein-labeled P85 for confocal microscopy, this study suggests that P85 accumulates in the cells and intracellular organelles such as the mitochondria where it can interfere with metabolic processes. Following exposure of BBMEC to P85, the ATP levels were depleted, and microviscosity of the cell membranes was decreased. Furthermore, P85 treatment decreased Pgp ATPase activity in membranes expressing human Pgp. A combination of experiments examining the kinetics, concentration dependence, and directionality of P85 effects on Pgp-mediated efflux in BBMEC monolayers suggests that both energy depletion (decreasing ATP pool available for Pgp) and membrane fluidization (inhibiting Pgp ATPase activity) are critical factors contributing to the activity of the block copolymer in the BBB. PMID- 11602659 TI - A growth factor mixture that significantly enhances angiogenesis in vivo. AB - Studies of therapeutic angiogenesis have generally focused on single growth factor strategies. However, multiple factors participate in angiogenesis. We evaluated the angiogenic potential of a growth factor mixture (GFm) derived from bovine bone. The major components of GFm (SDS-polyacrylamide gel electrophoresis, mass spectrometry, and Western blot) include transforming growth factor-beta1-3, bone morphogenic protein-2-7, and fibroblast growth factor-1. GFm was first shown to induce an angiogenic response in chorioallantoic membranes. Next, myocardial ischemia was induced in 21 dogs (ameroid) that were randomized 3 weeks later to received GFm 1 mg/ml (I), GFm 10 mg/ml (II), or placebo (P) (with investigators blinded to conditions) injected in and adjacent to ischemic myocardium. Dogs were assessed 6 weeks later using quantitative and semiquantitative measures. There were GFm concentration-dependent improvements in distal left anterior descending artery (LAD) opacification by angiography (P: 0.4 +/- 0.2, I: 1.1 +/- 0.14, II: 1.6 +/- 0.3, angiographic score p = 0.014). Histologically, there was also concentration-dependent vascular growth response of relatively large vessels (P: 0.21 +/- 0.15, I: 1.00 +/- 0.22, II: 1.71 +/- 0.18, vascular growth score p = 0.001). Resting myocardial blood flow (colored microspheres) was not significantly impaired in any group. However, maximum blood flow (adenosine) was reduced in ischemic territories and did not improve in GFm-treated hearts. GFm, a multiple growth factor mixture, is a potent angiogenic agent that stimulates large vessel growth. Although blood flow did not improve during maximal vasodilatory stress, large intramyocardial collateral vessels developed and angiographic visualization of the occluded distal LAD improved significantly. The use of multiple growth factors may be an effective strategy for therapeutic angiogenesis provided a more effective delivery strategy is devised that can achieve improved maximum blood flow potential. PMID- 11602660 TI - Modulation of N-type Ca2+ currents by A1-adenosine receptor activation in male rat pelvic ganglion neurons. AB - Modulation of voltage-activated Ca2+ channels by adenosine was investigated in male rat major pelvic ganglion (MPG) neurons by using the whole-cell variant of the patch-clamp technique. Adenosine inhibited high voltage-activated (HVA) Ca2+ currents in a concentration-dependent manner with an EC50 of 313 nM and a maximal inhibition of 36%, respectively. Inhibition of HVA Ca2+ currents in adrenergic and cholinergic MPG neurons was similar. Adenosine did not modulate T-type Ca2+ channels present in adrenergic MPG neurons. Reverse transcription-polymerase chain reaction analysis indicated that MPG neurons express mRNAs encoding A1 and A2a receptors. Ca2+ current inhibition by adenosine was mimicked by N6 cyclopentyladenosine, an A1-selective agonist (EC50 = 63 nM) and prevented by 100 nM 8-cyclopentyl-1,3-dipropylxanthine, an A1-selective antagonist. Conversely, CGS 21680, an A2a-selective agonist, displayed a relatively low potency (EC50 = 2200 nM) for inhibiting Ca2+ currents. The action of adenosine was significantly attenuated by 2 mM guanosine-5'-thiodiphosphate or 500 ng/ml pertussis toxin. The voltage dependence of adenosine-induced current inhibition was evident by 1) a bell-shaped profile between the current inhibition and test potentials, 2) kinetic slowing in the presence of agonist, and 3) relief of the current inhibition by a conditioning prepulse to +80 mV. Finally, 1 microM omega conotoxin GVIA occluded adenosine-induced current inhibition. Taken together, we concluded that adenosine inhibits N-type Ca2+ currents by activation of A1 receptors via a voltage-dependent and PTX-sensitive pathway in rat MPG neurons. Our data may explain how adenosine acts as an inhibitory modulator of ganglionic and neuromuscular transmission in the pelvic plexus. PMID- 11602661 TI - Differential effects of D1- and D2-like compounds on cocaine self-administration in Lewis and Fischer 344 inbred rats. AB - Genetic factors influence behavioral responses to cocaine as seen in comparisons of Lewis and Fischer 344 inbred rats. Lewis rats have lower D2-like receptor and Gi(alpha) levels in nucleus accumbens, an important area in behavioral responses to cocaine. This study assessed the effects of manipulating D2- and D1 levels pharmacologically in these strains. Experiment 1 investigated how the D2-like antagonist eticlopride (0.01-0.1 mg/kg), the D1-like antagonist SCH 23390 (0.005 0.05 mg/kg), the D2/D3 agonist quinpirole (0.001-0.1 mg/kg), and the partial D1 agonist SKF 38393 (0.1-10 mg/kg) affected responding for food under a fixed ratio 15 schedule. Quinpirole disrupted rates more readily in Lewis versus Fischer 344 rats. In experiment 2, the effects of these agents on cocaine discrimination (10 mg/kg) were examined. Quinpirole substituted and SCH 23390-attenuated cocaine discrimination in both strains. Doses of the drugs that did not disrupt responding in these experiments were tested in cocaine self-administration in experiment 3. Cocaine self-administration (0.25-1.0 mg/kg) was increased by eticlopride (0.03 mg/kg) in Lewis rats but had no effect in Fischer 344 rats, whereas SCH 23390 (0.01 mg/kg) led to greater increased cocaine self administration in Fischer 344 versus Lewis rats. The dopamine agonists had differential effects on cocaine self-administration in the strains. Cocaine self administration was decreased in Lewis rats and increased in Fischer 344 rats by SKF 38393 (1 mg/kg). These data show that manipulating D1- and D2-like receptor availability has strain-selective effects on the reinforcing, but not discriminative stimulus, effects of cocaine that are predicted by inherent differences in nucleus accumbens receptor populations. PMID- 11602662 TI - FR167653, a cytokine synthesis inhibitor, exhibits anti-inflammatory effects early in rat carrageenin-induced pleurisy but no effect later. AB - We prepared a pharmacological profile of FR167653 (1-[7- (4-fluorophenyl)-1,2,3,4 tetrahydro-8-(4-pyridyl) pyrazolo[5,1-c][1,2,4]triazin-2-yl]-2-phenylethanedion sulfate monohydrate), a cytokine synthesis inhibitor, on early (5 h after irritation) and late (14-24 h after irritation) phases of rat carrageenin-induced pleurisy and on mediator-induced plasma exudation, in comparison with that of dexamethasone. In the early phase, FR167653 (30 mg/kg) and dexamethasone (0.3 mg/kg) equipotently suppressed plasma exudation and leukocyte infiltration. Furthermore, both agents significantly lowered the prostanoid levels in the exudate. Expression of cyclooxygenase-2 protein on leukocytes in the early phase of inflammation was not affected by dexamethasone, but it was suppressed by FR167653. However, FR167653 did not significantly affect the leukocyte mRNA level of cyclooxygenase-2. Both agents significantly suppressed the levels of both tumor necrosis factor-alpha and interleukin-1beta. FR167653 had a different pharmacological profile from dexamethasone in the late phase of this model in that, unlike dexamethasone, it did not affect cyclooxygenase-2 expression in mesothelial cells, the 6-keto-prostaglandin F1alpha level in the exudate or hyperplasia of mesothelium. Furthermore, unlike dexamethasone, FR167653 did not consistently inhibit mediator-induced plasma exudation. These results suggest that FR167653 or one of its analogs may be new candidates for therapy with a spectrum of activity distinct from that of current anti-inflammatory steroids. PMID- 11602663 TI - Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent: supersensitivity of acetylcholinesterase knockout mouse to VX lethality. AB - The possibility that organophosphate toxicity is due to inhibition of targets other than acetylcholinesterase (AChE, EC 3.1.1.7) was examined in AChE knockout mice. Mice (34-55 days old) were grouped for this study, after it was determined that AChE, butyrylcholinesterase (BChE), and carboxylesterase activities had reached stable values by this age. Mice with 0, 50, or 100% AChE activity were treated subcutaneously with the nerve agent VX. The LD50 for VX was 10 to 12 microg/kg in AChE-/-, 17 microg/kg in AChE+/-, and 24 microg/kg in AChE+/+ mice. The same cholinergic signs of toxicity were present in AChE-/- mice as in wild type mice, even though AChE-/- mice have no AChE whose inhibition could lead to cholinergic signs. Wild-type mice, but not AChE-/- mice, were protected by pretreatment with atropine. Tissues were extracted from VX-treated and untreated animals and tested for AChE, BChE, and acylpeptide hydrolase activity. VX treatment inhibited 50% of the AChE activity in brain and muscle of AChE+/+ and +/- mice, 50% of the BChE activity in all three AChE genotypes, but did not significantly inhibit acylpeptide hydrolase activity. It was concluded that the toxicity of VX must be attributed to inhibition of nonacetylcholinesterase targets in the AChE-/- mouse. Organophosphorus ester toxicity in wild-type mice is probably due to inhibition or binding to several proteins, only one of which is AChE. PMID- 11602664 TI - Intravenous human interleukin-1alpha impairs memory processing in mice: dependence on blood-brain barrier transport into posterior division of the septum. AB - Peripherally administered cytokines profoundly affect the central nervous system (CNS). One mechanism by which they could affect the CNS is by crossing the blood brain barrier (BBB) to interact directly with brain receptors. Human and murine IL-1alpha (hIL-1alpha; mIL-1alpha) are transported across the murine BBB with a high rate of transport into the posterior division of the septum (PDS), but it is unknown whether BBB transport is relevant to their actions. Here, we injected species-specific blocking antibodies into the PDS to determine whether transport across the BBB is required for blood-borne hIL-1alpha to affect memory. Retention was impaired in a dose-dependent manner when hIL-1alpha was injected either by tail vein (i.v.) or into the PDS, with the PDS route being 1000 times more potent. About 70% of the memory impairment induced by i.v. hIL-1alpha was reversed by injecting a blocking antibody (Ab) specific for hIL-1alpha into the PDS. This shows that much of the memory impairment induced by hIL-1alpha depends on its ability to cross the BBB. Ab specific for mIL-1alpha was also effective in reversing memory impairment, showing that hIL-1alpha releases mIL-1alpha from endogenous stores. Whether the mIL-1alpha was released from peripheral stores, which would require it to cross the BBB, or from brain stores is unknown. In conclusion, these results show that exogenous, blood-borne hIL-1alpha affects memory by releasing mIL-1alpha from endogenous stores and by crossing the BBB to act at sites within the PDS. PMID- 11602665 TI - Low doses of nicotine and ethanol induce CYP2E1 and chlorzoxazone metabolism in rat liver. AB - The use of ethanol and nicotine is strongly linked; 80 to 95% of heavy alcohol users are also smokers. In humans, cigarette smoking significantly enhances CYP2E1 activity, as measured by increased metabolism of chlorzoxazone in vivo. CYP2E1 metabolizes ethanol and can generate toxic intermediates. CYP2E1 also bioactivates tobacco smoke and other procarcinogens and several hepatotoxins. We hypothesized that, like ethanol, nicotine increases CYP2E1 activity. Rats were treated once daily with saline, ethanol (0.3, 1.0, and 3.0 g/kg p.o.), or nicotine bitartrate (0.1, 0.3, and 1.0 mg base/kg s.c.) for 7 days. After ethanol or nicotine administration, immunostaining for CYP2E1 was increased in the centrilobular regions of rat liver. Western blot analyses revealed that hepatic CYP2E1 levels were increased by ethanol (1.6-2.4-fold) and nicotine (1.3-1.7 fold). In vitro chlorzoxazone 6-hydroxylation analyses demonstrated elevated Vmax values (compared with saline-treated animals) by using hepatic microsomes from high-dose ethanol (2.27 +/- 0.12 versus 1.18 +/- 0.23 nmol/mg/min, p < 0.001) or nicotine-treated rats (2.35 +/- 0.04 versus 1.32 +/- 0.55 nmol/mg/min, p < 0.005), with no change in affinity. The magnitude of enhanced chlorzoxazone metabolism by microsomes from drug-treated animals is consistent with the observed increase in CYP2E1 protein by immunoblot. These data suggest that nicotine may increase CYP2E1-induced toxicity and contribute to cross-tolerance in smokers and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis, neuropsychiatric motor disorders). PMID- 11602666 TI - Protein kinase C suppresses rat organic anion transporting polypeptide 1- and 2 mediated uptake. AB - Rat oatp1 (Slc21a1) and oatp2 (Slc21a5) transport many structurally unrelated endogenous and exogenous compounds across the sinusoidal membrane of hepatocytes in a sodium-independent manner. There are several potential protein kinase A (PKA) and protein kinase C (PKC) phosphorylation sites in both rat oatp1 and oatp2 proteins, suggesting that PKA and/or PKC may play a role in regulating their function. It is known that the activities of many transporters are subject to the short-term regulation by activation of PKA or PKC, and thus the purpose of the current study was to determine the effect of compounds that activate or inhibit PKA and PKC on the uptake function of rat organic anion transporting protein (oatp)1 and oatp2 when expressed in Xenopus laevis oocytes. In the present investigation, neither the PKA activator N-6-benz-cAMP (0.001-1 mM) nor the PKA inhibitor H7 (0.1-100 microM) affected the uptake mediated by rat oatp1 and oatp2. In contrast, the PKC activator phorbol-12-myristate-13-acetate (PMA) suppressed the uptake mediated by rat oatp1 and oatp2 in a concentration- and time-dependent manner. In addition, pretreatment with bisindolylmaleimide, a specific PKC inhibitor, partially reversed the suppression of PMA on rat oatp1-, and almost completely reversed the suppression of PMA on rat oatp2-mediated uptake. In conclusion, this study indicates that rat oatp1- and oatp2-mediated uptake is subject to the short-term regulation by PKC activation, but not by PKA activation. PMID- 11602667 TI - A novel thienylhydrazone, (2-thienylidene)3,4-methylenedioxybenzoylhydrazine, increases inotropism and decreases fatigue of skeletal muscle. AB - This study was designed to investigate the effects on single skeletal muscle fibers of a novel thienylhydrazone, referred to as LASSBio-294, which is a bioisoster of pyridazinone compounds that inhibit the cyclic AMP-specific phosphodiesterase (PDE) 4. Twitch and fatigue were analyzed in single skeletal muscle fibers isolated from either the semitendinous or the tibialis anterior muscles dissected from the frog Rana pipiens. LASSBio-294 (12.5-100 microM) increased twitch tension, accelerated the maximal rate of tension decay during relaxation, and had very little effect in the maximal rate of tension development of muscle fibers directly stimulated at < or =30 Hz. The positive inotropic effect of LASSBio-294 developed slowly, reaching its maximum at 40 min and was inversely proportional to the frequency of stimulation, becoming negligible at 60 and 90 Hz. The concentration-response relationship for LASSBio-294-induced potentiation of twitch tension was bell-shaped, with maximal effect occurring at 25 microM. In addition, LASSBio-294 reduced development of fatigue induced by tetanic stimulation of the muscle fibers and reduced the time needed for 80% prefatigue tension recovery after fatigue had developed to 50% of the maximal pretetanic force. These effects of LASSBio-294 can be fully explained by stimulation of the sarcoplasmic reticulum Ca2+ pump and could be ascribed to an increase in cellular levels of cyclic AMP due to PDE inhibition. The novel thienylhydrazone LASSBio-294 may be useful for treatment of patients suffering from conditions in which muscle fatigue is a debilitating symptom (e.g., chronic heart failure). PMID- 11602668 TI - Nucleoside phosphonate interactions with multiple organic anion transporters in renal proximal tubule. AB - The interactions of two antiviral, acyclic nucleoside phosphonates, adefovir and cidofovir, with xenobiotic transporters was studied in intact killifish (Fundulus heteroclitus) renal proximal tubules by using fluorescent substrates, confocal microscopy, and quantitative image analysis. Both drugs reduced in a concentration-dependent manner the transport of fluorescein on the classical organic anion system and transport of fluorescein-methotrexate on multidrug resistance-associated protein 2 (Mrp2). Neither drug inhibited transport of a fluorescent cyclosporin A derivative on P-glycoprotein. Inhibition of Mrp2 mediated transport was abolished by 50 microM p-aminohippurate, indicating that adefovir and cidofovir entered the cells at the basolateral membrane on the classical organic anion transport system (OAT1). Comparison of the inhibitory potencies of the nucleoside phosphonates with other substrates and inhibitors showed them to be moderate inhibitors of OAT1- and Mrp2-mediated transport. PMID- 11602669 TI - Correlation between epithelial cell permeability of cephalexin and expression of intestinal oligopeptide transporter. AB - The proton-coupled oligopeptide transporter (PEPT1) has been shown to mediate mucosal cell transport of di- and tripeptide, and some peptidomimetic drugs. In this study, we determined the correlation between PEPT1 protein expression and the permeability of cephalexin, a substrate of PEPT1, in human PEPT1 (hPEPT1) overexpressed Caco-2 cells (Caco-2/hPEPT1 cells) and rat jejunum. Caco-2/hPEPT1 cells with various levels of hPEPT1 expression were established by an adenoviral transfection system. The effective intestinal permeability (P(eff)) in rat jejunum was evaluated using a single pass in situ perfusion method. The level of PEPT1 in Caco-2/hPEPT1 cells and rat intestinal mucosal samples was quantitated by densitometry after immunoblotting and enhanced chemiluminescence detection. In Caco-2/hPEPT1 cells, an excellent correlation was observed between cephalexin uptake and hPEPT1 expression (R2 = 0.96, P < 0.005). This demonstrates that cephalexin uptake is directly proportional to hPEPT1 expression. In the rat perfusion study, the mean P(eff) +/- S.D. (n = 15) of cephalexin was 3.89 +/- 1.63 x 10(-5) cm/s. A very significant correlation between PEPT1 expression and cephalexin permeability with an R2 = 0.63 (P < 0.001) was observed. This indicates that the variation in PEPT1 expression is one of the major factors accounting for variable intestinal cephalexin absorption. To our knowledge, this is the most direct evidence that variation of PEPT1 expression is correlated with absorption permeability variation of peptide-like compounds in vitro and in vivo. PMID- 11602670 TI - Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells. AB - These studies report on the activation and induction of cGMP-dependent protein kinase (PKG) by exisulind and analogs and test the hypothesis that PKG is involved in the induction of apoptosis in colon tumor cells. Exisulind and analogs are proapoptotic drugs developed as inhibitors of cGMP phosphodiesterase gene families 5 and 2 that have been shown to sustain increased cGMP in SW480 and HT29 cells. At concentrations that induced apoptosis, both exisulind and CP461 increased PKG activity in SW480 cell supernatants. PKG activation was dose dependent and sustained. Activation of PKG by exisulind and analogs was also seen in the colon tumor cell lines HT29, T84, and HCT116. The guanylyl cyclase activators YC-1 and guanylin increased PKG activity secondary to increased cellular cGMP and induced apoptosis in colon tumor cells. Exisulind and CP461 had no direct effect on purified PKG activity or on basal and stimulated PKG activity from cell supernatants. An additional effect of exisulind after 8 h of drug treatment was a dose-dependent increase of PKG Ibeta protein expression. beta Catenin, a potential new substrate for PKG, whose regulation influences apoptosis, was phosphorylated by PKG in vitro. 32P-labeled cells treated with exisulind showed increased phosphorylation of beta-catenin. These data indicate that exisulind and analogs activate and induce PKG, resulting in increased phosphorylation of beta-catenin and enhanced apoptosis to promote colon tumor cell death. PMID- 11602671 TI - Differences in rapid desensitization of 5-hydroxytryptamine2A and 5 hydroxytryptamine2C receptor-mediated phospholipase C activation. AB - The serotonin (5-HT)2A and 5-HT2C receptors share a high degree of sequence homology and have very similar pharmacological profiles. Although it is generally believed that the cellular signal transduction mechanisms activated by these receptors are indistinguishable, recent data suggest significant differences in their signaling cascades. In this study we explored differences in the characteristics and mechanisms of rapid desensitization between the 5-HT2A and 5 HT2C receptor systems. For both receptor systems, pretreatment with 5-HT reduced the ability of a maximal concentration of 5-HT to stimulate phospholipase C mediated inositol phosphate accumulation by about 65%, although the 5-HT2C receptor system was more sensitive to the desensitizing stimulus. Differences in the concentration dependence of the rate constant for desensitization (k(des)) suggested different mechanisms of desensitization for the 5-HT2A and 5-HT2C receptor systems. At very high receptor occupancy (>99%), the responsiveness of the 5-HT2A, but not the 5-HT2C, receptor system returned to control levels despite the continued presence of the agonist. This resensitization was dependent upon the activity of protein kinase C (PKC). Agonist-induced desensitization of the 5-HT2A, but not the 5-HT2C, receptor system was reduced by the PKC inhibitors staurosporine and bisindolylmaleimide, and by down-regulation of PKC. In addition, inhibitors of calmodulin (W-7) or of calmodulin-dependent protein kinase II, reduced 5-HT2A, but not 5-HT2C, desensitization. Desensitization of the 5-HT2C, but not the 5-HT2A, receptor system was dependent on G protein receptor kinase activity. These data further emphasize the major differences in the signaling systems coupled to 5-HT2A/2C receptors. PMID- 11602672 TI - Protein kinase C-epsilon is a trigger of delayed cardioprotection against myocardial ischemia of kappa-opioid receptor stimulation in rat ventricular myocytes. AB - Kappa-opioid receptor (OR) stimulation with a selective agonist, U50,488H (U50), known to mediate the delayed cardioprotection of metabolic inhibition preconditioning (MIP) against cell injury/death in rat ventricular myocytes, has been shown to act via protein kinase C (PKC). We attempted to identify the PKC isoform(s) that is activated, thus triggering delayed cardioprotection of MIP and pretreatment with 10 microM U50 (U50 pretreatment, UP). Release of lactate dehydrogenase and exclusion of trypan blue by isolated rat ventricular myocytes were used as indices of cell injury and death, respectively. Both MIP and UP induced translocation of PKC-epsilon, but not other PKC isoforms, -alpha and delta, from cytosolic to membrane fractions. This was accompanied by reductions in cell injury/death induced by lethal simulated ischemia. The effects of MIP and UP were attenuated and abolished by 1 microM nor-binaltorphimine, a selective kappa-OR antagonist, administered before and during preconditioning/pretreatment, respectively. The effects were mimicked by 10 nM phorbol-12-myristate-13-acetate, a PKC activator, but attenuated by 5 microM chelerythrine, a PKC inhibitor. More importantly, 0.1 microM epsilonV1-2, a selective PKC-epsilon inhibitor administered before and during MIP/UP, also attenuated the effects of both treatments on cell injury/death and translocation of PKC-epsilon. On the other hand, 5 microM rottlerin, a selective PKC-delta inhibitor, did not alter the effects of either treatment on injury/death. The results indicate that both MIP and UP activate PKC-epsilon, leading to delayed cardioprotection in rat ventricular myocytes. PMID- 11602673 TI - Vicinal nitrohydroxyeicosatrienoic acids: vasodilator lipids formed by reaction of nitrogen dioxide with arachidonic acid. AB - Nitric oxide (NO)-derived species could potentially react with arachidonic acid to generate novel vasoactive metabolites. We studied the reaction of arachidonic acid with nitrogen dioxide (NO2), a free radical that originates from NO oxidation. The reaction mixture contained lipid products that relaxed endothelium removed bovine coronary arteries. Relaxation to the lipid mixture was inhibited approximately 20% by indomethacin and approximately 70% by a soluble guanylate cyclase (sGC) inhibitor (ODQ). Thus, novel lipid products, which activate sGC presumably through a mechanism involving NO, appeared to have contributed to the observed vasorelaxation. Lipids that eluted at 9 to 12 min during high performance liquid chromatography fractionation accounted for about one-half of the vasodilator activity in the reaction mixture, which was inhibited by ODQ. Lipid products in fractions 9 to 12 were identified by electrospray tandem mass spectrometry to be eight isomers having molecular weight of 367 and a fragmentation pattern indicative of arachidonic acid derivatives containing nitro and hydroxy groups and consistent with the structures of vicinal nitrohydroxyeicosatrienoic acids. These lipids spontaneously released NO (183 +/- 12 nmol NO/15 min/micromol) as detected by head space/chemiluminescence analysis. Mild alkaline hydrolysis of total lipids extracted from bovine cardiac muscle followed by isotopic dilution gas chromatography/mass spectrometry analysis detected basal levels of nitrohydroxyeicosatrienoic acids (6.8 +/- 2.6 ng/g tissue; n = 4). Thus, the oxidation product of NO, NO2, reacts with arachidonic acid to generate biologically active vicinal nitrohydroxyeicosatrienoic acids, which may be important endogenous mediators of vascular relaxation and sGC activation. PMID- 11602674 TI - Rational use of in vitro P-glycoprotein assays in drug discovery. AB - P-glycoprotein (Pgp) affects the absorption, distribution, and clearance of a variety of compounds. Thus, identification of compounds that are Pgp substrates can aid drug candidate selection and optimization. Our goal was to evaluate three assays used to determine whether compounds are Pgp substrates. Sixty-six compounds were tested in monolayer efflux, ATPase, and calcein-AM assays. Assay results yielded two categories of compounds. Category I (n = 35) exhibited concordance across the assays. Category II (n = 31) revealed differences among the assays that related to the apparent permeability (P(app)) of the compounds. Within category II, two groups were discerned based on the absence (group IIA, n = 10, nontransported substrates) or presence (group IIB, n = 21, transported substrates) of monolayer efflux. Detection of efflux (group IIB) was associated with compounds having low/moderate P(app) values (mean = 16.6 nm/s), whereas inability to detect efflux (group IIA) was associated with compounds having high P(app) values (mean = 535 nm/s). The calcein-AM and ATPase assays revealed Pgp interactions for highly permeable group IIA compounds but were less responsive than monolayer efflux for low/moderate P(app) compounds of group IIB. All assays detected substrates across a broad range of P(app), but the efflux assay was more prone to fail at high P(app), whereas the calcein-AM and ATPase assays were more prone to fail at low P(app). When P(app) is low, efflux is a greater factor in the disposition of Pgp substrates. The efflux assay is more reliable at low/moderate P(app) and is the method of choice for evaluating drug candidates despite low throughput and reliance on liquid chromatography with tandem mass spectrometry. PMID- 11602675 TI - Studies of tolerance and dependence with the delta-opioid agonist SNC80 in rhesus monkeys responding under a schedule of food presentation. AB - Tolerance and dependence after acute or chronic administration of the selective delta-opioid agonist SNC80 were assessed in rhesus monkeys (Macaca mulatta) responding under a schedule of food presentation. SNC80 dose dependently decreased response rates. These effects waned after 5 h. When administered as an acute 24-h pretreatment, SNC80 (1.0-10.0 mg/kg) produced tolerance as evidenced by dose-dependent rightward shifts in the SNC80 dose-effect curve. Pretreatments of 3.2 or 10.0 mg/kg SNC80 increased the SNC80 ED50 by 4- or 25-fold, respectively. Tolerance to acute SNC80 was also time-dependent as evidenced by increased ED50 values when administered as a 5-h (14-fold), 24-h (25-fold), or 3 day (11-fold) pretreatment. The SNC80 dose-effect curve was similar to control after a 7-day pretreatment. The selective delta-antagonist naltrindole (1.0 mg/kg) partially blocked tolerance to acute SNC80. Chronic SNC80 (1.0-10.0 mg/kg/day) also produced dose-dependent rightward shifts in the SNC80 dose-effect curve. Chronic SNC80 was more effective than acute SNC80 in producing tolerance. Moreover, tolerance to chronic SNC80 waned more slowly than to acute SNC80. Acute or chronic SNC80 (10.0 mg/kg/day) also produced cross-tolerance to the rate decreasing effects of other delta-agonists (SNC162 and SNC243A) but not to mu- (morphine) or kappa (U-50,488)-agonists. Changes in response rates or behavioral signs of withdrawal were not observed after the administration of opioid antagonists (i.e., naltrindole or naltrexone) in monkeys treated with SNC80. These data suggest that a pharmacologically selective tolerance develops to delta agonists after both acute and chronic administration of SNC80 with little or no dependence. PMID- 11602677 TI - Immunoglobulin treatment prevents congestive heart failure in murine encephalomyocarditis viral myocarditis associated with reduction of inflammatory cytokines. AB - We have previously shown that immunoglobulin therapy suppressed murine coxsackievirus B3 myocarditis. In the present study, we examined the effects of immunoglobulin upon murine myocarditis induced by encephalomyocarditis virus, which is not pathogenic to humans. Antiviral activity of immunoglobulin (Venilon) against encephalomyocarditis virus could not be detected in vitro. The production of cytokines was decreased in virus-infected macrophages by the treatment of immunoglobulin in vitro. Immunoglobulin (1 g/kg/day) was administered intraperitoneally to the virus-infected C3H/He mice daily for 2 weeks, beginning simultaneously with virus inoculation in experiment I and on day 14 after virus inoculation in experiment II. In experiment I, survival rate did not differ significantly between immunoglobulin-treated and untreated groups. In experiment II, survival rate was higher in immunoglobulin compared with control groups. Immunoglobulin administration suppressed the development of myocardial necrosis with T-lymphocyte infiltrates in mice not only in the acute viremic but in the chronic aviremic stages concomitantly associated with the reduction of inflammatory cytokines, i.e., tumor necrosis factor-alpha, interferon-gamma, macrophage inflammatory protein-2, and interleukin-6. Taken together, immunoglobulin therapy could have the potential to prevent congestive heart failure. PMID- 11602676 TI - Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration. AB - We investigated the potential of dietary saturated fatty acids to reverse alcoholic liver injury despite continued administration of alcohol. Five groups (six rats/group) of male Wistar rats were studied. Rats in groups 1 and 2 were fed a fish oil-ethanol diet for 8 and 6 weeks, respectively. Rats in groups 3 and 4 were fed fish oil and ethanol for 6 weeks before being switched to isocaloric diets containing ethanol with palm oil (group 3) or medium-chain triglycerides (MCTs, group 4) for 2 weeks. Rats in group 5 were fed fish oil and dextrose for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, nuclear factor-kappaB (NF-kappaB) activation, and mRNAs for cyclooxygenase-2 (Cox 2) and tumor necrosis factor-alpha (TNF-alpha). Endotoxin in plasma was determined. The most severe inflammation and fibrosis were detected in groups 1 and 2, as were the highest levels of endotoxin, lipid peroxidation, activation of NF-kappaB, and mRNAs for Cox-2 and TNF-alpha. After the rats were switched to palm oil or MCT, there was marked histological improvement with decreased levels of endotoxin and lipid peroxidation, absence of NF-kappaB activation, and reduced expression of TNF-alpha and Cox-2. A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis, inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased activation of NF-kappaB and reduced levels of TNF-alpha and Cox-2. PMID- 11602678 TI - OPC-28326, a selective femoral vasodilator, is an alpha2C-adrenoceptor-selective antagonist. AB - OPC-28326 has been reported to selectively increase femoral blood flow in open chest dogs and autoperfused canine femoral artery preparations. Preliminary data indicated that OPC-28326 has a high affinity at the alpha2-adrenoceptor. In the present study, we tested OPC-28326 in isoflurane anesthetized rats at a dose of 3 mg/kg of body weight, given intraduodenally. OPC-28326 significantly increased femoral blood flow, by 44.7 +/- 13.8%, 45 min after drug administration, whereas carotid blood flow increased by only 3.6 +/- 5.5% (n = 6). Chinese hamster ovary cell lines overexpressing rat alpha2D-, alpha2B-, or alpha2C-adrenoceptor were established. These cells also coexpress luciferase, driven by cAMP elevation. In radioligand binding assays using cell membrane preparations, OPC-28326 dose dependently competed with [3H]RX821002 binding, with calculated K(i) values of 3840 +/- 887, 633 +/- 46, and 13.7 +/- 1.9 nM on alpha2D-, alpha2B-, and alpha2C adrenoceptor, respectively. A similar affinity and rank order of potency were also found for OPC-28326 on the alpha2-subtypes using epinephrine as agonist in luciferase assays. No agonistic effect of OPC-28326 was detected on any of the alpha2-adrenoceptors. Finally, in situ hybridization performed on skeletal muscle tissue sections collected from rat hind limb (musculus gastrocnemius) demonstrated a high level expression of alpha2C in the vascular tissues. Thus, the abundance of alpha2C in the skeletal muscle may account for the selective effect of OPC-28326 in increasing femoral blood flow. PMID- 11602679 TI - Confluence of antianalgesic action of diverse agents through brain interleukin(1beta) in mice. AB - Spinal dynorphin A(1-17) (Dyn) has been shown previously to produce an antianalgesic action against intrathecal morphine in the tail-flick test in CD-1 mice. This action is known to be mediated indirectly from the spinal cord through an afferent pathway that activates flumazenil-sensitive benzodiazepine receptors in the brain and a descending circuit back down to the spinal cord sequentially involving cholecystokinin, leu-enkephalin, and N-methyl-D-aspartate receptors to produce antianalgesia. Interleukin (IL)-1beta is also known to act on peripheral afferent nerves to the brain to activate a descending circuit to release spinal cholecystokinin. The present investigation determined whether IL1beta is a supraspinal mediator for intrathecal Dyn-induced antianalgesia in CD-1 mice. Intracerebroventricular Lys193-D-Pro-Thr195, an IL1beta antagonist, or pretreatment with IL1beta antiserum eliminated intrathecal dynorphin antianalgesia, implicating brain IL1beta; 10 ng of IL(1beta) given intracerebroventricularly produced antianalgesia. Fittingly, Dyn was not antianalgesic in C3H/HeJ mice, which are genetically deficient in release of IL1beta. Activation of central benzodiazepine receptors preceded the IL1beta step because flumazenil inhibited Dyn but not IL1beta antianalgesia. On the other hand, [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide], an antagonist for peripheral benzodiazepine receptors that have also recently been detected in brain tissue, inhibited IL1beta antianalgesia; these latter benzodiazepine receptors formed a separate step after the flumazenil-sensitive benzodiazepine receptor step. IL1beta action in the brain was linked to the linear steps in the spinal cord (cholecystokinin/N-methyl-D-aspartate receptors) as shown by inhibition with appropriate antagonists. Thus, IL1beta is a central physiological mediator in the antianalgesic action evoked by spinal dynorphin. PMID- 11602680 TI - Trafficking-dependent and -independent pathways of neurotransmitter transporter regulation differentially involving p38 mitogen-activated protein kinase revealed in studies of insulin modulation of norepinephrine transport in SK-N-SH cells. AB - Presynaptic, cocaine- and antidepressant-sensitive norepinephrine (NE) transporters (NETs) dictate levels of extracellular NE after vesicular release. Recent studies suggest that G protein-coupled receptors linked to protein kinase C (PKC) down-regulate cell surface NET protein levels and diminish NE uptake capacity. We identified distinct phosphatidylinositol 3-OH kinase (PI3K)-linked pathways supporting basal and insulin-triggered NE transport in the human noradrenergic neuroblastoma, SK-N-SH. Acute (0-60 min) insulin treatments produced a time- and concentration-dependent stimulation of NE transport, resolved in kinetic studies as an enhancement of NE transport capacity (Vmax) without an alteration in NE Km. Basal and insulin-modulated NET activities were reduced by the tyrosine kinase inhibitor genistein and the PI3K inhibitors wortmannin and LY-294002, but not by the PKC inhibitor staurosporine. PI3K activation was found to support phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). However, basal and insulin-stimulated NET activities were differentiated by their reliance on p38 MAPK activation. Thus, the p38 MAPK inhibitor SB203580 and SB202190 abolished insulin activation of NE transport yet failed to impact basal NET activity. Moreover, p38 MAPK activation and insulin activation of NETs were found to be sensitive to external Ca2+ depletion, blockade of voltage-sensitive Ca2+ channels, and inhibition of protein phosphatase 2A. Effects of tyrosine kinase and PI3K inhibitors on basal NET uptake appear to arise from a loss of cell surface NET protein, whereas the p38 MAPK-dependent enhancement of NE transport occurs without a detectable enhancement of surface NET. Our findings establish two distinct pathways for regulation of NE uptake involving PI3K, one linked to transporter trafficking and a second linked to Ca2+-dependent, p38 MAPK phosphorylation that promotes activation of cell surface NETs. PMID- 11602681 TI - Regions in rat and human parathyroid hormone (PTH) 2 receptors controlling receptor interaction with PTH and with antagonist ligands. AB - The parathyroid hormone (PTH) 2 receptor is potently activated by tuberoinfundibular peptide (TIP39). Rat and human PTH2 receptors differ considerably in their PTH responsiveness. PTH weakly stimulates cAMP accumulation via the rat receptor, and here we show it did not detectably increase intracellular calcium ([Ca2+]i) and bound with low affinity (450 nM). For the human PTH2 receptor PTH was a full agonist for increasing cAMP, a partial agonist for increasing [Ca2+]i, and bound with high affinity (18 nM). In addition, the antagonists PTH(7-34) and TIP(7-39) bound with 10- to 49-fold lower affinity to the rat receptor. We investigated the molecular basis of differential PTH and antagonist interaction with human and rat PTH2 receptors by using chimeric human/rat PTH2 receptors. PTH cAMP-signaling efficacy (Emax) was determined by extracellular loop (EL) 1 and a region including EL2 and EL3. The N-terminal domain determined PTH binding selectivity at the inactive receptor state. Multiple regions throughout the receptor are required for the PTH-PTH2 receptor complex to adopt a high-affinity active state: inserting the rat receptor's N terminal domain, EL1 or EL2/3, into the human receptor increased PTH's EC50 and reciprocal exchanges did not reduce EC50. This suggests the global receptor conformation prevents the rat receptor from adopting a high-affinity state when in complex with PTH. N-terminal ligand truncation, producing the antagonists PTH(7-34) and TIP(7-39), altered ligand interaction with the membrane-embedded domain of the receptor, eliminating EL2/3 as a specificity determinant and lowering binding affinity. These insights should contribute to the development of a high-affinity PTH2 receptor antagonist, for investigating the receptor's physiological role. PMID- 11602682 TI - Effect of peroxisome proliferator-activated receptor alpha activation on leukotriene B4 metabolism in isolated rat hepatocytes. AB - Leukotriene B4 (LTB4) is a potent mediator of inflammation that recruits granulocytes to the site of injury during the inflammatory response. The biological activity of LTB4 is terminated by its metabolism into inactive metabolites. Recent studies have suggested that LTB4 may have additional activity as an endogenous ligand for the transcription factor peroxisome proliferator activated receptor alpha (PPARalpha). Based on the data presented, a model was proposed in which LTB4 acts in a negative feedback manner by inducing the transcription of genes involved its own metabolism. In the present study the effect of PPARalpha activation on LTB4 metabolism was directly investigated. Primary cultures of rat hepatocytes were treated with LTB4 or the PPARalpha agonist WY-14,643, and LTB4 metabolism was assessed by measuring levels of LTB4 and the formation of LTB4 metabolites. In addition, the effect of PPARalpha activation on levels of acyl-CoA oxidase mRNA and expression of CYP4F proteins, which are specific omega-hydroxylases for LTB4, was determined. Treatment of hepatocytes with WY-14,643, but not LTB4, was found to increase acyl-CoA oxidase mRNA and enhance expression of rat hepatic CYP4F proteins and CYP4A1. Neither WY 14,643 nor LTB4 caused an increase of the basal levels of LTB4 metabolism, and no novel metabolites were observed. These results do not support the hypothesis that a pathway of negative feedback regulation of LTB4 metabolism involving PPARalpha exists in hepatocytes, because activation of PPARalpha by LTB4 or other PPARalpha agonists did not correlate with an increase in LTB4 metabolism. PMID- 11602683 TI - Neurotensin levels in specific brain regions and hypnotic sensitivity to ethanol and pentobarbital as a function of time after haloperidol administration in selectively bred rat lines. AB - Evidence indicates that sensitivity to ethanol is a good predictor of the development of alcoholism. Thus, identification of neuronal processes that regulate ethanol sensitivity has been the subject of much recent research. The present studies were designed to further test the hypothesis that neurotensinergic processes mediate, in part, hypnotic sensitivity to ethanol. Single doses of haloperidol were administered to lines of rats [selectively bred for high and low sensitivity (HAS and LAS, respectively) to hypnotic effects of ethanol] to produce increases in neurotensin (NT) levels in brain regions. At 20 h after administration, haloperidol produced dose-dependent increases in NT immunoreactivity levels in nucleus accumbens (NA) and caudate putamen (CP) in both HAS and LAS lines. Levels of NT in NA and CP returned to control values at 48 h after 4 mg/kg haloperidol. These studies used two measures of hypnotic sensitivity to ethanol: duration of loss of righting reflex (sleep time) and blood ethanol concentration at regain of righting reflex (BECRR). At 20 h, but not 48 h, after haloperidol treatment, both HAS and LAS rats displayed increases in ethanol-induced sleep time with concomitant decreases in BECRR. Pentobarbital induced sleep time was not increased 20 h after administration of 4 mg/kg haloperidol; however, hypnotic sensitivity to both pentobarbital and ethanol was increased by acute (30-min) pretreatment with 1 mg/kg. These results suggest that NT levels in NA, acting via NT receptors, enhance hypnotic sensitivity to ethanol, but not pentobarbital. PMID- 11602684 TI - Lithium increases potency of lidocaine-induced block of voltage-gated Na+ currents in rat sensory neurons in vitro. AB - We and others have obtained data both in vivo and in isolated nerve preparations suggesting that Li+ increases the potency of local anesthetics in the block of conduction. In the present study we have tested the hypothesis that Li+ increases the potency of local anesthetic-induced block of conduction via a shift in the potency of local anesthetic-induced block of voltage-gated Na+ channels. To test this hypothesis we have used whole cell patch-clamp electrophysiological techniques on isolated adult rat sensory neurons. The presence of Li+ significantly increased the potency of lidocaine-induced block of both tetrodotoxin (TTX)-sensitive and TTX-resistant voltage-gated Na+ currents: ED50 values for lidocaine-induced block of both currents in the presence of Li+ were less than 35% of the values obtained in the presence of Na+. Li+ effects were dependent on the state of the Na+ channel. It increased the potency of lidocaine induced block of resting or closed channels, without a detectable influence on use-dependent block or block of channels in the inactivated state. Li+ alone had no detectable effect on the gating properties of voltage-gated Na+ currents present in sensory neurons. The effects of Li+ were concentration-dependent. These results support the suggestion that the influence of Li+ on lidocaine induced conduction block reflects an increase in potency of lidocaine-induced block of voltage-gated Na+ channels. This increase in potency appears to reflect an increase in the affinity of the low-affinity binding site for local anesthetics. Including Li+ in lidocaine preparations may be an effective way to increase the safety factor associated with the use of this anesthetic clinically. PMID- 11602685 TI - Use of the beta-imager for rapid ex vivo autoradiography exemplified with central nervous system penetrating neurokinin 3 antagonists. AB - The neurokinin 3 (NK3) receptor antagonists represent a novel class of pharmacological agents, which are currently under evaluation for the treatment of psychiatric disorders. An efficient brain penetration is one of the main prerequisites to further evaluate compounds displaying high potency to bind the NK3 receptor. The present report describes a method for determining the in vivo occupancy of central NK3 receptors after peripheral administration of drugs. An ex vivo measurement of NK3 receptor occupancy by quantitative autoradiography employing [3H]senktide as the radioligand has been developed. The speed of the method, which is usually considered low due to the time dedicated to film exposure (from weeks to months), has been considerably increased by the use of the beta-imager. The high sensitivity of this new radioimager was used to visualize and quantitatively analyze the [3H]senktide binding sites in brain sections within hours. Using this method, we have demonstrated that the reference NK3 antagonist SR142801 dose dependently occupied the NK3 receptors in the gerbil brain after subcutaneous administration with an ED50 of 0.85 mg/kg. The less active enantiomer SR142806 occupied the NK3 receptors only by 25% at the highest used dose of 10 mg/kg. These values are in accordance with the reported behavioral effects of the compounds. Our results indicate that ex vivo receptor occupancy measurements can be dependently used to predict the central activity of NK3 antagonists. More generally, the combination of ex vivo receptor autoradiography with the beta-imager detection constitutes a new and fast method to evaluate the brain penetration of drug candidates. PMID- 11602686 TI - Regulation of Cyp1a1 induction by dioxin as a function of cell cycle phase. AB - Analyses of CYP1A1 mRNA were used to monitor the responsiveness of murine hepatoma 1c1c7 and human monocytic U937 cells in different phases of the cell cycle to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Concentrations of TCDD capable of inducing CYP1A1 were not cytostatic to either cell line. Steady-state CYP1A1 mRNA contents were reduced (45-90%) in TCDD-treated cultures arrested in G2/M as a consequence of exposure to microtubule disrupters (Colcemid, estramustine, vinblastine) or the microtubule stabilizer Taxol, relative to TCDD treated asynchronous 1c1c7 cultures. The accumulation of mRNAs corresponding to Nmo1, another TCDD-inducible gene of the Ah battery, was also reduced in TCDD treated G2/M cultures. Quantitative reverse transcriptase-polymerase chain reaction analyses of CYP1A1 heterogeneous nuclear RNA (hnRNA) revealed that Cyp1a1 transcription was suppressed in G2/M cells. This suppression reflected neither changes in the relative content of the proteins comprising the aryl hydrocarbon receptor (AHR) complex nor a suppression of AHR activation and translocation to the nucleus. Release of 1c1c7 cultures arrested in G2/M restored TCDD responsiveness. Centrifugal elutriation of TCDD-treated asynchronously growing U937 cells was used to prepare populations of cells in specific phases of the cell cycle. Within 3 h of TCDD exposure late G1/early S phase cells had CYP1A1 mRNA contents approximately 1.4- and 3-fold higher than the contents of asynchronous/early G1 and G2/M cultures, respectively. These studies suggest that the transcriptional activation of members of the Ah battery by TCDD is cell cycle dependent, and markedly suppressed in G2/M cells. PMID- 11602687 TI - Functional characterization of alpha1-adrenoceptor subtypes in human subcutaneous resistance arteries. AB - The functional characteristics of the alpha1-adrenoceptor subtypes in human resistance arteries are still not clear. We recently reported that the alpha1A adrenoceptor predominantly mediates contraction to norepinephrine in human skeletal muscle resistance arteries. In this study we extended these investigations to human subcutaneous resistance arteries. Arterial segments were isolated from the inguinal subcutaneous fat and mounted on a small vessel wire myograph. Potencies of agonists and antagonists were examined. N-[5-(4,5-dihydro 1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulphonamide (A-61603) was found to be 10- and 54-fold more potent than norepinephrine and phenylephrine, respectively. Brimonidine (UK 14304) evoked significantly smaller contractile responses than norepinephrine and phenylephrine, showing the presence of a small population of alpha2-adrenoceptors in these arteries, and this was confirmed by the studies with selective alpha1- and alpha2-adrenoceptor antagonists prazosin and (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13a-decahydro-3 methoxyl-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine (RS 79948). Prazosin, 5-methyl-urapidil, and 2-[2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4 benzodioxane (WB 4101) shifted the potency of norepinephrine concentration dependently giving pA2 values of 9.4, 8.9, and 10.1, respectively, showing the presence of the alpha1A-subtype in these arteries. Pretreatment with 1 and 10 microM chloroethylclonidine did not affect the potency of and maximum responses to norepinephrine, ruling out the presence of the alpha1B-subtype in these arteries. 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane 7,9-dione (BMY 7378, 10 and 100 nM) did not affect the potency of norepinephrine but a small shift was observed by 1 microM BMY 7378, giving a pK(B) value of 7.1, much less than that reported for the alpha1D-subtype. These results suggest the predominant involvement of alpha1A-adrenoceptor in the contractile responses to norepinephrine in these arteries. The physiological role of this subtype in the maintenance of peripheral arterial resistance is yet to be confirmed. PMID- 11602688 TI - Differential kinetics of transport of 2',3'-dideoxyinosine and adenosine via concentrative Na+ nucleoside transporter CNT2 cloned from rat blood-brain barrier. AB - The concentrative Na+ nucleoside transporter type 2 (CNT2), cloned from a rat blood-brain barrier cDNA library, yields very high flux ratios for purine nucleosides after expression in frog oocytes. This high activity of the rat CNT2 produced from the blood-brain barrier-derived cDNA, designated clone A-11, enabled a kinetic analysis of 2',3'-dideoxyinosine transport via the rat CNT2. CNT2 transported both adenosine and 2',3'-dideoxyinosine. The 2',3' dideoxyinosine transport parameters included a Km of 29.2 +/- 8.3 microM, a V(max) of 0.40 +/- 0.11 pmol/oocyte/min, and a constant of nonsaturable transport (KD) of 15.7 +/- 0.6 nl/oocyte/min. The 2',3'-dideoxyinosine Vmax was 27-fold lower than the adenosine Vmax and the 2',3'-dideoxyinosine KD was >15-fold greater than the KD of adenosine transport. Adenosine inhibited both the saturable component of 2',3'-dideoxyinosine transport with a K(I) of 14.8 +/- 1.6 microM, and inhibited the nonsaturable component of 2',3'-dideoxyinosine transport. Both the saturable and nonsaturable components of 2',3'-dideoxyinosine transport were sodium-dependent with a sodium K0.5 of 8.7 +/- 0.9 mM, and a Hill coefficient of 1.00 +/- 0.10. The transport of 2',3'-dideoxyinosine was strongly inhibited by thymidine, whereas thymidine was a weak inhibitor of adenosine transport via rat CNT2. Thymidine was transported by rat CNT2 with a Km = 130 +/- 44 microM and a Vmax = 1.7 +/- 0.5 pmol/oocyte/min. These studies provide evidence for asymmetric transport sites on rat CNT2, where 2',3'-dideoxyinosine and thymidine compete selectively at a low Vmax site on the transporter, whereas adenosine is transported at a high Vmax site. PMID- 11602689 TI - Interaction of 2,3-dimercapto-1-propane sulfonate with the human organic anion transporter hOAT1. AB - The kidney is the primary target organ in which inorganic mercury (Hg2+) accumulates and expresses its toxic effects. The chelating agent 2,3-dimercapto-1 propanesulfonic acid (DMPS) can rapidly reduce the renal burden of mercury and increase the urinary excretion of mercury. However, the cellular and molecular basis of its efficacy is still unknown. A number of previous studies implicated the "classical organic anion secretory pathway" in the secretion of DMPS and its chelation products. In this study we used the human ortholog of the organic anion transporter (hOAT1) expressed in the Xenopus oocyte expression system to study the interaction of DMPS and its mercury chelates with hOAT1. [3H]PAH was used to show the transport activity of hOAT1 (Km = 3.9 +/-1.3 microM). Uptake of [3H]para aminohippuric acid (PAH) was inhibited by reduced DMPS (K(i) = 22.4 +/- 8.4 microM). We also investigated the interaction of oxidized DMPS with hOAT1 because it has been shown that at least 80% of DMPS in the blood is oxidized within 30 min. Oxidized DMPS also inhibited uptake of [3H]PAH (K(i) = 66 +/-13.6 microM). In contrast, we found no interaction of the DMPS-Hg chelate with hOAT1. To determine whether DMPS and oxidized DMPS are transported by hOAT1 we examined the effect of inwardly directed gradients these two compounds on efflux of [3H]PAH from HeLa cells transiently transfected with hOAT1. Gradients of both DMPS and oxidized DMPS significantly trans-stimulated efflux of [3H]PAH. These data suggest that hOAT1 can transport DMPS and oxidized DMPS, whereas the DMPS-Hg chelate has no significant affinity for the transporter. PMID- 11602690 TI - Purine nucleoside-dependent inhibition of cellular proliferation in 1321N1 human astrocytoma cells. AB - We examined the effects of purines and the pyrimidine UTP on cellular proliferation in the human astrocytoma cell line 1321N1. Treatment of cultured cells with 100 microM ATP or 2-chloroadenosine (2-CA) resulted in significant reductions in cell numbers after 2 days, whereas adenosine (ADO) exhibited a slower time course of inhibition of cell growth. Treatment with 100 microM UTP had no effect on cell numbers. 2-Chloroadenosine but neither ATP nor ADO resulted in an increase in cell death rates. A significant portion of the inhibitory response to ATP, ADO, or 2-CA was sensitive to the purine nucleoside transport inhibitor S-(p-nitrobenzyl)-6-thioguanosine, suggesting that uptake into cells was required for the inhibitory response. At least the majority of the observed responses to purines was not mediated by P1 (adenosine) receptors, because effects of ATP, ADO, or 2-CA were not affected by treatment of cells with the P1 receptor antagonist 8-(p-sulfophenyl)-theophylline. The absence of any known P2 (nucleotide) receptors in 1321N1 cells, coupled with the failure of the relatively stable ATP analog adenosine 5'-O-(3-thiotriphosphate) to alter cell growth rates, suggests that ATP acts indirectly to inhibit proliferation via one or more metabolic products. Although intracellular effects of purine nucleosides should be taken into account in future studies using 1321N1 cells, our findings also suggest 1321N1 cells as an excellent model for intracellular actions of nucleosides. PMID- 11602691 TI - Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation. AB - Blockade of phosphodiesterase 4 with rolipram reduced the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-5, IL-10, and IL-2 but poorly inhibited cell proliferation and interferon-gamma (IFN-gamma) production by activated human T cells. Addition of dibutyryl cAMP mimicked rolipram inhibitions on proliferation, IL-2, TNF-alpha, and IFN-gamma but not on IL-10 or IL-5 production. Moreover, the inhibitory effects of rolipram on proliferation, IFN gamma, and TNF-alpha but not of IL-10 production can be prevented by a specific protein kinase A inhibitor. Rolipram and pentoxifylline, a nonspecific phosphodiesterase inhibitor, decreased transcription of IL-2 and TNF-alpha promoters in transiently transfected normal T cells. Moreover, they inhibited the activation of nuclear factor-kappaB (NF-kappaB) and nuclear factor of activated T cells (NFAT) and stimulated activator protein-1 (AP-1) and cAMP response element binding proteins (CREBs). In contrast, dibutyryl cAMP inhibited NF-kappaB but not NFAT activation. Thus, our data indicate that blockade of phosphodiesterase 4 regulates transcription of a particular cytokine through inhibition of NF-kappaB and NFAT, and stimulation of AP-1 and CREB. PMID- 11602692 TI - Discriminative stimulus effects of intravenous heroin and its metabolites in rhesus monkeys: opioid and dopaminergic mechanisms. AB - Heroin has characteristic subjective effects that contribute importantly to its widespread abuse. Drug discrimination procedures in animals have proven to be useful models for investigating pharmacological mechanisms underlying the subjective effects of drugs in humans. However, surprisingly little information exists concerning the mechanisms underlying the discriminative stimulus (DS) effects of heroin. This study characterized the DS effects of heroin in rhesus monkeys trained to discriminate i.v. heroin from saline. In drug substitution experiments, heroin, its metabolites 6-monoacetylmorphine, morphine, morphine-6 glucuronide, and morphine-3-glucuronide, and the mu-agonists fentanyl and methadone engendered dose-dependent increases in heroin-lever responding, reaching average maximums of >80% (full substitution) at doses that did not appreciably suppress response rate. In contrast, the delta-agonist SNC 80, the kappa-agonist spiradoline, and the dopamine uptake blockers/releasers cocaine, methamphetamine, and GBR 12909 did not engender heroin-like DS effects regardless of dose. In antagonism studies, in vivo apparent pA2 and pK(B) values for naltrexone combined with heroin, morphine, and 6-monoacetylmorphine (8.0-8.7) were comparable with those reported previously for naltrexone antagonism of prototypical mu-agonists. The results show that the DS effects of heroin are pharmacologically specific and mediated primarily at mu-opioid receptors. Moreover, the acetylated and glucuronated metabolites of heroin appear to play significant roles in these effects. Despite previous speculation that morphine-3 glucuronide lacks significant opioid activity, it substituted fully for heroin in our study, suggesting that it can exhibit prominent mu-agonist effects in vivo. PMID- 11602693 TI - Colitis-induced alterations in adrenergic control of circular smooth muscle in vitro in rats. AB - The present study investigated inflammation-induced changes in adrenergic regulation of smooth muscle. Colitis was induced in rats by intrarectal administration of trinitrobenzenesulfonic acid in ethanol. After 4 h (acute) or 7 days (chronic), in vitro isometric tension was measured in strips of circular smooth muscle taken from the distal colon. In controls, the major inhibitory control of smooth muscle responses to nerve stimulation was mediated by nitric oxide and beta adrenergic receptors. There was less evidence of alpha adrenergic control. Studies with the beta3 receptor antagonist cyanopindolol and the beta3 receptor agonist BRL37344 revealed that beta adrenergic regulation of spontaneous contractions and responses to nerve stimulation were mediated primarily by the beta3 adrenoreceptor. Both acute and chronic colitis significantly increased responses to electrical field stimulation. This effect was attributed to a loss of inhibitory nitrergic regulation as well as to selective changes in the beta adrenergic control of colonic circular smooth muscle. Inflammation did not alter alpha adrenergic control. Chronic colitis also decreased the sensitivity to nerve stimulation and pharmacological contractile agents. Acute and chronic inflammation reduced the ability of BRL37344 to inhibit contractions in response to nerve stimulation. In addition, in inflamed colon, BRL37344 was less effective in relaxing carbachol-induced precontractions. Finally, inflammation resulted in a loss of the ability of the cyanopindolol to increase the amplitude of both spontaneous contractions and contractions in response to nerve stimulation. These effects indicated that colitis induced a down-regulation of inhibitory beta3 adrenergic control of colonic smooth muscle function. This loss of adrenergic regulation may contribute to the diarrhea in inflammatory bowel disease. PMID- 11602694 TI - Biodegradable nanoparticles for targeted drug delivery in treatment of inflammatory bowel disease. AB - The use of nanoparticles for targeted oral drug delivery to the inflamed gut tissue in inflammatory bowel disease was examined. Such a strategy of local drug delivery would be a distinct improvement compared with existing colon delivery devices for this disease. An experimental colitis was induced by trinitrobenzenesulfonic acid to male Wistar rats. Rolipram, an anti-inflammatory model drug, was incorporated within poly(lactic-coglycolic acid) nanoparticles, which were administered once a day orally for five consecutive days. A clinical activity score and myeloperoxidase activity were determined to assess the inflammation, whereas an adverse effect index reflected the remaining neurotropic effect of rolipram resulting from its systemic absorption. All nanoparticle formulations proved to be as efficient as the drug in solution in mitigating the experimental colitis. The clinical activity score and myeloperoxidase activity decreased significantly after the oral administration of rolipram nanoparticles or solution. During the next 5 days when animals were kept without drug treatment the drug solution group displayed a strong relapse, whereas the nanoparticle groups continued to show reduced inflammation levels. The rolipram solution group had a high adverse effect index, whereas the rolipram nanoparticle groups proved their potential to retain the drug from systemic absorption as evidenced by a significantly reduced index. This new delivery system enabled the drug to accumulate in the inflamed tissue with higher efficiency than when given as solution. The nanoparticle deposition in the inflamed tissue should be given particular consideration in the design of new carrier systems for the treatment of inflammatory bowel disease. PMID- 11602695 TI - The muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the rat. AB - The muscarinic receptor agonist xanomeline was examined and compared with the antipsychotics clozapine and/or haloperidol in the following in vivo rat models: apomorphine-induced disruption of prepulse inhibition (PPI), amphetamine-induced hyperlocomotion, and the conditioned emotional response (CER) test. The effects of xanomeline were also assessed ex vivo on dopamine turnover in the rat medial prefrontal cortex. Under conditions of varying dose and prepulse intensity, xanomeline, like haloperidol, had no effect on PPI. In contrast, the muscarinic receptor antagonist scopolamine and the muscarinic receptor agonist pilocarpine both induced significant dose-dependent deficits in PPI. Haloperidol and xanomeline, but not pilocarpine, dose dependently reversed apomorphine-induced disruption of PPI. Thus, xanomeline induced a clear antipsychotic-like effect in PPI, whereas pilocarpine appeared to induce a psychotomimetic-like effect. Xanomeline attenuated amphetamine-induced hyperactivity at doses that had no effect on spontaneous activity, possibly indicating a separation between attenuation of limbic hyperdopaminergic function and the induction of hypolocomotion. Haloperidol and clozapine also reversed amphetamine-induced hyperlocomotion, but at similar doses to those that reduced spontaneous locomotion. Clozapine, but not haloperidol had an anxiolytic-like effect in the CER test. The effects of xanomeline in the CER test were similar to those of clozapine, although at the anxiolytic dose it tended to disrupt baseline levels of lever pressing. Finally, haloperidol, clozapine, pilocarpine, and xanomeline, all induced an increase in dopamine turnover in medial prefrontal cortex. The antipsychotic-like effects of xanomeline in the animal models used here suggest that it may be a useful treatment for psychosis. PMID- 11602696 TI - Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation. AB - Whereas alpidem is hepatotoxic, zolpidem is not. Despite closely related chemical structures, alpidem, but not zolpidem, is a peripheral benzodiazepine receptor (PBR) ligand, and is also more lipophilic than zolpidem. We compared their effects in isolated rat liver mitochondria and rat hepatocytes. Zolpidem did not affect calcium-induced mitochondrial permeability transition (MPT) in mitochondria, caused little glutathione depletion in hepatocytes, and was not toxic, even at 500 microM. At 250 to 500 microM, alpidem prevented calcium induced MPT in isolated mitochondria, but caused severe glutathione depletion in hepatocytes that was increased by 3-methylcholanthrene, a cytochrome P4501A inducer, and decreased by cystine, a glutathione precursor. Although cell calcium increased, mitochondrial cytochrome c did not translocate to the cytosol and cells died of necrosis. Cell death was prevented by cystine, but not cyclosporin A, an MPT inhibitor. At low concentrations (25-50 microM), in contrast, alpidem accelerated calcium-induced MPT in mitochondria. It did not deplete glutathione in hepatocytes, but nevertheless caused some cell death that was prevented by cyclosporin A, but not by cystine. Alpidem (10 microM) also increased the toxicity of tumor necrosis factor-alpha (1 ng/ml) in hepatocytes. In conclusion, low concentrations of alpidem increase both calcium-induced MPT in mitochondria, and TNF-alpha toxicity in cells, like other PBR ligands. Like other lipophilic protonatable amines, however, alpidem inhibits calcium-induced MPT at high concentrations. At these high concentrations, toxicity involves cytochrome P4501A mediated metabolic activation, glutathione depletion, and increased cell calcium, without MPT involvement. In contrast, zolpidem has no mitochondrial effects, causes little glutathione depletion, and is not toxic. PMID- 11602697 TI - Propafenone modulates potassium channel activities of vascular smooth muscle from rat portal veins. AB - We have studied the effects of the class Ic antiarrhythmic propafenone on K+ currents in freshly isolated smooth muscle cells from rat portal veins and on the spontaneous contractions in whole tissues. Under Ca2+-free conditions, when cells were clamped at -80 mV (whole-cell configuration) depolarizing steps from -80 to +50 mV induced a family of K+ currents (I(Ktotal)) that mainly comprised the delayed rectifier current [I(K(V))], whereas when held at -10 mV only small amplitude, noninactivating, currents (I(NI)) were recorded. Propafenone (10 microM) markedly inhibited I(Ktotal), but at potentials positive to +30 mV it also induced a noisy outwardly rectifying current [I(BK(Ca))] that was abolished by iberiotoxin (0.1 microM). Inhibition of I(Ktotal) by propafenone was concentration-dependent (EC50 = 0.059 +/- 0.009 microM). Propafenone also inhibited the transient outward current [I(K(A))] and ATP-sensitive potassium current [I(K(ATP))] induced by levcromakalim (10 microM). Inhibition of I(K(V)), I(K(A)), and I(K(ATP)) by propafenone was voltage-independent. In Ca(2+) containing conditions propafenone inhibited I(K(V)) and I(BK(Ca)) and immediately abolished spontaneous outward transient K+ currents. In whole veins, propafenone behaved as the K(V) inhibitor 4-aminopyridine, increasing the amplitude and duration of spontaneous contractions. Propafenone also inhibited the inhibitory effects of the K(ATP) channel opener levcromakalim on spontaneous contractions. These results indicate that in vascular smooth muscle cells, propafenone inhibits K(V), K(A), BK(Ca), and K(ATP) channels. These actions correlated with its effects on mechanical activity in whole portal veins. PMID- 11602698 TI - Feline Pit2 functions as a receptor for subgroup B feline leukemia viruses. AB - Different subgroups of feline leukemia virus (FeLV) use different host cell receptors for entry. Subgroup A FeLV (FeLV-A) is the virus that is transmitted from cat to cat, suggesting that cells expressing the FeLV-A receptor are important targets at the earliest stages of infection. FeLV-B evolves from FeLV-A in the infected cat through acquisition of cellular sequences that are related to the FeLV envelope gene. FeLV-Bs have been shown to infect cells using the Pit1 receptor, and some variants can infect cells at a lower efficiency using Pit2. Because these observations were made using receptor proteins of human or rodent origin, the role that Pit1 and Pit2 may play in FeLV-B replication in the cat is unclear. In this study, the feline Pit receptors were cloned and tested for their ability to act as receptors for different FeLV-Bs. Some FeLV-Bs infected cells expressing feline Pit2 and feline Pit1 with equal high efficiency. Variable region A (VRA) in the putative receptor-binding domain (RBD) was a critical determinant for both feline Pit1 and feline Pit2 binding, although other domains in the RBD appear to influence how efficiently the FeLV-B surface unit can bind to feline Pit2 and promote entry via this receptor. An arginine residue at position 73 in VRA was found to be important for envelope binding to feline Pit2 but not feline Pit1. Interestingly, this arginine is not found in endogenous FeLV sequences or in recombinant viruses recovered from feline cells infected with FeLV-A. Thus, while FeLV-Bs that are able to use feline Pit2 can evolve by recombination with endogenous sequences, a subsequent point mutation during reverse transcription may be needed to generate a virus that can efficiently enter the cells using the feline Pit2 as its receptor. These studies suggest that cells expressing the feline Pit2 protein are likely to be targets for FeLV-B infection in the cat. PMID- 11602699 TI - Transgenically expressed T-Rep of tomato yellow leaf curl Sardinia virus acts as a trans-dominant-negative mutant, inhibiting viral transcription and replication. AB - We have previously shown that transgenic expression of a truncated C1 gene of Tomato yellow leaf curl Sardinia virus (TYLCSV), expressing the first 210 amino acids of the replication-associated protein (T-Rep) and potentially coexpressing the C4 protein, confers resistance to the homologous virus in Nicotiana benthamiana plants. In the present study we have investigated the role of T-Rep and C4 proteins in the resistance mechanism, analyzing changes in virus transcription and replication. Transgenic plants and protoplasts were challenged with TYLCSV and the related TYLCSV Murcia strain (TYLCSV-ES[1]). TYLCSV-resistant plants were susceptible to TYLCSV-ES[1]; moreover, TYLCSV but not TYLCSV-ES[1] replication was strongly inhibited in transgenic protoplasts as well as in wild type (wt) protoplasts transiently expressing T-Rep but not the C4 protein. Viral circular single-stranded DNA (cssDNA) was usually undetectable in transgenically and transiently T-Rep-expressing protoplasts, while viral DNAs migrating more slowly than the cssDNA were observed. Biochemical studies showed that these DNAs were partial duplexes with the minus strand incomplete. Interestingly, similar viral DNA forms were also found at early stages of TYLCSV replication in wt N. benthamiana protoplasts. Transgenically expressed T-Rep repressed the transcription of the GUS reporter gene up to 300-fold when fused to the homologous (TYLCSV) but not to the heterologous (TYLCSV-ES[1]) C1 promoter. Similarly, transiently expressed T-Rep but not C4 protein strongly repressed GUS transcription when fused to the C1 promoter of TYLCSV. A model of T-Rep interference with TYLCSV transcription-replication is proposed. PMID- 11602700 TI - The replicator of the Epstein-Barr virus latent cycle origin of DNA replication, oriP, is composed of multiple functional elements. AB - Replication of the Epstein-Barr virus genome initiates at one of several sites in latently infected, dividing cells. One of these replication origins is close to the viral DNA maintenance element, and, together, this replication origin and the maintenance element are referred to as oriP. The replicator of oriP contains four binding sites for Epstein-Barr virus nuclear antigen 1 (EBNA-1), the sole viral protein required for the replication and maintenance of oriP plasmids. We showed previously that these EBNA-1 sites function in pairs and that mutational inactivation of one pair does not eliminate replicator function. In this study we characterized the contribution of each EBNA-1 site within the replicator and flanking sequences through the use of an internally controlled replication assay. We present evidence that shows that all four EBNA-1 sites are required for an oriP plasmid to be replicated in every cell cycle. Results from these experiments also show that the paired EBNA-1 binding sites are not functionally equivalent and that the low affinity of sites 2 and 3 compared to that of sites 1 and 4 is not essential for replicator function. Our results suggest that a host cell protein(s) binds sequences flanking the EBNA-1 sites and that interactions between EBNA-1 and this protein(s) are critical for replicator function. Finally, we present evidence that shows that the minimal replicator of oriP consists of EBNA-1 sites 3 and 4 and two copies of a 14-bp repeat that is present in inverse orientation flanking these EBNA-1 sites. EBNA-1 sites 1 and 2, together with an element(s) within nucleotides 9138 to 9516, are ancillary elements required for full replicator activity. PMID- 11602701 TI - Simian virus 40 large-T-antigen-specific rejection of mKSA tumor cells in BALB/c mice is critically dependent on both strictly tumor-associated, tumor-specific CD8(+) cytotoxic T lymphocytes and CD4(+) T helper cells. AB - Protective immunity of BALB/c mice immunized with simian virus 40 (SV40) large T antigen (TAg) against SV40-transformed, TAg-expressing mKSA tumor cells is critically dependent on both CD8(+) and CD4(+) T lymphocytes. By depleting mice of T-cell subsets at different times before and after tumor challenge, we found that at all times, CD4(+) and CD8(+) cells both were equally important in establishing and maintaining a protective immune response. CD4(+) cells do not contribute to tumor eradication by directly lysing mKSA cells. However, CD4(+) lymphocytes provide help to CD8(+) cells to proliferate and to mature into fully active cytotoxic T lymphocytes (CTL). Depletion of CD4(+) cells by a single injection of CD4-specific monoclonal antibody at any time from directly before injection of the vaccinating antigen to up to 7 days after tumor challenge inhibited the generation of cytolytic CD8(+) lymphocytes. T helper cells in this system secrete the typical Th-1 cytokines interleukin 2 (IL-2) and gamma interferon. Because in this system TAg-specific CD8(+) cells secrete only minute amounts of IL-2, it appears that T helper cells provide these cytokines for CD8(+) T cells. Moreover, this helper effect of CD4(+) T cells in mKSA tumor rejection in BALB/c mice does not simply improve the activity of TAg-specific CD8(+) CTL but actually enables them to mature into cytolytic effector cells. Beyond this activity, the presence of T helper cells is necessary even in the late phase of tumor cell rejection in order to maintain protective immunity. However, despite the support of CD4(+) T helper cells, the tumor-specific CTL response is so weak that only at the site of tumor cell inoculation and not in the spleen or in the regional lymph nodes can TAg-specific CTL be detected. PMID- 11602702 TI - Replication from oriP of Epstein-Barr virus requires exact spacing of two bound dimers of EBNA1 which bend DNA. AB - oriP is a 1.7-kb region of the Epstein-Barr virus (EBV) chromosome that supports replication and stable maintenance of plasmids in human cells that contain EBV encoded protein EBNA1. Plasmids that depend on oriP are replicated once per cell cycle by cellular factors. The replicator of oriP is an approximately 120-bp region called DS which depends on either of two pairs of closely spaced EBNA1 binding sites. Here we report that changing the distance between the EBNA1 sites of a functional pair by inserting or deleting 1 or 2 bp abolished replication activity. The results indicated that, while the distance separating the binding sites is critical, the specific nucleotide sequence between them is unlikely to be important. The use of electrophoretic mobility shift assays to investigate binding by EBNA1 to the sites with normal or altered spacing revealed that EBNA1 induces DNA to bend significantly when it binds, with the center of bending coinciding with the center of binding. EBNA1 binding to a functional pair of sites which are spaced 21 bp apart center to center and which thus are in helical phase induces a larger symmetrical bend, which based on electrophoretic mobility approximates the sum of two separate EBNA1-induced DNA bends. The results imply that replication from oriP requires a precise structure in which DNA forms a large bend around two EBNA1 dimers. PMID- 11602703 TI - Structural analysis of the -1 ribosomal frameshift elements in giardiavirus mRNA. AB - The RNA polymerase of giardiavirus (GLV) is synthesized as a fusion protein through a -1 ribosomal frameshift in a region where gag and pol open reading frames (ORFs) overlap. A heptamer, CCCUUUA, and a potential pseudoknot found in the overlap were predicted to be required for the frameshift. A 68-nucleotide (nt) cDNA fragment containing these elements was inserted between the GLV 5' 631 nt cDNA and the out-of-frame luciferase gene that required a -1 frameshift within the 68-nt fragment for expression. Giardia lamblia trophozoites transfected with the transcript of this construct showed a frameshift frequency at 1.7%, coinciding with the polymerase-to-capsid protein ratio in GLV. The heptamer is required for the frameshift but can be replaced with other sequences of the same motif. Mutations placing stop codons in the 0 or -1 frame, located directly before or after the heptamer, implicated the latter as the site for the -1 frameshift. Shortening or destroying the putative stem decreased the frameshift efficiency threefold; the efficiency was fully recovered by mutations to restore the stem. Deleting 18 nt from the 3' end of the 68-nt fragment, which formed the second stem in the putative pseudoknot, had no effect on the frequency of the frameshift. Chemical probing of the RNA secondary structure in the frameshift region showed that bases resistant to chemical modification were clustered in the putative stem structures, thus confirming the presence of the postulated stem loop, while all the bases in the loop were chemically modified, thus ruling out their capability of forming a pseudoknot. These results confirmed the conclusion based on data from the mutation study that there is but a simple stem-loop downstream from the heptamer. Together, they constitute the structural elements for a -1 ribosomal frameshift in the GLV transcript. PMID- 11602704 TI - Rhabdoviruses and the cellular ubiquitin-proteasome system: a budding interaction. AB - The matrix (M) proteins of vesicular stomatitis virus (VSV) and rabies virus (RV) play a key role in both assembly and budding of progeny virions. A PPPY motif (PY motif or late-budding domain) is conserved in the M proteins of VSV and RV. These PY motifs are important for virus budding and for mediating interactions with specific cellular proteins containing WW domains. The PY motif and flanking sequences of the M protein of VSV were used as bait to screen a mouse embryo cDNA library for cellular interactors. The mouse Nedd4 protein, a membrane-localized ubiquitin ligase containing multiple WW domains, was identified from this screen. Ubiquitin ligase Rsp5, the yeast homolog of Nedd4, was able to interact both physically and functionally with full-length VSV M protein in a PY-dependent manner. Indeed, the VSV M protein was multiubiquitinated by Rsp5 in an in vitro ubiquitination assay. To demonstrate further that ubiquitin may be involved in the budding process of rhabdoviruses, proteasome inhibitors (e.g., MG132) were used to decrease the level of free ubiquitin in VSV- and RV-infected cells. Viral titers measured from MG132-treated cells were reproducibly 10- to 20-fold lower than those measured from untreated control cells, suggesting that free ubiquitin is important for efficient virus budding. Last, release of a VSV PY mutant was not inhibited in the presence of MG132, signifying that the functional L domain of VSV is required for the inhibitory effect exhibited by MG132. These data suggest that the cellular ubiquitin-proteasome machinery is involved in the budding process of VSV and RV. PMID- 11602705 TI - A short sequence within domain C of duck carboxypeptidase D is critical for duck hepatitis B virus binding and determines host specificity. AB - Virus-cell surface receptor interactions are of major interest. Hepadnaviruses are a family of partially double-stranded DNA viruses with liver tropism and a narrow host range of susceptibility to infection. At least in the case of duck hepatitis B virus (DHBV), host specificity seems controlled partly at the receptor level. The middle portion in the pre-S region of the viral large envelope protein binds specifically to duck carboxypeptidase D (DCPD) but not to its human or chicken homologue. Although domain C of DCPD is implicated in ligand binding, the exact pre-S contact site remains to be determined. We prepared and tested a panel of chimeric constructs consisting of DCPD and human carboxypeptidase D (HCPD). Our results indicate that a short region at the N terminus of domain C (residues 920 to 949) is critical to DHBV binding and is a major determinant for the host specificity of DHBV infection. Replacing this region of the DCPD molecule with its human homologue abolished the DHBV interaction, whereas introducing this DCPD sequence into HCPD conferred efficient DHBV binding. Extensive analysis of site-directed mutants revealed that both conserved and nonconserved residues were important for the pre-S interaction. There were primary sequence variations and secondary structural differences that contributed to the inability of HCPD to bind the DHBV pre-S domain. PMID- 11602706 TI - An attenuating mutation in the 2A protease of swine vesicular disease virus, a picornavirus, regulates cap- and internal ribosome entry site-dependent protein synthesis. AB - Virulent and avirulent strains of swine vesicular disease virus (SVDV), a picornavirus, have been characterized previously. The major determinants for attenuation have been mapped to specific residues in the 1D-2A-coding region. The properties of the 2A proteases from the virulent and avirulent strains of SVDV have now been examined. Both proteases efficiently cleaved the 1D/2A junction in vitro and in vivo. However, the 2A protease of the avirulent strain of SVDV was much less effective than the virulent-virus 2A protease at inducing cleavage of translation initiation factor eIF4GI within transfected cells. Hence the virulent virus 2A protease is much more effective at inhibiting cap-dependent protein synthesis. Furthermore, the virulent-virus 2A protease strongly stimulated the internal ribosome entry sites (IRESs) from coxsackievirus B4 and from SVDV, while the avirulent-virus 2A protease was significantly less active in these assays. Thus, the different properties of the 2A proteases from the virulent and avirulent strains of SVDV in regulating protein synthesis initiation reflect the distinct pathogenic properties of the viruses from which they are derived. A single amino acid substitution, adjacent to His21 of the catalytic triad, is sufficient to confer the characteristics of the virulent-strain 2A protease on the avirulent-strain protease. It is concluded that the efficiency of picornavirus protein synthesis, controlled directly by the IRES or indirectly by the 2A protease, can determine virus virulence. PMID- 11602707 TI - Isolation and characterization of noncytopathic pestivirus mutants reveals a role for nonstructural protein NS4B in viral cytopathogenicity. AB - Isolates of bovine viral diarrhea virus (BVDV), the prototype pestivirus, are divided into cytopathic (cp) and noncytopathic (ncp) biotypes according to their effect on cultured cells. The cp viruses also differ from ncp viruses by the production of viral nonstructural protein NS3. However, the mechanism by which cp viruses induce cytopathic effect in cell culture remains unknown. Here we used a genetic approach to isolate ncp variants that arose from a cp virus at low frequency. A bicistronic BVDV (cp strain NADL) was created that expressed puromycin acetyltransferase as a dominant selectable marker. This bicistronic virus exhibited slightly slower growth kinetics and smaller plaques than NADL but remained cp. A number of independent ncp variants were isolated by puromycin selection. Remarkably, these ncp variants produced NS3 and viral RNA at levels comparable to those of the cp parent. Sequence analyses uncovered no change in NS3, but for all ncp variants a Y2441C substitution at residue 15 of NS4B was found. Introduction of the Y2441C substitution into the NADL or bicistronic cp viruses reconstituted the ncp phenotype. Y2441 is highly conserved among pestiviruses and is located in a region of NS4B predicted to be on the cytosolic side of the endoplasmic reticulum membrane. Other engineered substitutions for Y2441 also affected viral cytopathogenicity and viability, with Y2441V being cp, Y2441A being ncp, and Y2441D rendering the virus unable to replicate. The ncp substitutions for Y2441 resulted in slightly increased levels of NS2-3 relative to NS3. We also showed that NS3, NS4B, and NS5A could be chemically cross-linked in NADL-infected cells, indicating that they are associated as components of a multiprotein complex. Although the mechanism remains to be elucidated, these results demonstrate that mutations in NS4B can attenuate BVDV cytopathogenicity despite NS3 production. PMID- 11602708 TI - Recruitment times, proliferation, and apoptosis rates during the CD8(+) T-cell response to lymphocytic choriomeningitis virus. AB - The specific CD8(+) T-cell response during acute lymphocytic choriomeningitis virus (LCMV) infection of mice is characterized by a rapid proliferation phase, followed by a rapid death phase and long-term memory. In BALB/c mice the immunodominant and subdominant CD8(+) responses are directed against the NP118 and GP283 epitopes. These responses differ mainly in the magnitude of the epitope specific CD8(+) T-cell expansion. Using mathematical models together with a nonlinear parameter estimation procedure, we estimate the parameters describing the rates of change during the three phases and thereby establish the differences between the responses to the two epitopes. We find that CD8(+) cell proliferation begins 1 to 2 days after infection and occurs at an average rate of 3 day(-1), reaching the maximum population size between days 5 and 6 after immunization. The 10-fold difference in expansion to the NP118 and GP283 epitopes can be accounted for in our model by a 3.5-fold difference in the antigen concentration of these epitopes at which T-cell stimulation is half-maximal. As a consequence of this 3.5-fold difference in the epitope concentration needed for T-cell stimulation, the rates of activation and proliferation of T cells specific for the two epitopes differ during the response and in combination can account for the large difference in the magnitude of the response. After the peak, during the death phase, the population declines at a rate of 0.5 day(-1), i.e., cells have an average life time of 2 days. The model accounts for a memory cell population of 5% of the peak population size by a reversal to memory of 1 to 2% of the activated cells per day during the death phase. PMID- 11602709 TI - A new RNA element located in the coding region of a murine endogenous retrovirus can functionally replace the Rev/Rev-responsive element system in human immunodeficiency virus type 1 Gag expression. AB - Nuclear export of incompletely spliced RNAs is a prerequisite for retroviral replication. Complex retroviruses like human immunodeficiency virus (HIV) encode a viral transport factor (Rev), which binds to its target sequence on the RNA genome and directs it into the Crm-1-mediated export pathway. Other retroviruses, like Mason-Pfizer monkey virus, contain cis-acting constitutive RNA transport elements (CTE) which achieve nuclear export of intron-containing RNA via cellular transport factors. Here, we describe the identification and characterization of a novel cis-acting orientation-dependent RNA expression element in the coding region of the murine intracisternal A-type particle (IAP) MIA14. This IAP expression element (IAPE) can functionally replace the Rev system in the expression of HIV-1 Gag proteins but functions independently of Crm-1. The presence of this element is needed for the expression of the IAP Gag proteins, indicating its biological significance. The IAPE can be functionally replaced by placing a CTE on the MIA14 RNA, further supporting its role in mRNA export. Northern blot analysis revealed that total RNA, as well as cytoplasmic RNA, was increased when the element was present. The element was mapped to a predicted stem-loop structure in the 3' part of the pol open reading frame. There was no overall homology between the IAPE and the CTE, but there was complete sequence identity between short putative single-stranded loops. Deletion of these loops from the IAPE severely reduced Rev-independent Gag expression. PMID- 11602711 TI - Poliovirus 5'-terminal cloverleaf RNA is required in cis for VPg uridylylation and the initiation of negative-strand RNA synthesis. AB - Chimeric poliovirus RNAs, possessing the 5' nontranslated region (NTR) of hepatitis C virus in place of the 5' NTR of poliovirus, were used to examine the role of the poliovirus 5' NTR in viral replication. The chimeric viral RNAs were incubated in cell-free reaction mixtures capable of supporting the sequential translation and replication of poliovirus RNA. Using preinitiation RNA replication complexes formed in these reactions, we demonstrated that the 3' NTR of poliovirus RNA was insufficient, by itself, to recruit the viral replication proteins required for negative-strand RNA synthesis. The 5'-terminal cloverleaf of poliovirus RNA was required in cis to form functional preinitiation RNA replication complexes capable of uridylylating VPg and initiating the synthesis of negative-strand RNA. These results are consistent with a model in which the 5' terminal cloverleaf and 3' NTRs of poliovirus RNA interact via temporally dynamic ribonucleoprotein complexes to coordinately mediate and regulate the sequential translation and replication of poliovirus RNA. PMID- 11602710 TI - Proteasome-independent disruption of PML oncogenic domains (PODs), but not covalent modification by SUMO-1, is required for human cytomegalovirus immediate early protein IE1 to inhibit PML-mediated transcriptional repression. AB - Human cytomegalovirus (HCMV) major immediate-early protein IE1 is an abundant 72 kDa nuclear phosphoprotein that is thought to play an important role in efficient triggering of the lytic cycle, especially at low multiplicity of infection. The best-known properties of IE1 at present are its transient targeting to punctate promyelocytic leukemia protein (PML)-associated nuclear bodies (PML oncogenic domains [PODs] or nuclear domain 10 [ND10]), with associated displacement of the cellular PML tumor suppressor protein into a diffuse nucleoplasmic form and its association with metaphase chromosomes. Recent studies have shown that the targeting of PML (and associated proteins such as hDaxx) to PODs is dependent on modification of PML by ubiquitin-like protein SUMO-1. In this study, we provide direct evidence that IE1 is also covalently modified by SUMO-1 in both infected and cotransfected cells, as well as in in vitro assays, with up to 30% of the protein representing the covalently conjugated 90-kDa form in stable U373/IE1 cell lines. Lysine 450 was mapped as the major SUMO-1 conjugation site, but a point mutation of this lysine residue in IE1 did not interfere with its targeting to and disruption of the PODs. Surprisingly, unlike PML or IE2, IE1 did not interact with either Ubc9 or SUMO-1 in yeast two-hybrid assays, suggesting that some additional unknown intranuclear cofactors must play a role in IE1 sumoylation. Interestingly, stable expression of either exogenous PML or exogenous Flag-SUMO-1 in U373 cell lines greatly enhanced both the levels and rate of in vivo IE1 sumoylation during HCMV infection. Unlike the disruption of PODs by the herpes simplex virus type 1 IE110(ICP0) protein, the disruption of PODs by HCMV IE1 proved not to involve proteasome-dependent degradation of PML. We also demonstrate here that the 560-amino-acid PML1 isoform functions as a transcriptional repressor when fused to the GAL4 DNA-binding domain and that wild type IE1 inhibits the repressor function of PML1 in transient cotransfection assays. Furthermore, both IE1(1-346) and IE1(L174P) mutants, which are defective in displacing PML from PODs, failed to inhibit the repression activity of PML1, whereas the sumoylation-negative IE1(K450R) mutant derepressed as efficiently as wild-type IE1. Taken together, our results suggest that proteasome-independent disruption of PODs, but not IE1 sumoylation, is required for efficient IE1 inhibition of PML-mediated transcriptional repression. PMID- 11602712 TI - The cis-acting family of repeats can inhibit as well as stimulate establishment of an oriP replicon. AB - Previously we have shown that the establishment of an oriP replicon is dependent on its epigenetic modification, which occurs in only 1 to 10% of proliferating cells (E. R. Leight and B. Sugden, Mol. Cell. Biol. 21:4149-4161, 2001). To gain insights into the cis-acting requirements for the establishment of oriP replicons, we monitored the replication of oriP plasmid derivatives for several weeks following their introduction into cells. In EBNA-1-positive 143B and H1299 cells, plasmids containing only the region of dyad symmetry (DS) of oriP replicated but were lost more rapidly from cells than were oriP plasmids, demonstrating that the family of repeats (FR) of oriP acts in cis to stimulate replication in these cells. Unexpectedly, we found that the DS plasmid was established efficiently in 293/EBNA-1 cells, being lost at a rate of only 8% per cell generation over 24 days posttransfection. However, plasmids containing the FR in addition to the DS of oriP replicated but were lost at a rate of approximately 30% per cell generation in 293/EBNA-1 cells, indicating that the FR inhibits oriP's establishment in this cell line. FR's enhancement of transcription of a promoter in cis and FR's ability to inhibit replication fork movement do not account solely for oriP's inefficient establishment. In addition, DNA looping between FR and DS neither stimulates nor inhibits replication. Deletion of 11 EBNA-1 binding sites in the FR or replacement of the FR with DS sequences, however, does overcome the inhibitory activity of the FR, thereby allowing efficient establishment of the oriP derivative in 293/EBNA-1 cells. PMID- 11602713 TI - Temporal regulation of herpes simplex virus type 2 VP22 expression and phosphorylation. AB - The VP22 protein of herpes simplex virus type 2 (HSV-2) is a major component of the virion tegument. Previous work with HSV-1 indicated that VP22 is phosphorylated during infection, and phosphorylation may play a role in modulating VP22 localization in infected cells. It is not clear, however, when phosphorylation occurs in infected cells or how it is regulated. Less is known about the synthesis and phosphorylation of HSV-2 VP22. To study the complete biosynthetic history of HSV-2 VP22, we generated a monoclonal antibody to the carboxy terminus of VP22. Using immunoprecipitation and Western blot analyses, we show that HSV-2 VP22 can be found in three distinct isoforms in infected cells, two of which are phosphorylated. Like HSV-1 VP22, HSV-2 VP22 is synthesized ca. 4 h after infection, and the isoform later incorporated into virions is hypophosphorylated. In addition, we demonstrate for the first time (i) that newly synthesized VP22 is phosphorylated rapidly after synthesis, (ii) that this phosphorylation occurs in a virus-dependent manner, (iii) that the HSV-2 kinase UL13 is capable of inducing phosphorylation of VP22 in the absence of other viral proteins, (iv) that phosphorylated VP22 is very stable in infected cells, (v) that phosphorylated isoforms of VP22 are gradually dephosphorylated late in infection to produce the virion tegument form, and (vi) that this dephosphorylation occurs independently of viral DNA replication or virion assembly. These results indicate that HSV-2 VP22 is a stable protein that undergoes highly regulated, virus-dependent phosphorylation events in infected cells. PMID- 11602714 TI - Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. AB - The mammalian Toll-like receptor 4, TLR4, is an important component in the innate immune response to gram-negative bacterial infection. The role of TLR4 in antiviral immunity has been largely unexplored. In this study, the in vivo immune responses to respiratory syncytial virus (RSV) and influenza virus infection were examined in TLR4-deficient (C57BL/10ScNCr) and TLR4-expressing (C57BL/10Sn) mice. TLR4-deficient mice challenged with RSV, but not influenza virus, exhibited impaired natural killer (NK) cell and CD14(+) cell pulmonary trafficking, deficient NK cell function, impaired interleukin-12 expression, and impaired virus clearance compared to mice expressing TLR4. These findings suggest that Toll signaling pathways have an important role in innate immunity to RSV. PMID- 11602715 TI - Induction of rapid and extensive beta-chemokine synthesis in macrophages by human immunodeficiency virus type 1 and gp120, independently of their coreceptor phenotype. AB - Human immunodeficiency virus type 1 (HIV-1) interacts with its target cells through CD4 and a coreceptor, generally CCR5 or CXCR4. Macrophages display CD4, CCR5, and CXCR4 that are competent for binding and entry of virus. Virus binding also induces several responses by lymphocytes and macrophages that can be dissociated from productive infection. We investigated the responses of macrophages to exposure to a series of HIV-1 species, R5 species that productively infect and X4 species that do not infect macrophages. We chose to monitor production of several physiologically relevant factors within hours of treatment to resolve virally induced effects that may be unlinked to HIV-1 production. Our novel findings indicate that independently of their coreceptor phenotype and independently of virus replication, exposure to certain R5 and X4 HIV-1 species induced secretion of high levels of macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, RANTES, and tumor necrosis factor alpha. However two of the six R5 species tested, despite efficient infection, were unable to induce rapid chemokine production. The acute effects of virus on macrophages could be mimicked by exposure to purified R5 or the X4 HIV-1 envelope glycoprotein gp120. Depletion of intracellular Ca(2+) or inhibition of protein synthesis blocked the chemokine induction, implicating Ca(2+)-mediated signal transduction and new protein synthesis in the response. The group of viruses able to induce this chemokine response was not consistent with coreceptor usage. We conclude that human macrophages respond rapidly to R5 and X4 envelope binding by production of high levels of physiologically active proteins that are implicated in HIV-1 pathogenesis. PMID- 11602716 TI - Selective loss of natural killer T cells by apoptosis following infection with lymphocytic choriomeningitis virus. AB - Natural killer T (NKT) cells, a unique subpopulation of T cells, coexpress markers also present on NK cells and recognize the major histocompatibility complex class I-like CD1d1 molecule. We studied the effect of an acute virus infection on NKT cells. Mice were infected with the nonhepatotropic Armstrong strain of lymphocytic choriomeningitis virus (LCMV), and at various times postinfection, mononuclear cells from the liver, peritoneum, and spleen were isolated. It was found that within 2 to 3 days, there was a selective loss of NKT cells from the liver with an apparent rapid recovery within 8 to 14 days. There was no increase in peritoneal or splenic NKT cells, indicating that NKT cells did not traffic to these tissues. This loss of NKT cells was independent of gamma interferon (IFN-gamma) and interleukin 12 (IL-12) production, but did occur in mice treated with poly(I-C), a classical inducer of IFN-alpha/beta. The reduction in NKT cells was CD28 and fas/fasL independent and occurred via apoptosis. It was not observed in LCMV-infected DNA fragmentation factor 45-deficient mice, and an increase in active caspase 3-specific staining was found in liver NKT cells from LCMV-infected and poly(I-C)-treated mice compared to uninfected wild-type mice. Interestingly, it was also found that liver NKT cells from LCMV-infected mice were themselves infected. These results suggest that the loss of NKT cells following an acute LCMV infection could be due to the induction of IFN-alpha/beta resulting in NKT-cell apoptosis and is important for the host's immune response to LCMV. PMID- 11602717 TI - Packaging of genomic and amplicon DNA by the herpes simplex virus type 1 UL25 null mutant KUL25NS. AB - The herpes simplex virus type 1 (HSV-1) mutant KUL25NS, containing a null mutation within the UL25 gene, was isolated and characterized by McNab and coworkers (A. R. McNab, P. Desai, S. Person, L. L. Roof, D. R. Thomsen, W. W. Newcomb, J. C. Brown, and F. L. Homa, J. Virol. 72:1060-1070, 1998). This mutant was able to cleave the concatemeric products of viral DNA replication into monomeric units, but in contrast to wild-type (wt) HSV-1, they were degraded by DNase treatment, indicating that they were not stably packaged into virus capsids. I have examined the packaging of the KUL25NS genome and an HSV-1 amplicon in cells infected with the mutant virus. In contrast to the previous results, a low level of KUL25NS DNA was resistant to DNase digestion, indicating that it was retained in capsids. The proportion of this packaged DNA present as full-length genomes was much lower than in cells infected by wt HSV-1, and there was a significant overrepresentation of the long terminus and underrepresentation of the short terminus. KUL25NS was less impaired in stably packaging amplicon DNA than in packaging its own genome, and the packaged molecules contained approximately equimolar amounts of the two terminal fragments. Below about 100 kbp, the packaged amplicon molecules exhibited an abundance and size distribution similar to those generated using wt HSV-1 as a helper, but the mutant was relatively impaired in packaging longer amplicon molecules. Both packaged genomic and amplicon DNAs were retained in the nuclei of KUL25NS-infected cells. These results suggest that the UL25 protein may play an important role during the later stages of the head-filling process, prior to release of capsids into the cytoplasm. PMID- 11602718 TI - CD4-independent use of Rhesus CCR5 by human immunodeficiency virus Type 2 implicates an electrostatic interaction between the CCR5 N terminus and the gp120 C4 domain. AB - Envelope glycoproteins (Envs) of human immunodeficiency virus type 2 (HIV-2) are frequently able to use chemokine receptors, CXCR4 or CCR5, in the absence of CD4. However, while these Envs are commonly dual-tropic, no isolate has been described to date that is CD4 independent on both CXCR4 and CCR5. In this report we show that a variant of HIV-2/NIHz, termed HIV-2/vcp, previously shown to utilize CXCR4 without CD4, is also CD4 independent on rhesus (rh) CCR5, but requires CD4 to fuse with human (hu) CCR5. The critical determinant for this effect was an acidic amino acid at position 13 in the CCR5 N terminus, which is an asparagine in huCCR5 and an aspartic acid in rhCCR5. Transferring the huCCR5 N terminus with an N13D substitution to CCR2b or CXCR2 was sufficient to render these heterologous chemokine receptors permissive for CD4-independent fusion. Chimeric Envs between HIV-2/vcp and a CD4-dependent clone of HIV-2/NIHz as well as site-directed Env mutations implicated a positively charged amino acid (lysine or arginine) at position 427 in the C4 region of the HIV-2/vcp env gene product (VCP) gp120 as a key determinant for this phenotype. Because CD4-independent use of CCR5 mapped to a negatively charged amino acid in the CCR5 N terminus and a positively charged amino acid in the gp120 C4 domain, an electrostatic interaction between these residues or domains is likely. Although not required for CD4-dependent fusion, this interaction may serve to increase the binding affinity of Env and CCR5 and/or to facilitate subsequent conformational changes that are required for fusion. Because the structural requirements for chemokine receptor use by HIV are likely to be more stringent in the absence of CD4, CD4-independent viruses should be particularly useful in dissecting molecular events that are critical for viral entry. PMID- 11602719 TI - Role of polypyrimidine tract binding protein in the function of the hepatitis B virus posttranscriptional regulatory element. AB - The hepatitis B virus posttranscriptional regulatory element (PRE) is an RNA element that increases the expression of unspliced mRNAs, apparently by facilitating their export from the nucleus. We have identified a cellular protein that binds to the PRE as the polypyrimidine tract binding protein (PTB), which shuttles rapidly between the nucleus and the cytoplasm. Mutants of the PRE with mutations in PTB binding sites show markedly decreased activity, while cells that stably overexpress PTB show increased PRE-dependent gene expression. Export of PTB from the nucleus, like PRE function, is blocked by a mutant form of Ran binding protein 1 but not by leptomycin B. Therefore, PTB is important for PRE activity and appears to function as an export factor for PRE-containing mRNAs. PMID- 11602720 TI - Assembly and maturation of the flavivirus Kunjin virus appear to occur in the rough endoplasmic reticulum and along the secretory pathway, respectively. AB - The intracellular assembly site for flaviviruses in currently not known but is presumed to be located within the lumen of the rough endoplasmic reticulum (RER). Building on previous studies involving immunofluorescence (IF) and cryoimmunoelectron microscopy of Kunjin virus (KUN)-infected cells, we sought to identify the steps involved in the assembly and maturation of KUN. Thus, using antibodies directed against envelope protein E in IF analysis, we found the accumulation of E within regions coincident with the RER and endosomal compartments. Immunogold labeling of cryosections of infected cells indicated that E and minor envelope protein prM were localized to reticulum membranes continuous with KUN-induced convoluted membranes (CM) or paracrystalline arrays (PC) and that sometimes the RER contained immunogold-labeled virus particles. Both proteins were also observed to be labeled in membranes at the periphery of the induced CM or PC structures, but the latter were very seldom labeled internally. Utilizing drugs that inhibit protein and/or membrane traffic throughout the cell, we found that the secretion of KUN particles late in infection was significantly affected in the presence of brefeldin A and that the infectivity of secreted particles was severely affected in the presence of monensin and N-nonyl-deoxynojirimycin. Nocodazole did not appear to affect maturation, suggesting that microtubules play no role in assembly or maturation processes. Subsequently, we showed that the exit of intact virions from the RER involves the transport of individual virions within individual vesicles en route to the Golgi apparatus. The results suggest that the assembly of virions occurs within the lumen of the RER and that subsequent maturation occurs via the secretory pathway. PMID- 11602721 TI - Overexpression of cytochrome C by a recombinant rabies virus attenuates pathogenicity and enhances antiviral immunity. AB - The pathogenicity of individual rabies virus strains appears to correlate inversely with the extent of apoptotic cell death they induce and with the expression of rabies virus glycoprotein, a major inducer of an antiviral immune response. To determine whether the induction of apoptosis by rabies virus contributes to a decreased pathogenicity by stimulating antiviral immunity, we have analyzed these parameters in tissue cultures and in mice infected with a recombinant rabies virus construct that expresses the proapoptotic protein cytochrome c. The extent of apoptosis was strongly increased in primary neuron cultures infected with the recombinant virus carrying the active cytochrome c gene [SPBN-Cyto c(+)], compared with cells infected with the recombinant virus containing the inactive cytochrome c gene [SPBN-Cyto c(-)]. Mortality in mice infected intranasally with SPBN-Cyto c(+) was substantially lower than in SPBN Cyto c(-)-infected mice. Furthermore, virus-neutralizing antibody (VNA) titers were significantly higher in mice immunized with SPBN-Cyto c(+) at the same dose. The VNA titers induced by these recombinant viruses paralleled their protective activities against a lethal rabies virus challenge infection, with SPBN-Cyto c(+) revealing an effective dose 20 times lower than that of SPBN-Cyto c(-). The strong increase in immunogenicity, coupled with the marked reduction in pathogenicity, identifies the SPBN-Cyto c(+) construct as a candidate for a live rabies virus vaccine. PMID- 11602722 TI - Human Mast cell progenitors can be infected by macrophagetropic human immunodeficiency virus type 1 and retain virus with maturation in vitro. AB - Mast cells are critical components of innate and adaptive immunity that differentiate in tissues in situ from circulating committed progenitor cells. We now demonstrate that human cord blood-derived mast cell progenitors are susceptible to infection with macrophagetropic (M-tropic) and dualtropic human immunodeficiency virus type 1 (HIV-1) isolates but not with T-cell-tropic (T tropic) strains. Mast cell progenitors (c-kit(+) CD13(+) cells with chloroacetate esterase activity) were purified from 4-week-old cultures of cord blood mononuclear cells maintained in stem cell factor, interleukin-6 (IL-6), and IL-10 using a CD14 depletion column. These progenitors expressed CCR3, CCR5, and CXCR4, as well as low levels of CD4. When infected in vitro with viruses pseudotyped with different HIV and simian immunodeficiency virus envelope glycoproteins, only M-tropic and dualtropic, but not T-tropic, viruses were able to enter mast cell progenitors. Both the CCR5-specific monoclonal antibody 2D7 and TAK-779, a nonpeptide inhibitor of CCR5-mediated viral entry, blocked HIV-1 strain ADA infection by >80%. Cultures infected with replication-competent virus produced progressively increasing amounts of virus for 21 days as indicated by p24 antigen detection. Mast cell progenitors that were exposed to an M-tropic, green fluorescent protein-expressing HIV-1 strain exhibited fluorescence indicative of viral entry and replication on a single-cell level and retained virus production during differentiation. The trafficking of mast cell progenitors to multiple tissues, combined with the long life span of mature mast cells, suggests that they could provide a widespread and persistent HIV reservoir in AIDS. PMID- 11602724 TI - Effects of deletion and overexpression of the Autographa californica nuclear polyhedrosis virus FP25K gene on synthesis of two occlusion-derived virus envelope proteins and their transport into virus-induced intranuclear membranes. AB - Partial deletions within Autographa californica open reading frame 61 (FP25K) alter the expression and accumulation profile of several viral proteins and the transport of occlusion-derived virus (ODV)-E66 to intranuclear membranes during infection (S. C. Braunagel et al., J. Virol. 73:8559-8570, 1999). Here we show the effects of a full deletion and overexpression of FP25K on the transport and expression of two ODV envelope proteins, ODV-E66 (E66) and ODV-E25 (E25). Deletion and overexpression of FP25K substantially altered the levels of expression of E66 during infection. Compared with cells infected with wild-type (wt) virus, the levels of E66 were reduced fivefold in cells infected with a viral mutant lacking FP25K (DeltaFP25K) and were slightly increased in cells infected with a viral mutant overexpressing FP25K (FP25K(polh)). In contrast, no significant changes were observed in the levels of E25 among wt-, DeltaFP25K-, and FP25K(polh)-infected cells. The changes observed in the levels of E66 among the different viral mutants were not accompanied by changes in either the time of synthesis, membrane association, protein turnover, or steady-state transcript abundance. Deletion of FP25K also substantially altered the transport and localization of E66 during infection. In cells infected with the DeltaFP25K mutant virus, E66 accumulated in localized regions at the nuclear periphery and the outer nuclear membrane and did not traffic to intranuclear membranes. In contrast, in cells infected with the FP25K(polh) mutant virus E66 trafficked to intranuclear membranes. For comparison, E25 was normally transported to intranuclear membranes in both DeltaFP25K- and FP25K(polh)-infected cells. Altogether these studies suggest that FP25K affects the synthesis of E66 at a posttranscriptional level, probably by altering the translation of E66; additionally, the block in transport of E66 at the nuclear envelope in DeltaFP25K infected cells suggests that the pathway of E66 trafficking to the inner nuclear membrane and intranuclear microvesicles is specifically regulated and must be influenced by factors that do not control the traffic of E25. PMID- 11602723 TI - C terminus of infectious bursal disease virus major capsid protein VP2 is involved in definition of the T number for capsid assembly. AB - Infectious bursal disease virus (IBDV), a member of the Birnaviridae family, is a double-stranded RNA virus. The IBDV capsid is formed by two major structural proteins, VP2 and VP3, which assemble to form a T=13 markedly nonspherical capsid. During viral infection, VP2 is initially synthesized as a precursor, called VPX, whose C end is proteolytically processed to the mature form during capsid assembly. We have computed three-dimensional maps of IBDV capsid and virus like particles built up by VP2 alone by using electron cryomicroscopy and image processing techniques. The IBDV single-shelled capsid is characterized by the presence of 260 protruding trimers on the outer surface. Five classes of trimers can be distinguished according to their different local environments. When VP2 is expressed alone in insect cells, dodecahedral particles form spontaneously; these may be assembled into larger, fragile icosahedral capsids built up by 12 dodecahedral capsids. Each dodecahedral capsid is an empty T=1 shell composed of 20 trimeric clusters of VP2. Structural comparison between IBDV capsids and capsids consisting of VP2 alone allowed the determination of the major capsid protein locations and the interactions between them. Whereas VP2 forms the outer protruding trimers, VP3 is found as trimers on the inner surface and may be responsible for stabilizing functions. Since elimination of the C-terminal region of VPX is correlated with the assembly of T=1 capsids, this domain might be involved (either alone or in cooperation with VP3) in the induction of different conformations of VP2 during capsid morphogenesis. PMID- 11602725 TI - Exogenous interleukin-2 administration corrects the cell cycle perturbation of lymphocytes from human immunodeficiency virus-infected individuals. AB - Human immunodeficiency virus (HIV)-induced immunodeficiency is characterized by progressive loss of CD4(+) T cells associated with functional abnormalities of the surviving lymphocytes. Increased susceptibility to apoptosis and loss of proper cell cycle control can be observed in lymphocytes from HIV-infected individuals and may contribute to the lymphocyte dysfunction of AIDS patients. To better understand the relation between T-cell activation, apoptosis, and cell cycle perturbation, we studied the effect of exogenous interleukin-2 (IL-2) administration on the intracellular turnover of phase-dependent proteins. Circulating T cells from HIV-infected patients display a marked discrepancy between a metabolic profile typical of G(0) and a pattern of expression of phase dependent proteins that indicates a more-advanced position within the cell cycle. This discrepancy is enhanced by in vitro activation with ConA and ultimately results in a marked increase of apoptotic events. Conversely, treatment of lymphocytes with IL-2 alone restores the phase-specific pattern of expression of cell cycle-dependent proteins and is associated with low levels of apoptosis. Interestingly, exogenous IL-2 administration normalizes the overall intracellular protein turnover, as measured by protein synthesis, half-life of newly synthesised proteins, and total protein ubiquitination, thus providing a possible explanation for the effect of IL-2 on the intracellular kinetics of cell cycle dependent proteins. The beneficial effect of IL-2 administration is consistent with the possibility of defective IL-2 function in vivo, which is confirmed by the observation that lymphocytes from HIV-infected patients show abnormal endogenous IL-2 paracrine/autocrine function upon in vitro mitogen stimulation. Overall these results confirm that perturbation of cell cycle control contributes to HIV-related lymphocyte dysfunction and, by showing that IL-2 administration can revert this perturbation, suggest a new mechanism of action of IL-2 therapy in HIV-infected patients. PMID- 11602727 TI - Role of immunoglobulin A in protection against reovirus entry into Murine Peyer's patches. AB - Reovirus type 1 Lang (T1L) infects the mouse intestinal mucosa by adhering specifically to epithelial M cells and exploiting M-cell transport to enter the Peyer's patches. Oral inoculation of adult mice has been shown to elicit cellular and humoral immune responses that clear the infection within 10 days. This study was designed to determine whether adult mice that have cleared a primary infection are protected against viral entry upon oral rechallenge and, if so, whether antireovirus secretory immunoglobulin A (S-IgA) is a necessary component of protection. Adult BALB/c mice that were orally inoculated on day 0 with reovirus T1L produced antiviral S-IgA in feces and IgG in serum directed primarily against the reovirus sigma1 attachment protein. Eight hours after oral reovirus challenge on day 21, the Peyer's patches of previously exposed mice contained no detectable virus whereas Peyer's patches of naive controls contained up to 2,300 PFU of reovirus/mg of tissue. Orally inoculated IgA knockout (IgA(-/ )) mice cleared the initial infection as effectively as wild-type mice and produced higher levels of reovirus-specific serum IgG and secretory IgM than C57BL/6 wild-type mice. When IgA(-/-) mice were rechallenged on day 21, however, their Peyer's patches became infected. These results indicate that intestinal S IgA is an essential component of immune protection against reovirus entry into Peyer's patch mucosa. PMID- 11602726 TI - Insertions in the gG gene of pseudorabies virus reduce expression of the upstream Us3 protein and inhibit cell-to-cell spread of virus infection. AB - The alphaherpesvirus Us4 gene encodes glycoprotein G (gG), which is conserved in most viruses of the alphaherpesvirus subfamily. In the swine pathogen pseudorabies virus (PRV), mutant viruses with internal deletions and insertions in the gG gene have shown no discernible phenotypes. We report that insertions in the gG locus of the attenuated PRV strain Bartha show reduced virulence in vivo and are defective in their ability to spread from cell to cell in a cell-type specific manner. Similar insertions in the gG locus of the wild-type PRV strain Becker had no effect on the ability of virus infection to spread between cells. Insertions in the gG locus of the virulent NIA-3 strain gave results similar to those found with the Bartha strain. To examine the role of gG in cell-to-cell spread, a nonsense mutation in the gG signal sequence was constructed and crossed into the Bartha strain. This mutant, PRV157, failed to express gG yet had cell-to cell spread properties indistinguishable from those of the parental Bartha strain. These data indicated that, while insertions in the gG locus result in decreased cell-to-cell spread, the phenotype was not due to loss of gG expression as first predicted. Analysis of gene expression upstream and downstream of gG revealed that expression of the upstream Us3 protein is reduced by insertion of lacZ or egfp at the gG locus. By contrast, expression of the gene immediately downstream of gG, Us6, which encodes glycoprotein gD, was not affected by insertions in gG. These data indicate that DNA insertions in gG have polar effects and suggest that the serine/threonine kinase encoded by the Us3 gene, and not gG, functions in the spread of viral infection between cells. PMID- 11602728 TI - Caveolae are involved in the trafficking of mouse polyomavirus virions and artificial VP1 pseudocapsids toward cell nuclei. AB - Electron and confocal microscopy were used to observe the entry and the movement of polyomavirus virions and artificial virus-like particles (VP1 pseudocapsids) in mouse fibroblasts and epithelial cells. No visible differences in adsorption and internalization of virions and VP1 pseudocapsids ("empty" or containing DNA) were observed. Viral particles entered cells internalized in smooth monopinocytic vesicles, often in the proximity of larger, caveola-like invaginations. Both "empty" vesicles derived from caveolae and vesicles containing viral particles were stained with the anti-caveolin-1 antibody, and the two types of vesicles often fused in the cytoplasm. Colocalization of VP1 with caveolin-1 was observed during viral particle movement from the plasma membrane throughout the cytoplasm to the perinuclear area. Empty vesicles and vesicles with viral particles moved predominantly along microfilaments. Particle movement was accompanied by transient disorganization of actin stress fibers. Microfilaments decorated by the VP1 immunofluorescent signal could be seen as concentric curves, apparently along membrane structures that probably represent endoplasmic reticulum. Colocalization of VP1 with tubulin was mostly observed in areas close to the cell nuclei and on mitotic tubulin structures. By 3 h postinfection, a strong signal of the VP1 (but no viral particles) had accumulated in the proximity of nuclei, around the outer nuclear membrane. However, the vast majority of VP1 pseudocapsids did not enter the nuclei. PMID- 11602729 TI - Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41. AB - The identification and epitope mapping of broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibodies (Abs) is important for vaccine design, but, despite much effort, very few such Abs have been forthcoming. Only one broadly neutralizing anti-gp41 monoclonal Ab (MAb), 2F5, has been described. Here we report on two MAbs that recognize a region immediately C-terminal of the 2F5 epitope. Both MAbs were generated from HIV-1-seropositive donors, one (Z13) from an antibody phage display library, and one (4E10) as a hybridoma. Both MAbs recognize a predominantly linear and relatively conserved epitope, compete with each other for binding to synthetic peptide derived from gp41, and bind to HIV 1(MN) virions. By flow cytometry, these MAbs appear to bind relatively weakly to infected cells and this binding is not perturbed by pretreatment of the infected cells with soluble CD4. Despite the apparent linear nature of the epitopes of Z13 and 4E10, denaturation of recombinant envelope protein reduces the binding of these MAbs, suggesting some conformational requirements for full epitope expression. Most significantly, Z13 and 4E10 are able to neutralize selected primary isolates from diverse subtypes of HIV-1 (e.g., subtypes B, C, and E). The results suggest that a rather extensive region of gp41 close to the transmembrane domain is accessible to neutralizing Abs and could form a useful target for vaccine design. PMID- 11602730 TI - Fine definition of the epitope on the gp41 glycoprotein of human immunodeficiency virus type 1 for the neutralizing monoclonal antibody 2F5. AB - Matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS), in combination with proteolytic protection assays, has been used to identify the functional epitope on human immunodeficiency virus envelope glycoprotein gp41 for the broadly neutralizing anti-gp41 human monoclonal antibody 2F5. In this protection assay-based procedure, a soluble gp140 protein with a stabilizing intermolecular disulfide bond between the gp120 and gp41 subunits (SOS gp140) was affinity bound to immobilized 2F5 under physiological conditions. A combination of proteolytic enzymatic cleavages was then performed to remove unprotected residues. Residues of SOS gp140 protected by their binding to 2F5 were then identified based on their molecular weights as determined by direct MALDI-MS of the immobilized antibody beads. The epitope, NEQELLELDKWASLWN, determined by this MALDI-MS protection assay approach consists of 16 amino acid residues near the C terminus of gp41. It is significantly longer than the ELDKWA core epitope previously determined for 2F5 by peptide enzyme-linked immunosorbent assay. This new knowledge of the structure of the 2F5 epitope may facilitate the design of vaccine antigens intended to induce antibodies with the breadth and potency of action of the 2F5 monoclonal antibody. PMID- 11602731 TI - Neuroadapted yellow fever virus 17D: genetic and biological characterization of a highly mouse-neurovirulent virus and its infectious molecular clone. AB - A neuroadapted strain of yellow fever virus (YFV) 17D derived from a multiply mouse brain-passaged virus (Porterfield YF17D) was additionally passaged in SCID and normal mice. The virulence properties of this virus (SPYF) could be distinguished from nonneuroadapted virus (YF5.2iv, 17D infectious clone) by decreased average survival time in SCID mice after peripheral inoculation, decreased average survival time in normal adult mice after intracerebral inoculation, and occurrence of neuroinvasiveness in normal mice. SPYF exhibited more efficient growth in peripheral tissues of SCID mice than YF5.2iv, resulting in a more rapid accumulation of virus burden, but with low-titer viremia, at the time of fatal encephalitis. In cell culture, SPYF was less efficient in replication than YF5.2iv in all cell lines tested. The complete nucleotide sequence of SPYF revealed 29 nucleotide substitutions relative to YF5.2iv, and these were distributed throughout the genome. There were a total of 13 predicted amino acid substitutions, some of which correspond to known differences among the Asibi, French viscerotropic virus, French neurotropic vaccine, and YF17D vaccine strains. The envelope (E) protein contained five substitutions, within all three functional domains. Substitutions were also present in regions encoding the NS1, NS2A, NS4A, and NS5 proteins and in the 3' untranslated region (UTR). Construction of YFV harboring all of the identified coding nucleotide substitutions and those in the 3' UTR yielded a virus whose cell culture and pathogenic properties, particularly neurovirulence and neuroinvasiveness for SCID mice, generally resembled those of the original SPYF isolate. These findings implicate the E protein and possibly other regions of the genome as virulence determinants during pathogenesis of neuroadapted YF17D virus in mice. The determinants affect replication efficiency in both neural and extraneural tissues of the mouse and confer some limited host-range differences in cultured cells of nonmurine origin. PMID- 11602732 TI - The UL6 gene product forms the portal for entry of DNA into the herpes simplex virus capsid. AB - During replication of herpes simplex virus type 1 (HSV-1), viral DNA is synthesized in the infected cell nucleus, where DNA-free capsids are also assembled. Genome-length DNA molecules are then cut out of a larger, multigenome concatemer and packaged into capsids. Here we report the results of experiments carried out to test the idea that the HSV-1 UL6 gene product (pUL6) forms the portal through which viral DNA passes as it enters the capsid. Since DNA must enter at a unique site, immunoelectron microscopy experiments were undertaken to determine the location of pUL6. After specific immunogold staining of HSV-1 B capsids, pUL6 was found, by its attached gold label, at one of the 12 capsid vertices. Label was not observed at multiple vertices, at nonvertex sites, or in capsids lacking pUL6. In immunoblot experiments, the pUL6 copy number in purified B capsids was found to be 14.8 +/- 2.6. Biochemical experiments to isolate pUL6 were carried out, beginning with insect cells infected with a recombinant baculovirus expressing the UL6 gene. After purification, pUL6 was found in the form of rings, which were observed in electron micrographs to have outside and inside diameters of 16.4 +/- 1.1 and 5.0 +/- 0.7 nm, respectively, and a height of 19.5 +/- 1.9 nm. The particle weights of individual rings as determined by scanning transmission electron microscopy showed a majority population with a mass corresponding to an oligomeric state of 12. The results are interpreted to support the view that pUL6 forms the DNA entry portal, since it exists at a unique site in the capsid and forms a channel through which DNA can pass. The HSV 1 portal is the first identified in a virus infecting a eukaryote. In its dimensions and oligomeric state, the pUL6 portal resembles the connector or portal complexes employed for DNA encapsidation in double-stranded DNA bacteriophages such as phi29, T4, and P22. This similarity supports the proposed evolutionary relationship between herpesviruses and double-stranded DNA phages and suggests the basic mechanism of DNA packaging is conserved. PMID- 11602734 TI - C-terminal domain of the Epstein-Barr virus LMP2A membrane protein contains a clustering signal. AB - The latency-regulated transmembrane protein LMP2A interferes with signaling from the B-cell antigen receptor by recruiting the tyrosine kinases Lyn and Syk and by targeting them for degradation by binding the cellular E3 ubiquitin ligase AIP4. It has been hypothesized that this constitutive activity of LMP2A requires clustering in the membrane, but molecular evidence for this has been lacking. In the present study we show that LMP2A coclusters with chimeric rat CD2 transmembrane molecules carrying the 27-amino-acid (aa) intracellular C terminus of LMP2A and that this C-terminal domain fused to the glutathione-S-transferase protein associates with LMP2A in cell lysates. This molecular association requires neither the cysteine-rich region between aa 471 and 480 nor the terminal three aa 495 to 497. We also show that the juxtamembrane cysteine repeats in the LMP2A C terminus are the major targets for palmitoylation but that this acylation is not required for targeting of LMP2A to detergent-insoluble glycolipid-enriched membrane microdomains. PMID- 11602733 TI - Human herpesvirus 8 (HHV-8)-encoded cytokines induce expression of and autocrine signaling by vascular endothelial growth factor (VEGF) in HHV-8-infected primary effusion lymphoma cell lines and mediate VEGF-independent antiapoptotic effects. AB - The potential roles of human herpesvirus 8 (HHV-8) cytokines in HHV-8 pathogenesis were investigated by determining the expression of the HHV-8 chemokines viral macrophage inflammatory protein 1A (vMIP-1A) and vMIP-1B in primary effusion lymphoma (PEL)-derived cell lines and examining the signaling activities of these chemokines and HHV-8-encoded vIL-6 in these cells. Secreted vMIP-1A and vMIP-1B were detected in biologically significant concentrations following tetradecanoyl phorbol acetate treatment, which induces productive replication. vIL-6 and vMIP-1A, added exogenously to cultures of four different PEL cell lines, induced the expression of vascular endothelial growth factor type B (VEGF-B) and VEGF-A, respectively. These cells were found to express VEGF receptor 1 (Flt-1) protein, and signaling by recombinant VEGF-A(165) was demonstrated for two of the PEL cell lines, indicating the potential for autocrine, as well as paracrine, effects of viral cytokine-induced VEGF. In addition, vMIP-1A and vMIP-1B, but not VEGF-A(165), were found to inhibit chemically induced apoptosis in PEL cells. Our data suggest that vIL-6 and vMIP 1A may influence PEL through VEGF autocrine and paracrine signaling that promotes PEL cell growth and extravascular effusion and that vMIP-1A and vMIP-1B can act independently of VEGF as antiapoptotic factors. PMID- 11602735 TI - Inhibition of human immunodeficiency virus type 1 gp120 presentation to CD4 T cells by antibodies specific for the CD4 binding domain of gp120. AB - Human immunodeficiency virus (HIV)-specific CD4 T-cell responses, particularly to the envelope glycoproteins of the virus, are weak or absent in most HIV-infected patients. Although these poor responses can be attributed simply to the destruction of the specific CD4 T cells by the virus, other factors also appear to contribute to the suppression of these virus-specific responses. We previously showed that human monoclonal antibodies (MAbs) specific for the CD4 binding domain of gp120 (gp120(CD4BD)), when complexed with gp120, inhibited the proliferative responses of gp120-specific CD4 T-cells. MAbs to other gp120 epitopes did not exhibit this activity. The present study investigated the inhibitory mechanisms of the anti-gp120(CD4BD) MAbs. The anti-gp120(CD4BD) MAbs complexed with gp120 suppressed gamma interferon production as well as proliferation of gp120-specific CD4 T cells. Notably, the T-cell responses to gp120 were inhibited only when the MAbs were added to antigen-presenting cells (APCs) during antigen pulse; the addition of the MAbs after pulsing caused no inhibition. However, the anti-gp120(CD4BD) MAbs by themselves, or as MAb/gp120 complexes, did not affect the presentation of gp120-derived peptides by the APCs to T cells. These MAb/gp120 complexes also did not inhibit the ability of APCs to process and present unrelated antigens. To test whether the suppressive effect of anti-gp120(CD4BD) antibodies is caused by the antibodies' ability to block gp120 CD4 interaction, APCs were treated during antigen pulse with anti-CD4 MAbs. These treated APCs remained capable of presenting gp120 to the T cells. These results suggest that anti-gp120(CD4BD) Abs inhibit gp120 presentation by altering the uptake and/or processing of gp120 by the APCs but their inhibitory activity is not due to blocking of gp120 attachment to CD4 on the surface of APCs. PMID- 11602736 TI - Molecular determinants of peptide binding to two common rhesus macaque major histocompatibility complex class II molecules. AB - Major histocompatibility complex class II molecules encoded by two common rhesus macaque alleles Mamu-DRB1*0406 and Mamu-DRB*w201 have been purified, and quantitative binding assays have been established. The structural requirements for peptide binding to each molecule were characterized by testing panels of single-substitution analogs of the two previously defined epitopes HIV Env242 (Mamu-DRB1*0406 restricted) and HIV Env482 (Mamu-DRB*w201 restricted). Anchor positions of both macaque DR molecules were spaced following a position 1 (P1), P4, P6, P7, and P9 pattern. The specific binding motif associated with each molecule was distinct, but largely overlapping, and was based on crucial roles of aromatic and/or hydrophobic residues at P1, P6, and P9. Based on these results, a tentative Mamu class II DR supermotif was defined. This pattern is remarkably similar to a previously defined human HLA-DR supermotif. Similarities in binding motifs between human HLA and macaque Mamu-DR molecules were further illustrated by testing a panel of more than 60 different single-substitution analogs of the HLA-DR-restricted HA 307-319 epitope for binding to Mamu-DRB*w201 and HLA DRB1*0101. The Mamu-DRB1*0406 and -DRB*w201 binding capacity of a set of 311 overlapping peptides spanning the entire simian immunodeficiency virus (SIV) genome was also evaluated. Ten peptides capable of binding both molecules were identified, together with 19 DRB1*0406 and 43 DRB*w201 selective binders. The Mamu-DR supermotif was found to be present in about 75% of the good binders and in 50% of peptides binding with intermediate affinity but only in approximately 25% of the peptides which did not bind either Mamu class II molecule. Finally, using flow cytometric detection of antigen-induced intracellular gamma interferon, we identify a new CD4(+) T-lymphocyte epitope encoded within the Rev protein of SIV. PMID- 11602737 TI - Biochemical and genetic studies of the initiation of human rhinovirus 2 RNA replication: purification and enzymatic analysis of the RNA-dependent RNA polymerase 3D(pol). AB - The replication of human rhinovirus 2 (HRV2), a positive-stranded RNA virus belonging to the Picornaviridae, requires a virus-encoded RNA polymerase. We have expressed in Escherichia coli and purified both a glutathione S-transferase fusion polypeptide and an untagged form of the HRV2 RNA polymerase 3D(pol). Using in vitro assay systems previously described for poliovirus RNA polymerase 3D(pol) (J. B. Flanegan and D. Baltimore, Proc. Natl. Acad. Sci. USA 74:3677-3680, 1977; A. V. Paul, J. H. van Boom, D. Filippov, and E. Wimmer, Nature 393:280-284, 1998), we have analyzed the biochemical properties of the two different enzyme preparations. HRV2 3D(pol) is both template and primer dependent, and it catalyzes two types of synthetic reactions in the presence of UTP, Mn(2+), and a poly(A) template. The first consists of an elongation reaction of an oligo(dT)(15) primer into poly(U). The second is a protein-priming reaction in which the enzyme covalently links UMP to the hydroxyl group of tyrosine in the terminal protein VPg, yielding VPgpU. This precursor is elongated first into VPgpUpU and then into VPg-linked poly(U), which is identical to the 5' end of picornavirus minus strands. The two forms of the enzyme are about equally active both in the oligonucleotide elongation and in the VPg-primed reaction. Various synthetic mutant VPgs were tested as substrates in the VPg uridylylation reaction. PMID- 11602738 TI - Biochemical and genetic studies of the initiation of human rhinovirus 2 RNA replication: identification of a cis-replicating element in the coding sequence of 2A(pro). AB - We have previously shown that the RNA polymerase 3D(pol) of human rhinovirus 2 (HRV2) catalyzes the covalent linkage of UMP to the terminal protein (VPg) using poly(A) as a template (K. Gerber, E. Wimmer, and A. V. Paul, J. Virol. 75:10969 10978, 2001). The products of this in vitro reaction are VPgpU, VPgpUpU, and VPg poly(U), the 5' end of minus-strand RNA. In the present study we used an assay system developed for poliovirus 3D(pol) (A. V. Paul, E. Rieder, D. W. Kim, J. H. van Boom, and E. Wimmer, J. Virol. 74: 10359-10370, 2000) to search for a viral sequence or structure in HRV2 RNA that would provide specificity to this reaction. We now show that a small hairpin in HRV2 RNA [cre(2A)], located in the coding sequence of 2A(pro), serves as the primary template for HRV2 3D(pol) in the uridylylation of HRV2 VPg, yielding VPgpU and VPgpUpU. The in vitro reaction is strongly stimulated by the addition of purified HRV2 3CD(pro). Our analyses suggest that HRV2 3D(pol) uses a "slide-back" mechanism during synthesis of the VPg-linked precursors. The corresponding cis- replicating RNA elements in the 2C(ATPase) coding region of poliovirus type 1 Mahoney (I. Goodfellow, Y. Chaudhry, A. Richardson, J. Meredith, J. W. Almond, W. Barclay, and D. J. Evans, J. Virol. 74:4590-4600, 2000) and VP1 of HRV14 (K. L. McKnight and S. M. Lemon, RNA 4:1569-1584, 1998) can be functionally exchanged in the assay with cre(2A) of HRV2. Mutations of either the first or the second A in the conserved A(1)A(2)A(3)CA sequence in the loop of HRV2 cre(2A) abolished both viral growth and the RNA's ability to serve as a template in the in vitro VPg uridylylation reaction. PMID- 11602739 TI - Multiple effects of codon usage optimization on expression and immunogenicity of DNA candidate vaccines encoding the human immunodeficiency virus type 1 Gag protein. AB - We have analyzed the influence of codon usage modifications on the expression levels and immunogenicity of DNA vaccines, encoding the human immunodeficiency virus type 1 (HIV-1) group-specific antigen (Gag). In the presence of Rev, an expression vector containing the wild-type (wt) gag gene flanked by essential cis acting sites such as the 5'-untranslated region and 3'-Rev response element supported substantial Gag protein expression and secretion in human H1299 and monkey COS-7 cells. However, only weak Gag production was observed from the murine muscle cell line C2C12. In contrast, optimization of the Gag coding sequence to that of highly expressed mammalian genes (syngag) resulted in an obvious increase in the G+C content and a Rev-independent expression and secretion of Gag in all tested mammalian cell lines, including murine C2C12 muscle cells. Mice immunized intramuscularly with the syngag plasmid showed Th1 driven humoral and cellular responses that were substantially higher than those obtained after injection of the Rev-dependent wild-type (wt) gag vector system. In contrast, intradermal immunization of both wt gag and syngag vector systems with the particle gun induced a Th2-biased antibody response and no cytotoxic T lymphocytes. Deletion analysis demonstrated that the CpG motifs generated within syngag by codon optimization do not contribute significantly to the high immunogenicity of the syngag plasmid. Moreover, low doses of coadministered stimulatory phosphorothioate oligodeoxynucleotides (ODNs) had only a weak effect on antibody production, whereas at higher doses immunostimulatory and nonstimulatory ODNs showed a dose-dependent suppression of humoral responses. These results suggest that increased Gag expression, rather than modulation of CpG-driven vector immunity, is responsible for the enhanced immunogenicity of the syngag DNA vaccine. PMID- 11602741 TI - Rotavirus 2/6 virus-like particles administered intranasally in mice, with or without the mucosal adjuvants cholera toxin and Escherichia coli heat-labile toxin, induce a Th1/Th2-like immune response. AB - We investigated the rotavirus-specific lymphocyte responses induced by intranasal immunization of adult BALB/c mice with rotavirus 2/6 virus-like particles (2/6 VLPs) of the bovine RF strain, by assessing the profile of cytokines produced after in vitro restimulation and serum and fecal antibody responses. The cytokines produced by splenic cells were first evaluated. Intranasal immunization with 50 microg of 2/6-VLPs induced a high serum antibody response, including immunoglobulin G1 (IgG1) and IgG2a, a weak fecal antibody response, and a mixed Th1/Th2-like profile of cytokines characterized by gamma interferon and interleukin 10 (IL-10) production and very low levels of IL-2, IL-4, and IL-5. Intranasal immunization with 10 microg of 2/6-VLPs coadministered with the mucosal adjuvants cholera toxin and Escherichia coli heat-labile toxin (LT) considerably enhanced the Th1/Th2-like response; notably, significant levels of IL-2, IL-4, and IL-5 were observed. Since rotavirus is an enteric pathogen, we next investigated the production of IL-2 and IL-5, as being representative of Th1 and Th2 responses, by Peyer's patch and mesenteric lymph node cells from mice immunized intranasally with 2/6-VLPs and LT. The results were compared to those obtained from splenic and cervical lymph node cells. We found that both cytokines were produced by cells from each of these lymphoid tissues. These results confirm the Th1/Th2-like response observed at the systemic level and show, on the assumption that T cells are the primary cells producing the cytokines after in vitro restimulation, that rotavirus-specific T lymphocytes are present in the intestine after intranasal immunization with 2/6-VLPs and LT. PMID- 11602740 TI - A phosphatidylinositol 3-kinase docking site in the cytoplasmic tail of the Jaagsiekte sheep retrovirus transmembrane protein is essential for envelope induced transformation of NIH 3T3 cells. AB - Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a transmissible lung cancer of sheep known as ovine pulmonary carcinoma. Recently, we have found that the expression of the JSRV envelope (Env) is sufficient to transform mouse NIH 3T3 cells in classical transformation assays. To further investigate the mechanisms of JSRV oncogenesis, we generated a series of envelope chimeras between JSRV and the JSRV-related endogenous retroviruses of sheep (enJSRVs) and assessed them in transformation assays. Chimeras containing the exogenous JSRV SU region and the enJSRV TM region were unable to transform NIH 3T3 cells. Additional chimeras containing only the carboxy-terminal portion of TM (a region that we previously identified as VR3) of the endogenous envelope with SU and the remaining portion of TM from the exogenous JSRV were also unable to transform NIH 3T3 cells. The VR3 region includes the putative membrane-spanning region and cytoplasmic tail of the JSRV TM glycoprotein; this suggested that the cytoplasmic tail of the JSRV Env mediates transformation, possibly via a cell signaling mechanism. Mutations Y590 and M593 in the cytoplasmic tail of the JSRV envelope were sufficient to inhibit the transforming abilities of these constructs. Y590 and M593 are part of a Y-X-X-M motif that is recognized by the phosphatidylinositol 3-kinase (PI-3K). PI-3K initiates a cell signaling pathway that inhibits apoptosis and is required for a number of mitogens during the G(1) to-S-phase transition of the cell cycle. PI-3K activates Akt by phosphorylation of threonine 308 and serine 473. We detected by Western blot analysis phosphorylated Akt in serum-starved MP1 cells (NIH 3T3 cells transformed by JSRV) but not in the parental NIH 3T3 cells. These data indicate that the cytoplasmic tail of the JSRV TM is necessary for cell transformation and suggest a new mechanism of retroviral transformation. In addition, the ability to dissociate the function of the JSRV envelope to mediate viral entry from its transforming capacity has direct relevance for the design of JSRV-based vectors that target the differentiated epithelial cells of the lungs. PMID- 11602742 TI - Identification of a hepatic factor capable of supporting hepatitis C virus replication in a nonpermissive cell line. AB - Although hepatitis C virus E2 protein can bind to human cells by interacting with a putative viral receptor, CD81, the interaction alone is not sufficient to establish permissiveness for hepatitis C virus infection. Using an Epstein-Barr virus-based extrachromosomal replication system, we have screened through a human liver cDNA library and successfully identified a cDNA capable of supporting hepatitis C virus replication in an otherwise nonpermissive cell line. This cDNA encodes a protein exhibiting homology to a group of proteins derived from various evolutionarily distant species, including Oryza sativa submergence-induced protein 2A. The mRNAs encoding this factor are heterogeneous at the 5' ends and are ubiquitously expressed in multiple tissues, albeit in a very small amount. The longest mRNA contains an in-frame and upstream initiation codon and codes for a larger protein. This 5'-extended form of mRNA was detected in hepatocellular carcinoma, but not in normal liver tissue. Immunofluorescence analysis demonstrated that the hepatic factor was distributed evenly in cells, but occasionally formed aggregations in the peri- or intranuclear areas. In summary, we have identified a hepatic factor capable of supporting hepatitis C virus replication in an otherwise nonpermissive cell line. This factor belongs to a previously uncharacterized protein family. The physiological function of this protein awaits further study. PMID- 11602743 TI - Infection and activation of monocytes by Marburg and Ebola viruses. AB - In this study we investigated the effects of Marburg virus and Ebola virus (species Zaire and Reston) infections on freshly isolated suspended monocytes in comparison to adherent macrophages under culture conditions. Our data showed that monocytes are permissive for both filoviruses. As is the case in macrophages, infection resulted in the activation of monocytes which was largely independent of virus replication. The activation was triggered similarly by Marburg and Ebola viruses, species Zaire and Reston, as indicated by the release of the proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor alpha, and IL-6 as well as the chemokines IL-8 and gro-alpha. Our data suggest that infected monocytes may play an important role in the spread of filoviruses and in the pathogenesis of filoviral hemorrhagic disease. PMID- 11602744 TI - Structure and assembly of intracellular mature vaccinia virus: isolated-particle analysis. AB - In a series of papers, we have provided evidence that during its assembly vaccinia virus is enveloped by a membrane cisterna that originates from a specialized, virally modified, smooth-membraned domain of the endoplasmic reticulum (ER). Recently, however, Hollinshead et al. (M. Hollinshead, A. Vanderplasschen, G. I. Smith, and D. J. Vaux, J. Virol. 73:1503-1517, 1999) argued against this hypothesis, based on their interpretations of thin-sectioned material. The present article is the first in a series of papers that describe a comprehensive electron microscopy (EM) analysis of the vaccinia Intracellular Mature Virus (IMV) and the process of its assembly in HeLa cells. In this first study, we analyzed the IMV by on-grid staining, cryo-scanning EM (SEM), and cryo transmission EM. We focused on the structure of the IMV particle, both after isolation and in the context of viral entry. For the latter, we used high resolution cryo-SEM combined with cryofixation, as well as a novel approach we developed for investigating vaccinia IMV bound to plasma membrane fragments adsorbed onto EM grids. Our analysis revealed that the IMV is made up of interconnected cisternal and tubular domains that fold upon themselves via a complex topology that includes an S-shaped fold. The viral tubules appear to be eviscerated from the particle during viral infection. Since the structure of the IMV is the result of a complex assembly process, we also provide a working model to explain how a specialized smooth-ER domain can be modulated to form the IMV. We also present theoretical arguments for why it is highly unlikely that the IMV is surrounded by only a single membrane. PMID- 11602745 TI - Structure and assembly of intracellular mature vaccinia virus: thin-section analyses. AB - In the preceding study (see accompanying paper), we showed by a variety of different techniques that intracellular mature vaccinia virus (vaccinia IMV) is unexpectedly complex in its structural organization and that this complexity also extends to the underlying viral core, which is highly folded. With that analysis as a foundation, we now present different thin-section electron microscopy approaches for analyzing the IMV and the processes by which it is assembled in infected HeLa cells. We focus on conventional epoxy resin thin sections as well as cryosections to describe key intermediates in the assembly process. We took advantage of streptolysin O's ability to selectively permeabilize the plasma membrane of infected cells to improve membrane contrast, and we used antibodies against bone fide integral membrane proteins of the virus to unequivocally identify membrane profiles in thin sections. All of the images presented here can be rationalized with respect to the model put forward for the assembly of the IMV in the accompanying paper. PMID- 11602746 TI - NS1- and minute virus of mice-induced cell cycle arrest: involvement of p53 and p21(cip1). AB - The nonstructural protein NS1 of the autonomous parvovirus minute virus of mice (MVMp) is cytolytic when expressed in transformed cells. Before causing extensive cell lysis, NS1 induces a multistep cell cycle arrest in G(1), S, and G(2), well reproducing the arrest in S and G(2) observed upon MVMp infection. In this work we investigated the molecular mechanisms of growth inhibition mediated by NS1 and MVMp. We show that NS1-mediated cell cycle arrest correlates with the accumulation of the cyclin-dependent kinase (Cdk) inhibitor p21(cip1) associated with both the cyclin A/Cdk and cyclin E/Cdk2 complexes but in the absence of accumulation of p53, a potent transcriptional activator of p21(cip1). By comparison, MVMp infection induced the accumulation of both p53 and p21(cip1). We demonstrate that p53 plays an essential role in the MVMp-induced cell cycle arrest in both S and G(2) by using p53 wild-type (+/+) and null (-/-) cells. Furthermore, only the G(2) arrest was abrogated in p21(cip1) null (-/-) cells. Together these results show that the MVMp-induced cell cycle arrest in S is p53 dependent but p21(cip1) independent, whereas the arrest in G(2) depends on both p53 and its downstream effector p21(cip1). They also suggest that induction of p21(cip1) by the viral protein NS1 arrests cells in G(2) through inhibition of cyclin A-dependent kinase activity. PMID- 11602747 TI - Replication-competent or attenuated, nonpropagating vesicular stomatitis viruses expressing respiratory syncytial virus (RSV) antigens protect mice against RSV challenge. AB - Foreign glycoproteins expressed in recombinant vesicular stomatitis virus (VSV) can elicit specific and protective immunity in the mouse model. We have previously demonstrated the expression of respiratory syncytial virus (RSV) G (attachment) and F (fusion) glycoprotein genes in recombinant VSV. In this study, we demonstrate the expression of RSV F and G glycoproteins in attenuated, nonpropagating VSVs which lack the VSV G gene (VSVDeltaG) and the incorporation of these RSV proteins into recombinant virions. We also show that intranasal vaccination of mice with nondefective VSV recombinants expressing RSV G (VSV-RSV G) or RSV F (VSV-RSV F) elicited RSV-specific antibodies in serum (by enzyme linked immunosorbent assay [ELISA]) as well as neutralizing antibodies to RSV and afford complete protection against RSV challenge. In contrast, VSVDeltaG-RSV F induced detectable serum antibodies to RSV by ELISA, but no detectable neutralizing antibodies, yet it still protected from RSV challenge. VSVDeltaG-RSV G failed to induce any detectable serum (by ELISA) or neutralizing antibodies and failed to protect from RSV challenge. The attenuated, nonpropagating VSVDeltaG RSV F is a particularly attractive candidate for a live attenuated recombinant RSV vaccine. PMID- 11602748 TI - Comparison of polymerase subunits from double-stranded RNA bacteriophages. AB - The family Cystoviridae comprises several bacteriophages with double-stranded RNA (dsRNA) genomes. We have previously purified the catalytic polymerase subunit (Pol) of one of the Cystoviridae members, bacteriophage phi6, and shown that the protein can catalyze RNA synthesis in vitro. In this reaction, both bacteriophage specific and heterologous RNAs can serve as templates, but those containing 3' termini from the phi6 minus strands are favored. This provides a molecular basis for the observation that only plus strands, not minus strands, are transcribed from phi6 dsRNA segments in vivo. To test whether such a regulatory mechanism is also found in other dsRNA viruses, we purified recombinant Pol subunits from the phi6-related bacteriophages phi8 and phi13 and assayed their polymerase activities in vitro. The enzymes catalyze template-dependent RNA synthesis using both single-stranded-RNA (ssRNA) and dsRNA templates. However, they differ from each other as well as from phi6 Pol in certain biochemical properties. Notably, each polymerase demonstrates a distinct preference for ssRNAs bearing short 3' terminal sequences from the virus-specific minus strands. This suggests that, in addition to other factors, RNA transcription in Cystoviridae is controlled by the template specificity of the polymerase subunit. PMID- 11602749 TI - Antigenic properties of the human immunodeficiency virus envelope during cell cell fusion. AB - Human immunodeficiency virus (HIV) fusion and entry involves sequential interactions between the viral envelope protein, gp120, cell surface CD4, and a G protein-coupled coreceptor. Each interaction creates an intermediate gp120 structure predicted to display distinct antigenic features, including key functional domains for viral entry. In this study, we examined the disposition of these features during the fusion of HeLa cells expressing either HIV(HXB2) envelope (Env cells) or CXCR4 and CD4 (target cells). Cell-cell fusion, indicated by cytoplasmic dye transfer, was allowed to progress for various times and then arrested. The cells were then examined for reactivity with antibodies directed against receptor-induced epitopes on gp120. Analyses of cells arrested by cooling to 4( degrees )C revealed that antibodies against the CD4-induced coreceptor binding domain, i.e., 17b, 48d, and CG10, faintly react with Env cells even in the absence of target cell or soluble CD4 (sCD4) interactions. Such reactivity increased after exposure to sCD4 but remained unchanged during fusion with target cells and was not intensified at the Env-target cell interface. Notably, the antibodies did not react with Env cells when treated with a covalent cross-linker either alone or during fusion with target cells. Immunoreactivity could not be promoted or otherwise altered on either temperature arrested or cross-linked cells by preventing coreceptor interactions or by using a 17b Fab. In comparison, two other gp120-CD4 complex-dependent antibodies against epitopes outside the coreceptor domain, 8F101 and A32, exhibited a different pattern of reactivity. These antibodies reacted with the Env-target cell interface only after 30 min of cocultivation, concurrent with the first visible transfer of cytoplasmic dye from Env to target cells. At later times, the staining surrounded entire syncytia. Such binding was entirely dependent on the formation of gp120-CD4-CXCR4 tricomplexes since staining was absent with SDF-treated or coreceptor-negative target cells. Overall, these studies show that access to the CD4-induced coreceptor-binding domain on gp120 is largely blocked at the fusing cell interface and is unlikely to represent a target for neutralizing antibodies. However, new epitopes are presented on intermediate gp120 structures formed as a result of coreceptor interactions. Such findings have important implications for HIV vaccine approaches based on conformational alterations in envelope structures. PMID- 11602750 TI - Human T-cell leukemia virus type 1 Tax protein binds to assembled nuclear proteasomes and enhances their proteolytic activity. AB - The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates the HTLV-1 long terminal repeat and key regulatory proteins involved in inflammation, activation, and proliferation and may induce cell transformation. Tax is also the immunodominant target antigen for cytotoxic T cells in HTLV-1 infection. We found that Tax bound to assembled nuclear proteasomes, but Tax could not be detected in the cytoplasm. Confocal microscopy revealed a partial colocalization of Tax with nuclear proteasomes. As Tax translocated into the nucleus very quickly after synthesis, this process probably takes place prior to and independent of proteasome association. Tax mutants revealed that both the Tax N and C termini play a role in proteasome binding. We also found that proteasomes from Tax transfected cells had enhanced proteolytic activity on prototypic peptide substrates. This effect was not due to the induction of the LMP2 and LMP7 proteasome subunits. Furthermore, Tax appeared to be a long-lived protein, with a half-life of around 15 h. These data suggest that the association of Tax with the proteasome and the enhanced proteolytic activity do not target Tax for rapid degradation and may not determine its immunodominance. PMID- 11602751 TI - Identification of aleutian mink disease parvovirus capsid sequences mediating antibody-dependent enhancement of infection, virus neutralization, and immune complex formation. AB - Aleutian mink disease parvovirus (ADV) causes a persistent infection associated with circulating immune complexes, immune complex disease, hypergammaglobulinemia, and high levels of antiviral antibody. Although antibody can neutralize ADV infectivity in Crandell feline kidney cells in vitro, virus is not cleared in vivo, and capsid-based vaccines have proven uniformly ineffective. Antiviral antibody also enables ADV to infect macrophages, the target cells for persistent infection, by Fc-receptor-mediated antibody-dependent enhancement (ADE). The antibodies involved in these unique aspects of ADV pathogenesis may have specific targets on the ADV capsid. Prominent differences exist between the structure of ADV and other, more-typical parvoviruses, which can be accounted for by short peptide sequences in the flexible loop regions of the capsid proteins. In order to determine whether these short sequences are targets for antibodies involved in ADV pathogenesis, we studied heterologous antibodies against several peptides present in the major capsid protein, VP2. Of these antibodies, a polyclonal rabbit antibody to peptide VP2:428-446 was the most interesting. The anti-VP2:428-446 antibody aggregated virus particles into immune complexes, mediated ADE, and neutralized virus infectivity in vitro. Thus, antibody against this short peptide can be implicated in key facets of ADV pathogenesis. Structural modeling suggested that surface-exposed residues of VP2:428-446 are readily accessible for antibody binding. The observation that antibodies against a single target peptide in the ADV capsid can mediate both neutralization and ADE may explain the failure of capsid-based vaccines. PMID- 11602752 TI - Induction of cell death in human immunodeficiency virus-infected macrophages and resting memory CD4 T cells by TRAIL/Apo2l. AB - Because the persistence of human immunodeficiency virus (HIV) in cellular reservoirs presents an obstacle to viral eradication, we evaluated whether tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) induces apoptosis in such reservoirs. Lymphocytes and monocyte-derived macrophages (MDM) from uninfected donors do not die following treatment with either leucine zipper human TRAIL (LZhuTRAIL) or agonistic anti-TRAIL receptor antibodies. By contrast, such treatment induces apoptosis of in vitro HIV-infected MDM as well as peripheral blood lymphocytes from HIV-infected patients, including CD4(+) CD45RO(+) HLA-DR( ) lymphocytes. In addition, LZhuTRAIL-treated cells produce less viral RNA and p24 antigen than untreated controls. Whereas untreated cultures produce large amounts of HIV RNA and p24 antigen, of seven treated CD4(+) CD45RO(+) HLA-DR(-) cell cultures, viral RNA production was undetectable in all, p24 antigen was undetectable in six, and proviral DNA was undetectable in four. These data demonstrate that TRAIL induces death of cells from HIV-infected patients, including cell types which harbor latent HIV reservoirs. PMID- 11602753 TI - The absence of glycoprotein gL, but not gC or gK, severely impairs pseudorabies virus neuroinvasiveness. AB - Penetration and propagation of herpesviruses in the nervous system require the action of several glycoproteins. To assay for a function of glycoproteins gC, gK, and gL in the neuroinvasiveness of pseudorabies virus (PrV), deletion mutants lacking one of these glycoproteins and corresponding rescuants were inoculated in the nasal cavity of adult mice. We demonstrate that the lack of gL almost prevented the virus from penetrating and propagating in trigeminal, sympathetic, and parasympathetic tracks innervating the nasal cavity, while the lack of gC and gK only slowed the invasion of the nervous system. The conclusion of this and previous studies is that only gB, gD, gH, and gL are indispensable for penetration into neurons, while gB, gH, and gL (and, in some categories of neurons, also gE and gI) are necessary for transneuronal transfer in the mouse model. The deletion of other glycoprotein genes has little effect on PrV neuroinvasiveness although it may affect the dissemination of the virus. PMID- 11602754 TI - Structural and functional analysis of interhelical interactions in the human immunodeficiency virus type 1 gp41 envelope glycoprotein by alanine-scanning mutagenesis. AB - Membrane fusion by human immunodeficiency virus type 1 (HIV-1) is promoted by the refolding of the viral envelope glycoprotein into a fusion-active conformation. The structure of the gp41 ectodomain core in its fusion-active state is a trimer of hairpins in which three antiparallel carboxyl-terminal helices pack into hydrophobic grooves on the surface of an amino-terminal trimeric coiled coil. In an effort to identify amino acid residues in these grooves that are critical for gp41 activation, we have used alanine-scanning mutagenesis to investigate the importance of individual side chains in determining the biophysical properties of the gp41 core and the membrane fusion activity of the gp120-gp41 complex. Alanine substitutions at Leu-556, Leu-565, Val-570, Gly-572, and Arg-579 positions severely impaired membrane fusion activity in envelope glycoproteins that were for the most part normally expressed. Whereas alanine mutations at Leu-565 and Val-570 destabilized the trimer-of-hairpins structure, mutations at Gly-572 and Arg-579 led to the formation of a stable gp41 core. Our results suggest that the Leu-565 and Val-570 residues are important determinants of conserved packing interactions between the amino- and carboxyl-terminal helices of gp41. We propose that the high degree of sequence conservation at Gly-572 and Arg-579 may result from selective pressures imposed by prefusogenic conformations of the HIV-1 envelope glycoprotein. Further analysis of the gp41 activation process may elucidate targets for antiviral intervention. PMID- 11602755 TI - Genome sequence of a baculovirus pathogenic for Culex nigripalpus. AB - In this report we describe the complete genome sequence of a nucleopolyhedrovirus that infects larval stages of the mosquito Culex nigripalpus (CuniNPV). The CuniNPV genome is a circular double-stranded DNA molecule of 108,252 bp and is predicted to contain 109 genes. Although 36 of these genes show homology to genes from other baculoviruses, their orientation and order exhibit little conservation relative to the genomes of lepidopteran baculoviruses. CuniNPV genes homologous to those from other baculoviruses include genes involved in early and late gene expression (lef-4, lef-5, lef-8, lef-9, vlf-1, and p47), DNA replication (lef-1, lef-2, helicase-1, and dna-pol), and structural functions (vp39, vp91, odv-ec27, odv-e56, p6.9, gp41, p74, and vp1054). Auxiliary genes include homologues of genes encoding the p35 antiapoptosis protein and a novel insulin binding-related protein. In contrast to these conserved genes, CuniNPV lacks apparent homologues of baculovirus genes essential (ie-1 and lef-3) or stimulatory (ie-2, lef-7, pe38) for DNA replication. Also, baculovirus genes essential or stimulatory for early-late (ie-1, ie-2), early (ie-0 and pe-38), and late (lef-6, lef-11, and pp31) gene transcription are not identifiable. In addition, CuniNPV lacks homologues of genes involved in the formation of virogenic stroma (pp31), nucleocapsid (orf1629, p87, and p24), envelope of occluded virions (odv-e25, odv e66, odv-e18), and polyhedra (polyhedrin/granulin, p10, pp34, and fp25k). A homologue of gp64, a budded virus envelope fusion protein, was also absent, although a gene related to the other category of baculovirus budded virus envelope proteins, Ld130, was present. The absence of homologues of occlusion derived virion (ODV) envelope proteins and occlusion body (OB) protein (polyhedrin) suggests that both CuniNPV ODV and OB may be structurally and compositionally different from those found in terrestrial lepidopteran hosts. The striking difference in genome organization, the low level of conservation of homologous genes, and the lack of many genes conserved in other baculoviruses suggest a large evolutionary distance between CuniNPV and lepidopteran baculoviruses. PMID- 11602756 TI - Human immunodeficiency virus type 1 entry into macrophages mediated by macropinocytosis. AB - Whereas human immunodeficiency virus (HIV) infects various cell types by fusion at the plasma membrane, we observed a different entry route in human primary macrophages, in which macropinocytosis is active. Shortly after exposure of macrophages to HIV-1 and irrespective of viral envelope-receptor interactions, particles were visible in intracellular vesicles, which were identified as macropinosomes. Most virions appeared subsequently degraded. However, fusion leading to capsid release in the cytosol and productive infection could take place inside vesicles when particles were properly enveloped. These observations provide new insights into HIV-1 interactions with a cell target relevant to pathogenesis. They may have implications for the design of soluble inhibitors aimed at interfering with the fusion or entry processes. PMID- 11602757 TI - Gamma interferon can prevent herpes simplex virus type 1 reactivation from latency in sensory neurons. AB - We recently demonstrated that CD8(+) T cells could block herpes simplex virus type 1 (HSV-1) reactivation from latency in ex vivo trigeminal ganglion (TG) cultures without destroying the infected neurons. Here we establish that CD8(+) T cell prevention of HSV-1 reactivation from latency is mediated at least in part by gamma interferon (IFN-gamma). We demonstrate that IFN-gamma was produced in ex vivo cultures of dissociated latently infected TG by CD8(+) T cells that were present in the TG at the time of excision. Depletion of CD8(+) T cells or neutralization of IFN-gamma significantly enhanced the rate of HSV-1 reactivation from latency in TG cultures. When TG cultures were treated with acyclovir for 4 days to insure uniform latency, supplementation with recombinant IFN-gamma blocked HSV-1 reactivation in 80% of cultures when endogenous CD8(+) T cells were present and significantly reduced and delayed HSV-1 reactivation when CD8(+) T cells or CD45(+) cells were depleted from the TG cultures. The effectiveness of recombinant IFN-gamma in blocking HSV-1 reactivation was lost when its addition to TG cultures was delayed by more than 24 h after acyclovir removal. We propose that when the intrinsic ability of neurons to inhibit HSV-1 gene expression is compromised, HSV-specific CD8(+) T cells are rapidly mobilized to produce IFN gamma and perhaps other antiviral cytokines that block the viral replication cycle and maintain the viral genome in a latent state. PMID- 11602758 TI - Structural features of nectin-2 (HveB) required for herpes simplex virus entry. AB - One step in the process of herpes simplex virus (HSV) entry into cells is the binding of viral glycoprotein D (gD) to a cellular receptor. Human nectin-2 (also known as HveB and Prr2), a member of the immunoglobulin (Ig) superfamily, serves as a gD receptor for the entry of HSV-2, variant forms of HSV-1 that have amino acid substitutions at position 25 or 27 of gD (for example, HSV-1/Rid), and porcine pseudorabies virus (PRV). The gD binding region of nectin-2 is believed to be localized to the N-terminal variable-like (V) Ig domain. In order to identify specific amino acid sequences in nectin-2 that are important for HSV entry activity, chimeric molecules were constructed by exchange of sequences between human nectin-2 and its mouse homolog, mouse nectin-2, which mediates entry of PRV but not HSV-1 or HSV-2. The nectin-2 chimeric molecules were expressed in Chinese hamster ovary cells, which normally lack a gD receptor, and tested for cell surface expression and viral entry activity. As expected, chimeric molecules containing the V domain of human nectin-2 exhibited HSV entry activity. Replacement of either of two small regions in the V domain of mouse nectin-2 with amino acids from the equivalent positions in human nectin-2 (amino acids 75 to 81 or 89) transferred HSV-1/Rid entry activity to mouse nectin-2. The resulting chimeras also exhibited enhanced HSV-2 entry activity and gained the ability to mediate wild-type HSV-1 entry. Replacement of amino acid 89 of human nectin-2 with the corresponding mouse amino acid (M89F) eliminated HSV entry activity. These results identify two different amino acid sequences, predicted to lie adjacent to the C' and C" beta-strands of the V domain, that are critical for HSV entry activity. This region is homologous to the human immunodeficiency virus binding region of CD4 and to the poliovirus binding region of CD155. PMID- 11602759 TI - PE2 cleavage mutants of Sindbis virus: correlation between viral infectivity and pH-dependent membrane fusion activation of the spike heterodimer. AB - The spike glycoprotein E2 of Sindbis virus (SIN) is synthesized in the infected cell as a PE2 precursor protein, which matures through cleavage by a cellular furin-like protease. Previous work has shown that SIN mutants impaired in PE2 cleavage are noninfectious on BHK-21 cells, the block in infection being localized at a step after virus-receptor interaction but prior to RNA replication. Here, we studied the membrane fusion properties of SIN PE2 cleavage mutants and observed that these viruses are impaired in their ability to form an E1 homotrimer and to fuse with liposomes at a mildly acidic pH. The block in spike rearrangement and fusion could be overridden by exposure of the mutant viruses to very low pH (<4.5). Cleavage mutants with second-site resuscitating mutations in PE2 were highly infectious for BHK-21 cells. The ability of these viruses to form E1 homotrimers and to fuse at a mildly acidic pH was completely restored despite a sustained lack of PE2 cleavage. PMID- 11602760 TI - Folding of hepatitis C virus E1 glycoprotein in a cell-free system. AB - The hepatitis C virus (HCV) envelope proteins, E1 and E2, form noncovalent heterodimers and are leading candidate antigens for a vaccine against HCV. Studies in mammalian cell expression systems have focused primarily on E2 and its folding, whereas knowledge of E1 folding remains fragmentary. We used a cell-free in vitro translation system to study E1 folding and asked whether the flanking proteins, Core and E2, influence this process. We translated the polyprotein precursor, in which the Core is N-terminal to E1, and E2 is C-terminal, and found that when the core protein was present, oxidation of E1 was a slow, E2 independent process. The half-time for E1 oxidation was about 5 h in the presence or absence of E2. In contrast with previous reports, analysis of three constructs of different lengths revealed that the E2 glycoprotein undergoes slow oxidation as well. Unfolded or partially folded E1 bound to the endoplasmic reticulum chaperones calnexin and (with lower efficiency) calreticulin, whereas no binding to BiP/GRP78 or GRP94 could be detected. Release from calnexin and calreticulin was used to assess formation of mature E1. When E1 was expressed in the absence of Core and E2, its oxidation was impaired. We conclude that E1 folding is a process that is affected not only by E2, as previously shown, but also by the Core. The folding of viral proteins can thus depend on complex interactions between neighboring proteins within the polyprotein precursor. PMID- 11602761 TI - Human cytomegalovirus open reading frame TRL11/IRL11 encodes an immunoglobulin G Fc-binding protein. AB - Several herpesviruses encode Fc receptors that may play a role in preventing antibody-mediated clearance of the virus in vivo. Human cytomegalovirus (HCMV) induces an Fc-binding activity in cells upon infection, but the gene that encodes this Fc-binding protein has not been identified. Here, we demonstrate that the HCMV AD169 open reading frame TRL11 and its identical copy, IRL11, encode a type I membrane glycoprotein that possesses IgG Fc-binding capabilities. PMID- 11602762 TI - Unique temperature-sensitive defect in vaccinia virus morphogenesis maps to a single nucleotide substitution in the A30L gene. AB - Marker rescue experiments demonstrated that the genetic lesion of a previously isolated vaccinia virus temperature-sensitive mutant which forms multilayered envelope structures with lucent interiors and foci of viroplasm with dense centers mapped to the A30L open reading frame. A single base change, resulting in a nonconservative Ser-to-Phe substitution at residue 17, was associated with degradation of the A30L protein at elevated temperatures. PMID- 11602763 TI - Functional correlates of insertion mutations in the protease gene of human immunodeficiency virus type 1 isolates from patients. AB - Twenty-four of over 24,000 patients genotyped over the past 3 years were found to have human immunodeficiency virus (HIV) isolates that possess an insert in the protease gene. In this report, we evaluated the spectrum of protease gene insertion mutations in patient isolates and analyzed the effect of these various insertion mutations on viral phenotypes. The inserts were composed of 1, 2, 5, or 6 amino acids that mapped at or between codons 35 and 38, 17 and 18, 21 and 25, or 95 and 96. Reduced susceptibility to protease inhibitors was found in isolates which possess previously reported drug resistance mutations. Fitness assays, including replication and competition experiments, showed that most of the isolates with inserts grew somewhat better than their counterparts with a deletion of the insert. These experiments demonstrate that, rarely, insertion mutations can develop in the HIV type 1 protease gene, are no more resistant than any other sequences which have similar associated resistance mutations, and can provide a borderline advantage in replication. PMID- 11602764 TI - Variability of viral load in plasma of rhesus monkeys inoculated with simian immunodeficiency virus or simian-human immunodeficiency virus: implications for using nonhuman primate AIDS models to test vaccines and therapeutics. AB - Viral RNA level in plasma is a sensitive experimental endpoint for evaluating the efficacy of AIDS vaccines or therapies in nonhuman primates. By quantifying viral RNA in the plasma of 77 rhesus monkeys for 10 weeks after inoculation with simian human immunodeficiency virus 89.6P (SHIV-89.6P) or simian immunodeficiency virus mac 251 (SIVmac 251), we estimated variability in three viral load (VL) measures: peak VL, the postacute set point VL, and VL decline from peak. Such estimates of biological variability are essential for determining the number of animals needed per group and may be helpful for selecting the most appropriate measure to use as the experimental endpoint. Peak VL was positively correlated with set point VL for both viruses. Variability (standard deviation) was substantially higher in monkeys infected with SIVmac 251 than in those infected with SHIV-89.6P for set point VL and VL decline. The variability of peak VL was less than one-half that of set point VL variability and only about two-thirds of that of VL decline, implying that the same treatment-related difference in peak VL could be detected with fewer animals than set point VL or VL decline. Thus, differences in VL variability over the course of infection and between viruses need to be considered when designing studies using the nonhuman primate AIDS models. PMID- 11602765 TI - N-terminal cleavage fragment of glycosylated Gag is incorporated into murine oncornavirus particles. AB - Glycosylated Gag (Glycogag) is a transmembrane protein encoded by murine and feline oncornaviruses. While the protein is dispensible for virus replication, Glycogag-null mutants of a neurovirulent murine oncornavirus are slow to spread in vivo and exhibit a loss of pathogenicity. The function of this protein in the virus life cycle, however, is not understood. Glycogag is expressed at the plasma membrane of infected cells but has not been detected in virions. In the present study we have reexamined this issue and have found an N-terminal cleavage fragment of Glycogag which was pelleted by high-speed centrifugation and sedimented in sucrose density gradients at the same bouyant density as virus particles. Its association with virions was confirmed by velocity sedimentation through iodixanol, which effectively separated membrane microvesicles from virus particles. Furthermore, the apparent molecular weight of the virion-associated protein was different from that of the protein extracted from the plasma membrane, suggesting some level of specificity or selectivity of incorporation. PMID- 11602766 TI - Fv-4: identification of the defect in Env and the mechanism of resistance to ecotropic murine leukemia virus. AB - Mice expressing the Fv-4 gene are resistant to infection by ecotropic murine leukemia viruses (MuLVs). The Fv-4 gene encodes an envelope (Env) protein whose putative receptor-binding domain resembles that of ecotropic MuLV Env protein. Resistance to ecotropic MuLVs appears to result from viral interference involving binding of the endogenously expressed Fv-4 env-encoded protein to the ecotropic receptor, although the immune system also plays a role in resistance. The Fv-4 env-encoded protein is processed normally and can be incorporated into virus particles but is unable to promote viral entry. Among the many sequence variations between the transmembrane (TM) subunit of the Fv-4 env-encoded protein and the TM subunits of other MuLV Env proteins, there is a substitution of an arginine residue in the Fv-4 env-encoded protein for a glycine residue (gly-491 in Moloney MuLV Env) that is otherwise conserved in all of the other MuLVs. This residue is present in the MuLV TM fusion peptide sequence. In this study, gly-491 of Moloney MuLV Env has been replaced with other residues and a mutant Env bearing a substitution for gly-487 was also created. G491R recapitulates the Fv-4 Env phenotype in cell culture, indicating that this substitution is sufficient for creation of an Env protein that can establish the interference-mediated resistance to ecotropic viruses produced by the Fv-4 gene. Analysis of the mutant MuLV Env proteins also has implications for an understanding of the role of conserved glycine residues in fusion peptides and for the engineering of organismal resistance to retroviruses. PMID- 11602767 TI - Sequences adjacent to oriP improve the persistence of Epstein-Barr virus-based episomes in B cells. AB - Epstein-Barr virus (EBV) oriP and the EBV nuclear antigen 1 (EBNA-1) protein allow persistence of EBV-based episomes. A nuclear matrix attachment region (MAR) spans oriP and the adjacent region of the EBV genome containing the EBV-expressed RNAs. Here, we show that episomes with the MAR are retained significantly more efficiently in EBV-positive B cells than episomes containing oriP alone. PMID- 11602768 TI - Kinetics of human immunodeficiency virus type 1 (HIV) DNA integration in acutely infected cells as determined using a novel assay for detection of integrated HIV DNA. AB - We have developed a novel linker-primer PCR assay for the detection and quantification of integrated human immunodeficiency virus type 1 (HIV) DNA. This assay reproducibly allowed the detection of 10 copies of integrated HIV DNA, in a background of 2 x 10(5) cell equivalents of human chromosomal DNA, without amplifying extrachromosomal HIV DNA. We have used this assay and a near synchronous one-step T-cell infection model to investigate the kinetics of viral DNA accumulation following HIV infection. We report here that integrated HIV DNA started accumulating 1 h after the first appearance of extrachromosomal viral DNA and accounted for approximately 10% of the total HIV DNA synthesized in the first round of viral replication. These results highlight the efficient nature of integrase-mediated HIV integration in infected T cells. PMID- 11602769 TI - Biogenesis of hepatitis C virus envelope glycoproteins. PMID- 11602770 TI - Localization of viral proteins in cells infected with bovine viral diarrhoea virus. AB - Bovine viral diarrhoea virus (BVDV) is a member of the genus Pestivirus within the family Flaviviridae. In this report, protein localization studies were performed to assess the mechanism for the release of mature virus particles from infected cells. Since BVDV is an enveloped virus, budding from either intra- or extracellular membranes is feasible. A prerequisite for the latter mechanism is the integration of viral glycoproteins into the host cell membrane. Using monoclonal antibodies (MAbs) directed against the viral envelope glycoproteins E2 and E(RNS), no specific signals were detected on the surface of BVDV-infected cells by indirect fluorescence, confocal microscopy or fluorescence-activated cell sorter analyses. Furthermore, biotin-labelled cell surface proteins of virus infected and non-infected cells were not detected by immunoprecipitation using MAbs directed against E(RNS) and E2 or the non-structural protein NS2-3. None of these proteins was detected on the cell surface. In addition, to analyse the intracellular localization of the two viral glycoproteins E(RNS) and E2 and the non-structural proteins NS2-3 and NS3, subcellular fractionation of virus infected cells followed by radioimmunoprecipitation with the MAbs were performed. These results led to the conclusion that the BVDV envelope glycoproteins E(RNS) and E2 as well as the non-structural proteins NS2-3 and NS3 were almost quantitatively associated with intracellular membranes. These findings indicate that BVDV is released by budding into the cisternae of the endoplasmic reticulum and that there seems to be no correlation between the location and function of the analysed proteins. PMID- 11602772 TI - High frequency RNA recombination in porcine reproductive and respiratory syndrome virus occurs preferentially between parental sequences with high similarity. AB - Two types of porcine reproductive and respiratory syndrome virus (PRRSV) exist, a North American type and a European type. The co-existence of both types in some countries, such as Denmark, Slovakia and Canada, creates a risk of inter-type recombination. To evaluate this risk, cell cultures were co-infected with either a North American and a European type of PRRSV or two diverse types of European isolate. Subsequently, an approximately 600 bp region of the PRRSV genome was tested for recombination by quantitative real-time RT-PCR. Between 0.1 and 2.5% RNA recombination was found between the European isolates, but no recombination was detected between the European and North American types. Calculation of the maximum theoretical risk of European-American recombination, based on the sensitivity of the RT-PCR system, revealed that RNA recombination between the European and North American types of PRRSV is at least 10 000 times less likely to occur than RNA recombination between diverse European isolates. PMID- 11602771 TI - Viable porcine arteriviruses with deletions proximal to the 3' end of the genome. AB - In order to obtain attenuated live vaccine candidates of porcine reproductive and respiratory syndrome virus (PRRSV), a series of deletions was introduced at the 3' end of the viral genome using an infectious cDNA clone of the Lelystad virus isolate. RNA transcripts from the full-length cDNA clones were transfected into BHK-21 cells. The culture supernatant of these cells was subsequently used to infect porcine alveolar macrophages to detect the production of progeny virus. It is shown that C-terminal truncation of the nucleocapsid (N) protein, encoded by ORF7, was tolerated for up to six amino acids without blocking the production of infectious virus. Mutants containing larger deletions produced neither virus nor virus-like particles containing viral RNA. Deletion analysis of the 3' UTR immediately downstream of ORF7 showed that infectious virus was still produced after removal of seven nucleotides behind the stop codon of ORF7. Deletion of 32 nucleotides in this region abolished RNA replication and, consequently, no infectious virus was formed. Serial passage on porcine alveolar macrophages demonstrated that the viable deletion mutants were genetically stable at the site of mutation. In addition, the deletions did not affect the growth properties of the recombinant viruses in vitro, while their antigenic profiles were similar to that of wild-type virus. Immunoprecipitation experiments with the six-residue N protein-deletion mutant confirmed that the truncated protein was indeed smaller than the wild-type N protein. The deletion mutants produced in this study are interesting candidate vaccines to prevent PRRS disease in pigs. PMID- 11602773 TI - Interaction of picornavirus 2C polypeptide with the viral negative-strand RNA. AB - The picornavirus membrane-associated polypeptide 2C is believed to be required for viral RNA synthesis. Hepatitis A virus (HAV)- and human rhinovirus (HRV) encoded recombinant 2C proteins have been expressed, purified and examined for their ability to interact with the terminal sequences of viral positive- and negative-strand RNAs. The results demonstrate that both the HAV- and the HRV encoded 2C polypeptide specifically interact with the 3'-terminal sequences of the negative-strand RNA, but not with the complementary sequences at the 5' terminus of the positive-strand RNA. This interaction was detected by both mobility gel shift and UV cross-linking assays. Furthermore, complex formation exhibited dose-dependency and competition assays confirmed specificity. These results are consistent with our previous observation using the poliovirus 2C protein. The implication of the picornavirus 2C protein binding to the 3' terminal sequence of the negative-strand untranslated region in viral RNA synthesis is discussed. PMID- 11602774 TI - Comparison of the complete nucleotide sequences of echovirus 7 strain UMMC and the prototype (Wallace) strain demonstrates significant genetic drift over time. AB - The complete nucleotide sequences are reported of two strains of echovirus 7, the prototype Wallace strain (Eo7-Wallace) and a recent Malaysian strain isolated from the cerebrospinal fluid of a child with fatal encephalomyelitis (Eo7-UMMC strain). The molecular findings corroborate the serological placement of the UMMC strain as echovirus 7. Both Eo7-Wallace and Eo7-UMMC belong to the species human enterovirus B and are most closely related to echovirus 11. Eo7-UMMC has undergone significant genetic drift from the prototype strain in the 47 years that separate the isolation of the two viruses. Phylogenetic analysis revealed that Eo7-UMMC did not arise from recombination with another enterovirus serotype. The molecular basis for the severely neurovirulent phenotype of Eo7-UMMC remains unknown. However, it is shown that mutations in the nucleotide sequence of the 5' untranslated region (UTR) of Eo7-UMMC result in changes to the putative structure of the 5' UTR. It is possible that these changes contribute to the neurovirulence of Eo7-UMMC. PMID- 11602775 TI - Equine rhinitis B virus: a new serotype. AB - Equine rhinovirus serotype 3 isolate P313/75 was assigned, with an unclassified genus status, to the family PICORNAVIRIDAE: The sequence from the 5' poly(C) tract to the 3' poly(A) tract of P313/75 was determined. The sequence is 8821 bases in length and contains a potential open reading frame for a polyprotein of 2583 amino acids. Sequence comparison and phylogenic analysis suggest that P313/75 is most closely related to the prototype equine rhinitis B virus (ERBV) strain P1436/71, formerly named equine rhinovirus type 2. A high degree of sequence similarity was found in the P2 and P3 regions of the two genomes. However, the deduced amino acid sequences of the P1 region of P313/75 and ERBV strain P1436/71 contained significant differences, which presumably account for the serological segregation of the two viruses. It is suggested that P313/75 can be classified as a new serotype of the genus Erbovirus, tentatively named ERBV2. Seroepidemiological data indicate that ERBV2 infection of horses may be common (24%) in Australia. PMID- 11602776 TI - Genetic variability of hepatitis A virus in South America reveals heterogeneity and co-circulation during epidemic outbreaks. AB - Genetic analysis of selected genome regions of hepatitis A virus (HAV) suggested that distinct genotypes of HAV could be found in different geographical regions. In order to gain insight into the genetic variability and mode of evolution of HAV in South America, an analysis was performed of sequence data obtained from the VP1 amino terminus and the VP1/2A region of HAV strains isolated over a short period of time in Uruguay, Argentina and Chile. Sequences obtained from 22 distinct HAV isolates were compared with published sequences from 21 different strains isolated all over the world. Phylogenetic analysis revealed that all strains isolated belong to a unique sub-genotype (IA). Strains isolated during an outbreak period showed a higher degree of heterogeneity than anticipated previously and the co-circulation of different isolates. The genetic variability among strains isolated in this region seems to be higher in comparison with strains isolated in other regions of the world. PMID- 11602777 TI - Establishment of an infectious RNA transcription system for Striped jack nervous necrosis virus, the type species of the betanodaviruses. AB - A system has been established to produce infectious RNA transcripts for Striped jack nervous necrosis virus (SJNNV), the type species of the betanodaviruses, which infect fish. An enzymological analysis suggested that both RNA1 and RNA2 of SJNNV have a 5' cap. Both RNAs were largely resistant to 3' polyadenylation and ligation, suggesting the presence of an interfering 3' structure, while a small quantity of viral RNAs were polyadenylated in vitro. The complete 5' and 3' non coding sequences of both segments were determined using the rapid amplification of cDNA ends method. Based on the terminal sequences obtained, RT-PCR was carried out and plasmid clones containing full-length cDNA copies of both RNAs, positioned downstream of a T7 promoter, were constructed. These plasmids were cleaved at a unique restriction site just downstream of the 3' terminus of each SJNNV sequence and were transcribed in vitro into RNA with a cap structure analogue. A mixture of the transcripts was transfected into the fish cell line E 11. Using indirect immunofluorescence staining with anti-SJNNV serum, fluorescence was observed specifically in these transfected cells; this culture supernatant exhibited pathogenicity to striped jack larvae. Northern blot analysis of E-11 cells infected with the recombinant virus or SJNNV showed small RNA (ca. 0.4 kb) that was newly synthesized and corresponded to the 3'-terminal region of RNA1. Finally, the complete nucleotide sequences of these functional cDNAs (RNA1, 3107 nt; RNA2, 1421 nt) were determined. This is the first report of betanodavirus cDNA clones from which infectious genomic RNAs can be transcribed. PMID- 11602778 TI - Increased replication of respiratory syncytial virus (RSV) in pulmonary infiltrates is associated with enhanced histopathological disease in bonnet monkeys (Macaca radiata) pre-immunized with a formalin-inactivated RSV vaccine. AB - The pathology of respiratory syncytial virus (RSV) disease in bonnet monkeys parallels findings with human RSV disease. RSV-infected animals pre-immunized with a formalin-inactivated (FI) RSV vaccine develop inflammation in peribronchiolar, perivascular, interstitial and intra-alveolar sites with lung inflammation scores significantly higher than animals with a primary RSV infection and those pre-immunized with an FI-Vero cell control vaccine (P=0.05). Animals previously infected and re-exposed to RSV had significantly lower alveolar, interstitial and total lung inflammation scores than in primary infection (P=0.05). Immunization with two intra-muscular doses of 0.5 ml of the FI-RSV vaccine administered 21 days apart resulted in little serum-neutralizing and ELISA antibody, low levels of secretory IgA and a low lymphocyte proliferative response that was significantly lower than the response observed in animals that were previously infected with live RSV. Higher RSV virus titres were detected in the lungs and lung lavage fluid of monkeys immunized with the FI-RSV vaccine than in those with a primary infection (P=0.001). RSV was detected by in situ hybridization in pulmonary inflammatory infiltrates, where the single most abundant infiltrating cellular species was macrophages, so it may be these cells that support the enhanced virus replication that contributes to the enhanced pulmonary pathology of FI-RSV immunization. PMID- 11602779 TI - Characterization of two decades of temporal co-circulation of four mumps virus genotypes in Denmark: identification of a new genotype. AB - Twenty-nine Danish virus isolates and 14 serum samples from patients with mumps were genotyped by nucleotide sequencing of the small hydrophobic (SH) protein gene and the deduced 57 amino acid sequences were aligned with sequences of mumps virus strains published previously. Four neurovirulent genotypes of the SH protein gene, genotypes C, D, H and a new genotype, designated J, were found. There was a dynamic fluctuation of the different genotypes over the two decade period of time. Genotype J was found from 1981 to 1988; genotypes C and H exhibited a similar distribution in time. Genotype D was found between 1979 and 1982, it then disappeared and reappeared again in 1996. From 1996 onwards, genotype D was found to be the predominant genotype, which is in contrast to the situation seen in the neighbouring country of Sweden, where, since 1985, only genotype A has been found. PMID- 11602780 TI - Conservation of coding potential and terminal sequences in four different isolates of Borna disease virus. AB - We determined the complete nucleotide sequences of two poorly characterized strains of Borna disease virus (BDV) and compared them to reference strains V and He/80. Strain H1766 was almost 98% and 95% identical to strains V and He/80, respectively, whereas strain No/98 was only about 81% identical to both reference strains. In contrast to earlier reports, we found an additional A residue at the extreme 3'-end of the single-stranded RNA genome in all four BDV strains. The exact numbers of nucleotides in the four BDV genomes could not be determined due to a micro-heterogeneity at the 5'-end. If our longest sequence is a correct copy of the viral RNA, the two ends of the BDV genome would show almost perfect complementarity. All three transcription start sites, all four termination sites, both splice donor sites and both major splice acceptor sites are highly conserved, whereas a minor alternative splice acceptor site is not. The L protein of No/98 differs at 7% of its amino acid positions from the polymerase in the other strains, with most differences mapping to the C-terminal moiety of the molecule. Re-evaluation of L protein sequences of strains V and He/80 revealed differences at several positions compared to published information, indicating that variant forms of the viral polymerase have previously been characterized. These results are important because correct structures of genome ends and of the polymerase gene are the most critical parameters for the future development of techniques that will permit the genetic manipulation of BDV. PMID- 11602781 TI - Molecular basis for the interaction between rabies virus phosphoprotein P and the dynein light chain LC8: dissociation of dynein-binding properties and transcriptional functionality of P. AB - The lyssavirus phosphoprotein P is a co-factor of the viral RNA polymerase and plays a central role in virus transcription and replication. It has been shown previously that P interacts with the dynein light chain LC8, which is involved in minus end-directed movement of organelles along microtubules. Co immunoprecipitation experiments and the two-hybrid system were used to map the LC8-binding site to the sequence (139)RSSEDKSTQTTGR(151). Site-directed mutagenesis of residues D(143) and Q(147) to an A residue abolished binding to LC8. The P-LC8 association is not required for virus transcription, since the double mutant was not affected in its transcription ability in a minigenome assay. Based on the crystal structure of LC8 bound to a peptide from neuronal nitric oxide synthase, a model for the complex between the peptide spanning residues 140-150 of P and LC8 is proposed. This model suggests that P binds LC8 in a manner similar to other LC8 cellular partners. PMID- 11602782 TI - Respiratory and systemic humoral and cellular immune responses of pigs to a heterosubtypic influenza A virus infection. AB - The level of heterosubtypic immunity (Het-I) and the immune mechanisms stimulated by a heterosubtypic influenza virus infection were investigated in pigs. Pigs are natural hosts for influenza virus and, like humans, they host both subtypes H1N1 and H3N2. Marked Het-I was observed when pigs were infected with H1N1 and subsequently challenged with H3N2. After challenge with H3N2, pigs infected earlier with H1N1 did not develop fever and showed reduced virus excretion compared with non-immune control pigs. In addition, virus transmission to unchallenged group-mates could be shown by virus isolation in the non-immune control group but not in the group infected previously with H1N1. Pigs infected previously with homologous H3N2 virus were protected completely. After challenge with H3N2, pigs infected previously with H1N1 showed a considerable increase in serum IgG titre to the conserved extracellular domain of M2 but not to the conserved nucleoprotein. These results suggest that antibodies against external conserved epitopes can have an important role in broad-spectrum immunity. After primary infection with both H1N1 and H3N2, a long-lived increase was observed in the percentage of CD8(+) T cells in the lungs and in the lymphoproliferation response in the blood. Upon challenge with H3N2, pigs infected previously with H1N1 again showed an increase in the percentage of CD8(+) T cells in the lungs, whereas pigs infected previously with H3N2 did not, suggesting that CD8(+) T cells also have a role in Het-I. To confer broad-spectrum immunity, future vaccines should induce antibodies and CD8(+) T cells against conserved antigens. PMID- 11602783 TI - Hepatitis delta virus genotypes I and II cocirculate in an endemic area of Yakutia, Russia. AB - Currently, three genotypes of hepatitis delta virus (HDV) are described. The most common, genotype I, has a worldwide distribution; in contrast, genotype II has been found previously only in Japan and Taiwan, while genotype III is found exclusively in South America. Considering the high prevalence of HDV in Northern Siberia (Russia), restriction fragment length polymorphism (RFLP) was used to analyse HDV genotypes from 29 infected patients living in Yakutia. Of these isolates, 11 were characterized by partial nucleotide sequencing and two isolates were completely sequenced. Phylogenetic inference methods included maximum parsimony, maximum likelihood and distance analyses. A restriction pattern consistent with HDV genotype I was found in 14 samples, while the remaining 15 showed a different restriction pattern, inconsistent with any known genotype. Five Yakutian HDV isolates with the type I restriction pattern were sequenced and confirmed to be affiliated with genotype I, although the phylogenetic results indicate that they were heterogeneous and did not cluster together. Sequencing of eight isolates with the new RFLP pattern revealed that these isolates were most closely related to HDV genotype II. In contrast to HDV Yakutian genotype I sequences, all of these type II sequences formed a well-defined clade on phylogenetic trees. Comparison of clinical presentations during hospitalization between patients infected with HDV type I (n=14) and type II (n=15) did not reveal any differences in the severity of infection. These data indicate that the distribution of genotype II is not restricted to Taiwan or Japan, but spreads over Northern Asia, appearing in the native population of Yakutia. Type II Yakutian strains appeared to form a well-defined subclade and could be associated with severe chronic hepatitis in this area. PMID- 11602784 TI - Interaction of human immunodeficiency virus type 1 Vif with Gag and Gag-Pol precursors: co-encapsidation and interference with viral protease-mediated Gag processing. AB - Interactions of human immunodeficiency virus type 1 (HIV-1) Vif protein with various forms of Gag and Gag-Pol precursors expressed in insect cells were investigated in vivo and in vitro by co-encapsidation, co-precipitation and viral protease (PR)-mediated Gag processing assays. Addressing of Gag to the plasma membrane, its budding as extracellular virus-like particles (VLP) and the presence of the p6 domain were apparently not required for Vif encapsidation, as non-N-myristoylated Deltap6-Gag and Vif proteins were co-encapsidated into intracellular VLP. Encapsidation of Vif occurred at significantly higher copy numbers in extracellular VLP formed from N-myristoylated, budding-competent Gag Pol precursors harbouring an inactive PR domain or in chimaeric VLP composed of Gag and Gag-Pol precursors compared with the Vif content of Pr55Gag VLP. Vif encapsidation efficiency did not seem to correlate directly with VLP morphology, since these chimaeric VLP were comparable in size and shape to Pr55Gag VLP. Vif apparently inhibited PR-mediated Pr55Gag processing in vitro, with preferential protection of cleavage sites at the MA-CA and CA-NC junctions. Vif was resistant to PR action in vitro under conditions that allowed full Gag processing, and no direct interaction between Vif and PR was detected in vivo or in vitro. This suggested that inhibition by Vif of PR-mediated Gag processing resulted from interaction of Vif with the Gag substrate and not with the enzyme. Likewise, the higher efficiency of Vif encapsidation by Gag-Pol precursor compared with Pr55Gag was probably not mediated by direct binding of Vif to the Gag-Pol-embedded PR domain, but more likely resulted from a particular conformation of the Gag structural domains of the Gag-Pol precursor. PMID- 11602785 TI - Genetic and functional analysis of the human immunodeficiency virus (HIV) type 1 inhibiting F12-HIVnef allele. AB - The primary human immunodeficiency virus type 1 (HIV-1) Nef mutant F12-HIVNef is characterized by three rare amino acid substitutions, G(140)E, V(153)L and E(177)G. It was reported previously that the expression of F12-HIVNef in the context of the highly productive NL4-3 HIV-1 strain blocks virus replication at the level of virus assembly and/or release by a mechanism depending on the presence of the CD4 intracytoplasmic tail. Here, it is reported that NL4-3 HIV-1 strains expressing F12-HIVnef alleles that were back-mutated in each amino acid substitution readily replicated in CD4(+) cells. Attempting to correlate possible functional alterations with antiviral effects, both F12-HIVNef and its back mutants were tested in terms of well-characterized markers of Nef expression. Both F12-HIVNef and its G(177)E back mutant did not down-regulate CD4 as the consequence of a greatly reduced rate of CD4 internalization. On the other hand, F12-HIVNef as well as the E(140)G and L(153)V back mutants failed to activate the p62 Nef-associated kinase (p62NAK). Thus, only F12-HIVNef was defective in both accelerated rates of CD4 internalization and p62NAK activation, whereas at least one Nef function was restored in all of the back mutants. Infection of cells expressing Nef-resistant CD4 molecules with HIV-1 strains encoding F12-HIVNef back mutants showed that both the lack of accelerated CD4 endocytosis and an, as yet, still unidentified function are required for the F12-HIVNef inhibitory phenotype. These results provide a detailed functional analysis of the F12-HIVnef allele and support the idea that both CD4 accelerated internalization and p62NAK activation are part of the essential steps in the virus replication cycle. PMID- 11602786 TI - Movements of vaccinia virus intracellular enveloped virions with GFP tagged to the F13L envelope protein. AB - Vaccinia virus produces several forms of infectious virions. Intracellular mature virions (IMV) assemble in areas close to the cell nucleus. Some IMV acquire an envelope from intracellular membranes derived from the trans-Golgi network, producing enveloped forms found in the cytosol (intracellular enveloped virus; IEV), on the cell surface (cell-associated enveloped virus) or free in the medium (extracellular enveloped virus; EEV). Blockage of IMV envelopment inhibits transport of virions to the cell surface, indicating that enveloped virus forms are required for virion movement from the Golgi area. To date, the induction of actin tails that propel IEV is the only well-characterized mechanism for enveloped virus transport. However, enveloped virus transport and release occur under conditions where actin tails are not formed. In order to study these events, recombinant vaccinia viruses were constructed with GFP fused to the most abundant protein in the EEV envelope, P37 (F13L). The P37-GFP fusion, like normal P37, accumulated in the Golgi area and was incorporated efficiently into enveloped virions. These recombinants allowed the monitoring of enveloped virus movements in vivo. In addition to a variety of relatively slow movements (<0.4 microm/s), faster, saltatory movements both towards and away from the Golgi area were observed. These movements were different from those dependent on actin tails and were inhibited by the microtubule-disrupting drug nocodazole, but not by the myosin inhibitor 2,3-butanedione monoxime. Video microscopy (5 frames per s) revealed that saltatory movements had speeds of up to, and occasionally more than, 3 microm/s. These results suggest that a second, microtubule-dependent mechanism exists for intracellular transport of enveloped vaccinia virions. PMID- 11602787 TI - Characterization of the DNA polymerase gene of varicella-zoster viruses resistant to acyclovir. AB - The nucleotide changes of the DNA polymerase gene and the susceptibility of acyclovir (ACV)-resistant varicella-zoster virus (VZV) mutants to anti-herpetic drugs were determined and compared to those of herpes simplex virus type 1 (HSV 1) mutants. The seven ACV-resistant VZV mutants were classified into three groups, N(779)S, G(805)C and V(855)M, according to the sequences of their DNA polymerase genes. The amino acid substitutions N(779)S and G(805)C were identical in position to the N(815)S and G(814)C mutations in the HSV-1 DNA polymerase mutants, respectively, and the V(855)M amino acid substitution was similar to the HSV-1 V(892)M mutation. All three groups of VZV mutants were susceptible to ACV, phosphonoacetic acid, vidarabine and aphidicolin, at levels similar to those seen with the respective HSV-1 mutants, except for subtle differences that were due possibly to the non-conserved regions in their sequences. Although both the HSV-1 and the VZV DNA polymerase genes show 53% sequence similarity, both viruses essentially show a similar biochemical behaviour. PMID- 11602788 TI - Selection of the same mutation in the U69 protein kinase gene of human herpesvirus-6 after prolonged exposure to ganciclovir in vitro and in vivo. AB - After serial passage in the presence of increasing concentrations of ganciclovir (GCV) in vitro, a human herpesvirus-6 (HHV-6) mutant exhibiting a decreased sensitivity to the drug was isolated. Analysis of drug susceptibility showed that the IC(50) of this mutant was 24-, 52- and 3-fold higher than that of the wild type (wt) IC(50) in the case of GCV, cidofovir and foscarnet, respectively. Genotypic analysis showed two single nucleotide changes as compared to the wild type: an A-->G substitution of the U69 protein kinase (PK) gene resulted in an M(318)V amino acid substitution and the other change, located in the C-terminal part of the U38 gene, resulted in an A(961)V amino acid substitution within the DNA polymerase. The M(318)V change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the M(460)V and M(460)I changes that had been reported previously within the consensus sequence DITPMN of the human cytomegalovirus (HCMV) UL97 PK and associated with the resistance of HCMV to GCV. The M(318)V change was also detected by PCR in HHV-6-infected PBMCs from an AIDS patient who had been treated with GCV for a long period of time and exhibited a clinically GCV-resistant HCMV infection. These findings provide strong circumstantial evidence that the M(318)V change of the PK gene is associated with resistance to GCV and raise the question of cross resistance to this drug among different betaherpesviruses. PMID- 11602789 TI - gpUL73 (gN) genomic variants of human cytomegalovirus isolates are clustered into four distinct genotypes. AB - Clinical isolates of human cytomegalovirus (HCMV) show differences in tissue tropism, severity of clinical manifestations and ability to establish persistent or latent infections, characteristics that are thought to be related to genomic variation among strains. This work analysed the genomic variants of a new HCMV polymorphic locus, open reading frame (ORF) UL73. This ORF encodes the envelope glycoprotein gpUL73 (gN), which associates in a high molecular mass complex with its counterpart, gM, and induces a neutralizing antibody response in the host. Detailed sequence analysis of ORF UL73 and its gene product from clinical isolates and laboratory-adapted strains shows that this glycoprotein is highly polymorphic, in the N-terminal region in particular. gpUL73 hypervariability is not randomly distributed, but the identified genomic variants are clearly clustered into four distinct genotypes (gN-1, gN-2, gN-3 and gN-4), which are not associated with the gB subtype. PMID- 11602790 TI - Ovine herpesvirus-2 glycoprotein B sequences from tissues of ruminant malignant catarrhal fever cases and healthy sheep are highly conserved. AB - Ovine herpesvirus-2 (OHV-2) infection has been associated with malignant catarrhal fever (MCF) in susceptible ruminants. In order to further investigate whether OHV-2 is an aetiological agent for sheep-associated (SA) MCF in cattle and bison, the entire sequences of OHV-2 glycoprotein B (gB) from different sources of viral DNA were compared. Target DNA was derived from tissues of bovine and bison cases of SA-MCF, from a lymphoblastoid cell line established from another bovine case of SA-MCF, and from a healthy sheep. The divergence between deduced amino acid sequences of OHV-2 gB ranged from 0.5 to 1.2%. The high degree of similarity between gB sequences from a healthy sheep and clinical cases of SA MCF in cattle and bison suggests that OHV-2 is an ovine virus that is occasionally transmitted to other ruminant species, in which it can cause severe disease. PMID- 11602791 TI - Immunity against both polyomavirus VP1 and a transgene product induced following intranasal delivery of VP1 pseudocapsid-DNA complexes. AB - Murine polyomavirus VP1 virus-like particles (VLPs) can bind plasmid DNA and transport it into cells both in vitro and in vivo. Long-term expression of the transgene can be observed, suggesting that VP1 VLPs may be used as DNA delivery vehicles for gene therapy. In this study we have analysed the in vitro efficiency of transfection using different DNA/VLP molar ratios and the immune response induced following intranasal administration of these complexes to mice. Our results indicate that in short-term in vitro culture VP1 VLP-DNA complexes appear to be as efficient as DNA alone at transfecting cell monolayers. They also show that VP1 VLPs are very immunogenic, inducing high proliferative cell responses and both serum and mucosal antibodies. Moreover, VP1 VLP-DNA complexes appear to be capable of inducing a stronger immune response to the transgene product (beta galactosidase) than immunization with DNA only. The results suggest that polyomavirus VP1 VLPs derived from the wild-type sequence may be too immunogenic for repeated use as gene delivery vehicles in gene therapy. However, due to their high immunogenicity and apparent adjuvant properties, they could be modified and used as vaccines either on their own or complexed with DNA. PMID- 11602793 TI - Nucleotide sequence analysis of a novel circovirus of canaries and its relationship to other members of the genus Circovirus of the family Circoviridae. AB - The circular, single-stranded DNA genome of a novel circovirus of canaries, tentatively named canary circovirus (CaCV), was cloned and sequenced. Sequence analysis indicated that the genome was 1952 nucleotides (nt) in size and had the potential to encode three viral proteins, including the putative capsid and replication-associated (Rep) proteins. The CaCV genome shared greatest sequence similarity (58.3% nt identity) with the newly characterized columbid circovirus (CoCV) and was more distantly related to the two porcine circovirus strains, PCV1 and PCV2, beak and feather disease virus (BFDV) and a recently isolated goose circovirus (GCV) isolate (46.8-50.9% nt identity). In common with other members of the Circovirus genus, several nt structures and amino acid motifs thought to be implicated in virus replication were identified on the putative viral strand. Phylogenetic analysis of both the capsid and Rep protein-coding regions provided further evidence that CaCV is more closely related to CoCV and BFDV and more distantly related to GCV, PCV1 and PCV2. PMID- 11602792 TI - Chimeric papillomavirus-like particles expressing a foreign epitope on capsid surface loops. AB - Neutralization capsid epitopes are important determinants for antibody-mediated immune protection against papillomavirus (PV) infection and induced disease. Chimeric L1 major capsid proteins of the human PV type 16 (HPV-16) and the bovine PV type 1 (BPV-1) with a foreign peptide incorporated into several capsid surface loops self-assembled into pentamers or virus-like particles (VLP). Binding patterns of neutralizing monoclonal antibodies (MAb) and immunization of mice confirmed (i) that regions around aa 282-286 and 351-355 contribute to neutralization epitopes and identified the latter region as an immunodominant site and (ii) that placing a foreign peptide in the context of an assembled structure markedly enhanced its immunogenicity. Pentamers disassembled from wild type HPV-16 and BPV-1 VLPs displayed some of the neutralization epitopes that were detected on fully assembled VLPs, but were deficient for binding a subset of neutralizing MAb that inhibit cell attachment. PMID- 11602794 TI - Identification of an enhancer-like element in the polyhedrin gene upstream region of Bombyx mori nucleopolyhedrovirus. AB - A series of deletions in the upstream region of the gene encoding polyhedrin (polh) of Bombyx mori nucleopolyhedrovirus (BmNPV) were generated in plasmid constructs and tested for transcription. In transient transfection assays in Bombyx mori-derived BmN cells with firefly luciferase as the reporter gene, a 293 bp fragment located 1.0 kb upstream with respect to the +1 ATG of polh showed 10 fold enhancement in expression from the minimal promoter. This increase in reporter activity was observed only when the fragment was positioned in cis with respect to the promoter and not in trans. The stimulation of reporter gene expression was independent of the orientation of the fragment and was due to increased transcription from the promoter. When placed upstream of another promoter, the viral very late gene p10 promoter, the enhancer brought about a 2 fold increase in expression. The region encompassing the enhancer was itself transcriptionally active, and transcripts corresponding to both of the encoded ORFs (N-terminal regions of ORF453 and ORF327, located in opposite orientations) were detected. Two AP1 sites (TGACTCG) in the 293 bp fragment did not appear to contribute to the enhancer function. Since repeat motifs, the hallmark of conventional enhancer sequences, were absent from this fragment, it is designated as an enhancer-like element. The influence of this region of the polh upstream sequence on expression from strong, very late viral promoters has not been reported previously. PMID- 11602795 TI - Genome organization of the densovirus from Bombyx mori (BmDNV-1) and enzyme activity of its capsid. AB - Bombyx mori densovirus (BmDNV-1), on the basis of the previously reported genome sequence, constitutes by itself a separate genus (Iteravirus) within the Densovirinae subfamily of parvoviruses. Inconsistencies in the genome organization, however, necessitated its reassessment. The genome sequence of new clones was determined and resulted in a completely different genome organization. The corrected sequence also contained conserved sequence motifs found in other parvoviruses. Some amino acids in the highly conserved domain in the unique region of VP1 were shared by critical amino acids in the catalytic site and Ca(2+)-binding loop of secreted phospholipase A2, such as from snake and bee venoms. Expression of this domain and determination of enzyme activity demonstrated that capsids have a phospholipase A2 activity thus far unknown to occur in viruses. This viral phospholipase A2, which is required shortly after entry into the cell, showed a substrate preference for phosphatidylethanolamine and phosphatidylcholine over phosphatidylinositol. PMID- 11602796 TI - Comparative reactions of recombinant papaya ringspot viruses with chimeric coat protein (CP) genes and wild-type viruses on CP-transgenic papaya. AB - Transgenic papaya cultivars SunUp and Rainbow express the coat protein (CP) gene of the mild mutant of papaya ringspot virus (PRSV) HA. Both cultivars are resistant to PRSV HA and other Hawaii isolates through homology-dependent resistance via post-transcriptional gene silencing. However, Rainbow, which is hemizygous for the CP gene, is susceptible to PRSV isolates from outside Hawaii, while the CP-homozygous SunUp is resistant to most isolates but susceptible to the YK isolate from Taiwan. To investigate the role of CP sequence similarity in overcoming the resistance of Rainbow, PRSV HA recombinants with various CP segments of the YK isolate were constructed and evaluated on Rainbow, SunUp and non-transgenic papaya. Non-transgenic papaya were severely infected by all recombinants, but Rainbow plants developed a variety of symptoms. On Rainbow, a recombinant with the entire CP gene of YK caused severe symptoms, while recombinants with only partial YK CP sequences produced a range of milder symptoms. Interestingly, a recombinant with a YK segment from the 5' region of the CP gene caused very mild, transient symptoms, whereas recombinants with YK segments from the middle and 3' parts of the CP gene caused prominent and lasting symptoms. SunUp was resistant to all but two recombinants, which contained the entire CP gene or the central and 3'-end regions of the CP gene and the 3' non coding region of YK, and the resulting symptoms were mild. It is concluded that the position of the heterologous sequences in the recombinants influences their pathogenicity on Rainbow. PMID- 11602797 TI - GB virus C/hepatitis G virus replicates in human haematopoietic cells and vascular endothelial cells. PMID- 11602798 TI - Developmental morphological and histological studies on structures of the human fetal shoulder joint. AB - In the present work, morphological changes in the interior structures of the developing human shoulder joint were studied at different prenatal ages (9, 12, 16, 23 and 40 weeks) and were compared with the same structures in the adult joint. It was found that the shoulder joint had gone through important developmental changes during the 12th week of the prenatal life and it is assumed that genetic factors operative during this stage of development were more important than mechanical factors. A subsequent development of the intracapsular glenohumeral ligaments was present at the 16th week. The glenoid labrum, the biceps tendon and the three glenohumeral ligaments formed a complete ring around the glenoid fossa which constituted a functional unit, which seemed to have a role in stabilizing the joint. In the present work, histological prenatal studies were done on sagittal and radial sections from the glenoid fossa and its associated structures and the results were compared with the same structures in adults. At a crown-rump length of 30 mm (9 weeks), intermingling of the collagen fibres of the superior labrum and the biceps tendon was observed and the superior labrum could be considered as an extension of the biceps tendon. While the superior and inferior parts of the labrum appeared fibrous, the posterior labrum appeared as a primitive cellular condensation. At the 12th week, it became a fibrocellular structure and changed to a fibrocartilaginous structure at the 16th week. But until full term, no definitive fibrocartilage was found due to its hypercellularity compared to the adult. It was found that at all ages, the capsule was formed of cellular and fibrous elements, its collagenous content was progressively increased with age and at full term, it became generally fibrous but was still different compared to adults. In all stages of development, the synovial tissue of different regions of the same joint exhibited marked variations in thickness, vascularity, cellular density and collagenous content. It lined the capsule, surrounded the biceps tendon and reflected on the labrum. Its cell density as well as their vascular and collagenous contents were progressively increased with age. At full term, the synovial tissue was thickest at its inferior reflection and forming large folds. The synovial tissue lining the capsule was thinner than the synovial tissue at its reflection from the labrum, many villi and processes arising from it and projecting into the joint cavity. PMID- 11602799 TI - Immunofluorescence and electron-microscopic observations of intermediate cells in the pancreas of mice, rats and humans. AB - The immunohistochemical method supplemented with a transmission electron microscopic survey was used to investigate the pancreas of mice, rats and humans to demonstrate intermediate cells. Indirect immunofluorescence was applied to paraffin sections of pancreatic samples of normal rats and autopsied humans to localize amylase in the islets and excretory duct cells. The amylase immunofluorescent spots were occasionally detected in the apices and perinuclear cytoplasm of few islet and excretory duct cells, which completely disappeared in the specificity control sections. These cells, respectively, represented the islet amylase and duct amylase intermediate cells. The ultrastructural survey was conducted on pancreatic tissue samples from normal and streptozotocin-diabetic mice and rats to prove the existence of these intermediate cells. Three morphologically distinct types of intermediate cells were recognized and characterized into beta-acinar, alpha-acinar and duct acinar types. The beta acinar and alpha-acinar cells contained numerous secretory granules with few large and dense, membrane-bound zymogen granules. No clear difference in the frequency of these cells between normal and diabetic tissues was qualitatively observed in either mice or rats. The duct acinar cells were occasionally seen in few small intercalated ducts of the normal mouse pancreas, which contained few dense, membrane-bound zymogen granules adjacent to a prominent Golgi complex. On the other hand, no delta-acinar, pancreatic polypeptide (PP)-acinar or acinoislet cells were observed in both normal and diabetic animals. In conclusion, the present study provides immunohistochemical and morphological evidence on the existence of different types of intermediate cells in the normal and streptozotocin-diabetic pancreas of mice, rats and humans. Although no prevalence of these cells in the streptozotocin-diabetic pancreas was observed qualitatively, their existence throws light on the possible transformation between structurally and functionally different pancreatic cells when subjected to pathological trauma. This concept might be of great significance in beta-cell regeneration in insulin-dependent diabetes mellitus. PMID- 11602800 TI - Argyrophilic and glucagon-immunoreactive cells in the ileum and colon of the developing opossum Didelphis albiventris (Marsupialia). AB - The ontogenesis of glucagon-producing cells of the ileum and colon of pouch young and of weaned and adult opossums Didelphis albiventris was studied in comparison with the endocrine argyrophilic cell population development. In the ileum, the mean population of argyrophilic cells/mm(2) increased with ontogenesis from 122.9 +/- 18.7 in the pouch young to 211.4 +/- 48.9 in adult animals, while the number of glucagon-immunoreactive cells/mm(2) remained practically constant, i.e. 29.2 +/- 7.3 in the pouch young and 28.1 +/- 5.0 in the adult animal. In the colon, the population of argyrophilic cells/mm(2) remained constant throughout ontogenesis, i.e. 45.8 +/- 6.2 in the pouch young and 48.9 +/- 10.4 in the adult animals. In turn, the enteroglucagon-producing cells increase in number from 4.5 +/- 2.9 to 14.6 +/- 5.2 cells/mm(2) from the pouch young to the adult. We conclude that the intestinal glucagon-producing cells of D. albiventris present a differentiated development in the ileum and colon. This fact suggests that glucagon-immunoreactive cells may play a distinct role in these segments of the intestine during ontogenesis. PMID- 11602801 TI - The ganoine membrane of the scales of Polypterus senegalus includes a labyrinth like structure. AB - The ganoine membrane is a basement membrane-like structure appearing between the maturation stage inner ganoine epithelium (IGE) and mineralized ganoine of polypterids and lepisosteids. In the present study, further ultrastructural investigation of the ganoine membrane of Polypterus senegalus was made and it was confirmed that it possessed a specialized labyrinth-like structure. The complete ganoine membrane was composed of six distinct zones: (1) a filamentous zone facing the distal plasmalemma of IGE, (2) lamella zone I, (3) vertical striation zone, (4) lamella zone II, (5) electron-dense zone, (6) electron-lucent zone directly facing the maturing ganoine surface. The ganoine membrane sometimes partially lacked some of these zones, but the electron-dense zone was usually present. Oblique or horizontal sections of the membrane showed that the vertical striation zone was made up of a typical labyrinth-like structure. Certain sulfated glycoconjugates were localized at the filamentous zone, especially adjacent to the lamella zone I and over the electron-dense zones. PMID- 11602802 TI - Morphology of the external nose in Hipposideros diadema and Lavia frons with comments on its diversity and evolution among leaf-nosed Microchiroptera. AB - In some bats, a noseleaf is thought to help focus echolocation calls emitted through the nostrils. I studied the ontogenetic mode of the rhinarial cartilages and the associated facial muscles to assess how these rhinarial infrastructures interact with the noseleaf, and the inferred function of such a rhinarial complex. This study focuses on developmental stages of Hipposideros diadema and Lavia frons. Based on new data on these two rhinolophoids and a review of former studies concerning rhinopomatids, rhinolophoids and phyllostomids, the functional and phylogenetic implications of the rhinarial complex among leaf-nosed Microchiroptera are evaluated by the current study. Nasal emitting forms evolved several times independently in the Microchiroptera and share various features, irrespective of their phylogenetic position: the nostrils lie dorsally; the noseleaf has a well-developed horseshoe-shaped plate; the cartilago cupularis bears a large processus cupularis; M(iv) is extended on the lateral plate of the processus alaris superior. The unique similarities of the ontogenetic process of the nasal 'resonators' support the assumption that the rhinolophids + megadermatids and rhinopomatids may represent a natural group. In some features, the rhinolophids + megadermatids differ significantly from the phyllostomids. The noseleaf has a median flap and anterior-facing pockets. The processus alaris superior is half-tube-shaped or included in the lateral wall of the cupula nasi anterior. The cartilago accessoria and the attendant musculature perform an important function for supporting and moving the noseleaf. Similar emission of the echolocation pulses but alternative constructional designs of the external nose structures suggest that a separate history of rhinolophoids and phyllostomids might account for these differences. PMID- 11602803 TI - Morphological evidence for secondary vestibular afferent connections to the dorsal cochlear nucleus in the rabbit. AB - An analysis of central afferent projections to the dorsal cochlear nucleus (dCo), one of the three target nuclei of the auditory nerve, was made using retrograde axonal tracer, wheat germ agglutinin-horseradish peroxidase (WGA-HRP) in the rabbit. The findings showed that, in addition to its afferents from the brainstem auditory nuclei (they are not described herein), the dCo received sparse bilateral connections from the caudal three quarters of the vestibular nuclear complex (VNC). Following selective iontophoretic injections of WGA-HRP into the dCo, a small number of labelled neurones (from 2 to 28 per case) was found in the rostral and caudal portions of the medial vestibular nucleus and in the inferior vestibular nucleus. These neurones were observed mainly in the lateral regions of the nuclei. No labelling appeared in other nuclei which belonged to the VNC. The secondary vestibulocochlear connections have not been reported before in any species. With the anatomical method used, however, their functional role is difficult to explain. Further study is necessary to identify the type of neurotransmitter as well as the physiological properties of vestibular neurones projecting to the dCo, in terms of their responses to a change of the head position and to sound. PMID- 11602804 TI - Cloning and expression of human sialic acid pathway genes to generate CMP-sialic acids in insect cells. AB - The addition of sialic acid residues to glycoproteins can affect important protein properties including biological activity and in vivo circulatory half life. For sialylation to occur, the donor sugar nucleotide cytidine monophospho sialic acid (CMP-SA) must be generated and enzymatically transferred to an acceptor oligosaccharide. However, examination of insect cells grown in serum free medium revealed negligible native levels of the most common sialic acid nucleotide, CMP-N-acetylneuraminic acid (CMP-Neu5Ac). To increase substrate levels, the enzymes of the metabolic pathway for CMP-SA synthesis have been engineered into insect cells using the baculovirus expression system. In this study, a human CMP-sialic acid synthase cDNA was identified and found to encode a protein with 94% identity to the murine homologue. The human CMP-sialic acid synthase (Cmp-Sas) is ubiquitously expressed in human cells from multiple tissues. When expressed in insect cells using the baculovirus vector, the encoded protein is functional and localizes to the nucleus as in mammalian cells. In addition, co-expression of Cmp-Sas with the recently cloned sialic acid phosphate synthase with N-acetylmannosamine feeding yields intracellular CMP-Neu5Ac levels 30 times higher than those observed in unsupplemented CHO cells. The absence of any one of these three components abolishes CMP-Neu5Ac production in vivo. However, when N-acetylmannosamine feeding is omitted, the sugar nucleotide form of deaminated Neu5Ac, CMP-2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (CMP KDN), is produced instead, indicating that alternative sialic acid glycoforms may eventually be possible in insect cells. The human CMP-SAS enzyme is also capable of CMP-N-glycolylneuraminic acid (CMP-Neu5Gc) synthesis when provided with the proper substrate. Engineering the CMP-SA metabolic pathway may be beneficial in various cell lines in which CMP-Neu5Ac production limits sialylation of glycoproteins or other glycans. PMID- 11602805 TI - Modulation of the regioselectivity of a Bacillus alpha-galactosidase by directed evolution. AB - Alpha-galactosidase AgaB of Bacillus stearothermophilus was subjected to directed evolution in an effort to modify its regioselectivity. The wild-type enzyme displays a major 1,6 and minor 1,3 regioselectivity. We used random mutagenesis and staggered extension process (StEP) to obtain mutant enzymes displaying modified regioselectivity. We developed a screening procedure allowing first the elimination of AgaB mutants bearing the 1,6 regioselectivity and secondly the selection of those retaining a 1,3 regioselectivity. Our results show that, among the evolved enzymes that have lost most of their activity towards the 1,6 linkage both in hydrolysis and in synthesis, one (E901) has retained its 1,3 activity. However the transglycosylation level reached by this mutant is quite low versus that of the native enzyme. This work constitutes the first example of modification of glycosylhydrolase regioselectivity by directed evolution. PMID- 11602806 TI - Galactosides and sialylgalactosides in O-linked oligosaccharides of the primordial germ cells in Xenopus embryos. AB - The primordial germ cells (PGCs) are covered by surface glycoconjugates; some of them, like galactose residues recognized by peanut agglutinin (PNA), have been reported to be implicated in the PGC migration process. The aim of this work was the characterization of galactosides and sialylgalactosides in N- and O-linked oligosaccharides of Xenopus PGCs. Galactose(Gal)- and sialic acid(Neu5Ac)-binding lectin cytochemistry, in combination with chemical and enzymatic deglycosylation methods, were used. PGCs were slightly labeled with PNA, RCA-I and BSI-B4, which suggests the presence of the sequences Gal(beta1,4)GlcNAc and Gal(alpha1,3)Gal. Moreover, there was no labeling when beta-elimination pre-treatment was performed, suggesting that galactosides were in O-linked oligosaccharides. The strong staining with DSA was probably due to GlcNAc. Furthermore, sialylgalactosides with the sequence Neu5Ac(alpha2,3)Gal(beta1,4)GlcNAc in O linked oligosaccharides have been shown by means of MAA, PNA and RCA-I. PMID- 11602807 TI - Different glycosphingolipid composition in human neutrophil subcellular compartments. AB - The binding of a number of carbohydrate-recognizing ligands to glycosphingolipids and polyglycosylceramides of human neutrophil subcellular fractions (plasma membranes/secretory vesicles of resting and ionomycin-stimulated cells, specific and azurophil granules) was examined using the chromatogram binding assay. Several organelle-related differences in glycosphingolipid content were observed. The most prominent difference was a decreased content of the GM3 ganglioside in plasma membranes of activated neutrophils. Gangliosides recognized by anti-VIM-2 antibodies were detected mainly in the acid fractions of azurophil and specific granules. Slow-migrating gangliosides and polyglycosylceramides with Helicobacter pylori-binding activity were found in all acid fractions. A non-acid triglycosylceramide, recognized by Gal(alpha)4Gal-binding Escherichia coli, was detected in the plasma membrane/secretory vesicles but not in the azurophil and specific granules. Although no defined roles of glycosphingolipids have yet been conclusively established with respect to neutrophil function, the fact that many of the identified glycosphingolipids are stored in granules, is in agreement with their role as receptor structures that are exposed on the neutrophil cell surface upon fusion of granules with the plasma membrane. Accordingly, we show that neutrophil granules store specific carbohydrate epitopes that are upregulated to the plasma membrane upon cell activation. PMID- 11602808 TI - Roles of galactose and sulfate residues in sulfatides for their antagonistic functions in the blood coagulation system. AB - We previously reported that the sulfatide (galactosylceramide I3-sulfate) may have contradictory functions, namely both coagulant and anticoagulant roles in vivo: sulfatide induced giant thrombi formation when injected into rats with vein ligation, whereas no thrombi were formed when sulfatide was injected into rats without vein ligation. Rather it prolonged bleeding time. To investigate the structural features of sulfatide for both functions, a synthetic sulfatide (galactosylceramide I6-sulfate) which does not occur naturally, cholesterol 3 sulfate and ganglioside GM4 were examined together with naturally occurring sulfatide. Both sulfatides and cholesterol 3-sulfate induced giant thrombi in the rats with vein ligation within ten minutes of injection, although cholesterol 3 sulfate exhibited weaker coagulant activity than the sulfatides. On the contrary, both sulfatides significantly prolonged bleeding time but cholesterol 3-sulfate barely prolonged it when injected without vein ligation. GM4 exhibited neither coagulant nor anticoagulant activity. These results suggested that sulfate moiety in the sulfatides is essential for coagulant activity and that galactose residue enhances the activity, whereas both galactose and sulfate residues seem to be important for anticoagulant activity. This is because the sulfatides possess both residues but GM4 possesses galactose without sulfate and cholesterol 3-sulfate possesses sulfate without galactose. We previously reported that the possible mechanism of anticoagulation by sulfatide was due to its binding to fibrinogen, thereby inhibiting the conversion to fibrin. In this paper we reveal that both sulfatides inhibited thrombin activity independent of heparin cofactor II, thus providing evidence of another anticoagulation mechanism for the sulfatides. PMID- 11602809 TI - In vitro binding of Helicobacter pylori to monohexosylceramides. AB - H. pylori is the major cause of human gastritis, duodenal ulcer and thus gastric adenocarcinoma. Many glycosphingolipid species have been postulated as receptors for H. pylori and it is likely that H. pylori attachment requires multiple, perhaps sequential receptor/ligand interactions. In this study, the binding of a number of H. pylori clinical isolates, as well as stock strains, to acid and neutral glycosphingolipids separated on thin-layer chromatograms was characterized under microaerobic conditions. All H. pylori clinical isolates, laboratory strains and type culture collection strains recognized galactosylceramide (Galbeta1Cer) with ceramide containing sphingosine and hydroxylated fatty acid (type I), or non-hydroxylated fatty acid (type II), on thin-layer chromatograms and when incorporated into liposomes. The clinical isolates bound stronger to Galbeta1Cer (type II) than Galbeta1Cer (type I) on TLC, whereas lab and culture collection strains showed the opposite binding preference. A clear preference in binding to Galbeta1Cer (type I) incorporated into liposome was shown by most tested strains. Clinical isolates bound well to glucosylceramide (Glcbeta1Cer) with hydroxylated fatty acid, whereas weak binding to this glycolipid was detected with the lab and type collection strains. None of the tested strains bound Glcbeta1Cer with non-hydroxylated fatty acid on the solid surface, but some strains of both clinical or type collection origins showed weak or very weak binding in the liposome assay. A clear distinction between the binding specificity of living organisms (under microaerobic conditions) as opposed to dying organisms (under normoxic conditions) illustrates the importance of cellular physiology in this process. These studies illustrate lipid modulation of the potential receptor function of monohexosylceramides and the distinction between the receptor repertoire of H. pylori clinical isolates and cultured strains commonly used to study host-cell adhesion. PMID- 11602810 TI - Increased alpha3-fucosylation of alpha1-acid glycoprotein in Type I diabetic patients is related to vascular function. AB - Diabetic mellitus is attended by the development of endothelial dysfunction which is suggested to be accompanied with a chronic low-degree of inflammation. During a chronic hepatic inflammatory response, specific changes in glycosylation of the acute phase protein alpha1-acid glycoprotein (AGP) can be detected. In this report we studied the changes in glycosylation of AGP in more detail and evaluated the relation between a change in glycosylation of AGP and urinary albumin secretion in Type I diabetic patients. The glycosylation of AGP, studied by crossed affinity immunoelectrophoresis (CAIE) and high pH anion exchange chromatography with pulse amperometric detection (HPAEC-PAD), showed an increase in alpha3-fucosylation. Staining with an antibody against sialyl Lewis(x) (sLe(x)) implied that part of the alpha3-fucosylation was present in a sLe(x) conformation. In the group of Type I diabetic patients with increased urinary albumin excretion, a significant increase in alpha3-fucosylation of AGP (p<0.0005) could be detected. Therefore, the increased alpha3-fucosylation of AGP can be used as an additional marker for the development of vascular complications in Type I diabetic patients. PMID- 11602811 TI - Ciprofibrate increases plasma concentration of platelet-derived growth factor AB in patients with advanced atherosclerosis and hyperlipidemia independently of its hypolipidemic effects. AB - Fibrates, besides their hypolipidemic action, share alternative effects, such as decreased plasma fibrinogen and uric acid levels. Because of their complex action, additional effects have been investigated. A group of 23 patients with clinical signs of atherosclerosis and hyperlipoproteinemia was randomly allocated after a 1-month washout period and treated with either 100 mg/d of ciprofibrate or 100 mg/d of aspirin for 2 months. Patients were then treated with a combination of these two agents for the next 2 months. Ciprofibrate decreased plasma concentrations of triglycerides (-29%) and very-low-density lipoprotein cholesterol (-27%) in monotherapy and a larger reduction was observed if ciprofibrate was added to the aspirin therapy: triglycerides (-39%), very-low density lipoprotein cholesterol (-33%), total cholesterol (-18%), low-density lipoprotein cholesterol (-17%), and increased high-density lipoprotein cholesterol (+36%). Ciprofibrate increased plasma levels of platelet-derived growth factor (PDGF) AB in both monotherapy patients (+162.9 pg/ml, +297%) and in aspirin-pretreated patients (+129.8 pg/ml, +134%); the increase of PDGF AB platelet store was significant only in aspirin-pretreated patients (+11.1 ng/ml, +51%). Aspirin in monotherapy did not modulate either plasma or platelet store of PDGF AB. Ciprofibrate did not inhibit thromboxane B 2 synthesis in platelets. Aspirin did not influence plasma thromboxane B 2 concentration at all, whereas it decreased thromboxane B 2 platelet production markedly in monotherapy (-85%) and in combination with ciprofibrate (-91%). Ciprofibrate increases PDGF AB content, which is amplified by aspirin pretreatment without correlation with its hypolipidemic action. The increase of PDGF production is suggested to participate in plaque stabilization. PMID- 11602812 TI - Tamoxifen is an acute, estrogen-like, coronary vasodilator of porcine coronary arteries in vitro. AB - Tamoxifen is a mixed estrogen antagonist and agonist. Observational data from breast cancer studies associate tamoxifen use with lesser rates of myocardial infarction. The authors sought to determine the acute vasoactive properties of tamoxifen compared with estradiol. Isolated coronary ring segments from female pigs were studied in organ baths. KCl-precontracted ring segments were exposed to increasing doses of both tamoxifen and estradiol (log-9-log-5 M ). Ring segments were also exposed to tamoxifen and estradiol in the presence of inhibitors of nitric oxide, glybenclamide, the hormone receptor antagonists ICI 182,780 and flutamide, and after de-endothelialization. Tamoxifen caused acute dilation of coronary arteries but less than estradiol. Tamoxifen-and estradiol-induced acute vasodilation was not nitric oxide- or endothelium-dependent, but was adenosine triphosphate-sensitive potassium channel-dependent. Tamoxifen-induced vasorelaxation was inhibited by antagonism of the classic estrogen receptor and antagonism of the androgen receptor with flutamide, whereas estrogen-induced vasorelaxation was inhibited partially by classic estrogen receptor antagonism but not by androgen receptor antagonism. Tamoxifen attenuated both the sensitivity of vasoconstriction to endothelin-1 and the maximal response. Tamoxifen and estradiol are both acute coronary vasodilators, with similar mechanisms of action. Tamoxifen also attenuates coronary vasoconstriction. Such properties may account for some of the observed cardiovascular clinical benefits seen in observational studies of tamoxifen use. PMID- 11602813 TI - Acute hemodynamic effects of beta-blockers in patients with severe congestive heart failure: comparison of celiprolol and esmolol. AB - The present study was designed to investigate, in patients with severe heart failure, the dose-dependent acute hemodynamic effects of celiprolol versus those of esmolol. Celiprolol is a beta 1 -receptor blocker with vasodilating properties, whereas esmolol is an ultra-short-acting beta 1 -blocker. Included were 14 patients with decompensated chronic heart failure (NYHA class IV) due to coronary heart disease (n = 8) or to dilated cardiomyopathy (n = 6). Each patient received both celiprolol and esmolol in random fashion. The beta-blockers were administered in four dose tiers, with an increase in dosage every 15 min. Hemodynamic measurements were obtained with a Swan-Ganz thermodilution catheter. Administration of celiprolol (5, 10, 20, and 50 microg/kg) took place intravenously. After intravenous administration of a loading dose of 500 microg/kg, we continuously infused esmolol at increasing doses, which were individually titrated for each patient. Mean infusion rates of esmolol were as follows: 40, 75, 140, and 230 micromol/kg per minute. Celiprolol and esmolol induced a comparable dose-dependent decrease in heart rate to a minimum of -10% below baseline. Esmolol caused a significant dose-dependent decrease (-25% below baseline at the highest dose level) in cardiac index (CI). After administration of celiprolol, CI decreased only transiently (-10% below baseline at the second and third dose level) and did not differ from the baseline at the highest dose level. For treatment of severe heart failure, initiation of intravenous beta blocker therapy with low doses of a beta 1 -blocker with vasodilating effects may have hemodynamic advantages over conventional beta-blockade. PMID- 11602814 TI - Inhibitory effect of telmisartan on the blood pressure response to angiotensin II challenge. AB - Telmisartan is a new angiotensin receptor antagonist possessing potent, selective, and insurmountable inhibitory activity specific to the angiotensin II type 1 (AT 1 ) receptor. The current study was performed to determine the inhibition of the angiotensin II pressor response by telmisartan in 48 healthy volunteers challenged with hypertension-inducing doses of i.v. angiotensin II. Subjects were challenged with this dose of angiotensin II at intervals between 0.25 and 48 h after double-blind single-dose oral administration of telmisartan 20 mg (n = 12), 40 mg (n = 12), or 80 mg (n = 12) or placebo (n = 12) in parallel groups. Diastolic and systolic blood pressure and pulse rate were recorded continuously using a servophotoplethysmograph. Urine samples were collected during the study for urinalysis. Tolerability of telmisartan, in comparison with placebo, was also monitored throughout the study. Telmisartan 20-80 mg dose dependently inhibited the increase in diastolic and systolic blood pressure induced by angiotensin II. Telmisartan 40 mg produced 80.1% maximum inhibition, and with 80 mg 89.6% maximum inhibition of diastolic blood pressure was achieved. Inhibition was apparent after 0.3-1.1 h and was still observed 48 h after administration for all telmisartan doses. The inhibitory effect of telmisartan 20, 40, and 80 mg, 48 h after dosing was significantly greater than that of placebo. A > 25% inhibition of the angiotensin II response on diastolic blood pressure was detected until 26.9, 35.4, and 40.5 h, respectively, after telmisartan 20 mg, 40 mg, and 80 mg. Anti-clockwise hysteresis was observed, indicating a delay and longer persistence of effect than to be expected from the plasma concentration-time course. The slow dissociation of telmisartan from the receptor probably contributed to this hysteresis. The incidence of adverse events was comparable in telmisartan-and placebo-treated subjects and was not dose dependent. In conclusion, telmisartan 40 mg provides rapid-onset, well-tolerated, and near-maximal inhibition of angiotensin II-induced hypertension, with maintenance of the inhibitory effect for 48 h. PMID- 11602815 TI - Inhibitory effect of prostaglandin E 1 on intimal thickening caused by poor runoff conditions in the canine autologous vein grafts. AB - The efficacy of ONO-1608, a newly developed liposomal formulation of prostaglandin E 1 prodrug, was evaluated on intimal hyperplasia of experimental canine autologous vein grafts under distal poor runoff conditions. The femoral vein was implanted into the femoral artery, preparing a distal poor runoff canine model. After 4 weeks of preparing the poor runoff model, the femoral vein was implanted into the femoral artery. They were then divided into two groups consisting of the control group and the ONO-1608 group. At 4 weeks, the grafts were harvested and intimal hyperplasia of the graft was measured with an ocular cytometer. Intimal cell proliferation was determined by bromodeoxyuridine incorporation 2 weeks after surgery. In addition, the effect of ONO-1608 on the proliferation of platelet-derived growth factor (PDGF)-stimulated human aortic smooth muscle cells (HASMCs) in culture was also investigated. At 4 weeks, the degree of intimal hyperplasia of the graft in the ONO-1608 group was significantly less than that of the control group. The bromodeoxyuridine labeling index 2 weeks after grafting was significantly lower in the ONO-1608 group compared with that in the control group. In addition, ONO-1608 significantly inhibited the proliferation of PDGF-stimulated HASMCs in culture. These results demonstrate the efficacy of ONO-1608 in reducing the degree of intimal hyperplasia of canine autogenous vein grafts under poor runoff conditions. The mechanism of reducing the intimal hyperplasia may be that ONO-1608 inhibited PDGF stimulated proliferation of the smooth muscle cell. These results suggest that the administration of ONO-1608 may be beneficial in patients who have undergone gone arterial reconstruction. PMID- 11602816 TI - Central and peripheral effects of angiotensin II on the cardiovascular response to exercise. AB - The authors tested the hypothesis that angiotensin II modulates cardiovascular responses to dynamic exercise via peripheral and central effects on the autonomic nervous system. Ten subjects performed three identical exercise tests during treatment with placebo, valsartan (an angiotensin II type 1 receptor blocker), or enalapril (an angiotensin-converting enzyme inhibitor). With placebo, plasma concentrations of angiotensin II, norepinephrine, and epinephrine were elevated during cycling at 80% of heart rate reserve (HRR). Enalapril attenuated increases in heart rate, mean arterial pressure (MAP), and catecholamines during cycling, whereas valsartan only attenuated MAP and rate-pressure product above 60% HRR, and norepinephrine. The different responses provoked by the two drug treatments suggest that angiotensin-converting enzyme inhibition affects cardiovascular responses to exercise by mechanisms unrelated to production of angiotensin II. Indices of autonomic function during dynamic exercise were not changed by either drug. Attenuation of norepinephrine release during exercise by valsartan suggests that angiotensin II facilitates the release of norepinephrine from sympathetic postganglionic neurons. Angiotensin II, therefore, contributes to the pressor response to exercise by inducing peripheral vasoconstriction and facilitation of norepinephrine release from postganglionic sympathetic nerve endings that are unrelated to central activation of the autonomic nervous system. PMID- 11602817 TI - Effects of E047/1, a new antiarrhythmic drug, on experimental atrial fibrillation in anesthetized dogs. AB - Effects of a new antiarrhythmic drug, E047/1, on atrial fibrillation were studied. Atrial conduction velocity and effective refractory period (ERP), electrocardiogram parameters (RR, PR, QRS, QT, and QTc intervals), systolic and diastolic blood pressure, and plasma concentrations of E047/1 were determined during the first 30 min after sequential administration of 1, 3, and 6 mg/kg of E047/1 in polysorbate 60 (Tween 60) to anesthetized, opened-chest dogs with vagally induced atrial fibrillation. Epicardial mapping (using 224 unipolar electrodes) was used to determine atrial fibrillation cycle length and activation sequence before and after drug administration. E0471, 3 mg/kg, prevented atrial fibrillation reinduction, and 6 mg/kg terminated atrial fibrillation. E047/1, 6 mg/kg, increased atrial ERP from 124 +/- 9 to 168 +/- 14 ms (p < 0.05). Conduction velocity decreased from 103 +/- 4 cm/s to 87 +/- 3 cm/s (p < 0.05). Epicardial mapping showed that under drug influence there was gradual reduction of wavelet number until termination of the reentrant excitation. Atrial fibrillation cycle length increased before atrial fibrillation termination from 93 +/- 4 to 137 +/- 12 ms (p < 0.05). The ability of E047/1 to terminate and prevent reinduction of experimental atrial fibrillation appears associated more with a significant prolongation of the atrial ERP than with a slowing of conduction. E047/1 appears to be a promising antifibrillatory agent. PMID- 11602818 TI - Losartan inhibits the angiotensin II-induced modifications on fibrinolysis and matrix deposition by primary human vascular smooth muscle cells. AB - Disorders in the fibrinolytic and renin-angiotensin-aldosterone systems and excessive extracellular matrix (ECM) deposition are determinant factors in several pathologic manifestations of vascular and cardiac tissue. We used primary human vascular smooth muscle cells (VSMC) and studied the effects of losartan on angiotensin II (Ang II)-mediated (a) DNA synthesis, (b) secretion of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), (c) secretion of matrix metalloprotease-2 (MMP-2) activity and tissue inhibitors of MMPs (TIMPs), and (d) synthesis of glycosaminoglycans. VSMC cultures, established from human pulmonary arteries, were treated with Ang II (0.1 nM -1 microM ) and/or losartan (0.1-10 microM ), for 24 or 48 h. DNA synthesis was assessed by incorporation of 3 H-thymidine into VSMC, secreted tPA, PAI-1, and TIMPs by enzyme-linked immunosorbent assay, MMP-2 activity by gelatin zymography, and glycosaminoglycan synthesis by 3 H-glucosamine incorporation. Ang II (1 microM ) enhanced DNA synthesis and secretion of PAI-1 and glycosaminoglycans and decreased secretion of MMP-2 activity and tPA, whereas it had no effect on secretion of TIMPs and glycosaminoglycans associated with cell layers. The Ang II mediated effects were reversed by losartan, in a concentration-dependent manner. Losartan alone increased secretion of tPA, MMP-2 activity, and TIMPs and decreased secretion of PAI-1. These results indicate that AT 1 receptors are implicated in Ang II-mediated disorders of fibrinolysis and excessive ECM deposition by VSMC. PMID- 11602819 TI - Effects of angiotensin II type 1 receptor antagonist (candesartan) in preventing fatal ventricular arrhythmias in dogs during acute myocardial ischemia and reperfusion. AB - Fatal arrhythmias may be prevented by long-term oral administration of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 (AT 1 ) receptor antagonists. However, there have been no studies evaluating the electrophysiologic changes that occur with the acute administration of AT 1 receptor antagonists during acute myocardial ischemia and reperfusion. This study aimed to evaluate the ability of candesartan to prevent fatal arrhythmias during acute myocardial ischemia and reperfusion. The left anterior descending (LAD) coronary artery was ligated for 10 min and then reperfused for 10 min in 45 adult mongrel dogs. Candesartan (1 mg/kg) or saline was administered intravenously 10 min before ligation of the LAD coronary artery (candesartan group [n = 20] and control group [n = 25], respectively). Changes in ventricular effective refractory period (ERP) and intramyocardial conduction time (ICT) in the risk area were compared during LAD occlusion and reperfusion. Ischemia-induced shortening of ERP was inhibited in the candesartan group compared with the control. There was a 4.7 +/- 5.8% increase in ERP in the candesartan group, compared with a 11.5 +/- 6.3% shortening in the control group (p < 0.01). Prolongation of ICT was inhibited in the candesartan group compared with the control group during both ischemia and reperfusion (maximal prolongation of ICT: 0.1 +/- 3.0% vs. 37.7 +/- 9.6%, respectively; p < 0.01). Incidence of ventricular fibrillation was lower in the candesartan group than in the control group (25% [5/20] vs. 72% [18/25], respectively; p < 0.01). Candesartan suppresses changes in ERP and ICT during acute myocardial ischemia and reperfusion, suggesting that candesartan can prevent the development of fatal arrhythmias. PMID- 11602820 TI - Drug block of I(kr): model systems and relevance to human arrhythmias. AB - The long QT-related arrhythmia torsades de pointes (TdP) can arise with mutations in HERG and during treatment with drugs that block cardiac I Kr, the current encoded by HERG. Multiple test systems have been used to assess drug block of I Kr. This study evaluated the I Kr blocking potency of a series of antiarrhythmics associated with a range of clinical risks of TdP in two such systems: mouse AT-1 cells (in which I Kr is the major repolarizing current) and Ltk cells transiently transfected with HERG (n = 4-10 cells per drug). For each compound, the concentration required to produce 50% block of I Kr or HERG tail currents (IC 50 ) was determined. There was an excellent correlation ( r = 0.98, p < 10 -5 ) between values obtained in the two systems. However, the relation between the liability of a drug to cause TdP appeared dissociated from I Kr blocking potency. Quinidine, dofetilide, ibutilide, procainamide, and disopyramide are all associated with TdP, but only the first three were potent blockers (IC 50 < or = 1 microM ), whereas procainamide and disopyramide were not (IC 50 > 50 microM ). Conversely, verapamil and amiodarone, drugs not associated with TdP, were also blockers (IC 50 < or = 1 microM ). We conclude that I Kr blocking potency can be readily assessed in either AT-1 cells or systems in which HERG is heterologously expressed. However, not all drugs causing TdP are potent I Kr blockers, and I Kr block is not necessarily associated with TdP. Other properties of these drugs, therefore, contribute to their propensity to cause TdP. PMID- 11602821 TI - Scavenger effect of experimental and clinically used cardiovascular drugs. AB - Oxygen free radicals play an important role in several physiologic and pathophysiologic processes. In pathophysiologic circumstances they can modify and damage biologic systems. Their functional properties (exposed to high oxygen tension) place red blood cells among the most susceptible cells to the harmful effect of free radicals. Because oxygen free radicals are involved in a wide range of diseases, scavenging these radicals should be an important therapeutic approach. In this study the antioxidant capacities of experimental and clinically used cardiovascular drugs were investigated. Phenazine methosulfate was used to generate free radicals and thus harden red blood cells. Filtration technique and potassium leaking were used to detect the scavenging effect of the examined drugs. The experimental drug H-2545 provided 43% protection against phenazine methosulfate-induced changes in red blood cell filterability (p < 0.001). Although some of the examined, clinically used cardiovascular drugs (carvedilol, metoprolol, verapamil, trimetazidine) also showed significant (p < 0.05) antioxidant effect, they were less efficient than H-2545. The scavenger effect of this novel drug exceeded the antioxidant properties of vitamin E. Modification of mexiletine with a pyrroline ring significantly improved its antioxidant capacity, suggesting that this molecular segment is responsible for the antioxidant effect. PMID- 11602822 TI - Testosterone facilitates the baroreceptor control of reflex bradycardia: role of cardiac sympathetic and parasympathetic components. AB - Reported clinical and experimental findings have shown that baroreflex control of heart rate is attenuated in women compared with men. This study investigated whether the sexual dimorphism in baroreflex function relates to the ability of the male hormone testosterone to facilitate baroreflex responsiveness. Relative contributions of the vagal and sympathetic autonomic components to testosterone modulation of baroreflex function were also investigated. Baroreflex curves relating changes in heart rate to increases or decreases in blood pressure evoked by phenylephrine and sodium nitroprusside, respectively, were constructed in sham operated rats and castrated rats with and without testosterone replacement. Slope of the curves was taken as an index of baroreflex sensitivity (BRS PE and BRS NP ). Castration (for 10 days) significantly reduced plasma testosterone levels and attenuated reflex bradycardia, as indicated by significantly smaller BRS PE in castrated rats compared with values in sham-operated rats (-0.85 +/- 0.07 vs. 1.51 +/- 0.10 beats/min per mm Hg). Testosterone replacement in castrated rats restored plasma testosterone and BRS PE to levels similar to those of sham operated rats. Muscarinic blockade by atropine caused 55% reduction in BRS PE in sham-operated rats, an effect that was significantly (p < 0.05) attenuated in castrated rats and restored to intact levels after testosterone supplementation. beta-Adrenergic blockade by propranolol caused slight and insignificant decreases in BRS PE. Castration and testosterone supplementation had no effect on BRS NP, ruling out a modulatory effect of testosterone on reflex tachycardia. These data provide the first experimental evidence of a favorable role for testosterone in baroreceptor control of reflex bradycardia. Further, baroreflex modulation by testosterone appears to be autonomically mediated and involves an enhancement of cardiomotor vagal activity. PMID- 11602823 TI - Evidence of an altered in vivo vascular cell turnover in spontaneously hypertensive rats and its modulation by long-term antihypertensive treatment. AB - The aims of this study were to measure in vivo cell turnover in the thoracic aorta from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and to investigate how it could be modulated by chronic antihypertensive treatment. Cell turnover was estimated in rats in which DNA had been prelabeled in utero with [ 3 H]-thymidine, by the rate of disappearance of total [ 3 H]-DNA from birth to 20 weeks of age. In SHR compared with WKY, neonatal relative aortic mass was transiently elevated and was reversed to hypotrophy at 8 weeks. At 20 weeks of age, aortic hypertrophy reappeared. Aortic DNA content reflected the morphologic changes observed with age. In both SHR and WKY, the decline with time in [ 3 H]-prelabeled aortic DNA coupled with the increase in total organ DNA demonstrated that cells prelabeled in utero died and were replaced. Decline in [ 3 H]-DNA from birth to 8 weeks of age was approximately threefold faster in the aorta from SHR than in WKY. In older SHR, the decrease in [ 3 H]-DNA was then slower and similar to that of WKY. Chronic treatment of SHR for 15 weeks from the age of 5 weeks, with hydralazine, enalapril, or nifedipine prevented the rise in systolic blood pressure, aortic mass, and DNA content. This was associated with an unchanged residual radioactivity of [ 3 H]-prelabeled aortic DNA over time, suggesting that the treatment did not stimulate cumulative cell death. We propose that the altered cell turnover is a component of aortic remodeling observed in hypertension. Our data also suggest that it is possible to modulate in vivo cell turnover and affect vascular remodeling by pharmacologic therapy. PMID- 11602824 TI - Interplay between inhibition of adenosine uptake and phosphodiesterase type 3 on cardiac function by cilostazol, an agent to treat intermittent claudication. AB - The authors have recently shown that cilostazol, a type 3 cyclic nucleotide phosphodiesterase (PDE3) inhibitor, has a much weaker positive inotropic effect than milrinone, a PDE3 inhibitor of similar potency. They have also shown that cilostazol inhibits adenosine uptake, whereas milrinone has no such effect. This study investigated the possible cardiac functional significance of cilostazol on adenosine uptake inhibition. In isolated rabbit hearts, 10 microM of cilostazol elevated adenosine concentration in interstitial dialysate (0.16 +/- 0.01 microM, or approximately 0.81 microM in the interstitial space when adjusted for recovery rate of microdialysis) and coronary effluent (0.69 +/- 0.03 microM ). The values are significantly higher than those for 10 microM of milrinone (0.11 +/- 0.1 microM in interstitial dialysate and 0.2 +/- 0.04 microM in coronary effluent). Although cilostazol increased contractility, heart rate, and coronary flow in isolated rabbit hearts, the effect on contractility and heart rate was significantly augmented in the presence of an adenosine A 1 receptor antagonist. Conversely, an adenosine A 1 receptor agonist or an adenosine uptake inhibitor attenuated the positive inotropic effect of milrinone. These results indicate that adenosine uptake inhibition by cilostazol increases interstitial and circulatory adenosine concentration, and antagonizes PDE3 inhibition-induced contractility and heart rate increases through an adenosine A 1 receptor-mediated mechanism. PMID- 11602825 TI - Endothelin-1-induced elevation in blood pressure is independent of increases in sympathetic nerve activity in normotensive rats. AB - This study was performed to determine if endothelin-1 (ET-1)-induced pressor responses in urethane-anesthetized, normotensive rats are due to increased sympathetic nerve activity. Renal sympathetic nerve activity (RSNA) was used as an index of sympathetic nerve activity. ET-1 (30- 1000 pmol/kg) or sarafotoxin (S6c, ET B receptor agonist, 10-3,000 nmol/kg) given by bolus injection produced transient decreases in mean arterial pressure (MAP) and increases in RSNA and heart rate (HR). ET-1 caused a delayed but sustained increase in MAP that was not inhibited by acute sinoaortic denervation or alpha 1 -adrenergic receptor blockade. ET-1 never caused a sustained change in HR or RSNA. A-192621 (ET B receptor antagonist, 12 mg/kg) increased MAP (10-20 mm Hg) and decreased HR and RSNA. A-192621 blocked the transient decrease in MAP and increase in RSNA and HR caused by ET-1 and S6c. In A-192621-treated rats, ET-1, but not S6c, caused a sustained increase in MAP and decrease in HR and RSNA. After A-192621 treatment, ET-1 infusion caused a sustained elevation in MAP; HR and RSNA decreased only after the highest ET-1 dose. These results indicate that the initial increase in RSNA after ET-1 or S6c is secondary to ET B receptor-mediated vasodilation. Increased RSNA does not contribute to ET-1-induced pressor responses; these responses are likely due to vasoconstriction in normotensive, anesthetized rats. Finally, baroreceptor reflexes function after ET-1 or S6c treatment. PMID- 11602826 TI - Endothelial adrenoceptors. AB - alpha2 -Adrenergic agonists cause endothelium-dependent relaxation in a number of isolated blood vessels. This effect is explained by the activation of endothelial alpha 2 -adrenoceptors linked to nitric oxide synthase by G i -coupling proteins. The endothelial response to alpha 2 -adrenergic agonists is blunted considerably after regeneration of the endothelium and in atherosclerotic arteries. The relaxation of isolated arteries caused by beta-adrenergic agonists is reduced by removal of the endothelium and, in most cases, by inhibitors of the l -arginine nitric oxide pathway. Likewise, in the intact animal and in the human forearm the vasodilatation to beta 2 -adrenergic agonists is blunted by inhibitors of nitric oxide synthase. Whether these findings reflect the presence of functional beta adrenoceptors on the endothelium remains controversial. Several beta-adrenergic blockers cause endothelium-dependent relaxation in vitro or augment the production of nitric oxide in vivo. However, these responses cannot be attributed to interactions with endothelial beta-adrenoceptors. PMID- 11602827 TI - OTA Presidential Address. Minding the store: practice management metrics for physician managers. PMID- 11602828 TI - Control of severe hemorrhage using C-clamp and pelvic packing in multiply injured patients with pelvic ring disruption. AB - OBJECTIVES: Evaluation of diagnostic and therapeutic workup in multiply injured patients with pelvic ring disruption and hemorrhagic shock. DESIGN: Prospective study. PATIENTS: Twenty consecutive multiply injured patients (ISS: 41.2 +/- 15.3 points) with pelvic ring disruption and hemorrhagic shock. INTERVENTION: A C clamp was used for primary stabilization of the pelvic ring instability. In patients with persistent or massive hemorrhage, laparotomy and pelvic packing were performed. Consecutive measurements of blood lactate levels during the early period after injury. MAIN OUTCOME MEASUREMENTS: Lactate, mortality. RESULTS: A C clamp was applied in all patients within 57.4 +/- 30.6 minutes of arrival. Fourteen patients underwent laparotomy with pelvic packing for control of hemorrhage, three patients additional resuscitation thoracotomy (aortic clamping: n = 2). Four patients died of exsanguinating hemorrhage during the first 5.4 +/- 3.3 hours from arrival, one patient because of septic multi-organ failure twenty three days after injury (total mortality: 5/20; 25 percent). Lactate levels at admission were elevated in all patients (5.1 +/- 2.6 mmol/l). Increased blood lactate levels (4.8 +/- 1.7 mmol/l) (+71 percent; p < 0.05) were observed in survivors undergoing laparotomy compared with survivors without laparotomy (2.8 +/- 1.1 mmol/l). In contrast, hemoglobin (7.0 +/- 2.6 g/dl versus 7.9 +/- 2.2 g/dl) and hematocrit (21.4 +/- 6.4 percent versus 23.2 +/- 6.8 percent) were similar in both groups. In patients who died during the first hours after admission, lactate levels were elevated (8.6 +/- 2.5 mmol/l) compared with survivors (4.2 +/- 1.8 mmol/l) and increased further. CONCLUSIONS: Sequential measurements of blood lactate levels during the early period after injury may provide a more rapid and reliable estimation of true severity of hemorrhage than routinely used parameters. Pelvic packing in addition to pelvic ring fixation with a C-clamp allows for effective control of severe hemorrhage in multiply injured patients with pelvic ring disruption. PMID- 11602829 TI - Anterior femoroacetabular impingement after femoral neck fractures. AB - OBJECTIVES: To verify whether anterior femoroacetabular impingement can be a reason for hip pain and loss of motion in patients with a healed femoral neck fracture. DESIGN: Retrospective clinical, radiologic, and surgical evaluation. SETTING: Third referral hospital. PATIENTS: Nine patients who previously sustained a femoral neck fracture were treated between 1995 and 1999 for hip pain and loss of motion. All these mostly young patients (mean age 33.3 years) complained of groin pain. During the physical examination, acute pain could be elicited by passively forcing the femoral neck against the acetabular rim in flexion, adduction, and internal rotation, motions that were all limited. METHODS: Conventional radiographs and, if possible, arthrographic magnetic resonance imaging scans were followed by a surgical subluxation or dislocation of the femoral head to analyze the sequelae of anterior femoroacetabular impingement. Treatment was based on improvement of the anterior offset (the difference between the anterior contour of the head and the femoral neck) or intertrochanteric osteotomy to ameliorate clearance of the joint. RESULTS: Intraoperatively in eight patients (one not operated), impingement was found to result from insufficient reduction of the fracture, already visible on the conventional radiographs. Retrotorsion (mean 20 degrees) of the head caused anterior impingement in all patients, additional varus position (mean caput collum diaphysis angle 115 degrees) of the head caused anterolateral impingement in two patients. In all patients, anterior labral and adjacent acetabular cartilage lesions were found during surgical subluxation or dislocation of the femoral head, comparable to those seen on the magnetic resonance imaging scan. They proved to result from repetitive abutment and compression between the head neck junction and the acetabulum. CONCLUSION: Femoroacetabular impingement can be a cause for hip pain and loss of motion in patients who previously sustained a femoral neck fracture. The condition causes degenerative anterior labral and adjacent acetabular cartilage lesions. Early treatment is essential to prevent further degeneration and osteoarthrosis of the joint. Prevention is predicated by initial precise anatomic reduction of such fractures in all planes. PMID- 11602830 TI - Biomechanical evaluation of the less invasive stabilization system for the internal fixation of distal femur fractures. AB - OBJECTIVE: Comparison between a Less Invasive Stabilization System (LISS) using monocortical screws with angular stability and two conventional plate systems Condylar Buttress Plate (CBP) and Dynamic Condylar Screw (DCS) for the treatment of distal femoral fractures with respect to biomechanical properties. DESIGN: Biomechanical study using paired cadaver femurs. In Test Configuration 1 (distal test), a ten-millimeter gap at the diaphysis-metaphysis junction simulates a supracondylar femoral fracture. Test Configuration 2 (proximal test) has the same configuration, but the gap was cut in the isthmic region. Proximal and distal plate ends were fixed to corresponding cortical bone fragments in both tests. Optical displacement transducers served to quantify the system's ability to withstand a stepwise increased load. Reversible (deflection) and irreversible deformation (subsidence) of the bone-plate construct was investigated. RESULTS: In Test Configuration 1, LISS showed less irreversible deformation in 72 percent of the left-right comparisons. No correlation between bone mineral density, cross section area of bones and the measured response of the construct under load was found between pairs. In Test Configuration 2, 83 percent of the left-right comparisons showed less permanent deformation but a higher elastic deformation for LISS. CONCLUSIONS: These results suggest an enhanced ability to withstand high loads when using the monocortical screw fixation technique with angular stability. A higher elastic deformation of LISS compared with conventional plating systems in distal femoral fractures can be explained by the lower bending stiffness caused by different design and material properties. PMID- 11602831 TI - Entry point soft tissue damage in antegrade femoral nailing: a cadaver study. AB - INTRODUCTION: Little attention is paid to insertion site morbidity associated with antegrade femoral nailing. However, residual peritrochanteric pain after nailing is not uncommon. Additionally, the end branches of the medial femoral circumflex artery (m.f.c.a.) supplying the femoral head are in close proximity to the insertion site of the nail, and the occurrence of avascular necrosis of the femoral epiphysis after nailing in adolescents is rather frequent. OBJECTIVE: The aim of this study was to assess iatrogenic soft tissue injuries at the site of nail insertion. MATERIALS AND METHODS: Nailing with a reamed AO universal femoral nail was performed on sixteen adult cadavers followed by dissection of the proximal part of the femur to assess possible damage to the soft tissues. Three entry portals were defined. (A) entry portal lateral to the junction of the neck and the greater trochanter; (B) entry portal at the base of the greater trochanter anterior to a line along the longitudinal axis of the femoral neck; and (C) entry portal at the base of the greater trochanter posterior to a line along the axis of the femoral neck (at the piriformis fossa). RESULTS: In Group A, partial avulsion of the piriformis and the obturator internus tendon were present in four and in one of five specimens, respectively. Group B showed injuries to the piriformis tendon in two and to the gluteus minimus tendon in one of four cases. In Group C, partial avulsion of the piriformis, obturator internus, and obturator externus tendon were encountered in five, six, and two of seven specimens, respectively. Anterior branches of the ramus profundus of the m.f.c.a. within the synovial fold were damaged in all of these cases. CONCLUSION: To select the best nail entry portal, the ease of nail insertion must be weighed against the resulting soft tissue damage at the site of insertion. The nail entry portal at the piriformis fossa, although geometrically ideal and most recommended, causes the most significant damage to muscle and tendons as well as to the blood supply to the femoral head. Therefore, even if reported only once, the occurrence of avascular necrosis of the femoral head after nailing in adults is a possible complication of this nail entry portal. The authors therefore prefer to avoid this entry portal in every case. The nail entry portal anterior to the longitudinal axis of the femoral neck, as in group B, although better with respect to the soft tissue damage, has the worst geometric and biomechanical disadvantages. The results of the current study favor the nail entry portal lateral at the greater trochanter as in Group A, which is equal to the entry portal B with respect to the soft tissue damage but allows introduction of the nail into the medullar cavity without difficulties. PMID- 11602832 TI - A fatigue life analysis of small fragment screws. AB - OBJECTIVES: To conduct a comparative fatigue analysis of several commonly used small fragment screws. DESIGN: Biomechanical laboratory study. SETTING: Research laboratory. MAIN OUTCOME MEASUREMENTS: A fatigue life analysis of seven different types of small fragment screws was conducted using a Wohler fatigue-testing machine. Four different types of 3.5-millimeter cortical screws were subjected to fatigue analysis. These included solid stainless steel screws from Synthes Ltd. (core diameter 2.4 millimeters), Zimmer Inc. (core diameter 2.4 millimeter), and Smith and Nephew Richards Inc. (core diameter 2.4 millimeters) and cannulated stainless steel screws from Synthes Ltd. (core diameter 2.5 millimeters). In addition, three types of 4.0-millimeter cancellous screws were tested. These included stainless steel screws from Synthes Ltd. (core diameter 1.9 millimeters), titanium screws from Synthes Ltd. (core diameter 2.0 millimeters), and titanium alloy screws from DePuy-Ace (core diameter 2.8 millimeters). Fatigue lives, as reflected by mean cycles to failure, were compared. RESULTS: The four types of cortical screws had longer fatigue lives than the Synthes cancellous screws did ( p < 0.001) but shorter fatigue lives than the DePuy-Ace cancellous screws did ( p < 0.0001). Among the cortical screws, the cannulated and solid Synthes screws and the solid Zimmer screws did not differ statistically. The Smith and Nephew Richards cortical screws failed at statistically fewer cycles than the Synthes solid and cannulated cortical screws did ( p < 0.003) but did not statistically differ from the Zimmer screws. The DePuy-Ace titanium alloy cancellous screw had the longest fatigue life of the tested implants by a large margin ( p < 0.0001). The Synthes pure titanium and stainless steel cancellous screws did not significantly differ. CONCLUSIONS: This analysis supports core diameter as the principal factor determining fatigue life as the results paralleled implant geometry. This design modification to improve bending and fatigue strength may come at a price to pullout strength, however, because of a decreased major-to-minor diameter and increased pitch. Cortical screws differed in fatigue performance despite identical dimensions, presumably highlighting the importance of implant processing and machining. Cannulated cortical screws performed well relative to solid screws, thereby supporting their clinical use. Pure titanium and stainless steel cancellous screws performed similarly in fatigue despite differing material properties, presumably because of geometric design differences. This report highlights some of the differences in the in vitro fatigue performance among several commonly used small fragment screws. PMID- 11602833 TI - Anterior iliac crest bone graft harvesting using the corticocancellous reamer system. AB - OBJECTIVE: To evaluate the anterior iliac crest bone graft harvesting procedure using a corticocancellous acetabular reamer system. DESIGN: A total of 390 bone grafting procedures were reviewed using retrospective chart review. Two hundred twenty procedures were performed using the reamer system, and 170 were performed using traditional techniques (cortical strip, tricortical wedge, and cancellous trap door grafts). SETTING: The Hospital for Special Surgery, New York, New York. PARTICIPANTS: Operative cases involving an anterior iliac crest bone graft procedure between January 1, 1991 and February 28, 1998. MAIN OUTCOME MEASUREMENTS: Complications were organized by the categories major, intermediate, and minor. Statistical analysis included assessment of comorbidity to determine risk factors that may be associated with a propensity for complications. RESULTS: Of the 390 patients reviewed, 13.1 percent (51 of 390) developed a total of seventy-one complications. Of the seventy-one complications, forty were reamer associated and thirty-one were traditional method-associated complications. As compared with the traditional group, major morbidity was lower in the reamer group (0.9 percent [2 of 220] as compared with 1.8 percent [3 of 170] [ p = 0.4]). Intermediate and minor morbidity were slightly higher in the reamer group than in the traditional group (5.9 percent [13 of 220] as compared with 5.3 percent [9 of 170] [ p = 0.7] and 9.5 percent [21 of 220] as compared with 7.1 percent [12 of 170] [ p = 0.4], respectively). Of the forty reamer-associated complications, 90 percent (36 of 40) resolved within ninety days (average 36.6 days). Of the thirty-one traditional method-associated complications, 74.2 percent (23 of 31) were resolved by 90 days (average 50.6 days). Using logistical regression analysis obesity (body mass index) ( p = 0.03) and smoking ( p = 0.03) were correlated with development of a complication. Furthermore, if a patient was obese and a smoker, the analysis predicted an 83 percent chance of developing a complication. CONCLUSIONS: The reamer technique was found to be safe and efficacious while producing a large amount of autogenous corticocancellous bone graft. Overall complication rates for the reamer and the traditional groups were comparable. The corticocancellous reamer system represents an effective option for bone graft harvesting. PMID- 11602834 TI - Cortex distraction forces caused by the insertion of external fixator pins. AB - OBJECTIVE: Insertion of a bicortical threaded external fixator pin can cause bone damage. An unexpected crack can propagate along the bone when the pin touches the far cortex. The objective of this study was to investigate whether drilling and inserting bicortical pins into the shafts of long bones can cause large distraction forces to be generated between the cortices. DESIGN: Two flat samples of bone or bone substitute (Tufnol) were mounted parallel at each end of a specially designed force measurement column. Three common pin designs were inserted into the samples: tapered, self-threading and self-drilling, and self threading pins. The axial thrust and the cortex distraction force between the two samples were measured as the pins were inserted. RESULTS: High distraction forces were measured between the cortices for all pin designs, typically 700 to 1,000 Newtons. CONCLUSIONS: The clinical significance of these findings is that the insertion of bicortical pins of the designs tested may generate a large distraction force between the cortices. This may drive a fracture apart or propagate an undisplaced fracture. Therefore, care must be taken to ensure that bicortical pins are inserted in locations free of local defects. PMID- 11602835 TI - Medial malleolar osteotomy for exposure of complex talar body fractures. AB - Traditional surgical approaches to the talus often fail to afford adequate exposure of the talar body, especially in the case of complex talar body fractures. Preservation of the remaining blood supply to the talus is a main concern during operative repair and can be difficult to accomplish when multiple approaches and forceful manipulations are required to gain satisfactory exposure. A medial malleolar osteotomy was used to gain access to the talar body in situations in which the traditional approaches did not provide adequate exposure. We describe our technique in a small series of patients. PMID- 11602836 TI - Open reduction internal fixation of a pelvic malunion through an anterior approach. AB - Whereas the initial treatment of pelvic fractures and their long-term outcomes have been well researched, little has been written concerning the surgical management of late pelvic malunions and nonunions causing residual pain and deformity. The available literature describes osteotomies usually done in multiple stages. The authors report the case of a progressive lateral compression pelvic disability treated in a unique one-stage procedure. This one-stage anterior approach allowed excellent correction of the deformity. In cases in which the deformity is purely one of internal or external rotation or medial or lateral displacement with no vertical migration, the authors think it is possible to adequately mobilize the pelvis to an anatomic reduction in a single-stage anterior approach. In cases in which vertical migration of the hemipelvis causes symptoms, it is probably necessary to approach the patient posteriorly to safely mobilize and adequately reduce the hemipelvis. With these factors in mind, the authors think a one-stage anterior approach can be an effective treatment for appropriately selected pelvic malunions. PMID- 11602837 TI - Stress fracture of the ulna associated with crutch use. AB - Stress fractures of the ulna are extremely rare. The purpose of this article is to report one more case of this occurrence in an eleven-year-old girl, who was using adjustable metal crutches, and to discuss the possible cause. PMID- 11602838 TI - Attitudes of orthopaedic trauma surgeons regarding current controversies in the management of pelvic and acetabular fractures. AB - A closed-ended questionnaire was mailed to all 363 active members of the Orthopaedic Trauma Association. It directed, toward practicing pelvic and acetabular surgeons, questions pertaining to practice demographics and preferred methods for detection and prevention of deep venous thrombosis (DVT), nerve injury, and heterotopic ossification (HO). Questionnaires were received from 226 surgeons (62 percent). Of the surgeons who responded, 181 (80 percent) perform pelvic-fracture and acetabular-fracture surgery; only questionnaires from this group were analyzed. Standard statistical methods were used to perform both univariate and multivariate analyses. Preoperative DVT screening was performed by 48 percent of the surgeons; ultrasound was the most commonly used modality (82 percent). Preoperative DVT prophylaxis was administered by 88 percent of those surveyed; the majority (78 percent) used sequential compression devices. Postoperative prophylaxis was used by 99 percent; the most commonly used modality was sequential compression devices. Analysis suggests that fellowship-trained surgeons and surgeons in practice for fewer than twenty years are more likely to use preoperative DVT prophylaxis. HO prophylaxis was administered by 88 percent; the most commonly used modality was indomethacin. Intraoperative nerve monitoring was performed by only 15 percent of the respondents. Most surgeons employed prophylactic measures to prevent DVT and HO. The wide variation in type of prophylaxis and reasons for use suggests that controversy will continue, and a standard of care for these conditions has yet to be defined. Very few surgeons use intraoperative nerve monitoring routinely. PMID- 11602839 TI - Angular malalignment after intramedullary nailing of the femoral shaft. PMID- 11602840 TI - Rapamycin: clinical results and future opportunities. PMID- 11602841 TI - Chemokines and allograft rejection: narrowing the list of suspects. PMID- 11602842 TI - Beneficial effects of targeting CCR5 in allograft recipients. AB - BACKGROUND: The chemokine receptor, CCR5, and its three high-affinity ligands, macrophage inflammatory protein- (MIP) 1alpha, MIP-1beta, and regulated on activation normal T cell expressed and secreted (RANTES), are expressed by infiltrating mononuclear cells during the rejection of clinical and experimental organ allografts, although the significance of these molecules in the pathogenesis of rejection has not been established. METHODS: We studied intragraft events in four allograft models. First, we studied cardiac transplants in fully MHC-mismatched mice that were deficient in CCR5 or two of its ligands, MIP-1alpha or RANTES. Second we tested the effects of a neutralizing rat anti mCCR5 monoclonal antibody on allograft survival. Third we assessed whether a subtherapeutic course of cyclosporine would potentiate enhance survival in CCR5 deficient recipients. Finally, we tested the effect of targeting CCR5 in a class II-mismatched model. RESULTS: Whereas mice deficient in expression of MIP-1alpha or RANTES reject fully MHC-mismatched cardiac allografts normally, CCR5-/- mice, or CCR5+/+ mice treated with a neutralizing mAb to mCCR5, show enhanced allograft survival. MHC class II-disparate mismatched are permanently accepted in CCR5-/- but not CCR5+/+ recipients. Finally, the beneficial effects of targeting of CCR5 are markedly synergistic with the effects of cyclosporine, resulting in permanent engraftment without development of chronic rejection. CONCLUSIONS: We conclude that CCR5 plays a key role in the mechanisms of host T cell and macrophage recruitment and allograft rejection, such that targeting of CCR5 clinically may be of therapeutic significance. PMID- 11602843 TI - Tissue-specific peptides influence human T cell repertoire to porcine xenoantigens. AB - BACKGROUND: Human CD8+ T cells elicit a vigorous response to allo- or xenogeneic MHC class I molecules. However, the influence of a given MHC-bound peptide to the responding allo- or xenoreactive T cell repertoire is not clear. METHODS: In this study, we analyzed individual T cell responses to unique tissue epitopes presented on syngeneic porcine endothelial and lymphoblastoid cells by limiting dilution analysis and analyzed the responding T cell repertoire by T cell receptor beta (TCR Vbeta) chain spectrotyping. RESULTS: Both porcine endothelial and lymphoblastoid cells were able to elicit swine leukocyte antigen (SLA) class I restricted and peptide-dependent cytotoxic T lymphocyte (CTL) responses. The responding human CD8+ T cells showed a heterogenous but limited TCR Vbeta gene usage. Interestingly, although a large portion of the selected TCR Vbeta gene usage in response to endothelial and lymphoblastoid cells were shared (i.e., Vbeta-1, 2, 6.1, 13), unique Vbeta usage was noted in T cells that respond to either endothelial (Vbeta-5.3) or lymphoblastoid cells (Vbeta-5.1, 11), suggesting that porcine tissue-specific epitopes play a role in modulating the responding T cell repertoire. Limiting dilution cloning analysis revealed that a majority (89%) of the CTL clones stimulated by porcine endothelial cells recognized shared peptides presented by both endothelial cells and syngeneic lymphoblastoid cells. However, a significant portion (11%) of the CTL clones recognized unique peptides presented only in the context of SLA class I molecules on endothelial cells. CONCLUSION: These results provide evidence for the first time that tissue-specific peptides can directly influence T cell repertoire in response to the xenogeneic stimulus. PMID- 11602844 TI - Serum citrulline and rejection in small bowel transplantation: a preliminary report. AB - BACKGROUND: There is no known serum marker for intestinal rejection. Serum concentrations of the amino acid citrulline arise almost exclusively from the intestinal mucosa. We examined the impact of acute cellular rejection (ACR) of intestinal allografts on serum citrulline levels. METHODS: Citrulline concentrations were assayed in serum samples of healthy volunteers (n=6) and seven patients who underwent small bowel transplants (SBTx). Trends in mean citrulline concentrations versus degree of ACR were assessed by matching posttransplantation citrulline concentrations with patients' grade of ACR at time of serum collection. Rejection was confirmed by biopsy and graded by following standardized criteria. An additional patient had citrulline concentrations determined for 31 sequential specimens 3-60 days posttransplant. RESULTS: Mean citrulline concentrations in controls were significantly higher than posttransplantation samples at any rejection grade. Mean concentrations declined significantly as rejection severity increased. The overall downward trend was statistically significant (P<0.05). In sequential measurements, citrulline levels increased significantly over time with declining severity of rejection. The increase in mean citrulline concentration between posttransplant days 3-16 and 52 60 was significant (P<0.01). CONCLUSIONS: Serum citrulline levels decline with increasing grade of ACR and may be a useful serum marker for intestinal rejection. PMID- 11602845 TI - The enhancement of endogenous cAMP with pituitary adenylate cyclase-activating polypeptide protects rat kidney against ischemia through the modulation of inflammatory response. AB - BACKGROUND: Cyclic nucleotide analogue administration improves ischemia reperfusion damage in several organs. The neuropeptide pituitary adenylate cyclase-activating polypeptide, PACAP-38, is a potent stimulus to enhance cellular cAMP levels. This study tested the protective effect of enhancing endogenous cAMP levels by PACAP-38 in a model of warm renal ischemia. METHODS: Sprague-Dawley rats underwent 40 min of bilateral warm renal ischemia. PACAP-38 continuous infusion began either before ischemia or at 6 hr or 18 hr after ischemia. A mini-osmotic pump infused PACAP-38 throughout 7 days of follow-up. Groups were constructed with sham, ischemic control, and dibutyryl cAMP treated animals, and four PACAP-38 treatment groups, using 16 pmol/hr or 160 pmol/hr of the compound, or delaying its administration by 6 hr or 18 hr after ischemia. Renal function was assessed by means of serum creatinine levels on days 1, 2, 3, and 7 after ischemia. Conventional histology was performed on day 7. Renal myeloperoxidase (MPO) activity, infiltrating CD45+ cells, plasma and tissue cAMP, and serum IL-6 were measured. RESULTS: Continuous administration of the high concentration of PACAP-38 ameliorated renal function and morphologic abnormalities induced by warm ischemia. Treatment with dibutyryl cAMP produced morphologic protection but only partial functional effect on the ischemic kidney. A 6-hour delay in the administration of the compound after ischemia offered similar protective effect, whereas an 18-hr delay did not. The neuropeptide clearly increased circulating cAMP after ischemia but not cAMP in renal tissue. PACAP-38 increased circulating IL-6, and minimized renal inflammatory cell infiltration induced by ischemia-reperfusion injury, as evidenced by a reduction of MPO activity and the number of CD45+ cells in ischemic renal tissue. CONCLUSIONS: Enhancement of endogenous circulating cAMP with PACAP-38 modulates postischemic inflammatory response and strongly protects from ischemic acute renal failure, even when administration is delayed for 6 hr after injury. PMID- 11602846 TI - Enhanced CD4 reconstitution by grafting neonatal porcine tissue in alternative locations is associated with donor-specific tolerance and suppression of preexisting xenoreactive T cells. AB - BACKGROUND: Donor-specific xenograft tolerance can be achieved by grafting fetal porcine thymus tissue to thymectomized (ATX) mice treated with natural killer (NK) and T-cell-depleting monoclonal antibodies plus 3 Gy of total body irradiation (TBI). Grafting of neonatal, instead of fetal, thymus, along with neonatal pig spleen, leads to a lower level of mouse CD4 cell reconstitution, with less reliable tolerance induction. For a number of reasons, it would be advantageous to use neonatal rather than fetal pigs as donors. We therefore investigated the possibility that grafting larger amounts of neonatal porcine thymus tissue to different sites could allow improved outcomes to be achieved. MATERIALS AND METHODS: Multiple or single fragments of neonatal porcine thymus tissue were grafted with a splenic fragment to different sites (mediastinum, mesentery, and kidney capsule) of ATX B6 mice treated with T- and NK-cell depleting antibodies and 3Gy TBI. Mice also received an intraperitoneal injection containing 1 x 10(7) donor splenocytes. Donor-specific skin graft tolerance was evaluated, and CD4 reconstitution and mouse anti-donor xenoantibodies were followed by flow cytometry. RESULTS: Peripheral repopulation of CD4+ cells occurred by 7 weeks after transplantation in mice grafted with four fragments of neonatal porcine tissue in either the mediastinum or the mesentery, but not in mice grafted under both kidney capsules with the same amount of tissue. The level of CD4 reconstitution correlated with skin graft tolerance and an absence of induced anti-donor xenoantibodies. Seventy-five percent of mice with >20% of CD4+ cells among peripheral blood lymphocytes (PBL) by 13 weeks posttransplantation accepted donor porcine skin, while rejecting either non-donor neonatal porcine or mouse BALB/c skin allografts. In contrast, only 29% of grafted mice with <20% CD4+ cells in the peripheral blood at 13 weeks accepted donor porcine skin. Grafted mice with poor reconstitution showed either low or high levels of anti pig xenoantibodies of the IgM, IgG1, and IgG2a isotypes. Grafted mice with >20% CD4+ cells all had low levels of anti-pig xenoantibodies of these isotypes and displayed mixed lymphocyte reaction (MLR) tolerance to donor pig major histocompatibility complex (MHC), with responsiveness to allogeneic mouse stimulators. CONCLUSION: Grafting neonatal porcine thymus into either the mediastinum or mesentery provides earlier and more efficient reconstitution of the CD4 compartment than does grafting under the kidney capsule. Good CD4 reconstitution was associated with optimal donor-specific skin graft tolerance and avoidance of the anti-donor xenoantibody responses observed in mice with poor CD4 reconstitution. These results also suggest that there is a suppressive component to the porcine xenograft tolerance induced with this approach. PMID- 11602847 TI - Orthotopic liver transplantation for Wilson's disease: a single-center experience. AB - BACKGROUND: Wilson's disease is an inherited disorder of copper metabolism characterized by reduced biliary copper excretion, which results in copper accumulation in tissues with liver injury and failure. Orthotopic liver transplantation (OLT) can be lifesaving for patients with Wilson's disease who present with fulminant liver failure and for patients unresponsive to medical therapy. The aim of this study is to review our experience with OLT for patients with Wilson's disease. METHODS: Between 1988 and 2000, 21 OLTs were performed in 17 patients with Wilson's disease. Patient demographics, pre-OLT laboratory data, operative data, and early and late postoperative complications were reviewed retrospectively. One-year patient and graft survival was calculated. RESULTS: Eleven patients had fulminant Wilson's disease; in six patients the presentation was chronic. Mean patient age at presentation was 28 years (range 4-51 years); mean follow-up was 5.27 years (range 0.4-11.4 years). Neurologic features of Wilson's disease were not prominent preoperatively and did not develop post-OLT except in one patient who developed acute neuropsychiatric illness and seizure. Renal failure, present in 45% of patients with fulminant Wilson's disease, resolved post-OLT with supportive care. One-year patient and graft survivals were 87.5% and 62.5%, respectively. Fifteen survivors have remained well with normal liver function and no disease recurrence. CONCLUSION: Liver transplantation for hepatic complications of Wilson's disease cures and corrects the underlying metabolic defect and leads to long-term survival in patients who present with either acute or chronic liver disease. Acute renal failure develops frequently in patients with fulminant Wilsonian hepatitis and typically resolves postoperatively. PMID- 11602848 TI - Defibrotide for the treatment of veno-occlusive disease after liver transplantation. AB - BACKGROUND: Veno-occlusive disease (VOD) after liver transplantation is associated with acute rejection and poor outcome. The use of antithrombotic and thrombolytic agents is limited by their toxicity. Defibrotide is a polydeoxyribonucleotide with thrombolytic and antithrombotic properties and no systemic anticoagulant effect. METHODS: Defibrotide, 35-40 mg/kg/day, was administered intravenously for 21 days on a compassionate-use basis to two patients aged 66 and 49 years. VOD had developed 6 weeks and 4 months after orthotopic liver transplantation for hepatitis C and hepatitis B infection, respectively. VOD was diagnosed clinically by findings of weight gain (8.5% and 16%), ascites, jaundice (serum bilirubin 5.4 mg/dl and 21.7 mg/dl), and severe coagulopathy (in one patient), and histologically by the presence of hemorrhagic centrilobular necrosis and fibrous stenosis of the hepatic venules. One of the patients had received azathioprine as part of the immunosuppressive regimen. There was no evidence of acute cellular rejection histologically. RESULTS: After 3 weeks of defibrotide administration, the first patient showed complete clinical resolution of the VOD, and serum bilirubin level normalized. He is alive 6 months after transplantation. The second patient, treated at a later stage of disease, showed marked improvement in the coagulopathic state, but there was no resolution of the VOD. He died 2 months later of multiorgan failure due to Escherichia coli sepsis. Neither patient had side effects from the drug. CONCLUSIONS: Defibrotide is a promising drug for the treatment of VOD after liver transplantation and needs to be evaluated in large, prospective studies. PMID- 11602849 TI - Postmenopausal tubo-ovarian abscess due to Pseudomonas aeruginosa in a renal transplant patient: a case report and review of the literature. AB - BACKGROUND: Pseudomonas aeruginosa is an uncommon cause of infection in the female genital tract. We report a case of postmenopausal tubo-ovarian abscess (TOA) due to P. aeruginosa in a renal transplant recipient. The presentation included mild abdominal symptoms with rapid progression of peritonitis and surgical abscess drainage. This is the first such case in an organ transplant recipient described in the English literature. METHODS AND RESULTS: Published reports of 1040 cases of TOA were reviewed. The most common features were a history of sexually transmitted disease or pelvic inflammatory disease, and symptoms including abdominal pain and fever. Escherichia coli, Bacteroides spp., and Klebsiella pneumoniae were the most frequently encountered pathogens. Neisseria gonorrhoeae and Chlamydia trachomatis, which are frequently isolated from cervical cultures, are uncommonly isolated from tubo-ovarian abscesses. Forty percent of patients were treated with antibiotics alone, 18.8% with abdominal surgery, and 32% with surgery and antimicrobial therapy. CONCLUSION: This report illustrates the muted presentation and atypical microbiology of gynecologic infection in an organ transplant recipient. PMID- 11602851 TI - Prevention of bone loss and fracture after lung transplantation: a pilot study. AB - BACKGROUND: Osteoporotic fracture is a significant source of morbidity after lung transplantation. Therapies to prevent posttransplant fracture are largely untested among lung transplant recipients. METHODS: In this prospective uncontrolled study, lung transplant referrals were assessed for bone health with metabolic, radiographic, and bone mineral density measurements. Transplant recipients were treated with an antiresorptive regimen that included a bisphosphonate starting before or after transplantation. One year after transplantation, the fracture rate and bone density of patients in each group were reassessed and compared to historical controls. Between January 1996 and August 1999, 45/50 (90%) lung transplant referrals underwent bone health assessment. Transplant candidates received calcium, vitamin D, and hormone replacement therapy as indicated for hypogonadism. After July 1998, bisphosphonate therapy was added for candidates with osteopenia or osteoporosis (T score <1). After transplantation, all patients received 90 mg of pamidronate i.v. every 12 weeks, regardless of pretransplant bone density. Radiologic evaluation was performed for clinical suspicion of fracture. Bone density was remeasured 1 year after transplantation. RESULTS: Most transplant referrals suffered from osteopenia or osteoporosis, and 29% of transplant referrals had prevalent vertebral compression fractures. Hypogonadism was untreated in 50% of men and 20% of women, and 15% of patients had hypovitaminosis D. Of the 21 patients assessed 1 year after transplantation, new fractures occurred in 4% of these patients. Lateral lumbar spine and hip bone density remained stable or improved in 65% and 86% of patients, respectively. Most of those who lost bone density had started bisphosphonate therapy after transplantation. CONCLUSIONS: Antiresorptive therapy with a bisphosphonate decreases the fracture rate and preserves bone mass 1 year after lung transplantation. In end-stage lung disease patients with osteopenia or osteoporosis, bisphosphonate therapy should be initiated before transplant surgery is contemplated. PMID- 11602850 TI - Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. AB - BACKGROUND: Sirolimus (Rapamune, rapamycin, RAPA) is a potent immunosuppressive drug that has reduced the rate of acute rejection episodes by more than 40% in phase III trials when added to an immunosuppression regimen of cyclosporine (CsA) and prednisone. However, RAPA treatment tends to increase lipid levels, particularly among patients with pre-existing hyperlipidemia. METHODS: To identify the metabolic pathway(s) leading to RAPA-mediated hyperlipidemia, five patients with renal transplants maintained on CsA+/-prednisone+/- azathioprine (AZA) were studied before and after 6 weeks of treatment with RAPA (off RAPA and on RAPA, respectively). Each study patient was infused with a single bolus of [2H4]-lysine to derive metabolic parameters for apoB100-containing lipoproteins by using kinetic analysis based upon quantitation of isotopic enrichment by gas chromatography-mass spectrometry. RESULTS: Serial lipid measurements revealed that four patients displayed increased plasma triglyceride levels after RAPA treatment, which coincided with significantly higher plasma VLDL-apoB100 concentrations (21.7+/-12.1 mg/dl off RAPA vs. 38.7+/-14.8 mg/dl on RAPA, mean+/ SD, P<0.05). Kinetic analysis showed that the RAPA-induced increase in VLDL apoB100 concentrations was due to a significant reduction in the fractional catabolic rate (FCR) of very low-density lipoprotein (VLDL) apoB100 (0.83+/-0.65 off RAPA vs. 0.24+/-0.10 on RAPA, mean+/-SD, P<0.05), rather than an enhanced VLDL-apoB100 synthesis. In one patient, RAPA treatment induced hypercholesterolemia but not hypertriglyceridemia. This hypercholesterolemia was due to elevated low-density lipoprotein (LDL) cholesterol levels, which coincided with a decreased FCR of LDL-apoB100. Heparin-induced lipoprotein lipase activity was significantly lower in the immunosuppressed hyperlipidemic patients than in normolipidemic controls. However, RAPA treatment did not significantly alter basal lipoprotein lipase activity in renal transplant patients in this study. CONCLUSIONS: This study indicates that for renal transplant patients in whom RAPA treatment induces hyperlipidemia, this effect is the result of reduced catabolism of apoB100-containing lipoproteins. PMID- 11602852 TI - Prognostic value of plasminogen activator inhibitor type 1 mRNA in microdissected glomeruli from transplanted kidneys. AB - BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) exerts antifibrinolytic and profibrotic activities. Inside the glomerulus, PAI-1 is mainly synthesized by mesangial cells. We hypothesized that thrombin, via its receptor protease activated receptor type 1 (PAR-1), present on the membrane of glomerular cells, is an important mediator of PAI-1 synthesis. METHODS: Using the technique of Peten et al., we microdissected the glomeruli of 23 kidney transplanted patients admitted in our department from 1993 to 1997, and we followed-up these patients for up to 5 years, with sometimes iterative renal biopsies. With this technique, we also microdissected the glomeruli of three patients who have had a nephrectomy for cancer (control patients). We investigated mRNA expression of the PAI-1, the thrombin receptor PAR-1, the alpha2 chain of type IV (alpha2 IV) collagen, and of a housekeeping gene (cyclophilin) by reverse transcription-polymerase chain reaction. The results were correlated with the renal function and the histological findings classified into acute rejection (9 biopsies), chronic rejection (22 biopsies), or normal (8 biopsies). RESULTS: A significant up-regulation of PAI-1 and alpha2 IV collagen mRNA was observed in acute rejection (P<0.05) when compared to normal kidneys. A positive correlation exists between alpha2 IV collagen mRNA level and the degree of cellular infiltration. A negative correlation was found between the level of mRNA of PAR-1 and the degree of vascular thrombosis (P=0.005) and glomerulosclerosis (P=0.04). A positive correlation was found between the degradation of renal function and the mRNA level of PAI-1 at the time of the renal biopsy (P<0.05). CONCLUSIONS: These results suggest that glomerular PAI-1 mRNA may be predictive of the long-term renal graft function. PMID- 11602853 TI - A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients. AB - BACKGROUND: A double-blind, placebo-controlled, randomized study was performed to assess whether immunoprophylaxis with basiliximab (Simulect) could reduce the incidence of acute rejection in kidney transplant recipients treated with cyclosporine (Neoral), steroids, and azathioprine. METHODS: Three hundred forty patients received either placebo or basiliximab at a dose of 20 mg, given intravenously on days 0 and 4. All patients received cyclosporine, steroids, and azathioprine. The primary endpoint was the incidence of acute rejection at 6 months. Secondary endpoints included the safety and tolerability of basiliximab and placebo, 1-year patient and graft survival, and significant medical events up to 12 months. RESULTS: During the first 6 months posttransplantation, acute rejection occurred in 20.8% of patients given basiliximab versus 34.9% of patients administered placebo (P=0.005). Similarly, there was a reduction in biopsy-proven acute rejection at 6 months in the patients receiving basiliximab (P=0.023). One-year patient survival was 97.6% with basiliximab and 97.1% with placebo, graft survival was 91.5% versus 88.4%, respectively (NS). The adverse events profile of patients treated with basiliximab was indistinguishable from that of patients treated with placebo. The number of patients with infections was similar (65.5% for basiliximab vs. 65.7% for placebo), including cytomegalovirus infections (17.3% vs. 14.5%, P=0.245). Nine neoplasms (three in the basiliximab group, six in the placebo arm) were recorded up to 1 year from transplantation. CONCLUSIONS: Basiliximab in combination with cyclosporine, steroids, and azathioprine triple therapy was highly effective in reducing the incidence of acute renal allograft rejection without increasing the incidence of infections and other side effects. PMID- 11602854 TI - Cyclosporine and long-term kidney graft survival. AB - BACKGROUND: Previous analysis of kidney transplant data from the Collaborative Transplant Study database showed that patients receiving cyclosporine 3-6 mg/kg/day 1 year posttransplantation had the best graft survival rate 7 years posttransplantation. Longer-term and additional analyses have now been performed. METHODS: Data from cadaver kidney transplants performed between 1985 and 1998 were analyzed retrospectively. Patients were included if they had a functioning graft 1 year posttransplantation, and the daily cyclosporine dose administered 1 year posttransplantation was reported. Data on cyclosporine dose, serum creatinine concentration, and systolic blood pressure were recorded 1 and 5 years after transplantation; information on graft survival was documented at yearly intervals. RESULTS: Patients receiving cyclosporine 3-6 mg/kg/day 1 year posttransplantation had the best graft survival rate 10 years posttransplantation. Cyclosporine <2 mg/kg/day was least beneficial overall and in subanalyses based on age, risk level, and 1-year serum creatinine concentration. The microemulsion cyclosporine formulation (Neoral) was associated with a significantly higher 4-year graft survival rate than the conventional formulation (Sandimmune; P=0.0001). Median systolic blood pressure 5 years posttransplantation was similar in each 1-year cyclosporine dose category (range of medians 139.0-140.0 mmHg). The percentages of patients with serum creatinine concentrations of <130, 130-260, 260-400, or >400 micromol/L 1 and 5 years posttransplantation were similar across 1-year cyclosporine dose categories, with the exception of >6 mg/kg/day, where there was a shift toward a less favorable serum creatinine concentration over time. CONCLUSIONS: The 1-year cyclosporine dose was significantly associated with long-term graft survival, with evidence of underimmunosuppression at doses <3 mg/kg/day and overimmunosuppression at doses >6 mg/kg/day, but had little influence on systolic blood pressure or serum creatinine concentration at doses up to 6 mg/kg/day. PMID- 11602855 TI - Kidney preservation with university of Wisconsin and Celsior solution: a prospective multicenter randomized study. AB - BACKGROUND: Although the University of Wisconsin (U.W.) solution continues to be the most commonly used for intra-abdominal organs, a new solution, Celsior, already used for heart and lungs, has been proposed for kidney and liver preservation. The aim of this research was to assess the effect of Celsior as compared with U.W. on immediate graft function and a 2-year follow-up of kidney transplants. METHODS: A prospective multicenter randomized study was designed to evaluate the efficacy of the Celsior solution in the clinical preservation of the kidney. In this report, we present the data collected as of September 2000. One hundred donors were included in the trial resulting in 187 renal transplants. Ninety-nine kidneys were stored in Celsior solution and 88 in U.W. solution. The groups were comparable with regard to donor and recipient characteristics. RESULTS: Delayed graft function occurred in 31.3% of the Celsior group and in 33.9% of the U.W. group (P=n.s.). Mean serum creatinine levels and mean daily urinary output were also comparable. Two year graft survival in kidneys preserved with Celsior was 84% as compared with 75% for U.W.-preserved kidneys without any significant statistical difference. CONCLUSIONS: Our data show that the preservation of kidneys in Celsior solution in a clinical setting is equivalent to that of U.W. solution. When using Celsior during multiple-organ donor harvesting it would be possible to perform an in situ flush of all intra abdominal and intrathoracic organs with a single cold storage solution. PMID- 11602856 TI - Clearance of mobilized porcine peripheral blood progenitor cells is delayed by depletion of the phagocytic reticuloendothelial system in baboons. AB - INTRODUCTION: Attempts to achieve immunological tolerance to porcine tissues in nonhuman primates through establishment of mixed hematopoietic chimerism are hindered by the rapid clearance of mobilized porcine leukocytes, containing progenitor cells (pPBPCs), from the circulation. Eighteen hours after infusing 1 2 x 10(10) pPBPC/kg into baboons that had been depleted of circulating anti alphaGal and complement, these cells are almost undetectable by flow cytometry. The aim of the present study was to identify mechanisms that contribute to rapid clearance of pPBPCs in the baboon. This was achieved by depleting, or blocking the Fc-receptors of, cells of the phagocytic reticuloendothelial system (RES) using medronate liposomes (MLs) or intravenous immunoglobulin (IVIg), respectively. METHODS: Baboons (preliminary studies, n=4) were used in a dose finding and toxicity study to assess the effect of MLs on macrophage depletion in vivo. In another study, baboons (n=9) received a nonmyeloablative conditioning regimen (NMCR) aimed at inducing immunological tolerance, including splenectomy, whole body irradiation (300 cGy) or cyclophosphamide (80 mg/kg), thymic irradiation (700 cGy), T-cell depletion, complement depletion with cobra venom factor, mycophenolate mofetil, anti-CD154 monoclonal antibody, and multiple extracorporeal immunoadsorptions of anti-alphaGal antibodies. The baboons were divided into three groups: Group 1 (n=5) NMCR+pPBPC transplantation; Group 2 (n=2) NMCR+ML+pPBPC transplantation; and Group 3 (n=2) NMCR+IVIg+pPBPC transplantation. Detection of pig cells in the blood was assessed by fluorescence activated cell sorter and polymerase chain reaction (PCR). RESULTS: PRELIMINARY STUDIES: ML effectively depleted macrophages from the circulation in a dose dependent manner. Group 1: On average, 14% pig cells were detected 2 hr postinfusion of 1 x 10(10) pPBPC/kg. After 18 hr, there were generally less than 1.5% pig cells detectable. Group 2: Substantially higher levels of pig cell chimerism (55-78%) were detected 2 hr postinfusion, even when a smaller number (0.5-1 x 10(10)/kg) of pPBPCs had been infused, and these levels were better sustained 18 hr later (10-52%). Group 3: In one baboon, 4.4% pig cells were detected 2 hr after infusion of 1 x 10(10) pPBPC/kg. After 18 hr, however, 7.4% pig cells were detected. A second baboon died 2 hr after infusion of 4 x 10(10) pPBPC/kg, with a total white blood cell count of 90,000, of which 70% were pig cells. No differences in microchimerism could be detected between the groups as determined by PCR. CONCLUSIONS: This is the first study to report an efficient decrease of phagocytic function by depletion of macrophages with MLs in a large animal model. Depletion of macrophages with MLs led to initial higher chimerism and prolonged the survival of circulating pig cells in baboons. Blockade of macrophage function with IVIg had a more modest effect. Cells of the RES, therefore, play a major role in clearing pPBPCs from the circulation in baboons. Depletion or blockade of the RES may contribute to achieving mixed hematopoietic chimerism and induction of tolerance to a discordant xenograft. PMID- 11602857 TI - Analysis of the CD40 and CD28 pathways on alloimmune responses by CD4+ T cells in vivo. AB - BACKGROUND: Blockade of the CD40 and CD28 pathways is a powerful strategy to inhibit CD4-mediated alloimmune responses. In this study, we examine the relative roles of the CD40 and CD28 pathways on CD4-mediated allograft rejection responses, and further characterize the role of these pathways on CD4+ T-cell activation, priming for cytokine production, and cell proliferation in response to alloantigen in vivo. METHODS: BALB/c skin allografts were transplanted onto C57BL/6 Rag 1-/- recipients reconstituted with CD4 cells from CD28-/- or CD40L-/- donors. The popliteal lymph node assay was used to study the role of these pathways on CD4-cell activation and priming in vivo. To investigate the role of CD40 and CD28 blockade on CD4-cell proliferation, the fluorescein dye carboxyfluorescein diacetate succinimidyl ester was used. We performed heterotopic cardiac transplantation using CD40-/- mice to evaluate the role of CD40 on donor versus recipient cells in CD4-mediated rejection. RESULTS: B6 Rag 1 /- recipients reconstituted with CD28-/- CD4+ T cells acutely rejected allografts (median survival time 15 days), whereas recipients reconstituted with CD40L-/- CD4+ T cells had significantly prolonged survival of BALB/c skin grafts (MST 71 days). CD40L blockade was equivalent to or inferior to CD28 blockade in inhibition of in vivo CD4-cell activation, priming for cytokine production, and proliferation responses to alloantigen. BALB/c recipients depleted of CD8 cells promptly rejected donor B6 CD40-/- cardiac allografts, whereas B6 CD40-/- recipients depleted of CD8 cells had significantly prolonged survival of BALB/c wild-type cardiac allografts. CONCLUSIONS: The CD40/CD40L pathway, but not the CD28/B7 pathway, is critical for CD4-mediated rejection responses, however, the responsible mechanisms remain unclear. PMID- 11602858 TI - Kinetics of leukocyte and myeloid cell traffic in the murine corneal allograft response. AB - BACKGROUND: Little information exists on the trafficking of myeloid and lymphoid cells between the transplanted cornea and the secondary lymphoid tissue. This study reports on changes in the cornea and the draining lymph node (DLN) from the time of graft emplacement. METHODS: Using a mouse corneal graft model (C57BL/10Sn to BALB/c), eyes and submandibular DLN were examined by immunohistochemistry and three-color flow cytometry for evidence of T cell activation and dendritic cell (DC) conditioning (up-regulation of costimulatory molecules) at various times (15 min to 24 days; n=4 for each time). RESULTS: In the DLN, early (2 hr) DC conditioning was sustained throughout allograft rejection whereas a remarkable drop in percentage of activated CD4+ and CD8+ T cells (P <0.001) was followed by a biphasic rise in activated CD4+ and, to a lesser extent, CD8+ T cells (24 hr, P <0.001 and 6 days, P <0.01). CD11b+ and MOMA-2+ macrophages, MHC Class II+ cells, CD86+ DC, and neutrophils were the earliest cells infiltrating the cornea (at 24 hr), whereas T cells appeared after 2 days, with CD4+ T cells being confined largely to the graft recipient border. CONCLUSIONS: Immediate and rapid changes in T cell and DC populations in the DLN correlate with the type of cellular infiltration in the corneal graft. The data are consistent with a model in which CD4+ T cell help for CD8+ cytotoxic T cells could be provided by sequential two way activation of T cells and DC in the DLN. The majority of cells infiltrating the graft were macrophages and neutrophils, with fewer DC and T cells. PMID- 11602859 TI - Modulation of platelet aggregation in baboons: implications for mixed chimerism in xenotransplantation. I. The roles of individual components of a transplantation conditioning regimen and of pig peripheral blood progenitor cells. AB - BACKGROUND: The induction of tolerance to pig antigens in primates may facilitate the development of successful clinical xenotransplantation protocols. The infusion of mobilized porcine peripheral blood leukocytes (PBPCs, comprised of approximately 2% peripheral blood progenitor cells) into splenectomized preconditioned baboons, intended to induce mixed hematopoietic cell chimerism, however, results in a severe thrombotic microangiopathy (TM) that includes pronounced thrombocytopenia. Because the mechanisms responsible for this phenomenon are unclear, we have explored the effects of individual components of the conditioning regimen, of therapeutic adjuncts, and of PBPCs on platelet aggregation. METHODS: Groups of splenectomized baboons (n = at least 2 in each group) were treated with single components of the conditioning regimen--whole body irradiation (WBI), antithymocyte globulin (ATG), extracorporeal immunoadsorption (EI), mycophenolate mofetil (MMF), anti-CD40L monoclonal antibody (mAb), cobra venom factor (CVF), pig hematopoietic growth factors (interleukin-3 (pIL3) and stem cell factor (pSCF))--or with potential adjuncts, prostacyclin (PGI2), heparin, methylprednisolone, and eptifibatide (a GPIIb/IIIa antagonist). Blood samples were collected and platelet-rich plasma (PRP) was prepared. Using light transmission aggregometry, the extent of aggregation induced by platelet agonists (thrombin, adenosine diphosphate (ADP), collagen, ristocetin, and arachidonic acid) was determined in vitro. PRP was also prepared from untreated baboons, PBPCs were added, and platelet aggregation was measured in the absence of exogenous platelet agonists. RESULTS: WBI, ATG, MMF, anti-CD40L mAb, CVF, pIL3, pSCF, and PGI2 had no effect on purified baboon platelet aggregation profiles in vitro. Eptifibatide markedly inhibited platelet aggregation induced by all standard agonists. EI or heparin inhibited thrombin induced platelet aggregation, and methylprednisolone inhibited ADP-induced aggregation to some extent. In vitro addition of PBPCs to PRP stimulated platelet aggregation in the absence of any agonists. Prior treatment of baboons with eptifibatide, however, inhibited this effect by 70% to 80%. CONCLUSIONS: Aggregation of baboon platelets and TM is directly induced by PBPCs, but not by individual components of the conditioning regimen. GPIIb/IIIa antagonists, such as eptifibatide, interfere directly with xenogeneic PBPC-platelet interactions and may further ameliorate TM in the pig-to-primate model. PMID- 11602860 TI - Modulation of platelet aggregation in baboons: implications for mixed chimerism in xenotransplantation. II. The effects of cyclophosphamide on pig peripheral blood progenitor cell-induced aggregation. AB - BACKGROUND: The induction of tolerance to pig antigens in primates may facilitate the development of successful clinical xenotransplantation protocols. The infusion of mobilized porcine peripheral blood leukocytes (PBPCs, comprised of approximately 2% peripheral blood progenitor cells) into splenectomized preconditioned (whole body irradiation (WBI)-based) baboons, intended to induce mixed hematopoietic cell chimerism, however, results in a severe thrombotic microangiopathy (TM) that includes pronounced thrombocytopenia. Previous studies have indicated that the infused PBPCs initiate platelet aggregation, but that the various individual components of the conditioning regimen are not associated with the development of aggregation. We have now investigated the effects of cyclophosphamide (CPP) as an alternative to WBI on platelet aggregation. METHODS: Splenectomized baboons (n=3) were treated with CPP. Blood samples were collected and platelet-rich plasma (PRP) was prepared. Using light transmission aggregometry, the extent of aggregation induced by platelet agonists (thrombin, adenosine diphosphate (ADP), collagen, ristocetin, and arachidonic acid) was determined in vitro. PRP was also prepared from untreated baboons and from baboons receiving CPP, PBPCs were added, and platelet aggregation was measured in the absence of exogenous platelet agonists. RESULTS: CPP markedly inhibited platelet aggregation induced by all standard agonists. In vitro addition of PBPCs to PRP stimulated platelet aggregation in the absence of any agonists. Prior treatment of baboons with CPP, however, inhibited this effect by 55% to 65%. TM was not evident in baboons receiving a conditioning regimen that included CPP instead of WBI. CONCLUSIONS: Aggregation of baboon platelets and TM is directly induced by PBPCs. CPP has direct anti-aggregatory properties and may provide an alternative strategy to WBI in this pig-to-primate model intended to induce mixed hematopoietic cell chimerism. PMID- 11602861 TI - The allogeneic T and B cell response is strongly dependent on complement components C3 and C4. AB - BACKGROUND: The mechanisms controlling the production of antibodies against histocompatibility antigens are of prime importance in organ transplantation. METHODS: We investigated the role of complement in the response to allogeneic stimulation, using mice deficient in C3, C4, or C5 to dissect the role of the alternative, classical, and terminal complement pathways. RESULTS: After fully major histocompatibility complex disparate skin grafts, the allospecific immunoglobulin (Ig)G response was markedly impaired in C3- and C4-, but not in C5 deficient mice. This defect was most pronounced for second set responses. C3 deficient mice also demonstrated a decreased range of IgG isotypes. In contrast, there was no impairment of the allospecific IgM response. In functional T cell assays, the proliferative response and interferon-gamma secretion of recipient lymphocytes restimulated in vitro with donor antigen was decreased two- to threefold in C3-deficient mice. CONCLUSIONS: These data show impairment of allogeneic T cell and B cell function in mice with defective complement activation and suggest a predominant role for the classical pathway in stimulating alloimmunity. The terminal pathway seems unimportant in this regard. This extends the results reported for soluble protein antigens and demonstrates a surprisingly marked effect on the alloresponse despite the presence of a stringent antigenic stimulus. These results have implications for the prevention of sensitization in naive transplant recipients. PMID- 11602862 TI - Human herpesvirus-8 seroconversions after renal transplantation. AB - BACKGROUND: Human herpesvirus-8 (HHV-8) is a new human herpesvirus that is clearly associated with Kaposi's sarcoma (KS). A previous study has reported that the prevalence of KS in a cohort of renal transplant recipients with previous HHV 8 infection was 28% and two other studies have shown that KS can be linked to HHV 8 seroconversion after graft. The aim of this study was to evaluate the HHV-8 seroconversion rate in a cohort of renal allograft recipients in Paris. METHODS: Two hundred eighty-seven patients who were HHV-8 seronegative before renal transplantation were tested for HHV-8 antibodies by an immunofluorescence assay 12 months after transplantation. RESULTS: Of the 287 patients, 6 (2.09%) seroconverted after renal transplantation. None of these 6 patients developed KS within 3 years of the first HHV-8 positive serum. None of the clinical manifestations that could be associated with HHV-8 primary infection were observed during the seroconversion. CONCLUSIONS: Our results demonstrated that HHV-8 seroconversion can be observed even in a low HHV-8 prevalence area and confirmed the need to perform systematic screening for HHV-8 antibodies in renal graft donors and recipients. PMID- 11602863 TI - Early peri-operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study. AB - BACKGROUND: Hyperglycemia alters the inflammatory response to infection and ischemia. We hypothesize that perioperative glycemic control could also influence the risk for allograft rejection. METHODS: Consecutive patients with established diabetes undergoing their first cadaveric renal transplantation and receiving steroid-sparing immunosuppression were identified (n=50). Records of capillary glucose observations over the first 100 hr following surgery and transplantation variables pertaining to graft function, acute rejection, and postoperative infection were identified and entered into multivariate analysis. RESULTS: Perioperative glycemic control was associated with an increased incidence of infection and acute rejection. Only 3 of 27 patients (11%) with optimal glycemic control during the 100 hr following surgery (mean<11.2 mmol/L) had rejection episodes compared with 58% of patients with poor control (>11.2 mmol/L). All patients with poor glycemic control experienced postoperative infection. CONCLUSIONS: This pilot study suggests that hyperglycemia may be associated with an increased risk of both allograft rejection and postoperative infection in patients with diabetes. PMID- 11602864 TI - Cytomegalovirus pp65 antigen-guided preemptive therapy with ganciclovir in solid organ transplant recipients: a prospective, double-blind, placebo-controlled study. AB - BACKGROUND: The aim of this study was to evaluate pp65 antigen-guided antiviral therapy in preventing human cytomegalovirus (HCMV) infection in solid organ transplant recipients. METHODS: Ten kidney and two liver transplant recipients with asymptomatic HCMV infection were randomized either for i.v. ganciclovir or placebo treatment in a prospective, double-blind study. All patients were positive by HCMV pp65 antigen test at levels >5 positive cells/2 x 10(5) investigated cells. RESULTS: No cases of HCMV end-organ disease occurred. In contrast to patients on placebo (5/7), none of the patients on ganciclovir (0/5) developed HCMV-associated symptoms (P=0.01). However, because of the small number of patients, all three high-risk patients (donor seropositive, recipient seronegative) were randomized to placebo and all three developed symptoms. CONCLUSIONS: Preemptive antiviral therapy guided by the pp65 antigen test seems to have a beneficial effect on preventing HCMV-associated symptoms in kidney and liver transplant recipients. PMID- 11602865 TI - Successful management of a B-type cardiac allograft into an O-type man with 3(1/2)-year clinical follow-up. AB - BACKGROUND: In May 1997, a 19-year-old male patient of histo-blood group type O suffering from congenital end-stage heart failure accidentally received a cardiac allograft of type B and is still alive in fair condition. METHODS: In addition to conventional immunosuppressive therapy, plasma exchange (PEX), extracorporeal immunoabsorption (EIA), intravenous immunoglobulins (IVIG), and C1 inhibitor were used. RESULTS: Such treatment successfully reduced both IgM and IgG anti-B levels and complement hyperactivity and allowed to reach the state of accommodation without obvious signs of rejection. The patient has been surviving for 42 months; retransplantation with an O-type heart remained unnecessary. CONCLUSION: Humoral rejection has been avoided in this patient, with PEX, EIA, IVIG, and C1 inhibitor substantially contributing to this success. With future availability of such combined therapies, preferably before transplantation, vascular rejection events caused by preformed antibodies and complement (ABO mismatch or anti-HLA) could be prevented or treated. PMID- 11602867 TI - Human cytomegalovirus productively infects porcine endothelial cells in vitro. AB - BACKGROUND: The possibility that human cytomegalovirus (HCMV) may infect porcine endothelial cells (ECs) was investigated. This may be relevant during xenotransplantation of porcine cells or organs into human recipients. METHODS: HCMV was inoculated into low-passage porcine ECs. Replication of virus was detected by development of characteristic cytopathogenic effect. Appearance of immediate early, early, and late antigens was studied by immunocytochemical staining. Infectious virus was detected in human fibroblast cells. Presence of HCMV RNA was studied by Northern Blot and reverse transcriptase polymerase chain reaction. RESULTS: All parameters indicated that a fresh clinical HCMV isolate productively infects porcine ECs. The same cells do not fully support replication of the laboratory strain Ad 169. CONCLUSION: Our results may indicate the possibility of cross-species infectivity of HCMV to porcine cells. PMID- 11602866 TI - Transient renal effects of sildenafil in male kidney transplant recipients. AB - BACKGROUND: Sildenafil (Viagra) improves erection by sustaining Guanosine 3', 5' cyclic monophosphate (cGMP)-mediated smooth muscle relaxation in the corpus cavernosum. It also induces systemic vasodilation, resulting in a minor decrease in blood pressure. We evaluated the effect of one dose of sildenafil on graft function and hemodynamics in impotent male transplant recipients. METHODS: Two sets of combined lithium, inulin, and p-amino hippurate clearance studies were conducted, with and without sildenafil (100 mg orally) in 11 male kidney transplant recipients (KTRs). RESULTS: Sildenafil increased glomerular filtration rate by 14+/-4 from the baseline value of 55+/-7 ml x min(-1) x 1.73 m2(-1) (P<0.01), whereas calculated renal vascular resistances decreased by 40+/-18 from the baseline value of 247+/-29 mmHg/L x min(-1) x 1.73 m2-1 (P<0.05). CONCLUSIONS: The oral administration of sildenafil in KTRs did not impair the function of the graft. In terms of renal physiology, the observed modifications did not warrant any specific precautions when offering sildenafil to KTRs suffering from erectile dysfunction. PMID- 11602868 TI - [Recovery room: between reality and utopia]. PMID- 11602869 TI - Advances on management of myocardial infarction. PMID- 11602870 TI - Intraoperative arrhythmias: diagnosis and management. PMID- 11602871 TI - Hypoxic reperfusion limits functional impairment following cardioplegic arrest in isolated rat heart. AB - BACKGROUND: Reperfusion injury decreases both systolic contractility and diastolic compliance. Several studies indicate that the sustained decrease in diastolic compliance is mainly due to reactive oxygen intermediates (ROI) generation and calcium overload. METHODS: Male Wistar isolated rat hearts were divided into 2 groups (n=10 each), perfused according to Langendorff technique and exposed to 45 min of ischemia. Hearts belonging to the first group were reperfused with Krebs-Henseleit solution at 600 mmHg pO2; a 150 mmHg pO2 perfusate was utilized in the second group during the first minute and switched to 600 mmHg pO2 thereafter. Modifications in diastolic compliance and systolic contractility were assessed by changes in left ventricular end-diastolic (LVEDP) and developed pressure (LVDP), and first derivative of the pressure curve (dP/dt). RESULTS: Increase in LVEDP values, with respect to pre-ischemic data, were detected at 1, 5, 10, 20 min following reperfusion at 600 mmHg pO2, and were respectively: +40.17+/-18.61, +57.5+/-28.8, +59.8+/-30.5 and +63.2+/-34.1 mmHg. At 150 mmHg pO2 they were: +15.69+/-13.13, +22.4+/-14.1, +26.2+/-13.7 and +28.9+/ 15.8, with a significant difference within the first 20 min (p<0.05). At high pO2 levels, LVDP decreased of 53.0+/-27.35, 60.5+/-22.6, 59.8+/-23.3 and 50.7+/-25.0 mmHg, versus 42.7+/-25.7, 38.0+/-29.5, 39.2+/-30.9 and 38.7+/-32.7 mmHg at lower pO2 (p=NS). The correspondent values of the dP/dt were 37.8+/-27.7, 30.1+/-17.2, 32.2+/-13.6 and 35.4+/-14.0% of pre-ischemic values at high pO2, versus 43.3+/ 27.09, 51.9+/-25.1, 50.1+/-24.6 and 53.1+/-29.9% at lower pO2. Statistical significance was lower for LVDP and dP/dt than LVEDP. CONCLUSIONS: Diastolic functional impairment was partially reduced within the first 20 min following low pO2 reperfusion, but without any significant improvement of contractility. PMID- 11602872 TI - [Prognostic systems in intensive care: TRISS, SAPS II, APACHE III]. AB - BACKGROUND: To validate the accuracy of SAPS II, APACHE III and TRISS for the prediction of mortality in Intensive Care Unit (ICU) at polytrauma patients admission. The outcome of multiple trauma patients is often linked to the degree of physiologic dysfunction and to the extension of anatomic lesions, the age of the patient and the lesion mechanism. METHODS: The study population consisted of 93 cases of multiple injured patients hospitalised at the ICU of the Padua hospital from October 1998 to October 1999; the term polytraumatized patient is referred to patients who have multiple lesions of which at least one potentially endangers, immediately or in a short term, their life. These cases were evaluated with the APACHE III, SAPS II, Revised Trauma Score and Injury Severity Score. The predictive power of each system was evaluated by using decision matrix analysis to compare observed and predicted outcome with a decision criterion of 0.50 and 0.40 for risk of hospital death. RESULTS: All trauma score systems under study showed high accuracy rates, above all if they are used with a 40% positive test. CONCLUSIONS: The prognostic scales used in this study showed a good correlation between expected and observed cases, particularly with TRISS and APACHE III systems. The APACHE III system seems to be the most reliable of the different methods analysed. These prognostic systems are seldom or occasionally used in the ICU, in Padua and in the whole of Italy, so Italian data are not suitable to be compared to international ones. Due to urgency, the importance of the evaluation scales is often underestimated, but even if they require time and attention, they surely can be useful in the evaluation of the treatment, and not only of a polytraumatized patient. PMID- 11602873 TI - [Recovery Room. Organization and clinical aspects]. AB - Correct administration in the early postoperative phase is decisive in the final outcome of surgery and the presence of the Recovery Room (RR) contributes significantly to a reduction in the post-operative risk rate. The objectives of the RR are: removal of the pharmacological effect of general anaesthesia; stabilization of vital parameters (circulation and ventilation); stabilization of body temperature; control of the hydro-electrolytic balance; intensive intervention in the case of an acute complication; prescribing a suitable postoperative analgesia; recovering movement in the case of loco-regional anesthesia. Organization of RR must take into consideration: 1) aspect of environment and location; 2) transport of the patient from the operating room to the RR; 3) definition of the equipment necessary for the RR; 4) definition of the role and qualification of the medical and nursing staff; 5) definition of regulations of assistance and the clinical file; 6) definition of criteria for discharge and transfer; 7) definition of means of adjournment, improvement and comparison with other similar structures. RR is administered by an Anesthetist with clinical, therapeutic and decision-making responsibility for the discharge of patients, while the supervision and assistance patients is entrusted to specialised professional nurses. From a clinical point of view the following data are monitored and recorded: the vital signs (passage of air-ways, cardiac and respiratory frequency, arterial pressure, saturation of O2, EtCO2 (in patient with air-way support), body temperature and the state of consciousness, instrumental monitoring of the patient (at pre-established time intervals), control of the skin, the peripheral circulation, surgical wounds, drainage and catheters. The percentage of incidence of complications in RR varies from 6-7 to 30% depending on various studies, probably in relation to the diversity of criteria in defining the complication. The principal complications which can be found in RR, reported in several studies are: respiratory (obstruction of the air way, hypoxemia, hypoventilation, inhalation), cardio-circulatory (hypotension, hypertension, arrhythmia, myocardial ischemia), postoperative nausea and vomiting, hypothermia and hyperthermia, delayed re-awakening, disorientation and hyper-excitability, postoperative shivering. As long as the patient can be discharged from the RR the following requisites must be satisfied: return of a state of consciousness, stable cardio-circulatory parameters, absence of respiratory depression, absence of bleeding, absence of nausea and vomiting, good analgesia and recovery of movement in the case of loco-regional anesthesia (on this last point not all authors agree). What has been said until now shows the function, usefulness and importance of RRs which must not replace the Intensive Therapy Units. In fact, they are places where the cure must be concluded, in which the Anesthetist is responsible for the whole process. This cure must begin in the preoperative period, continue in the intraoperative period and it is compulsory to proceed in the immediate postoperative period until such a time that, because of the anesthesia administered, the clinical situation of the patient ceases to be considered a potential medical-surgical urgency-emergency . PMID- 11602874 TI - [Recovery Room. One-year experience]. AB - BACKGROUND: The objective of our study is to present the analysis of the organizational and clinical work carried out in the first year of activity of the Recovery Room (RR) at the Azienda Ospedaliera Santa Maria degli Angeli of Pordenone and to compare personal experience with what is stated in the literature. METHODS: The RR is located at the center of the operating block (composed of 10 operating rooms), the number of bed is 6, 3 of which are equipped with ventilators. There is a central nursing station where it is possible to concentrate all data deriving from the single monitors on one single screen. The RR operates from Monday to Friday from 8.00 to 20.00. An Anesthetist is on duty for the 12 hours and has the clinical, therapeutic and decision-making responsibility regarding the discharge of patients, while nursing assistance is provided by 2 qualified professional nurses for shift, assisted by an auxiliary. In the first year of activity of the RR, a total of 11,626 surgical operations were carried out; of these 1,047 patients, equal to 9%, were assisted in the RR. The age of 51% of the patients was between 61 and 80 years; 53.3% belonged to the ASA 2 group and only 0.48% to the ASA 4 group. The operations were sub-divided as follows: 56.8% general, thoracic and vascular surgery, 15.3% urological, 10% orthopedic, 7.7% obstetrical and gynecological, 6.1% ENS, 3% stomatological, 1% others. 56.8% off the patients underwent general anesthesia, 30.5% combined anesthesia and 12.6% local-regional anesthesia. The time spent by the patients in RR was between 1 hour 30 minutes and 10 hours 45 minutes, with an average time of 3 hours 49 minutes. RESULTS: Of the 1,047 patients studied no case of cardio respiratory arrest or death was recorded, while the complications encountered were: 13.15% cardio-circulatory, 3.62% respiratory, 3.62% PONV, 2.1% oliguria, 1.24% hypothermia, 0.48% disoriented patients, 0.38% hyperthermia and 0.38% shivering. In the area of cardio-circulatory complications encountered, the most important was arterial hypertension (5.6%), followed by cardiac arrhythmia, such as bradycardia (2.5%) and tachycardia (2.6%). CONCLUSIONS: The conclusion is drawn that correct administration in the early postoperative period is decisive for the final outcome of surgery and that the presence of RR contributes significantly to a reduction in the postoperative morbidity rate. Our case-series leads us, however, to reflect on an excellent organization of the opening hours of RR. PMID- 11602875 TI - [Analysis and comparison of the guidelines regarding recovery-room management]. AB - The purpose of this study was to analyse and compare the guidelines regarding Recovery-Room (RR) management at international level, pointing out the main differences and common aspects. The guidelines on the RR management in various countries have been compared in particular the Italian, French, German, Australian, Canadian and American guidelines. In addition, the management of postoperative patients in some of these countries where guidelines on the subject have not yet been published have been analysed. In some countries, France for instance, the guidelines have been published as a ministerial decree (Decret n degrees 94-1050 du Decembre 1994) and are therefore a law with proper articles, in others (Italy for instance), they are mere recommendations, which do not have immediate effect and are regarded as a target to be achieved. SIAARTI considers that this is due to the dishomogeneity of the Italian hospital situation as far as medical and nursing staff as well as buildings and applied technology are concerned. The comparison between guidelines of different countries has shown that RR is a reality which has now existed for many years at international level and it has demonstrated that all guidelines agree on the fact that postoperative patients must be observed in a protected and safe environment. The following rules are common to all guidelines: the anaesthetist is responsible for the RR and for discharging the patient; there must be a clinical record and a written report which are considered to be essential (not in Italy); RR must be next to the surgical rooms; the patient must be escorted to RR by the anesthetist; monitoring must be guaranteed during transfer; monitoring continuity in RR (at regular and a appropriate intervals) is essential. The following rules are not common to all guidelines: numbers of beds in RR; the proportion between the number of nurses and the number of patients; regulation for day-surgery; specific regulations for obstetrical patients. Guidelines are subject, as any regulation, to continuous revision, and this is a very important requirement which helps keeping them always update and in line with scientific research. PMID- 11602877 TI - [Transesophageal echocardiography in dynamic obstruction of left ventricular outflow after mitral valve surgery]. AB - The authors report a case of dynamic obstruction of the ventricular outflow due to mitral valve surgery (valvuloplasty) in a 70-year-old woman with posterior leaflet mitral prolapse and severe regurgitation associated with anomalous implant of the posterior papillary muscle and increased thickness of the basal interventricular septum. Mitral valve surgery, possible for isolated prolapse of the LPM, although myectomy of the SIV has been performed, has determined onset of a systolic anterior motion (SAM), responsible of the dynamic obstruction. The diagnosis by means of transesophageal echocardiography (TEE) of the secondary SAM has allowed to optimise therapy (suspension of the inotropic drug, increase of volemia) with rapid improvement of hemodynamic conditions and in the following controls at is possible to observe a remodelling of the left ventricular geometry with pressure gradient reduction. PMID- 11602876 TI - The minimum effective dose of 0.5% hyperbaric spinal bupivacaine for cesarean section. AB - BACKGROUND: The aim of this prospective, blind study was to determine the minimum effective dose of hyperbaric bupivacaine required for cesarean section. METHODS: With Ethical Committee approval and written consent, 24 healthy women undergoing elective cesarean section received a combined spinal epidural anesthesia. We sought to determine the minimum effective dose of spinal bupivacaine using a staircase method. In each patient an arbitrary dose of 0.5% hyperbaric bupivacaine in relation to patient height was used. The initial dose was 0.075 mg/cm height, while the outcome of each patient's response determined the dose for the subsequent patient. When successful spinal block (sensory level = or < T4 with complete motor blockade) was achieved within 20 min from spinal injection, the dose of spinal bupivacaine for the next patient was decreased by 0.01 mg/cm height. Conversely, when successful spinal block was not observed, the dose of spinal bupivacaine for the next patient was increased by 0.01 mg/cm height. Sensory and motor blocks were evaluated every 5 min by an independent, blinded observer. If successful spinal block was not achieved within the designed period, a 5-8 ml epidural bolus of 2% lidocaine was given to achieve adequate surgical anesthesia. RESULTS: No complications were reported during the study, and all women delivered their baby uneventfully (APGAR scores 5 min after delivery ranged from 9 to 10) within 5 min from uterus incision. The duration of surgical procedure ranged from 30 to 48 minutes. The dose of hyperbaric bupivacaine providing adequate surgical anesthesia within 20 min from spinal injection in 50% of subjects was 0.036 mg/cm height (95% confidence intervals: 0.031-0.041 mg/cm height). The ED95 calculated from the probit transformation to provide effective spinal anesthesia for cesarean section was 0.06 mg/cm height. CONCLUSIONS: This prospective, blind study demonstrated that a dose as low as 0.06 mg/cm height represents the dose of intrathecal bupivacaine providing effective spinal block in 95% of women undergoing elective cesarean section. PMID- 11602878 TI - [Severe and prolonged EEG depression after induction of general anesthesia for carotid endarterectomy. Report of a clinical case]. AB - A large number of methods are available for intraoperative neurologic monitoring during endarterectomy, although no single method is infallible. Debate over choice of regional or general anesthesia for this surgery persists because of differing conclusions of various studies of risks and benefits. The case of patient undergoing left carotid endarterectomy under general anesthesia is described, in whom after the induction of anesthesia with: midazolam 2 mg, fentanyl 50 g, propofol (fractionate dose of 180 mg) and cisatracurium 12 mg, a total EEG depression occurred persisting for over 10 minutes and was followed by slow recovery, during the awakening of the patient. No significant hemodynamic changes were noted during the induction. No neurologic deficit was observed in the patient after arousal. It is suggested that the probable reason for the EEG response is the particular sensitivity of the patient to some of the induction drugs or to their association. Two weeks later surgery was successfully performed using cervical plexus block, without any anesthetic support. Regional anesthesia allows continuous neurologic assessment of the awaken patient, it is the most sensitive method for detecting inadequate cerebral perfusion and function. PMID- 11602879 TI - Discharge times for patients undergoing regional anesthesia for outpatient knee surgery. PMID- 11602880 TI - [Anesthesiology department]. PMID- 11602881 TI - Presidential address: stalled on the "on ramp". PMID- 11602882 TI - The impact of managed care and current governmental policies on an urban academic health care center. AB - BACKGROUND: Managed care and governmental policies have restructured hospital reimbursement. We examined reimbursement trends in trauma care to assess the impact of this market driven change on an urban academic health center. METHODS: Patients injured between January 1997 and December 1999 were analyzed for Injury Severity Score (ISS), length of hospital stay, hospital cost, payer, and reimbursement. RESULTS: Between 1997 and 1999, the volume of patients with an ISS less than 9 increased and length of stay decreased. In addition, overall cost, payment, and profit margin increased. Commercially insured patients accounted for this margin increase, because the margins of managed care and government insured patients experienced double-digit decreases. Patients with ISS of 9 or greater also experienced a volume increase and a reduction in length of stay; however, costs within this group increased greater than payments, thereby reducing profit margin. Whereas commercially insured patients maintained their margin, managed care and government insured patients did not (double- and triple-digit decreases). CONCLUSIONS: Managed care and current governmental policies have a negative impact on urban academic health center reimbursement. Commercial insurers subsidize not only the uninsured but also the government insured and managed care patients as well. National awareness of this issue and policy action are paramount to urban academic health centers and may also benefit commercial insurers. PMID- 11602883 TI - Pancreas transplantation in Ohio: a 15-year outcomes analysis. AB - BACKGROUND: Beginning in 1984, all pancreas transplantations performed in the state of Ohio have been tracked by the Ohio Solid Organ Transplantation Consortium (OSOTC). In this study the outcomes of these transplantations were compared across 3 eras to determine whether increasing experience has been beneficial. METHODS: Between July 1984 and December 1999, 765 kidney-pancreas (KPTx) and 76 pancreas only (Ptx) transplantations were performed. Outcomes measures for these 841 pancreas transplantations were compared over 3 eras, 1984 to 1989, 1990 to 1994, and 1995 to 1999. RESULTS: One-year patient survivals for KPTx patients were 87%, 92%, and 94% in the 3 eras, respectively. Graft survival at 1 year was also markedly improved between era 1 and era 3, increasing for PTx patients from 21% to 85% and for KPTx patients from 68% to 85%. Average waiting time increased from 132 to 318 days between era 1 and era 3. Conversely, average length of stay in hospital was significantly decreased from 34 to 18 days. The cost of the procedure, as measured by hospital charges, also decreased when compared in 1985 dollars as a technique to control for inflation. CONCLUSIONS: These data suggest that pancreas transplantation in Ohio has become a very successful and cost-effective therapeutic intervention for patients with type I diabetes with or without concomitant end-stage renal failure. PMID- 11602884 TI - Hepatocellular carcinoma: multimodality management. AB - BACKGROUND: Hepatocellular carcinoma is one of the most common tumors worldwide. Surgical resection has been the standard treatment but can only be applied to a small percentage of patients. In recent years, several other treatment options, including ablative procedures and transplantation, have been used in patients with hepatocellular carcinoma. METHODS: For 6 years, 110 patients with hepatocellular carcinoma were managed at the Medical College of Wisconsin. Fifty five patients received only chemotherapy (n = 5) or palliative treatment (n = 50) because of advanced cirrhosis (P <.03) or tumor. Thirty-one patients had tumor ablation with percutaneous ethanol injection, cryoablation, radiofrequency ablation, or arterial chemoembolization. Twenty-eight patients underwent surgical resection (n = 18) or hepatic transplantation (n = 10). Relatively more patients (38%; P <.001) were treated with ablation in the second period of the study (1998 2000). RESULTS: Thirty-day mortality was 3% with ablation and 0% with resection. Median survival was 6 months with no treatment, 27 months with ablation (P <.001), and 35 months with resection (P <.001). Patients who underwent liver transplantation had the longest median survival (53 months). A multivariate analysis suggested that treatment modality (ablation or resection; P <.001) and Child-Pugh classification (P <.01) were the most important factors predicting outcome. CONCLUSIONS: This study suggests that treatment of hepatocellular carcinoma requires multidisciplinary expertise and that ablation and operation can be performed safely. Outcome is influenced most by treatment modality and Child-Pugh classification. Patients in Child-Pugh classes A and B should be treated with ablation, surgical resection, or liver transplantation. PMID- 11602885 TI - The effect of hospital vascular operation capability on outcomes of lower extremity arterial bypass graft procedures. AB - BACKGROUND: The purpose of this study was to determine whether hospitals with a high capability for vascular operations have lower rates of inpatient mortality, major complication, and major amputation with lower extremity arterial bypass (LEAB) procedures than do less well-equipped hospitals after controlling for hospital procedure volume and patient characteristics. METHODS: Admissions of 16,422 northern Illinois residents to Illinois hospitals for aortoiliac (AI) or distal bypass operations during 1993 to 1999 were analyzed. Hospitals were considered to have a high capability for vascular operations if they had cardiac surgical facilities and either an accredited blood flow laboratory, general surgical residency, or fellowship training in vascular surgery. Logistic regression was used to model the effect of hospital capability on mortality after controlling for hospital LEAB procedure volume, operation level, severity of illness, age, sex, and emergent admission. RESULTS: Sixteen of 98 Illinois hospitals with 34.4% of the sample patients, including 8 of 18 hospitals with more than 40 admissions for LEAB procedures annually, were classified as having high surgical capability. Hospitals classified as having high versus low capability had lower mortality (2.8% vs 3.7%; P =.003) and amputation rates (4.6% vs 4.9% [not significant]) but higher major complication rates (9.8% vs 8.5%; P =.006). CONCLUSIONS: Mortality outcomes for LEAB procedures were superior at high capability hospitals, even after controlling for patient characteristics, disease severity, and LEAB volume. Hospital complication rates were not correlated with mortality rates and may not be a meaningful measure of quality of care. PMID- 11602886 TI - Thoracoscopic esophagomyotomy for achalasia: preoperative patterns of acid reflux and long-term follow-up. AB - BACKGROUND: The best technique for surgical esophagomyotomy to treat achalasia remains contentious. The controversies include the best approach (thoracoscopic or laparoscopic) and the need for an antireflux procedure. Postoperative pH studies have suggested pathologic gastroesophageal reflux (GER) in many cases; however, control studies of reflux patterns are scarce. This study presents pH studies before esophagomyotomy as well as long-term follow-up of patients undergoing esophagomyotomy. METHODS: Forty-nine patients underwent esophagomyotomy (45 thoracoscopically, 4 laparoscopically) for achalasia. Before treatment, 24-hour pH studies were conducted for 38 patients with achalasia. The patients were evaluated postoperatively for dysphagia and reflux. Results were classified as excellent, good, fair, or poor. RESULTS: The findings of the pretreatment pH studies were abnormal in 15 patients (39%). Twelve patients (32%) had GER either with esophageal fermentation (6 patients [16%]) or without fermentation (6 patients [16%]). Eight percent had esophageal fermentation alone. There was no correlation between GER and previous pneumatic dilatation. Twenty three patients (60%) had normal pH scores; of these, 24% had esophageal fermentation, whereas 29% had neither reflux nor fermentation. Operative results were excellent in 70% of patients, good in 10%, and fair in 20%. All patients considered their conditions improved. Four patients required a subsequent operation because of dysphagia (n = 3) or reflux (n = 1), and their original procedures were classified as failures. Their current status is fair (n = 2), good (n = 1), and excellent (n = 1). GER was documented before the original operation in 3 of the 4 patients in whom the procedure failed. Fifteen patients were eligible for 5-year follow-up. Their results are excellent or good (n = 11) (73%) and fair (n = 4) (27%). CONCLUSIONS: A high percentage of patients with achalasia exhibit pathologic GER before surgical therapy and seem to be at higher risk for failed surgical treatment. Thoracoscopic esophagomyotomy resulted in improvement in 92% of patients, and long-term follow-up indicates that these results are durable. PMID- 11602887 TI - The clinical diagnosis of chronic acalculous cholecystitis. AB - BACKGROUND: Chronic acalculous cholecystitis (CAC), a diagnosis of exclusion, appears to be more common than was previously thought. We correlated the pathology with test results and response to treatment in a prospective study to obtain data for evidence-based management. METHODS: The study subjects were patients with chronic biliary symptoms but had normal sonogram results. They were further investigated with esophagogastroduodenoscopy, multidiscipline evaluations, and cholecystokinin-stimulated scintigraphy (CCK-HIDA). They were offered laparoscopic cholecystectomy (LC) when the symptoms were intransigent, and the main abnormality was a low ejection fraction (EF) as determined by CCK HIDA. We analyzed the histologic findings of the gallbladder, CCK-HIDA EF, and clinical outcomes during the control period with a concurrent series of LC for calculus from the same surgeons. RESULTS: Of 176 cholecystectomies for biliary pain without stones, 152 had pathologically verified CAC. EF by CCK-HIDA was low in patients with CAC (18%) and low in normal gallbladders (26%). In the same period, 497 patients had cholecystectomies for cholelithiasis. Lasting symptom relief for CAC after LC was not different from that for calculous disease (85% vs 90%). CONCLUSIONS: The syndrome consisting of chronic biliary symptoms, stone free sonograms, low EF in CCK-HIDA, and absence of other pain sources is highly predictive for CAC, which is well treated with LC, with results similar to those for calculous disease. PMID- 11602888 TI - A single center experience with extrahepatic cholangiocarcinomas. AB - BACKGROUND: Few large Western series on cholangiocarcinoma have been reported in the literature. We reviewed 40 consecutive cases of extrahepatic cholangiocarcinomas referred to a single center. METHODS: From 1992 until 2000, 40 patients with extrahepatic cholangiocarcinomas were evaluated. The charts of all patients were reviewed to evaluate predictors of survival. Survival was calculated with the Kaplan-Meier method. RESULTS: Forty patients were referred for management of extrahepatic cholangiocarcinomas. Tumors were located in the distal common duct in 3 (7.5%), mid duct in 5 (12.5%), and at the bifurcation in 32 (80%). Surgical resection was attempted in 32 (80%) patients and was curative in 9 (22.5%), palliative in 11 (27.5%), and diagnostic in 12 (30%). Mean survival for all patients was 21.1 +/- 5.1 months and on the basis of tumor stage was 71.4 +/- 15.4, 39.7 +/- 10.6, 19.2 +/- 2.9, 3.9 +/- 1.8, and 6.9 +/- 1.3 months for stages I, II, III, IVA, and IVB, respectively. Mean survival was 51.1 +/- 13.5 months versus 10 +/- 1.8 months in those with curative and noncurative resections, respectively. The presence of a portal mass was associated with a reduction in mean survival from 28.4 +/- 7.2 months to 6.0 +/- 1.9 months. CONCLUSIONS: Extrahepatic cholangiocarcinoma remains a dismal disease with only a 22.5% chance of a curative surgical resection, achieving a 5-year survival rate of 44.4%. Only the absence of a portal mass was predictive of a possible curative resection and long-term survival. PMID- 11602889 TI - Predicting the biologic behavior of ductal carcinoma in situ: an analysis of molecular markers. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast encompasses a heterogeneous group of noninvasive cancers that now represents 19% of new breast cancer cases. Optimal treatment remains controversial. We undertook this study to characterize the relationship between angiogenic markers and the biologic behavior of various DCIS phenotypes. METHODS: We performed histopathologic review and immunohistochemistry for p53, vascular endothelial growth factor (VEGF), and factor VIII-related antigen on 103 specimens of pure DCIS. RESULTS: VEGF expression was seen in 89 tumors (86%) and correlated with microvessel density (MVD). Among VEGF-negative tumors, mean MVD (number of microvessels per square millimeter) was 48 +/- 19, versus 117 +/- 7 for tumors expressing VEGF (P =.001). Strong p53 expression was observed in 28 tumors (27%) and was associated with comedo histology, high tumor grade, necrosis, high MVD, and ipsilateral tumor recurrence (all P < or =.03). Among 8 patients with ipsilateral recurrence, 5 (63%) had tumors with strong p53 expression, whereas only 24% of patients without recurrence had tumors with strong p53 expression (P =.03). Although 7 of 8 patients with ipsilateral recurrence had tumors with VEGF and high MVD, neither parameter achieved statistical significance. CONCLUSIONS: These data suggest that molecular alterations may help predict the biologic aggressiveness of DCIS. Mutant p53 expression predisposes the patient toward ipsilateral recurrence, perhaps by promoting angiogenesis. Further investigation may identify clinically useful markers and novel treatment strategies. PMID- 11602890 TI - Cytokines and the pathogenesis of nosocomial pneumonia. AB - BACKGROUND: Nosocomial pneumonia (NP) in injured patients is a significant clinical problem. We hypothesize that the pathogenesis of NP in injured patients involves an imbalanced cytokine response within the alveolar airspace that may inhibit effector cell function. METHODS: Proinflammatory (IL-8) and anti inflammatory (IL-10) levels were measured in bronchoalveolar lavage (BAL) fluid from multitrauma patients on admission, 24, 48, and 72 hours post-injury and following lipopolysaccharide (LPS) induction of alveolar cells. Patients were compared based on IL-8 levels and the development of NP. RESULTS: A high level of IL-8 on admission was associated with the development of NP. In addition, levels of IL-8 were significantly greater in NP-positive patients at all time points. The IL-10 levels decreased from admission values in NP-negative patients but increased in NP-positive patients. Furthermore, a high level of IL-10 ( > 120 pg/mL) at 72 hours post-injury was associated with the development of NP. Alveolar cells from NP-positive patients produced significantly more IL-10 in response to LPS than cells from NP-negative patients. CONCLUSIONS: The pathogenesis of NP in injured patients involves an early and severe IL-8 process within the lung followed by an exaggerated IL-10 response that may inhibit effector cell function. PMID- 11602891 TI - Prophylactic total gastrectomy for familial gastric cancer. AB - BACKGROUND: An autosomal dominant syndrome of diffuse gastric cancer has been reported with germline mutations in the E-cadherin (CDH1) gene and has been identified in approximately 14 families and 50 individuals worldwide. Penetrance of the gene is 70% to 80%, and the average age of onset of gastric cancer is 37 years. These characteristics have led to the consideration of prophylactic total gastrectomy in family members with CDH1 mutations. METHODS: We report here the first use of prophylactic gastrectomy in 6 asymptomatic members of 2 families (2 males, 4 females; ages 22, 27, 28, 35, 39, and 40) based on family pedigree and genetic analysis. Total gastrectomy was performed via an upper midline incision, and reconstruction of the gastrointestinal tract was done via a Roux-en-Y esophagojejunostomy. Complete removal of all gastric mucosa was documented intraoperatively, and confirmation was made that only esophageal mucosa remained at the proximal specimen margin. RESULTS: The gastric specimens appeared normal, and the results of routine pathologic examination were negative for cancer. All specimens from patients who tested positive for E-cadherin mutations were subjected to a research protocol of microscopic sectioning in which 150 to 250 tissue blocks were examined. All of these patients had microscopic foci of cancer, often at multiple sites, with overlying normal gastric mucosa. CONCLUSIONS: E-cadherin gene mutations in association with familial gastric cancer is a new disease for which prophylactic surgery must be considered. The morbidity of this operation is much higher than that for other genetic diseases, but the alternative is a mortality risk of more than 80% at a young age. PMID- 11602892 TI - Complete 5-year follow-up of a prospective phase II trial of preoperative chemoradiotherapy for esophageal cancer. AB - BACKGROUND: Conclusive evidence supporting the routine use of multimodality therapy in esophageal cancer is lacking. However, since long-term survival after esophagectomy alone is unusual, clinical trials designed to identify effective therapeutic regimens are essential. We report here the 5-year results of a phase II induction chemoradiotherapy trial. METHODS: From August 1991 to January 1995, 44 patients with esophageal or gastroesophageal junction carcinoma were treated with a combination of 5-fluorouracil, cisplatin, and interferon-alpha with concurrent external beam radiotherapy. RESULTS: Forty-one (93%) patients completed chemoradiotherapy, with most toxic events recorded as grade I or II. Curative resection (all gross tumor removed) was achieved in 36 of 37 surgical explorations, with 10 tumors demonstrating complete pathologic response and 23 showing partial pathologic response. Median follow-up for survivors was 75 months (range, 60-100 months). Five-year survival for all patients was 32%, with a median survival of 28 months. Five-year disease-free survival in patients with curative resection was 36% (median, 26 months) and overall survival was 39% (median, 34 months). Five-year survival for patients with curative resection whose disease responded to chemoradiotherapy was 42% (median overall survival, 36 months). Local-regional recurrence alone occurred in 3 patients, distant failure alone in 12 patients, and combined local-regional and distant failure in 2 patients. A Cox proportional hazards model identified both pathologic tumor and nodal stage as independent predictors of disease-free survival. Fourteen patients (32%) were 5-year survivors; 1 of these patients later experienced disease recurrence and died. CONCLUSIONS: Preoperative chemoradiotherapy can result in a long-term and durable disease-free state. Only large, multi-institutional phase III trials can determine whether combined modality therapy is superior to resection alone. PMID- 11602893 TI - Outcomes analysis in patients undergoing laparoscopic adrenalectomy for hormonally active adrenal tumors. AB - BACKGROUND: Laparoscopic adrenalectomy (LA) has become the preferred method of removal of most adrenal neoplasms, but few studies have evaluated the functional outcomes of this approach. The purpose of this study was to analyze our operative results and the clinical and biochemical responses to LA in patients with various hormonally active adrenal tumors. METHODS: From 1993 through November 2000, 72 patients with functional adrenal tumors underwent attempted LA. Data were obtained retrospectively by review of medical records, during routine follow-up, and by patient questionnaire. RESULTS: Indications for adrenalectomy were pheochromocytoma (n = 35), aldosteronoma (n = 29), cortisol-producing adenoma (n = 5), and adrenocorticotropic hormone-dependent Cushing's syndrome (n = 3). LA was completed in 70 of 72 patients, with 2 conversions (3%) to open adrenalectomy. Mean operative time for unilateral LA was 176 +/- 60 minutes, and postoperative length of hospital stay averaged 3.0 +/- 1.7 days. Complications, most of which were minor, occurred in 19% of patients; there were no serious complications or perioperative deaths. Two patients were unavailable for follow up. At a mean follow-up interval of 37.6 months after LA (range, 2-90 months), resolution of clinical and biochemical signs of adrenal hyperfunction was accomplished in 34 of 34 patients with pheochromocytomas, 25 of 26 patients with aldosteronomas, 5 of 5 patients with cortisol-producing adenomas, and 3 of 3 patients with andrenocorticotropic hormone-dependent Cushing's syndrome. Two patients with multiple endocrine neoplasia (MEN) type 2 had contralateral pheochromocytomas removed 4 and 5 years after the initial surgery. Persistent hypertension necessitating medication was present in 72% of patients with aldosteronomas, although 92% of these patients had improved blood pressure control after LA. Recurrent hypokalemia developed in 1 patient (4%) with a cortical nodule in the contralateral adrenal. No local or distant tumor recurrences have occurred. CONCLUSIONS: LA results in an excellent clinical outcome in patients with various functional endocrine tumors. LA is associated with few major complications, and clinical and biochemical cure rates are comparable with those of open adrenalectomy during long-term follow-up. PMID- 11602894 TI - Fluorodeoxyglucose positron emission tomography as an adjunct to carcinoembryonic antigen in the management of patients with presumed recurrent colorectal cancer and nondiagnostic radiologic workup. AB - BACKGROUND: The purpose of this study was to determine the role of fluorodeoxyglucose positron emission tomography (PET) in localizing disease in patients with colorectal cancer with radiologically occult symptomatology or increases in carcinoembryonic antigen (CEA) level. METHODS: Two hundred seventy seven patients with colorectal cancer underwent PET scanning between November 1998 and September 2000 prompted by (1) increasing CEA level and nondiagnostic imaging or (2) symptoms with normal CEA level and nondiagnostic imaging. PET results were correlated with operative findings/histology, clinical follow-up data, and CEA level to determine PET's accuracy in determining the source of symptoms or CEA. RESULTS: Fifteen patients had increasing CEA levels, and 14 had abnormal PET. Two of these 14 were denied exploration because PET suggested widely metastatic disease. Nine patients underwent exploration with curative intent. In 1 patient, recurrence was not pathologically confirmed (false-positive rate, 8%). Two had disease beyond that predicted by PET, and 6 underwent complete resection and normalized their CEA levels. Four symptomatic patients with normal CEA levels and negative x-rays had abnormal PET; at exploration, 3 had no evidence of recurrence. CONCLUSIONS: PET imaging can often accurately localize the source of radiologically occult increases in CEA level and select that subset of patients eligible for therapeutic laparotomy. Symptomatic, PET-positive patients with normal CEA levels frequently undergo nontherapeutic laparotomy, and PET findings should be interpreted with caution in these patients. PMID- 11602895 TI - Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. AB - BACKGROUND: Calciphylaxis is a rare but life-threatening condition occasionally affecting patients with secondary hyperparathyroidism. Parathyroidectomy has been advocated as the only potentially curative intervention. METHODS: Between January 1989 and May 2000, 13 patients with pathologic/clinical criteria of calciphylaxis were treated at our institution. Of these 13 patients, 7 were managed with medical therapy alone, and 6 were referred for parathyroidectomy. The medical records were reviewed, and patients/relatives were interviewed. RESULTS: All patients had cutaneous wounds requiring local debridement predominantly located on the lower extremities or abdominal wall. Six patients underwent subtotal (3.5 gland) parathyroidectomy without morbidity. All 6 had significant reductions in parathyroid hormone levels after surgery (mean decrease, 94% +/- 0%), and all reported resolution of pain and healing of cutaneous wounds. Of the remaining 7 patients who had medical management alone, 5 eventually died of complications related to calciphylaxis. In comparing the 2 groups, patients who underwent parathyroidectomy had a significantly longer median survival than those who did not have surgery (36 vs 3 months, P =.021). CONCLUSIONS: Calciphylaxis frequently causes gangrene, sepsis, and eventual death. Parathyroidectomy can be performed with minimal morbidity and is associated with resolution of pain, wound healing, and a significantly longer median survival. Therefore, patients with secondary hyperparathyroidism and signs/symptoms of calciphylaxis should be referred promptly for consideration of parathyroidectomy. PMID- 11602896 TI - Minimally invasive repair of pectus excavatum: a single institution's experience. AB - BACKGROUND: The Nuss repair of pectus excavatum is a relatively new, minimally invasive surgical (MIS) alternative to the traditional open "Ravitch-type" operation. We have one of the larger single-center experiences to date, and we conducted this clinical study to evaluate our early experience, emphasizing initial outcome and technical modifications designed to minimize complications. METHODS: A retrospective chart review was performed on 112 patients who underwent 116 pectus excavatum repairs between January 1995 and January 2001. The Nuss procedure was performed in 80 patients, and open repair was performed in 32 patients. Information about demographics, deformity, operative course, complications, and early outcome was recorded. RESULTS: Operative duration was 143 minutes for the open group and 53 minutes for the Nuss MIS group (P <.001). Blood loss was 6 mL/kg for the open group and 0.5 mL/kg for the MIS group (P <.001). Postoperative hospitalization was 3.2 days for the open group versus 3.7 days for the MIS group (P<.05). CONCLUSIONS: The MIS pectus repair can be performed safely with minimal blood loss and reduced operative time. Short-term analysis of the quality of repair, including absence of preoperative symptoms, patient satisfaction, and cosmetic appearance are encouraging. PMID- 11602897 TI - Transmission of donor cancer into cardiothoracic transplant recipients. AB - BACKGROUND: The demand for transplantable organs exceeds donor supply. Patients with central nervous system (CNS) or other tumors are controversial donors, and the donor cancer transmission rates in cardiothoracic transplant recipients have not been determined. The Israel Penn International Transplant Tumor Registry (IPITTR) was queried to define the risk of donor cancer transmission in cardiothoracic transplant recipients. METHODS: All heart, lung, or heart-lung recipients of organs from donors with a history of malignancy were reviewed. Donor and recipient demographics, histologic findings, and recurrence were reviewed. RESULTS: Twenty-two patients received 17 hearts, 3 lungs, and 2 heart lung transplants from donors with known CNS or other malignancies. No malignancy transmissions were noted with astrocytomas (n = 3) or glioblastomas (n = 1), except a medulloblastoma that recurred at 6 months. The transmission rate for CNS tumors was 17% (1 of 6), and 1- and 3-year survivals were 67% and 50%, respectively. The most common non-CNS donor cancer was renal cell carcinoma (n = 5). Two renal cell cancer transmissions occurred, both when vascular extension was present. The most aggressive tumor transmission was choriocarcinoma (n = 2) and melanoma (n = 2). Two of 3 choriocarcinomas metastasized with 67% mortality, and both melanomas were transmitted and resulted in death. Other donor cancers included angiosarcoma (n = 2), cervical (n = 1), lung (n = 1), prostate (n = 1), and a liver adenocarcinoma. The transmission rate for all non-CNS groups was 56% (9 of 16) with a 2-year survival of 40%. CONCLUSIONS: The IPITTR experience indicates that tumor transmission is high (10 of 22, 45%) in cardiothoracic transplant recipients. Similar to intra-abdominal organ recipients in the IPITTR, (1) renal cell carcinomas without capsular invasion appear safe with no transmission, (2) vascular invasion in renal cell carcinoma appears to result in early tumor transmission, and (3) melanoma and choriocarcinoma have high rates of transmission with early and almost universal death. PMID- 11602898 TI - Mechanisms of human neutrophil oxidant production after severe injury. AB - BACKGROUND: The purpose of this study was to determine the mechanisms of enhanced oxidant production after severe injury. METHODS: Neutrophils were harvested from patients within 24 hours of admission who had an injury severity score greater than 16. Nonadherent and adherent neutrophil oxidant production was measured after N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. Translocation of cytochrome b558 and cytosolic components p47phox and p67phox were determined by oxidation-reduction spectroscopy and immunoblotting, respectively. Flow cytometry measured integrin expression. Integrin and p47phox colocalization was examined by confocal microscopy. RESULTS: Eighteen patients were studied within 15 +/- 1.4 hours. Four women and 14 men suffered a blunt injury and had a mean injury severity score of 22 (range, 16 to 34). Nonadherent patient neutrophils showed a decrease in fMLP-stimulated oxidant production, whereas adherent neutrophil oxidant production was increased in both the vehicle control and fMLP stimulated groups. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components p47phox and cytochrome b558 were mobilized to the plasma membrane, whereas p67phox showed minimal change. Integrin CD11b a chain showed a significant increase in expression. Confocal microscopy showed colocalization of p47phox and a chain CD11b on the plasma membrane of patient neutrophils. CONCLUSIONS: Colocalization of NADPH oxidase components and integrins may regulate the enhanced oxidant production in human neutrophils after severe injury. PMID- 11602899 TI - Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. AB - BACKGROUND: We reviewed 36 patients with liver metastases from islet cell tumors of the pancreas (n = 18) and carcinoid tumors (n = 18) who were treated with surgical resection (n = 16) or hepatic chemoembolization (n = 20). METHODS: All resections were complete and included 4 lobectomies, 6 segmental resections, and 6 wedge resections. There were no operative deaths. RESULTS: Median survival has not yet been reached, and the actuarial 5-year survival rate is 70%. Prognostic variables associated with improved disease-free survival included prior resection of the primary tumor and 4 or fewer metastases resected (P <.05). With an average of 3 chemoembolization procedures per patient, 17 of 20 patients (90%) demonstrated either a significant radiographic response (n = 5), stabilization of tumor mass (n = 2), or improvement of clinical symptoms (n = 10). Factors related to a sustained response (more then 1 year) included surgical resection of the primary tumor, 4 or more chemoembolization procedures, and liver metastases of 5 cm or smaller. Median survival after treatment was 32 months (range, 7-63 months), and the actuarial 5-year survival rate was 40%. CONCLUSIONS: Surgical resection of metastatic neuroendocrine tumors provides the best chance for extended survival. Chemoembolization effectively improves clinical symptoms and, in selected patients, may provide sustained tumor control. PMID- 11602900 TI - Laparoscopic fundoplication: a model for assessing new technology in surgical procedures. AB - BACKGROUND: Surgical success has traditionally been judged from the surgeon's perspective. A more complete evaluation of outcome incorporates the patient's, surgeon's, and payor's perspectives. Because gastroesophageal reflux disease (GERD) is primarily a quality-of-life (QOL) problem, the evaluation of laparoscopic fundoplication (LF) is a useful model for evaluating outcomes from these 3 perspectives. METHODS: Between 1995 and 2000, 74 patients underwent primary LF for GERD. In addition to undergoing physiologic testing, 63 patients (85%) were evaluated with use of a disease-specific health-related QOL scale (GERD-HRQL), scored from 0 (no symptoms) to 45 (incapacitating symptoms). Thirty three patients also completed a generic QOL questionnaire (SF-12), in which patient satisfaction was scored from 1 (very satisfied) to 5 (very dissatisfied). Preoperative and postoperative data were compared with use of the Wilcoxon signed rank test or the paired t test. RESULTS: The median GERD-HRQL score improved from 18 to 0 at 2 years postoperation (P <.01). The median satisfaction score improved from 5 to 1 (P <.01). The SF-12 summary scores also improved after 6 weeks postoperatively (P <.05). The mean +/- SD lower esophageal sphincter pressure rose from 7.3 +/- 4 mm Hg preoperatively to 17.5 +/- 6 postoperatively (P <.01), and the mean percentage of time that the esophagus was exposed to a pH of less than 4 declined from 14.7% +/- 12% to 1.1% +/- 2% (P <.01). The median operative time was 110 minutes, which declined with experience with the procedure (P <.01). Median postoperative stay was 2 days. CONCLUSIONS: In evaluating the outcomes of a new procedure, 3 overlapping points of view were addressed: the patient's (QOL, satisfaction), the surgeon's (physiologic changes), and the payor's (operating room time, hospital stay). With use of this framework, we found that LF for GERD improves QOL, corrects the physiologic abnormalities, and is associated with short hospitalization and operating time that declines with experience with the procedure. PMID- 11602901 TI - Burnout among American surgeons. AB - BACKGROUND: The long-term consequences of stress on the surgeon are unknown. One manifestation of stress is burnout. The purpose of this study was to measure the prevalence of burnout in actively practicing American surgeons. METHODS: The Maslach Burnout Inventory and a questionnaire of our own design were sent to 1706 graduates of various University of Michigan surgical residencies (1222) and members of the Midwest Surgical Association (484). The response rate was 44%. Responses from 582 actively practicing surgeons were the sample used for analysis. RESULTS: Thirty-two percent of actively practicing surgeons showed "high" levels of emotional exhaustion, 13% showed "high" levels of depersonalization, and 4% showed evidence for low personal accomplishment. Younger surgeons were more susceptible to burnout (r = -0.28, P <.01). Burnout was not related to caseload, practice setting, or percent of patients insured by a health maintenance organization. Important etiologic factors were a sense that work was "overwhelming" (r = 0.61, P <.01), a perceived imbalance between career, family, and personal growth (r = -0.56), P <.01), perceptions that career was unrewarding (r = -0.42, P <.01), and lack of autonomy or decision involvement (r = -0.39, P <.01). A strong association was noted between burnout elements and a desire to retire early (r = 0.50, P <.01). CONCLUSIONS: Burnout is an important problem for actively practicing American surgeons. These data could be used to modify existing surgical training curricula or as an aid to surgical leadership when negotiating about the surgical work environment. PMID- 11602902 TI - Admitting service influences the outcomes of patients with small bowel obstruction. AB - BACKGROUND: Small bowel obstruction (SBO) is a common problem that often requires operation. We tested the hypotheses that patients admitted to a surgical service have improved outcomes and that these outcomes are related to early operation. METHODS: Retrospective review of 281 patients with 336 episodes of SBO between 1992 and 1998 was performed. Parametric and nonparametric analysis was used as appropriate. RESULTS: There were 222 admissions to a surgical service and 114 admissions to a medical service. Patient characteristics were similar between groups. Eighty-seven percent of patients had a previous abdominal or pelvic operation. There were 211 patients (217 admissions) who required operation. Operated patients admitted to the surgical service had a shorter preoperative (2.7 vs 6.3 days, P <.01) and overall length of stay (LOS) (17.9 vs 22.8 days, P <.0001). There was no difference in time to resumption of diet between groups. The number of previous admissions or operations did not affect the need for operative intervention. Unoperated patients admitted to a medical service had a shorter time to resumption of diet (3.1 vs 4.3 days) and LOS (4.8 vs 7.2 days, both P <.05) than the surgical service group. Operative mortality was 3.4%. The likelihood of developing a complication was related to the occurrence of an enterotomy (n = 21, odds ratio = 2.69; 95% confidence interval [CI]: 1.1-6.7, P =.014) or the need for bowel resection (odds ratio = 1.97; 95% CI: 1.2-3.5, P =.02). The occurrence of a complication resulted in a 46% increase in LOS (P <.0001). Patients operated on within 24 hours of admission had a decreased LOS (P <.05) and mortality, with no difference in the occurrence of postoperative complications. CONCLUSIONS: Patients with SBO who require operation benefit from a shorter time to operation and reduced LOS when admitted to a surgical service. Early operation is associated with a reduction in mortality, and avoidance of enterotomy decreases the risk of complications. PMID- 11602903 TI - Roux-en-Y internal drainage is the best surgical option to treat patients with disconnected duct syndrome after severe acute pancreatitis. AB - BACKGROUND: Roux-en-Y (RNY) internal drainage has been our primary surgical strategy to definitively treat disconnected duct syndrome in patients after severe acute pancreatitis (SAP). This study compares the results of internal drainage with the results of distal pancreatectomy-splenectomy (DPS) performed in a contemporaneous group of patients. METHODS: For 5 years (June 1995 to June 2000), 27 consecutive patients with disconnected duct syndrome after SAP were identified: 13 treated with internal drainage and 14 with DPS. Fistula characteristics, operative management, and clinical outcome were analyzed. Comparisons between groups were made with the Student t test and Fisher exact test, with statistical significance defined as P <.05. RESULTS: Age, sex, etiology of pancreatitis, comorbid diseases, and prior operations were similar between groups. Internal drainage required less operative time (211 +/- 37 vs 269 +/- 88 minutes, P =.04), blood loss (735 +/- 706 vs 2757 +/- 3062 mL, P =.03), and transfusion requirements (0.69 +/- 1.7 vs 4.21 +/- 8.0 units, P =.05). Clinical outcomes--as measured by postoperative complication rate, reoperation rate, fistula recurrence rate, and death rate--were similar between groups. CONCLUSIONS: RNY internal drainage, when technically feasible, is the best surgical option to treat disconnected duct syndrome after SAP. PMID- 11602904 TI - Failed primary management of iatrogenic biliary injury: incidence and significance of concomitant hepatic arterial disruption. AB - BACKGROUND: Vasculobiliary injury (VBI) is a well-recognized complication of laparoscopic cholecystectomy (LC). In patients with failed primary management of bile duct injury (BDI), an assessment of the hepatic arterial system may be important to determine the presence of VBI. This study was conducted to determine the incidence of VBI in patients with failed primary management of LC-related BDI and to establish a potential correlation between the level of BDI and the incidence of VBI. METHODS: A retrospective review was conducted on 18 patients referred for failed primary management of LC-related BDI who underwent prospective arteriography as part of the preoperative work-up. RESULTS: Of the 18 patients who sustained BDI, Bismuth level 4 lesions were found in 7 patients (39%), level 3 in 8 patients (44%), and level 2 in 3 patients (17%). VBI was identified on arteriography in 11 patients (61%). VBI was present in 71% of patients with level 4 lesions, 63% of patients with level 3 lesions, and 33% of patients with level 2 lesions. The time interval from primary management to its failure was longer in VBI than in BDI alone. CONCLUSIONS: We have observed a high incidence of VBI in patients with failed primary management of LC-related BDI. Arterial disruption may affect the outcome of primary management of BDI. PMID- 11602905 TI - Atypical hyperplasia, proliferative fibrocystic change, and exogenous hormone use. AB - BACKGROUND: The association between breast cancer development and exogenous hormone use (EHU) is suggested by indirect clinical evidence. We undertook this study to better define the relationship that EHU has with proliferative fibrocystic change (PFC) and atypical hyperplasia (AH). METHODS: Women diagnosed with AH without associated carcinoma from January 1990 to December 1999 were compared with control subjects who underwent breast biopsy procedures during the same interval and who were diagnosed with either a proliferative fibrocystic change (PFC) or a nonproliferative fibrocystic change (NPFC). EHU was defined as the use of estrogen or progesterone taken together or separately within 3 months of biopsy. RESULTS: EHU was significantly higher in patients with AH compared with women with NPFC (P =.01). This observation was also significant if all proliferative change (both AH and PFC) was compared with NPFC (P =.03); it was not significant when PFC alone was compared with NPFC. No significant difference in EHU was demonstrated between women with AH and those with PFC. CONCLUSIONS: There is strong association between AH and EHU. These results support the theory that a continuum exists between hyperplasia and carcinoma and that EHU may influence the transition from one to the other in an undefined subset of women. We encourage our patients with AH to discontinue EHU. PMID- 11602906 TI - Renal allograft outcomes in African American versus Caucasian transplant recipients in the tacrolimus era. AB - METHODS: Between January 1995 and December 1999, 185 kidney transplants were performed with tacrolimus (TAC)-based immunosuppression including 120 African American (AA, 65%) and 65 Caucasian recipients (C, 35%). Mean follow-up was 34 months. The AA group was characterized by a higher incidence of renal disease due to hypertension (72% AA vs 37% C, P <.001), pretransplant dialysis (95% AA vs 82% C, P =.003), waiting time (1.9 years AA vs 1.1 years C, P =.02), cadaveric donation (88% AA vs 68% C, P =.01), HLA mismatching (mean 3.5 AA vs 2.4 C, P <.001), and delayed graft function (DGF; 50% AA vs 22% C, P =.001). RESULTS: The 5-year actuarial patient and graft survival rates were 96% AA versus 83% C (P = NS) and 83% AA versus 75% C, (P = NS), respectively. The incidence of acute rejection (21% AA vs 12% C, P = NS) and mean time to acute rejection (12 months AA vs 11 months C) were similar. Although the incidence of chronic allograft nephropathy (CAN) was comparable (7% AA vs 5% C), the mean time to CAN was shorter in AA recipients (18 months AA vs 37 months C, P =.03). CONCLUSIONS: These results suggest marked improvement in post-transplant outcomes in the TAC era in patients with multiple immunologic risk factors including AA ethnicity, cadaveric donor source, DGF, and HLA mismatching. PMID- 11602907 TI - Differences in arterial and mixed venous IL-6 levels: the lungs as a source of cytokine storm in sepsis. AB - BACKGROUND: Several investigators have shown that blood levels of interleukin 6 (IL-6) correlate with the severity of illness in critically ill or injured patients. However, little is known about differential arterial and venous blood levels of the cytokine, especially across the lungs. METHODS: We measured differences in IL-6 levels in pulmonary and systemic arterial blood and then documented the production or elimination of IL-6 by the lungs in 19 patients with severe illness. Prospective data were obtained from multiple, simultaneous systemic arterial (ART) and mixed venous (MV) blood samples that were drawn for IL-6 analysis from systemic arterial and pulmonary artery catheters in 7 patients awaiting vascular operation and in 12 trauma patients being treated in the intensive care unit. RESULTS: A lung disorder was present in 5 patients (pneumonia [n = 1], lung trauma [n = 4]) and absent in the remaining 14 patients. The following data were obtained (mean +/- SD) from the highest MV IL-6 levels (pg/mL) in each patient. In patients with a lung disorder (n = 5) compared with those with no disorder (n = 14), ART IL-6 was 9309 +/- 12,521 versus 134 +/- 128 (P =.010), MV IL-6 was 5516 +/- 7420 versus 137 +/- 129 (P =.011), the absolute difference was 3793 +/- 5271 versus -3 +/- 15 (P =.011), and the percentage difference was 37.4% +/- 29.8% versus 1.5% +/- 12.3% (P =.001). The ART and MV IL 6 levels tended to be much higher in the 5 patients with pneumonia (n = 1) and lung injuries (n = 4) than in the patients without apparent pulmonary problems. In addition, the patients with a primary lung disorder demonstrated a net increase in IL-6 levels across the lungs, whereas there was no increase, but rather, a net reduction of IL-6 levels across the lungs in patients without a lung disorder. CONCLUSIONS: The lung appears to be a major producer of IL-6 in patients with an inflammatory lung process. There is a 39% increase in the level of IL-6 as it passes through inflamed lung, producing a marked difference in ART and MV IL-6 levels. Normal lung demonstrated little effect on either ART or MV IL 6 levels. PMID- 11602908 TI - Repair of recurrent rectovaginal fistulas. AB - BACKGROUND: Recurrent rectovaginal fistulas (RRVFs) pose a challenging problem, which can be treated by different surgical procedures. We performed this study to determine the ultimate success rate of various repair techniques. METHODS: Using a standard data collection form, we retrospectively reviewed charts of patients treated for RRVF. RESULTS: Between 1991 and 2000, 57 procedures were performed in 35 women who presented with RRVF. Median follow-up was 4 months (interquartile range, 1,25). The causes of RRVF included obstetrical injury (n = 15), Crohn's disease (n = 12), fistula occurring after proctocolectomy with ileal pouch-anal anastomosis (for ulcerative colitis, n = 3; indeterminate colitis, n = 1; familial polyposis, n = 1), cryptoglandular disease (n = 2), and fistula occurring immediately after low anterior resection for rectal cancer (n = 1). The methods of repair used included mucosal advancement flap (n = 30), fistulotomy with overlapping sphincter repair (n = 14), rectal sleeve advancement (n = 3), fibrin glue (n = 1), proctectomy with colonic pull-through (n = 2), and ileal pouch revision (n = 6). Twenty-seven of 34 (79%) patients with adequate follow-up eventually healed after a median of 2 operations. Logistic regression was used to analyze outcome according to etiology of fistula, patient age, number of prior repairs, time interval between last repair and current repair, and presence of fecal diversion. Crohn's disease, the presence of a diverting stoma, and decreased time interval since prior repair were associated with a poorer outcome. CONCLUSIONS: Most RRVFs can be successfully repaired, although repeated operations may be necessary. Delaying repair may improve outcome. PMID- 11602909 TI - Operative management of "hockey groin syndrome": 12 years of experience in National Hockey League players. AB - BACKGROUND: At the elite level of hockey, groin injuries can threaten a player's career. The aim of this review is to describe the clinical presentation and evaluate our operative approach to "hockey groin syndrome" in National Hockey League (NHL) players. METHODS: Between November 1989 and June 2000, 22 NHL players with debilitating groin pain underwent operative exploration. A repair, including ablation of the ilioinguinal nerve and reinforcement of the external oblique aponeurosis with a Goretex (W.L. Gore & Associates, Inc, Flagstaff, Ariz) mesh, was performed. Medical records were reviewed, and the players or their trainers were contacted by telephone after a mean follow-up period of 31.2 months to assess function, symptoms, and overall satisfaction. RESULTS: All patients had tearing of the external oblique aponeurosis, with branches of the ilioinguinal nerve emerging from the torn areas. At follow-up, 18 players (82%) had no pain, whereas 4 (18%) reported mild, intermittent pain. All 22 patients returned to playing hockey, with 19 (85%) able to continue their careers in the NHL. CONCLUSIONS: The "hockey groin syndrome," marked by tearing of the external oblique aponeurosis and entrapment of the ilioinguinal nerve, is a cause of groin pain in professional hockey players. Ilioinguinal nerve ablation and reinforcement of the external oblique aponeurosis successfully treats this incapacitating entity. PMID- 11602910 TI - Primary closure of complicated perineal wounds with myocutaneous and fasciocutaneous flaps after proctectomy for Crohn's disease. AB - BACKGROUND: The purpose of this study is to detail the use of advanced tissue transfer techniques to achieve primary closure of the perineal wound after proctectomy for Crohn's disease. METHODS: Between October 1984 and March 2000, we performed proctectomy with permanent intestinal stoma in 97 patients with Crohn's disease. Twelve of these patients (12.4%) required at least 1 myocutaneous flap to achieve primary closure of the perineal wound. Details of each patient's perioperative course were recorded prospectively. RESULTS: All 12 patients had fistulizing perineal Crohn's disease combined with Crohn's proctitis. Two patients had a simultaneous anal adenocarcinoma. Indications for flap closure included management of large perineal skin defects (n = 11), reconstruction of the posterior vaginal wall (n = 2), and the need to fill a large pelvic dead space (n = 3). (Three patients had a combination of the previous indications). In total, 6 rectus abdominis, 5 gluteus maximus, 1 posterior thigh, 3 chimeric posterior thigh, and 1 latissimus dorsi flaps were performed. Six patients required more than 1 flap. Three patients had complications develop related to the flaps (2 wound hematomas and 1 seroma). Complete perineal healing was achieved in all patients. CONCLUSIONS: Complex tissue flap closure of the perineal wound after proctectomy for perineal complications of Crohn's disease should be considered when simple closure is not possible or when reconstruction of the posterior wall of the vagina is necessary. PMID- 11602911 TI - Long-term evaluation of extended thymectomy with anterior mediastinal dissection for myasthenia gravis. AB - BACKGROUND: Thymectomy for the treatment of myasthenia gravis (MG) is well established. The extent of resection, however, remains a source for debate. Outcomes for newer surgical techniques need to be compared to more extensive procedures. METHODS: A retrospective review was done of 64 consecutive patients who underwent transsternal thymectomy with extended anterior mediastinal dissection for MG between 1979 and 2000 and who were operated on by a single surgeon. RESULTS: Fifty-six patient charts were available, providing 58 operative procedures. Three patients had died of unrelated causes. The mean age of symptom onset was 36.0 +/- 2.5 years, with a mean duration of 3.3 +/- 0.5 years until surgery was undertaken. The mean length of follow-up was 6.8 +/- 0.8 years. Operative procedures were associated with a 10.3% major morbidity rate and no mortality. Drug-free remission was achieved in 50.0% of the patients, and symptoms were absent or improved in 76.8% of the patients. Patients followed up long-term (>10 years) achieved the greatest remission rate (71.4%) and symptomatic improvement (85.7%). After thymectomy, the mean dosages of prednisone and Mestinon decreased by 69.3% and 58.8%, respectively. CONCLUSIONS: Extended thymectomy provides excellent overall symptom improvement, which is enhanced over time. This review provides a basis for long-term comparison with other less invasive and perhaps less extensive procedures. PMID- 11602912 TI - [Focus subject: haematology/oncology]. PMID- 11602913 TI - [Allogeneic transplantation in malignant lymphoma]. AB - INTRODUCTION: Allogeneic transplantation of bone marrow and peripheral blood stem cells is a frequently discussed therapeutic option in the treatment of malignant lymphoma. By analysing the results of our own transplant program in patients with advanced lymphoma we tried to evaluate indications for allogeneic transplantations. METHODS: Data from lymphoma patients treated at the Klinikum Grosshadern between 1985 and 2001 were analysed retrospectively. RESULTS: 56 patients were included. 24 patients had low grade Non-Hogdkin's lymphoma (NHL) (follicular lymphoma: n = 8, mantle cell lymphoma: n = 6) or chronic lymphocytic leukemia (CLL: n = 10), 16 patients had high grade NHL (immunoblastic/lymphoblastic: n = 5; large cell/diffuse: n = 5) and 8 patients suffered from Hodgkins's disease. Median age was 41 years, 34 patients were transplanted from an HLA-identical sibling, 19 from an HLA-id. unrelated donor and three from an HLA-mismatched related donor. 30 patients received bone marrow and 26 peripheral blood stem cells. 22 pat. were treated with an intensive 12 Gy TBI containing conditioning regimen, whereas 34 patients were treated with a dose intensity reduced conditioning procedere. 25 patients are alive between 2 month and 15 years after transplantation. Overall survival after 2 years is 48 % for patients with low grade NHL (incl. CLL), 9.3 % for patients with high grade lymphoma and 25 % for patients with Hodgkin's disease. 1-year-transplant-related mortality (TRM) was 33.9 % in all patients. Dose-intensity-reduced conditioning was not able to reduce TRM. CONCLUSIONS: Allogeneic bone marrow or stem cell transplantation is able to induce long lasting complete remissions in patients with heavily pretreated malignant lymphoma. Results of allogeneic transplantation are encouraging in patients with follicular and other low grade lymphoma. However transplant-related toxicity is high. At present the impact of reducing the intensity of conditioning is not yet clear. PMID- 11602914 TI - [Multilocular Castleman's Disease of the mixed type. An rare differential diagnosis in lymphadenopathy with weakness, weight loss and night-sweats]. AB - HISTORY AND CLINICAL FINDINGS: A 36 years old nurse had been suffering from prolonged weakness, weight-loss of 6 kg, night-sweat and painful swelling of neck lymph nodes for one year. On admission she was in a reduced physical condition. Nuchal, cervical and inguinal lymphnodes were enlarged bilaterally. INVESTIGATIONS: Computed tomography showed enlarged lymph nodes in the neck and inguinally. Histology of the biopsies revealed the diagnosis of the mixed variant of Castleman's Disease. TREATMENT AND COURSE: A steroid treatment was initiated, administering 100 mg prednisone for 2 weeks, 75 mg for another 2 weeks and 50 mg for a month. The dose was then gradually reduced by steps of 10 mg. After 3 months the patient's physical state and lymph nodes were normalized. So treatment was terminated and the nurse was able to take up work again. CONCLUSION: If confronted with general lymphadenopathy associated with B-symptoms even without fever a Castleman's Disease should be taken into consideration. The prognosis of the multivariant form is uncertain. Transformation to malignant lymphoma is frequent. PMID- 11602916 TI - [Systemic treatment of renal-cell carcinoma--present status]. PMID- 11602915 TI - [Current therapeutic concept of acute promyelocytic leukemia]. PMID- 11602917 TI - [Documented infections during neutropenia--therapeutic and diagnostic recommendations. Study Group of Infections in Hematology and Oncology--Expert Group of the German Society for Hematology and Oncology]. PMID- 11602918 TI - [High-dosage treatment of breast cancer--in favour]. PMID- 11602919 TI - [High-dosage treatment of breast cancer - against]. PMID- 11602920 TI - [Inpatient violence: frequency, risk factors, preventive strategies]. AB - In contrast to Angloamerican and Scandinavian countries inpatient violence was not regarded as a problem in German-speaking countries for a long time. Only recently it has become a topic of increasing interest for clinical practice and research, whereby the present data exhibit significant parallels to the international development. After the discussion of methodological problems (e. g. varying definitions, sources of information, ways of registration) the paper presents the current state of knowledge about inpatient violence:Underestimation in general, mainly with respect to female patients; only a few patients are responsible for the majority of assaults; victims are rather staff members than fellow patients; discrepancy between the mostly minor physical, though major emotional consequences for victims; considerably negative effects on patient staff interactions and ward climate. Aside from patient-related actuarial and dynamic risk factors (social origin, previous history of aggressive behaviour, dissocial personality traits and - partly - diagnoses, acute intoxication, substance abuse, lack of insight and compliance, psychotic symptoms) external/contextual factors as patient-staff ratio, ward size, structure and climate, staff-attitudes, recognition of early warning signs and handling of risk situations are of major importance for the frequency and severity of incidents. Intervention and prevention strategies are focussing - aside from medication - on the aforementioned staff-related factors and patient-staff interactions. They are the principal basis for sufficient inpatient treatment beyond the problem of violence. PMID- 11602921 TI - [Symptoms from the spectrum of Attention-Deficit/Hyperactivity Disorder (ADHD) in sexual delinquents]. AB - The implications of ADHD for sexual delinquent behavior were investigated in a sample of 127 male sexual delinquents for whom social, forensic and psychiatric data were collected. For the retrospective evaluation of ADHD-symptoms, we used the Wender Utah Rating Scale (WURS, 61-item version). We also used the Eysenck Impulsiveness Questionnaire for the assessment of impulsivity. The prevalence of ADHD within the group of sexual delinquents was 27.6 % with a persistence rate of 14.2 % at a cut-off point of 90 in the WURS. The prevalence of ADHD within the control group was 7.8 % with a persistence rate of 3.0 %. The prevalence within the group of sexual delinquents dropped to 15.7 % for childhood ADHD-symptoms and 11.0 % for partial ADHD persistence in adulthood using a cut-off score of 100. In the control group the rates were 4.8 % and 2.4 % respectively. Based on ICD-10 criteria, 35.4 % of the sexual delinquents had no psychiatric disorder. We found personality disorders of the antisocial type (22.1 % of the sample) and paraphilias in 25.2 %. Approximately, half of the delinquents with paraphilia met the criteria of pedophilia. We also found schizophrenia, organic psychiatric disorders and mental retardations in less than 5 %. The criminal careers of the sexual delinquent group with a history of childhood ADHD symptoms started 10 years earlier. We also found a significant correlation between previous convictions and the retrospective diagnosis of ADHD symptoms. This was more prominent when a previous sexual offence could be found in their criminal record. These results illustrate the hypothesis, that in addition to paraphilias the presence of ADHD-symptoms might be an important vulnerability factor for sexual delinquency, esp. when there is a persistence into adulthood. This demonstrates the need for an early therapeutical intervention, since 44.1 % of the sample had previously undergone psychiatric treatment. PMID- 11602922 TI - [Cholesterol, omega-3 fatty acids, and suicide risk: empirical evidence and pathophysiological hypotheses]. AB - Studies in psychiatric patients described an association between lower serum cholesterol concentrations, suicidality, depression, impulsivity, and aggression which is not entirely attributable to depression-related malnutrition and weight loss. Several lines of evidence suggest that a serotonergic deficit in the prefrontal cortex may predispose vulnerable subjects to impulsive, autoaggressive, and suicidal behaviour in stressful life-events. In-vitro studies, animal experiments, and human in-vivo studies support the hypothesis that cholesterol reduction may contribute to the serotonergic abnormalities which have been postulated in suicidal subjects. Recently it was hypothesized that decreased consumption of polyunsaturated fatty acids, especially omega-3 fatty acids, may be a risk factor for depression and suicide. Data from human studies in healthy volunteers suggest that increasing the dietary intake of omega-3 fatty acids may increase central serotonergic activity and reduce impulsive and aggressive behaviours. Earlier epidemiological studies showed an association between low cholesterol concentrations and increased suicide risk. Recent epidemiological studies with greater samples and longer follow-up periods, however, even showed a positive correlation between cholesterol concentrations and suicide risk after controlling for potential confounding variables. Large trials of statins (simvastatin, lovastatin, pravastatin) did not show an increase of suicide mortality. PMID- 11602923 TI - [The indication for heroin prescription - considerations with the historical example of the opiate addicted Swiss author Friedrich Glauser (1896 - 1938)]. AB - Traditional indications for the prescription of opioids to addicts are continuous opioid abuse despite qualified addiction treatment or temporary substitution treatment, if temporarily detoxification is not possible due to external circumstances. These criteria are demonstrated by an historical example, the treatment of the opioid addicted Swiss author Friedrich Glauser (1896-1938). From a modern public health perspective, however, opioid abuse is mainly conceptualised as risk behaviour with aversive consequences for the individual abuser and the public. These consequences should be reduced by prescription of hygienically safe heroin. In this concept, the failure of former addiction treatment is not a necessary condition for heroin prescription. Difficulties in reaching an agreement about indications for heroin prescription are partially results of inherent contradictions between an individual centered traditional medical concept and a public health concept about the goals of opioid addiction treatment. PMID- 11602924 TI - [Frequency and causes of premature termination (drop-out) during in-patient opiate detoxification]. AB - A typical problem concerning in-patient detoxification is the high drop-out rate. This phenomenon represents a significant problem for both the patient and the therapeutic team, as it is a factor which reduces motivation. While several studies confirm a positive shift of early drop-out behavior with the aid of methadone-supported detoxification, the overall drop-out rate still saw no improvement. Unexpectedly the latter rate was found to be around 50 %. The aim of the present study was to determine the sociodemographic, dispositional and addiction-related factors, as well as subjective ratings of the present state, which have predictive value, i. e. which could discriminate drop-outs from those patients who bring their detoxification to a regular end. 176 patients from two different clinical detoxification wards of the Hannover Clinic of Psychiatry and Psychotherapy participated in the study. The overall drop-out rate was 49.4 %, the rate of female patients failing to conclude detoxification was significantly higher than that of males (68.4 % vs. 44.2 %). On average drop-out patients were 2.2 years younger and their former (i. e. uninterrupted) periods without drug consumption were shorter, while criminal circumstances (e. g. therapy as probation vs. voluntary participation) did not play a major role in influencing staying power. As expected, patients terminating their treatment against medical advice evaluated the therapeutic program more critically than the others. Interestingly drop outs rated their own mental and somatic condition very pessimistic. We concluded from these results two essentials being necessary to improve staying power of drug patients during clinical detoxification: systematic induction of (1) a positive self concept and (2) an optimistic view of chances to reach social adjustment and health. PMID- 11602925 TI - [Autistic hebephrenia: concepts and findings]. AB - The concept of hebephrenia according to Kleist and Leonhard describes distinct clinical entities with a chronically progressive course leading to residual syndroms with a clear cut symptom constellation which is stable over time. The main symptom is a specific kind of pathological affectivity resulting in a lack of profound future- orientated tension. In six case-reports we illustrate the characteristical clinical picture of the autistic hebephrenia, one of the four subforms of hebephrenic psychoses according to Leonhard. The characteristical clinical syndrom consists of an affective blunting, autistic withdrawal, unfathomable facial expression, unhappy mood and periods of moodiness with aggressive excitement. The concept of hebephrenia according to Kleist and Leonhard presents a promising heuristic attempt for biological-etiological research. In ICD-10 and DSM-IV the usual concept of hebephrenia is a rather vaguely defined nosological category with a polymorphous non-specific symptomatology. PMID- 11602926 TI - [Carl Wernicke: his impact past and present]. AB - From April 1904 until his premature death due to an accident in June 1905, Carl Wernicke was head of the Department of Psychiatric and Nervous Diseases at the University of Halle-Wittenberg, Germany. We report on Wernicke's work and activities during this short but influential period in the context of his biography and scientific development. Archive materials reveal some interesting details concerning Wernicke's appointment and his diagnostic practice in Halle. As the most outstanding representative of 19th century neuropsychiatry, Wernicke constantly strove to base his psychiatric doctrine on the brain research of the time. In Breslau, his former place of employment, his scientific working environment had dramatically deteriorated. In Halle, Wernicke found not only a well-functioning clinical institution but also an important neurobiological tradition inaugurated by Eduard Hitzig. He immediately resumed his research programme. Fields of interest included the implementation of his nosological system in clinical practice, the study of aetiological factors of mental diseases and the use of a new method of puncture for the localisation of brain tumours. Wernicke's biological research agenda was interrupted not only by his premature death but also by historical developments. Many aspects of this agenda, however, have been raised anew by today's psychiatry. PMID- 11602927 TI - [Virtual rendering techniques in otologic imaging]. AB - Virtual postprocessing techniques combine the advantages of condensing the large amounts of data provided by high-resolution (HR) cross-sectional imaging modalities with those of three-dimensional (3D) imaging. The techniques and indications for virtual representations in imaging of the middle ear (ME), internal ear (IE), and cerebellopontine angle (CPA) are presented together with practical examples. MATERIAL AND METHODS: HR data sets acquired by computed tomography (CT) and magnetic resonance imaging (MRI) in patients with ME, IE, and CPA pathologies were transferred to a workstation via an internal network to generate endo- or extraluminal 3D views by means of the volume rendering technique (VRT). The source data were acquired using scanners and imaging protocols with the highest resolution available at present: a multislice spiral CT (MSCT) with a slice thickness of 0.5 mm and a reconstruction increment of 0.2 mm and a 3D CISS sequence with a slice thickness of 0.5 mm for MRI. RESULTS: Virtual endoscopy was superior to cross-sectional images for assessing ME pathologies like dysplasia, postoperative changes, and destructive bone processes with extensive soft-tissue involvement; fibrous obliterations of the internal ear and labyrinthine dysplasia were depicted with a superior image quality on 3D renderings compared to conventional reconstruction techniques. Virtual endoscopy of the CPA and external acoustic meatus (EAM) was helpful in detecting and visualizing neurovascular conflicts and in assigning small intrameatal tumors to components of the acousticofacial bundle. A common feature of all applications was that the large numbers of source images could be reduced to a few 3D reconstructions for documentation and optimized communication of the findings between the radiologist and otologist. CONCLUSION: Virtual rendering makes an important contribution towards establishing, presenting, and documenting the findings when certain otologic pathologies have to be assessed. It can be used for routine imaging and allows for more efficient handling of the large amounts of imaging data generated by high-resolution cross-sectional imaging modalities. PMID- 11602928 TI - [Follow-up in patients with head and neck tumors: evaluation of CT criteria for local tumor recurrence]. AB - BACKGROUND: Aim of this study was to evaluate morphologic criteria for diagnosis of locally recurrent head and neck tumors in helical CT. METHODS: Retrospective study, 44 examinations with radiologically abnormal findings were re-read by two radiologists; findings were analysed and correlated with histological diagnosis and clinical findings. RESULTS: 25 cases of local tumor recurrence were confirmed histologically. The accuracy of helical-CT in our preselected examinations for a local tumor recurrence was 93.5 %, the specificity 83.3 %. But 13/44 cases showed radiologically equivocal findings, among them 6 tumor recurrences. The most common characteristics of the 25 proven tumor recurrences were: contrast medium enhancement (96 %), increased volume in comparison to previous examination (92 %), inhomogenity (72 %); however contrast medium-enhancement and increasing volume were also seen in 68.4 % and 63.1 % of the benign changes. CONCLUSION: Contrast medium enhancement and increasing volume are criteria with a high sensitivity but low specifity in predicting a local tumor recurrence in head and neck cancer. PMID- 11602929 TI - [CAS-System MKM(R): use and results in lateral skull base surgery]. AB - BACKGROUND: Computer assisted surgery has reached an advanced stage of development and offers new possibilities in daily surgical procedures. METHODS: The MKM(R) - is a navigation system fitted with a laser-guided, autofocus microscope for referencing purposes. The coordinates can be set using various marker systems and a special workstation is used for preoperative planning. It is possible to add landmarks and display them in the surgeon's eyepiece. The clinical integration, the time required for the use of the navigation system and the intraoperative accuracy of the system were evaluated on the basis of 136 lateral skull base procedures. RESULTS: The degree of accuracy is determined by the type, amount and positioning of markers. The adjustment of reference points should be carried out following macrosurgery in order to avoid shifting factors. For an additional increase in accuracy, an improvement in the spatial resolution of the CT scans is required, with a section thickness of 1 mm and a pixel size of 0.5mm. The bone-anchored structures of the temporal bone do not underlie shifting or extensive intraoperative swelling. Skull base surgery is, therefore, ideally suited for the application of CAS. We found that registration was accurate to less than 1 mm (0.68 mm +/- 0.17 mm) and that the MKM(R) system made an additional contribution to surgical safety by identifying important structures. CONCLUSIONS: A practical accuracy found to be approximately one millimetre suggests that the non-invasive referencing system may be effective, accurate and useful for computer assisted identification of vital structures. We expect navigation systems to improve the quality and reduce the risks of surgical intraventions. PMID- 11602930 TI - [Treatment of ASS-Associated Polyposis (ASSAP) with a cysteinyl leukotriene receptor antagonist - a prospective drug study on its antiinflammatory effects]. AB - BACKGROUND: In a high rate of cases with recurrent polyposis an association with ASS-intolerance is detectable despite missing pulmonary symptoms. New examinations of a disturbed arachidonic acid metabolism lead to the development of new therapeutical options. Treatment with leukotriene-receptor antogonists (LTA) showed primarily good results in therapy of ASS-associated asthma. METHODS: 18 patients with ASS-intolerance trias - diagnosed by oral provocation - were treated with the LTA Montelukast, after undergoing sinus surgery. Patients underwent a diagnostic pathway of provocation including four groups: recurrent chronic sinusitis, excessive polyposis, polyposis associated with asthma and anaphylactic symptoms after oral ASS-intake. Clinically we examined the following parameters periodically after sinus surgery: nasal and pulmonal symptoms by scoring levels, recurrency of polypoid hyperplasia by endoscopic follow-ups and serum ECP-levels. To evaluate antiinflammatory tissue effects of LTA EG1/EG2 labelled cells and cytokine levels of Interleukin 5 in mucosa samples of the lower turbinate were analysed under LTA-therapy. RESULTS: Under therapy with LTA we saw a beneficial effect on nasal and pulmonary symptoms and a significant reduction of recurrent polyposis in endoscopic examinations in relation to the untreated group. Results were proven by a permanent reduction of serum ECP-level. A reduction of the rate of EG2-positive cells according to decreased Interleukin 5 levels in the nasal mucosa unter LTA-treatment assumed antiinflammatory effects on ASS-associated polyposis. CONCLUSIONS: We could demonstrate antiinflammatory effects of Leukotriene-Receptor-Antagonists primarily during postoperative treatment of patients with ASS-associated nasal polyps. PMID- 11602931 TI - [Metastases to the paranasal sinuses: case report and review of the literature]. AB - The case of an 87-year old man with widespread prostatic cancer is reported. During the autopsy macroscopically visible metastases were found within the frontal sinuses. These tumor masses destroyed the posterior osseous wall of the frontal sinus and formed polypoid bulging masses. In contrast to the macroscopically unaffected mucous membrane of the sphenoid sinus the maceration specimen of the skull base demonstrated a spongious-mossy, osteoplastic metastasis, lining the sphenoid sinus like a tapestry. This affection started from an exhaustive osteoplastic metastasis within the clivus. No metastases could be found in both antrums or the ethmoids. Retrospectively no symptoms from the paranasal sinuses could be eruated, only occasional pain of the frontal bone. The review of the world literature with 123 reports revealed 169 cases. Renal cell carcinomas most frequently metastasize into the paranasal sinuses (67 cases), followed by bronchogenic carcinomas (15 cases). Thyroid cancers and cancers of the mammary gland are responsible for 13 respectively 14 cases. The prostate also adds 12 cases. The paranasal sinuses are affected in diminishing frequency: maxillary sinus (55 cases), sphenoid sinus (37 cases), ethmoidal cells (23 cases) and frontal sinus (15 cases). In 38 cases exhaustive metastases affecting two or more paranasal sinuses are reported. The statement of literature, that metastases affecting the paranasal sinuses are much more frequent than reported, cannot be supported by our study, because the intensive autoptic investigation of 50 skulls of patients suffering from widespread cancers revealed no further cases of metastatic processes of the paranasal sinuses. PMID- 11602932 TI - [Influence of genetic variation in the major histocompatibility complex on head and neck cancer susceptibility]. AB - BACKGROUND: While cigarette smoking and alcohol consumption are risk factors for squamous cell carcinomas (SCC) of the head and neck, genetic factors are also significant. The gene of tumor necrosis factor (TNF) is located in the major histocompatibility complex class III and the cytokine has pleiotropic actions some of which are anticarcinogenic. As this gene complex is polymorphic with microsatellite markers identified it is a further candidate for head and neck cancer susceptibility. METHODS: We used a case-control approach to study the influence of polymorphism at the A-D markers on susceptibility in 113 controls, 265 laryngeal and 123 oral cavity/pharyngeal SCC cases. Genotypes were identified on polyacrylamide gels in an automated DNA sequencer after amplification with fluorescently-labeled primers. RESULTS: We found no differences in allele frequencies between controls and oral cavity/pharyngeal SCC cases but the frequency of B3 was greater in the laryngeal SCC cases than controls (p = 0.004, odds ratio 2.8). Homozygosity for B3 conferred an increased risk of laryngeal cancer compared with controls (p = 0.021, odds ratio 10.8). CONCLUSIONS: The data provide the first evidence that allelism at MHC class III microsatellite markers is associated with risk to laryngeal SCC. PMID- 11602933 TI - [Subjective deafness in case of peri-synaptic audiopathy. Isolated defects of the inner haircells?]. AB - BACKGROUND: Damage to or functional impair of the inner hair cells, synapsis or dendrites of the ganglion cells of the auditory nerve result in specific audiometric findings. Due to the normal function of the outer hair cells otoacoustic emissions can be registered, ABR and ECochG show at least elevated thresholds or are absent. PATIENTS: We demonstrate 5 cases with these audiological findings described in the literature as Auditory Neuropathy. RESULTS: All patients have profound to severe hearing loss with poor speech understanding under best aided conditions with conventional hearing aids. 3 patients, which were implanted with a cochlear implant have speech understanding but one prelingually adult, also implanted, has only sound identification. CONCLUSIONS: Hypoxia, carboplatin, ototoxicity and metabolic disorders are possible etiologies for damage to the inner hair cells or synapsis. The results will be discussed with reference to the localisation of the pathology and the definition as Auditory Neuropathy. PMID- 11602934 TI - [Posterior crus stapedectomy: an obsolete method in otosclerosis surgery?]. AB - BACKGROUND: Stapedectomy and stapedotomy with interposition of prostheses are the methods of choice for surgical treatment of otosclerosis. For the present study we resumed and reevaluated the posterior crus stapedectomy, a method based on the principal of renouncing a prosthesis by cutting the posterior crus of the stapes close to the footplate and the anterior crus close to the stapes head. METHODS: The posterior crus is temporarily transposed with the incudostapedial joint remaining intact. After performance of platinectomy and sealing of the oval window with fascia it is repositioned onto the center of the window. RESULTS: 19 of 20 ears operated on applying this technique showed good results (closure of air bone gap) after a mean follow up of 24.6 months. One patient showed persistence of air bone gap of 32.5 dB. Revision surgery revealed that the posterior crus had migrated to the posterior rim of the oval window. No inner ear affection, perilymph fistula or sensorineural hearing loss were observed. CONCLUSIONS: The major advantage of this technique is the avoidance of incus necrosis and foreign body reactions related to the material of the prosthesis. Disadvantages are technical plus the longer duration of the procedure. PMID- 11602935 TI - [Assessment of the Dichotic Listening Test by Feldmann in children with developmental reading and spelling disorders]. AB - In Germany the dD by Feldmann is a frequently used test in child assessment. Unknown, however, is the validity of the dD in the assessment of children with specific developmental language disorders. The dD by Feldmann are pairs of three syllable content words which are presented dichotically. In this controlled cross sectional study 65 children took the dichotic listening test by Feldmann (dD). The experimental group comprised 34 children with developmental reading and spelling disorders. The control group comprised 31 children with normal reading and spelling development. Age and nonverbal IQ were matched in both groups. The mean age was 9.8 years (range 7 - 11 years). The dichotic listening performance of right and left ear was registered separately. Twenty word pairs were presented dichotically at a constant amplitude of 65 dB. Memorisation of word pairs was tested under free recall conditions. A score of 100 % can be attained, if all word pairs are repeated correctly. Results demonstrated that no child attained a score of 100 %. As expected, the children with the developmental reading and spelling disorders attained significantly lower scores than the children in the control group (42.4 % versus 64 %). The reason for the lower results in the experimental group was left ear dichotic listening performance. There were no significant differences in right dichotic listening performance. Raw score overlaps occurred to some extent in both groups, but scores of 30 % or less were only observed in the experimental group. Scores correlated significantly with age, but not with nonverbal IQ. However, dD performance significantly correlated with several measures of phonological and syntactic language development as well as with auditory working memory. Based on these results it is our opinion that performance scores of the dD by Feldmann should be interpreted cautiously until validation studies have been carried out. PMID- 11602937 TI - Rural health in the millennium. PMID- 11602936 TI - [Infected epidermoid cyst as cause of peripheral facial palsy. A case report]. AB - BACKGROUND: Extratemporal processes are rare causes of peripheral facial palsy. Only 17 cases of facial palsy in association with a suppurative or necrotic parotitis are reported in the literature. PATIENT AND RESULTS: We present a case of a peripheral facial palsy initiated by an infection of a epidermoid cyst, which consecutively involved the whole parotid gland. After abscess drainage and antibiotic therapy the inflammation process receded. The palsy persisted over a period of 4 weeks but improved completely. CONCLUSIONS: As the facial nerve was not enclosed by the abscess formation the palsy must have been caused indirectly. It may be assumed the inflammation spread into the Fallopian canal through the stylomastoid foramen and caused a metabolic imbalance similar to the supposed vicious circle for Bell's palsy. Due to the relapse tendency of inflammations of epidermoid cysts it is recommended to remove the entire cyst. PMID- 11602938 TI - What it takes to manage rural hospitals. PMID- 11602939 TI - Top 10 trends in rural health. PMID- 11602940 TI - Informed consent, the placebo effect, and the revenge of Thomas Percival. PMID- 11602941 TI - The origin of the medical expert witness. The insanity of Edward Oxford. PMID- 11602942 TI - The "Good Samaritan" in Jewish law. Lessons for physicians, attorneys, and laypeople. PMID- 11602943 TI - Admissibility and effects of videotapes of medical procedures in litigation. PMID- 11602944 TI - A pilot survey of orthodontic awareness among a group of young people in Singapore. AB - A questionnaire survey was conducted in 1995 on a group of students and their teachers (n = 80) from 3 Independent Schools in Singapore, to assess their orthodontic need, demand, attitude and awareness. Motivational factors and barriers to treatment were also analysed. 36% had orthodontic experience, another 49% perceived need but did not elect to have treatment. Parents and dentists remain the main motivational force behind orthodontic demand. The survey demonstrated high orthodontic utilisation in this group of subjects. PMID- 11602945 TI - Periodontal health of Singapore school children over two decades from 1970 to 1994. AB - Dental health surveys of school children in Singapore from the past two decades were reviewed to document changes in prevalence and severity of periodontal disease. In 1970, 1979, 1984, 1989 and 1994 a sample of 12,801, 10,232, 4,203, 4,733 and 5,005 school children aged 6-18 years respectively, were examined in schools by the Dental Division, Ministry of Health. Parameters examined were oral hygiene, calculus, gingival inflammation/bleeding and periodontal pockets. Oral hygiene was assessed by the Oral Hygiene Index of Greene and Vermillion. Periodontal condition was assessed by observation of presence or absence of gingival inflammation and periodontal pockets in the early surveys, and the Community Periodontal Index of Treatment Needs in 1989 and 1994. Findings demonstrated oral hygiene among children in Singapore was good. The mean Debris Scores for 6-11 year old were 0.74, 0.78 and 0.72 respectively in 1979, 1984 and 1989 while those of 12-18 year old were 0.43, 0.80 and 0.56 respectively for the corresponding years. Proportions of younger children with no periodontal disease were 32.2%, 60.0%, 59.0%, 31.0% and 34.4% in 1970, 1979, 1984, 1989 and 1994 respectively. For children aged twelve and above, proportions with no periodontal disease were 24.5%, 55.8%, 29%, 12% and 30% respectively in 1970, 1979, 1984, 1989 and 1994. Prevalence of gingivitis remained relatively high. However, a decrease in gingivitis from 1970 to 1979 in both age groups was noted. The period from 1984 to 1994, trends were dealt with cautiously due to changes in indices used. Severity of periodontal disease declined in terms of reduced mean number of diseased units/sextants and decrease in prevalence of periodontal pockets. Comparison of survey data for 1970, 1979, 1984, 1989 and 1994 shows improvement in periodontal health among children in Singapore over the past 2 decades. There is a continuing need for greater effort to promote better oral hygiene practices in view that only one third of children in 1994 had no periodontal disease. PMID- 11602947 TI - Dilaceration of a mandibular incisor: case report. AB - The various theories of tooth eruption are discussed and a dilacerated mandibular incisor which illustrates the diversity of potential for teeth to erupt, is reported. PMID- 11602946 TI - The prevalence of post-extraction complications in an outpatient dental clinic in Kuala Lumpur Malaysia--a retrospective survey. AB - The aim of this retrospective study is to report on the prevalence of post extraction complications among patients attending the Oral Surgery outpatient clinic of the Faculty of Dentistry, University of Malaya over a 12-month period from January to December, 1992. The prevalence of post-extraction complications which required further treatment was only 3.4% (n = 100), out of a total of 2968 patients who had extraction of one or more permanent teeth. Analysis based on complete clinical reports (n = 79) showed that dry socket accounted for nine out of ten cases of post-extraction complications. However the aetiology was largely unknown. No obvious association with medical history could be made. Lower teeth were more likely to have complications. The most common teeth associated with dry socket were the molars (76%) and premolars (19%). The most common molars to be affected are the first, followed by the third and lastly the second molars. A brief review of current aetiological factors of dry socket was discussed. PMID- 11602948 TI - Second premolars: a review and case report of two impaction cases. AB - A variety of dental findings may present in the second premolar region. This is a report of the management of two patients who presented with impacted premolars. "Fives do fight for their lives". PMID- 11602949 TI - Unusual tooth sensation due to maxillary sinusitis--a case report. AB - Maxillary sinusitis can cause pain or discomfort to the maxillary dentition but no report of patients complaining of a "jumping tooth sensation" during sinusitis has been recorded in the literature. This article presents a case of an unusual localised sensation from a maxillary right second premolar experienced while undergoing root canal treatment. This sensation was felt during walking while the patient was suffering an episode of influenza. This sensation first occurred following debridement of the root canal. However, it persisted even after the root canal had been sealed. A hypothetical explanation of this manifestation is proposed. PMID- 11602950 TI - Dental negligence. AB - Medical and dental errors and negligence are again in the spotlight in recent news report. Dead because of doctor's bad handwriting Prescribing drug overdoses Germ-infested soap pumps--infections in hospitals This articles explains dental negligence including dental duty of care and the standard of care expected of dentists in relation to the Bolam principle. PMID- 11602951 TI - Dentists--how to get out of legal trouble? PMID- 11602952 TI - The dental specialist register. PMID- 11602953 TI - Survey of dental fees charged by dentists in Singapore. AB - A survey on dental fees was conducted among all private dental clinics registered with the Medical Audit and Accreditation Unit of the Ministry of Health in Singapore. Replies were received from 74 dental clinics. Analysis of results showed that there was a general increase in the median of fees charged in 1998 compared to the fees listed in the Minimum Fee Schedule issued by the Singapore Dental Association in 1994. 93% of the respondents indicated that there is a need to revise the Minimum Fee Schedule. PMID- 11602954 TI - Effect of die relief on the seating, fit and retention of cast gold crowns cemented on human teeth. AB - Die relief, by means of a paint-on die spacing material, is the most common method of achieving sufficient space between metal castings and tooth surfaces for cement to flow during seating. Several studies have determined the influence of cementing variables on crowns made for metal and plastic test dies. This study assessed the influence of die relief upon the seating and retention of cast gold crowns constructed for natural human teeth. Standard full crown preparations were made for 10 matched pairs of extracted human third molars, one each of which had been relieved with die spacer of approximately 40 microns thickness. Crowns were made by the indirect technique and were cemented with zinc phosphate cement in a static/dynamic jig. Seating behaviour and vertical discrepancies were measured electronically. Tensile bond strengths were determined in a universal testing machine. Results showed that die relief reduced vertical seating discrepancy associated with cementation by up to 79 microns. Differences between paired relieved and unrelieved samples were significant (p < 0.05). There were no statistically significant differences in tensile bond between paired relieved and unrelieved crowns. PMID- 11602955 TI - Delving back in the historic library for some words of wisdom. PMID- 11602956 TI - Regulations and Instructions for the Medical Officers in His Majesty's Fleet. PMID- 11602957 TI - [The dangerous life of clinical research. Money from dubious sponsors better than no money at all?]. PMID- 11602958 TI - [Children born after in vitro fertilization in Sweden 1982-1997. Small, but significant increase of risks among test-tube children]. PMID- 11602959 TI - [GHB--dangerous, addictive and uncontrollable "party drug"]. AB - This report reviews the pharmacology, toxicity and abuse pattern of gamma hydroxybutyrate (GHB). The legislative changes pertaining to this substance are also addressed. Examples of abuse, driving under the influence and fatal intoxication are given. It is concluded that GHB is widely abused, particularly among the younger generation, and that further cases of severe intoxication are likely to occur as long as the substance is easily available from countless sources, including via the Internet. Despite the classification of GHB as a narcotic in Sweden and several other countries, continued problems are expected since the precursors gamma-butyrolactone (GBL) and 1,4-butanediol (BD) are widely -and legally--available. PMID- 11602960 TI - [A case report. NSAID can make psoriasis worse]. PMID- 11602961 TI - [Neuropathy of the lower legs and feet in acute intermittent porphyria. A comparison of patients with type 1 diabetes and patients with AIP]. AB - Distal neuropathy was assessed in 339 patients with acute intermittent porphyria (AIP). The chronic neurological signs were symmetrical and similar to those in Type 1 diabetic patients. Significant impairment was found concerning perception, extensor digitorum brevis test, lower leg pain, ankle and knee tendon reflexes but not concerning dry feet, loss of forefoot arch and hammer toes, when comparing patients with manifest vs. latent AIP. The neurological signs were more severe in the diabetic patients (n = 298). Five AIP patients had permanent quadriplegia and renal failure after severe attacks. Patients with manifest AIP had significantly more signs of distal chronic, symmetrical neuropathy of axonal type than had patients with latent AIP. More serious neurological lesions appear to develop after severe attacks. PMID- 11602962 TI - [Can the costs of future needs of health and social services for the elderly be calculated?]. AB - As a consequence of the increasing number of elderly people, the proportion of people of working age (20-65) vs. the oldest-old (80+) will decrease considerably. Today, the total annual cost for the care of the elderly (health care and social services) in Sweden is about SEK 110 billion (about 6% of the GNP). The costs of health care are better correlated with the number of remaining years of life than with number of years from birth. The cost of health care during the last year in life is higher for the oldest-old than for the young-old. Informal care of demented persons is about 4-5 times more extensive than formal care. There is a strong correlation between GNP per citizen and resources spent on health care. PMID- 11602963 TI - [Telemedicine in sparsely populated areas yields satisfied patients and better competence]. AB - A telemedical pilot-project involving two rural primary health care centers in Tarnaby/Storuman in Southern Lappland and the University Hospital of Umea was carried out during the period Sept. 1, 1996-Dec. 31, 1998. Out of 169 consultations in all, 40 pertained to dermatology, 50 to ENT, 40 to orthopedics, and a further 27 to other specialties (surgery, medicine and gynecology). Among the 169, 47 cases were successfully managed via telemedicine. 30% of consultations were made in order to secure a second opinion. The remaining 70% were made in order to seek advice concerning a possible referral. At the telemedical visit, patients indicated a satisfaction score of 5.5 on a scale up to 6.0. The GP's rated the educational value at 4.4. After completion of the pilot-project, a survey of acceptance and ratings of the future potential of telemedicine for the health care system was carried out among 191 doctors and other health care workers in Vasterbotten county. Using a similar graded scale up to 6.0, physicians rated telemedicine as regards utility for patients and quality of care at 4.6 and 4.5 respectively, somewhat higher than they rated the consequences of telemedical consulting for their working conditions and health care organizations, at 3.8 and 4.1 respectively. Despite a low volume of patients in the pilot project, we can conclude that telemedical consultations seem to reduce the number of referrals and raise the level of competency of the GP's. It's important to find further fields of application, as well as further ways of working and organizing the communication network in order to increase volume. PMID- 11602964 TI - ["Target groups 1-3" must be granted priority access to health care services. Health care needs of somatically and mentally disabled persons in Robetsfors]. AB - People with serious functional disabilities do not always call attention to their needs for care, and are therefore a vulnerable group in our society. In Sweden, The Act Concerning Support and Service for Persons with Certain Functional Impairments (LSS) is intended to provide for them. Our research found that people with serious physical or psychiatric disability suffer more often from intercurrent disease and have more problems with their eyesight, hearing and dental health than do other individuals. The responsibility for their respective health care needs must be clarified, so that the group is given priority access to the health care system and services for rehabilitation. PMID- 11602965 TI - [The connection of increased risk of thrombosis and long-haul flights is not proved]. PMID- 11602966 TI - ["I want to take care of my brother". Psychotherapeutic talks with siblings of seriously ill children]. PMID- 11602967 TI - [Time to reintroduce the cooperation between physicians and artists? Knowledge of anatomy was a basis for painting and sculpturing from renaissance to the end of 19th century]. PMID- 11602968 TI - [A reply to a book review: do openly account for and record the real use of euthanasia]. PMID- 11602969 TI - [The basis of health care quality work--order or chaos?]. PMID- 11602970 TI - [Unscientific information about alternative medicine in the supplementary volume of the national encyclopedia]. PMID- 11602971 TI - [General practice program designed for socially privileged areas]. PMID- 11602972 TI - [District General Practitioners?]. PMID- 11602973 TI - [Health care is a project of morals!]. PMID- 11602974 TI - [Why is the number of atypical mycobacteria increasing?]. PMID- 11602975 TI - [A complementary addition to the discussion on freon-based sprays]. PMID- 11602976 TI - The 2000 IAHSS survey--crime in hospitals. AB - The 2000 IAHSS crime survey continues to confirm the reported drop in property crimes--especially larceny theft. A smaller drop in violent crimes in 2000 compared to the average for the decade is reported. Increases were registered in three of 12 categories. PMID- 11602977 TI - Conducting a hospital maintenance department survey. AB - Maintenance Department employees can be your friends and allies or the source of your biggest headaches. By working with maintenance personnel, the securing of maintenance areas can be made a lot easier. PMID- 11602978 TI - Identity theft: when bad things happen to your patients' and employees' good name. AB - What should healthcare facility security directors and administrators do when patients or employees are the victims of identity theft? Taking the right steps to safeguard personal data won't insulate your facility from ever having to deal with this growing crime but, says the author, it will reduce the opportunity and desire for a criminal to steal the data. PMID- 11602979 TI - The drug thief at Georgetown U Medical Center. AB - The article gives the anatomy of a $2 billion class-action lawsuit. A drug abusing hospital employee may have exposed hundreds of patients to HIV, hepatitis, and other viruses during his period of employment. Not only has the episode been embarrassing for the prestigious medical center, but it also has focused attention on the potential consequences for hospitals that do not screen employees for drug use. PMID- 11602981 TI - When a disaster strikes without warning: how effective is your response plan? AB - When an outside high-pressure natural gas line was cut near the intakes to a hospital's ventilation system, gas was quickly dispersed throughout the building. The facility's disaster management plan faced a real-life test. PMID- 11602980 TI - ASIS healthcare security benchmarking study. AB - Effective security has aligned itself into the everyday operations of a healthcare organization. This is evident in every regional market segment, regardless of size, location, and provider clinical expertise or organizational growth. This research addresses key security issues from an acute care provider to freestanding facilities, from rural hospitals and community hospitals to large urban teaching hospitals. Security issues and concerns are identified and addressed daily by senior and middle management. As provider campuses become larger and more diverse, the hospitals surveyed have identified critical changes and improvements that are proposed or pending. Mitigating liabilities and improving patient, visitor, and/or employee safety are consequential to the performance and viability of all healthcare providers. Healthcare organizations have identified the requirement to compete for patient volume and revenue. The facility that can deliver high-quality healthcare in a comfortable, safe, secure, and efficient atmosphere will have a significant competitive advantage over a facility where patient or visitor security and safety is deficient. Continuing changes in healthcare organizations' operating structure and healthcare geographic layout mean changes in leadership and direction. These changes have led to higher levels of corporate responsibility. As a result, each organization participating in this benchmark study has added value and will derive value for the overall benefit of the healthcare providers throughout the nation. This study provides a better understanding of how the fundamental security needs of security in healthcare organizations are being addressed and its solutions identified and implemented. PMID- 11602982 TI - A chemical decontamination plan for an emergency department. AB - How a hospital with limited resources successfully implemented an effective emergency decontamination program. While the article addresses chemical decontamination specifically, the author believes the plan would be useful in managing potential victims of bioterrorism. PMID- 11602983 TI - Reducing employee injuries through preventing at-risk behaviors. AB - This article presents the experiences of officials at two medical centers in successfully reducing and preventing employee injuries. Guidance is also provided from psychologists and employee safety experts on ways to approach the problem. PMID- 11602985 TI - California hospitals set uniform emergency codes to ease staff confusion. AB - The Healthcare Association of Southern California has released the nation's first standardized hospital emergency codes. These universal codes, which can be adopted by all healthcare facilities, will minimize confusion and danger as well as improve staff response in the face of a crisis or disaster. PMID- 11602984 TI - Bloodborne pathogens: updating sharps safety. AB - OSHA's new compliance directive was a wake-up call telling healthcare employers they must use safer technology and safer work practices. PMID- 11602986 TI - Using hidden cameras to monitor suspected parental abuse. AB - In using hidden cameras to monitor suspected parental abuse a security requirement or an invasion of privacy? Covert surveillance of patients suspected of having Munchausen syndrome by proxy at an Atlanta children's hospital resulted in considerable media scrutiny when researchers published their findings. This article presents details of the research, the involvement of security officers, and the reactions of local authorities and health officials. PMID- 11602987 TI - Tailoring a hospital security department's initiatives to meet financial constraints. AB - One of healthcare security's greatest challenges, says the author, is fulfilling its duties, responsibilities, and services with reduced staffing and resources. Here he provides his experience in improving security with new initiatives and changes under a hospital downsizing and cost-containment program. PMID- 11602988 TI - A job well done. AB - The protective services department at Children's Hospital Medical Center in Cincinnati makes employee satisfaction a priority through ongoing recognition and professional development efforts. PMID- 11602989 TI - Contemporary review on nature of sonoluminescence and sonochemical reactions. AB - The major cases for a local electrification of bubbles in a cavitation field were considered: with the fragmentation of cavitation bubbles and also with only deformation of them. The problem of the uncompensated charge on the surface of the deformed cavitation bubble is solved in general view. The radial deformations approximated by the paraboloid of rotation and axial deformations by one cavity hyperboloid of rotation. The maximum electric strength is accounted. In the terms of electrical theory of the local electrification of cavitation bubbles the explanation of some physical and physico-chemical effects in the cavitation fields is proposed. The theory of local electrification now is single theory which correlates majority of experimental facts for multibubble cavitation fields. The theory of single bubble sonoluminescence was worked out. PMID- 11602990 TI - An ultrasound assisted extraction of the available humic substance from marine sediments. AB - In this paper an ultrasound assisted procedure for the extraction of the bio available fraction of humic substance in marine sediments is described. The proposed method is based on a preliminary 24 h 8 M HCl treatment already proposed in a previous paper [M. Mecozzi, E. Pietrantonio, M. Amici, Fres. Environ. Bull. 7 (1998) 605], followed by consecutive extractions by 0.5 M NaOH coupling to an ultrasonic treatment. The main advantages of the ultrasound procedure are the reduced times of extraction which take 30 min in contrast to the 24 h required by shaking method and the possibility to perform also the quantitative estimation of the extractable fraction of humic substance present in marine samples. PMID- 11602992 TI - Ultrasound mediated alkaline hydrolysis of methyl benzoate--reinvestigation with crucial parameters. AB - In the present work hydrolysis of methyl benzoate was carried out using aqueous sodium hydroxide solution at room temperature in the presence of ultrasound since otherwise the same reaction takes place at relatively high temperature. Also, the above hydrolysis reaction was investigated at a relatively larger scale with the variation in parameters influencing the emulsification process and hence the reaction rates. It has been observed that the position of ultrasound source on the liquid-liquid interface is a crucial parameter affecting the two-phase emulsification rates. The poor bulk mixing occurring in the presence of ultrasound alone with an increase in the volume of the reaction mixture and its consequent effect on the reaction kinetics has been conclusively established. These studies have shown that the use of ultrasound with mechanical stirring can result in substantial reduction in the overall power consumption, especially for reaction systems like hydrolysis that do not require very high temperatures and pressures generated by cavitation. PMID- 11602991 TI - Comparison of classical and ultrasound-assisted isolation procedures of cellulose from kenaf (Hibiscus cannabinus L.) and eucalyptus (Eucalyptus rodustrus Sm.). AB - A comparative study of classical and ultrasound-assisted extraction and purification of cellulose from kenaf (Hibiscus cannabinus L.) and eucalyptus (Eucalyptus rodustrus Sm.), has been conducted. The isolated cellulose samples were studied by diffuse reflectance infrared Fourier transform spectroscopy and 13C nuclear magnetic resonance (13C-NMR) spectroscopy and the crystallinity was also determined. The use of ultrasound decreased the total time of treatment, in addition the purity of the obtained cellulose was very high. PMID- 11602993 TI - Sonochemical chloro-oxidation of phenols using HCl-H2O2. AB - The reaction of phenol, 2-nitrophenol, thymol, 1-naphthol and 1-hydroxy-2 naphthoic acid with HCl-H2O2 was carried out in the presence and in the absence of ultrasound. In the presence of ultrasound phenol, 2-nitrophenol and thymol gave only the chlorinated products, while 1-naphthol and 1-hydroxy-2-naphthoic acid gave chlorinated quinones as the major products. The reactions with ultrasound were compared with those without ultrasound. PMID- 11602994 TI - Ultrasound-assisted extraction of water-soluble polysaccharides from the roots of valerian (Valeriana officinalis L.). AB - The insoluble plant residues, obtained after preparation of medicinal tinctures from the roots of valerian (Valeriana officinalis L.) by classical and ultrasound assisted extraction with aqueous ethanol in a pilot plant, were subsequently treated with hot water to isolate the accessible polysaccharide cell wall components. At almost equal amounts of the hot-water extractable material, the yields of the recovered polysaccharides were lower in the ultrasonical experiment. This is due to the fact that a part of accessible polysaccharides were already solubilised by the aqueous ethanol and recoverable from the medicinal tincture. Therefore, the net yield of extracted polysaccharides was enhanced in the ultrasonical procedure. This fact as well as the sugar composition and structural features of the isolated polysaccharides suggest that ultrasonication have attacked the integrity of cell walls, released and degraded its most accessible polysaccharides (pectic polysaccharides and starch) and increased also the extractibility of its less accessible components--xylan, mannan and glucan. The water-soluble polysaccharide fractions from both the conventional and ultrasonical experiments exhibit significant immunostimulatory activities in mitogenic and comitogenic thymocyte tests. PMID- 11602995 TI - Ultrasonication of aqueous and micellar suspensions of anthracene fixed on silica. AB - Degradation under ultrasound irradiation of silica supported anthracene (Ant) in aqueous suspension is studied. The initial degradation rate of Ant on silica is 28- and 6-fold lower than the degradation rate in water alone, at 506 and 20 kHz, respectively. Analysis of emission and excitation spectra demonstrates the presence of two kinds of adsorbed Ant species: a molecular form and crystals. The former species is assumed to be initially degraded at 506 kHz, while the latter species is more difficult to decompose. Specific irradiation of micro-crystals of Ant in aqueous/methanolic solution leads to the formation of CO and CO2. A pyrolytic mechanism is expected to occur on the surface of silica and the kinetic rates would depend on the chemical nature of Ant at the surface. Added surfactants decrease dramatically the degradation rates on silica, but solubilizes Ant in larger amounts than in pure water. Surfactants are pyrolysed in water with and without silica and act more as degradation inhibitors than as Ant extracting agents. PMID- 11602996 TI - Fixation of nitrogen with cavitation. AB - The sonochemical fixation of nitrogen to ammonia was investigated by sonolysis of liquids with nitrogen/hydrogen gas mixtures passing through them. The maximum rate (4 nmol min-1 W-1) was found in water irradiated with 900 kHz ultrasound with gas of a mole fraction 0.6 of nitrogen and the lowest temperature (278 K). Some traces of ammonia were found in the absence of external hydrogen gas, as hydrogen atoms are also formed in sonolysis of water. Thermodynamic calculations indicate that some ammonia formation should occur at the "hot spot" temperatures present in collapsing cavities. The decrease in the rate with bulk temperature suggests that kinetics, rather than thermodynamics, is the limiting condition for sonochemical synthesis of ammonia. Ammonia can be produced in organic media, but at a lower rate. A substantial portion of the ammonia in the experiments with alkanes exited with the sparging gas and was trapped in a dilute HCl solution. PMID- 11602997 TI - As good as it gets--training with Henry Kaplan and Saul Rosenberg during the Stanford studies on Hodgkin's disease and lymphoma. AB - The Stanford team of Drs. Henry S. Kaplan and Saul A. Rosenberg churned out an extensive amount of clinical research on the evaluation and treatment of Hodgkin's disease and other lymphomas throughout the 1960's, 70's and 80's. After Dr. Kaplan's death in 1983, Dr. Rosenberg continued clinical research in this area. A training experience under these physicians was both exhilarating and productive, as the discipline with which Drs. Kaplan and Rosenberg approached patients actually eclipsed the individual studies which were carried out. The overall product of their efforts, in conjunction with that of other investigators throughout the world, changed the mindset of physicians to approaching these patients with curative intent, rather than traditional palliation which had been the general policy up to the late 1950's. Today the vast majority of Hodgkin's patients who are treated get cured, although there is still some room for further improvement. The strong character traits of Drs. Kaplan and Rosenberg left lasting impressions, not only on other staff, but most especially on the young trainees who learned to accept and appreciate their efforts at excellence. Their method of approach and the gains achieved by it became the paradigm for the study of other malignant diseases. PMID- 11602998 TI - Gene therapy for the treatment of cancer. AB - The delineation of the molecular basis of neoplasia provides the possibility of specific intervention by gene therapy through the introduction of genetic material for therapeutic purposes. In this regard, several gene therapy approaches have been developed for the treatment of cancer: mutation compensation, genetic immunopotentiation, molecular chemotherapy, inhibition of angiogenesis, replicative vector oncolysis, and chemosensitization or radiosensitization. Clinical trials have been initiated to evaluate safety, toxicity, and efficacy of each of these approaches, based on promising preclinical results. Various limitations that have been identified include lack of in vivo selective tumor delivery of vectors, minimal expression of therapeutic genes, immune response against vectors, and normal tissue toxicity. Combined modality therapy with gene therapy and chemotherapy or radiation therapy has shown promising results. It is expected that as new therapeutic targets and approaches are identified, combined with advances in vector design, that gene therapy will play an increasing role in clinical cancer treatment. PMID- 11602999 TI - FDG-PET in adrenocortical carcinoma. AB - Adrenal cortical carcinoma (ACC) is a rare malignant neoplasm with a poor prognosis. Radical surgery of the primary tumor and of local as well as of distant recurrence is the only effective treatment, and requires accurate and early localization of recurrent tumors. In this regard, we prospectively scanned 10 patients with ACC, 8 during follow-up and 2 at primary work-up. In all patients PET scans from the neck to the upper thighs were obtained 45 minutes after injection of 370 MBq [18F]FDG. Reading was done visually, with the investigator blinded to the results of other diagnostic modalities. All known sites of ACC lesions showed markedly increased FDG uptake. In 3 patients, previously unknown lesions were identified by PET in the lung (one lesion), the abdomen (3 lesions), and the skeleton (multiple), respectively. One false positive liver focus was shown by PET aside from the true positive lung metastases in the same patient. The sensitivity/specificity of PET based on different organs was 100/97%, that based on the number of PET-detected lesions (N = 23) was 100/95%. PET altered or influenced the tumor stage in 3/10 patients, modifying the subsequent therapeutic management in 2/10 patients. We conclude that FDG-PET is highly useful in ACC and should be included in the work-up for initial staging as well as for follow-up. PMID- 11603000 TI - Positron emission tomography (PET) for staging low-grade non-Hodgkin's lymphomas (NHL). AB - Although positron emission tomography (PET) imaging is now recognized as a useful tool for staging intermediate and high-grade non-Hodgkin's lymphoma (NHL), few data are available regarding its accuracy in low grade NHL. We therefore studied 36 patients with histologically proven low-grade NHL. Whole-body 2-(fluorine-18) fluoro-2-deoxy-D-glucose (FDG) PET was performed at the time of initial diagnosis (n = 21) or for disease recurrence (n = 15) prior to any treatment. PET results were compared to those of physical examination and computed tomography (CT). PET studies were read without knowledge of any clinical data. Any focus of increased activity was described and given a probability of malignancy using a 5 point scale (0: normal to 4: definitively malignant). An individual biopsy was available for a total of 31 lesions. The sensitivity and specificity were 87% and 100% for FDG-PET, 100% and 100% for physical examination and 90% and 100% for CT respectively. In addition, 42 of 97 peripheral lymph node lesions observed by FDG PET were clinically undetected, whereas the physical examination detected 23 additional nodal lesions. PET and CT both indicated 12 extranodal lymphomatous localizations. FDG-PET showed 7 additional extranodal lesions while 5 additional unconfirmed lesions were observed on CT. Regarding bone marrow infiltration, PET and biopsy were concordant in 24 patients with 11 true positive (TP) and 13 true negative (TN). However PET was FN in 11 patients and no biopsy was performed in one patient. The combination PET/CT/physical examination seems to be more sensitive than the conventional approach for staging low grade NHL. Its sensitivity however is unacceptably low for diagnosing bone marrow infiltration. PMID- 11603001 TI - Intraperitoneal radioimmunochemotherapy of ovarian cancer: a phase I study. AB - A phase I trial was designed to examine the feasibility of combining interferon and Taxol with intraperitoneal radioimmunotherapy (177Lu-CC49). Patients with recurrent or persistent ovarian cancer confined to the abdominal cavity after first line therapy, Karnofsky performance status > 60, adequate liver, renal and hematologic function, and tumor that reacted with CC49 antibody were enrolled. Human recombinant alpha interferon (IFN) was administered as 4 subcutaneous injections of 3 x 10(6) U on alternate days beginning 5 days before RIT to increase the expression of the tumor-associated antigen, TAG-72. The addition of IFN increased hematologic toxicity such that the maximum tolerated dose (MTD) of the combination was 40 mCi/m2 compared to 177Lu-CC49 alone (45 mCi/m2). Taxol, which has radiosensitizing effects as well as antitumor activity against ovarian cancer, was given intraperitoneally (i.p.) 48 hrs before RIT. It was initiated at 25 mg/m2 and escalated at 25 mg/m2 increments to 100 mg/m2. Subsequent groups of patients were treated with IFN + 100 mg/m2 Taxol + escalating doses of 177Lu CC49. Three or more patients were treated in each dose group and 34 patients were treated with the 3-agent combination. Therapy was well tolerated with the expected reversible hematologic toxicity. The MTD for 177Lu-CC49 was 40 mCi/m2 when given with IFN + 100 mg/m2 Taxol. Interferon increased the effective whole body half-time of radioactivity and the whole body radiation dose. Taxol did not have a significant effect on pharmacokinetic or dosimetry parameters. Four of 17 patients with CT measurable disease had a partial response (PR) and 4 of 27 patients with non-measurable disease have progression-free intervals of 18+, 21+, 21+, and 37+ months. The combination of intraperitoneal Taxol chemotherapy (100 mg/m2) with RIT using 177Lu-CC49 and interferon was well tolerated, with bone marrow suppression as the dose-limiting toxicity. PMID- 11603002 TI - Serum factors attenuating the anti-tumor activity of 5-fluorouracil. AB - In sera of cachectic patients bearing advanced cancers, the concentration of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrotizing factor-alpha (TNF alpha), and interferon-gamma (IFN-gamma) have been reported to elevate. In this study, we investigated whether those cytokines influenced in vitro anti-tumor effect of 5-fluorouracil (5-FU) on a human colon tumor cell line, HCT-15. Pretreatment of HCT-15 cells with IL-1 beta, IL-6 or TNF-alpha did not affect the anti-tumor effect of 5-FU at various concentrations. However, IFN-gamma attenuated the anti-tumor effect of 5-FU at the concentrations of 0.1-10 IU/ml. An experiment with tritium thymidine showed that 0.1 IU/ml of IFN-gamma did not suppress the growth of HCT-15 cells. As low as 0.1 IU/ml of IFN-gamma attenuated the anti-tumor effect of 5-FU in another experimental system where HCT-15 cells were exposed to 0.1 IU/ml of IFN-gamma before and during the treatment with 5-FU. This system mimicked the clinical condition around in situ cancer cells. Treatment of HCT-15 cells with 0.1-10 IU/ml of IFN-gamma did not change their DNA histogram pattern. An immunoblotting with the antibodies to thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in HCT-15 cells revealed that 0.1 10 IU/ml of IFN-gamma enhanced their TS and DPD expressions. Results of the immunoblotting gave some explanation to attenuation in the sensitivity of HCT-15 cells to 5-FU. PMID- 11603003 TI - 13cis- and all-trans retinoic acid have antiproliferative effects on CML cells and render IFN alpha antiproliferative potency after combined treatment in vitro. AB - The treatment of CML with IFN alpha is limited due to resistance against this substance. Recent studies with different cells than chronic myelogenous leukemic cells revealed a synergistic effect of a combined use of Retinoids (RA) and IFN alpha. The purpose of the study was to detect possible interactions of IFN alpha and RA in CML considering also the effect of the BCR-ABL gene-product. Therefore, we investigated three CML cell lines in their proliferation after incubation with IFN alpha and Retinoids alone and in combination. We measured low susceptibility to IFN alpha but a marked influence of the Retinoids. In combination, the growth inhibition was enhanced potentially in response to an increased efficacy of IFN alpha. Even solely, ineffective concentrations of both substances lead to decreased proliferation. PMID- 11603004 TI - The anti-tumoral activity of neoadjuvant intra-arterial 131I-lipiodol treatment for hepatocellular carcinoma: a pilot study. AB - BACKGROUND: The high recurrence rate after curative resection has stimulated the development of adjuvant treatment modalities, such as local embolization. This study was set up to investigate the anti-tumoral potential of neo-adjuvant 131I lipiodol administration before liver transplantation. METHODS: In this preliminary, prospective study we treated 10 consecutive HCC patients by intra arterial injection of 131I-lipiodol into the hepatic artery followed by liver transplantation within 1-9 months (mean 3.4). After hepatic catheterization, 1332 2146 MBq (mean 1887 MBq) or 36-58 mCi (mean 51 mCi) was instilled as selective as possible, depending on the distribution of the tumors: non-selectively in the hepatic artery propria (n = 4), selectively in the right and/or left hepatic artery (n = 3) or super-selectively in segmental arteries (n = 3). RESULTS: Anti tumoral activity was regarded as obvious with 1) a strong decrease of alfa fetoprotein (AFP), comparing the highest recorded value before and after 131I lipiodol and/or 2) a downstaging in TNM classification on the posttherapy MRI as compared to the pre-therapy MRI and/or 3) tumors with > 50% necrosis on histo pathology of the explanted liver, without previous chemoembolization. Either of these criteria were met by 5/10 (50%) of patients. A 4) downstaging in pTNM classification on histopathology compared to the TNM classification of the MRI and/or a 5) tumor necrosis of only 10-50% were regarded as possibly tumor-related but were not accepted as a single criteria of anti-tumoral activity. This was seen in 3/10 (30%) of patients. Clinical side-effects of the 131I-lipiodol therapy were generally mild with a temperature rise in two cases, nausea without vomiting in another two and upper back pain in one patient. In one patient progressive liver failure developed one week after 131I-lipiodol therapy necessitating premature liver transplantation after 4 weeks. CONCLUSION: With the use of stringent anti-tumoral criteria, this study shows evidence of an anti tumoral effect in 50% of patients. Our data support the evaluation on larger patient numbers to confirm the promising anti-tumoral activity of 131I-lipiodol in HCC patients candidated for liver transplantation. PMID- 11603006 TI - Reflections of mature dentists. The hopes and regrets of life-long dentists. PMID- 11603005 TI - Dicarbonyl-nitrosyl-complexes of rhenium (Re) and technetium (Tc), a potentially new class of compounds for the direct radiolabeling of biomolecules. AB - Re- and Tc-complexes of the oxidation state (+I) offer a useful synthetic pool for the labeling of biomolecules due to their co-ordination properties and stability, which are superior to compounds of the oxidation state (+V). Based on the results for Tc-tricarbonyl complexes it was the topic of this work to develop an access to similar but higher charged compounds, which could be performed by replacing a neutral [CO]-group by a [NO](+)-group. The resulting Re(I)- and Tc(I) dicarbonyl-nitrosyl complexes, such as [N(CH2CH3)4][ReX3(CO)2(NO)], show a tendency for co-ordination at carboxylic and amine groups of biomolecules (X = Br, Cl). This was shown with picolinic acid (H-pic), a suitable model for amino acids, forming the neutral complex [ReX(pic)(CO)2(NO)]. In a similar fashion conjugation of [188Re(CO)2(NO)](2+)- or [99mTc(CO)2(NO)](2+)-compounds to proteins or antibodies is feasible. This approach opens a way to a potentially new class of radiopharmaceuticals. PMID- 11603007 TI - 'Why I became a dentist'. PMID- 11603008 TI - Planned giving: helping yourself and others as well. PMID- 11603009 TI - Taxing issues. PMID- 11603010 TI - Profiting from criticism. PMID- 11603011 TI - Dental dateline. Oral cancer. PMID- 11603012 TI - Doc Holliday. PMID- 11603013 TI - Any warm body. PMID- 11603014 TI - Unexpected budget crunch jolts legislators. PMID- 11603015 TI - New tax law: estate and gift taxes. PMID- 11603016 TI - Optimizing patient financing with CareCredit. PMID- 11603017 TI - Risk factors, indicators and predictors of periodontal disease. PMID- 11603018 TI - Dental assistants: laws, credentials and education. PMID- 11603019 TI - Washtenaw Community College Alternative Dental Assistant Education Project: an update. PMID- 11603020 TI - Viewpoint: it's time for mandatory licensure of clinical dental assistants. PMID- 11603021 TI - Hygiene, assisting surveys prompt action by MDA. PMID- 11603022 TI - [Classification of fractures of the skull vault bones]. AB - The proposed classification of fractures of the skull vault bones is based on fracture morphogenesis. Russian and foreign published data on skull vault fractures and the authors' own observations allowed some analogies and helped develop a new classification. PMID- 11603023 TI - [Role of alcoholization in pathogenesis of morphological changes in substance abusers]. AB - Morphological manifestations of combined intoxication with ethanol and narcotics are described. Special attention is paid to changes in the liver which were studied both qualitatively and quantitatively. Specific features in the pathological processes concomitant with combined intoxication are described; high incidence and expression of morphological markers of alcoholism in subjects abusing both ethanol and narcotics in comparison with "pure" alcoholics were determined. These features can be used in forensic medical and pathological (autopsy) diagnosis of chronic narcotic intoxication and its combination with alcoholism. PMID- 11603024 TI - [Morphological study of the corpus striatum in forensic medical diagnosis of chronic opiate abuse]. AB - Morphological analysis of the corpus striatum in morphine intoxication was carried out on experimental and autopsy specimens. The resultant morphometrical data characterize various stages of opium narcomania and abstinence. The severity of involvement of neuronal structures and specific features of the glial reaction are described, which can be used in forensic medical diagnosis of such intoxications. PMID- 11603025 TI - [Evaluation of the severity of harm to health by gastrointestinal injury caused by blunt trauma]. AB - A total of 226 forensic medical conclusions in traumas of the gastrointestinal tract with blunt objects, 111 of these with lethal outcomes, are analyzed. The types of injuries, clinical course, medical care, complications, flaws in medical care and their consequences, and pathomorphology of the injury were analyzed. Criteria of harm inflicted to health are determined and a table of qualifying signs is suggested for cases with blunt injuries of the gastrointestinal system, with consideration for the type of injury. PMID- 11603026 TI - [Categories of variability in the thickness of human skull bones]. AB - Problems in standardization of the thickness of skull vault bones at certain strictly determined points are discussed. Race, ethnic, regional, and sex associated variability of this criterion was studied on extensive material for many peoples of the world (1261 men, 549 women, and 570 men + women). The most significant differences are characteristic only for the male and female totalities. A table of categories of the skull bone thickness has been created, covering 5 intervals with the following incidence: 33% medium, 22% low and high (each), and 11% very low and very high (each). An expert example is offered. PMID- 11603027 TI - [Problems in organization and experience gained while working in the Department of Identifying and Examining Unrecognized Persons]. AB - Experience gained in organization and activities of department of unrecognized personality identification at the Khabarovsk Regional Bureau of Forensic Medical Expert Evaluations is presented. The period of 1998-2000 is analyzed. Programs developed at the department are presented and recommendations on the activities and organization of such departments are offered. PMID- 11603028 TI - [Determination of heavy metals in some human organs, tissue, and fluids under normal conditions]. AB - A table has been created, presenting normal levels of heavy metals (Hg, Cd, Cr, Cu, Fe, Mn, Pb, Ni, Zn, Sn, Tl, Ag) in human biological media. In contrast to other handbooks, the authors use the normal values derived on the basis of their own investigations at the spectral laboratory of Bureau of Forensic Medical Expert Evaluations, Public Health Committee of Moscow and published reports. Comparative analysis was carried out for each element in human organs, tissues, and urine, which will facilitate expert work. Every laboratory engaged in expert evaluations and analysis in cases with suspected poisoning with heavy metal salts is to have reference values of these elements' concentrations in human organs and tissues obtained in this very laboratory on available equipment with consideration for specific features of its biogeochemical region. PMID- 11603029 TI - [Diagnosing death from burn shock]. AB - Morphological changes were studied in the organs of 28 victims dead from burn shock at the age of 20-65 years and in rabbits in which burn shock was induced. Histological sections were stained with hematoxylin and eosin, Sudan III, by Regaud's method; brain sections were stained by Nissl's and Brachet's methods and examined by electron microscopy. Morphological criteria of burn shock were determined, underlying the specific features of thermal injury. PMID- 11603030 TI - [Death of a parachutist in flight as a result of a reflector heart arrest]. PMID- 11603031 TI - [Determination of the presence of a vomitus masses and their affiliation]. PMID- 11603032 TI - [Use of the Internet in forensic medicine]. PMID- 11603034 TI - [Modern concepts of the structure and function of erythrocyte antigens (review of the literature on the 100th anniversary of discovering blood groups)]. PMID- 11603033 TI - [Ultrastructural changes in the brain in forensic diagnosis of opiate abuse]. PMID- 11603035 TI - [Experience in using the "Termit-1" device for determining the time of death]. AB - The operating principle and utilization of a Termit-1 complex (equipment and software) is described. Expert cases are presented and recommendations are offered. PMID- 11603037 TI - [What can be done with stem cells?]. PMID- 11603036 TI - [Hypophyseal damage in persons with cerebrocranial injuries and who died in the hospital]. AB - The pituitary was examined in patients with craniocerebral injuries who died in hospital in various periods after treatment. Control group consisted of victims died at the site of accident. The results indicate the significance of examining the pituitary in craniocerebral injuries for the diagnosis of thanatogenesis, particularly in patients died in hospital. Causes of traumatic changes in the organ were determined, highly incident in the practice of forensic medical experts: directly during injury, as a result of skull bone fractures; during development of dislocation syndrome and in disorders of blood and lymph circulation in the brain matter; resultant from augmenting traumatic edema of the brain. PMID- 11603038 TI - [Better medical service in nursing homes!]. PMID- 11603039 TI - [...with an unfailing memory?]. PMID- 11603040 TI - [Are mobile telephones health hazards?]. PMID- 11603041 TI - [Trauma admissions at Norwegian hospitals]. PMID- 11603042 TI - [Organization of trauma admissions at Norwegian hospitals]. AB - BACKGROUND: Treatment of major trauma is a demanding challenge for most hospitals. The potential benefits of improvement are substantial: it has been calculated that approx. 6,000 person-years are lost each year because of suboptimal treatment of trauma in Norway. Trauma teams, paging criteria, and manuals for appropriate resuscitative and diagnostic interventions are needed for improving the structure and quality of this service. MATERIAL AND METHODS: A telephone survey to Norwegian hospitals. RESULTS: 27 (52%) of all 52 Norwegian hospitals receiving trauma victims had dedicated trauma teams, while 19 (37%) had paging criteria for trauma teams. 22 hospitals (42%) confirmed that they had manuals for the initial treatment of trauma victims. Smaller hospitals tended to have trauma teams and trauma manuals to a lesser extent. An interesting finding was that hospitals that participated in a collaborative project on trauma treatment (the so-called BEST network) were significantly more likely to have trauma teams, paging criteria, and trauma manuals. INTERPRETATION: The results show that structural issues in relation to optimal trauma treatment still need more attention in Norwegian hospitals. Collaborative programmes for training and exchange of experience and procedures seem to be one way to go. PMID- 11603043 TI - [Group therapy of anxiety--benefits and profits]. AB - BACKGROUND: Since 1988, the psychiatric outpatient clinic at Kongsberg Hospital has carried out group treatment for patients with anxiety disorders. This study assesses the effect of this treatment. MATERIAL AND METHODS: Nineteen of a total of 27 patients were included in the study. Diagnostic criteria were agoraphobia with or without panic disorder. The length of treatment was three months. Methods used were cognitive behavioural therapy, physiotherapy and group therapy. Ratings of the patients' symptoms were made before treatment, at termination of treatment and one to three years after. The Symptom Score Check List (SCL 90) rates the level of symptoms on nine different dimensions. RESULTS: Analysis of variance for repeated measures (ANOVA) indicates reduction on six of the symptom dimensions at termination of treatment. Significant values of reduction was achieved for anxiety and phobic anxiety. This was even further reduced one to three years later. INTERPRETATION: We could not establish whether the treatment has been effective concerning the symptoms being treated. PMID- 11603044 TI - [Psychiatric and cognitive aspects of hypothyroidism]. AB - BACKGROUND: Diffuse and initial changes of behaviour, mood and cognition in hypothyroidism represent diagnostic and therapeutic challenges. MATERIAL AND METHODS: We present four cases and discuss relevant literature. Patients were followed from time of diagnosis through the first 6-12 months of thyroxine treatment. Symptoms were identified using interviews, questionnaires and tests. RESULTS: The patients had reduced quality of life, depression, anxiety and impaired short time memory. All symptoms improved with thyroxine treatment, although patients did not necessarily reach premorbid functioning in 6-12 months. In the literature, depression in hypothyroidism is hypothesised to be at least partly caused by relative hypothyroidism in the central nervous system, and local brain triiodothyronine deficiency may be a possible explanation for affective and cognitive symptoms in subclinical hypothyroidism. INTERPRETATION: Physicians should actively address psychiatric and cognitive aspects of hypothyroidism and in addition to thyroxine offer supportive treatment, especially to those depressed. PMID- 11603045 TI - [Non-alcoholic steatohepatitis]. AB - BACKGROUND: There is a growing interest in nonalcoholic steatohepatitis (NASH), a disease entity which is quite similar to alcoholic liver disease. MATERIAL AND METHODS: We present three patients with nonalcoholic steatohepatitis, and review current opinion on this disease entity. RESULTS: Non-alcoholic steatohepatitis is very often associated with the insulin resistance syndrome. There is also an association with hepatic iron overload. In one of our patients, biochemical improvement occurred after treatment with phlebotomy. Insulin resistance, resulting in fat accumulation, seems to be an important first step in the pathogenesis. Free fatty acids, iron, and other sources of oxidative stress probably result in cell damage. In some patients, these events result in necroinflammation mediated by various cytokines and immunoactive cells. The prognosis in pure steatosis is usually good. Presence of necroinflammation or fibrosis indicates a risk of progressive liver disease, including cirrhosis. PMID- 11603046 TI - [Clostridium septicum infection and cancer]. AB - BACKGROUND: Unusual infections may occasionally be the first sign of cancer. MATERIAL, METHODS AND RESULTS: We present a patient admitted with septicaemia caused by Clostridium septicum. After successful treatment of the infection, cancer of the transverse colon was revealed by further examination. INTERPRETATION: In cases of unusual infections, underlying malignant disease should be suspected. PMID- 11603047 TI - [Lost and found--memories of sexual abuse in childhood]. AB - During the last ten years a polarised debate has revolved about recovered memories of childhood sexual abuse. Some researchers are going far in denying the possibility of recovered memories, regarding them as false memories. Others claim that there is solid evidence for the reality of the phenomena. A key question is how memory is working in general, and especially in relation to stressful events in early life. Since memory is reconstructive, false and distorted memories can arise. There is growing evidence drawn from empirical research that childhood sexual abuse, like other trauma, can be forgotten for years before being recalled, although difficulties in forgetting traumatic experiences are a more frequent problem. PMID- 11603048 TI - [When will mammography screening reduce breast cancer mortality?]. AB - BACKGROUND: Norwegian authorities have decided to start a mass mammography screening programme. One third of the population has been included in a pilot study from 1996. The Cancer Registry of Norway maintains that there will be at least a 30% reduction in mortality, but that an effect may not be detected until the ten-year follow-up. METHODS: We assume that the effect of mammography screening is constantly increasing over a ten-year period before maximum effect is reached. We also assume that the effect of screening in the age group 50-74 years is 80% of maximum effect. We simulate Norwegian breast cancer mortality rates under the assumption that mammography screening reduces breast cancer mortality in the age group 50-69 years with 15% and 30% effects, respectively. We also simulate 30% and 50% effect in the pilot study. RESULTS: If the effect in the Norwegian population is 30%, one may expect to see a significant decline after five years; however, if the effect is only 15%, one has to wait for a longer time. If the effect is 50%, as the Cancer Registry of Norway has argued, one should see a significant effect in the pilot study after six years. CONCLUSIONS: We think it a contradiction to argue that mammography screening reduces breast cancer mortality by 30%, but that one has to wait ten years to observe an effect on national mortality rates. We suggest that the breast cancer mortality rate in the pilot study is estimated. We also argue that observed reductions of less than 10% in Sweden, Finland and England are strong evidence that the effect of mammography today is far less than 30%. PMID- 11603049 TI - [Practical advice on withdrawal of benzodiazepines]. PMID- 11603050 TI - [Stem cells in adults]. AB - BACKGROUND: We present a literature review of the plasticity observed by adult stem cells. MATERIALS AND METHODS: We have reviewed the literature regarding stem cells from adults in order to summarise their ability to generate cells of other types than those of the tissue/organ from which they were isolated. RESULTS: Adult stem cells have recently been demonstrated to terminally differentiate into cells of other tissues than those from which they were originally isolated. For example, bone marrow cells have been shown to generate liver, nerve, heart and skeletal muscle cells in addition to their well-known ability to produce blood and mesenchymal cells. INTERPRETATION: Most studies demonstrate a proof-of principle in animal models; much more research is needed before adult stem cells can be utilised in human medicine. However, the published reports are encouraging and give reasons for a cautious optimism with regard to future clinical use. PMID- 11603051 TI - [High dose therapy with autologous stem cell support--finally a progress in myelomatosis]. AB - BACKGROUND: Since the introduction of the simple cyclic oral treatment with melphalan and prednisone in the late 1960s, there has been no substantial improvement in the therapy of multiple myeloma. In 1994, the Nordic Myeloma Study Group initiated a population-based, prospective study to evaluate the impact on survival of high dose chemotherapy in newly diagnosed, symptomatic patients under 60 years of age, compared to a conventionally treated control group. MATERIAL AND METHODS: 274 patients were treated according to a specified high dose protocol and compared to 274 patients from previous population-based trials fulfilling the same eligibility criteria. RESULTS: Median survival was 44 months in the control group and 62 months in the intensive treatment group (risk ratio 1.65; 95% CI = 1.28-2.14, P = 0.0001). A study of health-related quality of life (HRQoL) which was integrated in the trial showed a moderately reduced HRQoL associated with the intensive treatment phase, but no statistically significant difference beyond the first year of follow-up. In a cost-utility analysis of the trial, the cost per (quality-adjusted life years) was estimated at USD 26,000. INTERPRETATION: The incremental cost of the treatment is within what is usually thought to be acceptable limits. Further improvement of the results and reduction of stay in hospital would give an even more favourable cost-utility ratio. PMID- 11603052 TI - [Embryonic stem cells and therapeutic cloning]. AB - Increased interest in the therapeutic use of human stem cells has emerged following significant progress in ongoing research. The cloning of a sheep, the isolation of human embryonic stem cells, and the discovery that adult stem cells may be reprogrammed taken together give substance to hopes that novel principles of treatment may be developed for a variety of serious conditions. Embryonic stem cells are derived from pre-embryos at the blastocyst stage and may give rise to all bodily tissues and cells. Animal models have demonstrated that embryonic stem cells when transplanted into adult hosts may differentiate and develop into cells and tissues applicable for treatment of a variety of conditions, including Parkinson's disease, multiple sclerosis, spinal injuries, cardiac stroke and cancer. Transplanted embryonic stem cells are exposed to immune reactions similar to those acting on organ transplants, hence immunosuppression of the recipient is generally required. It is, however, possible to obtain embryonic stem cells that are genetically identical to the patient's own cells by means of therapeutic cloning techniques. The nucleus from a somatic cell is transferred into an egg after removal of the egg's own genetic material. Under specific condition the egg will use genetic information from the somatic cell in organising the formation of a blastocyst which in turn generates embryonic stem cells. These cells have a genetic composition identical to that of the patient and are suitable for stem cell therapy. PMID- 11603053 TI - [Therapeutic cloning--future medicine or an ethical dead end?]. AB - BACKGROUND: Treatment with stem cells has given promising results in animal experiments and may be relevant in a variety of diseases, including heart disease, cancer, diabetes, Parkinson's disease and Alzheimer's disease. However, the use of pluripotent stem cells grown from blastocysts available after in vitro fertilization or from fetuses raises difficult issues in medical ethics. The same goes for therapeutic cloning. RESULTS: Attitudes to this mode of treatment differ from country to country. In Britain, Parliament has accepted therapeutic cloning (February 2001), while the German Bundestag has banned the procedure. The EU Parliament has recommended European countries not to allow therapeutic cloning, and President George W. Bush takes a more critical stand than did the Clinton administration. DISCUSSION: The debate over embryonal cells and therapeutic cloning involves both scientists and politicians. In Norway, the Biotechnology Advisory Board wants to open up for research on fertilized eggs and for therapeutic cloning. The Storting, Norway's legislature, will have to reach a decision on these issues when the Biotechnology Act come up for revision, probably in 2002. In the debate in Norway, it has been claimed that accepting therapeutic cloning would be a violation of a traditional western norm: Man should always be an end onto himself, never be used as an instrument to other ends. Furthermore, some scientists think that one should use adult stem cells from adults--this also because the procedure seems less risky. Bone marrow transplantation with autologous bone marrow stem cells has been used for 30 years, and recent research has disclosed that such stem cells may be reprogrammed, for instance from bone marrow stem cells to nerve cells. PMID- 11603054 TI - [Female oversteering behind the scenes?]. PMID- 11603055 TI - [How much is enough?]. PMID- 11603056 TI - [The (Belgian) Journal of Medicine]. AB - During the second half of the 19th century, a growing tendency developed in the Flemish intellectual circles to promote the use of their own language for the cultural, social and scientific development of Flanders. The emergence of a Dutch language medical press formed an integral part of this movement. The attempt to regularly supply physicians in Flanders with scientific information on medical progress in their own language only succeeded in 1910 with the first issue of the "Geneeskundig Tijdschrift voor Belgie" (Belgian Medical Journal). This journal became increasingly successful, but its edition was interrupted in 1914 at the outbreak of World War I. In 1920, the aim of this publication was pursued by the "Vlaamsch Geneeskundig Tijdschrift" (Flemish Medical Journal) which was published without interruption until the end of World War II (1944). These two journals not only accomplished a task of disseminating scientific information; they also played an important role in the struggle for the recognition of the Dutch language in academic education which led to Dutch becoming first partially (1923) and then completely (1930) the instructional language at Ghent University. That same struggle resulted also in the creation of the "Koninklijke Vlaamsche Academie voor Geneeskunde" (Royal Flemish Academy of Medicine) in 1938. The actual "Tijdschrift voor Geneeskunde" (Medical Journal) that was launched shortly (1945) after World War II, took over the assignment of providing scientific information. Throughout its existence, the journal was backed by colleagues of the Faculties of Medicine of the Flemish universities and the various sections of the medical profession. As a result, in the fifty-six years of its existence the journal has grown into a permanent value in the field of medical information and continuing education of physicians in Flanders. On the threshold of the 21st century, the "Tijdschrift voor Geneeskunde" will have to take up the challenge to further closely follow the extremely fast advances in medical science and also in our society. It will have to make sustained efforts to continuously adapt itself to new circumstances in order to contribute in a correct way to a high-quality medicine in our community. PMID- 11603057 TI - [The treatment of internees: a breakthrough in a new law?]. AB - Mentally disordered offenders can be declared criminal irresponsible according the Belgian Law of Social Defense (1 July 1964) and as a consequence they are "interned". The treatment of this population of "internees" is inadequate and the law must be revised. A commission "internment" has, at the request of the Minister of Justice, put forward conclusions in his report of 1999. Proposals are made to introduce the multidisciplinary psychiatric expert report, to improve the labeling of the question asked to the experts according to current psychiatric knowledge, and to operationalise important concepts as for example "dangerousness". The quality of the psychiatric treatment in the Belgian Prison system is bad for all the categories of inmates, detainees on remand, condemned or interned. The commission proposed that the Minister(s) in charge of Public Health and Social Affairs should be responsible for the treatment for the treatment of psychiatric disordered offenders, be it inside or outside prison. The political authorities plan to review this law of Social Defense, but these efforts will remain vain if no decisions are taken to implement the medical requirements of the law, and if no valuable forensic psychiatric treatment network is developed. PMID- 11603058 TI - Increased lipogenesis in steroid-responsive cancer cells: mechanisms of regulation, role in cancer cell biology and perspectives on clinical applications. AB - Steroid hormones have a strong influence on the biology of several common human cancers, including cancer of the prostate, breast, endometrium and ovarium. To gain more insight into this process, a screening for androgen-regulated genes was set up in prostate cancer cells. In addition to their well known effects on cell survival, proliferation and differentiated function, androgens were found to markedly stimulate the expression of several lipogenic enzymes. In clinical cancer samples these enzymes are markedly overexpressed in comparison to normal tissues, allowing them to be used as cancer markers and as potential targets for antineoplastic therapy. Investigation of the underlying mechanisms of gene regulation revealed that androgens stimulate lipogenic gene expression through a novel indirect mechanism involving Sterol Regulatory Element-binding Proteins (SREBPs), lipogenic transcription factors that play a key role in the fundamental feedback mechanism of cellular lipid homeostasis. Interestingly, also growth factors, whose signaling pathways are frequently dysregulated and constitutively activated as prostate cancer progresses towards a more advanced disease, stimulate lipogenesis through the same SREBP-mediated mechanism. While studies on the role of enhanced intermediary metabolism in cancer cell biology are progressing, these findings provide important new insights into the long-known dysregulation of intermediary metabolism in cancer cells and open new perspectives for clinical diagnosis and therapeutic intervention. PMID- 11603059 TI - Retinal tissue modulates retinal arterial tone through the release of a potent vasodilating factor. AB - Various intercellular messenger molecules, such as nitric oxide, adenosine and prostanoids, released by perivascular tissue have been implicated in the control of local blood flow. The present work performed in vitro on isolated retinal arteries advances that perivascular retinal tissue releases yet another intercellular messenger molecule exerting a potent vasodilatory influence. In these experiments, isolated bovine retinal arteries (mounted in a wire-myograph) incompletely cleaned of retinal tissue contracted weaker in response to prostaglandin F2 alpha, than arteries without retinal tissue. This also applied for thromboxane-, endothelin-, and serotonin-induced contractions. Apposition of a piece of retinal tissue elicited a complete and reversible relaxation of a bovine retinal artery contracted with prostaglandin F2 alpha, suggesting that the inhibitory effect of adherent retinal tissue is mediated by a diffusible relaxing factor. Incubation of a bovine retina for 6 hours (37 degrees C, O2/CO2 95%/5%) yielded a solution which induced a relaxation of the retinal artery contracted with prostaglandin F2 alpha, further confirming the involvement of a diffusible chemical substance. The inhibitory effect of adherent retinal tissue on the contractile tone of isolated bovine retinal arteries could not be attributed to the release of NO, prostaglandins or adenosine. Nor did the characteristics of this factor correspond to any of the known vasoactive mediators formed within the retina. Further experiments demonstrated that the release of this elusive factor is probably linked to the oxygen tension, since hypoxia induced a vasodilation of preparations with adherent retinal tissue whereas preparations without retinal tissue were not affected by the change in oxygenation. The present work reveals a new form of intercellular communication in which (a) factor(s) derived from the retina profoundly relax(es) the smooth muscle cells of retinal arteries and hence modulate(s) retinal blood flow. The identity of this (these) factor(s) and the mechanisms by which this (these) factor(s) induce(s) vasodilation remain as yet to be determined. PMID- 11603060 TI - Legionellosis: a new disease of Western hemisphere? AB - Legionnaires' disease is an acute bacterial pneumonia caused by an organism of the family of Legionellaceae. L. pneumophila serotype 1 is responsible for most infections. The incidence of Legionnaires' disease in Belgium is not known because the diagnosis cannot be made based on clinical or radiological grounds and because there is a microbiological underdiagnosis. Legionellae are widely distributed in nature, as free living organisms, in protozoa, and in biofilms. As a consequence, these bacteria are particularly resistant to disinfection and heating. We recently investigated an outbreak of legionnaires' disease among visitors to a fair in Kapellen, Belgium. The annual commercial fair at Kapellen was held between October 29 to November 7, 1999. Ninety-three people, who met the case definition, were identified. Among these 93 patients, 41 could be considered as confirmed cases, 14 as presumptive, and 38 as possible cases. Five patients died in as a consequence of the epidemic. A case-control study showed a causal link between a visit to the fair and the occurrence of the infection. A contaminated aerosol from a whirlpool was probably responsible for the outbreak. This epidemic illustrates the need for preventive measures to control for the growth of Legionellae in aerosol producing instruments. PMID- 11603061 TI - Scientific advice in support to risk management with regard to BSE. AB - The paper provides an overview of the efforts put into place by the European Commission for assessing the risks for humans, animals and the environment resulting from the BSE epidemic. The risk assessments are carried out by the Scientific Steering Committee (SSC) and its TSE/BSE ad hoc Group. They are part of the EC's scientific advisory system in support of health and consumer protection policy, which comprises another 8 scientific committees. The process from the emergence of a possible reason for concern to the submission of a legislative proposal based on a scientific opinion is outlined and the careful, step-wise process of preparing a TSE risk assessment is explained. The TSE related assessments are mostly qualitative. An example of a possible quantitative approach is given and it is shown that appropriate data and current scientific knowledge still do not permit the preparation of fully comprehensive quantitative risk assessments. Moreover, given the many unknowns and uncertainties, it is not evident that quantitative risk assessments would automatically provide the risk managers with a more appropriate tool in support of decision making. The multi disciplinarity of the assessments is highlighted and an overview is given of the TSE-related risk assessments carried out since 1997. They cover a wide range of fields, including safe geographical sourcing of animals, infectivity inactivation by processing, human exposure and epidemiology. PMID- 11603062 TI - [Evaluation of continuing medical training in private sector French cardiologists in 1999]. AB - The authors present the results of a retrospective national enquiry which took place in 1999 and was mailed and faxed to the 3,800 cardiologists practising in the private sector in order to assess the different types of continuous, individual and collective postgraduate training which they had benefited from in the preceding 12 months. The data was analysed by comparison with that obtained from an individualized representative sample in a panel of private sector cardiologists. The results were then compared with the criteria of a yardstick proposed by the National Committee of Continuous Medical Education of 1997, according to the April 25th 1996 decree. The meeting of these criteria would require carrying out 114,000 to 76,000 hour-equivalents of continuous education whereas the present offer is about 100,000 hour-equivalents. The different forms of individual or collective training were compared in the 327 questionnaires which were exploitable following adhesion to the French Society of Cardiology, to the Cardiologists' Union, to local cardiological societies, by age, gender and type of practice. The average number of annual hours of collective education was 52.2 +/- 60.1 hours (25% quartile = 25 hours, 75% = 60 hours). The average value of hours of individual education was 89.7 +/- 89.3 hours (25% quartile = 25 hours; 75% = 120 hours). This evaluation indicates that about 15% of cardiologists practising in the private sector have inadequate continuous medical education and that 68% would satisfy the criteria laid down in 1997. Moreover, the present offer would seem to be adequate providing the criteria of accreditation have been met. PMID- 11603063 TI - [Resistance to ACE inhibitors. Myth or reality?]. AB - Angiotensin Converting Enzyme (ACE) inhibitors represent a major advance in the treatment of: hypertension, and generally speaking, in cardiovascular prevention; myocardial infarction; cardiac failure. They have a cardio and vascular protective action by tending to correct hypertension, left ventricular hypertrophy and remodelling, endothelial dysfunction, arterial smooth muscle proliferation and thrombotic phenomena. However, besides the cough that this therapeutic class engenders, a major question remains unanswered: is there resistance to this family of drugs? In other words, does left ventricular remodelling and arterial smooth muscle proliferation continue with regular treatment at the prescribed dosages? The synthesis of angiotensin II does not only depend on the angiotensin converting enzyme but also on the quality of angiotensin I and the presence of other enzymes such as chymase. A secondary increase of angiotensin II with ACE inhibitor therapy may reflect insufficient blockade of the renin-angiotensin system or a synthesis of angiotensin II by an alternative pathway to the converting enzyme. In vivo measurement of ACE inhibition shows that blockade of the renin-angiotensin system is automatically limited due to the very accurate regulation of angiotensin II concentrations. PMID- 11603064 TI - [Cardiogenic shock due to myocardial infarction: surgical revascularization with centrifugal left ventricular assistance. Report of 2 cases treated successfully]. AB - Cardiogenic shock in the acute phase of myocardial infarction still carries a high mortality. In young patients who cannot be revascularised by angioplasty, when medical therapy is failing, some workers recommend an energetic approach, even cardiac transplantation, often with the bridge of mechanical cardiac assistance. This is not possible everywhere, thus preventing possible myocardial salvage and resulting in fairly high mortality. The authors report two cases in which endoluminal revascularisation was not possible and so complete surgical revascularisation with left ventricular assistance was chosen. The two patients survived and one was successfully transplanted electively. This management may be proposed in young patients with multiple occlusions of large coronary arteries in post-infarction cardiogenic shock when medical management is failing despite intra-aortic balloon pumping. PMID- 11603065 TI - [Mobile right heart thrombus with minimal pulmonary embolism. A case report]. AB - The generalisation of the use of transthoracic echocardiography in the investigation of pulmonary embolism leads to the diagnosis of mobile right heart thrombus in about 5% of cases. A review of the literature shows that this association is mainly observed in clinically severe pulmonary embolism. The presence of a mobile right heart thrombus is associated with a poor prognosis and emergency treatment is based on thrombolytic therapy or surgical embolectomy. In minimal or infraclinical pulmonary embolism, the finding of a mobile right heart thrombus is rare and there is no consensus about its treatment. The authors report the case of a 61 year old man admitted to hospital for bilateral deep vein thrombosis with no symptoms of pulmonary embolism in whom investigations revealed a mobile right heart thrombus with minimal pulmonary embolism. The outcome was favourable with progressive resolution of the right heart thrombus with oral anticoagulation after three weeks of heparin therapy. PMID- 11603066 TI - [Citalopram and Torsades de Pointes. A case report]. AB - Inhibitors of serotonin uptake are drugs prescribed without recognised cardiovascular risk. The authors report a case of torsades de pointes following Citalopram ingestion. In this patient, the proof of reintroduction in a hospital environment resulted in prolongation of the QT interval. Screening of patients for acquired or congenital long QT intervals is therefore necessary before starting treatment with Citalopram. PMID- 11603067 TI - [Intra-arterial thrombolysis of a basilar vascular accident during coronary angiography]. AB - The authors report the case of a 67 year old man with a previous history of aortobifemoral arterial graft who had unstable angina after carotid endarterectomy. Coronary angiography by the right brachial artery was complicated by a cerebrovascular accident with a reactive coma, convulsions and respiratory problems. Selective angiography of the right vertebral artery showed an image of occlusive thrombosis of the basilar artery. In view of the clinical state and angiographic appearances, the authors decided on immediate intra-arterial thrombolysis with Urokinase which dissolved the clot and reestablished flow in the basilar artery, the cerebellar and posterior cerebral arteries. The outcome was favourable with immediate and good recovery of consciousness and hospital discharge on the sixth day without neurological or radiological sequellae. Cerebrovascular accident is a rare and potentially serious complication of left heart catheterisation which requires immediate cerebral angiography to determine the mechanism and propose an appropriate therapeutic approach. PMID- 11603068 TI - [Patient information and quality of the medical act]. PMID- 11603069 TI - [Patient information and coronary angiography: experience of the Rennes group]. AB - The object of this study was to assess the degree of patient information of subjects referred for coronary angiography and their reaction to a detailed protocol of information. The enquiry was performed in 3 stages: an oral evaluation of the degree of information with a standardised questionnaire; the giving of written documents from the French Federation and Society of Cardiology mentioning the risks of the procedure; the continuation of the interview with evaluation of the degree of satisfactions with the information provided. Two hundred and thirty one patients referred by cardiologists for non-urgent coronary angiography were interrogated (175 men, 56 women; mean age 63 years, range: 27-83 years). In the 164 subjects who had never had this investigation: 56 (34.1%) did not appreciate the invasive nature of the procedure 111 (67.6%) totally ignored the risks of the procedure 70 (42.6%) were not informed of the possibility of a surgical procedure or of an angioplasty as a result of the procedure. 89% were satisfied with the information concerning the risks of the investigation. In a second group of 100 patients, the comprehension of the information was checked by the same questionnaire used a posteriori. These results show that patient information is very often incomplete. Despite some reticence, the new procedures seem to be globally well accepted but would be more effective if used before hospital admission. PMID- 11603070 TI - [Patient information. First evaluation]. AB - The recent harmonisation of the jurisprudence between the Court of Appeal and State Council has affected medical responsibility because it is now the physician's obligation to prove that the information to the patient has been properly given: it is, therefore, a current issue. A first evaluation was undertaken to determine the modalities of patient information in cardiology by an enquiry of cardiologists working in the public and private sectors. The results show that information to patients was given concerning complementary investigations such as exercise stress testing, transoesophageal echocardiography, coronary angiography and cardiac pacing; the information was more often given for invasive procedures. In the great majority of cases (92%), it is the prescribing or operating physician who gives this information, usually the day before the procedure, with complementary oral explanations in about 90% of cases. Patient information, therefore, seems to be well done by cardiologists. However, the proof of information is not always easy, written consent, signed by the patient, not being compulsory at present. PMID- 11603071 TI - [Hypertrophic cardiomyopathy. Long-term clinical development in a regional cohort of 243 patients]. AB - This retrospective study was undertaken to assess the long-term clinical outcome of hypertrophic cardiomyopathy (HCM) in a regional cohort of 243 patients aged 40.4 years on average at the time of diagnosis and followed up for 12.3 +/- 8.1 years. Forty-one deaths were recorded during the follow-up period directly related to HCM (including 20 sudden deaths and 17 deaths due to cardiac failure), an annual cardiac mortality rate of 1.37%. In multivariate analysis, two factors were associated with extra mortality: occurrence of the first symptoms before the age of 20 (RR x 2.35) (p = 0.006) and NYHA functional classes III: IV at the latest clinical assessment (p = 0.005). The risk of sudden death increased significantly with septal wall thickness: RR x 2.34 (p = 0.05), RR x 3.27 (p = 0.007) and RR x 3.67 (p = 0.02) respectively, for septal thickness equal to or greater than 25, 30 and 35 mm. Eighty-three patients (34%) had major cardiovascular events (sudden death, congestive cardiac failure, cerebrovascular accident) during follow-up. However, at the latest clinical assessment, 79% were relatively unaffected by their disease, without treatment (12%) or with drug therapy alone (60%). In a minority of patients (28%) a more aggressive therapeutic approach was necessary: cardiac pacing (N = 48), implantable cardiac defibrillators (N = 2) myomectomy (N = 27) or cardiac transplantation (N = 6). The authors conclude that HCM is a complex disease, less serious than initially thought in the majority of patients, but the cause of major cardiovascular events and premature deaths which still remain difficult to prevent. PMID- 11603072 TI - [Does Doppler analysis of hepatic venous flow predict increased right atrial pressure and right ventricular dysfunction?]. AB - The aim of this study was to test the hypothesis that Doppler study of hepatic venous flow, reflecting right atrial pressures and right ventricular dysfunction, allows prediction of increased right atrial pressure and right ventricular dysfunction in patients with right ventricular infarction. The authors studied 30 patients (27 men, mean age 54 +/- 12 years) in sinus rhythm with acute inferior myocardial infarction who underwent right heart catheterisation and Doppler echocardiography including recording of regurgitant and hepatic vein flow within 48 hours of hospital admission. Hepatic venous flow was used to measure peak velocity and velocity time integrals (VTI) of the systolic (S), diastolic (D) and atrial (a) contraction waves. The fraction of systolic filling was calculated: VTI S/VTI S + VTI D. The pressure half-time of pulmonary regurgitant flow (PHT IP) was also measured. Using haemodynamic criteria (non-compliant right atrial pressure wave form or right ventricular end diastolic pressure/pulmonary capillary pressure > or = 0.8), patients were divided into two groups: Group 1: right ventricular infarction (VD+, N = 22). Group 2: no right ventricular infarction (VD-, N = 8). No correlation was observed between Doppler parameters of hepatic venous flow and haemodynamic data, in particular right atrial pressure and pressure wave form. Moreover, no statistically significant difference was observed between the two groups with respect to the Doppler parameters derived from hepatic venous flow. On the other hand, the results confirmed good diagnostic performance of Doppler analysis of pulmonary regurgitant flow: sensitivity 80%, specificity 83%, positive predictive value 94%, negative predictive value 55%. The authors conclude that, in patients with acute inferior wall infarction, Doppler analysis of hepatic venous flow does not allow assessment of right atrial pressure or of ischaemic right ventricular dysfunction. PMID- 11603073 TI - [Efficacy and safety of low-dose heparin (30 IU/kg) during coronary angioplasty]. AB - High doses of heparin are recommended during coronary angioplasty although platelet inhibition seems to play a role in the prevention of ischaemic complications. Low dose heparin could reduce the incidence of local complications without increasing that of major coronary events. The authors report the results of a prospective register of coronary angioplasties performed by the femoral approach with a single bolus of 30 IU/Kg of heparin and immediate withdrawal of the 6 French introducer. Only patients with recent infarction or left main stem disease were excluded. All underwent clinical examination and ultrasonic scanning of the puncture site the day after the procedure. Four hundred and eighteen patients were included (mean age: 63.3 +/- 11 years; 79% men; 77% stenting). The average dose of heparin was 2253 +/- 1056 IU; the average procedure time was 25 +/- 16 minutes, and a final activated clotting time was 174 +/- 69 ms. The duration of normal compression was 7.7 +/- 3 min. Eighty-three point five per cent of patients were discharged the day after the procedure with a global cardiovascular complication rate of 2.87%. At 1 month, 1.67% of secondary cardiovascular events was recorded. Ultrasonography of the puncture site was abnormal in 7.6% of patients. Only one serious vascular complication (0.24%) requiring transfusion and surgical repair, was observed. The authors conclude that the use of low dose heparin appears effective and safe in cases without acute myocardial infarction. This protocol allows faster mobilisation and earlier hospital discharge of patients. PMID- 11603074 TI - [Evaluation of outcome of patients hospitalized after pre-hospital cardiac arrest]. AB - The aim of this study was to assess management of patients resuscitated after pre hospital cardiac arrest, initially indicated to preserve neurological status, the aetiological investigation only being undertaken when the outcome is favourable. Eighty-nine pre-hospital cardiac arrests were analysed retrospectively. The hospital survival was 16%, death being due to neurological lesions (55%), uncontrollable haemodynamic instability -39%) or other causes (7%). One year after the initial episode, none of the survivors had died, all living autonomously without (8 patients) or with minimal neurological sequellae (5 patients). These results are concordant with reports in the literature. The 11 cases of cardiac arrest with a favourable outcome of presumed cardiac origin underwent coronary angiography (6 cases) or endocavitary electrophysiological investigation (8 cases). These investigations showed or suggested an ischaemic process in 4 cases, an arrhythmia in 6 cases and severe valvular heart disease in 1 case. The independent predictive factors of survival were a Glasgow score of 6 or more on admission, the persistence of a light reflex and benign EEG appearances according to Synek's classification. The authors conclude that these results are comparable to those reported in the literature with aetiological investigations reserved for cases of favourable neurological outcome. The investigations including coronary angiography and electrophysiological investigation are essential as shown by the diversity of the cardiac pathologies identified. PMID- 11603075 TI - [Intravascular detection of myocardial ischemia by spectrometry in the near infrared spectrum in experimental animals]. AB - Interruption of oxygen supply in acute myocardial ischaemia reduces venous return of oxygen at the coronary sinus. In this study, the oxygen content of venous return in the coronary sinus was measured by using spectrometry in the near infrared spectrum. The authors developed a new intravascular catheter made of fibre optics. After in vitro calibration by blood flow based on a standard gas mixture used in in vitro experiment, an in vivo application in 12 domestic pigs was undertaken. The catheter was positioned in the coronary sinus and ischaemia induced by temporary occlusion of the left anterior descending artery. Recordings of the near infrared spectrum and haemodynamic data were obtained during 90 minutes' ischaemia followed by 90 minutes reperfusion. Spectrometry in the near infrared range detected a marked difference between oxyhaemoglobin and deoxyhaemoglobin, especially when the oxygen concentration was less than 30%. The near infrared spectrum of liaison between haemoglobin and oxygen in the coronary sinus shows significant and reproducible differences between pre-ischaemia occlusion of the left anterior descending artery and reperfusion. The recordings of the near infrared also show variation in CO2, pH and temperature. The authors conclude that the use of intravascular spectrometry of the near infrared spectrum could be a permanent reliable tool for detection and follow-up of acute myocardial ischaemia. PMID- 11603076 TI - Sensitivity of the motor unit unfused tetanus to changes in the pattern of motoneuronal firing. AB - The effects of decreasing as well as increasing the interpulse intervals on the tension produced by motor units in the rat medial gastrocnemius muscle were investigated. The increase and decrease in tension, resulting from these changes in interpulse intervals were observed and compared for each motor unit in tetani fused to a various degree. It was found that amplitudes of both changes in tension were the same when the tetanic fusion index was approximately 0.70 and the tension corresponded to 40-50% of the maximal tetanic tension. This observation concerned the all three types of motor units. We also studied the effects of introducing a short interpulse interval ("doublet") at the beginning of the stimulation. The doublet produced an increased tetanic tension with a more fused profile, however the tension was similarly sensitive to an increase as well as a decrease in the interpulse interval when the tetanic fusion index was also about 0.70. Therefore, the extent of tetanic fusion determines the sensitivity of motor unit tetani to changes in a pattern of stimulation. The tetanus of the fusion index about 0.70 can be considered as the most sensitive to changes in the pattern of motoneuronal firing. PMID- 11603077 TI - The spatial substructure of visual receptive fields in the cat's superior colliculus. AB - Although the direction selective properties of the superficial layer cells of the cat's superior colliculus have been extensively studied, the mechanisms underlying this property remain controversial. With the aim to understand the mechanism(s) underlying directional selectivity of collicular neurons we examined the substructure of their visual receptive fields. 1. The strength of cell responses and the direction selectivity indices varied in relation to the location of the tested region within the receptive field and the amplitude of stimulus movement. 2. Decrease of the amplitude of motion resulted in a decrease of direction selectivity index both in the group of direction-selective cells and in the group of cells classified as direction nonselective but with a directional bias. 3. The decrease of direction selectivity for small amplitude movement resulted mainly from increase in the magnitude of response in the nonpreferred direction of movement. 4. These results suggest that the receptive fields of most collicular cells are composed of subregions with different response profiles and indicate that inhibitory mechanisms dictate direction selectivity of collicular cells. PMID- 11603078 TI - Glial cell and macrophage reactions in rat spinal ganglion after peripheral nerve lesions: an immunocytochemical and morphometric study. AB - Following peripheral nerve injury perineuronal satellite cell reaction in the corresponding spinal ganglion is observed. The mechanisms underlying the glial responses to axon injury remain unknown. In an immunocytochemical and morphometric study we investigated satellite cell and macrophage responses in the rat L4 and L5 dorsal root ganglia (DRG) during the seven days immediately after unilateral sciatic nerve crush or transection. Nerve lesion induced a significant increase of glial fibrillary acidic protein-immunoreactive (GFAP-IR) cells in the ipsilateral L4-L5 DRGs. The number of ED1-positive macrophages significantly increased as well. We found no significant differences between the increases provoked by the two types of nerve lesion, but the macrophage activation was detected earlier after nerve transection than after crush. No correlation was detected between satellite cells and macrophages reactions over the 7 day period we examined. These findings support the idea that intercellular neuron-glial diffusible signals play a major role in DRG glial cell response to peripheral nerve lesion. PMID- 11603079 TI - Information measures for conscious experience. AB - This paper argues that consciousness is integrated information, and introduces measures to assess it. These measures lead to the prediction that a physical system such as the brain gives rise to consciousness when some of its elements constitute a complex having high minimum information midpartition (MID) complexity. PMID- 11603080 TI - [Children of mentally ill parents in the awareness of professionals]. PMID- 11603081 TI - [Parenthood and psychiatric hospitalization]. AB - As a topic, parenthood by persons with severe mental disturbances has predominantly been investigated with regard to the effects of the disorder on the children. The present article, in contrast, focuses on the concerns of psychically ill parents. On the one hand, the study aimed to record the portion of treated stationary patients with children under age; on the other hand, the need of these parents for assistance with regard to their parenthood was to be explored. In the course of a five-month period, number and age of children of all patients entering the in-patient clinic (n = 614) were recorded. 101 persons, or 16.5%, were registered as being a parent of at least one minor child. Semi structured interviews were conducted with 44 parents, addressing the problems caused by the illness, contact with the children during hospitalisation, resources, familiarity and experience with assistance provided, as well as the need for further support. More than 2/3 of the patients expressed a need for help with informing their children of the illness and requested support in the form of parent groups at the clinic. Almost half of the patients were prepared to contact an expert at the clinic on questions relating to parent-child issues. Our findings reveal a great demand for support and that provision of assistance is imperative. PMID- 11603082 TI - [Biographical experiences of children of psychiatrically ill parents]. AB - In the literature you will find some references about the problems of children with parents with mental-health problems. However there is not enough knowledge about the question, how children experience such problems right inside and how their emotionally reaction about this is. Based on biographical interviews with grown-up children this article will show how they integrate the experience of the mental-health problems of their parents in their own live stories and how they interpret and value them in a retrospective view. This article focussed the regularities and commonness in the individual experiences in their childhood at thereby find generally statements about the life situation of children with mental-health parents. PMID- 11603084 TI - [Inpatient psychiatric treatment of mothers with their children]. AB - Proceeding from the increased incidence of postpartum psychiatric disorders the risk factors of postpartum psychosis and postpartum depression including cultural conditions will be described. In the following reasons for an inpatient treatment of mentally ill mothers together with their children are presented under the viewpoint of preventive treatment and illustrated by a clinical example. The psychotherapeutic and pedagogic oriented interventions during treatment will be demonstrated more precise reference to attachment theory. Finally the relevance of early intervention as well as the exchange and necessity of coordination between the involved institutions and occupational groups concerning the treatment of postpartum psychiatric disorders is pointed out. PMID- 11603083 TI - [Psychiatric illness from a multi-generational perspective: results of a longitudinal study with children and grandchildren of hospitalized depressed patients]. AB - In a longitudinal empirical study data from three generations were gathered: Generation 1: formerly depressive patients, who had been treated as inpatients; generation 2: children of these patients; generation 3: grandchildren of the former patients. The first investigation of the children was carried out in the seventies, the follow-up-assessment of children and grandchildren was done in 1996. In the follow-up-study the meanwhile grown-up children of the depressive patients showed to a high degree psychic disturbances and were in treatment because of these problems. The majority of the grandchildren showed no relevant deviations. The severity of the depressive illness (in generation 1) and the psychopathological status of the former inpatient's spouse proved to be relevant prognostic factors with regard to the long-term development and resilience of children and grandchildren. PMID- 11603085 TI - [Preventive treatment of mothers and their babies in a day care setting]. AB - Certain aspects of the communication between mother (and father) and baby are of major influence on the developmental outcome of the child. Mentally ill mothers in psychiatric day care are considerably limited in their communicative abilities, especially in themes of developmental relevance. As a consequence of their inherent ego weakness the mothers' flexible adaption to the babies' needs is impaired. Because of their own emotional neediness mothers are not sufficiently sensible and responsive to the babies' signals. Almost all of the mothers feel aggressive impulses towards their babies. Indication for day care depends to an essential part on the mothers' reflective function concerning aggression. Although there is some danger of child abuse, the joint treatment is considered to prevent early attachment disorders and/or a pathologic developmental outcome in the child. In addition, mother-baby-therapy is indicated in cases of severe regulation disorders. The specific models of our therapy are illustrated in two case examples. PMID- 11603086 TI - [Prevention groups for school-age children of mentally ill parents ("Auryn Groups")]. AB - Children of psychiatrically ill parents have a high risk themselves to develop a psychiatric illness in adulthood. Prevention aims at strengthening the resilience of these children and reducing psychosocial risk factors. This article found and describes a theoretical concept of prevention groups for children in schoolage (7 16 years) whose parents are psychiatrically ill. First practical experiences are depicted. The Hamburgian model of prevention works with closed and temporary limited groups of children as well as with the parents. It is based on supporting the children's existing coping strategies and the children are encouraged to exchange their individual experiences of the relationships within their families. One conclusion was, that the main thematic emphasis varied considerably depending on the age of the children. PMID- 11603087 TI - [KIPKEL--an interdisciplinary ambulatory prevention project for children with mentally ill parents]. AB - Children of psychiatrically ill parents up to now have hardly been perceived as a risk group. In order to prevent these children form becoming psychiatrically ill the practice for art-therapy and psychotherapy and the social psychiatric service of the city of Hilden have developed a programme for parents having children under 18 years of age in which at least one parent suffers from endogenous psychosis or severe personality disorder. The two initiators of the KIPKEL project describe the experiences they had during the preparatory phase and while securing the financial basis and building up solid structures of cooperation. The conceptual basis of the project and problems of practical realization are presented. Finally an example of a family who participated in the programme is given. It illustrates the complex arrangement of interpersonal relationship and the course of the carework. PMID- 11603088 TI - [Between psychiatry and youth welfare--help and support for children of mentally ill parents in the tension field of the disciplines]. AB - A mental illness of parents brings up a high burden for the affected children. The professionals working in psychiatry and social work are getting a rising knowledge of the specific problems these children have. Anyway, there are only a few useful treatments offered for this group of people. There are a lot of reasons for this lag in take care of. It's not only based on the financial situation or the personnel structure which must be mentioned as reasons for children of parents with mental illness for not asking for help. It's also the incomplete knowledge of the caregivers. But first of all the writer wants to show that the tension in this working field brings up the main problems. For solving these problems the article gives some advice for crossing over the borderlines and build up a communication between the institutions which are involved. PMID- 11603089 TI - [Tubal sterilization in mentally handicapped women]. AB - ETHICAL ISSUES: When performed for contraception purposes, tubular sterilization for mentally handicapped women poses important ethical issues, including patient's rights, body integrity, and the notion of informed consent. French law guarantees the respect and safety of all patients, but in everyday practice, patient's rights must be upheld by family and healthcare workers searching for the most adapted solutions for each individual situation. PROPOSITIONS: We present here our proposals for everyday practice. Our conclusions are based on an analysis of the notion of handicap as defined by the WHO and on the observed sexual activities of this type of patient. In this context, informed consent involves a number of subjective factors pointing out the difficulty encountered in providing dear comprehensible information. Finally we discuss the ethical issue of tubular sterilization which many consider to be a masked form of eugenism. PMID- 11603090 TI - [Chronic renal failure and hypertension in community cardiology practice]. AB - OBJECTIVE: A sustained increase in the incidence of vascular nephropa-thies has been recently documented in western countries and correlated with aging. Renal failure is often ignored in patients with hypertension and its diagnosis made too late, at the stage of replacement therapy, with an increased mortality rate and prolonged hospitalization time. In clinical practice, the diagnosis of renal insufficiency is based on the measurement of serum creatinine, which depends on muscular mass, gender and age of the subject and is regulated by glomerular filtration. Therefore, serum creatinine level does not give a correct estimate of renal function. According to Good Clinical Practice recommendations, serum creatinine must be used to calculate creatinine clearance, a surrogate of glomerular filtration. To avoid methodological constraints of clearance measurement with precise urine recollection, the index proposed by Cockcroft and Gault is highly reliable and widely used. PATIENTS AND METHOD: An epidemiological survey has been carried out to measure the prevalence of renal insufficiency in hypertensive patients regularly followed by cardiologists. This open, transverse study compared estimates of renal function based upon serum creatinine level and creatinine clearance using the Cockcroft and Gault's formula. Among 1,000 private cardiologists randomly selected in metropolitan France, 707 entered the study. During the last week of May 2000, they included 2,100 hypertensive patients using a questionnaire describing individual patient's demographic and clinical characteristics. RESULTS: The mean age of hypertensive patients was 65.9 +/- 12.2 years. They used antihypertensive drugs for a mean 10.3 +/- 7.7 years. The prevalence of renal failure, as defined by a creatinine clearance lower than 60 ml/min, was 32%, whereas 61% of the patients had a creatinine clearance below 80 ml/min. In contrast, 71% of the patients were subjectively considered to have a normal renal function. This discrepancy reflects underdiagnosis of mild to moderate renal failure. Hypertensive patients with renal failure did not present with excess cardiovascular risk factors and comorbidities when compared with those having a normal renal function. Prevalence of type 2 diabetes and hypercholesterolemia was similar in both groups. CONCLUSION: The present study outlines the discrepancy between theoretical knowledge and practical assessment of renal insufficiency in handling hypertensive patients, in the particular setting of cardiologist practice. In order to suppress this gap, the Cockcroft and Gault formula must be widely used. It is suggested that body weight, in addition to gender and age, may be printed together with serum creatinine concentration on the biology form given to patient. PMID- 11603091 TI - [Fatal fulminant acute amebic colitis in metropolitan France]. AB - BACKGROUND: Emergency care is required for patients presenting dysentery and fever. CASE REPORT: A 65-year old patient living in metropolitan France was hospitalized for watery diarrhea that had progressively worsened over the last month. Rectal bleeding was also noted. Serology tests at admission, together with parasitology examination of the fecal matter and colonoscopy led to the diagnosis of intestinal amebiasis a few hours before the patient's rapid death. Serology was positive for amebas and the diagnosis was confirmed by pathology examination of the colonoscopy biopsies. DISCUSSION: The diagnosis of amebiasis should be entertained even in Europe when there is no history of travel to endemic areas in patients who develop suggestive manifestations. Identification of amebas in the fecal matter and serology tests provide certain diagnosis. Clinicians should recall that rapidly fatal outcome is not uncommon in severe forms. Emergency care is mandatory. PMID- 11603092 TI - [Importance of blood glucose level when starting antipsychotic treatment]. PMID- 11603093 TI - [Value of saquinavir in antiretroviral treatment of adult HIV-1 infection in 2001]. AB - Saquinavir is an HIV protease inhibitor (PI) which, formulated as a hard-gel capsule (HCG), was the first drug of its class to become available for the treatment of patients with HIV infection. The limited bioavailability of this drug was responsible for a reduced number of prescriptions when new PI were available. Since 1997, combination therapy with ritonavir has improved the pharmacokinetics parameters resulting in a better clinical benefit. Saquinavir (HGC) monotherapy is not yet recommended. Soft gel capsule (SGC) has improved biodisponibility. Efficacy of SQV has been shown in clinical studies in first and second line of treatment with PI. Resistance profile is favorable considering the low level of cross resistance with other PI. Better knowledge of saquinavir could help giving back a place to this drug in the anti HIV arsenal. PMID- 11603094 TI - [Helicobacter pylori eradication. Therapeutic evolution, value of complementary studies]. AB - INDICATIONS: Eradication of Helicobacter pylori is needed for patients with a gastroduodenal ulcer associated with H. pylori gastritis. Eradication modifies the natural history of the disease and greatly reduces the risk of recurrence. Eradication is also indicated for patients with MALT lymphoma with a low degree of malignancy. Systematic eradication of H. pylori would not be necessary for patients with dyspepsia associated with H. pylori gastritis since a beneficial effect is achieved in only 5% of the treated patients. Systematic eradication in order to reduce the incidence of gastric adenocarcinoma is not recommended. DIAGNOSIS: Direct tests (urease, pathology) provide the diagnosis of H. pylori gastritis. Indirect tests (13C-labeled urea respiratory test) can be most useful to determine the efficacy of eradication treatments. THERAPY: A tri-therapy regimen given for 7 days combining a double-dosed proton pump inhibitor, amoxicillin (2 g/d), and clarithromycin (0.5 g b.i.d) is used to eradicate H. pylori. With this regimen, the mean rate of eradication achieved in France is 67%. The principal causes of failure are poor compliance and bacterial resistance to clarithromycin. Metronidazole (1 g/d) can be used for patients allergic to penicillin. A second cycle can be prescribed in case of failure, substituting metronidazole for clarithromycin. FOLLOW-UP: Eradication treatment is prescribed for patients with an ulcer after confirmation of infection by one or two direct tests. Treatment efficacy can be assessed by the respiratory test for patients with a duodenal ulcer but is not systematically needed. Biopsy of a gastric ulcer can also provide an assessment of treatment efficacy. For patients with a non complicated duodenal ulcer, antisecretion treatment is not required in addition to eradication treatment. PMID- 11603096 TI - Train your endothelium. PMID- 11603095 TI - [Eradication of Helicobacter pylori. Is it necessary to eradicate Helicobacter pylori in gastric reflux?]. AB - POTENTIAL PROTECTIVE EFFECT OF H. PYLORI: Epidemiological studies have not demonstrated an association between H. pylori infection and symptoms of gastroesophageal reflux, reflux esophagitis, or Barrett's esophagus with or without dysplasia or esophageal adenocarcinoma. On the contrary, an apparently favorable negative association has been identified suggested a potential protective effect of H. pylori. An inverse association is also observed between the severity of reflux complications and infection by strains of H. pylori expressing certain virulence markers (cogA) associated with the more severe gastric lesions. The prevalence of gastroesophageal reflux-related disease has increased steadily for more than fifty years while the incidence of H. pylori infection has decreased in developed countries. This observation might suggest that H. pylori infection plays a protective role. In addition, eradication of H. pylori could favor he development of gastroesophageal reflux or reflux esophagitis. The degree of risk is unknown. Pangastritis with significant lesions of the gastric body leading to a reversible decrease in the secretion of acid after H. pylori eradication might lower the risk of gastroesophageal reflux. POTENTIAL PROMOTION EFFECT: The relations between H. pylori and gastroesophageal reflux are complex. Reflux associated with duodenal ulcer appears to be improved by eradication of H. pylori suggesting that infection might promote the development of reflux. The causal mechanism would be increased acid secretion induced by antral gastritis predominantly resulting from the H. pylori infection. Further work is needed to determine the exact role of gastritis and perturbed acid secretion. PERSPECTIVES: Data on the role of H. pylori in transient relaxation of the lower esophageal sphincter, implicated in the pathogenesis of gastroesophageal reflux, are lacking. Antisecretion treatments reduce the quantity of gastric acid favoring H. pylori colonization of the fundic mucosa and possibly aggravating fundic gastritis. The risk of progression from H. pylori gastritis to atrophy or intestinal metaplasia of the fundus under prolonged proton pump inhibitor treatment remains to be determined. Eradication of H. pylori reduces the efficacy of antisecretory drugs according to poorly understood mechanisms. The potential effect of gastroesophageal reflux on the transmission of H. pylori infection remains to be established. PRACTICAL ATTITUDE: Much remains to be learned concerning the beneficial or deleterious effects of eradication of H. pylori on the course of gastroesophageal reflux. In clinical practice, eradication of H. pylori is not useful for patients with gastroesophageal reflux. PMID- 11603097 TI - Supplements of keto acids in patients with chronic renal failure--more than modulators of nitrogen economy. PMID- 11603098 TI - [Health care services for women with postpartum mental disorders--assessment of current options in Austria]. AB - For many women childbirth is one of the most impressive life-events, but this period of life may also be a phase of increased vulnerability for psychiatric illness. 10-15% of women develop a postnatal depression (PND) after the birth of a child, and 1@1000 suffer from a puerperal psychosis. Despite the high prevalence, with estimates of approximately 10,000 women suffering annually from postnatal psychiatric disturbances in Austria, there has been a lack of medical attendance for these women and their children. Motivated by a research initiative from the EU on transcultural aspects of postnatal depression (PND) with 17 participating research centers world-wide, a research team at the Vienna University Clinic for Psychiatry initiated the investigation of conditions for mother-child-admissions at 31 psychiatric wards in Austria. These departments were asked about the possibility of conjoint mother-child-admission, and their experiences with this form of admission; 23 departments (74.2%) provided information. A total of 12 departments responded that they theoretically accepted mothers with their babies; however, they also indicated that until now these conjoint admissions had been performed only very rarely or not at all. Based on many years of experience in the field of postpartum mental health in Great Britain, British researchers have developed guidelines for need assessment and health care provision for women with postpartum psychiatric disorders. With the help of these guidelines, the Viennese team of psychiatrists tried to develop fundamental concepts for need assessment, diagnosis, and treatment of patients suffering from postpartum mental illness in Austria. PMID- 11603099 TI - The gut as a neurological organ. AB - We refer to the gut as a neurological organ to emphasize the particular importance of the nervous system in the regulation of digestive functions, given that the gastrointestinal tract is innervated by five different classes of neurons: intrinsic enteric neurons, vagal afferents, spinal afferents, parasympathetic efferents and sympathetic efferents. Virtually each aspect of digestive activity is under the regulatory influence of neurons, among which the enteric nervous system (ENS) plays the most important part. The ENS acts like a brain in the gut that functions independently of the central nervous system, contains programmes for a variety of gastrointestinal behaviours and governs the activity of all gastrointestinal effector systems according to need. Intrinsic sensory neurons supply the ENS with the kind of information that this system requires for its autonomic control of digestion, whereas extrinsic afferents notify the brain about any data that are relevant to energy and fluid homeostasis and the sensation of discomfort and pain. Many diseases of the gut, particularly the functional bowel disorders, seem to be related to dysfunction of the ENS and other components of the gastrointestinal innervation. The ENS and extrinsic afferents are hence prime targets for the therapeutic management of gut diseases and for the relief of the pain and discomfort associated with these disorders. PMID- 11603100 TI - Metabolic effects of keto acid--amino acid supplementation in patients with chronic renal insufficiency receiving a low-protein diet and recombinant human erythropoietin--a randomized controlled trial. AB - Supplement with keto acids/amino acids (KA) and erythropoietin can independently improve the metabolic sequels of chronic renal insufficiency. Our study was designed to establish whether a supplementation with keto acids/amino acids (KA) exerts additional beneficial metabolic effects in patients with chronic renal insufficiency (CRF) treated with a low-protein diet (LPD) and recombinant human erythropoietin (EPO). In a prospective randomized controlled trial over a period of 12 months, we evaluated a total of 38 patients (20 M/18 F) aged 32-68 years with a creatinine clearance (CCr) of 20-36 ml/min. All patients were receiving EPO (40 U/kg twice a week s.c.) and a low-protein diet (0.6 g protein/kg/day and 145 kJ/kg/day). The diet of 20 patients (Group I) was supplemented with KA at a dosage of 100 mg/kg/day while 18 patients (Group II) received no supplementation. During the study period, the glomerular filtration rate slightly decreased (CCr from 28.2 +/- 3.4 to 26.4 +/- 4.1 ml/min and 29.6 +/- 4.8 to 23.4 +/- 4.4 ml/min in groups I and II, respectively and Cin); this however was more marked in Group II (Group I vs. Group II, p < 0.01). The serum levels of urea also declined (p < 0.01), more pronouncedly in Group I (p < 0.025). In Group I, there was a significant rise in the levels of leucine (p < 0.01), isoleucine (p < 0.01), valine (p < 0.02) and albumin (p < 0.01) and a decrease in protein-uria (p < 0.01). Analysis of the lipid spectrum revealed a mild yet significant decrease in total cholesterol and LDL-cholesterol (p < 0.02), more pronounced in Group I. In Group I, there was a decrease in plasma triglycerides (from 4.2 +/- 0.8 down to values a low as 2.2 +/- 0.6 mmol/L; p < 0.01) whereas HDL-cholesterol levels increased (from 0.9 +/- 0.1 to 1.2 +/- 0.1 mmol/L, p < 0.01). A further remarkable finding was a reduction in the serum concentration of free radicals (p < 0.01). We conclude that a KA supplementation in patients with CRF receiving LPD and EPO potentiates the beneficial effects on metabolism of proteins, amino acids and surprisingly, also lipids. Long-term co-administration of KA, EPO and LPD was also associated with a delay in progression of renal insufficiency and a reduction in proteinuria. Thus, concomitant administration of KA and EPO during a low-protein diet presents an effective treatment modality in the conservative management of CRF. PMID- 11603101 TI - Health related quality of life in patients with long-standing insulin dependent (type 1) diabetes mellitus: benefits of regular physical training. AB - BACKGROUND AND AIMS: Regular exercise is recommended to diabetic patients in addition to dietary restrictions and drug therapy. We have studied whether health related quality of life (HRQOL) can be improved by a regular physical training program. METHODS: 23 otherwise healthy patients with history of type 1 diabetes for 20 +/- 10 years were included. 15 patients (age: 41 +/- 2 years) participated in an aerobic physical training program over 4 months and 8 patients (33 +/- 11 years) served as a control group. HRQOL was assessed by a validated questionnaire (MOS SF-36). Tests were carried out at baseline and after 4 months. RESULTS: Physical training increased peak oxygen uptake (VO2max) by 27 +/- 13% after 4 months (p = 0.04) in the training group. There was no significant change in hand or leg isometric muscle strength. All HRQOL scales improved in the training group with significantly higher (p < 0.04) Social Functioning and Vitality scores, respectively. Moreover, insulin requirements decreased during physical training program (p < 0.05). CONCLUSIONS: Our data indicate that physical exercise training in patients with type I diabetes mellitus improves metabolic control and various aspects of HRQOL. Besides enhanced cardiorespiratory capacity, this is an important subjective benefit in patients with longstanding insulin dependent (type 1) diabetes mellitus. PMID- 11603102 TI - Procalcitonin as a diagnostic marker in patients with aspiration after closed head injury. AB - BACKGROUND: Aspiration of gastric content frequently induces early onset of pneumonia in patients with impaired consciousness after closed head injury and thus worsens the prognosis. Early detection of aspiration and appropriate therapy are essential. The purpose of the study was to assess the diagnostic value of procalcitonin (ProCT) in aspiration of gastric content and to evaluate its prognostic impact in patients with closed head injury. METHODS: Twenty-three patients with isolated closed head injury (Glasgow Coma Scale [GCS] score < or = 8) were studied. Bronchoscopy was done on admission; chest radiographs and routine laboratory examination including C-reactive protein were performed daily. ProCT was analyzed 12, 24, 36 and 72 hours after trauma using an immunoluminometric assay. RESULTS: ProCT was higher throughout the study period in 9 patients with persistent radiological signs suspect for aspiration of gastric content and there was evidence of aspiration of gastric content during bronchoscopy on admission. Median ProCT values of 1.397 ng/ml (range, 0.372 to 8.358 ng/ml) on admission increased to 2.144 ng/ml (range, 0.716 to 6.910 ng/ml) 24 hours after trauma, and then decreased to baseline values of 1.711 ng/ml (range, 0.611 to 6.639 ng/ml) as early as 36 hours after trauma. In patients without signs of aspiration of gastric content, ProCT values did not exceed 0.418 ng/ml. Non-survivors had higher serum levels of ProCT throughout the study period. CONCLUSION: Our findings suggest that ProCT is a useful diagnostic marker for detecting aspiration of gastric content while the prognostic value of ProCT for predicting survival after isolated closed head injury was moderate. PMID- 11603103 TI - [Surgery for non-colorectal and non-neuroendocrine liver metastases]. AB - INTRODUCTION: Hepatic resection has been shown to prolong survival in selected patients with colorectal liver metastases. Due to slow tumor growth patients with neuroendocrine liver metastases tend to have a good prognosis and benefit from chemo-embolisation and symptomatic treatment. The role of surgery in treating non neuroendocrine and non-colorectal liver metastases is discussed controversially, due to the limited knowledge on this subject. The aim of our study was, therefore, to evaluate our own experiences with hepatic surgery for non neuroendocrine, non-colorectal liver metastases. METHODS: A retrospective review of 72 patients (median age 60.9 years) who underwent 73 hepatic resections for non-neuroendocrine, non-colorectal liver metastases between 1980 and 2000 at a single tertial referral center was carried out. RESULTS: Hepatic resection was combined with surgery for the primary tumor in 30 cases (41.1%). Hospital mortality was 4.2%. 35 patients (47.9%) developed complications. The mean hospital stay was 17.5 days. In 64.4% of the cases a potentially curative resection was reached. Overall actuarial survival was 52.1% at 1 year, 25.3% at 3 years and 9.9% at 5 years. The respective median overall survival times were 7.1 months (gastric cancer metastases; n = 15), 4.9 months (cholangiocellular cancer metastases; n = 9), 5.6 months (gall bladder, bile duct cancer metastases; n = 8), 35.4 months (kidney cancer metastases; n = 8), 14.4 months (breast cancer metastases; n = 4), 15.3 months (pancreas and other adenocarcinoma metastases; n = 11), 49.9 months (sarcoma metastases; n = 10) and 32.9 months (other metastases; n = 7). CONCLUSIONS: In isolated hepatic metastases originating from sarcoma and hypernephroma radical resection can prolong survival. However, surgery cannot improve the prognosis in patients with liver metastases originating from the pancreas, gallbladder and the biliary tract. In selected patients with liver metastases from gastric and breast cancer long term survival seems possible after resection. PMID- 11603104 TI - The effect of a keto acid supplement on the course of chronic renal failure and nutritional parameters in predialysis patients and patients on regular hemodialysis therapy: the Hungarian Ketosteril Cohort Study. AB - The results of the Hungarian Ketosteril follow up cohort study are reported. Aim of the study was to evaluate the feasiblity and effects of a low protein diet supplemented with keto acids/amino acids (KA) on the progression of chronic renal failure (CRF) in a large group of predialysis patients (PRE) and on nutritional parameters in both PRE and dialysis patients (DIA). PATIENTS AND METHODS: PRE (N = 181) and DIA (N = 42) patients treated in 47 hungarian nephrology and dialysis centres were followed through 18 months. A standardized dietary and KA supplementation protocol was prescribed (PRE group: KA 0.1 g/kgBW/day; dietary protein 0.5-0.6 g/kgBW/day; energy 30 kcal/kgBW/day; DIA group: dietary protein 1.2 g/kgBW/day, KA and energy prescription similar to the PRE group). Progression of CRF was evaluated by linear regression analysis of 1/serum Creatinine (sCr) values versus time, subjective global assessment (SGA) scores were analyzed by Chi-square test, other metabolic parameters (serum albumin, parathormone [iPTH], Ca/P product) were analyzed by descriptive statistics. RESULTS: In PRE patients slopes of 1/sCr were in the range of 0.0022-0.0015 [100 ml/mg x month], showing no significant difference in the three subgroups of PRE patients (Group A: initial serum creatinine (sCr) 201-400, Group B: sCr 401-600, Group C: sCr > 600 mmol/L). Serum albumin levels below 35 g/L improved significantly, iPTH levels showed a tendency to improve during KA supplementation. In dialysis patients there was an improvement in SGA scores. Midweek predialysis blood urea and sCr levels did not change significantly. CONCLUSIONS: In a large group of PRE patients prescription of a low protein diet supplemented with KA is feasible and leads to a diminution of 1/sCr equation slopes independent from the degree of renal dysfunction, suggesting a retardation in the rate of CRF progression. There was an improvement in nutritional parameters both in PRE and DIA patients, the latter being characterized by improved SGA scores. PMID- 11603105 TI - Spontaneous vaginal delivery in the birth-chair versus in the conventional dorsal position: a matched controlled comparison. AB - AIM: The aim of the study was to assess the effect of a birth-chair on obstetric outcome. PATIENTS AND METHODS: We reviewed the hospital records of 220 consecutive pregnant women who gave birth on a birth-chair at our institution. The control group consisted of 440 pregnant women who preceded and followed the index cases and who had spontaneous vaginal deliveries in the conventional dorsal supine position. The controls were matched for parity and for the attending mid wife. RESULTS: Patients who delivered in the birth-chair had significantly lower rates of episiotomy and manual separation of the placenta. The umbilical blood cord pH was significantly higher in neonates of the birth-chair group. The duration of labour, rate of perineal and vaginal injury, Apgar scores and rate of admission to a neonatal intermediate care unit were not influenced by the mode of delivery. CONCLUSION: Our data support previous studies that a birth-chair delivery may be a safe alternative to conventional delivery in the supine position. PMID- 11603106 TI - Hypothenar hammer syndrome caused by posttraumatic aneurysm of the ulnar artery. AB - The so-called hypothenar hammer syndrome is a rare entity caused by lesions of the ulnar artery secondary to repetitive trauma to the hypothenar eminence, typically found in persons working with vibrating tools. Its clinical symptoms are pain, stiffness and whitening of the smitten fingers, sometimes in combination with Raynaud's syndrome. Angiographic evaluation of the smitten forearm and hand reveals occlusions, kinking, vasospasm and stenoses of the arteries in the hand and fingers. An aneurysm of the ulnar artery causing the hypothenar hammer syndrome is an even more rare morphological finding. The difficult aspect of treating a hypothenar hammer syndrome is to reopen the occluded vessels. Eventually, circulation deteriorates and skin lesions of the fingers may occur. The advantage of an isolated aneurysm of the ulnar artery is that normal circulation can be restored by vascular surgery, for example, with a vessel interponate. Surgical removal of the isolated aneurysm helps to prevent microembolism to the distal arteries and consequent deterioration of peripheral circulation. We report a young patient who presented with clinical symptoms of the hypothenar hammer syndrome and an aneurysm of the distal ulnar artery, diagnosed by magnetic resonance angiography. The only likely cause of the aneurysm was a bicycle accident some months prior to the occurrence of the aneurysm. The patient underwent vascular surgery and has been free of symptoms during six months of follow-up. A control magnetic resonance angiography performed one month after surgery revealed a normal vascular morphology. PMID- 11603107 TI - [Dr. Friedrich Keesbacher (1831-1901) ; a Tyrolean physician practicing in Slovenia. On the occasion of his 170th birthday and 100th anniversary of his death]. AB - With his exceptional personality, his wide knowledge and expertise, his social involvement and his generous spirit, Dr. Friedrich Keesbacher left an indelible mark on Ljubljana and Carniola. His life and work, his medical career in Ljubljana, his teaching and research work, and his involvement in both public health and health organisation are described in this jubilee commemoration. Beyond that, he was also a great connoisseur and lover of music, writing about both it and the philharmonic association of Ljubljana. He was an eminently learned and socially involved doctor of his time. PMID- 11603108 TI - [Legal aspects of euthanasia]. PMID- 11603109 TI - [Betaferon and therapy of multiple sclerosis--present and future]. PMID- 11603110 TI - [Current status of interferon beta-1b in multiple sclerosis therapy]. AB - BACKGROUND: With interferon beta-1b (IFN beta-1b), an effective therapeutic option for both relapsing-remitting and secondary progressive multiple sclerosis (RRMS and SPMS, respectively) was on trial. The effectiveness was shown by clinical parameters as well as sophisticated imaging techniques. Moreover, the effectiveness of IFN beta-1b could be directly compared to that of interferon beta-1a (IFN beta-1a) in patients suffering from RRMS in an independent trial. CLINICAL EFFICACY IN RRMS: In long-term application, the annual number of episodes under IFN beta-1b drops by about one third compared to placebo. The difference of the detectable cerebral lesion load in the same period totaled 17.3%. CLINICAL EFFICACY IN SPMS: For this type of MS, too, studies have shown positive results of treatment with IFN beta-1b. This applies both to clinical results and its effects on cognitive performance, quality of life and the number of cerebral lesions identifiable with MRI. COMPARISON OF BETA INTERFERONS: The preliminary evaluation of the data at 1 year of the comparative study "Independent Comparison of Interferon = INCOMIN" shows that IFN beta-1b (on alternate days w s.c.) prevented approximately twice as many attacks as IFN beta 1a (1x/w i.m.) in patients with RRMS. In that study, therefore, IFN beta-1b, administered every 2nd day, proved more effective in the period under observation. CONCLUSION: On the basis of clinical and MRI criteria, interferon beta-1b proved to be an effective treatment option in patients with RRMS or SPMS. The data show that IFN beta-1b can also be employed in the early stages of MS. The comparative study underscores the importance of frequent doses of interferon in the treatment of MS. PMID- 11603111 TI - [Early multiple sclerosis therapy in the effects of public health economics]. AB - BACKGROUND: Meanwhile, a number of drugs are available for the course-modifying therapy of multiple sclerosis. Their use depends on the individual indication as well as on the patient's compliance, but also increasingly on the economic considerations of the public health system. For years, the costs of multiple sclerosis and the critically evaluated cost-benefit analyses were based on estimated figures. PATIENTS AND METHODS: For better transparency of the actual costs of the disease, a cross-sectional study of multiple sclerosis patients was performed for the first time in Germany, where the patients answered questionnaires as to their financial resources and quality of life. Within this representative framework of questionnaires, data of 737 patients were evaluated. RESULTS: This study came up with a total cost of DM 65,400.-per patient and year. The complete costs of multiple sclerosis, based on an estimated number of 120,000 patients, thus run up to 7.85 bio. DM a year. Only a small percentage is caused by medication (7%), including the use of new extremely expensive drugs. There is a positive correlation between the severity of the disease and the underlying costs of treatment. CONCLUSION: Due to these results, concrete health-economic goals in the treatment of patients with multiple sclerosis should aim at stabilization on a low disability level at an early stage of the disease. PMID- 11603112 TI - [New approaches in research of therapy of multiple sclerosis]. AB - BACKGROUND: Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. With a prevalence of 0.1-0.15% in Germany multiple sclerosis is the most common cause of severe disability in young adults. PATHOGENESIS: Epidemiological and family studies demonstrate the role of environmental and genetic factors in the pathogenesis of multiple sclerosis. Based on those observations and findings in experimental animal models, it is believed that multiple sclerosis is caused by an autoimmune process. However, target antigens and mechanisms leading to tissue destruction are largely unknown. THERAPY: Since the efficacy of current immunomodulatory and immunosuppressive therapies (beta-interferons, glatiramer acetate, mitoxantrone) is limited, it is necessary to develop new strategies for the treatment of multiple sclerosis. To reach this goal, a much better understanding of disease pathogenesis is necessary which takes into account the clinical, paraclincial and histopathological heterogeneity of the disease. CONCLUSION: Only further intensive research activity on basic mechanisms of disease pathogenesis and a consequent development of resulting therapeutic strategies--from animal models to phase III studies- will result in significant improvement of the long-term course of multiple sclerosis. PMID- 11603113 TI - [A short history of beta-interferon therapy of multiple sclerosis]. AB - Basic sciences including biotechnology and diagnostic imaging as well as dedicated and substantial clinical research have contributed to the progress in the therapy of multiple sclerosis (MS) which is no longer an orphan disease. Pivotal studies using interferon beta-1b for early and later phases of MS are described in their historical context. In addition, possible mechanisms of action of interferon beta-1b and new directions for future research are discussed. Interferon beta-1b already now has become a global standard for the expected further therapeutic progress. PMID- 11603114 TI - [SSCP (single strand conformation polymorphism) analysis for detection of point mutations. A technique and its limits exemplified by dominantly inherited forms of diabetes (MODY)]. AB - BACKGROUND: Molecular biological techniques of mutation detection become more and more a focus of interest in clinical medicine because the responsible genes are now known for an increasing number of diseases and the detection is essential to enable reliable predictions and to design individual therapies. Therefore the SSCP (Single Strand Conformation Polymorphism) analysis is one of the most commonly applied methods in detection of point mutations. SSCP ANALYSIS: The use of SSCP for detection of the pathogenic mutations of MODY (Maturity Onset Diabetes in the Young) is described as an example. Handling, efficiency and costs are critically analyzed. In a blind test, this method was only partly suitable for reliable analysis. Particularly diseases without a distinct hotspot and with a widespread distribution pattern of mutations throughout the coding sequence require sequencing as the gold standard. PMID- 11603115 TI - [Recent aspects of palliative treatment of metastasized colorectal carcinoma]. AB - BACKGROUND: Despite a decrease in both the incidence of colorectal carcinoma and the mortality due to this disease, it is still the second most common cause of death in the Western world. Refined surgery and adjuvant chemotherapy have not been able to prevent the frequent recurrence of colorectal cancer, often in a nonresectable state. In this palliative situation, which may already occur during initial presentation, the following treatment is indicated: best supportive care and a differential and stepwise chemotherapy. Palliative chemotherapy retards the progression of cancer disease and improves survival (from 6-9 months to 15-18 months). Chemotherapy should already be started in asymptomatic patients, if cancer disease is progressive. CHEMOTHERAPY: 5-fluorouracil (5-FU) remains the key drug for palliative chemotherapy. Drug effects and side effects critically depend on the mode of application and on biomodulation (e.g. by folinic acid [leucovorin, LV]). Compared with the traditional bolus therapy of 5-FU/LV, we prefer infusional therapy for 24 hours because of its higher effectivity and fewer side effects. Further drugs that may be given in addition to or as an alternative to 5-FU, are sodium folinate, raltitrexed and oral fluoropyrimidines (so-called prodrugs, e.g., capecitabine and tegafur-uracil [UFT]). These drugs are still under clinical investigation. Capecitabine, in particular, appears to be a useful alternative for intravenous 5-FU therapy. When compared with the traditional 5-FU bolus therapy (Mayo regimen), capecitabine is at least equally effective, but has fewer side effects. Furthermore, it can be given orally. If treatment failure occurs under 5-FU, the application of oxaliplatin or irinotecan may be useful for second- and third-line therapy (partial remission rates of 10% or 13-15%). FIRST-LINE THERAPY: Four randomized Phase-III studies demonstrate the effectiveness of additional therapy with oxaliplatin and irinotecan in combination with 5-FU for first-line chemotherapy of colorectal cancer. Triple therapy improves remission rates, quality of life and (shown only for irinotecan/5-FU/LV) survival rate, but causes more side effects and costs. PMID- 11603116 TI - [Hereditary nonpolyposis colorectal carcinoma (HNPCC). Current review of etiology, clinical aspects, diagnosis and therapy]. AB - ETIOLOGY: The hereditary non-polyposis colorectal carcinoma (HNPCC) is the most common monogenic colon cancer syndrome. It is characterized by autosomal dominant inherited cancers of the colon, rectum, and the endometrium. Less frequently, cancer of the upper gastrointestinal tract, the hepatobiliary system and the urogenital tract may occur. Typical characteristics are an early onset, usually before the age of 50, manifestation of colorectal cancer proximal of the splenic flexure, and often poorly differentiated carcinomas. GENETICS: Recently, germline mutations in several DNA mismatch repair genes have been identified as the molecular basis of HNPCC, resulting in deficient DNA repair and genetic instability, indicated by microsatellite instability in tumor specimens. DIAGNOSIS: New insights into pathogenesis, clinical features, and diagnosis of HNPCC have improved the identification of HNPCC patients and persons at risk. Diagnosis of HNPCC is primarily based on family history and is complemented by molecular findings. After detection of the underlying germline mutation in families with HNPCC, screening procedures can be restricted to mutation carriers. TREATMENT: Recommendations for therapy and prevention are in part controversial and are under investigation in several studies. PMID- 11603117 TI - [Heterophile antibodies, lack of communication and the diagnostic dilemma]. AB - BACKGROUND: Heterophilic antibodies represent a great danger to clinical care by producing false-positive values for certain markers. Too large confidence in specificity of laboratory markers together with lack of communication between clinicians and clinical chemists may lead to unnecessary interventional diagnostic and therapeutic procedures. The prevalence of heterophilic antibodies is probably much higher than assumed up till now and several markers can be affected. AIM: In this review for clinicians, we explain formation of heterophilic antibodies, mechanisms of interference and present clinical data about affected markers and "side effects" from the literature. Furthermore we discuss possible alternatives and measures against this phenomenon. We consider broad awareness of this problem among clinicians the most important action to avoid further harm to patients. PMID- 11603118 TI - [Medical palliative therapy of meningiosis carcinomatosa of breast carcinoma with dissociated response in lumbar methotrexate instillation]. AB - CASE REPORT: We report the case of a 51-year-old woman who suffered from breast cancer and developed meningeal carcinomatosis of the brain stem with deafness and blindness. Radiotherapy was given but led to remarkable deterioration of the condition and strong headache. We performed intrathecal therapy with methotrexate (MTX) via lumbar application. Under this regimen, the patient immediately showed complete improvement of the headache and a partial recovery of hearing. There were no side effects apart from alopecia. MTX concentrations in liquor and blood were remarkably inconsistent. 4 weeks after MTX therapy, MRT revealed partial remission of the meningiosis of the brain stem but progression on both hemispheres. 5 weeks after the beginning of the intrathecal therapy, the patient died. CONCLUSION: Despite pharmacokinetic problems we consider lumbar intrathecal therapy with MTX a suitable procedure for patients with leptomeningeal carcinomatosis and poor performance status. PMID- 11603119 TI - [Association of primary sclerosing cholangitis and sarcoidosis]. AB - BACKGROUND: Primary sclerosing cholangitis and sarcoidosis are rarely associated diseases. CASE REPORT: We report the case of an 42-year-old woman with primary sclerosing cholangitis confirmed by endoscopic cholangiography, biopsy of the liver and serum neutrophil cytoplasmatic antibodies. Furthermore radiological and histological signs of pulmonary and hepatic manifestation of sarcoidosis were observed, besides there were alopecia areata and choledocholithiasis. CONCLUSION: The present case report gives a brief survey of the literature, reflects the theories to unknown etiology and reports actual aspects of diagnosis and therapy of both diseases. PMID- 11603121 TI - [Cutaneous leishmaniasis]. PMID- 11603120 TI - [Factitious disorders. Hematologic, neurologic and dermatologic symptoms in a physician with factitious disorder]. AB - HISTORY AND FINDINGS: A 38-year-old female physician was admitted with the suspected diagnosis of a myelodysplastic syndrome. The self-reported history was inconsistent and incoherent. On physical examination neurological and dermatological disorders could be found. EXAMINATIONS: A bone marrow puncture revealed a toxicity-induced bone marrow damage. Extensive examinations to evaluate the neurological symptoms did not show any pathological findings. A toxicological screening identified opioids, benzodiazepines and promethazine. TREATMENT AND COURSE: Because of the inconsistent history and the contradictory results of our clinical tests, we asked in other hospitals for past admissions and were thus able to have insight into a hospital career that grasped numerous different admission diagnoses. All presented symptoms, especially the bone marrow damage, were self-induced by the patient. CONCLUSIONS: For the first time in this patient's history, a factitious disorder was diagnosed after a hospital career of almost 10 years. In this publication, the case is thoroughly presented. Additionally, the current literature is reviewed with latest recommendations for therapeutic strategies about this poorly understood disorder. PMID- 11603122 TI - [Do ethics committees hinder progress in medicine?]. AB - Research Ethics Committees are instruments which allow the medical profession to control the research with human subjects. In this context, some medical researchers criticize the increasing bureaucracy and the hindrance of research which interfere with the ability to compete in international research. On the other hand, the public criticizes the missing transparency, independence and democratic legitimization of Research Ethics Committees as well as the possible conflicts of interests of their members. The medical research with human subjects who are incompetent to give informed consent serves as an example to show the necessity of quality control and standardized criteria of assessment. By comparison with the development of Institutional Review Boards in the United States, ideas for the necessary changes of Research Ethics Committees in Germany regarding their work, assembly and transparency are developed. PMID- 11603123 TI - [Methods of process analysis, instruments of quality management. Successful implementation of quality projects]. AB - Meaningful experience and knowledge--the prerequisite for the successful implementation of quality projects--are described in terms of their practical importance on the basis of the experience gained with quality management in the municipal hospital at Munchen-Schwabing (HMS). Against the background of the process of quality assurance or PDCA (Plan Do Check Act), the approach to the selection of suitable themes (problem selection), the prioritization of projects, the appropriate composition of the project group, the description of the problem, and the organization of the project, are discussed. The authors describe the implementation of methods of process analysis such as flow diagrams and cause-and effect diagrams. The importance of evaluation is justified, and pragmatic approaches are presented. The importance of project documentation and essential contents are discussed. PMID- 11603124 TI - Genes, work and health. PMID- 11603125 TI - Helicobacter pylori infection: epidemiology and occupational risk for health care workers. AB - INTRODUCTION: Helicobacter pylori has been recognised as a major cause of gastroduodenal diseases, including gastric and duodenal ulcers with faeco-oral, oro-oral and gastro-oral transmission occurring. With the close personal contact inherent in patient care, health care workers may be at an increased risk of acquiring H. pylori and subsequent development of associated conditions. The objective of this review was to review the transmission and the occupational risk for health care workers. METHODS: A literature search was performed using Pubmed (January 1990 to May 2001). Relevant key words were used and additional manual searches were made using the reference lists from the selected articles to retrieve other papers relevant to the topic. RESULTS: Current knowledge implies various pathways of agent transmission, favouring person-to-person mode of transmission early in life. Faeco-oral, oro-oral and gastro-oral transmissions are proposed and may be of different relevance among various populations. As for health care workers, after elimination of the methodological weak studies, the risk seems to be increased in gastroenterologists, endoscopy staff and intensive care nurses. Results in other groups are conflicting. CONCLUSIONS: H. pylori infection is an occupational risk in some groups of health care workers. Studies are needed to elucidate the risk in other occupational groups. PMID- 11603126 TI - N-acetyltransferase 2 phenotype in painters with bladder cancer and controls. AB - AIM: This study was designed to evaluate the impact of N-acetyltransferase 2 (NAT2, substrate: aromatic amines) in painters with bladder cancer and controls. BACKGROUND: Until the beginning of the 1960s, painters in Germany have used, among others, azo dyes based on carcinogenic aromatic amines. MATERIALS AND METHODS: Sixteen painters with bladder cancer and 26 healthy painters (controls) who were from the same area in Germany and in the same age group (+/-5 years) were recruited into the study. All subjects were phenotyped for NAT2 by the molar ratio of two caffeine metabolites in the urine which was determined by the high performance liquid chromatography (HPLC) method. The number of years working as a painter, age at first exposure to paints and the life-time smoking habits of subjects were noted. RESULTS: Fourteen cases and 23 controls had been exposed to paints before 1960. Age at first exposure to paint was 15.5 years (SD 5.3) in cases and 16.3 (SD 4.9) years in controls. Cases had worked 31.1 years (SD 15.0) and controls had worked 44.8 years (SD 7.2) as painters. Four cases and 7 controls were non-smokers. In this study, 88% of cases and 65% of controls were of the "slow" acetylation and phenotype, CONCLUSION: The result point to and impact of the slow acetylation status as an individual risk factor for bladder cancer in persons occupationally exposed to amounts of carcinogenic aromatic amines released from water-soluble azo dyes. PMID- 11603127 TI - Multifactorial aetiology of lung cancer among silica-exposed workers. AB - In 1997, the International Agency for Research on Cancer (IARC) upgraded its evaluation of crystalline silica to a Group 1 human carcinogen. Criticism against such decision is based on the lack of consistency in experimental results across animal species, violation of an important principle for causality, such as the replication of findings under different circumstances of exposure, and the lack of a clear dose-response curve. The most recent epidemiological literature on the silica-silicosis-lung cancer link replicates the inconsistent findings that have been characterising 50 years of scientific debate in the occupational arena. Exposure circumstances capable of modifying the silica-lung cancer association include chronic bronchitis, composition of the dust mixing, particularly concerning co-occurrence of other known or probable lung carcinogens, total respirable dust, concentration of silica in respirable dust, type of crystalline silica and particle surface characteristics. The hypothesis of a silicosis mediated pathway points toward an unspecific mechanism shared with other fibrotic conditions, for which silica might be just one of the triggers. In envisaging a multivariate multistep model of lung cancer among silica-exposed workers, silica might be considered as a "passive components of the sufficient cause", i.e., one of the associated risk factors, concurrent or subsequent to the "active component(s) of the sufficient cause" (including, for instance, smoking, asbestos, radon-daughters, arsenic, hexavalent chromium, nickel, polycyclic aromatic hydrocarbons (PAH), and diesel exhausts among the external risk factors; and DNA repair enzymes polymorphism and spontaneous inactivation of tumour suppressor genes among the internal risk factors), which adds up in modulating the tumoral development in not easily predictable directions. If silica acts as a human lung carcinogen depending on certain occupational exposure circumstances, perhaps those circumstances and not silica itself should be classified for their human carcinogenicity potential. PMID- 11603128 TI - Vascular changes in workers exposed to carbon disulfide. AB - AIM: To assess the effects of occupational exposure to carbon disulfide (CS2) concentrations below the threshold limit value (31 mg/m3) on the structural and the functional properties of the arteries, heart rate, blood pressure and lipids. METHODS: Study subjects were 85 male workers in the viscose industry and 35 men without such exposure. The CS2 concentration was determined by personal active sampling. From the common carotid artery diameter, the change in diameter (echography) during the heart cycle and the pulse pressure, local arterial distensibility and compliance were calculated. Global large and small artery elasticity were calculated from registrations of radial artery waveforms. Simultaneously, heart rate and blood pressure were recorded and blood samples were collected for lipid measurements. RESULTS: CS2 concentrations ranged from 2.34 to 32.4 mg/m3. No significant effect of CS2 on blood pressure, total cholesterol, HDL and LDL cholesterol or triglycerides was found. Among the vascular parameters under study, common carotid artery distensibility was significantly lower, and heart rate significantly higher in exposed workers compared to controls. The differences remained significant after adjustment for age, body mass index, smoking habits, alcohol consumption, heart rate and systolic blood pressure. Common carotid artery intima media thickness and global arterial indices did not differ significantly between the two groups. CONCLUSIONS: Exposure to CS2 under the current level may already cause alterations in common carotid artery elastic properties in apparently healthy individuals. Even before biochemical and clinical findings occur, important functional changes in the vessel wall were observed, at least in some vascular territories. PMID- 11603129 TI - The Paget-Schroetter syndrome: work accident and occupational disease. AB - INTRODUCTION: Primary thrombosis of the upper extremity (Paget-Schroetter syndrome, effort thrombosis) is usually not accepted either as a work-related accident or an occupational disease by the industrial injuries insurance authorities. This study aims to look at the circumstances under which this kind of thrombosis may be recognised as an occupational hazard. MATERIALS AND METHODS: After thoroughly studying the clinical records of 82 patients with thrombosis of the upper extremity in the outpatient department for angiology during a 10-year period, we found that in 51 cases the thrombosis was caused by secondary reasons (i.e., central venous catheterisation, malignoma, hypercoagulability, postoperative). In the remaining 31 patients, we painstakingly conducted a general and occupational history and further clinical, laboratory or technical investigations to differentiate the aetiology. RESULTS: Twenty-eight of 31 patients with suspected primary thrombosis of the axillary or subclavian vein (Paget-Schroetter syndrome) showed unusual private or occupational physical exercise as the underlying cause. Sixteen patients reported only short physical exercise up to several hours or acute trauma. Longer physical exercise periods (several days, months or even more) were found in 12 patients. Ten of the 28 patients who acquired the thrombosis doing occupational tasks covered by the industrial insurance, may be eligible for compensation. In 4 of these 10 insured cases, we found strong hints for work accidents, 6 patients of this group apparently revealed criteria of occupational diseases. Four of the 28 patients had a combination of physical effort and additional thrombogenic risk factors (cardiac pacemaker, hypercoagulability). CONCLUSION: Primary thrombosis of the upper extremity (Paget-Schroetter syndrome) should be announced to and compensated by the industrial injuries insurance either as work-related accident or occupational disease if the patient's occupational history shows close relationship between thrombosis manifestation and extraordinary physical efforts or exercises during occupational strains. For this reason, we recommend the recognition of the Paget-Schroetter syndrome in the national list of occupational diseases. PMID- 11603130 TI - Comparison of allergic contact dermatitis cases in the private and subsidized clinics in the National Skin Centre, Singapore. AB - INTRODUCTION: This is an epidemiologic study to compare allergic contact dermatitis patients in the private and subsidized clinics. PATIENTS AND METHODS: All patients diagnosed to have allergic contact dermatitis in the National Skin Centre from January 1999 to June 1999 were studied retrospectively. RESULTS: More private patients were evaluated for allergic contact dermatitis than subsidized patients in the study period (138 vs. 99). The female-to-male ratio in the paying clinics was greater than in the subsidized clinics (3:1 vs. 1:1). The mean age was the same for both groups i.e., 40 years. There was a greater proportion of unskilled workers attending the subsidized clinic (24.2% vs. 5.4%). The mean duration of rash before evaluation was longer for paying patients than for subsidized patients (31 vs. 22 months), but this was not statistically significant. A significant proportion of the patients had a history of atopic disease and endogenous dermatitis. The most frequent sites for allergic contact dermatitis were the face, hands and the exposed areas of the limbs. The most common allergens were nickel, cobalt and fragrance in the paying patients; and nickel, chromate and fragrance in the subsidized patients. CONCLUSION: More female patients with allergic contact dermatitis and more atopic patients were seen in the private clinics. The forearms, fingers, feet and ears were more commonly affected in the subsidized patients. PMID- 11603131 TI - Electromagnetic fields and health outcomes. AB - Over the past two decades, there has been increasing interest in the biological effects and possible health outcomes of weak, low-frequency electric and magnetic fields. Epidemiological studies on magnetic fields and cancer, reproduction and neurobehavioural reactions have been presented. More recently, neurological, degenerative and heart diseases have also been reported to be related to such electromagnetic fields. Furthermore, the increased use of mobile phones worldwide has focussed interest on the possible effects of radiofrequency fields of higher frequencies. In this paper, a summary is given on electromagnetic fields and health outcomes and what policy is appropriate--"no restriction to exposure", "prudent avoidance" or "expensive interventions"? The results of research studies have not been unambiguous; studies indicating these fields as being a health hazard have been published and so were studies indicating no risk at all. In "positive" studies, different types of effects have been reported despite the use of the same study design, e.g., in epidemiological cancer studies. There are uncertainties as to exposure characteristics, e.g., magnetic field frequency and exposure intermittence, and not much is known about possible confounding or effect-modifying factors. The few animal cancer studies reported have not given much help in risk assessment; and in spite of a large number of experimental cell studies, no plausible and understandable mechanisms have been presented by which a carcinogenic effect could be explained. Exposure to electromagnetic fields occurs everywhere: in the home, at work, in school, etc. Wherever there are electric wires, electric motors and electronic equipment, electromagnetic fields are created. This is one of the reasons why exposure assessment is difficult. For epidemiologists, the problems is not on the effect side as registers of diseases exist in many countries today. The problem is that epidemiologists do not know the relevant exposure characteristics to be used in their studies. In international guidelines, limits for restrictions of field exposure are several orders of magnitude above what can be measured from overhead power lines and found in "electrical" occupations. These guidelines emphasize that the state of scientific knowledge today does not warrant limiting exposure levels for the public and the work force, and that further data are required to confirm whether health hazards are present. In some countries, however, the "principle of caution" or "prudent avoidance" has been adopted; meaning the low-cost avoidance of unnecessary exposure as long as there is scientific uncertainty about its health effects. PMID- 11603132 TI - Exposure of airline pilots and cabin crew to cosmic radiation during flight- what's the fuss? AB - The International Commission on Radiological Protection (ICRP) had in 1990 recommended that civilian aircrew be classified as being occupationally exposed to low-dose ionizing radiation, in view of their increased exposure to cosmic rays at altitude. In 2000, the European Union had gone ahead with legislation which requires all European airlines to monitor cosmic radiation levels during flight and to inform aircrew of the possible health risks. However, the evidence for a causal link between cosmic radiation exposure and health risks remains elusive despite recent findings of increased cancer incidence among airline pilots and cabin crew. The inconclusiveness of the evidence notwithstanding, there are compelling reasons for adopting a prudent and precautionary stance. PMID- 11603133 TI - Impairment of endothelial function--a possible mechanism for atherosclerosis of a high-fat meal intake. AB - INTRODUCTION: Endothelial dysfunction is known to occur in patients with coronary artery disease. Flow-mediated dilation of the brachial artery using Doppler ultrasound is a non-invasive technique for the assessment of endothelial function. The objective of the study was to use the above method to evaluate the pathophysiology of high-fat (HF) intake on endothelial function in a local population. A popular local dish "nasi-lemak", a source of high saturated fat content from coconut milk, was chosen to represent a local high-fat meal (LHF). In addition, the effects of a Western high-fat (WHF) ("McDonald's") meal and a low-fat (LF) meal control on endothelial function were studied. MATERIALS AND METHODS: The study population consisted of 10 healthy male non-smoker (mean age 22 +/- 2 years) with normal body mass index, normal fasting sugar and lipid profiles. Nitric oxide dependent flow-mediated dilation and nitric oxide independent (GTN) dilation was assessed by Doppler flow in the brachial artery before and 4 hours after each meal on separate occasions by 2 experienced sonographers blinded to the type of meals. RESULTS: The baseline brachial artery size, baseline vessel flow and increase in flow after cuff deflation were similar for each of the six arterial studies. In response to reactive hyperaemia after cuff deflation, the endothelium-dependent dilation was significantly different between the meals. There was a marked decrease in endothelium-dependent dilation after the WHF meal compared to the LF meal (8.6 +/- 2.2% vs. -0.8 +/- 1.1%, P < 0.006). There was also a marked decrease in endothelium-dependent dilation after the LHF meal compared to the LF meal (7.7 +/- 2.1% vs. -0.8 +/- 1.1%, P < 0.001). When comparing between the two HF meals, the change in endothelium-dependent dilation was not significant (7.7 vs. 8.6%, P = 0.678). GTN-induced dilation was not significantly different before and after the LF, WHF or LHF (0.1 +/- 0.5% vs. 0.2 +/- 0.9% vs. 1.3 +/- 0.5%, P = 0.094). CONCLUSION: The results suggest that in a local population, impairment of endothelial function is a possible mechanism in the pathophysiology of atherosclerosis from HF intake, beyond just affecting lipid levels. This effect is observed after both a LHF and a WHF meal intake. This technique to study endothelial function may be a useful non-invasive screening tool in the study of other HF diet choices and provides further information for the education of the influence of dietary choices on atherosclerosis. PMID- 11603134 TI - Diagnosing and prognosticating acute meningitis in young infants within 24 hours of admission. AB - INTRODUCTION: The early diagnosis and prognosis of acute meningitis in young infants (infants 90 days old or younger) have not been well studied. We therefore investigated the diagnostic and prognostic factors for acute meningitis obtainable within 24 hours of admission. METHODS: Data were obtained through a retrospective case review of 55 young infants from 1991 to 1999 inclusive. RESULTS: The 3 commonest symptoms of acute meningitis were fever, abnormal activity and decreased feeding. The 3 commonest signs were temperature > 38.0 degrees C, irritability/crying and abnormal tone/reflexes. The best predictor of acute bacterial meningitis (ABM) was the cerebrospinal fluid (CSF)-to-blood glucose ratio. A glucose ratio of < or = 0.8 can be used to diagnose ABM with 100% sensitivity and 100% negative predictive value. Furthermore, a ratio < or = 0.3 can be used to diagnose ABM with 100% specificity and 100% positive predictive value. The best predictor of unfavourable neurological outcome (UFNO) was also the CSF-to-blood glucose ratio. A glucose ratio of < or = 0.3 again can be used to prognosticate for UFNO with 100% sensitivity and 100% negative predictive value. CONCLUSIONS: Diagnosis of acute meningitis by history and physical examination alone is difficult. However, with the aid of laboratory tests, in particular the CSF-to-blood glucose ratio, one can diagnose ABM and prognosticate for unfavourable neurological outcome with high sensitivity and high negative predictive value within 24 hours of admission. PMID- 11603135 TI - The Alvarado score and acute appendicitis. AB - INTRODUCTION: This is a retrospective study to assess the accuracy of the Alvarado score in predicting appendicitis for patients with right iliac fossa pain. MATERIALS AND METHODS: This is a retrospective study of consecutive patients with suspected appendicitis. The Alvarado score was computed from the admission notes and correlated with the final outcome of the patient. Patients discharged without surgery were reviewed in the outpatient's clinic to ascertain that they did not need surgery. RESULTS: There were 148 patients in the study and 63 had appendectomies with intention to treat appendicitis. The normal appendicectomy rate was 21%. The number of patients with score 1-4, 5-6, 7-8 and 9-10 were 46, 40, 44 and 18, respectively, while the number of appendicitis in each group were 0, 2 (5%), 30 (68%) and 18 (100%), respectively. The positive and negative predictive values of Alvarado's scores of 7 or more were 77% and 97.6%, respectively. CONCLUSION: Alvarado score is a useful tool in the diagnosis of appendicitis, especially at both ends of the scale. PMID- 11603136 TI - Spectrum of prostate cancer in the Singapore General Hospital (1980 to 1985). AB - INTRODUCTION: Serum prostate specific antigen (PSA) testing has contributed to a dramatic rise in the incidence of prostate cancer diagnosed in the last decade in the West as well as in Singapore. Now prostate cancer is ranked as the sixth commonest cancer among men in Singapore. To form the basis for comparisons and to assess the trends and impact of these changes, we analysed the presentation, disease characteristics and outcome of treatment of patients with prostate cancer diagnosed in the pre-PSA era at the Singapore General Hospital (SGH). MATERIALS AND METHODS: Of the 149 patients (1980 to 1985) registered in the database, 134 (90%) records with full follow-up data were available for the analysis. All patients were diagnosed and managed at SGH. Follow-up and death data were collected through clinic visit, phone interviews of the patients, relatives, family physicians and the death registry. Survival analysis was carried out using the Kaplan-Meier product limit method. RESULTS: The mean age at diagnosis was 69.8 years. There were no significant changes with reference to each year during 1980 to 1985 and the mean number of diagnoses per year was 22.3. Of the 134 patients, 86% had either retention of urine or severe lower urinary tract symptoms and 14% had metastatic disease at presentation. Most histological diagnosis was made during prostatectomy; wherein 82% was found with transurethral resection of the prostate (TURP) and 12% in open prostatectomy, respectively. Pathological analysis during diagnosis revealed that 72.4% patients had metastatic disease. Of which, 57.5% had high-grade (Gleason > 7) tumours. Among these, 82% underwent TURP to relieve urinary obstruction, while 26.1% received local irradiation to the prostate. Majority had hormone therapy shortly after diagnosis in the form of orchidectomy or oral diethylstilbestrol (76.1%). The median crude survival (26 months) was minimal for metastatic patients. CONCLUSION: The spectrum of prostate cancer in the pre-PSA era was characterised by high stages of high-grade disease, with very limited opportunity for successful treatment and hence survival. PMID- 11603137 TI - Intravenous regional anaesthesia using lignocaine and tramadol. AB - INTRODUCTION: This prospective, randomised, double-blind study was designed to assess if the addition of 50 mg tramadol to 30 mL 0.5% lignocaine would improve the efficacy of intravenous regional anaesthesia. MATERIALS AND METHODS: Fifty four adult patients undergoing upper limb surgery were randomly allocated to receive either 30 mL 0.5% lignocaine and 1 mL normal saline (group A) or 30 mL 0.5% lignocaine and 50 mg tramadol (group B). They were then assessed for onset of sensory and motor block and the VbAS score for tourniquet pain. RESULTS: Although more patients in group B had a faster onset of sensory and motor block, this was not significantly different. Patients in group B had a significantly lower VbAS score 30 min after tourniquet inflation and after change over to the distal tourniquet (P < 0.05). There were no complaints of postoperative nausea and vomiting. Two patients in group B developed localised skin urticaria of the forearm which resolved with the release of the tourniquet. CONCLUSION: There is a positive trend that tramadol might improve the quality of intravenous regional anaesthesia. PMID- 11603138 TI - The Singapore General Hospital early clinical experience with the 7.5F flexible ureterorenoscope. AB - INTRODUCTION: Reduced instrument size, increased flexibility, coupled with improved optics and larger working channels have enhanced the capabilities of the ureterorenoscope. MATERIALS AND METHODS: We present our initial experience with the new 7.5F flexible ureterorenoscope. A total of 29 flexible ureterorenoscopies were performed from July 1995 to December 1997 by a single surgeon. The indications for flexible ureterorenoscopy was therapeutic in 10 (34.5%) patients (all had urolithiasis) whilst it was diagnostic in 19 patients (65.5%). For the diagnostic cohort, 9 (31.0%) patients had haematuria with radiological upper tract filling defect, 8 (27.6%) had radiological upper tract filling defect alone and 2 (6.9%) had ureteropelvic junction narrowing for evaluation. RESULTS: Of the therapeutic cases, all 10 (100%) were stone free at 3 months. Of the diagnostic cases, 12 (63.2%) had normal findings, 4 (21.1%) had urolithiasis and 3 (15.8%) had transitional cell carcinoma (TCC). Of the 3 cases of TCC, one was managed endoscopically. CONCLUSIONS: The smaller calibre and actively deflectable 7.5F flexible ureterorenoscopes facilitate various endoscopic procedures thus broadening the diagnostic and therapeutic scope of the ureterorenoscope. PMID- 11603139 TI - Evaluation of problem-based learning: a lecturer's perspective. AB - INTRODUCTION: The exponential growth in medical/dental knowledge and the ever expanding influence and sophistication of information technologies have placed a burden of responsibilities on dental educators to fashion out a curriculum that can prepare students to face the coming challenges in the new millennium. Consequently, a curriculum reform took place in the Faculty of Dentistry, National University of Singapore in 1997. Problem-based learning (PBL) was first introduced to the Faculty in 1996 as a pilot project to the 4th year. The purpose of this project was to evaluate the 4-year experience in PBL teaching and learning from the lecturers' point of view. MATERIALS AND METHODS: All 12 lecturers, who had been involved in the PBL teaching, participated in this questionnaire survey, which was composed of 17 questions with a 5-digit Likert scale. Data analysis was carried out using the Spearman's correlation, t-test, and the Mann-Whitney U test. RESULTS: Six female, 5 male and 1 unidentified lecturers were recruited into this survey with a 100% response rate. In general, lecturers learned more in teaching PBL and significantly took pleasure in the interactive learning and self-directed learning modes inherent to PBL (P = 0.004). Compared to the male lecturers, female lecturers had a greater propensity to feel that PBL teaching might not be cost-effective (P = 0.03). Senior lecturers felt more fulfilled compared with the younger ones (P = 0.026). Those lecturers who enjoyed the interactive learning experience in PBL seemed to like the self-directed learning and felt more fulfilled through teaching PBL compared to the traditional teaching (TT) (P < 0.01). They also felt that PBL may be cost effective (P < 0.01). Lecturers did not have difficulties in being a facilitator (P = 0.04). Interestingly, lecturers who found difficulties in being a facilitator for the PBL class seemed to learn more in teaching PBL classes than in TT (P < 0.05). Overall, lecturers would like to suggest more PBL to be incorporated into the curriculum (P = 0.02). Nevertheless, lecturers were concerned about the knowledge gaps in students learning with PBL (P = 0.01) and the time constraint of students (P = 0.002). CONCLUSION: The results of this study reveal the pros and cons of the current PBL teaching method and may thus provide proper guidelines to shape the further development of PBL in our faculty. PMID- 11603140 TI - Plasma procalcitonin in sepsis and organ failure. AB - INTRODUCTION: Because the use of procalcitonin (PCT) as a marker of bacterial infection has been advocated, this study was carried out to determine the usefulness of plasma PCT in the early diagnosis and differentiation of patients with non-infectious systemic inflammatory response syndrome (SIRS) from those with sepsis, and the relationship between plasma PCT level and severity of organ failure. MATERIALS AND METHODS: Thirty-five patients with non-septic SIRS (n = 16), sepsis (n = 7) or septic shock (n = 12) were included in this study. PCT and C-reactive protein (CRP) levels were measured and sepsis-related organ failure assessment (SOFA) score was calculated for these patients. Plasma PCT was measured by immunoluminometric assay. RESULTS: The median (minimum, maximum) plasma PCT levels were 0.6 (0.1, 3.4) ng/mL in non-septic SIRS, 5.4 (0.9, 47.7) ng/mL in sepsis and 73.4 (9.6, 824.1) ng/mL in septic shock, and significant differences existed in plasma PCT levels among the three groups. The median (minimum, maximum) CRP levels were 13.8 (0.3, 48.8) mg/dL in non-septic SIRS, 23.3 (1.4, 26.6) mg/dL in sepsis and 17.4 (2.2, 34.1) mg/dL in septic shock, without significant differences among the three groups. A good correlation was found between plasma PCT level and SOFA score (rs = 0.766, P < 0.0001), although no correlation was found between CRP level and SOFA score. CONCLUSIONS: CRP is increased by inflammatory disease as well as infection and is therefore not a good indicator of infection in patients with severe SIRS. On the other hand, PCT is a good indicator of severity of sepsis and organ failure in patients with severe SIRS since PCT levels correlated with sepsis and SOFA scores. PCT level is useful for diagnosis of sepsis and as an indicator of severity of organ failure in patients with SIRS. PMID- 11603141 TI - Causes and management of Descemet's membrane detachment associated with cataract surgery--not always a benign problem. AB - INTRODUCTION: Detachments of Descemet's membrane (DM) occur with not uncommon frequency during cataract surgery. The figure for extracapsular cataract extraction (ECCE) is 2.6%, and that for phacoemulsification is 0.5%. Most detachments are small and of little visual consequence. Large detachments are rare but can lead to loss of vision. Early recognition and appropriate management is the key to a favourable outcome. This review provides cataract surgeons with guidelines to the management of this problem. METHODS: A review of reported studies on the subject was made using a MEDLINE search. A summary of the reviewed data is presented. RESULTS: The problem is fairly widespread, given the number of cataract operations done today. The important points with regard to aetiology, classification, recognition and appropriate management are presented in this article. CONCLUSION: DM detachment should not be taken lightly because of the potential for serious visual outcome. It may be avoided in a large majority of cases. Appropriate and prompt management may prevent the patient from suffering visual loss should it occur. PMID- 11603142 TI - Ossifying lipoma of the hand: a case report. AB - INTRODUCTION: Ossifying lipoma is an uncommon tumour and its occurrence in the hand is rare. It is often not diagnosed preoperatively. CLINICAL PICTURE: Our case presented with a lump in the hand which was painful with activity. The lipomatous component of the tumour was radiologically not distinguishable. TREATMENT: The hand was explored through a wide palmar incision, revealing a lipomatous tumour. The tumour was completely excised and diagnosis made after histological examination. OUTCOME: After 1 year, the patient has had normal function of the hand with no tumour recurrence. DISCUSSION: The diagnosis of ossifying lipoma could be made with certainty only after radiological examination, excision and histological examination. The bony component is of mesenchymal origin and may come about as a result of metaplastic transformation. PMID- 11603143 TI - Isolated non-compaction of ventricular myocardium: a report of three cases. AB - INTRODUCTION: Isolated non-compaction of ventricular myocardium (INVM) is a rare disorder of myocardial morphogenesis in the absence of other cardiac anomalies. Both sporadic and sex-linked recessive forms have been described. It can be identified with two-dimensional echocardiography. CLINICAL PICTURE: We report a series of 3 cases of adult males with INVM in June 2000. Clinical manifestations were congestive cardiac failure with severely depressed left ventricle systolic function and stroke. One patient had biventricular INVM. CONCLUSION: Early diagnosis of INVM is important as it is associated with a high incidence of cardiac failure, ventricular arrhythmia and remobilisation. Anticoagulation and screening of first-degree relatives is advisable. PMID- 11603144 TI - 188rhenium-TDD-lipiodol in treatment of inoperable primary hepatocellular carcinoma--a case report. AB - INTRODUCTION: The aim of this study was to investigate the potential of using 188Re Lipiodol for selective internal radiation therapy of inoperable hepatocellular carcinoma (HCC). CLINICAL PICTURE: A 33-year-old female with poorly-differentiated multicentric HCC, elevated alpha-fetoprotein (AFP) and increased serum alkaline phosphatase. TREATMENT: Over a 2-month interval, the patient was treated twice with 4GBq of 188Re-TDD-Lipiodol. OUTCOMES: There was good localisation of 188Re Lipiodol in the tumours, but also in thyroid (first treatment) and gastrointestinal tract (both treatments). So far (5 months post treatment), the patient remains well with stable disease. CONCLUSIONS: 188Re Lipiodol can be an effective radiopharmaceutical for the treatment of HCC; however, more work must be done to minimise the uptake in bowel. PMID- 11603145 TI - Clinical update on occupational asthma. AB - Occupational asthma is the most common occupational respiratory disease in many developed countries as well as in Singapore. About 4% to 9% of adult asthmatics may have occupational asthma. The condition is still under-diagnosed and under reported. Asking an adult asthma patient whether his or her symptoms improve when away from work and worsen during periods at work is important in detecting potential cases of occupational asthma. Serial peak expiratory flow rate (PEFR) monitoring during periods at work and away from work is useful for providing objective documentation of work-relatedness. Specific challenge testing is carried out to confirm a specific causative agent where a new agent is suspected, where there are multiple agents involved and it is important to establish the exact agent, and when it is not possible to carry out serial PEFR monitoring. Early diagnosis and removal from further exposure to the causative agent in the workplace will benefit the patient with occupational asthma. Preventive measures are important to protect other workers at risk. PMID- 11603146 TI - The need for collaboration between clinicians and statisticians: some experience and examples. AB - INTRODUCTION: Very often we see poor communication and collaboration between clinicians and statisticians. Both sides may fail to realise the importance of a truly collaborative effort. In this paper we give examples to illustrate some problems clinicians and statisticians may encounter when they do not have the full support of each other. The aim is to convince both parties the importance of a truly collaborative effort. METHODS: Real examples in various medical research areas are drawn from the authors' practical experience for illustration. The examples cover various research aspects such as the use of computer software, regression analysis and interpretation of findings. RESULTS: Superficial collaboration between clinicians and statisticians may lead to serious problems and sub-optimal research practice that may not be obvious in the first sight. Some of the barriers to effective communication and collaboration are discussed. CONCLUSIONS: On the one hand, robust statistical practice is vital in many medical research projects. On the other hand, medical thinking is important in the formulation and application of statistical strategies. Statistical inputs should be integrated into medical research projects throughout the whole research process. Sporadic contacts between clinicians and statisticians are not enough. Both parties must learn to communicate more effectively and to be willing to collaborate with each other. PMID- 11603147 TI - Fifty years of PULHHEEMS--the British Army's system of medical classification. PMID- 11603148 TI - Women and modern medicine. Introduction. PMID- 11603149 TI - Women doctors and gender identity in Weimar Germany (1918-1933). PMID- 11603150 TI - A suitable job for a woman: women doctors and birth control to the inception of the NHS. PMID- 11603151 TI - Listening to the Ga: Cicely Williams' discovery of kwashiorkor on the Gold Coast. PMID- 11603152 TI - Smooth, speedy, painless, and still midwife delivered? The Dutch midwife and childbirth technology in the early twentieth century. PMID- 11603153 TI - Ergot to ergometrine: an obstetric renaissance? PMID- 11603154 TI - 'Andromeda freed from her chains': attitudes towards women and the oral contraceptive pill, 1950-1970. PMID- 11603155 TI - 'Colonising women': female medical practice in colonial India 1880-1890. PMID- 11603156 TI - Pioneers of infertility treatment. PMID- 11603157 TI - An anatomy of desire: gender and difference in sex therapy. PMID- 11603158 TI - From bedpan to revolution: Qiu Jin and western nursing. PMID- 11603159 TI - 'Run by women, (mainly) for women': medical women's hospitals in Britain, 1866 1948. PMID- 11603160 TI - Women and macho medicine. PMID- 11603161 TI - If only we can stop the progression.... PMID- 11603162 TI - Extrapyramidal symptoms and signs in Alzheimer's disease: prevalence and correlation with the first symptom. AB - OBJECTIVES: To determine the prevalence and clinical correlates of extrapyramidal signs (EPS) in outpatients with probable Alzheimer's disease (AD); to examine the appearance of EPS in association with the first symptom that led the patient or family to ask for medical help; to examine the association of the prevalence of EPS with gender, age at onset of the disease, duration of the disease, severity of dementia, functional disability, and potential use of neuroleptics; and to address the issue of the possible role of EPS as a predictive factor for the clinical course of the disease. PATIENTS AND METHODS: We examined 126 patients meeting NINCDS-ADRDA* criteria for probable AD and 29 healthy, nondementia controls of comparable age and gender. Thirteen of the patients taking neuroleptics at the time of the examination were excluded from the main study group and formed a separate subgroup of AD/neuroleptics-positive. Twenty-eight of the AD/neuroleptics-free patients were re-examined during an 18-month period in order to determine the possible role of EPS as a predictive factor of the clinical course of the disease. RESULTS: Only 8 percent of the AD/neuroleptics free patients were free of EPS, while the corresponding percentage in the control group was 61.5 percent. The most common types of EPS presented in the patient group were hypomimia ([facial mask] 60 percent), difficulty in talking (53.66 percent), bradykinesia (51.4 percent), postural instability (47.33 percent), abnormal gait (34.66), and rigidity (26 percent), respectively. No significant differences were found when examining for the presence of resting tremor, other tremors, dystonias, and dyskinesias. With regard to the presence of EPS and the first symptom, no significant difference was found among patients whose first complaint was memory disorder (probable AD) and patients with other symptoms. When examining the association between the prevalence of EPS and gender or age at onset of the disease, no special correlation was detected. However, such a correlation was found between the prevalence of EPS and duration of the disease, as indicated by the fact that EPS appear in 78.9 percent of the patients with a duration of illness less than two years, but in 97 percent of the patients with a corresponding duration of two years or more. The mean duration of the disease in patients appearing with EPS is found to be 2.68 +/- 1.98 years. The presence of EPS increases proportionally with the progression of the disease and cognitive and functional decline. Patients with poor results in the MMSE (score of less than 11) appear to present EPS at a greater percentage than those with better performance on the examination (MMSE scores greater than 11). With regard to the association between EPS and functional ability in AD, it seems that the presence of EPS imposes difficulties in daily activities, as seen by the fact that patients with EPS have lower FRSSD scores (mean +/- SD: 14.87 +/- 10.53) than patients without EPS (5 +/- 2.58). After controlling for duration of the disease, the use of neuroleptics is found to influence the appearance of EPS in patients with AD. Almost all of the patients AD/neuroleptics-positive patients presented EPS (100 percent), while 92 percent of the AD/neuroleptics-free patients manifested such symptoms. Finally, we re-evaluated 28 patients, who were part of the initial AD/neuroleptics-free group, in order to determine whether the appearance of EPS could have prognostic value for the clinical course of the disease. Patients who presented EPS at initial examination appeared to deteriorate faster, mainly cognitively, but also functionally. The mean decrease in MMSE scores in patients with EPS was found to be 2.65 +/- 3.46; while in patients without EPS at initial visit, MMSE scores were 0.63 +/- 3.88. The functional decline seems to be less influenced by the presence of EPS. The corresponding mean decrease in FRSSD scores of the two groups was 2.1 +/- 5.55 and 1.8 +/- 2.1, respectively. PMID- 11603163 TI - The Alzheimer's Connections Demonstration Program: instituting a national case management program. AB - The Alzheimer's Connections Demonstration Program was designed to study the most effective ways of linking families with needed services and resources. The five year demonstration, begun in 1995, funded case management programs in 29 Alzheimer's Association chapters and served 2,313 families. This paper reports on the final two years of the project when all programs were operational. During this period, 800 families were served. The findings indicate that the programs complement the existing chapter services by offering a specific intervention with caregivers. At the end of the demonstration, all chapters planned to continue the program as case management increased their visibility in the community through their ability to offer direct services. PMID- 11603164 TI - Placement challenges: implications for long-term care of dementia sufferers. AB - Caregivers and long-term care staff seek appropriate placements for dementia sufferers, but there is little empirical research to guide such decision-making. However, recent national trends in mental health care have emphasized the placement of persons with serious mental illness in privatized, community-based residences. This body of empirical research has indicated that persons with psychosis, substance use disorder, assaultive behavior, and medication noncompliance have shorter tenure in these residential settings. These findings are also important for other, more traditional health care settings, as the patients discharged from community residences may require assistance on occasion from such other settings. This study continues the inquiry into the characteristics of patients with serious mental illness, who have shorter tenure in community residences. Dangerous behaviors, treatment-resistant psychosis, medical illnesses, and social-interpersonal skill deficiencies were common causes for discharge in this study. Since there remains a paucity of published empirical studies on the issue for patients with Alzheimer's disease and other dementias, we present the implications of, and guidelines for, addressing these issues in dementia sufferers in long-term care settings. PMID- 11603165 TI - Statewide survey to compare services provided for residents with dementia in special care units and non-special-care units. AB - To protect the consumer, consistency is needed in what one can expect when a long term care facility (LTCF) advertises having an Alzheimer's special care unit (SCU). Arkansas recently passed disclosure legislation, which has led to the development of criteria for licensure of SCUs. This study compared the extent to which Arkansas LTCFs, with and without SCUs, met these criteria. We conducted a statewide survey of 238 LTCFs prior to the enforcement of these regulations and will conduct the same survey following their enforcement. Of the 147 (62 percent) facilities responding, 24 (16 percent) had a SCU. None of the LTCFs with SCUs met all the state criteria. The number and quality of services provided in SCUs and non-SCUs were similar. PMID- 11603166 TI - Impact of dining room environment on nutritional intake of Alzheimer's residents: a case study. AB - This case study, in a Veterans Affairs Alzheimer's unit, was conducted to evaluate noise and lighting conditions at mealtimes and to assess the food intake of ambulatory dementia residents. The case study compared the noise, lighting, and nutritional intake of 16 Alzheimer's residents eating the same cycle menu in the extended-care (EC) dining room and the Alzheimer's unit (AU) dining room five weeks later. Noise was significantly lower in the EC (p < or = .02). Lighting was significantly higher in the EC (p < or = .001). Intake of calories and protein was slightly higher, with some days significantly higher, in the AU. Total five day fluid intake at breakfast was significantly higher in the AU (p < or = .02). Although residents' total food and fluid intake was higher in the AU, the project identified a need to decrease noise and increase lighting in the AU. Lighting enhancement and noise reduction may further improve intake, which, in turn, may promote improved nutritional status. PMID- 11603167 TI - Therapeutic kitchens for residents with dementia. AB - Long-term care facilities are increasingly incorporating some sort of kitchen, often referred to as a therapeutic kitchen, for resident, staff, and family use through remodeling efforts or new construction. A study, consisting of five site visits and a questionnaire mailed to 631 facilities providing dementia care, was conducted to identify physical features that are typically included in therapeutic kitchen design and to explore how these features support daily use in relation to activities programming and food service systems. Findings indicate that universal design features should be incorporated to a greater extent and certain features are more common, reinforce homelike imagery, or enhance safety. Results also suggest that a higher number of residents participate in more recreational activities, such as baking, than they do in household chores, such as meal set-up, and therapeutic kitchens are not always linked to food service systems. PMID- 11603168 TI - Onset of tuberculosis disease: new converters in long-term care settings. AB - Elders living in communal settings, such as nursing homes or other types of long term care facilities have a tuberculosis (TB) incidence rate of 39.2 per 1,000, nearly four times the rate of TB in the general population. This fact mandates routine screening, reporting, and strict follow-up of TB in long-term care facilities as well as recognizing and addressing barriers to worker and resident protection. As healthcare in this country evolves from acute care facilities to alternative ambulatory care settings, the focus for infection control personnel is to develop effective TB control plans appropriate to the care setting using current clinical guidelines set forth by the Centers for Disease Control and Prevention (CDC) or other agencies, the main goal of which is to reduce the number of infections and exposures to this disease. As the incidence of TB continues in long-term care settings, away from acute care facilities, public health officials, administrators, and infection control personnel need to develop TB control plans, risk assessment procedures, and appropriate follow-up on positive converters among the workers and the residents. The case study presented herein is a good example of an individual being offered a screening test for an infectious airborne disease and positive test results being disregarded. PMID- 11603169 TI - [The difference between obsessive-compulsive disorder in adolescence and in adults]. PMID- 11603170 TI - [The use of acetylcholinesterase inhibitors in Alzheimer's disease]. PMID- 11603171 TI - [Obsessive-compulsive disorder: a disease or anxiety disorder?]. PMID- 11603172 TI - [Risk of hypertension after heart transplantation in the follow-up period]. AB - From October 1988 to March 2000, 58 patients underwent orthotopic heart transplantation (HTX). Data of 220 heart recipients with the follow up > or = 3 months after HTX were analyzed using the average values of blood pressure measured with the sphigmo-manometer. 65% of patients were diagnosed with the hypertension (HA). 39.9% of those patients (NTA group) had the systolic blood pressure < or = 140 mmHg and diastolic blood pressure < or = 90 mmHg during pharmacotherapy. 60.1% of hypertensive patients (NTB group) had the systolic pressure > 140 mmHg and/or diastolic pressure > 90 mmHg despite pharmacotherapy. 35% of all patients had normal blood pressure after HTX (HNA group). Patients with hypertension were older and the end stage ischemic cardiomyopathy was more frequently indication for HTX. Significantly more females were in NTA group. We observed no influence of the daily dose of cyclosporine or other immunosuppressive drugs on HA. The average blood concentration of cyclosporine A and mycophenolate mofetil was similar in all groups. The calcium channel blockers and inhibitors of angiotensin converting enzyme were main tool of pharmacotherapy used. In NTA group calcium channels blockers were used more frequently. In NTB group there was a statistically significant higher blood level of creatinine. After HTX there is a high risk of HA, which: increases with age, with the ischemic cardiomyopathy as indication to HTX, is significantly higher in males, there is no correlation between HA and the dosage and blood level of cyclosporine, increases with kidney insufficiency. In monotherapy calcium channel blockers seem to be especially effective. PMID- 11603173 TI - [The comparison of clinical effectiveness of perindopril and acebutolol in the primary hypertension treatment]. AB - Hypertension is one of the most important risk factors for ischaemic heart disease and stroke. The aim of our study was to assess the antihypertensive effect of angiotensine converting enzyme inhibitor (perindopril) versus beta blocker (acebutolol) in hypertensive patients. It was a double blind, placebo controlled study performed in the group of 31 patients (16 males, 15 females; mean age 46.6 +/- 8.7 years) with newly diagnosed (previously not treated) mild to moderate hypertension. Each patient in the wash-out period (two weeks) was given placebo and then was randomized to active treatment: perindopril (4 mg/day) or acebutolol (400 mg/day) for 3 weeks, following these drugs were cross matched (after one week wash out period). Blood pressure (BP) with mercury sphygmomanometer was measured three times: after 2 weeks of placebo treatment, after 3 weeks of perindopril and 3 weeks of acebutolol treatment. Both perindopril and acebutolol proved to be effective in monotherapy of hypertension. After 3 weeks of the treatment we observed BP systolic and diastolic normalization, but more patients had systolic BP normalization after perindopril treatment. PMID- 11603174 TI - Acute haemodynamic effects of AV-synchronous pacemaker stimulation in patients with congestive heart failure and left bundle branch block. AB - INTRODUCTION: The therapeutical limits of drug and surgical therapy for severe chronic heart failure make the research for adjunctive treatment options necessary. After the positive effects of AV-synchronous pacemaker stimulation in patients with dilatative cardiomyopathy and 1st degree AV-block, this study was to evaluate the benefit of transient pacemaker stimulation in patients with dilated cardiomyopathy and left bundle branch block. METHODS AND PATIENTS: 19 patients (14 male, 5 female, age 60 +/- 8 yrs) were included in the study. Inclusion criteria were congestive heart failure, stage NYHA III or greater and left bundle branch block. Transient stimulation of the myocardium was applied via two electrodes (right atrium and right ventricle) in VDD mode, whereby a series of AV-delay-times between 80 and 180 ms was tested. Thermodilution was used to determine cardiac output, pulmonary capillary pressure and pulmonary arterial pressure. RESULTS: In 16 patients, pacemaker stimulation led to a significant increase of cardiac output (3.8 +/- 0.5 l/min to 4.6 +/- 0.5 l/min; p < 0.002), cardiac index (1.90 +/- 0.20 l/min/m2 to 2.3 +/- 0.2 l/min/m2; p < 0.002) and of stroke volume (51 +/- 8 ml to 62 +/- 6 ml; p < 0.002) as well as a significant reduction of mean pulmonary capillary pressure (19 +/- 1 mmHg to 15 +/- 1 mmHg; p < 0.01). The mean pulmonary arterial pressure remained unchanged. Three patients did not benefit from the treatment. CONCLUSION: AV-sequential pacemaker stimulation (right ventricular electrode placement) can be a valuable adjunctive therapy in selected patients with late stage congestive heart failure and left bundle branch block. PMID- 11603175 TI - [Platelet activation and endothelial factors in standard exercise test before and after menopause]. AB - OBJECTIVES: Postmenopausal lack of estrogens may accelerate cardiovascular atheromatic changes. Standard exercise test (SET) challenges hidden signs of the vascular involvement. Although the test is known not to carry a risk of thromboembolic complications, it may influence plasma concentrations of endothelial and platelet factors. The question is if and to what extend the menopause aggravates the SET induced changes. AIM: Plasma concentrations of nitric oxide, endothelin-1, beta-thromboglobulin and von Willebrand factor activity before, at the maximum exercise and 15 minutes after the SET referred to, as a recovery time were estimated. METHOD: SET was performed according to Bruce protocol in group of 31 premenopausal and 57 postmenopausal women. Standard RIA kits for plasma beta-thromboglobulin (beta-TG) (Boehringer Mannheim) and endothelin-1 (Et-1) (Blotrack) concentration were used. The von Willebrand factor (vWF) activity was assayed by ELISA system (Boehringer Manheim). Plasma nitric oxide (NO) concentration was calculated from nitrides/nitrates levels, by Griess reaction, modified by use of NADPH reductase. RESULTS: Mean plasma levels of beta TG, Et-1, NO and vWF activity do not differ between pre and postmenopausal women. The standard exercise test significantly increases both beta-TG plasma concentration and vWF activity (p < 0.00001). During the 15 minutes rest period the changed values do not return to preexercise levels. Neither plasma NO nor Et 1 plasma concentrations change during the exercise test. There was a similar increase in beta-TG plasma levels and vWF activity during the SET in pre- and postmenopausal women and a slighter increase of plasma Et-1 levels in postmenopausal women (p < 0.04). The close relationships between NO plasma concentration and both vWF activity (p < 0.002) and vascular endothelial growth factor (VEGF) level (p < 0.04) were observed in postmenopausal women. The vWF activity in postmenopausal; women inversely correlates with insulin-like growth factor-I (IGF-I) concentration (p < 0.001). In premenopausal women the important modulators of vWF activity were: body mass (p < 0.04), serum total cholesterol (p < 0.02) and sex hormone binding globulin (SHBG) levels (p < 0.04). The postmenopausal beta-TG increase during SET depends on body mass (p < 0.02), whereas the preexercise levels seem to be related to VEGF level (p < 0.03) and inversely to Et-1 (p < 0.007) and dehydroepiandrosterone sulfate (DHEAS) concentration (p < 0.03) Both the basal and stimulated by exercise vWF activity are higher in obese women (p < 0.003), but the net increase is larger in lean group (BMI < 30 kg/m2). In premenopausal women plasma NO concentration depends on 17 beta-estradiol serum level (p < 0.02). The higher VEGF (p < 0.01) levels as well as vWF activity was observed (p < 0.03) in hypercholesterolemic women. CONCLUSION: The standard exercise test increases the procoagulatory von Willebrand factor activity so as the platelets activity (beta-thromboglobulin concentration) in both pre and postmenopausal women. The slight endothelin-1 rise has been found at the maximum exercise in postmenopausal women. The close relation between plasma nitric oxide and endothelin-1 levels was found in postmenopausal women. Obesity and hypercholesterolemia may contribute to the observed changes. PMID- 11603176 TI - [Bone complication in diabetic subjects with good metabolic control and without any late complications: selected problems. Part I: calcium, phosphorus and magnesium metabolism]. AB - The aim of the study was to evaluate whether in diabetics with good metabolic control and without any diabetic complications, disturbances of calcium, phosphorus and magnesium metabolism or hormonal regulation (parathormone/calcitonin) were present, and if they depended on type of diabetes, duration time of diabetes, kind of hypoglycaemic treatment, sex or age of patients. 83 subjects were examined, including: 14 with type 1 diabetes mellitus, 49 with type 2 diabetes mellitus and 20 healthy persons. All tests were performed in standarized low-calcium diet conditions. In basal conditions both serum concentrations and daily urine excretion of calcium, phosphorus, magnesium were estimated. Oral and intravenous calcium load tests with simultaneous parathormone, calcitonin, calcium, magnesium and phosphorus concentrations estimation were done. The final conclusions were as follow: Both in type 1 diabetes mellitus and type 2 diabetes mellitus subjects with good metabolic compensation and without advanced diabetic complications a tendency to early disturbances of calcium-phosphorus metabolism is observed. Physiological hormonal control (parathormone/calcitonin) is preserved. Correlations between mineral metabolism and type of diabetes, duration time of diabetes, daily insulin dose, body mass index and sex are observed. Kind of hypoglycaemic treatment has only slight influence on the mineral metabolism. PMID- 11603177 TI - [The evaluation of the effectiveness of half-body irradiation as palliative treatment in patients with multiple bone metastases]. AB - The results of simplified method of hemibody irradiation of 23 patients with multiple painful bone metastases are presented. In all cases without proven bone metastases in skull and distal part of limbs, these parts of the body were excluded from irradiated field. The study comprised 25 cases of hemibody irradiation. The degree of pain relief and performance status improvement was assessed one and two months after treatment, depending on clinical and histopathological diagnosis and type of bone metastases. The best symptomatic results were obtained in the cases of multiple myelomas (100% of pain relief), prostate cancers (the average degree of 78%) and lung cancers (88%). Considering histopathological diagnosis, the best answer was found in multiple myeloma and squamous cell cancer (88%). Taking into account type of metastases the best result was obtained in the cases of osteolytic metastases (65%). No difference between upper and lower hemibody irradiation was found. The statistically significant correlation between pain relief, performance status improvement and decrease of analgetics use was found. The obtained results suggest that presented simplified form of hemibody irradiation is an effective symptomatic treatment modality in the cases with multiple painful bone metastases, giving an increase of life quality without significant radiation morbidity. PMID- 11603178 TI - [The evaluation of the relationship between malignancy grade and cytokeratin-10 accumulation in human skin squamous cell carcinoma]. AB - The aim of the study was analysis of CK-10 expression in human skin squamous cell carcinoma (SCC) basing on immunohistochemical procedure. The study was carried out on 43 samples of skin SCC which were evaluated histopathologically with regard to 3-grade scale (G) of malignancy. In each case immunohistochemical reactions by use of ABC method were carried out in order to detect CK-10 within cancer cells. The expression of CK-10 was evaluated in accordance with arbitrary 3 grade scale: from +++ to +. The obtained results revealed affection of CK-10 expression in cancer cells. In G1 and G2 skin SCC a moderate expression of CK-10 was found and this occurred in cells grouped in nests. In G3 SCC the expression of CK-10 was very low and this was noted in single cells only. The use of immunohistochemical methods in evaluation of CK-10 expression can be a useful tool in routine histopathologic examination of tumors of epithelial origin. PMID- 11603179 TI - [Should we operate goiter in the elderly?]. AB - The aim of this study was to compare the elderly patients group to the group of others undergoing surgical treatment due to goitre regarding type of goitre, extent of surgical procedures and postoperative follow-up (including early postoperative complications). 5872 patients with various type of goitre (between 1984 and 1998) were surgically treated, among them were 5244 (89.3%) females and 628 (10.7%) males (sex ratio as 8.1:1). The mean age was 46.1 (10 to 95 years). 278 (4.7%) patients were above 70 years of age (235-84.5% females and 43-15.5% males), their mean age was 73.7 years. The increase of malignant goitre was evident among the elderly patients (19.9% vs 5.5%). The dominant types were anaplastic cancers and malignant non-Hodgkin lymphomas. Much more frequently a giant goitre was diagnosed (20% vs 6.1%). It was localised substernally (39.6%) or intrathoracic (4.7%). The elderly prepared properly underwent surgical treatment quite well. Among early postoperative complications in the elderly dominant were surgical ones (6.8%), most frequently the injuries of the recurrent laryngeal nerve (4.67% vs 1.14%). Perioperative mortality regarded mostly the elderly with disseminated anaplastic cancer (3.6% vs. 0.2%). Surgical treatment of goitre in the elderly is a safe and justified method. High incidence of malignant tumours especially anaplastic cancers among the elderly should encourage to operation as early as possible. PMID- 11603180 TI - [QT interval variability and its influence on prediction of cardiac arrhythmia in hemodialyzed patients]. AB - The main cause of mortality in patients on renal replacement therapy are disturbances in circulatory system including sudden death. Cardiac hypertrophy, ischemic heart disease, degenerative changes as a consequence of uremic cardiomyopathy and electrolyte disturbances constitute the main cause of cardiac arrhythmia. The differences in duration of QT interval in ECG leads are known as QT dispersion and may indicate on prevalence of cardiac arrhythmia leading to sudden cardiac death. In the paper we described prognostic significance of QT dispersion in patients on maintenance dialysis. PMID- 11603181 TI - [Personality patterns in coronary artery disease]. AB - Relation of personality patterns and type A behaviour to the risk and prognosis of coronary artery disease was described. The particular interest of researchers was directed toward hostility, which correlated with the course of coronary artery disease. Finally, therapeutical implications, deriving from the holistic approach to cardiological patients, were proposed. PMID- 11603182 TI - [Restenosis after coronary balloon angioplasty. Prevention and treatment]. AB - The paper describes the mechanisms as well as clinical and angiographic risk factors for the development of restenosis after balloon coronary angioplasty. Based on literature findings and personal experience the ways of preventing restenosis were reviewed taking into account the optimisation of immediate angioplasty results based upon intracoronary ultrasound and physiological measurements of the coronary flow reserve. The paper also reviews the available techniques in the management of restenosis after balloon coronary angioplasty. PMID- 11603183 TI - [Atrial flutter: causes, electrophysiological characteristics, treatment with radiofrequency catheter ablation]. AB - Atrial flutter (TP) is one of the most common supraventricular tachyarrhythmias. Because of its influence on hemodynamics of the circulation, prolonged episode of paroxysmal TP can lead in as many as 1/3-1/2 patients to clinical signs of coronary insufficiency, decompensation of the circulatory system, or even such life-threatening states, like cardiac arrest. Patients with preexcitation syndrome, hyperthyroidism, as well as children, whose atrio-ventricular (AV) node can conduct in a 1:1 fashion, are in the group of particularly high risk of complications. Recurrent episodes of TP are also associated with frequent occurrence of thromboembolic events. Based on the electrocardiographic (ECG) pattern TP is divided into common type, with negative "sawtooth" in leads II, III, aVF, and uncommon type, which is characterised by other ECG morphologies. Experimental and clinical data have revealed, that common and some part of uncommon type are due to clockwise or counterclockwise reentry in the right atrium. These forms of TP can be treated with high success-rate with radiofrequency (CR) ablation. Because of difficulties in pharmacological conversion of the arrhythmia to the sinus rhythm and high frequency of recurrences, CR ablation seems to be a high effective method of treatment in patients with common and some forms of uncommon TP. PMID- 11603184 TI - [Histocompatibility HLA system of man. Consideration in the light of current concepts. I. Organization and polymorphism]. AB - The HLA system, which represents the major histocompatibility complex (MHC) of man, encompasses approximately one thousandth of the human genome and is localised on the short arm of chromosome 6 (band 6p 21.3). The HLA gene complex shows an extreme polymorphism which can be demonstrated by molecular genetic methods. The genes so far recognised in the HLA can be subdivided into three major classes: 1) the HLA class I (HLA-ABC) and class II genes (HLA-D); 2) immune function related genes (C2, C4A, C4B, TNFA and TNFB, transporter and proteasome genes); 3) other genes apparently not related to immune functions (CYP 21, valyl tRNA synthetase). The loci HLA-A, -B, and -C represent the classical HLA class I loci with gene products expressed on nearly all nucleated cells; HLA-E, -F and -G the non-classical HLA class I loci, code for products with a limited tissue distribution and a restricted polymorphism. Classical class I and II MHC antigens are integral membrane proteins composed of two pairs of structurally similar extracellular domains. The X-ray studies indicated the presence of peptides bound to HLA molecules within the groove. The groove has on its floor several amino acids where peptides, derived from the antigen being presented, are bound. Although the principle of allele specific motives ruling the peptide binding seems to be become more established, the further biological impact of the allelic variation remains subject for future studies. PMID- 11603185 TI - [Abdominal compartment syndrome: current view]. AB - In the last few years, physiological changes, symptoms, diagnostic tools, and treatment of abdominal compartment syndrome interest surgeons, trauma surgeons and anaesthetists. Sudden, dangerous basic vital function deterioration in patients managed in the intensive care unit, may be results of abdominal compartment syndrome. Abdominal compartment syndrome is secondary to massive intraabdominal haemorrhages, hepatic or retroperitoneal space "packing", fluid collection in tissues, including abdominal organs. Circulatory, respiratory and kidney dysfunction occur, when intraabdominal pressure measured in urinary bladder is 25 H2O or higher. In this condition, rapid surgical decompression is necessary. During decompression abdominal organs reperfusion may produce arterial hypotension and asystole. Abdominal closure must prevent abdominal hypertension. Temporary plastic patch, simple and cheap is the most popular technique. PMID- 11603186 TI - [A case of acute appendicitis with abdominal actinomycosis]. AB - The authors presented a rare case of acute appendicitis with abdominal actinomycosis. Diagnostic and therapeutic procedures for accidentally found abdominal actinomycosis were discussed based on current literature. PMID- 11603187 TI - [Disorders of the bone density in the chest x-ray examination in the course of myelosclerosis]. AB - The authors report a rare case of myelosclerosis diagnosed during hospital stay in internal Department on account of hepatosplenomegaly and anaemia. The case of patient described by authors was diagnosed on the ground of examination and executed additional investigations: morphology, peripheral blood picture, chest radiography, scintiscan of skeleton. PMID- 11603189 TI - [Kinematics and biomechanics of the elbow joint]. AB - An attempt has been made to describe the interaction of the different joint morphologies and the ligaments of the elbow in terms of the current literature. The physics of joint kinematics and biomechanics will be discussed and used to resolve current incomplete interpretations. The elbow is a very stable functional unit due to its bony tracking and "self-stabilising" ability especially in the humeroradial joint. In reconstruction and in total joint replacement, the different radii of curvature of the various surfaces have to be respected to redevelop full joint function. PMID- 11603190 TI - [Contracture of the elbow joint. Etiological review and general treatment concepts]. AB - The contracture of the elbow joint is a symptom of various local changes and systemic disorders. Appropriate therapy requires a distinct knowledge of the relevant anatomical structures as well as of the etiology and pathogenesis of the functional restriction. Systematically, intrinsic contractures coming from the synovial membrane and intra-articular structures are distinguished from extrinsic contractures involving extra-articular soft tissues. The etiology of heterotopic ossifications is still widely unknown. The classification of the contracture is defined by the by extent of the remaining range of motion. Indications for surgery in severe cases depend on the degree of pain and of functional loss. Surgical arthrolysis includes a large spectrum of possibilities ranging from endocopical procedures to prosthetic joint replacement. Complications are relatively frequent after surgery and the individual gain of function is not always predictable. PMID- 11603191 TI - [Radiological diagnosis in contracted elbow joint. Value of CT and MRI]. AB - A contracture of the elbow joint is a challenge for diagnostic radiology. Radiographs remain the method of choice for primary diagnosis, however, diagnostic confidence can be limited if periarticular ossifications or contracture do not permit evaluation of the whole joint. In these cases, CT or MRI can be used for specific diagnostic problems. Additional multiplanar or three dimensional reformations can be used by the orthopedic surgeon for planning the surgical procedure. MRI has a great advantage in allowing visualization of muscles, capsula-ligamentous complex and articular cartilage. The main disadvantages are duration of examination time and artifacts. CT is superior in terms of spatial resolution and visualization of bony structures. MRI and CT examinations of the elbow will increase with the number of minimal invasive surgical procedures. Protocols must therefore be optimized with attention to positioning, sequence selection and image processing. This article reviews the current standards of high resolution imaging with CT and MRI, including arthrographic techniques. The pros and cons of both methods are discussed in the setting of a contracture of the elbow joint. PMID- 11603192 TI - [Post-traumatic loss of function and malunion of the elbow]. AB - Post-traumatic contracture and malunion of the elbow in pediatric patients may result from a combination of injury-related, diagnostic-related and therapy related factors. Typical pediatric elbow injuries are associated with different patterns of these risk factors. Etiological differentiation allows for initial risk prediction, improves diagnostic awareness and provides adequate treatment in order to prevent unsatisfactory results. PMID- 11603193 TI - [Arthroscopic therapy in limited mobility of the elbow joint]. AB - Limitation of elbow mobility constitutes a grave problem for therapy. Arthroscopy offers a therapeutic option, but in cases of loss of motion poses a considerable challenge to the operative technique. Placement of the portals already carries an increased risk of neurovascular lesions due to the altered anatomy and reduced distension capacity of the joint. Thus, particular significance attaches to the standardized arthroscopic procedure for localization and placement of the cannulas, intra-articular assessment, differentiated evaluation of the dorsal joint regions, and operative tactics for transsection of cicatrization, removal of loose bodies, and excision of osteophytes. If extra-articular factors are involved in the genesis of the limited motion, arthroscopic treatment often does not achieve the desired result. It is therefore considered propitious to differentiate the causes of the loss of motion during clinical examination with imaging diagnostics, in particular to determine those caused by extra-articular elements. If, however, individually localized intra-articular adhesive bands or loose bodies are responsible, the prognosis for arthroscopic management is clearly more favorable. Patients with minor loss of motion (> 15 degrees) profit more from the arthroscopic operation than those with a extension or flexion deficit of more than 30 degrees. PMID- 11603194 TI - [Open arthrolysis in preserved joint surface geometry]. AB - This review article discusses the operative treatment options for release of essentially extracartilaginous contractures of the elbow (referred to as extrinsic contractures). Indications, preoperative work-up, specific operative strategy and techniques, rehabilitation, possible complications, and results are discussed and compared. Special reference is made to the technique of sequential surgical release based on the transhumeral approach. This technique makes it possible to optimize the articular offset while preserving the static and dynamic stabilizers of the joint. Treatment of contractures of the elbow remains dangerous and delicate. It deserves experienced surgical handling in order to avoid complications. Thus, it remains to be hoped that qualified management will help to improve the relatively mediocre functional results. PMID- 11603195 TI - [Treatment of united or malunited fractures of the elbow]. AB - Nonunions and malunions around the elbow are often due to incorrect initial treatment of a fracture. We have to differentiate between nonunions and malunion of adults and children. There are general principles for the treatment of nonunions and malunions of the distal humerus. They should not always be treated by decortication, internal fixation and bone graft. Removal of non-united fragments or a correction osteotomy may be good alternatives. A correct surgical approach and a biologically accurate osteosynthesis are necessary for good joint mobility, whereby the most difficult problem is to regain extension. An arthrolysis is not normally necessary during the first operation of a non- or malunion. It can be carried out, if necessary, on removal of implants. If these principles are followed, then the operation is usually successful and the patient satisfied. If treatment fails, the possibility of a joint replacement or an arthrodesis should not be forgotten. PMID- 11603196 TI - [Distraction arthrolysis with humero-ulnar motion fixator]. AB - Distraction arthroplasty in the treatment of elbow stiffness with an external fixator and subsequent fixator assisted mobilization is described. Joint distraction is employed to correct the shortened ligaments and capsule and permits the separation of articular surfaces. After intraoperative joint distraction, a phase of relaxation followed by fixator assisted mobilization is carried out. The use of the motion fixator is described and additional measures discussed. This technique is particularly valuable in joint subluxation or persistent joint dislocation and allows for reduction after distraction in order to secure joint congruity. Postoperative management is a key factor for the success of the management protocol. PMID- 11603197 TI - [Endoprosthetic joint replacement of the contracted elbow joint]. AB - In a retrospective study 14 patients were reviewed 63 months after the implantation of a semi-constrained total elbow prosthesis in fourteen stiff or ankylosed elbows with a preoperative range of elbow motion of 30 degrees or less. The result, according to the Mayo Elbow Performance score, was excellent for four elbows, good for four, fair for one, and poor for five. The average arc of flexion improved from 7 to 68 degrees postoperatively with an average increase of 34 degrees in flexion, and 27 degrees in extension. There were seven complications affecting seven of the 14 elbows and four of these seven elbows underwent a revision procedure. Replacement for a stiff elbow is the least predictable, has the lowest overall rate of success and highest complication rate, than any other procedure. Nevertheless, these disadvantages must be placed in the context of alternative intervention options. The semiconstrained total elbow arthroplasty seems to be a useful option for patients older than 50 years with intrinsic stiffness involving more than 50% of the articular surface and with an ankylosed or very stiff elbow. PMID- 11603198 TI - [Biomechanical properties of interference screw implantation in replacement of the anterior cruciate ligament with patellar and hamstring transplants. An experimental study using roentgen stereometry analysis (RSA)]. AB - This experimental roentgen stereometric analysis (RSA) study was performed to measure micromotions between the graft and tunnel under submaximal load in anterior cruciate ligament (ACL) reconstruction. The aim was to evaluate the maximum load at failure, linear stiffness, and slippage of bone-patellar-tendon bone (BPTB) grafts fixed with interference screws compared to quadrupled hamstring grafts fixed with interference screws. We used 15 porcine tibia specimens for the study. In the BPTB group, the 10 x 25-mm bone plugs were fixed in a tunnel with 10 mm in diameter using a 7 x 25-mm titanium interference screw (n = 5) or a biodegradable screw (n = 5). The five hamstring transplants were folded to a four-stranded graft and armed with a baseball stitch suture. The sutured side was fixed with a 7 x 25-mm biodegradable polylactide screw in an 8 mm tunnel. The tibial bones, tendon grafts, and interference screws were marked with tantalum beads. The grafts were mounted to a custom made load frame and loaded parallel to the axis under RSA control increasing the force in steps of 50 N. Micromotions between bone plug, screw, and tibia were measured with RSA. Accuracy of RSA for the in vitro study was evaluated as 0.05 mm. Hamstring grafts failed at significantly lower maximum loads (492 +/- 30 N) than BPTB grafts (658 +/- 98 N). Linear stiffness of the hamstring graft fixations was eight times lower compared to the BPTB grafts (403 +/- 141 N/mm vs 3500 +/- 1300 N/mm). There was no significant difference between the biodegradable and titanium screws in the BPTB group. Slippage of the graft started at 82 +/- 35 N load in the hamstring group and at 428 +/- 135 N in the BPTB group. Slippage of the graft at 75% of the maximum pull-out strength was measured as 0.36 +/- 0.25 mm in the BPTB and 2.58 +/- 1.08 mm in the hamstring group. The interference screw fixation of a quadrupled hamstring graft showed a lower linear stiffness and an earlier slippage compared to a patellar tendon bone plug. Slippage of the hamstring grafts at submaximal loads may result in fixation failure during rehabilitation. PMID- 11603199 TI - [Vascularized fibula transplantation in orthopedic oncology. Personal experience and review of the literature]. AB - Primary malignant bone tumors can be treated predominantly with limb salvage. After resection of large articular segments adjacent to the dia- or metaphysis of long bones modular endoprosthetic devices are most commonly used for reconstruction. In case non-vascularized corticocancellous bone is transplanted in order to bridge extensive bone defects, the risk of pseudarthrosis and fracture of the donor bone is significantly higher in comparison to a free vascularized transplant. From 1988 until 1999 we treated 20 patients with extensive bone defects after resection of tumors affecting the upper and lower extremity using a vascularized fibular graft. In this retrospective analysis we collected the data focusing on bone integration and functional outcome. The graft union was classified according to the standards of the "International Symposium of Limb Salvage". Evaluation of the functional outcome was quantified using the Enneking-score. The stabilisation of the transplant was obtained exclusively by plate fixation in the upper extremity. In 10 in a total of 12 patients the reconstruction using a vascularized fibula transfer was reinforced with an allograft in the lower extremity. The functional evaluation score reached 73% of normal function at the last follow-up. After 18 months the radiographic evaluation of graft union was "excellent" in 75%, "good" in 11%, "fair" in 6% and "poor" in 9% according to the criteria of the ISOLS. Main complications were graft fracture in of 15% and pseudarthrosis in 14.3%. Reconstruction of extensive bone defects using free vascularized fibula grafts are a demanding operative procedure. The procedure combines a biologic form of reconstruction with a legitimate expectation of good long term outcome and a relatively low rate of complications. PMID- 11603200 TI - [Computer assisted surgery, 2001 development and prospects. Results of a congress at Reisensburg Castle, 23-24 November 2000]]. AB - The progress in computer assisted surgery (CAS) is influenced by new technologies in imaging as well as by the input of the users. At present, CAS procedures are established in dorsal spine instrumentation, prosthetics and long bone surgery. Present status and future of CAS was a topic of an expert meeting at the Reisensburg castle. Imaging will speed up in the future using multi-detector techniques. C-arm navigation will gain more information using the 3D technology intraoperatively. CT based navigation procedures are standard in spine and will be established in pelvic surgery. CAS in robotics at the moment means the use of robot-assistance. A new concept is the modality-based navigated surgery, which can be used at various skeletal locations. Visualization of patient data will improve using 3D semi-transparencies with real time update. In the future it will be mandatory to find algorithms to fuse the different possibilities and techniques. A new concept of surgical training is necessary to teach CAS procedures. Therefore discussion must go on to improve these systems. PMID- 11603201 TI - [New arthroscopic procedures in treatment of calcaneus fractures]. PMID- 11603202 TI - [At the limits of psychotherapeutic medicine]. AB - Psychotherapeutic medicine combines somatical and psychological aspects of human medicine. On those areas, which are near an imaginated border, the dialogue with the patient, as well as the psychotherapeutic treatment and the good will of the psychotherapeutic doctors can come easily to a limit. In the following there will be given several examples, which illustrate the difficulties in psychotherapeutic treatment with certain patients. There are old people, people in extreme situations, people with aggression against themselves and against the others. PMID- 11603203 TI - [Psychotherapy in senile dementia?!]. AB - Psychotherapy for senile demented patients is feasible and should become a routine. However, it must be integrated psychotherapy that is not school-centred but patient-centered. Especially in the work with senile demented patients it must closely cooperate with all health professions that are in the field. These endeavours must be systematically coordinated. Analytic psychotherapy in the classical sense is not feasable. However, in old (and demented) patients sometimes a strong desire persists to tell out of the past. The therapist's task there is mainly listening and not interpreting. Children, animals, plush-animals, music and dance-therapy are not so well-known possibilities to find a psychotherapeutic approach to senile demented persons. The basic psychotherapy should be known to all health professions. Professional psychotherapy should be given more attention as to the psychotherapy of old people. PMID- 11603204 TI - [Scars of the soul--wounds of the body: plastic surgery and psychotherapy]. AB - With the example of two case reports of chronic wounds the connection between somatic and psycho-social factors is shown on the basis of the biopsycho-social model of disease. Both in aetiology as well as in therapy the dilemma of "somatic OR psychic" can thereby be solved. The inclusion of psychotherapeutic interventions in conservative or surgical strategies increases the probability of healing. PMID- 11603205 TI - [Psychosocial medicine--a vision needed in medical education and patient care]. AB - Psychosocial medicine represents the psychosocial aspects in a holistic patient orientated medicine. It is of great importance in medical education as well as in clinical in- and out-patient treatment. For the near future, further strengthening is necessary in order to prevent the psychosocial aspects from disappearing in medicine. The efficacy and effectiveness of psychosocial therapies need to be further improved. PMID- 11603206 TI - [Concepts of anthropological medicine]. AB - Medical anthropology is the teaching of the ill human being, of being ill; anthropological medicine is the realization of this teaching in practice. This concept was first developed and assessed in the "Gestaltkreis" and in the Pathosophy (44), in Medicine in Motion (39), and in the Bipersonality (10). The four most important concepts are represented, which have their origin and aim in anthropological medicine: anthropological medicine, Balint-work, family-oriented medicine, and salutogenesis. These concepts are exemplified in the Aachen psychosomatic liaison model, the Aachen Balint cooperation model, and the Aachen model of psychosomatic care. We wish to portray the meaning of these resources for the medicine of the future, since they have proven to be effective, cost saving, and easy to be handled. In the latter part of our presentation, we will document this point with a pilot study conducted in Israel and in our own clinic in Aachen. PMID- 11603207 TI - [Further development of established psychotherapies: "What you have inherited from your fathers..." (Goethe)]. AB - In a somehow playful creative "living-learning-process" a rich and differentiated "material" of more or less useful forms of communication will appear. After that, possibilities of a better, up to optimal and individual patterns of communication will be operated. Thereby, the following items will have a central position: 1. personality-/character-structural factors, 2. correlated individual tendencies and basic forms of anxieties, and 3. early considered availability of special Ego functions. PMID- 11603208 TI - [Paintings and their progress by psychiatric inpatients within the concept of integrative art therapy]. AB - Integrative painting therapy is a therapeutic concept for the treatment of psychiatric patients. It combines medical and therapeutic treatment strategies. The drawing and painting group takes the central part of this type of therapy. Its main focus is to capture psychodynamic processes with "inner pictures". Due to the creative process of painting the psychodynamic process becomes visible and can subsequently be worked on. According to specific rules the pictures reflect the psychopathology of different psychiatric disorders as well as their development throughout the therapeutic process. The pictures also serve as a starting point for group-, single and family therapy. The patients quickly gain access to their emotions and realize possible conflicts, which form the basis of their psychodynamics. Progress throughout therapy becomes visible and can be documented with the pictures. The structured course of the painting sessions provides additional information. The integration of various aspects helps expand our diagnostic frame. PMID- 11603209 TI - [Psychotherapy of alcohol addiction--principles and new findings of therapy research]. AB - The psychotherapy of alcohol dependence has for long been neglected by psychiatric research. Meanwhile a number of clinical and experimental studies have been performed to examine the efficacy of different kinds of psychotherapeutic approaches in alcoholism. Most clinical settings follow an integrative concept based on behavioural and coping skills therapy, psychodynamic or psychoanalytic and family therapy. Further therapy elements are self-help groups or muscular relaxation, among others. Most therapies are conducted as group therapy but individual therapy is a well-examined alternative. Early intervention in alcohol dependence is of special relevance. Motivational enhancement is a key goal of alcohol therapy and can already be implemented in early interventions or in the detoxification phase. Results of clinical studies suggest that after inpatient treatment 30-40% of patients remain abstinent. Outpatient treatment of alcoholism has for long been neglected, with only few prospective studies conducted so far. The most ambitious study has been the US Project Match. A difficult question remains the allocation of patients to different treatments. Current concepts of treatment for alcoholics are described and results of different treatment studies are given. PMID- 11603210 TI - [Expanded criteria for assessment of legal competence and testifying capacity in borderline cases of organic brain syndromes--an important field for cooperation between medicine and law]. AB - The three well-known criteria for legal competence and testamentary capacity, that is: consideration, awareness and the ability to express oneself in writing and speaking, ought to be extended by three further dimensions, namely: motivation, long-term intentions, gestures. This demands increased specialised competence and increased time, but seems indispensable in order to meet the postulate of human ethics: to give the patient the optimum support for a sensible realisation of will. This equally applies to medical experts and jurists (especially notaries and lawyers). The related demand to give increased time and attention to a patient, often in the form of repeated observation over several days, with detailed written documentation, shows that it is not at all a weakening, which is supported, but rather a more precise formation of concept. In this sense, we expect to meet better the demand of the best possible "objectivity" in evaluation, rather than within a merely schematic, single, short time assessment. We substantiate this with several examples, taken from various areas, namely: in isolated aphasic/agraphic disorders, testamentary capacity and even legal competence can be retained according to the above criteria (despite the inability to write and speak). In analogy, also "last minute" decisions of the incurably sick person must be taken into account. We also show, however, that an assertion of legal competence (unrestricted ability to reach a decision) based on merely formalistic guide-lines, without taking into account long-term intentions and motivation, might seriously harm a patient. There is the case of a post-apoplexy patient who demanded immediate discharge to return home. This patient proved fully aware in classical questions of reference, but, due to homesickness, post-apoplectic syndrome and senile stubbornness, failed to take into account her inability to walk and incontinence. A consolidated discharge, however, was very well possible several weeks later. At an earlier stage this would have led to disaster. There will always remain a zone in which it is not possible to reach clear expert decisions either pro or contra but by incorporating the criteria above quoted, it will be possible to considerably narrow this zone. This corresponds to an evaluation process, which cultivates both optimum objectivity and optimum fairness. PMID- 11603211 TI - [Psychopharmacotherapy in the 20th century]. AB - Neuroleptics, antidepressants, mood stabilizers and anxiolytics are the most frequently prescribed drugs in psychiatric therapy. Their introduction came largely in the past five decades. This review summarizes the history that led to their discovery and introduction to the market in the 20th century. PMID- 11603212 TI - [Neuromodulation as an alternative method in the treatment of refractory angina pectoris]. AB - Epidural stimulation of the spinal cord affects the activation of afferent nerve fibres. Patients refractory to conventional therapy of angina pectoris can be treated with epidural stimulation since 1985. The stimulation electrode is inserted by a small incision to the skin at Th4-Th5 and positioned to the epidural space at Th1-C7. The impulse generator is implanted to the lateral abdominal wall and connected to the stimulation electrode. This treatment should be restricted to patients refractory to--or not suited for--surgical and catheter based coronary revascularisation. Clinical trials demonstrated increased exercise tolerance, reduction in severity of exertional angina and ST-depression and reduction of nitrate dosage. No impairment of overall prognosis by neuromodulation has been shown in several clinical studies. Epidural spinal cord stimulation represents an alternative therapy for the treatment of selected patients with angina pectoris refractory to conventional therapy. PMID- 11603213 TI - Partial hydatidiform mole: clinicopathological features, differential diagnosis, ploidy and molecular studies, and gold standards for diagnosis. AB - Partial hydatidiform mole is optimally diagnosed histopathologically when four microscopic features coexist: 1) two populations of villi, 2) enlarged villi (> or = 3-4 mm) with central captivation, 3) irregular villi with geographic, scalloped borders with trophoblast inclusions, and 4) trophoblast hyperplasia (usually focal and involving syncytiotrophoblast). Pathologic mimics of partial mole include Beckwith-Wiedemann syndrome, placental angiomatous malformation, twin gestation with complete mole and existing fetus, early complete hydatidiform mole, and hydropic spontaneous abortion. Because partial hydatidiform mole results from diandric triploidy, flow cytometry (or another method to assess ploidy) can be utilized by pathologists for supporting diagnostic classification of problematic specimens, or for educational or quality assurance purposes. Confirmation of the histopathologic diagnosis by ploidy or molecular studies is important for scientific reports of partial hydatidiform mole, especially when unusual or aggressive outcomes (such as choriocarcinoma) are reported. PMID- 11603215 TI - Pathologic findings in eight cases of ovarian serous borderline tumors, three with foci of serous carcinoma, that preceded death or morbidity from invasive carcinoma. AB - We sought to assess the frequency of previously reported adverse histopathologic findings in ovarian serous borderline tumors (SBTs) in cases that preceded a patient's death or caused serious morbidity due to invasive carcinoma. SBTs with foci of invasive carcinoma that occupied a minority of the tumor and were associated with similar outcomes were also studied for potential additional insights. Eight cases were found over a 22-year period. Ten tumors in 5 patients were purely SBT; at initial staging, 1 patient had invasive peritoneal implants; 3 had noninvasive peritoneal implants; 1 was stage I. At last follow-up 3 of the 5 patients had died of carcinoma, 1 was alive with carcinoma, and 1 had no clinical evidence of disease 4 years after a sigmoid colectomy for invasive serous carcinoma of the bowel wall. Four tumors in 3 patients had foci of invasion that were more than microinvasive; at initial staging, all 3 patients had invasive peritoneal implants, and all died of carcinoma. All 14 of the ovarian tumors in the 8 cases had surface involvement by tumor cells, and in 8 tumors in 5 cases they were confined primarily to the ovarian surface. Foci of "micropapillary serous carcinoma" accompanied more obvious areas of infiltrative carcinoma in 2 of the 4 ovarian tumors, the peritoneal implants in 1 of the cases with purely SBTs, and a recurrence in this case and 1 other case. No morphologic finding in the 10 purely SBTs was predictive of subsequent malignant behavior. We conclude that extraovarian invasive serous carcinomas, either following or concurrent with an ovarian SBT, develop from borderline foci that may originate in the ovary, but frequently are likely to have arisen independently in the peritoneum. The carcinomas may be preceded or accompanied by noninvasive appearing micropapillary foci in the peritoneum in some cases, but micropapillary foci in the ovarian tumors are infrequent and not a necessary antecedent. PMID- 11603214 TI - Ovarian mixed-epithelial carcinomas with a microcystic pattern and signet-ring cells. AB - Primary ovarian carcinomas with unusual histologic patterns can be difficult to differentiate from metastases. In this study, we reviewed 15 cases of mixed epithelial carcinoma (12 serous, 1 serous and endometrioid, 1 endometrioid, 1 undifferentiated) with a predominant microcystic pattern and signet-ring cells. The patients' ages ranged from 31 to 78 (mean 58) years. The microcystic component in 11 patients had features of high-grade carcinoma and in 4 patients had features of low-grade carcinoma associated with areas of borderline tumor. The tumors in all 15 patients showed a predominant microcystic growth pattern composed of small cysts that were variable in size and shape. Signet-ring cells were also present in all cases (diffusely in nine cases, focally in six cases) within the neoplastic epithelial proliferation. Mucin was present in the lumina of some of the microcysts and in the cytoplasm of most of the signet-ring cells. A microcystic pattern and mucin-containing signet-ring cells can be seen as small foci or as a predominant component in primary epithelial nonmucinous ovarian carcinomas. It is important for pathologists to recognize these unusual findings in ovarian neoplasms, because they may produce a confusing apperance, even potentially suggesting a metastasis. PMID- 11603216 TI - Loss of heterozygosity at the RB-1 locus and pRB immunostaining in epithelial ovarian tumors: a molecular, immunohistochemical, and clinicopathologic study. AB - Alterations in the retinoblastoma gene (RB-1) are common in human neoplasia. The frequency of loss of heterozygosity (LOH) at the RB-1 locus on chromosome 13q14 was studied in a series of 51 epithelial ovarian tumors (10 benign, 7 borderline, and 34 malignant). LOH was scored by the absence or reduction of the signal to < 50% of one of the alleles in tumor DNA compared with normal DNA. LOH results were correlated with retinoblastoma protein (pRB) immunostaining. LOH at the RB-1 locus was observed in 9 tumors (17.6%), specifically in 1 of 7 borderline tumors and 8 of 34 ovarian carcinomas (23.5%). Among the malignant tumors, LOH occurred more frequently in carcinomas with serous differentiation (7/23; 30%). A heterogeneous (10% to 70% cells) or diffuse (> 70% cells) pRB immunostaining was less frequent in benign (1/10; 10%) and borderline (2/7; 28%) tumors than in ovarian carcinomas (15/34; 44%), an observation that correlated with the higher proliferative index in carcinomas than in benign and borderline tumors. However, lack or only focal (< 10% cells) pRB immunostaining occurred in the vast majority of tumors with LOH at the RB-1 locus (7/9; 77%), a finding that may suggest a tumor suppressor role for RB-1 in these tumors. The results suggest that RB-1 may play a role in a subset of ovarian carcinomas, particularly those exhibiting serous differentiation. PMID- 11603217 TI - Immunohistochemical comparison of primary peritoneal and primary ovarian serous papillary carcinoma. AB - Twenty-six patients, meeting strict criteria for primary peritoneal serous papillary carcinoma (PPSPC), were matched to 22 patients with ovarian serous papillary cancer (OSPC) for age and stage. Immunohistochemistry was used to determine the status of estrogen receptors (ER), progesterone receptors (PR), the expression of cell proliferation marker Ki-67, and the overexpression of HER 2/neu and p53 protein. Of the PPSPCs, 53.8% were poorly differentiated, as were 18.2% of the OSPCs (p = 0.012). Positive immunostaining for ER and PR was less in PPSPCs (30.8% and 46.2%, respectively) than OSPCs (72.7% and 90.9%; p = 0.003 and p = 0.001, respectively). Conversely, a significant increase in the expression of Ki-67 was found in PPSPCs (37.7%) versus OSPCs (26.8%) (p = 0.039). The same trend was found for HER-2/neu, being overexpressed in 38.5% of the PPSPC versus 9.1% of the OSPCs (p = 0.019). Overexpression of p53 was found in 30.8% of the PPSPCs and 45.4% of the OSPCs (not significant). There was a significantly worse survival rate for PPSPCs than for OSPCs (p = 0.017), yet none of the studied parameters were significantly correlated with survival within the PPSPC and OSPC groups. The significantly different immunohistochemical expression of ER, PR, Ki 67, and HER-2 in PPSPCs compared with OSPCs suggests that different molecular events may lead to tumorigenesis in these two cancers. PMID- 11603218 TI - Expression of calretinin in human ovary, testis, and ovarian sex cord-stromal tumors. AB - Calretinin, a calcium-binding protein, is primarily expressed in certain subtypes of neurons. It has also been found to be present in mesothelial cells and mesotheliomas but not in many types of carcinomas. Using a polyclonal anti calretinin antibody, we investigated the expression of calretinin immunohistochemically in nonneoplastic human ovaries and testes and ovarian sex cord-stromal tumors (SCSTs). In ovaries, calretinin was expressed in theca interna cells, hilus cells, and scattered individual stromal cells. Oocytes, granulosa cells, theca externa cells, rete ovarii, and most stromal cells were negative. Expression of calretinin was also seen in the ovarian surface epithelium and in collapsed and flat epithelial inclusion glands (EIGs), but not in round, columnar, and ciliated EIGs. In some glands, a transition from calretinin-positive to calretinin-negative epithelium was observed. In postpubertal testes, calretinin was expressed in Leydig cells, but not in germ cells or most rete testes and Sertoli cells. In ovarian SCSTs, strong calretinin staining was seen in all hilus cell tumors (4/4) and the Leydig cell component of Sertoli-Leydig cell tumors (10/10). The Sertoli cell component showed focal weak positivity in 5/10. Fibrothecomas were completely negative (0/8). In granulosa cell tumors, the tumor cells were either completely negative (8/14) or weakly positive at the periphery of the tumor (6/14) while scattered stromal cell staining was seen in 9/14 cases. The expression of calretinin in normal Leydig cells, theca interna cells, the Leydig cell component of Sertoli-Leydig cell tumors, and hilus cell tumors suggests its functional relationship with androgen production. Its pattern of expression in ovarian SCSTs is useful in the differential diagnosis of these tumors. The presence of a transition from calretinin-positive, flat, nonciliated epithelium to calretinin-negative, columnar, ciliated epithelium in the same glands provides strong evidence for mullerian metaplasia. PMID- 11603219 TI - Simultaneous squamous cell carcinomas of the uterine cervix and upper genital tract: loss of heterozygosity analysis demonstrates clonal neoplasms of cervical origin. AB - Five cases of cervical squamous cell carcinoma with synchronous superficial squamous cell carcinoma in the upper genital tract were genetically analyzed to demonstrate the possibility of a clonal neoplastic process. In these cases, the cervical lesions were squamous cell carcinoma in situ (cases 1, 2, and 3) and invasive squamous cell carcinoma (cases 4 and 5). Loss of heterozygosity (LOH) analyses with a panel of microsatellite markers revealed a monoclonal process in four of the five cases. Homogeneous LOH throughout the microdissected lesions was most frequently detected on 6p and 6q (3 cases), followed by 11p and 11q (2 cases), loci known to be commonly lost in typical cervical squamous cell carcinoma. In two cases, genetic progression in terms of additional LOH was found in the upper genital tract but not in the cervix. Most of these squamous cell carcinomas were monoclonal neoplasms originating from the cervical mucosa with subsequent superficial migration of the tumor clone to the upper genital mucosa, and in some cases, genetic progression. PMID- 11603220 TI - Cellular apoptosis susceptibility gene expression in endometrial carcinoma: correlation with Bcl-2, Bax, and caspase-3 expression and outcome. AB - Deregulation of proliferation and apoptosis is known to contribute to neoplastic transformation and growth. Using specific antibodies for the cellular apoptosis susceptibility (CAS) gene, caspase-3, Bcl-2, and Bax, we examined the protein expression in 89 endometrial carcinomas and in 56 samples of nonneoplastic adjacent endometrium for comparison. Immunostaining results were scored with regard to approximate percentage of positive tumor cells (< 10%, 10% to 50%, > 50%) and relative immunostaining intensity (1+, 2+, 3+). In nonneoplastic endometrium, CAS protein was expressed in 70.6%, Bax in 64%, caspase-3 in 52%, and Bcl-2 in 87%. In neoplastic tissue, CAS was present in 93% of the tumors, Bax in 88%, caspase-3 in 77%, and Bcl-2 in 51%. Bcl-2:Bax ratio was > 1 in 9 cases (10%). In cases of atrophy (n = 24) and simple (n = 10) and complex (n = 22) hyperplasia in the adjacent endometrium, lower levels of expression compared with carcinoma were observed for CAS (p = 0.003), caspase-3 (p = 0.034), and Bax (p = 0.04) and higher levels for Bcl-2, although for this protein the results were not statistically significant (p = 0.32). There was no association between immunoscores and FIGO stage. High caspase-3 levels were seen in endometrioid tumor type (p = 0.017). CAS expression was higher in grade 3 tumors (p = 0.002) and older patients (p = 0.013). All tumors of younger patients (< 50 years) were Bcl-2 negative (p = 0.037). Caspase-3 correlated positively with CAS (p = 0.008), Bax (p = 0.04), and low Bcl-2:Bax ratio (p = 0.043), and inversely (as a trend) with Bcl-2 (p = 0.056). Survival analysis (Kaplan-Meier and Cox regression) established a strong association between prognosis and stage, grade, and histologic type (all p < or = 0.0036). In addition, shorter survival was observed for patients whose tumors contained > 50% of positive cells for caspase-3 (p = 0.024) or for CAS (p = 0.04). Age, Bcl-2, Bax, and Bcl-2:Bax ratio did not provide prognostic information. Our results suggest a role of CAS, Bcl-2, Bax, and caspase-3, which are apparently involved in the progressive deregulation of proliferation and apoptosis leading from simple and complex hyperplasia to carcinoma. In addition, CAS and caspase-3 protein levels may be useful markers in predicting the outcome of the patients. PMID- 11603221 TI - Clinicopathologic and immunohistochemical features and microsatellite status of endometrial cancer of the uterine isthmus. AB - To clarify the clinicopathologic, molecular, and immunohistochemical characteristics of uterine isthmic endometrial cancer (UIE), we examined 13 cases of UIE and compared them with 33 cases of endometrial cancer of the uterine corpus (UCE) with respect to clinicopathologic factors, the expression of p53, the estrogen receptor (ER) and the progesterone receptor (PR) status, DNA ploidy, and microsatellite instability (MSI). Five (38.4%) of the UIE patients had stage I, two (15.4%) had stage II, and six (46.2%) had stage III disease (FIGO 1988). Myometrial invasion was confirmed in 92.3% of the UIE patients, and these patients had a higher (p < 0.05) frequency of > 50% myometrial invasion (46.2%) than the patients with UCE (15.2%). Moreover, the UIE patients had a higher frequency of positive peritoneal cytology (p < 0.05) and pelvic lymph node metastases (p < 0.05). No UIE tumors exhibited MSI, and the tumors in these patients had a higher expression of p53 (p < 0.01), a lower expression of ER (p < 0.05) and PR (p < 0.05), and a higher frequency of DNA aneuploidy (p < 0.01) than the UCE tumors. These findings suggest that the UIE is clearly different from UCE in the clinicopathologic, immunohistochemical features, and microsatellite status. PMID- 11603222 TI - Micronized progesterone regulation of the endometrial glandular cycling pool. AB - We sought to determine if micronized progesterone in estrogen-primed women has an effect on the available cycling pool of proliferating glandular cells by studying 107 postmenopausal women who participated in a double-blind cyclical HRT trial. Each received 0.625 mg/day of conjugated equine estrogen (Premarin) orally for 6 weeks (cycle 1), followed by a baseline endometrial biopsy. These women were randomized to one of four doses (100 through 400 mg/day) of progesterone taken the last 10 days of each cycle or to estrogen only. Cyclical HRT (25-day cycles) was continued for three more cycles. Endometrial biopsies were performed at the end of cycle 4 and 64 subjects demonstrated an adequate biopsy for immunohistochemical evaluation. The number of proliferating gland cells was determined by an immunohistochemical stain measuring positive MIB1 staining nuclei per thousand gland cells. The number of proliferating endometrial gland cells in the cycling pool of women receiving 300- and 400-mg daily doses of progesterone was low (mean 4.9 and 1.7, respectively) when compared with women receiving 100 mg progesterone (mean 27.0) or to unopposed estrogen (mean 30.3). Late secretory endometrium from 19 premenopausal women had a mean of 0.6. In the progesterone-treated subjects, biopsies showed that secretory maturation increased as the serum progesterone and doses of progesterone increased. We conclude that micronized progesterone given to estrogen-primed menopausal women results in a dose dependent decrease in endometrial gland proliferation. The use of an immunohistochemical stain and the diagnosis of histologic secretory maturation are complementary techniques in determining the inhibition of glandular proliferation. PMID- 11603224 TI - Peritoneal "melanosis" associated with a ruptured ovarian dermoid cyst: report of a case with electron-probe energy dispersive X-ray analysis. AB - A case of peritoneal "melanosis" due to a ruptured left ovarian dermoid cyst is described. Histology showed that the dermoid contained gastric mucosa associated with ulceration, necrosis, and hemorrhage. The areas of pigmentation within the dermoid, omentum, and peritoneal cavity were due to collections of heavily pigment-laden macrophages. The pigment lacked the histochemical features of either melanin or hemosiderin, but electron-probe energy dispersive x-ray analysis showed that the pigment contained a high concentration of iron. It is postulated that peptic ulceration with hemorrhage is the most likely source of the pigment and that the peritoneal pigmentation is secondary to spillage of the contents of the dermoid cyst. PMID- 11603223 TI - Immunohistochemical expression analysis of inhibin-alpha and -beta subunits in partial and complete moles, trophoblastic tumors, and endometrial decidua. AB - The expression of inhibin-alpha subunit has been described in normal placentas, hydatidiform moles, and trophoblastic tumors. We performed a double immunohistochemical expression analysis of inhibin-alpha and inhibin-beta subunits in a cytogenetically well characterized series of 21 complete and 22 partial hydatidiform moles, 2 placental site trophoblastic tumors, and one choriocarcinoma. Syncytiotrophoblastic cells were consistently inhibin-alpha and inhibin-beta positive in all hydatidiform moles and in the one choriocarcinoma. Cytotrophoblast was negative for both subunits in all trophoblastic lesions studied. While villous intermediate trophoblastic cells were consistently inhibin alpha negative in all hydatidiform moles, focal inhibin-beta immunoreactivity was detected in villous intermediate trophoblast in approximately one third of complete and partial hydatidiform moles. Decidual stromal cells in 40 hydatidiform moles were inhibin-alpha and inhibin-beta positive in approximately one third of cases. Both placental site trophoblastic tumors were inhibin-alpha positive but inhibin-beta negative. Our findings indicate that inhibin-alpha and beta subunits are consistently coexpressed in syncytiotrophoblast in complete and partial moles. Immunohistochemical detection of inhibin subunits may be useful in the differential diagnosis of trophoblastic lesions. PMID- 11603225 TI - Glomus tumor of the ovary: report of a case with immunohistochemical and ultrastructural observations. AB - A 54-year-old woman was found to have a right adnexal mass during routine pelvic examination. A total abdominal hysterectomy and salpingo-oophorectomy were performed. A well circumscribed, 2.5 cm right ovarian was composed of small spindle and epithelioid cells in solid perivascular nests. The tumor cells were reactive for vimentin and smooth muscle actin. Ultrastructurally, pinocytotic vesicles and basement membrane were prominent. This is the second reported case of glomus tumor of the ovary and the third occurring in the gonads. PMID- 11603226 TI - Extrauterine low-grade endometrial stromal sarcoma with florid endometrioid glandular differentiation. AB - Endometrial stromal sarcoma of the uterus (ESS) is a rare lesion that can cause diagnostic difficulty especially when it presents with unusual histologic features such as diffuse endometrioid glandular differentiation. Only three such cases have been reported, all primary in the uterus. We report the first case of an extrauterine low-grade ESS with extensive glandular differentiation that appeared to arise in endometriosis. PMID- 11603227 TI - Primary adenocarcinoma of the vagina arising in endocervicosis. AB - Endocervicosis is a rare condition, being one of the triad of non-neoplastic secondary mullerian lesions. This report describes a primary vaginal adenocarcinoma arising in endocervicosis. Histologic examination showed a mucin secreting adenocarcinoma admixed with benign mucin-containing endocervical-type glands with a transition from dysplastic glands to obvious adenocarcinoma. There were bilateral groin lymph node metastases at presentation and the tumor recurred locally 9 and 12 months after treatment. This is the second reported case of vaginal endocervicosis and the first documented report of adenocarcinoma arising in endocervicosis at any site. PMID- 11603228 TI - Malakoplakia involving the abdominal wall, urinary bladder, vagina, and vulva: case report and discussion of malakoplakia-associated bacteria. AB - A 29-year-old woman presented with a 3-month history of multiple purulent discharging nodules involving her lower abdomen, vulva, and left thigh. Physical examination also disclosed vaginal nodules and a left pelvic mass. Cystoscopy revealed multiple mucosal nodules and a perforation of the left vesical wall that appeared to communicate with the pelvic mass. Biopsies of the vesical and vulvar nodules revealed malakoplakia. Surgery and antibiotic therapy resulted in regression of all the lesions. PMID- 11603229 TI - Pathologic features of uterine leiomyomas following uterine artery embolization. PMID- 11603230 TI - Tularemia, biological warfare, and the battle for Stalingrad (1942-1943). PMID- 11603231 TI - Army clinical investigation of von Hippel-Lindau disease, 1977-2000. PMID- 11603232 TI - Surface temperature of two portable ventilators during simulated use under clinical conditions. AB - During performance testing of portable ventilators, it was noted that an area on the case of one of the devices, the LTV 1000, was noticeably warm. This investigation examined the case temperatures of this portable ventilator and a portable ventilator currently in the Department of Defense inventory, the Uni Vent 754, during simulated clinical conditions. Both have an integral method of producing compressed air. The hottest portion of the cases of the LTV 1000 and the Uni-Vent 754 reached temperatures of 39.9 to 46.7 degrees C and 35.4 to 35.9 degrees C, respectively, across a range of simulated clinical conditions. Investigations have found the risk of burns to increase with temperatures greater than 40 degrees C. The cases of these devices are not designed to be in contact with the skin. Personnel should properly position these and other devices during patient transport and not allow contact with the patient's skin. PMID- 11603233 TI - Interdisciplinary treatment of diabetes mellitus in a military treatment facility. AB - The American Diabetes Association emphasizes interdisciplinary management as the standard of care for patients with diabetes. Many times, however, interdisciplinary means various health care professionals treating a patient but not necessarily interacting with each other regarding the patient's care. Recently, Tripler Army Medical Center replicated the Joslin Diabetes Center's diabetes outpatient intensive treatment program as part of a Joslin Diabetes Center/Department of Defense/Veteran's Administration research collaboration. Tripler Army Medical Center named this interdisciplinary program Holopono, which is Hawaiian for success. Holopono is a team of health care professionals providing integrated care and education to a group of diabetes patients over 3.5 days. Individual care management, aided by an Internet-based telemedicine system, then continues for 1 year after entry into the program. This article describes the Holopono program, the role of each team member, and how the team functions together to provide comprehensive diabetes care. PMID- 11603234 TI - Comparison of oxygenated perfluorocarbon and humidified oxygen for rewarming hypothermic miniswine. AB - This study examines a method to rapidly rewarm the core using total liquid ventilation with warmed, oxygenated perfluorocarbon. Yucatan miniswine were splenectomized and surgically implanted with telemetry devices to transmit electrocardiographic response, arterial pressure, and core temperature. Hypothermia (core temperature = 25.9 +/- 1.3 degrees C) was induced by placing cold-water circulating blankets over the animals. Control animals (N = 7) were rewarmed using warm (37.8 degrees C), humidified oxygen. Experimental animals (N = 6) were rewarmed with oxygenated perfluorocarbon liquid (37.3 degrees C). The time to rewarm was significantly shorter in experimental animals (1.98 +/- 0.5 vs. 8.61 +/- 1.6 hours, p < 0.0001), with almost no afterdrop in the experimental group. Lactate dehydrogenase and aspartate aminotransferase were significantly increased in the control animals compared with the experimental animals. All animals that survived being chilled to 25 degrees C survived rewarming. This method may provide a means of more rapidly rewarming profoundly hypothermic victims while reducing the risks associated with current methods. PMID- 11603235 TI - Viral hepatitis in the U.S. military: a study of hospitalization records from 1974 to 1999. AB - Viral hepatitis remains a health threat for military forces. Most recently, there has been concern about hepatitis C virus transmission during military service because a high prevalence of hepatitis C virus infection has been found in some U.S. veteran populations. In this study, hospitalizations of active duty U.S. military personnel for hepatitis were evaluated using standardized computer records. Only the first hospitalization was assessed during the period January 1, 1989, to December 31, 1999. Among active duty forces, the rate of hospitalization for all types of acute hepatitis declined from 13 to 1.1 per 100,000 personnel from 1989 to 1999. Males, nonwhite racial/ethnic groups, and older troops were more likely to be hospitalized for acute hepatitis. This study's finding of declining rates of acute hepatitis is a continuation of a trend observed since 1974. The decreasing risk of viral hepatitis in the U.S. military is attributable to several factors, including reduced levels of injection drug use because of routine, randomized drug testing. PMID- 11603236 TI - Pharmacist-managed hypertension therapy conversion. AB - The cost of treating hypertension represents a substantial percentage of total pharmacy expenditures at medical centers and by managed care organizations in the United States. The present study evaluated improvements in blood pressure control and cost savings achieved by switching 543 hypertensive patients from nifedipine gastrointestinal therapeutic system (GITS) to amlodipine and concurrently instituting an educational program directed at prescribers, nursing and pharmacy staff, and patients and family members. Before the switch, 543 patients were being treated with nifedipine GITS: 259 with 30 mg/d, 209 with 60 mg/d, and 75 with 90 mg/d. The total annual cost of primary antihypertensive therapy for this patient population was $184,698. All patients were switched from nifedipine GITS to 5 mg of amlodipine. The pharmacist saw patients at the time of the switch and at 2, 4, and 6 to 8 weeks after the change in antihypertensive therapy. Patients who did not achieve systolic blood pressure < or = 140 mm Hg or diastolic blood pressure < or = 90 mm Hg by 6 to 8 weeks after the switch were titrated to 10 mg/d amlodipine. After the conversion, 417 patients were receiving amlodipine 5 mg/d and 126 patients were ultimately titrated to 10 mg/d. Measurements made during the first 6 to 8 weeks of treatment indicated that amlodipine therapy significantly reduced blood pressure. Overall, amlodipine produced further mean reductions in blood pressure, from 140/82 to 130/76 mm Hg (p < 0.00005). The mean reduction from the time of the switch to 6 to 8 weeks was from 138/81 to 129/74 mm Hg for the patients who received 5 mg/d amlodipine (p < 0.00001) and from 147/85 to 133/79 mm Hg for the patients ultimately titrated to 10 mg/d amlodipine (p < 0.05). The total annual cost for primary antihypertensive therapy after the conversion was $136,854. We observed that conversion from nifedipine GITS to amlodipine enhanced blood pressure control and saved $47,844 in the annual cost of primary antihypertensive medication. For the 543 patients undergoing the switch, annual cost savings was $47,844. When the cost of additional antihypertensive agents discontinued after the switch to amlodipine was added to the analysis, the net annual cost savings increased to $49,578, a 27% reduction in yearly drug costs. PMID- 11603237 TI - Risk propensity assessment in military special operations. AB - Risk taking, decision making, and stress factors are strongly associated in military operations. The authors used the Bond and Lader mood and alertness scale and a new scale, Evaluation of Risks (EVAR), to assess risk proneness in a maritime counter-terrorism exercise. EVAR items are distributed among five factors: self-control, danger seeking, energy, impulsiveness, and invincibility. In the study, 10 pilots were submitted to strenuous night flights with limited sleep deprivation. Compared with baseline data, pilots reported an increase in impulsiveness, whereas EVAR factors were consistent in a control group composed of 9 navy crew member. Correlations were observed between mood and alertness and risk factors. These results illustrate how EVAR can be used to evaluate change in risk proneness in individuals submitted to various stressors. But further studies are required to weigh stress factors and environmental conditions in risk propensity with a larger population of various age and personality traits. PMID- 11603239 TI - Developing a quick reference formulary. AB - The establishment of the Department of Defense Basic Core Formulary was an attempt by the Department of Defense to equilibrate its pharmacy benefit among military treatment facilities. Department of Defense military treatment facilities are required to make available to beneficiaries items on the Basic Core Formulary. Military treatment facilities may augment the Basic Core Formulary through local pharmacy and therapeutic committee actions that result in different formularies among military treatment facilities. Formulary differences among military treatment facilities also arise because the Coast Guard, which is under the jurisdiction of the Department of Transportation in peacetime, is not required to adhere to the Basic Core Formulary at present. Because of formulary differences, most military treatment facilities make available abbreviated, quick reference versions of their formularies to patients. This article describes the development of a quick reference formulary at a Coast Guard military treatment facility pharmacy. PMID- 11603238 TI - Primary care outcomes and provider practice styles. AB - The purpose of this study was to evaluate change in patient outcomes as a function of practice styles of primary care providers. A prospective, repeated measures, correlational design was used. Data were collected about (1) providers' self-ratings of practice styles, inclusive of practice model, confidence, autonomy, collaboration, information giving, and job satisfaction, and (2) primary care patients' self-ratings of health status, functional status, information seeking, and satisfaction. When severity and comorbidity were controlled, physicians, nurse practitioners, and physician assistants produced equivalent outcomes; neither practice style nor provider type resulted in differences in health outcomes of primary care patients. Practice style did affect patient satisfaction. Patients were least satisfied with providers who scored high on collaboration and most satisfied with providers who scored low on the practice model. Neither provider type nor interpersonal attributes had an effect on health outcomes; sicker patients got better and healthy patients stayed that way. PMID- 11603240 TI - Susceptibility to maladaptive responses to stress in basic military training based on variants of temperament and character. AB - The purpose of this study was to compare the relationship of Temperament and Character Inventory (TCI) scores of three groups of U.S. Air Force basic trainees. The following groups were used: those who were psychiatrically hospitalized, a control group, and a group identified as being at risk for early separation from basic training because of psychological reasons. The instrument used was the TCI. The data were analyzed with analysis of variance, Tukey post hoc comparisons, and stepwise backward discriminant analysis. The controls were found to have healthier temperament and character profiles than both the at-risk (p < 0.01) and hospitalized (p < 0.01) groups. No difference was found between the at-risk and hospitalized groups on TCI scores. The TCI was found to successfully predict 82% of controls, 25% of at-risk, and 64% of hospitalized recruits. Risk factors for maladaptive responses to stress and possible ways of primary prevention are presented. PMID- 11603241 TI - Personality type and success among female naval academy midshipmen. AB - There are relatively few studies regarding factors that predict success among female midshipmen at the U.S. Naval Academy (USNA). This study examined the personality characteristics of 1,568 women admitted to USNA between 1988 and 1996 to evaluate whether personality type was predictive of success vs. attrition. Participants completed the Myers-Briggs Type Indicator as well as a demographic questionnaire upon admission. Indicators of performance were gathered at graduation. Results indicated that most women at USNA are extroverts. Extroverted Sensing-Thinking-Judging types were more likely to graduate, whereas Feeling and Perceiving themes were associated with dropping out. Previous military service and higher Scholastic Aptitude Test Math scores were also predictive of success at USNA. In general, the Myers-Briggs Type Indicator was not a good predictor of academic or military success at USNA. Among women who graduate, Scholastic Aptitude Test (Verbal and Math) scores appear to be the best predictors of both academic and military ratings. PMID- 11603242 TI - Mental and physical health and acculturation among Hispanic Vietnam Veterans. AB - This study tested the associations between acculturation and mental and physical health among Hispanic Vietnam veterans. Secondary data analyses of the National Vietnam Veterans Readjustment Survey, an epidemiological study of a representative sample of veterans who served during the Vietnam era (N = 1,195), were conducted. An acculturation index was constructed using standard acculturation measures (range, 0-13), and its predictive validity was tested using nine outcome measures of physical health and eight measures of mental health. Among Puerto Rican and Mexican-American veterans, the scores on the acculturation index ranged from 0 to 12. Hispanic veterans were distributed across the acculturation continuum as follows: 0 to 3 (24%), 4 to 7 (59%), 8 to 12 (17%). The acculturation scores were not associated with mental or physical health risks for Hispanic veterans. Mexican Americans and Puerto Ricans did not differ in mental or physical health risk compared with non-Hispanic whites. The association between acculturation and mental and physical health among Hispanics may not be generalized to Hispanic veterans. Hispanics who have been through an intensive assimilating experience, such as being in the military, appear to have health outcomes similar to whites. PMID- 11603243 TI - Do post-traumatic stress disorder symptoms worsen during trauma focus group treatment? AB - Male inpatient veterans with chronic combat-related post-traumatic stress disorder (PTSD) participated in trauma focus group treatment and were assessed immediately before group participation and after group completion at time of discharge. Standard measures of core PTSD symptoms, depression, and anxiety were used. In addition, changes in PTSD symptoms were tracked on a weekly basis for the duration of group participation. Results indicated that a single direct elicitation of war-related traumatic memories in a group setting was not associated with symptom worsening. However, veterans also did not show improvement in symptoms severity. Possible reasons for this lack of impact are discussed along with implications for future treatment design and evaluation. PMID- 11603244 TI - Cigar and pipe smoking in the U.S. military: prevalence, trends, and correlates. AB - This article examines the prevalence, trends, and correlates in cigar/pipe smoking and their relation to cigarette smoking among active duty U.S. military personnel. An examination of the trends in cigar/pipe smoking was conducted with data from 1985 to 1998, and predictors of smoking were determined for 1998. Rates of cigar/pipe smoking declined from 1985 until about 1992 and then began to increase. From 1995 to 1998, there was a 75% increase in the prevalence of cigar/pipe smoking. Greater prevalence of cigar/pipe smoking was associated with male gender, younger age, relatively favorable beliefs and values toward smoking, and being a current cigarette smoker. Findings indicate a notable increase in past-year cigar/pipe smoking. These findings suggest that military tobacco prevention and early intervention programs would benefit from including components that deal specifically with cigar and pipe use in addition to cigarette smoking. PMID- 11603245 TI - A 38-year-old staff sergeant with fevers, chest pain, and shortness of breath. PMID- 11603246 TI - Acute management of exposure to liquid ammonia. AB - Ammonia injury is an uncommon injury, but it is associated with high morbidity and mortality. This case report demonstrates the pathophysiology and treatment of both cutaneous burn wounds and inhalation injury caused by ammonia. Frequent bronchoscopy was used to attempt to avoid intubation and its associated morbidity. The patient remained extubated, but later he required skin grafts to close his wounds after healing of his pulmonary injury. A review of the management of inhalation injury is also discussed. Ammonia injury can cause a severe inhalation injury. Bronchoscopy can be a useful tool to avoid intubation. PMID- 11603247 TI - Heterotopic bone in the ovary associated with a mucinous cystadenoma. AB - Bone formation in the ovary, with the exception of developing in the setting of a mature cystic teratoma, is exceedingly uncommon. We report a case of bone formation within a mucinous cystadenoma of the ovary. A 19-year-old active duty female presented with an asymptomatic pelvic mass; sonographic imaging revealed a 5.7-cm complex right adnexal mass. A laparoscopic cystectomy was performed. Pathologic evaluation of the cyst revealed a mucinous cystadenoma. Contained within several of the thick fibrous septae were areas of well-formed bone. Although a benign finding, bone formation and associated fibrosis may lead to sonographic findings of concern during the evaluation of patients with a pelvic mass. PMID- 11603248 TI - Transient vestibular balance dysfunction after primary blast injury. AB - Explosive munitions are used routinely in support of military operations. Moreover, service personnel are increasingly being deployed to regions where active conflict, terrorism, and land mines pose significant threats. Despite aggressive protective measures and safety practices, blast injury is an inherent risk. In contrast to secondary and tertiary blast injuries, primary blast injuries are generally limited to the air-filled organs of the respiratory, gastrointestinal, and auditory systems. We report the case of a Marine who entered the back-blast arc of a shoulder-launched multipurpose assault weapon at close range. Despite the magnitude of the blast, he sustained none of the classic findings suggestive of severe primary blast injury. However, he manifested unique vestibular balance abnormalities that precluded his return to full duty for several months. This suggests that personnel who sustain even a mild traumatic brain injury with vestibular manifestations may need prolonged observation and modified duty in certain military occupational specialties. PMID- 11603249 TI - The clinical experience of citalopram in the treatment of post-traumatic stress disorder: a report of two Persian Gulf War veterans. AB - OBJECTIVE: To determine the efficacy of the antidepressant citalopram in the treatment of post-traumatic stress disorder (PTSD). METHOD: The cases of two Persian Gulf War veterans are described to illustrate the effects of citalopram in treating their PTSD symptoms. RESULTS: In these two clinical case studies, citalopram led to remission of some of the PTSD symptoms. CONCLUSION: More controlled studies are warranted to further prove the efficacy of citalopram as an agent of choice for the treatment of PTSD. PMID- 11603250 TI - Prevention of hepatitis B infections: vaccination and its limitations. AB - Infection with hepatitis B virus has become a vaccine-preventable disease. The recombinant hepatitis B vaccines available today are safe and immunogenic. In order for these vaccines to eradicate HBV a universal vaccination of neonates and/or children needs to be implemented. Major obstacles on the road to global hepatitis B vaccination are poverty and scarcity of human resources in those parts of the world who are most badly in need of these vaccines. Despite their proven immunogenicity hepatitis B vaccines are unable to induce an adequate immune response in 5-10% of healthy adults. The non-responsiveness of these subjects is a selective phenomenon and not the expression of a general immune deficiency. Studies that correlated the HLA haplotype of vaccine recipients with their anti-HBs response patterns has led to the identification of markers of good and non/poor response. Universal vaccination of neonates and children has elicited questions about the durability of antibody persistence and the need for booster doses later in life. The European Consensus Group on Hepatitis B Immunity has proposed a series of recommendations that are summarized in this review. PMID- 11603251 TI - Age trend in hepatitis C virus genotype distribution as seen in a Brussels teaching hospital. AB - The hepatitis C virus genotype distribution was studied among age groups in 501 referred patients with chronic hepatitis C by INNO-LiPA HCV II (Innogenetics, Belgium). Ten patients had coinfection with several genotypes. Two hundred seventy of 491 singly infected individuals (57%) had 1b, 66 (13.4%) 3a, 57 (11.6%) 1a. HCV subtype 1b was predominant but its prevalence increased with age (76.5% of patients born in the '20s, 39.3% in the '70s) (P < 0.0001). Three possibilities could explain the shift towards a wider variety of genotypes in younger age. (1) 1b could be the original subtypes in this population, (2) the non-1b subtypes could give less chronic carriers, (3) the non-1b subtypes could have a higher mortality, which seems improbable. The 1b genotype seems the oldest subtype in our country while others were imported later through increased population movements and changing habits. PMID- 11603252 TI - The antibiotic and anti-inflammatory treatment of bacterial meningitis in adults: do we have to change our strategies in an era of increasing antibiotic resistance? AB - Community acquired bacterial meningitis remains a feared infection because of its high morbidity and mortality. During the last decade, the incidence and the microbial resistance patterns of pathogens causing bacterial meningitis have changed considerably. A sharp increase in meningococcal disease has been observed and meningitis caused by penicillin resistant Streptococcus pneumoniae emerged as a matter of major concern. Since pneumococcal resistance in Belgium to third generation cephalosporins remains rare and low level, addition of vancomycin to the initial empirical therapy including third generation cephalosporins is not yet necessary. However, the evolution of the resistance patterns of invasive S. pneumoniae should be followed very carefully. The emergence of penicillin resistant pneumococci also raises concern about the safety of adjuvant anti inflammatory therapy with dexamethasone. Although there is a growing evidence suggesting a decrease of neurological complications after administration of adjuvant dexamethasone, this therapy may lower the already borderline penetration through the blood-brain barrier of the currently used antibiotics. This may result in therapeutic failure. We therefore presently do not advocate the routine use of dexamethasone in the therapy of adult bacterial meningitis. PMID- 11603253 TI - IgE-mediated food allergy--extensive review of the literature. AB - Adverse reactions to food, i.e. food allergy and intolerance have gained considerable attention. This overview focuses on the diagnosis and management of IgE-mediated food allergy that is believed to be responsible for most immediate type food-induced hypersensitivity reactions. Clinically, these reactions are characterised by a variety of signs and symptoms that occur within minutes or hours after consumption of the offending food. Reactions may be limited or more generalised with involvement of the skin, nose, eyes, and/or lungs. In more severe cases, cardiovascular symptoms including hypotension, shock, cardiac dysrhythmias and death can occur. In food-allergic individuals, IgE is produced against naturally occurring food components, primarily glycoproteins that usually retain their allergenicity after heating and/or proteolysis. While adults tend to be allergic to fish, crustaceans, peanuts and tree nuts, children tend to be allergic to cow's milk, egg white, wheat and soy more frequently. "Emerging" food allergens include tropical fruits, sesame seeds, psyllium, spices and condiments. These allergies frequently represent a cross-allergy to an allergen derived from another source, e.g. pollens or natural rubber latex. The evaluation of IgE mediated food allergy relies on a careful history, physical examination, appropriate skin testing or in vitro testing with food extracts, and/or double blind, placebo-controlled food challenges. Avoidance remains the mainstay of therapy. However, allergens may be "hidden" and labelling can be non-precise or misleading, thereby severely hampering prevention. Patients with severe allergies should keep at hand an emergency kit with adrenaline, an antihistamine and an injectable rapid onset-of-action corticosteroid. At present there is no evidence to support the use of immunotherapy, except for research purposes. Production of "hypoallergenic" food is hampered by incomplete methods for assessing the allergenic potential of such novel foods. PMID- 11603254 TI - Gitelman's syndrome: an overlooked cause of chronic hypokalemia and hypomagnesemia in adults. AB - In 1966, Gitelman described a benign variant of classical Bartter's syndrome in adults characterized by consistent hypomagnesemia and hypocalciuria, hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism with normal blood pressure. A specific gene has been found responsible for this disorder, encoding the thiazide-sensitve Na-Cl coporter (TSC) in the distal convoluted tubule. Mutant alleles result in loss of normal TSC function and the phenotype is identical to patients with chronic use of thiazide diuretics. Gitelman's syndrome is a more common cause of chronic hypokalemia than Bartter's syndrome, with which it is often confused. The distinguishing features between both syndromes are discussed. PMID- 11603255 TI - Recurrent immuno-allergic hepatitis related to amoxicillin-clavulanic acid. AB - We report on a patient who presented, on 2 occasions at one-year interval after a treatment with the amoxicillin-clavulanic acid association, a clinical and biological picture in keeping with the diagnosis of immuno-allergic hepatocellular hepatitis. On liver biopsies, the most characteristic finding was portal and lobular eosinophilic infiltration without cholestasis and biliary ducts damage. PMID- 11603256 TI - Fatal overdose with trazodone: case report and literature review. AB - A fatal case of suicide with trazodone alone in a 40-year-old patient is reported. Life-threatening arrhythmias, such as torsades de pointes and complete AV block, are recorded. Blood collected at admission contained a trazodone toxic concentration of 25.4 micrograms/mL. The patient developed multiple organ failure and died less than 24 hours after his admission to the emergency department. The authors discuss the effects of overdose of trazodone, a well-known safe antidepressant drug. PMID- 11603257 TI - "Nothing specific, nothing human": the life and work of Piet Mondrian. PMID- 11603258 TI - Paul Klee: art, potential space and the transitional process. PMID- 11603259 TI - Civilization and its discontents: an ongoing update. Part 2: Homophobia in men. PMID- 11603261 TI - Mysticism and psychoanalysis. PMID- 11603260 TI - The psychoanalysts' nose. PMID- 11603262 TI - [Medicine in ancient Egypt, a fascinating level of modernity]. AB - Our knowledge about ancient Egyptian medicine (throughout more than three millennia) comes from some papyri, as those of Ebers and Smith, thousands of mummies or skeletons and multiple temples and tumbs decorations. Doctors were initially priests and embalmers which explain their good level in anatomy. The most famous of all, imhotep, who was also architect and minister, became a god of medicine. First hospitals developed from temples. Modern investigation tools are useful for studying on human remains the most prevalent diseases at these times which are comparable with our current medical problems. An increasing number of scientific data, which some examples are reported herein, argue in favor of a fascinating level of advancement of ancient Egyptian medicine in the field of diagnosis and therapy. PMID- 11603263 TI - [Public interest and service budget]. PMID- 11603264 TI - [Cognitive aging in chronic psychotic patients]. AB - OBJECTIVE: The cognitive aging of psychotic patients is still poorly apprehended and sometimes wrongly compared with demential or pseudo-demential deterioration. We studied the impact of chronic psychosis on cognitive performance in the elderly. PATIENTS AND METHODS: We estimated cognitive performance in two groups of 15 patients each among persons on old-age pensions or living in geriatric nursing homes. One group included patients who had already showed dissociative or non-dissociative chronic psychosis and the other group persons with no previous psychotic signs. Cognitive estimations were made on the basis of Folstein's Mini Mental State (MMS) score and Signoret's Battery of Cognitive Efficacy (BEC 96). Results obtained in the two groups were compared with the Mann and Whitney non parametric test. RESULTS: The psychiatric patients showed a significant deficiency compared with the others for memory and executive functions and also a much broader range of scores on the BEC96 that demonstrated deficiency among the psychiatric patients. DISCUSSION: Though these findings must be interpreted with caution, they do demonstrate a trend similar to that observed in young schizophrenics and also to that of the cognitive performances observed in older schizophrenics and demented subjects. Patients with dissociated or non dissociated psychotic disorders show an apparent relative cognitive deficiency irrespective of age. The psychotic elderly appear to exhibit a cognitive clash much more than a simple pseudo-demential deficiency. PMID- 11603266 TI - [Cardiac beriberi of non-alcohol-induced nutritional origin]. PMID- 11603265 TI - [Idiopathic segmental infarct of the omentum. Differential diagnosis in an obese patient]. AB - OBJECTIVE: Infarction of the greater omentum is a rare etiology of acute abdominal pain. The differential diagnosis, especially with appendicitis, is difficult to establish. CASE REPORT: A 29 years-old male presented with acute abdominal pain. He underwent a laparoscopic resection on the 5th hospital day because of persistant pain despite conservative management. Histopathological examination confirmed the diagnosis of omental infarction. DISCUSSION: Primary segmental necrosis of the omentum is a rare entity. Obesity and cardiovascular diseases are considered predisposing conditions. The infarctions tend to occur in the right side of the omentum. Abdominal pain is predominant in opposition to the patient's good general condition. Laboratory results are usually nonspecific. Abdominal ultrasound may show a solid, ovoid, hyperechoic lesion. CT-scan may depict a fatty oval-shaped mass below the right anterolateral parietal wall associated with a thickening of the anterior parietal peritoneum. CONCLUSION: The correct diagnosis of omental infarction is important to establish preoperatively in acute abdominal pain, as in uneventful courses surgery can be avoided. PMID- 11603267 TI - [Arthralgia induced by large doses of verapamil]. PMID- 11603268 TI - [Pericardial tamponade unmasking systemic lupus erythematosus]. PMID- 11603269 TI - [Role of local immunity in invasive pulmonary aspergillosis]. AB - A LEADING CAUSE OF MORTALITY: Inhalation of fungal spores may cause infection and/or inflammation, which is dependent on the nature of the fungus as well as the individual's immune status. Aspergillus fumigatus is responsible for a dramatic pathology, invasive aspergillosis (IA). IA has become a leading cause of death, mainly among bone marrow transplantation or solid-organ recipients, but also among AIDS patients. IMMUNE RESPONSE: The diversity of immune failure suggests that many lines of immunity are implicated in the A. fumigatus elimination process. Non specific immunity plays a major role in the defence against A. fumigatus, including three major lines: anatomical barriers, humoral components, phagocytic cells. But acquired immunity plays a role with different T cell subsets and their associated cytokines. FUNGUS-HOST RELATIONSHIPS: The relationship between the fungus and its host is complex and could be again study to improve the prevention and the treatment of IA. The aim of this review is a synthesis of the knowledge about the immunity response against Aspergillus fumigatus in IA. PMID- 11603270 TI - [Critical ischemia of the leg. A technique for distal anastomosis in a a small caliber artery]. AB - CRITICAL ISCHEMIA OF THE LOWER LIMBS: This type of lesion, which spontaneously progresses to gangrene and amputation, is encountered more and more frequently. Emergency endoluminal revascularization or bypass surgery is required. When conventional endoluminal techniques cannot be used, a distal graft using the autologous saphenous vein is a promising alternative to achieve patent vascularization and salvage the limb. IF VENOUS MATERIAL IS NOT AVAILABLE: Usable venous material is not always available due to varicosities, thrombus formation, small size or previous surgery (stripping, coronary surgery, prior revascularization procedure); rates reported range from 20 to 40%. For such patients, other veins (external saphenous, arm veins, superficial femoral veins) may be useful but are not always appropriate for distal repair. Different prostheses might also be used but again do not always provide improved permeability. Most teams however use a polytetrafluoroethylene stent for revascularization of the distal leg. Different technical improvements favor success of prosthetic bypasses, but when used below the knee, flow remains less satisfactory than with venous bypasses. VEIN CUFFS: This procedure is a common adjuvant technique positioning a venous cuff between the recipient artery and the prosthesis. The cuff avoids the direct contact between the prosthesis and the fragile artery that is often difficult to suture. RESULTS: Several series have demonstrated that the rate of success of vein cuff procedures remains lower than venous bypass procedures, but also that flow is better than with simple femorotibial prostheses. PATHOGENIC HYPOTHESES: The reduction of the neo-intimal hyperplasia observed in experimental models is insufficient to explain entirely the observed in vivo benefit. The fact that the suture is easier to make is one possible reason. Indeed the rate of failure of simple prosthetic bypass surgery is high in the immediate postoperative period. These cases of thrombosis result from technical insufficiencies and are undoubtedly overcome by the use of the venous cuff. PMID- 11603271 TI - [Managing vertigo and vertigo syndromes in the elderly]. PMID- 11603272 TI - [Introduction of Synercid]. PMID- 11603273 TI - [Epidemiological context: microbiological value of Synercid]. AB - MECHANISM OF ACTION: Synercid', an antibiotic designed around the concept of molecular synergism, is composed of 70% dafopristin or spectrogramin A and 30% quinupristin or spectrogramin B. First, dafopristin binds to the ribosomal 50S unit changing the conformation of the ribosome. This increases the affinity of quinupristin that in turn binds to the bacterial ribosome. This double binding interrupts protein synthesis and blocks bacterial growth. ACTIVITY: In vitro, Synercid is particularly active against Gram positive cocci, irrespective of the strain's resistance phenotype. It is notably active against meti-sensitive and meti-resistant S. aureus, S. pneumoniae, S. pyogenes and Enterococcus faecium. MECHANISMS OF RESISTANCE TO MACROLIDES/LINCOSAMIDES/STREPTOGRAMINS: The most frequently encountered mechanism is a modification of the ribosomal target. Two other mechanisms can also be operating: enzyme inactivation or efflux phenomenon. Another mechanism of resistance, LSA phenotype, remains poorly understood. Only a very small proportion of the patients are concerned by resistance (9 patients in a study enrolling 880 patients). PMID- 11603274 TI - [Experimental models: interactions Synercid and beta-lactam antibiotics]. AB - SYNERCID ALONE IN A RAT MODEL OF EXPERIMENTAL ENDOCARDITIS: Trials conducted using 2 injections daily showed that animals infected with meti-R resistant Staphylococcus aureus strains sensitive to erythromycin were cured in 3 days. The same is not true for infections caused by C-MLSB-R staphylococci. The daily dose cannot be increased due to the venous toxicity of Synercid, leading to the idea of testing Synercid in combination with other antibiotics. IN VITRO STUDIES: Several antibiotics have been tested in combination with Synercid. Several beta lactams have been shown to exhibit an additive or synergetic effect on a collection of meti-R and meti-S S. aureus strains. IN VIVO STUDIES: In animals infected with C-MLSB-R meti-R S. aureus, the combination Synercid + cefepime increases the activity of cefipime and prevents selection of beta-lactam highly resistant strains. The results obtained with the Synercid + cefpirome combination are even more eloquent. Finally, Synercid, alone or in combination with these 2 cephalosporins, does not select resistant strains. PMID- 11603275 TI - [Value of Synercid in clinical practice: from temporary approval to clinical trial authorization]. AB - NOSOCOMIAL PNEUMONIA DUE TO GRAM-POSITIVE COCCI: In a randomized multicentric trial comparing Synercid with vancomycin, the cure rate (56.3% vs 58.3%) were equivalent in the 2 treatment arms. Treatment failures were also similar: 44% vs 42%. Mortality (25% vs 22%) was likewise comparable, as was tolerance. SKIN AND SOFT TISSUE INFECTIONS: For erysipela, infections requiring surgical dissection, post-trauma infections, postoperative wound infections, or diabetes-related infections, the rate of success obtained in 2 open randomized comparative multicentric trials was equivalent in the 2 treatment arms: 68.2% for Syncercid, 70.7% for the compared treatments. EMERGENCY PRESCRIPTION: For E. faecium, the success rate was 74% based on clinical assessment and 70.5% based on bacteriological assessment. For meti-S S. aureus infections, the clinical success rate was 74% for all patients and 80% for bacteriologically evaluable patients; the bacteriological success rate was 74% and 71% respectively. In case of infection due to C-MLSB meti-R S. aureus, the percentage of clinical success was 89% for bacteriologically evaluable patients. PMID- 11603277 TI - Traditional herbal medicine, pharmacology and complementary alternative medicine (CAM): a preface to this special issue on herbal drugs. PMID- 11603276 TI - [Experimental models: interaction of Synercid with other anti-Gram positive agents]. AB - EXPERIMENTAL DATA: In case of resistance to quinupristin, the bacteriostatic synergism is preserved but the in vivo bactericidal effect of Synercid declines. On the other hand, no selection of resistant mutants has been observed. In case of isolated resistance to dafopristin, there is no reduction in the bactericidal effect of Synercid; there is however a possible risk of selecting resistant mutants. To become resistant to Synercid, S. aureus strains have to become resistant to both quinupristin and dafopristin, a highly unlikely situation. POTENTIAL COMBINATIONS: Among the combinations of Synercid with other antibiotics, the combination with vancomycin would have particular interest for clinical applications, increasing bactericidal activity. This would be the case for severe S. aureus infections with a large inoculum and even more so for meti-R resistant strains with a C-MLSB phenotype. Combination with rifampicin would be another possibility, but only for strains not resistant to quinupristin. PMID- 11603278 TI - Can coffee help fighting the drug problem? Preliminary results of a Brazilian youth drug study. PMID- 11603279 TI - Endocannabinoid immune and vascular signaling. PMID- 11603280 TI - Cardiovascular actions of Radix Stephaniae Tetrandrae: a comparison with its main component, tetrandrine. AB - A comparison of the cardiovascular actions of the extract of Radix Stephaniae Tetrandrae (RST), the root of a Chinese hero Stephania tetrandra S Moore, in rats with those of tetrandrine (Tet), the best known active component of RST was reviewed. The RST extract inhibits Ca2+ influx into the myocyte and reduces protein release during reperfusion with a Ca2+ containing solution following perfusion with a Ca2+ free solution (Ca2+ paradox), and arrhythmia during reperfusion in the isolated perfused heart. It also reduces the infarct size induced by ischemia/reperfusion in vitro and in vivo. In addition, the RST extract suppresses elevation of arterial blood pressure in DOCA-salt hypertensive rats. It does not further reduce the heart rate and coronary flow significantly during myocardial ischemia. The effects are similar to those of Tet. When compared with the same doses of Tet alone, the RST extract, of which 9% is Tet, produces equally potent effects on infarction, arrhythmias, coronary flow and heart rate, and has a greater inhibitory effect on protein release during Ca2+ paradox. The combination at 1:1 ratio of Tet and fangchinoline (Fan), another main component, which constitutes 6% of the RST extract and has no significant effects on the heart, produces comparable effects on protein release during Ca2+ paradox as Tet alone. The observations suggest that the efficacy of the RST extract cannot be accounted for by Tet alone. Some of the effects may be due to an interaction between the components of the extract. The RST extract also produces similar effects as verapamil, a prototype Ca2+ channel antagonist widely used in the treatment of ischemic heart diseases and hypertension, except that verapamil, at 1 mumol/L, a concentration that produces similar cardiac effects as the RST extract, further reduces heart rate significantly during ischemia. So the RST extract may be a therapeutically better agent in the treatment of ischemic heart diseases and hypertension than Ca2+ channel antagonists because of the absence of the inhibitory effect on heart rate during myocardial ischemia. PMID- 11603281 TI - Salvia miltiorrhiza and ischemic diseases. AB - The demonstration of beneficial effects of salvia miltiorrhiza (DanShen) on ischemic diseases has revolutionized the management of angina pectoris, myocardial infarction (MI) or stroke in Chinese society. Experimental studies have shown that DanShen dilated coronary arteries, increased coronary blood flow, and scavenged free radicals in ischemic diseases, so that it reduced the cellular damage from ischemia and improved heart functions. Clinical trials also indicated that DanShen was an effective medicine for angina pectoris, MI, and stroke. This review will focus on DanShen's effects in angina pectoris, MI and stroke. PMID- 11603282 TI - Effect of Korean red ginseng on blood pressure and nitric oxide production. AB - AIM: To investigate the effect of crude saponin and nonsaponin fraction of Korean red ginseng (KRG) on the blood pressure and nitric oxide (NO) production in the conscious rats and cultured endothelial cell line, ECV 304 cells. METHODS: Systolic blood pressure and heart rate were monitored in the conscious rats. Nitric oxide levels and the expression of nitric oxide synthase were measured by a spectrophotometric assay using Griess reagents and Western blotting, respectively. Nitric-oxide synthase activity was measured based on the conversion rate of [3H]arginine to [3H]citrulline. RESULTS: Systolic blood pressure was decreased by crude saponin (100 mg/kg, i.v.) of KRG in the conscious control and one-kidney, one-clip Goldblatt hypertensive (1K, 1C-GBH) rats. The hypotensive effect induced by crude saponin of KRG reached maximum at 2-4 min and slowly recovered after 20 min to the initial level in both groups. Crude saponin of KRG induced tachycardia in the conscious rats but induced bradycardia in the anesthetized rats. In contrast to crude saponin of KRG, hypotensive effect induced by saponin-free fraction was minimal. Nitric oxide concentrations were increased by the treatment of crude saponin in conscious rats as well as in the cultured ECV 304 cells. The protein expression level of endothelial constitutive nitric-oxide synthase (eNOS) in the aorta of rats was not increased by crude saponin (100 mg/kg, i.p. for 3 d). However, nitric-oxide synthase activity was increased by crude saponin of KRG in the aortic homogenate of rats. CONCLUSION: The hypotensive effect of red ginseng is mainly due to saponin fraction of KRG in the conscious rats, and this effect may be due to an increase in the nitric-oxide production by KRG. PMID- 11603283 TI - Effects of Panax notoginseng saponins on vascular endothelial cells in vitro. AB - AIM: To investigate the inhibition of endothelium-dependent in vitro vascular relaxation induced by the total saponins (gensenosides) from Panax notoginseng (PNS) and the effect of PNS on the cytosolic Ca2+ concentration on cultured bovine pulmonary artery endothelial cells. METHODS: The endothelial-dependent vascular relaxation was assessed using acetylcholine (ACh) or cyclopiazonic acid (CPA) induced relaxation in endothelium-intact rat aorta. Cytosolic Ca2+ level was assessed in real time using dynamic digital fluorescence ratio imaging. RESULTS: In addition to its direct relaxation of the smooth muscle cells at high concentrations, PNS, at 100 mg/L having little effect on smooth muscle, caused a marked inhibition of endothelium-dependent relaxation brought about by PNS. This inhibitory effect was due to its inhibition of elevation of cytosolic Ca2+, which is required for the activation of NO generation and release from the vascular endothelial cells. Nifedipine has no effect on either the endothelium-dependent relaxation or the cytosolic Ca2+ level in the cultured endothelial cells. CONCLUSION: Our findings are consistent with the known action of PNS on receptor operated Ca2+ channels and support our contention that PNS inhibits endothelium dependent relaxation by preventing the increase of Ca2+ level in endothelial cells via the receptor-operated Ca2+ channels in the presence of ACh or the non selective cation channels opened by CPA. PMID- 11603284 TI - 5-Hydroxytryptamine-inhibiting property of Feverfew: role of parthenolide content. AB - AIM: To study the mechanism of antimigraine activity of Tanacetum parthenium (Feverfew), its extracts and parthenolide, a component of Feverfew, by observing their effect on 5-HT storage and release, and stimulation of 5-HT2B and 5-HT2A receptors. Also to standardize a dosage form of Feverfew with respect to its parthenolide content. METHODS: Isometric responses to 5-HT and an indirect acting serotonergic, d-fenfluramine, were obtained on rat fundus and ileum. In one set of experiments the effect of dichloromethane extract of Feverfew and parthenolide was observed on the above. The extract was then thermally degraded upto 10%, 23%, and 33% with respect to its parthenolide content by keeping at 60 degrees C and 75% relative humidity and the experiments were repeated. In another set of experiments rats were fed with 20 mg/kg Feverfew powder (equivalent to a human dose of 500 micrograms parthenolide per day) for 30 d or were i.p. injected with parthenolide (23.4 micrograms/day) for 7 d. In the same set of experiments one group of rats were fed with 15% and 77% degraded Feverfew powder in the same dose as mentioned above. After 30 days the effects of the above were observed on 5-HT and d-fenfluramine. Feverfew was specially formulated and tested for stability under accelerated conditions. RESULTS: Parthenolide (1 x 10(-5) mol/L) non competitively antagonised the effects of d-fenfluramine but had no significant effect on 5-HT2B and 5-HT2A receptors in rat fundus and ileum at 30 min which turned significant on increasing the incubation time to 1.5 h, in rat fundus. Parthenolide (5 x 10(-5) mol/L) followed the same trend. However, Feverfew extract (1 x 10(-5) mol/L) potently and directly blocked 5-HT2B and 5-HT2A receptors and neuronally released 5-HT. At 5 x 10(-5) mol/L the extract potently and irreversibly blocked the above. Both parthenolide and Feverfew extract showed a time-dependency in their action. The extract when degraded thermally upto 10% could significantly block the 5-HT receptors and neuronal release of 5-HT, however, on further degradation it lost its inhibitory capacity markedly. Similar results were observed in rats fed orally with undergraded and degraded Feverfew powder and injected i.p. with parthenolide. Feverfew powder was more effective than any of its extracts or pure parthenolide. CONCLUSION: Feverfew powder is more potent than any of its extract or parthenolide alone in its antiserotonergic activity. Degraded Feverfew extracts show a marked decrease in their antiserotonergic activity. With thermally degraded Feverfew powder containing less contents of parthenolide no built-up antiserotonergic responses were observed after one month. This ascertains that Feverfew should be dispensed in a properly stabilized form wherein its parthenolide content is not degraded to less than 90% of the original content. PMID- 11603285 TI - Tetrandrine inhibits inward rectifying potassium current in cultured bovine aortic endothelial cells. AB - AIM: To study the effect of tetrandrine (Tet) on inward rectifying potassium current in cultured bovine aortic endothelial cells. METHODS: Inward rectifying potassium current (IRK) was observed by the whole cell patch-clamp technique. RESULTS: IRK was inhibited by Tet in a concentration-dependent manner and recovered to normal after wash with drug-free external solution. IRK was reduced from (582 +/- 48) pA to (221 +/- 40) pA at a holding potential of -70 mV by Tet 30 mumol/L. IC50 was 2.8 mumol/L. CONCLUSION: Tet inhibited inward rectifying potassium current in cultured bovine aortic endothelial cells. PMID- 11603286 TI - Role of endothelium/nitric oxide in vascular response to flavonoids and epicatechin. AB - AIM: To examine the role of endothelium in the vascular responses to flavonoids, baicalein, baicalin, cardamonin, alpinetin, and to purified jasmine green tea ( )epicatechin in the isolated rate mesenteric artery rings. METHODS: The isometric contraction was measured by Grass force-displacement transducers. RESULTS: Both baicalein and baicalin enhanced the phenylephrine-induced contractile response in the endothelium-intact rings. This enhancement was abolished by pretreatment with the nitric oxide inhibitor NG-nitro-L-arginine or in the absence of the endothelium. Both flavonoids also inhibited the acetylcholine-induced endothelial nitric oxide-dependent relaxation. In contrast, cardamonin, alpinetin or ( )epicatechin induced both endothelium-dependent and -independent relaxation. NG nitro-L-arginine meyhyl ester or endothelium denudation attenuated the endothelium-dependent relaxation to the same extent. CONCLUSION: Baicalein and baicalin enhanced the phenylephrine-induced contraction most likely through inhibiting production or/and release of endothelial nitric oxide. Whilst, cardamonin-, alpinetin- or (-)epicatechin-induced endothelium-dependent relaxation is primarily mediated through endothelial nitric oxide. PMID- 11603287 TI - Fast repairing of oxidized OH radical adducts of dAMP and dGMP by phenylpropanoid glycosides from Scrophularia ningpoensis Hemsl. AB - AIM: To investigate the antioxidative activity of the constituents of the roots of Scrophularia ningpoensis (Chinese name: Xuanshen). METHODS: The main compounds from the roots of Scrophularia ningpoensis were isolated and identified by chromatography and FABMS, NMR etc. Using the techniques of pulse radiolysis, the electron transfers from iridoid glycosides (IG) or phenylpropanoid glycosides (PG) to oxidized OH radical adducts of 2'-deoxyadenosine-5'-monophosphate acid (dAMP) or 2'-deoxyguanosine-5'-monophosphate acid (dGMP) were observed. RESULTS: Two IG: harpagoside and harpagide, two PG: angoroside C and acteoside were obtained as the main hydrophilic constituents of the plant. At 0.1 mmol/L concentration, angoroside C and acteoside were able to repair the oxidized OH adducts dAMP and dGMP significantly. However, harpagoside and harpagide had no such effect. The electron transfer rate constants of angoroside C with dAMP and dGMP were 4.2 x 10(8) and 10.3 x 10(8) L.mol-1.s-1; the electron transfer rate constants of acteoside with dAMP and dGMP were 5.3 x 10(8) and 20.2 x 10(8) L.mol 1.s-1. CONCLUSION: PG from Scrophularia ningpoensis have a potent antioxidative activity for reducing of the oxidized OH adducts of dAMP and dGMP. PMID- 11603288 TI - Long-term outcome of acute renal injury induced by Aristolochia manshuriensis Kom in rats. AB - AIM: To investigate the long-term functional and morphological changes of the kidney induced by acute intoxication of Aristolochia manshuriensis Kom in rats. METHODS: Experimental model of acute renal injury was established in the Sprague Dawley rats with oral administration of decoctions of Chinese herb, Aristolochia manshuriensis Kom, at dosages of 50 g.kg-1.d-1 and 30 g.kg-1.d-1 for 7 consecutive days, and 20 g.kg-1.d-1 for 15 consecutive days. Renal function was assayed at months 0 (right after treatment), 1, 3, and 6 of the experiment. Renal histological examination was also performed. RESULTS: 1) At month 0, the renal functional changes of acute renal injury included azotemia, low molecular weight proteinuria, glycosuria, hypoosmotic urine, and NAG enzymuria. Histopathological changes showed acute tubular necrosis, predominantly at the corticomedullary junction. 2) At months 1 and 3, the renal function of rats of the experiment was gradually restored and histopathologic examination suggested that the tubular lesions gradually recovered. In HE sections, basophilic deposits were observed in the tubular cytoplasm. And interstitial infiltration of inflammatory cells was not prominent. 3) At months 6, renal preneoplastic lesions, renal tumors, and extrarenal tumors occurred in rats. The occurrence of renal preneoplastic lesions at dosages of 50 g.kg-1.d-1, 30 g.kg-1.d-1, and 20 g.kg-1.d-1 were 100.0% at all three doses, renal tumors 42.8%, 25.0%, and 0%, respectively, extrarenal tumors 14.4%, 12.5%, and 12.5%, respectively, and systemic tumors 57.2%, 37.5%, and 12.5%, respectively. The occurrence of basophilic deposits, renal preneoplastic lesions, renal tumors, and extrarenal tumors in normal control group was nil. CONCLUSIONS: 1) Administration of large dosage of Aristolochia manshuriensis Kom induces acute renal failure in rats. 2) The long-term renal function and histopathologic changes of acute renal injury induced by Aristolochia manshuriensis Komrecover spontaneously. 3) Aristolochia manshuriensis Kom has been proved to be oncogenic for the first time. PMID- 11603289 TI - Chemical characterization and immunological activities of an acidic polysaccharide isolated from the seeds of Cuscuta chinensis Lam. AB - AIM: To study chemical characterization and immunological activities of an acidic polysaccharide, CHC-1, isolated and purified from the seeds of Cuscuta chinensis Lam. METHODS: Both chemical and spectral methods were used to investigate the chemical characterization of CHC-1. Effect of CHC-1 on the proliferation rates of T- and B-lymphocytes both in vivo and in vitro, and antibody production in vivo was measured at various concentrations of CHC-1. RESULTS: The molecular weight of CHC-1 was estimated to be more than 1.0 x 10(6). The analytical results of sugar components indicated that CHC-1 was composed of Rha, Ara, Gal, and GalA in a molar ratio of 0.8:1.0:1.5:0.3. Methylation analysis and 1H, 13C NMR further identified the linkages of the residues of CHC-1. CHC-1 0.1 g/L promoted remarkably the proliferation of T-cells and B-cells in vitro. CHC-1 25 mg/kg, 50 mg/kg caused an evident increase in spleen weight, lymphocyte proliferation, antibody production, etc. But its effect on IgG levels was not significant. CONCLUSION: CHC-1 is a highly branched heteropolysaccharide and possessed immune enhancement activities. PMID- 11603290 TI - Antioxidant activity of qizhu tang. AB - AIM: To study the antioxidant, activity of Qizhu Tang (QZT) both in vivo and in vitro. METHODS: QZT consists of 4 herbal constituents (Rhizoma Atractylodis Macrocephalae, Poria cocos, Kadix Notoginseng, and Radix Astragali), each of the components and their combinations were examined in vitro for 1, 1-diphenyl-2 picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities, and for the inhibition of thiobarbituric acid-reactive substances (TBARS) formation in rat liver homogenate. At the same time, their in vivo protective effect on cerebral ischemia-areperfusion injury was determined in rats. RESULTS: Only the preparations having a higher antioxidant activity comparable to QZT in all three in vitro assays were relatively active in vivo both for TBARS inhibition and glutathione peroxidase preservation, although the activities were much lower than that of QZT as a whole. CONCLUSION: QZT formula is a good natural antioxidant having an effective preventive effect against cerebral ischemia reperfusion damage. PMID- 11603291 TI - Chemical and pharmacological evaluation of Hypericum perforatum extracts. AB - AIM: To determine the concentrations of chemical characteristic to extracts of leaves and flowers of Hypericum perforatum (St John's wort) in a number of selected samples and, following chemical characterization, to investigate the effects of these extracts on several pharmacological properties including effects of the extracts on inhibition of 5-hydroxytryptamine (5-HT) uptake and on antioxidant properties. METHODS: The samples were analyzed for the presence of characteristic chemicals by high performance liquid chromatography (HPLC) directly coupled to ultraviolet wavelength absorbance and positive or negative mode electrospray mass spectrometric detection. The effects of extracts on 5-HT uptake were determined by quantifying 3H-5-HT incorporation into rat hippocampal prisms. Estimates of effects of extracts on free radical scavenging capacity were made using a dynamic assay based on the ability of compounds to prevent the initiation of a colored reaction produced by the horseradish peroxidase catalyzed formation of hydroxyl free radicals from hydrogen peroxide using 2',2'-azinobis (3-ethylbenzthiazoline-6-sulfonic acid) as the color indicator. RESULTS: The chemical profile of a number of extracts were determined and found to differ substantially from each other. Inhibition of 5-HT uptake was found to correlate with hyperforin content and free radical scavenging capacity was found to correlate with the content of several flavonoids including quercetin and hyperoside. CONCLUSION: Standardized extracts of H perforatum varied substantially in the concentration of several characteristic chemicals. The correlation between pharmacological activity and certain characteristic chemicals found in these extracts indicates that the medicinal benefit derived from selected extracts will vary considerably depending on their chemical composition. PMID- 11603292 TI - Protective effects of Ginkgo biloba extract on gastric mucosa. AB - AIM: To study the protective effects of Ginkgo biloba extract (GbE) on gastric mucosa. METHODS: By means of restaint-cold stress (RCS) in rats and 100% ethanol gavage in mice, the index of gastric mucosal injury was evaluated. The gastric juice was collected using pyloric ligation, and the volume and acidity of juice, and activity of pepsin were determined. The content of malondialdehyde (MDA) was measured by thiobarbituric acid (TBA) method. RESULTS: GbE (25, 50, and 100 mg/kg, bid x 5 d, ig) inhibited dose-dependently the gastric mucosal injury induced by RCS and 100% ethanol gavage. The index of gastric mucosal injury after RCS in groups pretreated with GbE was 58%, 43%, and 31% of control group respectively. The index of gastric mucosal injury induced by ethanol in groups pretreated with GbE was 62%, 36%, and 26% of the control group, respectively. And GbE enhanced the protective effects of cimetidine (Cim) on gastric mucosa. But it did not obviously influence the volume and acidity of gastric juice as well as the activity of pepsin. One hour after the administration of ig 100% ethanol, the contents of MDA in gastric mucosa and serum in mice increased (P < 0.01) vs the control group. But pretreatment with GbE (25, 50, and 100 mg/kg, ig) could inhibit this increase of MDA both in gastric mucosa and in serum. CONCLUSION: GbE had protective effects on gastric mucosa and GbE plus Cim possessed the synergism in the treatment of acute gastric mucosal lesions. PMID- 11603293 TI - Anti-diabetic property of ethanolic extract of Andrographis paniculata in streptozotocin-diabetic rats. AB - AIM: To investigate the anti-diabetic effect of a crude ethanolic extract of Andrographis paniculata in normal and streptozotocin (STZ)-induced diabetic rats. METHODS & RESULTS: Oral administration of the extract at different doses (0.1, 0.2, and 0.4 g/body weight) significantly reduced the fasting serum glucose level in STZ-diabetic rats compared to the vehicle (distilled water), but not in normal rats. This effect was dose-dependent. A similar result was seen with metformin (0.5 g/body weight). In the glucose tolerance test, an oral administration of the extract at the same doses suppressed the elevated glucose level in normal and diabetic rats, as did metformin. The effects were also dose-respondent. In the long-term experiment, the extract (0.4 g/body weight), metformin (0.5 g/body weight), and vehicle were given twice daily to diabetic rats for 14 d. On d 15, fasting serum glucose levels were found to be significantly lower in the extract- and metformin-treated groups (P < 0.001) than in the vehicle-treated group. The mean food and water intakes over 14 days were significantly lower in the extract treated group (P < 0.05, P < 0.01, respectively) and also in the metformin treated group (both P < 0.001) when compared to the vehicle-treated group. No significant change in insulin level was observed among the 3 groups of diabetic rats. The extract, like metformin, maintained the leptin levels after 14-d treatment, whereas this level was significantly decreased (P < 0.05) in the vehicle-treated group. The activity of hepatic glucose-6-phosphatase (G-6-Pase) was significantly reduced by the extract as well as by metformin (both P < 0.05). No significant difference in hepatic glycogen stores was noted among the 3 groups. The extract caused 49.8% reduction of fasting serum triglyceride levels, compared to 27.7% with metformin. However, neither the extract nor metformin significantly affected serum cholesterol level. CONCLUSION: The ethanolic extract of A paniculata possesses antidiabetic property. Its antidiabetic effect may be attributed at least in part to increased glucose metabolism. Its hypotriglyceridemic effect is also beneficial in the diabetic state. PMID- 11603294 TI - Dicentrine is preferentially antagonistic to rat aortic than splenic alpha 1 adrenoceptor stimulation. AB - AIM: Dicentrine is a known alpha 1-adrenoceptor antagonist, but its alpha 1 adrenoceptor subtype selectivity has not yet been determined. We therefore, investigated the putative alpha 1-adrenoceptor subtype selectivity of this agent. METHODS: Graded isometric contractile responses of rat aortic rings and spleen to phenylephrine were observed in the absence or presence of various concentrations of dicentrine. The pA2 values for dicentrine were determined. RESULTS: Aortic tissues were more sensitive to phenylephrine-induced contraction than the spleen tissues. Dicentrine was approximately 100 times more potent as an antagonist to the aortic contraction, than it was to the splenic contractions. CONCLUSION: Dicentrine is an alpha 1-adrenoceptor antagonist which is more selective towards the putative alpha 1D-adrenoceptor subtype of the rat aorta than the alpha 1B adrenoceptor of the spleen. PMID- 11603295 TI - Huperzine A reverses scopolamine- and muscimol-induced memory deficits in chick. AB - AIM: To study the effects of huperzine A on disruption of spatial memory induced by scopolamine (a muscarinic antagonist) and muscimol (a GABAA agonist) in passive avoidance task. METHODS: One-trial passive avoidance task was used to investigate the effects of huperzine A. The avoidance rate was used to evaluate memory retention. RESULTS: Both scopolamine (100 ng) and muscimol (50 ng), injected intracranially 5 min before training, resulted in a decreased avoidance rate. Huperzine A (25 ng), injected intracranially 15 min before training, reversed memory deficits induced by scopolamine and muscimol at 30 min after training, and this reversal persisted at least 1 h. The improving effects of huperzine A exhibited a bell-shaped dose-response curve. CONCLUSION: Huperzine A improved the process of memory formation not only by acting as a highly potent and selective inhibitor of AChE, but also by antagonizing effects mediated through the GABAA receptor. PMID- 11603296 TI - Stimulatory effect of trans-cinnamaldehyde on norepinephrine secretion in cultured pheochromocytoma (PC-12) cells. AB - AIM: The effect of trans-cinnamaldehyde (CNMA) on the release of norepinephrine (NE) from nerve terminal was investigated using rat pheochromocytoma 12 (PC-12) cells. METHODS: The amount of NA released from PC-12 cells incubated with CNMA or related substances was quantified by high performance liquid chromatography (HPLC)-electrochemical detection. The lipophilic anion bisoxonol was used to monitor the effect of CNMA on the membrane potential. RESULTS: CNMA stimulated the secretion of NE in a concentration-dependent manner from 5 mumol/L to 50 mumol/L, while the value of lactate dehydrogenase in the incubated medium was not influenced by CNMA. However, acetaldehyde, cinnamic acid, cinnamoyl chloride and cinnamamide failed to produce similar effect. The action of CNMA can thus be considered specific. The depolarizing effect of CNMA on the membrane potential was also illustrated by a concentration-dependent increase in the fluorescence of bisoxonol, a potential-sensitive dye. Saxitoxin attenuated the depolarizing action of CNMA at concentrations sufficient to block sodium channels. Besides, the effect of CNMA to depolarize the membrane potential in PC-12 cells is greater than that of 4-aminopyridine (4-AP). The action of CNMA on NE releasing depends on extracellular Ca2+ and is attenuated by 8-bromo-cAMP at concentrations sufficient to inhibit the action of cyclic AMP. CONCLUSION: These findings suggest that CNMA can depolarize the membrane to result in a Ca(2+)-dependent and cyclic AMP-related release of NE from PC-12 cells. PMID- 11603297 TI - Effects of polysaccharides (FI0-b) from mycelium of Ganoderma tsugae on proinflammatory cytokine production by THP-1 cells and human PBMC (I). AB - AIM: To compare the effects of water-soluble polysaccharides, FI0-b, and its formic acid-modified derivative, FI0-b-H, on production of human proinflammatory cytokines. METHODS: The polysaccharides were modified by formic acid. Cytokine production was quantitated by radioimmunoassay. mRNA for cytokines was measured by semi-quantitative RT-PCR. RESULTS: FI0-b and FI0-b-H 4, 40, and 400 mg/L significantly downregulated interleukin-1 alpha (IL-1 alpha) production by THP-1 cells induced by lypopolysaccharide (LPS) 1 or 10 mg/L and phorbol myristate acetate (PMA) 200 nmol/L. At lower stimulation with LPS 10 mg/L and PMA 200 nmol/L, both polysaccharides significantly upregulated tumor necrosis factor alpha (TNF alpha) production by THP-1 cells. However, at higher stimulation with LPS 100 mg/L and PMA 200 nmol/L, they downregulated TNF alpha production. FI0-b-H downregulated interleukin-8 (IL-8) production by THP-1 cells at a lower-dose of LPS 1 mg/L and PMA 200 nmol/L, but upregulated IL-8 production at a higher-dose of LPS 10 mg/L and PMA 200 nmol/L. Production of cytokines (IL-1 alpha and TNF alpha) was transcriptionally or post-transcriptionally regulated by FI0-b and FI0 b-H. CONCLUSION: The water-soluble polysaccharides of Ganoderma tsugae mycelium have bidirectional immunomodulatory effects on cytokine production in different stimulatory conditions in a dose-dependent manner. Compared with FI0-b, FI0-b-H has more marked effects on human proinflammatory cytokine production. PMID- 11603298 TI - Effects of polysaccharides (FI0-c) from mycelium of Ganoderma tsugae on proinflammatory cytokine production by THP-1 cells and human PBMC (II). AB - AIM: To study the effects of water-soluble polysaccharides. FI0-c, and its sulfated derivative, FI0-c-S, on production of human proinflammatory cytokines, interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF alpha). METHODS: The herbal polysaccharides were modified by chlorosulfornic acid in dimethyl sulfoxide (Me2SO). Cytokine production was measured by radioimmunoassay, mRNA for the cytokines was measured by semi-quantitative RT-PCR. RESULTS: FI0-c 4 mg/L itself induced IL-1 alpha production by THP-1 cells without stimulants, such as lipopolysaccharides (LPS) and phorbol myristate acetate (PMA). On the other hand, FI0-c and FI0-c-S inhibited the IL-1 alpha production by THP-1 cells with these stimulants. FI0-c and FI0-c-S significantly upregulated TNF alpha production by THP-1 cells without stimulants or at a low dose of LPS 10 mg/L and PMA 200 nmol/L, whereas these polysaccharides markedly downregulated the TNF alpha production by a high dose of LPS 100 mg/L and PMA. Human peripheral blood mononuclear cells (PBMC) responded to FI0-c and FI0-c-S in IL-1 alpha and TNF alpha production in a fashion similar to THP-1 cell responses. FI0-c 4 mg/L downregulated high-dose LPS- and PMA-induced IL-1 alpha or TNF alpha mRNA and their protein production by THP-1 cells. CONCLUSION: The water-soluble polysaccharides of Ganoderma tsugae mycelium have bidirectional immunomodulatory effects on cytokine production in different cell stimulatory conditions. Chemical modification of this polysaccharide changed the intensity of regulatory effect on cytokine production. PMID- 11603299 TI - Protective effect of gypenosides on DNA and RNA of rat neurons in cerebral ischemia-reperfusion injury. AB - AIM: To observe the protective effect of gypenosides (GP) on the neurons of hippocampus, cerebral cortex, corpus striatum, and dentate gyrus in cerebral ischemia-reperfusion injury of rats. METHODS: Modified 4-vessel occlusion (4-VO) method was used to establish the model of acute global ischemia. The acridine orange (AO) staining method was used to observe the DNA and RNA contents of cerebral ischemia-reperfusion injury model in the areas. RESULTS: The fluorescent intensity (reflecting DNA and RNA contents) of the DNA and RNA in the areas of cerebral ischemia-reperfusion injury was markedly abated compared with the normal control group. In the group of ig GP (100 mg/kg) it was enhanced compared with the model group and was the same as the normal control group. CONCLUSION: The injury of the DNA and RNA in the areas of ischemia-reperfusion model was decreased by GP. PMID- 11603300 TI - Effects of tripcholorolide on inflammatory reaction of mouse alveolar macrophages in vitro. AB - AIM: To observe the effects of tripcholorolide (T4) on inflammatory reaction of mouse alveolar macrophages. METHODS: RT-PCR was used to investigate tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), IL-6, IL-10, and inducible nitric-oxide synthase (iNOS) mRNA expression in alveolar macrophages after LPS 10 mg/L and T4 500 micrograms/L treatment. ELISA was used to detect TNF alpha, IL-1 beta, IL-6, and IL-10 protein expression. Nitrite was measured by Griess reaction. RESULTS: TNF alpha, IL-1 beta, IL-6, IL-10, and nitrite increased in supernatants, when alveolar macrophages were stimulated by LPS 10 mg/L at 24 h. Both T4 500 micrograms/L and dexamethasone 100 mumol/L had inhibitory effects on the production of TNF alpha, IL-1 beta, IL-6, IL-10, and nitric oxide. The mRNA expression of TNF alpha, IL-6, IL-10, and iNOS increased at 5 h after LPS stimulation which was decreased on addition of T4 500 micrograms/L or dexamethasone 100 mumol/L. T4 had no effect on stability of LPS induced mRNA expression in TNF alpha, IL-6, and IL-10. CONCLUSION: T4 had inhibitory effects on the expression of proinflammatory and antiinflammatory mediators. PMID- 11603301 TI - Health care manpower concerns. PMID- 11603302 TI - Assessing dental hygiene clinical competence for initial licensure: a Delphi study of dental hygiene program directors. AB - PURPOSE: The purpose of this study was to describe the best way to determine clinical competence prior to issuing the dental hygiene license. METHODS: Directors of dental hygiene programs in the United States, Puerto Rico, and the Virgin Islands were asked to describe the best way to determine clinical competence prior to issuing the dental hygiene license. Three rounds of the Delphi process were used to seek a level of consensus among panel members. A total of 44 directors (19% of the population) from dental hygiene schools participated in at least one round of the study. Sixteen directors participated in all three rounds. Likert scale and ranking questionnaires followed the initial open-ended question. RESULTS: A level of consensus was achieved on 47% of the initial statements describing the determination of clinical competence. A list of the top 10 most agreed upon responses to the initial question was generated. Ongoing process evaluations within the accredited dental hygiene program, was suggested as the best determination of clinical competence for dental hygiene licensure. CONCLUSION: The findings suggest that dental hygiene clinical competence is best determined throughout a continuum of process and product examinations, rather than in a one-time product evaluation. Accreditation was acknowledged as an important element in standardizing the assessment of clinical competence. Organized dental hygiene should develop a protocol for licensing new dental hygienists and work with state boards of dentistry on its implementation. PMID- 11603303 TI - Incidence of student exposures to blood and body fluids and postexposure management protocols in dental hygiene programs. AB - PURPOSE: The purpose of this study was to determine the incidence of occupational exposures to blood or body fluids reported in dental hygiene students from 1996 to 1998 as well as postexposure management protocols used in dental hygiene programs. METHODS: A 23-item, self-designed questionnaire was sent to the 214 dental hygiene programs that were accredited in 1996. Sixty-seven percent (143) of the sample completed the questionnaire. Data were analyzed using descriptive statistics, the Mann Whitney-U test, chi-square, and the Freedman test. RESULTS: Over the three-year evaluation period, 687 total occupational exposures were reported, with dental hygiene schools averaging less than 1.5 exposures per year. The overall exposure rate was 1.8 per 100 first year students and 5.1 per 100 second year students, with second year students experiencing a significantly greater number of exposures than first year students (P = .000). The vast majority (78%) of the exposures occurred as a result of an instrument puncture. In regards to postexposure management and protocols, more than one-fourth of the respondents reported that they did not have a policy for immediate postexposure management. The majority of the schools do not report on the amount of fluid or material involved, whether the source material contained HIV, depth of the injury, estimated volume of material involved, condition of skin, or duration of contact. CONCLUSIONS: Results of this study reveal that dental hygiene students are at a relatively low risk for occupational exposures to blood and body fluids, although the risk does increase as they progress from the first to second year. Additionally, many schools of dental hygiene should review current protocols for postexposure management and reporting in order to ensure they are complying with current standards for the management of occupational exposures. PMID- 11603304 TI - Prioritization of professional issues by Idaho Dental Hygienists. AB - PURPOSE: The Idaho Dental Hygienists' Association (IDHA) and other constituents use surveys to establish the goals of the association and better represent members. This study was conducted to assess dental hygienists' opinions about professional issues related to dental hygiene practice and legislative activities in Idaho. METHODS: In 1998, a questionnaire was mailed to all active Idaho dental hygiene licensees (N = 652). The coded questionnaire contained two sections. Section I included items on demographic and employment characteristics, and Section II included items on legislative and professional issues. Respondents were asked to rank 14 professional issues by selecting the top five concerns about dental hygiene practice in Idaho. Research questions asked included: 1) Do entry-level baccalaureate degrees in dental hygiene affect the ranking of professional concerns of Idaho dental hygienists? 2) Does being a member of the American Dental Hygienists' Association (ADHA) affect Idaho dental hygienists' ranking of professional concerns? Data were analyzed using frequency distributions and nonparametric tests of association. RESULTS: A 74% (N = 431) response rate was obtained after two mailings. Three professional issues were ranked as important concerns by at least 50% of respondents. They were 1) the "national trend to reduce entry-level education for dental hygienists," 2) "dental assistants performing dental hygiene services," and 3) "legalizing self regulation." CONCLUSIONS: It is incumbent upon constituent dental hygienists' associations to obtain and utilize information from members for strategic planning and legislative efforts. A statewide membership study clearly can provide direction. Idaho dental hygienists are concerned about maintaining quality education programs, reducing illegal practices, and regulating themselves. Also, the state association and regulatory agencies need to take an active role to assure that dentists, dental hygienists, and dental assistants are educated about state laws. PMID- 11603305 TI - Antimicrobials in periodontal maintenance. AB - Mechanical and chemical antimicrobial intervention is the mainstay of preventive periodontal therapy. Successful periodontal maintenance care depends upon the ability of oral health care professionals to combat periodontal infections, and patient compliance with prescribed follow-up care. Since tooth brushing, flossing, and oral rinsing do not reach pathogens present in furcations and at the depths of deep periodontal pockets, adequate oral hygiene should include subgingival treatment with home irrigators or other appropriate self-care remedies in patients with these conditions. Povidone-iodine for professional use and diluted bleach for self-care are inexpensive and valuable antimicrobial agents in periodontal maintenance. The present article outlines the prudent use of antimicrobial therapy in periodontal maintenance. PMID- 11603306 TI - A case report: arresting dental caries. AB - PURPOSE: To arrest dental caries in the dentin in a patient that had been refractory to other attempts at caries control. METHODS: Repeated applications of fluoride varnish (5%, Duraflor, Pharmascience Laboratories, Montreal) in the clinic every three months along with two daily two-minute rinses with sodium fluoride at home. RESULTS: Results over five years are presented. None of the lesions identified five years earlier had been restored. The teeth were monitored with frequent bitewing radiographs and clinical exams; the interproximal decay appears inactive clinically. CONCLUSION: This present case report shows that fluoride varnish may be a good addition to preventive therapy for arresting caries in adult patients in general practice. Surgical intervention may be avoided in patients whose risk has shifted to a lower level. PMID- 11603307 TI - Burning mouth syndrome. AB - A critical component of the dental hygiene process of care is assessment of the oral and general health conditions of clients. Some clients present with burning and painful sensations in the oral cavity in the absence of any noticeable disease. This condition has been referred to as burning mouth syndrome (BMS), an often complicated condition. Various local, systemic, and psychological factors have been linked with BMS, but its etiology is not fully understood. Yet as many as one million people are affected by it in the United States, and it is an increasingly-common problem in the aging population. Middle-aged women, mostly postmenopausal, are diagnosed with symptoms seven times more frequently than men. Careful diagnosis and treatment are necessary to alleviate the symptoms of this condition. Referral to a physician is warranted in some cases. The purposes of this course are to review the etiologic factors and clinical implications related to this condition and to discuss appropriate dental hygiene interventions. Collaboration among the client, dental hygienist, dentist, and physician provides for interdisciplinary actions that can lead to palliation of symptoms and evaluation of the possible underlying factors contributing to the condition. PMID- 11603308 TI - Public health or private profit: where does the American Public Health Association stand? PMID- 11603309 TI - Patent medicine. PMID- 11603310 TI - The "drug war" in Colombia: echoes of Vietnam. PMID- 11603311 TI - Licensed nursing staff reductions and substitutions in Pennsylvania hospitals, 1991-1997. AB - Nurses report a decline in RN/patient and skill mix in the 1990s while quantitative studies fail to confirm this. This study examines aggregate hospital nursing staff in Pennsylvania from 1991-1997, focusing on changes in licensed nursing staff. It finds that licensed nursing staff declined while nursing assistants increased in this period. With adjustment for patient acuity, there was a slight decrease in RN/adjusted patient days of care (APDC), a 23% decrease in LPN/APDC, and a 4% decrease in licensed nurse/APDC. The RN/nurse ratio increased slightly, and licensed nurse/nurse fell slightly. Since RNs often operate in environments which make use of teams of licensed staff, nurses' perceptions of a decline in the RN/patient ratio is a result of the decline in licensed staff/APDC, and of an increase in patient acuity. PMID- 11603312 TI - Reporting childhood asthma: why? Why not? What else? AB - Childhood asthma is a chronic inflammatory disorder of the airways. It is a multifactorial disease that has been associated with familial, infectious, environmental, socioeconomic, and psychosocial causes. In the US alone, asthma is the most common chronic disease of childhood. In 1999, the estimated annual cost of treating asthma in children in the US was $3.2 billion. Public health authorities have argued for making childhood asthma a notifiable disease, with the hopes of identifying modifiable sources and reducing adverse consequences. As of the end of the 20th century, however, no jurisdictions in North America require physicians to report pediatric asthma. Would mandatory reporting help public health agencies reduce the asthma burden? What harm might come from obliging physicians to report childhood asthma? In this article we provide a thorough evaluation of these issues, the rationale behind the controversy, and long-awaited answers to these difficult questions. PMID- 11603313 TI - The impact of the maquiladoras on health and health policy along the U.S.-Mexico border. AB - Over the last three and one-half decades, the development of twin industrial plants, maquilas, along the U.S.-Mexico border has resulted in industrialization of the northern tier of Mexican states and rapid population growth on both sides of the border. Maquilas have been responsible for some environmental contamination and may contribute to changes in family cohesiveness. At the same time they have not supported the needed expansion of public infrastructure. These are major public health consequences that must be considered by both countries. Solutions will require better cooperative efforts than have occurred in the past. PMID- 11603314 TI - Health, safety, and workers' rights in the Maquiladoras. PMID- 11603315 TI - Elder mistreatment: implications for public health dentistry. AB - Elder mistreatment has increasingly been recognized as a serious and complex health issue affecting large numbers of elders each year. Health professionals have been found to lack knowledge regarding assessment, diagnosis, intervention, and reporting criteria of this problem. In dentistry, there have been recent calls for more research and publications as well as requests for professional policy statements and guidelines. Public health dentistry, with its emphasis on prevention, can lend guidance and leadership at the primary, secondary, and tertiary levels. This article reviews the types and prevalence of elder mistreatment, discusses predisposing variables, and offers an ecological model that serves as a guide to interventions directed at all levels of elder mistreatment prevention. PMID- 11603316 TI - Oral cancer knowledge and opinions among Maryland nurse practitioners. AB - OBJECTIVES: As part of a Maryland statewide oral cancer needs assessment, a census of adult and family practice nurse practitioners was conducted to determine their knowledge of oral cancer risk factors, diagnostic procedures and related opinions. METHODS: Information was obtained through a pretested, 40-item, self-administered mail questionnaire of 389 nurse practitioners. A second complete mailing was sent three weeks after the initial mailing; two postal card reminders were mailed at 10 and 17 days after the second mailing, which yielded a response rate of 56 percent. RESULTS: Most nurse practitioners identified the use of tobacco, alcohol, and prior oral cancer lesions as real risk factors. But only 35 percent identified exposure to the sun as a risk for lip cancer. Respondents were not overly knowledgeable about the early signs of oral cancer, most common forms, or sites for oral cancer. Only 19 percent believed their knowledge of oral cancer was current. Nurse practitioners who reported having a continuing education course on oral cancer within the past two to five years were 3.1 times more likely to have a high score on knowledge of risk factors and 2.9 times more likely to have a high score on knowledge of both risk factors and of diagnostic procedures than were those who had never had a continuing education course. CONCLUSIONS: The reported knowledge of oral cancer, in conjunction with opinions about level of knowledge and training, point to a need for systematic educational updates in oral cancer prevention and early detection. PMID- 11603318 TI - At first glance: social meanings of dental appearance. AB - OBJECTIVES: An important factor in social interaction is physical appearance. Major elements in the evaluation of physical appearance are the mouth and teeth. The purpose of this study was to evaluate the effect of tooth appearance on the development of a first impression of the other person, with regard to the sex of both the respondent and the target. METHODS: Eight facial photographs of individuals with intact upper teeth were manipulated: one set was left untouched and the other was professionally altered so that the front anterior teeth appeared decayed. The photographs were randomly aligned in sets of eight, each set consisting of four individuals with an original, intact dentition and four other individuals with a "decayed" dentition. The sets of photographs were then presented to 115 respondents (65 males and 50 females). Evaluations were made according to three categories of traits--esthetic, social, and professional. RESULTS: For all three evaluation categories, the difference in scores between decayed and intact dentition given to targets were significantly higher when participants of one sex evaluated targets of the opposite sex, as compared to evaluating targets of their own sex. CONCLUSIONS: The effect of tooth appearance on the physical attractiveness stereotype is more evident when males evaluate females and vice versa, rather than when evaluating their own sex. PMID- 11603317 TI - Perspectives of Maryland adult and family practice nurse practitioners on oral cancer. AB - OBJECTIVES: Because oral and pharyngeal cancer mortality in Maryland ranks seventh among states and sixth for black males, a statewide oral cancer needs assessment was conducted. The purposes of this qualitative descriptive study were to obtain indepth information on nurse practitioners' awareness and opinions of oral cancer, oral cancer examinations, and related factors. These findings were intended to supplement a previous survey conducted among Maryland nurse practitioners. METHODS: A professional focus group moderator conducted one face to-face focus group with 11 nurse practitioners and one telephone focus group with eight nurse practitioners. Criterion-purposeful sampling and qualitative content analysis were employed. RESULTS: Findings showed that oral cancer is a neglected public health problem and, based on their formal training, not one considered by nurse practitioners to be their responsibility. Although aware of other cancers, none of the nurse practitioners recognized that oral cancer was a public health problem in the state. Numerous barriers were cited for this neglect, including their lack of training and, in one case, unpleasant feelings about examining the mouth. Participants concluded that oral cancer is part of their responsibilities and that they are interested in related continuing education courses. CONCLUSIONS: The focus groups of nurse practitioners provided rich and insightful suggestions for future strategies to help solve the oral cancer problem in Maryland, which supplemented the quantitative mail survey conducted earlier. PMID- 11603319 TI - Measuring orthodontic treatment satisfaction: questionnaire development and preliminary validation. AB - OBJECTIVES: The aims of this study were to develop a reliable self-report measure of consumer satisfaction with orthodontic treatment, and to preliminarily assess its validity. METHOD: Transcripts of qualitative interviews with patients, their parents, and practicing orthodontists together with items from existing dental satisfaction questionnaires were used to develop a pool of 41 items assessing satisfaction with various aspects of orthodontic care. These items were paired with five-point Likert scales (1 = strongly disagree, 5 = strongly agree) and were administered to 299 parents of children who had completed orthodontic treatment at two university-based clinics. RESULTS: Factor analyses and reliability analyses identified three main subscales with high reliabilities: 13 items assessing satisfaction with treatment process (Cronbach's alpha = .92), seven items assessing satisfaction with psychosocial effects of treatment (Cronbach's alpha = .87), and five items assessing satisfaction with overall treatment outcome (Cronbach's alpha = .79). Relationships among these three subscales and pre- and posttreatment variables were examined in a subset of 86 parents/patients. Forward stepwise regression with backward overlook revealed no significant relationships between any satisfaction subscale and demographic variables. Posttreatment overjet was inversely related to parental satisfaction with orthodontic treatment process (R2 = .13; P < .001), and parent satisfaction with treatment outcome (R2 = .28; P < .0001). Improvement in esthetics as measured by improvement in IOTN Aesthetic Component scores was positively related to satisfaction with psychosocial outcomes (R2 = .28; P < .0001). CONCLUSIONS: The present instrument is reliable and can be used to assess three dimensions of parental satisfaction with their child's orthodontic treatment. Relationships between visible orthodontic outcome variables and parent satisfaction provide preliminary validity support for the instrument. PMID- 11603320 TI - Community fluoridation status and caries experience in children. AB - OBJECTIVE: This study compares dental caries experience in fluoridated and nonfluoridated communities. METHODS: A dental health survey designed to collect data on caries experience and treatment needs for community-specific public health planning purposes was conducted in public elementary schools during the 1996-97 school year. Oral examinations of 17,256 children were completed, representing 93 percent of children residing in 62 East Tennessee communities. RESULTS: The analysis showed that water fluoridation was significantly related to caries experience in the primary (dfs) and permanent (DMFS) dentitions and to the proportion of caries-free children in the primary and permanent dentitions. When the data were adjusted for socioeconomic status, race, and age, caries levels were 21 percent lower in the primary dentition and 25 percent lower in the permanent dentition in fluoridated communities than in nonfluoridated communities. In addition, the proportion of children who were caries free was larger in fluoridated as compared with nonfluoridated communities by 19 percent in the primary dentition and 6 percent in the permanent dentition. CONCLUSION: Although the design of the study prevented the collection of individual fluoride and residency histories, findings suggest there was substantially lower caries experience in fluoridated communities than in nonfluoridated communities. PMID- 11603321 TI - Identifying communities with low dentist supply in California. AB - OBJECTIVES: This study estimates the supply and geographic distribution of dentists in California and examines the community characteristics associated with supply of dentists. METHODS: The number of practicing dentists was estimated from American Dental Association data on licensed dentists in California. Each dentist's address was geocoded and matched to a Medical Service Study Area (MSSA). Dentist-to-population ratios were computed, and the association between dentist supply and community characteristics was analyzed in regression models. RESULTS: Approximately 20 percent of California communities may have a shortage of dentists. Two-thirds of dental shortage communities are rural. Communities with a lower supply of dentists have higher percentages of minorities, children, and low-income persons. Minority dentists were more likely to practice in minority communities. CONCLUSIONS: Geographic maldistribution of dentists may contribute to poor access to dental care in many communities, especially in rural, low-income, and minority communities. Minority dentists are more likely to practice in minority communities, but are a small portion of the dental workforce. PMID- 11603322 TI - The John W. Knutson Distinguished Service Award in Dental Public Health--2000 recipient Alice M. Horowitz. PMID- 11603323 TI - Remarks on receiving the John W. Knutson Distinguished Service Award. PMID- 11603324 TI - [Dissecting aortic aneurysm and contrast magnetic resonance angiography]. AB - The propose of the present work is to study the potential of the 3-D contrast MR angiography (MRA) in diagnosis of aortic dissection. The studied group consisted of 45 patients who as expected might have aortic dissection. 15 patients was observed in dynamics after surgical treatment. Total number of me performed contrast-MRA was 72. MRA has been performed on 1.5T MR tomograph Magnetom Vision (Siemens) with the of ultrafast sequenses Fisp and turbo-flash. Aortic dissection was diagnosed in 18 patients. The method of ce-MRA enables to make a precise diagnose of acute and chronic aortic dissection. This method is used for a dynamic follow up of the patients after the performed surgery. PMID- 11603325 TI - [Magnetic resonance cholangiopancreatography and a problem in diagnosis of hepatopancreatoduodenal diseases]. AB - Based on the findings of 54 magnetic resonance studies, the authors used 19 of them authors to study the types of normalcy. A role of the new noninvasive technique magnetic resonance cholangiopancreatography (MRCPG) in the diagnosis of hepatopancreatoduodenal diseases is assessed. The potentialities of MRCPG in the detection of most common diseases and malformations of the biliary system are demonstrated. Comparative studies of MRCPG and endoscopic retrograde cholangiopancreatography (ERCPG) were conducted in 18 cases. The paper shows a methodological approach to MRCPG and analyzes the studies by describing the MR semiotics of major diseases. Emphasis is laid on how it is important to combine routine MRI and MRCPG in certain diagnostic situations. The authors consider that MRCPG is able to replace X-ray endoscopic studies and primarily ERCPG in diagnostic terms, by reserving their therapeutical functions for itself. MRCPG has great potentialities that, require further investigations and analysis. PMID- 11603326 TI - [Role of magnetic resonance imaging in the complex radiation diagnosis of hormonally active adrenal tumors]. AB - Based on the results of examination of 30 patients with hormonally active adrenal tumors, the authors consider the MRI sympatomatology of their different types and the potentialities of the technique in the complex radiation diagnosis of this pathology. The authors present their assessments of the relative intensity of a signal and the structure of each type of hormone-producing tumors of the glands by using different MRI pulse sequences that may be useful in establishing a presumptive morphological diagnosis. They identify MRI sequences that are of the greatest informative value for the diagnosis of each type of hormonally active adrenal tumors. There is evidence for that MRI is highly effective in detecting all types of hormonally active adrenal tumors and, in the context of their topographic and anatomic diagnosis, has an unquestionable advantage over ultrasonography and X-ray computed tomography in some cases. PMID- 11603327 TI - [Ultrasound and hydroultrasound diagnosis of colonic and rectal tumors]. AB - A method of US hydrocolonoscopy with the use of multicomponent contrast medium has been applied to examine 76 patients with tumors of the straight intestine and segmented one. Cancer has been diagnosed in 56 patients, benign tumors in 19 patients, lymphosarcoma of the blind gut has been revealed in one case. It is stated that a complex US examination of the straight and segmented intestines has a number of additional diagnostic potential in a visualization of the wall thickness, structure, tumor size and in a determination of the lesion length as compared with other radiation methods of observation. The use of survey US examination of the abdomen, USE with liquid echocontrast diagnostic medium and transrectal observation enable to solve in most cases severe problems in diagnosis and differential diagnosis of cancer of the straight intestine and segmented one. PMID- 11603328 TI - [Assessing the informative value of positron emission tomography with the new radiopharmaceutical Sodium 11C-butyrate versus small-dose dobutamine stress echocardiography in the diagnosis of myocardial viability in patients with coronary heart disease and left ventricular dysfunction]. AB - Myocardial viability in patients with coronary artery disease and heart failure was assessed by echocardiography with low doses of dobutamine and positron emission tomography with Sodium 11C-butyrate. Sensitivity and specificity of those methods were compared. Positron emission tomography and Sodium 11C-butyrate had quite high sensitivity and specificity, which could be compared with positron emission tomography and fluorine-18-deoxyglucose. Echocardiography with low doses of dobutamine had high specificity and its sensitivity was lower that one of positron emission tomography and Sodium 11C-butyrate. Thus, it is necessary to use the protocol of stress dobutamine echocardiography with high doses to avoid this problem. PMID- 11603329 TI - [X-ray study in the examination of patients with perineal fistulas]. AB - The paper discusses whether X-ray study of patients with perineal fistulas is required and justified. The main reason is that there is a diversity of diseases which display the same signs as paraproctitis. Of 426 examinees, perineal fistulas were mainly caused by chronic paraproctitis in 85% and by other various diseases showing the similar symptoms in 15%. The basic studies of these patients included fistulography made in 300 patients with external fistulas and proctofistulography performed in 126 patients with incomplete internal fistulas. Comparing the data of X-ray study with those of clinical and morphological ones showed the sensitivity of the former to be 94.5%. Based on the results of their own observations, the authors defined indications for fistulography or proctofistulography. In addition to the analysis of the findings, they present the main points of differential X-ray diagnosis of different diseases manifested by perineal fistulas. PMID- 11603330 TI - [Diagnosis of bilateral pulmonary thrombosis by electron radiation imaging and magnetic resonance imaging]. PMID- 11603331 TI - [Comprehensive approach to examining a patient followed up for renal cyst]. PMID- 11603332 TI - [Digital coronary angiography in prediction of the course of coronary heart disease]. PMID- 11603333 TI - Proceedings of the Collegium Oto-Rhino-Laryngologicum Amicitiae Sacrum. Washington, DC, USA. August 27-30, 2000. PMID- 11603334 TI - Abstracts of the International Symposium on Ultrasonic Imaging and Tissue Characterization. May 30-June 1, 2001. Arlington, Virginia, USA. PMID- 11603335 TI - Professor Jack Lowy. PMID- 11603337 TI - Proceedings of the symposium for the 100th anniversary of the University of Parma's pediatric studies. Parma, Italy, 24-25 March 2000. PMID- 11603336 TI - Annual Clinical Genetics Meeting. March 1-4, 2001. Miami, Florida, USA. Abstracts. PMID- 11603338 TI - [Teaching of pathological anatomy at the Imperial Moscow University in 1765 1804]. PMID- 11603339 TI - Frontiers in microsurgery: recent advances in experimental microsurgery. Proceedings of the 5th Congress of the International Society for Experimental Microsurgery. Catania, Italy, 3-6 September 2000. PMID- 11603340 TI - Origins of HIV and the AIDS epidemic. Papers of a discussion meeting. 11-12 September 2000. PMID- 11603341 TI - Recruitment and retention for affiliated groups. PMID- 11603342 TI - Online healthcare purchasing. PMID- 11603343 TI - Educating providers. PMID- 11603345 TI - Moving from telling to empowering. PMID- 11603344 TI - 360-degree physician evaluations. PMID- 11603346 TI - Advice from the expert. These tips can help you create a new position for yourself. PMID- 11603347 TI - Ethical guidance in Web site development. PMID- 11603348 TI - New tools to measure patient satisfaction. PMID- 11603349 TI - Public policy statement. Healthcare executives' responsibility to their communities. November 2000 (revised). PMID- 11603350 TI - Key industry facts. PMID- 11603351 TI - Clinical governance. PMID- 11603352 TI - Future tech devices. The information chain gets personal. PMID- 11603353 TI - [Metformin and anesthesia, how great is the risk of lactic acidosis?]. PMID- 11603354 TI - A novel catalase mutation (a G insertion in exon 2) causes the type B of the Hungarian acatalasemia. PMID- 11603355 TI - Factors influencing the accuracy of renal output efficiency. PMID- 11603356 TI - Which syringomyelia is truly associated with multiple sclerosis? AB - Necrosis of the spinal cord within multiple sclerosis (MS) lesions was suggested as a putative cause of syringomyelic cavity development in MS. A number of evidences suggest however that mechanisms other than necrosis are pathogenetically relevant for cavity formation, possibly depending on the atypical topographical distribution of the demyelinative lesion and on the increased cerebrospinal fluid pressure into the central canal below the compression. Not coincidentally, the hypothesis of post-necrotic and ex-vacuo mechanisms leading to cavitation derives from Japanese studies where MS is characterised by high tissue destructive capability and, besides its rarity, has many differences from the more common Western MS type and similarities with the acute disseminated encephalomyelitis (ADEM). Our opinion is that different MS types (Asian and Western) are accompanied by nonuniform mechanisms of syrinx formation and that the Asian MS type shares common, post-necrotic mechanisms with ADEM. PMID- 11603357 TI - Close correlation between fMRI and neural activity...or not? PMID- 11603359 TI - 8th European Meeting on the Neurogenetics of Drosophila. Alicante, Spain, 23-27 September 2000. Abstracts. PMID- 11603358 TI - Carnitine for high triglycerides. PMID- 11603360 TI - Efavirenz may have treatment advantage. PMID- 11603361 TI - Three-year durability for efavirenz. PMID- 11603363 TI - New PI may have limited lipid effects. PMID- 11603362 TI - Efavirenz switches may be beneficial. PMID- 11603364 TI - Racism may increase HIV rates. PMID- 11603365 TI - Canadian Cardiovascular Congress 2001 and 54th annual meeting of the Canadian Cardiovascular Society. October 20-24, 2001. Halifax, Nova Scotia, Canada. Abstracts. PMID- 11603366 TI - American Association of Electrodiagnostic Medicine glossary of terms in electrodiagnostic medicine. PMID- 11603367 TI - [Treatment of endometriosis, 1946]. PMID- 11603368 TI - Weekly update: West Nile virus activity--United States, September 19-25, 2001. PMID- 11603369 TI - Cyclic changes in the responsiveness of regressing corpora lutea to the luteolytic effects of prolactin in rats. AB - In cyclic rats, apoptosis of luteal cells during structural luteolysis occurs cyclically at the transition from pro-oestrus to oestrus in response to the preovulatory prolactin surge. This finding indicates that cyclic changes in apoptosis during luteolysis are dependent on prolactin surge cyclicity. In this study, the effects of prolactin on structural luteolysis were studied under different experimental conditions in relation to the phase of the oestrous cycle. In rats treated with prolactin at metoestrus and dioestrus, apoptosis did not occur in regressing corpora lutea, whereas in rats treated with prolactin on the morning of pro-oestrus, a 12.3-fold and 3.4-fold increase were observed in the number of apoptotic cells in regressing corpora lutea of the current and previous oestrous cycles, respectively. However, when the preovulatory prolactin surge and hence the subsequent apoptotic burst were blocked, prolactin treatment at the dioestrus phase induced a 13-fold increase in the number of apoptotic cells and significant changes in the volume of the corpus luteum (38% decrease) and the number of steroidogenic cells per corpus luteum (70% decrease). The results of this study indicate that the responsiveness of the regressing corpus luteum to the pro-apoptotic effects of prolactin are dependent on the phase of the oestrous cycle and on the presence or absence of an apoptotic burst in response to the preovulatory prolactin surge on the evening of pro-oestrus. Steroidogenic cells surviving to the apoptotic burst during the transition from pro-oestrus to oestrus became refractory to the lytic effect of prolactin. Furthermore, these cells also responded to the luteotrophic effects of prolactin, reaching full morphological luteinization, as indicated by the rescue of regressing cyclic corpora lutea during pregnancy. PMID- 11603370 TI - Abstracts from the 6th International ISSX Meeting. October 7-11, 2001. Munich, Germany. PMID- 11603371 TI - American College of Emergency Physicians Research Forum. October 15-16, 2001. Chicago, Illinois, USA. Abstracts. PMID- 11603372 TI - XXI Congress of the Polish Physiological Society. September 7-10, 1999. Poznan, Poland. Abstracts. PMID- 11603373 TI - Extragastroduodenal manifestations of H. pylori infection. 29-30 August 1999. Cracow, Poland. Abstracts. PMID- 11603374 TI - Abstracts of the 54th Annual Scientific Meeting of the Gerontological Society of America. November 15-18, 2001. Chicago, Illinois, USA. PMID- 11603375 TI - Abstracts for the IXth World Congress of Psychiatric Genetics. Saint Louis, Missouri, USA. October 6-10, 2001. PMID- 11603376 TI - 50th Annual North American Cystic Fibrosis Conference. Orlando, Florida, USA. October 25-28, 2001. Abstracts. PMID- 11603377 TI - 35th Malaysia-Singapore Congress of Medicine. 22-26 August 2001. Abstracts. PMID- 11603378 TI - XIVth International Workshop on Gastroduodenal Pathology and Helicobacter pylori. Strasbourg, France. 5-8 September 2001. Abstracts. PMID- 11603379 TI - Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. AB - Glut-1 deficiency syndrome was first described in 1991 as a sporadic clinical condition, later shown to be the result of haploinsufficiency. We now report a family with Glut-1 deficiency syndrome affecting 5 members over 3 generations. The syndrome behaves as an autosomal dominant condition. Affected family members manifested mild to severe seizures, developmental delay, ataxia, hypoglycorrhachia, and decreased erythrocyte 3-O-methyl-D-glucose uptake. Seizure frequency and severity were aggravated by fasting, and responded to a carbohydrate load. Glut-1 immunoreactivity in erythrocyte membranes was normal. A heterozygous R126H missense mutation was identified in the 3 patients available for testing, 2 brothers (Generation 3) and their mother (Generation 2). The sister and her father were clinically and genotypically normal. In vitro mutagenesis studies in Xenopus laevis oocytes demonstrated significant decreases in the transport of 3-O-methyl-D-glucose and dehydroascorbic acid. Xenopus oocyte membranes expressed high amounts of the R126H mutant Glut-1. Kinetic analysis indicated that replacement of arginine-126 by histidine in the mutant Glut-1 resulted in a lower Vmax. These studies demonstrate the pathogenicity of the R126H missense mutation and transmission of Glut-1 deficiency syndrome as an autosomal dominant trait. PMID- 11603381 TI - 2nd European Meeting of Vascular Biology and Medicine. Ulm, Germany, September 27 29, 2001. Abstracts. PMID- 11603380 TI - Elevated serum and cerebrospinal fluid levels of soluble human herpesvirus type 6 cellular receptor, membrane cofactor protein, in patients with multiple sclerosis. AB - Membrane cofactor protein (CD46) is a member of a family of glycoproteins that are regulators of complement and prevent activation of complement on autologous cells. Recently, CD46 has been identified as the cellular receptor for human herpesvirus Type 6 (HHV-6). Elevated levels of soluble CD46 have been described in several autoimmune disorders, and may be implicated in the pathogenesis of these diseases. As several reports have supported an association of HHV-6 and multiple sclerosis, it was of interest to compare levels of soluble CD46 in the sera of multiple sclerosis patients to that of healthy controls, other neurological disease controls, and other inflammatory disease controls. Using an immunoaffinity column comprised of immobilized monoclonal antibodies to CD46, serum levels of soluble CD46 were found to be significantly elevated in multiple sclerosis patients compared with healthy and other neurological disease controls. Moreover, multiple sclerosis patients who tested positive for HHV-6 DNA in serum had significantly elevated levels of soluble CD46 in their serum compared with those who were negative for HHV-6 DNA. A significant increase in soluble CD46 was also found in the serum of other inflammatory disease controls tested compared to healthy controls. Additionally, a significant correlation was demonstrated between levels of soluble CD46 in the serum and cerebrospinal fluid of multiple sclerosis patients. Collectively, these data suggest that elevated levels of soluble CD46 may contribute to the pathogenesis of inflammatory diseases, including multiple sclerosis. PMID- 11603382 TI - Re: Gomez-Mancilla et al. Safety and efficacy of PNU-142633, a selective 5-HT(1D) agonist, in patients with acute migraine. Cephalalgia 2001;21:727-32. PMID- 11603383 TI - Orthopaedic proceedings. 1999, 200, 2001. Abstracts. PMID- 11603384 TI - American Association for Cancer Education 35th annual meeting. October 18-21, 2001. Los Angeles, California, USA. Abstracts. PMID- 11603385 TI - Vitiligo: a retrospective comparative analysis of treatment modalities in 500 patients. AB - The major non-surgical re-pigmenting therapies for vitiligo include psoralens and corticosteroids, used both topically and systemically. In an attempt to determine the best therapeutic option, we compared the efficacy of various treatment regimens used in our department for the treatment of vitiligo. We report herein our results with six different regimens used in our clinic. Data from five hundred vitiligo patients who attended the pigmentary disorders clinic at the Nehru Hospital, PGI, Chandigarh, was analysed. For the purpose of analysis, patients were arbitrarily divided into two groups based upon the body surface area (BSA) involved: Group A (<10% BSA involved) and B (>10% BSA involved). Group A was further divided into three subgoups of patients depending upon what treatment they received: R-I [topical clobetasol propionate+sun exposure]; R-II [topical psoralen+sun exposure (topical PUVASOL)]; R-III [topical psoralen+UVA (topical PUVA)]. Group B was also subdivided into three subgroups of patients who received: R-IV [oral dexamethasone pulse therapy + sun exposure]; R-V [systemic psoralen + sun exposure (systemic PUVASOL)]; R-VI [systemic psoralen + UVA (systemic PULVA)]. Patients who had undergone, one of the above mentioned regimens and had a regular monthly follow up until total re-pigmentation or for at least one year, whichever was earlier, were included in the final assessment of the therapeutic efficacy of that regimen. At the end of the study in Group A, 207 (89%) patients out of 232 on R-I; 73 (93%) out of 78 on R-II, and 15 (79%) out of 19 patients on R-III showed moderate to excellent re-pigmentation, respectively. In group B, 45 (81%) patients out of 55 on R-IV, 48 (84%) out of 57 on RV, and 22 (84%) patients out of 26 on R-VI showed moderate to excellent re pigmentation. Statistically, in Group A, R-I & II were significantly better than R-III. However in Group B, there was no significant difference in the responses to R-IV, V, and VI. A positive family history of vitiligo did not seem to affect the response rate. Potent topical steroids used along with sun exposure and topical PUVASOL were the most effective forms of therapy for localised vitiligo. For the generalised form of the disease, we concluded that all the systemic modalities, oral steroids, PUVASOL and PUVA, are equally efficacious over a period of one year. Phototoxic reactions were, however, more common with PUVASOL. PMID- 11603386 TI - Surfactant protein D (SP-D) and systemic scleroderma (SSc). AB - We measured serum levels of SP-D in collagen diseases (110 cases) such as systemic scleroderma (SSc), scleroderma spectrum disorders (SSD), systemic lupus erythematodes (SLE), Sjogren syndrome (Sjs), dermatomyositis (DM), rheumatoid arthritis (RA), and dermatitis (DE) (109 cases) as a control. Additionally, we performad a correlation analysis to determine how these levels were related to pulmonary fibrosis and function test (vital capacity, %DLco). The serum levels of SP-D increased in SSc patients with Barnett type III more than in SSc patients with Barnett type I or II, while they increased slightly in SSD (incomplete type of SSc) patients. The differences in these figures were statistically significant between the SSc (SSc & SSD) and non-SSc (SLE, DM, Sjs & RA) groups (p<0.005). The serum levels of SP-D in SSc patients with anti-topoisomerase I antibodies were statistically higher than those in SSc patients with other types of anti-nuclear antibodies. There was a statistically significant correlation between the severity of pulmonary fibrosis and the serum levels of SP-D, and a statistically negative correlation between SP-D levels and vital capacity or %DLco, but there was no proportional correlation with the forced expiatory volume (FEV1.0%). There was no statistical relationship between pre- and post-therapy with photopheresis; however, there was a statistical correlation between the serum levels of SPD and KL-6. In the group of collagen diseases, plasma levels of SP-D were higher than serum levels of SP-D. Patients with SSc possess higher levels of SP-D than do those with other collagen diseases and dermatitis, which may correspond to the severity of pulmonary fibrosis. PMID- 11603387 TI - Detection of species of the subgenus Leishmania parasites using polymerase chain reaction and southern blotting. AB - In this study, an attempt was made to identify different Leishmania species by polymerase chain reaction (PCR). Fourteen Leishmania strains from stock were tested by PCR and Southern blotting. A pair of primers were employed that anneal to the kinetoplast DNA sequence conserved among subgenus Leishmania. Of the 14 Leishmania strains used in this study, six showed strong bands of approximately 170 bp, and all the positive strains belonged to the species of the subgenus Leishmania viz., Leishmania (Leishmania) garnhami, L. (L.) amazonensis, L. (L.) pifanoi, L. (L.) mexicana, L. (L.) chagasi, and L. (L.) major All the species belonging to the subgenus Viannia used in this study were negative by PCR. These results suggest that the primer pair may be useful for identification of the species belonging to the subgenus Leishmania of the New World as well as to distinguish subgenus Leishmania from subgenus Viannia. PMID- 11603388 TI - Oral ivermectin in scabies patients: a comparison with 1% topical lindane lotion. AB - Scabies. which constitutes a significant proportion of the outpatient attendance in tropical dermatology clinics, has so far been treated with lindane, crotamiton, sulphur, permethrin, etc. Ivermectin, an orally administered drug, was tried in scabies patients and compared with 1% topical lindane lotion to evaluate its effects and toxicity profile. Two hundred scabies patients were randomly allocated to one of two groups. One group received oral invermectin in a single dose of 200 micrograms/kg body weight. The other received 1% lindane lotion for topical application overnight. Patients were assessed after 48 hours, two weeks and four weeks. After a period of four weeks, 82.6% of the patients in the ivermectin group showed marked improvement; only 44.44% of the patients in the lindance group showed a similar response. A side effects in the form of severe headache were noted in one patient in group A. Oral ivermectin is an easy drug to administer. It is given as a single oral dose, unlike lindane, which has to be applied topically. The compliance is accordingly increased. Moreover, ivermectin induces an early and effective improvement in signs and symptoms. Thus, it may be a better option for scabies than the traditional topical linlane lotion. PMID- 11603389 TI - Treating ingrown toenails by nail splinting with a flexible tube: an Indian experience. AB - Ingrown toenail is a common problem, and currently available treatments are either quite invasive or associated with unacceptably high recurrence rate. Recently a new non-invasive therapy. "Nail splinting", has been introduced. In this procedure, the nail is splinted with a longitudinally incised plastic tube. We conducted the present study to evaluate the efficacy and safety of this procedure in fifty patients (68 nail edges in 61 nails) with ingrown toenails at all stages. The pain disappeared almost immediately, and inflammation subsided in about one week in all nail edges. Thirty-nine patients came for regular follow-up for six months after removal of the tube. Eight (20.5%) of these patients showed recurrence of the problem. No serious side effects were noted. PMID- 11603390 TI - Extensive partial unilateral lentiginosis. AB - Partial unilateral lentiginosis is a rare pigmentary disorder characterized by multiple lentigines on otherwise normal skin affecting one side of the body. The histology is that of a lentigo. We report two young men with an extensive form of partial unilateral lentiginosis affecting the skin. No systemic abnormalities could be identified. PMID- 11603391 TI - Two cases of unilateral pigmented purpuric dermatosis. AB - Two cases of pigmented purpuric dermatosis showing unusual distribution are reported. Case 1: 35-year-old female. A group of three asymptomatic purpuric macules developed on the ulnar side of the elbow flexure of the left forear 3-6 months before presentation. Histopathological analysis revealed a band-like inflammatory infiltrate in the Uppermost dermis and extravasation of red blood cells just beneath the epidermis, but there was no evidence of lichefaction degeneration in the basal layer of the epidermis. Case 2: 26-year-old female. Asymptomatic purpuric pigmentations developed on the flexure side of the right lower extremity in a linear arrangement 2-3 months before presentation. Histopathological analysis revealed focally perivascular inflammatatory infiltrates consisting mainly of lymphocytes and conspicuous extravasation of red blood cells into the papillary dermis. There was no histological evidence of vasculitis in either case. Hemosiderin deposits were more limited than expected in both patients. Both cases are compatible with diagnoses of pigmented purpuric dermatosis. Case 1 on the left arm was compatible with lichen purpuricus. Case 2 occurred in a linear arrangement on the right leg and had a history of aspirin use for chronic headache. We therefore suspected that medication had been an etiological or contributing factor. PMID- 11603392 TI - A case of acral lentginous melanoma: the correlation between CD95L expression on melanoma cells and apoptosis of tumor infiltrating lymphocytes. AB - There is an increasing amount of evidence that melanoma cells express the ligand for CD95 (CD95L), a potent inducer of apoptosis which contributes to creating the immune privileged circumstances of tumor sites. However, it still remains to be demonstrated whether the capacity of melanoma cells to express CD95L is acquired during the progression. We addressed this question with a case of acral lentiginous melanoma by employing immunostaining using an antibody directed against CD95L as well as by in situ TUNEL staining. H&E-staining of tumor specimens revealed that there were two different growth patterns. The central part of the tumor showed a deeper invasion into the dermis (Breslow thickness >4 mm). The horizontally growing edge of the tumor proliferated more superficially (Breslow thickness<3-mm). Relatively fewer lymphocytes were observed around the melanoma nests in central areas, which expressed detectable amounts of CD95L. In contrast, more lymphocytes were observed among the melanoma cells in the peripheral lesion, where CD95L was not detected. To evaluate the relevance of the CD95L expression, in situ TUNEL staining was performed. This indicated a significant correlation of lymphocyte apoptosis with CD95L expression on melanoma cells. Together the data suggest that expression of CD95L is turned on depending on the level of melanoma, and that it may tribute to creating immune privileged circumstances by initiating apoptosis of tumor filrating lymphocytes. PMID- 11603393 TI - Tuberculosis of the vulva masquerading as a sexually transmitted disease. AB - Tuberculosis of the vulva is a rare condition usually seen by a gynecologist. We report a case of chronic ulcer on the vulva of four months duration, which, on detailed investigation, turned out to be a case of primary inoculation tuberculosis. The patient was subsequently put on antitubercular therapy with a good the therapeutic response. The rarity of this presentation in dermato venereology is emphasized. PMID- 11603394 TI - Sneddon syndrome with multiple cerebral infarctions 12 years after the onset of livedo vasculitis: a possible involvement of platelet activation. AB - Sneddon syndrome is characterized by livedo reticularis and multiple cerebral infarctions. Skin and central nervous system symptoms usually have a synchronous onset and at times initial symptoms affect one of them, the other lagging several years behind. We here report a patient with Sneddon syndrome who developed multiple cerebral infarctions more than 10 years after the onset of livedo reticularis. While the neurological symptoms were apparent, the patient did not display active skin manifestations. Laboratory findings excluded collagen diseases, antiphospholipid antibody syndrome, and inherited quantitative deficiency of protein C, protein S and antithrombin III. Abnormal findings included extremely elevated levels of beta-thromboglobulin and platelet factor-4 in the blood, although these acute phase markers of thrombosis were examined several years after the onset of cerebral infarctions. Platelet activation may have caused Sneddon syndrome in the present case. PMID- 11603395 TI - A leg ulcer due to protein C deficiency: successful treatment with split thickness skin graft after protein C supplementation. PMID- 11603396 TI - A case of congenital tufted angioma mimicking cavernous hemangioma. PMID- 11603397 TI - Anhidrotic ectodermal dysplasia in a child with a fever of unknown origin. PMID- 11603398 TI - Space Life Sciences: Life in the Solar System: Prebiotic Chemistry, Chirality and Space Biology. Proceedings of the F3.4-2, F3.4-3 and F2.4 Symposia of COSPAR Scientific Commission F which were held during the Thirty-third COSPAR Scientific Assembly, Warsaw, Poland, July, 2000. PMID- 11603399 TI - Extraterrestrial organic chemistry: from the interstellar medium to the origins of life. Part 2: complex organic chemistry in the environment of planets and satellites. PMID- 11603401 TI - Back to the future? New cost and access challenges emerge. Initial findings from HSC's recent site visits. AB - Every two years, researchers at the Center for Studying Health System Change (HSC) interview health care leaders in 12 nationally representative communities to assess changes in local health care markets. The third round of site visits is under-way, and early findings from 2000-2001 indicate significant changes in health care financing and delivery are taking place across the country. This Issue Brief discusses developments in managed care, hospital consolidation, physician-hospital tensions, risk contracting and health plan premiums. State and federal policy makers charged with balancing cost, coverage, access and quality of health care should consider these emerging trends in their decision making. PMID- 11603400 TI - EXOCAM: Mars in a box to simulate soil-atmosphere interactions. AB - We present the principle of the EXOCAM chamber, devoted to the study of physical chemical interactions between the atmosphere and the surface and subsurface in Mars conditions. The purpose of this experiment is to reach a better knowledge of the physical and chemical processes that altered the atmosphere-soil coupled system. We describe the scientific goals of EXOCAM, the multiple fields that will benefit from this experiment and the instrumentation that is devoted to the analysis of the results. We also give a description of the chamber and its main devices. PMID- 11603402 TI - Stand-alone health insurance tax credits aren't enough. AB - Using health insurance tax credits to help reduce the ranks of the nearly 43 million uninsured Americans has attracted broad bipartisan support in Congress. But tax credits alone will not help many sick or older people obtain affordable coverage, according to an expert panel at an April 10, 2001, conference sponsored by the Center for Studying Health System Change (HSC). To make tax credits a viable option for eligible people, the individual insurance market would need significant reforms or a better way to spread risk-similar to large employers over a large and varied population. This Issue Brief highlights critical issues policy makers should consider when crafting tax credit proposals, including the use of purchasing pools. PMID- 11603404 TI - Tax credits and purchasing pools: will this marriage work? AB - Bipartisan interest is growing in Congress for using federal tax credits to help low-income families buy health insurance. Regardless of the approach taken, tax credit policies must address risk selection issues to ensure coverage for the chronically ill. Proposals that link tax credits to purchasing pools would avoid risk selection by grouping risks similar to the way large employers do. Voluntary purchasing pools have had only limited success, however. This Issue Brief discusses linking tax credits to purchasing pools. It uses information from the Center for Studying Health System Change's (HSC) site visits to 12 communities as well as other research to assess the role of purchasing pools nationwide and the key issues and implications of linking tax credits and pools. PMID- 11603403 TI - Race, ethnicity and preventive services: no gains for Hispanics. AB - Three years ago, the Clinton administration initiated multiple efforts to identify and eliminate health disparities among various populations, including ethnic minority groups. Recent findings from the Community Tracking Study Household Survey show that between 1997 and 1999 there was an increase in the percentage of white and African American persons receiving preventive care-such as mammography screening among women and physicians counseling cigarette smokers to quit-but that there was no such increase in preventive measures for Hispanics. If policy makers want to remove disparities in health status based on race and ethnicity, they need to promote preventive care for minorities and monitor progress by regularly measuring preventive care indicators. This Issue Brief focuses on change in key preventive care indicators between 1997 and 1999. PMID- 11603405 TI - Defined contributions: the search for a new vision. AB - Proponents of defined contributions for health benefits seek to broaden choice and control costs by raising employees' cost awareness. Although defined contributions for health benefits have sparked considerable debate, they have not yet caught on with large employers. Given the tight labor market and consumer resistance to paying more for health care, employers are not expected to adopt defined contributions in the short term, according to a panel of business and union representatives at a recent Center for Studying Health System Change (HSC) conference. This Issue Brief presents experts' outlooks on how likely employers are to embrace defined contributions, their views on the advantages and disadvantages and the potential for Internet solutions. Implications for policy makers are discussed. PMID- 11603406 TI - Emergency room diversions: a symptom of hospitals under stress. AB - Emergency room (ER) diversions-when ambulances are redirected from one hospital emergency room to another-are becoming common in communities across the country, raising concern that critically ill patients are increasingly confronting obstacles to timely medical care. Although hospitals have long diverted patients during the winter flu season, recent site visits conducted by the Center for Studying Health System Change (HSC) reveal that ER overflows are now a year-round problem. As this Issue Brief describes, difficulty obtaining emergency services may be just the most visible evidence of deeper problems facing many hospitals as they struggle to meet growing demand for services at a time of increasing capacity constraints. PMID- 11603407 TI - Provider network instability: implications for choice, costs and continuity of care. AB - Many health care issues of greatest concern to consumers-including provider choice, costs and continuity of care-depend on health plans' ability to maintain adequate networks of hospitals, physicians and other caregivers. When providers drop out of plan networks, consumers may suddenly face the choice of changing caregivers or paying more for out-of-network care. Network instability is increasingly common in health care markets across the country and can arise from health plan-provider contract disputes and provider organization insolvencies. This Issue Brief, which is based on the Center for Studying Health System Change's (HSC) 2000-01 site visits to 12 nationally representative communities, examines this growing trend and the implications for consumers, including diminished choice and higher costs. PMID- 11603408 TI - Health plan-provider showdowns on the rise. AB - During the past two years, increasing numbers of contract disputes between health plans and hospitals and physicians have erupted in local markets, according to recent Center for Studying Health System Change (HSC) visits to 12 nationally representative communities. Many providers are taking a hard line in negotiations, threatening to terminate health plan contracts if payment demands go unmet. These contract showdowns signal a shift in the balance of power in local markets toward hospitals and physicians and can potentially disrupt care for many patients, especially when the disputes involve communities' largest and most prominent hospitals and physician groups. This Issue Brief presents case studies of showdowns in Boston, Orange County, Calif., and Seattle, highlighting the changing market dynamics triggering these disputes and the implications for consumers, including rising costs and diminished access to care. PMID- 11603409 TI - Physicians pulling back from charity care. AB - Physicians have long provided care to the medically indigent for free or at reduced rates. However, recent findings from the Center for Studying Health System Change (HSC) indicate that the proportion of physicians providing charity care dropped from 76 percent to 72 percent between 1997 and 1999. In the short term, most medically indigent people are still getting care. But policy makers should take note that reduced physician participation in charity care will hurt the poor if-as projected-growth in physician supply slows and the number of uninsured rises along with escalating health care costs. This Issue Brief discusses the extent of the decline in physician provision of charity care, the reasons for the decline and implications for the future of the safety net. PMID- 11603410 TI - Wall Street comes to Washington: market watchers and policy analysts evaluate the health care system. AB - As health care costs surge again, most insured consumers are enjoying greater access to care, many health plans are prospering and employers are wringing their hands over how to pay for it all, according to market and health policy analysts at the Center for Studying Health System Change's (HSC) sixth annual Wall Street roundtable. Panelists discussed the outlook for managed care, including the Medicare+Choice program, hospitals and pharmaceutical costs; the untapped promise of evidence-based medicine to help control costs; and the growing animosity between health plans and providers. PMID- 11603411 TI - Deferiprone: new preparation. Poorly assessed. AB - Deferiprone, an oral iron chelator, has been licensed in Europe for the treatment of iron overload in patients with beta thalassaemia who cannot be treated with deferoxamine because of adverse effects or the difficult administration schedule. (2) The clinical dossier is thin and methodologically mediocre. Even the preclinical assessment dossier is insufficient (there are no studies of carcinogenicity or hepatotoxicity). (3) The only available comparative trial, involving a small number of patients, suggests that deferiprone is less effective than deferoxamine in reducing ferritin levels and hepatic iron stores. (4) A non comparative trial suggests that long-term deferiprone therapy would not only fail, but would also increase the risk of liver fibrosis in some patients. This doubt is not dispelled by the other available non-comparative trials. (5) Deferiprone carries a risk of agranulocytosis in an estimated 1.2% of patients. (6) Deferiprone is teratogenic in two animal species. PMID- 11603412 TI - Eptifibatide and tirofiban: new preparations. Limited benefit. AB - (1) Two antiplatelet drugs, eptifibatide and tirofiban, are licensed for the prevention of early myocardial infarction in patients with unstable angina or non Q-wave myocardial infarction. (2) These drugs appear to have a mechanism similar to that of abciximab. Abciximab reduced the incidence of myocardial infarction during the month following administration to patients with unstable angina who were scheduled for a percutaneous coronary procedure. (3) The clinical assessment files on eptifibatide and tirofiban are both centred on a large double-blind, placebo-controlled trial. (4) In patients with unstable angina or non Q-wave myocardial infarction, the PURSUIT trial, involving 10,948 patients, showed a lower incidence, at one month, of a combined end point (death or non fatal myocardial infarction) in patients on the eptifibatide + heparin + aspirin combination than in patients on the heparin + aspirin + placebo combination. A retrospective subgroup analysis raised the hypothesis that eptifibatide would be most beneficial in patients who had had coronary interventions. (5) In patients with unstable angina or non Q-wave myocardial infarction, the patients with unstable angina or non Q-wave myocardial infarction, the PRISM-PLUS trial, involving 1,915 patients, showed a reduction in the risk of myocardial infarction at 7 days in patients on the tirofiban + heparin + aspirin combination compared with those on the heparin +aspirin combination. Here too a retrospective subgroup analysis suggested that tirofiban would be most beneficial in patients who had had coronary intervention. (6) On the whole, these three antiplatelet drugs appear to benefit the same type of patient at high risk of myocardial infarction, but abciximab has been more thoroughly assessed than eptifibatide and tirofiban. Neither eptifibatide nor tirofiban (which were developed simultaneously) has been directly compared with abciximab. The value of antiplatelet drugs in patients treated with a low-molecular-weight heparin + aspirin combination is unknown. (7) These antiplatelet drugs carry a risk of haemorrhage and thrombocytopenia. On treatment cessation, coagulation function appears to normalise slightly more rapidly with eptifibatide (approximately 6 hours) and tirofiban (approximately 8 hours) than with abciximab (approximately 12 hours). PMID- 11603413 TI - Albendazole: new indication. Useful adjunct in hydatid disease. AB - (1) Albendazole, an antiparasitic drug belonging to the benzimidazoles, is indicated in France for the treatment of hydatid disease and alveolar echinococcosis. (2) According to non comparative data and a small comparative trial, albendazole is helpful when surgical removal and percutaneous drainage of a hydatid cyst are impossible. The best ways to use this treatment are not, however, known. One comparative trial showed the value of albendazole before surgery. Two other comparative trials showed the benefit of combining albendazole with percutaneous drainage, an approach that can replace surgical excision. (3) In the absence of comparative trials we do not know if the prognostic improvement seen in alveolar echinococcosis in recent years can be ascribed to albendazole. (4) Transaminase activity and blood cell counts should be checked regularly (there may be a small risk of neutropenia). PMID- 11603414 TI - Human immunoglobulin and the Guillain-Barre syndrome: new indication. An alternative to plasmapheresis. AB - (1) Human polyvalent immunoglobulin for intravenous administration has now been licensed in France for the treatment of adults with Guillain-Barre syndrome. (2) Its clinical assessment is mainly based on a comparative trial versus plasmapheresis, until now the reference treatment. (3) In this trial immunoglobulin was equivalent to plasmapheresis as regards the hastening of motor recovery and the prevention of complications. The combination of the two treatments was not superior to each treatment used alone. (4) The adverse effects of immunoglobulin are relatively infrequent and generally mild. (5) Immunoglobulin administration is simpler and safer than plasmapheresis. PMID- 11603415 TI - Severe cardiac arrythmia on cisapride. AB - (1) Cisapride prolongs the QT interval and can cause torsades de pointes and ventricular tachycardia. (2) Cases of cardiac arrhythmia and death have occurred, even in the absence of underlying factors such as high doses and interactions with enzyme-inhibiting drugs (especially macrolide antibiotics, HIV protease inhibitors and antifungal imidazoles). (3) Cisapride was withdrawn from the market in the United States on 14 July 2000 and in Canada on 7 August 2000. We recommend that this measure should be applied worldwide. PMID- 11603416 TI - Acute diarrhoea in infants: oral rehydration is crucial. AB - (1) Dehydration is the most immediate complication of acute diarrhoea. Infants still die by dehydration, or suffer severe repercussions. (2) Thirst is an early sign of dehydration in an infant. Other signs are delayed capillary filling, absence of tears, mucosal dryness and a "sickly" appearance. Fever or vomiting in the first 24 hours facilitate dehydration. Weight loss is the main clinical index of the degree of dehydration. (3) Oral rehydration with glucose-electrolyte solution is as effective as intravenous rehydration. It must start immediately dehydration occurs. Infants with signs of severe dehydration must be hospitalised. (4) Oral rehydration of a vomiting infant is feasible, by giving a teaspoonful of solution every one or two minutes. (5) A dehydrated infant rarely refuses oral rehydration solutions. (6) Beverages such as cola drinks are inappropriate for rehydration, as they contain too little sodium and are excessively hyperosmolar, which may worsen the diarrhoea. Rice gruel is better. (7) Antidiarrhoeal drugs do not prevent dehydration. (8) Feeding must be resumed as soon as dehydration has been corrected, as it shortens the course of diarrhoea. Continuing maternal breast-feeding reduces the severity of diarrhoea. Lactose-free "milk" has no demonstrated benefit. (9) Those in charge of an infant with diarrhoea must know how to prevent severe dehydration, which can occur very rapidly. Fluid intake must always be increased in an infant with diarrhoea. Sachets of powder for oral rehydration should be kept at home. Their prescription and dispensing should be accompanied by written instructions. PMID- 11603417 TI - Quinine and cramp: uncertainty efficacy, major risks. AB - (1) Simple muscle cramp is a mild condition. It is defined as painful involuntary muscle contraction that occurs at rest and resolves spontaneously. (2) Passive stretching of the affected muscle relieves cramp. (3) The clinical file on quinine in simple cramp is inadequate, being based on small trials with conflicting results. (4) Two meta-analysis of comparative cross-over trials suggest that the benefit of quinine is negligible in this setting (less than one cramp avoided per week of treatment). (5) Severe and even fatal adverse effects have been reported, especially haematological complications such as thrombocytopenia, haemolytic anaemia, pancytopenia, and disseminated intravascular coagulation. (6) Dose-dependent sensory manifestations of cinchonism are far from rare (especially tinnitus). (7) The risk-benefit ratio of quinine in cramp is too unfavourable to justify its use. PMID- 11603419 TI - The practice of medicine in the year 2010: revisited in 2001. PMID- 11603418 TI - Spironolactone in severe heart failure: enhances efficacy of diuretic + ACE inhibitor combinations. AB - (1) In patients with heart failure who remain symptomatic despite combination therapy with a diuretic and an angiotensin-converting-enzyme (ACE) inhibitor, a strictly conducted trial has shown that adding spironolactone at a mean dose of 25 mg/day reduces overall mortality by approximately 5% per year, and reduces the incidence of hospitalisation for heart disease and disability. (2) There is a risk of gynaecomastia (9%) and potentially severe hyperkalaemia. (3) It is crucial to follow the protocol used in the clinical trial, i.e. this treatment is contraindicated in severe renal failure or hyperkalaemia; creatinine and potassium levels must be monitored strictly; and spironolactone must be combined with a loop diuretic. PMID- 11603420 TI - Changing the way we think about medical technology policy. PMID- 11603421 TI - Thoracic surgical involvement in vascular surgery. PMID- 11603422 TI - Impact of hospital volume on clinical and economic outcomes for esophagectomy. AB - BACKGROUND: Several complex surgical procedures had a reduction in mortality when they were performed at high volume centers. We hypothesized esophagectomy procedures for cancer performed at high volume hospitals in the state of Massachusetts would show a similar relationship. METHODS: Data were obtained from the Massachusetts Health Data Consortium on discharge information for all acute care hospitals in Massachusetts regardless of payer from 1992 to 2000. The influence of hospital volume was related to days in the intensive care unit, length of stay, discharge disposition, hospital mortality, and total cost. Hospitals were stratified to low volume hospitals (< 6 cases per year) and high volume hospitals (> 6 cases per year). RESULTS: One thousand one hundred ninety three patients underwent esophagectomy during this 8-year study period in Massachusetts. Three high volume hospitals performed 56.5% of all resections (674 of 1,193). Sixty-one low volume hospitals performed 43.5% of the resections (519 of 1,193) with an average volume of only 1 case of esophagectomy per year. High volume hospitals were associated with a 2-day decrease in median length of stay (p < 0.001), a 3-day reduction in median intensive care unit stay (p < 0.001), an increased rate of home discharges (as opposed to rehabilitation hospitals) (p < 0.001), and a 3.7-fold decrease in hospital mortality (9.2% vs 2.5%; p < 0.001). The odds ratio of death at a low volume hospital was 4.3 (95% confidence interval, 2.3 to 7.7; p < 0.001). The median cost was $755 dollars greater at high volume hospitals (p = not significant). CONCLUSIONS: Hospitals that perform a high volume of esophagectomies have better results with early clinical outcomes and marked reductions in mortality compared with low volume hospitals. PMID- 11603423 TI - Laparoscopic repair of large paraesophageal hiatal hernia. AB - BACKGROUND: The objective of this study was to analyze our initial results after laparoscopic repair of large paraesophageal hiatal hernias. METHODS: Between October 1997 and May 2000, 37 patients (23 women, 14 men) underwent laparoscopic repair of a large type II (pure paraesophageal) or type III (combined sliding and paraesophageal) hiatal hernia with more than 50% of the stomach herniated into the chest. Median age was 72 years (range 52 to 92 years). Data related to patient demographics, esophageal function, operative techniques, postoperative symptomatology, and complications were analyzed. RESULTS: Laparoscopic hernia repair and Nissen fundoplication was possible in 35 of 37 patients (95.0%). Median hospitalization was 4 days (range 2 to 20 days). Intraoperative complications occurred in 6 patients (16.2%) and included pneumothorax in 3 patients, splenic injury in 2, and crural tear in 1. Early postoperative complications occurred in 5 patients (13.5%) and included esophageal leak in 2, severe bloating in 2, and a small bowel obstruction in 1. Two patients died within 30 days (5.4%), 1 from delayed splenic bleeding and 1 from adult respiratory distress syndrome secondary to a recurrent strangulated hiatal hernia. Follow-up was complete in 31 patients (94.0%) and ranged from 3 to 34 months (median 15 months). Twenty-seven patients (87.1%) were improved. Four patients (12.9%) required early postoperative dilatation. Recurrent paraesophageal hiatal hernia occurred in 4 patients (12.9%). Functional results were classified as excellent in 17 patients (54.9%), good in 9 (29.0%), fair in 1 (3.2%), and poor in 4 (12.9%). CONCLUSIONS: Laparoscopic repair of large paraesophageal hiatal hernias is a challenging operation associated with significant morbidity and mortality. More experience, longer follow-up, and further refinement of the operative technique is indicated before it can be recommended as the standard approach. PMID- 11603424 TI - Correlation between dysplasia and mutations of six tumor suppressor genes in Barrett's esophagus. AB - BACKGROUND: Barrett's esophagus (BE) may progress to adenocarcinoma through dysplastic progression. Classification of dysplasia in BE has significant interobserver variability. Our objective was to determine whether genetic alterations in BE correlate with degrees of histologic dysplasia. METHODS: Fixed tissue from 37 patients with BE and adenocarcinoma was studied for six tumor suppressor genes. Tissues were microdissected and analyzed for loss of heterozygosity. Microdissection of individual crypts showing metaplasia and dysplasia were performed and analyzed for 23 of the 37 patients whose tumors were heterozygous for at least four of the six genes studied. RESULTS: Frequency of alterations for MXI1, hOGG1, p53, MTS1, DCC, and APC were 7 of 32 (22%), 12 of 35 (34%), 12 of 26 (46%), 17 of 30 (57%), 17 of 27 (63%), and 23 of 36 (64%), respectively. Analysis of BE demonstrated that crypts with metaplasia, low-grade dysplasia, and high-grade dysplasia strongly correlated with alterations in tumor suppressor genes (p < 0.0001). CONCLUSIONS: This pilot study demonstrates that genetic analysis can be performed on individual crypts in patients with BE, and that alterations may facilitate objective classification of the severity of dysplasia. PMID- 11603425 TI - Photosensitization with hematoporphyrin derivative compared to 5-aminolaevulinic acid for photodynamic therapy of esophageal carcinoma. AB - BACKGROUND: Hematoporphyrin derivatives (HpD) as sensitizers for photodynamic therapy (PDT) in advanced esophageal cancer carry the risk of prolonged photosensitivity of the skin. New sensitizers such as 5-aminolaevulinic acid (ALA) with low rates of skin phototoxicity appear to be promising alternatives. The aim of this study was to evaluate the efficacy of ALA compared with HpD for PDT in advanced esophageal carcinoma regarding phototoxicity of the skin, reduction of dysphagia, tumor stenosis and length, and Karnovsky performance status. METHODS: After diagnostic workup, photosensitization was done in 22 patients with ALA (60 mg/kg body weight, oral, 6 to 8 hours before PDT) and in 27 patients with a hematoporphyrin derivative (2 mg/kg body weight, intravenously, 48 hours before PDT). The light dose was calculated as 300 J/cm fiber tip. Light at 630 nm was applied using a pumped dye laser. In both groups, additional hyperbaric oxygenation was applied at a level of 2 absolute atmospheric pressure. RESULTS: Improvement regarding dysphagia, stenosis diameter, and tumor length could be obtained in both treatment arms with a significant difference in favor of the HpD group (p = 0.02; p = 0.0000; and p = 0.000014, respectively). A questionnaire of patients in the HpD group confirmed that the ability of swallowing a meal was superior compared with the discomfort from limitation to sun exposure. No sunburn or other major treatment-related complication occurred in both treatment arms. CONCLUSIONS: Despite the limitations of a nonrandomized study, photosensitzation with HpD seems to be more effective in PDT of advanced esophageal carcinoma compared with ALA. PMID- 11603426 TI - Pharyngo-enteral anastomosis for esophageal reconstruction in diffuse corrosive esophageal stricture. AB - BACKGROUND: Diseases involving the entire esophagus usually require extensive surgical procedures to accomplish functional reconstruction. These procedures are extremely stressful for undernourished patients. We have utilized a simpler procedure for total esophageal reconstruction. METHODS: This retrospective report reviews the experience in 8 patients who underwent esophageal reconstruction by pharyngo-colo-gastrostomy or jejunostomy without any resection of bony structures. RESULTS: There was no operative or hospital death. Complications included anastomotic stenosis, transient leak from the ileal stump, and late enterocutaneous fistula, each in 1 patient. Laryngeal function was maintained without special treatments. After swallowing training for approximately 1 week, oral feeding was resumed. All patients have gained 7 to 21 kg at 35 to 67 months after surgery. CONCLUSIONS: Our surgical procedure is shown to be safe and effective in undernourished patients with diffuse esophageal stricture. PMID- 11603427 TI - Predicting the sites of metastases from lung cancer using molecular biologic markers. AB - BACKGROUND: The use of molecular markers in staging non-small cell lung cancer (NSCLC) has been supported in retrospective prognostic models but has not been evaluated in predicting sites of metastases. METHODS: Pathologic specimens were collected from 202 patients after complete resection for stage I NSCLC, who were subsequently found to have no metastases at 5 years (n = 108), isolated brain metastases (n = 25), or other distant metastases (n = 69). A panel of eight molecular markers of metastatic potential was chosen for immunohistochemical analysis of the tumor: p53, erbB2, angiogenesis factor viii, EphA2, E-cadherin, urokinase plasminogen activator (UPA), UPA receptor, and plasminogen activator inhibitor. RESULTS: Patients with isolated brain relapse had significantly higher expression of p53 (p = 0.02) and UPA (p = 0.002). The quantitative expression of E-cadherin was used to predict the site of metastases using recursive partitioning: 0 of 92 patients with E-cadherin expression of 0, 1, or 2 developed isolated cerebral metastases; 0 of 33 patients with E-cadherin expression of 3 with UPA of 1 or 2 and ErbB2 of 0 developed brain metastases. Of the remaining patients at risk (UPA = 3), the risk of isolated cerebral metastases was 21 of 57 patients (37%). CONCLUSIONS: This study demonstrates that molecular markers may predict the site of relapse in early stage NSCLC. If validated in an ongoing prospective study, these results could be used to select patients with isolated brain metastases for adjuvant therapy, such as prophylactic cranial irradiation. PMID- 11603428 TI - Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy. AB - BACKGROUND: The risks of complications in patients undergoing thoracotomy after neoadjuvant therapy for nonsmall cell lung cancer remain controversial. We reviewed our experience to define it further. METHODS: All patients undergoing thoracotomy after induction chemotherapy from 1993 through 1999 were reviewed. Univariate and multivariate methods for logistic regression model were used to identify predictors of adverse events. RESULTS: Induction chemotherapy included mitomycin, vinblastine, and cisplatin (179 patients), carboplatin and paclitaxel (152 patients), and other combinations (139 patients). Eighty-five patients (18%) received preoperative radiation. Operations were pneumonectomy (97 patients), lobectomy (297 patients), lesser resection (18 patients), and exploration only (58 patients). Total mortality was 7 of 297 (2.4%) and 11 of 97 (11.3%) for all lobectomies and pneumonectomies, respectively, but mortality was 11 of 46 (23.9%) for right pneumonectomy. Complications developed in 179 patients (38%). By multiple regression analysis, right pneumonectomy (p = 0.02), blood loss (p = 0.01), and forced expiratory volume in one second (percent predicted) (p = 0.01) predicted complications. No factor emerged to explain this high right pneumonectomy mortality rate. CONCLUSIONS: Pulmonary resection after neoadjuvant therapy is associated with acceptable overall morbidity and mortality. However, right pneumonectomy is associated with a significantly increased risk and should be performed only in selected patients. PMID- 11603430 TI - Significance of lymphangiosis carcinomatosa at the bronchial resection margin in patients with non-small cell lung cancer. AB - BACKGROUND: Treatment options for patients with microscopic residual disease at the bronchial margin (R1-resection) after resection for non-small cell lung cancer include observation, radiotherapy, reoperation, or even systemic therapy. The present study was performed to identify a parameter that would estimate the prognosis of these patients more precisely to permit a well-founded treatment recommendation for the individual patient. METHODS: A total of 1,162 patients with resected non-small cell lung cancer were analyzed in this retrospective study. Fifty-four patients (4.6%) had R1-resections at the bronchial margin. Type of residual disease (mucosal, extramucosal, or involvement of the entire bronchial wall) and occurrence of tumor cells in the lymphatic vessels (lymphangiosis carcinomatosa) were recorded as distinct parameters and analyzed by univariate and multivariate analyses (Log rank test; Cox regression model). RESULTS: Lymphangiosis carcinomatosa at the bronchial margin was detected in 22 patients (40.7%) and was associated with a significantly shortened survival (median survival with lymphangiosis carcinomatosa, 13.3 months; without lymphangiosis carcinomatosa, 20.1 months; p = 0.026). Early stage patients (stage I-II) without lymphangiosis carcinomatosa showed a median survival of 49 months. Multivariate analysis revealed that lymphangiosis carcinomatosa at the resection margin is an independent prognostic parameter (p = 0.038). Even after postoperative radiotherapy the prognosis was still poor if a lymphangiosis carcinomatosa was detected (median survival, 17.1 months). All other parameters (T-stage, N-stage, tumor histology, type of bronchial wall involvement) were not of prognostic significance in R1-resected patients. CONCLUSIONS: Lymphangiosis carcinomatosa at the bronchial resection margin predicts a poor prognosis in patients with non-small cell lung cancer. It is more than questionable whether these patients would benefit from local treatment options like radiotherapy. PMID- 11603429 TI - Results of surgical resection of patients with primary lung cancer: a retrospective analysis of 1,905 cases. AB - BACKGROUND: Surgical resection, combined therapies, and lymphadenectomy are extensively utilized in the treatment of patients with lung cancer. In the present study, we summarized the clinical data of patients with primary lung cancer after surgical resection alone or combined with adjuvant therapy, and evaluate the main factors influencing long-term survival. METHODS: A retrospective review of 1,905 consecutive patients with primary lung cancer treated at the Cancer Institute of the Chinese Academy of Medical Sciences from March 1961 through December 1995 was performed. Statistical analysis was done using STATA software. The survival rate was estimated using the life-table method. Survival differences were performed using the log-rank test. The modified 1997 TNM staging system was used. RESULTS: There was a 12.28% morbidity rate and a 1.31% hospital mortality in our series. The 5-year survival rate for the complete resection was 49.5% and for the palliative resection 18.8% (p < 0.01). The 5-year survival rate was 72.0% in stage IA and 61.0% in stage IB (p < 0.05), 32.9% in stage IIA and 34.5% in stage IIB, 22.6% in stage IIIA and 15.9% in stage IIIB (p < 0.05), and 7.1% in stage IV. CONCLUSIONS: Multiple factors influence the long-term survival of patients with primary lung cancer after surgery. They include TNM staging, the extent of surgical resection (complete or palliative), resection margin (positive or negative), pathologic type of tumors, and type of resection. PMID- 11603431 TI - Effect of a cyclooxygenase-2 inhibitor, FK3311, in a canine lung transplantation model. AB - BACKGROUND: In the process of ischemia-reperfusion, inflammatory cytokines and arachidonic acid metabolites are released and followed by tissue damage. FK3311 (FK) is a selective cyclooxygenase-2 inhibitor that inhibits conversion of arachidonic acid into thromboxane A2 or prostaglandin I2. We investigated the effects of FK in canine lung transplantation. METHODS: FK3311 was administered in the FK group, and vehicle was injected in the control group. The left lung was orthotopically transplanted after 12-hour preservation in Euro-Collins solution. After reperfusion, the right pulmonary artery and bronchus were ligated, and the animals were observed. Pulmonary gas exchange and hemodynamics were measured, histopathologic damages were investigated, and technetium-99m-labeled albumin scintigraphy was performed. The serum prostanoid levels were also measured. RESULTS: In the FK group, pulmonary gas exchange and hemodynamics were significantly (p < 0.05) better, histologic damage and neutrophil infiltration was reduced, and technetium-99m-albumin accumulation was considerably suppressed. Also, thromboxane B2 was significantly (p < 0.05) lower, but 6-keto-prostaglandin F1alpha was not significantly reduced. CONCLUSIONS: FK3311 generates protective effects on lung transplantation by a marked inhibition of thromboxane A2. PMID- 11603432 TI - Digitonin enhances the antitumor effect of cisplatin during isolated lung perfusion. AB - BACKGROUND: The antitumor effect of isolated lung perfusion with cisplatin was limited because the intracellular platinum concentration did not increase sufficiently. To solve this problem, digitonin, a detergent, was chosen to increase cell permeability and enhance intracellular uptake and antitumor effect. This study was designed to investigate toxicity, pharmacokinetics, and efficacy of isolated lung perfusion with the combined use of digitonin and cisplatin in Fischer 344 rats. METHODS: Systemic and local toxicities of isolated lung perfusion treatment were evaluated on the basis of body weight change, survival rate, and histologic findings. The maximal tolerated dose of digitonin was determined by assessing survival on day 21 after contralateral pneumonectomy, body weight change, and histologic findings. Pharmacokinetics were observed in a solitary lung tumor nodule model by measuring platinum concentration in tumor and normal lung tissue. The antitumor effect was evaluated by the number of tumor nodules in the left lung 21 days after isolated lung perfusion. Isolated lung perfusion was performed 7 days after 1.0 x 10(6) methylcholanthrene sarcoma cells were injected into the external jugular vein. RESULTS: The maximal tolerated dose of digitonin was 20 micromol/L. Platinum concentration of tumor nodules in the digitonin-cisplatin-treated rats was 20% higher than in the cisplatin-only group (5.48 +/- 0.64 microg/g tissue versus 4.50 +/- 1.09 microg/g tissue; p = 0.067). The number of pulmonary nodules decreased significantly by digitonin use (1.3 +/- 1.5 versus 9.7 +/- 2; p < 0.0001). CONCLUSIONS: Isolated lung perfusion with digitonin and cisplatin in combination was performed safely and enhanced the antitumor effect. These drugs in combination show promise for enhancing the effect of clinical isolated lung perfusion. PMID- 11603433 TI - Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study. AB - BACKGROUND: Neuroendocrine tumors of the thymus are rare, histologically diverse neoplasms with an unpredictable clinical behavior. This study provides a useful clinicopathological classification and determines the relevance of specific prognostic factors. METHODS: Ten neuroendocrine tumors of the thymus were analyzed for specific clinical and pathological features. Prognostic factors of these cases and 71 previously published cases were evaluated by Kaplan-Meier survival curves and Cox multivariate hazard model. RESULTS: There were 7 males and 3 females, with ages ranging from 26 to 77 years. Cases were classified as carcinoid tumor (2), atypical carcinoid tumor (6), and small cell carcinoma (2). An advanced clinical stage was evident in all instances with frequent recurrence (4) and metastases (8), and a short disease-free survival. Overall mortality was 60%. Statistical analysis of current and previously published cases (n = 81 total) revealed that unresectability (p = 0.0001), extent of surgical resection (p = 0.0002), and advanced clinical stage at presentation (p = 0.03) were associated with higher mortality. By multivariate Cox regression analysis, unresectability (p = 0.02) and advanced clinical stage (p = 0.03) were associated with decreased survival. CONCLUSIONS: Neuroendocrine tumors of the thymus can be classified into distinct clinicopathological entities, and specific factors have prognostic relevance. PMID- 11603434 TI - Heparin and the nonanticoagulant N-acetyl heparin attenuate capillary no-reflow after normothermic ischemia of the lung. AB - BACKGROUND: Ischemia-reperfusion injury of the lung frequently occurs after cardiopulmonary bypass, after pulmonary thromboendarterectomy, and especially after lung transplantation. Heparin is known to be protective in ischemia reperfusion injury, but the risk for bleeding disorders may restrict its use in a variety of diseased conditions. Therefore, we tested the efficiency of nonanticoagulant N-acetyl (NA) heparin to protect from postischemic reperfusion injury of the lung. METHODS: Pentobarbital-anesthetized, mechanically ventilated Lewis rats were heparinized (100 IU/kg) before insertion of catheters. Additionally, animals received either heparin (200 IU/kg; n = 7), NA heparin (1.1 mg/kg; n = 7), or saline (control, n = 7) before ischemia. After normothermic ischemia for 50 minutes, the left lung was reperfused for 120 minutes, or until the death of the animal. The nonischemic right lung was excluded after 10 minutes of reperfusion. RESULTS: Survival rate at 120 minutes of reperfusion was 7 of 7 and 6 of 7 in the heparin and the NA-heparin group, but 0 in 7 in the control group (p < 0.01). At 30 minutes of reperfusion, PaO2, blood flow through the ascending aorta and mean systemic blood pressure were also significantly higher in the heparin and the NA-heparin group when compared with the control group (p < 0.05). Pulmonary vascular resistance was significantly lower in the heparin and the NA-heparin groups, and histologic examination of the lungs from these groups confirmed reperfusion of nutritive alveolar capillaries by the presence of red blood cells. Lack of red blood cells in the alveolar capillaries of lung specimens from the control group indicated failure of capillary reperfusion. CONCLUSIONS: Heparin and NA heparin exert similar protection against capillary no reflow after normothermic ischemia of the lung. This implies that the protective effect of heparin is mediated by properties different from its anticoagulant activity. Thus the nonanticoagulant N-acetyl heparin may pose a safe new therapeutic approach in lung ischemia-reperfusion injury without increasing the risk of hemorrhagic complications. PMID- 11603435 TI - Tracheal allotransplantation in beagle dogs without immunosuppressants. AB - BACKGROUND: The antigenicity of tracheal grafts is still unclear. We investigated the possibility of performing tracheal allotransplantation without immunosuppressants. METHODS: Intrathoracic five-ring tracheal replacements were performed in beagle dogs without immunosuppressants (n = 18). The dogs were divided into 9 pairs, and grafts were exchanged within the pairs. In group 1 (n = 6), the paired dogs were blood relatives, whereas in group 2 (n = 12), the paired dogs were not related. Full-thickness skin transplantation was also performed in both groups. RESULTS: In group 1, 5 animals survived uneventfully for more than 3 months. No stenosis was observed in any of the dogs. In group 2, the grafts were incorporated by the host trachea in 2 dogs. Four animals died of airway obstruction within 3 months. Moderate or slight airway stenosis was observed in 6 dogs. Rejection was confirmed by histologic examination. In both groups, all of the skin allografts were destroyed within 2 weeks. CONCLUSIONS: After tracheal allotransplantation, long-term survival was achieved, especially in recipient dogs that were blood relatives of donors. We conclude that it is possible to perform tracheal allotransplantation using histocompatible matched grafts without immunosuppressants. PMID- 11603436 TI - Stroke after cardiac surgery: short- and long-term outcomes. AB - BACKGROUND: Stroke remains a devastating complication of cardiac surgery, but stroke prevention remains elusive. Evaluation of early and long-term clinical outcomes and brain-imaging findings may provide insight into stroke prognosis, etiology, and prevention. METHODS: Five thousand nine hundred seventy-one cardiac surgery patients were prospectively studied for clinical evidence of stroke. Stroke and nonstroke patients were compared by early outcomes. Data collected for stroke patients included brain imaging results, long-term functional status, and survival. Outcome predictors were then determined. RESULTS: Stroke was diagnosed in 214 (3.6%) patients. Brain imaging demonstrated acute infarction in 72%; embolic in 83%, and watershed in 24%. Survival for stroke patients was 67% at 1 year and 47% at 5 years. Independent predictors of survival were cerebral infarct type, creatinine elevation, cardiopulmonary bypass time, preoperative intensive care days, postoperative awakening time, and postoperative intensive care days. Long-term disability was moderate to severe in 69%. CONCLUSIONS: Stroke after cardiac surgery has profound repercussions that are independently related to infarct type and clinical factors. These data are essential for clinical decision making and prognosis determination. PMID- 11603437 TI - Evolution of mitral valve surgery: toward a totally endoscopic approach. AB - BACKGROUND: Our study evaluates a series of video-assisted minimally invasive mitral operations, showing safe progression toward totally endoscopic techniques. METHODS: Consecutive patients with isolated mitral valve disease underwent either manually directed (n = 55) or voice-activated robotically directed (n = 72) video assisted mitral operations. Cold blood cardioplegia, a transthoracic aortic clamp, a 5-mm endoscope, and a 5-cm minithoracotomy were used. This video assisted minimally invasive mitral operation cohort was compared with a previous sternotomy-based mitral operation cohort (n = 100). RESULTS: Group demographics, New York Heart Association classification, and cardiac function were similar. Repairs were performed in 61.8% manually directed (n = 34), 75.0% robotically directed (n = 54), and 54% sternotomy-based (N = 54) mitral operations. The robotically directed technique showed a significant decrease in blood loss, ventilator time, and hospitalization compared with the sternotomy-based technique. Manually directed mitral operations compared with robotically directed mitral operations had decreased arrest times (128.0 +/- 4.5 minutes compared with 90.0 +/- 4.6 minutes; p < 0.001) and decreased perfusion times (173.0 +/- 5.7 minutes compared with 144.0 +/- 4.6 minutes; p < 0.001). In the minimally invasive mitral operation cohort, complications included reexploration for bleeding (2.4%; n = 3) and one stroke (0.8%), whereas the 30-day mortality was 2.3% (n = 3). CONCLUSIONS: Video-assisted mitral surgery provides safe and effective results when compared with conventional sternal approaches. These positive results show a safe and stepwise evolution toward a totally endoscopic mitral valve operation. PMID- 11603438 TI - Prophylactic mitral reconstruction for mitral regurgitation. AB - BACKGROUND: Mitral regurgitation (MR) will produce myocardial dysfunction. The goal of this study was to review outcomes of mitral valve reconstruction in asymptomatic patients with severe MR. METHODS: From 1992 to 2000, 93 asymptomatic patients with degenerative disease and severe MR underwent mitral valve reconstruction. Mean preoperative left ventricular internal diameter diastole was 56 +/- 8 mm and ejection fraction was 60% +/- 6%. Mean age was 47 +/- 10 years and mean follow-up 23 +/- 27 months. All patients underwent complex reconstruction. RESULTS: There were no deaths and two late reoperations. One was for systolic anterior motion of the anterior leaflet of the mitral valve requiring valve replacement and one for hemolysis requiring re-repair. There was one perioperative transient ischemic attack and no late thromboembolic events. At follow-up all but 1 patient remains in NYHA class I and all had no MR except in 2 patients at 63 and 89 months. CONCLUSIONS: Mitral valve reconstruction for "asymptomatic" MR can be performed with no mortality and low morbidity before development of left ventricular dysfunction. Early prophylactic repair is advocated in the presence of severe MR if valve reparability is assured. PMID- 11603439 TI - Exercise hemodynamics of aortic prostheses: comparison between stentless bioprostheses and mechanical valves. AB - BACKGROUND: Nonstented bioprostheses have been associated with lower resting gradients than stented bioprostheses or mechanical valves. We compared the hemodynamic performance of nonstented bioprostheses and mechanical valves with normal native aortic valves at rest and exercise. METHODS: Dobutamine echocardiography was used to assess gradients and effective orifice area index at rest and exercise in patients with the Toronto stentless porcine valve (TSPV; n = 13; mean implant size 25.7 mm), Medtronic Freestyle (FR; n = 11; mean implant size 23.9 mm), Sorin Bicarbon (SOR; n = 11; mean implant size 24.5 mm), St. Jude Medical (SJM; n = 10; mean implant size 21.3 mm), and normal native aortic valves (NOR; n = 10). RESULTS: All groups demonstrated a major rise in cardiac output at maximal dobutamine infusion. At rest and exercise, respectively, mean gradients were 5.48 +/- 1.1 mm Hg and 5.83 +/- 0.9 mm Hg for TSPV, 5.68 +/- 1.2 mm Hg and 7.50 +/- 1.7 mm Hg for FR, 10.29 +/- 1.4 mm Hg and 20.78 +/- 2.7 mm Hg for SJM, 5.26 +/- 0.8 mm Hg and 11.1 +/- 1.8 mm Hg for SOR, and 1.54 +/- 0.4 mm Hg and 2.18 +/- 0.7 mm Hg for NOR. In comparison with normal valves, both stentless groups showed no change in mean gradient at exercise, whereas both mechanical groups showed an increase in gradient at exercise (p < 0.04). CONCLUSIONS: Stentless valves behave similarly to normal aortic valves in that there is almost no increase in gradient at exercise. Both mechanical valve groups showed increased gradients at exercise, suggesting that these valves obstruct blood flow. Our data add further evidence that stentless valves are hemodynamically superior to mechanical valves in the aortic position. PMID- 11603440 TI - Reoperation and coarctation of the aorta: the need for lifelong surveillance. AB - BACKGROUND: We report a series of reoperations in 23 patients who had undergone previous aortic coarctation repair. METHODS: The medical records of these patients were reviewed, and the patients were followed up by telephone interview. Mean age at reoperation was 25 years. There was a mean of 18 years between initial coarctation repair and reoperation. Indications for reoperation included recoarctation (9 patients), aortic aneurysm (8), aortobronchial fistulas with exsanguinating hemorrhage (2), subaortic stenosis (1), ruptured thoracic aneurysm (1), ruptured sinus of Valsalva aneurysm (1), and supramitral stenosing ring (1). RESULTS: There were no specific intraoperative complications. Three patients required reexploration for bleeding. An acutely ischemic lower limb developed in 1 patient secondary to a common femoral artery embolus, which necessitated embolectomy. CONCLUSIONS: Reoperation for postcoarctation repair patients can be performed with good results. Sudden life-threatening hemorrhage due to aortobronchial fistulas in patients having undergone Dacron patch aortoplasty, as well as long-term obstructive phenomena seen anywhere along the left ventricular outflow tract, make lifelong surveillance of these patients mandatory. PMID- 11603441 TI - Neurologic outcome after thoracic and thoracoabdominal aortic aneurysm repair. AB - BACKGROUND: Neurologic deficit (paraparesis and paraplegia) after repair of the thoracic and thoracoabdominal aorta remains a devastating complication. The purpose of this study was to determine the effect of cerebrospinal fluid drainage and distal aortic perfusion upon neurologic outcome during repair of thoracic and thoracoabdominal aortic aneurysm (TAAA) repair. METHODS: Between February 1991 and March 2000, we performed 654 repairs of the thoracic and thoracoabdominal aorta. The median age was 67 years and 420 (64%) patients were male. Forty-five cases (6.9%) were performed emergently. Distribution of TAAA was the following: extent I, 164 (25%); extent II, 165 (25%); extent III, 61 (9%); extent IV, 95 (15%); extent V, 23 (3.5%); and descending thoracic, 147 (22%). The adjuncts cerebrospinal fluid drainage and distal aortic perfusion were used in 428 cases (65%). RESULTS: Thirty-day mortality was 14% (94 of 654). The in-hospital mortality was 16% (106 of 654). Early neurologic deficits occurred in 33 patients (5.0%). Overall, 14 of 428 (3.3%) neurologic deficits were observed in the adjunct group, and 19 of 226 (8.4%) in the nonadjunct group (p = 0.004). When the adjuncts were used during extent II repair, the incidence was 10 of 129 (7.8%) compared with 11 of 36 (30.6%) in the nonadjunct group (p < 0.001). Multivariate analysis demonstrated that risk factors for neurologic deficit were cerebrovascular disease and extent of TAAA (II and III) (p < 0.05). CONCLUSIONS: The combined adjuncts of distal aortic perfusion and cerebrospinal fluid drainage demonstrated improved neurologic outcome with repair of thoracic and TAAAs. In extent II aneurysms, adjuncts continue to make a considerable difference in the outcome and to provide significant protection against spinal cord morbidity. Future research should focus on spinal cord protection in patients with high-risk extent II aneurysms. PMID- 11603442 TI - Single-stage transmediastinal replacement of the ascending, arch, and descending thoracic aorta. AB - BACKGROUND: Aneurysms of the ascending, arch, and descending thoracic aorta are typically managed with two operations. The first stage involves replacement of the ascending and arch aorta leaving a segment of graft in the proximal descending aorta with a mortality and stroke risk of 8%. The second stage involves replacement of the descending aorta with a mortality of 5% and a paraplegia risk of 5% to 10%. Some patients refuse surgical completion and others are at increased risk to undergo the second stage thoracotomy, leaving them with untreated descending thoracic aortic aneurysms vulnerable to rupture. A single stage transmediastinal operation used in 14 patients is described. METHODS: Under circulatory arrest, the descending thoracic aorta is opened. A wire is passed up to the arch and a graft is brought down and secured excluding the descending thoracic aneurysm. The arch vessels are attached as a single patch and the graft is brought forward, replacing the ascending aorta. RESULTS: Fourteen patients have undergone single-stage replacement of the ascending, arch, and descending aorta with a 14% mortality rate and 14% incidence of paraplegia. CONCLUSIONS: Patients with aneurysms of the ascending, arch, and descending thoracic aorta can be managed with a single operation with comparable mortality and morbidity of the two-stage approach. PMID- 11603443 TI - Tubercular pseudoaneurysms of aorta. AB - BACKGROUND: Tubercular pseudoaneurysm of aorta is a rare but important complication of tuberculosis. With worldwide resurgence of tuberculosis due to increasing incidence of drug-resistant tuberculosis and its association with acquired immunodeficiency syndrome, the tubercular pseudoaneurysm has become a real clinical entity. METHODS: In the past 3 years, 5 young patients (22 to 40 years) presented with tubercular pseudoaneurysm. Site of involvement included ascending aorta, distal aortic arch, proximal descending thoracic aorta, distal descending thoracic aorta, and infrarenal abdominal aorta. Two patients had macroscopic focus of tuberculosis in the nearby vicinity, and all 5 patients had evidence of active/treated pulmonary pericardial tuberculosis. All patients either had received antitubercular therapy previously or were receiving it at the time of presentation. Rapid deterioration in the clinical status was the most marked clinical feature. All patients underwent operation. Graft interposition was performed in 2, patch repair in 2, and direct closure of the rent was performed in 1 patient. All 5 patients received antitubercular therapy in the postoperative period. RESULTS: All patients survived the operation and were discharged from the hospital. One patient developed recurrence at the original site after 8 months and died at reoperation. The remaining patients are symptom free at 18 to 36 months postoperatively. CONCLUSIONS: A combination of chemotherapy and operation yields gratifying results for the treatment of tubercular pseudoaneurysm. PMID- 11603444 TI - Systemic adenosine A2A agonist ameliorates ischemic reperfusion injury in the rabbit spinal cord. AB - BACKGROUND: The adenosine A2A agonist ATL-146e (4-[3-[6-Amino-9-(5-ethylcarbamoyl 3,4-dihydroxytetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl] cyclohexanecarboxylic acid methyl ester) has been shown to prevent reperfusion injury in multiple organ systems through inhibition of activated leukocyte endothelial interaction. We hypothesized that systemic ATL-146e could reduce spinal cord reperfusion injury after aortic clamping. METHODS: Twenty-six rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group received intravenous ATL-146e for 3 hours during reperfusion. A second cohort received only vehicle and served as controls. Animals were assessed at 24 and 48 hours using the Tarlov (0 to 5) scoring system for hind limb function. To evaluate neuronal attrition, immunostaining of lumbar spinal cord sections was performed using anti-SMI 33 antibody against neurofilament. RESULTS: Systemic ATL 146e was tolerated without hemodynamic lability. Animals that received ATL-146e had significantly improved neurologic outcomes 24 and 48 hours after spinal cord ischemia (p < 0.001). There was preservation of neuronal architecture in the ventral horn of spinal cord sections from animals receiving ATL-146e compared with control animals. CONCLUSIONS: Intravenous ATL-146e given during reperfusion is tolerated without hemodynamic lability, and results in substantially improved spinal cord function after ischemia by preservation of ventral horn neurons. PMID- 11603445 TI - Predictors for atrial transport function after mini-maze operation. AB - BACKGROUND: Restoration of atrial transport function (ATF) is a major goal of the maze procedure. This prospective study was undertaken to evaluate predictors of left atrial transport function in patients undergoing a mini-variant of the maze III procedure 3 and 12 months postoperatively. METHODS: Mini-maze operation was performed in 72 patients with a mean age of 64 +/- 8.7 years during a 5-year period. Seventy of 72 (97%) had combined procedures. Clinical and electrophysiologic examination was carried out before surgery, and 3 and 12 months postoperatively. RESULTS: Early mortality was 1.4% (1 of 72 patients) and late death occurred in 5.6% (4 of 71 patients). After 3 months, 54 of 68 (80%) patients showed sinus rhythm, and 48 of 60 (80%) after 12 months. ATF was restored in 87% (echocardiography) and 82% (magnetic resonance imaging) after 3 months, and in 86% (echocardiography) and 78% (magnetic resonance imaging) after 12 months. Independent predictors for ATF restoration after 12 months were better preoperative left ventricular function (p = 0.02), and smaller preoperative left atrial diameter (p = 0.005). Correlation between echocardiography and magnetic resonance imaging was 80% after 12 months. CONCLUSIONS: Restoration of ATF after mini-maze procedure is achieved in over 80%. Independent predictors for ATF restoration are smaller preoperative left atrial diameter and better preoperative left ventricular ejection fraction. PMID- 11603446 TI - Magnesium infusion dramatically decreases the incidence of atrial fibrillation after coronary artery bypass grafting. AB - BACKGROUND: Atrial fibrillation (AF) is one of the most common complications of cardiac surgery. Magnesium, like several other pharmacologic agents, has been used in the prophylaxis of postoperative AF with varying degrees of success. However, the dose and the timing of magnesium prophylaxis need to be clarified. The purpose of this study was to assess the effect of intermittent magnesium infusion on postoperative AF. METHODS: A total of 200 consecutive patients who had elective, isolated, first-time coronary artery bypass grafting were prospectively randomized to two groups. Patients in the magnesium group (n = 100) received 6 mmol MgSO4 infusion in 100 mL 0.9% NaCl solution (25 mL/h) the day before surgery, just after cardiopulmonary bypass, and once daily for 4 days after surgery. Patients in the control group (n = 100) received only 100 mL 0.9% NaCl solution (25 mL/h) at the same time points. RESULTS: Postoperative AF occurred in 2 (2%) patients in the magnesium group and in 21 (21%) patients in the control group (p < 0.001). Atrial fibrillation started, on average, 49.4 +/- 16.8 hours postoperatively. The postoperative length of hospital stay was not significantly different in patients with AF (7.4 +/- 8.0 days) compared with patients without AF (5.4 +/- 1.1 days; p = 0.236). CONCLUSIONS: The use of magnesium in the preoperative and early postoperative periods is highly effective in reducing the incidence of AF after coronary artery bypass grafting. PMID- 11603447 TI - Relation of intraoperative flow measurement with postoperative quantitative angiographic assessment of coronary artery bypass grafting. AB - BACKGROUND: It is critical to evaluate the anastomotic quality of coronary artery bypass grafting (CABG) in the operating room. The aim of this study is to determine the validity of intraoperative flow measurement for predicting the quality of CABG by comparison with the postoperative quantitative angiographic evaluation of the grafts. METHODS: Eighty-two grafts, including 37 internal thoracic arteries, were examined intraoperatively with a transit-time flowmeter. Coronary angiograms were performed 14 +/- 5 days after CABG to quantify the diameters at the toe, heel, and anastomosis proper of the grafts. RESULTS: There were significant differences between patent and nonpatent grafts in all intraoperative flow parameters. However, the only cut-off value to distinguish patent from nonpatent was a fast Fourier transformation (FFT) ratio of 1.0. FFT is the ratio of powers of the fundamental frequency and its first harmonic. Postoperative quantitative angiography indicated that the stenosis was greatest at the heel of the anastomosis. The degree of stenosis at the heel of the anastomosis alone correlated significantly with intraoperative mean flow values. CONCLUSIONS: Fast Fourier transformation analysis of flow measurement may be useful to differentiate patent grafts intraoperatively. Intraoperative flow measurement may predict the most stenotic part of the anastomosis. PMID- 11603448 TI - Lambda graft with the radial artery or free left internal mammary artery anastomosed to the right internal mammary artery: flow dynamics. AB - BACKGROUND: The aim of this study was to evaluate the outcome and flow dynamics of the lambda graft configuration, relative to a second arterial graft. METHODS: From 1998 to 2000, 47 patients (mean age 55.5 +/- 4.7 years) with triple-vessel disease underwent arterial revascularization using the lambda graft. The in situ left internal mammary artery (LIMA) and right internal mammary artery (RIMA) were anastomosed to the left anterior descending (LAD) and obtuse marginal arteries, respectively. In 21 patients (group I) presenting proximal or middle-third LAD or right coronary (RC) arterial stenoses, the lambda graft was constructed by anastomosing the distal LIMA, as a free LIMA graft, to the RC and proximally to the in situ RIMA. In the other 26 patients (group II) presenting with middle distal third LAD or RC arterial stenoses, the radial artery (RA) was used to construct the lambda graft. All patients underwent transthoracic echo color Doppler before and after an adenosine test at 1 week and 3 months after operation. RESULTS: There were no hospital deaths. Overall, 47 lambda grafts were constructed. There was no difference between baseline and maximal flows and coronary flow reserve (CFR) between groups. CFR at IMA stems increased in both groups within 3 months versus 1 week [(LIMA)CFR = 2 +/- 0.3 vs 2.3 +/- 0.3 (p = 0.002) and (RIMA)CFR = 2.2 +/- 0.4 vs 2.5 +/- 0.3 (p = 0.009) in group I, and (LIMA)CFR = 2.12 +/- 0.33 vs 2.4 +/- 0.35 (p = 0.005) and (RIMA)CFR = 2.17 +/- 0.32 vs 2.52 +/- 0.26 (p = 0.001) in group II]. At 3 months versus 1 week, the (RIMA)diameter(i) (mm) at rest was 1.69 +/- 0.32 versus 1.48 +/- 0.2 (p = 0.015) in group I and 1.66 +/- 0.3 versus 1.47 + 0.2 (p = 0.01) in group II. At 6 +/- 2.4 months, all patients were free of angina. CONCLUSIONS: These data, almost identical for free LIMA and RA to RIMA using the lambda graft, demonstrate that RIMA flow reserve is adequate for multiple coronary anastomoses irrespective of the second arterial graft. PMID- 11603449 TI - Off-pump coronary artery bypass grafting decreases risk-adjusted mortality and morbidity. AB - BACKGROUND: The purpose of this study was to determine whether coronary artery bypass grafting without cardiopulmonary bypass (off-pump CABG) decreases risk adjusted operative death and major complications after coronary artery bypass grafting in selected patients. METHODS: Using The Society of Thoracic Surgeons (STS) National Adult Cardiac Surgery Database, procedural outcomes were compared for conventional and off-pump CABG procedures from January 1, 1998, through December 31, 1999. Mortality and major complications were examined, both as unadjusted rates and after adjusting for known base line patient risk factors. RESULTS: A total of 126 experienced centers performed 118,140 total CABG procedures. The number of off-pump CABG cases was 11,717 cases (9.9% of total cases). The use of an off-pump procedure was associated with a decrease in risk adjusted operative mortality from 2.9% with conventional CABG to 2.3% in the off pump group (p < 0.001). The use of an off-pump procedure decreased the risk adjusted major complication rate from 14.15% with conventional CABG to 10.62% in the off-pump group (p < 0.0001). Patients receiving off-pump procedures were less likely to die (adjusted odds ratio 0.81, 95% CI 0.70 to 0.91) and less likely to have major complications (adjusted odds ratio 0.77, 95% CI 0.72 to 0.82). CONCLUSIONS: Off-pump CABG is associated with decreased mortality and morbidity after coronary artery bypass grafting. Off-pump CABG may prove superior to conventional CABG in appropriately selected patients. PMID- 11603450 TI - Comparison of endothelium-dependent vasoactivity of internal mammary arteries from hypertensive, hypercholesterolemic, and diabetic patients. AB - BACKGROUND: Endothelium-dependent relaxation is abnormal in a variety of diseased states. Despite the widespread use of the internal mammary artery (IMA) in coronary artery bypass grafting, there is a lack of comparative studies on IMA endothelial-dependent function in patients with major cardiovascular risk factors. METHODS: An IMA segment from 48 selected patients undergoing coronary artery bypass grafting was harvested intraoperatively and assigned to one of four groups (n = 12): diabetics requiring therapy, hypertensives, hypercholesterolemic, and nondiabetic-normotensive-normocholesterolemic patients. Internal mammary artery specimens were cut into rings and suspended in organ bath chambers, and the isometric tension of vascular tissues was recorded. The IMA rings were (1) precontracted with norepinephrine, and the endothelium-derived relaxation was evaluated by cumulative addition of acetylcholine, (2) contracted with cumulative concentrations of endothelin-1, and (3) contracted with the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine. Furthermore, the release of prostacyclin by the IMA rings was directly measured during basal tone conditions and at the end of the various pharmacologic interventions. Histology of IMA rings was randomly performed. RESULTS: The results obtained in these experiments showed that IMA rings harvested from hypertensive patients have the greatest impairment of endothelium-dependent response to relaxant and contracting stimuli (p < 0.01 versus nondiabetic-normotensive-normocholesterolemic tissues; p < 0.05 versus hypercholesterolemic and diabetic tissues) and prostacyclin release in normal and stimulated conditions. To a lesser extent, hypercholesterolemic and diabetic tissues show similar depression (diabetic > hypercholesterolemic) both of relaxation and prostacyclin production, with respect to nondiabetic normotensive-normocholesterolemic specimens (p < 0.05). Histology findings (scanning electron microscopy) did not differ in multiple sections from vessel studies. CONCLUSIONS: Major cardiovascular risk factors affect the endothelium dependent vasoactive homeostasis of human IMA differently. Depression of relaxation is highest in patients with a history of hypertension. These findings may be pertinent to early and long-term treatment of patients undergoing coronary artery bypass grafting. PMID- 11603451 TI - A clinically relevant CTLA4-Ig-based regimen induces chimerism and tolerance to heart grafts. AB - BACKGROUND: We determined whether a nontoxic CTLA4-Ig-based conditioning regimen effected mixed chimerism and donor-specific tolerance when heart and bone marrow were transplanted simultaneously. METHODS: Fully mismatched rat strain combinations were used. Recipients received total-body irradiation (300 centigrays), bone marrow (10(8) cells), and cardiac transplants from the donor on day 0. Subsequently, recipient animals received CTLA4-Ig (2 mg/kg, every other day, x 5 doses), tacrolimus (1 mg/kg/day; days 0 to 9), and one dose (10 mg) of antilymphocyte serum on day 10. RESULTS: All bone marrow recipients (n = 7) developed mixed chimerism (mean = 25% +/- 9% at 1 year) and accepted cardiac allografts permanently (> 375 +/- 32 days). Recipients that received conditioning regimen but no bone marrow (n = 5) rejected donor hearts within 51 +/- 13 days (p < 0.01). Recipients that accepted heart grafts also permanently accepted (> 180 days) donor-specific skin grafts, but rapidly rejected (< 10 days) third-party skin grafts. CONCLUSIONS: A nontoxic CTLA4-Ig-based conditioning regimen effects mixed chimerism and donor-specific tolerance when heart and bone marrow are transplanted simultaneously. This regimen may have clinical application. PMID- 11603452 TI - Neurologic complications of the Novacor left ventricular assist device. AB - BACKGROUND: The left ventricular assist device (LVAD) is a bridging mechanism for patients with severe heart failure to remain viable until heart transplantation. The rate of cerebral embolism has been reported as high as 47% in some studies but the rate of other neurologic complications in patients with LVADs is not known. METHODS: Retrospective chart review of all patients who had LVADs implanted at our hospital from September 1993 until September 1997. Complications from the time of implantation until heart transplantation or death and functional outcome were assessed. RESULTS: Twenty-three patients had LVADs placed in the four-year period. Of 23 patients, 9 had neurologic complications after placement of the LVAD. These included four strokes, three seizures, and two cases of delirium. The 3 patients with seizures all died from multiorgan failure. All of the patients with strokes received a transplant. One patient with delirium died from multiorgan failure and another received a transplant. The most devastating medical complication was renal failure, which occurred in 7 patients and was associated with 100% mortality. All surviving patients with neurologic complications went on to transplant and good functional outcome. CONCLUSIONS: Neurologic complications are common in patients with LVADs, occurring in 9 out of 23 patients in our series. Seizures are a poor prognostic indicator and were associated with 100% mortality. Strokes did not have a negative impact on outcome. Patients with delirium had a mixed outcome, which reflects the multifactorial nature of delirium. Further study needs to be done to limit the neurologic complications associated with LVADs and further improve outcomes. PMID- 11603453 TI - Preoperative administration of steroids: influence on adhesion molecules and cytokines after cardiopulmonary bypass. AB - BACKGROUND: Cardiopulmonary bypass (CPB) is associated with tissue damage mediated by adhesion molecules and cytokines. Prebypass steroid administration may modulate the inflammatory response, resulting in improved postoperative recovery. METHODS: Fifty patients undergoing elective coronary operations under normothermic CPB were randomized into two groups: group A (n = 24) received intravenous methylprednisolone (10 mg/kg) 4 hours preoperatively, and group B (n = 26) served as controls. Cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin-2R [IL-2R], IL-6, IL-8), soluble adhesion molecules (sE-selectin, sICAM-1), C-reactive protein, and leukocytes were measured before steroid application, then 24 and 48 hours, and 6 days postoperatively. Adhesion molecules were measured by enzyme-linked immunosorbent assay, cytokines by chemiluminescent immunoassay. Postoperatively, hemodynamic measurements, inotropic agent requirements, blood loss, duration of mechanical ventilation, and intensive care unit stay were compared. RESULTS: Aortic cross-clamp and CPB time was similar in both groups. Prednisolone administration reduced postoperative levels of IL-6 (611 versus 92.7 pg/mL; p = 0.003), TNF-alpha (24.4 versus 11.0 pg/L, p = 0.02), and E-selectin (327 versus 107 ng/mL, p = 0.02). Postoperative recovery did not differ between groups. CONCLUSIONS: Preoperative administration of methylprednisolone blunted the increase of IL-6, TNF-alpha, and E-selectin levels after CPB but had no measurable effect on postoperative recovery. PMID- 11603454 TI - Influence of steroids on microvascular perfusion injury of the bowel induced by extracorporeal circulation. AB - BACKGROUND: Extracorporeal circulation is associated with gastrointestinal complications. By means of intravital microscopic methods, we investigated whether preoperative treatment with steroids can attenuate the impairment of the bowel microcirculation. METHODS: In 20 pigs, a partial left heart bypass (pLHB) was established. A loop of the terminal ileum was exteriorized for intravital microscopic observation. Seven sham-operated animals served as controls. In 13 animals, pLHB was established for 2 hours with a flow rate of 2,000 mL per minute; 7 of the animals received 20 mg/kg body weight prednisolone preoperatively. The microcirculatory network was analyzed before, during pLHB, and 2 hours after bypass. RESULTS: Despite unchanged macro-hemodynamics, pLHB resulted in a significant microvascular perfusion injury of the small bowel. Arteriolar vasoconstriction and a reduction of perfused capillaries per unit area (functional capillary density) to 30% of prebypass values could be found. Blood cell velocities were reduced in submucuous collecting venules. In the steroid treated animals, the functional capillary density remained normal. In addition, arteriolar vasoconstriction could be prevented. CONCLUSIONS: Treatment with prednisolone largely prevents the microcirculatory alterations in the small bowel induced by extracorporeal circulation. PMID- 11603455 TI - Autologous transfusion of shed mediastinal blood after coronary artery bypass grafting and bacterial contamination. AB - BACKGROUND: Autologous transfusion of shed mediastinal blood is often used after coronary artery bypass grafting (CABG). Shed blood has in a few studies been cultured during the first postoperative hours. However, autologous transfusion might in some cases be continued for several hours and no study has yet examined the bacterial contamination of shed blood later than 6 hours postoperatively. METHODS: Seventy-five patients undergoing electively performed CABG were included. Cultures of shed blood were taken at initiation of the autologous transfusion and the following morning. Infection variables were measured preoperatively and postoperatively. Infectious complications during the first postoperative week were registered. RESULTS: The frequency of patients with bacterial growth in the first culture was 0.22 (95% confidence interval: 0.12 to 0.31) compared with 0.04 (95% confidence interval: -0.044 to 0.087) in the second culture (p < 0.002). We found no significant difference in infection variables between patients with or without bacterial growth in the cultures. No patients suffered from early postoperative infectious complications. CONCLUSIONS: There is no further contamination of the shed blood during the period between initiating the autologous transfusion and the following morning. PMID- 11603456 TI - Carbon dioxide management and the cerebral response to hemodilution during hypothermic cardiopulmonary bypass in dogs. AB - BACKGROUND: Increases in blood flow support oxygen (O2) delivery with hemodilution. However, with alpha-stat management, the cerebral response to hemodilution is blunted. We tested the hypothesis that carbon dioxide (CO2) management is a primary determinant of the cerebral blood flow (CBF) response to hemodilution during hypothermic bypass. METHODS: Following Animal Care Committee approval, 15 dogs underwent bypass at 18 degrees C (pH-stat, n = 7 or alpha-stat, n = 8). Measurements were obtained after progressive hemodilution, and cerebral blood flow was determined by sagittal sinus outflow. Arterial pressure was maintained at 60 to 70 mm Hg. The CBF response to hemodilution and cerebral metabolic rate were compared in the two groups of animals. RESULTS: In both groups, hemodilution increased CBF. At every hematocrit, CBF and O2 delivery in the pH-stat group exceeded that of alpha-stat group, although O2 demand did not differ between groups. While absolute CBF in the pH-stat group was greater at every hematocrit, the relative change in CBF from control and the slope of the CBF-Hct relationship did not differ between groups. CONCLUSIONS: pH-stat management is associated with a greater absolute CBF and a greater ratio of cerebral O2 supply to demand for any degree of hemodilution. However, over the range of hematocrits common in practice, CO2 management per se does not determine the cerebral response to hemodilution. PMID- 11603457 TI - Physiologic characteristics of canine skeletal muscle: implications for timing skeletal muscle cardiac assist devices. AB - BACKGROUND: Optimal clinical stimulation for skeletal muscle cardiac assist systems (such as dynamic cardiomyoplasty) is not clearly defined. The pressure generating capacity of canine skeletal muscle ventricles (SMVs) at a variety of preloads and stimulation frequencies was examined as was time for SMVs to develop peak pressure. METHODS: SMVs were analyzed just after construction and after 3 months of electrical conditioning. Pressure generation and time to develop peak pressure were determined using a distensible mandrel. RESULTS: Higher preloads resulted in increased pressure generation; conditioned SMVs generated significantly less pressure than unconditioned SMVs. Increasing stimulation frequency from 20 to 50 Hz increased pressure-generating capacity; increases beyond 50 Hz did not result in further increases. Time to 90% peak pressure was least at 10 HZ and 65 Hz. CONCLUSIONS: Higher stimulation frequencies and preloads result in a more quickly contracting muscle, which generates more pressure. Midrange stimulation frequencies of 30 Hz provide optimal muscle strength and minimize time to develop peak pressure. Initiation of contraction should begin before the time maximal pressure is desired. PMID- 11603459 TI - Evolving strategies and improving outcomes of the modified norwood procedure: a 10-year single-institution experience. AB - BACKGROUND: This study reviews our 10-year experience with the modified Norwood procedure to determine its early and midterm outcomes. The focus is on the impact of evolving management strategies and accumulated institutional experience. METHODS: A modified Norwood operation was performed in 171 infants over a 10-year period. Sixty-eight percent of the infants were male, the median age at operation was 6 days (range 1 to 175 days), and the median weight was 3.3 kg (range 1.7 to 4.8 kg). The 10-year period was divided into three eras: era I; 1990 through 1993; era II; 1994 through 1997; and era III; 1998 into 2000. Outcomes and risk factors for mortality were sought. RESULTS: Hypoplastic left heart syndrome or a variant was the primary diagnosis in 118 infants (69%). The overall 5-year survival rate was 43%. Multivariate analysis revealed that only need of preoperative ventilatory support, earlier date of operation, and lower weight at operation were significant independent predictors of increased time-related mortality. Morphologic features such as a diagnosis other than hypoplastic left heart syndrome, ascending aortic size, and noncardiac anomalies were not significantly associated with an increased risk of death. The hospital survival rate for stage-one palliation in era III was 82%, significantly better than that in the preceding eras (p < 0.001). Attrition between stages one and two accounted for a 15% mortality rate among hospital survivors. CONCLUSIONS: With increasing experience and improvements in perioperative care and surgical technique, good outcomes can be expected for the first-stage modified Norwood procedure. Greater monitoring of patients in the interstage period may reduce interval mortality and improve overall survival. PMID- 11603458 TI - De Vega tricuspid annuloplasty for tricuspid regurgitation in children. AB - BACKGROUND: Significant tricuspid valve regurgitation (TR) occurs with other congenital heart defects, typically after repair of right-sided obstructive lesions. Since 1991, we applied the De Vega tricuspid annuloplasty technique for TR in children. METHODS: Forty-one children, aged 5 months to 22.7 years (mean, 9.9 years) underwent 42 De Vega tricuspid annuloplasties for moderate or severe TR during correction of other heart defects. One child had a De Vega during primary ventricular septal defect repair. The remaining patients had prior repair of tetralogy of Fallot or pulmonary atresia, or both (19 patients), double-outlet right ventricle (6 patients), pulmonary stenosis (4 patients), pulmonary atresia and intact ventricular septum (3 patients), complete atrioventricular septal defect (3 patients), and other diagnoses (6 patients). At the time of the De Vega, 37 patients (88%) had pulmonary valve replacement or right ventricular to pulmonary artery conduit replacement. Other procedures included aortic or mitral repair or replacement (6 patients), atrial septal defect and ventricular septal defect closure (5 patients), pulmonary arterioplasty (6 patients), and tracheoplasty (1 patient). RESULTS: There were no deaths at follow-up of 3.4 +/- 2.1 years; 1 child required cardiac transplantation 17 months postoperatively. Early postrepair echocardiography quantified TR as absent or mild (34 patients; 81%), mild-to-moderate (4 patients), moderate (3 patients), and severe (1 patient). The most recent echocardiogram showed moderate TR in 11 patients and severe TR in 2 patients (both with recurrent right ventricular hypertension). One child required tricuspid valve replacement 3 years later and 1 child had redo De Vega at the time of conduit re-replacement. No other child has symptomatic TR, significant tricuspid stenosis, or De Vega-related pacemaker implantation. CONCLUSIONS: The De Vega tricuspid annuloplasty safely provides excellent relief of TR, usually in children undergoing pulmonary valve replacement or conduit replacement. Although echocardiographic TR tends to increase with time (especially with right ventricular hypertension), it rarely requires reintervention or causes symptoms. PMID- 11603460 TI - Totally endoscopic computer-enhanced atrial septal defect closure in six patients. AB - BACKGROUND: Totally endoscopic procedures have been introduced into cardiac surgery with the application of telemanipulating robotic systems. We report 6 cases of closed-chest atrial septal defect (ASD) closure using a robotic device. METHODS: After deflating the right lung, the endoscopic camera and two robotic arms were inserted into the right hemithorax through 8-mm ports. An accessory port was placed for blood suction and for introduction of ancillary endoscopic instruments. After femoral-femoral cannulation for cardiopulmonary bypass (CPB), aortic occlusion, and cardioplegia delivery, the intracardiac correction was carried out in 5 patients with an ostium secundum ASD and in 1 patient with a patent foramen ovale (PFO) and atrial septal aneurysm (ASA). The ASDs were closed with a continuous braided polyester suture. The PFO closure with septal aneurysm plication was carried out with interrupted stiches. RESULTS: Mean CPB and cross clamp times were 106 +/- 22 and 67 +/- 13 minutes, respectively. Extubation was carried out within the seventh postoperative hour. All patients returned to normal function within the first postoperative week. CONCLUSIONS: Totally endoscopic ASD closure can be carried out safely using robotic techniques with rapid postoperative recovery and an excellent cosmetic result. PMID- 11603461 TI - A new percutaneously adjustable, thoracoscopically implantable, pulmonary artery banding: an experimental study. AB - BACKGROUND: In patients who undergo left ventricular retraining, multiple reoperations are often necessary to adjust the pulmonary artery banding. The availability of a percutaneously adjustable band would be very useful. METHODS: Ten lambs (10 to 25 kg) underwent pulmonary artery banding using a new device, 7 by thoracotomy and 3 by thoracoscopy. The possibility of percutaneously adjusting the band was evaluated immediately after operation in 10 animals and at 3 months in 8 animals. RESULTS: One death occurred on the day of the procedure from displacement of the device and another death was from infection. Immediate hemodynamic studies proved the feasibility of increasing right ventricular afterload in a precise and reversible way. After 3 months the band could still be precisely loosened or tightened in all but 1 animal. Autopsy revealed that all the devices were in the correct position and no fibrosis or adhesions were present around the devices, and there was no residual stenosis noted on the pulmonary artery. CONCLUSIONS: This new device may be a valuable alternative to the repeated pulmonary artery banding needed for ventricular preparation. PMID- 11603462 TI - Necrotizing fasciitis of the chest wall. AB - Necrotizing fasciitis is a highly morbid soft tissue infection that rarely involves the upper torso. An extremely unusual case of necrotizing fasciitis of the chest wall is reported, including the method by which an open thoracic cage was managed. This represents the second reported case of a patient surviving necrotizing fasciitis of the chest wall requiring rib resection and chest wall reconstruction. PMID- 11603463 TI - Suicidal nonfatal impalement injury of the thorax. AB - We treated an impalement injury of the thorax resulting from a suicide attempt in the form of a road traffic accident. The patient survived and was discharged 5 weeks after his injury. The surgical management of thoracic impalement injuries and the rationale behind a multidisciplinary approach are discussed. PMID- 11603464 TI - Thoracoscopic thoracic duct ligation for traumatic chylothorax. AB - Traumatic chylothorax requires surgical intervention when conservative medical management fails to reduce chyle leakage. This usually entails thoracotomy or laparotomy. We report a case in which successful ligation of a torn thoracic duct was achieved using a video-assisted thoracoscopic technique. PMID- 11603465 TI - Multilocular thymic cyst associated with Sjogren's syndrome. AB - A 61-year-old woman, who had been diagnosed as having Sjogren's syndrome, developed an anterior mediastinal mass. She was diagnosed with Sjogren's syndrome with thymoma, preoperatively. Extended thymectomy was performed. Macroscopically, the mediastinal mass showed thick-walled multiloculated cavities filled with turbid yellow fluid. Microscopically, the cyst lining was continuous with thymic lobules in the wall with inflammatory process, cholesterol granuloma formation, and prominent lymph follicular hyperplasia. She was diagnosed with multilocular thymic cysts associated with Sjogren's syndrome. PMID- 11603466 TI - Ventricular septal rupture caused by myocardial bridging. AB - A 70-year-old woman was referred to us with postinfarction angina. During cardiac catheterization the only coronary abnormality found was myocardial bridging in the mid and distal parts of the left anterior descending coronary artery, despite a large ventricular septal rupture. The pulmonary-to-systemic flow ratio was 2.5:1. Her operation was successful. PMID- 11603467 TI - Congenital pericardial defect and concomitant coronary artery disease. AB - Chest pain is the most common presenting symptom among patients with congenital pericardial defects. A delay in diagnosis of a congenital pericardial defect occurred in a patient because he had concomitant atherosclerotic coronary artery disease. Multiple radiological studies had suggested the diagnosis. The pericardial defect caused myocardial ischemia by obstructing flow in three coronary arteries. Surgical repair of the pericardial defect along with coronary artery bypass grafting was performed to correct the problem. PMID- 11603468 TI - Giant coronary artery aneurysm arising from sinus node artery. AB - A giant coronary aneurysm arising from the sinus node artery is reported. Diagnosis of this lesion by computed tomography and angiography is illustrated. The operative management is described. "Off-pump" aneurysmectomy was successfully performed. The role of occlusion test of the aneurysm inflow tract is emphasized. PMID- 11603469 TI - Coronary artery aneurysm in a patient with Marfan syndrome. AB - True aneurysm of the coronary artery in Marfan syndrome is very rare. We present a patient with Marfan syndrome who had aneurysms from the ascending aorta to the thoracoabdominal aorta and a large aneurysm of the left main coronary artery after an original Bentall operation. Prosthetic graft replacement of total aorta, coronary artery bypass grafting, and removal of the aneurysm of the left main coronary artery were successfully performed. PMID- 11603470 TI - Aneurysmal change in an internal mammary artery-pulmonary artery fistula. AB - We treated a rare case of aneurysm of the internal mammary artery-pulmonary artery fistula in a 32-year-old woman with unrepaired pulmonary atresia and ventricular septal defect. This aneurysm communicated with the pulmonary artery system through an aortopulmonary collateral. Aneurysmectomy was successful. PMID- 11603471 TI - Management of porcelain aorta and calcified great vessels in coronary artery bypass grafting with off-pump and no-touch technology. AB - A 69-year-old woman presented with postinfarct unstable angina and decreased ventricular function secondary to significant left main coronary artery stenosis in combination with total right coronary artery occlusion. We did successful off pump coronary revascularization in this patient with severely calcified ascending aorta and great vessels, subtotal aortobiiliac stenoses, a history of previous stroke, and right carotid endarterectomy. PMID- 11603472 TI - Minimally invasive coronary bypass without general endotracheal anesthesia. AB - This report describes the case of a 51-year-old man with myocardial ischemia resulting from in-stent restenosis of the left anterior descending coronary artery who underwent a minimally invasive direct coronary artery bypass using thoracic epidural analgesia while awake, without general endotracheal anesthesia. PMID- 11603473 TI - Ruptured papillary muscle after mitral valve replacement with preservation of chordae tendineae. AB - Many cardiac surgeons believe strongly that every effort should be made to preserve the continuity of the mitral anulus, chordae tendineae, and papillary muscles during mitral valve replacement in order to maximize ventricular function and maintain normal ventricular geometry. We treated a patient with spontaneous papillary muscle rupture after mitral valve replacement in whom efforts had been made to preserve continuity of the mitral mechanism. PMID- 11603474 TI - Congenital mitral regurgitation from absence of the anterolateral papillary muscle. AB - A 21-year-old woman had congenital mitral regurgitation. Echocardiography showed absence of the anterolateral papillary muscle and corresponding marginal chordae. This rare abnormality was corrected by anterolateral commissural annuloplasty and insertion of artificial chordae to prevent prolapse of the anterior leaflet. Postoperatively, there was no regurgitation, and an appropriate mitral valve area was achieved. PMID- 11603475 TI - Iatrogenic left ventricular pseudoaneurysm. AB - A case of iatrogenic left ventricular pseudoaneurysm in a male patient, with a diagnosis of pericarditis, is presented. The patient developed severe complications after an attempted diagnostic and therapeutic pericardiocentesis. Six months later, after corrective surgery, the pseudoaneurysm recurred. The patient had a second operation and two connections to the left ventricle were found. One year later the patient is well. PMID- 11603476 TI - Delayed postoperative paraplegia complicating repair of type A dissection. AB - We describe the very rare event of delayed transient paraplegia after repair of type A dissection of the aorta and discuss therapeutic options. We also suggest insertion of a spinal catheter as soon as there are signs or symptoms of spinal cord injury to drain spinal fluid and maximize the effect of elevated spinal cord perfusion pressure. PMID- 11603477 TI - Ventricular septal defect closure in a neonate with combined methylmalonic aciduria/homocystinuria. AB - Methylmalonic acidemia with associated homocystinuria is a rare inborn error of amino acid metabolism affecting energy supply on the cellular level. Its effects on recovery from surgically induced organ ischemia are largely unknown. We report the successful closure of a nonrestrictive ventricular septal defect by following a normothermic strategy combined with ample metabolic substrate supply. PMID- 11603478 TI - Total cavopulmonary connection using a pedicled pericardial conduit for a patient with apicocaval juxtaposition. AB - A 5-year-old boy, with a double inlet solitary ventricle, pulmonary atresia, and apicocaval juxtaposition underwent an extracardiac total cavopulmonary connection. A pedicled pericardial conduit was placed behind the ventricle to make a straight pathway between the inferior vena cava and pulmonary artery. This report presents a solution for managing patients with complicated heart defects with apicocaval juxtaposition during the completion of a total cavopulmonary connection. PMID- 11603480 TI - Anomalous origin of the pulmonary artery from the right coronary artery. AB - A 5-year-old boy who had an anomalous origin of a stenotic pulmonary artery from the right coronary artery with ventricular septal defect and pulmonary atresia is reported. The diagnosis was made at operation. Successful repair was achieved for the complex anomaly by using a pulmonary artery homograft as a conduit and closing the ventricular septal defect. PMID- 11603479 TI - Unusual form of coarctation of the distal thoracic aorta. AB - We report the case of a 3-month-old girl with a rare form of coarctation involving the lower descending thoracic aorta. Because of clinical findings of congestive heart failure and hypertension, early repair was recommended. Surgical intervention in young patients with this unusual localization presents a complex challenge. Aortic reconstruction was carried out by patching the stenotic segment with autologous arterial tissue. Three years after the repair, there is no evidence of recoarctation or aneurysmal dilation. PMID- 11603481 TI - Images in cardiothoracic surgery. Bifurcating radial artery. PMID- 11603482 TI - Images in cardiothoracic surgery. Traumatic rib fracture caused by a pulse generator. PMID- 11603483 TI - Isolation technique for stroke prevention in patients with a mobile atheroma. AB - Mobile atheroma in the proximal aorta is a risk factor for brain complication after cardiovascular operation. We report a new technique of replacing the ascending and transverse aorta by establishing selective hypothermic antegrade cerebral perfusion. After cooling, cerebral vessels are clamped and systemic perfusion is started. This technique was applied in 5 patients. All patients woke up normally and recovered without neurologic complication. PMID- 11603484 TI - Novel technique to repair type A acute aortic dissection in patients with a left ventricular assist device. AB - Acute type A aortic dissection is an uncommon complication with left ventricular assist device insertion, but is often fatal even if successfully repaired with conventional techniques including aortic valve repair. Residual aortic insufficiency is common because this valve is now subjected to systolic pressure. We present a novel technique for the repair of type A acute aortic dissection in patients with a left ventricular assist device with no chance of residual aortic insufficiency. PMID- 11603485 TI - Modification of bicaval anastomosis technique for orthotopic heart transplantation. AB - A modified bicaval anastomosis technique was utilized for 4 consecutive patients undergoing heart transplantation. Instead of transecting the superior and inferior vena cavae, a strip of the posterior right atrial wall was left undivided as a bridge connecting the superior and inferior vena cavae. This minor modification perfectly prevented shrinkage and retraction of the caval tissue, thus providing easier anastomotic orientation and better estimation of the appropriate tissue length that fits well, particularly when a small donor heart was available. PMID- 11603486 TI - Extracorporeal membrane oxygenation before induction of anesthesia in critically ill thoracic transplant patients. AB - Cardiorespiratory failure just before surgery in critically ill thoracic transplant patients can have catastrophic consequences. We judged the cardiorespiratory condition in three of 160 thoracic transplant procedures performed in our center too unstable for a safe induction of anesthesia. In these 3 patients, extracorporeal membrane oxygenation support was installed before induction of anesthesia to maintain an adequate cardiorespiratory state. This strategy was successful for all 3 patients, and long-term survival was achieved with a good quality of life. Guidelines for indications to follow this strategy are discussed. PMID- 11603488 TI - A rational approach to wound difficulties after sternotomy: the problem. AB - One hundred fifty-one patients with mediastinitis after median sternotomy were treated by a single surgeon over a 6-year period. The infections were analyzed in regard to the depth of infection, time of presentation, and the mediastinal defect. Preoperative evaluations included computed tomographic (CT) scans, testing for sternal stability, and the level of contamination. Intraoperative evaluations included bone, inflammatory tissues, Gram stain, and cultures. Treatment options included rewire procedures (20 patients), immediate reconstruction (63 patients), or delayed reconstructions (88 patients). The issues of exposed prosthetic material, right ventricular laceration, long-term intravenous antibiotics, Candida infections, and reexploration of the healed mediastinum after flap reconstruction are discussed. The overall approach to postoperative healing difficulties after sternotomy is examined. PMID- 11603487 TI - Vacuum-assisted closure in the treatment of a 9-year-old child with severe and multiple dog bite injuries of the thorax. AB - The vacuum-assisted closure (VAC; KCI International, San Antonio, TX) device is a negative pressure dressing, which we have used in the treatment of wounds with devitalized or infected tissues. Although introduced in plastic and reconstructive surgery, its use has extended to orthopedic and cardiothoracic surgical practice in the treatment of infected joint replacement and sternal wound infections, respectively. Although the VAC is becoming more widely used in surgical practice, only a small number of case reports exist in addition to the original case series by Argenta and Morykwas in 1997. Previously, the device was described in treating single wounds in adult patients. We report a case where it was successfully used to treat multiple dog bite injuries in a 9-year-old child. PMID- 11603490 TI - Esophageal adenocarcinoma. PMID- 11603489 TI - A rational approach to wound difficulties after sternotomy: reconstruction and long-term results. AB - One hundred fifty-one patients were reconstructed after median stemotomy by a single plastic surgeon over a 6-year period. The treatment included immediate reconstruction (63 patients) and delayed reconstructions (88 patients). Ninety eight percent of the patients had definitive healing at 6 weeks with an overall 30-day mortality of 4 percent. The issues of long-term intravenous antibiotics, perceived skin deficiency, cardiac decompensation, Candida infections, and reexploration of a healed mediastinum after flap reconstruction are discussed. Follow up (4 months to 6 years) of patients treated with reconstruction compared favorably with patients treated with rewiring procedures (20 patients) in regard to strength, chest wall stability, pulmonary function testing, and functional return to hobbies and employment. PMID- 11603491 TI - "Change in the wind": report from the 2000 Thoracic Surgery Directors Association retreat on Thoracic Surgery Graduate Medical Education. PMID- 11603493 TI - Boundary between N1 and N2 stations in lung cancer: back to the future of anatomy. PMID- 11603492 TI - A response to "Clinical trials in lung cancer: truth, justice, and the American way". PMID- 11603494 TI - Embolization of anomalous systemic lobar artery. PMID- 11603495 TI - Focus on cosmesis in thymectomy for myasthenia gravis. PMID- 11603496 TI - We devalue ourselves and our patients if we go quietly. PMID- 11603497 TI - Vineberg procedure combined with therapeutic angiogenesis: old wine in a new bottle. PMID- 11603498 TI - Aortocoronary bypass surgery and ascending aortic dissection: letter 1. PMID- 11603499 TI - Aortocoronary bypass surgery and ascending aortic dissection: letter 2. PMID- 11603500 TI - Ventricular containment technique in ischemic cardiomyopathy. PMID- 11603501 TI - Does adenosine have cerebro-protective effect during cardiopulmonary bypass? PMID- 11603502 TI - Regulation of mandibular growth and morphogenesis. AB - The development of the vertebrate face is a dynamic process that starts with the formation of facial processes/prominences. Facial processes are small buds made up of mesenchymal masses enclosed by an epithelial layer that surround the primitive mouth. The 2 maxillary processes, the 2 lateral nasal processes, and the frontonasal processes form the upper jaw. The lower jaw is formed by the 2 mandibular processes. Although the question of the embryonic origin of facial structures has received considerable attention, the mechanisms that control differential growth of the facial processes and patterning of skeletal tissues within these structures have been difficult to study and still are not well understood. This has been partially due to the lack of readily identifiable morphologically discrete regions in the developing face that regulate patterning of the face. Nonetheless, in recent years there has been significant progress in the understanding of the signaling network controlling the patterning and development of the face (for review, see Richman et al., 1991; Francis-West et al., 1998). This review focuses on current understanding of the processes and signaling molecules that are involved in the formation of the mandibular arch. PMID- 11603503 TI - Genetics of acid adaptation in oral streptococci. AB - A growing body of information has provided insights into the mechanisms by which the oral streptococci maintain their niches in the human mouth. In at least one case, Streptococcus mutans, the organism apparently uses a panel of proteins to survive in acidic conditions while it promotes the formation of dental caries. Oral streptococci, which are not as inherently resistant to acidification, use protective schemes to ameliorate acidic plaque pH values. Existing information clearly shows that while the streptococci are highly related, very different strategies have evolved for them to take advantage of their particular location in the oral cavity. The picture that emerges is that the acid-adaptive regulatory mechanisms of the oral streptococci differ markedly from those used by Gram negative bacteria. What future research must determine is the extent and complexity of the acid-adaptive systems in these organisms and how they permit the organisms to maintain themselves in the face of a low-pH environment and the microbial competition present in their respective niches. PMID- 11603504 TI - Therapeutic uses of non-steroidal anti-inflammatory drugs in dentistry. AB - The non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used classes of drugs for the management of acute and chronic pain in dentistry. Their therapeutic efficacy and toxicity are well-documented and provide evidence that NSAIDs generally provide an acceptable therapeutic ratio of pain relief with fewer adverse effects than the opioid-mild analgesic combination drugs that they have largely replaced for most dental applications. The great many studies done with the oral surgery model of acute pain indicate that a single dose of an NSAID is more effective than combinations of aspirin or acetaminophen plus an opioid, with fewer side-effects, thus making it preferable for ambulatory patients. The combination of an NSAID with an opioid generally results in marginal analgesic activity but with an increased incidence of side-effects, which limits its use to patients in whom the NSAID alone results in inadequate analgesia. The selective COX-2 inhibitors hold promise for clinical efficacy with less toxicity from chronic administration and may prove advantageous for the relief of chronic orofacial pain. The use of repeated doses of NSAIDs for chronic orofacial pain should be re-evaluated in light of a lack of documented efficacy and the potential for serious gastrointestinal and renal toxicity with repeated dosing. PMID- 11603507 TI - Access to elective vascular surgery within the recommended time according to emergency referrals. AB - BACKGROUND: Referral pattern is a potential confounding factor when waiting-list performance is reported across hospitals or periods. A common concern is the ability to accurately estimate proportions of patients undergoing surgery in the recommended time without considering emergency caseload. In this study, the relation between emergency referrals and the rate of elective admissions to hospital within the recommended time was estimated. DESIGN: A prospective cohort study. SETTING: An acute care hospital in Kingston, Ont. PATIENTS: Between 1994 and 1999, 1,173 consecutive patients accepted for elective vascular surgery. MAIN OUTCOME MEASURES: The proportion of patients who underwent surgery within the recommended time, and time to surgery. STUDY VARIABLES: The weekly number of emergency cases, enrolment periods, urgency and type of surgery. RESULTS: Overall, the proportion of patients who underwent surgery within recommended time was 0.45, (95% confidence interval [CI], 0.42-0.48). Adjusted for enrolment period, urgency and type of surgery, the estimated proportion was 0.57, (95% CI, 0.49-0.64). Compared with surgery for peripheral vascular disease, the odds of the procedure being done within the recommended time were 34% lower for aortic abdominal aneurysm repair and 41% lower for carotid endarterectomy. After adjustment for the case-mix and access attributes, the rate of elective admission within recommended time was on average 30% lower for weeks in which there were 1 to 2 emergency cases (rate ratio [RR] = 0.70, [95% CI, 0.53- 0.93]), and 39% lower for weeks with 3 or more emergency cases (RR = 0.61 [95% CI, 0.53-0.83]), relative to weeks with no emergency cases. CONCLUSIONS: When there is an increase in the number of emergency cases, a lower proportion of patients undergo elective surgery within the recommended time. Thus, when performance of surgical servces is evaluated, the probability of patients undergoing elective surgery on time should be adjusted relative to the number of emergency referrals. PMID- 11603505 TI - Proteoglycans in dentinogenesis. AB - The predominant proteoglycans present in predentin and dentin are the chondroitin sulphate-rich decorin and biglycan and the keratan-sulphate-rich lumican and fibromodulin. These are small, interstitial, leucine-rich proteoglycans which have recently been shown to exist in gradients across the predentin. Antibodies recognizing chondroitin sulphate show a decreasing gradient from the pulpal aspect toward the mineralizing front, the converse being true for keratan sulphate. Antidecorin shows an increase toward the mineralization front. Evidence from biochemical, autoradiographic, and immunohistochemical studies implies that such changes may be brought about by gradients of metalloproteinases. This offers the possibility that the proteoglycans organize the collagen network for receipt of phosphoproteins and phospholipids, the former being evident only at the onset of dentin formation. The suggestion is raised that glycosaminoglycan-depleted leucine-rich protein cores act as sequester points for receipt of phosphoproteins in particular. The rigid, spatially oriented glycosaminoglycan chains on decorin and biglycan are known to bind calcium and may feature directly in mineral initiation. PMID- 11603506 TI - Fatigue of restorative materials. AB - Failure due to fatigue manifests itself in dental prostheses and restorations as wear, fractured margins, delaminated coatings, and bulk fracture. Mechanisms responsible for fatigue-induced failure depend on material ductility: Brittle materials are susceptible to catastrophic failure, while ductile materials utilize their plasticity to reduce stress concentrations at the crack tip. Because of the expense associated with the replacement of failed restorations, there is a strong desire on the part of basic scientists and clinicians to evaluate the resistance of materials to fatigue in laboratory tests. Test variables include fatigue-loading mode and test environment, such as soaking in water. The outcome variable is typically fracture strength, and these data typically fit the Weibull distribution. Analysis of fatigue data permits predictive inferences to be made concerning the survival of structures fabricated from restorative materials under specified loading conditions. Although many dental-restorative materials are routinely evaluated, only limited use has been made of fatigue data collected in vitro: Wear of materials and the survival of porcelain restorations has been modeled by both fracture mechanics and probabilistic approaches. A need still exists for a clinical failure database and for the development of valid test methods for the evaluation of composite materials. PMID- 11603508 TI - Use of vitamins, minerals and herbs: a survey of patients attending family practice clinics. AB - OBJECTIVE: To examine the use of vitamin, mineral and herbal supplements in patients attending family practice clinics. DESIGN: A prospective 1-year cohort study. SETTING: Sixteen family practices in Calgary. PARTICIPANTS: One hundred and eighteen patients (more than 18 years of age) were initially interviewed; 12 patients were lost to follow-up. MAIN OUTCOME MEASURES: Number and type of supplements used, duration of use, sources of patient information, beliefs about supplement efficacy and safety, reporting use to physicians, costs and changes in pattern of use over 1 year. RESULTS: Supplement use was unrelated to age, but more women (73%) used supplements than men (44%). Relative to age, more patients younger than 50 years believed supplements were safer than prescription medications (82% v. 43%, p = 0.0005). Younger patients were less likely than those over 50 years old to have received supplement information from physicians (10% v. 37%, p = 0.0008) and were less compliant than older patients with manufacturers' recommended dosages (p = 0.02). Whereas 74% of those over the age of 50 years informed their physician that they used supplements, only 30% of younger patients did so (p = 0.0006). At 1-year follow-up, the number of supplements taken per patient increased (p < 0.05), and there was a tendency for more patients to take supplements (61% v. 70%, p = NS). CONCLUSIONS: The majority of patients attending family practices in Calgary use vitamin, mineral or herbal supplements, and monitoring of supplement use by health care professionals is minimal. Young patients, in particular, tend not to report their use of supplements. They also believe the supplements are safer and more effective than prescription medications and obtain information from nonmedical sources. Physicians should enhance patient understanding of these products and include supplement use in all medical histories. In particular, younger patients require more reliable information on supplements. PMID- 11603509 TI - Inflammatory bowel disease: lessons from the IL-10 gene-deficient mouse. AB - The pathogenesis of Crohn's disease likely involves multifactorial interactions between genetic factors and environmental triggers. The most recent studies suggest that luminal bacteria are a significant factor in the onset and chronicity of inflammation. In interleukin-10 (IL-10) gene-deficient mice a Crohn's-like colitis develops when the mice are raised under conventional animal care facilities but fails to develop when they are raised under germ-free conditions. These mice demonstrate significant alterations in the species and the levels of bacteria colonizing the colon, suggesting that genetic factors in the host may be critical in controlling bacterial colonization. In addition, early treatment of IL-10 gene-deficient mice with antibiotics can prevent the development of colitis in later life, suggesting that early events during the neonatal period can influence later disease progression. Recent work has focused on using probiotic bacterial mixtures to alter the microbial balance in the colon in attempts to reduce inflammation. The use of the VSL-3 probiotic mixture in the IL-10 gene-deficient mouse resulted in a complete normalization of physiological transport function and barrier integrity, in conjunction with a reduction in mucosal secretion of TNF-alpha and IFN-gamma. Further, it would appear that a soluble factor is released from a bacterium found in the VSL-3 mixture that can act directly on the epithelium to enhance barrier integrity. Results from animal models of inflammatory bowel disease suggest that genetically susceptible hosts can mount a pathogenic cellular immune response to specific nonpathogenic bacterial species, as a consequence of defective immunologic tolerance and lack of appropriate mucosal defences. Probiotic bacteria appear to be a promising new alternative for the treatment of clinical conditions that are associated with alterations in gut barrier function, including Crohn' s disease. PMID- 11603510 TI - Statin myopathies: pathophysiologic and clinical perspectives. PMID- 11603511 TI - The state of the articular cartilage at the time of surgery as an indication for rotational acetabular osteotomy. AB - We have studied whether the state of the articular cartilage at the time of rotational acetabular osteotomy for dysplasia of the hip affects the outcome 2 to 5.5 years after surgery. Arthroscopy in 57 patients (59 joints) at the time of the operation showed grade-0 changes in seven, grade-1 in nine, grade-2 in 17, grade-3 in 14 and grade-4 in 12 joints, according to the classification of Outerbridge. There was radiological evidence of the progression of arthritis in four joints which were classified at arthroscopy as grade 4. Stepwise regression analysis showed that damage to acetabular or femoral articular cartilage significantly affected the progression of arthritis. We conclude that the short term results of successful rotational acetabular osteotomy for dysplasia are affected by the state of the articular cartilage. PMID- 11603512 TI - The use of polymethylmethacrylate in the management of hydatid disease of bone. AB - Hydatid disease of bone is rare. It probably represents between 0.5% and 4% of all human hydatid disease and, in about 60% of patients, affects the spine or pelvis. Between 1986 and 1998, we treated 15 cases of bone hydatidosis. Curettage, swabbing with povidone iodine and filling the defect with polymethylmethacrylate (PMMA) were carried out in ten patients. Three of these had a recurrence after five years, but seven had no signs of relapse during a mean follow-up of 52 months. We believe that the combination of antihelminthic therapy, wide resection and the use of PMMA gives the best outcome in the treatment of bone hydatidosis. PMID- 11603513 TI - Evaluation of electromyographic monitoring during insertion of thoracic pedicle screws. AB - We prospectively studied the use of intercostal EMG monitoring as an indicator of the accuracy of the placement of pedicle screws in the thoracic spine. We investigated 95 thoracic pedicles in 17 patients. Before insertion of the screw, the surgeon recorded his assessment of the integrity of the pedicle track. We then stimulated the track using a K-wire pedicle probe connected to a constant current stimulator. A compound muscle action potential (CMAP) was recorded from the appropriate intercostal or abdominal muscles. Postoperative CT was performed to establish the position of the screw. The stimulus intensity required to evoke a muscle response was correlated with the position of the screw on the CT scan. There were eight unrecognised breaches of the pedicle. Using 7.0 mA as a threshold, the sensitivity of EMG was 0.50 in detecting a breached pedicle and the specificity was 0.83. Thoracic pedicle screws were accurately placed in more than 90% of patients. EMG monitoring did not significantly improve the reliability of placement of the screw. PMID- 11603514 TI - Measuring physical activity in patients after surgery for a malignant tumour in the leg. The reliability and validity of a continuous ambulatory activity monitor. AB - A continuous ambulatory activity monitor allows objective measurement of the amount and intensity of physical activity. We examined the reliability and validity of this device in the assessment of seven aspects of function over a period of 24 hours in 20 patients who had undergone limb salvage or amputation for a tumour in the leg. The test-retest reliability was determined by undertaking identical assessments on two separate days. The measurements were compared with other indicators of functional status and quality of life in order to determine the validity of the monitor. Its reliability was satisfactory, with intraclass correlation coefficients ranging from 0.65 to 0.91. Significant correlations were seen between the 'time spent walking' and the Musculoskeletal Tumor Society rating scales and the Rand-36 physical functioning score. There was also a significant association between the 'movement intensity during walking' and the Musculoskeletal Tumor Society score. The satisfactory reliability and validity of the monitor shows considerable promise for its use as a device for measuring physical activity objectively in patients after surgery for limb salvage or an amputation. PMID- 11603515 TI - Intraneural mucoid pseudocysts. A report of ten cases. AB - A mucoid pseudocyst of a peripheral nerve is a rare and benign tumour of controversial origin. We have reviewed ten patients with a mean follow-up of 3.2 years. The tumour affected the common peroneal nerve in eight and the ulnar nerve in two. The mean time between the onset of symptoms and diagnosis was 7.4 months (1.2 months to 2 years). On examination, there was pain in eight patients and swelling in seven. Motor deficit in the corresponding nerve territory was found in all. The diagnosis was usually confirmed by MRI. Treatment was always surgical. All the patients recovered, with a mean time to neurological recovery of 10.75 months. Recurrence was seen in only one patient and was treated successfully by further surgery. Our results are similar to those reported by other authors. A successful surgical outcome depends on early diagnosis before neurological damage has occurred. PMID- 11603517 TI - Changes in ulnar variance in relation to forearm rotation and grip. AB - We studied radiographs of the wrists of 120 healthy volunteers in order to determine the normal range of ulnar variance. They had been taken in various positions under both unloaded (static) and loaded (dynamic) conditions. Pronation posteroanterior, supination anteroposterior and neutral posteroanterior views were taken of each wrist before and during a maximum grip under identical conditions. The mean normal ulnar variance in neutral rotation was +0.74+/-1.46 mm, a value which was significantly lower in males than in females. We found negative variance in 26% of cases. We measured maximum ulnar variance (UVmax +1.52+/-1.56 mm) when gripping in pronation and minimum ulnar variance (UVmin +0.19+/-1.43 mm) when relaxed in supination. We subtracted UVmin from UVmax to calculate a mean maximum dynamic change in ulnar variance of 1.34+/-0.53 mm. We consider this database of normal values to be useful for both the diagnosis and treatment of conditions related to discrepancy in radio-ulnar length and for clinical research. PMID- 11603518 TI - Medial unicompartmental arthroplasty after failed high tibial osteotomy. AB - Satisfactory selection criteria are essential for the successful outcome of unicompartmental knee arthroplasty (UCA). We report the frequency of revision of the Oxford medial unicompartmental arthroplasty in knees previously treated for anteromedial osteoarthritis by high tibial osteotomy (HTO). The combined results from three sources were used to allow statistical analysis of this uncommon subgroup. In the combined series of 631 knees (507 patients) which had medial unicompartmental replacement, 613 were primary procedures and 18 were for a failed HTO. The mean follow-up times of the two groups were similar (5.8 years and 5.4 years, respectively). At review, 19 (3.1%) of the primary procedures and five (27.8%) of those undertaken for a failed HTO had been revised to total knee replacement. Survival analysis revealed the ten-year cumulative survivals to be 96% and 66%, respectively. The log-rank comparison of these survivals revealed a highly significant difference (p < 0.0001). We recommend that the Oxford UCA should not be used in knees which have previously undergone an HTO. PMID- 11603516 TI - Treatment of isolated injuries of the lunotriquetral ligament. A comparison of arthrodesis, ligament reconstruction and ligament repair. AB - We studied 57 patients with isolated lunotriquetral injuries treated by arthrodesis, direct ligament repair, or ligament reconstruction. The outcomes were compared by using written questionnaires, the Disabilities of the Arm, Shoulder and Hand (DASH) score, range of movement, strength, morbidity and rates of reoperation. Isolated lunotriquetral injury was confirmed by arthroscopy or arthrotomy. The mean age of the patients was 30.7 years (15.4 to 53.7) and the injuries were subacute or chronic in 98.2%. Eight patients underwent lunotriquetral reconstruction using a distally-based strip of the tendon of extensor carpi ulnaris, 27 had lunotriquetral repair and 22 had lunotriquetral arthrodesis. The mean follow-up was 9.5 years (2 to 22). The probability of remaining free from complications at five years was 68.6% for reconstruction, 13.5% for repair, and less than 1% for arthrodesis. Of the lunotriquetral arthrodeses, 40.9% developed nonunion and 22.7% developed ulnocarpal impaction. The probability of not requiring further surgery at five years was 68.6% for reconstruction, 23.3% for repair and 21.8% for arthrodesis. The DASH scores for each group were not significantly different. Objective improvements in strength and movement, subjective indicators of pain relief and satisfaction were significantly higher in the lunotriquetral repair and reconstruction groups than in those undergoing arthrodesis. PMID- 11603519 TI - The effect of partial and full weight-bearing on venous return in the lower limb. AB - We studied the effect of full and partial weight-bearing on venous peak velocity in the legs of 73 subjects. We used colourflow Duplex ultrasound to determine the minimal amount of weight-bearing required to produce the same venous peak velocity as full weight-bearing. We found that the venous peak velocity remains the same in the femoral vein during partial weight-bearing (196 N and above). This is important for postoperative physiotherapy and thromboprophylaxis. The median peak velocity was 30 cm/s. This corresponds to an amplification factor of four in relation to the individual resting level (peak velocity). In addition, we found that partial weight-bearing at 196 N can reliably be reproduced. The median value of partial weight-bearing after a three-day training programme was 206 N. PMID- 11603520 TI - Assessment of Ilizarov correction of club-foot deformity using pedobarography. A preliminary report. AB - Relapsed congenital talipes equinovarus is difficult to assess and treat. Pedobarography provides dynamic measurement of the pressures under the foot, and may be used in the assessment of these patients both before and after operation. Our findings showed a statistically significant difference in the distribution of pressure across the foot after treatment by the Ilizarov technique. PMID- 11603521 TI - The timing of reduction and stabilisation of the acute, unstable, slipped upper femoral epiphysis. AB - We reviewed the management of 100 cases of slipped upper femoral epiphysis treated over a period of 26 years. A total of 14 slips was identified as unstable on admission. These underwent reduction and stabilisation within 24 hours of the onset of severe symptoms. Of the 86 stable slips four progressed to avascular necrosis (AVN), which was not seen in the unstable slips. The literature on slipped upper femoral epiphysis suggests that the acute unstable slip is at higher risk of developing AVN. We recommend reduction and stabilisation of unstable slips within 24 hours of the onset of symptoms in order to reduce the risk of AVN. PMID- 11603522 TI - Infected joint replacements in HIV-positive patients with haemophilia. AB - Joint replacement in HIV-positive patients remains uncommon, with most experience gained in patients with haemophilia. We analysed retrospectively the outcome of 102 replacement arthroplasties in 73 HIV-positive patients from eight specialist haemophilia centres. Of these, 91 were primary procedures. The mean age of the patients at surgery was 39 years, and the median follow-up was for five years. The overall rate of deep sepsis was 18.7% for primary procedures and 36.3% for revisions. This is a much higher rate of infection than that seen in normal populations. A total of 44% of infections resolved fully after medical and/or surgical treatment. The benefits of arthroplasty in haemophilic patients are well established but the rates of complications are high. As this large study has demonstrated, high rates of infection occur, but survivorship analysis strongly suggests that most patients already diagnosed with HIV infection at the time of surgery should derive many years of symptomatic relief after a successful joint replacement. Careful counselling and education of both patients and healthcare workers before operation are therefore essential. PMID- 11603523 TI - Effect of displacement of fractures of the greater tuberosity on the mechanics of the shoulder. AB - Using a dynamic biomechanical model of malunion of the shoulder, we have determined the change in deltoid force required for abduction with various combinations of superior and posterior displacement of fractures of the greater tuberosity of the humerus. We tested eight fresh human cadaver shoulders in a dynamic shoulder-testing apparatus during cycles of glenohumeral abduction from 0 degrees to 90 degrees. The greater tuberosities were osteotomised and stabilised to represent malunion with combinations of superior and posterior displacements of 1 cm and less. The peak force was measured for each displacement in each specimen and statistically compared with values of no displacement using a repeated-measures analysis of variance. The abduction force was significantly increased by 16% (p = 0.006) and 27% (p = 0.0001) by superior displacements of 0.5 cm and 1 cm, respectively, while combined superior and posterior displacement of 1 cm gave an increase in force of 29% (p = 0.001). While treatment criteria for acceptable residual displacement of the greater tuberosity are widely used, there is little information on the direct biomechanical effects of displacement on shoulder mechanics. Although the results of conservative treatment are influenced by a number of factors, including associated injuries, rehabilitation and the pre-existing function of the shoulder, our data suggest that small amounts of residual displacement may alter the balance of forces required to elevate the arm at the glenohumeral joint. PMID- 11603524 TI - The treatment of osteomyelitis with gentamicin-reconstituted bone xenograft composite. AB - We have developed a new drug-delivery system using reconstituted bone xenograft to treat chronic osteomyelitis. This material, which has the capabilities of osteoinduction and osteoconduction, was supplemented with up to 2000 times the minimum inhibitory concentration of gentamicin against Staphylococcus aureus to prepare a gentamicin-reconstituted bone xenograft-composite (G-RBX-C). In a rabbit model, we evaluated the release of gentamicin from this composite in vivo, its capability for induction of ectopic bone and the repair of segmental defects of the radius. There was a high level of concentration of antibiotics, which was sustained for at least ten days. In the study of induction of ectopic bone, there was abundant woven bone in the G-RBX-C group two weeks after operation. At 16 weeks after implantation of G-RBX-C the radial defects had been repaired, with the formation of lamellar bone and recanalisation of the marrow cavity. Our findings suggest that G-RBX-C may be useful in the treatment of chronic osteomyelitis. PMID- 11603525 TI - Intravenous pamidronate reduces osteoporosis and improves formation of the regenerate during distraction osteogenesis. A study in immature rabbits. AB - We examined the effect on bone mineral density (BMD) of a single dose of 3 mg/kg of the bisphosphonate, pamidronate (Novartis) in distraction osteogenesis in immature rabbits. Seventeen rabbits (9 control, 8 given pamidronate) were examined by dual-energy x-ray absorptiometry. There was a significant increase in the BMD in the pamidronate group compared with the control animals. The mean areal BMD (g/cm2) in the bone proximal and distal to the regenerate was increased by 40% and 39%, respectively, compared with the control group (p < 0.05). The BMD of the regenerate bone was increased by a mean of 43% (p < 0.05). There was an increase of 22% in the mean area of regenerate formed in the pamidronate group (p < 0.05). Histological examination of bone in nine rabbits (5 control, 4 pamidronate) showed an increase in osteoblastic rimming and mineralisation of the regenerate, increased formation of bone around the pin sites and an increase in the cortical width of the bone adjacent to the regenerate in the rabbits given pamidronate. Pamidronate had a markedly positive effect. It reduced the disuse osteoporosis normally associated with lengthening using an external fixator and increased the amount and density of the regenerate bone. Further study is required to examine the mechanical properties of the regenerate after the administration of pamidronate. PMID- 11603526 TI - Increased chromosome translocations and aneuploidy in peripheral blood lymphocytes of patients having revision arthroplasty of the hip. AB - The long-term biological effects of wear debris are unknown. We have investigated whether there is any evidence of cumulative mutagenic damage in peripheral blood lymphocytes of patients undergoing revision arthroplasty of predominantly metal on-plastic total hip replacements compared with those at primary arthroplasty. There was a threefold increase in aneuploidy and a twofold increase in chromosomal translocations which could not be explained by the confounding variables of smoking, gender, age and diagnostic radiographs. In the patients with TiVaAl prostheses there was a fivefold increase in aneuploidy but no increase in chromosomal translocations. By contrast, in patients with cobalt chrome prostheses there was a 2.5-fold increase in aneuploidy and a 3.5-fold increase in chromosomal translocations. In six patients with stainless-steel prostheses there was no increase in either aneuploidy or chromosomal translocations. Our results suggest that future epidemiological studies of the putative long-term risks of joint replacement should take into account the type of alloy used in the prosthesis. PMID- 11603527 TI - Reamed nailing of Gustilo grade-IIIB tibial fractures. PMID- 11603528 TI - Radiation therapy for the prevention of heterotopic ossification at the elbow. PMID- 11603529 TI - Conservative versus operative treatment for displaced ankle fractures in patients over 55 years of age. PMID- 11603530 TI - Conservative versus operative treatment for displaced ankle fractures in patients over 55 years of age. PMID- 11603531 TI - Conservative versus operative treatment for displaced ankle fractures in patients over 55 years of age. PMID- 11603532 TI - Anterior knee pain. PMID- 11603533 TI - Surgical treatment of lumbar spinal stenosis. Five-year follow-up. AB - We carried out a retrospective review of 155 patients with lumbar spinal stenosis who had been treated surgically and followed up regularly: 77 were evaluated at a mean of 6.5 years (5 to 8) after surgery by two independent observers. The outcome was assessed using the scoring system of Roland and Morris, and the rating system of Prolo, Oklund and Butcher. Instability was determined according to the criteria described by White and Panjabi. A significant decrease in low back pain and disability was seen. An excellent or good outcome was noted in 79% of patients; 9% showed secondary radiological instability. Surgical decompression is a safe and efficient procedure. In the absence of preoperative radiological evidence of instability, fusion is not required. PMID- 11603534 TI - The natural history of post-tubercular kyphosis in children. Radiological signs which predict late increase in deformity. AB - The progression of post-tubercular kyphosis in 61 children who received ambulatory chemotherapy was studied prospectively. The angles of deformity and kyphosis were measured for each patient at diagnosis, 3, 6, 9, 12 and 18 months later and every year thereafter for 15 years. During the course of the disease signs of instability appeared on the radiographs of some of the children. These were dislocation of the facets, posterior retropulsion of the diseased fragments, lateral translation of the vertebrae in the anteroposterior view and toppling of the superior vertebra. Each sign was allocated one point to create a spinal instability score. The influence on the progression of the deformity of the level of the lesion, the vertebral body loss, the number of segments involved, the angle of deformity before treatment and the spinal instability score was analysed. The mean angle of deformity at the start of treatment was 35 degrees. This increased to 41 degrees at 15 years. Progression occurred during the active phase of the disease and again after cure when variations in progression were observed. Type-I progression showed an increase in deformity until growth had ceased. This could occur either continuously (type Ia) or after a lag period of three to five years (type Ib). Type-II progression showed decrease in deformity with growth. This could occur immediately after the active phase (type IIa) or after a lag period of three to five years (type IIb). Type-III progression showed minimal change during either the active or healed phases and was seen only in those with limited disease. Multiple regression analysis showed that a spinal instability score of more than 2 was a reliable predictor of patients with an increase of more than 30 degrees in deformity and a final deformity of over 60 degrees. Since signs of radiological instability appear early in the disease, they can be reliably used to identify children whose spine is at risk for late progressive collapse. Surgery is advised in these cases. PMID- 11603535 TI - The coagulative and cardiorespiratory responses to reamed intramedullary nailing of isolated fractures. AB - We measured the changes during operation in seven markers of coagulation in a prospective series of 84 patients with fractures of the tibia or femur who were undergoing reamed intramedullary nailing. All patients were also continually monitored using transoesophageal echocardiography to assess marrow embolism. In a subset of 40 patients, intraoperative cardiopulmonary function was monitored, using pulmonary and systemic arterial catheterisation. The procedure produced a significant increase in prothrombin time, activated partial thromboplastin time, the level of prothrombin fragments F1+2 and D-dimers, and a decrease in the fibrinogen level, suggesting activation of both the coagulation and fibrinolytic pathways. There was evidence of both platelet hyper-reactivity and depletion, as estimated by an increase in beta-thromboglobulin levels and a decrease in the platelet count. In the patients who had invasive monitoring there was an incremental increase in mean pulmonary arterial pressure, with the changes being greatest during insertion of the guide-wire and reaming. The change in markers of coagulation, pulmonary artery pressure and arterial oxygen partial pressures correlated with the intraoperative embolic response. Greater changes in these parameters were observed during stabilisation of pathological fractures and in those patients in whom surgery had been delayed for more than 48 hours. Seven patients with pathological fractures developed more severe hypoxic episodes during reaming, which were associated with significantly greater arterial hypoxaemia, a fall in the right ventricular ejection fraction and an increase in the mean pulmonary artery pressure, pulmonary capillary wedge pressure, central venous pressure and the pulmonary vascular resistance index. These changes suggested that the patients had transient intraoperative right heart strain. Eight patients developed significant postoperative respiratory compromise. They all had severe intraoperative embolic responses and, in the three who had invasive monitoring, there was a significantly greater increase in pulmonary artery pressure and alveolar-arterial oxygen gradient, and a fall in the ratio of arterial partial pressure of oxygen to the inspired oxygen concentration. Operative delay, intraoperative paradoxical embolisation and the scores for the severity of the coagulative and embolic responses were predictive of the development of postoperative respiratory complications on univariate logistic regression analysis. On multivariate analysis, however, only the embolic and coagulative scores were significant independent predictors of respiratory complications. PMID- 11603536 TI - Total elbow replacement for complex fractures of the distal humerus. An option for the elderly patient. AB - The treatment of multifragmentary, intra-articular fractures of the distal humerus is difficult, even in young patients with bone of good quality, but is worse in elderly patients who have varying degrees of osteopenia. We have evaluated the functional outcome of primary total elbow replacement (TER) in the treatment of these fractures in ten elderly patients followed for a minimum of one year. There were no complications in regard to the soft tissues, bone or prosthesis. The mean range of flexion obtained was 125 degrees (110 to 140) and loss of extension was 23.5 degrees (0 to 50). The mean Mayo score was 94 points (80 to 100) and patient satisfaction was high. We feel that TER provides an alternative to open reduction and internal fixation in the management of these complicated fractures in the elderly. PMID- 11603537 TI - Hydroxyapatite-coated versus grit-blasted femoral stems. a prospective, randomised study using EBRA-FCA. AB - We have carried out a prospective, randomised study designed to compare the long term stability of the stem of cementless femoral implants with differing surface configurations. A total of 50 hips (46 patients) was randomised into two groups, according to whether the medullary stem had been grit blasted (GB) or coated with hydroxyapatite (HA). Both femoral prostheses were of the same geometrical design. We used Ein Bild Roentgen Analyse femoral component analysis (EBRA-FCA) to assess the stability of the stem. The mean follow-up was for 8.66 years. The mean migration of the stem was 1.26 mm in the HA group compared with 2.57 mm in the GB group (Mann-Whitney U test, p = 0.04). A mixed model ANOVA showed that the development of subsidence was statistically different in the two groups during the first 24 months. After this subsidence increased in both groups with no difference between them. Our results indicate that, with the same design of stem, HA coating enhanced the stability of the femoral stem when compared with GB stems. PMID- 11603538 TI - The hip in hereditary multiple exostoses. AB - We defined the characteristics of dysplasia and coxa valga in hereditary multiple exostoses (HME) by radiological analysis of 24 hips in 12 patients. The degree and effect of the 'osteochondroma load' around the hip were quantified. We investigated the pathology of the labrum and the incidence of osteoarthritis and of malignant change in these patients. Coxa valga and dysplasia were common with a median neck-shaft angle of 156 degrees, a median centre-edge angle of 23 degrees and Sharp's acetabular angle of 44 degrees. There was overgrowth of the femoral neck with a significantly greater ratio of the neck/shaft diameter in HME than in the control hips (p < 0.05), as well as correlations between the proximal femoral and pelvic osteochondroma load (p < 0.05) and between the proximal femoral osteochondroma load and coxa valga (p < 0.01). Periacetabular osteochondromas are related to Sharp's angle as an index of dysplasia (p < 0.05), but not coxa valga. No correlation was found between dysplasia and coxa valga. These data suggest that HME may cause anomalies of the hip as a reflection of a generalised inherited defect, but also support the theory that osteochondromas may themselves precipitate some of the characteristic features of HME around the hip. PMID- 11603539 TI - Phase transformation of a zirconia ceramic head after total hip arthroplasty. AB - We report two cases of surface deterioration of a zirconia ceramic femoral head associated with phase transformation after total hip arthroplasty. One head was retrieved at revision due to recurrent dislocation after six years and the other because of failure of the locking mechanism of the polyethylene liner after three years. The monoclinic content of the zirconia ceramics rose from 1% to about 30% on the surface of the heads. SEM revealed numerous craters indicating extraction of the zirconia ceramics at the surface. Surface roughness increased from an initial value of 0.006 microm up to 0.12 microm. This is the first report to show that phase transformation of zirconia ceramics causes deterioration of the surface roughness of the head in vivo after total hip arthroplasty. PMID- 11603540 TI - Desmoplastic melanoma. AB - Desmoplastic melanoma is an uncommonly encountered variant of malignant melanoma. Three histological subtypes exist: desmoplastic, neurotropic, and neural transforming. Desmoplastic melanoma commonly presents in conjunction with existing melanocytic lesions or as an amelanotic firm nodule. Local recurrences are common. Thirty patients over a 6-year period were treated at our institution for desmoplastic melanoma. All lesions were treated with local excision. Local recurrence occurred in seven patients (23%) and was treated by aggressive re excision in each instance. Clinical regional metastasis (lymph nodal basins) were detected in two patients (6%). Distant metastasis (lung) developed in two patients (6%). Twenty-three patients (76%) were found to have desmoplastic subtype, whereas five (17%) had neurotropic subtype. Six patients (20%) had associated pigmented melanotic lesions. Average length of follow-up has been 18 months. Overall survival is 96 per cent. Presentations and histologic diagnosis can sometimes be difficult and misleading. Treatment is aggressive local excision with follow-up necessary to detect resectable recurrent lesions. PMID- 11603541 TI - Benign anatomical mistakes: the thoracic outlet syndrome. PMID- 11603542 TI - The origins of blood transfusion: the later phase. PMID- 11603543 TI - Re: Splenic abscess: report of six cases and review of the literature. PMID- 11603544 TI - Use of the prolene hernia system for inguinal hernia repair: retrospective, comparative time analysis versus other inguinal hernia repair systems. AB - No data are available for the duration of surgery for the various procedures currently used in hernia repair. This retrospective study was undertaken to determine the time required for the surgical repair of unilateral primary inguinal hernias using currently available procedures and to show specifically that the duration of surgery using the PROLENE Hernia System (PHS) was equal to or less than the duration of surgery using a plug-and-patch device. Data were collected from 1032 sequential hernia procedures performed by 16 surgeons at a community hospital between 1997 and 1999. To gain more accurate information to compare the PHS and plug-and-patch procedures data from four surgeons who had performed at least five of each procedure were used as the primary analysis database. The two most frequently used devices were the PHS (35.9%) and plug and patch (41.0%). The average times of surgery for these procedures were not significantly different (25.4 vs 27.2 minutes, respectively; P = 0.236). A significant variability was observed between surgeons in the duration of surgery and there was evidence for an inverse relationship between the duration of surgery and the number of procedures a surgeon had performed. Both procedures take approximately the same time to perform. PMID- 11603545 TI - Bowel injury as a complication of induced abortion: a case report and literature review. AB - Intestinal perforation is a rare complication of induced abortion. It is most commonly seen in countries in which abortions are performed by people without proper training and with improvised instruments. Bowel perforation occurs when the posterior vaginal wall or uterus is violated, allowing the instrument to pierce underlying structures. The ileum and sigmoid colon are the most commonly injured portions of bowel due to their anatomic location. A case is reported of a 17-year-old woman who sustained a perforation of her anterior rectal wall from an abortion in Haiti. The literature on this type of injury is reviewed as well as the surgical management of these injuries. PMID- 11603546 TI - Bleeding hepatic adenoma: expectant treatment to limit the extent of liver resection. AB - Hepatic adenomas (HAs) are benign but can present as an acute surgical emergency. The relationship between HA and oral contraceptives (OCs) has been well documented and there have been several reports of tumor regression after the withdrawal of hormonal agents. However, not all HAs regress in this manner; have been reported to remain stable, increase in size, hemorrhage, or rarely, undergo malignant transformation. Given the unpredictable nature of these lesions they are generally treated surgically. In July 1995 a patient with a 6-year history of OC use was admitted with a history of sudden-onset right upper quadrant abdominal pain of 2 days' duration. The clinical picture and imaging studies led to the diagnosis of a bleeding hepatic adenoma without rupture. She was treated expectantly for a period of 14 months before surgery. This allowed the tumor to significantly decrease in size and thus limit the extent of resection. If the patient presented in this case had undergone surgery at the time of initial diagnosis a right hepatic lobectomy as opposed to a wedge resection would have been required. Treating this patient expectantly significantly decreased the potential morbidity associated with a larger resection. PMID- 11603547 TI - Evaluating blunt abdominal trauma with sonography: a cost analysis. AB - Ultrasonography (US) is becoming increasingly utilized in the United States for the evaluation of blunt abdominal trauma (BAT). The objective of this study was to assess the cost impact of utilizing US in the evaluation of patients with BAT in a major trauma center. All patients sustaining BAT during a 6-month period before US was used at our institution (Jan-Jun 1993) were compared to BAT patients from a recent period in which US has been utilized (Jan-Jun 1995). The numbers of US, computed tomography (CT), and diagnostic peritoneal lavage (DPL) were tabulated for each group. Financial cost for each of these procedures as determined by our finance department were as follows: US $96, CT $494, DPL $137. These numbers are representative of actual hospital expenditures exclusive of physician fees as calculated in 1994 U.S. dollars. Cost analysis was performed with t test and chi squared test, and significance was defined as P < 0.05. There were 890 BAT admissions in the 1993 study period and 1033 admissions in the 1995 study period. During the 1993 period, 642 procedures were performed on the 890 patients to evaluate the abdomen: 0 US, 466 CT, and 176 DPL (see table) [table: see text]. This compares to 801 procedures on the 1,033 patients in 1995: 552 US, 228 CT, and 21 DPL. Total cost was $254,316 for the 1993 group and $168,501 for the 1995 group. Extrapolated to a 1-year period, a significant (P < 0.05) cost savings of $171,630 would be realized. Cost per patient evaluated was significantly reduced from $285.75 in 1993 to $163.12 in 1995 (P < 0.05). This represents a 43 per cent reduction in per patient expenditure for evaluating the abdomen. By effectively utilizing ultrasonography in the evaluation of patients with blunt abdominal trauma, a significant cost savings can be realized. This effect results chiefly from an eight-fold reduction in the use of DPL, and a two fold reduction in the use of CT. PMID- 11603548 TI - Management of failed or failing infrainguinal bypasses with distal correctable lesions. AB - The goal of this study was to assess the management of failed or failing infrainguinal bypasses with distal correctable lesions. A retrospective analysis of 94 procedures was performed for 72 (77%) failed and 22 (23%) failing infrainguinal bypasses with distal correctable lesions in 94 patients. The 94 procedures included 50 (53%) balloon angioplasties and 44 (47%) distal vein graft extensions from the previous graft to the distal artery. Preprocedural thrombolytic therapy was performed in 62 of 94 limbs with a failed graft, and complete thrombolysis was achieved in 30 of 94. The results of thrombolytic therapy (complete or incomplete thrombolysis) or the means of revision procedure (balloon angioplasty or distal vein graft extension) did not affect the patency. Lower patency was observed for women, patients with a secondary bypass, and grafts with multiple episodes of revision. We conclude that the patency of failing infrainguinal bypasses after revision of distal lesions was affected not by means of therapy but by previous vascular procedures, the usual risk factors, and female gender. PMID- 11603549 TI - "General surgical pearls" for the anterior exposure of vertebral fractures. AB - Recently interest has been increasing in the anterior surgical approach for spinal cord decompression and bony stabilization of vertebral compression fractures. Our neurosurgical spine service routinely consults us to provide anterior operative exposure and wound closure for all levels of the thoracic and lumbar vertebral spine. Averaging about 30 exposures per year we have developed an excellent operative experience with these vertebral exposures. With no complete general surgery reference on anterior vertebral identified this summary of our "general surgical pearls" that we have learned and/or have developed should significantly aid other general and trauma surgeons who may be asked by their neurosurgical and/or orthopedic surgical colleagues for assistance with these operations. PMID- 11603550 TI - Merkel cell carcinoma: important aspects of diagnosis and management. AB - Merkel cell carcinoma (MCC) is a highly aggressive primary neuroendocrine tumor. It is suggested in the literature that postoperative radiotherapy may decrease local recurrence and improve overall survival. The purpose of this retrospective review was to determine our experience and review the literature on this aggressive malignancy. Charts of ten patients with MCC seen between 1985 and 1997 were reviewed to obtain clinicopathological data. Eight patients were male with a mean age of 72 years (range 49-90). The head and neck was the most common site, affecting 50 per cent of patients. All patients had primary excisions with documented negative margins. Pathological size ranged from 10 to 40 mm. Initial pathological diagnosis was lymphoma in three cases requiring immunohistochemistry for cytokeratin and neuron-specific enolase for definitive diagnosis. Lymphatic invasion was noted in three patients but only one of these patients had clinical lymph node involvement. The mean follow-up was 54 months (range 6-114) with an 80 per cent one-year survival and 30 per cent 2-year survival. Postoperative radiotherapy was administered to five patients. Of these three died with evidence of both local and distant recurrence. This small retrospective review highlights important points in the management of MCC including pathological diagnosis and benefits of adjuvant radiation therapy. PMID- 11603551 TI - Anastomotic technique influences outcomes after partial gastrectomy for adenocarcinoma. AB - The proper reconstructive technique after partial gastrectomy for adenocarcinoma of the stomach is often debated, but few data exist to clarify the issue. We evaluated outcomes after different anastomoses used during partial gastrectomy for gastric adenocarcinoma. We reviewed the hospital records of all 277 patients who underwent operation for gastric cancer at our institution from 1970 to 1996. Of 118 partial gastrectomies performed with curative intent 57 anastomoses were Billroth II gastrojejunostomies, 22 were Billroth I gastroduodenal reconstructions, and 39 were Roux-en-Y gastrojejunostomies. There was no difference in the incidence of early gastric emptying problems or early or late postoperative obstruction among the groups. Average hospital stay was 14 days for the Billroth I group, 15 days for those with Billroth II reconstructions, and 22 days for the Roux-en-Y cohort. Documented late gastric outlet obstruction occurred in 29 per cent of patients having Billroth I and in 33 per cent of those with Billroth II anastomoses. Antecolic anastomoses represented 30 (53 per cent) and retrocolic 27 (47 per cent) of the 57 Billroth II reconstructions performed. Late gastric outlet obstructions occurred in seven (23 per cent) patients who had antecolic reconstructions and in just one (4 per cent) with a retrocolic anastomosis (P < 0.05). Five-year cumulative survival was lower for patients having Billroth I reconstructions than for those with Billroth II (P < 0.05). Among patients with Billroth II reconstructions, 5-year cumulative survival was lower for those with antecolic reconstructions compared with those with retrocolic anastomoses (P < 0.05). Although conventional teaching dictates otherwise our data indicate that retrocolic Billroth II anastomoses are preferable to antecolic Billroth II reconstructions after partial gastrectomy for adenocarcinoma of the stomach, as there is a diminished risk of late gastric outlet obstruction and a greater 5-year survival among patients having the former procedure. Survival is unacceptably low after Billroth I anastomoses. PMID- 11603552 TI - Disseminated brown tumors from hyperparathyroidism masquerading as metastatic cancer: a complication of parathyroid carcinoma. AB - Osteitis fibrosa cystica (brown tumors) can be a skeletal manifestation of advanced hyperparathyroidism, including parathyroid cancer. Severe osteitis fibrosa cystica can mimic metastatic bone diseases especially in patients with a history of cancer. Because the treatment and prognosis of these two problems differ greatly considering hyperparathyroidism in the differential diagnosis of patients found to have osteolytic lesions is critical for the appropriate management of these patients. In this case report we describe a patient with a history of renal cell cancer and presumed osteolytic bone metastases. During prophylactic intramedullary rodding to prevent pathologic fracture of her femur she was found to have a benign lesion related to her previously undiagnosed hyperparathyroidism caused by an underlying parathyroid cancer. A detailed review of this disease and the associated bone changes is also included to underscore the importance of an adequate differential diagnosis as well as optimal management. Patients with hypercalcemia or bony lesions should not automatically be treated palliatively for metastatic disease just because of a past medical history of cancer. Hyperparathyroidism is a readily curable problem if properly diagnosed. PMID- 11603553 TI - Neoadjuvant therapy for esophageal cancer: standard of care or elusive myth? AB - Although surgical resection as the sole treatment modality for esophageal carcinoma has historically been associated with poor survival rates, improvements have recently been reported using varied neoadjuvant chemo-radiation protocols. This study evaluates the outcome of patients undergoing surgery for esophageal carcinoma at the University of Miami/Jackson Memorial Hospital between July 1991 and June 1996. Seventy-two patients underwent esophageal resection; 51 males and 21 females with a median age of 62.5 years (range = 42-82). Histology was equally distributed between adenocarcinoma (36 patients; 50%) and squamous cell carcinoma (36 patients; 50%). Pathological stage distribution consisted of 6 stage 0 (8%), 10 stage I (14%), 23 stage II (32%), 31 stage III (43%), and 2 stage IV (3%) lesions. Patients were divided into three groups according to the type of preoperative treatment; Group 1 (n = 44); surgery alone; Group 2 (n = 18); neoadjuvant 5-fluorouracil based chemotherapy, and Group 3 (n = 9); neoadjuvant 5 fluorouracil based chemotherapy in conjunction with external beam radiation (XRT). One patient received preoperative XRT alone. All survivors were followed for a minimum of 1 year and statistical analysis was performed using Kaplan-Meier curves, log-rank, and chi-square tests. In the 28 patients receiving any form of neoadjuvant therapy only one patient had a pathological complete response (CR) (3.5%). The overall 5 year and median survival rates were 18 per cent and 20.5 months (range = 0-73), respectively. Individual treatment group survival rates at 5 years were 28% for Group 1; 21% for Group 2; and 0% for Group 3, showing no survival difference between Groups 1 and 2; Group 3 fared significantly worse than the other two, probably as a result of the high operative mortality in this group. These results indicate that surgical resection continues to be an important treatment modality for esophageal carcinoma. Neoadjuvant chemotherapy in our experience failed to improve these survival rates and pre-operative chemoradiation was associated with a high perioperative mortality rate. Chemotherapy regimens with higher CRs may further improve these survival rates. PMID- 11603554 TI - Chest wall metastasis from recurrent meningioma. AB - Meningiomas are generally considered benign lesions. A minority, however, are capable of metastasis. The ones most likely to do so are commonly recurrent or frankly malignant in nature. The optimal management of such metastases is unclear. This is the first reported case of meningioma presenting as an isolated metastasis to the chest wall. This case involves a 64-year-old woman without significant medical or family history who underwent resection of a meningioma of the right cerebral hemisphere. She was treated 10 years later for recurrence by stereotactic radiosurgery. Three years after that, the patient's family noticed a mass on the left chest wall. A CT scan revealed destruction of the ninth rib laterally and subpleural extension. The patient subsequently underwent resection of full-thickness chest wall for a presumed soft-tissue sarcoma. Further pathologic evaluation including electron microscopy and immunohistochemistry revealed metastatic meningioma. The patient received adjuvant radiation to the chest wall and is currently free of disease at the chest wall one year after surgery. This case illustrates the difficulty in establishing an accurate diagnosis of metastatic meningioma. Consequently in selected patients with a history of the disease the diagnosis of metastatic meningioma must at least be considered. Resection of an isolated metastasis in this setting appears warranted. PMID- 11603555 TI - Preoperative radiographic staging for ureteral injuries is not warranted in patients undergoing celiotomy for trauma. AB - Preoperative radiographic staging of the urinary tract has been shown to be inaccurate with regard to the ureter. The purpose of this study was to assess the need for radiographic staging of the injured patient for the diagnosis of ureteral injury before operative exploration. We conducted a retrospective review of all patients who sustained injury of the ureter as the result of external trauma over an 8 Y2-year period at an urban and suburban Level I trauma center. All patients were injured through penetrating mechanisms and underwent laparotomy. Only three patients had preoperative radiographic staging of the urinary tract. No ureteral injuries were missed. We conclude that surgical exploration of the ureter is sufficiently accurate to obviate the need for preoperative radiographic staging of the ureters in patients who have sustained penetrating injury and warrant laparotomy. PMID- 11603556 TI - Octylcyanoacrylate tissue adhesive as an alternative to mechanical fixation of expanded polytetrafluoroethylene prosthesis. AB - In minimally invasive incisional hernia repair positioning and fixation of the expanded polytetrafluoroethylene (ePTFE) mesh prosthesis on the deep surface of the abdominal wall may be facilitated using tissue adhesives. Octylcyanoacrylate (OCTYL), a new adhesive, forms a strong flexible bond with antimicrobial properties. In a rabbit model for incisional hernia we investigated characteristics of the bond created by OCTYL between ePTFE and abdominal wall musculature. We studied initial bond strength and the postoperative host response to the adhesive over a 6-week period. We compared sutured, stapled, and glued mesh prostheses and examined the tissue-prosthesis interface. The ePTFE mesh was fixed successfully to the abdominal wall with OCTYL and remained tightly attached at 6 weeks. Prostheses fixed with OCTYL and spiral tacks induced few intra abdominal adhesions compared with sutured mesh. All prostheses were completely reperitonealized at 2 weeks. The force required to displace mesh fixed with sutures and staples was greater than mesh fixed with OCTYL. Analysis of the ePTFE/tissue interface by light and scanning electron microscopy showed host cellular migration into the interstices of the mesh with fixation by tacks and suture, whereas an inflammatory infiltrate was seen on the muscular surface with OCTYL fixation of the mesh. PMID- 11603557 TI - Mucoepidermoid carcinoma of the thyroid gland: a case report and suggested surgical approach. AB - Mucoepidermoid carcinoma (MEC) of the thyroid gland is a rare neoplasm with 40 cases reported in the world literature to date. Controversy surrounds the treatment of this rare neoplasm. It has been described as a low-grade indolent tumor that rarely metastasizes and only recurs locally without morbidity. Suggested treatment has consisted of a lobectomy or subtotal thyroidectomy. We report a case of a 63-year-old woman with a 15-year history of a multinodular goiter with a dominant left lobe nodule. Fine-needle aspiration was inconclusive. The patient opted for a total thyroidectomy. Final pathology yielded a diagnosis of mucoepidermoid carcinoma. We propose that despite its low-grade appearance the morbidity and mortality associated with its ability to locally recur and metastasize justify the need for more aggressive surgical therapy. PMID- 11603558 TI - Endometriosis in abdominal scars: a report of three cases diagnosed by fine needle aspiration biopsy. AB - Endometrioma in an operative scar is rare. The majority of patients have no prior history of endometriosis, and symptoms may mimic postoperative hernias. Fine needle aspiration biopsy (FNAB) can be a valuable diagnostic aid in the evaluation of these subcutaneous abdominal masses. We present the cytologic findings in three cases of abdominal wall endometriomas diagnosed by FNAB. The patients ranged from 31 to 51 years of age. None had a history of endometriosis, but all had prior abdominal operations (two abdominal hysterectomies for fibroids and one cesarean section). They presented 6 months to 7 years later with painful subcutaneous abdominal nodules in their scars ranging from 2 to 6 cm. FNAB was performed by a cytopathologist. The smears were cellular and comprised two distinct cell populations. An epithelial component consisted of flat sheets of polygonal cells with round to oval nuclei and scant cytoplasm. The second component consisted of clusters of fusiform stromal cells. Numerous hemosiderin laden macrophages were noted in the background. Cytokeratin highlighted the epithelial clusters, and vimentin stained the stromal cells. Electron microscopy showed two epithelial cell types: one with cilia and abundant rough endoplasmic reticulum and the other with numerous microvilli and scattered mitochondria indicative of endometrial differentiation. FNAB provided a rapid and accurate preoperative diagnosis in each case. PMID- 11603559 TI - Laparoscopic hiatal hernia repair in patients with poor esophageal motility or paraesophageal herniation. AB - Laparoscopic repair for gastroesophageal reflux disease is now an accepted therapy. However, controversy exists with regard to the choice of operation between complete 360-degree Nissen fundoplication versus partial 270-degree Toupe fundoplication. In addition there is some controversy with regard to the proper choice of operation in patients with poor esophageal motility. Another class of hiatal hernia patients are those patients with paraesophageal herniation. Questions regarding the approach to these patients include whether or not to use a reflux procedure at the time of repair and the role of mesh in repair of these large hernias. This retrospective study was undertaken to compare the results of laparoscopic Nissen fundoplication and Toupe fundoplication in patients with both normal and abnormal esophageal motility. In addition the subset of patients with paraesophageal herniation was studied in an effort to ascertain the best surgical approach in these patients. In this study a retrospective analysis was performed on 188 consecutive patients during the period 1995 to 2001. All patients who presented with hiatal hernia surgical problems during this period were included. Endoscopy was performed in all patients with esophageal reflux. Manometry was performed in all patients except those presenting as emergency incarcerations. pH probe testing was performed in those patients in whom it was deemed necessary to establish the diagnosis. Upper gastrointestinal radiographs were used to define anatomy in paraesophageal hernia patients when possible. All patients with esophageal reflux were first treated with a trial of medical therapy. Patients with esophageal reflux and normal esophageal motility underwent 360-degree Nissen fundoplication. Those patients with poor esophageal motility (less than 65 mm of mercury) underwent laparoscopic 270-degree Toupe fundoplication. Patients presenting with paraesophageal herniation underwent laparoscopic repair. When possible esophageal manometry was performed on these patients preoperatively and if normal peristalsis was documented a Nissen fundoplication was performed. If poor esophageal motility was documented before surgery a Toupe fundoplication was performed. Mesh reinforcement of the diaphragmatic hiatus was used if necessary to complete a repair without tension. Patients were followed both by their primary gastroenterologist and their surgeon. Follow-up studies including endoscopy, pH probe, and upper gastrointestinal series were used as necessary in the postoperative period to document any problems as they occurred. Of the 188 patients in the study 141 patients underwent Nissen fundoplication, 21 patients underwent Nissen fundoplication and repair of paraesophageal hernia, 15 underwent Toupe fundoplication, seven underwent Toupe and paraesophageal hernia repair, and four paraesophageal hernia repair alone. One hundred eighty-three patients underwent a laparoscopic operation. Five patients of the 188 underwent an initial open operation-two of these patients because of the size of their paraesophageal hernia. Three of these patients had reoperations of remote operations done years before at other institutions. Twenty-two patients with poor esophageal motility (11.7 %) were included in the study. Fifteen patients required Toupe fundoplication whereas seven patients required Toupe fundoplication and repair of paraesophageal hernias. Mesh repair of paraesophageal hernias was accomplished in ten patients. Patients undergoing Toupe fundoplication had a 13 per cent dysphagia rate less than 4 weeks postoperatively and a 0% dysphagia rate greater than four weeks postoperatively. Patients undergoing Nissen fundoplication had a 16 per cent dysphagia rate less than 4 weeks postoperatively, 2 per cent dysphagia rate greater than 4 weeks postoperatively and no dysphagia at 6 weeks postoperatively. Recurrent symptomatic reflux occurred in 1.4 per cent of Nissen fundoplications and 6.7 per cent of Toupe fundoplications. Of Nissen and paraesophageal repairs 14.2 per cent had reflux and 14.3 per cent of Toupe and paraesophageal repairs had recurrent symptomatic reflux. Overall, complication rate was low. Use of mesh to repair large paraesophageal hernias resulted in a recurrence rate of 0 per cent. There was no instance of infection or bowel fistulization related to the use of mesh. We conclude that laparoscopic Nissen fundoplication in patients with normal esophageal motility is associated with a low rate of dysphagia and a low rate of recurrent reflux. Toupe fundoplication when used in reflux patients with poor esophageal motility is associated with a low rate of dysphagia and an acceptable rate of recurrent reflux. Laparoscop PMID- 11603560 TI - A loop-forming duplicate recurrent laryngeal nerve: report of a case and clinical relevance in thyroid surgery. AB - This is a report of a unilateral loop-forming duplicate recurrent laryngeal nerve and its clinical relevance. A 72-year-old woman with a giant goiter underwent a total thyroidectomy. At operation we identified two recurrent laryngeal nerves on the right side and one on the left side. The nerve on the right was smaller and displaced laterally by the goiter, whereas the other was adjacent to the trachea and behind the goiter, and it was accidentally divided. Both nerves were united before innervating the larynx. The divided nerve was microsurgically reanastomosed but a postoperative assessment revealed hoarseness. This case report of an anomalous loop-forming duplicate recurrent laryngeal nerve indicates that it may not be sufficient to identify a single recurrent laryngeal nerve on one side during thyroid surgery especially when the observed recurrent nerve is relatively smaller than usual. PMID- 11603561 TI - Breast conservation: trends in a major southern metropolitan area compared with surrounding rural counties. AB - Despite randomized prospective studies and National Institutes of Health recommendations, surgeons especially in the southern United States have been slow to adopt breast conservation surgery (BCS). Data were analyzed regarding 3,349 cases of stage 0, I, and II breast cancer (1991-1998) from Charlotte-Mecklenburg County, NC; 1057 cases from six surrounding rural counties (1995-1997); and 90,398 cases (1995) from the National Cancer Data Base. During 1995 through 1997 Charlotte-Mecklenburg County had statistically significantly higher rates of BCS compared with six surrounding rural counties for stage I (59% and 42% respectively, P = 0.001) and stage II (37% and 19%, respectively, P = 0.001) breast cancer. The BCS rates in Charlotte-Mecklenburg County (1991-1998) showed the following: Stage 0 rate increased from 17 per cent in 1991 to 78 per cent in 1998 (P = 0.001), stage I rate increased from 31 per cent in 1991 to 65 per cent in 1998 (P = 0.001), and stage II rate increased from 18 per cent in 1991 to 42 per cent in 1998 (P = 0.001). BCS rates for early-stage breast cancer in Charlotte-Mecklenburg County have increased over the last 8 years and now equal national rates; however, patients in surrounding rural counties are not receiving BCS as frequently. There is a need for more widespread education of surgeons, other health care providers, and the general public to increase the use of BCS. PMID- 11603562 TI - Prospective trial for the treatment of malignant peritoneal mesothelioma. AB - Malignant peritoneal mesothelioma (MPM) is a rare and often rapidly fatal disease with median survival of 5 to 12 months for untreated cases and 16 months reported after multimodality treatment. We report a prospective clinical treatment study using cytoreductive surgery combined with intraoperative intraperitoneal heated chemotherapy (IPHC) perfusion using mitomycin C for MPM. Twelve patients (11 male with a mean age 51 years) were treated. Seven patients presented with bulky disease and seven with ascites. All underwent exploratory laparotomy with histologically confirmed diagnosis of MPM. Surgical debulking as feasible was performed. Complete gross tumor removal was possible in only one patient. Cytoreduction was followed by a 2-hour closed low-volume IPHC using mitomycin C. One patient died 50 days postoperatively from complications relating to small bowel perforation. Hematologic toxicity of the procedure was minimal. Ascites was controlled in all patients and permanently in 86 per cent of patients presenting with ascites. To date median survival is 34.2 months with median follow-up of 45.2 months. One patient was re-explored for ventral hernia 2 years post-IPHC, had negative peritoneal biopsies, and remains disease-free at 5 years. Given the dismal prognosis associated with MPM the results of treatment with cytoreductive surgery combined with IPHC perfusion are encouraging. The rarity of MPM makes appropriately powered prospective randomized trials unlikely. Therefore, we now offer this approach off protocol; however, further study of this combined modality therapy is warranted. PMID- 11603563 TI - Cellular integration of thyrocytes and thyroid folliculogenesis: a perspective for thyroid tissue regeneration and engineering. AB - Thyroid gland is composed of many spheroid structures called thyroid follicles, in which thyrocytes are integrated in their specific structural and functional polarization. In conventional monolayer and floating cultures, the cells cannot reorganize follicle structures with normal polarity. By contrast, in a 3-D collagen gel culture thyrocytes easily and stably reconstruct follicles with physiological polarity. Integration of thyrocyte growth and differentiation appears to result in eventual thyroid folliculogenesis. 3-D collagen gel culture and subacute thyroiditis, a specific thyroid disorder, are the promising models for addressing the mechanism of thyroid folliculogenesis. Because formation of 3 D follicles actively occurs both in this culture system and at the regenerative stage of the disease. The understanding of the mechanistic basis of folliculogenesis is prerequisite for establishment of an artificial thyroid tissue, which would enable a more physiological approach to the treatment of hypothyroidism caused by various diseases and surgical processes than conventional hormone replacement therapy. In this review, we have discussed thyrocyte integration, and thyroid folliculogenesis and tissue regeneration, to further thyroid biology. Also, we briefly discussed a perspective on thyroid tissue regeneration and engineering. PMID- 11603564 TI - The molecular basis of vitamin D-dependent rickets type I. AB - Vitamin D 1alpha-hydroxylase is a key enzyme for the vitamin D-calcium homeostasis. Recently, 1alpha-hydroxylase cDNA and gene were cloned. Human 1alpha hydroxylase gene is located at chromosome 12q13.3. Several inactivating mutations in the 1alpha-hydroxylase gene were found in VDDR I patients, and it was established that 1alpha-hydroxylase gene is responsible for VDDR I. To date, various mutations spreading over all exons have been reported. The cloning of 1alpha-hydroxylase gene will further lead to the better understanding of vitamin D regulation in both normal and pathological states. In addition, 1alpha hydroxylase knock-out mice, which is recently generated, would be a useful model animal for VDDR I. PMID- 11603565 TI - Platelet-derived growth factor BB-induced p38 mitogen-activated protein kinase activation causes cell growth, but not apoptosis, in vascular smooth muscle cells. AB - The aim of this experiment was to examine the regulation of p38 mitogen-activated protein (MAP) kinase by platelet-derived growth factor (PDGF)-BB and its biological effects on rat cultured vascular smooth muscle cells (VSMCs). VSMCs were obtained from aortae of male Wistar rats by the media explant technique. After being stimulated by PDGF-BB with or without the p38 MAP kinase-specific inhibitor, SB-203580, the cells were solubilized, and the levels of phosphorylated p38 MAP kinase were examined by immunoblot analysis. The amounts of DNA synthesis and content were measured by using [3H]-thymidine and Hoechst 33258 dye, respectively. The detection of apoptotic cells was evaluated by the TUNEL method. PDGF-BB could phosphorylate p38 MAP kinase dose-dependently, and the phosphorylation was specifically inhibited by SB-203580 in a dose-dependent manner. However, PDGF-BB did not affect the protein level of p38 MAP kinase. Both [3H]-thymidine incorporation and total cellular DNA content were increased by PDGF-BB, and these elevations were prevented by SB-203580. In contrast, PDGF-BB stimulated VSMCs did not show apoptotic change in spite of the presence or absence of SB-203580. These results established that PDGF-BB activated p38 MAP kinase and subsequently regulated cell growth in VSMCs, providing a molecular mechanism by which p38 MAP kinase can cause the development of cardiovascular diseases, including atherosclerosis. PMID- 11603566 TI - Interleukin-1beta stimulates transendothelial mobilization of human peripheral blood mononuclear cells with a potential to differentiate into osteoclasts in the presence of osteoblasts. AB - There is accumulating evidence that interleukin-1 (IL-1) levels are increased locally at the site of active bone resorption in a variety of diseases including osteoporosis, periodontal disease and rheumatoid arthritis. However, the pathogenic role of IL-1 in bone loss remains to be fully elucidated. We present here additional evidence that IL-1beta enhances endothelial activation and thereby stimulates mobilization of peripheral blood mononuclear cells (PBMCs) from luminal to abluminal spaces across the endothelium. Furthermore, IL-1beta stimulates the differentiation of PBMCs into osteoclast-like cells with bone resorbing activity in the presence of human osteoblastic SaOS-2 cells without systemic hormones. These findings provide circumstantial evidence for the hypothesis that IL-1beta generated in the bone microenviroment plays a stimulatory role in PBMC mobilization from the peripheral circulation and their subsequent differentiation into osteoclast-like cells in the bone tissue. In addition, the present study supports the notion that osteoclast progenitor cells might be derived from the peripheral circulating blood mononuclear cells in human. PMID- 11603567 TI - A case of familial isolated hyperparathyroidism with ectopic parathyroid cancer. AB - We report the kindred with familial isolated hyperparathyroidism with parathyroid cancer. The proband was diagnosed as having primary hyperparathyroidism at age 43. The same disorder was also found in his daughter who had low bone mass. His son was found to have primary hyperparathyroidism by family screening. The pathological diagnosis of the resected parathyroid in both father and daughter was parathyroid cancer, and that in son was parathyroid adenoma. The right lower gland of the proband and the left lower gland of the son were present in thymus. No mutations were found in the sequences of MEN1 gene, hence gene(s) other than MEN1 gene may have contributed to the malignant potency in our cases. PMID- 11603568 TI - Hyperintensity of posterior pituitary on MR T1WI in a boy with central diabetes insipidus caused by missense mutation of neurophysin II gene. AB - We present a 10-year old boy with central diabetes insipidus (CDI) showing hyperintensity in a normal-sized posterior pituitary on magnetic resonance (MR) T1-weighted image (T1WI). He complained of nocturnal enuresis and polyuria. Daily urine volume increased to 4 to 5 L, and AVP plasma level was very low. Polymerase chain reaction (PCR)-amplified exons of the arginine vasopressin (AVP) neurophysin (NP) II gene were sequenced. Nucleotide-1884 guanine in Exon 2 was substituted with thymine, which induced a substitution of glycine for valine at amino acid position 65 in the NP II moiety. However, MR imaging showed hyperintensity in the posterior pituitary on T1WI. These results suggest that the MR findings of the posterior pituitary in CDI may vary. PMID- 11603569 TI - The novel untranslated exon "exon 0T" encoded between the exon 0 and exon 1 of the rat estrogen receptor alpha (ER alpha) gene. AB - We have recently isolated two untranslated first exons, exon 0N and exon 0S, of rat estrogen receptor alpha (ER alpha) gene from the liver by use of 5'-rapid amplification of the cDNA ends (5'-RACE) method. In this communication, we further analyzed the 5'-untranslated region (UTR) of the ER alpha mRNA in rat anterior hypophysis in order to investigate the existence of the other 5' untranslated exon(s) of rat ER alpha gene. Total RNA from the anterior hypophysis of 8-week-old female Wistar strain male rats was subjected to 5'-RACE with antisense primers located in exon 1 of the rat ER alpha gene and one of the positive clones (clone 35) was sequenced. The nucleotide sequence of clone 35 revealed the insertion of a previously unidentified exon (which we termed "exon 0T") between exon 0 (the first reported 5'-UTR form of rat ER alpha mRNA) and exon 1 of rat ER alpha mRNA. Analysis of rat genomic DNA indicated that exon 0T was located between exon 0 and exon 1 of rat ER alpha gene. We further investigated the distribution of ER alpha mRNA containing exon 0T in several brain regions and various peripheral tissues of 8-week-old male and female Wistar strain rats by use of reverse transcription-polymerase chain reaction (RT-PCR). The distribution of the ER alpha mRNA (0T-1) was essentially similar to that of ER alpha mRNA in which exon 0 was spliced onto exon 1 reported previously. These results indicate that (1) exon 0T is a novel untranslated exon of rat ER alpha gene which is located between exon 0 and exon 1 on rat genomic DNA, (2) exon 0T is inserted between exon 0 and exon 1 of ER alpha mRNA by alternative splicing, and (3) this alternative splicing may occur in tissues where the transcription of ER alpha gene is initiated from exon 0. PMID- 11603570 TI - Effect of Ferula hormonis extract on social aggression, fertility and some physiological parameters in prepubertal male mice. AB - The effects of an aqueous extract of Ferula hormonis on social aggression, fertility and some physiological and biochemical parameters were investigated in male mice. The ingestion of 3 mg/kg of aqueous extract of F. hormonis for six weeks clearly inhibited social aggression. Body wet weight and other sex accessory organ weights were significantly reduced by this treatment. The ingestion of this extract by male mice resulted in a significant reduction of their fertility. This treatment caused a significant decrease in the number of pregnant females, number of implantations and viable fetuses in females impregnated by males that ingested this extract. Additionally, the numbers of epididymal sperm and their motility were dramatically reduced in F. hormonis treated mice. Concomitant increases in sperm abnormalities were also observed when compared with control. These data indicate that F. hormonis exposure during this period puts the exposed animals at significant risk for reduced reproductive capacity in adulthood. PMID- 11603572 TI - Relationship between anti-insulin antibodies and albuminuria or proteinuria in human insulin-treated type 2 diabetes mellitus. AB - In order to examine the relationship between anti-insulin antibodies (AIA) caused by extrinsic human insulin and albuminuria or proteinuria, 53 human insulin treated type 2 diabetics were divided into two groups: (AIA(+) group) 27 patients with a titer of AIA greater than 7.6% and (AIA(-) group) 26 patients with a titer of AIA less than 7.5%. Although no significant difference was found between the two groups for age, gender, body mass index, duration of diabetes, duration of insulin treatment, blood pressure, serum creatinine, glycosylated hemoglobin (HbA1c), daily dose of insulin, daily insulin injection times, or treatment of hypertension, the AIA(+) group had a significantly higher urinary albumin to creatinine ratio and urinary protein to creatinine ratio than the AIA(-) group (p < 0.05). It is suggested that AIA in type 1 diabetics might be insulin autoantibodies, which is not the case with type 2 diabetics. To our knowledge this is the first study demonstrating the relationship between AIA induced not by porcine or bovine insulin, but by human insulin and albuminuria or proteinuria in type 2 diabetics. PMID- 11603571 TI - Spontaneous recovery from hypopituitarism in a man with lymphocytic hypophysitis: a case report. AB - A 50-year-old man presented with hypopituitarism and a pituitary lesion on magnetic resonance imaging scan. He was diagnosed as having lymphocytic hypophysitis, and replacement therapy with hydrocortisone and thyroxine was started. He regained normal pituitary function after 10 months. Reports of spontaneous recovery from lymphocytic hypophysitis in men are rare. While the natural history of lymphocytic hypophysitis remains elusive and its management is not well established, our report shows that spontaneous resolution may occur with steroid supplementation even in men. PMID- 11603573 TI - Infarction followed by hemorrhage in pituitary adenoma due to endocrine stimulation test. AB - A 63-year-old man, who presented with visual field loss due to pituitary tumor, received an intravenous bolus injection of thyrotropin and gonadotropin releasing hormones and insulin as a preoperative evaluation. He complained of severe headache and nausea 2 hours after injection. Emergent CT scan showed no evidence of intratumoral hemorrhage. The next day, his visual field became null. MR images revealed heterogeneous mixed intensity lesions. Under diagnosis of pituitary apoplexy, he underwent transsphenoidal tumor removal 30 hours after onset. Intraoperative and pathological findings showed tumor hemorrhage and adjacent necrotic change. Fourteen cases with sufficient clinical detail in the literature are reviewed: All of the cases had macroadenoma with suprasellar extension. Testing agents were gonadotropin and thyrotropin releasing hormones in 92.9% and 85.7% of cases, respectively. Headache was an initial symptom and started within two hours in all cases but one. Half of the cases showed no change on CT scan. However, tumor hemorrhage was evidenced in 92.9% of cases with or without necrosis due to ischemic change, intraoperatively or pathologically. It is speculated that pituitary apoplexy often starts with infarction possibly due to vasoactive effect of testing agents and later develops into hemorrhage. Therefore, it is necessary to observe patients closely at least a few hours after endocrine stimulation test, and MR imaging may make an earlier diagnosis for the pituitary apoplexy since CT scan often shows no density change in the pituitary adenoma. PMID- 11603574 TI - A case of adrenocortical tumor coexisted with paragangliomas. AB - We report a case of adrenocortical tumor that coexisted with paragangliomas. A 35 year-old woman was admitted to the hospital because of left upper abdominal pain. A palm-sized mass was palpated at left upper quadrant. Hormonal studies revealed the features of pheochromocytoma. An emergency operation was performed because hemorrhage of the tumor was suspected. A 10 cm diameter ruptured mass was found in the left adrenal area and other tumors were also noted adjacent to inferior vena cava (IVC). The pathologic report revealed that the adrenal mass was an adrenocortical tumor with hemorrhagic necrosis and that the tumors adjacent to IVC were paragangliomas. This was the first case of adrenocortical tumor with paragangliomas in our Medline search result, hence we report the case with a review of the literature. PMID- 11603576 TI - Perioperative changes in circulating leptin levels in women undergoing total abdominal hysterectomy. AB - To investigate the effects of total abdominal hysterectomy on circulating leptin levels, 16 pre- and 8 postmenopausal patients with uterine leiomyoma or carcinoma in situ of the uterine cervix were enrolled. Serum levels of leptin and fasting blood sugar (FBS) were determined before (day -7) and after surgery (day +1 and +7). Body mass index (BMI) was recorded at day -7 and +7. Anesthesia duration, surgical duration, hematology, and blood loss during surgery were recorded. Relations of these variables to serum leptin levels were investigated. Serum leptin levels rose from 7.3+/-4.7 ng/mL to 9.3+/-5.8 ng/mL at day +1 (P < 0.01), then decreased to 4.9+/-3.0 ng/mL at day +7 (P < 0.05 vs. values at day -7 and +1). FBS levels also rose from 89.4+/-7.5 mg/dL to 119.3+/-24.0 mg/dL (P < 0.01), then returned to normal at day +7 (96.2+/-9.0 mg/dL). However, there was no significant correlation observed between FBS and leptin levels at each time point (r < or = 0.22). BMI decreased from 22.7+/-3.0 kg/m2 to 21.7+/-2.9 kg/m2 at day +7 (P < 0.001). At day -7 and +7, leptin levels were positively correlatd with BMI (r = 0.79, P < 0.001 and r = 0.71, P < 0.001, respectively). Circulating leptin levels were increased on day one after total abdominal hysterectomy. PMID- 11603575 TI - Corticotroph cell adenoma without typical manifestations of Cushing's disease presenting with cavernous sinus syndrome following pituitary apoplexy. AB - This report presents a unique case of corticotroph cell adenoma in a 30-year-old man without acromegaly or features typical of Cushing's disease, who developed cavernous sinus syndrome following pituitary apoplexy. Magnetic resonance imaging revealed a large intrasellar/suprasellar mass with pituitary hemorrhage and extension of a hematoma to the anterior base of the skull. Urgent transnasal pituitary surgery revealed an acidophilic pituitary adenoma, with immunoreactivity for ACTH and GH and expression of proopiomelanocortin (POMC) and GH messenger ribonucleic acid (mRNA) demonstrated by in situ hybridization. To our knowledge, a silent corticotroph cell adenoma with GH production has never been reported. This type of adenoma may potentially enlarge and develop tumoral hemorrhage because it is free of endocrinological symptoms. PMID- 11603577 TI - Osteomalacia in a vitamin D-deficient woman with Graves' disease. PMID- 11603578 TI - Mechanical properties of artificial tracheas composed of a mesh cylinder and a spiral stent. AB - Much work has been done on the materials used for mesh-type artificial tracheas, but a precise mechanical evaluation of these structures has not yet been performed. In the present study, we determined the mechanical properties of typical mesh-type artificial tracheas and compared them with those of native trachea. Four types of artificial trachea were made and used for the mechanical tests. The basic frame of all the specimens was composed of a mesh cylinder and a spiral stent. The specimen whose mesh was sealed with collagen sponge showed almost the same behavior in the force-strain curve under compression, suggesting that collagen sealing has little effect on mechanical properties. Agreement between measured and estimated mechanical properties was good, especially in the low strain region, suggesting that artificial tracheas can be designed in terms of mechanical properties by mainly considering the basic frame structure. PMID- 11603579 TI - Investigation of the solubility and ion release in the glass system K2O-Na2O-CaO P2O5. AB - Glasses from the quaternary glass system K2O-Na2O-CaO-P2O5 were produced by standard glass forming techniques. The compositions were limited by fixing the P2O5 at 45 mol%, fixing the CaO content at either 20, 24 or 28 mol%. The K2O and Na2O made up the residual varying from 0 to 25 mol% K2O. General trends showed that with increasing CaO content, the glasses showed a decrease in solubility as expected. For a single system of fixed CaO content, with increasing K2O content, there was an increase in solubility. This was seen at all three CaO contents. All the glasses showed an initial increase in pH followed by a gradual decrease with time and this was accounted for by the initial release of Na+ ions into solution. For the ion release curves, for all fixed CaO contents, the glass with 0 mol% K2O showed the lowest Ca2+ release. This was accounted for as being due to the low solubility compared to the K2O containing glasses. The Na+ release appeared anomalous, as it was higher than all the K2O containing glasses. Even though the glasses with 0 mol% K2O showed the lowest solubility, the amount of Na+ contained in the glass was high, hence the high levels of release. PMID- 11603580 TI - The influence of the restoration-tooth interface in light cured composite restorations: a finite element analysis. AB - This study examines the early shrinkage behaviour of dental composite resins, and in particular the interfacial stresses around the margins of a composite restoration. The development of stresses at the restoration-tooth interface can have a detrimental effect on the longevity of a restoration. The influence of this interface on the stress system generated in the tooth was examined using finite element analysis. The restoration-tooth interface was simulated using spring elements of varying spring constants (k = 1, 10(2), 10(4), 10(10) N/mm). Interfacial stresses varied from -0.15 to 0.42 MPa for a spring constant of 1 N/mm, and from -19 to 68 MPa for a spring constant of 10(10) N/mm. Correlations between stiffness at the restoration-tooth interface and higher shrinkage stresses due to restricted shrinkage were found. Interfacial failure at the upper and lower regions of the interface, as well as cuspal movements of the order of 2 microm were predicated for the model of the highest spring constant, 10(10) N/mm. The restoration-tooth interface modelled by the spring elements was seen to have a conclusive effect on the ensuing stress system, as well as the longevity of the restoration. PMID- 11603582 TI - A chemical analysis of the clogging process of polymeric biliary endoprostheses. AB - Insertion of polymeric biliary endoprostheses is widely used as a method of palliation of malignant strictures of the biliary tree. Despite the success of this technique, clogging of the stent in a few months is still an existing problem. The aim of the present study has been to investigate the causes of the obstruction, considering both the stent material and the composition of the obstructing deposit. 16 ready-to-implant and 33 occluded retrieved prostheses were analysed by ATR-FTIR spectroscopy. The clogging sludge was recovered and studied by FTIR spectroscopy and pyrolysis derivatisation/gas chromatography/mass spectrometry (Py/GC/MS). The results of the analyses showed that the deposit was mainly formed by proteins, bilirubin, calcium palmitate and bilirubinate, cholesterol and its fatty acids salts. It was found that approximately 50% of the examined ready-to-implant samples were made of ethylene-vinylacetate copolymer (EVA) instead of polyethylene (PE), as was stated in the producer declaration. Moreover, 94% of the retrieved samples were found to be made of EVA indicating that this material is less suitable than PE for this application. All retrieved PE and EVA stents showed a protein-like black layer strongly absorbed on the surface. PMID- 11603581 TI - Effect of chemical composition on hydrophobicity and zeta potential of plasma sprayed HA/CaO-P2O5 glass coatings. AB - Multilayered plasma sprayed coatings on the surface of Ti-6Al-4V alloys have been prepared, which were composed of an underlayer of HA and a surface layer of a CaO P2O5 glass-HA composite, with 2 or 4wt% of glass. Contact angle and surface tension variation with time, for both water and a protein solution, were determined by the sessile and pendent drop methods respectively using the ADSA-P software. Wettability studies showed that hydrophobicity of the coatings increase with the glass addition. The work of adhesion of albumin was also altered in a controlled manner by the addition of the CaO-P2O5 glass, being lower on the composite coatings than on HA. Zeta potential (ZP) results showed that composite coatings presented a higher net negative charge than HA coatings and that ZP values were also influenced by the content of the glass. This study demonstrated that the surface properties of those coatings may be modified by the addition of CaO-P2O5 glass. PMID- 11603583 TI - UV-irradiation-induced DNA immobilization and functional utilization of DNA on nonwoven cellulose fabric. AB - Immobilization of double-stranded DNA onto nonwoven cellulose fabric by UV irradiation and utilization of DNA-immobilized cloth were examined. The immobilized DNA was found to be stable in water, with the maximum amount of fabric-immobilized DNA being approximately 20 mg/g of nonwoven fabric. The DNA immobilized cloth could effectively accumulate endocrine disruptors and harmful DNA intercalating pollutants, such as dibenzo-p-dioxin, dibenzofuran, biphenyl, benzo[a]pyrene and ethidium bromide. Additionally, DNA-immobilized cloth was found to bind metal ions, such as Ag+, Cu2+, and Zn2+. The maximum amounts of bound Ag+, Cu2+, and Zn2+ onto DNA-immobilized cloth (1 g) were approximately 5, 2, and 1 mg, respectively. DNA-immobilized cloth containing Ag+ showed antibacterial activity against Escherichia coli and Staphylococcus aureus. DNA immobilized cloth without metal ion and with Cu2+ or Zn2+ did not show antibacterial activity. These results suggest that immobilized DNA imparts useful functionality to cloth. DNA-immobilized cloth prepared by UV irradiation has potential to serve as a useful biomaterial for medical, engineering, and environmental application. PMID- 11603584 TI - Fracture toughness of bovine bone: influence of orientation and storage media. AB - Using the single-edge notched bending (SENB) test, two fracture toughness parameters of longitudinal and transverse bovine bone specimens were evaluated: the critical stress intensity factor, Kc, determined from the peak load to initiate fracture, and the energy or work of fracture, Wf, the energy required to extend a crack through a notched specimen. It was found that preservation of bone in alcohol resulted in a 25-45% higher Kc value compared to control specimens stored in physiological saline; whereas the work of fracture, Wf, demonstrated the opposite behaviour, with the alcohol stored specimens having a 28-56% lower value than the saline control specimens. It was established that the effect of alcohol is reversible upon the bone being restored in saline. Consistent with previous studies, it was found that cracks oriented in the longitudinal direction resulted in both a significantly lower fracture toughness and lower work of fracture than those cracks directed transversely. The results are discussed in terms of the proposed deformation and fracture mechanisms known to occur in bone. PMID- 11603585 TI - Interactions between glass ionomer cement and alkali metal fluoride solutions: the effect of different cations. AB - This study examines the effect of different cations in equimolar alkali metal fluoride solutions on their interactions with glass ionomer cements. Uptake of both fluoride and cation were measured together with change in solution pH and morphological changes in the cement surface. Two cements were used; AH2, a dental restorative cement containing both fluorine and alkali metal (Na) as glass components and LG30, which contained neither. Discs of cement 1 x 10 mm were set in moulds at 37 degrees C for 1 h then, stored in water for 3 days at 37 degrees C. Discs in each test group (N = 5) were immersed in 10 ml of solutions of either NaF, KF, or RbF, all containing 900ppm F, control discs were stored in water, all at 37 degrees C for 24h. Solutions were analysed for F- by ISE potentiometry, Na+ by the same technique and K+ and Rb+ were analysed by atomic absorption spectrometry. Uptake was obtained by difference between solution used for immersion and the control solution. Solution pH was measured potentiometrically. The surface roughness of the discs was measured by linear stylus profilometry. Fluoride ion uptakes for AH2 were 451 micromol/g NaF, 378 KF, and 318 RbF. The comparable figures for LG30 were 202, 161, and 159. Differences between cements were all statistically significant and also between solutions pairings except for the KF/LG30 vs. RbF/LG30. Uptake of cations was equimolar for AH2/ NaF, AH2/RbF and LG30/KF but M+:F- ratios were significantly above unity for AH2/KF and LG30/NaF and significantly below unity for LG30/RbF. The pH changes were all positive and were significantly higher for AH2 than LG30 and for RbF compared to the other fluoride solutions for each cement (probably because of its lower initial pH). The final pH of all solutions were less than I pH unit from neutral (pH7). The AH2 cement test discs all showed significant increase in roughness (Ra) compared to control discs stored in water whereas the LG30 discs showed no such difference. Regression analysis showed a significant positive correlation between fluoride uptake and Ra. It was concluded that changing the alkali metal cation influenced all four variables examined (F- uptake, M+ uptake, pH change and extent of cement surface roughening). PMID- 11603586 TI - Retention of endothelium on ovine collagen biomatrix vascular conduits under physiological shear stress. AB - This study evaluates the adhesion of endothelial cells to 4 mm internal diameter, ovine collagen biomatrix vascular conduits. The biomatrix conduit is formed in a living animal and the wall consists of a complete, naturally produced matrix reinforced with polyester mesh. We propose that the microarchitecture of the matrix lining the lumen may promote endothelial cell attachment without pretreatment with adhesive proteins or extra cellular matrix components. Endothelial cell adhesion to the biomatrix surface was assessed by subjecting conduits seeded with ovine aortic endothelial cells (OAEC) to physiological range shear stresses of 16 and 32 dyn/cm2 in vitro. OAECs were isolated, cultured and seeded (1 x 10(6) cells/ml) by rotation onto the luminal surface of 20 cm lengths of biomatrix vascular conduits (n = 36). The seeded conduits were divided into three groups and cultured either for 24 h (n = 12), 48 h (n = 12) or 72 h (n = 12). Following culture, the conduits from each group were subjected to flow rates of either 240 ml/min (n = 6) or 480 ml/min (n = 6) with heparinized sheep blood for 1 h. Luminal surface cell cover was determined pre- and post-flow from Datura stramonium lectin labeled en face preparations. Histological analysis demonstrated that OAECs attach to the luminal surface of biomatrix conduits and form confluent monolayers within 24-48 h. Flow testing revealed that, for both flow rates and independent of the time in culture, there was no significant decrease in cell cover after flow (p = 0.13). The results support the hypothesis that a vascular conduit, engineered from a naturally formed biomatrix, provides a suitable substrate for the formation of flow resistant endothelium. PMID- 11603587 TI - The effects of cross-linking of collagen-glycosaminoglycan scaffolds on compressive stiffness, chondrocyte-mediated contraction, proliferation and biosynthesis. AB - The healing of articular cartilage defects may be improved by the use of implantable three-dimensional matrices. The present study investigated the effects of four cross-linking methods on the compressive stiffness of collagen glycosaminoglycan (CG) matrices and the interaction between adult canine articular chondrocytes and the matrix: dehydrothermal treatment (DHT), ultraviolet irradiation (UV), glutaraldehyde treatment (GTA), and 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDAC). The degree and kinetics of chondrocyte mediated contraction, chondrocyte proliferation, and protein and glycosaminoglycan synthesis were evaluated over a four-week period in vitro. Cell mediated contraction of the matrices varied with cross-linking: the most compliant DHT and UV matrices contracted the most (60% reduction in matrix diameter) and stiffest EDAC matrices contracted the least (30% reduction in matrix diameter). All cross-linking protocols permitted cell proliferation and matrix synthesis as measured by DNA content and radiolabeled sulfate and proline incorporation, respectively. During the first week in culture, a lower level of proliferation was seen in the GTA matrices but over the four-week culture period, the GTA and EDAC matrices provided for the greatest cell proliferation. On day 2, there was a significantly lower rate of 3H-proline incorporation in the GTA matrices (p<0.003) although at later time points, the EDAC and GTA matrices exhibited the highest levels of matrix synthesis. With regard to cartilage specific matrix molecule synthesis, immunohistochemistry revealed a greater amount of type II collagen in DHT and UV matrices at the early time points. These findings serve as a foundation for future studies of tissue engineering of articular cartilage and the association of chondrocyte contraction and the processes of mitosis and biosynthesis. PMID- 11603588 TI - Characterization of rat meningeal cultures on materials of differing surface chemistry. AB - To better understand the interactions of cells derived from meningeal tissues with the surfaces of devices used for the treatment of central nervous system disorders, the behavior of primary postnatal day 1 rat meningeal cultures was evaluated on biomaterials of differing surface chemistry. Meningeal cultures in serum containing media were analyzed for attachment, spread cell area, proliferation, the production of extracellular matrix (ECM), and neuronal outgrowth. In general, both cell attachment as well as cell spread area decreased with increasing substrate hydrophobicity, whereas cell division as indicated by BrdU incorporation and time to confluence, was lower on the most hydrophobic materials. We suggest that such differences immediately after cell seeding were most likely mediated by differences in surface adsorption of proteins. In longer term experiments, most of the materials were colonized by meningeal cultures irrespective of surface chemistry, and all cultures were equally inhibitory to neuronal outgrowth suggesting that over time, cells can modify the substrate perhaps by secretion of extracellular matrix molecule proteins. Our data suggests that cell type-specific differences in response to different biomaterials may play an important role in determining the ultimate nature and composition of the CNS at the host-biomaterial interface. PMID- 11603589 TI - The stiffness of bone marrow cell-knit composites is increased during mechanical load. AB - A novel device for mechanical stimulation of primary adult rat bone marrow cells cultured on three-dimensional knitted textiles has been prototyped. A method has been developed ensuring a well-defined, high-density, and reproducible cell seeding on the knitted fabric. After culturing for 18-52 days the cell-knit composites were subjected to uniaxial 2% stretching and relaxation. The frequency was altered between 0.1 Hz (196 min, loading phase) and 0.01 Hz (360 min, resting phase). Identically treated knits without cells exhibited a slight stiffness reduction, whereas the stiffness of knits with cells increased from cycle to cycle. The stiffness increase was found to depend on the duration of the culture period before mechanical loading. Our data suggest that the extracellular matrix deposited by the cells on the knit and intact microtubuli of living cells cause the observed stiffness increase. In comparison to the unstrained static cell-knit composites cell proliferation and bone cell differentiation were reduced by the mechanical load. PMID- 11603590 TI - A study on grafting and characterization of HMDI-modified calcium hydrogenphosphate. AB - It is known that the organic molecules can provide an effective means to manipulate the surface properties of the biodegradable ceramic. There are two ways to modify the surface of the biodegradable ceramic by organic molecules. The first one is through surface adsorption but organic molecules will easily be washed out in the physiological environment. The second approach is to graft organic molecules through covalent bond to the hydroxyl groups that are available on the surface of the ceramics. Isocyanate group has been reported as a coupling agent for hydroxyapatite and organic molecule. The studies showed that the isocyanate could react with hydroxyl groups of hydroxyapatite and form a covalent bond between isocyanate and hydroxyapatite. In the study, hexamethylene diisocyanate (HMDI) was used as coupling agent and calcium hydrogenphosphate (CaHPO4, CHP) was the candidate ceramic. CHP will react with HMDI at the temperature of 20 degrees C, 30 degrees C, 40 degrees C, 50 degrees C, 60 degrees C, and 70 degrees C for 4h. Dibutyltin dilaurate and hydroquinone were used as catalyst and inhibitor, respectively. The effect of reaction temperature on the grafted yield will be described. The linkage between CHP and HMDI will be characterized by DTA, TGA, FTIR, XRD, and 31P, 13C liquid state NMR. From the results, we successfully modified the surface of CHP with coupling agent of HMDI. The grafted yield of HMDI on CHP was increasing with the reaction temperature. The best temperature for CHP modified by HMDI is around 50 degrees C. The linkage between HMDI and the surface of CHP is a urethane linkage as CHP-O-CO-NH-(CH2)6 N=C=O. After further treatment, the terminal group of CHP treated with HMDI (MCHP) will be converted into a primary amine group as the formula of CHP-O-CO-NH (CH2)6-NH2. If reaction temperature is 60 degrees C, long extension chain will occur with a urea linkage between the isocyanate groups as the formula of CHP-O CO-NH-(CH2)6-(NH-CO-NH-(CH2)6)n-NH2. At reaction temperature higher than 60 degrees C, the HMDI will become prepolymerized forms in solution. The prepolymerized forms such as allophanate, biuret, uretidione and urea linkage will turn the solution into gel type mixture, which will lead to low grafted yield of HMDI on CHP. When MCHP prepared at the temperature 20 degrees C, there is no evidence of long extension but the grafted yield is the lowest only 0.9 wt% around. PMID- 11603591 TI - Effect of polyacrylic acid on the apatite formation of a bioactive ceramic in a simulated body fluid: fundamental examination of the possibility of obtaining bioactive glass-ionomer cements for orthopaedic use. AB - Glass-ionomer cements, which consist of CaO-Al2O3-SiO2-CaF2 glass powders and a polyalkenoic acid solution, such as polyacrylic acid (PAA), have been widely used in dentistry. They set rapidly without any shrinkage, the lack of temperature increase on reaction, and develop high mechanical strength. Therefore, if bioactive glass-ionomer cements can be obtained, such cements are expected to be useful as cements for fixing orthopaedic implants to the surrounding bone. In the present study, to examine the possibility of obtaining bioactive glass-ionomer cements, the effect of PAA on the apatite formation on bioactive ceramics in a simulated body fluid was investigated. It was revealed that presence of even a small quantity of PAA inhibits the apatite formation in the body environment. It is speculated that when glass-ionomer cements are implanted into the body, PAA can be released from the glass-ionomer cements and inhibits the apatite formation on their surfaces. It is reasonable to suppose that this will occur with any glass-ionomer cement that contains PAA. Therefore, it might be considered difficult to obtain bioactive glass-ionomer cements. PMID- 11603592 TI - Bioresorbable devices made of forged composites of hydroxyapatite (HA) particles and poly L-lactide (PLLA). Part II: practical properties of miniscrews and miniplates. AB - Miniscrews and miniplates made of forged composites composed of raw hydroxyapatite (u-HA) particles (particle size 0.2-20 microm, averaging 3.0 microm, Ca/p = 1.69 and containing CO3(2-)) and a poly L-lactide (PLLA, Mv: about 180 kDa, containing residual 0.05 wt% lactide) with osteological bioactivity such as direct bonding to bone and osteoconductivity, total resorbability and radiopacity were examined for various mechanical properties in order to evaluate their usefulness for cranio-, oral and maxillo-facial as well as plastic and reconstructive surgeries with PLLA-only or titanium devices. The composites containing u-HA particles at 30wt% for miniscrews and 40wt% for miniplates were selected based on total mechanical strengths and bioactivity, respectively. It was found that the composite devices generally had slightly different mechanical properties than forged PLLA-only devices of which strengths are ranked the highest among the reinforced PLLA-only ones that having been used in many clinical cases to date, in spite of their approximate 2 or 3 times lower absolute strengths than those of titanium ones. However, a remarkable distinction that makes the composite miniplates stand above the titanium ones was confirmed on their fatigue resistance to alternate bendings such that they retained 70% of their initial strength even after 60 times without revealing any damage, whereas the metallic devices fully broke off at only 8 times. This behavior was similar to that of forged PLLA-only devices but is unique as composites made of organic polymers divided by inorganic particles. In addition, profile plates such as L-, T-, X, T, C-, Mesh-, Box-, and Barhole types which were processed by forging twice exhibited nearly directional isotropy in strength and could be deformed in situ at ordinary temperatures to adjust their shapes along the surface undulations of the skull, mandible, maxilla, zygomatic bone and the like without thermoforming and did not return to their original shapes inside an alive body due to the high PLLA's Tg (65 degrees C) over an alive body temperature (37 degrees C). Since it had already been confirmed in previous papers that these stiff and tough composites have the osteological bioactivity which is missing from both PLLA-only and titanium ones, and radiopacity which is wanting in PLLA only ones, these various small and thin screws and plates have conclusively less objectionable practicality for use in oral-maxillo and craniofacial as well as plastic and reconstructive surgeries. PMID- 11603593 TI - The Society for Heart Valve Disease 2001 honored lecture. Where do we go from here. PMID- 11603594 TI - Differences in heart valve procedures between North American and European centers: a report from the Artificial Valve Endocarditis Reduction Trial (AVERT). AB - BACKGROUND AND AIM OF THE STUDY: Differences in heart valve procedures between North American (NA) and European (EU) centers were evaluated in a multicenter trial. METHODS: Between July 1998 and January 2000, 807 patients from 12 NA (n = 446) and seven EU centers (n = 361) were randomized to receive either Silzone or conventional valves in the Artificial Valve Endocarditis Reduction Trial (AVERT). Subanalysis was performed to compare demographics, patient risk profile, surgical techniques and perioperative management of patients in NA and EU centers. RESULTS: Mean age was significantly younger and body mass index higher in NA. Patients' risk profiles showed significantly higher incidences of previous myocardial infarction, congestive heart failure, angina, prior cardiovascular surgery, and history of smoking in NA. A different distribution of implant position was observed between groups: aortic valve/mitral valve/double valve replacement in 54.0, 35.7 and 10.3% in NA, and 64.5, 27.4 and 8.0% in EU (p <0.01). Concomitant coronary artery bypass grafting was performed in 31.6% of NA patients and 19.4% of EU patients (p <0.001). Timing of surgery showed a higher incidence of urgent procedures in NA centers. Distribution of valve sizes and perioperative complication rate were similar, but length of hospital stay was longer in EU centers. CONCLUSION: Surprisingly, surgeons in NA and EU centers are faced by different patient populations requiring mechanical heart valve replacement. NA patients were younger, but required more extensive surgery. Surgical technique and perioperative management appear to differ in NA and EU centers. These differences in reporting heart valve procedures might have been influenced by variable interpretations of definitions and different patient expectations, although a uniform study protocol with consistent definitions was used at all sites. PMID- 11603595 TI - Risk factors for early mortality after valve surgery in Europe in the 1990s: lessons from the EuroSCORE pilot program. AB - BACKGROUND AND AIM OF THE STUDY: The characteristics of valve surgery are evolving. The study aim was to explore its demographics and risk factors in Europe in the 1990s, using the EuroSCORE database. METHODS: For the EuroSCORE program, information on 98 variables regarding risk factors, procedures and outcome were collected for 5,672 patients undergoing valve surgery under cardiopulmonary bypass in 128 European centers. Bivariate (i.e. Mann-Whitney test or chi-square when appropriate), then logistic regression analyses were carried out to identify risk factors for early mortality. The predictive value of EuroSCORE was analyzed using the Hosmer-Lemershow test and by computing the area under the receiver operating characteristic (ROC) curve. RESULTS: Aortic valve stenosis was the most common diagnosis (47.6%), whilst mitral valve surgery accounted for 42% of procedures. Coronary surgery was performed concomitantly in 21% of cases. Hospital mortality was 6.1%. Predictive factors for early mortality were: age (p = 0.0001), preoperative serum creatinine >200 micromol/l (p = 0.014), previous heart surgery (p = 0.0001), poor left ventricular function (p = 0.008), chronic congestive heart failure (p = 0.0001), pulmonary hypertension (p = 0.0001), active acute endocarditis (p = 0.0001), emergency procedure (p = 0.05), critical preoperative status (p = 0.0001), tricuspid surgery (p = 0.015), aortic and mitral surgery (p = 0.002), combined thoracic surgery (p = 0.0001), and combined coronary surgery (p = 0.0001). The predictive value of EuroSCORE for mortality was good (area under the ROC curve = 0.75). CONCLUSION: The 'valve' subset of the EuroSCORE database provides an instant picture of European valve surgery in the 1990s that can be used either for individual assessment, or for country- or institution-based epidemiological studies of risk factors and practices. PMID- 11603596 TI - Minimally invasive video-assisted mitral valve repair: short and mid-term results. AB - BACKGROUND AND AIM OF THE STUDY: Port-Access video-assisted surgery for mitral valve repair has become an alternative for mid-sternotomy. However, mid-term results are not yet available. METHODS: Between February 1997 and December 1999, 121 patients underwent mitral valve surgery through a 4- to 5-cm right anterolateral thoracotomy using the Heartport endovascular cardiopulmonary bypass system; among these patients, 77 (57 males, 20 females; mean age 59 years; range 31-84 years) underwent mitral valve repair. Severe (4+) mitral regurgitation (MR) was seen in 63 patients (82%). Mean NYHA class was 2.5+/-0.4. Standard Carpentier mitral valve repair procedures were used in all patients; 11 received PTFE chordae for anterior leaflet prolapse. RESULTS: Pathologies were degenerative (n = 69), chronic endocarditis (n = 4), annular dilatation (n = 3) and rheumatic (n = 1). Hospital mortality was 1.3% (n = 1). Two patients (2.6%) had conversion to sternotomy for aortic dissection caused by the Endo-Aortic Clamp. Nine patients (11%) underwent revision for bleeding. Mean cross-clamp and perfusion times were 103 min (range: 24-160 min) and 140 min (range: 75-215 min), respectively. Mean hospital stay was eight days (range: 4-36 days). During follow up (mean 31 months; range: 17-51 months) all patients improved their NYHA class; eight (11%) remained in class II. Left ventricular (LV) end-diastolic and LV end-systolic diameters decreased from 61+/-7.3 mm to 53+/-6.9 mm (p <0.01) and from 37+/-6.8 mm to 34+/-6.9 mm (p <0.05), respectively. Sixty-two patients (88%) had no or trivial MR, and nine (12%) had moderate MR (2+). There were two late valve replacements for endocarditis, and no late deaths. CONCLUSION: Port-Access mitral valve repair constitutes a valid alternative to the standard procedure, and has good mid-term results. Video-assisted mitral valve repair appears to be safe and reproducible. PMID- 11603598 TI - Left-side approach to the mitral valve. AB - BACKGROUND AND AIM OF THE STUDY: The standard, minimally invasive surgical approach to the mitral valve is usually accomplished from the right side, through a longitudinal incision posterior and parallel to the interatrial groove. The left-side approach should perhaps be reconsidered for its suitable exposure of the mitral valve. METHODS: Eleven consecutive patients underwent mitral valve surgery via a left lateral minithoracotomy, with cardiopulmonary bypass performed through the left femoral artery and vein. The left internal mammary artery was used as a coronary graft in one patient. Cardioplegic solution was delivered through the ascending aorta. After direct aorta cross-clamping, mitral surgeries were performed, including mechanical and bioprosthetic implants, redo operations, annuloplasties and repairs. RESULTS: An excellent view of the mitral valve was obtained in all cases, with optimal vision of the whole annulus, chordae tendineae, papillary muscles and aortic valve possible. Exposure of the mitral valve was superior to that achieved with the standard approach from the right, notably with a wider angle of vision and greater flexibility of movement available. Moreover, mitral valve structures were closer to the operator, making the procedure easier to perform. CONCLUSION: The left-side approach to the mitral valve offers excellent vision and exposure of the valve. Although awaiting additional cases to validate results, in the absence of major complications we recommend this technique. PMID- 11603597 TI - The preferred approach for mitral valve surgery after CABG: right thoracotomy, hypothermia and avoidance of LIMA-LAD graft. AB - BACKGROUND AND AIM OF THE STUDY: An alternative to avoid redo sternotomy in patients with patent left internal mammary artery-left anterior descending coronary artery (LIMA-LAD) grafts undergoing mitral valve surgery is right thoracotomy with moderate-deep hypothermia (approximately 20 degrees C) and fibrillatory arrest without aortic cross-clamping. Few reports exist which directly compare re-sternotomy and right thoracotomy. METHODS: Between July 1992 and February 2000, 47 patients (39 males, eight females; median age 66 years; range: 41-83 years; 41 in NYHA class III or IV) with patent LIMA-LAD grafts underwent mitral valve surgery. Thirty-seven patients were approached through a right thoracotomy with moderate-deep hypothermia (median 20 degrees C) and fibrillatory arrest (right thoracotomy group), and 10 were approached through a re-sternotomy, with aortic cross-clamping and cardioplegic arrest. The median ejection fraction was 42% (range: 20-71%). Univariate analysis was used to determine predictors of outcome, as well as to evaluate differences in characteristics between groups. RESULTS: Operative mortality (OM) and perioperative myocardial infarction for the entire cohort was 11% and 10%, respectively, and there were no inter-group differences. No preoperative characteristics were associated with OM. Two LIMA-LAD graft injuries occurred in the re-sternotomy group compared with none in the right thoracotomy group (20% versus 0%, p = 0.04). Transfusion requirements were also greater in the redo sternotomy group (median 7 versus 2 packed red blood cell units, p = 0.04). CONCLUSION: Right thoracotomy with moderate-deep hypothermia and fibrillatory arrest is the preferred approach for reoperative mitral valve surgery after coronary artery bypass grafting in the presence of patent LIMA-LAD grafts. These data suggest that this approach is associated with decreased incidence of LIMA LAD graft injury, as well as reduced transfusion requirements. PMID- 11603599 TI - Valve repair for rheumatic mitral disease. AB - BACKGROUND AND AIM OF STUDY: Mitral valve repair is the standard reparative technique for degenerative mitral disease, but results of valve repair in rheumatic disease are also encouraging. The outcomes after mitral valve repair for rheumatic disease at young age was evaluated for suitability of repair. METHODS: A total of 319 patients (246 females, 73 males; mean age 31.3+/-0.5 years) underwent mitral valve repair for rheumatic mitral disease at the authors' institution between 1991 and 1998. Mean follow up was 51.9+/-1.2 months (range: 9 98 months), and was 88.7% complete. RESULTS: Preoperatively, 47.6% of patients were in NYHA classes III and IV. Mitral stenosis was present in 87.5%, insufficiency in 5.3%, and stenosis/insufficiency in 7.2%. Concomitant procedures were performed in 32% of patients who had associated cardiac lesions. The intraoperative mortality, reoperation and reoperation mortality rates were 0.9%, 6.7% and 0%, respectively. During follow up there were 10 late deaths (3.5%), six of which were cardiac disease-related (2.1%). Postoperatively, 98% of patients were in NYHA classes I and II. CONCLUSION: Valve repair in mitral disease is a standard technique, with low mortality, complication and reoperation rates, and good cardiac function and late survival. This approach is equally applicable to rheumatic mitral valve repair; hence, rheumatic mitral valves should also be repaired. PMID- 11603601 TI - Influence of prosthesis size and left ventricular mass on left ventricular diastolic reserve in patients with aortic valve prostheses. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to determine the influence of valve size and left ventricular (LV) mass on long-term LV diastolic reserve in patients subjected to aortic valve replacement for stenosis. METHODS: Seventy four patients (33 women, 41 men; mean age 64 years) after aortic valve replacement with 40 pericardial bioprostheses and 34 bileaflet mechanical prostheses were studied. All valves were of nominal size 19, 21 or 23 mm. The patients were studied by Doppler echocardiography, at rest and during peak effort, between 12 and 47 months after valve replacement. RESULTS: All patients achieved significantly increased heart rate, blood pressure and cardiac output in response to effort. Effort also significantly modified transvalvular pressure drops and valve areas. The mean diastolic reserve was 29.3 ml, and mean stroke volume reserve 23.2 ml; in neither case were there any significant differences between valve types, or among valve sizes. CONCLUSION: At about one year after surgery, the diastolic reserve of patients subjected to aortic valve replacement on account of stenosis was considerable, and independent of valve size. Despite the persistence of LV hypertrophy after valve replacement, LV diastolic function during effort was similar to that of the normal heart. PMID- 11603600 TI - Left ventricular mass regression after aortic valve replacement with CryoLife O'Brien stentless aortic bioprosthesis. AB - BACKGROUND AND AIM OF THE STUDY: Left ventricular (LV) hypertrophy has been shown adversely to affect LV function and late outcome after aortic valve replacement (AVR). The study aim was to assess the time course of LV mass regression (LVMR) after AVR with a CryoLife-O'Brien stentless bioprosthesis, and to identify factors affecting late reduction of myocardial hypertrophy. METHODS: In total, 113 patients (60 males, 73 females; mean age 70.9+/-6.5 years) were studied by echocardiography preoperatively, at discharge, at six and 12 months postoperatively, and yearly thereafter. LV diameter and thickness were measured using M-mode echocardiography; LV mass was calculated using the Devereux formula and indexed by body surface area (BSA). RESULTS: LV end-systolic diameter, end diastolic diameter, septal thickness and wall thickness decreased significantly after surgery (p <0.001). LV mass index (LVMI) was reduced by 16.6, 13.6, 10.1, 3.1, 3.3, 1.7, 2.6, and 1.8% at discharge and at 6 months and 1, 2, 3, 4, 5, and 6 years, respectively. Most LVMR occurred within the first year, with further (not significant) reductions at later examinations. Male sex (p = 0.002), arterial blood pressure > or =150 mmHg (p <0.001), LV ejection fraction (LVEF) < or =35% (p = 0.01), NYHA functional class > or = III (p = 0.01), atrial fibrillation (p <0.001), mean transvalvular gradient > or =40 mmHg (p = 0.001), and prevalent aortic incompetence (p <0.001) were factors influencing LVMR, independently of baseline effective orifice area and prosthesis size. CONCLUSION: AVR with the CryoLife-O'Brien stentless prosthesis resulted in significant LVMR. These findings encourage the use of this bioprosthesis in appropriate patients. PMID- 11603602 TI - Chitra heart valve: results of a multicenter clinical study. AB - BACKGROUND AND AIM OF THE STUDY: The Chitra tilting disc valve was developed in India to meet the need for a low-cost cardiac valve. The valve has an integrally machined cobalt-based alloy cage, an ultra-high molecular-weight polyethylene disc, and a polyester suture ring. An important feature of this valve is its soft closing sound, by virtue of a plastic occluder. METHODS: Between December 1990 and January 1995, 306 patients underwent isolated aortic (AVR, n = 101) or mitral valve replacement (MVR, n = 205) at six institutions in India. The early mortality rate was 6.9% (seven after AVR; 14 after MVR). A total of 285 survivors was followed up until September 1998; total follow up was 1212 patient-years (pt yr) (AVR, 445 pt-yr; MVR, 767 pt-yr). RESULTS: There were 52 late deaths (4.3%/pt yr; AVR 2.2%/pt-yr; MVR 5.5%/pt-yr). Thirty-five deaths were valve-related (23 were due to unknown causes). One AVR patient (0.2%/pt-yr) and 12 MVR patients (1.6%/pt-yr) developed valve thrombosis, and embolic episodes occurred in 25 patients (seven after AVR, 1.6%/pt-yr; 18 after MVR, 2.4%/pt-yr). Bleeding events and infectious endocarditis occurred infrequently (AVR 0.9 and 0.7%/pt-yr; MVR 0.4 and 0.5%/pt-yr, respectively). There was no incidence of paravalvular leak or structural dysfunction of the valve. Actuarial survival rates at seven years were 82.4+/-4.0% for AVR and 65.2+/-5.0% for MVR. During the same interval, thrombus free and embolism-free survival after AVR and MVR occurred in 98.9+/-1.1% and 94.1+/-1.9%, and 92.3+/-2.8% and 82.1+/-5.7% of patients, respectively. Freedom from all valve-related mortality and morbidity at seven years was 81.5+/-4.1% after AVR, and 64.2+/-5.1% after MVR. CONCLUSION: The Chitra valve appears to be safe and to have performance comparable with that of other currently used tilting disc valves. This valve costs substantially less than other valves, and is therefore within reach of a larger subset of Indian patients. PMID- 11603603 TI - Clinical results of the ATS prosthetic valve in 240 implants and review of the literature. AB - BACKGROUND AND AIM OF THE STUDY: Despite having been used in many thousands of implants, few published data exist concerning the ATS valve. Clinical data from ATS valve implants are presented, and the first two cases of mitral valve thrombosis with the ATS valve reported. Published data are also reviewed comparatively. METHODS: Between September 1998 and July 2000, 240 ATS valve prostheses were implanted in 199 patients, of whom 88 (36.6%) had mitral (MVR), 70 (29.1%) aortic (AVR), and 41 (17.1%) double valve replacements (DVR). Additional procedures were performed in 31 patients (15.6%). Transvalvular gradients and effective orifice areas were measured by transthoracic echocardiography. Total cumulative follow up of all patients was 241.6 patient years (pt-yr); mean (+/-SE) follow up was 1.25+/-0.51 years. RESULTS: There were six early deaths (3.0%). Overall and event-free survival rates during follow up were 98.96+/-0.73% and 97.90+/-1.22%, respectively. Anticoagulant-related hemorrhage occurred in one patient. The global incidence of hemorrhagic complications was 0.41 per 100 pt-yr. One patient with AVR was reoperated on for periprosthetic leakage in the first postoperative week. Valve thrombosis occurred in two patients with MVR at 12 and 14 months postoperatively. The incidence of valve thrombosis in MVR patients was 1.84 per 100 pt-yr (0.82 per 100 pt-yr overall). Hemolysis was seen only in one patient, echocardiographic examination revealing periprosthetic leakage. CONCLUSION: The short-term outcome in 240 implants showed the ATS valve to be safe, to have a low incidence of complications, and to provide excellent hemodynamic performance. PMID- 11603605 TI - Homografts in patients with combined disease of the aortic valve and the ascending aorta: an alternative to the classical Bentall procedure. AB - BACKGROUND AND AIM OF THE STUDY: In patients with aneurysms or dissections of the ascending aorta and additional aortic valve disease, valve-containing composite grafts are used in clinical routine. The study aim was to present our experience with homografts for aortic valve replacement extended by a vascular prosthesis as an alternative to the classical Bentall procedure. METHODS: Thirty consecutive patients (mean age 46+/-14 years) were included in this study. Indications for valve replacement were aortic stenosis (n = 15), aortic insufficiency (n = 6), combined aortic valve disease (n = 6), endocarditis of the native valve (n = 1), and endocarditis of a previously placed bioprosthesis (n = 2). The mean diameter of the ascending aorta was 5.6+/-0.5 cm; one patient had an acute dissection (diameter 4.4 cm). For valve replacement, cryopreserved homografts (mean size 24+/-2 mm) were used in a mini-root technique, and the ascending aorta was replaced by collagen-coated vascular prostheses (mean diameter 28+/-3 mm). The size of the vascular prosthesis was adjusted to the diameter of the sinutubular junction of the implanted homograft. Follow up included annual clinical examinations, transthoracic echocardiography and ultrafast computed tomography (CT) scans. RESULTS: All patients survived surgery, and no deaths occurred during follow up. None of the patients had postoperative anticoagulation, and no thromboembolic events were noted. Follow up was complete, with an average 48 months (range: 6 to 84 months). Doppler echocardiography revealed trivial to mild aortic regurgitation in nine patients postoperatively, with no deterioration during follow up. No pathologic pressure gradients over the aortic valves were measured at Doppler echocardiography; the mean valvular orifice area was 2.5+/ 0.3 cm2. At ultrafast CT, normal homograft anatomy including the sinotubular junction, no calcifications, and no signs of annular dilatation were seen. In the patient who had surgery for acute endocarditis of the native valve, ultrafast CT revealed a small pseudoaneurysm below the left coronary artery, without need for reoperation. CONCLUSION: Short- and mid-term results show that cryopreserved homografts extended by small-sized vascular prostheses can be used safely for Bentall procedures in selected cases where the diameter of the aortic valve annulus is moderately dilated. PMID- 11603604 TI - The role of thrombolysis in the management of left-sided prosthetic valve thrombosis: a study of 85 cases diagnosed by transesophageal echocardiography. AB - BACKGROUND AND AIM OF THE STUDY: Treatment strategies of prosthetic valve thrombosis (PVT) are controversial. The aim of this study was to compare the efficacy and safety of thrombolysis, surgery and heparin therapy in patients with either obstructive or non-obstructive PVT. METHODS: Between 1993 and 2000, 85 episodes of PVT were found (82 in the mitral position, three in the aortic) in 59 patients (22 males, 37 females; mean age 53 years; range: 28-80 years) by multiplane transesophageal echocardiography (TEE). Obstructive PVT was defined as restricted leaflet (occluder) motion with increased gradient, even if thrombus was not seen by TEE; non-obstructive PVT was considered as normal leaflet motion, irrespective of the gradients. Thrombolysis was given in 43 episodes (streptokinase, n = 37) by standard dosage protocols, surgery was performed in 20, and i.v. heparin was used in 22. Recurrence rate was calculated in 26 survivors of successful thrombolysis based on six months to six years follow up. Treatment with thrombolysis and heparin was monitored using TEE. RESULTS: There were 54 cases of obstructive PVT and 31 cases of non-obstructive PVT. Anticoagulation was inadequate in 82% of cases. Thrombolysis was completely successful in 37 cases (86% success rate); in 27 of 32 patients with obstructive PVT (in both cases of aortic location), and in 10 of 11 non-obstructive PVT. Heparin was successful in only nine of 18 non-obstructive PVT, and in none of four obstructive cases. Nine patients died, all with obstructive PVT, and all but one were in NYHA class IV; two were treated by thrombolysis (5% mortality), six by surgery (30% mortality) and one with heparin (5% mortality). Complications of thrombolysis included two strokes and two transient ischemic attack episodes (9%), and bleeding in one case (2%). There were six complications due to heparin treatment: newly developed obstruction in five patients and stroke in one patient. Recurrence was diagnosed in eight episodes in six patients with obstructive PVT after successful thrombolysis (22%); rethrombolysis was successful in four of five cases. CONCLUSION: Thrombolysis was shown to be superior to surgery in obstructive PVT, especially in NYHA class IV patients. Severe complications of thrombolysis were noted only in the critically ill. As heparin treatment appeared ineffective and unsafe for the treatment of PVT, thrombolysis appeared to be the optimal therapeutic choice in this condition. PMID- 11603606 TI - Fixation-related autolysis and bioprosthetic aortic wall calcification. AB - BACKGROUND AND AIM OF THE STUDY: It has been established previously that immediate fixation and increased glutaraldehyde (GA) concentrations are required to prevent severe autolytic tissue damage during bioprosthetic aortic root production. The study aim was to verify that structure-preserving fixation also reduces aortic wall calcification. METHODS: Porcine aortic roots were fixed either instantly or after being kept on ice for 48 h (phosphate-buffered saline, PBS). Two concentrations of GA (0.2% and 3.0%) were chosen (4 degrees C, seven days, PBS). Discs of aortic wall tissue (1.2 cm diameter) were implanted subcutaneously in rats for 60 days (n = 10 per group), while aortic roots were implanted in the distal aortic arch of sheep for six weeks (n = 3 per group) and six months (n = 4 per group). Calcification was assessed by atomic absorption spectrophotometry and light microscopy. Fixation-related tissue damage was determined by transmission electron microscopy, and correlated with calcification. RESULTS: No significant difference in calcification was found between immediate and delayed fixation if tissue was fixed with 0.2% GA. In the 3.0% GA group, both animal models showed a significantly lower level of calcification if tissue was immediately fixed. In the subcutaneous rat model, immediate fixation reduced calcification by 26% (p <0.0001). In the circulatory sheep model immediate fixation did not affect calcification in the short-term six week implants, but markedly lowered it by 37% (p = 0.035) after six months. Ultrastructurally, there was a significant correlation between membrane damage, vacuolization and vesicle shedding on the one hand, and calcification on the other. CONCLUSION: Coincidental fixation-related ultrastructural damage and increased calcification was demonstrated in bioprosthetic aortic wall tissue. PMID- 11603607 TI - Mechanisms of mechanical heart valve cavitation: investigation using a tilting disk valve model. AB - BACKGROUND AND AIM OF THE STUDY: The induction of mechanical heart valve (MHV) cavitation was investigated using a 27 mm Medtronic Hall (MH27) tilting disk valve. METHODS: The MH27 valve was mounted in the mitral position of a simulating pulse flow system, and stroboscopic lighting used to visualize cavitation bubbles on the occluder inflow surface at the instant of valve closure. MHV cavitation was monitored using a digital camera with 0.04 mm/pixel resolution sufficient to render the tiny bubbles clearly visible on the computer monitor screen. RESULTS: Cavitation on MH27 valve was classified as five types according to the time, site and shape of the cavitation bubbles. Valve cavitation occurred at the instant of occluder impact with the valve seat at closing. The impact motion was subdivided into three temporal phases: (i) squeezing flow; (ii) elastic collision; and (iii) leaflet rebound. MHV cavitation caused by vortices was found to be initiated by the squeezing jet and/or by the transvalvular leakage jets. By using a tension wave which swept across the occluder surface immediately upon elastic impact, nuclei in the vortex core were expanded to form cavitation bubbles. CONCLUSION: Analysis of the shape and location of the cavitation bubbles permitted a better understanding of MHV cavitation mechanisms, based on the fluid dynamics of jet vortex and tension wave propagations. PMID- 11603609 TI - Radiation-associated valvular heart disease in Hodgkin's disease is associated with characteristic thickening and fibrosis of the aortic-mitral curtain. AB - Radiation-associated valvular dysfunction is characterized by variable aortic and mitral valve thickening. A review of three patients assessed echocardiographically revealed that radiation-associated valvular dysfunction after radiation treatment for Hodgkin's disease may be characterized by a unique and consistent pattern of thickening of the aortic and mitral valves involving the aortic-mitral curtain. PMID- 11603608 TI - Aortic valve implantation in the calf: a successful approach using Heartport cannulation and minimally invasive techniques. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve replacement (AVR) for mechanical prosthetic valvular testing has not been performed in calves because of anatomic difficulties, and sheep have traditionally been used in this situation. Hemodynamically, however, the calf constitutes an excellent model due to vigorous myocardial contractility, high stroke volumes and high cardiac output, and so has been used for preclinical evaluation of mechanical assist devices and mechanical valves in the mitral and tricuspid positions, which can be approached with relative surgical ease. Recently, a juvenile bovine model has been used to test a newly developed mechanical valve in the aortic position. METHODS: Ten calves (body weight 91+/-11 kg) underwent AVR with a 21-mm mechanical prosthesis via a small left intercostal thoracotomy with the aid of a Heartport cannulation device. A standard cardiopulmonary bypass (CPB) circuit was used. To circumvent the short bovine ascending aorta and to gain additional space to perform the aortotomy, two aortic cannulas were inserted for arterial-systemic perfusion. Nine calves each received a 21-mm experimental trileaflet aortic central flow valve prosthesis, and one calf received a 21-mm St. Jude Medical prosthesis. RESULTS: Mean CPB duration was 154.2+/-44.4 min, and mean ischemic time 80.1+/ 15.9 min. Mean study duration was 42.6+/-53.7 days. Three calves were killed prematurely: two on days 2 and 7 due to complications arising from inadvertent entrapment of the right coronary artery ostium by a suture, and one on day 0 due to an accidental overdose of magnesium. Three calves, all of which had a first version test valve, were killed electively due to valve malfunction secondary to early valvular thrombosis. Four animals (three with the final version valve and one with a standard valve as a control) survived until killed electively (range: 33-172 days). CONCLUSION: Results indicate that replacement of the native bovine aortic valve with a mechanical prosthesis can be performed safely in calves. Complication-free survival of up to six months can be achieved in the growing calf, provided that the test valve design satisfies minimum hemodynamic and coagulation criteria. PMID- 11603610 TI - Cardioscopy and robotic assistance for the diagnosis of intraventricular endocarditis. AB - A 44-year-old male patient with an undefined mass in the left ventricular endocardium was scheduled for minimally invasive cardiac surgery. Ventricular investigation and tissue biopsies were completed with the help of a voice controlled robotic arm. Pathologic examination revealed non-bacterial thrombotic endocarditis. In addition to videoscopy, robotic assistance allows an easier diagnostic and therapeutic approach of intraventricular pathologies. PMID- 11603612 TI - Left ventricular outflow tract obstruction unmasked by nifedipine: a therapeutic pitfall in the management of chronic aortic regurgitation. AB - This case report illustrates the aggravation of a clinically silent left ventricular outflow tract obstruction by maintenance use of nifedipine in a patient with chronic severe aortic regurgitation, and demonstrates a potential limitation of vasodilator therapy in the management of this patient population. Recognition of this clinical scenario is imperative, as decision making in patients with chronic severe aortic regurgitation rests on the development of symptoms and/or left ventricular dysfunction in relation to the regurgitant volume. The importance of echocardiography in the detection of this valvular finding and in the follow up of these patients is emphasized. PMID- 11603611 TI - Prosthetic valve endocarditis in a patient with Marfan's syndrome following acupuncture. AB - Active prosthetic valve endocarditis (PVE) as a complication of acupuncture requiring valve surgery has not been reported previously. We report a case of PVE in a patient with Marfan's syndrome as a complication of acupuncture, who underwent emergency redo aortic root and valve replacement with a homograft. This report highlights the need for prophylactic antibiotics before acupuncture in patients with prosthetic valves, and also describes the use of a homograft as an effective surgical strategy. PMID- 11603613 TI - Multiple sclerosis 2000: a critical review. PMID- 11603614 TI - The prevalence of multiple sclerosis in the world: an update. AB - The systematic study of multiple sclerosis (MS) in populations, started in 1929 by Sydney Allison, now consists of over 400 publications dealing with the prevalence of MS throughout the world. However, any attempt to redefine the pattern of geographical differences in MS frequency remains as difficult as ever. The comparison of prevalence studies carried out in different areas and times is made difficult by the variability in surveyed population sizes, age structures, ethnic origins and composition, and the difficult quantification of numerators, especially regarding the recognition of benign and very early cases. Additionally, complete case ascertainment depends on access to medical care, local medical expertise, number of neurologists, accessibility and availability of new diagnostic procedures, the degree of public awareness about MS, and the investigators' zeal and resources. Critical examination of the more recent data on MS prevalence leads to some revisions of previously held concepts, the most interesting of which is the appreciation of the greater influence of genetic factors on disease acquisition. The rarity of MS among Samis, Turkmen, Uzbeks, Kazakhs, Kyrgyzis, native Siberians, North and South Amerindians, Chinese, Japanese, African blacks and New Zealand Maoris, as well as the high risk among Sardinians, Parsis and Palestinians, clearly indicate that the different susceptibilities of distinct racial and ethnic groups are an important determinant of the uneven geographic distribution of the disease. The updated distribution of MS in Europe, showing many exceptions to the previously described north-south gradient, requires more explanation than simply a prevalence-latitude relationship. Prevalence data imply that racial and ethnic differences are important in influencing the worldwide distribution of MS and that its geography must be interpreted in terms of the probable discontinuous distribution of genetic susceptibility alleles, which can however be modified by environment. Because the environmental and genetic determinants of geographic gradients are by no means mutually exclusive, the race versus place controversy is, to some extent, a useless and sterile debate. PMID- 11603615 TI - Pathological abnormalities in the normal-appearing white matter in multiple sclerosis. AB - In established cases of multiple sclerosis (MS), the normal-appearing white matter (NAWM), as defined for magnetic resonance imaging (MRI), is abnormal in the majority of cases. The clinical significance of these NAWM abnormalities is the subject of debate, but there is strong correlation with degree and progression of disability. New lesions form in NAWM before blood-brain barrier breakdown, as evidenced by gadolinium enhancement. The pathological basis of these neuroimaging abnormalities is largely unknown. Definitive pathological studies on the NAWM are few and are often based on small numbers of samples and of cases. Despite a variety of MS NAWM pathological studies, major research questions, of importance to our understanding of basic pathogenetic mechanisms and consequent rational therapies, remain unanswered. These relate to the frequency and extent of oligodendrocyte/myelin and axonal abnormalities in MS NAWM, and to the cellular basis of very early MS lesions detected by neuroimaging. In a pilot study of MS NAWM, microglial activation was demonstrated in 9 of 10 MS cases. We are currently testing the hypothesis that microglial activation, as defined by altered phenotype and HLA-DR positivity, will act as a marker for oligodendrocyte/myelin and axonal pathology in MS NAWM. PMID- 11603616 TI - Clues to the immunopathogenesis of multiple sclerosis by investigating untreated patients during the very early stage of disease. AB - Plethora of abnormalities of the immune system has been described in multiple sclerosis (MS). They include a number of myelin antigens (e.g. MBP, MOG, PLP, MAG), the presence of reactive T cells in blood and, further enriched, in the cerebrospinal fluid (CSF), large numbers of B cells in the CSF secreting antibodies of multiple but unknown specificities, an increase of mononuclear cells (MNC) expressing and secreting both pro- and anti-inflammatory cytokines, including Th1 cytokines interferon-gamma (IFN-gamma) and interleukin (IL)-6, the Th2 related IL-4 and IL-10, and the Th3-driven TGF-beta, elevated numbers of MNC in both blood and CSF expressing a spectrum of metalloproteinases and their inhibitors, as well as many other aberrations. However, no consistent patterns have emerged that relate any, of these findings to clinical variables such as exacerbations, duration of disease, disability, or lesions in the central nervous system (CNS) detected at magnetic resonance imaging. In order to elucidate the relevance of these immunological abnormalities in the pathogenesis of MS, my colleagues and I studied patients with acute monosymptomatic optic neuritis (ON) and compared them with patients with clinically definite MS (CDMS). The patients have not been treated and have not received corticosteroids or interferon-beta. When comparing these two groups, we were unable to identify any differences in any of the variables mentioned. Thus, very early MS, as represented by ON, shows the same full-blown pattern of immunological abnormalities seen in CDMS. Furthermore, a complete epitope spread affecting MBP, MOG, PLP, MAG and other myelin components is already present in ON. Whether any of these alterations play a pathogenetic role is still unsettled. PMID- 11603617 TI - Vaccinations and multiple sclerosis. AB - Two problems must be considered in regard to the relationship between vaccinations and MS: Do vaccinations favour the first attack of MS? Do they increase the short- or long-term risk in patients with known disease? Answers to these questions are difficult due to the paucity of reported cases, our ignorance of the precise frequency of neurological adverse events in vaccines based on prospective studies, and finally by the lack of a well established pathophysiology. In most instances, the role of the vaccine is based on a temporal link between the injection and the onset of neurological disease, and more rarely to a positive reintroduction. Acute disseminated encephalomyelitis (ADEM), a monophasic and multifocal illness of the white and grey matter, has been observed following various viral or bacterial infections as well as vaccine injections for diseases such as pertussis, tetanus and yellow fever. The similarities between ADEM and experimental allergic encephalitis (EAE) are suggestive of an immunological process. In addition to the dramatic presentation of ADEM, more limited white matter involvement, such as optic neuritis or myelitis, has been reported following vaccine injections, and has occasionally been counted as the first attack of MS. In France, 25 million inhabitants, almost half of the population, were vaccinated against hepatitis B (HB) between 1991 and 1999. Several hundred cases of an acute central demyelinating event following HB vaccination were reported to the pharmacovigilance unit, leading to a modification of vaccination policy in the schools and the initiation of several studies designed to examine the possible relationship between the vaccine and the central demyelinating events. The results of these studies failed to establish the causality of the HB vaccine. Nevertheless, molecular mimicry between HB antigen(s) and one or more myelin proteins, or a non-specific activation of autoreactive lymphocytes, could constitute possible pathogenetic mechanisms for these adverse neurological events. PMID- 11603618 TI - A case of multiple sclerosis triggered by organic solvents. AB - The neurotoxicity of organic solvents has long been recognized. Some are used as anesthetic agents, others in various industries. Their acute effect has been well documented since the nineteenth century, but more recently they have become notorious as the cause of addiction to glue sniffing. They may alter the immune system by causing lymphopenia, impairing phagocytosis and decreasing the level of serum complement, as well as altering the impermeability of the blood-brain barrier and leading to the appearance of white matter lesions in the brain. The following case study explores the possible role of organic solvents in the pathogenesis of multiple sclerosis. PMID- 11603619 TI - Stress, glucocorticoids and the susceptibility to develop autoimmune disorders of the central nervous system. AB - Alterations of the immunoendocrine circuit along the hypothalamic-pituitary adrenocortical (HPA) axis in various autoimmune diseases have recently been observed, suggesting a modulatory role of this feedback regulation in the pathogenesis of autoimmune diseases. Susceptibility to experimental autoimmune encephalomyelitis (EAE) may be influenced by variations in the production of endogenous glucocorticoid hormones (GC). The adrenocortical response is central to recovery from EAE in the Lewis rat, as reflected by increased severity of the disease in adrenalectomized animals. The key role of GC in modifying the induction and progression of EAE is also emphasized by a reversal of corticoid mediated effects through treatment with glucocorticoid receptor (GR) antagonists. We studied the relationship between defective GR function and susceptibility to EAE in transgenic (Tg) mice expressing GR antisense RNA. EAE was induced with the encephalitogenic myelin oligodendrocyte peptide (pMOG 36-50) in wild type (Wt) and transgenic (Tg) female mice bearing GR antisense RNA. pMOG 36-50 induced typical EAE in Wt mice but not in Tg mice. Histological examination of brains and spinal cords of Wt mice showed the presence of inflammation and/or demyelination, whereas in Tg mice neither were present. Although the mechanisms underlying the resistance of Tg mice to EAE induction are not yet clarified, compensatory changes at different levels of the HPA-immune axis in response to the potent immunogenic challenge are likely to participate in the observed effects. This work underlies the plasticity of the HPA-immune axis and suggests that pharmacological manipulation of neuroendocrine-immune networks may be a therapy of multiple sclerosis. PMID- 11603620 TI - Multiple sclerosis prevalence among Sardinians: further evidence against the latitude gradient theory. AB - A descriptive epidemiological survey was extended to the whole province of Sassari, northern Sardinia between latitudes 40 degrees 30' N and 41 degrees N. Results showed a crude total prevalence rate of 144.4 per 100000 on prevalence day (31 December 1997), and an onset-adjusted prevalence rate of 149.7 per 100000. The total average annual incidence rate was 4.9 per 100000 for the whole time interval studied (1968-1997), having increased from 2.0 in 1968-1972 to 6.8 in the last quinquennium considered. A substantial improvement in MS case ascertainment due to the introduction of new diagnostic procedures might account for such rates in Sardinia as well as in other Italian regions. However, when comparing our data with those obtained in the province of Ferrara, in the same time frames (1968-1997), a nine-fold versus a five-fold increase of MS prevalence was detected in Ferrara and Sassari, respectively. MS incidence temporal trend also notably increased in Sassari, but remained substantially stable in Ferrara. The progressive shortening of the time interval between clinical onset and diagnosis, and the proportion of benign-mild MS cases, were similar in both studies, thus suggesting a similar diagnostic accuracy. In our opinion, the repeatedly assessed increase of MS frequency in our province, at least partially does represent an actual rise of MS risk among Sardinians, thus disproving the latitude gradient-based theory (i.e. prevalence rates correlate with geographical latitudes) and supporting the hypothesis of a "Sardinian focus" of MS in a genetically susceptible population. PMID- 11603622 TI - Multiple sclerosis and multiple sclerosis-associated retrovirus in Sardinia. AB - The island of Sardinia has a high and increasing incidence of multiple sclerosis (MS). In a search for environmental factors that may account for this anomalously high incidence, we looked for evidence of multiple sclerosis-associated retrovirus (MSRV) that has previously been found in the plasma and cerebrospinal fluid of MS patients. We studied 25 MS patients and 25 matched healthy controls of ascertained Sardinian lineage. Blood samples were processed for extracellular RNA extraction. RNAs underwent reverse transcription/nested polymerase chain reaction (RT-PCR) with primers specific for MRSV-pol gene. We found a striking correlation between MSRV positivity and MS disease, but the virus was found also only in controls (100% and 12% respectively; Fisher's exact test, p<0.00001). It is unclear whether MSRV exerts any pathogenic role in MS. It is possible that this is simply an epiphenomenon, but even then, it may constitute a diagnostic marker. PMID- 11603621 TI - Immunogenetic heterogeneity of multiple sclerosis in Sardinia. AB - Multiple sclerosis (MS) predisposition is thought to be influenced by a complex, yet unclear interaction of genetic and environmental factors. Studying ethnically selected populations may reduce genetic and environmental heterogeneities and help clarify the underlying mechanisms of MS susceptibility. Sardinians kept a homogeneous genetic structure and have among the highest MS frequency rates worldwide. Interestingly, MS in Sardinia is linked to otherwise rare HLA alleles. In this light, recent findings from epidemiological and immunogenetic studies of Sardinian MS are presented. Results confirm that, likely due to significant genetic differences at a microgeographic level, even in this homogeneous population MS is immunogenetically heterogeneous and tends to preferentially cluster in some more archaic areas of the island. PMID- 11603623 TI - Epidemiology of multiple sclerosis in Sicily. AB - From epidemiological data obtained over more than 20 years by surveys conducted in different parts of Sicily, it is evident that Sicily is a high-risk area for multiple sclerosis (MS). This is in sharp contrast with the gradient hypothesis. High frequencies have been found in different parts of the island having different geoclimatic features, but at least two cities (Monreale and Enna) had had a prolonged Norman domination. This is in agreement with the hypothesis that MS originated in Northern Europe and spread around the world throughout the raids of the northern peoples. The increase in frequency estimated by follow-up and incidence studies is well established and is only in part linked to the improvement in diagnostic techniques. Finally, it is noteworthy that in the islands of Malta, a few sea miles away from Sicily, the MS prevalence rates are in the range of 4-8 cases per 100000 persons. This occurrence represents a natural model to investigate MS etiology through analytic studies and genetic analyses. PMID- 11603624 TI - Multiple sclerosis: infectious hypothesis. AB - In the search for the etiology of multiple sclerosis (MS), consideration has been given in turn to infectious agents, to genetic markers, and more recently to a combination of genetic and environmental factors, but after over a century of research, a definite conclusion has not been reached. The hypothesis that an infectious agent is responsible for triggering MS is perhaps one of neurology's most enduring notions. Interest in an infectious etiology has waxed and waned over the last two centuries since Pierre Marie first proposed that MS often starts as an infectious process. The possible role of infectious agents has been suggested by: the different geographic gradients in frequency among Caucasians; changes in prevalence due to migration, and the effect of age at migration; the suggestion of epidemics and clusters of cases in some small communities; and the remarkably low degree of concordance in monozygotic twins. The infectious hypothesis is strongly supported by the different temporal patterns of the disease in different geographic areas. Incidence rates have remained stable in some areas, but have changed over time in other regions. On the other hand, the hypothesis is hampered by the lack of evidence for a specific agent, and the weakness of the results of analytical studies that have tested the association between MS and previous infections. Despite these drawbacks, recent studies of a few select pathogens suggest that viral or bacterial infections or reactivations may trigger clinical exacerbations in relapsing-remitting MS. PMID- 11603625 TI - Twenty questions about multiple sclerosis clinical trials methodologies. AB - The heterogeneity of methods used in multiple sclerosis (MS) clinical trials prevents fair comparison of trials and reduces confidence in the validity of the therapeutic claims made. The validity of recent clinical trials is lessened by the following factors: MS shows variability in type and in rates of disease progression; primary progressive MS may not be the same disease as typical MS, and inclusion of subjects with this condition may have skewed results of trials to date. Using a new model, "relapsing-remitting" and "secondary progressive" MS are considered to represent earlier and later stages of the same disease. The variety of endpoints used in clinical trials impairs comparisons. The differences between EDSS stages vary at different levels and it is concluded that this is no longer the most appropriate tool, although it could be improved by modifying the scoring or scales to assess certain focused items. The clinical significance of a reduction in relapse rate is questioned, as are the inclusion criteria employed in recent trials. Drug doses based upon body mass differ from those based on surface area, making it hard to compare the effects of trial agents. The definitions of "sustained worsening" are not uniform and the concept is complicated by regression to the mean. Trials should continue for long enough to be sure that any beneficial effects noted are permanent. Although extensions provide better long-term data, they are usually statistically underpowered and clinically and demographically imbalanced. Ethically, if benefit is determined to be present, a trial should be stopped so that all subjects may be offered the beneficial agent, but determination of benefit may be imperfect. The "intention to treat" paradigm is a shibboleth, providing data on effectiveness rather than efficacy. The simple listing and addition of unwanted effects (UEs) is unproductive. Trivial UEs detract little from quality of life and are unimportant. The remainder should be separated between the notable and the serious, judging the net benefit of the agent causing them accordingly. Conventional MRI measures the density of hydrogen protons and thus is a map of water, which implies edema and thus the presence of a local inflammatory response, but conventional images do not inform on de- or re-myelination, axonal loss or gliosis and correlate poorly with clinical scores. It is concluded that recent MS therapeutic trials are subject to important criticism. PMID- 11603626 TI - Non-conventional MR techniques to monitor the evolution of multiple sclerosis. AB - In multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) has proved to be sensitive for detecting lesions and their changes over time. However, conventional MRI cannot characterize and quantify the tissue damage within and outside such lesions. Other quantitative MR techniques, including MR spectroscopy (MRS), magnetization transfer imaging (MTI) and diffusion-weighted imaging (DWI) have the potential to overcome this limitation and, as a consequence, to provide complementary information to conventional MRI. MTI- and DWI-derived measurements quantify the structural changes occurring within and outside lesions seen on conventional MRI scans, and MRS adds information on the biochemical nature of such changes. The application of these MR techniques to the study of MS is dramatically increasing our understanding of how MS causes irreversible deficits, and it is likely to provide useful insights into the pathophysiology of other white matter diseases in the future. The present review summarizes the major contributions made by these three MR techniques in the understanding of MS evolution. PMID- 11603627 TI - Interferon-beta dose and efficacy: the OPTIMS study. AB - Interferon beta (IFN-beta) reduces exacerbation rates in patients with relapsing remitting multiple sclerosis (MS), but some patients do not respond to treatment. Recent studies have shown a clear dose-response effect on the reduction of exacerbation rates, and on burden of disease accumulation and active lesion frequency seen on MRI. During treatment with 8 MIU IFN-beta we noticed a 30% rate of treatment failure. We then treated non-responders with 12 MIU IFN-beta and observed significant improvement in the clinical signs of disease activity. In order to compare the efficacy of two different doses of IFN-beta-1b, a multicenter study for the optimization of interferon for MS (OPTIMS) has been organized. The design of the study is presented here. PMID- 11603628 TI - To treat or not to treat the person with clinical multiple sclerosis--a dilemma. AB - Disease-modifying therapies for MS are believed to reduce the exacerbation frequency and thus perhaps improve a patient's "quality of life". Increasingly, such therapies are being offered to young persons with relatively mild or very early disease. Concerns about whom to treat, based on knowledge about the role of genetics on "MS risk" and the possible teratogenic effects of disease-modifying treatments on a developing fetus, are discussed. PMID- 11603629 TI - Low-dose oral methotrexate treatment in chronic progressive multiple sclerosis. AB - We aimed to further assess the safety and efficacy of low-dose oral methotrexate (LDOM) treatment for chronic progressive MS (CPMS). We studied 20 CPMS patients, including 16 with secondary progressive MS who had shown disease progression in the previous year. The mean follow-up was 23 months. The mean EDSS score was 6.3+/-1.1 before treatment and 6.4+/-1.1 after one year of treatment. At one year, 15 of 20 patients were still being treated, and 10 were stable. Twelve patients have completed 18 months of treatment, and eight are stable. Two patients stopped treatment because of side effects, two more because they did not perceive benefit, and one was lost to follow-up. Six patients had mild, transient increases in liver enzymes not requiring treatment interruption, and two had localized herpes zoster. Magnetic resonance imaging (MRI) performed before treatment and at one year remained unchanged in responders. We confirm that LDOM is safe in carefully selected and monitored CPMS patients. MTX is inexpensive and, given its anti-inflammatory and immunomodulatory properties, may be used as add-on therapy in non-responders to interferon beta, although hepatic toxicity may be a problem in long-term treatment. PMID- 11603630 TI - Nurses, midwives, and international health: building partnerships for development. PMID- 11603631 TI - International connections among midwives. AB - Women's health throughout the world is adversely affected by low status and literacy, poor nutrition, environmental toxins, violence, and other social, cultural, and economic factors. The majority of maternal deaths and disability occur in the developing nations of the world, such as Africa, where being born female is often a tragedy. The International Confederation of Midwives and the American College of Nurse-Midwives have nearly a century of commitment to making pregnancies and births safer and women's lives better. The shared vision of women as persons who are due full human rights guides the efforts of nurses and midwives in their global efforts of working with women and childbearing families and promoting health for all. PMID- 11603632 TI - Impact of traditional birth attendant training in Mozambique: a controlled study. AB - This study was designed to assess the utility and impact on perinatal mortality of a model traditional birth attendant (TBA) training program in rural Mozambique by comparing birth attendance and outcomes in similar communities with and without trained TBAs. Birth attendants and pregnancy outcomes were compared in 1) communities with good access to trained TBAs, 2) randomly selected, comparable communities with no access to trained TBAs, and 3) communities with good access to functioning maternities. Information was collected by interviews with women in randomly selected households. A total of 4,169 women were interviewed who reported on 3,616 completed pregnancies, which resulted in a birth or fetal death. Among women with good access to trained TBAs, 33% reported giving birth attended by a trained TBA, 43% reported giving birth at a health facility, and 24% reported giving birth attended by an untrained person. Among women without access to trained TBAs, 58% reported giving birth at health facilities, and 42% reported attendance by untrained persons. Among women with access to functioning maternity centers, 77% reported giving birth at a health facility and 22% said their birth was attended by an untrained person. There was no significant difference in perinatal or infant mortality among the groups. This study demonstrated a preference for health facility deliveries among rural Mozambican women with good access to trained TBAs. It also failed to demonstrate a reduction in perinatal or infant mortality associated with TBA training. Women said they preferred to deliver in health facilities because conditions were considered better and interventions could be performed if needed. The preference for health facility birth over home birth with a TBA may have been related to difficulties with TBA neighbors and their families or fear of potential witchcraft. Efforts to promote TBA training should be balanced with support for birthing services based in health facilities. PMID- 11603633 TI - Two models of in-service training to improve midwifery skills: how well do they work? AB - This program evaluation compared the knowledge, confidence, and skills of Indonesian village midwives who attended an intensive in-service training with midwives who received an internship program and midwives who attended no program. The five key skills compared were prevention of infection, use of the partograph, manual removal of placenta, bimanual uterine compression, and neonatal resuscitation. Midwives from the intensive in-service that combined competency based skill training with peer review and continuing education scored higher on the knowledge test and demonstration of the five key skills and reported managing complications better than midwives who attended no training program. Midwives from the internship program scored intermediate between the intensively trained and the untrained midwives. Overall, skill scores were 71% for midwives in the intensive program, 62% for the interns, and 51% for midwives with no in-service training. Village midwives from the intensive program scored significantly higher in the practical demonstration of manual removal of placenta, bimanual compression, and neonatal resuscitation than the interns, but the scores on infection prevention and use of the partograph were not different between the two groups. Differences in the volume of training opportunities between the two programs could be responsible for the different outcomes. PMID- 11603635 TI - The global HIV/AIDS epidemic. PMID- 11603634 TI - Views on involving a social support person during labor in Zambian maternities. AB - Because social support persons are excluded from modern obstetric care in Zambia, the aim of this study was to explore the views of 84 mothers and 40 health staff about allowing women to be attended by a supportive companion during labor in Zambian urban and rural maternities. Most of the mothers wanted a companion present to provide emotional and practical support. Those who were opposed to the idea had nobody to ask to be with them, or they had relatives who would interfere with the care provided. All health staff cited hospital policy as the principal reason for prohibiting social support persons from staying with laboring women. They also said that the health staff's role is to care for laboring women, and they worried that social support persons could interfere with their work by giving the laboring women traditional medicine. However, most health staff also said that a social support person could help the laboring women and give her a sense of security. The study concludes that Zambian maternity staff should be exposed to new research findings about the benefits of social support during childbirth and that this practice should be encouraged in Zambia. Ultimately, it should be the laboring woman who decides whether she wants to bring a social support person to the labor ward. PMID- 11603636 TI - Mother to child HIV transmission. PMID- 11603637 TI - The 2001 reproductive risk report card. PMID- 11603638 TI - The Bonnie Westenberg Pedersen International Midwife Award. PMID- 11603639 TI - Health care-seeking practices of pregnant women and the role of the midwife in Cape Town, South Africa. AB - The objective of this study was to investigate the health-seeking practices of pregnant women in a periurban area in Cape Town, South Africa. This qualitative study was based on 103 minimally structured in-depth interviews of 32 pregnant women. Most women were interviewed on several occasions, and a group discussion was held with women. The interviews were taped, transcribed, analyzed ethnographically, and, if necessary, translated into English. Antenatal care attendance was influenced by a number of factors, including women's knowledge of the role of antenatal care, perceived health needs, booking systems, nurse patient relationships, economics, child care, and transport. The expected benefits were weighed against the anticipated costs before decisions about seeking care were made. The findings highlight the importance of women's perceptions of quality of care in influencing their health seeking practices. The study suggests that considerably more attention needs to be given to this aspect of maternity services. PMID- 11603640 TI - Change in maternal concerns during the 6 weeks postpartum period: a study of primaparous mothers in Dar es Salaam, Tanzania. AB - The purpose of this study was to describe the postpartum concerns of primiparas. A cohort study included 79 mothers in Dar es Salaam, Tanzania. Mothers sorted topics into worry, interest, and confidence. Trends of decreasing worry and increasing interest and confidence for baby-related and mother-related topics were observed from 1 to 6 weeks. At 1 week mothers worried about baby's eyes, respiration, temperature, safety, and crying; but, at 6 weeks only crying was a problem. Need for information was constant about general health, baby behavior, and care of the baby. At 1 week mothers worried about swollen perineum, and feeling tired and nervous. They wanted information about preventing hemorrhage and infection and taking care of the perineum, breasts, and nipples. Trends of increasing worry and decreasing confidence were observed with respect to family relationships. At 6 weeks, mothers worried about the husband/partner's reaction to themselves and to the baby. Confidence in relatives' reaction to themselves and the baby decreased. Being aware of the changes in the way concerns are expressed may guide nursing/midwifery interventions for mothers as to the content and timing. PMID- 11603641 TI - Home based life saving skills: promoting safe motherhood through innovative community-based interventions. AB - In much of the developing world, home birth with unskilled attendants is the norm, and maternal and neonatal mortality rates are high. A comprehensive approach to address this problem needs to upgrade referral facilities and strengthen the skills of trained health care providers. To improve pregnancy outcomes, a program must also provide education, motivation, and mobilization of pregnant women, families, and communities (whose members must come to a common understanding of the need for and the means to prevent death of a woman or neonate). Consequently, the American College of Nurse Midwives (ACNM) has expanded the Life Savings Skills Series to include Home Based Life Saving Skills (HBLSS). HBLSS is a community and competency-based program that aims to reduce maternal and neonatal mortality by increasing access to basic life saving measures within the home and community and by decreasing delays in reaching referral facilities where life-threatening problems can be managed. PMID- 11603642 TI - Midwives and maternal child health: building resource capacity. PMID- 11603643 TI - Synergy between medical and nutrient therapies: George Washington meets Rodney Dangerfield. AB - Although medical therapies are widely accepted by health practitioners, sometimes without adequate testing, nutritional therapy is frequently looked upon uniformly as without merit. There are many reasons for this attitude. However, a substantial body of literature has accumulated that objectively demonstrates the value of adding nutritional therapy to the prevention or treatment of some diseases or specific risk factors for diseases. Examples of successful nutrition therapy that can be combined with medical management include treatment of hypertension, hyperlipidemia, intermittent claudication, osteoporosis, respiratory distress syndrome, and arthritis. PMID- 11603644 TI - Soy isoflavones--benefits and risks from nature's selective estrogen receptor modulators (SERMs). AB - Phytoestrogens have become one of the more topical areas of interest in clinical nutrition. These non-nutrient bioactive compounds are ubiquitous to the plant kingdom and possess a wide range of biological properties that contribute to the many different health-related benefits reported for soy foods and flaxseeds--two of the most abundant dietary sources of phytoestrogens. Reviewed is the recent knowledge related to their pharmacokinetics and clinical effects, focusing mainly on isoflavones that are found in high concentrations in soy foods. Arguments are made for considering soy isoflavones as natural selective estrogen receptor modulators (SERMs) based upon recent data of their conformational binding to estrogen receptors. Rebuttal is made to several key and important issues related to the recent concerns about the safety of soy and its constituent isoflavones. This article is not intended to be a comprehensive review of the literature but merely highlight recent research with key historical perspectives. PMID- 11603645 TI - Use of antioxidant nutrients in the prevention and treatment of type 2 diabetes. AB - Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), is increasingly common throughout the world. The World Health Organization has predicted that between 1997 and 2025, the number of diabetics will double from 143 million to about 300 million. The incidence of NIDDM is highest in economically developed nations, particularly the U.S., where approximately 6.5% of the population (17 million people) have either diagnosed or undiagnosed diabetes. The two most important factors contributing to the development of NIDDM are obesity and physical inactivity. The leading cause of mortality and morbidity in people with NIDDM is cardiovascular disease caused by macro- and microvascular degeneration. Current therapies for NIDDM focus primarily on weight reduction. Indeed, several investigations indicate that 65% to 75% of cases of diabetes in Caucasians could be avoided if individuals in this subgroup did not exceed their ideal weight. The success of this approach has been, at best, modest. An alternate approach to the control of Type 2 diabetes is to arrest the progress of the pathology until a cure has been found. To this end, some investigators suggest that dietary antioxidants may be of value. Several studies in humans and laboratory animals with NIDDM indicate that vitamin E and lipoic acid supplements lessen the impact of oxidative damage caused by dysregulation of glucose metabolism. In this brief review, we discuss the incidence, etiology, and current therapies for NIDDM and further explore the usefulness of dietary antioxidants in treating this disorder. PMID- 11603646 TI - Konjac-Mannan and American ginsing: emerging alternative therapies for type 2 diabetes mellitus. AB - Despite significant achievements in treatment modalities and preventive measures, the prevalence of diabetes has risen exponentially in the last decade. Because of these limitations there is a continued need for new and more effective therapies. An increasing number of people are using dietary and herbal supplements, even though there is a general lack of evidence for their safety and efficacy. Consequently, science based medical and government regulators are calling for more randomized clinical studies to provide evidence of efficacy and safety. Our research group has selected two such promising and functionally complementary therapies for further investigation as potentially emerging alternative therapies for type 2 diabetes: Konjac-mannan (KJM) and American ginseng (AG). We have generated a mounting body of evidence to support the claim that rheologically selected, highly-viscous KJM, and AG with a specific composition may be useful in improving diabetes control, reducing associated risk factors such as hyperlipidemia and hypertension, and ameliorating insulin resistance. KJM has a demonstrated ability to modulate the rate of absorption of nutrients from the small bowel, whereas AG has post-absorptive effects. Consequently, it appears that KJM and AG are acting through different, yet complementary, mechanisms: KJM by increasing insulin sensitivity and AG likely by enhancing insulin secretion. Before the therapeutic potential of KJM and AG as novel prandial agents for treatment of diabetes can be fully realized, further controlled trials with larger sample sizes and of longer duration are required. A determination of the active ingredients in AG, and the rheology-biology relationship of KJM are also warranted. PMID- 11603647 TI - Antioxidants and viral infections: host immune response and viral pathogenicity. AB - Malnutrition has long been associated with increased susceptibility to infectious disease. The increase in severity from and susceptibility to infectious disease in malnourished hosts is thought to be the result of an impaired immune response. For example, malnutrition could influence the immune response by inducing a less effective ability to manage the challenge of an infectious disease. Work in our laboratory has demonstrated that not only is the host affected by the nutritional deficiency, but the invading pathogen is as well. Using a deficiency in selenium (Se) as a model system, mice deficient in Se were more susceptible to infection with coxsackievirus, as well as with influenza virus. Se-deficient mice develop myocarditis when infected with a normally benign strain of coxsackievirus. They also develop severe pneumonitis when infected with a mild strain of influenza virus. The immune system was altered in the Se-deficient animals, as was the viral pathogen itself. Sequencing of viral isolates recovered from Se-deficient mice demonstrated mutations in the viral genome of both coxsackievirus and influenza virus. These changes in the viral genome are associated with the increased pathogenesis of the virus. The antioxidant selenoenzyme, glutathione peroxidase-1, was found to be critically important, as glutathione peroxidase knockout mice developed myocarditis, similar to the Se-deficient mice, when infected with the benign strain of myocarditis. This work points to the importance of host nutrition in not only optimizing the host immune response, but also in preventing viral mutations which could increase the viral pathogenicity. PMID- 11603648 TI - Antiinflammatory activities of lactoferrin. AB - Lactoferrin is a non-heme iron binding glycoprotein produced during lactation and by epithelial cells at mucosal surfaces. The protein is a prominent component of the first line of mammalian host defense and its expression is upregulated in response to inflammatory stimuli. In this paper, the antibacterial and immune modulatory properties of lactoferrin that contribute to host defense are reviewed. In addition, the results of recent preclinical and clinical studies demonstrating that lactoferrin acts as an inhibitor of dermal inflammatory cytokine production are summarized. The results indicate that lactoferrin may act as a potent anti-inflammatory protein at local sites of inflammation including the respiratory and gastrointestinal tracts. PMID- 11603649 TI - The role of phytoestrogens in the prevention and treatment of osteoporosis in ovarian hormone deficiency. AB - Ovarian hormone deficiency is a major risk factor for osteoporosis in postmenopausal women. Hormone replacement therapy (HRT) is perhaps the most effective treatment, as it has been demonstrated to both reduce the rate of bone loss and risk of fracture, including hip fracture. However, not all women who may benefit from HRT are willing to initiate this treatment due to fear of cancer and contraindications. Other therapeutic agents currently available are also associated with certain adverse effects. As a result, postmenopausal women are more inclined to use natural remedies to alleviate postmenopausal symptoms and help reduce their risk for chronic diseases such as osteoporosis. Recent reports support the notion that certain bioactive constituents, e.g., phytoestrogens, in plants play a role in maintaining or improving skeletal health. The main consumable plant sources of phytoestrogens include isoflavones and lignans found mainly in soybeans and flaxseed, respectively. Although this paper primarily focuses on the effects of soy protein or its isoflavones on bone, additional statements regarding the role of flaxseed and dried plums, a rich source of polyphenols, with respect to bone will be made. PMID- 11603650 TI - Constructive interactions among nutrients and bone-active pharmacologic agents with principal emphasis on calcium, phosphorus, vitamin D and protein. AB - Current and emerging bone active pharmacologic agents are capable of producing substantial gains in bone mass. However, nutrition must be adequate if this potential is to be realized. Calcium and vitamin D supplementation, for example, have both been demonstrated to augment substantially the skeletal response to estrogen therapy in postmenopausal women. The bisphosphonates and selective estrogen receptor modulator (SERMs) have all been tested only in the context of supplemental calcium and vitamin D. Therefore, it cannot be assumed that these bone active agents would be effective in the absence of these nutrients. Adequate protein intake has also been demonstrated to protect bone mass in the elderly and to improve recovery from osteoporotic fractures. Phosphorus intake, less extensively studied, may be more important than currently recognized, particularly in elderly individuals living alone, eating little meat, and receiving anti-osteoporosis treatment agents. PMID- 11603651 TI - Nutraceutical fatty acids as biochemical and molecular modulators of skeletal biology. AB - Several systemic hormones and localized growth factors coordinate events of bone formation and resorption to support bone growth in the young and maintain bone mineral content in the adult. Some of the more important factors produced in the bone microenvironment that impact skeletal biology include prostaglandins, cytokines, and insulin-like growth factors. Dietary fat sources that exert potent biological effects on the skeletal tissues belong to the omega-6 and omega-3 families of essential fatty acids. Specific long-chain polyunsaturated fatty acids (PUFA) belonging to these families are substrates for prostanoids that influence the differentiation and activity of cells in bone and cartilage tissues. These PUFA appear to alter prostanoid formation, cell-to-cell signaling processes, and impact transcription factors in vivo. Hence, these biologically active PUFA can be called nutraceutical fatty acids. This review highlights the role of nutraceutical fatty acids on bone metabolism and joint disease. The recent discovery of transcription factors controlling osteoblast function, and soluble proteins directing osteoclastogenesis and osteoblastogenesis offer new research opportunities for studying nutraceutical fatty acids in skeletal biology. PMID- 11603652 TI - Dietary effects on cardiovascular disease risk factors: beyond saturated fatty acids and cholesterol. AB - Hypercholesterolemia represents a significant risk for cardiovascular disease (CVD). While diet intervention remains the initial choice for the prevention and treatment of CVD, the nature of the dietary modification remains controversial. For example, reducing calories from total fat, without decreasing saturated fat intake results in insignificant changes in low density lipoprotein cholesterol (LDL-C). Similarly, diet interventions that focus solely on lowering dietary cholesterol and saturated fat intake not only decrease LDL-C, but also high density lipoprotein cholesterol (HDL-C) and therefore may not improve the lipoprotein profile. This brief review summarizes dietary interventions that lower LDL-C without affecting HDL-C levels. These interventions include soy protein, soluble fiber, soy lecithin and plant sterols. This review also includes some of the reported dietary interventions, such as polyphenols, isoflavones, folic acid and vitamins B6 and B12, which reduce the risk of CVD without changes in lipoprotein cholesterol. PMID- 11603653 TI - Calcium modulation of hypertension and obesity: mechanisms and implications. AB - Regulation of intracellular calcium plays a key role in hypertension and obesity. Dysregulation of calcium homeostasis appears to be a fundamental factor linking these conditions. Regulation of intracellular calcium in key disease-related target tissues by calcitrophic hormones provides the opportunity to modulate disease risk with dietary calcium. Overall, sub-optimal calcium intakes contribute to the etiology of salt-sensitivity and hypertension. High salt diets exert a calciuretic effect, serving to exacerbate the physiological consequences of sub-optimal calcium diets. Among these are increases in 1,25-dihydroxyvitamin D, which increases vascular smooth muscle intracellular calcium, thereby increasing peripheral vascular resistance and blood pressure. Dietary calcium reduces blood pressure in large part via suppression of 1,25-dihydroxyvitamin D, thereby normalizing intracellular calcium. The practical relevance of this approach has been confirmed in the DASH (Dietary Approaches to Stop Hypertension) trial, which demonstrated that increasing low-fat dairy product and fruit and vegetable consumption exerted profound blood pressure-lowering effects. The magnitude of this effect among hypertensives was comparable to that typically found in pharmacological trials of mild hypertension. 1,25-dihydroxyvitamin D also stimulates calcium influx in human adipocytes, resulting in stimulation of lipogenesis, inhibition of lipolysis and expansion of triglyceride stores. Accordingly, suppression of 1,25-dihydroxyvitamin D by dietary calcium has been identified as a target, which may contribute to the prevention and management of obesity. Indeed, laboratory, clinical and population data all indicate a significant anti-obesity effect of dietary calcium, although large-scale prospective clinical trials have not yet been conducted to definitively demonstrate the scope of this effect. Thus, available evidence indicates that increasing dietary calcium intakes may result in reductions in fat mass as well as in blood pressure. PMID- 11603654 TI - Chocolate: food as medicine/medicine as food. AB - Cocoa and chocolate products have been delicacies for hundreds of years. Only recently have they been recognized as significant sources of phytochemicals with healthful effects. These foods are among the most concentrated sources of the procyanidin flavonoids, catechin and epicatechin. Recent studies have shown that these polyphenols are absorbed from the intestine of animals and humans with epicatechin absorbed much more than catechin. These flavonoids have potent antioxidant and antiplatelet activities following consumption of cocoa or chocolate. PMID- 11603655 TI - Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer? AB - Most metastatic tumors, such as those originating in the prostate, lung, and gastrointestinal tract, respond poorly to conventional chemotherapy. Novel treatment strategies for advanced cancer are therefore desperately needed. Dietary restriction of the essential amino acid methionine offers promise as such a strategy, either alone or in combination with chemotherapy or other treatments. Numerous in vitro and animal studies demonstrate the effectiveness of dietary methionine restriction in inhibiting growth and eventually causing death of cancer cells. In contrast, normal host tissues are relatively resistant to methionine restriction. These preclinical observations led to a phase I clinical trial of dietary methionine restriction for adults with advanced cancer. Preliminary findings from this trial indicate that dietary methionine restriction is safe and feasible for the treatment of patients with advanced cancer. In addition, the trial has yielded some preliminary evidence of antitumor activity. One patient with hormone-independent prostate cancer experienced a 25% reduction in serum prostate-specific antigen (PSA) after 12 weeks on the diet, and a second patient with renal cell cancer experienced an objective radiographic response. The possibility that methionine restriction may act synergistically with other cancer treatments such as chemotherapy is being explored. Findings to date support further investigation of dietary methionine restriction as a novel treatment strategy for advanced cancer. PMID- 11603656 TI - Scientific rationale for using high-dose multiple micronutrients as an adjunct to standard and experimental cancer therapies. AB - We have hypothesized that high-dose multiple micronutrients, including antioxidants, as an adjunct to standard (radiation therapy and chemotherapy) or experimental therapy (hyperthermia and immunotherapy), may improve the efficacy of cancer therapy by increasing tumor response and decreasing toxicity. Several in vitro studies and some in vivo investigations support this hypothesis. A second hypothesis is that antioxidants may interfere with the efficacy of radiation therapy and chemotherapy. This hypothesis is based on the concept that antioxidants will destroy free radicals that are generated during therapy, thereby protecting cancer cells against death. None of the published data on the effect of antioxidants in combination with radiation or chemotherapeutic agents on tumor cells supports the second hypothesis. Scientific rationale in support of a micronutrient protocol to be used as an adjunct to standard or experimental cancer therapy is presented. PMID- 11603657 TI - The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. AB - Cellular oxidants, called reactive oxygen species (ROS), are constantly produced in animal and human cells. Excessive ROS can induce oxidative damage in cell constituents and promote a number of degenerative diseases and aging. Cellular antioxidants protect against the damaging effects of ROS. However, in moderate concentrations, ROS are necessary for a number of protective reactions. Thus, ROS are essential mediators of antimicrobial phagocytosis, detoxification reactions carried out by the cytochrome P-450 complex, and apoptosis which eliminates cancerous and other life-threatening cells. Excessive antioxidants could dangerously interfere with these protective functions, while temporary depletion of antioxidants can enhance anti-cancer effects of apoptosis. Experimental data are presented supporting these notions. The human population is heterogeneous regarding ROS levels. Intake of exogenous antioxidants (vitamins E, C, beta carotene and others) could protect against cancer and other degenerative diseases in people with innate or acquired high levels of ROS. However, abundant antioxidants might suppress these protective functions, particularly in people with a low innate baseline level of ROS. Screening human populations for ROS levels could help identify groups with a high level of ROS that are at a risk of developing cancer and other degenerative diseases. It also could identify groups with a low level of ROS that are at a risk of down-regulating ROS-dependent anti cancer and other protective reactions. Screening populations could provide a scientifically grounded application of antioxidant supplements, which could significantly contribute to the nation's health. PMID- 11603658 TI - Complications of total ankle replacement. AB - Total ankle arthroplasty is emerging as a viable treatment for patients with symptomatic tibiotalar arthritis who have not responded to nonoperative treatment. First generation ankle replacement prostheses had significant complications, leading many orthopaedic surgeons to abandon their use. Second generation designs have attempted to address some of these problems with innovative new designs. Ankle arthritis differs from other forms of degenerative arthritis in that the majority is posttraumatic in origin, and occurs in a younger age group. Correction of alignment is complicated by deformity of the foot distal to the ankle. Published results of second generation ankle replacement systems are limited, and the understanding of them is necessarily anecdotal. In the current study, complications of current second generation total ankle arthroplasty are divided into preoperative or patient selection problems, complications related to prosthetic design, intraoperative, and postoperative complications. Solutions, or the controversies surrounding those complications that have no obvious solution, will be discussed when appropriate. Total ankle arthroplasty with these second generation prostheses is gaining increasing popularity. The surgeon contemplating total ankle arthroplasty should have an understanding of anatomy and lower extremity biomechanics, and a thorough knowledge of the total ankle system he or she decided to use. PMID- 11603659 TI - Complications of ring fixators in the foot and ankle. AB - The current review reports the author's 12-year experience with the Ilizarov ring external fixator for the treatment of foot and ankle disorders. The complications caused by the use of this apparatus also will be presented. In the beginning, the complications were attributable to inexperience and the lack of literature available at that time (1987); afterward, the complications were attributable to excess of confidence and the belief that the external fixator could be the universal solution for all patients. The current review has two main purposes: to show the more frequent complications that arise during the use of the external fixators, and to present methods on how to prevent the complications and how to manage them once they occur. The majority of complications presented in the current review are related directly to the use of the external fixator. These complications could be called minor complications that frequently are seen during treatment. However, there are major complications that can be avoided with adequate application and control of the external fixator during treatment. PMID- 11603660 TI - Complications of lateral ankle ligament reconstruction. AB - Complications after ankle ligament reconstruction are infrequent, but present significant challenges to the treating orthopaedist. Local wound problems and nerve injuries may cause difficulty in the early postoperative period. Recurrent instability may be attributable to failure of the operation, poor rehabilitation, reinjury, or unrecognized predisposing factors. Postoperative stiffness of the subtalar and ankle joints frequently is reported after anatomic and nonanatomic tenodesis procedures and may cause significant morbidity. The current author reviews reported complications and treatment options in failed lateral ankle ligament surgery. PMID- 11603661 TI - Complications of achilles and posterior tibial tendon surgeries. AB - Surgery of the Achilles and posterior tibial tendons requires finesse to achieve optimal function. Although superficial in anatomic location, various critical neurovascular structures exist in close proximity. The superficial blood supply is fragile, requiring a delicate touch to prevent problems with wound healing. Damaged tendon tissue often is friable, making it difficult to sew or anchor. Adjusting the tendon length to the appropriate tension requires good judgment and affects long-term outcome through power and range of motion. Finally, surgery on these two tendons significantly affects function of the ankle and longitudinal arch, where small changes are magnified into large changes in maintaining normal gait. The current authors review the complications encountered in various common surgeries of the Achilles and posterior tibial tendons. PMID- 11603662 TI - Complications in surgery of the foot and ankle in patients with rheumatoid arthritis. AB - Complications occur in patients with rheumatoid arthritis who require surgical correction of painful deformities of the foot and ankle. These patients probably are more likely to have complications develop because they: (1) have a systemic disease; (2) use medications that may lead to complications; (3) require multiple operations; and (4) usually have advanced deformities resulting in extensive complicated operations. Despite these difficulties, results of surgical procedures in patients with rheumatoid arthritis remain uniformly excellent. Most complications can be treated successfully, and the overall failure of selected operations is low. However, surgical reconstruction of foot and ankle deformities in patients with rheumatoid arthritis must be meticulously planned and done. These operations are most successful in eliminating pain and in correcting severe deformities. PMID- 11603663 TI - Complications of foot and ankle surgery in patients with diabetes. AB - Treatment of the foot and ankle in patients with diabetes often is fraught with complications, frequently multifactorial in nature. Because of the multidisciplinary approach to the patient with diabetes, it is imperative that the patient and all healthcare professionals who are treating the patient recognize the foot at risk, and the clinical hallmarks of Charcot neuroarthropathy. Failure to do so often leads to disastrous results, such as ulceration, destruction of normal foot architecture, and progressive deformity too severe to accommodate a brace, thereby necessitating surgical intervention. The surgical treatment of the foot in a patient with diabetes requires knowledge of the pathophysiology of the neuroarthropathic (Charcot) foot, so that the appropriate timing, extent of surgical intervention, and postoperative treatment in this unique population assures a higher success rate. One also must recognize associated factors that may be present in these patients, such as peripheral vascular compromise and poor nutritional status. PMID- 11603664 TI - Foot and ankle infections after surgery. AB - Infection after foot and ankle surgery or trauma can range from the common superficial cellulitis to the less common deep soft tissue or bone infections that can have disastrous consequences. The emergence of antibiotic-resistant organisms has made treatment of infection more difficult, even though promising new antibiotics are being developed. Prevention of infection, through proper patient selection and meticulous surgical technique, is essential to satisfactory outcomes. PMID- 11603665 TI - Pitfalls in the treatment of fractures of the ankle and talus. AB - Displaced fractures of the ankle are a common component of current orthopaedic practice, whereas displaced fractures of the talus are unusual. Ankle fractures generally are produced by indirectly applied, relatively low energy forces, whereas talus fractures are created by higher energy axial loading. Despite these inherent differences, the end result of either injury can be avascular necrosis, posttraumatic arthritis, or soft tissue loss. Complications and poor results can arise from the inherent characteristics of the injury, from failure to accomplish appropriate treatment objectives, from overzealous treatment goals, or from overlooking subtle clinical or radiographic signs. The goal of the current study is to provide a method of evaluating the characteristics of these injuries to optimize functional outcomes and avoid morbidity. PMID- 11603666 TI - Complex salvage procedures for severe lower extremity nerve pain. AB - From 1995 to 1999, the senior author did revision nerve release and vein wrapping (58 limbs in 58 patients) or peripheral nerve stimulation (62 limbs in 62 patients) to relieve intractable lower extremity nerve pain. Vein wrapping was done if the patient had temporary relief after a previous nerve release, if there was evidence of scarring around the nerve, and if nerve pain was triggered by mechanical stimulation. Peripheral nerve stimulation was done when previous nerve operations provided no relief or if the nerve pain was more constant and spontaneous without mechanical provocation. The duration of symptoms preoperatively averaged 52 months, and the number of previous peripheral neurosurgical interventions averaged 2.5. Postoperatively, the average pain improvement was rated as 60% for the patients who had vein wrapping and 41% for the patients who had peripheral nerve stimulation. Of the patients who had vein wrapping, 53% were satisfied, 14% were somewhat satisfied, and 33% were dissatisfied. Of the patients who had peripheral nerve stimulation, 61% were satisfied, 21% were somewhat satisfied, and 18% were dissatisfied. Most patients (78%) stated they would undergo the procedures again. PMID- 11603667 TI - Complications of surgery of the foot and ankle in hereditary neurologic disorders. AB - The hereditary motor and sensory neuropathies are one of a group of hereditary neurologic disorders. Patients with these disorders initially may present with a deformity of the feet and toes. Complications in the treatment of these deformities can be minimized by a proper diagnosis, identifying the components of the deformity, and selecting the appropriate procedure(s). Correcting the muscle imbalance and the deformity will be necessary in most patients and most patients will require a combination of surgical procedures. PMID- 11603668 TI - Ulnar deviation after volar subluxation of the proximal interphalangeal joint. AB - A rare case of irreducible and progressive ulnar deviation after volar subluxation of the proximal interphalangeal joint is presented. An immobilized proximal interphalangeal joint with remaining volar subluxation after improper reduction showed ulnar deviation at 3 weeks after injury. During surgery, the radial collateral ligament was found to be ruptured at its origin, with formation of concomitant scar tissues. There were no apparent lesions at the central slip, lateral band, and volar plate. Interposition of the ruptured ligament and infiltration of the surrounding scar tissues into the proximal interphalangeal joint were identified. Surgical incision of the capsule along the dorsal margin of the radial collateral ligament readily produced successful reduction. The irreducible and progressive ulnar deviation of the proximal interphalangeal joint seemed to result from gradual infiltration of the scar tissues, subsequent to remaining volar subluxation because of interposition of the ruptured collateral ligament. PMID- 11603669 TI - Safety and efficacy of intraarticular hip injection using anatomic landmarks. AB - This study tests the hypotheses that the hip can be injected safely and reliably, using anatomic landmarks, without fluoroscopic guidance. Fifteen human cadavers (30 hips) were injected, each receiving one anterior hip injection and one lateral hip injection with methylene blue dye. Anatomic dissections were done on all 30 specimens to determine the rate of success and the proximity of the needle to the neurovascular structures about the hip with each approach. Neither the anterior nor the lateral injection approach, using published techniques based on anatomic landmarks, was sufficiently reliable to recommend for clinical use without radiographic guidance; the anterior approach was successful in only 60% of injections, and the lateral technique was successful in 80% of injections. In addition, the anterior approach, which is recommended in more reference works than any other approach, resulted in significantly more risk to the femoral nerve than did the lateral approach. The needle pierced or contacted the femoral nerve in 27% of anterior injections and was within 5 mm of the femoral nerve in 60% of anterior attempts. The anterior injection approach also resulted in needle placements significantly closer to the femoral artery and the lateral femoral cutaneous nerve than did the lateral approach. Using the lateral approach, the needle was never within 25 mm of any neurovascular structure in any injection. Some form of radiographic or sonographic guidance is recommended for needle placement during hip injections and aspirations; the lateral approach for needle placement seems safer than the anterior approach, with respect to the possibility of neurovascular injury. PMID- 11603670 TI - Analysis of survivorship after total hip arthroplasty using a ceramic head. AB - To determine the clinical efficacy of an alumina ceramic head, 119 cemented total hip arthroplasties in 97 patients using an alumina head coupled with ethylene oxide gas sterilized polyethylene were reviewed. Eighty-two patients (101 hips) with greater than 10 years followup were evaluated clinically and radiographically (range, 10-17.6 years), and 97 patients (119 hips) were evaluated for survivorship analysis (range, 0.6-17.6 years). The average functional hip scores according to Merle d'Aubigne and Postel improved from 8.6 preoperatively to 15.0 at the final followup, and 57 patients (64 hips) had no pain. The average polyethylene wear rate was 0.15 mm/year (range, 0.04-0.34 mm/year). Patients with polyethylene wear greater than 3 mm showed significantly higher rates of acetabular loosening. Fifteen-year survival rates (with 95% confidence intervals) with radiographic evidence of aseptic loosening as the end point were 46.8% +/- 13.4% in acetabular components and 91.9% +/- 6.6% in femoral components. Fifteen-year survival rates of hip arthroplasties with revision because of aseptic loosening as the end point were 75.3% +/- 10.2% and 97.9% +/- 3.0%, respectively. Results of the current study suggest that using an alumina head instead of a metal head may not be beneficial when coupled with ethylene oxide gas sterilized polyethylene. PMID- 11603671 TI - Effects of posterior cruciate ligament resection on the tibiofemoral joint gap. AB - The effect of posterior cruciate ligament resection on the tibiofemoral joint gap was analyzed in 30 patients with varus osteoarthritis of thee knee who underwent total knee replacement. The medial soft tissue was released and the bone cut was made without preserving the bone segment of the tibia to which the posterior cruciate ligament was attached. Then the medial and lateral joint gaps in full extension and 90 degrees flexion were measured before and after the posterior cruciate ligament was resected using a tensioning device. After the resection, the flexion gap significantly increased in the medial and the lateral sides (4.8 +/- 0.4 and 4.5 +/- 0.4 mm, respectively, mean +/- standard error) compared with those seen in the extension gap (0.9 +/- 0.2 and 0.8 +/- 0.2 mm). There was no significant difference between the changes in the medial and lateral gaps. The mean value of the flexion gap was 2 mm smaller than the extension gap before the resection and 1.7 mm larger after the sacrifice. Overall, posterior cruciate ligament resection resulted in an increase in the flexion gap and made space for approximately 3-mm thicker polyethylene. The flexion gap can be controlled selectively with posterior cruciate ligament release. PMID- 11603672 TI - What went wrong in triple arthrodesis? An analysis of failures in 21 patients. AB - Three hundred seven triple arthrodeses were done on 282 patients with rheumatic diseases between 1995 and 1999. Solid and painless fusion was achieved in 261 patients (93%, 286 arthrodeses). Twenty-one arthrodeses (in 21 patients) that failed were analyzed. Fourteen (66%) malunions, six (29%) nonunions, and one (5%) painful foot without malunion or nonunion were found. Of the failed procedures, valgus alignment was present in 13 feet and varus alignment was present in eight feet. The most common cause of failure was a misjudgment in the surgical technique, which occurred in 12 of 21 (57%) patients based on inadequate correction and repositioning of hindfoot deformity. In four (19%) patients, additional ankle destruction and instability was overlooked as a cause of malalignment. Revision triple arthrodesis was successful in 18 of 21 (86%) patients. Triple fusion offers challenges in surgical technique, postoperative treatment, and rehabilitation. Understanding the complexity of the rheumatic hindfoot is important when performing triple arthrodesis in patients with severe deformities manifesting typically as calcaneovalgus and pes planus. PMID- 11603673 TI - Chondrosarcoma of bone: analysis of 108 cases and evaluation for predictors of outcome. AB - Chondrosarcoma is the second most common malignant bone tumor and is relatively unresponsive to chemotherapy and radiation regimens. In addition, the clinical course of chondrosarcoma is difficult to predict. The purpose of this study was to review the authors' experience with chondrosarcoma and ascertain any factors related to prognosis and clinical outcome. The medical records of 108 patients followed up for a minimum of 2 years were retrospectively reviewed. There were 31 low-grade and 77 high-grade chondrosarcomas. One hundred one patients underwent surgical resection. There was a statistically significant association between positive margins and local recurrence, metastasis, and death. Tumor grade was not predictive of outcome. Proliferation indices (MIB-1 expression determination through immunohistochemistry) were quantitated in 39 patients. A significant association was seen between MIB-1 expression and recurrence and death. Thus, objective quantitation of tumor proliferation was more predictive than was histologic grade of outcome in chondrosarcoma. Although histologic grade continues to be the standard grading system for chondrosarcoma, the current study contributes to ongoing research and validation of alternative techniques that may be more reliable in guiding prognosis and treatment of chondrosarcoma. PMID- 11603674 TI - Patellar metastasis from a squamous carcinoma of the lung: a case report. AB - Bone is a common site of metastasis from lung cancer. Metastasis to the patella, however, is rare. A 76-year-old man presented with knee pain caused by an isolated patellar metastasis from squamous cell carcinoma of the lung. Treatment was delayed secondary to delay in diagnosis. In cases of bone pain that are unexplained or out of proportion to a traumatic event, more extensive diagnostic studies should be done. PMID- 11603675 TI - Development of acute myeloid leukemia after chemotherapy for osteosarcoma. AB - The current study describes two patients with osteosarcoma who had acute myeloid leukemia develop after treatment with multiagent chemotherapy. The incidence density for the chemotherapy protocol was 129.8 per 10,000 person-year of followup. Karyotype analysis of 16 reported patients (including the current two patients) indicated that most leukemias after treatment of osteosarcoma correlated with the use of topoisomerase II inhibitors, such as doxorubicin. The deoxyribonucleic acid-damaging activity of doxorubicin reinforced by the use of alkylating agents is highly suspected as a causative event in the development of leukemia after treatment of osteosarcoma. As the next step in the development of treatment for patients with osteosarcoma, the type and intensity of treatment must be evaluated to minimize possible leukemogenic effects without compromising the potential for cure. PMID- 11603676 TI - Concomitant fractures of the femoral head and neck without hip dislocation. AB - This case report describes two patients who sustained ipsilateral fractures of the femoral head and femoral neck without dislocation of the hip. The fractures in the two patients resulted from vehicle accidents. The femoral head was fractured in the sagittal plane, and the femoral neck was fractured at the subcapital portion. However, the hip was not dislocated in either patient. Both patients were treated using cementless total hip arthroplasty. These unusual hip injuries have not been reported previously and are not categorized according to any known classification system of hip injuries. PMID- 11603677 TI - Bilateral humeral lengthening in achondroplasia. AB - Twenty humeral lengthenings were done on 10 achondroplastic dwarfs using the Ilizarov circular fixator. There were five female and five male patients from 6 years 11 months to 17 years 8 months of age (mean, 12 years 10 months) at the time of the operation. Mean length obtained was 7.8 cm (range, 3.5 cm-10 cm). External fixation time ranged from 105 days to 368 days (mean, 221 days). Healing index averaged 30 days/cm (27 days/cm when two patients with radial nerve palsy were excluded). Two half pins in one patient required replacement. Two humeral fractures occurred, one while in the fixator and the other after removal of the apparatus. Transient radial nerve palsy developed during lengthening in two patients, and lengthening was discontinued. Symptoms of radial nerve palsy resolved completely in both patients, but one patient required an additional surgery to explore the radial nerve for persistent paresthesia of the forearm. Although preexisting loose shoulders deteriorate during lengthening and sometimes cause pain and discomfort, they always resolve spontaneously as lengthening proceeds. Bilateral humeral lengthening was very effective for improving function and overall proportion in patients with achondroplasia. PMID- 11603678 TI - Differentiation of psoas muscle abscess from septic arthritis of the hip in children. AB - A 20-year review was conducted of children presenting with psoas abscess at two major pediatric hospitals. Eleven children with psoas abscesses were identified. The extreme variability in the clinical presentation of this condition is shown. Psoas abscess was most difficult to differentiate from septic arthritis of the hip in pediatric patients. This study also shows the often circuitous investigative route traversed before arriving at the diagnosis of psoas abscess. Atypical features, such as femoral nerve neurapraxia or bladder irritability in association with hip pain, should alert the clinician to consider psoas abscess. Based on this study, a diagnostic algorithm to differentiate between psoas abscess and septic hip was formulated. PMID- 11603679 TI - Complications of forefoot and midfoot fractures. AB - Complications of the forefoot and midfoot are not as common as injuries to the hindfoot. The problem areas that the author will focus on with these injuries will be open injuries, unstable fractures, slow or poor healing fractures, and neurovascular injuries. The author also will discuss the toes, metatarsals, tarsometatarsal, cuneiforms, and talonavicular areas. Because the forefoot and midfoot must support as much as four times the body weight, alterations caused by injury to the weightbearing surface can have significant consequences. Treatment rationale to maintain a sound weightbearing plantar surface will be discussed. Each region will be highlighted with respect to the complications that can occur. Anatomic alignment with stable fixation and good soft tissue coverage in an appropriate rehabilitation program are the principles that should be followed and discussed. PMID- 11603681 TI - Effects of a tensioned tendon graft in a bone tunnel across the rabbit physis. AB - Children who sustain anterior cruciate disruption often are denied the standard reconstructive procedures because of the concern that drilling across the physis of the tibia and femur and compression from a tensioned graft will result in growth plate arrest. To test this concept and to assess whether a tendon placed in the tunnel would function in a manner similar to a fat graft after the resection of a physeal bar, tunnels were made across the proximal tibial physis and distal femoral physis in a group of immature rabbits. Four tunnel diameters were used from 1.95 to 3.97 mm, in three rabbits at each diameter, with patellar tendon autografts being used as the reconstruction of the anterior cruciate ligament in two of the animals. The knees were radiographed every 4 weeks, and the animals were euthanized 4 months after surgery. The surgically treated and control knees were salvaged, and each knee was examined grossly, radiographically, and histologically. Eight of the 11 animals had growth arrest of one or both physes. The larger the drill hole diameter the more marked was the deformity. The proximal tibial physis seemed to be the most vulnerable for growth arrest, occurring in eight of the knees. The insertion of a tendon did not seem to offer any protection to physeal arrest. Because of these findings, it is not recommended that tunnels involving 1% or more of the area of the physis be placed across the tibial and femoral physis to reconstruct the anterior cruciate in very skeletally immature children. PMID- 11603680 TI - Strain in the human medial collateral ligament during valgus loading of the knee. AB - The medial collateral ligament is one of the most frequently injured ligaments in the knee. Although the medial collateral ligament is known to provide a primary restraint to valgus and external rotations, details regarding its precise mechanical function are unknown. In this study, strain in the medial collateral ligament of eight knees from male cadavers was measured during valgus loading. A material testing machine was used to apply 10 cycles of varus and valgus rotation to limits of +/- 10.0 N-m at flexion angles of 0 degrees, 30 degrees, 60 degrees, and 90 degrees. A three-dimensional motion analysis system measured local tissue strain on the medial collateral ligament surface within 12 regions encompassing nearly the entire medial collateral ligament surface. Results indicated that strain is significantly different in different regions over the surface of the medial collateral ligament and that this distribution of strain changes with flexion angle and with the application of a valgus torque. Strain in the posterior and central portions of the medial collateral ligament generally decreased with increasing flexion angle, whereas strain in the anterior fibers remained relatively constant with changes in flexion angle. The highest strains in the medial collateral ligament were found at full extension on the posterior side of the medial collateral ligament near the femoral insertion. These data support clinical findings that suggest the femoral insertion is the most common location for medial collateral ligament injuries. PMID- 11603682 TI - Integrated health systems: success or failure? AB - There continues to be an increasing number of healthcare delivery systems as a result of marketplace changes that include declining reimbursement and increasing costs for healthcare. However, the majority of these systems fail. Failures are a consequence of poor management, lack of a common mission and business rationale, individual's interests that outweigh the entity's interests, and the conflict of cultures. Incremental changes will continue, but the healthcare environment will remain unstable for the foreseeable future. PMID- 11603683 TI - Mergers involving academic health centers: a formidable challenge. AB - Escalating economic pressures on the clinical enterprise threaten the missions of education and research in many of the most prestigious academic health centers. Following the model of industry, mergers of the healthcare delivery systems of teaching hospitals and clinics held promise for economies of scale and an improved operating margin. Failure to follow business principles in constructing the merged entity, differences in organizational governance and culture, and inability of physician leadership to prioritize, downsize, and consolidate clinical programs to optimize operational efficiencies all compromise the success of such mergers in academic medicine. Academic institutions and their respective governing boards need to exercise greater discipline in financial analysis and a willingness to make difficult decisions that show favor to one parent institution over another if mergers are to be effective in this setting. To date, an example of a vibrant and successful merger of academic health centers remains to be found. PMID- 11603684 TI - The impact of the Tulane-HCA joint venture on academic and clinical missions. AB - As with any joint venture in any given industry, positive and negative impacts are felt. Tulane University School of Medicine experienced impacts on its academic and clinical missions as a result of the joint venture between Tulane University and HCA, a for-profit public company. The laws of business had entered the halls of medicine. Although patients, personnel, and physicians experienced culture shock and inconveniences, Tulane University School of Medicine has been able to maintain viable training programs, and its faculty physicians have a hospital and corporately run clinics across the street. In addition, multidisciplinary centers of excellence, long spoken of in the academic realm, came to fruition through the corporate world. This may not have been the case, had Tulane University not entered into ajoint venture with HCA. Is it worth the effort? For Tulane University, whether one likes the entire package or not, the answer must be yes. The greatest impact is that the orthopaedic surgeons still are in a position to fulfill their academic and clinical missions. PMID- 11603685 TI - Structure and function as seen in the foot. 1949. PMID- 11603687 TI - The femoral component in total knee arthroplasty. PMID- 11603686 TI - Knee pain in a 16-year-old girl. PMID- 11603688 TI - Complications of ankle and tibiotalocalcaneal arthrodesis. AB - Arthrodesis has remained the mainstay for treating arthritis and deformities of the ankle and hindfoot for more than a century. Formidable technical challenges exist in achieving a successful result, leading to numerous complications as high as 50% in some series. The most frequent complications after tibiotalar and tibiotalocalcaneal arthrodesis involve nonunion, malunion, infection, and wound complications among others. Meticulous preoperative consideration for the technical and biologic issues involved may lead to diminished complication rates. With advances in implant technology, revision arthrodesis can, in most cases, be expected to yield outcomes comparable with those of a primary procedure. Algorithms for the treatment of the most frequent complications are presented. PMID- 11603689 TI - Complications of midfoot and hindfoot arthrodesis. AB - Midfoot and hindfoot arthrodeses traditionally have been done to treat deformities resulting from paralytic disorders, residual clubfoot deformity, and posttraumatic arthritis. The surgical indications for midfoot and hindfoot arthrodeses more recently have been expanded to include painful arthritic deformities associated with neuroarthropathy, seropositive or seronegative arthropathies, and neurologic disorders. Regardless of the joint fused or the technique used, the goal of each remains similar: the creation of a painless, plantigrade foot capable of being fitted into, at the very least, a custom shoe. The aim of the current study is to describe the major complications associated with midfoot and hindfoot fusions in adults, and the prevention and the treatment of these complications. PMID- 11603690 TI - Complications after surgery of the hallux. AB - The great toe is affected by many congenital and acquired conditions including arthritis, hallux valgus, and hallux rigidus and disease of the hallucal sesamoids. Many surgical procedures have been described for the treatment of these conditions. With the increased popularity of forefoot surgery comes the potential for complications even when the surgery is done meticulously by an experienced surgeon under well-planned conditions. When a complication occurs, it can present difficult and challenging problems. It is, therefore, important to recognize a complication early so it may be analyzed and treated successfully. When recognized, a plan should be developed to identify, quantify, control, and resolve the problem. The current review defines some common complications and treatment options. Several problems may exist at the same time. A solution addressing all aspects of the problem must be designed so as not to augment the presenting complications. Salvage operations and long-term treatment are included to provide a perspective on treatment of residual deformity. It is important to realize that there often are several solutions to a difficult problem. Many factors influence the surgeon's choice and implementation of a solution, but the ultimate outcome always depends on a well thought out plan. PMID- 11603691 TI - Complications of intraarticular calcaneal fractures. AB - The treatment of intraarticular calcaneal fractures remains a controversy in orthopaedics because of the associated complications. The authors present a systematic review of complications associated with calcaneal fractures. A MEDLINE search was conducted to review the results of operative and nonoperative treatment of calcaneal fractures to determine the most common complications reported. The following were reported to be the most common complications: swelling and fracture blisters, compartment syndrome, wound dehiscence and infection, neurovascular injury, tendon injury, heel pad pain and heel exostosis, malunion, and arthritis. Each complication was reviewed as to etiology, incidence, diagnosis, prevention, and treatment. Increased awareness of these complications and their prevention will aid the practitioner in decision-making and result in better treatment outcomes for this fracture. PMID- 11603692 TI - Complications of lesser toe surgery. AB - Surgical procedures for lesser toe problems are among the most common surgeries done on the foot. In a shoe wearing population, the incidence of lesser toe pathologic disorders is high. The complications associated with lesser toe surgery can be troublesome for patients and physicians. Understanding the possible common complications and how to avoid them is essential to maximizing satisfactory clinical results. PMID- 11603693 TI - Complications in foot and ankle arthroscopy. AB - Arthroscopy of the foot and ankle has become an important diagnostic and therapeutic tool for the orthopaedic surgeon. A thorough knowledge of foot and ankle anatomy and intraarticular anatomy is critical to avoid complications in foot and ankle arthroscopy. Numerous complications can occur in foot and ankle arthroscopy, such as neurologic, tendon, and ligament injuries, wound complications, infections, and instrument breakage. The most common complication is neurologic injury. The overall complication rate is 9%. Most complications associated with foot and ankle arthroscopy are transient and tend to resolve within 6 months. The only complication that persisted at 10 years followup was a neurologic injury, specifically, numbness at the incision site. Because the difficulty of procedures has increased, so has the complication rate. Knowledge of the more common complications in foot and ankle arthroscopy and improved techniques and instruments may reduce the overall complication rate. PMID- 11603694 TI - Cartilage damage by matrix degradation products: fibronectin fragments. AB - Catabolic cytokines play a major role in cartilage degradation not only in rheumatoid arthritis but also in osteoarthritis. Although the major source in rheumatoid arthritis may be mononuclear cells and synovial tissue and the cause of release may be multifactorial, the source of cytokines in osteoarthritis would be mostly from chondrocytes. However, there are few explanations of how upregulation of the cytokines might occur in osteoarthritis. One possibility is that degradation products of the extracellular matrix arising from elevated protease levels, substrate, or both, might regulate cytokine activities. Fragments of the extracellular matrix protein, fibronectin, upregulate cytokine expression and induce the events of suppressed matrix synthesis and upregulation of matrix metalloproteinases, characteristic of osteoarthritis. The catabolic aspects of this system are short term, subsequently serve to enhance anabolic processes above untreated levels, and condition the tissue against additional insult. It will be necessary to determine whether in vivo these degradation products precede cytokine expression and act early and are targets for intervention or instead are a consequence of cytokine damage. Whether they regulate anabolism and catabolism, blocking of their activities may not be ideal. PMID- 11603696 TI - In vivo changes after mechanical injury. AB - Chondrocytes undergo apoptosis in response to mechanical injury in vitro. The current clinical study correlates arthroscopic and magnetic resonance imaging results with biopsy specimens of cartilage from patients with knee injury. Twenty patients were evaluated at a mean 2.7 months after acute knee injury. The mean age of the patients was 32 years and the mean weight was 83 kg. Cartilage lesions were graded separately on magnetic resonance images and arthroscopy in a blinded manner. During arthroscopy, a 1.8 mm diameter biopsy specimen was obtained from the edge of cartilage lesion. The biopsy specimen underwent histologic examination by safranin O staining and detection of chondrocyte apoptosis by the presence of deoxyribonucleic acid fragmentation. There was a positive correlation in 50% (10 of 20) when the presence or absence of cartilage lesions by magnetic resonance imaging was correlated with arthroscopy. All cases of partial thickness or full-thickness cartilage loss that were seen by arthroscopy also were detected by magnetic resonance images. Apoptotic cells were significantly more numerous in biopsy specimens from lesions compared with control biopsy specimens. The findings of reduced cell viability attributable to apoptosis may have profound implications for cartilage repair. This opens potential therapeutic avenues for the treatment of posttraumatic cartilage lesions through apoptosis prevention. PMID- 11603695 TI - Cytokines in cartilage injury and repair. AB - Joint injury results in cartilage lesions that are characterized by a poor repair response, and such lesions often progress to osteoarthritis. Acute joint injury or chronic exposure of cartilage to an abnormal biochemical or biomechanical environment results in the activation of chondrocytes. This chondrocyte response is manifested by enhanced cell proliferation and death, matrix degradation, and new matrix synthesis. Cytokines are important stimuli of this chondrocyte activation response and trigger joint inflammation that can accompany cartilage injury. The presence of cytokines in cartilage is associated with abnormal extracellular matrix remodeling and loss, therefore defining them as a class of targets for therapeutic interventions. Insight into intracellular signaling mechanisms that are activated by cytokines may provide the basis for pharmacologic interventions that promote cartilage repair. PMID- 11603697 TI - Differences in mesenchymal tissue repair. AB - Variations in certain mesenchymal tissue healing processes are not widely recognized. The current review summarizes key differences in healing mechanisms and healing potential after injury to soft tissues having different healing outcomes. PMID- 11603698 TI - Symptomatic articular cartilage degeneration: the impact in the new millennium. AB - The symptomatic degeneration of articular cartilage and associated arthritis is among the most prevalent chronic conditions in the United States and the population most at risk is increasing. It is the leading cause of limitations in activities of daily living and is second to heart disease in causing work disability. The current and future socioeconomic impact of chronic articular cartilage disease on the healthcare system will be magnified by increasing numbers of patients who will seek relief of their symptoms and their disability to remain active. Because these individuals live longer and remain active, the proportion of their life living with symptoms and disability from articular cartilage degeneration increases. The economic, psychologic, and social impact of degenerative articular cartilage can be enormous for these individuals but it also impacts their family and society. The direct traditional medical costs and indirect economic and wage loss from arthritis in individuals the United States has reached in excess of $65 billion annually and is expected to increase as the population ages. In addition, the expenditures for complementary and alternative professional services and therapies for arthritis is increasing and is also in the billions of dollars annually. Because of these escalating costs, documenting the value of the patient and cost effectiveness to society of prevention and treatment programs for symptomatic articular cartilage degeneration will be required. PMID- 11603699 TI - Differences in repair responses between immature and mature cartilage. AB - Cartilage has a poor reparative capacity although it is unclear as to what extent this may be dependent on age or maturation. In the current study, the cellular responses of chondrocytes to experimental wounding in vitro using embryonic, immature, and mature cartilage have been compared. In all cases, the response was consistent (a combination of cell death that included apoptosis and proliferation). The speed of response varied in terms of cell death with embryonic cartilage showing the most rapid response and mature cartilage showing the slowest response. Intrinsic repair as assessed by the ability to heal the lesion was not detected in any of the culture systems used. It was concluded that the poor repair potential of cartilage is not maturation dependent in the systems studied. PMID- 11603700 TI - Age-associated changes in cartilage matrix: implications for tissue repair. AB - The structure of the extracellular matrix of articular cartilage varies considerably with age. These changes are attributable to variations in molecular abundance and structure, and they can affect all the matrix components, but none more so than the proteoglycans. Some of these changes are attributable to variations in synthesis whereas others are attributable to variations in degradation, some of the changes occur during juvenile development whereas others occur throughout life, and some of the changes are beneficial to cartilage function whereas others are detrimental. These variations result in a cartilage that not only changes in its phenotype with age, but also in one whose functional properties are changing continuously throughout life. In a similar manner, the cartilage formed during repair also may show considerable variation in structure and function, depending on whether tissue is being replaced or regenerated and whether mature or immature cells are being used. Because all cartilage is not ceated equal, different repair techniques may not be equally efficacious. PMID- 11603701 TI - Cartilage regeneration using principles of tissue engineering. AB - It is well known that articular cartilage in adults has a limited ability for self-repair. Numerous methods have been devised to augment its natural healing response, but these methods generally lead to filling of the defect with fibrous tissue or fibrocartilage, which lacks the mechanical characteristics of articular cartilage and fails with time. Recently, tissue engineering has emerged as a new discipline that amalgamates aspects from biology, engineering, materials science, and surgery and that has as a goal the fabrication of functional new tissues to replace damaged tissues. The emergence of tissue engineering has facilitated the generation of new concepts and the revival of old ideas all of which has allowed a fresh approach to the repair or regeneration of tissues such as cartilage. The collaborations between scientists with different backgrounds and expertise has allowed the identification of some key principles that serve as the basis for the development of therapeutic approaches that now are less empiric and more hypothesis-driven than ever before. The current authors review some of the considerations regarding the various models used to test and validate the above repair methods and to address different aspects of the cartilage repair paradigm. Also, some key principles identified from past and current research, the need for the development of new biomaterials, and considerations in scale-up of cell biomaterial constructs are summarized. PMID- 11603702 TI - Chondrogenesis in cartilage repair is induced by members of the transforming growth factor-beta superfamily. AB - The authors recently reported on the principle of an intrinsic repair strategy for partial-thickness articular cartilage defects, which is based on the introduction of a biocompatible and biodegradable matrix loaded with a free chemotactic and mitogenic agent (transforming growth factor-beta 1, at low concentration) and a liposome-encapsulated chondrogenic factor (transforming growth factor-beta 1 at high concentration). In the current study, the potential of other members of the transforming growth factor-beta superfamily (transforming growth factor-beta 2, transforming growth factor-beta 3, bone morphogenetic protein-2 and bone morphogenetic protein-13), and of insulinlike growth factor-1, epidermal growth factor, transforming growth factor-alpha, and Tenascin-C, to induce chondrogenesis within the authors' adult miniature pig articular cartilage defect model, was evaluated. The degree of chondrogenic tissue differentiation was assessed 6 weeks after surgery, on a semiquantitative basis, histologic assessment of cell morphologic features, and intercellular matrix staining being used as the relevant criteria. All selected members of the transforming growth factor-beta superfamily were efficacious in inducing chondrogenic tissue transformation, whereas the other signaling substances tested were not. When encapsulated at high activity levels, bone morphogenetic proteins were less prone than transforming growth factor-beta 1, transforming growth factor-beta 2, and transforming growth factor-beta 3 to evoke undesired side effects as a result of incidental leakage into the joint cavities and subsynovial connective tissue spaces, and therefore they are potentially more suitable candidates for use in human patients. PMID- 11603703 TI - Structural barrier principle for growth factor-based articular cartilage repair. AB - A growth factor-based strategy recently has been shown to induce the intrinsic repair of partial-thickness articular cartilage lesions, thereby obviating the need for transplanting cells or tissue. It was the purpose of the current study to ascertain whether this principle could be applied to full-thickness articular cartilage defects created in adult rabbits and mature miniature pigs. The transforming growth factor-beta1 contained within the authors' chondrogenic matrix-complex proved to be potent in its osteogenic capacity when liberated into the bone compartment of such lesions, inducing the rapid upgrowth of osseous tissue and vascular buds into the cartilage compartment. This is an unwanted response that must be prevented. A cell and blood vessel-excluding membrane (Millipore in rabbits and Goretex in miniature pigs) was inserted at the interface between cartilage and bone compartments, both of which were filled at the appropriate juncture with the chondrogenic matrix-complex. These structural barriers were effective in obstructing the up-growth of blood vessels into the cartilage compartment and in preventing the osteogenic tissue differentiation attributable to the presence of a vasculature. PMID- 11603704 TI - The role of periosteum in cartilage repair. AB - Periosteum, which can be grown in cell and whole tissue cultures, may meet one or more of the three prerequisites for tissue engineered cartilage repair. Periosteum contains pluripotential mesenchymal stem cells with the potential to form either cartilage or bone. Because it can be transplanted as a whole tissue, it can serve as its own scaffold or a matrix onto which other cells and/or growth factors can be adhered. Finally, it produces bioactive factors that are known to be chondrogenic. The chondrocyte precursor cells reside in the cambium layer. These vary in total density and volume with age and in different donor sites. The advantages of whole tissue periosteal transplants for cartilage repair include the fact that this tissue meets the three primary requirements for tissue engineering: a source of cells, a scaffold for delivering and retaining them, and a source of local growth factors. Many growth factors that regulate chondrocytes and cartilage development are synthesized by periosteum in conditions conducive to chondrogenesis. These include transforming growth factor-beta 1, insulinlike growth factor-1, growth and differentiation factor-5, bone morphogenetic protein 2, integrins, and the receptors for these molecules. By additional study of the molecular events in periosteal chondrogenesis, it may be possible to optimize its capacity for articular cartilage repair. PMID- 11603705 TI - Human meniscus cell: characterization of the primary culture and use for tissue engineering. AB - Human meniscus cells from 47 surgically excised menisci were grown in primary culture. Cell proliferation and morphologic features were evaluated in three different culture media. Human meniscus cells showed three distinguishable cell types in monolayer culture: elongated fibroblastlike cells, polygonal cells, and small round chondrocytelike cells. These cells proliferated in Dulbecco's modified Eagle's medium, but by Day 7, elongated fibroblastlike cells became predominant. Cells did not proliferate in Ham's nutrient mixture-F-12. In a mixture of Ham's nutrient mixture-F-12 and Dulbecco's modified Eagle's medium, cells proliferated, maintaining their morphologic features and their ability to express messenger ribonucleic acids for aggrecan and Types I, II, and III collagen. Hyaluronan enhanced cellular proliferation without altering morphologic features or chondroitin sulfate production. Cultured human meniscus cells attached to a porous collagen sponge after cell seeding. Gene transfer was successful and an introduced gene was expressed by the cells, indicating that human meniscus cells can undergo gene manipulation. The finding that cells collected from small surgical specimens of human meniscus could be cultured, propagated, and seeded onto a collagen scaffold holds promise for the development of a cell-based, tissue engineered collagen meniscus. PMID- 11603707 TI - Improved cartilage repair after treatment with low-intensity pulsed ultrasound. AB - Low-intensity pulsed ultrasound accelerates bone healing via upregulation of cartilage formation and maturation phases of endchondral bone formation. The current authors evaluated the effect of ultrasound therapy on the repair of full thickness osteochondral defects. Bilateral, 3.2 mm diameter by 5.0 mm deep osteochondral defects were created in the patellar groove of 106 adult male New Zealand rabbits. The defects were treated with daily low-intensity pulsed ultrasound therapy on the right knee. The left knee was not treated. In Part I, the effect of ultrasound therapy was evaluated at 4, 8, 12, 24, and 52 weeks after surgery. In Part II, the effect of the length of treatment (5, 10, or 40 minutes of daily ultrasound therapy) compared with standard 20 minute therapy was evaluated. The repair cartilage was evaluated and graded on a standard scale for the gross and histologic appearance. Ultrasound treatment significantly improved the morphologic features and histologic characteristics of the repair cartilage compared with nontreated controls. Earlier, better repair with less degenerative changes at later times was observed in defects treated with ultrasound. Doubling the treatment time to 40 minutes daily significantly increased the histologic quality of the repair cartilage. In the current animal model, daily low-intensity pulsed ultrasound had a significant positive effect on the healing of osteochondral defects. PMID- 11603706 TI - Chondral defects in animal models: effects of selected repair procedures in canines. AB - The defect made to the level of the tidemark in a canine model has been used in several prior investigations of various articular cartilage repair procedures. Direct comparison of the repair method, 15 weeks postoperatively, showed a significant correlation between the degree to which the calcified cartilage layer and subchondral bone were disrupted and the amount of tissue filling. Moreover, when it forms, hyaline cartilage most frequently occurs superficial to intact calcified cartilage. Many of the chondrocytic cells and fibroblasts expressed the gene for a contractile muscle actin, alpha-smooth muscle actin. However, the role of this actin isoform is yet in question. These findings may inform future strategies for cartilage repair. PMID- 11603708 TI - Growth factors and cartilage repair. AB - Growth factors are obvious tools to enhance cartilage repair. Understanding of reactivities in normal and arthritic cartilage and potential side effects on other compartments in the joint will help to identify possibilities and limitations. Growth factor responses have been evaluated in normal and diseased murine knees. The main cartilage anabolic factor, insulinlike growth factor-1, shows great safety, but has little contribution in diseased cartilage because of insulinlike growth factor nonresponsiveness of arthritic chondrocytes. Transforming growth factor-beta can overrule interleukin-1 catabolic effects and can enhance cartilage repair in arthritic tissue, unlike bone morphogenetic protein-2 that only is capable of enhancing chondrocyte proteoglycan synthesis in the absence of interleukin-1. Transforming growth factor-beta and bone morphogenetic protein-2 induce chondrophyte formation at the margins of the joint. Studies with scavenging transforming growth factor beta soluble receptor identified endogenous transforming growth factor-beta involvement in spontaneous cartilage repair and chondrophyte and subsequent osteophyte formation in arthritic conditions. Osteophyte induction may hamper intraarticular transforming growth factor-beta application in the joint and warrants targeted growth factor application to cartilage lesion sites only. PMID- 11603709 TI - Biodegradable polymer scaffolds for cartilage tissue engineering. AB - Cartilage defects are common, painful conditions and none of the currently available treatment options are satisfactory. Tissue engineering techniques involving scaffolds made from biodegradable synthetic polymers hold great promise for the future. These materials can be manufactured in an injectable form for minimally invasive procedures or in a preformed state to treat large irreparable lesions including arthritis. The mechanical and biologic properties of synthetic polymers can be tailored to different clinical applications and engineering strategies. The scaffold serves as a mechanical substrate for cells and bioactive factors and can help direct and organize the process of regeneration. The ultimate goal of tissue engineering is to recapitulate normal organogenesis to create histologically and functionally normal tissue. A review of the characteristics and potential of synthetic polymers shows that these substances will play a major role in treating cartilage disorders. PMID- 11603711 TI - Matrices for cartilage repair. AB - Techniques for repairing focal articular cartilage defects are evolving from methods that induce a local stimulation of fibrocartilaginous repair to methods that will lead to a hyaline articular cartilage repair. Mosaicplasty and autologous chondrocyte implantation are examples of the latter. A tissue engineered hyaline cartilage implant that could be used off the self would minimize the morbidity of these techniques. However, there are significant questions that still need to be resolved before such tissue-engineered implants will be practical. Principally among these is the question of what is the ideal matrix for such an implant, particularly from the standpoint of the best material and architecture. Second, what is the ideal cell source to use with these implants. A third major unknown is what is the most ideal way to use growth factors to enhance the repair. As these issues are resolved, the prospects of a tissue engineered cartilage replacement will advance from theory to practice. PMID- 11603710 TI - Composition and structure of articular cartilage: a template for tissue repair. AB - The authors review the structure and composition of articular cartilage. This tissue is composed of an extensive extracellular matrix synthesized by chondrocytes. It contains different zones with respect to depth from the articular surface and has a regional organization around the chondrocytes. Its composition varies regionally and zonally in its collagen and proteoglycan contents and those of other matrix molecules. There is a macrofibrillar collagen network and a microfilamentous network about which other noncollagenous molecules are organized. Its structure and composition are reflective of its special mechanical properties that primarily reflect its tensile strength (collagens) and compressive stiffness (proteoglycan aggrecan) and cell-matrix interactions (noncollagenous proteins). PMID- 11603712 TI - In vitro generation of scaffold independent neocartilage. AB - A novel serum-free culture system was developed in an attempt to generate a three dimensional hyalinelike neocartilage independent of polymer scaffolds. Neocartilage disks as much as 1.5 mm thick were produced, which were characterized by synthesis of the normal articular cartilage collagens and proteoglycans. In contrast to growth in serum-containing media, chondrocytes from juveniles maintained in static culture under defined serum-free conditions deposited an extracellular matrix that accumulated in the form of tissue disks. Electron microscopic evaluation of neocartilage disks revealed collagenous matrices characteristic of articular cartilage from human infants. The neocartilage did not show terminal chondrocyte differentiation as shown by the absence of Type X collagen production and lack of cellular hypertrophy. Although chondrocytes from preadolescent donor cartilage recapitulated embryonic development in the absence of exogenous factors, chondrocytes from articular cartilage from adults failed to produce neocartilage when grown under identical conditions. This is the first demonstration that autocrine morphogens are sufficient to guide production of hyaline cartilage in vitro. In addition to providing a unique model system to compare the healing response of mature and immature articular chondrocytes, this technology may be of clinical importance in the development of new biomaterials for repair of articular cartilage defects. PMID- 11603713 TI - Functional tissue engineering: the role of biomechanics in articular cartilage repair. AB - Articular cartilage shows little or no intrinsic capacity for repair in response to injury or disease, and even minor lesions or injuries may lead to progressive damage and joint degeneration. Tissue engineering is a relatively new but rapidly growing field that has sought to use combinations of implanted cells, biomaterials, and biologically active molecules to repair or regenerate injured or diseased tissues. Despite many advances, tissue engineers have faced significant challenges in repairing or replacing tissues that serve a predominantly biomechanical function, such as articular cartilage. An evolving discipline termed functional tissue engineering seeks to address these challenges by emphasizing and evaluating the role of biomechanical factors in the intrinsic and engineered repair of tissues and organs. In the current study, the authors describe some of the fundamental issues involving the interaction of biomechanical stresses in vivo and in vitro with native and repair articular cartilage and with other biomechanically functional tissues. A more thorough and formal investigation of these issues may provide a basis for developing rational design principles for tissue engineered replacement or repair of load-bearing structures in the body. PMID- 11603714 TI - Arthroscopic abrasion arthroplasty: a review. AB - Arthroscopic abrasion arthroplasty is an elaborate description for an extensive multiple tissue debridement for patients seeking an alternative to total knee replacement. The operation is palliative, not curative. In patients seeking an alternative to total knee replacement, the definitive operation may be avoided or deferred in a high percentage of patients as many as 5 years. Because the abrasion portion of the operation is accompanied by multiple tissue type debridement, it is not known what clinical benefit the abrasion aspect contributes. Furthermore, no prospective randomized clinical studies have been done and most clinicians reporting on their experience with the procedure have varied the indications, technique, and/or postoperative treatment. Future investigation may answer these clinical questions. It is known that fibrocartilage forms at the abrasion site. The reparative tissue has many of the characteristics of cartilage, but does not have the biomechanical properties of articular cartilage. The fibrocartilage has shown durability for many years confirmed during opportunistic second look arthroscopy. The applications of growth factor science or genetic engineering may provide means of converting the regenerative tissue of abrasion arthroplasty to mature articular cartilage. PMID- 11603715 TI - Long-term followup of fresh femoral osteochondral allografts for posttraumatic knee defects. AB - Fresh osteochondral allografts were used to repair articular defects in the distal femur in 72 patients. Sixty patients were available for long-term followup (mean, 10 years) to determine graft survivorship and patient outcomes using a modified Hospital for Special Surgery score. Twelve of 60 grafts have failed with three having graft removal alone and nine being converted to total knee replacement. Kaplan-Meier survivorship analysis showed 85% graft survival at 10 years and 74% survival at 15 years. Patients with surviving grafts had good function, with a mean Hospital for Special Surgery score of 83 points at 10 years followup. Ten patients (17%) required meniscal transplantation whereas 41 (68%) required realignment osteotomy done simultaneously with the osteochondral allograft. Patients requiring meniscal transplantation, limb realignment, or both, had equally good outcomes at 10 years as those who underwent osteochondral transplantation alone. Likewise, transplantation to the medial or the lateral condyle had no bearing on long-term outcomes. Radiographs were available for 38 patients. These radiographs showed that 18 (48%) patients had no or mild arthritis, 10 (26%) had moderate, and 10 (26%) had severe arthritis. Late osteoarthritic degeneration as seen on radiographs was associated with outcomes, with patients with more severe arthritis having lower Hospital for Special Surgery scores. The authors think that osteochondral allograft transplantation is a valuable treatment option in patients with large osteochondral defects in the distal femoral articular surface. PMID- 11603716 TI - Mosaicplasty for the treatment of articular defects of the knee and ankle. AB - Efficacious treatment of full-thickness cartilage defects of the weightbearing surfaces is a multi-faceted challenge for the orthopaedic surgeon. Autologous osteochondral transplantation represents one solution: to bring about a hyaline or hyalinelike repair of the defected area. The current authors discuss the experimental background and their 8 years of clinical experience with the autologous osteochondral mosaicplasty. Several series of animal studies and subsequent clinical practice have confirmed the survival of the transplanted hyaline cartilage. Hyaline cartilage and fibrocartilage fill the donor sites located on the nonweightbearing surfaces and surfaces that bear less weight. Clinical scores, imaging techniques, control arthroscopies, histologic examination of biopsy samples, and cartilage stiffness measurements were used to evaluate the clinical outcomes and quality of the transplanted cartilage. According to these investigations, femoral condylar implantations have shown good to excellent results in 92%, tibial resurfacing in 88%, patellar and/or trochlear mosaicplasties in 81%, and talar procedures in 94% of patients. The Bandi score showed long-term donor site disturbances in 3% of patients. Fifty-eight of the 68 control arthroscopies had good gliding surfaces, histologically-proven survival of the transplanted hyaline cartilage, and fibrocartilage covering of the donor sites. In the entire series, there were four deep infections and 34 painful hemarthroses after surgery. A multicentric, comparative, prospective evaluation of 413 arthroscopic resurfacing procedures (mosaicplasty, Pridie drilling, abrasion arthroplasty, and microfracture cases in homogenized subgroups) showed that mosaicplasty gave a more favorable clinical outcome in the long-term followup, than the other three techniques. Intermediate-term evaluation of the femoral condylar implantations (3-6-years followup) and talar mosaicplasties (3-7 years followup) confirmed the durability of the early results. From these encouraging results from an increasingly large series and similar results from other centers, it seems that autologous osteochondral mosaicplasty may be a viable alternative treatment of localized full-thickness cartilage damage of the weightbearing surfaces of the knee and other weightbearing synovial joints. PMID- 11603717 TI - Autologous chondrocytes used for articular cartilage repair: an update. AB - Articular cartilage in adults has a poor ability to self-repair after a substantial injury; however, it is not known whether there is a cartilage resurfacing technique superior to the existing techniques. It is not satisfactory that at the beginning of the new millennium, there still is a lack of randomized studies comparing different cartilage repair techniques and there still is little knowledge of the natural course of a cartilaginous lesion. To date, various articular cartilage resurfacing techniques have the potential to improve the repair of cartilage defects and reduce the patient's disability. One such cartilage repair technique is autologous chondrocyte transplantation combined with a periosteal graft. Since the first patient was operated on in 1987, much interest in cartilage repair and cell engineering has emerged. The experience with autologous chondrocyte transplantation during the past 13 years with in vitro chondrocyte expansion, cartilage harvest, and postoperative biopsy technique is discussed, and the latest followup of 213 consecutive patients in different subgroups with 2 to 10 years followup is presented. The technique gives stable long-term results with a high percentage of good to excellent results (84% 90%) in patients with different types of single femoral condyle lesions, whereas patients with other types of lesions have a lower degree of success (mean, 74%). PMID- 11603718 TI - Autologous chondrocyte implantation for focal chondral defects of the knee. AB - Autologous chondrocyte implantation has been used since March 1995 in a prospective cohort evaluation. One hundred sixty-nine patients, 13 to 58 years, have been treated as of December 1999. One hundred seven patients have greater than 12 months followup, and 56 have greater than 24 months followup. Overall 87% of patients improved. Patient assessment instruments include the modified Cincinnati knee rating scale, Short Form-36, Knee Society score, Western Ontario McMaster Universities Osteoarthritis Index score, and patient satisfaction survey. Treatment cases included the following categories: Simple (N = 12) isolated femoral condyles; Complex (N = 86) nonarthritic knees with multiple defects on the femur, or isolated lesions to the patella or tibia; and Salvage (N = 71) knees with early arthritic changes. The areas treated were large: Simple, 4.3 cm2 (one defect); Complex, 6.75 cm2 (4.5 cm2 per defect x 1.5 defects per case), and Salvage, 11.66 cm2 (5.3 cm2 per defect x 2.2 defects per case). Patients who had complex and salvage treatments (N = 107) with greater than 1 year followup frequently had adjuvant treatments including valgus tibial (N = 24) or tibial tubercle (N = 15) osteotomies or ligament reconstruction (N = 5). At the 2-year followup, statistically significant functional improvements occurred in the patients in the Simple and Complex categories (Cincinnati score; Simple, baseline 3.57, 24 months = 5.38; Complex, baseline 3.40, 24 months = 6.06). Patients in the Salvage category had statistically significant improvement in Short Form-36 quality of life scores (Physical summary, 24 months) and an increase in the Cincinnati rating scale when the patellofemoral joint was not involved. Patient satisfaction at 24 months for Simple, Complex, and Salvage categories was 60%, 70%, and 90%, respectively. There were 22 failures in 169 patients treated (13%), which was defined as no clinical improvement or graft failure. PMID- 11603719 TI - Microfracture: surgical technique and rehabilitation to treat chondral defects. AB - Full-thickness articular cartilage defects rarely heal spontaneously. Some patients may not have clinically significant problems from chondral defects, but most eventually have degenerative changes. Techniques to treat chondral defects include abrasion, drilling, autografts, allografts, and cell transplantation. The senior author (JRS) developed the microfracture technique to enhance chondral resurfacing by providing a suitable environment for new tissue formation and taking advantage of the body's own healing potential. Microfracture has been done in more than 1800 patients. Specially designed awls are used to make multiple perforations, or microfractures, into the subchondral bone plate. Perforations are made as close together as possible, but not so close that one breaks into another. They usually are approximately 3 to 4 mm apart. The integrity of the subchondral bone plate must be maintained. The released marrow elements (including mesenchymal stem cells, growth factors, and other healing proteins) form a surgically induced super clot that provides an enriched environment for new tissue formation. The rehabilitation program is crucial to optimize the results of the surgery. It promotes the ideal physical environment for the marrow mesenchymal stem cells to differentiate into articular cartilagelike cells, ultimately leading to development of a durable repair cartilage that fills the original defect. PMID- 11603720 TI - Cartilage imaging techniques: current clinical applications and state of the art imaging. AB - The high incidence of cartilage lesions, coupled with the recent advances for their surgical and nonsurgical treatment, have necessitated the development of techniques for accurate diagnosis and monitoring of these lesions. Although arthroscopy has been the standard for cartilage evaluation, magnetic resonance imaging has emerged as the imaging method of choice, allowing analysis of its infrastructure and surface abnormalities. The authors will focus on current clinical applications for articular cartilage analysis and advances and the future direction of the imaging of articular cartilage. PMID- 11603721 TI - Magnetic resonance imaging of articular cartilage. AB - Magnetic resonance imaging is the optimal modality for assessing articular cartilage because of superior soft tissue contrast, direct visualization of articular cartilage, and multiplanar capability. Despite these advantages, there has been disagreement as to the efficacy of magnetic resonance imaging of articular cartilage. The reason for this controversy is multifactorial but in part is attributable to the lack of the use of optimized pulse sequences for articular cartilage. The current authors will review the current state of the art of magnetic resonance imaging of articular cartilage and cartilage repair procedures, discuss future new directions in imaging strategies and methods being developed to measure cartilage thickness and volume measurements, and propose a magnetic resonance imaging protocol to evaluate cartilage that is achievable on most magnetic resonance scanners, vendor independent, practical (time and cost efficient), and accepted and used by a majority of musculoskeletal radiologists. PMID- 11603722 TI - Preclinical cartilage repair: current status and future perspectives. PMID- 11603723 TI - Clinical objectives for cartilage repair. PMID- 11603725 TI - Age changes in articular cartilage. 1969. PMID- 11603724 TI - Integrin-interleukin-4 mechanotransduction pathways in human chondrocytes. AB - Mechanical stimuli are known to have major influences on chondrocyte function. The molecular events that regulate chondrocyte responses to mechanical stimulation are beginning to be understood. In vitro analyses have allowed identification of mechanotransduction pathways that control molecular and biochemical responses of human articular chondrocytes to cyclical mechanical stimulation. These studies have shown that human articular chondrocytes use alpha5beta1 integrin as a mechanoreceptor. After stimulation of this integrin by mechanical stimulation, there is activation of a signal cascade, involving stretch-activated ion channels, the actin cytoskeleton and tyrosine phosphorylation of the focal adhesion complex molecules pp125 focal adhesion kinase and paxillin, and beta-catenin. Subsequently, there is secretion of interleukin-4, which acts in an autocrine manner via Type II receptors, to induce membrane hyperpolarization, increase levels of aggrecan messenger ribonucleic acid, and decrease levels of matrix metalloproteinase 3 messenger ribonucleic acid. Chondrocytes from osteoarthritic cartilage also use alpha5beta1 integrin as a mechanoreceptor, but downstream signaling cascades and cell responses including changes in aggrecan messenger ribonucleic acid are different. Abnormalities of chondroprotective mechanotransduction pathways in osteoarthritis may contribute to disease progression. PMID- 11603726 TI - In vitro models for investigation of the effects of acute mechanical injury on cartilage. AB - Traumatic injury to a joint is known to increase the risk for the development of secondary osteoarthritis, but it is unclear how this process occurs. The existence of such a discrete event that can lead to an increased risk of osteoarthritis has spurred interest in developing in vitro models of traumatic joint injury. The current authors review some of the recent insights gained from these model systems into the pathogenesis of osteoarthritis, including the evidence for an initial, irreversible insult to chondrocytes during mechanical injury, the occurrence of apoptotic chondrocyte death, and attempts to identify the effects of trauma on chondrocyte metabolic response. Results also are presented from the authors' ongoing studies of the degradative pathways initiated by traumatic mechanical loads, the mechanism by which chondrocytes are affected during compression, and possible contributions of the joint capsule to posttraumatic cartilage degradation. PMID- 11603728 TI - Impact of mechanical trauma on matrix and cells. AB - Posttraumatic arthritis is one of the most common causes of secondary osteoarthritis. The contribution of cell death to matrix degradation has not been characterized fully. The current study was designed to determine the effect of mechanical injury on chondrocyte viability and matrix degradation. Full-thickness bovine and human cartilage explants, 5 mm in diameter were subjected to mechanical loads representative of traumatic joint injury. Glycosaminoglycan release and percent apoptotic cells were measured. Unilateral patellas in eight anesthetized rabbits were subjected to an impact load. Rabbits were euthanized at 96 hours after injury and patellar cartilage was harvested for analysis. The effect of a pan-caspase inhibitor, z-VAD.fmk [benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone] in preventing chondrocyte apoptosis in human articular cartilage explants was determined. A significant increase in the number of apoptotic cells was observed in response to mechanical loading. The mean in vivo apoptotic rates were 1% in control rabbits and 15% in impacted patellas. Caspase inhibition reduced chondrocyte apoptosis from 34% to 25% after mechanical injury and was associated with reduction in glycosaminoglycan release. Mechanical injury induces chondrocyte apoptosis that is sensitive to pharmacologic inhibition. This identifies a new approach to limit traumatic cartilage injury and the subsequent development of secondary osteoarthritis. PMID- 11603727 TI - The role of the extracellular matrix in articular chondrocyte regulation. AB - The in vivo role of the extracellular matrix and the manner in which it interfaces with soluble regulators remains largely unknown. The current study reports the extracellular Type II collagen modulation of transforming growth factor-beta 1-stimulated proliferation, proteoglycan synthesis, messenger ribonucleic acid expression for transforming growth factor-beta 1, and integrin messenger ribonucleic acid expression in articular chondrocytes from adults. This study shows that this cytokine modulation occurs through a mechanism initiated by the attachment of Type II collagen to the beta1-integrin. Transforming growth factor-beta 1 stimulated deoxyribonucleic acid and proteoglycan synthesis in a bimodal fashion. Extracellular Type II collagen increased transforming growth factor-beta 1-stimulated deoxyribonucleic acid and proteoglycan synthesis, aggrecan gene expression as much as 400%, and alpha1(II) procollagen gene expression as much as 180% in a dose-dependent fashion. Heat inactivation of the Type II collagen abrogated the observed effects on deoxyribonucleic acid and proteoglycan synthesis. In contrast to Type II collagen, heat-denatured collagen and bovine serum albumin showed none of the observed effects. The presence of Type II collagen in the alginate bead cultures was found to diminish the messenger ribonucleic acid expression for alpha2 integrin and alter the cellular distribution pattern of the beta1 integrin receptors. Blocking of the beta1 integrin with cyclic-peptides containing the Arg-Gly-Asp sequences and antibodies reduced chondrocyte attachment to Type II collagen by 93%. The physiologic effects shown by the chondrocyte as a result of blocking this attachment to Type II collagen were a significant reduction in transforming growth factor-beta 1 stimulated deoxyribonucleic acid and proteoglycan synthesis. The conclusions elucidate the role played by the extracellular matrix in cytokine-specific regulation of the articular chondrocyte. The authors have shown that extracellular Type II collagen acts through a beta1-integrin mediated mechanism to modulate the chondrocyte response to transforming growth factor-beta 1. PMID- 11603729 TI - Genetic diversity and phylogeny of the Kanzawa spider mite, Tetranychus kanzawai, in Japan. AB - Two types are known in the Kanzawa spider mite, Tetranychus kanzawai (K and T; see Gotoh et al., 1999), which differ in host range and have a unidirectional incompatibility. Prior to DNA analyzes, crossing between females of a known K type and males of each of 17 strains collected in Japan showed that six of the strains were of the K type, live were the T type and the rest consisted of a mixture of the two types. In order to elucidate the genetic diversity and phylogenetic relationship of T kanzawai in Japan, we analyzed the DNA sequences of two regions--the internal transcribed spacer 1 (ITS1) of the nuclear ribosomal DNA (rDNA) and a fragment of the cytochrome oxidase subunit I gene (COI) of mitochondrial DNA - using 11 strains (six K-type strains and five T-type strains). Base substitutions were detected on 25 sites of COI (375bp) and 19 sites of ITS1 (486bp), resulting in eight and 17 haplotypes, respectively. The phylogenetic trees constructed using the DNA sequences failed to clearly distinguish between the two types. The results suggested that the T type was derived from the K type. PMID- 11603731 TI - Population dynamics of phytophagous and predatory mites (Acari: Tetranychidae, Eriophyidae, Phytoseiidae) on bamboo plants in Fujian, China. AB - The seasonal cycle and population dynamics of Schizotetranychus nanjingensis Ma and Yuan, Aponychus corpuzae Rimando (Tetranychidae), Aculus hambusae Kuang (Eriophyidae) and their natural enemy Tvphlodromus bambusae Ehara (Phytoseiidae) were studied during 1996-1998 in moso bamboo forests in Nanping, Fujian, China. Damage to bamboo leaves was often caused by mixed populations of the three phytophagous species, which displayed different seasonal dynamics: S. nanjingensis fed actively and reproduced in May and from late July to late October (aestivating from June to mid July), Ap. corpuzae was active and reproduced from mid July to late November, and Ac. bambusae from July to next February. During Spring S. nanjingensis was the dominant species with the greatest niche width, but in Summer Ac. bambusae and Ap. corpuzae became dominant and had greater niche widths. In Autumn, Ac. bambusae decreased but both S. nanjingensis and Ap. corpuzae mites increased and the latter became dominant. In winter all species decreased sharply in number. The two spider mite species (S. nanjingensis and Ap. corpuzae) had high niche overlaps in all four seasons. Niche overlaps between the eriophyid Ac. bambusae and the two spider mites were similarly high except during the spring when Ac. bambusae was absent. The predatory mite (T. bambusae) had higher niche overlap with Ap. corpuzae than with others during Autumn and Winter, but during Spring and Summer niche overlap was higher with S. nanjingensis. PMID- 11603730 TI - Trade-offs in performance on different plants may not restrict the host plant range of the phytophagous mite, Tetranychus urticae. AB - We examined sib-mated lines of the phytophagous mite, Tetranychus urticae Koch, for trade-offs in performance on different plants. We found no significant trade offs among 10 potential host plants examined. Trade-offs in performance were not detected in most cases, even when the variations in general performance (mean performance on all potential host plants) among the sib-mated lines were statistically adjusted, denying the possibility that this may be due to the variations in general performance among the lines. No evidence for trade-offs was obtained in an artificial selection experiment; on all tested plants, a line adapted to one marginal host plant exhibited higher performance than the control line. However, the general performance seemed to be negatively correlated with other adaptive traits of the mite, such as competition ability of adult males for their mates and overcrowding response of adult females. Such correlations may contribute to the maintenance of genetic variation in the general performance of T. urticae. PMID- 11603733 TI - Quantitative classification of life-style types in predaceous phytoseiid mites. AB - Classification of species into different functional groups based on biological criteria has been a difficult problem in ecology. The difficulty mainly arises because natural classification patterns are not necessarily mutually exclusive. The more group characteristics overlap, the more difficult it is to identify the membership of a species in the overlapping portions of any two groups. In this paper, we present an application of discriminant analysis by creating classification models from life history and morphological data for two specialist and two generalist life-styles type of predaceous phytoseiid mites. Two stages can be distinguished in our method: life-style group membership assignment and trait variable evaluation. We use a Bayesian framework to create a classifier system to locate or assign species within a mixture of trait distributions. The method assumes that a mixture of trait distributions can represent the multiple dimensions of biological data. The mixture is most evident near the boundaries between groups. Because of the complexity of analytical solution, an iterative method is used to estimate the unknown means, variances, and mixing proportion between groups. We also developed a criterion based on information theory to evaluate model performance with different combinations of input variables and different hypotheses. We present a working example of our proposed methods. We apply these methods to the problem of selecting key species for inoculative release and for classical introductions of biological pest control agents. PMID- 11603732 TI - Seasonal occurrence of specialist and generalist insect predators of spider mites and their response to volatiles from spider-mite-infested plants in Japanese pear orchards. AB - In two adjacent Japanese pear orchards (orchards I and 2), we studied the seasonal occurrence of the Kanzawa spider mite. Tetranychus kanzawai, and its predators. Also the response of these predators to the volatiles from kidney bean plants infested with T kanzawai was investigated using trap boxes in orchard 1. The mite density in orchard 1 was unimodal. with one peak at the end of August. In this orchard, population development of the specialist insect predators, Scolothrips takahashii, Oligota kashmiria benefica and Stethorus japonicus was almost synchronized with that of the spider mites. These predators disappeared when the density of their prey became very low in mid-September. Both S. takahashii and O. kashmirica benefica abruptly increased in number in orchard 2 when the spider mite population in orchard 1 decreased. These results suggested that some of the predators migrated from orchard 1 to orchard 2. In this period, predator-traps with T kanzawai-infested bean plants attracted significantly more S. takahashii than traps with uninfested plants. Very few individuals of S. japonicus and O. kashimirica benefica were found in the traps, despite their abundance in orchard 1. The generalist insect predator, Orius sp., was attracted to the traps throughout the experimental period irrespective of the density of spider mites, although this predator was never observed inside the orchards. PMID- 11603734 TI - Automatic mass-rearing of Amblyseius womersleyi (Acari: Phytoseiidae). AB - Using incorporated devices, Tetranychus urticae spider mites were rinsed from hydroponically-grown lima bean plants, collected, separated and blow-dried. This yielded a reliable and large volume of eggs and larvae, which were fed to Amblyseius womersleyi rearings on 15 x 5 cm2 polyethylene arenas. Of several feeding regimes tested, daily feeding of 10 mg T. urticae eggs and larvae resulted in the highest predator population levels. The best harvest period was between 15 and 27 days, when predator density exceeded 600 mites per arena. A preliminary automatic mass-rearing device was tested for A. womerslyi. This incorporated both rearing and harvesting procedures. A micro-feeder was developed to supply the required volume of spider mites and maize pollen (1:1 mixture) to the predators. A Bakelite rearing arena reduced the space requirements of a polyethylene arena, was more durable and an essential component in the automatic mass-rearing and harvesting. Mite harvesting is carried out through the use of a vacuum-head harvester. Supplements of (sterilized) spider mites, pollen, vermiculite and wheat bran are automatically added to the predators. The devices for harvesting, filling and packing are incorporated and synchronized and the entire system is controlled by a single slide-switch. The design and system can be expanded without changing the basic processes and program, for example to adopt it for other species of predaceous mites. PMID- 11603735 TI - Phytoseiid predators as potential biological control agents for Bemisia tabaci. AB - Mites of the family Phytoseiidae are known to be predators of whiteflies in several agroecosystems, especially of Bemisia tabaci Gennadius, a pest with high resistance to chemical insecticides that occurs in greenhouses in temperate regions. We collected predatory mites that were found to co-occur with whiteflies in the Middle East for control of B. tabaci: Tvphlodromus athiasae (Porath and Swirski), Neoseiulus barkeri Hughes, Tvphlodromips swirskii (Athias-Henriot), Euseius scutalis (Athias-Henriot), Phytoseius finitimus Ribaga. As a first step in the evaluation of these species as biological control agents, we measured their life-history traits when feeding on whiteflies. The intrinsic rates of increase (rm) of the predatory mite species ranged between 0.131 and 0.215 per day and E. scutalis had the highest rm estimated. Comparisons with the rm of B. tabaci indicate that some of the species should be capable of suppressing local populations of whitefly. The ability of predators to use alternative food was also tested, since it facilitates the setup of mass cultures and it can promote their persistence in the crop, even if the prey is scarce. All predatory mite species tested were able to survive and reproduce on a diet of broad bean pollen. PMID- 11603737 TI - The development of bifenthrin resistance in two-spotted spider mite (Acari: Tetranychidae) from Australian cotton. AB - Bifenthrin (Talstar) was registered at the beginning of the 1993/94 season for control of Helicoverpa spp. and Tetranychus urticae in Australian cotton. Resistance was monitored in T. urticae following registration but despite the implementation of resistance management, resistance evolved in the 1996/97 cotton growing season after only four seasons use. During the following three seasons resistance increased progressively both in level (from 1.2- to 109-fold at LC50) and abundance (from 20 to 90% strains) and was linked to field control failures. The evolution of resistance has now reduced the reliability of bifenthrin for T. urticae control in Australian cotton. The impact of bifenthrin resistance in T urticae and its continued management in Australian cotton is discussed. PMID- 11603736 TI - Comparative susceptibility and possible detoxification mechanisms for selected miticides in banks grass mite and two-spotted spider mite (Acari: Tetranychidae). AB - The susceptibility and possible detoxification mechanisms of the Banks grass mite (BGM), Oligonychus pratensis (Banks), and the two-spotted spider mite (TSM), Tetranychus urticae Koch, to selected miticides were evaluated with and without synergists. BGM was 112-fold more susceptible to the organophosphate dimethoate, and 24-fold more susceptible to both the pyrethroids bifenthrin and lambda cyhalothrin than TSM. The synergist triphenyl phosphate (TPP) enhanced the toxicities of bifenthrin and lambda-cyhalothrin against BGM by 3.0- and 4.2-fold, respectively, and enhanced the toxicities of bifenthrin, lambda-cyhalothrin, and dimethoate against TSM by 6.2-, 1.9-, and 1.7-fold, respectively. The synergist diethyl maleate (DEM) enhanced the toxicities of bifenthrin and lambda cyhalothrin against BGM by 2.2- and 2.9- fold, respectively, and enhanced the toxicity of bifenthrin against TSM by 4.1-fold. On the other hand, the synergist piperonyl butoxide (PBO) increased the toxicities of bifenthrin and lambda cyhalothrin by 6.0- and 2.6-fold, respectively, against BGM, and by 4.5- and 1.9 fold, respectively, against TSM. The significant synergism with these pyrethroids of all three tested synergists (except for DEM with lambda-cyhalothrin against TSM) suggests that esterases, glutathione S-transferases, and cytochrome P450 monooxygenases all play important roles in their detoxification. However, the toxicity of dimethoate was not enhanced by these synergists in either mite species (except for TPP against TSM). Apparently, these metabolic enzymes play less of a role in detoxification of this organophosphate in these mites. PMID- 11603738 TI - Sublethal effects of esfenvalerate residues on pyrethroid resistant Typhlodromus pyri (Acari: Phytoseiidae) and its prey Panonychus ulmi and Tetranychus urticae (Acari: Tetranychidae). AB - The effect of residues of esfenvalerate on oviposition of the resistant strain of the predatory mite Typhlodromus pyri and its main prey, European red mite Panonychus ulmi and two-spotted spider mite Tetranychus urticae, were investigated. T. pyri showed a significant linear reduction in oviposition after 24 h in the presence of increasing levels of esfenvalerate residue applied at the field rate. Furthermore, when given a choice, T. pyri preferred to lay eggs on residue-free surfaces. Of the two prey species, only P. ulmi showed significant avoidance of increasing levels of residues of the field rate concentration of esfenvalerate, as measured by runoff mortality, however both P. ulmi and T urticae, when given a choice, showed a preference for esfenvalerate-free surfaces. As with the predatory mite T. pyri, both prey species showed a significant linear reduction of oviposition with increasing esfenvalerate residues and a preference to lay eggs on esfenvalerate-free surfaces. Esfenvalerate residues as high as 15X field rate were not repellent to pyrethroid resistant T. pyri. The possible effects of these sublethal effects on predator prey dynamics and implications for integrated mite control programmes in apple orchards are discussed. PMID- 11603739 TI - Varroa destructor reproduction during the winter in Apis mellifera colonies in UK. AB - The reproductive behaviour of female Varroa destructor mites invading worker brood cells during the winter months (January to mid-March) was investigated in four Apis mellifera colonies in UK. The number of viable offspring produced during a reproductive cycle, per mite, was only 0.5 during winter compared with 1.0 during the summer. This was mainly due to a large increase in the population of non-reproductive mites (winter 20%, summer 8%). This increase can be explained by the high level of male offspring mortality observed in winter (42% vs. 18% in summer), which results in nearly half of the newly reared female mites being unfertilised. Since mites that do reproduce lay a similar number of eggs in winter (X = 4.7) as in summer (X = 4.9), and the level of mortality suffered by the first female offspring is similar in winter (7%) as in summer (6%), it is probably not the internal physiological state of the host which causes the high level of winter non-reproduction, as has been previously suspected. PMID- 11603740 TI - Morphology and structural organization of gene's organ in Dermacentor reticulatus (Acari: Ixodidae). AB - Scanning and transmission electron microscopical investigations revealed that Genes organ in unfed and ovipositing females of Dermacentor reticulatus is formed as a double-sac-structure consisting of an outer epithelial and an inner cuticular sac. In ovipositing ticks the latter emerges through the camerostomal aperture to the exterior. Genes organ in unfed ticks consists of a corpus, two posterior horns and a pair of undeveloped glands at each side, which differentiate in ovipositing ticks to compound, branched tubular glands with a main efferent duct for each gland opening into the lumen between the epithelial and the cuticular sac. Genes organ of egg-laying females corresponds basically in morphology and structural organization to that of unfed ticks. Compared with unfed ticks, however, in ovipositing ticks the corpus and horns are longer and broader, the glands are fully developed and the cuticular sac is evertable. The epithelial sac as the outermost part of Genes organ is continuous with the hypodermis of the basis capituli and the scutum, arises at the camerostomal aperture, forms the corpus and the two blind-ending horns, passes into the epithelium of the main excretory ducts of the glands and envelops the cuticular sac. The cuticular sac passes into the cuticle of the basis capituli and the scutum, arises at the camerostomal aperture, is folded, expands into the horn tips and consists inwards of a smooth epicuticula and outwards of a fibrous endocuticula. Muscles originating from the scutum pass caudomedially through the epithelial sac and are inserted into the cuticular sac. The entire surface of the maximally everted cuticular sac is covered with an amorphous mass. In cleaned samples, ledge-like structures appear on the lateral surface. These ledges turn into balloon-like structures which extend over the medial and dorsal surface. The entire surface including the balloon-like structures and the ledges are provided with numerous cribrate pits. PMID- 11603741 TI - Residency education in surgery. PMID- 11603742 TI - Musculoskeletal images. Ganglion cyst of Guyon's canal causing ulnar nerve compression. PMID- 11603743 TI - Soft-tissue images. Ecthyma gangrenosum: a deceptively benign skin lesion in febrile neutropenia. PMID- 11603744 TI - Musculoskeletal case 18. Radiation-induced osteosarcoma of the sacrum. PMID- 11603745 TI - Soft-tissue case 41. Bouveret's syndrome. PMID- 11603746 TI - Trauma to the thoracic and lumbar spine in the adolescent. AB - During adolescence the spine undergoes rapid growth and changes in anatomy and biomechanical properties. Fractures of the adolescent spine are relatively uncommon but may give rise to serious problems. This review describes thoracolumbar fractures in adolescents with respect to epidemiology, anatomy, mechanisms of injury, clinical and radiologic assessment, and nonoperative and operative treatment. The treatment of these injuries follows many of the same principles as spinal fractures in adults but nonoperative treatment is used more frequently because there is less spinal instability and better tolerance of bed rest and spinal immobilization in this young population. PMID- 11603747 TI - Users' guide to the surgical literature: how to use an article on economic analysis. PMID- 11603748 TI - Is homologous blood transfusion a risk factor for infection after hip replacement? AB - OBJECTIVES: To assess the risk of postoperative infection associated with blood transfusion in patients who undergo primary total hip arthroplasty. DESIGN: A retrospective cohort study. SETTING: Victoria General Hospital, Halifax, (a tertiary-care centre). PATIENTS: All patients who underwent primary total hip replacement between 1990 and 1995 (N = 1206). INTERVENTIONS: Hip replacement with or without perioperative blood transfusion. OUTCOME MEASURES: The rate of postoperative infection, the number of blood transfusions, patient age and sex, duration of surgery and the surgeon who performed the procedure. Victoria General Hospital medical records, the transfusion services record and the Dalhousie University Hip Study databases were integrated and analyzed using a standard statistical package. RESULTS: The incidence of infection postoperative was 9.9% overall, 8.4% in patients receiving no transfusion, and 14% in those receiving homologous transfusion (p = 0.035). There were no infections in the 11 patients who received an autologous blood transfusion. Significant predictors of postoperative infection were sex, age and duration surgery; these were not confounding variables multivariate analysis). Neither the operating surgeon nor the blood product transfused affected the infection rate. CONCLUSIONS: These findings suggest an increased risk of postoperative infection in patients who undergo primary hip replacement and receive homologous blood transfusions perioperatively. PMID- 11603749 TI - Transverse sacral fractures: case series and literature review. AB - OBJECTIVES: To report experience with transverse sacral fracture, an uncommon injury frequently associated with neurologic deficit, and to perform a meta analysis of the literature in order to define the role of decompression for the management of sacral fractures. DESIGN: A review of 7 cases. SETTING: A university-affiliated tertiary care centre. PATIENTS: Seven patients with transverse fractures of the sacrum. The mean follow-up was 13 months. INTERVENTIONS: A review of the clinical data and a search of the literature for studies that reported on 4 or more patients with a transverse sacral fracture. MAIN OUTCOME MEASURES: Mechanism of injury, type of neurologic deficit and its management. RESULTS: The most common mechanism in the 7 study patients was a fall from a height. Six patients had neurologic deficits, mostly in the form of bowel or bladder disturbance. Five of these were treated with surgical decompression, and 4 of them had an improvement in neurologic function. The 7 original studies from the literature dealt with a total of 55 patients. As in the study patients, falls from a height and motor vehicle accidents predominated as the mechanisms of injury. In contrast to patients in this study, 20 of 48 patients in the literature review with neurologic deficits were treated conservatively. CONCLUSIONS: The outcomes in this study are similar to those reported in the literature. The place of surgical decompression for patients with neurologic deficit cannot be clearly determined from the evidence currently available. PMID- 11603750 TI - Current practice of abdominal fascial closure: a survey of Ontario general surgeons. AB - OBJECTIVES: To determine the current practice of abdominal fascial closure among provincial general surgeons. The primary objective was to determine the proportion of surgeons choosing absorbable versus nonabsorbable sutures. Secondary objectives included determining knowledge and attitudes of surgeons to evidence-based medicine and concordance of current practice with level I evidence. DESIGN: A survey. SETTING: The province of Ontario. PARTICIPANTS: One hundred general surgeons. METHODS: A stratified random sample of community and academic surgeons was assembled and a questionnaire was mailed to them. Common clinical scenarios and questions pertaining to attitudes and knowledge of evidence-based medicine were included. MAIN OUTCOME MEASURES: Use of absorbable versus nonabsorbable suture material. Willingness to change current practice on evidence-based level I reports. RESULTS: Most surgeons (86%) chose an absorbable suture for abdominal fascial closure. Nonabsorbable suture was chosen by 58% of surgeons in the highly contaminated surgical scenario. Eighty-one percent of surgeons indicated they would be willing to change their current practice of fascial closure if there was evidence that the incidence of wound complications was reduced. Polyglactin (Vicryl) was the most commonly chosen suture. CONCLUSIONS: The current practice of abdominal fascial closure among Ontario general surgeons is in disagreement with the findings from a recent meta analysis, recommending a nonabsorbable suture for a 32% relative risk reduction in the incisional hernia rate. The majority of surgeons employ a continuous absorbable closure in common surgical scenarios. A definitive randomized controlled trial comparing continuous nonabsorbable closure versus continuous absorbable closure is warranted. PMID- 11603751 TI - Cystadenomas of the liver: a spectrum of disease. AB - OBJECTIVES: To describe the wide variation in presentation of cystadenomas of the liver and to delineate useful tests for diagnosis and effective surgical treatment. DESIGN: A case series. SETTING: A university-affiliated hospital. PATIENTS: Four patients (3 women, 1 man) having cystadenoma of the liver, 2 of whom had associated mesenchymal stroma. MAIN OUTCOME MEASURES: Serum and cyst fluid carcinoembryonic antigen (CEA) and CA19-9 levels, type of surgery, morbidity and recurrence rates. RESULTS: Cyst fluid CEA and CA19-9 levels were elevated. One patient had resection, 2 had complete enucleation and 1 had partial enucleation. There were no deaths. Morbidity included 1 wound infection; there were no biliary fistulas. The patient with partial enucleation had a radiologically confirmed recurrence. CONCLUSIONS: Analysis of cyst fluid CEA and CA19-9 is useful for diagnosis; besides hepatic resection, complete enucleation should be considered as a reasonable treatment for patients with this disease. PMID- 11603752 TI - Results of curative surgery and postoperative chemoradiation for rectal adenocarcinoma in British Columbia, 1985 to 1994. AB - OBJECTIVE: To assess factors affecting survival and pelvic recurrence after surgery and postoperative chemoradiation for rectal cancer in order to design improved management strategies. DESIGN: A chart review. SETTING: The British Columbia Cancer Agency. PATIENTS: One hundred and ninety-one consecutive patients who had rectal cancer treated between 1985 and 1994. Median follow-up was 39 months. INTERVENTIONS: Surgical excision of the cancer with intent to cure followed by chemoradiation. OUTCOME MEASURES: Multivariate analysis, to determine whether survival and pelvic recurrence were affected by tumour stage, nodal status, type of surgical procedure and presence of residual disease, and the quality of pathology reporting with respect to evaluation of radial resection margins and number of lymph nodes examined. RESULTS: Overall 5-year disease specific survival was 60% and pelvic recurrence was 25%. Survival was affected by tumour stage (p < 0.02), nodal status (p < 0.001), type of surgical procedure (p < 0.04), presence of residual disease (p < 0.02) and pelvic recurrence (p < 0.0001). Pelvic recurrence was affected by the presence of residual disease (p < 0.001) but not by tumour stage (p < 0.14), nodal status (p < 0.37) or type of surgcial procedure (p < 0.20). Radial margins were evaluated in 44% of pathology reports and the median number of lymph nodes assessed was 6. CONCLUSIONS: Survival was most significantly affected by pelvic recurrence. Strategies to minimize pelvic recurrence including preoperative radiation and the principle of careful mesorectal excision to maximize the achievement of negative radial resection margins and negative residual disease are recommended. Also needed are standards for evaluating radial margins and lymph nodes to improved pathology reports. PMID- 11603753 TI - Amphotericin B-loaded bone cement to treat osteomyelitis caused by Candida albicans. PMID- 11603754 TI - Pneumothorax following tube thoracostomy and water seal drainage. PMID- 11603755 TI - Progress in laryngeal framework surgery. AB - This paper reviews progress in laryngeal framework surgery since it was first reported about 25 years ago. The success of this type of surgery requires both a basic knowledge of the physiology of phonation, in order to make decisions about the surgical procedure, and surgical skill, in order to accomplish the intended procedure successfully. The main reason for hoarseness is imperfect closure of the glottis, but the second most important reason for hoarseness, increased stiffness of the vocal fold, cannot be corrected by mere medialization of the vocal fold. Laryngeal framework surgery is different in concept from conventional surgery, which is intended to remove the lesion. Controversial points discussed here regarding type I thyroplasty include: (i) whether the cartilage window should be removed; (ii) materials for fixation of the window; and (iii) comparison of type I thyroplasty with arytenoid adduction. A new surgical treatment for spasmodic dysphonia and its results in three patients are described briefly. Surgery for raising the vocal pitch requires further improvement. In the future, laryngeal framework surgery will have wider application in treatment of dysphonias, such as asthenic voice due to atrophy in professional singers or aging, pitch problems in females and gender identity disorder and spasmodic dysphonia. PMID- 11603756 TI - Serotonergic innervation of the organ of Corti. AB - The olivocochlear efferent system of the mammalian cochlea, which is divided into two lateral and medial bundles, contains numerous neuroactive substances (acetylcholine, GABA, dopamine, enkephalins, dynorphins and CGRP). These have been located at the brainstem in neurons belonging to the lateral superior olive (lateral efferent system) or in neurons of the periolivary region around the medial superior olive and the trapezoid body (medial efferent system). All of these substances were found in well-characterized projections corresponding to lateral and medial nerve fibres and terminals which connect to the type I afferent dendrites and the outer hair cells, respectively. All could be involved in the modulation of the auditory process, as is suggested by the cochlear turnover increases observed in some of them (i.e. enkephalins or dopamine) induced by sound stimulation. Recently, the presence and distribution of serotonin-containing fibres has been included in the long list of cochlear neuroactive substances. However, its highly particular peripheral pattern of distribution together with the lack of response to sound stimulation could suggest that serotonergic fibres constitute a previously unknown cochlear innervation. PMID- 11603757 TI - GJB2 gene mutations in childhood deafness. AB - The frequency of childhood deafness is estimated at 1:1,000 and at least half of these cases are genetic. Recently, mutations in the GJB2 gene have been found in a great number of familial and sporadic cases of congenital deafness in Caucasians. The most common mutation (70%) is the frameshift mutation of a single guanine in position 35 (35delG). More than 20 mutations in the GJB2 gene are associated with DFNB1, a prevalent type of autosomal recessive non-syndromic neurosensory deafness. Last year we initiated a systematic screening programme to evaluate the causes of deafness in the population of prelingually deaf children who are referred to our cochlear implant programme. All of the deaf children and their parents undergo a comprehensive medical review, directed to identify causes of acquired deafness and manifestations of syndromic hearing impairment. DNA is extracted from the blood of all of the children. The technique AS-PCR (allele specific polymerase chain reaction) is used for the identification of the mutation 35delG. Screening for other GJB2 gene mutations is carried out by single strand conformation polymorphisms (SSCP). Our results on the identification of DFNB1 will be presented, as well as a discussion on the implications of an aetiological diagnosis in cochlear implantation. PMID- 11603758 TI - Mutations of the Pendred syndrome gene (PDS) in patients with large vestibular aqueduct. AB - A recent report demonstrated the presence of a mutation in the Pendred syndrome gene (PDS) of patients with large vestibular aqueducts but without goitre. We studied PDS mutations in members of four Japanese families, among which five affected members showed bilateral enlarged vestibular aqueducts. All affected members exhibited moderate to severe bilateral fluctuating sensorineural hearing loss and the absence of goitre. Three members also suffered from recurrent episodic vertiginous spells. Analysis of PDS mutation revealed two single base changes (mis-sense mutations) in exons 19 and 10. The first was an A-->G transition at nucleotide position 2168, resulting in a predicted His-->Arg substitution at position 723 (H723R), whereas the second was a C-->T transition at nucleotide position 1229, resulting in a predicted Thr-->Met substitution at position 410 (T410M). Both mutations are situated in the extracellular domain close to the C terminal. It thus appears that PDS mutations can lead not only to classic Pendred syndrome, but also to large vestibular aqueduct syndrome. PMID- 11603759 TI - Epidermal growth factor upregulates production of supernumerary hair cells in neonatal rat organ of corti explants. AB - The organ of Corti is highly ordered, with a single row of inner hair cells and three rows of outer hair cells. The number of hair cells produced was thought to be limited by the time of their terminal mitosis (i.e. E14 in the mouse). However, exogenous application of retinoic acid has been shown to stimulate the formation of supernumerary hair cells in organ of Corti explants from E13 to E16 mouse embryos. Using late embryonic and neonatal rat organ of Corti explants, we investigated the potential for production of supernumerary hair cells in more mature auditory sensory epithelia. When newborn rat organ of Corti explants were cultured under control conditions, an area of supernumerary hair cells was observed in a segment of organ of Corti that was at the junction between the basal and middle turns. In these areas of supernumerary hair cells the number of hair cells increased per unit of length, but remained constant per surface unit, further demonstrating the supernumerary character of this phenomenon. Organ of Corti explants treated with epidermal growth factor (EGF) showed a 50% increase in the length of the organ of Corti segment containing supernumerary hair cells. Upregulation of supernumerary hair cell formation by EGF was found to start and be maximal at birth (P0) and to disappear by 2 days after birth (P2). Treatment of EGF stimulated P0 explants with an antimitotic drug, cytosine arabinoside (ARAc), demonstrated that the production of supernumerary hair cells occurred independently of cell division. PMID- 11603760 TI - Expression of heat shock protein 72 in rat cochlea with cisplatin-induced acute ototoxicity. AB - Cisplatin ototoxicity is known to involve mainly the organ of Corti. Outer hair cells (OHCs). especially in the basal turn, are preferentially involved. One possible mechanism of ototoxicity might be alteration of the antioxidant system causing an increase in free radicals. It has been demonstrated that heat shock proteins (HSPs), which are believed to protect cells by dissolving and refolding misfolded or denatured protein are induced by various form of stress. HSP is also demonstrated to be induced by free radicals. The purpose of this study was to evaluate HSP 72 induction in cochlea following cisplatin injection in the animal model. Sprague-Dawley (SD) rats were injected intraperitoneally with normal saline as control or cisplatin at a dose of 5, 10 or 20 mg/kg. Cochleae were harvested 1, 3, 6 and 12 h after injection and compared with those of controls. Immunocytochemical study with surface preparation and Western blotting were performed to investigate the expression of HSP 72. Auditory brainstem response (ABR) was also recorded to assess functional change according to the dosage of cisplatin and duration after injection. In the 5 and 10 mg/kg groups, immunostaining for HSP 72 in the OHCs reached a plateau level at 3 h, which was maintained until 12 h after injection. The amount of immunoreactive OHCs in the 20 mg/kg group was smaller than those in 5 and 10 mg/kg groups and declined after 6 h. The bands for HSP 72 became less intense as the cisplatin dosage increased from 5 to 10 and 20 mg/kg in Western blotting. The change in ABR threshold was small in the 5 and 10 mg/kg groups and a marked change in threshold was observed in the 20 mg/kg group. Detection of HSP 72 after cisplatin injection could confirm the OHCs as one of the major injured cells in the cochlea. With a lethal dosage of cisplatin (20 mg/kg), HSP 72 expression was less prominent and declined after 6 h. PMID- 11603761 TI - Postural stability using different neck positions in normal subjects and patients with neck trauma. AB - Subjects with neck problems, such as whiplash injuries, often complain of disturbed equilibrium and, in some instances, provocation of the neck position can elicit such problems. The importance of neck proprioceptors for maintaining balance is gaining increased interest, moreover the function or malfunction of the otoliths may disturb equilibrium in certain head positions. The aim of the study was to create a reference material for postural control and its dependence on head position in healthy subjects and to compare this with a set of patients with known neck problems and associated vertiginous problems. A total of 32 healthy subjects (16 men, 16 women, age range 21-58 years) as well as 10 patients age range 27-62 years (mean 44 years) with neck problems and associated balance problems since a whiplash injury were tested for postural control using the EquiTest dynamic posturographic model. The normal subjects were initially split into four age groups in order to estimate the effects of age on performance. The postural stability was evaluated for dependence of support surface conditions (stable or sway-referenced), visual input (eyes open or closed) and head position (neutral, left rotated, right rotated, extended backwards or flexed forward) using analysis of variance (ANOVA) with Tukey's post hoc test in case of a significant factor effect. As expected, visual cues as well as stable support surface improve postural stability (p < 0.001). Postural stability is statistically different in the head extended backwards condition compared with the other four head positions (p < 0.001 in all cases) in both patients and controls. Eliminating this test condition from the analysis, only a slight (p < 0.05) difference between head forwards and head turned left remained. This pattern of results remained if the normal subjects were only split into two age groups instead of four. Finally, the patient group exhibited significantly lower postural performance than all the groups of normal subjects (p <0.01), but none of the normal groups differed significantly from each other. It is concluded that the postural control system is significantly challenged in the head extended backwards condition in both normal subjects and patients with previous whiplash injury and persistent neck problems. The patient group differed statistically from all groups of normal subjects. This suggests that neck problems impair postural control, and that the head extended position is a more challenging task for the postural system to adapt to. Whether this is due to utricular malpositioning, central integrative functions or cervical proprioceptive afferents is not within the scope of this study to answer. PMID- 11603762 TI - Identification of uridine 5'-triphosphate receptor mRNA in rat cochlear tissues. AB - Previous investigations have reported the presence of uridine 5'-triphosphate (UTP) and adenosine 5'-triphosphate (ATP) receptors triggering phospholipase C (PLC) activation in the frog semicircular canal. The aim of this work was to characterize the molecular subtypes of these nucleotide receptors. Due to the lack of molecular tools for purinoceptors in amphibia, this study was performed on the rat. The stria vascularis, organ of Corti and spiral ligament were microdissected from Long Evans rat cochlea. RNA was extracted from four cochleas and polymerase chain reaction (PCR) was performed after reverse transcription (RT) using oligonucleotides for sequences of P2Y1, P2Y2, P2Y4 and P2Y6 receptors. Various tissues were used as negative controls (testis for P2Y1 and P2Y6 receptors, brain for P2Y2 and P2Y4 receptors and liver for P2Y4 receptors). Data show the expression of the four transcripts in the stria vascularis, organ of Corti and spiral ligament. When results were normalized to the signal obtained with S14 mRNA, a ribosomal protein used as an internal standard, expressions were similar in the three structures. In conclusion, these results demonstrate the mRNA expression of the three UTP receptors (P2Y2, P2Y4 and P2Y6) and of the P2Y1 ATP receptor in both sensory and secretory structures of the rat inner ear. Their functional roles remain to be defined. PMID- 11603763 TI - Reoperations after cochlear implantation. AB - During the 14-year history of cochlear implantation at Semmelweis University, 95 implantations were performed. There were 15 reoperations, and 2 patients had been operated 3 times. All of the reoperated patients received round window or intracochlear MedE1 devices. Successful reinsertion of the electrode was performed without significant difficulty, though in some cases osteoneogenesis was found in the round window or in the scala tympani. None of the patients suffered any inner ear abnormalities due to the first implant, and even the patient with a third implant in the same ear had excellent results and obtained better discrimination scores with the new device. In the authors' opinion, on the basis of the accumulated experience of nearly 100 implantations and 15 reoperations, replacement of the early generation extracochlear implants is most advisable and can be accomplished without adverse effects. PMID- 11603764 TI - Petrous apex cholesteatoma. AB - Primary or secondary petrous apex cholesteatoma requires surgical management. We describe here live patients with cholesteatoma in the petrous apex on whom different surgical approaches to this region were used. Translabyrinthine transcochlear (transotic) approach with VII-XII anastomosis was used in four patients. In one patient middle fossa approach with otic capsule and facial canal leaving intact was used. All patients are without recurrence of cholesteatoma with improving of the facial nerve function in one case. We discuss specific pathologies of the petrous apex, the surgical approach to this region indicated according to the size and type of pathology diagnosed, hearing loss and facial nerve function. Possible complications of this surgical procedure and their management are also discussed. PMID- 11603765 TI - Postural behaviour responses to visual stimulation in patients with vestibular disorders. AB - Patients with different vestibular disorders exhibit changes in postural behaviour when they receive visual stimuli, reproducing environmental stimulation. Postural control was studied using an AMTI Accusway platform, measuring the confidential ellipse (CE) and sway velocity (SV). Postural responses were recorded according to the following stimulation paradigm: i) without specific stimuli; ii) smooth pursuit with pure sinusoids of 0.2 Hz (foveal stimulation); and iii) optokinetic stimulation (retinal stimuli). Patients with central vestibular disorders (CVD), cerebellar damage and unilateral peripheral vestibular lesions (UPVL) in asymptomatic periods were studied. A group of normal subjects was studied as control. Signal processing was done with a scalogram by wavelets in order to observe the relation between time and frequency in postural control. While patients with CVD and cerebellar disease showed a significant increase in CE and SV in the three conditions of the paradigm compared to the normal group, the patients with UPVL showed no change. Wavelets processing showed that the main sway occurs in the Y axis (antero posterior) and below at 0.4 Hz in normal subjects, while the CVD and cerebellar patients showed sway frequencies in both the X and Y axes. The clinical implications of these findings are discussed. PMID- 11603766 TI - Influence of gravity on the spatial orientation of eye nystagmus induced by unilateral lesion of horizontal semicircular canal. AB - The influence of gravity in the orientation and slow phase eye velocity of the ocular nystagmus following unilateral damage of the cupula in the ampulla of the horizontal semicircular canal (UHCD) was investigated. The nystagmus was analysed at different sagittal head positions using the x-y infrared eye monitor technique. The nystagmus was almost horizontal at 0 degrees head pitch angle and remained partially fixed in space when the head was pitched upward or downward. The reorientation gain of the slow and quick phases was high (about 0.75) within +/- 45 degrees of head pitch angle, but beyond this range, it decreased greatly. The gain value depended on the lesion extension to otolithic receptors. The absolute value of the slow phase eye velocity of UHCD nystagmus was also modified systematically by the head pitch, showing a reduction in the upward and an increase in the downward. PMID- 11603767 TI - Head-shaking nystagmus (HSN): the theoretical explanation and the experimental proof. AB - Head-shaking nystagmus (HSN) is induced by oscillating the head at high frequency in the horizontal plane. This test is used in the clinic to detect the presence of a unilateral loss of vestibular function. HSN has been described as monophasic with fast-phase direction towards either side, or biphasic with the direction of fast phases reversing after a few seconds. Loss of vestibular function amplifies existing non-linearities in the vestibular system, so that imposed sinusoids can induce biases which are the source of HSN. Fifty-one patients suffering from loss of peripheral vestibular function (43 partial, 11 total unilateral tests) were exposed to whole-body sinusoidal stimulation, with increasing head velocities (90 220 degrees/s) at 1/6Hz, to explore the consistency of per-rotatory induced biases. A bias was induced in all cases, but it wandered on either side, healthy or pathologic, unless test head velocities were larger than approximately 180 degrees/s. Given this condition, the slow-phase bias was located towards the pathologic side for all patients with significant bias ( > 5 degrees/s). These observations demonstrate that the sign and amplitude of the bias is variable and is not correlated with the lesioned side, unless high head velocities are imposed. This explains why the direction of the initial phase of HSN in the clinic seems so labile. Subsequent monophasic or biphasic characteristics of HSN are simply the reflection of interactions between two main time constants associated with "velocity storage" and "gaze holding" in the vestibular central processes. PMID- 11603768 TI - Influence of vibration to the neck, trunk and lower extremity muscles on equilibrium in normal subjects and patients with unilateral labyrinthine dysfunction. AB - To investigate the role of proprioceptors of different skeletal muscles in postural control, in normal subjects and patients with unilateral labyrinthine dysfunction (ULD), the effect of vibration on these muscles was studied by postulography. The subjects comprised 59 normal subjects and 12 patients with ULD due to resection of acoustic tumours. Sagittal body sway was observed during vibration to the triceps surae, tibialis anterior and upper dorsal neck muscles. No significant change in sway was observed in the frontal plane in normal subjects. Significant differences between normal subjects and patients were found on stimulation of the muscle groups of triceps surae and biceps femoris during vibration. In patients with ULD, vibration to the dorsal neck muscles caused a deviation towards the diseased side. It can be speculated that the upper dorsal neck muscle plays an important role in maintaining the body balance in the frontal plane in patients with ULD. On the other hand, the lower extremity muscles, especially the muscles on the dorsal side of the body, play a significant role in adjusting the standing posture in the sagittal plane. PMID- 11603769 TI - Long-term vestibulo-ocular reflex changes in patients with vestibular ablation. AB - Long-term changes in the parameters of the vestibulo-ocular reflex (VOR) were evaluated using recently developed multilevel statistical modelling techniques in a group of patients who had undergone ablative inner ear procedures. Data from 84 patients were available for study. The most dramatic recovery in the VOR occurred during the first 60 postoperative days, however, slow changes continued, levelling off at about 120 days. While frequency was a highly significant predictor of outcomes in all parameters, age showed significant predictive value only to phase measures (p = 0.006) and gender had no effect. Sum gain at the lowest frequency tested remained below the 5th percentile and at the higher frequencies remained below the 50th percentile for normal subjects. Phase decreased exponentially, but remained above the 95th percentile for normal subjects, except at the highest frequency where it remained above the 50th percentile. DC bias decreased exponentially, dropping to the 50th percentile by day 146. Asymmetry stayed between the 50th and 95th percentile, except at the highest frequency, where it was at the 50th percentile by day 125. PMID- 11603770 TI - Compound action potential and cochlear microphonic extracted from electrocochleographic responses to condensation or rarefaction clicks. AB - In electrocochleography (ECochG) compound action potential (CAP) and summation potential (SP) are usually separated from the cochlear microphonic (CM) by the CM cancellation technique consisting in averaging the responses evoked by rarefaction and condensation clicks. With the aim of analysing the ECochG responses evoked by monophasic clicks, we developed a numerical method based on the theory of optimal filtering, which makes no assumptions about the unknown potentials. The application of the filtering technique to the ECochG recordings obtained from 6 normally hearing children and 10 children with cochlear hearing loss allowed us to perform CAP extraction in cases where CM was not cancelled by the conventional method. Differences in SP amplitude and polarity were found between rarefaction and condensation click-evoked responses in cochlear hearing losses. PMID- 11603771 TI - The role of a family history in King Kopetzky Syndrome (obscure auditory dysfunction). AB - King Kopetzky Syndrome (KKS) is a common condition in which individuals with normal audiograms complain of hearing difficulties, particularly in noisy places. Several studies have shown many patients with KKS to have a family history of hearing problems. In 82 consecutive patients with KKS and normal middle ear function, we compared the performance of those with and without a family history of hearing impairment on a number of sensitized tests. Those with a family history were more likely to have notches on Audioscan testing (p < 0.005) and these notches were broader than those found in patients with no family history (p < 0.05). There was also a tendency for those with a family history to be more likely to have notches on DPOAEs (p < 0.07), and the reproducibility of the TOAEs was poorer in those with a family history. Psychological testing showed males with a family history to have higher scores on free-floating anxiety (p < 0.01) and obsessionality (p < 0.05). PMID- 11603772 TI - Auditory neuropathy in children. AB - Auditory neuropathy is a sensorineural disorder characterized by absent or abnormal auditory brainstem evoked potentials and normal cochlear outer hair cell function. A variety of processes is thought to be involved in its pathophysiology and their influence on hearing may be different. We present here the diagnostic sequence and management of two new cases of auditory neuropathy in breastfeeding children. PMID- 11603774 TI - Speech perception performance in prelingually deaf children with cochlear implants. AB - The goals of this study were to report on mean values of speech perception performance in prelingually deaf children implanted with a Combi 40/40 + cochlear implant. A total of 31 patients were included in the study. The time span ranged over 3 years, during which time the Evaluation of Auditory Responses to Speech (EARS) test battery was used with the children. The EARS battery contains four measures of closed-set speech perception and three open-set tests. The mean test results exhibited steady improvement on all parts of the EARS test battery, even up to 3 years post-implantation. The preoperative scores for the Listening Progress Profile (LiP) were 4%, rising to 93% at 36 months post-implantation. Results for the open-set testing measures were most encouraging, with some children reaching fairly high levels of speech perception, receiving scores as high as 100%, by the 36-month evaluation. The congenitally and prelingually deaf children in our study showed continuous improvement in both closed and open set speech perception following cochlear implantation, although variability in individual performance among the children was noted. PMID- 11603773 TI - Long-term outcome of childhood hearing deficiency. AB - This report is based on the questionnaire responses of 95 young hearing-impaired adults (39 with moderate, 20 with severe and 36 with profound hearing loss) who were investigated in the department of paediatric audiology during childhood. Half of the individuals were educated in ordinary school (integration) and half in an institution for hearing-impaired children. Responses on social and professional insertion were compared with audiometric threshold and educational setting. Results indicate that both hearing level and educational environment influence current mode of communication and use of hearing aids. Familial factors also seem to have an influence. Oral communication is a poor predictor of employment, whereas professional qualifications enhance the chances of finding a job. Obtaining a non-professional degree appears to be unsuited for improving the employment rate of the hearing-impaired child. PMID- 11603776 TI - Chinese tonal language rehabilitation following cochlear implantation in children. AB - Cantonese language rehabilitation in 28 prelingually deaf children who underwent cochlear implantation was evaluated. All patients were implanted with multichannel devices and the operations went smoothly. They all had improved scores on audiological assessments and speech perception tests. The speech evaluation tests included the recognition of sounds, vowels, consonants and tone. Sentence recognition and story comprehension were both improved after training for 2 years. Cochlear implantation is a useful measure for the speech rehabilitation of prelingually profound deaf children when hearing aids are of no benefit. The multichannel implant device is of clinical significance in the rehabilitation of those patients using tonal language. PMID- 11603775 TI - Effect of stimulation parameters on electrically evoked auditory brainstem responses. AB - It is evident that the conventional technique for cochlear implant adjustment is not suitable for children in their first years of life. In order to find a solution to this problem, the possibility of electrically evoked auditory brainstem response (EABR) recording was investigated. EABRs were recorded in 9 patients with the Nucleus multichannel cochlear implant. The main problems that have to be solved during EABR recording in cochlear implantees are: i) EABR distortion due to the stimulus artefact: and ii) difference in the stimulus presentation rate during EABR registration (low pulse rate) and conventional psychophysical threshold estimation (high pulse rate) in cochlear implant patients. The influence of stimulus artefact on the recording results was minimized by setting the implant to the widest amplifier frequency band and by zeroing the initial segment containing the stimulus artefact with subsequent zero phase digital filtering. The dependence of the EABR amplitude and latency on the stimulus intensity, width, electrode location and interstimulus interval was investigated. It was concluded that despite the difference revealed between absolute values of EABR thresholds and psychophysical threshold levels, it is possible to calculate implant adjustment parameters based on the EABR data with the proper correction applied. PMID- 11603777 TI - A fractal approach to normal and pathological voices. AB - Using the box-counting method, we demonstrated recently that the stationary signal of vowels is not fractal, but provides the opportunity to design in the smallest scale a kind of signature for each vowel. This fractal approach to these components of speech allows us to quantify the roughness of the voice, between I (sinusoidal complex signal) and 2 (white noise). We used this method to compare these values in normal and pathological voices. We studied the speech of 10 normal speakers, 6 patients suffering from unilateral vocal fold palsy and 6 suffering from various other dysphonias. The meaning of this fractal measurement is discussed and compared with electroglottogram and spectrographic analysis. PMID- 11603778 TI - Organization of tinnitus management in Poland. AB - Spontaneous idiopathic tinnitus is a significant interdisciplinary therapeutic problem. Based on different programs of tinnitus treatment, we organized a team of physicians, psychologists and engineers in order to establish the needs for the first Tinnitus Clinic in Poland. At the same time, together with number of clinical centres, scientific societies and non-governmental organizations, we carried out training and an information campaign throughout the country and initiated the first epidemiological studies survey about tinnitus in Poland. Over a period of 2 years we have provided care for almost 1000 patients, including them in a IS 24-month therapeutic program at the clinic. As a method of choice, Tinnitus Retraining Therapy (TRT) based on a neurophysiological model of tinnitus origin is used. We present here epidemiological data on tinnitus and hyperacusis in Poland. PMID- 11603779 TI - Paradoxical effects of contralateral white noise on evoked otoacoustic emissions in ears with acoustic neuroma. AB - A contralateral suppression effect on evoked otoacoustic emissions (EOAEs) is usually present in normally hearing subjects and in patients with sensorineural hearing loss, while it is absent or reduced in ears to which the vestibular nerve has been cut and in ears with acoustic neuroma (AN). To date, a paradoxical effect, that is an increase in EOAE amplitude during contralateral stimulation, has been described in one ear with sensorineural hearing loss of unknown aetiology and in three ears with AN (two in the present paper). Evidence has been provided that the contralateral suppression effect on EOAEs is accomplished largely, if not entirely, via the medial olivocochlear bundle (OCB). According to clinical data the absence or the reduced amount of contralateral suppression effect on EAOEs may be attributed to a totally, or partially, damaged or malfunctioning medial OCB. The way in which a contralateral noise may increase EOAE amplitude is more difficult to explain. One attractive hypothesis is that this paradoxical effect is a result of some pathological adaptive process in the medial OCB. PMID- 11603780 TI - Can the impact of hearing impairments be modelled? AB - The effects of two simulated hearing impairments (presbyacusis) on speech perception were investigated in two groups of normally hearing subjects (30 and 48 subjects, respectively). Eight patients with presbyacusis with similar hearing impairment to those in the latter simulation served as the clinical material. Word recognition scores were measured in quiet and in cocktail party noise (S/N + 18 dB and + 12 dB). The recognition scores deteriorated in the less favourable listening conditions. Somewhat surprisingly, the hearing impaired subjects showed better word recognition scores in quiet and especially in moderate noise. Subjective complaints on speech perception difficulties in noise on a visual analogue scale behaved quite logically; the hearing impaired subjects' subjective experiences were no milder than those of the normally hearing during the simulation. The better results in word recognition shown by the hearing aid candidates may be explained by habituation to the hearing impairment. PMID- 11603781 TI - Ecological aspects of auditory rehabilitation. AB - Speech and language communication represents an important aspect of interaction between humans and their social environment. In this respect, communication can be analysed in analogy with ecological systems. A conceptual framework based on this analogy has been presented recently and is further developed in this paper. In particular, the consequences for design and accomplishment of auditory rehabilitation are discussed in relation to our own studies. The ecological model contains three levels of interpersonal interaction: signal, message and behaviour, as well as an interaction with the social and physical background. Sensory information is treated in afferent neural systems, processed in language centres and expressed via the vocal system. The communication situation is evaluated and compared with the internal reference "preferendum". The discrepancy between this internal template, a self-image and the perceived reality gives rise to a feedback signal that acts on the components of the communication process within the individual and in the environment, on the one hand, and on the preferendum, on the other. The role of language training, speaking behaviour, meta-communication, e.g. reporting lack of understanding or acknowledging understood messages, are made apparent through an application of the model to rehabilitation. PMID- 11603782 TI - Informational masking in normal-hearing and hearing-impaired listeners. AB - The present study aimed to test whether central, across-channel, informational auditory processing abilities are altered by hearing loss. The informational masking effect exerted on a 1 kHz tone-pip by a simultaneous four-tone masker, whose spectral content changed within as well as across trials, was measured in the left and right ears of normal-hearing subjects and hearing-impaired subjects with either symmetrical or asymmetrical hearing loss between the two ears. In the subjects with normal-hearing or symmetrical hearing loss, the level of the masker was set to 40 dB SL in each ear, in the subjects with asymmetrical hearing loss, the masker was set to 40 dB SL in the best ear and loudness-balanced in the other ear. The results failed to reveal significant differences in informational masking between normal-hearing and hearing-impaired subjects. However, in subjects with asymmetric hearing loss, less informational masking was observed in the ear with the more elevated absolute thresholds than in the opposite ear. Since the latter finding can be explained in terms of across-ear differences in loudness recruitment, it is suggested that central, across-channel, informational processing abilities are not substantially different in hearing-impaired than in normal-hearing ears. PMID- 11603783 TI - Synaptic alterations in the vestibulocerebellar system in Alzheimer's disease--a Golgi and electron microscope study. AB - Alzheimer's disease is one of the main causes of cognitive impairment in the presenium and senium. Despite increased efforts in investigations of the aetiological background of the disease, most of the pathogenetic mechanisms remain unclear. From the morphological point of view, neurofibrillary degeneration and neuritic plaques, the main hallmarks of Alzheimer's disease, are mostly seen in the hippocampus and the cortex of the cerebral hemispheres. In contrast, the cerebellum and brain stem demonstrate minimal aggregates of neurofibrillary tangles. In addition, the neuronal population is better preserved in the cerebellum in contrast to the cortex of the brain hemispheres. In this study we attempted to detect alterations to the synapses in the vestibulocerebellar system, which is better preserved than the other structures in the central nervous system, even in the advanced stages of Alzheimer's disease. The morphological analysis is based on examination of 10 brains via electron microscopy and silver impregnation in the nodule, flocculus and vestibular nuclei. Morphological analysis revealed a limited number of neuritic plaques and minimal neurofibrillary tangles. However, synaptic alterations of the mossy fibres, granule cell dendrites, parallel fibres and Purkinje cell dendritic spines were extensively seen in Alzheimer's brains, in contrast to normal controls. In the granule layer, granule and Golgi cells were considerably decreased in number. The synapses between the mossy fibres and the granule cell dendrites were also decreased. Some of the synapses contained a limited number of polymorphous synaptic vesicles, numerous atypical mitochondria and dense bodies. Most synaptic alterations were in the mossy fibres' presynaptic terminals. The number of synaptic contacts between the mossy fibre terminals and the dendrites of the granule and Golgi cells was dramatically decreased. In the vestibular nuclei, substantial loss of synapses among the local neuronal circuits was also observed. Morphological alterations of the Golgi apparatus were seen in several neurons of the medial and lateral vestibular nuclei. In conclusion, these observations obviously plead in favour of a synaptic pathology among the primary pathogenetic processes in Alzheimer's. PMID- 11603784 TI - Metabotropic transmitter actions in auditory thalamus. AB - Neurons in the ventral partition of the medial geniculate body (MGBv), the primary auditory thalamus, receive afferent input from the inferior colliculus via excitatory glutamate-ergic and inhibitory GABA-ergic input fibres. The feedback from the auditory cortex to the thalamic relay also is mediated via neuron systems using glutamate and GABA as transmitters. We studied effects on excitability mediated by these transmitters via G-protein coupled metabotropic receptors. In a slice preparation of rat thalamus we investigated the membrane responses of MGBv neurons using the whole cell recording technique. Application of a metabotropic glutamate receptor (mGluR) agonist, ACPD (5-100 microM), depolarized MGBv neurons. As a result, the burst mode of firing, which characterizes states of sleep at hyperpolarized potentials was replaced by the tonic mode, which is compatible with sound signal transmission during alertness. The depolarization was caused by an inward current (I(ACPD)) that persisted during blockade of Na+ channels with tetrodotoxin (TTX) and of Ca2+ channels with Cd2+. The I(ACPD) depended, however, on extracellular Na+, which could be replaced with Li+, excluding a major contribution of the Na+/Ca2+ exchange current. ACPD application also inhibited an inwardly rectifying K+ current at hyperpolarized potentials and activated an outward current in the depolarized range. Application of the GABA(B) agonist, baclofen (10 microM), hyperpolarized MGBv neurons by activation of an inwardly rectifying K+ current. The corresponding membrane conductance acted as a powerful shunt that reduced voltage responses and inhibited firing in both the tonic and burst modes. Thus, the effects of GABA(B) receptor activation would suppress auditory signal transfer, whereas mGluR activation enhances excitability, possibly accounting for the alerting effects of certain auditory stimuli. PMID- 11603785 TI - Local haemodynamic changes associated with neural activity in auditory cortex. AB - We used an optical technique to study haemodynamic changes associated with acoustically driven activity in auditory cortex of the chinchilla. Such changes are first detectable c. 0.5 s after stimulation, peak at 2-3 s, and decay within a further 3-6 s. This intrinsic signal imaging reveals activity in separate cortical areas, including primary auditory cortex (AI), secondary auditory cortex (AII) and an anterior auditory field (AAF). We have measured the timing of haemodynamics associated with each area, and find that AI has a different time course from AII and AAF; its haemodynamic change recovers more rapidly. We also show that within AI and AII, place specific activity related to acoustic stimulus frequency can be resolved by this optical imaging method. Our results show the close association between blood flow change and the local metabolic demands of neural activity. The data provide information about the potential of other functional imaging methods (e.g. PET, fMRI) which rely on activity related haemodynamic events. PMID- 11603786 TI - Neuropathology of auditory agnosia following bilateral temporal lobe lesions: a case study. AB - Our patient was first diagnosed with auditory agnosia following his second cerebral vascular accident (CVA) in 1975 when he was 37 years old. Comprehensive follow-up examinations of auditory function were periodically conducted until his sudden death 15 years later. His brain was studied postmortem for neuropathology. Initial pure-tone audiometry revealed moderate sensorineural hearing loss in the right ear and mild sensorineural hearing loss in the left ear. However, repeated pure-tone audiometry revealed that thresholds became progressively poorer over time, bilaterally. Speech audiometry of both ears consistently revealed that the patient was unable to discriminate any monosyllabic words (i.e. speech intelligibility scores were 0%, bilaterally). In general, speech and hearing tests demonstrated that he could not comprehend spoken words, but could comprehend written commands and gestures. Postmortem neuropathological study of the left hemisphere revealed total defect and neuronal loss of the superior temporal gyrus, including Heschl's gyrus, and total gliosis of the medial geniculate body. In the right hemisphere, examination revealed subcortical necrosis, gliosis in the centre of the superior temporal gyrus and partial gliosis of the medial geniculate body. The pathological examination supports clinical results in which the patient's imperception of speech sounds, music and environmental sounds could be caused by progressive degeneration of bilateral medial geniculate bodies. PMID- 11603787 TI - Cortical mechanisms for auditory spatial illusions. AB - Frequency transformation by the external ears provides the spectral cues for localization of broadband sounds in the vertical plane. When human subjects listen to spectrally-impoverished narrowband sounds presented in a free field, the perceived locations vary with the centre frequency and are largely independent of the actual source locations. The present study explored the substrate of spatial illusion by examining the responses of cortical neurons to narrowband stimuli. Single-unit responses were recorded in area A2 of anaesthetized cats. Broadband noise bursts were presented at 14 locations in the vertical median plane, from 60 degrees below the front horizon, up and over the head, to 20 degrees below the rear horizon. Narrowband (1/6-oct) noise bursts were presented at + 80 degrees elevation. An artificial neural network was trained to recognize the spike patterns elicited by broadband noise and, thereby, to register the spike patterns with sound-source elevation. When the trained network was presented with neural responses elicited by narrowband noise, the elevation estimated by the neural network varied with the centre frequency of the narrowband stimuli. Consistent with psychophysical results in human, the locations associated with a given centre frequency could be predicted by comparing the stimulus spectrum with the directional transfer functions of the cat's external ear. The results support the hypothesis that full spike patterns (including spike counts and spike timing) of cortical neurons code information about sound location and that the auditory cortical neurons play a pivotal role in localization behaviour. PMID- 11603788 TI - Inverted papilloma of the nasal cavity and paranasal sinuses: clinical data, surgical strategy and recurrence rates. AB - BACKGROUND: In the last decade inverted papillomas of the nasal cavity and paranasal sinuses have been observed in increasing numbers, and treatment modalities have ranged from extensive open radical procedures to microinvasive endonasal surgical excision. OBJECTIVE: To establish criteria for selecting patients for open osteoplastic or endonasal surgery according to clearly defined pathological and clinical data. MATERIAL AND METHOD: In a retrospective study, clinical data of 55 patients treated surgically in the University ENT Clinic Giessen from 1991 to 1998 were analysed. In 33 patients (60%) endonasal excision of the papillomas was carried out and in 22 (40%) osteoplastic lateral rhinotomy or maxillotomy were performed. All histological specimens were revised. Patients were followed up and endoscopically examined until 31 March 1999. RESULTS: In 22 patients, tumours involving the frontal sinus, maxillary sinus, parts of the frontal skull base and anterior ethmoid, and the orbit were operated on using open osteoplastic procedures, with 4 (18%) recurrences observed. Tumours excised endonasally showed the same recurrence rate: 6 out of 33 (18%). These tumours were smaller in size and localized in the nasal cavity, the middle and posterior parts of the ethmoid involving the sphenoid, and the medio-posterior wall of the maxillary sinus. The functional outcome was excellent for all patients; two patients developed a mucocele. Cancerization was observed in three cases. CONCLUSIONS: In select cases the endonasal microsurgical approach to inverted papillomas has the same good results concerning function and tumour control as osteoplastic open rhinotomy. This method should still be preferred in tumours localized in the frontal sinus, anterior ethmoid. anterior. caudal and lateral parts of the maxillary sinus and beyond the sinuses. PMID- 11603789 TI - Morphometric study of the paranasal sinuses in normal and pathological conditions. AB - Prospective and retrospective morphometric CT (axial and coronal) research was performed with 100 healthy persons and 163 patients (145 males, 118 females, mean age 50 years, range 1-88 years). The patients were classified into the following groups: chronic sinusitis (n = 85), polyposis (n = 25), mucoceles (n = 13), benign tumors (n = 20) and malignant tumors (n = 20). After initial calibration with the scale (in cm) displayed on the CT image, each paranasal sinus was outlined following its bone inner surface. The data were processed with a high resolution analysis system, and volumes were calculated using an integration areas rule. The ethmoid, maxillary and sphenoid sinuses exhibited an increase in volume for a period of up to 15 years, afterwards maintaining similar values. The frontal sinus grows in a monomodal pattern (peak at 30 years). The volumetric results (mean and standard deviation) in the normal adult group were as follows: maxillary sinus 13.07 cm3 (6.8), ethmoid 5.5 cm3 (2.0), sphenoid 3.5 cm3 (2.6) and frontal 3.7 cm3 (3.6). Primary frontal and maxillary sinus hypoplasia appeared in 3.9% and 1.3% of cases, respectively. The anatomic variations were as follows: concha bullosa 8.3%, Haller cells 3.2% and Onodi cells 8.3%. The sinusitis values (adults) were greater than those in the normal group: 14.4 cm3 (7.3), 6.8 cm3 (2.9), 2.9 cm3 (1.9) and 4.2 cm3 (5.2), with the exception of the sphenoid, but the difference was not statistically significant. Finally, we propose a new classification for paranasal sinus tumors (benign and malignant), volumetric T (vT), taking into account the morphometric tumoral volume and the mean volumetric value of normal sinuses. PMID- 11603790 TI - Experimental intravenous inoculation of Klebsiella rhinoscleromatis bacilli in albino rats: a histopathological and bacteriological study. AB - Scleroma, chronic specific granuloma of the nose and upper respiratory tract, is endemic in Egypt and many other countries. The exact pathogenesis of the disease as regards the aetiological role of Klebsiella rhinoscleromatis is contradictory. This work investigated the effect of experimental intravenous injection of K. rhinoscleromatis in albino rats to demonstrate that the micro-organism can fulfil Koch's postulates. Micro-organisms were isolated from biopsy specimens taken from nasal lesions of 10 patients in the granulomatous stage of scleroma. Specimens were subjected to bacteriological and histopathological examinations to confirm the diagnosis. A 100 microl volume of freshly prepared bacterial inoculum containing 10(8) cfu/ml was injected weekly in the tail vein of each of 30 albino rats for 5 consecutive weeks. Biopsy specimens were taken from sacrificed animals and subjected to bacteriological and histopathological examinations. Positive histopathological diagnosis of scleroma was reported in the nose of 66.7% of rats, the larynx of 46.7%, the lungs of 26.7% and liver of 20% of rats. Bacteriological techniques were successful in revealing K. rhinoscleromatis from the nose of 36.7% of rats, the larynx of 30% and the lungs of 20% of rats. Various techniques were carried out to demonstrate the micro-organisms in tissue sections. Two histochemical stains for bacteria were employed: silver and Periodic Acid Schiff (PAS) stains. Immunoperoxidase technique using Klebsiella capsular type 3 antiserum was applied. It gave positive results in 66.7% of the 6 stained liver sections in spite of negative bacteriological cultures. The histiocytic nature of the Mikulicz cells was confirmed using alpha-1 antitrypsin, an immunohistochemical marker of histiocytes, and by studying the ultrastructural features of Mikulicz cells using the transmission electron microscope. PMID- 11603791 TI - Nicotine-induced endocytosis of amiloride-sensitive sodium channels in human nasal epithelium. AB - In previous studies we developed and introduced a method to examine the transport mechanisms of ions in primary cell cultures of human nasal epithelium. In the current study, substances, especially nicotine, that influence these mechanisms are investigated. Specimens of nasal and paranasal epithelium of patients treated by endonasal surgery because of chronic sinusitis (n = 217) were used as primary cell cultures. Cell cultures of smokers (n = 83) and non-smokers (n = 134) were differentiated. Transepithelial Ussing chamber measurements were performed to examine sodium channel functions and to evaluate the influence of nicotine. These examinations were accompanied by simultaneous continuous capacitance measurements. Whereas transepithelial parameters, such as short-circuit current, (Isc), potential (Vt) and resistance (Rt), in tissues derived from smokers and non-smokers showed no difference, the transepithelial conductance was reduced immediately in cell cultures with apical application of nicotine (2 mM). This decrease was accompanied by a marked reduction of epithelial surface area. In the presence of nicotine, amiloride (100 microM) completely lost its inhibitory capacity. Amiloride-insensitive sodium channels were unaffected by nicotine, as proved by Na+ substitution. Furthermore, the Na+ channel blocker was accompanied by an increase in intracellular Ca2+. We conclude that the nicotine-induced increase in intracellular calcium (Ca2+) has stimulated Ca2+-dependent protein kinase (PKC). PKC promotes endocytosis removing amiloride-sensitive Na+ channels from the cell membrane into the cell by means of vesicular transport. PMID- 11603792 TI - Ciliary function analysis for the diagnosis of primary ciliary dyskinesia: advantages of ciliogenesis in culture. AB - The gold standard for the diagnosis of primary ciliary dyskinesia (PCD) is a dynein deficiency shown with transmission electron microscopy. However, there are many cases of PCD without dynein deficiency. When considering ciliary function, there are similar problems of sensitivity in diagnosis and there is also a major lack of specificity. Based on the normal ciliary function and ultrastructure and the absence of secondary abnormalities after ciliogenesis in sequential monolayer suspension culture, the diagnostic value of ciliary function analysis after ciliogenesis was investigated in more than 70 PCD and 640 non-PCD cases. In biopsies, ciliary immotility was found in 66% of PCD cases but was also found in 8% of non-PCD cases. PCD was later confirmed in 61% of the biopsies with ciliary immotility. Normal ciliary beat frequency (CBF) was found in 20% of PCD biopsies. Coordinated ciliary activity was observed in 10% of PCD cases. After ciliogenesis in culture, ciliary immotility was present in 78% of the PCD cases but never in non-PCD cases. CBF was normal after ciliogenesis in 7% of the PCD cases and was always found in non-PCD cases. Absence of coordinated ciliary activity was found in 100% of PCD cases and 0% of non-PCD cases. In conclusion, while ciliary function analysis in a biopsy never proves, nor excludes the diagnosis of PCD, after ciliogenesis in culture CBF measurement can be diagnostic for PCD and reaches 100% specificity and sensitivity when considering coordinated ciliary activity, making it the single 100% diagnostic parameter for PCD. PMID- 11603793 TI - Detection of fungi in sinus fluid of patients with allergic fungal rhinosinusitis. AB - We aim to develop a rapid, accurate and sensitive diagnostic assay with which to detect the surface antigens of fungi thought to be involved in allergic fungal rhinosinusitis (AFRS), by assessing the usefulness of immunofluorescence microscopy (IMF) and enzyme linked immuno-absorbent assays (ELISA). The age, sex, clinical symptoms and signs, imaging (CT and/or MRI), microbiological subculture data, sinus contents, blood eosinophilia, aspergillosis precipitins, radioallergoabsorbent technology (RAST) for fungal allergens and histopathology were performed on individuals undergoing endoscopic sinus surgery for suspected AFRS. Thirteen patients were examined, and five monoclonal antibodies raised to the surface washings of various fungi were found to recognize and differentiate between fungal species implicated in sinus disease, i.e. Aspergillus niger, Alternaria alternata, Cochliobolus lunata, Penicillium expansum and Cladosporium species. The IMF microscopy proved to be a useful assay to distinguish visually between the cultured fungi, but was less useful for visualization of fungi in the patient samples. However, ELISA assays with 5 monoclonal antibodies gave clear and unambiguous data as to the presence of certain fungi within the patient samples. There is good correlation between the ELISA data and the pathology findings. This preliminary study suggests that both IMF and ELISA techniques may offer an important advance in this area. PMID- 11603794 TI - Sniffin'Sticks: a new olfactory test battery. AB - The olfactory test battery "Sniffin'Sticks" comprises a perception threshold test, an odour discrimination test and an odour identification test. The purpose of this study was to examine the suitability of the Sniffin'Sticks for use in everyday practice and to obtain (at least provisional) normal values. Thirty normosmic and 15 anosmic volunteers were examined with the Sniffin'Sticks and the "University of Pennsylvania Smell Identification Test" (UPSIT). All three Sniffin'Sticks tests distinguish between normosmics and anosmics in a highly significant manner. The good correlation of the individual tests with each other and with the results of the UPSIT documents the reliability of the test results. Critical mention must be made of the overly complex determination of the olfactory threshold. In conclusion, the Sniffin'Sticks test battery provides a validated instrument adapted to European conditions for the examination of olfactory disorders. It has proven successful in everyday clinical practice and constitutes a major aid for compiling medical certificates. PMID- 11603795 TI - Capsaicin significantly reduces sinonasal polyps. AB - Some reports indicate that topical nasal treatment with capsaicin, which is usually effective in reducing symptoms of vasomotor rhinitis, may also reduce symptoms in patients with nasal polyps. The aim of this study was to investigate the effect of topical capsaicin treatment in severe sinonasal polyposis. Nine non allergic, non-asthmatic patients with diffuse eosinophilic nasal polyposis were subjected to topical capsaicin treatment: for 3 consecutive days 0.5 ml 30 micromol/l capsaicin solution and on days 4 and 5 100 micromol/l capsaicin solution was sprayed into each nostril. Coronary computed tomography (CT) images were made shortly before treatment. Baseline nasal lavages and a questionnaire containing subjective symptoms and nasal endosocpy were taken just prior to the first application. Nasal lavages were performed prior to and after the last treatment and over 4 weeks, endoscopy and subjective scores at each weekly visit, and correspondent CT scans 4 weeks after the treatment. CT images were analysed by computer, calculating the nose sinuses air volume (NSAV) from the surface of aerated parts of nasal and sinus cavities for each slice per patient prior to and after treatment. Statistical analysis was performed comparing NSAV, subjective scores, endoscopy scores and eosinophil cationic protein (ECP) levels in nasal lavages prior to and after treatment. Topical treatment with capsaicin significantly increased NSAV and very significantly improved subjective and endoscopy scores, but did not significantly alter ECP levels in nasal lavages. PMID- 11603796 TI - Techniques for the improvement of the internal nasal valve in functional-cosmetic nasal surgery. AB - The internal nasal valve (INV) refers to the slit-like region between the caudal end of the upper lateral cartilage (ULC) and the nasal septum. It is the narrowest portion and primary regulator of the nasal airway. Reduction rhinoplasty decreases the nasal airway cross-sectional area and may cause symptoms, unless additional surgical measures are taken. Rhinoplasty or septorhinoplasty was performed for 76 patients with a nasal hump, using an external approach. As a consequence of the nasal hump removal, the ULCs were separated from the septal cartilage. All patients underwent one of the three forms of cartilaginous nasal dorsum reconstruction: primary closure (PC) (50 patients); spreader graft (SG) (19 patients); or upper lateral splay graft (ULSG) (7 patients). At least 3 months postoperatively. INV obstruction was evaluated by asking the patients about nasal obstruction symptoms and visually examining the INV with an otoscope. Nasal obstruction complaints and INV constriction found among patients in the PC. SG and ULSG groups were 16 (32%), 2 (10.5%) and none, respectively. The results of the PC group were compared statistically with the combined results of the SG and the ULSG groups. The patients in the combined SG ULSG group had significantly less nasal obstruction complaints and INV angle constriction compared with the PC group. Due to the higher rate of postoperative INV stenosis. PC should be avoided. The author uses ULSG when the septal cartilage appears straight and sturdy and SGs when the straightened septal cartilage looks weak and vulnerable, since SGs not only improve the INV, but also reinforce the septal cartilage. PMID- 11603797 TI - Smell impairment in workers occupationally exposed to cadmium. AB - ENT and olfactometric examinations were carried out on 73 workers at an electrochemical plant involved in the production of cadmium-nickel batteries, where cadmium fumes were emitted into the workplace. Exposure levels exceeded the maximum allowable concentrations by about 1-2 times. The controls included 43 non exposed, age- and cigarette-smoking-matched people. The olfactometric tests were carried out by the blast injection method, using natural coffee, aniseed, lemon and mint oils; two threshold measurements were assessed: maximum perceptible odour (MPO) and minimum identifiable odour (MIO). In addition, blood chemistries and urinalysis were carried out. The study revealed the smell lesion in 45.2% of the exposed group vs 4.6% of the controls. A statistically significant correlation between olfactory dysfunction and cadmium concentrations in the blood and urine was found; however, no correlation with the duration of employment was observed. It seems most likely that cigarette smoking, which is a considerable source of cadmium, may intensify this dysfunction, hence heavy smokers should not work in conditions of cadmium exposure. PMID- 11603798 TI - Long-term results and reasons for failure of intranasal endoscopic dacryocystorhinostomy. AB - The aim of this study was to evaluate the long-term results and the factors influencing the success in patients with nasolacrimal duct obstruction treated with intranasal endoscopic dacryocystorhinostomy (DCR) and silicone tube intubation (STI). We prospectively investigated 158 patients with lacrimal obstruction in two groups, one of which comprised 108 patients treated primarily with intranasal endoscopic DCR by experienced surgeons and the other comprised 50 patients who were operated on by inexperienced surgeons. In a mean follow-up time of 49 months the surgical success was 94.4% in experienced hands and 58.0% in inexperienced hands. The endoscopic examination of six patients with failure in the first group revealed granulation tissue around the tube in four, atonic sac in one and persistence of bone that was supposed to have been excised in the nasal cavity in one. There were 21 failures out of 50 patients in the second group: granulation tissue in 2 cases, fenestration to the nasolacrimal duct instead of the sac in 6 cases, synechia between the lateral nasal wall and the middle turbinate in 2 cases, bony spicles causing obstruction in 5 cases and fenestration anterior to the sac in 2 cases. In 4 cases no reasons were found for failure, but perhaps the small fenestration and failure to remove the medial half of the membranous sac wall was the reason. DCR and STI can be performed for primary treatment in lacrimal obstruction. There is a learning curve for the operation. False localization of the lacrimal sac, granulation tissue formation around the tubes, retained bony spicles, inadequate removal of the medial wall of the sac and the synechia between the lateral wall and the middle turbinate are the most common causes of failure. PMID- 11603799 TI - Assessment of smell and taste in patients with allergic rhinitis. AB - We examined the senses of smell and taste in 240 patients with verified hypersensitivity reactions of the respiratory tract. Olfactometry was performed according to Elsberg and Levy's method and followed by electrogustometry. The examinations revealed that the incidence of smell and taste disorders in patients with allergic rhinitis is 21.4% and 31.2%, respectively. No significant relationships between smell and taste dysfunction were found. We evaluated statistically positive correlations between the olfactory and gustatory thresholds compared with 78 qualitative and quantitative factors assessed in the study. There was a statistically significant relationship between the olfactory thresholds and levels of eosinophils in blood and in nasal discharge. acid reaction of the nasal mucosa, coexisting nasal polyps and X-ray changes in the ethmoid sinuses. There was a positive influence of pharmacotherapy as well as specific desensitization and surgery on the impairment of the sense of smell in allergic rhinitis. PMID- 11603800 TI - Induction of nitric oxide synthase activity in nucleus ambiguus motoneurons after injury to the rat recurrent laryngeal nerve. AB - Recent studies have implicated nitric oxide (NO) in neuronal degeneration and plasticity in the motor nervous system. In the present study, we investigated the induction of nitric oxide synthase (NOS) in the motoneurons in the nucleus ambiguus (NA) after injury to the rat recurrent laryngeal nerve (RLN) using nicotinamide-adenine-dinucleotide-phosphate-diaphorase (NADPH-d) histochemistry. NADPH-d reactivity was clearly induced in motoneurons in the ipsilateral NA after transection or avulsion of the RLN, compared with control animals. This finding suggests that NO may play an important role in the pathogenesis of RLN paralysis. Another interesting finding in the present study was the induction of NADPH-d reactivity in nerve terminals of the NA after RLN injury. This finding suggests that RLN injury has some effect on nitrergic input to the NA and a direct effect on the motoneurons. PMID- 11603801 TI - Aerodynamic and acoustic parameters in CO2 laser posterior transverse cordotomy for bilateral vocal fold paralysis. AB - The aim of this prospective study was to analyse airway improvement and acoustic and aerodynamic parameters after CO2 laser posterior transverse cordotomy (LPTC) in bilateral vocal fold paralysis (BVFP). Four patients (2 males, 2 females) were recorded pre- and post-operatively at 1, 3, 6, 12 and 24 months. Forced inspiratory volume during the first second (FIV), vital capacity, peakflow, and forced expiratory volume during the first second (FEV) were measured with the Gould II spirometer. Acoustic frequency features (average fundamental frequency, standard deviation, jitter, shimmer and harmonic-to-noise ratio) and speech duration parameters (maximum phonation time, number of words read per minute, and number of words per breath) were measured. Aerodynamic parameters were measured with the Aerophone II. Three tasks were completed. Pneumo-phonatory parameters in "maximum sustained phonation" and in "comfortable phonation", and laryngeal aerodynamic parameters (intraoral air pressure, oral airflow and sound pressure level) were measured non-invasively. Glottal resistance and vocal efficiency were calculated. FIV increased significantly after LPTC (p = 0.01). Postoperatively, frequency features were undetectable by standard commercialized algorithms. Acoustic and aerodynamic parameters improved in the measures obtained at the 6th postoperative month. These results were stable 2 years postoperatively in all cases. We conclude that laryngeal aerodynamic parameters can be used objectively to follow patients longitudinally after LPTC. PMID- 11603802 TI - Fibroblasts in geriatric vocal fold mucosa. AB - Fifty fibroblasts in the macula flava (MF) and 50 fibroblasts in the Reinke's space (RS) of geriatric vocal folds were studied by transmission electron microscopy. Five larynges from autopsy cases in the age range 74-83 years were included in the study. The results were compared with those obtained previously from younger adults. The majority of fibroblasts in RS were spindle-shaped and those in MF were stellate. This was the case with younger adults. The nucleus/cytoplasm (N/C) ratio was 0.5-2.0 in most fibroblasts in RS and MF. Again, this was in common with the findings in younger adults. The development of rough endoplasmic reticulum (rER) and Golgi apparatus (GA) in MF was less marked in the geriatric group than in adults. Glycogen particles were observed in 28 fibroblasts in MF. Lipofuscin granules were found in 12 fibroblasts of RS and 9 cells of MF. The findings suggest a decrease in activities and the presence of ageing processes in fibroblasts of geriatric vocal fold mucosa, to which geriatric changes in the vocal ligament can be attributed. PMID- 11603804 TI - Cerebrovascular damage in young rabbits after intravenous administration of Shiga toxin 2. AB - Acute encephalopathy associated with Shiga toxin-producing Escherichia coli (STEC) primarily affects children. To elucidate the age-dependent vulnerability of the central nervous system (CNS), we injected Shiga toxin 2 (Stx2) intravenously to young rabbits and examined the clinical and pathological effects on the CNS. Although neurological disorders caused by Stx2 were similar between young and adult rabbits, the dose required to produce them in the young was one third of that required for the adults. Vascular lesions appeared as early as 24 h after injection in the young, but not at all in the adult. Arteriolar changes, such as hydropic swelling of the endothelial cells and karyorrhexis of the medial cells, were specific to the CNS of young animals. Evidence for apoptosis of vascular cells was scarce because DNA strand breaks and activation of caspases-3 and -9 were absent in the vast majority. Given our results, we conclude that the cerebral blood vessels of immature brains are more vulnerable to Stx2 than those of adults in the rabbit. PMID- 11603803 TI - CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. AB - Cytosolic Cu/Zn superoxide dismutase (SOD1) is a ubiquitous small cytosolic metalloenzyme, which catalyses the conversion of superoxide anion to hydrogen peroxide. Mutations in the SOD1 gene cause a familial form of amyotrophic lateral sclerosis (fALS). The mechanism by which mutant SOD1s cause the degeneration of motor neurons is not understood. Transgenic mice expressing multiple copies of fALS-mutant SOD1s develop an ALS-like motor neuron disease. Vacuolar degeneration of mitochondria has been identified as the main pathological feature associated with motor neuron death and paralysis in several lines of fALS-SOD1 mice. Using confocal and electron microscopy we show that mutant SOD1 is present at a high concentration in vacuolated mitochondria, where it colocalises with cytochrome c. Mutant SOD1 is also present in mildly swollen mitochondria prior to the appearance of vacuoles, suggesting that the leakage or translocation of mutant human SOD1 in mitochondria may be the primary event triggering their further degeneration. Vacuolated mitochondria containing SOD1 also occur in transgenic mice expressing a high concentration of wildtype human SOD1. In sum, our data suggest that both fALS-mutant and wild-type SOD1 may cross the mitochondrial outer membrane, and by doing so induce the degeneration of these mitochondria. PMID- 11603805 TI - NG2 immunoreactivity on human brain endothelial cells. AB - In this study, we evaluated the expression of NG2 on human brain endothelial cells derived from temporal lobe tissue resected as a treatment for intractable epilepsy. Using dissociated cell cultures, we found expression of NG2 on both proliferating and non-proliferating cells, at the mRNA level by reverse transcription-polymerase chain reaction analyses, and at the protein level by immunocytochemistry and immunoblotting. We further observed that human cerebral microvessels in nonmalignant CNS tissues immunoreacted with NG2. NG2 protein was detected using both a rabbit antibody raised against the rodent NG2 and a monoclonal antibody raised against the human NG2 (9.2.27). Our findings further define the range of resident cells of the CNS that can express NG2 and indicate that expression of NG2 by endothelial cells is not restricted to proliferating CNS endothelial cells or to endothelial cells found in brain tumors. PMID- 11603806 TI - Three-dimensional structures of canine senile plaques. AB - In this study, the three-dimensional structures of two types of canine senile plaques (SP), diffuse plaques (DP) and mature plaques (MP), were compared using a confocal laser scanning microscope. The three-dimensional observation revealed that canine DP were uneven nebula-like assemblies of amyloid-beta (Abeta), while MP were comparatively uniform assemblies of membrane-like or fibrous Abeta materials with some differences among subtypes (primitive, classic and compact). We also noticed the presence of areas with low-density Abeta deposition inside DP and MP, indicating degradation of Abeta. Double staining for Abeta and other SP constituents was also conducted. Amyloid precursor protein (APP) was mainly deposited as rough granules around Abeta assemblies in DP and both inside and around Abeta assemblies in MP. The patten of ubiquitin deposition was quite similar to that of APP. Glial fibrillary acidic protein-positive astroglial projections were found around and inside Abeta assemblies in both types of SP, but were more prominent in MP than DP. DP were often invaded by neurofilament positive neuronal processes (neurites), while no such neurites were observed inside MP. Dystrophic neurites were, however, frequently detected around MP. These results clearly showed that canine DP and MP have completely different three-dimensional structures, consistent with different processes of DP and MP formation. PMID- 11603807 TI - Alpha-synuclein has an altered conformation and shows a tight intermolecular interaction with ubiquitin in Lewy bodies. AB - Alpha-synuclein, a protein in which two mutations have been identified that cause autosomal dominant Parkinson's disease, is thought to serve as a nidus for the development of a Lewy body. We hypothesized that alpha-synuclein would display different intra- and intermolecular associations in Lewy bodies than it does in its normal intracellular compartments. Using sensitive fluorescence resonance energy transfer (FRET) techniques, we found evidence that alpha-synuclein is more compact and in closer association with other alpha-synuclein molecules in Lewy bodies than it is in the neuropil. In addition, we found evidence of a close, direct intermolecular interaction between the N terminus of alpha-synuclein and ubiquitin. These observations provide support for the hypothesis that in Lewy bodies alpha-synuclein adopts an altered three-dimensional structure and undergoes N-terminal ubiquitination. PMID- 11603809 TI - Pathology of the rat vestibular sensory epithelia during subchronic 3,3' iminodipropionitrile exposure: hair cells may not be the primary target of toxicity. AB - 3,3'-Iminodipropionitrile (IDPN) is a neurotoxic compound that causes proximal neurofilamentous axonopathy and loss of the vestibular sensory hair cells. During subchronic exposure, the hair cells are eliminated by extrusion of the virtually intact cell from the sensory epithelia towards the luminal cavity. We describe the alterations of the vestibular epithelia before and during hair cell extrusion. Adult male Long-Evans rats were exposed to 0.2% IDPN in the drinking water for 1, 3, 5, 8 or 14 weeks, or to 0.1% IDPN for 14 weeks. Protrusion and subsequent extrusion of hair cells were observed in the cristae and utricular maculae of rats exposed to 0.2% IDPN for at least 5 weeks. At earlier time points and at lower doses, we observed the following pathological signs: blebbing of hair cells, swelling, retraction and fragmentation of the afferent nerve terminals, detachment of hair cells from the surrounding structures and loss of the pre- and post-synaptic membrane thickenings between hair cells and their afferent terminals. Widespread enlargement of the intercellular spaces also preceded and accompanied the extrusion process. The present data challenge the hypothesis that IDPN specifically affects hair cells. PMID- 11603808 TI - Circulatory disturbance of rat spinal cord induced by occluding ligation of the dorsal spinal vein. AB - Spinal cord infarction can be caused by venous disturbances due to trauma or cancer invasion. However, the precise mechanism of venous infarction is not fully understood. To characterize disorders associated with spinal venous occlusion, we performed time-kinetic pathological analyses of rat spinal cord infarction induced by transdural ligation of the dorsal spinal vein at the levels of the T10 T13 vertebrae. One day after ligation congestion, edema and hemorrhage were observed mainly in the dorsal funiculus. Axons were well preserved, but on the 3rd day axonal degeneration became evident. On the 7th day, the necrotic lesion was confined to the dorsal funiculus and was round in shape with foamy macrophage infiltration and astrocytic gliosis. On the 14th day, the involved cord became atrophic, and infiltration of foamy macrophages and astrocytosis became more prominent. After 21-28 days, the infarction focus decreased in size due to gliosis, and residual macrophages were observed. The main lesion was confined to the dorsal funiculus at all times. However, the severity of the softening varied among rats. Thus, we conclude that the disturbance of venous drainage actually results in spinal cord softening. The variability in the lesions is probably due to the presence of unexpected anastomoses of the spinal venous system. PMID- 11603810 TI - CD34 and dural fibroblasts: the relationship to solitary fibrous tumor and meningioma. AB - Intracranial solitary fibrous tumors (SFTs) are typically dural-based, CD34 positive neoplasms of uncertain histogenesis. We examined ten cases of meninges obtained at autopsy from patients with no history of neurological illness, head trauma, or neurosurgical intervention, and ten cases of typical meningiomas with attached dural margins not involved by tumor. All cases were immunostained with CD34. CD34 reactivity was noted in the long, thin delicate processes of dural fibroblasts preferentially located in the meningeal portion of the dura rather than the periosteal portion. No CD34 reactivity was identified in the arachnoid or pia mater, except in some endothelial cells. One supratentorial dural-based fibrous nodule and one SFT within the confines of the fourth ventricle showed strong and diffuse reactivity to CD34, bcl-2, and vimentin, and were negative for epithelial membrane antigen (EMA), S-100 protein, glial fibrillary acidic protein, smooth muscle actin, and desmin. We also describe a meningothelial meningioma within which a well circumscribed SFT-like nodule was embedded. The SFT-like nodule was strongly CD34 positive and EMA negative, and the meningioma was strongly EMA positive and CD34 negative. Fibroblasts of the dural border cell layer are attached to the underlying arachnoid, and their inclusion with arachnoidal stromal elements and pial-based tela choroidea during formation of choroid plexus interstitium may account for intraventricular SFTs. Our results suggest that SFTs and dural-based fibrous nodules derive from CD34-positive dural based fibroblasts, and that CD34 reactivity in meningiomas may result from inclusion of dural fibroblasts within the neoplasm. PMID- 11603811 TI - Cortical Lewy body pathology in the diagnosis of dementia. AB - Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are distinguishable clinically but often not neuropathologically. This study aims to test whether the distribution of cortical Lewy bodies differs in these clinicopathological groups and to develop diagnostic protocols for their differentiation. Brains were obtained at autopsy from cases recruited from prospective clinical studies of dementia or movement disorders. All cases with significant pathologies other than Lewy bodies or plaques were excluded. Cases were categorised into either PD without dementia, DLB (dementia first or within 2 years of disease onset), or PD with a later onset of dementia (PDD). The distribution and density of Lewy bodies and Lewy neurites was determined using antibodies to ubiquitin and alpha synuclein. Cortical Lewy body densities could not separate cases of DLB from those with PDD. However, semiquantitative thresholds in the parahippocampus could separate demented from non-demented cases with high sensitivity and specificity. Interactions between multiple pathologies were determined using factor analysis. Although many cases had CA2 Lewy neurites, this was not associated with severity or duration of either dementia or parkinsonism. Most DLB cases had significant plaque pathology, and severity and duration of dementia was related to both increasing parahippocampal Lewy body densities and neuritic plaque grade. Weighted kappa statistics revealed that the combination of these pathologies indicated a more severe dementia. These results suggest that dual pathologies cause DLB, and high densities of parahippocampal Lewy bodies indicate dementia regardless of additional pathologies. PMID- 11603812 TI - Correlation between the number of epineurial and endoneurial blood vessels in diseased human sural nerves. AB - In a preceding study it was shown that changes in the number of epineurial blood vessels may be a prominent feature in angiopathic and other peripheral neuropathies, for instance in vasculitis, diabetes mellitus, or cerebral autosomal dominant angiopathy with multiple infarcts and leukoencephalopathy (CADASIL). Endoneurial blood vessels usually may also show significant structural alterations in a broad spectrum of neuropathic conditions, although these are not as prominent as in the epineurium. However, the relationship between changes in the number of epineurial and endoneurial blood vessels in diseased human sural nerves, and the impact of the loss of myelinated nerve fibers on the number of endoneurial blood vessels has thus far not been determined. Therefore, we investigated and compared the number of epineurial and endoneurial blood vessels in 50 human sural nerve biopsy specimens, representing a variety of peripheral neuropathies. We found that despite a significant increase of the number of epineurial blood vessels in cases with vasculitic neuropathy (P<0.05) and neuropathy with other types of microangiopathy (P<0.01), the number and density of the endoneurial blood vessels remained remarkably constant. In cases with an axonal type of neuropathy, severe neuropathic changes were associated with a decreased epineurial blood vessel number and a simultaneous, relative increase in the endoneurial blood vessel density. No significant correlation was found between (1) the number of epineurial and endoneurial blood vessels, and (2) the severity of the neuropathy and the number or density of epineurial and endoneurial blood vessels. PMID- 11603813 TI - Anterior cingulate cortex pathology in schizophrenia and bipolar disorder. AB - To explore possible morphological abnormalities in the dorsal and subgenual parts of anterior cingulate cortex in mood disorders and schizophrenia, we performed a quantitative postmortem study of 44 schizophrenic patients, 21 patients with sporadic bipolar disorder, 20 patients with sporadic major depression, and 55 age and sex-matched control cases. All individuals were drug naive or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Neuron densities and size were estimated on cresyl violet-stained sections using a stereological counting approach. The distribution and density of microtubule-associated (MAP2, MAP1b) and tau proteins were assessed by immunocytochemistry and quantitative immunodot assay. Mean total and laminar cortical thicknesses as well as mean pyramidal neuron size were significantly decreased in the dorsal and subgenual parts of areas 24 (24sg) in schizophrenic cases. Patients with bipolar disorder showed a substantial decrease in laminar thickness and neuron densities in layers III, V, and VI of the subgenual part of area 24, whereas patients with major depression were comparable to controls. Immunodot assay showed a significant decrease of both MAP2 and MAP1b proteins in bipolar patients but not in patients with schizophrenia and major depression. The neuroanatomical and functional significance of these findings are discussed in the light of current hypotheses regarding the role of areas 24 and 24sg in schizophrenia and bipolar disorder. PMID- 11603814 TI - Analysis of the TSC2 gene in human medulloblastoma. AB - Medulloblastoma (MB) represents the most frequent malignant brain tumor of childhood. Recent studies have shown that deregulation of developmental control genes may play an important role in its pathogenesis. Tuberous sclerosis is associated with hamartomas and cortical tubers, consisting of both glial and neuronal cellular components. MBs can also show markers of these lineages, raising the question of the potential involvement of TSC genes in these malignant tumors. Here we investigated tuberous sclerosis 2 (TSC2), one of the two genes responsible for tuberous sclerosis, in sporadic MBs. We analyzed MBs for allelic losses at the TSC2 locus and for the frequency of a polymorphism first described in gangliogliomas. Sixty-eight MBs were examined for this polymorphism located in intron 4, 3 base pairs 5' to the first coding nucleotide of exon 5. The distribution of the alleles was significantly different in MBs as compared to 208 control samples, (P=0.0017, Chi-square test). In MBs the frequency of the rare allele (A2) was 0.184 (18.4%), whereas in the control group it occurred in a frequency of 8.7%. Microsatellite analysis of the TSC2 region in 50 tumors did not identify allelic losses. TSC2 mRNA transcript was detectable via reverse transcription-PCR in all tumors as well as in normal cerebellum. Northern blot analysis of an MB cell line homozygous for the rare allele of the polymorphism and two other cell lines homozygous for the frequent allele revealed normal splicing patterns and normal expression levels of the TSC2 transcript. These findings may indicate that the presence of the rare TSC2 allele is associated with a predisposition for the development of MBs. PMID- 11603815 TI - CCR2A and CCR2B, the two isoforms of the monocyte chemoattractant protein-1 receptor are up-regulated and expressed by different cell subsets in idiopathic inflammatory myopathies. AB - The idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM), polymyosititis (PM) and inclusion body myositis (IBM), are a group of autoimmune diseases characterized by chronic lymphocytic and macrophagic infiltration in muscle. The mechanism for recruitment of these cells probably involves chemokines. We have previously reported that monocyte chemoattractant protein-1 (MCP-1), a beta chemokine, seems to play a major role in mononuclear cell recruitment especially in DM. Here we have investigated the distribution of the main MCP-1 receptors CCR2A and CCR2B in IIM by polymerase chain reaction (PCR), immunohistochemistry and in situ hybridization. We have shown by reverse transcription-PCR that both CCR2A and CCR2B were expressed at low level in normal muscle and that CCR2A was up-regulated in IIM (P=0.02) and was higher in PM and IBM than in DM (P=0.04). By immunohistochemistry and in situ hybridization we have observed that CCR2 isoforms were expressed by different cell subsets in both normal and IIM muscle. CCR2A was expressed in vessel walls and by some mononuclear cells, especially in cells involved in partial invasion in PM and IBM. CCR2B expression was observed in all satellite cells, in the muscular domain of neuromuscular junctions and in some regenerative fibers of IIM, but not in inflammatory exudates. In conclusion, the present study highlights the major role played by MCP-1 and its counter-receptor CCR2 in the pathophysiology of IIM, and shows that the CCR2 receptors are cell specific. The variation of the total amount of CCR2A and its local distribution according to the type of IIM might be a new path towards the understanding of the constitution of mononuclear infiltrates in IIM. PMID- 11603816 TI - Lethal X-linked microcephaly with dysmorphic features, bilateral optic pathway aplasia and normal eyes. AB - We describe a family, consisting of two brothers and a maternal uncle who died of an apparently identical condition, within a few days of birth, suggestive of an X linked mode of inheritance. The propositus (the older sibling) was investigated in detail and showed the following clinical features: microcephaly, facial dysmorphism, malformations of hands and feet, and cryptorchidism. Examination of the brain revealed arhinencephaly, a primitive gyral pattern, arrested cortical maturation, absence of corticofugal tracts and corpus callosum, agenesis of the optic pathway with preserved eyes and oculomotor system, absent auditory pathway, agenesis of the pars compacta of the substantia nigra and severe hypoplasia of the cerebellum and its connections. This family belongs to the group of X-linked microcephalies and has some features in common with the Juberg-Marsidi syndrome. The fact that the CNS abnormalities were incompatible with life and the facial dysmorphic features were quite different makes it unlikely that the affected individuals in this family had Juberg-Marsidi syndrome. However, this does not exclude the possibility that more restricted anterior induction defects may occur in some X-linked microcephalies such as Juberg-Marsidi syndrome resulting in prolonged survival. PMID- 11603818 TI - Clear cell pleomorphic xanthoastrocytoma: case report. AB - Pleomorphic xanthoastrocytoma (PXA) is a well-described astrocytic neoplasm with distinctive clinical and pathological features. Although most patients with PXAs are cured by surgical excision, other patients experience malignant progression and tumor recurrence. We describe a 47-year-old woman with a left temporal lobe PXA that had classic histopathological characteristics as well as extensive clear cell and focal papillary changes, and some anaplastic findings. The patient has now suffered two recurrences after complete resection. The case illustrates a rare, previously undescribed histological variant of PXA, with a prominent clear cell and focal papillary morphology. The study of histologically similar cases is needed to determine whether this variant is always associated with a greater likelihood of recurrence. PMID- 11603817 TI - Cushing's disease due to plurihormonal adrenocorticotropic hormone and gonadotropin-producing pituitary adenoma. AB - A 67-year-old woman presented with clinical features of hypercortisolism in association with an invasive pituitary macroadenoma. Adrenocorticotropic hormone (ACTH)-dependent Cushing's disease was documented, and the resected tumor was chromophobic, weakly positive with periodic-Schiff reagent, and showed immunostaining for ACTH and beta-endorphin in a minority of adenoma cells. Both luteinizing hormone and alpha-subunit staining were also observed, but no follicle-stimulating hormone reactivity was seen. Ultrastructurally, the tumor showed typical features of a gonadotroph adenoma of female type. Immunoelectron microscopy showed that ACTH was not produced in corticotrophs, but in cells with the characteristic features of gonadotrophs. This represents the second report of a plurihormonal gonadotroph adenoma producing sufficient ACTH to result in pituitary-dependent Cushing's disease. PMID- 11603819 TI - Anti-myelin-associated glycoprotein antibodies and endoneurial cryoglobulin deposits responsible for a severe neuropathy. AB - A 73-year-old man was investigated for a peripheral neuropathy which occurred in the course of a Waldenstrom's macroglobulinemia. Serum immuno-fixation electrophoresis demonstrated two IgM monoclonal gammopathies of the kappa and lambda chain isotypes, and one had the physical characteristics of cryoglobulin. Immunoblot studies on the patient's serum revealed antibodies which reacted with peripheral nervous system proteins of different molecular weights including the myelin-associated glycoprotein (MAG). An immunofluorescence study of a superficial peroneal nerve biopsy revealed not only a binding of IgM and kappa light chain on several myelin sheaths but also the presence of IgM and kappa light chain deposits in the endoneurium. On electron microscopic examination, numerous fibres presented a widely spaced myelin and the endoneurial deposits had the ultrastructure of cryoglobulin. This is the first case presenting features of widely spaced myelin related to serum anti-MAG activity associated with monoclonal cryoglobulin deposits in the endoneurium. PMID- 11603820 TI - Elimination of mercury from amalgam in rats. AB - The aim of this study was to measure the urinary mercury excretion in rats exposed to amalgam over a two months period. Animals were either exposed to mercury from 4 dental amalgams or fed the diet containing powdered amalgams. The results showed significantly higher mercury amount in urine of both exposed groups than in control. Even two months after the amalgam had been placed in rats teeth, the amount of mercury in the urine remained 4-5 times higher than in control, and 4 times higher than in rats exposed to diet containing powdered amalgam. The elevated urinary Hg amount was accompanied by an increased level of total protein in urine. In the same exposure period the excretion of total protein in urine of rats with amalgam fillings was 2 times higher than in control and 1.5 times higher than in rats exposed to amalgam through diet. Concentrations of mercury in the sera of all groups were below the detection limit of the method. The results show that amount of mercury and protein in the urine of rats were related to the mercury release from dental malgam. PMID- 11603821 TI - Changes in selenium, zinc, copper and cadmium contents in human milk during the time when selenium has been supplemented to fertilizers in Finland. AB - Sodium selenate has been supplemented to all agricultural fertilizers used in Finland since 1984. We followed the changes in selenium, cadmium, zinc and copper content in Finnish human milk between the years 1987 and 1993-1995. A total of 257 milk samples was collected, four weeks after delivery, in two areas: In Helsinki, an urban area, and in Kuopio, a rural area, where elevated copper concentrations have been found in the bedrock. Direct atomic absorption spectrophotometric methods without digestion were used for the analyses. The dependence of trace element content on study time, living area, smoking habits, fish eating frequency, and parity of mothers was studied by analysis of covariance. Inter-element correlations and correlations with mothers' age and fat content in milk were studied by partial correlation. Significant increases were observed in mean selenium (16.4 microg/l and 18.9 microg/l, p < 0.001) and in fat contents (3.4% and 4.0%, p < 0.001), whereas significant decreases were seen in mean zinc (3.00 mg/l and 1.47 mg/l, p < 0.001), copper (0.52 mg/l and 0.43 mg/l, p < 0.001) and cadmium contents (0.095 microg/l and 0.062 microg/l, p < 0.01). In 1987, zinc had a positive correlation with copper and fat. Copper correlated inversely with the mothers' age. In 1993-1995, selenium correlated positively with copper, and zinc correlated inversely with mothers' age. Mothers living area had an effect on copper content in milk. Our results confirm that selenium supplementation to fertilizers in Finland has increased the selenium level in human maternal milk and most likely it also has an effect on the zinc and copper concentrations in maternal milk. PMID- 11603822 TI - Effects of type of fat in the diet on iron bioavailability assessed in suckling and weanling rats. AB - Differences in iron bioavailability from human milk and milk formulas may in part be due to differences in lipid composition. We investigated the short and long term effects of diets based on different fats [corn, coconut, olive, or soy oil, human milk fat (HMF) and a formula fat blend (FF)] on iron absorption in rats. Suckling rat pups dosed with 59Fe-labeled diets containing different fat sources were killed after 6 h, and blood and individual tissues were counted. Iron availability was estimated by % 59Fe in blood. Pups dosed with a more saturated fat (coconut oil) had a higher % 59Fe in blood than those fed other fat sources. Weanling rats were used to determine iron bioavailability from fat sources using both the hemoglobin repletion method and whole body counting. Hemoglobin regeneration was significantly higher for rats fed the HMF diet (8.4 +/- 0.5 g/dl) than from the FF diet (6.5+/-0.6 g/dl) or the corn oil diet (less saturated) (6.4 +/- 0.3 g/dl). Rats fed diets based on coconut oil (more saturated) had significantly higher % 59Fe retention (61.6 +/- 1.4) than rats fed diets based on FF (49.8 +/- 3.4). There was a significant positive association between oleic acid in the diet and oleic acid in the intestinal mucosa (r = 0.95, p < 0.05) and between linoleic acid in the diet and linoleic acid in the intestinal mucosa (r = 0.97, p < 0.05) suggesting that the dietary treatment altered the fatty acid composition of the brush border membrane. Our results suggest that saturated fats may increase iron absorption and that part of this may be achieved by changes in the fatty acid composition of the intestinal mucosa. Hemoglobin regeneration and % 59Fe retention data suggest that differences in iron absorption from infant diets may in part be due to differences in fat composition. Therefore, lipid composition of infant formulas should also be taken into consideration as a factor influencing iron bioavailability. PMID- 11603823 TI - Relation between serum lipoperoxide concentrations and iron or copper status over one year in Cuban adult men. AB - The aims of this study were to determine the relations between iron and copper status and lipid peroxidation at different periods over one year in low-income and low-energy intake healthy subjects. The study was conducted in 199 middle aged healthy Cuban men from March 1995 to February 1996. Iron status was assessed by the determination of serum ferritin, transferrin saturation, whole blood hemoglobin and iron intakes. Copper status was evaluated by the determination of serum copper and copper intakes. Serum thiobarbituric acid substances (TBARS) determination was used as an index of lipid peroxidation. Rank correlations were observed between serum TBARS concentrations and iron or copper status indices at different periods. In period 3 (end of the rainy season), serum TBARS and ferritin concentrations were maximum whereas blood hemoglobin levels and iron intake were minimum. Serum TBARS concentrations were significantly higher than the reference values of the laboratory whereas, iron and copper status were within the reference ranges. These results suggested that iron and copper status may be associated with lipid peroxidation in subjects without metal overloads and that variations over the year needed to be taken in account. PMID- 11603824 TI - Leucocyte copper, a marker of copper body status is low in coronary artery disease. AB - To elucidate the relationship between leucocyte copper as a reliable, sensitive index of copper body status and extent of atherosclerosis in patients with Coronary Artery Disease (CAD) the present case-control study was carried out. 80 subjects were studied (23 females and 57 males), aged between 30-70, due to have a angiography. Individual angiograms were scored by combining the individual scores in all the major coronary arteries into one score of a scale 1.00 for patency to 0.00 for severe CAD. Serum and leucocyte copper and zinc were determined by GFAAS. No significant difference between patients with advanced CAD and relatively normal arteries were observed in the lipid profile and levels of plasma copper. Leucocyte copper had a significant link with the severity of atherosclerosis which was independent of sex. There was a linear relationship between the degree of decreasing leucocyte copper concentration and angiogram score. These findings give support to the hypothesis that marginal copper status, assessed by decreased leucocyte copper level, is associated with developing CAD. PMID- 11603825 TI - A search for calcium, magnesium and zinc levels in fingernails of 135 patients with osteogenesis imperfecta. AB - Calcium (Ca), magnesium (Mg) and zinc (Zn) levels of fingernails were measured in 135 patients with osteogenesis imperfecta (OI) and compared with the sex- and age matched healthy controls. Zinc levels in OI nails were significantly higher than that in normal subjects, but in cases and controls Ca and Mg levels were not significantly different. The ratios of Ca/Zn and Mg/Zn in OI nails differed significantly from those in controls, but a similar Ca/Mg ratio was found in nails of both groups. These results suggest that Zn levels in fingernails may reflect abnormal Zn metabolism in OI. To determine Zn metabolism changes in OI, further studies are needed. PMID- 11603826 TI - Assessment of the contamination from devices used for sampling and storage of whole blood and serum for element analysis. AB - An assessment of potential contamination risk associated with devices routinely used in hospitals and clinical laboratories for sampling and storage of whole blood and serum was made by analysis of leachates from the devices. The devices checked were disposable stainless steel needles, different types of blood collection tubes; serum separation tubes, disposable plastic pipettes and plastic vials used for serum storage. Concentrations of about 70 elements in solution after leaching with 0.05 mol l(-1) HNO3 were determined by double focusing sector field inductively coupled plasma mass spectrometry (sector field ICP-MS). For the elements present in blood/serum at concentrations higher than 10 ng ml(-1) (Na, Ca, Mg, P, Fe, Br, Si, Zn, Cu, Rb, Se and I) contribution from devices was as a rule negligible (less than 1% of expected concentrations in the body fluids), but for the majority of trace and ultra-trace elements it may significantly affect or even prevent accurate determination. The highest trace element contribution was found to derive from commercially available blood collection and serum separation tubes. Apparent concentrations of Al, Ba, Th, rare earth, and some other elements resulting from contamination were higher than normal serum concentrations all types of tubes tested for. PMID- 11603827 TI - Elemental anomalies in hair as indicators of endocrinologic pathologies and deficiencies in calcium and bone metabolism. AB - Analytical results obtained by ICP-MS of hair samples from a group of women from Rio de Janeiro city show that abnormal Ca and P concentrations in this compartment can be an indication of pathologies affecting the metabolism of these elements. The study was conducted initially on 900 women (outpatients, >40 years). From this group, approx. 24% showed anomalously high or low Ca concentrations in hair, in some cases correlated to anomalies of other elements. In 144 cases (16%), very high concentrations of Ca (up to 8,285 mg/kg) were measured, frequently correlated with a high concentration of P (up to 4,720 mg/kg), exceeding by far the reference intervals for this age/sex group. Follow up studies of a few individuals from this group gave first indications that their abnormal hair compositions were related to endocrinologic pathologies affecting calcium/bone metabolism. Very low hair Ca-concentrations were observed in older women (72 cases, age >60 years) and related to senile osteoporosis. Complementary investigations of patients with recognized endocrinologic pathologies (hyperthyroidism, hyper- and hypoparathyroidism) and osteomalacia gave statistical support for the hypothesis that hair concentrations of Ca, P and various other trace elements are influenced characteristically by these diseases. In patients with hyperparathyroidism and hyperthyroidism, both elements showed significant increase in hair, whereas patients with rickets/osteomalacia had only elevated Ca concentrations, together with suspiciously high toxic levels of Cd and various other elements (Fe, Mn, Mg, Sr, Ba). Patients with hypoparathyroidism had significantly decreased Ca and P concentrations in hair. Statistical evaluation of these data by multivariant analysis (MANOVA) using a contrast matrix and by discriminant analysis showed that elemental hair anomalies can be used to diagnose correctly the above-mentioned pathologies, demonstrating the usefulness of hair analysis as a complementary tool for the detection of disturbances in calcium/bone metabolism. PMID- 11603828 TI - Zinc intervention on macrophages and lymphocytes response. AB - Normal zinc levels are essential for the development and maintenance of immune functions; Zn deficiency is detrimental to the embryo and offspring of experimental animals, especially concerning immune development. It is known that Zn supplementation improves immune responses. To further explore the relation between Zn administration and the metal in vitro effects, we studied zinc (500 mg/l) supplementation impact on lymphocytes and macrophages and zinc in vitro effects, in BALB/c mice supplemented from gestation to lactation. Results show a significant increase in proliferation (assessed by 3H incorporation) in lymphocytes exposed to Zn (0.1 mM) in vitro, in 3-wk-old mice; this effect is annulled when the supplementation period is lengthened, indicating saturation of the mechanisms involved in zinc induced stimulation. Macrophages functional capacity assessed by erythrophagocytosis was also improved by Zn supplementation and furthermore by the in vitro exposure to the metal, in mice 3 wk old, this was also depressed by Zn accumulation due to the supplementation period extension (9 weeks). Results show an improvement in the immune parameters analysed due to zinc supplementation and to zinc in vitro exposure. Results also suggest the accumulation of zinc as a result of prolonged supplementation periods, suppresses the cells response to zinc in vitro. PMID- 11603830 TI - Trace elements concentrations from papio hamadryas teeth sequences. PMID- 11603829 TI - A simplified method for determination of radioactive iron in whole-blood samples. AB - For studies on iron absorption in man radioisotopes represent an easy and simple tool However, measurement of the orbital electron emitting radioiron, 55Fe, in blood is difficult and insufficiently described in the literature. The present study describes a relatively simple method for simultaneous determination of 55Fe and 59Fe in blood, using a dry-ashing procedure and recrystallization of the remaining iron. The detection limit of the method permits measurements of 0.1 Bq/ml blood thus allowing detection of less than 1% absorption from a 40 kBq dose, which is ethically acceptable in humans. The overall recovery of radioiron from blood is more than 90%, and the coefficient of variation, as judged by the variation in the ratio 55Fe/59Fe is in the order of 4%. Combined with whole-body counting of 59Fe and direct gamma-counting of 59Fe on blood samples, this method represents a sensitive method for studying the intestinal absorption of 55Fe and 59Fe in man and at the same time allows estimation of the amount of radioiron located in the vascular compartment. PMID- 11603832 TI - Gabriel Bertrand: a life devoted to trace elements! Awarding of the Gabriel Bertrand Medal to Thressa C. Stadtman under the auspices of FESTEM. PMID- 11603833 TI - Triplet states as non-radiative traps in multichromophoric entities: single molecule spectroscopy of an artificial and natural antenna system. AB - Energy transfer in antenna systems, ordered arrays of chromophores, is one of the key steps in the photosynthetic process. The photophysical processes taking place in such multichromophoric systems, even at the single molecule level, are complicated and not yet fully understood. Instead of directly studying individual antenna systems, we have chosen to focus first on systems for which the amount of chromophores and the interactions among the chromophores can be varied in a systematic way. Dendrimers with a controlled number of chromophores at the rim fulfill those requirements perfectly. A detailed photophysical study of a second generation dendrimer, containing eight peryleneimide chromophores at the rim, was performed 'J. Am. Chem. Soc., 122 (2000) 9278'. One of the most intriguing findings was the presence of collective on/off jumps in the fluorescence intensity traces of the dendrimers. This phenomenon can be explained by assuming a simultaneous presence of both a radiative trap (energetically lowest chromophoric site) and a non-radiative trap (triplet state of one chromophore) within one individual dendrimer. It was shown that an analogue scheme could explain the collective on/off jumps in the fluorescence intensity traces of the photosynthetic pigment B-phycoerythrin (B-PE) (Porphyridium cruentum). The different values of the triplet lifetime that could be recovered for a fluorescence intensity trace of B-PE were correlated with different intensity levels in the trace, suggesting different chromophores acting as a trap as function of time. PMID- 11603834 TI - A new analysis method of single molecule fluorescence using series of photon arrival times: theory and experiment. AB - Up to now, single molecule fluorescence experiments were performed by dividing the time into a set of intervals and to observe the number of fluorescence photons arriving in each interval. It is obvious that the detected photons carry less information than the arrival times of the photons themselves. From the arrival times, one can still calculate the number of photons in any user-defined interval; whereas, when only the number of photons in an interval are recorded, information about their positions in time is lost. Therefore, we present a new analysis method of single molecule fluorescence data based on the positions in time of the detected fluorescence photons. We derive mathematically different statistical characteristics describing the single molecule fluorescence experiment assuming an immobilized molecule. The theory of point processes using the generating functionals formalism is ideally suited for a consistent description, linking the statistical characteristics of the excitation and detected photons to the statistical characteristics of the single motionless molecule. We then use computer-generated data sets mimicking the single molecule fluorescence experiment to explore the parametric estimation of mono- and bi exponential single molecule impulse response functions (SMIRFs) via the following statistical characteristics: the probability density distributions (pdd) of the single and first photocount time positions in a user-defined detection interval, the probability distribution of the number of photocounts per user-defined detection interval, the time correlation function and the pdd of the time interval between two consecutive photocounts. It is shown that all of the above characteristics ensure a satisfactory recovery of the decay time of mono exponential SMIRFs for a broad range of excitation intensities and widths of user defined detection intervals. For bi-exponential SMIRFs, the selection of the experimental conditions is more critical and dependent on the detection procedure. At lower excitation intensities it is advantageous to use the pdds of the single and first photocount time occurrences in the user-defined detection interval. To show the practical usefulness of the new analysis method, series of photon arrival times from immobilized single molecules of DiI and rhodamine 6G were analyzed to estimate triplet lifetimes and intersystem crossing yields. PMID- 11603835 TI - Fluorescence correlation spectroscopy of flavins and flavoenzymes: photochemical and photophysical aspects. AB - Fluorescence Correlation Spectroscopy (FCS) was used to investigate the excited state properties of flavins and flavoproteins in solution at the single molecule level. Flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD) and lipoamide dehydrogenase served as model systems in which the flavin cofactor is either free in solution (FMN, FAD) or enclosed in a protein environment as prosthetic group (lipoamide dehydrogenase). Parameters such as excitation light intensity, detection time and chromophore concentration were varied in order to optimize the autocorrelation traces. Only in experiments with very low light intensity ( < 10 kW/cm2), FMN and FAD displayed fluorescence properties equivalent to those found with conventional fluorescence detection methods. Due to the high triplet quantum yield of FMN, the system very soon starts to build up a population of non-fluorescent molecules, which is reflected in an apparent particle number far too low for the concentration used. Intramolecular photoreduction and subsequent photobleaching may well explain these observations. The effect of photoreduction was clearly shown by titration of FMN with ascorbic acid. While titration of FMN with the quenching agent potassium iodide at higher concentrations ( > 50 mM of I-) resulted in quenched flavin fluorescence as expected, low concentrations of potassium iodide led to a net enhancement of the de-excitation rate from the triplet state, thereby improving the fluorescence signal. FCS experiments on FAD exhibited an improved photostability of FAD as compared to FMN: As a result of stacking of the adenine and flavin moieties, FAD has a considerably lower triplet quantum yield. Correlation curves of lipoamide dehydrogenase yielded correct values for the diffusion time and number of molecules at low excitation intensities. However, experiments at higher light intensities revealed a process which can be explained by photophysical relaxation or photochemical destruction of the enzyme. As the time constant of the process induced at higher light intensities resembles the diffusion time constant of free flavin, photodestruction with the concomitant release of the cofactor offers a reasonable explanation. PMID- 11603836 TI - A biomimetic approach to artificial photosynthesis: Ru(II)-polypyridine photo sensitisers linked to tyrosine and manganese electron donors. AB - The paper describes recent advances towards the construction of functional mimics of the oxygen evolving complex in photosystem II (PSII) that are coupled to photoinduced charge separation. Some key principles of PSII and artificial systems for light-induced charge accumulation are discussed. Systems are described where biomimetic electron donors--manganese complexes and tyrosine- have been linked to a Ru(II)-polypyridine photosensitiser. Oxidation of the donors by intramolecular electron transfer from the photo-oxidised Ru(III) complex has been studied using optical flash photolysis and EPR experiments. A step-wise electron transfer Mn(III,III)-->tyrosine Ru(III) has been demonstrated, in analogy to the reaction on the donor side of PSII. Electron transfer from the tyrosine to Ru(III) was coupled to tyrosine deprotonation. This resulted in a large reorganisation energy and thus a slow reaction rate, unless the tyrosine was hydrogen bonded or already deprotonated. A comparison with analogous reactions in PSII is made. Finally, light-induced oxidation of a manganese dimer linked to a Ru(II)-photosensitiser has been observed. Preliminary results suggest the possibility of photo-oxidising manganese dimers in several steps, which is an important advancement towards water oxidation. PMID- 11603837 TI - Flipping the light switch 'on'--the design of sensor molecules that show cation induced fluorescence enhancement with heavy and transition metal ions. AB - Real-time and real-space analysis of heavy and transition metal ions employing fluorescent sensor molecules has received much attention over the past few years. Since many of these cations possess intrinsic properties that usually quench the fluorescence of organic dye molecules, a lot of research has lately been devoted to designing fluorescent probes that show complexation-induced fluorescence enhancement. Such an analytical reaction would be highly desirable in terms of increased sensitivity and selectivity. However, in this particular field of sensor research, the photophysical and photochemical mechanisms involved as well as the chemical constitutions of the sensor molecules employed are rather diverse and up to now, very few attempts have been made to establish some general concepts for rational probe design. By analyzing various systems published by other researchers as well as own work, this contribution aims at an elucidation of some of the underlying principles of heavy and transition metal ion-enhanced emission. PMID- 11603839 TI - Control of electron transfer in supramolecular systems. AB - The fluorescence quantum yield of zinc porphyrin (ZnP) covalently linked to 9,10 bis(phenylethynyl)anthracene (AB) is strongly dependent upon the solvent properties. The bichromophoric system ZnP-AB exhibits 'normal' zinc porphyrin fluorescence in solvents that cannot coordinate to the central zinc atom. In contrast, if a Lewis base, such as pyridine, is added to a sufficiently polar solvent, the fluorescence is significantly quenched. Picosecond transient absorption measurements, in conjunction with fluorescence quenching and cyclic voltammetric measurements, suggest that the quenching mechanism is intramolecular electron transfer from ZnP to AB. The charge separated state. ZnP*+-AB*-, has a lifetime of not more than 220 ps before recombining. If a secondary electron acceptor, iron(III) porphyrin (FeP), is covalently connected to the AB unit, a second electron transfer from AB*- to FeP occurs and the charge separated state, ZnP*+-AB-FeP*-, has a lifetime of at least 5 ns. This demonstrates that electron transfer might be sensitively tuned (switched on) by specific solvent effects. PMID- 11603838 TI - Homogeneous time resolved fluorescence resonance energy transfer using rare earth cryptates as a tool for probing molecular interactions in biology. AB - A homogeneous assay technology using time resolved fluorescence and fluorescence resonance energy transfer is described. A new class of fluorescent complexes, the cryptates, have been used as fluorescent donor with cross-linked allophycocyanin as acceptor. This new donor/acceptor shows an exceptionally high Forster distance R0 of 9 nm. This allows to build up a set of strategies to probe the interactions of biomolecules in biology, particularly for high throughput screening applications. In this article, we describe the basics of the technology and review applications developed for studying different key molecular interactions involved in cellular processes. PMID- 11603841 TI - Molecular distribution sensing in a fluorescence resonance energy transfer based affinity assay for glucose. AB - A newly developed method for determining molecular distribution functions is applied to a widely researched glucose affinity sensor. The reduction in fluorescence resonance energy transfer (FRET) to a malachite green (MG)-dextran complex from allophycocyanin (APC) bound to concanavalin A (ConA) due to displacement of the complex by glucose from ConA provides the basis of the assay. The higher sensitivity and specificity of a new approach to fluorescence decay analysis, over the methods based on conventional Forster-type models, is demonstrated and critical parameters in competitive binding FRET sensing derived. PMID- 11603840 TI - Charge-transfer emission of compact porphyrin-fullerene dyad analyzed by Marcus theory of electron-transfer. AB - A porphyrin-fullerene dyad, which is characterized by a close proximity of the porphyrin donor and the fullerene acceptor, was found to undergo a photoinduced electron transfer both in solutions and in solid films. Near-infrared charge transfer (CT) emission was observed and analyzed in frame of the semi-classical Marcus electron-transfer theory yielding values for the reaction free energy, deltaG degrees = 1.75 eV, the internal reorganization energy, lambdav = 0.05 eV, and the donor-acceptor vibrational energy, hv(v) = 0.14 eV, both in solution and in solid film. The influence of the environment on the CT properties of the dyad is described by a single parameter, the outer-sphere reorganization energy, lambdas, which varies from 0.05 eV in non-polar solvents and films to 0.13 eV in solvents of moderate polarity. At low temperatures (T< 200 K), the CT emission consists of distinct bands shifted from each other by value hv(v). This is the first direct observation of the vibrational frequencies of a porphyrin-fullerene donor-acceptor system. PMID- 11603842 TI - The analysis of time resolved protein fluorescence in multi-tryptophan proteins. AB - In the last decades, considerable progress has been made in the analysis of the fluorescence decay of proteins with more than one tryptophan. The construction of single tryptophan containing proteins has shown that the lifetimes of the wild type proteins are often the linear combinations of the family lifetimes of the contributing tryptophan residues. Additivity is not followed when energy transfer takes place among tryptophan residues or when the structure of the remaining protein is altered upon the modification. Progress has also been made in the interpretation of the value of the lifetime and the linkage with the immediate environment. Probably all the irreversible processes leading to return to the ground state have been catalogued and their rate constants are documented. Also, the process of electron transfer to the peptide carbonyl is becoming more and more documented and is linked to the rotameric state of tryptophan. Reversible excited state processes are also being considered, including reversible interconversions between rotamers. Interesting information about tryptophan and its environment comes also from anisotropy measurements for proteins in the native, the denatured and the molten globule states. Alterations of protein fluorescence due to the effects of ligand binding or side chain modifications can be analyzed via the ratio of the quantum yields of the modified protein and the reference state. Using the ratio of quantum yields and the (amplitude weighted) average lifetime, three factors can be identified: (1) a change in the apparent radiative rate constant reflecting either static quenching or an intrinsic change in the radiative properties; (2) a change in dynamic quenching; and (3) a change in the balance of the populations of the microstates or local static quenching. PMID- 11603843 TI - New fluorescent markers for the red region. AB - Two new classes of fluorescent dyes have been developed as labels for the red region of the spectrum: amide-bridged benzopyrylium dyes and carbopyronin dyes. The fluorescence quantum yield ranges from 20 to 90%, the decay time from 1 to 4 ns. The pH- and solvent-dependence of absorption and fluorescence are described in detail. Covalent attachment is possible via activated carboxyl groups. PMID- 11603844 TI - Fluorescent carbohydrate probes for cell lectins. AB - Fluorescein labeled carbohydrate (Glyc) probes were synthesized as analytical tools for the study of cellular lectins, i.e. SiaLe(x)-PAA-flu, Sia2-PAA-flu, GlcNAc2-PAA-flu, LacNAc-PAA-flu and a number of similar ones, with PAA a soluble polyacrylamide carrier. The binding of SiaLe(x)-PAA-flu was assessed using CHO cells transfected with E-selectin, and the binding of Sia2-PAA-flu was assessed by COS cells transfected with siglec-9. In flow cytometry assays, the fluorescein probes demonstrated a specific binding to the lectin-transfected cells that was inhibited by unlabeled carbohydrate ligands. The intense binding of SiaLe(x)-PAA 3H to the E-selectin transfected cells and the lack of binding to both native and permeabilized control cells lead to the conclusion that the polyacrylamide carrier itself and the spacer arm connecting the carbohydrate moiety with PAA did not contribute anymore to the binding. Tumors were obtained from nude mice by injection of CHO E-selectin or mock transfected cells. The fluorescent SiaLe(x) PAA-flu probe could bind to the tumor sections from E-selectin positive CHO cells, but not from the control ones. Thus, these probes can be used to reveal specifically the carbohydrate binding sites on cells in culture as well as cells in tissue sections. The use of the confocal spectral imaging technique with Glyc PAA-flu probes offered the unique possibility to detect lectins in different cells, even when the level of lectin expression was rather low. The confocal mode of spectrum recording provided an analysis of the probe localization with 3D submicron resolution. The spectral analysis (as a constituent part of the confocal spectral imaging technique) enabled interfering signals of the probe and intrinsic cellular fluorescence to be accurately separated, the distribution of the probe to be revealed and its local concentration to be measured. PMID- 11603845 TI - Probing the lateral organization of membranes: fluorescence repercussions of pyrene probe distribution. AB - Phospholipids pyrene labeled are widely used to investigate dynamics and organizations of membranes. We studied pyrene probe lateral distribution by analyzing the variations of the molar absorption coefficient (epsilon) versus probe concentrations, in small unilamellar vesicles (SUV) made of phospholipids and/or glycolipids, with pyrene labeled phosphatidylcholine (PyPC) or phosphatidylglycerol (PyPG). The results were interpreted according to an infinite associative model. They indicated that an effective self-association process corresponding to K ranging from 30 to 100 M(-1) occurred with those probes incorporated in dimannosyl diacylglycerol (DMDG). In contrast, after SUV labeling of egg yolk phosphatidylcholine (EggPC) or phosphatidylglycerol (EggPG), K values < 1 M(-1) were determined. The corresponding percentages of various stacked forms of pyrene probes were calculated. They indicated that, for a 3% PyPG labeling, the monomer represented 21% of n-mers in DMDG and 94% in EggPC. The analysis of fluorescence experiments carried out on the same samples indicated that: (i) the fluorescence process of pyrene probes was generated by the monomers: and (ii) the excimer forming resulted from a diffusional encounter between one excited and one non-excited monomer. A correction of fluorescence data allowing a more correct interpretation of fluorescence measurements was proposed. PMID- 11603846 TI - Multiphoton excited fluorescence spectroscopy of biomolecular systems. AB - Recent work on the emerging application of multiphoton excitation to fluorescence studies of biomolecular dynamics and structure is reviewed. The fundamental principles and experimental techniques of multiphoton excitation are outlined, fluorescence lifetimes, anisotropy and spectra in membranes, proteins, hydrocarbons, skin, tissue and metabolites are featured, and future opportunities are highlighted. PMID- 11603847 TI - Biological and clinical significance of the JAK-STAT pathway; lessons from knockout mice. AB - Originally described as the signal-transducing pathway of interferons, the JAK STAT pathway soon turned out to participate in the signalling of numerous other immune and even non-immune mediators. Several murine knockout models have been described that underline the biological significance of this signalling system. Some human diseases (mainly neoplastic) are also known where malfunctioning of the JAK-STAT pathway is considered to participate in the pathogenesis. In this brief review article we will try to make a synopsis of its biological and clinical significance. PMID- 11603848 TI - Efficacy and safety of freeze-dried cat's claw in osteoarthritis of the knee: mechanisms of action of the species Uncaria guianensis. AB - AIM: The purpose of this investigation was to evaluate the ability of cat's claw, an Amazonian medicinal plant, to treat osteoarthritis of the knee, collect safety and tolerance information and compare the antioxidant, and anti-inflammatory actions of Uncaria guianensis and Uncaria tomentosa in vitro. MATERIALS AND METHODS: Forty-five patients with osteoarthritis of the knee were recruited, 30 were treated with freeze-dried U guianensis, and 15 with placebo. Hematological parameters were assessed on entry and exit of the four-week trial. Pain, medical and subject assessment scores and adverse effects were collected at weeks 1, 2 and 4. The antioxidant and anti-inflammatory activity of the cat's claw species was determined by the alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) free radical scavenging method. Inhibition of TNFalpha and prostaglandin E2 (PGE2) production was determined in RAW 264.7 cells by ELISA. RESULTS: Cat's claw had no deleterious effects on blood or liver function or other significant side-effects compared to placebo. Pain associated with activity, medical and patient assessment scores were all significantly reduced, with benefits occurring within the first week of therapy. Knee pain at rest or at night, and knee circumference were not significantly reduced by cat's claw during this brief trial. In vitro tests indicated that U guianensis and U. tomentosa were equivalent at quenching DPPH radicals (EC50, 13.6-21.7 microg/ml) as well as inhibiting TNFalpha production. However, the latter action was registered at much lower concentrations (EC50, 10.2-10.9 ng/ml). Cat's claw (10 microg/ml) had no effect on basal PGE2 production, but reduced LPS-induced PGE2 release (P < 0.05), but at higher concentrations than that required for TNFalpha inhibition. CONCLUSION: Cat's claw is an effective treatment for osteoarthritis. The species, U guianensis and U tomentosa are equiactive. They are effective antioxidants, but their anti-inflammatory properties may result from their ability to inhibit TNFalpha and to a lesser extent PGE2 production. PMID- 11603849 TI - Localisation of mRNAs for diamine oxidase and histamine receptors H1 and H2, at the feto-maternal interface of human pregnancy. AB - OBJECTIVE AND DESIGN: To localise mRNAs for the histamine receptors H1, H2 and H3, and for diamine oxidase, in the placenta and decidua of the human feto maternal interface. MATERIALS AND METHODS: Complementary DNA for each mRNA of interest was amplified by polymerase chain reaction. Sub-cloned sequences were used to prepare probes for in situ hybridisation, and these were employed to localise the expression of mRNAs for histamine receptors H1 and H2, and for diamine oxidase. RESULTS: mRNA for histamine receptors H1 and H2, and for diamine oxidase could be detected at the feto-maternal interface of human pregnancy, and localised to both decidual and placental cells. CONCLUSION: The co-expression of these receptors and DAO is consistent with a role for histamine at the feto maternal interface of human pregnancy. PMID- 11603850 TI - The effect of a bradykinin B2 receptor antagonist, NPC-567, on allergen-induced airway responses in a porcine model. AB - OBJECTIVE AND DESIGN: In order to assess the effect of selective blocking of the bradykinin (BK) B2 receptor in allergic airway reactions, the BK B2 receptor antagonist NPC-567 was administered to sensitized pigs before allergen challenge. MATERIAL: Fourteen specific pathogen-free pigs sensitized to Ascaris suum were used. TREATMENT: NPC-567 (2.5 mg, in 1 ml saline) was delivered as an aerosol twice to six pigs. METHODS: Ascaris antigen (in 2 ml saline) was given as an aerosol to all pigs and airway mechanics were monitored for 8 h. NPC-567 (2.5 mg) was given at t = -30 min (in 1ml saline) and mixed with the antigen at t = 0 to six pigs. RESULTS: Allergen challenge caused an acute reaction with a rapid, significant increase in airways resistance from 4.1 +/- 0.5 cm H2O/l/s to a maximum of 16.2 +/- 3.0 cm H2O/l/s in the control pigs. In the NPC-567-treated pigs, the resistance only increased from 2.9 +/- 0.3 cm H2O/l/s to 6.5 +/- 0.9 cm H2O/l/s (p<0.005 compared to controls). There was also a higher reduction in dynamic lung compliance in the controls than in the treated animals upon allergen challenge. The histamine concentration in urine in the control pigs was markedly elevated after allergen challenge peaking at 15-30 min. This release was inhibited in the NPC-567-treated pigs. CONCLUSIONS: The BK B2 receptor antagonist NPC-567 seems to be effective in inhibiting the acute response to allergen in the pig airways, possibly due to inhibition of mast cell activation via indirect mechanisms. The late obstructive response was reduced as well, probably as a consequence of the reduced mediator release in the acute reaction. PMID- 11603851 TI - Influence of type 2 diabetes on the inflammatory response in rats. AB - OBJECTIVES AND DESIGN: To verify whether the inflammatory responses in animals with type 2 diabetes are altered to an extent similar to that in type 1 diabetes. MATERIALS: Male newborn (2 days old) Wistar rats were made diabetic by streptozotocin (160 mg/kg, i.p.) and used 8-10 weeks later (10 rats/group). METHODS: The inflammatory responses were evaluated using paw edema (induced by local injection of carrageenan or dextran), pleurisy (by pleural injection of carrageenan), increases in vascular permeability (induced by intradermal injection of histamine, serotonin and bradykinin) and leukocyte counts in peripheral blood and pleural exudate. RESULTS: Diabetic animals showed reduced inflammatory responses to carrageenan but not to dextran. The increase in vascular permeability induced by serotonin and bradykinin was reduced whereas that to histamine was not altered in diabetic compared to control rats. Although the pleural exudate was reduced, leukocyte counts were similar in diabetic and control rats. Insulin (2 IU, 4 h before), though effective in reducing blood sugar levels, did not restore the altered responses in diabetic rats. In contrast to that in rats with type 1 diabetes, in rats with type 2 diabetes, removal of the adrenal glands restored the reduced inflammatory responses. CONCLUSIONS: Insulin resistance in type 2 diabetic rats led to reduced inflammatory responses, which were partially corrected by adrenalectomy. PMID- 11603852 TI - Involvement of thromboxane A2 and peptide leukotrienes in early and late phase nasal blockage in a guinea pig model of allergic rhinitis. AB - OBJECTIVE AND DESIGN: We investigated the effects of the thromboxane (TX) A2 antagonist seratrodast, the peptide leukotriene (p-LT) antagonist pranlukast, the antihistaminic drug terfenadine and the glucocorticoid dexamethasone on antigen induced sneezing, biphasic nasal blockage and nasal hyperresponsiveness to histamine using a guinea pig model of allergic rhinitis. SUBJECTS: Male Hartley guinea pigs were used. TREATMENT: Intranasally sensitized guinea pigs were challenged once every week for 13 weeks by inhalation of Japanese cedar pollen as the antigen. Dexamethasone and other agents were administered orally 3 and 1 h, respectively, before the 4th, 6th and 13th challenge. METHODS: Sneezing frequency and the change in specific airway resistance (sRaw) were measured at these challenges. Two days after the 13th challenge, nasal responsiveness to histamine was evaluated by measuring sRaw after intranasal instillation of increasing doses of histamine. Moreover, the levels of TXB2, p-LTs and histamine were estimated in nasal cavity lavage fluid (NCLF) collected at the 13th challenge. RESULTS: Only terfenadine (10 mg/kg) significantly inhibited sneezing at any challenge time. Seratrodast (3 and 10 mg/ kg), pranlukast (30 mg/kg) and dexamethasone (10 mg/kg), but not terfenadine, suppressed both the early and late phase elevation of sRaw (biphasic nasal blockage), although the degree of inhibition on the early phase response varied with the challenge time. In contrast, the development of nasal hyperresponsiveness to histamine was inhibited by only dexamethasone. Furthermore, biphasic increases in TXB2, p-LTs and histamine in NCLF were observed after the challenge in sensitized animals. CONCLUSIONS: These results suggest that TXA2 and p-LTs, but not histamine, play important roles in both the early and the late phase nasal blockage in this model of allergic rhinitis. PMID- 11603853 TI - Pharmacological characterization of the leukocyte kinetics after intranasal antigen challenge in a guinea pig model of allergic rhinitis. AB - OBJECTIVE AND DESIGN: We characterized the leukocyte kinetics after antigen challenge, and investigated the effects of the thromboxane (TX) A2 antagonist seratrodast, the peptide leukotriene (p-LT) antagonist pranlukast, the antihistaminic drug terfenadine and the glucocorticoid dexamethasone on this leukocyte response in a guinea pig model of allergic rhinitis. SUBJECTS: Male Hartley guinea pigs were used. TREATMENT: Intranasally sensitized guinea pigs were challenged once every week for 15 weeks by inhalation of Japanese cedar pollen as the antigen. Dexamethasone and other agents were administered orally 3 and 1 h, respectively, before the 15th challenge. METHODS: The time-related changes in the numbers of differential leukocytes in nasal cavity lavage fluid (NCLF) and in peripheral blood after pollen inhalation challenge were investigated. The effects of the drugs on the antigen-induced changes in the leukocyte counts were evaluated. In addition, histopathological examination of the nasal mucosa was also performed 5 h after the challenge. RESULTS: There was a marked increase in the number of leukocytes in NCLF, especially of eosinophils, which peaked at 5 h, after antigen challenge in this model. This response was also accompanied by the peripheral blood eosinophilia and neutrophilia. Seratrodast (30 mg/kg), pranlukast (30 mg/kg) and dexamethasone (10 mg/kg) inhibited the eosinophilia in all of the blood, the nasal mucosa and NCLF seen 5 h after the antigen challenge. Terfenadine (10 mg/kg) had no apparent effect on the blood and the mucosal eosinophilia, although it tended to suppress the eosinophil accumulation in NCLF. CONCLUSIONS: These results suggest that the present model is useful for analyzing the mechanisms of antigen-induced eosinophilic inflammation in allergic rhinitis and that both TXA2 and p-LTs, but not histamine, contribute to the antigen-induced eosinophilia in this model of allergic rhinitis. PMID- 11603854 TI - Media for the isolation and enumeration of bifidobacteria in dairy products. AB - Bifidobacteria are commonly used for the production of fermented milks, alone or in combination with other lactic acid bacteria. Bifidobacteria populations in fermented milks should be over 10(6) bifidobacteria/g at the time of consumption of strain added to the product. Hence, rapid and reliable methods are needed to routinely determine the initial inoculum and to estimate the storage time period bifidobacteria remain viable. Plate count methods are still preferable for quality control measurements in dairy products. It is, therefore, necessary to have a medium that selectively promotes the growth of bifidobacteria, whereas other bacteria are suppressed. The present paper is an overview of media and methods including summaries of published comparisons between different selective media. Culture media for bifidobacteria may be divided into basal, elective, differential and selective culture medium. Non-selective media are useful for routine enumeration of bifidobacteria when present in non-fermented milks. Reinforced Clostridial Agar and De Man Rogosa Sharpe (MRS) supplemented with cysteine and agar available commercially are the media of choice for industrial quality control laboratories. Several media for selective or differential isolation have been described for enumeration of bifidobacteria from other lactic acid bacteria. From the large number of selective media available, it can be concluded that there is no standard medium for the detection of bifidobacteria. However, Columbia agar base media supplemented with lithium chloride and sodium propionate and MRS medium supplemented with neomycin, paromomycin, nalidixic acid and lithium chloride can be recommended for selective enumeration of bifidobacteria in dairy products. PMID- 11603855 TI - Traditional Maori food preparation methods and food safety. AB - Descriptions were obtained from Maori elders knowledgeable in traditional methods for the processing of Tiroi (mussels and Puha), Kina (sea urchins), Kanga Kopiro (fermented maize) and Titi (muttonbird). Information for a number of variations of each method was transformed into process flow charts, and these charts were analysed using a HACCP-based approach. Two of the processes (Kanga Kopiro and Titi) were found to be likely to produce safe foods as Kanga Kopiro undergoes an acid fermentation and Titi preparation involves significant cooking steps. However, the information regarding Tiroi and Kina processing did not supply the necessary data to identify definitely whether fermentations were involved, and if they were, what kind they may be. New Zealand has only experienced one outbreak of botulism, and this was associated with the consumption of Tiroi. It is, therefore, desirable to identify the processes occurring in these foods where the nature of these processes is not understood in order to facilitate their safe future production. PMID- 11603857 TI - Binding of collagen I to Escherichia coli O157:H7 and inhibition by carrageenans. AB - Research at USDA attempts to eliminate or reduce Escherichia coli contamination in meat and poultry foods by understanding the attachment mechanisms. This study utilizes a surface plasmon resonance (SPR) biosensor to determine the interactions of the immobilized E. coli O157:H7 surface with collagen I and selected polysaccharides. The binding and dissociation kinetics of collagen I with E. coli surface molecules had a mean affinity constant (K) of 3 x l0(8) (M( 1)) while the dissociation rate was 4.4 x l0(-5) (S(-1)). Using the SPR biosensor, carrageenan, sodium alginate and pectin were evaluated for their interactions with collagen I and the E. coli surface. Results showed 89% to 100% inhibition by carrageenans and about 50% by sodium alginate and less than 10% by pectin. The biosensor binding studies were augmented by the scanning electron microscopy studies, which also showed the attachment of E. coli to the collagen fibrils of the bovine tissues. These studies serve as the basis for developing new strategies to block bacterial attachment or detach pathogens from animal carcasses. PMID- 11603856 TI - Growth and survival of clinical vs. environmental species of Aeromonas in tap water. AB - The ability of four species of Aeromonas (two of clinical and two of environmental origin) to survive and/or grow in tap water microcosms supplemented with sodium thiosulphate was tested. After bottling, the autochthonous microflora reached 6 x 10(5) cfu ml(-1) after a 5-day incubation period in tap water unfiltered and which was non-autoclaved. In filtered tap water, "ultramicrocells" were detected and final populations of ca. 10(6) cfu ml(-1) after 7 days were obtained. Aeromonas was inoculated at an initial cell concentration of ca. 10(4) cfu ml(-1). All strains were able to grow in tap water samples, which were filtered and autoclaved, and a final concentration of 10(5)-10(6) cfu ml(-1) was observed. Any inherent capability of Aeromonas to grow in tap water was eliminated by the presence of autochthonous microflora and "ultramicrocells" bacteria. Survival rates were strain- and microcosm-dependent. In unfiltered-non autoclaved water, viable counts declined to below the detection limit (i.e. 1 log cfu ml(-1)) in 1.5 to 20 days. The declines in viable counts were even more pronounced in the filtered microcosm. Although inoculation ratios (100/1 in unfiltered-non-autoclaved and 1,000/1 in filtered microcosms) were favourable for aeromonads, at least for I to 3 days, the organisms disappeared in these microcosms. Thus, competition for nutrients was an unlikely cause of the limitation of aeromonads. The bacteriolytic effect of enzymes released by membrane vesicles from the autochthonous microflora and of "tail phage-like particles" bacteriocins were suggested as an in situ control of aeromonad populations. The present study showed that environmental strains of Aeromonas had no ecological advantage over clinical isolates. Thus, waterborne infections and contaminations of foods by pathogenic Aeromonas species could not be discounted. PMID- 11603858 TI - Considering uncertainty in comparing the burden of illness due to foodborne microbial pathogens. AB - The uncertainty attendant to burden-of-illness estimates should be taken into account in comparing the public health impact of different foodborne pathogens. In this paper, decision analysis concepts are applied to the comparisons of pathogen-specific burden-of-illness estimates. In situations wherein the magnitude of uncertainty varies, the rank order of pathogen-specific burden-of illness estimates is sensitive to the decisional criteria applied. To illustrate the magnitude of attendant uncertainty in pathogen-specific foodborne-illness estimates, probabilistic risk assessment methods are used to characterize the uncertainty regarding the burden of illness due to Escherichia coli O157:H7. The magnitude of uncertainty about the burden of food-related illness due to E. coli O157:H7 is substantial, ranging from less than 50,000 to more than 120,000 cases/year. This example underscores the importance of considering the uncertainty attendant to burden-of-illness estimates in comparing the public health impacts of different pathogens. Although some would argue that the expected value of the number of illnesses provides the "best estimate" for decision-making, this merely reflects a decision-making rule of convention and not a scientific truism. PMID- 11603859 TI - Inhibitory activity of honey against foodborne pathogens as influenced by the presence of hydrogen peroxide and level of antioxidant power. AB - Antimicrobial activity of honey has been attributed to hydrogen peroxide, which is produced by naturally occurring glucose oxidase, and phenolic compounds, although lethality of and inhibition by these and other components against microorganisms vary greatly, depending on the floral source of nectar. This study was undertaken to compare honeys from six floral sources for their inhibitory activity against Escherichia coli O157:H7, Salmonella typhimurium, Shigella sonnei, Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus. A disc assay revealed that development of zones of inhibition of growth depends on the type and concentration of honey, as well as the test pathogen. Growth of B. cereus was least affected. The inhibition of growth of S. sonnei, L. monocytogenes, and S. aureus in 25% solutions of honeys was reduced by treating solutions with catalase, indicating that hydrogen peroxide contributes to antimicrobial activity. Darker colored honeys were generally more inhibitory than light colored honeys. Darker honeys also contained higher antioxidant power. Since antimicrobial activity of the darker colored test honeys was not eliminated by catalase treatment, non-peroxide components such as antioxidants may contribute to controlling the growth of some foodborne pathogens. The antibacterial properties of honeys containing hydrogen peroxide and characterized by a range of antioxidant power need to be validated using model food systems. PMID- 11603860 TI - Random amplification of polymorphic DNA typing of Listeria monocytogenes isolated from meat. AB - To investigate the epidemiological characteristics of Listeria monocytogenes isolated from imported or domestic meats, L. monocytogenes was isolated and identified through biochemical and serological tests, and epidemiological analysis of the isolates was carried out through the random amplification of polymorphic DNA (RAPD) method. Fifty-four isolates were identified as L. monocytogenes through biochemical tests, of which 36 (67%) were confirmed as serotype 1, and 18 (33%) were serotype 4, through the microagglutination test. In the molecular epidemiological analysis using RAPD method, the isolates could be classified into 10, 6 and 6 types using three random primers, PB1, PB4, and HLWL74, respectively. Forty composite profiles were identified by a combination of the three primers. RAPD analysis demonstrated the relationships between the isolates from beef from Korea and the USA, pork from Korea and Denmark. These results suggested that RAPD could be a useful typing tool for the epidemiological study of L. monocytogenes and other bacteria. PMID- 11603861 TI - Growth and toxin profiles of Bacillus cereus isolated from different food sources. AB - Eleven strains of Bacillus cereus isolated from milk and meat products have been used to study growth and sporulation profiles in detail. Polymerase chain reaction (PCR) using primers detecting cold shock protein A gene signatures (cspA), showed that none of the strains were the newly suggested species in the B. cereus group, B. weihenstephanensis, comprising psychrotolerant cereus strains, although one of the strains grew at 4 degrees C, two at 6 degrees C and seven grew at 7 degrees C. One of the two strains that grew at 6 degrees C had a maximum growth temperature of 42 degrees C, while the remaining 10 strains all grew at temperature of 43 degrees C or higher. Only three strains grew at 48 degrees C. At 42 degrees C, the generation time varied between 11 and 34 min. Spore germination was much faster for the two strains that grew at 6 degrees C than for the other nine strains in milk at 7 degrees C and 10 degrees C. All strains were cytotoxic and contained the non-haemolytic enterotoxin gene (nhe), 10 strains contained the enterotoxin T gene (bceT), and only six had the gene (hbl) encoding haemolytic enterotoxin. Two strains showed some microheterogeneity in the nhe operon. but contained all three genes. We can conclude that true B. cereus strains can have growth profiles as expected for B. weihenstephanensis, and that nhe and bceT were not correlated with growth profiles. However, the two psychrotolerant strains with minimal growth temperature of 4 degrees C and 6 degrees C did not contain hbl, as judged from our PCR results. PMID- 11603863 TI - Bibliography of food microbiology. PMID- 11603862 TI - Selection of primers for specific detection of Clostridium botulinum types B and E neurotoxin genes using PCR method. AB - Improved oligonucleotide primers were designed to flank 370- and 307-bp fragments of the bont genes encoding botulinum neurotoxins types B and E, respectively. Primer specificity was confirmed for reference strains of Clostridium botulinum types B and E for strains representing bacterial species common in food, and for the DNA mixtures of C. botulinum types B and E in the presence of background DNA isolated from cold smoked salmon and ham. The detection limit of template DNAs of C. botulinum types B and E from the DNA mixtures increased from 1 to 0.1 ng by raising annealing temperature from 50 degrees C to 62 degrees C. PMID- 11603864 TI - Regulation of immunological mucosal tolerance. AB - Mucosal tolerance is an immunological phenomenon specific to mucosal surfaces as found in the lungs and gastrointestinal tract. It results in the suppression of immune responses to inhaled or ingested antigens and prevents the body from unwanted and unnecessary immunological responses to harmless molecules, such as grass-pollen or food constituents. This imposes the difficult task for the immune system of keeping a balance between reacting and non-reacting, and disturbances of this balance result in allergies and, possibly, autoimmunity, as well as opportunistic infections and even an escape from tumor surveillance. Understanding the mechanisms that underlie mucosal tolerance is, therefore, important from different viewpoints. Maintenance or (re)induction of mucosal tolerance to, e.g., food proteins, airborne allergens or autoantigens is desirable to prevent or cure allergies and autoimmune diseases. However, induction of mucosal tolerance is an unwanted phenomenon in mucosal vaccination and in the case of mucosal tumors. PMID- 11603866 TI - Regulation of immune responses by natural killer T cells. AB - Natural killer T (NKT) cells, which comprise a minor population of T cells in primary and secondary lymphoid organs, possess phenotypic characteristics of both NK and T cells. NKT cells respond to various external stimuli by an early burst of cytokines, including IL-4 and IFN-gamma. Thus, a key immunoregulatory role has been attributed to them. Autoimmune diseases, especially type I diabetes (TID), may be caused by dysregulation of the immune system, which leads to hyporesponsiveness of regulatory T helper 2 (Th2) cells and promotion of autoimmune Th1 cells. Furthermore, several lines of evidence exist to support the notion that an NKT cell deficiency in individuals at risk of TID may be causal to TID. As a result, targeting NKT cells using immunotherapeutic agents may prove beneficial in the prevention or recurrence of TID. Indeed, our data demonstrate that stimulation of NKT cells with a specific ligand prevents the onset and recurrence of TID in nonobese diabetic (NOD) mice. PMID- 11603865 TI - Two receptor theory in innate immune activation: studies on the receptors for bacillus Culmet Guillen-cell wall skeleton. AB - Activation of the innate immune system is a prerequisite for the maturation of dendritic cells (DC) and macrophages (Mphi) followed by clonal expansion of the lymphocytes, targeting cells expressing "non-self' antigens. Microbes usually have a component competent to activate DC/Mphi for antigen presentation. This component has been called adjuvant, but recently renamed "pathogen-associated molecular pattern" (PAMP) or modulin based on its molecular identification. Here, we propose the hypothesis that DC/Mphi express two sorts of receptors for PAMP, whose signaling pathways lead to a sufficient antigen (Ag)-presenting state. In bacterial infection, a Toll-like receptor (TLR) and an uptake receptor participate in DC maturation and Mphi activation. Likewise, with a number of viruses, two of the receptors, with short consensus repeats (SCR), immunoglobulin like domains or chemokine receptor-like motifs etc. induce functional modulation of DC/Mphi. In immune therapy for cancer, primary activation of the innate system would be essential for tumor Ag-specific T cell augmentation. Cancer cells express tumor-associated Ag but barely co-express PAMP, which situation does not allow for the activation of innate immune responses. Supplementing tumor associated Ag with PAMP may be an effective therapy for patients with cancer. Here, we discuss the possibility of an innate immune therapy for cancer with reference to bacillus Culmet Guillen cell-wall skeleton (BCG-CWS). PMID- 11603867 TI - The social life of NK cells. AB - Natural killer (NK) cells represent a distinct population of lymphocytes originally identified by its ability to kill transformed cell lines in vitro. It is now clear that these cells also play an important role in the innate immune response against a variety of pathogens, such as virus, bacteria and parasites. In the past few years, different protocols have been developed to activate NK cells ex vivo, allowing a detailed molecular analysis of the interaction of these cells with their cellular targets. NK activity is regulated by signals generated by both inhibitory and stimulatory receptors expressed by target cells. Indeed, recent results indicate that, while major histocompatibility complex class I molecules expressed on target cells inhibit NK lytic activity by engaging surface inhibitory receptors, costimulatory molecules, such as B7-1, B7-2 and CD40, are able to actively trigger NK activity. This review discusses the most recent findings on the role of costimulation on NK activation and forsees the possible consequences of the interaction between NK cells and dendritic cells on the development of an adaptive immune response. PMID- 11603868 TI - Local tissue complement synthesis--fine tuning a blunt instrument. AB - Complement is important to host defense and the regulation of inflammation. The liver is overwhelmingly the major source of circulating complement. However, many other organs are capable of synthesizing some or all of the complement components in a regulated tissue-specific manner. There is increasing evidence that this locally generated complement is biologically active and exerts powerful effects within the local environment. We review the role of local complement synthesis within different organs and speculate on its implication for immune and metabolic functions. PMID- 11603869 TI - Role of antigen-presenting cells in innate immune system. AB - Activation of antigen-presenting cells (APC) and natural killer (NK) cells initiates the production of various proinflammatory cytokines including interleukin 12 (IL-12), interferon gamma (IFN-gamma) and nitric oxide (NO), which are important in the innate immune response for controlling infection by intracellular pathogens. In this review, we focus on these cytokines produced by APC and summarize the current understanding of how APC functions are regulated by cytokines in innate immunity. PMID- 11603870 TI - Effect of cyclosporine A on the non-specific, innate antiviral immunity of mice. AB - Different infections are the most common complication of immunosuppressive therapy. In this context, the effect of cyclosporine A (CsA) on the innate antiviral immunity of mice was studied. The presence of immunity was shown by infection of resident peritoneal cells (RPC) of BALB/c mice with herpes simplex virus type 1 (HSV-1) and vesicular stomatitis virus (VSV). While the cells infected immediately after isolation were resistant to the viruses, the cells cultured for several days before infection lost the immunity. The lack of activity to neutralize HSV-1 and VSV in the sera of the mice excluded a participation of specific antibodies in the resistance. To study the effect of CsA on the innate immunity, BALB/c mice were intraperitoneally (i.p.) injected with cyclosporine (20 or 100 microg/mouse, twice a day) for 3 days. The other group of animals was injected in the same way with PBS only. Then the peritoneal cells were isolated and infected with VSV immediately after cell isolation. The kinetics of viral replication in the control and CsA-treated groups was compared. While in the cells from the control group VSV did not multiply, in the cells from the CsA-treated mice the virus reached considerable titers. The cyclosporine effect on VSV replication was dose dependent and statistically significant. We conclude that innate antiviral immunity was suppressed in the cyclosporine treated mice and that this mechanism may be involved in the high susceptibility of patients to viral infections during immunosuppressive therapy. PMID- 11603871 TI - Liver sinusoidal endothelial cells: a new type of organ-resident antigen presenting cell. AB - The induction of peripheral immune tolerance in the liver is a well-known phenomenon that is operative in different situations, such as tolerance to organ transplants and tolerance to oral antigens. The mechanisms leading to peripheral immune tolerance in the liver are still incompletely understood. While different cell populations of the liver have been implicated in and probably contribute in concert to the induction of hepatic immune tolerance, one hepatic cell type in particular seems to be suited for tolerance induction: liver sinusoidal endothelial cell (LSEC). LSEC are microvascular endothelial cells with a unique phenotype reminiscent of dendritic cells and a unique function as antigen presenting cells for CD4+ T cells. The hepatic microenvironment, i.e. portal venous constituents and soluble mediators from sinusoidal cell populations, tightly control antigen presentation by LSEC to avoid immune-mediated damage. LSEC, in contrast to other endothelial cells, have the capacity to prime naive CD4+ T cells and induce cytokine release. Importantly, naive CD4+ T cells primed by antigen-presenting LSEC differentiate into regulatory T cells, whereas T cells primed by bone marrow-derived professional antigen presenting cells differentiate into Th1 cells. Thus, LSEC represent a new type of organ-resident "non professional" antigen-presenting cell that appears to be involved in the local control of the immune response and the induction of immune tolerance in the liver. PMID- 11603872 TI - Pediatric hematology-oncology fellowship training: new paradigms for the 21st century. AB - The author reviews the 63 currently accredited fellowship training programs in pediatric hematology-oncology in the United States and Puerto Rico. Goals of the programs and guidelines for their conduct are discussed. Conditions for certification are described. PMID- 11603873 TI - Breast disease and undergraduate medical education: a randomized trial to assess the effect of a home study module on medical student performance. AB - BACKGROUND: This study sought to demonstrate the effectiveness of a home study module (HSM) on student performance at a large urban medical school. METHOD: Second-year students were randomized to receive: 1) a HSM in addition to regular teaching of clinical breast examination or, 2) the regular teaching alone. The HSM included adult learning principles, problem-based learning, and practice guidelines. Students completed a pretest, a post-test, and course evaluation. The pre- and post-tests examined students' knowledge and comfort levels. RESULTS: Of 176 students, 136 agreed to participate and 127 completed both pre- and post tests. Baseline pretest indicated no significant difference between the intervention and control groups. Post-test showed that students receiving the HSM gained significantly more knowledge than had the control group, and their comfort levels shifted nonsignificantly more. Student evaluations indicated perceived value of the HSM. INTERPRETATION: Student performance can be enhanced and comfort levels increased by providing a critical core of knowledge in the form of a HSM. This approach may be applicable to other important subjects. PMID- 11603874 TI - Radiotherapy education among family physicians and residents. AB - BACKGROUND: This study was performed to assess radiotherapy education among family physicians. METHODS: A questionnaire evaluating radiotherapy training and knowledge was given to participants of a palliative care conference. RESULTS: Thirty-four physicians completed the survey (71% response rate). Major deficiencies in radiotherapy education were identified and 88% of respondents stated that they did not have adequate knowledge. Only 33% had received formal training in radiotherapy and the majority (77%) thought that they would benefit considerably from continuing medical education. CONCLUSIONS: Better education about radiotherapy is required for family physicians and could lead to increased patient referral for such treatment. PMID- 11603875 TI - Undergraduate oncology nursing education in the Balkans and the Middle East. AB - BACKGROUND: The levels of undergraduate oncology nursing education in the Balkans and the Middle East had not been determined. METHODS: The authors used a questionnaire to survey representatives of nine Balkan and Middle East countries about the oncology nursing education available in undergraduate nursing programs in their countries. Admission criteria, the educational requirements for teachers providing the education, and the levels of nursing credentials in the country were investigated. RESULTS: Years of schooling needed for admission ranged from eight to 12. Requirements for teachers varied widely, from none to academic degrees and experience, as did levels of nurses in the countries. Israel, Slovenia, and Greece had fairly substantial oncology nursing education programs, while some countries, especially in the Balkans, offered none at all. CONCLUSIONS: There is a need for routine inclusion of required oncology training in the nursing programs of these countries. PMID- 11603876 TI - Native American cancer education: genetic and cultural issues. AB - BACKGROUND: The authors met with intertribal groups to learn about cultural issues related to cancer genetics. The information gathered from these meetings identified issues that are incorporated into the Genetic Education for Native Americans (GENA) interactive, innovative and multidisciplinary curriculum. METHODS: To address the diverse cultural and scientific issues, the faculty presented customized workshops during conferences for Native American college students. RESULTS: The authors discuss current issues and techniques in cancer education in Native American communities. CONCLUSIONS: Better understanding of tribal culture among researchers will enhance Native Americans' collaboration in research. PMID- 11603877 TI - Cancer education for clergy and lay church leaders. AB - BACKGROUND: Reaching diverse population subgroups with information about cancer prevention/early detection, pain management, and clinical trials has historically been a significant public health challenge. A partnership between clergy and cancer educators might help reduce this challenge. METHODS: Participating churches were randomized into two programs for delivering cancer education after their church leaders completed a baseline survey about their knowledge, attitudes, and roles related to the cancer ministry. RESULTS: Clergy reported opportunities to use their acquired cancer knowledge, a high receptivity to their information, comfort discussing cancer care and clinical trials, and a strong recommendation that the educational program/partnership continue to be offered. PMID- 11603878 TI - U.S. dental hygienists' knowledge and opinions related to providing oral cancer examinations. AB - BACKGROUND: Because U.S. dental hygienists play a significant role in providing prevention and early-detection services, it is important to describe and evaluate their oral cancer knowledge and opinions. METHODS: A pretested survey, cover letter, and prepaid return envelope were mailed to 960 dental hygienists, followed by three complete follow-up mailings. RESULTS: The respondents were not as knowledgeable about oral cancer risk factors and diagnostic procedures as hypothesized. Although the respondents were well informed about certain key aspects of oral cancer risk factors and diagnostic procedures, there were many aspects of these topics in which they were deficient and in some cases misinformed. CONCLUSIONS: Dental hygiene curricula should be updated and continuing education coursesabout oral cancer should be developed and implemented. PMID- 11603879 TI - Design and validation of instruments to measure knowledge. AB - BACKGROUND: Measuring health care providers' learning after they have participated in educational interventions that use experimental designs requires valid, reliable, and practical instruments. METHODS: A literature review was conducted. In addition, experience gained from designing and validating instruments for measuring the effect of an educational intervention informed this process. RESULTS: The eight main steps for designing, validating, and testing the reliability of instruments for measuring learning outcomes are presented. The key considerations and rationale for this process are discussed. Methods for critiquing and adapting existent instruments and creating new ones are offered. CONCLUSIONS: This study may help other investigators in developing valid, reliable, and practical instruments for measuring the outcomes of educational activities. PMID- 11603880 TI - Using standardized patients to teach end-of-life skills to clinical clerks. AB - BACKGROUND: This study examines the use of standardized patients to teach end-of life skills to clinical clerks. METHODS: Forty-four third-year clinical medical students participated in a half-day standardized patient workshop that was precepted by faculty members. The students were asked to report on their perceived abilities prior to the workshop and these were compared with post workshop responses. The students were also asked to provide an overall evaluation of the standardized patient workshop as a learning experience. RESULTS: The students uniformly found the workshop to be realistic, found the faculty facilitators to be helpful, and found the workshop effective in enhancing their end-of-life skills. Following participation in the workshop, students reported significant improvements in their perceived abilities to deal with pain, to appreciate cultural differences in the dying process, to deliver bad news, and to understand the legalities of do-not-resuscitate orders. CONCLUSIONS: Standardized patient workshops are useful for teaching end-of-life skills. PMID- 11603882 TI - Mechanisms of antipsychotic-induced weight gain. AB - The estimated percentage of persons with schizophrenia who are overweight is higher than the percentage of persons in the general population who are overweight. The increased mortality rate for persons with schizophrenia is largely due to obesity-related diseases. The atypical antipsychotics offer an improved therapeutic index when compared with the conventional agents, but may impart serious adverse events such as weight gain. This brief review is intended to provide the practicing clinician with an update of disparate research paradigms under investigation in an attempt to delineate the biological mechanisms that presage weight gain. Research success in this area may invite novel prevention strategies and hint at potential mechanisms of antipsychotic drug action. PMID- 11603881 TI - Epidemiology, morbidity, and treatment of overweight and obesity. AB - Although still considered more of a cosmetic problem by both the general public and some areas of the medical community, overweight and obesity have reached epidemic proportions worldwide. Overweight and obesity have not only a significant psychological impact but also result in an increased risk for development of numerous chronic and sometimes fatal diseases. The morbidity from obesity-associated disorders increases with higher body mass index and begins within the normal weight range. The costs (direct and indirect) associated with treating obesity and its comorbid conditions are notable and increasing. Obesity rates in patients with schizophrenia are at least as high, if not higher, than in the general population. This article reviews the epidemiology and burden of obesity and its associated comorbid disorders. The guidelines from the National Heart, Lung, and Blood Institute of the National Institutes of Health for diagnosing and treating obesity are also discussed. PMID- 11603883 TI - Hyperglycemia associated with the use of atypical antipsychotics. AB - The available literature suggests that patients with schizophrenia are at risk for diabetes mellitus and taking antipsychotic medication further increases the chance of developing non-insulin-dependent hyperglycemia. Case reports, chart reviews, and some results from clinical drug trials implicate a relationship between glucose levels and treatment with clozapine or olanzapine in patients with schizophrenia, although a few cases of hyperglycemia have also been reported in patients taking risperidone and quetiapine. These studies indicate that hyperglycemia is not dose dependent, is reversible on cessation of treatment with clozapine or olanzapine, and reappears on reintroduction of these therapies. The postulated underlying mechanisms involved in this process in patients with schizophrenia include (1) a decreased sensitivity to insulin that is independent of atypical medication, (2) an increased insulin resistance related to atypical medications, (3) the effects of atypical medications on serotonin receptors, and (4) overuse of insulin due to weight gain. These mechanisms are discussed in detail, and recommendations for the administration of atypical antipsychotics are offered. Overweight, ethnicity, family or personal history of diabetes mellitus or hypertension, and weight gain during the course of treatment have all been identified as risk factors in the development of hyperglycemia in patients with schizophrenia. However, it is difficult to statistically assess the true incidence of diabetes within each type of antipsychotic medication group with the exclusive dependence on available case studies and without proper epidemiologic research. PMID- 11603884 TI - Clozapine: diabetes mellitus, weight gain, and lipid abnormalities. AB - Clozapine remains the most effective agent for treatment-resistant patients with schizophrenia. Recently, treatment with clozapine has been linked to a number of metabolic disturbances, including weight gain, diabetes mellitus, and serum lipid abnormalities. Despite the potential risks of medical morbidities, clozapine continues to have a major role in the care of treatment-resistant patients with schizophrenia. This article discusses the diagnosis and significance of the above metabolic abnormalities and potential mechanisms for these abnormalities as well as recommendations for monitoring and treatment. PMID- 11603885 TI - Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. AB - Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYPIA2); the beta3 and alpha,alpha adrenergic receptor genes (ADRB3/ADRAIA); and tumor necrosis factor alpha (TNF alpha). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-alpha, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing. PMID- 11603886 TI - Review of atypical antipsychotics and weight gain. AB - Prescribing an antipsychotic for a patient with schizophrenia requires a risk benefit analysis. Weight gain has become an issue recently as a result of reports that 2 of the atypical antipsychotic agents, clozapine and olanzapine, are associated with a higher risk than other drugs of causing excessive weight gain. Some degree of weight gain may occur with any atypical antipsychotic agent, particularly early in treatment. A more important consideration is the long-term effects of the atypical antipsychotic on body weight, since many of the patients in this population require chronic therapy. This is important because weight gain is an adverse effect that is associated with noncompliance and medical problems. In this article, I review recent reports about the weight effects of different atypical antipsychotic drugs. To provide accurate understanding of the effects of atypical antipsychotic agents, data analyses should include both short-term and long-term findings, the relationship of changes in body weight to pretreatment body mass index (BMI), relationship to dose, both intent-to-treat and complete analyses, and presentation of both mean and median changes in weight. It is also important to know whether the studies have been done in an inpatient or outpatient setting, since patients who are institutionalized may be less likely to exhibit increases in body weight. Such complete information and multidimensional analysis would minimize obfuscation about the true nature of a drug's impact on body weight. PMID- 11603887 TI - Radiology and the internet: a systematic review of patient information resources. AB - AIM: To determine whether the internet is a useful resource for patients seeking information on radiological procedures. MATERIALS AND METHODS: A systematic search of the world wide web was performed by means of four general search engines (AltaVista, Yahoo!, Infoseek and Excite). Twenty-eight suitable patient directed websites on arteriography were identified for analysis. The value of this material was measured by establishing inclusion or exclusion of a number of factors relating to the procedure. Readability of the materials was evaluated using the Flesch reading ease score. RESULTS: Advice on preparation was included in 21 (75%) sites. Contraindications were found in 16 (57%) sites, risks in 6 (21%) and aftercare in 25 (89%). Result availability was discussed in 15 (54%) sites, with links to other radiology sites in 13 (46%). Visual aids were used in 6 (21%) sites and a contact address found in 27 (96%). Mean Flesch reading ease score was 57, with 46% of sites below the preferred minimum of 60. CONCLUSIONS: Few sites provide the range of information a patient needs before arriving for a procedure. In addition, the readability of the material on these sites is frequently set at a level incomprehensible to patients with lower levels of literacy. PMID- 11603888 TI - Uroradiology: imaging in prostate cancer. PMID- 11603889 TI - Low dose computed tomography in suspected acute renal colic. AB - AIM: To evaluate whether computed tomography (CT) of the renal tract in suspected renal colic using reduced exposure factors maintains diagnostic accuracy. METHODS: Prospective multi-centre cohort study. Patients with suspected renal colic were examined using computed tomography (CT) of the renal tract followed by intravenous urography (IVU) in four different centres with five different CT systems. RESULTS: Sixty-nine patients with suspected renal colic had CT of the renal tract followed by IVU. CT was performed with reduced exposure factors, giving a mean CT effective dose of 3.5 (range 2.8-4.5) mSv compared with 1.5 mSv for IVU. Ureteric calculi were detected in 43 patients: CT and IVU detected 40 (93%) ureteric calculi. CT identified other lesions causing symptoms in five patients and identified renal calculi in 24 patients. IVU identified renal calculi in six patients and made false positive diagnosis of renal calculi in seven patients. Mean examination time for CT was 5 minutes and for IVU was 80 minutes. CONCLUSION: CT examination at reduced exposure factors maintains the diagnostic accuracy recorded in other series. PMID- 11603890 TI - The natural history of disappearing bone tumours and tumour-like conditions. AB - We describe 27 cases of bone tumours or tumour-like lesions where there was spontaneous regression. The follow-up period was 2.8-16.7 years (average, 7.0 years). Fourteen of these cases were no longer visible on plain radiographs. Histological diagnosis included exostosis, eosinophilic granuloma, fibrous dysplasia, fibrous cortical defect, non-ossifying fibroma, osteoid osteoma and bone island. Most cases began to reduce in adolescence or earlier, although sclerotic type lesions showed their regression in older patients. All lesions thought to be eosinophilic granuloma began to regress after periods of less than 3 months, while the duration of the other lesions showed wide variation (1-74 months). As resolution of the lesions took between 2 and 79 months (mean, 25.0 +/ 20.3 months) we consider that the most likely mechanism was recovery of normal skeletal growth control. In exostosis with fracture, alteration of vascular supply may contribute to growth arrest, but not to subsequent remodelling stage. In inflammatory-related lesions such as eosinophilic granuloma, cessation of inflammation may be the mechanism of growth arrest, whilst temporary inflammation may stimulate osteogenic cells engaged in remodeling. In the sclerotic type, growth arrest is a less probable mechanism. Necrosis within the tumour and/or local changes in hormonal control, plus remodelling of the sclerotic area takes longer. Knowledge of the potential for spontaneous resolution may help in management of these tumour and tumour-like lesions of bone. PMID- 11603891 TI - 3D gadolinium-enhanced MRI venography: evaluation of central chest veins and impact on patient management. AB - AIM: To assess the value of a simplified 3D gadolinium-enhanced magnetic resonance imaging (MRI) venography for central chest veins. MATERIALS AND METHODS: In this retrospective study of 24 patients, the MRI findings and medical records were reviewed to determine whether MRI results correlated with subsequent findings, and to determine the effect on clinical management. 3D steady state gradient-echo sequence, fast imaging with steady state precession (FISP), was used. We employed a simplified protocol not requiring bolus timing or subtraction to achieve rapid data acquisition and hence good compliance in this group of frail patients. Following intravenous administration of a bolus of gadolinium, two acquisitions were obtained in order to ensure adequate opacification of all veins. Individual partitions and maximum intensity projections were then analysed to determine whether the veins were patent, stenosed or occluded. RESULTS: The indications for MRI were to assess the patency of central veins for the purpose of cannulation or arteriovenous fistula formation in 17 patients. Out of the 12 patients who proceeded to an intervention, MRI venography successfully predicted an appropriate site in 10 patients. In the remaining seven patients, MRI venography was valuable in confirming or excluding the clinical suspicion of central venous thrombosis and directly influenced the management in five patients. CONCLUSION: 3D gadolinium-enhanced MRI venography is a valuable means of providing a global representation of the central venous system and guiding subsequent central venous cannulation. PMID- 11603892 TI - Percutaneous ethanol injection of autonomous thyroid nodules with a volume larger than 40 ml: three years of follow-up. AB - AIM: Autonomous thyroid nodules are conventionally treated by surgery or radioiodine. Percutaneous ethanol injection is a recognized alternative approach. An assessment of the long-term success and safety was conducted. MATERIALS AND METHODS: Thirty-four patients (seven men and 27 women; age range: 32-80 years; mean: 56 +/- 13 years) with an autonomous thyroid nodule (ATN) > 40 ml (volume range 41-180 ml; mean: 63.6 +/- 34.5 ml) were treated with ultrasound-guided percutaneous ethanol injection (PEI). All patients were hyperthyroid with increased radionuclide uptake in the nodule at scintigraphy. Serial serum (free T3, free T4 and thyroid-stimulating hormone (TSH)) and ultrasound studies were performed at 3, 6, 12, 18, 24 and 36 months after the first PEI session. Scintigraphy was performed before treatment and 1 month after the serum TSH became detectable or alternatively after 6 months, even if the TSH was still undetectable. RESULTS: Each patient had 1-11 sessions of PEI, with an injection of 3-14 ml of ethanol per session (total amount of ethanol per patient: 20-125 ml). Within 3 months from the end of the treatment, the recovery of extranodular uptake on isotope scan and the normalization of TSH levels were observed in 30/34 patients. A reduction (average: 62.9%) of nodule volume was recorded in all patients and only 4/34 patients were refractory to PEI. The responsiveness of ATN to PEI appeared to be dependent on the initial nodule volume (3/4 failures in patients had nodule volumes > 60 ml). Side-effects were always self-limiting. During follow-up (6-36 months) no recurrence was observed. CONCLUSION: In conclusion, the treatment of ATN > 40 ml with PEI would appear to be a valid alternative approach to traditional methods of treatment. It is safe, well tolerated and inexpensive. Its acceptability when compared with surgery and radiodioine has still to be assessed. PMID- 11603893 TI - Radiological percutaneous gastrostomy. AB - Long-term gastrostomy tubes have a widely accepted role in providing nutritional support. Traditionally, they have been placed by surgeons and by endoscopists. In the last decade, radiologists have come to play a major role in the placement of gastrostomy and gastrojejunostomy devices, and can usually do so as effectively and at lesser expense. A technique for placement is outlined, with a discussion of patient selection and complications. A review of the literature is provided. PMID- 11603894 TI - Liver iron estimation in beta-thalassaemia: comparison of MRI biochemical assay and histological grading. AB - AIMS: The aims of the study were to compare the efficacy of magnetic resonance imaging (MRI), biochemical assay and histological grading in estimating liver iron content, and to evaluate the value of liver to muscle signal intensity ratio (L/M ratio) on spin-echo T1-weighted images in this role. MATERIALS AND METHODS: Thirty-nine homozygous beta-thalassaemics had their L/M ratio measured on MRI, followed by ultrasound-guided liver biopsies with histological grading of iron storage and biochemical quantification of liver iron concentration (LIC-b) using atomic absorption spectrophotometry. RESULTS: A significant difference in L/M ratios between the four grades of iron storage on histology was observed (P < 0.001). The coefficient of correlation was -0.67 between L/M ratio and LIC-b ranging from 2 to 21.6 mg/g dry weight. Specific values of L/M ratio reliably reflected liver iron content at clinically important levels. A L/M ratio of < 0.6 has 86% sensitivity and 100% specificity in the prediction of grade 3 or 4 iron storage histologically and 81% sensitivity and 81% specificity in predicting LIC b > 15 mg/g. A L/M ratio of > 0.8 predicts a histological iron storage grading of 0 or 1 with a 100% sensitivity and 74% specificity. CONCLUSION: L/M ratio on MRI is of value as a non-invasive alternative to repeated liver biopsies for estimating liver iron content at clinically important thresholds. PMID- 11603895 TI - Closing the loop: the role of audit in reducing groin complications associated with coronary angiography. AB - BACKGROUND: Local vascular complications of coronary angiography present a significant but often ignored clinical problem. This audit was performed because of a perception that the number of false aneurysms requiring surgical repair was increasing. STANDARD: An acceptable incidence of false aneurysm was derived from series in which ultrasound examinations were only performed if a false aneurysm was suspected (0.06-0.7%). The success rate of ultrasound (US) directed compression ranged from 50% to 93%. ASSESSMENT OF LOCAL PRACTICE: Data were retrieved from cardiology, radiology and vascular surgery databases in addition to case note review. The incidence of false aneurysm was significantly higher than that of historical control groups from the authors' institution (1.5% vs 0.5%, P < 0.05) and in published series used as the standard. The success rate of US directed compression was also poor compared to historical controls (25% vs 55%,P < 0.05) and previously published series. IMPLEMENTATION OF CHANGE: Recommended changes included the use of fluoroscopy to identify the femoral head to avoid low puncture, strict adherence to the existing protocol for sheath removal and the use of adequate analgesia and sedation prior to attempted US compression. REASSESSMENT OF LOCAL PRACTICE: The incidence of false aneurysm fell to that of the standard set by previous studies. US directed compression was successful in 100%. CONCLUSIONS: The audit was successful in that the incidence of false aneurysm fell and the success rate of US directed compression increased, but the specific reasons for the improvements remain unclear. PMID- 11603896 TI - Limited magnetic resonance imaging in low back pain instead of plain radiographs: experience with first 1000 cases. AB - AIM: We report our experience with the first 1000 patients with non-traumatic low back pain (LBP) without radiculopathy undergoing limited sequence magnetic resonance imaging (MRI) instead of plain radiography. METHODS: Between January 1996 and December 1998, 1042 patients with low back pain unresponsive to conservative treatment were examined using a limited MR protocol comprising sagittal T1-weighted and STIR imaging. Plain radiographs were not performed. RESULTS: Malignancy, infection, vertebral fracture, spondylitis, pars defects and cord tumours were detected in 20%. Of the 82 osteoporotic vertebral fractures detected, 51 (62%) were recent and 31 had normal marrow signal indicating that they were old. Eighty pars defects were identified, 45(56%) had spondylolisthesis, 29(37%) were undisplaced and 6 (7%) had pars oedema only. Neoplastic disease was found in 17(8%) of which none was suspected before imaging. Benign neoplastic diseases such as vertebral AVM/haemangiomata were excluded. Twenty-one patients had a variety of disorders including ankylosing spondylitis (7), large vessel aneurysm (3), discitis (2), ovarian cyst (2), sequestered disc (2), sacral insufficiency fracture (2) and one patient each with burst fracture, retroperitoneal haematoma and a previously unsuspected horseshoe kidney. CONCLUSION: The majority of patients with LBP are best assessed clinically and imaging is usually not required. In patients with worrying symptoms, MRI with a limited protocol detects a greater number of abnormalities than previously reported studies using plain radiographs and has replaced plain radiography in our hospital. We report our experience with the first 1000 patients and highlight issues such as protocols, detection rates and communication issues. PMID- 11603898 TI - Femoral artery catheterization and retroperitoneal haematoma formation. PMID- 11603897 TI - Facial nerve palsy: evaluation by contrast-enhanced MR imaging. AB - AIM: The purpose of this study was to investigate the value of contrast-enhanced magnetic resonance (MR) imaging in patients with peripheral facial nerve palsy. MATERIALS AND METHODS: MR imaging was performed in 147 patients with facial nerve palsy, using a 1.0 T unit. All of 147 patients were evaluated by contrast enhanced MR imaging and the pattern of enhancement was compared with that in 300 control subjects evaluated for suspected acoustic neurinoma. RESULTS: The intrameatal and labyrinthine segments of the normal facial nerve did not show enhancement, whereas enhancement of the distal intrameatal segment and the labyrinthine segment was respectively found in 67% and 43% of patients with Bell's palsy. The geniculate ganglion or the tympanic-mastoid segment was enhanced in 21% of normal controls versus 91% of patients with Bell's palsy. Abnormal enhancement of the non-paralyzed facial nerve was found in a patient with bilateral temporal bone fracture. CONCLUSION: Enhancement of the distal intrameatal and labyrinthine segments is specific for facial nerve palsy. Contrast-enhanced MR imaging can reveal inflammatory facial nerve lesions and traumatic nerve injury, including clinically silent damage in trauma. PMID- 11603900 TI - Hypertensive pulmonary oedema is due to diastolic dysfunction. PMID- 11603901 TI - ESPRIT in context: pharmacology matters! PMID- 11603902 TI - Head-up tilt testing in children. PMID- 11603903 TI - The value of continuous ST segment monitoring in patients with unstable angina. PMID- 11603904 TI - All stents are not alike or is the difference in the eye of the observer only? PMID- 11603905 TI - Failing ageing hearts. PMID- 11603906 TI - Why is recurrent myocardial ischaemia a predictor of adverse outcome in unstable angina? An observational study of myocardial ischaemia and its relation to coronary anatomy. AB - OBJECTIVE: To establish why recurrent myocardial ischaemia predicts adverse outcome in patients with refractory unstable angina on maximal medical treatment. DESIGN: Prospective observational study in 101 patients with refractory unstable angina who underwent continuous ST-segment monitoring and kept detailed pain charts prior to cardiac catheterization. Setting Tertiary referral centre. RESULTS: Significant coronary disease was identified in 90 subjects with 74 (82%) having multivessel disease, 41 (46%) complex lesion morphology, and 10 (11%) subjects with definite features of intra-coronary thrombus. The frequency of complex lesions or intra-coronary thrombus did not differ in relation to the extent of coronary disease. Recurrent chest pain was present in 72 of the 90 (80%) subjects, while transient ischaemia was detected in 26 (29%). The presence of transient ischaemia was a powerful predictor of complex lesions or thrombus (odds ratio 7.1;P<0.001). Subjects with severe recurrent chest pain had a greater frequency of intracoronary thrombus (odds ratio 9.5;P<0.05). CONCLUSIONS: In unstable angina once the normal mechanisms causing myocardial ischaemia (i.e. increased myocardial demand and coronary vasoconstriction) have been treated using maximal antianginal treatment, the continued development of transient myocardial ischaemia is strongly associated with complex coronary lesion morphology and intracoronary thrombus. It is already known that patients with complex lesion morphology and intracoronary thrombus have an adverse outcome in unstable angina and therefore it is this association that explains why transient ischaemia is a predictor of poor outcome in unstable angina. PMID- 11603907 TI - Recurrent ischaemia during continuous multilead ST-segment monitoring identifies patients with acute coronary syndromes at high risk of adverse cardiac events; meta-analysis of three studies involving 995 patients. AB - AIMS: Recurrent ischaemia, detected by continuous ECG monitoring, in patients with unstable angina increases the risk of unfavourable outcome. Studies that evaluated this relationship have been limited by the small series of patients. By combining data from three studies, the present analysis aims to provide an accurate assessment of the impact of recurrent ischaemia detected by multilead ECG-ischaemia monitoring on the occurrence of death and myocardial infarction in patients with acute coronary syndromes. METHODS AND RESULTS: Data were obtained from CAPTURE, PURSUIT and FROST, three trials evaluating glycoprotein IIb/IIIa blockers in patients with non-ST-elevation acute coronary syndromes. Patients were monitored for 24 h after enrollment with a computer-assisted 12-lead or a vectorcardiographic ECG-ischaemia monitoring device. In a retrospective blinded analysis, recurrent ischaemic episodes were identified by a computer algorithm. The number of ischaemic episodes was normalized to 24 h. Ischaemic episodes were detected in 271 (27%) of 995 patients. There was a direct proportional relationship between the number of ischaemic episodes per 24 h and the probability of cardiac events at 5 and 30 days. The 30-day composite of death and myocardial infarction occurred in 5.7% of patients without episodes and increased to 19.7% in patients with >/=5 episodes. After adjustment for baseline predictors of adverse outcome, the relative risk of death or myocardial infarction at 5 and 30 days increased by 25% for each additional ischaemic episode per 24 h. CONCLUSIONS: This analysis emphasizes the need for integration of multilead ECG ischaemia monitoring systems in coronary care units and emergency wards to improve early risk stratification in patients with acute coronary syndromes. PMID- 11603908 TI - Stent design related neointimal tissue proliferation in human coronary arteries; an intravascular ultrasound study. AB - AIMS: Histological restenosis models in animals have indicated that stent design has a significant impact on vessel trauma during stent implantation and on the amount of subsequent neointimal tissue proliferation. The impact of different stent designs on intimal hyperplasia in human atherosclerotic coronary arteries has not been determined. METHODS AND RESULTS: Angiographic and intravascular ultrasound studies were performed at the 6 month follow-up in 131 consecutive native coronary lesions of 131 patients treated with 50 Multi-Link stents, 40 InFlow stents and 41 Palmaz-Schatz stents. Lumen and stent cross-sectional areas (CSA) were measured at 1 mm axial increments. Mean intimal hyperplasia cross sectional area (stent CSA-lumen CSA) and mean intimal hyperplasia thickness were calculated. Intravascular ultrasound demonstrated different levels of intimal hyperplasia proliferation for the three stents. Mean intimal hyperplasia thickness was 0.16+/-0.08 mm for Multi-Link stents, 0.26+/-0.19 mm for Palmaz Schatz stents and 0.39+/-0.14 mm for Inflow stents (P<0.001). Multivariate analysis proved that stent type was the only independent predictor of intimal hyperplasia thickness at follow-up (P<0.001). CONCLUSION: Coronary stent design has a significant impact on subsequent intimal hyperplasia after implantation into atherosclerotic human coronary arteries. The corrugated ring design of the Multi-Link stent proved to result in less tissue proliferation at 6-month follow up than the tubular slotted design of Palmaz-Schatz and InFlow stents. PMID- 11603910 TI - Public risk factor screening on the occasion of the ESC meeting in Amsterdam- results from "For Your Heart's Sake". PMID- 11603909 TI - The impact of high pressure vs low pressure stent implantation on intimal hyperplasia and follow-up lumen dimensions; results of a randomized trial. AB - AIMS: Histology and retrospective clinical studies have indicated that the amount of neointimal hyperplasia is dependent on the arterial injury induced during stent implantation. This study analysed, prospectively, the impact of high vs low pressure stent implantation techniques using a second generation stent on intimal hyperplasia and follow-up lumen dimensions. METHODS AND RESULTS: Post intervention and follow-up (mean[+/-SD] 5.5+/-1.3 months) angiographic and intravascular ultrasound studies were performed on 120 Multi-Link HP stents randomized to implantation at either low (8-10 atm) or high (16-20 atm) pressure. Intravascular ultrasound measurements of the external elastic membrane, stent, and lumen cross-sectional area were performed at 1 mm axial increments. Peri stent plaque+media cross-sectional area (external elastic membrane-stent cross sectional area, intimal hyperplasia cross-sectional area (stent-lumen cross sectional area at follow-up), intimal hyperplasia thickness and peri-stent tissue growth cross-sectional area (Deltapersistent plaque+media cross-sectional area) were calculated. Intravascular ultrasound demonstrated a larger minimal lumen cross-sectional area post-intervention in the high pressure group (7.3+/-2.0 vs 6.2+/-1.8 mm(2), P<0.001, high vs low pressure group, respectively). At follow up, the mean intimal hyperplasia cross-sectional area (1.7+/-0.9 vs 1.5+/-0.8 mm(2), P=0.708), the mean intimal hyperplasia thickness (0.16+/-0.12 vs 0.16+/ 0.12 mm, P=0.818) and peri-stent tissue proliferation cross-sectional area were not greater in the high pressure group. Thus, the minimal lumen cross-sectional area at follow-up continued to be greater (5.5+/-2.0 vs 4.7+/-1.7 mm(2), P=0.038) in the high pressure group. CONCLUSIONS: High pressure stent implantation results in greater stent expansion even with the less rigid second generation Multi-Link stent. Larger lumen dimensions persist at follow-up, while intimal hyperplasia is not significantly greater after high pressure implantation compared to the low pressure technique. PMID- 11603911 TI - Gender differences in recurrent coronary events. The FINMONICA MI register. PMID- 11603912 TI - From COURT to HOMBURG: in search of the optimal contrast agent. PMID- 11603915 TI - Ionic or non-ionic contrast media in stent placement. PMID- 11603917 TI - Autoantibodies: emerging upstream targets of arrhythmias and sudden death in patients with idiopathic dilated cardiomyopathy. PMID- 11603918 TI - Transcription factors and heart failure: does the stressed heart need a hand? PMID- 11603919 TI - The cell cycle can be a new target for the treatment of cardiac hypertrophy? PMID- 11603920 TI - Death by protein kinase C inhibitor: a stressful event. PMID- 11603921 TI - Decreased expression of insulin-like growth factor-1 and apoptosis of vascular smooth muscle cells in human atherosclerotic plaque. AB - Insulin-like growth factor-1 (IGF-1) plays an important role in migration, cell cycle progression and survival of vascular smooth muscle cells (VSMC). We investigated the specific localization of IGF-1 and its receptor (IGF-1R) and their association with apoptosis and the expression of apoptosis-related proteins in early and advanced atherosclerotic lesions. Human atherosclerotic plaques (n=23) from patients undergoing aortic, carotid or femoral arterial surgery were studied. Immunohistochemistry and in situ hybridization revealed significantly higher expression of IGF-1 and IGF-1R in the media than in the intima of early atherosclerotic lesions (P<0.01). Medial VSMC positive for BAX, a proapoptotic protein of the B-cell CLL/lymphoma 2 (BCL2) family, showed colocalization of IGF 1. Apoptosis, as detected by DNA in situ terminal deoxynucleotidyl transferase end labeling (TUNEL), was not present in these early lesions. In advanced atherosclerotic plaques, the expression of IGF-1 and IGF-1R was significantly lower in the intimal regions with macrophage infiltration than in those without macrophage infiltration or than in the media (P<0.01). Furthermore, IGF-1 and IGF 1R immunoreactivity was markedly lower in intimal TUNEL-positive VSMC compared with intimal BAX-positive and medial VSMC (P<0.01). We conclude that IGF-1 and IGF-1R expression are reduced in the deep intima of early atherosclerotic lesions and in areas of advanced plaques with macrophage infiltration. Since IGF-1 is a potent survival factor for VSMC, poor expression of IGF-1 and IGF-1R in intimal regions with macrophage infiltration would likely contribute to triggering VSMC apoptosis potentially leading to plaque weakening, plaque rupture and acute coronary events. PMID- 11603922 TI - Protein kinase C(epsilon) modulates apoptosis induced by beta -adrenergic stimulation in adult rat ventricular myocytes via extracellular signal-regulated kinase (ERK) activity. AB - Beta-adrenergic stimulation of ventricular myocytes has been shown to induce apoptosis; however, the cellular mechanisms involved in this pathway have not been completely characterized. This study examines the role of protein kinase C (PKC) in the signaling cascade that mediates beta-adrenergic stimulation-induced apoptosis. Stimulation of beta-adrenergic receptors using isoproterenol (ISO, 1 10 microm, 24 h) induced apoptosis in cultured adult rat ventricular myocytes (ARVM) in a dose-dependent manner. Treatment with ISO significantly resulted in the membrane translocation of PKC(epsilon), but not of PKC alpha or delta in ARVM. The activation of PKC(epsilon) by ISO was confirmed using an immune complex kinase assay. To address whether PKC(epsilon) is involved in the mechanism of ISO induced apoptosis, we used the PKC(epsilon)-specific translocation inhibitor peptide, epsilonV1-2. Peptide epsilonV1-2 significantly blocked the translocation of PKC(epsilon), as well as the enzymatic action of PKC(epsilon), resulting from ISO stimulation. The inhibition of PKC(epsilon) attenuated ISO-induced apoptosis as measured by terminal deoxynucleotidyltransferase nick-end labeling (TUNEL) assay (18.2+/-3.8%v 49.0+/-2.4%P<0.05), while a PKC delta-specific peptide translocation inhibitor (delta V1-1) failed to do so (39.8+/-7.8%). In the presence of ISO, PKC(epsilon) inhibition by epsilonV1-2 was found to significantly enhance activity of ERK, but not that of Akt/PKB. Inhibition of ERK activation by PD 98059 (10-50 microm) attenuated the epsilonV1-2 peptide-mediated anti-apoptotic effect, thus suggesting that ERK activation is involved in this anti-apoptotic effect. Therefore, our results suggest that activation of PKC(epsilon) downstream of beta-adrenergic stimulation promotes apoptosis largely via inhibition of an ERK activation-dependent anti-apoptotic effect. PMID- 11603923 TI - Reactive oxygen species mediate cyclic strain-induced endothelin-1 gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in endothelial cells. AB - Endothelin-1 (Et-1) is a peptide synthesized by endothelial cells (ECs) both in culture and in vivo. Cyclic strain induces gene expression of Et-1, however, the molecular mechanisms remain unclear. Since cyclic strain induces a sustained increase in intracellular reactive oxygen species (ROS), we hypothesized that the ROS could be a modulator in strain-induced Et-1 gene expression. Human umbilical vein ECs (HUVECs) subjected to cyclic strain had increased Et-1 secretion. Pretreatment of HUVECs with antioxidants, catalase (300 U/ml) or 1,3-dimethyl-2 thiourea (DMTU, 0.1 mm), abolished the strain-induced Et-1 release. ECs strained for 6 h had elevated Et-1 mRNA levels. In contrast, ECs treated with catalase or DMTU did not have increase Et-1 mRNA levels stimulated by cyclic strain. Bovine aortic ECs (BAECs) transfected with fusion plasmid containing Et-1 5'-flanking sequence (4.4 kb) and chloramphenicol acetyltransferase reporter gene produced a maximal Et-1 promoter activity after undergoing strain for 6 h, whereas pretreatment with catalase decreased this activity. BAECs cotransfected with a dominant negative mutant of Ras (RasN17), Raf-1 (Raf301), or catalytically inactive mutant of extracellular signal-regulated kinase (mERK2) had inhibited strain-induced Et-1 promoter activity, indicating the Ras/Raf/ERK pathway was involved; moreover, ERK phosphorylation was induced in ECs which were strained. This strain-activated ERK phosphorylation was attenuated in the presence of catalase. Functional analysis of the Et-1 promoter with site-directed mutagenesis indicates that the activator protein-1 (AP-1) binding site had to be within 143 base-pairs upstream of transcription initiation site for strain-induced promoter activity. Pretreatment of ECs with catalase also decreased the strain-induced promoter activity in the minimal construct (-143 bp). Our data demonstrate that strain-induced Et-1 gene expression is modulated by ROS via Ras/Raf/ERK signaling pathway, and indicate the responsiveness of the AP-1 binding site for strain induced Et-1 expression. PMID- 11603924 TI - A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. AB - Tropomyosin, an essential component of the sarcomere, regulates muscle contraction through Ca(2+)-mediated activation. Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in numerous cardiac sarcomeric proteins, including myosin heavy and light chains, actin, troponin T and I, myosin binding protein C, and alpha-tropomyosin. This study developed transgenic mouse lines that encode an FHC mutation in alpha-tropomyosin; this mutation is an amino acid substitution at codon 180 (Glu180Gly) which occurs in a troponin T binding region. Non-transgenic and control mice expressing wild-type alpha tropomyosin demonstrate no morphological or physiological changes. Expression of exogenous mutant tropomyosin leads to a concomitant decrease in endogenous alpha tropomyosin without altering the expression of other contractile proteins. Histological analysis shows that initial pathological changes, which include ventricular concentric hypertrophy, fibrosis and atrial enlargement, are detected within 1 month. The disease-associated changes progressively increase and result in death between 4 and 5 months. Physiological analyses of the FHC mice using echocardiography, work-performing heart analyses, and force measurements of cardiac myofibers, demonstrate dramatic functional differences in diastolic performance and increased sensitivity to calcium. This report demonstrates that mutations in alpha-tropomyosin can be severely disruptive of sarcomeric function, which consequently triggers a dramatic hypertrophic response that culminates in lethality. PMID- 11603925 TI - Chelerythrine rapidly induces apoptosis through generation of reactive oxygen species in cardiac myocytes. AB - The role of protein kinase C (PKC) inhibition in cardiac myocyte apoptosis has not been well understood. We investigated the mechanism, by which chelerythrine, a commonly used PKC inhibitor, induces potent myocyte death. Chelerythrine (6-30 microm) rapidly induced pyknosis, shrinkage and subsequent cell death in cardiac myocytes. Chelerythrine-induced myocyte death was accompanied by nuclear fragmentation and activation of caspase-3 and -9, while it was prevented by XIAP, suggesting that the cell death is due to apoptosis. Higher concentrations of chelerythrine caused necrotic cell death where neither cell shrinkage nor caspase activation was observed. Intravenous injection of chelerythrine (5 mg/kg) also increased apoptosis in adult rat hearts in vivo. Downregulation of the phorbol 12 myristate 13-acetate (PMA)-sensitive PKC failed to affect chelerythrine-induced apoptosis, while anti-oxidants, including N-acetyl-L-cysteine (NAC) and glutathione, inhibited it, suggesting that generation of reactive oxygen species (ROS) rather than inhibition of PMA-sensitive PKC mediates chelerythrine-induced cardiac myocyte apoptosis. Chelerythrine caused cytochrome c release from mitochondria, which was significantly inhibited in the presence of NAC, suggesting that ROS mediates chelerythrine-induced cytochrome c release. Partial inhibition of cytochrome c release by Bcl-X(L) significantly reduced chelerythrine-induced apoptosis. These results suggest that chelerythrine rapidly induces cardiac myocyte apoptosis and that production of ROS, possibly H(2)O(2), and subsequent cytochrome c release from mitochondria play an important role in mediating chelerythrine-induced rapid cardiac myocyte apoptosis. PMID- 11603926 TI - Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma. AB - Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater beta-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon gamma (INF-gamma, 5000 units). LPS/INF-gamma depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. beta-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-gamma hearts. Additionally isoproterenol stimulated cAMP elaboration was less in old (1950+/-160 fmol/min/g) v young (2440+/-170 fmol/min/g, P=0.05) LPS/INF-gamma hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed beta adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-gamma was approximately 2-3 fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-gamma. These findings indicate that advanced age is associated with augmented cardiac beta-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes. PMID- 11603927 TI - Reperfusion-induced Ins(1,4,5)P(3) generation and arrhythmogenesis require activation of the Na(+)/Ca(2+) exchanger. AB - Reperfusion of globally ischemic rat hearts causes rapid generation of inositol(1,4,5) trisphosphate [Ins(1,4,5)P(3)] and the development of arrhythmias, following stimulation of alpha(1)-adrenergic receptors by norepinephrine released from the cardiac sympathetic nerves. The heightened inositol phosphate response in reperfusion depends on the activation of the Na(+)/H(+) exchanger, which might reflect a central role for increased Ca(2+)following reverse mode activation of the Na(+)/Ca(2+) exchanger (NCX). Isolated, perfused rat hearts were subjected to 20 min ischemia followed by 2 min reperfusion and the content of Ins(1,4,5)P(3) measured by mass analysis or by anion-exchange high performance liquid chromatography (HPLC) following [(3)H]inositol labeling. Reperfusion caused generation of Ins(1,4,5)P(3) (1266+/ 401 to 3387+/-256 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01) and the development of arrhythmias. Inhibition of NCX either by reperfusion at low Ca(2+) (1133+/-173 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01 relative to reperfusion control) or by adding 10 microm KB-R7943, an inhibitor of reverse mode Na(+)/Ca(2+) exchange, prevented the Ins(1,4,5)P(3) response (1151+/-243 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01 relative to reperfusion control) and the development of ventricular fibrillation. Lower concentrations of KB-R7943 were less effective. Reverse mode activation of NCX is therefore required for the enhanced Ins(1,4,5)P(3) response in early reperfusion, and inhibitors of this transporter may be useful in the prevention of arrhythmias under such conditions. PMID- 11603928 TI - Apoptosis in the skeletal muscle of rats with heart failure is associated with increased serum levels of TNF-alpha and sphingosine. AB - Skeletal muscle in congestive heart failure (CHF) is responsible for increased fatigability, decreased endurance and exercise capacity. A specific myopathy with increased expression of fast myosin heavy chains (MHCs), myocyte atrophy, secondary to myocyte apoptosis, that is triggered by high levels of circulating tumor necrosis factor (TNF-alpha) has been described. However, a direct effect of TNF-alpha on skeletal muscle has not been described yet. In this paper we put forward the hypothesis that TNF-alpha plays an indirect effect on skeletal myocytes. In an animal model of CHF, the monocrotaline-treated rat, we have observed a significant (P<0.001) increase of circulating TNF-alpha that is paralleled by increased serum levels of the endogenous second messenger, sphingosine (SPH), (from 0.71+/-0.15 to 1.32+/-0.39 nmoles/ml, P<0.01). In the tibialis anterior (TA) muscle we found a marked increase of myocyte apoptosis (from 1.4+/-2.4 to 40.1+/-39.5 nuclei/mm(3), P<0.04). We correlated plasma levels of TNF-alpha with those of SPH and in turn with the magnitude of apoptosis. Linear regression showed a significant correlation between TNF-alpha, SPH, and apoptosis (r(2)=0.74, P=0.004 and r(2)=0.87, P=0.001 respectively). Analysis of covariance showed that TNF-alpha and SPH were independently correlated with the number of apoptotic nuclei (P=0.0001). In parallel in vitro experiments, where increasing concentrations of SPH were applied to skeletal muscle cells in culture, we observed a dose-dependent increase in apoptosis. These results suggest that TNF-alpha-induced SPH production may be responsible for skeletal muscle apoptosis. The link between TNF-alpha and skeletal muscle apoptosis could be represented by the second messenger SPH, which can directly induce apoptosis in these cells. PMID- 11603929 TI - Cardiovascular genomics: estimating the total number of genes expressed in the human cardiovascular system. AB - The number of genes encoded by the human genome has long sought to be determined. With the recent publications of the complete sequence of the human genome, the number of genes encoded by the human genome has now been estimated to be approximately 32,000-38,000. Now the next step will be to determine which of these genes are expressed in a given cell, tissue or organ. Using three unique approaches taking advantage of our current cardiovascular EST database and the complete nucleotide sequence of human chromosomes 21 and 22 as well as cDNA microarray hybridization, we estimate that between 20,930-27,160 genes are expressed in the cardiovascular system. PMID- 11603930 TI - Chloride channel inhibition does block the protection of ischemic preconditioning in myocardium. PMID- 11603932 TI - Phylogenetic relationships within the cyst-forming nematodes (Nematoda, Heteroderidae) based on analysis of sequences from the ITS regions of ribosomal DNA. AB - The ITS1, ITS2, and 5.8S gene sequences of nuclear ribosomal DNA from 40 taxa of the family Heteroderidae (including the genera Afenestrata, Cactodera, Heterodera, Globodera, Punctodera, Meloidodera, Cryphodera, and Thecavermiculatus) were sequenced and analyzed. The ITS regions displayed high levels of sequence divergence within Heteroderinae and compared to outgroup taxa. Unlike recent findings in root knot nematodes, ITS sequence polymorphism does not appear to complicate phylogenetic analysis of cyst nematodes. Phylogenetic analyses with maximum-parsimony, minimum-evolution, and maximum-likelihood methods were performed with a range of computer alignments, including elision and culled alignments. All multiple alignments and phylogenetic methods yielded similar basic structure for phylogenetic relationships of Heteroderidae. The cyst forming nematodes are represented by six main clades corresponding to morphological characters and host specialization, with certain clades assuming different positions depending on alignment procedure and/or method of phylogenetic inference. Hypotheses of monophyly of Punctoderinae and Heteroderinae are, respectively, strongly and moderately supported by the ITS data across most alignments. Close relationships were revealed between the Avenae and the Sacchari groups and between the Humuli group and the species H. salixophila within Heteroderinae. The Goettingiana group occupies a basal position within this subfamily. The validity of the genera Afenestrata and Bidera was tested and is discussed based on molecular data. We conclude that ITS sequence data are appropriate for studies of relationships within the different species groups and less so for recovery of more ancient speciations within Heteroderidae. PMID- 11603933 TI - Phylogenetic relationships of the Cochliopinae (Rissooidea: Hydrobiidae): an enigmatic group of aquatic gastropods. AB - Phylogenetic analysis based on a partial sequence of the mitochondrial cytochrome c oxidase subunit I gene was performed for 26 representatives of the aquatic gastropod subfamily Cochliopinae, 6 additional members of the family Hydrobiidae, and outgroup species of the families Rissoidae and Pomatiopsidae. Maximum parsimony analysis yielded a single shortest tree which resolved two monophyletic groups: (1) a clade containing all cochliopine taxa with the exception of Antroselates and (2) a clade composed of Antroselates and the hydrobiid genus Amnicola. The clade containing both of these monophyletic groups was depicted as more closely related to members of the family Pomatiopsidae than to other hydrobiid snails which were basally positioned in our topology. New anatomical evidence supports recognition of the cochliopine and Antroselates-Amnicola clades, and structure within the monophyletic group of cochliopines is largely congruent with genitalic characters. However, the close relationship between the Pomatiopsidae and these clades is in conflict with commonly accepted classifications and suggests that a widely accepted scenario for genitalic evolution in these snails is in need of further study. PMID- 11603934 TI - The phylogenetic relationships of the bilby, Macrotis lagotis (Peramelimorphia: Thylacomyidae), to the bandicoots- DNA sequence evidence. AB - Partial sequencing of the 12S ribosomal RNA gene was used to test two competing hypotheses concerning the phylogenetic relationship of the bilby (Macrotis lagotis) to the Australian and New Guinean species of bandicoot. The first hypothesis proposes that the Australian and New Guinean bandicoots are in a monophyletic clade to the exclusion of the bilbies, whereas the second hypothesis proposes that the bilby is monophyletic with the Australian bandicoots to the exclusion of the New Guinean bandicoots. Phylogenies determined by both maximum likelihood and neighbour-joining approaches supported the first hypothesis in which the bilby is excluded from the clade represented by the Australian and New Guinean bandicoots. Monophyly of the Australian and New Guinean bandicoots is consistent with the biogeographical scenario in which Australia and Papua New Guinea have undergone repeated connection and disconnection over the last 20 million years. PMID- 11603935 TI - Phylogenetic position of Eulipotyphla inferred from the cDNA sequences of pepsinogens A and C. AB - Although to date the phylogenetic position of the provisional order Eulipotyphla has been assessed by various molecular markers, it has not been conclusively clarified due to low statistical supporting values and inconsistent results. To clarify the phylogenetic position of Eulipotyphla, we cloned cDNAs for pepsinogens A and C from five mammalian species belonging to four different orders and determined their nucleotide sequences. Molecular phylogenetic analysis based on the 1st and 2nd codon positions of the protein-coding region of cDNA sequences strongly supported the close relationship between Eulipotyphla and Chiroptera. Carnivora was found to be a sister group to these two orders. The monophyly of the order Rodentia and that of the cohort Glires (Rodentia and Lagomorpha) was also shown by the present phylogenetic trees of pepsinogens. PMID- 11603936 TI - Sources of incongruence among mammalian mitochondrial sequences: COII, COIII, and ND6 genes are main contributors. AB - To investigate the origins of incongruence among mammalian mitochondrial protein coding genes, we compiled a matrix that included 13 protein-coding-genes for 41 mammals from 14 different orders. This matrix was examined for congruence using different partitioning strategies. The incongruence length difference test showed significant incongruence among the 13 gene partitions used simultaneously, and the result was not affected by third codon or transversion weighting. In the pair wise comparisons, significant incongruence was detected between NADH:ubiquinone oxidoreductase subunit 6 gene (ND6), cytochrome oxidase subunit II (COII), or cytochrome oxidase subunit III (COIII) gene partitioned individually against the rest of the genes. Omission of any of the 14 mammalian orders alone or in combinations from the matrix did not result in a statistically significant improvement of congruence, suggesting that taxonomic sampling will not improve congruence among the data sets. However, omission of the ND6, COII, and COIII significantly improved congruence in our data matrix. Possible origins of unusual phylogenetic properties of the three genes are discussed. PMID- 11603937 TI - Molecular phylogenies of fig wasps: partial cocladogenesis of pollinators and parasites. AB - Figs (Ficus spp., Moraceae) and their pollinating wasps form an obligate mutualism, which has long been considered a classic case of coevolution and cospeciation. Figs are also exploited by several clades of nonpollinating wasps, which are parasites of the mutualism and whose patterns of speciation have received little attention. We used data from nuclear and mitochondrial DNA regions to estimate the phylogenies of 20 species of Pleistodontes pollinating wasps and 16 species of Sycoscapter nonpollinating wasps associated with Ficus species in the section Malvanthera. We compare the phylogenies of 15 matched Pleistodontes/Sycoscapter species pairs and show that the level of cospeciation is significantly greater than that expected by chance. Our estimates of the maximum level of cospeciation (50 to 64% of nodes) are very similar to those obtained in other recent studies of coevolved parasitic and mutualistic associations. However, we also show that there is not perfect congruence of pollinator and parasite phylogenies (for any substantial clade) and argue that host plant switching is likely to be less constrained for Sycoscapter parasites than for Pleistodontes pollinators. There is perfect correspondence between two terminal clades of two sister species in the respective phylogenies, and rates of molecular evolution in these pairs are similar. PMID- 11603939 TI - Phylogenetic relationships within the class Spirotrichea (Ciliophora) inferred from small subunit rRNA gene sequences. AB - The small subunit rDNAs of five species belonging to the Euplotidae and eight species of the Oxytrichidae were sequenced to obtain a more detailed picture of the phylogenetic relationships within the Spirotrichea (Ciliophora). Various tree reconstruction algorhythms yielded nearly identical topologies. All Euplotidae were separated from the other Spirotrichea by a deep split. Further, a large genetic distance between the marine genus Moneuplotes and the freshwater species of Euplotoides was found. Differences between the methods used occurred only within the Oxytrichidae. Whereas the monophyly of the Stylonychinae was supported in all trees, the monophyly of the Oxytrichinae was not. However, the molecular data support the morphological and ontogenetic evidence that the pattern of 18 frontal-ventral-transversal cirri evolved in the stemline of the Oxytrichidae and was modified several times independently. Our results are also in agreement with taxonomic revisions: the separation of both Sterkiella nova from Oxytricha and Tetmemena pustulata from Stylonychia. PMID- 11603940 TI - The evolution of nuclear receptors: evidence from the coral Acropora. AB - We have amplified and sequenced PCR products derived from 10 nuclear receptor (NR) genes from the anthozoan cnidarian Acropora millepora, including five products corresponding to genes not previously reported from the phylum Cnidaria. cDNAs corresponding to seven of these products were sequenced and at least three encode full-length proteins, increasing the number of complete cnidarian NR coding sequences from one to four. All clear orthologs of Acropora NRs either lack an activation domain or lack a known ligand, consistent with the idea that the ancestral nuclear receptor was without a ligand. Phylogenetic analyses indicate that most, and possibly all, presently identified cnidarian NRs are members of NR subfamily 2, suggesting that the common ancestor of all known nuclear receptors most resembled members of this subfamily. PMID- 11603938 TI - Evaluation of relationships within the endemic Hawaiian Platynini (Coleoptera: Carabidae) based on molecular and morphological evidence. AB - Relationships among 69 species of Hawaiian Platynini, a monophyletic beetle radiation, was investigated based on evidence from five data partitions, comprising mitochondrial and nuclear DNA sequences (cytochrome oxidase II, 624 bp; cytochrome b, 783 bp; 28S rDNA, 668 bp; wingless; 441 bp) and morphology (206 features of external and internal anatomy). Results from individual and combined data analyses generally support the monophyly of three putative divisions within Platynini in Hawaii: Division 0 (Colpocaccus species group), Division 1 (Blackburnia species group), and Division 2 (Metromenus species group). However, relationships within and among these three divisions differ from previous morphological hypotheses. An extensive series of sensitivity analyses was performed to assess robustness of recovered clades under a variety of weighted parsimony conditions. Sensitivity analyses support the monophyly of Divisions 0 and 1, but were equivocal for the monophyly of Division 2. A phylogeny based on combined data suggests at least four independent losses/reductions of platynine flight wings. The combined analysis provides corroboration for biogeographic hypotheses, including (1) colonization of Kauai by Hawaiian Platynini with subsequent dispersal and colonization along the island chain from Oahu to Maui Nui to Hawaii Island and (2) incongruent area relationships among Eastern Molokai, West Maui, and Haleakala for two species triplets. PMID- 11603941 TI - Phylogenetics of Planipapillus, lawn-headed onychophorans of the Australian Alps, based on nuclear and mitochondrial gene sequences. AB - We addressed phylogenetic relationships among species of Planipapillus, a clade of oviparous onychophorans from southeastern mainland Australia, to create a framework for understanding the evolution of the modified male head papillae used in mating in this clade. We sequenced fragments of two mitochondrial genes, COI and 12S rRNA, and a nuclear intron from the fushi tarazu gene, for individuals from 14 putative species of Planipapillus and six outgroups. We analyzed these data under both parsimony and likelihood criteria, incorporating heterogeneous parameter fitting guided by likelihood ratio tests. These analyses result in strong, congruent support for many clades. We infer multiple independent origins of spikes in Planipapillus male head structures. PMID- 11603943 TI - Molecular evolution of viral fusion and matrix protein genes and phylogenetic relationships among the Paramyxoviridae. AB - Phylogenetic relationships among the Paramyxoviridae, a broad family of viruses whose members cause devastating diseases of wildlife, livestock, and humans, were examined with both fusion (F) and matrix (M) protein-coding sequences. Neighbor joining trees of F and M protein sequences showed that the Paramyxoviridae was divided into the two traditionally recognized subfamilies, the Paramyxovirinae and the Pneumovirinae. Within the Paramyxovirinae, the results also showed groups corresponding to three currently recognized genera: Respirovirus, Morbillivirus, and Rubulavirus. The relationships among the three genera of the Paramyxovirinae were resolved with M protein sequences and there was significant bootstrap support (100%) showing that members of the genus Respirovirus and the genus Morbillivirus were more closely related to each other than to members of the genus Rubulavirus. Both F and M phylogenies showed that Newcastle disease virus (NDV) was more closely related to the genus Rubulavirus than to the other two genera but were consistent with the proposal (B. S. Seal et al., 2000, Virus Res. 66, 1-11) that NDV be classified as a separate genus within the Paramyxovirinae. Both F and M phylogenies were also consistent with the proposal (L. Wang et al., 2000, J. Virol 74, 9972-9979) that Hendra virus be classified as a new genus closely related and basal to the genus Morbillivirus. Rinderpest was most closely related to measles and a more derived virus than to canine distemper virus, phocine distemper virus, or dolphin morbillivirus. PMID- 11603942 TI - Phylogeographic structure in the bogus yucca moth Prodoxus quinquepunctellus (Prodoxidae): comparisons with coexisting pollinator yucca moths. AB - The pollination mutualism between yucca moths and yuccas highlights the potential importance of host plant specificity in insect diversification. Historically, one pollinator moth species, Tegeticula yuccasella, was believed to pollinate most yuccas. Recent phylogenetic studies have revealed that it is a complex of at least 13 distinct species, eight of which are specific to one yucca species. Moths in the closely related genus Prodoxus also specialize on yuccas, but they do not pollinate and their larvae feed on different plant parts. Previous research demonstrated that the geographically widespread Prodoxus quinquepunctellus can rapidly specialize to its host plants and may harbor hidden species diversity. We examined the phylogeographic structure of P. quinquepunctellus across its range to compare patterns of diversification with six coexisting pollinator yucca moth species. Morphometric and mtDNA cytochrome oxidase I sequence data indicated that P. quinquepunctellus as currently described contains two species. There was a deep division between moth populations in the eastern and the western United States, with limited sympatry in central Texas; these clades are considered separate species and are redescribed as P. decipiens and P. quinquepunctellus (sensu stricto), respectively. Sequence data also showed a lesser division within P. quinquepunctellus s.s. between the western populations on the Colorado Plateau and those elsewhere. The divergence among the three emerging lineages corresponded with major biogeographic provinces, whereas AMOVA indicated that host plant specialization has been relatively unimportant in diversification. In comparison, the six pollinator species comprise three lineages, one eastern and two western. A pollinator species endemic to the Colorado Plateau has evolved in both of the western lineages. The east-west division and the separate evolution of two Colorado Plateau pollinator species suggest that similar biogeographic factors have influenced diversification in both Tegeticula and Prodoxus. For the pollinators, however, each lineage has produced a monophagous species, a pattern not seen in P. quinquepunctellus. PMID- 11603944 TI - Evolution of East Asian ninespine sticklebacks as shown by mitochondrial DNA control region sequences. AB - Evolutionary processes in East Asian ninespine sticklebacks (Pungitius spp.), including both extremes of armor morphology in the genus, were demonstrated with mitochondrial DNA control region (CR) phylogeny. Entire CR sequences (830-930 bp long) were determined for three species: the most heavily armored (P. sinensis), the most reduced (P. tymensis), and an intermediate (P. pungitius). The former two species are endemic to East Asia, the latter being circumpolar. Three major lineages (A, B, and C) were revealed, whereas both the phylogenetic trees and the insertion sequence dynamics supported the polyphyly of P. sinensis. Haplotypes of the mainland populations of P. sinensis possessed lineage B, being the sister group of P. tymensis lineage A. Island populations of P. sinensis, however, possessed lineage C, along with all P. pungitius haplotypes. A molecular clock hypothesis was clearly rejected for the CR sequences, significantly slower evolutionary rates being observed in the P. tymensis lineage. The split of mainland P. sinensis and P. tymensis was considered to have preceded that of the lineage C colonization in East Asia. The contrasting morphology is probably attributable to adaptation of P. tymensis to island freshwater environments and an ecological interaction between P. tymensis and lineage C emigrants. PMID- 11603945 TI - A molecular phylogeny of Heterodonta (Bivalvia) based on small ribosomal subunit RNA sequences. AB - Within Heterodonta, phylogenesis has so far been studied almost exclusively on the basis of morphological data. Results have often been discordant, and an exhaustive molecular approach has not yet been attempted. The present study was undertaken to clarify the phylogenetic relationships obtaining among Heterodonta families through the analysis of 18S rRNA gene. To do this, the whole sequence of this gene was analyzed in 29 species of eight superfamilies of the order of Veneroida (Arcticoidea, Cardioidea, Galeommatoidea, Mactroidea, Solenoidea, Tellinoidea, Tridacnoidea, and Veneroidea) and in two superfamilies of Myoida (Pholaloidea and Myoidea). The study was extended by constructing phylogenetic trees using partial sequences. This strategy made it possible to include 11 additional species by introducing three further superfamilies: Chamoidea, Corbiculoidea, and Hiatellinoidea. At variance with the conclusions reached on the basis of morphological features, the molecular data clearly show that the Myoida species included in this study belong to Veneroida, thus undermining the legitimacy of the division of Heterodonta into two orders, and that considerable differences in the phylogenetic relationships obtain among superfamilies. PMID- 11603946 TI - Phylogeny of Cryptocercus species (Blattodea: Cryptocercidae) inferred from nuclear ribosomal DNA. AB - The wood-feeding cockroaches of the genus Cryptocercus occur in temperate forests. Of the seven known species, five occur in the United States and two in Eurasia. Until 1997, all populations in the United States were considered a single species. Populations in the western United States were elevated to a species status based on variation in DNA sequence and morphology. In 1999, three new species were described from the eastern United States based on variation in chromosome number and mitochondrial DNA, bringing the number of species in the United States to five. The objective of this study was to determine if the DNA sequence of nuclear rRNA also signals the existence of four species in the eastern United States and to compare the inferred relationships with those proposed based on mitochondrial sequences. We obtained the DNA sequence from a portion of the 5.8S and 28S rRNA genes and the entire ITS2 region from 38 individuals and 30 additional clones to assess intraindividual, intraspecific, and interspecific variation. We found extensive sequence variation among the various species and little or no intraindividual and intraspecific variation. Phylogenetic analysis indicated the existence of monophyletic lineages among the eastern United States samples, which largely corresponded to the four species previously described. The inferred relationships were well-supported by bootstrap analysis and decay indices. Although the nuclear rRNA sequences resulted in a coherent phylogenetic tree, the ITS2 region contained many insertions and deletions, which may introduce homoplasy and ambiguity in alignment as more taxa are added to the data set. PMID- 11603948 TI - Clinical application of forced oscillation. AB - This review summarizes current clinical use of the forced oscillation technique (FOT) for analysis of lung function. It presents an intuitive approach to FOT pattern recognition for interpretation of results in human subjects, and the view that FOT is now well established and, clinically, eminently useful in patients with airflow obstruction. The focus of this review is on findings that relate directly to clinical utility, with less emphasis on theoretical mechanisms. The major thrust for clinical application of FOT derives from a number of European clinical research centers. Farre and Navajas and their colleagues in Barcelona, Harf and the Lorinos and their coworkers in Paris, Peslin and Duvivier and their coworkers in Vandoeuvre-les-Nancy, Pride and coworkers in London, and Van de Woestijne, Clement, Demedts, Landser, Van Noord, and their colleagues in Leuven have essentially been responsible for clinical development of FOT over the past 25 years. Publishing space does not permit an exhaustive listing of the many contributions of these investigators, but it is intended that the present review will provide a useful infrastructure from which the reader may progress to other research citations as desired. PMID- 11603947 TI - Histamine and serotonin. PMID- 11603949 TI - Pressurized metered dose inhalers and add-on devices. AB - Metered dose inhalers (MDIs) which have a valve holding chamber plus a mouthpiece or mask have, in recent years, markedly improved the ease, speed and reliability of aerosol therapy for reversible airflow obstruction in adults, children and infants. MDIs, effective and easily accessible when patients are away from home, are the gold standard for the treatment of reversible airflow obstruction since they provide reliable, reproducible, effort-independent dosing, protection of their contents from environmental humidity and bacterial infection and at the same time are the most readily pocketable, efficient and least expensive aerosol therapy devices available. When combined with add-on devices they are also the most versatile delivery system because they are well suited to a variety of patients and virtually any therapeutic task. With our improved understanding of the importance of drug targeting to the site of action, the most important aspects of the relationship between particle size and drug deposition throughout the lower respiratory tract are discussed. This review also looks at add-on devices and training issues related to the proper co-ordination of drug delivery with inhalation, and reports on new technology and non-ozone depleting propellants. PMID- 11603950 TI - Advances in the research and development of chemotherapeutic agents for respiratory tract bacterial infections. AB - The activity of existing antibiotics is diminishing due to the increasing number of resistant strains and by the increase of infections with naturally resistant microorganisms. New agents are urgently needed to meet this challenge and the molecular strategies adopted for the discovery of these compounds must focus on minimizing the emergence of future resistance to them. Novel compounds can be grouped on the basis of their mechanism of action: inhibitors of nucleic acid synthesis (fluoroquinolones), inhibitors of protein synthesis (ketolides, oxazolidinones, streptogramins, and glycylcyclines), inhibitors of peptidoglycan synthesis (beta-lactams and glycopeptides), and agents interfering with membrane function (cationic peptides, and lipopeptides). Regarding the agents that are already in the research and development pipeline, only the oxazolidinones, the cationic peptides and the lipopeptide antibiotics can be truly considered as structurally novel inhibitors because the other agents are analogues of existing compounds that have been in use for many years. PMID- 11603952 TI - Vasoactive intestinal polypeptide as mediator of asthma. AB - Vasoactive intestinal polypeptide (VIP) is one of the most abundant, biologically active peptides found in the human lung. VIP is a likely neurotransmitter or neuromodulator of the inhibitory non-adrenergic non-cholinergic airway nervous system and influences many aspects of pulmonary biology. In human airways VIP immunoreactive nerve fibres are present in the tracheobronchial airway smooth muscle layer, the walls of pulmonary and bronchial vessels and around submucosal glands. Next to its prominent bronchodilatory effects, VIP potently relaxes pulmonary vessels. The precise role of VIP in the pathogenesis of asthma is still uncertain. Although a therapy using the strong bronchodilatory effects of VIP would offer potential benefits, the rapid inactivation of the peptide by airway peptidases has prevented effective VIP-based drugs so far and non-peptide VIP agonists did not reach clinical use. PMID- 11603951 TI - Endogenous opioids as mediators of asthma. AB - Changes in airway innervation are believed to play a key role in the pathophysiology of asthma. A group of regulatory peptides which act as neuroregulators is resembled by the opioids. Their localization to neurons projecting into airways suggested a possible role as regulators of neurogenic inflammation, bronchoconstriction and mucus secretion. They mainly act through modification of tachykinergic and cholinergic impulses and their ability to inhibit bronchoconstriction prompted discussion of their potential value in asthma therapy. Apart from the presence of the classical opioids and their receptors in the lung and their functional role, a new group of peptides such as nociceptin and endomorphins have been characterized in the airways. Whereas at least endomorphin-1 acts via the classical OP(3) (mu) receptor, nociceptin binds to a new receptor termed opioid receptor-like-receptor (ORL(1)) and inhibits tachykinergic constriction. Contrary to these promising modulatory effects on airway smooth muscle tone, effective therapeutic strategies have not been developed yet. In conclusion, opioids resemble a group of regulatory peptides which are present within airway-innervating nerve fibres and influence a multitude of airway functions via modification of neural transmission. PMID- 11603953 TI - All-trans-retinoic acid (ATRA) is of no benefit in bleomycin-induced lung injury. AB - All-trans-retinoic acid (ATRA) has anti-fibrotic and antiinflammatory properties, and may be useful as a therapeutic agent in lung fibrosis. To test this hypothesis we investigated the effect of ATRA on bleomycin-induced lung fibrosis in Sprague-Dawley rats. Treatment groups included: (1) a single intratracheal (i.t.) instillation of bleomycin and daily intraperitoneal (i.p.) injection of 0.5 mg/kg per day ATRA; (2) i.t. bleomycin and i.p. ATRA, 2 mg/kg per day, (3) i.t. bleomycin and i.p. diluent (cottonseed oil); (4) i.t. saline and i.p. ATRA, 0.5 mg/kg per day, (5) i.t. saline and i.p. ATRA, 2 mg/kg per day; and (6) i.t. saline and i.p. diluent. Animals were studied 14 days after i.t. instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semi-quantitative morphological index of lung injury, and by biochemical analysis of lung hydroxyproline content. Overt signs of lung injury were apparent in bleomycin-treated rats by all measures. These changes were not affected by treatment with ATRA at either dose. This study does not support the use of ATRA to prevent or ameliorate lung fibrosis. PMID- 11603954 TI - Weight of evidence for an association between adverse reproductive and developmental effects and exposure to disinfection by-products: a critical review. AB - Disinfection by-products (DBP) are a side effect of water chlorination. Some toxicological studies suggest an association between DBP exposure and adverse reproductive and developmental effects. This investigation considered all toxicological and epidemiological evidence for the various effects, outcome by outcome. The weight of evidence demonstrated that no association with DBP exposure exists for over a dozen outcomes including low and very low birth weight, preterm delivery, some specific congenital anomalies, and neonatal death. The analysis found inconsistent or very weak results for all congenital anomalies/birth defects, all central nervous system anomalies, neural tube defects, spontaneous abortion, and stillbirth. The weight of evidence suggested a positive association with DBP exposure for some measure of growth retardation (such as intrauterine growth retardation or small for gestational age) and for urinary tract anomalies. Having catalogued these effects, it should be noted that exposure assessment in the epidemiological studies published to date has been inadequate to definitively demonstrate an association of small magnitude. Exposure to DBP primarily has been based on routine (i.e., quarterly) monitoring of public water supplies for trihalomethanes (THM) matched to maternal residence. In order to determine whether an association exists between adverse reproductive and developmental effects and exposure to DBP, studies must consider the THM concentration and the quantity of the water actually consumed by pregnant women. PMID- 11603955 TI - Evaluation of residual and therapeutic doses of tetracycline in the human-flora associated (HFA) mice model. AB - In order to evaluate an in vivo model system for assessing the effect of therapeutic and residue levels of tetracycline on human intestinal microflora, tetracycline was administered via drinking water (1, 10, and 100 mg/liter) to human-flora-associated (HFA) male and female mice. The effects of the antibiotic on fecal aerobic and anaerobic populations, selection of bacteria resistant to tetracycline, metabolic parameters of the microflora, and maintenance of the intestinal barrier against exogenous Salmonella (resistance to colonization) were recorded. In both sexes of mice, tetracycline exposure at 10 and 100 mg/liter induced the selection of several resistant bacterial species (Gram-positive anaerobes, Bacteroides fragilis, enterobacteria, and enterococci). This effect was also observed at the lowest dose (1 mg/liter) in female mice and indicates the potential sensitivity of this endpoint for evaluating the microbiological risk of tetracycline residues. The resistance to colonization was impaired at 100 mg/liter, a concentration corresponding to about half of the therapeutic doses in humans and animals. Metabolic parameters of the microflora were not affected by tetracycline at all levels. In this study, the no-observed-effect level (NOEL) of tetracycline on intestinal flora in this study was less than 1 mg of tetracycline per liter of drinking water. This concentration in the mouse corresponds to 0.125 mg of tetracycline per kilogram of body weight per day. Within the constraints of the experimental design employed here, the HFA mice model proved to be acceptable for studying dose-related effects of tetracycline on human intestinal microflora. PMID- 11603956 TI - Determination of an acute no-observed-adverse-effect level (NOAEL) for copper in water. AB - A prospective, double-blind controlled study was designed to determine the acute no-observed-adverse-effect level (NOAEL) of nausea in an apparently healthy population of 179 individuals who drank copper-containing water as the sulfate salt. Subjects were recruited at three different international sites and given a blind, randomly selected dose (0, 2, 4, 6, or 8 mg Cu/L) in a bolus of 200 ml (final total copper dose was equivalent to 0, 0.4, 0.8, 1.2, and 1.6 mg) once weekly over a consecutive 5-week period. Gastrointestinal (GI) symptoms of nausea, abdominal pain, vomiting, or diarrhea were screened for a period of up to 24 h. Nausea was the most frequently reported effect and was reported within the first 15 min of ingestion. For the combined trisite population (n=179), 8, 9, 14, 25, and 44 subjects responded positively to one or more GI symptoms at 0, 2, 4, 6, and 8 mg Cu/L, respectively. Analysis of the data demonstrated a clear dose response to the combined positive GI effects and to nausea alone. Statistically significant greater reporting of effects occurred at 6 and 8 mg Cu/L. Therefore, an acute NOAEL and lowest-observed-adverse-effect level of 4 and 6 mg Cu/L (0.8 and 1.2 mg Cu), respectively, were determined in drinking water for a combined international human population. PMID- 11603957 TI - IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis. AB - The International Programme on Chemical Safety (IPCS) is leading an activity to harmonize approaches to cancer risk assessment as a part of its larger project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. Through a series of workshops and the evaluation of case studies, a number of key components of risk assessments relating to harmonization were identified: transparency, terminology, weight of evidence, flexibility, and accessibility/communication. A major impediment to harmonization identified in the consideration of weight of evidence was the evaluation of mode of action. To address this need, a conceptual framework was developed, based on the general principles involved in considering the chemical induction of a specific tumor in animals. This is based partly on the Bradford Hill criteria for causality as modified by Faustman et al. (1997) for developmental toxicity. The framework is described in this paper followed by a worked example. It is recognized that the framework addresses only one stage in the overall characterization of hazard to humans of chemical carcinogens. Another important but separate step is the assessment of relevance to humans. This is a priority area for future work in this project. PMID- 11603958 TI - Procedures for health risk assessment in Europe. AB - This report compares cancer classification systems, health risk assessment approaches, and procedures used for establishing occupational exposure limits (OELs), in various European countries and scientific organizations. The objectives were to highlight and compare key aspects of these processes and to identify the basis for differences in cancer classifications and OELs between various scientific organizations and countries. Differences in cancer classification exist in part due to differences in the ultimate purpose of classification and to the relative importance of different types of data (i.e., animal vs human data, mechanistic data, and data from benign vs malignant tumors). In general, the groups surveyed tend to agree on classification of chemicals with good evidence of carcinogenicity in humans, and agree less on classification of chemicals with positive evidence in animals and inadequate or limited evidence in humans. Most entities surveyed distinguish between genotoxic and nongenotoxic chemicals when conducting risk assessments. Although the risk assessment approach used for nongenotoxic chemicals is fairly similar among groups, risk assessment approaches for genotoxic carcinogens vary widely. In addition to risk assessment approaches, other factors which can affect OELs include selection of the critical effect, use of health-based vs technology-based exposure limits, and consideration of technological feasibility and socioeconomic factors. PMID- 11603959 TI - Malignant mesothelioma and asbestos exposure among auto mechanics: appraisal of scientific evidence. AB - In 1986 the U.S. Environmental Protection Agency (EPA) issued an official guideline on the prevention of asbestos disease among auto mechanics. In the EPA guideline, malignant mesothelioma was listed as a consequence of exposure to asbestos fibers from brake linings and clutch facings among auto mechanics. EPA formulated its 1986 opinion by relying solely on a few outdated case reports and not on epidemiologic studies. A review of the literature indicates that there are six epidemiologic studies providing relevant information on malignant mesothelioma among auto mechanics. Three of the six studies had already been published by 1986, the year in which EPA issued its guideline. The results of the six studies were remarkably consistent in that all six studies reported no increased risk of malignant mesothelioma among auto mechanics. The relative risks reported in the six studies ranged from 0.62 to 1.00. Based on a meta-analysis of the combined data of all six studies consisting of approximately 1500 malignant mesothelioma cases, the mesothelioma relative risk for auto mechanics is 0.90 (95% confidence interval 0.66-1.23). An application of Hill's causation criteria to epidemiologic data of malignant mesothelioma among auto mechanics clearly demonstrates that auto mechanics do not have an increased risk of malignant mesothelioma as a result of exposure to asbestos fibers from brake linings and clutch facings. However, in spite of the scientific evidence, EPA has not modified or revised its 1986 guideline. Occupational regulatory policies and guidelines, when based on proper scientific evidence, are invaluable and can prevent avoidable diseases in workers or other exposed individuals in the general public. On the other hand, it is the regulators' responsibility to develop, modify, and revise policies and guidelines in accordance with the most relevant and the latest scientific data. In this instance EPA as a regulator has not fulfilled its responsibility of providing the most accurate and up-to-date information to the workers or the general public. PMID- 11603960 TI - Randomized, double-blind, placebo-controlled, food allergy challenge to olestra snacks. AB - Following approval of the fat replacer olestra for use in preparing savory snacks, Procter & Gamble implemented a postmarketing surveillance program to monitor marketplace introduction. Three and one-half percent of all health effects reported by consumers to the surveillance toll-free number were allergy type symptoms (e.g., rash, itching, edema, hives, dyspnea). Because of these reports, we investigated whether olestra or some component of olestra snacks was a likely allergen in some subset of the population. A single center, randomized, double-blind, placebo-controlled, within-subject crossover food challenge study was conducted to confirm or refute the allergenicity of olestra snacks. Of the 65 subjects who reported symptoms consistent with immediate hypersensitivity to olestra's postmarketing surveillance program, 14 men and women traveled to the Arkansas Children's Hospital Research Institute to participate in this study. Each subject underwent a standard skin prick test at the beginning of the study, to help determine what component, if any, of the olestra product was allergenic. Following the skin prick test, subjects ate in random order, olestra-containing potato chips and regular fat-containing potato chips. The dose of potato chips consumed at each challenge was at least the amount alleged to have caused the symptoms that prompted the consumer to phone the postmarketing surveillance toll free number. No subject experienced an allergic reaction after consuming the olestra-containing chips. Nor did any subject elicit a positive response to olestra following the skin prick testing. Two subjects had positive reactions consistent with immediate hypersensitivity after consuming the regular-fat, placebo potato chips. The results of this study confirm that olestra is unlikely to have an allergenic potential. PMID- 11603961 TI - Glucuronidation of nonylphenol and octylphenol eliminates their ability to activate transcription via the estrogen receptor. AB - Both p-nonylphenol (NP) and p-octylphenol (OP) exhibit weak estrogen-like activity in in vitro and in some rodent assays. To help understand the biochemical and molecular basis for these effects, and thus to permit extrapolation of risk to human health, it is important to establish whether these activities are retained by their metabolites. These data are particularly important in light of the knowledge that both NP and OP are rapidly and extensively metabolized to their glucuronide conjugates in rats. The activity of these glucuronide metabolites, however, is unknown. These studies investigated the intrinsic ability of NP, OP, and their principal mammalian metabolites, nonylphenol glucuronide (NPG) and octylphenol glucuronide (OPG), to affect estrogen receptor (ER)- or androgen receptor (AR)-mediated transcription in a yeast transcriptional activation system. Specifically, the estrogen-, anti estrogen-, androgen-, and anti-androgen-like activities of NP, OP, NPG, and OPG have been assessed using recombinant yeast strains that express either human ER or AR. The two parent compounds, NP (EC(50) 110 nM) and OP (EC(50) 700 nM), exhibited intrinsic estrogen-like activity in this system, and consistent with numerous studies with these chemicals, they were 3-4 orders of magnitude less potent than 17beta-estradiol (EC(50) 500 pM). However, in contrast to the parent molecules, neither NPG nor OPG exhibited any evidence of estrogen-, antiestrogen , androgen-, or anti-androgen-like activity in these recombinant yeast strains. Therefore, the weak estrogen-like activity noted for NP and OP in vivo at high doses is likely to reflect saturation of parent molecule glucuronidation. At anticipated levels of human exposure to NP and OP such a saturation of detoxification is highly unlikely; therefore, these in vitro data support the conclusion that the potential endocrine hazard posed by NP and OP to humans is likely to be negligible. PMID- 11603963 TI - Is benzene oxide homoaromatic? A microcalorimetric study. AB - Rate constants and heats of reaction for the aromatization of benzene oxide (1) and the acid-catalyzed aromatization of benzene hydrate (2) in highly aqueous solution giving phenol and benzene, respectively, have been measured by heat-flow microcalorimetry. The measured heat of reaction of benzene oxide, DeltaH = -57.0 kcal mol(-1), is much larger than that of benzene hydrate, DeltaH = -38.7 kcal mol(-1), despite an unusually low reactivity of benzene oxide, rate ratio 0.08. The measured enthalpies agree with those calculated using the B3LYP hybrid functional corrected with solvation energies derived from semiempirical AM1/SM2 calculations. Comparison with the measured enthalpies of the corresponding reactions of the structurally related 1,3-cyclohexadiene oxide (3) and 2 cyclohexenol (4) of DeltaH = -24.9 kcal mol(-1) (includes a small calculated correction of -1.2 kcal mol(-1)) and DeltaH approximately 0 kcal mol(-1), respectively, gives a smaller aromatization energy for the benzene oxide than for the benzene hydrate reaction (DeltaDeltaDeltaH = 6.6 kcal mol(-1)). This suggests that benzene oxide is unusually stabilized by a significant amount of homoaromatization as has been proposed previously (J. Am. Chem. Soc. 1993, 115, 5458). This unusual stability accounts for more than half of the approximately 10(7) times lower than expected reactivity of benzene oxide toward acid-catalyzed isomerization. The rest is suggested to originate from an unusually high energy of the carbocation-forming transition state. PMID- 11603962 TI - Replacement of surgical castration by GnRH-inhibition or Leydig cell ablation in the male rat Hershberger antiandrogen assay. AB - An obstacle to the widespread adoption of the Hershberger antiandrogen assay is the surgical castration procedure required to produce androgen deficiency in the test animals. Here we describe two chemical treatments that produce similar effects to surgical castration. The first is use of ethane dimethane sulphonate (EDS), a specific toxin to the testosterone-producing Leydig cells of the mature testes. The second class of compound is the decapeptide inhibitors of the gonadotrophin-releasing hormone (GnRH), compounds such as Antarelix and Antide. Administration of either EDS or the GnRH inhibitors results in loss of weight of the testes, epididymides, and sex-associated tissues. Co-administration of testosterone to these animals leads to reversal of the induced effects. The basic test protocol for both of these assay modifications is described. Flutamide was used as a representative potent antiandrogen, and DDE as an example of a weakly active antiandrogen. The 5alpha-reductase inhibitor finasteride was used to inhibit the transformation of testosterone to dihydrotestosterone. It is shown that the EDS assay is sensitive to the antiandrogen flutamide, but that it fails to detect the weaker antiandrogen DDE. In contrast, the Antarelix assay performs as well as does the classical castration assay, leading to the detection as antiandrogens of flutamide, DDE, and finasteride. It is concluded that the GnRH inhibition Hershberger assay is more convenient to conduct than the original surgical castration assay, and it involves less stress to the test animals. PMID- 11603964 TI - Amplification of chirality: the "sergeants and soldiers" principle applied to dynamic hydrogen-bonded assemblies. AB - The amplification of supramolecular chirality has been studied in dynamic chiral hydrogen-bonded assemblies 1(3).(CA)(6) using "Sergeants and Soldiers" experiments. Previously, we have shown that chiral centers present in either the dimelamine component 1 or the cyanurate component CA quantitatively induce one handedness (M or P) in the assembly. This offers the possibility to study the amplification of chirality under two different kinetic regimes. When chiral dimelamines 1 are used, the exchange of chiral components and (M/P) interconversion, i.e., interconversion between the (M)- and (P)-isomers of assembly 1(3).(CA)(6), take place via identical pathways (condition A). When chiral cyanurates CA are used, the exchange of chiral components occurs much faster than (M/P)-interconversion (condition B). Experimentally, a much stronger chiral amplification is observed under condition B. For example, the observed chiral amplification for a mixture of chiral and achiral components (40:60) is 46% under condition B and 32% under condition A. Kinetic models were developed to fit the experimental data and to simulate chiral amplification in dynamic systems in general. These simulations show that it is theoretically possible that the diastereomeric excess in a dynamic system is more than 99% with less than 1% chiral component present! PMID- 11603965 TI - Structural features of aliphatic N-nitrosamines of 7-azabicyclo[2.2.1]heptanes that facilitate N-NO bond cleavage. AB - N-Nitrosamines can be considered as potential nitric oxide (NO)/nitrosonium ion (NO(+)) donors. However, the relation of the structures of N-nitrosamines, in particular of aliphatic N-nitrosamines, to the characteristics of release of NO or NO(+) remains unclear. Here we show that aliphatic N-nitrosoamines of 7 azabicyclo[2.2.1]heptanes can undergo heterolytic N-NO bond cleavage. On the basis of the observation of reduced rotational barriers of the N-NO bonds in solution and nitrogen-pyramidal structures of the N-nitroso group in the solid state, we postulate that N-NO bond cleavage of N-nitrosamines is enhanced by a reduction of the resonance in the N-NO group. Computational studies suggest that these structural features of the N-nitrosamines of 7-azabicyclo[2.2.1]heptane are derived from angle strain imposed on the CNC angles. PMID- 11603967 TI - Efficient, high-yield route to long, functionalized p-phenylene oligomers containing perfluorinated segments, and their cyclodimerizations by zirconocene coupling. AB - Linear oligophenylene diynes containing 6, 9, and 12 phenylene rings were synthesized in high yields using the nucleophilic aromatic substitution (S(N)Ar) of perfluoroarenes by aryllithium reagents as the key carbon-carbon bond-forming reaction. This reaction was demonstrated to proceed readily at low temperatures with sterically hindered substrates and in the presence of base-sensitive silylalkynyl groups. Diynes synthesized by this methodology were readily zirconocene-coupled into large dimeric macrocycles using the zirconocene reagent Cp(2)Zr(py)(Me(3)SiC triple bond CSiMe(3)). PMID- 11603966 TI - Hydroaromatic equilibration during biosynthesis of shikimic acid. AB - The expense and limited availability of shikimic acid isolated from plants has impeded utilization of this hydroaromatic as a synthetic starting material. Although recombinant Escherichia coli catalysts have been constructed that synthesize shikimic acid from glucose, the yield, titer, and purity of shikimic acid are reduced by the sizable concentrations of quinic acid and 3 dehydroshikimic acid that are formed as byproducts. The 28.0 g/L of shikimic acid synthesized in 14% yield by E. coli SP1.1/pKD12.138 in 48 h as a 1.6:1.0:0.65 (mol/mol/mol) shikimate/quinate/dehydroshikimate mixture is typical of synthesized product mixtures. Quinic acid formation results from the reduction of 3-dehydroquinic acid catalyzed by aroE-encoded shikimate dehydrogenase. Is quinic acid derived from reduction of 3-dehydroquinic acid prior to synthesis of shikimic acid? Alternatively, does quinic acid result from a microbe-catalyzed equilibration involving transport of initially synthesized shikimic acid back into the cytoplasm and operation of the common pathway of aromatic amino acid biosynthesis in the reverse of its normal biosynthetic direction? E. coli SP1.1/pSC5.214A, a construct incapable of de novo synthesis of shikimic acid, catalyzed the conversion of shikimic acid added to its culture medium into a 1.1:1.0:0.70 molar ratio of shikimate/quinate/dehydroshikimate within 36 h. Further mechanistic insights were afforded by elaborating the relationship between transport of shikimic acid and formation of quinic acid. These experiments indicate that formation of quinic acid during biosynthesis of shikimic acid results from a microbe-catalyzed equilibration of initially synthesized shikimic acid. By apparently repressing shikimate transport, the aforementioned E. coli SP1.1/pKD12.138 synthesized 52 g/L of shikimic acid in 18% yield from glucose as a 14:1.0:3.0 shikimate/quinate/dehydroshikimate mixture. PMID- 11603968 TI - Metal ion-catalyzed cycloaddition vs hydride transfer reactions of NADH analogues with p-benzoquinones. AB - 1-Benzyl-4-tert-butyl-1,4-dihydronicotinamide (t-BuBNAH) reacts efficiently with p-benzoquinone (Q) to yield a [2+3] cycloadduct (1) in the presence of Sc(OTf)(3) (OTf = OSO(2)CF(3)) in deaerated acetonitrile (MeCN) at room temperature, while no reaction occurs in the absence of Sc(3+). The crystal structure of 1 has been determined by the X-ray crystal analysis. When t-BuBNAH is replaced by 1-benzyl 1,4-dihydronicotinamide (BNAH), the Sc(3+)-catalyzed cycloaddition reaction of BNAH with Q also occurs to yield the [2+3] cycloadduct. Sc(3+) forms 1:4 complexes with t-BuBNAH and BNAH in MeCN, whereas there is no interaction between Sc(3+) and Q. The observed second-order rate constant (k(obs)) shows a first order dependence on [Sc(3+)] at low concentrations and a second-order dependence at higher concentrations. The first-order and the second-order dependence of the rate constant (k(et)) on [Sc(3+)] was also observed for the Sc(3+)-promoted electron transfer from CoTPP (TPP = tetraphenylporphyrin dianion) to Q. Such dependence of k(et) on [Sc(3+)] is ascribed to formation of 1:1 and 1:2 complexes between Q(*)(-) and Sc(3+) at the low and high concentrations of Sc(3+), respectively, which results in acceleration of the rate of electron transfer. The formation constants for the 1:2 complex (K(2)) between the radical anions of a series of p-benzoquinone derivatives (X-Q(*)(-)) and Sc(3+) are determined from the dependence of k(et) on [Sc(3+)]. The K(2) values agree well with those determined from the dependence of k(obs) on [Sc(3+)] for the Sc(3+)-catalyzed addition reaction of t-BuBNAH and BNAH with X-Q. Such an agreement together with the absence of the deuterium kinetic isotope effects indicates that the addition proceeds via the Sc(3+)-promoted electron transfer from t-BuBNAH and BNAH to Q. When Sc(OTf)(3) is replaced by weaker Lewis acids such as Lu(OTf)(3), Y(OTf)(3), and Mg(ClO(4))(2), the hydride transfer reaction from BNAH to Q also occurs besides the cycloaddition reaction and the k(obs) value decreases with decreasing the Lewis acidity of the metal ion. Such a change in the type of reaction from a cycloaddition to a hydride transfer depending on the Lewis acidity of metal ions employed as a catalyst is well accommodated by the common reaction mechanism featuring the metal-ion promoted electron transfer from BNAH to Q. PMID- 11603969 TI - Total synthesis of bafilomycin A(1) relying on iterative 1,2-induction in acyclic precursors. AB - The macrolide bafilomycin A(1) was synthesized starting from D-valine and D mannitol as chiral progenitors of propionate units. Acyclic subunits corresponding to different parts of the molecule were constructed based on an iterative 1,2-asymmetric induction protocol as a distinctive feature of the synthesis. The assembly of two segments encompassing the entire carbon framework of the macrolide was achieved by using a Stille coupling. The resulting seco ester was further manipulated to provide crystalline bafilomycin A(1) via a conventional carbodiimide-mediated Keck-type macrolactonization. PMID- 11603970 TI - Synthesis, characterization, and applicability of neutral polyhydroxy phospholane derivatives and their rhodium(I) complexes for reactions in organic and aqueous media. AB - Two different protocols for the preparation of water-soluble, enantiomerically pure polyhydroxybisphospholanes from acid-labile acetal and tert butyldimethylsilyl-protected derivatives are reported. These procedures circumvent two of the commonly encountered limitations in the synthesis of these potentially important ligands: (a) formation of phosphonium salts from the highly basic phosphine under acidic conditions, and (b) the need to start with preformed, fully protected cationic metal complex. Thus, cationic Rh complexes of these ligands have been prepared in a separate step, and they have been found to be excellent catalysts for organic and aqueous phase hydrogenation of dehydroamino acids. The viability of catalyst recovery has been demonstrated in three different systems, including two cases where > 99% ee can be achieved under recycling conditions. PMID- 11603971 TI - Innovative synthesis of 4-carbaldehydepyrrolin-2-ones by zwitterionic rhodium catalyzed chemo- and regioselective tandem cyclohydrocarbonylation/CO insertion of alpha-imino alkynes. AB - The tandem cyclohydrocarbonylative/CO insertion of alpha-imino alkynes employs CO, H(2), and catalytic quantities of zwitterionic rhodium complex (eta(6) C(6)H(5)BPh(3))(-)Rh(+)(1,5-COD) and triphenyl phosphite affording aldehyde substituted pyrrolinones in 67-82% yields. This unique transformation is readily applied to imino alkynes containing alkyl, alkoxyl, vinyl, and aryl substituents. The ability to prepare highly functionalized pyrrolinones makes this an attractive route to these important and versatile pharmaceuticals. PMID- 11603972 TI - Intramolecular hydrophosphination/cyclization of phosphinoalkenes and phosphinoalkynes catalyzed by organolanthanides: scope, selectivity, and mechanism. AB - Organolanthanide complexes of the general type Cp'(2)LnE(TMS)(2) (Cp' = eta(5) Me(5)C(5); Ln = La, Sm, Y, Lu; E = CH, N; TMS = SiMe(3)) serve as effective precatalysts for the rapid intramolecular hydrophosphination/cyclization of the phosphinoalkenes and phosphinoalkynes RHP(CH(2))(n)()CH=CH(2) (R = Ph, H; n = 3, 4) and H(2)P(CH(2))(n)C triple bond C-Ph (n = 3, 4) to afford the corresponding heterocycles and respectively. Kinetic and mechanistic data for these processes exhibit parallels to, as well as distinct differences from, organolanthanide mediated intramolecular hydroamination/cyclizations. The turnover-limiting step of the present catalytic cycle is insertion of the carbon-carbon unsaturation into the Ln-P bond, followed by rapid protonolysis of the resulting Ln-C linkage. The rate law is first-order in [catalyst] and zero-order in [substrate] over approximately one half-life, with inhibition by heterocyclic product intruding at higher conversions. The catalyst resting state is likely a lanthanocene phosphine phosphido complex, and dimeric [Cp'(2)YP(H)Ph](2) was isolated and cystallographically characterized. Lanthanide identity and ancillary ligand structure effects on rate and selectivity vary with substrate unsaturation: larger metal ions and more open ligand systems lead to higher turnover frequencies for phosphinoalkynes, and intermediate-sized metal ions with Cp'(2) ligands lead to maximum turnover frequencies for phosphinoalkenes. Diastereoselectivity patterns also vary with substrate, lanthanide ion, and ancillary ligands. Similarities and differences in hydrophosphination vis-a-vis analogous organolanthanide-mediated hydroamination are enumerated. PMID- 11603973 TI - First successful molecular design of an artificial Lewis oligosaccharide binding system utilizing positive homotropic allosterism. AB - We have designed phenylboronic acid group appended Ce(IV) bis(porphyrinate) double decker 1 and meso-meso linked porphyrin 2, useful for the allosteric binding of biologically important saccharides, Lewis oligosaccharides. Compound 1 binds Lewis oligosaccharides in aqueous media because of the boronic acid-diol interaction, but the complexation event can occur only above the critical concentrations because of the sigmoidal [oligosaccharide] versus [complex] isotherm. Compound 1 has a sufficiently high affinity with Lewis oligosaccharides (K = 10(5)-10(6) M(-2)) with Hill coefficients n of 1.8-2.0, and Lewis(X) series and Lewis(a) series give opposite, symmetrical CD spectra. This is the first example of efficient binding of Lewis oligosaccharides to the artificial receptor, which has become possible by positive homotropic allosterism. PMID- 11603974 TI - Optimal N-caps for N-terminal helical templates: effects of changes in H-bonding efficiency and charge. AB - A family of efficient helix-initiating N-terminal caps X-Hel is introduced that expand the scope and versatility of the previously reported reporting conformational template Ac-Hel, (Kemp, D. S.; Allen, T. J.; Oslick, S. J. Am. Chem. Soc. 1995, 117, 6641-6657) and a working principle for predicting cap performance is described, based on structurally specific intramolecular hydrogen bond formation. Replacement of the N-acetyl by urethane, urea, or sulfonamide generated less efficient polypeptide helix inducers. The N-formyl cap is found to be equivalent to the N-acetyl and may provide more convenient quantitative helix reporting properties. Anionic N-caps derived from the series X = (-)O(2)C (CH(2))(n)-CO, 0 < or = n < or = 3, are superior to N-acetyl, as are N-acylglycyl and N-acyl-beta-aspartyl. The latter pair of caps permit introduction of the X Hel functionality within a polypeptide chain, allowing control of helicity of a peptide sub-sequence. Applications of these capping functions are discussed. This work has been focused primarily on immediate practical goals directed toward enhancing the maximum helicity of isolated short to medium-sized peptides in aqueous solution, but its developing concepts and working hypotheses are likely to significantly enhance our understanding at a chemical level of the protein folding problem. PMID- 11603975 TI - Helix-loop-helix peptides as scaffolds for the construction of bridged metal assemblies in proteins: the spectroscopic A-cluster structure in carbon monoxide dehydrogenase. AB - Four helix-loop-helix 63mer peptides were designed and synthesized in order to assess the utility of peptides as scaffolds for the stabilization of complex metal sites in proteins. Bridged assembly [Ni(II)-(mu(2)-S.Cys)-Fe(4)S(4)], consistent with spectroscopic information on the A-cluster of carbon monoxide dehydrogenase, was chosen as the target assembly. The peptides consist of two helices with approximately 20 residues connected by a flexible loop containing the ferredoxin consensus sequence Cys-Ile-Ala-Cys-Gly-Ala-Cys to bind the Fe(4)S(4) cluster. A fourth cysteine was positioned to serve as the bridging ligand between the cluster and Ni(II). Three other binding residues were incorporated in appropriate positions to constitute a binding site for Ni(II). One of the peptides was designed with an N(3)S (His(3)Cys) site, and each of the other three with N(2)S(2) (His(2)Cys(2)) sites. A detailed account of the synthesis and characterization of the peptides and their metalloderivatives is presented. The four peptides were synthesized using an Fmoc/t-Bu-based solid phase strategy, purified by reversed-phase HPLC, and characterized by ES-MS. On the basis of size-exclusion chromatography and circular dichroism spectropolarimetry, these peptides appear to dimerize in solution to form four helix bundles of high helical contents. Reactions of the peptides with preformed cluster [Fe(4)S(4)(SCH(2)CH(2)OH)(4)](2)(-) and subsequent purification by column chromatography yield a product consistent with the incorporation of one [Fe(4)S(4)](2+) cluster per 63mer, as judged from absorption and Mossbauer spectra. Addition of a Ni(II) salt to the [Fe(4)S(4)]-peptides results in an apparent equilibrium between free Ni(II) and a peptide-bound nickel form, as established by column chromatography studies. Nickel EXAFS data (Musgrave, K. B.; Laplaza, C. E.; Holm, R. H.; Hedman, B.; Hodgson, K. O. Results to be published.) provide strong evidence that the peptide-bound nickel binds in the desired site in two of the metallopeptides. This work represents the first exploration of peptides as scaffolds for the support of biologically relevant bridged assemblies containing iron-sulfur clusters. PMID- 11603976 TI - Enantiomerically pure chiral coordination polymers: synthesis, spectroscopy, and electrochemistry in solution and on surfaces. AB - The two enantiomerically pure bridging ligands (+/-)-[ctpy-x-ctpy] have been prepared employing a two-fold stereospecific alkylation reaction of the enantiomerically pure, chiral terpyridyl-type ligands (+/-)-ctpy. The reaction of each of the enantiomerically pure bridging ligands with Fe(2+) gives rise to chiral coordination polymers whose formation and stoichiometry were followed spectrophotometrically. An assignment of the absolute configuration of the formed helical polymeric structures was carried out on the basis of circular dichroism studies. Highly ordered domains (as determined from STM imaging) of the enantiomerically pure chiral redox polymers could be prepared via the interfacial reaction, over an HOPG substrate, of the bridging ligand in CH(2)Cl(2) and FeSO(4) in water. The degree of polymerization was estimated to be up to 60 from analysis of the STM images of the highly ordered domains on HOPG. The helicality of the domains was compared to the configuration obtained from the circular dichroism studies. The electrochemical properties of the polymers were investigated using cyclic voltammetry and the results compared to those of the respective monomeric complexes. The redox behavior of the iron centers in the polymer was comparable to that of the monomeric complex [Fe((-) ctpy)(2)](PF(6))(2) as well as to that of [Fe(tpy)(2)](PF(6))(2). The polymeric materials undergo electrodeposition following the two-electron reduction of each bridging ligand unit (one electron per terpyridine group). No ligand-mediated metal-metal interactions were evident from the cyclic voltammetric measurements, suggesting that the metal centers act independently. Moreover, oxidation of the metal centers within the polymeric materials did not give rise to electrodeposition. PMID- 11603977 TI - Bond energies and attachments sites of sodium and potassium cations to DNA and RNA nucleic acid bases in the gas phase. AB - Gas-phase metal affinities of DNA and RNA bases for the Na(+) and K(+) ions were determined at density functional level employing the hybrid B3LYP exchange correlation potential in connection with the 6-311+G(2df,2p) basis set. All the molecular complexes, obtained by the interaction between several low-lying tautomers of nucleic acid bases and the alkali ions on the different binding sites, were considered. Structural features of the sodium and potassium complexes were found to be similar except in some uracil and thymine compounds in which the tendency of potassium ion toward monocoordination appeared evident. B3LYP bond energies for both metal ions were in agreement with the available experimental results in the cases of uracil and thymine for which the most stable complex was obtained starting from the most stable tautomer of the free nucleic acid base. For adenine, although the interaction of the ions with the most stable free tautomer generated the least stable molecular complex, the best agreement with experiment was found in just this case. For the remaining cytosine and guanine bases, our calculations indicated that the metal ion affinity value closest to experiment should be determined taking into account the role played by the different tautomers of the free bases with similar energy and all the possible complexes obtained by them. PMID- 11603978 TI - Catalytic mechanism of glyoxalase I: a theoretical study. AB - Hybrid density functional theory is used to study the catalytic mechanism of human glyoxalase I (GlxI). This zinc enzyme catalyzes the conversion of the hemithioacetal of toxic methylglyoxal and glutathione to nontoxic (S)-D lactoylglutathione. GlxI can process both diastereomeric forms of the substrate, yielding the same form of the product. As a starting point for the calculations, we use a recent crystal structure of the enzyme in complex with a transition state analogue, where it was found that the inhibitor is bound directly to the zinc by its hydroxycarbamoyl functions. It is shown that the Zn ligand Glu172 can abstract the substrate C1 proton from the S enantiomer of the substrate, without being displaced from the Zn ion. The calculated activation barrier is in excellent agreement with experimental rates. Analogously, the Zn ligand Glu99 can abstract the proton from the R form of the substrate. To account for the stereochemical findings, it is argued that the S and R reactions cannot be fully symmetric. A detailed mechanistic scheme is proposed. PMID- 11603979 TI - A model for sequential threading of alpha-cyclodextrin onto a guest: a complete thermodynamic and kinetic study in water. AB - The first variable-temperature and variable-pressure stopped-flow spectrophotometric study of the sequential threading of alpha-cyclodextrin (alpha CD) onto the guest dye Mordant Orange 10, S, is reported. Complementary (1)H one dimensional (1D) variable-temperature kinetic studies and two-dimensional (2D) rotating-frame nuclear Overhauser effect spectroscopy (ROESY) and EXSY NMR studies are also reported. In aqueous solution at 298.2 K, the first alpha-CD threads onto S to form a 1:1 complex S.alpha-CD with a forward rate constant k(1,f) = 15 200 +/- 200 M(-1) s(-1) and dethreads with a reverse rate constant k(1,r) = 4.4 +/- 0.3 s(-1). Subsequently, S.alpha-CD isomerizes to S.alpha-CD (k(3,f) = 0.158 +/- 0.006 s(-1), k(3,f) = 0.148 +/- 0.006 s(-1)). This process can be viewed as a thermodynamically controlled molecular shuttle. A second alpha CD threads onto S.alpha-CD to form a 1:2 complex, S.(alpha-CD)(2), with k(2,f) = 98 +/- 2 M(-1) s(-1) and k(2,r) = 0.032 +/- 0.002 s(-1). A second alpha-CD also threads onto S.alpha-CD to form another 1:2 complex, S.(alpha-CD)(2), characterized by k(4,f) = 9640 +/- 1800 M(-1) s(-1) and k(4,r) = 61 +/- 6 s(-1). Direct interconvertion between S.(alpha-CD)(2) and S.(alpha-CD)(2) was not detected; instead, they interconvert by dethreading the second alpha-CD and through the isomerization equilibrium between S.alpha-CD and S.alpha-CD. The reaction volumes, DeltaV(0), were found to be negative for the first three equilibria and positive for the fourth equilibrium. For the first three forward and reverse reactions, the volumes of activation are substantially more negative, indicating a compression of the transition state in comparison with the ground states. These data were used in conjunction with DeltaH, DeltaH degrees, DeltaS, and DeltaS degrees data to deduce the dominant mechanistic threading processes, which appear to be largely controlled by changes in hydration and van der Waals interactions, and possibly by conformational changes in both S and alpha-CD. The structure of the four complexes were deduced from (1)H 2D ROESY NMR studies. PMID- 11603981 TI - Syntheses, structural characterizations, and optical and electrochemical properties of directly fused diporphyrins. AB - Directly fused diporphyrins display the extensive pi conjugation as evinced by highly perturbed electronic absorption spectra as well as lowered and largely split first oxidation potentials. Such diporphyrins prepared include meso-beta doubly linked diporphyrins 7, meso-meso beta-beta beta-beta triply linked diporphyrins 8, and meso-meso beta-beta doubly linked diporphyrins 9. Oxidation of 5,15-diaryl-substituted and 5,10,15-triaryl-substituted Ni(II)-, Cu(II)-, and Pd(II)-porphyrins with tris(4-bromophenyl)aminium hexachloroantimonate (BAHA) in CHCl(3) afforded 7, and triply linked Cu(II)-diporphyrins 8a and 8g were respectively prepared by the oxidation of meso-meso singly linked Cu(II) diporphyrins 5c and 5f with BAHA. Meso-meso beta-beta doubly linked Ni(II) diporphyrin 9a was isolated along with triply linked Ni(II)-diporphyrin 8e from the similar oxidation of meso-meso singly linked Ni(II)-diporphyrin 5a. Doubly linked diporphyrins 7 and 9a both exhibit significantly perturbed electronic absorption spectra, in which the Soret-like bands are largely split at around 405 418 and 500-616 nm and the Q-bandlike absorption bands are substantially intensified and red-shifted at 748-820 nm, probably as a consequence of symmetry lowering. Triply linked diporphyrins 8 display more strongly perturbed electronic absorption spectra with split Soret-like bands at 408-419 and 567-582 nm and Q bandlike absorption bands reaching far-infrared region. Structures of three types of fused diporphyrins 7b and 7c, 8g and 8j, and 9a have been unambiguously determined by X-ray crystallography to be nearly coplanar. Both the triply linked diporphyrins 8g and 8j exhibit very flat structures, whereas the doubly linked diporphyrins 7b and 7c exhibit ruffled structures. The doubly linked diporphyrin 9a shows a helically twisted conformation with larger ruffling toward the opposite directions and has been actually separated into two enantiomers, which display strong Cotton effects in the CD spectra. The first oxidation potentials (E(OX1)) decrease in the order of 5 > 7 > or = 9 > 8, indicating lift-up of HOMO orbital in this order, and split potential differences DeltaE = E(OX1) - E(OX2), in turn, increase in the reverse order of 5 < 7< or = 9 < 8. The (1)H NMR spectra have indicated that the aromatic porphyrin ring current becomes weakened in the order of 5 > 7 > 8. Collectively, the electronic interactions between the diporphyrins have been concluded to increase in the other of 5 << 7 < or = 9 < 8. PMID- 11603980 TI - Tetrameric fluorophosphazene, (NPF(2))(4), planar or puckered? AB - The results obtained in a comprehensive experimental study on the redetermination of the structure of N(4)P(4)F(8) with single-crystal X-ray diffraction, gas electron diffraction (GED), and differential scanning calorimetry (DSC) establish clearly that, in contrast to the previous report, the eight-membered heterocycle is not planar. Above the phase transition temperature of -74 degrees C, the ring appears pseudoplanar. However, the N(4)P(4) ring is disordered and is puckered above the phase transition when the disorder is modeled correctly. Below the phase transition the ring clearly resembles that of the saddle (K form) of N(4)P(4)Cl(8). The unit cell of the low-temperature phase is derived from that of the higher temperature phase by doubling the c-axis and removing one-half of the symmetry elements. Full structure optimizations were performed at the HF/6-31G and B3LYP/6-31G levels and fully support the experimental diffraction data. PMID- 11603982 TI - Butalene and related compounds: aromatic or antiaromatic? AB - Density functional theory (DFT) has been used to study the first three members of the condensed cyclobutadienoid series, butalene (3), bicyclobutadienylene (12), and dicyclobutenobutalene (20). The first is planar and is judged "aromatic" by comparisons with suitable models using both energetic and magnetic criteria. The second is nonplanar, and not aromatic, but not so antiaromatic as cyclobutadiene (11). The third is slightly more antiaromatic and best viewed as a butalene fused to two cyclobutadiene rings; its properties are the sum of aromatic and antiaromatic components, like benzocyclobutadiene. Ring-opening transition states for both 3 and 12 have been located, and these are conrotatorily twisted. The ring-opening barrier for 12 is more than twice that for 3. Ring-opening of 20 involves ring inversion as the only barrier. PMID- 11603983 TI - Dynamics of mononuclear cadmium beta-lactamase revealed by the combination of NMR and PAC spectroscopy. AB - The two metal sites in cadmium substituted beta-lactamase from Bacillus cereus 569/H/9 have been studied by NMR spectroscopy ((1)H, (15)N, and (113)Cd) and PAC spectroscopy ((111m)Cd). Distinct NMR signals from the backbone amides are identified for the apoenzyme and the mononuclear and binuclear cadmium enzymes. For the binuclear cadmium enzyme, two (113)Cd NMR signals (142 and 262 ppm) and two (111m)Cd PAC nuclear quadrupole interactions are observed. Two nuclear quadrupole interactions are also observed, with approximately equal occupancy, in the PAC spectra at cadmium/enzyme ratios < 1; these are different from those derived for the binuclear cadmium enzyme, demonstrating interaction between the two metal ion binding sites. In contrast to the observation from PAC spectroscopy, only one (113)Cd NMR signal (176 ppm) is observed at cadmium/enzyme ratios < 1. The titration of the metal site imidazole (N)H proton signals as a function of cadmium ion-to-enzyme ratio shows that signals characteristic for the binuclear cadmium enzyme appear when the cadmium ion-to-enzyme ratio is between 1 and 2, whereas no signals are observed at stoichiometries less than 1. The simplest explanation consistent with all data is that, at cadmium/enzyme ratios < 1, the single Cd(II) is undergoing exchange between the two metal sites on the enzyme. This exchange must be fast on the (113)Cd NMR time scale and slow on the (111m)Cd PAC time scale and must thus occur in a time regime between 0.1 and 10 micros. PMID- 11603984 TI - Ultrafast excited-state energy migration dynamics in an efficient light harvesting antenna polymer based on Ru(II) and Os(II) polypyridyl complexes. AB - A detailed study of the excited state energy migration dynamics that take place within an assembly of Ru(II) and Os(II) polypyridyl complexes linked together through a polymer backbone is presented. The energy migration process is initiated by the photoexcitation of the metal-to-ligand charge transfer (MLCT) transition in one of the Ru(II) complexes and terminated by energy transfer to a lower energy Os(II) trap. Energy transfer sensitization of Os(II) can occur in a single step if the excited state is formed adjacent to a trap, or after a series of hops between isoenergetic rutheniums prior to reaching a trap. The dynamics of the energy transfer process are followed by monitoring the growth of Os(II) luminescence at 780 nm. The kinetics of the growth are complex and can be fit by a sum of two exponentials. This kinetic complexity arises both from the presence of a distribution of donor-acceptor distances and the variety of time scales by which Os(II) can be formed. We have augmented the time-resolved experiments with Monte Carlo simulations, which provide insight into the polymer array's structure and at the same time form the basis of a molecular-level description of the energy migration dynamics. The simulations indicate that the most probable Ru- >Os energy transfer time is approximately 400 ps while the time scale for Ru-->Ru hopping is approximately 1-4 ns. The time scale for Ru-->Ru hopping relative to its natural lifetime (1000 ns) suggests that this polymer system could be extended to considerably longer dimensions without an appreciable loss in its overall efficiency. PMID- 11603985 TI - Mechanistic aspects of the abstraction of an allylic hydrogen in the chlorine atom reaction with 2-methyl-1,3-butadiene (isoprene). AB - The different channels for the abstraction of an allylic hydrogen in the chlorine atom reaction with isoprene were explored using ab initio methodology. It is shown that the metathesis reaction proceeds through an association-elimination mechanism in which a weakly bound intermediate (HCl.C(5)H(7)(*)) is formed first (formal addition). Further evolution by HCl elimination leads to the final C(5)H(7)(*) radical. QCISD(T)/aug-cc-pVDZ//MP2/6-31G(d,p) calculations show that for two of the possible pathways the barrier heights involved are moderate and the formation of the intermediates are exergonic (DeltaG < 0). Therefore, the mechanism proposed is both kinetically and thermodynamically feasible. The pressure dependence experimentally observed for the Cl + isoprene reaction can be rationalized in terms of the association-elimination mechanism proposed. PMID- 11603986 TI - Heteronuclear recoupling in solid-state magic-angle-spinning NMR via overtone irradiation. AB - A heteronuclear dipolar recoupling scheme applicable to I-S spin pairs undergoing magic-angle-spinning (MAS) is introduced, based on the overtone irradiation of one of the coupled nuclei. It is shown that when I is a quadrupole, for instance (14)N, irradiating this spin at a multiple of its Larmor frequency prevents the formation of MAS dipolar echoes. The ensuing S-spin signal dephasing is significant and dependent on a number of parameters, including the I-S dipolar coupling, the magnitude of I's quadrupolar coupling, and the relative orientations between these two coupling tensors. When applied to a spin-1 nucleus, this overtone recoupling method differs from hitherto proposed recoupling strategies in that it involves only the +/-1> I(z) eigenstates. Its dephasing efficiency becomes independent of first-order quadrupolar effects yet shows a high sensitivity to second-order offsets. A constant-time/variable-offset recoupling sequence thus provides a simple route to acquire, in an indirect fashion, (14)N overtone spectra from rotating powders. The principles underlying this kind of S-(14)N experiments and different applications involving S = (13)C, (59)Co sites are presented. PMID- 11603987 TI - An experimental and theoretical investigation of the chemical shielding tensors of (13)C(alpha) of alanine, valine, and leucine residues in solid peptides and in proteins in solution. AB - We have carried out a solid-state magic-angle sample-spinning (MAS) nuclear magnetic resonance (NMR) spectroscopic investigation of the (13)C(alpha) chemical shielding tensors of alanine, valine, and leucine residues in a series of crystalline peptides of known structure. For alanine and leucine, which are not branched at the beta-carbon, the experimental chemical shift anisotropy (CSA) spans (Omega) are large, about 30 ppm, independent of whether the residues adopt helical or sheet geometries, and are in generally good accord with Omega values calculated by using ab initio Hartree-Fock quantum chemical methods. The experimental Omegas for valine C(alpha) in two peptides (in sheet geometries) are also large and in good agreement with theoretical predictions. In contrast, the "CSAs" (Deltasigma) obtained from solution NMR data for alanine, valine, and leucine residues in proteins show major differences, with helical residues having Deltasigma values of approximately 6 ppm while sheet residues have Deltasigma approximately 27 ppm. The origins of these differences are shown to be due to the different definitions of the CSA. When defined in terms of the solution NMR CSA, the solid-state results also show small helical but large sheet CSA values. These results are of interest since they lead to the idea that only the beta-branched amino acids threonine, valine, and isoleucine can have small (static) tensor spans, Omega (in helical geometries), and that the small helical "CSAs" seen in solution NMR are overwhelmingly dominated by changes in tensor orientation, from sheet to helix. These results have important implications for solid-state NMR structural studies which utilize the CSA span, Omega, to differentiate between helical and sheet residues. Specifically, there will be only a small degree of spectral editing possible in solid proteins since the spans, Omega, for the dominant nonbranched amino acids are quite similar. Editing on the basis of Omega will, however, be very effective for many Thr, Val, and Ileu residues, which frequently have small ( approximately 15-20 ppm) helical CSA (Omega) spans. PMID- 11603988 TI - DNA excited-state dynamics: ultrafast internal conversion and vibrational cooling in a series of nucleosides. AB - To better understand DNA photodamage, several nucleosides were studied by femtosecond transient absorption spectroscopy. A 263-nm, 150-fs ultraviolet pump pulse excited each nucleoside in aqueous solution, and the subsequent dynamics were followed by transient absorption of a femtosecond continuum pulse at wavelengths between 270 and 700 nm. A transient absorption band with maximum amplitude near 600 nm was detected in protonated guanosine at pH 2. This band decayed in 191 +/- 4 ps in excellent agreement with the known fluorescence lifetime, indicating that it arises from absorption by the lowest excited singlet state. Excited state absorption for guanosine and the other nucleosides at pH 7 was observed in the same spectral region, but decayed on a subpicosecond time scale by internal conversion to the electronic ground state. The cross section for excited state absorption is very weak for all nucleosides studied, making some amount of two-photon ionization of the solvent unavoidable. The excited state lifetimes of Ado, Guo, Cyd, and Thd were determined to be 290, 460, 720, and 540 fs, respectively (uncertainties are +/-40 fs). The decay times are shorter for the purines than for the pyrimidine bases, consistent with their lower propensity for photochemical damage. Following internal conversion, vibrationally highly excited ground state molecules were detected in experiments on Ado and Cyd by hot ground state absorption at ultraviolet wavelengths. The decays are assigned to intermolecular vibrational energy transfer to the solvent. The longest time constant observed for Ado is approximately 2 ps, and we propose that solute-solvent H-bonds are responsible for this fast rate of vibrational cooling. The results show for the first time that excited singlet state dynamics of the DNA bases can be directly studied at room temperature. Like sunscreens that function by light absorption, the bases rapidly convert dangerous electronic energy into heat, and this property is likely to have played a critical role in life's early evolution on earth. PMID- 11603989 TI - On the origin of cytotoxicity of the natural product varacin. A novel example of a pentathiepin reaction that provides evidence for a triatomic sulfur intermediate. AB - A density functional theoretical study is presented, which implicates a novel S(3)-cleavage in the decomposition of a pentathiepin. This study predicts an interconversion between a pentathiepin and an open-chain polysulfur ion intermediate from which a key determinant in the chemistry then follows. Expulsion of diatomic sulfur, S(2), is unlikely from the unimolecular collapse of the open-chain polysulfur ion. Instead, S(3) can dissociate due to an unusually long and weak sulfur-sulfur (S4-S5) bond. A mechanistic picture now emerges which predicts that the novel S-S cleavage reaction and the unanticipated S(3) fragmentation are a result of delocalization of the negative charge within the remaining carbon-sulfur fragment. The computed results presented here reveal a new aspect to the chemistry of pentathiepins, that of S(3) unit transfer, which is proposed to have significance in the mechanism of cytotoxicity of the natural product varacin, 1. PMID- 11603990 TI - The formation of a surprisingly stable HO(2)-H(2)SO(4) complex. PMID- 11603991 TI - Thermally driven intramolecular charge transfer in an oxo-molybdenum dithiolate complex. PMID- 11603992 TI - An unusual reduction of an imine bond: the isolation of a stable pi-iminium intermediate. PMID- 11603993 TI - Chemically reversible organogels: aliphatic amines as "latent" gelators with carbon dioxide. PMID- 11603994 TI - Chiral porous solids based on lamellar lanthanide phosphonates. PMID- 11603995 TI - Metal nanowire formation using Mo(3)Se(3)(-) as reducing and sacrificing templates. PMID- 11603996 TI - The (129)Xe chemical shift tensor in a silicalite single crystal from hyperpolarized (129)Xe NMR spectroscopy. PMID- 11603998 TI - Observation of a hysteretic phase transition in a crystalline dinitroxide biradical that leads to magnetic bistability. PMID- 11603997 TI - Strikingly simple direct alpha-allylation of aldehydes with allyl alcohols: remarkable advance in the Tsuji-Trost reaction. PMID- 11603999 TI - Asymmetric catalysis of planar-chiral cyclopentadienylruthenium complexes in allylic amination and alkylation. PMID- 11604000 TI - Palladium-catalyzed arylative carbon-carbon bond cleavage of alpha,alpha disubstituted arylmethanols. PMID- 11604001 TI - Three-component catalytic asymmetric synthesis of aliphatic amines. PMID- 11604002 TI - Polymer-stabilized gold nanoparticles and their incorporation into polymer matrices. PMID- 11604003 TI - LaPdO(3): the first Pd(III) oxide with the Perovskite structure. PMID- 11604004 TI - Nonactin biosynthesis: disruption of the polyketide synthase genes, nonKJ, in Streptomyces griseus leads to an overall 96 decrease in macrotetrolide production, yet a net increase in nonactin analogues which incorporate isobutyrate. PMID- 11604005 TI - Olefin metathesis involving ruthenium enoic carbene complexes. PMID- 11604006 TI - Highly regio- and stereoselective 1,1-cycloaddition of carbon monoxide with 1,4 dilithio-1,3-dienes. Novel synthetic methods for 3-cyclopenten-1-one derivatives. PMID- 11604007 TI - Unmasking of deuterium kinetic isotope effects on the methane monooxygenase compound Q reaction by site-directed mutagenesis of component B. PMID- 11604008 TI - The syntheses of amphiphilic camouflaged carboranes as modules for supramolecular construction. PMID- 11604009 TI - The photochemistry of pyrylium salts: new photohydrations and photoamidations of heterocycles leading to bicyclic oxazolines and functionalized cyclopentenes. PMID- 11604010 TI - Statistical analysis of DOE EML QAP data from 1982 to 1998. AB - The historical database from the Environmental Measurements Laboratory's Quality Assessment Program from 1982 to 1998 has been analyzed to determine control limits for future performance evaluations of the different laboratories contracted to the U.S. Department of Energy. Seventy-three radionuclides in four different matrices (air filter, soil, vegetation, and water) were analyzed. The evaluation criteria were established based on a z-score calculation. PMID- 11604011 TI - Representation of molecular configurations by CAST coding method. AB - A configurational CAST (CAnonical representation of STereochemistry) coding method, which represents relative and absolute configuration, is described. The configurational CAST codes are constructed by canonical rotation of the dihedral angles of the input structure before the CAST codes are assigned. Using the configurational CAST, configurational differences can be distinguished independently of conformational differences. Representation of enantiomers is also achieved by a mirror image conversion method. The CAST representation shows the distinctive characteristics of several diastereomers and conformers that were examined. The method clearly represents the differences in configurations. Applications to organic molecules having complex stereochemistry are also demonstrated. PMID- 11604012 TI - Chemical markup, XML and the World-Wide Web. 2. Information objects and the CMLDOM. AB - We describe the development of a structured method of representing chemistry on the World-Wide Web using an object-oriented approach to information objects. We show how a document object model (DOM) for chemistry can be constructed using as its basis Chemical Markup Language (CML). Application of the CMLDOM to the development of chemical tools is described. PMID- 11604013 TI - Chemical markup, XML and the World-Wide Web. 3. Toward a signed semantic chemical web of trust. AB - We describe how a collection of documents expressed in XML-conforming languages such as CML and XHTML can be authenticated and validated against digital signatures which make use of established X.509 certificate technology. These can be associated either with specific nodes in the XML document or with the entire document. We illustrate this with two examples. An entire journal article expressed in XML has its individual components digitally signed by separate authors, and the collection is placed in an envelope and again signed. The second example involves using a software robot agent to acquire a collection of documents from a specified URL, to perform various operations and transformations on the content, including expressing molecules in CML, and to automatically sign the various components and deposit the result in a repository. We argue that these operations can used as components for building what we term an authenticated and semantic chemical web of trust. PMID- 11604014 TI - A framework for the evaluation of chemical structure databases. AB - Access to desk-top structure and reaction databases through applications such as Chemical Abstracts' SciFinder, MDL's Beilstein CrossFire, and ISIS Reaction Browser has led to changes in information seeking habits of research chemists, the impact of which has implications when database purchasing decisions are made. A semiquantitative assessment is proposed which takes into account key aspects of structure and reaction databases. Assessment criteria are identified which can be weighted according to an organization's information needs. Values are then assigned to criteria for each data source, after which a formula is applied which leads to an indication of the relative value of systems under consideration. The formula takes into account the cost of database products and also the incremental benefit of adding a new system to an existing collection. This work is presented as a generic approach to the evaluation of databases and is not limited in scope to only structure and reactions databases. PMID- 11604015 TI - A program for linear regression with a common point of intersection: the isokinetic relationship. AB - A program is described for statistically correct calculations of the enthalpy entropy relationship, applicable also generally for linear regression when several regression lines are constrained by a common point of intersection. Examples from the chemical literature show the difference between a correct and incorrect statistical treatment. PMID- 11604016 TI - Using protochirons for three-dimensional coding of certain chemical structures. AB - For three-dimensional coding (including enantiomerism) of staggered paths and circuits on the diamond lattice, or paths/circuits with angles 90 degrees or 180 degrees on the cubic lattice, use is made of the previously defined paths-3 (paths of length three bonds defining two intersecting planes). The two cases mentioned above are examined and exemplified. In the diamond lattice there are three kinds of diamond-paths-3: one is achiral (Z) and two are chiral and enantiomeric (R and S). In the cubic lattice there are six kinds of orthopaths-3, of which only two are chiral and enantiomeric (R and S) and four are achiral (I, L, U, and Z). The chiral paths-3 are the previously defined protochirons in the respective lattice. Coding ascribes to each bond the letter that would characterize it if it were the central bond of an isolated path-3. To obtain a unique code out of several equally correct ones it is proposed to use the convention of inverse alphabetic priority in the above system of letters. PMID- 11604017 TI - Prediction of Henry's law constants by a quantitative structure property relationship and neural networks. AB - Multiple linear regression analysis and neural networks were employed to develop predictive models for Henry's law constants (HLCs) for organic compounds of environmental concern in pure water at 25 degrees C, using a set of quantitative structure property relationship (QSPR)-based descriptors to encode various molecular structural features. Two estimation models were developed from a set of 303 compounds using 10 and 12 descriptors, one of these models using two descriptors to account for hydrogen-bonding characteristics explicitly; these were validated subsequently on an external set of 54 compounds. For each model, a linear regression and neural network version was prepared. The standard errors of the linear regression models for the training data set were 0.262 and 0.488 log(H(cc)) units, while those of the neural network analogues were lower at 0.202 and 0.224, respectively; the linear regression models explained 98.3% and 94.3% of the variance in the development data, respectively, the neural network models giving similar quality results of 99% and 98.3%, respectively. The various descriptors used describe connectivity, charge distribution, charged surface area, hydrogen-bonding characteristics, and group influences on HLC values. PMID- 11604019 TI - A fuzzy ARTMAP based on quantitative structure-property relationships (QSPRs) for predicting aqueous solubility of organic compounds. AB - Quantitative structure-property relationships (QSPRs) for estimating aqueous solubility of organic compounds at 25 degrees C were developed based on a fuzzy ARTMAP and a back-propagation neural networks using a heterogeneous set of 515 organic compounds. A set of molecular descriptors, developed from PM3 semiempirical MO-theory and topological descriptors (first-, second-, third-, and fourth-order molecular connectivity indices), were used as input parameters to the neural networks. Quantum chemical input descriptors included average polarizability, dipole moment, resonance energy, exchange energy, electron nuclear attraction energy, and nuclear-nuclear (core-core) repulsion energy. The fuzzy ARTMAP/QSPR correlated aqueous solubility (S, mol/L) for a range of -11.62 to 4.31 logS with average absolute errors of 0.02 and 0.14 logS units for the overall and validation data sets, respectively. The optimal 11-13-1 back propagation/QSPR model was less accurate, for the same solubility range, and exhibited larger average absolute errors of 0.29 and 0.28 logS units for the overall and validation sets, respectively. The fuzzy ARTMAP-based QSPR approach was shown to be superior to other back-propagation and multiple linear regression/QSPR models for aqueous solubility of organic compounds. PMID- 11604018 TI - Theoretical descriptors for the correlation of aquatic toxicity of environmental pollutants by quantitative structure-toxicity relationships. AB - Quantitative structure-toxicity relationships were developed for the prediction of aqueous toxicities for Poecilia reticulata (guppy) using the CODESSA treatment. A two-parameter correlation was found for class 1 toxins with R(2) = 0.96, and a five-parameter correlation was found for class 2 toxins with R(2) = 0.92. A five-parameter correlation for class 3 toxins had R(2) = 0.85. The correlations for class 4 toxins were less satisfactory. All the descriptors utilized are calculated solely from the structures of the molecules, which makes it possible to predict unavailable or unknown toxins. PMID- 11604020 TI - Prediction of aqueous solubility of organic compounds by the general solubility equation (GSE). AB - The revised general solubility equation (GSE) is used along with four different methods including Huuskonen's artificial neural network (ANN) and three multiple linear regression (MLR) methods to estimate the aqueous solubility of a test set of the 21 pharmaceutically and environmentally interesting compounds. For the selected test sets, it is clear that the GSE and ANN predictions are more accurate than MLR methods. The GSE has the advantages of being simple and thermodynamically sound. The only two inputs used in the GSE are the Celsius melting point (MP) and the octanol water partition coefficient (K(ow)). No fitted parameters and no training data are used in the GSE, whereas other methods utilize a large number of parameters and require a training set. The GSE is also applied to a test set of 413 organic nonelectrolytes that were studied by Huuskonen. Although the GSE uses only two parameters and no training set, its average absolute errors is only 0.1 log units larger than that of the ANN, which requires many parameters and a large training set. The average absolute error AAE is 0.54 log units using the GSE and 0.43 log units using Huuskonen's ANN modeling. This study provides evidence for the GSE being a convenient and reliable method to predict aqueous solubilities of organic compounds. PMID- 11604021 TI - Toward an optimal procedure for variable selection and QSAR model building. AB - In this work, we report the development of a novel QSAR technique combining genetic algorithms and neural networks for selecting a subset of relevant descriptors and building the optimal neural network architecture for QSAR studies. This technique uses a neural network to map the dependent property of interest with the descriptors preselected by the genetic algorithm. This technique differs from other variable selection techniques combining genetic algorithms to neural networks by two main features: (1) The variable selection search performed by the genetic algorithm is not constrained to a defined number of descriptors. (2) The optimal neural network architecture is explored in parallel with the variable selection by dynamically modifying the size of the hidden layer. By using both artificial data and real biological data, we show that this technique can be used to build both classification and regression models and outperforms simpler variable selection techniques mainly for nonlinear data sets. The results obtained on real data are compared to previous work using other modeling techniques. We also discuss some important issues in building QSAR models and good practices for QSAR studies. PMID- 11604022 TI - A novel index for the description of molecular linearity. AB - To investigate the description of molecular shape, a heterogeneous data set of 200 compounds was designed. The compounds included many disparate molecular shapes, and a total of 64 descriptors was calculated including topological indices, surface areas, molecular volumes, measures of molecular dimensions, and ratios of moments of inertia. Cluster analysis on the variables indicated that there are four major categories of steric descriptors, those for molecular bulk, dimensions, and two clusters representing varying aspects of shape. To describe molecular shape more efficiently, a novel linearity index based upon ratios of moments of inertia and the molecular weight is proposed. PMID- 11604023 TI - Prediction of aqueous solubility of heteroatom-containing organic compounds from molecular structure. AB - The use of quantitative structure-property relationships (QSPRs) to predict aqueous solubilities (log S) of heteroatom-containing organic compounds from their molecular structure is presented. Three data sets are examined. Data set 1 contains 176 compounds having one or more nitrogen atoms with some oxygen (log S[mol/L] range is -7.41 to 0.96). Data set 2 contains 223 compounds having one or more oxygen atoms, with no nitrogen (log S[mol/L] range is -8.77 to 1.57). Data set 3 contains all 399 compounds from sets 1 and 2 (log S/mol/L] range is -8.77 to 1.57). After descriptor generation and feature selection, multiple linear regression (MLR) and computational neural network (CNN) models are developed for aqueous solubility prediction. The best results were obtained with nonlinear CNN models. Root-mean-square (rms) errors for training with the three data sets ranged from 0.3 to 0.6 log units. All models were validated with external prediction sets, with the rms errors ranging from 0.6 log units to 1.5 log units. PMID- 11604024 TI - E-state modeling of corticosteroids binding affinity validation of model for small data set. AB - Data for 31 steroids binding to the corticosteroid binding globulin (CBG) were modeled using E-state molecular structure descriptors and a kappa shape index. Both E-state and hydrogen E-state descriptors appear in the model in atom-level and atom-type descriptors. A four-variable model is obtained that is statistically satisfactory: r (2) = 0.81, s = 0.51; r (2)(press) = 0.72; s(press) = 0.62. Structure interpretation is given for each variable in the model. A leave group-out (LGO) approach to model-validation is presented in which each observation is removed from the data set three times in random groups of 20% of the whole data set. The average of the resulting predicted values constitutes consensus predictions for these data for which r (2)(LOO) = 0.70. These collective results support the claim that the E-state model may be useful for prediction of pK binding values for new compounds. PMID- 11604026 TI - A nonlinear group contribution method for predicting the free energies of inclusion complexation of organic molecules with alpha- and beta-cyclodextrins. AB - A group-contribution method was developed for calculating the binding constants or the free energies of complexation between native alpha- or beta-cyclodextrin (CD) and organic guest molecules. The nonlinear models for binary (1:1 stoichiometry) complexes of alpha- and beta-CDs were derived with squared correlation coefficients (r(2)) of 0.868 and 0.917 based on a database consisting of 102 and 218 diverse guest molecules, respectively. The parameters used in the models are first-order molecular connectivity index as a measure of molecular bulk and atom/group counts in the guest molecules. The models allow accurate estimations for the wide range of guests containing C, H, N, O, S, and/or all halogens by summing the contribution values of each defined group present in the chemical structure of the guest along with guest's molecular size factors (linear and square terms) and then the summation to a constant coefficient value. The predictive performance of the models was tested by extra set of 27 compounds which were not included in the original data set. The predicted values by the models are in good agreement with the experimentally determined data. PMID- 11604025 TI - QSARs for 6-azasteroids as inhibitors of human type 1 5alpha-reductase: prediction of binding affinity and selectivity relative to 3-BHSD. AB - Quantitative structure-activity relationships (QSARs) are developed to describe the ability of 6-azasteroids to inhibit human type 1 5alpha-reductase. Models are generated using a set of 93 compounds with known binding affinities (K(i)) to 5alpha-reductase and 3beta-hydroxy-Delta(5)-steroid dehydrogenase/3-keto-Delta(5) steroid isomerase (3-BHSD). QSARs are generated to predict K(i) values for inhibitors of 5alpha-reductase and to predict selectivity (S(i)) of compound binding to 3-BHSD relative to 5alpha-reductase. Log(K(i)) values range from -0.70 log units to 4.69 log units, and log(S(i)) values range from -3.00 log units to 3.84 log units. Topological, geometric, electronic, and polar surface descriptors are used to encode molecular structure. Information-rich subsets of descriptors are identified using evolutionary optimization procedures. Predictive models are generated using linear regression, computational neural networks (CNNs), principal components regression, and partial least squares. Compounds in an external prediction set are used for model validation. A 10-3-1 CNN is developed for prediction of binding affinity to 5alpha-reductase that produces root-mean square error (RMSE) of 0.293 log units (R(2) = 0.97) for compounds in the external prediction set. Additionally, an 8-3-1 CNN is generated for prediction of inhibitor selectivity that produces RMSE = 0.513 log units (R(2) = 0.89) for the external prediction set. Models are further validated through Monte Carlo experiments in which models are generated after dependent variable values have been scrambled. PMID- 11604027 TI - Topological analysis of long-chain branching patterns in polyolefins. AB - Patterns in molecular topology and complexity for long-chain branching are quantitatively described. The Wiener number, the topological complexity index, and a new index of 3-starness are used to quantify polymer structure. General formulas for these indices were derived for the cases of 3-arm star, H-shaped, and B-arm comb polymers. The factors affecting complexity in monodisperse polymer systems are ranked as follows: number of arms >> arm length > arm central position approximately equal to arm clustering > total molecular weight approximately equal to backbone molecular weight. Topological indices change rapidly and then plateau as the molecular weight of branches on a polyolefin backbone increases from 0 to 5 kD. Complexity calculations relate 2-arm or 3-arm comb structures to the corresponding 3-arm stars of equivalent complexity but much higher molecular weight. In a subsequent paper, we report the application of topological analysis for developing structure/property relationships for monodisperse polymers. While the focus of the present work is on the description of monodisperse, well-defined architectures, the methods may be extended to the description of polydisperse systems. PMID- 11604028 TI - Prediction of enzyme binding: human thrombin inhibition study by quantum chemical and artificial intelligence methods based on X-ray structures. AB - Thrombin is a serine protease which plays important roles in the human body, the key one being the control of thrombus formation. The inhibition of thrombin has become a target for new antithrombotics. The aim of our work was to (i) construct a model which would enable us to predict Ki values for the binding of an inhibitor into the active site of thrombin based on a database of known X-ray structures of inhibitor-enzyme complexes and (ii) to identify the structural and electrostatic characteristics of inhibitor molecules crucially important to their effective binding. To retain as much of the 3D structural information of the bound inhibitor as possible, we implemented the quantum mechanical/molecular mechanical (QM/MM) procedure for calculating the molecular electrostatic potential (MEP) at the van der Waals surfaces of atoms in the protein's active site. The inhibitor was treated quantum mechanically, while the rest of the complex was treated by classical means. The obtained MEP values served as inputs into the counter-propagation artificial neural network (CP-ANN), and a genetic algorithm was subsequently used to search for the combination of atoms that predominantly influences the binding. The constructed CP-ANN model yielded Ki values predictions with a correlation coefficient of 0.96, with Ki values extended over 7 orders of magnitude. Our approach also shows the relative importance of the various amino acid residues present in the active site of the enzyme for inhibitor binding. The list of residues selected by our automatic procedure is in good correlation with the current consensus regarding the importance of certain crucial residues in thrombin's active site. PMID- 11604029 TI - Prediction of biological activity for high-throughput screening using binary kernel discrimination. AB - High-throughput screening has made a significant impact on drug discovery, but there is an acknowledged need for quantitative methods to analyze screening results and predict the activity of further compounds. In this paper we introduce one such method, binary kernel discrimination, and investigate its performance on two datasets; the first is a set of 1650 monoamine oxidase inhibitors, and the second a set of 101 437 compounds from an in-house enzyme assay. We compare the performance of binary kernel discrimination with a simple procedure which we call "merged similarity search", and also with a feedforward neural network. Binary kernel discrimination is shown to perform robustly with varying quantities of training data and also in the presence of noisy data. We conclude by highlighting the importance of the judicious use of general pattern recognition techniques for compound selection. PMID- 11604030 TI - Polarizability fields for use in three-dimensional quantitative structure activity relationship (3D-QSAR). AB - Comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) technique, has proven to be a valuable tool in the field of rational drug design. In its native form, CoMFA utilizes a pseudoreceptor, in the form of a regularly spaced lattice of probe atoms, to characterize the steric and electrostatic properties of a series of mutually superimposed molecules. Statistical analyses are performed in an attempt to correlate changes in these shape and charge related fields to observed differences in biological activities at a given target. Graphical analyses of the resulting "negative receptor images" have been demonstrated to provide insight into the physicochemical requirements of novel ligands. Several groups have previously demonstrated the benefits of additional or alternative fields for these types of analyses. In this report, a novel molecular potential field derived from atomistic contributions to molecular polarizability is presented. Comparison studies will be presented using literature data sets and CoMFA models derived from steric, electrostatic, and polarizability fields. The overall conclusion is that molecular polarizability fields derived from semiempirically determined atomic polarizabilities are highly predictive and graphically descriptive supplements to, and perhaps surrogates for, the standard CoMFA steric and electrostatic fields. PMID- 11604031 TI - Is there a difference between leads and drugs? A historical perspective. AB - To be considered for further development, lead structures should display the following properties: (1) simple chemical features, amenable for chemistry optimization; (2) membership to an established SAR series; (3) favorable patent situation; and (4) good absorption, distribution, metabolism, and excretion (ADME) properties. There are two distinct categories of leads: those that lack any therapeutic use (i.e., "pure" leads), and those that are marketed drugs themselves but have been altered to yield novel drugs. We have previously analyzed the design of leadlike combinatorial libraries starting from 18 lead and drug pairs of structures (S. J. Teague et al. Angew. Chem., Int. Ed. Engl. 1999, 38, 3743-3748). Here, we report results based on an extended dataset of 96 lead drug pairs, of which 62 are lead structures that are not marketed as drugs, and 75 are drugs that are not presumably used as leads. We examined the following properties: MW (molecular weight), CMR (the calculated molecular refractivity), RNG (the number of rings), RTB (the number of rotatable bonds), the number of hydrogen bond donors (HDO) and acceptors (HAC), the calculated logarithm of the n octanol/water partition (CLogP), the calculated logarithm of the distribution coefficient at pH 7.4 (LogD(74)), the Daylight-fingerprint druglike score (DFPS), and the property and pharmacophore features score (PPFS). The following differences were observed between the medians of drugs and leads: DeltaMW = 69; DeltaCMR = 1.8; DeltaRNG = DeltaHAC =1; DeltaRTB = 2; DeltaCLogP = 0.43; DeltaLogD(74) = 0.97; DeltaHDO = 0; DeltaDFPS = 0.15; DeltaPPFS = 0.12. Lead structures exhibit, on the average, less molecular complexity (less MW, less number of rings and rotatable bonds), are less hydrophobic (lower CLogP and LogD(74)), and less druglike (lower druglike scores). These findings indicate that the process of optimizing a lead into a drug results in more complex structures. This information should be used in the design of novel combinatorial libraries that are aimed at lead discovery. PMID- 11604032 TI - QSAR study of 1,8-naphthyridin-4-ones as inhibitors of photosystem II. AB - The effect of substituents on in vitro activity of 20 1,8-naphthyridin-4-ones, a novel class of photosystem II inhibitors, was studied. A four-parameter QSAR model based on the molecular connectivity indices was developed which accounts for about 87% of the variations in inhibitory potencies of these compounds. The model suggests that the position, size, and polarity of substituents are factors that predominantly control their activity. By using physicochemical constants, a quantitative model for both 1,8-naphthyridin-4-ones and structurally related 2 trifluoromethyl-4-hydroxyquinoline derivatives was proposed. PMID- 11604033 TI - Models of polychlorinated dibenzodioxins, dibenzofurans, and biphenyls binding affinity to the aryl hydrocarbon receptor developed using (13)c NMR data. AB - Quantitative spectroscopic data-activity relationship (QSDAR) models for polychlorinated dibenzofurans (PCDFs), dibenzodioxins (PCDDs), and biphenyls (PCBs) binding to the aryl hydrocarbon receptor (AhR) have been developed based on simulated (13)C nuclear magnetic resonance (NMR) data. All the models were based on multiple linear regression of comparative spectral analysis (CoSA) between compounds. A 1.0 ppm resolution CoSA model for 26 PCDF compounds based on chemical shifts in five bins had an explained variance (r(2)) of 0.93 and a leave one-out (LOO) cross-validated variance (q(2)) of 0.90. A 2.0 ppm resolution CoSA model for 14 PCDD compounds based on chemical shifts in five bins had an r(2) of 0.91 and a q(2) of 0.81. The 1.0 ppm resolution CoSA model for 12 PCB compounds based on chemical shifts in five bins had an r(2) of 0.87 and a q(2) of 0.45. The models with more compounds had a better q(2) because there are more multiple chemical shift populated bins available on which to base the linear regression. A 1.0 ppm resolution CoSA model for all 52 compounds that was based on chemical shifts in 12 bins had an r(2) of 0.85 and q(2) of 0.71. A canonical variance analysis of the 1.0 ppm CoSA model for all 52 compounds when they were separated into 27 strong binding and 25 weak binding compounds was 98% correct. Conventional quantitative structure-activity relationship (QSAR) modeling suffer from errors introduced by the assumptions and approximations involved in calculated electrostatic potentials and the molecular alignment process. QSDAR modeling is not limited by such errors since electrostatic potential calculations and molecular alignment are not done. The QSDAR models provide a rapid, simple and valid way to model the PCDF, PCDD, and PCB binding activity in relation to the aryl hydrocarbon receptor (AhR). PMID- 11604034 TI - On graphical and numerical characterization of proteomics maps. AB - We outlined a mathematical approach suitable for characterization of experimental data given by 2-D densitograms. In particular we consider numerical characterization of proteomics maps. The basis of our approach is to order "spots" of a 2-D map and assign them unique labels (that in general will depend on the criteria used for ordering). In this way a map is "translated" into a sequence. In the next step one associates with the generated sequence a geometrical path and views such a path as a mathematical object that needs characterization. We have ordered spots representing proteins in 2-D gel plates according to their relative intensities which results in a zigzag path that produces a complicated "fingerprint" pattern. Mathematical characterization of zigzag pattern follows similar mathematical characterizations of embedded patterns based on matrices, the elements of which are given as quotients of Euclidean distance between spots and the distance along the zigzag path. The leading eigenvalue of constructed matrices is taken to represent characterization of the original 2-D map. Comparison of different 2-D maps (simulated by using random generator) allows one to construct partial order, which although qualitative in nature gives some insight into perturbation induced by foreign agents to the proteome of the control cell. PMID- 11604035 TI - On 3-D graphical representation of proteomics maps and their numerical characterization. AB - We consider numerical characterization of proteomics maps by representing a map as a three-dimensional graphical object based on x, y coordinates of the spots and using their relative abundance as the z coordinate. In our representation the protein spots are first ordered based on their relative abundance and labeled accordingly. In the next step a 3-D path is constructed connecting spots having adjacent labels. Finally a matrix is constructed by assigning to each pairs of labels (i, j) matrix element, the numerical value of which is based on the quotients of the Euclidean distance and the distance along the 3-D zigzag between the two points. The approach has been illustrated on a fragment of a proteomics map and compared with 2-D graphical representation of proteomics maps. PMID- 11604036 TI - QSAR analysis of hypoglycemic agents using the topological indices. AB - The molecular topology model and discriminant analysis have been applied to the prediction of some pharmacological properties of hypoglycemic drugs using multiple regression equations with their statistical parameters. Regression analysis showed that the molecular topology model predicts these properties. The corresponding stability (cross-validation) studies performed on the selected prediction models confirmed the goodness of the fits. The method used for hypoglycemic activity selection was a linear discriminant analysis (LDA). We make use of the pharmacological distribution diagrams (PDDs) as a visualizing technique for the identification and selection of new hypoglycemic agents, and we tested on rats the predictive ability of the model. PMID- 11604037 TI - Estimating the water solubilities of crystalline compounds from their chemical structures alone. AB - Partial atomic charges are significant descriptors in predicting the water solubilities of crystalline organic compounds from their chemical structures. Lipophilicity remains the predominant factor. It was also found that quantitative estimates of hydrogen bond strengths (hydrogen bond factors) play important roles. These descriptors can be easily interpreted to guide chemists to the synthesis of compounds with increased or decreased water solubility. This work is based on a set of 22 compounds the aqueous solubilities of which were determined by a new potentiometric method, pSOL, and were confirmed, in part, by the traditional shake-flask method. A new software package, HYBOTPLUS, furnished the partial atomic charges and hydrogen bond factors. PMID- 11604038 TI - (13)C NMR quantitative spectrometric data-activity relationship (QSDAR) models of steroids binding the aromatase enzyme. AB - Five quantitative spectroscopic data-activity relationships (QSDAR) models for 50 steroidal inhibitors binding to aromatase enzyme have been developed based on simulated (13)C nuclear magnetic resonance (NMR) data. Three of the models were based on comparative spectral analysis (CoSA), and the two other models were based on comparative structurally assigned spectral analysis (CoSASA). A CoSA QSDAR model based on five principal components had an explained variance (r(2)) of 0.78 and a leave-one-out (LOO) cross-validated variance (q(2)) of 0.71. A CoSASA model that used the assigned (13)C NMR chemical shifts from a steroidal backbone at five selected positions gave an r(2) of 0.75 and a q(2) of 0.66. The (13)C NMR chemical shifts from atoms in the steroid template position 9, 6, 3, and 7 each had correlations greater than 0.6 with the relative binding activity to the aromatase enzyme. All five QSDAR models had explained and cross-validated variances that were better than the explained and cross-validated variances from a five structural parameter quantitative structure-activity relationship (QSAR) model of the same compounds. QSAR modeling suffers from errors introduced by the assumptions and approximations used in partial charges, dielectric constants, and the molecular alignment process of one structural conformation. One postulated reason that the variances of QSDAR models are better than the QSAR models is that (13)C NMR spectral data, based on quantum mechanical principles, are more reflective of binding than the QSAR model's calculated electrostatic potentials and molecular alignment process. The QSDAR models provide a rapid, simple way to model the steroid inhibitor activity in relation to the aromatase enzyme. PMID- 11604039 TI - Estimation of molecular similarity based on 4D-QSAR analysis: formalism and validation. AB - The 4D-QSAR paradigm has been used to develop a formalism to estimate molecular similarity measures as a function of conformation, alignment, and atom type. It is possible to estimate the molecular similarity of pairs of molecules based upon the entire ensemble of conformational states each molecule can adopt at a given temperature, normally room temperature. Molecular similarity can be measured in terms of the types of atoms composing each molecule leading to multiple measures of molecular similarity. Multiple measures of molecular similarity can also arise from using different alignment rules to perform relative molecular similarity, RMS, analysis. An alignment independent method of determining molecular similarity measures, referred to as absolute molecular similarity, AMS, analysis has been developed. Various sets and libraries of compounds, including the amino acids, are analyzed using 4D-QSAR molecular similarity analysis to demonstrate the features of the formalism. Exploration of molecular similarity as a function of chirality, identification of common embedded 3D pharmacophores in compounds, and elucidation of 3D-isosteric compounds from structurally diverse libraries are carried out in the application studies. PMID- 11604040 TI - The influence of different structure representations on the clustering of an RNA nucleotides data set. AB - The last couple of years an overwhelming amount of data has emerged in the field of biomolecular structure determination. To explore information hidden in these structure databases, clustering techniques can be used. The outcome of the clustering experiments largely depends, among others, on the way the data is represented; therefore, the choice how to represent the molecular structure information is extremely important. This article describes what the influence of the different representations on the clustering is and how it can be analyzed by means of a dendrogram comparison method. All experiments are performed using a data set consisting of RNA trinucleotides. Besides the most basic structure representation, the Cartesian coordinates representation, several other structure representations are used. PMID- 11604041 TI - Protocols for bridging the peptide to nonpeptide gap in topological similarity searches. AB - Similarity searches based on chemical descriptors have proven extremely useful in aiding large-scale drug screening. Typically an investigator starts with a "probe", a drug-like molecule with an interesting biological activity, and searches a database to find similar compounds. In some projects, however, the only known actives are peptides, and the investigator needs to identify drug-like actives. 3D similarity methods are able to help in this endeavor but suffer from the necessity of having to specify the active conformation of the probe, something that is not always possible at the beginning of a project. Also, 3D methods are slow and are complicated by the need to generate low-energy conformations. In contrast, topological methods are relatively rapid and do not depend on conformation. However, unmodified topological similarity methods, given a peptide probe, will preferentially select other peptides from a database. In this paper we show some simple protocols that, if used with a standard topological similarity search method, are sufficient to select nonpeptide actives given a peptide probe. We demonstrate these protocols by using 10 peptide-like probes to select appropriate nonpeptide actives from the MDDR database. PMID- 11604042 TI - Prediction of n-octanol/water partition coefficients from PHYSPROP database using artificial neural networks and E-state indices. AB - A new method, ALOGPS v 2.0 (http://www.lnh.unil.ch/~itetko/logp/), for the assessment of n-octanol/water partition coefficient, log P, was developed on the basis of neural network ensemble analysis of 12 908 organic compounds available from PHYSPROP database of Syracuse Research Corporation. The atom and bond-type E state indices as well as the number of hydrogen and non-hydrogen atoms were used to represent the molecular structures. A preliminary selection of indices was performed by multiple linear regression analysis, and 75 input parameters were chosen. Some of the parameters combined several atom-type or bond-type indices with similar physicochemical properties. The neural network ensemble training was performed by efficient partition algorithm developed by the authors. The ensemble contained 50 neural networks, and each neural network had 10 neurons in one hidden layer. The prediction ability of the developed approach was estimated using both leave-one-out (LOO) technique and training/test protocol. In case of interseries predictions, i.e., when molecules in the test and in the training subsets were selected by chance from the same set of compounds, both approaches provided similar results. ALOGPS performance was significantly better than the results obtained by other tested methods. For a subset of 12 777 molecules the LOO results, namely correlation coefficient r(2)= 0.95, root mean squared error, RMSE = 0.39, and an absolute mean error, MAE = 0.29, were calculated. For two cross-series predictions, i.e., when molecules in the training and in the test sets belong to different series of compounds, all analyzed methods performed less efficiently. The decrease in the performance could be explained by a different diversity of molecules in the training and in the test sets. However, even for such difficult cases the ALOGPS method provided better prediction ability than the other tested methods. We have shown that the diversity of the training sets rather than the design of the methods is the main factor determining their prediction ability for new data. A comparative performance of the methods as well as a dependence on the number of non-hydrogen atoms in a molecule is also presented. PMID- 11604043 TI - How does consensus scoring work for virtual library screening? An idealized computer experiment. AB - It has been reported recently that consensus scoring, which combines multiple scoring functions in binding affinity estimation, leads to higher hit-rates in virtual library screening studies. This method seems quite independent to the target receptor, the docking program, or even the scoring functions under investigation. Here we present an idealized computer experiment to explore how consensus scoring works. A hypothetical set of 5000 compounds is used to represent a chemical library under screening. The binding affinities of all its member compounds are assigned by mimicking a real situation. Based on the assumption that the error of a scoring function is a random number in a normal distribution, the predicted binding affinities were generated by adding such a random number to the "observed" binding affinities. The relationship between the hit-rates and the number of scoring functions employed in scoring was then investigated. The performance of several typical ranking strategies for a consensus scoring procedure was also explored. Our results demonstrate that consensus scoring outperforms any single scoring for a simple statistical reason: the mean value of repeated samplings tends to be closer to the true value. Our results also suggest that a moderate number of scoring functions, three or four, are sufficient for the purpose of consensus scoring. As for the ranking strategy, both the rank-by-number and the rank-by-rank strategy work more effectively than the rank-by-vote strategy. PMID- 11604044 TI - Distinct molecular surfaces and hydrophobicity of amino acid residues in proteins. AB - Hydrophobicity is a useful concept to rationalize the role played by amino acid residues in terms of buried or exposed conformation with regard to the aqueous environment in proteins. The relationship of this concept with distinct approaches to represent the molecular surface is analyzed by computing reliable surface areas for three definitions namely the van der Waals, solvent-accessible, and solvent-excluded molecular surfaces. The surface areas are obtained for all of the naturally occurring amino acids by first setting a proper reference standard state and then calculating their values for a database of proteins containing a total of 4297 residues. Despite the great differences in these molecular surfaces, proper indexes are here defined for handling the information of interest to study the hydrophobic behavior of amino acids provided by such surfaces. PMID- 11604045 TI - Gene therapy for muscular dystrophies: current status and future prospects. AB - Since the identification in 1987 of the gene for Duchenne muscular dystrophy (DMD), research on the molecular pathogenesis of muscular dystrophy has progressed extensively. In particular, discovery of the DMD gene product, dystrophin, led to the identification of dystrophin-associated proteins and, subsequently, the recognition of other types of muscular dystrophy caused by the defects in each of the sarcoglycan genes. On the other hand, effective therapy for DMD has not yet been established. Some of the viral vectors, such as adeno associated virus vectors or lentiviral vector, have been proven to enable the long-term expression of the exogenous gene without overt host immune reactions. However, dystrophin cDNAs are too large (14kb) to be accommodated in these viral vectors. To solve this problem, we and other research groups succeeded in truncating full-length dystrophin cDNA to small dystrophin cDNA (4 to 5kb), the products of which protect dystrophin-deficient mdx muscle from contraction induced membrane damage when introduced by viral vectors or as a transgene into mdx mice. The usefulness of these truncated dystrophin cDNAs should be confirmed using other animal models such as dystrophic dogs. To develop successful treatment of DMD, the authors believe that several different approaches should be used, such as cell transfer therapy, drug design to up-regulate utrophin, or a strategy to repair the mutation in vivo. PMID- 11604046 TI - Innovative therapies for sepsis. AB - Sepsis and septic shock continue to be a major cause of morbidity and mortality. Despite numerous advances in the supportive care of patients with sepsis, the overall mortality has changed little in the past 20 years. Many innovative therapies have been attempted in the field of sepsis, primarily aimed at stopping the cycle of cytokine activation which is part of the systemic inflammatory response. Therapies have also targeted other molecular mediators of inflammation and coagulation. Despite encouraging preliminary preclinical results, most of the early trials in sepsis research have failed to offer hope of improving survival with the use of these innovative therapies. Postulated reasons for the failure of clinical trials include the disparity between animal models and clinical reality, the heterogeneous nature of patient populations and sepsis, and the complexity of the inflammatory cascade. On a more hopeful note, three recent trials assessing corticosteroids, anti-tumour necrosis factor strategy and drotrecogin alfa (rhAPC), respectively, have proclaimed positive results. However, only the drotrecogin alfa trial has been peer reviewed and published. PMID- 11604047 TI - Role of anti-interleukin-2 receptor antibodies in kidney transplantation. AB - From the early 1960s, the mainstay of immunosuppression for kidney transplantation has been corticosteroids. Since then, many new drugs have been developed to maintain the renal allograft. Current maintenance immunosuppression commonly consists of corticosteroids, antiproliferative agents and calcineurin inhibitors (e.g. cyclosporin). More recently, antihuman antibodies, either monoclonal or polyclonal, have been developed to use for induction at the time of transplantation or to treat rejection. With the advances in molecular technology, a new class of antihuman antibodies [the anti-interleukin-2 receptor (IL-2R) antibodies] has emerged that incorporate a murine antigen-binding site on to a human immunoglobulin backbone. Such methodology creates antihuman antibodies with high affinity for the epitope and with prolonged serum antibody half-lives. Interleukin-2 and its receptor are central to lymphocyte activation and are the main targets of calcineurin inhibitors. In addition, the anti-IL-2R antibodies inhibit a key target in immune activation. Daclizumab and basiliximab have been shown to significantly reduce the incidence of acute rejection in kidney transplantation. Since these anti-IL-2R antibodies are well tolerated and since calcineurin inhibitors are intrinsically nephrotoxic, anti-IL-2R antibodies have been used in an attempt to avoid cyclosporin after transplantation. Data from clinical trials seem to indicate that the addition of an anti-IL-2R antibody is not sufficient to warrant complete withdrawal of calcineurin inhibitors for more than a very short period after transplantation. A more promising role for anti-IL 2R antibodies may be in renal transplant recipients with delayed graft function (DGF). Recent data on the use of either low-dose calcineurin inhibitors or sirolimus (rapamycin) in conjunction with the anti-IL-2R antibodies for patients with DGF showed no increased risk of acute rejection. Long-term graft survival with use of these low-dose calcineurin inhibitor protocols has yet to be established. PMID- 11604048 TI - New perspectives in dendritic cell-based cancer immunotherapy. AB - Dendritic cells are professional antigen-presenting cells with the unique capacity to initiate primary immune responses. Recently, several procedures to generate large numbers of dendritic cells from circulating precursors, including peripheral blood monocytes and CD34+ stem cells, have been developed. Stimulation with antigen-loaded dendritic cells was shown to break tolerance to tumour associated antigens and to induce antitumour cytotoxic immune responses in vivo. Hence, numerous attempts to optimise delivery of tumour antigens to dendritic cells, as well as routes and schedules of administration to cancer patients, are currently under way. The first dendritic cell clinical studies have indicated this form of vaccination as feasible and safe; furthermore, in some cases, objective clinical responses were observed, even in patients heavily pretreated with standard chemo/radiotherapy approaches. These preliminary data, although encouraging, require further extensive investigations, which should address the technical and biological problems of manipulating human dendritic cells, as well as the clinical settings which could benefit from an immunotherapeutic approach. PMID- 11604049 TI - Theoretical basis for the activity of thalidomide. AB - The revival of thalidomide began shortly after the drug was withdrawn from the market because of its teratogenic properties. Therapeutic effects of thalidomide were found accidentally in leprosy patients with erythema nodosum leprosum (ENL). Subsequent research widened the understanding of the activity of thalidomide, and with improved methodology and the augmented background knowledge of immunology it was possible to interpret the properties of thalidomide more coherently. Effects on tumour necrosis factor-alpha (TNFalpha) release play an important role in the ability of thalidomide to affect the immune system. Alteration of synthesis and release of cytokines such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 and interferon-gamma is involved in the complex mechanisms of thalidomide. Thalidomide targets leucocytes, endothelial cells and keratinocytes, affecting them in a different manner and at different cellular levels. Changes in the density of adhesion molecules alter leucocyte extravasation and the inflammatory response in the tissue involved. Several mechanisms for the teratogenic action of thalidomide are currently under review, but this mode of action of the drug still remains unclear and we review evidence-based hypotheses for the teratogenicity of thalidomide. Thalidomide shows significant clinical impact in several diseases such as ENL in lepromatous leprosy, chronic graft-versus-host disease, systemic lupus erythematosus, sarcoidosis, aphthous lesions in HIV infection, wasting syndrome in chronic illness, inflammatory bowel disease, multiple myeloma and some solid tumours. In 1998 the US Food and Drug Administration approved thalidomide exclusively for the treatment of ENL, and strict conditions were stipulated for its use in order to prevent teratogenic adverse effects. However, despite the promising findings of thalidomide at the molecular level, namely its anti-TNFalpha properties and its intercalation with DNA, and activity in clinical trials, there is still a great need for more intensive research. PMID- 11604050 TI - Development of a treatment planning protocol for prostate treatments using intensity modulated radiotherapy. AB - We have developed a treatment planning protocol for intensity-modulated radiation therapy of the prostate using commercially available inverse planning software. Treatment plans were developed for ten patients using the Corvus version 3.8 planning system, testing various prescription options, including tissue types, dose volume histogram values for the target and normal structures, beam arrangements, and number of intensity levels. All plans were scaled so that 95% of the clinical target volume received 75.6 Gy; mean doses to the prostate were typically 79 Gy. The reproducibility of the inverse planning algorithm was tested by repeating a set of the plans five times. Plans were deemed acceptable if they satisfied predefined dose constraints for the targets and critical organs. Figures of merit for target coverage, target dose uniformity, and organ sparing were used to rank acceptable plans. Certain systematic behaviors of the optimizer were noted: the high dose regions for both targets and critical organs were 5-10 Gy more than prescribed; reducing bladder and rectum tolerance increased the range of doses within the target; increasing the number of fields incrementally improved plan quality. A set of planning parameters was found that usually satisfied the minimum requirements. Repeating the optimization with different beam order produced similar but slightly different dose distributions, which was sometimes useful for finding acceptable solutions for difficult cases. The standard set of parameters serves as a useful starting point for individualized planning. PMID- 11604051 TI - Geometry function of a linear brachytherapy source. AB - An equation is derived for the TG43 geometry function, G(r,theta), of a linear brachytherapy source in terms of its active length. This equation is validated by comparison to published values. It is then used to calculate values of the geometry function for the Model 200 (103)Pd seed, which is a segmented linear source. PMID- 11604052 TI - Verification of tangential breast treatment dose calculations in a commercial 3D treatment planning system. AB - The accuracy of the photon convolution/superposition dose algorithm employed in a commercial radiation treatment planning system was evaluated for conditions simulating tangential breast treatment. A breast phantom was fabricated from machineable wax and placed on the chest wall of an anthropomorphic phantom. Radiographic film was used to measure the dose distribution at the axial midplane of the breast phantom. Subsequently, thermoluminescent dosimeters (TLDs) were used to measure the dose at four points within the midplane to validate the accuracy of the film dosimetry. Film measurements were compared with calculations performed using the treatment planning system for four types of treatment: optimized wedged beams at 6 and 18 MV and two-dimensional compensated beams at 6 and 18 MV. Both the film- and TLD-measured doses had a precision of approximately 0.6%. The film-measured doses were approximately 1.5% lower than the TLD-measured doses, ranging from 0-3% at 6 MV and 0.5-1% at 18 MV. Such results placed a high level of confidence in the accuracy and precision of the film data. The measured and calculated doses agreed to within +/-3% for both the film and TLD measurements throughout the midplane exclusive of areas not having charged particle equilibrium. Good agreement was not expected within these regions due to the limitations in both film dosimetry and the dose-calculation algorithm. These results indicated that the treatment planning system calculates doses at the midplane with clinically acceptable accuracy in conditions simulating tangential breast treatment. PMID- 11604053 TI - The measurement of three dimensional dose distribution of a ruthenium-106 ophthalmological applicator using magnetic resonance imaging of BANG polymer gels. AB - The BANG (MGS Research Inc., Guilford, CT) polymer gel has been used as a dosimeter to determine the three-dimensional (3D) dose distribution of a ruthenium-106 (Ru-106) ophthalmologic applicator. An eye phantom made of the BANG gel was irradiated with the Ru-106 source for up to 1 h. The phantom and a set of calibration vials were scanned simultaneously in a GE 1.5 T MR imager using the Hahn spin-echo pulse sequence with a TR of 2000 ms and two TEs of 20 ms and 100 ms. The T(2) values were evaluated on a pixel-by-pixel basis using custom-built software on a DEC alpha workstation and converted to dose using calibration data. Depth doses and isodose lines of the Ru-106 eye-plaque were generated. It is concluded that the BANG gel dosimetry offers the potential for measuring the 3D dose distributions of an ophthalmologic applicator, with high spatial resolution and relatively good accuracy. PMID- 11604054 TI - Evaluation of a quality control phantom for digital chest radiography. AB - RATIONALE AND OBJECTIVES: To examine the effectiveness and suitability of a quality control (QC) phantom for a routine QC program in digital radiography. MATERIALS AND METHODS: The chest phantom consists of copper and aluminum cutouts arranged to resemble the appearance of a chest. Performance of the digital radiography (DR) system is evaluated using high and low contrast resolution objects placed in the "heart," "lung," and "subdiaphragm" areas of the phantom. In addition, the signal levels from these areas were compared to similar areas from clinical chest radiographs. RESULTS: The test objects included within the phantom were effective in assessing image quality except within the subdiaphragm area, where most of the low contrast disks were visible. Spatial resolution for the DR systems evaluated with the phantom ranged from 2.6 lp/mm to 4 lp/mm, falling within the middle of the line pair range provided. The signal levels of the heart and diaphragm regions relative to the lung region of the phantom were significantly higher than in clinical chest radiographs (0.67 versus 0.21 and 0.28 versus 0.10 for the heart and diaphragm regions, respectively). The heart-to diaphragm signal level ratio, however, was comparable to those in clinical radiographs. CONCLUSION: The findings suggest that the attenuation characteristics of the phantom are somewhat different from actual chests, but this did not appear to affect the post-processing used by the imaging systems and usefulness for QC of these systems. The qualitative and quantitative measurements on the phantom for different systems were similar, suggesting that a single phantom can be used to evaluate system performance in a routine QC program for a wide range of digital radiography systems. This makes the implementation of a uniform QC program easier for institutions with a mixture of different digital radiography systems. PMID- 11604055 TI - Comment on "Independent corroboration of monitor unit calculations performed by a 3D computerized planning system" [J. Appl. Clin. Med. Phys. 1, 120-125 (2000)]. PMID- 11604057 TI - The proteasome in cancer biology and treatment. AB - During the last 30 years, investigation of the transcriptional and translational mechanisms of gene regulation has been a major focus of molecular cancer biology. More recently, it has become evident that cancer-related mutations and cancer related therapies also can affect post-translational processing of cellular proteins and that control exerted at this level can be critical in defining both the cancer phenotype and the response to therapeutic intervention. One post translational mechanism that is receiving considerable attention is degradation of intracellular proteins through the multicatalytic 26S proteasome. This follows growing recognition of the fact that protein degradation is a well-regulated and selective process that can differentially control intracellular protein expression levels. The proteasome is responsible for the degradation of all short lived proteins and 70-90% of all long-lived proteins, thereby regulating signal transduction through pathways involving factors such as AP1 and NFKB, and processes such as cell cycle progression and arrest, DNA transcription, DNA repair/misrepair, angiogenesis, apoptosis/survival, growth and development, and inflammation and immunity, as well as muscle wasting (e.g. in cachexia and sepsis). In this review, we discuss the potential involvement of the proteasome in both cancer biology and cancer treatment. PMID- 11604058 TI - Space radiation and cataracts in astronauts. AB - For over 30 years, astronauts in Earth orbit or on missions to the moon have been exposed to space radiation comprised of high-energy protons and heavy ions and secondary particles produced in collisions with spacecraft and tissue. Large uncertainties exist in the projection of risks of late effects from space radiation such as cancer and cataracts due to the paucity [corrected] of epidemiological data. Here we present epidemiological [corrected] data linking an increased risk of cataracts for astronauts with higher lens doses (>8 mSv) of space radiation relative to other astronauts with lower lens doses (<8 mSv). Our study uses historical data for cataract incidence in the 295 astronauts participating in NASA's Longitudinal Study of Astronaut Health (LSAH) and individual occupational radiation exposure data. These results, while preliminary because of the use of subjective scoring methods, suggest that relatively low doses of space radiation may predispose crew to [corrected] an increased incidence and early appearance of cataracts. PMID- 11604059 TI - No evidence for chromosomal instability in radiation workers with in vivo exposure to plutonium. AB - The availability of cultured lymphocyte preparations from radiation workers with internal deposits of plutonium provided the opportunity to examine whether irradiation of bone marrow cells had induced a transmissible genomic instability manifesting as an increase in de novo chromosome aberrations in descendant cells in the peripheral blood. The men were originally classified as having more than 20% of the maximum permissible body burdens of plutonium, and recent red bone marrow dose calculations provided individual cumulative estimates at the time of sampling ranging up to 1.8 Sv. The initial sampling occurred approximately 10 years after the main major intake, and samples were subsequently taken during three further periods over the following 20 years. Control samples were available from three of the four sampling times. Chromosome analysis of solid Giemsa stained material revealed no significant differences either in comparisons between the total group of plutonium workers and controls for comparable periods or when the comparisons were restricted to a group of plutonium workers with initial red bone marrow plutonium doses greater than 0.25 Sv. However, the frequencies of cells containing chromatid exchanges, chromatid breaks, and chromosome and chromatid gaps decreased significantly over the study period for both the plutonium workers as a whole and the controls, and a similar fluctuating pattern was seen when sequential samples from groups of the same individuals were examined. Cells with dicentrics, centric rings and excess acentric fragments remained at similar frequencies throughout the study period. There was therefore no evidence from the study of blood lymphocytes for the induction of persistent transmissible genomic instability in the bone marrow of radiation workers with internal deposits of plutonium. The work has, however, confirmed the need for appropriate controls when conducting studies of cytogenetic end points of instability. PMID- 11604060 TI - Monohydroxylated fatty acid content in peripheral blood mononuclear cells and immune status of people at long times after the Chernobyl accident. AB - The monohydroxylated fatty acid content of peripheral blood mononuclear cells from 23 cleanup workers and 16 unexposed individuals was studied in relation to their immune status after the Chernobyl accident. Men with absorbed doses below 0.32 Gy showed higher levels of free and esterified 12-hydroxyeicosatetraenoic acid (12-HETE) than unexposed men, whereas 15-HETE and the 17-hydroxy derivative of C22 fatty acid (17-OH 22), either free or esterified in phospholipids, were increased in a dose-dependent manner. The percentage of CD4-positive cells was also increased significantly in heavily irradiated men, whereas the percentage of CD8-positive cells tended to decrease with dose. Furthermore, the absolute count of CD4-positive cells was correlated positively with the amount of esterified 15 HETE in the phospholipid fraction of the mononuclear cells and with the total 15 HETE. These results show for the first time that the accumulation of autoxidized/lipoxygenase products of polyunsaturated fatty acids in the mononuclear cells of irradiated individuals was associated with immune imbalance. This may be the basis for certain late effects of radiation such as autoimmune disorders, somatic and neoplastic diseases, and early aging. PMID- 11604062 TI - Effect of exposure to 900 MHz radiofrequency radiation on intrachromosomal recombination in pKZ1 mice. AB - Radiofrequency (RF) radiation emitted from mobile phones is not considered to be directly genotoxic, but it may have downstream effects on cellular DNA. We studied the effect of 4 W/kg pulsed 900 MHz RF radiation on somatic intrachromosomal recombination in the spleen in the pKZ1 recombination mutagenesis model. Somatic intrachromosomal recombination inversion events were detected in spleen tissue of pKZ1 mice by histochemical staining for E. coli beta galactosidase protein in cells in which the lacZ transgene has undergone an inversion event. pKZ1 mice were exposed daily for 30 min to plane-wave fields of 900 MHz with a pulse repetition frequency of 217 Hz and a pulse width of 0.6 ms for 1, 5 or 25 days. Three days after the last exposure, spleen sections were screened for DNA inversion events. There was no significant difference between the control and treated groups in the 1- and 5-day exposure groups, but there was a significant reduction in inversions below the spontaneous frequency in the 25 day exposure group. This observation suggests that exposure to RF radiation can lead to a perturbation in recombination frequency which may have implications for recombination repair of DNA. The biological significance of a reduction below the spontaneous frequency is not known. The number of mice in each treatment group in this study was small (n = 10 or n = 20). Therefore, repetition of this study with a larger number of animals is required to confirm these observations. PMID- 11604063 TI - Improved tumor response by combining radiation and the vascular-damaging drug 5,6 dimethylxanthenone-4-acetic acid. AB - The interaction between 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and radiation was investigated in two different mouse tumor models and a normal mouse tissue. C3H mouse mammary carcinomas transplanted in the feet of CDF1 mice and KHT mouse sarcomas growing in the leg muscles of C3H/HeJ mice were used. DMXAA was dissolved in saline and injected intraperitoneally. Tumors were irradiated locally in nonanesthetized mice, and response was assessed using tumor growth for the C3H mammary carcinoma and in vivo/in vitro clonogenic cell survival for the KHT sarcoma. DMXAA alone had an antitumor effect in both tumor types, but only at doses above 15 mg/kg. DMXAA also enhanced radiation damage, and again there was a threshold dose. No enhancement was seen in the C3H mammary carcinoma at 10 mg/kg and below, while in the KHT sarcoma, doses above 15 mg/kg were necessary. This enhancement of radiation damage was also dependent on the sequence of and interval between the treatments with DMXAA and radiation. Combining radiation with DMXAA at the maximum tolerated dose (i.e., the highest dose that could be injected without causing any lethality) of either 20 mg/kg (CDF1 mice) or 17.5 mg/kg (C3H/HeJ mice) gave an additive response when the two agents were administered simultaneously. Even greater antitumor effects were achieved when DMXAA was administered 1-3 h after irradiation. However, when administration of DMXAA preceded irradiation, the effect was similar to that seen for radiation alone, suggesting that appropriate timing is essential to maximize the utility of this agent. When such conditions were met, DMXAA was found to increase the tumor response significantly in the absence of an enhancement of radiation damage in normal skin, thus giving rise to therapeutic gain. PMID- 11604061 TI - Transgenerational effects of preconception paternal contamination with (55)Fe. AB - The conjecture that germline mutations induced by radiation exposure before conception may predispose subsequent offspring to cancer remains contentious. Previous experimental studies have shown that preconception paternal irradiation with (239)Pu induces perturbations in the hemopoietic systems of offspring and influences sensitivity to a secondary carcinogen. In the present study, male DBA2 mice were injected intravenously with the Auger electron emitter (55)Fe (4 kBq g( 1)) 18 or 84 days before mating with normal females. Comet analysis showed an increased incidence of DNA strand breaks in sperm from contaminated animals after 84 days, but not after 18 days, indicating spermatogonial rather than spermatid damage. Offspring were either assayed for changes in bone marrow stem cells and committed progenitors or challenged with the chemical carcinogen methyl nitrosourea (MNU, 50 mg/kg) at 10 weeks of age and monitored for the onset of malignancy. Offspring from irradiated fathers had normal peripheral blood profiles, although the stem cell population was amplified in offspring arising from those exposed to (55)Fe at 84 days before conception. Exposure to MNU significantly increased the incidence of lympho-hemopoietic malignancies in offspring from the 84-day group, but not in those from the 18-day group. These findings support the hypothesis that aberrations that are potentially leukemogenic may be transmitted to offspring after radiation damage to the paternal germline. PMID- 11604064 TI - Tumor oxygen dynamics with respect to growth and respiratory challenge: investigation of the Dunning prostate R3327-HI tumor. AB - We recently described a novel approach to measuring regional tumor oxygen tension using (19)F nuclear magnetic resonance echo planar imaging relaxometry (FREDOM) of hexafluorobenzene. We have now applied this technique to evaluate in detail the oxygen tension dynamics in the relatively slowly growing, moderately well differentiated Dunning prostate R3327 HI rat tumor with respect to tumor growth and respiratory challenge. Seven individual tumors were assessed repeatedly over a period of 5 weeks ( approximately 4 volume doubling times). For small tumors (<1 cm(3)), the mean pO(2) ranged from 28 to 44 Torr under baseline conditions, decreasing to less than 10 Torr when the tumors reached 5 to 6 cm(3), with a strong inverse correlation between the baseline tumor oxygen tension and the tumor size. The hypoxic fraction (defined as the percentage of the voxels with pO(2) <10 Torr) increased significantly with tumor growth. Administration of oxygen or carbogen produced a significant increase (P < 0.0001) in tumor oxygenation at all stages of tumor growth. Most interestingly, even regions of these tumors that were initially poorly oxygenated responded rapidly, and significantly, to respiratory intervention, in contrast to the behavior of the faster-growing rat prostate tumors investigated previously. PMID- 11604065 TI - HPRT mutants induced in bystander cells by very low fluences of alpha particles result primarily from point mutations. AB - We have shown previously that damage signals may be transmitted from irradiated cells to nonirradiated cells in monolayer cultures, leading to changes in gene expression and an enhanced frequency of mutations in these "bystander" cells. The present study was designed to test the hypothesis that mutations occurring in bystander cells result from a different mechanism than those occurring in irradiated cells, and thus show differences in molecular structure. Structural changes in the HPRT gene of Chinese hamster ovary (CHO) cells were determined by multiplex PCR analysis. A total of 790 mutant clones derived from monolayer cultures exposed to mean doses of 0, 0.5 or 10 cGy of alpha-particle radiation (0, 3% or 44%, respectively, of nuclei traversed by one or more alpha particles) were examined. Whereas mutations induced by 10 cGy included a high frequency of deletions, nearly all mutations occurring in bystander cells in cultures irradiated with 0.5 cGy involved point mutations, confirming our hypothesis that they are induced by a different mechanism. PMID- 11604066 TI - Low-dose hypersensitivity in Chinese hamster V79 cells targeted with counted protons using a charged-particle microbeam. AB - The Gray Laboratory charged-particle microbeam has been used to assess the clonogenic ability of Chinese hamster V79 cells after irradiation of their nuclei with a precisely defined number of protons with energies of 1.0 and 3.2 MeV. The microbeam uses a 1-microm silica capillary collimator to deliver protons to subcellular targets with high accuracy. The detection system is based on a miniature photomultiplier tube positioned above the cell dish, which detects the photons generated by the passage of the charged particles through an 18-microm thick scintillator placed below the cells. With this system, a detection efficiency of greater than 99% is achieved. The cells are plated on specially designed dishes (3-microm-thick Mylar base), and the nuclei are identified by fluorescence microscopy. After an incubation period of 3 days, the cells are revisited individually to assess the formation of colonies from the surviving cells. For each energy investigated, the survival curve obtained for the microbeam shows a significant deviation below 1 Gy from a response extrapolated using the LQ model for the survival data above 1 Gy. The data are well fitted by a model that supports the hypothesis that radioresistance is induced by low-dose hypersensitivity. These studies demonstrate the potential of the microbeam for performing studies of the effects of single charged particles on cells in vitro. The hypersensitive responses observed are comparable with those reported by others using different radiations and techniques. PMID- 11604067 TI - Identification of KIN (KIN17), a human gene encoding a nuclear DNA-binding protein, as a novel component of the TP53-independent response to ionizing radiation. AB - Ionizing radiation elicits a genetic response in human cells that allows cell survival. The human KIN (also known as KIN17) gene encodes a 45-kDa nuclear DNA binding protein that participates in the response to UVC radiation and is immunologically related to the bacterial RecA protein. We report for the first time that ionizing radiation and bleomycin, a radiomimetic drug, which produce single- and double-strand breaks, increased expression of KIN in human cells established from tumors, including MeWo melanoma, MCF7 breast adenocarcinoma, and ATM+ GM3657 lymphoblast cells. KIN expression increased rapidly in a dose dependent manner after irradiation. Under the same conditions, several genes controlled by TP53 were induced with kinetics similar to that of KIN. Using the CDKN1A gene as a marker of TP53 responsiveness, we analyzed the up-regulation of KIN and showed that is independent of the status of TP53 and ATM. In contrast, the presence of a dominant mutant for activating transcription factor 2 (ATF2) completely abolished the up-regulation of KIN. Our results suggest a role for ATF2 in the TP53-independent increase in KIN expression after gamma irradiation. PMID- 11604068 TI - Large-mutation spectra induced at hemizygous loci by low-LET radiation: evidence for intrachromosomal proximity effects. AB - A mathematical model is used to analyze mutant spectra for large mutations induced by low-LET radiation. The model equations are based mainly on two-break misrejoining that leads to deletions or translocations. It is assumed, as a working hypothesis, that the initial damage induced by low-LET radiation is located randomly in the genome. Specifically, we analyzed data for two hemizygous loci: CD59- mutants, mainly very large-scale deletions (>3 Mbp), in human-hamster hybrid cells, and data from the literature on those HPRT- mutants which involve at least deletion of the whole gene, and often of additional flanking markers (approximately 50-kbp to approximately 4.4-Mbp deletions). For five data sets, we estimated f, the probability that two given breaks on the same chromosome will misrejoin to make a deletion, as a function of the separation between the breaks. We found that f is larger for nearby breaks than for breaks that are more widely separated; i.e., there is a "proximity effect". For acute irradiation, the values of f determined from the data are consistent with the corresponding break misrejoining parameters found previously in quantitative modeling of chromosome aberrations. The value of f was somewhat smaller for protracted irradiation than for acute irradiation at a given total dose; i.e., the mutation data show a decrease that was smaller than expected for dose protraction by fractionation or low dose rate. PMID- 11604069 TI - Direct evidence for the spatial correlation between individual particle traversals and localized CDKN1A (p21) response induced by high-LET radiation. AB - The spatial correlation between individual particle traversals and the nuclear CDKN1A (p21) response after high-LET irradiation of human fibroblasts was investigated. The experiments were based on a technique for the retrospective detection of particle traversals by means of nuclear track detectors, which were used as the cell substratum. This technique requires the precise repositioning of a sample at different steps of the experimental procedure and uses a computerized microscope stage control. The precision of the spatial correlation is further enhanced by means of reference marks in the track etch material that are produced by preirradiation of the plates with charged-particle beams at low fluences. The pattern of the CDKN1A foci that were induced by charged-particle traversals at 1 h postirradiation was found to coincide extremely well with the pattern of particle tracks. This represents direct evidence that CDKN1A foci are located at the sites of particle traversals and thus provides further evidence that the radiation-induced accumulation of the CDKN1A protein takes place at the sites of the primary damage. PMID- 11604070 TI - IL2 release in atomic bomb survivors. PMID- 11604072 TI - Julie Denekamp--her life and achievements (1943-2001): a brief account. PMID- 11604073 TI - Preface. PMID- 11604074 TI - A review of studies of ionizing radiation-induced double-strand break clustering. AB - Underpinning current models of the mechanisms of the action of radiation is a central role for DNA damage and in particular double-strand breaks (DSBs). For radiations of different LET, there is a need to know the exact yields and distributions of DSBs in human cells. Most measurements of DSB yields within cells now rely on pulsed-field gel electrophoresis as the technique of choice. Previous measurements of DSB yields have suggested that the yields are remarkably similar for different types of radiation with RBE values < or = 1.0. More recent studies in mammalian cells, however, have suggested that both the yield and the spatial distribution of DSBs are influenced by radiation quality. RBE values for DSBs induced by high-LET radiations are greater than 1.0, and the distributions are nonrandom. Underlying this is the interaction of particle tracks with the higher-order chromosomal structures within cell nuclei. Further studies are needed to relate nonrandom distributions of DSBs to their rejoining kinetics. At the molecular level, we need to determine the involvement of clustering of damaged bases with strand breakage, and the relationship between higher-order clustering over sizes of kilobase pairs and above to localized clustering at the DNA level. Overall, these studies will allow us to elucidate whether the nonrandom distributions of breaks produced by high-LET particle tracks have any consequences for their repair and biological effectiveness. PMID- 11604075 TI - Computational approach for determining the spectrum of DNA damage induced by ionizing radiation. AB - To study the characteristics of molecular damage induced by ionizing radiation at the DNA level, Monte Carlo track simulation of energetic electrons and ions in liquid water, a canonical model of B-DNA, and a comprehensive classification of DNA damage in terms of the origin and complexity of damage were used to calculate the frequencies of simple and complex strand breaks. A threshold energy of 17.5 eV was used to model the damage by direct energy deposition, and a probability of 0.13 was applied to model the induction of a single-strand break produced in DNA by OH radical reactions. For preliminary estimates, base damage was assumed to be induced by the same direct energy threshold deposition or by the reaction of an OH radical with the base, with a probability of 0.8. Computational data are given on the complexity of damage, including base damage by electrons with energies of 100-4500 eV and ions with energies of 0.3-4.0 MeV/nucleon (59-9 keV microm(-1) protons and 170-55 keV microm(-1) alpha particles). Computational data are presented on the frequencies of single- and double-strand breaks induced as a function of the LET of the particles, and on the relative frequencies of complex single- and double-strand breaks for electrons. The modeling and calculations of strand breaks show that: (1) The yield of strand breaks per unit absorbed dose is nearly constant over a wide range of LET. (2) The majority of DNA damage is of a simple type, but the majority of the simple single-strand breaks are accompanied by at least one base damage. (3) For low-energy electrons, nearly 20-30% of the double-strand breaks are of a complex type by virtue of additional breaks. The proportion of this locally clustered damage increases with LET, reaching about 70% for the highest-LET alpha particles modeled, with the complexity of damage increasing further, to about 90%, when base damage is considered. (4) The extent of damage in the local hit region of the DNA duplex is mostly limited to a length of a few base pairs. (5) The frequency of base damage when no strand breaks are present in the hit segment of DNA varies between 20-40% as a function of LET for protons and alpha particles. PMID- 11604076 TI - Response of base excision repair enzymes to complex DNA lesions. AB - There is now increasing evidence that ionizing radiation generates complex DNA damage, i.e. two or more lesions--single-strand breaks or modified nucleosides- located within one to two helical turns on the same strand or on opposite strands. Double-strand breaks are the most readily recognizable clustered lesions, but they may constitute a relatively minor fraction of the total. It is anticipated that clustered lesions may play a significant role in cellular response to ionizing radiation since they may present a major challenge to the DNA repair machinery. The degree of lesion complexity increases with increasing LET. This has potential implications for space travel because of exposure to high LET cosmic radiation. It is therefore critical that we begin to understand the consequences of such damaged sites, including their influence on DNA repair enzymes. This paper presents a short review of our current knowledge of the action of purified DNA repair enzymes belonging to the base excision repair pathway, including DNA glycosylases and apurinic/apyrimidinic endonucleases, on model complex lesions. PMID- 11604077 TI - Contribution of base lesions to radiation-induced clustered DNA damage: implication for models of radiation response. AB - Biophysical modeling of radiation-induced DNA damage shows that significant yields of clustered DNA damage are formed after energy deposition by a single radiation track. To date, the majority of studies on radiation-induced DNA damage in cells have concentrated on determination of the yields of single- and double strand breaks (DSBs), the latter representing one type of clustered DNA damage. It was recognized, however, that clustered DNA damage, which does not contain a DSB, might contain a combination of DNA base lesions and single-strand breaks in proximity. This mini-review discusses some of the recent experimental data confirming the induction of non-DSB, clustered DNA damage by radiation. PMID- 11604078 TI - Extrapolation of the dna fragment-size distribution after high-dose irradiation to predict effects at low doses. AB - The patterns of DSBs induced in the genome are different for sparsely and densely ionizing radiations: In the former case, the patterns are well described by a random-breakage model; in the latter, a more sophisticated tool is needed. We used a Monte Carlo algorithm with a random-walk geometry of chromatin, and a track structure defined by the radial distribution of energy deposition from an incident ion, to fit the PFGE data for fragment-size distribution after high-dose irradiation. These fits determined the unknown parameters of the model, enabling the extrapolation of data for high-dose irradiation to the low doses that are relevant for NASA space radiation research. The randomly-located-clusters formalism was used to speed the simulations. It was shown that only one adjustable parameter, Q, the track efficiency parameter, was necessary to predict DNA fragment sizes for wide ranges of doses. This parameter was determined for a variety of radiations and LETs and was used to predict the DSB patterns at the HPRT locus of the human X chromosome after low-dose irradiation. It was found that high-LET radiation would be more likely than low-LET radiation to induce additional DSBs within the HPRT gene if this gene already contained one DSB. PMID- 11604079 TI - Rejoining of isochromatid breaks induced by heavy ions in G2-phase normal human fibroblasts. AB - We reported previously that exposure of normal human fibroblasts in G2 phase of the cell cycle to high-LET radiation produces a much higher frequency of isochromatid breaks than exposure to gamma rays. We concluded that an increase in the production of isochromatid breaks is a signature of initial high-LET radiation-induced G2-phase damage. In this paper, we report the repair kinetics of isochromatid breaks induced by high-LET radiation in normal G2-phase human fibroblasts. Exponentially growing human fibroblasts (AG1522) were irradiated with gamma rays or energetic carbon (290 MeV/nucleon), silicon (490 MeV/nucleon), or iron (200 MeV/nucleon) ions. Prematurely condensed chromosomes were induced by calyculin A after different postirradiation incubation times ranging from 0 to 600 min. Chromosomes were stained with Giemsa, and aberrations were scored in cells at G2 phase. G2-phase fragments, the result of the induction of isochromatid breaks, decreased quickly with incubation time. The curve for the kinetics of the rejoining of chromatid-type breaks showed a slight upward curvature with time after exposure to 440 keV/microm iron particles, probably due to isochromatid-isochromatid break rejoining. The formation of chromatid exchanges after exposure to high-LET radiation therefore appears to be underestimated, because isochromatid-isochromatid exchanges cannot be detected. Increased induction of isochromatid breaks and rejoining of isochromatid breaks affect the overall kinetics of chromatid-type break rejoining after exposure to high-LET radiation. PMID- 11604080 TI - Probabilities of radiation-induced inter- and intrachromosomal exchanges and their dependence on the DNA content of the chromosome. AB - A biophysical model has been developed that is based on the assumptions that an interphase chromosome occupies a spherical territory and that chromosome exchanges are formed by the misrejoining of two DNA double-strand breaks induced within a defined interaction distance. The model is used to explain the relative frequencies of inter- and intrachromosomal exchanges and the relationship between radiation-induced aberrations in individual chromosomes and the DNA content of the chromosome. Although this simple model predicts a higher ratio of inter- to intrachromosomal exchanges for low-LET radiation than for high-LET radiation, as has been suggested by others, we argue that the comparison of the prediction of the model with experimental results is not straightforward. With the model, we also show that the probability of the formation of interchromosomal exchanges is proportional to the "surface area" of the chromosome domain plus a correction term. The correction term is small if the interaction distance is less than 1 microm for both low- and high-LET radiations. PMID- 11604081 TI - Mutations in mammalian cells induced by heavy charged particles: an indicator for risk assessment in space. AB - Induction of mutations at the HPRT locus in V79 Chinese hamster cells by heavy charged particles is reviewed. A unique dependence of mutation induction cross sections on LET or any other physical parameter of the particles cannot be found. There is, however, a general trend showing an increase up to about 100 keV/microm and an indication of a saturation with higher LET. An empirical expression is given approximating the data which may be useful for practical purposes. On the basis of this expression, it is suggested that the formula used by the ICRP for the quality factor overestimates the risk for very heavy particles. This may have implications for the assessment of the risk of exposure to iron ions in space. PMID- 11604082 TI - The potential impact of bystander effects on radiation risks in a Mars mission. AB - Densely ionizing (high-LET) galactic cosmic rays (GCR) contribute a significant component of the radiation risk in free space. Over a period of a few months sufficient for the early stages of radiation carcinogenesis to occur-a significant proportion of cell nuclei will not be traversed. There is convincing evidence, at least in vitro, that irradiated cells can send out signals that can result in damage to nearby unirradiated cells. This observation can hold even when the unirradiated cells have been exposed to low doses of low-LET radiation. We discuss here a quantitative model based on the a formalism, an approach that incorporates radiobiological damage both from a bystander response to signals emitted by irradiated cells, and also from direct traversal of high-LET radiations through cell nuclei. The model produces results that are consistent with those of a series of studies of the bystander phenomenon using a high-LET microbeam, with the end point of in vitro oncogenic transformation. According to this picture, for exposure to high-LET particles such as galactic cosmic rays other than protons, the bystander effect is significant primarily at low fluences, i.e., exposures where there are significant numbers of untraversed cells. If the mechanisms postulated here were applicable in vivo, using a linear extrapolation of risks derived from studies using intermediate doses of high-LET radiation (where the contribution of the bystander effect may be negligible) to estimate risks at very low doses (where the bystander effect may be dominant) could underestimate the true risk from low doses of high-LET radiation. It would be highly premature simply to abandon current risk projections for high-LET, low dose radiation; however, these considerations would suggest caution in applying results derived from experiments using high-LET radiation at fluences above approximately 1 particle per nucleus to risk estimation for a Mars mission. PMID- 11604083 TI - Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability. AB - Cell growth, differentiation and death are directed in large part by extracellular signaling through the interactions of cells with other cells and with the extracellular matrix; these interactions are in turn modulated by cytokines and growth factors, i.e. the microenvironment. Here we discuss the idea that extracellular signaling integrates multicellular damage responses that are important deterrents to the development of cancer through mechanisms that eliminate abnormal cells and inhibit neoplastic behavior. As an example, we discuss the action of transforming growth factor beta (TGFB1) as an extracellular sensor of damage. We propose that radiation-induced bystander effects and genomic instability are, respectively, positive and negative manifestations of this homeostatic process. Bystander effects exhibited predominantly after a low-dose or a nonhomogeneous radiation exposure are extracellular signaling pathways that modulate cellular repair and death programs. Persistent disruption of extracellular signaling after exposure to relatively high doses of ionizing radiation may lead to the accumulation of aberrant cells that are genomically unstable. Understanding radiation effects in terms of coordinated multicellular responses that affect decisions regarding the fate of a cell may necessitate re evaluation of radiation dose and risk concepts and provide avenues for intervention. PMID- 11604084 TI - Risk analysis: divergent models and convergent interpretations. AB - Material presented at a NASA-sponsored workshop on risk models for exposure conditions relevant to prolonged space flight are described in this paper. Analyses used mortality data from experiments conducted at Argonne National Laboratory on the long-term effects of external whole-body irradiation on B6CF1 mice by 60Co gamma rays and fission neutrons delivered as a single exposure or protracted over either 24 or 60 once-weekly exposures. The maximum dose considered was restricted to 1 Gy for neutrons and 10 Gy for gamma rays. Proportional hazard models were used to investigate the shape of the dose response at these lower doses for deaths caused by solid-tissue tumors and tumors of either connective or epithelial tissue origin. For protracted exposures, a significant mortality effect was detected at a neutron dose of 14 cGy and a gamma ray dose of 3 Gy. For single exposures, radiation-induced mortality for neutrons also occurred within the range of 10-20 cGy, but dropped to 86 cGy for gamma rays. Plots of risk relative to control estimated for each observed dose gave a visual impression of nonlinearity for both neutrons and gamma rays. At least for solid-tissue tumors, male and female mortality was nearly identical for gamma-ray exposures, but mortality risks for females were higher than for males for neutron exposures. As expected, protracting the gamma-ray dose reduced mortality risks. Although curvature consistent with that observed visually could be detected by a model parameterized to detect curvature, a relative risk term containing only a simple term for total dose was usually sufficient to describe the dose response. Although detectable mortality for the three pathology end points considered typically occurred at the same level of dose, the highest risks were almost always associated with deaths caused by tumors of epithelial tissue origin. PMID- 11604085 TI - Radiation and germline mutation at repeat sequences: Are we in the middle of a paradigm shift? AB - Two assumptions are commonly made in the estimation of genetic risk: (1) that the seven specific loci in the mouse constitute a suitable basis for extrapolation to genetic disease in humans, and (2) that mutations are induced by radiation damage (energy-loss events leading to double-stranded damage) occurring within the gene and are induced linearly with dose, at least at low doses. Recent evidence on the mutability of repeat sequences is reviewed that suggests that neither of these assumptions is as well founded as we like to think. Repeat sequences are common in the human genome, and alterations in them may have health consequences. Many of them are unstable, both spontaneously and after irradiation. The fact that changes in DNA repeat sequences can clearly arise as a result of radiation damage outside the sequence concerned and the likely involvement of some sort of signal transduction process mean that the nature of the radiation dose response cannot be assumed. While the time has not come to abandon the current paradigms, it would seem sensible to invest more effort in exploring the induction of changes in repeat sequences after irradiation and the consequences of such changes for health. PMID- 11604087 TI - Impact of cancer predisposition and radiosensitivity on the population risk of radiation-induced cancers. AB - This paper provides a brief overview of the current evidence for cancer predisposition and for an increased sensitivity of individuals carrying such predisposing mutations to cancers induced by ionizing radiations. We also discuss the use of a Mendelian one-locus, two-allele autosomal dominant model for predicting the impact of cancer predisposition and increased radiosensitivity on the risk of radiation-induced cancers in the population and in relatives of affected individuals using breast cancer due to BRCA1 mutations as an example. The main conclusions are the following: (1) The relative risk ratio of the risks of radiation-induced cancer in a heterogeneous population which has subgroups of normal and cancer-predisposed individuals to the risks in a homogeneous population (i.e., one which does not have these subgroups) increases with increasing dose; however, the dose dependence of the RR decreases at higher doses because of the fact that at high doses, the radiation risk to a homogeneous population will already be high. (2) The attributable risk (the proportion of cancers attributable to increased cancer susceptibility and increased radiosensitivity) follows a similar pattern. (3) When the proportion of cancers due to the susceptible genotypes is small (< 10%), as is likely to be the case for breast cancers in non-Ashkenazi Jewish women, the increases in risk ratios and attributable risks are small, and become marked only when there are very large increases in cancer susceptibility (> 1000-fold) and radiosensitivity (> 100-fold) in the susceptible group. (4) When the proportion of cancers due to the susceptible genotypes is appreciable (> or = 10%), as may be the case for breast cancers in Ashkenazi Jewish women, there may be significant increases in the risk ratios and attributable risk for comparatively moderate increases in cancer susceptibility (> 10-fold) and radiosensitivity (> 100-fold) in the susceptible subpopulation. (5) The ratio of the risk of radiation-induced cancer in relatives to that in unrelated individuals in the population increases with the biological relatedness of the relative, being higher for close than for distant relatives; however, even when the mutant BRCA1 gene frequency and the proportion of breast cancers due to these mutations are high, as in Ashkenazi Jewish women, for values of predisposition strength and radiosensitivity differential < 10, the increase in breast cancer risks is only marginal, even for first-degree relatives. PMID- 11604086 TI - The role of ATM in telomere structure and function. AB - Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with a wide variety of phenotypic manifestations. AT patients are cancer prone and hypersensitive to ionizing radiation. Cells derived from AT patients require higher levels of serum factors, exhibit cytoskeletal defects, and undergo premature senescence in culture. The gene responsible for AT is ATM (ataxia telangiectasia mutated), and its product has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, and cell cycle control. Because of the homology of the human ATM gene to the TEL1 and rad3 genes of yeast, it has been suggested that mutations in ATM could lead to defective telomere maintenance. The ATM gene product influences chromosome end associations, telomere length, and telomere clustering. The defective telomere metabolism in AT cells could be due to altered interactions between the telomeres and the nuclear matrix. These interactions were studied in nuclear matrix halos before and after irradiation. Altered telomere-nuclear matrix interactions were observed in cells derived from individuals with AT. AT cells also had different nucleosomal periodicity in their telomeres from normal cells. Both telomere nuclear matrix interactions and nucleosomal periodicity were altered by treatment of primary AT fibroblasts with ionizing radiation. This effect was not observed in cells derived from normal individuals. A link was also found between altered telomere-nuclear matrix interactions, aberrant telomere clustering, and gonadal atrophy. The telomere defect was not corrected by the ectopic expression of the catalytic subunit of telomerase (TERT). Since alteration of the yeast telomere chromatin structure is known to influence gene expression, we compared expressed sequence tags (ESTs) of Atm-null mouse cells and normal mouse cells. Several ESTs were found to be aberrantly expressed in Atm-null mouse cells. This paper summarizes our recent publications and presents some new data on the influence of ATM on telomere metabolism. PMID- 11604088 TI - Induction of gene expression as a monitor of exposure to ionizing radiation. AB - The complex molecular responses to genotoxic stress are mediated by a variety of regulatory pathways. The transcription factor TP53 plays a central role in the cellular response to DNA-damaging agents such as ionizing radiation, but other pathways also play important roles. In addition, differences in radiation quality, such as the exposure to high-LET radiation that occurs during space travel, may influence the pattern of responses. The premise is developed that stress gene responses can be employed as molecular markers for radiation exposure using a combination of informatics and functional genomics approaches. Published studies from our laboratory have already demonstrated such transcriptional responses with doses of gamma rays as low as 2 cGy, and in peripheral blood lymphocytes (PBLs) irradiated ex vivo with doses as low as 20 cGy. We have also found several genes elevated in vivo 24 h after whole-body irradiation of mice with 20 cGy. Such studies should provide insight into the molecular responses to physiologically relevant doses, which cannot necessarily be extrapolated from high-dose studies. In addition, ongoing experiments are identifying large numbers of potential biomarkers using microarray hybridization and various irradiation protocols including expression at different times after exposure to low- and high LET radiation. Computation-intensive informatics analysis methods are also being developed for management of the complex gene expression profiles resulting from these experiments. With further development of these approaches, it may be feasible to monitor changes in gene expression after low-dose radiation exposure and other physiological stresses that may be encountered during manned space flight, such as the planned mission to Mars. PMID- 11604089 TI - Risk estimation based on chromosomal aberrations induced by radiation. AB - The presence of a causal association between the frequency of chromosomal aberrations in peripheral blood lymphocytes and the risk of cancer has been substantiated recently by epidemiological studies. Cytogenetic analyses of crew members of the Mir Space Station have shown that a significant increase in the frequency of chromosomal aberrations can be detected after flight, and that such an increase is likely to be attributed to the radiation exposure. The risk of cancer can be estimated directly from the yields of chromosomal aberrations, taking into account some aspects of individual susceptibility and other factors unrelated to radiation. However, the use of an appropriate technique for the collection and analysis of chromosomes and the choice of the structural aberrations to be measured are crucial in providing sound results. Based on the fraction of aberrant lymphocytes detected before and after flight, the relative risk after a long-term Mir mission is estimated to be about 1.2-1.3. The new technique of mFISH can provide useful insights into the quantification of risk on an individual basis. PMID- 11604090 TI - Gene expression responses in lymphoblastoid cells after radiation exposure. AB - Individual differences in response to radiation are well known, but the molecular basis for these differences is not well understood, and molecular indicators that are useful in assessing individual variation are lacking. Cells from patients developing unexpected radiation responses have occasionally been analyzed for rare genetic anomalies (such as alleles of the ATM gene), but few data exist on the long-term effects of genetic variation on radiation response. We hypothesize that much of the variation in the response to radiation is due to differences in the genes that respond to radiation exposure, and that changes in gene expression may serve as surrogate markers of individual response. As a first step in developing a selection of suitable markers of gene expression, we used cDNA microarrays to identify genes that were altered in expression in lymphoblastoid cells 4 h after exposure to 1 Gy X rays. We found changes in gene expression ranging from a 10-fold repression to a 12-fold induction. Some of the responsive genes have been noted previously in other cell types, whereas others are reported for the first time. Using these data, we are beginning to characterize the range of structural, temporal and functional variations in the responsive genes. The results of this work will assist in developing response markers both for prescreening for sensitive individuals and for risk assessment. PMID- 11604091 TI - A mathematical model of radiation carcinogenesis with induction of genomic instability and cell death. AB - We developed a mathematical model of carcinogenesis that incorporates genomic instability, a feature characterized by long-term destabilization of the genome in irradiated cells that leads to an increase in cancer risk in the exposed individuals at the cancer-prone age. This model also considers the induction of cell death, another important effect of radiation on cells. It is assumed that cell killing by radiation may occur at all stages of the carcinogenic process. The resulting model can explain not only the paradoxical relationship between low mutation rates and high cancer incidence but also the low-order dose-response relationship of cancer risk. PMID- 11604092 TI - The two-stage clonal expansion model as an example of a biologically based model of radiation-induced cancer. AB - A model with two stages and clonal expansion (TSCE) is reviewed as a prototype for biologically based models of cancer development. Applications of the TSCE model to data sets for animals and humans for particle radiation (alpha particles) are presented. The results suggest that the radiation not only influences the initiating mutation, but may also act as a promoter. A possible mechanism for the promoting action is described. The consequences of these results for the shapes of the radiation dose-response curves at low doses and dose rates are discussed. PMID- 11604093 TI - Space radiation cancer risks and uncertainties for Mars missions. AB - Projecting cancer risks from exposure to space radiation is highly uncertain because of the absence of data for humans and because of the limited radiobiology data available for estimating late effects from the high-energy and charge (HZE) ions present in the galactic cosmic rays (GCR). Cancer risk projections involve many biological and physical factors, each of which has a differential range of uncertainty due to the lack of data and knowledge. We discuss an uncertainty assessment within the linear-additivity model using the approach of Monte Carlo sampling from subjective error distributions that represent the lack of knowledge in each factor to quantify the overall uncertainty in risk projections. Calculations are performed using the space radiation environment and transport codes for several Mars mission scenarios. This approach leads to estimates of the uncertainties in cancer risk projections of 400-600% for a Mars mission. The uncertainties in the quality factors are dominant. Using safety standards developed for low-Earth orbit, long-term space missions (>90 days) outside the Earth's magnetic field are currently unacceptable if the confidence levels in risk projections are considered. Because GCR exposures involve multiple particle or delta-ray tracks per cellular array, our results suggest that the shape of the dose response at low dose rates may be an additional uncertainty for estimating space radiation risks. PMID- 11604094 TI - Health risks from radiation exposure for civilian aviation flight personnel: a study of Italian airline crew members. AB - A study of the effects of exposures of civilian aviation flight personnel to atmospheric ionizing radiation (including high-energy neutrons) is being performed. The results of previous studies and of the criteria required for a more satisfactory outcome in future studies are presented, along with a description of the protocol for the Italian national study. A description of the cohort is given in terms of its size, composition and member eligibility. The various ways of determining the exposure and the health status of past and current aircrew members are discussed, and follow-up procedures are described. An overview of the data management and processing philosophy adopted in the Italian study is given with regard to flight routes, radiation dose evaluation along the flight paths, and construction of exposure matrices. Other studies of potential interest are also discussed. The study is still in progress, so the results are preliminary. PMID- 11604095 TI - Use of human cell lines: yet more skeletons in the cupboard? PMID- 11604096 TI - The role of ECVAM in promoting the regulatory acceptance of alternative methods in the European Union. European Centre for the Validation of Alternative Methods. AB - The roles played by the European Centre for the Validation of Alternative Methods (ECVAM) and its advisory committee, the ECVAM Scientific Advisory Committee (ESAC), in the evolution of alternative methods are described. Particular emphasis is given to the process by which ECVAM and the ESAC assess the scientific validities of alternative methods, and, in appropriate cases, initiate the progression of scientifically validated methods toward regulatory acceptance. PMID- 11604097 TI - Co-occurring words and retrieval efficiency: finding information about alternatives to animal testing in relation to skin irritation testing. AB - Words appearing in abstracts of scientific articles are often useful as search terms, particularly those words and word patterns that are unique to the relevant field of endeavour. In view of the heightened interest in obtaining information about alternatives to animal testing, efforts directed toward enhancing retrieval of pertinent references from the biomedical literature are warranted. Words and phrases, and word-phrase co-occurrences describing methods of experimentation in abstracts about alternatives to skin-irritation testing in animals, were evaluated with regard to retrieval efficiency in the National Library of Medicine database, Toxline(. Precision of retrieval was defined as the number of pertinent references found in the total number of citations retrieved. Retrieval precision values ranged from 0.25% to 100%. PMID- 11604099 TI - The use of bootstrap resampling to assess the variability of Draize tissue scores. AB - The acute dermal and ocular effects of chemicals are generally assessed by performing the Draize skin and eye tests, respectively. Because the animal data obtained in these tests are also used for the development and validation of alternative methods for skin and eye irritation, it is important to assess the inherent variability of the animal data, since this variability places an upper limit on the predictive performance that can be expected of any alternative model. The statistical method of bootstrap resampling was used to estimate the variability arising from the use of different animals and time-points, and the estimates of variability were used to determine the maximal extent to which Draize test tissue scores can be predicted. PMID- 11604098 TI - Evaluation of the toxicity of substituted benzthioanilides by using in vitro tests. AB - The cytotoxicity of 12 benzthioanilides substituted in the N-aromatic ring, and of two commercial preparations (imaverol and thiuram) for comparison, was studied with clone 81 cat cells, by determining the highest tolerated dose, and by using the neutral red uptake assay and the kenacid blue assay for total protein. The concentrations that induced 20%, 50% and 80% (IC20, IC50 and IC80) inhibition relative to controls were calculated from dose-response curves. For some compounds, rat LD50 values were also determined. All the benzthioanilide preparations showed in vitro toxicities lower than those of the fungicides imaverol and thiuram. It was confirmed that the cytotoxicities of the compounds depend on the type of substituent. The least toxic compound contained a CONHCH(2)CO(2)H substituent in the para position of the N-aromatic ring, and the most toxic compounds contained chloro and fluoro, or three chloro substituents in the anilide moiety. All the benzthioanilides tested showed fungistatic activity for dermatophytes; two of the compounds (compound 5 and compound 12) also inhibited the development of yeasts at concentrations lower than those which caused toxicity in vitro. The LD50 values and the cytotoxic concentrations in vitro were linearly related. PMID- 11604100 TI - The neutral red release assay: a review. AB - The neutral red release (NRR) assay is a cytotoxicity test that can be used to measure the immediate toxic effects of test substances on the cell membrane, resulting in the leaking of intracellular contents. The assay has already been used for several years to evaluate the cytotoxicities of various kinds of products, such as cosmetics, pharmaceuticals, industrial chemicals and household products. It has undergone in-house validation by many companies, and has been found to be particularly useful for identifying substances that are potentially capable of causing adverse reactions on coming into brief contact with the eye or the skin at relatively high concentrations, such as might occur in an adventitious splash into the eye or onto the skin, followed by a quick rinse. Because of the relatively long existence of the NRR assay, its practicality and its proven usefulness for particular purposes, ECVAM decided to review the status of the method, in order to decide whether prevalidation and formal validation studies on the test might be profitable. The review of the status of the test was carried out by performing a comprehensive review of the literature, and by conducting a survey involving companies and institutes with experience in using the test. Both the review and the survey revealed that the assay could provide extremely valuable information when it was used for particular purposes, such as for the evaluation and comparison of immediate toxic effects on the eye or the skin caused by certain products or chemicals such as surfactants. Most of those who responded in the survey favoured a prevalidation/validation study. PMID- 11604101 TI - In vitro assessment of cytotoxicity and carcinogenic potential of chemicals: evaluation of the cytotoxicity induced by 58 metal compounds in the Balb/3T3 cell line. AB - A new, mechanistically based, in vitro strategy involving Balb/c 3T3 clone A 31-1 1 mouse embryo fibroblasts has been proposed for the determination of the carcinogenic potential of inorganic chemicals, in order to establish priority of metal compounds to be tested and, whenever possible, to compare the in vitro results with the corresponding in vivo data. As a first step in this research, this study reports on the cytotoxic effects of 58 metal compounds in the Balb/3T3 cell line. After harmonisation and standardisation of the Balb/3T3 protocol, cells were exposed for 72 hours to a fixed dose (100 microM) of 58 individual compounds. The cytotoxicity induced by some metal compounds was found to be related to their chemical form (for example, Cr(NO(3))(3) and Na(2)CrO(4)), suggesting that the Balb/3T3 cell line is a valuable cellular model in relation to this aspect of metal speciation. The results of the systematic study on the metal-induced cytotoxic effects in the Balb/3T3 cell line could be arbitrarily classified into three groups according to the degree of cytotoxicity. Group I includes 26 species that induced no observable effect or only a slight cytotoxic effect; Group II includes 13 metal compounds that exhibited an obvious degree of cytotoxicity; and Group III includes 19 metal species that displayed a strong cytotoxic response. Metal compounds of Groups II and III are considered to be of the highest priority for setting of dose-effect relationships for a subsequent in vitro study on metal-induced concurrent cytotoxicity and morphological transformation in the Balb/3T3 cell line. PMID- 11604102 TI - Characterization of the mouse Dazap1 gene encoding an RNA-binding protein that interacts with infertility factors DAZ and DAZL. AB - BACKGROUND: DAZAP1 (DAZ Associated Protein 1) was originally identified by a yeast two-hybrid system through its interaction with a putative male infertility factor, DAZ (Deleted in Azoospermia). In vitro, DAZAP1 interacts with both the Y chromosome-encoded DAZ and an autosome-encoded DAZ-like protein, DAZL. DAZAP1 contains two RNA-binding domains (RBDs) and a proline-rich C-terminal portion, and is expressed most abundantly in the testis. To understand the biological function of DAZAP1 and the significance of its interaction with DAZ and DAZL, we isolated and characterized the mouse Dazap1 gene, and studied its expression and the subcellular localization of its protein product. RESULTS: The human and mouse genes have similar genomic structures and map to syntenic chromosomal regions. The mouse and human DAZAP1 proteins share 98% identity and their sequences are highly similar to the Xenopus orthologue Prrp, especially in the RBDs. Dazap1 is expressed throughout testis development. Western blot detects a single 45 kD DAZAP1 protein that is most abundant in the testis. Although a majority of DAZAP1 is present in the cytoplasmic fraction, they are not associated with polyribosomes. CONCLUSIONS: DAZAP1 is evolutionarily highly conserved. Its predominant expression in testes suggests a role in spermatogenesis. Its subcellular localization indicates that it is not directly involved in mRNA translation. PMID- 11604103 TI - Clinical treatment reverses attentional deficits in congestive heart failure. AB - BACKGROUND: Congestive heart failure (CHF) is associated with cognitive deficits, particularly of memory and attention. The present study aims to clarify whether clinical treatment can reverse the attentional deficits of patients with CHF. METHODS: A convenience sample of 50 patients with CHF functional class IV and 30 elderly controls were recruited from a teaching hospital in Brazil. Participants received a clinical and cognitive examination that included the Mini-Mental State Examination (MMSE), Cambridge Cognitive Examination of the Elderly (CAMCOG), Digit Span, Digit-Symbol Substitution, and Letter Cancellation test. The cognitive performance of CHF patients was reassessed 6 weeks after the introduction of clinical treatment. RESULTS: Twenty-seven CHF subjects had MMSE<24, compared to only 10 of the controls (p = 0.07). CHF patients also had lower CAMCOG scores (mean = 71.8) than controls (mean = 82.0; p < 0.01). Digit Span, Digit Symbol and Letter Cancellation scores were lower for patients with CHF than controls (p < 0.01). Similarly patients with CHF took longer to complete the Trail Making A (p = 0.07) and B (p < 0.01). CAMCOG scores and left ventricular ejection fraction were moderately correlated (rho = 0.4, p < 0.01). Nineteen patients were lost for follow-up (11 deceased). Clinical treatment was associated with significant improvement of cognitive scores, particularly on the Digit Symbol (p < 0.01) and Letter Cancellation Tests (p < 0.01). Digit Span, Digit Symbol, Letter Cancellation and Trail Making scores of treated CHF patients and controls were similar (p > 0.10). CONCLUSIONS: CHF is associated with deficits in attention and psychomotor speed. These deficits improve with clinical treatment. PMID- 11604104 TI - Mannosylerythritol lipid, a yeast extracellular glycolipid, shows high binding affinity towards human immunoglobulin G. AB - BACKGROUND: There have been many attempts to develop new materials with stability and high affinity towards immunoglobulins. Some of glycolipids such as gangliosides exhibit a high affinity toward immunoglobulins. However, it is considerably difficult to develop these glycolipids into the practical separation ligand due to their limited amounts. We thus focused our attention on the feasible use of "mannosylerythritol lipid A", a yeast glycolipid biosurfactant, as an alternative ligand for immunoglobulins, and undertook the investigation on the binding between mannosylerythritol lipid A (MEL-A) and human immunoglobulin G (HIgG). RESULTS: In ELISA assay, MEL-A showed nearly the same binding affinity towards HIgG as that of bovine ganglioside GM1. Fab of human IgG was considered to play a more important role than Fc in the binding of HIgG by MEL-A. The bound amount of HIgG increased depending on the attached amount of MEL-A onto poly (2 hydroxyethyl methacrylate) (polyHEMA) beads, whereas the amount of human serum albumin slightly decreased. Binding-amount and -selectivity of HIgG towards MEL-A were influenced by salt species, salt concentration and pH in the buffer solution. The composite of MEL-A and polyHEMA, exhibited a significant binding constant of 1.43 x 10(6) (M(-1)) for HIgG, which is approximately 4-fold greater than that of protein A reported. CONCLUSIONS: MEL-A shows high binding-affinity towards HIgG, and this is considered to be due to "multivalent effect" based on the binding molar ratio. This is the first report on the binding of a natural human antibody towards a yeast glycolipid. PMID- 11604105 TI - Computerized clinical documentation system in the pediatric intensive care unit. AB - BACKGROUND: To determine whether a computerized clinical documentation system (CDS): 1) decreased time spent charting and increased time spent in patient care; 2) decreased medication errors; 3) improved clinical decision making; 4) improved quality of documentation; and/or 5) improved shift to shift nursing continuity. METHODS: Before and after implementation of CDS, a time study involving nursing care, medication delivery, and normalization of serum calcium and potassium values was performed. In addition, an evaluation of completeness of documentation and a clinician survey of shift to shift reporting were also completed. This was a modified one group, pretest-posttest design. RESULTS: With the CDS there was: improved legibility and completeness of documentation, data with better accessibility and accuracy, no change in time spent in direct patient care or charting by nursing staff. Incidental observations from the study included improved management functions of our nurse manager; improved JCAHO documentation compliance; timely access to clinical data (labs, vitals, etc); a decrease in time and resource use for audits; improved reimbursement because of the ability to reconstruct lost charts; limited human data entry by automatic data logging; eliminated costs of printing forms. CDS cost was reasonable. CONCLUSIONS: When compared to a paper chart, the CDS provided a more legible, compete, and accessible patient record without affecting time spent in direct patient care. The availability of the CDS improved shift to shift reporting. Other observations showed that the CDS improved management capabilities; helped physicians deliver care; improved reimbursement; limited data entry errors; and reduced costs. PMID- 11604106 TI - Immunogenetic analysis of variable regions encoding AB1 and gamma-type AB2 antibodies from the NeuGc-containing ganglioside family. AB - The variable regions from P3, a murine monoclonal antibody (MAb) against NeuGc containing gangliosides, and two anti-idiotype MAbs directed to P3 MAb were cloned and sequenced. Comparisons with previously reported sequences showed that P3 is a germline antibody encoded by genes from the V(H)Q52 and V(kappa)19 families. Analysis of nucleotides at the heavy chain CDR3 (H-CDR3) showed the presence of an extensive 3' N region that contains almost 50% of the nucleotides of this CDR. In addition, amino acid sequence analysis of the H-CDRs of this MAb revealed the presence of three arginines, two of which are present in the H-CDR3, that could be involved in the interaction of P3 MAb with its electronegative epitope on gangliosides. Anti-idiotype 1E10, which seems to define a "regulatory" idiotope on P3 MAb (it induces Id+ Ab3), represents a germline Ab2 that belongs to the V(H)J558 and V(kappa)10 gene families. By contrary, the anti-idiotype 3B11 is an extensively mutated antibody that belongs to the V(H)3660 and V(kappa)4/5 gene families, defining a "private" idiotope on P3 MAb. Even when different V genes contribute to the variable regions of 1E10 and 3B11 MAbs, they share an acidic motif E/D-D-Y/D-Y-D in H-CDR3, suggesting that both Ab2s recognize paratope positive residues on the Ab1. Therefore, complementary electrostatic interactions involving H-CDR3 from both Ab1 and Ab2, might provide a clue to understand the molecular basis for the generation of gamma-type anti-idiotype antibodies to V regions recognizing glycolylated ganglioside antigens. PMID- 11604107 TI - A monoclonal antibody, MIN/3/60, that recognizes the sulpho-Lewis(x) and sulpho Lewis(a) sequences detects a sub-population of epithelial glycans in the crypts of human colonic epithelium. AB - Monoclonal antibodies (MAbs) directed to Lewis(x) (Le(x)) and related carbohydrate sequences have been invaluable in anticipating biological roles for these oligosaccharides by detecting the remarkable changes that occur in their expression from the earliest stages of embryogenesis, through development and sequential stages of cell differentiation and maturation. A notable impact has been in the molecular dissection of ligand-receptor interactions in key cell adhesion events at the initial stages of leukocyte recruitment in inflammation, and almost certainly in the metastasis of epithelial tumours. Antibodies that recognise Le(x) and the 3'-sialyl forms were observed to identify leukocyte subsets; these were subsequently found to match those recognized by the leukocyte endothelium adhesion molecules, the E- and P-selectins. We now describe a MAb (rat hybridoma MIN/3/60) raised to 3'-sulpho-Le(x), a carbohydrate sequence which, in vitro, is bound not only by the E-, L-, and P-selectins, but also by the cysteine-rich domain of the macrophage endocytosis receptor. We observe that MIN/3/60 is bispecific, however; it binds 3'-sulpho-Le(a) as well as 3'-sulpho Le(x). Nevertheless, our exploratory studies reveal that it may be a useful histochemical reagent when used in conjunction with a monospecific antibody to 3' sulpho-Le(a). The MIN/3/60 antibody reveals a sub-population of epithelial glycans in the crypts of Lieberkuhn in normal human colon. PMID- 11604108 TI - Identification of the target of monoclonal antibody A6H as dipeptidyl peptidase IV/CD26 by LC MS?MS. AB - The monoclonal antibody (MAb) A6H, originally developed to fetal renal tissues, was found to be highly reactive to renal cell carcinoma and was subsequently demonstrated to co-stimulate a subpopulation of T cells. The A6H antigen had not been identified heretofore. Antigen from detergent extracts of renal cell carcinoma cells (7860) was immunoabsorbed with A6H-agarose, and the resin-bound proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The antigen had a molecular weight of approximately 120 kDa as determined by Western blots. The 120-kDa protein band was excised and subjected to in-gel tryptic digestion, and the resulting peptides were separated and analyzed by liquid chromatography tandem mass spectrometry (LC MS?MS). The tandem mass spectra of the eluting peptides were used in combination with the SEQUEST computer program to search a human National Cancer Institute (NCI) protein database for the identity of the protein. The target antigen was shown to be dipeptidyl peptidase IV (DPP IV), which is also known as the cluster differentiation antigen CD26. Flow analysis of the expression of the A6H antigen and of CD26 on 7860 cells and on peripheral blood lymphocytes supported the identification of the A6H antigen as DPP IV. Recognition that the A6H antigen is DPP IV/CD26 afforded the opportunity to compare previous studies on A6H with those on other anti-CD26 antibodies in terms of expression in cancer cell lines and various tissues and as co-stimulators of T-cell activation. PMID- 11604109 TI - Production, characterization, and epitope mapping of monoclonal antibodies against human polydeoxyribonucleotide kinase. AB - Polydeoxyribonucleotide kinase (PNK) is a mammalian DNA repair enzyme that has the capacity to phosphorylate 5' DNA termini and dephosphorylate 3' DNA termini. A series of murine monoclonal antibodies (MAbs) was raised against the full length recombinant human PNK. Seven of these antibodies were selected and characterized by enzyme immunoassay, Western blot analysis, and their capacity to immunoprecipitate PNK. The epitope location was defined by cyanogen bromide digestion and by using a truncated PNK for Western blot analysis. All of the MAbs recognize a single 60-kDa protein in human cell extracts. PNKs from calf, monkey, and Chinese hamster cell and tissue extracts were also detected by some or all of the MAbs. These antibodies can be successfully used for the cellular, biochemical, and functional analysis of PNK in different mammalian cell lines. PMID- 11604110 TI - Evaluation of clinical significance of isoferritin by development of new monoclonal antibodies specific for acidic isoferritin. AB - We produced monoclonal antibodies (MAbs) against acidic isoferritin (AIF) of primary hepatic carcinoma (PHC) and human placental tissues. Competitive enzyme linked immunosorbent assay (ELISA) revealed that each MAb bound to different antigenic determinants of AIF, but there is the same epitope between PHC AIF and placental AIF. Sandwich-type ELISA was developed to measure the concentration of serum AIF in the patients with PHC, chronic hepatitis, and cirrhosis. In most of cases of PHC, serum AIF levels were found to be significantly elevated, but were in low levels in almost all of the patients with chronic hepatitis and cirrhosis. On the other hand, we have studied the expression of AIF in liver tissue. Immunohistochemical study using MAb4c9 specific for PHC AIF and MAb7a9 specific for placental AIF has shown that AIF positive staining rates of hepatocytes with liver tissues of PHC, nonmalignant live diseases and normal control were 81.6, 6.7, 0%, and 73.7, 10, 0%, respectively. We also studied the p53 protein expression in those liver tissues (47.4, 0, 0% in PHC, nonmalignant liver diseases and normal liver, respectively). Our data indicated that there was significant correlation between AIF and p53 expression in liver tissues of PHC. Taken together, the results suggested that AIF is probably synthesized and secreted by the tumor cells of PHC and its production may reflect carcinogenesis of hepatocytes. Anti-PHC AIF MAb was clearly superior in diagnosis of PHC to antiplacental AIF MAb, and has potential application of immunotherapy. PMID- 11604111 TI - Monoclonal antibodies against human telomerase reverse transcriptase (hTERT): preparation, characterization, and application. AB - The catalytic subunit of human telomerase reverse transcriptase (hTERT), is the necessary and rate-limiting component to telomerase activation in cancer cells. To develop monoclonal antibodies (MAbs) against hTERT, a peptide-hTERT(9)-derived from specific motif T of hTERT was synthesized. Through fusion of splenocytes of BALB/c mice immunized with hTERT(9) with mouse myeloma cells, hybridomas were generated and clones secreting anti-hTERT(9) antibody were screened. After three rounds of limited dilution of candidate clones, three of which present stable and constant antibody production. The MAbs were hTERT(9)-specific and reactive with native hTERT of human cancer cells or tissues in Western blot and immunohistochemistry. The heavy chain variable regions from three hybridomas were cloned and sequenced confirming their mouse Ig derivation. The described investigation suggested that the generated MAbs to hTERT(9) could recognize native hTERT and be useful to cancer research. PMID- 11604112 TI - Generation and characterization of monoclonal antibodies against the E6 and E7 oncoproteins of HPV. AB - Generation of three monoclonal antibodies (MAbs) to the major oncoproteins of human papillomavirus (HPV) was accomplished by an intense prime/boost regimen. Mice were primed with expression vectors expressing either the E6 or E7 oncoproteins of HPV-16 followed by boosting with a vaccinia virus construct and a replication-defective E1-deleted adenoviral recombinant of the human strain 5, and last, with baculovirus-derived HPV-16 E6 and E7 proteins in incomplete Freunds' adjuvant. Splenocytes were then fused with a myeloma cell line. The vaccination protocol generated one anti-E7 MAb of the IgM isotype and two anti-E6 MAbs of the IgG1 subisotype. The MAbs were tested for functionality in standard laboratory assays and found to detect the E6 and E7 proteins, respectively. The E7 MAb cross-reacted with the HPV-1a E7 oncoprotein. The binding sites of the MAbs were mapped to defined regions of each viral protein. PMID- 11604113 TI - Characterization of monoclonal antibodies against carcinoembryonic antigen (CEA) and expression in E. coli. AB - Eight monoclonal antibodies (MAbs) against carcinoembryonic antigen (CEA) were characterized. Five clones are IgG(1), two clones are IgM and one clone is IgG(2b); all have kappa light chain. The affinities are in the range of 1.1 x 10( 7) approximately 2.4 x 10(-9) M; the affinities of two IgM clones could not be estimated because of their low enzyme-linked immunoadsorbent assay (ELISA) signal. Each clone was constructed as single-chain Fv (scFv) and expression was performed in E. coli. Four clones out of 8 could express scFv soluble to culture media and the expression was confirmed further by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. The nucleotide and amino acid sequences of V(H) and V(L) of four scFvs were deduced and their family and subgroup were analyzed. We found that the clones that do not express the scFv have aberrant kappa chain (incorrect V/J recombination or stop codon); in contrast, their heavy chain sequences proved correct. The E. coli-expressed scFvs showed 1.5 x 3.4-fold lower affinities (2.8 x 10(-8) approximately 3.6 x 10(-9) M) than those of hybridoma-derived parental antibodies except the one clone (C5), which exhibited approximately 10(-6) M of affinity. PMID- 11604114 TI - A monoclonal antibody specific for Pseudomonas aeruginosa amidase. AB - Amidase from Pseudomonas aeruginosa was purified by anionic exchange chromatography and used to immunise female Balb/c mice. Monoclonal antibodies (MAbs) were raised by hybridoma technology using Sp2/0 myeloma cells as fusion partner. A selected IgM subclass MAb was purified from in vitro hybridoma cell line supernatant by a two-step anionic exchange chromatography. The MAb was specific for amidase from P. aeruginosa as determined by Western blotting and recognized the native and denatured forms of the enzyme. PMID- 11604120 TI - On the evolution of early development in the Nematoda. AB - The phylum Nematoda serves as an excellent model system for exploring how development evolves, using a comparative approach to developmental genetics. More than 100 laboratories are studying developmental mechanisms in the nematode Caenorhabditis elegans, and many of the methods that have been developed for C. elegans can be applied to other nematodes. This review summarizes what is known so far about steps in early development that have evolved in the nematodes, and proposes potential experiments that could make use of these data to further our understanding of how development evolves. The promise of such a comparative approach to developmental genetics is to fill a wide gap in our understanding of evolution--a gap spanning from mutations in developmental genes through to their phenotypic results, on which natural selection may act. PMID- 11604121 TI - Developmental genetic evidence for a monophyletic origin of the bilaterian brain. AB - The widely held notion of an independent evolutionary origin of invertebrate and vertebrate brains is based on classical phylogenetic, neuroanatomical and embryological data. The interpretation of these data in favour of a polyphyletic origin of animals brains is currently being challenged by three fundamental findings that derive from comparative molecular, genetic and developmental analyses. First, modern molecular systematics indicates that none of the extant animals correspond to evolutionary intermediates between the protostomes and the deuterostomes, thus making it impossible to deduce the morphological organization of the ancestral bilaterian or its brain from living species. Second, recent molecular genetic evidence for the body axis inversion hypothesis now supports the idea that the basic body plan of vertebrates and invertebrates is similar but inverted, suggesting that the ventral nerve chord of protostome invertebrates is homologous to the dorsal nerve cord of deuterostome chordates. Third, a developmental genetic analysis of the molecular control elements involved in early embryonic brain patterning is uncovering the existence of structurally and functionally homologous genes that have comparable and interchangeable functions in key aspects of brain development in invertebrate and vertebrate model systems. All three of these findings are compatible with the hypothesis of a monophyletic origin of the bilaterian brain. Here we review these findings and consider their significance and implications for current thinking on the evolutionary origin of bilaterian brains. We also preview the impact of comparative functional genomic analyses on our understanding of brain evolution. PMID- 11604123 TI - New perspectives on the evolution of protochordate sensory and locomotory systems, and the origin of brains and heads. AB - Cladistic analyses generally place tunicates close to the base of the chordate lineage, consistent with the assumption that the tunicate tail is primitively simple, not secondarily reduced from a segmented trunk. Cephalochordates (i.e. amphioxus) are segmented and resemble vertebrates in having two distinct locomotory modes, slow for distance swimming and fast for escape, that depend on separate sets of motor neurons and muscle cells. The sense organs of both amphioxus and tunicate larvae serve essentially as navigational aids and, despite some uncertainty as to homologies, current molecular and ultrastructural data imply a close relationship between them. There are far fewer signs of modification and reduction in the amphioxus central nervous system (CNS), however, so it is arguably the closer to the ancestral condition. Similarities between amphioxus and tunicate sense organs are then most easily explained if distance swimming evolved before and escape behaviour after the two lineages diverged, leaving tunicates to adopt more passive means of avoiding predation. Neither group has the kind of sense organs or sensory integration centres an organism would need to monitor predators, yet mobile predators with eyes were probably important in the early Palaeozoic. For a predator, improvements in vision and locomotion are mutually reinforcing. Both features probably evolved rapidly and together, in an 'arms race' of eyes, brains and segments that left protochordates behind, and ultimately produced the vertebrate head. PMID- 11604122 TI - Reconstructing the eyes of Urbilateria. AB - The shared roles of Pax6 and Six homologues in the eye development of various bilaterians suggest that Urbilateria, the common ancestors of all Bilateria, already possessed some simple form of eyes. Here, we re-address the homology of bilaterian cerebral eyes at the level of eye anatomy, of eye-constituting cell types and of phototransductory molecules. The most widespread eye type found in Bilateria are the larval pigment-cup eyes located to the left and right of the apical organ in primary, ciliary larvae of Protostomia and Deuterostomia. They can be as simple as comprising a single pigment cell and a single photoreceptor cell in inverse orientation. Another more elaborate type of cerebral pigment-cup eyes with an everse arrangement of photoreceptor cells is found in adult Protostomia. Both inverse larval and everse adult eyes employ rhabdomeric photoreceptor cells and thus differ from the chordate cerebral eyes with ciliary photoreceptors. This is highly significant because on the molecular level we find that for phototransduction rhabdomeric versus ciliary photoreceptor cells employ divergent rhodopsins and non-orthologous G-proteins, rhodopsin kinases and arrestins. Our comparison supports homology of cerebral eyes in Protostomia; it challenges, however, homology of chordate and non-chordate cerebral eyes that employ photoreceptor cells with non-orthologous phototransductory cascades. PMID- 11604124 TI - Developmental genetics in primitive chordates. AB - Recent advances in the study of the genetics and genomics of urochordates testify to a renewed interest in this chordate subphylum, believed to be the most primitive extant chordate relatives of the vertebrates. In addition to their primitive nature, many features of their reproduction and early development make the urochordates ideal model chordates for developmental genetics. Many urochordates spawn large numbers of transparent and externally developing embryos on a daily basis. Additionally, the embryos have a defined and well-characterized cell lineage until the end of gastrulation. Furthermore, the genomes of the urochordates have been estimated to be only 5-10% of the size of the vertebrates and to have fewer genes and less genetic redundancy than vertebrates. Genetic screens, which are powerful tools for investigating developmental mechanisms, have recently become feasible due to new culturing techniques in ascidians. Because hermaphrodite ascidians are able to self-fertilize, recessive mutations can be detected in a single generation. Several recent studies have demonstrated the feasibility of applying modern genetic techniques to the study of ascidian biology. PMID- 11604125 TI - Thoughts on the development, structure and evolution of the mammalian and avian telencephalic pallium. AB - Various lines of evidence suggest that the development and evolution of the mammalian isocortex cannot be easily explained without an understanding of correlative changes in surrounding areas of the telencephalic pallium and subpallium. These are close neighbours in a common morphogenetic field and are postulated as sources of some cortical neuron types (and even of whole cortical areas). There is equal need to explain relevant developmental evolutionary changes in the dorsal thalamus, the major source of afferent inputs to the telencephalon (to both the pallium and subpallium). The mammalian isocortex evolved within an initially small dorsal part of the pallium of vertebrates, surrounded by other pallial parts, including some with a non-cortical, nuclear structure. Nuclear pallial elements are markedly voluminous in reptiles and birds, where they build the dorsal ventricular ridge, or hypopallium, which has been recently divided molecularly and structurally into a lateral pallium and a ventral pallium. Afferent pallial connections are often simplified as consisting of thalamic fibres that project either to focal cell aggregates in the ventral pallium (predominant in reptiles and birds) or to corticoid areas in the dorsal pallium (predominant in mammals). Karten's hypothesis, put forward in 1969, on the formation of some isocortical areas postulates an embryonic translocation into the nascent isocortex of the ventropallial thalamorecipient foci and respective downstream ventropallial target populations, as specific layer IV, layers II- III, or layers V-VI neuron populations. This view is considered critically in the light of various recent data, contrasting with the alternative possibility of a parallel, separate evolution of the different pallial parts. The new scenario reveals as well a separately evolving tiered structure of the dorsal thalamus, some of whose parts receive input from midbrain sensory centres (collothalamic nuclei), whereas other parts receive oligosynaptic 'lemniscal' connections bypassing the midbrain (lemnothalamic nuclei). An ampler look into known hodological patterns from this viewpoint suggests that ancient collothalamic pathways, which target ventropallial foci, are largely conserved in mammals, while some emergent cortical connections can be established by means of new collaterals in some of these pathways. The lemnothalamic pathways, which typically target ancestrally the dorsopallial isocortex, show parallel increments of relative size and structural diversification of both the thalamic cell populations and the cortical recipient areas. The evolving lemnothalamic pathways may interact developmentally with collothalamic corticopetal collaterals in the modality-specific invasion of the emergent new areas of isocortex. PMID- 11604126 TI - Origins of anteroposterior patterning and Hox gene regulation during chordate evolution. AB - All chordates share a basic body plan and many common features of early development. Anteroposterior (AP) regions of the vertebrate neural tube are specified by a combinatorial pattern of Hox gene expression that is conserved in urochordates and cephalochordates. Another primitive feature of Hox gene regulation in all chordates is a sensitivity to retinoic acid during embryogenesis, and recent developmental genetic studies have demonstrated the essential role for retinoid signalling in vertebrates. Two AP regions develop within the chordate neural tube during gastrulation: an anterior 'forebrain midbrain' region specified by Otx genes and a posterior 'hindbrain-spinal cord' region specified by Hox genes. A third, intermediate region corresponding to the midbrain or midbrain-hindbrain boundary develops at around the same time in vertebrates, and comparative data suggest that this was also present in the chordate ancestor. Within the anterior part of the Hox-expressing domain, however, vertebrates appear to have evolved unique roles for segmentation genes, such as Krox-20, in patterning the hindbrain. Genetic approaches in mammals and zebrafish, coupled with molecular phylogenetic studies in ascidians, amphioxus and lampreys, promise to reveal how the complex mechanisms that specify the vertebrate body plan may have arisen from a relatively simple set of ancestral developmental components. PMID- 11604127 TI - Embryology of the lamprey and evolution of the vertebrate jaw: insights from molecular and developmental perspectives. AB - Evolution of the vertebrate jaw has been reviewed and discussed based on the developmental pattern of the Japanese marine lamprey, Lampetra japonica. Though it never forms a jointed jaw apparatus, the L. japonica embryo exhibits the typical embryonic structure as well as the conserved regulatory gene expression patterns of vertebrates. The lamprey therefore shares the phylotype of vertebrates, the conserved embryonic pattern that appears at pharyngula stage, rather than representing an intermediate evolutionary state. Both gnathostomes and lampreys exhibit a tripartite configuration of the rostral-most crest-derived ectomesenchyme, each part occupying an anatomically equivalent site. Differentiated oral structure becomes apparent in post-pharyngula development. Due to the solid nasohypophyseal plate, the post-optic ectomesenchyme of the lamprey fails to grow rostromedially to form the medial nasal septum as in gnathostomes, but forms the upper lip instead. The gnathostome jaw may thus have arisen through a process of ontogenetic repatterning, in which a heterotopic shift of mesenchyme-epithelial relationships would have been involved. Further identification of shifts in tissue interaction and expression of regulatory genes are necessary to describe the evolution of the jaw fully from the standpoint of evolutionary developmental biology. PMID- 11604129 TI - The ectodermal placodes: a dysfunctional family. AB - The ectodermal placodes are focal thickenings of the cranial embryonic ectoderm that contribute extensively to the cranial sensory systems of the vertebrates. The ectodermal placodes have long been thought of as representing a coherent group, which share a developmental and evolutionary history. However, it is now becoming clear that there are substantial differences between the placodes with respect to their early development, their induction and their evolution. Indeed, it is now hard to consider the ectodermal placodes as a single entity. Rather, they fall into a number of distinct classes and it is within each of these that the members share a common development and evolution. PMID- 11604128 TI - The genetic basis of modularity in the development and evolution of the vertebrate dentition. AB - The construction of organisms from units that develop under semi-autonomous genetic control (modules) has been proposed to be an important component of their ability to undergo adaptive phenotypic evolution. The organization of the vertebrate dentition as a system of repeated parts provides an opportunity to study the extent to which phenotypic modules, identified by their evolutionary independence from other such units, are related to modularity in the genetic control of development. The evolutionary history of vertebrates provides numerous examples of both correlated and independent evolution of groups of teeth. The dentition itself appears to be a module of the dermal exoskeleton, from which it has long been under independent genetic control. Region-specific tooth loss has been a common trend in vertebrate evolution. Novel deployment of teeth and reacquisition of lost teeth have also occurred, although less frequently. Tooth shape differences within the dentition may be discontinuous (referred to as heterodonty) or graded. The occurrence of homeotic changes in tooth shape provides evidence for the decoupling of tooth shape and location in the course of evolution. Potential mechanisms for region-specific evolutionary tooth loss are suggested by a number of mouse gene knockouts and human genetic dental anomalies, as well as a comparison between fully-developed and rudimentary teeth in the dentition of rodents. These mechanisms include loss of a tooth-type-specific initiation signal, alterations of the relative strength of inductive and inhibitory signals acting at the time of tooth initiation and the overall reduction in levels of proteins required for the development of all teeth. Ectopic expression of tooth initiation signals provides a potential mechanism for the novel deployment or reacquisition of teeth; a single instance is known of a gene whose ectopic expression in transgenic mice can lead to ectopic teeth. Differences in shape between incisor and molar teeth in the mouse have been proposed to be controlled by the region-specific expression of signalling molecules in the oral epithelium. These molecules induce the expression of transcription factors in the underlying jaw mesenchyme that may act as selectors of tooth type. It is speculated that shifts in the expression domains of the epithelial signalling molecules might be responsible for homeotic changes in tooth shape. The observation that these molecules are regionally restricted in the chicken, whose ancestors were not heterodont, suggests that mammalian heterodonty may have evolved through the use of patterning mechanisms already acting on skeletal elements of the jaws. In general, genetic and morphological approaches identify similar types of modules in the dentition, but the data are not yet sufficient to identify exact correspondences. It is speculated that modularity may be achieved by gene expression differences between teeth or by differences in the time of their development, causing mutations to have cumulative effects on later-developing teeth. The mammalian dentition, for which virtually all of the available developmental genetic data have been collected, represents a small subset of the dental diversity present in vertebrates as a whole. In particular, teleost fishes may have a much more extensive dentition. Extension of research on the genetic control of tooth development to this and other vertebrate groups has great potential to further the understanding of modularity in the dentition. PMID- 11604130 TI - Comparative genomics provides evidence for an ancient genome duplication event in fish. AB - There are approximately 25 000 species in the division Teleostei and most are believed to have arisen during a relatively short period of time ca. 200 Myr ago. The discovery of 'extra' Hox gene clusters in zebrafish (Danio rerio), medaka (Oryzias latipes), and pufferfish (Fugu rubripes), has led to the hypothesis that genome duplication provided the genetic raw material necessary for the teleost radiation. We identified 27 groups of orthologous genes which included one gene from man, mouse and chicken, one or two genes from tetraploid Xenopus and two genes from zebrafish. A genome duplication in the ancestor of teleost fishes is the most parsimonious explanation for the observations that for 15 of these genes, the two zebrafish orthologues are sister sequences in phylogenies that otherwise match the expected organismal tree, the zebrafish gene pairs appear to have been formed at approximately the same time, and are unlinked. Phylogenies of nine genes differ a little from the tree predicted by the fish-specific genome duplication hypothesis: one tree shows a sister sequence relationship for the zebrafish genes but differs slightly from the expected organismal tree and in eight trees, one zebrafish gene is the sister sequence to a clade which includes the second zebrafish gene and orthologues from Xenopus, chicken, mouse and man. For these nine gene trees, deviations from the predictions of the fish-specific genome duplication hypothesis are poorly supported. The two zebrafish orthologues for each of the three remaining genes are tightly linked and are, therefore, unlikely to have been formed during a genome duplication event. We estimated that the unlinked duplicated zebrafish genes are between 300 and 450 Myr. Thus, genome duplication could have provided the genetic raw material for teleost radiation. Alternatively, the loss of different duplicates in different populations (i.e. 'divergent resolution') may have promoted speciation in ancient teleost populations. PMID- 11604131 TI - Plexin signaling via off-track and rho family GTPases. AB - Two papers in this issue of Neuron examine new aspects of Semaphorin signaling via Plexin receptors. Winberg et al. present evidence that the transmembrane protein Off-track (OTK) interacts biochemically and genetically with Plexin A and is important for Sema 1a repulsive signaling. Hu et al. examine the coupling of Plexin B to Rac and RhoA and propose that Plexin B signaling involves inhibition of Rac function by direct sequestration and simultaneous activation of RhoA. PMID- 11604132 TI - Unwebbing the presynaptic web. AB - The release of neurotransmitter from nerve terminals occurs at a specialized region of the presynaptic plasma membrane called the active zone. A dense matrix of proteins associated with the active zone, called the presynaptic web, is thought to play a fundamental role in defining these neurotransmitter release sites. In this issue of Neuron, Phillips et al. have identified conditions for the biochemical purification of the presynaptic web and show that the web is comprised of proteins involved in the docking, fusion, and recycling of synaptic vesicles. PMID- 11604133 TI - Attention, adaptation, and the motion aftereffect. AB - Activation of the human visual motion area V5/MT was previously thought to be the basis of the motion aftereffect. New findings suggest that previous observations were confounded by attention and arousal, providing evidence that adaptation of directionally selective neurons in area V5/MT represents the fundamental substrate for the motion aftereffect. PMID- 11604134 TI - Phosphoinositides as key regulators of synaptic function. AB - Phosphoinositides have recently emerged as key regulators of a variety of synaptic processes, including neurosecretory vesicle targeting, exo-endocytosis, and ion channel modulation. These pleiotropic activities derive from their ability to serve either as membrane targeting sites for cytosolic factors, as allosteric ligands, or as nucleation points for coat proteins and cytoskeletal elements. This versatility depends upon the existence of highly diversified enzymatic machinery for their synthesis and degradation, which governs, both temporally and spatially, their appearance in the microenvironment of the synapse. PMID- 11604135 TI - Identification of a novel tetramerization domain in large conductance K(ca) channels. AB - More than 50 genes are known to encode K(+) channel monomers and can coassemble to form hetero-tetrameric K(+) channels. However, only a subset of possible monomer combinations come together to form functional ion channels. The assembly and tetramerization of appropriate channel monomers is mediated by association domains (ADs). To identify such domains in human large-conductance Ca(2+) activated K(+) channels (hSlo1), we screened hSlo1 domains for self-association using yeast two-hybrid assays. Putative ADs were subjected to functional assays in Xenopus oocytes and further characterized by coprecipitation, native gel electrophoresis, and sucrose density gradient centrifugation assays. This led to the identification of a single intracellular association domain localized near the channel pore and required for channel function. We conclude that this novel tetramerization domain, referred to as BK-T1, promotes the assembly of hSlo1 monomers into functional K(Ca) channels. PMID- 11604136 TI - C. elegans slit acts in midline, dorsal-ventral, and anterior-posterior guidance via the SAX-3/Robo receptor. AB - Robo receptors interact with ligands of the Slit family. The nematode C. elegans has one Robo receptor (SAX-3) and one Slit protein (SLT-1), which direct ventral axon guidance and guidance at the midline. In larvae, slt-1 expression in dorsal muscles repels axons to promote ventral guidance. SLT-1 acts through the SAX-3 receptor, in parallel with the ventral attractant UNC-6 (Netrin). Removing both UNC-6 and SLT-1 eliminates all ventral guidance information for some axons, revealing an underlying longitudinal guidance pathway. In the embryo, slt-1 is expressed at high levels in anterior epidermis. Embryonic expression of SLT-1 provides anterior-posterior guidance information to migrating CAN neurons. Surprisingly, slt-1 mutants do not exhibit the nerve ring and epithelial defects of sax-3 mutants, suggesting that SAX-3 has both Slit-dependent and Slit independent functions in development. PMID- 11604137 TI - Plexin B mediates axon guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling. AB - Plexins are neuronal receptors for the repulsive axon guidance molecule Semaphorins. Previous studies showed that Plexin B (PlexB) binds directly to the active, GTP-bound form of the Rac GTPase. Here, we define a seven amino acid sequence in PlexB required for Rac(GTP) binding. The interaction of PlexB with Rac(GTP) is necessary for Plexin-mediated axon guidance in vivo. A different region of PlexB binds to RhoA. Dosage-sensitive genetic interactions suggest that PlexB suppresses Rac activity and enhances RhoA activity. Biochemical evidence indicates that PlexB sequesters Rac(GTP) from its downstream effector PAK. These results suggest a model whereby PlexB mediates repulsion by coordinately regulating two small GTPases in opposite directions: PlexB binds to Rac(GTP) and downregulates its output by blocking its access to PAK and, at the same time, binds to and increases the output of RhoA. PMID- 11604138 TI - The transmembrane protein Off-track associates with Plexins and functions downstream of Semaphorin signaling during axon guidance. AB - The Plexin family of transmembrane proteins appears to function as repulsive receptors for most if not all Semaphorins. Here, we use genetic and biochemical analysis in Drosophila to show that the transmembrane protein Off-track (OTK) associates with Plexin A, the receptor for Sema 1a, and that OTK is a component of the repulsive signaling response to Semaphorin ligands. In vitro, OTK associates with Plexins. In vivo, mutations in the otk gene lead to phenotypes resembling those of loss-of-function mutations of either Sema1a or PlexA. The otk gene displays strong genetic interactions with Sema1a and PlexA, suggesting that OTK and Plexin A function downstream of Sema 1a. PMID- 11604139 TI - The presynaptic particle web: ultrastructure, composition, dissolution, and reconstitution. AB - We report the purification of a presynaptic "particle web" consisting of approximately 50 nm pyramidally shaped particles interconnected by approximately 100 nm spaced fibrils. This is the "presynaptic grid" described in early EM studies. It is completely soluble above pH 8, but reconstitutes after dialysis against pH 6. Interestingly, reconstituted particles orient and bind PSDs asymmetrically. Mass spectrometry of purified web components reveals major proteins involved in the exocytosis of synaptic vesicles and in membrane retrieval. Our data support the idea that the CNS synaptic junction is organized by transmembrane adhesion molecules interlinked in the synaptic cleft, connected via their intracytoplasmic domains to the presynaptic web on one side and to the postsynaptic density on the other. The CNS synaptic junction may therefore be conceptualized as a complicated macromolecular scaffold that isostatically bridges two closely aligned plasma membranes. PMID- 11604140 TI - PIP kinase Igamma is the major PI(4,5)P(2) synthesizing enzyme at the synapse. AB - Disruption of the presynaptically enriched polyphosphoinositide phosphatase synaptojanin 1 leads to an increase of clathrin-coated intermediates and of polymerized actin at endocytic zones of nerve terminals. These changes correlate with elevated levels of PI(4,5)P(2) in neurons. We report that phosphatidylinositol phosphate kinase type Igamma (PIPKIgamma), a major brain PI(4)P 5-kinase, is concentrated at synapses. Synaptojanin 1 and PIPKIgamma antagonize each other in the recruitment of clathrin coats to lipid membranes. Like synaptojanin 1 and other proteins involved in endocytosis, PIPKIgamma undergoes stimulation-dependent dephosphorylation. These results implicate PIPKIgamma in the synthesis of a PI(4,5)P(2) pool that acts as a positive regulator of clathrin coat recruitment and actin function at the synapse. PMID- 11604141 TI - T-type Ca(2+) channels mediate neurotransmitter release in retinal bipolar cells. AB - Transmitter release in neurons is thought to be mediated exclusively by high voltage-activated (HVA) Ca(2+) channels. However, we now report that, in retinal bipolar cells, low-voltage-activated (LVA) Ca(2+) channels also mediate neurotransmitter release. Bipolar cells are specialized neurons that release neurotransmitter in response to graded depolarizations. Here we show that these cells express T-type Ca(2+) channel subunits and functional LVA Ca(2+) currents sensitive to mibefradil. Activation of these currents results in Ca(2+) influx into presynaptic terminals and exocytosis, which we detected as a capacitance increase in isolated terminals and the appearance of reciprocal currents in retinal slices. The involvement of T-type Ca(2+) channels in bipolar cell transmitter release may contribute to retinal information processing. PMID- 11604142 TI - Ca(2+) binding protein frequenin mediates GDNF-induced potentiation of Ca(2+) channels and transmitter release. AB - Molecular mechanisms underlying long-term neurotrophic regulation of synaptic transmission and plasticity are unknown. We report here that long-term treatment of neuromuscular synapses with glial cell line-derived neurotrophic factor (GDNF) potentiates spontaneous and evoked transmitter release, in ways very similar to presynaptic expression of the Ca(2+) binding protein frequenin. GDNF enhances the expression of frequenin in motoneurons, and inhibition of frequenin expression or activity prevents the synaptic action of GDNF. GDNF also facilitates Ca(2+) influx into the nerve terminals during evoked transmission by enhancing Ca(2+) currents. The effect of GDNF on Ca(2+) currents is blocked by inhibition of frequenin expression, occluded by overexpression of frequenin, and is selective to N-type Ca(2+) channels. These results identify an important molecular target that mediates the long-term, synaptic action of a neurotrophic factor. PMID- 11604143 TI - Visualization of IP(3) dynamics reveals a novel AMPA receptor-triggered IP(3) production pathway mediated by voltage-dependent Ca(2+) influx in Purkinje cells. AB - IP(3) signaling in Purkinje cells is involved in the regulation of cell functions including LTD. We have used a GFP-tagged pleckstrin homology domain to visualize IP(3) dynamics in Purkinje cells. Surprisingly, IP(3) production was observed in response not only to mGluR activation, but also to AMPA receptor activation in Purkinje cells in culture. AMPA-induced IP(3) production was mediated by depolarization-induced Ca(2+) influx because it was mimicked by depolarization and was blocked by inhibition of the P-type Ca(2+) channel. Furthermore, trains of complex spikes, elicited by climbing fiber stimulation (1 Hz), induced IP(3) production in Purkinje cells in cerebellar slices. These results revealed a novel IP(3) signaling pathway in Purkinje cells that can be elicited by synaptic inputs from climbing fibers. PMID- 11604144 TI - Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. AB - Long-lasting forms of synaptic plasticity like the late phase of LTP (L-LTP) typically require an elevation of cAMP, the recruitment of the cAMP-dependent protein kinase (PKA), and ultimately the activation of transcription and translation; some forms also require brain-derived neurotrophic factor (BDNF). Both cAMP and BDNF can activate mitogen-activated protein kinase (MAPK/ERK), which also plays a role in LTP. However, little is known about the mechanisms whereby cAMP, BDNF, and MAPK interact. We find that increases in cAMP can rapidly activate the BDNF receptor TrkB and induce BDNF-dependent long-lasting potentiation at the Schaffer collateral-CA1 synapse in hippocampus. Surprisingly, in these BDNF-dependent forms of potentiation, which are also MAPK dependent, TrkB activation is not critical for the activation of MAPK but instead appears to modulate the subcellular distribution and nuclear translocation of the activated MAPK. PMID- 11604145 TI - Temporal interaction between single spikes and complex spike bursts in hippocampal pyramidal cells. AB - Cortical pyramidal cells fire single spikes and complex spike bursts. However, neither the conditions necessary for triggering complex spikes, nor their computational function are well understood. CA1 pyramidal cell burst activity was examined in behaving rats. The fraction of bursts was not reliably higher in place field centers, but rather in places where discharge frequency was 6-7 Hz. Burst probability was lower and bursts were shorter after recent spiking activity than after prolonged periods of silence (100 ms-1 s). Burst initiation probability and burst length were correlated with extracellular spike amplitude and with intracellular action potential rising slope. We suggest that bursts may function as "conditional synchrony detectors," signaling strong afferent synchrony after neuronal silence, and that single spikes triggered by a weak input may suppress bursts evoked by a subsequent strong input. PMID- 11604146 TI - Functional convergence of response properties in the auditory thalamocortical system. AB - One of the brain's fundamental tasks is to construct and transform representations of an animal's environment, yet few studies describe how individual neurons accomplish this. Our results from correlated pairs in the auditory thalamocortical system show that cortical excitatory receptive field regions can be directly inherited from thalamus, constructed from smaller inputs, and assembled by the cooperative activity of neuronal ensembles. The prevalence of functional thalamocortical connectivity is strictly governed by tonotopy, but connection strength is not. Finally, spectral and temporal modulation preferences in cortex may differ dramatically from the thalamic input. Our observations reveal a radical reconstruction of response properties from auditory thalamus to cortex, and illustrate how some properties are propagated with great fidelity while others are significantly transformed or generated intracortically. PMID- 11604147 TI - Neuronal basis of the motion aftereffect reconsidered. AB - Several fMRI studies have reported MT+ response increases correlated with perception of the motion aftereffect (MAE). However, attention can strongly affect MT+ responses, and subjects may naturally attend more to the MAE than control trials without MAE. We found that requiring subjects to attend to motion on both MAE and control trials produced equal levels of MT+ response, suggesting that attention may have confounded the interpretation of previous experiments; in our data, attention accounts for the entire effect. After eliminating this confound, we observed that direction-selective motion adaptation produced a direction-selective imbalance in MT+ responses (and earlier visual areas), and yielded a corresponding asymmetry in speed discrimination thresholds. These findings provide physiological evidence that population level response imbalances underlie the MAE, and quantify the relative proportions of direction-selective neurons across human visual areas. PMID- 11604148 TI - Adaptive frequency decomposition of EEG with subsequent expert system analysis. AB - We present a hybrid system for automatic analysis of clinical routine EEG, comprising a spectral analysis and an expert system. EEG raw data are transformed into the time-frequency domain by the so-called adaptive frequency decomposition. The resulting frequency components are converted into pseudo-linguistic facts via fuzzification. Finally, an expert system applies symbolic rules formulated by the neurologist to evaluate the extracted EEG features. The system detects artefacts, describes alpha rhythm by frequency, amplitude, and stability and after artefact rejection detects pathologic slow activity. All results are displayed as linguistic terms, numerical values and maps of temporal extent, giving an overview about the clinical routine EEG. PMID- 11604149 TI - Electroencephalogram analysis using fast wavelet transform. AB - The continuous wavelet transform is a new approach to the problem of time frequency analysis of signals such as electroencephalogram (EEG) and is a promising method for EEG analysis. However, it requires a convolution integral in the time domain, so the amount of computation is enormous. In this paper, we propose a fast wavelet transform (FWT) that the corrected basic fast algorithm (CBFA) and the fast wavelet transform for high accuracy (FWTH). As a result, our fast wavelet transform can achieve high computation speed and at the same time to improve the computational accuracy. The CBFA uses the mother wavelets whose frequencies are 2 octaves lower than the Nyquist frequency in the basic fast algorithm. The FWT for high accuracy is realized by using upsampling based on a L Spline interpolation. The experimental results demonstrate advantages of our approach and show its effectiveness for EEG analysis. PMID- 11604150 TI - AR spectral analysis of EEG signals by using maximum likelihood estimation. AB - In this study, EEG signals were analyzed using autoregressive (AR) method. Parameters in AR method were realized by using maximum likelihood estimation (MLE). Results were compared with fast Fourier transform (FFT) method. It is observed that AR method gives better results in the analysis of EEG signals. On the other hand, the results have also showed that AR method can also be used for some other researches and diagnosis of diseases. PMID- 11604151 TI - Computer visualisation of the moving human lumbar spine. AB - Disorders of the spine which lead to back pain are often mechanical in origin and, despite extensive research, diagnosis of the underlying cause remains problematical, yet back pain is one of the most common rheumatological symptoms presented to the general practitioner. Diagnosis must frequently be based upon evidence gathered at the segmental level which invariably means that imaging is used in the process. In addition, surgical fixation is increasingly used when the spinal column is considered to exhibit instability. A solid model of the spine creates the possibility of visualising spine motion, of assessing the effects of loading of the spinal column in conjunction with finite element analysis to investigate the consequences of vertebral fusion, and of planning surgical intervention. Such a model could also be valuable in medical education and for demonstrating spine motion to a patient to highlight abnormalities or the effects of treatment. This paper describes a three-dimensional visualisation of the human lumbar spine which runs on a personal computer operating under the Windows environment. The user interface enables the clinician to select the viewpoint for the spine model to allow the motion to be studied from different angles. Motion data are currently acquired from fluoroscopic image sequences but the model could be used to display data from different imaging modalities when they are developed sufficiently for spine motion studies. PMID- 11604153 TI - Ventricular shape visualization using selective volume rendering of cardiac datasets. AB - In this paper, we present a novel technique of improving volume rendering quality and speed by integrating original volume data and global model information attained by segmentation. The segmentation information prevents object occlusions that may appear when volume rendering is based on local image features only. Thus the presented visualization technique provides meaningful visual results that enable a clear understanding of complex anatomical structures. In the first part, we describe a segmentation technique for extracting the region of interest based on an active contour model. In the second part, we propose a volume rendering method for visualizing the selected portions of fuzzy surfaces extracted by local image processing methods. We show the results of selective volume rendering of left and right ventricle based on cardiac datasets from clinical routines. Our method offers an accelerated technique to accurately visualize the surfaces of segmented objects. PMID- 11604152 TI - Assessment of cerebral autoregulation using time-domain cross-correlation analysis. AB - Time domain cross-correlation analysis of pre-filtered mean arterial blood pressure (MABP) and mean cerebral blood flow velocity (MCBFV) was applied to assess the cerebral autoregulation (CA). Beat-to-beat time series of spontaneous arterial blood pressure and cerebral blood flow velocity were obtained from 13 young normal volunteers with the Finapres device and the transcranial Doppler for periods of approximately 5 min in the supine position. Cross-correlation functions (CCFs) were estimated using a 64 beat wide moving window. Mean CCF patterns were obtained for each subject and for the entire population. The MABP and MCBFV signals were bandpass filtered in the very low-frequency range (VLF, 0.015-0.07 Hz), low-frequency range (LF, 0.07-0.15 Hz) and high-frequency range (HF, 0.15-0.40 Hz) before applying CCF for the purpose of studying the effect of different bandwidths on the resulting mean CCFs. Results revealed that the corresponding time lags of the peak values of the MABP-MCBFV CCFs increased significantly between the LF and HF frequency ranges (LF: -1.20+/-0.91 s, HF: 0.07+/-0.42 s,p < 0.001; paired sign test). The left-shift (negative lag) of the CCF peak between MABP and MCBFV is a result of the phase-lead property. The increasing time lag of the CCF peak indicated evidence of the autoregulatory disturbance. The CCF of pre-filtered spontaneous MABP and MCBFV could be a useful tool to estimate the CA dynamic response. PMID- 11604154 TI - Computer simulations of lung airway structures using data-driven surface modeling techniques. AB - Knowledge of human lung morphology is a subject critical to many areas of medicine. The visualization of lung structures naturally lends itself to computer graphics modeling due to the large number of airways involved and the complexities of the branching systems. In this study, a method of generating three-dimensional computer simulations of human lung airway networks using data driven, surface modeling techniques is presented. By simulating the tubular airway structures and realistic bifurcation shapes, anatomically accurate representations of human lungs are obtained. These computer models are designed for use in computational fluid dynamic applications and particle trajectory analyses, and to be complimentary to medical imaging (gamma scintigraphy) protocols. PMID- 11604155 TI - A model approach to sharing electronic medical records between and within the state hospitals in Turkey. AB - It has always been a research interest to solve hospital management problems with systematic approach by using modern management tools. Almost all the Hospital Information System (HIS) software packages in Turkey keep track of local transactions in administrative activities and material flow. In state hospitals in Turkey, very little medical information is processed and most of the records are still kept manually and archived on papers. In this paper, a cost-effective, flexible and easy-to-use Hospital Information System model is proposed in order to give better diagnostic and treatment services. It is also demonstrated that this model makes it possible to exchange information between and within the hospitals over Transmission Control Protocol/Internet Protocol (TCP/IP) network. User needs are taken into consideration during model development and the benefits of model implementation to the hospital administration are stated. According to the model proposed in this paper, only a single health care record number (HCRN) is required for a patient to access all her/his medical records stored in different locations, from any state hospital in Turkey. PMID- 11604157 TI - Studies on the antibody response of Lama glama--evaluation of the binding capacity of different IgG subtypes in ELISAs for clenbuterol and BSA. AB - Camelidae are known to produce three subtypes of immunoglobulin G (IgG), two of which are devoid of light chains. Two llamas (Lama glama) were immunised against clenbuterol-bovine serum albumin (BSA). Enzyme-linked immunosorbent assays (ELISAs) for clenbuterol and BSA on the basis of protein A-coated microtitration plates were established to investigate the titre development. Three subclasses of IgG (IgG(1): 29+66KDD, IgG(2): 52KDD, IgG(3): 56KDD) depending on their different binding properties to protein A and protein G could be separated chromatographically. Only IgG(1), which consists of conventional four-chain antibodies, bound to clenbuterol, whereas all forms of heavy-chain antibodies merely bound BSA. PMID- 11604158 TI - Separation of bovine bone marrow into maturation-related myeloid cell fractions. AB - A prerequisite for studies on bovine myeloid cells in relation to maturity is a reliable separation method, in order to obtain enriched and partially purified cell fractions of different maturation stages. Since current techniques for bovine bone marrow cell isolation fall short of this requirement, a technique for fractionating bovine bone marrow using a three-layer discontinuous Percoll gradient was developed. Three maturation-dependent myeloid cell fractions were obtained at specific densities, as maturation of cells is accompanied with a progressive density increase. Early immature myeloid cells, i.e. myeloblasts and promyelocytes, were found at a density of 1.060g/ml. Late immature myeloid cells, i.e. myelocytes and metamyelocytes, were retrieved at 1.080g/ml. Bands and segmented cells, representing the mature fraction, accumulated in the high density pellet (>1.080g/ml). Myeloid cell populations were identified in each fraction by flow cytometry based on their forward and side scatter pattern. Confirmation was provided by light microscopy of flow cytometrically sorted myeloid populations, using morphological characteristics. The developed method provides a unique tool for studying maturation-dependent functions in bovine bone marrow. PMID- 11604159 TI - Globotriaosylceramide (Gb(3)/CD77) is synthesized and surface expressed by bovine lymphocytes upon activation in vitro. AB - Neutral glycosphingolipids (GSLs) are considered activation markers on human lymphocytes, which are fundamental for studying the immune system. For cattle, only a limited number of activation markers has yet been identified. We recently showed that Shiga toxin 1, known to use globotriaosylceramide (Gb(3) syn. CD77) as a cellular receptor, depresses proliferation of activated bovine lymphocytes [Infect. Immunol. 67 (1999b) 2209]. In order to confirm the expression of Gb(3)/CD77 on bovine lymphocytes, we flowcytometrically examined a bovine B lymphoma cell line (BL-3) and bovine peripheral blood mononuclear cells (PBMC) before and after mitogenic stimulation and biochemically characterized neutral GSLs extracted from PBMC. CD77 was detected on the surface of BL-3 cells and cultured PBMC essentially after mitogenic stimulation. Although expressed by all PBMC subpopulations identified, the portion of CD7+ cells was highest for BoCD8+ cells, followed by B-cells and BoCD4+ cells at day 4 of cultivation. Ceramide trihexoside of stimulated PBMC was structurally determined as Gal(alpha1-4)Gal(1 4)Glc(1-1)ceramide (Gb(3)). Biochemically, Gb(3) was also detected within unstimulated PBMC which contained ceramide monohexoside (CMH) and Gb(3) in a ratio of about 4:1. However, stimulation induced an increase of CMH and Gb(3) by a factor of 2.5 and 10, respectively, implicating that bovine lymphocytes regulate surface expression of Gb(3)/CD77 predominantly by quantitative changes in the Gb(3) metabolism. This report presents Gb(3)/CD77 as the first GSL identified on bovine immune cells and highly recommends this activation dependent antigen as a useful tool to investigate lymphocyte activation within the bovine immune system. PMID- 11604160 TI - Distribution of immune cells in the female reproductive tract in uninfected and FIV infected cats. AB - Cell-free and cell-associated FIV effectively cross the mucosa of the feline female reproductive tract. To identify possible cellular targets of FIV and to characterize changes in mucosal immunity after infection, we examined the types and numbers of immune cells residing in the reproductive tracts of control and intravaginally FIV-infected cats. Sections of the vestibule, vagina, cervix, uterus, and ovaries, were examined by immunohistochemistry for CD4+ and CD8+ T lymphocytes, CD22+ B lymphocytes, CD1a+ dendritic cells, and CD14+ macrophages. The reproductive tract of uninfected cats contained substantial numbers of CD8+ T lymphocytes, CD4+ T lymphocytes and macrophages, as well as moderate numbers of CD1a+ dendritic cells, and few B lymphocytes. The most prominent change between FIV- and FIV+ cats was a marked decrease in the concentration of CD4+ T lymphocytes resulting in inverted CD4+:CD8+ ratios throughout the reproductive tract of infected cats. There was also a trend towards increasing numbers of CD1a+ dendritic cells in the intravaginally-infected FIV+ cats, and decreasing numbers of macrophages and CD22+ B lymphocytes. This study indicates that similar to the peripheral immune system, FIV infection is associated with CD4+ cell loss and reduced CD4+:CD8+ ratios in the female reproductive mucosal tissue. PMID- 11604161 TI - Immunohistochemical characterisation of the lymph node reaction in pig post weaning multisystemic wasting syndrome (PMWS). AB - The superficial inguinal lymph nodes of 10 piglets which had died spontaneously of post-weaning multisystemic wasting syndrome (PMWS), in which the porcine circovirus type II (PCV-II) genome was revealed by PCR, were submitted to immunohistochemical investigation for CD4, CD8, IgM, MAC387, S-100 protein, vimentin and F-VIII-RA and compared with three normal cases. The lymph node reaction was graded as initial, intermediate and end stage according to histological criteria. In the initial and intermediate stages, absence of follicles and depletion of lymphocytes were evident. Associated with this was a reduction in numbers of interfollicular dendritic cells and interdigitating cells and a reduction/absence of B cells and mainly CD4+ T lymphocytes. In the end stage the reduced expression of high endothelial venules and the prevalence of the stromal component of the lymph node was prominent, as well as the above changes. It is concluded that more than one mechanism is involved in the immunosuppressive ability of PCV-II: reduction of the antigen presenting ability and reduction of B cells and CD4+ T cell function. PMID- 11604162 TI - IgE reactivity and cross-reactivity to Japanese cedar (Cryptomeria japonica) and cypress (Chamaecyparis obtusa) pollen allergens in dogs with atopic dermatitis. AB - The natural occurrence of Japanese cedar (Cryptomeria japonica) pollinosis has been reported in dogs with atopic dermatitis. However, the reactivity to Japanese cypress (Chamaecyparis obtusa) pollen allergens in these dogs has not been reported. The present study was designed to investigate the reactivity to Japanese cypress pollen allergens in dogs sensitized to Japanese cedar pollen allergens. In 19 dogs with specific IgE to C. japonica pollen allergen, we measured the specific IgE to C. obtusa pollen allergen and examined the reactivity to the allergen by intradermal test. Of the 19 dogs, 18 had specific IgE to crude and purified major allergens (Cha o 1) of C. obtusa pollen. Most of the dogs showed a positive reaction to C. obtusa pollen allergens in the intradermal test. Allergenic cross-reactivity between Cha o 1 and Cry j 1 (a major allergen in C. japonica pollen) was observed by the ELISA inhibition method. Dogs sensitized to Japanese cedar pollen allergens demonstrate reactivity to Japanese cypress pollen allergens. PMID- 11604163 TI - Fusion of C3d molecule with bovine rotavirus VP7 or bovine herpesvirus type 1 glycoprotein D inhibits immune responses following DNA immunization. AB - The binding of the complement C3d molecule with receptors on B cells and/or follicular dendritic cells (FDCs) influences the induction of humoral immune responses. For example, C3d fused to an antigen has been shown to have a strong adjuvant effect on antibody production. We investigated the possibility that co expression of antigen and C3d as a fusion protein could enhance antigen-specific immune responses, following plasmid immunization. One or two copies of murine C3d cDNA, C3d or (C3d)(2), respectively, were cloned together with bovine rotavirus (BRV) VP7 or bovine herpesvirus type 1 (BHV-1) glycoprotein D (gD) genes. All constructs contained a signal peptide that resulted in the secretion of the expressed proteins. In vitro, the characterization of the chimeric proteins indicated that both VP7 and gD retained their antigenicity and the C3d remained biologically active. However, immunization with plasmids encoding VP7-C3d chimeras did not enhance rotavirus-specific antibody responses and the frequency of BRV-specific IFN-gamma secreting cells in the spleens were significantly lower in mice immunized with pVP7-(C3d)(2) when compared with mice immunized with plasmid encoding VP7. The same pattern of immune responses was observed for plasmids encoding gD-C3d. Both gD-specific antibody responses and the frequency of gD-specific IFN-gamma secreting cells were significantly lower in mice immunized with plasmid expressing gD-C3d chimeras when compared with mice immunized with plasmid encoding gD alone. These results indicate that co expression of C3d with an antigen actually inhibit both humoral and cell-mediated antigen-specific immune responses. PMID- 11604164 TI - Induction of systemic and mucosal immune response in cattle by intranasal administration of pig serum albumin in alginate microparticles. AB - Biodegradable microparticles are an efficient mucosal delivery system that protect antigens from the harsh mucosal environment and facilitate their uptake by M cells at the epithelium of mucosal-associated lymphoid tissue. In this study, we determined the systemic and mucosal immune response in calves following intranasal and oral immunization with pig serum albumin (PSA) encapsulated in alginate microparticles. The size of the particles ranged from 1 to 50 microm in diameter, with 95% of the particles being smaller than 5 microm. High levels of anti-PSA IgG1 antibodies were found in the serum, nasal secretions, and to a less extent in saliva of calves vaccinated intranasally, but not orally, with PSA microparticles. There was no significant increase of PSA-specific IgA. A weak lymphocyte proliferative immune response was observed in peripheral blood mononuclear cells (PBMCs), and few anti-PSA antibody-secreting cells (ASC) were detected in the blood of calves immunized intranasally. The combined systemic and mucosal response observed in intranasally immunized animals may be attributed to the wide variation in the size of the alginate microparticles, with smaller particles translocating to regional lymph nodes and inducing a systemic immune response, and larger particles being retained in the NALT and inducing a mucosal immune response. The procedure presented here may be useful as an intranasal vaccine against respiratory diseases in cattle. PMID- 11604165 TI - Simulated solar UVB exposure inhibits transcutaneous immunization to cholera toxin via an irradiated skin site in cattle. AB - Transcutaneous immunization (TCI) is a new needle-free vaccination technology with the potential to reduce the risk of needle-borne disease transmission and carcass damage within the livestock industries. The principal antigen-presenting cell involved in TCI is thought to be the epidermal Langerhans cell. Langerhans cell function is inhibited by cutaneous ultraviolet-B radiation (UVB) exposure. Such exposure may inhibit TCI through sun exposed skin sites due to the phenomenon of local low dose photoimmunosuppression. TCI of cattle to cholera toxin (CT) resulted in the generation of a serum anti-CT-specific IgG(2) response. However, exposure of cattle to a sub-inflammatory dose of simulated solar UVB (2.43 x 10(3)J/m(2)) significantly (P<0.05) inhibited TCI to CT via irradiated skin sites. PMID- 11604166 TI - Recombinant canine IL-13 receptor alpha2-Fc fusion protein inhibits canine allergen-specific-IgE production in vitro by peripheral blood mononuclear cells from allergic dogs. AB - Human IL-13, like IL-4, is involved in the regulation of B-cell development, IgE synthesis and allergic responses. However, because IL-13 does not affect either murine Ig class switching or IgE production in vitro, the use of murine models to study the role of IL-13 in IgE-mediated diseases has been limited. In this communication, we report that recombinant protein of canine IL-13 (rcaIL-13) stimulates production of allergen-specific-IgE in vitro by peripheral blood mononuclear cells (PBMC) from flea allergen-sensitized dogs, and that this stimulation activity is specifically inhibited by recombinant protein of canine IL-13Ralpha2 and Fc fragment of canine IgG heavy chain (rcaIL-13Ralpha2-Fc). The data suggest that the regulatory effects of IL-13 on IgE production in canine PBMC are similar to those reported in humans. Thus, canine IL-13 may be a central mediator of allergic diseases in dogs, and allergic dogs may be excellent models for research on IgE-mediated diseases in humans. PMID- 11604167 TI - Effect of organics on sulfur-utilizing autotrophic denitrification under mixotrophic conditions. AB - Sulfur-utilizing denitrification can be performed by denitrifying sulfur bacteria under autotrophic and heterotrophic conditions. To investigate the effect of organics (methanol and landfill leachate) on sulfur-utilizing denitrification, six laboratory-scale sulfur packed columns were operated under autotrophic, mixotrophic and heterotrophic conditions for approximately 1 year. The performance of the columns was monitored by measuring the pH, nitrate, nitrite, sulfate, sulfide, alkalinity dissolved organic carbon (DOC), and turbidity. These tests indicated that the mixotrophic column had a higher nitrate removal capacity than the autotrophic column. It was also found that under mixotrophic conditions, some portion of nitrate was removed heterotrophically and the remainder was denitrified by sulfur-utilizing autotrophic bacteria without inhibition by organics. In addition, sulfate production and alkalinity consumption were reduced under mixotrophic conditions. These results suggest that mixotrophic conditions that allow simultaneous reactions of autotrophic and heterotrophic denitrification provide significant advantages in terms of nitrate and DOC removal, sulfate production decrease, and alkalinity consumption over obligate autotrophic or heterotrophic denitrification. PMID- 11604168 TI - Molecular cloning and expression of a cDNA encoding the luciferase from the firefly, Pyrocoelia rufa. AB - To clone a cDNA encoding the luciferase of the firefly, Pyrocoelia rufa, we have constructed a cDNA library and isolated the luciferase gene using PCR with gene specific primers. Sequence analysis of the cDNA encoding the luciferase of P. rufa revealed that the 1647 bp cDNA has an open reading frame of 548 amino acid residues. The deduced amino acid sequences of the luciferase gene of P. rufa showed 98.9% homology to that of P. miyako. Phylogenetic analysis further confirmed the deduced amino acid sequences of the P. rufa luciferase gene belonged to the same subfamily, Lampyrinae. Southern blot analysis suggested possible presence of the P. rufa luciferase gene as a single copy and Northern blot analysis confirmed light organ-specific expression pattern at the transcriptional level. The cDNA encoding the luciferase of P. rufa was expressed as a 69 kDa band in baculovirus-infected insect cells and the recombinant baculovirus-infected cell extracts emitted luminescence in the luciferase activity assay. PMID- 11604169 TI - Efficient and selective microbial esterification with dry mycelium of Rhizopus oryzae. AB - The use of dry mycelium of Rhizopus oryzae as biocatalyst for ester production in organic solvent has been studied. Mycelia with notable carboxylesterase activity were produced when different Tweens (20, 40, 60 and 80) were employed as main carbon source for the growth. Dry mycelium of four strains of Rhizopus oryzae proved effective for efficiently catalysing the synthesis of different flavour esters (hexylacetate and butyrate, geranylacetate and butyrate) starting from the corresponding alcohol and free acid, including acetic acid. The esterification of the racemic mixture of 2-octanol and butyric acid proceeded with high enantioselectivity (R-ester produced with enantiomeric excess > or =97%) when Rhizopus oryzae CBS 112.07 and Rhizopus oryzae CBS 260.28 were employed. PMID- 11604170 TI - Multidrug resistance as a dominant molecular marker in transformation of wine yeast. AB - Pure wine yeast cultures are increasingly used in winemaking to perform controlled fermentations and produce wine of reproducible quality. For the genetic manipulation of natural wine yeast strains dominant selective markers are obviously useful. Here we demonstrate the successful use of the mutated PDR3 gene as a dominant molecular marker for the selection of transformants of prototrophic wine yeast Saccharomyces cerevisiae. The selected transformants displayed a multidrug resistance phenotype that was resistant to strobilurin derivatives and azoles used to control pathogenic fungi in agriculture and medicine, respectively. Random amplification of DNA sequences and electrophoretic karyotyping of the host and transformed strains after microvinification experiments resulted in the same gel electrophoresis patterns. The chemical and sensory analysis of experimental wines proved that the used transformants preserved all their useful winemaking properties indicating that the pdr3-9 allele does not deteriorate the technological properties of the transformed wine yeast strain. PMID- 11604171 TI - A new approach for weed control in a cucurbit field employing an attenuated potyvirus-vector for herbicide resistance. AB - Expression of bar, a phosphinothricin acetyltransferase, in plant tissues, leads to resistance of these plants to glufosinate ammonium based herbicides. We have created a bar expressing, attenuated zucchini yellow mosaic potyvirus-vector, AGII-Bar, to enable herbicide use in cucurbit fields. The parental vector, ZYMV AGII, has been rendered environmentally safe by both disease-symptom attenuation and aphid-assisted virus transmission abolishment. The recombinant AGII-Bar virus encoding cDNA, when inoculated on diverse cucurbits was highly infectious, accumulated to similar levels as AGII, and elicited attenuated AGII-like symptoms. Potted cucurbits inoculated with AGII-Bar became herbicide resistant about a week post-inoculation. Herbicide resistance was sustained in squash over a period of at least 26 days and for at least 60 days in cucumber grown in a net house under commercial conditions. To test the applicability of AGII-Bar use in a weed-infested field, a controlled experiment including more than 450 plants inoculated with this construct, was performed. Different dosages of glufosinate ammonium were sprayed, 2 weeks after planting, on the foliage of melons, cucumbers, squash, and watermelons. AGII-Bar provided protection to all inoculated plants, of every variety tested, at each dosage applied, including the highest doses that totally eradicated weeds. This study demonstrates that AGII Bar can be utilized to facilitate weed control in cucurbits and exemplifies the practical potential of attenuated virus-vector use in agriculture. PMID- 11604172 TI - Strategies to modulate BHK cell proliferation by the regulation of IRF-1 expression. AB - Activation of the constitutively expressed interferon-regulatory-factor 1/estrogen receptor fusion protein (IRF-1-hER) in BHK cells was accomplished through the addition of estradiol to the culture medium, which enabled IRF-1 to gain its transcriptional activator function and inhibit cell growth. With the addition of 100 nM estradiol at the beginning of the exponential phase of a cell suspension culture, IRF-1 activation led to a rapid cell growth inhibition but also to a significant decrease in cell viability. To apply this concept in industry, a reduction of the time span of estradiol exposure is required. Cycles of estradiol addition and removal were performed in 2-l stirred tank bioreactors operated under perfusion, where an initial step addition of 100 nM estradiol was performed, followed, after 48-72 h, by a slow dilution with estradiol-free fresh medium (perfusion rate varying between 0.7 and 1.4 per day). Cell growth inhibition was successfully achieved for three consecutive cycles. Diluting the estradiol by perfusing medium without estradiol to concentrations lower than 10 nM led to cell growth and viability recovery independently of the perfusion rate used. These observations permitted the definition of operational strategies for regulated IRF-1 BHK cell growth by pulse estradiol addition, followed by a period of 48 h in the presence of estradiol and by fast perfusion to estradiol concentrations lower than 10 nM. Cell growth response to IRF-1 activation and following estradiol removal by perfusion was also evaluated with an IRF-1-hER regulated clone expressing constitutively Factor VII, where the time of estradiol exposure and perfusion rate were varied. This clone presented a stronger response to IRF-1 activation without an increase in Factor VII specific productivity after cell growth inhibition; this clearly indicates that the stationary phase obtained is clone dependent. This work proves that it is possible to modulate the IRF-1 effect for cell growth control by the manipulation of cycles of addition and removal of estradiol, potentially representing a new generation of culture procedures for controlled growth production purposes. PMID- 11604173 TI - Enzymatic hydrolysis of (chloromethyldimethylsilyl)-2-propenyl acetate isomers: atypic specificity of Candida antarctica lipase. AB - Enzymatic hydrolysis of a mixture of (chloromethyldimethylsilyl)-2-propenyl acetate isomers was investigated by using immobilized Candida antarctica lipase as biocatalyst. TLC analysis and 1H NMR spectroscopy were used to monitor the extent of the reaction. At 60 degrees C, the enzyme exhibited a high selectivity towards 3-(chloromethyldimethylsilyl)-2-propenyl acetate which was almost quantitatively hydrolyzed, whereas, only 11% of 2-(chloromethyldimethylsilyl)-2 propenyl acetate reacted with the lipase. Consequently, the unreacted acetate was readily purified from the reaction medium by flash column chromatography and deacetoxylated in acidic methanol to give the corresponding hydroxy compound in a 71% global yield. On the other hand, without lipase, chemical treatment of the acetate mixture resulted in much lower yields in hydroxy compounds followed by a tedious purification process. PMID- 11604174 TI - Higher production of rabies virus in serum-free medium cell cultures on microcarriers. AB - Rabies virus suspensions were obtained from VERO cells cultivated on solid microcarriers in a bioreactor after infection with the Pasteur rabies virus strain (PV). Virus production-serum free medium (VP-SFM) or Leibovitz 15 (L15) medium supplemented or not with fetal calf serum (FCS) were used to cultivate the VERO cells, before and after virus infection. The cell growth was shown to reach higher densities (1.6 x 10(6) cellsmol(-l)), when VP-SFM supplemented with 1% of FCS was used during the cell growth phase of culture, and then replaced by VP-SFM alone for the virus multiplication phase. In the cultures performed from the beginning with VP-SFM, lower densities accompanied by an altered cell morphology and detachment from the microcarriers were always observed. In rabies virus infected cultures, kinetic studies showed that higher virus yields (10(4.7) FFD(50) per 0.05 ml) were always obtained in cultures performed initially on VP SFM supplemented with 1% FCS and after infection on VP-SFM alone. In agreement with that, rabies virus production, as measured by the average of virus titers in harvests obtained at different times after infection were shown to be 5.5 times higher in the cell cultures using initially VP-SFM+1%FCS and, following infection, VP-SFM alone. Besides the advantages of using media with a well controlled composition, these data indicate the usefulness of serum free media also in terms of virus productivity. PMID- 11604178 TI - Doppler ultrasonography of the human fetal pulmonary circulation. PMID- 11604179 TI - Maternal mortality in Greece (1980-1996). AB - OBJECTIVE: To use data from the National Statistical Service of Greece to examine trends in maternal mortality and risk factors for maternal deaths. STUDY DESIGN: Maternal mortality in Greece has been studied from years 1980 to 1996 in total, by cause of death, by residency (urban/rural) and by maternal age. The maternal mortality ratio (MMR) has been defined as the number of deaths per 100,000 live births. RESULTS: From years 1980 to 1996, there have been 136 maternal deaths (MMR: 7). The number of deaths has significantly decreased during this period and six major causes of death have been identified, resulting in 80% of maternal deaths. A simulation of maternal mortality between urban and rural areas has been achieved during the last decade. Also, maternal mortality rises dramatically with age. CONCLUSIONS: Although overall rates of maternal mortality in Greece have been significantly decreased over the last years, an improved recording of maternal deaths is necessary for identifying preventable factors and developing effective interventions. PMID- 11604180 TI - Blood velocity in the fetal vein of Galen and the outcome of high-risk pregnancy. AB - BACKGROUND: Pulsation in the flow velocity waveform in the umbilical vein is related to perinatal mortality but the flow velocity waveform in the fetal vein of Galen is normally even and without fluctuation. OBJECTIVES: To establish whether blood flow velocity pulsations in the vein of Galen in high-risk pregnancies are related to outcome. STUDY DESIGN: The vein of Galen was located by colour Doppler ultrasound in 102 pregnancies complicated by severe pregnancy induced hypertension. The blood velocity waveform was recorded by pulsed Doppler within 2 days of delivery and the presence pulsations related to pregnancy outcome, including emergency operative intervention and neonatal distress. Umbilical artery and vein and uterine artery blood flow velocity waveform were also recorded at the same time. The clinicians managing the women were unaware of the venous flow results. RESULTS: Pulsation were present in the vein of Galen in 68 cases and in the umbilical vein in 21. Both were significantly related to adverse outcome. Pulsations in the vein of Galen were seen in all seven perinatal deaths. CONCLUSIONS: Since umbilical venous pulsation are a late sign of fetal compromise, and pulsations in the vein of Galen seem to appear earlier, thus being an intermediate sign of fetal compromise that might be of great value for fetal surveillance. PMID- 11604181 TI - Chromosomal defects and associated malformations in fetal cleft lip with or without cleft palate. AB - OBJECTIVE: To describe the incidence, associated features including chromosomal defects in fetuses, with cleft lip and/or palate and assess the need for karyotyping. METHODS: Retrospective study of 62 cases of prenatally diagnosed facial cleft lip and/or palate in a tertiary fetal medicine unit between January 1991 and December 1999. Chromosome analysis was performed in all fetuses with associated ultrasound findings and in 14 (39%) fetuses with isolated facial clefts. RESULTS: Associated abnormalities were detected in 26 (42%) of the 62 fetuses of which 22 (35%) fetuses had multiple other abnormalities. Central nervous system abnormalities and limb malformations were the most common. Three fetuses had genetic syndromes confirmed after birth. All fetuses with isolated clefts were chromosomally normal, whereas 15 of the 26 with additional abnormalities (58 or 24% of the total group) had chromosomal defects (eight cases of trisomy 13, five of trisomy 18, one unbalanced translocation between chromosomes 7 and 8, and one deletion 4p-). All 22 women who chose not to undergo fetal karyotype analysis delivered phenotypically normal infants. There were five midline clefts; each of them was associated with additional sonographic findings and four were associated with holoprosencephaly. CONCLUSION: Isolated facial clefting is not associated with an increased risk for chromosomal defect. Amniocentesis is recommended when facial cleft is found in association with additional ultrasonographic abnormalities as it is unnecessary for isolated clefts. PMID- 11604183 TI - Meconium-stained amniotic fluid in labor: a randomized trial of prophylactic amniofusion. AB - OBJECTIVES: To investigate the effect of amnioinfusion in women with meconium stained amniotic fluid on the rate of cesarian sections and on neonatal morbidity. STUDY DESIGN: A randomized controlled trial. A total of 206 women with meconium-stained amniotic fluid were assigned to receive amnioinfusion via two way catheter or no amnioinfusion (control group). The catheter was inserted and other treatment was the same in both groups. RESULTS: Amnioinfusion decreased the rate of cesarian sections for fetal distress (RR 0.23, 95% CI 0.07-0.79) and increased mean pH at birth (7.24+/-0.1 versus 7.21+/-0.1, P<0.05). It also decreased the frequency of variable fetal heart rate decelerations (RR 0.74, 95% CI 0.59-0.92), and of meconium below the vocal cords in neonates (RR 0.37, 95% CI 0.19-0.69). CONCLUSIONS: Amnioinfusion improves the neonatal outcome and reduces the frequency of cesarian sections. PMID- 11604182 TI - Inhibitory effects of methylxanthines on the pre-eclamptic-like symptoms in ewes. AB - OBJECTIVE: Our objective was to determine whether two methylxanthines, pentoxifylline (PTX) and allopurinol, would have beneficial effects on experimental pregnancy-induced pre-eclampsia- like disease in ewes. STUDY DESIGN: 20 animals at the gestational age of 130-135 days were divided into four groups (control; fasting; fasting, pentoxifylline-treated; and fasting, allopurinol treated). The illness was provoked with a 4-day fasting period. Electrolytes, glucose, conventional parameters, plasma haem content, indirect bilirubin concentration and free thiol levels were measured. RESULTS: Unlike in the fasting group, conventional signs of the disease, such as hypertension, kidney and liver injury and platelet count decrease, were all mitigated in the fasting, drug treated animals. In the treated animals plasma haem content increased by a less significant level, while indirect bilirubin concentration showed a more rapid rise. CONCLUSIONS: Both methylxanthines partly inhibited the pre-eclamptic-like symptoms in ewes. We speculate that the better induction of haem oxygenase might play an important role in this inhibitory effect on this particular animal model. PMID- 11604184 TI - Doppler velocimetry and thrombophilic screening at middle trimester of gestation: preliminary data. AB - OBJECTIVE: To establish whether asymptomatic normotensive pregnant women with an abnormal uterine Doppler velocimetry, have haematological changes characteristic of congenital or acquired thrombophilia, and whether this information improve predict in pregnancy complications. STUDY DESIGN: A prospective study involved the enrolment of 30 healthy normotensive pregnant women between the 23rd and 27th week of gestation, subdivided into group A (normal uterine Doppler velocimetry) and group B (abnormal uterine Doppler velocimetry). Besides uterine velocimetry (resistence index and presence/absence of notch), at enrolment in the study the PI of the umbilical artery and of the middle cerebral artery were measured, in addition to the usual foetal biometric parameters (biparietal diameter and abdominal circumference). Contemporaneously, a 20 ml blood sample was taken for the dosage of protein C, protein S, antithrombin III, activated protein C resistance, antiphospholipid antibodies and platelet functionality. Subsequently, for all the remaining period of the pregnancy, data were collected relating to the onset of any materno-foetal complications and modality of delivery, as well as neonatal data up to the first 20 days of life. RESULTS: The incidence of adverse perinatal outcomes (pre-eclampsia, gestational hypertension, abruptio placentae, endouterine foetal death, preterm birth, caesarean section because of maternal or foetal problems, APGAR score lower than 7 at the 5th minute of life, small for gestational age) resulted as being 75% in group B versus 11% in group A (P<0.001). The mean gestational age at delivery was 34 weeks (range 27-41) in group A versus 39 weeks (range 37-42) in group B (P<0.001). No difference emerged as to either the mean activity in the plasma levels of the coagulation protein studied in patients with normal and abnormal uterine velocimetry. The same consideration is also true if the population is analysed in relation to the lesser or greater seriousness of the Doppler velocimetry abnormalities. Subdividing the patients in relation to the absence and to the presence of unfavourable perinatal outcomes, the thrombophilic indices appear to be substantially comparable. CONCLUSION: Uterine Doppler velocimetry, carried out between the 24th and the 26th week of pregnancy, proves its validity by identifying a population at high risk of adverse perinatal outcomes. In contrast, the investigations carried out on the haematological abnormalities characteristic of thrombophilia do not reveal any significant differences, either between patients with normal and those with abnormal velocimetry, or between patients with adverse perinatal outcomes and those without. It is thus unlikely that these preliminary data will lead to an improvement in the clinical reliability of uterine velocimetry. PMID- 11604185 TI - Abnormal placentation and selective embolization of the uterine arteries. AB - OBJECTIVE: Abnormal placentation accounts for more than 50% of uterine artery embolization failure. The authors report their experience in this situation. STUDY DESIGN: Seven women presented with abnormal placentation. Uterine artery embolization was carried out in emergency or prophylactic control of postpartum bleeding. RESULTS: In five patients, control of postpartum hemorrhage was obtained without hysterectomy. In two cases with no placental removal and prophylactic procedures, hysterectomy and blood transfusion were not necessary. The manual removal of the placenta was achieved secondarily, respectively on the 25th and the 12th day. CONCLUSIONS: The success rate of uterine artery embolization for postpartum bleeding appears to be lower with abnormal placentation. In none of the cases with the placenta present was it possible to leave the residual placenta in place. However, embolization may permit a safe waiting period and spontaneous migration of the placenta. When the diagnosis is made before delivery, prophylactic uterine artery embolization without placental removal should be considered to reduce blood transfusion and preserve fertility. PMID- 11604186 TI - Serum alpha-1-antitrypsin concentration during normal and diabetic pregnancy. AB - OBJECTIVES: The aim of this study was a comparison of serum alpha-1-antitrypsin (AAT) concentration in the course of normal and diabetic pregnancy. METHODS: Serum AAT concentration was determined on NOR-Partigen plates (Behring Diagnostics GmbH, Marburg). The studied material included healthy women without pregnancy (n=14), healthy pregnant women in the first trimester (n=12), second trimester (n=15), third trimester (n=15), and 16 pregnant women with type-1 diabetes mellitus studied prospectively in successive stages of pregnancy. RESULTS: In the first trimester of normal pregnancy, a significant increase of serum AAT concentration was observed in comparison with healthy women without pregnancy (P<0.01). In all stages of pregnancy with type-1 diabetes mellitus, a higher increase of AAT concentration was found as compared with healthy pregnant women (P<0.0001), especially in third trimester. There was no correlation shown between concentration of AAT and fructosamine in the serum of healthy and diabetic pregnant women (P>0.05). CONCLUSIONS: During normal and diabetic pregnancy, an increase of serum AAT concentration occurred with the regression lines exhibiting a different slopes. The highest AAT concentration was observed in third trimester of diabetic pregnancy. Increase in concentration of AAT in the serum of pregnant women with diabetes does not depend on the value of glycaemic control. PMID- 11604187 TI - Surgical treatment of HELLP syndrome-associated liver rupture -- an update. AB - In some 2% of the cases of the HELLP syndrome, severe spontaneous bleeding into the liver accompanied by haemorrhagic liver cell necrosis and rupture of the organ occurs and represents one of the main cause of death. On the basis of our own experience with four cases, a review of the literature is presented with particular focus on a therapeutic concept based on appropriate surgery. Within a MEDLINE search covering the period 1990-1999, the case reports of this kind of liver complication in the literature were analysed in terms of clinical course and outcome.In addition to our own four patients, a total of 49 cases with rupture of the liver were found in the literature. Despite surgical interventions, HELLP syndrome-associated liver rupture carried a mortality of 39%. Most patients died of haemorrhagic shock and organ failure. In order to improve survival, patients with ruptured liver or hepatic failure should be transferred to a centre with the necessary experience in liver surgery including liver transplantation. An interdisciplinary approach is required, including the use of temporary packing of the liver to control the bleeding, and during the further course of the condition, possibly even liver transplantation, as in one of our own cases. PMID- 11604188 TI - Fetal autopsy: a review of recent developments. AB - OBJECTIVE: To analyze recent changes in fetal autopsy in response to developments in prenatal medicine. METHOD: During the period 1988 through 1997, 783 fetuses (75% induced abortions, 18% spontaneous abortions, and 7% stillbirths, all between the 12th and 40th week of gestation) with prenatally diagnosed congenital malformations and chromosomal aberrations were analyzed. We divided the autopsies into two periods: period A (1988-92, n=370) and period B (1993-97, n=413). All fetuses were analyzed before completion of 20 weeks of gestation. The malformations of the organ systems were presented according to their frequency for fetuses independent of the weeks of gestation. RESULTS: An autopsy was performed prior to the completion of 20 weeks of gestation for 24% of the fetuses in period A and 45% in period B (P<0.0001). The number of diagnosed congenital heart malformations increased from 16% in period A to 23% in period B. The number of congenital heart malformations before completion of 20 weeks of gestation was only 21% in period A as compared to 42% in period B. CONCLUSIONS: In period B, clinical questions were raised in a more concrete form and ultrasound images gave more detailed information than in period A. Access to prenatal findings prior to postmortem examination has helped investigators to develop a specific, clinically oriented, autopsy strategy based on the prenatal findings which makes it possible to diagnose very small malformations and to select sectional planes of special interest. The use of an interdisciplinary database is required for communication. PMID- 11604189 TI - The effect of steroids on the biophysical profile and Doppler indices of umbilical and middle cerebral arteries in healthy preterm fetuses. AB - OBJECTIVE: To examine the effect of antenatal steroids on the biophysical profile and the Doppler parameters of umbilical and middle cerebral arteries of healthy fetuses. STUDY DESIGN: Thiry-five singleton pregnancies between the gestational ages of 28 and 34 weeks, who received two consecutive doses of betamethasone 24h apart to accelerate pulmonary maturation were prospectively studied. Fetal biophysical profile and Doppler assessment were performed at 0 (pre-steroid), 24, 48, 72, 96 and 120 h after the administration of first dose. We compared the percentage of the fetuses with biophysical parameters present for each of the five components of the biophysical profile and the Doppler indices, using Cochran's Q-test, Friedman's test and one way analysis of variance of repeated measures where appropriate. The statistical significance was defined as P<0.05. RESULTS: The mean delivery time was 36.9(+/-1.8) weeks. There was a statistically significant difference in the frequency of the following findings in the pre- compared to post-steroid measurements: absence of body movements (48 h, P<0.05), non-reassuring fetal heart rate tracings (24, 48 and 72 h, P<0.05) and absence of breathing movements (24, 48 and 72 h, p<0.05). Initially none of the biophysical profile score was 8 h), allows for D2 and D3 to play a more prominent role in the acute regulation of peripheral thyroid hormone metabolism than D1. PMID- 11604219 TI - The effect of leptin on Na(+)-H(+) antiport (NHE 1) activity of obese and normal subjects erythrocytes. AB - Obesity is currently considered as a chronic metabolic disease, associated with a high risk of cardiovascular complications. Leptin, an adipocyte-derived hormone has a variety target cells influencing a wide range of processes. Possible counteractions of hyperleptinaemia are currently investigated. The Na(+)-H(+) exchanger (NHE 1) is involved in multiple cellular functions and its activation has been related to hypertension and obesity. NHE 1 is present on erythrocytes and can be stimulated by various hormones. Erythrocytes have on their surface a variety of receptors with mostly unknown function. In the present paper, the effect of leptin on erythrocytes NHE 1 activity has been investigated. For this reason, the intracellular pH and sodium influxes were measured before and after addition of leptin in erythrocyte suspensions from normal and obese individuals. Amiloride, a specific NHE 1 inhibitor, and staurosporine a protein kinase C inhibitor were used to inhibit erythrocyte NHE 1. For the binding study leptin was labeled with fluorescein isothiocyanate (FITC) and the binding on erythrocytes was estimated by Scatchard analysis. NHE 1 activity increased in the presence of leptin but significantly less in the obese than in the control group. Furthermore the concentrations of leptin binding sites on the surface of erythrocytes were lower in erythrocytes drawn from obese individuals than in erythrocytes drawn from normal subjects. Since NHE 1 activity has been associated with insulin resistance and hypertension, the activation of this antiport by leptin may represent a link between adipose tissue hypertrophy and cardiovascular complications of obesity. PMID- 11604220 TI - Repression of androgen-regulated gene expression by dominant negative androgen receptors. AB - The androgen receptor (AR) is a ligand-dependent transcription activator responsible for male sexual development. In order to specifically inhibit the AR pathway, dominant negative ARs were constructed by inactivation of the major transactivation domains of the wild type AR and fusing this mutant (AR122) to the Kruppel-associated box (KRAB) repressor domain and/or histone deacetylase (HDAC1). The HDAC1-KRAB-AR122 protein was the most successful dominant negative AR, capable of repressing the wild type AR ninefold when co-expressed at a 1:1 plasmid ratio. A maximal repression of 41-fold was achieved when HDAC1-KRAB-AR122 was cotransfected with the wild type AR at a 4:1 plasmid ratio. HDAC1-KRAB-AR122 repressed transcription in a ligand-dependent manner since it inhibited a constitutively active AR mutant (AR5) only in the presence of agonists. High concentrations of partial agonists such as RU486, cyproterone acetate, and estradiol were also capable of triggering repression by HDAC1-KRAB-AR122. The potent dominant negative AR proteins might prove useful tools to inhibit AR function in vitro and in vivo. PMID- 11604221 TI - Hypothalamic dysfunction. AB - A pulsatile GnRH stimulus is required to maintain gonadotropin synthesis and secretion. The frequency and amplitude of GnRH pulses determine gonadotropin subunit gene expression and secretion of pituitary LH and FSH. Rapid frequency (more than 1 pulse per h) GnRH pulses favor LH while slower frequencies favor FSH secretion. During ovulatory cycles, an increase in GnRH frequency during the follicular phase favors LH synthesis prior to the LH surge, while following ovulation, luteal steroids slow GnRH pulses to favor FSH synthesis. Thus, a changing frequency of GnRH stimulation of the gonadotrope is one of the mechanisms involved in differential gonadotropin secretion during ovulatory cycles. In hypothalamic amenorrhea a majority of women exhibit a persistent slow frequency of LH (GnRH) pulses, which reflects excess hypothalamic opioid tone and can be temporarily reversed by opioid antagonists. At the other end of the spectrum, in polycystic ovarian syndrome, LH (GnRH) pulses are persistently rapid and favor LH synthesis, hyperandrogenism and impaired follicular maturation. Administration of progesterone can slow GnRH pulse secretion, favor FSH secretion and induce follicular maturation. Thus, the ability to change the pattern of GnRH secretion is an important factor in the maintenance of cyclic ovulation, and loss of this function leads to anovulation and amenorrhea. PMID- 11604222 TI - Molecular cloning and characterization of reptilian estrogen receptor cDNAs. AB - cDNAs encoding alligator (caiman), Caiman crocodilus and whiptail lizard, Cnemidophorus uniparens estrogen receptors (ERs) were cloned and sequenced. This is the first report of full-length cDNA sequences for reptilian ERs, to our knowledge. The full-length alligator (caiman) ER cDNA (1764 bp, 587 amino acid residues) shows 68% amino acid homology with the full-length whiptail lizard ER cDNA (1746 bp, 581 amino acid residues). The respective ligand binding E domains have 87 and 83% amino acid homology with human ER while the DNA binding C domains show 100% amino acid homology with the human, rat and chicken forms. When the cDNAs were inserted into the pRc/RSV vector and transfected into HeLa cells with a reporter plasmid, the encoding proteins were confirmed to be functional through the interaction of the receptor-ligand complex with the estrogen responsive element (ERE). PMID- 11604223 TI - A constitutive nitric oxide synthase modulates insulin secretion in the INS-1 cell line. AB - We provide immunocytochemical evidence that the neuronal isoform of constitutive NO synthase (cNOS) is expressed in the rat insulinoma cell line INS-1. Furthermore, using N omega-nitro-L-arginine methyl ester (L-NAME), a pharmacological inhibitor of cNOS activity, we show that this enzyme is implicated in the modulation of insulin secretion in INS-1 cells. Indeed, in the presence of 2.8 mM glucose, L-NAME induced a specific and dose-dependent increase in insulin release, suggesting that cNOS exerts an inhibitory tone on basal insulin secretion. Moreover, L-arginine, the physiological substrate of cNOS, significantly reduced the marked enhancing effect of L-NAME on insulin release and to a lesser extent, at low concentrations, that of 10 mM KCl. L-NAME also potentiated the insulin secretion stimulated by 5.5 and 8.3 mM glucose, but in this case, its effect was not reduced by L-arginine. In conclusion, our data show that the neuronal isoform of cNOS exerts a negative modulation on insulin secretion in INS-1 cells, confirming the previous results obtained in the isolated perfused rat pancreas or pancreatic islets. PMID- 11604224 TI - Differential phosphorylation of Janus kinase 2, Stat5A and Stat5B in response to growth hormone in primary rat adipocytes. AB - In vitro growth hormone (GH) stimulation of Janus kinase 2 (Jak2) tyrosine phosphorylation and activation has been detected in rat adipocytes where GH exerts both chronic diabetogenic and acute insulin-like effects but not in adipocytes where only chronic diabetogenic effects are exerted. The 95 kDa transcription factor Stat5, which is tyrosine phosphorylated in response to GH in both cases, is here identified as the 5A-isoform. Stat5B was not tyrosine phosphorylated in response to GH in adipocytes but subject to a gel supershift indicating regulation by serine and/or threonine phosphorylation. The differential tyrosine phosphorylation of these proteins suggests involvement of a kinase other than Jak2 in Stat5A activation. However, in adipocytes where GH exerts both diabetogenic and insulin-like effects, and both Jak2 and Stat5A were activated, their phosphorylation kinetics and downregulation of tyrosine phosphorylation were almost identical. We conclude that Stat5A is important for the diabetogenic actions of GH and that Jak2 still is the most probable candidate kinase for Stat5A in primary adipocytes. PMID- 11604225 TI - Tibolone: a compound with tissue specific inhibitory effects on sulfatase. AB - The aim was to test whether sulfatase activity is differently regulated by tibolone in human bone, endometrium and breast cells since selective inhibition of sulfatases in various tissues may contribute to the tissue-specificity of tibolone. Tibolone, its 3 alpha- and 3 beta-hydroxy metabolites and their 3 sulfated forms, and its Delta(4)-isomer strongly (70-90%) inhibited the sulfatase activity in human breast cell lines (two T-47D clones) and intermediately (8-43%) in human endometrial cells (HEC-1A). In contrast, they did not inhibit sulfatase in two human osteoblast-like cell lines (MG 63, HOS TE-85). The specific sulfatase inhibitor, EMATE, showed inhibition in all cell lines. Just as estrone sulfate, 3 alpha-sulfated tibolone was also converted by sulfatase to the unconjugated 3 alpha-hydroxy-tibolone intracellularly in all cell lines. The tissue specific inhibition pattern of sulfatase activity by tibolone and its metabolites suggest that tibolone could be protective against development of mammary carcinomas, whereas it retains favorable estrogenic effects on bone. PMID- 11604226 TI - Regulation of IRS-2 tyrosine phosphorylation in fasting and diabetes. AB - Intracellular insulin signaling involves a series of alternative and complementary pathways created by the multiple substrates of the insulin receptor (IRS) and the various isoforms of the SH2 domain signaling molecules that can interact with substrate. In this study we investigated IRS-1 and IRS-2 tyrosine phosphorylation, their association with PI3-kinase and the phosphorylation of Akt, a serine-threonine kinase situated downstream to PI 3-kinase, in liver and muscle of two animal models of insulin resistance: 72 h of fasting and STZ diabetic rats. There was an upregulation in insulin-induced IRS-1 and IRS-2 tyrosine phosphorylation and association with PI3-kinase in liver and muscle of both animal models of insulin resistance. However, Akt phosphorylation showed different regulation, increasing in fasting and decreasing in STZ-diabetic rats. Since an important difference between these two animal models of insulin resistance is the plasma glucose levels, we can suggest that in STZ diabetic rats, the reduction in Akt phosphorylation is probably related to hyperglycemia and may certainly contribute to the molecular mechanism of insulin resistance observed in these animals. PMID- 11604227 TI - Regulation of human cbfa1 gene transcription in osteoblasts by selective estrogen receptor modulators (SERMs). AB - Cbfa1, a transcription factor critical for bone formation, plays a key role in osteoblast recruitment and differentiation. We have cloned and characterized a 3.0 KB 5'-flanking region of the human cbfa1 gene isolated from a P1 human genomic library. DNA sequencing revealed several known canonical nuclear transcription factor binding sites, including two AP1 and six OSE2 binding sites in the proximal promoter region. Although no estrogen (E2)-response element (ERE) binding sites were identified, E2 has been shown to regulate gene activity via AP1 promoter sites. We examined the effect of selective estrogen receptor modulators (SERMs) on human cbfa1 gene promoter activity using cell-based luciferase reporter transcriptional assays. Three characterized SERMs, tamoxifen, raloxifene, and ICI 178,180, all upregulated cbfa1-luciferase (cbfa1Luc) gene activity 5- to 10-fold in a dose-dependent manner. This effect was mediated by both ER alpha and ER beta. Mutational analysis demonstrated that the minimal promoter region for basal of SERM-activated transcription was mapped to adjacent AP1-like and OSE2 binding sites within -93 and +7 of the transcription start condon. Further, electrophoretic mobility shift assays (EMSAs) demonstrate that ICI 178,180 increased binding of AP1 and OSE2 site by ER alpha and cbfa1, respectively. These studies suggest that SERMs can modulate bone-specific cbfa1 gene expression in a human osteosarcoma cell line. PMID- 11604228 TI - Identification and characterization of functional angiotensin II type 1 receptors on immortalized human fetal aortic vascular smooth muscle cells. AB - Studies investigating the mechanisms that govern the expression of the human angiotensin II type 1 receptor (hAT(1)R) gene have progressed slowly due to the lack of human cell lines that express the AT(1)R. Recently, however, an immortalized human fetal aortic vascular smooth muscle cell line (FLTR) was generated using an amphotropic recombinant retroviral construct containing the E6/E7 open reading frames of the human papillomavirus type 16. Radioligand binding studies were undertaken to determine whether angiotensin II (Ang II) receptors were expressed on these cells. FLTR cell membranes were shown to express high-affinity Ang II receptors having a B(max) value of 324+/-43 fmol/mg protein and a K(d) of 0.36+/-0.1 nM. In both membranes and intact cells, Ang II, Ang III and the selective AT(1)R antagonist, Losartan, all had a high affinity for the receptor, suggesting that FLTR cells express the AT(1)R subtype. The expression of the hAT(1)R was validated by Northern and Western blot and RT-PCR experiments. In intact FLTR cells, Ang II (100 nM) evoked an increase in intracellular calcium ([Ca(2+)](i)) and induced hyperplasia. Additionally, our results demonstrated that FLTR cells were readily transfected, and hAT(1)R promoter luciferase constructs exhibited robust promoter activity (i.e. approximately 22-fold increase over pGL3-Basic only). Finally, our results demonstrated that the hAT(1)R gene is differentially regulated in FLTR cells vs. H295-R cells, a human adrenocarcinoma cell line that also abundantly expresses the AT(1)R. Taken together, our results suggest that FLTR cells express functional AT(1)Rs and will provide an excellent model system in which to investigate hAT(1)R gene regulation. PMID- 11604229 TI - Induction of vitellogenin gene transcription in vitro by juvenile hormone in Blattella germanica. AB - In the cockroach Blattella germanica, the synthesis of vitellogenin is juvenile hormone III (JH III)-dependent. We have studied the effect of JH III upon vitellogenin gene expression in periovaric fat bodies incubated in vitro. Periovaric fat bodies were obtained from cardioallatectomized females. The response to JH III was measured in terms of vitellogenin and vitellogenin mRNA after 7 h of incubation. A hormonal concentration as low as 1 nM was enough to induce vitellogenin production and its release to the medium, whereas the concentration of 10 nM produced the maximal effects. Although the response of the vitellogenin gene to JH III is fast and efficient, it seems that the action is mediated by protein factors, given that cycloheximide treatment impairs the hormonal effect. The presence in the medium of brain extract (0.5 equivalents), corpora cardiaca (one pair) or hypertrehalosemic hormone (10(-7) or 10(-8) M), partially inhibited the response to JH III. PMID- 11604230 TI - Specific DNA binding and transactivation potential of recombinant, purified Stat5. AB - The signal transducers and activators of transcriptions (Stats) are central mediators of cytokine responses especially in hematopoietic cells. The detailed molecular mechanisms of Stat activation, particularly the role of post translational modifications and co-operation with cellular transcription factors are subject to intense investigation. The phosphorylation of a tyrosine residue in the carboxyl terminal domain is a common characteristic for the biologically active state of all known Stats. We studied the biological potential of purified recombinant murine Stat5a and Stat5b. These proteins were expressed in Sf9 insect cells upon infection with Stat5 encoding baculoviruses. We also obtained the tyrosine phosphorylated, activated forms of the Stat5 proteins by expressing the tyrosine kinase Janus kinase2 (Jak) in the same cells through co-infection with a kinase encoding virus. After purification, only the tyrosine phosphorylated form was able to bind specifically in vitro to the Stat5 DNA response element. This activated form of Stat5 is also able to support specific cell free in vitro transcription of a gene with a Stat5 response element in its promoter region. The recombinant purified Stat5 proteins were treated with the tyrosine specific protein phosphatase or with potato acidic phosphatase, which removes phosphate groups from serine and tyrosine residues. Phosphatase treatment resulted in the loss of specific DNA binding ability. This property could be restored by an in vitro reaction with recombinant, purified EGF or PDGF receptor kinases. Tyrosine rephosphorylation in vitro also restored the transactivation potential of Stat5. This modification is, therefore, a sufficient prerequisite for transcriptional induction by Stat5. PMID- 11604231 TI - Sam68 is a docking protein linking GAP and PI3K in insulin receptor signaling. AB - The 68 kDa Src substrate associated during mitosis (Sam68) is an RNA binding protein with Src homology (SH) 2 and 3 domain binding sites. We have recently found that Sam68 is a substrate of the insulin receptor (IR) and that Tyr phosphorylated Sam68 associates with the SH2 domains of p85 PI3K. In the present work, using HTC-IR cells, we have found that insulin stimulation promotes the relocalization of Sam68 from the nucleus to the cytoplasm, and we have further studied the role of Sam68 in insulin receptor signaling complexes, by co precipitating experiments. Thus, Sam68 is co-precipitated with p85 PI3K, IRS-1 and IR. The association of Sam68 with these complexes is mediated by the SH2 domains of PI3K. Moreover, we have found that Sam68 is a p120GAP associated protein after Tyr-phosphorylation by the IR. This association is mediated by the SH2 domains of GAP (preferentially the C-terminal SH2). Thus, Sam68 is linking p120GAP to PI3K signaling pathway. In fact, PI3K activity was increased in both anti-Sam68 and anti-GAP immmunoprecipitates upon insulin stimulation. We propose that the recruitment of the docking protein Sam68 to the PI3K pathway may serve to allow the association of other signaling molecules, i.e. p120GAP. In this way, these signaling complexes may modulate other signaling cascades of IR, such as p21Ras pathway. PMID- 11604232 TI - The reproductive importance of P-type ATPases. AB - P-type ATPases are integral membrane proteins that use the free energy of ATP hydrolysis to generate transmembrane electrochemical ion gradients to support a variety of cellular processes. They have eight signature motifs, eight or ten transmembrane domains, highly conserved phosphorylation and ATP-binding sites, and similar hydropathic profiles. This review summarizes recent insights in the relationship of P-type ATPases to successful reproduction, and the hormone dependence of some family members. Because protein topology is central to understanding the pump action of this family of enzymes, this review also describes the dramatic change in the primary structure of one family member that may mediate transcription in the uterus. PMID- 11604233 TI - Reciprocal mutagenesis between human alpha(L349, M528) and rainbow trout (M317, I496) estrogen receptor residues demonstrates their importance in ligand binding and gene expression at different temperatures. AB - Several fish proteins exhibit compromised function at temperatures outside of their normal physiological range. In this study, the effect of temperature on the ligand binding and the transactivation abilities of the rainbow trout estrogen receptor (rtER) and human estrogen receptor alpha (hER alpha) were examined. Saturation analysis and gene expression assays, using GST-ER and Gal4-ER fusion proteins consisting of the D, E and F domains of human (hER alpha def) and rainbow trout (rtERdef) receptors, show that GST-rtERdef E2 binding affinity and transactivation ability decrease with increasing temperature. A comparison of the amino acid sequence differences between their ligand binding pockets identified two conservative amino acid residue substitutions in rtER (M317, I496) and hER alpha (L349, M528). The effect of these substitutions on ligand binding and transactivation were examined by constructing reciprocal mutants, which effectively exchanged the binding pockets between rtER and hER alpha. The rtERdef M317L:I496M double mutant exhibited increased E2 binding affinity and transactivation ability at higher temperatures, and displayed hER alpha phenotypic behavior for the phytoestrogen, coumestrol. The hER alpha def L349M:M528I double mutant also exhibited a modest trend towards adopting the rtER phenotype. These studies demonstrate that conservative changes in residue hydrophobicity and volume can significantly affect ER ligand binding and transactivation ability in a temperature-dependent manner. The lack of a complete exchange of phenotypes between rtER and hER alpha indicates that factors outside of the ligand binding pocket are also involved. PMID- 11604234 TI - Synthetic low-calcaemic vitamin D(3) analogues inhibit secretion of insulin-like growth factor II and stimulate production of insulin-like growth factor-binding protein-6 in conjunction with growth suppression of HT-29 colon cancer cells. AB - The aims of the present study were to compare the ability of various synthetic analogues of 1 alpha,25-dihydroxyvitamin D(3) [1 alpha,25-(OH)(2)D(3)] to inhibit proliferation of HT-29 cells, a human colon adenocarcinoma cell line. HT-29 cells were incubated for 144 h with various concentrations (0-100 nM) of 1 alpha,25 (OH)(2)D(3), or the analogues EB1089, CB1093 or 1 beta,25-(OH)(2)D(3). All these analogues except 1 beta,25-(OH)(2)D(3) inhibited cell proliferation, but relative potencies and efficacies of EB1089 and CB1093 were much greater than that of the native vitamin. Cells grew in serum-free medium, reaching a plateau density at day 10 of culture, and addition of 10 nM 1 alpha,25-(OH)(2)D(3) or 1 beta,25 (OH)(2)D(3) did not alter the long-term growth characteristics of HT-29 cells. However, cells treated with 10 nM EB1089 or CB1093 grew at a rate slower than control and reached final densities that were 53+/-1 and 36+/-2% lower than control, respectively. Immunoblot analysis of serum-free conditioned medium using a monoclonal anti-insulin-like growth factor-(IGF)-II antibody showed that both 10 nM EB1089 and CB1093 markedly inhibited secretion of both mature 7500 M(r) and higher M(r) forms of IGF-II. Ligand blot and immunoblot analyses of conditioned media revealed the presence of IGFBPs of M(r) 24,000 (IGFBP-4), 30,000 (glycosylated IGFBP-4), 35,000 (IGFBP-2) and 32,000-34,000 (IGFBP-6). The level of IGFBP-2 was decreased by 42+/-8 and 49+/-7% by 10 nM EB 1089 and CB1093, respectively, compared to controls. IGFBP-6 was increased approximately twofold by EB1089 and CB1093, and exogenously added IGFBP-6 inhibited HT-29 cell proliferation. These results suggest that inhibition of HT-29 cell proliferation by EB1089 and CB1093 may be attributed, at least in part, to the decreased secretion of IGF-II. The increase in IGFBP-6 concentration coupled with its high affinity for IGF-II may also contribute to decreased cellular proliferation by an indirect mechanism involving sequestration of endogenously produced IGF-II. PMID- 11604235 TI - Role of serine phosphorylation of Stat5a in prolactin-stimulated beta-casein gene expression. AB - Milk production remains suppressed in mammals during late pregnancy despite high levels of lactogenic polypeptide hormones. At parturition, associated with a precipitous fall in circulating progesterone, rising glucocorticoid levels synergize with prolactin to initiate copious milk production. This synergy is mediated at least in part through the coordinated activation of glucocorticoid receptors and transcription factor Stat5, particularly Stat5a. Here we show that two proline-juxtaposed serine residues within the transactivation domain of Stat5a are phosphorylated in the mammary gland during late gestation and lactation, and that these phosphorylation sites inhibit the transcriptional activity of Stat5a in the absence of glucocorticoid receptor costimulation. Specifically, transfection assays revealed that phosphorylation of residues S725 and S779 of Stat5a cooperatively suppressed prolactin-stimulated transcription from the beta-casein promoter in both COS-7 kidney and MCF-7 mammary cells. This suppression was associated with shortened duration and reduced amplitude of nuclear DNA binding activity of wild type Stat5a relative to that of the serine phosphorylation-defective Stat5 mutant. However, costimulation of glucocorticoid receptors completely reversed the suppressive effect of Stat5a serine phosphorylation on beta-casein gene transcription. We propose that serine phosphorylation within the transactivation domain may limit the activity of Stat5a in the absence of proper coactivation by glucocorticoid receptors. PMID- 11604236 TI - Modulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in Ishikawa cells is associated with changes in cellular proliferation. AB - An important determinant of the potency of steroid hormones is the presence of activating and inactivating enzymes in target cells. The 11 beta-hydroxysteroid dehydrogenase type 1 and type 2 enzymes (11 beta HSD1 and 11 beta HSD2) modulate glucocorticoid action and may be important in regulating cellular growth. In the present study we examined 11 beta-hydroxysteroid dehydrogenase in Ishikawa endometrial cancer cells to see if modulation of enzyme activity could potentiate the antiproliferative effects of glucocorticoids. Ishikawa cells contain an NAD dependent enzyme migrating at 41 kDa on Western blots, consistent with the presence of the glucocorticoid-inactivating enzyme 11 beta HSD2, while the NADP dependent 11 beta HSD1 is barely detectable. Given that glucocorticoids decrease cellular proliferation we asked whether inhibition of 11 beta HSD2 could further enhance this effect. Cultivation of cells in the presence of 1 microM cortisol resulted in an elevation of 11 beta HSD2 and this was associated with a decrease in cell number. Enzyme activity and cell proliferation showed a biphasic response to the synthetic anti-progestin and anti-glucocorticoid RU38486, with < or =10 nM exerting agonistic effects and > or =100 nM producing antagonist effects in the presence of 1 microM cortisol. Inhibition of 11 beta HSD2 activity by glycyrrhetinic acid did not enhance the anti-proliferative effects of 1 microM cortisol, but the inhibitor showed significant antiproliferative activity in the absence of added glucocorticoid, consistent with protection of the low levels of glucocorticoids present in culture medium. Interestingly, the commonly used 11 beta HSD inhibitor, Carbenoxolone, did not block 11 beta HSD2 activity in whole Ishikawa cells, and there was no effect on cell proliferation, however, complete inhibition of 11 beta HSD2 was achieved in cellular homogenates suggesting that a barrier exists to entry of the inhibitor into intact cells. This study suggests that inhibition of 11 beta HSD2 activity can enhance the antiproliferative effects of low, but not high concentrations of glucocorticoids, and that beneficial effects may be attained in vivo at the nadir of diurnal glucocorticoid levels. PMID- 11604237 TI - Stage-dependent role of growth differentiation factor-9 in ovarian follicle development. AB - GDF-9 was shown to be essential for follicle progression and is the only factor secreted by the oocyte shown to increase the number of primordial and primary follicles in vivo. Furthermore, GDF-9 is a major growth factor involved in the oocyte control of granulosa cell differentiation. A concentration gradient of the paracrine factor GDF-9 established by the oocyte could provide the basis to explain the stratification of granulosa cells in antral and preovulatory follicles. The stimulatory effects of GDF-9 on early follicle development provide a basis for the use of GDF-9 in the treatment of infertility. PMID- 11604238 TI - Leptin attenuates follicular apoptosis and accelerates the onset of puberty in immature rats. AB - Human and rat granulosa cells express receptors to leptin which synergies with glucocorticoid hormones in stimulation of ovarian steroidogenesis. To examine whether leptin affects follicular development and maturation, we injected recombinant ovine leptin (300 ng-10 microg/animal) daily to immature 21 day-old female rats. Non-treated rats reached puberty at 44.5+/-1.6 (n=9) days. In contrast, in leptin treated animals, puberty was reached at 34.5+/-1.6 (n=9) days. Ovarian sections revealed hypertrophy of granulosa cells in leptin treated animals. Moreover, the number of ovulations was 2-fold higher in the treated animals compared to controls (3-4 ovulations versus 7-8 on the first three estrous cycles, P<0.001). Leptin dramatically reduced incidence of follicular apoptosis measured by TUNEL, and was already evident after 7 days of leptin injection (12% of apoptosis in leptin treated group compared to 52% in controls, P<0.001). Maximal protection against apoptosis was achieved at 1-3 microg leptin/animal. The levels of FSH, LH, progesterone and the steroidogenic factors ADX and STAR were elevated earlier in development in the leptin treated animals compared to control animals which is in line with the achievement of early puberty in the leptin treated animals compared to non treated ones. To reveal whether modulation of death and survival genes is involved in leptin attenuation of follicular apoptosis, we examined the expression of the survival gene Bcl-2 and the death gene Bax in Western blots of ovarian homogenates. There was a pronounced elevation in Bcl-2 expression during 7-14 days of leptin injections up to 16.3-fold (P<0.001) compared to Bcl-2 expression in controls. Bax expression was elevated only 3.4 fold (P<0.001), leading to an increase in the Bcl-2/Bax ratio of 4.7 fold (P<0.001). Expression of the tumor suppressor gene p 53 and the oncogene Mdm2 did not change significantly. Our data suggests that leptin may be involved in accelerating follicular maturation by attenuating follicular atresia and increasing the ratio of Bcl-2/Bax. PMID- 11604239 TI - Is the in vitro maturation of germ cells accelerated in co-culture with Sertoli cells? PMID- 11604241 TI - Localization of GABA(B) receptors in midbrain monoamine containing neurons in the rat. AB - The localization of gamma-aminobutyric acid (GABA)(B) receptors in the midbrain of the rat was examined in multiple labeling studies using antibodies directed against the GABA(B) receptor and either tryptophan hydroxylase or tyrosine hydroxylase. Almost all of the serotonergic and dopaminergic cell bodies in the midbrain displayed GABA(B) receptor-like immunoreactivity. Conversely, most neurons in the raphe nuclei and ventral tegmentum which exhibited intense immunoreactivity for GABA(B) receptors were also immunopositive for serotonergic or dopaminergic markers. These results demonstrate directly that GABA(B) receptors are present in monoaminergic neurons in certain regions of the midbrain. PMID- 11604242 TI - The electroretinogram and visual evoked potential of freely moving rats. AB - The vascularised rat retina could be one of the most useful experimental objects in visual neuroscience to understand human visual physiological and pathological processes. We report here on a new method of implantation for studying the visual system of freely moving rats that provides a rat model for simultaneous recording at corneal and cortical level and is stable enough to record for months. We implanted light emitting diodes onto the skull behind the eyeball to stimulate the eye with flashes and to light adapt the retina with constant light levels. A multistrand, stainless steel, flexible fine wire electrode placed on the eyeball was used for electroretinogram recording and screw electrodes (left/right visual and parietal cortical) were used to record the visual evoked potential and the electroencephalogram. In the present report we focus on the new method of implantation for recording the corneal flash electroretinogram of normal, freely moving rats simultaneously with the visual evoked cortical potential showing examples in various visual experiments. We also introduce a program for retinogram and visual evoked potential analysis, which defines various measures (latencies, areas, amplitudes, and durations) and draw attention to the benefits of this method for those involved in visual, functional genomic, pharmacological, and human ophthalmologic research. PMID- 11604243 TI - Histochemical and immunocytochemical investigations of the marginal nuclei in the spinal cord of pigeons (Columba livia). AB - In birds there are segmentally organized marginal nuclei at the lateral or ventrolateral border of the spinal cord. In most regions of the spinal cord these nuclei are within the outline of the cord. However, in the lumbosacral region they form accessory lobes protruding into the vertebral canal. Histochemical and immunocytochemical investigations were performed to study the neurochemical features of the marginal nuclei of the pigeon. Despite histological differences (only accessory lobe neurons are embedded in glia-derived glycogen cells), there was no difference in the chemical neuroanatomy of the two types of marginal nuclei. These nuclei contained cholinergic neurons and there was also evidence for a cholinergic innervation. NADPH-diaphorase activity, which is considered to indicate nitric oxide synthesis, was faint in marginal neurons. No serotonin immunoreactivity was found. However, all neurons showed immunoreactivity to glutamate and glycine, and some were immunoreactive to gamma-aminobutyric acid (GABA). A GABAergic innervation of non-GABAergic neurons could also be demonstrated. The lack of difference in the chemical neuroanatomical features between cervical marginal nuclei and lumbosacral accessory lobes suggests a similar origin of all marginal neurons. A comparison with the chemical neuroanatomy of marginal neurons in other vertebrates shows both similarities and differences. PMID- 11604244 TI - Renin antisense injected intraventricularly decreases blood pressure in spontaneously hypertensive rats. AB - Brain renin-angiotensin system plays an important role in blood pressure regulation and is suggested to play a role in the development and maintenance of hypertension. To test the hypothesis that brain renin may play a significant role in hypertension in spontaneously hypertensive rats (SHR), phosphorothioated antisense oligodeoxynucleotides targeted to renin mRNA were administered intracerebroventricularly in SHR. Administration of an antisense but not its sense oligodeoxynucleotide produced a prolonged duration of decrease in blood pressure. Intra-arterial administration of the antisense oligodeoxynucleotide at the same dose that decreased blood pressure when administered intraventricularly did not affect blood pressure. Furthermore, renin mRNA but not angiotensin AT1 receptor mRNA levels were decreased in the hypothalamus of the antisense oligodeoxynucleotide-treated rats. These results suggest that brain renin may play a significant role in hypertension in SHR. PMID- 11604245 TI - Sustained, long-lasting inhibition of nitric oxide synthase aggravates the neural damage in some models of excitotoxic brain injury. AB - Brain nitric oxide (NO) can be a mediator of physiological and neuroprotective actions and an effector of neural damage. The effectiveness of acute or chronic inhibition of NO production in in vivo experiments of neurotoxicity/neuroprotection is controversial. We report here on the effects of a chronic, sustained inhibition of nitric oxide synthase (NOS) on the neurodegenerative damage caused by three different excitotoxic lesions. The damage caused by intrastriatal injection of ibotenic or kainic acid was aggravated in rats subjected to chronic NOS inhibition. On the contrary, the drop of cortical cholinergic input consequent to ibotenic acid-mediated degeneration of basal forebrain neurons was not altered by chronic NOS inhibition. The worsening of the damage was not related to any overt differential sensitivity to excitotoxicity of NOS-containing striatal neurons under conditions of NOS inhibition. These results suggest that, contrary to what has been often reported for short-term, mild inhibition of NO production, chronic and sustained NOS inhibition may exacerbate neuropathology. Thus, long-lasting shortage of NO may be detrimental when neuroprotective mechanisms related to the physiological action of this free radical are severely impaired. Although we cannot exclude that inhibition of the endothelial NOS isoform could have contributed to the worsening of neuropathology, differences among the paradigms of neurotoxicity used in the present study suggest a primary involvement of the neuronal NOS isoform. In view of the potential therapeutic use of NOS inhibitors, the effects of a too drastic alteration of the balance between neuroprotective and neurodegenerative actions of NO should be carefully considered. PMID- 11604247 TI - Progesterone receptor isoforms expression pattern in human astrocytomas. AB - Progesterone receptors (PR) have been detected in human astrocytomas; however, the expression pattern of PR isoforms in these brain tumors is unknown. Progesterone receptor isoforms expression was studied in 13 biopsies of astrocytomas (6 grade III, and 7 grade IV) from adult Mexican patients by using reverse transcription-polymerase chain reaction and immunohistochemistry. Progesterone receptor expression was observed at mRNA and at protein levels in 66% and 83% of astrocytomas grade III, respectively, whereas 100% of astrocytomas grade IV expressed PR. Almost all PR mRNA content in astrocytomas grades III and IV corresponded to PR-B. The number of immunoreactive cells expressing PR-B was higher than that expressing PR-A in 73% of the cases. Estrogen receptor-alpha protein was only observed in 33% of astrocytomas grade III, whereas no astrocytomas grade IV expressed it. These data suggest that PR-B is the predominant isoform expressed in human astrocytomas grades III and IV, and that estrogen receptor-alpha is not expressed in astrocytomas grade IV. PMID- 11604246 TI - TGF-alpha induces a stationary, radial-glia like phenotype in cultured astrocytes. AB - Transgenic mice studies have suggested that transforming growth factor-alpha (TGF alpha) influences the postnatal differentiation of astrocytes. To understand the role of TGF-alpha during astrocytic differentiation, it is important to determine how this factor affects astrocytes in the absence of other influences. We have thus examined in vitro under serum-free medium conditions the effect of TGF-alpha on the properties of astrocytes derived from the cerebral cortex of newborn rats. When TGF-alpha is added to serum-free medium, most astrocytes lose their polygonal shape and extend two long processes running in opposite directions. This bipolar morphology strikingly resembles that of radial glial cells. Intriguingly, serum inhibits this morphological transformation. TGF-alpha also triggers an increase in glial fibrillary acidic protein (GFAP) expression and a decrease in nestin expression. Another major effect of TGF-alpha is to practically abolish the motility of astrocytes. TGF-alpha, however, does not appear to influence the proliferation and apoptosis of astrocytes. These results suggest that polygonal astrocytes are derived primarily from radial glial cells, and that in vivo TGF-alpha may be instrumental in determining the shape and migratory potential of radial glial cells. PMID- 11604248 TI - Basolateral amygdala lesions disrupt latent inhibitionin rats. AB - Latent inhibition (LI) refers to the retardation of acquisition of conditioned responding produced by repeated non-reinforced preexposure to the conditioned stimulus (CS) prior to its pairing with the unconditioned stimulus (US) during conditioning. LI has recently been shown to depend upon the integrity of temporal lobe structures, including regions of the hippocampal formation such as the entorhinal cortex. The present study investigated the effects of excitotoxic lesions of another temporal lobe structure, the basolateral nucleus of the amygdala (BLA), on LI. LI was studied in a within-subjects appetitive conditioning preparation in which an auditory CS was paired with food US. In this procedure, preexposure to the CS results in slower acquisition of magazine approach behaviour. Lesions of the BLA reduced the effect of preexposure, disrupting LI. This result suggests that the BLA can play a crucial role in LI. The possible involvement of interactions between BLA and entorhinal cortex in LI is discussed. PMID- 11604249 TI - Stereoselective effect of (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinolines on a mouse model of Parkinson's disease. AB - We carried out behavioral, pathological, and biochemical studies in order to determine whether the stereo-structure of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) affects the onset of Parkinson's disease-like symptoms, which are induced by 1,2,3,4-tetrahydroisoquinoline (TIQ) in mice. Pretreatment with (R)-1 MeTIQ or its racemate (RS)-1-MeTIQ prevented the TIQ-induced bradykinesia. Pretreatment with a combination of L-DOPA and carbidopa significantly prevented subsequent TIQ-induced bradykinesia. Furthermore, the pathological study demonstrated that either (R)-1-MeTIQ or its racemate protected against TIQ induced loss of tyrosine hydroxylase-positive cells of the substantia nigra pars compacta. (R)-1-MeTIQ and its racemate also prevented the TIQ-induced reduction in the levels of dopamine and its metabolites in the striatum. Serotonin and its metabolite were not affected by repeated administration of (RS)-1-MeTIQ or its derivatives. On the other hand, (S)-1-MeTIQ induced moderate but significant bradykinesia, whereas (R)-1-MeTIQ did not induce this behavioral abnormality at all. In addition, (S)-enantiomer prevented the onset of TIQ-induced bradykinesia, though to a lesser extent than did either (R)-enantiomer or its racemate. However, (S)-enantiomer did not prevent the loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta. We concluded that (R)-1-MeTIQ, and not (S)-enantiomer, plays a crucial role in protection against TIQ-induced parkinsonism, a fact which suggests that enantiomeric biochemical events such as 1-MeTIQ biosynthesis may participate in the pathogenesis of Parkinson's disease. PMID- 11604251 TI - Role of pH on the calcium ion dependence of the nitric oxide synthase in the carp brain. AB - The role of pH on the calcium dependence of nitric oxide synthase (NOS) of Cyprinus carpio brain was investigated. This fish is known to survive prolonged periods of hypoxia. Under this condition, cerebral blood flow is no longer regulated by nitric oxide (NO). Nitric oxide synthase activity is pH dependent in the range of pH between 7.4 and 6.2 with a decrease when tissue acidifies. At acidic pH, the dependence of the NOS activity on the free Ca(2+) concentrations changes considerably and shows an EC(50) of 0.13 microM at pH 7.1 and of 5.1 microM at pH 6.2 for the soluble enzyme. The variation in the Ca(2+) dependence with acidification is greater for the soluble than for the particulate enzyme. This may be the main factor protecting sudden NO formation mainly during anoxic normoxic transitions. PMID- 11604250 TI - Prostaglandins may participate in opioidergic and cholinergic control of the diurnal changes of tuberoinfundibular dopaminergic neuronal activity and serum prolactin level in ovariectomized, estrogen-treated rats. AB - The roles of prostaglandins (PGs) involved in opioidergic, cholinergic, and serotonergic regulation of the diurnal changes of tuberoinfundibular dopaminergic (TIDA) neuronal activities were investigated in ovariectomized, estrogen-treated rats. Treatment with naloxone [10 mg/kg, intraperitoneal (i.p.)], atropine (5 mg/kg, i.p.), or ketanserin (10 mg/kg, i.p.) at either 1200 or 1400 h prevented the afternoon decrease of TIDA neuronal activity and the prolactin (PRL) surge. Intracerebroventricular (i.c.v.) injection of PGE(1) (5 microg/3 microl/rat) at 1500 h significantly reversed the effects of naloxone and atropine, but not that of ketanserin. In ovariectomized, estrogen-primed rats pretreated with indomethacin, i.c.v. injection of either nicotine (10 ng/rat) or fentanyl (10 ng/rat) failed to suppress the TIDA neuronal activity and to stimulate the PRL secretion. These data suggest that PG may be involved in opioidergic and cholinergic control of the diurnal changes of TIDA neuronal activity and the PRL secretion in ovariectomized (OVX) + E(2) rats. PMID- 11604253 TI - Gene delivery with synthetic (non viral) carriers. AB - Non-viral gene delivery involving the use of cationic polymer and cationic lipid based carriers still continues to enjoy a high profile due to the safety advantages offered by these systems when compared with viruses. However, there are still problems associated with the use of these agents, notably their comparatively low efficiency and the inability to target gene expression to the area of pathology. On intravenous administration gene expression is found predominantly in the first capillary bed encountered-the lung endothelium. The clinical use of non-viral gene delivery systems in cystic fibrosis or cancer has involved their direct application to the site of pathology due to the targeting difficulties experienced. For gene expression to occur genes must be transported to the interior of the cell nucleus and a number of biological barriers to effective gene delivery have been identified. These may be divided into extracellular such as the targeting barrier mentioned above and intracellular such as the need for endosomal escape after endocytosis and the inefficient trafficking of genes to the nucleus. Targeting ligands have been used with moderate success to overcome the targeting barrier while endosomal escape and nuclear targeting peptides are some of the strategies, which have been employed to overcome the problems of endosomal escape and nuclear trafficking. It is hoped that the next generation of carriers will incorporate mechanisms to overcome these barriers thus improving the efficacy of such materials. PMID- 11604252 TI - The development of sex differences in the locus coeruleus of the rat. AB - Development of sex differences in the locus coeruleus (LC) is investigated. The LC is a sexually dimorphic structure in which the female manifests a larger volume and greater number of neurons than do males. Male and female Wistar rats were sacrificed on prenatal days (E) 16 and 20 and postnatally (P) on days 1, 3, 7, 15, 35, 45, 60, and 90. Male and female rats show a continuous increase in the number of neurons after birth that stops in the males by P45 and in females by P60. These findings point out the existence of different patterns of development in male and female rats and may suggest that sex differences could be established because of the existence of a differential period of neurogenesis in both sexes in the postpubertal period. PMID- 11604254 TI - In vitro binding studies of the peroxisomicine A1-BSA and -HSA interactions. AB - Peroxisomicine A1 (PA1) is a dimeric hydroxyanthracenone isolated from fruits of plants belonging to the genus Karwinskia. Showing selective toxicity between malignant and benign cell lines, it is currently under screening as an antineoplastic agent. Very little is known about its mechanism of action. In the present work the extent of binding of this substance with Bovine Serum Albumin (BSA) and Human Serum Albumin (HSA) at pH 7.2 and 7.4 has been evaluated using the spectrophotometric method. Absorbance of PA1 was altered by the presence of albumin and this property was used to generate binding isotherms. The investigation was carried out at four different temperatures. The data were analyzed by assuming two types of binding sites. Results indicated that PA1 binds to both albumins at physiological pH, which is reflected by the affinity constants of the order of 10(5). There are two types of binding sites in the albumin for PA1; with the electrostatic forces being discarded, the hydrophobic and hydrogen bond are more probable. Binding with HSA is stronger than with BSA. PMID- 11604255 TI - In situ gelling xyloglucan formulations for sustained release ocular delivery of pilocarpine hydrochloride. AB - Thermoreversible gels formed in situ by aqueous solutions of an enzyme-degraded xyloglucan polysaccharide were evaluated as sustained release vehicles for the ocular delivery of pilocarpine hydrochloride. In vitro release of pilocarpine from gels formed by warming xyloglucan sols (1.0, 1.5 and 2.0% w/w) to 34 degrees C followed root-time kinetics over a period of 6 h. The miotic responses in rabbit following administration of xyloglucan sols were compared with those from in situ gelling Pluronic F127 sols and from an aqueous buffer solution containing the same drug concentration. Sustained release of pilocarpine was observed with all gels, the duration of miotic response increasing with increase of xyloglucan concentration. The degree of enhancement of miotic response following sustained release of pilocarpine from the 1.5% w/w xyloglucan gel was similar to that from a 25% w/w Pluronic F127 gel. PMID- 11604256 TI - Effect of passive and iontophoretic skin pretreatments with terpenes on the in vitro skin transport of piroxicam. AB - The enhancing effect of several terpenes (thymol, menthone and 1,8-cineole) in the percutaneous permeation of piroxicam (Px), either passive or iontophoretically, was investigated. These terpenes were applied, on the skin membrane, as a passive and iontophoretic skin pretreatment. Px was delivered from carbopol gels containing hydroxypropyl-beta-cyclodextrin (2% w/w Px). An increase in Px flux values, both passive and iontophoretic after skin pretreatment with 5% terpenes/50% EtOH, was found to be in the following order: thymol>menthone>1,8 cineole. Iontophoretic skin pretreatment with terpenes produced a slight increase in the passive flux of Px, in comparison with the passive skin pretreatment. This result indicated that iontophoresis could modify the skin morphology and consequently, increase the passive transport of Px. However, when Px was transported iontophoretically, passive skin pretreatment with terpenes, produced higher flux values than iontophoretic skin pretreatment. These results could be explained by the fact that with the iontophoretic pretreatment, terpenes could penetrate into the skin and limitate the movement of the ionized species, across the skin, during the iontophoretic experiments. The amount of Px retained in the skin after all experiments was related to flux values across skin. PMID- 11604257 TI - Effects of cysteine on the pharmacokinetics of intravenous phenytoin in rats with protein-calorie malnutrition. AB - The effects of cysteine on the pharmacokinetics of phenytoin and one of its metabolites, 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) were investigated after intravenous administration of phenytoin, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (protein-calorie malnutrition, 4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily starting from the fourth week). In rats with PCM and PCMC, the phenytoin hydroxylation (to form pHPPH) activities were significantly smaller (164, 103 and 95.3 pmol/min per mg protein for the control rats, and rats with PCM and PCMC, respectively) than that in control rats. In rats with PCMC, the intrinsic clearance of phenytoin, CL(int) was significantly slower than those in control rats and rats with PCM (0.175, 0.131 and 0.044 ml/min). The above data suggested that the formation of pHPPH could be reduced in rats with PCM and PCMC. This was supported by significantly smaller 24-h urinary excretion of pHPPH (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) in rats with PCM and PCMC than that in control rats. In rats with PCM, the maximum velocity (0.344, 0.203 and 0.196 microg/min), apparent volume of distribution in central compartment (44.4, 65.4 and 72.2 ml/kg) of phenytoin, and total area under the plasma concentration-time curve from time zero to time infinity (609, 714 and 1210 microg min/ml), renal clearance (20.5, 13.4 and 4.67 ml/min per kg) and 24-h urinary excretion (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) of pHPPH were not returned to control levels by cysteine supplementation (rats with PCMC). This could be mainly due to the fact that the phenytoin hydroxylation activity in rats with PCMC was not returned to control level. PMID- 11604258 TI - The effect of pH and concentration upon aggregation transitions in aqueous solutions of poloxamine T701. AB - Thermally induced aggregation transitions have been investigated for aqueous solutions of the poloxamine block copolymer T701 (OE(4)OP(13))(2)NCH(2)CH(2)N(OP(13)OE(4))(2)-using differential scanning calorimetry. The calorimetric signals obtained were fitted to a mass action model description of aggregation using a previously reported analytical procedure (Patterson et al., Langmuir 13 (1997) 2219). The presence of a central ethylene diamine moiety in the molecular structure renders the T701 molecule basic; this was confirmed and measured by acid/base titration. Basicity is shown to have an important impact upon aggregation. At low pH (2.5), the poloxamine exists in its protonated form and the bulk solution proton concentration is sufficient to suppress de-protonation, aggregation-as a consequence-is shifted to a higher temperature range. Any increase in pH reduces the temperature range over which aggregation occurs. The derived experimental calorimetric parameters, obtained from model fitting procedures, can be used to compute the fraction of poloxamine existing in an aggregated form, at any particular temperature. The data sets obtained were interpolated to show that at human body temperature (310.6 K) the fraction of poloxamine found in its aggregated form is zero at a pH of 2.5. However at a pH of 6.8, the percentage aggregation increases to about 85%. These aggregation characteristics of T701 have important implications for the design of drug delivery systems, which incorporate poloxamines. PMID- 11604259 TI - Progesterone freeze-dried systems in sublingual dosage form. AB - Various polymer matrices were tested to enhance progesterone bioavailability as part of an emergency therapy. Among the different polymers used, i.e. poly(N vinylpyrrolidone) (PVP), poly(ethylene oxide) (PEO), Dextran T70 and partially saponified poly(methyl glyoxylate) (PMGz), the latter gives the fastest solubilization rate. The best results were obtained with the lyophilized dosage form instead of a simple mixture of the drug within the polymer matrix. A nearly instantaneous solubilization was observed with PMGz copolymers bearing 10-40% of carboxylic groups and containing up to 20% of the drug. The instantaneous solubilization of the PMGz matrix is due to the hydrophilic moieties, and the presence of hydrophobic zones in PMGz promotes good affinity with the drug and optimal dispersion into the matrix. PMID- 11604261 TI - UV-spectrophotometry study of membrane transport processes with a novel diffusion cell. AB - A novel diffusion cell has been constructed which allows study of membrane diffusion processes without the need for sampling of the receiver compartment, that is highly sensitive and, being based around a diode array spectrophotometer also allows for continuous, real-time recording of multi-species concentration changes in the receiving compartment. The system is controlled to operate isothermally (via a Peltier control system) at temperatures between 15 and 85 degrees C. To examine the performance of this novel design, the transfer of tetracaine from a preparation in PEG 400 (20% tetracaine in PEG 400) has been studied. The results have been used to determine flux, lag time and related parameters. The performance of the novel cell is compared with results from traditional Franz cell diffusion studies. PMID- 11604260 TI - Potency of select statin drugs in a new mouse model of hyperlipidemia and atherosclerosis. AB - Poloxamer-407 (P-407) is a nonionic surfactant that induces atheroma formation in the aortas of C57BL/6 mice with long-term (14 weeks) administration. The objectives of the present study were to determine the mechanism(s) responsible for the induction of hypercholesterolemia as well as to determine whether this animal model may be of potential use in rank ordering the efficacy (lipid lowering) of various statin drugs. The effect of long-term (16 weeks) administration of P-407 on the catalytic activities of rate-limiting enzymes of cholesterol biosynthesis [HMG-CoA reductase (HMGR)] and catabolism [microsomal cholesterol 7alpha-hydroxylase (C7alphaH) and mitochondrial sterol 27 hydroxylase (S27H)] was assessed in C57BL/6 mice. Effects of P-407 on these enzymes were compared in mice fed an atheroma-inducing diet (high-cholesterol, supplemented with cholic acid) and animals maintained on a basal diet and injected with saline (controls) after 16 weeks. The mean value for the activities of C7alphaH in P-407 injected mice was 24.3+/-3.8 pmol min(-1) mg(-1) and was significantly (P<0.05) less than the mean value determined for sham-injected control animals (37.0+/ 14.3 pmol min(-1) mg(-1)). In contrast, the mean values for the catalytic activities of S27H and HMGR did not change with P-407 administration. Neither C7alphaH nor S27H activity in mice fed the high-cholesterol diet differed from values for control animals, whereas the mean HMGR activity was drastically reduced (-94%, P<0.05). The hypercholesterolemic effect of P-407 is not due to altered cholesterol biosynthesis, but is mediated by reduced cholesterol catabolism due to decreased activity of the rate limiting enzyme (C7alphaH) in the classic bile acid synthetic pathway. Plasma triglyceride lowering resulting from the oral administration of equal doses of various statin drugs appeared, in general, to be positively correlated with their relative aqueous solubility and paralleled the efficacy of these agents to lower low-density-lipoprotein associated cholesterol (LDL-C) in humans. The plasma triglyceride lowering effect of the five statin drugs tested produced the following rank order; pravastatin sodium (-44%)>atorvastatin calcium (-36%)>simvastatin (-33%)>lovastatin ( 25%)>fluvastatin sodium (-19%). While reductions in plasma total cholesterol following administration of the statin drugs was not as profound as that observed with triglycerides, the relative rank order or trend was preserved. The percent reduction in plasma triglycerides in the present model appears to be a useful parameter with which to predict the relative reduction in plasma LDL-C expected for these agents in humans. PMID- 11604262 TI - Theoretical considerations on the in vivo intestinal permeability determination by means of the single pass and recirculating techniques. AB - This paper deals with the development of proper mathematical models for the calculation of the in vivo rat intestinal drug permeability resorting to two different kinds of experimental methods: the single pass and the recirculating perfusion techniques. In particular, in the single pass case, attention is focused on the effect of water exchange between the flowing solution and the intestinal wall, as this can sensibly affect the permeability determination. In both the single pass and the recirculating perfusion method, a complete radial mixing of the flowing solution is supposed to hold, so that drug concentration and solution velocity are radius independent. Nevertheless, they depend on the intestinal axial position. Accordingly, two distinct models are built up by resorting to microscopic mass balances. The reasonably good data fitting performed by the recirculating perfusion model ensures that the most important factors affecting the passive drug (Antipyrine) diffusion through a rat intestinal wall are properly accounted for. Moreover, the reliability of the developed models and the experimental tests is proved by the fact that the drug (Antipyrine) permeability determined by means of the two methods is statistically equal. PMID- 11604263 TI - Microencapsulation of dissociable human growth hormone aggregates within poly(D,L lactic-co-glycolic acid) microparticles for sustained release. AB - For the sustained release formulation of recombinant human growth hormone (rhGH), dissociable rhGH aggregates were microencapsulated within poly(D,L-lactic-co glycolic acid) (PLGA) microparticles. rhGH aggregates were first produced by adding a small volume of aqueous rhGH solution into a partially water miscible organic solvent phase (ethyl acetate, EtAc) containing PLGA. These rhGH aggregates were then microencapsulated within PLGA polymer phase by extracting EtAc into an aqueous phase pre-saturated with EtAc. Release profiles of rhGH from these microparticles were greatly affected by changing the volume of incubation medium. The released rhGH species consisted of mostly monomeric form having a correct conformation. This study reveals that sustained rhGH release could be achieved by microencapsulating reversibly dissociable protein aggregates within biodegradable polymers. PMID- 11604264 TI - Interaction of liposome formulations with human skin in vitro. AB - The interaction of liposome formulations consisting of Phospholipon 80 and sphingomyelin with human skin was investigated. These formulations were shown previously to have a composition-dependent effect on the penetration of Heparin into the skin. Fluorescence labelled phosphatidylethanolamine (PE-NBD) was incorporated in the liposomes and the depth in which the fluorescent phospholipid label enters into epidermal membrane and full thickness skin was studied by confocal laser scanning microscopy (CLSM). Confocal sections parallel to the surface of the skin were recorded in heat separated epidermis. An even distribution of phospholipid in the lipid matrix of the stratum corneum surrounding the corneocytes was observed with Phospholipon 80 but not when sphingomyelin was included in the formulation. The addition of Heparin which formed a coating around the liposomes, caused a strong localization of fluorescence within the epidermis. For full thickness skin, mechanical cross sections of skin were made and optical sections were recorded parallel to the plane of cut. Phospholipid penetrated and was distributed fairly homogeneously in the lower dermis layers within 30 min of application regardless of liposome composition and the presence of Heparin. This rather quick penetration process seemed to follow distinct pathways along the epidermis and the upper dermis, notably the hair follicle route. Thus, a strong and in some respects composition dependent interaction of phospholipids with skin is evident. These observations, however, are limited to the level of phospholipid molecules, rather than of entire liposomes interacting with skin. PMID- 11604266 TI - Comparative study of the leachability of di(2-ethylhexyl) phthalate and tri(2 ethylhexyl) trimellitate from haemodialysis tubing. AB - The leachability of both Di(2-ethylhexyl) phthalate (DEHP) and Tri(2-ethylhexyl) trimellitate (TEHTM) or Trioctyl trimellitate (TOTM) from haemodialysis tubing was investigated in 20 patients with chronic renal failure undergoing maintenance haemodialysis. The blood tubing made of common polyvinyl chloride (PVC) plasticized with DEHP (group 1 patients) were replaced with tubing plasticized with TOTM-DEHP (group 2 patients). The patient blood obtained from the inlet and the outlet of the dialyzer was analyzed during a 4 h-dialysis session. Thus, the circulating concentrations of both DEHP and TOTM resulting from the release from dialyzer tubes were estimated using High-performance Liquid chromatograph (HPLC). With the common PVC-DEHP blood tubing, a DEHP quantity of 122.95+/-33.94 mg was extracted from tubing during a single dialysis session (ranging from 55 to 166.21 mg). During the same period, the total amounts of DEHP retained by the patients were 27.30+/-9.22 mg (ranging from 12.50 to 42.72 mg). As for blood tubing plasticized with TOTM-DEHP, 41.80+/-4.47 mg of DEHP and 75.11+/-25.72 mg of TOTM were extracted. During the same period, the amounts of DEHP and TOTM retained by the patients were 3.42+/-1.37 mg and 4.87+/-2.60 mg, respectively. The extraction rate both plasticizers was correlated with serum lipid content (cholesterol+triglyceride) (r(2)=0.75 for DEHP and r(2)=0.64 for TOTM). In the present investigation, less TOTM and DEHP were apparently released from haemodialysis tubing plasticized with TOTM-DEHP than DEHP released from haemodialysis tubing plasticized with DEHP only. TOTM seems to be a superior alternative to DEHP for use in medical devices because of its potential lower leachability. To recommend it as an alternative plasticizer, its possible toxicity towards human body should be investigated before it can be used routinely. However, patients undergoing haemodialysis using tubing plasticized with DEHP only are regularly exposed to non negligible amounts of DEHP. In view of several biological effects previously reported, it is time to reconsider the use of DEHP only as a plasticizer. PMID- 11604265 TI - Comparison of the effect of ultrasound and of chemical enhancers on transdermal permeation of caffeine and morphine through hairless mouse skin in vitro. AB - The effect of ultrasound (US) on permeation of two model drugs, caffeine (CAF) and morphine (MOR), through hairless mouse skin in vitro was compared with that of three chemical enhancers. Low-frequency (40 KHz), low-power (<0.5 W/cm(2)) US was used; the effect of high-frequency US (1.5-3.0 MHz) was also evaluated in the case of CAF. The chemical enhancers, tested in combination with propylene glycol (PG), were benzalkonium chloride (BAC) oleyl alcohol (OA) and alpha-terpineol (TER). The high-frequency US enhancement of CAF transdermal flux was not statistically significant, while low frequency produced a small but significant increase of the enhancement factor. The effect of US on CAF permeation, however, was lower than that produced by chemical enhancers, in particular OA. The effect of low-frequency US on permeation of MOR was significantly greater (about 10 fold) when compared, on the same frequency and intensity basis, with the effect on CAF. The most active chemical enhancer for MOR, OA, had practically the same effect as low-frequency US. Sonicated skin, although showing slight histological changes, recovered its original low permeability characteristics after turning off sonication. Within the tested system, chemical enhancement appears to offer some advantages over low-frequency US. PMID- 11604267 TI - Pharmacokinetics of gacyclidine enantiomers in plasma and spinal cord after single enantiomer administration in rats. AB - The purpose of this study was to determine the pharmacokinetics of gacyclidine, a non-competitive NMDA antagonist, in plasma and spinal cord extracellular fluid (ECF) after IV administration of single enantiomers in rats. After implantation of microdialysis probes in spinal cord, concentrations in plasma and ECF dialysates were determined by a chiral GC/MS assay over 5 h after administration of either (+)-gacyclidine or (-)-gacyclidine (1.25 mg/kg). Plasma protein binding was estimated in vitro by equilibrium dialysis. Plasma concentrations decayed in parallel in a biphasic manner (t(1/2)alpha approximately 9 min; t(1/2)beta approximately 90 min) with no significant difference between the two enantiomers. Clearance of (+)-gacyclidine and (-)-gacyclidine (291 versus 275 ml/min per kg, respectively), volume of distribution (Vdbeta: 38 versus 40 l/kg), and protein binding (90 versus 89%) were not stereoselective. Both gacyclidine enantiomers were quantifiable in spinal cord ECF 10 min after drug administration and their concentrations remained stable over the duration of the experiment in spite of changing blood concentrations. Penetration of the two enantiomers in spinal cord ECF was similar although highly variable between animals. Exposure of spinal cord ECF was comparable for both enantiomers, and not correlated with plasma AUCs. This study showed the absence of any pharmacokinetic difference between the two enantiomers when administered individually, and no enantiomeric inversion. Both gacyclidine enantiomers penetrate rapidly and extensively into spinal cord ECF, and their distribution may involve an active transport system. PMID- 11604268 TI - Citric acid as excipient in multiple-unit enteric-coated tablets for targeting drugs on the colon. AB - Delivery of drugs to the large bowel has been extensively investigated during the last decade. The aim of this study was to investigate whether enteric-coated tablets could be made from enteric-coated matrix granules and drug release targeted to the colon. Whether in vitro drug release rate and in vivo absorption could be delayed by adding citric acid to the granules and/or to the tablet matrix was also studied. Ibuprofen was used as model drug because it is absorbed throughout the gastrointestinal tract. Eudragit S and Aqoat AS-HF were used as enteric polymers. Drug release rates were studied at different pH levels and drug absorption was studied in bioavailability tests. The conclusion was that citric acid retarded in vitro drug release when used in multiple-unit tablets. In vivo absorption of ibuprofen was markedly delayed when citric acid was included in both granules and tablet matrix. Further studies are needed to determine the optimal amount of citric acid in formulations. PMID- 11604269 TI - Improvement of some pharmaceutical properties of DY-9760e by sulfobutyl ether beta-cyclodextrin. AB - The interaction of DY-9760e, a novel cytoprotective agent, with sulfobutyl ether beta-cyclodextrin (SBE-beta-CyD) in phosphate buffered saline (PBS) at various pH and ionic-strengths was studied by spectroscopic methods and the solubility method, and the results were compared with that of 2-hydroxypropyl-beta cyclodextrin (HP-beta-CyD). The circular dichroism (CD) spectroscopic studies suggested that both beta-CyDs form the inclusion complexes with DY-9760e in a molar ratio of 1:1, and the interaction of DY-9760e with SBE-beta-CyD is much stronger than that with HP-beta-CyD at any pH studied, in terms of a synergetic effect of hydrophobic and electrostatic interactions. The different intermolecular interaction between the SBE-and HP-beta-CyD complexes was clearly reflected in the stability constant (K'), e.g. the different dependence of K' value on pH and ionic strength of solutions. 1H- and 13C-NMR studies suggested that HP-beta-CyD interacts preferably with the benzene ring of DY-9760e, whereas SBE-beta-CyD interacts not only with the benzene ring via hydrophobic interaction but also with the piperazine ring of the drug via electrostatic interaction. The solubilizing ability of SBE-beta-CyD against DY-9760e was much greater than that of HP-beta-CyD at any pH studied. Furthermore, SBE-beta-CyD markedly suppressed the photo-degradation of DY-9760e in aqueous solution and reduced the adsorption of DY-9760e from PBS to polyvinyl chloride (PVC) tubes after incubation. The results suggest that SBE-beta-CyD is useful in preparing parenteral solutions of poorly water-soluble drugs with positive charge such as DY-9760e. PMID- 11604270 TI - Dextran-methylprednisolone succinate as a prodrug of methylprednisolone: dose dependent pharmacokinetics in rats. AB - The dose-dependency in the pharmacokinetics of a macromolecular prodrug of methylprednisolone (MP), dextran-methylprednisolone succinate (DMP), was investigated in rats. Single doses (MP equivalent) of 2.5, 5.0, 10, 20, and 30 mg/kg of DMP were administered intravenously to rats (n=5/group), and serial blood samples (0-96 h) and spleen and liver tissues (96 h) were collected. The concentrations of DMP in plasma and spleen were analyzed using a size-exclusion chromatographic method. The concentrations of DMP in the liver samples were determined by an indirect method after sequential hydrolysis by dextranase and esterase enzymes, followed by HPLC analysis of MP. The kinetics of DMP were analyzed by non-compartmental methods. The systemic clearance of DMP decreased approximately 5-fold (from 42.1+/-11.0 to 7.72+/-1.84 ml/h per kg) when the dose was increased from 2.5 to 30 mg/kg. The nonlinearity in the clearance of DMP could be adequately described by a Michaelis-Menten type elimination with a maximum velocity of elimination of 1.72 mg/h per kg and a constant of 24.9 microg/ml. Additionally, the percent of the dose of DMP found at 96 h in the liver and spleen, where the prodrug is sequestered and gradually eliminated, significantly decreased with an increase in the dose. It is concluded that the clearance of DMP in rats is modestly dose-dependent in the dosage range of 2.5-30 mg/kg. PMID- 11604271 TI - Kinetic phenotypic diagnosis of N-acetylation polymorphism in patients based on ratio of urinary metabolites of salicylazosulfapyridine. AB - We found that N-acetylation polymorphism can be evaluated from the disposition kinetics of sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA) and their acetylated metabolites generated by N-acetyltransferase (NAT2) after oral administration of salicylazosulfapyridine (SASP). In 126 Japanese subjects, the homozygote of NAT2*4 was the most frequent (40%), followed by heterozygotes of NAT2*4 and mutant genes (28% NAT2*4/*6A, 15% NAT2*4/*7B, and 2% NAT2*4/*5B). Combinations of mutant genes accounted for 16%. When the relationship between the molar ratio of N-acetyl-SP (Ac-SP)/SP or N-acetyl-5-ASA(Ac-5-ASA)/5-ASA in serum and five genotypes of polymorphic NAT2* was examined in patients who received multiple doses of SASP, the molar ratios of Ac-SP/SP, rather than Ac-5-ASA/5-ASA tended to decrease according to the classification of genotype. We calculated the pharmacokinetic parameters in healthy subjects with various genotypes of polymorphic NAT2* after a single p.o. administration of SASP, according to a model of the SP metabolic pathways. The molar ratios of Ac-SP/SP in serum and urine were simulated using these parameters, and the molar ratio of Ac-SP/SP in urine at 4 days after the first administration could be categorized into ranges that were specific to various NAT2* genotypes. Thus, we were able to predict the N-acetylation polymorphic genotypes of patients by measuring the molar ratio of Ac-SP/SP in urine, after administration of SASP. PMID- 11604272 TI - Processing factors in development of solid solution formulation of itraconazole for enhancement of drug dissolution and bioavailability. AB - This study investigated solid solutions of itraconazole, a water insoluble antifungal, for improved dissolution and improved bioavailability. Influence of processing factors on drug and carrier properties in solid solution and subsequently on drug dissolution behavior was also studied. An optimized solid solution formulation was compared with marketed product in healthy human subjects under fasted and fed conditions for bioequivalency. Polyethylene glycol (PEG) and drug were made into a solid solution at 120 degrees C. The cooled, solid solution was then ground into granules of different sizes. Solid solutions of lower drug concentration dissolved at a faster rate, and drug dissolution improved considerably with increasing molecular weight of PEG. Initial treatment of itraconazole with the wetting agent/cosolvent glycerol prior to making itraconazole into a solid solution improved drug dissolution, and also reduced the PEG amount required to dissolve drug to form solid solution. Addition of a polymer such as HPMC to the solid solution eliminated precipitation of drug following dissolution. As the granule size of the solid solution was reduced, precipitation of drug during dissolution became prominent. Equivalence of two formulations could not be shown for pharmacokinetic parameters C(max) and AUC, under both fasting and fed conditions. PMID- 11604273 TI - Determination of dexamethasone and two excipients (creatinine and propylparaben) in injections by using UV-spectroscopy and multivariate calibrations. AB - The use of multivariate spectrophotometric calibration for the simultaneous determination of dexamethasone and two typical excipients (creatinine and propylparaben) in injections is presented. The resolution of the three-component mixture in a matrix of excipients has been accomplished by using partial least squares (PLS-1). Notwithstanding the elevated degree of spectral overlap, they have been rapidly and simultaneously determined with high accuracy and precision (comparable to the HPLC pharmacopeial method), with no interference, and without resorting to extraction procedures using non-aqueous solvents. A simple and fast method for wavelength selection in the calibration step is used, based on the minimisation of the predicted error sum of squares (PRESS) calculated as a function of a moving spectral window. PMID- 11604274 TI - Physicochemical investigations on microemulsification of eucalyptol and water in presence of polyoxyethylene (4) lauryl ether (Brij-30) and ethanol. AB - The microemulsification of eucalyptol/polyoxyethylene(4)lauryl ether (Brij 30)/ethanol/water has been investigated. The phase behaviours of the mixed system in pseudoternary and tetrahedral representations have been examined to understand the topological nature of the multicomponent mixtures. Phase volumes of the heterogeneous combinations have been estimated to understand the mixing efficacy of the combinations. Shear viscosities of different monophasic compositions have been measured at different shear rates and temperatures, and the activation parameters for the viscous flow have been evaluated. The dimensions of the nanodispersions of w/o and o/w types, their diffusion coefficients and the polydispersity have been determined by the DLS method. The energetics of solubilisation (dissolution) of water in oil+Brij-30+ethanol as well as oil in water+Brij-30+ethanol forming w/o and o/w microemulsions, respectively, have been calorimetrically determined. Considering the phase separation point to be the point of maximum solubility, the energetic parameters (enthalpy, free energy and entropy) of the microemulsification process have been estimated. PMID- 11604276 TI - Scurvy identified in the emergency department: a case report. AB - Scurvy, caused by a lack of Vitamin C in the diet, is thought to occur only sporadically in developed countries. The signs and symptoms are diverse but generally follow a predictable progression most striking for their hemorrhagic component, particularly of the skin, gums, and joints. We report a case of scurvy in an elderly, alcoholic woman. The diagnosis was contemplated based on dermatologic findings and a dietary history. All symptoms resolved within 10 days of oral ascorbic acid supplementation. Patients most at risk for developing scurvy include food faddists, the isolated elderly, and the mentally ill. PMID- 11604275 TI - It is safe to manage selected patients with acute coronary syndromes in unmonitored beds. AB - This prospective, observational study evaluated the safety of the Western Hospital admission protocol for patients with suspected acute coronary syndromes. The study included all patients admitted from the Emergency Department with an admission diagnosis of unstable angina, post infarct angina, atypical chest pain, or chest pain for evaluation. Data collected included demographic data, admission diagnosis, location of admission (bed with or without cardiac monitoring), past medical history and presenting chest pain history to determine Agency for Health Care Policy (AHCPR) and Western Hospital (WH) protocol classifications, cardiac enzyme assays, electrocardiogram analysis, adverse outcomes [death, myocardial infarction (MI), dysrhythmia, acute pulmonary edema, recurrent pain], diagnosis at hospital discharge, and length of stay-(LOS). There were 508 patients with a mean age of 63.7 years enrolled in the study. Three hundred nineteen (62.8%) were admitted to beds without any cardiac monitoring. There was one unexpected death in the unmonitored group, an 85 year-old patient who suffered a presumed dysrhythmia and whom the treating physician had decided was not for resuscitation. Twelve patients suffered nonfatal MI, and none suffered pulmonary edema. All MI patients made an uneventful recovery, and none required thrombolysis. If all patients had been admitted to an area of care based on AHCPR guidelines, an additional 310 admissions to monitored beds would have been required. The results of this study suggest that selected patients with suspected acute coronary syndromes can be safely managed in beds without continuous cardiac monitoring. PMID- 11604277 TI - Abdominal pain in a child after blunt abdominal trauma: an unusual injury. AB - We report a case of perforation of a walled off appendiceal abscess in a 5-year old boy who sustained blunt abdominal trauma. The past medical history was significant only for a 4-day episode of abdominal pain 1 month prior to this presentation. Initial laboratory studies were unremarkable, and radiographic studies showed free fluid in the pelvis with no evidence of solid organ injury, but inflammation of the right colon. The final diagnosis was made at laparotomy. We emphasize this unique presentation and review the literature on traumatic appendicitis in children. PMID- 11604278 TI - Acute myocardial infarction and renal failure following naphtha ingestion. AB - We present a case of a non-Q wave myocardial infarction and acute renal failure following an ingestion of naphtha, a petroleum distillate composed primarily of hydrocarbons. The patient's renal, metabolic, and cardiac status improved over several days with aggressive volume replacement and bicarbonate therapy. Acute cardiotoxic effects of hydrocarbon exposure generally manifest as dysrhythmias, secondary to myocardial sensitization to circulating catecholamines, or, possibly, coronary vasospasm. Ischemia from associated hypotension or direct myocardial toxicity are other potential causes of naphtha-related cardiac injury. PMID- 11604279 TI - A flood-related outbreak of carbon monoxide poisoning--Grand Forks, North Dakota. AB - Post-disaster carbon monoxide (CO) poisoning is a growing problem in the United States. This study describes a documented outbreak of CO poisoning associated with flooding. Health department staff investigated cases of CO poisoning following the severe flood of 1997 in Grand Forks, North Dakota. Thirty-three laboratory-confirmed cases were identified, involving 18 separate incidents. Patients ranged in age from 7 to 67 years, and most were men. One patient lost consciousness and was admitted to the hospital; all others were released after receiving supplemental oxygen. Every incident involved gasoline-powered pressure washers being used in basements. Five incidents among professional cleaners accounted for 16 cases; the remaining incidents involved noncommercial use. Thirty patients, from 15 incidents, reported the basement was ventilated while the pressure washer was in use. CO poisoning must be considered a potential hazard after major floods. PMID- 11604280 TI - Pulmonary embolism with ST segment elevation in leads V1 to V4: case report and review of the literature regarding electrocardiographic changes in acute pulmonary embolism. AB - A 62-year-old man presented to the Emergency Department (ED) after having three short syncopal episodes earlier that day soon after experiencing acute onset of shortness of breath. He had no significant past medical history and was a nonsmoker. Initially in the Emergency Department he was without any complaints, but then became acutely short of breath and hemodynamically unstable and died despite resuscitative efforts. His electrocardiogram showed ST segment elevations in leads V1 to V4, which is consistent with an anteroseptal myocardial infarction. Autopsy revealed that this patient did not have a myocardial infarction, but rather died of a pulmonary embolism (PE). This case demonstrates how a PE can mimic an anteroseptal myocardial infarction on electrocardiogram. This patient's lack of risk factors for PE also makes this case unusual. PMID- 11604281 TI - Electrocardiographic manifestations: pulmonary embolism. AB - The electrocardiographic findings associated with pulmonary embolism have been well described in the medical literature for over 50 years. These abnormalities include changes in rhythm, QRS axis, and morphology, particularly in the QRS and T waves. Such findings may reflect hemodynamic changes, such as right heart strain, as well as myocardial ischemia associated with the disease. Although certain findings may correlate with the severity of pulmonary embolism, the overall utility of the electrocardiogram is limited due to the variable presence, frequency, and transient nature of most of the abnormalities associated with the disease. PMID- 11604282 TI - Wide complex tachycardia. PMID- 11604283 TI - Confined perforation of a post-bulbar duodenal ulcer. PMID- 11604284 TI - A case of pneumocephalus secondary to blunt head trauma. PMID- 11604285 TI - Scimitar syndrome. PMID- 11604286 TI - Carbon monoxide poisoning and gas powered equipment. PMID- 11604287 TI - Mitigating medical maladies in disasters. PMID- 11604288 TI - A case of open-air carbon monoxide poisoning in a 10-year-old boy. PMID- 11604289 TI - Blood pressure reduction and stroke. PMID- 11604291 TI - Central nervous system involvement in childhood brucellosis. PMID- 11604292 TI - Walking and talking victims of strangulation. Is there a new epidemic? A commentary. PMID- 11604293 TI - Survey results of women who have been strangled while in an abusive relationship. AB - Few studies attempt to examine individual methods of domestic abuse. The objectives of this study are to evaluate strangulation as a method of domestic violence abuse: to determine the incidence of strangulation occurrence within the cycle of domestic violence, the subjective medical symptoms experienced by victims of intimate partner strangulation, and the elective utilization of health care following a strangulation incident. Sixty-two women were surveyed at two women's shelters in Dallas, Texas and Los Angeles, California and the Parkland Health & Hospital (PHHS) Violence Intervention Prevention (VIP) Center in Dallas, Texas. Each patient was individually interviewed and verbal responses were recorded. Statistics were performed using the SPSS program. Of the 62 surveyed, 42 (68%) had been strangled by their intimate partner who was a husband (23, 55%), boyfriend (13, 31%), or fiance (2, 5%), by a mother, stranger, or friend (1 each). Strangulation, as a method of domestic violence, is quite common in women seeking medical help or shelter in a large urban city. This study suggests that strangulation occurs late in the abusive relationship; thus, women presenting with complaints consistent with strangulation probably represent women at higher risk for major morbidity or mortality. PMID- 11604294 TI - A review of 300 attempted strangulation cases. Part I: criminal legal issues. AB - Three hundred strangulation cases, submitted for misdemeanor prosecution to the San Diego City Attorney's Office, were evaluated to determine the signs and symptoms of attempted strangulation that could be used to corroborate the victim's allegation of being "choked" for purposes of prosecution. The study reveals that a lack of training may have caused police and prosecutors to overlook symptoms of strangulation or to rely too heavily on the visible signs of strangulation. Because most victims of strangulation had no visible injuries or their injuries were too minor to photograph, opportunities for higher level criminal prosecution were missed. PMID- 11604295 TI - A review of 300 attempted strangulation cases Part II: clinical evaluation of the surviving victim. AB - Medical literature describing victims who survive strangulation is scant. The majority of articles on strangulation are found in the forensic literature, describing the post-mortem findings on autopsy. This article presents a suggested protocol for the evaluation and treatment of the surviving victim of strangulation, based upon a review of the available literature. It also corroborates the findings of Strack et al., in the study by the San Diego City Attorney's Office, described in Part I of this series. PMID- 11604296 TI - A review of 300 attempted strangulation cases Part III: injuries in fatal cases. AB - A review of 300 cases of alleged strangulation assault, submitted for misdemeanor prosecution by the San Diego City Attorney's Office, led to a search for medical evidence that would be useful to prosecute these cases (see Strack et al. in this issue of the Journal). The injuries identified in these non-fatal cases are similar to injuries found in fatal domestic violence strangulation assaults. This article reviews the injuries recognizable at autopsy in cases of strangulation in domestic violence victims. PMID- 11604297 TI - Frequency and relationship of reported symptomology in victims of intimate partner violence: the effect of multiple strangulation attacks. AB - The objective of this study is to examine the correlation between the number of times a victim of intimate partner violence (IPV) has been strangled and symptom development subsequent to the attacks. One hundred and one female subjects responded to a series of questions regarding the history and characteristics of the strangulation and the development of specific medical symptoms. Multiple strangulation victims, individuals who had experienced more than one strangulation attack, on separate occasions, by the same abuser, reported neck and throat injuries, neurologic disorders, and psychological disorders with increased frequency. Despite the increased frequency of symptoms, only 39% of the multiple strangulation victims sought medical care. These observations strongly support the need for health care professionals to inquire about the incidence of strangulation, examine the victim closely for evidence of injuries caused by the attacks, and recommend immediate care in anticipation of the potentially long term medical needs. PMID- 11604300 TI - Bullous disorders: from histology to molecular biology. PMID- 11604301 TI - Adhesion molecules in keratinocyte. PMID- 11604302 TI - Molecular organization of the cutaneous basement membrane zone. PMID- 11604304 TI - Immune functions of the skin. PMID- 11604305 TI - T cell costimulatory blockade as a novel immune intervention in autoimmune diseases. PMID- 11604303 TI - Defensins and complement systems from the perspective of skin immunity and autoimmunity. PMID- 11604306 TI - Autoreactive T cells as potential targets for immunotherapy of autoimmune bullous skin diseases. PMID- 11604307 TI - A stepwise approach to the diagnosis of blisters in the clinic(1). PMID- 11604308 TI - Direct immunofluorescence microscopy in the diagnosis of autoimmune bullous dermatoses. PMID- 11604309 TI - Indirect immunofluorescence microscopy for the serological diagnosis of autoimmune blistering skin diseases: a review. PMID- 11604310 TI - Immunoblot assay in differential diagnosis of autoimmune blistering skin diseases. PMID- 11604311 TI - Electron microscopy in diagnosis of autoimmune bullous disorders. PMID- 11604312 TI - Immunogold electron microscopy using skin in Michel's medium intended for immunofluorescence analysis. PMID- 11604317 TI - Vectors to express foreign genes and techniques to monitor gene expression in Pseudomonads. AB - Improved tools for Pseudomonas research include small, broad-host-range vectors that allow regulated expression from the lac operon and T7 promoters whose biology is well understood and adaptable to many bacteria. To facilitate studies on gene regulation, tracking and monitoring of bacteria in diverse environments, and the construction of biosensors, various reporter genes with versatile assay formats have been developed that can be delivered on plasmid, transposon and integration-proficient vectors. PMID- 11604318 TI - Expression systems for use in actinomycetes and related organisms. AB - There have been significant advances in genetic and molecular approaches to understanding the physiology of organisms belonging to the genera Mycobacterium, Corynebacterium, Nocardia and Streptomyces. This review discusses recent advances in heterologous protein expression in members of the actinomycete group, including codon usage, post-translational modification and inducible gene expression. PMID- 11604319 TI - Transgenic plants as protein factories. AB - Transgenic plants are showing considerable potential for the economic production of proteins, with a few already being marketed. Recent clinical trials of pharmaceuticals produced from transgenic plants are encouraging, with plant glycans showing reassuringly poor immunogenicity. Our increasing understanding of protein targeting and accumulation should further improve the potential of this new technology. PMID- 11604320 TI - Gene expression monitoring in soils by mRNA analysis and gene lux fusions. AB - Two methods recently developed to monitor the gene expression of microbial communities in soil are the extraction and detection of messenger RNA from soil microorganisms and the construction and use of lux-based bioreporter strains. The goal of these approaches is to assess microbial activity in natural and impacted soil environments. PMID- 11604321 TI - Retargeting gene delivery using surface-engineered retroviral vector particles. AB - Retroviral vectors with the capacity to deliver transgenes to specific tissues are expected to be of great value for various gene transfer applications in vivo. Initial attempts to modify vector host-range by the insertion of ligands on their surface glycoproteins have frequently failed, essentially owing to the impairment of the fusogenicity of the vector particles bound to the targeted cell-surface molecules. Several strategies aimed to recover the fusogenic activity of surface engineered vector particles have recently been explored and have given rise to novel concepts in the field. PMID- 11604322 TI - Transfer of eukaryotic expression plasmids to mammalian host cells by bacterial carriers. AB - The concept of transkingom transfer of DNA from bacteria to other organisms has recently been extended to include eukaryotic host cells. Intracellular bacteria have been shown to transfer eukaryotic expression plasmids to mammalian host cells in vitro and in vivo. This can be used to induce immune responses towards protein antigens encoded by the plasmid, to complement genetic defects or even to direct the production of proteins in appropriate organs. The ease of generating such vehicles makes this a highly attractive area for further research. PMID- 11604323 TI - Coping with kinetic and thermodynamic barriers: RMCE, an efficient strategy for the targeted integration of transgenes. AB - Site-specific recombinases have become powerful tools for the targeted integration of transgenes into defined chromosomal loci. They have been successfully used both to achieve predictable gene expression in cell culture and for the systematic creation of transgenic animals. A recent improvement of this method, the recombinase-mediated cassette exchange procedure (RMCE), permits expression in the absence of any co-expressed selection marker gene. PMID- 11604325 TI - General introduction to the importance of genomics in food biotechnology and nutrition. AB - Knowledge of the human genome and other genomes, the selection of health beneficial components, information and communication technology (ICT)-driven plant cultivation and small-scale processes will together change the agrofoods business from a rather low-tech to a high-tech (functional) foods business. ICT will provide consumers with information that in combination with their private genetic passport may be used to select those functional foods that are most beneficial for them. PMID- 11604327 TI - Advances in genomics for microbial food fermentations and safety. AB - The exponentially growing collection of genomic sequence information, the high throughput analysis of expression products, and the ability to order this information using advanced bioinformatics are expected to affect biotechnology and life sciences in a profound and unprecedented way. These developments offer many possibilities to improve the functionality of fermentations by food-grade microorganisms and to increase the microbial safety of foods. It will be necessary to combine functional studies with comparative genomics approaches to provide effective strategies for improving the functionality and safety of foods. PMID- 11604326 TI - Plant-based raw material: improved food quality for better nutrition via plant genomics. AB - Plants form the basis of the human food chain. Characteristics of plants are therefore crucial to the quantity and quality of human food. In this review, it is discussed how technological developments in the area of plant genomics and plant genetics help to mobilise the potential of plants to improve the quality of life of the rapidly growing world population. PMID- 11604328 TI - Food processing: probiotic microorganisms for beneficial foods. AB - Human studies have demonstrated that selected probiotic strains can influence the composition of the intestinal microflora and modulate the host immune system. Considerable promise was also demonstrated for the application of probiotics in human disease. However, the extension of probiotic applications demands increasing scientific attention to their functionality and the identification of molecular structures. PMID- 11604329 TI - Mutagenesis in the post genomics era: tools for generating insertional mutations in the lactic acid bacteria. AB - The increasing availability of whole genome sequences has increased the demand for effective tools to generate insertional mutations in the lactic acid bacteria (LAB). Several novel approaches, such as shuttle-, transposome- and intron-based mutagenesis methods, are possible additions to the existing repertoire of transposon- and recombination-based tools available for mutagenesis of LAB. PMID- 11604330 TI - Edible genetically modified microorganisms and plants for improved health. AB - The development of new strategies for the delivery of vaccine antigens or immune modulators to the mucosal tissue includes innovative approaches such as the use of genetically modified food microorganisms and plants. Even though the 'proof-of concept' has recently been established for these two systems, key questions mainly related to efficacy and risk of breaking oral tolerance remain to be critically addressed in the immediate future. PMID- 11604331 TI - Genomics: food and nutrition. AB - Nutrition is traditionally a multidisciplinary field applying principles of molecular biochemistry and statistical epidemiology to integrative metabolism and population health. Genomics, with its global perspective, is now reinventing the future of human metabolic health. Creative experimental designs are addressing metabolic questions in nutrition ranging from energy regulation to aging, and from mechanisms of absorption to the interspecies molecular crosstalk of bacteria and human cells within the intestine. PMID- 11604332 TI - Sutureless vascular anastomosis: the VCS clip. AB - Non-penetrating, arcuate-legged clips facilitate vascular reconstructions and significantly reduce the incidence of anastomotic neointimal hyperplasia. Though originally developed as a microvascular-approximating instrument, by far the largest application has been for hemodialysis vascular access. Long-term studies comparing suture to clip for access creation have demonstrated the clear technical and biological superiority of the clip for this procedure. This "sutureless" vascular anastomotic technique is more demanding than conventional suturing, requiring precise vessel preparation and supervised training. PMID- 11604333 TI - The utility of the VCS clip for creation of vascular access for hemodialysis: long-term results and intraoperative benefits. AB - The purpose of this study was to compare the effectiveness of the VCS vascular clip approximating system for the creation of hemodialysis access fistulas. 173 new vascular accesses were created, 92 prosthetic grafts and 81 autologous fistulas over a 40-month period. 50 sutured and 42 clipped fistulas comprised the prosthetic graft series, and 33 sutured and 48 clipped cases the autologous series. Risk factors associated with access patency were correlated and the primary patencies compared in the suture versus clipped group. A significant improvement in primary patency was noted for the clipped prosthetic group at all time points studied, with a positive trend also noted for clipped autologous fistulae. CONCLUSIONS: The vascular clipping system (the VCS system) provides both long-term and immediate advantages for vascular access construction. Clips have been used successfully to treat seven consecutive patients with upper extremity arterial steal syndrome without the technical difficulties associated with traditional methods of repair. PMID- 11604334 TI - An alternative system for cerebrovascular reconstructions: non-penetrating arcuate-legged clips. AB - Non-penetrating, arcuate-legged titanium clips (VCS) have been utilized successfully over the past five years for a variety of cerebrovascular reconstructions. These applications, including both micro and macrovascular reconstructions, their clinical outcomes and technical considerations are described. Applications include patch angioplasty of cervical carotid endarterectomies, superficial temporal to middle cerebral artery 'bypass' procedures, Takayasu's arteritis and cavernous carotid reconstructions. The non penetrating clip has proven to be a safe and reliable alternative to suture for these demanding reconstructions. Clips provide the advantages of improved anastomotic compliance, reduced operative time, and reduced incidence of post operative anastomotic intimal hyperplasia and stenosis. Clip related pitfalls are discussed with recommendations regarding usage. PMID- 11604335 TI - Impact of nonpenetrating clips on intimal hyperplasia of vascular anastomoses. AB - Non-penetrating, arcuate-legged titanium clips create an interrupted, non penetrated, yet compliant vascular anastomoses that is associated with significantly reduced anastomotic neointimal hyperplasia. Recent experimental and clinical studies provide evidence that the non-suture alternative changes the biology of vessel-to-vessel and graft-to-vessel connections that reduces the stimulus for hyperplasia at a number of critical points in the response to injury schema. The compliant, "blood-tight" characteristics of clipped vascular reconstructions are associated with no endothelial injury or intraluminal foreign body, minimal platelet aggregation and laminal flow. Clinical applications including vascular access, femoropopliteal bypass, and closure of carotid endarterectomies are remarkable for the absence of restenosis and preserved anastomotic patency. PMID- 11604336 TI - Femoropopliteal and distal bypasses with arterial anastomsis performed by titanium clips. PMID- 11604337 TI - Reconstructive surgery for carotid artery occlusive disease in the elderly--a high risk operation? AB - Patients over 80 yr of age may require carotid surgery for symptomatic or critical asymptomatic carotid artery occlusive disease.A total of 2262 operations were performed between 1990 and 1999; 76 (3.4%) were carotid reconstructions in 70 patients over 80 yr of age. Twenty patients (26%) presented with asymptomatic critical stenosis. Transient ischemic symptoms were the reason for presentation in 35 patients (46%). Progressive stroke was documented in two patients (3%) and a stroke with persisting neurological deficit was demonstrated in 19 cases (25%). Coronary artery disease was present in 47 patients (38%) and arterial hypertension in 55 (72%). Fifty-nine patients (84%) were classified as ASA group 3. Seventy-one thromboendarterectomies of the carotid bifurcation with vein-patch closure were performed. Five patients had other types of reconstruction. Simultaneous operations (aorto-coronary vein-bypass, aortic interposition graft etc.) were performed in nine patients. Postoperative complications occurred in three patients. One had a transient neurological deficit and another a lethal stroke; the third patient died from myocardial infarction. The in-hospital mortality was 2.9%, which was not significantly higher than the results of the other 2186 reconstructions (1.5%). Surgery for carotid artery occlusive disease can be safely performed in selected patients of more than 80 yr of age. PMID- 11604338 TI - Endovascular AAA repair in patients with renal insufficiency: strategies for reducing adverse renal events. AB - Vascular imaging, usually employing nephrotoxic contrast agents is relied upon for all aspects of endovascular AAA repair causing some to consider renal insufficiency a relative contraindication. We sought to determine if endovascular AAA evaluation and repair could be successfully accomplished by minimally or non nephrotoxic modalities. Records and results for 98 consecutive patients undergoing endovascular AAA repair were reviewed. Patients requiring dialysis preoperatively were excluded (N=3). The average volume of iodinated contrast agent employed for intraoperative imaging was 152 cc (35-420 cc). Twenty patients (20%) had baseline renal insufficiency (serum creatinine > or =1.3 mg/dl). A rise in serum creatinine above baseline was observed in 23 (24%) patients following repair; for 15 (16%) this was permanent. Creatinine rise occurred in patients with both normal (15) and abnormal (8) baseline values (P=0.09). Rise in creatinine was independent of contrast volume employed and of the use of infrarenal vs suprarenal device fixation (P>0.05). Two (2%) patients required permanent dialysis, one of which had a normal baseline creatinine and unclear etiology for renal failure, the other had a baseline creatinine of 2 and required device placement over an accessory renal artery. Strategies to minimize the use of nephrotoxic contrast for patients with renal insufficiency included the use of MRA, rather than contrast-CT for pre and postoperative imaging (7, 35%) and use of Gadolinium rather than iodinated contrast for performance of intraoperative arteriography (5, 25%). Endovascular grafts were successfully designed and implanted based upon MRA as the sole preoperative imaging modality in every case in which it was attempted (7). Mortality was not significantly different between those with and without abnormal baseline renal function (P>0.05). Adverse events (access failures, arterial injuries, blood loss, endoleaks) were not significantly correlated with baseline renal insufficiency, rise in creatinine from baseline, use of MRA or intraoperative Gadolinium angiography (P>0.05).Pre- and postoperative evaluation and performance of endovascular AAA repair can be accomplished in patients with renal insufficiency without increasing the rate of mortality or adverse events employing a strategy which minimizes the use of nephrotoxic contrast agents, relying upon Gadolinium arteriography and MRA. Endovascular grafts can be successfully planned and followed employing MRA as the sole imaging modality. PMID- 11604339 TI - Wet gangrene in hemodialysis patients with calciphylaxisis is associated with a poor prognosis. AB - Calciphylaxis is a rare syndrome characterized by progressive vascular calcification and ischemic tissue loss in patients with chronic renal failure. We report our five-year experience with five patients who developed foot gangrene due to calciphylaxis. All five patients had characteristic clinical, laboratory, and radiologic findings of the disorder, but no diagnostic variable was uniformly present. All five had progressed to advanced gangrene at the time of surgical consultation. Despite aggressive local attempts to control infection, all five patients died of septic complications. Parathyroidectomy was performed in three patients but did not alter the course in any case. This small experience suggests that the outcome of foot gangrene associated with calciphylaxis is predicated on the degree of tissue loss. Aggressive local wound care does not appear to be adequate to control infection in patients who have already developed gangrene. Although parathyroidectomy may have important long-term advantages in patients with calciphylaxis, it does not appear to affect outcome in these advanced cases. PMID- 11604340 TI - Vena caval filter placement by intravascular ultrasound. AB - OBJECTIVE: Placement of vena caval filters under fluoroscopic surveillance incurs significant expense and potential risks associated with the transportation of critically ill patients. Intravascular ultrasound (IVUS) allows direct intraluminal visualization of the vena cava and the renal veins. The purpose of this study is to evaluate the accuracy of vena caval filter placement under IVUS in an animal model. METHODS: Fifteen Simon-Nitinol venal cava filters (C.R. Bard, Inc., Covington, GA) were placed under IVUS guidance into four anesthetized sheep. Twelve were placed transfemorally, and three were placed transjugularly. Accuracy of placement was confirmed with fluoroscopy by measurement between the filter tip and the targeted side branch. RESULTS: The vena caval filters placed femorally averaged 0.33+/-0.42 cm distance from the target vein side branch. Jugular approach filter placement was less accurate. Although two out of three filters placed from the jugular vein were correctly positioned, the distance from the target vein side branch was much greater averaging 2.5+/-1.04 cm. CONCLUSION: Femoral placement of vena caval filters under IVUS is extremely accurate. The transjugular route, however, was technically challenging and standard fluoroscopic vena caval filter placement appears to be more appropriate. Our success with the femoral approach merits further clinical investigation in the use of IVUS for critically ill patients that would benefit from bedside vena caval filter placement. PMID- 11604341 TI - The impact of ischaemic preconditioning on spinal cord blood flow and paraplegia. AB - PURPOSE: We investigated the effect of ischaemic preconditioning (IP) on ischaemic spinal cord injury in a rabbit model. METHODS: Fourteen rabbits were divided into IP and control groups of seven rabbits each. We repeated 3-min clamping of the infrarenal abdominal aorta and 3-min reperfusion twice (preconditioning), followed by 15 min clamping in the IP group. In the control group, the aorta was clamped for 15 min without preconditioning. Lumbar cord blood flow and systemic blood pressure were measured until 3 h of reperfusion. Another 14 rabbits underwent the same procedures with or without IP and neurologic status was assessed on the second postoperative day. RESULTS: The percent change in lumbar cord blood flow after reperfusion was significantly greater (P=0.013) in the IP group despite lower mean blood pressure. There was no significant difference in overall neurologic status (P=0.461) but the incidence of spastic paraplegia in the IP group was lower (14%, 1/7) than that of control group (43%, 3/7). CONCLUSION: IP increased postischaemic lumbar cord blood flow and contributed to lower incidence of spastic paraplegia. PMID- 11604342 TI - The Hemashield Woven prosthesis in the thoracic aorta: a prospective computer tomography follow-up study. AB - BACKGROUND: Dacron prostheses in humans have been documented to present long-term fiber alterations, that may account for late graft dilatation. Late dilatation has been documented mainly in knitted prostheses, implanted in the abdominal and thoracic aorta. Dilatation of the collagen-impregnated Hemashield Woven prosthesis has not been studied prospectively in the thoracic aorta. METHODS: Twenty patients were prospectively included. The intraoperative performance of the graft and mid-term clinical behaviour were studied. The graft distensibility was evaluated by postoperative, 1 and 3 yr computed tomographic diameter follow up. RESULTS: There were no hospital deaths. Two graft-unrelated deaths occurred at 3 yr. The graft performance was excellent or good for most aspects. No significant changes in CT diameter occurred throughout the 3 yr follow-up. CONCLUSION: The collagen-impregnated Hemashield Woven prosthesis is considered safe in replacements of the thoracic aorta. Future evaluation should focus on the very long-term behaviour in young adults. PMID- 11604343 TI - Different behavior of sequential versus single left internal mammary artery to left anterior descending area grafts(1). AB - To study echo Doppler characteristics of sequential versus single left internal mammary artery (LIMA) to left anterior descending (LAD) area grafts transthoracic echo Doppler at the LIMA origin and angiography were performed pre- and postoperatively. In 17 patients single LIMA to LAD (group I) and in 45 patients sequential LIMA to LAD area (group II) bypass grafting was performed. All patients show an early postoperative shift towards diastolic coronary Doppler velocity spectra. Only group II shows a further significant late increase in diastolic, velocity time integral and some systolic echo Doppler parameters at rest. Diastolic peak and diastolic as well as total mean and velocity time integral maximal values are significantly higher in group II in late postoperative hyperemic response. Preoperative and late control angiography showed no significant differences in overall grading of native LAD stenosis between both groups. The large coronary reserve in LIMA sequential grafts may contribute to an improved long-term patency. PMID- 11604344 TI - Effect of retroviral transduction of canine microvascular endothelial cells on beta(1) integrin subunit expression and cell retention to PTFE grafts. AB - This study evaluated the effect of retroviral transduction on canine microvascular endothelial cell (CMVEC) detachment from fibrin glue coated expanded polytetrafluoroethylene (ePTFE) graft material. CMVEC were isolated from adipose tissue by fluorescent activated cell sorting (FACS). Three treatment groups were evaluated: G-I, transduced CMVEC, selected in antibiotic G418 for 10 days (n=5); G-II, CMVEC selected in G418 and recovered from selection for 4 days (n=5); and G-III, control group of naive CMVEC (n=6). (3)H-thymidine labeled endothelial cells were seeded on fibrin glue coated four-mm diameter PTFE. Grafts were exposed to physiologic shear stresses of 16 dyn/cm(2). Cell detachment was determined by (3)H-thymidine counts in the circuit effluent. beta(1) integrin subunit expression was measured by flow cytometry. After 2 hours of flow exposure, G-I and G-II demonstrated significantly greater cell detachment rates compared with the control seeded grafts. Median peak channel beta(1) integrin subunit value for G-III CMVEC was 2311+/-481.7 vs. 31.5+/-4.51 and 26.3+/-2.0 in the transduced cell groups (p=0.00043). Low beta(1) integrin expression correlated with flow induced high detachment rates of retrovirally-transduced CMVEC. PMID- 11604345 TI - Is deep hypothermia necessary for unilateral antegrade cerebral perfusion during circulatory arrest? A magnetic resonance study in a pig model. AB - OBJECTIVE: Localized (31)P magnetic resonance spectroscopy (MRS) was used to investigate whether unilateral antegrade cerebral perfusion (U-ACP) could maintain normal energy metabolism and intracellular pH (pHi) in both hemispheres of the brain during deep (15 degrees C) and moderate (28 degrees C) hypothermic circulatory arrest (HCA). METHODS: Eleven pigs were exposed to 120 min of U-ACP during HCA at 15 degrees C (group I, n=6) or 28 degrees C (group II, n=5), followed by 60 min of cardiopulmonary bypass (CPB) at 37 degrees C. Localized (31)P MR spectra were acquired every 30 min. Histopathology was performed at the completion of each experiment. RESULTS: MR recorded no changes in energy metabolites (phosphocreatine and ATP), or pHi during U-ACP in either group, and no significant differences were found in any of the energy metabolites or pHi between the left and right hemispheres. Histopathology showed no significant morphological changes in the neurons. CONCLUSIONS: During either deep or moderate HCA, unilateral ACP through the right axillary artery prevents ischemic events in both hemispheres of normal pig brains. Deep hypothermia may not be necessary when using U-ACP. PMID- 11604346 TI - Beating heart myocardial revascularization on extracorporeal circulation in patients with end-stage coronary artery disease. AB - OBJECTIVES: To evaluate in a cohort of ESCAD patients (pts) the effects of on pump/beating-heart versus conventional CABG in terms of early and mid-term survival and morbidity and LV function improvement. METHODS: Between January 1993 and December 2000, 78 (Group I) ESCAD pts underwent on-pump/beating-heart surgery. Mean age in Group I was 66.2+/-6 (58-79), NYHA and CCS class were 3.2+/ 0.6 and 3.3+/-0.4 respectively, Myocardial viability index 0.69+/-0.1 (%), LVEF (%) 24.8+/-4, LVEDP (mmHg) 28.1+/-5.8 and LVEDD(mm) 69.5+/-6. Group II consisted in 78 ESCAD patients undergoing conventional CABG selected in a randomized fashion from an age, sex, and LVEF corrected group of patients. Mean age in Group II was 65.7+/-5 (57-78), NYHA 3.1+/-0.7, CCS 3.4+/-0.8, LVEF(%) 25+/-5, LVEDP(mmHg) 27.9+/-4.4 and LVEDD(mm) 69.2+/-7.2. RESULTS: Postoperatively, 5(7.7%) patients died in Group I versus 7(11.5%) patients in Group II (P>0.1). CPB time resulted to be in Group II patients (P=0.001) and the mean distal anastomoses per patient was similar between groups (P=Ns). Perioperative AMI (P=0.039), LCOS (P=0.002), necessity for ultrafiltration (P=0.018) and bleeding>1000 ml (P=0.029) were significantly higher in Group II. None of the Group I patients underwent surgical revision for bleeding versus 8(10.3%) patients in Group II (P=0.011). At 6 months after surgery, the LV function improved significantly in Group I patients, demonstrated by an increased LVEF=27.2+/-4(%)(P=0.001), lower LVEDP=26.4+/-3(mmHg)(P=0.029) and LVEDD=67+/ 4(mm) (P=0.004) instead of a lower LVEDD=66.8+/-6(mm)(P=0.032) versus the preoperative data in Group II. The actuarial survival at 1, 3 and 5 yr were 90, 82 and 71% in Group I and 89, 83 and 74% in Group II (P=Ns). CONCLUSION: In ESCAD patients who may poorly tolerate cardioplegic arrest, on-pump/beating-heart CABG may be an acceptable alternative associated with lower postoperative mortality and morbidity. Such a technique offers a better myocardial and renal protection associated with lower postoperative complications due to intraoperative hypoperfusion. PMID- 11604347 TI - Inflammatory solitary iliac artery aneurysms: a report of two cases. AB - Inflammatory abdominal aortic aneurysms are associated with atherosclerosis, which are characterized by specific clinical manifestation. We treated two patients with unilateral solitary iliac artery aneurysms with perianeurysmal fibrosis which compressed the ureter resulting in ipsilateral hydronephrosis. After the iliac artery aneurysm was repaired with a prosthetic graft, the hydronephrosis resolved. Microscopically, there was clear evidence of atherosclerosis in one case. There was a characteristic inflammatory reaction around the adventitia in both aneurysms. Localized iliac perianeurysmal fibrosis has not been particularly described. The clinicopathologic similarities between these cases and inflammatory abdominal aortic aneurysms suggest the same pathogenesis. PMID- 11604348 TI - Outcome of transaxillary rib resection for thoracic outlet syndrome--a 10 year experience. AB - BACKGROUND: This study assessed the outcome of transaxillary first and/or cervical rib resection in a unit, which has a policy of combined assessment by a neurologist and vascular surgeon. METHODS: 61 patients underwent 83 transaxillary rib resections for thoracic outlet syndrome. A retrospective case note review of these patients was undertaken. All patients completed a telephone questionnaire regarding long-term outcome. RESULTS: Post-operative outpatient assessment at a median of 6 months recorded 91.5% improved, of whom 61.5% were symptom-free. 61% were available for the telephone questionnaire at a median follow-up of 4 yr. 74% reported an improvement, with complete resolution in 58%. Six described temporary improvement following surgery. CONCLUSION: Transaxillary rib resection is a safe and effective procedure, allowing almost two thirds of patients a return to normal activity. Combined assessment by vascular and neurological teams may help in patient selection for surgery, as well as the accurate long-term assessment of outcome. PMID- 11604351 TI - [High-dose chemotherapy for tumor treatment: the end of the beginning ?]. PMID- 11604352 TI - [Hematopoietic cell transplantation: some historic milestones]. PMID- 11604353 TI - [Cellular therapy for intensification in oncology and hematology: manipulation of peripheral blood stem-cell products]. AB - Peripheral blood stem cells transplantation after high dose chemotherapy is increasingly used for the treatment of hematological malignancies and solid tumors. Autologous transplantation are now used as first line therapy. The use of hematopoietic growth factors allowed to collect peripheral hematopoietic progenitors in quantity large enough for several autologous reinfusions. As for bone marrow, peripheral blood stem cells allow fast and long-term hematopoietic reconstitution. The fast regeneration is strictly correlated to the number of hematopoietic progenitors infused. Some questions are still opened anyway, notably about the tumoral contamination of the graft which has been clearly demonstrated. Even if residual tumor cells are clearly shown to participate to relapse, the interest of ex vivo purging is still matter of debate. Several techniques of positive selection are now available, selecting normal stem cells thanks to the CD34+ antigen. Negative selection is also available either using clinical purging or monoclonals antibodies against tumoral antigens. Endly, ex vivo expansion of hematopoietic stem cells is under investigation using medical progress in the field of growth factors. Therefore, improvement of mobilisation protocols, of technology for positive or negative selection, as well as the strategy for ex vivo expansion will be the tools for the development of the treatment of some hematological malignancies and solid tumors reducing the hematopoietic and extra hematopoietic toxicity. PMID- 11604354 TI - [General principles of dose-effect relationship]. AB - The principles of chemotherapy administration are based on its haematological toxicity. In 1979, Goldie and Coldman described a mathematical model to demonstrate the link between the dose schedule and the cytotoxicity. Some years later, Norton and Simon developed this concept by integrating a tumour growth model taking into account the parameters of the in vivo tumoral homeostasis. The limits of the results obtained in the treatment of many cancers and the recent development of haematopoietic supports has led the clinicians to reconsider the therapeutic modalities and to intensify the treatments. We recall herein the principles of therapeutic intensification. In introduction of the various clinical applications, this chapter briefly calls back the theoretical bases of the concepts of dose response, dose-density and dose-intensity. PMID- 11604355 TI - [High-dose chemotherapy with hematopoietic stem-cell support in breast cancer]. PMID- 11604356 TI - [High-dose chemotherapy in advanced epithelial ovarian cancer]. AB - Since more than thirty years, ovarian cancer is wellknown to be chemosensitive. However, long term results of advanced stages remain low with 5 years overall survival around 20%. That's why high-dose chemotherapy in this chemosensitive disease has to be considered. Here, authors report the french, european and american experiences in three clinical settings: first in consolidation after complete or very good partial response, second after relapse or for refractory disease, third as first line treatment to increase clinical and pathological complete responses and improve prognosis. The more promising results concern high dose chemotherapy as consolidation setting. The preliminary results of the french multicentric randomized phase III study (high-dose versus conventional dose) gives a favorable trend for high-dose approach as consolidation. This unique trial would definitively establish the place of high-dose chemotherapy in the first line treatment of advanced epithelial ovarian cancer. PMID- 11604357 TI - [Is still there an indication for high-dose chemotherapy with hematopoietic stem cell support in the treatment of germ-cell tumors?]. AB - Germ-cell tumor patients are cured in 80% of cases. Twenty per cent of patients had a relapse or an incomplete response after first line chemotherapy, and only one third of them are alive free of disease at long term. Different approaches were performed to increase the results either in first line chemotherapy of poor prognosis patients or in first salvage. High dose chemotherapy with stem-cell support is one of them. The drugs infused are etoposide, carboplatin, cyclophosphamide and ifosfamide. Actually, no randomized performed trial showed the superiority of high dose chemotherapy in first line or in salvage treatment. Randomized trials are on going in these two settings. High dose chemotherapy is not actually a standard treatment in germ cell tumors. PMID- 11604358 TI - [High-dose chemotherapy in soft tissue sarcomas of adults]. AB - Few cytotoxic agents are active for the treatment of soft tissue sarcomas of adults: drugs active in monotherapy are doxorubicin, ifosfamide, dacarbazine and ET743. In patients with advanced stage soft tissue sarcomas (ASTS), a dose response relationship has been established for doxorubicin and ifosfamide. Intensive combination chemotherapy regimens at conventional doses (MAID, or AI) yield higher objective response rates than monochemotherapy regimens, ranging between 25% and 44%, but failed improve survival rates as comparted to less intensive regimens. Recently, several phase I or II studies have investigated the use of high dose chemotherapy regimens as consolidation therapy in ASTS in response to conventional regimens. HDCT regimens have been reported to yield response rates ranging between 18% and 66%. Some of these patients with ASTS achieved long term complete remission, in particular in the subgroup of patients in complete remission after conventional chemotherapy in advanced phase. Phase III studies are required to confirm that survival may be improved by HDCT in subgroups of patients with ASTS. PMID- 11604359 TI - [Dose intensity of chemotherapy in small-cell lung carcinoma]. AB - Small cell lung cancer accounts for 20% of the primitive lung carcinomas. The pronostic is unfavourable, since two thirds of the patients present with extensive stage at diagnosis. The median survival without treatment is less than 3 months. Chemotherapy is the standard front line therapy. In selected patients, chest irradiation and so-called prophylactic cerebral irradiation are current options. Small cell lung cancer is a chemosensitive disease. Indeed, the response rate is around 80-95% of in limited disease patients of which 50-60% are complete responses. Despite these results, the median survival does not exceed 16 months. Early recurrences after initial response probably reflect various resistances mechanisms. Furthermore, small cell lung cancer is associated with a high fraction of dividing cells. It is a clinical model where the dose-response relationship concept is worth testing, and dose-intensity may be integrated into the therapeutic strategies. Therefore, many clinical trials have assessed these principles during the past 20 years. We present here the different methods of therapeutic intensification in small cell lung cancer: with or without hematopoietic supports, using initial high dose of cytotoxic drugs, either at the beginning or at the end of induction treatment, or by increasing the dose density. PMID- 11604360 TI - [Role of high-dose chemotherapy with hemopoietic stem-cell support in the treatment of adult patients with high-grade glioma]. AB - Despite surgery, post-operative irradiation and adjuvant conventional chemotherapy, prognosis of high-grade gliomas remains poor. Carmustine (BCNU) has been shown to have limited activity at conventional dosage but is still the standard chemotherapy. Activity of chemotherapy is limited by the blood-brain barrier impermeability and high levels of expression of multidrug resistance proteins on tumor and/or endothelial cells. Despite high response rates, development of intra-arterial chemotherapy remains limited because of frequent acute brain toxicity related to drug administration. High-dose intravenous chemotherapy rescued by autologous hemopoietic stem cell transplantation is an alternative that might increase drug delivery through the blood-brain barrier and tumor control. Several phase I-II trials using high-dose BCNU were published. The maximum tolerated dose seems to be 800 mg/m2 and interstitial pneumonitis and hepatitis are dose-limiting toxicities. Few phase I-II trials of high-dose therapy were published using drug combinations. High response rates in patients with progressive tumor were observed and in adjuvant setting, encouraging results in terms of median survival time and long survivors were published. No phase III trial was reported to date. Future investigations should include randomized trials comparing high-dose and conventional-dose chemotherapy and development of new high-dose regimens that incorporate new drugs such as temozolomide. PMID- 11604361 TI - [Therapy intensification with autologous transplantation in non-Hodgkin's lymphomas]. AB - The rational for intensive chemo- or/and radiotherapy is based on the dose-effect relation in non-Hodgkin's lymphoma. In follicular lymphomas, candidates to intensification are patients with poor prognosis in relapse or with histological transformation. The efficacy of intensification to improve survival in first line treatment is not proven in follicular lymphoma. Due to the frequent marrow and blood involvement by tumoral cells in these lymphomas and the prognosis impact of this contamination, many efforts have been done to eliminate tumoral cells from the graft. Monoclonal anti-CD20 antibodies (rituximab) are indeed the best treatment to purge in vivo from tumoral cells marrow and blood. In aggressive lymphomas, intensifications are now the standard regimen in case of sensitive relapse. Probably it is also true in case of partial response or in first line after complete response in patients with 2 or 3 adverse prognostic factors. However intensification is not recommended in case of refractory disease or in first line treatment for standard-risk patients. High relapse rate after autograft justifies to test immunotherapy against minimal residual disease. The role of allogeneic transplantation, monoclonal antibodies or cytokines remains to be defined. PMID- 11604363 TI - [Economic evaluation of blood stem-cells autologous transplantation]. AB - Economic evaluation of autologous peripheral blood stem cell (PBSC) transplantation certainly played a role in the very fast substitution from bone marrow to BC autograft. Economic evaluation is still ongoing about the optimization of the procedure by assessing the cost-effectiveness ratio of each new improvement of the technique. Among these improvements we present the administration of high dose CD34+ cells, the delayed administration of G-CSF and the outpatient management of post-graft follow-up. It is still very rare in the field of health economics to notice such an early and ongoing economic evaluation of an innovation. PMID- 11604362 TI - [Autograft and multiple myeloma: experience of the Intergroupe Francais du Myelome]. AB - This article summarizes the different clinical results of the IFM trials: high dose therapy supported with autologous stem cells improves survival, melphalan 200 mg/m2 is the best preparative regimen, unpurged peripheral blood stem cells are the recommended source of stem-cells to support high dose therapy, tandem transplants significantly improve survival. However, despite these encouraging results, long term survival needs inovative strategies evaluated with the current IFM 99 protocol. PMID- 11604364 TI - [Allogeneic hematopoietic cell transplantation in solid tumors]. AB - Allogeneic bone marrow transplantation is being used to treat hematologic malignancies after induction. The efficacy of this procedure is due to both myeloablative conditioning and graft versus leukemia (GvL). However, the disadvantages of allogenic transplantation include graft versus host disease (GvH), the susceptibility of patients to opportunistic infections, and relapse from the original tumor. Since 1995 is used conditioning regimen which are deeply immunosuppressive and non myeloablative. The therapeutic toxicity related to myeloablation and drug side effects should be reduced. Lately, allogeneic transplantation has been developed to treat solid tumors, with the expectation that graft versus tumor (GvT), like GvL, will have a significant anti-tumoral effect. According to the literature, the feasibility of this procedure seems demonstrated. The fist available results in renal carcinomas are encouraging. However, the efficacy of this procedure remains uncertain for other potential indications. After presenting the published results, we will discussed the actual difficulties and the future potential developments. PMID- 11604366 TI - European family practice and public accountability. PMID- 11604367 TI - New developments in genetics-knowledge, attitudes and information needs of practice nurses. AB - BACKGROUND: In response to increased referrals to geneticists and the predicted patient demand for genetic counselling, it has been proposed that some genetics services should be provided in primary care. Practice nurses are ideally placed to collect family history information and advise patients accordingly in new patient, family planning, well women/men and chronic disease clinics, but little is known about their knowledge, skills and attitudes towards providing genetic advice. OBJECTIVES: The survey aimed to measure the current situation with regard to: the prevalence of family history recording by practice nurses; confidence in collecting and acting upon family history; and practice nurses' knowledge about familial disorders and genetics. It also investigated what practice nurses think their role should be in relation to the delivery of genetic services; their educational needs; and the most appropriate ways of delivering training/support. METHODS: A postal questionnaire survey was carried out of all practices nurses (n = 909) in four Health Authorities in England (Oxfordshire, Northamptonshire, Nottingham and North Nottinghamshire) and one Health Board in Scotland (Lothian). Analyses were primarily descriptive. RESULTS: A total of 600 nurses (response rate = 66.0%) returned a completed questionnaire. Ninety-six per cent of practice nurses reported that they routinely collect family history information. Over half of the respondents had been consulted in the previous 3 months by patients with a worry about family history of cancer. Approximately 60% of nurses felt confident about collecting the relevant details regarding a family history of breast cancer but felt less confident in collecting the information regarding familial colorectal cancer. Nurses were also unsure how to proceed, with over a third of nurses referring patients to the GP even if they thought the patient was at population risk or, conversely, not referring those that they thought were at considerably higher risk to the GP. There was a reported need for education about familial disease in general and overall agreement that nurses could play a role in genetics in primary care. CONCLUSION: This study provides evidence of considerable activity from practice nurses regarding routine collection of family history. There is a need for further education for practice nurses regarding family history information and the new genetics so that this information is managed appropriately. PMID- 11604365 TI - [Allogeneic hematopoietic stem-cell transplantation for hematological malignancies]. AB - Allogeneic transplantation of hematopoietic stem cells (HSC) is a curative treatment for hematological malignancies aiming to eradicate the malignant clone using the immunological conflict inherent to donor HSC installation in the recipient. The different possible sources of HSCs (bone marrow, blood, and cord blood) and better knowledge of HLA typing has led to the development of new transplantation techniques and modalities (transplantations after non myeloablative conditioning, haploidentical transplantations, etc.), which should improve patient survival and extend allograft indications. HSC allografting is subject to immunological reactions stemming from the histocompatibility discrepancy between donor and recipient. For the most part, these are reactions of the graft against the host (graft-versus-host disease: GVHD) and graft rejection (host-versus-graft: HVG). This immunological conflict can also be responsible for recognizing and destroying the recipient's residual tumor cells, which carry specific tumor antigens and/or minor antigens of histocompatibility (graft-versus-leukemia effect, GVL or graft-versus-malignancy effect, GVM). The posttransplantation period can also be riddled with various complications such as veno-occlusive disease, endocrine complications, as well as complications arising from infections and secondary neoplasms because of a more or less substantial and durable immune deficiency. Acute and chronic leukemias are the major indications for HSC allogeneic transplantation, for which the results are variable and closely related to the patient status, the hematological disease, and the transplant procedure. Other hematological diseases are also indications for allogeneic transplantation but are rarer, for which allogeneic transplantation remains nevertheless the only curative treatment, despite an overly high level of toxicity. Improvement in the results of unrelated transplantations, use of peripheral HSC or cord blood cells, development of non-myeloablative conditioning regimens, and techniques of ex vivo manipulation of the graft have allowed HSC allogeneic transplantation indications to be extended. The antitumor efficacy of donor lymphocytes infusion for relapses after transplantation mirrors the GVL effect and is the first stage in a targeted cellular immunotherapy using sensitized lymphocytes or dendritic cells. PMID- 11604368 TI - Referral of patients with a family history of breast/ovarian cancer--GPs' knowledge and expectations. AB - BACKGROUND: Primary care is expected to play a significant role in the management of patients with genetic problems. Currently, this particularly involves patients with a family history of cancer. If GPs are to exercise their gatekeeper role efficiently in this area, they must be able to evaluate genetic risk and make appropriate referral decisions. OBJECTIVES: The aim of this study was to examine GPs' ability to assess risk and to make appropriate referral decisions for women with a family history of breast/ovarian cancer, and to determine their expectations of a referral to secondary care. METHOD: A questionnaire survey was carried out of the 282 GP principals working within Bedfordshire Health Authority. GPs were asked to make decisions for six simulated cases of women presenting with a family history of breast or ovarian cancer. RESULTS: A total of 164 (58%) GPs returned completed questionnaires. Across the six family histories, the percentage of GPs making an appropriate risk assessment ranged from 21% [95% confidence interval (CI) 14-27%] to 63% (95% CI 56-71%), and an appropriate referral decision ranged from 40% (95% CI 32-48%) to 80% (95% CI 73-86%). Regardless of their accuracy of risk assessment, most GPs were consistent in deciding not to refer low risk women and to refer moderate and high risk women (range 71-85% of GPs for the six family histories). Only 43 (26%, 95% CI 20-33%) of GPs knew the three most important criteria for risk assessment. CONCLUSIONS: GPs require more help and education to enable them to perform their gatekeeper role satisfactorily when assessing patients with a family history of breast/ovarian cancer. PMID- 11604369 TI - Experiences and expectations of the new genetics in relation to familial risk of breast cancer: a comparison of the views of GPs and practice nurses. AB - BACKGROUND: Advances in genetics may change the practice of medicine in many ways. Ascertaining practitioners' perceptions about managing the risk of familial breast cancer can give an insight into the current and expected impact on general practice to inform relevant education. Little is known about the practice nurses' (PNs) views of the new genetics in comparison with those of the GP. OBJECTIVES: Our aim was to describe and compare the views of GPs and PNs on their experiences and expectations of the new genetics in relation to managing familial risk of breast cancer. METHOD: A questionnaire, assessing views on the current and future impact of genetic advances in general and on the management of women with a familial risk of breast cancer, was sent to all GPs and PNs in the 66 practices of the Cambridge and Huntingdon Health Authority. RESULTS: There was a 69% response rate. The words 'cautious', 'mixed feelings', 'hopeful' and 'optimistic' were used most frequently in response to views on genetic advances, but PNs chose more positive words than GPs (P < 0.001). PNs were also more optimistic than GPs in relation to the future positive impact of genetics on practice (P < 0.0001). Sixty-one per cent of GPs and 45% of PNs agreed that genetic advances in relation to breast cancer were already affecting their work. A minority of practitioners had attended recent educational events in risk assessment for breast cancer, and only 8% of GPs reported a practice policy on familial breast cancer risk management. CONCLUSIONS: GPs and PNs show a cautious optimism in relation to advances in genetics, with PNs most optimistic. Many perceive that genetic advances in relation to breast cancer are already affecting their workloads, yet educational attendance and practice policies are lacking. Given PN involvement, multi-professional education may be appropriate. Education about risk management, including family history and genetics, might be better integrated into more general teaching on the prevention and management of breast cancer, than taught alone. PMID- 11604371 TI - Knowing patients and knowledge about patients: evidence of modes of reasoning in the consultation? AB - BACKGROUND: The idea that the patient is in some way known to the doctor is an important one in general practice. The thrust towards patient-centred medicine, the promotion of open and negotiative consultation skills and the development of a biopsychosocial model of primary care medicine all rely on the patient providing a history composed of more than a list of facts. OBJECTIVE: Our aim was to explore the nature and importance of doctors' knowledge about patients. METHODS: Fifteen GPs audio-recorded 25-30 consultations with consecutive consenting patients. They scored each consultation according to how satisfying they found it. Semi-structured interviews based on a selection of consultations were conducted to draw out the doctor's views on the factors that were important to their satisfaction. The interviews were transcribed verbatim. Qualitative analysis was inductive and iterative. RESULTS: Within doctors' narratives, we found accounts of two ways of 'knowing' the patient. The first was a deductive mode of reasoning derived from facts about the patient. The facts that were known were specific to the context of the general practice consultation and led to biomedical and biographical knowledge. The second was an inductive mode of reasoning derived from a contextual interpretation of the facts about the patient which resulted in knowledge of their behaviour and cognitions. Both modes of reasoning gave the doctor knowledge of the patient and permitted action by the doctor in the consultation but led to different interpretations of the patient and different experiences of the consultation. CONCLUSION: 'Knowing the patient' is important to the way GPs attribute meaning to their work. Doctors were more likely to identify as 'known' those patients with whom they adopted an inductive mode of reasoning. In addition, their experience of the consultation was more likely to be positive. PMID- 11604370 TI - The 'difficult patient' as perceived by family physicians. AB - OBJECTIVES: The aim of this study is to understand in depth the experience of the family physician faced with the patient that he perceives as 'difficult'. This was done by means of the 'long interview' as a method of qualitative research. METHOD: We interviewed 15 randomly selected Board-certified family physicians, with five or more years experience as specialists, employed in the northern district of the 'Clalit Health Services', the major sick fund in Israel. RESULTS: The participants stated that the 'difficult' patients are not those with difficult medical problems but rather those who are violent, demanding, aggressive, rude and who seek secondary gain. Patients with multiple non-specific complaints and those with psychosomatic problems are also difficult for the family physician. Appropriate use of patient-doctor communication skills and an effort to improve relations with the patient through empathy, tolerance and non judgmental listening were suggested by the physicians as ways of making the difficult encounter easier. CONCLUSIONS: Family physicians acknowledge their responsibility for the 'difficult' patient, and seek innovative and creative ways to cope with the difficult medical encounter. The more experienced the doctor is, the less he perceives patients as 'difficult', as he learns to accept greater diversity of behaviours in his patients. PMID- 11604372 TI - Inside the routine general practice consultation: an observational study of consultations for sore throats. AB - OBJECTIVES: The aims of this study were to examine how GPs manage the consultation for upper resiratory tract infections (URTIs) and the prescribing of antibiotics, to understand what skills and strategies are used in managing URTIs without antibiotics, and to note evidence of pressure on doctors to prescribe and whether there are signs of overt disagreement about prescribing in the consultation. METHODS: A qualitative analysis of audiotaped consultations was carried out. The setting was a general practice in South Wales and the subjects were five GPs and 29 parents presenting children with URTIs over a 2-week period. The main outcome measures were skills and strategies identified from audiotapes of consultations. RESULTS: This group of GPs used a set of readily identifiable consulting skills for managing the consultation without prescribing. Their consultations had a highly routinized quality. There was little evidence of either conflict or overt pressure from parents to prescribe. The word 'antibiotics' was seldom mentioned. Clinicians did not elicit patient expectations for receiving antibiotics. CONCLUSIONS: Doctors use a set of readily identifiable skills in managing the URTI consultation. Avoiding the prescribing of antibiotics is not necessarily a simple and straightforward matter. Since patients apparently want antibiotics less than anticipated, eliciting expectations might be a way of reducing prescribing and broadening the approach to meeting patient needs. Whether doctors can adjust their routinized consulting patterns in the time-limited context of general practice remains an open question. PMID- 11604373 TI - Sexualization of the doctor-patient relationship: is it ever ethically permissible? AB - Whilst having sexual relationships with current patients is clearly unethical, the ethics of such a relationship between a doctor and former patient is more debatable. In this review of the current evidence, based on major articles listed in Medline and Bioethicsline in the past 15 years, the argument is made here that such relationships are almost always unethical due to the persistence of transference, the unequal power distribution in the original doctor-patient relationship and the ethical implications that arise from both these factors especially with respect to the patient's autonomy and ability to consent, even when a former patient. Only in very particular circumstances could such relationships be ethically permissible. PMID- 11604374 TI - GPs' views on their management of sexual dysfunction. AB - BACKGROUND: Sexual dysfunction is an important aspect of sexual heath that is prevalent in the population but frequently goes undetected. OBJECTIVE: The aim of this study was to investigate the role of the GP in the management of problems of sexual dysfunction. METHODS: A postal questionnaire was sent to the 218 GPs on the Camden and Islington Health Authority List. The questionnaire collected demographic information on the GPs, their clinical interests, experience, postgraduate qualifications and their view of the clinical importance of sexual dysfunction. Their clinical management of the most recent patient encounter in the previous month was explored using a critical incident technique and they were asked to list their views on barriers to the management of sexual dysfunction and to provide a list of suggestions for tackling these barriers. RESULTS: A total of 133 GPs responded to the questionnaire. Although only eight had a special interest in sexual health, 41 and 50 reported a special interest in mental and women's health, respectively. Forty-six had received postgraduate training in taking a sexual history, 45 in the diagnosis of a sexual problem, 49 in the management of sexual dysfunction, 39 in psychosexual counselling and 24 had training in all four areas. Most GPs (87) categorized sexual dysfunction as medium priority, 25 as high priority and 18 as low priority; three GPs did not respond to this query. Several barriers to the management of sexual dysfunction in general practice were identified. Most doctors identified more than one barrier. CONCLUSIONS: The participating GPs offered specific suggestions that focused on the need for more professional and patient education, consultation time, psychosexual counsellors and relevant secondary care service. PMID- 11604375 TI - Medically unexplained symptoms--GPs' attitudes towards their cause and management. AB - BACKGROUND: Medically unexplained physical symptoms present one of the most common problems in modern medical practice but often prove difficult to manage. The central position of the GP in the care of patients with medically unexplained symptoms has been emphasized repeatedly, but little is known about the attitudes of GPs to this role. Understanding how GPs view these patients may inform the development of effective strategies for management. OBJECTIVE: Our aim was to survey the attitudes of UK GPs towards medically unexplained symptoms (MUS) and somatization. METHODS: A random sample of 400 GPs in the South Thames (West) region were surveyed using a postal questionnaire. Respondents' attitudes toward the cause and management of MUS were recorded. RESULTS: A total of 284 completed questionnaires were returned (22 returned incomplete), giving an adjusted response rate of 75%. Although it was broadly felt that patients with MUS are difficult to manage, most GPs felt that patients with MUS should be managed in primary care. Providing reassurance, counselling and acting as a 'gatekeeper' to prevent inappropriate investigations were considered important roles for GP management. A majority felt that patients with MUS have personality problems or psychiatric illness. Fewer than half of the respondents felt that there are effective treatments available for somatization. CONCLUSION: GPs consider the management of patients with MUS to be an important part of their workload, but there is a perception that effective management strategies are lacking. Psychiatrists need to offer greater support and training for GPs in this area of health care. PMID- 11604377 TI - Structuring prescribing data into traffic-light categories; a tool for evaluating treatment quality in primary care. AB - BACKGROUND: Prescribing feedback based on aggregated data alone does not give the information needed to improve treatment quality. OBJECTIVES: Our aim was to develop a new method, or tool, of presenting prescribing feedback which, combined with guideline recommendations, makes it possible for doctors to judge their own prescribing as good or bad. METHODS: Asthma was chosen as a disease model, as treatment recommendations are readily available published as national and international guidelines. Four mean daily dosage intervals of inhaled short acting beta-agonists and four mean daily dosage intervals of inhaled steroids were combined into a 4 x 4 matrix. This matrix of 16 combined dosage boxes was presented to 68 Norwegian GPs participating in peer review groups. As a first step, the GPs in the groups reached consensus on what they considered to be appropriate and inappropriate combined dosage intervals of these drugs based on national guideline recommendations and their joint clinical experience. Accordingly, traffic-light colours, green and red, were assigned to the combined dosage boxes in the matrix. Treatments in boxes difficult to judge were coloured yellow. During a 1-year period prior to the consensus meetings, the dispensed inhaled short-acting beta-agonists and inhaled steroids of each of the doctors' patients were recorded at the local pharmacies. As a second step in developing the new method, the number of patients treated within each of the coloured boxes was presented to the GPs in the peer review groups. These combined presentations provided an overview to the whole group, and individually to each GP, of how many patients were actually given appropriate or inappropriate treatment according to their own agreed upon standard. RESULTS: The GPs categorized 34% of 1122 evaluated patients receiving inhaled short-acting beta-agonists or inhaled steroids as treated inappropriately during the 1-year registration period. Appropriate treatment was given to 47% of the patients, and in 19% of the cases the treatment was difficult to evaluate. CONCLUSIONS: A method has been developed enabling GPs to categorize prescribing information into good (green), bad (red) and difficult to judge (yellow) treatment qualities, based on guideline recommendations and clinical experience. The actual prescribing data for each GP were labelled according to the same colour scheme, thus revealing to each GP his or her own actual prescribing compared with their own treatment standard, yielding information and motivation for quality improvement efforts. PMID- 11604378 TI - Attitudes of the general public to the expanding role of community pharmacists: a pilot study. AB - BACKGROUND: The extension of the role of the community pharmacist in the UK has been under discussion for several years. Professional opinions have been reported. It is important to investigate consumer attitudes towards the acceptability of the proposed new role of the pharmacist. OBJECTIVES: This pilot study investigated the attitudes of consumers to the proposed extended role of the community pharmacist. METHODS: A total of 173 printed questionnaires were mailed to a random sample of patients stratified by age and sex, registered with an urban general practice in the north east of Scotland. The questionnaire asked subjects their views on ideas for new services to be provided by community pharmacists. RESULTS: A total of 96 questionnaires were returned (response rate 55%). Respondents were in favour of community pharmacist involvement in non medicine-related roles such as 'healthy living' advice but less in favour of roles where the pharmacist would have access to selected information from medical records. CONCLUSION: This pilot study has indicated a range of attitudes towards the extended role of the community pharmacist. It is important to investigate fully consumer attitudes towards the acceptability of the new role of the pharmacist. PMID- 11604376 TI - Are headache patients who initiate their referral to a neurologist satisfied with the consultation? A population study of 927 patients--the North Norway Headache Study (NNHS). AB - BACKGROUND: Headache is a common problem in primary care. Although most patients are treated by GPs, many are referred to specialist consultation. Knowledge of how the referrals can be improved is therefore an important issue. OBJECTIVES: The aim of this study was to determine the relationship between self-initiating referral to a neurologist and the patient's satisfaction with the specialist consultation. METHODS: All patients who had been examined by a neurologist for headache within a 2-year period from three neurological centres in North Norway completed a questionnaire. RESULTS: A total of 1052 patients from a population of 1403 headache patients (75%) returned the questionnaire while 927 patients answered questions about initiating the referral to the specialist. Two hundred and twenty patients (24%) initiated the referral to the neurologist themselves; 52% of those who self-initiated the referral were dissatisfied with the specialist consultation compared with 42% of those referred by the doctor, P = 0.002. Chronic headache, tension-type headache (TTH) and daily use of analgesic drugs were associated with dissatisfaction. CONCLUSIONS: Patients with headache who initiated the referral to a neurologist themselves were less satisfied with the specialist consultation. Selecting referrals containing proper medical information may improve satisfaction in severe headache patients treated in a neurological practice. PMID- 11604380 TI - Reflections from organization science on the development of primary health care research networks. AB - In the UK, policy changes in primary health care research and development have led to the establishment of primary care research networks. These organizations aim to increase research culture, capacity and evidence base in primary care. As publicly funded bodies, these networks need to be accountable. Organizational science has studied network organizations including why and how they develop and how they function most effectively. This paper draws on organizational science to reflect on why primary care research networks appear to be appropriate for primary care research and how their structures and processes can best enable the achievement of their aims. PMID- 11604379 TI - Impact of community-based education on health care evaluation in patients with acute chest pain syndromes: the Wabasha Heart Attack Team (WHAT) project. AB - BACKGROUND: Community education programmes focused on raising public awareness of the symptomatology of acute coronary syndromes have had mixed results. OBJECTIVES: The Wabasha Heart Attack Team project, a unique multidisciplinary public education effort in Minnesota, sought to educate area citizens about signs and symptoms of acute myocardial infarction (MI). METHODS: After an intensive 1 month education period, we compared presentations for emergency evaluation of chest pain during the study period with baseline data from the same seasonal period of the preceding year. RESULTS: Visits to the Emergency Room for symptomatic heart disease increased significantly during the study period (56 patients versus 46 patients during the baseline period), as did the percentage of patients presenting with acute MI (18% versus 12%, P < 0.05). Use of emergency medical services for pre-hospital evaluation was significantly increased (41% versus 27%, P < 0.05). CONCLUSION: A community education campaign can significantly increase use of pre-hospital emergency medical service resources and may increase the number of patients presenting with acute chest pain symptoms, including MI. PMID- 11604381 TI - Residential rehabilitation for drug users: a review of 13 months' intake to a therapeutic community. AB - BACKGROUND: Residential rehabilitation based on 'therapeutic community' treatment for drug users is a treatment option which is attractive to GPs and others referring drug users for treatment. Whilst there is evidence that maintenance based programmes for drug users are effective, there have been fewer attempts to evaluate the effectiveness of abstinence-based programmes which are relatively more intensive and expensive interventions. OBJECTIVE: This paper reports and evaluates the outcomes for 13 months' intake of 138 drug users to a residential community. METHODS: We carried out a retrospective cohort study using existing clinical and residential record data. The setting is a residential rehabilitation centre run by the charity Phoenix House in Sheffield, UK, offering a 1-year programme for heroin addicts including community detoxification overseen by primary care specialist doctors and residential rehabilitation. Participants were all patients who entered treatment between 1 February 1998 and 28 February 1999 inclusive. An analysis was carried out of clinical records and other records kept by clinicians and staff at the centre. Outcome measures were numbers of days of retention in treatment and reasons for departure, categorized as completed treatment, planned or unplanned departure and expulsion from the programme. For patients who underwent in-house detoxification, a further outcome measure was whether or not detoxification was complete at discharge. RESULTS: Heroin was the main drug of abuse in 85% of admissions. Mean length of time for which individuals had been drug dependent was 8 years (range 1.3-20.1 years). The mean length of stay was 80.2 days (range 1-394, 95% confidence interval 61.8-98.6). Thirty-four individuals (25%) completed 90 days or more. No association was found between length of stay and age, sex, route of administration, polydrug use, length of time addicted or age of first addiction. Sixty-five per cent of those who received in-house detoxification completed the detoxification period. When patients were classified as 'successes' or 'failures' by reason for departure from the programme, 94 (68.1%) were classified as failures and 18 (13.0%) as successes. Data were unavailable for 26 patients. Success was not associated with any characteristic at entry apart from being drug free as opposed to requiring detoxification (P = 0.048, chi-square = 6.06, df = 2). CONCLUSION: This study shows overall low levels of programme completion and high levels of unplanned departure and eviction from the programme amongst these long-term drug users. On the other hand, the importance of abstinence for those who achieve it in residential rehabilitation should not be underestimated, nor should the possibility that long-term outcomes are influenced by the learning process involved in the intervention. It may be possible to operate better selection procedures in order to optimize outcomes. PMID- 11604382 TI - Management of dementia in primary health care: the experiences of collaboration between the GP and the district nurse. AB - OBJECTIVE: The objective of this study was to explore the context and experiences of collaboration between the GP and the district nurse (DN) in diagnosing dementia, in order to identify possible procedures to improve care. METHODS: Two group interviews were conducted with four DNs and five GPs, respectively, working in the municipality of Copenhagen. RESULTS: The group interviews revealed that the suboptimized collaboration could be due to different inter-professional diagnostic strategies and a lack of understanding of the importance of early, shared, decision making. This could create conflicts between the groups. CONCLUSIONS: This study indicates a possibility for improved collaboration between the two professional groups in diagnosing dementia. Possible approaches for improved care should focus on an inter-professional understanding of the importance of early, shared, decision making, emphasizing early identification and care of diagnosed demented patients. Establishing a shared collaboration model including out-patient memory clinics, GPs and DNs could be a first step. This model should also take into account an evaluation of possible consequences for the diagnosed demented patients in terms of treatment and care and consider the indication for referrals to a comprehensive diagnostic evaluation. We are at present planning a study to address these aspects. PMID- 11604383 TI - Validation study of a diary for use in acute lower respiratory tract infection. AB - BACKGROUND: Despite lower respiratory tract infection (LRTi) being the most common illness treated by doctors, no validated outcome measure to assess symptom duration and severity has been developed for patient self-completion. METHODS: As part of a randomized control trial researching management of acute LRTi, an easy self-completion diary was formulated and validated against the 'measure yourself medical outcome profile 2' (MYMOP2), an instrument previously validated in general practice. RESULTS: Spearman rank correlations of the diary profile versus MYMOP2 profile at baseline (r = 0.62), day 11 (r = 0.81) and change in score over time (r = 0.51) indicate that our diary correlates significantly with MYMOP2. The standardized response mean of the diary profile (mean change/SD change) = 1.48, indicating sensitivity to change. CONCLUSION: This study shows that a simple symptom diary is internally reliable, valid and sensitive to change for acute LRTi. This instrument could be used as a routine measure of LRTi in further research in both primary and secondary care. PMID- 11604384 TI - Selections from current literature. Re-thinking the management of atrial fibrillation: a new approach. PMID- 11604387 TI - Revealing the involvement of extended hydrogen bond networks in the cooperative function between distant sites in bacterial reaction centers. AB - In reaction center proteins of photosynthetic bacteria, the amplitude of proton uptake induced by the one-electron reduction of either of the two quinone electron acceptors (Q(A) and Q(B)) is an intrinsic observable of the electrostatic interactions associated with the redox function of the complex. We report here that, in Rhodobacter capsulatus, complete restoration of proton uptake (upon formation of Q(A)(-) and Q(B)(-)) to the level found in the wild type is observed in a mutant reaction center in which a tyrosine substitution in the Q(A) environment (Ala(M274) --> Tyr) is coupled with mutations of acidic residues near Q(B) (Glu(L212) --> Ala/Asp(L213) --> Ala) that initially cancel the proton uptake above pH 8. This result demonstrates that proton uptake occurs by strong cooperation between structural motifs, such as hydrogen-bonded networks, that span the 18 A distance between the two quinone acceptors. PMID- 11604388 TI - The cyclin-dependent kinases cdk2 and cdk5 act by a random, anticooperative kinetic mechanism. AB - cdk2.cyclin E and cdk5.p25 are two members of the cyclin-dependent kinase family that are potential therapeutic targets for oncology and Alzheimer's disease, respectively. In this study we have investigated the mechanism for these enzymes. Kinases catalyze the transfer of phosphate from ATP to a protein acceptor, thus utilizing two substrates, ATP and the target protein. For a two-substrate reaction, possible kinetic mechanisms include: ping-pong, sequential random, or sequential ordered. To determine the kinetic mechanism of cdk2.GST-cyclin E and cdk5.GST-p25, kinase activity was measured in experiments in which concentrations of peptide and ATP substrates were varied in the presence of dead-end inhibitors. A peptide identical to the peptide substrate, but with a substitution of valine for the phosphoacceptor threonine, competed with substrate with a K(i) value of 0.6 mm. An aminopyrimidine, PNU 112455A, was identified in a screen for inhibitors of cdk2. Nonlinear least squares and Lineweaver-Burk analyses demonstrated that the inhibitor PNU 112455A was competitive with ATP with a K(i) value of 2 microm. In addition, a co-crystal of PNU 112455A with cdk2 showed that the inhibitor binds in the ATP binding pocket of the enzyme. Analysis of the inhibitor data demonstrated that both kinases use a sequential random mechanism, in which either ATP or peptide may bind first to the enzyme active site. For both kinases, the binding of the second substrate was shown to be anticooperative, in that the binding of the first substrate decreases the affinity of the second substrate. For cdk2.GST-cyclin E the kinetic parameters were determined to be K(m, ATP) = 3.6 +/- 1.0 microm, K(m, peptide) = 4.6 +/- 1.4 microm, and the anticooperativity factor, alpha = 130 +/- 44. For cdk5.GST-p25, the K(m, ATP) = 3.2 +/- 0.7 microm, K(m, peptide) = 1.6 +/- 0.3 microm, and alpha = 7.2 +/- 1.8. PMID- 11604389 TI - Suppression of tumor-related glycosylation of cell surface receptors by the 16 kDa membrane subunit of vacuolar H+-ATPase. AB - The glycosylation of integrins and other cell surface receptors is altered in many transformed cells. Notably, an increase in the number of beta1,6-branched N linked oligosaccharides correlates strongly with invasive growth of cells. An ectopic expression of the Golgi enzyme N-acetylglucosaminyltransferase V (GlcNAc TV), which forms beta1,6 linkages, promotes metastasis of a number of cell types. It is shown here that the 16-kDa transmembrane subunit (16K) of vacuolar H(+) ATPase suppresses beta1,6 branching of beta(1) integrin and the epidermal growth factor receptor. Overexpression of 16K inhibits cell adhesion and invasion. 16K contains four hydrophobic membrane-spanning alpha-helices, and its ability to influence glycosylation is localized primarily within the second and fourth membrane-spanning alpha-helices. 16K also interacts directly with the transmembrane domain of beta(1) integrin, but its effects on glycosylation were independent of its binding to beta(1) integrin. These data link cell surface tumor-related glycosylation to a component of the enzyme responsible for acidification of the exocytic pathway. PMID- 11604390 TI - The low density lipoprotein receptor-related protein contributes to selective uptake of high density lipoprotein cholesteryl esters by SW872 liposarcoma cells and primary human adipocytes. AB - The concept that selective transfer of high density lipoprotein (HDL)-derived cholesteryl esters (CE) does not require lipoprotein internalization has been challenged recently by evidence that implicates HDL recycling during the selective uptake process. This has prompted us to examine the role of the low density lipoprotein receptor-related protein (LRP) in selective uptake. LRP is an endocytic receptor for lipoprotein lipase (LpL) and apolipoprotein E (apoE) ligands that are able to mediate selective uptake. We report that molecules that interfere with ligand binding to LRP, such as the receptor-associated protein (RAP), suramin, alpha(2)-macroglobulin, or lactoferrin, inhibit HDL-CE selective uptake by human primary adipocytes and SW872 liposarcoma cells by 35-50%. This partial inhibition of selective uptake from total HDL was not due to preferential inhibition of the HDL(2) or HDL(3) subfractions. Selective uptake by the scavenger receptor BI was not inhibited by RAP, excluding its involvement. Furthermore, in SW872 cells in which LRP was reduced to 14% of control levels by stable antisense expression, selective uptake was attenuated by at least 33%, confirming a role for LRP in this process. RAP, alpha(2)-macroglobulin, lactoferrin, and suramin (individually or in paired combinations) also attenuated selective uptake of HDL-CE by primary human adipocytes by about 40%. On the other hand, human skin fibroblasts express LRP abundantly but lack the capacity for selective uptake, demonstrating that other molecules are required. In SW872 cells, exogenous apoE or LpL can facilitate selective uptake but only the apoE enhanced uptake can be inhibited by RAP, implicating apoE as a likely co mediator. We discuss the possible mechanisms by which the endocytic receptor, LRP, can mediate selective uptake. PMID- 11604391 TI - Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. AB - We have demonstrated that the angiotensin-converting enzyme (ACE) genotype is associated with Alzheimer's disease (AD) in the Japanese population (). To determine why ACE affects susceptibility to AD, we examined the effect of purified ACE on aggregation of the amyloid beta-peptide (A beta) in vitro. Surprisingly, ACE was found to significantly inhibit A beta aggregation in a dose response manner. The inhibition of aggregation was specifically blocked by preincubation of ACE with an ACE inhibitor, lisinopril. ACE was confirmed to retard A beta fibril formation with electron microscopy. ACE inhibited A beta deposits on a synthaloid plate, which was used to monitor A beta deposition on autopsied brain tissue. ACE also significantly inhibited A beta cytotoxicity on PC12 h. The most striking fact was that ACE degraded A beta by cleaving A beta-(1 40) at the site Asp(7)-Ser(8). This was proven with reverse-phase HPLC, amino acid sequence analysis, and MALDI-TOF/MS. Compared with A beta-(1-40), aggregation and cytotoxic effects of the degradation products A beta-(1-7) and A beta-(8-40) peptides were reduced or virtually absent. These findings led to the hypothesis that ACE may affect susceptibility to AD by degrading A beta and preventing the accumulation of amyloid plaques in vivo. PMID- 11604392 TI - SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. AB - SOCS (suppressor of cytokine signaling) proteins are inhibitors of cytokine signaling involved in negative feedback loops. We have recently shown that insulin increases SOCS-3 mRNA expression in 3T3-L1 adipocytes. When expressed, SOCS-3 binds to phosphorylated Tyr(960) of the insulin receptor and prevents Stat 5B activation by insulin. Here we show that in COS-7 cells SOCS-3 decreases insulin-induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase. This mechanism points to a function of SOCS-3 in insulin resistance. Interestingly, SOCS-3 expression was found to be increased in the adipose tissue of obese mice, but not in the liver and muscle of these animals. Two polypeptides known to be elevated during obesity, insulin and tumor necrosis factor-alpha (TNF alpha), induce SOCS-3 mRNA expression in mice. Insulin induces a transient expression of SOCS-3 in the liver, muscle, and the white adipose tissue (WAT). Strikingly, TNF-alpha induced a sustained SOCS-3 expression, essentially in the WAT. Moreover, transgenic ob/ob mice lacking both TNF receptors have a pronounced decrease in SOCS-3 expression in the WAT compared with ob/ob mice, providing genetic evidence for a function of this cytokine in obesity-induced SOCS-3 expression. As SOCS-3 appears as a TNF-alpha target gene that is elevated during obesity, and as SOCS-3 antagonizes insulin-induced IRS-1 tyrosine phosphorylation, we suggest that it is a player in the development of insulin resistance. PMID- 11604393 TI - CASK and protein 4.1 support F-actin nucleation on neurexins. AB - Rearrangements of the actin cytoskeleton are involved in a variety of cellular processes from locomotion of cells to morphological alterations of the cell surface. One important question is how local interactions of cells with the extracellular space are translated into alterations of their membrane organization. To address this problem, we studied CASK, a member of the membrane associated guanylate kinase homologues family of adaptor proteins. CASK has been shown to bind the erythrocyte isoform of protein 4.1, a class of proteins that promote formation of actin/spectrin microfilaments. In neurons, CASK also interacts via its PDZ domain with the cytosolic C termini of neurexins, neuron specific cell-surface proteins. We now show that CASK binds a brain-enriched isoform of protein 4.1, and nucleates local assembly of actin/spectrin filaments. These interactions can be reconstituted on the cytosolic tail of neurexins. Furthermore, CASK can be recovered with actin filaments prepared from rat brain extracts, and neurexins are recruited together with CASK and protein 4.1 into these actin filaments. Thus, analogous to the PDZ-domain protein p55 and glycophorin C at the erythrocyte membrane, a similar complex comprising CASK and neurexins exists in neurons. Our data suggest that intercellular junctions formed by neurexins, such as junctions initiated by beta-neurexins with neuroligins, are at least partially coupled to the actin cytoskeleton via an interaction with CASK and protein 4.1. PMID- 11604394 TI - Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology. AB - The small GTPase Rac and its effectors, the Pak1 and p35/Cdk5 kinases, have been assigned important roles in regulating cytoskeletal dynamics in neurons. Our previous work revealed that the neuronal p35/Cdk5 kinase associates with Pak1 in a RacGTP-dependent manner, causing hyperphosphorylation and down-regulation of Pak1 kinase activity. We have now demonstrated direct phosphorylation of Pak1 on threonine 212 by the p35/Cdk5 kinase. In neuronal growth cones, Pak1 phosphorylated on Thr-212 localized to actin and tubulin-rich areas, suggesting a role in regulating growth cone dynamics. The expression of a non-phosphorylatable Pak1 mutant (Pak1A212) induced dramatic neurite disorganization. We also observed a strong association between p35/Cdk5 and the Pak1 C-terminal kinase domain. Overall, our data show that in neurons, membrane-associated, active Pak1 is regulated by the p35/Cdk5 kinase both by association and phosphorylation, which is essential for the proper regulation of the cytoskeleton during neurite outgrowth and remodeling. PMID- 11604396 TI - Isothermal titration calorimetry reveals a zinc ion as an atomic switch in the diadenosine polyphosphates. AB - Diadenosine polyphosphates (diadenosine 5',5'''-P(1),P(n)-polyphosphate (Ap(n)A)) are 5'-5'''-phosphate-bridged dinucleosides that have been proposed to act as signaling molecules in a variety of biological systems. Isothermal titration calorimetry was used to measure the affinities of a variety of metal cations for ATP, diadenosine 5',5'''-P(1),P(3)-triphosphate (Ap(3)A), diadenosine 5',5''' P(1),P(4)-tetraphosphate (Ap(4)A), and diadenosine 5',5'''-P(1),P(5) pentaphosphate (Ap(5)A). The binding of Mg(2+), Ca(2+), and Mn(2+) to ATP is shown to take place with the beta,gamma-phosphates (primary site) and be endothermic in character. The binding of Ni(2+), Cd(2+), and Zn(2+) to ATP is found to take place at both the primary site and at a secondary site identified as N-7 of the adenine ring. Binding to this second site is exothermic in character. Generally, the binding of metal cations to diadenosine polyphosphates involves a similar primary site to ATP. No exothermic binding events are identified. Critically, the binding of Zn(2+) to diadenosine polyphosphates proves to be exceptional. This appears to involve a very high affinity association involving the N-7 atoms of both adenine rings in each Ap(n)A, as well as the more usual endothermic association with the phosphate chain. The high affinity association is also endothermic in character. A combination of NMR and CD evidence is provided in support of the calorimetry data demonstrating chemical shift changes and base stacking disruptions entirely consistent with N-7 bridging interactions. N-7 bridging interactions are entirely reversible, as demonstrated by EDTA titration. Considering the effects of Zn(2+) on a wide variety of dinucleoside polyphosphate-metabolizing enzymes, we examine the possibility of Zn(2+) acting as an atomic switch to control the biological function of the diadenosine polyphosphates. PMID- 11604397 TI - DNA converts cellular prion protein into the beta-sheet conformation and inhibits prion peptide aggregation. AB - The main hypothesis for prion diseases proposes that the cellular protein (PrP(C)) can be altered into a misfolded, beta-sheet-rich isoform (PrP(Sc)), which in most cases undergoes aggregation. In an organism infected with PrP(Sc), PrP(C) is converted into the beta-sheet form, generating more PrP(Sc). We find that sequence-specific DNA binding to recombinant murine prion protein (mPrP-(23 231)) converts it from an alpha-helical conformation (cellular isoform) into a soluble, beta-sheet isoform similar to that found in the fibrillar state. The recombinant murine prion protein and prion domains bind with high affinity to DNA sequences. Several double-stranded DNA sequences in molar excess above 2:1 (pH 4.0) or 0.5:1 (pH 5.0) completely inhibit aggregation of prion peptides, as measured by light scattering, fluorescence, and circular dichroism spectroscopy. However, at a high concentration, fibers (or peptide aggregates) can rescue the peptide bound to the DNA, converting it to the aggregating form. Our results indicate that a macromolecular complex of prion-DNA may act as an intermediate for the formation of the growing fiber. We propose that host nucleic acid may modulate the delicate balance between the cellular and the misfolded conformations by reducing the protein mobility and by making the protein-protein interactions more likely. In our model, the infectious material would act as a seed to rescue the protein bound to nucleic acid. Accordingly, DNA would act on the one hand as a guardian of the Sc conformation, preventing its propagation, but on the other hand may catalyze Sc conversion and aggregation if a threshold level is exceeded. PMID- 11604395 TI - Isomerization of 11-cis-retinoids to all-trans-retinoids in vitro and in vivo. AB - The regeneration of 11-cis-retinal, the universal chromophore of the vertebrate retina, is a complex process involving photoreceptors and adjacent retinal pigment epithelial cells (RPE). 11-cis-Retinal is coupled to opsins in both rod and cone photoreceptor cells and is photoisomerized to all-trans-retinal by light. Here, we show that RPE microsomes can catalyze the reverse isomerization of 11-cis-retinol to all-trans-retinol (and 13-cis-retinol), and membrane exposure to UV light further enhances the rate of this reaction. This conversion is inhibited when 11-cis-retinol is in a complex with cellular retinaldehyde binding protein (CRALBP), providing a clear demonstration of the protective effect of retinoid-binding proteins in retinoid processes in the eye, a function that has been long suspected but never proven. The reverse isomerization is nonenzymatic and specific to alcohol forms of retinoids, and it displays stereospecific preference for 11-cis-retinol and 13-cis-retinol but is much less efficient for 9-cis-retinol. The mechanism of reverse isomerization was investigated using stable isotope-labeled retinoids and radioactive tracers to show that this reaction occurs with the retention of configuration of the C-15 carbon of retinol through a mechanism that does not eliminate the hydroxyl group, in contrast to the enzymatic all-trans-retinol to 11-cis-retinol reaction. The activation energy for the conversion of 11-cis-retinol to all-trans-retinol is 19.5 kcal/mol, and 20.1 kcal/mol for isomerization of 13-cis-retinol to all-trans retinol. We also demonstrate that the reverse isomerization occurs in vivo using exogenous 11-cis-retinol injected into the intravitreal space of wild type and Rpe65-/- mice, which have defective forward isomerization. This study demonstrates an uncharacterized activity of RPE microsomes that could be important in the normal flow of retinoids in the eye in vivo during dark adaptation. PMID- 11604398 TI - Parathyroid hormone (PTH)-(1-14) and -(1-11) analogs conformationally constrained by alpha-aminoisobutyric acid mediate full agonist responses via the juxtamembrane region of the PTH-1 receptor. AB - The N-terminal portion of parathyroid hormone is critical for PTH-1 receptor (P1R) activation and has been postulated to be alpha-helical when bound to the receptor. We investigated whether substitution of the sterically hindered and helix-promoting amino acid alpha-aminoisobutyric acid (Aib) in N-terminal PTH oligopeptides would improve the capacity of the peptide to activate the P1R. Analysis of the effects of individual Aib substitutions at each position in [Ala(3,12),Gln(10),Har(11),Trp(14)]PTH(1-14)NH(2) ([M]PTH(1-14)) on cAMP stimulating potency in HKRK-B28 cells revealed that Aib at most positions diminished potency; however, Aib at positions 1 and 3 enhanced potency. Thus [Aib(1,3),M]PTH(1-14) was approximately 100-fold more potent than [M]PTH(1-14) (EC(50) = 1.1 +/- 0.1 and 100 +/- 20 nm, respectively), approximately 100,000 fold more potent than native PTH(1-14), and 2-fold more potent than PTH(1-34). The shorter peptide, [Aib(1,3),M]PTH(1-11), was also fully efficacious and 1,000 fold more potent than [M]PTH(1-11) (EC(50) 4 +/- 1 nm versus 3 +/- 1 microm). In cAMP stimulation assays performed in COS-7 cells expressing P1R-delNt, a receptor that lacks most of the N-terminal extracellular domain, [Aib(1,3),M]PTH(1-14) was 50-fold more potent than [M]PTH(1-14) (EC(50) = 0.7 +/- 0.2 versus 40 +/- 2 nm) and 1,000-fold more potent than PTH(1-34) (EC(50) = 700 nm). [Aib(1,3),M]PTH(1 14), but not PTH(1-34), inhibited the binding of (125)I [Aib(1,3),Nle(8),Gln(10),Har(11),Ala(12),Trp(14),Arg(19),Tyr(21)]PTH(1-21)NH(2) to hP1R-delNt (IC(50) = 1,600 +/- 200 nm). The Aib(1,3) substitutions in otherwise unmodified PTH(1-34) enhanced potency and binding affinity on hP1R delNt, but they had no effect for this peptide on hP1R-WT. Circular dichroism spectroscopy demonstrated that the Aib-1,3 substitutions increased helicity in all peptides tested, including PTH(1-34). The overall data thus suggest that the N-terminal residues of PTH are intrinsically disordered but become conformationally constrained, possibly as an alpha-helix, upon interaction with the activation domain of the PTH-1 receptor. PMID- 11604400 TI - C-terminal periplasmic domain of Escherichia coli quinoprotein glucose dehydrogenase transfers electrons to ubiquinone. AB - Membrane-bound quinoprotein glucose dehydrogenase (GDH) in Escherichia coli donates electrons directly to ubiquinone during the oxidation of d-glucose as a substrate, and these electrons are subsequently transferred to ubiquinol oxidase in the respiratory chain. To determine whether the specific ubiquinone-reacting site of GDH resides in the N-terminal transmembrane domain or in the large C terminal periplasmic catalytic domain (cGDH), we constructed a fusion protein between the signal sequence of beta-lactamase and cGDH. This truncated GDH was found to complement a GDH gene-disrupted strain in vivo. The signal sequence of the fused protein was shown to be cleaved off, and the remaining cGDH was shown to be recovered in the membrane fraction, suggesting that cGDH has a membrane interacting site that is responsible for binding to membrane, like peripheral proteins. Kinetic analysis and reconstitution experiments revealed that cGDH has ubiquinone reductase activity nearly equivalent to that of the wild-type GDH. Thus, it is likely that the C-terminal periplasmic domain of GDH possesses a ubiquinone-reacting site and transfers electrons directly to ubiquinone. PMID- 11604399 TI - A single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors. AB - The phospholipid growth factors sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are ligands for the related G protein-coupled receptors S1P(1)/EDG1 and LPA(1)/EDG2, respectively. We have developed a model of LPA(1) that predicts interactions between three polar residues and LPA. One of these, glutamine 125, which is conserved in the LPA receptor subfamily (LPA(1)/EDG2, LPA(2)/EDG4, and LPA(3)/EDG7), hydrogen bonds with the LPA hydroxyl group. Our previous S1P(1) study identified that the corresponding glutamate residue, conserved in all S1P receptors, ion pairs with the S1P ammonium. These two results predict that this residue might influence ligand recognition and specificity. Characterization of glutamate/glutamine interchange point mutants of S1P(1) and LPA(1) validated this prediction as the presence of glutamate was required for S1P recognition, whereas LPA recognition was possible with either glutamine or glutamate. The most likely explanation for this dual specificity behavior is a shift in the equilibrium between the acid and conjugate base forms of glutamic acid due to other amino acids surrounding that position in LPA(1), producing a mixture of receptors including those having an anionic glutamate that recognize S1P and others with a neutral glutamic acid that recognize LPA. Thus, computational modeling of these receptors provided valid information necessary for understanding the molecular pharmacology of these receptors. PMID- 11604401 TI - Identification of a C-terminal region that regulates mitogen-activated protein kinase kinase-1 cytoplasmic localization and ERK activation. AB - The C-terminal region of mitogen-activated protein kinase kinase-1 and 2 (MKK1 and MKK2) may function in regulating interactions with upstream kinases or the magnitude and duration of ERK mitogen-activated protein kinase activity. The MKK C-terminal region contains a proline-rich region that reportedly functions in regulating interactions with the Raf-1 kinase and ERK activity. In addition, phosphorylation sites in the C terminus of MKK1 have been suggested to either sustain or attenuate MKK1 activity. To further understand how phosphorylation at the C terminus of MKK1 and protein interactions regulate MKK1 function, we have generated several MKK1 C-terminal deletion mutants and examined their function in regulating MKK1 localization, ERK protein activation, and cell growth. A deletion of C-terminal amino acids encompassing two putative alpha-helices between residues 330 and 379 caused a re-distribution of mutant MKK1 proteins to membrane compartments. Immunofluorescence analysis of MKK1 mutants revealed a loss of homogenous cytosolic distribution that is typically observed with MKK1 wild type, suggesting this region regulates MKK1 cellular localization. In contrast, MKK1 C terminal deletion mutants localized to various sized punctate regions that overlapped with lysosome compartments. ERK activation in response to constitutively active Raf-1 or growth factor stimulus was attenuated in cells expressing MKK1 C-terminal deletion mutants. This could be partly explained by the inability of Raf-1 to phosphorylate MKK1 C-terminal deletion mutants even though the phosphorylation sites were intact in these mutants. Finally, we show that cells expressing MKK1 C-terminal deletion mutants displayed characteristic patterns of apoptotic cell death and reduced cell proliferation. These findings identify a novel C-terminal region between amino acid residues 330 and 379 on MKK1 that is necessary for regulating the cytoplasmic distribution and subsequent ERK protein activation necessary for cell survival and viability. PMID- 11604402 TI - cag+ Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. AB - The gastric pathogen Helicobacter pylori is known to activate epithelial cell signaling pathways that regulate numerous inflammatory response genes. The aim of this study was to elucidate the pathway leading to extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in H. pylori-infected AGS gastric epithelial cells. We find that H. pylori, via activation of the epidermal growth factor (EGF) receptor activates the small GTP-binding protein Ras, which in turn, mediates ERK1/2 phosphorylation. cag+ strains of H. pylori are able to induce greater EGF receptor activation than cag- strains, and studies with isogenic mutants indicate that an intact type IV bacterial secretion system is required for this effect. Blockade of EGF receptor activation using tyrphostin AG1478 prevents H. pylori-mediated Ras activation, inhibits ERK1/2 phosphorylation, and substantially decreases interleukin-8 gene expression and protein production. Investigations into the mechanism of EGF receptor activation, using heparin, a metalloproteinase inhibitor and neutralizing antibodies reveal that H. pylori transactivates the EGF receptor via activation of the endogenous ligand heparin binding EGF-like growth factor. Transactivation of gastric epithelial cell EGF receptors may be instrumental in regulating both proliferative and inflammatory responses induced by cag+ H. pylori infection. PMID- 11604403 TI - Assembly of glycoprotein-80 adhesion complexes in Dictyostelium. Receptor compartmentalization and oligomerization in membrane rafts. AB - The phospholipid-anchored membrane glycoprotein (gp)-80 mediates cell-cell adhesion through a homophilic trans-interaction mechanism during Dictyostelium development and is enriched in a Triton X-100-insoluble floating fraction. To elucidate how gp80 adhesion complexes assemble in the plasma membrane, gp80-gp80 and gp80-raft interactions were investigated. A low density raft-like membrane fraction was isolated using a detergent-free method. It was enriched in sterols, the phospholipid-anchored proteins gp80, gp138, and ponticulin, as well as DdCD36 and actin, corresponding to components found in the Triton X-100-insoluble floating fraction. Chemical cross-linking revealed that gp80 oligomers were enriched in the raft-like membrane fraction, implicating stable oligomer-raft interactions. However, gp80 oligomers resisted sterol sequestration and were partially dissociated with Triton X-100, suggesting that compartmentalization in rafts was not solely responsible for their formation. The trans-dimer known to mediate adhesion was identified, but cis-oligomerization predominated and displayed greater accumulation during development. In fact, oligomerization was dependent on the level of gp80 expression and occurred among isolated gp80 extracellular domains, indicating that it was mediated by direct gp80-gp80 interactions. Rafts existed in gp80-null cells and such pre-existent membrane domains may provide optimal microenvironments for gp80 cis-oligomerization and the assembly of adhesion complexes. PMID- 11604405 TI - Phosphorylation of cysteine string protein by protein kinase A. Implications for the modulation of exocytosis. AB - Cyclic AMP-dependent protein kinase (PKA) enhances regulated exocytosis in neurons and most other secretory cells. To explore the molecular basis of this effect, known exocytotic proteins were screened for PKA substrates. Both cysteine string protein (CSP) and soluble NSF attachment protein-alpha (alpha-SNAP) were phosphorylated by PKA in vitro, but immunoprecipitation of cellular alpha-SNAP failed to detect (32)P incorporation. In contrast, endogenous CSP was phosphorylated in synaptosomes, PC12 cells, and chromaffin cells. In-gel kinase assays confirmed PKA to be a cellular CSP kinase, with phosphorylation occurring on Ser(10). PKA phosphorylation of CSP reduced its binding to syntaxin by 10-fold but had little effect on its interaction with HSC70 or G-protein subunits. Furthermore, an in vivo role for Ser(10) phosphorylation at a late stage of exocytosis is suggested by analysis of chromaffin cells transfected with wild type or non-phosphorylatable mutant CSP. We propose that PKA phosphorylation of CSP could modulate the exocytotic machinery, by selectively altering its availability for protein-protein interactions. PMID- 11604404 TI - Cloning of a functional splice variant of L-type calcium channel beta 2 subunit from rat heart. AB - L-type Ca(2+) channels are heteromultimeric and finely tuned by auxiliary subunits in different tissues and regions. Among auxiliary subunits, beta subunit has been shown to play important roles in many functional aspects of Ca(2+) channel. Rat heart was reported to specifically express beta(2a) subunit. However, the slow inactivation rates of Ca(2+) currents recorded from recombinant Ca(2+) channels with the beta(2a) subunit, and the reported inability to detect beta(2a) subunit in rabbit heart by reverse transcription-PCR analysis raise the possibility of the existence of other beta subunits. We cloned a splice variant of beta(2) subunit from rat heart, using rapid amplification of cDNA 5' ends. The splice variant is highly similar to human beta(2c) subunit that was cloned from human ventricle. Northern blot analysis detected the rat beta(2c) subunit abundantly in rat heart and brain. The deduced amino acid sequence of the beta(2c) subunit was different from that of the beta(2a) subunit only in the N terminal region. When the beta(2c) subunit was expressed along with alpha(1c) and alpha(2)delta subunits in baby hamster kidney cells, the inactivation rates were comparable with those from native cardiac myocytes, although those with the beta(2a) subunit were slow. Taken together, these observations suggest that the beta(2c) subunit is a functional beta(2) subunit expressed in heart and that the short N-terminal region plays a major role in modifying inactivation kinetics. PMID- 11604406 TI - Reduced cell surface expression of CCR5 in CCR5Delta 32 heterozygotes is mediated by gene dosage, rather than by receptor sequestration. AB - Macrophage tropic (M-tropic) human immunodeficiency virus (HIV) infection of primary human T cells and macrophages requires optimal cell surface expression of the chemokine receptor CCR5 in addition to CD4. Natural mutations of CCR5 that impair surface expression bestow in the homozygous state complete resistance to M tropic HIV infection. ccr5Delta32 is the major prototype of such mutants. ccr5Delta32 heterozygosity is associated with delayed onset of AIDS and reduced risk of initial transmission, and this correlates with reduced levels of CCR5 and reduced infectability of CD4+ cells. In addition to gene dosage, sequestration of wild type (WT) CCR5 by mutant protein has been proposed as a mechanism to explain reduced surface expression of CCR5 in cells from ccr5Delta32 and CCR5-893(-) heterozygotes. However, here we demonstrate that a molar excess of ccr5Delta32 or related deletion mutants does not significantly impair the cell surface density of co-expressed WT receptor either in human epithelial cells or Jurkat T cells. Further, ligand-dependent signaling and M-tropic HIV usage of WT receptor are also unaffected. Nascent WT receptor does associate with ccr5Delta32 and related mutant proteins and with other unrelated CC and CXC chemokine receptors under transient labeling conditions. However, using confocal microscopy, we demonstrate that in the steady state, WT and truncated CCR5 proteins segregate into nonoverlapping subcellular compartments. These findings together with the observed and known variability in the cell surface density of CCR5 on quiescent PBLs lead us to conclude that reduced CCR5 gene dosage rather than receptor sequestration is the major determinant of reduced CCR5 expression in cells from ccr5Delta32 heterozygotes. PMID- 11604407 TI - Characterization of nucleophosmin (B23) as a Myc target by scanning chromatin immunoprecipitation. AB - The genetic program through which a specific transcription factor regulates a biological response is fundamental to our understanding how instructions in the genome are implemented. The emergence of DNA microarray technology for gene expression analysis has generated vast numbers of target genes resulting from specific transcription factor activity. We use the oncogenic transcription factor c-Myc as proof-of-principle that human genome sequence analysis and scanning of a specific gene by chromatin immunoprecipitation can be coupled to identify target transcription factor binding sequences. We focused on nucleophosmin, also known as B23, which was identified as a candidate Myc-responsive gene from a subtractive hybridization screen, and we found that sequences in intron 1, and not 5' sequences in the proximal promoter, are bound by c-Myc in vivo. Hence, a scanning chromatin immunoprecipitation (SChIP) strategy is useful in analyzing functional transcription factor-binding sites. PMID- 11604408 TI - SERPINB12 is a novel member of the human ov-serpin family that is widely expressed and inhibits trypsin-like serine proteinases. AB - Members of the human serpin family regulate a diverse array of serine and cysteine proteinases associated with essential biological processes such as fibrinolysis, coagulation, inflammation, cell mobility, cellular differentiation, and apoptosis. Most serpins are secreted and attain physiologic concentrations in the blood and extracellular fluids. However, a subset of the serpin superfamily, the ov-serpins, also resides intracellularly. Using high throughput genomic sequence, we identified a novel member of the human ov-serpin gene family, SERPINB12. The gene mapped to the ov-serpin cluster at 18q21 and resided between SERPINB5 (maspin) and SERPINB13 (headpin). The presence of SERPINB12 in silico was confirmed by cDNA cloning. Expression studies showed that SERPINB12 was expressed in many tissues, including brain, bone marrow, lymph node, heart, lung, liver, pancreas, testis, ovary, and intestines. Based on the presence of Arg and Ser at the reactive center of the RSL, SERPINB12 appeared to be an inhibitor of trypsin-like serine proteinases. This hypothesis was confirmed because recombinant SERPINB12 inhibited human trypsin and plasmin but not thrombin, coagulation factor Xa, or urokinase-type plasminogen activator. The second-order rate constants for the inhibitory reactions were 2.5 +/- 1.6 x 10(5) and 1.6 +/- 0.2 x 10(4) M(-1) S(-1), respectively. These data show that SERPINB12 encodes for a new functional member of the human ov-serpin family. PMID- 11604409 TI - Active site residues of cephalosporin acylase are critical not only for enzymatic catalysis but also for post-translational modification. AB - Cephalosporin acylase (CA) is a recently identified N-terminal hydrolase. It is also a commercially important enzyme in producing 7-aminocephalosporanic acid (7 ACA), a backbone chemical in synthesizing semi-synthetic cephalosporin antibiotics. CA is translated as an inactive single chain precursor, being post translationally modified into an active enzyme. The post-translational modification takes place in two steps. The first intramolecular autocatalytic proteolysis takes place at one end of the spacer peptide by a nucleophilic Ser or Thr, which in turn becomes a new N-terminal Ser or Thr. The second intermolecular modification cleaves off the other end of the spacer peptide by another CA. Two binary structures in complex with glutaryl-7-ACA (the most favored substrate of CAs) and glutarate (side chain of glutaryl-7-ACA) were determined, and they revealed the detailed interactions of glutaryl-7-ACA with the active site residues (Y. Kim and W. G. J. Hol (2001) Chem. Biol., in press). In this report: 1) we have mutated key active site residues into nonfunctional amino acids, and their roles in catalysis were further analyzed; 2) we performed mutagenesis studies indicating that secondary intermolecular modification is carried out in the same active site where deacylation reaction of CA occurs; and 3) the cleavage site of secondary intermolecular modification by another CA was identified in the spacer peptide using mutational analysis. Finally, a schematic model for intermolecular cleavage of CA is proposed. PMID- 11604410 TI - HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. AB - Inhibitor of apoptosis (IAP) proteins inhibit caspases, a function counteracted by IAP antagonists, insect Grim, HID, and Reaper and mammalian DIABLO/Smac. We now demonstrate that HtrA2, a mammalian homologue of the Escherichia coli heat shock-inducible protein HtrA, can bind to MIHA/XIAP, MIHB, and baculoviral OpIAP but not survivin. Although produced as a 50-kDa protein, HtrA2 is processed to yield an active serine protease with an N terminus similar to that of Grim, Reaper, HID, and DIABLO/Smac that mediates its interaction with XIAP. HtrA2 is largely membrane-associated in healthy cells, with a significant proportion observed within the mitochondria, but in response to UV irradiation, HtrA2 shifts into the cytosol, where it can interact with IAPs. HtrA2 can, like DIABLO/Smac, prevent XIAP inhibition of active caspase 3 in vitro and is able to counteract XIAP protection of mammalian NT2 cells against UV-induced cell death. The proapoptotic activity of HtrA2 in vivo involves both IAP binding and serine protease activity. Mutations of either the N-terminal alanine of mature HtrA2 essential for IAP interaction or the catalytic serine residue reduces the ability of HtrA2 to promote cell death, whereas a complete loss in proapoptotic activity is observed when both sites are mutated. PMID- 11604416 TI - The concept of self-organization in cellular architecture. AB - In vivo microscopy has recently revealed the dynamic nature of many cellular organelles. The dynamic properties of several cellular structures are consistent with a role for self-organization in their formation, maintenance, and function; therefore, self-organization might be a general principle in cellular organization. PMID- 11604417 TI - Regulation of nucleocytoplasmic trafficking by cell adhesion receptors and the cytoskeleton. AB - It has become widely accepted that adhesion receptors can either directly activate, or significantly modulate, many of the signaling cascades initiated by circulating growth factors. An interesting recent development is the realization that adhesion receptors and their cytoskeletal partners can regulate the trafficking of signaling proteins between the cytoplasm and nucleus. Cell adhesion molecule control of nucleocytoplasmic trafficking allows adhesion to influence many cell decisions, and highlights the diversity of nuclear import and export mechanisms. PMID- 11604418 TI - Generation of high curvature membranes mediated by direct endophilin bilayer interactions. AB - Endophilin 1 is a presynaptically enriched protein which binds the GTPase dynamin and the polyphosphoinositide phosphatase synptojanin. Perturbation of endophilin function in cell-free systems and in a living synapse has implicated endophilin in endocytic vesicle budding (Ringstad, N., H. Gad, P. Low, G. Di Paolo, L. Brodin, O. Shupliakov, and P. De Camilli. 1999. Neuron. 24:143-154; Schmidt, A., M. Wolde, C. Thiele, W. Fest, H. Kratzin, A.V. Podtelejnikov, W. Witke, W.B. Huttner, and H.D. Soling. 1999. Nature. 401:133-141; Gad, H., N. Ringstad, P. Low, O. Kjaerulff, J. Gustafsson, M. Wenk, G. Di Paolo, Y. Nemoto, J. Crun, M.H. Ellisman, et al. 2000. Neuron. 27:301-312). Here, we show that purified endophilin can directly bind and evaginate lipid bilayers into narrow tubules similar in diameter to the neck of a clathrin-coated bud, providing new insight into the mechanisms through which endophilin may participate in membrane deformation and vesicle budding. This property of endophilin is independent of its putative lysophosphatydic acid acyl transferase activity, is mediated by its NH2-terminal region, and requires an amino acid stretch homologous to a corresponding region in amphiphysin, a protein previously shown to have similar effects on lipid bilayers (Takei, K., V.I. Slepnev, V. Haucke, and P. De Camilli. 1999. Nat. Cell Biol. 1:33-39). Endophilin cooligomerizes with dynamin rings on lipid tubules and inhibits dynamin's GTP-dependent vesiculating activity. Endophilin B, a protein with homology to endophilin 1, partially localizes to the Golgi complex and also deforms lipid bilayers into tubules, underscoring a potential role of endophilin family members in diverse tubulovesicular membrane trafficking events in the cell. PMID- 11604420 TI - Interactions with PIP2, ADP-actin monomers, and capping protein regulate the activity and localization of yeast twinfilin. AB - Twinfilin is a ubiquitous actin monomer-binding protein that regulates actin filament turnover in yeast and mammalian cells. To elucidate the mechanism by which twinfilin contributes to actin filament dynamics, we carried out an analysis of yeast twinfilin, and we show here that twinfilin is an abundant protein that localizes to cortical actin patches in wild-type yeast cells. Native gel assays demonstrate that twinfilin binds ADP-actin monomers with higher affinity than ATP-actin monomers. A mutant twinfilin that does not interact with actin monomers in vitro no longer localizes to cortical actin patches when expressed in yeast, suggesting that the ability to interact with actin monomers may be essential for the localization of twinfilin. The localization of twinfilin to the cortical actin cytoskeleton is also disrupted in yeast strains where either the CAP1 or CAP2 gene, encoding for the alpha and beta subunits of capping protein, is deleted. Purified twinfilin and capping protein form a complex on native gels. Twinfilin also interacts with phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2), and its actin monomer-sequestering activity is inhibited by PI(4,5)P2. Based on these results, we propose a model for the biological role of twinfilin as a protein that localizes actin monomers to the sites of rapid filament assembly in cells. PMID- 11604419 TI - Apoptotic death of neurons exhibiting peripherin aggregates is mediated by the proinflammatory cytokine tumor necrosis factor-alpha. AB - Peripherin, a neuronal intermediate filament protein associated with axonal spheroids in amyotrophic lateral sclerosis (ALS), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. To further clarify the selectivity and mechanism of peripherin-induced neuronal death, we analyzed the effects of peripherin overexpression in primary neuronal cultures. Peripherin overexpression led to the formation of cytoplasmic protein aggregates and caused the death not only of motor neurons, but also of dorsal root ganglion (DRG) neurons that were cultured from dissociated spinal cords of peripherin transgenic embryos. Apoptosis of DRG neurons containing peripherin aggregates was dependent on the proinflammatory central nervous system environment of spinal cultures, rich in activated microglia, and required TNF-alpha. This synergistic proapoptotic effect may contribute to neuronal selectivity in ALS. PMID- 11604421 TI - A two-tiered mechanism by which Cdc42 controls the localization and activation of an Arp2/3-activating motor complex in yeast. AB - The establishment of cell polarity in budding yeast involves assembly of actin filaments at specified cortical domains. Elucidation of the underlying mechanism requires an understanding of the machinery that controls actin polymerization and how this machinery is in turn controlled by signaling proteins that respond to polarity cues. We showed previously that the yeast orthologue of the Wiskott Aldrich Syndrome protein, Bee1/Las17p, and the type I myosins are key regulators of cortical actin polymerization. Here, we demonstrate further that these proteins together with Vrp1p form a multivalent Arp2/3-activating complex. During cell polarization, a bifurcated signaling pathway downstream of the Rho-type GTPase Cdc42p recruits and activates this complex, leading to local assembly of actin filaments. One branch, which requires formin homologues, mediates the recruitment of the Bee1p complex to the cortical site where the activated Cdc42p resides. The other is mediated by the p21-activated kinases, which activate the motor activity of myosin-I through phosphorylation. Together, these findings provide insights into the essential processes leading to polarization of the actin cytoskeleton. PMID- 11604422 TI - Rapid nitric oxide-induced desensitization of the cGMP response is caused by increased activity of phosphodiesterase type 5 paralleled by phosphorylation of the enzyme. AB - Most of the effects of the signaling molecule nitric oxide (NO) are mediated by cGMP, which is synthesized by soluble guanylyl cyclase and degraded by phosphodiesterases. Here we show that in platelets and aortic tissue, NO led to a biphasic response characterized by a tremendous increase in cGMP (up to 100-fold) in less than 30 s and a rapid decline, reflecting the tightly controlled balance of guanylyl cyclase and phosphodiesterase activities. Inverse to the reported increase in sensitivity caused by NO shortage, concentrating NO attenuated the cGMP response in a concentration-dependent manner. We found that guanylyl cyclase remained fully activated during the entire course of the cGMP response; thus, desensitization was not due to a switched off guanylyl cyclase. However, when intact platelets were incubated with NO and then lysed, enhanced activity of phosphodiesterase type 5 was detected in the cytosol. Furthermore, this increase in cGMP degradation is paralleled by the phosphorylation of phosphodiesterase type 5 at Ser-92. Thus, our data suggest that NO-induced desensitization of the cGMP response is caused by the phosphorylation and subsequent activity increase of phosphodiesterase type 5. PMID- 11604423 TI - Fusion pore expansion is a slow, discontinuous, and Ca2+-dependent process regulating secretion from alveolar type II cells. AB - In alveolar type II cells, the release of surfactant is considerably delayed after the formation of exocytotic fusion pores, suggesting that content dispersal may be limited by fusion pore diameter and subject to regulation at a postfusion level. To address this issue, we used confocal FRAP and N-(3 triethylammoniumpropyl)-4-(4-[dibutylamino]styryl) pyridinium dibromide (FM 1 43), a dye yielding intense localized fluorescence of surfactant when entering the vesicle lumen through the fusion pore (Haller, T., J. Ortmayr, F. Friedrich, H. Volkl, and P. Dietl. 1998. Proc. Natl. Acad. Sci. USA. 95:1579-1584). Thus, we have been able to monitor the dynamics of individual fusion pores up to hours in intact cells, and to calculate pore diameters using a diffusion model derived from Fick's law. After formation, fusion pores were arrested in a state impeding the release of vesicle contents, and expanded at irregular times thereafter. The expansion rate of initial pores and the probability of late expansions were increased by elevation of the cytoplasmic Ca2+ concentration. Consistently, content release correlated with the occurrence of Ca2+ oscillations in ATP treated cells, and expanded fusion pores were detectable by EM. This study supports a new concept in exocytosis, implicating fusion pores in the regulation of content release for extended periods after initial formation. PMID- 11604427 TI - Contrasts in service provision. PMID- 11604424 TI - Clathrin exchange during clathrin-mediated endocytosis. AB - During clathrin-mediated endocytosis, clathrin-coated pits invaginate to form clathrin-coated vesicles (CVs). Since clathrin-coated pits are planar structures, whereas CVs are spherical, there must be a structural rearrangement of clathrin as invagination occurs. This could occur through simple addition of clathrin triskelions to the edges of growing clathrin-coated pits with very little exchange occurring between clathrin in the pits and free clathrin in the cytosol, or it could occur through large scale exchange of free and bound clathrin. In the present study, we investigated this question by studying clathrin exchange both in vitro and in vivo. We found that in vitro clathrin in CVs and clathrin baskets do not exchange with free clathrin even in the presence of Hsc70 and ATP where partial uncoating occurs. However, surprisingly FRAP studies on clathrin-coated pits labeled with green fluorescent protein-clathrin light chains in HeLa cells show that even when endocytosis is blocked by expression of a dynamin mutant or depletion of cholesterol from the membrane, replacement of photobleached clathrin in coated pits on the membrane occurs at almost the same rate and magnitude as when endocytosis is occurring. Furthermore, very little of this replacement is due to dissolution of old pits and reformation of new ones; rather, it is caused by a rapid ATP-dependent exchange of clathrin in the pits with free clathrin in the cytosol. On the other hand, consistent with the in vitro data both potassium depletion and hypertonic sucrose, which have been reported to transform clathrin coated pits into clathrin cages just below the surface of the plasma membrane, not only block endocytosis but also block exchange of clathrin. Taken together, these data show that ATP-dependent exchange of free and bound clathrin is a fundamental property of clathrin-coated pits, but not clathrin baskets, and may be involved in a structural rearrangement of clathrin as clathrin-coated pits invaginate. PMID- 11604428 TI - A mayor for London. PMID- 11604429 TI - Implementing public health at the national level. PMID- 11604425 TI - Molecular analysis of the interaction of LCMV with its cellular receptor [alpha] dystroglycan. AB - alpha-Dystroglycan (DG) has been identified as the cellular receptor for lymphocytic choriomeningitis virus (LCMV) and Lassa fever virus (LFV). This subunit of DG is a highly versatile cell surface molecule that provides a molecular link between the extracellular matrix (ECM) and a beta-DG transmembrane component, which interacts with the actin-based cytoskeleton. In addition, DG exhibits a complex pattern of interaction with a wide variety of ECM and cellular proteins. In the present study, we characterized the binding of LCMV to alpha-DG and addressed the role of alpha-DG-associated host-derived proteins in virus infection. We found that the COOH-terminal region of alpha-DG's first globular domain and the NH2-terminal region of the mucin-related structures of alpha-DG together form the binding site for LCMV. The virus-alpha-DG binding unlike ECM alpha-DG interactions was not dependent on divalent cations. Despite such differences in binding, LCMV and laminin-1 use, in part, an overlapping binding site on alpha-DG, and the ability of an LCMV isolate to compete with laminin-1 for receptor binding is determined by its binding affinity to alpha-DG. This competition of the virus with ECM molecules for receptor binding likely explains the recently found correlation between the affinity of LCMV binding to alpha-DG, tissue tropism, and pathological potential. LCMV strains and variants with high binding affinity to alpha-DG but not low affinity binders are able to infect CD11c+ dendritic cells, which express alpha-DG at their surface. Infection followed by dysfunction of these antigen-presenting cells contributes to immunosuppression and persistent viral infection in vivo. PMID- 11604430 TI - Making the most of Pap tests. PMID- 11604431 TI - Glossary: unemployment, job insecurity, and health. PMID- 11604432 TI - Effects of screening on cervical cancer incidence and mortality in New South Wales implied by influences of period of diagnosis and birth cohort. AB - STUDY OBJECTIVES: Cervical cancer incidence and mortality in NSW during 1972-1996 is examined under counterfactual assumptions to estimate the number of new cervical cancer cases averted and deaths avoided, with projections to 2006. SETTING: Cervical cancer incident cases and deaths in NSW for 1972-96 were obtained from the NSW Central Cancer Registry, Sydney, Australia. DESIGN: Data were analysed by age-period-cohort (APC) modelling, using Poisson regression. Projection of incidence to 2006 was based on a linear trend for period effects. A counterfactual scenario was constructed assuming stable period effects (1972-74), but modelled cohort effects. Modelled rates were converted to cases and deaths (using mortality:incidence ratios for cervical cancer), and compared with actual data to estimate cancers prevented and deaths averted due to screening. RESULTS: Rising cohort effects with recency of birth were found after controlling for age and period of diagnosis, and declining period effects were identified after controlling for age and birth cohort. The estimated cumulated number of new cases of cervical cancer prevented during 1972-1996 was 3440. The cumulated number of averted deaths over 1972-1996, derived from incident cases, was estimated to be 1610 (including actual declines in the M/I ratio). With no change in the M/I ratio from 1972, estimated cumulated mortality averted due to cervical cancer for 1972-1996 was 1210 deaths. CONCLUSIONS: Cervical screening has prevented a substantial number of new cases of cervical cancer and deaths. In addition, secondary prevention and improved treatment has contributed further to cervical cancer deaths averted. PMID- 11604433 TI - Risk of injury and the consumption of different types of beverage: Is there an association? PMID- 11604434 TI - Diastolic blood pressure and area of residence: multilevel versus ecological analysis of social inequity. AB - STUDY OBJECTIVES: To study geographical differences in diastolic blood pressure and the influence of the social environment (census percentage of people with low educational achievement) on individual diastolic blood pressure level, after controlling for individual age and educational achievement. To compare the results of multilevel and ecological analyses. DESIGN: Cross sectional analysis performed by multilevel linear regression modelling, with women at the first level and urban areas at the second level, and by single level ecological regression using areas as the unit of analysis. SETTING: Malmo, Sweden (population 250 000). PARTICIPANTS: 15 569 women aged 45 to 73, residing in 17 urban areas, who took part in the Malmo Diet and Cancer Study (1991-1996). MAIN RESULTS: In the "fixed effects" multilevel analysis, low educational achievement at both individual (beta=1.093, SE=0.167) and area levels (beta=2.966, SE=1.250) were independently associated with blood pressure, although in the "random effects" multilevel analysis almost none of the total variability in blood pressure across persons was attributable to areas (intraclass correlation=0.3%). The ecological analysis also found an association between the area educational variable and mean diastolic blood pressure (beta=4.058, SE=1.345). CONCLUSIONS: The small intraclass correlation found indicated very marginal geographical differences and almost no influence of the urban area on individual blood pressure. However, these slight differences were enough to detect an effect of the social environment on blood pressure. The ecological study overestimated the associations found in the "fixed" effects multilevel analysis, and neither distinguished individual from area levels nor provided information on the intraclass correlation. Ecological analyses are inadequate to evaluate geographical differences in health. PMID- 11604435 TI - Misconceptions about efficacy of mammography screening: a public health dilemma. AB - OBJECTIVE: This study assessed accuracy of women's opinions about reduction in mortality from breast cancer attributable to mammography screening. DESIGN: Cross sectional survey. SETTING: General population of Geneva, Switzerland. PARTICIPANTS: 895 randomly selected women aged 40 to 80 years, free of breast cancer. RESULTS: Women estimated the proportion of deaths from breast cancer that regular mammography screening prevents in women over age 50. Only 19.3% of the respondents assessed screening efficacy realistically (that is, reduction by about one fourth); 52.0% overestimated efficacy; 26.0% "didn't know", and 2.6% stated that screening prevents no death. Women who believed mammography screening to be effective had more positive attitudes toward screening (higher scores of pros and lower scores of cons) and were more likely to plan to have a mammogram (both p<0.001). Lack of opinion about the benefit of mammography screening was more common among women who had not consulted a gynaecologist recently (p=0.02) nor had had a mammogram during the past two years (p=0.009), who had no opinion about their risk of breast cancer (p<0.001), and who were 70 to 80 years old (p=0.04). Compared with women who provided realistic estimates of screening efficacy, those who overestimated efficacy believed to be at higher risk of breast cancer than other women (p=0.04) and were more likely to be Swiss nationals (p=0.001). CONCLUSIONS: Most women overestimated and many were uninformed about the efficacy of mammography screening. Therefore, few women were able to take truly informed decisions about screening mammography. PMID- 11604436 TI - Self reported non-insulin dependent diabetes, family history, and risk of prevalent colorectal cancer: population based, cross sectional study. PMID- 11604437 TI - Risk behaviours and self rated health in Russia 1998. AB - OBJECTIVES: As self rated health and mortality represent different dimensions of public health and as risk behaviours have been closely related to mortality, we wanted to examine whether (poor) self rated health on the one hand and risk behaviours on the other can be attributed to different causes. METHODS: The Taganrog household survey (1998) was conducted in the form of face to face interviews and included 1009 people and their families. To estimate health differences and differences in risk behaviours between groups, logistic regressions were performed. RESULTS: In Taganrog between 1993/94 and 1998, changes in self rated health seem to have been much more dramatic than changes in smoking and different in direction from changes in heavy alcohol consumption. Moreover, self rated "poor" health was especially common among those whose economic situation was worse in 1998 than 10 years before. However, having a poorer economy during the period 1988-1998, does not seem to have affected drinking or smoking habits significantly. CONCLUSIONS: Self rated health seems to be closely related to three indicators of economic circumstances. Risk behaviours are probably important for the poor state of public health in Russia, but may be less sensitive to the economic aspects of the transition than is self rated health. PMID- 11604438 TI - Predictors of incidence and prevalence of green tobacco sickness among Latino farmworkers in North Carolina, USA. AB - STUDY OBJECTIVE: The characteristics of some populations make epidemiological measurement extremely difficult. The objective of this study is to identify risk factors that explain variation among incidence densities and proportions of one occupational illness, green tobacco sickness, within one such special population, Latino migrant and seasonal farmworkers in the United States. DESIGN: Prospective cohort study. SETTING: 37 farmworker residential sites located in Granville and Wake Counties, North Carolina, USA. PARTICIPANTS: 182 migrant and seasonal farmworkers that included 178 Latino men, three Latino women, and one non Hispanic white man. MAIN RESULTS: Green tobacco sickness had a prevalence of 0.082, and an incidence density of events per 100 days of 1.88 among the farmworkers. Prevalence and incidence density increased from early to late agricultural season. Major risk factors included lack of work experience, work activities, and working in wet clothes. Tobacco use was protective. CONCLUSION: Green tobacco sickness has a high incidence among migrant and seasonal farmworkers. Because workers have little control over most risk factors, further research is needed to identify ways to prevent this occupational illness. PMID- 11604439 TI - Mortality among male and female smokers in Sweden: a 33 year follow up. AB - STUDY OBJECTIVE: It is still unclear if men and women are equally susceptible to the hazards of tobacco smoking. The objective of this study was to examine smoking related mortality among men and women. DESIGN: In 1963 a questionnaire concerning tobacco smoking habits was sent out to a random sample from the 1960 Swedish census population. Date and cause of death have been collected for the deceased in the cohort through 1996. SETTING: Sweden. PARTICIPANTS: The survey included a total of 27 841 men and 28 089 women, aged 18-69 years. The response rate was 93.1% among the men and 95.4% among the women. MAIN RESULTS: After adjustment for age and place of residence positive associations were found between cigarette smoking and mortality from ischaemic heart disease, aortic aneurysm, bronchitis and emphysema, cancer of the lung, upper aerodigestive sites, bladder, pancreas in both men and women, but not from cerebrovascular disease. When the effect of amount of the cigarette consumption was considered, female smokers displayed, for example, slightly higher relative death rates from ischaemic heart disease. However, no statistically significant gender differential in relative mortality rates was observed for any of the studied diseases. CONCLUSIONS: Women and men in this Swedish cohort seem equally susceptible to the hazards of smoking, when the gender differential in smoking characteristics is accounted for. Although the cohort under study is large, there were few female smokers in the high consuming categories and the relative risk estimates are therefore accompanied by wide confidence intervals in these categories. PMID- 11604440 TI - Wellbeing of professionals at entry into the labour market: a follow up survey of medicine and architecture students. AB - STUDY OBJECTIVE: Knowledge about changes in wellbeing during the passage from professional studies to working life is scarce and controversial. This study examined these changes among university graduates with good and poor employment prospects. DESIGN: A longitudinal study with four postal questionnaire surveys of a closed cohort. SETTING: Cohorts of graduating Finnish physicians and architects were followed up from 1994 to 1998. In 1994 Finland's national economy was still struggling to break loose from a period of severe recession, and unemployment rates were high even among educated professionals. As economic growth eventually got under way the unemployment situation began to ease for physicians but not for architects. PARTICIPANTS: Architecture students (n = 189) from Finland's three technical universities and medical students (n = 638) from Finland's five medical faculties. Both had started their studies in 1989. RESULTS: In the first questionnaire survey there were no differences between the professions in strain resistance resources, as indicated by Sense of Coherence (SOC), or in psychological distress, as indicated by General Health Questionnaire (GHQ). Profession emerged as a significant between subject factor in analysis of variance for repeated measures of both SOC and GHQ. Physicians' scores on the 13 item SOC questionnaire improved during the follow up from 62.6 to 67.5 and on the 12 item GHQ questionnaire from 24.2 to 22.2. Among architects the corresponding scores remained unchanged (62.5-62.2 and 23.1-22.6). The significance of profession remained unchanged when gender and individuals' graduation and total work experience were introduced to the statistical models as between subject factors. CONCLUSIONS: Improved SOC in physicians but not in architects supports the hypothesis that good employment prospects are important to employee wellbeing. Although less consistent, indicating fluctuations in day to day psychological distress, GHQ findings are also in line with the hypothesis. In both professions the indicators studied were independent of individuals' graduation and career. It is concluded that rather than individually, the mechanisms that connect employment prospects with wellbeing operate collectively within the whole profession. Highly educated professionals do not complete their studies until almost 30, and if for reasons of insecure employment they are unable to develop their SOC to the optimum level at that age, their resources for resisting health endangering strain may remain permanently poor. PMID- 11604441 TI - Self rated health: Is it as good a predictor of subsequent mortality among adults in lower as well as in higher social classes? AB - STUDY OBJECTIVE: To analyse the predictive power of self rated health for mortality in different socioeconomic groups. DESIGN, SETTING, PARTICIPANTS: Analysis of mortality rates and risk ratios of death during follow up among 170 223 respondents aged 16 years and above in the Swedish Survey of Living Conditions 1975-1997, in relation to self rated health stated at the interview, by age, sex, socioeconomic group, chronic illness and over time. MAIN RESULTS: There was a strong relation between poor self rated health and mortality, greater at younger ages, similar among men and women and among persons with and without a chronic illness. The relative relation between self rated health and subsequent death was stronger in higher than in lower socioeconomic groups, possibly because of the lower base mortality of these groups. However, the absolute mortality risk differences between persons reporting poor and good self rated health were similar across socioeconomic groups within each sex. The mortality risk difference between persons reporting poor and good self rated health was considerably higher among persons with a chronic illness than among persons without a chronic illness. The mortality risk among persons reporting poor health was increased for shorter (<2 years) as well as longer (10+ years) periods of follow up. CONCLUSIONS: The results suggest that poor self rated health is a strong predictor of subsequent mortality in all subgroups studied, and that self rated health therefore may be a useful outcome measure. PMID- 11604442 TI - Folic acid: Is self reported use of supplements accurate? PMID- 11604443 TI - Unexplained illness and deaths among injecting drug users in England: a case control study using Regional Drug Misuse Databases. PMID- 11604444 TI - Does sending a home safety questionnaire increase recruitment to an injury prevention trial? A randomised controlled trial. PMID- 11604445 TI - The physiological ecology of vascular epiphytes: current knowledge, open questions. AB - The current knowledge of the physiological ecology of vascular epiphytes is reviewed here with an emphasis on the most recent literature. It is argued that by far the most relevant abiotic constraint for growth and vegetative function of vascular epiphytes is water shortage, while other factors such as nutrient availability or irradiation, are generally of inferior importance. However, it is shown that the present understanding of epiphyte biology is still highly biased, both taxonomically and ecologically, and it is concluded that any generalizations are still preliminary. Future studies should include a much wider range of taxa and growing sites within the canopy to reach a better understanding how abiotic factors are limiting epiphyte growth and survival which, in turn, should affect epiphyte community composition. Finally, a more integrative approach to epiphyte biology is encouraged: physiological investigations should be balanced by studies of other possible constraints, for example, substrate instability, dispersal limitation, competition or herbivory. PMID- 11604446 TI - Transgenic tobacco plants that overexpress alfalfa NADH-glutamate synthase have higher carbon and nitrogen content. AB - This work reports the characterization of transgenic tobacco (Nicotiana tabacum L.) plants that constitutively overexpress NADH-GOGAT. Three independent transformants, designated GOS10, GOS13 and GOS19 (for GOGAT sense), with stable integration of the chimeric alfalfa NADH-GOGAT gene fused to the CaMV 35S promoter were studied. The transgene was stably integrated and inherited by the progeny. In these GOS lines, the expression of NADH-GOGAT mRNA and protein was detected at low levels in roots and leaves, while the expression of the host tobacco NADH-GOGAT gene was nearly undetectable. The roots of GOS lines showed an elevated (15-40%) enzyme activity as compared to control plants. When GOS plants were grown under greenhouse conditions and fed with either nitrate or ammonium as the sole nitrogen source, they showed higher total carbon and nitrogen content in shoots and increased shoot dry weight when plants were entering into the flowering stage, as compared to control plants. The observed phenotype of GOS plants was interpreted as reflecting a higher capacity to assimilate nitrogen due to a higher NADH-GOGAT activity. PMID- 11604447 TI - An improved procedure for production of white spruce (Picea glauca) transgenic plants using Agrobacterium tumefaciens. AB - An efficient and reproducible procedure for the transformation of white spruce (Picea glauca [Moench] Voss) embryogenic tissues was developed using A. tumefaciens-mediated gene transfer. Rapidly dividing white spruce embryogenic tissues were co-cultivated with disarmed A. tumefaciens strains containing additional copies of the virulence regions from plasmid PToK47. The plasmid pBi121, containing the neomycin phosphotransferase II (nptII) gene providing kanamycin resistance as a selectable marker and the beta-glucuronidase (uidA) reporter gene, was used as binary vector. The highest frequency of transformation (15 transformed tissues g(-1) FW of treated embryogenic tissue) was obtained with 5-d-old tissues grown in liquid medium and co-cultivated with Agrobacterium for 2 d in the same medium but containing 50 microM acetosyringone. Recovery of kanamycin-resistant tissues was improved when tissues were first grown for 10 d on a timentin-containing medium (400 mg l(-1)), to prevent bacterial overgrowth, before application of the selection pressure. After 6 weeks on kanamycin selection medium, resistant tissues were obtained and showed stable uidA expression. The presence of the transgenes was demonstrated by PCR analysis and their integration into the genome was confirmed by Southern hybridization. Transgenic plants were regenerated from transformed tissues within 4 months after co-culture. PMID- 11604448 TI - Abscisic acid-specific binding sites in the flesh of developing apple fruit. AB - Abscisic acid (ABA) specific-binding sites localized in the cytosol were identified and characterized in the flesh of developing apple (Malus pumila L. cv. Starkrimon) fruit. ABA binding activity was scarcely detectable in the microsomes but high ABA binding activity in the cytosolic fraction was detected. The ABA-binding sites possessed a protein nature with both active serine residues and thiol-groups of cysteine residues in their functional binding sites. ABA binding was shown to be saturable, reversible and of high affinity. A Scatchard plot provided evidence for two different ABA binding proteins, one with higher affinity (K(d)=2.3 nM) and the other with lower affinity (K(d)=58.8 nM). Phaseic acid, trans-ABA and (-)-ABA had essentially no affinity for the binding proteins, indicating their stereo-specificity to bind physiologically active cis-(+)-ABA. The time-course, pH- and temperature-dependence of the ABA-binding proteins were determined. It is hypothesized that the detected ABA-binding proteins may be putative ABA-receptors that mediate ABA signals during fruit development. PMID- 11604449 TI - Desiccation tolerance of protoplasts isolated from pea embryos. AB - To facilitate studies of desiccation tolerance at the cellular level, a technique to isolate protoplasts from desiccation-tolerant pea (Pisum sativum L. cv. Alaska) embryos has been developed. Using FDA (fluorescein diacetate) as a probe, viability of the protoplasts was investigated before and after drying to determine whether the protoplasts could survive desiccation in a manner similar to the tissue from which they were isolated. Protoplasts were isolated from 12 h imbibed pea axes, suspended in several different sugar solutions, then dried to water contents less than 0.2 g H(2)O g(-1) DW. Protoplasts only survived drying if the rate was rapid (<2 h), while slow drying (24 h) was lethal. Maximal survival (75%) was obtained after drying protoplasts with a mixture of sucrose and raffinose, while pure sucrose and trehalose were somewhat less effective protectants. Low survival was obtained after drying protoplasts with monosaccharides and pure raffinose. Protoplasts isolated from germinated seedlings did not survive dehydration below 0.2 g H(2)O g(-1) DW. Transmission electron microscopy revealed that dried desiccation-tolerant protoplasts appeared shrunken, with folded membranes, while dried protoplasts from sensitive tissue had disrupted membranes. While isolated protoplasts maintained some of the desiccation tolerance of orthodox seeds, their inability to survive complete drying and their sensitivity to drying rate is similar to the behaviour of recalcitrant embryos. PMID- 11604450 TI - Cadmium-induced changes in the growth and oxidative metabolism of pea plants. AB - The effect of growing pea (Pisum sativum L.) plants with CdCl(2) (0-50 microM) on different plant physiological parameters and antioxidative enzymes of leaves was studied in order to know the possible involvement of this metal in the generation of oxidative stress. In roots and leaves of pea plants Cd produced a significant inhibition of growth as well as a reduction in the transpiration and photosynthesis rate, chlorophyll content of leaves, and an alteration in the nutrient status in both roots and leaves. The ultrastructural analysis of leaves from plants grown with 50 microM CdCl(2), showed cell disturbances characterized by an increase of mesophyll cell size, and a reduction of intercellular spaces, as well as severe disturbances in chloroplast structure. Alterations in the activated oxygen metabolism of pea plants were also detected, as evidenced by an increase in lipid peroxidation and carbonyl-groups content, as well as a decrease in catalase, SOD and, to a lesser extent, guaiacol peroxidase activities. Glutathione reductase activity did not show significant changes as a result of Cd treatment. A strong reduction of chloroplastic and cytosolic Cu,Zn-SODs by Cd was found, and to a lesser extent of Fe-SOD, while Mn-SOD was only affected by the highest Cd concentrations. Catalase isoenzymes responded differentially, the most acidic isoforms being the most sensitive to Cd treatment. Results obtained suggest that growth of pea plants with CdCl(2) can induce a concentration dependent oxidative stress situation in leaves, characterized by an accumulation of lipid peroxides and oxidized proteins as a result of the inhibition of the antioxidant systems. These results, together with the ultrastructural data, point to a possible induction of leaf senescence by cadmium. PMID- 11604451 TI - The position of localized soil compaction determines root and subsequent shoot growth responses. AB - Plants growing in soils typically experience a mixture of loose and compact soil. The hypothesis that the proportion of a root system exposed to compact soil and/or the timing at which this exposure occurs determines shoot growth responses was tested. Broccoli (Brassica oleracea var. italica cv. Greenbelt) seedlings were grown in pot experiments with compact, loose and localized soil compaction created by either horizontal (compact subsoils 75 or 150 mm below loose topsoil) or vertical (adjacent compact and loose columns of soil) configurations of loose (1.2 Mg m(-3)) and compact (1.8 Mg m(-3)) soil. Entirely compact soil reduced leaf area by up to 54%, relative to loose soil. When compaction was localized, only the vertical columns of compact and loose soil reduced leaf area (by 30%). Neither the proportion of roots in compact soil nor the timing of exposure could explain the differing shoot growth responses to localized soil compaction. Instead, the strong relationship between total root length and leaf area (r(2)=0.92) indicated that localized soil compaction reduced shoot growth only when it suppressed total root length. This occurred when isolated root axes of the same plant were exposed to vertical columns of compact and loose soil. When a single root axis grew through loose soil into either a shallow or deep compact subsoil, compensatory root growth in the loose soil maintained total root length and thus shoot growth was unaffected. These contrasting root systems responses to localized soil compaction may explain the variable shoot growth responses observed under heterogeneous conditions. PMID- 11604452 TI - Stem diameter variations and cold hardiness in walnut trees. AB - The effect of freezing temperatures on stem diameter was measured in the field and in climatic chambers using linear variable differential transformers (LVDT sensors). In acclimated stems, there was reversible stem shrinkage associated with freeze-thaw cycles. The maximum shrinkage correlated with stem diameter (thickness of the bark). The wood was responsible for only 15% of the shrinkage associated with a freeze event, and experiments with isolated bark showed that connection with the wood was not necessary for most of the freeze-induced shrinkage to occur. Considering the amount of stem shrinkage associated with summer drought in walnut, the amount of contraction of the bark with freezing was actually much less than might be predicted by water relations theory. Reversible stem shrinkage occurred in living tissues, but not in autoclaved tissues. For the latter, swelling was observed with freezing and this swelling could be explained by the bark alone. Similar swelling was observed during September and October for non-acclimated plants. Water was lost with each freeze-thaw cycle starting with the first, and freezing injury of the bark, with discoloration of tissues, was also observed in non-acclimated plants. Given that the diameter fluctuation patterns were dramatically different for acclimated versus non-acclimated plants, and for living versus autoclaved tissues, LVDT sensors could represent a novel, non-invasive approach to testing cold hardiness. PMID- 11604453 TI - Effect of top excision and replacement by 1-naphthylacetic acid on partition and flow of potassium in tobacco plants. AB - The effect of removal of the shoot apex of 92-d-old tobacco plants and its replacement by 1-naphthylacetic acid (NAA) on sink-source relationships and on the flows and partitioning of potassium and water has been studied over a short term period of 7 d (intact control plants) or 8 d (decapitated and NAA-treated plants). For determining flows an upper, middle and lower stratum of three leaves each were analysed. Within the study period three new leaves were formed in control plants and 57.7% of the total dry matter increment during the experimental period was allocated to the apex and these newly formed leaves. An even higher proportion of the K+ taken up (93.8%) was deposited in these organs and this was imported via xylem (72%) and phloem (28%). Only 18.7% and 9.8% of the total dry matter increment were found in the previously present upper leaves and the roots, respectively, and substantial net K+ export occurred from middle and lower leaves and roots. Decapitation removed the dominant phloem sink and caused marked changes in sink-source relationships. After decapitation the net increase in root dry matter was twice that of control plants. 56.2% of the total net increments in dry matter and 70% of the absorbed K+ were deposited in upper leaves (below the excised apex). There was only slight net K+ export from the middle leaves. Application of NAA on the cut surface of the stem stump did not change the growth of plants that much, apart from a substantial increase in stem growth, correspondingly it stimulated the partitioning of K+ into the upper leaves and most dramatically into the stem, which deposited 64.5% or 27% of the K+ uptake, respectively. In these plants K+ uptake was increased and the K+ concentrations in upper, middle and lower leaves were increased from 4.7, 5.4 and 5.6 to 5.1, 6.1 and 6.1% of dry matter, respectively. Possible mechanisms of this effect of NAA on the improvement of K+ concentration in tobacco leaves are discussed in detail. PMID- 11604454 TI - Correlative controls of senescence and plant death in Arabidopsis thaliana (Brassicaceae). AB - Like most monocarpic plants, longevity of Arabidopsis thaliana plants is controlled by the reproductive structures; however, they appear to work differently from most dicots studied. Neither male- and female-sterility mutations (ms1-1 and bell1, respectively) nor surgical removal of the stems with inflorescences (bolts) at various stages significantly increased the longevity of individual rosette leaves, yet the mutants and treated plants lived 20-50 d longer, measured by the death of the last rosette and/or the last cauline leaf. A series of growth mutations (clv2-4, clv3-2, det3, vam1 enh, and dark green) also increased plant longevity by 20-30 d but did not delay the overall development of the plants. The mutations prolonged plant life through the production of new leaves and stems with inflorescences (bolts) rather than by extending leaf longevity. In growing stems, the newly-formed leaves may induce senescence in the older leaves; however, removal of the younger leaves did not significantly increase the life of the older leaves on the compressed stems of Arabidopsis. Since plants that produce more bolts also live longer, the reproductive load (dry weight) of the bolts did not seem to drive leaf or whole plant senescence here. The developing reproductive structures caused the death of the plant by preventing regeneration of leaves and bolts, which are green and presumably photosynthetic. They also exerted a correlative control (repression) on the development of additional reproductive structures. PMID- 11604455 TI - Ion fluxes, auxin and the induction of elongation growth in Nicotiana tabacum cells. AB - Immobilized cultured tobacco cells become polarized upon the addition of naphthalene-1-acetic acid and start to elongate from an initial spherical shape. The question as to how a diffuse-growing cell forms a polar axis is addressed here with approaches successfully applied to the study of tip growth. With two kinds of vibrating probes the electric current flow and proton fluxes were mapped around such elongating cells. No consistent polar pattern of ion fluxes, which is typical for actively tip-growing cells, was detected. Therefore, other signals must provide the positional information needed for polar axis formation. Furthermore, neither a specific pattern of intracellular Ca(2+) concentration nor a polar distribution of putative ion-channel antagonist-binding sites were found in elongating tobacco cells. Auxin flux, on the other hand, was found to be important as TIBA, an inhibitor of polar auxin transport, clearly inhibited elongation in a concentration-dependent way. Cross-linking of arabinogalactan proteins with the beta-Yariv reagent also resulted in inhibition of elongation. A model is proposed for the induction of polar growth where localized auxin efflux starts a signal cascade that triggers molecules that reorient microtubules. These then guide cellulose deposition in the cell wall, which in turn alters cell wall mechanics and leads to elongation. In this scheme, arabinogalactan-proteins are not causal agents but are probably important regulators of growth and survival of the cell. PMID- 11604456 TI - Activities of starch hydrolytic enzymes and sucrose-phosphate synthase in the stems of rice subjected to water stress during grain filling. AB - To understand the effect of water stress on the remobilization of prestored carbon reserves, the changes in the activities of starch hydrolytic enzymes and sucrose-phosphate synthase (SPS) in the stems of rice (Oryza sativa L.) during grain filling were investigated. Two rice cultivars, showing high lodging resistance and slow remobilization, were grown in the field and subjected to well watered (WW, psi(soil)=0) and water-stressed (WS, psi(soil)=-0.05 MPa) treatments 9 d after anthesis (DAA) till maturity. Leaf water potentials of both cultivars markedly decreased during the day as a result of WS treatment, but completely recovered by early morning. WS treatment accelerated the reduction of starch in the stems, promoted the reallocation of prefixed (14)C from the stems to grains, shortened the grain filling period, and increased the grain filling rate. More soluble sugars including sucrose were accumulated in the stems under WS than under WW treatments. Both alpha- and beta-amylase activities were enhanced by the WS, with the former enhanced more than the latter, and were significantly correlated with the concentrations of soluble sugars in the stems. The other two possible starch-breaking enzymes, alpha-glucosidase and starch phosphorylase, showed no significant differences in the activities between the WW and WS treatments. Water stress also increased the SPS activity that is responsible for sucrose production. Both V(limit) and V(max), the activities of the enzyme at limiting and saturating substrate concentrations, were enhanced and the activation state (V(limit)/V(max)) was also increased as a result of the more significant enhancement of V(limit). The enhanced SPS activity was closely correlated with an increase of sucrose accumulation in the stems. The results suggest that the fast hydrolysis of starch and increased carbon remobilization were attributed to the enhanced alpha-amylase activity and the high activation state of SPS when the rice was subjected to water stress. PMID- 11604457 TI - Redifferentiation of bacteria isolated from Lotus japonicus root nodules colonized by Rhizobium sp. NGR234. AB - In most studies concerning legume root nodules, the question to what extent the nodule-borne bacteroids survive nodule senescence has not been properly addressed. At present, there is no "model system" to study these aspects in detail. Such a system with Lotus japonicus and the broad host range Rhizobium sp. NGR234 has been developed. L. japonicus L. cv. Gifu was inoculated with Rhizobium sp. NGR234 and grown over a 12 week time period. The first nodules could be harvested after 3 weeks. Nodulation reached a plateau after 11 weeks with a mean of 64 nodules having a biomass of nearly 100 mg FW per plant. Nodules were harvested and homogenized at different stages of plant development. Microscopic inspection of the extracts revealed that, typically, nodules contained c. 15x10(9) bacteroids g(-1) FW, and that about 60% of the bacteroids were viable as judged by vital staining. When aliquots of the extracts were plated on selective media, a substantial number of "colony-forming units" was observed in all cases, indicating that a considerable fraction of the bacteroids had the potential to redifferentiate into growing bacteria. In nodules from the early developmental stages, the fraction of total bacteroids yielding CFUs amounted to about 20%, or one-third of the bacteroids judged to be viable after extraction, and it increased slightly when the plants started to flower. In order to see how nodule senescence affected the survival and redifferentiation potential of bacteroids, some plants were placed in the dark for 1 week. This led to typical symptoms of senescence in the nodules such as an almost complete loss of nitrogenase activity and a considerable decrease in soluble proteins. However, surprisingly, the number of total and viable bacteroids g(-1) nodule FW remained virtually constant, and the fraction of total bacteroids yielding CFUs did not decrease but significantly increased up to 75% of the bacteroids judged to be viable after extraction. This result indicates that during nodule senescence bacteroids might be induced to redifferentiate into the state of free-living, growing bacteria. PMID- 11604459 TI - How the roots contribute to the ability of Phaseolus vulgaris L. to cope with chilling-induced water stress. AB - Intact plants and stem-girdled plants of Phaseolus vulgaris grown hydroponically were exposed to 5 degrees C for up to 4 d; stem girdling was used to inhibit the phloem transport from the leaves to the roots. After initial water stress, stomatal closure and an amelioration of root water transport properties allowed the plants to rehydrate and regain turgor. Chilling augmented the concentration of abscisic acid (ABA) content in leaves, roots and xylem sap. In intact plants stomatal closure and leaf ABA accumulation were preceded by a slight alkalinization of xylem sap, but they occurred earlier than any increase in xylem ABA concentration could be detected. Stem girdling did not affect the influence of chilling on plant water relations and leaf ABA content, but it reduced slightly the alkalinization of xylem sap and, principally, prevented the massive ABA accumulation in root tissues and the associated transport in the xylem that was observed in non-girdled plants. When the plants were defoliated just prior to chilling or after 10 h at 5 degrees C, root and xylem sap ABA concentration remained unchanged throughout the whole stress period. When the plants were chilled under conditions preventing the occurrence of leaf water deficit (i.e. at 100% relative humidity), there were no significant variations in endogenous ABA levels. The increase in root hydraulic conductance in chilled plants was a response neither to root ABA accretion, nor to some leaf-borne chemical signal transported downwards in the phloem, nor to low temperature per se, as indicated by the results of the experiments with defoliated or girdled plants and with plants chilled at 100% relative humidity. It was concluded that the root system contributed substantially to the bean's ability to cope with chilling-induced water stress, but not in an ABA-dependent manner. PMID- 11604458 TI - Seed reserve-dependent growth responses to temperature and water potential in carrot (Daucus carota L.). AB - Both temperature and soil moisture vary greatly in the surface layers of the soil through which seedlings grow following germination. The work presented studied the impact of these environmental variables on post-germination carrot growth to nominal seedling emergence. The rapid pre-crook downward growth of both the hypocotyl and root was consistent with their requirement for establishment in soil drying from the surface. At all temperatures, both hypocotyl and root growth rates decreased as water stress increased and there was a very distinct temperature optimum that tended to occur at lower temperatures as water stress increased. A model based on the thermodynamics of reversible protein denaturation was adapted to include the effects of water potential in order to describe these growth rate responses. In general, the percentage of seedlings that reached the crook stage (start of upward hypocotyl growth) decreased at the extremes of the temperature range used and was progressively reduced by increasing water stress. A model was developed to describe this response based on the idea that each seedling within a population has lower and upper temperature thresholds and a water potential threshold which define the conditions within which it is able to grow. This threshold modelling approach which applies growth rates within a distribution of temperature and water potential thresholds could be used to simulate seedling growth by dividing time into suitable units. PMID- 11604460 TI - Exogenous ascorbic acid (vitamin C) increases resistance to salt stress and reduces lipid peroxidation. AB - The transition from reversible to permanent wilting, in whole tomato seedlings (Lycopersicon esculentum Mill. cv. M82) following severe salt-stress by root exposure to 300 mM NaCl, was investigated. Salinized seedlings wilted rapidly but recovered if returned to non-saline nutrient solution within 6 h. However, after 9 h of salt-treatment 100% of the seedlings remained wilted and died. Remarkably, the addition of an anti-oxidant (0.5 mM ascorbic acid) to the root medium, prior to and during salt-treatment for 9 h, facilitated the subsequent recovery and long-term survival of c. 50% of the wilted seedlings. Other organic solutes without known anti-oxidant activity were not effective. Salt-stress increased the accumulation in roots, stems and leaves, of lipid peroxidation products produced by interactions with damaging active oxygen species. Additional ascorbic acid partially inhibited this response but did not significantly reduce sodium uptake or plasma membrane leakiness. PMID- 11604461 TI - Long-term anoxia tolerance in leaves of Acorus calamus L. and Iris pseudacorus L. AB - Mature green leaves of Acorus calamus and Iris pseudacorus have been shown to survive at least 28 d of total anoxia in the dark during the growing season, increasing up to 75 d and 60 d in overwintering leaves in A. calamus and I. pseudacorus, respectively. During the period of anaerobic incubation the glycolytic rate is reduced, carbohydrate reserves are conserved and ethanol levels in the tissues reached an equilibrium. Prolonged anoxia significantly suppressed leaf capacity for respiration and photosynthesis. After 28 d of anoxia, respiratory capacity was reduced in A. calamus and I. pseudacorus by 80% and 90%, respectively. The photosynthetic capacity of leaves decreased by 83% in A. calamus and by 97% in I. pseudacorus after 28 d of anoxia. This reduction in photosynthetic capacity was accompanied by a modification of the chlorophyll fluorescence pattern indicating damage to the PSII reaction centre and subsequent electron transport. Chlorophyll content was only slightly reduced after 28 d under anoxia and darkness in A. calamus, whereas there was a 50% reduction in I. pseudacorus. On return to air A. calamus leaves that endured 28 d of anoxia recovered full photosynthetic activity within 7 d while those of I. pseudacorus had a lag phase of 3-10 d. This well-developed ability to endure prolonged periods of oxygen deprivation in both these species is associated with a down regulation in metabolic activity in response to the imposition of anaerobiosis. It is suggested that when leaf damage eventually does take place in these species after protracted oxygen deprivation, it is anoxic rather than post-anoxic stress that is responsible. PMID- 11604462 TI - Sunflower (Helianthus annuus L.) response to broomrape (Orobanche cernua Loefl.) parasitism: induced synthesis and excretion of 7-hydroxylated simple coumarins. AB - The interaction of the parasitic plant Orobanche cernua with resistant and susceptible cultivars of Helianthus annuus L. was investigated. Using different bioassays to evaluate the early stages of the parasite life cycle (germination, attachment, penetration, and establishment), differences were observed between O. cernua-resistant and O. cernua-susceptible sunflower varieties. Germination of O. cernua seeds in the presence of resistant sunflower roots was approximately half that of germination in the presence of susceptible roots, and germinated seeds displayed enhanced browning symptoms. Parasite radicles or host-tissue around the contact point turned brown after O. cernua attachment to sunflower roots, especially in the resistant varieties. These observations suggested the possible accumulation of toxic compounds as a defence strategy in the resistant sunflower varieties. Sunflower 7-hydroxylated simple coumarins may play a defensive role against O. cernua parasitism by preventing successful germination, penetration and/or connection to the host vascular system. This hypothesis is supported by the following data: (i) coumarins inhibited the in vitro germination of O. cernua seeds induced by the strigol analogue GR(24) and caused a browning reaction in germinated seeds and (ii) resistant sunflowers accumulated higher levels of coumarins in roots and excreted greater amounts than susceptible varieties in response to O. cernua infection. PMID- 11604463 TI - Leaf O(2) uptake in the dark is independent of coincident CO(2) partial pressure. AB - Elevated CO(2), in the dark, is sometimes reported to inhibit leaf respiration, with respiration usually measured as CO(2) efflux. Oxygen uptake may be a better gauge of respiration because non-respiratory processes can affect dark CO(2) efflux in elevated CO(2). Two methods of quantifying O(2) uptake indicated that leaf respiration was unaffected by coincident CO(2) level in the dark. PMID- 11604464 TI - DNA replication in plants: characterization of a cdc6 homologue from Arabidopsis thaliana. AB - Cdc6 is a key regulator of DNA replication in eukaryotes. In this work, the expression pattern of an Arabidopsis cdc6 homologue is characterized by RT-PCR and in situ hybridization. The data suggest that cdc6At expression is cell cycle regulated. During development, high cdc6At mRNA levels are found in regular cycling cells. In addition, cdc6At expression is also observed in cells that are probably undergoing endoreduplication, suggesting a possible role of Cdc6At in this process in plants. PMID- 11604465 TI - Cloning of cDNAs encoding SODs from lettuce plants which show differential regulation by arbuscular mycorrhizal symbiosis and by drought stress. AB - In the present study three cDNA fragments were cloned using degenerate primers for Mn-sod genes and PCR: two showed a high degree of identity with Mn-sods from plants and the third with Fe-sod. Arbuscular mycorrhizal (AM) symbiosis down regulated their expression pattern under well-watered conditions. In contrast, AM symbiosis in combination with drought stress considerably increased the expression of the Mn-sod II gene and this correlated well with plant tolerance to drought. These results would suggest that mycorrhizal protection against oxidative stress caused by drought may be an important mechanism by which AM fungi protect the host plant against drought. PMID- 11604467 TI - A predisposition supposition for glioma. PMID- 11604468 TI - Light at night, shiftwork, and breast cancer risk. PMID- 11604469 TI - Australian report urges nationwide radiation therapy plan. PMID- 11604470 TI - Rapamycin's resurrection: a new way to target the cancer cell cycle. PMID- 11604471 TI - Rapamycin may prevent post-transplant lymphoma. PMID- 11604472 TI - The age of breast cancer awareness: what is the effect of media coverage? PMID- 11604474 TI - Ethnicity may affect alternative, complementary therapy choices. PMID- 11604475 TI - Esophageal cancer prevention in zinc-deficient rats: rapid induction of apoptosis by replenishing zinc. AB - BACKGROUND: Nutritional zinc deficiency in rats increases esophageal cell proliferation and the incidence of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors. Replenishing zinc with a zinc-sufficient diet reduces these effects in zinc-deficient (ZD) rats. We investigated whether apoptosis was involved in the reduction of NMBA-induced esophageal tumors when ZD rats consumed a zinc-sufficient diet. METHODS: Weanling rats were fed a ZD diet (zinc at 3-4 ppm) for 5 weeks to establish esophageal cell proliferation, then treated once with NMBA (2 mg/kg body weight), and divided into the following five groups (47 100 per group). One ZD group was fed the ZD diet, and four zinc-replenished (ZR) groups, ZR(1), ZR(24), ZR(72), and ZR(432), were fed a zinc-sufficient diet (zinc at 74-75 ppm) beginning 1, 24, 72, and 432 hours, respectively, after NMBA treatment. From 24 hours to 2 weeks after beginning a zinc-sufficient diet, esophagi from all ZR groups were analyzed for apoptosis and cell proliferation; ZD esophagi were the controls. Tumor incidence was determined 15 weeks after zinc replenishment. All statistical tests were two-sided. RESULTS: Zinc replenishment initiated shortly after NMBA treatment effectively reduced esophageal tumorigenesis; 8% (three of 37) of ZR(1), 14% (five of 37) of ZR(24), 19% (five of 26) of ZR(72), and 48% (19 of 40) of ZR(432) rats developed esophageal tumors compared with 93% (14 of 15) of ZD animals (all P<.001). Importantly, 24 and 30 hours after zinc replenishment, esophagi had numerous apoptotic cells (% apoptotic cells: 0 hour = 2.9%, 95% confidence interval [CI] = 2.5% to 3.3%; 24 hours = 9.4%, 95% CI = 8.2% to 10.6%), and the expression of the proapoptotic Bax protein doubled. Within 48 hours, the ZR(1) epithelium was three to five cell layers thick compared with 10-20 layers before zinc replenishment. CONCLUSIONS: Zinc replenishment of NMBA-treated ZD rats rapidly induces apoptosis in esophageal epithelial cells and thereby substantially reduces the development of esophageal cancer. PMID- 11604476 TI - 1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice. AB - BACKGROUND: Defective mismatch repair (MMR) in humans is particularly associated with familial colorectal cancer, but defective repair in mice is generally associated with lymphoma in the absence of experimental exposure to carcinogens. Loss of MMR also confers resistance to the toxic effects of methylating agents. We investigated whether resistance to methylation contributes to increased susceptibility to colorectal cancer in mice by exposing mice with defects in the MMR gene msh2 to a methylating agent. METHODS: Tumor incidence and time of death in msh2(+/+), msh2(+/-), and msh2(-/-) mice were analyzed after weekly exposure (until tumor appearance) to the methylating agent 1,2-dimethylhydrazine (DMH). Chemically induced and spontaneous tumors were characterized by frequency, type, and location. The tumor incidence in untreated and treated mice of each genotype was compared by a Mann-Whitney U test. Carcinogen-induced apoptosis in histologic sections of small and large intestines was also determined. All statistical tests were two-sided. RESULTS: Homozygous inactivation of the msh2 gene statistically significantly accelerated (P<.0001) death due to the development of DMH-induced colorectal tumors and lymphomas. Rates of death from DMH-induced colorectal adenocarcinoma were similar in msh2 heterozygous and wild-type mice, but only msh2 heterozygotes (msh(+/-)) developed additional, noncolorectal malignancies (notably trichofolliculoma [two of 21], angiosarcoma of the kidney capsule [two of 21], and lymphoma [one of 21]), suggesting that heterozygosity for msh2 slightly increases DMH susceptibility. DMH induced apoptosis in small intestinal and colonic epithelial crypts that was dependent on active msh2. CONCLUSIONS: Inactivation of msh2 allows the proliferation of gastrointestinal tract cells damaged by methylating agents. Furthermore, MMR constitutes a powerful defense against colorectal cancer induced by DNA methylation. PMID- 11604477 TI - Effects of survivin antagonists on growth of established tumors and B7-1 immunogene therapy. AB - BACKGROUND: Survivin, a member of the inhibitor of apoptosis (IAP) protein family, is detectable in most types of cancer, and its presence is associated with a poor prognosis. We determined the effects of gene-based therapies that inhibit survivin function in a mouse tumor model. METHODS: Using five to six mice per treatment group, we injected tumors derived from mouse EL-4 thymic lymphoma cells with plasmids encoding antisense survivin, a dominant-negative mutant survivin, and the T-cell costimulator B7-1. Expression of endogenous survivin and the proteins encoded by the injected plasmids were examined by immunohistochemical staining of tumor sections and by western blot and flow cytometry analyses of isolated tumor cells. Tumor growth, the generation of antitumor cytotoxic T-lymphocyte (CTL) activity, apoptosis, and the contribution of leukocyte subsets to antitumor activity were measured. All statistical tests were two-sided. RESULTS: Large (1.0-cm diameter) tumors had approximately 10-fold more survivin than small (0.2-cm diameter) tumors. At 28 days after injection, antisense and dominant-negative mutant survivin plasmids statistically significantly inhibited the growth of both small (P =.006 and P =.0018, respectively) and large (P<.001 for both plasmids) EL-4 tumors compared with tumors injected with empty plasmid. The growth of large tumors was further inhibited by intratumoral injection with antisense survivin and B7-1 (P =.004); thus, inhibition of survivin expression renders large tumors susceptible to B7-1 mediated immunotherapy. Mice whose tumors were completely eradicated by injection of B7-1 remained tumor free for 26 days after re-injection with EL-4 cells (when the experiment ended). Compared with tumors injected with empty plasmid, tumors injected with survivin-based plasmids had increased apoptosis, and animals bearing such tumors generated more antitumor CTLs. CONCLUSION: Intratumoral injection of plasmids that block survivin expression and stimulate the generation of tumor-specific CTLs may be beneficial for the treatment of large lymphomas. PMID- 11604478 TI - Gamma-radiation sensitivity and risk of glioma. AB - BACKGROUND: About 9% of human cancers are brain tumors, of which 90% are gliomas. gamma-Radiation has been identified as a risk factor for brain tumors. In a previous pilot study, we found that lymphocytes from patients with glioma were more sensitive to gamma-radiation than were lymphocytes from matched control subjects. In this larger case-control study, we compared the gamma-radiation sensitivity of lymphocytes from glioma patients with those from control subjects and investigated the association between mutagen sensitivity and the risk for developing glioma. METHODS: We used a mutagen sensitivity assay (an indirect measure of DNA repair activity) to assess chromosomal damage. We gamma-irradiated (1.5 Gy) short-term lymphocyte cultures from 219 case patients with glioma and from 238 healthy control subjects frequency matched by age and sex. After irradiation, cells were cultured for 4 hours, and then Colcemid was added for 1 hour to arrest cells in mitosis. Fifty metaphases were randomly selected for each sample and scored for chromatid breaks. All statistical tests were two-sided. RESULTS: We observed a statistically significantly higher frequency of chromatid breaks per cell from case patients with glioma (mean = 0.55; 95% confidence interval [CI] = 0.50 to 0.59) than from control subjects (mean = 0.44; 95% CI = 0.41 to 0.48) (P<.001). Using 0.40 (the median number of chromatid breaks per cell in control subjects) as the cut point for defining mutagen sensitivity and adjusting for age, sex, and smoking status, we found that mutagen sensitivity was statistically significantly associated with an increased risk for glioma (odds ratio = 2.09; 95% CI = 1.43 to 3.06). When the data were divided into tertiles, the relative risk for glioma increased from the lowest tertile to the highest tertile (trend test, P<.001). CONCLUSION: gamma-Radiation-induced mutagen sensitivity of lymphocytes may be associated with an increased risk for glioma, a result that supports our earlier preliminary findings. PMID- 11604479 TI - Night shift work, light at night, and risk of breast cancer. AB - BACKGROUND: Exposure to light at night may increase the risk of breast cancer by suppressing the normal nocturnal production of melatonin by the pineal gland, which, in turn, could increase the release of estrogen by the ovaries. This study investigated whether such exposure is associated with an increased risk of breast cancer in women. METHODS: Case patients (n = 813), aged 20-74 years, were diagnosed from November 1992 through March 1995; control subjects (n = 793) were identified by random-digit dialing and were frequency matched according to 5-year age groups. An in-person interview was used to gather information on sleep habits and bedroom lighting environment in the 10 years before diagnosis and lifetime occupational history. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by use of conditional logistic regression, with adjustment for other potential risk factors. RESULTS: Breast cancer risk was increased among subjects who frequently did not sleep during the period of the night when melatonin levels are typically at their highest (OR = 1.14 for each night per week; 95% CI = 1.01 to 1.28). Risk did not increase with interrupted sleep accompanied by turning on a light. There was an indication of increased risk among subjects with the brightest bedrooms. Graveyard shiftwork was associated with increased breast cancer risk (OR = 1.6; 95% CI = 1.0 to 2.5), with a trend of increased risk with increasing years and with more hours per week of graveyard shiftwork (P =.02, Wald chi-squared test). CONCLUSION: The results of this study provide evidence that indicators of exposure to light at night may be associated with the risk of developing breast cancer. PMID- 11604480 TI - Rotating night shifts and risk of breast cancer in women participating in the nurses' health study. AB - BACKGROUND: Melatonin shows potential oncostatic action, and light exposure during night suppresses melatonin production. There is little information, however, about the direct effect of night work on the risk of cancer. We investigated the effect of night work in breast cancer. METHODS: We examined the relationship between breast cancer and working on rotating night shifts during 10 years of follow-up in 78 562 women from the Nurses' Health Study. Information was ascertained in 1988 about the total number of years during which the nurses had worked rotating night shifts with at least three nights per month. From June 1988 through May 1998, we documented 2441 incident breast cancer cases. Logistic regression models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs), adjusted for confounding variables and breast cancer risk factors. All statistical tests were two-sided. RESULTS: We observed a moderate increase in breast cancer risk among the women who worked 1-14 years or 15-29 years on rotating night shifts (multivariate adjusted RR = 1.08 [95% CI = 0.99 to 1.18] and RR = 1.08 [95% CI = 0.90 to 1.30], respectively). The risk was further increased among women who worked 30 or more years on the night shift (RR = 1.36; 95% CI = 1.04 to 1.78). The test for trend was statistically significant (P =.02). CONCLUSIONS: Women who work on rotating night shifts with at least three nights per month, in addition to days and evenings in that month, appear to have a moderately increased risk of breast cancer after extended periods of working rotating night shifts. PMID- 11604481 TI - Prevalence of human herpesvirus 8 antibodies in young adults in Denmark (1976 1977). PMID- 11604482 TI - Testing for colon neoplasia susceptibility variants at the human Cox2 locus. PMID- 11604483 TI - Breast cancer screening for women aged 40-49 years: screening may not be the benign process usually thought. PMID- 11604485 TI - Re: methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. PMID- 11604486 TI - Re: metabolites of a tobacco-specific lung carcinogen in nonsmoking women exposed to environmental tobacco smoke. PMID- 11604490 TI - The notch intracellular domain can function as a coactivator for LEF-1. AB - Notch signaling commences with two ligand-mediated proteolysis events that release the Notch intracellular domain, NICD, from the plasma membrane. NICD then translocates into the nucleus and interacts with the DNA binding protein CSL to activate transcription. We found that NICD expression also potentiates activity of the transcription factor LEF-1. NICD stimulation of LEF-1 activity was context dependent and occurred on a subset of promoters distinct from those activated by beta-catenin. Importantly, the effect of NICD does not appear to be mediated through canonical components of the Wnt signaling pathway or downstream components of the Notch pathway. In vitro assays show a weak association between the C-terminal transactivation domain of NICD and the high-mobility group domain of LEF-1, suggesting that the two proteins interact in vivo. Our data therefore describe a new nuclear target of Notch signaling and a new coactivator for LEF-1. PMID- 11604491 TI - Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization. AB - Trophic factor withdrawal induces cell death by mechanisms that are incompletely understood. Previously we reported that withdrawal of interleukin-7 (IL-7) or IL 3 produced a rapid intracellular alkalinization, disrupting mitochondrial metabolism and activating the death protein Bax. We now observe that this novel alkalinization pathway is mediated by the pH regulator NHE1, as shown by the requirement for sodium, blocking by pharmacological inhibitors or use of an NHE1 deficient cell line, and the altered phosphorylation of NHE1. Alkalinization also required the stress-activated p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK activity with pharmacological inhibitors or expression of a dominant negative kinase prevented alkalinization. Activated p38 MAPK directly phosphorylated the C terminus of NHE1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on NHE1, Thr 717, Ser 722, Ser 725, and Ser 728. Thus, loss of trophic cytokine signaling induced the p38 MAPK pathway, which phosphorylated NHE1 at specific sites, inducing intracellular alkalinization. PMID- 11604492 TI - Autoregulation of the human liver X receptor alpha promoter. AB - Previous work has implicated the nuclear receptors liver X receptor alpha (LXR alpha) and LXR beta in the regulation of macrophage gene expression in response to oxidized lipids. Macrophage lipid loading leads to ligand activation of LXRs and to induction of a pathway for cholesterol efflux involving the LXR target genes ABCA1 and apoE. We demonstrate here that autoregulation of the LXR alpha gene is an important component of this lipid-inducible efflux pathway in human macrophages. Oxidized low-density lipoprotein, oxysterols, and synthetic LXR ligands induce expression of LXR alpha mRNA in human monocyte-derived macrophages and human macrophage cell lines but not in murine peritoneal macrophages or cell lines. This is in contrast to peroxisome proliferator-activated receptor gamma (PPAR gamma)-specific ligands, which stimulate LXR alpha expression in both human and murine macrophages. We further demonstrate that LXR and PPAR gamma ligands cooperate to induce LXR alpha expression in human but not murine macrophages. Analysis of the human LXR alpha promoter led to the identification of multiple LXR response elements. Interestingly, the previously identified PPAR response element (PPRE) in the murine LXR alpha gene is not conserved in humans; however, a different PPRE is present in the human LXR 5'-flanking region. These results have implications for cholesterol metabolism in human macrophages and its potential to be regulated by synthetic LXR and/or PPAR gamma ligands. The ability of LXR alpha to regulate its own promoter is likely to be an integral part of the macrophage physiologic response to lipid loading. PMID- 11604493 TI - Hsp104 interacts with Hsp90 cochaperones in respiring yeast. AB - The highly abundant molecular chaperone Hsp90 functions with assistance from auxiliary factors, collectively referred to as Hsp90 cochaperones, and the Hsp70 system. Hsp104, a molecular chaperone required for stress tolerance and for maintenance of [psi(+)] prions in the budding yeast Saccharomyces cerevisiae, appears to collaborate only with the Hsp70 system. We now report that several cochaperones previously thought to be dedicated to Hsp90 are shared with Hsp104. We show that the Hsp90 cochaperones Sti1, Cpr7, and Cns1, which utilize tetratricopeptide repeat (TPR) domains to interact with a common surface on Hsp90, form complexes with Hsp104 in vivo and that Sti1 and Cpr7 interact with Hsp104 directly in vitro. The interaction is Hsp90 independent, as further emphasized by the fact that two distinct TPR domains of Sti1 are required for binding Hsp90 and Hsp104. In a striking parallel to the sequence requirements of Hsp90 for binding TPR proteins, binding of Sti1 to Hsp104 requires a related acidic sequence at the C-terminal tail of Hsp104. While Hsp90 efficiently sequesters the cochaperones during fermentative growth, respiratory conditions induce the interaction of a fraction of Hsp90 cochaperones with Hsp104. This suggests that cochaperone sharing may favor adaptation to altered metabolic conditions. PMID- 11604494 TI - Overproduction of PDR3 suppresses mitochondrial import defects associated with a TOM70 null mutation by increasing the expression of TOM72 in Saccharomyces cerevisiae. AB - Most mitochondrial proteins are synthesized with cleavable amino-terminal targeting signals that interact with the mitochondrial import machinery to facilitate their import from the cytosol. We previously reported that the presequence of the F(1)-ATPase beta subunit precursor (pre-F(1)beta) acts as an intramolecular chaperone that maintains the precursor in an import-competent conformation prior to import (P. Hajek, J. Y. Koh, L. Jones, and D. M. Bedwell, Mol. Cell. Biol. 17:7169-7177, 1997). We also found that a mutant form of pre F(1)beta with a minimal targeting signal (Delta 1,2 pre-F(1)beta) is inefficiently imported into mitochondria because it rapidly folds into an import incompetent conformation. We have now analyzed the consequences of reducing the pre-F(1)beta targeting signal to a minimal unit in more detail. We found that Delta 1,2 pre-F(1)beta is more dependent upon the Tom70p receptor for import than WT pre-F(1)beta is, resulting in a growth defect on a nonfermentable carbon source at 15 degrees C. Experiments using an in vitro mitochondrial protein import system suggest that Tom70p functions to maintain a precursor containing the Delta 1,2 pre-F(1)beta import signal in an import-competent conformation. We also identified PDR3, a transcriptional regulator of the pleiotropic drug resistance network, as a multicopy suppressor of the mitochondrial import defects associated with Delta 1,2 pre-F(1)beta in a tom70 Delta strain. The overproduction of PDR3 mediated this effect by increasing the import of Delta 1,2 pre-F(1)beta into mitochondria. This increased the mitochondrial ATP synthase activity to the extent that growth of the mutant strain was restored under the selective conditions. Analysis of the transcription patterns of components of the mitochondrial outer membrane import machinery demonstrated that PDR3 overproduction increased the expression of TOM72, a little studied TOM70 homologue. These results suggest that Tom72p possesses overlapping functions with Tom70p and that the pleiotropic drug resistance network plays a previously unappreciated role in mitochondrial biogenesis. PMID- 11604495 TI - Reduced rates of gene loss, gene silencing, and gene mutation in Dnmt1-deficient embryonic stem cells. AB - Tumor suppressor gene inactivation is a crucial event in oncogenesis. Gene inactivation mechanisms include events resulting in loss of heterozygosity (LOH), gene mutation, and transcriptional silencing. The contribution of each of these different pathways varies among tumor suppressor genes and by cancer type. The factors that influence the relative utilization of gene inactivation pathways are poorly understood. In this study, we describe a detailed quantitative analysis of the three major gene inactivation mechanisms for a model gene at two different genomic integration sites in mouse embryonic stem (ES) cells. In addition, we targeted the major DNA methyltransferase gene, Dnmt1, to investigate the relative contribution of DNA methylation to these various competing gene inactivation pathways. Our data show that gene loss is the predominant mode of inactivation of a herpes simplex virus thymidine kinase neomycin phosphotransferase reporter gene (HSV-TKNeo) at the two integration sites tested and that this event is significantly reduced in Dnmt1-deficient cells. Gene silencing by promoter methylation requires Dnmt1, suggesting that the expression of Dnmt3a and Dnmt3b alone in ES cells is insufficient to achieve effective gene silencing. We used a novel assay to show that missense mutation rates are also substantially reduced in Dnmt1-deficient cells. This is the first direct demonstration that DNA methylation affects point mutation rates in mammalian cells. Surprisingly, the fraction of CpG transition mutations was not reduced in Dnmt1-deficient cells. Finally, we show that methyl group-deficient growth conditions do not cause an increase in missense mutation rates in Dnmt1-proficient cells, as predicted by methyltransferase-mediated mutagenesis models. We conclude that Dnmt1 deficiency and the accompanying genomic DNA hypomethylation result in a reduction of three major pathways of gene inactivation in our model system. PMID- 11604496 TI - CpG binding protein is crucial for early embryonic development. AB - Epigenetic modification of DNA via CpG methylation is essential for the proper regulation of gene expression during embryonic development. Methylation of CpG motifs results in gene repression, while CpG island-containing genes are maintained in an unmethylated state and are transcriptionally active. The molecular mechanisms involved in maintaining the hypomethylation of CpG islands remain unclear. The transcriptional activator CpG binding protein (CGBP) exhibits a unique binding specificity for DNA elements that contain unmethylated CpG motifs, which makes it a potential candidate for the regulation of CpG island containing genes. In order to assess the global function of this protein, mice lacking CGBP were generated via homologous recombination. No viable mutant mice were identified, indicating that CGBP is required for murine development. Mutant embryos were also absent between 6.5 and 12.5 days postcoitum (dpc). Approximately, one-fourth of all implantation sites at 6.5 dpc appeared empty with no intact embryos present. However, histological examination of 6.5-dpc implantation sites revealed the presence of embryo remnants, indicating that CGBP mutant embryos die very early in development. In vitro blastocyst outgrowth assays revealed that CGBP-null blastocysts are viable and capable of hatching and forming both an inner cell mass and a trophectoderm. Therefore, CGBP plays a crucial role in embryo viability and peri-implantation development. PMID- 11604497 TI - Distinct effects of mitogens and the actin cytoskeleton on CREB and pocket protein phosphorylation control the extent and timing of cyclin A promoter activity. AB - Soluble mitogens and adhesion-dependent organization of the actin cytoskeleton are required for cells to enter S phase in fibroblasts. The induction of cyclin A is also required for S-phase entry, and we now report that distinct effects of mitogens and the actin cytoskeleton on the phosphorylation of CREB and pocket proteins regulate the extent and timing of cyclin A promoter activity, respectively. First, we show that CREB phosphorylation and binding to the cyclic AMP response element (CRE) determines the extent, but not the timing, of cyclin A promoter activity. Second, we show that pocket protein inactivation regulates the timing, but not the extent, of cyclin A promoter activity. CREB phosphorylation and CRE occupancy are regulated by soluble mitogens alone, while the phosphorylation of pocket proteins requires both mitogens and the organized actin cytoskeleton. Mechanistically, cytoskeletal integrity controls pocket protein phosphorylation by allowing for sustained ERK signaling and, thereby, the expression of cyclin D1. Our results lead to a model of cyclin A gene regulation in which mitogens play a permissive role by stimulating early G(1)-phase phosphorylation of CREB and a distinct regulatory role by cooperating with the organized actin cytoskeleton to regulate the duration of ERK signaling, the expression of cyclin D1, and the timing of pocket protein phosphorylation. PMID- 11604498 TI - The transcription elongation factor CA150 interacts with RNA polymerase II and the pre-mRNA splicing factor SF1. AB - CA150 represses RNA polymerase II (RNAPII) transcription by inhibiting the elongation of transcripts. The FF repeat domains of CA150 bind directly to the phosphorylated carboxyl-terminal domain of the largest subunit of RNAPII. We determined that this interaction is required for efficient CA150-mediated repression of transcription from the alpha(4)-integrin promoter. Additional functional determinants, namely, the WW1 and WW2 domains of CA150, were also required for efficient repression. A protein that interacted directly with CA150 WW1 and WW2 was identified as the splicing-transcription factor SF1. Previous studies have demonstrated a role for SF1 in transcription repression, and we found that binding of the CA150 WW1 and WW2 domains to SF1 correlated exactly with the functional contribution of these domains for repression. The binding specificity of the CA150 WW domains was found to be unique in comparison to known classes of WW domains. Furthermore, the CA150 binding site, within the carboxyl terminal half of SF1, contains a novel type of proline-rich motif that may be recognized by the CA150 WW1 and WW2 domains. These results support a model for the recruitment of CA150 to repress transcription elongation. In this model, CA150 binds to the phosphorylated CTD of elongating RNAPII and SF1 targets the nascent transcript. PMID- 11604499 TI - Role of an ING1 growth regulator in transcriptional activation and targeted histone acetylation by the NuA4 complex. AB - The yeast NuA4 complex is a histone H4 and H2A acetyltransferase involved in transcription regulation and essential for cell cycle progression. We identify here a novel subunit of the complex, Yng2p, a plant homeodomain (PHD)-finger protein homologous to human p33/ING1, which has tumor suppressor activity and is essential for p53 function. Mass spectrometry, immunoblotting, and immunoprecipitation experiments confirm the stable stoichiometric association of this protein with purified NuA4. Yeast cells harboring a deletion of the YNG2 gene show severe growth phenotype and have gene-specific transcription defects. NuA4 complex purified from the mutant strain is low in abundance and shows weak histone acetyltransferase activity. We demonstrate conservation of function by the requirement of Yng2p for p53 to function as a transcriptional activator in yeast. Accordingly, p53 interacts with NuA4 in vitro and in vivo, an interaction reminiscent of the p53-ING1 physical link in human cells. The growth defect of Delta yng2 cells can be rescued by the N-terminal part of the protein, lacking the PHD-finger. While Yng2 PHD-finger is not required for p53 interaction, it is necessary for full expression of the p53-responsive gene and other NuA4 target genes. Transcriptional activation by p53 in vivo is associated with targeted NuA4 dependent histone H4 hyperacetylation, while histone H3 acetylation levels remain unchanged. These results emphasize the essential role of the NuA4 complex in the control of cell proliferation through gene-specific transcription regulation. They also suggest that regulation of mammalian cell proliferation by p53 dependent transcriptional activation functions through recruitment of an ING1 containing histone acetyltransferase complex. PMID- 11604500 TI - Mechanisms of CAS substrate domain tyrosine phosphorylation by FAK and Src. AB - Tyrosine phosphorylation of CAS (Crk-associated substrate, p130(Cas)) has been implicated as a key signaling step in integrin control of normal cellular behaviors, including motility, proliferation, and survival. Aberrant CAS tyrosine phosphorylation may contribute to cell transformation by certain oncoproteins, including v-Crk and v-Src, and to tumor growth and metastasis. The CAS substrate domain (SD) contains 15 Tyr-X-X-Pro motifs, which are thought to represent the major tyrosine phosphorylation sites and to function by recruiting downstream signaling effectors, including c-Crk and Nck. CAS makes multiple interactions, direct and indirect, with the tyrosine kinases Src and focal adhesion kinase (FAK), and as a result of this complexity, several plausible models have been proposed for the mechanism of CAS-SD phosphorylation. The objective of this study was to provide experimental tests of these models in order to determine the most likely mechanism(s) of CAS-SD tyrosine phosphorylation by FAK and Src. In vitro kinase assays indicated that FAK has a very poor capacity to phosphorylate CAS SD, relative to Src. However, FAK expression along with Src was found to be important for achieving high levels of CAS tyrosine phosphorylation in COS-7 cells, as well as recovery of CAS-associated Src activity toward the SD. Structure-functional studies for both FAK and CAS further indicated that FAK plays a major role in regulating CAS-SD phosphorylation by acting as a docking or scaffolding protein to recruit Src to phosphorylate CAS, while a secondary FAK independent mechanism involves Src directly bound to the CAS Src-binding domain (SBD). Our results do not support models in which FAK either phosphorylates CAS SD directly or phosphorylates CAS-SBD to promote Src binding to this site. PMID- 11604501 TI - Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. AB - The ARF and p53 tumor suppressors mediate Myc-induced apoptosis and suppress lymphoma development in E mu-myc transgenic mice. Here we report that the proapoptotic Bcl-2 family member Bax also mediates apoptosis triggered by Myc and inhibits Myc-induced lymphomagenesis. Bax-deficient primary pre-B cells are resistant to the apoptotic effects of Myc, and Bax loss accelerates lymphoma development in E mu-myc transgenics in a dose-dependent fashion. Eighty percent of lymphomas arising in wild-type E mu-myc transgenics have alterations in the ARF-Mdm2-p53 tumor suppressor pathway characterized by deletions in ARF, mutations or deletions of p53, and overexpression of Mdm2. The absence of Bax did not alter the frequency of biallelic deletion of ARF in lymphomas arising in E mu myc transgenic mice or the rate of tumorigenesis in ARF-null mice. Furthermore, Mdm2 was overexpressed at the same frequency in lymphomas irrespective of Bax status, suggesting that Bax resides in a pathway separate from ARF and Mdm2. Strikingly, lymphomas from Bax-null E mu-myc transgenics lacked p53 alterations, whereas 27% of the tumors in Bax(+/-) E mu-myc transgenic mice contained p53 mutations or deletions. Thus, the loss of Bax eliminates the selection of p53 mutations and deletions, but not ARF deletions or Mdm2 overexpression, during Myc induced tumorigenesis, formally demonstrating that Myc-induced apoptotic signals through ARF/Mdm2 and p53 must bifurcate: p53 signals through Bax, whereas this is not necessarily the case for ARF and Mdm2. PMID- 11604503 TI - Dual function for U2AF(35) in AG-dependent pre-mRNA splicing. AB - The splicing factor U2AF is required for the recruitment of U2 small nuclear RNP to pre-mRNAs in higher eukaryotes. The 65-kDa subunit of U2AF (U2AF(65)) binds to the polypyrimidine (Py) tract preceding the 3' splice site, while the 35-kDa subunit (U2AF(35)) contacts the conserved AG dinucleotide at the 3' end of the intron. It has been shown that the interaction between U2AF(35) and the 3' splice site AG can stabilize U2AF(65) binding to weak Py tracts characteristic of so called AG-dependent pre-mRNAs. U2AF(35) has also been implicated in arginine serine (RS) domain-mediated bridging interactions with splicing factors of the SR protein family bound to exonic splicing enhancers (ESE), and these interactions can also stabilize U2AF(65) binding. Complementation of the splicing activity of nuclear extracts depleted of U2AF by chromatography in oligo(dT)-cellulose requires, for some pre-mRNAs, only the presence of U2AF(65). In contrast, splicing of a mouse immunoglobulin M (IgM) M1-M2 pre-mRNA requires both U2AF subunits. In this report we have investigated the sequence elements (e.g., Py tract strength, 3' splice site AG, ESE) responsible for the U2AF(35) dependence of IgM. The results indicate that (i) the IgM substrate is an AG-dependent pre mRNA, (ii) U2AF(35) dependence correlates with AG dependence, and (iii) the identity of the first nucleotide of exon 2 is important for U2AF(35) function. In contrast, RS domain-mediated interactions with SR proteins bound to the ESE appear to be dispensable, because the purine-rich ESE present in exon M2 is not essential for U2AF(35) activity and because a truncation mutant of U2AF(35) consisting only of the pseudo-RNA recognition motif domain and lacking the RS domain is active in our complementation assays. While some of the effects of U2AF(35) can be explained in terms of enhanced U2AF(65) binding, other activities of U2AF(35) do not correlate with increased cross-linking of U2AF(65) to the Py tract. Collectively, the results argue that interaction of U2AF(35) with a consensus 3' splice site triggers events in spliceosome assembly in addition to stabilizing U2AF(65) binding, thus revealing a dual function for U2AF(35) in pre mRNA splicing. PMID- 11604504 TI - Nucleosomes are translationally positioned on the active allele and rotationally positioned on the inactive allele of the HPRT promoter. AB - Differential chromatin structure is one of the hallmarks distinguishing active and inactive genes. For the X-linked human hypoxanthine phosphoribosyltransferase gene (HPRT), this difference in chromatin structure is evident in the differential general DNase I sensitivity and hypersensitivity of the promoter regions on active versus inactive X chromosomes. Here we characterize the nucleosomal organization responsible for the differential chromatin structure of the active and inactive HPRT promoters. The micrococcal nuclease digestion pattern of chromatin from the active allele in permeabilized cells reveals an ordered array of translationally positioned nucleosomes in the promoter region except over a 350-bp region that is either nucleosome free or contains structurally altered nucleosomes. This 350-bp region includes the entire minimal promoter and all of the multiple transcription initiation sites of the HPRT gene. It also encompasses all of the transcription factor binding sites identified by either dimethyl sulfate or DNase I in vivo footprinting of the active allele. In contrast, analysis of the inactive HPRT promoter reveals no hypersensitivity to either DNase I or a micrococcal nuclease and no translational positioning of nucleosomes. Although nucleosomes on the inactive promoter are not translationally positioned, high-resolution DNase I cleavage analysis of permeabilized cells indicates that nucleosomes are rotationally positioned over a region of at least 210 bp on the inactive promoter, which coincides with the 350 bp nuclease-hypersensitive region on the active allele, including the entire minimal promoter. This rotational positioning of nucleosomes is not observed on the active promoter. These results suggest a model in which the silencing of the HPRT promoter during X chromosome inactivation involves remodeling a transcriptionally competent, translationally positioned nucleosomal array into a transcriptionally repressed architecture consisting of rotationally but not translationally positioned nucleosomal arrays. PMID- 11604502 TI - Peripheral mitochondrial inner membrane protein, Mss2p, required for export of the mitochondrially coded Cox2p C tail in Saccharomyces cerevisiae. AB - Cytochrome oxidase subunit 2 (Cox2p) is synthesized on the matrix side of the mitochondrial inner membrane, and its N- and C-terminal domains are exported across the inner membrane by distinct mechanisms. The Saccharomyces cerevisiae nuclear gene MSS2 was previously shown to be necessary for Cox2p accumulation. We have used pulse-labeling studies and the expression of the ARG8(m) reporter at the COX2 locus in an mss2 mutant to demonstrate that Mss2p is not required for Cox2p synthesis but rather for its accumulation. Mutational inactivation of the proteolytic function of the matrix-localized Yta10p (Afg3p) AAA-protease partially stabilizes Cox2p in an mss2 mutant but does not restore assembly of cytochrome oxidase. In the absence of Mss2p, the Cox2p N terminus is exported, but Cox2p C-terminal export and assembly of Cox2p into cytochrome oxidase is blocked. Epitope-tagged Mss2p is tightly, but peripherally, associated with the inner membrane and protected by it from externally added proteases. Taken together, these data indicate that Mss2p plays a role in recognizing the Cox2p C tail in the matrix and promoting its export. PMID- 11604505 TI - Identification of a role for the sialomucin CD164 in myogenic differentiation by signal sequence trapping in yeast. AB - Determination and differentiation of skeletal muscle precursors requires cell cell contact, but the full range of cell surface proteins that mediate this requirement and the mechanisms by which they work are not known. To identify participants in cell contact-mediated regulation of myogenesis, genes that encode secreted proteins specifically upregulated during differentiation of C2C12 myoblasts were identified by the yeast signal sequence trap method (K. A. Jacobs, L. A. Collins-Racie, M. Colbert, M. Duckett, M. Golden-Fleet, K. Kelleher, R. Kriz, E. R. La Vallie, D. Merberg, V. Spaulding, J. Stover, M. J. Williamson, and J. M. McCoy, Gene 198:289-296, 1997), followed by RNA expression analysis. We report here the identification of CD164 as a gene expressed in proliferating C2C12 cells that is upregulated during differentiation. CD164 encodes a widely expressed cell surface sialomucin that has been implicated in regulation of cell proliferation and adhesion during hematopoiesis. Stable overexpression of CD164 in C2C12 and F3 myoblasts enhanced their differentiation, as assessed by both morphological and biochemical criteria. Furthermore, expression of antisense CD164 or soluble extracellular regions of CD164 inhibited myogenic differentiation. Treatment of C2C12 cells with sialidase or O-sialoglycoprotease, two enzymes previously reported to destroy functional epitopes on CD164, also inhibited differentiation. These data indicate that (i) CD164 may play a rate limiting role in differentiation of cultured myoblasts, (ii) sialomucins represent a class of potential effectors of cell contact-mediated regulation of myogenesis, and (iii) carbohydrate-based cell recognition may play a role in mediating this phenomenon. PMID- 11604506 TI - Targeted Disruption of the Myocilin Gene (Myoc) Suggests that Human Glaucoma Causing Mutations Are Gain of Function. AB - Glaucoma is a heterogeneous eye disease and a major cause of blindness worldwide. Recently, primary open angle glaucoma (POAG)-associated mutations have been found in the trabecular meshwork inducible glucocorticoid response gene (TIGR), also known as the myocilin gene (MYOC), at the GLC1A locus on chromosome 1q21-q31. These mutations occurred in a subset of patients with juvenile- and adult-onset POAG and exhibited autosomal dominant inheritance. Ocular expression and its involvement in POAG suggest that TIGR/MYOC may have a role(s) in regulating intraocular pressure (IOP). Here, we report the generation and analysis of mice heterozygous and homozygous for a targeted null mutation in Myoc. Our study shows that Myoc mutant mice are both viable and fertile. Our in vivo findings further demonstrate that Myoc is not required for normal IOP or normal ocular morphology. The lack of a discernable phenotype in both Myoc-heterozygous and Myoc-null mice suggests that haploinsufficiency is not a critical mechanism for POAG in individuals with mutations in MYOC. Instead, disease-causing mutations in humans likely act by gain of function. PMID- 11604507 TI - The gypsy insulator can act as a promoter-specific transcriptional stimulator. AB - Insulators define chromosomal domains such that an enhancer in one domain cannot activate a promoter in a different domain. We show that the Drosophila gypsy insulator behaves as a cis-stimulatory element in the larval fat body. Transcriptional stimulation by the insulator is distance dependent, as expected for a promoter element as opposed to an enhancer. Stimulation of a test alcohol dehydrogenase promoter requires a binding site for a GATA transcription factor, suggesting that the insulator may be facilitating access of this DNA binding protein to the promoter. Short-range stimulation requires both the Suppressor of Hairy-wing protein and the Mod(mdg4)-62.7 protein encoded by the trithorax group gene mod(mdg4). In the absence of interaction with Mod(mdg4)-62.7, the insulator is converted into a short-range transcriptional repressor but retains some cis stimulatory activity over longer distances. These results indicate that insulator and promoter sequences share important characteristics and are not entirely distinct. We propose that the gypsy insulator can function as a promoter element and may be analogous to promoter-proximal regulatory modules that integrate input from multiple distal enhancer sequences. PMID- 11604508 TI - Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress. AB - The hepatitis B virus X protein (HBx) plays essential roles in viral replication and the generation of hepatocellular carcinoma. In spite of a large number of suggestive cellular targets and functions, a clear picture of its mechanism(s) of action has remained elusive. In this report, we continue to characterize its recently described mitochondrial association and further examine its impact on mitochondrial functions. HBx was previously shown to bind to a voltage-dependent anion channel (VDAC3) and alter the mitochondrial transmembrane potential (Delta Psi(m)). Here we show that, as a consequence of association with mitochondria, HBx constitutively induces activation of transcription factors, which include STAT-3 and NF-kappa B. This induction of activation was sensitive to the antioxidants N-acetyl L-cysteine and pyrrolidine dithiocarbamate, as well as to overexpression of Mn-superoxide dismutase. These results therefore implicate a potential role of reactive oxygen species (ROS) in a process that ultimately leads to the activation of STAT-3 and NF-kappa B. Evidence is also presented for the HBx-induced generation of ROS. The ability of HBx to induce the activation of STAT-3 and NF-kappa B was demonstrated by mobility shift and reporter gene expression assays with lysates from HBx-transfected HepG2 cells. A C-terminal HBx deletion mutant, HBx Delta 99, failed to bind VDAC3 and activate STAT-3 and NF kappa B. These studies shed new light on the physiological significance of HBx's mitochondrial association and its role in inducing oxidative stress which can contribute to the liver disease pathogenesis associated with the hepatitis B virus infection. PMID- 11604509 TI - A well-connected and conserved nucleoplasmic helicase is required for production of box C/D and H/ACA snoRNAs and localization of snoRNP proteins. AB - Biogenesis of small nucleolar RNA-protein complexes (snoRNPs) consists of synthesis of the snoRNA and protein components, snoRNP assembly, and localization to the nucleolus. Recently, two nucleoplasmic proteins from mice were observed to bind to a model box C/D snoRNA in vitro, suggesting that they function at an early stage in snoRNP biogenesis. Both proteins have been described in other contexts. The proteins, called p50 and p55 in the snoRNA binding study, are highly conserved and related to each other. Both have Walker A and B motifs characteristic of ATP- and GTP-binding and nucleoside triphosphate-hydrolyzing domains, and the mammalian orthologs have DNA helicase activity in vitro. Here, we report that the Saccharomyces cerevisiae ortholog of p50 (Rvb2, Tih2p, and other names) is required for production of C/D snoRNAs in vivo and, surprisingly, H/ACA snoRNAs as well. Point mutations in the Walker A and B motifs cause temperature-sensitive or lethal growth phenotypes and severe defects in snoRNA accumulation. Notably, depletion of p50 (called Rvb2 in this study) also impairs localization of C/D and H/ACA core snoRNP proteins Nop1p and Gar1p, suggesting a defect(s) in snoRNP assembly or trafficking to the nucleolus. Findings from other studies link Rvb2 orthologs with chromatin remodeling and transcription. Taken together, the present results indicate that Rvb2 is involved in an early stage of snoRNP biogenesis and may play a role in coupling snoRNA synthesis with snoRNP assembly and localization. PMID- 11604510 TI - RasGAP-associated endoribonuclease G3Bp: selective RNA degradation and phosphorylation-dependent localization. AB - Mitogen activation of mRNA decay pathways likely involves specific endoribonucleases, such as G3BP, a phosphorylation-dependent endoribonuclease that associates with RasGAP in dividing but not quiescent cells. G3BP exclusively cleaves between cytosine and adenine (CA) after a specific interaction with RNA through the carboxyl-terminal RRM-type RNA binding motif. Accordingly, G3BP is tightly associated with a subset of poly(A)(+) mRNAs containing its high-affinity binding sequence, such as the c-myc mRNA in mouse embryonic fibroblasts. Interestingly, c-myc mRNA decay is delayed in RasGAP-deficient fibroblasts, which contain a defective isoform of G3BP that is not phosphorylated at serine 149. A G3BP mutant in which this serine is changed to alanine remains exclusively cytoplasmic, whereas a glutamate for serine substitution that mimics the charge of a phosphorylated serine is translocated to the nucleus. Thus, a growth factor induced change in mRNA decay may be modulated by the nuclear localization of a site-specific endoribonuclease such as G3BP. PMID- 11604511 TI - p300 acts as a transcriptional coactivator for mammalian Notch-1. AB - Notch-1 belongs to a family of transmembrane receptor proteins that direct the decisions as to various cell fates. After ligand binding, a proteolytic cleavage step occurs and the intracellular part of Notch-1, Notch-1-IC, translocates into the nucleus, where it targets the DNA binding protein RBP-J kappa/CBF1. RBP-J kappa mediates repression through recruitment of a histone deacetylase-containing complex. The Notch-1-IC/RBP-J kappa complex overcomes repression and activates the transcription of Notch target genes. We have identified a novel domain in Notch-1-IC, the EP domain, which is indispensable for full transcriptional activation. This transactivation domain is localized adjacent to the ankyrin repeats of Notch-1-IC. In cotransfection experiments, Notch-1-IC-mediated transcriptional activation was inhibited by E1A12S and p53, two proteins, which interfere with the function of the common coactivator p300. Protein-protein interaction assays demonstrated the association of Notch-1-IC and the CH3 region of p300. In addition, the interaction of mammalian Notch-1-IC with p300 was destabilized after deletion of the EP domain of Notch-1-IC. Based on physical interaction with Notch-1-IC and coactivator functions of p300, we propose a model for Notch-1-mediated gene regulation via p300. PMID- 11604512 TI - N-terminal domains of the human telomerase catalytic subunit required for enzyme activity in vivo. AB - Most tumor cells depend upon activation of the ribonucleoprotein enzyme telomerase for telomere maintenance and continual proliferation. The catalytic activity of this enzyme can be reconstituted in vitro with the RNA (hTR) and catalytic (hTERT) subunits. However, catalytic activity alone is insufficient for the full in vivo function of the enzyme. In addition, the enzyme must localize to the nucleus, recognize chromosome ends, and orchestrate telomere elongation in a highly regulated fashion. To identify domains of hTERT involved in these biological functions, we introduced a panel of 90 N-terminal hTERT substitution mutants into telomerase-negative cells and assayed the resulting cells for catalytic activity and, as a marker of in vivo function, for cellular proliferation. We found four domains to be essential for in vitro and in vivo enzyme activity, two of which were required for hTR binding. These domains map to regions defined by sequence alignments and mutational analysis in yeast, indicating that the N terminus has also been functionally conserved throughout evolution. Additionally, we discovered a novel domain, DAT, that "dissociates activities of telomerase," where mutations left the enzyme catalytically active, but was unable to function in vivo. Since mutations in this domain had no measurable effect on hTERT homomultimerization, hTR binding, or nuclear targeting, we propose that this domain is involved in other aspects of in vivo telomere elongation. The discovery of these domains provides the first step in dissecting the biological functions of human telomerase, with the ultimate goal of targeting this enzyme for the treatment of human cancers. PMID- 11604514 TI - Huntingtin interacting protein 1 Is a clathrin coat binding protein required for differentiation of late spermatogenic progenitors. AB - Huntingtin-interacting protein 1 (HIP1) interacts with huntingtin, the protein whose gene is mutated in Huntington's disease. In addition, a fusion between HIP1 and platelet-derived growth factor beta receptor causes chronic myelomonocytic leukemia. The HIP1 proteins, including HIP1 and HIP1-related (HIP1r), have an N terminal polyphosphoinositide-interacting epsin N-terminal homology, domain, which is found in proteins involved in clathrin-mediated endocytosis. HIP1 and HIP1r also share a central leucine zipper and an actin binding TALIN homology domain. Here we show that HIP1, like HIP1r, colocalizes with clathrin coat components. We also show that HIP1 physically associates with clathrin and AP-2, the major components of the clathrin coat. To further understand the putative biological role(s) of HIP1, we have generated a targeted deletion of murine HIP1. HIP1(-/-) mice developed into adulthood, did not develop overt neurologic symptoms in the first year of life, and had normal peripheral blood counts. However, HIP1-deficient mice exhibited testicular degeneration with increased apoptosis of postmeiotic spermatids. Postmeiotic spermatids are the only cells of the seminiferous tubules that express HIP1. These findings indicate that HIP1 is required for differentiation, proliferation, and/or survival of spermatogenic progenitors. The association of HIP1 with clathrin coats and the requirement of HIP1 for progenitor survival suggest a role for HIP1 in the regulation of endocytosis. PMID- 11604513 TI - Srg3, a mouse homolog of yeast SWI3, is essential for early embryogenesis and involved in brain development. AB - Srg3 (SWI3-related gene product) is a mouse homolog of yeast SWI3, Drosophila melanogaster MOIRA (also named MOR/BAP155), and human BAF155 and is known as a core subunit of SWI/SNF complex. This complex is involved in the chromatin remodeling required for the regulation of transcriptional processes associated with development, cellular differentiation, and proliferation. We generated mice with a null mutation in the Srg3 locus to examine its function in vivo. Homozygous mutants develop in the early implantation stage but undergo rapid degeneration thereafter. An in vitro outgrowth study revealed that mutant blastocysts hatch, adhere, and form a layer of trophoblast giant cells, but the inner cell mass degenerates after prolonged culture. Interestingly, about 20% of heterozygous mutant embryos display defects in brain development with abnormal organization of the brain, a condition known as exencephaly. Histological examination suggests that exencephaly is caused by the failure in neural fold elevation, resulting in severe brain malformation. Our findings demonstrate that Srg3 is essential for early embryogenesis and plays an important role in the brain development of mice. PMID- 11604515 TI - Specific double-stranded RNA interference in undifferentiated mouse embryonic stem cells. AB - Specific mRNA degradation mediated by double-stranded RNA (dsRNA) interference (RNAi) is a powerful way of suppressing gene expression in plants, nematodes, and fungal, insect, and protozoan systems. However, only a few cases of RNAi have been reported in mammalian systems. Here, we investigated the feasibility of the RNAi strategy in several mammalian cells by using the enhanced green fluorescent protein gene as a target, either by in situ production of dsRNA from transient transfection of a plasmid harboring a 547-bp inverted repeat or by direct transfection of dsRNA made by in vitro transcription. Several mammalian cells including differentiated embryonic stem (ES) cells did not exhibit specific RNAi in transient transfection. This long dsRNA, however, was capable of inducing a sequence-specific RNAi for the episomal and chromosomal target gene in undifferentiated ES cells. dsRNA at 8.3 nM decreased the cognate gene expression up to 70%. However, RNAi activity was not permanent because it was more pronounced in early time points and diminished 5 days after transfection. Thus, undifferentiated ES cells may lack the interferon response, similar to mouse embryos and oocytes. Regardless of their apparent RNAi activity, however, cytoplasmic extracts from mammalian cells produced a small RNA of 21 to 22 nucleotides from the long dsRNA. Our results suggest that mammalian cells may possess RNAi activity but nonspecific activation of the interferon response by longer dsRNA may mask the specific RNAi. The findings offer an opportunity to use dsRNA for inhibition of gene expression in ES cells to study differentiation. PMID- 11604516 TI - Mice with a targeted deletion of the tetranectin gene exhibit a spinal deformity. AB - Tetranectin is a plasminogen-binding, homotrimeric protein belonging to the C type lectin family of proteins. Tetranectin has been suggested to play a role in tissue remodeling, due to its ability to stimulate plasminogen activation and its expression in developing tissues such as developing bone and muscle. To test the functional role of tetranectin directly, we have generated mice with a targeted disruption of the gene. We report that the tetranectin-deficient mice exhibit kyphosis, a type of spinal deformity characterized by an increased curvature of the thoracic spine. The kyphotic angles were measured on radiographs. In 6-month old normal mice (n = 27), the thoracic angle was 73 degrees +/- 2 degrees, while in tetranectin-deficient 6-month-old mice (n = 35), it was 93 degrees +/- 2 degrees (P < 0.0001). In approximately one-third of the mutant mice, X-ray analysis revealed structural changes in the morphology of the vertebrae. Histological analysis of the spines of these mice revealed an apparently asymmetric development of the growth plate and of the intervertebral disks of the vertebrae. In the most advanced cases, the growth plates appeared disorganized and irregular, with the disk material protruding through the growth plate. Tetranectin-null mice had a normal peak bone mass density and were not more susceptible to ovariectomy-induced osteoporosis than were their littermates as determined by dual-emission X-ray absorptiometry scanning. These results demonstrate that tetranectin plays a role in tissue growth and remodeling. The tetranectin-deficient mouse is the first mouse model that resembles common human kyphotic disorders, which affect up to 8% of the population. PMID- 11604517 TI - Integrase mediates nuclear localization of Ty3. AB - Retroviruses in nondividing cells and yeast retrotransposons must transit the nuclear membrane in order for integration to occur. Mutations in a bipartite basic motif in the carboxyl-terminal domain of the Ty3 integrase (IN) protein were previously shown to block transposition at a step subsequent to 3'-end processing of Ty3 extrachromosomal DNA. In this work, the Ty3 IN was shown to be sufficient to target green fluorescent protein to the nucleolus. Mutations in the bipartite basic motif abrogated this localization. The region containing the motif was shown to be sufficient for nuclear but not subnuclear localization of a heterologous protein. Viruslike particles (VLPs) from cells expressing a Ty3 element defective for nuclear localization were inactive in an in vitro integration assay, suggesting that nuclear entry is required to form active VLPs or that this motif is required for post-nuclear entry steps. Ty3 inserts at transcription initiation sites of genomic tRNA genes and plasmid-borne 5S and U6 RNA genes transcribed by RNA polymerase III. In situ hybridization with Ty3- and Ty3 long terminal repeat-specific probes showed that these elements which are associated with tRNA genes do not colocalize with the ribosomal DNA (rDNA). However, a PCR assay of cells undergoing transposition showed that Ty3 insertion does occur into the 5S genes, which, in yeast, are interspersed with the rDNA and therefore, like Ty3 IN, associated with the nucleolus. PMID- 11604518 TI - A truncation mutant of the 95-kilodalton subunit of transcription factor IIIC reveals asymmetry in Ty3 integration. AB - Position-specific integration of the retroviruslike element Ty3 near the transcription initiation sites of tRNA genes requires transcription factors IIIB and IIIC (TFIIIB and TFIIIC). Using a genetic screen, we isolated a mutant with a truncated 95-kDa subunit of TFIIIC (TFIIIC95) that reduced the apparent retrotransposition of Ty3 into a plasmid-borne target site between two divergently transcribed tRNA genes. Although TFIIIC95 is conserved and essential, no defect in growth or transcription of tRNAs was detected in the mutant. Steps of the Ty3 life cycle, such as protein expression, proteolytic processing, viruslike particle formation, and reverse transcription, were not affected by the mutation. However, Ty3 integration into a divergent tDNA target occurred exclusively in one orientation in the mutant strain. Investigation of this orientation bias showed that TFIIIC95 and Ty3 integrase interacted in two-hybrid and glutathione S-transferase pulldown assays and that interaction with the mutant TFIIIC95 protein was attenuated. The orientation bias observed here suggests that even for wild-type Ty3, the protein complexes associated with the long terminal repeats are not equivalent in vivo. PMID- 11604519 TI - Activation of protein kinase C zeta induces serine phosphorylation of VAMP2 in the GLUT4 compartment and increases glucose transport in skeletal muscle. AB - Insulin stimulates glucose uptake into skeletal muscle tissue mainly through the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. The precise mechanism involved in this process is presently unknown. In the cascade of events leading to insulin-induced glucose transport, insulin activates specific protein kinase C (PKC) isoforms. In this study we investigated the roles of PKC zeta in insulin-stimulated glucose uptake and GLUT4 translocation in primary cultures of rat skeletal muscle. We found that insulin initially caused PKC zeta to associate specifically with the GLUT4 compartments and that PKC zeta together with the GLUT4 compartments were then translocated to the plasma membrane as a complex. PKC zeta and GLUT4 recycled independently of one another. To further establish the importance of PKC zeta in glucose transport, we used adenovirus constructs containing wild-type or kinase-inactive, dominant-negative PKC zeta (DNPKC zeta) cDNA to overexpress this isoform in skeletal muscle myotube cultures. We found that overexpression of PKC zeta was associated with a marked increase in the activity of this isoform. The overexpressed, active PKC zeta coprecipitated with the GLUT4 compartments. Moreover, overexpression of PKC zeta caused GLUT4 translocation to the plasma membrane and increased glucose uptake in the absence of insulin. Finally, either insulin or overexpression of PKC zeta induced serine phosphorylation of the GLUT4-compartment-associated vesicle associated membrane protein 2. Furthermore, DNPKC zeta disrupted the GLUT4 compartment integrity and abrogated insulin-induced GLUT4 translocation and glucose uptake. These results demonstrate that PKC zeta regulates insulin stimulated GLUT4 translocation and glucose transport through the unique colocalization of this isoform with the GLUT4 compartments. PMID- 11604520 TI - CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z DNA binding domain. AB - RNA editing of specific residues by adenosine deamination is a nuclear process catalyzed by adenosine deaminases acting on RNA (ADAR). Different promoters in the ADAR1 gene give rise to two forms of the protein: a constitutive promoter expresses a transcript encoding (c)ADAR1, and an interferon-induced promoter expresses a transcript encoding an N-terminally extended form, (i)ADAR1. Here we show that (c)ADAR1 is primarily nuclear whereas (i)ADAR1 encompasses a functional nuclear export signal in the N-terminal part and is a nucleocytoplasmic shuttle protein. Mutation of the nuclear export signal or treatment with the CRM1 specific drug leptomycin B induces nuclear accumulation of (i)ADAR1 fused to the green fluorescent protein and increases the nuclear editing activity. In concurrence, CRM1 and RanGTP interact specifically with the (i)ADAR1 nuclear export signal to form a tripartite export complex in vitro. Furthermore, our data imply that nuclear import of (i)ADAR1 is mediated by at least two nuclear localization sequences. These results suggest that the nuclear editing activity of (i)ADAR1 is modulated by nuclear export. PMID- 11604522 TI - Electrostatic contributions to protein-protein interactions: fast energetic filters for docking and their physical basis. AB - The methods of continuum electrostatics are used to calculate the binding free energies of a set of protein-protein complexes including experimentally determined structures as well as other orientations generated by a fast docking algorithm. In the native structures, charged groups that are deeply buried were often found to favor complex formation (relative to isosteric nonpolar groups), whereas in nonnative complexes generated by a geometric docking algorithm, they were equally likely to be stabilizing as destabilizing. These observations were used to design a new filter for screening docked conformations that was applied, in conjunction with a number of geometric filters that assess shape complementarity, to 15 antibody-antigen complexes and 14 enzyme-inhibitor complexes. For the bound docking problem, which is the major focus of this paper, native and near-native solutions were ranked first or second in all but two enzyme-inhibitor complexes. Less success was encountered for antibody-antigen complexes, but in all cases studied, the more complete free energy evaluation was able to identify native and near-native structures. A filter based on the enrichment of tyrosines and tryptophans in antibody binding sites was applied to the antibody-antigen complexes and resulted in a native and near-native solution being ranked first and second in all cases. A clear improvement over previously reported results was obtained for the unbound antibody-antigen examples as well. The algorithm and various filters used in this work are quite efficient and are able to reduce the number of plausible docking orientations to a size small enough so that a final more complete free energy evaluation on the reduced set becomes computationally feasible. PMID- 11604521 TI - Initiator recognition in a primitive eukaryote: IBP39, an initiator-binding protein from Trichomonas vaginalis. AB - While considerable progress has been made in understanding the mechanisms of transcription in higher eukaryotes, transcription in single-celled, primitive eukaryotes remains poorly understood. Promoters of protein-encoding genes in the parasitic protist Trichomonas vaginalis, which represents one of the deepest branching eukaryotic lineages, have a bipartite structure with gene-specific regulatory elements and a conserved core promoter encompassing the transcription start site. Core promoters in T. vaginalis appear to consist solely of a highly conserved initiator (Inr) element that is both a structural and a functional homologue of its metazoan counterpart. Using DNA affinity chromatography, we have isolated an Inr-binding protein from T. vaginalis. Cloning of the gene encoding the Inr binding protein identified a novel 39-kDa protein (IBP39). We show that IBP39 binds to both double and single Inr motifs found in T. vaginalis genes and that binding requires the conserved nucleotides necessary for Inr function in vivo. Analyses of the cloned IBP39 gene revealed no homology at the protein sequence level with identified proteins in other organisms or the presence of known DNA-binding domains. The relationship between IBP39 and Inr-binding proteins in metazoa presents interesting evolutionary questions. PMID- 11604523 TI - Reconstitution of a native-like SH2 domain from disordered peptide fragments examined by multidimensional heteronuclear NMR. AB - The N-terminal SH2 domain from the p85alpha subunit of phosphatidylinositol 3' kinase is cleaved specifically into 9- and 5-kD fragments by limited proteolytic digestion with trypsin. The noncovalent SH2 domain complex and its constituent tryptic peptides have been investigated using high-resolution heteronuclear magnetic resonance (NMR). These studies have established the viability of the SH2 domain as a fragment complementation system. The individual peptide fragments are predominantly unstructured in solution. In contrast, the noncovalent 9-kD + 5-kD complex shows a native-like (1)H-(15)N HSQC spectrum, demonstrating that the two fragments fold into a native-like structure on binding. Chemical shift analysis of the noncovalent complex compared to the native SH2 domain reveals that the highest degree of perturbation in the structure occurs at the cleavage site within a flexible loop and along the hydrophobic interface between the two peptide fragments. Mapping of these chemical shift changes on the structure of the domain reveals changes consistent with the reduction in affinity for the target peptide ligand observed in the noncovalent complex relative to the intact protein. The 5-kD fragment of the homologous Src protein is incapable of structurally complementing the p85 9-kD fragment, either in complex formation or in the context of the full-length protein. These high-resolution structural studies of the SH2 domain fragment complementation features establish the suitability of the system for further protein-folding and design studies. PMID- 11604524 TI - The crystal structures of glutathione S-transferases isozymes 1-3 and 1-4 from Anopheles dirus species B. AB - Glutathione S-transferases (GSTs) are dimeric proteins that play an important role in cellular detoxification. Four GSTs from the mosquito Anopheles dirus species B (Ad), an important malaria vector in South East Asia, are produced by alternate splicing of a single transcription product and were previously shown to have detoxifying activity towards pesticides such as DDT. We have determined the crystal structures for two of these alternatively spliced proteins, AdGST1-3 (complexed with glutathione) and AdGST1-4 (apo form), at 1.75 and 2.45 A resolution, respectively. These GST isozymes show differences from the related GST from the Australian sheep blowfly Lucilia cuprina; in particular, the presence of a C-terminal helix forming part of the active site. This helix causes the active site of the Anopheles GSTs to be enclosed. The glutathione-binding helix alpha2 and flanking residues are disordered in the AdGST1-4 (apo) structure, yet ordered in the AdGST1-3 (GSH-bound) structure, suggesting that insect GSTs operate with an induced fit mechanism similar to that found in the plant phi- and human pi-class GSTs. Despite the high overall sequence identities, the active site residues of AdGST1-4 and AdGST1-3 have different conformations. PMID- 11604525 TI - Influence of a sulfhydryl cross-link across the allosteric-site interface of E. coli phosphofructokinase. AB - To assess the role of quaternary stability on the properties of Escherichia coli phosphofructokinase (PFK), a disulfide bond has been introduced across the subunit interface containing the allosteric binding sites in E. coli phosphofructokinase by changing N288 to cysteine. N288 is located in close proximity to the equivalent residue on an adjacent subunit. Although SDS-PAGE of oxidized N288C indicates monomeric protein, blocking the six native cysteine residues with N-ethyl maleimide (NEM) reveals dimers of N288C on non-native gels. Subsequent addition of dithiothreitol (DTT) to NEM-labeled N288C regenerates the monomer on SDS-PAGE, reflecting the reversibility of intersubunit disulfide bond formation. KSCN-induced hybrid formation between N288C and the charged-tagged mutant E195,199K exhibits full monomer-monomer exchange only upon DTT addition, providing a novel assessment of disulfide bond formation without NEM treatment. N288C also exhibits a diminished tendency toward nonspecific aggregation under denaturing conditions, a phenomenon associated with monomer formation in PFK. Pressure-induced dissociation and urea denaturation studies further indicate that oxidized N288C exhibits increased quaternary stability along both interfaces of the tetramer, suggesting a synergistic relationship between active site and allosteric site formation. Although the apparent binding affinities of substrates and effectors change somewhat upon disulfide formation in N288C, little difference is evident between the maximally inhibited and activated forms of the enzyme in oxidizing versus reducing conditions. Allosteric influence, therefore, is not correlated to subunit-subunit affinity, and does not involve substantial interfacial rearrangement. PMID- 11604526 TI - Solvent-induced collapse of alpha-synuclein and acid-denatured cytochrome c. AB - The effects of solution conditions on protein collapse were studied by measuring the hydrodynamic radii of two unfolded proteins, alpha-synuclein and acid denatured ferricytochrome c, in dilute solution and in 1 M glucose. The radius of alpha-synuclein in dilute solution is less than that predicted for a highly denatured state, and adding 1 M glucose causes further collapse. Circular dichroic data show that alpha-synuclein lacks organized structure in both dilute solution and 1 M glucose. On the other hand, the radius of acid-denatured cytochrome c in dilute solution is consistent with that of a highly denatured state, and 1 M glucose induces collapse to the size and structure of native cytochrome c. Taken together, these data show that alpha-synuclein, a natively unfolded protein, is collapsed even in dilute solution, but lacks structure. PMID- 11604527 TI - Structural features underlying selective inhibition of protein kinase CK2 by ATP site-directed tetrabromo-2-benzotriazole. AB - Two novel crystal structures of Zea mays protein kinase CK2alpha catalytic subunit, one in complex with the specific inhibitor 4,5,6,7 tetrabromobenzotriazole (TBB) and another in the apo-form, were solved at 2.2 A resolution. These structures were compared with those of the enzyme in presence of ATP and GTP (the natural cosubstrates) and the inhibitor emodin. Interaction of TBB with the active site of CK2alpha is mainly due to van der Waals contacts, with the ligand fitting almost perfectly the cavity. One nitrogen of the five membered ring interacts with two charged residues, Glu 81 and Lys 68, in the depth of the cavity, through two water molecules. These are buried in the active site and are also generally found in the structures of CK2alpha enzyme analyzed so far, with the exception of the complex with emodin. In the N-terminal lobe, the position of helix alphaC is particularly well preserved in all the structures examined; the Gly-rich loop is displaced from the intermediate position it has in the apo-form and in the presence of the natural cosubstrates (ATP/GTP) to either an upper (with TBB) or a lower position (with emodin). The selectivity of TBB for CK2 appears to be mainly dictated by the reduced size of the active site which in most other protein kinases is too large for making stable interactions with this inhibitor. PMID- 11604528 TI - Characterization of ostrich (Struthio camelus) beta-microseminoprotein (MSP): identification of homologous sequences in EST databases and analysis of their evolution during speciation. AB - Beta-microseminoprotein, alternatively called prostatic secretory protein of 94 amino acids, is a hydrophilic, unglycosylated, small protein rich in conserved half-cystine residues. Originally found in human seminal plasma and prostatic fluids, its presence was later shown in numerous secretions and its homologs were described in many vertebrate species. These studies showed that this protein had rapidly evolved, but they failed to unambiguously identify its biological role. Here, we show that a protein isolated from ostrich pituitary gland is closely related to a similar one isolated from chicken serum and that the two are structurally related to the mammalian beta-microseminoprotein. The complete 90 amino acid sequence of the ostrich molecule was established through a combination of automated Edman degradation and matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometric procedures, including postsource decay (PSD) and ladder sequencing analyses. This study documents for the first time that beta-microseminoprotein is present in aves. It is also the first report of a C-terminal amidated form for a member of this protein family and the first in which the disulfide linkages are established. Database searches using the herein-described amino acid sequence allowed identification of related proteins in numerous species such as cow, African clawed frog, zebrafish, and Japanese flounder. These small proteins show a strikingly high rate of amino acid substitutions, especially across phyla boundaries. Noticeably, no beta microseminoprotein-related gene could be found in the recently completed fruit fly genome, indicating that if such a gene exists in arthropods, it must have extensively diverged from the vertebrate ones. PMID- 11604529 TI - Peptide-plane flipping in proteins. AB - A peptide-plane flip is a large-scale rotation of the peptide plane that takes the phi,psi angles at residues i and i + 1 to different structural regions in the Ramachandran plot with a comparatively small effect on the relative orientation of their side chains. This phenomenon, which is expected to play an important role during the early stages of protein folding, has been investigated using 76 proteins for which two high-resolution X-ray conformations are available. Peptide plane flips are identified by looking for those cases where changes in /psi(i)/ + /phi(i + 1)/ are large (>200 degrees), but changes in /psi(i) + phi(i + 1)/ are comparatively small (<50 degrees). Of a total of 23 cases, the most common peptide-plane flip was identified to be the type I to type II beta-turn interconversion. Although individually rarer, there are many other types of flips that are collectively more common. Given the four main accessible regions alpha(R), alpha(L), beta and epsilon, identified from the phi,psi distribution corresponding to non-hydrogen-bonded peptide planes, 32 main types of peptide plane flip are identified. Only 8 of these are "passive," in that they require only relatively minor adjustments in the orientation of adjacent peptide planes. Of these, only the type I to type II beta-turn interconversion, denoted, beta(i) + alpha(L)(i + 1) <--> alpha(R)(i) + alpha(R)(i + 1), and the rarer alpha(R)(i) + alpha(L)(i + 1) <--> beta(i) + alpha(R)(i + 1), do not involve the epsilon region. "Active" peptide-plane flips affect the orientation of adjacent peptide planes. The flip, alpha(L)(i) + alpha(L)(i + 1) <--> beta(i) + beta(i + 1), of which one example was found, shows how concerted peptide-plane flips can convert the alpha(L) structure to the beta structure without affecting the relative orientations of the side chains. PMID- 11604530 TI - Key interactions in the immunoglobulin-like structure of apo-neocarzinostatin: evidence from nuclear magnetic resonance relaxation data and molecular dynamics simulations. AB - The three-dimensional structure of apo-neocarzinostatin (apo-NCS, MW: ca.11000, antitumoral chromophore carrier protein) is based on a seven-stranded antiparallel beta-sandwich, very similar to the immunoglobulin folding domain. We investigated the backbone dynamics of apo-NCS by (13)C-NMR relaxation measurements and molecular dynamics simulation. Model-free parameters determined from the experimental data are compared with a 1.5-nsec molecular simulation of apo-NCS in aqueous solution. This comparison provides an accurate description of both local and collective movements within the protein. This analysis enabled us to correlate dynamic processes with key interactions of this beta-protein. Local motions that could be relevant for the intermolecular association with the ligand are also described. PMID- 11604531 TI - Structure of the transmembrane region of the M2 protein H(+) channel. AB - The transmembrane domain of the M2 protein from influenza A virus forms a nearly uniform and ideal helix in a liquid crystalline bilayer environment. The exposure of the hydrophilic backbone structure is minimized through uniform hydrogen bond geometry imposed by the low dielectric lipid environment. A high-resolution structure of the monomer backbone and a detailed description of its orientation with respect to the bilayer were achieved using orientational restraints from solid-state NMR. With this unique information, the tetrameric structure of this H(+) channel is constrained substantially. Features of numerous published models are discussed in light of the experimental structure of the monomer and derived features of the tetrameric bundle. PMID- 11604532 TI - Identification of disulfide-linked peptides by isotope profiles produced by peptic digestion of proteins in 50% (18)O water. AB - Determination of the disulfide-bond arrangement of a protein by characterization of disulfide-linked peptides in proteolytic digests may be complicated by resistance of the protein to specific proteases, disulfide interchange, and/or production of extremely complex mixtures by less specific proteolysis. In this study, mass spectrometry has been used to show that incorporation of (18)O into peptides during peptic digestion of disulfide-linked proteins in 50% (18)O water resulted in isotope patterns and increases in average masses that facilitated identification and characterization of disulfide-linked peptides even in complex mixtures, without the need for reference digests in 100% (16)O water. This is exemplified by analysis of peptic digests of model proteins lysozyme and ribonuclease A (RNaseA) by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) and electrospray ionization (ESI) mass spectrometry (MS). Distinct isotope profiles were evident when two peptide chains were linked by disulfide bonds, provided one of the chains did not contain the C terminus of the protein. This latter class of peptide, and single-chain peptides containing an intrachain disulfide bond, could be identified and characterized by mass shifts produced by reduction. Reduction also served to confirm other assignments. Isotope profiling of peptic digests showed that disulfide-linked peptides were often enriched in the high molecular weight fractions produced by size exclusion chromatography (SEC) of the digests. Applicability of these procedures to analysis of a more complex disulfide-bond arrangement was shown with the hemagglutinin/neuraminidase of Newcastle disease virus. PMID- 11604533 TI - E. coli methionine sulfoxide reductase with a truncated N terminus or C terminus, or both, retains the ability to reduce methionine sulfoxide. AB - The monomeric peptide methionine sulfoxide reductase (MsrA) catalyzes the irreversible thioredoxin-dependent reduction of methionine sulfoxide. The crystal structure of MsrAs from Escherichia coli and Bos taurus can be described as a central core of about 140 amino acids that contains the active site. The core is wrapped by two long N- and C-terminal extended chains. The catalytic mechanism of the E. coli enzyme has been recently postulated to take place through formation of a sulfenic acid intermediate, followed by reduction of the intermediate via intrathiol-disulfide exchanges and thioredoxin oxidation. In the present work, truncated MsrAs at the N- or C-terminal end or at both were produced as folded entities. All forms are able to reduce methionine sulfoxide in the presence of dithiothreitol. However, only the N-terminal truncated form, which possesses the two cysteines located at the C-terminus, reduces the sulfenic acid intermediate in a thioredoxin-dependent manner. The wild type displays a ping-pong mechanism with either thioredoxin or dithiothreitol as reductant. Kinetic saturation is only observed with thioredoxin with a low K(M) value of 10 microM. Thus, thioredoxin is likely the reductant in vivo. Truncations do not significantly modify the kinetic properties, except for the double truncated form, which displays a 17-fold decrease in k(cat)/K(MetSO). Alternative mechanisms for sulfenic acid reduction are also presented based on analysis of available MsrA sequences. PMID- 11604534 TI - Proteins of circularly permuted sequence present within the same organism: the major serine proteinase inhibitor from Capsicum annuum seeds. AB - The major serine proteinase inhibitor from bell pepper (Capsicum annuum, paprika) seeds was isolated, characterized, and sequenced, and its disulfide bond topology was determined. PSI-1.2 is a 52-amino-acid-long, cysteine-rich polypeptide that inhibits both trypsin (K(i) = 4.6 x 10(-9) M) and chymotrypsin (K(i) = 1.1 x 10( 8) M) and is a circularly permuted member of the potato type II inhibitor family. Mature proteins of this family are produced from precursor proteins containing two to eight repeat units that are proteolytically cleaved within, rather than between, the repeats. In contrast, PSI-1.2 corresponds to a complete repeat that was predicted as the putative ancestral protein of the potato type II family. To our knowledge, this is the first case in which two proteins related to each other by circular permutation are shown to exist in the same organism and are expressed within the same organ. PSI-1.2 is not derived from any of the known precursors, and it contains a unique amphiphilic segment in one of its loops. A systematic comparison of the related precursor repeat-sequences reveals common evolutionary patterns that are in agreement with the ancestral gene-duplication hypothesis. PMID- 11604535 TI - Insights into the alkaline transformation of ferricytochrome c from (1)H NMR studies in 30% acetonitrile-water. AB - Recently, we found that ferricytochrome c (ferricyt c) undergoes significant structural changes in mixed aqueous-nonaqueous media, resulting in the formation of a mixture of alkaline-like species. The equilibrium composition of this mixture of species is dependent on the dielectric constant of the mixed solvent medium. One-dimensional (1D) and two-dimensional (2D) (1)H nuclear magnetic resonance (NMR) methods have now been used to study these alkaline-like forms in 30% acetonitrile-water solution. A native-like (M80-ligated) III* form, two lysine-ligated forms (IVa* and IVb*), and a hydroxide-ligated form (V*) were observed. Heme proton resonance assignments for these forms were accomplished using 1D (1)H NMR and 2D nuclear Overhauser effect spectroscopy methods at 20 degrees C and 35 degrees C. The chemical exchange between the alkaline forms in 30% acetonitrile solution facilitated heme proton resonance assignments. Based on examination of the heme proton chemical shifts and several highly conserved amino acid residues, the electronic structure, secondary structure, and hydrogen bond network in the vicinity of the heme in the III* form were found to be intact. Similarly, the heme electronic structure of the IVa* form was found to be comparable to that of the IVa form. Differences in the order of the heme methyl resonances in the IVb* form, however, suggest that the heme active site in this form is somewhat different from that observed in aqueous alkaline solution. In addition, resonance assignments for the 8- and 3-methyl heme protons were made for the hydroxide-ligated V* form for the first time. The observation of chemical exchange peaks between all species except IVb* and IVa* or V* was used to propose an exchange pathway between the different forms of ferricyt c in 30% acetonitrile solution. This pathway may be biologically significant because ferricyt c, which resides in the intermembrane space of mitochondria, is exposed to medium of relatively low dielectric constant when it interacts with the mitochondrial membrane. PMID- 11604537 TI - Implications of secondary structure prediction and amino acid sequence comparison of class I and class II phosphoribosyl diphosphate synthases on catalysis, regulation, and quaternary structure. AB - Spinach 5-phospho-D-ribosyl alpha-1-diphosphate (PRPP) synthase isozyme 4 was synthesized in Escherichia coli and purified to near homogeneity. The activity of the enzyme is independent of P(i); it is inhibited by ADP in a competitive manner, indicating a lack of an allosteric site; and it accepts ATP, dATP, GTP, CTP, and UTP as diphosphoryl donors. All of these properties are characteristic for class II PRPP synthases. K(m) values for ATP and ribose 5-phosphate are 77 and 48 microM, respectively. Gel filtration reveals a molecular mass of the native enzyme of approximately 110 kD, which is consistent with a homotrimer. Secondary structure prediction shows that spinach PRPP synthase isozyme 4 has a general folding similar to that of Bacillus subtilis class I PRPP synthase, for which the three-dimensional structure has been solved, as the position and extent of helices and beta-sheets of the two enzymes are essentially conserved. Amino acid sequence comparison reveals that residues of class I PRPP synthases interacting with allosteric inhibitors are not conserved in class II PRPP synthases. Similarly, residues important for oligomerization of the B. subtilis enzyme show little conservation in the spinach enzyme. In contrast, residues of the active site of B. subtilis PRPP synthase show extensive conservation in spinach PRPP synthase isozyme 4. PMID- 11604536 TI - Role of conserved residues in structure and stability: tryptophans of human serum retinol-binding protein, a model for the lipocalin superfamily. AB - Serum retinol binding protein (RBP) is a member of the lipocalin family, proteins with up-and-down beta-barrel folds, low levels of sequence identity, and diverse functions. Although tryptophan 24 of RBP is highly conserved among lipocalins, it does not play a direct role in activity. To determine if Trp24 and other conserved residues have roles in stability and/or folding, we investigated the effects of conservative substitutions for the four tryptophans and some adjacent residues on the structure, stability, and spectroscopic properties of apo-RBP. Crystal structures of recombinant human apo-RBP and of a mutant with substitutions for tryptophans 67 and 91 at 1.7 A and 2.0 A resolution, respectively, as well as stability measurements, indicate that these relatively exposed tryptophans have little influence on structure or stability. Although Trp105 is largely buried in the wall of the beta-barrel, it can be replaced with minor effects on stability to thermal and chemical unfolding. In contrast, substitutions of three different amino acids for Trp24 or replacement of Arg139, a conserved residue that interacts with Trp24, lead to similar large losses in stability and lower yields of native protein generated by in vitro folding. The results and the coordinated nature of natural substitutions at these sites support the idea that conserved residues in functionally divergent homologs have roles in stabilizing the native relative to misfolded structures. They also establish conditions for studies of the kinetics of folding and unfolding by identifying spectroscopic signals for monitoring the formation of different substructures. PMID- 11604539 TI - Structural comparison of recombinant human macrophage colony stimulating factor beta and a partially reduced derivative using hydrogen deuterium exchange and electrospray ionization mass spectrometry. AB - Hydrogen deuterium exchange, monitored by electrospray ionization mass spectrometry, has been employed to characterize structural features of a derivative of recombinant human macrophage colony stimulating factor beta (rhm CSFbeta) in which two of the nine disulfide bridges (Cys157/Cys159 Cys'157/Cys'159) were selectively reduced and alkylated. Removal of these two disulfide bridges did not affect the biological activity of the protein. Similarities between CD and fluorescence spectra for rhm-CSFbeta and its derivative indicate that removing the disulfide bonds did not strongly alter the overall three-dimensional structure of rhm-CSFbeta. However, differences between deuterium exchange data of the intact proteins indicate that more NHs underwent fast deuterium exchange in the derivative than in rhm-CSFbeta. Regions located near the disulfide bond removal site were shown to exhibit faster deuterium exchange behavior in the derivative than in rhm-CSFbeta. PMID- 11604538 TI - Salt-dependent monomer-dimer equilibrium of bovine beta-lactoglobulin at pH 3. AB - Although bovine beta-lactoglobulin assumes a monomeric native structure at pH 3 in the absence of salt, the addition of salts stabilizes the dimer. Thermodynamics of the monomer-dimer equilibrium dependent on the salt concentration were studied by sedimentation equilibrium. The addition of NaCl, KCl, or guanidine hydrochloride below 1 M stabilized the dimer in a similar manner. On the other hand, NaClO(4) was more effective than other salts by about 20-fold, suggesting that anion binding is responsible for the salt-induced dimer formation, as observed for acid-unfolded proteins. The addition of guanidine hydrochloride at 5 M dissociated the dimer into monomers because of the denaturation of protein structure. In the presence of either NaCl or NaClO(4), the dimerization constant decreased with an increase in temperature, indicating that the enthalpy change (DeltaH(D)) of dimer formation is negative. The heat effect of the dimer formation was directly measured with an isothermal titration calorimeter by titrating the monomeric beta-lactoglobulin at pH 3.0 with NaClO(4). The net heat effects after subtraction of the heat of salt dilution, corresponding to DeltaH(D), were negative, and were consistent with those obtained by the sedimentation equilibrium. From the dependence of dimerization constant on temperature measured by sedimentation equilibrium, we estimated the DeltaH(D) value at 20 degrees C and the heat capacity change (DeltaC(p)) of dimer formation. In both NaCl and NaClO(4), the obtained DeltaC(p) value was negative, indicating the dominant role of burial of the hydrophobic surfaces upon dimer formation. The observed DeltaC(p) values were consistent with the calculated value from the X-ray dimeric structure using a method of accessible surface area. These results indicated that monomer-dimer equilibrium of beta-lactoglobulin at pH 3 is determined by a subtle balance of hydrophobic and electrostatic effects, which are modulated by the addition of salts or by changes in temperature. PMID- 11604540 TI - Chaperone-like activity of peptidyl-prolyl cis-trans isomerase during creatine kinase refolding. AB - Porcine kidney 18 kD peptidyl-prolyl cis-trans isomerase (PPIase) belongs to the cyclophilin family that is inhibited by the immunosuppressive drug cyclosporin A. The chaperone activity of PPIase was studied using inactive, active, and alkylated PPIase during rabbit muscle creatine kinase (CK) refolding. The results showed that low concentration inactive or active PPIase was able to improve the refolding yields, while high concentration PPIase decreased the CK reactivation yields. Aggregation was inhibited by inactive or active PPIase, and completely suppressed at 32 or 80 times the CK concentration (2.7 microM). However, alkylated PPIase was not able to prevent CK aggregation. In addition, the ability of inactive PPIase to affect CK reactivation and prevent CK aggregation was weaker than that of active PPIase. These results indicate that PPIase interacted with the early folding intermediates of CK, thus preventing their aggregation in a concentration-dependent manner. PPIase exhibited chaperone-like activity during CK refolding. The results also suggest that the isomerase activity of PPIase was independent of the chaperone activity, and that the proper molar ratio was important for the chaperone activity of PPIase. The cysteine residues of PPIase may be a peptide binding site, and may be an essential group for the chaperone function. PMID- 11604541 TI - Pcons: a neural-network-based consensus predictor that improves fold recognition. AB - During recent years many protein fold recognition methods have been developed, based on different algorithms and using various kinds of information. To examine the performance of these methods several evaluation experiments have been conducted. These include blind tests in CASP/CAFASP, large scale benchmarks, and long-term, continuous assessment with newly solved protein structures. These studies confirm the expectation that for different targets different methods produce the best predictions, and the final prediction accuracy could be improved if the available methods were combined in a perfect manner. In this article a neural-network-based consensus predictor, Pcons, is presented that attempts this task. Pcons attempts to select the best model out of those produced by six prediction servers, each using different methods. Pcons translates the confidence scores reported by each server into uniformly scaled values corresponding to the expected accuracy of each model. The translated scores as well as the similarity between models produced by different servers is used in the final selection. According to the analysis based on two unrelated sets of newly solved proteins, Pcons outperforms any single server by generating approximately 8%-10% more correct predictions. Furthermore, the specificity of Pcons is significantly higher than for any individual server. From analyzing different input data to Pcons it can be shown that the improvement is mainly attributable to measurement of the similarity between the different models. Pcons is freely accessible for the academic community through the protein structure-prediction metaserver at http://bioinfo.pl/meta/. PMID- 11604542 TI - Native-state conformational dynamics of GART: a regulatory pH-dependent coil helix transition examined by electrostatic calculations. AB - Glycinamide ribonucleotide transformylase (GART) undergoes a pH-dependent coil helix transition with pK(a) approximately 7. An alpha-helix is formed at high pH spanning 8 residues of a 21-residue-long loop, comprising the segment Thr120 His121-Arg122-Gln123-Ala124-Leu125-Glu126-Asn127. To understand the electrostatic nature of this loop-helix, called the activation loop-helix, which leads to the formation and stability of the alpha-helix, pK(a) values of all ionizable residues of GART have been calculated, using Poisson-Boltzmann electrostatic calculations and crystallographic data. Crystallographic structures of high and low pH E70A GART have been used in our analysis. Low pK(a) values of 5.3, 5.3, 3.9, 1.7, and 4.7 have been calculated for five functionally important histidines, His108, His119, His121, His132, and His137, respectively, using the high pH E70A GART structure. Ten theoretical single and double mutants of the high pH E70A structure have been constructed to identify pairwise interactions of ionizable residues, which have aided in elucidating the multiplicity of electrostatic interactions of the activation loop-helix, and the impact of the activation helix on the catalytic site. Based on our pK(a) calculations and structural data, we propose that: (1) His121 forms a molecular switch for the coil-helix transition of the activation helix, depending on its protonation state; (2) a strong electrostatic interaction between His132 and His121 is observed, which can be of stabilizing or destabilizing nature for the activation helix, depending on the relative orientation and protonation states of the rings of His121 and His132; (3) electrostatic interactions involving His119 and Arg122 play a role in the stability of the activation helix; and (4) the activation helix contains the helix-promoting sequence Arg122-Gln123-Ala124-Leu125-Glu126, but its alignment relative to the N and C termini of the helix is not optimal, and is possibly of a destabilizing nature. Finally, we provide electrostatic evidence that the formation and closure of the activation helix create a hydrophobic environment for catalytic-site residue His108, to facilitate catalysis. PMID- 11604543 TI - Proton transfer dynamics of GART: the pH-dependent catalytic mechanism examined by electrostatic calculations. AB - The enzyme glycinamide ribonucleotide transformylase (GART) catalyzes the transfer of a formyl group from formyl tetrahydrofolate (fTHF) to glycinamide ribonucleotide (GAR), a process that is pH-dependent with pK(a) of approximately 8. Experimental studies of pH-rate profiles of wild-type and site-directed mutants of GART have led to the proposal that His108, Asp144, and GAR are involved in catalysis, with His108 being an acid catalyst, while forming a salt bridge with Asp144, and GAR being a nucleophile to attack the formyl group of fTHF. This model implied a protonated histidine with pK(a) of 9.7 and a neutral GAR with pK(a) of 6.8. These proposed unusual pK(a)s have led us to investigate the electrostatic environment of the active site of GART. We have used Poisson Boltzmann-based electrostatic methods to calculate the pK(a)s of all ionizable groups, using the crystallographic structure of a ternary complex of GART involving the pseudosubstrate 5-deaza-5,6,7,8-THF (5dTHF) and substrate GAR. Theoretical mutation and deletion analogs have been constructed to elucidate pairwise electrostatic interactions between key ionizable sites within the catalytic site. Also, a construct of a more realistic catalytic site including a reconstructed pseudocofactor with an attached formyl group, in an environment with optimal local van der Waals interactions (locally minimized) that imitates closely the catalytic reactants, has been used for pK(a) calculations. Strong electrostatic coupling among catalytic residues His108, Asp144, and substrate GAR was observed, which is extremely sensitive to the initial protonation and imidazole ring flip state of His108 and small structural changes. We show that a proton can be exchanged between GAR and His108, depending on their relative geometry and their distance to Asp144, and when the proton is attached on His108, catalysis could be possible. Using the formylated locally minimized construct of GART, a high pK(a) for His108 was calculated, indicating a protonated histidine, and a low pK(a) for GAR(NH(2)) was calculated, indicating that GAR is in neutral form. Our results are in qualitative agreement with the current mechanistic picture of the catalytic process of GART deduced from the experimental data, but they do not reproduce the absolute magnitude of the pK(a)s extracted from fits of k(cat)-pH profiles, possibly because the static time-averaged crystallographic structure does not describe adequately the dynamic nature of the catalytic site during binding and catalysis. In addition, a strong effect on the pK(a) of GAR(NH(2)) is produced by the theoretical mutations of His108Ala and Asp144Ala, which is not in agreement with the observed insensitivity of the pK(a) of GAR(NH(2)) modeled from the experimental data using similar mutations. Finally, we show that important three-way electrostatic interactions between highly conserved His137, with His108 and Asp144, are responsible for stabilizing the electrostatic microenvironment of the catalytic site. In conclusion, our data suggest that further detailed computational and experimental work is necessary. PMID- 11604544 TI - Distance mapping of protein-binding sites using spin-labeled oligosaccharide ligands. AB - The binding of a nitroxide spin-labeled analog of N-acetyllactosamine to galectin 3, a mammalian lectin of 26 kD size, is studied to map the binding sites of this small oligosaccharide on the protein surface. Perturbation of intensities of cross-peaks in the (15)N heteronuclear single quantum coherence (HSQC) spectrum of full-length galectin-3 owing to the bound spin label is used qualitatively to identify protein residues proximate to the binding site for N-acetyllactosamine. A protocol for converting intensity measurements to a more quantitative determination of distances between discrete protein amide protons and the bound spin label is then described. This protocol is discussed as part of a drug design strategy in which subsequent perturbation of chemical shifts of distance mapped amide cross-peaks can be used effectively to screen a library of compounds for other ligands that bind to the target protein at distances suitable for chemical linkage to the primary ligand. This approach is novel in that it bypasses the need for structure determination and resonance assignment of the target protein. PMID- 11604545 TI - High and low oxygen affinity conformations of T state hemoglobin. AB - To understand the interplay between tertiary and quaternary transitions associated with hemoglobin function and regulation, oxygen binding curves were obtained for hemoglobin A fixed in the T quaternary state by encapsulation in wet porous silica gels. At pH 7.0 and 15 degrees C, the oxygen pressure at half saturation (p50) was measured to be 12.4 +/- 0.2 and 139 +/- 4 torr for hemoglobin gels prepared in the absence and presence of the strong allosteric effectors inositol hexaphosphate and bezafibrate, respectively. Both values are in excellent agreement with those found for the binding of the first oxygen to hemoglobin in solution under similar experimental conditions. The corresponding Hill coefficients of hemoglobin gels were 0.94 +/- 0.02 and 0.93 +/- 0.03, indicating, in the frame of the Monod, Wyman, and Changeux model, that high and low oxygen-affinity tertiary T-state conformations have been isolated in a pure form. The values, slightly lower than unity, reflect the different oxygen affinity of alpha- and beta-hemes. Significantly, hemoglobin encapsulated in the presence of the weak effector phosphate led to gels that show intermediate oxygen affinity and Hill coefficients of 0.7 to 0.8. The heterogeneous oxygen binding results from the presence of a mixture of the high and low oxygen-affinity T states. The Bohr effect was measured for hemoglobin gels containing the pure conformations and found to be more pronounced for the high-affinity T state and almost absent for the low-affinity T state. These findings indicate that the functional properties of the T quaternary state result from the contribution of two distinct, interconverting conformations, characterized by a 10-fold difference in oxygen affinity and a different extent of tertiary Bohr effect. The very small degree of T-state cooperativity observed in solution and in the crystalline state might arise from a ligand-induced perturbation of the distribution between the high- and low-affinity T-state conformations. PMID- 11604546 TI - Macromolecular organization of the Yersinia pestis capsular F1 antigen: insights from time-of-flight mass spectrometry. AB - Mass spectrometry has been used to examine the subunit interactions in the capsular F1 antigen from Yersinia pestis, the causative agent of the plague. Introducing the sample using nanoflow electrospray from solution conditions in which the protein remains in its native state and applying collisional cooling to minimize the internal energy of the ions, multiple subunit interactions have been maintained. This methodology revealed assemblies of the F1 antigen that correspond in mass to both 7-mers and 14-mers, consistent with interaction of two seven-membered units. The difference between the calculated masses and those measured experimentally for these higher-order oligomers was found to increase proportionately with the size of the complex. This is consistent with a solvent filled central cavity maintained on association of the 7-mer to the 14-mer. The charge states of the ions show that an average of one and four surface accessible basic side-chains are involved in maintaining the interactions between the 7-mer units and neighboring subunits, respectively. Taken together, these findings provide new information about the stoichiometry and packing of the subunits involved in the assembly of the capsular antigen structure. More generally, the data show that the symmetry and packing of macromolecular complexes can be determined solely from mass spectrometry, without any prior knowledge of higher order structure PMID- 11604547 TI - Is dimerization of chemokine receptors functionally relevant? AB - Chemokines activate lymphocytes by initiating signaling cascades through cell surface receptors that couple to heterotrimeric GTP-binding proteins. Thelen and Bagglioni describe why the recent proposal that these receptors form heterodimers and activate the Jak kinases for transducing signals should be viewed with caution. PMID- 11604548 TI - Bridging with GAPs: receptor communication through RGS proteins. AB - The regulators of heterotrimeric guanosine triphosphate (GTP)-binding protein (G protein) signaling (RGS proteins) were named for their ability to act as GTP activating proteins (GAPs) for G proteins and, thus, limit the signal generated by G protein-coupled receptors (GPCRs). In addition to this characteristic biochemical trait, RGS proteins constitute a large family of structurally diverse proteins with variable sequence motifs that permit additional specific interactions. RGS proteins may also serve as a bridge from GPCRs to receptor tyrosine kinases or transmembrane channels, allowing signals from GPCRs to regulate signaling through other types of receptors, and vice versa. PMID- 11604549 TI - Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins. AB - Beta-adrenergic receptor (AR) subtypes are archetypical members of the G protein coupled receptor (GPCR) superfamily. Whereas both beta1AR and beta2AR stimulate the classic G(s)-adenylyl cyclase-3',5'-adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling cascade, beta2AR couples to both G(s) and G(i) proteins, activating bifurcated signaling pathways. In the heart, dual coupling of the beta2AR to G(s) and G(i) results in compartmentalization of the G(s)-stimulated cAMP signal, thus selectively affecting plasma membrane effectors (such as L-type Ca(2+) channels) and bypassing cytoplasmic target proteins (such as phospholamban and myofilament contractile proteins). More important, the beta2AR-to-G(i) branch delivers a powerful cell survival signal that counters apoptosis induced by the concurrent G(s)-mediated signal or by a wide range of assaulting factors. This survival pathway sequentially involves G(i), G(beta)(gamma), phosphoinositide 3 kinase, and Akt. Furthermore, cardiac-specific transgenic overexpression of betaAR subtypes in mice results in distinctly different phenotypes in terms of the likelihood of cardiac hypertrophy and heart failure. These findings indicate that stimulation of the two betaAR subtypes activates overlapping, but different, sets of signal transduction mechanisms, and fulfills distinct or even opposing physiological and pathophysiological roles. Because of these differences, selective activation of cardiac beta2AR may provide catecholamine-dependent inotropic support without cardiotoxic consequences, which might have beneficial effects in the failing heart. PMID- 11604550 TI - Capecitabine: a novel agent for the treatment of solid tumors. AB - Although 5-fluorouracil (5-FU) has been used to treat breast and colorectal cancers for several decades, bolus 5-FU has disappointing efficacy. Prolonged infusion schedules and biomodulation with leucovorin have resulted in improved response rates, but these have not translated into significant improvements in survival in patients with metastatic disease. Furthermore, prolonged infusion is inconvenient for patients and can result in medical complications. New oral fluoropyrimidines, including capecitabine, are promising alternatives to i.v. 5 FU. Capecitabine generates 5-FU preferentially within tumors through exploitation of the high intratumoral activity of thymidine phosphorylase. The tumor selectivity of capecitabine has been confirmed in a clinical study of colorectal cancer patients. Clinical trials have shown that capecitabine is an effective, well-tolerated treatment for breast and colorectal cancer, with response rates of 20-26% in anthracycline- and taxane-pretreated metastatic breast cancer. As first line monotherapy, capecitabine produces response rates of 25-27% in metastatic colorectal cancer and 30% in metastatic breast cancer. In all studies to date, capecitabine has been well tolerated, with adverse events typical of infusional 5 FU and manageable with treatment interruption/dose modification. Myelosuppression and alopecia are rare. Capecitabine is also being investigated in other solid tumors (including ovarian, pancreatic and gastric cancers) as adjuvant monotherapy in breast and colorectal cancer, and in combination with other cytotoxic agents. Results of ongoing trials are eagerly awaited. PMID- 11604551 TI - Multicenter phase II study of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer. AB - Gemcitabine has activity in advanced ovarian cancer, with responses in platinum resistant disease. This study assessed the activity of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer. All patients had histologically verified invasive epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease and no prior chemotherapy. Patients received gemcitabine 1250 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Radiological response was assessed after two cycles. Between December 1992 and October 1995, 35 patients were enrolled. Of 33 evaluable patients, there was one complete response and five partial responses, for an overall response rate of 18% (95% confidence interval 7-36%). Forty-two percent of patients had a greater than 50% decrease in their CA-125 levels. Of the 25 patients who received platinum-based chemotherapy following treatment with gemcitabine, 12 achieved an overall response rate of 48%. Toxicity was mild, with two episodes of WHO grade 4 neutropenia (not associated with fever) and two episodes of grade 4 thrombocytopenia (not associated with bleeding). Gemcitabine has single-agent activity for poor-prognosis patients with advanced ovarian cancer. Similar results with subsequent platinum-based therapy indicate a lack of cross-resistance. This, combined with gemcitabine's favorable toxicity profile, warrants testing in comparative trials. PMID- 11604552 TI - Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man. AB - Ecteinascidin 743 (ET-743) is a potent anti-tumoral agent of a marine origin. It is currently being tested in phase II clinical trials using a 3-weekly 24-h i.v. infusion of 1500 microg/m(2) and 3-h infusions of 1650 microg/m(2). Knowledge of the metabolism of ET-743 is, however, still scarce. In the present study, a qualitative chromatographic discovery of metabolites of ET-743 in man is reported. ET-743 and its demethylated analog ET-729 were incubated at 37 degrees C in the presence of enzyme systems, pooled human microsomes, pooled human plasma and uridine 5'-diphosphoglucuronyltransferase, respectively, in appropriate media. Reaction products were investigated chromatographically using photodiode array and ion spray-mass spectrometric detection (LC-MS). The main reaction products in microsomal incubations of ET-743 resulted from a remarkable breakdown of the molecule. In plasma the drugs were deacetylated, and the transferase did actually yield a glucuronide of both ET-743 and ET-729. In contrast, screening of urine, plasma and bile, collected from patients treated with ET-743 at the highest dose levels, using a sensitive LC-MS assay, did not result in detection of ET-729 and metabolites which were generated in vitro. The urinary excretion of ET-743 in man was lower than 0.7% of the administered dose for a 24-h infusion. PMID- 11604553 TI - Adaptive intrapatient dose escalation of cisplatin in patients with advanced head and neck cancer. AB - The purpose of this study was to explore the feasibility and toxicity of intrapatient dose adjustment using predefined levels of exposure to cisplatin, with the ultimate goal to further improve the antitumor activity of the treatment. The primary parameter for adaptive dosing was the level of platinum DNA adducts in peripheral white blood cells (WBC) and the secondary parameter the area under the curve (AUC) of unbound platinum in plasma, which were determined during the applied courses. Target levels had been defined in a previously performed pharmacologic study. The concept of adaptive dosing was tested in 16 patients with locally advanced head and neck (H/N) cancer who would receive six weekly courses of cisplatin at a starting dose level of 80 mg/m(2), which was previously investigated in a phase II study. Forty-seven percent of patients received a dose increase varying from 10 to 40%. Only two patients had exposure levels significantly below the defined target levels for DNA adducts and AUC. The majority of patients reached the defined target levels by modest dose increases of 10-20% during course 2. Relevant but reversible ototoxicity (temporary grade 3 in two patients) and renal toxicity (temporary grade 2 in two other patients) were observed. The pattern and severity of the toxicity was comparable to that encountered in the previous phase II study in H/N cancer patients. We conclude that the strategy of intrapatient dose adjustment for cisplatin is practically feasible in a research setting even when a short turn around time of 1 week is the limit for reporting results. Although in some patients the dose increase that had to be applied to reach target levels was substantial (up to 40%), this approach in H/N cancer patients is not expected to improve the response rate significantly, because these significantly underdosed patients represented only a small percentage of the investigated population. The great majority of patients needed only limited (10-20%) dose increases which very likely will not improve the response rate to a clinically significant extent. The outlined concept is currently being explored in other tumor types and schedules of cisplatin. PMID- 11604554 TI - Granulomatous tubulointerstitial nephritis induced by all-trans retinoic acid. AB - We report the first case of granulomatous tubulointerstitial nephritis induced by all-trans retinoic acid (ATRA) in a patient with acute promyelocytic leukemia (APL). Acute renal failure during treatment with ATRA has been previously reported as a part of an ATRA syndrome or a thrombotic complication of a hypercoagulable state. This case indicates an alternative mechanism of acute renal failure occurring during ATRA therapy. PMID- 11604555 TI - Therapy-related CD7+ acute myeloid leukemia with trisomy 8 following acute monocytic leukemia. AB - We report a patient who developed CD7+ therapy-related acute myeloid leukemia (t AML) with trisomy 8 after chemotherapy for AML. PMID- 11604556 TI - Evidence for epidermal growth factor receptor-enhanced chemosensitivity in combinations of cisplatin and the new irreversible tyrosine kinase inhibitor CI 1033. AB - Irreversible inhibitors of the epidermal growth factor receptor (EGFR) are showing promise in clinical trials. This report is the first to show that inhibition of the EGFR tyrosine kinase by an irreversible binder synergizes with cisplatin, at least in EGFR-overexpressing tissue culture cell lines in vitro. Unlike previous synergies demonstrated between ErbB2 blockade and DNA-damaging drugs, the synergy between the irreversible EGFR inhibitor and cisplatin does not appear to involve the repair of DNA-cisplatin adducts. Given the current clinical data, this combination may be of more than theoretical interest. PMID- 11604557 TI - Docetaxel alone or orally combined with 5-fluorouracil and its derivatives: effects on mouse mammary tumor cell line MM2 in vitro and in vivo. AB - Although docetaxel (Taxotere; TXT), a taxoid anticancer drug, is clinically and experimentally very effective against breast cancer, its antitumor effect is of very short duration. We addressed whether 5-fluorouracil (5-FU) and its derivatives can act synergistically with TXT against mammary tumors, with placing particular stress on their use by oral route. Mouse mammary tumor cell line, MM2, was propagated in culture and as ascites in mice. Carmofur (HCFU) and doxifluridine (5'-DFUR) were used as 5-FU derivatives. In vitro, the cytotoxic effects of antitumor drugs on MM2 cells were examined by MTS assay. In vivo, mice inoculated i.p. with MM2 cells were treated with i.p. injection of TXT and/or oral administration of 5-FU or its derivatives, and observed for curing tumor. In vitro, the synergistic effects were observed in the combination of TXT and 5-FU or HCFU, but not in that of TXT and 5'-DFUR. In vivo, all of these combinations cured tumors far more effectively than TXT alone. The discrepant result of the combination of TXT and 5'-DFUR between in vitro and in vivo was ascribed to up regulation of pyrimidine phosphorylase in tumor cells in vivo by TXT. Thus, 5-FU, its masked compounds like HCFU and its prodrugs like 5'-DFUR can act synergistically with TXT in the therapy of cancer even when administered by the oral route. PMID- 11604558 TI - Characteristics of etoposide-induced apoptotic cell death in the U-937 human lymphoma cell line. AB - Cell death induced by etoposide in the human lymphoma cell line U-937 GTB was characterized. Activity of caspases -3, -8 and -9 was measured by spectrophotometric detection of specific cleavage products, DNA fragmentation by TdT-mediated dUTP nick end-labelling (TUNEL), and apoptotic morphology by conventional staining and microscopy, as well as by a novel method-the microculture kinetics (MiCK) assay. Synthesis of protein and DNA during exposure was monitored by incorporation of radioactive leucine and thymidine, respectively. The effects of caspase inhibitors on total viability, as well as early and late morphological changes were studied. Etoposide rapidly induced apoptosis, dependent on caspase-3 and -8, but inhibition of these caspases did not prevent major cell death, but promoted a switch in late morphology. The novel MiCK assay added valuable information on early morphological events during cell death. Hence, this study provides support for caspase-8-mediated apoptosis in U 937 GTB when exposed to etoposide. General caspase inhibition switches cell death to one with a different morphology. PMID- 11604559 TI - Glutathione-S-transferase-pi expression regulates sensitivity to glutathione doxorubicin conjugate. AB - We have reported that glutathione-doxorubicin conjugate (GSH-DXR) exhibited potent cytotoxicity against tumor cells and inhibited glutathione-S-transferase (GST) enzyme activity. In order to determine whether or not the expression of GST pi lowered the cytotoxicity of GSH-DXR, cytocidal activity of the conjugate was examined using tumor cells in which the level of GST-pi expression was regulated by transfecting GST-pi cDNA in the correct or reverse direction and comparing with that of DXR. Enhancement of GST-pi expression by transfecting GST-pi sense cDNA into human hepatoblastoma HepG2 cells in which GST-pi expression was extremely low caused an increase in GST activity from 0.26 to 55.0 nmol/mg/min and a marked reduction in transfectant sensitivity to GSH-DXR to 1/120 (0.15-18 nM IC50) although the sensitivity to DXR was slightly decreased to 1/2.6 (380-990 nM IC50). By contrast, a high GST-pi-expressing human colon cancer cell line, HT29, showed a decrease in GST enzyme activity from 72.0 to 45.9 nmol/mg/min after transfecting GST-pi antisense cDNA and a marked improvement in transfectant sensitivity to GSH-DXR was observed (28-2.9 nM IC50) compared with the transfectant sensitivity to DXR (1020-320 nM IC50). Additionally, the expression of GST-pi in HepG2 cells caused a decrease in GSH-DXR-induced activation of caspase-3, which was an apoptotic marker, whereas the suppression of GST-pi in HT29 cells showed an increase in caspase-3 activation. These results suggested that the cytocidal efficacy of GSH-DXR, but not that of DXR, was controlled by the level of GST-pi expression in the cells. PMID- 11604560 TI - Platelets, leukocytes, and coagulation. AB - Considerable data now support the hypothesis that platelets actively regulate the propagation of coagulation by (1) expressing specific, high-affinity receptors for coagulation proteases, zymogens, and cofactors; (2) protecting the bound coagulation enzymes from inactivation/inhibition; (3) restricting coagulant activity to the site of vascular injury; and (4) amplifying the initiating stimulus to lead to explosive thrombin generation. Thrombin generation is sustained at the site of vascular injury by the recruitment of circulating monocytes and neutrophils to the growing thrombus via the interaction of PSGL-1, which is constitutively expressed by leukocytes, with P-selectin, which is expressed by activated platelets. Unique among cells, monocytes can provide the appropriate membrane surface for the assembly and function of all the coagulation complexes required for tissue factor-initiated thrombin production. More studies are required to further delineate the roles of neutrophils and lymphocytes in the procoagulant response. This review will discuss the recent investigations and controversies regarding the various mechanisms by which platelets and leukocytes function in, and regulate, thrombin generation. PMID- 11604561 TI - Mechanisms of platelet aggregation. AB - Platelet aggregation is initiated by receptor activation coupled to intracellular signaling leading to activation of integrin alphaIIbbeta3. Recent advances in the study of platelet receptors for collagen, von Willebrand factor, thrombin, and adenosine diphosphate are providing new insights into the mechanisms of platelet aggregation. PMID- 11604562 TI - The role of platelet collagen receptor (glycoprotein Ia/IIa; integrin alpha2 beta1) polymorphisms in thrombotic disease. AB - Differences in rates of platelet activation induced by extracellular matrix components such as collagens markedly influence normal hemostasis and the pathologic outcome of thrombosis. Thus, platelet collagen receptors, the integrin alpha2beta1, glycoprotein VI, and the glycoprotein Ib complex, represent unexploited targets of pharmacologic control. Polymorphisms of these receptors are now understood as factors that potentially contribute to thrombotic risk. There is substantial evidence that the GPIbalpha variable number of tandem repeats A or B alleles, the -5C allele of GPIbalpha, and the integrin alpha2 allele 1 (T807) each contribute to risk for and morbidity from thrombotic disease. The extent of their individual contributions is disputed. More well designed, large, prospective, genetic and epidemiologic studies are needed to clarify the role of these and other platelet receptor polymorphisms, and additional in vitro studies are needed to provide a sound biologic explanation for the outcomes of clinical correlations. PMID- 11604563 TI - Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. AB - Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is an inclusive term describing diverse syndromes of multiple etiologies with the common features of thrombocytopenia and microangiopathic hemolytic anemia. Other organ involvement, including renal failure, neurologic abnormalities, and gastrointestinal symptoms, is common. Adverse reactions to drugs increasingly are reported as a potential cause of TTP-HUS. More than 50 drugs and other substances have been associated with the development of TTP-HUS, but many case reports are difficult to interpret because there is uncertainty regarding the diagnosis of TTP-HUS and because there is uncertainty regarding the relation of drug exposure to the onset of TTP-HUS. A systematic analysis of reports of drug-associated TTP HUS will be required to better understand the strength of clinical evidence linking drugs to the etiology of TTP-HUS. In this review, five drugs that have been the subject of the most and the most recent reports of drug-associated TTP HUS are discussed: mitomycin C, cyclosporine, quinine, ticlopidine, and clopidogrel. The clinical features of TTP-HUS associated with these drugs are different, suggesting two principal mechanisms by which drugs may cause TTP-HUS: dose-related toxicity (mitomycin C, cyclosporine), and immune-mediated reaction (quinine, ticlopidine, clopidogrel). The role of plasma exchange is uncertain, but this treatment is appropriate because of the high mortality and morbidity of drug-associated TTP-HUS. Recognition of a drug-associated etiology in a patient with TTP-HUS is critical to avoid re-exposure and recurrent illness. PMID- 11604564 TI - Molecular mechanisms of drug-induced thrombocytopenia. AB - A wide range of drugs can induce thrombocytopenia. Molecular mechanisms for the formation of specific epitopes for all the drug-dependent antibodies appear to be very similar. A restricted set of glycoproteins on the platelet surface interacts with the drugs to form neoepitopes, to which the drug-dependent antibodies bind. Molecular mapping of antigenic sites may help characterize genetic polymorphisms that predispose to the formation of the antibody binding sites. Identification of antibody binding sites will enhance our understanding of the pathogenesis of immune drug-induced thrombocytopenia. PMID- 11604565 TI - Platelet kinetics in immune thrombocytopenic purpura and human immunodeficiency virus thrombocytopenia. AB - Platelet kinetics studies are capable of measuring in vivo platelet survival and platelet turnover rates. These studies can be helpful in elucidating mechanisms of thrombocytopenia, particularly in complicated clinical situations. Numerous studies over the past 30 years have established the abnormalities in platelet kinetics associated with immune thrombocytopenic purpura (ITP). It is now well known that many patients infected with HIV type-1 will develop thrombocytopenia, and that at least 10% will develop a thrombocytopenic disorder clinically indistinguishable from immune thrombocytopenic purpura. Platelet kinetics studies in this group of patients may prove of great benefit in understanding the mechanisms underlying thrombocytopenia and in making accurate diagnoses. For all patients with ITP-like disorders, these studies may also prove helpful in understanding and improving current therapies. PMID- 11604566 TI - Diagnosis and incidence of inherited von Willebrand disease. AB - Von Willebrand disease is the most commonly inherited bleeding disorder, caused by the inheritance of a quantitative or qualitative abnormality of von Willebrand factor. Clinical manifestations of this disorder are diverse, and traditional diagnostic tools vary in sensitivity, specificity, and overall usefulness. However, as more accurate diagnostic testing is developed and implemented, determination of the disease's incidence and prevalence will improve, allowing the identification and treatment of patients who suffer from this disorder. PMID- 11604567 TI - Use of recombinant factor VIIa in hereditary bleeding disorders. AB - Recombinant factor VIIa is effective as a factor VIII or IX bypassing agent and is relatively safe for the management of bleeding and surgical procedures in patients with factor VIII or IX inhibitors (congenital or acquired hemophilia). It is one of several options in the overall treatment strategy for patients with these difficult conditions. This drug has also been used off label in a limited number of patients with other hereditary bleeding disorders (e.g., factor VII deficiency or antibodies to other clotting factors, and platelet disorders such as Glanzmann thrombasthenia). This paper reviews the proposed mechanisms of action, clinical effectiveness, and safety of rFVIIa for treatment of these disorders and points out areas that require further studies. With expanding indications and more widespread use, thromboembolic complications must be carefully monitored, especially in patients at risk for thromboembolism. The high cost of this drug may be a limiting factor. PMID- 11604568 TI - Acute bleeding complications in patients after bone marrow transplantation. AB - Acute bleeding is a frequent complication that commonly associates with increased morbidity after bone marrow transplantation. Except for diffuse alveolar hemorrhage and cerebral hemorrhage, bleeding is infrequently recorded as a direct cause of death. Yet outcome analyses showed that bleeding from any reviewed site was associated with reduced survival. Reduced survival was correlated with bleeding intensity and the number of bleeding sites. These data point to the need to monitor all manifestations of bleeding, as bleeding may identify patients at risk for bone marrow transplantation toxicity. Until recently, prophylactic platelet transfusions were commonly given at a trigger of 20 x 10(9)/L. Whereas bleeding is more likely to occur when platelet counts drop to low levels, most bleeding episodes were recorded with platelet counts greater than 20 x 10(9)/L, suggesting causes other than profound thrombocytopenia in the pathogenesis of bleeding. Given that a trigger of 10 x 10(9)/L has become accepted for prophylactic platelet transfusions, care should be taken to ensure that parameters other than the incidence of bleeding have not been adversely affected. PMID- 11604571 TI - Transplantation hematopoiesis. AB - Hematopoietic reconstitution after transplantation relies on a small number of hematopoietic stem cells that selectively migrate from the bloodstream to the hematopoietic microenvironment. In the first phase of engraftment, an extreme proliferative demand causes a limited stem cell fraction and its progeny to divide continuously, showing a significant telomere shortening. When all hematopoietic compartments are fully reconstituted, progenitor cell replication stabilizes and the stem cell pool reverts to a quiescent state. In transplant recipients, the hematopoietic microenvironment and stem cell reservoir remain defective for a prolonged period. However, in most patients donor-derived polyclonal hemopoiesis results, and the system is not exhausted but is capable of sustained normal counts and eventually overcomes stressed conditions. PMID- 11604572 TI - Trends in transplantation of hematopoietic stem cells from unrelated donors. AB - Transplants of hematopoietic stem cells from unrelated donors have become feasible for patients with a growing variety of hematologic disorders. The probability of finding a suitable donor has increased because of the expansion of the network of registries containing more than seven million HLA-typed donors worldwide. The selection of compatible donors has become more effective, thanks to the discovery of new HLA alleles and the development of precise and efficient HLA typing methods using DNA technology. Improved methods for transplantation may provide the opportunity to further decrease treatment-related toxicity and improve survival. PMID- 11604573 TI - Reducing transplant toxicity. AB - Conventional myeloablative allogeneic hematopoietic cell transplantation produces considerable morbidity and mortality. These generally limit this treatment to patients in good medical condition who are younger than 55 years of age. T-cell mediated graft-versus-tumor effects play a key role in the elimination of malignancy after allografting. Several investigators have sought to reduce regimen-related toxicities while optimizing graft-versus-tumor effects. Strategies can be broadly classified as (1) reduced-intensity regimens that retain some toxicity, and (2) minimally myelosuppressive regimens that rely on immunosuppression for allogeneic engraftment and resultant graft-versus-tumor effects. Although follow-up has been short, preliminary results are encouraging. Current challenges include defining a regimen that will facilitate full donor engraftment while minimizing toxicities and graft-versus-host disease. If long term efficacy is demonstrated, such strategies will expand the options for patients who would not qualify for conventional allogeneic transplants. PMID- 11604574 TI - Cellular therapy: donor lymphocyte infusion. AB - The dose escalation of chemoradiotherapy that is achievable with stem cell transplantation is often insufficient to eradicate malignancy, and an associated immune-mediated graft-versus-malignancy effect may be equally important for many diseases. The most directly compelling evidence for its presence is the efficacy of donor lymphocyte infusions in generating anti-tumor responses, particularly for relapsed chronic-phase chronic myeloid leukemia. Response rates and durability appear lower with myeloma and acute myeloid leukemia and myelodysplasia syndrome, and minimal with acute lymphoblastic leukemia. There is relatively little data on indolent lymphoid malignancies. Issues that remain to be resolved include the precise nature of the effector cells and their target antigens, the best strategies for separating graft-versus-malignancy from graft versus-host disease (GVHD) and their effect on the durability of responses, and the role of adjuvant chemotherapy/cytokines. Similar issues surround routine combination with nonmyeloablative transplantation protocols and preliminary data suggests that GVHD may continue to provide a major obstacle. PMID- 11604575 TI - Cellular therapy: exploiting NK cell alloreactivity in transplantation. AB - Allogeneic hematopoietic transplantation relies on T-cell alloreactions for engraftment and the graft-versus-leukemia (GVL) effect. In human leukocyte antigen (HLA) haplotype-mismatched transplants, extensive T-cell depletion of the graft is essential to prevent GVHD. This raises the question of whether mismatched transplants exert any GVL effect and whether it will ever be possible to reduce the intensity of preparative regimens. Because natural killer (NK) cells are negatively regulated by MHC class I-specific inhibitory receptors, mismatched transplants may trigger NK-cell alloreactivity. HLA class I disparities driving NK-cell alloreactions in the GVH direction mediate strong GVL effects, produce higher engraftment rates, and do not cause GVHD. In murine MHC mismatched transplant models with no donor T-cell reactivity against the recipient, the pre-transplant infusion of donor-vs-recipient alloreactive NK cells conditioned the recipients to bone marrow transplantation without GVHD. NK cell alloreactivity may be a unique therapeutic tool for tolerance induction and clearance of leukemia in hematopoietic transplantation. PMID- 11604576 TI - Correction of genetic blood defects by gene transfer. AB - Recent clinical trials in patients with a severe combined immunodeficiency disease demonstrate that gene therapy is a powerful tool in the treatment of genetic blood defects. Recent identification of the genes involved in the pathogenesis of inherited lymphohemopoietic disorders led to animal models of gene transfer. Extensive preclinical studies have overcome some of the obstacles involved in the transduction of hemopoietic cells. These promising results led to the approval of several clinical trials that are currently underway. This review focuses on the clinical outcome in patients with genetic blood defects treated by gene transfer and examines the progress achieved to date and the problems that have been encountered. Despite the obstacles, improved clinical results for several of these diseases are expected within the next 5 years. PMID- 11604578 TI - Variant Creutzfeldt-Jakob disease and blood transfusion. AB - Variant Creutzfeldt-Jakob disease (vCJD) was first described in the United Kingdom in 1996 and is thought to have been transmitted from cattle infected with bovine spongiform encephalopathy probably via the food chain. Thus far just over 100 definite or probable clinical cases have been described, though the number of people currently infected and the eventual size and geographic distribution of any future clinical epidemic remain uncertain. There is little evidence that sporadic CJD is transmitted by blood transfusion. However, the same cannot necessarily be assumed to apply to the new variant strain of disease in which involvement of peripheral lymphoid tissues has been demonstrated. In the face of uncertainty surrounding the risk of transmission of vCJD by blood products, blood transfusion services in a number of countries have implemented precautionary policies, though whether in the long term these will prove to have been necessary or sufficient remains to be seen. PMID- 11604579 TI - Transfusion-related bacterial sepsis. AB - Transfusion-associated bacterial sepsis is a persistent problem in transfusion medicine, posing a greater threat than the combined risks of receiving a blood product contaminated with HIV-1 or 2, hepatitis C virus (HCV), hepatitis B virus (HBV), and human T-cell lymphtrophic virus (HTVL) -I or -II. This article provides a brief overview of the current incidence, clinical presentation, associated blood products and organisms, and the most feasible and effective methods available to reduce the potential risk of transfusion-associated sepsis. Because bacterial contamination of blood products is the most frequent cause of transfusion-transmitted infectious disease, and as no single existing strategy can completely eliminate its risk, it is important that clinical suspicion be high, and any partial solutions additively be implemented. PMID- 11604580 TI - Transfusion triggers for blood components. AB - Whereas there are general guidelines for acceptable transfusion therapy, optimal transfusion therapy has not been determined for most clinical settings. Recent research has focused on controlled studies of red cell transfusion in specific clinical settings. Better determinations of oxygen delivery and consumption are needed to guide clinicians in determining whether transfusion is justified for patients during the perioperative period, those with coronary artery disease, and those in intensive care units. For sickle cell disease, the role of transfusion for acute complications can be life saving; however, the role of chronic transfusion regimens awaits further research into efficacy. Finally, whereas criteria for the prophylactic transfusion of platelets in hematologic diseases are well described, relatively little information is available on the value of platelet transfusion where the absolute count is less than 100,000 but greater than 50,000. The value of fresh frozen plasma components, both standard and sterilized, also requires elucidation. PMID- 11604581 TI - Single donor versus pooled random donor platelet concentrates. AB - Both platelet concentrates (PC) derived from whole blood or single donor platelets (SDP) obtained from a single donor by apheresis are indicated to treat acute hemorrhage secondary to thrombocytopenia or to provide prophylaxis from hemorrhage in patients with bone marrow aplasia. Currently platelet transfusion therapy is limited by several concerns, including the consequences of alloimmunization in chronically transfused patients and septic reactions caused by bacterial contamination. There is debate about which platelet product should be used; many transfusion services favor the primary use of PC, whereas others favor SDP. This review will discuss five areas that should be considered when considering the use of SDP or PC: (1) the impact on infectious complications, (2) transfusion reaction rate, (3) leukodepletion, (4) reduction of transfusion frequency in patients with bone marrow suppression and, (5) the treatment and prevention of alloimmunization. The authors believe that SDP offers major advantages over PC for most of these issues, particularly when improved patient care is given primary emphasis. PMID- 11604582 TI - Pretransfusion compatibility testing for red blood cell administration. AB - The purpose of pretransfusion compatibility testing is to prevent incompatible red blood cell transfusions that could lead to immune mediated hemolytic transfusion reactions. Some hemolytic transfusion reactions may have serious sequelae including hemoglobinemia, disseminated intravascular coagulation, renal failure, and death. This article reviews the most comprehensive recent analyses of the laboratory methods used during pretransfusion compatibility testing in the United States. Most of the laboratory practice data have been published in the College of American Pathologists Transfusion Medicine Survey Sets and in a national survey called the Pre-Transfusion Testing Survey. This article couples and trends the data of these comprehensive surveys with an assessment of the literature to present the current practice of pretransfusion compatibility testing. PMID- 11604583 TI - Erythropoietin therapy versus red cell transfusion. AB - Erythropoietin therapy was approved for use as a blood conservation intervention beginning in 1989 for patients with medical anemia and in 1997 for surgical patients. The adoption of this strategy has been rapid in some settings (such as renal failure patients), progressive in others ( eg, cancer patients), and slow in others (surgery patients, for instance). At the same time, the risks of blood transfusion have declined substantially whereas the costs of blood transfusion have increased significantly. The evolution of new techniques such as acute normovolemic hemodilution (ANH) and the novel erythropoiesis-stimulating protein (NESP) bring new options to allogeneic blood transfusion. Erythropoietin therapy, with or without autologous blood procurement, is undergoing new scrutiny as an alternative to blood transfusion. This is not only because of traditional concerns regarding blood risks but because of new blood inventory and cost considerations. PMID- 11604584 TI - Treatment of autoimmune hemolytic anemias. AB - Treatment of autoimmune hemolytic anemias varies depending on whether the patient has autoimmune hemolytic anemia of warm antibody type, cold agglutinin syndrome, paroxysmal cold hemoglobinuria, or autoimmune hemolytic anemia secondary to an underlying disorder. Initial therapy for warm antibody autoimmune hemolytic anemia should be corticosteroids, such as prednisone at conventional doses of 1 to 1.5 mg/kg/d orally. Criteria must be established to determine whether the therapeutic response is adequate, because long-term therapy may lead to significant detrimental side effects. Splenectomy has the advantage over therapeutic options in that it has the potential for complete and long-term remission. The major adverse effect is the syndrome of overwhelming postsplenectomy infection. Other therapeutic options, which are less likely to have long-term benefit, are immunosuppressive drugs, danazol, intravenous immunoglobulin, and plasma exchange. Therapy of cold agglutinin syndrome often is unsatisfactory. All patients should avoid exposure to cold, and if additional therapy is necessary, the therapies used for warm antibody autoimmune hemolytic anemia may be tried with less likelihood of response. Paroxysmal cold hemoglobinuria requires aggressive supportive therapy, generally supplemented by corticosteroids. Hemolysis usually terminates spontaneously. Patients with secondary autoimmune hemolytic anemia may be treated similarly to those with idiopathic autoimmune hemolytic anemia, and additional therapy for the underlying disorder also may result in remission of the hemolysis. PMID- 11604585 TI - Intravenous Rh immune globulin for treating immune thrombocytopenic purpura. AB - Intravenous Rh [corrected] immune globulin was licensed by the U. S. Food and Drug administration in 1995 for the treatment of acute and chronic immune thrombocytopenic purpura in children and chronic immune thrombocytopenic purpura in adults. In 1996, the American Society of Hematology published a practice guideline for immune thrombocytopenic purpura, but treatment recommendations of necessity were formulated using only results of early clinical trials with intravenous Rh immune globulin. To date, there are no published results of large scale clinical trials comparing conventional doses of intravenous immune globulin with the most promising dose range for intravenous Rh immune globulin (50-75 microg/kg). However, clinical experience is accumulating to indicate that intravenous Rh immune globulin is as effective, probably safer, and easier to administer than intravenous immune globulin. Acute intravascular hemolysis after infusions of intravenous Rh immune globulin for immune thrombocytopenic purpura has been reported with an estimated incidence of 1 in 1,115 patients. The risk factors for this adverse event have not been defined. PMID- 11604586 TI - Accelerated atherosclerosis in systemic lupus erythematosus: implications for patient management. AB - One of the most compelling clinical challenges in the management of systemic lupus erythematosus (SLE) is the high incidence of atherosclerotic cardiovascular disease (ASCVD). Potential mechanisms for accelerated atherosclerosis in SLE include chronic inflammation, excess of traditional risk factors, and corticosteroid therapy. Given the high prevalence of atherosclerosis in SLE patients relative to young women in the general population, we propose that the presence of SLE constitutes a sufficiently potent risk factor for ASCVD to warrant more aggressive goals for risk factor reduction and strategies to reduce inflammation. PMID- 11604587 TI - Mortality and causes of death in systemic lupus erythematosus. AB - Cohort studies of survival in systemic lupus erythematosus (SLE) often have been limited by methodologic problems. In studies of inception cohorts of patients followed since 1980, survival at 5 years has exceeded 90%. These estimates are generally higher than survival estimates from earlier studies, suggesting that short-term survival in SLE has improved. There is less evidence to support major improvements over time in survival after 10 years or more of SLE. Infections, atherosclerotic disease, and active systemic lupus erythematosus or organ damage caused by SLE are the main causes of death in patients with SLE, but the proportion of early deaths caused by active SLE has decreased over time. PMID- 11604588 TI - Murine lupus genetics: lessons learned. AB - Recent reverse genetic studies in murine lupus have taught us the following lessons: (1) Lupus is extremely polygenic; (2) A single locus may be associated with many different phenotypes; (3) What appears to be a single locus may turn out to be a cluster of loci; (4) Different loci facilitate different immunologic steps leading to lupus; (5) Epistatic interactions between loci may engender novel autoimmune phenotypes; (6) Whereas some loci may be pathogenic, others may confer disease resistance; (7) Whereas the expression of some loci is sex dependent, the expression of others clearly is not; (8) Two or more loci may have an impact on the same phenotype; (9) Lupus susceptibility loci appear to co cluster with other autoimmunity susceptibility loci; (10) Lupus genes are likely to be polymorphic alleles with subtle impacts, rather than outright mutations with extreme functions. In contrast, forward genetic studies have revealed that molecules that impact apoptosis, the clearance of apoptotic cells, B-cell or T cell function, and end-organ pathology can all potentially contribute to lupus. Collectively, the loci and genes identified by these two different approaches factorize into a few distinct pathways leading to lupus. Delineating the molecular mediators of these distinct checkpoints is the challenge that lies ahead. PMID- 11604589 TI - Regulation of CD40 ligand expression in systemic lupus erythematosus. AB - Production of pathogenic autoantibodies in systemic lupus erythematosus (SLE) requires T cell help, along with ligation of the B cell surface immunoglobulin receptor by antigen. It is likely that macrophages, dendritic cells, and endothelial cells are also activated by interactions with T cells and contribute to lupus pathology. CD40 ligand (CD40L, CD154), a member of the tumor necrosis factor family of cell surface molecules, mediates these contact dependent signals delivered by CD4 + T helper cells to CD40 + target cells. Recent data from SLE patients and murine lupus models have demonstrated prolonged expression of CD40L on lupus T cells and its capacity to mediate excessive B cell activation. This review summarizes the current information regarding transcriptional and post transcriptional regulation of CD40L expression in normal and SLE T cells. More complete characterization of the mechanisms that regulate the magnitude and duration of CD40L expression should suggest new approaches to modulate this promising therapeutic target. PMID- 11604590 TI - Role of viruses in systemic lupus erythematosus and Sjogren syndrome. AB - Systemic lupus erythematosus and Sjogren syndrome remain elusive in the description of their underlying etiologic causes and pathogenic mechanisms. Although underlying genetic predisposition appears to contribute to both diseases based on twin and other genetic studies, additional factors must play a role. Over the decades additional factors, such as hormonal influence, UV light, environmental exposures (e.g., silica, solvents), and infectious agents have been postulated to play a role. Over the past few years additional information has been published concerning roles of various infectious agents in both lupus and Sjogren syndrome. Although the understanding of this field is still incomplete, significant advances are being made. PMID- 11604591 TI - Pathogenic mechanisms mediating antiphospholipid syndrome. AB - Antiphospholipid antibodies are the marker for antiphospholipid syndrome. There is evidence that these autoantibodies lead to both thrombotic diathesis and obstetrical manifestations. Besides the known interaction with soluble coagulation factors, in vitro and in vivo experimental models and studies in humans recently have shown the ability of antiphospholipid antibodies to modulate functions of cells involved in coagulation homeostasis. These findings support a new hypothesis to explain the paradox of the prolongation of coagulation assays in vitro and the association with thrombophilic diathesis in vivo. Obstetrical manifestations have been linked to a direct antibody effect on the trophoblast leading to defective placentation that is not necessarily associated with thrombotic phenomena. Phospholipid binding proteins such as beta 2 -glycoprotein I appear to behave as a bridge between circulating antiphospholipid antibodies and cellular targets. PMID- 11604592 TI - Imaging modalities in central nervous system systemic lupus erythematosus. AB - Within the past few years, a clearly defined case definition system for central nervous system systemic lupus erythematosus (CNS-SLE) has been established. This has allowed cross-study comparisons of patients fulfilling the specific case definitions. New imaging techniques used on the subgroup of CNS-SLE patients that did not have any evidence for infarctions suggest that in these patients symptoms are associated with a diffuse process in the brain. Most likely this process leads to axonal damage and demyelination, ultimately leading to cerebral atrophy. With respect to the diagnostic work-up of SLE patients with neuropsychiatric symptoms, it has become clear that cranial magnetic resonance imaging is the technique of choice. Preliminary studies using quantitative magnetic resonance imaging techniques suggest that patients with neuropsychiatric symptoms caused by active CNS-SLE can be differentiated from patients with the same symptoms caused by residual disease. PMID- 11604594 TI - Juvenile idiopathic arthritis. AB - A significant amount of work has been performed over the past 2 years further defining the pathophysiology of juvenile idiopathic arthritis (JIA). The development of the biologic agent etanercept represents successful translational research. This genetically engineered fusion protein targets tumor necrosis factor, binding and inactivating this important component of inflammation. This advance has been accompanied by refinements in classification, as well as further elucidation of the natural disease course of JIA. Recent work continues to demonstrate the widespread nature of JIA, as well as its severity in adulthood. PMID- 11604595 TI - Osteoporosis in juvenile idiopathic arthritis. AB - Osteoporosis is characterized by loss of both bone mass and microarchitectural integrity, resulting in an increased risk of fractures with associated morbidity and mortality. Awareness of this condition is increasing in pediatrics, including pediatric rheumatology. Reduced bone mineral density is now well recognized in children and young adults with juvenile idiopathic arthritis and is multifactorial in origin. The problems of interpretation of bone analysis techniques during childhood and adolescence are highlighted. Recent studies have reported on the use of newer methods of imaging, including quantitative ultrasound and bone single photon emission computed tomography techniques. Attempting to disentangle the relative effects of disease activity, corticosteroids, nutrition, and physical activity in the development of osteoporosis in juvenile idiopathic arthritis is the focus of several studies. Finally, early optimistic reports of the use of bisphosphonates in juvenile idiopathic arthritis are welcome additions to the growing body of literature in this area. PMID- 11604596 TI - Psychosocial aspects of pediatric rheumatic diseases. AB - Pediatric rheumatic diseases present psychosocial challenges for patients and their families. These include (1) adjusting and coping with disease symptoms and limitations; (2) adhering to complex and demanding medical regimens; and (3) coping with chronic pain. This article reviews recent studies on these psychosocial issues for children with pediatric rheumatic diseases. There is a paucity of empirical studies addressing these issues and a clear need for multisite collaborative studies to address the psychosocial needs of patients and families. PMID- 11604597 TI - New drug therapies for the pediatric rheumatic diseases. AB - Such developments as the introduction of whole new drug classes, as well as the general increase in pediatric drug trials, have led to a revolution in pediatric rheumatology care. For example, selective cyclooxygenase-2 inhibitors can provide the same symptomatic relief as nonselective nonsteroidal anti-inflammatory agents without the same concerns over significant gastrointestinal toxicity. Biologic agents, notably the tumor necrosis factor inhibitors, have effected dramatic improvements in many patients with severe disease who previously were often significantly disabled. New immunosuppressives, such as mycophenolate mofetil, also have promise for ameliorating systemic lupus and vasculitic conditions, perhaps with reduced toxicity compared with other agents. New strategies for the use of older agents have also been further substantiated, such as intra-articular steroid and alternate-day high-dose steroid in chronic arthritis, and broader use of sulfasalazine. Evidence for the use of these therapies is discussed, as are potential toxicities. PMID- 11604598 TI - Systemic lupus erythematosus and antiphospholipid syndrome in children and adolescents. AB - Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) can be associated with significant morbidity in children and adolescents. Renal involvement in SLE appears to be more severe and more frequent in the pediatric age group, with the major predictors for poor outcome being the severity of histopathologic lesions, severity of renal impairment at diagnosis, and hypertension. In addition to currently recognized cardiovascular and pulmonary involvement, accelerated atherosclerosis is of increasing concern in young individuals with SLE, because of both disease effects and medication usage. Neuropsychiatric SLE seen in childhood ranges from subtle cognitive dysfunction to severe central nervous system involvement; however, there is controversy over the value of different diagnostic studies. APS in children may be associated with SLE, idiopathic, or associated with viral infections. Systemic anticoagulation is recommended for patients with thrombotic events, but long-term management has not been well studied in children. PMID- 11604599 TI - Vasculitis in childhood. AB - Inadequate understanding of the pathogenesis and etiology of vascular inflammation continues to hinder progress in the diagnosis and treatment of pediatric vasculitis. The greatest amount of work is being done in the most common vasculitides of childhood, including Kawasaki disease and Henoch-Schonlein purpura. Discussion of rarer types of vasculitis, on the other hand, such as antineutrophil cytoplasmic antibody-positive small vessel diseases, is largely restricted to case reports. Most aspects of the care of children with Wegener granulomatosis and microscopic polyangiitis are derived by extrapolating from data about adults. Virtually no data are available concerning ways in which these diseases may be different in children. PMID- 11604600 TI - Myositis in children. AB - Idiopathic inflammatory myositis in children includes multiple disease entities, but is primarily made up of juvenile dermatomyositis and, to a lesser degree, juvenile polymyositis. Much new information has been published in the last few years about these diseases, including the epidemiology, pathogenesis, clinical diagnosis, and outcomes and treatment. This includes information on onset of symptoms, potential inciting agents, and regional differences. Exciting data have emerged in our understanding of the immune response gene associations and the description of chimerism in children with these disorders. Finally, new advances in clinical evaluations and outcomes have been described as well as new treatment protocols to provide a more effective therapy with less toxicity. Continued investigation is needed to further understand these diseases, but great strides are being made in our understanding and ability to care for children with idiopathic inflammatory myositis. PMID- 11604601 TI - Lyme disease in children. AB - Lyme borreliosis is a multisystem disorder caused by Borrelia burgdorferi and transmitted by ticks in the northern hemisphere. The disease is common in children. In addition to frequently recognized manifestations such as erythema migrans, neuroborreliosis, and Lyme arthritis, rarer manifestations, including eye and ear disease, are increasingly understood. Clinical diagnosis is supported by serologic confirmation. Improvement of laboratory methodology, especially polymerase chain reaction-based tests, is continuing. Actual treatment recommendations based on controlled studies reflect expanding scientific knowledge. In the United States, license of a vaccine to prevent infection in children is awaited. Lyme borreliosis is an intriguing human example of bacterial persistence in the presence of the host immune system. Chronic Lyme arthritis is a model of chronic arthritis resembling forms of arthritis of unknown cause, such as rheumatoid arthritis and juvenile idiopathic arthritis. PMID- 11604602 TI - Local factors in osteoarthritis. AB - Osteoarthritis is widely believed to be the result of local factors acting within the context of systemic susceptibility. Local factors, which are specific to joint site and in some instances specific to joint compartment, are receiving increasing attention in natural history studies of osteoarthritis. This review focuses on epidemiologic investigations dealing with these local factors. Local factors may be further characterized as extrinsic or intrinsic to the joint organ. In the past, the epidemiologic literature has emphasized the extrinsic category, factors and events that have an origin external to the joint and its immediate environment--for example, physical activity and injury. In recent years, intrinsic factors such as alignment, strength, laxity, and proprioception have begun to receive more attention. Ultimately, epidemiologic studies aid the development of strategies to prevent disease development or modify its course. Such strategies may be especially powerful for local factors, given the vicious cycles set in motion by these factors and the effect of these factors on neighboring joint-organ structures. PMID- 11604603 TI - Epidemiology of risk factors for osteoarthritis: systemic factors. AB - Osteoarthritis (OA) appears to be a mechanically driven but chemically mediated disease process in which there is attempted (or aberrant) repair. Well established risk factors for OA include aging, obesity, gender, and, in selected subgroups, congenital anomalies. This review addresses less well established risk factors for OA that can impact joints through their effect on systemic metabolism rather than their contribution to local joint geometry and structure. These systemic risk factors include obesity; bone and bone density; nutrients, particularly those that function as antioxidants; and genetic factors. There is great opportunity for new prevention and intervention strategies as we expand our understanding of the role of these systemic risk factors. PMID- 11604604 TI - Lessons from animal models of osteoarthritis. AB - Characterization of transgenic murine osteoarthritis (OA) models and analysis of anterior cruciate ligament and meniscectomy models in various species, including rodents, has provided insight into pathogenic mechanisms and impact of loading. Development of a transgenic murine OA model by postnatal expression in hyaline cartilage of constitutively expressed human matrix metalloproteinase-13 emphasizes the potential role of this enzyme. On the other hand, collagenase involvement in OA models seems a confined focal process, complicating therapeutic approaches. The potential role of interleukin-1 still needs further confirmation. Apart from destructive cytokines, disturbed growth factor responses seems obvious. Transforming growth factor-beta is a crucial mediator in osteophyte formation, but its role in cartilage destruction has not yet been clarified. Nitric oxide appears involved in chondrocyte apoptosis and blocking of nitric oxide provides protection against joint pathology in OA models. Treatment with a range of disease-modifying drugs showed some efficacy in a number of OA models, but its predictive value for human OA remains obscure. PMID- 11604605 TI - Craniofacial distraction osteogenesis: a review of 3278 cases. AB - The nascent field of craniofacial distraction osteogenesis has not yet been subjected to a rigorous evaluation of techniques and outcomes. Consequently, many of the standard approaches to distraction have been borrowed from the experience with long bones in orthopedic surgery. The ideal "latency period" of neutral fixation, rate and rhythm of distraction, and consolidation period have not yet been determined for the human facial skeleton. In addition, because the individual craniofacial surgeon's experience with distraction has generally been small, outcomes and meaningful complication rates have not yet been published. In this study, a four-page questionnaire was sent to 2476 craniofacial and oral/maxillofacial surgeons throughout the world, asking about their experiences with distraction osteogenesis. Information about the types of cases, indications for surgery, surgical techniques, postoperative management, outcomes, and complications were tabulated. Of 274 respondents (response rate, 11.4 percent), 148 indicated that they used distraction in their surgical practice. One hundred forty-five completed surveys were entered into a database that provided information about 3278 craniofacial distraction cases. Statistical analyses were performed comparing the rates of premature consolidation, fibrous nonunion, and nerve injury, on the basis of the use of a latency period and different rates and rhythms of distraction. In addition, the rates of all complications were determined and compared on the basis of the number of distraction cases performed per surgeon. The results of the study clearly show a wide variation in the surgical practice of craniofacial distraction osteogenesis. Although the cumulative complication rate was found to be 35.6 percent, there is a pronounced learning curve, with far fewer complications occurring among more experienced surgeons (p < 0.001). The presence of inferior alveolar nerve injury as a result of mandibular distraction was much lower for respondents whose distraction regimens consisted of no more than 1 mm of distraction per day (19.5 percent versus 2.4 percent; p < 0.001). No evidence was found to support the use of a latency period or to divide the daily distraction regimen into more than one session per day. Conclusions could not be drawn from this study regarding the length of the consolidation period. Overall, the surgeon-reported outcomes are comparable with those published for other craniofacial procedures, despite the higher incidence of complications. Although conclusions made on the basis of a subjective questionnaire need to be interpreted cautiously, this study has strength in the large numbers of cases reviewed. Because of the anonymity of responses, it has been assumed that surgeons who responded to the survey reported accurate numbers of complications and successful outcomes. Finally, additional clinical and animal studies that will be of benefit in advancing the field of craniofacial distraction osteogenesis are outlined. PMID- 11604607 TI - Nose muscular dynamics: the tip trigonum. AB - In 1995, the senior author (E.E.F.) published an article in which he described the musculus digastricus septi nasi labialis. In the article presented here, work carried out by anatomists and other researchers who, over the last two centuries, studied nose muscular dynamics is described. The present study is based on Gray's Anatomy, which, in 1858, first described the nasal tip muscles, along with the other nasal muscles. Later works not only used different terminology for these muscles but also ignored some, creating tremendous confusion. The study presented here provides an update of the exact terms, location, insertions, and muscle functions of the muscles of the nose. Each nose muscle is described with regard to the two portions able to produce separate contractions. In this study, the term "dual function" is used and characterizes the nasal mimetic muscles that do not have well-defined fascia. Therefore, there is doubt about the existence of a real nasal superficial muscle aponeurotic system. The musculus myrtiformis seems to have a dual function, inserting in the canine fosse and in the periosteum of the central incisors, forming two portions-one to the septum and the other to the nostril-each of which has specific functions. This study has been based on research in physiognomy, the science of expression. With regard to the basis for nose expressions, common anatomical research is excluded because it provides a different view of the dynamics studied to date. The term trigonum musculare apicis nasi defines the interaction of the musculi compressor narium minor and dilator naris anterior, connecting with the columellar bundle of the musculus digastricus and levering the nasal spine. This muscular trigone creates circular concentric and eccentric movements of the nasal tip. PMID- 11604608 TI - Radical correction of secondary nasal deformity in unilateral cleft lip patients presenting late. AB - It is universally acknowledged that correction of a cleft lip nasal deformity continues to be a difficult problem. In developing countries, it is common for patients with cleft lip deformities to present in their early or late teens for correction of severe secondary lip and nasal deformities retained after the initial repairs were carried out in infancy or early childhood. Such patients have never had the benefit of primary nasal correction, orthodontic management, or alveolar bone grafting at an appropriate age. Along with a severe nasal deformity, they present with alveolar arch malalignments and anterior fistulae. In the study presented here, a strategy involving a complete single-stage correction of the nasal and secondary lip deformity was used. In this study, 26 patients (nine male and 17 female) ranging in age from 13 to 24 years presented for the first time between June of 1996 and December of 1999 with unilateral cleft lip nasal deformity. Eight patients had an anterior fistula (diameter, 2 to 4 mm) and 12 patients had a secondary lip deformity. An external rhinoplasty approach was used for all patients. The corrective procedures carried out in a single stage in these patients included lip revision; columellar lengthening; repair of anterior fistula; augmentation along the pyriform margin, nasal floor, and alveolus by bone grafts; submucous resection of the nasal septum; repositioning of lower lateral cartilages; fixation of the alar cartilage complex to the septum and the upper lateral cartilages; augmentation of nasal dorsum by bone graft; and alar base wedge resections. Medial and lateral nasal osteotomies were performed only if absolutely indicated. The median follow-up period was 11 months, although it ranged from 5 to 25 months. Overall results have been extremely pleasing, satisfactory, and stable. In this age group (13 years of age or older), it is not fruitful to use a technique for nasal correction that corrects only one facet of the deformity, because no result of nasal correction can be satisfactory until septal deviations and maxillary deficiencies are addressed along with any alar repositioning. The results of complete remodeling of the nasal pyramid are also stable in these patients because the patients' growth was nearly complete, and all the deformities could be corrected at the same time, leaving no active deforming vector. These results would indicate that aesthetically good results are achievable even if no primary nasal correction or orthodontic management had been previously attempted. PMID- 11604609 TI - Localization of the cortical response to smiling using new imaging paradigms with functional magnetic resonance imaging. AB - Functional magnetic resonance imaging (fMRI) can serve to localize activity in the cerebral cortex. The present study was performed to develop a quantitative means of describing the cortical location activated during voluntary smiling in multiple subjects and to determine whether this location is specific to smiling when compared with other motor tasks. Five human subjects were instructed to smile or to tap the fingers of both hands. Both tasks were performed in a blocked trial paradigm that consisted of alternating 15-second blocks of a repetitive motor task and 15 seconds of rest. Smiling was also performed as an event-related paradigm in which the subject smiled briefly once every 15 seconds for 20 repetitions that were combined to produce an average response to a single smile. A series of 300 images was acquired using an echo-planar imaging sequence (24-cm field of view; 5-mm slice thickness; repetition time/echo time, 1000/27.2 msec). Each subject's three-dimensional brain images were transformed to Talairach coordinates by stretching or compressing the brain images to fit the standard brain as defined in the Talairach atlas. This allowed data from five subjects to be combined for a numeric description. Functional activation maps acquired by use of the event-related paradigm contained significantly fewer motion artifacts than maps acquired with the blocked-trial paradigm, allowing better visualization of functionally active areas. Three-dimensional Talairach coordinates to describe the locations of peak cortical activity after smiling and finger tapping were established. These coordinates were consistent among subjects. During smiling, statistically significant activation was seen in the motor cortex, primarily along the precentral sulcus; this was inferior and anterior to the region that was associated with finger tapping. This study demonstrates that motion artifacts associated with traditional blocked-trial fMRI protocols can be overcome by employing an event-related paradigm to obtain an average response from a single smile. With the implementation of new imaging paradigms with fMRI, an area of the cerebral cortex has been identified that is specifically activated during voluntary smiling, and remains consistent among subjects. Quantification of fMRI data represents a powerful tool by which to study the cortical response to motor activity and to monitor possible alteration in this activity after injury or surgery. When combined with biofeedback therapy, this technique may help to improve the outcome of facial reanimation procedures in the future. PMID- 11604610 TI - Total ear reconstruction in the devascularized temporoparietal region: I. Use of the contralateral temporoparietal fascial free flap. AB - Total ear reconstruction by the use of contralateral temporoparietal fascial free flap and autogenous costal cartilage was performed in 16 patients presenting with a devascularized temporoparietal region resulting from trauma or prior surgery. The microsurgical success rate was 87.5 percent (14 of 16 transplants). On evaluation of the final aesthetic result in 11 patients followed up for more than 3 years, nine patients were graded good-to-excellent and two patients exhibited fair-to-poor results. Despite the relatively long operating hours and the comparatively low microsurgical success rate, ear reconstruction by autogenous tissue transplantation has proved to be an encouraging and worthwhile experience. This article presents the clinical cases and discusses the technical details. PMID- 11604611 TI - The outcome of failed free flaps in head and neck and extremity reconstruction: what is next in the reconstructive ladder? AB - The indications for free flaps have been more or less clarified; however, the course of reconstruction after the failure of a free flap remains undetermined. Is it better to insist on one's initial choice, or should surgeons downgrade their reconstructive goals? To establish a preliminary guideline, this study was designed to retrospectively analyze the outcome of failed free-tissue transfers performed in the authors hospital. Over the past 8 years (1990 through 1997), 3361 head and neck and extremity reconstructions were performed by free-tissue transfers, excluding toe transplantations. Among these reconstructions, 1235 flaps (36.7 percent) were transferred to the head and neck region, and 2126 flaps (63.3 percent) to the extremities. A total of 101 failures (3.0 percent total plus the partial failure rate) were encountered. Forty-two failures occurred in the head and neck region, and 59 in the extremities. Evaluation of the cases revealed that one of three following approaches to handling the failure was taken: (1) a second free-tissue transfer; (2) a regional flap transfer; or (3) conservative management with debridement, wound care, and subsequent closure by secondary intention, whether by local flaps or skin grafting. In the head and neck region, 17 second free flaps (40 percent) and 15 regional flaps (36 percent) were transferred to salvage the reconstruction, whereas conservative management was undertaken in the remaining 10 cases (24 percent). In the extremities, 37 failures were treated conservatively (63 percent) in addition to 17 second free flaps (29 percent) and three regional flaps (5 percent) used to salvage the failed reconstruction. Two cases underwent amputation (3 percent). The average time elapsed between the failure and second free-tissue transfer was 12 days (range, 2 to 60 days) in the head and neck region and 18 days (range, 2 to 56 days) in the extremities. In a total of 34 second free-tissue transfers at both localizations, there were only three failures (9 percent). However, in the head and neck region, seven of the regional flaps transferred (47 percent) and four cases that were conservatively treated (40 percent) either failed or developed complications that lengthened the reconstruction period because of additional procedures. Six other free-tissue transfers had to be performed to manage these complicated cases. Conservative management was quite successful in the extremities; most patients' wounds healed, although more than one skin-graft procedure was required in 10 patients (27 percent). In conclusion, a second free tissue transfer is, in general, a relatively more reliable and more effective procedure for the treatment of flap failure in the head and neck region, as well as failed vascularized bone flaps in the reconstruction of the extremities. Conservative treatment may be a simple and valid alternative to second (free) flaps for soft-tissue coverage in extremities with partial and even total losses. PMID- 11604613 TI - Single-stage, autologous breast restoration. AB - The skin-sparing mastectomy, when performed with immediate reconstruction, is a major advance in breast reconstruction. Traditionally, reconstruction of the nipple-areola complex is performed as a subsequent procedure. In this study, 17 patients (mean age, 43 years; range, 35 to 53 years) underwent one-stage breast and nipple-areola reconstruction over a 21-month period. In all cases of breast reconstruction, a buried transverse rectus abdominis musculocutaneous (TRAM) flap was used, and all patients had a simultaneous nipple-areola complex reconstruction performed. Nine patients had a Wise keyhole pattern used and contralateral reduction performed. Four patients retained all their breast skin, and a TRAM skin island was used in another four. It has recently been shown that patients with early-stage breast cancer and peripherally sited tumors have a very low risk of nipple-areola involvement. In 10 patients with early disease and peripheral tumors, the areola was retained (as a thin full-thickness graft), but more recently, in three patients with early-stage disease, the entire nipple areola complex was used as a thin full-thickness graft. The thin full-thickness skin graft is removed from the breast in an apple-coring fashion, so that most of the ducts are retained as part of the mastectomy specimen. (There was histological confirmation of absence of tumor in the nipples of these patients.)One-stage autologous reconstruction should be considered for all patients undergoing immediate breast reconstruction. In patients with early-stage disease and peripheral tumors, the nipple-areola complex may be retained through the use of a thin full-thickness graft that is applied to a deepithelialized CV flap on the TRAM flap. This allows the best method of nipple-areola complex reconstruction: by retaining the original breast envelope, the color match and texture in the reconstruction are ideal. Patient satisfaction in this study was high. Necrosis of the mastectomy flaps impaired the cosmetic results in some patients. A large multicenter study is required to confirm the effectiveness of this procedure. PMID- 11604615 TI - Simultaneous bilateral breast reconstruction using latissimus dorsi myocutaneous flaps: a retrospective review of an institutional experience. AB - A single institution's experience in the simultaneous reconstruction of both breasts using bilateral latissimus dorsi myocutaneous flaps is presented. The procedure was performed on 24 patients by the attending staff of the department of plastic surgery at St. Joseph Hospital in Houston, Texas, between 1979 and 1999. Of the 24 patients reviewed, six had immediate reconstructions, 13 had delayed primary reconstructions, and five had secondary reconstructions of failed or unsatisfactory primary procedures. In the group with delayed reconstructions, the average time between mastectomy and reconstruction was 46.4 months, with a range from 7 days to 21 years. The operative method, results, and outcomes of our experience in these patients is presented. PMID- 11604617 TI - The use of vacuum-assisted closure therapy for the treatment of lower-extremity wounds with exposed bone. AB - Lower-extremity wounds with exposed tendon, bone, or orthopedic hardware present a difficult treatment challenge. In this series of patients, subatmospheric pressure therapy was applied to such lower-extremity wounds. Seventy-five patients with lower-extremity wounds, most of which were the result of trauma, were selected for this study. Dressings made of sterile open-cell foam with embedded fenestrated tubing were contoured to the wound size and placed into the wound. The site was covered with an adhesive plastic sheet. The sheet was placed beneath any external fixation devices, or the fixation device was enclosed within the sheet. The tubing was connected to the vacuum-assisted closure pump. Continuous subatmospheric suction pressure (125 mmHg) was applied to the wound site. The wounds were inspected and the dressings were changed every 48 hours.Vacuum-assisted closure therapy greatly reduced the amount of tissue edema, diminishing the circumference of the extremity and thus decreasing the surface area of the wound. Profuse granulation tissue formed rapidly, covering bone and hardware. The wounds were closed primarily and covered with split-thickness skin grafts, or a regional flap was rotated into the granulating bed to fill the defect. Successful coverage was obtained without complication in 71 of 75 patients. Wounds have been stable from 6 months up to 6 years. PMID- 11604618 TI - The recurrent neurotrophic buttock ulcer in the meningomyelocele paraplegic: a sensate flap solution. AB - A large percentage of meningomyelocele paraplegic patients have a distal zone of sensation-bearing skin on their thighs. This sensate skin can be used as a fasciocutaneous flap to resurface a recidivistic ulcer after excision. In this study, because the transposition distance was significant, the flap length-width ratio was greater than normal and, therefore, required a 3-week elevation delay. This also permitted appraisal of the sensate flap after the first stage. The wound-healing was excellent after both stages. This reconstructive procedure was completed in four patients, with an average follow-up period of 13 years. These patients remain chronic sitters in administrative jobs and have been pressure sore-free after flap repair. PMID- 11604619 TI - Clinical application of the free thin anterolateral thigh flap in 31 consecutive patients. AB - In this retrospective study, 31 reconstructions using thin anterolateral thigh flaps and six cadaveric dissections of the thigh were investigated in consideration of the anatomic variations of the perforator vessels in the adipose layer, the safe area of flap circulation, and the clinical indications. Three variations of the perforator vessel course in the adipose layer were predicted correctly. The safe radius of a thin anterolateral thigh flap with a thickness of 3 to 4 mm was determined to be approximately 9 cm from the point where the perforator met the skin. The use of a thin anterolateral thigh flap for reconstruction of the neck, axilla, anterior tibial area, dorsum of the foot, circumference on the ankle, forearm, and dorsum of the hand was therefore recommended. PMID- 11604621 TI - Microsurgical tissue transplantation or replantation in patients with psychoneurological impairment. AB - Sometimes patients with a psychoneurological impairment present with a traumatic injury that requires either microsurgical replantation or free-tissue transfer. We reviewed 38 patients undergoing 40 microvascular operations; the patients included 26 patients with psychological impairment (group 1), 3 with mental disability (group 2), and 9 with an acquired head injury and consciousness disturbance (Glasgow Coma Scale score < or =14) (group 3). Patients with a psychological impairment, especially those with a self-inflicted injury, are often uncooperative and do not recognize the necessity of restorative procedures. A multidisciplinary approach by the trauma surgeon, plastic surgeon, psychiatrist, and neurosurgeon, with coordinated assistance from the physician, nurse, therapist, and family, is required for treatment. In our study the success rate of replantation was 77.8 percent (14 of 18); for free tissue transfer the success rate was 95.5 percent (21 of 22). The overall success rate of microsurgical procedures (87.5 percent, 35 of 40) was similar to that in the population at large. Patients with psychological impairment tend to be lost during follow-up; therefore, their functional results may be poorer than expected. Nonetheless, patients with psychological impairment should not be deprived of the benefits of restorative surgery. PMID- 11604623 TI - Metacarpal synostosis: a simple classification and a new treatment technique. AB - The current classification of metacarpal synostosis is based on the extent of the synostosis. The authors propose a new classification that takes into account the shape of the metacarpal bones, the curvature of the epiphysis, and the discrepancy in length between the two bones. This classification provides better guidelines for the correction of all components of the deformity. The classification is based on the authors' observations of and experience with 36 cases of metacarpal synostosis; 13 of the deformities were surgically corrected. The I-shaped deformity, whether with distinct (type d) or fused (type f) metacarpophalangeal joints, does not require surgical correction. The U-shaped deformity has parallel epiphysis and does not require surgery unless the two metacarpals are asymmetrical in length (type a) or tightly fused (type t); in these cases, simple lengthening or widening of the space with a bone graft is sufficient. Y-shaped synostosis should be separated whether the branches are symmetrical or asymmetrical, the latter having one branch shorter than the other. Because the epiphyses are already divergent, simple separation does not effectively correct Y-shaped synostosis. The authors propose an osteotomy to isolate a trapezoidal segment of bone from the bifurcation. The isolated bone segment is then reversed in the proximal-distal direction to provide a "plateau" upon which the two distal metacarpals can be realigned. Two cases of Ys (symmetrical) synostosis were successfully treated with this technique; one case of Ya (asymmetrical) synostosis also required distraction lengthening of the shorter metacarpal to achieve an excellent result. One of the most difficult types of metacarpal synostosis to treat is k-shaped synostosis, observed only between the fourth and fifth metacarpals; in this type, the head of the short fifth metacarpal abuts the metaphysis of the fourth. Osteotomy and distraction lengthening provide predictable results for correction of this deformity. The authors suggest that k-shaped synostosis might represent a late evolution of untreated Ua synostosis. PMID- 11604622 TI - The effects of a single dose of 5-fluorouracil on keloid scars: a clinical trial of timed wound irrigation after extralesional excision. AB - The possibility of altering the pathophysiology of keloid scars was investigated in 11 patients, using a single application of 5-fluorouracil solution for 5 minutes after extralesional excision was performed. Similar excisional wounds treated with phosphate-buffered saline for 5 minutes served as synchronous controls. An objective scoring system and subjective assessment were made to assay the change in the quality of the wound-healing and scar tissue produced by this treatment. A keloid scar score was used at regular time intervals after treatment to assess the quality of scar produced, thereby enabling the treated and control scars to be clinically compared. Biopsies were taken of the control and treated scars 1 month after treatment; the biopsy specimens were then subjected to immunohistochemical analysis as well as a functional assessment of cultured keloid fibroblasts. The immunohistochemical antigens assayed were Ki-67 (also called MIB-1; a marker of cell proliferation); vascular cell adhesion molecule-1 (a marker of inflammation); transforming growth factor beta-1 (a factor involved in scarring) and CD-68 (a macrophage-specific marker). Fibroblast populated collagen lattices provided a functional assessment of fibroblast contraction. All treated and control wounds healed without any dehiscence or infection. The keloid scar score revealed that there was a perceived improvement in condition for those treated with 5-fluorouracil, compared with the control specimens, during the 6-month follow-up period in the five patients who attended all their clinic appointments; data on later recurrence are not complete as yet. The wounds treated with 5-fluorouracil produced scars that had a significant (p < 0.01) reduction in all the markers assayed, apart from CD-68. Functionally, the keloid fibroblasts from three of five of the treated patients showed reduced contractile capacity. This pilot study demonstrates that a "single-touch" technique with 5-fluorouracil can produce a change in the characteristics of the healing keloid wound after extralesional excision. Long-term studies are required to elucidate the correct dosage and time of exposure to improve the efficacy of this potential treatment. PMID- 11604625 TI - Donor modification leads to prolonged survival of limb allografts. AB - Chronic immunosuppression is essential for maintaining human hand transplant survival because composite tissue allografts are as susceptible to rejection as visceral organ allografts. Limb allografts comprise different types of tissues with varying antigenicities, and the immunosuppressive doses required for these allografts are as high or higher than those required for solid organ allotransplantation. In particular, bone marrow is an early target of the host immune response. This study reports on donor limb modification of the marrow compartment leading to prolonged survival of limb allografts. Chimeric limb allografts comprising a Lewis rat vascularized allograft and Brown Norway rat bone marrow were created. These chimeric limbs were transplanted into three recipients: (1) Buffalo rats (n = 12), where the chimeric limb was allogeneic for both vascular graft and bone marrow; (2) Lewis rats (n = 12), where the limb was allogeneic for marrow alone; and (3) Brown Norway rats (n = 12), where the limb was allogeneic for graft alone. This study found that Brown Norway recipients elicited significantly reduced cell-mediated and humoral immune responses in comparison with the Buffalo and Lewis recipients (p < 0.001 and p < 0.01, respectively). The Buffalo and Lewis recipients both elicited high cell-mediated and humoral responses. The Brown Norway recipients also had prolonged survival of limb tissue allograft in comparison with the other experimental groups. PMID- 11604628 TI - Differential cytokine expression in skin graft healing in inducible nitric oxide synthase knockout mice. AB - Inducible nitric oxide synthase (iNOS) and its product, nitric oxide, have been shown to play important roles in wound biology. The present study was performed to investigate the role of iNOS in modulating the cytokine cascade during the complex process of skin graft wound healing.Fifteen iNOS-knockout mice and 15 wild-type C57BL/6J mice were subjected to autogenous 1-cm2 intrascapular full thickness skin grafts. Three animals in each group were killed on postoperative days 3, 5, 7, 10, and 14. Specimens were then analyzed using nonisotopic in situ hybridization versus mRNA of tumor growth factor-beta1, vascular endothelial growth factor, iNOS, endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha, and basic fibroblast growth factor, as well as positive and negative control probes. Positive cells in both grafts and wound beds were counted using a Leica microgrid. Scar thickness was measured with a Leica micrometer. Data were analyzed using the unpaired Student's t test. Expression of iNOS was 2- to 4-fold higher in knockout mice than in wild-type mice on postoperative days 5, 7, and 14. Expression of eNOS was 2- to 2.5-fold higher in knockout mice than in wild-type mice on postoperative days 5 and 7. Tumor necrosis factor-alpha expression was 2- to 7-fold higher in knockout mice than in wild-type mice on all postoperative days. In contrast, expression levels of angiogenic/fibrogenic cytokines (vascular endothelial growth factor, basis fibroblast growth factor, and tumor growth factor-beta1) were 2.5- to 4-fold higher in wild-type mice than in knockout mice. Scars were 1.5- to 2.5-fold thicker in knockout mice than in wild-type mice at all time points. All of the above results represent statistically significant differences (p < 0.05). Significantly different patterns of cytokine expression were seen in knockout and wild-type mice. Although the scar layer was thicker in knockout mice, it showed much greater infiltration with inflammatory cells. These data further delineate the modulatory effect of iNOS and nitric oxide in healing skin grafts. PMID- 11604626 TI - p63 expression during normal cutaneous wound healing in humans. AB - p63, a recently identified member of the p53 family, was shown to play a role in morphogenesis and, probably, in tumors of keratinocyte origin. Because p63 seems to be a marker of keratinocytes with a high proliferative potential, the expression of this protein was studied along with another marker of cell proliferation, Ki67, during normal epidermal regeneration in humans. Serial biopsies of human skin healing by a secondary intention were taken at various time intervals (between days 2 and 21 after the injury) and were studied immunohistochemically with the use of a 4A4 monoclonal antibody against the DeltaNp63 variant and MM1 monoclonal antibody against the Ki67 antigen. In the normal and injured skin, the expression of the DeltaNp63 protein was restricted to the epidermal keratinocytes and hair follicle keratinocytes. In the first days of the healing process, there was a dramatic down-regulation of both DeltaNp63 and Ki67 expression in the area of the epidermal tongue invading under the crust. Five days after the injury, induction of DeltaNp63 in the basal keratinocytes could be detected, followed by a gradual increase of its expression in subsequent days. Several days after complete wound closure, DeltaNp63 was still strongly expressed not only in the basal keratinocytes but also in the entire spinous layer, whereas the Ki67 expression was restricted to single cells in the basal layer. The results indicate that DeltaNp63 could be involved in the control of physiologic processes, such as cell proliferation and migration, related to epidermal repair during healing of normal skin in humans. PMID- 11604629 TI - Differential expression of transforming growth factor-beta receptors in a rabbit zone II flexor tendon wound healing model. AB - Flexor tendon repair in zone II is complicated by adhesions that impair normal postoperative gliding. Transforming growth factor-beta (TGF-beta) is a family of growth factors that has been implicated in scar formation. The TGF-beta family of proteins binds to three distinct classes of membrane receptors, termed RI, RII, and RIII. In this study, we analyzed the temporal and spatial distribution of TGF beta receptor isoforms (RI, RII, and RIII) in a rabbit zone II flexor tendon wound healing model.Twenty-eight adult New Zealand White rabbit forepaws underwent isolation of the middle digit flexor digitorum profundus tendon in zone II. The tendons underwent transection in zone II and immediate repair. The tendons were harvested at increasing time points: 1, 3, 7, 14, 28, and 56 days postoperatively (n = 4 at each time point). The control flexor tendons were harvested without transection and repair (n = 4). Immunohistochemical analysis was used to detect the expression patterns for TGF-beta receptors RI, RII, and RIII. Immunohistochemical staining of the transected and repaired tendons demonstrated up-regulation of TGF-beta RI, RII, and RIII protein levels. TGF-beta receptor production in the experimental group (transection and repair) was concentrated in the epitenon and along the repair site. Furthermore, the TGF-beta receptor expression levels peaked at day 14 and decreased by day 56 postoperatively. In contrast, minimal receptor expression was observed in the untransected and unrepaired control tendons. These data provide evidence that (1) TGF-beta receptors are up-regulated after injury and repair; (2) peak levels of TGF-beta receptor expression occurred at day 14 and decreased by day 56 after wounding and repair; and (3) both the tendon sheath and epitenon have the highest receptor expression, and both may play critical roles in flexor tendon wound healing. Understanding the up-regulation of TGF-beta isoforms and the up regulation of their corresponding receptors during flexor tendon wound healing provides new targets for biomolecular modulation of postoperative scar formation. PMID- 11604630 TI - A comparison of scar revision with the free electron and carbon dioxide resurfacing lasers. AB - Laser scar revision was studied to measure the effects of targeting extracellular matrix protein versus tissue water on scar revision. We compared the free electron laser used at 7.7 microm (the amide III protein absorption band) to the carbon dioxide (CO2) laser and dermabrasion.Nude mice (n = 40) that had rejected skin grafts on their dorsal surface and developed mature scars were used as a model for scar revision. One-half of each scar was revised with either the free electron laser at 7.7 microm (32 to 38 mJ, nonoverlapping pulses delivered with a computerized adjustable pattern generator at 30 Hz, and two to three passes), a 100-microsec CO2 resurfacing laser (500 mJ, 5.0 Hz, and two to five passes), or dermabrasion. The untreated portion of each scar served as an internal control. Evaluation was by measurement of the clinical size of the scar using photography with quantitative computer image analysis to compare the data and histology to evaluate the quality and depth of the scars. The free electron laser at 7.7 microm was significantly better than the CO2 laser and dermabrasion for scar size reduction (p < 0.046 and p < 0.018). The CO2 laser and a highly skilled dermabrader were not statistically significantly different (p < 0.44). The result seen with less skilled dermabraders was significantly worse than all other methods (p < 0.009). The free electron laser at 7.7 microm, which is preferentially absorbed by the proteins of the extracellular matrix, provided better scar reduction than the CO2 resurfacing laser and dermabrasion. Dermabrasion by a skilled operator resulted in improvement similar to the results obtained with the CO2 resurfacing laser, but less skilled operators had significantly poorer results. PMID- 11604631 TI - Keratoderma hereditarium mutilans (Vohwinkel syndrome): an unsolved surgical mystery. PMID- 11604632 TI - Cleft palate lateral synechia syndrome. PMID- 11604633 TI - Sternal stabilization using allograft fibula following cardiac transplantation. PMID- 11604634 TI - Refrigeration of a "spare part": a salvage procedure for preservation of the knee joint in a patient with multiple trauma. PMID- 11604636 TI - Anchoring correction of eyebrow ptosis in facial palsy. PMID- 11604637 TI - A subperiosteal approach to harvesting the free serratus anterior and rib myo osseous composite flap. PMID- 11604638 TI - Reversed neurofasciocutaneous island flap based on the vascular supply accompanying the superficial peroneal nerve. PMID- 11604639 TI - The use of a tie-over stent wound suturing technique revisited. PMID- 11604640 TI - Prenatal sonographic diagnosis of major craniofacial anomalies. PMID- 11604641 TI - Standardizing digital photography: it's not all in the eye of the beholder. AB - Advances in digital photography have made it an efficient and economically appealing alternative to conventional photography. Nevertheless, as objective observers and clinical photographers, we must realize that all digital cameras are not created equal. Different digital cameras frequently used in plastic surgery practices (Olympus 600DL, Olympus 2500, Sony DSC-D700, Nikon Coolpix 950, and Nikon D1) were evaluated, using a subject photographed with each camera in the identical lighting conditions, to determine inherent differences in quality, color, and contrast of the resultant photographs. Three different lighting conditions were examined: single soft-box lighting, dual studio flash boxes, and operating room lighting with on-camera flash. The same digital settings (program mode, ISO camera default setting, high quality setting with JPEG compression) were used. Each camera was digitally color balanced using an 18 percent gray card. Raw and color-balanced images were viewed side-by-side. The macro-image capabilities of each camera were also examined. Conventional 35-mm photographs using a 105 macro-lens on Kodachrome and Ektachrome slide film were obtained for comparison. All of the digital cameras performed with noticeable differences, but they maintained consistency in the three different lighting conditions. Digital photographs differed most greatly with respect to quality and contrast, which was especially obvious once color balancing was performed. Marked differences in quality and ability were observed with respect to macro-image capabilities. Inherent differences in features among digital cameras produce dramatically different photographic results with regard to color, contrast, focus, and overall quality. With the increasing use of digital photography in plastic surgery journals and presentations, it must be recognized that digital cameras do not all display photographs of similar quality, especially when used to evaluate skin appearance. To standardize digital photography, the surgeon must realize that switching digital cameras is akin to switching film types. Standardization of digital photographs should include image resolution between 1.5 and 2.7 million pixels, ISO default setting, color balancing with an 18 percent gray card and software, consistency in focal distance, JPEG compression of medium-to-high quality, and backgrounds of medium blue or 18 percent gray. PMID- 11604642 TI - Breast reconstruction with free-tissue transfer. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the rationale for the use of free tissue transfer for breast reconstruction. 2. Understand the indications, advantages, and disadvantages of this method of reconstruction. The authors discuss the indications, advantages, and disadvantages of free-tissue transfer for breast reconstruction. The most common free flaps used today are individually discussed. Details about indications, contraindications, pertinent anatomy, pedicle characteristics, flap pliability, perfusion characteristics, advantages, and disadvantages for each of these flaps are presented. Details pertaining to the more common recipient vessels are presented. Future considerations are also briefly discussed. PMID- 11604643 TI - Minimizing and preventing the "wear-you-out" syndrome in cosmetic surgery. PMID- 11604644 TI - Volumetric face lifting. AB - The evolution of the face-lift technique used by the author, and the major contribution toward this development from Sydney Coleman's description of lipostructure, are described. At present, the superficial adipocutaneous system (SACS) face lift is almost always associated with a lipostructure performed in the same operative session. In most anatomical locations the structural fat grafting is done before the subfat undermining, although some minor touch-up lipostructure may be done at the end of the face lift. PMID- 11604648 TI - Histopathologic and morphometric evaluation of the skin abnormalities induced by erbium:YAG and carbon dioxide lasers in 10 patients. AB - In the 1960s, carbon dioxide (CO2) laser therapy started to be applied to eliminate wrinkles, actinic scars, and acne because of its capacity of induce intracellular water vaporization. However, recent studies have shown the efficacy of the erbium laser in removing delicate and moderate scars. Furthermore, the postoperative lesions induced by the erbium laser seem to resolve faster and with less erythematous pattern compared with lesions induced by the CO2 laser. The purpose of this study was to determine the immediate pathologic alterations caused by single applications of CO2 and erbium lasers and their association in human skin shreds. Ten white female patients aged 30 to 63 years underwent rhytidectomy, and their respective shreds, which were prepared for excision, were tattooed with the CO2 laser, the erbium laser, or a combination of both in random order and number of applications, before final removal. This project was approved by the local ethical committee. After surgical removal, these tattooed shreds were fixed in 10% buffered formalin and submitted to histopathologic analysis. Morphometric studies demonstrated the normal skin thickness and thickness of the laser-treated area, and their subtraction resulted in the ablation damage values. Residual thermal damage corresponded to the thickness of the affected skin from the most superficial layer of tissue in the laser-treated area down to the deepest dermal area with basophilic degeneration of collagen fibers. Our results showed that two CO2 applications resulted in greater ablation and residual thermal damage when compared with only one CO2 application. The same was true in comparisons of one and two applications of the erbium laser. Both results were statistically significant (p < 0.05). When one isolated erbium and one isolated CO2 application were compared, ablation damage was greater in the former group, although with no statistical significance. One CO2 plus one erbium application compared with one isolated CO2 application showed similar ablation damage but greater residual thermal damage in the latter group (p < 0.05). These observations might contribute to our understanding of the lesions caused in the human skin by erbium and CO2 lasers and eventually help determine the ideal laser combination for the appropriate surgical treatment. PMID- 11604649 TI - Keeping the transumbilical breast augmentation procedure safe. AB - The transumbilical breast augmentation procedure has proved to be highly effective and safe when performed properly, as outlined herein. In the author's opinion, the popularity of the procedure will continue to increase among both surgeons and patients. This article focuses on the steps necessary to maximize the continuing safety of the procedure. The three most critical points are that no sharp instruments are used, the surgeon's handling of the instrument prevents any long thrusts, and at no time does any instrument point toward the abdominal or thoracic cavity. These and numerous other safety tips are presented here. PMID- 11604652 TI - The evolution of the brow lift in aesthetic plastic surgery. AB - For nearly 100 years, aesthetic improvement of the aging face has included surgical elevation of the brow. Early attempts to correct brow ptosis were largely unsuccessful. Recognizing the need to modify the frown muscles heralded the achievement of results previously unobtainable. Within the past decade, the minimal incision approach to brow lifting afforded with the endoscope radically changed surgical options in forehead rejuvenation. Further advances have added to these options and have provided a palette of alternatives in aesthetic correction of the upper one-third of the aging face. PMID- 11604653 TI - Alar rim excision: a method of thinning bulky nostrils. PMID- 11604654 TI - Turfing our turf. PMID- 11604655 TI - Power-assisted lipoplasty. PMID- 11604656 TI - Medicines...allergies...herbs? PMID- 11604657 TI - Cosmetic dentistry: tooth whitening. PMID- 11604658 TI - Legality of the use of silicone injections in cosmetic surgery. PMID- 11604659 TI - Replantation of an amputated tongue. PMID- 11604660 TI - A practical solution for a broken reconstruction plate. PMID- 11604661 TI - Roberts syndrome from the plastic surgeon's viewpoint. PMID- 11604662 TI - Autologous skin graft transplantation for refractory ulcer hand associated with congenital erythropoietic porphyria. PMID- 11604663 TI - Central segment expansion for release of web space contractures. PMID- 11604664 TI - Managed care's attempt to capture aesthetic surgery. PMID- 11604665 TI - A lifelong journey and passion. PMID- 11604666 TI - From a distance. PMID- 11604667 TI - Reduction mammaplasty: a preference for the inferior pedicle technique. PMID- 11604668 TI - Ten-year experience with a textured silicone breast implant. PMID- 11604669 TI - Frequency of seroma in abdominal lipectomies. PMID- 11604670 TI - Liposuction fat versus total aspirate: a time for more precise terminology. PMID- 11604671 TI - Extended neurolysis of the posterior tibial nerve to improve sensation in diabetic neuropathic feet. PMID- 11604672 TI - An interesting anomaly of the penis. PMID- 11604673 TI - New concept of balloon-compression wear for the treatment of keloids and hypertrophic scars. PMID- 11604674 TI - Metachronous inflammatory pseudotumor ("myofibroblastoma"). PMID- 11604675 TI - "Round-block" purse-string suture on skin graft. PMID- 11604676 TI - Treatment precautions for paraplegic and quadriplegic patients with sacral decubitus ulcers. PMID- 11604677 TI - Black nodes: no melanoma. PMID- 11604678 TI - Securing skin grafts using a surgical glove. PMID- 11604679 TI - Medical definitions. PMID- 11604680 TI - A new, custom-made, protective rat vest for flap studies. PMID- 11604681 TI - [Nothing will ever be perfect. But improvement is on way]. PMID- 11604682 TI - [Evaluation of practices in liberal medicine, the medical audit: a current topic]. PMID- 11604683 TI - [Evidence-based medicine: towards evidence-based radiology]. AB - PURPOSE: To present evidence-based medicine (EBM), a concept that has been emerging over the decade, and to propose a reflexion about the role of radiologists in this new paradigm of medical practice. Clinical decision making. This new paradigm proposes the use of the best evidence and patient's participation in making medical decisions with de-emphasizing of intuition and empirical medicine. Application to a practice policy. EBM imposes new skills for physicians: clinical practice guideline is a witness of its importance. The main objective of EBM is to assist practitioners in their decision making process, but limits of this new concept must be known when it is used to control health-care resources or practice policies. Towards evidence-based radiology. What is the place for radiologists (diagnosis or interventional) in this new very popular paradigm? PMID- 11604684 TI - [Imaging of syringomyelia]. AB - This review reports the value of current imaging techniques in the diagnosis of syringomyelia excluding tumoral causes. The value of imaging techniques for evaluation of extension, detection of associated anomalies, and pre- and postoperative evaluation are detailed. PMID- 11604685 TI - [Elaboration of a tool for an audit of radiology reports]. AB - PURPOSE: Elaboration of a tool for an Audit of radiology reports in a department of radiology. Materials and methods. We have made a grid and a guide to evaluate the relevance and the quality of the radiology reports. We have tested this tool on 120 reports from in-patients of the gastroenterology department. The test has been done by two radiologists (blinded test) to verify if the answers were identical. We have calculated for each item the Kappa coefficient (inter-observer agreement). RESULTS: This study has validated most of the items of our grid, some have been deleted, and others modified. CONCLUSION: Our study shows that our tool can evaluate the radiology reports of a radiology department, an audit can thus be conducted using that tool. PMID- 11604686 TI - [Value of CT guided renal biopsies: retrospective review of 67 cases]. AB - PURPOSE: To assess the value of the CT guided percutaneous biopsy of renal tumors and to promote the interest of this procedure. MATERIAL AND METHODS: We report a retrospective study of 67 patients (average age, 51 years) who underwent CT guided biopsy of a single renal mass. The average size of tumors was 5 centimeters. The biopsy of tumors was carried out with needles between 16 and 21 gauge by using a conventional CT. Two to three passes per tumor were obtained. RESULTS: Biopsy material was sufficient for diagnosis in 48 cases (72%). A renal cell carcinoma was found in 29 (43%) samples of biopsy. The remainder included 13 metastases or lymphomas (18%). A benign lesion was found in 6 cases (9%). 59 patients had a final diagnosis. Accuracy of the biopsy for histopathologic evaluation was 81%. The average lesion size of failed biopsies was 1.5 centimeters. Morbidity occurred in 13% of cases, without immediate life threatening consequence. CONCLUSION: CT-guided renal biopsy is an effective means of obtaining tissue for the diagnosis of focal renal masses. The indications are renal lesions locally advanced, multimetastatic patients, mass in patients with a single kidney and focal lesions in patients with prior history of malignancy. PMID- 11604687 TI - [Imaging features of retained surgical foreign bodies]. AB - PURPOSE: To study the clinical and radiological manifestations in patients with retained surgical foreign bodies. PATIENTS AND METHODS: Over the last five years, seven patients were found to have retained surgical foreign bodies after abdominal surgery. An analysis of the clinical signs, laboratory findings and imaging features was performed. RESULTS: The clinical and laboratory data were non-specific. The diagnosis of textiloma was suggested based on imaging findings and surgical history before surgical exploration. The characteristic imaging findings at ultrasound and computed tomography consisted of a fluid collection with internal wavy structures. The differential diagnosis includes pyogenic abscesses, hematomas and ruptured hydatid cysts. CONCLUSION: Ultrasonography and computed tomography are essential for the diagnosis and management of retained surgical foreign bodies after abdominal surgery. PMID- 11604688 TI - [CT and MRI features of spinal hydatidosis. A report of 8 cases]. AB - PURPOSE: Hydatidosis affects the bone in 0.5 to 2% of cases, with 44% of these cases involving the spine. We report 8 cases of vertebral involvement evaluated by CT and/or MRI. Materials and Methods. This retrospective study from January 1996 to August 2000 included seven patients (5 men and 3 women) aged between 28 and 65 years old. The mean age was 45 years old. Five patients underwent CT scan (one by CT-myelography). MRI was available in 4 cases. RESULTS: Imaging showed multicystic bony lesions. Thoracic involvement was present in 4 cases, lumbar involvement in 2 cases, and sacral involvement in 2 cases. The process involved 2 adjacent vertebrae in 4 cases at the thoracic and lumbar levels and the entire sacrum in the other cases. Only one case of vertebral collapse was noted, but extension into the spinal canal was noted in all cases. Other sites of involvement were also noted, especially in adjacent soft tissues, liver and spleen. CONCLUSION: The presence of multicystic vertebral lesions with involvement of adjacent soft tissues and/or distant organs should raise the possibility of spinal hydatidosis in endemic countries. PMID- 11604689 TI - [An assessment of low-dose high resolution CT in the detection of benign asbestos related pleural abnormalities]. AB - PURPOSE: To assess the reliability of low-dose high-resolution computed tomography (HRCT) in the detection of benign asbestos-related pleural abnormalities. METHODS: Fourty-one patients exposed to asbestos were imaged on two occasions; the first time with conventional HRCT parameters: 140kVp, 220mAs; the second time with low-dose HRCT parameters: 120kVp, 60mAs. RESULTS: The qualitative assessment dit not show any difference in the visibility of benign pleural abnormalities from one technique to the other in 98% cases. CONCLUSION: The detection of pleural plaques and thickening did not vary with the two scanning protocols and, when compared with conventional HRCT, low-dose HRCT allows reduced radiation exposure by at least 76.5%, with an absorbed dose close to that delivered when using conventional chest radiography. Nevertheless, low dose HRCT is a complementary study to helical acquisitions. PMID- 11604690 TI - [Gastric pneumatosis as a sign of duodenal stenosis in a child with Down syndrome]. AB - A case of gastric pneumatosis is described in a 6 month old girl with Down syndrome. Plain abdominal radiographs showed a radiolucent rim within the gastric wall and a dilated stomach. Ultrasonography showed diffuse echoic streaks of air in the gastric wall, pneumobilia and gastroduodenal dilatation. Upper GI series showed duodenal stenosis. Gastric pneumatosis (air within the gastric wall), is an unusual radiographic finding. It may be of mechanical or inflammatory origin or, in some rare cases, remain unexplained. PMID- 11604691 TI - [MRI appearance of a primary leiomyosarcoma of bone with epiphyseal involvement]. AB - Primary leiomyosarcoma of bone is a rarely reported tumor of elderly subjects. It usually shows an aggressive osteolytic pattern on plain radiographs and involves predominantly the metaphyses of long bones. We report a case of primary leiomyosarcoma of bone, which is atypical by its epiphyseal location, a non aggressive pattern on plain radiographs and its MR imaging features. PMID- 11604692 TI - [Sigmoid volvulus: value of CT]. AB - We report a case of sigmoid volvulus. CT findings are presented. The value of CT compared to abdominal plain radiographs and contrast enema is described. PMID- 11604693 TI - [A case of muscular and canal of nuck involvement by endometriosis]. AB - Endometriosis is defined by the presence of endometrial tissue outside the uterine cavity and having the functional property of menstrual bleeding. We report a case of endometriosis involving the abdominal wall muscles and canal of Nuck in a 28 year old woman. Abdominal wall sonography showed a hypoechoic lesion at the rectus abdominis insertion. T1W and T2W MRI images showed a hemorrhagic high signal intensity lesion in the muscle. MRI also showed a similar lesion in the canal of Nuck. PMID- 11604694 TI - [A rare cause of pulmonary metastasis: benign metastazing leiomyoma]. AB - The authors report a rare cause of pulmonary metastasis of a benign tumor, uterine leiomyoma, observed in a black African woman. Plain chest radiograph showed multiple pulmonary nodules. These features were confirmed at CT. Transbronchial and surgical lung biopsies were consistent with pulmonary metastases from benign uterine leiomyoma. Hormonal treatment was instituted and resulted in regression of nearly all lesions at one year. Benign metastazing leiomyoma is a rare condition, in spite of the high rate of uterine leiomyoma in black African women. PMID- 11604695 TI - Groupware for case management and inter-organizational collaboration: the virtual rehabilitation team. AB - This paper presents LINDA, a prototype system designed to support virtual rehabilitation teams. LINDA enables professionals from different welfare-state agencies to collaborate in case management. Our approach to supporting teamwork involves the sharing of minimal case sets across organizational borders needed to provide a shared situation assessment among team members. The system provides a shared workspace for the team; a lightweight client-database, visualization of case histories and plans, and means to communicate effectively in the team using yellow sticker-notes. We present LINDA and discuss how we approached the problem to design groupware to support work under changing and uncertain conditions. PMID- 11604696 TI - IP videoconferencing using a quality of service public network. AB - Videoconferencing in the medical world has been successfully used for quite a few years. Nevertheless it has not spread significantly in daily use. Some of the problems rely on the infrastructure needed to set up a video session: one or more ISDN lines or a fast Internet connection. The first is not easily available everywhere in a building; the latter is rarely so fast to allow for a smooth operation with no quality drops. The use of Videonet, the first European commercial public Internet link with guaranteed Quality of Service (QoS), has the potential to be a breakthrough in videoconferencing. We describe this new system and its applications, with the first tests in a hospital environment. Our results show that there are still problems to be solved in order to achieve a quality comparable to ISDN. PMID- 11604697 TI - A formal framework for modelling and validating medical systems. AB - Medical computerised systems which have a major effect on human lives (e.g. those used for diagnosis, therapy, surgery, in the intensive care units, etc) are considered as safety critical systems. Such systems are sometimes responsible for major damages and injuries due to unpredicted malfunction. Misleading user requirements, errors in the specification and in the implementation are the usual reasons responsible for non-safe systems. This paper advocates the use of an integrated formal framework based on a computational machine (X-Machine), in the development of safety critical medical systems. This formal framework gives the ability to intuitively as well as formally model a system, then automatically check if the produced model has all the desired properties, and finally test if the implementation is equivalent to the specification by applying a complete set of test cases. Therefore, the use of this framework in the development of systems in safety critical medical domains can assure that the final product is valid with respect to the user requirements by revealing errors during the whole development life cycle and subsequently add to the confidence of their use. The proposed framework is accompanied by an example, which demonstrates the use of X Machines in specification, testing and verification. PMID- 11604698 TI - An open, component-based information infrastructure to support integrated regional healthcare networks. AB - A fundamental requirement for achieving continuity of care is the seamless sharing of multi-clinical information. Several different technological approaches can be followed to enable the sharing of health record segments. In all cases interoperability between systems is a prerequisite and this requires presently a major technological challenge. Inter-operability can be achieved either through messages or through a more advanced approach based on a federation of autonomous systems. Message based integration is centered mainly on the exchange of HL7 and DICOM messages for achieving the functional integration of clinical information systems (CIS) at institutional or regional level. The federated approach is principally used for facilitating the virtual view of the Integrated Electronic Health Record (I-EHR), without having to replicate unnecessary information. Within the context of HYGEIAnet, which is the regional health telematics network of Crete, both approaches have been utilized for providing end users with seamless access to clinical information. Both are based on an open architecture, which provides the framework for the reuse of standardized common components and public interfaces. This work presents the experiences related to the implementation of "messaging" and "federating" in HYGEIAnet, which are used complementary to each other. A comparison of the two parallel approaches, together with their strengths and weaknesses is described, and evaluation is given from the technological as well as the end users' perspective. Emphasis is given on the technological challenges in developing open, component-based information infra-structure to support integrated service delivery. PMID- 11604699 TI - A virtual intranet and data-warehousing for healthcare co-operation. AB - As patient's medical data is disseminated in different health structures, developing a medical or epidemiological patient-oriented data warehouse has some specific requirements compared to intra healthcare structure data-warehousing projects. The difference is that the healthcare structures implicated in a patient-oriented data warehouse project require some considerations about the confidentiality of the patient data and of the activities of healthcare structures. Building a data-warehousing system at a regional level, for example in cancerology, requires the participation of all concerned health structures, as well as different health professionals. The heterogeneity of sources medical data of has to be taken into account for choosing between several organizational configurations of the data warehousing system. In top of data warehousing, we propose a concept of Virtual Intranet, which provides a solution to the problem of medical information security arising from heterogeneous sources. PMID- 11604700 TI - Ngi and Internet2: accelerating the creation of tomorrow's internet. AB - Internet2 is a consortium of leading U.S. universities working in partnership with industry and the U.S. government's Next Generation Internet (NGI) initiative to develop a faster, more reliable Internet for research and education including enhanced, high-performance networking services and the advanced applications that are enabled by those services [1]. By facilitating and coordinating the development, deployment, operation, and technology transfer of advanced, network based applications and network services, Internet2 and NGI are working together to fundamentally change the way scientists, engineers, clinicians, and others work together. [http://www.internet2.edu] The NGI Program has three tracks: research, network testbeds, and applications. The aim of the research track is to promote experimentation with the next generation of network technologies. The network testbed track aims to develop next generation network testbeds to connect universities and federal research institutions at speeds that are sufficient to demonstrate new technologies and support future research. The aim of the applications track is to demonstrate new applications, enabled by the NGI networks, to meet important national goals and missions [2]. [http://www.ngi.gov/] The Internet2/NGI backbone networks, Abilene and vBNS (very high performance Backbone Network Service), provide the basis of collaboration and development for a new breed of advanced medical applications. Academic medical centers leverage the resources available throughout the Internet2 high performance networking community for high-capacity broadband and selectable quality of service to make effective use of national repositories. The Internet2 Health Sciences Initiative enables a new generation of emerging medical applications whose architecture and development have been restricted by or are beyond the constraints of traditional Internet environments. These initiatives facilitate a variety of activities to foster the development and deployment of emerging applications that meet the requirements of clinical practice, medical and related biological research, education, and medical awareness throughout the public sector. Medical applications that work with high performance networks and supercomputing capabilities offer exciting new solutions for the medical industry. Internet2 and NGI,strive to combine the expertise of their constituents to establish a distributed knowledge system for achieving innovation in research, teaching, learning, and clinical care. PMID- 11604701 TI - Linking personal and public health information: a vision for community-centered health information systems. AB - As health care in the U.S. and worldwide has shifted from a centralized, institution-based model to a distributed process occurring largely in the communities, Integrated Advanced Information Management Systems (IAIMS) initiatives must also move toward addressing the challenges of integrating health information at the community level. The Wisconsin IAIMS initiative strives to create such a solution, anchoring its efforts in a regional health information technology architecture by partnering with Wisconsin-area communities as the foundation that will ensure the establishment of the appropriate collaborations to gain adequate investment and generate sustainable solutions for health information integration. PMID- 11604702 TI - The Brazilian National Health Informatics Strategy. AB - This paper describes the Brazilian National Strategy for the development of the national Health Informatics Infrastructure. An overall description of the use of IT in the Brazilian Health scenario is presented with emphasis on the federal initiatives by DATASUS, the informatics division of the Ministry of Health. The national health card project is discussed and the strategies to establish interoperability among systems are presented. The adopted standards and methodologies used are also discussed. PMID- 11604703 TI - Web architecture for the remote browsing and analysis of distributed medical images and data. AB - To provide easy retrieval, integration and evaluation of multimodal medical images and data in a web browser environment, distributed application technologies and Java programming were used to develop a client-server architecture based on software agents. The server side manages secure connections and queries to heterogeneous remote databases and file systems containing patient personal and clinical data. The client side is a Java applet running in a web browser and providing a friendly medical user interface to perform queries on patient and medical test data and integrate and visualize properly the various query results. A set of tools based on Java Advanced Imaging API enables to process and analyze the retrieved bioimages, and quantify their features in different regions of interest. The platform-independence Java technology makes the developed prototype easy to be managed in a centralized form and provided in each site where an intranet or internet connection can be located. Giving the healthcare providers effective tools for browsing, querying, visualizing and evaluating comprehensively medical images and records in all locations where they can need them - e.g. emergency, operating theaters, ward, or even outpatient clinics- the implemented prototype represents an important aid in providing more efficient diagnoses and medical treatments. PMID- 11604704 TI - Enhancing communications and connectivity in Africa: the multilateral initiative on malaria (MIM) model. AB - The U.S. National Library of Medicine, working in concert with the Multilateral Initiative on Malaria (MIM), has developed and implemented a unique organizational and technical strategy to connect malaria research sites to the Internet for purposes of facilitating North-South scientific communications and access to electronic information resources on the Web. The model employs microwave and VSAT technologies, and shares bandwidth and costs among participating malaria research sites and their respective research funders in Mali, Kenya, Ghana, Tanzania and other sub-Saharan locations affiliated with MIM. The concept of institutional partnership is an essential element of this information technology capacity building effort, which may find applicability in other developing regions of the world with similar communications and research networking needs and capabilities. PMID- 11604705 TI - "THE PILOT": a tool for connecting existing HIS to an extranet quickly, easily and smoothly. AB - Migrations and expansions of information systems are constantly at the front line of all the computer science problems to be overcome in medical / health informatics systems. It is shown here that one effective way to open the communication between heterogeneous systems is depending upon the ease of putting all the systems at work together using the middleware level to facilitate the interconnection between heterogeneous applications. However the most difficult application to migrate is certainly the ADT. It is shown here how the Pilot could facilitate the migration of applications namely with the migration of the ADT itself from a centralized platform to a full scale distributed system. Indeed the Pilot has been developed up to the stage of a pre-product and is on sale already. It has been experienced satisfactorily and is presented here. PMID- 11604706 TI - Object-oriented business process analysis of the cooperative soft tissue sarcoma trial of the german society for paediatric oncology and haematology (GPOH). AB - The German Society for Paediatric Oncology and Haematology (GPOH) runs nation wide multicentre clinical trials to improve the treatment of children suffering from malignant diseases. We want to provide methods and tools to support the centres of these trials in developing trial specific modules for the computer based DOcumentation System for Paediatric Oncology (DOSPO). For this we carried out an object-oriented business process analysis for the Cooperative Soft Tissue Sarcoma Trial at the Olgahospital Stuttgart for Child and Adolescent Medicine. The result is a comprehensive business process model consisting of UML-diagrams and use case specifications. We recommend the object-oriented business process analysis as a method for the definition of requirements in information processing projects in the field of clinical trials in general. For this our model can serve as basis because it slightly can be adjusted to each type of clinical trial. PMID- 11604707 TI - Integrating medical applications in an open architecture through generic and reusable components. AB - Allowing exchange of information and cooperation among network-wide distributed and heterogeneous applications is a major need of current health care information systems. It forces the development of open and modular integration architectures. Major issues in the development include defining a flexible and robust federation model, developing interaction and communication facilities as well as the mechanism insuring semantic interoperability. We developed generic and reusable software components to ease the construction of any integration platform. The Pilot and the Mediator Service components facilitate the execution of services and the meaningful transformation of information. They have been tested in the context of the SynEx European project to construct a multi-agents based integration architecture. The possibility of such architectures to take into account the issue of semantic interoperability is further discussed. PMID- 11604708 TI - How the open-source development model can improve medical software. AB - The current system of proprietary software development for healthcare applications is inadequate to meet the needs of providers, administrators, and patients. A recent advance in the field of Internet programming is the release of large-scale software projects as "open-source". The advantages of this method of development include higher quality, lower cost, and increased adherence to established standards. There are several hurdles to be overcome before the healthcare field can take full advantage of this development model. The implementation of open-source development of medical software could greatly improve clinical and research software and elevate the academic standards of the field of medical informatics. PMID- 11604709 TI - XML and the VITAL standard: the document-oriented approach for open telemedicine applications. AB - This paper describes an effort to create a common, document-oriented architecture for the interchange of medical data in healthcare telemedicine applications. Key components are: The VITAL standard specifying a common (medical device independent) representation of Vital Signs Information and the Extensible Markup Language (XML) specifying the document specifications form, an architecture that, in aggregate, define the semantics and structural constraints necessary for the exchange of vital signs and related medical data. The modelling and design technique for the described application has been the Unified Modelling Language (UML). The XMI (XML Metadata Interchange Format) of the Object Management Group (OMG) provided the meta-model for this application, for sharing objects using XML, via the transfer of the application's UML model to XML documents and DTDs. PMID- 11604710 TI - Semantic features of an enterprise interface terminology for SNOMED RT. AB - OBJECTIVE: To evaluate the utility of SNOMED RT in support of a natural language interface for encoding of clinical assessments. METHOD: Using a random sample of clinical terms from the UNMC Lexicon, I mapped the terminology into canonical data entries using SNOMED RT. Working from the source term language, I evaluated lexical mapping to the SNOMED term set, and the function of the SNOMED RT semantic network in support of a language-based clinical coding interface. RESULTS: Ambiguity in the source terms was low at 0.3%. Lexical (language-based) mapping could account for only 48.8% of meaning from the source terms. The RT semantic network accounted for 39.5% of meaning, and supplementing the lexical map this led to 80.2% capture of source content. Error rates in the segment of RT which I reviewed were low at 0.6%. 97.6% of source content could be accurately captured in SNOMED RT. CONCLUSION: SNOMED RT supported an accurate and reliable representation of clinical assessment data in this sample. The semantic network of RT substantially enhanced the encoding of concepts relative to lexical mapping. However these data suggest that natural language encoding with SNOMED RT in an enterprise environment is unlikely at this time. PMID- 11604712 TI - Harmonization of patient data card structure with messaging standards. AB - Harmonization of patient data card (PDC) structure with messaging standards is discussed on example of pilot project of patient data card system implemented by the Medical Center of the Russian Federation President's Management Department. Such a harmonization may help to improve medical PDC interoperability on the seventh, application level. PMID- 11604711 TI - A survey to identify the clinical coding and classification systems currently in use across Europe. AB - INTRODUCTION: This is a survey to identify what clinical coding systems are currently in use across the European Union, and the states seeking membership to it. We sought to identify what systems are currently used and to what extent they were subject to local adaptation. BACKGROUND: Clinical coding should facilitate identifying key medical events in a computerised medical record, and aggregating information across groups of records. The emerging new driver is as the enabler of the life-long computerised medical record. A prerequisite for this level of functionality is the transfer of information between different computer systems. This transfer can be facilitated either by working on the interoperability problems between disparate systems or by harmonising the underlying data. This paper examines the extent to which the latter has occurred across Europe. METHOD: Literature and Internet search. Requests for information via electronic mail to pan-European mailing lists of health informatics professionals. RESULTS: Coding systems are now a de facto part of health information systems across Europe. There are relatively few coding systems in existence across Europe. ICD9 and ICD 10, ICPC and Read were the most established. However the local adaptation of these classification systems either on a by country or by computer software manufacturer basis; significantly reduces the ability for the meaning coded with patients computer records to be easily transferred from one medical record system to another. CONCLUSIONS: There is no longer any debate as to whether a coding or classification system should be used. Convergence of different classifications systems should be encouraged. Countries and computer manufacturers within the EU should be encouraged to stop making local modifications to coding and classification systems, as this practice risks significantly slowing progress towards easy transfer of records between computer systems. PMID- 11604713 TI - The creation of an ontology of clinical document names. AB - The efficient use of documents from heterogeneous computer systems is hampered by differences in document-naming practices across organizations. Using an open consensus method, the Document Ontology Task Force, with support from the Veterans Health Administration, addressed this pervasive problem by developing a clinical document ontology. Based on the analysis of over 2000 clinical document names, the ontology was used to formulate a terminology model which is currently being used to guide the creation of fully-specified document names in LOINC (Logical Observations, Identifiers, Names and Codes). Incorporation into LOINC will enable homogeneous management of documents in a widely distributed environment and will also give rise to a rich polyhierarchy of document names. PMID- 11604714 TI - Achieving reuse of computable guideline systems. AB - We describe an architecture for reusing computable guidelines and the programs used to interpret them across varied legacy clinical systems. Developed for the PRODIGY 3 project, our architecture aims to support interactive, point of care use of guidelines in primary care. Legacy medical record systems in UK primary care are diverse, using different terminologies, different data models, and varying user-interface philosophies. However, our goal is to provide common guideline knowledge bases and system components, while achieving full integration with the host medical record system, and a user interface tailored to that system. In conjunction with system suppliers, we identified areas of standardization required to achieve this goal. Firstly, standardized interfaces were created for mediation with the legacy system medical record and for act management. Secondly, a standard interface was developed for communication with the User Interface for guideline interaction. Thirdly, a terminology mapping knowledge base and system component was provided. Lastly, we developed a numeric unit conversion knowledge base and system component. The standardization of this architecture was achieved by close collaboration with existing vendors of Primary Care computing systems in the UK. The work has been verified by two suppliers successfully building and deploying systems with User Interfaces which mirror their normal look and feel, communicating fully with existing medical records, while using identical Guideline Interpreter components and knowledge bases. Encouragingly further experiments in other areas of clinical decision support have not required extension of our interfaces. PMID- 11604715 TI - Ontological and epistemological views of 'headings' in clinical records. AB - This paper presents a theoretical framework for analyzing the structure and use of headings in clinical narrative. We are researching the proposed UK national standard of headings for communicating clinical information. We investigate three topics with respect to these headings) conformance to standards and systems) coverage and reliability) navigation and interpretation. The method described here is used to analyse the three distinct topics in a coherent and systematic way deploying a variant of functional analysis to consider the meaningfulness and interpretation of headings from both the clinician' and system' perspectives. PMID- 11604716 TI - An exchange format for use-cases of hospital information systems. AB - Object-oriented software development is a powerful methodology for development of large hospital information systems. We think use-case driven approach is particularly useful for the development. In the use-cases driven approach, use cases are documented at the first stage in the software development process and they are used through the whole steps in a variety of ways. Therefore, it is important to exchange and share the use-cases and make effective use of them through the overall lifecycle of a development process. In this paper, we propose a method of sharing and exchanging use-case models between applications, developers, and projects. We design an XML based exchange format for use-cases. We then discuss an application of the exchange format to support several software development activities. We preliminarily implemented a support system for object oriented analysis based on the exchange format. The result shows that using the structural and semantic information in the exchange format enables the support system to assist the object-oriented analysis successfully. PMID- 11604717 TI - The Cancer Informatics Infrastructure (CII): an architecture for translating clinical research into patient care. AB - Today, the clinical trial process remains slow and paper-based. The creation of a Cancer Informatics Infrastructure (CII) can provide the architectural base across the continuum of cancer research and cancer care. Recommendations of a Long Range Planning Committee identified near-term activities for the Office of Informatics at the National Cancer Institute (NCI). These include participating in national standards development; fostering oncology-related terminology and standards, e.g., Common Data Elements (CDEs); and leveraging mainstream informatics and Internet technologies, using the successful Internet model that focuses on facilitating stakeholder participation, sponsoring the CII rather than subsidizing it, and providing a test bed as well as an infrastructure. Diffusion tactics include extending the CII concept beyond its "early adopters" to the wider community through recommendations for the near-term and development of a major document defining next-phase activities. PMID- 11604718 TI - A methodology for web-enabling a computer-based patient record with contributions from cognitive science. AB - Cognitive science is a rich source of insight for creative use of new Web technologies by medical informatics workers. I outline a project to Web-enable an existing computer-based patient record (CPR) in the context of ideas from philosophy, linguistics, artificial intelligence, and cognitive psychology. Web prototypes play an important role (a) because Web technology lends itself to rapid prototype development, and (b) because prototypes help team members bridge among disparate medical, computing, and business ontologies. Six Web-enabled CPR prototypes were created and ranked. User scenarios were generated using a user communication matrix. Resulting prototypes were compared according to the degree to which they satisfied medical, computing, and business constraints. In a different organization, or at different time, candidate prototypes and their ranking might have been different. However, prototype generation and comparison are fundamentally influenced by factors usefully understood in a cognitive science framework. PMID- 11604719 TI - Using cognitive work analysis to design clinical displays. AB - In today's ICUs clinicians routinely integrate huge numbers of discrete data points to arrive at a coherent picture of their patients' status. Often the clinician must obtain those data elements from many devices, which makes the problem more difficult. Because presenting data visually amplifies cognition by capitalizing on well-known human perceptual capabilities, it is not surprising that a growing body of research is directed at the effective presentation of visual information in clinical displays. However, developing clinical displays that effectively support clinicians' integration and understanding of many discrete data elements in complex, high technology work domains such as ICUs remains elusive. It may be that traditional analysis and design methods simply are inadequate for this kind of complex environment. Vicente has described a new methodology, called "cognitive work analysis" (CWA), which is targeted at the analysis of complex work domains. The analysis differs from traditional analytic methods in significant ways, particularly in its primary focus on analysis of the work domain, but also in its prescription for explicitly collecting information at five levels (the work domain, diagnostic and treatment tasks, diagnostic strategies, socio-organizational, and clinician skills) that place constraints on the ultimate display design. In this model, the order of data collection is also crucial. Because the work domain constraints tend to be the most permanent, they are likely to have the most impact on design, and so analysis starts there. As the analysis proceeds through the subsequent levels, additional design constraints are identified. We recently used CWA to analyze the information needs for interactive graphical displays that will integrate and represent data in structures that help clinicians visualize a patient's physiological status. We found that the analysis was an effective way to identify information needs at multiple levels. Based on our experience, CWA is a generic methodology that is highly applicable to medical informatics. PMID- 11604720 TI - Capitalizing on knowledge for an adaptive user interface. AB - Hypermedia data browsing is a mean for improving information access. However, the overload and the heterogeneity of medical information, as well as the multitude of possible navigational paths, turn the consultation of data into a difficult task. We present in this paper a solution for the development of adaptive user interfaces in a hypermedia data browsing environment. It is based on the capitalization of the users knowledge in the decision-making process, expressed in terms of navigational paths and of data presentation modes that are customized to the user's preferences. This capitalization offers the user a way to reuse the cumulative experiences in browsing through patient records. We illustrate our approach with the implementation of HEMA, a clinical workstation prototype. PMID- 11604721 TI - Healthcare applications based on software agents. AB - Healthcare has been recognised as one of the most important areas for enterprise applications and services. Presently, information technologists and systems engineers all over the world are working towards achieving better efficiency and quality of service in various sectors of healthcare, such as telemedicine, hospital management, patient-care, and treatment. This paper addresses the issue of more effective and efficient handling of doctor-patient relationship. The idea is to use Software Agent technology to extend the patient-doctor relationship beyond the physical and logistical limitation of face-to-face consultations in patient management. Software agents can provide an extension of the doctor by interacting with the patient via a computer and the Internet. The agent is visualised as an anthropomorphic figure to further enhance the patient interaction. PMID- 11604722 TI - Optimal data entry by patients: effects of interface structure and design. AB - Direct electronic acquisition of data from patients possesses accuracy and diagnostic value. The mechanics of how best to capture historical information from patients using electronic interfaces are not well studied. We undertook an iterative usability experiment to answer 2 questions: 1) How can maximal electronic data input from a patient be achieved, and 2) Do varying structures for data entry promote differential documentation of specified data elements? METHODS: A series of four trials comprised the testing cycle. Unstructured text entry, directed text entry, and closed ended questions were tested in combination against outcomes of word count, time to task completion, and user preferences. Covariates of interest included participants' technologic experience and ergonomic experience with keyboards, as well as self-report of educational status, literacy, and primary language. RESULTS: Participants clearly preferred the order of initial closed-ended questions followed by unstructured text entry, and this ordering was not associated with decrements in word count or increase in time. When compared to unstructured text entry, directed text entry provided higher documentation of data for past medical history and questions which parents wished to discuss with the clinician. A closed-end question structure, when compared to directed text entry, provided higher capture of parents' questions for discussion. CONCLUSIONS: Optimal design of an electronic interview for the capture of medical histories will benefit from a mixed structure of directed text entry and closed-ended questions. For historical or clinically relevant items where maximal capture of data is desired, a structure with closed-ended questions would be preferred. PMID- 11604723 TI - An evaluation of the utility of the CEN categorical structure for nursing diagnoses as a terminology model for integrating nursing diagnosis concepts into SNOMED. AB - We evaluated the utility of the CEN Categorical Structure for Nursing Diagnoses as a terminology model for integrating nursing diagnosis concepts into SNOMED. First, we dissected nursing diagnosis term phrases from two source terminologies (North American Nursing Diagnosis Association (NANDA) Taxonomy 1 and Omaha System) into the semantic categories of the CEN categorical structure. Second, we critically analyzed the similarities between the semantic links in the CEN model and the semantic links used to formally define diagnostic concepts in SNOMED RT and SNOMED CT. Our findings demonstrated that focus, bearer, and judgment were present in 100% of the NANDA and Omaha term phrases. The Omaha term phrases contained no additional descriptors beyond those considered mandatory in the CEN model. In contrast, at least 3% of NANDA diagnoses included a term in each semantic category of the categorical structure. The comparison among the semantic links showed that neither SNOMED RT and SNOMED CT currently contain all the semantic links needed to model the two source terminologies for integration. In conclusion, our findings support the potential utility of the CEN categorical structure as a terminology model for dissecting nursing diagnostic concepts for integration into SNOMED RT and SNOMED CT. However, in order to accomplish this task, appropriate semantic links must be added to SNOMED RT and SNOMED CT. PMID- 11604724 TI - Conceptual search in electronic patient record. AB - Search by content in a large corpus of free texts in the medical domain is, today, only partially solved. The so-called GREP approach (Get Regular Expression and Print), based on highly efficient string matching techniques, is subject to inherent limitations, especially its inability to recognize domain specific knowledge. Such methods oblige the user to formulate his or her query in a logical Boolean style; if this constraint is not fulfilled, the results are poor. The authors present an enhancement to string matching search by the addition of a light conceptual model behind the word lexicon. The new system accepts any sentence as a query and radically improves the quality of results. Efficiency regarding execution time is obtained at the expense of implementing advanced indexing algorithms in a pre-processing phase. The method is described and commented and a brief account of the results illustrates this paper. PMID- 11604725 TI - An object-oriented model for representing semantic locality in the UMLS. AB - Several information models have been developed for the Unified Medical Language System (UMLS). While some models are term-oriented, a knowledge-oriented model is needed for representing semantic locality, i.e. the various semantic links among concepts. We propose an object-oriented model in which the semantic features of the UMLS are made available through four major classes for representing Metathesaurus concepts, semantic types, inter-concept relationships and Semantic Network relationships. Additional semantic methods for reducing the complexity of the hierarchical relationships represented in the UMLS are proposed. Implementation details are presented, as well as examples of use. The interest of this approach is discussed. PMID- 11604726 TI - Expression and meaning of medical language: building an epistemological framework for the study of semantic distance. AB - The use of language for communication purposes introduces a semantic gap in data processing. We have developed a new tool called semantic distance to overcome this gap. A previous presentation of our tool was based on an empirical approach. Here, we examine the properties and theoretical foundation of semantic distance from a rationalistic perspective. We present an epistemological framework to explain the meaning of semantic distance. As a tool, the purpose of semantic distance is the exchange of data or knowledge based on linguistic expressions between software components. We propose a review of the relationship between language and its representation for data processing based on the underlying philosophical assumptions. Description logic is a new paradigm in the medical informatics community to express relations between terms in "is-a" hierarchies. The utility of semantic distance is compared to description logic for communication purposes in different use cases. PMID- 11604727 TI - Methods for exploring the semantics of the relationships between co-occurring UMLS concepts. AB - OBJECTIVE: To characterize the relationships among UMLS concepts that co-occur as MeSH descriptors in MEDLINE citations (1990-1999). DESIGN: 18,485 UMLS concepts involved in 7,928,608 directed pairs of co-occurring concepts were studied. For each directed pair of concepts C1-C2: (i) the "family" of C1 was built, using the UMLS Metathesaurus, and we tested whether or not C2 belonged to C1's family; (ii) we used the semantic categorization of Metathesaurus concepts through the UMLS Semantic Network and Semantic Groups to represent the semantics of the relationships between C1 and C2. RESULTS: In 6.5% of the directed pairs, the co occurring concept C2 was found within the "family" of C1. Detailed results are given. The most frequent co-occurrences involved "Chemicals and Drugs" and "Chemicals and Drugs", as well as "Disorders" and "Chemicals and Drugs". DISCUSSION: This work takes advantage of both symbolic and statistical information represented in the UMLS, and analyzes their overlap. Further research is suggested. PMID- 11604728 TI - Challenges in the development and testing of a reference terminology model for nursing interventions. AB - The purpose of this paper is to report the work of the Interventions Group of the first Nursing Terminology Summit (1999) and to describe the challenges and insights of this group as they have evolved a reference terminology model for nursing interventions. When the group began its work as part of the first meeting of the Nursing Terminology Summit, it had the overall objective of proposing the intervention component of a reference terminology model for nursing. Although there is not a definitive proposal for this to date, the group's exploration and analysis has clarified and explicated both the types of models of clinical information and the current " state of the art" of formal representations of nursing interventions as well as the relationship of nursing languages to these formal representations. In addition, it is our perspective that the work of this group is representative of the process and challenges facing many similar groups currently engaged in modeling efforts. Consequently, critical success factors of such efforts are identified and discussed. This paper reports both the specific outputs of the group related to progress in defining a terminology model of nursing interventions and observations and lessons learned regarding consensus modeling work. PMID- 11604729 TI - Empirical formulation of a generic query set for clinical information retrieval systems. AB - Information needs in clinical practice take the form of specific questions about a given clinical situation, and are best satisfied by concise and specific information retrieval. We sought to develop a comprehensive set of generic queries for information retrieval from electronic medical information resources. We collected one hundred and ten real-world questions asked at the point of care in a variety of settings, and from these developed a set of generic queries of which each of the real-world queries could be shown to be a special case. To provide allowed values for each of the concept terms in the queries, we defined generic nouns as unions of UMLS semantic types, and specified which of these were appropriate to each query. We have begun to use the set to index reference texts from general and subspecialty medicine, and found it capable of full text indexing in the clinical domain. We hypothesize that the query set can serve as a basis for more specialized query sets, and that it will remain generalizable to other electronic medical resources, indexing tasks, and non-UMLS controlled vocabularies. PMID- 11604730 TI - Computerization of guidelines: towards a "guideline markup language". AB - Medical decision making is one of the most difficult daily tasks for physicians. Guidelines have been designed to reduce variance between physicians in daily practice, to improve patient outcomes and to control costs. In fact, few physicians use guidelines in daily practice. A way to ease the use of guidelines is to implement computerised guidelines (computer reminders). We present in this paper a method of computerising guidelines. Our objectives were: 1) to propose a generic model that can be instantiated for any specific guidelines; 2) to use eXtensible Markup Language (XML) as a guideline representation language to instantiate the generic model for a specific guideline. Our model is an object representation of a clinical algorithm, it has been validated by running two different guidelines issued by a French official Agency. In spite of some limitations, we found that this model is expressive enough to represent complex guidelines devoted to diabetes and hypertension management. We conclude that XML can be used as a description format to structure guidelines and as an interface between paper-based guidelines and computer applications. PMID- 11604731 TI - Guideline for health informatics: controlled health vocabularies--vocabulary structure and high-level indicators. AB - Developers and purchasers of controlled health terminologies require valid mechanisms for comparing terminological systems. By Controlled Health Vocabularies we refer to terminologies and terminological systems designed to represent clinical data at a granularity consistent with the practice of today's healthcare delivery. Comprehensive criterion for the evaluation of such systems are lacking and the known criteria are inconsistently applied. Although there are many papers, which describe specific desirable features of a controlled health vocabulary, to date there is not a consistent guide for evaluators of terminologies to reference, which will help them compare implementations of terminological systems on an equal footing 1,2 This guideline serves to fill the gap between academic enumeration of desirable terminological characteristics and the practical implementation or rigorous evaluations which will yield comparable data regarding the quality of one or more controlled health vocabularies. PMID- 11604732 TI - From paper-based to electronic guidelines: application to French guidelines. AB - In order to develop an internet-based decision support system, making available for French general practitioners several prevention guidelines is was necessary to implement paper based guideline. We propose a framework allowing to transform paper based practice guideline into their electronic form. Three different problems were identified: computability (e.g. determinism of the eCPG), logic (e.g. ambiguities when combining Booleans operators) and external validity (i.e. stability of decision for variations around thresholds and proportion of subjects classified in the various terminal nodes). The last problem concerned documentation of evidence: the level of evidence was associated only with the terminal decision node and not with the pathway through the decision tree. We concluded that computerisation of guidelines is not possible without expertise or authors advice. To improve computability it is necessary to provide authors with a framework that checks ambiguities, and logical errors. PMID- 11604734 TI - A clustering method based on rough sets and its application to knowledge discovery in the medical database. AB - This paper proposes a clustering method for nominal and numerical data based on Rough Sets and its application to knowledge discovery in the medical database. Classification is performed according to the indiscernibility relations defined on the basis of relative similarity between objects. The similarity is defined as a combination of two types of similarity measures: the Hamming distance for nominal attributes and the Mahalanobis distance for numerical attributes. Excessive generation of small category is suppressed by modifying similar equivalence relations into the same equivalence relation. An analysis of the meningoencephalitis diagnosis database was performed to validate this method. The result showed that this method could deal well with both types of attributes and discover the primary factors for diagnosis. PMID- 11604733 TI - Sharable computer-based clinical practice guidelines: rationale, obstacles, approaches, and prospects. AB - Clinical practice guideline automation at the point of care is of growing interest, yet most guidelines are authored in unstructured narrative form. Computer-based execution depends on a formal structured representation, and also faces a number of other challenges at all stages of the guideline lifecycle: modeling, authoring, dissemination, implementation, and update. This is because of the multiplicity of conceptual models, authoring tools, authoring approaches, intended applications, implementation platforms, and local interface requirements and operational constraints. Complexity and time required for development and structure are also huge obstacles. These factors argue for convergence on a common shared model for representation that can be the basis of dissemination. A common model would facilitate direct interpretation or mapping to multiple implementation environments. GLIF (GuideLine Interchange Format) is a formal representation model for guidelines, created by the InterMed Collaboratory as a proposed basis for a shared representation. GLIF currently addresses the process of authoring and dissemination; the InterMed team's major focus now is on tools to facilitate these tasks and the mapping to clinical information system environments. Because of limitations in what can be done by a single team with finite resources, however, and the variety of additional perspectives that need to be accommodated, the InterMed team has determined that further development of a shared representation would be best served as an open process in which the world community is engaged. Under the auspices of the HL7 Decision Support Technical Committee, a GLIF Special Interest Group has been established, which is intended to be a forum for collaborative refinement and extension of a standard representation that can support the needs of the guideline lifecycle. Significant areas for future work will need to include demonstrations of effective means for incorporating guide-lines at point of care, reconciliation of functional requirements of different models and identification of those most important for supporting practical implementation, im-proved means for authoring and management of complexity, and methods for automatically analyzing and validating syntax, semantics, and logical consistency of guidelines. PMID- 11604735 TI - Visualizing complex notions of time. AB - Time plays an important role in medicine. Conditions are not just evaluated at single instances in time, but traced over periods. Medications must be administered within specified temporal limits, and their effects observed with regard to time. When planning treatments, the temporal aspect becomes even more complicated. The planner has to deal with uncertainty and allowable intervals. A visual representation of the information would be helpful, but there are few visualizations of time that are powerful enough. We present a visualization that graphically represents a complex notion of time, and has also been implemented in a program that allows users to directly specify this information. The results of a small user study are reported. PMID- 11604736 TI - Aggregating UMLS semantic types for reducing conceptual complexity. AB - The conceptual complexity of a domain can make it difficult for users of information systems to comprehend and interact with the knowledge embedded in those systems. The Unified Medical Language System (UMLS) currently integrates over 730,000 biomedical concepts from more than fifty biomedical vocabularies. The UMLS semantic network reduces the complexity of this construct by grouping concepts according to the semantic types that have been assigned to them. For certain purposes, however, an even smaller and coarser-grained set of semantic type groupings may be desirable. In this paper, we discuss our approach to creating such a set. We present six basic principles, and then apply those principles in aggregating the existing 134 semantic types into a set of 15 groupings. We present some of the difficulties we encountered and the consequences of the decisions we have made. We discuss some possible uses of the semantic groups, and we conclude with implications for future work. PMID- 11604737 TI - Building a knowledge base to support a digital library. AB - As part of an effort to develop a knowledge base to support searching online medical literature according to individual needs, we have studied the possibility of using the co-occurrence of MeSH terms in MEDLINE citations associated with the search strategies optimal for evidence based medicine to automated construction of a knowledge base. This study evaluates the relevance of the relationships between the semantic relationship pairs generated by the process, and the clinical validity of the semantic types involved in the process. From the semantic pairs proposed by our method, a group of clinicians judge sixty percent to be relevant. The remaining forty percent included semantic types considered unimportant by clinicians. The knowledge extraction method showed reasonable results. We believe it can be appropriate for the task of retrieving information from the medical record in order to guide users during a searching and retrieval process. Future directions include the validation of the knowledge, based on an evaluation of system performance. PMID- 11604738 TI - An automated tool for an analysis of compliance to evidence-based clinical guidelines. AB - Evidence-based clinical guidelines have been developed in an attempt to decrease practice variation and improve patient outcomes. Although a number of studies and a few commercial products have attempted to measure guideline compliance, there still exists a strong need for an automated product that can take as input large amounts of data and create systematic and detailed profiles of compliance to evidence-based guidelines. The Guideline Compliance Assessment Tool is a product presently under development in our group that will accept as input medical and pharmacy claims data and create a guideline compliance profile that assesses provider practice patterns as compared to evidence-based standards. The system components include an episode of care grouper to standardize classifications of illnesses, an evidence-based guideline knowledge base that potentially contains information on several hundred distinct conditions, a guideline compliance scoring system that emphasizes systematic guideline variance rather than random variances, and an advanced data warehouse that would allow drilling into specific areas of interest. As provider profiling begins to shift away from a primary emphasis on cost to an emphasis on quality, automated methods for measuring guideline compliance will become important in measuring provider performance and increasing guideline usage, consequently improving the standard of care and the potential for better patient outcomes. PMID- 11604739 TI - Enabling guidelines for computer-based decision support--process and tools. AB - Many guideline only implicitly or vaguely define the process of health care delivery. However, an explicit model of the medical tasks comprising this process is needed before active decision support at the patient encounter can take place. We propose to use a structured, but semi-formal representation as intermediate step in the process of enacting a guideline. This allows for the application independent representation of the content of a guideline enabled for decision support. The process and the tools of the methodology have been applied to enable guidelines from the field of Diabetes mellitus. PMID- 11604740 TI - The nursing terminology summit: collaboration for progress. AB - The Nursing Terminology Summit has used collaborative processes to bring about significant changes in the development of terminology standards for nursing. This paper draws on agendas, reports, notes, and other documents from the Summit, in addition to the authors' own experience as Organizer, Steering Committee, and participants, to provide a brief history of the Summit process. The analysis identifies factors that increased the risk of failure as well as factors that fostered success. The paper concludes with lessons learned that can be applied in other arenas to promote change in medical informatics. PMID- 11604741 TI - Handling expressiveness and comprehensibility requirements in GLIF3. AB - Clinical guidelines are aimed at standardizing patient care and improving its quality and cost effectiveness. Guidelines represented in a computer interpretable (CI) format can be used to provide automatic decision support applied to individual patients during the clinical encounter. The process of creating computer-interpretable guidelines (CIG) re-moves ambiguities contained in paper-based guidelines, thus making the guideline more comprehensible. For these reasons, CIGs may have a larger impact on clinician behavior than paper based guidelines. Since much effort goes into creating guidelines in a CI format, it is desirable that different institutions and software systems share them. In a guideline representation workshop hosted by the InterMed Collaboratory in March 2000, the need for a standard representation format for sharable CIGs was recognized. As a first step towards achieving this goal, we proposed a set of functional requirements for sharable CIGs. The requirements encompass the entire life cycle of a CIG: development, implementation, use and maintenance. In this paper we discuss requirements that are important during the development stage of a CIG. We have abstracted the requirements into two groups: expressiveness--the ability to ex-press the knowledge content of different types of guidelines--and comprehensibility--the ability to manage complexity, facilitate coherence, and visualize a guideline model to aid in human comprehension. The Guideline Interchange For-mat version 3 (GLIF3) is a language for structured representation of CIGs. It is under development to facilitate sharing CIGs among different institutions and systems. We illustrate how GLIF3 meets the specified development requirements. PMID- 11604742 TI - The interface between information, terminology, and inference models. AB - The interface between information, terminology, and inference (problem solving) models is now a central issue for the development of standards and of principled information systems. There is potential overlap amongst the models, and principled means are required to choose how to allocate information items amongst them. Any given set of choices implies mutual constraints and obligations amongst the models which together form a well defined interface allowing work on each to proceed independently of the other. This paper outlines the criteria for these choices and a possible notation for recording these choices and their consequences. PMID- 11604743 TI - Development of a template model to represent the information content of chest radiology reports. AB - The authors describe the application of a methodology for developing representational models for loosely structured medical domains. The methodology is subdivided in two interrelated tasks: terminology acquisition and template generation. The methodology is applied to the domain of chest radiology, producing a domain-specific lexicon and a series of templates to represent all the relevant clinical information stated on a chest x-ray report. Details about the successive application of the methodology and the resulting versions of the lexicon and templates are presented. The most relevant aspects of the methodology utilization are discussed and compared with evidence from other authors. PMID- 11604744 TI - GALEN ten years on: tasks and supporting tools. AB - The GALEN technology has matured over more than a decade of use. We describe a set of software tools and associated methodologies that together are supporting ontological engineering in a production, rather than a research setting. PMID- 11604746 TI - Indexing medical WWW documents by morphemes. AB - Assisting users to search medical information on the WWW is here considered from two perspectives--the linguistic complexity of medical terms, nominal compounds in particular, and cross-lingual relationships between monolingual medical terminologies. In order to solve the first problem, we present an approach to automatic indexing in which medically plausible morphological units are used. Semantic value is added to these index terms by a compact domain-specific thesaurus. We further discuss tools for morphological segmentation and morphosemantic normalization of HTML documents, as well as an adaptation of a standard WWW search engine for morpheme-based retrieval. The second problem, cross-lingual medical document retrieval, is dealt with by defining cross-lingual equivalence relations on the emerging morpheme sets. PMID- 11604745 TI - Comparing general and medical texts for information retrieval based on natural language processing: an inquiry into lexical disambiguation. AB - In this paper we compare two types of corpus, focusing on the lexical ambiguity of each of them. The first corpus consists mainly of general newspaper articles and literature excerpts, while the second belongs to the medical domain. To conduct the study, we have used two different disambiguation tools. First, each tool was validated in its respective application area. We then use these systems in order to assess and compare both the general ambiguity rate and the particularities of each domain. Quantitative results show that medical documents are lexically less ambiguous than unrestricted documents. Our conclusions emphasize the importance of the application area in the design of NLP tools. PMID- 11604747 TI - An approach to guideline implementation with GEM. AB - Implementation of practice guidelines refers to the creation of strategies and systems to operationalize the knowledge and recommendations set forth by guideline developers. We describe an approach to guideline implementation that makes direct use of the guideline document as a knowledge base. The Guideline Elements Model (GEM) provides an XML-based guideline document model that facilitates implementation of guidelines. Knowledge extraction using GEM requires document markup rather than programming and can promote authenticity and consistent knowledge encoding. Knowledge customization for the local enterprise requires addition of meta-information to pertinent components of the GEM hierarchy in a design database. GEM provides an audit trail to track local adaptation. Knowledge integration with patient data can be promoted using information management services. A design goal is to devise a system that can be applied by local clinical domain experts, quality assurance experts, and information systems programmers without requiring trained informaticians and knowledge engineers to serve as intermediaries PMID- 11604748 TI - Indexing of medical diagnoses by word affinity method. AB - Automated coding of medical diagnoses is still an unsolved problem. Our goal in recent work was to find efficient, cheap and easy to implement method to assist the work of human encoders in hospitals. The proposed method is based on a vector space model especially adapted to deal with short expressions, like clinical diagnoses. Using a set of coded diagnoses the co-occurrence of codes and words is more or less characteristic. The method describes these characteristics mathematically, by introduction of the so-called word adhesion. Two human encoders were asked to code the same set of 92 clinical diagnoses. Their results were compared to the ranked list of codes, produced by the computer. The results were better where the two human encoders agreed, and the overall results demonstrate the feasibility of the approach. PMID- 11604749 TI - Modeling data and knowledge in the EON guideline architecture. AB - Compared to guideline representation formalisms, data and knowledge modeling for clinical guidelines is a relatively neglected area. Yet it has enormous impact on the format and expressiveness of decision criteria that can be written, on the inferences that can be made from patient data, on the ease with which guidelines can be formalized, and on the method of integrating guideline-based decision support services into implementation sites' information systems. We clarify the respective roles that data and knowledge modeling play in providing patient specific decision support based on clinical guidelines. We show, in the context of the EON guideline architecture, how we use the Protege-2000 knowledge engineering environment to build (1) a patient-data information model, (2) a medical-specialty model, and (3) a guideline model that formalizes the knowledge needed to generate recommendations regarding clinical decisions and actions. We show how the use of such models allows development of alternative decision criteria languages and allows systematic mapping of the data required for guideline execution from patient data contained in electronic medical record systems. PMID- 11604750 TI - Representation of clinical practice guidelines for computer-based implementations. AB - Representation of clinical practice guidelines is a critical issue for computer based guideline development, implementation and evaluation. We studied eight types of computer-based guideline representation models. Typical primitives for these models include decisions, actions, patient states and execution states. Temporal constraints and nesting are important aspects of guideline structure representation. Integration of guidelines with electronic medical records can be facilitated by the introduction of formal models of patient data. Patient states and execution states are closely related to one another. Data collection, decision, patient state and intervention are four basic steps in a guideline's logic flow. PMID- 11604751 TI - Building a text corpus for representing the variety of medical language. AB - Medical language processing has focused until recently on a few types of textual documents. However, a much larger variety of document types are used in different settings. It has been showed that Natural Language Processing (NLP) tools can exhibit very different behavior on different types of texts. Without better informed knowledge about the differential performance of NLP tools on a variety of medical text types, it will be difficult to control the extension of their application to different medical documents. We endeavored to provide a basis for such informed assessment: the construction of a large corpus of medical text samples. We propose a framework for designing such a corpus: a set of descriptive dimensions and a standardized encoding of both meta-information (implementing these dimensions) and content. We present a proof of concept demonstration by encoding an initial corpus of text samples according to these principles. PMID- 11604752 TI - Health informatics: managing information to deliver value. AB - Can informatics improve health? This paper answers yes, exploring its components, benefits, and effect on a wide variety of health-related activities. We first examine how information technology enables health informatics, supporting information management and knowledge creation through its four cornerstones. Success factors in using informatics are covered next, including human factors, the role of trained health informaticians, and the importance of matching informatics initiatives with business goals and establishing and measuring value. We demonstrate the potential effect of the Internet on health services through such e-health applications as enterprise-wide patient records, state-of-the-art call centers, and data repositories. For current evidence that informatics is already improving health, we turn to such topics as disease management, telehealth, patient safety, and decision support. As more organizations move informatics from theory into practice and realize its value, they will transform inefficient processes and improve care for all. PMID- 11604753 TI - HONselect: multilingual assistant search engine operated by a concept-based interface system to decentralized heterogeneous sources. AB - Any new user to the Internet will think that to retrieve the relevant document is an easy task especially with the wealth of sources available on this medium, but this is not the case. Even experienced users have difficulty formulating the right query for making the most of a search tool in order to efficiently obtain an accurate result. The goal of this work is to reduce the time and the energy necessary in searching and locating medical and health information. To reach this goal we have developed HONselect [1]. The aim of HONselect is not only to improve efficiency in retrieving documents but to respond to an increased need for obtaining a selection of relevant and accurate documents from a breadth of various knowledge databases including scientific bibliographical references, clinical trials, daily news, multimedia illustrations, conferences, forum, Web sites, clinical cases, and others. The authors based their approach on the knowledge representation using the National Library of Medicine's Medical Subject Headings (NLM, MeSH) vocabulary and classification [2,3]. The innovation is to propose a multilingual "one-stop searching" (one Web interface to databases currently in English, French and German) with full navigational and connectivity capabilities. The user may choose from a given selection of related terms the one that best suit his search, navigate in the term's hierarchical tree, and access directly to a selection of documents from high quality knowledge suppliers such as the MEDLINE database, the NLM's ClinicalTrials.gov server, the NewsPage's daily news, the HON's media gallery, conference listings and MedHunt's Web sites [4, 5, 6, 7, 8, 9]. HONselect, developed by HON, a non-profit organisation [10], is a free online available multilingual tool based on the MeSH thesaurus to index, select, retrieve and display accurate, up to date, high-level and quality documents. PMID- 11604754 TI - Doc'CISMEF: a search tool based on "encapsulated" MeSH thesaurus. AB - In the year 2000, the Internet became a major source of health information for the health professional and the Netizen. The objective of Doc'CISMeF (D'C) was to create a powerful generic search tool based on an structured information model which a encapsulates' the MeSH thesaurus to index and retrieve quality health resources on the Internet. To index resources, D'C uses four sections in its information model: 'meta-term', keyword, subheading, and resource type. Two search options are available: simple and advanced. The simple search requires the end-user to input a single term or expression. If this term belongs to the D'C information structure model, it will be exploded. If not, a full-text search is performed. In the advanced search, complex searches are possible combining Boolean operators with meta-terms, keywords, subheadings and resource types. D'C uses two standard tools for organising information: the MeSH thesaurus and the Dublin Core metadata format. Resources included in D'C are described according to the following elements: title, author or creator, subject and keywords, description, publisher, date, resource type, format, identifier, and language. PMID- 11604755 TI - Kaiser Permanente's "metadata-driven" national clinical intranet. AB - This paper describes the approach taken to build Kaiser Permanente's national clinical intranet. A primary objective for the site is to facilitate resource discovery, which is enabled by the use of "metadata", or data (fields and field values) that describe the various resources available. Users can perform full text queries and/or fielded searching against the metadata. Metadata serves as the organizing principle of the site--it is used to index documents, sort search results, and structure the site's table of contents. The site's use of metadata- what it is, how it is created, how it is applied to documents, how it is indexed, how it is presented to the user in the search and the search results interface, and how it is used to construct the table of contents for the web site--will be discussed in detail. The result is that KP's national clinical intranet has coupled the power of Internet-like full text search engines with the power of MedLine-like fielded searching in order to maximize search precision and recall. Organizing content on the site in accordance with the metadata promotes overall consistency. Issues currently under investigation include how to better exploit the power of the controlled terminology within the metadata; whether the value gained is worth the cost of collecting metadata; and how automatic classification algorithms might obviate the need for manual document indexing. PMID- 11604756 TI - Analysis and modelling of the multi-professional treatment process: preliminary results. AB - This paper presents first results of a research project aimed at improving co operative work initiatives in hospitals. A holistic analysis of the treatment process is presented as a precondition for process reengineering, quality measurements and improvement of multi-professional co-operation. Treatment process modelling attempts within the last years have concentrated on specialised points of views, such as business process modelling or communication modelling. In contrast, we have developed a framework consisting of several views of the treatment process. We tested our framework in a broad system analysis within the Department of Child and Adolescent Psychiatry of the Heidelberg University Hospitals. Our preliminary results support the framework. Weaknesses were described precisely in both the field of organisational procedures and information management. PMID- 11604757 TI - Characterization of heart atrial fibrillation: proposal for a deterministic model. AB - Atrial Fibrillation (AFib) has been shown (e.g. Framingham Study) to increase stroke risk and to induce low cardiac output in patients. It is generally accepted that the mechanism of Atrial Fibrillation is reentry. In order to ease the study of AFib's, we propose a deterministic model that could be used in the characterization cardiac signals. The model is based on a linear combination of several "Atrial Flutter"-like signals. We therefore obtained AFib-like aspects. To demonstrate its usefulness we performed a power spectrum transform (i.e. scalar Fast Fourier Transform) of this model. As a result we found that this transform could not be used as is, could lead to errors in the interpretation of results. We expect that this model will help us to evaluate the relevance of mathematical transforms. This may lead to new findings in the classification of AFib, as well as to improvements in patients treatment, follow-up and survival. PMID- 11604758 TI - A multilingual medical thesaurus browser for patients and medical content managers. AB - This paper introduces a user-friendly browser interface which integrates multilingual search and browsing functionalities within medical thesauri via the internet. The tool is being developed as part of the GIN Austria Patient Information System and is based on an adapted datamodel of the MeSH thesaurus. A prototype offers the possibility to build up queries and export lists of MeSH main headings collected during browsing the relevant MeSH trees. The thesaurus browser can be used both by patients and citizens to build queries based on a controlled vocabulary to match them with existing documents within GIN and by medical information managers to find out appropriate keywords for interactive tagging or indexing of medical contents. A key component of this tool is the flexible choice of different languages of the MeSH datasource as well as of the user interface. Both can be changed independently at any point during a session. Another central aspect is the use of the UMLS Metathesaurus in combination with localized Thesaurus versions due to existing international character set problems. PMID- 11604759 TI - Information needs in primary care: a survey of rural and nonrural primary care physicians. AB - OBJECTIVE: To compare the self-reported information needs of rural and nonrural primary care physicians. DESIGN AND PARTICIPANTS: Mail survey of active non academic primary care physicians. DATA COLLECTION: A 60 item questionnaire regarding 1) demographic and practice setting data; 2) medical information needs; 3) medical knowledge resource availability and use; and 4) physician information seeking behavior. MAIN RESULTS: The response rate was higher among rural than non rural physicians (55% vs. 42%, p< 0.001) and among Family Physicians than others (Family Medicine 53%, Internal Medicine 43%, Pediatrics 48%, p=0.015.) Rural physicians reported working more hours per week (45.3 vs. 42.7, p=0.033,) and seeing more patients per day (24.6 vs. 22.3, p=0.005) than their nonrural counterparts. Both groups reported a median of about 1 question for every 10 patients they see, with great variance among responses. Both groups reported pursuing answers to about 57% of their questions, and finding answers to about 70% of those they pursue. Knowledge resource preferences of the two groups were similar. Both groups reported frequent use of consultants, drug compendia, colleagues, and textbooks, and little use of library- or computer-based sources. Compared to nonrural physicians, rural physicians reported less frequent use of consultants, colleagues, librarians, and bound journals. These differences were small, and paralleled differences in availability. The two groups had equal access to textbooks and drug compendia, but for rural physicians, other resources were locally available significantly less often. CONCLUSIONS: Rural and nonrural primary care physicians reported equal information needs, similar information seeking, and similar resource preferences. Rural physicians reported less access to some information resources, but little difference in use of resources. Further studies are needed to determine how these differences impact rural practitioners and their patients. PMID- 11604760 TI - ARIANE: a mediation framework with health information sources. AB - OBJECTIVES: to design and implement mediators dedicated to access heterogeneous information sources in a homogeneous way. METHOD: processes translate a query into the syntax of a target source built thanks to the UMLS knowledge sources and a catalog of information sources. Communication services connect users with information sources at the point they deliver results. RESULTS: examples show the benefits healthcare professionals may found in searching information in this way. DISCUSSION: improvements on the current developments may be done according to the current architecture of ARIANE. Specially, the user interface should be easier to use than the present one. PMID- 11604761 TI - A new approach to the concept of "relevance" in information retrieval (IR). AB - The concept of "relevance" is the fundamental concept of information science in general and information retrieval, in particular. Although "relevance" is extensively used in evaluation of information retrieval, there are considerable problems associated with reaching an agreement on its definition, meaning, evaluation, and application in information retrieval. There are a number of different views on "relevance" and its use for evaluation. Based on a review of the literature the main problems associated with the concept of "relevance" in information retrieval are identified. The authors argue that the proposal for the solution of the problems can be based on the conceptual IR framework built using a systems analytic approach to IR. Using this framework different kinds of "relevance" relationships in the IR process are identified, and a methodology for evaluation of "relevance" based on methods of semantics capturing and comparison is proposed. PMID- 11604762 TI - Information system for the support of research, diagnosis and therapy of inborn metabolic diseases. AB - We developed an information system for inborn metabolic diseases. The system consists of three parts. The first part is the MD-Cave for information on laboratory findings, genes, enzymes and metabolic pathways. The second part (ASDB) concerns with active agents and their different mechanisms of action inside the metabolic pathway and possible therapeutic treatment of these illnesses. The third part deals with the integration of these and other data bases for easy access to different information. This information system can be helpful for scientists and physicians working in the field of inborn metabolic diseases. PMID- 11604763 TI - Health informatics world wide--a WWW service for the health informatics community. AB - Health Informatics World Wide, a Web index of research and educational institutions in the fields of Health Informatics and Medical Informatics has been available to WWW users since 1995. In this paper we report on the original conception of this service, its subsequent modifications and address its maintenance and related problems. Access statistics are presented which demonstrate its relevance as well as the geographical focus of Health Informatics research and development. PMID- 11604764 TI - An informatics system to support knowledge management in the health sector--the South African National Health Knowledge Network. AB - This paper discusses the planning and development of a South African national health knowledge network. The methodology is in essence based on the principles of knowledge management and the drivers of a system of innovation. The knowledge network, SA HealthInfo, aims to provide a one-stop interactive forum/resource, for quality-controlled and evidence-based health research information, to a wide spectrum of users, at various levels of aggregation, with the necessary security arrangements and facilities for interaction among users to promote explicit (codified) and tacit knowledge flow. It will therefore stimulate the process of innovation within the South African health system. PMID- 11604765 TI - XML transcription method for biomedical acoustic signals. AB - We have proposed applying MIDI technology to coding of biomedical acoustic signals such as heart sounds used in medical diagnosis for constructing medical audio databases. According to our several experiments, we could correspond encoded MIDI event data or musical notes with heart sound components used for clinical diagnosis. However, precise discrimination among abnormal heart sounds and murmurs was difficult owing to insufficiency of analysis precision in our proposed method. Then we have improved its coding precision and supported harmonic or formant analysis in order to extend our application to multimedia low bit-rate audio coding, especially representation of vocal sounds by MIDI codes. In these efforts, we can describe precisely heart-sound components with MIDI codes and segment converted MIDI codes into heart sound components; about 80% automatically in 55 cases. In this paper, we are going to describe our novel heart sound automatic XML transcription method. This XML document includes MIDI data reflecting numerical detailed information for each segmented heart sound component and can reproduce heart sound signals by a browser and MIDI sequencer plug-in. PMID- 11604766 TI - Automatic extraction of acronym-meaning pairs from MEDLINE databases. AB - Acronyms are widely used in biomedical and other technical texts. Understanding their meaning constitutes an important problem in the automatic extraction and mining of information from text. Here we present a system called ACROMED that is part of a set of Information Extraction tools designed for processing and extracting information from abstracts in the Medline database. In this paper, we present the results of two strategies for finding the long forms for acronyms in biomedical texts. These strategies differ from previous automated acronym extraction methods by being tuned to the complex phrase structures of the biomedical lexicon and by incorporating shallow parsing of the text into the acronym recognition algorithm. The performance of our system was tested with several data sets obtaining a performance of 72 % recall with 97 % precision. These results are found to be better for biomedical texts than the performance of other acronym extraction systems designed for unrestricted text. PMID- 11604767 TI - Impact of a modelization of the task allocation problem on the design of a prescription management software for intensive care units. AB - After having studied the coordination in Intensive care Units we have proposed a dynamic model for improving coordination in respect of human control over the work. We have performed simulations for analysing the impact of different strategies on coordination and we have found that our task centred coordination model could be efficient to improve the health care actors coordination and the efficiency of care delivery. We have built a first prototype based on this model. This implementation uses Internet technologies. PMID- 11604768 TI - Comparing frequency of content-bearing words in abstracts and texts in articles from four medical journals: an exploratory study. AB - BACKGROUND: Retrieval tests have assumed that the abstract is a true surrogate of the entire text. However, the frequency of terms in abstracts has never been compared to that of the articles they represent. Even though many sources are now available in full-text, many still rely on the abstract for retrieval. METHODS: 1,138 articles with their abstracts were downloaded from Journal of the American Medical Association, New England Journal of Medicine, Lancet, and the British Medical Journal. Words were extracted from the articles and their abstracts and the frequency of each word was counted in both sources. Each article and its abstract were tested using a chi-squared test to determine if the words in the abstract occurred as frequently as would be expected. RESULTS: 96% of the abstracts tested as samples of the article they represented. CONCLUSION: In these four journals, the abstracts are lexical, as well as intellectual, surrogates for the documents they represent. PMID- 11604769 TI - Reading factor: a bibliometric tool to manage a virtual library. AB - Among the many bibliometric criteria used to evaluate biomedical journals, the impact factor is the most commonly used. Despite its limitations, it quantifies the influence of a journal on secondary publications. It does not however evaluate the practical usefulness of primary documents. Usefulness is field related and varies greatly among specialities. We introduce a new bibliographic criterion, the "reading factor", and define it as the ratio between the number of electronic consultations of a particular journal (i.e., number of clicks on a hyper-link) and the mean number of electronic consultations of all the journals studied (itself calculated by dividing the total number of electronic accesses by the number of journals in the database). We describe its observed distribution, relative to that of the impact factor, based on electronic consultation records from our University Hospital medical digital library, where full-text electronic versions of 45 major biomedical journals have been available since December 1997. From this analysis we found no correlation between the 1999 reading factor and the 1998 impact factor of these 45 journals, and we observed a dramatic change in the hierarchy of journals upon using the reading factor as the yardstick rather than the impact factor. Moreover, we describe how using the reading factor has helped in managing the collection of our University Hospital's virtual library. The selection of journals to be discarded from the virtual library for the year 2001 was based on journals' RF values and this process will repeated over the coming years. The reading factor also permits a cost-analysis of a virtual library. CONCLUSION: The measurement of the reading factor is highly automated, practical and efficient. It appears as a new tool for electronic collection management by librarians, well fitting with economical data. PMID- 11604770 TI - Enhancing retrieval of best evidence for health care from bibliographic databases: calibration of the hand search of the literature. AB - BACKGROUND: Medical practitioners have unmet information needs. Health care research dissemination suffers from both "supply" and "demand" problems. One possible solution is to develop methodologic search filters ("hedges") to improve the retrieval of clinically relevant and scientifically sound study reports from bibliographic databases. To develop and test such filters a hand search of the literature was required to determine directly which articles should be retrieved, and which not retrieved. OBJECTIVE: To determine the extent to which 6 research associates can agree on the classification of articles according to explicit research criteria when hand searching the literature. DESIGN: Blinded, inter rater reliability study. SETTING: Health Information Research Unit, McMaster University, Hamilton, Ontario, Canada. PARTICIPANTS: 6 research associates with extensive training and experience in research methods for health care research. MAIN OUTCOME MEASURE: Inter-rater reliability measured using the kappa statistic for multiple raters. RESULTS: After one year of intensive calibration exercises research staff were able to attain a level of agreement at least 80% greater than that expected by chance (kappa statistic) for all classes of articles. CONCLUSION: With extensive training multiple raters are able to attain a high level of agreement when classifying articles in a hand search of the literature. PMID- 11604771 TI - Is the internet an integral part of general practice in Australia? AB - Computerisation has seen significant changes in information management and procedures in General Practice. Whilst the majority of changes to date, have been apparent in administration, the clinical aspect of primary care is now increasingly taking advantage of the computer and significantly, the Internet. The professional obligation to maintain currency in medical developments has provided an opportunity to use the Internet as a low cost method to access a wide range of medical research information worldwide. Furthermore traditional methods of communication within the medical community have the potential to be transformed by the availability and use of electronic communication techniques such as email. The incorporation of these new technologies in clinical practice is not without its challenges, and includes quality, timeliness, information management and attitudes to Internet based information. This paper presents the results of a preliminary study of GP's undertaken in Western Australia analysing the usage of, and attitude to, the Internet in clinical practice. PMID- 11604772 TI - Patient and clinician vocabulary: how different are they? AB - Consumers and patients are confronted with a plethora of health care information, especially through the proliferation of web content resources. Democratization of the web is an important milestone for patients and consumers since it helps to empower them, make them better advocates on their own behalf and foster better, more-informed decisions about their health. Yet lack of familiarity with medical vocabulary is a major problem for patients in accessing the available information. As a first step to providing better vocabulary support for patients, this study collected and analyzed patient and clinician terms to confirm and quantitatively assess their differences. We also analyzed the information retrieval (IR) performance resulting from these terms. The results showed that patient terminology does differ from clinician terminology in many respects including misspelling rate, mapping rate and semantic type distribution, and patient terms lead to poorer results in information retrieval. PMID- 11604773 TI - Implementation of an expert system to determine eligibility and priorities for bone marrow transplants. AB - The Bone Marrow Transplant Unit (BMTU) (Servico de Transplante de Medula Ossea) at HC-UFPR, in Curitiba, Brazil, commonly receives a large number of candidates for bone marrow transplants (BMT). Managing information on the BMTU's waiting list is extremely complex and vital to services as eligibility and priorities are established with implications on both pre and post transplant survival. Consequently, physicians working at the BMTU have to regularly evaluate each candidate to determine his or her eligibility and priority for a BMT. This report describes the implementation of an expert system (ES) in aiding the assessment of candidates for BMT. The ES prototype was created as a means to help healthcare providers define eligibility and priority by using production rules and the Bayesian net (BN). Some factors contributed a lot to test and to validate the systems of this project. Real cases were tested, therefore BMTU presents a database (DB) with all the patients that are awaiting transplant. The system was capable of determining all the patients' eligibility with the diagnosis of Chronic Myeloid Leukemia (CML) and to indicate transplant priority. PMID- 11604774 TI - A before-after study using OncoDoc, a guideline-based decision support-system on breast cancer management: impact upon physician prescribing behaviour. AB - Guideline-based decision support systems have been developed to influence the prescribing behaviour of clinicians, but they have not yet shown to increase physician compliance with best practices in routine. OncoDoc is a non-automated system that allows flexibility in guideline interpretation to obtain best patient specific recommendations at the point of care. OncoDoc is applied to breast cancer management. We have experimented the system at the Institut Gustave Roussy with a before-after study in which treatment decisions for breast cancer patients were measured before and after using the system in order to evaluate its impact upon physicians' prescribing behaviour. After 4 months, 127 decisions were recorded. Physicians compliance with OncoDoc was significantly improved (p < 10( 4) ) to reach 85.03% after using the system. Comparison of initial and final decisions showed that physicians modified their prescription in 31% of the cases. Clinical trial accrual rate increased of 50%, though not statistically significant because estimated on small figures. PMID- 11604775 TI - Development of an intelligent laboratory information system for community health promotion center. AB - This study aimed to develop an Intelligent Laboratory Information System (ILIS) for the community health promotion center in Kwachun city to help process an increasing number of laboratory test data in an efficient manner, and to support the clinical decision-making of public health doctors. A sample of 170 cases was used for validation of the system. Overall, the system correctly predicted 92.5% of the cases. This paper also analyzed the economic feasibility of the ILIS based on the Information Economics approach. The results showed that the ILIS not only helps screen more people by increasing the capacity of a health promotion center, but also brings in more revenue to the center. PMID- 11604776 TI - DIAMED: a probabilistic diagnostic aid system on the web. AB - DIAMED is a system to assist the physicians in the diagnostic process using probabilistic networks as knowledge representation. These networks make it possible to reason on medical data by applying Bayesian methods and to take into account uncertainties of the facts in the resolution of the clinical cases. The proposed model re-uses knowledge contained in an existing knowledge base (ADM). An interface of DIAMED developed on a Web server remotely assists the experts of each medical specialty in updating and validating the knowledge base. Most of the data processing is automated while being based on information preexistent in the ADM base : Constitution of lexicons starting from the existing dictionaries of the ADM system, are then used to work out the requests for selection and update of the knowledge base. One of its assets resides in its pseudo-segmented structure in several layers. The propagation of information is thus limited to only one part of the probabilistic network and calculations are therefore limited. PMID- 11604777 TI - Application of a new logic domain method for the diagnosis of hepatocellular carcinoma. AB - In this paper we describe the application of a new learning tool for the diagnosis of hepatocellular carcinoma. The method adopted operates in the logic domain and presents several interesting features for the development of medical diagnostic systems. We consider a database of 128 patients, 64 of which affected by hepatocellular carcinoma, while the others affected by cirrhosis but not from hepatocellular carcinoma. Each patient is described by a number of attributes measured in non-invasive way. The system, after the training, is able to correctly separate the 64 patients affected by cirrhosis from the others 64 affected by hepatocellular carcinoma and is now ready to produce automatic diagnosis for new patients. The hepatocellular carcinoma is one of the most widely spread malignant tumors in the world. The ability to detect the tumor in its early stages in a minimally invasive way is crucial to the treatment of patients with this disease. PMID- 11604778 TI - Guideline development: focus on breast cancer screening in the EsPeR project. AB - We describe in this paper, the implementation of a clinical practice guideline focused on breast cancer screening. Our aim in conceiving such a computerized guideline was first to help general practitioners in appreciating the risks their female patients might develop breast cancer and secondly to suggest them the screening measures adapted to each particular case. This implementation enables us to present our general methodology to elaborated and promulgate guidelines within the EsPeR project. This methodology aims at providing guidelines based on knowledge validated according to the EBM principles, that can be used in real time and updated according to current knowledge. PMID- 11604779 TI - A neural network approach for predicting and modelling the dynamical behaviour of cardiac ventricular repolarisation. AB - Physiological signals are usually patient specific, and they are difficult to predict, especially for the cardiovascular system. New methods capable to be adapted to each case and to learn the singular behavior of heart functions should be developed to support physicians in their decision-making. One of the most widely studied relations is the QT-RR one, between the total duration of the ventricle activation and inactivation, and the heart rate. In the past, different studies were made to approach this relation in the steady state. In this paper, a new method for modeling and predicting the transient dynamic behaviour of QT interval in relation to changing RR intervals is presented using artificial neural networks. PMID- 11604780 TI - Influence of missing values on artificial neural network performance. AB - The problem of databases containing missing values is a common one in the medical environment. Researchers must find a way to incorporate the incomplete data into the data set to use those cases in their experiments. Artificial neural networks (ANNs) cannot interpret missing values, and when a database is highly skewed, ANNs have difficulty identifying the factors leading to a rare outcome. This study investigates the impact on ANN performance when predicting neonatal mortality of increasing the number of cases with missing values in the data sets. Although previous work using the Canadian Neonatal Intensive Care Unit (NICU) Network s database showed that the ANN could not correctly classify any patients who died when the missing values were replaced with normal or mean values, this problem did not arise as expected in this study. Instead, the ANN consistently performed better than the constant predictor (which classifies all cases as belonging to the outcome with the highest training set a priori probability) with a 0.6-1.3% improvement over the constant predictor. The sensitivity of the models ranged from 14.5-20.3% and the specificity ranged from 99.2- 99.7%. These results indicate that nearly 1 in 5 babies who will eventually die are correctly classified by the ANN, and very few babies were incorrectly identified as patients who will die. These findings are important for patient care, counselling of parents and resource allocation. PMID- 11604781 TI - Are clinicians correct when they believe they are correct? Implications for medical decision support. AB - The process of clinical decision support is linked to the validity of clinicians' confidence in their judgments. Clinicians who are appropriately confident-highly confident when they are correct and less confident when they are incorrect-will access computer-based and other information resources only when they are needed. Clinicians who are consistently underconfident will rely on external resources when they are not needed. Those who are overconfident, who believe they are correct when in fact they are not, will be prone to medical errors. An extensive literature indicates a general tendency toward overconfidence in human judgment. This study explores the relationship between confidence and "correctness", across three levels of clinical experience, in the task domain of diagnosis in internal medicine. We created detailed synopses of 36 diagnostically challenging cases and divided them into four equivalent sets of nine cases each. We asked 216 subjects at three experience levels (72 senior medical students, 72 senior medical residents, and 72 faculty attendings) to generate a differential diagnosis for each of the nine cases in one randomly-assigned set, and simultaneously to indicate their level of confidence in each of their diagnoses. We then examined the relationship between the correctness of these diagnoses (the appearance of the correct diagnosis anywhere in the hypothesis list) and these confidence judgments, for all subjects and separately for subjects at each experience level. Results indicate a small but statistically significant relationship associating correctness with higher confidence for all subjects (Kendall's tau b =.-106;p <.0001). This statistical relationship is strongest for the students ( tau b =. 121;p <.001), somewhat lesser but still significant for the faculty-level attendings ( tau b =.-103;p <.005), and non-significant ( tau b =.-041 ) for the residents. (The negative correlations are a coding artifact.) Subjects in this study showed a tendency toward underconfidence: they had low confidence in correct diagnoses more often than they had high confidence when wrong. Nonetheless, they were overconfident and thus "error prone" for 17% of cases overall. The medical students were possibly overmatched by the difficulty of the cases, so their concordance between confidence and correctness may have resulted from an awareness that they were often guessing. The relatively low concordance seen in the residents and attendings makes a strong argument that decision support systems to reduce medical errors should include both "push" and "pull" models. In sum, these results indicate that medical decision support systems cannot rely exclusively on clinicians' perceptions of their information needs, as such perceptions will frequently be incorrect. PMID- 11604782 TI - Risk assessment in genetics: a semi-quantitative approach. AB - Public awareness of genetic predisposition to diseases such as breast cancer threatens to put severe strain on genetics services. Computer-based decision support for general practitioners (GPs) has the potential to reduce unnecessary referrals, but issues of communicating about levels of risk and uncertainty must be addressed. An argumentation logic formalism can subsume both traditional probability theory and more qualitative, reason-based approaches to communicating uncertainty, and we propose that qualitative, argument-based presentation will make uncertainty information more accessible and comprehensible to both patient and GP. We describe software that uses an argumentation approach to assess genetic risk during a GP consultation and provide referral advice along with detailed qualitative explanations for its advice. The software was evaluated in real-life GP consultations in which actors played patients concerned about genetic risk, and in use by GPs evaluating simulated cases. Significant improvement in accuracy of assessment and appropriateness of referrals was found. GPs viewed the software and the qualitative reporting approach highly favourably. PMID- 11604783 TI - Medical decision support via the internet: PROforma and Solo. AB - This paper describes the development and application of an integrated technology to support the authoring of intelligent medical knowledge services, such as decision and guideline support, and disseminate them over the Internet. Decision support and guideline enactment are provided by the PROforma technology which is described in detail elsewhere. Solo is a communications infrastructure that supports the delivery of PROforma services over the Internet using a web browser. The PROforma-Solo technology brings together techniques from knowledge engineering and artificial intelligence with software engineering and the Internet to flexibly support decision making and patient management at the point of care. A variety of clinical applications have been implemented and are briefly described. PMID- 11604784 TI - A comprehensive computerized critical laboratory results alerting system for ambulatory and hospitalized patients. AB - Automatic alerting systems for key events in medical practice have been proven effective in improving the clinician's response to the event. Most of the systems described in current literature are hospital based, some in intensive care units. We designed a clinical alerting system that screens laboratory results of both hospitalized patients and most of Israel's Southern region ambulatory patients for critical results, using an integrative CDR and its interfaces to the hospital's laboratory information systems. New alerts can be defined and activated using a rule editor. Alerts are generated by screening all new laboratory results that are entered in to the CDR, by a decision engine. The alerts are dispatched to clinicians through a customizable preferred alerting device that can be either e-mail, fax or cellular phone SMS, and enables additional alerting devices as they become available. Clinicians may customize both the alerting method and the critical levels for alert generation, according to individual specific needs. We hope that this versatile and customizable alerting system will suite the needs of both the hospital and the community clinical staff. The system will be implemented and tested in the near future. PMID- 11604785 TI - On classification capability of neural networks: a case study with otoneurological data. AB - We investigated the capability of multilayer perceptron neural networks and Kohonen neural networks to recognize difficult otoneurological diseases from each other. We found that they are efficient methods, but the distribution of a learning set should be rather uniform. Also it is important that the number of learning cases is sufficient. If the two mentioned conditions are satisfied, these neural networks are similarly efficient as some other machine learning methods. The conditions are known in the theory of neural networks [1,2], but not often taken seriously in practice. Both networks functioned as well, excluding the case with several input variables, where the Kohonen neural networks surpassed the perceptron. PMID- 11604786 TI - A design and prototype for a decision-support system in the field of urinary tract infections--application of OpenGALEN techniques for indexing medical information. AB - Differences in expert and end-user contexts may be detrimental to the use of decision-support systems. A way to attend to this problem is to triangulate decision-support methods and information sources such as in the case of the expertext system model. To organize the information contained in the system, a common domain model is suggested as a instrument for annotating information. In this paper, a design and a prototype for a decision-support system in the field of urinary tract infections using techniques and methods developed in the GALEN projects is presented. PMID- 11604787 TI - Knowledge-based interpretation of toxoplasmosis serology test results including fuzzy temporal concepts--the ToxoNet system. AB - Transplacental transmission of Toxoplasma gondii from an infected, pregnant woman to the unborn that occurs with a probability of about 60 percent [1] results in fetal damage to a degree depending on the gestational age. The computer system ToxoNet processes the results of serological antibody tests having been performed during pregnancy by means of a knowledge base containing medical knowledge on the interpretation of Toxoplasmosis serology tests. By applying this knowledge ToxoNet generates interpretive reports consisting of a diagnostic interpretation and recommendations for therapy and further testing. For that purpose it matches the results of all serological investigations of maternal blood with the content of the knowledge base returning complete textual interpretations for all given findings. The interpretation algorithm derives the stage of maternal infection from these that is used to infer the degree of fetal threat. To consider varying immune responses of particular patients, certain time intervals have to be kept between two subsequent tests in order to guarantee a correct interpretation of the test results. These time intervals are modelled as fuzzy sets, since they allow the formal description of the temporal uncertainties. ToxoNet comprises the knowledge base, an interpretation system, and a program for the creation and modification of the knowledge base. It is available from the World Wide Web by starting a standard browser like the Internet Explorer or the Netscape Navigator. Thus ToxoNet supports the physician in Toxoplasmosis diagnostics and in addition allows to adopt the way of making decisions to the characteristics of the particular laboratory by modifying the underlying knowledge base. PMID- 11604788 TI - Neural network and wavelet recognition of facial electromyographic signals. AB - The present aim was to explore the possibilities of using neural networks for recognizing significant changes in electrical activity of human facial muscles. We used multilayer perceptron neural networks to recognize bursts of electromyographic signals recorded with bipolar surface electrodes from two subject's facial muscles. Wavelets were applied for the detection of high frequency components of electromyographic signals. Coefficients of wavelets were used as an input to a neural network in order to differentiate bursts from the signals. The results showed that the recognition of bursts was very successful resulting to 84-97 percent total accuracies. The results were very encouraging and suggest further that the measurement of facial muscle activity may be a potentially useful computer input signal, for example, for affective computing which can be seen as a future versatile interaction between the computer and the user. PMID- 11604789 TI - Automatic identification of patients eligible for a pneumonia guideline: comparing the diagnostic accuracy of two decision support models. AB - BACKGROUND: In busy clinical settings, physicians often do not have enough time to identify patients for specific therapeutic guidelines. As a solution, decision support systems could automatically identify eligible patients and trigger computerized guidelines for specific diseases. Applying this idea to community acquired pneumonia (CAP), we developed a Bayesian network (BN) and an artificial neural network (ANN) for identifying patients who have CAP and are eligible for a pneumonia guideline. OBJECTIVE: The aim of this study was to determine whether the diagnostic accuracy of these two decision support models differs in terms of identifying CAP patients. METHODS: We trained and tested the networks with a data set of 32,662 adult patients. For each network, we (1) calculated the specificity, the positive predictive value (PPV), and the negative predictive value (NPV) at a sensitivity of 95%, and (2) determined the area under the receiver operating characteristic curve (AUC) as a measure of overall accuracy. We tested for statistical difference between the AUCs using the correlated area z statistic. RESULTS: At a sensitivity of 95%, the respective values for specificity, PPV, and NPV were: 92.3%, 15.1%, and 99.9% for the BN, and 94.0%, 18.6%, and 99.9% for the ANN. The BN had an AUC of 0.9795 (95% CI: 0.9736, 0.9843), and the ANN had an AUC of 0.9855 (95% CI: 0.9805, 0.9894). The difference between the AUCs was statistically significant (p=0.0044). CONCLUSIONS: The networks achieved high overall accuracies on the testing data set. Because the difference in accuracies is statistically significant but not clinically significant, both networks are equally suited to drive a guideline. PMID- 11604790 TI - Intelligent knowledge retrieval for decision support in medical applications. AB - Knowledge management and retrieval are key issues to be addressed in the medical domain, where a large amount of information is generally available, and where the expert's skills need to be properly shared across the organisation, with the aim of improving the quality of care. Case Based Reasoning (CBR) is a very well suited methodology for the Knowledge Management task, when knowledge is in the operative form. Nevertheless, also well-assessed, formalised medical knowledge, such as clinical guidelines, should be made available to physicians in order to optimise their reasoning process. To take advantage of both knowledge types, we have defined a Multi Modal Reasoning methodology, that integrates CBR and Rule Based Reasoning, for supporting context detection, information retrieval and therapy revision in diabetes care. PMID- 11604791 TI - On conceptualization of a decision support system in health informatics. AB - A decision support system can be approached from two major disciplinary perspectives, those of information systems science (IS) and artificial intelligence (AI). We present in this study an extended ontology for a decision support system in health informatics, which is founded on experience from related research fields as well as being informed by our case studies. The ontology emphasises the need to cover environmental and contextual variables as an integral part of a decision support systems development methodology. With the addition of these variables, the focus in decision support systems development shifts from a task ontology towards a domain ontology. The results of this study help the system developers to take the system's context into account through the set of defined variables that are linked to the application domain. These variables explicate relevant constructs and present a vocabulary for a decision support system. However, applying the ontology requires a more thorough analysis of the domain and therefore more qualified resources for systems development. This indicates the need to focus more on education and training in health informatics. PMID- 11604792 TI - RASTA: a distributed temporal abstraction system to facilitate knowledge-driven monitoring of clinical databases. AB - The time dimension is very important for applications that reason with clinical data. Unfortunately, this task is inherently computationally expensive. As clinical decision support systems tackle increasingly varied problems, they will increase the demands on the temporal reasoning component, which may lead to slow response times. This paper addresses this problem. It describes a temporal reasoning system called RASTA that uses a distributed algorithm that enables it to deal with large data sets. The algorithm also supports a variety of configuration options, enabling RASTA to deal with a range of application requirements. PMID- 11604793 TI - Employment of intra-individual variability to improve computerized ECG interpretation. AB - One of the reasons for the limited practical utility of computer programs for interpretation of electrocardiograms (ECGs) is their susceptibility to intra individual variability. Two of the most prominent sources of intra-individual variability in ECGs, electrode placement variations and respiration, were studied for their effects on computerized ECG interpretation. Previous research has shown that the effects of intra-individual variability on computerized ECG interpretation depend largely on the individual ECG. To enable the assessment of chest electrode position variations for individual standard 12- lead ECGs, ECGs resulting from simulations of such position variations were interpreted. Variability due to respiration was assessed by interpreting all individual ECG beats instead of an averaged beat. In this paper two methods are presented that employ information about the intra-individual variability in individual ECGs. The first method provides an estimate of the reliability of the interpretation, the second attempts to improve the interpretation itself. In the first method we quantified the variation in interpretation caused by the two sources of intra individual variability with the use of a stability index, a high index value indicating a low variation in interpretation. This index was subsequently studied using two sets of ECGs. For the first set a a clinical' reference interpretation was obtained from discharge letters. For the second set three cardiologists provided a a cardiologists' reference. The performance of subgroups of ECGs having stability indices higher than a particular value was computed. It appeared that for the a cardiologists' reference, the interpretations of ECGs with a high stability index were more often correct. No effect was found for the a clinical' reference. In the second method we attempted to improve the original interpretation by combining the alternative interpretations into a new interpretation. This was done by taking the median or the average of the quantified alternatives. These combined interpretations proved to perform better than the original interpretation when a cardiologist's interpretation was taken as a reference. This paper shows that intra-individual ECG variability can be used to improve original interpretations. This can be done without having to record multiple ECGs, provided that a model is available to simulate intra individual variability. The presented methods do not depend on the classification algorithm that is used. They can be used both during classifier design to correct imperfections, and in routine use of the classifier to produce more representative classifications. PMID- 11604794 TI - Medical case-based reasoning systems: experiences with architectures for prototypical cases. AB - In this paper we discuss the importance to create prototypes automatically within medical Case-based Reasoning systems. We present some general ideas about prototypes deduced from analyses of our experiences with prototype designs in domain specific medical CBR systems. Four medical Case-based Reasoning systems are described. As they use prototypes for different purposes, the gained improvement is different as well. Furthermore, we claim that the generation of prototypes is an adequate technique to learn the intrinsic case knowledge, especially if the domain theory is weak. PMID- 11604795 TI - Algorithm-based decision rules to safely reduce laboratory test ordering. AB - PURPOSE: Our study develops decision rules to define appropriate intervals at which repeat tests might be indicated for commonly ordered laboratory tests for hospitalized patients. METHODS: The final data set includes 5,632 adult patients admitted to the University of Virginia Hospital between July 1995 and December 1999. These patients had a hospital length of stay of five days or more and had results recorded for three routinely ordered laboratory tests for each of the first five days of their hospitalization. We use the serum potassium test to illustrate our algorithm-based decision rule methodology. RESULTS: Our decision rule begins with testing on the first two days of hospitalization and allows for repeat testing after observation of any non-normal values. The results show that the algorithm-based decision rule would lead to a 34% reduction for serum potassium tests for the first five days of hospitalization. Only one out of the 5,632 patients in our sample had a critical value that occurred only on a non test day and, thus, was missed by the algorithm. CONCLUSIONS: The algorithm results are encouraging. We demonstrate that the number of tests can be reduced while missing critical values in only a small fraction of patients. Testing algorithms such as these can be used to reduce laboratory test ordering without compromising the quality of patient care. PMID- 11604796 TI - ASTI: a guideline-based drug-ordering system for primary care. AB - Existing computer-based ordering systems for physicians provide effective drug centered checks but offer little assistance for optimizing the overall patient centered treatment strategy. Evidence-based clinical practice guidelines have been developed to disseminate state-of-the-art information concerning treatment strategy but these guidelines are poorly used in routine practice. The ASTI project aims to design a guideline-based ordering system to enable general practitioners to avoid prescription errors and to improve compliance with best therapeutic practices. The " critic mode " operates as a background process and corrects the physician's prescription on the basis of automatically triggered elementary rules that account for isolated guideline recommendations. The " guided mode " directs the physician to the best treatment by browsing a comprehensive guideline knowledge base represented as a decision tree. A first prototype, applied to hypertension, is currently under development. PMID- 11604797 TI - Combining diagnosis and treatment using Asbru. AB - Traditionally, diagnosis and treatment have been seen as two distinct tasks. Consequently, most approaches to computer supported health care focus on one of the two - mostly on diagnosis or rather on the interpretation of measurements which is much better understood and formalized. However, in practice diagnosis and treatment overlap and influence each other in many ways. Combinations range from repeatedly going through the diagnosis-treatment loop over a period of time to permanent monitoring of the patients' health condition as it is done in intensive care units. In this paper we describe how to model these combinations using the clinical protocol-representation language Asbru. It implements treatment steps in a hierarchy of skeletal, time-oriented plans. Diagnosis can either be described in a declarative way in the conditions, under which treatment steps are taken or it can be modelled explicitly as plans of their own right. We demonstrate our approach using examples taken from the American Association of Paediatricians' guideline for the treatment of hyperbilirubinemia in the new born. PMID- 11604798 TI - Building an explanation function for a hypertension decision-support system. AB - ATHENA DSS is a decision-support system that provides recommendations for managing hypertension in primary care. ATHENA DSS is built on a component-based architecture called EON. User acceptance of a system like this one depends partly on how well the system explains its reasoning and justifies its conclusions. We addressed this issue by adapting WOZ, a declarative explanation framework, to build an explanation function for ATHENA DSS. ATHENA DSS is built based on a component-based architecture called EON. The explanation function obtains its information by tapping into EON's components, as well as into other relevant sources such as the guideline document and medical literature. It uses an argument model to identify the pieces of information that constitute an explanation, and employs a set of visual clients to display that explanation. By incorporating varied information sources, by mirroring naturally occurring medical arguments and by utilizing graphic visualizations, ATHENA DSS's explanation function generates rich, evidence-based explanations. PMID- 11604799 TI - A new prognosis factor analysis based on nonhomogeneous Markov description. AB - To evaluate prognosis factors, Cox's proportional hazard model has been used. But it was found that the analytical ability was not sufficient. So we propose a new evaluation method combining Markov chain model and multiple logistic regression analysis to estimate the prognosis factors. Stage II breast cancer was chosen as the subject. The data was retrospective data gathered in National Cancer Center Central Hospital. As first step, a simple Markov chain model was constructed to describe the state transition of a breast cancer. Then the multiple property of each state transition was investigated in detail. And the patients who had gotten a recurrence for the first two and a half years were discriminated as the poor prognosis group by a nonparametric test (p < 0.05). And the result proved to corresponding with the clinical experience. As second step, three factors (n classification of pathological diagnosis, ductal spread, and estrogen receptor) were selected as the prognosis factors for the early death in Stage II breast cancer by a multiple logistic regression analysis. This new prognosis factor analysis could find out some scientific evidences. Especially, it was found to be remarkable efficient in proving clinically experienced observation. PMID- 11604800 TI - Combining decision support and image processing: a PROforma model. AB - This paper addresses two important problems in medical image interpretation:(1) integration of numeric and symbolic information, (2) access to external sources of medical knowledge. We have developed a prototype in which image processing algorithms are combined with symbolic representations for reasoning, decision making and task management in an integrated, platform-independent system for the differential diagnosis of abnormalities in mammograms. The prototype is based on PROforma, a generic technology for building decision support systems based on clinical guidelines. The PROforma language defines a set of tasks, one of which, the enquiry, is used as means of interaction with the outside world. However, the current enquiry model has proved to be too limited for our purposes. In this paper we outline a more general model, which can be used as an interface between symbolic functions and image or other signal data. PMID- 11604801 TI - Supporting medical decisions with vector decision trees. AB - The article presents the extension of a common decision tree concept to a multidimensional - vector - decision tree constructed with the help of evolutionary techniques. In contrary to the common decision tree the vector decision tree can make more than just one suggestion per input sample. It has the functionality of many separate decision trees acting on a same set of training data and answering different questions. Vector decision tree is therefore simple in its form, is easy to use and analyse and can express some relationships between decisions not visible before. To explore and test the possibilities of this concept we developed a software tool--DecRain--for building vector decision trees using the ideas of evolutionary computing. Generated vector decision trees showed good results in comparison to classical decision trees. The concept of vector decision trees can be safely and effectively used in any decision making process. PMID- 11604803 TI - A prototype decision support system for MR spectroscopy-assisted diagnosis of brain tumours. AB - Our objective is to develop a decision support system that improves the accuracy of non-invasive brain tumour diagnosis and grading by enabling radiologists to use data from Magnetic Resonance Spectroscopy (MRS). The system, which uses pattern recognition techniques, is trained on a validated database of spectra and associated clinical information to provide automated classification of spectra from brain tumours. An innovative user-interface presents classification results as a two-dimensional overview plot in which points representing cases of different diseases form distinct clusters. Users can inspect any cases in these plots and compare them with the new, unknown spectrum. Hence, the overview plot can both communicate the classification of a case and help provide explanation for that classification in part by supporting human case-based reasoning. This paper describes the development of a prototype system implemented in JAVA. PMID- 11604802 TI - Survival and viral load in four groups of HIV-1 infected hemophiliacs compared by three-way data clustering. AB - We assigned a total of 131 hemophiliacs infected with HIV-1 into four clusters by applying a 3-way data analysis method. Sequentially acquired CD4+ and CD8+ cell counts obtained longitudinally over an observation period from 1986 to 1992 were analyzed. During the successive observation in this interval, a clustering of patients is not always coincident over all the times, because the cell counts vary with time. Therefore, the 3-way data clustering is to obtain the optimal result of the classification of patients through all the interval of observation. Examining patients' survival after that period, the cumulative mortality rate was highest among the 36 hemophiliacs in Cluster 1. Less mortality was found in Cluster 2, consisting of 49 hemophiliacs and none was reported in Clusters 3 and 4, which included 33 and 13 hemophiliacs, respectively. However, a significantly lower blood viral copy number was found in Cluster 3 than in Cluster 4. A total of six long-term non-progressors was found, five in Cluster 3 and one in Cluster 4, while none was found in Cluster 1 or 2. As demonstrated in this analysis, 3 way data clustering may represent a good data mining technique for handling various types of clinical data. PMID- 11604804 TI - Decisions at hand: a decision support system on handhelds. AB - One of the applications of clinical information systems is decision support. Although the advantages of utilizing such aids have never been theoretically disputed, they have been rarely used in practice. The factor that probably often limits the utility of clinical decision support systems is the need for computing power at the very site of decision making--at the place where the patient is interviewed, in discussion rooms, etc. The paper reports on a possible solution to this problem. A decision-support shell LogReg is presented, which runs on a handheld computer. A general schema for handheld-based decision support is also proposed, where decision models are developed on personal computers/workstations, encoded in XML and then transferred to handhelds, where the models are used within a decision support shell. A use case where LogReg has been applied to clinical outcome prediction in crush injury is presented. PMID- 11604805 TI - XML-based application interface services--a method to enhance integrability of disease specific systems. AB - Disease specific systems usually offer excellent functionality for the management of the covered diseases. But the restriction to a certain disease also often hampers their wide spread use since they aren't optimised for clinical workflow. The Giessener Tumordokumentationssystem (GTDS) is such a disease specific system. It is not only designed for the use in tumour registries but also to support clinical care. In order to integrate it into hospital information systems, we implemented standard communication interfaces, but this measure is not sufficient since it doesn't consider aspects of the normal workflow of a clinical user. Therefore, we developed a strategy that should ease the access to the system in the environment of existing systems. From the technical point of view, XML with its capabilities to represent even complex data in a rather simple way helped to implement this strategy. We use it to communicate with API-like services and also created a WWW environment to demonstrate the access to these services. Since this environment itself is a means to integrate systems, we intend to expand this environment to an appropriate region based means to improve the communication with registries. multidisciplinary environments [3]. The large amount of useful functions and its adaptability has made GTDS (http://www.gtds.de) a successful system in more than 30 various registries. PMID- 11604806 TI - Ranking of information in the computerized problem-oriented patient record. AB - We propose a framework for a problem-oriented patient record for general practice 1 and defend that the problem-oriented medical record represents an intuitive way to organize the patient record. By adding a layer of knowledge to the electronic patient record the record system is able to better utilize the information stored in the record. If a record system is process aware, having knowledge of work processes and is able to distinguish between different contexts in use, the system can provide relevant and useful information during the handling of patients' medical problems. Information is ranked according to its relevancy in a given context by using action patterns - traces. Traces give valuable indications of what is going on during the process of patient care. Decision frames represents relevant contexts based on the information in the record. Both decision frames and traces provide an environment in which more optimal medical decisions can be made. PMID- 11604807 TI - Implementing real-time system interfaces to support the shared care of diabetes patients. AB - This paper describes a collaborative project: the Medway Integrated Care Support (MEDICS) Project, involving GP and Hospital system suppliers, an NHS Trust, General Practitioners and the NHS Information Authority. The objective of the project is to assess the Object Management Group's (OMG/CORBAMed) Clinical Observations Access Service (COAS) standard, by demonstrating its use in implementing a real-time interface between a GP system and a hospital clinical system, supporting the shared care of diabetes patient. PMID- 11604808 TI - End-user support: a necessary issue in the implementation and use of EPR systems. AB - A successful integration of an IT-system is dependent not only of the quality of the information and the user interface features of the system but also of the organizations ability to support the users learning process. As IT is becoming more and more pervasive in the Health Care sector as such there is a need for a systematic approach to the question on how to support end-users. Based on an empirical study of an implementation process in a Danish Primary Health Care Services the concept of end-user support is discussed and it is argued that there is a need for a distinction between different kinds of support depending of the type of activity involved. First the organizations strategy for learning when the system was implemented is described. The evaluation of the learning strategy revealed that there was a need for different kinds of knowledge involving qualitatively different kinds of learning. Second the area of end-user support is discussed and it is argued that the common understanding of end-user support as something provided by DP staff, vendors or manuals are to narrow. Third a more differentiated way of thinking of support that link the need for different kind of knowledge and learning processes to different kinds of support is proposed. Finally Activity Theory is put forward as a possible basis that provide the opportunity of discussing issues belonging to different kinds of end-user support within an integrated framework. PMID- 11604809 TI - Structured data entry of clinical information for documentation and data collection. AB - Routine databases containing large amounts of clinical data represent a tremendous opportunity for the evaluation of health care practices and outcomes. However, data collected for administrative purposes has limitations in content, accuracy and completeness. Routine entry of clinical information directly into clinical information systems by care providers is one strategy to address this problem. We developed a structured data entry method, the Clinical Data Framework (CDF), which has been used to support the capture of clinical information by clinicians in the normal process of care delivery. A study of the CDF over a two month period showed that it improved the accuracy of completeness of data collection over a coding method which was based on selection of ICD-9-CM codes. PMID- 11604810 TI - Structured physical examination data: a modeling challenge. AB - The success of systems facilitating collection of structured data by clinicians is largely dependent on the flexibility of the interface. The Open Record for CAre (ORCA) makes use of a generic model to support knowledge-based structured data entry for a variety of medical domains. An endeavor undertaken recently aimed to cover the broader area of Physical Examination by expanding the contents of the knowledge base. The model was found to be adequately expressive for supporting this task. Maintaining the balance between flexibility of the interface and constraints dictated by reliable retrieval, however, proved to be a considerable challenge. In this paper we illustrate through specific examples the effect of this trade off on the modeling process, together with the rationale for the chosen solutions and suggestions for future research focus. PMID- 11604811 TI - The MOSORIOT medical record system (MMRS) phase I to phase II implementation: an outpatient computer-based medical record system in rural Kenya. AB - The authors of this paper describe the second phase of the implementation of the Mosoriot Medical Record System (MMRS) in a remote health care facility on the outskirts of Eldoret, Kenya, located in sub-Saharan Africa. We describe of the collaboration between Indiana University (IU) and the Moi University (MU), and the process that led to the development of the computer-based Mosoriot Medical Record System (MMRS) is provided. We then provide the conceptualization and initial implementation of this basic electronic medical record system. We also describe the different processes for assessing the MMRS' effects on health care, including time-motion studies and a strict implementation plan that is necessary for the successful implementation of the system. The MMRS project has many features that make it significant in the domain of CBPR systems. It may serve as a model for establishing similar, basic electronic record systems in the developed and developing world. In developing countries there are few (if any) projects that have attempted to implement such a system. This paper describes the planning, end-user education to new technologies, and time-motion studies necessary for the successful implementation of the MMRS. The system will be used to improve the quality of health data collection and subsequently patient care. It will also be used to link data from ongoing public health surveys and this can be used in public health research programs of the Moi University. PMID- 11604812 TI - Meta-modelling: the appropriate solution for a family of applications. AB - The aim of this paper is to present an appropriate framework able to generate models and to implement them, in the objective of computerizing a family of medico-technical reports. The accelerated rate of technical development makes it necessary to design computerized applications independently of data-processing technology. This apparent paradox is a quite real challenge which needs research and development software environments to support frameworks. In this article, we present a meta-model (i.e. a generic structure - supported by the Meta-Gen software tool) ) which is able to generate various models of medico-technical reports. These models in turn are able to generate various types of instances. This meta-model is a "Meta-medical record", it is constituted of basic concepts : " User Semantic Group " to which are attached a set of " sentence-type ", a set of several corpus of variables with a set of graphs ("navigators"). Five models (echocardiography for hospital "A", echocardiography for hospital "B", gastroscopy, fibercoloscopy A.E.P.). were already generated from this "Meta Medical Record". A beginning of implementation in echocardiography report is presented here. The advantages are a very thorough personalization of the document for the user, and a greater independence of the design diagram from the technological platform. PMID- 11604813 TI - A web-based rapid prototyping and clinical conversational system that complements electronic patient record system. AB - Even the most extensive hospital information system cannot support all the complex and ever-changing demands associated with a clinical database, such as providing department or personal data forms, and rating scales. Well-designed clinical dialogue programs may facilitate direct interaction of patients with their medical records. Incorporation of extensive and loosely structured clinical data into an existing medical record system is an essential step towards a comprehensive clinical information system, and can best be achieved when the practitioner and the patient directly enter the contents. We have developed a rapid prototyping and clinical conversational system that complements the electronic medical record system, with its generic data structure and standard communication interfaces based on Web technology. We believe our approach can enhance collaboration between consumer-oriented and provider-oriented information systems. PMID- 11604814 TI - Medical records and electronic documents: a proposal. AB - This article presents a global view of our proposal for a medical information system of the future. This information system focuses on patient medical records management. As most of the existing systems, it proposes to store information from patient records in a database. But records capture is different: we propose to use weakly-structured documents. Such documents contain paragraphs with some specific constraints represented by XML tags. The end-user writes new information under the form of weakly-structured documents. An internal system translates theses documents into new data for the internal database. Such a document-based user interface provides much more freedom to the end-user, and certainly reduces the distance between the physicians' way of working and the capture system. PMID- 11604815 TI - Paragraph-oriented structure for narratives in medical documentation. AB - The authors present a 6 years experiment using a document- centered electronic patient record, based on a central document repository. The document management system is paragraph oriented and all documents are built automatically before editing using predefined ordered sets of para-graphs. Paragraphs can be preloaded with templates, text or images. Once edited, signed and printed, documents are again decomposed in paragraphs and permanently stored. This system, though the compositional aspect of paragraphs is limited and their semantic content wide, offers numerous advantages. The typology is easy to build and to maintain, it has been implemented widely in our hospitals without need for any natural language processing techniques and is used daily within commercially available text editors. The actual state of the system is discussed, emphasizing the structure of the documents, the various attributes and properties that have been needed in order to meet user's needs. PMID- 11604816 TI - Extracting clinical cases from XML-based electronic patient records for use in web-based medical case based reasoning systems. AB - Development and usage of Case Based Reasoning (CBR) driven medical diagnostic system requires a large volume of clinical cases that depict the problem-solving methodology of medical experts. Successful usage of CBR based systems in healthcare is constrained by the need for a continuous supply of current and correct clinical cases (in an electronic medium) from medical experts. To address this constraint we present a strategy to pro-actively transform generic Electronic Patient Records (EPR) to Operable CBR-oriented Cases (OCC) that are compliant to specialised CBR-based medical systems. EPR-OCC transformation methodology is based on XML parse-trees, Unified Medical Language Source (UMLS) meta-thesauri and medical knowledge ontologies. The featured work involves the implementation of a Java-based computer system for the automatic transformation of XML-based EPR-originating from heterogeneous EPR repositories accessible over the Internet/WWW-to specialised OCC that can then be seamlessly incorporated within Intelligent CBR-based Medical Diagnostic Systems. PMID- 11604817 TI - Dynamic viewer of medical events in electronic medical record. AB - Medical record should enable doctors to comprehend the patient's history and select suitable medical treatment. In paper based medical records, medical events (examination, treatment etc.) are recorded successively, and problem oriented recording is difficult to be applied to patients with much information and a long history. Consequently it is not easy to understand the patient's history from paper based medical records. In order to solve this problem, we developed the flow sheet system in our electronic medical record (EMR). To make a flow sheet, we analyzed the structure of the medical event data. In this paper we introduced the medical event information model for our EMR. Furthermore, we clarified the specification of the data presentation on the flow sheet. We developed the flow sheet on the basis of these analyses. Because there are 3 layers in the vertical axis of the flow sheet, many items of the medical event can be displayed on the screen. When user clicks the cell, the corresponding detail data including images are shown. This system functions to link medical event items with a problem, and shows the bundled items on the flow sheet when the user selects the problem. We implemented this system in Osaka University Hospital. The number of the types of medical events and those of detail events in inpatients are 5.0+1.7 (mean+SD) and 60+47, respectively. The medical doctors in Osaka University Hospital evaluated this system, and concludes that the flow sheet data presentation makes comprehension of the patient's history easier than paper based records. As to the function of bundling the items relevant to the problem, they feel it is especially useful for patients with chronic disease. Thus the flow sheet data presentation in EMR is useful for medical practice. PMID- 11604818 TI - Recording clinical data--from a general set of record items to case report forms (CRF) for clinics. AB - Standardising a documentary language makes only sense if we use it for documentation consequently. Using an example of Paediatric Oncology in Germany we have developed a procedure that generates CRFs from a documentary language. The introduced procedure has proved to be feasible in practice. With it we can support developers of documentation systems in creating their CRFs; through the guaranteed use of the documentation terminology we further achieve that information recorded with the created CRFs may be statistically analysed across different institutions. PMID- 11604819 TI - Integration of clinical practice guidelines into a distributed regional electronic patient record for tumour-patients using XML: a means for standardization of the treatment processes. AB - With the rising efforts to guarantee a high quality treatment in medicine and to reduce the costs in the health care system, Clinical Practice Guidelines (CPG) have developed into a very important reference in medicine. CPGs are especially useful for the standardization of multi-professional treatment processes like the care for patients with malignant diseases. The Tumour-Centre Heidelberg/Mannheim (Germany) leads a project to build up a regional, virtual distributed Electronic Patient Record (EPR) for patients with malignant diseases in the Rhein-Neckar Area. Aims of the first stages of the project are the introduction of the distributed EPR to two co-operating pilot-clinics. In this context we intend to provide access for medical professionals not only to the data of the jointly treated patients, but also to relevant existing CPGs and other medical knowledge sources like Medline and Cochrane-Library. Knowledge and Patient data should be interlinked to offer patient-specific views on the CPG-information. As all professions have different information needs, this views should be presented individualized according to the demands of the users. We analysed three relevant CPGs and defined a meta-structure that will be refined to a common meta-structure for CPGs in Oncology. CPGs as well as structured patient-documents will be implemented in the Extensible Markup Language (XML), as this platform-independent technology seems to suit our needs for data exchange and presentation purposes best. The implementation process will be accompanied tightly with evaluations to gain experience for further expansions of the EPR. The vision of the project is, that by integrating CPGs in a shared distributed EPR, the way towards standardized treatment processes in a local, but multi-professional setting, and the efforts to guarantee a high quality treatment in Oncology can sufficiently be supported. PMID- 11604820 TI - Patient empowerment and the electronic health record. AB - This paper presents the results of an investigation into the issue of patients viewing and controlling their Electronic Health Record (EHR), and some of the issues that an EHR would raise in terms of patient empowerment. The research was carried out with a random sample of patients from the Hadfield Medical Centre (HMC), Derbyshire and utilised a survey methodology supplemented by a few interviews. The research investigated the nature and scope of demand from patients for empowerment in terms of their own health, and the EHR. It took into account demographics. It was found that a majority of patients wish to be empowered through viewing their health record, though most prefer to use paper rather than an electronic medium. A significant majority of patients do not want to control their health record. It was found that of the demographic variables investigated, age and level of education were the only ones that had a significant impact on a patient's desire to be empowered and their desire to view their health records. The results have implications both locally and nationally for the development of electronic health records and the ultimate acceptance of such records may be linked to the general extent of computer literacy within the population rather than the views of individuals about their health. PMID- 11604821 TI - Why implementing EPR's does not bring about organizational changes--a qualitative approach. AB - Politicians and hospital management in Sweden and Denmark focus on IT and especially Electronic Patient Record, EPR as a tool for changes that will lead to better economy as well as better quality and service for the patients. These changes are not direct effects of the new medium for patient records but indirect effects due to the possibilities embedded in the new technology. This paper describes how clinicians as well as management in two hospitals interpret and uses the EPR. The findings clearly show that the intended changes i.e. the objectives for the implementation, never occurred. The interpretation of the interviews makes it possible to understand that one of the reasons is the lack of correlation between the conception and use of the EPR on one hand and the fact that the management and the clinicians do not share the same vision and mental picture of the future organization on the other. PMID- 11604822 TI - Shared experience in 13 local Danish EPR projects: the Danish EPR Observatory. AB - In 1996 a national strategy for the development of electronic patient records (EPR) for the Danish hospitals and primary care was launched. An element in the strategy was to support a number of regional EPR development projects. The EPR Observatory has in the two recent years collected data from the regional projects, dealing with the expectations in four areas: 1) Impact on organisational issues, 2) Benefits of EPR, 3) Integration of EPR with other information systems and 4) security aspects of EPR. Among the observations an increasing teamwork and im-proved knowledge about the patient was found. What was expected, but not found, was resistance to EPR, as a result of changes in skills and power. The most obvious benefits are increased data accessibility and improved decision ma-king. The most considerable disadvantage is an enormous growth in discontent with the systems performance and the fact, that all the projects are delayed. Many different types of integration solutions are chosen, because of a lack of a common model for integration. Generally the projects find, that EPJ yields increased security, but logistical problems arise in having the systems running 24 hours 7 days a week. Economical benefits cannot be documented. This relates to the fact, that the regional projects are stand-alone projects. The ongoing growth in discontent with the EPR-systems and the fact, that all the projects are delayed must be subject to further exploration. PMID- 11604823 TI - Clinical benchmarking enabled by the digital health record. AB - Office-based physicians are often ill equipped to report aggregate information about their patients and practice of medicine, since their practices have relied upon paper records for the management of clinical information. Physicians who do not have access to large-scale information technology support can now benefit from low-cost clinical documentation and reporting tools. We developed a hosted clinical data mart for users of a web-enabled charting tool, targeting the solo or small group practice. The system uses secure Java Server Pages with a dashboard-like menu to provide point-and-click access to simple reports such as case mix, medications, utilization, productivity, and patient demographics in its first release. The system automatically normalizes user-entered clinical terms to enhance the quality of structured data. Individual providers benefit from rapid patient identification for disease management, quality of care self-assessments, drug recalls, and compliance with clinical guidelines. The system provides knowledge integration by linking to trusted sources of online medical information in context. Information derived from the clinical record is clinically more accurate than billing data. Provider self-assessment and benchmarking empowers physicians, who may resent "being profiled" by external entities. In contrast to large-scale data warehouse projects, the current system delivers immediate value to individual physicians who choose an electronic clinical documentation tool. PMID- 11604824 TI - Clinical narrative and clinical organisation: properties of radiology reports. AB - Radiology reports, as a form of clinical narrative, are more than a repository of patient information but are active in patient care. They are not unique and individual to each patient but have structured content suitable for supporting the activities of care. We consider these activities of care and how they manifest in the report. This recognition of the infusion of clinical organisation in clinical narrative leads to the recognition of seven properties of radiology reports: labels, concepts, genre, structure, author, subject, reader. These properties exist across two relationships: the intertextual relationship between radiology reports and the interpersonal relationship between a radiology report and people. PMID- 11604825 TI - Dissemination of electronic patient records using primary care referrals as a vector for change. AB - The Online Medical Record (OMR) is a full-featured shared electronic patient record in use since 1989 at Beth Israel Deaconess Medical Center in Boston. The first practice to use the OMR was a primary care practice. We observed the pattern of voluntary adoption of the OMR and the referral patterns from primary care to specialists. Adoption of the OMR among specialists has accelerated in recent years, in many cases mirroring the referral patterns from primary care to specialists. We hypothesize that referral of patients from primary care providers to specialists exposes these specialists to the benefits the electronic patient record and may promote the use of this technology. We conclude that these referral patterns provide a vector for the dissemination of electronic patient records. The important lesson is that EPR implementation in a health care network should begin with primary care to ensure the most efficient diffusion of this technology throughout the enterprise. PMID- 11604826 TI - Application of an intelligent graphical interface to electronic patient records. AB - Physicians are under a lot of pressure to perform. The power of the computer can be used to reduce the cognitive stresses. The use of an intelligent graphical interface can tailor the information that is presented to the physician. The user can be assured that all the information is presented and that important facts are brought to the users attention. The screen displays can be made to be self organizing. This saves the user the effort of moving and resizing windows. The technology to do this has been developed and has been applied to a web browser interface. This paper describes the advantages of applying this technology to medical records databases. PMID- 11604827 TI - A multi-disciplinary approach to a user interface for structured data entry. AB - Physician data entry (PDE) is still an obstacle to the adoption of a CPR that replaces the paper chart. Most interfaces have been designed primarily on the basis of the functional requirements. Few studies document methods to elicit interface preferences from the clinician-user. We used insights from the fields of both medicine and Human Computer Interfaces to explore interface alternatives for structured data entry (SDE). We present and discuss three designs as alternatives for the SDE module in ORCA (Open Record for CAre). The methodology is applied to SDE in particular, but many aspects also apply to CPRs in general. PMID- 11604828 TI - Using the eXtensible Markup Language (XML) in a regional electronic patient record for patients with malignant diseases. AB - Communication between different institutions which are responsible for the treatment of the same patient is of outstanding significance, especially in the field of tumor diseases. Regional electronic patient records could support the co operation of different institutions by providing ac-cess to all necessary information whether it belongs to the own institution or to a partner. The Department of Medical Informatics, University of Heidelberg is performing a project in co-operation with the Thoraxclinic-Heidelberg and the Department of Clinical Radiology, University of Heidelberg with the goal: to define an architectural concept for interlinking the electronic patient record of the two clinical institutions to build a common virtual electronic patient record and carry out an exemplary implementation, to examine composition, structure and content of medical documents for tumor patients with the aim of defining an XML based markup language allowing summarizing overviews and suitable granularities, and to integrate clinical practice guidelines and other external knowledge with the electronic patient record using XML-technologies to support the physician in the daily decision process. This paper will show, how a regional electronic patient record could be built on an architectural level and describe elementary steps towards a on content-oriented structuring of medical records. PMID- 11604829 TI - Migration of the Japanese healthcare enterprise from a financial to integrated management: strategy and architecture. AB - The Hospital Information System (HIS) has been positioned as the hub of the healthcare information management architecture. In Japan, the billing system assigns an "insurance disease names" to performed exams based on the diagnosis type. Departmental systems provide localized, departmental services, such as order receipt and diagnostic reporting, but do not provide patient demographic information. The system above has many problems. The departmental system's terminals and the HIS's terminals are not integrated. Duplicate data entry introduces errors and increases workloads. Order and exam data managed by the HIS can be sent to the billing system, but departmental data cannot usually be entered. Additionally, billing systems usually keep departmental data for only a short time before it is deleted. The billing system provides payment based on what is entered. The billing system is oriented towards diagnoses. Most importantly, the system is geared towards generating billing reports rather than at providing high-quality patient care. The role of the application server is that of a mediator between system components. Data and events generated by system components are sent to the application server that routes them to appropriate destinations. It also records all system events, including state changes to clinical data, access of clinical data and so on. Finally, the Resource Management System identifies all system resources available to the enterprise. The departmental systems are responsible for managing data and clinical processes at a departmental level. The client interacts with the system via the application server, which provides a general set of system-level functions. The system is implemented using current technologies CORBA and HTTP. System data is collected by the application server and assembled into XML documents for delivery to clients. Clients can access these URLs using standard HTTP clients, since each department provides an HTTP compliant web-server. We have implemented an integrated system communicating via CORBA middleware, consisting of an application server, endoscopy departmental server, pathology departmental server and wrappered legacy HIS. We have found this new approach solves the problems outlined earlier. It provides the services needed to ensure that data is never lost and is always available, that events that occur in the hospital are always captured, and that resources are managed and tracked effectively. Finally, it reduces costs, raises efficiency, increases the quality of patient care, and ultimately saves lives. Now, we are going to integrate all remaining hospital departments, and ultimately, all hospital functions. PMID- 11604830 TI - A program designed to monitor the course and management of depressive illness across the primary/secondary interface. AB - Information Technology (IT) is an increasingly important area for all aspects of life in the twenty first century. Computers have an impact on both our home life and our work life with information on many aspects of our lives being held on computer systems, some of which we are unaware. Despite this universal progression towards IT, certain areas within the National Health Service are still considered to be somewhat old fashioned in their tendency to resolutely adhere to recording information on paper. One of these areas is that of the mental health services, which perhaps given the nature of having a number of care sites makes it well suited to having the use of a well designed computer system capable of collating and co-ordinating all aspects of patient's management. This paper describes the development and implementation of a computer system designed to hold information on patients with depressive disorder across all mental health sites within both primary and secondary care. Data were manually input from patients' case notes onto a specially designed system at all sites and were then merged onto a master database by use of a patient's NHS number. Ultimately the master database held data on the entire course and management of 914 patients who suffered from depressive disorder that came within the two general practice catchment area. Professional perceptions of the usefulness of the database are discussed along with suggestions for promoting the implementation of such a system within mental health services nationwide. PMID- 11604831 TI - Community health information and its management system: a new form for the next century. AB - The development of community health service brings a new branch of Medical Informatics, Community health care informatics and a new management system, Community Health Care Information System in the beginning of nest century. The paper first advance and explore this new concept. It states the focus of Community health care informatics as the promotion of health for the whole community. It not only gives treatment to individual patients through ways of disease management and information network, but also improves health condition of the whole community by "diagnosis of community health" and "prescription for community health". The paper also introduces the community health information system and its formation, technology, function and practical use, pointing out the crucial point of its research work to be precisely discovering the "information origin" and "three-in-one" working group. PMID- 11604832 TI - New millennium hospital management information system: experience of the National Cancer Institute--Cairo University. AB - The National Cancer Institute-Cairo University (NCI) is a leading cancer center in the Middle East and Africa. It serves more than 15,000 new cases and more than 250,000 patient visit every year. The implementation of its Hospital Management Information System was completed and the system was operational in 1992. Although different modules were added to the HMIS, the core of the system has never been changed or updated. NCI evaluated its current system. NCI also evaluated the modern tools in databases and programming. NCI came to the conclusion that a new HMIS need to be installed. The needs of NCI staff were analyzed with consideration to budget issues and the limitations of a developing country. Different hardware, networking and software issues had to be considered in the updating. Arabization and customization were main factors in decision making. PMID- 11604833 TI - Use of HL7 to integrate a HIS-subsystem: limits and possibilities. AB - Modern computer-based hospital information systems are mostly distributed with several heterogeneous subsystems connected together by specialized communication services. The common standard to integrate subsystems is HL7. By the example of subsystem integration for a pulmonary function test lab, we discuss the possibilities of HL7, the limits we encountered and how we overcame these. PMID- 11604834 TI - Experience with an XML/HTTP-based federative approach to develop a hospital-wide clinical information system. AB - The authors present a two-year experience with an approach aimed at federating applications into a component-based hospital-wide clinical information system. Recognizing the need for better integration, clearer separation of knowledge from applications, as well as the necessity to respect and integrate the diversity of roles in a healthcare network, a strategy was implemented that included the development of a shared vision, organizational changes to promote appropriation at all levels, and the elaboration and maintenance of a common architecture and terminology by an instrumental technical group. Choices for federative technologies were in part based on their level of acceptance and potential to evolve. XML was used as the syntactic framework and HTTP as the transfer protocol. Within twelve months, the shared vision was developed, the architecture was specified, the key central components implemented, incorporated into the applications, and applications teams started producing shareable services using XML and HTTP. PMID- 11604835 TI - Human resource assignment and role representation mechanism with the "cascading staff-group authoring" and "relation/situation" model. AB - We have previously reported the access control mechanism and audit strategy of the "patient-doctor relation and clinical situation at the point-of-care" model with multi-axial access control matrix (ACM). This mechanism overcomes the deficit of ACM in the aspect of data accessibility but does not resolve the representation of the staff's affiliate and/or plural membership in the complex real world. Care groups inside a department or inter-department clinical team plays significant clinical role but also spend great amount of time and money in the hospital. Therefore the impact of human resource assignment and cost of such stakeholders to the hospital management is huge, so that they should be accurately treated in the hospital information system. However multi-axial ACM has problems with the representation of staff groups due to static parameters such as department/license because staffs belong to a group rather temporarily and/or a medical staff may belong to plural groups. As a solution, we have designed and implemented "cascading staff-group authoring" method with "relation and situation" model and multi-axial ACM. In this mechanism, (i) a system administrator certifies "group chief certifying person" according to the request and authorization by the department director, (ii) the "group chief certifying person" certifies "group chief(s)", (iii) the "group chief" recruits its members from the medical staffs, and at the same time the "group chief" decides the profit distribution policy of this group. This will enable medical staff to access EMR according to the role he/she plays whether it is as a department staff or as a group member. This solution has worked successfully over the past few years. It provides end-users with a flexible and time-to-time staff-group authoring environment using a simple human-interfaced tool without security breach and without system administration cost. In addition, profit and cost distribution is clarified among departments and inter-departments groups. PMID- 11604836 TI - From legacy and client/server systems to components in healthcare information systems in Finland. AB - A strategy and toolset (FixIT) for migrating a specific type of legacy systems- based on the FileMan DBMS of the U.S. Department of Veterans Affairs--to a two tier client/server and web browser-based architecture was presented in MEDINFO'98. In the current paper we discuss the further migration to a multitier software component architecture. A literature survey and industry contacts were used to specify an open, component-based target architecture for healthcare information systems to be reached by the year 2005, as well as a phased migration strategy from the present FileMan/FixIT-based systems towards the target. The target architecture is based on large-grained business components and accommodates heterogeneous elements on the intra-component, intra-application, intra-organization and inter-organizational levels. Four logical tiers are identified within a business component. Three migration paths are specified for different cases: the tier-by-tier, piece-by-piece, and web-wrapping paths. It is argued that the architecture, supported by off-the-shelf toolsets, application frameworks and a new software development process, makes it possible to turn legacy systems into a valuable asset, split monolithic applications into reusable components, and ultimately replace the legacy parts at a feasible pace PMID- 11604837 TI - The telematic network of referee hospital "V. Monaldi" in Naples: state of the art and perspectives. AB - The new advances in I.T. both in Hardware (wideband network) and in Software are rapidly changing the Health Information Systems scenario. In many hospitals of Campania Region this leads in many case to rebuild, starting from zero, both infrastructure and applications. Ericsson Enterprise has recently developed for the A.O. Monaldi and Integrated information System which consists of an advanced LAN (Local Area Network), a number of software infrastructures and some application systems as WEB site, Dicom PACS, E-mail server, Streaming Video from Operating Theatres, Internal TV Network. This integrated system represents the starting point for modern health information systems, which is compliant with new standards. The start-up of such systems represents always a problem for the organization and management point of view, therefore a number of problems concerning: training, education, security, privacy, operative procedures, co ordination with existing applications, system management at the start-up and after. This paper deals with the technical aspects of this information system and discusses the problem met in introducing these IT products in a big and important hospital of Campania Region in Italy, in order to suggest a model, useful for other similar experiences. PMID- 11604838 TI - The early days of health computing in the UK. AB - The invention of RAM in Manchester, UK, in 1948 and the subsequent commercial production of computers paved the way for their wide-spread use in industry and commerce. This Paper details the problems and the successes as computers were introduced into the UK National Health Service. It covers the computers and their uses and lists also the personnel involved. On a broader front it sets the UK scene against the wider international scene, again mentioning those other pioneers elsewhere in the world. It should bring a sense of nostalgia to some and helpful advice to those countries about to go down a similar road. PMID- 11604839 TI - Development and evaluation of a nursing service management and administration information system at district hospital. AB - The rapid development of information technology and the multiple usage of Information Systems make indisputable their appliance in all the sectors including the Nursing Service area. Information Systems that have been developed for the Nursing Service Administration are extremely useful in the processing and the categorisation of a large number of information, providing significant advantages such as information storage, information availability, information precision and reliability. In addition, the appliance of Information Systems provides important advantages in the administration of the nursing personnel's data, contributing to the improvement of the operating effectiveness of the Nursing Service. This paper describes the development and the evaluation of an Information System for the Nursing Service Administration that classifies all the information related to the nursing personnel and helps the administration to handle the appropriate nursing data. The method of Life Cycle Model was decided as the most appropriate for the development of the System, because of the important advantages that it offers. For the evaluation of our own designed system we based on the standards, which are used for evaluating Information Systems in general. The evaluation of this Information System is carried out by a survey among the undergraduate and the postgraduate students of the Nursing Department of the University of Athens and the Nursing Personnel of a number of Hospitals. Useful conclusions have been derived concerning those characteristics, which should be fulfilled by the system. Important conclusions have been also drown out concerning the dependencies of the variables under study, the future readjustments of the system, and the general perception of the newcomers in health profession towards the application of the information technology. PMID- 11604840 TI - Use of handheld computers as bedside information providers. AB - Access to clinical reference information at the point-of-care is a goal that is difficult to achieve by lack of really portable reference material. Handheld computers have matured to the point where they are powerful enough to be used as clients of a distributed knowledge system serving reference information and decision-aid applications in a highly portable form factor. We describe a pilot project launched at the Geneva University Hospital studying the use of handhelds and associated clinical applications in two internal medicine clinics. Results garnered by this study will help answer the many questions raised by the use of handhelds in medical practice, in term of cost, benefits, risk and change in workflow. PMID- 11604841 TI - Economic motives to use a participatory design approach in the development of public-health information systems. AB - Within public health, there is a tradition of co-operation between researchers and communities in planning and implementation of health promotion programs. As a consequence, public-health organizations are characterized by having complex multidisciplinary structure and dynamic organizational goals. In this paper, we discuss the economic impacts from the use of Participatory Design for development of public-health information systems. Creation of systems that have both utility and usability is suggested to be highlighted as the central goal. The identified pre-requisites for a positive impact are that the new system should be of high quality, appropriate to the nature of the health promotion tasks, and to how activities are coordinated and integrated both between and within the stakeholder groups involved. We argue further that a method that minimizes the information asymmetry in the development process is necessary for avoiding market failures 1. The conclusion is that participatory design will diminish transaction costs, will help to avoid sunk costs, and will contribute to rich efficient use of human and economic resources in public-health organizations. PMID- 11604842 TI - Developing a District Health Information System in South Africa: a social process or technical solution? AB - South Africa initiated a national District Health Information System rollout strategy in the latter half of 1999. Experience has demonstrated that the implementation of an information system as a vehicle for the delivery of accountability in the management of health services, demands organisational change within a framework of human resource development and technical support. The aim of training, to empower facility and district staff to use locally generated information to improve coverage and quality of primary health care services, can only be realized if training and innovation for change are appropriately marketed and supported. The appeal of HISP software, a locally developed application system lies in its user acceptance. While computers form a vital tool in providing easily accessible information for decision-making, their use must not be seen as a panacea for all information problems in primary health care services. Strategies for promoting sustainability of DHIS implementation lie in the social processes of human resource development, changing organisational infrastructure and the use of ongoing evaluation rather than those of technical infrastructure. South Africa has developed a variety of mechanisms to facilitate this process. PMID- 11604844 TI - Improving dialysis services through information technology: from telemedicine to data mining. AB - This paper discusses the issues related to use of Information Technology (IT) solutions in dialysis, and describes the implementation of some of them in a medium size dialysis center. First, starting from the analysis of the organization of public-health nephrology services, the potential role of IT is highlighted. Second, the main directions for IT exploitation in dialysis, namely telemedicine and automated monitoring of dialysis sessions are discussed. Third, the on-field implementation of these services is described, together with some preliminary results. The work here presented shows how IT may improve dialysis services by ameliorating quality and reducing costs. PMID- 11604843 TI - A UML-based ontology for describing hospital information system architectures. AB - To control the heterogeneity inherent to hospital information systems the information management needs appropriate hospital information systems modeling methods or techniques. This paper shows that, for several reasons, available modeling approaches are not able to answer relevant questions of information management. To overcome this major deficiency we offer an UML-based ontology for describing hospital information systems architectures. This ontology views at three layers: the domain layer, the logical tool layer, and the physical tool layer, and defines the relevant components. The relations between these components, especially between components of different layers make the answering of our information management questions possible. PMID- 11604845 TI - Zora: a pilot virtual community in the pediatric dialysis unit. AB - We describe a five-month pilot project conducted in the dialysis unit at Boston's Children's Hospital. Pediatric patients with renal disease used the Zora therapeutic community program while undergoing hemodialysis. Zora is a 3D multi user computer environment designed at the MIT Media Laboratory to help young people explore issues of identity, while engaging in a virtual community. Users build "virtual rooms" and populate them with objects and characters, program them with storytelling behaviors, and converse with other young people in real-time through a virtual character representing themselves. It was specifically designed to help young people explore issues of identity, while engaging in a participatory virtual community. This paper presents the experience and evaluates the feasibility and safety of using Zora in a hospital setting. It describes how Zora facilitated explorations of identity and mutual patient support and interaction. Finally it also presents design recommendations for future interventions of this kind. More generally, this paper explores the potential of technology specifically designed with therapeutic purposes to help patients cope with their illness. PMID- 11604846 TI - Anamnesis via the internet--prospects and pilot results. AB - A comprehensive computerized questionnaire was developed to obtain the anamnesis of patients seeking contact with a physician for any type of new problem. The purpose of this pilot study was to investigate if a structured questionnaire filled out by the patient and complementing an interview at the physician's office would contribute to a better quality of the total anamnesis and/or lead to savings in time at the visit. The results encourage further developments in this direction. The potential uses proposed are, in addition to being used to improve a visit, the correct assessment of the history for prioritization and scheduling of visits and in some situations, the anamnesis obtained over the net may be the basis for medical advice without a visit. This study emphasizes the great improvement of information captured by this type of questionnaire based on medical knowledge about associated symptoms and relevant questions depending on the problem presented compared to the results obtained by a simple open question used in many e-health services today. PMID- 11604847 TI - Development and implementation of the home asthma telemonitoring (HAT) system to facilitate asthma self-care. AB - National Asthma Education and Prevention Program (NAEPP) suggests using asthma action plans for patient self-care. Recent studies reported that many asthma patients had difficulties in following action plans on a daily basis and had low compliance to medication regimens. The goal of our study was to design and evaluate the Home Asthma Telemonitoring (HAT) system aimed to help asthma patients to follow their self-care plans according to the NAEPP recommendations. Our study resulted in the development of the system which provided patients with continuous individualized help in the daily routine of asthma self-care and notified heath care providers if certain clinical conditions occurred. This allowed early recognition of potentially dangerous situations and timely intervention. The evaluation of the HAT system underwent several stages. First we showed, that the HAT system provides reliable reciprocal exchange of all relevant information between a physician and asthma patient in home settings. Further evaluation demonstrated that lung function test results collected during home asthma telemonitoring are comparable to those collected under the supervision of trained professionals, and Internet-based home asthma telemonitoring can be successfully implemented in a group of patients without previous computer experience. Preliminary results of an on-going HAT evaluation showed higher patient compliance to asthma action plans in comparison to the compliance reported for patients in standard care. The clinical impact of HAT on asthma outcomes is being currently evaluated in a randomized clinical trial funded by NIH. HAT has a potential for improving clinical outcomes and quality of life in the studied patient population and may be a model for monitoring and self management of patients with other chronic health conditions. PMID- 11604848 TI - TeleMedMail: free software to facilitate telemedicine in developing countries. AB - Telemedicine offers the potential to alleviate the severe shortage of medical specialists in developing countries. However lack of equipment and poor network connections usually rule out video-conferencing systems. This paper describes a software application to facilitate store-and-forward telemedicine by email of images from digital cameras. TeleMedMail is written in Java and allows structured text entry, image processing, image and data compression, and data encryption. The design, implementation, and initial evaluation are described. PMID- 11604849 TI - Review of virtual reality treatment for mental health. AB - This paper describes recent research that proposes virtual reality techniques as a therapy for patients with cognitive and psychological problems. Specifically this applies to victims of conditions such as traumatic brain injury, Alzheimers and Parkinsons. Additionally virtual reality therapy offers an alternative to current desensitization techniques for the treatment of phobias Some important issues are examined including means of user interaction, skills transfer to the real world, and side-effects of virtual reality exposure. PMID- 11604850 TI - Use of an electronic medical record in disease management programs: a case study in hyperlipidemia. AB - Disease management programs seek to improve the health of a population of patients with a disease through a multidisciplinary approach founded in the collection, analysis and feedback of disease-specific outcomes. Currently, the majority of disease management programs have been conducted by insurers or external vendors. Limitations of these programs derive from separation of care from primary care and the inability to rapidly and accurately obtain the necessary clinical data. The utility offered by an electronic medical record allows physician organizations to conduct disease management programs of higher quality at lower cost. PMID- 11604851 TI - Experiences from development of home health care applications based on emerging Java technology. AB - Home health care is an expanding area within the health care system. The idea of moving parts of the health care process from expensive specialised hospital care to primary health care and home health care might be attractive in a cost perspective. The introduction of home health care applications must be based on a rigorous analysis of necessary requirements to secure a safe and reliable health care. This article reports early experiences from the development of a home health care application based on emerging Java technologies such as the OSGi platform. A pilot application for follow-up of diabetes patients is presented and discussed in relation to a list of general requirements on home health care applications. PMID- 11604852 TI - The role of wireless technology in home care delivery. AB - Health care delivery is changing drastically. In its current state it tends to use the home care model in order to increase quality of life, to rationalize costs and to achieve wellness. Pivotal to these purposes are contact centers, which act as mediators between the medical staff and the citizens seeking advice and/or therapy. Main platforms used for the development of such applications are the INTERNET and PCs, and the telecommunication networks, including mobile solutions. In this paper, a generic contact center model shall be presented, which is under development in the context of an IST European project in health telematics entitled a Distance Information Technologies for Home care. The Citizen Health System (CHS)'. After the description of this generic contact center, an application for health care delivery to diabetic patients shall be described. In this application we shall see the possible use of the Wireless Application Protocol (WAP) scheme. This application proves the usefulness of wireless technology in providing health care services all around the clock and everywhere the citizen is located, it shows the necessity for restructuring the medical knowledge for education delivery to the patient, and it shows the virtue of interactivity by means of using the limited, yet useful browsing capabilities of the WAP technology. PMID- 11604853 TI - Ambulatory monitoring of behavior in daily life by accelerometers set at both near-sides of the joint. AB - In this paper we examined a new joint motion monitoring method by use of accelerometers to monitor subjects' detailed motion in daily activities. In this method two accelerometers are set at as near points of both sides around the joint as possible. The difference between these two sensors' outputs mainly depend on the joint angle because the centrifugal and the turning acceleration occurred by the rotation around the joint can be neglected. In the experiments we tried to monitor various subject's behaviors of his upper and lower extremities and whole body motion, and could show this method is useful for the ambulatory monitoring of behavior in daily life. PMID- 11604854 TI - Survey and analysis of satellite-based telemedicine projects involving Japan and developing nations: investigation of transmission rates, channel numbers, and node numbers. AB - We surveyed interactive telemedicine projects via telecommunications satellite (AMINE-PARTNERS, Post-PARTNERS, and Shinshu University Project using Inmarsat satellites) offered by Japan as assistance to developing countries. The survey helped clarify channel occupation time and data transfer rates. Using our survey results, we proposed an optimized satellite model with VSATs simulating the number of required channels and bandwidth magnitude. For future implementation of VSATs for medical use in developing nations, design of telecommunication channels should take into consideration TCP/IP-based operations. We calculated that one hub station with 30-76 VSATs in developing nation can be operated on bandwidth 6 Mbps using with 128 Kbps videoconferencing system for teleconsultation and teleconference, and linking with Internet. PMID- 11604855 TI - Towards virtual reality stimulation in force platform posturography. AB - We developed a stimulation technique on the basis of virtual reality methods for balance investigation performed in balance laboratories of otorhinolaryngological clinics and institutes of occupational health. Such a stimulation technique is greatly progressive in the sense that by creating virtual moving views and "virtual worlds" inside which the subject is located it is possible to make effective stimuli that would be very difficult or even impossible to set in any real environment. We tested our system on healthy subjects and found out that this kind of virtual reality stimulation system is very useful for balance analysis. PMID- 11604856 TI - EMR-based TeleGeriatric system. AB - INTRODUCTION: As medical services improve due to new technologies and breakthroughs, it has lead to an increasingly aging population. There has been much discussion and debate on how to solve various aspects such as psychological, socio-economic and medical problems related to aging. Our effort is to implement a feasible telegeriatric medical service with the use of the state of the art technology to deliver medical services efficiently to remote sites where elderly homes are based. The TeleGeriatric system will lead to rapid decision-making in the presence of acute or subacute emergencies. This triage will also lead to a reduction of unnecessary admission. It will enable the doctors who visit these elderly homes once a week basis to improve their geriatric management skills by communication with geriatric specialist. Nursing skills in the geriatric care will also benefit from this system. Integrated electronic medical record (EMR) system will be indispensable in the face of emergency admissions to hospitals. Evolution of EMR database would lead to future research in telegeriatrics and will help to identify the areas where telegeriatrics can be optimally used. METHODOLOGY: This system is based on current web browsing technology and broadband communication. The TeleGeriatric web based server is developed using Java Technology. The TeleGeriatric database server was developed using Microsoft SQL server. Both are based at the Medical Informatics Programme, National University of Singapore. Two elderly homes situated in the periphery of Singapore and a leading government hospital in geriatric care have been chosen for the project. These 3 institutions and National University of Singapore are connected via ADSL protocol. ADSL connection supports high bandwidth, which is necessary for high quality videoconferencing. Each time a patient needs a teleconsultation a nurse or a doctor in the remote site sends the patient's record to the TeleGeriatric server. The TeleGeriatric server forwards the request to the Alexandra Hospital for consultation. Geriatrics specialists at the Alexandra Hospital carry out teleward rounds twice weekly and on demand basis. SUMMARY OF RESULTS: Following the implementation of the system, a trial run has been done. Total results have demonstrated a high degree of coordination and cooperation between remote site and the Alexandra Hospital. Also the patient compliance is very high and they prefer teleconsultation. CONCLUSION: Initial results show that the TeleGeriatric system has definite advantages in managing geriatric patients at a remote site. As the system evolves, further research will show the areas where telegeriatrics can be used optimally. PMID- 11604857 TI - An estimation of economic effects of tele-home-care: hospital cost-savings of the elderly. AB - Tele-home-care (or tele-medicine) is being implemented by the application of multimedia such as CATV and ISDN. In this paper, by focusing on the so-called "social hospitalization of the aged," we carry out an estimation of the extent to which tele-home-care based on multimedia can help in saving the cost of hospitalization of the aged in the future. Estimation consists of the following two parts. First, we estimate the trends of the aged population and their hospital expenses using the regression analysis. Second, we assume that new technology such as multimedia and new medical instruments develop according to a logistic curve. Thus, we estimate the rate of diffusion of CATV and ISDN by logistic curves. Then, by multiplying this number by hospital costs per elderly patient as estimated previously, we have been able to calculate the extent to which hospitalization costs can be saved in the entire economy. Our results indicated that in the year 2050, US$257.3 billion, or nearly 7.4% of total hospitalization costs of the aged could be saved by tele-home-care. PMID- 11604858 TI - Design and implementation of an urban/rural Telehealth Network for the Evaluation of Abused Children: implications for global primary care applications. AB - To meet the increasing need for rapid medical evaluation of allegations of child abuse in rural areas and the paucity of trained professionals to provide these evaluations, a model telemedicine network was designed and implemented initially in the State of Florida, USA. The utilization of various types of equipment, transmission modes, and electronic peripherals, will be discussed, as well as utilization of physician extenders for assessment. The expansion of this system for other medical uses will be summarized. Experiences in replication of the model in a southern Alabama rural county will be detailed. PMID- 11604859 TI - Evaluation of a telemedicine system for supporting thyroid disease diagnosis. AB - A telemedicine system connecting Japan and Belarus via a communication satellite and the international ISDN has been in use since February, 1999. Two relational databases, which are essentially the same, are set respectively at Nagasaki University School of Medicine and Gomel Regional Specialized Dispensary in Belarus for management of patients' data and for research including epidemiologic studies. The thyroid ultrasonographic images, microscopic images of cytological findings and other information on patients are sent from Gomel to Nagasaki once a week with diagnoses and comments by physicians at Gomel Regional Specialized Dispensary for cases whom they found difficult to diagnose. Thyroid specialists at Nagasaki University School of Medicine correct the diagnoses, if necessary, on the basis of information from Gomel and send their comments and instructions to Gomel for improving diagnosis skills of physicians at Gomel. The findings of 330 cases have been sent from Gomel to Nagasaki by September, 2000 since the commencement of the system in February, 1999. Of the 329 cases, thyroid diagnosis was made at Gomel for 261 cases in whom two or more diagnoses were made for 35 cases. As of the end of October, 2000, the Gomel diagnoses have been reviewed for 217 cases and the remaining 112 cases are under review at Gomel. The diagnoses made at Gomel and Nagasaki were in agreement for 110 (50.7%) of 217 cases. Thyroid cancer was diagnosed in 8 cases in whom 6 had been diagnosed at Gomel while the other 2 were diagnosed anew at Nagasaki. The usefulness of the system for improving thyroid diagnosis in Belarus was indicated. PMID- 11604860 TI - From data to knowledge--the Visible Human Project continues. AB - The U. S. National Library of Medicine (NLM) has long been a world leader in the archiving and distribution of the print-based images of biology and medicine. NLM has also been a pioneer in the use of computer systems to encode and distribute textual knowledge of the life sciences. NLM's Long Range Planning effort of 1985 86 foresaw a coming era where NLM's Bibliographic and factual database services would be complemented by libraries of digital images, distributed over high speed computer networks. The NLM Planning Panel on Electronic Imaging recommended that NLM should undertake the building a digital image library consisting of computerized tomography (CT) and magnetic resonance (MR) images, and cryosection images of a representative, carefully selected and prepared male and female cadaver--the "Visible Human Project ." The male and female Visible Human data sets are now being made available through a license agreement with the NLM. The data sets are supporting a wide range of educational, diagnostic, treatment planning, and commercial uses. The NLM, in partnership with other U.S. government research agencies has begun a three prong effort within the Visible Human Project to address: the creation of a new online, interactive, digital head-and-neck atlas; the development of a tool kit of computational programs capable of automatically performing many of the basic data handling functions required for using Visible Human data in applications; and the improved resolution of future Visible Human data sets through the reduction of the anatomical artifacts introduced by the methods used to stabilize and section the anatomical materials and the development of staining and wide-spectrum methods for increasing tissue contrast. PMID- 11604861 TI - Mimos: a description framework for exchanging medical image processing results. AB - Image processing plays increasingly important role in using medical images, both for routine as for research purposes, due to the growing interest in functional studies (PET, MR, etc.). Unfortunately, there exist nearly as many formats for data and results coding as image processing procedures. If Dicom presently supports a kind of structured reporting of image studies, it does not take into account the semantics of the image handling domain. This can impede the exchange and the interpretation of processing results. In order to facilitate the use of image processing results, we have designed a framework for representing image processing results. This framework, whose principle is called an "ontology" in the literature, extends the formalism, which we have used in our previous work on image databases. It permits a systematic representation of the entities and information involved in the processing, that is not only input data, command parameters, output data, but also software and hardware descriptions, and relationships between these different parameters. Consequently, this framework allows the building of standardized documents, which can be exchanged amongst various users. As the framework is based on a formal grammar, documents can be encoded using XML. They are thus compatible with Internet / Intranet technology. In this paper, the main characteristics of the framework are presented and illustrated. We also discuss implementation issues in order to be able to integrate documents, and correlated images, handling these with a classical Web browser. PMID- 11604862 TI - Fusion in medical imaging: theory, interests and industrial applications. AB - The accumulation of several data coming from medical images and signals, expert knowledge and databases is becoming very common for the study of a given pathology. The aggregation of all this information is mentally performed by a clinician, and generally allows for a better medical decision in clinical studies. We propose in this article a fusion method that models this aggregation process. This method is a three step scheme, that first transforms all the available information in a common theoretical frame, then aggregates these data using their redundancy and their conflicts, and finally computes a new information synthesizing all the initial knowledge. We first introduce in this article the fusion scheme and its theoretical aspects, and we particularly focus on the three steps of the process. We then detail the software implementation of this concept, achieved in collaboration with SEGAMI Corporation Inc. We finally apply this concept to a real clinical problem, the study of Alzheimer's disease using MR and SPECT images, and we show very encouraging preliminary results. PMID- 11604863 TI - Biomedical image skeletonization: a novel method applied to fibrin network structures. AB - To understand the rheological behavior of fibrin clots, we must obtain quantitative measurements of morphometric parameters of the networks formed under various conditions. The networks are so complex that researchers must currently manually segment the images of network samples and estimate the parameters from them. Skeletonization is a promising tool for automating this task. We here propose a method that rapidly constructs a coarse representation of a skeleton graph and, using the snake model, deforms the graph to obtain smooth skeletons. Unlike many existing approaches, our method does not involve explicit object boundary information or high order derivatives. Since our method processes a given image as a whole, the presence of multiple objects in an image is automatically detected and the skeletons of these objects are computed simultaneously. PMID- 11604864 TI - Experimental and theoretical analysis of wavelet-based denoising filter for echocardiographic images. AB - One of the most significant features of diagnostic echocardiographic images is to reduce speckle noise and make better image quality. In this paper we proposed a simple and effective filter design for image denoising and contrast enhancement based on multiscale wavelet denoising method. Wavelet threshold algorithms replace wavelet coefficients with small magnitude by zero and keep or shrink the other coefficients. This is basically a local procedure, since wavelet coefficients characterize the local regularity of a function. After we estimate distribution of noise within echocardiographic image, then apply to fitness Wavelet threshold algorithm. A common way of the estimating the speckle noise level in coherent imaging is to calculate the mean-to-standard-deviation ratio of the pixel intensity, often termed the Equivalent Number of Looks(ENL), over a uniform image area. Unfortunately, we found this measure not very robust mainly because of the difficulty to identify a uniform area in a real image. For this reason, we will only use here the S/MSE ratio and which corresponds to the standard SNR in case of additivie noise. We have simulated some echocardiographic images by specialized hardware for real-time application;processing of a 512*512 images takes about 1 min. Our experiments show that the optimal threshold level depends on the spectral content of the image. High spectral content tends to over estimate the noise standard deviation estimation performed at the finest level of the DWT. As a result, a lower threshold parameter is required to get the optimal S/MSE. The standard WCS theory predicts a threshold that depends on the number of signal samples only. PMID- 11604865 TI - Management and transmission of DICOM files using PC to PC multicasting methodology. AB - The PACS system built and used in hospitals nowadays has quite significant overload on its central server because of both treatment of very large data and full management of medical images. We suggest a distributed communication and management methodology using PC to PC multicasting strategy for efficient management of medical images produced by DICOM modalities. It is absolutely necessary for reducing strict degradation of PACS system due to large size of medical images and its very high transport rates. DICOM PC to PC component is composed a service manager to execute requested queries, a communication manager to take charge of file transmission, and a DICOM manager to manage stored data and system behavior. Each manager itself is a component to search for requested file by interaction or transmit the file to other PCs. Distributed management and transformation of medical information based on PC to PC multicasting methodology will enhance performance of central server and network capacity reducing overload on them. PMID- 11604866 TI - PACS linked to EPR. AB - We developed a new PACS linked to Electronic Patient Record system (EPR). It was a hospital-wide PACS storing all the radiological examinations. The images and reports were linked on EPR. The concept of navigation servers and segment servers was introduced for prefetchig and quick displaying. After the start of operation, increasing retrieval indicated its effectiveness on practical work in spite of remaining delivery of radiographs. PMID- 11604867 TI - Modelling space perception in human early vision: a computational approach. AB - A computational approach in studying vision is important for understanding the biological mechanisms, as well as for integrating the known cortical architecture of primary visual area (V1) and the physiological functions (some of them experimentally proved, some only presumed). We present, in parallel, two models for early vision mechanisms: one for obtaining the disparity map in stereo vision, and the other for edges enhancement in contour integration, both of them seen from such a computational perspective. We implemented the two models and the results of the simulation were consistent with the biological data. They also account for the importance of interactions between parallel channels of visual information processing. PMID- 11604868 TI - Haptic reproduction and interactive visualization of a beating heart based on cardiac morphology. AB - A goal of this work is proposal and construction of simulation methods of haptic reproduction and interactive visualization of a beating heart in cardiovascular surgical training and education. The data for the beating heart model was obtained from ECG-gated 3D MRI of a normal volunteer. The elastic information was assumed as a uniform value with clinically experienced elasticity. Using a real time 3D graphics and a haptic device, a simulation environment of the beating heart was designed and implemented. After the construction, some cardiovascular surgeons evaluated the implemented system. Its visualization and haptic expression were scored excellent, but some details in haptic interface were remained to be improved. Finally, for more realistic cardiovascular surgical simulation, future development of the method is discussed. PMID- 11604869 TI - Structural connectivity in white matter using the projected diffusion-tensor distance. AB - Diffusion tensor imaging (DTI) has become a powerful tool for analyzing the structure of white matter. We have proposed a method for detecting nerve fiber bundles in white matter using diffusion tensor images and have applied the method to in vivo brain measurements. Although there are many methods to investigate the connectivity of white matter that are based on principal eigenvector or full tensor propagation. In the proposed method, we use directional diffusion measurements to infer regional white matter connectivity. To assess the connectivity, we compose the map based on the projected tensor distance, then we put a label on the constructed map and segment regionally connected white matter using labels. The purpose of this study is to obtain a quantitative map of white matter connectivity in vivo using diffusion tensor properties. PMID- 11604870 TI - Measurement of in-vivo local shear modulus by combining multiple phase offsets mr elastography. AB - To provide realistic surgical simulation, haptic feedback is important. In the existing surgical simulators, the fidelity of the deformation and haptic feedback is limited because they are based on the subjective evaluation of the expert-user and not on an objective model-based evaluation. To obtain elastic modulus of in vivo human tissues, magnetic resonance elastography (MRE) was developed. MRE is a phase-contrast- based method that can visualize propagating strain waves in materials. The quantitative values of shear modulus can be calculated by estimating the local wavelength of the wave pattern. Low frequency mechanical motion must be used for soft tissue-like materials, because strain waves rapidly attenuate at higher frequency. Therefore, wavelength in MRE is long. It is difficult to estimate local wavelength with high spatial resolution especially from noisy MRE. In the MRE sequence, motion-sensitizing gradient (MSG) are synchronized with the mechanical cyclic motion. MRE with multiple initial phase offsets can be generated with increasing delays between the MSG and mechanical excitation. In this paper, we describe a method of measuring local wavelength with high spatial resolution by combining multiple phase offsets MRE. To confirm the reliability of this method, a computer simulation and phantom study were performed. The shear modulus measured with various elastic objects was well consistent with the value obtained by MRE and the mechanical method. The shear moduli of excised porcine liver and in-vivo human calf muscle were also analyzed by this method. on the subjective evaluation of an expert-user and not on objective model-based methods. PMID- 11604871 TI - A review of technical advances in virtual colonoscopy. AB - Early detection of polyps has proven to lead to a decrease in incidence of colon cancer. In the past few years, virtual colonoscopy has been developed as a patient-friendly screen-ing technique. The procedure comprises the following steps. First, the patient's colon is cleansed and transanally inflated with air. Subsequently, a 3D image volume is acquired of the abdomen by CT or MRI. Finally, the bowel surface is extracted and visualized, after which the physician virtually navigates through the colon and examines the surface for abnormalities. This paper describes the progress in research for virtual colonoscopy. PMID- 11604872 TI - Bioinformatics in medical practice: what is necessary for a hospital? AB - Building bioinformatic facilities for a university hospital is pretty similar to using standardized building blocks to construct a house. Starting with the intention to built a dwelling house, a factory or just a shelter the architect draws a construction plan and determines the material to be used. In general, the building is then constructed by the workmen following exactly the plan. However, for particular reasons, minor alterations may be needed to improve the construction of the building. Here we use the metaphor of constructing a "bio informatics building" to describe the steps needed to support the daily tasks of a university hospital medical microbiology department which uses genomic methods quite extensively for pathogen identification. Today the Giessen "bioinformatics building" is not yet complete but we have been able to lay solid foundations and erect the ground floor which is functional already. Using a combination of standard tools, internet accessible genomic databases and some own software tools we can support genome sequencing from the raw sequence to pathogen identification. PMID- 11604873 TI - GenePath: a computer program for genetic pathway discovery from mutant data. AB - The sequencing of the human genome and the genomes of several model organisms is the first step toward the long-term objective of genetic research: the identification of all genes, and the discovery of their functions and mutual interactions. This article presents a methodology and a computer program called GenePath to support the discovery of gene function. GenePath uses mutant data and available genetic knowledge to identify potential genetic pathways. Several pilot applications based on experimental results from Dictyostelium and C. elegans confirmed the usefulness of the proposed schema. Our results suggest that GenePath is a valuable tool that can be used as an intelligent assistant to support genetic reasoning. PMID- 11604874 TI - On approximate string matching of unique oligonucleotides. AB - The current research considers the approximate string matching search for important subsequences from DNA sequences, which is essential for numerous bioinformatics computation tasks. We tested several approximate string matching algorithms and furthermore developed one for DNA data. Run times of the algorithms are important, since the amount of data is very large. PMID- 11604875 TI - Protein structural domain parsing by consensus reasoning over multiple knowledge sources and methods. AB - Domain parsing, or the detection of signals of protein structural domains from sequence data, is a complex and difficult problem. If carried out reliably it would be a powerful interpretive and predictive tool for genomic and proteomic studies. We report on a novel approach to domain parsing using consensus techniques based on Hidden Markov Models (HMMs) and BLAST searches built from a training set of 1471 continuous structural domains from the Dali Domain Dictionary (DDD). Validation on an independent test sample of family-matched structural domain sequences from the Scop database yields a consensus prediction performance rate of 75.5%, well above the 58% obtained by simple agreement of methods. PMID- 11604876 TI - RAMEDIS- rare metabolic diseases publishing tool for genotype-phenotype correlation. AB - To gain further knowledge about rare genetic diseases, a world wide method for data collection via the Internet has been established. This new approach will improve collecting valuable data from single case reports. RAMEDIS saves standardised patient data which will be usable for statistics, longitudinal examinations and co-operative studies in future time. Embedded in the scene of the German Human Genome Project, RAMEDIS directly will enable phenotype-genotype correlation's. Technically RAMEDIS is based on the Oracle database management system with some additional tools. Since November 2000 first case reports are committed online. Beside the better characterisation of clinical heterogeneity of rare diseases, there may be a great benefit for the treatment of these patients in whom prospective studies are otherwise expensive and difficult to perform. Quality of clinical diagnostic process and therapy will increase. PMID- 11604877 TI - Virtual reality system using force feedback device for molecular modeling. AB - We designed two new concept of computer aided molecular modeling system using virtual reality technologies. Although it is still a prototype, the most characteristic function of the system is enabling its user to "touch" and feel the electrostatic potential field of a protein or a drug molecule. User can scan surface of a protein using a globular probe, which is given an electrostatic charge, controlled by a force feedback devise. The electrostatic force between the protein and the probe is calculated in real time, and immediately fed back into the force feedback device. The user can easily search interactively for positions where the probe is strongly attracted to the force field. Such positions can be regarded as candidate sites where small chemical groups corresponding to the probe, functional parts of lead compounds, can bind to the target protein. We also developed a binding simulator which we can bind a small molecule (drug) to a large molecule (protein). In this system, we placed a camera, so that we can not only "feel" but also "see" how drug fits into the binding site. Our prototype system has the potential to serve as a new application method as well as being applicable to conventional VR technologies, especially to force feedback technologies. PMID- 11604878 TI - Inference and prediction of courses of the diseases caused by pathologic viruses by estimating molecular evolution of within-host virus. AB - A new approach for inferring the evolutionary process of within-host virus is presented in this study. This approach includes a sequential-linking algorithm developed by us that can deal with the sequential viral samples that are obtained at different time points from the same host, and reconstruct a longitudinal phylogenetic tree in which the evolutionary relations between viral variants can be shown. A codon-based model, which uses a Markov process to describe substitutions between codons, is also employed in this approach to calculate synonymous and non-synonymous substitution rates and to distinguish positive selection and neutral evolution. The approach is applied to a data set of the V3 region of the HIV-1 envelope genes sequenced in different years after infection of a single patient. The results suggest that this approach may provide a more realistic description of viral evolution than the traditional evolution models because it accounts for both neutral and adaptive evolution. Most important of all, since this approach make it possible to follow up the evolutionary process of within-host virus by analyzing the sequential viral samples, it could be used in inference and prediction of the course of the diseases caused by pathologic viruses and evaluation of the treatment. PMID- 11604879 TI - The structure of networks in living systems. AB - It is known today there are many networks existing in living systems like signal transduction, transcriptional regulation, immanence response and like so on. These networks, like all the other networks, are based on relationships between elements. In this contribution, we propose a network model of living systems. It possesses information of connections among nodes, which stand for critical elements in a network. We formulate it as a simple model of probability theory and find interesting phenomena in it. PMID- 11604880 TI - A new network-based biologic database system. AB - Bioinformatics is playing an increasingly important role in the processing and analysis of biomedical data. The collection, storage and analysis of biologic information are key components of bioinformatics. In the genome era, with the explosion of sequence and structural information available to researchers, the structure of biologic databases is becoming more complicated, the contents is becoming larger, and the management and development is also becoming more difficult. A network-based biologic database has been developed. This database system integrates administration, development and analysis of bioinformatics with common and friendly interface. For the life scientists without much computer programming expertise, the system is easy to master. PMID- 11604881 TI - A cognitive approach for designing a computer-based learning tool in dentistry: ODONTOS application. AB - This work emphasises a cognitive approach to build ODONTOS, a computer-based education system in dentistry. It aims at providing for both instructors and students without any particular knowledge in computer programming; a tool dedicated to dental disease learning. For instructors, it implements for knowledge construction e.g. creating and proposing clinical cases according to student learning style, using multimedia technology. For students it is a tool, which privileges their learning style in order to solve uniform and inflexible learning problem. World Wide Web (WWW) technology has allowed us to offer flexible learning program without any pressure of time and place to student. 13 instructors and 84 students tested the ODONTOS prototype via Internet and answered to the questions related to their habit regarding learning style for the students and knowledge construction for the instructors. Although video data have emerged as an important learning support for the students (82 out of 84), their use in knowledge construction still remains unusual comparative with the use of text and picture (10 out of 13 instructors). It appears that, the integration of video data should be more used by instructors (2 out of 13) while textual data are overwhelmingly used in knowledge construction (13 out of 13). We introduce ODONTOS, and discuss the concrete contributions of this work. PMID- 11604882 TI - Comparing student attitudes to different models of the same virtual patient. AB - AIMS: Two types of virtual patient designs can be distinguished - a 'narrative' structure and a 'problem-solving' structure (1). This study assesses attitudes of students with respect to learning communication skills via a virtual patient; and compares acceptability of the two different types of virtual patient designs. METHODS: Two virtual patients were constructed around the same case, each emphasising a narrative or problem-solving model. Undergraduate medical students used the simulations as part of a communication skills program. A computer-based survey was used to assess attitude. RESULTS: There was general acceptance of the use of the computer-based simulated patient. Students who generally performed better at communication skills, were more positive towards the virtual patient. There was no quantitative difference in acceptability between the two designs, but there were clear qualitative differences. CONCLUSIONS: While students were moderately positive about both simulations, qualitative data indicated that their were clear differences in attitude between the two different designs. PMID- 11604883 TI - The development of model curricula for Health Informatics. AB - We have developed model Health Informatics (HI) curricula for the education of three categories of professionals: Applied Health Informaticians, the professionals that deploy information technologies, Research and Development Health Informaticians those that develop new concepts, techniques, and solutions, and what we have called Clinician Health Informaticians, providers who use HI capabilities to support their professional work. The curricula specify the competencies that each type of professional must acquire. PMID- 11604884 TI - Simulated learning environments in anatomy and surgery delivered via the next generation internet. AB - The Next Generation Internet (NGI) will provide high bandwidth, guaranteed Quality of Service, collaboration and security, features that are not available in today's Internet. Applications that take advantage of these features will need to build them into their pedagogic requirements. We present the Anatomy Workbench and the Surgery Workbench, two applications that require most of these features of the NGI. We used pedagogic need and NGI features to define a set of applications that would be difficult to operate on the current Internet, and that would require the features of the NGI. These applications require rich graphics and visualization, and extensive haptic interaction with biomechanical models that represent bony and soft tissue. We are in the process of implementing these applications, and some examples are presented here. An additional feature that we required was that the applications be scalable such that they could run on either on a low-end desktop device with minimal manipulation tools or on a fully outfitted high-end graphic computer with a realistic set of surgical tools. The Anatomy and Surgery Workbenches will be used to test the features of the NGI, and to show the importance of these new features for innovative educational applications. PMID- 11604885 TI - Proofs of the necessity of medical informatics for the physicians in Bulgaria. AB - It is obvious that medical practice needs to sustain a radical quality change due the fast penetration of information technologies in medicine and healthcare. One of the major problems of this change is the adequate education of the medical specialists to use these information and communication technologies, including Hospital information systems and electronic medical records. A study has been carried out among the physicians in Bulgaria. The aim of the study was to check weather the Bulgarian physicians are ready to face the challenges of modern information technologies in their daily medical practice. The results show that although 97.5% of the Bulgarian physicians have a positive attitude to information technologies and 86.7% recognise the need of using computers in medicine, 84.1% of them do not have the necessary skills and knowledge to use computers in their daily medical practice. They are absolutely unaware what the electronic medical record might contribute to their practice. Their knowledge of the subject, principles and methods of medical informatics tends to nil. The study was the first of the kind carried out in Bulgaria. It proved our initial hypothesis that Bulgarian physicians need to be educated not only how to use computers, they are in badly need of education in medical informatics. The study proved that the adequate education in medical informatics is one of the most important parameters for the implementation of information technologies, especially electronic medical records in medical practice. Its result may form the background for the preparation of the strategy of teaching medical informatics in Bulgaria. The first step of the implementation of this strategy is to include medical informatics in the regular curriculum of students of medicine. PMID- 11604886 TI - Implementation and evaluation of a distance learning introductory course in medical informatics. AB - CONTEXT: There is a growing interest in and need for continuing education in medical informatics delivered by distance learning. OBJECTIVES: Implement and evaluate a distance learning introductory course in medical informatics. METHODS: A Web-based version of our on-campus "Introduction to Medical Informatics" course was implemented using streaming audio lectures, threaded discussion boards, and several other teaching modalities. Evaluation was performed using an adaptation of our on-campus course evaluation instrument. RESULTS: The course was implemented with no major technological or pedagogical problems. Student satisfaction with teaching modalities and other course modalities was high. CONCLUSIONS: The learning technologies used in this course were implemented successfully and a Graduate Certificate Program is planned to further meet educational needs in medical informatics. PMID- 11604887 TI - A survey of academic and industry professionals regarding the preferred skillset of graduates of medical informatics programs. AB - Identification of the skills needed by graduates of medical informatics masters degree programs is needed so that students will know what is desired in the workplace and curriculum designers can assure that courses cover relevant areas. We conducted a mail survey of representatives of the informatics job market to discover what they think is most important. A survey instrument was designed after analyses of job ads and curricula in the U.S. and interviews with representative employers. The survey was mailed to 1000 randomly selected members of AMIA and HIMMS plus EMR vendors. Respondents were asked to rank skills and groups of skills according to perceived utility. The results indicate higher rankings for organizational and interpersonal skills than for more technical credentials. Statistical analysis indicates the existence of relatively few underlying constructs to the skill list. PMID- 11604889 TI - Developing CD-ROM based multimedia digital textbook of 'San-Yin-Jiao(SP-6) pressure for reducing the labor pain and shortening the labor time'. AB - The computer-based textbook is a new educational tool that promises to play a prominent role in the coming years. Classical instructional technologies, such as video, stills, audio files and computer programs with a textbook orientation, have been merged into one multimedia computer system and have created additional opportunities for learning in medical, dental and nursing education. The authors developed a hypermedia textbook of a San-Yin-Jiao pressure for reducing the labor pain and shortening the labor time' using a personal computer with hypermedia software that contains texts, images, videos, audios and literature citations. The target population of this educational CD-ROM would be nurse midwives, clinical nurses working for the obstetric units, and faculty members who teach the Maternity and Women's Health Nursing. Valuable and practical experiences were obtained and shared. PMID- 11604888 TI - Informatics for Peru in the new millennium. AB - INTRODUCTION: As efforts continue to narrow the digital divide between the North and South, a new biomedical and health informatics training effort has been launched in Peru. This report describes the first year of work on this collaborative effort between the University of Washington (Seattle) Universidad Peruana Cayetano Heredia and Universidad Nacional de San Marcos (Peru) OBJECTIVES: To describe activities in the first year of a new International Research and Training Program in Biomedical and Health Informatics. METHODS: Descriptive analysis of key activities including an assessment of electronic environment through observation and survey, an in country short course with quantitative evaluation, and first round of recruitment of Peruvian scholars for long-term training in Seattle. RESULTS: A two-week short course on informatics was held in the country. Participants' success in learning was demonstrated through pretest/posttest. A systematic assessment of electronic environment in Peru was carried out and two scholars for long-term training were enrolled at the University of Washington, Seattle. DISCUSSION: Initial activity in the collaborative training effort has been high. Of particular importance in this environment is orchestration of efforts among interested parties with similar goals in Peru, and integration of informatics skills into ongoing large-scale research projects in country. PMID- 11604890 TI - GOLEM--multimedia simulator for medical education. AB - We created multimedia medical training simulator "GOLEM" for learning diagnostics and therapy of the critical clinical disorders. The theoretical basis of the simulator is the mathematical formulation of the relationship of homeostasis of the internal environment (acid/base and electrolyte equilibrium, of transport of blood gases, of osmotic and volume homeostasis), respiration, circulation and kidneys including regulatory influence of relevant hormones and the influence of some therapeutic procedures. Mathematical description consists of 39 non-linear differential equations and containing 89 input and 179 output variables. For the development of the simulation models developer's tools from MathWorks (Matlab and Simulink) has been used. The integration of the multimedia components, hypertext and simulation models interface was achieved by using Control Web, developed by Moravian Instruments, originally designed for long distance controls using PC and Internet. We have used our simulator as an efficient educational tool to help medical students learn circulatory, respiratory, acid-base, electrolyte, osmotic and volume disorders and train the diagnostic and therapeutic decisions by executing simulated interventions on virtual "patients". PMID- 11604891 TI - Intelligent systems for nursing education. AB - Health care is one of the fastest growing areas in terms of care, treatment and the exploitation of new technology in Slovenia. There is a great need for new approaches ensuring that education and work of health care professionals will be built upon the state of the art in nursing. As a consequence the educational, governmental and "industrial" institutions from Slovenia, UK, Italy and Greece have determined to work on above problem. EU agreed to support the project under the Phare Tempus Framework and the aim of this paper is to present an educational approach based on intelligent systems and its application in nursing education. PMID- 11604892 TI - Student-centered distance learning in health and medical informatics. AB - Learning and teaching of health and medical Informatics is currently supported by web based material, which in the main has been derived from traditional texts. Aided by contributions from the expert community, the web site of the handbook of Medical Informatics has been developed to incorporate increased interactivity (with question and answers related to each section). This approach has proved beneficial to both student and teacher. To further increase the interactivity of the WWW we investigate the suitability of authoring tools for developing complex simulations and interactive tutorials, using an example from the area of quantitative decision support (Bayes Theorem). We propose that these tools provide a suitable platform for the preparation and delivery of collaboratively produced HMI courses, which address open and distance learning and pedagogic issues. PMID- 11604893 TI - Design of a CSCL environment for clinical reasoning learning and problem-based learning in medicine. AB - The medical curriculum is changing, student-centered learning is currently used in medical schools. Problem-based Learning and Clinical Reasoning Learning develop the students' reasoning strategies. CSCW (Computer-Supported Cooperative Work) technology is used in Problem-Based Learning systems. We have designed a CSCL (Computer-Supported Collaborative Learning) environment for improving group coordination and communication in Clinical Reasoning Learning sessions. To support these new educative technologies, a prototype has been developed. PMID- 11604894 TI - Project-based teaching in health informatics: a course on health care quality improvement. AB - Teaching the skills and knowledge required in health informatics [1] is a challenge because the skill of applying knowledge in real life requires practice. We relate the experience with introducing a practice component to a course in "Health Care Quality Improvement". Working health care professionals were invited to bring an actual quality problem from their place of work and to work alongside students in running the problem through a quality improvement project lifecycle. Multiple technological and process oriented teaching innovations were employed including project sessions in observation rooms, video recording of these sessions, generation of demonstration examples and distance education components. Both students and their collaborators from the work place developed proficiency in applying quality improvement methods as well as in experiencing the realities of group processes, information gaps and organizational constraints. The principles used to achieve high involvement of the whole class, the employed resources and technical support are described. The resulting academic and practical achievements are discussed in relation to the alternative instructional modalities, and with respect to didactic implications for similar endeavors and beyond to other fields such as systems engineering. PMID- 11604895 TI - Training in medical informatics: combining onsite and online instruction. AB - The Internet is promoting active exchange of teaching materials and discussion among geographically distant collaborators. We envision that training in medical informatics can be better achieved if both onsite and online instruction are combined, provided that cultural and technological barriers are anticipated and the training program is prepared accordingly. We describe our Brazil/USA program in medical informatics, which includes components of on-site and online education, and discuss lessons learned during its ongoing implementation. Three onsite courses and one workshop have been planned, and two online courses are being developed. PMID- 11604896 TI - Evaluation of the outcomes of a multi-professional education programme in health informatics. AB - A multi-professional continuing education programme on healthcare information systems was designed on the basis of the IMIA WG 1 recommendations for teaching health informatics. This paper presents the outcomes of the education programme on the basis of the participants' (n=19) narrative assessments and a questionnaire. According to the results, the participants were very satisfied with their personal learning outcomes and they felt that the programme content was useful for their duties at work. They regarded that particularly the multi professional group had given them many ideas and rewarding discussions. The learning arrangements were assessed very successful and the learning methods rewarding. In conclusion we suggest that it is important to include different professions--healthcare and technical--into the same continuing education programmes in health informatics, and to include real life-like team projects. The validity of the results to undergraduate education programmes should be studied. PMID- 11604897 TI - An adaptive medical e-learning environment: the MEDIDACTE project. AB - Most e-learning systems offer the same tools and resource materials to students who are different in terms of motivations, training backgrounds, technical skills and learning objectives. Adaptive systems development is a challenge intended to improve the efficiency of these systems. This communication presents the design and implementation of an adaptive medical e-learning environment. The authors describe the MEDIDACTE architecture developed in three levels namely, the educational resource, educational project and user level. Current MEDIDACTE implementation and integration in Marseille Medical University curriculum are presented. PMID- 11604898 TI - Evaluation of guideline quality using GEM-Q. AB - A variety of rating instruments that evaluate the quality of practice guidelines have been published. Application of these instruments can be difficult and time consuming. In a literature review, we identified two evaluation instruments that are comprehensive, have clearly defined constructs, and have undergone validation/testing-the Guidelines Quality Assessment Questionnaire (GQAQ) and the Appraisal Instrument for Clinical Guidelines (AICG). Overall, the AICG is more comprehensive. The AICG addresses the implementability of a guideline, which is not evaluated by the GQAQ. However, the GQAQ is more amenable to computerization. GEM-Q is a Guideline Elements Model (GEM)-derived application intended to facilitate automated evaluation of guideline quality using one of the published instruments. To develop GEM-Q, various items in the GQAQ were mapped to corresponding elements in the GEM hierarchy and a customized XSL stylesheet was designed based on this mapping. GEM-Q selectively extracts text components of the guideline relevant to quality evaluation and displays the results in HTML format. GEM-Q was applied to a set of six guidelines to test its reliability. It ranked two guidelines as of "good" quality, two as "intermediate", and two as "poor". In all six instances, GEM-Q ranked guidelines in the same order of quality as the experts who validated the GQAQ. This work demonstrates the feasibility of developing an application to facilitate automated guideline quality evaluation. PMID- 11604899 TI - Systematic evaluation of computer-based nursing documentation. AB - The documentation of the nursing process is an important, but often neglected part of clinical documentation. Paper-based systems have been introduced to support nursing process documentation. Frequently, however, problems, such as low quality, are reported and it is still unclear if computer-based documentation systems can reduce these problems. We therefore introduced a computer-based nursing documentation system on four wards of the University Hospitals of Heidelberg. We systematically evaluated its preconditions and its effects in a pre-test post-test intervention study. We combined objective data (e.g., based on quality checklists) with subjective data drawn from questionnaires and interviews. In this paper, we present preliminary results, focussing on detailed results from the first two wards. PMID- 11604901 TI - Reliability of the assessment of appropriateness of diagnostic test request behavior. AB - We describe the reliability of the assessment of the appropriateness of requested diagnostic tests. We used a retrospective random selection of 253 request forms with in total 1217 requested tests. Three experts made an independent assessment of each requested test. Interrater kappa values ranged from 0.33 to 0.44. The kappa values of intrarater agreement ranged from 0.65 to 0.68. The reliability coefficient for all three reviewers was 0.66. This reliability is not sufficient to make case-by-case decisions, for example to give individual feedback on the appropriateness of requested tests. Sixteen reviewers are necessary to obtain a reference with a reliability of 0.95. PMID- 11604900 TI - Investigating physician order entry in the field: lessons learned in a multi center study. AB - The progress of studies by this team of researchers concerning computerized physician order entry (POE), beginning with a mail survey and moving to qualitative multi-center studies, is reviewed, with emphases on lessons learned and future directions. While mail surveys were appropriate to answer initial research questions about diffusion of POE in the U.S., multiple qualitative methods became the methods of choice for answering more complex questions. Results of the latter include articulation of multiple perspectives on both positive and negative aspects of POE and a description of what may be important for successful implementation of POE in the future. The present economic environment of hospitals may be inhibiting widespread diffusion of POE, not only because of the direct cost, but also indirectly by affecting relations with practitioners. Analysis of successful past implementations can provide guidance when the time is right. PMID- 11604902 TI - Data quality probes--a synergistic method for quality monitoring of electronic medical record data accuracy and healthcare provision. AB - Increasing reliance is being placed on electronic medical records to support clinical care and achieve improved quality standards. In order for clinical information systems (CIS) to deliver, the data within needs to be complete, consistent and accurate. This data of course only forms part of the process in delivering quality health care during the clinician-patient encounter. This paper outlines a method of assessing the quality of the processes involved in healthcare provision and data quality within a CIS. It proposes a principle of Data Quality Probes (DQP) that can be used to assess the performance of the whole encounter system. The main feature of this is the generation of a query which clinical knowledge predicts should not retrieve any cases in a system performing flawlessly. This approach is applied practically within the paradigm of a UK family practice testing the DQP that only patients who have had a hysterectomy should be prescribed unopposed oestrogen hormone replacement therapy. PMID- 11604903 TI - Computer-based diagnostic support systems in histopathology: what should they do? AB - In many fields in histopathology diagnosis making is notoriously difficult. We explored the diagnostic process in the area of CL and related disorders. The field of cutaneous lymphomas (CL) and borderline lesions is complex and representative for the type of diagnostic problems encountered. A review of diagnostic support systems in diagnostic pathology revealed that the usefulness of these systems has been disappointing. We contribute this to the fact that these systems target only part of the diagnostic process. A tentative model of diagnosis making in pathology is presented. This model assumes a two-step process, from observation to feature recognition and from features to diagnosis. In a retrospective study of existing skin biopsy pathology reports we assessed detail and scope of the histological descriptions. In a second, prospective study, a pathologist panel described a set of 16 skin biopsies using a standard set of descriptors. The retrospective study showed a large variability in the nature and details of described features, whereas the prospective study showed lack of consensus regarding both feature descriptions and diagnostic category. Both studies provide an indication that lack of consensus in feature recognition may be an important contributor to lack of consensus at the diagnostic level. Diagnostic expert systems target the step from feature to diagnosis. Evidently different input into such systems produces different output. We conclude that support of the feature recognition step can contribute to better diagnostic consensus because of more uniform interpretation of observations. PMID- 11604904 TI - An innovative approach to research and development: the CEFRIEL experience. AB - CEFRIEL (Centre for Research and Training in Information Technology) is a non profit organization that represents a point of contact among University, Technological Companies and Public Government. Since its foundation in 1988 its goal has been related to the education and the research in Information and Communication Technology (ICT). CEFRIEL constitutes itself in seven areas embracing all the aspects of ICT, from hardware design to software engineering. The enormous number of trained specialized technicians represents the most important result of the Centre: more than 500 specialists and about 100 researchers for the ICT sector. In 1998 CEFRIEL created a new area, the Information and communication TEchnology for Medicine area (ITEM), as the result of the previous positive experiences in the healthcare field. In the last two years the results obtained by the ITEM area show that CEFRIEL's approach could be profitable also in the healthcare sector. These activities represent a natural outlet for the expertise and skills collected and enrich the contents of the training courses through continuous reference to the realities of the Industry and the Service sector. PMID- 11604905 TI - Technology as an aid to coping with caring: a usability evaluation of a telematics intervention. AB - This paper presents evaluation data for an interactive software program designed to provide family carers with information, advice and psychological support by way of feedback of their coping capacity. The multimedia program consists of an information-based package that provides carers with advice on health promotion and relaxation and offers them a range of coping strategies (for example, positive self-talk, assertiveness training and relaxation tapes and videos). The program also includes a carer's self-assessment instrument, designed to provide both family and professional carers with information to assess how family carers are coping with their care-giving role. As part of the usability evaluation, casual users (family carers, professional carers and older people) were invited to test the program and were administered a program evaluation questionnaire measuring quality and efficiency in utility and usability. Quantitative data were analysed by using the Statistical Package for the Social Sciences (SPSS) and qualitative data were analysed by content analysis. Findings indicated that the program is visually pleasant, easily understood, responds quickly and corresponds with user expectations. A number of recommendations are made for improvement of the navigation of the program. PMID- 11604906 TI - Computerised clinical pathway as process quality improvement tool. AB - Experiences from other industries show that process quality improvement (PQI) is far more effective than product quality assurance in ensuring quality outputs and cost savings. The PQI approach is becoming more important to the healthcare industry as healthcare professionals struggle to cope with increasing demands for productivity gains, the raising patient acuity and need to curtail the large number of adverse medical events. This paper presents a continuous process quality improvement operational model for healthcare quality improvement and operationalization of the model through the implementation of a computerised clinical pathway management system (CCPMS). It also reports on a small-scale evaluative study conducted to assess the effectiveness of the PQI approach using the CCMPS prototype. PMID- 11604907 TI - Telehealth technology: consequences for structure through use. AB - In recent years the focus of ICTs in healthcare has changed from the a back office' to the front end of patient care. These changes have been brought about by a number of factors including the potential of technologies, pressures for modernisation and administrative reforms, including blurring of the boundaries between different organisations (within and beyond the health sector), and which break down traditional barriers between administration of health services and the practice of medicine In this paper we explore in particular how technology is implicated in such changes, focussing on the consequences of the use of the new telehealth technologies, as seen in a set of linked case studies from an inner city borough in London. The paper addresses the way these technologies, through routine use, become (or not) resources and rules that embody new structures for health care. PMID- 11604908 TI - Telehealth success: evaluation framework development. AB - Implementing telehealth applications represents a substantial investment of resources, which is one reason why success is of great interest. Many research and evaluation studies have investigated measures of successful telehealth systems. However, the term "telehealth" represents a wide range of variables including clinical application, characteristics of the information being transmitted, temporal relationships of data transfer and the organizational context. These sources of variability pose many challenges for evaluation as well as for building a cumulative history of research. A conceptual framework is required that assists in categorizing results and drawing conclusions based on an accumulation of findings. One measure of "success" in health care is quality patient care and this reflects a primary reason for ICT investments. For this reason, Donabedian's work in evaluating quality provides the basis for the proposed framework. DeLone and McLean's definitions of IS success assist in conceptualizing Donabedian's structure-outcome-process variables in a telehealth context. Multiple evaluation approaches have been used to address different types of questions. Prior to the technologies being introduced to clinical care, there are usually many studies to demonstrate their effectiveness. Health Technology Assessment examines a broader context than the technology alone, including costs and comparing alternatives that would exist in the absence of telehealth. It considers performance measures; outcomes; summary measures, operational considerations, and other issues. Program Evaluation examines use of the technology to provide a service or deliver a program. Evaluation questions often address whether the program goals have been met and if it is operating as expected. Perhaps of greater concern than the evaluation approach taken is generalizability of findings. Recent studies have given inadequate attention to defining what is done (i.e. comparison of telehealth to most appropriate alternative), identifying the beneficiaries of telehealth (i.e. ensuring randomly selected participants take part) and what is measured (i.e. including benefits, drawbacks and side effects of telehealth). Evaluation efforts and frameworks have identified "success" factors such as technical acceptability of the system, cost/benefit/effectiveness, organizational support, satisfaction, recruitment and retention, client outcomes such as quality of life, acceptance by consumers and providers. Less is known about the relationship among these variables and whether the findings around one variable are generalizable to other settings or applications. For example, organizational support may be essential for successful provider-patient interactions via videoconference, which result in higher quality of life. A conceptual framework would assist in accumulating this type of evidence and supporting more advanced research efforts. PMID- 11604909 TI - Investigation and evaluation of the change in the outpatients flow before and after the move of the hospital. AB - In order to estimate the changes in the service for outpatients with hospital movement, patient flow investigation has been performed at both old and new hospitals. IC memory card was handed out to each outpatient, and timestamps and places were recorded on the card at the places that the patient have been by using card writers set at each department. By comparing with two results, old and new hospitals, patient-waiting time at payment counter was remarkably shortened because of the effect of order-entry system. However, there were few changes in stay time at clinical departments. From the results, it is found that optimization of booking system was required for improvement of patients flow at clinical departments. PMID- 11604910 TI - The power distance between users of information technology and experts and satisfaction with the information system: implication for cross cultural transfer of IT. AB - There is a need for research into Information Technology (IT) transfer from one culture to another. Two of the more important cultural factors which affects IT transfer are power distance and uncertainty avoidance. The IT expert, by virtue of specialized knowledge is in a position of power. The user of information technology may or may not accept the authority of the IT professional. When the user and the expert is in agreement on the issue of power-distance the IT systems provided will be viewed in a more positive light. This hypothesis is tested and confirmed in the present study. A list of twelve statements expressing special IT knowledge and authority was constructed and a sample of IT experts and users were asked to rate their level of agreement with these on a scale 0 to 5. The simple sum of respondent rating was used as a measure of acceptance of IT authority and power. Users were also asked to rate their level of satisfaction with the progress of a new Hospital Information System been implemented. The IT acceptance score of users who were satisfied with implementation progress did not differ from IT personnel but differed significantly from users who were not satisfied with progress. This study has implications for cross culture transfer of IT. PMID- 11604911 TI - Workflow design as a basis for component interaction. AB - This paper presents a workflow case study on radiation therapy. The workflow model was developed with a conventional CASE tool aiming to effectively support further developments in respective directions of simulation, effects on organisational structures, quality assurance, component interaction and logistics of information with efficient human-computer interactions. PMID- 11604912 TI - The coming of age of computerized ECG processing: can it replace the cardiologist in epidemiological studies and clinical trials? AB - In spite of decades of research and widespread use of computer programs for the analysis of electrocardiograms (ECGs), the accuracy and usefulness of computerized ECG processing has been questioned. To determine whether ECG computer programs can replace cardiologists in epidemiological studies and clinical trials, we reviewed the literature for evidence, concentrating on one influential ECG measurement, viz. QT interval duration, and one classification method, the Minnesota Code, which is the de facto standard for ECG coding. We compared interobserver variabilities of cardiologists with differences between computer programs and cardiologists, in order not to prejudice against the computer. Studies that contain this type of information indicate that interobserver variabilities are at least as large as differences between computer and cardiologist. This suggests that ECG computer programs perform at least equally well as human observers in ECG measurement and coding, and can replace the cardiologist in epidemiological studies and clinical trials. PMID- 11604913 TI - Economic analysis of a filmless system based on the hospital information system. AB - A filmless system (FLS) based on a picture archiving and communication system (PACS) equipped with UNIX work- stations and a local area network (LAN) specialized for viewing radiographs has not been deemed acceptable, for reasons of economics. However, personal computers (PCs) have recently become more powerful, to the point where PCs approach UNIX workstations in terms of capabilities. As a result, a PC-based image viewing workstation (IVW) has sufficient functions for practical use. Diagnostic resolution is not equal to that of film, but is comparable. Since the hospital information system (HIS) includes many PC terminals connected by a LAN, the cost problem can be resolved by using these PC terminals as the IVWs. In order to investigate the practicability of this idea, two types of FLSs using HIS facilities were designed: one is a system based on the use of high-resolution cathode ray tubes (H-CRTs), and the other is based on the use of conventional CRTs and radiologist reports, minimizing the number of H-CRTs. The total costs of the two systems were analyzed. As a result, the former FLS was found to be about 15% more expensive than the latter, which was less expensive than a film-based system (FBS). However, whether the FLS is more profitable than the FBS from the viewpoint of hospital management strongly depends on the medical insurance system. PMID- 11604914 TI - A system for evaluating inpatient care cost-efficiency in a hospital. AB - The cost-efficiency evaluation is one important aspect in the health care organization performance assessment. This paper introduces the ratio of exact cost to Relative Intensity Weights, cost per case weight, as one indicator. A statistical approach for cost-efficiency analyses is presented in this paper. The analyses would be done at the population level and patient level. The linkage between population and individual patients provides the capability to review the distributions of several cost-efficiency measures and to do further studies, including factor adjustment. A well established health care data warehouse is to accomplish a timely and evaluation of the cost-efficiency in hospital. PMID- 11604915 TI - Design of a computerized system for the retrospective analysis by the physician of his own drug prescriptions. AB - The quality of drug prescription is known to be poor in many medical domains. Feedback information may help the physician to improve this component of his medical activity. The increasing use of computerized drug prescription systems makes possible the retrospective processing of prescriptions made over a given time period. This paper describes the design of a computerized system for providing feedback information to the physician about the quality of his drug prescribing activity. It is designed to be used by the physician himself. The analysis is based on two groups of quantitative indicators, simple and composite. The constraints that must be satisfied to calculate these indices automatically are given. They are related to the coding systems used for drug prescription, knowledge on drugs and patient data. The system design is based on modeling according to UML formalism. We give also a concrete view of the main functions of the system, based on a pictorial illustration with a component of the user interface. Some limitations and the possible extensions of this system for analyzing simultaneously the prescriptions made by set of physicians are discussed. PMID- 11604916 TI - Adaptation of the critical incident technique to requirements engineering in public health. AB - The introduction of modern information systems in public health provides new possibilities for improvements in public health services and hence also of population's health. However, development of information systems that truly supports public health practices requires that technical, cognitive, and social issues be taken into consideration. In requirements engineering for public health, a notable problem is that of capturing all aspects of the future user's voices, i.e., the viewpoints of different public health practitioners. Failing to capture these voices will result in inefficient or even useless systems. The aim of this paper is to report a requirements-engineering instrument to describe problems in the daily work of public health professionals. The issues of concern thus captured can be used as the basis for formulating the requirements of information systems for public health professionals. PMID- 11604917 TI - IT sophistication in hospitals : a field study in Quebec. AB - The Quebec health sector has been experiencing a period of great turmoil over the last five years and hospitals are faced with huge pressures from government funding cuts. Several empirical studies in the information systems field have shown that the use of computer-based information systems could have positive impacts on organizational performance. Many agree to say that health care institutions are no exceptions. But if one wishes to identify the effects of IT on the delivery of care, one must be able to characterize IT for operationalization purposes. Our main objective consists in developing and validating a measurement instrument of IT sophistication in hospitals. Such instrument should provide hospital managers with a diagnostic tool capable of indicating the profile of their respective institutions in regard to IT use and comparing this profile to those of other similar health institutions. PMID- 11604918 TI - Simulation of a stroke unit careflow. AB - This paper describes the development and use of a simulation model representing part of the medical practice within a Stroke Unit. In particular, we modelled the medical activities as described in a guideline for the ischemic stroke treatment, adopted by the Stroke Unit of our hospital. The Petri net formalism has been chosen for the model representation. The numerical parameters have been estimated both using a database of about 100 patients collected during the last two years, and eliciting knowledge from the neurologists. A commercial tool was used for performing simulations, while ad-hoc routines were written for tailoring the result presentation to the specific context. We consider simulation a very useful preliminary step for the subsequent implementation of a patient workflow (careflow) management system. In fact, simulation is based on the process model (the clinical practice guideline) and on the organisation model (human and technological resources), so allowing to detect bottlenecks in the care delivery organisation and to find the optimal resource allocation. For example, we show that simulation has been able to find some of the causes of the delay in the patients treatment, and accordingly, to suggest changes in the organisation. PMID- 11604920 TI - Evaluation: 16 powerful reasons why not to do it--and 6 over-riding imperatives. AB - Evaluation is a concept which appears logical, and supplies the evidence which is sought by policy makers and those interested in obtaining and implementing an information system. However, it is difficult to obtain resources or other support to undertake evaluation studies, and indeed active opposition is often encountered. Unless this mistaken attitude is analysed and overcome, it will be impossible to optimise system applications, produce sound information policies, or practice evidence-based decision making in the information field. Experience is drawn from a range of applications in order to analyse the issues. PMID- 11604919 TI - Academic and commercial development of open source applications in international health informatics. Opposite sides of the same coin? AB - Whilst covertly in the past many ideas developed in academic environments have made their way into commercial applications, there is growing acknowledgment that this model may be necessary for both funding academics and for project enrichment in private ventures. This paper seeks to explore and expound on the various pressures related to protocol development and the creation of a MAP (Multiphasic Algorithimic Protocol) Engine as a commercial venture based on an evolution from an academic environment, into a service oriented commercial product. It has been determined in a series of symposia that an Object Oriented; Open Source (OS) environment may best meet the needs for this endeavor. Numerous barriers and agreements remain, and explorations of these will, we believe, bring out the best of both sides of the coin - reflecting the strengths of both cultures. PMID- 11604921 TI - An information system to improve financial management, resource allocation and activity planning: evaluation results. AB - An important strategy for improving resource management and cost containment in health care is to develop information systems that assist hospital managers in financial management, resource allocation, and activity planning. A crucial part of such development is a rigorous evaluation to assess whether the system accomplishes it's intended goals. PURPOSE: To evaluate CLASSICA, a Decision Support System (DSS), that assists nurse managers in financial management, resource allocation, staffing, and activity planning. METHODS: Using a pre-post test design with control units, CLASSICA was evaluated in four test units. Baseline data and simultaneous parallel measures were collected prior to system implementation at test sites and control units. Using expense reports, staffing and financial statistics, surveys, interviews with nurse managers, and logs as data sources, CLASSICA was evaluated on: cost reduction, quality of management information; usefulness as decision support for improved financial management and decision-making; user satisfaction; and ease of use. RESULTS: Evaluation results showed a 41% reduction in expenditures for overtime and extra hours as compared to a 1.8% reduction in control units during the same time period. Users reported a significant improvement in management information; nurse managers stated that they had gained control over costs. The system helped them analyze the relationships between patient activity staffing, and cost of care. Users reported high satisfaction with the system, the information and decision support it provided, and its ease of use. These results suggest that CLASSICA is a DSS that successfully assists nurse managers in cost effective management of their units. PMID- 11604922 TI - Comparison of time spent writing orders on paper with computerized physician order entry. AB - Computerized physician order entry (CPOE) has been shown to improve quality, and to reduce resource utilization, but most available data suggest that it takes longer to enter orders using CPOE. We had previously implemented a CPOE system, and elected to evaluate its impact on physician time in the new setting. To do this, we performed a prospective study using random reminder methodology. Key findings were that interns spent 9.0% of their time ordering with CPOE, compared to 2.1% before, although CPOE saved them an additional 2% of time, so that the net difference was 5% of their total time. However, this is counterbalanced by decreased time for other personnel such as nursing and pharmacy, and by the quality and efficiency changes. We conclude that while CPOE has many benefits, it represents a major process change, and organizations must factor this in when they implement it. PMID- 11604923 TI - Electronic health summaries--building on the foundation of Scottish Record Linkage system. AB - Developing electronic patient records is currently a priority for Health Services, so that the clinician treating the patient has all the relevant information available on the desktop. However, as with paper records, there is the danger of information overload, with key information being missed. It is now recognized that electronic health summaries of patient events will be needed. This paper describes the Scottish Record Linkage system, which has been routinely used over the last 10 years to build event histories for patients in the NHS in Scotland. Probability matching has been used to identify records belonging to an individual since a unique patient identification number has not been in general use. We present examples of use of this rich information resource, either for clinical decision making, evidence based medicine, or population needs assessment, and investigate how the system may be developed in a data-warehousing environment to populate electronic health summaries for the five million residents of Scotland. PMID- 11604924 TI - Info-vigilance or safety in health information systems. AB - The paper examines the issues of security and safety in Health Information Systems and focuses the need for the development of appropriate Guidelines for the effective use of IEC 61508 standard. PMID- 11604925 TI - Enhanced security services for enabling pan-European healthcare networks. AB - Establishing the Shared Care environment, communication and co-operation between healthcare establishments involved must be provided in a trustworthy way. This challenge is even more important for health networks using the Internet. In that context, services assuring both communication security and application security must be provided. Especially in the e-health environment, additionally to identity-related services certifying data or properties of principals, trustworthiness or authorisation for objects, components and functions must be established by Trusted Third Parties (TTP). Within the European Commission's Information Society Technologies (IST) Programme, the HARP project provides the "HARP Cross-Security Platform (HCSP)" needed in the open Web environment of pan European networks. The solutions are under implementation and evaluation in the German ONCONET enabling a trustworthy framework for both health professionals and patients as well as supporting clinical studies. PMID- 11604926 TI - The Swiss solution for anonymously chaining patient files. AB - Being able to link the successive hospitalizations of a given patient for epidemiological surveys together by preserving patient anonymity requires a specific procedure. For its medical hospital statistics, Switzerland has adopted anonymous record linkage procedure, ensuring an irreversible transformation of identity and allowing the linkage of anonymous files. Concepts, algorithms and organization have been developed by the Federal Statistical Office. Algorithms are closed to those developed in Dijon University Hospital. PMID- 11604927 TI - An overview in healthcare information systems security. AB - The scope of this paper is to present the current needs and trends in the field of healthcare systems security. The approach applied within the described review was based on three major steps. The first step was to define the point and ways of penetration and integration of security services in current healthcare related applications addressing technical, organisational and legal/regulatory issues. The second step was to specify and evaluate common security technologies applied in healthcare information systems pointing out gaps and efficient solutions, whereas the third was to draw conclusions for the present conditions and identify the future trends of healthcare information security. A number of EU RTD Projects were selected, categorised, analysed and comparatively evaluated in terms of security. The technical focus was on key security technologies, like Public Key Infrastructures (PKIs) based on Trusted Third Parties (TTPs) in conjunction with other state-of-the-art security components (programming tools, data representation formats, security standards and protocols, security policies and risk assessment techniques). The experience gained within this review will provide valuable input for future security applications in the healthcare sector, solving existing problems and addressing real user needs. PMID- 11604928 TI - Security architecture for HL/7 message interchange. AB - The promotion of quality medical treatment is very important to the healthcare providers as well as to patients. It requires that the medical resources of different hospitals be combined to ensure that medical information is shared and that resources are not wasted. A computer-based patient record is one of the best methods to accomplish the interchange of the patient's clinical data. In our system, the Health Level/Seven (HL/7) format is used for the interchange of the clinical data, as it has been supported by many healthcare providers and become a a standard'. The security of the interchange of clinical data is a serious issue for people using the Internet for data communication. Several international well developed security algorithms, models and secure policies are adopted in the design of a security handler for an HL/7 architecture. The goal of our system is to combine our security system with the end-to-end communication systems constructed from the HL/7 format to establish a safe delivery channel. A suitable security interchange environment is implemented to address some shortcomings in clinical data interchange. located at the application layer of the ISO/OSI reference model. The medical message components, sub-components, and related types of message event are the primary goals of the HL/7 protocols. The patient management system, the doctor's system for recording his advice, examination and diagnosis as well as any financial management system are all covered by the HL/7 protocols. Healthcare providers and hospitals in Taiwan are very interested in developing the HL/7 protocols as a common standard for clinical data interchange. PMID- 11604929 TI - Electronic signature and certification models in health care. AB - Recently, Belgian legislation has enabled the practical use of electronic signatures. Several implementation options are still open and different models for deployment on a wide scale are possible. This document describes two models that can be applied to the healthcare domain and summarises the recommendations as issued by the Belgian Health Telematics Standards Committee PMID- 11604930 TI - Towards second-generation smart card-based authentication in health information systems: the secure server model. AB - Conventional smart card-based authentication systems used in health care alleviate some of the security issues in user and system authentication. Existing models still do not cover all security aspects. To enable new protective measures to be developed, an extended model of the authentication process is presented. This model includes a new entity referred to as secure server. Assuming a secure server, a method where the smart card is aware of the status of the terminal integrity verification becomes feasible. The card can then act upon this knowledge and restrict the exposure of sensitive information to the terminal as required in order to minimize the risks. The secure server model can be used to illuminate the weaknesses of current approaches and the need for extensions which alleviate the resulting risks. PMID- 11604931 TI - Expert systems, security and quality assurance: implications of patient records as data-space. AB - The concept of data-space is fruitful in trying to understand the ethical rights and duties that surround the treatment of patient records. However, it also provides a solution to three apparently unconnected problems: the construction of expert diagnostic systems, the development of an internal security element within the sphere of permitted data-access for health care professionals, and the development of a professional quality assurance mechanism. This paper presents a model of how these diverse aims may be achieved. It does so by developing the notion of the logical form of data within a data-space and by showing how the path taken by a health care professional through a profession-relative data-space can provide checks for the security, quality and appropriateness of the path itself. The result is important in that it provides an integrated method for information specialists to meet their fiduciary obligations towards the patients whose records are in their care, and towards the institutions that employ them. PMID- 11604932 TI - Security development of a pocket-sized teleradiology consultation system. AB - Telemedicine widens the access to sensitive data and therefore data security development is an essential part of telemedicine projects. Publicly available security evaluation methods provide a good starting point for security work. We built a mobile teleradiology consultation system that is integrated into hospital information system and systematically evaluated possible security threats that may endanger it. Based on the analysis, a security model was designed and implemented. We conclude that systematic approach to data security development facilitates the process but does not give all answers to the practical questions. PMID- 11604933 TI - Establishing a national patient information system on the internet in Denmark. AB - During 2000 - 2001 a pilot project is being carried out in Denmark with the aim of establishing the opportunity to look up patient information via the Internet. While this presents great opportunities, it also involves major organisational and technical challenges. PMID- 11604934 TI - The construction of a public key infrastructure for healthcare information networks in Japan. AB - The digital signature is a key technology in the forthcoming Internet society for electronic healthcare as well as for electronic commerce. Efficient exchanges of authorized information with a digital signature in healthcare information networks require a construction of a public key infrastructure (PKI). In order to introduce a PKI to healthcare information networks in Japan, we proposed a development of a user authentication system based on a PKI for user management, user authentication and privilege management of healthcare information systems. In this paper, we describe the design of the user authentication system and its implementation. The user authentication system provides a certification authority service and a privilege management service while it is comprised of a user authentication client and user authentication serves. It is designed on a basis of an X.509 PKI and is implemented with using OpenSSL and OpenLDAP. It was incorporated into the financial information management system for the national university hospitals and has been successfully working for about one year. The hospitals plan to use it as a user authentication method for their whole healthcare information systems. One implementation of the system is free to the national university hospitals with permission of the Japanese Ministry of Education, Culture, Sports, Science and Technology. Another implementation is open to the other healthcare institutes by support of the Medical Information System Development Center (MEDIS-DC). We are moving forward to a nation-wide construction of a PKI for healthcare information networks based on it. PMID- 11604935 TI - Medical internet ethics: a field in evolution. AB - As in any new field, the merger of medicine, e-commerce and the Internet raises many questions pertaining to ethical conduct. Key issues include defining the essence of the patient-provider relationship, establishing guidelines and training for practicing online medicine and therapy, setting standards for ethical online research, determining guidelines for providing quality healthcare information and requiring ethical conduct for medical and health websites. Physicians who follow their professional code of ethics are obligated not to exploit the relationship they have with patients, nor allow anyone else working with them to do so. Physicians and therapists are obligated to serve those who place trust in them for treatment, whether in face-to-face or online Internet encounters with patients or clients. This ethical responsibility to patients and clients is often in direct conflict with the business model of generating profits. Healthcare professionals involved in Medical Internet Ethics need to define the scope of competent medical and healthcare on the Internet. The emerging ethical issues facing medicine on the Internet, the current state of medical ethics on the Internet and questions for future directions of study in this evolving field are reviewed in this paper. PMID- 11604936 TI - Privacy of genetic information: a review of the laws in the United States. AB - This paper examines the privacy of genetic information and the laws in the United States designed to protect genetic privacy. While all 50 states have laws protecting the privacy of health information, there are many states that have additional laws that carve out additional protections specifically for genetic information. The majority of the individual states have enacted legislation to protect individuals from discrimination on the basis of genetic information, and most of this legislation also has provisions to protect the privacy of genetic information. On the Federal level, there has been no antidiscrimination or genetic privacy legislation. Secretary Donna Shalala of the Department of Health and Human Services has issued proposed regulations to protect the privacy of individually identifiable health information. These regulations encompass individually identifiable health information and do not make specific provisions for genetic information. The variety of laws regarding genetic privacy, some found in statutes to protect health information and some found in statutes to prevent genetic discrimination, presents challenges to those charged with administering and executing these laws. PMID- 11604937 TI - Suggested principles of professional ethics for the online provision of mental health services. AB - The goal of this project was to suggest principles of professional ethics for the online provision of clinical mental health services that could guide both clinicians who provide and patients who receive such services. A joint committee of the International Society for Mental Health Online (ISMHO) and the Psychiatric Society for Informatics (PSI) was formed. Discussion and development of these principles took place online. A set of principles was produced and endorsed by ISMHO on January 9, 2000, and by PSI on May 13, 2000. The principles involve informed consent (about the process, the clinician, the potential risks and benefits, safeguards, and alternatives), standard operating procedure (competence, legal requirements, the structure of the services, evaluation, multiple treatment providers, confidentiality, records, and existing guidelines), and emergencies (procedures and local backup). This project demonstrates that traditional principles of professional ethics can be extended to online services, that comprehensive ethical principles can be developed by groups that cross disciplinary and national boundaries, and that productive collaboration can take place entirely online; and suggest that online clinicians have the potential to regulate themselves. PMID- 11604938 TI - Barriers and resistance to informatics in behavioral health. AB - The levels of resistance to a new informatics system can vary widely both between and among specific groups. The relevance to today's behavioral medicine area is obvious. The aim of effective change management techniques is not to eliminate all resistance. This is typically impossible when a group of any size is involved. The aims are (1) to keep initial general resistance at reasonable levels, (2) to pre-vent that initial resistance from growing to serious levels, and (3) to identify and deal with any pockets of serious resistance that do occur despite the previous efforts. His article outlines areas of resistance to behavioral informatics and offers suggestions for overcoming the resistance. PMID- 11604939 TI - Diagnosis supporting rules of the Hepar system. AB - The "Hepar" system comprises a clinical database and the shell of procedures that aim at data analysis and the support of diagnosis. The database consists of hepatological patient cases. Each case is described by about 200 medical findings and histopathologically verified diagnosis. The diagnosis supporting rules of "Hepar" are based on visualizing data transformations and on the similarity based techniques. The applied linear visualizing transformations of data sets on the plane aim at separating of the groups of patients associated with different diseases. The resulting diagnostic maps by the visual inspection allow to find such cases in the database that are similar to the previously diagnosed patients. This paper examines combining of data transformations with the nearest neighbors techniques in the support of diagnosis. We report the results on the experimental comparisons of different decision rules including the feature selection procedure. PMID- 11604940 TI - Logistic regression model: an assessment of variability of predictions. AB - Risk prediction models available for cardiovascular prevention are statistical or based on machine learning methods. This paper investigates whether the logistic regression method can be considered as reference for validation of other methods. In order to test the stability of the predictions using this method, we performed two types of analyses on 50 random training and test samples drawn from the same database. In first analyses three models were obtained by forced entry of different sets of four variables. In second analyses, models were built with increasing number of predictive variables. The predictive performance was assessed by the area under the ROC curve. Although across-samples variability is low for a given model, it is large enough to lead to wrong conclusions when comparing different prediction methods. We also suggest that a low events-per variable ratio alters the stability of a model's coefficients but does not affect the variability of prediction performance. PMID- 11604941 TI - A demographic database for monitoring community life support skills. AB - Training in community life support has been shown to lessen the mortality from sudden myocardial events 1. Such community training is badly quantified and its efficacy difficult to prove. In a diversity of communities in the West of Scotland emergency life support (ELS) training schemes have been set up in localities ranging from isolated islands to urban centres with considerable social disadvantage. An Access database 2 was created that has captured demographic data about those trained. This simple technique, with data-capture from a wide range of lay trainers, is demonstrating at its crudest exactly how many have been trained. It can show population rates of training and compare these with the international target of 20% of the population. It highlights the age bands of those trained and whether the socially disadvantaged are having equitable training. UK Post-code (Zip-code) has in parallel with other Scottish work 3 been used as a proxy for social circumstances. The greatest value of the database is that it is ready to be married up with national data from the Scottish Ambulance Service and allied studies 4 to show over time how effective the training is in altering mortality. The effort in creating and maintaining such an epidemiological database requires faith. It is the "posterity planting" of modern public health medicine. PMID- 11604942 TI - XML-based visual data mining in medicine. AB - Medical databases in general are characterized by a high degree of complexity in terms of quantity of items, number of parameter values and data types (free text, categorical, numerical and other). Substantial domain knowledge is required for adequate formalization of medical entities. In this context we developed medical database plot (mdplot), a data mining tool to visualize both structure and quality of data in medical databases to identify items suitable for evaluation. Data models are provided in XML format. Missing data is identified to enable targeted efforts to improve data quality prior to analysis. Database items are classified as 1:1- related to the patient (i.e. variables are collected once per patient) and 1:n related. mdplot provides a list of all classes contained in a database, the number of records each and a condensed bar chart for semi quantitative description of completeness according to four types of items: categorical, numerical, text and other. All items in a category are grouped from left to right, the height of each bar represents the proportion of non-missing values with respect to the total number of records in the class; thus the amount of content in a specific class is visualized. By selection of a specific class, a detailed description of it is provided including mean completeness in each item category as well as number of values per item. The new methodology was applied to a cardiological research database consisting of 619 items on 88 patients. PMID- 11604943 TI - From data collection to knowledge data discovery: a medical application of data mining. AB - Prison inmates are exposed to a variety of major risk factors (psychiatric disorders, suicide attempts, illicit drug use). From 1986 to 1996, the USA prison population more than doubled while in France, it increased from 35655 in 1980 to 51623 in 1995. In spite of these findings, very little information concerning the inmates population is available. At the present time, there is a desire to adopt a policy based on the prevention of recidivism, on adequate release planning and referrals to community-based services. The aim of the RAPPEL project was to build an information system for assessing the social and health status of prison inmates. The pilot project was set up at the prison of Loos and allowed the collection and analysis of nearly 15000 records. The aim of this paper is to present the extension of the project consisting in developing a regional network grouping 11 jails. Information locally available will serve as the basis for the information system of regional jails. Data mining techniques will provide solutions for the extraction of new information. Three data mining tools were experimented : association rules, classification trees and clustering. Further extension consists in a distributed approach allowing direct access to the information system by WEB tools. PMID- 11604944 TI - Exploiting the nursing minimum data set for the Netherlands. AB - The purpose of this overview is to examine and illustrate the feasible options for the statistical analysis of the Nursing Minimum Data Set for the Netherlands. Distinct purposes for information use and for the presentation of information require different approaches for data collection and data analysis. Several explorative studies are discussed, illustrating their goals, data collection methods, data analysis and results. The overview ends with general recommendations for data collection and analysis of nursing minimum data sets. PMID- 11604945 TI - Studies on improved model for cerebrovascular blood circulation. AB - For the elastic cavity model adopted in the existing cerebrovascular hemodynamics analyzers was too simple, we developed the improved model for cerebrovascular blood circulation to describe more exactly the physiologic nature of both sides cerebrovascular blood circulation and the relation between them (Willis Circle). It was a network consisting of 2 inputs, 9 arteries and 4 terminal flow resistances. For two cases, constant flow and pulsating flow, the further improved models for calculability were analyzed and the mathematical equations describing the model was obtained; some algorithms were given to solve the positive and negative problems to the mathematical functions; the physiologic means to parameters in the model were defined; at last, the possible applications of the models in basic research and clinic about cerebrovascular disease were stated as well. In the paper, we compared our portable cerebrovascular hemodynamics analyzer with the improved model to other analyzers with the elastic cavity model, and concluded that because of providing additional M-style ultrasonic detector for measuring the diameters of blood vessels and improving the Doppler ultrasonic detector for measuring the velocity of blood flow of the internal carotid artery we could accept the improved model to obtain more exact and more details and the relation about cerebrovascular blood circulation and hemodynamics. PMID- 11604946 TI - Supporting discovery in medicine by association rule mining in Medline and UMLS. AB - The paper presents an interactive discovery support system for the field of medicine. The intended users of the system are medical researchers. The goal of the system is: for a given starting concept of interest, discover new, potentially meaningful relations with other concepts that have not been published in the medical literature before. The known relations between the medical concepts come from the Medline bibliographic database and the UMLS. We use association rules for discovering the relationship between medical concepts. We evaluated the system by testing how successfully it predicted future discoveries (new relations between concepts). We first divided the Medline database into two segments (older and newer) using the publication date. Then we calculated how many of the new relations found by the system in the older segment become known relations in the newer segment. We found out with statistical significance that the system predicts new relations better then someone predicting randomly. The evaluation showed that our approach for supporting discovery in medicine is successful, but also that some improvements are needed, especially on limiting the number of potential discoveries the system generates. PMID- 11604947 TI - The use of consequential reasoning in cancer chemotherapy. AB - Knowledge-based decision support systems traditionally rely on condition-action rule structures, an adequate representation for simple decisions. In complex domains an important part of decision-making includes analysis of the consequences of a decision. Consequential reasoning is particularly important in medicine as potential risk and/or benefit can be included. In this paper, a knowledge structure and inference engine is described that permits the representation and analysis of consequential reasoning in a computer-assisted decision support system. The use of consequential reasoning is then illustrated in an application designed to assist in cancer chemotherapy decisions. The result is a method that is sensitive to individual patient reactions to chemotherapy agents, permitting an individualized approach to therapy. Individualized drug therapy is becoming increasingly feasible due to advances made in the field of genomics. The system is structured so that new information can be incorporated easily. Although the application shown here is to chemotherapy, the general methodology can be used in any area in which the consequences should significantly influence the decision. PMID- 11604948 TI - Knowledge discovering from clinical data based on classification tasks solving. AB - After the abundant literature on normative decision analysis centered on Bayes' rule, the artificial intelligence approach left aside the proposed formalism in favor of symbolic approach. Thus, diagnosis was identified as a dynamic cognitive process, characterized by the search for evidence to test a given hypothesis where heuristic thinking plays a significant role. Approach presented in this study is knowledge discovering system to test a given (manually or automatically) hypothesis, based on three mathematical models of classification: model of classes stability, model of linear envelope, model of multilayer neural network. All the models characterizes as quantitative methods, and works as cognitive tools for new laws searching. PMID- 11604949 TI - UMIN--key information infrastructure for the Japanese medical community. AB - University hospital Medical Information Network (UMIN) was established in 1989 as a collaborative project of national university hospitals in Japan funded by the Ministry of Education, Science, Sports, and Culture, and it started its Internet based service for medical professionals in 1995. Since then, many services including those for academic societies and research groups have been added. Currently, due to batch registration of the members of large academic societies, the number of registered users and Web accesses are rapidly increasing (about 87,000 registered users and 4,500,000 page views in November, 2000). More than one hundred homepages of academic societies and research groups (including forty- two member-only ones) and one thousand mailing lists are operated. More than one hundred thirty academic societies collect abstracts using the UMIN server. All the Internet-based clinical and epidemiological research projects in Japan are now under way using UMIN. The characteristics of UMIN are its large variety of services and large number of user accounts of medical professionals, which are beneficial to both users and information service providers. UMIN is now important for some medical specialties and will be so for further ones in the future. UMIN is, in fact, evolving into a collaborative project of the Japanese medical community and is considered as its key information infrastructure. PMID- 11604950 TI - Sharing medical data for patient path analysis with data mining method. AB - The Agora Data project started in October 1997 in France. The objective was to share medical data between several medical institutions to analysis medical care pathways for patients that suffer from low back pain. The analysis of the medical records decomposed in three steps allowed us to produce knowledge on medical contacts of patients with the health care system. In order to study the relations between these contacts, we created medical path of patients within the framework of the possible contacts we had isolated. This work relates the implementation and the first results of the pilot study. PMID- 11604951 TI - Assessment of the GALEN methodology on holistic classifications for professions allied to medicine. AB - In the field of health care terminology it has proven to be difficult, but not impossible, to build a formal Reference Model (knowledge-model) for medical terminology. The intuition is that it is even more difficult to build such a reference model for the so called a holistic' classification schemes as used by Nursing and Allied Health Care Professionals. There is a growing perceived need for formal reference models for specific professional groups. These reference models are used in many different ways, such as for building, maintaining and manipulating classification schemes. This paper focuses on the usability of the GALEN methodology for the formalisation of the Dutch Classification of Pain (NCP) as an example of such a a holistic classification'. The first results of this exploration show that the GALEN methodology is very useful for analysing and understanding a' holistic classification'. A high number of necessary concepts from the NCP already exist within the OpenGalen Common Reference Model-2 (OCRM2). A substantial number of concepts from the NCP do not yet exist in the OCRM2 or are underspecified. Additional modelling of the OCRM2 has to be performed, to enrich the expressivity of the model. PMID- 11604952 TI - Domain analysis and modeling to improve comparability of health statistics. AB - Health statistics is an essential element to improve the ability of managers of health institutions, healthcare researchers, policy makers, and health professionals to formulate appropriate course of reactions and to make decisions based on evidence. To ensure adequate health statistics, standards are of critical importance. A study on healthcare statistics domain analysis is underway in an effort to improve usability and comparability of health statistics. The ongoing study focuses on structuring the domain knowledge and making the knowledge explicit with a data element dictionary being the core. Supplemental to the dictionary are a domain term list, a terminology dictionary, and a data model to help organize the concepts constituting the health statistics domain. PMID- 11604953 TI - Analysis of patient flows via data mining. AB - The paper presents DoMiner, a data mining tool for the analysis of patient flows among public hospitals and care units. DoMiner is based on the theory of rough sets, and allows for the extraction of association rules from data base tables. The paper describes both the clustering and rule extraction algorithm of DoMiner, and illustrates an introductory analysis example. PMID- 11604954 TI - Adding value to clinical data by linkage to a public death registry. AB - We describe the methodology and impact of merging detailed statewide mortality data into the master patient index tables of the clinical data repository (CDR) of the University of Virginia Health System (UVAHS). We employ three broadly inclusive linkage passes (designed to result in large numbers of false positives) to match the patients in the CDR to those in the statewide files using the following criteria: a) Social Security Number; b) Patient Last Name and Birth Date; c) Patient Last Name and Patient First Name. The results from these initial matches are refined by calculation and assignment of a total score comprised of partial scores depending on the quality of matching between the various identifiers. In order to validate our scoring algorithm, we used those patients known to have died at UVAHS over the eight year period as an internal control. We conclude that we are able to update our CDR with 97% of the deaths from the state source using this scheme. We illustrate the potential of the resulting system to assist caregivers in identification of at-risk patient groups by description of those patients in the CDR who were found to have committed suicide. We suggest that our approach represents an efficient and inexpensive way to enrich hospital data with important outcomes information. PMID- 11604955 TI - Constructing influence views from data to support dynamic decision making in medicine. AB - A dynamic decision model can facilitate the complicated decision-making process in medicine, in which both time and uncertainty are explicitly considered. In this paper, we address the problem of automatic construction of a dynamic decision model from a large medical database. Within the DynaMoL (a dynamic decision modeling language) framework, a model can be represented in influence view. Thus, our proposed approach first learns the structures of the influence view based on the minimal description length (MDL) principle, and then obtains the conditional probabilities of the model by Bayesian method. The experiment results demonstrate that our system can efficiently construct the influence views from data with high fidelity. PMID- 11604956 TI - Nonparametric techniques to extract fuzzy rules for breast cancer diagnosis problem. AB - This paper addresses breast cancer diagnosis problem as a pattern classification problem. Specifically, the problem is studied using Wisconsin-Madison breast cancer data set. Fuzzy rules are generated from the input-output relationship so that the diagnosis becomes easier and transparent for both patients and physicians. For each class, at least one training pattern is chosen as the prototype, provided (a) the maximum membership of the training pattern is in the given class, and (b) among all the training patterns, the neighborhood of this training pattern has the least fuzzy-rough uncertainty in the given class. Using the fuzzy-rough uncertainty, a cluster is constructed around each prototype. Finally, these clusters are interpreted as the fuzzy rules that relate the prognostic factors and the diagnosis results. The advantages of the proposed algorithm are, (a) there is no need to know the structure of the training data, (b) the number of fuzzy rules does not increase with the increase of the number of input dimensions, and (c) small number of fuzzy rules is generated. With the three generated fuzzy rules, 96.20% classification efficiency is achieved, which is comparable to other rule generation techniques. PMID- 11604957 TI - Mining association rules from clinical databases: an intelligent diagnostic process in healthcare. AB - Data mining is the process of discovering interesting knowledge, such as patterns, associations, changes, anomalies and significant structures, from large amounts of data stored in databases, data warehouses, or other information repositories. Mining Associations is one of the techniques involved in the process mentioned above and used in this paper. Association is the discovery of association relationships or correlations among a set of items. The algorithm that was implemented is a basic algorithm for mining association rules, known as a priori. In Healthcare, association rules are considered to be quite useful as they offer the possibility to conduct intelligent diagnosis and extract invaluable information and build important knowledge bases quickly and automatically. The problem of identifying new, unexpected and interesting patterns in medical databases in general, and diabetic data repositories in specific, is considered in this paper. We have applied the a priori algorithm to a database containing records of diabetic patients and attempted to extract association rules from the stored real parameters. The results indicate that the methodology followed may be of good value to the diagnostic procedure, especially when large data volumes are involved. The followed process and the implemented system offer an efficient and effective tool in the management of diabetes. Their clinical relevance and utility await the results of prospective clinical studies currently under investigation. PMID- 11604958 TI - Method to determine the bed capacity, different approaches used for the establishment planning project in the University Hospital of Nancy. AB - In France hospital bed capacity is determined according to a national and regional authorization which has been established by the regional hospital agency. The bed capacity evolution in a hospital is fixed by considering the different proposals of the hospital in negotiation with the regional hospital agency. Types of beds are differentiated according to the patients' needs : medicine, surgery and obstetrics. The first approach is taken at the national level and then at the regional level using a specific ratio of beds for 100,000 inhabitants in each category. For a given hospital, the authorized number of beds takes into consideration their occupation. Target bed occupation ratios were fixed in 1992 and are still in use. In the establishment project of the University Hospital of Nancy (developed over a five year period) four approaches have been formulated and their results have been compared. In this study, the two traditional methods of bed ratio per 100,000 inhabitants and target bed occupation have been updated according to the present conditions of hospitalisation; the third method is based on the reapportionment of the present patients and the possible risk to the hospital for refusing patients. The last method consists of determining the expected pathologies five years in advance in Lorraine and the beds needed to treat them. These four methods have given consistent results under the accepted revised target occupation bed ratios in accordance with the reduction of the length of stay between 1992 and 1999. PMID- 11604959 TI - Record linkage of healthcare insurance claims. AB - Limitations of current record linkage techniques include difficulty in handling large and heterogeneous data sets, low sensitivity in deterministic matching, the necessity to provide a priori weights for probabilistic matching, low computational efficiency, and complex software. This paper provides a detailed description of a method developed for purposes of linking records of individuals across time and geography. The procedure for record-linkage consists of three major components: data standardization, weight estimation, and matching. The proposed method was designed to incorporate a combination of exact and probabilistic matching techniques. The procedure was validated using convergent, divergent, and criterion- validity measures. The authors feel that the procedure outlined in this paper is a first step in addressing the current trend toward larger and more complex databases. PMID- 11604960 TI - Comparison of three databases with a decision tree approach in the medical field of acute appendicitis. AB - Decision trees have been successfully used for years in many medical decision making applications. Transparent representation of acquired knowledge and fast algorithms made decision trees one of the most often used symbolic machine learning approaches. This paper concentrates on the problem of separating acute appendicitis, which is a special problem of acute abdominal pain from other diseases that cause acute abdominal pain by use of an decision tree approach. Early and accurate diagnosing of acute appendicitis is still a difficult and challenging problem in everyday clinical routine. An important factor in the error rate is poor discrimination between acute appendicitis and other diseases that cause acute abdominal pain. This error rate is still high, despite considerable improvements in history-taking and clinical examination, computer aided decision-support and special investigation, such as ultrasound. We investigated three different large databases with cases of acute abdominal pain to complete this task as successful as possible. The results show that the size of the database does not necessary directly influence the success of the decision tree built on it. Surprisingly we got the best results from the decision trees built on the smallest and the biggest database, where the database with medium size (relative to the other two) was not so successful. Despite that we were able to produce decision tree classifiers that were capable of producing correct decisions on test data sets with accuracy up to 84%, sensitivity to acute appendicitis up to 90%, and specificity up to 80% on the same test set. PMID- 11604961 TI - Patient empowerment via 'pushed' delivery of Personalised Healthcare educational content over the internet. AB - We present an Internet-based Personalised Healthcare Information (PHI) dissemination system. Information personalisation is guided by the individual's current health profile as recorded in his/her EMR. A PHI package is composed by intelligently selecting and synthesizing various topic-specific documents, each corresponding to some health parameter noted in the EMR. To ensure medical consistency, constraint satisfaction techniques are employed during the information selection phase. The resultant PHI package--covering both long-term and immediate health-maintenance requirements--can be pro-actively pushed to the individual via email, thereby ensuring the timely availability of situation specific health maintenance information. The featured work is in line with the Malaysian Multimedia Super Corridor Telemedicine initiative and can serve as a test-bed to evaluate the effectiveness of PHI, system design and operational considerations for larger-scale deployment. PMID- 11604962 TI - An Australian case study of patient attitudes towards the use of computerised medical records and unique identifiers. AB - Research into patient attitudes towards the use of technology in health care needs to be given much greater attention within health informatics. Past research has often focused more on the needs of health care providers rather than the end users. This article attempts to redress this knowledge bias by reporting on a case study of the responses gained from patients in a selected Australian medical practice towards the use of computerised medical records and unique identifiers. The responses (n=138) were gained from a survey of patients over a 13 day period of practice operation. This case study serves as an example of the type of future consumer health informatics research which can be undertaken not just in Australia but also in other countries, both at local regional levels and at a national level. PMID- 11604963 TI - Consumer satisfaction with telehealth advice-nursing. AB - An increase in interest in the establishment of telephone advice services has resulted in the proliferation of call centers. Despite their wide usage, research for the most part has not addressed the quality of care in relation to consumer satisfaction. This paper examines consumer outcomes of satisfaction, and follow up with recommendations, within a framework of the nursing process and its associated components of assessment (including problem identification), care planning, intervention, and evaluation. The data for the study were obtained from seven after-hours call centers operating under the auspices of health maintenance organizations, preferred provider organizations, and private insurance companies. A sample of 157 non-redundant telephone calls from adults with medical-surgical problems were audiotaped with providers' and callers' consent. Sociodemographic information of the advice nurses, and chief complaints of the callers were obtained. The quality of nursing of the audiotaped calls was rated through an implicit review method by registered nurse raters using an advice nurse structured implicit review (AN-SIR) form developed for the study. Follow-up information was obtained through telephone calls to ascertain the consumers' perceptions of satisfaction, helpfulness, and follow-through with recommendations. Results indicated that consumers calling with a variety of general complaints contacted 32 nurses in advice nurse call centers. The quality of nursing process was found to be the best in the area of intervention. Evaluation was also well above the midpoint on a transformed scale of zero to 100. Assessment, although slightly above midpoint, was the lowest of the three components of the nursing process examined. Consumer satisfaction was high with 95.4 percent of the consumers rating the calls as completely or at least somewhat satisfied, and 93.2 percent, stating the advice was very or somewhat helpful. Exploratory regression analysis showed that the component of intervention was significantly related to consumer satisfaction. The present study pioneers the way to rate the quality of the advice nurses' interactions with consumers, and lays the groundwork for further investigations of health care provider behavior and consumer outcomes. Further studies are recommended to investigate predictors of consumer satisfaction, and cost-benefit in terms of consumer expenditures of time, funds, and energy. PMID- 11604964 TI - What do patients do with access to their medical records? AB - We sought to study the phenomenon of patients having access to their own medical records in order to determine the impact on them and on their relationship with their health care providers. We created the Patient Clinical Information System (PatCIS) to interface with the clinical data repository at New York Presbyterian Hospital to allow patients to add to and review their medical data. We also provided educational resources and automated advice programs. We provided access to the system to thirteen subjects over a nineteen-month period and reviewed their activities in the system's usage log. We also collected data via questionnaire and telephone interview. We found that patients varied in their use of the system, from once a month or less to one or more times per day. All patients primarily used the system to review laboratory results. Both they and their physicians believed that use of the system enhanced the patients' understanding of their conditions and improved their communication with their physicians. There were no adverse events encountered during the study. PMID- 11604965 TI - Design of a consumer health record for supporting the patient-centered management of chronic diseases. AB - This paper describes and discusses the design and usage of a shareable consumer health record system to investigate whether these systems can assist in the management of chronic diseases. This web-based system that can be used both by care providers and patients contains medical and patient information, provides access to websites that contain quality information, provides guideline-based advice, allows discussion between patients and allows us to interrogate both patients and care providers on a regular basis in order to get a good impression of the utility of such a consumer record for both chronic patients and the physicians and nurses. A health record system that was developed for the area of Diabetes is presented as an example. PMID- 11604966 TI - A framework for improving the quality of health information on the world-wide-web and bettering public (e-)health: the MedCERTAIN approach. AB - There has been considerable debate about the variable quality of health information on the world-wide-web and its impact on public health. While central authorities to regulate, control, censor, or centrally approve information, in formation providers or websites are neither realistic nor desirable, public health professionals are interested in making systems available that direct patient streams to the best available information sources. National governments and medical societies have also recognized their responsibility to help users to identify "good quality" information sources. But what constitutes good quality, and how can such a system be implemented in a decentralized and democratic manner? This paper presents a model which combines aspects of consumer education, encouragement of best practices among information providers, self-labeling and external evaluations. The model is currently being implemented and evaluated in the MedCERTAIN project, funded by the European Union under the Action Plan for Safer Use of the Internet. The aim is to develop a technical and organisational infrastructure for a pilot system that allows consumers to access metainformation about web-sites and health information providers, including disclosure information from health providers and opinions of external evaluators. The paper explains the general conceptual framework of the model and presents preliminary experiences including results from an expert consensus meeting, where the framework was discussed. PMID- 11604967 TI - Reinventing patient-centered computing for the twenty-first century. AB - Despite evidence over the past decade that patients like and will use patient centered computing systems in managing their health, patients have remained forgotten stakeholders in advances in clinical computing systems. We present a framework for patient empowerment and the technical realization of that framework in an architecture called CareLink. In an evaluation of the initial deployment of CareLink in the support of neonatal intensive care, we have demonstrated a reduction in the length of stay for very-low birthweight infants, and an improvement in family satisfaction with care delivery. With the ubiquitous adoption of the Internet into the general culture, patient-centered computing provides the opportunity to mend broken health care relationships and reconnect patients to the care delivery process. CareLink itself provides functionality to support both clinical care and research, and provides a living laboratory for the further study of patient-centered computing. PMID- 11604968 TI - CHESS: ten years of research and development in consumer health informatics for broad populations, including the underserved. AB - This paper reviews the research and development around a consumer health informatics system CHESS (The Comprehensive Health Enhancement Support System) developed and tested by the Center for Health Systems Research and Analysis at the University of Wisconsin. The review will place particular emphasis on what has been found with regard to the acceptance and use of such systems by high risk and underserved groups. PMID- 11604969 TI - Using the internet in patient-centred diabetes care for communication, education, and decision support. AB - The New England Journal of Medicine 329 (1993) 977- The present paper describes two systems for communication, education, and decision support in patient-centred diabetes care. Both systems are developed under the assumption that while the clinical resources in the health care sector are limited, patients' resources and new information technology may be able to play a much more central role. With DiasNet patients can experiment with their own data. They can, retrospectively, adjust insulin doses or meals sizes, and thereby learn how to cope with various situations. DiabVision, brings together algorithms for detection of retinal lesions in digital images and for aligning time series of retinal images. While the former algorithms are aimed at automated procedures for screening for diabetic retinopathy, the latter can be used to enable motivated patients to see the actual retinal lesions in their own eyes, illustrating how the changes appear, and perhaps disappear, as a consequence of changes in lifestyle and glycaemic control. One of the long-term goals of our work is to assess the potential of integrating all health related information for patients with diabetes and other major chronic diseases. One solution to these problems would be to organise data and information as one virtual database, which then could be accessed by both health professionals and by patients. This structure would facilitate easy access, a clear overview, and quality control. A web site taking the first step in this process has been launched. PMID- 11604970 TI - The accessibility of computer-based health information for patients: kiosks and the web. AB - The Internet is a rich source of health information but it is not as accessible as many claim. This paper brings together three projects to illustrate technical and cost barriers and some options to overcome them. (1) A survey amongst a representative sample of 180 patients in rural Spain showed a marked age gradient in computer access. None over the age of 50 had, and less than 10% planned, access to the Internet whereas a quarter were prepared to use health centre based touchscreen kiosks. (2) Half the commonly used search engines did not include the two most relevant websites for Glasgow colorectal cancer patients in the first ten documents listed, showing the difficulty facing patients in finding relevant information. Selection of information would help patients avoid being overwhelmed with information. (3) One method to improve accessibility is to download websites to kiosks but two projects showed that considerable work is required to reformat the information. Public access computing, such as kiosks, could help make the Internet more accessible. We discuss whether Web sites which structure their information according to method of access, place and person provide a way forward. PMID- 11604972 TI - An experimental health smart home and its distributed internet-based information and communication system: first steps of a research project. AB - We present a study and whole experimental tele-monitoring and medical tele surveillance system for maintaining patients at home. The project features networked sensors, in a fully equipped apartment, operated by an advanced information and communication system based on Internet, Java, and object oriented modeling. The sensors are connected, mainly wirelessly, with a in-home software module devoted to signals analysis and detection of critical situation such as falls, sickness, sudden palsy, stroke, hypothermia, etc. This module communicates, either via modem or ethernet network, with a remote medical control station in charge of appropriate response to received information and alarms. The system is designed to be a powerful information and communication tools for medical and social workers. It offers a series of functions such as medical file management, user profiles and rights management, drafting and management of ordinances and visit notes, confidentiality of medical information, and management of scenarios of detectable events. The access to the system is allowed to authorized users only (physicians, emergentists, social workers, etc.), and is available on as much authorized computers as needed, by means of a Java applet invoked from any traditional web browsers. PMID- 11604971 TI - Developing tailored theory-based educational content for WEB applications: illustrations from the MI-HEART project. AB - This paper describes how theory facilitated the development of educational content for the MI-HEART project, a tailored Web-based intervention designed to favorably influence the appropriateness and rapidity of decision-making in patients suffering from symptoms of acute myocardial infarction. There were five steps involved: 1) formulating the behavioral goal, 2) defining intervention objectives based on an analyses of the determinants of behavior, 3) developing an assessment tool to measure a person's status on these determinants, 4) creating tailored content that address individual variation on determinants of the health behavior and, 5) developing algorithms and a computer program that link responses from the assessment to specific tailored communication. The approach we describe largely distinguishes Web-based applications that are designed to change health behavior from those that simply impart information. Developers of Web-based applications that propose to improve health status by modifying health-related behaviors need the understanding that although it is said that we live in an "information age", simply increasing knowledge has not been effective in changing behaviors in most instances. Furthermore, the one-size fits all approach to developing educational content cannot address the needs, concerns and interests of different individuals. With informatics technology, our ability to collect information from individuals and provide educational content tailored to the specific information collected is not only possibly, but practical. PMID- 11604973 TI - Personal health information-seeking: a qualitative review of the literature. AB - This qualitative review establishes Personal Health Information-Seeking (PHIS) as a more accurate description of the patient and health education information seeking activity commonly known as Consumer Health Information Seeking. This review introduces multiple knowledge or domain facets which need to be considered in order to understand the complexities of this behavior by providing a brief overview of key empirical and theoretical work framed around Metoyer-Duran's ethnolinguistic community information theoretical model originally published in 1991, which should guide PHIS system development. PMID- 11604974 TI - The role of glycoprotein IIb/IIIa inhibition in the management of acute coronary syndromes. AB - Recent advances in the understanding of the pathophysiology of thrombus formation and the role of platelet adhesion have led to a new pharmacologic era in cardiology. The advent of the glycoprotein IIb/IIIa inhibitor, primarily used in conjunction with percutaneous coronary intervention, has proved to be beneficial beyond the confines of the cardiac catheterization laboratory. The glycoprotein IIb/IIIa inhibitor has inspired much research in the past few years of its use in the management of acute coronary syndromes. The CAPTURE, PURSUIT, PRISM, and PRISM-PLUS trials have all documented the beneficial effects of glycoprotein IIb/IIIa inhibition that have reduced 2 of the major sequelae of acute coronary syndromes: myocardial infarction and death. Through the implementation of primary research-based data, it is the job of practitioners to appropriately stratify and implement judicious use of glycoprotein IIb/IIIa inhibition with the population affected by acute coronary syndromes. PMID- 11604975 TI - Evaluation of 3 quality of life measurement tools in patients with chronic heart failure. AB - OBJECTIVE: The objectives of this study are to (1) Address issues related to selecting a quality of life (QOL) measuring tool; and (2) Present data from a pilot test comparing 3 QOL tools (Medical Outcomes Study Short Form-36 [SF-36], the Minnesota Living with Heart Failure Questionnaire [LHFQ], and a visual analogue scale). DESIGN: Descriptive comparative. SETTING: A Southern university affiliated tertiary medical center outpatient heart failure clinic. PATIENTS: Thirty adults, randomly selected from those treated in a multidisciplinary, nurse practitioner-managed heart failure clinic. RESULTS: Significant correlations were found among the global or broader measures of QOL (visual analog scale and LHFQ Total score) and the component scores (LHFQ Emotional, LHFQ Physical, SF-36 Mental [MCS], and SF-36 Physical [PCS]), with the only exception being that of the LHFQ Total and the SF-36 PCS. Mental and physical components of QOL were not related within the SF-36 or between the SF-36 PCS and the LHFQ Emotional score. However, the emotional and physical scores were highly and significantly related within the LHFQ and between the SF-36 MCS and the LHFQ Physical score. CONCLUSIONS: The SF-36 was better able to differentiate physical and emotional aspects of QOL in this sample. The LHFQ subscales may be less useful in QOL assessment than the total score. PMID- 11604976 TI - Decisive situations influencing spouses' support of patients with heart failure: a critical incident technique analysis. AB - OBJECTIVE: The aim of this study was to describe decisive situations experienced by spouses of patients with heart failure that could potentially affect their ability to provide social support to the patient. METHODS: A qualitative descriptive design with a critical incident technique was used. Twenty-three informants, 15 women and 8 men, who were spouses of patients with severe heart failure were strategically chosen to ensure maximal variation in sociodemographic data and experiences as a spouse. RESULTS: Decisive situations influenced the experience of spouses of patients with heart failure in a manner that was either positive (involvement with others) or negative (feeling like an outsider). When spouses were given attention and treated like persons of value, they experienced involvement with others. In these cases, spouses had someone to turn to and were included in the physical care. In contrast, when spouses were kept at a distance by the patient, were socially isolated, and received insufficient support from children, friends, and health care professionals, they experienced feeling like an outsider. CONCLUSIONS: By identifying spouses' experiences, health care professionals can assess which kind of specific interventions should be used to improve the life situation of the patient with heart failure and his or her spouse. PMID- 11604977 TI - Self-care abilities of patients with heart failure. AB - BACKGROUND: Self-care is difficult for patients with heart failure (HF) because early symptoms are subtle and the treatment regimen is complex. The primary purpose of this study was to describe HF self-care abilities and the difficulties that patients have in achieving success in self-care. A secondary purpose was to compare self-care abilities in patients experienced with HF with those patients who are newly diagnosed. METHODS: Descriptive, cross-sectional, comparative surveys were conducted to assess demographic and clinical factors that may interfere with self-care and lifestyle changes made to accommodate the diagnosis of HF. Symptoms the patients had and self-care responses to those symptoms were assessed by using the Self-Management of Heart Failure questionnaire. RESULTS: The 139 patients were primarily elderly, male, retired, unmarried, and earning less than $20,000 annually. Hearing and eyesight were impaired and most patients were functionally compromised. Most of the group had multiple HF symptoms during the past year, yet their knowledge of the importance of signs and symptoms was poor and many misperceptions were evident. Recognition of changes in signs and symptoms was difficult for most patients, but easier for those more experienced with HF. Experienced patients were more likely to use appropriate self-care remedies than newly diagnosed patients. Few patients were comfortable evaluating the effectiveness of their self-care actions and most had low self-confidence in their ability to perform self-care. CONCLUSIONS: With the low level of self-care ability and the number of difficulties these patients face, it is not surprising that rehospitalization rates remain high. Specific recommendations for the teaching and delivery of care are provided. PMID- 11604978 TI - Arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - Arrhythmogenic right ventricular dysplasia (ARVD/C) is one cause of death in young adults in the United States, representing approximately 17% of all ARVD/C cases reported. This study presents 2 cases of ARVD/C diagnosed at a central Texas hospital and reviews the literature regarding this disease. The diagnosis, histology, presentation, prognosis, and therapy are addressed because the rare nature of this disease within the United States makes diagnosis and treatment difficult and creates problems of adaptation for the patient. Clinicians must become more familiar with this potentially fatal cardiac disorder that can create vulnerability within a young adult population. PMID- 11604979 TI - Reactive oxygen species in acute respiratory distress syndrome. AB - In the metabolism of almost all human cells, a sequential addition of electrons to oxygen leads to the formation of reactive oxygen species (ROS). ROS have been implicated in more than 100 diseases and may be the common denominator in the pathogenesis of the most important health problems facing the world today. The last decade has been characterized by a progressive increase in the understanding of oxidant chemistry and the role of ROS in pulmonary disease. The majority of deaths among critically ill patients are the result of sepsis and its sequelae, including acute respiratory distress syndrome (ARDS). Nurses must understand the processes involving ROS that are in play when they are caring for patients with ARDS. This article describes what is known about the formation of ROS, the pathophysiology of ARDS, and the role ROS play in the pathogenesis of ARDS. PMID- 11604980 TI - Effects of music therapy on anxiety in ventilator-dependent patients. AB - OBJECTIVE: The purpose of this study was to assess the effectiveness of music therapy in decreasing anxiety in ventilator-dependent patients. DESIGN: A crossover repeated measures design with random assignment was used. SETTING: The intensive care unit of a university hospital in Hong Kong was used as the setting for this study. PATIENTS: Twenty patients who were ventilator-dependent were recruited for the study. They were all Chinese with a mean age of 58.25 years (range, 19-84 y). Most (75%) were men. OUTCOME MEASURES: Physiologic measures of anxiety assessed in this study were mean blood pressure and respiratory rate. An additional measure was the Chinese version of the Spielberger State-Trait Anxiety Inventory. INTERVENTION: Patients were randomized to receive either 30 minutes of uninterrupted rest and then 30 minutes of music therapy or the music therapy first and then the uninterrupted rest period. Patients listened to relaxing music by using audiocassette players and headphones. Subjects selected the music of their choice from a selection including both Chinese and Western music. Subjects had physiologic measures taken immediately before the intervention (or rest period) and at 5-minute intervals throughout the intervention. The Chinese version of Spielberger's State-Trait Anxiety Inventory was completed before the intervention and immediately after the intervention. RESULTS: Findings indicated that music therapy was more effective in decreasing state anxiety than was an uninterrupted rest period (P <.01). As measured by analysis of variance with repeated measures, blood pressure and respiratory rate showed no significant differences in the 2 conditions over time. However, significant differences were observed at the end of the intervention (after 30 minutes) between the 2 conditions, with music therapy being superior to the rest period. CONCLUSION: Music therapy is an effective nursing intervention in decreasing anxiety in ventilator-dependent patients and its use should be incorporated into the care of mechanically ventilated patients. For the Chinese patients, culture and language were the predominant factors in their choice of music. PMID- 11604981 TI - Tuberculosis and sudden death: a case report and review. AB - Although deaths from tuberculosis (TB) are increasing, TB-related sudden death (TBRSD) is rarely reported in the literature. We present a case report of fatal pulmonary TB with extrapulmonary extension in a patient infected with the human immunodeficiency virus (HIV) and a review of published reports of TBRSD in MEDLINE (1966 to October 2000). Forty-six cases of TBRSD were reported. The most common cause of TBRSD was tuberculous bronchopneumonia in 30 (64%) patients, followed by hemoptysis in 14 (30%) patients. Tuberculous myocarditis and isolated TB of the adrenal glands are seldom causes of TBRSD. The early detection of TB, use of directly observed therapy, and individualization of treatment can be helpful in decreasing the incidence of TBRSD. PMID- 11604982 TI - The challenge of culturally competent health care: applications for asthma. AB - To better serve the increasingly diverse ethnic and racial communities in the United States, health care professionals must develop a knowledge base of cultural health practices. In asthma, a common disease, ethnic minority populations experience poorer outcomes when compared with whites. It is, therefore, imperative that providers have an improved understanding of how patients make decisions concerning their health. Cultural health practices, in concert with conventional treatments, often form a comprehensive asthma management strategy for the patient. The potential implication of alternative explanations for disease, as well as the role of diet and botanical supplements, is explored in this article in an effort to increase providers' sensitivity to nonbiomedical models of disease causality. This sensitivity is the first step in developing cultural competency. PMID- 11604983 TI - nm23 expression in malignant ascitic effusions of serous ovarian adenocarcinoma. AB - The aim of this study was to evaluate nm23 expression as detected in malignant cells of neoplastic ascites and to verify its relationship with the presence of tissue nm23 and p53 in primitive neoplasia. Using an immunocytochemical assay with a specific anti-nm23 polyclonal antibody, nm23 expression was evaluated in ascitic effusions of 45 patients with ovarian serous adenocarcinoma and ascites in normal and/or hyperplastic mesothelial cells from 37 women with various neoplasms (12 ovarian neoplasms) free of malignant cells as controls. nm23 and p53 tissue expression was also detected in 21 corresponding tumor samples, including 11 bilateral lesions. nm23 was expressed in 57% of malignant effusions compared to 43% in controls: the two groups were not correlated. nm23 in effusions agreed with tissue expression (p=0.02) but a direct correlation was not demonstrated. The incidence of nm23 was more frequent in stage III than in stage IV disease (p=0.08) and was associated with mutated p53 expression (p=0.01). Using the Wilcoxon test for unpaired data, a higher incidence (p=0.05) of p53 positive tumors in bilateral cancers was found while a higher expression of nm23 in effusions of patients with monolateral lesions was observed (p=0.08). The presence of p53 was correlated with that of nm23 in both cytologic (p=0.005) and histological samples (p=0.01). Our findings, together with the diversity in biological behaviour present in various tumors, suggest that nm23 is a family of genes with differing biological functions which act as tumor-specific inhibiting factors within a complex process also involving other genes. Due to the analogies and correlations between nm23 and p53, the role of nm23 as a potential predictive factor of response to chemotherapy and in DNA repair is emphasized. PMID- 11604984 TI - MSH2 and MLH1 immunodetection and the prognosis of colon cancer. AB - MSH2 and MLH1 are proteins involved in DNA reparation. They are mutated in some forms of colon cancer, i.e. hereditary non-polyposis carcinomas and a subset of sporadic carcinomas. We have studied the expression of MSH2 and MLH1 in a retrospective series of 225 colorectal carcinomas by immunohistochemistry. The results were compared to molecular tests of microsatellite instability using amplification by PCR of BAT-25 and BAT-26 repeated sequences and to histoclinical data. Positivity of both proteins was never associated with MSI phenotype. MSH2 and/or MLH1 negative tumors were frequently tumors of the proximal colon; in this subpopulation or proximal tumors, MSH2 and/or MLH1 negativity was associated with a longer disease-free survival. PMID- 11604985 TI - Treatment with BAT monoclonal antibody decreases tumor burden in a murine model of leukemia/lymphoma. AB - BAT is a monoclonal antibody produced against membranes of Daudi cells that induces anti-tumor activity in mice against a variety of solid murine and human tumors, mediated by its immune stimulatory properties on murine and human lymphocytes. The present study analyzes the effect of BAT on leukemia/lymphoma using the BCL1 model of leukemia/lymphoma in BALB/C mice. BAT antibody binds to BCL1 leukemia cells and recognizes a 48 kDa protein similar to the antigen on Daudi cells. Mice inoculated with leukemia cells were treated either by direct BAT injections or by adoptive transfer of lymphocytes from BAT-injected mice. Administration of BAT monoclonal antibody was either once, on day 14, or daily on days 10-13 post tumor inoculation. A single injection of BAT resulted in reduction of peripheral blood tumor cells, however additional injections further decreased the tumor cell number reaching a 95-fold reduction on day 20 post tumor inoculation. Anti-tumor effect was also obtained when animals were injected with splenocytes from BAT-treated donor mice. A significant prolongation of survival of BAT-treated mice was observed although with no cure. The results of this study indicate that BAT might be used for reducing the tumor burden in leukemia for immunotherapy and in combination with other treatment modalities. PMID- 11604986 TI - A new in vivo model for studying invasion and metastasis of esophageal squamous cell carcinoma. AB - The aim of our current study was to establish an orthotopic inoculation model for studying invasion and metastasis of esophageal squamous cell carcinoma (SCC). Male BALB/c nude mice were used for the experiment. A midline incision was made from the upper to middle abdomen. The abdominal esophagus was carefully exposed. Human esophageal T.Tn SCC cells or human cervical HeLa SCC cells, were injected into the submucosa of the lower esophagus. One of the mice injected with T.Tn cells was sacrificed at 5 weeks, and the remaining five sacrificed at 13 weeks after inoculation. The mice injected with HeLa cells were sacrificed at 3-4 weeks after inoculation. T.Tn cells and HeLa cells formed tumors at the esophagus, but did not metastasize to lymph nodes or lungs. HeLa cells produced peritoneal implants, and directly invaded the stomach and the liver. In the present study, we established a novel orthotopic inoculation model of esophageal SCC. This system is an appropriate and a useful model for studying invasion and metastasis of esophageal SCC, and can also be used as a model for developing therapeutic strategies for esophageal cancer in vivo. PMID- 11604987 TI - Combining transcatheter arterial chemoembolization with percutaneous ethanol injection therapy for small size hepatocellular carcinoma. AB - For patients with unresectable small size HCC, percutaneous ethanol injection therapy (PEIT) is used as a non-surgical treatment because it is difficult to achieve complete tumor necrosis by transcatheter arterial chemoembolization (TAE) alone. However, some small HCCs (<21 mm in diameter) are resistant to PEIT with incomplete tumor necrosis, which is associated with insufficient ethanol injection to the tumor. For more effective treatment for HCC, we performed a combination of TAE and PEIT on patients with small size HCC and evaluated the cumulative recurrence and survival rates. The recurrence rate in patients treated with the combination was less than that of TAE or PEIT alone. There were five patients without tumor recurrence during the follow-up period and three out of these underwent the combination treatment. The period of no recurrence was 33.4 months on average. In conclusion, we recommend combination therapy with TAE and PEIT for patients to accomplish more effective treatment of small size HCC. PMID- 11604988 TI - Role of galectin-3 in adenocarcinoma liver metastasis. AB - Galectin-3 is a lactosamine-specific lectin that binds to laminin sugar-sites, and up-regulated expression of galectin-3 in primary colorectal cancer is involved in cancer progression and metastasis. Inhibitory effects of cell adhesion and liver metastasis of adenocarcinoma via portal vein by lectin-binding sugar and anti-galectin-3 antibody was examined to determine the role of galectin laminin binding in cancer liver metastasis. Highly metastatic adenocarcinoma cell lines XK4-A3 and RPMI4788 were used in in vitro cell attachment and nude mice liver metastatic experiments, and inhibitory effects of anti-galectin-3 antibody or lectin-binding sugars were examined. The in vitro adhesion assay demonstrated that the anti-galectin-3 antibody and alpha-lactose inhibited XK4-A3 and RPMI4788 cell adhesion to laminin in a dose-dependent manner. The liver metastasis of XK4 A3 and RPMI4788 was reduced 50 and 60%, respectively (P<0.001) by alpha-lactose treatment. Anti-galectin-3 antibody also inhibited liver metastasis in a dose dependent manner, and maximum inhibition rate was 66% for XK4-A3 and 90% for RPMI4788. Galectin-3 plays an important role in liver metastasis of adenocarcinoma by the mechanisms of galectin-3 binding to laminin. Inhibition of galectin-3 on cancer cell surface induces reduced cell attachment to laminin and liver metastasis. PMID- 11604989 TI - Unique action determinants of double acting topoisomerase inhibitor, TAS-103. AB - O6-methylguanine-DNA methyltransferase (MGMT), gamma-glutamylcysteine synthetase (gamma-GCS), and glutathione (GSH) are found to participate in resistance to TAS 103, a topoisomerase I/II inhibitor. In 13 human cancer cell lines, MGMT expression correlated with IC50 for TAS-103, whereas gamma-GCS expression inversely correlated with the IC50 value, suggesting MGMT may work to decrease TAS-103 activity but gamma-GCS may increase it. A reduced gamma-GCS and GSH, and an increased MGMT were associated with the development of resistance in A549 and DLD cells, and gamma-GCS inhibition by buthionine sulphoximine increased the TAS 103 resistance, whereas MGMT inhibition by both O6-benzyl-guanine and MGMT antisense transfection sensitized cells to TAS-103. PMID- 11604990 TI - Chemoprevention of azoxymethane-induced rat colon carcinogenesis by dietary capsaicin and rotenone. AB - The modifying effects of dietary administration of capsaicin, which is the principal pungent capsicum fruit, and rotenone, which is a naturally occurring pesticide derived from Derris and Lonchorcarpus species, on azoxymethane (AOM) induced colon tumorigenesis were investigated in male F344 rats. Gavage with capsaicin and rotenone significantly elevated phase II enzymes, glutathione S transferase (GST) and quinone reductase (QR), in the liver and colon. In an aberrant crypt foci (ACF) bioassay, feeding of capsaicin and rotenone at a dose of 500 ppm for 4 weeks significantly inhibited ACF formation induced by AOM (20 mg/kg body weight, once a week for 2 weeks). In a subsequent long-term study designed to confirm the protective effects of both compounds on ACF development, one group was treated with AOM alone and four other groups received the carcinogen treatment plus diets containing 500 ppm test compounds for 4 weeks (initiation phase) and for 34 weeks (post-initiation phase). Two groups were treated with capsaicin or rotenone alone (500 ppm in diet) and one group was maintained on the basal diet. At the termination of the study, dietary exposure of capsaicin during the initiation phase was found to significantly reduce the incidence of colonic adenocarcinoma (60% vs. 24%, 60% reduction, P=0.0407). Rotenone feeding during the post-initiation phase also reduced the frequency of colonic adenocarcinoma (60% vs. 19%, 68% reduction, P=0.0226). Our results suggest that two natural compounds, capsaicin and rotenone, might be useful for the prevention of human colon cancers. PMID- 11604991 TI - Ley glycolipid-recognizing monoclonal antibody inhibits procoagulant activity and metastasis of human adenocarcinoma. AB - Tumor procoagulant is associated with cancer at advanced stages of malignancy such as infiltration and metastasis. In the present study, we investigated the role of Ley glycolipid in the mechanism of cancer metastasis. Ley glycolipid acts as an important cofactor in the expression of the blood-coagulating activity of cancer cell-derived coagulating activity 1 (CCA-1), which is one of the known tumor procoagulants. Monoclonal antibody (MoAb) FS01, which serves as the Ley recognizing epitope, inhibits the procoagulant activity of CCA-1 was found to dose-dependently inhibit the procoagulant activity of normal plasma induced by the human lung adenocarcinoma cell line, HAL8, which shows a high level of Ley expression. It did not, however, inhibit the procoagulant activity of the human colon cancer cell line, RPMI4788, which does not express Ley. Administration of FS01 MoAb inhibited lung metastasis of HAL8 cells, but not that of RPMI4788. The absence of antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity of FS01 MoAb against the HAL8 cell line suggests that the inhibition of HAL8 metastasis by FS01 MoAb derives from the inhibition of blood-coagulating activity of the latter. These findings indicate that Ley glycolipid plays an important role in the mechanism of cancer metastasis via the procoagulant activity of CCA-1. PMID- 11604992 TI - Molecular cloning and characterization of WNT14B, a novel member of the WNT gene family. AB - WNT14B was cloned and characterized in this study. WNT14B encoded 357-amino acid WNT family protein with the signal peptide and an N-linked glycosylation site. WNT14B was most homologous to WNT14 (61.4% total amino acid identity). WNT15 cDNA fragment previously isolated by another group corresponds to a part of ORF of the WNT14B cDNA (codon 216-335). Exon-intron boundaries were conserved between WNT14B and WNT14 genes. WNT14B and WNT3 genes were clustered in the human chromosome 17q21 region in head to head manner. Intergenic region between WNT14B and WNT3 genes was about 33 kb in size. The 6.6-kb WNT14B mRNA was moderately expressed in fetal kidney and adult kidney. Although WNT14B mRNA was not detected in fetal brain and adult brain by northern blot analyses, WNT14B mRNA was detected in brain, especially in occipital lobe, by RNA dot blot analysis. Among 48 human cancer cell lines derived from various tissues, WNT14B was expressed in a teratocarcinoma cell line NT2 with the potential to differentiate into neuronal cells. WNT14B mRNA was significantly up-regulated by all-trans retinoic acid in NT2 cells. These results strongly suggest that WNT14B might be implicated in the early process of neuronal differentiation of NT2 cells induced by retinoic acid. PMID- 11604994 TI - Effects of retinoic acid and interferon-gamma on expression of the retinoic acid receptor in mouse renal cell carcinoma. AB - The clinical outcome of interferon-gamma treatment of metastatic renal cell carcinoma remains unsatisfactory. To overcome this, a reagent that has a different action on cancer cells is desired. One such candidate may be 13-cRA (cis retinoic acid), a vitamin A derivative known to markedly regulate the differentiation and proliferation of normal and neoplastic cells. Moreover, 13 cRA demonstrates a remarkable synergistic effect with IFN-gamma in certain types of cancer. We investigated the efficacy of concomitant administration of 13-cRA and IFN-gamma. The in vivo anti-tumor effects were evaluated in a lung metastasis model using a mouse renal cell carcinoma cell line (RenCa). The in vitro anti tumor effects were also assessed by MTT assay. The presence of retinoic acid receptors (RAR)-alpha, -beta and -gamma was examined by PCR analysis. The influence of IFN-gamma on these retinoic acid receptors was evaluated by Northern blotting. IFN-gamma showed anti-tumor effects both in vivo and in vitro. This effect was enhanced synergistically with concomitant 13-cRA treatment. RenCa cells expressed RAR-alpha, and -gamma, but not -beta according to PCR analysis. IFN-gamma treatment increased the expression level of RAR-alpha and RAR-gamma according to Northern blot analysis. Combination therapy using IFN-gamma and 13 cRA showed synergistic anti-tumor effects, which exceeded those of each therapy alone. Moreover, IFN-gamma treatment increased RAR-alpha and RAR-gamma expression. Thus, the augmented anti-tumor effects of IFN-gamma and 13-cRA may be attributable to enhanced expression of RAR-alpha and RAR-gamma by IFN-gamma treatment. PMID- 11604993 TI - Dihydropyrimidine dehydrogenase mRNA level correlates with the response to 5 fluorouracil-based chemo-immuno-radiation therapy in human oral squamous cell cancer. AB - The measurement of the intra-tumoral level of thymidylate synthetase (TS), and dihydropyrimidine dehydrogenase (DPD), may be useful in predicting tumor sensitivity to 5-fluorouracil (5-FU). In this study, we examined the mRNA levels of DPD and TS in 28 oral squamous cell carcinomas (SCC), and 22 salivary gland tumors by semi-quantitative reverse transcription polymerase chain reaction. Then we examined the correlation of the responsiveness of the patients with oral SCC to 5-FU with the intra-tumoral levels of DPD and TS mRNA. All specimens were obtained at the biopsy before treatment, and then the patients were treated by oral administration of a 5-FU compound (UFT), the irradiation of cobalt-60 (upto 60 Gy) and injection of an immuno-potentiator (OK-432). Intra-tumoral levels of DPD mRNA in the patients who showed CR (complete response) and PR (partial response) were significantly lower than those in the patients who showed NC (no change). However, intra-tumoral levels of DPD mRNA did not correlate with the local recurrence of the tumor during the observation period after initial treatment with or without surgical resection of the residual tumors. On the other hand, TS mRNA levels in the tumors did not correlate with any clinico pathological parameters. These observations suggest that intra-tumoral levels of DPD mRNA may predict the tumor response to 5-FU-based chemo-immuno-radiation therapy in the patients with oral SCC. PMID- 11604995 TI - Molecular cloning, gene structure, and expression analyses of NKD1 and NKD2. AB - Mouse Nkd is a Dishevelled-binding protein, functioning as a negative regulator of WNT - beta-catenin - TCF signaling pathway. Here, human NKD1 and NKD2 were cloned and characterized. NKD1 and NKD2 were predicted to encode 470- and 451 amino-acid polypeptide, respectively. NKD1 and NKD2, showing 43.8% total amino acid identity, were more homologous in the NH1, NH2, NH3, and NH4 domains. The NH2 domain of NKD1 and NKD2 contained the EF-hand motif. Exon-intron structures of NKD1 and NKD2 genes, consisting of 10 exons, were well conserved. NKD1 was highly expressed in fetal kidney, while NKD2 was moderately expressed in fetal kidney, lung, and adult lung. NKD1 was up-regulated in colorectal cancer cell line SW480, gastric cancer cell line TMK1, and pancreatic cancer cell line Hs700T. NKD2 was up-regulated in gastric cancer cell line MKN45, pancreatic cancer cell line BxPC-3, and esophageal cancer cell lines TE6, and TE13. NKD1 and NKD2 were up-regulated together in 1 case of primary gastric cancer out of 10 cases, and were down-regulated together in 2 cases. Up-regulation of NKD1 or NKD2 might be due to a negative feed-back mechanism. Alternatively, genetic alteration of NKD1 or NKD2 might lead to activation of the WNT - beta-catenin - TCF signaling pathway. PMID- 11604996 TI - K-ras and rho A mutations in malignant pleural effusion. AB - Mutations of the Kristen ras (K-ras) gene have been implicated in the pathogenesis of human lung cancer, especially adenocarcinoma, and have been proposed to be a prognostic factor. The K-ras mutation in codon 12 is detectable even in cell-free fluids by using the enriched polymerase chain reaction (PCR) technique. On the other hand, based on experimental results, the rho A mutation in codon 14 is also proposed to be oncogenic as observed in the K-ras mutation. Malignant pleural effusion is a common complication of lung cancer. We studied the point mutation of K-ras codon 12 and rho A codon 14 using enriched PCR in specimens of pleural effusion. Forty patients with pleural effusion were enrolled in this study. The causes of pleural effusion were non-small cell lung cancer (18 cases), small cell lung cancer (6 cases), malignant mesothelioma (2 cases), metastatic lung tumor (5 cases), thymoma (1 case), malignant lymphoma (1 case), and pleuritis tuberculosa (7 cases). The K-ras mutation was detected in 4 of 14 cases with adenocarcinoma, 1 of 3 cases with squamous cell carcinoma, 1 of 1 case with large cell carcinoma, and 1 of 5 cases with metastatic lung tumor, respectively. The rho A mutation was not detected in any pleural effusion examined in this study. Our study demonstrates the usefullness of pleural effusion as a clinical specimen for a search of point mutation of oncogenes. The K-ras codon 12 mutation is readily detected in pleural effusion, and the demonstration of this mutation has potentially important implications for the diagnosis of malignant pleural effusion. PMID- 11604997 TI - Molecular cloning and characterization of human WNT3. AB - Mouse Wnt-3 is a proto-oncogene, which is activated by mouse mammary tumor virus (MMTV). Human WNT3 cDNA fragment, previously isolated by another group, corresponds to a partial coding sequence. WNT3 cDNA, spanning the complete coding sequence, was isolated in this study. WNT3 encoded 355-amino-acid polypeptide with the N-terminal signal peptide and two N-linked glycosylation sites. WNT3 was most homologous to WNT3A (84.2% total amino-acid identity) among human WNTs. The WNT3 gene on the human chromosome 17q21 region consisted of five exons. WNT3 mRNAs were detected in fetal brain, adult brain, and testis by Northern blot analyses. WNT3 mRNA was relatively highly expressed in A549 cells (lung cancer) and MKN45 cells (gastric cancer) among 37 human cancer cell lines. WNT3 was significantly up-regulated in a case of primary breast cancer and in a case of primary rectal cancer among various types of human primary cancers. These results strongly suggest that WNT3 might play a key role in some cases of human breast, rectal, lung, and gastric cancer through activation of the WNT - beta-catenin - TCF signaling pathway, similar to mouse Wnt-3. PMID- 11604998 TI - Quantitative assessment of the expression of melanoma-associated antigens by non competitive reverse transcription polymerase chain reaction. AB - The assessment of tumor-associated antigens (TAA) recognized by T lymphocytes is a prerequisite for diagnosis and immunotherapy of melanoma. Different reverse transcription-polymerase chain reaction (RT-PCR) protocols allowing the quantification of the TAA mRNA expression in the solid tumor or the detection of circulating melanoma cells have been described. We have recently shown a positive correlation between the amount of specific product formed by RT-PCR and the staining intensity in immunohistochemical analysis of the corresponding sample. Here we describe a quantification procedure based on the direct digitization of the PCR products after separation on ethidium bromide-stained agarose gels, followed by computer-assisted densitometry. To standardize our method, we examined the linear range of the densitometric quantification procedure as reflected by the correlation of signal intensity to the amount of the corresponding DNA. As an internal measure for the so-termed cDNA in the different samples after RNA isolation and reverse transcription, a beta-actin PCR was introduced. Subsequently, we chose four sets of primers for the melanoma associated antigens MAGE1, tyrosinase, Melan A/MART-1 and gp100/Pmel17 and performed PCR analysis over a range of cycle numbers. In each case, the amplification rate remained constant up to at least 26 cycles under the respective conditions. Plotting the logarithm of the amount of product against the cycle number yields a slope that equals the logarithm of the amplification rate. The amount of starting material can be determined from the intercept with the ordinate. In summary, the method introduced in the present work allows the quantification of TAA in melanoma which might be important for the monitoring of disease. Technically the method is sound and sensitive, avoids post-PCR manipulations and can be performed with the standard equipment of a molecular biology laboratory. It can be applied also to other solid tumors and leukemias. PMID- 11604999 TI - Significance of lymphoscintigraphic mapping with Tc-99m human serum albumin and tin colloid in sentinel lymph node biopsy in breast cancer. AB - Sentinel lymph node biopsy (SLNB) in breast cancer is considered in order to spare node-negative patients from axillary lymph node dissection. To assess the clinical significance of lymphoscintigraphic mapping in SLNB, we analyzed the lymphatic drain to the sentinel lymph nodes (SLNs) in terms of the pattern and direction of the hot spot. Twenty-three breast cancer patients were enrolled for SLNB. Before surgery, lymphoscintigraphic mapping of SLN was performed using Tc 99m human serum albumin (HSA) and tin colloids, and the hot spot was marked. The Tc-99m HSA and tin colloids were subcutaneously injected above the tumor and peritumor sites, respectively, and lymphoscintigraphic scanning was monitored every 5 to 10 min, for up to 2 h after injection. The SLN was identified using a combination of a blue dye, indigocalmine, and a gamma probe during surgery. The hot spot pattern and direction of the lymphatic drains were evaluated in 21 of 23 cases. Two cases did not have a hot spot. Single, double, and multiple hot spots were observed in 12 cases (52.1%), 8 cases (34.7%), and 1 case (4.3%), respectively. The positions of the hot spots were: axillary (n=17, 80.9%), axillary and sternal (n=3, 14.2%), and phrenic (n=1, 4.7%). The sensitivity and specificity rates in SLNB were 66.6% and 100%, respectively, and the overall predictive rate was 85.7%. Lymphoscintigraphy produced false negatives in three cases (33.3%), including one on the phrenic side. Lymphoscintigraphic mapping with Tc-99m HSA and tin colloids is useful for determining the SLN, and avoiding a false negative. The pattern and direction of the lymphatic drain to the SLN in scintigraphy need to be considered for the elimination of axillary lymph node dissection in node-negative patients with breast cancer. PMID- 11605000 TI - Expression of WNT10A in human cancer. AB - WNT signaling pathway is implicated in carcinogenesis and embryogenesis. We have previously cloned and characterized WNT10A, and demonstrated up-regulation of WNT10A in gastric cancer. Here, we investigated expression of WNT10A mRNA in various types of human cancer. WNT10A mRNA was detected in 10 out of 12 esophageal cancer cell lines by cDNA-PCR, and was significantly up-regulated in esophageal cancer cell lines TE2, TE3, TE4, and a brain tumor cell line A-172. WNT10A mRNA was not up-regulated by retinoic acid in a teratocarcinoma cell line NT2. TFF1/pS2 mRNA, but not WNT10A mRNA, was up-regulated by beta-estradiol in a breast cancer cell line MCF-7. Expression of WNT10A mRNA in various types of primary cancers was next investigated by using Matched tumor/normal expression array filter. WNT10A mRNA was significantly up-regulated in 2 out of 8 cases of primary gastric cancer, and in 1 out of 7 cases of primary rectal cancer. Expression of WNT10A mRNA in esophageal cancer was not investigated, because such samples were not blotted on the expression array filter. Up-regulation of WNT10A mRNA might play key roles in some cases of esophageal, gastric, and colorectal cancer. PMID- 11605001 TI - Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer. AB - WNT2 is one of proto-oncogenes with the potential to activate the WNT - beta catenin - TCF signaling pathway, which is most homologous to WNT2B among members of the human WNT gene family. Here, expression of WNT2 mRNA was comprehensively investigated. WNT2 mRNAs were highly expressed in fetal lung, and weakly expressed in placenta. Among 2.0-, 2.9-, 4.1-, and 6.0-kb WNT2 mRNAs, the 2.0-kb WNT2 mRNA was the major transcript in fetal lung. In 3 cases of prostate cancer and 1 case each of lung cancer and cervical cancer, WNT2 was over-expressed in non-cancerous portion as well as in primary tumor. WNT2 was up-regulated in 14 out of 18 cases of primary colorectal cancer, 4 out of 7 cases of uterus tumor, 2 out of 9 cases of breast cancer, and in 2 out of 14 cases of kidney tumor. Up regulation of WNT2 was also detected in 4 out of 8 cases of primary gastric cancer by using expression array filter hybridization, and in 10 out of another 10 cases of primary gastric cancer by using cDNA-PCR. Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer might play a key role in carcinogenesis through activation of the WNT - beta-catenin - TCF signaling pathway. PMID- 11605002 TI - High fat diet enhances colonic cell proliferation and carcinogenesis in rats by elevating serum leptin. AB - We postulated that high fat diet enhances colon cell proliferation and carcinogenesis by elevating serum leptin. To examine this possibility, the present study was conducted to investigate the effect of leptin on the growth of human colon cancer cells (HT29) and the relationship between serum leptin and colon cell proliferation and aberrant crypt foci (ACF) in the 1,2 dimethylhydrazine-treated rats fed graded levels of dietary fat for 28 days. In cell culture experiments, leptin stimulated the growth and proliferation (BrdU incorporation) of colon cancer cells and the expression of c-fos protein. In the in vivo experiments, an elevation of dietary fat caused higher serum leptin and adipose-tissue weight. Colonic cell proliferation (BrdU incorporation), c-fos protein expression and ACF were elevated with increasing dietary fat. There was a significant correlation between serum concentration of leptin and colon cell proliferation and ACF. The results suggest that the enhancement of colon cell proliferation and carcinogenesis by high fat diet is mediated through elevating serum leptin. PMID- 11605004 TI - Toxicological testing of cytotoxic drugs (review). AB - Cytotoxic drugs are a unique therapeutic class of fundamental importance in current antineoplastic chemotherapy. These drugs belong to many chemical and chemotherapeutic classes. They are cytotoxic by design and are able to cause serious dose-limiting adverse effects at therapeutic doses. Most antineoplastic dosing strategies focus on minimizing cytotoxicity rather than optimizing efficacy. In turn, cytotoxicity is interconnected with other therapeutic considerations, including cell status (renewing vs. non-renewing cell types), cell membrane transport integrity, intracellular activation status, immune system integrity, cellular repair status, and drug resistance. Regulatory requirements for the development of cytotoxic drugs are not well characterized, and differences exist in regional requirements. A safety assessment package which is utilized and accepted world-wide does not yet exist, despite many efforts of harmonization. In this report, the authors introduce a comprehensive safety assessment package for cytotoxic drugs, based on institutional experience acquired globally with this class of drugs, that fulfills both scientific and world-wide regulatory requirements for this very important therapeutic category. PMID- 11605003 TI - A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter. AB - Telomerase activity has a close relationship with malignancies in many cell types and it is tightly regulated at the transcriptional level of human telomerase reverse transcriptase (hTERT). Utilizing the hTERT promoter, the authors developed a gene delivery system of Fas associated protein with death domain (FADD) (hTERT/FADD). FADD is a protein which plays an important role in the apoptotic pathway of Fas. Over-expression of FADD induces apoptosis in the cells regardless of Fas expression on the cell surface. We hypothesized that we might be able to restrict the expression of FADD in malignant glioma cells if we use the gene transfer system under the control of hTERT promoter. This study was designed to investigate whether the hTERT/FADD construct induces apoptosis effectively in malignant glioma cells while keeping normal cells intact. First, using the reverse transcription-polymerase chain reaction (RT-PCR) technique, we confirmed that hTERT mRNA was expressed in human malignant glioma cells (U373-MG, A172 and GB-1), but not in cultured astrocytes (TEN) or fibroblasts (MRC5). After transient transfection with the hTERT/FADD construct, a significant number of FADD-positive cells and apoptotic cells were detected in hTERT-positive malignant glioma cells. In contrast, hTERT-negative astrocytes and fibroblasts remained intact. Furthermore, subcutaneously implanted U373-MG tumors treated with the hTERT/FADD construct reduced in volume significantly compared to the conrol treatment (p=0.0001). Gene transfer of FADD under the control of the hTERT promoter may be a novel and promising therapy to kill hTERT-positive malignant glioma cells while sparing normal brain cells lacking hTERT. PMID- 11605005 TI - Establishment of a new scirrhous gastric cancer cell line with loss of heterozygosity at E-cadherin locus. AB - Scirrhous gastric carcinoma, characterized by carcinoma cell proliferation and infiltration with extensive fibrosis in the stroma, frequently causes peritoneal metastasis. We describe here a newly established cell line, OCUM-6, derived from ascites effusion of a scirrhous gastric cancer patient. The cells are floating and round shape, similar to other scirrhous gastric carcinoma cell lines previously reported. Histologic findings of xenografted tumor obtained from OCUM 6 cells showed medullary growth with a poorly differentiated adenocarcinoma containing signet ring cells. LOH at E-cadherin locus 16q22 was observed in the OCUM-6 cells. LOH at E-cadherin locus might be closely associated with histologic findings and metastatic process of scirrhous gastric cancer. The scirrhous gastric cancer cell line, OCUM-6, may be useful for investigation of the mechanisms of peritoneal dissemination and carcinogenesis. PMID- 11605007 TI - Potential of adenoviral p53 gene therapy and irradiation for the treatment of malignant gliomas. AB - We investigated the combined effects of p53 gene transfer and irradiation and its still unclear interaction mechanism in human gliomas. Four human glioma cell lines expressing mutant type p53 (U373 and A172) and wild-type p53 (D54MG and EFC 2) were transfected by adenoviral vectors bearing p53 gene at 50 multiplicity of infection. Two days after transfection, cells were irradiated (3, 6, and 9 Gy). The cytotoxicity was evaluated by clonogenic assay. The quantitative analysis of apoptosis and cell cycle analysis were performed using flow cytometry. Irradiation combined with adenoviral p53 transfection significantly increased cytotoxicity, which was additive in cell lines with wild-type p53 and more than additive in cell lines with mutant p53. The combination of two modalities increased the apoptotic population by 14% in A172 cells and 20% in D54 MG cells, which were the sum of apoptosis from each modality. Adenoviral p53 transfection increased the G1 phase fraction and concomitant decrease of radioresistant S phase fraction in A172 and D54MG cells. Our study demonstrated that p53 gene transfer combined with irradiation increased absolute cytotoxicity in human glioma cells used in this experiment. The interaction mechanism for increased cytotoxicity involved, in part, increased apoptosis and change of cell cycle profile. PMID- 11605006 TI - Presence of antibodies against retinoblastoma tumor suppressor protein in patients with lung cancer. AB - Retinoblastoma (RB) protein and antibody against RB protein in sera from 45 lung cancer patients and 30 healthy volunteers were examined using bacterially synthesized glutathione S-transferase (GST) RB fusion protein and immunoblot analysis. RB protein was not detected in sera from any individuals with lung cancer or in any healthy volunteers. Sera from 6 patients, including 4 with non small cell carcinoma and 2 with small cell carcinoma, reacted to a GST-RB fusion protein but not with a GST protein. Sera from 30 normal volunteers reacted to neither GST-RB fusion protein nor GST protein. The backgrounds such as age, gender, performance status, histology, stage, smoking history, and prior treatment were not significantly different between the patients with and without anti-RB antibodies. This is the first report describing the presence of anti-RB antibody in patients with malignant tumors. Further studies are needed to establish clinical significance for anti-RB antibody. PMID- 11605008 TI - Effect of platelet activating factor and butyrate on the expression of interleukin-2 receptor alpha in nasopharyngeal carcinoma cells. AB - Serum level of soluble interleukin-2 receptor alpha (sIL-2Ralpha) has been shown to correlate with disease progression and prognosis of cancer patients. However, the available information about the source and the pathophysiological regulation of IL-2Ralpha in cancer cells is limited. This study addressed the questions of prognostic value and the source of sIL-2Ralpha in patients with nasopharyngeal carcinoma (NPC). Biological regulation of IL-2Ralpha was characterized in NPC cell lines. Serum sIL-2Ralpha levels of 113 NPC patients were measured by enzyme linked immunosorbent assay (ELISA). Levels of sIL-2Ralpha in NPC patients were significantly higher than that in the healthy controls, and sIL-2Ralpha levels were correlated with disease progression and patient survival. IL-2Ralpha was identified in cancer cells by immunocytochemistry. In vitro, IL-2Ralpha expression was markedly increased following treatment with platelet activating factor and/or n-sodium butyrate. Increased secretion of IL-2Ralpha was also detected in the culture media. The secreted IL-2Ralpha could functionally bind IL 2. These results indicate that elevated sIL-2Ralpha was often detected in patients with advanced NPC. The elevated sIL-2Ralpha could be shed from NPC cells by a yet to be determined mechanism and IL-2Ralpha expression in NPC cells could be upregulated by platelet activating factor and butyrate. PMID- 11605009 TI - Cytokine-induced p38 activation feedback regulates the prolonged activation of AKT cell survival pathway initiated by reactive oxygen species in response to UV irradiation in human keratinocytes. AB - A previous study has shown that UV activates the PI3K/AKT cell survival pathway while inducing cell death in human skin in vivo and cultured human keratinocytes in vitro, and yet the upstream pathway leading to the activation of AKT has not been thoroughly investigated. In this study we found that UV-induced phosphorylation of p38 and AKT in a time-dependent manner. The phosphorylation of p38 started at 5 min post UV irradiation, peaked at about 30 min, and remained elevated up to 2 h. The phosphorylation of AKT started at 15 min post UV treatment, peaked at about 1 h, and remained elevated up to 2 h. We also found that H2O2 induced phosphorylation of p38 and AKT in a time- dependent manner. Pretreatment with NAC abolished UV-induced AKT phosphorylation, suggesting the involvement of reactive oxygen species in AKT activation. Interestingly, SB203085, a known p38 inhibitor, had partially inhibited UV-induced AKT phosphorylation. Further studies showed that cytokines such as TNF-alpha and IL 1beta induced AKT phosphorylation in a time-dependent manner. Pretreatment with SB203085 inhibited IL-1beta-induced p38 and AKT phosphorylation. Collectively, our data suggest that UV activation of PI 3-kinase/AKT pathway is initiated by ROS and prolonged by feedback activation of p38 induced by released cytokines in response to UV irradiation in cultured human keratinocytes. PMID- 11605010 TI - Diagnostic and prognostic relevance of expression of human telomerase subunits in oral cancer. AB - Telomerase activity (TA) is associated with most malignant human tumors but is not detected in normal somatic cells with a few exceptions. Three major subunits (hTR, hTP1 and hTERT) of telomerase have been identified. To investigate the clinical implications of the mRNA detection of these components as useful diagnostic and prognostic markers in oral cancer, we examined TA, hTR, hTP1 and hTERT mRNA expressions in 46 oral squamous cell carcinomas (OSCC) and 15 normal oral mucosal tissues from healthy volunteers using a highly sensitive TRAP assay and RT PCR. In all specimens hTR and hTP1 mRNA were detected regardless whether TA was expressed or not. On the contrary, a significant correlation between hTERT expression and TA was shown indicating that the activity of telomerase could be regulated by the extent of hTERT transcription. In addition, hTERT expression showed close association to malignancies. None of the normal mucosal specimens expressed the hTERT subunit, but 76% (35/46) of the tumor specimens did. None of other clinico-pathological and prognostic parameters showed significant relationship with TA or hTERT expression. These results suggest that the detection of hTERT expression may be another useful diagnostic marker, especially for early detection of OSCC, and for distinguishing healthy tissues from neoplastically transformed ones. PMID- 11605011 TI - The differentiation inducers phenylacetate and phenylbutyrate modulate camptothecin sensitivity in colon carcinoma cells in vitro by intracellular acidification. AB - Aromatic fatty acids such as phenylbutyrate (PB) and its metabolite phenylacetate (PA) induce growth arrest, differentiation and apoptosis in solid tumor cells. Despite their antiproliferative action they were reported to exhibit a synergistic effect in combination with cytotoxic drugs like topotecan, and others. Since the activity of the camptothecines (CPTs) depends on local pH conditions, we investigated, whether PB/PA modulate CPT effects indirectly by affecting intracellular pH in SW620 and SW480 colon cancer cells. The results for the colon carcinoma cells show an antagonistic interaction for the combination of CPT and 0.25-5 mM PA in viability assays, resulting in an approximately 3-fold increase in IC50 (control: 20+/-7 nM). A synergistic effect with significantly increased numbers of late apoptotic/necrotic cancer cells (difference +21+/-4%) and 1.4-fold sensitization were detected upon inclusion of 2.5 mM PA during a 4-h CPT (10 micro;M) loading phase. In response to 0.25-1 mM PA/PB the cells exhibit a reversible decrease of pHi (0.1-0.31 pH units) in HEPES- or bicarbonate buffered media. Dose-dependent acidification and pHi-recovery occurred following addition of PA and PB after an acid load and inhibition of the Na+/H+-antiporter and bicarbonate exchangers, pointing to a possible intracellular mechanism of cytoplasmic acidification. It is concluded that the synergistic modulation of CPT toxicity by short-term PA/PB treatment in colon carcinoma cells is caused by changes in intracellular pH, possibly affecting quantity and localization of the active closed lactone form of this drug. PMID- 11605012 TI - A pitfall in the survival benefit of adjuvant chemotherapy for node- and hormone receptor-positive patients with breast cancer: the paradoxical role of Bcl-2 oncoprotein (review). AB - The survival benefit of adjuvant chemotherapy in node-positive patients with breast cancer compared with surgery alone has been established. The survival benefit differs considerably between hormone receptor-positive and -negative patients, and it is believed that the effectiveness of adjuvant chemotherapy can be increased by hormonal therapy with tamoxifen. In the present review, we discuss the rationale behind the effectiveness of combination treatment with anticancer drugs and tamoxifen in terms of the paradoxical role of Bcl-2 in apoptosis in breast cancer. The survival benefit between receptor-positive and negative patients was assessed using previous reports of randomized controlled studies for postoperative adjuvant chemotherapy in node-positive breast cancer. Tamoxifen induces the anti-apoptotic gene, Bcl-2, by its effect on estradiol (E2), via an E2-response element in the promotor region of Bcl-2. The efficicacy of chemoendocrine therapy was assessed in terms of the influence of tamoxifen on the effect of anticancer drugs. Adjuvant chemotherapy, including anthracycline and non-anthracycline based regimens, has an overall survival benefit in node positive breast cancer, with a 23.5% reduction in the annual odds of recurrence and a 15% reduction in mortality (P<0.00001). A comparison of the reduction of the relative risk indicates that the survival benefit in receptor-negative patients is superior to that in receptor-positive patients by approximately 3 fold. Further, in contrast to receptor-negative patients, there is no additional benefit from paclitaxel over doxorubicin and cyclophosphamide (AC) in receptor positive patients. The possible reasons that the chemotherapy benefit in receptor positive patients is small and marginal are the following: i) concurrent treatment or pretreatment with tamoxifen can increase plasma E2 levels in premenopausal patients, thereby inducing Bcl-2 in residual cancer cells, which might decrease drug-sensitivity in combination with chemotherapy; ii) induction of Bcl-2 might be involved predominantly in the resistance to taxanes, the cytotoxic action of which targets Bcl-2. Co-treatment or pretreatment with tamoxifen for adjuvant therapy might decrease the efficacy of anticancer drugs, an effect that is mediated by induction of Bcl-2, especially in premenopausal patients with node-positive breast cancer. Treatment with anticancer drugs should be followed by treatment with tamoxifen to produce a survival benefit from combination therapy in receptor-positive patients. PMID- 11605013 TI - The current status of structural studies on proteins of the myelin sheath (Review). AB - Myelin, the multilayered membrane structure surrounding axons, provides a unique environment to its proteins, which are either transmembrane proteins or interacting intimately with the membrane surface. Although myelin-specific proteins have been studied for decades, remarkably little is known of their three dimensional structures. In addition, the exact functions of myelin proteins are to a large extent unknown. In this report, our current knowledge of peripheral nervous system myelin protein structures is reviewed, and the current status of attempts to solve the structures of full-length myelin proteins is evaluated. Furthermore, molecular models for the extracellular domain of the myelin associated glycoprotein and the putative kinase-like domain of 2',3'-cyclic nucleotide 3'-phosphodiesterase are presented and discussed. PMID- 11605014 TI - Reactivation of liver-specific gene expression in an immortalized human hepatocyte cell line by introduction of the human HNF4alpha2 gene. AB - An immortalized human hepatocyte cell line (OUMS-29) was established from fetal liver by transfection with the SV-40 large T antigen gene that has certain liver specific functions such as albumin production and enzyme activities of CYP1A1, 1A2, and 2E1. To make OUMS-29 cells express other liver-specific functions, the human hepatocyte nuclear factor 4alpha2 (HNF4alpha2) gene was introduced into the cells, because this gene was found to be markedly down-regulated. The transduced HNF4alpha2 was overexpressed in the nuclei of the transfected cells, and its DNA binding activity was also detected. The liver-specific genes such as apolipoprotein AI, CII, CIII, blood coagulation factor X, alpha1-antitrypsin, and HNF1alpha were up-regulated. Thus, this cell line is expected to be a useful tool for studying the differentiated human hepatocyte functions. PMID- 11605015 TI - Elevated gastrin secretion by in vivo gene electroporation in skeletal muscle. AB - Whether or not in vivo gene transfer of gastrin gene into skeletal muscle by electroporation could modify gastrin secretion was examined. The expression plasmid vector, either pMEPrGaspA encoding the rat gastrin gene or pEGFP-N1 encoding the GFP reporter gene was injected into M. rectus abdominis of rats or M. biceps formis of mice. Subsequently, square electric pulses of direct current were applied six times at 25 V with a loading period of 100 msec per pulse. Clear foreign gene expression in the skeletal muscle was demonstrated by both GFP fluorescence and immunostaining of rat gastrin. Time course changes in plasma gastrin levels after transfection revealed that in rats, gastrin gene transfer significantly increased the plasma gastrin level for 4 weeks post-transfection (P<0.05), but the difference diminished at the end of the 10-week period. In mice, plasma gastrin level elevated similarly for 3 weeks, and pH of gastric contents decreased in the gastrin gene transfected group compared with the control counterpart (P<0.05). These findings suggest that localized in vivo gene transfer by electroporation allows skeletal muscle to become an artificial endocrine tissue for hormonal manipulation of animals. PMID- 11605016 TI - Expression of cyclooxygenase-2 in ovarian mature cystic teratomas with malignant transformation. AB - Cyclooxygenase-2 (COX-2) has been reported to be associated with tumor progression and angiogenesis and we previously reported that an increase in COX-2 expression might be associated with malignant transformation and tumorigenesis of epithelial ovarian neoplasms. In this study, COX-2 expression of ovarian mature cystic teratomas with malignant transformation, a rare entity accounting for just 1.8% of all mature cystic teratomas, was investigated using immunohistochemical techniques. There were 89 cases of mature cystic teratomas treated with surgery as their initial therapy at Osaka City University Medical School Hospital between 1995 and 2001. Ten cases of these were selected for study; five cases of mature cystic teratoma with malignant transformation, and five cases of mature benign teratoma. Expressions of CD34, vascular endothelial growth factor (VEGF), and COX 2 were investigated. Expressions of VEGF and COX-2 were strong in tissues of mature cystic teratomas with squamous cell carcinoma; however, expressions of them were hardly apparent in mature benign teratomas and in mature cystic teratomas with adenocarcinomas. These results tend to suggest that COX-2 is associated with tumor growth and progression in mature cystic teratomas with squamous cell carcinoma, as opposed to mature benign teratomas and mature cystic teratomas with adenocarcinomas. PMID- 11605017 TI - Angiogenesis in adipose tissues and skeletal muscles with rebound weight-gain after diet-restriction in rabbits. AB - The mechanisms of excessive body weight gain after diet-restriction are still unclear. In this study, we investigated expression of angiogenic factors in adipose tissue and skeletal muscle of rabbits which had rebound weight gains; trying to make inquiries into the mechanisms of this rebound weight gain. Ten rabbits were divided into two groups. One group had free food intake (group C), and the other group had restricted food intake until day 40 of the experiments and then had free food intake (group DR). Specimens of adipose tissue and skeletal muscle were collected from each rabbit on days 20, 40, and 60 after the initial examination, and expressions of CD34, vascular endothelial growth factor (VEGF), and platelet-derived endothelial cell growth factor (PD-ECGF) were investigated. Expression of VEGF was significantly strong in the adipose tissue of group DR at the recovery period of body weight. In conclusion, rebound weight gain after a restricted-diet may be associated with angiogenesis in adipose tissue, and the angiogenesis may be induced by VEGF. PMID- 11605018 TI - Pyridoxal 5'-phosphate and pyridoxal inhibit angiogenesis in serum-free rat aortic ring assay. AB - Supraphysiological doses of vitamin B6 has been reported to suppress tumor growth and metastasis in rodents. To examine if its anticancer effect is due to suppression in angiogenesis, this study was conducted to investigate the antiangiogenic effect of pyridoxal 5'-phosphate (PLP), pyridoxine, pyridoxal and pyridoxamine in an ex vivo serum-free matrix culture model using rat aortic ring. Rat aortic rings were incubated with PLP or pyridoxine (25 micromol/l to 5 mmol/l). Higher concentrations of PLP (2.5 and 5 mmol/l) and pyridoxine (5 mmol/l) caused complete inhibition of microvessel outgrowth. However, the addition of pyridoxine at 2.5 mmol/l did not show complete inhibition of angiogenesis. PLP inhibited microvessel outgrowth almost completely at a concentration of 500 micromol/l and showed antiangiogenic effect in a dose dependent manner within the range of 25-500 micromol/l. At 250 micromol/l, pyridoxal was as effective as PLP, but pyridoxamine was inactive, implying that the aldehyde group relates to the antiangiogenic effect. These results indicated the antiangiogenic effect of PLP and pyridoxal, and suggested that the antitumor effect of high levels of vitamin B6 might be mediated through suppression of angiogenesis. PMID- 11605019 TI - Single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic American populations. AB - To investigate the prevalence of the C677T and A1298C single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in Caucasian and Hispanic populations, EDTA-anticoagulated whole blood specimens were collected from a total of 100 random patients, 50 Caucasians and 50 Hispanics of Puerto Rican dissent. The prevalence of the two MTHFR SNPs was determined by polymerase chain reaction (PCR) mediated restriction fragment length polymorphism analysis. In the Caucasian population, homozygosity for the MTHFR A1298C SNP was detected in 4% (2/50) of the individuals tested, while 42% (21/50) were heterozygous for this SNP. Among Hispanics, 4% (2/50) were homozygous and 38% (19/50) heterozygous for the A1298C SNP. Homozygosity for the C677T MTHFR SNP was detected in 16% (8/50) and 10% (5/50) of Caucasians and Hispanics, respectively. In this study, the frequency of the C677T heterozygotes was very high at 56% (28/50) and 52% (26/50) Caucasians and Hispanics, respectively. C677T and A1298C are common SNPs in the MTHFR gene. The high prevalence of these SNPs in both Caucasian and Hispanic populations demonstrates the possibility of compounding effects of these SNPs in the pathogenesis of human diseases. While subgroups of patients may exhibit some clinical phenotype linked to these SNPs, our analysis demonstrates the need for careful interpretation of SNP data in the context of population screening. PMID- 11605020 TI - Molecular cloning and sequencing of the cDNA coding for a novel regucalcin gene promoter region-related protein in rat, mouse and human liver. AB - The molecular cloning and sequencing of the cDNA coding for a novel regucalcin gene promoter region-related protein (RGPR) was investigated using rat, mouse and human liver cDNA library with a yeast one-hybrid system and a rapid amplification of cDNA ends (RACE) method. The clone coding an unknown protein was isolated, and a novel protein was identified. This protein was termed as RGPR-p117. RGPR-p117 in rat, mouse and human liver consisted of 1058, 1051 and 1060 amino acid residues with calculated molecular mass of 117, 115 and 117 kDa and estimated pI of 5.69, 5.70 and 5.71, respectively. The homologies of amino acids among rat, mouse and human RGPR-p117 were at least 70%. RGPR-p117 had a leucine zipper motif. The expression of RGPR-p117 mRNA was found in the liver, kidney, heart, spleen, and brain of rats. The database search of the human RGPR-p117 showed that its gene consisted of at least 26 exons spanning approximately 4.1 kbp and localized on human chromosome 1q25.2. Furthermore, we found a cDNA clone which was highly identical to a front half part of the human RGPR-p117 cDNA, using the BLAST search of human RGPR-p117. This cDNA clone was a splicing variant of human RGPR-p117, which derived from human placental choriocarcinoma. Our study demonstrates that a novel gene coding RGPR-p117 is present in rat, mouse and human. PMID- 11605021 TI - Induction of apoptosis by Hypericin through activation of caspase-3 in human carcinoma cells. AB - Potent photosensitizer Hypericin (HY), is a lipid soluble perylquinone derivative of the genus Hypericum and has a strong photodynamic effect on tumors and viruses. However, the mechanisms of tumor cell death induced by this compound is still unclear. Furthermore, there are no reports on mechanisms in cell apoptosis induced by perylquinones in human nasopharyngeal carcinoma (NPC) and other mucosal cells. We studied the photodynamic effects of HY compound in poorly differentiated (CNE2) and moderately differentiated (TW0-1) human NPC cells as well as human mucosal colon (CCL-220.1) and bladder (SD) cells. Using these cell lines we investigated few hall marks of apoptotic commitments in a drug and light dose dependent manner. Tumor cells photoactivated with HY showed cell size shrinkage and an increase in the sub-diploid DNA content. A loss of membrane phospholipid asymmetry associated with apoptosis was induced in all tumor cell lines as evidenced by the externalization of phosphatidylserine. Under apoptotic conditions, Western blot analysis of poly (ADP-ribose) polymerase, a caspase substrate, showed the classical cleavage pattern (116-85 kDa) associated with apoptosis in PDT-treated cell lysates. In addition, 85 kDa cleaved product was blocked by using tetrapeptide caspase inhibitors such as DEVD-CHO or z-VAD-fmk. These results demonstrate that tumor cell death induced by photoactivated HY is mediated by caspase proteases. This study also identifies that CNE2, CCL-220.1 (colon) and SD (bladder) cell lines are more sensitive than TW0-1 cell line to PDT using perylquinone HY. PMID- 11605022 TI - Potentiation by glutamic acid dimethyl ester of GLP-1 insulinotropic action in fed anaesthetized rats. AB - The dimethyl ester of L-glutamic acid (DMG) stimulates insulin release and was proposed as a possible insulinotropic tool in the treatment of non-insulin dependent diabetes. In such a perspective, it was investigated whether DMG enhances the B-cell secretory response to GLP-1 in fed anaesthetized rats. The primed constant infusion of DMG (1.0 micromol and then 0.5 micromol/min, both per g body wt.) provoked a rapid and sustained increase in plasma insulin concentration and augmented the release of insulin caused by GLP-1. Thus, DMG indeed appears as a suitable tool to potentiate the insulinotropic action of GLP 1. PMID- 11605023 TI - Involvement of angiogenesis in weight-loss in tumor-bearing and diet-restricted animals. AB - The body's weight loss mechanism while in a tumor-bearing state is still unclear. In this study, we investigated expressions of angiogenic factors in the adipose tissue of tumor-bearing and diet-restricted rabbits evaluating the differences between the two groups. We postulated that low nutrition induced vasculogenesis to transport nutrition in the adipose tissues of diet-restricted rabbits, unlike in tumor-bearing rabbits, and that vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) were related to angiogenesis of the adipose tissues. Although we investigated the expressions of VEGF and PD-ECGF immunohistochemically in tumor-bearing and diet-restricted rabbits, there was no significant difference between the two groups. Whether angiogenesis of the adipose tissue in the diet-restricted animals may be observed during the nutritional recovery period should be investigated. PMID- 11605024 TI - The genetic events of HPV-immortalized esophageal epithelium cells. AB - We studied cytogenesis, telomere and telomerase, and c-myc, ras, bcl-2, and p53 genes of cells in the progressive process of immortal epithelial cells from embryonic esophagus induced by human papillomavirus (HPV). The SHEE cell line, established by us, consist of immortalized epithelial cells from the embryonic esophagus induced by genes E6E7 of HPV type 18. It was in initial malignant transformation when cultivated over 60 passages without co-carcinogens. Cells of the 10th, 31st, and 60th passages were represented in the progressive process within the immortal period. In these three stages of the cell line, the modal number of chromosome and karyotypes were analyzed. The telomere length was assayed by Southern blot methods, and the telomerase activity was analyzed by hTR and hTERT assay. C-myc, p53, bcl-2, ras genes were assayed by the multi-PCR method. The morphology of the 10th passage cells exhibited good differentiation, the 60th passage cells were relatively poorly differentiated, and the 31st passage cells differentiated in two distinct ways. The growth characteristics of the 31st and 60th passage cells were weakened at contact-inhibition and anchorage dependent growth. Karyotypes of three cell passages belonged to hyperdiploid and hypotriploid with abnormal chromosomes +1, +3, +7, +9, +17, +18; del(1)(p32); der(4), t(4;?)(q31;?); der(5),t(5;?)(q31;?); der(13),t(13;13)(p11;q11) and others. Bimodal distribution of chromosomes with more aberrant chromosomes appeared in the 31st and 60th passage cells. Telomere length sharply shortened from normal fetal esophagus to the 10th and 31st passage step by step, but was stable from the 31st to the 60th passage and the telomerase activities measured were expressed at late two passages. p53 mutant was positive in three passages, c myc was positive in the 31st and the 60th passage K-ras only in the last. The results reveal that changes of chromosomes, telomere length, telomerase activity and certain gene expressions are important events of HPV-immortalized esophageal epithelium cells. All of these changes occurred in dynamic progressive process. This cell line may be useful for the elucidation of the genetic mechanism of cellular immortalization. PMID- 11605025 TI - Comparison of expression of apoptosis regulatory proteins in the adipose tissue of tumor-bearing and diet-restricted rabbits. AB - We investigated the expression of apoptosis regulatory proteins in the adipose tissue of tumor-bearing and diet-restricted rabbits, and analyzed the differences between the two groups. The apoptotic index in the tumor-bearing group was 25.1+/ 12.4 on day 10 and increased to 27.2+/-14.4 by day 20. Thereafter, however, it gradually decreased, falling to 11.2+/-7.8 on day 30 and 0.67+/-0.88 on day 40. By contrast, no apoptotic cells were detected in the diet-restricted group at any of the times examined. Bcl-2 immunoreactivity was either not detected at all, or was only weakly observed in both groups. Bax expression, on the other hand, gradually increased after implantation in the tumor-bearing group. In 2 of the 5 tumor-bearing rabbits, Bax expression in adipocytes was moderate 10 days after tumor implantation, and strong by day 20, but steadily decreased thereafter. By contrast, hardly any Bax-immunopositive cells were detected in the diet restricted group. These results suggested that loss of body weight in the tumor bearing group was different from that in the diet-restricted group, and that it was related to adipocyte apoptosis. PMID- 11605026 TI - Human herpesvirus 8 DNA in HIV-negative Japanese patients with multicentric Castleman's disease and related diseases. AB - Multicentric Castleman's disease (MCD) is a lymphoproliferative disorder characterized by systemic lymphadenopathy and hypergammaglobulinemia. Recently, a French group reported that human herpesvirus 8 (HHV8) DNA was detected in tissue samples of MCD patients. The detection rate was especially high in human immunodeficiency virus (HIV)-positive MCD patients. Thus, HHV8 infection seems to be closely related to HIV infection. In Japan, the HIV infection rate in the general population is very low. To examine whether HHV8 is actually related to MCD in Japan, we performed nested polymerase chain reaction for the HHV8 genome using DNA samples from 7 patients with MCD and 23 patients with related diseases such as POEMS syndrome, amyloidosis, myeloma and lymphoma. They were all HIV negative Japanese. Three of 7 MCD patients were positive for HHV8. There were no clear differences in clinical characteristics between HHV8-positive patients and negative ones. All other patients were negative for HHV8. Thus, we have shown that some MCD patients in Japan are also infected with HHV8. PMID- 11605027 TI - Dimethyl sulfoxide inhibits dimethylnitrosamine-induced hepatic fibrosis in rats. AB - We studied the preventive effects of dimethyl sulfoxide (DMSO) on experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN caused a significant decrease in body and liver weight. Oral DMSO (2 ml/kg daily for 4 weeks) essentially prevented this DMN-induced body and liver weight loss with no major side effects. DMSO suppressed the induction of hepatic fibrosis, as determined by histological evaluation, and reduced hepatic hydroxyproline. It also suppressed the expression of mRNA for type I collagen in the liver. Because hepatic stellate cells (HSC) are the major cellular source of the collagen in hepatic fibrosis, we examined the effects of DMSO on collagen production in vitro using rat primary HSC culture. However, it was found that DMSO did not inhibit the collagen production in vitro. We next evaluated the effects of DMSO on tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) production by Kupffer cells, because these factors represent major activator of HSC, and because monocyte-macrophage infiltration has been implicated as being pathogenetically important for hepatic fibrosis induced by DMN. DMSO inhibited lipopolysaccharide (LPS)-induced TNFalpha and NO production, and reduced TNFalpha mRNA levels. DMSO also suppressed the LPS-induced nuclear factor kappa B activation in a murine macrophage-like cell line. These results suggest that the inhibitory effects of DMSO on hepatic fibrosis may be primarily exerted via blocking of DMN-induced inflammation. These results also implied that DMSO may be potentially useful for preventing the development of hepatic fibrosis. PMID- 11605028 TI - Diltiazem, a calcium antagonist, inhibits matrix metalloproteinase-1 (tissue collagenase) production and collagenolytic activity in human vascular smooth muscle cells. AB - Calcium antagonists (CAs) are widely prescribed for patients with cardiovascular diseases. CAs have been reported to inhibit smooth muscle cell (SMC) proliferation in addition to their effects on vascular tone. To determine whether CAs potentially affect vascular remodeling, we measured the expression of matrix degrading enzymes in growth factor-stimulated SMC. Human cultured SMC were stimulated with 10 ng/ml of platelet-derived growth factor (PDGF)-BB with or without a calcium antagonist, diltiazem. In the cell counting assay, diltiazem (10-5 M) alone had no effect on the proliferation of quiescent SMC, however 10-6 10-5 M of diltiazem dose-dependently inhibited PDGF-stimulated SMC proliferation. The inhibitory effects of diltiazem on SMC proliferation were further confirmed by a 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and flow cytometry. In Western blotting, matrix metalloproteinase (MMP)-1 (tissue collagenase) but not MMP-2 (72-kDa gelatinase) expression was upregulated by PDGF and phorbol ester (TPA), which were reduced by diltiazem in a dose-dependent manner. The downregulation of MMP-1 expression was consistent with the reduction of collagenolytic activity measured by a FITC-conjugated type I collagen breakdown assay. PDGF-stimulated c-Jun/AP-1 expression, a major transcriptional factor for MMP-1, was not affected by diltiazem. In contrast, intracellular calcium ions measured with a fluorometric assay of Fluo-3AM-loaded cells revealed that the PDGF-stimulated increase in the intracellular calcium content was dose dependently reduced by diltiazem. Our data suggest that diltiazem inhibits not only proliferation but also MMP-1 expression and collagenolytic activity in PDGF stimulated SMC. The administration of CAs potentially influences the process of vascular remodeling, and this possibility should be further verified in vivo. PMID- 11605029 TI - Cold single-strand conformation polymorphism analysis: optimization for detection of APC gene mutations in patients with familial adenomatous polyposis. AB - Over 200 adenomatous polyposis coli (APC) gene mutations have been described in familial adenomatous polyposis (FAP) patients. Recent single-strand conformation polymorphism (SSCP) screening methods have introduced minigel runs, simple ethidium bromide staining and external temperature control without any loss of sensitivity (cold-SSCP). In order to test the effectiveness in APC mutation detection, cold-SSCP was employed following polymerase chain reaction (PCR) amplification in three patients with FAP. Different running parameter combinations were compared. The three mutations already known were all diagnosed by cold-SSCP. The gel concentration was found to be essential in detecting the single-base substitution in fragments of different lengths. The observation of deletions was not affected by gel concentrations and heteroduplex bands were always produced. The temperature or glycerol addition did not significantly affect sensitivity. This modified cold-SSCP method provides a simple and effective way for detecting several known Apc gene mutations without any loss of sensitivity and could be useful for large-scale molecular diagnosis of FAP. PMID- 11605030 TI - The suitability of DNA extracted from formalin-fixed, paraffin-embedded tissues for double differential polymerase chain reaction analysis. AB - Formalin-fixed, paraffin-embedded (FFPE) tissues are one of the popular sources of diagnostic materials, the easiest to store and transport. They are often used as the source of nucleic acids for retrospective molecular analyses based on DNA amplification by polymerase chain reaction (PCR). However, it is known that nucleic acids from paraffin-embedded tissues are much worse templates than those recovered from fresh tissues. It is exceptionally important in a quantitative analysis, including double differential PCR (ddPCR). Therefore, a pilot study comparing quantity and quality of DNA extracted with various paraffin removal and DNA isolation procedures from FFPE tissues was conducted. Furthermore, the suitability of DNA isolated with optimized procedure for the assessment of erbB-2 average gene copy number (AGCN) was checked. Specimens for comparison of extraction and isolation procedures were generated from the same human normal thyroid tissue embedded in paraffin to eliminate variabilities in tissue processing and sample size. Three procedures of paraffin removal and three procedures of DNA extraction from deparaffinized tissue were compared. Only one procedure provided DNA, which was efficiently amplified in ddPCR. The material obtained with this optimized procedure was used to check the precision of ddPCR by evaluation of AGCN of erbB-2 oncogene. Low variability of obtained results close to expected AGCN value (AGCN=1) indicates high reproducibility of the method, as well as its high accuracy, if the normal value of erbB-2 AGCN in the examined tissue is assumed. PMID- 11605031 TI - An anti-GD2 single chain Fv selected by phage display and fused to Pseudomonas exotoxin A develops specific cytotoxic activity against neuroblastoma derived cell lines. AB - Since the disialoganglioside GD2 is abundantly present on the surface of neuroblastoma cells, we constructed a new recombinant immunotoxin for possible clinical use in patients with neuroblastoma. A functional 14.18 scFv-phage was obtained by selection of an anti-GD2 hybridoma derived phage antibody mini library on the neuroblastoma-derived, GD2-expressing cell line IMR5. By insertion into the bacterial expression vector pBM1.1 the selected scFv was fused to a deletion mutant of Pseudomonas exotoxin A (ETA'). Periplasmically expressed 14.18(scFv)-ETA' bound to the GD2 expressing cell line IMR5, but not to the GD2 negative Hodgkin-derived cell line L540Cy as documented by ELISA and flow cytometry. The recombinant immunotoxin (rIT) inhibited cell viability of IMR5 cells by 50% at concentrations (IC(50)) of 0.326 microg/ml. This recombinant immunotoxin will be further investigated in vivo for its value as a new immunotherapeutic agent for the treatment of patients with neuroblastoma. PMID- 11605032 TI - Protein polymorphism of human IL-18 identified by monoclonal antibodies. AB - Six mAbs were raised against human "functionally inactive" recombinant IL-18, ELISA for determination of "functionally inactive" forms of IL-18 were established using two of these mAbs (#21 and #132), and inactive species of IL-18 protein were examined with human blood plasma and macrophages (Mp). In 6-day GM CSF-treated monocytes, namely Mp, the mAb #21 recognized the IL-18 proform (24 kDa) and a 48 kDa dimer by immunoblotting. In contrast, only the 24 kDa species was detected as a relatively faint band with a commercial mAb against "active" IL 18. No IL-18 species was detected in premature monocytes. Thus, the dimeric IL-18 was produced in Mp and detectable with the mAb we established. In blood plasma of normal subjects and patients, the #21-recognizable IL-18 was also detected by ELISA, the levels of which were not consistent with those obtained with the commercially available kit for determination of "functionally active" IL-18. We designated the former as type 2 and the latter as type 1. Strikingly, IL-18 type 1 was detected in all volunteers while type 2 was detected in approximately 30% of healthy subjects, and the levels of type 2 were high (10-100 ng/ml) compared to those of type 1 (0.02-0.55 ng/ml) in their blood plasma. In patients with atopic dermatitis, the mean value of type 1 was high (200 ng/ml) compared to those of normal subjects (0.122 ng/ml) and patients with lung cancer (0.113 ng/ml). Production of high type 1 may be associated with an immunomodulatory state in atopic dermatitis. The levels and frequencies of IL-18 type 2 were not significantly changed among these populations. Hence, large amounts of type 2 species are produced in monocyte-Mp differentiation, and their levels and frequencies are unchanged in blood plasma irrespective of the levels of type 1. PMID- 11605033 TI - Genetic instability and the evolution of angiogenic tumor cell lines (review). AB - Advanced tumor growth requires the formation of new blood vessels (angiogenesis). Whether new blood vessels are formed or not depends on a balance between angiogenesis inhibitors and promoters. Host tissue, as well as tumor cells, express inhibitory factors preventing angiogenesis. During cancer progression, tumor cell lines evolve which produce factors promoting the angiogenic switch. We use mathematical models in order to examine the conditions required for angiogenic cell lines to emerge and hence for the disease to progress. We find that genetic instability, defined as a much elevated mutation rate of somatic cells, is required for the emergence of angiogenic tumor cells. This is because a high mutation rate ensures that within a short period of time, a sufficiently high number of angiogenic cells are generated. This founder population of mutant cells is large enough to overcome the inhibitory factors produced by the tissue thereby inducing the angiogenic switch through the production of promoters. In the absence of genetic instability, angiogenic cells cannot fix, even if the relevant mutations are generated at low levels in the tumor cell population. This is because angiogenic promoters will not be sufficiently abundant to counter the influence of inhibitory factors. In this context, the inhibition of angiogenesis can be viewed as a host defense ensuring that the tumor need be genetically unstable if it is to grow and progress beyond a certain size limit. We observe that genetic instability is of value early in tumorigenesis but becomes a liability later. This is because instability decreases the fitness of the angiogenic tumor once it has become established. PMID- 11605034 TI - Signaling molecules implicated in heregulin induction of growth arrest and apoptosis. AB - Heregulin (HRG) is one of the groups of polypeptide growth factors that activate the erbB-2 receptor via induction of heterodimerization with erbB-3 and erbB-4 receptors. The biological effects of HRG have been extensively studied. The vast majority of the reports indicate that HRG induces cell growth in breast cancer cells expressing normal levels of erbB-2 and growth inhibition and apoptosis in cells over-expressing erbB-2. However, the mechanism by which HRG promotes cell growth inhibition and apoptosis is still unknown. Previously we reported that constitutive expression of HRG in an erbB-2-overexpressing cell line (SKBr-3) induced growth arrest and apoptosis. We also demonstrated that constitutive expression of HRG promoted a marked morphological change, G2/M delay of the cell cycle, and DNA fragmentation. In this study, we demonstrate the mechanism by which HRG induces these cellular effects. The doubling time of the SK/HRG cells increased in relation to the level of HRG expression, and the level of HRG expression dictates the morphological change of the cells as well as their ability to grow or not grow in an anchorage-independent manner. We demonstrate that these effects are accompanied by downregulation of both erbB-2 and erbB-3 receptors at the transcriptional and translational levels and that down regulation of the erbB-receptors results in reduced receptor tyrosine phosphorylation. The decrease in erbB-receptor phosphorylation in turn results in a marked reduction of ERK activity and a significant increase in JNK activity. Consequently, overexpression of HRG promoted the expression of PEA3, an Ets nuclear transcription factor. Taken together, our data demonstrate that the cellular effects induced by constitutive expression of HRG in SKBr-3 cells are correlated with the level of HRG expression. This is a first report demonstrating that HRG induction of apoptosis is directly correlated with decreased MAPK activity, increased JNK activity resulting in upregulation of PEA3 and down regulation of the erbB-2 receptor. Overall, these data provide important clues regarding the mechanism and downstream molecules involved in HRG induction of apoptosis that can be used as targets for therapeutic prevention. PMID- 11605035 TI - Overexpression of the p53 gene product in canine mammary tumors. AB - p53, a tumor suppressor gene, is a target of genetic alternations in many human and animal cancers. Compared to normal tissues, cancer tissues overexpress mutant p53 protein thus allowing their detection by a number of immunochemical procedures. To what extent the expression of mutant p53 correlates with dog mammary tumorigenesis has not been fully studied. In the present study, 20 spontaneously arising canine mammary tumors were examined for overexpression of mutant p53. Two different monoclonal antibodies, BP53-12 and PAb122, which recognize different epitopes of the p53 product, were used. The canine tumors in the present study exhibited five different histological types: i) osteosarcoma (n=7); ii) carcinosarcoma (n=4); iii) solid carcinoma (n=5); iv) complex carcinoma (n=3); and v) tubulopapillar carcinoma (n=1). The positive ratios against BP53-12 and PAb122 antibodies were 50% (10/20) and 60% (12/20) respectively. Among these positive samples, 35% (7/20) reacted to both antibodies. Finally, 15 out of 20 tumors showed positivity against one of the monoclonal antibodies. Mostly, as in human mammary tumor cells, BP53-12 staining was observed in the nuclei of tumor cells. PAb122 staining, however, was confined to cytoplasm of osteosarcoma or carcinosarcoma cells. To confirm the location of the staining, immunoelectron microscopy was done. The results showed that the cytoplasm of cartilage cells in the sarcomas had positive staining. These results indicate that anti-p53 antibodies BP53-12 and PAb122, generated against human p53 are cross reacting with the same molecule in canine cells and that the role of p53 in tumorigenesis is not only confined to tumors in human. Our finding suggests that a combination of p53 monoclonal antibodies should be used to screen, not only canine mammary tumors but also human mammary tumors, to obtain a better tumor prognosis. PMID- 11605036 TI - Up-regulation of neuroendocrine differentiation in prostate cancer after androgen deprivation therapy, degree and androgen independence. AB - The up-regulation of neuroendocrine (NE) differentiation after hormonal therapy, as well as the relationship between the degree of NE differentiation and androgen independence was investigated. One hundred and thirty-seven whole prostate specimens that were derived from surgery and autopsy (group A: no hormonal therapy, 44 patients; group B: with hormonal therapy less than 12 months, 25 patients; group C: with hormonal therapy more than 13 months, 68 patients) were studied. Neuroendocrine differentiation was evaluated by immunostaining with chromogranin A. The degree of NE differentiation was evaluated by the percentage area of positive NE cell expression (grade 0, negative; grade 1, 1-33%; grade 2, 34-66%; grade 3, 67-100%). The degree of NE differentiation was compared in androgen-independent and -dependent tumors in group C. Neuroendocrine differentiation was expressed as 31.8% in group A, 44% in group B and 70.5% in group C (p<0.001, Chi-squared test). Group C included 20 androgen-independent cases in which 3 cases were grade 0, 2 were grade 1, 6 were grade 2 and 9 were grade 3. Conversely, for androgen-dependent cases, there were 16, 16, 11 and 5 cases, respectively. Neuroendocrine cells, whether positive or not, alone was not significantly different (p=0.124, Chi-squared test); however, the percentage area of positive NE cell expression was significantly different between the androgen independent and -dependent tumors (p=0.0044, Chi-squared test). Hormonal therapy may play an important role in the up-regulation of NE differentiation. As well as NE cell expression, whether positive or not, the degree of expression should also be observed to evaluate a poor prognosis, tumor progression and androgen independence. PMID- 11605037 TI - Cyclooxygenase-2 expression in malignant mesenchymal tumors and related uterine lesions. AB - The aim of this study was to determine whether the expression of cyclooxygenase-2 (COX-2) in uterine sarcoma cells and carcinosarcoma cells is associated with cell type. Nineteen sections of tissues from uterine sarcomas, carcinosarcomas, and an adenosarcoma, and endometrial stromal sarcomas, were immunohistochemically analyzed for the cellular expression of COX-2. Positive immunostaining for COX-2 was observed in 88.9% (8/9) uterine carcinosarcomas, uterine adenosarcomas but was not observed in uterine sarcomas and the endometrial stromal sarcoma (0/10). But positive immunostaining for COX-2 was observed in some sarcomatoid cells in carcinosarcoma tissue. These findings suggest that some of the sarcoma cells in uterine carcinosarcomas resemble epithelial malignant cells in regard to the increase in COX-2 expression, and support the hypothesis that some uterine carcinosarcomas are combination tumors. This may serve as a basis for new chemoprevention and treatment strategies for uterine carcinosarcomas through the inhibition of COX-2 activity. PMID- 11605038 TI - Genetic imbalances in preinvasive tissue of hypopharynx provide evidence for cytogenetic heterogeneity. AB - Multiple chromosomal aberrations have been reported in head and neck squamous cell carcinoma (HNSCC). But less information is available on specific patterns of chromosomal amplifications which distinguish different areas of head and neck tumors. To elucidate genetic mechanisms causing the aggressive growth and high proliferation of hypopharyngeal squamous cell carcinoma (SCC), we performed reverse chromosome painting (RCP) on a total of eight hypopharyngeal SCC including invasive carcinoma and preinvasive tissue. Five hypopharyngeal invasive carcinomas showed amplifications on chromosome 3q. Furthermore, we detected gains on chromosomes 11q and 6p. Compared to the histologically classified preinvasive tissues, we found amplified alterations on chromosome 6p, 11q and 12q, but none of them showed gains on chromosome 3q. This observed heterogeneity in hypopharyngeal SCC might reflect a specific role of chromosome 3q as a late event in the highly invasive capacity of these SCC. PMID- 11605039 TI - Fhit protein expression in human gastric cancer and related precancerous lesions. AB - The FHIT gene is altered in several types of tumors and abnormal expression of Fhit protein have also been reported in some preneoplastic lesions. We have determined the Fhit expression on histological samples of 26 patients affected by preneoplastic lesions who developed a gastric cancer within 2 years. The expression of the Fhit protein was always present in all preneoplastic lesions, while the Fhit protein immunostaining was distributed unevenly in 10 cases and completely lost in 6. The complete loss of Fhit expression only in areas of neoplastic low differentiation suggests that FHIT gene takes part in late gastric carcinogenesis. PMID- 11605040 TI - Splenic metastasis of lung cancer. AB - Splenic metastasis from a lung cancer is infrequently noted, however, the pattern of the metastasis has not been studied, thus we conducted a retrospective study. Twelve of the consecutive 997 patients with lung cancer, who were admitted to our division, developed splenic metastasis. The pattern of splenic metastasis involved solitary nodule in 7 patients (58.3%); multiple nodules in 4, and microscopic metastasis in 1. All of the 12 patients had other abdominal organ metastasis. Splenic mass accompanying metastasis to other abdominal organs in a patient with a known lung cancer should be regarded as a metastasis. PMID- 11605041 TI - Primary peritoneal clear cell carcinoma: excellent results from paclitaxel and carboplatin combination chemotherapy. AB - While papillary serous adenocarcinomas are histocytologically common in primary peritoneal carcinomas, clear cell carcinomas are rare. We report a new regimen for the treatment of recurrent clear cell carcinomas of the peritoneum. A 45-year old woman was referred to our hospital and underwent optimal debulking surgery. Thirty-two months after the operation, lymph node swelling and elevation of serum CA19-9 were detected and recurrence was diagnosed. Paclitaxel (175 mg/m(2)) in a 3-hour and carboplatin (300 mg/m(2)) in a 1-hour infusion were repeated at three week intervals. After completion of four courses, abdominal CT and serum CA19-9 were undertaken and results compared. Lymph node swelling was significantly decreased and the serum CA19-9 level was decreased to within a normal range. Paclitaxel and carboplatin combination chemotherapy may be effective in preventing the recurrence of peritoneal carcinomas. PMID- 11605042 TI - Over-expression of vascular endothelial growth factor after preoperative radiation therapy for rectal cancer. AB - Vascular endothelial growth factor expression before and after preoperative radiation therapy was examined in 16 stage III rectal carcinoma patients. The biopsied tissues before preoperative radiation therapy and the tissues at operation were immunohistochemically stained. Four cases were negative for VEGF expression before radiation, but the other 12 cases were positive, with 4 cases showing strong immunoreactivity. After radiation, all except 1 case showed VEGF positive patterns, in which 14 cases demonstrated strong staining. In 12 cases, VEGF expression became higher after radiation therapy than before, as compared to the only 1 case that showed lower expression than before. PMID- 11605043 TI - Lung cancer patients with cardio- and cerebrovascular diseases. AB - Cardio- and cerebrovascular diseases (CCVD) and cancer are the leading causes of death for humans. The aim of this study was to demonstrate clinicopathological features of lung cancer patients with CCVD. Nine hundred and sixty-six patients with lung cancer were consecutively admitted to our division over a 24-year period. Among them, 254 (26.3%) patients were diagnosed as having CCVD based on medical records. One hundred and ninety-one were men and 143 were 70 years of age or older. There was a difference in smoking habit (p=0.0029) and 30 pack year or more history of smoking (p<0.0001) between lung cancer patients with or without CCVD. Among the 254 patients, 97 patients had stage IA-IIIA disease, however, 27 patients received chest irradiation or supportive care because of coexistence of CCVD. In 157 patients with locally advanced or metastatic disease, 58 patients had less intensive therapy. In multivariate analysis, existence of CCVD in patients with non-small cell lung cancer (NSCLC) was proven to be a prognostic factor (p=0.0466). Our results imply that existing CCVD do adversely affect the outcome of NSCLC. When we decide whether or not to offer an intensive therapy which may increase treatment-related mortality, patients' medical condition including CCVD should be taken into consideration. PMID- 11605044 TI - Transient shrinkage of a uterine leiomyosarcoma treated with GnRH agonist for a presumed uterine leiomyoma: comparison of magnetic resonance imaging finding before and during GnRH agonist treatment. AB - We present a case of a premenopausal woman treated with GnRH agonist for a presumed uterine leiomyoma. This tumor reduced at first, but subsequent surgical specimens revealed a leiomyosarcoma. Magnetic resonance imaging (MRI), one of the most useful modalities for distinguishing between uterine leiomyoma and leiomyosarcoma, was undertaken twice, before GnRH agonist administration and then after 6 months of GnRH agonist administration. Apparent differences were observed between these MRI findings. Tumor-size reduction with GnRH agonist treatment does not always mean that the possibility of a leiomyosarcoma should be ruled out. PMID- 11605045 TI - Association between overexpression of cyclooxygenase-2 and suppression of apoptosis in advanced cancer of the uterine cervix after cyclic balloon-occluded arterial infusion. AB - Recent advances in cancer chemotherapy have drawn the attention of investigators to the usefulness of chemotherapy for cancer of the uterine cervix in general, and we ourselves have previously reported satisfactory therapeutic results of cisplatin-based cyclic balloon-occluded arterial infusion chemotherapy (BOAI), which enabled treatment by hysterectomy in patients with advanced cervical cancer. Nevertheless, there have been some patients in whom CDDP therapy by BOAI was ineffective, and hysterectomy was impracticable. In the present study we investigated the expression of cyclooxygenase-2 (COX-2) in these cases in an attempt to identify the cause of the lack of efficacy. The subjects of the study were 38 women with advanced cervical cancer classified as FIGO (International Federation of Gynecology and Obstetrics) stage III or higher who were admitted to the Department of Gynecology of Osaka City University Medical School Hospital between July 1993 and April 2000. All of these patients were treated by BOAI, and expression of COX-2, angiogenic factors, and cancer cell apoptosis, before and after BOAI were examined, and survival rates were compared. The 18 patients in whom BOAI was ineffective showed significantly higher expression of COX-2 after BOAI, and cancer cell apoptosis was inhibited. The 5-year survival rate of these patients was 16.8%, as opposed to 54.1% in the 20 patients in whom BOAI was effective. These results suggest that overexpression of COX-2 inhibits cancer cell apoptosis and adversely influences the prognosis. PMID- 11605046 TI - Clinical significance of urinary vascular endothelial growth factor in patients with superficial bladder tumors. AB - Vascular endothelial growth factor (VEGF) is an important mediator of tumor angiogenesis and has been shown to be excreted in the urine of bladder cancer patient. The goal of this study was to evaluate urinary VEGF levels of patients with superficial bladder transitional cell carcinoma (TCC) and to determine its predictive value for recurrence. Pre-operative urinary VEGF levels were determined in 31 patients with superficial bladder TCC and 10 control patients. A quantitative enzyme immunoassay was used to measure urinary VEGF levels and the urine VEGF concentration was corrected by the creatinine concentration in a 24-h urine specimen. The corrected urinary VEGF levels were higher in patients than controls (p=0.003). Ten of 31 patients had TCC recurrences during this study. Corrected urinary VEGF levels were significantly higher in recurrent vs. non recurrent patients (p=0.001). A cut-off value of 0.32 (corrected urinary VEGF levels) was valuable for predicting recurrences in this prospective study. However, there was no statistical correlation between VEGF levels and tumor stage (Ta or T1), tumor size or tumor grade. Pre-operative urinary VEGF levels are associated with a risk of recurrence in patient with superficial bladder TCC. Quantification of urinary VEGF may prove to be a valuable, non-invasive indicator of carcinoma recurrence in patients with superficial bladder TCC. Urinary VEGF may be a therapeutic target for intravesical therapy. However, because of the small number of cases, further studies with larger number of patients will be needed to clarify this issue. PMID- 11605048 TI - Immunohistochemical findings of nitric oxide synthase expression in urothelial transitional cell carcinoma including dysplasia. AB - Several in vitro studies have shown that nitric oxide (NO) produced by NO synthase (NOS), such as inducible NOS (iNOS) play an important role in tumor biology. We immunohistochemically examined the expression of iNOS and p53 proteins in patients with transitional cell carcinoma (TCC) of the urinary tract, including adjacent dysplastic lesions to determine the significance of the tumor behavior. Of total 94 tumors, in the present study, 41 (43.6%) tumors exhibited homogeneous immunostaining (diffuse strong positivity in tumor cells, >60%) and 53 (56.4%) tumors heterogeneous staining (variable positivity in tumor cells, 20 60%). No TCCs exhibited negative iNOS immunostaining was found. Thirty (31.9%) of 94 TCCs were positive with anti-p53 antibody, including 23 of homogeneous and 7 of heterogeneous staining. Of 23 TCCs with homogeneous p53 immunostaining, 11 tumors exhibited homogeneous iNOS immunoreaction. In the present study, dysplastic lesions adjacent to carcinomas were detected in 64 cases including 36 TCCs with homogeneous iNOS expression. All dysplastic lesions adjacent to the 36 TCCs with homogeneous iNOS immunostaining exhibited homogeneous iNOS immunostaining. No significant association between iNOS immunoreactivity and any clinicopathological factors as well as p53 immuno-reactivity were found. These in vivo findings provide evidence for frequent iNOS protein expression in TCC. In addition, our observations indicate that overexpression of iNOS expression may be one of the early events in the carcinogenesis of TCC. PMID- 11605047 TI - Pharmacokinetics and pharmacodynamics of serum platinum of gynecologic cancer patients treated with nedaplatin. AB - Nedaplatin (cis-diammine glycolate platinum) is one of the effective platinum agents for gynecologic carcinoma. In order to assess the pharmacokinetics and pharmacodynamics of serum platinum of gynecologic cancer patients treated with nedaplatin, we calculated 10 course AUCs (area under the curve) of the free and total platinum from blood samples of 4 patients. Peak serum platinum concentrations were dependent on infusion times. In the case of a patient with renal dysfunction or ascites, the concentration of serum platinum tended to stay at a high level for a long time. Serum-free platinum ratios were maintained longer than cisplatin. Low dose nedaplatin administration and divided administration were effective, but total AUC was not so great. The relation between AUC ratio (free platinum AUC/total platinum AUC) and dose/m(2) was not clarified. PMID- 11605049 TI - A case of undifferentiated carcinoma of the gallbladder with anomalous arrangement of the pancreaticobiliary ductal system. AB - Anomalous junction of the pancreaticobiliary duct (AJPBD) is a congenital anomaly associated with gallbladder carcinoma. Especially patients with noncystic dilatation and without dilatation of the biliary tract are at risk of gallbladder carcinoma. A 56-year-old woman with advanced gallbladder cancer associated with AJPBD but without dilatation of the biliary tract was treated at our hospital. Although histologically cancer cells remained in the layer of the proprial mucosa, extensive metastases to lymph nodes including the paraaorta and peripancreas were detected. According to the TNM classification this case was of Stage IVB. The cancer consisted of medullary round cells, and was diagnosed as undifferentiated carcinoma. After surgery poor prognosis was expected, but three years have elapsed with no recurrence. The case is of interest because of two points of discrepancy: the primary cancer did not show deep invasion but demonstrated extensive lymph node metastases; the cancer was histologically malignant but prognosis was relatively good. PMID- 11605050 TI - Expression and cisplatin sensitivity of copper-transporting P-type adenosine triphosphatase (ATP7B) in human solid carcinoma cell lines. AB - One of the most important clinical problems in the treatment of human solid carcinoma is the intrinsic/acquired resistance. Cisplatin is a platinum compound that is one of the most effective agents in clinic. Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance by the experiment of transfection of full cDNA of ATP7B into KB3-1 lacking ATP7B. We examined the relationship between mRNA expression level of ATP7B and sensitivity to cisplatin in nine human ovarian carcinoma cell lines to extend these findings. mRNA expression level of ATP7B was significantly correlated with cisplatin-sensitivity in nine cell lines, raising the possibility that ATP7B could be a chemoresistance marker in some types of human solid carcinoma. PMID- 11605051 TI - Fibronectin gene polymorphism in patients with lung cancer. AB - Fibronectin (FN) is a glycoprotein component of connective tissue. It is involved in cancer progression. FN plays a role in non-neoplasmatic lung pathology in which fibronectin gene polymorphisms (RFLPs) have been studied. The aim of our work was to evaluate the frequency of two of fibronectin RFLPs: genotypes AB, AA, BB (HaeIII) and CD, CC, DD (MspI) in patients with lung cancer. The studied group consisted of 63 patients with squamous cell lung cancer and 53 controls without any malignant or proliferative disease. There were no statistically significant differences in the distribution of studied genotypes between lung cancer patients and controls. PMID- 11605052 TI - Proximal gastrectomy and jejunal pouch interposition: evaluation of postoperative symptoms and gastrointestinal hormone secretion. AB - Reflux esophagitis, dumping syndrome and malnutrition are included in the postgastrectomy complications. To prevent or minimize such sequelae, proximal gastrectomy with an interposed jejunal pouch has been advocated as an organ preserving surgical strategy to improve quality of life for the patients. Proximal gastrectomy was performed in 44 patients with tumors in the upper third of the stomach; 21 had reconstruction using jejunal pouch interposition between the esophagus and the remnant stomach (JP group), while 23 had reconstruction by esophagogastrostomy (EG group). Re-construction method was selected by each patient on the basis of the informed consent. Thirty-five patients had early gastric cancer. Postoperative courses of patients were reviewed in terms of symptoms, weight maintenance, nutritional status, blood chemistry values, endoscopic findings, and radiographic appearances after a barium meal. Concentrations of gastrointestinal hormones were measured in response to a test meal. The JP procedure permitted increased dietary volume. The JP group showed fewer severe postoperative symptoms than the EG group. After operation, all patients examined in both groups showed hypergastrinemia and all patients examined in the JP group showed hypersecretinemia. In proximal gastrectomy, the JP procedure improved patient's post-operative quality of life. PMID- 11605053 TI - Fibroblast growth factor receptor 3 S249C mutation in virus associated squamous cell carcinomas. AB - An S249C mutation in fibroblast growth factor receptor 3 (FGFR3) gene was recently identified in patients with cervical carcinomas (CC). However, its importance in cervical tumorigenesis is still inconclusive. Apart from CC, nasopharyngeal carcinoma (NPC) is the other major virus associated squamous cell carcinoma. We sought to clarify the frequency of the FGFR3 S249C mutation in 75 primary CC in the Thai population and to determine its prevalence in 69 primary NPC by PCR and restriction enzyme digestion. None of the patients but one NPC showed the enzyme digestion pattern consistent with the mutation. This is the first report demonstrating the role of FGFR3 in the development of human NPC. This study confirms the low frequency of the FGFR3 S249C mutation in CC. Nevertheless, the discovery of the mutation, not only in CC as reported by previous studies, but in NPC based on this report, suggests that FGFR3 may play a significant role in human CC and NPC development. PMID- 11605054 TI - Peritoneal carcinomatosis in lung cancer patients. AB - Metastatic involvement of the peritoneum is not a very rare autopsy finding. Clinically, however, peritonitis carcinomatosis from a lung cancer is infrequently encountered and the pattern of the metastasis has not been studied. A total of 1041 patients with lung cancer who were admitted to our division over a 26-year period were retrospectively analyzed. Twelve (1.2%) of the 1041 patients with advanced lung cancer developed peritoneal carcinomatosis in their clinical courses. The incidence of peritoneal carcinomatosis was high in patients with large cell carcinoma and adenocarcinoma. Six and 9 of the 12 patients had metastases in intra-abdominal sites and pleural seeding, respectively. The median survival time from the diagnosis of peritoneal carcinomatosis was 2 months. Ascites accompanying metastasis to abdominal organs and pleural seeding in a patient with a known lung cancer would be regarded as a metastasis. PMID- 11605055 TI - Probucol decreases total body fat loss in VX2-carcinoma-induced cachectic rabbits. AB - We previously reported the continuous decrease of total body fat in VX2-carcinoma bearing rabbits after tumor implantation, as well as changes in the serum lipid profile. Probucol, an antioxidant drug, has a cholesterol lowering effect against hyperlipidemic subjects. VX2-carcinoma-bearing rabbits fed with a diet containing 1% probucol did not show any difference in serum lipid compositions as compared with rabbits fed with a control diet. Similarly serum lipolytic activity showed no differences, whether probucol was administered or not, while the decrease in total body fat was significantly less when probucol was administered. PMID- 11605056 TI - Obstructing carcinomas of the colon and rectum have a smaller size compared with those of non-obstructing carcinomas. AB - The aim of the current study was to elucidate the histopathological characteristics of obstructing carcinoma of the colon and rectum. We studied 72 patients with colorectal carcinoma, including 13 with obstructing carcinoma. The obstruction carcinomas occurred in sigmoid colon significantly more frequently than did non-obstructing carcinomas (p=0.007). The mean size of the obstructing carcinomas was 3.7+/-0.9 cm, which was significantly smaller than that of non obstructing carcinomas (5.4+/-1.9 cm, p=0.003). The proportion of lymph node metastasis in obstructing carcinomas was 66.9%, which was significantly higher than that in non-obstructing carcinomas (42.4%, p=0.021). The proportion of carcinomas classified into Dukes' C or D in obstructing carcinomas was 84.6% and was significantly higher than that in non-obstructing carcinomas (52.5%, p=0.026). The pathogenesis of obstruction in colorectal carcinoma can be also derived from the contraction of the intestinal lumen caused by the condensation of cancer cells. PMID- 11605057 TI - Expression of angiogenic factors in extrapelvic endometriosis. AB - The expression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) were immunohistochemically examined in both pelvic and extrapelvic endometriotic lesions. Different expressions of VEGF and COX-2 were observed in both lesions. VEGF immunoreactivity was distributed mainly in the cytoplasm of the adenocytes in inguinal tumors, but was not seen in ovarian tumors. COX-2 showed the same findings. These results suggest that angiogenesis may be involved in the pathogenesis of extrapelvic endometriosis. PMID- 11605058 TI - Cyclooxygenase-2 level and culture conditions influence NS398-induced apoptosis and caspase activation in lung cancer cells. AB - Cyclooxygenases (COXs) catalyze the synthesis of prostaglandins (PGs) from arachidonic acid. Overexpression of COX-2 is frequently found in human cancers and is suggested to play an important role in tumorigenesis. Recent studies indicated that COX-2 inhibitors exert potent anti-cancer effects on a number of cancers. Interestingly, some COX-2 inhibitors potently induce apoptosis, while other COX-2 inhibitors primarily induce growth inhibition. Therefore, there is a variability in the effects that different COX-2 inhibitors have on cancer cells. In this study, we demonstrated that induction of apoptosis of high COX-2 expressing A549 lung cancer cells by a specific COX-2 inhibitor NS398 was observed in cells cultured under serum-free condition. However, this drug induced G1 growth arrest rather than apoptosis in A549 cells maintained in 10% serum medium. Conversely, low COX-2-expressing H226 lung cancer cells were resistant to NS398-induced apoptosis under both serum-free and serum-containing conditions. Moreover, our results showed that NS398-induced apoptosis is associated with activation of caspase-3, a cysteine protease that plays a crucial role in the execution phase of apoptosis. These results suggest that the cytotoxic effect of COX-2 inhibitors on cancer cells may be influenced by extracellular environments and the anti-cancer action of these inhibitors in vivo needs careful evaluation. Additionally, a correlation between the level of COX-2 expression and the extent of apoptosis induced by COX-2 inhibitors was found. PMID- 11605059 TI - Long-term effect and tolerance of talc slurry for control of malignant pleural effusions. AB - Drainage of malignant pleural effusions (MPE) by thoracocenthesis and subsequent pleurodesis is an established means of symptomatic relief in terminally-ill patients, but the optimal therapy remains unclear. Among many sclerosing agent, talc is the most widely used, but its intrapleural administration and dosage have not been clearly determined. To assess the efficacy of using talc slurry with high dose (8 g) as a sclerosing agent instilled into the pleural space at the patient bedside, we carried out a study in 31 patients suffering from symptomatic MPE, followed until death or up to 1 year with radiographs. Patients were evaluated for immediate tolerance (31 patients), and for efficacy and long-term tolerance (27 patients) of the talc therapy. We have shown, that pleurodesis was satisfactory in 22/27 patients (81.4%). This result appeared comparable with other series. Moreover, we observed a long-lasting efficacy: within 6 months and within 12 months after talc instillations, 20/20 patients and 9/9 patients respectively were symphysed with efficacy. Complications related to talc (8 g) were rare and moderate (pain, fever). Taking into account some technical aspects of talc instillation for good performance of the therapy, we recommend this method as the optimal route of administration. PMID- 11605060 TI - Absence of Bcl10 gene mutations in Ewing's sarcomas. AB - The Bcl10 gene was recently isolated from the breakpoint region of t(1;14)(p22;q32) in mucosa-associated lymphoid tissue (MALT) lymphomas. Somatic mutations of Bcl10 were found in not only t(1;14)-bearing MALT lymphomas, but also a wide range of other tumors. To clarify the actual frequency and spectrum of Bcl10 mutations in primary malignant Ewing's sarcomas, we examined 31 cases of Ewing's sarcomas. Polymerase chain reaction single-stranded conformation polymorphism (PCR-SSCP) and sequencing analyses were done. No Bcl10 mutations were found in our series of Ewing's sarcomas. While screening for mutations, we found three polymorphisms at codons 8 exon 1 of the Bcl10 gene. Our results strongly suggest that somatic mutations of Bcl10 are extremely rare in Ewing's sarcomas and do not commonly contribute to their molecular pathogenesis. PMID- 11605061 TI - In vivo and in vitro nuclear magnetic resonance spectroscopy investigation of an intracranial mass. AB - This study shows how 1H magnetic resonance spectroscopy (1H MRS) can help to elucidate a clinical case when MR images suggest a diagnosis of central nervous system (CNS) neoplasm. The in vivo MRS metabolic profile in our cases did not correspond to literature reports of brain tumors, but reflected the histopathological response of hematoma and the in vitro 1H MR spectra of the biopsy obtained at surgery. The in vitro spectrum of the aqueous extracts of the examined lesion were compared with those of two common CNS tumors. The lipid fraction spectrum of the lesion agreed with both the spectrum of the aqueous extracts and the histological diagnosis. PMID- 11605062 TI - Prevention of the development of preneoplastic lesions, aberrant crypt foci, by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male F344 rats. AB - The modifying effects of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (MAK) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. Rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for three weeks to induce ACF and fed on diets containing 0, 1.25, 2.5 and 5.0% MAK for five weeks, starting one week before the first dose of carcinogen. MAK significantly and dose-dependently prevented the development of ACF, decreasing the total number of AC and inhibiting cyst formation. MAK (2.5 and 5.0%) also significantly reduced the longitudinal-cross section areas of colon epithelium. MAK in all doses significantly reduced the PCNA positive index, area of the germinal region and number of cells per half crypt. In an additional in vitro experiment, MAK inhibited anchorage-independent growth of several colon carcinoma cell lines. The present results thus indicate that dietary MAK could act as a preventive agent for colon carcinogenesis. PMID- 11605063 TI - Evaluation of the c-Met immunostain to detect malignant cells in body cavity effusions. AB - The cytologic diagnosis of malignant cells in serous effusions can be difficult. A wide variety of immunostains and other diagnostic techniques have been studied but without widespread acceptance of one staining panel or technique. Expression of the tyrosine kinase c-Met has been associated with several malignancies but not with benign mesothelium. We investigated the diagnostic value of the c-Met immunostain in serous effusions. Cell block material from 76 cases of unequivocally benign or malignant effusions were studied. Cases were stained with c-Met using the avidin-biotin complex method following antigen retrieval. The presence of strong granular cytoplasmic staining that was distinct from background staining was considered positive. Positive cells were identified in 38 of 42 (90%) malignant cases and in 18 of 34 (53%) benign cases. Typically, benign cases contained only individual positive cells, but positive cell clusters were also identified. The c-Met immunostain lacks sufficient specificity to be clinically useful in this cytologic setting. The expression of c-Met in benign mesothelium may reflect mesothelial proliferation. PMID- 11605064 TI - Plasma and tissue prolactin detection in colon carcinoma. AB - Serum concentrations of prolactin, a trophic hormone produced by the pituitary gland, have been shown to be raised in certain group of patients with cancer. Prolactin was detected in 0-20% of the colon cancer by immunohistochemistry and in plasma in 6-53% of the patients. These conflicting results do not support the hypothesis of an ectopic prolactin production by colon carcinoma. The aim of this study was to confirm the reported incidence of hyper-prolactinemia in colorectal cancer and to find further evidence for an ectopic prolactin production by the tumor. Thirty consecutive patients with colon carcinoma were studied. Before surgery all the patients underwent blood sample collection to assay plasma prolactin levels. All patients underwent colectomy. All the neoplastic specimens were tested with antiprolactin antibody. In none of the patients were significantly high preoperative levels of plasma prolactin found. Prolactin immunostaining was not identified in any of the tumor specimens. We could not confirm previous reports of frequent hyperprolactinemia in patients with cancer. This is the first report in which the incidence of both hyperprolactinemia and prolactin positive immunostaining was 0%. Our study was unable to demonstrate the synthesis of prolactin by colorectal cancers. The tumor is unlikely to be the source of hormone production. Our results suggest that circulating prolactin levels cannot be used as prognostic marker in patients with colon cancer. PMID- 11605065 TI - Livistona extract inhibits angiogenesis and cancer growth. AB - In a screen for naturally occurring angiogenic inhibitors, we have identified an extract from the seed of the plant Livistona chinensis, which has potent anti angiogenic and anti-tumor activity. The aqueous extract inhibits the in vitro proliferation of endothelial cells and multiple tumor cell lines including mouse fibrosarcoma and human breast and colon cancer. In mouse experiments, this extract suppresses the growth of the subcutaneous fibrosarcoma tumors. When the seed is separated into different components, the shell including the seed skin appears more potent than the inner kernel in tumor suppression. Our results suggest that the extract from the shell of Livistona chinensis may be a potential supplemental source for cancer treatment. PMID- 11605066 TI - Inactivation of the p16INK4A gene by methylation is not a frequent event in sporadic ovarian carcinoma. AB - The p16INK4A tumour suppressor gene (p16) encodes for a cyclin-dependant kinase inhibitor which plays a role in the phosphorylation of the retinoblastoma protein (pRb) during regulation of the G1-S phase of the cell cycle. Loss of heterozygosity at 9p21, the chromosomal location of the p16 gene, has been reported in a broad range of tumours and this is usually indicative of the presence of a tumour suppressor gene, the second allele being frequently inactivated by mutation or deletion. The p16 gene, however, is often found not be mutated or deleted and it has been suggested that hypermethylation of the CpG islands of the gene may be an alternative mechanism of gene inactivation. We sought to determine the levels of p16 abnormality in a series of epithelial ovarian carcinomas in an attempt to clarify the presently conflicting evidence of whether or not hypermethylation of the p16 gene plays a role in ovarian carcinogenesis. We analysed 57 primary ovarian tumours and their corresponding blood DNA using SSCP analysis, sequencing and the methylation specific PCR (MSP) technique. We found low levels of mutation (6.7% of malignant tumours) and no evidence of methylation in any of our samples, suggesting that neither mutation or hypermethylation of the CpG islands of the p16 gene play an important role in ovarian carcinogenesis. PMID- 11605067 TI - Characterization of anti-BRCA2 antibodies in cell lines by Western blot analysis. AB - BRCA2 is a tumor suppressor gene associated with familial predisposition to breast and ovarian cancer. BRCA2 has been implicated in response to DNA damage, cell cycle control and transcription. However, the mechanisms by which the BRCA2 protein suppresses tumor cell growth are largely unknown. To begin to understand the contribution of BRCA2 protein to tumorigenesis, we evaluated the specificity of 4 anti-BRCA2 antibodies directed against several different epitopes using immunoblotting techniques. The two monoclonal antibodies (3E6 and 5F6) detected a specific 384-kDa protein in human breast cancer cell lines (MCF7 and MDA-MB 231) and in a human colon carcinoma cell line (CCL 221). The two polyclonal antibodies (9433 and 9434) recognized the 384-kDa BRCA2 protein respectively in MCF7 and in CCL 221 cells, but both BRCA2 polyclonal antibodies also cross-reacted with smaller proteins. PMID- 11605068 TI - ELISA-based Ki-ras gene mutation analyses in pancreatic and cholangiocarcinoma cells and tissues. AB - Detection of Ki-ras mutations is one possible modality for diagnosis of human neoplasms, particularly of the gastrointestinal tract. Little is known about the protein expression levels of ras p21. Here we show a semi-quantitative analysis of mutated ras p21 in protein extracts from pancreatic and cholangiocarcinoma cell lines and from tumor tissues. Comparison with DNA sequencing data confirmed the specificity of the ELISA-mediated mutation analysis. Epithelial cell content from stroma rich tissues was estimated by measuring the CK 8, 18 and 19 concentration in protein extracts from tissue samples comparing this with the average keratin content in extracts from 21 GI-carcinoma cell lines. The combination of both tests allowed the analysis of the ras p21 content of tissues with as little as 5% tumor cell content. PMID- 11605070 TI - Mutational analysis of the PTEN/MMAC1 tumour suppressor gene in primary human malignant mesotheliomas. AB - Eighteen primary human malignant mesotheliomas obtained from 18 patients were screened for point mutations and microdeletions/insertions in all exons of the tumour suppressor gene PTEN/MMAC1 by SSCP analysis. No mutation could be found. Our preliminary data indicate that disarrangements of PTEN/MMAC1 are at least not frequently involved in mesothelioma formation. PMID- 11605069 TI - Chemoimmunotherapy of cancer: potentiated effectiveness of granulocyte-macrophage colony-stimulating factor and ifosfamide derivative CBM-4A. AB - The effectiveness of combined chemoimmunotherapy with ifosfamide derivative CBM 4A and granulocyte-macrophage colony-stimulating factor (GM-CSF) was investigated in two experimental tumor models, 3MC-induced MHC class I+ sarcoma Mc12 and HPV16 E6/E7 oncogene-induced MHC class I- carcinoma MK16, transplanted in syngeneic mice. Treatment of Mc12 and MK16 tumor-bearing mice with GM-CSF or CBM-4A alone produced moderate anti-tumor effects. However, when the tumor-bearing mice were first treated i.p. with a single dose of CBM-4A (150 mg/kg) and three days later peritumorally with five daily doses of GM-CSF (100 ng/day), substantially stronger tumor-inhibitory effects were observed. The results indicate that in both, MHC class I+ and MHC class I- tumors, the combined chemoimmunotherapy can inhibit tumor progression more effectively than GM-CSF therapy or chemotherapy alone, and they suggest that GM-CSF should be considered as adjuvant to chemotherapy in clinical trials with HPV 16-associated neoplasms. PMID- 11605071 TI - Modulation of soluble CD44 concentrations by hormone and anti-hormone treatment in gynecological tumor cell lines. AB - Serum levels of CD44 (sCD44) are increased in a variety of human diseases including gynecological malignancies showing hormone-dependent growth and proliferation. Very little is known about the mechanisms underlying the processing of soluble CD44 and influencing its release. Due to their major impact on gene transcription and cell proliferation steroid hormones or their antagonists might influence sCD44 processing. We investigated the effects of different hormonal conditions on overall soluble CD44 (sCD44std) concentrations in a subset of gynecological tumor cell lines. Established human breast and endometrium cancer cell lines were characterized for their membrane-bound CD44 protein, CD44 mRNA expression and steroid receptor status prior and after incubation with 17beta estradiol (E2), medroxyprogesterone acetate (MPA), 4 hydroxy-tamoxifen (4-OH-Tam) and the gonadotropin releasing hormone (GnRH) agonist busereline. An enzyme linked immuno-sorbent assay (ELISA) using a monoclonal antibody directed against an epitope common to all CD44 isoforms was used to determine sCD44 levels in the supernatants of the tested cell lines. Interestingly, a strong correlation between sCD44 levels and the receptor status of the cells was seen. However, membrane-bound CD44 expression was not influenced by the hormonal environment. Our results indicate that distinct steroid hormones can specifically influence concentrations of soluble CD44. How this effect is involved in the tumorigenesis of gynecological malignancies and whether it might contribute to the biological behavior of special tumors should be investigated in further studies. PMID- 11605072 TI - Effects of a 15% orange-pulp diet on tumorigenesis and immune response in rats with colon tumors. AB - This study evaluated whether the feeding of rats with a 15% orange-pulp diet affects the lymphatic system and the tumorigenic response in rats exposed to a high dose of carcinogen. Five-week-old Sprague Dawley rats were divided into 2 groups fed a control chow diet or the same diet with 15% orange pulp. All rats were injected with 1,2-dimethylhydrazine (DMH) (20 mg/kg) weekly for 6 weeks. At 8 months, tumors, spleens and descending colon were taken from each group for analyses. Feeding rats the 15% orange-pulp diet did not reduce the tumor number but modified the number of adenocarcinomas found in the orange-pulp group compared to controls: 66.7% vs. 93.7%. The number of endophytic tumors was also significantly lower in the experimental group: 6.3% vs. 32.3% in controls. DMH affected the size of the splenic structures. The size of follicles and germinal centers decreased significantly in tumor-bearing rats compared to tumor-free rats. This effect was changed in rats fed the orange-pulp diet. In tumor-bearing rats from this group, only the area of the marginal zone decreased and the red pulp increased compared to tumor-free rats. The size of germinal centers significantly increased compared to tumor-bearing rats in controls. The total number of lymphoid cells decreased in germinal centers of spleens obtained from control tumor-bearing rats compared to tumor-free rats. DMH alone significantly increased the total number of cells in the colon mucosa of the rats fed the control diet. In tumor-bearing rats exposed to the carcinogen and fed the 15% orange-pulp diet, the total number of cells and the number of Ki-67+ cells increased in the depth of tumors whereas the number of CD8+ T cells increased in the colon mucosa, at the border of tumors and its depth. The caspase-3 protein a cysteine protease was elevated in tumors from rats fed the orange-pulp diet. Although the 15% orange-pulp diet did not change the number of tumors in the tumor-bearing rats, feeding rats orange pulp significantly decreased the number of endophytic tumors and increased the number of exophytic tumors. Increased activity of T cell killers in tumors and higher level of proteins involved with apoptosis following consumption of the orange pulp indicate a clear tumor suppressor effect of these dietary fibers. PMID- 11605073 TI - Comparison of 18FDG-PET with CT scans in the evaluation of patients with residual and recurrent Hodgkin's lymphoma. AB - The reliable assessment of residual masses after treatment as well as of new lesions suspected for relapse remains a diagnostic problem in patients with Hodgkin's disease (HD). The current study compares the results obtained by CT scan to FDG-PET imaging in a blind analysis with respect to the viability of residual masses and in case of suspected relapse. Between 1/94 and 10/99, 47 comparisons of PET and corresponding CT scans - 26 comparisons in 24 patients with residual tumors and 21 comparisons in 20 patients with suspected relapse of HD - were evaluated by independent reviewers blinded to he results of each other. Patients with primary diagnosis had been treated within trials of the German HD Trial study group. Relapsed patients received intensified salvage chemotherapy regimens. PET was assessed visually and by quantifying glucose uptake (SUV). Changes in size of tumor lesions as well as contrast medium enhancement served as criteria for assessment by CT scans. Results were validated either by histologic examination of a resected mass or biopsy (n=17) or by a clinical follow-up over 6 months following treatment (n=30). In 26 cases with residual lesions FDG-PET showed an increased tracer uptake in 8, 7 of which were true positive (TP) and 1 false positive (FP). Eighteen cases were classified as being negative (no viable HD), 17 true negative (TN) and 1 FN. In the blinded reading of the corresponding CT scans, 10 cases with residual lesions were considered to contain vital lymphoma (2 TP, 8 FP). Sixteen CT scans were classified as negative (10 TP, 6 FN). The resulting sensitivity and specificity of PET were 87.5% and 94.4% in contrast to only 25% and 56% for CT scans. The positive and negative predictive values of PET and CT scans were 87.5% and 94.4% and 20% and 62.5%, respectively. In patients with suspected relapse, sensitivity and positive predictive value for the diagnosis of the relapse were 100% and 86%, respectively, yielding the same results for both methods. FDG-PET performed in HD patients with residual masses appears to offer important additional information regarding the presence of viable HD in these residual lesions. In patients with suspected relapse of HD, FDG-PET seems not to offer any information over CT scans. Using SUVs is not superior to visual assessment of PET alone. PMID- 11605074 TI - Predictive value of altered p27Kip1 and p21WAF/Cip1 protein expression for the clinical prognosis of patients with localized prostate cancer. AB - The p21WAF/Cip and the p27Kip1 genes have been identified as inductors of cell cycle arrest at the G1-checkpoint. Alterations of both genes have been suggested to be involved in the development of a variety of human malignancies due to a loss of critical antiproliferative mechanisms. To evaluate the prognostic importance of these alterations for patients with clinically localized prostate cancer, in 86 specimens (T1-T4) from 86 patients undergoing radical prostatectomy at the Department of Urology at Hannover University Medical School, were investigated. The immunohistochemical expression of the p27Kip1 and p21WAF/Cip protein was correlated to recurrence-free and long-term survival, age, depth of tumour infiltration, histological grade and lymph node status in these patients. After a median follow-up of 71 months (1-198 months), 14 of 20 (70%) patients (Group 1) with loss of p27Kip1 protein expression or a relative amount of < 10% of positively stained tumour cells developed recurrent disease in contrast to 18 of 66 (27%) patients (Group 2) with retained p27Kip1 protein expression (> or = 10% of positively stained tumour cells). The median recurrence-free survival times were 39 (4-134) months and 67 (4-198) months for patients in Groups 1 and 2 (p < 0.01), respectively. In multivariate analysis, loss of p27Kip1 protein expression was identified as the only independent prognostic parameter for recurrence-free survival. Univariate analysis (log-rank test) identified histological grading (p < 0.01) and reactivity for p27Kip1 (p = 0.046) (> or = 10% positivity) as prognostic factors for disease-specific long-term survival. However, during multivariate analysis none of the biological variables investigated retained independent prognostic importance regarding overall survival. Neither a low or a high expression of p21Waf/Cip could be correlated with the clinical prognosis of the patients following radical prostatectomy. This study confirms the independent prognostic value of decreased p27Kip1 protein expression in patients with localized prostate cancer, while a prognostic importance of p21Waf/Cip in addition to established patients' and tumour characteristics like tumour stage and histological grading appears rather unlikely. PMID- 11605075 TI - Upregulation of non-mutated H-ras and its upstream and downstream signaling proteins in colorectal cancer. AB - We analyzed H-ras protein expression in 38 human colon cancers and the paired normal tissues. H-ras levels were significantly higher in the malignant tumor (average 0.19+/-0.27) than in its normal adjacent tissues (average 0.06+/-0.15) (p<0.05). The H-ras protein expressed in colon carcinomas contained activated form of H-ras without mutation, based on the findings obtained by RBD-binding (ras binding domain of Raf protein) assay and PCR-SSCP analysis. In addition, we found that H-ras expression was higher in female patients than male, and in cancers with distant metastasis compared to those with non-distant metastasis. Good correlation between H-ras expression levels and those of the upstream and downstream signaling proteins of EGFR, MEK and ERK was found, suggesting that H ras may play a significant role in carcinogenesis of colorectal cancer. PMID- 11605077 TI - The behavioral effects of acute and chronic JL 13, a putative antipsychotic, in Cebus non-human primates. AB - RATIONALE: Neuroleptic or antipsychotic drugs are the mainstay of treating acute and chronic psychosis. However, their efficacy is offset by a wide array of side effects, especially extrapyramidal syndromes (EPS). In an attempt to develop novel antipsychotic agents, several animal models have been developed to characterize the profile of new chemical entities. OBJECTIVE: To evaluate the behavioral characteristics of JL 13, a potentially unique antipsychotic agent, three separate studies across a wide dose range in Cebus monkeys were conducted and compared with two studies of oral and parenteral haloperidol. METHODS: Twelve Cebus monkeys were tested with single i.m. doses of JL 13 (0.1-2.5 mg/kg), single p.o. doses (1.0-50.0 mg/kg), and 35 days of continuous p.o. (up to 25 mg/kg) treatments and were blindly evaluated. The same twelve monkeys were also tested with haloperidol i.m. (0.01-0.25 mg/kg) and nine of the monkeys also received haloperidol p.o. (0.1-5.0 mg/kg). Behaviors scored included sedation/arousal, locomotor activity, EPS of parkinsonism and dystonia, as well as reactivity. RESULTS: JL 13 produced mild to moderate and dose-related increased sedation and decreased locomotor activity. Minimal decreases in eye blinking rates were also noted as a consequence of sedation. Mild dystonia and parkinsonian symptoms of slow movement developed at the highest dose tested of 50 mg/kg p.o. in only 6 of 12 monkeys. This is 50 times higher than oral doses of haloperidol that would be needed to produce similar EPS effects. Dose-related EPS of dystonia and bradykinesia occurred in relation to decreased locomotor activity and reactivity to stimuli with haloperidol i.m. and p.o., which are features characteristically seen with traditional neuroleptics. CONCLUSIONS: The behavioral effects of JL 13 in non-human primates suggest this compound is well tolerated and may have a favorable antipsychotic benefit/risk ratio in the clinic, especially if antipsychotic efficacy occurs at doses well below those that can cause EPS. PMID- 11605076 TI - Acute effects of D-fenfluramine on simultaneous measures of aggressive escape and impulsive responses of adult males with and without a history of conduct disorder. AB - RATIONALE: The role of serotonin in human aggression was evaluated by administering D-fenfluramine and comparing the effects on laboratory measures of aggression, escape and impulsivity among subjects with and without a history of conduct disorder. METHODS: Ten male subjects with a history of criminal behavior participated in experimental sessions that measured aggressive and impulsive responses. Five subjects had a history of childhood conduct disorder (CD+) and five control subjects did not. Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP), which provides subjects with an aggressive, escape and monetary reinforced response options. Impulsive responses were measured using a paradigm that gives subjects choices between small rewards after short delays versus larger rewards after long delays. RESULTS: Acute doses (0.1, 0.2 and 0.4 mg/kg) of D-fenfluramine produced significant decreases in aggressive responses in CD+ subjects and large decreases in escape responses for CD+ subjects and smaller decreases for control subjects. Impulsive responses were decreased slightly and monetary reinforced responses were not changed in either group. Decreases in aggressive responses were not selective, since escape responses were also decreased, but such effects could not be attributed to a non specific sedative action because monetary reinforced responses were increased and reaction times were decreased, indicative of central nervous system stimulation. CONCLUSIONS: Release of serotonin by D-fenfluramine is the possible mechanism for reductions in aggressive responses. These results are consistent with a large body of data linking reduced serotonin function and aggressive behavior. PMID- 11605078 TI - In vivo (123)I IBZM SPECT imaging of striatal dopamine 2 receptor occupancy in schizophrenic patients. AB - RATIONALE: Single photon emission computed tomography (SPECT) using (123)I iodobenzamide (IBZM) as tracer substance has been shown to be a useful tool to visualize dopamine 2 (D2) receptor occupancy. OBJECTIVES: We investigated the striatal D2 receptor occupancy of zotepine which is referred to the class of atypical antipsychotic drugs. METHODS: (123)I IBZM and SPECT were used to visualize striatal dopamine 2 (D2) receptor occupancy in zotepine-treated schizophrenic patients. Two groups of schizophrenic patients receiving either 150 mg/day zotepine (n=6) or 300 mg/day (n=6) underwent examination. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to untreated healthy controls (n=8) reported earlier. RESULTS: Zotepine led to a mean overall striatal D2 receptor occupancy of 73%. Patients with 150 mg daily showed a significantly lower occupancy (65.8%, SD=6.2) than patients with 300 mg/day (77.8%, SD=10.7; P<0.05). No clinically relevant extrapyramidal side effects occurred during treatment with zotepine. CONCLUSIONS: There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement. PMID- 11605079 TI - Acute doses of d-amphetamine and bupropion increase cigarette smoking. AB - RATIONALE: Bupropion is used clinically as a treatment for smoking cessation, but the processes by which it reduces smoking are poorly understood. Bupropion shares some neurochemical actions and behavioral effects with the psychostimulant amphetamine, and it has been shown that amphetamine increases smoking when administered acutely. The effects of single doses of bupropion on smoking have not been studied but, based on its similarities to amphetamine, we postulated that acute bupropion would also increase smoking. OBJECTIVE: To measure the effects of single doses of amphetamine and bupropion on smoking and craving for cigarettes in smokers. METHODS: Cigarette smokers who were not trying to quit participated in a three-session study in which they received placebo and a single dose of either d-amphetamine sulfate (10 and 20 mg; n=10) or bupropion hydrochloride (150 and 300 mg; n=12) after overnight abstinence. The three outcome measures were: i) subjective and behavioral effects of amphetamine and bupropion after a period of acute abstinence, ii) effects of amphetamine and bupropion on subjective responses to a single, smoked cigarette, and iii) effects of the drugs on number of cigarettes smoked during an ad libitum smoking period. RESULTS: After the acute abstinence and before smoking, both amphetamine and bupropion increased self-reported mood and euphoria, but did not change ratings of craving or withdrawal. After subjects smoked a single smoked cigarette, they reported that bupropion reduced ratings of "buzzed" and "intensity". During the period of ad libitum smoking both amphetamine and bupropion increased the number of cigarettes smoked. CONCLUSION: Acute doses of both bupropion and amphetamine increase smoking in non-treatment-seeking smokers without altering ratings of craving or withdrawal. Bupropion reduced some of the sensory responses to the smoked cigarette. It remains to be determined why bupropion increases smoking when administered acutely under controlled conditions, while it helps to reduce smoking in patients trying to quit. PMID- 11605080 TI - SR141716, a CB1 receptor antagonist, decreases the sensitivity to the reinforcing effects of electrical brain stimulation in rats. AB - RATIONALE: The endogenous cannabinoid system is thought to play a role in reinforcement processes. OBJECTIVES: We tested the effects of five doses of the cannabinoid receptor 1 (CB1) antagonist SR141716 [0, 0.3, 1, 3 and 10 mg/kg intraperitoneal (IP)] on intracranial self-stimulation at the level of the median forebrain bundle (MFB). Self-stimulation was assessed 30 min and 210 min after SR141716 administration. We compared the effect of SR141716 with the effect of a decrease in the magnitude of stimulation (-100 microA) and the effects of a cocaine injection (1, 5 and 10 mg/kg IP). METHODS: a protocol of rate-frequency curve for self-stimulation was applied. Two rate-frequency curves were established daily, 3 h apart. The frequency required to produce half-maximal performance (M50) and the maximal performance (RMax) were used as the parameters to characterize the rate-frequency functions. RESULTS: SR141716 decreased the sensitivity to the electrical brain stimulation. SR141716 induced a shift to the right of the rate-frequency curve. This effect depended on the dose administered and the time after injection. Thirty minutes after the injection, 1, 3 and 10 mg/kg SR141716 induced a significant decrease in sensitivity to electrical stimulation, as shown by an elevation in the M50 value. RMax showed a tendency to decrease with increasing doses. At 210 min after administration, 3 and 10 mg/kg SR141716 maintained their decreasing effect on the sensitivity to the stimulation as shown by the significant increase of the M50, however, the maximal response was restored to the basal value. A decrease in self-stimulation intensity produced an effect comparable to the one observed 30 min after either 3 or 10 mg/kg SR141716, while cocaine (5 and 10 mg/kg) produced the opposite effect. Neither condition affected the rate-frequency curve measured 3 h later. CONCLUSIONS: In accordance with recent observations, these experiments suggest that the endogenous cannabinoid system facilitates the perception or the effects of positive reinforcers. They also suggest that this neurochemical system could be a target of interest for treating psychopathologies implicating the reinforcing system. PMID- 11605081 TI - Role of the dopamine transporter and the sodium channel in the cocaine-like discriminative stimulus effects of local anesthetics in rats. AB - RATIONALE: Local anesthetics bind to the dopamine transporter (DAT), inhibit dopamine (DA) uptake and have been reported to have cocaine-like discriminative stimulus effects. The hypothesis of the present study was that affinity at the DAT and potency as a DA uptake blocker determines potency as a cocaine-like discriminative stimulus among local anesthetics, and maximum DA uptake inhibition determines maximum cocaine-like discriminative stimulus effects. OBJECTIVES: Cocaine-like discriminative potency was compared to DAT affinity and DA uptake inhibition potency, and maximum cocaine-like discriminative stimulus effects were compared to maximum DA uptake inhibition for procaine, chloroprocaine, dimethocaine, tetracaine and lidocaine. METHODS: Discriminative stimulus effects were determined in two groups of rats using 10 mg/kg and 3.0 mg/kg cocaine training doses. DAT affinity and DA uptake inhibition effects were determined in vitro in rat caudate nucleus tissue. Additionally, sodium channel affinity was determined in rat frontal cortex tissue. RESULTS: In the 10 mg/kg group, none of the local anesthetics fully substituted for cocaine and all decreased response rate. Rate decreasing potencies were positively correlated with sodium channel affinities. In the low training dose group, all the local anesthetics except tetracaine substituted fully for cocaine. Discriminative potencies were positively correlated with sodium channel affinities. Maximum DA uptake inhibition did not adequately predict maximum discriminative stimulus effects. CONCLUSIONS: Cocaine-like discriminative stimulus effects of local anesthetics were more prominent at a low than at a high training dose of cocaine. Sodium channels seem to have a direct influence on discriminative effects at low cocaine doses, whereas they have an indirect influence on discriminative effects at high cocaine doses by decreasing response rates. PMID- 11605082 TI - Individual differences in sucrose consumption in the rat: motivational and neurochemical correlates of hedonia. AB - RATIONALE: Rats exhibit marked individual differences in consumption of freely available sucrose; however, the underlying mechanism(s) contributing to such interindividual differences remain unclear. OBJECTIVES: The current study examined whether: 1) motivational differences (as reflected by the degree of operant output to procure sucrose reward) underlie variability in sugar consumption, and 2) whether potential differences in dopaminergic and/or opioidergic systems contribute to such differences. METHODS: In the initial experiment, Sprague-Dawley rats were divided into those that spontaneously consumed High or Low amounts of sucrose, based on the consumption of freely available sugar (+/-2 SD from group median) over 7 consecutive test days. The potential differences in their motivation to seek and "earn" sucrose solution rewards were measured using the progressive ratio (PR) schedule of reinforcement. RESULTS: Performance of both groups on the PR schedule was sensitive to the concentration of sucrose (i.e. the higher the concentration, the greater the behavioral output). Furthermore, the High sucrose consumers earned a greater number of reinforcements (20% sucrose solution) than the Low group. Parenthetically, the degree of behavioral output by the High (but not the Low) group was comparable to that emitted for water under water-deprived condition. Treatment with the opioid antagonist, naloxone, attenuated PR performance for sucrose, whereas d-amphetamine (0.5 mg/kg) enhanced it. Furthermore, naloxone attenuated amphetamine-enhanced responding for sucrose reward, suggesting an interaction between the dopaminergic and opioidergic systems in the mediation of sucrose reward. CONCLUSIONS: These results support the contention that motivational differences may partially account for individual variability in sucrose consumption, and that dopaminergic and/or opioidergic agents differentially affect the "wanting" and/or "liking" of sucrose in the High and Low sucrose consumers. PMID- 11605083 TI - Efficacy of kava-kava in the treatment of non-psychotic anxiety, following pretreatment with benzodiazepines. AB - A 5-week randomized, placebo-controlled, double-blind study was carried out to investigate the efficacy of kava-kava special extract WS1490 in non-psychotic nervous anxiety, tension and restlessness states. During the first treatment week, the study dose drug was increased from 50 mg to 300 mg per day and pretreatment with benzodiazepines was tapered off over 2 weeks. These dosage adjustments were followed by 3 weeks of monotherapy with WS1490 or placebo. Outcome measures were the differences between baseline and end of treatment on the Hamilton Anxiety Scale (HAMA) and on a subjective well-being scale (Bf-S), as well as the benzodiazepine withdrawal symptoms. Changes in the Erlanger Anxiety, Tension and Aggression Scale (EAAS) and Clinical Global Impressions (CGI) were analyzed as secondary measures. Treatment safety was checked by interviews, adverse event reports and laboratory investigations. Forty patients (2x20) were included into the study. WS1490 was superior to placebo regarding the HAMA (P=0.01) and Bf-S (P=0.002) total scores and all secondary efficacy measures. The tolerance of WS1490 was not inferior to placebo. The study confirms the anxiolytic efficacy and good tolerance of WS1490 and shows that a further symptom reduction is possible after a change-over from benzodiazepine treatment. PMID- 11605084 TI - Short and long term effects of antipsychotic medication on smooth pursuit eye tracking in schizophrenia. AB - RATIONALE: Smooth pursuit abnormalities have been observed in antipsychotic naive first-episode patients, suggesting that they are intrinsic to the illness. However, it is not clear whether these abnormalities are as severe as those observed in more chronic patients. In addition, although research suggests that there are no short-term effects of conventional antipsychotic medication, the effects of long-term antipsychotic medication on smooth pursuit eye movements are relatively unknown. OBJECTIVES: To determine the short and long term effects of antipsychotic medication on the smooth pursuit performance of first-episode and chronic patients with schizophrenia. METHODS: We compared the smooth pursuit performance of antipsychotic-treated and untreated first-episode and chronic schizophrenic patients with healthy controls using a comprehensive range of performance measures. This included velocity gain, the number, type and size of intrusive and corrective saccades, and the average time between the change in direction of the target and the change in direction of the eye movement, a measure of subjects' ability to predict target movement. RESULTS: Chronic schizophrenic patients had significantly reduced velocity gain, took longer to respond to the change in target direction and made more catch-up saccades than both first-episode schizophrenic patients and controls. First-episode patients were impaired relative to controls only on the measure of velocity gain. There were no differences between antipsychotic-naive and treated first-episode patients. Antipsychotic-free chronic patients were significantly less impaired on velocity gain than matched continuously treated chronic patients. These results were not influenced by group differences in age and symptom severity. CONCLUSIONS: These results show that: 1) the main index of smooth pursuit, velocity gain, is impaired early in the course of schizophrenia; 2) whereas velocity gain is unaffected by short-term (weeks) medication, it is worsened by chronic (years) treatment; 3) other indices of smooth pursuit, catch-up saccades and ability to predict target movement, are adversely influenced by illness chronicity rather than medication. PMID- 11605085 TI - Activation of 5-HT(2C) receptors reduces the locomotor and rewarding effects of nicotine. AB - RATIONALE: Various compounds believed to selectively interact with the 5-HT(2C) receptor have been demonstrated to alter the functioning of ascending dopamine systems. We postulated that this functional interaction may extend to the behavioural effects of drugs of abuse whose rewarding properties are critically dependent upon mesolimbic DA activity. OBJECTIVES: The present studies focussed on interactions between 5-HT(2C) receptor function and behaviours either supported or induced by nicotine. METHODS: The effect of Ro 60-0175, a 5-HT(2C) agonist, was assessed for its ability to modify 1) nicotine-induced locomotor activity in nicotine-treated rats, 2) lever pressing maintained by either food or IV administration of nicotine, and 3) the development of nicotine-induced hyperactivity. The specificity of this effect was further measured in locomotor activity studies by additional administration of the selective 5-HT(2C) antagonist SB 242,084. RESULTS: Ro 60-0175 (0.3-3 mg/kg SC) dose-dependently reduced nicotine-induced activity, an effect which was reversed by SB 242,084 (0.5 mg/kg IP), thus confirming receptor selectivity of the response. Responding both for food and nicotine on an FR5TO1 min schedule of reinforcement was reduced by Ro 60-0175 (0.1-1 mg/kg) with proportionally similar effects on responses for both types of reinforcer. Co-administration of Ro 60-0175 (1 mg/kg SC) and nicotine (0.4 mg/kg SC) for 10 days blocked the sensitised response that developed in subjects treated with nicotine alone. CONCLUSIONS: The present data support an involvement for the 5-HT(2C) receptor in mediating mesolimbic DA functioning as assessed by changes in behaviours indicative of nicotine reward. PMID- 11605086 TI - The GABA(A) agonist gaboxadol improves the quality of post-nap sleep. AB - RATIONALE: Previous studies demonstrated that gaboxadol, a selective GABA(A) agonist, increases both non-REM sleep and EEG delta activity within non-REM sleep in rats and slow wave sleep (SWS) as well as low-frequency activity in the EEG within non-REM sleep in healthy humans under normal conditions. OBJECTIVE: Because the hypnotic actions of drugs may be more readily demonstrated under conditions of poor sleep quality, we investigated the influence of gaboxadol on postnap sleep. METHODS: In a randomized, placebo-controlled cross-over study using a late afternoon nap model, we assessed the effects of a single oral dose of 20 mg gaboxadol on disturbed nighttime sleep in young, healthy subjects. RESULTS: Comparisons of visually scored sleep parameters between baseline and placebo postnap nights showed that the nap prolonged sleep latency, decreased total sleep time and SWS and attenuated delta, theta and alpha activity in the EEG within non-REM sleep. Compared with the placebo postnap night, gaboxadol tended to shorten sleep latency, significantly decreased intermittent wakefulness, increased total sleep time and SWS and enhanced delta and theta activity in the non-REM EEG. Furthermore, gaboxadol increased subjective sleep quality. CONCLUSIONS: These data show that gaboxadol counteracts the disrupting effects of a nap on subsequent sleep and suggest that, in addition to promoting deep sleep and sleep maintenance, gaboxadol is able to facilitate sleep initiation and thus, exhibits significant hypnotic actions under conditions in which sleep quality is experimentally reduced. PMID- 11605087 TI - Early neonatal experience of Long-Evans rats results in long-lasting changes in morphine tolerance and dependence. AB - RATIONALE: Daily, 3-h separations from the dam on postnatal days 2-14 produce long-lasting changes in behavioral and neuroendocrine responses to stressors and sensitivity to acute morphine in Long-Evans rats. OBJECTIVE: We tested whether offspring that were separated from their dam for 3 h daily (MS) on postnatal days 2-14 exhibit altered sensitivity to chronic morphine, compared to animals that experienced only brief (15 min) separations (H) from the dam or that were left undisturbed (NH) during the same period. METHODS: Subjects received 1 week SC infusion of either morphine, or saline via osmotic pumps. Twenty-hours after pump removal, the global opioid withdrawal scores were recorded. Four hours later, animals were tested for antinociception (tail-flick and hot-plate tests) during cumulative morphine administration. RESULTS: MS males and MS females undergoing withdrawal from chronic morphine had higher global withdrawal scores compared to NH controls. MS males (but not MS females) were less sensitive to the antinociceptive effects of morphine compared to H and NH controls, primarily in the hot-plate test, regardless of whether they had received a saline or a morphine infusion. MS males consistently exhibited significant morphine tolerance, whereas control males failed to exhibit tolerance either in the hot plate test (NH group) or in both antinociception assays (H group). In contrast, tolerance was exhibited by all females in both tests for antinociception. CONCLUSIONS: These data indicate that repeated neonatal maternal separation alters sensitivity to chronic morphine administration in a sex-dependent manner. PMID- 11605088 TI - Similar enhancement of the discriminative stimulus effects of cocaine and GBR 12909 by heroin in squirrel monkeys. AB - RATIONALE AND OBJECTIVES: Heroin previously was shown to engender partial cocaine like discriminative stimulus (DS) effects in squirrel monkeys. The present study assessed the degree to which heroin modified the DS effects of cocaine and the cocaine-like DS effects of the selective dopamine transport blocker GBR 12909. METHODS AND RESULTS: In squirrel monkeys discriminating cocaine (0.3 mg/kg) from saline, cocaine and GBR 12909 dose-dependently engendered levels of responding on the cocaine-associated lever greater than or equal to 90% (full substitution). Heroin engendered full substitution for cocaine in two monkeys, partial substitution (75%) in a third monkey, and no substitution in the fourth monkey. When administered as a pretreatment, heroin shifted the dose-response function for cocaine to the left in the three monkeys for which heroin engendered cocaine lever responding, but did not alter the DS effects of cocaine in the fourth monkey. Heroin pretreatment also shifted the dose-response function for the cocaine-like DS effects of GBR 12909 to the left in the former three monkeys, and did not alter the effects of GBR 12909 in the fourth monkey. Isobolographic analysis of the DS effects of cocaine-heroin and GBR 12909-heroin combinations in the former three monkeys revealed that the potencies of the combinations were not different from predicted values based on dose-additive effects. CONCLUSIONS: These findings show that heroin can enhance similarly the DS effects of cocaine and GBR 12909, suggesting that activation of dopaminergic systems underlies enhancement of the interoceptive effects of cocaine by heroin. PMID- 11605089 TI - Discriminative learning occasioned by the administration of a dopamine agonist. AB - RATIONALE: The repeated administration of psychostimulants usually brings about a progressive increment of the behavioral responses that they induce. We examined to what extent this sensitization is due to an associative learning process. OBJECTIVES: The dopamine agonist apomorphine elicits stereotyped pecking in pigeons, a response that increases with successive intramuscular injections. We tested whether this sensitized pecking would be discriminatively directed at environmental stimuli that had been present during the sensitization phase. METHODS: In a preliminary experiment we identified a pair of stimulus compounds that attracted an equal number of apomorphine peck responses. During discrimination training naive pigeons were exposed on 5 days to both a cage furnished with one of these stimuli after having been injected with apomorphine and to a cage furnished with the other stimuli after having been injected with saline. Then the birds were administered apomorphine (or saline) and tested in a cage that offered both compound stimuli simultaneously. A discrimination reversal training and renewed tests followed. RESULTS: The tests under apomorphine and saline showed that the pecking by the pigeons was virtually exclusively aimed at the specific environmental stimuli under which the sensitization to apomorphine had taken place. This discriminative stimulus control was reversed after the pigeons had been retrained with converse stimulus compound allocations. CONCLUSIONS: The sensitized apomorphine pecking of pigeons was subject to close control by environmental stimuli. The results thus support the hypothesis that the sensitization to psychostimulants may be due to a conditioning process. The conditioning occasioned by apomorphine injections in birds could be a useful model for the study of sensory-motor learning processes. PMID- 11605090 TI - Are African American patients at a higher risk for olanzapine-induced glucose intolerance? PMID- 11605091 TI - Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders. AB - RATIONALE: There exists a wide range of animal models and measures designed to assess anxiety or fearfulness. However, the relationship between these models and clinical anxiety symptoms and syndromes is unclear. The National Institute of Mental Health convened a workshop to discuss the relationship between existing behavioral models of anxiety and the clinical profile of anxiety disorders. A second goal of this workshop was to outline various approaches towards modeling components of anxiety disorders. OBJECTIVES: To briefly describe epidemiological and behavioral manifestations of clinical anxiety syndromes and how they relate to commonly employed animal models of anxiety. To describe approaches and considerations for developing, improving, and adapting anxiety models to better understand the neurobiology of anxiety. METHODS: Clinicians, psychiatrists and clinical and basic neuroscientists presented data exemplifying different approaches towards understanding anxiety and the role of animal models. Panel members outlined what they considered to be critical issues in developing and employing animal models of anxiety. RESULTS: This review summarizes the discussions and conclusions of the workshop including recommendations for improving upon existing models and strategies for developing novel models. CONCLUSIONS: The probability of developing comprehensive animal models that accurately reflect the relative influences of factors contributing to anxiety disorder syndromes is quite low. However, ample opportunity remains to better define and extend existing models and behavioral measures related to specific processes that may be disrupted in anxiety disorders and to develop new models that consider the impact of combined factors in determining anxious behaviors. PMID- 11605092 TI - Serotonin depletion attenuates cocaine seeking but enhances sucrose seeking and the effects of cocaine priming on reinstatement of cocaine seeking in rats. AB - RATIONALE: Acute serotonin (5-HT) depletion by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine, attenuates cocaine seeking in rats. OBJECTIVE: The present study examined the effects of chronic 5-HT depletion on cocaine- and sucrose seeking using the 5-HT-selective neurotoxin 5,7 dihydroxytryptamine (5,7-DHT). METHODS: Separate groups of rats were trained to lever press for cocaine infusions (0.33 mg/kg/0.1 ml, i.v.) or for sucrose pellets (45 mg Noyes) on a fixed ratio (FR) 1 schedule of reinforcement during daily 2-h sessions. Subsequently, animals received i.c.v. infusions of either vehicle or 5,7-DHT (150 microg/6 microl or 200 microg/20 microl). After a minimum of 10 days post-lesion, cocaine- and sucrose seeking were measured as lever presses in the absence of reinforcement (extinction). Some cocaine-trained animals were also assessed for the re-establishment of self-administration and reinstatement of extinguished cocaine seeking by i.v. cocaine priming injections and response-contingent presentations of cocaine-paired stimuli. RESULTS: 5-HT depletion by the 150 microg/6 microl dose of 5,7-DHT failed to alter cocaine- and sucrose seeking despite producing a 42-77% depletion of 5-HT in limbic terminal regions. The 200 microg/20 microl dose of 5,7-DHT attenuated cocaine seeking but enhanced sucrose seeking during extinction and produced a 55-85% depletion of 5 HT. In addition, cocaine-paired cues and cocaine priming reinstated cocaine seeking behavior, and responding was enhanced in 5,7-DHT-treated animals relative to vehicle-treated controls at the 1 mg/kg/0.1 ml priming dose. However, re establishment of cocaine self-administration was not altered by 5,7-DHT. CONCLUSION: The results suggest that 5-HT depletion may attenuate cocaine seeking but may enhance sucrose seeking when animals are tested during extinction. Furthermore, 5-HT depletion may enhance cocaine seeking produced by cocaine itself. Together these findings suggest that 5-HT depletion may have opposite effects on incentive motivation for cocaine during abstinence versus relapse. PMID- 11605093 TI - Long-lasting rebound cue effects following single doses of nicotine and amphetamine: implications for understanding tolerance. AB - RATIONALE: Previous drug-discrimination studies have, with the exception of nicotine (NIC), demonstrated tolerance to the cue effects of a broad range of drugs of abuse. Barrett et al. have shown that tolerance to a drug's cue properties reflects drug-induced rebound shifts in the discrimination baseline and not a weakened or less salient cue. OBJECTIVES: The objective of the present study was to use a discrimination task sensitive to bidirectional cue changes to characterize the interoceptive cues associated with both the primary and rebound cues produced by nicotine in an attempt to understand why a recent study by Shoaib et al. failed to observe tolerance to the nicotine cue. METHODS: Since dopamine (DA) has been implicated in mediating the NIC cue, rats were trained to discriminate between 0.25 mg/kg amphetamine (AMPH), an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D2 receptor site. Training doses were chosen so that rats responded about equally on both levers when tested on saline (SAL) following acquisition. This procedure provided a behavioral baseline to assess NIC-related changes along a presumed continuum of DA-mediated cues. Following acquisition of the discrimination: (i) NIC substitution tests were conducted, (ii) rats were tested for lever choice at intervals from 2 h to 48 h following treatment with single doses of 0.25 mg/kg and 0.50 mg/kg NIC, and (iii) rats were challenged with test doses of NIC during a period of NIC rebound. RESULTS: (i) NIC substituted for AMPH in a dose- dependent manner. (ii) At short intervals after treatment with 0.25 mg/kg and 0.50 mg/kg NIC, rats responded primarily on the AMPH lever followed by a shift to predominant responding on the HAL lever 16-24 h post-treatment, before returning to predrug levels. (iii) No evidence was observed for acute tolerance to NIC. CONCLUSIONS: The robust and long-lasting rebound cues associated with training level doses of NIC suggest that maximal tolerance would likely develop to the NIC cue during the acquisition phase of the conventional NIC-saline discrimination study. PMID- 11605094 TI - Differential effects of alprazolam on the baseline and fear-potentiated startle reflex in humans: a dose-response study. AB - RATIONALE: The "fear-potentiated startle" paradigm has been extensively used in animal studies, and more recently in human experimental psychopharmacology to evaluate the effects of anxiogenic and anxiety-relieving drugs. Previous human studies have shown that both the baseline and the fear-potentiated responses can be inhibited by anxiety-relieving drugs, suggesting drug activity on two different emotional states, the former reflecting a resting condition and the latter more akin to pathological anxiety. OBJECTIVES: To examine to which extent the reductions induced by a benzodiazepine on the basic and the fear-potentiated startle responses are of equal intensity, and whether or not the drug shows a predominant, i.e., selective, effect on either. METHODS: The effects of three increasing doses of the benzodiazepine alprazolam (0.25, 0.5, and 1.0 mg) were assessed on the human baseline and fear-potentiated startle responses. Twelve healthy volunteers attended the laboratory on four experimental days and received either alprazolam or placebo according to a double-blind crossover balanced design. Startle recordings were undertaken 2 h after drug intake. Fear potentiation was implemented by means of an electric-shock-anticipation experimental procedure. Additionally, subjective self-reports of sedation and anxiety and psychomotor performance were obtained at 2 and 3 h, respectively, after drug administration. RESULTS: Alprazolam dose-dependently impaired psychomotor performance and produced increases in subjective anxiolytic activity and sedation, although the latter did not reach statistical significance. Additionally, the drug reduced the magnitude of the startle response both in the absence and in the presence of a threat-related cue, although a differentially greater inhibitory effect was seen on the fear-potentiated response as the dose increased. CONCLUSIONS: Alprazolam showed a greater inhibitory effect on the fear potentiated startle than on the baseline reflex, suggesting a more selective action of the drug on those structures mediating potentiation of the behavioral response by anxiety. PMID- 11605095 TI - Autonomic responses of blood vessels and sweat glands in patients with schizophrenia treated with olanzapine or clozapine. AB - RATIONALE: Data comparing the in vivo effects on autonomic nervous system function of standard clinical doses of olanzapine and clozapine are sparse. OBJECTIVE: The goal of this study was to compare the skin conductance response (which is peripherally mediated via muscarinic m3-receptors) and the inspiratory gasp response (which is peripherally mediated via adrenergic receptors) between healthy controls and schizophrenics treated with clozapine or olanzapine. METHODS: Twenty patients with schizophrenia (according to DSM-III-R criteria) treated with either clozapine (200-500 mg/day) or olanzapine (10-20 mg/day) as well as ten matched controls underwent simultaneous recordings of the skin conductance response (SCR) of sweat glands and of the inspiratory gasp response (IGR) of acral blood vessels. A single, deep inspiration was used as the stimulus. Group differences for the SCR amplitudes and the post-IGR redilation times were compared using the Mann-Whitney test. RESULTS: Both clozapine- and olanzapine-treated patients showed a significant SCR reduction compared to controls. Interestingly, the reduction in SCR was significantly larger in the clozapine group compared to the olanzapine group (P<0.05). Moreover, only clozapine-treated patients showed a statistical trend towards a longer IGR redilation time compared to controls. CONCLUSION: The significantly stronger SCR reduction amongst clozapine-treated compared to olanzapine-treated patients suggests that olanzapine at a standard clinical dose exhibits a significantly smaller anticholinergic effect at peripheral m3-receptors in vivo compared to clozapine. The prolongation of IGR redilation can be explained by a prolonged release of noradrenaline due to the alpha2-antagonistic effect of clozapine. PMID- 11605096 TI - Effects of caffeine, caffeine-associated stimuli, and caffeine-related information on physiological and psychological arousal. AB - RATIONALE: To test the classical conditioning and expectancy theories of placebo effects. OBJECTIVE: Two experiments investigated whether administration of caffeine-associated stimuli elicited conditioned arousal, and whether information that a drink contained or did not contain caffeine modulated arousal. METHOD: Experiment 1 (n=21) used a 2 Caffeine (0 and 2 mg/kg) x 2 Solution (Coffee, Juice) x 2 Information (Told caffeine, Told not-caffeine) within-subjects design. Experiment 2 (n=48) used a 2 Solution (Coffee, Orange juice) x 3 Information (Told caffeine, Told not-caffeine, No information) between-subjects design. Indexes of arousal were skin conductance responses and levels, startle eyeblink reflexes, cardiovascular measures, and the Bond and Lader 1974 mood scale. RESULTS: Caffeine-associated stimuli increased alertness, contentedness and skin conductance levels, and information that the drink contained caffeine decreased calmness in Experiment 1. However, unexpected information about the caffeine content of the drink, and the order of the conditions, could have masked some effects of the experimental manipulations. Experiment 2 followed up this hypothesis. The results showed a conditioned increase in startle eyeblink reflexes, and that caffeine-associated stimuli together with information that the drink contained caffeine increased contentedness. CONCLUSIONS: Caffeine associated stimuli increased arousal, and information about the content of the drink modulated arousal in the direction indicated by the information. Thus, both the classical conditioning and expectancy theories of placebo effects received support, and placebo effects were strongest when both conditioned responses and expectancy-based responses acted in the same direction. PMID- 11605098 TI - The effect of glucocorticoids on the anxiolytic efficacy of buspirone. AB - RATIONALE: The serotonergic system and the hypothalamus-hypophysis-adrenocortical axis reciprocally influence each other. Therefore, the interaction between stress and serotonergic anxiolytics should be of major concern for both laboratory investigations and clinical treatment. OBJECTIVES: We have studied the effects of the serotonergic anxiolytic buspirone in rats in which basal levels of glucocorticoids were low and stable, while acute stress reactions were inhibited or exogenously induced. METHODS: Rats were adrenalectomised. Subcutaneous corticosterone pellets maintained basal glucocorticoid concentrations while acute changes were mimicked by corticosterone injections. Anxiety was assessed by the social interaction test. Temporal changes were evaluated by submitting rats to the same manipulations three times at two-day intervals. RESULTS: Buspirone applied to animals with stable and low plasma glucocorticoid concentrations induced a dramatic increase in social interactions. A slight locomotor suppressive effect was also noticed. The effects of buspirone proved to be stable over time in these animals. Acute treatment with corticosterone doubled the locomotor suppressive effects of buspirone and reversed its anxiolytic effects: the buspirone-corticosterone combination was anxiogenic after the first application. During the second and third treatment, the impact of corticosterone on buspirone efficacy gradually decreased, but the combined treatment remained about half as effective in reducing anxiety as buspirone alone. PMID- 11605097 TI - Effect of gabapentin-like compounds on development and maintenance of morphine induced conditioned place preference. AB - RATIONALE: Psychological dependence to the opioid analgesic morphine is attributable to the rewarding properties of the drug, and its evolution can be divided into two distinct phases: development and maintenance. Both phases can be studied using conditioned place preference (CPP). OBJECTIVES: To determine whether the two phases can be influenced by pre-treatment with gabapentin-like compounds. METHODS: CPP to morphine was used to demonstrate the rewarding properties of morphine in the presence or absence of gabapentin-like compounds. In-vivo microdialysis in the nucleus accumbens was used to determine the effects of gabapentin or pregabalin on morphine-induced dopamine release. RESULTS: Pretreatment with either gabapentin (10-100 mg/kg p.o.) or pregabalin (3-30 mg/kg p.o.) attenuated CPP induced by a submaximal dose of morphine (0.75 mg/kg). Neither gabapentin nor pregabalin had any effect alone in the CPP test. Both gabapentin-like compounds blocked the effect of morphine (0.75 mg/kg s.c.) to increase the release of dopamine in the nucleus accumbens. Studies of the maintenance of CPP to morphine showed CPP was maintained for at least 4 days after the initial test. In a second experiment, it was found that pregabalin (injected once, 24 h after CPP had been demonstrated) was able to reverse morphine-induced CPP. CONCLUSIONS: Neither gabapentin nor pregabalin induced CPP, but both compounds blocked the development of CPP to morphine and also blocked morphine's effects on dopamine release. Furthermore, pregabalin blocked the maintenance of morphine-induced CPP. It is concluded that gabapentin-like compounds, which have no intrinsic rewarding properties, may have some therapeutic use in the treatment of opioid dependence. PMID- 11605099 TI - Free L-tryptophan plasma levels in antisocial violent offenders. AB - RATIONALE: Several studies have shown that impulsive violent behavior is associated with reduced serotonin metabolism in the brain, but no data exist on possible alterations of the serotonin precursor (free L-tryptophan) levels among violent offenders. OBJECTIVES: To study free L-tryptophan and kynurenine plasma levels among antisocial violent offenders. METHODS: Free L-tryptophan and competing amino acid (CAA) plasma levels were measured among 19 male impulsive antisocial violent offenders and 19 age-matched healthy male controls. RESULTS: Mean free L-tryptophan/(CAA) plasma levels were 160% (95% CI 116%-204%) higher among offenders than controls (P=0.000). Seventeen of the 19 offenders (89.5%) had values of more than 2 SD above the mean value of controls. The levels of kynurenine, the major metabolite of tryptophan, were slightly increased in offenders. CONCLUSION: Free plasma L-tryptophan/CAA levels were markedly increased among antisocial violent offenders indicating a disturbed tryptophan metabolism. PMID- 11605100 TI - Pressure-sensitive and -insensitive coupling in gamma-aminobutyric acid(A) receptors. AB - RATIONALE: Previous behavioral and biochemical studies suggest that allosteric coupling processes initiated by benzodiazepines, barbiturates and neuroactive steroids can be sub-categorized on the basis of their sensitivities to antagonism by increased atmospheric pressure. However, biochemical evidence supporting this hypothesis was limited to single concentration studies in long sleep (LS) mice. OBJECTIVE: The present paper addresses these issues by extending biochemical investigation of pressure effects on allosteric modulators across a range of concentrations that allosterically enhance gamma-aminobutyric acid (GABA)A receptor function and alter behavior using two mouse genotypes. In addition, the effects of pressure on ligand binding were explored to further investigate the mechanism of pressure antagonism of allosteric modulation. METHODS: The effects of 12 times normal atmospheric pressure (ATA) of helium-oxygen gas (heliox) on allosteric modulation of GABA(A) receptor function and [3H]flunitrazepam binding was tested in LS and C57BL mouse brain membranes (microsacs) using chloride flux and high-affinity binding assays. RESULTS: In both genotypes, exposure to 12 ATA heliox antagonized the allosteric enhancement of GABA(A) receptor function by flunitrazepam (0.1-10 microM) and pentobarbital (0.1-50 microM) but did not affect allosteric modulation by 3alpha-hydroxy-5beta-pregnan-20-one (0.1-1 microM). Pressure did not affect benzodiazepine receptor affinity (Kd) or the number of benzodiazepine receptors (Bmax). CONCLUSIONS: THE RESULTS: (1) confirm that there are differences in sensitivity to pressure antagonism of allosteric coupling among GABA(A) allosteric modulators; (2) demonstrate that these differences are not concentration or genotype dependent; (3) add evidence that pressure antagonizes allosteric modulation by uncoupling the receptor and (4) support the hypothesis that allosteric modulation of receptor function can be sub categorized on the basis of sensitivity to pressure antagonism. PMID- 11605101 TI - A low dose alcohol drug discrimination in social drinkers: relationship with subjective effects. AB - RATIONALE: Although well characterised in animals, relatively little is known about alcohol discriminative stimulus effects in humans. OBJECTIVE: The study was carried out to investigate the correspondence of subjective effects and the discriminative response during the acquisition of a low dose alcohol discrimination in humans. METHODS: Healthy volunteers completed an Alcohol Use Questionnaire and were then trained to discriminate a dose of 0.2 g/kg alcohol from placebo using a money reinforced technique. Subjects sampled drinks during training, but also completed rating scales measuring Taste, Like/Dislike and Subjective Effects for each drink. RESULTS: Thirty-two subjects learned the discrimination (discriminators; Ds). In these subjects, differences between placebo scores and alcohol scores for Lightheadedness, Relaxed, Arousal and Fatigue were greater following acquisition of the discrimination, compared with differences at the start of training. Differences in other measures remained consistent. Twenty-six of the volunteers failed to learn the discrimination (non discriminators; NDs). These subjects reported drinking approximately twice as much alcohol during the preceding 6 months, as the Ds (4.35+/-0.53 g/kg per week versus 2.08+/-0.19 g/kg per week, respectively, P<0.001). There were no alcohol specific differences in ratings for Lightheadedness, Relaxed, Arousal or Fatigue between the Ds and the NDs. However, Dislike scores did differentiate between the Ds and the NDs in that the NDs had reduced ratings for the alcohol drink only compared with the Ds (P<0.02). CONCLUSIONS: These results support the suggestion from animal studies, that the alcohol stimulus is a compound, and characterise the subjective effects which contribute to a low dose cue in humans. In addition, the data suggest that previous drinking experience may selectively alter aversive responses to alcohol and that this, in addition to differences in general arousal levels, may have affected subjects' ability to learn the discrimination. PMID- 11605102 TI - Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline. AB - RATIONALE: In order to model heightened aggression after alcohol consumption and to study the inhibitory influence of 5-HT1B receptors on drinking and fighting, an experimental procedure should enable self-administration of precise amounts of alcohol in a limited period of time before an aggressive confrontation. OBJECTIVES: To design a new device that can reinforce operant responding by the delivery of sweet alcohol in the resident mouse home cage, where aggressive behavior toward an intruder can subsequently be examined, and to demonstrate inhibition of alcohol-heightened aggression by 5-HT1B receptor agonist treatment. METHODS: Within one experimental session, all singly housed CFW male mice (n=26) performed a nose-poke response that was reinforced by 0.05 ml sucrose. Using the sucrose fading technique, eventually the mice consumed a 6% ethanol/4% sucrose solution after each fifth nose poke during daily 15-min experimental sessions. The number of ethanol reinforcements was adjusted so that 0.6, 1.0, 1.7, and 3.0 g/kg doses were consumed in 15 min or less. Assays confirmed blood alcohol levels at 68.1 mg/dl for intake of 1.0 g/kg. After consuming a specific dose of ethanol in the form of a fixed number of response-dependent deliveries, the response panel was removed from the home cage and, 15 min later, the resident confronted a male intruder. Anpirtoline was administered either before alcohol self administration or before the aggressive confrontation. RESULTS: After being reinforced with 1.0 g/kg or 1.7 g/kg sweet ethanol, the mice significantly increased attack and threat behavior relative to their aggressive behavior following sucrose or water consumption only. Treatment with the 5-HT1B receptor agonist anpirtoline (0.125, 0.25, 0.5 mg/kg, i.p.) before the confrontation decreased alcohol-heightened aggression and species-typical aggression in the absence of changes in other elements of the behavioral repertoire. Anpirtoline affected ethanol-reinforced behavior only at doses that were 5-10 times higher than those producing anti-aggressive effects. CONCLUSIONS: Self-administration of alcohol in the home cage of mice is readily accomplished with the aid of a simple, removable panel. The effective inhibition of high levels of aggressive behavior due to alcohol consumption after anpirtoline treatment confirm the 5 HT1B receptor as a critical site in the termination of aggression. PMID- 11605103 TI - Eating soya improves human memory. AB - RATIONALE: Soya foods are rich in isoflavone phytoestrogens with weak agonist activity at oestrogen receptors. Oestrogen treatment has been found to improve memory in men awaiting gender reassignment and in post-menopausal women. OBJECTIVE: To examine the effects of supervised high versus low soya diets on attention, memory and frontal lobe function in young healthy adults of both sexes. METHODS: Student volunteers were randomly allocated to receive, under supervision, a high soya (100 mg total isoflavones/day) or a low soya (0.5 mg total isoflavones/day) diet for 10 weeks. They received a battery of cognitive tests at baseline and then after 10 weeks of diet. RESULTS: Those receiving the high soya diet showed significant improvements in short-term (immediate recall of prose and 4-s delayed matching to sample of patterns) and long-term memory (picture recall after 20 min) and in mental flexibility (rule shifting and reversal). These improvements were found in males and females. In a letter fluency test and in a test of planning (Stockings of Cambridge), the high soya diet improved performance only in females. There was no effect of diet on tests of attention or in a category generation task. Those on the high soya diet rated themselves as more restrained and, after the tests of memory and attention, they became less tense than did those on the control diet. CONCLUSIONS: Significant cognitive improvements can arise from a relatively brief dietary intervention, and the improvements from a high soya diet are not restricted to women or to verbal tasks. PMID- 11605104 TI - Raising the bar. Laparoscopic resection of colorectal cancer. PMID- 11605105 TI - Surgery for hiatal hernia and GERD. Time for reappraisal and a balanced approach ? PMID- 11605107 TI - A new robotic endoscope manipulator. A preliminary trial to evaluate the performance of a voice-operated industrial robot and a human assistant in several simulated and real endoscopic operations. AB - We report our learning experience in simulated and real surgical tasks with a new voice-controlled robotic endoscope manipulator: an industrial robot with the tool holder arm modified to support the optic and camera. The manipulator control-card programs have been rewritten to meet the needs of endoscopic surgeons. For this preliminary work, systems engineers with an additional monitor monitored, recorded, and compared the percentage effectiveness and precision of the responses of the robotic and human assistant to successive oral commands during the several different experimental surgical tasks. Simultaneously, to help develop this voice-commanded system for future, more precise robotic manipulation of surgical instruments, they measured the cartesian and spherical coordinates of successive positions of the optic. In unexpectedly difficult experimental conditions, the tireless robot proved more precise and effective than the demonstrably fatigable human: the steadier screen images of the robotic manipulations helped the surgeon tie knots in 7-0 sutures. PMID- 11605106 TI - Evaluation of telesurgical (robotic) NISSEN fundoplication. AB - BACKGROUND: The laparoscopic surgical approach has proven its benefit for the patient. There are however several shortcomings, which have triggered considerable research for improvement. One improvement may be the introduction of telesurgery by the interposition of a computer interface between surgeon and patient. MATERIAL AND METHODS: A prospective randomized study was conducted in an advanced laparoscopic procedure, Nissen fundoplication. The control group underwent the conventional laparoscopic approach, while the investigational group underwent the telesurgical approach. RESULTS: Feasibility was 100%. The procedure was more time consuming in the Telesurgical group, at all stages of the operation. Mortality was nil and morbidity was comparable in both groups. CONCLUSION: The telesurgical approach is feasible in advanced laparoscopic procedures like Nissen fundoplication. At the present time there is however no obvious added benefit from this new technique. PMID- 11605108 TI - Laparoscopic vs open gastrectomy. A retrospective review. AB - BACKGROUND: The totally laparoscopic approach to partial gastrectomy had not been compared previously with results of the open technique. This study compares the results of a series of laparoscopic cases with matched open cases. METHODS: A retrospective case-matched study was performed in 36 patients (18 laparoscopic surgeries, 18 open surgeries). Each laparoscopic case was matched for patient age and indication for surgery. The intraoperative and postoperative details of the two groups were compared. RESULTS: Laparoscopic surgery resulted in less blood loss, although operative time was increased. Nasogastric tubes were less likely to be used after laparoscopic surgery, and patients in the laparoscopic group had an earlier return to normal bowel function than those in the open group. Length of hospital stay was 2 days shorter in the laparoscopic group. CONCLUSIONS: The totally laparoscopic approach to partial gastrectomy is an excellent alternative to the more traditional open approach. It results in a more rapid return of intestinal function and a shorter hospital stay. PMID- 11605109 TI - Resection and advancement of esophageal mucosa. A potential therapy for Barrett's esophagus. AB - BACKGROUND: Barrett's esophagus affects 5-10% of patients with gastroesophageal reflux disease (GERD) and is associated with a 40-fold increased risk of malignant transformation. Ablative therapies may lead to esophageal perforation or stricture formation if applied too liberally and residual glandular tissue and persistent cancer risk if utilized too sparingly. METHODS: Ten pigs underwent gastrotomy. Mucosa below the gastroesophageal (GE) junction was elevated by saline injections, circumferentially incised, and secured to an orogastric tube. By traction, the distal esophageal mucosa was inverted 10 cm proximally, then returned to the gastric lumen. In group A (n = 4), the mucosa (5 cm) was resected and the remnant was allowed to retract. In group B (n = 4), the mucosa was simply sutured back into its native position. In group C (n = 2), the mucosa (5 cm) was resected and the proximal segment was advanced and sutured to the gastric mucosa. At 6 weeks, or sooner if stricture developed, the animals were killed. Stricture formation was determined by ex vivo barium esophagram and gross assessment. The extent of fibrosis and epithelial healing were established histologically. RESULTS: Group A (mucosa resected) developed weight loss and anorexia within 4 weeks. Pathology revealed dense fibrotic stricture without reepithelialization. Group B (mucosa elevated/replaced) gained weight after the operation. Histology demonstrated mucosal healing without significant stricture or fibrosis. Group C (mucosa resected/advanced) also thrived postoperatively. Histology confirmed mucosal healing without evidence of retraction or dense stricture. CONCLUSIONS: Exposure of submucosal tissues causes esophageal stricture. Mucosal coverage minimizes submucosal fibrosis after injury. Mucosal resection and advancement allows healing without stricture and may have therapeutic potential for patients with Barrett's esophagus. PMID- 11605110 TI - Preinsertion local anesthesia at the trocar site improves perioperative pain and decreases costs of laparoscopic cholecystectomy. AB - BACKGROUND: Local anesthesia at the trocar site in laparoscopic cholecystectomy is expected to decrease postoperative pain and hence expedite recovery. The aims of this prospective randomized study were to investigate the effect of local anesthesia and to discover whether it is cost effective. METHODS: For this study, 100 patients undergoing laparoscopic cholecystectomy were randomized into two groups. The 43 study patients were injected with 0.5% bupivacaine hydrochloride at the trocar site before the trocars were inserted. They then were compared with 41 control patients who received no local anesthesia. The remaining 16 patients were excluded from the study. The postoperative pain was evaluated at the standard four trocar sites at 4 h and 24 h after surgery on a scale 1 (the mildest pain the patient had ever experienced) to 10 (the most severe pain the patient had ever experienced). Postoperative pain medications and their cost were evaluated. RESULTS: There was no difference between the two groups with regard to gender, age, weight, operative time, estimated operative blood loss, and bile culture. The patients who received bupivacaine at the trocar site clinically had less pain (p < 0.001 for all four sites) both at 4 and 24 h after surgery. The treatment group patients used less mepiridine and promethzine than the control group (p = 0.001 and 0.002, respectively) postoperatively. Overall, the patients who had local anesthesia used less postoperative pain and antiemetic medication than the control patients (p = 0.02). This afforded a significant decrease in the costs and charges of these medications (p = 0.004 and 0.005, respectively). Three patients in the study group were discharged from the hospital the day of surgery. CONCLUSION: Preinsertion of local anesthesia at the trocar site in laparoscopic cholecystectomy significantly reduces postoperative pain and decreases medication usage costs. PMID- 11605111 TI - Laparoscopic transabdominal preperitoneal (TAPP) hernia repair. A 7-year two center experience in 3017patients. AB - BACKGROUND: This report reviews our experience with 3530 transabdominal preperitoneal (TAPP) hernia repairs in 3017 patients (513 bilateral) over the 7 year period from May 1992 to July 1999. We have continually audited our practice and modified the techniques in response. METHODS: Unless contraindicated, laparoscopic TAPP repair is considered the procedure of choice at our institution for all reducible inguinal hernias. We initially stapled an 11 x 6 cm polypropylene mesh in the preperitoneal space but now place a 15 x 10 cm mesh in the preperitoneal space with sutured peritoneal closure. RESULTS: There have been a total of 22 recurrences, of which 17 were identified in the first 325 repairs (5%) using the 11 x 6 cm mesh. Five recurrences occurred in the later 3205 repairs (0.16%) (median follow up of 45 months). There was one 30-day death unrelated to the procedure. There have been seven conversions (four due to irreducibility, two due to extensive adhesions, one due to bleeding). Bladder perforations have occurred in seven cases, of which six were recognized immediately and treated laparoscopically without sequelae. There have been seven cases of small bowel obstruction from herniation through the peritoneal closure. Sutured repair of the peritoneum has reduced the incidence of this complication. Four patients had mesh infections, of whom three were treated conservatively. The incidence of postoperative seroma and hematoma was 8%. Median operation time remains at 40 min with a mean hospitalization of 0.9 nights. Sixty percent of TAPP hernia repairs are now performed on the Day Surgical Unit with a 3% admission rate. Median return to normal activities is 7 days. Forty percent of patients require no postoperative analgesia. These figures remain the same whether the hernia is primary, recurrent, unilateral, or bilateral. Consultants performed most operations early in the series, but latterly surgical trainees have performed the majority of these procedures under supervision. CONCLUSIONS: Laparoscopic TAPP hernia repair is technically difficult, but in the hands of a well-trained surgeon, it is safe and effective with a high degree of patient satisfaction. The low recurrence rate compares favorably to other tension-free mesh hernia repairs. PMID- 11605112 TI - Endoscopic sphincterotomy for stenosis of the sphincter of Oddi. AB - BACKGROUND: Sphincter of Oddi dysfunction (SOD) is one of the causes of postcholecytectomy syndrome and biliary pain. Endoscopic sphincterotomy (EST) is recommended in some cases for patients refractory to conservative treatment. By the Milwaukee classification, patients with biliary pain can be divided into three groups. Group I patients show all the objective signs suggestive of a disturbed bile outflow-i.e., elevated liver function tests, dilated common bile duct (CBD), and delayed contrast drainage during endoscopic retrograde cholangio pancreatography (ERCP). Group II patients have biliary-type pain along with one or two of the criteria from group I. Group III patients have only biliary pain, with no other abnormalities. This study confirms the effectiveness of EST for the relief of symptoms in group I patients (papillary stenosis). METHODS: Between 1989 and 1999, we treated eight patients clinically diagnosed as having group I papillary stenosis by EST. Their ages ranged from 52 to 73 years. In addition to biliary pain, all patients were found to have dilated CBD, elevated enzyme levels, and delayed contrast drainage at ERCP. None of the patients had CBD stones or other causes of obstruction. Sphincter of Oddi manometry was not performed. RESULTS: EST was successfully performed in eight patients. Each patient had a very large papilla. A false orifice was found in one patient. In five patients, endoscopic cannulation of the bile duct was very difficult. The use of a long, tapered catheter and guidewire papillotomy was necessary in four patients. A precut papillotomy was performed in one patient. All patients achieved resolution of their symptoms after EST. There were no complications. The average length of the follow-up period was 26 months. CONCLUSIONS: SOD is a real entity that continues to pose a diagnostic dilemma. EST is an effective and safe modality for the treatment of papillary stenosis (group I patients). SOD manometry is not necessary before EST in group I patients. PMID- 11605113 TI - The development and implementation of a computerized database for clinical research in minimal access surgery. An international pilot study. AB - BACKGROUND: The measurement of outcomes after minimal access surgery (MAS) relies on the maintenance of an accurate, prospective clinical database. The development of a system for data management often proves to be challenging, expensive, and extremely time-consuming. METHODS: We developed a computerized relational database for MAS using Microsoft Access 97 to reside on a hospital server, taking advantage of existing network connections, security, and backup systems. The design of the database includes a point-and-click approach with dropdown boxes for diagnoses, procedures, and complications (limited free-text entry). A fundamental feature of this database allows surgeons and surgical trainees to record clinical information at the point and time of data acquisition. RESULTS: A "beta version" or fully functional draft of the database was presented to a group of surgeons from a variety of specialties (n = 8), and a structured interview based on a questionnaire was used to elicit the surgeon's evaluations of the database. Using the information from the interviews, the database was extensively revised and restructured. CONCLUSIONS: We have developed a relational database that reflects the needs of surgeons interested in clinical research. This database may serve as a template for other centers. It can be expanded to adopt new procedures or modified for other surgical specialties. PMID- 11605114 TI - Holmium: YAG laser lithotripsy for gallstones. A preliminary report. AB - BACKGROUND: Most retained gallstones can be extracted at the time of operative exploration or endoscopic retrograde cholangiopancreatography (ERCP). Infrequently, impaction or associated anatomic abnormalities may prevent their clearance. We assessed the efficacy of the holmium:YAG laser in managing retained biliary calculi that had proven refractory to the usual methods of extraction. METHODS: Two patients with calculi impacted in the intrapancreatic common bile duct and one patient with residual stones in a nonfunctional gallbladder were treated with holmium:YAG laser lithotripsy. Two of these patients were treated under conscious sedation, and one received a general endotracheal anesthetic. Laser energy was delivered by a 272-mm optical fiber inserted through a 7-Fr fiberoptic endoscope. The ablative effects were monitored continuously via videoscopic. RESULTS: All of the stones were cleared successfully in a single therapeutic setting. In one patient, fragments of the impacted intraductal stone were extracted with an endoscopic wire basket. In the other two patients, stone debris was completely cleared with saline irrigation. No complications developed, and all patients remained free of recurrence during a 6-month follow-up period. CONCLUSIONS: The holmium:YAG laser is a multidisciplinary instrument that is safe and effective in the fragmentation of both urinary and biliary calculi. Because it can be delivered through a small-caliber fiberoptic endoscope, it should be particularly useful to laparoscopic surgeons who manage complicated biliary tract disease. PMID- 11605117 TI - Are radially dilating trocars better than alternatives? PMID- 11605116 TI - Revisiting Amyand's hernia in the laparoscopic era. PMID- 11605115 TI - Minimally invasive management of insulinomas. A case report. AB - BACKGROUND: Recently, preoperative endoscopic ultrasonography (EUS) was shown to be less time consuming, posing less risk of adverse events than other more invasive diagnostic procedures used for locating insulinomas. Furthermore, laparoscopy can be part of a less aggressive approach in the management of such tumors, avoiding open surgery, which is used all out of proportion for benign small-size lesions, as insulinomas frequently are. CASE REPORT: The reported case of pancreatic insulinoma involved a 45-year-old woman suffering from a neuroglycopenic syndrome. Tumor location was possible with endoscopic ultrasonography, which detected a hypoechoic 10 x 10-mm mass in the pancreatic tail. Tumor enucleation was accomplished laparoscopically. CONCLUSIONS: Insulinomas may be managed with videolaparoscopy, but this approach, which is not applicable for multiple or malignant tumors, must be contraindicated also in single insulinomas located on the posterior wall or deeply in the head of the pancreas. The disadvantages of the laparoscopic approach, as compared with conventional surgery, are the absence of palpation and difficulty exploring the whole pancreas, which is partly overcome, but not completely eliminated, by EUS. The advantages are the absence of a parietal incision and good postoperative comfort. The reported low-invasive EUS laparoscopy sequence may be successful in selected cases of pancreatic insulinomas. However, it seems this treatment could be proposed for many patients affected by this benign disease. PMID- 11605118 TI - [Surgical reduction of lung volume - NETT determines contraindications]. PMID- 11605119 TI - [The way to the first S3-guideline in pneumology]. PMID- 11605120 TI - [Guidelines to long-term oxygen therapy]. PMID- 11605121 TI - [RC-Cornet(R) improves the bronchodilating effect of Ipratropiumbromide (Atrovent(R)) inhalation in COPD-patients]. AB - In 35 patients with severe COPD and tracheal-bronchial instability the bronchodilatory effect of salbutamol (Salbulair(R) Autohaler) was tested prospectively, randomized and crossover on two consecutive days by bodyplethysmography. Following the salbutamol inhalation, the effect of ipratropiumbromide inhalation (by Pariboy and LC-plus-nebulizer) was evaluated in group A with an oscillating PEP-system (RC-Cornet(R), Position 1) in the expiratory outlet of the nebulizer and in group B with conventional inhalation by the Pari-system. The bronchodilatory effect was statistically significant better in group A inhaling ipratropiumbromide with the RC-Cornet(R) in the expiratory limb of the nebulizer in comparison to "normal" inhalation (decrease in airway resistance p < 0.0002, increase in vitacapacity p < 0.0051, increase in FEV1 p < 0.0161, Wilcoxon-Test for matched pairs). Using an oscillating PEP-system in the expiratory outlet of a nebulizer does not only increase the bronchodilatory effect of ipratropiumbromide but also shortens by combining inhalation and physiotherapy the time necessary for therapy in those patients. PMID- 11605122 TI - [The education program for patients with COPD from Bad Reichenhall]. AB - An education program for patients with COPD is presented. This program was created for inpatient pulmonary rehabilitation at the Klinik Bad Reichenhall. We intend to improve the patients' acceptance of disease and their understanding of therapy. Furthermore we want to impart basic knowledge about COPD and its treatment. The patients should be motivated to manage the disease in an active and more independent way: They should control the natural course of their disease by learning preventive and restorative health care behaviours and self-help activities in case of acute exacerbations. The aim is to attain the acceptance of changing life-style. PMID- 11605123 TI - [Malnutrition in COPD]. AB - During the last years our knowledge about the malnutrition of patients with COPD has grown. Weight loss is a problem of some patients with COPD, but, as we know today by techniques of body composition measurement much more patients have reduced muscle mass. The reason for this is complex and involves many body systems. Nutritional intervention alone is not successful in many patients. We have to accept that COPD is a kind of systemic disease which does not only involve the lung. Thus, future therapies have to include not only treatment of the bronchial system. PMID- 11605124 TI - [Anxiety: an aspect of the interaction of doctor and patients on the waiting-list and after lung-transplantation]. AB - Anxiety occurs frequently in patients who are on the waiting-list for a lung transplantation or have already been transplanted. In this context anxiety is a theme of every interaction of doctor and patient but often remains unrecognized because it hides behind bodily symptoms and mechanisms of defense. Anxiety affects patients' behavior and compliance and may afflict - especially if not recognized - doctors' decisions and thus patients' health and survival. It is therefore necessary to recognize and to openly handle anxiety in the interaction of doctor and patient. PMID- 11605125 TI - [COPD Therapy 2001: bronchodilation is not everything - Congress report on expert workshop 18-21 January 2001 in Seefeld, Tyrolia]. PMID- 11605127 TI - [Instruments for the economical evaluation of psychiatric service systems: methodological foundations of the European standardisation and the German adaptation]. AB - OBJECTIVE: In the project "Cost-effectiveness of psychiatric service systems. A European comparison" a German version of instruments for the assessment of needs for services (CAN-EU), service satisfaction (VSSS-EU) relatives' burden of care (IEQ-EU) and costs of psychiatric services (CSSRI-EU) was developed in close cooperation with the EPSILON Study group. METHOD: The English original versions of the instruments were translated into German and a back-translation into the original language was carried out by a second translator. The back-translation was screened by the first author of the original version. The German versions of all instruments were tested for comprehensibility and practicability by means of focus groups. The internal consistency of all instruments were tested on a representative sample of 307 patients with schizophrenia according to ICD-10 F20. Test-retest reliability and inter-rater reliability was tested by a sub-sample of 50 patients. RESULTS: Psychometric properties of the translated instruments will be presented and discussed. CONCLUSIONS: Statistical methods for the assessment of the reliability coefficients were identical with those of the EPSILON study, therefore the psychometric properties of the German version of the CAN-EU are directly comparable with the other European versions of the instrument. PMID- 11605128 TI - [The standardized assessment of the need for treatment and support in severe mental illness: the development and testing of the German version of the Camberwell assessment of Need-EU]. AB - OBJECTIVE: The development and the psychometric testing of the German version of the Camberwell Assessment of Need-EU will be presented. METHOD: The internal consistency of the subscales total needs, met needs and unmet needs was tested by the application of the CAN-EU on a representative sample of 307 patients with schizophrenia according to ICD-10 F20.0. Test-retest-reliability and inter-rater reliability was tested with a sub-sample of 41 patients. RESULTS: The internal consistency and the test-retest-reliability of the German version of the CAN-EU is satisfying and slightly higher in comparison with the other European versions. The inter-rater-reliability is also satisfying but smaller in comparison with the other European versions. CONCLUSIONS: In general, the psychometric properties of the German version of the CAN-EU are satisfying but the lower inter-rater reliability in comparison with the other European versions suggests that more precise coding rules for the German version of the CAN-EU must be formulated to improve the inter-rater agreement of the instrument. PMID- 11605129 TI - [German adaptation of the client sociodemographic and service receipt inventory - an instrument for the cost of mental health care]. AB - AIM: Psychiatric health services research has to consider health economic points of view more than before as a result of the present-day financial problems in our health care system. Therefore an instrument was developed, which is suitable for the evaluation of cost of mental health care in Germany. METHOD: The Client Sociodemographic and Service Receipt Inventory (CSSRI-EU), which was developed in the UK, was adapted to the German situation and for the first time used in a cost effectiveness-analysis of mental health care. The adaptation process of the instrument and the practical application are explained and pros and cons considered. RESULTS: The German adaptation of the CSSRI-EU has proven effective in practical application. The instrument offers feasible solutions for many problems with the cost of mental health care. The instrument can be used for the calculation of direct and indirect costs and gives information about service utilization and medication profiles of the clients. CONCLUSION: The German adaptation of the CSSRI-EU is a feasible instrument for the evaluation of the cost of mental health care in Germany. PMID- 11605130 TI - [The German adaptation of the Verona Service Satisfaction Scale: an instrument for patients' satisfaction with mental health care]. AB - The German Adaptation of the Verona Service Satisfaction Scale: An Instrument for Patients' Satisfaction with Mental Health Care. AIM: Measuring effectiveness and quality of care became an important topic in psychiatry. Considering that objective criteria were not sufficient in the past, the subjective perspective gained growing interest. Client satisfaction is an important variable to evaluate psychiatric care. Patient satisfaction can influence treatment outcome as well as it determines the psychiatric system itself. METHOD: The Italian original version of the Verona Service Satisfaction Scale (VSSS-54) was translated and adapted to the German language. The instrument has been tested in the project "Cost effectiveness of psychiatric service systems". The process of development, the psychometric testing and the practical application of the German version will be presented in this paper. Additional advantages and disadvantages are discussed. RESULTS: As psychometric properties of the instrument correspond to conventional standards, they are comparable with the results of an international study. The drop out of items cannot be controlled, therefore analysing the data is difficult. CONCLUSION: Although the VSSS shows various methodological limitations, it is at the moment an appropriate instrument for measuring patient satisfaction in the German language. PMID- 11605131 TI - [The assessment of burden on relatives of mentally ill people: the German version of the involvement evaluation questionnaire (IEQ-EU)]. AB - AIMS: The German Version of the Involvement Evaluation Questionnaire (IEQ-EU), developed for the assessment of burden on relatives of mentally ill people will be presented. Also the results of the reliability analysis will be presented. METHOD: After translation and adaptation of the Dutch version of the IEQ-EU into German, the instrument was tested in the study "Cost-effectiveness of psychiatric service systems". RESULTS: The internal consistency was tested on a sub-sample of 138 relatives and the Test-Retest-Reliability on a sub-sample of 37 relatives. The internal consistency (Cronbachs alpha) is moderate or good and slightly lower in comparison with the other European versions. With the exception of one subscale the results for the intraclass correlation coefficient are equal to the European versions. CONCLUSIONS: The IEQ-EU is an instrument with moderate or good psychometric properties. It covers all important domains, is easy to understand and not time-consuming. PMID- 11605132 TI - [The analysis of the cost structures of the treatment of schizophrenia by means of standardized assessment instruments]. AB - OBJECTIVE: Aims of the study are the analysis oft the structures and influence factors causing direct costs of schizophrenic diseases by means of international standardized assessment instruments. METHOD: Annual costs of treatment were assessed for a sample of 258 patients with the diagnosis of schizophrenia (ICD-10 F20) by means of the German version of the CSSRI. For the analysis of cost variance a regression model was computed using functional level (GAF), symptoms (BPRS 4.0), needs for care (CAN), service satisfaction (VSSS) and subjective quality of life (LQoLP) as predictors. RESULTS: The average yearly treatment costs for the study sample were 12 726,- DM. Costs for sheltered accommodation and for psychiatric inpatient treatment were found to be the largest elements of the entire costs followed by the costs for ambulant medications. Results of the regression analysis show that illness history, the severity of symptoms and the need for care explain the greatest proportion of variance. CONCLUSIONS: The standardized instruments developed in the project enable a systematic and international comparable assessment of the costs in the treatment of schizophrenic diseases. Furthermore the instruments allow to explain 38 % of the cost variance. The impact of the severity of symptoms under statistical control of the functional impairment and the needs for care suggests that an effective reduction of symptoms could lead to savings in the entire treatment costs. However, the great influence of the illness history and, irrespective of the functional impairment, the need for care show that the possibilities for cost savings in the treatment of schizophrenia are generally low. PMID- 11605134 TI - Does a suitable animal model for research on partial left ventriculectomy exist? Animal models for PLV. AB - Partial left ventriculectomy is a new surgical option quickly introduced into clinical use worldwide for treating end-stage heart failure in patients with dilated cardiomyopathy. Due to the overwhelming success of this new kind of surgical treatment for dilated cardiomyopathy, experimental research on the physiological and pathophysiological basis was initially not performed. Now, demands for an appropriate animal model have arisen more and more since the outcome of patients treated by partial left ventriculectomy has differed considerably. This review summarizes available experimental models for heart failure in large animals, and discusses their suitability for research on partial left ventriculectomy. PMID- 11605136 TI - Lipopolysaccharide-binding protein (LBP) and markers of acute-phase response in patients with multiple organ dysfunction syndrome (MODS) following open heart surgery. AB - Cardiopulmonary bypass (CPB) is associated with an immunological injury that may cause pathophysiological alterations in the form of a systemic inflammatory response syndrome (SIRS) or a multiple organ dysfunction syndrome (MODS). Previous studies on this issue have reported different changes of immunological parameters during and after CPB, but there are no reports about the lipopolysaccharide-binding protein (LBP) in relationship to other markers of inflammation in patients with MODS following cardiovascular surgery. In the present study, we investigated the acute-phase response of patients with MODS of infectious and non-infectious origin following open-heart-surgery. Plasma levels of procalcitonin (PCT), c-reactive protein (CRP), interleukin-6 (IL-6), and LBP were measured in the first four postoperative days in 12 adult male patients with the signs of SIRS and two or more organ dysfunctions after myocardial revascularization (MODS-group), and 12 patients without organ insufficiencies (SIRS-group). There were no significant differences regarding age, weight, height, preoperative NYHA-classification, preoperative LVEDP, or the number of anastomosis. Patients with MODS had a significantly longer operation time, duration of ischemia, and duration of extracorporeal circulation. None of the patients in the SIRS group died, whereas in the MODS group, 4 patients died due to septic multiorgan failure. Plasma PCT and IL-6 concentrations were significantly elevated in all MODS patients. CRP and LBP showed no differences between the MODS and the SIRS group. Comparing the MODS patients with and without positive microbial findings, we found significantly elevated levels of PCT and LBP in those patients with documented infections. Our results indicate that LBP may be a new marker for the differentiation between a severe non-infectious SIRS and an ongoing bacterial sepsis in the early postoperative course following CPB, while a microbiological result is still missing. PMID- 11605135 TI - Age-dependent myocardial reinduction of apoptosis inhibitors under VAD in heart failure. AB - Hemodynamic unloading using the ventricular assist device [VAD] results in partial functional recovery of failing hearts that show increased susceptibility to cardiomyocyte apoptosis. The caspase cascade is the central element of the apoptotic process in cells. We therefore tested expression shifts of left ventricular mRNA of caspases and their endogenous inhibitors from 15 patients with VAD support and successful bridging to transplantation using semiquantitative RT-PCR. Cardiac unloading was shown by the reduction in ventricular Pro-ANP mRNA under VAD. No alteration of mRNA expression under VAD could be observed for initiator caspases, for their selective inhibitors or for apoptotic signal molecules from the mitochondrial intermembrane space. Only two unselective cardiac IAPs (inhibitor of apoptosis protein) were increased under VAD with better recovery in younger patients. In conclusion, our findings indicate that successful hemodynamic unloading by VAD support causes only minor, age-dependent recovery in the expression of IAPs, while presumed alterations in antiapoptotic modulator systems upstream of the caspase cascade still remain to be identified. PMID- 11605137 TI - Preliminary clinical experience with the Heartflo anastomosis device. AB - A clinical, prospective trial to evaluate a multi-suture anastomotic device (Heartflo) is currently underway. This new surgical tool can be used during CABG to perform end-to-side or side-to-side coronary arteries anastomoses with interrupted suture technique. This reports our interim preliminary clinical experience. METHODS: From February to November 2000, we attempted 15 anastomoses with the multi-suture anastomotic device (Heartflo) in 11 patients with coronary artery disease. RESULTS: 7 males, 4 females, mean age 64 +/- 3 yrs received 15 anastomoses with the device. The target vessels were: 8 RCA, 3 LAD, 4 OM. Mean coronary diameter was 2 +/- 0.3 mm. Grafts used were 14 saphenous veins and 1 IMA. 13/15 anastomoses were completed with the device. 5/13 required 0 - 1 additional stitches versus 8/13 requiring more due to inappropriate tissue capture on the native coronary side. Average time was 17.7 +/- 2 min. In 2/15 cases, the procedure was converted to a traditional handsaw anastomosis. Postoperative CK movement without Q-wave in the EKG was observed in 1/11 patients. CONCLUSIONS: This device is a reliable instrument that provides reproducible coronary anastomoses with interrupted suture technique, although it also requires additional measures to improve tissue capture and process of handling sutures before extensive clinical application. PMID- 11605138 TI - Aortic arch surgery using moderate systemic hypothermia and antegrade cerebral perfusion via the right subclavian artery. AB - BACKGROUND: Surgery of the aortic arch avoiding profound systemic hypothermia and using antegrade or retrograde cerebral perfusion has recently been popularized. This usually renders the CPB and surgical field set-up more complex. We propose a simple method achieving a similar effect. METHODS: During a 6-month period, 7 patients (median age 72 years) underwent surgery involving the aortic arch with cannulation of the right subclavian artery for arterial return. There were 6 acute type A dissections and one ascending aorta and arch aneurysm. After commencing CPB, the ascending aorta was clamped and reconstruction of aortic valve and root were initiated. Patients were cooled to a tympanic temperature of 25 - 27 degrees C. CPB was then stopped, and the arch was opened and inspected from inside. While resuming arterial perfusion via the right subclavian artery, the arch branches were clamped sequentially from right to left under observation for back flow. Bilateral radial artery pressure and temporal transcutaneous oxygen saturation were always monitored. RESULTS: In all cases, the aortic valve was spared using remodeling and resuspension techniques. 2 complete arch, 2 partial arch and 3 proximal arch replacements were performed. Mean times were 183 (113 - 321) minutes for CPB and 120 (67 - 213) minutes for aortic cross-clamping. Maximal systemic circulatory arrest time was 82 min. One patient died in the hospital due to MRSA sepsis with a normal CCT scan. All others were discharged in good condition. CONCLUSION: The initial experience with this simple technique of antegrade cerebral perfusion avoiding profound systemic hypothermia and the possible disadvantages of femoral artery cannulation appears promising. PMID- 11605139 TI - Tissue engineering: complete autologous valve conduit--a new moulding technique. AB - OBJECTIVE: The use of fibrin gel, which can be produced from patients' blood, was investigated as an autologous, biodegradable scaffold. A new moulding technique was developed to create a complete aortic root. METHODS: A new moulding technique was generated for the creation of complete valve conduit. On the basis of biomechanical valve design studies, a tricuspid "ventricular" and "aortic" stamp were developed. A silicone-coated aluminum cylinder was used to circumferentially limit the mould. The cell/gel suspension was filled into the mould and polymerization was started. RESULTS: The creation of complex structures such as complete valve conduits is possible with the moulding technique described. With a layer thickness of up to 2 mm, histological investigations showed excellent tissue development with viable fibroblasts surrounded by collagen bundles. CONCLUSION: Fibrin gel unifies many properties of an ideal scaffold: The formation of complex structures is possible, the degradation and polymerization is controllable and the formation of the extracellular matrix is excellent. PMID- 11605140 TI - A novel perfusion catheter for hybrid procedures in minimally invasive bypass surgery. AB - BACKGROUND: Combined off-pump bypass grafting and percutaneous coronary intervention (hybrid procedures) is supposed to be beneficial for high-risk patients. We developed a novel perfusion catheter to facilitate these hybrid interventions. METHODS: First, we tested coagulatory activation in vitro. Afterwards, 6 landrace pigs underwent active coronary perfusion of the LAD. In a second study, 15 pigs underwent off-pump bypass surgery (LIMA to LAD grafting) and the catheter was used to provide myocardial perfusion and prevent bleeding at the site of the coronary anastomosis. RESULTS: In the in vitro perfusion studies, no activation of coagulation or clotting occurred. Active coronary perfusion was feasible without signs of regional myocardial ischemia or coagulation over a 50 minute period. During off-pump bypass surgery, the catheter prevented bleeding in the operation field and facilitated the surgical procedure. CONCLUSION: The new perfusion catheter can optimize the conditions of off-pump bypass surgery by preventing bleeding in the operation field, maintaining myocardial perfusion and allowing direct angiographic control of the anastomosis. Therefore, this new technique could be an important tool to facilitate hybrid interventions. PMID- 11605141 TI - Outpatients on biventricular assist devices. AB - As waiting times for transplants have lengthened, long-term mechanical circulatory support (MCS) has become more common in patients who present with severe cardiogenic shock leading to multiorgan failure. With these patients, we used the biventricular assist device (BVAD, Berlin Heart). In this report, we will describe our 4 years of experience with 11 patients on a BVAD who were discharged home while awaiting transplantation. The 11 patients underwent BVAD implantation from 1997 to 2000. These were 2 women and 9 men. The mean support time was 382 days (range: 156 - 567). The indication for BVAD was cardiomyopathy- six dilated, one restrictive and four ischemic. These patients were monitored for infections, thromboembolic events, bleeding complications, and psychological effects during the time they spent at home. Our experience shows that all of the patients could leave hospital following sufficient training for dressings and anticoagulation after recovering completely from secondary organ dysfunction. The mean time period the patients spent at home was 48 days (range: 3 - 182) days. Seven patients (63 %) had to be readmitted to the hospital--due to transitory ischemic attacks in two cases, hemorrhoidal bleeding in one and wound infections in four cases. One patient died of a traumatic accident during sexual activity. The use of a BVAD is feasible for outpatient use as a bridge to transplantation. It ensures the survival of the patient, enables recovery from multiorgan failure and offers an acceptable quality of life. PMID- 11605142 TI - The Ross operation as a combined procedure and in complicated cases--is there an increased risk? AB - BACKGROUND: In this report we address the question whether the Ross operation can be recommended in combined and complicated cardiac procedures. METHODS: From February 1995 to July 2000, we performed 203 Ross operations, 129 with ideal clinical presentation (group 1: mean age 41 +/- 13 years, male 105). In 74 patients, the clinical presentation was complex (group 2: mean age 35 +/- 17 years, male 57), defined as previous aortic or cardiac operations in 32, active endocarditis in 8 or combined procedures in 40 patients. Follow-up is 95 % complete. RESULTS: Neither early mortality nor thromboembolic events were observed. Complications in group 1 vs. group 2 were prolonged ventilation in 1 vs. 1, pacemaker insertion in 1 vs. 2, minor myocardial infarction in none vs. 2 and postoperative bleeds in 2 vs. 3 patients. In group 1, one patient died of hemoptysis at 25 months, and in group 2 one sudden death occurred at 5 months. In the long term, two patients required reoperation for autograft failure in group 1, and one on group 2. Pulmonary stenosis required surgical treatment in one patient of group 2. Echocardiography revealed physiological gradients across the autograft with no significant regurgitation in either group. CONCLUSION: The Ross operation has excellent mid-term results and is a safe and attractive therapeutic approach, both in combined procedures and complex clinical presentations. PMID- 11605143 TI - Primary pigmented malignant schwannoma in the posterior mediastinum. AB - This paper describes a rare case of primary pigmented malignant schwannoma arising from the sympathetic trunk in the posterior mediastinum. A 30-year-old woman underwent a thoracoscopic tumor extirpation. A primary pigmented malignant schwannoma was diagnosed histologically. The tumor presented fascicles and whorls of pigmented plump spindle cells and positive immunoreactivity to S-100 protein, vimentin, and HMB-45. Postoperative radiotherapy of the mediastinum was performed. Our case demonstrates the successful thoracoscopic resection and postoperative radiation treatment of a malignant schwannoma. PMID- 11605144 TI - Gastropleural fistula originating from the lesser curve: a recognised complication, an uncommon pathway of communication. AB - Fistulous communications between the abdominal and the pleural cavity are rare; they implicate intra-abdominal sepsis. We present a rare case of subphrenic abscess following gastric perforation, which resulted in thoracic empyema. This report emphasises that gastropleural fistulas, although uncommon, should be considered in differential diagnoses of thoracic empyema, especially when there is a longstanding history of peptic ulceration. PMID- 11605145 TI - Near-fatal hemoptysis and emergency surgical repair after aortic patch-plasty. AB - A 38-year-old man presented with massive hemoptysis followed by hemorrhage shock. The patient's history revealed a Dacron patch repair for aortic coarctation and recoarctation carried out twice, once 23 and once 10 years ago. Diagnosis of a ruptured descending aortic aneurysm with an aortobronchial fistula into the left lower lobe was established using CT scan. Emergency surgery consisted of left pneumonectomy and descending aortic graft replacement during deep hypothermic circulatory arrest. The patient was discharged 12 days later. PMID- 11605146 TI - Floating thrombus on an ASD occluder device in a patient with hemophilia A. AB - The case presented is that of a 29-year-old man with a history of hemophilia A who was admitted with recurrent onsets of transient cerebrovascular ischemia; he had undergone a transvenous closure of an atrial septal defects with an occluder device (Cardioseal Starflex) two months ago. Due to a factor-VIII deficiency, no further anticoagulation therapy was initiated. On admission, transesophageal echocardiography revealed a floating thrombus on the left atrial side of the umbrella. The device was explanted via a right minithoracotomy, and the atrial septal defect was closed. The patient had an uneventful recovery. PMID- 11605147 TI - Combined thoracoabdominal aneurysm repair and off-pump coronary artery surgery. AB - Off-pump coronary revascularization using local stabilizing devices and less invasive methods are getting more interest with good results. To our knowledge we report the first operation of which concomitant coronary revascularization using "Octopus" device and thoracoabdominal aneurysm repair has been done without extracorporeal circulation with successful outcome. Repair of the aorta and patency of the descending aorta to coronary saphenous bypass graft were showed with angiography at postoperative 6 month. PMID- 11605148 TI - Treatment strategy and perioperative risk in patients with idiopathic thrombocytopenic purpura undergoing cardiac surgery. AB - Patients suffering from idiopathic thrombocytopenic purpura undergoing cardiac surgery with extracorporeal circulation may be at increased risk for postoperative bleeding complications. Therefore, different treatment strategies, such as conservative treatment, splenectomy, transfusion of platelet concentrates and therapy with immunoglobulins have been proposed. We report on our experiences with preoperative immunoglobulin treatment in selected patients with special regard on the optimal dosage. PMID- 11605149 TI - In situ DNA nick-end labeling positive reaction around laser channels. PMID- 11605150 TI - Low fecal elastase-1 in type I diabetes mellitus. AB - BACKGROUND: Previous studies suggested impaired pancreatic exocrine function in type I diabetes patients, but have been limited by small or highly selected samples. Fecal elastase-1 has facilitated evaluation of pancreatic dysfunction in population-based studies. METHODS: 112 type I diabetic patients (age +/- SD: 37 +/- 11 years; 47 % males; diabetes duration: 12.5 +/- 10.5 years) were consecutively selected from main regional diabetes centers in Essen, West Germany. 116 non-diabetic control subjects, similar with respect to age and sex, were recruited from the same geographical region. Elastase-1 measurement was performed centrally by ELISA (ScheboTech, Germany). RESULTS: Elastase-1 concentrations in type I diabetic patients were significantly lower than in control subjects (median; inter-quartile range: diabetic patients: 227, 98-386 microgram/g stool; non-diabetic subjects: 544, 377-702 microgram/g stool) (p < 0.01). Elastase-1 < 100 microgram/g stool (E1 < 100) was found in 25.9 % of diabetic and 5.2 % of non-diabetic subjects, yielding an age-sex-adjusted prevalence Odds ratio (POR; 95 % CI) for diabetes and E1 < 100 of 6.9 (2.8-19.6). After adjusting for potential confounders (history of gastrointestinal diseases, smoking, alcohol consumption) the strong association remained (POR: 6.7; 2.7 19.2). Among patients with diabetes, E1 < 100 was associated with quality of glycemic control (HbA1c, change per 1 %: POR 1.5; 1.1-2.0), diabetes duration (per year: POR 1.1; 1.03-1.2), and age at diabetes onset (per age year: POR 1.1; 1.02-1.1). No association was found with history of gastrointestinal diseases, smoking, or alcohol consumption (current, life-time). CONCLUSIONS: Fecal elastase 1 concentrations were lower in type I diabetes patients compared to control subjects, indicating impaired pancreatic exocrine function. Low elastase-1 was associated with poor metabolic control and longer diabetes duration. PMID- 11605151 TI - Effect of balloon compliance on symptomatic success of pneumatic dilation in achalasia patients. AB - BACKGROUND: Pneumatic dilation is the standard non-surgical treatment of achalasia. The dilation devices in use differ in their physical properties, particularly with regard to balloon compliance. PATIENTS AND METHODS: 35 achalasia patients (18male, 20-82 years, median 45 years) diagnosed by accepted criteria were prospectively and randomly assigned to 39 dilation procedures by either a low compliance dilation device (LCDD, polyethylene balloon, Rigiflex(trade mark), Microvasive Boston Scientific, USA, n = 18) or a high compliance dilation device (HCDD, latex balloon, Rusch Inc., Germany, n = 17). Individual complaints were graded by a standardized questionnaire before treatment and prospectively after a median of 3 and 13 months. Furthermore, the patients' readiness to retrospectively re-consent (treatment satisfaction) and treatment complications were recorded. RESULTS: Patient groups did not differ with regard to age, sex, number of previous dilations, and duration of follow-up (Mann-Whitney U-test, p > 0.05). 2 patients were excluded from follow-up, with one individual (HCDD) having suffered a dilation-related perforation (2.6 %) and another subject (LCDD) having not been able to re-contact. Initial and post treatment symptom scores as well as treatment complications were similar in both treatment groups (p > 0.05). Treatment satisfaction was 90 % for the LCDD and 82 % for the HCDD group at first control, and 89 % and 87 % at second control, respectively (p > 0.05). In both patient groups, dilation therapy best improved the symptom "dysphagia" (Wilcoxon rank sum test, p < 0.05). CONCLUSIONS: Achalasia patients' satisfaction of dilation treatment is high, with their dysphagia benefiting most from therapy. Low and high compliance balloon devices did not differ from each other with regard to symptomatic efficacy and safety in forceful dilation of these individuals. PMID- 11605152 TI - Autoimmune hepatitis associated with coagulation disorders and immunethyreopathy. AB - We present the case of a 42-year-old female patient with the diagnoses of autoimmune hepatitis type I and autoimmune thyroiditis. Furthermore this patient had an unusual combination of coagulation disorders with homozygous Factor V Leiden mutation (APC resistance) and presence of antiphospholipid antibodies, leading to deep vein thromboses and miscarriages. Only few cases with the combination of autoimmune hepatitis and antiphospholipid antibodies have been described and almost all of them had become symptomatic with the antiphospholipid syndrome. As both autoimmune phenomenons furthermore share similar HLA-patterns, their coincidence is probably not as uncommon as the limited number of case reports suggests. Therefore attention in patients with autoimmune hepatitis should be focused on thrombophilia. PMID- 11605153 TI - [Incarceration of a pancreatic stone fragment in the distal pancreatic duct after ESWL-therapy]. AB - Incarceration of a pancreatic stone fragment in the distal pancreatic duct after ESWL-therapy.A partial or total absence of stones in pancreaticolithiasis therapy can be reached by using ESWL. We report on a patient who happened to get an incarceration of a fragment in the distal pancreatic duct after having been treated by ESWL without a previous sphincterotomy to the ductus Wirsungianus. This emphasizes the recommendation to carry out a papillotomy of the pancreatic main duct before applying ESWL to pancreatic stones. PMID- 11605155 TI - European roots of American gastroenterology - The Ismar Boas Lecture of the 56th Annual Meeting of the German Society of Gastroenterology, Munster, 13 September 2001. PMID- 11605154 TI - Acute Budd-Chiari syndrome, portal and splenic vein thrombosis in a patient with ulcerative colitis associated with antiphospholipid antibodies and protein C deficiency. AB - We report the case of a female patient who had severe thrombotic complications in peripheral (V. jugularis, subclavia, brachialis, poplitea) and visceral (portal and splenic) veins 4 years after the first diagnosis of severe ulcerative pancolitis. A thrombolysis therapy for subclavian and jugular vein thrombosis was performed without complication, but she soon developed acute thrombosis of the hepatic veins (acute Budd-Chiari syndrome). She quickly recovered after liver transplantation and now - 6 years later - she lives a normal life with continuous anticoagulation and medical therapy of the colitis.3 possible causes for the severe coagulation defect in this patient can be supposed: Thrombocytosis, protein C deficiency and an antiphospholipid antibody syndrome. PMID- 11605156 TI - [Pathobiology of dysplasia in chronic inflammatory bowel disease: Current recommendations for surveillance of dysplasia]. AB - Pathobiology of dysplasia in chronic inflammatory bowel disease: Current recommendations for surveillance of dysplasia. Patients with ulcerative colitis and Crohn's disease bear an about 10- and 4-fold increased risk, respectively, for developing colorectal carcinoma. Apart from typical locations of colorectal carcinoma in the sigmoid colon and rectum other locations were also often observed, e. g. right hemicolon or multifocal distribution. Histologically colorectal neoplasms frequently present as mucinous adenocarcinoma (signet-ring cell carcinoma). The risk for neoplasm depends on extension, severity, duration and therapeutic responsiveness of chronic colonic inflammation, and it seems pathogenetically to be similar in ulcerative colitis and Crohn's disease. Colorectal carcinoma in inflammatory bowel disease arises from epithelial dysplasia. Since there are no reliable biological markers available to date, surveillance-programs continue to rely on the discovery of dysplasia (unequivocal intraepithelial neoplasia). Detection of dysplasia by colonoscopy achieves 70-85 % sensitivity.Endoscopic surveillance should start after 8 years of disease's duration in pancolitis, after 10-12 years in left- sided colitis and after 12 years in Crohn's disease of the colon, with regular intervals every 1-2 years. 3 5 biopsies should be done every 10 cm from mucosa free of inflammation. Additionally, every fine or discrete alteration of the mucosal surface should be recorded. Multiple biosies should also be taken from such minimal lesions as well as from more macroscopically suspicious areas like plaques, nodular lesions or stenosis. The clinical consequence of a positive screening for dysplasia is colectomy because of an assumed risk of cancer of about 40-70 %. Dysplasia in macroscopically suspect areas bear the highest risk of cancer (non-adenoma like dysplasia), followed by multiple high-grade lesions without a macroscopic lesion, and multiple low-grade dysplasias. Detection of single dysplastic lesions in flat mucosa should be followed by a control endoscopy after 2-6 months, and if dysplasia is seen again, colectomy is recommended. PMID- 11605157 TI - [Virtual colonoscopy: Already a standard procedure?]. PMID- 11605158 TI - [Differential expression of metastasis-associated genes in papilla of Vater and pancreatic cancer correlates with disease stage]. PMID- 11605160 TI - Inotropes and beta-blockers: is there a need for new guidelines? AB - Beta-adrenergic blocking agents are standard treatment for patients with mild-to moderate heart failure. When patients receiving beta-blockers decompensate they often need treatment with a positive inotropic agent. The beta-agonist dobutamine may not produce much increase in cardiac output during full-dose beta-blocker treatment and may increase systemic vascular resistance via alpha-adrenergic stimulation. In contrast, phosphodiesterase inhibitors (PDEIs) such as milrinone or enoximone retain full hemodynamic effects during complete beta-blockade because the site of action of PDEIs is beyond the beta-adrenergic receptor and because beta-blockade reverses some of the desensitization phenomena that account for the attenuation of PDEI response in heart failure related to upregulation in G(alphai). Inotrope-requiring subjects with decompensated heart failure who are undergoing long-term therapy with beta-blocking agents should be treated with a type III-specific PDEI, not a beta-agonist such as dobutamine. PMID- 11605161 TI - Practical approaches to treating patients with acute decompensated heart failure. AB - Finding a simple blood test to aid in the diagnosis and treatment of patients with congestive heart failure would have a favorable impact on the costs associated with the disease. B-type natriuretic peptide (BNP) is synthesized in the cardiac ventricles and correlates with left ventricular pressure, amount of dyspnea, and the state of neurohormonal modulation, making this peptide the first potential "white count" for heart failure. Data indicate that serial point-of care testing of BNP should be helpful in patients presenting to urgent care clinics with dyspnea. BNP might serve as a screen for patients referred for echocardiography. A low BNP level makes echocardiographic indices of left ventricular dysfunction (both systolic and diastolic) highly unlikely. BNP may also be effective in improving in-hospital management of patients admitted with decompensated congestive heart failure. In some cases BNP levels may obviate the need for invasive hemodynamic monitoring and, when such monitoring is used, may help tailor treatment of decompensated patients. Finally, the role of BNP in outpatient cardiac or primary care clinics may be important in the titration of therapies and assessment of the state of neurohormonal compensation of patients. PMID- 11605159 TI - The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. AB - Hereditary paragangliomas are usually benign tumors of the autonomic nervous system that are composed of cells derived from the primitive neural crest. Even though three genes (SDHD, SDHC, and SDHB), which encode three protein subunits of cytochrome b of complex II in the mitochondrial respiratory chain, have been identified, the molecular mechanisms leading to tumorigenesis are unknown. We studied a family in which the father and his eldest son had bilateral neck paragangliomas, whereas the second son had a left carotid-body paraganglioma and an ectopic mediastinal pheochromocytoma. A nonsense mutation (R22X) in the SDHD gene was found in these three affected subjects. Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor but not in peripheral leukocytes. Assessment of the activity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, that was not detected in six sporadic pheochromocytomas. In situ hybridization and immunohistochemistry experiments showed a high level of expression of markers of the angiogenic pathway. Real-time quantitative reverse transcriptase (RT)-PCR measurements confirmed that vascular endothelial growth factor and endothelial PAS domain protein 1 mRNA levels were significantly higher (three- and sixfold, respectively) than those observed in three sporadic benign pheochromocytomas. Thus, inactivation of the SDHD gene in hereditary paraganglioma is associated with a complete loss of mitochondrial complex II activity and with a high expression of angiogenic factors. PMID- 11605162 TI - Surgical issues in heart failure: what's new? AB - Despite major advances in inotropic medications and our understanding of their proper use, surgical management of heart failure is the fastest-growing aspect of cardiovascular surgery. In addition to causing 750,000 deaths annually, myocardial infarctions leave an estimated 60,000 more patients in severe congestive heart failure and several times more individuals with compromised ventricular function. As these patients are offered reparative surgical options, surgeons, anesthesiologists, and cardiologists face physiologic challenges that can be optimally overcome only by modifying treatment strategies to address patients who have failed appropriate medical therapy, including milrinone, vasopressin, and nitric oxide. As our comfort with mechanical support increases, the threshold for embarking on these lines of treatment will be altered. Innovative devices have been created to meet this clinical need, but they must provide adequate quality of life to create sustainable value and health for society. PMID- 11605163 TI - Overview: old and new controversies in the treatment of advanced congestive heart failure. AB - In 2001, patients with decompensated congestive heart failure can be treated with various intravenous inotropic agents, vasodilator agents, invasive hemodynamic monitoring, ventricular assist devices, and cardiac transplantation. The use of many of these agents is limited by toxicities and potentially incremental costs associated with intensive care unit stays. As new pharmacologic therapies become available, such as beta-blockers and natriuretic peptides, the combinatorial use of agents for the treatment of patients with decompensated heart failure presents new opportunities with potentially reduced toxicities. Finally, given the natural history of patients with advanced heart failure, it behooves all caregivers to understand the wishes and preferences of the patients who face life-threatening decompensation. This is particularly true with long-term intravenous inotropic therapy. This review article addresses some of the issues that can affect the balance between efficacy, toxicity, and patient preferences for end-of-life care. PMID- 11605165 TI - Sickle cell disease: current clinical management. AB - The phenotypic expression of sickle cell disease (SCD) varies greatly among patients and longitudinally in the same patient. The phenotype influences all aspects of the life of affected individuals including social interactions, intimate relationships, family relations, education, employment, and spirituality. The clinical, manifestations of SCD are protean and fall into three major categories: (1) anemia and its sequelae; (2) pain and related issues; and (3) end-organ failure including infection. This review will emphasize the pathophysiology and management of sickle cell pain, as well as organ failure and its management. PMID- 11605166 TI - Principles and problems of transfusion in sickle cell disease. AB - Sickle cell disease (SCD) is associated with red blood cell (RBC) abnormalities and moderate to severe anemia, and blood transfusion is naturally a mainstay of treatment. However, transfusion therapy for SCD may incur special and distinctive adverse effects. Thus, it is important to understand the indications for and goals of transfusion therapy and to be aware of the potential side effects of therapy. Years of unsystematic clinical observations, followed by more carefully designed and in some cases randomized studies, have contributed substantially to our knowledge of transfusion therapy in SCD. However, much remains unknown and areas of controversy persist. In addition, serologic barriers pose enduring roadblocks to the optimization of transfusion therapy for patients with SCD, and the syndrome of massive hemolytic transfusion reactions and hyperhemolysis in SCD persists as a life-threatening complication for which appropriate clinical management is not yet defined. PMID- 11605164 TI - Pathophysiology of sickle cell disease: role of cellular and genetic modifiers. AB - Sickle hemoglobin (HbS), caused by a point mutation in the beta-globin gene of hemoglobin, polymerizes when deoxygenated. The pathophysiology of sickle cell disease results from cellular defects caused directly by the hemoglobin mutation interacting with the environment and many other gene products--a few known, but most yet unidentified--a typical example of epistasis. How normal tissue perfusion is interrupted is complex and why the phenotype of sickle cell disease differs from patient to patient is poorly understood. We review the "classic" aspects of the pathophysiology of sickle cell disease and focus on known and potential modulators of the phenotype of this disorder. PMID- 11605167 TI - Erythrocyte-active agents and treatment of sickle cell disease. AB - The sickle hemoglobin (HbS)-containing erythrocyte and its membrane represent a logical target for sickle cell disease therapy. Several antisickling agents which interfere with HbS polymerization have been studied over the last 30 years, but none has overcome the challenge of delivering high concentrations inside the sickle red blood cell without toxicity. The sickle erythrocyte membrane has also been targeted for therapeutic developments. Prevention of sickle cell dehydration by use of specific blockers of ion transport pathways mediating potassium loss from the sickle erythrocyte has been shown to be a feasible strategy in vitro, in vivo in transgenic sickle mice, and in patients. Other approaches have focused on improving the hemorheology of sickle erythrocytes and reducing their abnormal adhesion to endothelial cells. These potential treatments could be used alone or in combination with other approved therapies, such as hydroxyurea. PMID- 11605168 TI - Nitric oxide therapy in sickle cell disease. AB - Recent clinical and experimental data suggest that nitric oxide (NO) may play a role in the pathogenesis and therapy of sickle cell disease. NO, a soluble gas continuously synthesized in endothelial cells by the NO synthase (NOS) enzyme systems, regulates basal vascular tone and endothelial function, and maintains blood oxygenation via hypoxic pulmonary vasoconstriction and reduced shunt physiology. These vital homeostatic processes may be impaired in sickle cell disease and contribute to its pathogenesis. Therapeutic NO inhalation exerts significant direct effects on the pulmonary vasculature to reduce pulmonary pressures and increase oxygenation that may prove beneficial in acute chest syndrome and secondary pulmonary hypertension. Delivery of NO bound to hemoglobin or in plasma may improve blood flow and hemoglobin saturation, and thus reduce ischemia-reperfusion injury. Other NO-related effects on adhesion molecule expression and fetal hemoglobin induction are of interest. While direct evidence for a clinical benefit of NO therapy in sickle cell disease has not been reported, studies are underway to determine if inhaled NO will reduce the substantial morbidity and mortality suffered by these patients. PMID- 11605169 TI - Pathophysiology of alpha- and beta-thalassemia: therapeutic implications. AB - At the molecular level, the underlying cause of thalassemia is any of a number of genetic lesions that reduce or abolish the production of the globin chains of hemoglobin. The resulting chain imbalance is the key factor initiating the damage to the red blood cell (RBC) and it is the major pathophysiological event in all forms of the thalassemia syndromes. In this review we will outline some of the cellular and systemic processes that have been implicated in the development of the disease. When relevant, we will discuss the ways in which these processes can be altered in a therapeutic manner. PMID- 11605170 TI - Clinical management of beta-thalassemia major. AB - Management of patients with beta-thalassemia is based on adequate, safe blood transfusions (free of transfusion-transmitted diseases) and prevention of iron overload. Iron overload causes multiple endocrinopathies, contributes to osteoporosis, and is the cause of cardiac disease. Cardiac disease, secondary to iron damage, causes death in developed countries as a result of noncompliance to deferoxamine from the third decade of life. In underdeveloped countries, cardiac death starts from 12 years of age, due to nonavailability of deferoxamine. With the emergence of the advanced cardiac magnetic resonance imaging technique, early diagnosis of heart iron will allow the currently available iron-chelating agents (oral and parenteral) to be used in an innovative way to improve the quality of life and improve survival of patients with beta-thalassemia. PMID- 11605171 TI - Chelation therapy in beta-thalassemia: an optimistic update. AB - Iron chelation therapy with desferrioxamine (DFO) has dramatically improved the outlook in beta-thalassemia. Parenteral DFO reduces tissue iron stores, prevents iron-induced organ damage, and reduces morbidity and mortality, with little serious toxicity. However, the burden of prolonged subcutaneous portable pump infusions, high cost, and patient noncompliance have prompted the development of new methods of administration and new formulations of DFO as well as oral iron chelators. Deferiprone (L1), the only oral iron chelator studied in large long term clinical trials, is less effective and more toxic than DFO and may not adequately control iron overload; however, compliance and quality of life are improved. Combinations of two iron chelators (such as parenteral DFO plus oral L1, or 2,3-DHB; or oral L1 plus HBED) have been shown to produce additive and synergistic effects, explained by the shuttle hypothesis. Iron bound to a "shuttle"--an oral agent that mobilizes tissue iron--is exchanged in the bloodstream with a "sink"--such as parenteral DFO--and excreted via the kidneys, while the shuttle is reutilized. Combination therapy may produce enhanced iron excretion, target specific iron compartments, minimize side effects, increase treatment options, improve compliance, and facilitate individualization of therapy. Better understanding of the kinetics of iron metabolism, iron overload, and chelation should improve therapeutic strategies. PMID- 11605172 TI - Pharmacological induction of fetal hemoglobin in sickle cell disease and beta thalassemia. AB - A number of pharmacological agents are currently available for the induction of fetal hemoglobin (HbF) in patients with sickle cell disease and beta-thalassemia. Here we review the development of this new class of therapeutics and summarize the clinical trials that investigate their efficacy in patients with hemoglobin disorders. Hydroxyurea is the first of these drugs to be approved by the Food and Drug Administration for the treatment of sickle cell disease. Currently, the major focus is the development of safer agents and combinations of drugs that can increase HbF to levels high enough to prevent all complications of the disease. Progress in adapting the same strategy to the treatment of thalassemic disorders has been much slower. Although all the agents that are effective in sickle cell disease have similar HbF-inducing activity in beta-thalassemia, their use has rarely resulted in significant amelioration of the anemia. More research and more effective agents will be needed to make a significant impact on thalassemia. Nonetheless, success in this relatively young field has been very gratifying; before the end of this decade, clinically meaningful induction of HbF may become an achievable goal in most patients with hemoglobin disorders. PMID- 11605173 TI - Cell culture and animal models to screen for promising fetal hemoglobin stimulating compounds. AB - Sickle cell anemia (SCA) and the thalassemias are globally the most common class of inherited single-gene disorders. Current treatment options are limited, especially in developing countries. More practical and cheaper therapies are urgently needed. Since high fetal hemoglobin (HbF) levels ameliorate the clinical symptoms of these diseases, one current approach is to use pharmacological agents to reactivate the gamma-globin genes and stimulate the production of HbF. Several in vitro and in vivo experimental models developed for this purpose are the subject of this review. The models include in vitro established erythroid-like cell lines and primary cultures (both in semisolid and liquid media) of erythroid progenitor cells obtained from normal donors and patients with SCA and beta thalassemia, as well as in vivo models in genetically modified (transgenic) and unmodified animals. These experimental systems are useful for large-scale screening of compounds for HbF-stimulating potential, for determining the mechanism of action of potent compounds at the cellular and molecular levels, and for studying the pharmacology, pharmacokinetics, and toxicology of the drugs. These models are essential to find, test, and develop new drugs that will be effective and safe for clinical use in adults and children. PMID- 11605174 TI - Toward gene therapy for disorders of globin synthesis. AB - Inherited disorders of hemoglobin remain desirable targets for genetically based therapies. That stem cell replacement reverses the phenotype of both thalassemia and sickle cell anemia has been well established through allogeneic bone marrow transplantation studies, yet significant toxicities and finite donor availability limit this approach to a minority of affected individuals. Genetically based strategies that have as their goal addition of a normal copy of the human beta globin gene along with key regulatory sequences to autologous hematopoietic stem cells represent a viable alternative to allogeneic transplantation, but this approach has been impeded by formidable obstacles over the last decade. Large animal models have become the standard for the development of clinically relevant gene addition strategies, and significant progress in the techniques used to deliver potentially therapeutic genes has been achieved. The clinical application of such strategies may be close at hand, at least for disorders in which modest level, constitutive expression is sufficient to correct the phenotype. For the thalassemias and hemoglobinopathies, complex, regulated, lineage specific expression of the beta-globin gene at relatively high levels will be required. The discovery of the beta-globin locus control region renewed interest in the thalassemias and sickle cell anemia as targets for gene transfer, but difficulties in attaining high-titer vectors along with a tendency toward rearrangement when segments of the locus control region (LCR) were incorporated into retroviral vectors stalled further progress. Recent advances in vector construction have circumvented this problem and others limiting both gene transfer efficiency and regulation of transgene expression, offering new hope for clinical application. PMID- 11605176 TI - European perspectives on paclitaxel/platinum-based therapy for advanced non-small cell lung cancer. AB - Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown high clinical antitumor activity in several tumor types, including ovarian, breast, and lung carcinoma. Preclinical studies have shown that paclitaxel has an additive effect when combined with platinum compounds. Early clinical trials confirmed these data and established the dose range for both drugs. In recent years, several studies were developed in Europe using the combination of paclitaxel and platinum in non-small cell lung cancer, and four large randomized trials have been completed in Europe. The first study compared paclitaxel/cisplatin with teniposide/cisplatin, which was the control arm of the European Organization for Research and Treatment of Cancer at that time. The second study evaluated the benefit of the addition of paclitaxel to cisplatin. The third study compared paclitaxel/cisplatin with paclitaxel/carboplatin, and the fourth compared two doses of paclitaxel combined with carboplatin. Another large randomized study is currently being performed by the European Organization for Research and Treatment of Cancer. Combinations using paclitaxel-based regimens in the preoperative setting are under investigation. An ongoing European Organization for Research and Treatment of Cancer trial compares surgery with radiotherapy following various induction chemotherapy combinations, among which paclitaxel/platinum is one of the most frequently used. Another induction regimen is currently being evaluated by the University Medical School of Essen and Institut Gustave Roussy in Villejuif, France. In this trial, paclitaxel/cisplatin is delivered before etoposide/cisplatin and concurrent radiotherapy followed by surgery in locally advanced non-small cell lung cancer. Preclinical studies underline the radiosensitizing effect of paclitaxel, and many clinical studies are being conducted with radiotherapy in association with paclitaxel alone or in combination with platinum compounds. The use of paclitaxel in regimens without platinum and in triplet combinations is also being studied, and the optimal manner in which to administer this active agent clearly is of interest. PMID- 11605177 TI - Weekly paclitaxel in advanced non-small cell lung cancer. AB - Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most commonly used agents in treating patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). It is usually given once every 3 weeks. We have evaluated paclitaxel given once per week for 3 weeks every 4 weeks for patients with recurrent or metastatic NSCLC. Two consecutive studies using weekly paclitaxel were performed. The first study was a dose-escalation study with paclitaxel beginning at 50 mg/m(2) days 1, 8, and 15 every 4 weeks. Subsequent dose escalation was performed with 10 mg/m(2) increments per week. The second phase II study used paclitaxel at 80 mg/m(2) days 1, 8, and 15 every 4 weeks. The phase I study showed that the maximum tolerated dose was 90 mg/m(2)/wk for 3 weeks with 1 week off. The efficacy and side effects of both phase I and II were quite similar; therefore, the results were combined. Seventeen patients were in the phase I and 30 patients in the phase II study. The mean age was 72 years. Twenty-three patients had Eastern Cooperative Oncology Group performance status of 2 and 16 patients had received prior chemotherapy. One complete and 13 partial responses were observed with response duration ranging from 1 to 18+ months. Overall response rate was 30% (95% confidence interval, 18.5% to 42%). Overall median survival was 184 days. Grade 3/4 neutropenia was 8.5%, grade 3/4 infections was 6.4%, and grade 2 peripheral neuropathy was also 6.4%. Hyperglycemia with random blood sugar levels greater than 250 mg/dL was 6.4% and grade 3 fatigue was 4.3%. In general, treatment was well tolerated. In the best prognostic group of 16 patients without prior chemotherapy and with performance status 0 to 1, the response rate was 37.5% with a 1-year survival rate of 44% and median survival of 305 days. Prior chemotherapy, poor performance status, age higher than 70 years, and male gender carried a worse prognosis. In both phase I and II studies we observed limited myelosuppression, peripheral neuropathy, and constitutional symptoms. Weekly paclitaxel, delivered at our schedule, is an active and well-tolerated regimen. The role of weekly paclitaxel in NSCLC should be better defined in future randomized studies. PMID- 11605178 TI - Interim analysis of a phase II study of induction weekly paclitaxel/carboplatin regimens followed by maintenance weekly paclitaxel for advanced and metastatic non-small cell lung cancer. AB - This multi-institutional randomized phase II study was designed to compare the efficacy and toxicity of three different weekly paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin schedules in patients with advanced and metastatic non-small cell lung cancer. The second part of the trial evaluated the role of maintenance weekly paclitaxel for those with response or stable disease after 16 weeks of initial treatment. Patients in arm 1 received paclitaxel 100 mg/m(2)/wk for 3 weeks along with carboplatin (area under the curve of 6) on day 1 every 4 weeks. The treatment in arm 2 was the same as in arm 1 except that carboplatin was also administered weekly (area under the curve of 2) for 3 weeks. Patients in arm 3 received paclitaxel 150 mg/m(2)/wk and carboplatin (area under the curve of 2 per week) during the second 8-week cycle. The total duration of this initial therapy was 16 weeks. All regimens were well tolerated. Arm 1 has the best therapeutic index and will exceed the median survival seen in previous phase III trials with traditional schedules of paclitaxel and carboplatin. PMID- 11605179 TI - The current state of paclitaxel and radiation in the combined-modality therapy of non-small cell lung cancer. AB - The results of randomized trials have prompted an evolution in the treatment approach to inoperable locally advanced non-small cell lung cancer, from radiotherapy alone to sequential chemoradiotherapy and now to concurrent chemoradiotherapy. The improvement in outcome seen with a concurrent chemoradiotherapy approach may be because of spatial cooperation, enhanced radiosensitization, and/or enhanced cytotoxicity. The taxanes, specifically paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), delivered in combination with radiation have been extensively examined in both preclinical and clinical studies. Several mechanisms have been suggested to explain the enhanced tumor cell kill seen with paclitaxel and radiation, and phase II studies have examined this combination in the setting of inoperable stage III non-small cell lung cancer. This review will explore some of the studies with this treatment approach in locally advanced disease. We also will briefly discuss some of the ongoing trials that are attempting to refine the delivery of concurrent thoracic radiation and paclitaxel-based chemotherapy. PMID- 11605180 TI - Adjuvant and neoadjuvant therapy for early stage non-small cell lung cancer. AB - Lung cancer is the number one cause of cancer-related death in both men and women in the United States. Non-small cell lung cancer accounts for approximately 85% of these cases. Despite complete resection, long-term survival for patients with operable disease remains poor. Studies exploring postoperative chemotherapy have not shown improved survival. Preoperative chemotherapy has shown promise in stage III disease and is currently under investigation for patients with early stage non-small cell lung cancer. PMID- 11605181 TI - Overview of the role of neoadjuvant chemotherapy for early stage non-small cell lung cancer. AB - Preoperative chemotherapy has been intensively studied in stage IIIA non-small cell lung cancer and, to a lesser extent, in stage IIIB. For a considerable time period, early stage non-small cell lung cancer was dropped from studies. For early investigators, shrinking the tumor size, thus allowing complete resection of initially unresectable tumors, appeared as important as destroying micrometastases. Nevertheless, analysis of relapse patterns shows that preoperative chemotherapy appears to act more on micrometastases than on local control. The first randomized studies of preoperative chemotherapy were conducted only among patients with stage IIIA disease. The French Cooperative Oncology Group presented a large randomized study among 373 stage IB, II, and IIIA patients at the American Society of Clinical Oncology meeting in May 1999. A Cox multivariate analysis showed a protective effect of preoperative chemotherapy, and this effect seemed to preferentially involve patients with early stage disease. Ongoing studies of most US and European oncology groups are including early stage tumors, as in the Southwest Oncology Group trial 9901. The new Intergroupe Francophone de Cancerologie Thoracique also is ready to start a preoperative randomized chemotherapy study in stage I and II non-small cell lung cancer, that will compare two different strategies of preoperative chemotherapy in responding patients. Patients will be randomized to two groups: one group will receive chemotherapy before surgery and the other group will receive it before and after surgery. PMID- 11605182 TI - Predicting response to paclitaxel/carboplatin-based therapy in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is a systemic illness. The majority of newly diagnosed patients depend on systemic chemotherapy to improve outcome. Among the new chemotherapeutic agents recently tested, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown convincing single-agent activity in advanced NSCLC. The two initial phase II studies using paclitaxel alone showed a 1-year survival rate of 40%, comparable to that seen with combination regimens. Paclitaxel/carboplatin is one of several standard regimens for patients with stage IIIB to IV disease. It is as effective as any other new agent/platinum combination studied to date; it is easy to administer and well tolerated. Identification of the molecular and genetic events involved in each step of tumor progression seems to be crucial both to understanding lung cancer and for the development of new pharmacologic compounds that target specific cellular processes affecting growth and proliferation. An innovative strategy is to combine established chemotherapy with these new compounds. Resistance to available chemotherapy drugs is the major obstacle to effective chemotherapy. Genetic abnormalities could play a role in outlining some patterns of chemoresistance. Acquired resistance to paclitaxel can be mediated by several mechanisms, including overexpression of p-glycoprotein, altered expression of beta-tubulin isotypes, intrinsic or acquired mutations in beta-tubulin, and expression of novel genes. Beta-tubulin mutations were recently identified in 33% of 49 NSCLC patients, none of whom had an objective response to paclitaxel treatment. Cisplatin resistance is associated with several molecular alterations, including overexpression of metallothionein and the mRNA level of the excision repair cross-complementing (ERCC1) gene. Early detection of circulating cancer cells in peripheral blood would enable more accurate lung cancer staging. Furthermore, sequential measurements of DNA concentration may be used to monitor the effects of therapy. Serum DNA can be used as a surrogate for detecting genetic abnormalities and as a potential guide for customizing treatment. We analyzed the presence of beta-tubulin mutations in serum DNA from NSCLC patients and from healthy individuals. Beta-tubulin mutations were detected in 42% of the 131 patients and in none of the control group. Several clinical studies are proposed to develop more customized approaches in lung cancer. PMID- 11605183 TI - Novel approaches for the treatment of non-small cell lung cancer. AB - Non-small cell lung cancer is a major worldwide health problem. Approximately 80% of non-small cell lung cancer patients present with advanced disease for which there is little or no chance of cure. Although survival in stage IV non-small cell lung cancer patients is prolonged by treatment with combination chemotherapy regimens, all of these patients develop disease that is refractory to currently available systemic therapy. Basic scientists have identified a number of new therapeutic targets that offer the potential for novel therapeutic interventions, which might control chemotherapy-refractory disease or potentiate the effectiveness of chemotherapy and radiation therapy. The new targets include tumor-associated angiogenesis, biochemical pathways that stimulate tumor proliferation, and programmed cell death (apoptosis). Each of these novel targets will be discussed briefly in this review. PMID- 11605184 TI - Gene therapy approaches for the management of non-small cell lung cancer. AB - Targeting the specific genetic lesions responsible for carcinogenesis and cancer progression is an attractive strategy for developing more effective anticancer therapies and reducing treatment-related toxicity. The restoration of defective tumor suppressor gene pathways by replacement of tumor suppressor genes in cancer cells has been studied in lung cancer. The most extensively studied agent is the wild-type p53 tumor suppressor gene delivered by an adenoviral vector. Clinical trials to date in non-small cell lung cancer and head and neck cancer have consistently shown evidence of gene transduction and expression, mediation of apoptosis, and clinical responses including pathologic complete responses. However, it also is clear that this approach can be improved. Promising avenues for investigation include improved gene delivery systems, induction of bystander effects, and adjuvant use of gene therapy with conventional chemotherapy, radiation therapy, and surgery. However, these strategies will need further refinement to succeed clinically. This review examines several important issues in cancer gene therapy in general and the most recent achievements in gene therapy for non-small cell lung cancer. PMID- 11605185 TI - [Studies of anti-cytomegalovirus IgG antibody positive rate and cytomegalovirus mononucleosis in adults]. AB - We analyzed anti-Cytomegalovirus (CMV) IgG and IgM antibody (EIA) and anti Epstein-Barr virus (EBV) viral capsid antigen (VCA) IgG and IgM antibody (FA) in adults during 1994-1999. We examined these IgM sero-positive patient's medical records, and diagnosed CMV mononucleosis and EBV mononucleosis. Anti-CMV antibody positive rates decreased from 87.6% in 1994 to 77.8% in 1999. Especially in twenties, anti-CMV antibody positive rates decreased from 65.2% in 1994 to 53.3% in 1999. On the other hand, anti-EBV VCA antibody positive rates were not changed (91-94%). Number of cases of CMV mononucleosis increased from 2 cases in 1994 to 16 cases in 1999, but EBV mononucleosis was not changed. These results suggested that increasing cases of CMV mononucleosis was influenced by decreasing anti-CMV antibody positive rate. PMID- 11605186 TI - [A clinical study on patients detected Pasteurella multocida from sputum]. AB - We reported ten cases, (four female and six male), whose sputum cultures positive for Pasteurella multocida from 1990 to 2000. In the past eleven years increasing numbers of cases have appeared in our hospital. The majority of the cases with P. multocida possessed some underlying pulmonary diseases (seven cases, 70%), inactive lung tuberculosis or bronchiectasis. There were compromised hosts such as high ages person, steroids dependent person and diabetes mellitus patients. P. multocida was almost susceptible to antibioticus (penicillin and cephalosporins), although some erythromycin resistant strains were identified. The cats' oral cavities in our two cases were cultured and P. multocida were isolated. In our survey the prevalence of this organism is as high as 85% in cats. Our data suggests that patients who are in the high infection risk category are easily infected to P. multocida. PMID- 11605187 TI - [Increasing fluoroquinolone low-sensitivity in enterotoxigenic Escherichia coli isolated from diarrhea of overseas travelers in Tokyo]. AB - Drug resistance trends were investigated for 1,318 enterotoxigenic Escherichia coli (ETEC) isolated from overseas traveler's diarrheal cases in Tokyo during 1988-1999. A total of 1.6% (21 strains) were nalidixic-acid resistant and fluoroquinolones (NFLX, OFLX, CPFX, LVFX, TFLX, SPFX; FQ) low-sensitive (or low level-resistant). None of the strains were high-level-resistant to FQ. The FQ low sensitive strains were isolated in 1996 for the first time, and increased from 3.4% in 1996 to 15.8% in 1999. Countries visited by travelers with the FQ low sensitive ETEC were India (16 cases), Nepal (3 cases), Cambodia (1 case), and Egypt (1 case). Drug resistance-patterns of the FQ low-sensitive strains, including other drugs (CP, TC, SM, KM, ABPC, ST, NA, and FOM) tested, varied among the 6 types. Among those, multidrug resistant strains accounted for 57.1% (12 strains). The enterotoxin producing types of strains were LT (4 strains), ST (10 strains), and both (7 strains). The serotypes of the strains were classified into 16 types. The quinolone resistance determining regions (QRDRs) of the gyrA genes of the FQ low-sensitive strains were sequenced. The mutations of a Ser to a Leu at position 83 (Ser-83-->Leu) was found in 19 strains, and Asp-87-->Tyr was found in 2 strains. PMID- 11605188 TI - [Evaluation of immunochromatography method for rapid detection of influenza A and B viruses]. AB - We have evaluated a new rapid detection kit for influenza A and B viruses, known as the QuickVue Influenza test (Quidel Coporation, USA); which is based on immunochromatography using virus isolates and clinical specimens. Twelve strains of influenza A and B were tested for evaluate the reactivity and detection limits of this test. The QuickVue Influenza test showed a positive result for all twelve strains of influenza virus and a negative result for fourteen different kinds of other respiratory viruses. The detection limits for six strains were 5 to 30 pfu/ml for a cell culture, 1.0 x 10(3) to 6.0 x 10(4) pfu/ml for 1st PCR, 1 to 50 pfu/ml for nested PCR, 3.0 x 10(5) to 6.0 x 10(5) pfu/ml for the QuickVue Influenza test, 1.5 x 10(5) to 1.0 x 10(6) pfu/ml for the Directigen Flu A, and 7.5 x 10(5) to 5.0 x 10(6) pfu/ml for the FLU OIA. Furthermore, the QuickVue Influenza test were clinically evaluated using 92 throat swab specimens collected from patients with influenza-like illnesses. By cell culture, influenza viruses were detected in 49 of the 92 specimens (AH1N1: 20, AH3N2: 7, B: 22); the titers of the influenza viruses were between 2.5 pfu/ml and 7.0 x 10(5) pfu/ml. Compared to cell culture, the QuickVue Influenza test showed a sensitivity of 75.5%, a specificity of 93.0%, a positive predictive value of 92.5%, a negative predictive value of 76.9%, and an efficiency value of 83.7%. On the other hand, influenza viruses were detected in 54 of the 92 specimens (AH1N1: 19, AH 3N2: 10, B: 25) by RT-PCR. Compared to RT-PCR, the QuickVue Influenza test showed a sensitivity of 72.2%, a specificity of 97.4%, a positive predictive value of 97.5%, a negative predictive value of 71.2%, and an efficiency value of 82.6%. Overall, only one throat swab specimen produced a false positive result using the QuickVue Influenza test; thus, this test appears to have a high specificity. We conclude that the QuickVue Influenza test is a simple one-step test with a sensitivity and specificity equivalent to those of other conventional diagnostic kits. The test is useful and suitable for the diagnosis of influenza and for identifying influenza patients requiring antiviral therapy. PMID- 11605189 TI - [Patient assessment for zanamivir therapy--a survey of patients with influenza who were prescribed zanamivir during the 2000/2001 season in Japan]. AB - Patients clinically diagnosed as influenza who were prescribed zanamivir were surveyed from December 2000 to March 2001 in Japan. A total of 723 survey questionnaires were returned. Following the first zanamivir treatment, symptom relief was reported by 34.9% of the patients within 12 hours, 63.1% within 24 hours and 85.7% within 48 hours. 46.1% of the patients resumed normal activities within 48 hours and 78.0% within 72 hours. 98.8% of the patients reported that the Diskhaler could be used as instructed by the doctor or pharmacist and 92.5% found the device easy or very easy to use. 70.8% of the patients were satisfied or very satisfied with zanamivir, and 89.0% of the patients would recommend zanamivir to a friend. These results showed that 1) the effect of zanamivir started very fast, especially for the vaccinated patients where the effect was more rapid, 2) most of the patients managed to use the diskher properly and felt "very easy to use" or "easy to use", 3) there is no difference of efficacy in spite of with/without underlying disease, and the diskhaer was well accepted by pediatric and elderly patients. PMID- 11605190 TI - [Two patients with Bartonella henselae infection from a dog]. AB - Two patients were reported as having been infected with Bartonella henselae after having contact with a dog. Both of the patients owned a dog, but had no contact with cats. One patient was a 10-year-old boy who had experienced a fever of 38-39 degrees C for 11 days, as well as having bilateral cervical lymphadenopathy. The boy's serum IgM antibodies to B. henselae were negative on the 6th and 16th day of his illness, whereas his IgG value, using indirect fluorescence antibody (IFA) method, was found to be elevated from 1:256 to 1:1,024. B. henselae DNA was detected, by PCR method, in swabs from the gingiva and buccal membrane of the dog with which the boy had been in contact. The boy was first treated with cefdinir (300 mg daily) for 6 days without beneficial effect. He responded, however, to minocycline (100 mg daily) with symptom resolution in four days. The other patient was a 64-year-old man who had experienced a fever of 38-39 degrees C for 27 days, as well as having right inguinal lymphadenopathy. The man's serum IgM antibody to B. henselae was negative, although his IgG value, determined by IFA, was 1:1,024. In addition, B. henselae DNA was detected, by PCR method, in parafin embedded tissue obtained from the biopsied inguinal lymph nodes. The man was treated with cefazolin (2 g daily). His fever resolved, but his lymph nodes remained swollen. After a regimen of erythromycin (1,200 mg daily), the swelling in his inguinal lymphnodes gradually disappeared. Careful review of suspected CSD victims' history of contact with animals is important in making a prompt diagnosis of B. henselae infection. PMID- 11605191 TI - A patient with Japanese spotted fever complicated by meningoencephalitis. PMID- 11605192 TI - [Multidrug-resistant and fluoroquinolone-resistant Salmonella enterica serotype Typhimurium definitive phage type 12 isolated from infantile diarrhea]. AB - A 35-day-old male infant was admitted to our hospital, presenting a high fever, vomiting, and diarrhea. Multidrug-resistant and fluoroquinolon-resistant Salmonella serotype Typhimurium was isolated from his stool. The phage type of the strain was DT12. The strain was resistant to ampicillin, streptomycin, gentamicin, tetracycline, chloramphenicol, sulfamethoxazole-trimethoprim, and fluoroquinolones (levofloxacin; MIC 8 micrograms/ml, norfloxacin; 24 micrograms/ml, ciprofloxacin; 16 micrograms/ml, sparfloxacin; 32 micrograms/ml). He was cured by antibiotic therapy using fosfomycin (< or = 1 microgram/ml). We could not determine a route of infection. Domestic surveillance for fluoroquinolon-resistant Sallmonella is necessary. PMID- 11605193 TI - [Gonococcal abscess in the prepuce: a case report]. AB - We reported a case of gonococcal abscess in the prepuce not accompanied with urethritis. As initial therapy fluoroquinolone was ineffective, the abscess spread to the subcutaneous tissue around the penile root. After intravenous administration of cefodizime, the clinical symptoms improved, and Neisseria gonorrhoeae was eradicated. PMID- 11605194 TI - [A case of falciparum malaria successfully treated with intravenous artesunate]. AB - The case was a 47-year-old Nigerian male who was thought to have contracted malaria in Nigeria and then manifested fever with chill, arthralgia and diarrhea in Japan. The blood test at International Medical Center of Japan revealed thrombocytopenia and anemia. Ring forms of 0.03% of his RBCs and ICT Malaria P.f/P.v test was also positive for Plasmodium falciparum. We prescribed mefloquine to him, but the number of the paresites in his peripheral blood did not decrease, and, in fact, they came to increase (maximum 6.66%) 20 hours after the drug treatment. As clinical condition of malaria were liable to change seriously, intravenous Artesunate (a qinghaosu derivative) was decided to be given additionally to the patient. Consequently the parasites disappeared in 20 hours from his blood but a low grade fever still continued possibly because of cholecystitis. At the same time of Artesunate treatment, hemoglobinuria started and anemia worsened partly because of his G-6-PD deficiency. All pending problems were improved by the time he left Japan and those parasites were finally found to be susceptible for mefloquine by the in vitro susceptibility test. This is the first reported case of falciparum malaria successfully treated with intravenous Artesunate in Japan. PMID- 11605195 TI - [Cell differentiation and chondroid formation in salivary pleomorphic adenomas]. PMID- 11605196 TI - [The problem of dental treatment related to dental materials]. PMID- 11605197 TI - [A clinical investigation of oro-maxillary sinus-perforation due to tooth extraction]. AB - Oro-maxillary sinus perforation occurs occasionally at the extraction of a maxillary tooth, and it may be a cause of maxillary sinusitis or antro-oral fistula. Our purpose was to investigate the most frequent site of perforation, and to understand the clinical course of patients after perforation. We examined 2,038 maxillary teeth extracted from 1,337 patients (473 males and 864 females) at the First Department of Oral and Maxillofacial Surgery, Tokyo Medical and Dental University, from January 1991 to December 1993. Perforation occurred in 77 of all 2,038 teeth (3.8%). Of these, 38 teeth were from males (38/733; 5.2%), and 39 were from females (39/1,305; 3.0%). The perforation rate was significantly higher in males. Perforation occurred most often with extraction of an upper first molar, and in the third decade of life. The perforation rate gradually decreased with higher age. We classified 38 cases into 3 categories according to panorama X-P: 1) The tip of the root crossed over the bottom line of the maxillary sinus (29 cases), 2) Not crossed over distinctly (4 cases), 3) Just lie on, or whether the tip of the root crossed over the bottom line of the maxillary sinus was not distinct (5 cases). As to treatment, 30 perforations (39.0%) closed spontaneously in the course of observation, irrigation with physiological saline was used in 43 cases (55.8%), radical sinusotomy accompanied by closure of the perforation was performed in 4 cases, and only flap closure was used in 7 cases. There were no cases of relapse. PMID- 11605198 TI - [A clinical and physiological evaluation of prosthodontic treatment by removable partial dentures with free-end saddles--a 3.5-year follow-up study]. AB - The aim of this study was to evaluate the longitudinal clinical and physiological changes in jaw elevator muscle activity of partially edentulous patients, for approximately 3.5 years after treatment by removable partial dentures with free end saddles. Seven patients (4 males and 3 females, aged 38-68 years) who visited a university dental hospital, and were found to have no signs and symptoms of TMJ disorders, participated in the follow-up study. The functional impression method with wax was used in the treatment process of these patients. At the follow-up times of 0.5, 1, 2, 3, and 3.5 years after denture deriverly, EMG activities using bipolar surface electrodes were recorded from masseter and anterior temporal muscle on both sides during maximal voluntary clenching and tapping, and at the same time the maximal bite force was also recorded using the Dental Prescale System. The integrated EMG, the correlation coefficient between muscle activities of both sides, bite force, and the location of the occlusal load center, were analyzed using repeated measured ANOVA. A comparison between each measuring session was carried out using Bonferroni's method. Results were as follows: i) The muscle function of partially edentulous patients was clearly activated by wearing a removable partial denture, and the activation was kept at the same level until 3.5 years after denture deriverly. ii) The activation of jaw elevator muscles by wearing a denture was greater in masseter muscle than in anterior temporal muscle. This finding reflected the effect of the recovered occlusal contact. iii) The occlusal load center of the recovered dentition by a removable partial denture shifted antero-posteriorly close to the end abutment teeth. PMID- 11605199 TI - [Aging society and an adult guardianship system]. AB - Prior to recent revisions, civil law had established a system of interdict and quasi-incompetency. This system was begun in 1898 and, up until the revisions of April 2000, it had spanned more than one hundred years without undergoing any major changes. Statistically, there was a steady increase in the number of pronouncements and retractions of incompetency in recent years. A 1980 survey showed that people in their 40s were the most common, and that the proportions of psychiatric disorder, mental retardation, and dementia were of nearly the same level. A 1996 survey, in contrast, showed a greater proportion of elderly, with about half of cases being dementia or a vegetative state. The new adult guardianship system currently in place, as well as a voluntary guardianship system (enduring power of attorney), was established together with the change from the interdict/quasi-incompetency system to a system of assistance, curatorship, and guardianship. The care insurance system that was put in effect at the same time shifted from an enforcement system to a contract system, so the judgment ability of the person at the time of the decision to enter the contract has become an issue. Finally, in dealing with people with dementia, especially mild dementia, problems arise as to the best method of informed consent, including notifying people of their specific disease, and who should decide the treatment for incompetent people with dementia. PMID- 11605200 TI - [Tauopathy]. PMID- 11605201 TI - [Geriatric diseases and advanced medicine]. PMID- 11605202 TI - [Treatment of dysphagia in elderly patients]. PMID- 11605203 TI - [Risk factors for ADL dependency in community-dwelling elderly]. PMID- 11605204 TI - [Molecular pathogenesis of Alzheimer's disease]. PMID- 11605205 TI - [The diagnosis, management, and prevention of pulmonary diseases in the elderly]. PMID- 11605206 TI - [Acute stroke management in elderly patients. The present and future]. PMID- 11605207 TI - [Treatment of ischemic heart disease in the elderly]. PMID- 11605208 TI - [Treatment for elderly hypertension]. PMID- 11605209 TI - [Epidemiology of cardiovascular disease in Japanese]. PMID- 11605210 TI - [Future direction for the study of elder diabetic patients]. PMID- 11605211 TI - [Relative hypotension in the elderly hypertension]. PMID- 11605212 TI - [Hypertension and vascular remodeling]. PMID- 11605213 TI - [Compliance and knowledge about prescribed medication among elderly home-care recipients by method of providing medications]. AB - After long-term care insurance commenced in April 2000, various types of in-home care began, including delivery of prescriptions medicines to the elderly. However, the effects of in-home care workers on patient drug compliance are unclear as yet. In this study, we examined the characteristics of the care workers who delivered prescription medicines to the elderly, and analyzed the effects on patient drug compliance and knowledge about medication. The subjects included 163 homecare recipients aged 60 and older, who were taking more than one prescribed drug, who ranked worse than J-2 who were physically disabled, and cognitively normal. The rate of good compliance was 71.1% when pharmacists provided the prescribed drugs and counseled the patients at home, which rate was significantly higher than that of self-supply by the patient (35.0%), caregiver supply (44.7%), and home-helper supply (0.0%). The difference in compliance may be explained by the possibility that when caregivers and home-helpers provided prescribed medications, thorough and accurate information about the drugs were not clearly imparted to the elderly, whereas when pharmacists provided prescribed medications, a pharmacological examination was performed and thorough and accurate information was communicated to the elderly. In the group counseled by pharmacists, knowledge about the effects and purpose of medication positively correlated with drug compliance. However, in the group provided drugs by caregivers, knowledge about the effects and purpose of medication inversely correlated with drug compliance. These findings suggested that the elderly in the latter group chose, to some degree, not to comply. Many elderly people had difficulty getting to hospital, and 23.1% of the patients in this study had not consulted the doctor for more than 2 months. Our data suggest that drugs provided by pharmacists and the availability of pharmacist counseling play an important role in preventing drug noncompliance and in making home care more effective, and also suggest that it is important for pharmacists to cooperate with other care workers, including a care-manager, and to provide written information on prescription medicine to caregivers and home-helpers as well as to elderly patients. PMID- 11605214 TI - [Findings of bedside swallowing assessment and brain computerized tomography in patients with chronic cerebral infarction, and their outcome]. AB - To estimate the usefulness of the bedside swallowing assessment proposed by Smithard et al and neuroimaging findings characteristic for dysphagia, we studied the outcome of 102 patients with chronic cerebral infarction after assessment of swallowing by this test with brain computerized tomography (CT). All patients had a variety of motor disturbance and were admitted on a long-term medicare basis. They were divided into two groups according to the findings: the positive group (n = 33), who showed any of the listed types of difficulty in swallowing water, and the negative group (n = 69). Followed up to 2.2 years, their outcomes were studied. CT findings were studied on type of infarction, number and laterality of infarction, grade of periventricular lucency (PVL), presence of ventricular dilatation (VD), and severity of cortical atrophy (CA). The mean age was 76.4 years at registration and 61 were men. The frequency of severe dementia and disturbed ADL were significantly higher in the positive group. Eighteen patients died during the observation period and 15 of those were in the positive group, indicating higher annual death rate (29.9% vs 2.2% in the negative group). All of the 15 patients in the positive group died of pneumonia. CT findings showed high incidence of multiple infarction, bilateral hemispheric lesion, severe PVL, VD, and severe CA in the positive group. These findings indicated that this evaluation method was useful in screening swallow function for patients with cerebral infarction in the chronic phase. Furthermore, CT findings suggested that severe white matter lesion, VD, and severe CA as well as multiple infarction seen in bilateral hemisphere was related to dysphagia, probably due to multiple factors involving pyramidal- and extrapyramidal-tracts with higher brain function. PMID- 11605215 TI - [Evaluation of animal-assisted therapy for the elderly with senile dementia in a day care program]. AB - We conducted animal-assisted therapy (AAT) for the elderly with senile dementia in a day care center. AAT was performed between July 27 and October 12, 1999 for a total of six biweekly sessions. The AAT group consisted of 7 subjects; 5 with senile dementia of Alzheimer's type (SDAT) and 2 with vascular dementia (VD). The control group was 20 elderly subjects (7 SDAT, 13 VD). The results were as follows: Comparing between MMS scores at the baseline and those three months later, the average score on MMS before AAT (baseline) was 11.43 (+/- 9.00), and that three months later was 12.29 (+/- 9.69). In the AAT group, the average baseline N-ADL score was 28.43 (+/- 14.00) and that after ATT was 29.57 (+/- 14.47). In the AAT group, the average baseline score on Behave-AD was 11.14 (+/- 4.85), and that three months after AAT was 7.29 (+/- 7.11) (p < 0.05). In the control group, the average baseline score was 5.45 (+/- 3.27) and that three month later was 5.63 (+/- 3.59). However, the results of eight subscales of communication behavior three months later were significantly low comparing to those at the baseline in the control group. The evaluation of CgA, which was a mental stress index, showed a decreasing tendency in the AAT group. Our findings suggested we should use several evaluation methods for evaluation of the changes of patients receiving AAT. PMID- 11605216 TI - [A comparison of differences in the outcome (hospitalization and mortality) between two special nursing homes of the same size managed by the same organization]. AB - The purpose of this study was to examine the usefulness of information about outcome in evaluation of the quality of special nursing homes. Two special nursing homes A and B were selected. These two facilities were the same in their service capacity and are also owned as well as managed by the same organization. There were no differences in the structural elements between the two facilities. The hospitalization and mortality rate of the two facilities were compared. There were no significant differences in terms of the distribution of the characteristics of the residents between facility A and B at the time of their admission. However, the average survival time of the persons who died was significantly shorter in facility B than that in facility A. (A facility = 1,165 days, B facility = 831 days; p < 0.05). There were significant differences in cumulative survival and non-hospitalization rate of residents in the two facilities (p < 0.05). The differences were seen even after controlling for the prognostic factors by Cox's proportional hazard model (hazard rate: mortality = 1.562, hospitalization = 2.526, p < 0.01). Furthermore, the proportion of residents hospitalized right after their first visit to the hospital was significantly higher in facility B than that in facility A (A = 9.6%, B = 19.3%; p < 0.05). Also, the mortality risk of hospitalized persons was significantly higher than non-hospitalized persons in facility B (p < 0.05), although there was no significant difference in terms of the mortality risk between the two groups in facility A. Because the differences in the cumulative survival and non hospitalization rate could occur in the facilities that are similar in institutional structures, it suggests that these outcomes are indicators of the quality of special nursing homes. It would be, therefore, important to collect the information about outcome including cumulative survival and non hospitalization rate of the residents in order to evaluate the quality of special nursing homes. PMID- 11605217 TI - [Structural quantification of bone from radiographs using power spectral analysis]. AB - Bone mineral density (BMD) and bone structure are very important indices for prevention of fracture. However, it is very difficult to quantify bone structure, and only a few indices for structural quantification of bone have been reported. The purpose of this research was to investigate a new index for bone structure. The subjects were 52 women aged from 20 to 85 years. Directivity index (DI) is a new index of bone structure calculated by directivity of power spectrum from radiographs of metacarpal bone using fast Fourier transform (FFT). DI was obtained by subtracting the integral power value at 0 and 90 degree directions on the x-y plane of the two-dimensional power spectrum of bone from the integral power value at a direction of 45 degrees. A significant relationship between BMD and DI was indicated by correlation coefficient. However, no significant relationship between BMD and the first moment of the Fourier power spectrum or the fractal dimension was found. There is a possibility that DI estimates a slight deformation of bone structure. In the future, we will apply DI to the prevention of fractures and osteoarthritis. PMID- 11605218 TI - [A case of malignant lymphoma concomitant with multiple myeloma]. AB - A 75-year-old woman was referred to us because of cough, high fever and skin erythema in April 1999. Malignant lymphoma (diffuse mixed cell type) was previously diagnosed in 1990 and she achieved complete remission after treatment with a series of CHOP regimen treatments. In 1998, multiple myeloma (IgG lambda type) was diagnosed and she was treated with a combination of melphalan and prednisolone. On physical examination, superficial lymphadenopathy and skin erythema were noted. Biclonal gammopathy (IgG kappa/lambda) was shown in serum, and Bence Jones protein in urine. Computed tomography showed pleural effusion and swelling of paraaortic lymph nodes. The bone marrow examination showed an increased number of abnormal plasma cells (19.2%) and no evidence of lymphoma. Left axillary lymph node biopsy revealed that she had non-Hodgkin's lymphoma (immunoblastic lymphadenopathy-like T cell lymphoma). She was treated with the CHOP regimen at reduced doses for both diseases. The lymphoadenopathy reduced after 6 courses of CHOP and 4 courses of CHOPE (CHOP + VP16), however, she had bone pain on November 1999 and received treatment with MCNU-VMP (MCNU + VDS + L PAM + PSL). Her rib pain improved, but she died of systemic infection of herpes zoster virus. We report here a rare case of malignant lymphoma concomitant with multiple myeloma. PMID- 11605219 TI - [Successful non-surgical treatment of acute coronary syndrome involving the left main coronary trunk in four elderly patients]. AB - We encountered 4 patients aged over 80 with acute coronary syndrome involving the left main coronary trunk (LMT) who obtained a successful outcome by non-surgical management. CASE 1: An 80-year-old women suffered acute myocardial infarction. A coronary stent was placed at the orifice of the LMT for dilatation of severe 90% stenosis. Cardiac function was markedly improved after treatment during the chronic period. CASE 2: An 81-year-old man who developed non-sustained ventricular tachycardia. Coronary angiography demonstrated severe stenosis with haziness of the LMT. Intra-aortic balloon pumping was performed for one whole day after the attack and the follow-up study performed one month later revealed that the stenosis was markedly diminished to an insignificant grade without residual ischemia. CASE 3: An 81-year-old man developed acute inferior wall infarction with a background of severe triple vessel disease accompanied by an LMT lesion. Coronary stents were placed at three sites, i.e., the right coronary, LMT, and left anterior descending branch. Though initial treatment was successful, this patient died due to severe arrhythmia. Patients in who CABG is strongly indicated due to LMT lesion complicated with multiple organ disorders will increase as the population of the aged continues to increase in Japan. We obtained satisfactory results by intensive intense non-surgical management including PTCA. From our experience, adequate selection of therapeutic regimens for individual patients is important to improve the long-term prognosis as well as the immediate outcome in the acute stage. PMID- 11605220 TI - [A case of sarcoidosis with muscle nodules]. AB - A 65-year-old man with sarcoidosis, accompanied by muscle nodules, noticed a painless and enlarged nodule in his forearm. MRI of the nodule showed that a star shaped area of lower signal intensity was surrounded by an area of higher signal intensity. Histological examination showed granulomas composed of multinuclear giant cells and epithelioid cells. Sarcoidosis was diagnosed. Eight months later, he was admitted to our hospital because of enlargement of the nodular region with pain and stiffness. Marked uptake of 67Ga was observed in the right arm and leg. MRI revealed sarcoid nodules in these regions. An enlargement of the higher signal intensity area was observed in the right forearm nodule. We started administration of prednisolone. Forty days later, his symptoms had disappeared and the size of higher signal intensity area of the nodule had reduced dramatically. 67Ga scintigram and MRI were useful for diagnosis and monitoring during therapy in this patient. PMID- 11605221 TI - [A case of elderly onset Parkinson's disease complicated by dropped head syndrome]. AB - An 86-year old man presented with a 7-year history of gait disturbance. He was admitted to our hospital on April 2000 because he was experiencing difficulty eating due to progression of dropped head syndrome. Upon standing and sitting, remarkable dropped head and kyphosis were observed. When lying, the patient was able to stretch his neck, and he could stand and walk with the aid of a walker. Rigidity and resting tremor were present predominantly in the lower limbs. Parkinson's disease was diagnosed therefore L-dopa and Cabergoline were administered. Parkinsonism and dropped head syndrome improved in response to treatment. Cases involving dropped head syndrome due to Parkinson's disease are reportedly improved by L-dopa, but exasperated by dopamine agonists. The mechanism of dropped head is thought to be an imbalance in the tonus of the anterior and posterior neck muscles. Dropped head in the present case may have been a complication of Parkinson's disease since it improved in response to L dopa. PMID- 11605222 TI - [A case of severe systemic edema in an elderly hypertensive patient with systemic lupus erythematodes during long-term treatment with anti-hypertensive drugs]. AB - A 71-year-old woman receiving both angiotensin II receptor antagonist and calcium antagonist suffered severe systemic edema. She had been treated for essential hypertension with amlodipine for 2 years and candesartan for 3 months, and systemic lupus erythematodes (SLE) with steroids. During treatment, severe systemic edema appeared, mainly on her face, arms, and legs. At first, we suspected drug-induced edema by candesartan, so it was halted, but the edema still continued. We then considered amlodipine to be the culprit, and finally, the severe systemic edema disappeared after cessation of amlodipine. To control her blood pressure, we recommended candesartan, but 3 months late she suffered severe systemic edema again, thus the causative we drugs of her edema were thought to be both amlodipine and candesartan. Edema is a common symptom in elderly patients and we frequently observe drug-induced edema. In this case, there was underlying acceleration of blood vessel permeability induced by SLE and steroids and moreover, vasodilatation by candesartan and/or amlodipine further accelerated blood vessel permeability, and thus might have caused severe edema. It is very difficult to determine the cause of edema, especially in elderly patients, but we should consider not only one but also two or more drugs as being involved in drug-induced edema. PMID- 11605223 TI - [A case of chronic bromvalerylurea intoxication due to habitual use of commercially available nonsteroidal anti-inflammatory drugs presenting an indefinite hyperchloremia]. AB - A 75-year-old man was admitted to our hospital with disorientation and progression of speech disturbance and gait disturbance. He had been given a diagnosis of cervical spondylosis about four years previously, and gait disturbance and numbness in his extremities have been gradually increasing. Hyperchloremia and a careful history taking, which led to the discovery of habitual use of an analgesic containing bromvalerylurea, suggested bromism. A high level of bromide in serum yielded a diagnosis of bromism. Disorientation and speech disturbance were treated and improved by infusion diuresis. Gait disturbance only partly improved. There is a possibility that not only cervical spondylosis, but also chronic bromvalerylurea intoxication, may have contributed to the neurological disturbance resulting in gait disturbance and numbness. Bromvalerylurea, which is contained in many commercially available analgesics, should be noted as a possible cause of neurological disturbance. PMID- 11605224 TI - [Surgical results of canal wall reconstruction tympanoplasty in middle ear cholesteatoma]. AB - Materials were 236 ears of 213 patients with middle ear cholesteatoma undergoing canal wall reconstruction during 1993-1998. Subjects were followed up for at least 1 year after final operation. Of 236 ears, 147 (62%) underwent 1-stage operation and 89 ears (38%) required 2-stage operation. Hearing results were successful in 157 ears (67%) based on criteria proposed by the Otological Society of Japan. The success in ears undergoing 1-stage operation was 74% and 54% in ears undergoing 2-stage operation. Postoperative hearing and air-bone gap in the 1-stage group were significantly better than in the 2-stage group. For tympanoplasty, success was 97% in type I, 64% in type III, and 53% in type IV. The likelihood of undergoing 2-stage operation increased with the type of tympanoplasty, from type I to IV. Postoperative hearing was significantly worse in older age groups. Of the 89 ears, 13 (15%) had recurrent cholesteatoma and 29 (33%) had residual cholesteatoma at 2-stage operation. In the 135 in the 1-stage group, recurrent cholesteatoma was observed at follow-up in 13 ears (9.6%). When we analyzed clinical risk factors for both recurrent and residual cholesteatoma in age, gender, otorrhea, types of cholesteatoma, and types of tympanoplasty, no significant factors were seen for recurrent or residual cholesteatoma. These results indicate that canal wall reconstruction tympanoplasty for middle ear cholesteatoma yields relatively good hearing results. However, more effort is needed to reduce the incidence of recurrent and residual cholesteatoma. PMID- 11605225 TI - [Evaluation of RI scintiscanning to parotid gland tumors]. AB - We retrospectively evaluated preoperative radioisotope (RI) scintiscans in 275 patients (283 glands) with parotid tumors who undergoing surgery between 1987 and 2000. Technetium-99m-pertechnetate (Tc) scintigraphy was conducted on 201 glands. Oncocytoma and Warthin's tumor showed a high positive rate. In evaluating Warthin's tumor with Tc scintigraphy, sensitivity was 75% and specificity 88%; above the age of 40 years, specificity exceeded 90%. Gallium-67-citrate (Ga) scintigraphy was conducted on 207 glands. Malignant parotid tumors showed high positivity (85%), but the specificity of positive findings was quite low (38%) because 44% of benign pleomorphic adenoma, which occupied major material, showed Ga-positive findings. Ga-negative findings indicated high probability (95%) of benign tumors. Thus, Tc scintigraphy is effective in diagnosing Warthin's tumor, while Ga scintigraphy is effective in diagnosing benign tumors. PMID- 11605227 TI - [Clinical significance of the Streptococcus milleri group in peritonsillar abscesses]. AB - Few researchers have microbiologically studied peritonsillar abscesses in detail, and their results have been conflicting. Although Streptococcus pyogenes (Group A beta-streptococcus) is commonly considered an important pathogen in this infection, recent studies have demonstrated the recovery of many other streptococci mainly consisting of alpha-streptococci. Few studies have identified these streptococci at the species level, however. We studied details of bacteriology in 31 cases of peritonsillar abscess treated between 1991 and 2000. The Streptococcus milleri group was most frequently isolated (25.8%), followed by Eikenella corrodens (9.7%), Staphylococcus aureus (6.5%), and S. pyogenes (3.2%). The S. milleri group, consisting of 3 species of Streptococcus constellatus, S. intermedius, and S. anginosus, forms part of the normal flora most commonly found in the mouth, throat, gastrointestinal tract, and genital tract. These species have become known as an important pathogen in abscess disease but little attention has been paid to their role in peritonsillar abscesses. To adequately culture the S. milleri group, incubation in air containing carbon dioxide or in an anaerobic condition is required, and then the differentiation of the 3 species requires the biochemical reactivity tests. Since hemolytic patterns of the S. milleri group vary, we studied the population of alpha-, beta-, and gamma hemolytic strains among 36 strains of this group. We found 32 (88.8%) to be alpha hemolytic. Although not all alpha-hemolytic strains belong to the S. milleri group, a considerable number of this group could be missed among alpha streptococci isolated from the peritonsillar abscess. As antibiotics began being used widely, normal flora such as the S. milleri group may have become an important pathogen in peritonsillar abscesses due to an imbalance between organisms and host defense. PMID- 11605226 TI - [Clinical analysis of 16 cases of malignant head and neck melanoma]. AB - Subjects were 16 patients--5 men and 11 women aged 46-82 years (mean: 61 years)- with malignant melanoma of the head and neck treated at our clinic from 1972 to 1988. Histologically, 1 subjects was amelanotic and 15 melanotic type. Primary lesions were 10 involving the nasal cavity, 2 the paranasal sinus, 2 the gingiva, 1 the lip, and 1 primary unknown. They were treated with or without multimodal surgery, radiation, chemotherapy, and immunotherapy. Of 12 treated using local surgery, local recurrence was seen in 6 in 7 areas. Two-year survival was 44% and 5-year survival 22%. The prognosis of malignant head and neck melanoma is poor but has gradually improved due to preoperative decisions on disease spread and the introduction of multimodal therapy. PMID- 11605228 TI - [CT screening of vertebrarterial circulatory disorder]. AB - The frequency of MR angiography (MRA) used to diagnose vertebrobasilar insufficiency appears high. Findings of abnormality by MRA show cases with maldescription of hemivertebral artery. In such cases, it is unclear whether these are due to anaplasia of the vertebral artery or to the existence of morbid constriction, thus requiring confirmation by a vertebral arteriography (VAG). We observe the vascular morphology of vertebral artery by Computed tomography (CT) scanning for screening circulatory disorders. In photography and CT scan reading, the region was severally photographed between foramen magnum and aortic arch by plain CT and contrast CT at a slice of 5 mm. The constrictive region of the vertebral artery was estimated by comparing plain and contrast CT. Subjects were 34 clinical cases of vascular maldescription in the vertebrobasilar artery, nearly no blood vessel description, or blood vessel winding or inclination. We determined the constrictive morbid state of the vertebral or subclavian artery and cervical vertebra deformity. In findings of maldescription by MRA, it was suggested that discrimination is feasible to a certain degree, whether the vertebral artery has a morbid constrictive region or due to anaplasia. Our results suggest that screening by CT scanning may be more efficient than that by MRA. PMID- 11605229 TI - Out of the consulting room and into the world: hermeneutic dialogue, phronesis, and psychoanalytic theory as practice. AB - One of the relics of positivism has been an underappreciation of the moral and ethical dimensions of psychoanalytic theory and practice. In a positivist metapsychology, cure and therapeutic gain were often defined instrumentally, with relatively little consideration given to aspects of human experience (e.g., moral, cultural, spiritual) that did not fit within a positivist framework. Conceptual and paradigmatic shifts in psychoanalysis have occurred, in part, because of the inability of the classical model to provide a language that adequately captures deeply felt human values and beliefs. Aided by hermeneutic and postmodern influences, many contemporary psychoanalytic theories are beginning to focus greater attention on the notion that analytic therapy is empowered by a set of ethical convictions, beliefs, and commitments, which are tied to a certain understanding of the good life. Along these lines, the author argues that developing a fresh understanding of the moral and ethical dimensions of psychoanalysis requires elaborating a new ontology of human subjectivity and social life. The author offers a sketch of how this gargantuan task might be started by integrating psychoanalysis within a hermeneutic perspective on dialogue, by suggesting that it would be helpful to view psychoanalysis as promoting Aristotelian practical wisdom or phronesis, and by rethinking psychoanalytic theory and interpretation as a form of practice. PMID- 11605230 TI - Auto-sensuous shapes: prototypes for creative forms. AB - The author looks at some of the more normative, adaptive, and creative aspects of what have been called 'autistic' or 'auto-sensuous' shapes by Tustin and others. She explores the construct from several frameworks, including the literature on early sensory experience and that on the empathic attunement between infant and caretaker in which interpersonal rhythms and meanings are built. The views of Bion and Matte-Blanco are utilized to help explore the processes by which meaning is created from experience, while the works of Segal and Milner are used to focus more explicitly on the role of symbol formation in the creative process. Finally, it is suggested that these auto-sensuous shapes can become prototypes for creative endeavours, including the creative process we call psychoanalysis. The author uses examples from her own experience in deriving pattern from basic sensory experience, toward the creation of poetry, drawings, and the establishment of attunement and 'meaning-making' within the analytic setting. PMID- 11605231 TI - Subject in first person--subject in third person: subject, subjectivity, and intersubjectivity. AB - In this article, the author traces the history of the concepts of subject, subjectivity, and intersubjectivity in different psychoanalytic theories in the last decades. She argues that the uniqueness of these concepts and their different implications were not emphasized enough. The author discusses the various implications and contexts of the concept of subject in psychoanalytic theory proper and to relate as to: (1). The need to distinguish between the concepts of subject and subjectivity; (2). The mutual interdependence of the subject and his subjectivity and the intersubjective domain (both in the development of the individual and in theoretical thought pertaining to it). Her point of departure is from the position of the subject as a free creature, the centrality of the experiencing individual, from his/her perspective--the subject in the first person. She tries to explain the paradox implicit in the experiential dimension, the place of the other as participant, as both negating and recognizing--the subject in the third person. She suggests the interdependency of the first-person experience of subjectivity on the intersubjective dimension. PMID- 11605232 TI - Ego atrophy in substance abuse: addiction from a socio-cultural perspective. AB - The use of intoxicants is indexed in American history adopting a social perspective of the role of alcoholism in traditional American society. Appealing to societal patterns, the elaboration of substance abuse as a disease is explored with a diagnostic focus on intervention as it relates to pathogenesis. Using clinical vignettes, the ego is proposed as the focus of pathology in the addiction process, featuring a regression to the defenses of projection and denial. Following the model proposed in Zinberg's seminal paper on addiction and ego function, various deficits are annotated that typify such regression. The ultimate clinical picture is one of ego atrophy, where basic interests and object relations are usurped by the all-consuming preoccupation with the substance of abuse. PMID- 11605233 TI - [On control of radioactive-chemical protection and point mutations by inhibitors of free radical reactions]. AB - An opportunity to control the DNA protection against radiation in cells and the formation of 2-desoxyribose residue epimers (sites of potential point mutations) by using a set of free radical scavengers differing by parameters of availability (molecular mask and access window) is discussed. The values of steric probability (efficiency) of formation of a chemical bond between atoms Cn of a 2 desoxyribosyl radical (n from 1 to 5) and H-atom of a scavenger donor group were determined. It was shown that the maximum effect of radioprotection determined, for example, by transformations of C2 radical reached 25% (4-oxy-3,5-di-tert butyl-alpha-methylbenzylamine) and maximum yield of C4-epimer was 15.5% (L cysteine). PMID- 11605234 TI - [Comparative study of RBE of densely ionizing radiation for various types of cell death in yeast]. AB - A comparative study of the relative biological effectiveness (RBE) of alpha particles 249Pu for reproductive and interphase forms of killing of haploid and diploid yeast cells of wild-type and their radiosensitive mutants has been carried out. The correlation between the RBE of alpha-particles and cell repair capacity was confirmed for reproductive death: it was the highest for diploid cells, smaller for haploid cells and the smallest for their radiosensitive mutants. To achieve the interphase cell killing much higher irradiation doses were used after which cells were incapable of liquid-holding recovery during the storing of exposed cells in non-nutrient media at 30 degrees C. The RBE values for this form of killing were significantly lower in comparison with reproductive death. These data are an additional argument supporting the point of view that the RBE of densely ionizing radiation is determined not merely by physical processes of energy absorption as it is traditionally believed but also by ability of cells to recover from DNA damages inflicted by ionizing radiation. PMID- 11605235 TI - [Apoptosis of peripheral lymphocytes of healthy donors and patients with laryngeal neoplasms after gamma-irradiation in vitro]. AB - Apoptosis in peripheral blood lymphocytes of healthy donors and cancer patients after gamma-irradiation with different doses was studied by the flow cytometry method. Wide intra- and interindividual variabilities of the lymphocyte radiosensitivity were observed. The radiosensitivity did not depend on the subpopulation composition of the lymphocyte pool. The persons with very low and high lymphocyte radiosensitivities were found significantly more often among the cancer patients than among the healthy donors. One can suggest that this method is useful as a biomarker of future cancer risk and prognosis of radiotherapy efficiency. PMID- 11605236 TI - [The status of ovary capillaries in fetuses of White rats after irradiation in various periods of its embryogenesis ]. AB - The peculiarities of reactions of blood capillaries and their cell structures in the ovary of 20-days old foetus to the irradiation in embryogenesis were revealed; it was shown for the first time that the character and direction of changes in principal morphofunctional parameters depended on the dosage, power of gamma-irradiation and the age of the developing organism by the exposure moment. PMID- 11605237 TI - [Parameters of proliferative activity of hematopoietic cells in mice protected from irradiation by indralin in combination with Zn-metallothionein]. AB - One day after the irradiation (dose 6 Gy) of mice protected by the injection of Zn-metallothionein (Zn-MT) in doze 8.6 mg/kg, 10-20 min before irradiation, then alpha-adrenomimetic indraline (150 mg/kg) 5-10 min before irradiation the increase in nucleic cell number, [3H] thymidine incorporation, and antioxidant activity in bone marrow in comparison with the control and indraline per se was revealed. In mice protected according to the scheme: Zn-MT in the same doze, then indraline (100 mg/kg) one day after, and then in 5-10 min exposure to 6 Gy it was found more than 9 times increase of endogeneous CFC in spleen on 8th day while indraline per se raised CFC number only 4.8 times. It was found that Zn-MT reduce the indraline acute toxicity. The data on radioprotective activity of monomeric and polymeric Zn-MT forms are submitted. PMID- 11605238 TI - [Effect of low doses of low-intensity irradiation on the incidence and progress of spontaneous leukosis in AKR mice]. AB - Development of spontaneous leukosis in AKR mice is accelerated by irradiation with low doses (1.2-2.4 cGy, dose-rate 0.6 cGy/day): the leukoses incidence rate increases, deaths of the animals from leukosis occurs earlier, shortening the average and maximum life-spans of the animals. The dynamics of changes in the mass of organs of the immune systems (thymus and spleen) shown extrema. The moment of reaching the extremum correlates with the maximum rate of animals' deaths. PMID- 11605239 TI - [Dose-effect and time-effect characteristics in process of tumorigenesis under combined action of ionizing radiation and chemical carcinogen]. AB - Studying of dose and time dependences of frequency of adenomas appearing under the combined effect of radiation and urethane ingressed during different terms after irradiation has show that the frequency of tumours is determined both by radiation dose, and the time interval between irradiation and ingressing of cancerogenic substance. The data obtained show the period of preservation of the induced damages and non-linearity of the process of tumour-formation under the combined effect of radiation and toxic factors on the organism. The latter is necessary to be taken into account when forecasting the radiation risk under the real ecological conditions. PMID- 11605240 TI - [The effect of low intensity electromagnetic irradiation on hydration of DNA film]. AB - By using the IR-spectroscopy it has been shown that electromagnetic radiation (frequency 8.15-10.0 GHz, energy flux density 5 microWt/cm2) reduces the rate of water desorption from DNA films. It was found that the irradiation of samples with high humidity did not change spectral characteristics of DNA molecules in the range of 900-4000 cm-1, that means their molecular structure remains intact. At the same time the irradiation changed conformation liability of these biopolymeric molecules, that is their ability of conformational transformations under the influence of outer factors. Drying of non-irradiated humid films induced rapid (for a few minutes) transition of DNA from B to A conformational state, whereas in the irradiated films this transition took several hours after humidity reducing. PMID- 11605241 TI - [Effect of low-frequency pulse-modulated 460 MHz electromagnetic irradiation on Drosophila embryos]. AB - Effect of electromagnetic radiation 460 MHz with 2.5-40 Hz pulse modulation rate on Drosophila embryos of 15 h 10 m age was studied. It was demonstrated that a 5 min irradiation with 0.12 W/kg average SAR (3 W/kg pulsed SAR) alters the Drosophila percentage of interrupted development. The effect strength depended on the modulation rate with a pronounced decrease at 10 and 16 Hz. A hypothesis about the presence of thermal and non-thermal mechanisms of action of pulse modulated microwave radiation diversely effecting the embryos has been put forward and grounded. PMID- 11605242 TI - [Effect of low-intensity electromagnetic fields of industrial frequency on the ultrastructure and proliferative activity of rat's thymus cells]. AB - Effects of two types of low-intensity electromagnetic fields (EMF) of industrial frequency (50 Hz) on the fine structure and proliferative activity of thymic cells in white rats were studied. It was found that a weak EMF with a prevailing electrical component (380-480 V/m, 120-140 nT1) did not affect the DNA synthesis intensity. An EMF with a stronger magnetic induction (10-15 V/m, 800-1500 nT1) diminished the glucose-6-phosphate dehydrogenase activity and proliferative processes in cultured stimulated lymphocytes. Electron microscopic investigation of the thymus after both types of exposure revealed an accumulation of lymphocytes with pyknotic nuclei and electron-dense cytoplasm, as well as hypoplasia of the vascular endothelium. At the same time, EMF with a prevailing magnetic component produced a more marked negative effect on the ultrastructure of thymic cells, which indicated a lowered secretory activity of epitheliocytes. PMID- 11605243 TI - [Aerial contamination of agroecosystems following the accident at the Chernobyl Nuclear plant]. AB - The regularities of the aerial contamination of agricultural ecosystems are described in the early period after the Chernobyl NPP accident. The aerial contamination is shown to be caused by the development of the above-ground biomass of plants and fallout characteristics. A specific coefficient of primary retention varied between 0.46 and 1.2 m2 kg-1 for 137Cs. The first half-life period varies from 9.7 to 13.4 days. The second period varies from 46.2 to 52.2 days. It has been found that parameters of aerial contamination from the Chernobyl accident well correlate with the results of observation in the period of global fallout. PMID- 11605245 TI - [The assessment of the impact of different radon sources into indoor air]. AB - The contributions of different radon sources into total indoor radon level can differ in some times depending on geographical and climatic features of the locality, building characteristics, lifestyle and habits of the population. The revealing of most significant radon sources for examined locality and the assessment of their relative contributions will allow planning expected radon levels during building design stage. The analysis of the factors influencing indoor radon levels and the computation of radon enter to dwellings from different sources were carried out in Tomsk. About 200 dwellings were investigated on the radon presence by solid state track detectors. The results of the comparative analysis of the theoretical and experimental sets are discussed in this paper. PMID- 11605244 TI - [Methodological approach to countermeasure options in rural settlements in the long terms after the accident at the Chernobyl NPP]. AB - A methodological approach for the justification of rational countermeasure options in agricultural production in the long term after the Chernobyl NPP accident is presented. The decrease in the scale of countermeasures in 1993-1996 in the most affected regions has resulted to a rise in internal exposure doses to the population. A need for further application of protective measures in the long term after the Chernobyl NPP accident is estimated. It has been shown that the remediation of some rural settlements should be continued till 2045. PMID- 11605246 TI - [Quantitative evaluation of 90Sr, 137Cs, 239Pu, 241Am transfer from polluted soil to gastric and intestine juice of cows]. AB - Quantitative parameters of 90Sr, 137Cs, 239Pu and 241Am transfer from solid phase of soil to gastric, intestine juice of cows as well as to imitating solutions have been estimated on the base of results of laboratory incubation experiments. A prevailing role of enzyme complex and microflora of gastrointestinal tract in radionuclides transfer from solid phase of soil to solution has been shown. PMID- 11605247 TI - Power to the people? PMID- 11605248 TI - Guidance on aseptic processing practice. PMID- 11605249 TI - Collecting the massive amount of information. PMID- 11605250 TI - Characterization of filter extractables by proton NMR spectroscopy: studies on intact filters with process buffers. AB - Studies were conducted to characterize potential extractables from sterilizing grade filters. The focus of this report is the 0.22 micron Durapore (hydrophilic modified PVDF) filter which is used throughout our recovery processes. The objectives of this study are (1) to identify potential filter extractables from the hydrophilic PVDF filters; (2) to show that NMR spectroscopy may be used to detect filter extractables in the presence of product and excipients; and (3) to establish levels of filter extractables obtained by extraction with a variety of buffers. The data show that the primary source of filter extractables is the hydrophilic modification of the PVDF membrane surface. Extractables from the modified hydrophilic PVDF filter include propylene glycol (PG) and soluble oligomers of the hydroxypropyl acrylate and cross-linker. Propylene glycol, arising from the hydrolysis of the hydroxypropyl acrylate, appears to be the primary extractable in buffers above pH 11. Since the 1H-NMR method can easily detect the methyl proton signals of PG, an NMR assay was developed to detect PG in the presence of buffer excipients and final product. Propylene glycol can be used as a marker for the extractables from Durapore hydrophilic PVDF filters. Although numerous buffers were used to generate extractables from the PVDF filter, significant extractables (PG and soluble oligomers) were found only in high pH extraction buffers. As a result of this finding, only a limited number of new buffers or new PVDF filters will require testing for future validation studies. Process validation studies have shown that neither PG nor soluble oligomers are at levels that impact the quality or safety of the product. PMID- 11605251 TI - Rapid methods for the microbiological surveillance of pharmaceuticals. AB - The use of rapid microbiological methods in pharmaceutical laboratories has improved the quality control analysis of water, products, raw materials, and enhanced the antimicrobial effectiveness testing of pharmaceutical finished products. Rapid release of samples has resulted in the optimization of manufacturing, product testing, and release allowing high throughput and simultaneous analysis of pharmaceutical formulations. ATP Bioluminescence, Impedance, Direct Viable Counts, and Flow Cytometry determine the total microbial content in a given pharmaceutical sample while PCR and Immunoassays detect the presence or absence of specific microbial species. Rapid methods provide reliable and cost effective analysis for the microbiological evaluation of pharmaceutical environments. The dramatic reduction in detection times and analysis, e.g., from 30 hours to 90 minutes, by using rapid methods will ultimately lead the pharmaceutical industry closer to real time monitoring of processes and samples. PMID- 11605252 TI - PCR detection of Salmonella typhimurium in pharmaceutical raw materials and products contaminated with a mixed bacterial culture using the BAX system. AB - The BAX system, a PCR-based assay, was evaluated for detecting Salmonella typhimurium in pharmaceutical raw materials and products contaminated with mixed bacterial cultures of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella typhimurium. Artificially contaminated samples were preenriched in lactose broth with and without Tween 20. After preenrichment, samples were analyzed by PCR and standard methods. Ten of 25 samples did not show presence of the specific Salmonella spp. 740-base pair DNA fragment. However, S. typhimurium was isolated and identified by standard methods from all 25 samples. To optimize S. typhimurium detection in PCR negative samples, lactose broth was replaced by buffered peptone water (BPW) as the preenrichment broth. When BPW was used, all 10 samples were PCR positive. BPW enrichments increased S. typhimurium growth resulting in rapid PCR detection. The presence of non-Salmonella bacteria influenced the performance of the PCR-based assay. Optimization of S. typhimurium PCR detection in mixed culture required the use of different preenrichment broths. However, the BAX system detected S. typhimurium within 27 hours while standard methods required 5-7 days. PMID- 11605253 TI - How to develop and validate a total organic carbon method for cleaning applications. AB - Good Manufacturing Practices require that the cleaning of drug manufacturing equipment be validated. Common analytical techniques used in the validation process include HPLC, UV/Vis, and Total Organic Carbon (TOC). HPLC and UV/Vis are classified as specific methods that identify and measure appropriate active substances. TOC is classified as a non-specific method and can detect all carbon containing compounds, including active substances, excipients, and cleaning agents. The disadvantage of specific methods is that a new procedure must be developed for every active drug substance that is manufactured. This development process can be very time consuming and tedious. In contrast, one TOC method can potentially be used for all products. A TOC method is sensitive to the ppb range and is less time consuming than HPLC or UV/Vis. USP TOC methods are standard for Water for Injection and Purified Water, and simple modifications of these methods can be used for cleaning validation. The purpose of this study is to demonstrate how to develop and validate a TOC method for cleaning applications. Performance parameters evaluated in this study include linearity, MDL, LOQ, accuracy, precision, and swab recovery. PMID- 11605254 TI - BSE/TSE risks associated with active pharmaceutical ingredients and starting materials: the situation in Europe and the global implications for healthcare manufacturers. PMID- 11605255 TI - Cerebrospinal fluid. PMID- 11605256 TI - Apoptosis, Part II: The role of mutated Fas genes in tumorigenesis. PMID- 11605257 TI - Noncompetitive immunoassays for small molecules with high sensitivity and specificity. PMID- 11605258 TI - DNA genotyping. PMID- 11605259 TI - Biochemical hematology of platelets and leukocytes. PMID- 11605260 TI - Apoptosis, Part I: Biochemical assessment. PMID- 11605261 TI - Spiers Memorial Lecture. Comparative studies of cluster dynamics in the gas and condensed phases. AB - Although an overview of the field of cluster dynamics is impossible to give in this Introductory Lecture, several important themes have emerged that can provide a backdrop for this Faraday Discussion. As a result, the first part of this paper introduces some of these themes, using results from the literature to illustrate some of the important issues. Although much of the work on clusters is being carried out in the gas phase (usually in free jet expansions and molecular beams), new approaches have recently been developed that permit the study of the same complexes in or on nanoscale clusters. In particular, recent developments in the field of superfluid helium droplet spectroscopy (SHEDS) permit high resolution studies of atoms, molecules and clusters in this exotic quantum fluid. After introducing this new field, the author will discuss experiments from his own laboratory to illustrate some of the capabilities of the technique. PMID- 11605262 TI - Intermolecular potentials with flexible monomers. AB - Most available intermolecular potentials assume rigid monomers. Such an assumption is a reflection of a trivial observation that if monomer degrees of freedom are considered, the dimensionality of an intermolecular potential increases dramatically even for few-atom monomers. This puts strict limits on the sizes of clusters with flexible monomers that can be treated by ab initio methods since the number of grid points needed to fit a potential surface quickly becomes enormous. Most of the literature flexible-monomer potentials were obtained from the so-called site-site rigid-monomer potentials by simply allowing the sites to move with atomic nuclei as the monomers are deformed. This simple atom-following approach has been investigated in the present work, using water dimer and Ar-HF as test systems, and shown to be not adequate. A method has been proposed which uses properties of isolated flexible monomers to improve upon the atom-following approach without performing any dimer calculations outside the rigid-monomer grid. The method is shown to give for Ar-HF a 3D representation of the dispersion energy that should be adequate for HF motion in the ground and first excited vibrational states. PMID- 11605263 TI - Vibrational predissociation dynamics of methane-Ar: an ab initio approach. AB - We calculated the cross sections for vibrational predissociation of methane-Ar induced by excitation of the methane nu 3 mode with the aid of an ab initio CH4 Ar potential depending explicitly on the nu 3 and nu 1 normal coordinates of the CH4 monomer. We found that dissociation into CH4 fragments excited in the nu 1 mode, a V-->V' process with very low kinetic energy release, strongly dominates over direct dissociation into Ar and ground state CH4, and is responsible for the line broadening observed experimentally. The (observed and calculated) strong variation of the line widths for the Van der Waals levels excited in combination with the nu 3 mode (giving states of A, F and E symmetry) is related to the opening up of appropriate nu 1 dissociation channels and the occurrence of rotational resonances in the nu 1 continuum in the energy range of the quasi bound nu 3 levels. PMID- 11605264 TI - Global optimization and the energy landscapes of Dzugutov clusters. AB - The global minima of clusters bound by a Dzugutov potential form non-compact polytetrahedral clusters mainly composed of interpenetrating and face-sharing 13 atom icosahedra. As the size increases, these icosahedral units first form linear arrays, then two-dimensional rings, then three-dimensional networks. Characterization of the energy landscapes of these clusters shows that they are particularly rough and generally exhibit a multiple-funnel topography. These results provide new insights into the structure and dynamics of bulk supercooled Dzugutov liquids and the form of the bulk phase diagram. PMID- 11605265 TI - Spectroscopy of OCS-hydrogen clusters in He droplets. AB - Clusters of para-hydrogen (pH2) and ortho-deuterium (oD2) have been assembled around an OCS chromophore molecule inside He droplets in a molecular beam and studied via IR diode laser depletion spectroscopy (nu approximately 2060 cm-1). The superfluid 4He droplets provide a gentle host ensuring a constant low temperature of either T = 0.38 K for 4He droplets or T = 0.15 K for both the pure 3He and mixed 4He-3He droplets. The spectra show well resolved rotational structure of the vibrational bands for each attached hydrogen molecule in the range n = 1-8. With only one (n = 1) attached pH2, HD or an oD2 molecule the best fit rotational constants were used to determine the structure of the complex, which was found to be in surprisingly good agreement with quantum chemical calculations for the free complex. With n = 5 and 6 the Q-branch disappears for the pH2 clusters but not for the oD2 clusters which is consistent with a donut model. The moments of inertia of the pH2 and the oD2 complexes are explained by a new model in which each of the 18 attached helium atoms in a shell surrounding the OCS molecule are assigned a mass of 0.55, while each attached H2 and D2 molecule has an effective mass of about 10 and 12 u, respectively. PMID- 11605266 TI - Dynamics of harpooning studied by transition state spectroscopy. Part III. Li...FCH3. AB - The Van der Waals complex Li...FCH3 has been formed in a crossed molecular beam apparatus. The transition state (TS) for the reaction Li*(2p 2P) + FCH3-->LiF + CH3 was accessed at various configurations by laser-excitation of the Li...FCH3 complex by tunable visible radiation, lambda 1. Photoinduced depletion of the complex by excitation to this TS was found to occur across a broad range of lambda 1 from 570 to 850 nm. This 'action spectrum' consisted of two broad regions located to either side of the atomic transition line of Li (2p 2P<--2s 2S). The first region, between 700 and 850 nm, was dominated by sharp maxima in the depletion intensity. A broad peak with weakly-resolved structure characterized the second region, between 570 and 680 nm. These findings were interpreted by means of high-level ab initio calculations of the potential-energy surfaces in the TS region. The peaks in the photodepletion spectrum were assigned to specific electronic transitions, their shapes and intensities being explained in terms of calculated transition-dipole moments and rovibrational wavefunctions. PMID- 11605267 TI - Excited state reactions of metals in clusters: pluridimensional harpoon and solvation effects. AB - Excited state reactions of metals produce electronically excited products efficiently, as revealed by studies performed both in the gas phase and in free Van der Waals complexes. The reaction mechanism is assigned to an excited state charge transfer from the metal to the molecular reactant (i.e. a harpoon mechanism). The present work uses the well established cluster isolated chemical reaction (CICR) technique and addresses these processes when the metal ... molecule Van der Waals pair is deposited at the surface of a large argon cluster. Such work is aimed at investigating the effect of the cluster substrate on the preparation and dynamics of the reaction. We have revisited the pluridimensional character of the harpoon reaction in these systems. More specifically, we studied the reaction of excited calcium with HBr near the calcium resonance line at 422.7 nm, forming CaBr in the A and B states. As in previous Van der Waals experiments, we could explore the dynamics of the reaction by recording action spectra. These spectra exhibit noticeable differences from those observed for unsupported Ca...HBr complexes. In particular the bending movement of the Ca...HBr complex which gives access to the transition state of the reaction is partly hindered by the presence of the argon cluster. PMID- 11605268 TI - Transition state spectroscopy of the I + HI reaction in clusters: photoelectron spectroscopy of IHI-.Arn (n = 1-15). AB - We have investigated effects of solvation on the transition state spectroscopy and dynamics of the I + HI reaction by measuring the anion photoelectron (PE) spectra of the clusters IHI-.Arn (n = 1-5). Argon clustering results in a successive shift of the PE spectra to lower electron kinetic energies with increasing cluster size. It also leads to significant vibrational cooling in the PE spectra and facilitates the observation of features associated with symmetric stretch vibrations and hindered rotational motions of the transition state complex IHI. The shifts in electron binding energy suggest that the first six argon atoms form a ring around the waist of the IHI- anion, just as in I2-.Arn. The spacing of the antisymmetric stretch features evolves with cluster size and is attributed at least in part to perturbation of the IHI- geometry in larger argon clusters. Intensities of features due to hindered rotation are enhanced for larger clusters, possibly due to solvent perturbation of the neutral transition state region. PMID- 11605269 TI - Photodissociation and caging of HBr and HI molecules on the surface of large rare gas clusters. AB - Photodissociation experiments were carried out at a wavelength of 243 nm for single HBr and HI molecules adsorbed on the surface of large Nen, Arn, Krn and Xen clusters. The average size is about = 130; the size ranges = 62-139 for the system HBr-Arn and = 110-830 for HI-Xen were covered. In this way the dependence of the photodissociation dynamics on both the size and the rare gas host cluster was investigated. The main observable is the kinetic energy distribution of the outgoing H atoms. The key results are that we do not find any size dependence for either system but that we observe a strong dependence on the rare gas clusters. All systems exhibit H atoms with no energy loss that indicate direct cage exit and those with nearly zero energy that are an indication of complete caging. The intensity ratio of caged to uncaged H atoms is largest for Nen, decreases with increasing mass of the cage atoms, and is weakest for Xen. On the basis of accompanying calculations this behaviour is attributed to the large amplitude motion of the light H atom. This leads to direct cage exit and penetration of the atom through the cluster with different energy transfer per collision depending on the rare gas atoms. The differences between HBr and HI molecules are attributed to different surface states, a flat and an encapsulated site. PMID- 11605270 TI - Size evolution of the vibrational predissociation process in Br2...Nen clusters: simulation and kinetic study. AB - A hybrid quantum-classical simulation of the vibrational predissociation of Br2...Nen, (n = 2-11) clusters in the B electronic state is carried out. The time evolution of the reactants, products, and intermediates is analyzed by a kinetic mechanism consisting of three elementary steps: direct vibrational predissociation (VP), intramolecular vibrational redistribution (IVR), and evaporative cooling (EC). The importance of intramolecular vibrational redistribution followed by evaporative cooling relative to direct vibrational predissociation is shown to increase rapidly with increasing cluster size. Final product state distributions reveal that only one or less Br2 stretching quantum per neon atom is required in order to achieve complete dissociation (n quanta for n < or = 9 and n - 1 for n = 10 and 11). The proportion of available energy going into translation is proposed as a parameter to study the statistical behavior of the Van der Waals clusters. It is shown to depend only on the number of remaining degrees of freedom, a characteristic of a statistical behavior, for n > or = 3. PMID- 11605271 TI - Formation of novel rare-gas-containing molecules by molecular photodissociation in clusters. AB - Recent work by Rasanen and coworkers showed that photolysis of hydrides in rare gas matrices results in part in formation of novel, rare-gas-containing molecules. Thus, photolysis of HCl in Xe and of H2O in Xe result respectively in formation of HXeCl and HXeOH in the Xe matrices. Ab initio calculations show that the compounds HRgY so formed are stable in isolation, and that by the strength and nature of the bonding these are molecules, very different from the corresponding weakly bound clusters Rg...HY. This paper presents a study of the formation mechanism of HRgY following the photolysis of HY in clusters Rgn(HY). Calculations are described for HXeCl, as a representative example. Potential energy surfaces that govern the formation of HXeCl in the photolysis of HCl in xenon clusters are obtained, and the dynamics on these surfaces is analyzed, partly with insight from trajectories of molecular dynamics simulations. The potential surfaces are obtained by a new variant of the DIM (diatomics in molecules) and DIIS (diatomics in ionic systems) models. Non-adiabatic couplings are also obtained. The main results are: (1) Properties of HXeCl predicted by the DIM-DIIS model are in reasonable accord with results of ab initio calculations. (2) The potential along the isomerization path HXeCl-->Xe...HCl predicted by DIM is in semiquantitative accord with the ab initio results. (3) Surface-hopping molecular dynamics simulations of the process in clusters, with "on the fly" calculations of the DIM-DIIS potentials and non-adiabatic couplings are computationally feasible. (4) Formation of HXeCl, following photolysis of HCl in Xe54(HCl), requires cage-exit of the H atom as a precondition. The H atom and the Cl can then attack the same Xe atom on opposite sides, leading to charge transfer and production of the ionic HXeCl. (5) Non-adiabatic processes play an important role, both in the reagent configurations, and at the charge-transfer stage. The results open the way to predictions of the formation of new HRgY species. PMID- 11605272 TI - Quantum/classical studies of photodissociation and reaction dynamics in clusters. AB - In this paper, a multiple configurational time-dependent self-consistent field (TDSCF) approach for studying photodissociation and reaction dynamics is described. This approach has been applied to studies of several benchmark systems and is found to provide an accurate description of the reactions. The focus of the present work is on investigations of processes in cluster environments. Specifically, the dynamics of the O(3P) + HCl reaction and H2O photodissociation dynamics in isolation and in Van der Waals complexes with one argon atom are compared. The nature and importance of quantum mechanical effects in these systems are investigated through an analysis of the results of the quantum/classical simulations and a comparison of these results with those obtained from previously reported experimental and classical studies on these systems. It is found that, although the effects of complexation are subtle, they are not negligible. In addition, most of them can be understood in terms of kinematic and steric factors, although electronic effects cannot be dismissed. PMID- 11605273 TI - Fluorescence-dip IR spectra of jet-cooled benzoic acid dimer in its ground and first excited singlet states. AB - The IR spectra of three isotopomers of the benzoic acid dimer have been recorded under jet-cooled conditions using the double resonance method of fluorescence-dip IR spectroscopy. In so doing, the spectra are assuredly due exclusively to dimers in the ground-state zero-point level at a rotational temperature of 3-5 K. Even under these conditions, the three isotopomers have remarkably broad spectra, extending from 2600 to almost 3150 cm-1. The spectra show extensive substructure consisting of some 15-20 transitions where only a single OH stretch fundamental should appear in the harmonic limit. The comparison of the undeuterated d0-d0 dimer with the ring-deuterated d5-d5 dimer tests the effect of mixing with the C H stretches and overtones of the C-H bends. The mixed OH/OD ring-deuterated d6-d5 dimer shifts the frequency and changes the form of the OH stretch normal mode. The analogous OH stretch IR spectrum of the d0-d0 dimer out of the S1 excited state zero-point level has also been recorded. In this case, much of the closely spaced substructure is not apparent. What remains is a set of three bands separated from one another by about 180 cm-1. Preliminary results of model calculations of the anharmonic coupling, responsible for the broadening and substructure, are presented. These calculations indicate that it is OH stretch-OH bend coupling, rather than coupling with the intermolecular stretch, that is responsible for much of the observed structure and breadth. PMID- 11605274 TI - Dynamics of the 1 3 pi g state of K2 on helium nanodroplets. AB - Fluorescence following optical excitation of the 1 3 sigma u+ state of K2 prepared on helium nanodroplets to the predissociative 1 3 pi g state yields molecular emission from both the (B)1 1 pi u and (A)1 1 sigma u+ K2 states as well as atomic emission from the expected 4 2P3/2, 1/2-->4 2S1/2 dissociation channel. A approximately 12 cm-1 red shift is observed in the molecular emission excitation spectrum compared to the atomic emission excitation spectrum. Time correlated photon counting measurements demonstrate the rise time for both atomic and molecular products to be < 80 ps, independent of vibrational level excited. This lifetime is interpreted as the total depopulation time for the optically excited 1 3 pi g state, which is dominated by intersystem crossing at low vibrational energy and by predissociation at the highest vibrational level. It is deduced that the timescale for intersystem crossing must be of the order of 10 ps. Symmetry restrictions for the isolated K2 imply that the intersystem crossing from the 1 3 pi g state to the (B)1 1 pi u and (A)1 1 sigma u+ states must be induced by interaction with the helium nanodroplet. PMID- 11605275 TI - Ragout-jet FTIR spectroscopy of cluster isomerism and cluster dynamics: from carboxylic acid dimers to N2O nanoparticles. AB - Direct absorption supersonic jet Fourier transform spectroscopy provides a panoramic view of the dynamics of molecular clusters over the entire IR spectral range. The new and generally applicable ragout-jet technique compensates for the sensitivity limits inherent in the incoherent FTIR approach by the use of synchronized giant gas pulses expanding into a large vacuum buffer. A modification based on fragmented interferograms is proposed and demonstrated, by which the spectral resolution can be extended to the limit of the available FTIR spectrometer. The power of the method is illustrated for two classes of compounds. For acetic acid and its isotopomers, the supersonic jet spectra of dimers and oligomers are investigated for the first time, concentrating on the very complex OH/CH stretching domain and on the more regular C=O/C-O stretching range. Issues of cluster isomerism, hydrogen exchange tunneling, anharmonic resonances, intermolecular Franck-Condon sequences, methyl group substitution and cluster coating with argon are explored. For the more weakly interacting nitrous oxide, stretching fundamentals and combination bands of clusters in the 1-3 nm range are studied as a function of composition. Surface vibrations are investigated in detail and modeled quantum mechanically. The semiempirical AM1 approach is found to provide a remarkably accurate description of the cluster structure, energetics and dynamics. PMID- 11605276 TI - Mapping the OH + CO-->HOCO reaction pathway through IR spectroscopy of the OH-CO reactant complex. AB - A hydrogen-bonded complex composed of the OH and CO reactants has been identified along the OH + CO-->HOCO reaction pathway. IR action spectroscopy in the OH overtone region has been used to examine the vibrational modes of the linear OH CO complex, including intermolecular bending modes that probe portions of the reaction path leading to HOCO. The spectroscopic measurements have accessed highly excited intermolecular levels, with energies up to 250 cm-1 above the zero point level, which lie in close proximity to the transition state for reaction. The OH-CO binding energy, D0 < or = 430 cm-1, has also been established from the quantum state distribution of the OH fragments following vibrational predissociation of the OH-CO complex. Complementary electronic structure calculations have been performed to characterize the OH-CO and OH-OC complexes, the transition state for HOCO formation, and the direct reaction path that connects the experimentally observed OH-CO complex to the HOCO intermediate. PMID- 11605277 TI - Electronic spectroscopy and excited state dynamics of the Al-H2/D2 complex. AB - The electronic spectra of the Al-H2 and Al-D2 complexes are investigated in a collaborative experimental and theoretical study. The complexes were prepared in a pulsed supersonic beam and detected with laser fluorescence excitation spectroscopy. Transitions to bound vibrational levels in electronic states correlating with the excited-state Al(3d, 4p, 4d) + H2/D2 asymptotes were observed by monitoring emission from lower excited Al atomic levels, formed in the non-radiative decay of the excited complex. Fluorescence depletion has also been used to verify that the observed Al-H2 bands all involve the same molecular carrier. The bands have been assigned to the more strongly bound Al-oH2 and Al pD2 nuclear spin modifications. In contrast to our previous observations for Al(5s)-H2 [X. Yang and P. J. Dagdigian, J. Chem. Phys., 1998, 109, 8920], for which only one potential energy surface (PES) emanates from the dissociation asymptote, the Lorentzian widths of the different vibrational bands in the 3d, 4p, 4d<--3p transitions vary widely, in some cases allowing resolution of the rotational structure of the bands. With the help of the calculated Al(3p)-oH2/pD2 dissociation energies, binding energies of the observed excited vibronic levels are reported. The mechanism of predissociation is investigated theoretically through ab initio calculation of C2 nu cuts of the excited PESs. It is concluded that predissociation occurs through coupling with the repulsive Al(4s)-H2 PES. With these calculations, a qualitative interpretation of the observed bands could be made. PMID- 11605278 TI - Clusters containing open-shell molecules: minimum-energy structures and low-lying isomers of ArnCH (X 2 pi), n = 1 to 15. AB - The size evolution of the equilibrium structures of open-shell ArnCH (X 2 pi) Van der Waals clusters is investigated for n = 1 to 15. We describe a method for combining pair potentials for Ar-CH and Ar-Ar interactions to obtain potential energy surfaces for ArnCH clusters. For each cluster size considered, the global and a few energetically close local minima are calculated using simulated annealing followed by a direct minimization scheme. Ar2CH is found to have an unusually stable planar structure, which persists as a motif in larger ArnCH clusters and has a strong effect on their optimal geometries. The lowest-energy isomers of ArnCH with n = 3 to 11 have all Ar atoms in a shell around CH. The only exception is Ar4CH, where the fully solvated isomer is 3 cm-1 higher in energy than the optimal isomer with CH bound to the surface of the Ar4 tetrahedron. For n = 7 to 11, the minimum-energy structure of ArnCH derives from the global minimum of the Arn + 1 cluster, by replacing the Ar atom at the bottom of the pentagonal bipyramid with CH. The lowest-energy structure of Ar12CH is that of the optimal icosahedral Ar13 cluster, with CH replacing one of the Ar atoms on the cluster surface. This structure supports the proposition based on the spectroscopic data, that for ArnCH clusters with about 10 to 50 Ar atoms CH resides on the surface of Arn. PMID- 11605279 TI - Theoretical investigations of proton-bound cluster ions. AB - Several proton-bound cluster ions have been studied by means of coupled cluster calculations with large basis sets. Among these are complexes of a krypton or xenon atom with the cations HCO+, HN2+ and HNCH+. Various spectroscopic properties have been calculated in all cases. Effects of vibrational anharmonicity are particularly pronounced for the intramolecular stretching vibrations of Kr...HN2+ and Xe...HN2+. The proton stretching vibration of (N2)H+(N2) is predicted around 800 cm-1, with a large transition dipole moment of 1.15 D. Both (N2)H+(N2) and (HCN)H+(NCH) have linear centrosymmetric equilibrium structures. Those of (OC)H+(CO) and (HCC-)H+(CCH-) are asymmetric with barrier heights to the centrosymmetric saddle points of 382 and 2323 cm-1, respectively. The dissociation energy of the anionic complex Cl-...HCCH is calculated to be Do = 3665 cm-1, 650 cm-1 larger than the corresponding value for Br-...HCCH. The complex between a fluoride ion and acetylene is more strongly bound and shows strongly anharmonic behaviour, similar to the bihalides FHF- or ClHCl-. Strong Fermi resonance interaction is predicted between nu 3 (approximately proton stretch) and 2 nu 4 (first overtone of intermolecular stretch). PMID- 11605280 TI - Internal rotation in NH4(+)-Rg dimers (Rg = He, Ne, Ar): potential energy surfaces and IR spectra of the nu 3 band. AB - The intermolecular potential energy surfaces for the electronic ground states of the ammonium ion-rare gas dimers NH4(+)-He and NH4(+)-Ne are calculated at the MP2 and CCSD(T)/aug-cc-pVXZ (X = D/T/Q) levels of theory. The global minima of both potentials correspond to proton (vertex)-bound structures, Re = 3.13 A, De = 171 cm-1 (He) and Re = 3.21 A, De = 302 cm-1 (Ne). The face- and edge-bound structures are local minima and transition states for the internal rotation dynamics, corresponding to barriers of approximately 20 (He) and 50 cm-1 (Ne). The ab initio potentials are employed in numerical solutions to the rotation intermolecular vibration Hamiltonian to determine the term values and the rotational and distortion constants for the lowest bound levels in the intramolecular ground vibrational state of both complexes. The results are used to assess the accuracy of two-dimensional (fixed-R) representations of the potentials for determining the internal rotor levels in the ground and nu 3 vibrational states. This model is employed to produce simulations of the IR nu 3 transitions, which are compared to the experimental spectra recorded using photofragmentation spectroscopy. In the case of NH4(+)-Ne the potential parameters are least-squares fitted to the experimental spectrum. The trends within the NH4(+)-Rg series (Rg = He, Ne, Ar) revealed by both the IR spectra and theoretical calculations are discussed. PMID- 11605281 TI - Sigma bond activation by cooperative interaction with s2 atoms: B+ + nCH4, n = 1, 2. AB - Ab initio investigations at the MP2 and CCSD(T) level with augmented double and triple zeta basis sets have identified various stationary points on the B+/nCH4, n = 1, 2 hypersurfaces. The electrostatic complexes show a strong variation in the sequential binding energy with De for the loss of one CH4 molecule calculated to be 16.5 and 6.8 kcal mol-1 for the n = 1 and n = 2 complexes, respectively. The covalent molecular ion, CH3BH+, is found to have the expected C3 nu geometry and to be strongly bound by 84.0 kcal mol-1 with respect to B+ + CH4. The interaction of CH4 with CH3BH+ is qualitatively very similar to the interaction of CH4 with HBH+, however, the binding is only about 50% as strong due to the electron donating characteristic of the methyl group. Of particular interest are the insertion transition states which adopt geometries allowing the B+ ion to interact with multiple sigma bonds. In the n = 1 case, the interaction with two CH bonds lowers the insertion activation energy by about 25 kcal mol-1 from that expected for a mechanism involving only one sigma bond. For n = 2, B+ interacts with two CH sigma bonds from one CH4 and one CH sigma bond from the other CH4 leading to an additional activation energy decrease of about 15.7 kcal mol-1 relative to B+ + nCH4. PMID- 11605282 TI - High-resolution IR studies of hydrogen bonded clusters: large amplitude dynamics in (HCl)n. AB - Structural and dynamical information on small hydrogen-bonded systems is revealed by high-resolution IR spectroscopy of HCl dimer, trimer and tetramer. In (HCl)2, four combination bands tentatively assigned to the Van der Waals stretch nu 4 and geared band nu 5 vibrations are observed. The study focuses on two unexpected results: (i) all of the observed bands are built only on the bound HCl stretch nu 2, and (ii) the bands predominantly originate from the 9-fold less populated upper tunneling level of the ground state. Model 3D quantum calculations are presented to show that both these surprising trends originate from the large amplitude tunneling dynamics in the dimer. The (HCl)3 spectra are assigned and analyzed for multiple isotopomeric contributions. The spectral fit reveals large homogeneous line broadening indicating the excited state lifetime of approximately 1.6 ns and tentatively associated with dynamics of intramolecular vibrational energy distribution (IVR) induced trimer ring opening. Finally, first high-resolution data on the HCl stretch fundamental spectrum of (HCl)4 are presented. PMID- 11605283 TI - Complete characterization of the (D2O)2 ground state: high Ka rotation-tunneling levels. AB - We report the observation of extensive a- and c-type rotation-tunneling (RT) spectra of (D2O)2 for Ka = 0-4. These data allow quantification of molecular constants and tunneling splittings for a number of previously unobserved RT states of (D2O)2. The vibrational ground state has thus been characterized to energies as high as those of some of the intermolecular vibrations, and we present the first test of the VRT(ASP-W) potential at these high Ka states. PMID- 11605284 TI - Diffusion Monte Carlo simulations on uracil-water using an anisotropic atom-atom potential model. AB - We have developed an anisotropic atom-atom intermolecular potential model for the interaction of uracil with water. The potential consists of a distributed multipole analysis (DMA) model for the electrostatic energy, and a 6-exp potential to represent the repulsion-dispersion term. The repulsion-dispersion potential parameters are adjusted to yield good agreement with accurate ab initio data on the minima and transition states of the uracil-water complex. We have used this potential in diffusion Monte Carlo simulations of uracil-water, uracil (water)2 and uracil-(water)3. The uracil-water simulations show that the theoretically based potential gives a qualitatively different picture of uracil hydration than that provided by a standard isotropic atom-atom point charge model, which is shown to underestimate the delocalized motion of the water hydrogen atoms. Plots of the vibrational probability density of the hydrogen atoms show the delocalized motion of the water hydrogen atoms that are not involved in hydrogen bonding. PMID- 11605285 TI - [100 years of orthopedics in Germany]. PMID- 11605286 TI - [Cell proliferation in human arthrotic joint cartilage]. AB - OBJECTIVE: Osteoarthritic (OA) cartilage is histologically characterized by the appearance of cell clusters, which are probably generated by mitotic cell division. The aim of this study was to analyze the distribution and amount of proliferating chondrocytes in healthy and osteoarthritic cartilage systematically. MATERIALS AND METHODS: 6 normal and 43 osteoarthritic cartilage/bone samples were obtained during autopsies or total knee replacements. The cartilage specimens were stained with safranin-o and scored according to the Mankin-System. Proliferating chondrocytes were identified by immunohistochemical detection of the antigen PCNA. The number of proliferating chondrocytes was determined by counting 100 chondrocytes in each cartilage layer. RESULTS: In normal and osteoarthritic human cartilage, proliferating chondrocytes were detected. The amount of proliferating chondrocytes increased during the progression of OA cartilage changes. Expression of PCNA was determined in single chondrocytes and clustered chondrocytes. Chondrocyte cell division was activated specifically in cartilage with severe OA changes. CONCLUSIONS: Osteoarthritic chondrocytes, which are known to increase the synthesis of different matrix proteins, show the phenomenon of mitotic cells division. Whether the increased amount of proliferating chondrocytes fails to compensate the rate of apoptotic chondrocytes, or whether the generation of cell clusters represents only a fruitless repair effort is a subject of recent research. However, the induction of chondrocyte proliferation is a potential target in the treatment of OA. PMID- 11605287 TI - [Healing of osteochondral transplants--animal experiment studies using a sheep model]. AB - AIM: Autologous grafting has developed into one of the preferred methods of treatment for focal osteochondral lesions, although basic research on this topic remains sparse. In an animal study, questions regarding the healing of such osteochondral transplants are clarified. METHOD: An autologous osteochondral transplantation was performed on the ovine knee using the standard operative protocol. Two groups, consisting of 10 sheep each, were evaluated after 3 and 6 months, respectively. RESULTS: During the clinical evaluation of the specimens, neither osteophytes nor synovial changes were observed. The consistency of the cartilaginous tissue began to reach a level equivalent to the surrounding tissue only after 6 months. Macroscopically, the superficial border of the transplanted osteochondral plug could easily be outlined at both time points. Radiographically, a solid osteointegration of the graft could already be documented at 3 months. In contrast, integration of the chondral surface of the OAT was not seen macro- or microscopically at any point in time. A firm physical interdigitation of the reconstructed joint surface could not be demonstrated. CONCLUSIONS: The lack of integration of the cartilaginous portion of the transplanted plugs into the reconstructed joint surface leads to questions regarding the long-term survival of the joint itself. PMID- 11605288 TI - [Valgus tibial head reconstruction, monocondylar sled prosthesis or bicondylar gliding surface replacement in therapy of medial gonarthrosis--a cost analysis]. AB - AIM: Three to a certain extent competing methods for the treatment of unicompartmental osteoarthritis of the knee are compared regarding the costs they cause. These methods comprise the high tibial valgus osteotomy (HTO), the unicompartmental knee arthroplasty (UKA), and the total knee arthroplasty (TKA). METHODS: We compared the in-patient costs and out-patient costs of 20 patients (drawn by lot) in each group who received one of the above-named operative methods at our hospital between 1988 and 1993. The results were extrapolated according to the expected survival rate of the applied method. RESULTS: The average total costs of patients who received a HTO were 9.487,-; for the unicompartmental arthroplasty the average cost were 11.687,-; the implantation of a TKA resulted in average costs of 16.940,-. All operative procedures exceeded a particular global amount, the socalled "Fallpauschale". CONCLUSION: Regarding the total costs that arise for the operative treatment of the degenerative arthritis of the knee, the HTO (with or without hardware removal) proves to be the cheapest of the applied methods. Projecting the results on the survival rate of each treatment method, no statistically significant differences could be recognized between the three operative procedures. PMID- 11605289 TI - [Prospective randomized comparative study of early functional outcome of 2 knee joint endoprosthesis systems--rotation plateau versus fixed polyethylene inlay]. AB - AIM: Different systems are used for total knee arthroplasty (TKA). Compared were a press-fit femur condyle replacement system with fixed tibial PE-inlay versus a rotating tibia component system with an emphasis on the early functional results. METHOD: Patient selection and the use of the Knee Society Score for this randomized and prospective study were based on the directives for TKA of the german Society for Orthopaedic and Trauma Surgery (DGOT). We examined the patients post-operatively after 1 week, 2 weeks, 6 weeks, 3 months, 6 months, and 1 year. RESULTS: After 6 weeks an increase of the total knee score could be seen in both groups. The total knee score of the rotating tibia component increased from 93.96 pre-operatively to 113.57 after 6 weeks, to 139.82 after 3 months, to 154.32 after 6 months, and to 159.65 after one year. The total score with the fixed PE-inlay increased from 79.75 to 111.5 after 6 weeks, to 128.25 after 3 months, to 134.08 after 6 months, and to 130.08 after one year. CONCLUSION: After 6 weeks the implant with the rotating tibia component showed a lasting higher score as compared to the implant with a fixed PE-inlay component using the same early rehabilitation and mobilization techniques. PMID- 11605290 TI - [Comparison of extracorporeal shockwave therapy (ESWT) with roentgen irradiation in supraspinatus tendon syndrome--a prospective randomized single-blind parallel group comparison]. AB - AIM: Extracorporal shock wave therapy (FSWT) is applied in the case of supraspinatus tendinitis if conservative therapies have failed. So far there has been no controlled study comparing the effectiveness of ESWT with an established conservative method of therapy such as X-ray stimulation radiotherapy. METHOD: Thirty patients with chronic supraspinatus tendinitis were admitted into the prospective randomised study. After randomisation, the patients were treated either three times with 2000 pulses (energy flux density ED+ 0.33 mJ/mm2) with a Storz Minilith SL1 after one week, or with X-ray stimulation radiotherapy with 6 x 0.5 Gy on the ICRU reference point (1 neutral fraction/day) with cobalt 60 gamma rays. Primary endpoint was the age-corrected constant score. RESULTS: In the ESWT group the average age-corrected constant score rose from 50.1 points before ESWT to 91.5 points after 12 weeks and to 97.8 after 52 weeks. In the radiotherapy group it improved from 47.6 through 79.5 points to 87.4 points. CONCLUSION: No statistically significant differences were proven between ESWT and radiotherapy. ESWT appears to be at least equivalent to radiotherapy in treating chronic supraspinatus tendinitis syndrome and can avoid a dose of radiation for patients and staff. A comprehensive randomised study is, however necessary to ensure the equivalence of ESWT. PMID- 11605291 TI - [Transposition operation in paralysis of extensor muscles of the hand- intermediate-term results]. AB - AIM: The surgical reconstruction of the dorsiflexion of the wrist and the abduction of the thumb in paralyzed radial nerve for the improvement of the useability of the hand is described. Likewise, the early functional subsequent treatment is described. Indications and contraindications are represented in detail. METHOD: Between October 1997 and May 2000 we treated 10 patients by the following method: The musculus flexor carpi ulnaris tendon is cut near the pisiform bone, transferred subcutaneously and fixed on the tendons of the extensor communis digitorum communis muscle. The tendon of the palmaris longus muscle is fixed on the tendon of the extensor pollicis longus muscle. After the swelling in the hand has subsided, the patients are supplied with a dynamic splint in order to avoid adhesions. RESULTS: According to the score suggested by Haas, 9 patients achieved a very good result (median: 30 degrees dorsiflexion), one patient had a good result (0 degree dorsiflexion). CONCLUSION: Adhesions could be avoided and the time of rehabilitation could be shortened by the operation method described. The operations result in an improvement of hand function and as well as patient satisfaction. PMID- 11605292 TI - [Effect of femoral intramedullary irrigation on periprosthetic cement distribution: jet lavage versus syringe lavage]. AB - INTRODUCTION: The purpose of this experimental study was to determine quantitatively the cement penetration into periprosthetic femoral bone by Icomparing the use of jet-lavage with the conventional syringe irrigation. METHODS: 10 pairs of fresh-frozen human cadaver femora were used for cemented stem implantation, The left femora were irrigated with a syringe device, the right femora with a jet-lavage system. After implantation, all femora were cut into 5-mm slices from proximal to distal with a diamond saw. The scanned slices were analysed using an image processing system which provided a discrimination between implant, cement, and bone as well as an exact determination of the cement area. RESULTS: In all 10 femora, a recognizable improvement of the cement penetration into the periprosthetic bone was demonstrated using the jet-lavage. In the proximal part, the mean cement penetration was 8.6% higher in the jet lavage group than in the syringe device group. An equivalent tendency towards the jet-lavage pretreated femora was seen in the middle part with 8.7% on average mean and in the distal part with 6.4% on average. Also, when subdividing the periprosthetic area into 4 quadrants, a significant improvement of the cement penetration was found with the exception of the ventro-medial region. CONCLUSION: Cement distribution and penetration is improved using the jet-lavage technique for cleaning the medullary canal of the femur. Therefore, the jet-lavage should be used as a standard procedure in clinical cementing techniques. PMID- 11605293 TI - [Staged diagnosis of septic hip endoprosthesis loosening with laboratory parameters and antigranulocyte scintigraphy]. AB - AIM: The value of serial diagnosis of septic loosening of hip endoprosthesis using laboratory parameters and antigranulocytes scintigraphy was investigated and compared to joint aspiration. METHOD: In 35 patients with intraoperative verification of infection, we calculated sensitivity, specify and prevalence dependent positive and negative predictive values for antigranulocyte scintigraphy, laboratory tests and the most suitable combination of both. We also calculated predictive values of joint aspiration using sensitivity and specify values given in the literature. RESULTS: From negative and positive predictive values, of the sedimetation rate and leukocyte count provided no increase of information. We found the same result for positive predictive values of C reactive protein. For antigranulocyte scintigraphy alone, we found a distinct but still unsatisfying increase of information. Nevertheless, in both cases infection could be excluded definitely. Therefore, the combination of C-reactive protein and antigranulocyte scintigraphy was suitable and the positive predictive values of this combination were only about 5% lower than those of joint aspiration. But with joint aspiration, infection could not be excluded. CONCLUSION: A positive result in serial diagnosis using C-reactive protein and antigranulocyte scintigraphy leads to an distinct increase in the probability of infection which is comparable to that of joint aspiration. The additional advantages of this procedure are the certain exclusion of infection and the absence of invasiveness. PMID- 11605294 TI - [Cement-free ACA hip total endoprosthesis--5 years results]. AB - AIM: Since 1994 the cementlesss AlloClasssicAdditional (ACA) total hip replacement system is used in the 1st Orthopedic Department of the Hesssing Stiftung, Augsburg/Germany. Oblique steps on the medial and lateral side of the stem turn negative retrotorsional forces into axial forces and increase rotational stability. The new shape of the self-cutting metric thread of the dual radius designed acetabular component provides excellent primary fixation without secondary takeover of the force transmission. We checked the medium-term results. METHODS: The titanium prosthesis (distributed by Sulzer Orthopedics/Switzerland) was used for primary total hip replacement as a complete system in 1320 cases, as a hybrid system in 96 patients. In revision arthroplasty 156 components have been implanted up to now. All patients are included in a prospective study with radiological and clinical examinations. 176 of 242 primary implanted total hip systems with a minimum follow-up of 5 years had been reviewed. RESULTS: For the minimum 5 years implanted complete systems, the Harris Hip Score rose from 42 to 91 points. 94% of the patients were mostly or completely satisfied. Thigh pain was reported in 4%. Two aseptic loosenings of the acetabular component and one aseptic loosening of the stem occurred. CONCLUSION: A high degree of osseo integration and complications below 2% proves encouraging outcomes but final acceptance must await long-term follow-up. PMID- 11605295 TI - [Thread design of screw-in acetabulum prostheses]. AB - INTRODUCTION AND AIM OF STUDY: The screw-in behaviour and correct positioning of threaded cups is largely determined by the design of the thread. Up to now the various thread designs have not been systematically classified. METHODS: The thread designs of 10 first generation and 27 second generation threaded cups were analyzed using a tool setter and a no-touch light section technique. The following parameters were evaluated: thread shape, pitch, number of turns, rows of teeth, tooth length and shape. RESULTS: Threads of the first generation were V cut or saw shaped. Thread depth was 3.1 mm on average; the mean width was 0.9-3 mm. Single-thread patterns predominated. The number of turns ranged from 1-7; the pitch was from 2.5-5 mm (single thread), or up to 20 mm (triple and quadruple threads). Cups had 3-16 rows of teeth. Threads of the second generation are V cut, saw or flat shaped. Thread depth is 3 mm on average; mean width ranges from 0.3-2.2 mm. 72% of the threads have single-thread patterns. The number of turns ranges from 2-5; the pitch is from 2.5-6.2 mm (single thread). Cups have 4-24 rows of teeth. CONCLUSIONS: There are many different thread patterns with widely varying parameters. Contemporary threaded cups have a narrow V-cut and saw shaped threads or flat thread with depths up to 3 mm, no more than 5 turns, and pitch values of approx. 4.5 mm. PMID- 11605296 TI - [Short-term results of modified chevron osteotomy with soft tissue technique and guide wire fixation--a prospective study]. AB - AIM: A Chevron osteotomy with lateral soft-tissue release was performed at our department in 1993. In 1994 a prospective study to evaluate the temporary Kirschner wire fixation was started. Aim of this prospective study was to analyse the short-term clinical and radiological results with special attention to stability, necroses, and luxation of the first metatarsal head. METHOD: Between February 1994 and October 1995 45 patients (55 feet) were treated with a Chevron osteotomy combined with a lateral soft-tissue release and temporary Kirschner wire fixation. The average follow-up was 33.9 months. All patients were seen and evaluated preoperatively and at a minimum follow-up of 24 months using a standardized questionnaire based on the Hallux metatarsophalangeal interphalangeal Scale (HMIS) of the American Foot and Ankle Society. RESULTS: Results of the survey of patient satisfaction revealed excellent and good results in 83%, fair in 8%, and poor in 9%. The median HMIS at final follow-up was 86.9 pints of 100 points. The average hallux valgus angle correction was 19.8 (from 28.7 to 8.9) and the average first intermetatarsal angel correction was, 8.2 (from 14.4 to 6.2). No avascular necrosis of the first metatarsal head and no loss of correction were noted. In one case a luxation of the metatarsal head was observed. CONCLUSION: Combining the Chevron osteotomy with an excessive lateral soft-tissue release increases the likelihood of instability of the metatarsal head and consecutive loss of correction. The temporary Kirschner wire fixation increases the stability of the Chevron osteotomy and prevents the loss of correction. The disadvantage of this method is, that the wire has to be removed after 6 weeks. PMID- 11605297 TI - [Clinical pedographic radiological findings after basal valgus osteotomy of metatarsal 1--a prospective study]. AB - AIM: This study investigated the influence of valgusizing base wedge osteotomy of metatarsal 1 (MT 1) subsequently on the entire forefoot. METHOD: Pre- and post operatively 22 cases were investigated between 1998 and 2000 both clinically and radiologically with pedographic analysis in 20 of these cases. RESULTS: According to the Kitaoka Score we could establish preoperative 37 and postoperative 72 out of 100 possible points. Following the MT 1-base wedge osteotomy with a distal soft-tissue procedure, the central forefoot region (MT 2/3) showed reduced pressure-induced pain, unchanged callus development, and reduced maximum load pressure. When the Plus-Index (MT 1 longer than MT 2) could be preserved in the valugusizing MT 1-base wege osteotomy, the metatarsalgia in the central forefoot region not only improved generally, but also the maximum loading pressure was clearly reduced. In cases with a post-operative Minus-Index (MT 1 shorter than MT 2), as well as in those Plus-Index cases undergoing a Keller procedure in the valgusizing base wedge osteotomy, the elevated pressure values in the central forefoot region persisted. CONCLUSION: In valgusizing MT 1-base wege osteotomy with preservation of the Plus-Index (MT 1 longer MT 2), metatarsalgia can be improved and the maximum loading pressure in the central forefoot can be reduced. PMID- 11605298 TI - [Clavicular pseudarthrosis in childhood: differential diagnosis, clinical aspects, therapy and results]. AB - AIM: Both congenital as well as post-traumatic pseudarthroses of the clavicle are very rare diagnoses in childhood. This study evaluates operative and non operative therapy in relation to diagnosis, clinical appearance, and results. METHODS: A retrospective study was performed on all patients with pseudarthrosis of the clavicle in childhood. The data were obtained from medical records. Follow ups were performed on patients who had undergone surgery. RESULTS: A total of 15 patients with 16 pseudarthroses were included, of these five patients had congenital and nine patients had post-traumatic pseudarthroses. One patient with a bilateral defect was diagnosed as having cleidocranial dysostosis. Concerning the patients with congenital pseudarthrosis, cosmetic appearance was the leading complaint while patients with post-traumatic pseudarthrosis suffered from pain and impaired function of the shoulder joint. Nine patients underwent surgery, including two patients with congenital, and seven with post-traumatie lesions. CONCLUSION: While patients with congenital pseudarthrosis mostly achieve good functional results by means of conservative therapy, surgery is optional in relation to the severity of cosmetic damage. However, the majority of post traumatic lesions require operative therapy due to associated pain and restricted function. PMID- 11605299 TI - [Experiences with calcitonin treatment of patients with type I complex regional pain syndrome (CRPS I--Sudeck disease)]. AB - PURPOSE/METHODS/PATIENTS: Calcitonin is a common treatment in patients suffering from Complex Regional Pain Syndrome Type 1 (CRPS I), although its effects are being controversially discussed. In a prospective study of 24 patients with CRPS I of the upper limb, we examined the tolerance of daily doses of 0.5 mg human calcitonin administered subcutaneously over 8 weeks. To assess the benefit of this therapy, the patients were clinically examined every second week. The results were compared to a consecutive group of 25 CRPS 1 patients who received only analgetics and physiotherapy. RESULTS: With regard to all examined parameters (spontaneous pain, grip strength, edema, hand function, systematic temperature difference), the patients treated with calcitonin showed an improvement during the observation time. However, a statistically significant difference to the control group was calculated only for the reduction of the edema (P < 0.01). 83% (20/24 patients) of the calcitonin-treated patients suffered from severe, mostly gastroenterological side-effects. Hence therapy had to be discontinued in 3 cases (13%). CONCLUSION: The therapy with calcitonin has the burden of numerous unpleasant side-effects and causes only a slight therapeutic improvement. Thus, calcitonin must only be prescribed with reservations for patients suffering from CRPS I. PMID- 11605300 TI - [Pregnancy-associated symphysis damage from the orthopedic viewpoint--studies of changes of the pubic symphysis in pregnancy, labor and post partum]. AB - AIM: Is the sonographic measurement of the symphysis pubis enough to enable a prognosis of the occurrence of symphyseal pain during pregnancy and birth? METHOD: First of all, a simplified definition of symphyseal pain was categorized in order to make the classification more easy. The symphyseal widths of 171 pregnant women were measured during pregnancy and after birth. Our control group consisted of 25 non-pregnant women. 15 of the 171 patients suffered from symphyseal pain; however, 156 of the 171 did not. Additionally, we measured the intrapartal symphyseal width in 11 of the women. RESULTS: The average symphyseal width of non-pregnant women was 4.07 mm (s = 0.79; n = 25). Pre- and postpartally we measured 6.32 mm (s = 1.71; variation of 3 to 16 mm) in pregnant asymptomatic women. A significant increase in width was recorded in the 15 women with pain in the symphysis: the symphyseal width was 10.62 mm (s = 2.37; Variation from 6.7 to 15.25 mm). Intrapartally the symphyseal width varied between 5.8 and 1.2 mm. CONCLUSION: Ultrasound measurement of the symphyseal width shows around 4 mm in non-pregnant women. Asymptomatic pregnant women have an average width of 6.3 mm. The majority of pregnant women with 9.5 mm or more have symphyseal pain. If that is the case then conservative treatment is usually sufficient to cure this complaint. PMID- 11605301 TI - [Graf reference standard, a "standard sector", in ultrasound examination of anatomic preparations of infant acetabuli]. PMID- 11605302 TI - [Opioids: treatment anxiety of physicians and patients in management of chronic backache]. PMID- 11605303 TI - [Correlation between surgical timing and incidence of complication in treatment of distal radius fracture]. PMID- 11605304 TI - [Classification of recurrent shoulder joint instability]. PMID- 11605305 TI - [Femoro-acetabular impingement--an underestimated pathogenetic factor in coxarthrosis]. PMID- 11605306 TI - [Histology versus measuring bone density in osteoporosis]. PMID- 11605307 TI - [Tissue engineering of cartilage replacement tissue in an improved alginate matrix]. PMID- 11605308 TI - [Experimental comparison of arthroscopic and robot-assisted anterior cruciate ligament tunnel reconstruction]. PMID- 11605309 TI - [Does magnetic resonance tomography replace arthroscopy in diagnosis of knee cartilage damage?]. PMID- 11605310 TI - [Acetaminophen use by chronic alcohol abusers: a therapeutic dose may be too much for the liver]. AB - Two patients, both women aged 31 and 73 years, were admitted with chest pain and coma, respectively. They had very high aspartate aminotransferase levels, accompanied by relatively low alanine aminotransferase levels. The second patient had developed acute liver failure and hepatic encephalopathy. Both patients were chronic alcohol abusers and had taken therapeutic doses of acetaminophen for a couple of days. The marked elevation of the aminotransferase levels and the rapid decline of these levels after discontinuing the use of acetaminophen and alcohol led to the diagnosis of acetaminophen hepatotoxicity. In chronic alcohol abusers, cytochrome P450 2E1 is induced and the amount of glutathione is depleted. This combination causes the formation of a relatively large amount of the radical N acetyl-p-benzoquinone imine and a low potential to detoxify this metabolite, so that even small amounts of acetaminophen may cause liver damage. It is recommended that chronic alcohol abusers (more than four alcoholic beverages per day) use no more than 2 g acetaminophen per day. PMID- 11605311 TI - [Gender identity disorders as a symptom of psychosis, schizophrenia in particular]. AB - In the Netherlands it has recently become possible for transsexual patients to receive hormonal treatment from the onset of puberty. Until the age of 16, pubertal development can be prevented with luteinizing hormone-releasing hormone (LHRH) agonists. From 16 years of age onwards, gender adjustment can be initiated by administration of hormones of the opposite sex. Surgical treatment can be offered once the patient reaches 18 years of age. Although such treatment will only be initiated with reticence and after a long phase of intense diagnostic screening, the question arises whether a clear differentiation can be made between pure gender identity disorders and secondary transsexual feelings that are part of an ongoing psychopathological development, such as schizophrenia. The potential diagnostic confusion is illustrated by a case history of a male schizophrenic patient. This patient had been treated hormonally for transsexualism for years before acute psychotic decompensation occurred. Neuroleptic treatment of the psychosis rapidly reduced the psychotic symptoms. In retrospect, the patient regards his transsexual period as a 'mistake'. Delusions about one's physical appearance and the urge to drastically change the way one looks appear to be relatively common in patients suffering from schizophrenia. PMID- 11605312 TI - [Treatment of rheumatoid arthritis by inhibition of tumor necrosis factor with infliximab or etanercept]. AB - The current pharmacotherapy of rheumatoid arthritis (RA) consists of non steroidal anti inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) such as sulphasalazine, leflunomide and methotrexate. DMARDs can be given as monotherapy or in combination. However, not all patients show an adequate response due to toxicity or lack of efficacy. From animal studies and clinical studies in patients with RA, we know that tumour necrosis factor (TNF) is directly involved in the pathogenesis of RA. Two forms of TNF inhibition therapy have been extensively investigated in RA: anti-TNF monoclonal antibodies (infliximab) and TNF receptor-Fc fusion protein (etanercept). Both types of TNF inhibition induce a rapid improvement in multiple clinical measures of disease activity and patient functional status. Furthermore, a beneficial effect was demonstrated on radiographic progression of joint damage. Etanercept and the combination infliximab-methotrexate are generally well tolerated. PMID- 11605313 TI - [Diagnostic image (57). Tenosynovial swelling with cholesterol crystals in rheumatoid arthritis]. AB - In a 69-year-old female patient with erosive rheumatoid arthritis for 8 years, aspiration of a tenosynovial swelling on the dorsum of the right wrist yielded a puslike substance with many birefringent platelike cholesterol crystals. PMID- 11605314 TI - [Stomach ache and fever after consumption of watercress in Turkey: fascioliasis]. AB - A 52-year-old woman presented several months after returning from a visit to Turkey with stomach-ache and fever. Laboratory results showed leucocytosis with marked eosinophilia. Furthermore, serum liver enzyme activities were slightly elevated. A CT scan of the abdomen showed several spots which, on a later scan, had migrated. Serologic tests confirmed the clinical diagnosis of fascioliasis. The patient was successfully treated with triclabendazole. Infection presumably occurred after eating watercress which the patient had bought on a market in Turkey. PMID- 11605315 TI - [Increased Neisseria gonorrhoeae quinolone resistance in Amsterdam]. AB - In addition to a rise in the number of cases of gonorrhoea, the susceptibility of Neisseria gonorrhoeae to antibiotics is also a cause for concern. After a period of high resistance rates to penicillin and tetracycline between 1985 and 1995, resistance rates have dropped considerably in recent years, probably due to changes in treatment regimens. However, recently we have seen an increasing number of quinolone-resistant N. gonorrhoeae isolates in Amsterdam, the Netherlands, a development that has previously been reported in other parts of the world. Some form of national resistance monitoring for gonococci is therefore urgently required to allow timely detection of changes in N. gonorrhoeae resistance. PMID- 11605316 TI - [Medical research and the pharmaceutical industry. Uneasy bedfellows or a prenuptial agreement?]. PMID- 11605317 TI - [Medical research and the pharmaceutical industry. Uneasy bedfellows or a prenuptial agreement?]. PMID- 11605318 TI - [Medical research and the pharmaceutical industry. Uneasy bedfellows or a prenuptial agreement?]. PMID- 11605319 TI - [Abdominal obesity: metabolic complications and consequences for the liver]. PMID- 11605320 TI - [Facial paresis in children; consider Lyme disease]. PMID- 11605321 TI - [New oral hypoglycemic agents]. PMID- 11605322 TI - [Six-month old girl with an anaphylactic reaction to rice flour, a rare food allergy]. PMID- 11605324 TI - Occupational exposure to endocrine-disrupting pesticides and the potential for developing hormonal cancers. AB - It is suspected that endocrine-disrupting pesticides are involved in the development of several cancer and noncancer health risks in humans and wildlife. A large number of pesticides show endocrine-disrupting activities. The potential for human and animal exposure to such pesticides is very high. Farmers, as a group, may be particularly at risk, because they are subject to higher-than average levels of exposure to pesticides over longer-than-average periods. Recent studies have shown that the incidence of hormone-related organ cancers, or hormonal cancers, is elevated among farmers. Exposure to endocrine-disrupting pesticides, particularly to DDT and phenoxy herbicides, is suspected of involvement in some of these hormonal cancers. There is a clear need for a refined epidemiological study that focuses on specific pesticides, accurately assesses exposure, and then examines any association between pesticides and hormonal cancers among farmers. PMID- 11605323 TI - [CBO guideline 'Bacterial meningitis']. PMID- 11605325 TI - Cryptosporidium inactivation by low-pressure UV in a water disinfection device. AB - Using animal infectivity tests, the authors evaluated a water disinfection device, UV Waterworks (UVW), for its ability to inactivate Cryptosporidium parvum oocysts. The UVW employs low-pressure, germicidal ultraviolet (UV) light, delivering a dose of approximately 120 millijoules per square centimeter (mJ/cm2) under ideal water conditions at a flow rate of 4 gallons per minute (gpm). Dechlorinated tap water containing live oocysts was passed through the UVW at 4 gpm. The oocysts were captured on a filter, separated from the filter, and concentrated into inocula--10 microliters (microL) each, containing between 10(3) and 10(7) oocysts--which were administered orally into 60 neonatal mice. After one week, the mice were killed, and sections of their terminal ilea were analyzed microscopically for signs of Cryptosporidium infection. In spite of the high dose of oocysts, none of the mice showed signs of infection. A process control run with the UV lamp off resulted in 95 percent infection at a dose of 10(3) oocysts per inoculum. The calculated reduction in oocyst infectivity from passage through UV Waterworks was at least 5.4 orders of magnitude. The authors conclude that exposure to low-pressure UV at 120 mJ/cm2 effectively disables Cryptosporidium. PMID- 11605326 TI - Reinventing the programmatic and legal basis of food safety: the Wyoming experience. AB - On March 13, 2000, the governor of Wyoming signed into law a comprehensive farm to-table food safety statute. The new law collected all food safety requirements into a single statute and consolidated food inspection activities in the Wyoming Department of Agriculture. A sweeping reform of state food safety programs eliminated the cumbersome patchwork of laws that legislators had been amending for a century. To accomplish this formidable task, Governor Jim Geringer had authorized the formation of the Wyoming Food Safety Task Force in 1997. The task force comprised local, state, and federal government agencies; legislators; the University of Wyoming; and segments of private industry. Using a strategic planning process to build consensus, the task force developed a new system that was unanimously supported. This unified approach contributed to the success of the legislative effort. PMID- 11605327 TI - Acetone. PMID- 11605329 TI - Microbes and the dust they ride in on. PMID- 11605330 TI - Antibiotics in eggs and chicken meat. PMID- 11605331 TI - New methods of identifying microbes in water. PMID- 11605332 TI - Variant Creutzfeldt-Jakob disease--information from the World Health Organization. PMID- 11605333 TI - A model for forecasting emergency hospital admissions: effect of environmental variables. AB - This study modeled patterns and trends in emergency hospital admissions at a hospital in Madrid, Spain. The purpose was to quantify qualitative associations that have been detected between such admissions and a number of environmental variables. The following data were used: unscheduled daily emergency hospital admissions, Madrid air pollution data, and meteorological data. Time-series analysis was performed, with Box-Jenkins modeling. A multivariate model was constructed, incorporating the different causes of admissions and the respective environmental variables. Statistically significant associations were found between hospital admissions and other variables, indicating relationships with temperature, relative humidity, and mean daily tropospheric ozone concentrations. Whereas the effect of heat on admissions was short term, that of cold was in evidence from the second week. The association with ozone showed a seven-day lag and basically manifested itself as an influence on admissions for circulatory disease. PMID- 11605334 TI - Binding of the Hoechst 33342 dye in the monomer and sandwich form with poly[d(AT)].poly[d(AT)] and the self-complementary dodecamer 5'-CGTATATATACG-3'. PMID- 11605335 TI - Effect of allantoin on the activity of enzymes providing regulation of the ROS dependent status of an organism. PMID- 11605336 TI - Effect of new synthetic growth regulators, isomeric 1-(dimethyloctyl), 1 alkylpiperidinium and morpholinium halides on morphogenesis of Aster chinensis L. as a function of their molecular structure. PMID- 11605338 TI - Catalytic sites of enzymes as conserved elements of amino acid sequence alignment: a unique role of glycine and aspartic acid in formation of enzyme active sites. PMID- 11605337 TI - Intracellular antibodies do not affect transport of protein toxins. PMID- 11605339 TI - Species-specific differences in the organization of the complement-binding protein of orthopoxviruses. PMID- 11605340 TI - Chlorophyll a fluorescence in leaves of cucumber plants grown under continuous or natural illumination. PMID- 11605341 TI - Ferredoxin-NADP reductase is involved in the ferredoxin-dependent cyclic electron transport in isolated thylakoids. PMID- 11605342 TI - Synthesis of stress proteins in hyperthermia in the presence of cytotoxic agents. PMID- 11605343 TI - Effect of low-intensity coherent radiation on callusogenesis in wild grasses. PMID- 11605344 TI - Neurons of the ventral horns of the spinal cord participate in visceral innervation during early postnatal ontogeny. PMID- 11605345 TI - A conceptual approach to the phenomenon of antagonistic and synergistic interactions in compound parasitic systems. PMID- 11605346 TI - The dependence of seasonal movements of female polar bears on the reproductive status. PMID- 11605347 TI - New derivatives of fumaric acid as plant growth regulators. PMID- 11605348 TI - Evolution of diversity measures as a reflection of the process of primary soil formation in a model soil-plant system. PMID- 11605349 TI - Development and differentiation of multipotent human neural cells in vitro. PMID- 11605350 TI - The effect of gender on age-related blood pressure changes and the prevalence of isolated systolic hypertension among older adults: data from NHANES III. AB - OBJECTIVE: To examine gender differences in age-related blood pressure changes and the prevalence of isolated systolic hypertension. DESIGN: Third National Health and Nutrition Examination Survey, 1988-1994. SETTING: 89 mobile examination centers and household questionnaire. PARTICIPANTS: 6635 men and 7189 women over the age of 18 years who were not under treatment for high blood pressure. MAIN OUTCOME MEASURES: Levels of systolic blood pressure, diastolic blood pressure, and pulse pressure by age and gender; prevalence of isolated systolic hypertension (ISH). RESULTS: Systolic blood pressures (SBP) and pulse pressures (PP) were higher in males than in females among adults less than 45 years old. After age 45, SBP and PP were higher in females. Diastolic blood pressures were lower among adult females across all age categories. The prevalence of stages 1 and 2/3 ISH were higher among females after age 44 years. The magnitude of the gender differences in the prevalence of ISH was also age dependent. CONCLUSIONS: ISH was higher in elderly women than men. These age related blood pressure changes may account in part for the higher cardiovascular mortality reported among elderly females compared with elderly males and should be considered an important target for cardiovascular preventive strategy, particularly in elderly females. PMID- 11605351 TI - Urinary incontinence in women and men. AB - Urinary incontinence is one of the top 10 chronic health conditions in the United States and affects the lives of 13 million Americans. Although common in both men and women, it is a gender-specific condition whose lifetime distribution, incidence, and etiology differ between the two sexes. Recent advances in health care, along with the increasing aging of the population, create a demand for the treatment of urinary incontinence. This article reviews the currently available treatment options, many of which vary inter- and intra-gender. PMID- 11605352 TI - Myocardial blood flow and flow reserve in response to short-term cyclical hormone replacement therapy in postmenopausal women. AB - OBJECTIVES: To measure the effects of combined cyclical hormone replacement therapy (HRT) on myocardial blood flow (MBF) in postmenopausal women at high risk for coronary heart disease (CHD) and in women with documented CHD. BACKGROUND: Estrogen restores endothelium-dependent vasodilation in response to acetylcholine in postmenopausal women, and it has a direct, endothelium-independent vasodilatory effect on coronary arteries. METHODS: To determine whether coronary microcirculation can be affected by short-term, combined HRT, we performed positron emission tomography (PET) in two groups of women without previous HRT. Group I (n = 10) had one or more risk factors for CHD; group II (n = 8) had documented CHD and previous myocardial infarction. Group II was older (54 +/- 4 vs 59 +/- 5 y, P = .03) and had lower total cholesterol levels at baseline because of lipid-lowering therapy (244 +/- 31 vs 203 +/- 40 mg/dL, P = .03). Patients underwent baseline dynamic PET with N-13 ammonia at rest and during maximal adenosine-induced hyperemia to assess MBF. Each then began taking HRT (conjugated equine estrogen alone or with medroxyprogesterone acetate (MPA), administered in cyclical fashion), and returned for follow-up PET 46 +/- 12 days later. RESULTS: There was no difference in resting MBF between groups I and II prior to starting therapy or at follow-up. Stress MBF and flow reserve (FR) tended to be higher in group I patients at baseline. MBF values remained unchanged at follow-up and resulted in similar FR values at baseline and during HRT for both groups. Women using only estrogen (n = 6) tended to show higher FR values after estrogen therapy, however. CONCLUSIONS: Short-term HRT in postmenopausal women did not lead to improvements in MBF or FR. Combined cyclical HRT may not exert measurable effects on coronary microcirculation. MPA may attenuate estrogen effects on the coronaries, which may be largely endothelium dependent. PMID- 11605353 TI - Impact of gender on diabetes mellitus and its associated cardiovascular risk factors. AB - Diabetes mellitus is a common disorder associated with devastating chronic complications involving end-organ damage and cardiovascular disease. In addition, diabetes imposes a heavy burden due to medical costs, hospitalization, and time lost from work. Women who suffer from the condition have a high risk of developing the complications that stem from it, and, therefore, there must be unknown factors contributing to high mortality and morbidity among women with diabetes. There is a great need for future research to address the issues regarding women and diabetes to help clinicians develop preventive and management strategies that target this population. PMID- 11605354 TI - Mechanisms of cardiac arrhythmias: focus on atrial fibrillation. AB - Atrial fibrillation (AF) is a major cause of morbidity in the aging population. Initially preponderant in men over age 60, it ultimately becomes a disease of women, in part perhaps because of their greater longevity. The subject of AF is an extremely complex one, as described in this article. The author deals with atrial size and atrial pressure, atrial structure, and electrophysiologic correlates of chronic AF in human subjects. He also discusses pacing-induced models of AF and ionic determinants of pacing-induced AF. He emphasizes the changes that occur in the atrium as a result of rapid rate and/or fibrillation and the interdependence of AF and changes in myocardial structure. PMID- 11605355 TI - Does sex matter? The Institute of Medicine answers "yes.". PMID- 11605356 TI - Gender in oral health. PMID- 11605357 TI - The risks of geriatric fatherhood: schizophrenia. PMID- 11605358 TI - Alzheimer's disease: an issue for women's health care. PMID- 11605359 TI - Canadian guidelines for the investigation and follow-up of individuals under medical surveillance for tuberculosis after arrival in Canada. PMID- 11605360 TI - Tuberculosis diagnostic initiative. PMID- 11605362 TI - Relational frame theory: a post-Skinnerian account of human language and cognition. PMID- 11605361 TI - Variability in children's reasoning. PMID- 11605363 TI - The continuity of depression across the adolescent transition. PMID- 11605364 TI - The time of our lives: self-continuity in native and non-native youth. PMID- 11605365 TI - Fuzzy-trace theory: dual processes in memory, reasoning, and cognitive neuroscience. AB - Fuzzy-trace theory has evolved in response to counterintuitive data on how memory development influences the development of reasoning. The two traditional perspectives on memory-reasoning relations--the necessity and constructivist hypotheses--stipulate that the accuracy of children's memory for problem information and the accuracy of their reasoning are closely intertwined, albeit for different reasons. However, contrary to necessity, correlational and experimental dissociations have been found between children's memory for problem information that is determinative in solving certain problems and their solutions of those problems. In these same tasks, age changes in memory for problem information appear to be dissociated from age changes in reasoning. Contrary to constructivism, correlational and experimental dissociations also have been found between children's performance on memory tests for actual experience and memory tests for the meaning of experience. As in memory-reasoning studies, age changes in one type of memory performance do not seem to be closely connected to age changes in the other type of performance. Subsequent experiments have led to dual process accounts in both the memory and reasoning spheres. The account of memory development features four other principles: parallel verbatim-gist storage, dissociated verbatim-gist retrieval, memorial bases of conscious recollection, and identity/similarity processes. The account of the development of reasoning features three principles: gist extraction, fuzzy-to-verbatim continua, and fuzzy processing preferences. The fuzzy-processing preference is a particularly important notion because it implies that gist-based intuitive reasoning often suffices to deliver "logical" solutions and that such reasoning confers multiple cognitive advantages that enhance accuracy. The explanation of memory-reasoning dissociations in cognitive development then falls out of fuzzy-trace theory's dual-process models of memory and reasoning. More explicitly, in childhood reasoning tasks, it is assumed that both verbatim and gist traces of problem information are stored. Responding accurately to memory tests for presented problem information depends primarily on verbatim memory abilities (preserving traces of that information and accessing them when the appropriate memory probes are administered). However, accurate solutions to reasoning problems depend primarily on gist-memory abilities (extracting the correct gist from problem information, focusing on that gist during reasoning, and accessing reasoning operations that process that gist). Because verbatim and gist memories exhibit considerable dissociation, both during storage and when they are subsequently accessed on memory tests, dissociations of verbatim-based memory performance from gist-based reasoning are predictable. Conversely, associations are predicted in situations in which memory and reasoning are based on the same verbatim traces (Brainerd & Reyna, 1988) and in situations in which memory and reasoning are based on the same gist traces (Reyna & Kiernan, 1994). Fuzzy-trace theory's memory and reasoning principles have been applied in other research domains. Four such domains are developmental cognitive neuroscience studies of false memory, studies of false memory in brain-damaged patients, studies of reasoning errors in judgment and decision making, and studies of retrieval mechanisms in recall. In the first domain, the principles of parallel verbatim-gist storage, dissociated verbatim-gist retrieval, and identity/similarity processes have been used to explain both spontaneous and implanted false reports in children and in the elderly. These explanations have produced some surprising predictions that have been verified: false reports do not merely decline with age during childhood but increase under theoretically specified conditions; reports of events that were not experienced can nevertheless be highly persistent over time; and false reports can be suppressed by retrieving verbatim traces of corresponding true events. In the second domain, the same principles have been invoked to explain why some forms of brain damage lead to elevated levels of false memory and other forms lead to reduced levels of false memory. In the third domain, the principles of gist extraction, fuzzy-to-verbatim continua, and fuzzy-processing preferences have been exploited to formulate a general theory of loci of processing failures in judgment and decision making, cluminating in a developmental account of degrees of rationality that distinguishes more and less advanced reasoning. This theory has in turn been used to formulate local models, such as the inclusion illusions model, that explain the characteristic reasoning errors that are observed on specific judgment and decision-making tasks. Finally, in the fourth domain, a dual-process conception of recall has been derived from the principles of parallel verbatim-gist storage and dissociated verbatim-gist retrieval. In this conception, which has been used to explain cognitive triage effects in recall and robust false recall, targets are recalled either by directly accessing their verbatim traces and reading the retrieved information out of consciousness or by reconstructively processing their gist traces. PMID- 11605366 TI - [Cosmophysical effects in processes of various nature]. AB - The explanations to the special number of journal "Biophysics" are presented. PMID- 11605367 TI - [Macroscopic fluctuations of discrete distribution forms as a consequence of the arithmetic and cosmophysical causes]. AB - The recent investigations are reviewed of the "macsroscopic fluctuations", i.e. synchronous on local time changes in probability of the appearance of the same detailed structure of distribution (histograms) of the rates of different processes, at the same or at different geographic points. Gravitation nonhomogeneousity is considered as a probable cause of these phenomena. PMID- 11605368 TI - [Forms of histograms constructed from measurements of alpha-decay of 228Ra in Lindau (Germany) and neutron fluxes in Moscow change synchronously according to the local time]. AB - In joint experiments performed at Max Plank Institute of Aeronomy (Germany) and the Institute of Theoretical and Experimental Biophysics in Pushchino, the main manifestations of the phenomenon of macroscopic fluctuations were confirmed. An increased probability of the similarity in synchronous histograms in independent measurements performed by two installations in one laboratory and in two laboratories separated by a distance of 2000 km was shown. In the latter case, the similarity of histograms is most probable at the same local time. PMID- 11605369 TI - [Correlation of fine structures of distributions of amplitudes of a photomultiplier dark current fluctuations with the Earth rotations about its axis]. AB - The fine structures of distributions of photomultiplier dark current fluctuations measured in two laboratories 2000 km distant from other: in the international Institute of Biophysics (Neuss, Germany) and in the Moscow State University (Moscow, Russia) were compared. It is shown that similar forms of appropriate histograms are apparently more often realized at both locations at the same local time. This confirms the previous conclusion that the fine structure of distributions correlates with rotation of the Earth about its axis. PMID- 11605370 TI - [Comparison of forms of "unfit histograms" by a wavelet transform method]. AB - Two methods checking changes in time of histogram patterns were investigated. These methods are relied on discrete wavelet transform. The result is that in the some cases these methods can more effectively to examine latency in the behavior of histograms form constructed by on overlapping short segments of experimental data. PMID- 11605371 TI - [A possible relationship between the scatter in results of measurements of 239Pu alpha-activity and quasiperiodic fluctuations in a geophysical medium]. AB - A correlation between quasiperiodic variations in 239Pu alpha-activity and geophysical periods was revealed. PMID- 11605372 TI - [Regular changes in histogram forms in physical measurements and mathematical modeling]. AB - A study of macroscopic fluctuations for objects separated by large distances confirmed the conclusion drawn earlier that, if the objects being measured are in different time zones, the increase in the probability of occurrence of histograms of similar form corresponds to the difference in the local time at the points of measurement. It was also found that, upon realization of pseudo-random sequences of numbers in mathematical generators, sequences of histograms very similar to those in real physical series can be realized. This suggests the presence of previously unknown regularities, both physical and mathematical, in sequences traditionally considered as absolutely random. PMID- 11605373 TI - [Relationship between the fine structure and statistic fluctuations in measurement result distributions]. AB - The "near zone effect" described first in the macroscopic fluctuations researches was studied by numerical modeling. Possible mechanisms of its formation were proposed, and the lengths of portions of experimental data that retain the fine structure of histograms necessary for studying the "near zone effect" and provide the minimum level of statistical noise. PMID- 11605374 TI - [The "near zone" effect in dynamic chaos]. AB - The dynamics of the system with a determined chaotic behavior (Lorentz system) was studied by comparing the histograms. It was shown that the dynamics of the system exhibits phenomena similar to those observed in studies of fluctuations in physical systems. In particular, upon comparison of histograms constructed from different time intervals, the "near zone" effect makes itself evident. It was shown that a very slight modulation of only one parameter of the system leads to a change in behavior. PMID- 11605375 TI - [A possible correlation between "anomalous" signals in the Wheatstone bridge and positions of planets]. AB - Current fluctuations in diagonal of nonbalanced Wheatstone bridge were investigated. Correlations of parameters of these fluctuations with culmination times of Moon, Sun and some planet configurations were revealed. The probably biological importance of these phenomena is discussed. PMID- 11605376 TI - [The use of a detector of the extremely weak radiation as a variometer of gravitation field]. AB - It was shown that the detector of extremely weak radiation with selectively increased sensitivity to the nonelectromagnetic, including the gravitational component of the spectrum of active physical fields can be used as the basis for constructing a variometer of gravitational field of a new type. PMID- 11605377 TI - [Random fluctuations in readings of measurement devices: cosmophysic effects?]. AB - Fluctuations of "computer time" provided by the PC quartz generator were studied. It was shown that variations in the yearly course of the quartz generator frequency occur with periodicities of 13-15 days and 28-30 days. Regular fluctuations with periods of 0.5 and 1.0 min are typical of the short-term spectral component. Impulses of sharp and intense deceleration of "computer time" are often observed against the background of these regular fluctuations. The conclusion is made that fluctuations of "computer time" are of cosmophysical origin. PMID- 11605378 TI - [Study with a quartz resonator of a new natural informational channel associated with quantum properties of the physical space (vacuum)]. AB - The results on long-time measurements of differential frequency of two quartz generators are presented. One generator is placed into magnetic system creating a vector potential field, and the other (calibration generator) is situated out of this system. It was found that oscillations of frequency difference occur with periods to 20 h and 22.5 h were revealed. Tangents to the Earth parallel at the moments of observation of value minima form three distinct subsets of directions. The traditional physical concepts do not explain these results. These results are in a good agreement with hypothesis about the anisotropic interaction of objects in nature (due to the new fundamental vector constant, cosmological vector potential Ag) and hence a new informational channel. The possibility is discussed that external factors affect biological objects via the new information channel. PMID- 11605379 TI - [Correlation of the solar activity with water electrical conductivity]. AB - A correlation between the solar activity (Wolf numbers) and electric conductivity of water was found. It was suggested that changes in the electric conductivity of water are the primary cause of the known correlations between the solar activity and various processes in the biosphere. PMID- 11605380 TI - [Periodical changes of various hematological parameters of the human body adaptation and gravitation fields variations]. AB - Monitoring the content of lymphocytes and nucleated neutrophils (observation period 10.5 months) and the determination of the values of leucocytes coefficient and erythrocyte sedimentation rate in chronic patients revealed rhythms of oscillations of these parameters (from 3-5 to 33 days). The coincidence of these rhythms with the rhythms of variations of gravitational field indicates that gravitational field affects the quantitative blood cell composition and the rheological properties of blood. PMID- 11605381 TI - [Variations in the intensity of solar neutrinos as a problem for physical chemistry]. AB - A comparison of variations in the solar neutrino flux in Brookhaven measurements with solar activity indices clearly shows that the neutrino flux is controlled by surface solar processes. These processes can lead to changes in the efficiency of registrations of the neutrino flux. From this view point, the results of the measurements of the neutrino flux on the Brookhaven detector in 1970-1994 (108 runs) were analyzed. It was found that the neutrino flux depends on the heliogeophysical situation. The well known anticorrelation between the neutrino flux and Wolf numbers is observed only for odd cycle of solar activity. A similar regularity occurs for critical frequencies of E-ionosphere. By contrast, the correlation between the neutrino flux and the Ap-index is observed only for the even activity cycle. The predominance of the sign of radial component of the interplanetary magnetic field in the last 7-14 days of exposure has the greatest effect on the neutrino flux (this sign changes as the sign of the total magnetic field of the Sun changes). In short runs, the neutrino flux changes more than threefold. The conclusion is made that variations of the solar neutrino flux are falcious. These fictitious variations are caused probably by the action of very low-frequency electromagnetic emissions of the magnetosphere upon the substance of the target and the technology of the extraction of 37Ar atoms from perchloretylene. PMID- 11605383 TI - [Diurnal variations in the alpha-particles flux as a possible evidence for changes in the movement velocity vector of an experimental set-up relative to a relic system]. AB - The variations in the fine structure of distributions of the results of alpha radioactivity measurements are explained by changes in the velocity of Earth's movement relative to some selected frame of reference. PMID- 11605382 TI - [Probability of disturbance of Poisson statistics in radioactive decay type processes]. AB - The phenomenon of regular dynamics of fine structure of sampling distributions in processes of radioactive decay type is discussed. The time dependence of the probability of their similarity indicates that the process measured is nonstationary. The most natural explanation for the disturbance of stationarity is the influence of gauging equipment, which in principle cannot be avoided completely. However, the universality of the effect and the presence of the correlation of the fine structure in independent synchronous processes leads one to suggest the existence of some global source. A mechanism of the generation of fine structure as a result of the influence of nontrivial topology of space on the decay process is proposed. PMID- 11605384 TI - [A possible explanation of the phenomenon of cosmophysical macrofluctuations]. AB - The conception of relic radiation advanced by the author was used to explain the phenomenon of macroscopic fluctuations. PMID- 11605385 TI - [A theoretical approach to "macroscopic fluctuations" effect]. AB - At present there is no generally accepted theory of the effect of macroscopic fluctuations. It the article, an attempt is made to relate this effect to some basic properties of quantum systems, in particular, to the formal absence of dynamic chaos in these systems. Based on this approach, it was shown why the level of the effect must be of the same order of magnitude as the level of noise and cannot exceed this level as the number of experiments increases. It was shown qualitatively what is the cause of the similarity of histograms observed in different experiments. PMID- 11605386 TI - [Quantum transitions between states and cosmophysical fluctuations]. AB - An explanation of the appearance of the reproducible fine structure of the histograms corresponding to different processes from simple chemical reactions to radioactive decays is developed. Earlier this explanation was reduced to extremely strong influence of small changes between energy levels of a quantum system under study and its environment on the transition probability of the system (chemical reaction, radioactive decay, e.t.c.) from the system last quantum state to final result of the studied process. In the present paper it is supposed that the main factors determining this probability is the periodical or quasi-periodical low frequency changes of local gravitational field leading to corresponding changes of the system mass (the quantum transition probability depends exponentially on the latter). This approach seems to able to propose non contradictory explanation of many manifestations of macroscopic fluctuation. PMID- 11605387 TI - [A source of energy for survival and amplification of heterotrophic microorganisms in the absence of organic substrate. I. Formulation of a hypothesis]. AB - The dynamic characteristics of populations of heterotrophic microorganisms Escherichia coli incubated in a medium devoid of organic substrate were studied. It was found that the population dynamics is related to the electromagnetic environment. A mathematical and physical models of cell multiplication in a medium free of organic substrate were constructed. In these models the natural electromagnetic background near the Earth surface serves as a source of free energy. PMID- 11605388 TI - [A source of energy for survival and amplification of heterotrophic microorganisms in the absence of organic substrate. II. Substantiation of a hypothesis]. AB - Statistical characteristics of E. coli heterotroph populations upon incubation in a substrate-free medium were investigated. It was shown that the model of Langmuir proton oscillations in water media is adequate to experimental data. PMID- 11605390 TI - [Physical mechanism of cell number self-regulation in a population]. AB - It was shown that concentration of cells in a culture of Protozoa phylum (Infusoria) depends on cultivation volume. To explain the effect, a mechanism is proposed by which the maximum possible amount of cells in the culture is regulated. The mechanism is related to the density of radiation (electromagnetic or acoustic) flux emitted by cells. The radiation density increases with the cellularity in the cultivation volume and therefore can provide information on the total number of cells in the volume. The rations of cell concentrations in different volumes calculated under this assumption are in a good agreement with experimental data. It is proposed that a similar mechanism operates in the feed back chain that regulates the cellularity in growing organs of multicellular organisms. It was concluded that, owing to this mechanism, mitoses during the growth of the organ would occur with increasing frequency at the periphery rather than in the center of the organ. Experimental evidence in support of this conclusion is presented. PMID- 11605389 TI - [A source of energy for survival and amplification of heterotrophic microorganisms in the absence of organic substrate. III. Essential and sufficient conditions]. AB - Theoretical estimates and experimental data obtained upon incubation of steady state populations of microorganisms in the absence of organic substrates were compared. The physiological parameters of water microorganisms and the physicochemical properties of water were analyzed. PMID- 11605391 TI - [Regularities and cellular mechanism of spontaneous mutations in enterobacteria]. AB - The regularities and a possible mechanism of the formation of spontaneous mutations in enterobacteria were studied. Possible causes and the mechanism of these processes were analyzed. It was shown that the mechanism of formation of spontaneous mutations is not related to the replication process and DNA polymerase errors. Mutations arise abruptly within 10-20 min due to a cosmophysical factor of unknown origin. It is assumed that cosmophysical radiation makes cell membranes excitable. Upon membrane pulsation, different volumes (portions) of cell substance are ejected through expanding pores. From this substance, viable heteromorphous mutant forms of colonies and cells (bio- and serum variants, L-forms, "parastrains", and new ecoforms of bacteria) are formed. PMID- 11605392 TI - [Coherent electromagnetic fields in the remote intercellular interaction]. AB - The distant interactions various organisms and their communities and the effect of coherent electromagnetic radiation on intercellular relations were studied. The ability of fruit crops male gametophyte to control the germination of pollen tube at the field level (nonchemical) was established. The cooperative character of this process is shown. It is stimulated directly or indirectly, by low intensity coherent radiation through a bioinductor. The conclusion is made that spontaneous chemiluminescence cannot be considered as an information channel of distant intercellular interaction. PMID- 11605393 TI - [A role of various components of the diffuse neuroendocrine system in the realization of magnetobiological effects]. AB - It was shown in experiments on white mongrel rats that some components of the diffuse neuroendocrine system are involved in the realization of magnetobiological effects. PMID- 11605394 TI - [Correlation of biophysical parameters of biologically active points and variations of heliogeophysical factors]. AB - The correlation between the parameters of biologically active points and the dynamics of solar activity was studied. Statistically significant correlations between electroconductivity of biologically active points and solar activity indices (sunspot number, Ap-index, solar radiowave flux) were revealed. The spectral analysis of the temporal organization of biologically active points revealed a set of periods present in the dynamics of solar activity. It was concluded that bioelectric system of the human organism is a complicated multilevel time-structure, which effectively reacts to changes in heliogeophysical dynamics. The bioelectric system of biologically active points is considered to be one of general information channels of electromagnetic nature, which realize the connection of organism with environment. PMID- 11605395 TI - [Effect of the ecologically significant variable magnetic field on metabolic parameters in the animal brain]. AB - The influence of an ecologically significant magnetic field (8 Hz) on metabolic processes in brain regions of animals with different constitutional features was studied. Oppositely directed metabolic changes in the brain of animals with different behavior in the "open field" test were revealed. It was found that the right brain hemisphere dominates in system reaction to extremely low-frequency magnetic fields. PMID- 11605396 TI - [Effect of the variable magnetic field of the extremely low frequency on metabolic processes in the liver of animals with various individual and typological characteristics]. AB - The effect of alternating magnetic field (8 Hz, 5 microT) on lipid peroxidation, thiol-disulfide exchange, the antioxidant system, and energy metabolism in liver of animals was studied. It was found that metabolic changes caused by the application of magnetic field vary in animals with different behavior in the "open field". Statistically significant changes in the activity of some enzymes involved in the antioxidant system and thiol-disulfide exchange were revealed. PMID- 11605397 TI - [Geomagnetic activity and human embryonic development]. AB - A retrospective analysis of weekly values of geomagnetic activity during embryonal development for healthy and mentally diseased people was performed. A statistically significant in the aa-index for mentally diseased people by 4.5-5.5 week of embryonic growth was revealed. This suggesting that the level of geomagnetic activity affects the laying and development of the central nervous system. PMID- 11605398 TI - [A possible biophysical mechanism of the solar activity effect on the central nervous system in man]. AB - A biophysical mechanism of interaction between the man and environment is proposed, which treats these components as two correlated oscillation contours with discrete resonance frequencies. The coincidence of biocurrent frequencies of the human brain with the resonance frequencies of the cavity formed by the Earth surface and the lower ionosphere boundary allows one to consider the influence of solar flares on the human organism in terms of variations of the cavity frequencies due to changes in the parameters of its upper wall. PMID- 11605399 TI - [Severe trauma rate during planet geomagnetic storms]. AB - The growth of the diurnal frequency of appearance of heavy traumas during planetary geomagnetic storms is shown and statistically justified. No effect of short-term geomagnetic disturbances of natural and technogenic nature on the occurrence of acute mental and cardiovascular pathologies was detected on the basis of diurnal data. PMID- 11605400 TI - [Biotropic effects of geomagnetic storms and their seasonal variations]. AB - A substantial effect of geomagnetic storms on human health with a confidential probability P = 0.95 was revealed. The quantitative estimates of the biotropic effect are presented. For example, the frequency of occurrence of bursts exceeding the average number of hospitalized patients with mental and cardiovascular diseases during magnetic storms increases approximately 2 times compared with quiet periods (based on the data on 1983-84). The frequency of occurrence of myocardial infarction, angina pectoris, violation of cardial rhythm, acute violation of brain blood circulation during storms increases 2.1; 1.6; 1.6; 1.5 times, respectively compared with magnetically quiet periods (based on the data of 1992-96). A similarity of the seasonal distribution of the magnitude of the biotropic effect is revealed in the case of myocardial infarction and the number of magnetic storms: a maximum in the equinox and a minimum in summer. PMID- 11605401 TI - [Geomagnetic and artificial weak magnetic fields of superlow frequency as factors changing the body radiosensitivity]. AB - Geomagnetic disturbances and experimentally generated weak variable superlow frequency magnetic fields have either a radioprotecting or radiosensitizing effect on the mouse body depending on the time, intensity, and mode of influence. PMID- 11605402 TI - [The human body response to factors related to solar activity variations]. AB - The effect of nonstationary solar processes on human organism was studied. Daily measurements of electrical conductivity of 22 biologically active points on human skin, arterial pressure, and pulse frequency of 30 persons were performed, and their subjective sensations were registered. A comparative analysis of the data and variations in environment parameters, such as local A-index, atmospheric pressure, temperature, and indices of cosmic rays indicated a coincidence of their main periods. The conclusion is made that the reaction of the human organism on abrupt solar disturbances is biphasic and that there is a semiannual wave of synchronization of work of internal organs. The results are confirmed by simultaneous measurements in different cities. PMID- 11605403 TI - [The non-contact effect of substances containing benzene rings and heterocycles on biological systems]. AB - It was found that some substances containing benzolic rings and heterocyclic structures have a noncontact effect on biosystems. Some results of experiments dealing with the noncontact effect on enzyme molecules, cells, and uni- and multicellular organisms are presented. Factors influencing the efficiency of the noncontact effect were revealed. PMID- 11605404 TI - [Pyramid effect]. AB - The effect of a model pyramid of Egyptian type on plants, aqueous solutions, and solids was studied. It was found that a presowing holding of dry barley seeds in the pyramid stimulated the growth of this plant. On the contrary, "pyramid" water, when used in sowing, suppressed the early growth of plants. The pH of the water held in a pyramid changed compared to the norm. A threefold increase in the rate of decomposition of hydrogen peroxide was observed when an aqueous H2O2 solution was held in a pyramid. It was also found that the masses of both biological objects (seeds) and inorganic solids (quartz) changed in the intrapyramidal space. PMID- 11605405 TI - [Vertebrate crystallins- from proteins to genes]. AB - A review of literature on tissue-specific proteins of the vertebrate eye lens and genes coding for these proteins is presented. Particular attention is paid to the most heterogeneous family of crystallins: beta- and gamma-crystallins, their nomenclature, and the structure of their genes. It is pointed out that mutations in gene coding for ubiquitous crystallins may be related to some forms of cataracts. PMID- 11605406 TI - [Morphogenetic effects of the interaction of floral mutations petal-sepal and anther in petal in Papaver somniferum l]. AB - The morphogenetic effects of the interaction of the floral mutations petal-sepal and anther in petal in Papaver somniferum L. with a monocarpic shoot were studied. During analysis of the mutations controlled by the genes ptsp and Ant, no plants of the double-mutant class were found in the second generation, in which microsporangia form on the corolla sepal structures. The ratio of phenotypic classes obtained in the experiment corresponds to that inheritance, when the genetic control of mutant characters is realized by nonallele nonlinked genes Ant and ptsp upon epistatic interaction of these genes. These data were confirmed by analysis of the genotypes of F2 plants from the phenotypic class petal-sepal, which include plants that carry both mutant genes Ant and ptsp. The results obtained suggest that the gene Ant, which controls the formation of microsporangia in the corolla metameres, is not expressed in the presence of a mutation of the gene ptsp; i.e., microsporangia are not formed in tissues with photosynthesizing cells. It is evident that the development of microsporangia is determined by the level of a product of the gene Ptsp. The role of flavonols (quercetin), inhibitors of photosynthesis, as a mechanism of regulation of activity of the genes controlling morphogenesis of the corolla elements and differentiation of microsporangia, is discussed. PMID- 11605407 TI - [Phenomenon of DNA-abzyme cross-reactivity and its significance for the mechanisms of cytotoxicity and apoptosis]. AB - The physiological role of DNA-abzymes and their involvement in pathogenesis of different autoimmune disorders is still unknown. At the same time, a variety of properties and features of DNA-hydrolyzing autoantibodies have been studied. Here, the phenomenon of the cross-reactivity of DNA-abzymes with the nuclear matrix proteins was studied. The possible value of the phenomenon for the cytotoxic activity of DNA-hydrolyzing autoantibodies was debated as well. A new hypothesis is put forward regarding the DNA-abzymes formation based on the phenomenon of the cross-reactivity of polyclonal DNA-abzymes with nuclear matrix proteins free of native DNA. Preliminary results suggest that there are mechanisms of cytotoxicity mediated by DNA-abzymes and independent from the system of complement and cytotoxic T-lymphocytes. PMID- 11605408 TI - [Different influences of genomic imprinting on the development of parthenogenetic cell clones in C57BL/6 and CBA mice]. AB - Clonal analysis of parthenogenetic chimeric mouse embryos C57B1/6(PG)<-->BALB/c has shown that parthenogenetic cell clones C57BL/6 are present in the brain, liver, and kidneys of 14- and 18-day-old embryos. The content of the parthenogenetic component (PG) in these organs on day 18 was lower than on day 14, and, in some 18-day-old embryos, parthenogenetic cell clones were absent from the liver and/or kidneys. These data suggest that, during the embryogenesis of parthenogenetic chimeras, parthenogenetic cell clones of mostly endodermal and mesodermal origins were actively eliminated. Therefore, in such parthenogenetic adult chimeras, parthenogenetic clones of mostly ectodermal origins were preserved. In parthenogenetic chimeras CBA(PG)<-->BALB/c, parthenogenetic cell clones were actively eliminated at early embryonic stages, and, as a result, they were absent at the post-implantation stages. Hence, during development of parthenogenetic cell clones, the effects of genomic imprinting are expressed unequally in C57BL/6 and CBA mice. PMID- 11605409 TI - [Nucleocytoplasmic incompatibility in androgenetic fish hybrids can be overcome]. AB - Many androgenetic fish hybrids are nonviable due to the disturbed interaction between the foreign nucleus and the cytoplasm. It has been proposed that this incompatibility can be overcome if eggs from interspecific hybrids and sperm from one of the parental species are used for diploid androgenesis. Indeed, the androgenetic progeny obtained as a result of the insemination of the enucleated eggs of goldfish and carp hybrids by the carp spermatozoa proved to be viable and fertile. This approach may be used for reconstitution of the genotypes of rare or disappearing fish species with the help of induced androgenesis, if their native or cryoconserved sperm is available. PMID- 11605411 TI - [Different functional and structural properties of lactate dehydrogenase isozymes at different stages of Danio rerio ontogenesis]. AB - We studied properties of lactate dehydrogenase isozymes expressed at different stages of Danio rerio ontogenesis. H4-LDH and a minor fraction H3M1 are expressed during embryonic development. The muscle isozyme (M4) appears after the beginning of muscle contractions in the embryo. H4 and M4 isozymes isolated from the heart and skeletal muscle of the adult fish, respectively, show significant differences in terms of Km, activation energy (AE), and inactivation temperature. H4-LDH isozymes isolated from unfertilized eggs, the skeletal muscle of larvae, and the heart of the adult fish differ in Km and activation energy, as well as in inactivation temperature. We propose that these differences may be associated with a ligand interacting with the H4 isozyme at different steps of ontogenesis. PMID- 11605412 TI - [Characteristics of Actinomycin D-induced segregation of a "noncanonical" nucleolus of the sea urchin Paracentrotus lividus]. AB - The structure of a "noncanonical" nucleolus of vitellogenic oocytes in the sea urchin Paracentrotus lividus was studied using the inhibitor of transcription actinomycin D. In the control cells, the nucleolus consists of two separated structural subdomains: the dense fibrillar-granular peripheral area and the fibrillar central area. The nucleolus did not contain subdomains corresponding to the fibrillar center and dense fibrillar component of "typical" nucleoli. After treatment with actinomycin D, numerous argyrophilic granules appeared in the karyoplasm, the intranucleolar DNA became compact, and the nucleolar material was segregated into two or three separated zones, the residual peripheral area being the densest and largest. Lesser zones had a decreased electron density and contained argyrophilic proteins and, apparently, the nucleolar organizer material. These results suggest that, for normal rRNA expression and processing, the presence of structural subdomains in the nucleolus, such as fibrillar complexes and a dense fibrillar component, is not essential. PMID- 11605410 TI - [Myogenic differentiation of Mytilus larval cells in vitro]. AB - A myogenic differentiation program can be realized during the cultivation of Mytilus trossulus cells derived from larvae in premyogenic developmental stages. About 10-15% of cells in such cultures showed that they are capable of contracting actively. The shape of such cells and the high concentration of actin microfilaments indicate a similarity with smooth muscle cells. However, the pattern of contractile activity and the protein composition of these cells differ significantly from the corresponding characteristics of differentiated smooth muscle cells. The proportion between the main proteins of the thick fiber, paramyosin, and myosin in cultivated cells is far lower than in the muscles of larvae or adult molluscs. We also found that substrates with different adhesional characteristics may determine cell development towards one or the other phenotype. Cells attached to the collagen substrate, but not spread on it, had high proliferative potential; the collagen substrate, however, inhibited myogenic differentiation. PMID- 11605414 TI - [Theory of phyllotaxis. I. A geometric model for helical forms of consecutive phyllotaxis]. AB - We have developed a geometric model for helical forms of consecutive phyllotaxis on the basis of an axiomatic approach. It follows from the model that rudiment growth and the movement of the cylindrical rudiment surface in the absence of a displacement in the direction along the rudiment axis leads to a repeating transition of tetragonal packaging of the rudiment into hexagonal packaging and vice versa. Under these conditions, sequences of rudiments produce left-handed and right-handed helices, the number of which at the circumference of the cylinder corresponds to adjacent numbers of the Fibonacci series. We demonstrate that the left-handed and right-handed isomers of helical forms of the consecutive phyllotaxis appear as a result of the transition of an unstable symmetric structure of the embryo at early developmental stages into stable left-handed or right-handed structures. PMID- 11605413 TI - [Comparison of the effects of gonadotropic preparations of the carp and stellate sturgeon pituitaries on in vivo and in vitro oocyte maturation in the Siberian sturgeon Acipenser baeri brandt]. AB - Injections of 2.5 mg/kg of stellate sturgeon (Acipenser stellatus Pall.) pituitary extract and 5 mg/kg of carp (Cyprinus carpio L.) pituitary extract in Siberian sturgeon (Acipenser baeri Brandt) females did not reveal significant differences in the effects of these preparations. There were no differences in the percentage of females that responded by ovulation, duration of the period from injection to ovulation, rate of ovulation, or quality of mature eggs as estimated by the percentage of fertilization or percentage of normal embryos at the small yolk plug stage. Thus, an insufficient efficiency in the artificial reproduction of the Siberian sturgeon grown in captivity is not related to the use of the carp pituitary preparation as a stimulus. Estimation of the ratio of specific activities of the pituitary extracts and purified gonadotropins of the stellate sturgeon and carp by in vitro oocyte maturation has shown that it varies within wide limits as a function of the medium composition and physiological state of follicles. Hence, the ratio of activities of the gonadotropins of different species as determined by in vitro maturation of sturgeon oocytes may markedly differ from that upon injection of these preparations in breeders. PMID- 11605415 TI - [Estimating probabilities and dealing with mutations in paternity testing- verification of DNA testing with commercially available STR kits]. AB - Since Jeffreys devised a DNA fingerprint in 1985, DNA analysis has been applied to paternity testing. The progress of the techniques, especially the development of polymerase chain reaction (PCR), makes it possible to type 10-15 short tandem repeat (STR) loci in paternity testing by a single test tube. When using a well qualified database, we can now obtain a paternity index (PI) as high as 10(6) in usual trio cases. Furthermore, the DNA testings are now applied to unusual cases, such as personal identification of Japanese war orphans left in China. Here, we reviewed how to calculate the PI likelihood ratio and exclusion probability in a trio case, a motherless case, parent identification without reliable evidence of mother and child relationship, and a sibling case. We also reviewed how to handle single exclusion cases usually derived from a single mutation that is no longer rare when many STR loci are used. Finally, we emphasized the importance of ethical, legal and social counseling for clients in paternity testing. From that point of view, paternity tests by mail should not be allowed because of lack of such counseling. PMID- 11605416 TI - [Causes of dementia and bed-ridden state in elderly victims of road traffic accidents in Japan]. AB - BACKGROUND: In Japan, autopsies are seldom performed for the victims of road traffic accidents (RTA). Thus, when an elderly RTA victim dies after long-term hospitalization, the actual cause of death is hard to determine. SUBJECTS: Eight hundred eleven road traffic victims (69 +/- 16 years, M/F = 592/219) for whom insurance companies required us to judge the medical causal relation between the accident and the death from the view point of clinical forensic medicine. METHODS: We discussed and reevaluated the cause of death and decided the cause and effect relation based on medical information. RESULTS: The number of subjects was equivalent to 8.4% of the yearly deaths by RTA in the investigated area, 19.3% of the aged death by RTA. An autopsy was performed only for 5%, ISS was 17.0 +/- 11.5; 94% were hospitalized; 62% continued to be unconscious, involving dementia (32%), persistent vegetative state (17%), coma or semi-coma (13%). Of the cases investigated, 89% died after becoming bedridden, which in 87% of cases was due to the RTA. The odds ratios of a bedridden state for head AIS > = 3, lower limbs AIS > = 2, lower limbs AIS > = 3, spinal AIS > = 3, chest AIS > = 2 were 3.1, 3.2, 7.2, 2.5, 1.8, respectively. The odds ratios of dementia for head AIS > = 3, head AIS > = 4, chest AIS > = 4 were 29.2, 35.9, 1.2, respectively. Patients with head injuries were more likely to be bedridden and senile, and patients with leg fractures tended to be bedridden, particular in the aged. When elderly traffic victims became bedridden or senile, most of them, 399 bedridden victims and 53 non-bedridden victims, died within 242 +/- 283 days, and 356 +/- 284 days from the RTA, respectively. The cause of death could be classified into five categories; pneumonia, other infection, malnutrition and/or dehydration, malnutrition and/or dehydration with pneumonia, malnutrition and/or dehydration with other infection. Traffic deaths were recorded on 31% of death certificates, but were 77% by our reevaluation (p < 0.00001), because the cause-of-death can be difficult to determine in elderly traffic victims. Logistic regression was used to calculate the risk of dementia caused by bone fractures after adjusting for age and gender. The risk of dementia due to bone fractures was influenced by the number of the long fractured bones, a high age group, a lower ADL, and a past history of dementia. Thus, we speculate that traumatic dementia based on bone fractures may occur. PMID- 11605417 TI - [The legal status of a human corpse]. AB - A human corpse presents a number of difficulties, one of which involves difficulties associated with its legal status. A human body, once dead, is considered only as a weight of material, although it signifies continuity of what used to be a living being. A corpse is not an integral part of a human being any more. Legal human rights are only applicable to living humans, and not to a corpse. A fertilized human ovum, a human embryo, a fetus or a separated part of a (live) human body has legal-status problems that are similar to those of a corpse. In Japan, destruction, abandonment or ryotoku (take illegal possession) of a corpse, is forbidden by Japanese Criminal Law #190. This law aims to respect popular religious beliefs, rather than to protect personal rights of a given dead person. Our society needs some other way to provide a dead person with legal protection. Those of us practicing in legal medicine should remind the students in our classroom as well as ourselves of the problems just mentioned. We must always keep in mind that autopsy is exceptionally permitted by law with respect to a corpse for the larger good of society at large. PMID- 11605418 TI - [An autopsy case of accidental hanging during home care]. AB - A 73-year-old man who had suffered from old myocardial and cerebral infarction for 4 years had been secured in wheelchair due to left hemiplegia and aphasia and also been received a home care of his wife. One day, his wife tied a cloth belt around his head and secured it to the wheelchair to prevent the flexion of his neck. One hour later, he was found dead by his wife. He also had slipped down in his wheelchair. The autopsy performed 24 hours after death revealed a ligature marks on the front of the neck. Petechial hemorrhages, visceral congestion and fluid blood, compatible with asphyxial death, were also found. Although severe cerebral cortical atrophy, old myocardial infarction, moderate to severe atherosclerosis and decubitus of the back were also found, they were not considered primary cause of death. No other anatomical or toxicological cause of death was present. Therefore, we concluded that the man died of accidental hanging. Recently, the home care of aged or handicapped patient is a social problem in Japan due to the increase in the number of elderly people. The death was caused by the inappropriate restraints used by his wife. This case suggests the importance of proper advice to non-professional caretakers from care professionals. PMID- 11605419 TI - [Legal and technical issues of formalin disposition in association with autopsy]. AB - The Ministry of Public Welfare notified on the disposition of formalin, which was used in the histological examination in association with forensic or pathological autopsy. However, those who concerned on the issue had not known exactly how they dispose formalin. The news on the illegal disposition of formalin from our department drew attention to the legal disposition of formalin. These situations led us to investigate the legal and technical aspects of formalin disposition. We examined the legally-described methods such as oxidation, incineration and activated sludge processes and other methods such as formose, supercritical water oxidation, and wet oxidation processes. From legal point of view, we must process poisonous formaldehyde into non-poisonous products under the control of The Poisonous and Peleterious? Substances Control Law. Additionally, the products are under the control of The Sewage Water Law and Water Pollution Control Law, particularly in terms of Biological Oxygen Demand (BOD). After careful investigation, we tentatively conclude that incineration method is the best at present, though the supercritical oxidation and wet oxidation processes may be better in order to cope with the worldwide movement toward the control of environmental hormones and warm climate. PMID- 11605420 TI - [Orienting reflex: "targeting reaction" and "searchlight of attention"]. AB - The concept of orienting reflex based on the principle of vector coding of cognitive and executive processes is proposed. The orienting reflex to non-signal and signal stimuli is a set of orienting reactions: motor, autonomic, neuronal, and subjective emphasizing new and significant stimuli. Two basic mechanisms can be identified within the orienting reflex: a "targeting reaction" and a "searchlight of attention". In the visual system the first one consists in a foveation of a target stimulus. The foveation is performed with participation of premotor neurons excited by saccadic command neurons of the superior colliculi. The "searchlight of attention" is based on the resonance of gamma-oscillations in the reticular thalamus selectively enhancing responses of cortical neurons (involuntary attention). The novelty signal is generated in novelty neurons of the hippocampus, which are selectively tuned to a repeatedly presented standard stimulus. The selective tuning is caused by the depression of plastic synapses representing a "neuronal model" of the standard stimulus. A mismatch of the novel stimulus with the established neuronal model gives rise to a "novelty signal" enhancing the novel input. The novelty signal inhibits current conditioned reflexes (external inhibition) contributing to redirecting the behavior. By triggering the expression of early genes the novelty signal initiates the formation of the long-term memory connected with neoneurogenesis. PMID- 11605421 TI - [Role of the right brain hemisphere in training for the operator work]. AB - Functional state of the human right brain hemisphere was studied during simulation of 4-hour operator's training work with a computer in novel conditions. Participants of the experiments differed in the degree of extraversion and baseline level of cortical activity. The obtained results suggest that the role of the right hemisphere in the process of simulated activity consists in reception and primary processing of information. This hemisphere is not involved in the correction of cortical activation to the optimal level of activity, which is necessary for the efficient performance of a task. PMID- 11605423 TI - [Cortical connectivity in schizophrenic patients with positive and negative symptoms ]. AB - The paper is dedicated to the problem of disturbed "connectivity" between different cortical areas in schizophrenic patients with the dominance of "negative" and "positive" symptoms. The architecture of cortical connections in high-frequency range of the beta rhythm (beta 2, 20-40 Hz) was studied in three groups of right-handed men: healthy control group (16 subjects) and schizophrenic patients with the dominance of positive (16 subjects) and negative (22 subjects) symptoms assessed by the SAPS and SANS scales. Two versions of the Intracortical Interaction Mapping (IIM) technique of examination of cortical connections were used. In the 1st version, mean connection frequencies in the beta 2-rhythm for each group were analyzed. In the 2nd version, the most typical for a given group connection frequencies were studied. Additionally, since the IIM technique is rather new, coherence function in the beta 2-rhythm calculated by the standard way was also taken into account. The obtained results made it possible to reveal the derangements in the system of cortical interactions in schizophrenic patients. PMID- 11605422 TI - [Recognition of joy, anger, and fear by face expression in humans]. AB - Behavioral and neurophysiological characteristics of a visual recognition of emotions of joy, anger, and fear were studied in 9 young healthy men and 10 women. It was shown that these emotions were identified by subjects with different rate and accuracy; significant gender differences in recognition of anger and fear were found. Recording of visual evoked potentials (VEP) from the occipital (O1/2), medial temporal (T3/4), inferior temporal (T5/6), and frontal (F3/4) areas revealed differences (related with the type of emotion) in the latencies of P150, N180, P250, and N350 waves and in the amplitude of VEP components with the latencies longer than 250 ms. These differences were maximally expressed in T3/4 derivation. The subjects could be divided in two groups. The first group was characterized by increased VEP latencies and higher amplitudes of VEP components later than 250 ms in response to anger (in comparison with other types of emotions). These phenomena were observed in all the derivations but were most pronounced in T3/4. In the second group, only late P250 and N350 components had shorter latencies during recognition of fear. VEP amplitude variations related with the type of emotions were insignificant and were recorded in the occipital and frontal areas. The two groups of subjects also differed in psychoemotional personality characteristics. It is suggested that primary recognition of facial expression takes place in the temporal cortical areas. A possible correlation of electrophysiological indices of emotion recognition with personality traits is discussed. PMID- 11605424 TI - [Correlation of the unit activity of the right and left lateral hypothalamus in food motivation]. AB - Correlation between activities of neurons in the right and left lateral hypothalamus of a rabbit recorded during quiet wakefulness, after 24-h food deprivation, and after satiation was studies by plotting cross- and autocorrelation histograms. A predominant order in correlated bilateral discharges of hypothalamic neurons was revealed in hungry animals: in a significantly greater number of cases (59%) the left-side discharges led the right-side ones with time delays to 200 ms (peaks at 30 and 160 ms). The opposite order of discharges was less common (21%). In the state of hunger, the probability of appearance of theta-range frequencies in correlated neuronal discharges increased (from 11 to 29%). PMID- 11605425 TI - [Interaction of stereotypic behavior in mice and effects of activation of presynaptic dopaminergic receptors in extinction and amnesia]. AB - Using the methods of agonistic confrontations of C57BL/6J mice for formation of aggressive and submissive types of behavior and passive avoidance training we investigated the influence of activation of dopamine presynaptic receptors on retention of a memory trace during extinction and amnesia. Autoreceptor agonist (+)3PPP (2 mg/kg, intraperitoneal injection) impaired learning and retention of a memory trace during extinction and strengthened the amnestic influence of animal detention in a dangerous compartment on the training day only in aggressive mice. In submissive mice, (+) 3PPP improved the retrieval of passive avoidance during extinction but did not change the development of amnesia. This work was the first to demonstrate that the effects of dopamine autoreceptor activation on the passive avoidance retrieval depend on behavioral stereotype (aggressive or submissive). It is suggested that different basic states of the dopaminergic system in aggressive and submissive mice are responsible for different (+) 3PPP effects. PMID- 11605426 TI - [Effect of neurotensin injections into caudate nuclei on realization and extinction of conditioned motor reflex in rats]. AB - It was shown that neurotensin microinjections into the caudate nuclei facilitated of a conditioned reflex but not affected its realization. Besides, neurotensin was shown to have a positive aftereffect on extinction. Motor activity of rats in the "open field" was augmented after neurotensin administration. A conclusion was drawn that the functional effect of neurotensin administration into the caudate nuclei is connected with the normalization of the motivational and emotional state of an animal rather than with the regulation of the motor function. PMID- 11605427 TI - [Classification of the forebrain striatum neurons in birds]. AB - Polymorphism of neurons in the basic fields of the forebrain striatum of birds was described using specially developed classification of neurons in Nissl preparations. Birds with different degrees of development of elementary rational activity were studied: Corvus monedula, Columba livia, Coturnix coturnix, and Melopsittacus undulatus. According to the proposed method, the neurons were classified in 3 basic types and 2 additional, 6 subtypes and 26 classes. It was found that in the higher brain regions of Corvus monedula, birds with advanced rational activity, there are a greater variety and number of complex associative stellate cells than in birds with poorly developed rational activity (Columba livia and Coturnix coturnix). PMID- 11605428 TI - [Comparison of cholinergic systems in Ep neocortical regions of cats with high and low cognitive ability]. AB - Cats were behaviorally tested for the ability to solve the abstraction and generalization tasks. Fractions of light (C) and heavy (D) synaptosomes of the associative temporal (Ep) areas were prepared, and subfractions of synaptic membranes and synaptoplasm were isolated. Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity and the content of protein and protein sulphydric (SH-) groups were measured in synaptic subfractions. All the studied characteristics were lower in subfractions C of cats with higher cognitive abilities. In subfractions D, the ChAT activity was correlated neither with ChAT activity in the respective C fraction, nor with cognitive abilities of cats. It is suggested that cholinergic terminals originating from neurons of the basal magnocellular nuclei are concentrated in the C fractions, and those from the cortical cholinergic neurons are concentrated in the D fractions. Physiological significance of the "deficiency" of cholinergic inputs of the Ep areas from the basal magnocellular nuclei in animals with higher cognitive abilities is discussed. PMID- 11605429 TI - [Alteration in the brain electrical activity, diurnal sleep structure, and the rat behavior after immunization with bovine serum albumin conjugated with dopamine]. AB - Male Wistar rats (380-430 g) were immunized with bovine serum albumin conjugated with dopamine (2 mg/kg, 0.25 ml) mixed with Freund's adjuvant complete (0.25 ml) or with bovine serum albumin mixed with Freund's adjuvant complete in the same doses. One week after the immunization with bovine serum albumin conjugated with dopamine, irregular spike activity and high-amplitude spindles associated with the state of awake immobility were recorded in the rat neocortex and caudate putamen, the relative power of the electrical activity in the caudate putamen was decreased in the alpha band, while the relative power of the beta 1 in the cortical EEG was increased. In the structure of 4-hour diurnal sleep, a decrease in the mean duration of sleep episodes and a reduction in the REM sleep content were observed. The parameters of the electrical activity and diurnal sleep structure returned to normal during the following 4 weeks. The open-field behavior 2 weeks after the second immunization (without Freund's adjuvant complete) did not differ from that of the control rats immunized only with bovine serum albumin. Titres of antibodies to dopamine after the second antigen injection were 1:32-1:64 in the electrophysiological series and 1:128-1:256 in behavioral experiments. PMID- 11605430 TI - [Is dehydroepiandrosterone sulfate an anxiolytic agent?]. AB - Effects of dehydroepiandrosterone sulfate (DHEAS, 30 mg/kg, i.p., 4 and 28 hours after the injection) were studied in CBA/Lac male mice different in the level of anxiety resulting from repeated social victories (winners) or social defeats (losers) in 10 daily agonistic confrontations. The losers demonstrated high level of anxiety estimated by the "partition" test. The DHEAS and saline injections had different effects on winners, losers, and intact mice. DHEAS prevented the development of anxiety in losers 28 hours after the injection. In these experimental conditions DHEAS exerted no effect on winners. It was concluded that the DHEAS effect depends on the psychoemotional state of an animal. The anxiolytic effect of the exogenous DHEAS may be also characteristic of the endogenous hormone secreted by the adrenal glands and in the central nervous system. PMID- 11605431 TI - [Effects of pyramidotomy on instrumental reflexes in rats depend on the duration of its execution]. AB - The effects of unilateral transection of bulbar pyramids on instrumental conditioned reflexes in rats were shown to be in direct relationship with the time of its execution. In rats with stable conditioned reflexes, pyramidotomy impaired conditioned performance, on the average, for 3.9 days. However, preliminary transection of the pyramid delayed operant conditioning and its stabilization, on the average, by 16.5 day. The findings are discussed in terms of the mechanisms of switching over descending influences of the cortico-spinal and cortico-rubrospinal systems. PMID- 11605432 TI - [Characteristics of heterochromatin of heterophase nuclei from interphase neurons of various brain structures selected for the nervous system excitability]. AB - Quantitative characteristics (the area and number of chromocenters) of the interphase C-heterochromatin in the nuclei of pyramidal neurons of the midbrain reticular formation, sensorimotor cortex, and hippocampus (CA3) of rat strains with different genetically determined excitability were studied in the normal state of the animals and after exposure to a short-term emotional pain stress. The results indicate a relationship between the excitability of the nervous system and structural-functional state of the neuronal interphase heterochromatin. The role of cytogenetic features of different brain structures in the CNS functioning and behavior and their relation with genetically determined excitability of the nervous system are discussed. PMID- 11605434 TI - [Substrate-inhibitor analysis of the hemolymph cholinesterase from the Pacific ocean Neptunea eulimata (Mollusca)]. PMID- 11605433 TI - [Divergent and convergent mechanisms of the integrative activity of the mammalian brain]. AB - Convergent intercellular synaptic interaction is actualized, mainly, by two neurotransmitter systems: glutamate- and GABA-ergic (excitatory and inhibitory postsynaptic potentials, respectively). Fast and slow postsynaptic receptors of glutamate- and GABA-ergic synapses are described. All other brain systems are divergent neuromodulators. Modulators are released into the intercellular space and simultaneously interact with a large population of neurons. A hypothesis of divergent modulatory integration is described: the divergently functioning neuromodulators actualize stable functional states of the brain via appropriate long-term modification-inducing receptors. These stable states are a biochemical basis of the motivational and emotional states. Mechanisms of the secondary nuclear signaling triggered by the long-term modification-inducing receptors consolidate the stable states. The hypothesis of divergent modulatory integration is substantiated in the paper on the basis of the evidence obtained by the author and his collaborates. The haloperidol catalepsy and pentile-netetrazole kindling are considered as a behavioral model of the divergent modulatory integration. The experimental data suggest that divergently functioning neuromodulators actualize and consolidate general motivational and emotional states via the appropriate long-term modification-inducing receptors. The consolidation is structurally specific. The motivational and emotional states concomitant of learning and memory are a specific variation of the general motivational and emotional state depending on the learning situation. PMID- 11605435 TI - [The role of oxidative metabolism in energy supply for active potassium transport in erythrocytes of Lampetra fluviatilis]. PMID- 11605436 TI - [Comparative study of catalytic properties of the liver monoamine oxidase from the squid Todarodes pacificus and the Wistar rat]. PMID- 11605437 TI - [Characteristics of activation of glycogenolysis enzymes in the skeletal muscle of the trout Salmo trutta morpha fario]. PMID- 11605438 TI - [Superoxide dismutase and catalase in organs of mammalians with various ecological genesis]. PMID- 11605439 TI - [Seasonal adaptation of general metabolism and energy metabolism in the elk Alces alces from Pechora taiga]. PMID- 11605440 TI - [Dependence of electrical activity of motor neurons and locomotor behavior of Lymnaea stagnalis on environmental temperature]. PMID- 11605441 TI - [Synchronization of the endogenous somato- and visceral motor activity in rat during ontogenesis]. PMID- 11605442 TI - [TSKY peptide inhibits the ground squirrel recovery after hibernation]. PMID- 11605443 TI - [Changes in motor and sensory asymmetries in highly qualified athletes]. PMID- 11605444 TI - [Effect of selection for behavior on the morphofunctional status of the pineal gland in gray rats]. PMID- 11605445 TI - [Physiological adaptation (exotrophy in fishes)]. PMID- 11605446 TI - [All-Russian symposium on comparative endocrinology dedicated to the memory of professor L G Leibson (on his 100th birthday)]. PMID- 11605447 TI - [Factors determining choline mimetic activity of dicholine esters of dicarboxylic acids in neurons of the Planorbarius corneus (Mollusca)]. PMID- 11605448 TI - [Functional properties of hemoglobins of various bony fishes]. PMID- 11605449 TI - [Characteristics of fry growth in light gradient conditions]. PMID- 11605451 TI - [Demographic structure of the population of taiga tick (Ixodidae) in coniferous forests of the Kemchug upland in 1986-1991]. AB - It is recovered, that full engorged females of Ixodes persulcatus lay average of 25,250 eggs per 1 ha during the season in the test area. It produces 13,750 larvae. The abundance of hungry larvae is reduced up to 12,500 during the winter period. 11,643 larvae become engorged. The total abundance of hungry nymphs counts: 10,933 in autumn, and 9895 in spring. The total abundance of hungry adults, half of which is represented by females, makes 1774 in autumn, and 1084 in spring. About 10 females found their hosts and became successfully engorged. PMID- 11605450 TI - [Various aspects of the use of primates in physiological experiments]. PMID- 11605453 TI - [The first find of the feather mite from Apionacaridae family (Astigmata: Analgoidea) on the passerines ( Passeriformes)]. AB - A representative of the family Apionacaridae is recorded from the passerine birds Passeriformes for the first time. Fringillosphaera bochkovi gen. n., sp. n. is described from the chaffinch Fringilla coelebs (Fringillidae). The new genus obtains main diagnostic characters as follows. Vertical setae vi absent. Prodorsal shield free from scapular sheilds and epimerites Ia. Humeral sheilds present. Epimerites I convergent, connected by sclerotized plate. Lateral setae f2 and pseudanal setae ps3 absent. Coxal fields I-IV sclerotized. In male: legs IV present, genital apparatus at level of trochanters IV, genital arch with divergent branches. Epiandrium absent. Coxal setae 3a absent. Morphological peculiarities, host associations and phylogenetic relationships of the family Apionacaridae are briefly discussed. It is suggested that this family represents and ancient and relic phylogenetic branch, which had split rather early from the common ancestor of the superfamily Analgoidea in the period of formation of the Neognathae birds. PMID- 11605452 TI - [The oribates (Oribatei) in the feathers of birds]. AB - The authors confirm the fact of disperiosn of oribate mites by birds, that was earlier noticed in acarological references. More than 400 individuals of 53 virds species belonging to different ecological groups have been examined. About 50 species alive oribates were collected in bird feathers: Liochthonius sellnicki, Brachychthonius sp., Hypochthonius rufulus, Nothrus palustris, Malaconothrus egregius, Camisia segnis, Camisia sp., Hermanniella granulata, Trhypochthonius tectorum, Oribatula tibialis, Zigoribatula exilis, Scheloribates laevigatus, Sch. latipes, Suctobelba trigona, Suctobelbella sp., Fosseremaeus laciniatus, Tectocepheus velatus, T. knullei, Nanhermannia coronata, Achpteria coleoptrata, Parachipteria punctata, Damaeus riparius, Eremaeus oblongus, Diapterobates notatus, D. humeralis, Carabodes areolatus, C. marginatus, Sphaerozetes tricuspidatus, Ceratozetes parvulus, C. cisalpinus, Mycobates sp., Punctoribates punctum, Trichoribates trimaculatus, Galumna sp., Oribella paoli, Chamobates laciniatus, Neoribates roubali, Neoliodes farinosus, Oppiella nova, O. unicarinata, O. fallax, Oppia ornata, Steganacarus striculum, Steganacarus applicatus, Tropacarus carinatus, Protoribates capucinus, Scutovertex minutus, Autognetha willmanni, A. longilamellata, Belba sp., Metabelba pulverulenta, Gustavia microcephala, Fuscozetes fuscipes [symbol: see text] Pergalumna nervosa. Carabodes marginatus were met most often, on 8 species of birds, Tectocepheus velatus, on 12 species, Oppiella unicarinata--at 7 species. Some oribate species constantly occur in bird feathers. PMID- 11605454 TI - [Peculiarities of thoracic and abdominal combs of fleas (Siphonaptera)]. AB - The structure of pseudosetae, spinelets, and spines of combs (ctenidia) was studied by means of light and SE microscopy in 80% of genera and subgenera of the World fauna. It is found out that peculiarities of ctenidiae in the prothorax and in tergites of the abdomen are characteristics of families and infraorders of fleas. Some characters of ctenidiae found in certain flea genera are reductions and apparently caused by habitation in some extremal conditions. An absence of ctenidiae in the unfraorder Pulicomorpha is compensated by more developed posterior margin of prothorax and general abbreviation of all thoracal segments. Reasons of ctenidiae absence, which is observed in certain genera of the infraorders Ceratophyllomorpha, Pygiopsyllomorpha and Hystricopsillomorpha associated with the same hosts, is not clear. It is confirmed, that distance between ctenidiae in different flea species associated with the same species host species, however it is recovered, that this distance correlates with the diameter of most thin hair of host. In some flea species the distance between ctenidia spices in females is larger, than in males. It is found, that sexual dimorphism by this character may not be expressed in certain species of closely related species group of fleas. It is suggested that ctenidiae were present even in the common ancestor of fleas. The hypothesis on origin of spines and pseudosetae from setae of the posterior walls of toracal and abdominal segments in the common ancestor of fleas is proposed. PMID- 11605455 TI - [The organization of germinal material and dynamics of mother sporocyst reproduction in the genus Echinostoma (Trematoda: Echinostomatidae)]. AB - The reproduction in the first parthenogenetic generation--mother sporocyst (MS) in two species of echinostomes (E. caproni, E. paraensei) is investigated. A group of densely packed cells, which noticeably differ from others, occupies the posterior part of the miracidium. They are characterized by large sizes and a large bubble-shaped nucleus with heterogeneous nucleolus and strong dispersed chromatin. The use of histological and electron microscopic methods has shown that with observed similarity these cells are classified in two tyoes and have a completely different origin. First of all, large secretory cells stand out. In E. caproni miracidia their number averages 6.8 +/- 0.2 and linear sizes is 10-12 microns. Secretory cells possess a large bubble-shaped nucleus. The caryoplasm looks optically empty because of strong dispersion of chromatin. A large nucleolus occupies a bit eccentric position. Eosinophilic cytoplasm contains poorly noticeable at light-optical level accumulation of small granules. The second group of cells is represented by typical germinal cells (GC). The number of GC does not exceed six. Their polymorphy is well above that of secretory cells. The sizes of GC vary from 5.4 to 9 microns. The largest cells (8.1-9 microns) occupy the front position and usually are located between secretory cells. Intensively basophilic cytoplasm surrounds bubble-shaped nucleus with a large nucleolus like border with uniforming thickness. The heterochromatin is evenly distributed over the caryoplasm. Its content of nuclei is more than that in nuclei of secretory cells. That is why they do not look optically empty. So, it is "mature" germinal cells. Four or five cells are located directly behind "mature" cells. Their sizes are gradually decrease towards the posterior of the miracidium (the diameter of the smallest cells reaches 5.4 microns). Nuclei with a centrally located nucleolus are characterized by larger amount and more condensation of the heterochromatin than those in "mature" cells. Meanwhile, they concern to nuclei of bubble-shaped type. In general, all cells of second type represent the primary germinal cells distinguished by the stage of their differentiation. Also, 2-3 undifferentiated cells occupy the most posterior part of the miracidium. Their sizes average 5.55 +/- 0.18 microns. The nucleus contains a lot of densely packed heterochromatin. On parasitic phase of MS development undifferentiated cells give rise to secondary GC. Electron microscopic data in details confirm the situation described above. The essentially similar results were received during the investigation of E. Paraensei miracidia. The differences are observed in parameterical characteristics of germinal material and in small variability of the extent of germinal material development. With E. paraensei, germinal material may be represented by not only GC and undifferentiated cells, but one germ as well. So, our investigation has shown that germinal material of echinostomes represents typical germinal mass. The germinal material condition does not change on parasitic phase of E. caproni MS development during the first day of post infection (PI). The activization of germinal material coincides in the time with the beginning of schizocoel formation in 2 Days PI. On the 3rd day of PI, the proliferation of undifferentiated cells begins and the first germs are free to float in enormous schizocoel. After 8 days of PI, MS release the first rediae. During the following 2-3 days the other rediae formed by primary GC left MS. The release of rediae derived from secondary GC was observed later. So, E. caproni MS give rise to 12-16 rediae which is much less than the number of GC formed in MS. The earlier release of the first E. paraensei rediae by MS is predetermined by the difference in the structure of germinal mass in E. paraensei miracidia. Therefore, Echinostomatidae is intermediate between two groups of trematodes. The first group has MS that completely realize reproductive function in the time of miracidial formation; but the second group includes higher trematodes characterized by the transfer of reproductive time on a parasitic phase of MS development. The question concerning to so-called "pedogenetic larvae of trematodes" is discussed. PMID- 11605456 TI - [The effect of copper sulfate on the heart rate of Lymnaea stagnalis (Mollusca: Gastropoda; Pulmonata) infected with trematode parthenites]. AB - The influence of different concentrations of the copper sulfate (0.2, 1, 1.8 mg/l) on the Lymnaea stagnalis heart rate in a control and in the case of the trematode infection was examined. Concentrations which cause the decrease and the increase of heart rate were estimated. Pathological reactions in infected individuals are more expressed and appear earlier. PMID- 11605457 TI - [Respiration and motor activity of cercariae of three trematode species from the intertidal mollusc Littorina littorea L (Gastropoda) from the White sea]. AB - The age dynamics in oxygen consumption of the cercariae Himasthla elongata, Cryptocotyle lingua and Cercaria parvicaudata (Renicola sp.) was studied using modified Winkler's method. It was detected that under stable temperature and water salinity conditions the rate of oxygen uptake depends directly on cercariae size. The highest intensity of energetic metabolism was recorded in the first few hours of cercariae life when their movement activity was maximal. The following reduction of oxygen consumption passed unequally in three cercariae species studied. Large, long-lived H. elongata cercariae after relatively short period of active swimming turn to crawling on the bottom. The rate of oxygen uptake in such cercariae was two times less than in free-swimming ones and remained approximately invariable up to the cercariae death. The smaller sized, short lived Renicola sp. cercariae swim actively in the water and during this time the level of their energetic metabolism remains more or less stable. It decreased drastically after cercariae sinking to the bottom, after that they perished very soon. Also relatively small C. lingua cercariae alternate the active and passive phases of swimming. Thanks to that they consume the energetic resources economically and prolong their longevity. During free-swimming period the rate of oxygen uptake of C. lingua cercariae remains more or less stable. As in the case of Renicola sp. cercariae, it decreased drastically after the cercariae sinking to the bottom. Apparently such cercariae lose their ability to infect the second intermediate host (fish). PMID- 11605459 TI - [Analysis of possible mechanisms of orthonectid emergence from their hosts]. AB - In the present study authors claim that the adult orthonectids can not move through host tissues by themselves. In various species of these enigmatic parasites there are at least two different mechanisms of emission of males and females from the host body. Intoshia linei, the orthonectid from Lineus ruber (Heteronemertini), and Intoshia variabili, the parasite of a flatworm Macrorhynchus crocea, realize the first way of emission. The plasmodium of these species forms tube-like outgrowths, which pierce the host tissues reaching the host body surface. The cytoplasm structure of these outgrowths differs from the cytoplasm of the central mass of plasmodium. Small mitochondria with electron dense matrix, lipid granules and vesicular bodies being common in the central part are absent in these outgrowths. Plasmodial outgrowths reach the host body surface and adult orthonectids move inside them using their cilia and stopping from time to time. The plasmodial outgrowths penetrate the ciliated epithelium, then males and females leave the host. Duration of emission may vary in different species from 6 to 13 days. The second mechanisms of emission is common for the orthonectid parasites of mollusks. Our observations of Rhopalura philinae from the gastropod Philine scabra lead to the conclusion that males and females leave their host practically simultaneously. When the plasmodium attains the terminal stage of its development most of the host entrails are already displaced by plasmodial mass. It causes breaks in host body walls and hence to emission of sexual individuals. During this process, which lasts about 24 hours, the mollusk dies. The same mechanism was observed in Rhopalura littoralis--parasite of the gastropod Onoba aculeus. Our investigations of emission ways reveal that the plasmodium of orthonectids has a potency of directing growth and can form certain structures. The process of forming the plasmodial outgrowths is coordinated in time and space. These outgrowths have certain directions inside the host body and the maturation of sexual individuals is clear related with the development of plasmodium outgrowth system. Our results suggest that forming of plasmodial outgrowths is an element of development of the united and highly integrated system. It is necessary to emphasize the capability of plasmodium to accomplish such morphogenetic transformations. This fact argues that plasmodium is a part of parasite organism and not host cells modified, like some experts supposed. PMID- 11605458 TI - [A novel subspecies of entomopathogenic nematode Steinernema feltiae protense subsp. N.(Nematoda: steinernematidae) from Iakutiia]. AB - A new subspecies of entomopathogenic nematode, Steinernema feltiae protense subsp. n., isolated from Yakutia grasslands is described. These nematodes demonstrate a high invasion activity to insect-hosts at 6 degrees C, maximum infestation of insect-hosts was registered at 13-21 degrees C. PMID- 11605460 TI - [Characteristics of the parasite fauna of the Atlantic salmon fry (Salmo salar L.) in the Teno river system of North Finland]. AB - The diversity of parasite fauna of the Atlantic salmon parr from the Teno River and its tributaries recovered in 1993-1995 is discribed. 35 parasite species were found, the majority of them are represented by the parasites with a direct cycle of development. High prevalence of infection with Chloromyxum januaricus wes detected. PMID- 11605461 TI - [New findings of the family Trilosporidae (Myxosporida: Multivalvulida) from fishes of Pacific ocean]. AB - Three new species of the family Trilosporidae (Myxosporidia) from fishes of the northern Pacific are described: Trilospora sphaerica sp. n., Unicapsula pacifica sp. n., U. schulmani sp. n. PMID- 11605462 TI - [Occurrence and parasite fauna of Dressena bugensis in the Rybinsk reservoir]. AB - The zebra mussel Dreissena bugensis (Andrusov), a representative of mollusc fauna in the Dnieper-Bug estuary, have been found for the first time in the Rybinsk reservoir (the Volga reach, Shumorovka River). In pericardial and mantle cavities and inner organs of molluscs the following parsites have been found: Aspidogaster limacoides, Caspiobdella fadejevi, Helobdella stagnalis, eggs of the water mites of the genus Unionicola, and representatives of nonspecific saprotrophic fungi of the genus Acremonium. It is shown that composition of parasites and free-living organisms in D. bugensis is similar to that in D. polymorpha. PMID- 11605463 TI - [Pathogen-induced plant proteins]. AB - Pathogen-induced plant proteins are classified by their functional characteristics: (a) involvement in plant cell signaling; (b) inhibition of enzymes excreted by the pathogens; (c) stabilization of plant cell walls or ability to trigger apoptosis; (d) enzymatic activity producing lysis of cell walls of pathogenic fungi and bacteria; (e) enzymatic activity in metabolic pathways of phenylpropane and terpene phytoalexins; and (f) ability to affect the pathogens directly, by disturbing the function of their cell membranes or by inactivating their ribosomes. Examples of transgenic plants with increased immunity against pathogens are also provided. PMID- 11605464 TI - [Role of isoprenoid compounds in plant adaptation to biogenic stress caused by parasitic nematodes]. AB - Parasitic nematodes are considered as a biogenic stress factor in plants. The effects of various plant isoprenoids, including mono-, sesqui-, di-, and triterpenoids, sterols, and steroid glycosides, on parasitic nematodes are reviewed. Certain isoprenoids can be placed in the class of natural plant adaptogens. PMID- 11605465 TI - [Biodegradation of oil products by degrader strains and their associations in liquid media]. AB - The degrading activities of selected bacterial strains and their associations directed towards fuel oil and diesel fuel in liquid media were studied. Two member associations composed preferably by Rhodococcus and Pseudomonas strains demonstrated the highest degrading efficiencies. No enhancement was achieved when the number of association members was increased to three, four, or five strains. The population stability of any member strain was found to depend on the association composition. PMID- 11605466 TI - [Extracellular metabolites of hydrocarbon-oxidizing bacteria as a substrate for sulfate reduction]. AB - The relationship between bacterial oxidation of hydrocarbons and sulfate reduction was studied in the experimental system with liquid paraffin was used as a source of organic compounds inoculated with silt taken from a reservoir. Pseudomonads dominated in the hydrocarbon-oxidizing silt bacteriocenosis. However, Rhodococcus and Arthrobacteria amounted to not more than 3%. Arthrobacteria dominated the microbial association formed in the paraffin film of the model system. Sulfate-reducing bacteria were represented by genera Desulfomonas, Desulfotomaculum, and Desulfovibrio. The growth of sulfate-reducing bacteria in media containing with paraffin, successive products of its oxidation (cetyl alcohol, stearate, and acetate), and extracellular metabolites of hydrocarbon-reducing bacteria was studied. The data showed that sulfate-reducing bacteria did not use paraffin or cetyl alcohol as growth substrates. However, active growth of sulfate-reducing bacteria was observed in the presence of stearate and extracellular water-soluble or lipid metabolites of Arthrobacteria. PMID- 11605467 TI - [Features of lipoxygenase from cells of Mortierella species mushrooms]. AB - The specific activity of lipoxygenase from several strains of the zygomycete Mortierella varied from 1.02 to 2.02 microMol diene per min per mg protein). The enzyme equally used linoleic or arachidonic acid as a substrate. An increase in lipoxygenase activity was observed after adding corn oil to the culture medium. Tests with inhibitors having different chemical structures revealed that the lipoxygenase activity from Mortierella cells was inhibited only by esculetin, ethanol and nordihydroguaiaretic acid (NDGA). NDGA inhibited the enzyme in vitro (IC50 = 142 microM), but its addition in the exponential phase of growth activated the enzyme. PMID- 11605468 TI - [Formation of an extracellular system of enzymes during growth of Geotrichum candidum 3C on cell walls isolated from cereal grain capsules]. AB - The activities of extracellular systems of hemicellulases, pectinases, and cellulases was studied during a 72-h cultivation of Geotrichum candidum 3C. The culture was grown on a medium containing 3% cell walls isolated from wheat grain capsules, which served as the sole carbon source. Enzymes catalyzing the degradation of pectin substances (beet pectin, alpha-L-arabinan, and 1,4-beta-D galactan), as well as beta-D-galactosidase and alpha-L-arabinofuranosidase involved in their hydrolysis, were formed first (4 h after the beginning of cultivation). Enzymes hydrolyzing 4-O-methyl-alpha-D-glucurono-beta-D-xylan and sodium carboxymethyl xylan were also found in the culture liquid after 4 h of fungal growth. The contents of pectin-degrading and xylanolytic enzymes reached their maximum levels after 52-56 and 72 h of growth, respectively. Cellulolytic enzymes were detected after 8-28 h of cultivation. Enzymes degrading alpha-D galacto-beta-D-mannan were found 24 h after the beginning of growth; their content was maximum after 72 h of cultivation. PMID- 11605469 TI - [Conditions for forming ethanol during bioconversion of cellulose-containing raw material]. AB - Several natural associations composed by thermophilic anaerobic bacteria capable of utilizing various cellulose materials at 60 +/- 2 degrees C and pH 6.0-7.0 were isolated from the sludge of Kamchatka geothermal springs. The rate of ethanol production (up to 1.7 g/l per day) and the concentration of ethanol in the medium (up to 1.2%), as well as the fermentation period (10-15 days) were determined under anaerobic conditions in the presence of cellulose, coniferous sawdust, newsprint, or paper pulp as a carbon source. Microorganisms were found that inhibited the production of ethanol. The initial pH value was found to influence both the ethanol production rate and ethanol/acetate ratio. A pH decrease from 7.0 to 5.0 led to 6.7-fold increased the ethanol production and caused a 23.8-fold increase in the ethanol/acetate ratio. PMID- 11605471 TI - [Effect of culture media on the composition of free amino acids in Saccharomyces cerevisiae yeast]. AB - The quantitative and qualitative compositions of free amino acids of the yeast Saccharomyces cerevisiae Y-503 cultivated in different nutrient media were studied by liquid chromatography. The yeast grown in the medium containing geothermal water was shown to accumulate more amino acids. During lyophilization, the stabilization of the physiological activity of the yeast in this nutrient medium was observed. The increased biological value of dry yeast was shown to depend on the content of free amino acids, including essential amino acids: arginine, histidine, leucine, isoleucine, lysine, threonine, serine and phenylalanine. PMID- 11605470 TI - [Formation of xylitol in Candida guilliermondii 2581 culture]. AB - The yeast strain Candida guilliermondii 2581 was chosen for its ability to produce xylitol in media with high concentrations of xylose. The rate of xylitol production at a xylose concentration of 150 g/l is 1.25 g/l per h; the concentration of xylitol after three days of cultivation is 90 g/l; and the relative xylitol yield is 0.6 g per g substrate consumed. The growth conditions were found that resulted in the maximum relative xylitol yield with complete consumption of the sugar: xylose concentration, 150 g/l; pH 6.0; and shaking at 60 rpm. It was shown that the growth under conditions of limited aeration favors the reduction of xylose. PMID- 11605472 TI - [Analysis of kinetic parameters of gas phase bioreactors]. AB - The dependence of toluene elimination capacity on its load was obtained in five small-scale reactors filled with glass beads carrying biocatalyst cells. With increase in operation time the calculated maximal elimination capacity was shown to increase along with biomass density in the biocatalyst bed. Fivefold increase in trickling intensity did not affect the reactor performance. A simplified mathematical model for evaluation of minimal required biocatalyst bed volume at certain loading was developed based on experimental dependence of elimination capacity vs. loading. PMID- 11605473 TI - [Relationship between celandine isoquinoline alkaloids with macro- and microelements]. AB - Numerous linear and nonlinear correlations between the contents of alkaloids and mineral elements in the aerial parts and roots of greater celandine (Chelidonium majus L.) were revealed by means of correlation and regression analyses. These relationships became more significant with the transition from the sum of alkaloids to individual groups or fractions, which included compounds of similar compositions. The mathematical models describing the regulation of alkaloid metabolism by some mineral elements (Ba, Mg, Sr, Co, Cr, Zn, etc.) were developed in the analytical form. These models were tested in experiments with geochemical modeling using Zn. PMID- 11605474 TI - [Immunosuppressors in pathogenesis of potato-pathogen blight]. AB - The properties and effects of two plant resistance suppressors (1,3-beta-1,6-beta glucan and a pentasaccharide of xyloglucan origin) involved in the pathosystem of potato (Solanum tuberosum) and the causal agent of blight (Phytophthora infestans (Mont) de Bary) were compared. The microbial 1,3-beta-1,6-beta-glucan suppressed the defense response over a narrow concentration range (10(-2) M), whereas the plant pentasaccharide had a broad range of effective concentrations (10(-12) to 10(-6) M). In the pathosystem of potato-causal agent of late blight, the beta glucan caused a local and race-specific suppressor effect on the plant host defense response. In contrast, the pentasaccharide caused both local and systemic suppression of potato resistance, and the presence of terminal fucosyl residue in the xyloglucan oligosaccharine played a decisive role in its effect. The recognition of both suppressors by potato cell membrane sites is discussed. PMID- 11605475 TI - [Effect of elicitors on accumulation of protease inhibitors in injured potato tubers]. AB - The time course of accumulation and the composition of proteinase-inhibiting proteins in diffusates from potato tubers treated with elicitors such as salicylic, jasmonic, and arachidonic acids were studied. The 40-kDa reserve protein patatin and the chymotrypsin inhibitors, among which proteins of 24.6, 22.0, and 16.0 kDa were prevalent, accumulated in diffusates from potato tubers. Jasmonic and arachidonic acids activated the accumulation of the chymotrypsin inhibitors in tubers in response to the injury stress, whereas salicylic acid inhibited this process. The effects of jasmonic and arachidonic acids increased when their concentrations decreased to 10(-6) M. The data suggest an important role of the lipoxygenase metabolism in signal transduction of the anti-injury defense system in the dormant potato tubers. PMID- 11605476 TI - [Effect of proteinaceous polygalacturonase inhibitors from apple seed tissue on an enzyme isolated from phytopathogenic fungi]. AB - A protein polygalacturonidase inhibitor isolated from fruit of the apple varieties Antonovka and Mantuanskoe differently affects the polygalacturonidases of different phytopathogenic fungi. Three groups of fungi were recognized by the sensitivity of their polygalacturonidases to the inhibitory effect. Storage of apples after harvesting is accompanied by changes in the inhibitor activity, and the time pattern of these changes depends on the variety. An increase in the inhibitor activity occurs concurrently with the elevation in ethylene release characteristic of the stage of elevated respiration (a climacteric increase). The data suggest that a decrease in the apple fruit resistance to microbes at the end of the storage period is related, along with other reasons, to a change in the activity of the protein polygalacturonidase inhibitor. PMID- 11605477 TI - [Effect of growth regulators on proton transport through cytoplasmic membrane of potato tuber cells]. AB - Effects of the growth regulators epibrassinolide-694 (EB), gibberellic acid (GA), and abscisic acid (ABA) on the ATP-dependent translocation of H+ through the membranes of plasma membrane vesicles of potato (Solanum tuberosum L.) tuber cells were studied. The ATP-dependent accumulation of H+ in the plasma membrane vesicles from dormant tubers was inhibited by EB and ABA and stimulated by GA. After the break of dormancy, the stimulatory effect of GA increased, the inhibitory effect of ABA decreased, and EB stimulated the accumulation of H+ in the vesicles. The data suggest that the plasma membrane H+ ATPase is a target of phytohormones that regulate the dormancy of potato tubers. PMID- 11605478 TI - [Forms of silicon in medicinal plants]. AB - The contents of three forms of silicon (organic, soluble mineral, and polymeric) were determined in leaves of 21 medicinal plants. At a total content of silicon 0.74 to 3.59% the organic, soluble mineral, and polymeric forms accounted for 0.51-1.91%, 0.05-0.51%, and 0.1-1.21%, respectively. An analysis of silicon in the condensed polyphenol fraction was performed for the first time revealing the presence of a covalently bound form in the amounts of 0.1 to 0.2% of the total silicon content in the leaves. These results are of interest for food or medical applications of the plants studied. PMID- 11605479 TI - [Aroma-forming substance from a culture of the mold fungus Penicillium roqueforti during growth on milk curds]. AB - Production of aroma-forming substances by Penicillium roqueforti strains no. 31 and no. 541-A grown on curd was studied. The data showed that the strain no. 541 A is the most promising producer of cheese flavor. The flavor acquired a soily scent after a long-term (4-5 days) cultivation, which may hamper the use of these cultures (particularly, no. 31) in the food industry. PMID- 11605480 TI - [Isolation and some properties of a lectin from the venom of the Vietnamese scorpion Buthus occitanus sp]. AB - A lectin was isolated from the venom of scorpion Buthus occitanus sp. by means of Sephadex G-50 gel filtration and CM-cellulose ion exchange chromatography. The homogeneous lectin preparation consisted of homodimeric molecules with a subunit Mr of 9.3 kDa. Glycine, alanine, and serine dominated in the lectin amino acid composition. The lectin was a glycoprotein containing 20% carbohydrates (predominantly mannose and glucose). Trypsin-treated murine erythrocytes agglutinated at the lectin concentration of 32 micrograms/ml. Hemagglutination was inhibited by carbohydrates (L-fucose > D-glucose > L-rhamnose > D-xylose). The lectin revealed no phospholipase or hyaluronidase, nor toxic activity. PMID- 11605481 TI - [Enzymatic hydrolysis of proteins from crustaceans of the Barents Sea]. AB - Enzymatic preparations from king crab hepatopancreas were shown to be capable, in principle, of producing protein hydrolysates. Hydrolysis of protein-containing waste of deep-water prawn and king crab occurs most successfully at pH 8.0-8.5 and 50-55 degrees C for 5-6 h in the presence of 6 g enzyme per kg substrate. The total chemical composition of the hydrolysates, the molecular weight distributions of proteins and polypeptides, and the contents of free amino acids were studied in dry hydrolysates. PMID- 11605483 TI - [Effects of surface pattern of polymers on adhesion characteristics of transformed human embryonic tendon cells]. AB - Effects of surface pattern of polymers on adhesion characteristics of transformed human embryonic tendon cells (THETCs) have been examined by using a micropipette aspiration technique, which is a cellular mechanical method. The results showed that the adhesion characteristics of THETCs depend on the surface pattern of polymers, and the adhesion force of THETCs to porous films is higher than that to non-porous films and fibers. The adhesion force bears relationships with the aperture of porous films and has a stronger dependence on the large aperture (150 500 microns) than on the small aperture (< 150 microns) of porous films. The adhesion force of THETCs to fibers is increased slightly with the diameter of fibers (P > 0.05). These demonstrate that the tissue-engineered tendon scaffolds made of porous polymer foam with specially designated aperture, or of polymer fiber with specially designated diameter, may serve as a good attachment substrate for THETCs. PMID- 11605484 TI - [Preparation, characterization and characteristics of copolypeptide consisting of L-aspartic acid and L-glutamic acid]. AB - For the purpose of increasing the hydrophilicity of poly-aspartic acid, a copolypeptide consisting of L-aspartic acid and L-glutamic acid (8: 2 mol/mol) was prepared. The copolymer was characterized by 1H NMR, 13C NMR, differential scanning calorimetry, X-ray and element analysis. 3-hydroxyamino, as a side chain, was linked to the polymer, and poly-(3-hydroxypropyl)-L-aspartamide-L glutamide (PHPAG) was obtained. The molecular weight of PHPAG was determined by GPC. Tests of the PHPAG on laboratory animals corroborated its potential use as a drug carrier. Acute toxicity studies revealed no death in animals treated, other studies recorded no notable difference between treated and control animals either in terms of principal haematological parameters or in micronucleus test. In vitro enzymatic hydrolysis for the co-polymer was performed using chymotrypsin, fungi protease and trypsin. It showed that these proteins could degrade the copolymer to some degree. The effects of pH, light and humidity on PHPAG were also investigated. The results indicated that it was stable under the experiment conditions. PMID- 11605485 TI - [Investigation of water sorption and solubility of three denture soft lining materials]. AB - This assay was made to investigate the water sorption and solubility of autopolymerizing hydrogel, acrylic resin and silicone denture soft lining materials. The test discs with 50 mm in diameter and 1 mm in thickness were prepared according to powder and liquid ratio. The weight of sample was measured after 24 h drying (m1). The sample was put into artificial saliva and distilled water for 7 d and 28 d, the moisture weight was measured after soaking (m2). After drying again, the last data of weight (m3) was acquired till the constant mass was recorded. Finally the values of water sorption and water solubility were calculated respectively with statistical analysis. The results showed the means of percentage about absorption at 7 d and 28 d were 28.62% and 24.96% for hydrogel, 1.89% and 1.65% for acrylic resin, 0.25% and 0.29% for silicone in artificial saliva. The percentage solubility at two stages were 0.56% and 0.51% for hydrogel, 0.74% and 0.83% for acrylic resin, 0.10% and 0.12% for silicone. In distilled water, the means of percentage about absorption at 7 d and 28 d were 30.15% and 27.85% for hydrogel, 3.64% and 6.17% for acrylic resin, 0.83% and 0.98% for silicone. The percentage solubility at two stages were 0.79% and 1.16% for hydrogel, 0.86% and 1.01% for acrylic resin, 0.10% and 0.14% for silicone respectively. The conclusion is that the order of percentage about absorption for these three denture soft lining materials were hydrogel > acrylic resin > silicone. The percentage solubility of acrylic resin was higher than that of the other two materials because of the plasticizer existing in acrylic resin material. In some degree, the ionic component increased may affect water sorption and solubility. Further clinical demonstration is needed for this hydrogel with higher percentage absorption. PMID- 11605486 TI - [Study on preparation and properties of moisture permeable polyurethane membrane used for dressings]. AB - A new hydrophilic polyurethane(PU) performed-polymer has been developed with polyethylene glycol(PEG) instead of general polyether. The solution of performed polymer is poured casting a permeable membrane used for the outer layer of the bilayer dressings. The effects of molecular weigh (Mn) of PEG, the usage of cross link agents, solvents and water in the solution on the moisture permeation of PU membrane have been studied. It has been shown that the membrane prepared is a porous moisture permeable membrane. The optimum conditions of preparing membrane are: Mn of PEG is 2,000-4,000, the mixture of acetone and N,N-dimethylformamide (DMF) is used as solvents, and the temperature of performance membrane is 50 degrees C-80 degrees C. The moisture permeability of the PU membrane is 49-60 g/m2.h at 35 degrees C, which can meet the requirement of the wound dressings. In addition, the mechanism of the moisture permeation of PU membrane has been discussed. PMID- 11605487 TI - [Study on the adsorption of collagen onto surfaces with imaging ellipsometry]. AB - The adsorption of collagen onto hydrophilic and hydrophobic surfaces was studied with imaging ellipsometry in different pH, adsorption time, ion strength and BSA existence. The results showed that there was more collagen adsorbed onto hydrophobic surfaces than onto hydrophilic surfaces. The maximum collagen adsorption was observed at pH 7.2. The existence of BSA affected the adsorption of collagen onto hydrophobic surfaces more than that onto hydrophilic surfaces. PMID- 11605488 TI - [A simulating study of biophysical features along meridians on a gel model]. AB - A physical model was used to study the mechanism of specific biophysical features along the classic acupuncture meridian lines. A sol channel within a gel bed was made by a resistance string heating during electrification. A saline channel was produced by withdrawing some fibers in the gel bed and injecting saline into the gaps. A hydraulic resistance instrument composed by two pressure transducers was used to measure the hydraulic resistance across the two kinds of channels. The impedance on both channels was measured by a four-electrode impedance instrument with 5 KHz constant current. A vibration generator was put on one set of the channel to produce about 50 Hz sound waves. The signal was detected by a crystal pickup on the other set of the channel to examine the transmission of the wave along the two kinds of channels. The results showed that the low hydraulic resistance appeared on saline channel while no such feature on sol channel. Both channels showed low impedance while saline channel had more marked low impedance than control area. There was a better transmission of sound wave along saline channel while a bad transmission along the sol channel. The results suggest that the specific biophysical feature along meridians may be caused by a continuous rich distribution of interstitial fluid which mainly contains salt, water and protein. PMID- 11605489 TI - [Design of multi-channel EEG collection system for stereoscopic VEP and study of the VEP evoked by binocular disparity]. AB - A multi-channel EEG collection system has been constructed for visual evoked potentials (VEP) studies, using IBM compatible PC and clinical EEG amplifier. The collection system not only is suitable for investigative and clinical use, but also works perfectly in the EEG collection and signal processing of stereoscopic VEP. The characters of the depth related VEP evoked by binocular disparity were identified after analysing and comparing the VEP superposition results. The partial results of the VEP extraction are in accord with the previous studies. The system serves as a helpful tool in studies of stereoscopic cognition and brain function. PMID- 11605490 TI - [A lumped parameter model of the peripheral extra-corporeal circulation]. AB - A three-element model of lumped parameter in peripheral extra-corporeal circulation of an animal has been proposed and set up according to the fluid network theory. GEAR method, appropriate for the computation of the rigid problems, was used to solve the ordinary differential equations, so that a good convergence of the solution to the equations has been achieved. Physiological data of a 20 kg dog, obtained from our animal experiments were used to calculate the pressure and flow rate of important organs. The results of the mathematical model and animal tests showed that the peripheral extra-corporeal circulation could supply enough blood to the important organs, e.g. heart and brain, when the natural heart beating stopped. The results from both theoretical and experiments are critical to the cardiopulmonary cerebral resuscitation for the animals as well as for human beings. PMID- 11605492 TI - [Automatic analysis and research on the trend of ST-T segment based on KL transform]. AB - In view of the limitation of monitoring the trend of ST segment with the traditional method(ST level), we introduce a new monitor method based on KL transform. This method has overcome many disadvantages of ST level, e.g. the susceptibility to interference, a large variation of performance and the reflection of isolated characteristic. This method can characterize the signals stably and adequately. We have made experiment and analyzed the property of this method by using the standard database. The results indicate that the KL transform is of great clinical significance in detecting and monitoring the abnormality of the ST-T segment waveform over a long period of time, and the effect of monitor is also laid on the selection of KL series. PMID- 11605491 TI - [Simulation study of electrode configurations for cardiac stroke volume calculation by 3-dimensional finite element method]. AB - This is a research in Kubicek electrode configurations for cardiac stroke volume calculation from the angle of Kubicek model simulation by 3-dimensional finite element method. In the process of computer simulation, we have studied, respectively, the effect of the width, thickness, and material property (specific resistance) of potential electrode band on cardiac stroke volume calculation in order to guide the choice of electrode configurations in the clinic. The simulation results showed that in Kubicek electrode configurations, its all properties of the potential electrode band affected the impedance results for cardiac stroke volume calculation, one main factor of which is the choice of the material property. Therefore, we have to attend to the choice of Kubicek electrode configurations while calculating SV by Kubicek method in order to improve the accuracy of SV calculation. PMID- 11605493 TI - [Detection of spikes in epileptic EEG based on Multiresolution Tsallis' entropy]. AB - In this paper, the detection of the spikes in the epileptic EEG signal was studied based on Multiresolution Tsallis' entropy (MRET). First, EEG signals were decomposed into wavelet series, and then, at every scale, the abnormal spikes were distinguished from normal background EEG activities by using MRET. The analysis of 6 patients' EEG data showed that the abnormal epileptiform spikes in EEG can be accurately detected with this method, which opens up the perspectives of building up automatic detection devices for spikes in EEG. Compared with the Shannon entropy, the MRET provides one with more detailed information. PMID- 11605494 TI - [Biomechanical properties of arteries in experimental hypotensive rats]. AB - To study the changes of biomechanical properties after arterial remodeling in hypotension, a model of hypotension was established in rats by constricting the abdominal aorta below the orifice of the left renal artery. The change of opening angles of the abdominal aorta, femoral artery and anterior tibial artery, and the compliance of the abdominal aorta were studied. The relationship between the pressure and volume of the abdominal aorta were also observed in vivo. The results show that non-uniformal remodeling of the hypotensive artery induces the reduction of opening angles in the zero-stress state, the C/E rate of the abdominal artery decreases while the compliance increases. PMID- 11605495 TI - [The research of mathematical model for inositol-1,4,5-triphosphate-induced Ca2+ oscillations]. AB - This article mainly illustrates the model for agonist-stimulated Ca2+ oscillations that involves two roles for cytosolic Ca2+: (a) inositol-1.4.5 triphosphate(IP3) inhibits Ca2+ release from the endoplasmic reticulum (ER); (b) IP3 acts on phosphate C, via a Gq protein related mechanism and hence stimulates Ca2+ release from ER. The model assumes that the ER IP3 receptor is a tetramer of independent subunit that can bind both Ca2+ and IP3. The reason for inhibition of Ca2+ oscillations is that IP3-receptor/Ca(2+)-channel slowly comes back to the beginning stable state. The key parameter for Ca2+ oscillations is the ratio of Maximum Ca2+ dependent IP3 input rate (v6) to IP3 decay rate constant (v7): I when v6/v7 < 0.28, no oscillation could be found; II when 0.28 < v6/v7 < 0.572, oscillation starts; III when v6/v7 > 0.572, Ca2+ ceases and arrives at a stable state quickly. PMID- 11605496 TI - [Cytotoxicity of the strontium-substituted hydroxyapatite evaluated by MTT colorimetry]. AB - This study was conducted to evaluate the cytotoxicity of strontium-substituted hydroxyapatite by methyl thiazolyl tetrazolium (MTT) colorimetry. We used the MTT method to assay the cytotoxicity of the strontium-substituted hydroxyapatite containing different strontium concentrations (1%, 5%, 10%, 100% Sr2+) and the pure hydroxyapatite. The results showed that the cytotoxicity scores of the different materials were grade 0 or grade 1. These led us to the conclusion that strontium-substituted hydroxyapatite has good biocompatibility. PMID- 11605498 TI - [The electric pulse caused pore in the skin observed by fluorescence microscopy]. AB - The objective of this study was to enunciate the difference in skin morphological changes between iontophroresis and electroporation for transdermal drug delivery (TDD). Fluorescence microscope was employed to observe the skin structure of human and snake in passive diffusion (control); iontophoresis was performed using direct current(0.5 mA/cm2) and electroporation was performed using intensive 380 V, pulse rate 4 ppm, pulse duration 5.5 ms, pulse number 100 and electric capacity 22 microF. Fluorescein was FITC. The results showed that for human skin in the passive, these were a few highlight fluorescent blots with scale of 15-30 microns and rough edge, but the edge of the blots became smooth and the scale did not change in the iontophoresis; when the scale of the blots was extended to 80 90 microns, the edge was smooth. For the snakes shin, the highlight blots were not sighted in the passive and iontophoresis, but they were found to be 25-30 microns in the electroporation. These data demonstrate that electric pulse can cause pore in the skin, thus creating a new route for drug permeation through skin. PMID- 11605497 TI - [Pulsatile rotary pumps with low hemolysis]. AB - As is well known, a pulsatile flow is important in assisted-circulation but it is difficult to produce a pulsatile flow with rotary pump, because excessive hemolysis will be generated. The authors have found that the turbulent shear is the main factor for red cell damage and therefore the key point of pulsatile rotary pumps is to reduce the turbulence by producing a pulsatile flow. In the authors' pulsatile axial pump, the pulsatile flow is obtained by axial reciprocation of constant rotating impeller; the rotation and reciprocation of the impeller are driven separately by a DC motor and a pneumatic device. Though a physiological pulsatile flow could be achieved and turbulence would not increase remarkably because the impeller rotates constantly, a second driver except a DC motor is nevertheless necessary, thus the system will become complicated. In the authors' pulsatile radial pump, a pulsatile flow is achieved by changing the rotating speed of the impeller periodically. Turbulence is minimized by a special design of twisted vanes which enable the blood flow to change its direction rather than its dimension during periodic change of rotating speed. Hemolysis tests demonstrated that the index of hemolysis(IH) of the author's pulsatile radial pump is 0.020, with is slightly more than that of the author's nonpulsatile radial pump(IH = 0.015). Animal experiments indicated that the pulsatile radial pump can assist the circulation of calves for several months without harm to blood elements and organ functions of the recipients. PMID- 11605499 TI - [A research on the quantification of retinal blood vessels in cases of arteriovenous crossing pressure syndrome caused by hypertension]. AB - The method for quantification of retinal blood vessels in cases of arteriovenous crossing pressure syndrome caused by hypertension was studied. The matched filtering pre-processing of image enhancement for local retinal blood vessels and closing of mathematical morphology for image smoothing, and the method of scale up lineation for contour determination of retinal blood vessels and optimal seeking algorithm with reversible quantification were used to measure the pathological deformation of vessel, thus providing a computer method for auxiliary diagnosis of relative diseases. PMID- 11605500 TI - [Characteristic analysis of modulation transfer function curve of retina-brain system]. AB - This study was aimed to find some parameters for characterizing the modulation transfer function (MTF) specific to diagnosing eye diseases. Least-square regression method was used for MTF curve (at logarithmic axis) fitting with quadratic equation so as or cubic equation to obtain the desired parameters. The data of normal and some eye diseases were fitted by quadratic and cubic equations. Three or four parameters were obtained from the curve fitting. The fitting curves were also expressed with figures along with the original data. For symmetric MTF, parameters k1, k2 and k3 were used to characterize the eye diseases. For asymmetric MTF, an additional parameter k4 was used to show the different injures of frequency channels. PMID- 11605501 TI - [A study on quantitative assessment of osteoporosis based on texture analysis]. AB - A quantitative assessment on osteoporosis by using texture analysis has been developed on the basis of coherence mapping, two-dimensional power spectral estimation with modulated transfer function correction and fractal features analysis on trabecular pattern of bone X-ray images. Three objective features of trabecular pattern are selected to form a feature set that can be used in automatic classification for two grades of bone: normal bone and the bone with a medium degree of osteoporosis. This set of features is extracted from each of 16 sample bone X-ray images. With the use of Euclidean norm in the feature space, a center of cluster of each grade of bone is defined as the prototype. For each bone X-ray image, the distance from its features to the two prototypes in feature space is computed to provide an objective judgement on the degree of osteoporosis. The machine classification of 10 bone X-ray images based on the developed prototype is given, and the result indicates that the proposed method is potentially applicable to the objective diagnosis of osteoporosis. PMID- 11605502 TI - [Ectopic expression of human brain derived neurotrophic factor gene in fibroblasts]. AB - The full-length sequence encoding hBDNF was inserted down into the enhancer promotor regulatory element of Colia1 to construct minigene Colia1-BDNF. The recombinant eukaryotic expression plasmid pSCEPBFCAT was transfected into human fetal tendon fibroblasts in culture to realize ectopic expression of hBDNF gene in fibroblasts. The results of immuno-dot blot, Elisa and Western hybridization confirm that the expression protein with apparent molecular weight 27 kDa in pSCEPBFCAT transfected fibroblasts possesses antigen activity specific for the antibodies to BDNF. PMID- 11605503 TI - [A simple and reliable spectrophotometric method for quantification of pyridine nucleotides in serum]. AB - Pyridine nucleotides plays an important role in the maintenance of cellular homeostasis and its disturbance also involves in many perturbance of metabolism, so a simple and reliable assay for determination of oxidized and reduced pyridine nucleotides in serum would be significantly necessary in understanding the redox status of body. A novel modified method, which is based on Nisselbam and making use of a cycling enzymatic reaction and spectrophotometric assay to measure the pyridine nucleotides in serum, showed good results. The standard curve has fine linear relationship; the recovery of added standard samples is almost perfect. Twenty-seven samples from 27 normal subjects were examined by the method. The results were: NADPH 8.385 +/- 1.516 nmol/ml, NADP+ 3.624 +/- 0.985 nmol/ml, and NADPH/NADP+ 2.3612 +/- 0.8057; no significant difference in the variables was found between the male and female. This is a sensitive, simple, reliable and easy practicing method for oxidized and reduced pyridine nucleotides assay. PMID- 11605505 TI - [The development and identification of animal osteoblasts from bone marrow culture]. AB - This study was aimed to evaluate a modified method for animal osteoblast marrow culture on the basis of previously published method. The marrow mononuclear cells(MMNC) in femoral bone-marrow of SD rat were gained with Ficoll-Hapaque centrifuge, which were then cultured in 5 x 10(5) cells/cm3 on the 96-well culture plates with RPMI 1640 medium containing 30% horse serum in a humidified atmosphere of 5% carbon dioxide at 37 degree Celsius. The medium was changed every three days. Cultured cells were identified with inverted microscopy for observing the shape of living cells, and with Wright-Geimsa mixture stain and Alkaline phosphatase (ALP) stain. In order to avoid false positive reaction, we caused damage to the ALP in cultured cells and stained the cells with ALP again for comparison. The results of inverted microscopy showed that the small spherical mononuclear cells became polygonal, spindle-shaped or squamous successively from the fifth day onward. Wright-Geimsa staining showed the specific property of osteoblast. ALP stain positive reaction was between "2+" and "3+", then ALP stain negative reaction was noticed after the damage to ALP. These data demonstrated that MMNC in SD rat could become osteoblast in RPMI 1640 medium containing 30% horse serum. The modified osteoblast marrow culture method has the advantages of short time, less risk of contamination and higher efficiency. PMID- 11605504 TI - [Rat keratinocyte primary cultures based on conductive polypyrrole primary cell culture technique]. AB - Orthogonal experimental design has been applied to study the suitable cell culture medium and condition of conductive polypyrrole on rat keratinocyte cell cultures. The results showed that one thousand milliliters of complete minimum essential medium(CMEM) which contained 900 ml minimum essential medium(MEM), 10% fetal bovine serum(FBS), 1% NEAA, 6 ml insulin and 10 mg hydrocortisone was fit for keratinocyte cell culture. And the conductive polypyrrole obtained with 10 mA current density for 100 second switching times, given 100 mV electrical stimulation voltage for 2 hours, would stimulate the growth of rat keratinocyte cell in vitro cultures. The cell density under culture conditions described above was 1.30 times as high as that under routine culture conditions. PMID- 11605506 TI - [A study for optimal method of separating and cultivating embryonic rat cerebral neurons]. AB - In order to improve the method of separating and cultivating the embryonic rat cerebral neurons in vitro, we compared different digestive enzymes, mechanical separating methods and two different mediums. It was found that highly purified and active embryonic rat cerebral neurons could be harvested by cultivating the neurons in the standard neurobasal medium with B-27 supplement, 10% horse serum, 10% fetal bovine serum and L-Glutamine after separated by digestion with the use of 0.05% trypsin and 0.05% collagenase II. PMID- 11605507 TI - [Hypoglycemic effect of chitosan-microcapsulated insulin on the blood glucose level of streptozotocin-diabetic Wistar rats]. AB - This study was conducted to observe the hypoglycemic effect of chitosan microcapsulated insulin (insulin-microspheres) on blood glucose (BG), in diabetic rats by gavage. Using the scanning electron microscope, we observed the shape and distribution of insulin-microspheres in the tissues of liver, spleen, and small intestine of normal rats after gavage. The following groups of rats were studied: normal control rats (NC, n = 5); streptozotocin (STZ)-inducing diabetic control rats(DC, n = 6); STZ-diabetic rats treated with insulin-microsphere [120 u/kg] by gavage (DF, n = 6); STZ-diabetic rats treated with subcutaneous insulin injection [24 u NPH/kg] (DT, n = 6). Blood glucose was measured at 0-7 days after the treatments. The insulin-microspheres was found in small intestine, liver and spleen at 1, 2, 3 and 7 days. In DF group, the average blood glucose level decreased significantly from 24.7 +/- 3.2 mmol/L to 16.9 +/- 5.5 mmol/L during the first day of treatment and reached the lowest level (12.1 +/- 5.7 mmol/L) on the second day. From the third day on, the BG gradually elevated to the level before treatment; the maximum decrease of blood glucose level was 50.2%. In DT group, the average blood glucose level decreased from 25.2 +/- 3.8 mmol/L to 10.4 +/- 5.2 mmol/L during the first day of treatment and then went up gradually from the 2nd day on; the maximum decrease of glucose level was 58.7%. No significant difference was seen in maximum decrease between the two groups. These data demonstrate that oral chitosan-microcapsulated insulin has the antihyperglycemic effect on the blood glucose level of streptozotocin-diabetic rats. PMID- 11605508 TI - [Analysis and experimental study of reasons for breakage in the bone fracture plate during internal fixation]. AB - Bone fracture plate has been in clinical use for internal fixation of fracture, however, during healing, the steel plate breaks occasionally. This paper applied the static strength theory to imitate the pressed down combination out of shape that was borne by single limb of human body standing. Fracture was made on low limbs of the fresh dead body, fixed with a bone fracture plate. Strain measure was made on a bone fracture plate. Additionally, fatigue experiment and four point bending experiment were carried out on a bone fracture plate. The reason for a breakage in the bone fracture plate was analyzed with static strength theory and low period fatigue theory. PMID- 11605509 TI - [Study on the timing of cerebral hemorrhage attacks]. AB - This study sought to disclose the circadian rhythmicity of cerebral hemorrhage attacks. We defined every two hours as a period of time from zero hour, investigated the attacks of 364 cerebral hemorrhage patients in each period, and analyzed the attack time, the sites of hemorrhage, the presence or absence of hypertension and the relevant treatments. The results revealed an obvious time difference of cerebral hemorrhage attacks with the peak time of incidence in the 6:00-12:00 periods, the medium in the 16:00-18:00 periods, the lowest in the 22:00-6:00 periods. The sites of cerebral hemorrhage were found to be related with the attack time. The peak time of cerebral hemorrhage in basalganglia was seen in the 8:00-12:00 periods and that of cerebral hemorrhage in non basalganglia in the 16:00-20:00 periods. The variable about hypertension and relevant treatment was also found to be closely related to the attack time of cerebral hemorrhage. The patients who had contracted hypertension and had not been treated were liable to have hemorrhage attack in the 16:00-20:00 periods, but those who had been treated or had normal blood pressure usually had attacks in the 8:00-12:00 periods. In conclusion, cerebral hemorrhage attack is periodic. The attack time is closely related to the sites of cerebral hemorrhage, the presence or absence of hypertension and the relevant treatment. PMID- 11605510 TI - [An improved auto-correlation method for Doppler fetal heart rate measurement]. AB - It is very important to monitor the fetal heart rate in the clinical management of pregnancies antenatally. The most commonly employed non-invasive method uses Doppler ultrasound. Because of the complexity of Doppler fetal signals, the signal processing is difficult. In this paper, we describe an improved method for the determination of fetal heart rate from Doppler ultrasound signals. Using an exponentially weighted auto-correlation technique with an automatic adaptation algorithm, we have developed the method which can provide accurate fetal heart rate records, especially in the cases of reduced signal and loss of signal. PMID- 11605511 TI - [The language healing system of deaf children based on wavelet transform]. AB - In the language healing system of deaf children, the wavelet transform method is employed to describe the time-varying characteristics of speech signals, improve the resolution of speech spectrum and make the speech characteristics more obvious. The speech spectrum information shown in this system is easier for deaf children to observe and understand and it is of great importance to the language healing of deaf children. PMID- 11605512 TI - [Preliminary reports about EEG recorded from different periods of morphine addicted rat]. AB - According to the typical behaviors from different periods of morphine addicted rat, EEG records were classified into six groups: control, addiction, short term abstinence, long term abstinence, relapse and naloxone. The results indicated that there were typical wave forms in different periods. PMID- 11605513 TI - [The outlook of using chitosan related materials in nerve regeneration]. AB - Chitosan is a kind of biodegradable materials with excellent biocompatibility. This article interpreted the progress and outlook of using chitosan related materials in nerve regeneration from the following points: the positive charges on chitosan, its ability to adsorb proteins, the specific adhesion of nerve cells on chitosan, and the surface roughness, aperture and surface topography of chitosan. PMID- 11605514 TI - [Research development of polylactide and its composites in bone-tissue engineering]. AB - Polylactide has good biocompatibility and biodegradability in the body and is one of the biomaterials approved by FDA. The research development in the application of polylactide(PLA), hydroxylapatite(HA)/ PLA composites and bioactive organic materials/ PLA composites in bone-tissue engineering are reviewed in this paper. PMID- 11605515 TI - [Current evolution of plasma sprayed hydroxyapatite coating]. AB - The present attempt is to briefly review the processing and properties of plasma sprayed hydroxyapatite coatings in terms of characteristics of hydroxyapatite ceramics, plasma spraying technology, titanium-ceramic interfacial cracking and component designing of hydroxyapatite coating based composite. The coating is a weak part in implant system. The main purpose of research on plasma spraying technology and component designing is to improve coating integrality and coating matrix adhesion strength. Functionally gradient materials can provide a new route to solve the above two problems. PMID- 11605516 TI - [Trends in the pharmaceutical research of ribonucleases and their therapeutic uses]. AB - As one of the most popular model enzymes, the structure and evolution of ribonucleases (RNases) have been studied thoroughly. But until recently, scientists found out that RNases demonstrated a series of important biological functions, such as controlling blood vessel formation, killing tumor cells and inhibiting virus. Now immunotoxin, the antibody-toxin conjugate, becomes a research hot spot. RNases with cytotoxicity are the candidates for the toxin moiety of the immunotoxins. In this paper, the newly found cytotoxic functions of RNases are discussed in detail. PMID- 11605517 TI - [The study on the shear stress responsive element in endothelial cells]. AB - Vascular endothelial cells, by virtue of their unique anatomical position, are constantly exposed to the fluid mechanical forces generated by flowing blood. The fluid forces could influence endothelial cell's gene expression. At a molecular level, fluid shear stress is known to increase or decrease the expression of a wide variety of genes. The shear stress responsive element (SSRE) was proposed after the identification of the first SSRE, the GAGACC sequence identified in the platelet-derived growth factor (PDGF) B chain promoter and subsequently identified in other genes whose promoters respond to shear stress. In addition, there are the existence of other positive shear responsive regulatory elements. There is a report on the activation of these promoters in vitro and in vivo and propose an application of these mechanically inducible promoters in the treatment of vascular diseases. PMID- 11605518 TI - [Micropore filters for measuring red blood cell deformability and their pore diameters]. AB - Micropore filters are the most important components in micropore filtration testes for assessing red blood cell (RBC) deformability. With regard to their appearance and filtration behaviors, comparisons are made for different kinds of filters currently in use. Nickel filters with regular geometric characteristics are found to be more sensitive to the effects of physical, chemical, especially pathological factors on the RBC deformability. We have critically reviewed the following viewpoint that filters with 3 microns pore diameter are more sensitive to cell volume than to internal viscosity while filters with 5 microns pore diameter are just the opposite. After analyzing the experiment results with 3 microns and 5 microns filters, we point out that filters with smaller pore diameters are more suitable for assessing the RBC deformability. PMID- 11605519 TI - [The current situation and future of extracellular matrix materials for bone tissue engineering]. AB - The requirements of ideal extracellular matrix materials for bone tissue engineering were stated, and the advantages and disadvantages of bioceramics, biodegradable synthetic polymers and natural polymers were analyzed. Based on these, we highlight a point that the ideal extracellular matrix materials for bone tissue engineering should be made up of bioceramics materials, synthetic polymers or natural polymers. These materials should possess a morphological structure of three-dimensional foam and have a self-mediated drug delivery system of bone growth factors. The design and manufacture of such compound extracellular matrix materials for bone tissue engineering is a very important and urgent challenge. PMID- 11605520 TI - [Advances of research on stereo localization in computer assisted surgery]. AB - In this paper several kinds of localization technologies used in computer assisted surgery are analyzed, especially the optical stereo localization methods. Finally directions of research and development in the field are given. PMID- 11605521 TI - [Research current status and prospect of the stress and remodeling adaptation models in living bone tissue]. AB - The remodeling processes in living bone are the mechanisms by which bone tissue adapts its overall structure to changes in its mechanical load environment. In this paper, based on literature, the research current status of the stress and remodeling adaptation models in living bone tissue is reviewed and evaluated. Its future research direction and how to break the back of it are also prospected in the paper. PMID- 11605522 TI - [Magnetic stimulation: theory and advance]. AB - Magnetic stimulation is a noninvasive diagnostic and therapeutic technique. The basic theory of magnetic stimulation is presented briefly. Its advances are elaborated in three aspects of mechanism, instrumentation and applications. The problems in focality, location, safety and its trend are discussed. PMID- 11605523 TI - [The complexity measure and its application to EEG analysis]. AB - In this paper are reviewed the conceptions, characteristics and application of the complexity measure in studying EEG. The reviewers expound the advantages and problems of using complexity measure in the analysis of EEG in different physiological states and deem it a new way to study and understand the human brain function. PMID- 11605524 TI - [The progress of electrogastrogram]. AB - This paper reviews the advances in basic researches on the physiological factors and other factors that influence electrogastrogram and summarizes the clinical application of electrogastrogram in the diagnoses and studies of gastric dyspepsia, gastroparesis, delayed gastric emptying, kinetia and gastrohelcosis. PMID- 11605525 TI - [Design and implementation of mini PACS in the hospital]. AB - This paper introduces the principle and classification of picture archiving and communication system (PACS) and some pertinent technologies, including the capture methods of pictures data, images storage equipment and the choice of medium, and the network of images transmission. Also presented is an analysis of the merit and demerit of different kinds of PACS, and in the end we put forward a PACS design method and network framework based on practical implication in the Jinwei project experimental hospital. PMID- 11605526 TI - [Transcription factors and the nuclear matrix]. AB - Data on nuclear matrix-associated transcription factors are summarized. These transcription factors ensure the proper spatial arrangement of gene promoters and enhancers, interacting with DNA at matrix attachment regions (MARs) and with other nuclear matrix proteins. More than 50 individual proteins are considered and classified by the DNA-binding domain. PMID- 11605527 TI - [Recombinational repair in Schizosaccharomyces pombe: role in maintaining genomic integrity]. AB - Recombinational repair was first detected in budding yeast Saccharomyces cerevisiae and was also studied in fission yeast Schizosaccharomyces pombe over the recent decade. The discovery of Sch. pombe homologs of the S. cerevisiae RAD52 genes made it possible not only to identify and to clone their vertebrate counterparts, but also to study in detail the role of DNA recombination in certain cell processes. For instance, recombinational repair was shown to play a greater role in maintaining genome integrity in fission yeast and in vertebrates compared with S. cerevisiae. The present state of the problem of recombinational double-strand break repair in fission yeast is considered with a focus on comparisons between Sch. pombe and higher eukaryotes. The role of double-strand break repair in maintaining genome stability is discussed. PMID- 11605528 TI - [Structural aspects of homeodomain interactions with DNA]. AB - This review is devoted to the structural aspects of interaction of homeodomains with DNA. Presented are the list of all homeodomains with known spatial structure and the alignment of their amino acid sequences. The structure of homeodomains and contacts of their amino acid residues with DNA bases and sugar-phosphate backbone are described. The role of water molecules in DNA binding is discussed. Structures of multicomponent protein complexes on DNA including homeodomains are characterized. PMID- 11605529 TI - [Brain-specific sequence Hfb1 is part of the 3'-untranslated region of the human complexin 2 gene: new data from in vitro and in silico experiments]. AB - A genomic clone hybridizing with brain-specific sequence Hfb1 was isolated from a chromosome 5 consmid library. Hfb1 proved to correspond to a new gene exon which codes for a large 3'-untranslated region of the mRNA for synaptic protein complexin 2. Together with the 985-nt Hfb1 cDNA (EMBL Y15167) isolated previously from a cDNA library of the frontal cerebral cortex, the primary structure was established for genomic clone Ghfb sized more than 4 kb. A GenBank search revealed complete identity of the 5' end of Ghfb and the 3'-untranslated region (878-933) of the human complexin 2 mRNA. Large transcripts with the 5' end corresponding to the complexin 2 mRNA and the 3' end to Ghfb were detected in total mRNA of the human brain by means of RT-PCR. The size of the 3'-untranslated region of the human complexin 2 mRNA was estimated at 4 kb. PMID- 11605530 TI - [Connection of HindIII-polymorphism in the lipoprotein lipase gene with myocardial infarct and life span in elderly ischemic heart disease patients]. AB - Allele and genotype frequencies of the HindIII polymorphism of the lipoprotein lipase (LPL) gene were studied in patients with myocardial infarction (MI) and stable angina of effort (SAE), including long-lived people (over 90). The polymorphism proved to be associated with MI and with the life span, genotype H+/H+ being predisposing to MI and allele H- being protective. The allele and genotype frequencies of long-lived people differed significantly from the Hardy Weinberg proportions and from those of SAE patients aged up to 90. An excess of heterozygotes in this group suggests a selective pressure which eliminates homozygotes. Possibly, heterozygotes H+/H- have an adaptive advantage, which provides for their longevity. PMID- 11605531 TI - [Genomic organization and chromosomal localization of a new repeat MS7, specific for heterochromatin of sex chromosomes in Microtus species voles of the arvalis group]. AB - The tandemly arranged MS4 repeat with monomeric units of 4.1 kb is species specifically distributed in heterochromatin of sex chromosomes of four common vole species of genus Microtus, group arvalis [1, 2]. In this work, we studied the genomic organization of the MS4 homolog in euchromatin of the X chromosome of M. arvalis. It has been shown by analyzing the phage genomic clones that one MS4 copy makes a part of a monomeric unit exceeding 8.5 kb that also includes a new MS7 repeat and, possibly, LINE fragments. MS7 is located together with MS4 in heterochromatin of common vole sex chromosomes, but in a substantially lesser amount. Probably, as a result of an evolutionary transition of an original repeat from euchromatin of the X chromosome to heterochromatin of the Y chromosome, MS4 underwent multiple amplification, and MS7 spread throughout heterochromatin, being surrounded by the MS4 tandem arrays. PMID- 11605532 TI - [Deletion of YNZ22 and ALU-VPA/MYCL1 loci in human colonic adenocarcinoma and postoperative prognosis]. AB - Since deletions of the short arm of chromosome 17 are the most common genetic defects in human colorectal carcinoma (CC), we tested the YNZ22 locus (D17S30, 17p13.3) for loss of heterozygosity (LH) in adenocarcinoma and in the normal colonic mucosa of 49 CC patients, and studied the association of LH with clinicomorphological features of the tumor. Allele frequency distribution of YNZ22 did not differ for the patients and healthy people. LH in YNZ22 in the tumor was found in 33% (13/39) of all informative cases, its frequency being thrice higher in men than in women (chi 2 = 5.21, p = 0.022). The defect was associated with moderate or poor histological differentiation (P2 = 0.0055) and polyploidy > 3n (P2 = 0.0035) of tumor cells and with high incidence of post surgery relapse or metastasis. Analysis of both YNZ22 and Alu-VpA/MycL1 (1p34.3) loci in the tumor allowed reliable relapse prognosis in 76% of the CC patients. The probability of post-surgery relapse or metastasis was estimated at no less than 67% for patients with LH in at least one of the two loci in the tumor, and at somewhat more than 20% for patients without LH. PMID- 11605533 TI - [Structure and evolutionary role of the Penelope mobile element in Drosophila species of the virilis group]. AB - The mobile element Penelope is activated and mobilizes several other transposons in dysgenic crosses in Drosophila virilis. Its structure proved to be complex and to vary greatly in all examined species of the virilis group. Phylogenetic analysis of the reverse transcriptase (RT) domain assigned Penelope to a new branch, rather than to any known family, of LTR-lacking retroelements. Amino acid sequence analysis showed that the C-terminal domain of the Penelope polyprotein is an active endonuclease, which is related to intron-encoded endonucleases and to bacterial repair endonuclease UrvC, and may act as an integras. Retroelements coding for a putative endonuclease that differs from typical integrase have thus far not been known. The N-terminal domain of the Penelope polyprotein was shown to contain a protease with significant homology to HIV-1 protease. Phylogenetic analysis divided the Penelope copies from several virilis species into two subfamilies, one including virtually identical full-length copies, and the other comprising highly divergent defective copies. The results suggest both vertical and horizontal transfer of the element. Possibly, Penelope invasion recurred during evolution and contributed to genome rearrangement in the virilis species. Chromosome aberrations detected in D. virilis, which is now being invaded by Penelope, is direct evidence for this assumption. PMID- 11605534 TI - [Subforms of transcription factor Oct-1 synthesized in lymphocytes]. AB - Transcription factor Oct-1 is ubiquitous, participating in expression of the cell housekeeping genes as well as in differentiation of lymphocytes and activation of transcription of immunoglobulin genes in B cells. A new tissue-specific form of Oct-1 (Oct-1L) was found in lymphoid cells of bone marrow, lymph nodes, spleen, thymus, as well as in the cell lines of B and T lymphocytes at different stages of differentiation. This isoform was not found in embryonal and nonlymphoid tissues and cell lines. The complete structure of the oct-1L mRNA was determined, which generally corresponds to the structure of mouse Oct-1b. The difference between oct-1L and isoforms oct-a, b, and c functioning in all cells is replacement of the long first 5'-terminal exon (the 1U exon) encoding 21 amino acid residues with a short one encoding 10 amino acids in the isoforms Oct-1L and Oct-1R. Interestingly, attempts to find mature oct-1 mRNA simultaneously containing the 1L and 1U exons were unsuccessful. The parallel synthesis of "ubiquitous" isoforms Oct-1a, b, and c as well as tissue-specific Oct-1L and Oct 1R in lymphocytes and their precursors may be due either to a high demand of these cells for Oct-1 or to selective participation of different Oct-1 isoforms in regulation of the housekeeping genes and genes involved in the B and T cell differentiation and synthesis of imminoglobulins. PMID- 11605535 TI - [A cytoplasmic male sterility-associated rearrangement of the mitochondrial cob gene region in the sugar beet (Beta vulgaris L.) genome]. AB - Physical maps of the cob mtDNA region were constructed and compared between sugar beet Beta vulgaris L. plants with normal fertility and with cytoplasmic male sterility (CMS). A CMS-associated rearrangement did not affect the coding region of cob and combined two mtDNA regions which are normally about 150 kb apart. Two point substitutions were found in the 3'-untranslated region of cob. PMID- 11605536 TI - [Interaction of human replication protein A with DNA-duplexes, containing gaps of varying sizes]. AB - Replication protein A (RPA) is a heterotrimeric protein that has high affinity for single-stranded (ss) DNA and is involved in DNA replication, repair, and recombination in eukaryotic cells. Photoaffinity modification was employed in studying the interaction of human RPA with DNA duplexes containing various gaps, which are similar to structures arising during DNA replication and repair. A photoreactive dUMP derivative was added to the 3' end of a gap-flanking oligonucleotide with DNA polymerase beta, and an oligonucleotide containing a 5' photoreactive group was chemically synthesized. The 5' end predominantly interacted with the large RPA subunit (p70) regardless of the gap size, whereas interactions of the 3' end with the RPA subunits depended both on the gap size and on the RPA concentration. Subunit p32 was mostly labeled in the case of a larger gap and a lower RPA concentration. The results confirmed the model of polar RPA-DNA interaction, which has been advanced earlier. PMID- 11605538 TI - [Interaction of HIV-1 reverse transcriptase and bacteriophage T7 RNA polymerase with NTP phosphonate analogs and inorganic pyrophosphate]. AB - We have examined the interaction of human immunodeficiency virus reverse transcriptase (HIV RT) and T7 RNA polymerase (T7 RNAP) with modified nucleoside triphosphates and inorganic pyrophosphate (PPi) analogs containing nonhydrolyzable bisphosphonate groups. We have synthesized a number of derivatives of bisphosphonic acid having different aromatic and nonaromatic side substituents, as well as the NTP derivatives whose incorporation into the growing nucleotide chain during the polymerization reaction results in formation of bisphosphonates as leaving groups. The competitive character of inhibition of both enzymes has been revealed for all the compounds under study, and the inhibition constants have been estimated. One of PPi analogs containing a bulky aromatic substituent is characterized by similar inhibition constants for both T7 RNAP and RT. The universal character of this inhibitor can serve as evidence for a similar structure of the NPT-binding sites in the two polymerases. It has been shown that nonsubstituted methylenebisphosphate is a better leaving group than that containing additional methyl and hydroxyl groups. The NTP analogs are very weak inhibitors of T7 RNAP, whereas HIV-1 RT is more sensitive to this type of compounds. On the basis of the X-ray crystallographic data on the T7 RNAP complex with a template and NTP, we have modeled the binding of some derivatives of bisphosphonic acid in the active center of the enzyme. The peculiarities observed in the model correlate well with the experimental data on inhibition. PMID- 11605537 TI - [Formation of recognition site in transcription factors: repressor of phage lambda and a murine immunoglobulin factor]. AB - IPolar interactions between protein and the major groove of double-stranded DNA have been analyzed on the basis of a structural study of the complexes formed by two transcription factors: phage lambda repressor and murine immunoglobulin transcription factor NF kappa B-p50. Two identical molecules of these two factors form two binding sites within two different parts of a single DNA molecule. This allows one to study formation of the recognition module by comparing the binding pattern of two different parts of the DNA operator. We have shown that formation of the DNA-binding sites for the three structurally different protein domains (one in repressor and two in the immunoglobulin factor) involves polar residues selected from the largest polar cluster on the surface of the protein molecule. It was also shown that the same polar residues bind with different points of DNA sites. This result provides understanding of the recognition module adaptation to varying nucleotide sequence of the operator sites and shows the way of binding site formation. PMID- 11605539 TI - [Crystallization of a complex of components of A and B methane monooxygenase]. PMID- 11605540 TI - [Conformational polymorphism and extensibility of DNA quadruplexes formed from d(GT)n repeats]. AB - We showed earlier that oligonucleotides 3'-d(GT)5-pO(CH2CH2O)3p-d(GT)5-3' form bimolecular quadruplexes with parallel orientation of their strands, which are held by guanine quartets alternating with unpaired thymines (GT quadruplex). This work deals with the conformational polymorphism and extensibility of G quadruplexes in complex with molecules of an intercalating agent ethidium bromide (EtBr). A cooperative mechanism of EtBr binding to the GT quadruplex was revealed. The binding constant K = (3.3 +/- 0.1) x 10(4) M-1, cooperativity coefficient omega = 2.5 +/- 0.2, and maximal amount of EtBr molecules intercalated in GT quadruplex (N = 8) were determined. It was proved experimentally by analysis of adsorption isotherms and theoretically by mathematical modeling that the GT quadruplex is capable of double extension, which is indicative of the high elasticity of this four-stranded helix. Two most stable conformations of GT quadruplexes with thymine residues intercalated and/or turned outside were found by mechanico-mathematical modeling. The equilibrium is shifted toward the conformation with the looped out thymine residues upon intercalation of EtBr molecules into the GT quadruplex. PMID- 11605541 TI - [Analysis of complex formation of daunomycin with the deoxyhexanucleotide 5' d(TpApCpGpTpA) in an aqueous solution from NMR-spectroscopy data]. AB - Self-association of hexadeoxynucleotide 5'-d(TpApCpGpTpA) and its complexation with antitumor antibiotic daunomycin were studied by one- and two-dimensional homonuclear 1H NMR spectroscopy and heteronuclear 1H-31P NMR spectroscopy in water-salt solution. The concentration and temperature dependences of proton chemical shifts of the hexadeoxynucleotide and the ligand were measured, and equilibrium constants and thermodynamic parameters of corresponding reactions were calculated on this basis using models for the formation of hexadeoxynucleotide duplex and its complex with the antibiotic. The spatial structure of daunomycin-d(TACGTA)2 complex in solution was calculated using X PLOR software on the basis of 2D NOE spectral data and the limit values of proton chemical shifts of the ligand. Comparative analysis of different intermolecular interactions in sequence-specific binding of the antibiotic to the DNA fragment was carried out. PMID- 11605542 TI - [A kinetic model of the cleavage of permutational variants of the antigenomic HDV ribozyme]. AB - The kinetic characteristics have been studied for noncircularly permuted variants of the human hepatitis delta virus (HDV) antigenomic ribozyme to find out the cause of the two-phase kinetics of the self-cleavage reaction. Different ways of reaction initiation, suboptimal conditions, and jumpwise changes of reaction conditions have been used, and the temperature dependences have been studied. A correlation has been shown between the apparent kinetic constant of the first reaction phase and the portion of the ribozyme molecules that self-cleaved during the first phase. Partial restoration of the initial reaction characteristics has been shown by the reinitiation of reaction being stopped after completing the first phase. On the basis of all the data obtained, a scheme of the self-cleavage reaction has been proposed including: (i) activation of the ribozyme with energy of 40-50 kcal/mol and a characteristic time of several deciminutes under optimal reaction conditions; (ii) fast and reversible reaction of the phosphodiester bond cleavage; (iii) reaction leading to isomerization of the 3',5'-phosphodiester bond to the 2',5' bond in the self-cleavage site with a characteristic activation time of tens of minutes; and (iv) practically irreversible conformational change leading to fixation of the cleavage by immobilization of the 5'-terminal nucleotide of the product in the center of the formed structure and displacement of the 3'-terminal nucleotide to the periphery. The latter process has a characteristic time of tens of minutes and a low activation energy. PMID- 11605543 TI - [Cloning of genes activated in murine embryonal stem cells during differentiation in suspension]. AB - Embryonic stem cells (ESC) are widely employed as an experimental model owing to the similarity of molecular events occurring in their in vitro differentiation and in early embryo development. Subtraction hybridization was used to clone genes that display enhanced transcription in simple embryoid bodies (EB), which are formed on ESC culturing in suspension and are characterized by the presence of endodermal cells. The cloned sequences proved to include three new genes lacking homologs in databases. Northern analysis of the transcript tissue distribution in adult mice confirmed higher expression of these genes in differentiated cells compared with ESC. PMID- 11605544 TI - [Effect of azidothymidine on reactivation of DNA synthesis in macrophage nuclei contained in heterokaryons]. AB - EIn heterokaryons, DNA synthesis is reactivated in macrophage nuclei only in the case of fusion with immortal cells. Assuming that telomerase is responsible for reactivation, the effect of its inhibitor azidothymidine (AZT) was studied in heterokaryons of mouse resident peritoneal macrophages and immortal 3T3 Swiss cells. AZT suppressed reactivation of DNA synthesis in macrophage nuclei and had no effect on DNA synthesis in 3T3 Swiss cell nuclei, suggesting an altered telomere structure in normal mouse macrophages. PMID- 11605545 TI - [Primary structure of hairpin 35 and 48 small rRNA is proof that Trefusiidae is a subtaxon of marine Enoplida (Nemotoda)]. AB - A rare nucleotide substitution was found in the evolutionarily conserved loop of hairpin 35 of the 18S rRNA gene of marine free-living nematode, Trefusia zostericola (Nematoda: Enoplida). The same substitution was found in all the marine Enoplida studied but not in other nematodes. Such a molecular synapomorphy indicates that marine enoplids are more closely related to T. zostericola than to freshwater Triplonchida. Maximum parsimony, neighbor-joining, and maximum likelihood analyses of complete nucleotide sequences of the gene, with the heterogeneity of nucleotide sites in evolution rates taken into account, support this conclusion. Hence, the hypothesis of particular primitiveness of Trefusiidae among nematodes should be rejected. Phylogenies based on molecular data support the morphological reduction of metanemes in Trefusiidae. Alongside with the unique change in hairpin 35 loop among marine Enoplida (including T. zostericola), hairpin 48 is also modified by a rare transversion which could be found among Mesorhabditoidea nematodes, in related genera Pelodera, Mesorhabditis, Teratorhabditis, Parasitorhabditis, Crustorhabditis, and Distolabrellus, and in 11 orders of Rhodophyta. Rare mutations in hairpins 35 and 48 tend to be fixed correlatively in evolution and could be found in all the Acanthocephala species. X-Ray data show that these regions (H31 and H43, in alternative nomenclature) are spatially brought together in native ribosomes. The nature and distribution of molecular autoapomorphies in phylogenetic trees of high-rank taxa are discussed. PMID- 11605546 TI - [Expression of a cloned hemagglutinin-neuraminidase gene from Newcastle disease virus in murine myeloma cells]. AB - Vaccination with autologous cancer cells expressing a potent foreign antigen is promising for immunotherapy of tumors. A construct was obtained to transfect cancer cells with the hemagglutinin-neuraminidase (HN) gene of the Newcastle disease virus (NDV). Specific primers were designed, and the HN cDNA was amplified from RNA isolated from the allantoid fluid of NDV-infected embryonated chicken eggs. The amplified fragment was cloned in pCR2.1, sequenced, and recloned in expression vector pCDNA3.1/Zeo(+). The resulting construct was used to transfect mouse myeloma cells SP2/0. Production of HN was checked by ELISA and by a neuraminidase activity assay. Cell agglutination on ice was proposed as a test for surface HN. PMID- 11605547 TI - [Classification of organisms and structuralism in biology]. AB - Structuralism in biology is the oldest trend oriented to the search for natural "laws of forms" comparable with laws of growth of crystal, was revived at the end of 20th century on the basis of structuralist thought in socio-humanitarian sciences. The development of principal ideas of the linguistic structuralism in some aspects is similar to that of biological systematics, especially concerning the relationships between "system" and "evolution". However, apart from this general similarity, biological structuralism is strongly focused on familiar problems of the origin of diversity in nature. In their striving for the renovation of existing views, biological structuralists oppose the neo-darwinism emphasizing the existence of "law of forms", that are independent on heredity and genetic "determinism". The trend to develop so-called "rational taxonomy" is also characteristic of biological structuralism but this attempt failed being connected neither with Darwin's historicism nor with Plato's typology. PMID- 11605548 TI - [Methodology of biological thought in works of V. N. Beklemisheva (1890-1862)]. AB - During his work in Perm University (1918-1932) Vladimir Nikolaevich Beklemishev created theoretical and methodological foundations for the concepts of constructive morphology and structure of the living cover of the Earth. His conclusions about topical problems of general biology are still valuable for biological thinking. PMID- 11605549 TI - [First experience with using a series of generalized golden proportions for studying the shell of brachiopod and mollusks]. AB - Symmetry of shells of clams (Veneridae: Katelysia, Venus, Periglypta; Fimbriidae: Corbis fimbriata) and brachioipods (Cancrinella undata, Echinoconhus punctatus, Reticulatia inflatiformis and Neophricodothyris waageni) was studied geometrically with spiral symmetry and connected mathematical methods (complex proportions and Fibonacci numbers). Location regularity of the elements of concentrical sculpture connected with shell growth is interpreted as unrolling of logarithmic spiral in the process of growth. Correlations of radius of sculpture circles were studied with the raw of generalized golden sections of V.I. Korobko and G.N. Primak. The discovered regularities of circles location being similar to some peculiarities of phyllotaxis are governed by the rules of the raw of generalized golden sections. Two spiral folds could keep correspondence between the increase in mass of growing animal and the increase in intensity of water drawing by ciliate apparatus. PMID- 11605550 TI - [The biological essence of golden sections]. AB - Using the examples of phyllotaxis and the process of graduated development of plant photosynthetic apparatus the author shows that the principle of golden section is an implication of the principle of optimal construction (maximal simplicity). The principle of optimal construction is characterized by minimum of numerical relations between integer and its parts, that indicate the fractal character of studied objects and processes organized according to the golden section principle. PMID- 11605552 TI - [Morphological diversity of Pandorina morum (Mull.) Vory (Volvocaceae) colonies]. AB - Morphological variability of polyhedral colonies of green algae (Volvocaceae) were studied using some elements of combinative theory of polyhedron and the theory of diophantine equations. These colonies are considered as results of self organization according to topological regularities of sphere dissection by convex polygons. It was shown that in three-dimensional Euclidean space for each colony of Pandorina morum (Mull.) Bory only three different forms are possible. One of them has no plane of symmetry and, thus, has two enantiomorphous varieties. It is suggested that frequency spectrum of forms can be used as potential indicator of environment pollution. PMID- 11605551 TI - [Self-recovery of plant communities: examples, mechanisms, and approaches for description]. AB - Autogenic (self-recovering) plant communities that need no transitional stages of succession for their recovery after damage are widespread in different areas of the Globe. They are typical for tundras, but also common in boreal forests, alpine belts, deserts and Mediterranean biomes. Such communities usually dominate the landscape. The authors examine in details the communities of cottongrass (Eriophorum vaginatum) wet tussock tundras of North-Eastern Asia and Alaska, the dryad (Dryas punctata) lichen dry patchy tundras of the same region and Scots pine (Pinus sylvestris) lichen-feathermoss forests on fluvial-glacial deposits of Fennoscandia and Russian Plain. Although authogenic plant communities are serial, they exist side by side with proper edaphic variants of climaxes but don't appear to be replaced by the latter, being even more stable. Moreover, they even seem to "compete" for the space with the climax communities. Stabilization of autogenic communities is primarily induced by the impact of abiotic disturbance factors, like periodic fires, permafrost action or scree sliding, and afterwards maintained by several mechanisms of community structure organization. Such mechanisms of self-recovery act at the levels of both plant population and community as a whole. Specific adaptions of dominant species to typical kinds of disturbance (at a scale of either the community, or its local parts) illustrate the first level, whereas close co-adaptations between dominants and accompanying species refer to the second one. Such co-adaptations are present as complementarity of plant life strategies and growth forms within a community and/or as a shifting-mosaic steady state which leads to quick recovery of local disturbances. Among different possible approaches to simulation of community autogenesis those of combinatorial simulation seem to be especially perspective. PMID- 11605553 TI - [Behavioral reactions of Bufo bufo L. tadpoles to chemical excretion of adult toads and changes during larval development]. AB - The reactions of toad (Bufo bufo L.) tadpoles to chemical excretes of adults were studied. In double-choice test aquarium tadpoles demonstrated avoidance reactions (swimming away from the place of stimulus delivering, reduction time of spent in stimulus part of aquarium and reduction of movement activity). Efficiency of stimulus reduced when its concentration decreased. The thresholds of tadpoles sensitivity estimated according to the reduction of time spent in stimulus part of aquarium decreased in onthogeny: they were near 500 x 10(-5) g hour/l at 36-39 developmental stages and 500 x 10(-4) g.hour/l at 40-41 stages. PMID- 11605554 TI - [Geometrization of biological ideas: probablistic model of evolution]. AB - The paper deals with mathematical explication of such fundamental notions of theoretical biology as space of morphological properties, proper time, diversity of forms and phenomena, spontaneous changes. The author developed a nationally geometrical picture of the animate world. A probabilistic approach is used to describe the process of evolution, whose mechanism is given by the Bayesian syllogism. It is shown how the Bayesian approach can formally describe evolutionary changes of the whole pattern of properties. The author discusses some ideas dealing with the possibility of constructing a general field theory, embracing both such phenomena that are beyond the framework of physical science. PMID- 11605555 TI - Testing architectures of the decision-confidence relation. AB - Two experiments examined the effect of rendering confidence judgments on the properties of the comparative decision process. In Experiment 1, participants worked for 12 sessions that required two-alternative perceptual, line-length comparisons. For sessions 1-4 and sessions 9-12, confidence judgments were not required. For sessions 5-8, participants provided confidence reports following each comparative judgment. The requirement of confidence judgments significantly increased decisional response time, suggesting that some confidence processing occurs in parallel with the primary decision process. Concomitantly, an examination of the properties of the time to determine confidence during sessions 5-8 revealed clear evidence of postdecisional confidence processing. These results were replicated in a second experiment requiring two-alternative comparative judgments of Canadian city populations. We conclude that confidence processing occurs both during the decision process and postdecisionally, and we discuss the implications of the present findings for current theories of confidence in human judgment. PMID- 11605556 TI - Specificity of practice in a ball interception task. AB - Learning of an aiming task has been shown to be specific to the sources of afferent information available during practice. However, this has not been the case when a one-hand ball-catching task has been used. The goal of the present study was to determine the cause of these conflicting results. Participants practiced an interception task in either a normal vision condition or a ball-only condition. They were all then transferred to the ball-only condition, using either the same ball trajectories as in acquisition or different ones. Being transferred from a normal vision condition to a ball-only condition resulted in a significant increase in spatial interception errors, thus supporting the specificity of practice hypothesis. Using new ball trajectories in transfer caused a significant increase in error for all participants. The pattern of errors observed when new ball trajectories were used suggests that participants had difficulty correlating information about the location of their arm via proprioception and a combination of retinal and extra-retinal information about the ball trajectory. PMID- 11605557 TI - Taking a bright view of negative priming in the light of dim stimuli: further evidence for memory confusion during episodic retrieval. AB - A same-different letter-matching task was used to examine the effects of stimulus intensity on negative priming, which is poorer performance when target letters have been presented as distractor letters on the immediately preceding trial. In Experiment 1, stimulus intensity was manipulated between-participants, whereas in Experiment 2, it varied randomly from trial-to-trial within-participants. In Experiment 1, negative priming was equivalent for both stimulus intensities. In Experiment 2, negative priming effects were larger for repeated intensity stimuli than for nonrepeated intensity stimuli, when stimulus intensity was dim. Furthermore, for repeated intensity stimuli, negative priming effects were enhanced when the overt response required to the stimulus was repeated from prime to probe trial. These results are consistent with the hypothesis that negative priming may be due to memory confusion, rather than to inhibition of the distractor stimuli. PMID- 11605558 TI - Encoding specificity revisited: the role of semantics. AB - Three experiments examined the effects of semantic characteristics of word pairs on memory using the encoding specificity paradigm. The paradigm involved four phases: (a) an encoding phase to relate cues and targets, (b) a phase in which words were generated to new cues, (c) a phase for recognition of generated targets, and (d) a cued-recall phase using the original encoding cues. Encoding pairs were classified a priori as either semantically similar (e.g., alluring PRETTY), semantically contrasting (e.g., drab-PRETTY), or semantically unrelated (e.g., sore-PRETTY). Generation pairs were classified a priori as either semantically similar (e.g., beautiful-PRETTY) or semantically contrasting (e.g., ugly-PRETTY). For recall, the results showed that both the semantic relations between the encoding cue and target and the reprovision of the encoding cue at retrieval were important factors. In the case of recognition, however, both the semantic congruence between the encoding and generation contexts and the amount of semantic elaboration provided by the encoding context were important factors. PMID- 11605559 TI - The contribution of category relationships to similarity ratings. AB - Two experiments produced evidence that category relationships contribute to similarity ratings. In Experiment 1, participants gave similarity ratings with respect to a semantic category (VEGETABLE) and a set of exemplars, some of which were members of the category (e.g., BROCCOLI) and some of which were not (e.g., BANANA). A regression analysis was used to predict the similarity ratings in terms of numbers of common and distinctive features, as reported by other participants. Perceived similarity was greater for examplars that were members of the category, independently of feature overlap. Experiment 2 examined similarity ratings with respect to pairs of exemplars. In some cases, both exemplars were members of the same category (e.g., BROCCOLI/CUCUMBER). In other cases, one exemplar was a member of the category and the other was not (e.g., BROCCOLI/BANANA). A regression analysis was used to predict the similarity ratings in terms of numbers of common and distinctive features. Perceived similarity was greater when both exemplars were members of the same category, independently of feature overlap. PMID- 11605560 TI - Measuring threshold shifts for brain stimulation reward using the method of limits. AB - Thresholds determined from the frequency of pulses and the current for rewarding brain stimulation were obtained from rats with lateral hypothalamic electrodes. The threshold, defined as the frequency or current corresponding to one-half the maximum response rate, was interpolated from reward summation functions. Daily trials of both ascending and descending sequences of frequency and current yielded no significant difference between order of presentation. While there was more variability in the maximum response rates across the sessions, neither frequency- nor current-based threshold evaluations yielded significant rate effects. Our findings suggest that the threshold procedure is generally not influenced by the sequence of delivery of stimulus values and, thus, may be regarded as a reliable measure of the reinforcing properties of brain-stimulation reward. PMID- 11605561 TI - Is position "special" in visual attention? Evidence that top-down processes guide visual selection. AB - The role of spatial position in selective visual processing has been the source of recent debate. Experiments by Tsal and Lavie (1988) and van der Heijden et al. (1996) have been designed to establish the status of position in visual selection. Tsal and Lavie found that observers tend to select letters from a briefly presented array according to position. Using the same paradigm, van der Heijden et al. found that observers tend to select according to colour, except under conditions of low contrast and unrestricted eye movements. The present study attempted to reconcile these findings by exploring the influence of top down processes (task instructions) while explicitly controlling for eye movements. Experiment 1 demonstrated there was no inherent selection bias for stimuli similar to those used by van der Heijden et al., suggesting that the tendency to select according to colour found by van der Heijden et al. was due to task demands. Experiment 2 further established the role of top-down factors by replicating the results of van der Heijden et al. with our stimuli. Experiment 3 demonstrated that selection can be switched from colour to position by changing the demands of the task. These results suggest that selection may be accounted for by task demands (e.g., instructions) with no priority access for position information. PMID- 11605562 TI - Tympanosclerosis (cosmetic). PMID- 11605563 TI - Concha bullosa of a superior turbinate. PMID- 11605564 TI - Sulcus vocalis concealed by a hemorrhagic polyp. PMID- 11605565 TI - Sinusoidal vertical-axis rotation test in a patient with a long history of vestibular complaints. PMID- 11605566 TI - Labyrinthitis ossificans. PMID- 11605567 TI - Laryngeal and esophageal histoplasmosis. PMID- 11605568 TI - Recent advances in radiotherapy for head and neck cancers. AB - Advancements in surgery have made it possible to resect cancers that had previously been regarded as incurable. Similarly, new developments in radiation oncology have helped improve the outlook for patients with locally advanced or recurrent head and neck cancers. Among these advancements are refinements in altered fractionation, three-dimensional conformal radiotherapy, intensity modulated radiotherapy, stereotactic radiosurgery and fractionated stereotactic radiotherapy, neutron-beam radiotherapy, charged-particle radiotherapy, and intraoperative radiotherapy. These recent developments have allowed radiation oncologists to escalate the dose of radiation delivered to tumors while minimizing the dose delivered to surrounding normal tissue. Additionally, more continues to be learned about the optimum delivery of chemotherapy. This article provides an update on the status of these new developments in the treatment of head and neck cancers. PMID- 11605569 TI - The 'parachute' bolster technique for securing intraoral skin grafts. AB - Successful skin grafting of intraoral defects can be challenging. The tie-over bolster method is the most popular technique in use today. We describe an alternate method of securing intraoral skin grafts--the "parachute" bolster technique--and we present a case report. PMID- 11605570 TI - Unusual paranasal sinus tumors in two patients with common nasal complaints. AB - Common nasal complaints are managed by both the otolaryngologist and the primary care physician. We describe the cases of two patients with nasal obstruction who were referred to us for evaluation--one with severe headache and the other with profuse epistaxis. Their histories prior to referral included long-term, common rhinologic complaints of low-grade headache and mild epistaxis. Neither patient had been referred to us until their symptoms had become severe. Our examination revealed that both patients had rare paranasal sinus pathology. One patient had a fibroxanthoma of the frontal sinus, and the other had extramedullary hematopoiesis of the maxillary sinus. Fibroxanthoma of the frontal sinus is rare, and extramedullary hematopoiesis of the maxillary sinus has not been previously reported. These two unique cases serve as a reminder that long-term common rhinologic complaints can occasionally be a sign of life-threatening pathology and require a full evaluation by an otolaryngologist. PMID- 11605571 TI - Concomitant vagal neurofibroma and aplasia of the internal carotid artery in neurofibromatosis type 1. AB - We report the case of a patient with neurofibromatosis type 1 who had both aplasia of an internal carotid artery (ICA) and a vagal neurofibroma. To our knowledge, this is the first report in the literature of the simultaneous presence of these two rare disorders in a single patient. We believe that this is also the first report of an absence of an ICA in a patient with neurofibromatosis type 1. The patient was a 19-year-old woman who complained of a slowly growing neck mass. The mass occupied the right parapharyngeal space and upper cervical region. The patient had no other masses on physical examination, but widespread cafe au lait spots were evident. This led us to suspect the presence of a vagal neurofibroma. The tumor was removed, and pathology confirmed the diagnosis. No intracranial aneurysms were detected on cerebral angiography. PMID- 11605572 TI - Midfacial osteomyelitis in a chronic cocaine abuser: a case report. AB - We describe the case of a 56-year-old man who was admitted for treatment of a progressive destruction of his hard palate, septum, nasal cartilage, and soft palate that had been caused by chronic cocaine inhalation. Biopsy of the bony septum revealed acute osteomyelitis and an extensive overgrowth of bacteria and Actinomyces-like organisms. There was no evidence of granuloma or neoplasm. The patient received intravenous ampicillin/sulbactam for 6 weeks, followed by lifetime oral amoxicillin. When there was no further evidence that destruction was progressing, the patient underwent nasal reconstruction with a cranial bone graft. The surgery was completed with no complications. To our knowledge, this is the first reported case of midfacial osteomyelitis associated with chronic cocaine abuse. The severity of this patient's complications, coupled with the success of his reconstructive surgery, makes this case particularly interesting. We believe that it is important for physicians to understand that septal perforation in a cocaine abuser should not be underestimated because it could result in a secondary bone infection. Nasoseptal destruction secondary to intranasal cocaine abuse is a result of cocaine's vasoconstrictive properties, and a decrease in the oxygen tension of intranasal tissue can facilitate the growth of anaerobic pathogens. PMID- 11605573 TI - Aspirated foreign body in a laryngectomized patient: case report and literature review. AB - The presence of a permanent tracheal stoma in a laryngectomized adult is a predisposing factor for foreign-body aspiration, as are conditions that impair normal protective airway mechanisms. Such an aspiration can cause significant morbidity if it is not properly managed. The use of rigid bronchoscopy to remove an aspirated object can be difficult in these patients, and a high percentage of them require thoracotomy, especially for the removal of sharp objects. An emphasis on patient education regarding the handling of objects around the stoma in laryngectomized adults is key to preventing aspiration and its complications. PMID- 11605574 TI - Pneumolabyrinth: a late complication of stapes surgery. AB - As temporal bone imaging techniques continue to improve, it is likely that we will see an increase in the detection of pneumolabyrinth. Several mechanisms have been proposed to explain how air enters the labyrinth. A small number of authors has reported an association between pneumolabyrinth and temporal bone fractures, perilymphatic fistulae, and displaced stapes prostheses. In this article, we describe a new case of pneumolabyrinth that was seen as a late complication of stapes surgery, and we summarize what is known about this rare condition. PMID- 11605575 TI - Cowden's disease with vocal fold involvement. AB - Cowden's disease is a hereditary disorder characterized by oropharyngeal fibrosis and multiple hamartomas with potential malignant changes. We treated a 47-year old man who had fibrotic lesions on the left vocal fold and an extensive amount of papillomatous lesions on the mucosa of the lips, tongue, and pharyngeal wall and on the skin of the axillae and buttocks. The pattern of distribution and the histopathologic features of these mucocutaneous lesions were diagnostic of Cowden's disease. To the best of our knowledge, this is the first reported case of Cowden's disease involving a vocal fold. PMID- 11605576 TI - Treatment strategies in chronic ear disease. PMID- 11605577 TI - Do not overlook Pendred's syndrome in children with sensorineural hearing loss. PMID- 11605578 TI - [Clinical evaluation of isopropyl unoprostone (Rescula), in the adjunctive treatment of primary open angle glaucoma]. AB - AIM: To investigate the clinical characteristics of docosanoid derivative, isopropyl unoprostone in the treatment of primary open angle glaucoma (POAG). MATERIAL AND METHODS: In 17 patients (22 eyes) with POAG we analysed prospectively the effect of Rescula upon intraocular pressure, aqueous flare, pupil size, ocular signs and symptoms. Patients were followed up every 2 weeks for at least 8 weeks with complete ocular examination. Concomitant topical therapeutics were used in the study: 0.5% Timolol--group I (16 eyes), and 0.5% Timolol + 2% Dorzolamide--group II (6 eyes). RESULTS: Mean (+/- SD) pretreatment pressure was 24.7 +/- 4.3 mm Hg in group I and it was reduced by 3.7 mm Hg (13.5%) (p < 0.05) at the end of the follow up. In group I Rescula was very effective (delta T% > 25%) in 6/16 eyes (37.5%) and it was ineffective (delta T% < 10%) in the same number of eyes. In group II pretreatment pressure was 24.8 +/- 2.6 mm Hg and it was reduced by 2.6 mm Hg (10.6%) (p = 0.1). Rescula induced no elevation of the aqueous flare during the treatment. No effect on pupil size was observed, either. Eye stinging/conjunctival hyperaemia was noted in 2/17 patients and punctate epitheliopathy in 1 patient (5.9%) that caused discontinuation of drops. CONCLUSIONS: Unoprostone produced significant additive effect to Timolol. Thus, it may be a valuable option for adjunctive therapy. However, interindividual differences need to be considered, as in some patients the response was insignificant. PMID- 11605579 TI - [Vitrectomy in the treatment of endophthalmitis]. AB - PURPOSE: To present our experience with the surgical management of endophthalmitis. MATERIAL AND METHODS: The results of 27 pars plana vitrectomies in 19 patients with clinical evidence of endophthalmitis were analysed. The endophthalmitis was considered as endogenous in 4 cases and exogenous in 15 cases. RESULTS: With the use of vitrectomy good anatomical and functional results were obtained. Pre-operative visual acuity was worse than 1/50 in 16 patients and ranged from 1/50 to 4/50 in 3 patients. Postoperative visual acuity was worse than 1/50 in 7 patients, ranged from 1/50 to 4/50 in 3 patients and was better than 5/50 in 9 patients. CONCLUSIONS: Pars plana vitrectomy in the management of endophthalmitis makes it possible to collect material for culture, removal of viable organisms and inflammatory products. In cases of posttraumatic endophthalmitis vitrectomy allows to prevent future complications. PMID- 11605580 TI - [Localization of intraocular foreign bodies using computed tomography]. AB - PURPOSE: To present the evaluation of computed tomography (CT) application for detecting the intraocular foreign bodies. MATERIAL AND METHODS: Sixteen computed tomographies of orbit to localise a foreign body were performed in the 2nd Radiology Department at Lublin University School of Medicine from May 1995 to October 1998. During examination 2 mm computed tomography cuts were taken. In almost all cases fundus examination was not possible because of hazy media (cataract, vitreous haemorrhage, endophthalmitis). Pars plana vitrectomy was applied to remove foreign body in all cases. RESULTS: In 14 cases a foreign body was localised inside the eye (3 of them were embedded in the wall of the eye) and in 2 cases a double perforation was noticed. With pars plana vitrectomy 12 of 14 intraocular foreign bodies were removed. Two foreign bodies deeply embedded in the wall of the eye were left. One of the two foreign bodies after double perforation was removed from the orbit and the second, which was localized deeply in the orbit, was left. CONCLUSION: The localisation of the foreign bodies using the computed tomography is a very accurate and sensitive method, facilitating further surgery. PMID- 11605581 TI - [Influence of cornea thickness changes after refractive surgery on intraocular pressure measurements]. AB - PURPOSE: Assessment of influence of of the cornea thickness decrease on intraocular pressure (IOP) measurements with Goldmann applanation tonometry in patients after refractive surgery procedures (PRK and LASIK). MATERIAL AND METHODS: 80 eyes in 40 patients (pts) qualified for myopia correction with laser surgery were divided into two groups: in Ist group--20 pts (40 eyes)--PRK procedure was performed and in IInd group--40 eyes (20 pts) LASIK was performed. IOP was measured by Goldmann applanation tonometry. The cornea thickness was assessed in its central region with endothelial microscope with pachymetric facility (Cooper Vision). The eyes were evaluated twice: before and 1 month after the procedure. RESULTS: In all eyes after laser surgery procedures IOP was lower because of the decrease of central cornea thickness. CONCLUSIONS: The central cornea thickness is an important factor influencing intraocular pressure measurements with Goldmann applanation tonometry. Refractive surgery procedures leading to the decrease of central cornea thickness result in lower intraocular pressure measurements in applanation tonometry. PMID- 11605582 TI - [Corneal scars: confocal images as the basis of qualifying for PTK or PK]. AB - PURPOSE: The study aimed to evaluate corneal scars of various origin using confocal microscopy in order to qualify patients for phototherapeutic keratectomy or penetrating keratoplasty. MATERIAL AND METHODS: We studied 21 patients with scars of various origins in 28 corneas. The age of patients (9 women and 12 men) ranged from 27 to 47 years (mean 31.8). In 10 patients (17 corneas) scars were caused by superficial or profound inflammatory processes of viral, bacterial or fungal origin. In 7 patients (7 corneas) the causative factor was blunt or lacerating injury (linear and planar) and in 4 patients (4 corneas) scars developed after the removal of foreign bodies. All corneas were examined using a ConfoScan-P4 scanning slit confocal microscope (Tomey). RESULTS: Post inflammation scars differed in microscopic appearance, depending on the etiology and clinical state, which affected the mode of treatment. Three scars caused by penetrating trauma were qualified for penetrating keratoplasty. Out of 4 scars caused by non-penetrating trauma, 2 were treated by PTK and 2 by penetrating keratoplasty. In patients with impaired vision after the removal of corneal foreign bodies, confocal microscopy revealed focal areas of increased illumination and intracorneal encrustations. CONCLUSIONS: Confocal microscopy enabled us to determine the structure of corneal scar and the depth at which each scar was located, which helped us to choose between PTK and penetrating keratoplasty. The presence or absence of needle-like structures allowed us to detect inflammatory processes within the scar and to evaluate the state of the remaining corneal tissue. PMID- 11605583 TI - [Change of self-concept in patients after radial keratotomy]. AB - PURPOSE: The study is focused on the problem of self-concept change following radial keratotomy. MATERIAL AND METHODS: 25 patients (17 F, 8 M) were investigated 0.5-1.5 year after the surgery by means of the Adjective Check List by Gough and Heilbrun with double instruction concerning actual self-concept (after the surgery) and retrospective self-concept (before the surgery). RESULTS: In the actual self-concept the patients obtained significantly higher results in the following measures: 1) number of positive words used for self description (Fav, p < 0.05; Iss, p < 0.05); 2) some need scales like affiliation (Aff, p < 0.005), heterosexuality (Het, p < 0.01), and interception (Int, p < 0.05); 3) self-confidence (S-cfd, p < 0.01), military leadership (Mls, p < 0.05), and Adult (A, p < 0.05); 3) two Welsh's scales (A-3, p < 0.05; A-4, p < 0.05). CONCLUSIONS: Patients after radial keratotomy perceive themselves in a more positive way, as more self confident in interpersonal functioning than before. The result suggests that the main reason of the differences resolve in higher well being stemming from the surgical correction of vision. PMID- 11605584 TI - [Diagnosis and surgical treatment of idiopathic macular holes]. AB - AIM: Evaluation of diagnostical methods and pars plana vitrectomy (ppv) in surgical treatment of idiopathic macular holes. MATERIAL AND METHODS: Group of 16 patients, 15 women and 1 man, aged between 48 and 78 years, mean age 63 years. The surgical treatment--ppv were performed in all patients with macular holes stage II-IV. In all patients the following examinations were performed: distant and near visual acuity, ophthalmoscopy in Volk 60 lens, Amsler test, colour vision test with anomaloscope IF2, ultrasonic evaluation of vitreous chamber and particularly of premacular region, and electrophysiological tests-visual evoked potentials (VEP) and electroretinography (ERG). 12 patients were treated by ppv with exchange fluid-gas SF6, and in 4 patients extra adjuvant--own patient's serum was injected after earlier exchange fluid-air-gas SF6. RESULTS: In 80% of cases there was an improvement of vision observed by patients, improvement of near visual acuity and reduction of metamorphopsia in Amsler test. In USG examination the reduction of macular thickening, lack of operculum and presence of complete posterior vitreous detachment in the region of macula were observed after surgery. In electrophysiological investigations there was the improvement of VEP parameters using 1/4 visual field as a stimulus. In 1 case treated with adjuvants, there was endophtalmitis with secondary retinal detachment after ppv. CONCLUSIONS: Ppv in nearly all cases gave good results for patients--improvement of visual comfort and reduction of central defect of vision. It also gave good surgical--anatomical results. Using of adjuvant--own patient's serum, did not improve in particular way the functional and anatomical results of surgery. PMID- 11605585 TI - [Analysis of combined glaucoma and cataract operations with intraocular lens implantation: a study based on own material]. AB - PURPOSE: To analyse results and complications of glaucoma and cataract surgery with IOL implantation. MATERIAL AND METHODS: 28 patients (32 eyes) underwent glaucoma and cataract surgery with IOL implantation during the period of January 1998-December 1999. The follow up time ranged from 6 to 30 months. RESULTS: Postoperative visual acuity was 5/12-5/5 in 78.13% of cases. Intraoperatively there were 4 patients of posterior capsule tears with vitreous loss. The most common postoperative complications were Descemet's membrane folds (28.13%), corneal oedema (21.87%) and increased intraocular pressure (18.75%), but they were only transitory. Finally postoperative intraocular pressure was good in 93.76%. In 2 cases glaucoma medication was longer required. Delayed follow-up showed that visual field deteriorated before surgery had not worsened. CONCLUSIONS: Combined, simultaneous operation of glaucoma and cataract does not seem to give rise to more complications than both procedures performed separately. The procedure is safe and gives good visual rehabilitation. PMID- 11605586 TI - [Ocular manifestations of tuberous sclerosis]. AB - A case of tuberous sclerosis in a 5-year old boy with ocular manifestations and other organ abnormalities (dermatologic, neurologic, renal pathology) is presented. Ophthalmological changes (astrocytic hamartomas of the retina, gelatinous tumor, vascular sheathing) are described. Differential diagnosis is presented. PMID- 11605587 TI - [The effect of gamma-aminobutyric acid injected into lateral brain ventricle of rats after prenatal cadmium intoxication on flash visual evoked potentials (FVEP)]. AB - PURPOSE: To find out any influence of gamma-aminobutyric acid (GABA) injected into lateral brain ventricle in newborn rats prenatally exposed to cadmium (Cd). METHOD: 18 white, Wistar, offspring rats were divided into 3 groups, each consisting of 6 rats (control, 5 ppm and 50 ppm of Cd in drinking water). Newborns were examined when they were 3-6 months old. FVEP were recorded before and after GABA injections. Two doses of GABA were used, 10 and 100 nmols. The statistic analysis with the test of t-Student was performed to estimate the amplitudes and latencies of the negative wave N1 and the next positive one P2. p < 0.05 was used to indicate significant difference. RESULTS: No significant changes in the latencies of peak N1 and P2 in the control and Cd 5 ppm groups (101-103%) after 10 nmols GABA were observed. However, the shortened (91-97%) of them was observed after both doses of GABA in Cd 50 ppm group. The mean value of amplitude of N1 in control rats increased to 127% after 10 nmols GABA and 142% after 100 nmols GABA. Moreover, the mean amplitude of P2 in this group increased to 108% and 146%, respectively. The high significant increase of the amplitudes of N1 (181-280%) and P2 (160-177%) waves were received after both doses of GABA in Cd groups. CONCLUSION: Cadmium increased the sensitivity of GABA-receptors in the OUN. PMID- 11605588 TI - [Familial corneal degeneration in 3 first-degree relatives: a case study]. AB - Corneal degeneration may differently impair visual acuity. Amniotic membrane grafts produce a favourable effect on the corneal structure and therefore they are used in the treatment of severe corneal degenerations. Amniotic membrane grafts can be used to cover conjunctival defects. THE AIM of this paper is to describe 3 cases of severe corneal degeneration manifesting in pseudopterygium in first-degree relatives who were treated with amniotic membrane grafts. MATERIAL AND METHODS: Six eyes in 3 patients (first-degree relatives) were studied. In 3 eyes (2 patients) pathological corneal lesions were removed, the conjunctiva was reconstructed and covered with amniotic membrane grafts. The follow-up period ranged from 9 to 16 months. RESULTS: The results of the above-mentioned procedure were very promising with respect to visual acuity, corneal structure (assessed by confocal microscopy) and alleviation of symptoms. CONCLUSIONS: Amniotic membrane grafts constitute a promising method for the treatment of severe familial corneal degeneration manifesting in pseudopterygium. PMID- 11605589 TI - [Recurrent pterygium: removal and plastic procedure with the use of amniotic membrane: a case history]. AB - AIM: Pterygium is the primitive degenerative and hyperplastic pathology of the conjunctiva. The origin and nature of the primary pterygium lesion is still not fully understood. Surgery is used as a treatment for primary and recurrent pterygium. The surgical techniques applied range from simple surgical removal to complex procedures comprising the treatment of the optical zone and the repair of the conjunctiva. Conjunctival reconstruction may be carried out with free graft of the amniotic membrane. MATERIAL AND METHODS: The paper presents a case history of a patient with 18-fold pterygium removal during the period of last 6 years. The mean recurrence time during the last 2 years ranged between 2-3 months. The pterygium was again removed, and conjunctivoplasty was performed using amniotic membrane. The paper presents the steps of the surgery and the patient's postoperative course. The clinical state and subjective symptoms improved in the postoperative period. The follow-up time was 6 months. RESULTS: The amniotic membrane graft for pterygium surgery is useful for recurrent pterygium in achieving a lower recurrence rate, quicker rehabilitation and agreeable cosmetic result. PMID- 11605590 TI - [Complicated cataract. Part I: complicated cataract in uveitic patients]. AB - The paper shows pathognomonique cases of complicated cataracts concerning the prognostic aspects of surgical treatment. The article presents methods of treatment in cases with uveitic cataract. Modern diagnostic methods are discussed, how to choose the safest surgical technique and to reach the desired postoperative refraction. More effective ways of cataract surgery in uveitis patients are proposed. PMID- 11605591 TI - [Complicated cataract: Part II: complicated cataract in glaucoma. Part II: Complicated cataract in retinal degenerative disorders]. AB - The paper shows pathognomonique cases of complicated cataracts concerning the prognostic aspects of surgical treatment. The article presents surgical methods of treating patients with secondary cataract in high myopia and glaucoma. Modern diagnostic methods are discussed, how to choose the safest surgical technique and to reach the desired postoperative refraction. More effective ways of cataract surgery in patients with glaucoma and in high myopia are suggested. PMID- 11605592 TI - [Assessment of cornea thickness in patients after refractive surgery]. AB - PURPOSE: To assess changes of central cornea thickness after Excimer laser procedures--photorefractive keratectomy (PRK) and in situ keratomileusis (LASIK). MATERIAL AND METHODS: In 80 eyes of 40 patients the Excimer laser procedure was performed. Patients were divided into 2 groups: the 1st after PRK and the 2nd after LASIK procedure. Pachymetric measurements of cornea were performed before and 6 months after procedure. RESULTS: In both groups the thickness of the cornea was significantly lower after procedure. In the 2nd group the changes were greater. CONCLUSION: Excimer laser refractive surgery produces significant decrease in cornea thickness. The change in corneal thickness correlates with the change in spherical equivalent refraction. PMID- 11605593 TI - Medical bankruptcies. PMID- 11605594 TI - Shoring up Medicaid. PMID- 11605595 TI - Health versus money. PMID- 11605596 TI - Staying in debt. PMID- 11605597 TI - Observation or inpatient? PMID- 11605598 TI - Hepatitis B and C among adolescents at an STD clinic on the US-Mexico border. AB - Risky sexual behavior and drug use are factors associated with acquisition of hepatitis B and C. This cross-sectional study investigated hepatitis B and C among 296 adolescents at a sexually transmitted disease clinic in El Paso, Texas, between April 1, 1997, and February 1, 1998. Questionnaires, medical record abstraction, and serum antibody tests provided data on demographics, risk factors, and seroprevalence status. Only 15% of participants always used condoms, 23% had a previous sexually transmitted disease, 46% had more than 1 sexual partner in the last 6 months, and 7% used intravenous drugs. Results showed low seroprevalence of hepatitis B (4.1%) and hepatitis C (3.1%). No significant risk factors were associated with hepatitis B seroprevalence. In contrast, male gender, speaking Spanish, not attending school, having more than 1 sexual partner, and injection drug use were all associated with hepatitis C. Hepatitis B and C seroprevalence rates among high-risk adolescents are lower in El Paso than in other similar US populations, presenting an ideal climate for prevention programs. PMID- 11605600 TI - AMA seeks full conflict disclosure. PMID- 11605599 TI - Post-discharge surgical wound surveillance. PMID- 11605601 TI - Workshop on Life. Sept. 3-8, 2000, Modena, Italy. PMID- 11605602 TI - Reference laboratories for rare tests. PMID- 11605603 TI - Intraductal ultrasonography of the bile duct system. PMID- 11605604 TI - Comment on: Leung JW, Neuhaus H, Chopita N: mechanical lithotripsy in the bile duct. Endoscopy 2001; 33: 800-804. PMID- 11605605 TI - ESGE recommendations for quality control in gastrointestinal endoscopy: guidelines for image documentation in upper and lower GI endoscopy. PMID- 11605606 TI - Life resumes. Tending the wounds. PMID- 11605607 TI - Expectations in the treatment of retinal diseases: neuroprotection. PMID- 11605608 TI - Well developed: the SDB reaches 60. Society for Developmental Biology. PMID- 11605609 TI - Early intervention promotes intellectual development of premature infants: a preliminary report. Early Intervention of Premature Infants Cooperative Research Group. AB - OBJECTIVE: To evaluate the effect of early intervention on the intellectual development of the premature infants. METHODS: Premature infants at gestational age of 28-36.9 weeks were randomly divided into two groups: intervention and conventional care groups. Normal newborn infants during the same period were included in the control group (routine care). Up to March 1996, 156 cases were over the age 1.5-2 years (corrected age), 52 in the intervention group, 51 in the conventional care group and 53 in the normal control group. Parents were taught to carry out the 0-2 year intervention program, which included motor, cognitive, speech development and social behavior. Every three months, height, weight and head circumference were measured. At the age of one and a half and two years, all infants in the three groups received infant development tests of Child Development Center of China (CDCC) scale. The examiner did not know which infant had received intervention. RESULTS: There was no significant difference in biological factors among the two premature groups and in cultural and social factors among the three groups. Intelligence tests at the age of one and a half and two years showed that the average mental development index (MDI) in the intervention group was 13.8 and 14.6 higher than those in the conventional care group and the differences were significant. The psychomotor development index (PDI) was 5.2 and 4.7 higher but the differences were not significant. The MDI and PDI in the intervention group and normal control were quite close, but at two years, the MDI and PDI in the intervention group were 5.7 and 7.3 higher than those in the normal control and the differences were significant (P < 0.05). Compared with the normal control, the MDI in conventional care group at one and a half and two years of age were 11.5 and 8.9 lower. The difference was very significant. There were four cases of mental retardation, whose mental development index (MDI) was less then 70 in the conventional care group, but none in the intervention group. CONCLUSIONS: Early intervention can promote intellectual development of the premature infants and may be beneficial to the prevention of mental retardation. Early and intensive intervention can produce better results. Bringing parent's initiative into full play through deepening their understanding of the importance of early intervention is the key to success. PMID- 11605610 TI - Methylmercury and total mercury in estuarine organisms from Rio de Janeiro, Brazil. AB - Guanabara Bay (GB), located in the Rio de Janeiro State, is still a productive estuary on the south-eastern Brazilian coast. It is an ecosystem heavily impacted by organic matter, oil and a number of other toxic compounds, including Hg. The present study aimed to comparatively evaluate the aquatic total mercury (THg) and MeHg contamination, and the ratios of MeHg to THg (% MeHg), in 3 species of marine organisms, Micropogonias furnieri-carnivorous fish (N = 81), Mugil spp.- detritivorous fish (N = 20) and Perna perna--filter-feeding bivalves (N = 190), which are widely consumed by the population. A total of 291 specimens were collected at the bay in different periods between 1988 and 1998. THg concentrations were determined by cold vapour AAS with stannous chloride as a reducing agent. MeHg was extracted by dithizone-benzene and measured by GC-ECD. Analytical quality was checked through certified standards. All organisms presented both low THg and MeHg concentrations and they were below the maximum limit of 1,000 micrograms Hg.kg-1 wet wt. as established for human intake of predatory fish by the new Brazilian legislation. Carnivorous fish showed higher THg and MeHg concentrations, and also % MeHg in muscle tissues, than organisms with other feeding habits and lower trophic levels. The average of THg concentrations in carnivorous fish was 108.9 +/- 58.6 micrograms.kg-1 wet wt. (N = 61) in 1990 and 199.5 +/- 116.2 micrograms.kg-1 wet wt. (N = 20) in 1998, but they presented different total length and body weights. The average THg content in detritivorous fish was 15.4 +/- 5.8 micrograms.kg-1 wet wt., whereas THg concentrations ranged from 4.1 to 53.5 micrograms.kg-1 wet wt. for the molluscs. The THg and MeHg contents of mussel varied according to the sampling point and water quality. MeHg concentration in detritivorous fish was similar to MeHg concentration in molluscs, but there was a significant difference in the MeHg/THg ratio: the carnivorous fish presented higher MeHg percentages (98%) than the detritivorous fish (54%) and the molluscs (33%). Weight-normalised average concentration of THg in carnivorous fish collected in 1990 (0.18 +/- 0.08 microgram.g-1/0.7 kg wet wt.) and in 1998 (0.16 +/- 0.09 microgram.g-1/0.7 kg wet wt.) presented no significant difference (t = 1.34; P < 0.5). In conclusion, the low THg and MeHg concentrations in the organisms from the GB ecosystem, are related to its eutrophic conditions and elevated amounts of suspended matter. In this situation, Hg could be strongly complexed or adsorbed by the particulate, which would dilute the Hg inputs and reduce its residence time in the water column, with a consequent decrease in its availability to organisms. PMID- 11605611 TI - Evaluation of the passive particle agglutination test in the serodiagnosis and follow-up of syphilis. AB - We performed the present study to determine the rate of concordance of the fluorescent treponemal antibody absorption test (FTA-ABS) and of the microhemagglutination assay for antibodies to Treponema pallidum (MHA-TP) with the passive particle agglutination test (TP.PA) in patients with early syphilis and to observe the reactivity of the rapid plasma reagin (RPR), MHA-TP, and the TP.PA tests for 1 year after therapy. The study included 449 people who were given therapy if they had syphilis and followed up for 1 year. The rate of concordance of the TP.PA with the MHA-TP was 98.4%, and it was 98.9% with the FTA ABS. During follow-up, a significant decrease of antibodies was found in 56%, 26%, and 70% of the patients when using the RPR, the MHA-TP, and the TP.PA, respectively. The TP.PA seems to be an adequate routine assay for the diagnosis of syphilis, being as sensitive as the FTA-ABS test in primary syphilis and as useful as the RPR test in monitoring therapy. PMID- 11605612 TI - [New developments in Alzheimer therapy. Vaccination against dementia?]. PMID- 11605613 TI - Initial prospective multicenter clinical trial of robotically-assisted coronary artery bypass grafting. AB - BACKGROUND: This multicenter prospective trial was designed to assess the safety and efficacy of using a robotically-assisted microsurgical system to create endoscopic coronary anastomoses. METHODS: . Thirty-two patients scheduled for elective primary coronary surgery underwent endoscopic anastomosis of the left internal thoracic artery (LITA) to the left anterior descending (LAD) artery. Three thoracic ports (two for instruments and one for a camera) were placed, and a robotic system was used to perform the LITA-LAD graft. Conventional techniques were used to perform the other grafts. Thirty-one patients underwent median sternotomy and 1 patient underwent a limited anterior thoracotomy. RESULTS: . Graft flow was measured in the operating room and averaged 37 +/- 19 mL/min. Mean anastomosis time was 24 +/- 9 minutes. There were three intraoperative revisions (9%). Two were for inadequate flow and one for an inadvertent injury. Each of these grafts was successfully revised by hand. There were no technical failures of the robotic system. Average postoperative length of stay was 5.5 +/- 2.7 days. There were three reoperations for bleeding, but none of these were related to the LAD anastomosis. Two months following the operation, selective angiography revealed a graft patency of 93%. The patients have been followed for 16 +/- 4 months. CONCLUSIONS: This initial prospective multicenter trial documents the feasibility of robotically-assisted coronary bypass grafting. Further trials are warranted to establish the safety and efficacy of this new technology. PMID- 11605614 TI - A cost comparison of heart transplantation versus alternative operations for cardiomyopathy. AB - BACKGROUND: Heart transplantation is an established therapy for cardiomyopathy but is limited by organ shortage and expense. As a result, alternative operations have been proposed including coronary bypass, mitral valve repair, and left ventricular reconstruction. Because it is unknown whether alternative operations are less expensive than replacing the diseased heart, we compared in-hospital costs and early outcome of these operations with elective heart transplantation. METHODS: We compared clinical and financial data of 268 patients with ejection fraction less than 30% who underwent elective heart transplantation (n = 52, UNOS status 2 only), coronary bypass (n = 176), mitral repair (n = 15), or left ventricular reconstruction (n = 25). Data were evaluated for between-group differences, with p less than 0.05 as significant. RESULTS: Preoperative ejection fraction, although similar for heart transplantation (21.2% +/- 1.3%), coronary bypass (25.8% +/- 0.4%), mitral repair (22.9% +/- 1.5%), and left ventricular reconstruction (24.2% +/- 2.1%), was significantly different between the former two (p < 0.001). There was no difference in operative mortality: 5.8% (3 of 52), 3.4% (7 of 176), 6.7% (1 of 15), and 4.0% (1 of 25), respectively (p = 0.8). However, total hospital cost of heart transplantation was significantly greater than all others: $75,992 +/- $5,380, $25,008 +/- $1,446, $32,375 +/- $2,379, and $26,584 +/- $4,076, respectively (p < 0.001). Organ procurement expenses alone comprised 39.7% ($30,169) of total transplant cost. Kaplan-Meier survival analysis failed to show any survival difference between the various groups (p = 0.86) CONCLUSIONS: Compared with heart transplantation, alternative operations yield a comparable early outcome and long-term survival, and are markedly less expensive. The cost of transplantation, which is largely due to procurement expenses, is yet another reason to attempt alternative operations for cardiomyopathy whenever feasible. PMID- 11605615 TI - Minimally invasive removal of a dislocated stent from the right atrium after previous CABG. AB - Repeat sternotomy after previous open heart operations constitutes a serious risk factor for cardiac injury, particularly in the presence of a patent internal thoracic artery. We report a case of successful minimally invasive removal of a dislocated subclavian vein stent entangled in the tricuspid valve in a patient 5 years after coronary artery bypass surgery. PMID- 11605616 TI - Bibliography of toxinology. PMID- 11605617 TI - Hydrological investigations of forest disturbance and land cover impacts in South East Asia: a review. AB - Investigations of land management impacts on hydrology are well developed in South-East Asia, having been greatly extended by national organizations in the last two decades. Regional collaborative efforts, such as the ASEAN-US watershed programme, have helped develop skills and long-running monitoring programmes. Work in different countries is significant for particular aspects: the powerful effects of both cyclones and landsliding in Taiwan, the significance of lahars in Java, of small-scale agriculture in Thailand and plantation establishment in Malaysia. Different aid programmes have contributed specialist knowledge such as British work on reservoir sedimentation, Dutch, Swedish and British work on softwood plantations and US work in hill-tribe agriculture. Much has been achieved through individual university research projects, including PhD and MSc theses. The net result is that for most countries there is now good information on changes in the rainfall-run-off relationship due to forest disturbance or conversion, some information on the impacts on sediment delivery and erosion of hillslopes, but relatively little about the dynamics and magnitude of nutrient losses. Improvements have been made in the ability to model the consequences of forest conversion and of selective logging and exciting prospects exist for the development of better predictions of transfer of water from the hillslopes to the stream channels using techniques such as multilevel modelling. Understanding of the processes involved has advanced through the detailed monitoring made possible at permanent field stations such as that at Danum Valley, Sabah. PMID- 11605618 TI - Dynamics of the forest communities at Pasoh and Barro Colorado: comparing two 50 ha plots. AB - Dynamics of the Pasoh forest in Peninsular Malaysia were assessed by drawing a comparison with a forest in Panama, Central America, whose dynamics have been thoroughly described. Census plots of 50 ha were established at both sites using standard methods. Tree mortality at Pasoh over an eight-year interval was 1.46% yr(-1) for all stems > or = 10 mm diameter at breast height (dbh), and 1.48% yr( 1) for stems > or = 100 mm dbh. Comparable figures at the Barro Colorado Island site in Panama (BCI) were 2.55% and 2.03%. Growth and recruitment rates were likewise considerably higher at BCI than at Pasoh. For example, in all trees 500 700 mm in dbh, mean BCI growth over the period 1985-1995 was 6 mm yr(-1), whereas mean Pasoh growth was about 3.5 mm yr(-1). Examining growth and mortality rates for individual species showed that the difference between the forests can be attributed to a few light-demanding pioneer species at BCI, which have very high growth and mortality; Pasoh is essentially lacking this guild. The bulk of the species in the two forests are shade-tolerant and have very similar mortality, growth and recruitment. The Pasoh forest is more stable than BCI's in another way as well: few of its tree populations changed much over the eight-year census interval. In contrast, at BCI, over 10% of the species had populations increasing or decreasing at a rate of >0.05 yr(-1) compared to just 2% of the species at Pasoh). The faster species turnover at BCI can probably be attributed to severe droughts that have plagued the forest periodically over the past 30 years; Pasoh has not suffered such extreme events recently. The dearth of pioneer species at Pasoh is associated with low-nutrient soil and slow litter breakdown, but the exact mechanisms behind this association remain poorly understood. PMID- 11605619 TI - The role of extreme events in the impacts of selective tropical forestry on erosion during harvesting and recovery phases at Danum Valley, Sabah. AB - Ten years' hydrological investigations at Danum have provided strong evidence of the effects of extremes of drought, as in the April 1992 El Nino southern oscillation event, and flood, as in January 1996. The 1.5 km2 undisturbed forest control catchment experienced a complete drying out of the stream for the whole 1.5 km of defined channel above the gauging station in 1992, but concentrated surface flow along every declivity from within a few metres of the catchment divide after the exceptional rains of 19 January 1996. Under these natural conditions, erosion is episodic. Sediment is discharged in pulses caused by storm events, collapse of debris dams and occasional landslips. Disturbance by logging accentuates this irregular regime. In the first few months following disturbance, a wave of sediment is moved by each storm, but over subsequent years, rare events scour sediment from bare areas, gullies and channel deposits. The spatial distribution of sediment sources changes with time after logging, as bare areas on slopes are revegetated and small gullies are filled with debris. Extreme storm events, as in January 1996, cause logging roads to collapse, with landslides leading to surges of sediment into channels, reactivating the pulsed sediment delivery by every storm that happened immediately after logging. These effects are not dampened out with increasing catchment scale. Even the 721 km2 Sungai Segama has a sediment yield regime dominated by extreme events, the sediment yield in that single day on 19 January 1996 exceeding the annual sediment load in several previous years. In a large disturbed catchment, such road failures and logging-activity-induced mass movements increase the mud and silt in floodwaters affecting settlements downstream. Management systems require long-term sediment reduction strategies. This implies careful road design and good water movement regulation and erosion control throughout the logging process. PMID- 11605620 TI - Primary forest dynamics in lowland dipterocarp forest at Danum Valley, Sabah, Malaysia, and the role of the understorey. AB - Changes in species composition in two 4-ha plots of lowland dipterocarp rainforest at Danum, Sabah, were measured over ten years (1986-1996) for trees > or = 10 cm girth at breast height (gbh). Each included a lower-slope to ridge gradient. The period lay between two drought events of moderate intensity but the forest showed no large lasting responses, suggesting that its species were well adapted to this regime. Mortality and recruitment rates were not unusual in global or regional comparisons. The forest continued to aggrade from its relatively (for Sabah) low basal area in 1986 and, together with the very open upper canopy structure and an abundance of lianas, this suggests a forest in a late stage of recovery from a major disturbance, yet one continually affected by smaller recent setbacks. Mortality and recruitment rates were not related to population size in 1986, but across subplots recruitment was positively correlated with the density and basal area of small trees (10-< 50cm gbh) forming the dense understorey. Neither rate was related to topography. While species with larger mean gbh had greater relative growth rates (rgr) than smaller ones, subplot mean recruitment rates were correlated with rgr among small trees. Separating understorey species (typically the Euphorbiaceae) from the overstorey (Dipterocarpaceae) showed marked differences in change in mortality with increasing gbh: in the former it increased, in the latter it decreased. Forest processes are centred on this understorey quasi-stratum. The two replicate plots showed a high correspondence in the mortality, recruitment, population changes and growth rates of small trees for the 49 most abundant species in common to both. Overstorey species had higher rgrs than understorey ones, but both showed considerable ranges in mortality and recruitment rates. The supposed trade-off in traits, viz slower rgr, shade tolerance and lower population turnover in the understorey group versus faster potential growth rate, high light responsiveness and high turnover in the overstorey group, was only partly met, as some understorey species were also very dynamic. The forest at Danum, under such a disturbance-recovery regime, can be viewed as having a dynamic equilibrium in functional and structural terms. A second trade-off in shade-tolerance versus drought-tolerance is suggested for among the understorey species. A two-storey (or vertical component) model is proposed where the understorcy-overstorey species' ratio of small stems (currently 2:1) is maintained by a major feedback process. The understorey appears to be an important part of this forest, giving resilience against drought and protecting the overstorey saplings in the long term. This view could be valuable for understanding forest responses to climate change where drought frequency in Borneo is predicted to intensify in the coming decades. PMID- 11605621 TI - The effects of selective logging on the distribution of moths in a Bornean rainforest. AB - The effects of selective logging on the diversity and species composition of moths were investigated by sampling from multiple sites in primary forest, both understorey and canopy, and logged forest at Danum Valley, Sabah, Malaysia. The diversity of individual sites was similar, although rarefied species richness of logged forest was 17% lower than for primary forest (understorey and canopy combined). There was significant heterogeneity in faunal composition and measures of similarity (NESS index) among primary forest understorey sites which may be as great as those between primary understorey and logged forest. The lowest similarity values were between primary forest understorey and canopy, indicating a distinct canopy fauna. A number of species encountered in the logged forest were confined to, or more abundant in, the canopy of primary forest. Approximately 10% of species were confined to primary forest across a range of species' abundances, suggesting this is a minimum estimate for the number of species lost following logging. The importance of accounting for heterogeneity within primary forest and sampling in the canopy when measuring the effects of disturbance on tropical forest communities are emphasized. PMID- 11605622 TI - Termite assemblages, forest disturbance and greenhouse gas fluxes in Sabah, East Malaysia. AB - A synthesis is presented of sampling work conducted under a UK government-funded Darwin Initiative grant undertaken predominantly within the Danum Valley Conservation Area (DVCA), Sabah, East Malaysia. The project concerned the assemblage structure, gas physiology and landscape gas fluxes of termites in pristine and two ages of secondary, dipterocarp forest. The DVCA termite fauna is typical of the Sunda region, dominated by Termes-group soil-feeders and Nasutitermitinae. Selective logging appears to have relatively little effect on termite assemblages, although soil-feeding termites may be moderately affected by this level of disturbance. Species composition changes, but to a small extent when considered against the background level of compositional differences within the Sunda region. Physiologically the assemblage is very like others that have been studied, although there are some species that do not fit on the expected body size-metabolic rate curve. As elsewhere, soil-feeders and soil-wood interface-feeders tend to produce more methane. As with the termite assemblage characteristics, gross gas and energy fluxes do not differ significantly between logged and unlogged sites. Although gross methane fluxes are high, all the soils at DVCA were methane sinks, suggesting that methane oxidation by methanotrophic bacteria was a more important process than methane production by gut archaea. This implies that methane production by termites in South-East Asia is not contributing significantly to the observed increase in levels of methane production worldwide. Biomass density, species richness, clade complement and energy flow were much lower at DVCA than at a directly comparable site in southern Cameroon. This is probably due to the different biogeographical histories of the areas. PMID- 11605623 TI - Mechanisms of maintenance of tropical freshwater fish communities in the face of disturbance. AB - Community resistance to, and resilience from, perturbation will determine the trajectory of recovery from disturbance. Although selective timber extraction is considered a severe disturbance, fish communities from headwater streams around Danum Valley Field Centre, Sabah, Malaysia, showed few long-term changes in species composition or abundance. However, some species showed short-term (< 18 months) absence or decrease in abundance. These observations suggested that both resistance and resilience were important in maintaining long-term fish community structure. Resistance to perturbation was tested by monitoring fish communities before and after the creation of log-debris dams, while resilience was investigated by following the time-course of recolonization following complete removal of all fish. High community resistance was generally shown although the response was site-specific, dependent on the composition of the starting community, the size of the stream and physical habitat changes. High resilience was demonstrated in all recolonization experiments with strong correlations between pre- and post-defaunation communities, although there was a significant difference between pool and riffle habitats in the time-course of recovery. These differences can be explained by the movement characteristics of the species found in the different habitats. Resilience appeared to be a more predictable characteristic of the community than resistance and the implications of this for ensuring the long-term persistence of fish in the area are discussed. PMID- 11605624 TI - Studying insect diversity in the tropics. AB - Understanding the extent and causes of insect diversity in the humid tropics is one of the major challenges in modern ecology. We review some of the current approaches to this problem, and discuss how future progress may be made. Recent calculations that there may be more than 30 million species of insect on earth have focused attention on the magnitude of this problem and stimulated several new lines of research (although the true figure is now widely thought to be between five and ten million species). We discuss work based on insecticidal logging surveys; studies of herbivore and parasitoid specificity; macroecological approaches; and the construction of food webs. It is argued that progress in estimating insect diversity and in understanding insect community dynamics will be enhanced by building local inventories of species diversity, and in descriptive and experimental studies of the trophic structure of communities. As an illustration of work aimed at the last goal, we discuss the construction and analysis of quantitative host-parasitoid food webs, drawing on our work on leaf miner communities in Central America. PMID- 11605625 TI - Effects of nitrogen and phosphorus fertilization in a lowland evergreen rainforest. AB - A nutrient addition experiment was set up in August 1993 in a species-rich primary lowland dipterocarp forest in Barito Ulu, Central Kalimantan, Indonesia. The following treatments were applied: control, +N, +P and +NP. There were five blocks of four 50 m x 50 m plots with a separate treatment for each plot. Fine litterfall was measured on all the plots from 1 May 1994 for 12 months. Litterfall mass and phosphorus concentrations were significantly higher in all the fertilizer treatments compared with the controls. All trees (> or = 10 cm dbh) were measured in August 1993 and in August 1998, and there was no significant girth increment response to fertilization in dipterocarps or non dipterocarps. Dipterocarps of the red meranti group showed a doubling of girth increment in the +NP treatment, however, the difference from the control fell short of significance. PMID- 11605627 TI - Growth and survivorship of dipterocarp seedlings: differences in shade persistence create a special case of dispersal limitation. AB - A series of growth experiments and observations on natural populations have been carried out on dipterocarp species of contrasting ecology growing in artificial gaps and the forest understorey. These studies have demonstrated that although differences exist between species in photosynthetic and growth responses to the high-light environment, competition for light in canopy gaps is highly asymmetrical and tends to reinforce any pre-existing dominance hierarchy. We propose that differences in seedling persistence in forest canopy shade are highly influenced by species-specific biotic and abiotic interactions. Our experiments suggest that as seedlings, dipterocarp species trade off traits which enhance persistence and growth in shade against those that enhance their ability to exploit gaps. Less competitive species survive for progressively longer periods of time after a gregarious fruiting event. This leads to significant shifts with time in the number of species present in the seedling bank and hence in the importance of interspecific competition in determining which species dominates regrowth in gaps. We propose that this special case of dispersal limitation is more likely to account for coexistence of dipterocarp species than differences in growth responses to gaps of different size, with stochastic and environmental variables interacting to determine species distribution and abundance. PMID- 11605626 TI - Parsimonious modelling of water and suspended sediment flux from nested catchments affected by selective tropical forestry. AB - The ability to model the suspended sediment flux (SSflux) and associated water flow from terrain affected by selective logging is important to the establishment of credible measures to improve the ecological sustainability of forestry practices. Recent appreciation of the impact of parameter uncertainty on the statistical credibility of complex models with little internal state validation supports the use of more parsimonious approaches such as data-based mechanistic (DBM) modelling. The DBM approach combines physically based understanding with model structure identification based on transfer functions and objective statistical inference. Within this study, these approaches have been newly applied to rainfall-SSflux response. The dynamics of the sediment system, together with the rainfall-river flow system, were monitored at five nested contributory areas within a 44 ha headwater region in Malaysian Borneo. The data series analysed covered a whole year at a 5 min resolution, and were collected during a period some five to six years after selective timber harvesting had ceased. Physically based and statistical interpretation of these data was possible given the wealth of contemporary and past hydrogeomorphic data collected within the same region. The results indicated that parsimonious, three-parameter models of rainfall-river flow and rainfall-SSflux for the whole catchment describe 80 and 90% of the variance, respectively, and that parameter changes between scales could be explained in physically meaningful terms. Indeed, the modelling indicated some new conceptual descriptions of the river flow and sediment-generation systems. An extreme rainstorm having a 10-20 year return period was present within the data series and was shown to generate new mass movements along the forestry roads that had a differential impact on the monitored contributory areas. Critically, this spatially discrete behaviour was captured by the modelling and may indicate the potential use of DBM approaches for (i) predicting the differential effect of alternative forestry practices, (ii) estimating uncertainty in the behaviour of ungauged areas and (iii) forecasting river flow and SSflux in terrain with temporal changes in rainfall regime and forestry impacts. PMID- 11605628 TI - Interesting times on Krakatau: stand dynamics in the 1990s. AB - The Krakatau Islands, Indonesia, have provided an opportunity for ecologists to track primary succession from the 'clean slate' of 1883, through forest closure in the 1920s, to the contemporary period, in which successional changes take the form of alterations in composition and stature of forest stands rather than gross changes in ecosystem type. This paper reports on permanent forest plots established on the islands in 1989, and fully surveyed again in both 1992 and 1997. Since 1989, the plots have been subject to natural disturbance phenomena in the form of varying combinations of, for example, deposition of volcanic ejecta, landslides, lightning strikes, storm damage and drought. These effects have been concentrated between 1992 and 1997, during which the volcano Anak Krakatau has deposited ash on the islands of Sertung and Panjang, but not on Rakata. Data on stand responses are presented for growth rates (dbh (diameter at breast height, 1.3 m) increment), stem recruitment and mortality, biomass changes partitioned into mortality, ingrowth and growth of established trees), and compositional shifts. The discussion focuses on evaluation of questions and successional models framed earlier in the programme. One general finding is that the stand dominants as of 1989 have tended to decline in number within the plots, generally through low levels of recruitment failing to balance rates of mortality. The effects of disturbance to the plots appear to be evident in terms of mortality and recruitment, dbh increment, and changes in biomass. The patterns of change in the eight plots are quite varied, such that relatively few generalizations are possible. The difficulties of establishing meaningful baseline rates for tree growth and stand biomass are discussed. PMID- 11605629 TI - The ecoclimatology of Danum, Sabah, in the context of the world's rainforest regions, with particular reference to dry periods and their impact. AB - Climatic records for Danum for 1985-1998, elsewhere in Sabah since 1879, and long monthly rainfall series from other rainforest locations are used to place the climate, and particularly the dry period climatology, of Danum into a world rainforest context. The magnitude frequency and seasonality of dry periods are shown to vary greatly within the world's rainforest zone. The climate of Danum, which is aseasonal but subject, as in 1997-1998, to occasional drought, is intermediate between less drought-prone north-western Borneo and the more drought prone east coast. Changes through time in drought magnitude frequency in Sabah and rainforest locations elsewhere in South-East Asia and in the Neotropics are compared. The 1997-1998 ENSO-related drought event in Sabah is placed into a historical context. The effects of drought on tree growth and mortality in the tropics are assessed and a model relating intensity and frequency of drought disturbance to forest structure and composition is discussed. PMID- 11605630 TI - Interdependence of peat and vegetation in a tropical peat swamp forest. AB - The visual uniformity of tropical peat swamp forest masks the considerable variation in forest structure that has evolved in response to differences and changes in peat characteristics over many millennia. Details are presented of forest structure and tree composition of the principal peat swamp forest types in the upper catchment of Sungai Sebangau, Central Kalimantan, Indonesia, in relation to thickness and hydrology of the peat. Consideration is given to data on peat geochemistry and age of peat that provide evidence of the ombrotrophic nature of this vast peatland and its mode of formation. The future sustainability of this ecosystem is predicted from information available on climate change and human impact in this region. PMID- 11605631 TI - Growth responses of cartilage to static and dynamic compression. AB - During skeletal development, growth, and maturation, gradual changes in the material properties and physical dimensions of cartilage occur under the influence of mechanical loading. The objective of the current study was to compare glycosaminoglyean biosynthesis and cell proliferation in fetal, calf, and adult bovine cartilage explants, isolated from defined depths from the articular surface, in response to controlled compressive loads. Mechanical testing confirmed that for all cartilage samples subjected to load, there was a marked time-averaged (static) compression, whereas the addition of dynamic load at a frequency of 0.01 Hz induced dynamic strain with amplitude and phase shift characteristics typical of stimuli that previously were found to be associated with stimulation of glycosaminoglycan synthesis. In metabolic studies, the application of static loading (84 kPa) for 24 hours inhibited glycosaminoglycan and deoxyribonucleic acid synthesis in all cultured cartilage samples. The superposition of dynamic loading (200 kPa, 0.01 Hz) induced a 20% stimulation of glycosaminoglycan biosynthesis in calf cartilage from the middle-deep zones over statically-loaded samples and an additional approximate 50% suppression of deoxyribonucleic acid synthesis in fetal and calf cartilage from the articular surface. These results indicate that synthesis of glycosaminoglycan and deoxyribonucleic acid, two distinct indices of cartilage growth, are regulated independently by mechanical loading and that cartilage responds differently to static and dynamic loading at different stages of maturation. PMID- 11605632 TI - Detection of martian amino acids by chemical derivatization coupled to gas chromatography: in situ and laboratory analysis. AB - If there is, or ever was, life in our solar system beyond the Earth, Mars is the most likely place to search for. Future space missions will have then to take into account the detection of prebiotic molecules or molecules of biological significance such as amino acids. Techniques of analysis used for returned samples have to be very sensitive and avoid any chemical or biological contamination whereas in situ techniques have to be automated, fast and low energy consuming. Several possible methods could be used for in situ amino acid analyses on Mars, but gas chromatography would likely be the most suitable. Returned samples could be analyzed by any method in routine laboratory use such as gas chromatography, already successfully performed for analyses of organic matter including amino acids from martian meteorites. The derivatization step, which volatilizes amino acids to perform both in situ and laboratory analysis by gas chromatography, is discussed here. PMID- 11605633 TI - Formation of bioorganic compounds in simulated planetary atmospheres by high energy particles or photons. AB - Various types of organic compounds have been detected in Jupiter, Titan, and cometary coma. It is probable that organic compounds were formed in primitive Earth and Mars atmospheres. Cosmic rays and solar UV are believed to be two major energy sources for organic formation in space. We examined energetics of organic formation in simulated planetary atmospheres. Gas mixtures including a C-source (carbon monoxide or methane) and a N-source (nitrogen or ammonia) was irradiated with the followings: High energy protons or electrons from accelerators, gamma rays from 60Co, UV light from a deuterium lamp, and soft X-rays or UV light from an electron synchrotron. Amino acids were detected in the products of particles, gamma-rays and soft X-rays irradiation from each gas mixture examined. UV light gave, however, no amino acid precursors in the gas mixture of carbon monoxide, nitrogen and nitrogen. It gave only a trace of them in the gas mixture of carbon monoxide, ammonia and water or that of methane, nitrogen and water. Yield of amino acid precursors by photons greatly depended on their wavelength. These results suggest that nitrogen-containing organic compounds like amino acid precursors were formed chiefly with high energy particles, not UV photons, in Titan or primitive Earth/Mars atmospheres where ammonia is not available as a predominant N-source. PMID- 11605634 TI - Experimental simulation of early Martian volcanic lightning. AB - A mixture of possible Martian volcanic gases were reproduced and irradiated by a high-energy infrared laser to reproduce the effects of lightning on the production of prebiotic molecules. The analysis of products were performed by a gas chromatograph interfaced in parallel with a FTIR-detector and a quadrupole mass spectrometer equipped with an electron impact and chemical ionization modes. The main products identified were hydrocarbons and an uncharacterized yellow film deposit. Preliminary results indicate the presence of hydrogen cyanide among the resultant compounds. PMID- 11605635 TI - Production of nitrogen oxides by lightning and coronae discharges in simulated early Earth, Venus and Mars environments. AB - We present measurements for the production of nitrogen oxides (NO and N2O) in CO2 N2 mixtures that simulate different stages of the evolution of the atmospheres of the Earth, Venus and Mars. The nitrogen fixation rates by two different types of electrical discharges, namely lightning and coronae, were studied over a wide range in CO2 and N2 mixing ratios. Nitric oxide (NO) is formed with a maximum energy yield estimated to be ~1.3 x 10(16) molecule J-1 at 80% CO2 and ~1.3 x 10(14) molecule J-1 at 50% CO2 for lightning and coronae discharges, respectively. Nitrous oxide (N2O) is only formed by coronae discharge with a maximum energy yield estimated to be ~1.2 x 10(13) molecule J-1 at 50% CO2. The pronounced difference in NO production in lightning and coronae discharges and the lack of formation of N2O in lightning indicate that the physics and chemistry involved in nitrogen fixation differs substantially in these two forms of electric energy. PMID- 11605636 TI - Catalysis of peptide formation by inorganic oxides: high efficiency of alumina under mild conditions on the Earth-like planets. AB - Amino acid condensation catalyzed by inorganic oxides is a widely recognized way for prebiotic peptide formation. Silica and alumina are widely distributed in the Earth-like planets' crust as minerals of different complexity, and thus are attractive model catalysts for the studies of abiotic peptide synthesis. Experiments performed in other laboratories have shown that this process can be efficient at > 80 degrees C, which is not easy to find on the planetary surface in combination with sufficient concentrations of amino acids and necessary catalysts. In the present work we tested catalytic activity of three forms of alumina (which proved to be an efficient catalyst for this process) in the intermolecular condensation of L-alanine. We expanded the temperature interval down to 55 degrees C and used the simplest permanent heating procedure, without employing fluctuating drying/wetting conditions. The most important finding is that even under the lowest temperature considered (i.e. 55 degrees C), short peptide formation can be detected already after 10-30 days of heating. This fact implies that the abiotic peptide formation might occur in a wide variety of planetary environments, without need for high temperatures, given the presence of amino acid building blocks and alumina-containing minerals. PMID- 11605637 TI - Survivability of biomolecules during extraterrestrial delivery: new results on pyrolysis of amino acids and poly-amino acids. AB - The hypothesis on exogenous origin of organic matter on the early Earth is strongly supported by the detection of a large variety of organic compounds (including amino acids and nucleobases) in carbonaceous chondrites. Whether such complex species can be successively delivered by other space bodies (comets, asteroids and interplanetary dust particles) is unclear and depends primarily on capability of the biomolecules to survive high temperatures during atmospheric deceleration and impacts to the terrestrial surface. Recent simulation experiments on amino acid and nucleic acid base pyrolysis under oxygen-free atmosphere demonstrated that simple representatives of these (considered thermally unstable) compounds can survive at 1-10% level a rapid heating at 500 600 degrees C. In the present work, we report on new data on the pyrolysis of amino acids and their homopolymers and discuss implications of their thermal behavior for extraterrestrial delivery. PMID- 11605638 TI - Organics produced by ion irradiation of ices: some recent results. AB - Some results, recently obtained from laboratory experiments of ion irradiation of ice mixtures containing H, C, N, and O, are here summarized. They are relevant to the formation and evolution of complex organics on interstellar dust, comets and other small bodies in the external Solar System. In particular the formation of CN-bearing species is discussed. Interstellar dust incorporated into primitive Solar System bodies and subsequently delivered to the early Earth, may have contributed to the origin of life. The delivery of CN-bearing species seems to have been necessary because molecules containing the cyanogen bond are difficult to be produced in an environment that is not strongly reducing as that of the early Earth probably was. Moreover we report on an ongoing research program concerning the interaction between refractory materials produced by ion irradiation of simple ices and biological materials (amino acids, proteins, cells). PMID- 11605639 TI - Partial pressures and nature of products. Application to the photolysis of PH3 and NH3 in the atmosphere of Jupiter and Saturn. AB - The photolysis of mixtures of gases containing NH3 or PH3 presents important differences mainly due to the strength of the X-H bond. On some examples, these differences are evidenced and the consequences for mixtures of gases containing these two compounds are shown: the photolysis of ammonia and ethylene mainly gives ethyl-, butyl- and hexylamine whereas the photolysis of phosphine and ethylene leads to ethyl- and vinylphosphine. When gaseous mixtures of NH3, PH3 and ethylene are photolyzed together, the presence of phosphine dramatically decreases the formation of nitrogen derivatives. The relevance of such lab studies to the atmospheres of Jupiter and Saturn is discussed. PMID- 11605640 TI - Quantum chemical calculations of infrared spectra for the identification of unknown compounds by GC/FTIR/MS in exobiological simulation experiments. AB - Gas chromatography/Fourier transform IR spectroscopy/mass spectrometry (GC/FTIR/MS) is a powerful tool for the separation and unambiguous identification of complex mixtures of organic compounds, where the use of two kinds of spectra allows to significantly increase identification reliability. The simplest situation is when acquired spectra can be found in IR and MS databases, or appropriate standards are available; but this is not always the case. Some simulation experiments related to the origins of life and exobiology (e.g., simulation of amino acid pyrolysis during atmospheric entry of space bodies) can be a typical example when one encounters with numerous unknown compounds. To assist their identification by GC/FTIR/MS, recently we suggested quantum chemical calculations of infrared spectra in order to compare them to IR spectra acquired experimentally. The present work summarizes the results obtained by semi empirical and ab initio methods, discusses their advantages and limitations, considering as test compounds some cyclic amides and amidines derived from amino acids, saturated and unsaturated nitriles (including those of interest for the Titan atmospheric chemistry), acetylenes and some other nitrogen compounds. PMID- 11605641 TI - Possible contribution of different energy sources to the production of organics in Titan's atmosphere. AB - A quantitative comparison of the products arising from the irradiation of a Titan's simulated atmosphere is presented. The energy sources used represent some of the main events that occur in the satellite's atmosphere. All of the compounds identified are classified in the hydrocarbon and nitrile chemical families. Almost all of the detected compounds in Titan's atmosphere are produced by one or more energy sources. The compounds with the highest energy yields include the C2 hydrocarbons, methanonitrile and ethanonitrile. The possibility of using some of the produced organics as tracer compounds during the Huygens descend to identify the leading energy form in the different atmospheric levels remains open. PMID- 11605643 TI - IR and UV spectroscopic data for polyynes: predictions for long carbon chain compounds in Titan's atmosphere. AB - A better understanding of the complex organic chemistry occurring in the methane rich atmosphere of Titan can be achieved via the comparison of observations with results obtained by theoretical models. Available observations are still few but their analysis requires the knowledge of a large set of data, namely frequencies and absolute band intensities. Cross sections are also needed to develop the chemical schemes of photochemical models, in particular the schemes leading to the formation of haze particles visible on Titan. Unfortunately, some of these parameters are not well known, especially if one takes into account the extreme physical conditions of the studied object. This lack of data is particularly enhanced for polyynes because these compounds are highly unstable at the usual pressure and temperature conditions of a laboratory and therefore are very difficult to study. We have developed UV and IR studies, coupling experimental and theoretical approaches, in order to extrapolate the parameters available for short polyynes to longer carbon chains. In the mid-UV range, when the length of the chain increases, the absorption system of polyynes is shifted to longer wavelength and its oscillator strength increases linearly. In the IR range, with the increase of the number of carbon bonds, the positions of the CCC and CCH bending modes shift to lower energy, the latest converging rapidly to a fixed value of 620.5 cm-1 for an infinite length polyyne. Implications for detection and evolution of polyynes in Titan's atmosphere are emphasised. PMID- 11605642 TI - Production of hydrocarbons and nitriles by electrical processes in Titan's atmosphere. AB - Although lightning has not been observed in Titan's atmosphere, the presence of methane rain in the troposphere suggests the possibility of electrical activity in the form of corona and/or lightning discharges. Here we examine the chemical effects of these electrical processes on a Titan simulated atmosphere composed of CH4 in N2 at various mixing ratios. Corona discharges were simulated in two different experimental arrays. For the detection of reactive intermediates we used a mass spectrometer to study the main positive ions arising by bombarding low-energy electrons from a hot filament into low-pressure methane. The final stable products, generated by applying a high voltage in a coaxial reactor with either positive or negative polarity, were separated and detected by gas chromatography-Fourier transform infrared spectroscopy and electron impact mass spectrometry (GC-FTIR-MS). Lightning discharges were simulated by a hot and dense plasma generated by a Nd-YAG laser and the final products were separated and detected by GC-FTIR-MS. Corona discharges produce linear and branched hydrocarbons as well as nitriles whereas lightning discharges generate mainly unsaturated hydrocarbons and nitriles. Lightning discharges are about 2 orders of magnitude more efficient in product formation than corona discharges. PMID- 11605644 TI - Chemical and optical behaviour of tholins, laboratory analogues of Titan aerosols. AB - Since 1997, after having identified for the first time C4N2 (the only molecule detected on Titan and undetected in the laboratory at this date) in a simulated atmosphere of Titan, our group intended to determine several properties (including optical behavior) of laboratory analogues of Titan's tholins. This article summarizes the results obtained in the frame of that program (observation by microscopy, solubility in hydrocarbons and nitriles, chemical composition, and optical behavior in the 200-900nm range), and finally investigates the following items: what are the key questions still remaining?; how to answer them? PMID- 11605645 TI - Solid organic matter in the atmosphere and on the surface of outer Solar System bodies. AB - Many bodies in the outer Solar System display the presence of low albedo materials. These materials, evident on the surface of asteroids, comets, Kuiper Belt objects and their intermediate evolutionary step, Centaurs, are related to macromolecular carbon bearing materials such as polycyclic aromatic hydrocarbons and organic materials such as methanol and related light hydrocarbons, embedded in a dark, refractory, photoprocessed matrix. Many planetary rings and satellites around the outer gaseous planets display such component materials. One example, Saturn's largest satellite, Titan, whose atmosphere is comprised of around 90% molecular nitrogen N2 and less than 10% methane CH4, displays this kind of low reflectivity material in its atmospheric haze. These materials were first recorded during the Voyager 1 and 2 flybys of Titan and showed up as an optically thick pinkish orange haze layer. These materials are broadly classified into a chemical group whose laboratory analogs are termed "tholins", after the Greek word for "muddy". Their analogs are produced in the laboratory via the irradiation of gas mixtures and ice mixtures by radiation simulating Solar ultraviolet (UV) photons or keV charged particles simulating particles trapped in Saturn's magnetosphere. Fair analogs of Titan tholin are produced by bombarding a 9:1 mixture of N2:CH4 with charged particles and its match to observations of both the spectrum and scattering properties of the Titan haze is very good over a wide range of wavelengths. In this paper, we describe the historical background of laboratory research on this kind of organic matter and how our laboratory investigations of Titan tholin compare. We comment on the probable existence of polycyclic aromatic hydrocarbons in the Titan Haze and how biological and nonbiological racemic amino acids produced from the acid hydrolysis of Titan tholins make these complex organic compounds prime candidates in the evolution of terrestrial life and extraterrestrial life in our own Solar System and beyond. Finally, we also compare the spectrum and scattering properties of our resulting tholin mixtures with those observed on Centaur 5145 Pholus and the dark hemisphere of Saturn's satellite Iapetus in order to demonstrate the widespread distribution of similar organics throughout the Solar System. PMID- 11605646 TI - Space life sciences: gravity perception and transduction in plants, fungi and unicellular organisms. Proceedings of the F1.1 Symposium of COSPAR Scientific Commission F which was held during the Thirty-second COSPAR Scientific Assembly, Warsaw, Poland, July, 2000. PMID- 11605647 TI - Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitor. AB - Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), which is a key enzyme in coagulation cascade responsible for the generation of thrombin by limited proteolysis of its zymogen, prothrombin. We have investigated 1-arylsulfonyl-3-piperazinone derivatives, containing a 4 (piperidino)pyridine group in place of guanidino and/or amidino groups, and discovered compound M55113 (30a: 4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4 pyridinyl)-4-piperidinyl]methyl]piperazinone), as a potent inhibitor of FXa (IC50=0.06 microM) with high selectivity for FXa over trypsin and thrombin. PMID- 11605648 TI - Thermal behaviour of diclofenac sodium: decomposition and melting characteristics. AB - The thermal behaviour and melting characteristics of diclofenac sodium were investigated using various instrumental techniques--differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy and thin layer chromatography (TLC). DSC analysis of diclofenac sodium performed under dynamic flow of either synthetic air or helium or nitrogen did not produce any sharp endothermic peak characteristic of melting peak of a pure substance. Both the rate of scanning of the sample and the environmental atmospheric condition significantly affected the thermographic profile of diclofenac sodium. An exothermic peak prior to an endothermic peak corresponding to melting of the substance appeared when heated under dynamic flow of synthetic air suggesting oxidation (decomposition) of diclofenac sodium before reaching its melting point. In fact, at a scanning rate of 1 degree C/min only the exothermic peak appeared in the thermogram, suggesting complete decomposition prior to melting under the dynamic flow of synthetic air. DSC, FT-IR and TLC data obtained from samples heated under the dynamic flow of either helium or nitrogen revealed formation of a related compound, 1-(2,6-dichlorophenyl)-indolin-2-one, an indol-cyclic amide, as a result of an intramolecular cyclization reaction during the heating process. TGA data demonstrated a loss of 11.4-20.2% of the mass of diclofenac sodium when heated under various environmental conditions, and also supported the oxidative nature of degraded product(s) when the thermal process occurred slowly under a dynamic flow of synthetic air. PMID- 11605649 TI - Molecular modelling and 1H-NMR: ultimate tools for the investigation of tolbutamide: beta-cyclodextrin and tolbutamide: hydroxypropyl-beta-cyclodextrin complexes. AB - A structural study of the inclusion compound of tolbutamide (TBM) with beta cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was attempted by means of 1H-nuclear magnetic resonance (1H-NMR) experiments and computer molecular modelling. To establish the stoichiometry and stability constant of the beta-CD:TBM complex, the continuous variation method was used. The presence of true inclusion complexes between TBM and beta-CD or HP-beta-CD in solution was clearly evidenced by the 1H-NMR technique. Changes in chemical shifts of H-3 and H-5 protons, located inside the CD cavity, associated with variations in the chemical shifts of TBM aromatic protons provided clear evidence of inclusion complexation, suggesting that the phenyl moiety of the drug molecule was included in the hydrophobic cavity of CDs. This view was further supported by the observation of intermolecular NOEs between TBM and beta-CD and by the aid of a molecular modelling program, which established the most probable structure of the complex. The molecular graphic computation confirmed that the minimum energy, positioning TBM relative to beta-CD, occurs when the aromatic ring of TBM is included within the beta-CD cavity by its wider side, leaving the aliphatic chain externally, which is in good agreement with the results of 1H-NMR studies. PMID- 11605650 TI - Cathodic adsorptive stripping square-wave voltammetry of the anti-inflammatory drug meloxicam. AB - The adsorptive behavior of the anti-inflammatory drug meloxicam was studied by cyclic, differentia-pulse and square-wave voltammetry on a hanging mercury drop electrode (HMDE). The drug was accumulated at HMDE and a well-defined stripping peak current was obtained at -1.42 V vs. Ag/AgCl (saturated KCl) electrode in acetate buffer solution (pH 5.0). A voltammetric procedure was developed for the determination of meloxicam using square-wave cathodic adsorptive stripping voltammetry (SW-CASV). The optimum working conditions for the determination of the drug were established. The analysis of meloxicam in human plasma was carried out satisfactorily. PMID- 11605651 TI - Preparation and characterization of insulin-loaded acrylic hydrogels containing absorption enhancers. AB - The objectives of this study were to prepare insulin-loaded acrylic hydrogel formulations containing various absorption enhancers, to perform in vitro and in vivo characterization of these formulations, and to evaluate the factors which affecting insulin availability on rectal delivery of insulin using this hydrogel system. The acrylic block copolymer of methacrylic acid and methacrylate, Eudispert, was used to make the hydrogel formulations. As absorption enhancers, 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD), lauric acid (C12), or the sodium salt of C12 (C12Na), were incorporated into the hydrogels. In an in vitro release test, the release rate of insulin from the hydrogels decreased as the polymer concentration of the hydrogel increased. The addition of C12Na to the hydrogel further increased the insulin release rate, which was greater at higher concentrations of the enhancer. A portion of the C12Na was found to remain bound to the acrylic polymer in dissolution medium. Serum insulin levels were determined at various time points after the administration of insulin solution or insulin-loaded (50 units/kg body weight) Eudispert hydrogels containing 5% (w/w) of C12, C12Na, or DM-beta-CyD to in situ loops in various regions of the rat intestine. The most effective enhancement of insulin release was observed with formulations containing C12Na. The bioavailability of insulin from the hydrogels was lower than that from the insulin solutions. Hydrogel formulations containing 7% or 10% Eudispert remained in the rectum for 5 h after rectal administration. However, the 5% (w/w) C12Na solution stained with Evan's-blue had diffused out and the dye had reached the upper intestinal tract within 2 h. Finally, the rectal administration of insulin-loaded hydrogels, containing 4%, 7%, or 10% (w/w) Eudispert and 5% (w/w) of enhancer (C12, C12Na, or DM-beta-CyD) to normal rats was shown to decrease serum glucose concentrations. The greatest effect was found with insulin-loaded 7% (Eudispert) hydrogel containing C12Na which having cosiderable large insulin release rate and bioadhesive characteristics. PMID- 11605652 TI - In vitro release of metoclopramide from hydrophobic matrix tablets. influence of hydrodynamic conditions on kinetic release parameters. AB - There has been growing interest in the subject of drug delivery and the design and evaluation of controlled-release systems. The simplest way to control the release of an active agent is to disperse it in an inert polymeric matrix. Controlled-release systems are of interest because they are technologically simple, relatively cheap, and practically unaffected by physiological changes. In this study, a new matrix system was formed by an active principle, metoclopramide hydrochloride, scattered into a biocompatible hydrophobic polymerical mesh, polyamide 12, to achieve sustained and controlled delivery of metoclopramide hydrochloride. This research was conducted to investigate the in vitro drug release behavior from these new inert polymeric matrix tablets. The drug release process was investigated both experimentally and by means of mathematical models. Different models were applied for the evaluation of drug release data. On the basis of our results, a biexponential equation was proposed, Q=Qfast(1)(1 - e( Kfast t)) + Qslow(2)(1 - e(-Kslow t)), in an attempt to explain the mechanism responsible for the release process. Additionally, the influence of the experimental conditions of the dissolution devices, such as rate of flow and pH of dissolution medium, on the parameters that characterize the release mechanism was studied, and it was found that the main factor was the hydrodynamic condition of rate of flow. PMID- 11605653 TI - Design and synthesis of carboxylate inhibitors for matrix metalloproteinases. AB - A series of carboxylate compounds were prepared from N(alpha)-substituted 2,3 diaminopropionic acid and were tested for efficacy as matrix metalloproteinase (MMP) inhibitors. During modeling of the initial compound 10a, we utilized three dimensional structure modeling software (InsightII/Discover Ver. 2.98). Some of the prepared carboxylate derivatives, such as carbamate compounds (12c,d, 22) and sulfonamide compounds (14b,c), proved to be effective MMP-1 inhibitors (with IC50 values of a 10(-6) M order), depending on the substituent at the N(alpha) position of 2,3-diaminopropionic acid. Some of them were also evaluated for inhibition of stromelysin-1 (MMP-3), and the sulfonamide compound 14c exceeded the lead compound 5b in its MMP-3 inhibitory potency. For the carbamate compounds, we investigated the minimum molecular size at which the MMP-1 inhibitory potency was maintained, and found that this was P3-P1' compound 10b. PMID- 11605654 TI - Pyrrolo[2,3-d]pyrimidine thymidylate synthase inhibitors: design and synthesis of one-carbon bridge derivatives. AB - A series of novel pyrrolo[2,3-d]pyrimidine derivatives was designed and synthesized as thymidylate synthase (TS) inhibitors. Molecular design was performed on the human TS complex model built on the basis of the reported structure of TS-deoxyuridinemonophosphate (dUMP)-CB3717 ternary complex. From a docking study, we expected that a one-carbon bridge between pyrrolo[2,3 d]pyrimidine and an aromatic ring was suitable. Moreover, we found that the bridge carbon could be replaced with an alkyl group to fill out the unoccupied space. Based on this design, we synthesized five pyrrolo[2,3-d]pyrimidine derivatives with one-carbon bridge and evaluated their TS inhibitory activities. All synthesized compounds inhibited TS more potently than compound 2 (LY231514), and the C8-ethyl analogue (7) showed a remarkable inhibitory activity against TS (IC50=0.017 microM). PMID- 11605655 TI - Studies on anthracenes. 3. Synthesis, lipid peroxidation and cytotoxic evaluation of 10-substituted 1,5-dichloro-9(10H)-anthracenone derivatives. AB - The synthesis of a series of 1,5-dichloro-9(10H)-anthracenones bearing O-linked and N-linked substituents in the 10-position are described. Previous studies have shown that 9-acyloxy 1,5-dichloroanthracenes and 9-acyloxy 1,8 dichloroanthracenes displayed a potential cytotoxic effect. These results have encouraged us in further investigation of potential anthracenone derivatives. Therefore, a series of 10-substituted 1,8-dichloro-9(10H)-anthracenone derivatives were synthesized. These compounds were evaluated for their ability to inhibit the growth of human oral epidermoid carcinoma cells (KB cell line), human cervical carcinoma cells of ME 180 (GBM 8401) and Chinese hamster ovary (CHO) cells, respectively. Compounds 3c and 4c of this series compare favorably in the KB cellular assay with mitoxantrone. Compound 4c showed combined inhibitory action against KB, GBM and CHO cell growth, respectively. In addition, redox property of the compounds for the inhibition of lipid peroxidation in model membranes was determined. Compounds 4b and 4d exhibited stronger antioxidant activity than ascorbic acid, (+)-alpha-tocopherol and mitoxantrone, respectively. PMID- 11605656 TI - Alkaloids from the leaves of Cryptocarya chinensis Hemsl. AB - Investigation of the leaves of Cryptocarya chinensis resulted in the isolation of three new alkaloids, named (-)-isocaryachine-N-oxide, isoboldine-beta-N-oxide, and 1-hydroxycryprochine, together with seven known compounds. Their structures were elucidated by spectral analysis. The structures of (-)-isocaryachine-N-oxide and 1-hydroxycryprochine were further confirmed by X-ray techniques. PMID- 11605657 TI - Five new peltogynoids from underground parts of Iris bungei: a Mongolian medicinal plant. AB - Five new peltogynoids, irisoids A-E (1-5), have been isolated from the underground parts of Iris bungei. The structures of the new compounds were established on the basis of spectroscopic methods and were found to be 1,8,10 trihydroxy-9-methoxy-[1]benzopyrano-[3,2-c][2]-benzopyran-7(5H)-one (1), 1,8 dihydroxy-9,10-dimethoxy-[1]benzopyrano-[3,2-c][2]-benzopyran-7(5H)-one (2), 1,10 dihydroxy-8,9-dimethoxy-[1]benzopyrano-13,2-c][2]-benzopyran-7(5H)-one (3), 1,8 dihydroxy-9,10-methylenedioxy-[1]benzopyrano-[3,2-c][2]-benzopyran-7(5H)-one (4), and 1,8,11-trihydroxy-9,10-methylenedioxy-[1]benzopyrano-[3,2-c][2]-benzopyran 7(5H)-one (5). The structure of irisoid B (2) was established unambiguously by X ray diffraction study. PMID- 11605658 TI - Structural and thermodynamic behavior of eukaryotic initiation factor 4E in supramolecular formation with 4E-binding protein 1 and mRNA cap analogue, studied by spectroscopic methods. AB - The structural and thermodynamic behavior of the complex formation of eIF4E with either or both mRNA cap analogue (m7GTP, m7GpppA, or m7GpppG) and 4EBP1 has been investigated by spectroscopic measurements. Although the circular dichroism (CD) spectrum of eIF4E was little affected by the association with any cap analogue, the association constant of eIF4E with m7GpppA/G, estimated from the fluorescence quenching, was about 10 times larger than that with m7GTP. The van't Hoff analyses showed that the m7GpppA/G binding is enthalpy-driven with a large negative deltaH(o), and this is in contrast with the entropy-driven binding of m7GTP, where the positive deltaS(o) is large enough to overcome an increase of deltaH(o). This different behavior obviously originates in the interaction of the second nucleotide in m7GpppA with eIF4E, suggesting the importance of the nucleotide sequence linked to the m7Gppp terminal moiety, in addition to the specific interaction with the m7G base, for the recognition of mRNA cap structure by eIF4E. On the other hand, the CD spectra indicated that the binding of 4EBP1, an endogenous eIF4E-regulatory protein without having any defined secondary structure, shifted the m7GTP- or m7GpppA/G-bound eIF4E to an irregular structure, although such a structural change was not observed for eIF4E alone. The association constant of 4EBP1 with m7GTP- or m7GpppA/G-bound eIF4E was by two orders of magnitude larger than that with eIF4E alone. These results suggest the close interrelation in the supramolecular formation of 4EBP-eIF4E-mRNA cap structure. PMID- 11605659 TI - 1-Oxo-2-hydroxy-1,2-dihydroacronycine: a useful synthon in the acronycine series for the introduction of amino substituents at 6-position and for the conversion into isopropylfuroacridones. AB - Thermic aromatic nucleophilic displacement of the methoxy group at C-6 of (+/-)-1 oxo-2-hydroxy-1,2-dihydroacronycine (2) by an amine is a reaction that gives a facile entry to acronycine derivatives bearing an amino substituent at this position. The introduction of the amino substituents was confirmed with a long range 1H-15N correlation NMR spectrum at natural abundance. Under basic conditions, compound 2 can also be rearranged to the corresponding isopropylfuroacridone 12, in 80% yield. PMID- 11605660 TI - Stereochemistry of new nitrogen containing heterocyclic aldehyde. VII. Potentiometric, conductometric and thermodynamic studies of novel quinoline azodyes and their metal complexes with some transition metals. AB - A novel series of quinoline azodyes (5-(4'-derivatives phenyldiazo)-8-hydroxy-7 quinolinecarboxaldehyde)) (HL1-HL5) has been prepared and characterized by elemental analyses, 1H-NMR and IR spectra. The IR spectral data indicate that the compounds can exist in two resonance structures. Proton-ligand dissociation constants of quinoline azodyes and their subsituted derivatives, and metal-ligand stability constants of their complexes with bivalent (Mn2+, Co2+, Ni2+, Cu2+) metal ions have been determined potentiometrically in 0.1 m KCl and 40% (v/v) dimethylformamide (DMF)-water mixture. The influence of substituents on the dissociation and stability constants was examined on the basis of the electron repelling property of the substituent. The order of the stability constants of the formed complexes was found to be Mn2+ < Co2+ < Ni2+ < Cu2+. The effect of temperature was studied and the corresponding thermodynamic parameters (deltaG, deltaH, deltaS) were derived and discussed. The stoichiometries of these complexes were determined conductometrically and indicated the formation of 1:1 and 1:2 (metal:ligand) complexes was indicated. PMID- 11605661 TI - New mu-opioid receptor agonists with piperazine moiety. AB - New mu-opioid receptor (MOR) agonists containing piperazine and homopiperazine moieties in the structures were synthesized and their affinities to and agonist potencies on MOR were evaluated. Among the synthesized compounds, 4-[4-(2 methoxyphenyl)piperazin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide (20 Aa) showed the highest affinity to the human MOR expressed in Chinese hamster ovary (CHO)-K1 cells, and the highest agonist potency on the MOR in isolated guinea-pig ileum preparation. PMID- 11605662 TI - Characterization of polymorphs of a novel quinolinone derivative, TA-270 (4 hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone). AB - The polymorphic forms and amorphous form of TA-270 (4-hydroxy-1-methyl-3-octyloxy 7-sinapinoylamino-2(1H)-quinolinone), a newly developed antiallergenic compound, were characterized by powder X-ray diffractometry, thermal analysis, infrared spectroscopy and solid state 13C-NMR. The intrinsic dissolution rates of polymorphic forms were measured using the rotating disk method at 37 degrees C. The dissolution rates correlated well with the thermodynamic stability of each polymorphic form. These dissolution properties were clearly reflected in the oral bioavailability of TA-270 in rats. The transition behavior for each polymorph and for the amorphous form was studied under the high temperature and humidity conditions. The beta- and delta-forms were transformed into the alpha-form by heating. The amorphous form was also easily crystallized into alpha-form by heating, however it was relatively stable under humidified conditions. The internal molecular packing of each polymorph was estimated from IR and solid state NMR spectral analysis. PMID- 11605663 TI - Evaluation of flow properties of dry powder inhalation of salbutamol sulfate with lactose carrier. AB - The effects of the flow and packing properties of a drug/carrier powder mixture on emission of drug adhering to the carrier from capsules and inhalation devices were investigated. Model powder mixtures were designed consisting of lactose carriers with different particle shapes were prepared by surface treatment and micronized salbutamol sulfate. These powder mixtures were aerosolized by a Spinhaler, and in vitro deposition properties of salbutamol sulfate were evaluated by a twin impinger. The flow properties of the mixed powders were evaluated by the Carr's flowability index (FI) and Hausner's ratio (HR). The packing properties of the mixed powders were determined employing the tapping method. Compared with the powder mixed with the untreated lactose carrier, the FI, HR, and the constant K in Kawakita's equation of the powder mixture prepared using the surface-treated lactose carrier were significantly different, showing that the flow and packing properties of the drug/carrier powder mixture were improved. Using this surface-treated system, the handling of the powder mixture when packing into capsules is improved, which is desirable for handling dry powder inhalants. The fraction (%) of drug emitted from capsules and devices (EM) and the FI of the powder mixture were correlated. As the flow properties improved, the outflow of the powder mixture from capsules and devices became easier, and emission of drug adhering on the carrier from capsules and devices improved. Improvement of the inhalation process, such as the drug particles emitted from the inhalation system, is valuable for increasing inhalation properties of dry powder inhalation. PMID- 11605664 TI - Emulsifying potency of new amino acid-type surfactant (II): stable water-in-oil (W/O) emulsions containing 85 wt% inner water phase. AB - The ternary phase diagram for N-[3-lauryloxy-2-hydroxypropyl]-L-arginine L glutamate (C12HEA-Glu), a new amino acid-type surfactant, /oleic acid (OA)/water system was established. The liquid crystal and gel complex formations between C12HEA-Glu and OA were applied to a preparation of water-in-oil (W/O) emulsions. Stable W/O emulsions containing liquid paraffin (LP) as the oil and a mixture of C12HEA-Glu and OA as the emulsifier were formed. The preparation of stable W/O emulsions containing 85 wt% water phase was also possible, in which water droplets would be polygonally transformed and closely packed, since the maximum percentage of inner phase is 74% assuming uniformly spherical droplets. Water droplets would be taken into the liquid crystalline phase (or the gel complex) and the immovable water droplets would stabilize the W/O emulsion system. The viscosity of emulsions abruptly increased above the 75 wt% water phase (dispersed phase). The stability of W/O emulsions with a lower weight ratio of OA to C12HEA Glu and a higher ratio of water phase was greater. This unusual phenomenon may be related to the formation of a liquid crystalline phase between C12HEA-Glu and OA, and the stability of the liquid crystal at a lower ratio of oil (continuous phase). W/O and oil-in-water (O/W) emulsions containing LP were selectively prepared using a mixture of C12HEA-Glu and OA since the desirable hydrophile lipophile balance (HLB) number for the emulsification was obtainable by mixing the two emulsifiers. PMID- 11605665 TI - A new method for evaluating the bitterness of medicines by semi-continuous measurement of adsorption using a taste sensor. AB - We describe a new method for the evaluation of the bitterness of medicines by semi-continuous measurement of adsorption using a multichannel taste sensor or 'electric tongue'. The bitterness of 10 basic medicines was evaluated by both the taste sensor and in human gustatory sensation tests with 11 volunteers. The sensor part of the taste sensor consists of eight electrodes made of lipid/polymer membranes. Three variables were obtained from the taste sensor data: sensor output (S), the change of membrane potential caused by adsorption, corresponding to aftertaste (C), and the ratio C/S. These variables were used to predict an estimated bitterness score in multiple regression analysis. Semi continuous measurement of C (every 30 s up to 150 s) was adopted as an additional explanatory variable, and the attenuation rate of C was defined as C'. These data were also subjected to multiple regression analysis. The correlation coefficient (r) estimated for the bitterness score predicted by the taste sensor, using C' for channel 2 and C/S for channel 4, and the score obtained by human gustatory sensation, was 0.824. This value was greater than that obtained using C/S for both channels 2 and 4 (0.734). The method described in the present study seems to offer good predictability for the evaluation of bitterness. PMID- 11605666 TI - Synthesis of cis- and trans-5,8-dihydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone. AB - Cis- and trans-5,8-dihydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone (1a, 1b) were for the first time synthesized from 5,8-dihydroxy-1,4-naphthoquinone (naphthazazine) (6) as a starting material and racemic triol (3) was first synthesized from 7. The configuration of 1a was determined by X-ray analysis. PMID- 11605667 TI - Glycosides of benzyl and salicyl alcohols from Alangium chinense. AB - From the water-soluble fraction of the dried leaves of Alangium chinense, three new glycosides, benzyl alcohol beta-D-glucopyranosyl-(1 --> 2)-[beta-D xylopyranosyl-(1 --> 6)]-beta-D-glucopyranoside, 2'-O-beta-D glucopyranosylsalicin, and 2'-O-beta-D-glucopyranosyl-6'-O-beta-D xylopyranosylsalicin were isolated along with seven known glycosides. The structures of the new compounds were determined by spectroscopic and chemical means. PMID- 11605668 TI - Studies on anthracenes. 2. Synthesis and cytotoxic evaluation of 9-acyloxy 1,8 dichloroanthracene derivatives. AB - The synthesis and cytotoxic evaluation of 9-acyloxy 1,8-dichloroanthracene derivatives are described. The system selectively reduces the carbonyl group flanked by the peri substituents of the anthracenediones to give the corresponding 1,8-dichloro-9(10H)-anthracenone. Simple acylation of anthracenone occurred with appropriate acyl chlorides in CH2Cl2 with a catalytic amount of pyridine to give the 9-acyloxy-1,8-dichloroanthracene derivatives. Considerable interest has developed in the mechanism of how anthracenones achieve this desirable selectivity. These compounds were evaluated in vitro for their ability to inhibit the growth of human oral epidermoid carcinoma cells (KB cell line), human cervical carcinoma cells of ME 180 (GBM 8401) and Chinese hamster ovary (CHO) cells, respectively, as compared to mitoxantrone. The in vitro cytotoxicity evaluation of 9-acyloxy 1,8-dichloroanthracenes against these above cell lines revealed for most of the compounds a cytotoxic potency lower than that of mitoxantrone. The most active compounds were thus selected for further in vitro biological evaluation and structural modification. PMID- 11605669 TI - Anodization in oligo(ethylene glycol) as an initial derivatization tool for preparing glassy carbon electrodes covalently modified with amino compounds: effective access to a 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO)-modified glassy carbon electrode. AB - Anodization in HO(CH2CH2O)nH (1a, n=2; 1b, n=3; 1c, n=4) as an initial derivatization tool for preparing glassy carbon (GC) electrodes covalently modified with amino compounds was explored. As an amino compound to be immobilized, 4-amino-2,2,6,6-tetramethylpiperidinyl-1-oxyl (4-amino-TEMPO) was selected. When GC electrodes anodized at 2.0 V vs. Ag wire coated with AgCl in 1 containing RCH2CH2SO3Na (2a, R=H; 2b, R=OH) were treated with a N,N dimethylformamide (DMF) or CH2Cl2 solution of 4-amino-TEMPO and 1,3 dicyclohexylcarbodiimide (DCC), TEMPO-modified GC electrodes were afforded. Coverage (gammaTEMPO) of the electrode surfaces by TEMPO was estimated by cyclic voltammetry in CH3CN containing NaClO4. A TEMPO-modified GC electrode with the best gammaTEMPO (1.36 x 10(-10) mol/cm2) was obtained by anodization in 1b containing 2a at the expense of 3.0 C followed by amidization in DMF for 7 d. On cyclic voltammetry, the TEMPO-modified GC electrode showed good and stable electrocatalytic ability for oxidation of allyl alcohol in the presence of 2,6 lutidine. PMID- 11605670 TI - Alkylation of 2-phenyl-4-quinolones: synthetic and structural studies. AB - The alkylation of 2-phenyl-4-quinolones was investigated and showed that the N alkylation versus O-alkylation is highly dependent on whether C-5 is hydroxylated or not. N-Alkylation is favoured by the presence of a 5-hydroxyl group. The synthetic and the NMR structural studies are reported. PMID- 11605671 TI - Isolation and identification of two new flavanones and a chalcone from Citrus kinokuni. AB - Two new flavanones and one chalcone were isolated from the peel of Citrus kinokuni Hort. ex Tanaka and identified as (2S)-5,6,7,8,4'-pentamethoxyflavanone (1), (2S)-5,6,7,3',4'-pentamethoxyflavanone (2) and 2'-hydroxy-3,4,3',4',6' pentamethoxychalcone (3). The structures of new compounds were elucidated by spectroscopic analysis. PMID- 11605672 TI - An antifungal cadinanolide from Pseudoelephantopus spicatus. AB - A new sesquiterpene lactone was obtained from the chloroform extract of Pseudoelephantopus spicatus. Its structure was elucidated by extensive one dimentional (1D) and 2D NMR spectroscopy and mass spectrometry. It was found to exhibit moderate antifungal activity against C albicans and A. niger, and low activity against T. mentagrophytes, S. aureus, E. coli and P. aeruginosa. It was inactive against B. subtilis. PMID- 11605673 TI - Two new pyrrolidine alkaloids, radicamines A and B, as inhibitors of alpha glucosidase from Lobelia chinensis Lour. AB - Two new pyrrolidine alkaloids, radicamines A and B were isolated as inhibitors of alpha-glucosidase from Lobelia chinensis Lour. (Campanulaceae). Radicamines A and B were formulated as (2S,3S,4S,5S)-2-hydroxymethyl-3,4-dihydroxy-5-(3-hydroxy-4 methoxyphenyl)-pyrrolidine (1) and (2S,3S,4S,5S)-2-hydroxymethyl-3,4-dihydroxy-5 (4-hydroxyphenyl)-pyrrolidine (2) on the basis of spectroscopic analyses and chemical methods. PMID- 11605674 TI - Biosynthetic study of amphidinolide B. AB - The biosynthetic origins of amphidinoide B (1) were investigated on the basis of 13C-NMR data of 13C-enriched samples obtained by feeding experiments with [1 (13)C], [2-(13)C], and [1,2-(13)C2] sodium acetates in cultures of a dinoflagellate Amphidinium sp. These incorporation patterns suggested that 1 was generated from three successive polyketide chains, an isolated C1 unit from C-2 of acetates, six branched C1 units from C-2 of acetates, and an "m-m" and an "m-m m" unit derived only from C-2 of acetates. The labeling patterns of amphidinolide B (1) were different from those of amphidinolide H (2), a 26-membered macrolide closely related to 1. PMID- 11605675 TI - Medicinal foodstuffs. XXVII. Saponin constituents of gotu kola (2): structures of new ursane- and oleanane-type triterpene oligoglycosides, centellasaponins B, C, and D, from Centella asiatica cultivated in Sri Lanka. AB - Ursane- and oleanane-type triterpene oligoglycosides, centellasaponins B, C, and D, were isolated from the aerial parts of Centella asiatica (L.) Urban cultivated in Sri Lanka together with madecassoside, asiaticoside, asiaticoside B, and sceffoleoside A. The chemical structures of centellasaponins B, C, and D were determined on the basis of chemical and physicochemical evidence to be madecassic acid 28-O-beta-D-glucopyranosyl(1-->6)-beta-D-glucopyranoside, madasiatic acid 28 O-alpha-L-rhamnopyranosyl(1-->4)-beta-D-glucopyranosyl(1-->6)-beta-D glucopyranoside, and 3beta,6beta,23-trihydroxyolean-12-en-28-oic acid 28-O-alpha L-rhamnopyranosyl(1-->4)-beta-D-glucopyranosyl(1-->6)-beta-D-glucopyranoside, respectively. PMID- 11605677 TI - Regioselective biomimetic oxidation of etodolac with iodosylbenzene catalyzed by halogenated and perhalogenated metalloporphyrins in dichloromethane. AB - The biomimetic oxidation of etodolac, an anti-inflammatory drug (1) with iodosylbenzene catalyzed by 5,10,15,20-tetraarylporphyrinatoiron(III) chlorides TAPFe(III)Cl (7a-e) in dichloromethane gives 4-hydroxyetodolac (6) and 4 oxoetodolac (5) regioselectively in moderate yields. PMID- 11605676 TI - Novel neuronal nitric oxide synthase (nNOS) selective inhibitor, aplysinopsin type indole alkaloid, from marine sponge Hyrtios erecta. AB - Two novel aplysinopsin-type indole alkaloids, 1 and 2, and three known indole alkaloids were isolated from the marine sponge Hyrtios erecta. These compounds exhibited selective inhibitory activity against the neuronal isozyme of nitric oxide synthase (nNOS). Furthermore, new quinolone 7 was also isolated from the same marine sponge. The chemical structures of these new compounds were elucidated on the basis of spectroscopic analysis. PMID- 11605678 TI - Two novel cucurbitacins, neocucurbitacins A and B, from the Brazilian folk medicine "Buchinha" (Luffa operculata) and their effect on PEBP2alphaA and OCIF gene expression in a human osteoblast-like Saos-2 cell line. AB - Two novel cucurbitacins designated as neocucurbitacins A (1), possessing inhibitory activity of polyoma enhancer binding protein 2alphaA (PEBP2alphaA) and osteoclastogenesis-inhibitory factor (OCIF) gene expression in human osteoblast like cells, and B (2) were isolated from the fruit of Luffa operculata. Their structures have been determined by extensive spectroscopic investigation. PMID- 11605679 TI - Occurrence of polygodial and 1-(2,4,6-trimethoxyphenyl)-but-2-en-1-one from some ferns and liverworts: role of pungent components in bryophytes and pteridophytes evolution. AB - The New Zealand fern Blechnum fluviatile and liverwort, Hymenophyton flabellatum produce the characteristic pungent compounds, (-)-polygodial, a sesquiterpene dialdehyde, and 1-(2,4,6-trimethoxyphenyl)-but-2-en-1-one, respectively. The former compound has been isolated from the Japanese liverwort, Porella vernicosa complex and the latter one from the Japanese fern, Arachinoides standishii. The occurrence of both compounds in both pteridophytes and bryophytes provides another important link between bryophytes and ferns. PMID- 11605680 TI - Resolved sudden hearing loss as a presenting symptom of retrocochlear lesion. AB - OBJECTIVE: To determine whether acoustic neuroma-induced sudden hearing loss is associated with hearing recovery and, if so, to characterize its clinical, audiometric and imaging manifestations. METHODS: The files of 72 patients with sudden hearing loss evaluated between 1989 to 2001 were reviewed. All patients underwent pure tone audiometry, acoustic reflex and auditory brain revoked response (ABR) test. Magnetic resonance imaging (MRI) was performed followed by a second hearing test after one month. The findings were compared between patients with and without evidence of tumors on imaging, and between patients with tumors with and without recovery. RESULTS: Twenty-five patients (35%) had a diagnosis of acoustic tumor. Of these, six (24%) recovered hearing after one month. Five of them had small intracanicular tumors and one had a small extracanicular tumor. There was variability in the hearing loss. Five had a pathological ABR and one had normal ABR. CONCLUSIONS: We conclude that recovery from hearing loss does not exclude acoustic tumors and these patients therefore require full evaluation including MRI. PMID- 11605681 TI - Echo suppression in the human cortex is affected by the spatial and temporal proximity of the primary sound and echo. AB - Echo suppression in the human auditory cortex was studied with auditory middle latency evoked potentials (AMEP) using virtual reality acoustic stimuli, including distance and elevation cues, presented by earphones. The purpose of the study was to assess the effect of proximity of the source sound and echo on the degree of echo suppression. Sixteen subjects were presented with source-echo pairs in which the preceding source sound was always at the vertex, and the echo varied among ten positions on the coronal plane. Positions varied in elevation, distance and time lag between source and echo. The psychoacoustic location judgment of the fused source-echo pair was closer to the source sound (more echo suppression) the nearer the echo drew to the source in its elevation and time. The equivalent dipole magnitudes of the cortical components of AMEP were significantly reduced (more suppression) with shorter echo lags and when echo elevation was similar to that of the source sound. The distances used in this study did not significantly affect echo suppression. These results indicate that echo suppression in the auditory cortex is more pronounced the closer are the primary sound and echo in locational attributes and timing. As source sound and echo draw apart, echo suppression in the cortex decreases and the perceived localization of the fused source-echo is more biased toward the echo. PMID- 11605682 TI - Pitch discrimination: are professional musicians better than non-musicians? AB - Musicians are typically considered to exhibit exceptional auditory skills. Only few studies, however, have substantiated this in basic psychoacoustic tasks. The purpose of the present investigation was to expand our knowledge on basic auditory abilities of musicians compared to non-musicians. Specific goals were: (1) to compare frequency discrimination thresholds (difference limen for frequency [DLF]) of non-musical pure tones in controlled groups of professional musicians and non-musicians; (2) to relate DLF performance to musical background; and (3) to compare DLF thresholds obtained with two threshold estimation procedures: 2- and 3- interval forced choice procedures (2IFC and 3IFC). Subjects were 16 professional musicians and 14 non-musicians. DLFs were obtained for three frequencies (0.25, 1 and 1.5 kHz) using the 3IFC adaptive procedure, and for one frequency (1 kHz) also using the 2IFC. Three threshold estimates were obtained for each frequency, procedure and subject. The results of the present study support five major findings: (a) mean DLFs for musicians were approximately half the values of the non-musicians; (b) significant learning for both groups during the three threshold estimations; (c) classical musicians performed better than those with contemporary musical background; (d) performance was influenced by years of musical experience; and (e) both groups showed better DLF in a 2IFC paradigm compared to the 3IFC. These data highlight the importance of short-term training on an auditory task, auditory memory and factors related to musical background (such as musical genre and years of experience) on auditory performance. PMID- 11605683 TI - Auditory backward masking and the effect of training in normal hearing adults. AB - Recent renewed interest in auditory backward masking has stemmed from studies of children with language impairments who were found to have significant, elevated thresholds for this paradigm, compared to normal cohorts. There are, however, many unresolved theoretical and procedural issues. The present study was conducted to investigate some of these issues. Specific purposes were: 1) To establish the differences between backward masking and simultaneous masking in normal hearing subjects; 2) To investigate the effect of listening conditions, i.e., monaural versus binaural; 3) To measure the effect of training on the performance of a backward masking paradigm; and 4) To measure generalization of the trained condition to untrained conditions. Two experiments were conducted: In experiment I, we compared the performance of 10 normal-hearing adult subjects for backward masking and simultaneous masking paradigms in both monaural and binaural modes of presentation. Stimuli consisted of a 1000 Hz pure-tone and bandpass masker (600-1400 Hz). Tone thresholds for backward masking were significantly lower than those of the simultaneous masking. The binaural mode of presentation yielded lower thresholds than those of the monaural mode only for the backward masking condition. A significantly large inter- and intra-subject variability was observed in the backward masking paradigm. Experiment II was conducted to measure the effects of training and generalization. Two groups of subjects were included: a trained group and a control group of six and eight normal hearing adults, respectively. The trained group received 10 sessions of backward masking training with feedback. The control group was tested only twice, with a 2-week interval between testing. Only the trained group showed a significant improvement in backward masking thresholds, which amounted to an average of 10.7 dB. No significant improvement was observed in the non-trained group. A nonsignificant trend of generalization occurred for the trained task to the untrained ear. No generalization was evident in the untrained condition (simultaneous masking). The data have important clinical and theoretical implications regarding the ability to train for auditory tasks in general, and for backward masking in particular. PMID- 11605684 TI - The pathway for the transmission of external sounds into the fetal inner ear. AB - After at least 20 weeks gestation, the human fetus in utero is able to hear and respond to external and internal (maternal) sounds. The external sounds are attenuated by maternal tissues and fluids - higher frequencies by about 20 dB, and lower frequencies are only slightly reduced. The sounds in the amniotic fluid, which completely envelops the fetus, then reach the fetal inner ear by bone conduction. The sound pressure in the amniotic fluid induces skull vibrations which are transmitted directly into the contents of the cranial cavity (brain and CSF) and from there, presumably by fluid channels connecting them, into the cochlear fluids. A further stage of conductive attenuation is probably involved in this transmission. Since the fetus in utero receives oxygen by placental diffusion (less efficient than pulmonary diffusion), the fetal inner ear is hypoxic compared to that following birth (pulmonary oxygen diffusion). This leads to a reduction in the magnitude of the endocochlear potential, to a depression of cochlear transduction and amplification, and thus to an additional sensorineural component of threshold elevation in the fetus. Upon birth, these conductive and sensorineural attenuations are removed. PMID- 11605685 TI - T-cell immunity in acute coronary syndromes. AB - Acute coronary syndromes (ACS) are complications of atherosclerotic vascular disease that are triggered by the sudden rupture of an atheroma. Atherosclerotic plaque stability is determined by multiple factors, of which immune and inflammatory pathways are critical. Unstable plaque is characterized by an infiltrate of T cells and macrophages, thereby resembling a delayed hypersensitivity reaction. On activation, T cells secrete cytokines that regulate the activity of macrophages, or the T cells may differentiate into effector cells with tissue-damaging potential. Constitutive stimulation of T cells and macrophages in ACS is not limited to the vascular lesion but also involves peripheral immune cells, suggesting fundamental abnormalities in homeostatic mechanisms that control the assembly, turnover, and diversity of the immune system as a whole. This review gives particular attention to the emergence of a specialized T-cell subset, natural killer T cells, in patients with ACS. Natural killer T cells have proinflammatory properties and the capability of directly contributing to vascular injury. PMID- 11605686 TI - Pathogenesis, diagnosis, and treatment of alcoholic liver disease. AB - Alcohol-related liver disease is a major cause of morbidity and mortality in the United States. Alcoholic liver disease encompasses a clinicohistological spectrum, including fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Fatty liver is a benign and reversible condition, but progression to alcoholic hepatitis and cirrhosis is life-threatening. Alcoholic hepatitis is diagnosed predominantly on clinical history, physical examination, and laboratory testing, although liver biopsy is often necessary to secure the diagnosis. The major focus of management is abstinence from alcohol, supportive care, treatment of complications of infection and portal hypertension, and maintenance of positive nitrogen balance through nutritional support. Corticosteroid therapy is controversial but should be considered in patients with a discriminant function greater than 32 and/or presence of spontaneous hepatic encephalopathy in the absence of infection, gastrointestinal bleeding, and renal failure. The only curative therapy for advanced alcoholic cirrhosis is liver transplantation. Several recent advances in understanding the pathogenesis of alcoholic liver disease may lead to novel future treatment approaches, including inhibition of tumor necrosis factor a, antioxidant therapy, stimulation of liver regeneration, and stimulation of collagen degradation. PMID- 11605687 TI - Current role of endomyocardial biopsy in the management of dilated cardiomyopathy and myocarditis. AB - Dilated cardiomyopathy is a common cause of congestive heart failure. Despite a thorough cardiovascular evaluation, a specific cause is frequently not found, and the disorder then is considered idiopathic. Endomyocardial biopsy (EMB) may yield diagnostic and prognostic information in patients with idiopathic dilated cardiomyopathy; however, the yield of useful information with this procedure among patients with heart failure is low, and the risks of occasional cardiac perforation and death further limit its use. Recent publications in the field of myocarditis and cardiomyopathy have renewed interest in the use of EMB in select patients to diagnose specific and potentially treatable myocarditides; however, the role of EMB in the work-up of patients with dilated cardiomyopathy is not well defined. In this article, we discuss the risks and utility of EMB in the management of patients with dilated cardiomyopathy and specific myocarditides. PMID- 11605688 TI - Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia. AB - The advent of treatment with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors has meant that, with a combination of diet and drug therapy, adequate control of serum cholesterol concentrations can be achieved in most patients with hypercholesterolemia. However, some patients, primarily those with familial hypercholesterolemia (FH), may require additional therapy to lower their cholesterol levels. In recent years, low-density lipoprotein (LDL) apheresis has emerged as an effective method of treatment in these patients. The criteria for commencement of LDL apheresis are LDL cholesterol levels of 500 mg/dL or higher for homozygous FH patients, 300 mg/dL or higher for heterozygous FH patients in whom medical therapy has failed, and 200 mg/dL or higher for heterozygous FH patients with documented coronary disease and in whom medical therapy has failed. In addition to cholesterol lowering in patients with FH, other indications for LDL apheresis are emerging. These include its use in the treatment of graft vascular disease in patients receiving cardiac transplants as well as in the treatment of certain glomerulonephritides. This review examines the role of LDL apheresis in the management of lipid disorders and the evidence available to support its use in clinical practice. PMID- 11605689 TI - Approach to patients with heart failure and normal ejection fraction. AB - Approximately 50% of patients with a firm clinical diagnosis of heart failure (HF) have a normal ejection fraction. Some patients have valvular disease, but most have underlying diastolic dysfunction that leads to pulmonary and systemic congestion and signs and symptoms of HF. Although diastolic HF is clinically and radiographically indistinguishable from HF with depressed left systolic ventricular function, knowledge of which patients are at risk of diastolic HF, the common clinical profiles, and the common echocardiographic findings enhances the clinician's ability to diagnose diastolic HF with confidence. The prognostic implications of a diagnosis of diastolic HF and the therapeutic approach to such patients are reviewed. PMID- 11605690 TI - 61-year-old woman with increasing thirst, lethargy, and renal failure. PMID- 11605691 TI - Patent foramen ovale transcatheter closure device thrombosis. AB - The role of patent foramen ovale (PFO) in patients with cryptogenic stroke (stroke of unknown cause) remains controversial, although an association seems likely in younger patients with atrial septal aneurysms and PFO. The mechanism of cryptogenic stroke in these patients is presumed to be paradoxical embolism via right-to-left shunt across the PFO. The available options for treatment include medical therapy with antiplatelet or anticoagulant therapy or closure of the PFO surgically or with use of transcatheter PFO closure devices. We describe 2 cases of bilateral device thrombosis associated with use of a transcatheter PFO closure device (CardioSEAL). To our knowledge, only 1 other case of thrombosis associated with use of this device has been reported. PMID- 11605692 TI - Images and reflections from Mayo Clinic heritage. PMID- 11605693 TI - Successful treatment of Whipple disease diagnosed 36 years after symptom onset. AB - Whipple disease is a rare infectious disorder with multiorgan manifestations and a widely varied clinical presentation. Involvement of the small intestine with resultant malabsorption is a classic finding, although extraintestinal manifestations such as fever and arthralgias may precede gastrointestinal symptoms by many years. We describe a 63-year-old man in whom Whipple disease was diagnosed 22 years after his initial presentation (36 years after symptom onset) with lymphadenopathy, when a biopsy yielded nonnecrotizing granulomas. His recent symptoms included persistent fatigue, weight loss, fever, and arthralgias. Endoscopic biopsy specimens from the distal duodenum showed features consistent with Whipple disease, and Tropheryma whippelii DNA was detected in both the small bowel biopsy specimen and the blood specimen by polymerase chain reaction and DNA probe hybridization. His symptoms resolved with long-term co-trimoxazole therapy. We discuss the protean manifestations of Whipple disease, the difficulties in clinical diagnosis, and the recent advances in the molecular diagnosis of this disorder. PMID- 11605695 TI - Man and Freedom has a new home. PMID- 11605694 TI - Vertebral osteomyelitis and prosthetic joint infection due to Staphylococcus simulans. AB - Staphylococcus simulans, a coagulase-negative staphylococcus, is a common animal pathogen that is rarely encountered in human infections. We describe a 70-year old man who developed multifocal vertebral osteomyelitis and late prosthetic joint infection caused by this pathogen. The patient was a farmer who had daily contact with cows and drank unpasteurized milk, although the portal of the pathogen's entry remains speculative. Culture of the vertebral disk biopsy specimen and cultures during resection arthroplasty yielded S. simulans. A review of the literature suggests that S. simulans may be more virulent than other species of coagulase-negative staphylococci. Accurate identification of S. simulans isolates would facilitate studies to further define its pathogenic role in human infections. PMID- 11605696 TI - Robert C. Gallo--discoverer of the AIDS virus. PMID- 11605697 TI - The shortage of anesthesiologists: an unwelcome lesson for other medical specialties. PMID- 11605698 TI - Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary hypercholesterolemia: a 24-week randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy, tolerability, and safety of colesevelam hydrochloride, a new nonsystemic lipid-lowering agent. PATIENTS AND METHODS: In this double-blind, placebo-controlled trial performed in 1998, 494 patients with primary hypercholesterolemia (low-density lipoprotein [LDL] cholesterol level > or = 130 mg/dL and < or = 220 mg/dL) were randomized to receive placebo or colesevelam (2.3 g/d, 3.0 g/d, 3.8 g/d, or 4.5 g/d) for 24 weeks. Fasting serum lipid profiles were measured to assess efficacy. Adverse events were monitored, and discontinuation rates and compliance rates were analyzed. The primary outcome measure was the mean absolute change of LDL cholesterol from baseline to the end of the 24-week treatment period. RESULTS: Colesevelam lowered mean LDL cholesterol levels 9% to 18% in a dose-dependent manner (P<.001), with a median LDL cholesterol reduction of 20% at 4.5 g/d. The reduction in LDL cholesterol levels was maximal after 2 weeks and sustained throughout the study. Mean total cholesterol levels decreased 4% to 10% (P<.001), while median high-density lipoprotein cholesterol levels increased 3% to 4% (P<.001). Median triglyceride levels increased by 5% to 10% in placebo and colesevelam treatment groups relative to baseline (P<.05), but none of these differences were significantly different from placebo. Mean apolipoprotein B levels decreased 6% to 12% in an apparent dose-dependent manner (P<.001). No significant differences occurred in adverse events or discontinuation rates between groups, and compliance rates were between 88% and 92% for all groups. CONCLUSIONS: Colesevelam was efficacious, decreasing mean LDL cholesterol levels by up to 18%, and well tolerated without serious adverse events. PMID- 11605699 TI - Seizures in patients with multiple sclerosis seen at Mayo Clinic, Rochester, Minn, 1990-1998. AB - OBJECTIVE: To evaluate seizure type, electroencephalographic findings, and response to antiepileptic drug (AED) treatment in patients with multiple sclerosis (MS) and coexistent seizure activity. PATIENTS AND METHODS: We reviewed the medical records of all patients seen at the Mayo Clinic in Rochester, Minn, with the diagnosis of MS and seizures between 1990 and 1998. RESULTS: During the study period, 5715 patients with MS were identified. Of these 5715 patients, 51 (0.89%) experienced seizure activity. The most common ictal behavior was a generalized tonic-clonic seizure in 35 patients (68.6%). Simple or complex partial seizures occurred in 11 patients (21.6%), and 18 patients (35.3%) had only 1 seizure episode. Focal motor status epilepticus, ie, epilepsia partialis continua, occurred in 3 patients (5.9%) and was associated with cognitive impairment. In 37 patients (72.5%), the initial seizure presentation was after the diagnosis of MS. A seizure resulted in the diagnosis of MS or occurred before the diagnosis of MS but after other symptoms or signs of demyelinating disease in 14 patients (27.4%). Electroencephalography was performed in 43 patients. Electroencephalographic findings included diffuse or localized nonspecific background slowing in 19 patients (44.2%), unilateral or bilateral frontotemporal spike discharges in 9 (20.9%), generalized atypical spike-and-wave or multifocal independent epileptiform alterations in 6 (14.0%), and normal results in 11 (25.6%). Of the 45 patients who received AED therapy, 35 (77.8%) had an excellent response, ie, they were seizure free. Five treated patients (11.1%) had an intractable seizure disorder. CONCLUSION: Most of the patients with MS who experienced seizure activity had a benign and transient disorder that was responsive to AED treatment or required no therapy. PMID- 11605700 TI - Esophageal dysmotility in patients undergoing photodynamic therapy. AB - OBJECTIVE: To study the esophageal motility of patients with esophageal adenocarcinoma or Barrett esophagus with high-grade dysplasia before and after photodynamic therapy. PATIENTS AND METHODS: In this prospective study conducted between January 1998 and October 1999, esophageal motility testing of the lower esophageal sphincter and esophageal body was performed with a water-perfused catheter, 2 days before and at least 3 weeks after patients underwent photodynamic therapy for esophageal adenocarcinoma or Barrett esophagus. Results were classified as normal motility, ineffective esophageal motility, or aperistalsis. RESULTS: Twenty-three patients were studied, 13 with carcinoma and 10 with Barrett esophagus. Overall, 11 patients (48%) had normal motility, 6 (26%) had ineffective esophageal motility, and 6 (26%) had aperistalsis. Five patients with aperistalsis had carcinoma. Follow-up tracings after photodynamic therapy found that 6 patients (26%) had normal motility, 7 (30%) had ineffective esophageal motility, and 10 (43%) had aperistalsis. CONCLUSIONS: Esophageal dysmotility is common in patients with esophageal adenocarcinoma or Barrett esophagus. Photodynamic therapy may worsen esophageal motility in some patients. Dysphagia after photodynamic therapy therefore may be related to underlying esophageal dysmotility and may not always be caused by stricture or underlying carcinoma. PMID- 11605701 TI - Forced inspiratory nasal flow-volume curves: a simple test of nasal airflow. AB - OBJECTIVE: To observe and describe normal and abnormal inspiratory nasal flow volume patterns. PATIENTS AND METHODS: In this observational case series, individuals with and without nasal symptoms underwent forced inspiratory nasal flow-volume (FINFV) curve measurements. The participants were volunteer adults from the staff and patients of a pulmonary subspecialty private practice office. To examine the flow patterns from the FINFV curves, definitions of normal and abnormal were established. Normal curves were defined as those from participants who had no nasal symptoms and a peak inspiratory nasal flow greater than 2.5 L/s. Abnormal curves were defined as those from participants who had 1 or more nasal symptoms, a peak inspiratory nasal flow lower than 2.5 L/s, and normal oral inspiratory flow. RESULTS: Study participants consisted of 10 staff and 58 patients. Fourteen individuals (21%) met the definition of normal and had FINFV curves that mimicked the shapes of normal oral flow-volume curves; 39 (57%) met the definition of abnormal and had FINFV curves that mimicked the patterns of abnormal oral flow-volume curves. The abnormal curves showed both fixed (33/39 [85%]) and variable (6/39 [15%]) patterns of obstruction. Fifteen participants (22%) did not meet either established definition. CONCLUSIONS: Forced inspiratory nasal flow-volume curves are a potentially useful clinical tool to measure nasal airflow. Normal and abnormal flow patterns are easily identifiable. PMID- 11605702 TI - Evidence of a current and lasting national anesthesia personnel shortfall: scope and implications. AB - OBJECTIVES: To prove the existence of a current anesthesiologist shortage, and to project the balance of labor supply and demand in the future. METHODS: To quantify the current supply we used published health personnel data from federal agencies and the American Medical Association, as well as membership data from the American Society of Anesthesiologists. We estimated anesthesiologist supply in 2001 based on the number of graduating residents and fellows, taking into account the loss of a portion of graduating residents due to temporary visa status. We assumed that neither a shortage nor an oversupply existed in 1994 and that demand for anesthesiologists was approximated by the number of surgical procedures reported by federal agencies. In modeling future supply and demand for anesthesiologists, we assumed that the current health care policy and economic climates will continue. We extrapolated demand using 1.5% to 3% yearly growth rates based on a synthesis of recent and projected procedure growth rates, procedure rates for the elderly, and population aging trends. We estimated the supply for 2001 through 2003 based on the current resident cohort modified by their projected graduation rate. Accounting for attrition during residency and the effect of fellowship training, we assumed that after 2003 the number of American medical graduates will initially increase by 15% annually and that the number of international medical graduates will decrease to a stable level of 500 trained each year. We assumed an average retirement age of 65 years. RESULTS: Our model suggests that there is currently a 3.6% to 10.9% shortage of anesthesiologists nationwide, depending on the assumption of a 2% or 3% increase in annual demand since 1994 and a constant pattern of work distribution by anesthesia providers. This amounts to approximately 1200 to 3800 anesthesiologists. If projected demand continues to increase at the rate of 1.5% to 2% annually, the shortfall will amount to 2.6% to 12.0% of the labor supply by 2005, representing a deficit of 1000 to 4500 anesthesiologists. By 2010, this shortfall is projected to disappear or continue to amount to about 11% of the anesthesiologist supply, depending on the assumptions about the rate of demand for anesthesiologists. Compared with the expected graduating class of 1100 anesthesiology residents in 2001, our model calls for nearly 1600 graduates by 2005 and 2000 by 2010. CONCLUSION: A substantive shortfall of anesthesia personnel exists in 2001 and will continue for years to come, fueled by changing population demographics, population health trends, and accelerating advancements in surgical technology, as well as growth in ambulatory and office-based surgery, pain medicine, and intensive care. In addition to focusing on financing, national health policy needs to address the adequacy of health care personnel resources for an aging population, in particular when they require surgery, are afflicted by painful conditions, or become critically ill. PMID- 11605703 TI - A 10-year review of research on chaplains and community-based clergy in 3 primary oncology nursing journals: 1990-1999. AB - A manual examination of 3 primary oncology nursing journals was conducted to identify quantitative studies about chaplains and community-based clergy that were published between 1990 and 1999. This systematic review identified 7 studies involving chaplains and/or clergy dealing with a range of issues. Although the rate at which such studies were published in the oncology nursing literature was relatively low (1 in 123 studies), this rate far exceeds the rate found in a similar review of psychology journals (1 in 600 studies). The nature of the 7 studies and the issues they addressed are discussed and the authors make recommendations for future collaborative efforts. PMID- 11605704 TI - Sunbathing and sun-protection behaviors and attitudes of young Swedish adults with hereditary risk for malignant melanoma. AB - The aim of the study was to describe attitudes toward sunbathing and sun protection, to examine sun-related behaviors, and to present an effort to change sun-related behaviors among young adults without a cancer diagnosis in melanoma prone families. Ten patients were interviewed, and questionnaires were sent on 3 occasions during a 15-month period to the total population (n = 87) meeting the inclusion criteria. Data from interviews and questionnaires showed extensive ultraviolet-exposure behaviors in this high-risk group for melanoma, although not always expressed in terms of sunbathing. When asked about sunbathing, 1/3 reported sunbathing "Often" or "Very often," despite a decrease in sunbathing during the study period. In addition, 35% reported current sun bed use. The most important reason for sunbathing was attractiveness. The risk of getting skin cancer was the most important reason to refrain from sunbathing. The majority estimated their own risk for melanoma as equal or lower compared with the general population. The planned intervention failed due to low attendance. Ultraviolet exposure is extensive. The individual perception of personal risk and the motivation to change behaviors are important factors to consider when designing a preventive program. Interest for group information was low in this age group. PMID- 11605705 TI - Satisfaction with information and quality of life in patients undergoing chemotherapy for cancer. The role of individual differences in information preference. AB - Earlier studies have shown that patients are dissatisfied with the information they receive from doctors and nurses. The purpose of this study was to analyze satisfaction with information and quality of life in patients with cancer undergoing chemotherapy, considering the patient's information preference. Data were collected during interviews with 30 consecutive patients undergoing chemotherapy for cancer. The subject of the interviews was the satisfaction of patients with the information they received, and additional measures used were the Miller Behavioral Styles Scale and EORTC-QLQ-30. The results showed that 21 of 30 patients were satisfied with the information they received from health care. Married patients or cohabitants were satisfied more often than single patients. No significant differences in quality of life could be found between satisfied and dissatisfied patients. Regarding information preferences, the dissatisfied patients reported more information-avoiding behavior than those who were satisfied. The results must be interpreted cautiously because of the study's limitations, but one clinical implication can be stated: There is value in being aware of patients' information-seeking/avoiding behavior before starting to inform them. PMID- 11605706 TI - Genes and inheritance. AB - The information gained from the Human Genome Project and related genetic research will undoubtedly create significant changes in healthcare practice. It is becoming increasingly clear that nurses in all areas of clinical practice will require a fundamental understanding of basic genetics. This article provides the oncology nurse with an overview of basic genetic concepts, including inheritance patterns of single gene conditions, pedigree construction, chromosome aberrations, and the multifactorial basis underlying the common diseases of adulthood. Normal gene structure and function are introduced and the biochemistry of genetic errors is described. PMID- 11605707 TI - A longitudinal study of physical activity and breast cancer prediction. AB - Physical activity was analyzed as a predictor of breast cancer in the Aerobic Center Longitudinal Study. The study sample included 4,520 healthy women, with 150 incident cases of breast cancer. The study sample was limited to women who did not have a diagnosis of breast cancer at initial entry to the Aerobic Center Longitudinal Study. Women in the study were predominantly from an upper-middle class, college-educated, Caucasian American group being evaluated at a world famous fitness center. Women with and without breast cancer had similar reports for diet history, alcohol and tobacco use, body composition, and breast health history. Women with breast cancer were older and had an earlier menarche and later menopause. Logistic regression analysis of physical activity for women with and without breast cancer was performed controlling for age. Intensity and duration of physical activity were not predictors of breast cancer. Less frequency of jogging was a significant predictor of breast cancer among women in the sample, O.R.=1.14, P =.04. Women who reported jogging as a type of activity were less likely to develop breast cancer than those who did not report jogging, O.R.=2.32, P=0.05. PMID- 11605708 TI - Pain management strategies used by patients with breast and gynecologic cancer with postoperative pain. AB - Many people with cancer will experience pain when they are outside of structured care settings. Patients must provide their own self-care, drawing on instructions from healthcare providers and on independently developed plans for pain management. With growing interest in complementary therapies, the scope of nonpharmacologic interventions used by patients with cancer to manage pain may be very different than 10-15 years ago. The purpose of this study was to describe steps taken by patients with breast and gynecologic cancer to manage pain after discharge from a surgical hospitalization. A secondary analysis was completed using data from 34 women who participated in a randomized trial of guided imagery. Techniques used included positioning, distraction, relaxation, heat, and eating/drinking. Compared to results of previous studies, increased use of relaxation strategies (breathing, imagery, music, meditation) was noted in the current study. The majority of participants used nonpharmacologic strategies in addition to analgesic medications. Pain-related outcomes were similar among persons who used analgesic medications alone and those who used a combination of analgesics and nonpharmacologic strategies. Nurses may benefit from knowing which pain management strategies patients find helpful so that they can encourage their use and teach similar strategies to the patients who find them useful. PMID- 11605709 TI - Traveling through the cancer trajectory: social support perceived by women with gynecologic cancer in Hong Kong. AB - A qualitative research design was selected to gather data on the experiences of social support for Chinese women with gynecologic cancer. Eighteen women were recruited and interviewed at an oncology unit of a teaching hospital in Hong Kong. Content analysis of the interview data showed Chinese women with gynecologic cancer placed enormous emphasis on their human relationships. Family members were especially significant to them although not all identified their family relations as satisfactory or helpful. Their social network comprised 4 major sources, including family and friends, work and colleagues, health professionals, and religion and spiritual beliefs. Each network offered significant reciprocal relations, authoritative relations, or entrusting relations. The positive appraisal of the support function was linked to the Chinese value of food, work ethics, the Confucian and religious philosophy, whereas negative aspects of support, such as the stress of maintaining relationships and inadequate information, conjoined with the Chinese suppression of emotion and the busyness of health professionals. Future studies, including social relations as a determinant, should ensure a broad and multifunctional view of social support and acknowledge the cultural influences on the perspective of support. PMID- 11605710 TI - Perceived quality of life and coping for Swedish women with breast cancer who choose complementary medicine. AB - The aim of the present study, which is part of a major clinical controlled study of the life situation of women with breast cancer, was to compare two groups of women concerning perceived quality of life and coping. The women were treated in two different cancer treatment programs: complementary treatment, which included anthroposophic therapy, and conventional cancer treatment. A total of 120 women were included, 60 women treated with anthroposophic medicine, and 60 individually matched women treated with conventional medicine only. Quality of life was measured by the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Core 30, and the Life Satisfaction Questionnaire. Coping was measured by the Mental Adjustment to Cancer scale. The results showed that the women who chose anthroposophic therapy perceived their quality of life to be lower on admission to the hospital and showed more anxious preoccupation than the women in conventional medicine. It can be concluded that, due to the careful matching procedure, the women in the two groups are comparable in a medical sense but not from the perspective of quality of life and coping. PMID- 11605711 TI - Caring for dying children: a comparative study of nurses' experiences in Greece and Hong Kong. AB - The purpose of this transcultural descriptive study was to explore the subjective experiences of 63 oncology and critical care nurses who provide care to dying children in Greece and Hong Kong. Semistructured interviews were conducted with 39 Greek and 24 Chinese nurses who described their experiences and responses to the dying process and death of children. The data were analyzed qualitatively and quantitatively, and nurses' responses were compared for their work setting (oncology versus critical care) and their ethnic background (Greek versus Chinese). Findings revealed that most nurses experience a sense of helplessness when caring for a dying patient and difficulties in their communication with the child and parents during the terminal phase of the disease. The large majority acknowledge that the impending or actual death of a patient elicits a grieving process, which is characterized by a fluctuation between experiencing and avoiding loss and grief. Greek and Chinese nurses differ in their expression of their grief and how they attribute meaning to childhood death. Despite the suffering caused by multiple deaths, nurses report significant rewards from caring for chronically and acutely ill children, and the majority are satisfied with their job, despite the difficulties they encounter, in both countries, mostly as a result of shortage in personnel and cooperation problems with physicians. PMID- 11605712 TI - Caregivers' insights on the dying trajectory in hematology oncology. AB - It is increasingly acknowledged in the research literature that palliative care is not offered to patients with a hematologic malignancy. The evidence indicates that patients are not dying at home or in the comfort of the hospice setting but are more likely to end up in the high-tech care of an intensive care unit. The holistic, compassionate care of the hospice/palliative care philosophy is not routinely made available to either these patients or the families who care for them. However, little is known about what the end-of-life experience is for such patients and their families and how they are managing to negotiate their dying experience in a system that is designed to cure not to palliate. In particular, there is a dearth of information on what happens to the caregivers during what is characteristically a prolonged and difficult period of sustained caring within the high-tech system. This discussion presents findings from recent research that is beginning to document the experience of the dying trajectory for patients from these diagnostic groups and their families. The hope and expectation from such research is that the information will make a contribution to building multidisciplinary plans of care for hematologic malignancies during the dying trajectory, to ensure that patients and their families are appropriately referred to the palliative system or, at least, are given sensitive palliative care within the curative system. PMID- 11605713 TI - Quantitative drug interactions prediction system (Q-DIPS): a dynamic computer based method to assist in the choice of clinically relevant in vivo studies. AB - Metabolic drug interactions are a major source of clinical problems, but their investigation during drug development is often incomplete and poorly specific. In vitro studies give very accurate data on the interactions of drugs with selective cytochrome P450 (CYP) isozymes, but their interpretation in the clinical context is difficult. On the other hand, the design of in vivo studies is sometimes poor (choice of prototype substrate, doses, schedule of administration, number of volunteers), with the risk of minimising the real potential for interaction. To link in vitro and in vivo studies, several authors have suggested using extrapolation techniques, based on the comparison of in vitro inhibition data with the active in vivo concentrations of the inhibitor. However, the lack of knowledge of one or several important parameters (role of metabolites, intrahepatocyte accumulation) often limits the possibility for safe and accurate predictions. In consequence, these methods are useful to complement in vitro studies and help design clinically relevant in vivo studies, but they will not totally replace in vivo investigation in the future. We have developed a computerised application, the quantitative drug interactions prediction system (Q DIPS), to make both qualitative deductions and quantitative predictions on the basis of a database containing updated information on CYP substrates, inhibitors and inducers, as well as pharmacokinetic parameters. We also propose a global approach to drug interactions problems--'good interactions practice--to help design rational drug interaction investigations, sequentially associating in vitro studies, in vitrolin vivo extrapolation and finally well-designed in vivo clinical studies. PMID- 11605714 TI - Clinical pharmacokinetics and pharmacodynamics of insulin aspart. AB - Insulin aspart is a novel rapid-acting insulin analogue with improved subcutaneous absorption properties when compared with soluble human insulin. Pharmacokinetic studies show an absorption profile with a time to reach peak concentration (t(max)) about half that of human insulin, a peak plasma drug concentration (Cmax) approximately twice as high and shorter residence time. The potency and bioavailability of insulin aspart are similar to those of human insulin. The pharmacokinetics of insulin aspart have been studied in healthy Caucasian and Asian-Japanese volunteers, in patients with type 1 and 2 diabetes mellitus, and in children with diabetes, with both pre- and postprandial administration and during continuous subcutaneous insulin infusion (CSII). The pharmacokinetic profile was similar to that of another rapid-acting insulin analogue, insulin lispro, on the basis of published information for that agent. Pharmacodynamic studies show a smaller excursion of postprandial glucose with insulin aspart injected subcutaneously just before the meal compared with soluble human insulin injected 30 minutes before the meal in patients with type 1 diabetes mellitus, and an equivalent control in patients with type 2 diabetes displaying residual insulin production. In a treatment study, glucose excursions evaluated from 24-hour glucose profiles showed less variability with insulin aspart compared with human insulin. Adverse events, including hypoglycaemia induced ventricular repolarisation and hypoglycaemic threshold and awareness, did not differ between insulin aspart and human insulin. The available data suggest that subcutaneous injections of insulin aspart just before meals better mimic the endogenous insulin profile in blood compared with human insulin, resulting in improved glucose control in a meal-related insulin regimen. This review summarises the clinical pharmacokinetics and pharmacodynamics of insulin aspart in relation to human insulin and insulin lispro. PMID- 11605716 TI - Clinical use of ceftriaxone: a pharmacokinetic-pharmacodynamic perspective on the impact of minimum inhibitory concentration and serum protein binding. AB - Ceftriaxone is a third-generation cephalosporin that is used for a variety of infections such as meningitis, gonorrhoea and community-acquired pneumonia. The most important aspects of its pharmacokinetics include a long half-life, excellent tissue penetration and saturable (dose-dependent) serum protein binding of the drug. A pharmacodynamic analysis [total area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC)] was performed in several populations (healthy volunteers, children, the elderly, and patients with renal and hepatic impairment) against various bacterial species (Streptococcus pneumoniae, the Enterobacteriacieae, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa). AUC/MIC [area under the inhibitory time curve (AUIC)] was chosen as the pharmacodynamic parameter for this analysis since ceftriaxone is a time-dependent killer and high peak concentrations are not needed. In addition, there is a significant correlation between AUIC, time when concentration exceeds the MIC (t > MIC) and time to eradication. Total and free AUICs (assuming a free fraction = 10%) were calculated since it is highly protein bound. It was postulated that a free AUIC of at least 125 would be required to achieve efficacy. From our analysis of these various populations, we were able to conclude that the free AUIC values support the use of Ig daily in infections where MIC values are below 2 mg/L. In addition, consistent with its reported good activity against CSF organisms with MICs < or =1.0 mg/L and marginal activity against organisms with MICs > or =2.0 mg/L, we also recommend the target free AUIC values of at least 125 for patients with severe infections such as meningitis. Patients with mild infections may recover with values below 125 but they may remain at risk of the development of resistant organisms. Furthermore, it is essential to further validate these findings in patients who have received treatment, calculate AUICs and correlate these parameters with both clinical and microbiological outcomes. PMID- 11605717 TI - Comparison of the plasma pharmacokinetics of lamivudine during twice and once daily administration in patients with HIV. AB - OBJECTIVE: To compare the plasma pharmacokinetics of lamivudine 150mg twice daily and 300mg once daily in patients with HIV-1 infection. DESIGN: Nonblind, sequential, pharmacokinetic study. PARTICIPANTS: 13 patients with HIV-1 infection (median age 36 years). METHODS: Patients were tested during twice daily and then once daily regimens of lamivudine. In both regimens, the total daily dose of lamivudine was identical (300 mg/day). Blood samples for pharmacokinetic analysis were taken over a 12-hour period after > or =7 days of twice daily administration, and again over a 24-hour period after 7 days of once daily administration,. RESULTS: 12 patients completed the study. Lamivudine pharmacokinetic parameters (mean +/- SD) after administration of 150mg twice daily were: peak plasma concentration (Cmax) 2077+/-816 microg/L; trough plasma concentration (Cmin) 332+/-219 microg/L; elimination half-life (t 1/2beta) 6.1+/ 1.9h; time to Cmax (t(max)) 1.6+/-0.7h; average concentration over the dosage interval (Cav) 711+/-269 microg/L; and area under the concentration-time curve (AUC) over 2 dosage intervals (24h) 17085+/-6464 microg x h/L. Corresponding values after administration of 300mg once daily were: Cmax 3461+/-854 microg/L; Cmin 146+/-87 microg/L; t1/2 7.9+/-3.4h; t(max) 2.2+/-1.3h; Cav 705+/-177 microg/L; and AUC over 1 dosage interval (24h) 16644+/-4150 microg x h/L. Statistical analysis showed a significant difference (p < 0.05) between the 2 schedules for Cmax and Cmin values, whereas no significant differences emerged for the other parameters. CONCLUSIONS: Once daily lamivudine leads to a similar exposure in plasma as twice daily administration of the same total daily dose. Since once daily administration may result in improved compliance, these results provide the pharmacokinetic basis for using lamivudine in a once daily regimen. Randomised clinical studies are needed to confirm this pharmacokinetic finding. PMID- 11605715 TI - The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments. AB - Nicotine inhaled in smoke is the most rapid form of delivery of the drug. With smoking, arterial boli and high venous blood nicotine concentrations are produced within seconds and minutes, respectively. The potency of nicotine as the primary reinforcement in tobacco addiction is attributed to this rapid rate of delivery. By design, nicotine treatments reduce the rate and extent of drug delivery for weaning from nicotine during smoking cessation. Theoretically, they prevent relapse by reducing withdrawal and craving associated with the abrupt cessation of cigarettes. The nicotine inhaler treats the complexity of smoking through weaning both from the drug and from the sensory/ritual components associated with smoking. The inhaler is 'puffed' but not lit and there is considerable 'puffing' required to achieve slower rising and lower nicotine concentrations. These factors allow it to be used as a nicotine reduction treatment. One inhaler contains 10 mg of nicotine (and 1 mg of menthol) of which 4 mg of nicotine can be extracted and 2mg are systemically available. Shallow or deep 'puffing' results in similar nicotine absorption. Nicotine is delivered mainly to the oral cavity, throat and upper respiratory tract with a minor fraction reaching the lungs. This was confirmed with positron emission tomography and by assessment of arterial concentrations. A single inhaler can be used for one 20-minute period of continuous puffing or periodic use of up to 400 puffs per inhaler. With controlled puffing in laboratory testing, venous plasma nicotine concentrations from a single inhaler puffed 80 times over 20 minutes averaged 8.1 microg/L at 30 minutes. Lower concentrations of 6.4 to 6.9 microg/L have been reported for self administration under clinical conditions. The time to peak plasma concentrations varies but is always significantly longer than with cigarette delivery. Estimates of nicotine intake from cotinine concentrations were higher than expected (60 to 70% of baseline smoking concentrations). This elevation may be due to the swallowing of nicotine and subsequent first-pass biotransformation to cotinine. In general, venous blood nicotine concentrations are considerably lower than with smoking and are within the range observed for other nicotine reduction therapies. Efficacy trials show consistent superiority of the inhaler over placebo. Despite the 'cigarette-like' appearance of the inhaler and the associated sensory/ritual elements, little treatment dependence or abuse has been reported. This is attributed to the slow rise time and low nicotine blood concentrations. The inhaler is a valuable addition to treatment of tobacco dependence and can be used alone or with other treatments. PMID- 11605718 TI - Memorial tribute to Vince L. Hutchins, MD, MPH, 1928-2001. PMID- 11605719 TI - Stressful life events and physical abuse among pregnant women in North Carolina. AB - OBJECTIVES: This study estimates the prevalence of stressful life events and physical abuse among North Carolina women prior to infant delivery, and examines potential associations between abuse and the other stressors. METHODS: Data were from the North Carolina Pregnancy Risk Assessment Monitoring System, a statewide representative survey of over 2,600 postpartum women. The survey assessed women's sociodemographic characteristics and their experiences of physical abuse and 13 other stressful life events before delivery. The prevalences of each life event and abuse were estimated. Logistic regression modeled the probability of women having high levels of stressful life events in relation to physical abuse and sociodemographics. RESULTS: Most women were married, white, high school graduates, aged 20 or older. The most common stressful life events were residential moves, increased arguing with husbands/partners, family member hospitalizations, financial hardship, and deaths of loved ones. Fourteen percent of women had high levels of stressful events (5 or more), and almost 9% were physically abused. Abuse was positively associated with increased arguing with husbands/partners, physical fighting, having someone close with an alcohol/drug problem, becoming separated/divorced, and financial hardship. Logistic regression analysis showed that a high level of stressful life events was significantly more likely among women abused both before and during pregnancy (OR = 11.94) and among women abused before but not during pregnancy (OR = 14.19). CONCLUSIONS: The high frequency of multiple stressful events and abuse in women's lives suggests that women's care providers should ask their patients about these issues, and offer appropriate referral/interventions to those in need. PMID- 11605720 TI - Why do women douche? Results from a qualitative study. AB - OBJECTIVES: To explore women's attitudes and practices related to douching. METHODS: We conducted focus groups between July and December 1999 with 34 black and 27 white women enrolled in a managed care plan in Memphis, Tennessee. Participants were at least 18 years of age and had douched at some time in their lives. Five groups were held with black women and five with white women. RESULTS: The focus groups identified 13 themes that fell in four broad categories: general perceptions about feminine hygiene, douching behavior, factors perpetuating douching, and health information. Each of these categories is briefly discussed with supporting evidence. CONCLUSIONS: First, women have deeply-rooted beliefs about the critical role of douching in making them feel clean. Second, douching generally starts at a young age and is reinforced by family, friends, and the media. Third, douching is a very difficult behavior to change; any efforts to influence this behavior must consider women's beliefs and the media marketing efforts that promote douching. Finally, simplistic interventions that only provide risk information about douching are not likely to result in behavior change. PMID- 11605721 TI - Ecological analysis of teen birth rates: association with community income and income inequality. AB - OBJECTIVES: To examine whether per capita income and income inequality are independently associated with teen birth rate in populous U.S. counties. METHODS: This study used 1990 U.S. Census data and National Center for Health Statistics birth data. Income inequality was measured with the 90:10 ratio, a ratio of percent of cumulative income held by the richest and poorest population deciles. Linear regression and analysis of variance were used to assess associations between county-level average income, income inequality, and teen birth rates among counties with population greater than 100,000. RESULTS: Among teens aged 15 17, income inequality and per capita income were independently associated with birth rate; the mean birth rate was 54 per 1,000 in counties with low income and high income inequality, and 19 per 1,000 in counties with high income and low inequality. Among older teens (aged 18-19) only per capita income was significantly associated with birth rate. CONCLUSIONS: Although teen childbearing is the result of individual behaviors, these findings suggest that community level factors such as income and income inequality may contribute significantly to differences in teen birth rates. PMID- 11605722 TI - Risk-adjusted primary cesarean delivery rates for managed care plans in New York State, 1998. AB - OBJECTIVE: To demonstrate the effect of risk adjustment methodologies compared to crude rates in evaluating the rate of primary cesarean deliveries in managed care plans, after accounting for known demographic and clinical factors. Risk adjustment allows for a more accurate comparison of primary cesarean delivery rates among plans, eliminating potential confounding factors that could influence rates. METHODS: Data was collected from managed care plans as part of their 1998 Quality Assurance Reporting Requirements (QARR). Medicaid and commercial populations were matched to New York State Department of Health Vital Statistics birth file to produce a crude measure of cesarean deliveries per plan. Logistic regression models were then used to adjust for maternal education, age, race/ethnicity, obstetrical history, preexisting comorbid conditions, obstetrical conditions, and pregnancy-related conditions to produce adjusted rates. RESULTS: For Medicaid, the crude analysis showed four plans that were significantly lower than the statewide Medicaid managed care rate of 9.5 per 100 live births. One plan was significantly higher. The risk-adjusted results showed one plan being significantly lower than the statewide average and none being higher. For the commercial population, seven plans were significantly lower than the average of 16.3 and four plans were higher. After risk-adjusting, three plans were significantly lower and three plans were significantly higher than the statewide average. CONCLUSIONS: Risk-adjustment of primary cesarean delivery rates allows for a more accurate comparison among managed care plans. It is hoped that the generation and publication of more accurate rates will facilitate the acceptance and use of this information by clinicians in managed care plans to focus on improving health outcomes. PMID- 11605724 TI - A preterm birth prevention project in Nova Scotia, Canada. AB - OBJECTIVE: The Halifax County Preterm Birth Prevention Project was designed to evaluate the effectiveness of a population-based preterm birth (PTB) prevention program in Nova Scotia from January 1995 through June 1997 (n = 10,326). METHODS: Preterm birth rates, adjusted for risk status and maternal age, were evaluated over time in Halifax County and compared to non-Halifax County parturients in Nova Scotia. Physician participation was evaluated by means of a mailed survey. RESULTS: There was no appreciable change in the overall (<37 weeks) or early (<34 weeks) PTB rates within or outside Halifax County during the intervention period compared to the preintervention period. Although not significant, the very (<30 weeks) PTB rate in Halifax County decreased by 40% from 0.53 to 0.32%, while outside Halifax County it remained stable (0.43-0.42%). There was a statistically significant decrease in early and very PTB associated with spontaneous labour, as well as an apparent shift in the timing of delivery from very preterm to preterm (> or =30 weeks). Participation among responding physicians was greater for high risk than low-risk women, but full compliance with project recommendations was low. CONCLUSION: The overall ineffectiveness of the Halifax County Preterm Birth Prevention Project may reflect the reluctance of practitioners to fully incorporate the recommended prevention strategies into their practice. However, such interventions may reduce the risk of spontaneous early preterm birth. PMID- 11605723 TI - Racial and ethnic disparities in the discordance between women's assessment of the timing of their prenatal care entry and the first trimester standard. AB - OBJECTIVE: The purpose of this study was to investigate whether the discordance between women's assessment of the adequacy of the timing of their prenatal care entry and the standard of first trimester initiation was associated with maternal race or ethnicity. METHODS: A population-based surveillance system, the California Pregnancy Risk Assessment Monitoring System, provided data on a stratified random sample of 4,987 women. The women delivered live-born infants from 1994-95 in three perinatal regions. Respondents completed an in-hospital, self-administered questionnaire. Weighted data were analyzed with multiple logistic regression. RESULTS: Twenty-two percent of the women in the sample initiated prenatal care after the first trimester of pregnancy (n = 1,097). Among the women with untimely care, 57% (n = 591) were satisfied with the time of care initiation. Discordance between the women's perception of the adequacy of the time of care initiation and the public health standard of first trimester initiation was associated with maternal ethnicity. After controlling for potential confounders, Mexican-born women with untimely care were more likely to report being satisfied with the time of initiation than were white non-Latina women with untimely care (OR = 4.03, CI = 2.46, 6.59). CONCLUSIONS: The design of public health interventions to increase the timeliness of prenatal care initiation will require a greater understanding of pregnant women's own perceptions of their needs for prenatal care, and the differences in perceptions across ethnic groups. PMID- 11605725 TI - State welfare reform policies and maternal and child health services: a national study. AB - OBJECTIVES: Welfare reform (Personal Responsibility and Work Opportunity Reconciliation Act of 1996) resulted in dramatic policy changes, including health related requirements and the administrative separation of cash assistance from Medicaid. We were interested in determining if changes in welfare and health policies had had an impact on state MCH services and programs. METHODS: We conducted a survey in fall 1999 of state MCH Title V directors. Trained interviewers administered the telephone survey over a 3-month period. MCH directors from all 50 states, Washington, DC, and Puerto Rico participated (n = 52; response rate = 100%). RESULTS: Among the most noteworthy findings is that similar proportions of respondents reported that welfare policy changes had either helped (46%) or hindered (42%) the agency's work, with most of the positive impact attributed to increased funding. MCH data linkages with welfare and other social programs were low. Despite welfare reform's emphasis on work, limited services and exemptions were available for mothers with CSHCN. Almost no efforts have been undertaken to specifically address the needs of substance abusers in the context of new welfare policies. CONCLUSIONS: Few MCH agencies have developed programs to address the special needs of women receiving TANF who either have health problems themselves or have children with health problems. Recommendations including increased MCH and family planning funding and improved coordination between TANF and MCH to facilitate linkages and services are put forth in light of reauthorization of PRWORA. PMID- 11605726 TI - "The Embarrassment of Riches;" an historical theme for a children's health agenda in 21st century America. AB - How can the United States use its immense wealth to create an agenda for children in the 21st century? The field of maternal and child health must strengthen and broaden the social strategies needed to overcome the changing demography and diminished political place of children in society, globally. Four approaches are proposed: First, adopting a life-course orientation emphasizes the continuities of the early part of life with the conditions, developmental tasks, and health problems of the rest of the life cycle; it makes maternal and child health relevant to health and well being across the entire life span. Second, shifting to a focus on the multiple determinants of population health will overcome the limitations of a medical model that is narrowly concerned with etiological risk factors for disease and medical interventions; in particular, poverty among children must be addressed on a global scale. Third, promoting social justice for children demands an open political discussion of the moral and ethical foundations of child health. Finally, preventing health problems across the life span requires a new set of population level, univeral intervention strategies. These fundamental principles are proposed to stimulate a discussion of how to make our field more influential in the 21st century. PMID- 11605727 TI - Role of coactivators and corepressors in steroid and nuclear receptor signaling: potential markers of tumor growth and drug sensitivity. AB - Nuclear receptors regulate target gene expression in response to steroid and thyroid hormones, retinoids, vitamin D and other ligands. These ligand-dependent transcription factors function by contacting various nuclear cooperating proteins, called coactivators and corepressors, which mediate local chromatin remodeling as well as communication with the basal transcriptional apparatus. Nuclear receptors and their coregulatory proteins play a role in cancer and other diseases, one leading example being the estrogen receptor pathway in breast cancer. Coregulators are often present in limiting amounts in cell nuclei and modifications of their level of expression and/or structure lead to alterations in nuclear receptor functioning, which may be as pronounced as a complete inversion of signaling, i.e. from stimulating to repressing certain genes in response to an identical stimulus. In addition, hemizygous knock-out of certain coactivator genes has been demonstrated to produce cancer-prone phenotypes in mice. Thus, assessment of coactivator and corepressor expression and structure in tumors may turn out to be essential to determine the role of nuclear receptors in cancer and to predict prognosis and response to therapy. PMID- 11605728 TI - Loss of heterozygosity on chromosomes 1, 2, 8, 9 and 17 in cerebral atherosclerotic plaques. AB - OBJECTIVE: Atherosclerosis is a fibroproliferative disease which has been attributed to several factors including genetic and molecular alterations. Initial studies have shown genetic alterations at the microsatellite level in the DNA of atherosclerotic plaques. Extending our initial findings, we performed a microsatellite analysis on cerebral atherosclerotic plaques. METHODS: Twenty seven cerebral atherosclerotic plaques were assessed for loss of heterozygosity (LOH) and microsatellite instability (MI) using 25 microsatellite markers located on chromosomes 2, 8, 9 and 17. DNA was extracted from the vessels as well as the respective blood from each patient and subjected to polymerase chain reaction. RESULTS: Our analyses revealed that specific loci on chromosomes 2, 8, 9 and 17 exhibited a significant incidence of LOH. Forty-six percent of the specimens showed loss of heterozygosity at 2p13-p21, 48% exhibited LOH at 8p12-q11.2, while allelic imbalance was detected in 47% of the cases. The LOH incidence was 39%, 31% and 27% at 17q21, 9q31-34 and 17p13, respectively. Genetic alterations were detected at a higher rate as compared to the corresponding alterations observed in plaques from other vessels. DISCUSSION: This is the first microsatellite analysis using atherosclerotic plaques obtained from cerebral vessels. Our results indicate an elevated mutational rate on specific chromosomal loci, suggesting a potential implication of these regions in atherogenesis. PMID- 11605729 TI - Immunohistochemical study of the BCAR1/p130Cas protein in non-malignant and malignant human breast tissue. AB - BCAR1/p130Cas is a docking protein involved in intracellular signaling pathways and in vitro resistance of estrogen-dependent breast cancer cells to antiestrogens. The BCAR1/p130Cas protein level in primary breast cancer cytosols was found to correlate with rapid recurrence of disease. A high BCAR1/p130Cas level was also associated with a higher likelihood of resistance to first-line tamoxifen treatment in patients with advanced breast cancer. Using antibodies raised against the rat p130Cas protein, we determined by immunohistochemical methods the BCAR1/p130Cas localization in primary breast carcinomas, in tumors of stromal origin, and in non-neoplastic breast tissues. The BCAR1/p130Cas protein was detected in the cytoplasm of non-malignant and neoplastic epithelial cells and in the vascular compartment of all tissue sections analyzed. Immunohistochemistry demonstrated variable intensity of BCAR1/p130Cas staining and variation in the proportion of BCAR1/p130Cas-positive epithelial tumor cells for the different breast carcinomas. Double immunohistochemical staining for BCAR1/p130Cas and estrogen receptor confirmed coexpression in non-malignant luminal epithelial cells and malignant breast tumor cells. The stromal cells in non-malignant tissues and tumor tissues as well as breast tumors of mesodermal origin did not stain for BCAR1/p130Cas. This immunohistochemical study demonstrates a variable expression of BCAR1/p130Cas in malignant and non malignant breast epithelial cells, which may be of benefit for diagnostic purposes. PMID- 11605730 TI - Predicting prostate biopsy outcome by findings at digital rectal examination, transrectal ultrasonography, PSA, PSA density and free-to-total PSA ratio in a population-based screening setting. AB - The study offers a retrospective analysis of the positive predictive value (PPV) of several variables, i.e. digital rectal examination (DRE), transrectal ultrasonography (TRUS), PSA value, PSA density (PSAD), and free/total PSA ratio (F/T), for the histologic outcome of 179 prostate biopsies performed within a population-based screening trial. The ratio of spared benign biopsies to missed cancers (SBB/MC) if biopsy results had been decided on the basis of single variables was also evaluated. PPV was 82.9% for DRE, 56.3% for TRUS, 26.6% for PSA (cutoff > or =4 ng/mL), 47.4% for PSA (cutoff > or =10 ng/mL), 42.0% for PSAD (cutoff 0.15), 59.2% for PSAD (cutoff 0.20), 34.9% for F/T (cutoff 0.20) and 40.0% for F/T (cutoff 0.15). SBB/MC was 121/23 for DRE, 96/12 for TRUS, 11/10 for PSA (cutoff > or =4 ng/mL), 107/34 for PSA (cutoff > or =10 ng/mL), 87/23 for PSAD (cutoff 0.15), 109/26 for PSAD (cutoff 0.20), 45/8 for F/T (cutoff 0.20) and 70/14 for F/T (cutoff 0.15). Multivariate analysis of the association with biopsy outcome showed the highest odds ratio for TRUS (13.24, 95% CI=4.4-30.7), and considerably lower values for DRE (4.17, 95% CI=2.0-8-9), PSAD (cutoff 0.20: 3.24, 95% CI=-1.8-5.7) and F/T (cutoff <0.15: 3.16, 95% CI=1.7-1.8). None of the possible variable combinations was clinically useful: the highest PPV (83.3%) was obtained with a combination of suspicious DRE/TRUS, PSAD >0.20 and F/T <0.15, which nevertheless missed 20 of 52 cancers. PMID- 11605731 TI - Clinical significance of epidermal growth factor receptor content in gastric cancer. AB - The objective of this work was to evaluate the epidermal growth factor receptor (EGFR) content in gastric cancer, its possible relationship with clinicopathological parameters of tumors and its prognostic significance. Membranous EGFR levels were examined by radioligand binding assays in 110 patients with gastric cancer. The mean follow-up period was 30.7 months. EGFR levels of tumors ranged widely, from 0.3 to 510 fmol/mg protein. EGFR levels were significantly higher (p<0.0005) in neoplastic tissue than in paired adjacent mucosa samples (median) (n= 84; 8.7 vs. 3.9 fmol/mg protein). Intratumoral EGFR levels were significantly correlated with tumor stage (p<0.05), and were higher in patients with stage III tumors (median) (7.6, 6.4, 12.3 and 7.5 fmol/mg protein for stages I, II, III and IV, respectively). In addition, the tumor/mucosa ratios of the EGFR content were significantly higher (p<0.05) in patients with stage III tumors (1, 1.8, 3.9, and 0.92, respectively). Although there was no significant relationship between EGFR levels of tumors and overall survival, the results suggest a role for EGFR in tumor progression of gastric cancer. PMID- 11605732 TI - SPan-1 and exocrine pancreatic carcinoma. The clinical role of a new tumor marker. AB - AIMS OF THE STUDY: Considerable progress has been made in imaging techniques over the past few years, yet this has not resulted in the ability to reach an earlier diagnosis of exocrine pancreatic cancer. The search for a noninvasive diagnostic tool capable of early diagnosis has led to the development of a series of serum tumor markers. This article discusses the clinical evaluation of SPan-1 and its comparison with established markers such as CA 19.9, CEA, TPA and CA 242. METHODS: The markers were measured in preoperative serum samples collected from 46 patients who had undergone surgery for ductal carcinoma of the pancreas, 20 patients with chronic pancreatitis, and 23 patients with other digestive neoplasms. RESULTS: The sensitivity, specificity and diagnostic accuracy for pancreatic cancer were as follows: [table: see text] CONCLUSIONS: The antigenic determinant SPan-1, recognized by monoclonal antibodies, is elevated in sera of patients with exocrine pancreatic cancer. SPan-1 may be considered as an additional useful and reliable serum marker for the detection of this neoplasm, but it does not significantly improve the diagnostic accuracy obtained with CA 19.9. PMID- 11605733 TI - Some notes about statistical approaches adopted in assessing relationships between measurement methods of biomarkers. PMID- 11605734 TI - Does bone density predict fractures comparably in men and women? PMID- 11605735 TI - Short-term precision for morphometric X-ray absorptiometry. AB - Morphometric X-ray absorptiometry (MXA) is a low-radiation technique used for the identification of vertebral deformities. The reliability of MXA measurements is dependent on the precision of the technique, and this is influenced by system error, variability associated with morphometric analysis, and variability within study populations. Short-term precision in vivo affects the identification of prevalent deformities, and may vary according to the age and health status of the study population. The aims of this study were to measure short-term precision in vitro and in vivo for MXA, and to compare intraoperator variability for repeat marking of radiographs in morphometric radiography (MRX) and scan images in MXA. For short-term precision in vitro (based on 30 consecutive MXA phantom scans), the coefficient of variation (CV) was approximately 1%. Intraoperator variability for repeat marking of baseline radiographs and MXA scans (marked without the compare facility) in a population-based group of 32 postmenopausal women, was significantly lower for MRX (CV for vertebral heights = 1.5%) than for MXA (CV = 2.9%). The CV for duplicate same-day MXA scans performed in subjects with osteoporosis (n = 20) was 2.2% for vertebral heights between T8 and L4 using the compare facility, and 4.8% when scans were analyzed without the compare facility. We conclude that short-term precision for MXA is good for vertebrae T8 to L4, but the technique is limited due to poor image resolution in the upper thoracic vertebrae. Intraoperator variability for repeat marking was lower for MRX, but the error associated with marking MXA scans remained below the minimum change required for identification of a vertebral deformity. PMID- 11605736 TI - Comparison of four morphometric definitions and a semiquantitative consensus reading for assessing prevalent vertebral fractures. AB - The assessment of vertebral fracture in patients with osteoporosis by conventional radiography has been improved over the past 10 years using either the semiquantitative (SQ) method devised by Genant et al. or quantitative morphometry. However, there is still no internationally agreed definition for vertebral fracture and there have been few comparative studies between these different approaches. Our study assessed the reproducibility of the SQ method and of four commonly used morphometric algorithms (Melton's, Eastell's, Minne's and McCloskey's methods) for assessing prevalent vertebral fractures, and examined the agreement of each morphometric algorithm with a SQ consensus reading performed by three experts. With this consensus reading in place of a gold standard, we determined relative measures of sensitivity, specificity and optimal cutoff threshold for each morphometric algorithm. The study was conducted in 39 postmenopausal women who had at least one osteoporotic vertebral fracture. Normal values were derived from 84 healthy postmenopausal women with apparently normal vertebral bodies. Our results indicate that the concordance of SQ method was excellent (intraobserver agreement on serial radiographs = 96.4%, kappa = 0.91; agreement between individual readings and the consensus reading = 98%, kappa = 0.95). Three morphometric approaches demonstrated good intra- and interobserver concordance (Melton: intraobserver agreement on serial radiographs = 92.7%, kappa = 0.82, interobserver agreement = 91.1%, kappa = 0.79; Eastell: intraobserver agreement on serial radiographs = 87.6%, kappa = 0.66, interobserver agreement = 88.6%, kappa = 0.68; McCloskey: intraobserver agreement on serial radiographs = 91.5%, kappa = 0.72, interobserver agreement = 93.9%, kappa = 0.78). Except for McCloskey's method, the optimal cutoff thresholds defined in our study by highest kappa score or Youden index in comparison with the SQ consensus reading were near the cutoff thresholds that were arbitrarily fixed. The four morphometric algorithms provided a good agreement with the results of the SQ consensus reading, but the more complex algorithm did not provide better results and even if we adjusted the cutoff threshold, no morphometric algorithm agreed perfectly with the SQ consensus reading. We conclude that morphometric approaches currently used should not be employed alone to detect prevalent vertebral fractures in studies on osteoporosis, but should rather be used in combination with a visual assessment. The SQ approach that allows differential diagnosis of vertebral deformities and has demonstrated a better reproducibility can be employed alone when it is performed by experienced and well-trained readers. PMID- 11605737 TI - Sodium is the leading dietary factor associated with urinary calcium excretion in Hong Kong Chinese adults. AB - We conducted a cross-sectional population-based study comprising 1010 Hong Kong Chinese (500 men and 510 women) aged 25-74 years during 1995-6. The study examined the important dietary, lifestyle and anthropometric factors associated with urinary calcium excretion. Dietary intakes were assessed by means of food frequency questionnaire. Spot urine was collected to measure the urinary excretion profiles of calcium (Ca), sodium (Na), potassium (K) and creatinine (Cr). When expressed as ratios of cations to urinary Cr, significant relationships were noted between urinary Ca and Na (r: approximately 0.6), and between urinary Ca and K (r: 0.17-0.21). Stepwise multiple linear regression analyses were carried out separately in men and women aged below and above 50 years. We found that urinary Na/Cr was the leading independent factor associated with urinary Ca/Cr in all four age and sex groups. It accounted for 22% of urinary Ca/Cr variations in women aged below 50 years, and 35-43% in the other three age and sex groups. We estimated that urinary Ca excretion increased by about 1.4 (range 1.37-1.43) mmol per 100 mmol increase in urinary Na. Except in men aged 50 years and over, urinary K/Cr was inversely associated with urinary Ca/Cr in all groups. Age was independently and positively associated with urinary Ca/ Cr in subjects aged below 50 years. We did not observe any significant relation between urinary Ca/Cr and dietary protein, phosphorus, alcohol drinking and smoking. In conclusion, we found that urinary Na/Cr, but not dietary protein, Ca or phosphorus, is the most important factor influencing urinary Ca/Cr excretion in our population. Urinary K is a potential factor for Ca conservation. PMID- 11605738 TI - The effects of pregnancy and lactation on bone mineral density. AB - We performed a prospective study of bone mineral density (BMD) in 38 women during their first full-term pregnancy until 12 months postpartum. BMD measurements at lumbar spine [L2-L4 (LS)] and forearm [distal 33% (RD) and ultradistal (RUD) region of the radius] were made within 3 months before conception, after delivery, and at 6 and 12 months postpartum. In mid-pregnancy the DXA examination was carried out only at the forearm. Patients were grouped according to duration of lactation as group I, II or III (0-1, 1-6, 6-12 months respectively). During pregnancy there was a significant difference between baseline and delivery (p< 0.001) in the LS, RUD and RD BMD values. In group I there was no statistically significant difference in LS BMD between visits following pregnancy. The RUD BMD loss was recovered by 6 months postpartum (PP6). Group II showed continuous bone loss from delivery until PP6 at LS and RUD. In group III the LS BMD loss continued throughout the lactation period. The RUD BMD dropped (4.9%) until PP6 then increased by 3.0% as measured at 12 months postpartum (PP12). There was no significant change in RD BMD in any of three groups during lactation. At LS bone loss between delivery and PP12 correlated well with the duration of lactation (r = -0.727; p<0.001). We suggest that calcium needed for fetal skeletal growth during pregnancy was gained from maternal trabecular and cortical sites and that calcium needed for infant growth during lactation was drawn mainly from the maternal trabecular skeleton in our patients. The effect of pregnancy and lactation on the maternal bone mass was spontaneously compensated after weaning. PMID- 11605739 TI - Correlation between vertebral body rotation and two-dimensional vertebral bone density measurement. AB - The aim of this study was to determine the effect of vertebral rotation, as seen in idiopathic scoliosis, on bone mineral density determination for the lumbar spine. Bone mineral content, biplanar vertebral segment area and calculated bone mineral density of each vertebra from L1 to L4 were obtained for a human cadaveric specimen. The average density for the entire L1-L4 segment was also recorded. This was done with the spine in the midline position as well as in rotation up to a maximum of 60 degrees either side of the midline. The spine was rotated in each direction using 10 degrees increments and two bone density readings were done at each rotation interval. The measured biplanar vertebral segment area increased with increasing rotation from 0 degrees to 50 degrees but decreased after 50 degrees of rotation (r = 0.73, p<0.001). The bone mineral density was significantly negatively correlated with the degree of rotation (r = 0.92, p<0.001). The decrease in measured bone mineral density was nearly 20% when the lumbar spine was rotated from neutral to 60 . This study demonstrates that degree of spinal rotation influences apparent bone mineral density by increasing the apparent vertebral segment area. The measurement change may be as high as 20%. This fact should be considered when investigating scoliotic patients with vertebral segment rotation. PMID- 11605740 TI - Cut-off values determined for vertebral fracture by peripheral quantitative computed tomography in Japanese women. AB - In spite of the benefits of bone mass measurement by dual-energy X-ray absorptiometry (DXA), the use of DXA has limitations. It is unable to assess a true bone density, and cannot discriminate between the trabecular and cortical bone compartments. Ultradistal radius bone density was measured using peripheral quantitative computed tomography (pQCT) to determine reference values for total bone density (BD), trabecular bone density (TBD), polar strength strain index (pSSI), total bone mineral content (BC), trabecular bone mineral content (TBC), cortical bone density (CBD), cortical bone mineral content (CBC) and polar cross sectional moment of inertia (pCSMI) in the Japanese female population, and to ascertain the cut-off values of the measured indicators that could most efficiently discriminate osteoporotic subjects with vertebral fractures. A total of 5266 healthy Japanese women aged 20-89 years were included in this study to determine Japanese reference values. Additionally, 621 who had undergone radiographic examination of the thoracic and lumbar spine at the time of pQCT measurement were selected to determine the cut-off values of BD, TBD, pSSI and other indicators for vertebral fractures. All the healthy subjects were divided into 5 year age groups. The BD showed nonsignificant changes from the 20-24 year age group to the 45-49 year age group, and fell significantly thereafter. The TBD maintained a plateau until the 40-44 year group, which corresponds to the young adult mean (YAM) values of the lumbar spine, femoral neck and radius BMDs measured using DXA. The TBD decreased significantly thereafter. The pSSI did not change significantly from the 20-24 year age group to the 45-49 year age group, and decreased slightly in the 50-54 year age group and markedly after 55-59 years. The cut-off values for the discrimination of vertebral fractures were obtained by the calculation of sensitivities, specificities and the area under the curves obtained using age-adjusted receiver operating characteristics (ROC) analysis. Odds ratios and 95% confidence limits (CL) were calculated using age adjusted logistic analysis. The cut-off values for vertebral fractures, the area under the ROC curves (AUC) and odds ratios were 270.1 mg/cm3 (-2.2 SD, 66.6% of YAM), 0.689+/-0.025, 2.10 (1.63, 2.70) for BD, 104.8 mg/cm3 (-2.2 SD, 53.5% of YAM), 0.699+/-0.023, 2.17 (1.69, 2.77) for TBD and 192.8 mm3 (-1.9 SD, 59.8% of YAM), 0.631+/-0.028, 1.72 (1.34, 2.21) for pSSI, respectively. These findings suggest that ultradistal radius BMD measured using pQCT can be used to discriminate women with vertebral fractures. PMID- 11605741 TI - Bone metabolism and gonad function in male patients undergoing liver transplantation: a two-year longitudinal study. AB - Osteodystrophy is a major complication of end-stage liver disease, especially in postmenopausal women. Our aim in this study was to evaluate bone metabolism and gonad function in men undergoing orthotopic liver transplantation (OLTx). Twenty three consecutive men (mean age 48+/-13 years) evaluated for OLTx were studied, assessing the following parameters at baseline and 3, 6, 12 and 24 months after OLTx: lumbar spine (L2-L4) bone mineral density (BMD), parathyroid hormone (PTH), osteocalcin (BGP), 25-hydroxyvitamin D (25OHD), free testosterone (FT) and gonadotropins (FSH, LH). At baseline, 12 patients (52%) had a T-score <-2.5 SD and the mean BMD was 0.806+/-0.11 g/cm2 (range 0.470-1.045 g/cm2). The BMD was lower 3 months after OLTx and significantly higher 12 and 24 months after OLTx. A significant increase in serum BGP was observed at 6, 12 (p<0.05) and 24 months (p<0.005) after OLTx. The mean serum PTH level was 26.6+/-3.1 pg/ml at baseline and increased significantly at 12 and 24 months (to 49.4+/-9.9 and 61.2+/-10.1 pg/ml, respectively; p<0.05). 25OHD serum levels were low at baseline and returned to the normal range after 12 and 24 months (baseline, 8.73+/-1.54 ng/ ml; 12 months, 16.4+/-2.6 ng/ml; 24 months, 17.67+/-3.1 ng/ml; p<0.05). FT was significantly lower at baseline than in a group of 10 healthy controls (5.09+/ 10.99. vs 10.3+/-1.1 pg/ml; p<0.0001). After OLTx a significant increase in FT was recorded at 6, (p<0.05) and 24 months (p<0.005). FT was not correlated with BMD, however. After OLTx an increase in FSH and LH was observed (but failed to reach statistical significance) at 3 and 6 months, followed by a slight reduction at 12 and 24 months. Thus a high proportion of men with end-stage liver disease do have osteoporosis. After OLTx, an early recovery of gonad function is observed, followed by an increase in bone mass, which occurs from the sixth month onward. PMID- 11605742 TI - Reference data and predictive diagnostic models for calcaneus bone mineral density measured with single-energy X-ray absorptiometry in 7428 Chinese. AB - Calcaneus bone mineral density (BMD) of 7428 Chinese (4126 women, 3302 men; aged 22-94 years) was measured using single-energy X-ray absorptiometry (SXA). A reference range of calcaneus BMD values for healthy Chinese men and women was established and the usefulness of this method for screening and diagnosis in osteoporosis was evaluated. The peak BMD occurred at 20-24 years old and peak BMD in women was significantly lower than in men. BMD loss in the calcaneus started at the age of 35 years for women, and at 63 years in men. BMD loss rate was 1.2%/year for women and 0.56%/year for men after 50 years. The young normal reference for calcaneus BMD was 442.1+/-69.6 mg/cm2 for men and 388.3+/-61.7 mg/cm2 for women calculated from the mean BMD value of subjects whose age ranged from 20 to 49 years. The accumulated BMD loss in the calcaneus is similar to that of Ward's triangle. Multiple linear regression showed that both age and weight were important factors. The incidence of osteoporosis in older men and women (> or = 60 years) is 6.6% and 32.1% respectively. We conclude that calcaneus BMD measurement is useful and sensitive for the screening and diagnosis of osteoporosis. A predictive diagnostic model for osteoporosis based on the calcaneus was constructed using multiple linear regression and the WHO criteria for diagnosing osteoporosis can be applied to calcaneus BMD. PMID- 11605743 TI - Weight loss from maximum body weight among middle-aged and older white women and the risk of hip fracture: the NHANES I epidemiologic follow-up study. AB - Although weight loss increases bone loss and hip fracture risk in older women, little is known about the relation between weight loss in middle-aged women and subsequent hip fracture risk. The objective of this study was to determine the association between weight loss from reported maximum body weight in middle-aged and older women and the risk of hip fracture. Data were from a nationally representative sample of 2180 community-dwelling white women aged 50-74 years from the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey (NHEFS). In this prospective cohort study, incident hip fracture was ascertained during 22 years of follow-up. The adjusted relative risks associated with weight loss of 10% or more from maximum body weight were elevated for both middle-aged (RR 2.54; 95% CI 1.10-5.86) and older women (RR 2.04; 95% CI 1.37-3.04). For both ages combined, women in the lowest tertile of body mass index at maximum who lost 10% or more of weight had the highest risk of hip fracture (RR 2.37; 95% CI 1.32-4.27). Weight loss from maximum reported body weight in women aged 50-64 years and 65-74 years increased their risk of hip fracture, especially among those who were relatively thin. Weight loss of 10% or more from maximum weight among both middle-aged and older women is an important indicator of hip fracture risk. PMID- 11605744 TI - Bone-resorbing cytokines from peripheral blood mononuclear cells after hormone replacement therapy: a longitudinal study. AB - Conflicting results have been reported in several cross-sectional studies measuring cytokine production from adherent monocytes in pre- and postmenopausal women. Furthermore, the target cells for the action of estrogen are still debated. We therefore assessed in a longitudinal manner the cytokine production from different fractions of peripheral blood mononuclear cells (PBMC) cultured for 48 h. PBMC were obtained from 30 postmenopausal women before and after 6 months of hormone replacement therapy (HRT). Women were randomly allocated to two groups: an adherent PBMC group (n = 20) and a total PBMC group (n = 9). After 6 months of treatment, urinary pyridinoline levels were markedly decreased in both groups (353+/-24 vs 114+/-13 microg/mmol creatinine and 325+/-35 vs 164+/-31 microg/mmol creatinine respectively, p<0.01). Culture supernatants were assayed for interleukin 1beta (IL-1beta), interleukin 6 (IL-6), soluble IL-6 receptor (IL 6rs) and tumor necrosis factor alpha (TNF-alpha). In the adherent PBMC group, HRT induced a nonsignificant trend toward decreased levels of IL-1beta (35+/-10 vs 13+/-5 pg/ml), TNF-alpha (333+/-58 vs 222+/-30 pg/ml) and IL-6 (115+/-70 vs 17+/ 10 pg/ml). In contrast, in the total PBMC group, HRT induced a consistent and dramatic decrease in levels of IL-1beta (104+/-22 vs 25+/-8 pg/ml), IL-6 (5950+/ 1041 vs 1011+/-361 pg/ml), IL-6rs (148+/-33 vs 35+/-12 pg/ml) (p<0.01) and TNF alpha (1468+/-315 vs 585+/-207 pg/ml, p = 0.05). We then evaluated whether HRT had the same effect in vitro. Adherent or total PBMC of 8 postmenopausal women were cultured with or without 10(-8) M 17beta-estradiol or tibolone for 48 h. Production of IL-1beta, TNF-alpha, IL-6 and IL-6rs was not affected by the presence of 17beta-estradiol or tibolone in cultures of these cell fractions. In conclusion, our data indicate that non-adherent PBMC could mediate the response to HRT. HRT may exert its action indirectly via noncirculating cells, as suggested by the absence of an in vitro effect. PMID- 11605745 TI - Reproductive, menstrual and menopausal factors: which are associated with bone mineral density in early postmenopausal women? AB - The associations between a number of reproductive and menopausal factors and bone mineral density (BMD) were studied in a sample of early postmenopausal women. The study included 580 women aged 45-61 years who completed a risk factor questionnaire containing sections on obstetric and menstrual history. BMD measurements were taken at the anteroposterior (AP) spine, greater trochanter, femoral neck, total radius and whole body, along with whole body bone mineral content (BMC). In analyses adjusting for key confounders, number of pregnancies was more strongly associated with increased BMD than number of live births at all sites (p<0.05 at femoral neck and total radius), and menstrual years was more strongly associated with increased BMD than years since menopause (p<0.05 at all sites). Hysterectomized women had a significantly higher adjusted mean BMD than non-hysterectomized women at all sites (AP spine: 0.999 g/cm2 vs 0.941 g/cm2, p<0.001), although there were no significant differences in BMD between hysterectomized women who had a bilateral oophorectomy and those whose ovaries were preserved. Negative associations between the duration of hot flushes and BMD were statistically significant (p<0.05) at the three non-hip sites. In multiple regression analyses containing all reproductive terms, duration of hormone replacement therapy (HRT) use, menstrual years and hysterectomy status were significantly associated with BMD at all five sites, whilst oral contraceptive use before the age of 23 years was significantly associated with increased BMD at all sites except the total radius. Breastfeeding duration, the duration of oral contraceptive use and premenopausal amenorrhea were found to have no association with BMD. Results for whole body BMC were consistent with those for the five BMD sites, across all the variables considered here. These findings confirm the importance of HRT use and duration of menses as predictors of BMD, whilst the results for hysterectomy status and early oral contraceptive use require further consideration. PMID- 11605746 TI - Comparison of calcaneal ultrasound and DXA to assess the risk of corticosteroid induced osteoporosis: a cross-sectional study. AB - Patients on long-term oral corticosteroids have an increased risk of low bone mass and fragility fractures. Fracture risk rises soon after commencement of corticosteroid therapy and it is possible that these agents adversely influence bone architecture disproportionately to their effect on bone mass. The best means of assessing bone status in patients using corticosteroids remains uncertain, but quantitative ultrasound of the calcaneus may provide evidence of microarchitectural changes not detected by dual-energy X-ray absorptiometry (DXA). Patients with Crohn's disease have an increased risk of low bone mineral density (BMD), the etiology of which is multifactorial but includes corticosteroid use. We studied 118 consecutive patients with Crohn's disease, 21 of whom used continuous oral corticosteroids, 70 of whom were intermittent users, and 27 who had never used the drug. All patients received DXA of the lumbar spine, hip and calcaneus and quantitative ultrasound (QUS) of the calcaneus. The different techniques were compared using a femoral neck T-score < or = -1.5 as the threshold of corticosteroid-induced osteoporosis. When compared with the femoral neck T-score, there were no significant differences between the predictive values of lumbar spine DXA, calcaneal DXA or calcaneal QUS to identify low femoral neck BMD. However, the absolute T-score required to give similar discriminatory capacity to femoral neck T-score varied substantially (T= -0.81 to -1.5) between the different measurement techniques and sites. PMID- 11605747 TI - Acceptance of hip protectors for hip fracture prevention in nursing homes. AB - In order to prevent hip fractures 548 fall-prone senior citizens living in 20 nursing homes participated in a randomized controlled trial of hip protectors. One hundred and sixty-four were randomly selected into the control group and 384 into the intervention group. Of the patients in the intervention group 138 (35.9%) wore the protector throughout the whole 10 months of the study's duration, 124 (32.3%) quit wearing the protectors after an initial wearing period and 122 (31.8%) refused to wear them at all. The regular wearers had the protector on during an average of roughly 12 hours a day, so they were protected for 50% of their exposure time (including at night). Fifty-nine percent of the drop-outs stopped wearing the protectors in the first two study months, mostly for non-medical reasons. Calculation by a forecasting model showed that those senior citizens who were initially prepared to wear the protector tended to be those who were physically restricted. PMID- 11605749 TI - Double molecular imprinting--a new sensor concept for improving selectivity in the detection of polycyclic aromatic hydrocarbons (PAHs) in water. AB - Highly selective and robust polymer coatings for the detection of polycyclic aromatic hydrocarbons (PAHs) in liquid media have been generated by use of an innovative method of molecular imprinting. By imprinting with two different templates, the selectivity of the polyurethanes used was increased by creating diffusion pathways and molecular cavities. Analyte inclusion was detected both by fluorescence and by use of mass-sensitive transducers. It is possible to optimize layers in respect of the extraction of two different analytes or to achieve extremely high selectivity for a distinct analyte. In this way coatings can be tuned to the lean chrysene, e.g., and it is enriched by a factor of approximately fifty compared with the more quadratic pyrene with the same number of aromatic rings. Measurements of PAHs in water were also performed with a quartz crystal microbalance, which shows that humic acids are not incorporated by the layers and thus do not influence the fluorescence properties of the layers. PMID- 11605748 TI - Correct regimen of fluoride and calcium reduces the risk of vertebral fractures in postmenopausal osteoporosis. PMID- 11605750 TI - Multidimensional on-line solid-phase extraction (SPE) using restricted access materials (RAM) in combination with molecular imprinted polymers (MIP). AB - A novel, multidimensional SPE sample-processing platform for complex fluids, which relies on the combination of small LC columns packed with restricted access materials (RAM) and molecular imprinted polymers (MIP) is described. It is called the Six-S ProcEdure (Six-SPE). Six-SPE involves a size-selective sample separation step followed by a solvent-switch. Six-SPE efficiently removes interfering matrix components of complex aqueous samples and creates optimal conditions for selective recognition, i.e. binding of the imprinted target analyte(s). A Six-SPE analysis cycle consists of four distinct steps: 1. separation of a given sample (e.g. plasma, urine, saliva, milk, etc.) by adsorptive extraction (e.g. reversed-phase partitioning) of low molecular weight components on to the stationary phase of a RAM column and simultaneous size exclusion, i.e. quantitative disposal of macromolecular matrix constituents to waste; 2. desorption and transfer of the extract from the RAM column on to a series-connected MIP column using a pure organic mobile phase (e.g. acetonitrile) [solvent switch]; 3. molecular recognition, i.e. selective binding of the target analyte(s) by a tailor-made MIP column; and 4. desorption and transfer of the analyte fraction on to a series-connected separation (e.g. HPLC) and/or detection system (e.g. UV, FD, MS). As a first application we coupled the Six-SPE platform to a conventional HPLC system for on-line analysis of the analgesic drug Tramadol in human plasma using LiChrospher ADS RP-18 as a RAM precolumn for the fractionation step in the first and second chromatographic dimension and a Tramadol imprinted polymer for the molecular recognition step, i.e. third chromatographic dimension. PMID- 11605751 TI - Tribute to J.F.K. Huber. PMID- 11605752 TI - Modification of the surface of integrated optical wave-guide sensors for immunosensor applications. AB - Methods have been developed which enable attachment amino and epoxy groups to the surface of integrated optical wave-guide sensors for immunosensor applications. The SiO2-TiO2 surfaces were modified by use of the trifunctional silane reagents gamma-aminopropyltriethoxysilane (APTS) and gamma-glycidoxypropyltrimethoxysilane (GOPS) in organic and/or in inorganic phases. Silanization methods were optimized taking into consideration the concentration of silane reagent used and the temperature and time of reaction. To evaluate the layers formed, immobilization experiments were undertaken on the modified surfaces using the bovine serum albumin (BSA)-anti-BSA IgG antibody model molecule pair. The regenerability of the sensitized surfaces was also studied. PMID- 11605753 TI - Partial-filling micellar electrokinetic chromatography and non-aqueous capillary electrophoresis for the analysis of selected agrochemicals. AB - Selected agrochemicals (s-triazines and phenoxy acids) have been investigated with partial-filling micellar electrokinetic chromatography (PFMEKC) and non aqueous capillary electrophoresis (NACE). Because these two techniques are compatible for coupling of capillary electrophoresis with mass spectrometry, different conditions affecting the separation efficiency (reproducibility, method linearity) were systematically tested, and the results were compared with those from classical MEKC. The conditions tested included buffer molarity, pH, the concentrations of the organic modifier and surfactant, the applied voltage, the injection time of the sample, and the length of the partial-filling plug. The respective limits of detection (LOD) using UV-detection were determined. Reduction of the electrophoretic raw data using the mobility scale transformation (micro-scale) improved qualitative comparison of the electropherograms and the reproducibility of quantitative data (integrated peak area) thus extending this data treatment from CZE to other endoosmotic flow-driven CE-techniques such as PFMEKC and NACE. PMID- 11605754 TI - Interference of sulfate(VI) with poly(pyrrole) electrochemistry. AB - The effect of the SO4(2-) anion on both potentiometry and voltammetry with poly(pyrrole) films doped with chloride or hexacyanoferrate(II/III) ions has been studied and compared with the responses obtained in KCl solutions. Strong interference was observed when the SO4(2-) to Cl- molar ratio was 1:1000, leading to a decrease in polymer film electroactivity at higher sulfate concentrations. The effect is attributed to incorporation of the divalent anion into the polymer film structure, a hypothesis supported by analysis of the composition of the elemental film. PMID- 11605755 TI - Comparison of denuder and impinger sampling for determination of gaseous toluene diisocyanate (TDI). AB - An air-sampling method employing denuders coated inside with a chemisorptive stationary phase has been evaluated for analysis of the hazardous gaseous 2,4 and 2,6 isomers of toluene diisocyanate (TDI). The denuder stationary phase consisted of polydimethylsiloxane (SE-30) to which dibutylamine (DBA) was added as a reagent for derivatization of TDI. The accuracy and precision of sampling by means of denuders were shown to differ only slightly from those of the established impinger method. The denuder method was, however, also shown to be suitable for long-term measurements (up to 8 h). The limit of determination (LOD) of the method, including LC-APCI-MS-MS analysis, was found to be 1.9 microg m(-3) and 1.2 microg m(-3) for 2,4- and 2,6-TDI, respectively, for short-term measurements (15 min). Significant lower LOD was obtained for long-term measurements. This is well below the Occupational Safety and Health Administration (OSHA) 8-h TWA (time-weighted average) exposure limit, which is 40 microg m(-3) for the sum of the TDI isomers. The denuder method was also found to be robust and easy to handle. The samplers can be prepared several days before sampling with no loss in performance. The contents of denuders should, on the other hand, be extracted immediately after sampling to prevent degradation of the isocyanate derivatives formed. PMID- 11605756 TI - Internet-assisted exercises in structural analysis. AB - In this report we describe our experience in the analytical chemistry curriculum of teaching spectrometer principles and preparing spectroscopy laboratory exercises by means of virtual instruments. The benefits of the intensified preparation of laboratory exercises by virtual instruments will be evaluated with respect to the subsequent handling of real instruments. The utilization of in house electronic media with Internet resources for elucidation and verification of a structural assignment will also be considered. PMID- 11605757 TI - Fluorimetric determination of copper(II) in aqueous solution using lucifer yellow CH as selective metal reagent. AB - Lucifer yellow CH is shown to be a highly selective fluorescent reagent for the determination of Cu(III) in the microg L(-1) concentration range. The fluorophore is statically quenched by Cu(II); the carbohydrazide group was assigned as the complexing part of the dye molecule. A total range of Cu(II) determination from 0.06 mg L(-1) (1 micromol L(-1)) to 6.3 mg L(-2) (100 micromol L(-1)) with a limit of detection of 0.019 mg L(-1) (0.3 micromol L(-1)) was obtained, along with surprisingly high selectivity. There was no interference from alkaline and earth alkaline metal ions. The cross sensitivity to heavy metal ions was evaluated by the separate solution method and by competitive binding experiments. Calibration plots are shown for Cu(II) determination at different pH and the dissociation constant was determined. The application of the reagent was demonstrated by the determination of the Cu(II) content of tap water samples. PMID- 11605758 TI - Determination of traces of 237Np in environmental samples by ICP-MS after separation using TOA extraction chromatography. AB - A simple, rapid, cost-efficient, and robust method for separation of 237Np with an extraction chromatographic column (TOA: tri-n-octylamine on Teflon powder) is outlined in detail and further improved for direct ICP-MS analysis. The column efficiently retained 237Np in 2 mol L(-1) HNO3 medium and all of the 237Np was easily eluted with 0.02 mol L(-1) oxalic acid in 0.16 mol L(-1) HNO3 at 95 degrees C. The separated solutions were free from most matrix elements and were aspirated into the ICP-MS directly. The decontamination factor for 238U is more than 10(4). The instrumental detection limit for 237Np was 0.46 pg mL(-1), which corresponds to 1.2 x 10(-5) Bq mL(-1). The method is more rapid than traditional radiometric techniques. It is also considered to be more suitable for environmental monitoring than existing methods based on TOA. PMID- 11605759 TI - Clarification by TEM and SIMS of abnormal Ti depth distribution in chemical solution-deposited SrTiO3/La0.5Sr0.5CoO3. AB - A chemical solution-deposited multilayer system of SrTiO3 ("STO")/La0.5Sr0.5CoO3 ("LSCO") on a platinized wafer with a layer sequence Pt/TiO2/SiO2/Si(bulk) has been investigated by dynamic SIMS (secondary ion mass spectroscopy) and TEM (transmission electron microscopy); element determination was performed with EELS (electron energy-loss spectroscopy). The STO layer is intended to serve as a dielectric layer for a microelectronic capacitor; the conducting LSCO layer is a buffer layer intended to eliminate fatigue effects which usually occur at the STO/Pt interface. The SIMS depth profiles obtained for the main components revealed intense diffusion processes which must have occurred during the deposition/crystallization processes. Ti is found to diffuse from the (insulating) STO layer into the conductive LSCO layer where a region of constant concentration is observable. TEM-EELS experiments showed that these Ti plateaus are caused by precipitates approximately 20-80 nm in diameter. PMID- 11605760 TI - Chiral discrimination of limonene by use of beta-cyclodextrin-coated quartz crystal-microbalances (QCMs) and data evaluation by artificial neuronal networks. AB - The enantiomeric composition of the chiral flavoring agent limonene was analyzed by means of a quartz-crystal microbalance (QCM) sensor. As chiral selectors three different modified beta-cyclodextrins were investigated. The selector molecules were applied as mixtures in different polysiloxane matrices. The chiral separation factors alpha for limonene obtained at 30 degrees C by gas chromatography and by use of the QCM sensor were comparable. Evaluation of sensor data was performed by use of an artificial neuronal network (ANN); this enabled prediction of the enantiomeric composition of the gas mixtures. PMID- 11605761 TI - Determination of benzylpenicillin, oxacillin, cloxacillin, and dicloxacillin in cows' milk by ion-pair high-performance liquid chromatography after precolumn derivatization. AB - A high-performance liquid-chromatographic method has been developed for the determination of five penicillin compounds (benzylpenicillin, phenoxymethylpenicillin, oxacillin, cloxacillin, and dicloxacillin) at trace levels in commercially available milk samples. This method comprises extraction of the lipids with ethyl acetate, clean-up and concentration on a C-18 solid phase extraction column, and derivatization with 1,2,4-triazole and mercury(II) chloride solution, pH 8, at 65 degrees C for 10 min. The derivatized compounds are eluted from a C-2 column with a mobile phase containing acetonitrile and phosphate buffer loaded with sodium thiosulfate and tetrabutylammonium hydrogen sulfate as ion-pairing reagent. The limit of determination was found to be 4 microg L(-1) milk for benzylpenicillin and 10 microg L(-1) for the others. This meets EU criteria according to decision No. 93/256/EEC. PMID- 11605762 TI - Improvement of the HPLC analysis of anthocyanins in red wines by use of recently developed columns. AB - Comparison of the separation performance of five newly developed pH-stable HPLC columns is described for the analysis of anthocyanins in red wines. Separation of twenty anthocyanins in a single run is described using the most appropriate method. PMID- 11605763 TI - Determination of flavonoids and stilbenes in red wine and related biological products by HPLC and HPLC-ESI-MS-MS. AB - To investigate probable health benefits of flavonoids and stilbenes in red wine a new reversed-phase (RP) high-performance liquid-chromatographic (HPLC) method with enhanced separation efficiency and improved selectivity, sensitivity, and speed has been established for determination of the flavonoids quercetin, myricetin and kaempferol and the stilbenes cis- and trans-resveratrol, in a single run . UV-absorbance, fluorescence (FLD), and mass-spectrometric (MS) detection were also evaluated. UV-absorbance detection at 320 nm for stilbenes and 377 nm for flavonoids enables their determination up to the nanogram range with a linearity of R2>0.9999 (linear range 50 ng mL(-1)-50 microg mL(-1)). Calculated values of average recoveries were between 95 and 105% for all analytes. For resveratrol, fluorescence detection was highly selective and twice as sensitive as UV detection, and linearity was satisfactory (R2>0.9996; linear range see UV detection). For the detection of the hydrophilic glycosidic compounds piceid and rutin, which are coeluted with other hydrophilic ingredients, the validated RP HPLC system was coupled to a quadrupole ion-trap mass-spectrometer (MS) via an electrospray interface (ESI) with 25% ammonia solution as sheath liquid. MS detection was, highly linear (R2>0.9878; linear range 50 ng mL(-1)-50 microg mL(-1)) for all investigated analytes and the limits of detection were in the low nanogram range. Compared with UV detection MS detection resulted in a 200% increase in signal intensity for myricetin and 400% increases for quercetin and kaempferol, but equal signal intensity for resveratrol. Calculated values of average recoveries were 102% for myricetin and 79% for piceid. Collision induced dissociation (CID) was also used to obtain characteristic fragmentation fingerprints to facilitate qualitative and quantitative analysis even in complex matrices. Finally, this hyphenated HPLC-ESI MS method was highly suitable and an essential improvement compared with UV- and fluorescence detection. PMID- 11605764 TI - Identification of plant and animal glues in museum objects by GC-MS, after catalytic hydrolysis of the proteins by the use of a cation exchanger, with simultaneous separation from the carbohydrates. AB - A method is described which enables the group-separation of proteinaceous binding media from vegetable glues (carbohydrates), and simultaneous hydrolysis of the proteins in mixtures of both. The mixtures of the binders are suspended in aqueous-ethanolic solvent with the H+ form of a strong cation exchanger and treated at elevated temperature in sealed vials. The polypeptides are cleaved by H+-catalysed hydrolysis. On abstraction the amino acids are transformed into the ammonium ions by the protons, and the cations are adsorbed by the exchanger resin. The amino acids are removed from solution in this way, thus suppressing interfering reactions with other binders, e.g. humin formation with carbohydrates. Clear and colourless solutions were obtained with all mixtures of vegetable and animal glues. Two fractions can be obtained after separation of the solid resin from the liquid supernatant - the resin fraction with the adsorbed amino acids, and the aqueous-ethanolic solution with the carbohydrates. In each of these fractions the two classes of binder can be identified separately by GC MS; this avoids the occurrence of unresolved GC peaks and superimposed mass spectra. The method has been used to identify the binder found between fabric layers of a Burgundian liturgical vestment of the Order of the Golden Fleece from the first half of the 15th century, the Cope of the Virgin Mary. With the aid of the GC pattern obtained, and the mass spectra of the main peaks, which were identified as glucopyranose anomers, the binding medium was identified as starch. PMID- 11605766 TI - The interaction between copper and coronary risk indicators. AB - We studied the effects of external copper exposure on plasma copper, serum lipids, lipoproteins and apolipoproteins in workers who have excessive contact with copper. Fifty-eight healthy Turkish males who were working in the copper processing industry and 33 control subjects were examined. Copper concentration was measured by flame atomic absorption spectrometry, lipid and lipoprotein levels were detected by spectrophotometry and apolipoproteins were measured with a nephelometer. There was no significant difference in plasma copper between the workers and the controls. However, in the worker group, the mean levels of TC, LDL-C, apoAI, apoB and Lp (a) were significantly higher while the mean level of HDL-C was significantly lower than that of the controls. In addition, there was a significant positive correlation between plasma copper and LDL-C only in the workers group. Our findings suggest that excessive contact with copper may contribute to coronary risk factors. PMID- 11605765 TI - Usefulness of carperitide for the treatment of refractory heart failure due to severe acute myocardial infarction. AB - Carperitide (synthetic atrial natriuretic peptide) is a newly developed drug for the treatment of heart failure. Although this drug has been used for various types of heart failure, it remains unknown whether it has additive effects on hemodynamic parameters or renal excretory function during intensive treatment for acute refractory heart failure. We have examined the cardiorenal and hormonal effects of carperitide (0.05-0.10 microg / min / kg) in 9 patients (mean age: 67+/-8 years) with severe heart failure complicated with acute myocardial infarction, in which a range of intensive treatments have already been started. Hemodynamic parameters were determined before and 4, 24 and 48 hours after initiation of carperitide. Pulmonary capillary wedge pressure (mean+/-SD) had decreased dramatically from 21+/-6 to 11+/-5 mmHg (p<0.01) 4 hours after the treatment without significant renal effects. Heart rate and systemic blood pressure were not significantly changed. These beneficial effects were maintained for at least 24 hours. Plasma aldosterone levels fell significantly in response to the drug (from 148+/-68 to 56+/-29 pg / ml; p<0.05). However, mean hourly urine output remained unchanged after carperitide. In conclusion, intravenous infusion of carperitide promptly and persistently reduces left ventricular filling pressure without diuresis, hypotension, reflex tachycardia, or neurohormonal activation in patients with refractory heart failure due to severe acute myocardial infarction. PMID- 11605767 TI - Evaluation of signal-averaged electrocardiography for clinical diagnosis in arrhythmogenic right ventricular dysplasia. AB - Arrhythmogenic right ventricular dysplasia (ARVD) is a heart muscle disorder of unknown etiology that is characterized pathologically by fibrofatty replacement of the right ventricular myocardium. We investigated the relationship between the electrocardiogram (ECG) appearances and signal-averaged ECG (SAECG) in 7 cases with ARVD, and evaluated the usefulness of SAECG as a screening test to detect patients with ARVD. Compared with the conventional 12-lead ECG, the SAECG detects abnormalities at a higher rate in ARVD patients (57% versus 86%). SAECG was more sensitive as a screening test to detect patients with ARVD than 12-lead ECG. PMID- 11605768 TI - Age and sex differences in the P-wave signal-averaged electrocardiogram in a Japanese study population. AB - Normal P wave signal-averaged electrocardiogram (SAE) values were determined in 120 healthy Japanese adults (56 men, 64 women), aged 44.5+/-10.2 years (mean+/ SD). The P wave trigger method was used with a Fukuda FDX6500 recorder. We used bipolar Frank leads (X,Y,Z), and recordings were made with forward and backward digital Butterworth filters [40 Hz (18 dB / oct) - 300 Hz (12 dB / oct)]. The recordings were taken for the following five parameters: forward and backward filtered P wave duration [fPd (F); tPd (B)]; bidirectionally corrected fPd [tPd (C)]; and 20 ms of the terminal portions of voltage at forward and backward filtering (RMS20). Overall, fPd (F) was 117.8-136.4 ms, fPd (B) 116.4-134.4 ms, fPd (C) 97.4-115.2 ms, RMS20 (F) 1.6-3.6 microV, and RMS20 (B) was 2.2-5.4 microV. Between the sexes, there were significant differences in fPd (F) (p<0.001) and fPd (B) (p<0.01) and in RMS20 (F) (p<0.05) and RMS20 (B) (p<0.05). Weak positive correlations were observed between fPd (F) and body surface area, fPd (F) and age, fPd (B) and body surface area, fPd (B) and age, fPd (C) and body surface area, and fPd (C) and age. There was no evident correlation, however, between either forward or backward RMS20 and body surface area or between forward or backward RMS20 and age. Differences in the normal P wave values between the sexes and age groups were evaluated in this study. PMID- 11605769 TI - Transdermal estrogen replacement therapy and vasomotor response. AB - Previous studies have shown that acute administration of estrogen improves endothelial function in postmenopausal women, but there has been little investigation of the chronic effects of transdermal estrogen replacement therapy. The present study assessed the effect of transdermal estrogen replacement therapy (0.025 mg / day for 4 weeks, the normally applied dosage in Japan) on flow mediated endothelium-dependent vasodilation of the brachial artery (B-mode ultrasound) and forearm cutaneous blood flow (laser Doppler flowmetry), and plasma hormonal and lipid levels in 12 normolipidemic postmenopausal women. Neither resting vascular diameter, flow-mediated vasodilation, nor time to peak vasodilation, showed significant changes after the estrogen therapy. In contrast, resting forearm cutaneous blood flow decreased significantly after the estrogen therapy. The time to the peak reactive hyperemia in the forearm skin was slightly shortened, and the % change in reactive hyperemia decreased slightly after the therapy. These findings seemed to reflect the inhibition of hot-flush symptoms associated with vasomotor abnormalities in cutaneous tissue. The lack of improvement in flow-mediated vasodilation of the brachial artery despite the inhibitory effect on cutaneous vasomotor abnormalities may be related to the low plasma estradiol concentration obtained with the present transdermal therapy (42.4+/-15.2 pg / ml), a finding which supports the estrogen threshold hypothesis in hormone replacement therapy. PMID- 11605770 TI - Calcium-activated potassium channels mask vascular dysfunction associated with oxidized LDL exposure in rabbit aorta. AB - Endothelium-dependent vasodilation is impaired in atherosclerosis. Oxidized low density lipoprotein (ox-LDL) plays an important role, possibly through alterations in G-protein activation. We examined the effect of acute exposure to ox-LDL on the dilator responses of isolated rabbit aorta segments. We sought also to evaluate the specificity of this dysfunction for dilator stimuli that traditionally operate through a Gi-protein mechanism. Aortic segments were prepared for measurement of isometric tension. After contraction with prostaglandin F2alpha, relaxation to thrombin, adenosine diphosphate (ADP), or the endothelium-independent agonists, sodium nitroprusside (SNP) or papaverine was examined. Maximal relaxation to thrombin was impaired in the presence of ox LDL (17.7+/-3.7% p<0.05) compared to control (no LDL) (52.6+/-4.0%). Ox-LDL did not affect maximal relaxation to ADP or SNP. However, in the presence of charybdotoxin (CHTX: calcium-activated potassium channel inhibitor) ox-LDL impaired relaxation to ADP (17.4+/-3.2%). CHTX did not affect control (no LDL) responses to ADP (69.6+/-5.0%) or relaxation to thrombin or papaverine. In conclusion, ox-LDL impairs relaxation to thrombin, but in the case of ADP, calcium-activated potassium channels compensate to maintain this relaxation. PMID- 11605771 TI - Coenzyme Q10 exogenous administration attenuates cold stress cardiac injury. AB - The influence of coenzyme Q10 (CoQ10) in cold stress test (-15 degrees C for 4 hours) cardiac functional impairment was studied in isolated isovolumic heart of control rats (C; n=12) and of placebo (P; n=11) and treated rats (CoQ10; n=10). In addition, electron microscopic evaluation of left ventricular (LV) slices (n=3 in each group) allowed us to analyze the myocardial ultrastructure. Maximal values of developed pressure (DPmax) were similarly decreased in cold stressed animals (C=129+/-3.9 mmHg; P=106+/-6.7 mmHg; CoQ10=91+/-3.9 mmHg); however, volume-induced enhancement of pressure generation (slope of DP volume relations: C=0.248+/-0.0203 mmHg / microl; P=0.2831+/-0.0187 mmHg / microl; CoQ10=0.2387 ( 0.0225 mmHg / microl; p > 0.05), and the duration of systole (C=80+/-1.6 ms; P=78+/-1.3 ms; CoQ10=80+/-2.7 ms) were not altered. Myocardial relaxation, evaluated by the relaxation constant (C=39+/-1.9 ms; P=42+/-3.4 ms; CoQ10=51+/ 6.0 ms), as well as resting stress / strain relations were unaffected by cold stress. Myocardial samples showed that pretreatment with CoQ10 attenuates myofibrillar and mitochondrial lesions, and prevents mitochondrial fractional area increase (P: 53.11%>CoQ10: 38.78%=C: 33.87%; p< 0.005) indicating that the exogenous administration of CoQ10 can reduce cold stress myocardial injury. PMID- 11605772 TI - Enhancement of endothelial nitric oxide production by chenodeoxycholic acids in patients with hepatobiliary diseases. AB - The purpose of this study was to clarify whether physiological concentrations of bile acids could affect endothelial nitric oxide production. We investigated the relationships between clinical concentrations of individual bile acids observed in patients with hepatobiliary diseases and endothelial nitric oxide production induced by each bile acid. Fifteen serum bile acids were measured using high performance liquid chromatography combined with enzymatic fluorometry in 8 patients with liver cirrhosis, obstructive jaundice, and 8 healthy subjects. The effects of individual bile acids on nitric oxide production were examined in human umbilical endothelial cells by measuring the concentration of NO2- in the cultured medium. NO release in the blood was also determined by measuring the NO2 /NO3- concentration in these patients. In patients with hepatobiliary diseases, the plasma concentrations of chenodeoxycholic acid, ursodeoxycholic acid and cholic acid (free acid, taurine and glycine conjugates) were markedly elevated. Incubation of cells with chenodeoxycholic acid and deoxycholic acid (free acid, taurine and glycine conjugates) enhanced NO2- production in a concentration dependent manner, while cholic acid (free and its conjugates) did not. The effects of individual bile acids on nitric oxide production were additive. Patients with liver cirrhosis and obstructive jaundice had higher plasma levels of NO2-/NO3- levels than the control subjects. These results suggest that increased plasma concentrations of chenodeoxycholic acid (free, taurine and glycine conjugates) in patients with hepatobiliary diseases may induce endothelial nitric oxide production. Thus, nitric oxide production induced by bile acids may be involved in the pathogenesis of circulatory abnormalities in patients with liver diseases. PMID- 11605773 TI - Reversible left ventricular systolic dysfunction--reversibility of coronary microvascular abnormality. AB - Reversible left ventricular wall motion abnormalities mimicking myocardial infarction have been reported in patients with a noncardiac illness. Their coronary angiograms do not demonstrate organic stenosis or epicardial coronary vasospasm. In this article, two cases of reversible left ventricular contraction abnormality are presented. Electrocardiography showed deep inverted T waves in precordial leads, and the echocardiography revealed diffuse akinesis of the apical region in the acute phase. Coronary angiography showed no significant stenosis or occlusion in either patient. Thallium scintigraphy showed no defect, while the metaiodobenzylguanidine scintigraphy demonstrated significant defects in the apex. The relative coronary flow reserve ratio, measured with an intracoronary Doppler flow wire, was significantly reduced in both patients. Myocardial contrast echocardiography revealed a reversible perfusion defect in the apex in the acute phase in case 2. Transiently impaired coronary microcirculation was thought to be involved in the pathogenesis of the reversible left ventricular dysfunction observed in these patients. PMID- 11605775 TI - Myocardial ischemia induced by anomalous aortic origin of the right coronary artery in a patient with atrial septal defect. AB - A 27-year-old woman with atrial septal defect (ASD) and a sensation of squeezing in the anterior chest by effort was admitted to our hospital. In addition to the ASD, the coronary angiogram showed an abnormal anomalous position of the right coronary artery. Exercise thallium (Tl)-201 cardiac scintigram with an electrocardiogram clearly detected myocardial ischemia in the inferior area. In the operative findings, the orifice of the right coronary artery was positioned high above the commissure between the right and left sinuses of Valsalva, and it ran between the aorta and pulmonary trunk. Considering myocardial ischemia possibly caused by the anomalous origin of the right coronary artery, a coronary artery bypass graft (CABG) was simultaneously performed to the right coronary artery with direct closure of ASD. The myocardial ischemic finding in the inferior area disappeared after the operation, and she was also relieved from the chest pain. In view of these findings, we suggest that an active combination treatment such as CABG and ASD closure is highly successful in a patient with a threatening coronary anomaly and congenital heart disease. PMID- 11605774 TI - Acute myocardial infarction showing total occlusion of right coronary artery and thrombus formation of left anterior descending artery. AB - A 33-year-old Japanese man had an attack of chest pain associated with ST-segment elevation in the inferolateral leads on his electrocardiogram. Emergency coronary angiography showed total obstruction in the mid right coronary artery (RCA) and a movable thrombus in the proximal left anterior descending artery (LAD). We performed emergency percutaneous transluminal coronary angioplasty (PTCA) for the RCA lesion. The operation was successful and we then conducted intracoronary thrombolysis (ICT) with tisokinase 6,400,000 IU for the LAD thrombus. Its size was reduced by ICT. He had an uneventful hospital course. After 1 month, repeat coronary angiography showed no significant stenosis in the RCA nor thrombus in the LAD. A coronary spasm provocation test was performed using acetylcholine. Coronary spasm in the LAD was induced by an intracoronary injection of 100 microg acetylcholine. In this case, we observed a unique condition suggesting simultaneous double coronary artery occlusion. PMID- 11605776 TI - Ventricular outflow tract obstruction secondary to leiomyosarcoma of the right ventricle. AB - Primary leiomyosarcomas of the heart, particularly those affecting the right ventricle, are uncommon. We report the case of a 70-year-old Belgian woman presenting with the symptoms of progressive exertional dyspnea and left-sided pleuritic pain. A leiomyosarcoma which originated from the right lateral ventricle wall, causing pulmonary outflow obstruction, was diagnosed. Pathology revealed a neoplasm with a myxoid stroma, high mitotic activity and nuclei expressing atypia. Immunohistochemical staining was positive for vimentine and desmin. Seven months after complete surgical resection the tumor relapsed. This case demonstrates the poor outcome, the high relapse rate and inefficiency of treatment associated with primary cardiac leiomyosarcomas. The current literature regarding the incidence, diagnostic techniques, treatment strategies and survival rates of this rare but terminal disease is reviewed. PMID- 11605777 TI - Metastatic synovial sarcoma of the left ventricle. AB - A metastatic synovial sarcoma of the left ventricle is described. A 26-year-old Japanese woman underwent resection of a synovial sarcoma of the right thigh 8 years prior to admission, which was followed by multiple surgical procedures for pulmonary metastasectomy. Echocardiography demonstrated obstruction of the outflow tract of the left ventricle caused by a metastatic tumor, which was surgically resected on the day of admission. The histologic characteristics of the cardiac tumor were identical to those of the pulmonary metastases. Additional cardiac metastasectomy was performed 9 months later. She complained of dyspnea on exertion 8 months after the second cardiac metastasectomy due to recurrence in the heart. Radiotherapy with LINAC (a total dose: 50 Gy) diminished the size of the tumor temporarily. The patient died 20 months after the initial cardiac metastasectomy. PMID- 11605778 TI - Development of community- and state-based immunization registries. CDC response to a report from the National Vaccine Advisory Committee. AB - Immunization registries are confidential, population-based computerized systems that contain information regarding children's vaccinations. Registries provide a critical tool for increasing and sustaining vaccination coverage. A national health objective for 2010 is to increase to 95% the proportion of children aged <6 years who participate in fully operational population-based immunization registries. According to 2000 data, 24% of U.S. children are participating in population-based immunization registries. In 1998, to facilitate community- and state-based immunization registry development in the United States, the National Vaccine Advisory Committee (NVAC) launched the Initiative on Immunization Registries. Through public hearings and parent focus groups, NVAC identified four concerns that needed to be addressed to increase registry participation: a) protecting each person's privacy and the confidentiality of registry information; b) ensuring participation of vaccination providers and recipients; c) overcoming technical and operational challenges; and d) determining resources needed to develop and maintain immunization registries. In January 1999, NVAC approved the report Development of Community- and State-Based Immunization Registries (available at ; accessed July 30, 2001). The following report summarizes NVAC's recommendations and describes CDC's National Immunization Program activities in response to NVAC's recommendations. PMID- 11605779 TI - Renal hemodynamic effect of tacrolimus in renal transplanted children. AB - Like cyclosporine (CsA), tacrolimus acts through the inhibition of renal phosphatase calcineurin. CsA induces reversible vasoconstriction, causing a transient reduction of renal plasma flow in patients with renal transplantation. The aim of this study was to determine the effect of tacrolimus on renal plasma flow in renal transplanted children. Eight children were studied with a median age of 10.6 years, a mean glomerular filtration rate (inulin clearance) of 55 ml/min per 1.73 m2 (range 29-95), and a mean follow-up after transplantation of 5.6 months. Effective renal plasma flow (ERPF) was studied in each patient for 12 h after tacrolimus administration. Clearances were obtained every 2 h for 12 h after drug administration. Tacrolimus pharmacokinetics was also studied. Average ERPF at the start of the test was 289 ml/min per 1.73 m2 (range 177-404, SD +/- 106). Variation in each of the 2-h periods was not significant, although a mild reduction of plasma flow was observed in three of the eight children. No correlation was found between tacrolimus AUC, peak, or trough levels and renal blood flow variations. Despite the relatively small number of patients studied, these data suggest that, in vivo, a therapeutic oral dose of tacrolimus is not necessarily followed by a significant reduction of ERPF in renal transplanted children. PMID- 11605780 TI - Use of rapamycin in a transplant patient who developed cyclosporin neurotoxicity. AB - We describe the case of a paediatric kidney transplant patient who developed cyclosporin neurotoxicity on day 7 post-transplant. Consequently, her cyclosporin was stopped and she was commenced on rapamycin. Over the next 3 weeks her creatinine remained elevated and she had several episodes of biopsy proven rejection, despite increasing the initial dose of rapamycin by tenfold. Her whole blood rapamycin levels also remained well below the target range of 10-20 ng/ml. On day 38 post-transplant, the decision was made to add tacrolimus to her immunosuppression. At the same time, phenytoin, which had been commenced during her episode of cyclosporin neurotoxicity, was withdrawn. After this point her rapamycin blood levels rapidly increased to within the therapeutic range and she improved clinically. We propose that phenytoin, as a p450 cytochrome enzyme inducer, increased the metabolism of rapamycin in this patient and hence decreased the initial therapeutic effectiveness of this drug. PMID- 11605781 TI - Maintenance intravenous iron therapy in pediatric hemodialysis patients. AB - Iron supplementation is required for optimal response to erythropoietin (EPO) in hemodialysis patients. This is due to blood lost in the dialysis tubing after dialysis and the increased demand for iron by EPO therapy. Maintenance intravenous (IV) iron was administered according to a standardized protocol to pediatric patients on hemodialysis in our institution. The effect of this protocol on EPO dose, iron indices, anemia, and medication costs was evaluated. Data on two groups of patients were retrieved from the health records. Group 1 (n=14) consisted of patients treated in the 18 months prior to the protocol. These patients received oral iron supplements and occasional IV iron. Group 2 (n=5) consisted of all patients treated with the IV iron protocol. There was no difference in clinical characteristics and mean values for monthly hemoglobin, serum iron, ferritin, and transferrin saturation between groups. The dose of EPO was significantly reduced in group 2 compared with group 1 (193.9 +/- 121.4 vs. 73.9 +/- 39.0 units/kg per week, P<0.05). Medication costs were reduced by 26% in group 2. No significant adverse events were seen. Maintenance IV iron reduced the dose of EPO required to maintain blood hemoglobin levels. Our results also suggest that maintenance IV iron is a more-economic method of iron supplementation for pediatric hemodialysis patients. PMID- 11605782 TI - Treatment of severe theophylline toxicity with hemodialysis in a preterm neonate. AB - Theophylline, a drug frequently used to treat apnea of prematurity, has a prolonged half-life of 30 h in neonates. Severe overdoses of theophylline have an associated 10% mortality and significant morbidity. We describe a 1,220-g neonate who developed status epilepticus due to a theophylline overdose. Hemodialysis was instituted to increase elimination of theophylline. The patient tolerated the procedure without complication. The half-life of theophylline was 0.7 h during dialysis. No reported therapies used in neonates have achieved this magnitude of clearance. In fact, the clearance of theophylline in this neonate approached that obtained with hemoperfusion, the standard therapy for theophylline overdose in adult patients. This case demonstrates that hemodialysis is a safe and effective means of enhancing theophylline elimination for neonatal theophylline overdose. PMID- 11605783 TI - Gastrostomy tube leak in a patient receiving peritoneal dialysis. AB - Aggressive nutritional support is imperative to ensure an optimal quality of life in the management of children with end stage renal disease (ESRD). Supplemental enteral feeds using a gastrostomy tube (G-tube) are commonly used for nutritional support to overcome the barrier posed by anorexia. Some of the reported complications of G-tube feeds in children simultaneously receiving peritoneal dialysis include G-tube exit site infection with concomitant peritonitis and G tube obstruction. We are reporting our experience in managing an 8-year-old Caucasian male with ESRD who, while receiving peritoneal dialysis and G-tube feeds, developed medically intractable peritonitis due to separation of the stomach wall from the anterior abdominal wall, resulting in peritoneal contamination with gastric contents. This complication, which has not previously been reported in patients receiving peritoneal dialysis, had devastating consequences, culminating in the death of our patient. PMID- 11605784 TI - Abnormal DNA-binding of transcription factors in minimal change nephrotic syndrome. AB - The activation of transcription factors such as nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) plays an important role in regulating the expression of target genes, including those for cytokines involved in pathogenesis of minimal change nephrotic syndrome (MCNS). The therapeutic effects of glucocorticoids depend on the glucocorticoid receptor (GR) acting on gene transcription and interacting with certain transcription factors. To explore the role of transcription factors in the pathogenesis of MCNS and the therapeutic effects of glucocorticoids, we examined the DNA-binding abilities of NF-kappaB, AP-1, and GR in peripheral blood mononuclear cells (PBMC) from 6 children with MCNS and 6 healthy controls by electrophoretic mobility shift assay (EMSA). NF kappaB and AP-1 DNA-binding abilities were significantly increased both at baseline and after stimulation by phorbol 12-myristate 13-acetate (TPA) in PBMC from MCNS patients compared with controls, but declined to normal levels after treatment with dexamethasone (DEX). GR DNA-binding abilities were significantly reduced at baseline and after treatment with TPA, but were enhanced markedly by DEX. There were strong correlations between urinary protein and the baseline DNA binding ability of NF-kappaB or AP-1, or GR. These results suggested that the abnormal activation of NF-kappaB and AP-1 and the reduction of GR DNA-binding abilities may be involved in the pathogenesis of MCNS. Inhibition of NF-kappaB and AP-1 and enhancement of GR DNA-binding abilities by DEX may form the molecular basis of the effects of glucocorticoids in MCNS. PMID- 11605785 TI - Ifosfamide nephrotoxicity in pediatric cancer patients. AB - The renal functions in pediatric cancer patients who received ifosfamide (IFO) treatment were evaluated and the risk factors related to IFO nephrotoxicity were determined. The medical records of all children treated with IFO were reviewed, and 62 with normal renal function before IFO treatment were selected. Nephrotoxicity was diagnosed by measuring urine beta2-microglobulin and glucose, and serum phosphate, bicarbonate, and creatinine. Forty-eight (77.4%) had a history of previous cisplatin treatment. Nephrotoxicity was detected in 20 patients (32.3%). beta2-Microglobulinuria was observed in all 20, hypophosphatemia in 10 (16.1%), hypocarbia in 2 (3.2%), glucosuria in 5 (8.1%), and decreased creatinine clearance in 7 (11.3%). The cumulative dose of IFO and a history of previous cisplatin therapy were related to nephrotoxicity. Among the 20 patients with nephrotoxicity, the median cumulative dose of IFO in patients with a low (<500 mg/m2) and high (>500 mg/m2) cumulative dose of previous cisplatin was 80 g/m2 (73-102 g/m2) and 45 g/m2 (11-76 g/m2), respectively. Most of the nephrotoxicity persisted after cessation of IFO treatment. In conclusion, close monitoring of IFO nephrotoxicity should be started earlier in patients with high-dose cisplatin pretreatment. Tubular proteinuria, as indicated by beta2 microglobulinuria, was the most-sensitive marker for IFO nephrotoxicity. Long term follow-up study for reversibility of IFO nephrotoxicity is in progress. PMID- 11605786 TI - Prognostic value of the acute DMSA scan in children with first urinary tract infection. AB - We attempted to verify in a group of 101 children with first urinary tract infection whether it was possible to identify groups of patients with different risks of developing renal scarring by taking into account both the extent of kidney involvement documented in the acute phase of infection using a dimercaptosuccinic acid (DMSA) scan, and the presence or absence of vesicoureteral reflux (VUR). The frequency of persistent lesions in kidneys with mild-moderate lesions (less than 50% of kidney involvement) in the presence of VUR or in non-refluxing kidneys was similar (P=0.1447), while the frequency of persistent lesions in kidneys with severe lesions in the presence of VUR was significantly higher than the frequency of persistent lesions in non-refluxing kidneys (P=0.0089). The extent of kidney involvement and the presence of VUR make possible the identification of different categories of risk of scarring: in the "low risk group" (normal kidney with/without VUR) the risk of scarring is 0%; in the "intermediate risk group" (mild lesions with/without VUR; extensive lesions without VUR) the risk of scarring is between 14% and 38%, while in the "high risk group" (extensive lesions with VUR) the risk of scarring is 88%. Quantifying the risk of scarring could help in planning the treatment or in modifying the later strategy. PMID- 11605787 TI - Plasma homocysteine concentration in children with chronic renal failure. AB - Hyperhomocysteinemia, a risk factor for vascular disease, is commonly found in adult patients with end-stage renal disease. Major determinants of elevated plasma homocysteine levels in these patients include deficiencies in folate and vitamin B12, methylenetetrahydrofolate reductase (MTHFR) genotype and renal function. Little information is available for children with chronic renal failure (CRF). The prevalence and the factors that affect plasma homocysteine concentration were determined in children. Twenty-nine children with various degrees of CRF (15 were dialyzed, 14 were not dialyzed) were compared with 57 age and sex-matched healthy children. Homocysteine concentrations were higher in patients than controls (17.3 micromol/l vs 6.8 micromol/l, P<0.0001) and hyperhomocysteinemia (>95th percentile for controls: 14.0 micromol/l) was seen in 62.0% of patients and 5.2% of controls. Folate concentrations were lower in patients (9.9 nmol/l) than controls (13.5 nmol/l), P<0.01. Vitamin B12 was similar in patients (322 pmol/l) and controls (284 pmol/l). Dialyzed patients have a higher prevalence of hyperhomocysteinemia than nondialyzed patients (87% vs 35%). Dialyzed patients with MTHFR mutation have higher plasma homocysteine (28.5 micromol/l) than nondialyzed patients with the mutation (10.7 micromol/l), P<0.002. In our study, differences between controls and patients in plasma homocysteine concentrations are observed when age is greater then 92 months, folate less than 21.6 nmol/l and vitamin B12 less than 522 pmol/l. Our study shows that hyperhomocysteinemia is common in children with CRF and is associated with low folate and normal vitamin B12 status, compared to normal children. Among the patients, the dialyzed patients with the MTHFR mutation are particularly at risk for hyperhomocysteinemia. Further studies are needed to investigate therapeutic interventions and the potential link with vascular complications in these patients. PMID- 11605788 TI - Ambulatory blood pressure monitoring after recovery from hemolytic uremic syndrome. AB - The outcome of acute renal failure due to diarrhea-associated hemolytic uremic syndrome (D+ HUS) is generally predicted to be good. However, there are only a few long-term observations with detailed reports on long-term sequelae. Specifically, adequate long-term blood pressure (BP) evaluations are scarce. The present study evaluated BP in pediatric patients after childhood D+ HUS. The study group comprised 28 patients (20 males) aged 6-23.5 years (median 10.1 years). All patients had a history of D+ HUS at a median age of 1.1 years (range 0.5-6 years). Based on the duration of oliguria and/or anuria, the primary disease was classified as mild (n=6), moderate (n=6), or severe (n=16). The BP in these patients was studied at a median time of 8.4 years (range 2.3-22.9 years) after manifestation of D+ HUS by means of office BP measurements and 24-h ambulatory BP monitoring (ABPM) using a Spacelabs 90207 oscillometric monitor. Measurements were compared with normal values of published standards for healthy children and adolescents. Conventional office BP measurements were above the 95th percentile in 1 patient. By ABPM, 2 patients were diagnosed to have mean systolic daytime and nighttime values in the hypertensive range, and systolic and diastolic hypertension was confirmed in the first patient. All these patients had a severe form of D+ HUS in the past. By applying ABPM, BP anomalies were detected in 5 additional patients. Elevated systolic BP loads were found in 4 patients, and daytime systolic and diastolic hypertension in the other 1. At the time of the study, 2 of them were classified as "recovered." The late outcome of D+ HUS may be worse than anticipated. BP anomalies as long-term sequelae of D+ HUS could be identified by ABPM but not by office BP measurements. These findings may represent an isolated sign of residual renal disturbance. PMID- 11605789 TI - Methylprednisolone pulse therapy in Japanese children with severe lupus nephritis. AB - Six Japanese children with severe lupus nephritis received prompt initiation of methylprednisolone pulse therapy (MPT). After three courses of MPT, oral prednisolone combined with a 12-week course of oral cyclophosphamide was given and prednisolone was tapered. At presentation, urine protein excretion and histological indices of the mean activity index and the mean chronicity index in the patients were 2.2 +/- 1.5 g/day, 10.3 +/- 2.0, and 2.8 +/- 1.2, respectively. Urine protein excretion and the activity index decreased significantly at the second renal biopsies obtained at a mean interval of 8 months after the first [0.1 +/- 0.1 g/day and 3.5 +/- 1.4 (P<0.05), respectively], while the chronicity index did not change. At the latest observation (mean interval 53 months), all showed clinical and serological improvement. Complete remission was achieved in two patients, and no patient showed renal impairment. Although this case series is without controls, our treatment protocol may be of benefit to Japanese children with severe lupus nephritis. PMID- 11605790 TI - Impaired urinary water excretion in a three-generation family. AB - We report on a three-generation family (daughter, mother, and maternal grandmother) with a syndrome of inappropriate secretion of antidiuretic hormone (SIADH)-like condition in the absence of inappropriate ADH secretion. In the three females, a water load test showed severely reduced urinary water excretion, with the ratio of urine volume to the loaded water being 10-33% (normal value: 70.2 +/- 7.8%). Urinary AQP2 excretion was normal, as was the DNA sequence of AVPR2 and AQP2. The results suggest the presence of a new dominantly inherited disorder for tubular water resorption. PMID- 11605791 TI - Pathogenesis of Shiga toxin-induced hemolytic uremic syndrome. AB - The term hemolytic uremic syndrome (HUS) was first introduced to describe a heterogeneous group of diseases characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Substantial progress has been made in our understanding of the etiology and pathogenesis of HUS. This article reviews some of the classic and new concepts related to the pathogenesis of Shiga toxin (Stx)-HUS and discusses their clinical relevance for the diagnosis and treatment of this syndrome. Infection with Stx-producing bacteria can induce HUS after a prodromal illness with or without diarrhea. Stx-induced renal endothelial injury is the primary pathogenic event. However, Stx also damages mesangial cells, as well as glomerular and renal tubular epithelial cells. Young children are at greatest risk for Stx-HUS because they express high levels of Stx receptors in renal glomeruli. Older children and adults express lower levels of glomerular Stx receptors and may develop Stx-HUS whenever the combined effects of lipopolysaccharide and cytokines upregulate the expression of Stx receptors and sensitize glomerular endothelial cells to Stx-induced injury, activate the coagulation-fibrinolytic system, and induce endothelial injury. Chemokine receptors and cytokines released by inflammatory cells (i.e., monocyte chemoattractant protein-1, interleukin-6, interleukin-8,) or injured endothelial cells (i.e., basic fibrobast growth factor) may play roles in this process. Measurement of the activity of a von Willebrand factor protease in plasma may help distinguish patients with thrombotic thrombocytopenic purpura from those with Stx-HUS. PMID- 11605792 TI - Streptococcus pneumoniae-induced hemolytic uremic syndrome: report of a further case. PMID- 11605793 TI - Reliability (and uncertainty) of radionuclide dose coefficients. PMID- 11605794 TI - Reliability of the ICRP's dose coefficients for members of the public. 1. Sources of uncertainty in the biokinetic models. AB - During the decade following the Chernobyl accident, the International Commission on Radiological Protection (ICRP) developed dose coefficients (doses per unit intake) for ingestion or inhalation of radionuclides by members of the public. The level of uncertainty in those coefficients varies considerably from one radionuclide to another, due largely to differences in the level of understanding of the biological behaviour of different elements in the human body. This paper is the first in a series that examines the sources and extent of uncertainties in the ICRP's biokinetic and dosimetric models for members of the public and the dose coefficients derived from those models. The present paper describes the different types of information generally used to develop biokinetic models for radionuclides, the main sources of uncertainty associated with each type of information, and the approach used in subsequent papers in this series to quantify the uncertainties in biokinetic and dosimetric estimates. PMID- 11605796 TI - Fit of second order thermoluminescence glow peaks using the logistic distribution function. AB - A new thermoluminescence glow curve deconvolution (GCD) function is introduced which accurately describes second order thermoluminescence (TL) curves. The logistic asymmetric (LA) statistical probability function is used with the function variables being the maximum peak intensity (Im), the temperature of the maximum peak intensity (Tm) and the LA width parameter a2. An analytical expression is derived from which the activation energy E can be calculated as a function of Tm and the LA width parameter a2 with an accuracy of 2% or better. The accuracy of the fit was tested for E values ranging from 0.7 to 2.5 eV, for s values between 10(5) and 10(25) s(-1), and for trap occupation numbers no/N between 1 and 10(-6). The goodness of fit of the logistic asymmetric function is described by the Figure of Merit (FOM) which is found to be of the order of 10( 2). Preliminary results show that the GCD described here can easily be extended to the description of general order TL glow curves by varying the asymmetry parameter of the logistic asymmetric function. It is concluded that the TL kinetic analysis of first, second and general order TL glow curves can be performed with high accuracy and speed by using commercially available statistical packages that incorporate the Weibull and logistic asymmetric functions. PMID- 11605795 TI - Age-dependent protection quantities for external photon irradiation. AB - The age-dependent conversion coefficients of the protection quantities, the equivalent dose and the effective dose defined by the International Commission on Radiological Protection (ICRP), are obtained. A Monte Carlo computer code and the age-dependent hermaphrodite mathematical phantoms of six age groups: newborn, 1, 5, 10, 15 years old and adult are used for the evaluation. Twenty-three photon source energies from 10 keV to 10 MeV and six kinds of irradiation geometries: AP, PA, RLAT, LLAT, ROT, and ISO are chosen in the calculation. The evaluated conversion coefficients for the adult are compared with those in ICRP Publication 74 with good agreement. The conversion coefficients of the equivalent dose and the effective dose increase while the age of the phantom decreases, but with some exceptions for the AP irradiation geometry under certain conditions. PMID- 11605797 TI - Characterisation of laboratory-produced CANDU-like workplace neutron fields. AB - Two neutron fields were produced in the Neutron Irradiation Facility (NIF) at the Chalk River Laboratories of the Atomic Energy of Canada Ltd. by directing (d,D) neutrons from a 150 kV neutron generator through a specially designed moderator assembly. Bonner sphere and proton recoil spectrometry systems were used to characterise these fields to determine whether they were CANDU-like*, i.e. whether they resembled neutron fields found in workplaces around pressurised heavy-water moderated power reactors such as CANDU reactors. Similarities were found between the distributions in energy of neutron fluence and ambient dose equivalent of the neutron fields produced in the NIF and those measured previously in power plants. In addition, there was agreement between theoretical (Monte Carlo) data and measured data, thereby validating continued use of Monte Carlo modelling for field characterisations in the NIF. The CANDU-like fields add to the repertoire of neutron fields available in the NIF and are expected to be useful for evaluating neutron dosemeters. PMID- 11605799 TI - A fence line noble gas monitoring system for nuclear power plants. AB - A noble gas monitoring system has been installed at Ontario Power Generation's Pickering Nuclear Generating Station (PNGS) near Toronto, Canada. This monitoring system allows a direct measure of air kerma from external radiation instead of calculating this based on plant emission data and meteorological models. This has resulted in a reduction in the reported effective dose from external radiation by a factor of at least ten. The system consists of nine self-contained units, each with a 7.6 cm x 7.6 cm (3 inch x 3 inch) NaI(TI) detector that is calibrated for air kerma. The 512-channel gamma ray spectral information is downloaded daily from each unit to a central computer where the data are stored and processed. A spectral stripping procedure is used to remove natural background variations from the spectral windows used to monitor xenon-133 (133Xe), xenon-135 (135Xe), argon 41 (41Ar), and skyshine radiation from the use of radiography sources. Typical monthly minimum detection limits in air kerma are 0.3 nGy for 133Xe, 0.7 nGy for 35Xe, 3 nGy for 41Ar and 2 nGy for skyshine radiation. Based on 9 months of continuous operation, the annualised air kerma due to 133Xe, 135Xe and 41Ar and skyshine radiation were 7 nGy, 8 nGy, 26 nGy and 107 nGy respectively. PMID- 11605798 TI - Uncertainty in particulate deposition for 1 microm AMAD particles in an adult lung model. AB - The ICRP 66 lung model may be used to determine dose estimates for members of the public via the inhalation pathway. A significant source of uncertainty in internal dosimetric modelling is due to particulate deposition in regions of the respiratory tract. Uncertainties in estimates of particulate deposition are present because model input parameters have their own inherent variability. These sources of uncertainty need to be examined in an effort to understand better model processes and to estimate better the doses received by individuals exposed through the inhalation pathway. An improved understanding of the uncertainty in particulate deposition will further guide research efforts and improve our ability to quantify internal dose estimates. The ICRP 66 lung deposition model is most sensitive to breathing rate when 1 microm AMAD particles are inhaled by members of the public. Uncertainties in deposition fractions are shown to span an order of magnitude with their distributions varying by gender for a particular lung region. The largest fractional deposition occurs in the deep lung alveolar and extrathoracic regions. PMID- 11605800 TI - Entrance surface, organ and effective doses for some of the patients undergoing different types of X ray procedures in Bangladesh. AB - Entrance surface doses (ESDs) were measured for the most common types of X ray procedures, such as chest PA, lumber spine AP, lumber spine lateral, skull AP, skull lateral and pelvis AP in four major hospitals of Dhaka, the capital city of Bangladesh. Organ/tissue doses for 29 organs/tissues and effective doses for the patients were also calculated using the entrance surface dose as the input quantity. Organ/tissue doses and effective doses were calculated by using XDOSE software based on the Monte Carlo computation method. It was observed that the fluctuation of the entrance surface dose was too large. The ratio of maximum and minimum ESD values ranged from 4.8 to 35.9. Consequently, variation of organ doses was large even in the same type of X ray examination and in the same facility. Mean effective doses for the above mentioned X ray procedures were also determined and compared with the effective doses of some other countries. In most cases effective doses measured for the different types of X ray procedures were found to be lower than the effective doses of some other countries. PMID- 11605802 TI - Transmutation of commercial waste should precede geological storage. PMID- 11605801 TI - Radiological significance of building bricks in Pakistan. AB - Baked clay bricks samples were collected from both urban and rural areas of the North West Frontier Province of Pakistan and natural radioactivity due to 40K, 226Ra and 232Th has been measured in these samples. The specific absorbed dose rates due to natural radioactivity emanating from the walls, floors and ceilings of the typical model rooms made of these building bricks have been calculated applying the mesh size adaptive volume integral methodology. The occupancy factor, representing the weighted average of all the population in the country, was taken to be 0.3 in this study. The values of estimated annual effective dose rates for whole body were found to be 0.38 and 0.35 mSv.y(-1) for the two types of model rooms. These values are smaller than those predicted by UNSCEAR for normal background areas. Thus the building bricks analysed in this study do not pose any significant health problem to the population. PMID- 11605803 TI - Measurements in an aircraft during an intense solar flare, ground level event 60, on April 15, 2001. PMID- 11605804 TI - Current status of human parasitic infections in Taiwan. AB - The eradication of the 2 mosquito-borne parasitic diseases, malaria and lymphatic filariasis, is one of the greatest achievements of the parasite control campaigns in Taiwan. Most of the soil-transmitted nematode infections, with the exception of pinworm infection, are currently well controlled and limited to some aboriginal areas. Food-borne parasitic zoonosis such as infections with Angiostrongylus cantonensis, Clonorchis sinensis, and Taenia saginata asiatica are not rare, but the former is seasonal and the latter 2 are ethnically and geographically associated. Intestinal protozoal infections with Giardia lamblia and Cryptosporidium parvum are at low levels but may be widely distributed. Opportunistic protozoal infections among patients with acquired immunodeficiency syndrome, which included amebic colitis, Pneumocystis carinii pneumonia, and cerebral toxoplasmosis, are becoming increasingly important. The rapid increase in international travel and the introduction of large numbers of foreign workers from other countries in Southeast Asia may change the epidemiological patterns of parasitic infections in Taiwan. PMID- 11605805 TI - Factors affecting the recovery of Legionella pneumophila serogroup 1 from cooling tower water systems. AB - A total of 20 water samples collected from the cooling towers at 20 different sites were analyzed under various conditions for the presence of Legionella pneumophila serogroup 1. A comparative assessment was performed to evaluate methods of sample collection (spray drops, beneath water at 20- to 40-cm depth, and water outlet), concentration (filtration and centrifugation), acid buffer treatment (no treatment, treatment for 3, 5, and 15 min), and CO2 incubation or candle jar incubation. The reduction in viable colonies and false negative rate were compared for the different factors. No quantitative differences in isolation of L. pneumophila serogroup 1 was found among samples collected from water at a depth of 20 to 40 cm, from water outlet, and from spray drops. Treatment in an acid buffer for 15 min significantly reduced the recovery rate, with a reduction in bacterial counts of about 40%, compared with a 3-min (12%) or a 5-min (25%) treatment. Acid buffer treatment for 3 or 5 min reduced the overgrowth of commensal flora. This treatment improved the selectivity but not the sensitivity for L. pneumophila serogroup 1. Colonies on plates incubated at 37 degrees C in a candle jar with a humidified atmosphere grew better than those incubated at 35 degrees C with 5% CO2. These results demonstrate that methods of sample collection, concentration, and incubation, but not collection site, can affect the isolation rate for L. pneumophila serogroup 1. PMID- 11605806 TI - Duration of enterovirus shedding in stool. AB - Excretion of enterovirus (EV) may persist for months after an EV infection; the exact duration of excretion, however, is not yet known. Twelve children who were infected with EV between September 1998 and June 1999 were enrolled into this study. The patients included 4 boys and 8 girls, aged from 1 month to 5 years. Six patients were asked to join this virus isolation program, and the other 6 were followed-up regularly. Only 2 of the patients were infected with EV 71. To delineate the duration of EV shedding in each case, throat swabs for virus isolation were performed every 1 or 2 weeks for at least 1 month, and stools were analyzed for at least 2 months following the same schedule. After the infection, EV was identifiable in the throat in 4 patients for 1 to 2 weeks. Excretion of EV through stool was evidenced for up to 7 weeks in 6 patients, 8 weeks in 3, and 11 weeks in 1. In the 2 patients who failed to show up for follow-up visits from the 7th week, excretion of EV through stool was recorded for at least 7 weeks. Different serotypes of EV could be isolated from the same patient who was not experiencing febrile illness in 2 instances in a series of virus cultures. Coexistence of vaccine poliovirus and non-polio EV, both isolated from stool, was evidenced in 2 patients. Results from this study suggest that EV may not be identified from the throat 2 weeks after the infection, but its excretion through stool can persist for up to 11 weeks. This study also demonstrated that subclinical EV coinfection could occur, and that live vaccine poliovirus did not interfere with the invasion of other non-polio EV. PMID- 11605807 TI - Factors accounting for misidentification of Candida species. AB - From April 15 through June 15, 1999, a total of 660 yeast isolates were collected from 22 hospitals in Taiwan to investigate factors determining the accuracy of yeast identification. The germ tube test was the method most frequently used by hospitals for yeast identification, followed by the API-32C, cornmeal agar window test, and assimilation method. All of the submitted isolates were re-speciated in the National Health Research Institutes laboratory. The frequencies of inconsistent identification of isolates between hospitals and the National Health Research Institutes laboratory varied with the location and the type of hospital. The sensitivity and specificity of the germ tube test were 95% and 98.6%, respectively. This study showed that hospitals using the germ tube test as the first step in yeast identification had fewer inconsistent identifications of isolates than those using other methods. The VITEK Yeast Biochemical Card and API 32C had a sensitivity of 92.6% and 98.3%, respectively. No single method consistently identified all yeast isolates. Thus, every laboratory should have at least 2 methods available for yeast identification. PMID- 11605808 TI - In vitro activity of moxifloxacin against common clinical bacterial isolates in Taiwan. AB - The in vitro antimicrobial activities of moxifloxacin were compared with 7 other antimicrobial agents. A total of 707 isolates of 11 common pathogenic bacteria were collected from the National Taiwan University Hospital; antimicrobial activities against these isolates were evaluated by minimum inhibitory concentration using an agar-dilution method. Most common pathogenic bacteria were susceptible to moxifloxacin, including methicillin-susceptible and -resistant Staphylococcus aureus, methicillin-susceptible and -resistant Staphylococcus epidermidis, Streptococcus pneumoniae, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, and Stenotrophomonas maltophilia. For many of these bacterial species, moxifloxacin was the most active antimicrobial agent compared with the third- and fourth- generation cephalosporins, carbapenems, monobactam, and other quinolones. Some strains of methicillin-resistant S. aureus and methicillin-resistant S. epidermidis demonstrated very low levels of minimum inhibitory concentration for moxifloxacin, suggesting the potential application of the drug to treat some drug-resistant gram-positive bacterial infections. Moxifloxacin was less active against P. aeruginosa, but was more active against S. maltophilia when compared with other fluoroquinolones. In conclusion, moxifloxacin exhibits an increased potency against gram-positive bacteria as compared with other tested antimicrobial agents, while preserving excellent activity against gram-negative bacteria. The drug appears to be a promising agent expressing activity against a wide variety of bacteria in Taiwan. PMID- 11605809 TI - Comparative study of ceftibuten and cefixime in the treatment of complicated urinary tract infections. AB - Between August 1996 and May 1998, a total of 62 patients who had complicated urinary tract infections treated at the Taipei Veterans General Hospital were enrolled into this study. This prospective, randomized, open-labeled trial aimed at comparing the efficacy and safety of ceftibuten and cefixime, prescribed each at a dose of 200 mg twice daily, in treating complicated urinary tract infection. Seventeen patients were later excluded from the analysis because of resistant pathogens (7 patients), uncomplicated urinary tract infection (6), initial culture negative for bacteria (3), and infective endocarditis (1). The remaining 45 patients were categorized into ceftibuten (n=23; mean age, 71.3 years) and cefixime (n=22; mean age, 62.8 years) treatment groups. No significant difference in demographic data and clinical characteristics was found between the 2 groups. The clinical efficacy rate (78.3% vs 77.3%, p=0.9) and bacteriological eradication rate (52.2% vs 63.6%, p=0.08) were similar between the ceftibuten and the cefixime group. Adverse effects caused by ceftibuten treatment included diarrhea and slight elevation of the serum level of liver transaminase in 2 (6.5%) patients. Those caused by cefixime treatment included slight elevation of serum level of liver transaminase in 2 (6.5%) patients and skin rash in 1 (3.2%) patient. All of these adverse effects resolved quickly after the regimen had been completed, and no patient discontinued the regimen because of the adverse effects. The results suggest that oral administration of ceftibuten 200 mg twice daily is as effective and safe as oral administration of cefixime 200 mg twice daily in the treatment of complicated urinary tract infections. PMID- 11605810 TI - Pathogens in the middle ear effusion of children with persistent otitis media: implications of drug resistance and complications. AB - Acute otitis media (AOM) is the most common disease for which pediatricians prescribe antimicrobial agents. Middle ear fluid were collected from 243 children with AOM that failed to respond to a previous course of antimicrobial therapy and who had then received myringotomy from September 1997 through August 1999. Bacterial cultures were done and antimicrobial susceptibilities were analyzed. Streptococcus pneumoniae (21.8%) was the most common causative organism, followed by Haemophilus influenzae (10.2%), Staphylococcus aureus (7%), and Pseudomonas aeruginosa (1.8%), while Moraxella catarrhalis (0.7%) and group A beta-hemolytic streptococcus (0.2%) were rarely isolated. In patients whose condition failed to improve after a course of antibiotic treatment, drug resistance became a serious problem. Fourteen percent of the patients in this series had complications, which included recurrent AOM, persistent middle ear effusion necessitating ventilation tube insertion, hearing impairment, mastoiditis, meningitis, chronic otitis media, brain abscess, and sepsis. Possible risk factors such as young age, male sex, underlying diseases, and a culture of S. pneumoniae or H. influenzae were not significantly associated with an increased incidence of complications. More stringent diagnosis and the correct choice of antibiotic treatment combined with the introduction of potential virus and bacterial vaccines are promising ways to reduce the morbidity of AOM in children. PMID- 11605811 TI - Characteristics of group A streptococcal bacteremia with comparison between children and adults. AB - This retrospective study aimed to compare the characteristics of group A streptococcal bacteremia in children and adults. A total of 76 (12 children and 64 adults) patients with group A streptococcal bacteremia treated from October 1995 through September 2000 at the Linko Chang Gung Memorial Hospital were included. The mean age was 47.6 years (range, 12 days-90 years). Forty-four (57.9%) patients had predisposing medical conditions. Malignant cancer (23.7%) and diabetes (22.4%) were the 2 most common conditions, which occurred only in adults. Two (16.7%) children had chickenpox associated with secondary group A streptococcal bacteremia. Skin and soft tissue infection (60.5%) was the most common clinical manifestation. The mortality rate related to group A streptococcal bacteremia was 25%. Twelve patients met the criteria of streptococcal toxic shock syndrome and 6 (50%) were children (p<0.05). Despite immediate and aggressive treatment, mortality due to streptococcal toxic shock syndrome was 66.7%. The incidence of streptococcal toxic shock syndrome was much higher in children (50%) than in adults (9.4%). Early diagnosis of invasive group A streptococcal infections and streptococcal toxic shock syndrome requires awareness of the presentations and a high level of suspicion. For fulminant group A streptococcal infection, a combination of a beta-lactam antibiotic plus clindamycin and/or adjuvant therapy with intravenous immunoglobulin is recommended. PMID- 11605812 TI - Klebsiella pneumoniae psoas abscess: predominance in diabetic patients and grave prognosis in gas-forming cases. AB - Seven cases of psoas abscess caused by Klebsiella pneumoniae were observed at the National Cheng Kung University Hospital within a period of 4.5 years. These cases constituted 25% of a total 28 episodes of non-tuberculous psoas abscess, ranking second to those caused by Staphylococcus aureus (8 cases). Eight cases of psoas abscess caused by K. pneumoniae were identified from Medline, and 5 of which were reported from Taiwan. Of these 8 cases, 1 neonatal case was excluded, and the remaining 7 adult cases were combined with the 7 cases in this series for analysis. The mean age was 53.8 years, and diabetes mellitus was the most common underlying disease. Fever and pain on the flank and back area were the common findings. The interval between the onset of symptoms and diagnosis ranged from 1 to 60 days. The most common sites of concurrent infection were the urinary tract (6 cases; 43%) and bone (3 cases; 21%). All patients received percutaneous or surgical drainage in addition to antibiotic treatment. Gas formation was present in 5 of the 12 patients recorded, and 4 of them died during hospitalization. Only 1 patient had a metastatic infection with osteomyelitis of the left radius and right humerus; he had experienced 5 episodes of recurrent K. pneumoniae infections in different sites. We concluded that K. pneumoniae should be considered as an important endemic pathogen of psoas abscess in diabetics in Taiwan. The high mortality rate in the gas-forming cases should also be highlighted. Early recognition, empiric antimicrobial coverage for K. pneumoniae, and aggressive drainage or debridement are indicated in these patients. PMID- 11605813 TI - Clinical characteristics of Behcet's disease in southern Taiwan. AB - A total of 22 patients were found to have Behcet's disease during the period from 1991 through 1999 in the Chang Gung Memorial Hospital in Kaohsiung, Taiwan. Diagnosis of Behcet's disease was made according to the criteria proposed by the International Study Group for Behcet's Disease. Oral lesions were found in all patients, ocular lesions in 55% of patients, genital lesions in 55%, skin lesions in 90.9%, pathergy reaction in 22.7%, arthritis in 31.8%, gastrointestinal involvement in 31.8%, involvement of the central nervous system in 27.2%, and thrombophlebitis in 18%. The mean age was 35.5 years with a biphasic age distribution. The clinical characteristics of patients in this series were different from patients in other Asian countries, which suggests that geographic and genetic factors are important in the pathogenesis of the disease. PMID- 11605814 TI - Clinical characteristics of juvenile rheumatoid arthritis in Taiwan. AB - This study aimed to investigate the clinical features of juvenile rheumatoid arthritis among Taiwan children. The medical records of 228 children who had juvenile rheumatoid arthritis treated in the Chang Gung Medical Center in Taiwan from 1978 through 1998 were retrospectively reviewed. A total of 146 boys and 82 girls (M:F ratio, 1.8:1) were included in this study. Clinical and laboratory data of these patients were collected from medical charts. Pauciarticular onset (56%) was the most common type of juvenile rheumatoid arthritis, followed by polyarticular (36%) and systemic (8%) type. The positive rate for rheumatoid factor, human leukocyte antigen B27, and antinuclear antibody were 9.2%, 55.2%, and 16.2%, respectively. Uveitis was observed in 5.7% of patients. Compared with previous reports in other regions and populations, remarkably different features of juvenile rheumatoid arthritis were found in this study, which included a higher prevalence among boys than girls, a high positive rate of human leukocyte antigen B27, and a low rate of uveitis. PMID- 11605815 TI - Characteristics of patients with Burkholderia cepacia bacteremia. AB - Burkholderia cepacia has become an important pathogen of infections in immunocompromised and nosocomial patients. The characteristics of 42 episodes of B. cepacia bacteremia in 40 patients admitted to the Taipei Veterans General Hospital between January 1997 and December 1999 were retrospectively analyzed. Factors that adversely influenced the mortality rate included respiratory failure, an unknown infection source, a period in an intensive care unit, and shock. Most of the patients had serious underlying diseases, such as diabetes mellitus, malignancy, congestive heart failure, and chronic obstructive pulmonary disease. The mean time for a positive blood culture was 45 days after admission. The overall mortality rate was 28.6% (12/42), and 44.4% (12/27) of all deaths were directly related to B. cepacia bacteremia. Polymicrobial bacteremia was found in 5 patients. Ceftazidime was the most effective antimicrobial agent in vitro, whereas chloramphenicol, imipenem, and trimethoprim/sulfamethoxazole were less effective alternatives. Appropriate antibiotic therapy was given to 30 patients, most of whom responded to the therapy except for 5 who died despite receiving appropriate treatment. Although B. cepacia infection develops in a relatively small proportion of hospitalized individuals, it has a major impact on morbidity and mortality. In view of the fact that B. cepacia develops resistance to a wide range of antimicrobial agents, ceftazidime and/or trimethoprim/sulfamethoxazole should be the drug of choice for empiric therapy. PMID- 11605816 TI - Childhood serum sickness: a case report. AB - Childhood serum sickness is a rare allergic disease that follows the administration of a foreign antigenic material, most commonly caused by injecting a protein or haptenic drug. The disease is a type III hypersensitivity reaction mediated by deposits of circulating immune complexes in small vessels, which leads to complement activation and subsequent inflammation. The clinical features are fever, cutaneous eruptions, lymphadenopathy, arthralgias, albuminuria, and nephritis. Serum sickness is an acute self-limited disease. We report a 3-year old child who presented with fever and a rash; an invasive bacterial infection was strongly suspected. He was therefore given penicillin and gentamicin and responded well. At day 4 after admission, he developed a serum sickness reaction and showed symptoms of arthralgias, generalized edema, purpura, and gross hematuria. The white blood cell count was 12 190/mm3 with 7% eosinophils. Urinalysis revealed red blood cell above 100 per high power field, white blood cell 10 to 15 per high power field, and proteinuria. The antibiotics were discontinued and hydrocortisone (20 mg/kg/d), diphenhydramine HCl (4 mg/kg/d), aspirin (66 mg/kg/d) was administered, plus 1 dose of epinephrine (0.01 mL/kg) administered intramuscularly. On day 7, the 3rd day after withholding antibiotics, his condition dramatically improved. The clinical symptoms resolved progressively and his urinalysis returned to normal. PMID- 11605817 TI - Guidelines for the use of antiretroviral agents in HIV infections in Taiwan. PMID- 11605818 TI - The role of adenosine in neurogenic syncope: much ado about something? PMID- 11605819 TI - Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. AB - Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by muscle weakness and autonomic dysfunction. Recent ex vivo and in vitro studies demonstrate that autoantibodies to the P/Q-subtype of voltage-gated calcium channel inhibit transmitter release from parasympathetic, sympathetic, and enteric neurons, a mechanism likely to underlie the widespread autonomic dysfunction in LEMS. This review summarizes clinical studies characterizing the autonomic symptoms and signs in LEMS and the effectiveness of treatment in alleviating these symptoms. Serological assays and in vitro pharmacologic and electrophysiologic studies are also discussed. PMID- 11605820 TI - Role of endogenous adenosine in vasovagal syncope. AB - Adenosine may be a potential mediator in the pathogenesis of vasovagal syncope. Intravenous adenosine increases sympathetic discharge and provokes vasovagal syncope in sensitive subjects. No data are available for endogenous adenosine. The authors compared the results of head-up tilt-table testing (HUT) (45 minutes at 60 degrees) of three arbitrary groups of subjects: sensitive (n = 25, age 34 y, vasovagal syncope, positive HUT), moderately sensitive (n = 28, age 34 y, vasovagal syncope, negative HUT), and nonsensitive (n = 19, age 30 y). A positive test result produced syncopal symptoms with hypotension and/or bradycardia. Single-lead electrocardiogram (ECG) was recorded, and arterial pressure was measured noninvasively. Fourier transform was used for power-spectral heart rate variability (HRV) analysis of 5-minute ECG data. In the nonsensitive and moderately sensitive groups, HUT was repeated with intravenous dipyridamole, an adenosine transport blocker. In the sensitive group, HUT was repeated with oral theophylline, an adenosine receptor blocker, or placebo. In the moderately sensitive group, a third HUT was performed with dipyridamole and oral theophylline. If adenosine plays a role in vasovagal syncope, then dipyridamole would induce more positive HUT responses, a positive HUT response would be prevented by theophylline, and hemodynamic and HRV data in positive HUT responses induced by dipyridamole should reproduce those observed during spontaneous positive HUT responses. Dipyridamole induced positive HUT responses in 57% of the moderately sensitive group and 21% of the nonsensitive group (p < 0.05). Theophylline treatment was not efficient in preventing HUT-induced syncope in sensitive subjects; however, it prevented dipyridamole-induced syncope in 75% of the moderately sensitive group. Dipyridamole immediately increased arterial pressure, heart rate, and total HRV in all (p <0.05). In sensitive subjects, these responses were different: small for arterial pressure and for total and low frequency HRV, and large for heart rate. It is concluded that endogenous adenosine, like exogenous adenosine, may induce vasovagal syncope. However, the mechanism of adenosine-induced syncope is probably different from that of HUT induced vasovagal syncope. PMID- 11605821 TI - The cardiovascular effects of metoclopramide in multiple system atrophy and pure autonomic failure. AB - Metoclopramide (MCP), a central and peripheral dopaminergic blocker with cholinergic activity, has been proposed to treat orthostatic hypotension (OH) on the basis that it could antagonize the vasodilator and natriuretic effects of dopamine. The authors evaluated cardiovascular responses to MCP in 11 subjects with OH: 6 with multiple system atrophy (MSA) and 5 with pure autonomic failure (PAF), along with 6 healthy control subjects. Supine blood pressure (BP), heart rate (HR), and breathing were continuously monitored before, during, and after MCP infusion. The pre-MCP head-up tilt test was tolerated at 65 degrees for 10 minutes in all subjects except in one with PAF, who tolerated 30 degrees for only 5 minutes. Tilting confirmed the OH in patients with MSA (change in mean arterial pressure [deltaMAP] = -31 +/- 13 mm Hg) and PAF (AMAP = -34 +/- 8 mm Hg). Infusion of MCP was given in four 5-mg doses every 5 minutes, with the subject in a supine position. Infusion of MCP induced the following effects: (1) A transient hypotensive effect occurred after each infusion in both patients and control subjects, the fall in MAP being counteracted by an increase in HR in control subjects but not in patients; this acute MAP fall was mo resevere in patients. (2) A progressive reduction of MAP occurred during the test,which never returned to preinfusion levels in patients; this effect was so pronounced in two PAF patients as to prevent them from receiving the last dose. Post-MCP tilting was tolerated in control subjects but in only in 5 MSA patients and 4 PAF patients. In those patients who tolerated the test, the MAP fall was similar to, or worse than, that before MCP (MSA: deltaMAP = -28 +/- 16 mm Hg; PAF: deltaMAP = -38 +/- 16 mm Hg). The cardiovascular effect of MCP in normal subjects was a transient hypotension counterbalanced by reflex tachycardia. The lack of an HR increase and the progressive fall in supine BP in MSA and PAF patients, together with worsening orthostatic tolerance after MCP infusion, are effects that should strongly discourage the use of this drug in the treatment of OH. PMID- 11605822 TI - Empowerment, span of control, and safety performance in work teams after workforce reduction. AB - Relationships of empowerment and span of control with 2 safety measures (unsafe behaviors and accidents) were investigated among 24 workgroups comprising 531 employees of a large chemical company in 3 U.S. states. The company recently implemented a reengineering process. Data were from an anonymous survey (unsafe behaviors), company records (accidents, span of control), and trained expert raters (empowerment). Span of control (positively) and level of empowerment (negatively) correlated with both measures of poor safety performance, but only empowerment predicted unique variance in safety criteria. Together, these structural measures predicted one third of the variance in safety measures. Structural variables such as span of control and team empowerment have been largely overlooked in past safety research but can be important. PMID- 11605823 TI - Perceived work stress and major depression in the Canadian employed population, 20-49 years old. AB - Data from the Canadian National Population Health Survey (1994-1995) were used to evaluate the associations between work stress and major depression (N = 7,344). Major depression was evaluated using the World Health Organization's Composite International Diagnostic Interview- Short Form. Work stress was measured by a 12 item scale in 6 dimensions. Significant associations between work stress and major depression were found. Gender may alter the type of work stress that is most strongly associated with major depression: psychological demands for men and physical demands for women. Some forms of work stress were more strongly associated with major depression in smokers than in nonsmokers. PMID- 11605824 TI - Job control mediates change in a work reorganization intervention for stress reduction. AB - This longitudinal, quasi-experiment tested whether a work reorganization intervention can improve stress-related outcomes by increasing people's job control. To this end, the authors used a participative action research (PAR) intervention that had the goal of reorganizing work to increase the extent to which people had discretion and choice in their work. Results indicated that the PAR intervention significantly improved people's mental health, sickness absence rates, and self-rated performance at a 1-year follow-up. Consistent with occupational health psychology theories, increase in job control served as the mechanism, or mediator, by which these improvements occurred. Discussion focuses on the need to understand the mechanisms by which work reorganization interventions affect change. PMID- 11605825 TI - From inequity to burnout: the role of job stress. AB - This research examined burnout (i.e., emotional exhaustion, depersonalization, and lack of personal accomplishment) among 2 samples of Dutch teachers as a function of inequity and experienced job stress in 3 different exchange relationships (with students, colleagues, and the school). It was hypothesized that inequity would be linked to burnout through the stress resulting from this inequity. Analysis of a cross-sectional sample (N = 271) revealed that this was indeed the case. Findings were replicated longitudinally using an independent sample of 940 teachers. It is concluded that the often-reported effect of inequity on burnout can partly be interpreted in terms of elevated levels of job stress. Implications of the findings are discussed. PMID- 11605827 TI - Claiming in the name of fairness: organizational justice and the decision to file for workplace injury compensation. AB - This article explored the relationship among injured workers' perceptions of workplace justice (i.e., distributive, interactional, and procedural), perceptions of employers' disability-related policies, and the decision to file a workers' compensation claim. Using a 2-wave sample of 1,077 workers with repetitive motion injuries, the authors tested a structural equation model. Results revealed that Time 1 interactional justice was negatively related to filing a claim, whereas Time 1 distributive justice was positively related to perceptions of employer disability-related practices measured a year after the date of injury report. At Time 2, the claim decision was unrelated to perceptions of justice, yet perceptions of disability-related practices were significantly related to all 3 types of justice. PMID- 11605826 TI - The relative effects of deprivation of the latent and manifest benefits of employment on the well-being of unemployed people. AB - This study investigated the relative contributions of the individual latent and manifest benefits of employment to well-being in a sample of 248 unemployed people. Participants completed measures of well-being and the latent (time structure, activity, status, collective purpose, and social contact) and manifest (financial strain) benefits of employment. Significant associations were found between the latent benefits and well-being and between the manifest benefits and well-being. Both latent and manifest benefits contributed significantly to the prediction of well-being, with the manifest benefit accounting for the largest proportion. Although all latent benefits contributed significantly, status emerged as the most important contributor, followed by time structure and collective purpose. Results are discussed in the context of M. Jahoda's (1982) latent deprivation model and D. Fryer's (1986) agency restriction model. PMID- 11605828 TI - Chronic and acute stressors among military personnel: do coping styles buffer their negative impact on health? AB - This study examined the moderating impact of positive and negative coping styles on the relationship of acute and chronic job stressors with self-reported health symptoms of 521 military personnel. The number of acute work-related events was associated with a high frequency of self-reported symptoms. Similarly, role ambiguity, overload, and lack of job stimulation were associated with increased symptoms. Only the negative coping styles (i.e., venting of negative emotions and denial/disengagement) were uniquely associated with symptoms. Only 5 of the 13 proposed Stressor x Coping interactions were significant, and they all involved the negative coping styles. That is, instead of alleviating the negative outcomes of work stressors, these coping styles were associated with high strain, regardless of the amount of stressor, and, in some cases, these coping styles exacerbated the negative effect of the stressor on the strain outcomes. PMID- 11605829 TI - Social support at work, heart rate, and cortisol: a self-monitoring study. AB - This study assessed the influence of work social support on self-monitored heart rate, blood pressure, and salivary cortisol recorded on 3 work days and 2 leisure days from 61 nurses and 32 accountants (40 men, 53 women). Heart rate and blood pressure were higher during the day at work than in the evening or on leisure days. Cortisol was higher on leisure than work days and was lower in the evening than in the day. Low social support at work was associated with elevated heart rate during the daytime and evening of work days, an effect that persisted after controlling for psychological distress, age, sex, smoking, and physical activity. Work social support was not related to cortisol on work days, but on leisure days cortisol was elevated among individuals reporting high social support. There were few differences between men and women, and no important occupational effects. PMID- 11605830 TI - Determination of cell viability in single or mixed samples using capillary electrophoresis laser-induced fluorescence microfluidic systems. AB - The advent of high-efficiency microbial separations will have a profound effect on both chemistry and microbiology. For the first time, it appears that it may be possible to obtain qualitative and quantitative information on microbial systems with the accuracy, precision, speed, and throughput that currently is found for chemical systems. Recently it was suggested that an analytical separations-based approach for determining the viability of cells would be advantageous. The feasibility of such an approach is demonstrated using CE-LIF of two bacteria and yeast. The analytical procedures and figures of merit are outlined. High throughput analyses and evaluation of microorganisms now appear to be possible. PMID- 11605831 TI - Characterization of surfactant coatings in capillary electrophoresis by atomic force microscopy. AB - This paper describes the adsorption mechanisms and aggregation properties of cetyltrimethylammonium bromide (CTAB) and didodecyldimethylammonium bromide (DDAB) surfactants that are used for dynamic coatings in capillary electrophoresis (CE). Atomic force microscopy is used to directly visualize surfactant adsorption on fused silica. It was found that the single-chained surfactant CTAB forms spherical aggregates on silica while the double-chained surfactant DDAB forms a bilayer. Aggregation at the surface occurs at approximately the same surfactant concentration in which EOF reversal is observed in CE. The nearest-neighbor distance between CTAB aggregates varies inversely with buffer pH and becomes constant at the point when the silanol groups are fully ionized. DDAB forms a flat, uniform coating independent of pH. Increasing the buffer ionic strength changes the morphology of the CTAB aggregates from spherical to cylindrical. The change in morphology can alter the surface coverage, which is related to the "normalized" EOF measured in identical buffers. The morphology of a surfactant coating is also shown to affect its ability to inhibit protein adsorption to the capillary wall. Specifically, the full surface coverage provided by DDAB proved superior in a head-to-head comparison with CTAB. PMID- 11605833 TI - Heterogeneity assessment in individual CaCO3-CaSO4 particles using ultrathin window electron probe X-ray microanalysis. AB - In our previous studies, it has been demonstrated that both the excitation interactions between electrons and the atoms of the matrix and the matrix and geometric effects of electron-induced X-ray signals can be described by Monte Carlo simulation for low-Z elements, such as carbon, nitrogen, and oxygen, in individual atmospheric microparticles. In addition, by the application of a quantification method, which employs Monte Carlo simulation combined with successive approximations, at least semi-quantitative specification of the chemical compositions could be done. This has enlarged the scope of electron probe X-ray microanalysis (EPMA) for the single particle analysis of atmospheric environmental aerosol particles. In this work, we demonstrate that the heterogeneity of individual particles, even of micrometer size, can be characterized by the application of EPMA. X-ray photons obtained with different primary electron beam energies carry information on the chemical compositions for different regions in the particles. Artificially generated heterogeneous CaCO3 CaSO4 individual particles were measured at different accelerating voltages, and it was found that the Monte Carlo calculation is a powerful technique to extract the information on the heterogeneity of the particles that is contained in the measured X-ray data. Our approach can even estimate the thickness of the surface CaSO4 species by the application of the Monte Carlo calculation. A preliminary result for carbon-coated glass particles is also presented. The complexity involved in the analysis of real world particles is briefly mentioned with a result for heterogeneous SiO2 particle. PMID- 11605832 TI - Bioinformatics and mass spectrometry for microorganism identification: proteome wide post-translational modifications and database search algorithms for characterization of intact H. pylori. AB - MALDI-TOF mass spectrometry has been coupled with Internet-based proteome database search algorithms in an approach for direct microorganism identification. This approach is applied here to characterize intact H. pylori (strain 26695) Gram-negative bacteria, the most ubiquitous human pathogen. A procedure for including a specific and common posttranslational modification, N terminal Met cleavage, in the search algorithm is described. Accounting for posttranslational modifications in putative protein biomarkers improves the identification reliability by at least an order of magnitude. The influence of other factors, such as number of detected biomarker peaks, proteome size, spectral calibration, and mass accuracy, on the microorganism identification success rate is illustrated as well. PMID- 11605835 TI - Optical sensors and the salt effect: a dual-transducer approach to acidity determination in a salt-containing concentrated strong acid. AB - A dual-transducer approach has been developed to decompose the optical signals of acid sensors in salt-containing concentrated acid solutions and to give acid and salt concentrations in concentrated LiCl-HCl, CaCl2-HCl, and AICl3-HCl solutions, respectively. The optical acid sensors in this approach are films of porous sol gel SiO2 or SiO2-Nafion composite doped with low-pKa indicators. A novel linear relationship (dA/dCsalt)cCacid = beta x (dA0/dCacid)Csalt = 0 (A = absorbance of the sensor in a salt-containing HCl solution; A0 = absorbance of the sensor in a salt-free acid solution) was found, and the current approach is based on a set of nonlinear equations derived from this relationship. PMID- 11605834 TI - Characterization of molecularly imprinted polymers with the Langmuir-Freundlich isotherm. AB - The majority of binding models that have been applied to molecularly imprinted polymers (MIPs) have been homogeneous models. MIPs, on the other hand, are heterogeneous materials containing binding sites with a wide array of binding affinities and selectivities. Demonstrated is that the binding behavior of MIPs can be accurately modeled by the heterogeneous Langmuir-Freundlich (LF) isotherm. The applicability of the LF isotherm to MIPs was demonstrated using five representative MIPs from the literature, including both homogeneous and heterogeneous MIPs. Previously, such comparisons required the use of several different binding models and analyses, including the Langmuir model, the Freundlich model, and numerical approximation techniques. In contrast, the LF model enabled direct comparisons of the binding characteristics of MIPs that have very different underlying distributions and were measured under different conditions. The binding parameters can be calculated directly using the LF fitting coefficients that yield a measure of the total number of binding sites, mean binding affinity, and heterogeneity. Alternatively, solution of the Langmuir adsorption integral for the LF model enabled direct calculation of the corresponding affinity spectrum from the LF fitting coefficients from a simple algebraic expression, yielding a measure of the number of binding sites with respect to association constant Finally, the ability of the LF isotherm to model MIPs suggests that a unimodal heterogeneous distribution is an accurate approximation of the distribution found in homogeneous and heterogeneous MIPs. PMID- 11605836 TI - A chronoamperometric method to estimate changes in the membrane composition of ion-selective membranes. AB - A new chronoamperometric method is used to estimate changes in the membrane composition of mobile-site, ionophore-based membranes. The characteristic features of the chronoamperometric curves (initial current, slope, break time) of valinomycin-based, potassium-selective membranes loaded with potassium tetrakis(4 chlorophenyl)borate are correlated with the mobile-site and free ionophore concentration in the membrane. limiting cases for strong and negligible ion pair formation are distinguished. Replicate measurements indicate a relative standard deviation in the calculated values less than 10%. The practical applicability of the method was tested with membranes incorporated into conventional ion-selective electrode bodies or cast onto microfabricated planar sensor structures. PMID- 11605837 TI - Evaluations of the stability of sheathless electrospray ionization mass spectrometry emitters using electrochemical techniques. AB - The processes that cause the failure of sheathless electrospray ionization (ESI) emitters, based on different kinds of gold coatings on fused-silica capillaries, are described and explained. The methods chosen for this study include electrochemical methods, ICPMS analysis of the electrolytes used, SEM studies, and electrospray experiments. Generally, the failure occurs by loss of the conductive coating. It is shown that emitters with sputter-coated gold lose their coatings because of mechanical stress caused by the gas evolution accompanying water oxidation or reduction. Emitters with gold coatings on top of adhesion layers of chromium and nickel alloy withstand this mechanical stress and have excellent durability when operating as cathodes. When operating as anodes, the adhesion layer is electrochemically dissolved through the gold film, and the gold film then flakes off. It is shown that the conductive coating behaves as a cathode even in the positive electrospray mode when the magnitude of a superimposed reductive electrophoretic current exceeds that of the oxidative electrospray current. Fairy-dust coatings developed in our laboratory (see Barnidge, D. R.; etal.Anal. Chem. 1999, 71, 4115-4118,) bygluing gold dust onto the emitter, are unaffected by the mechanical stress due to gas evolution. When oxidized, the fairy-dust coatings show an increased surface roughness and decreased conductivities due to the formation of gold oxide. The resistance of this oxide layer is however negligible in comparison with that of the gas phase in ESI. Furthermore, since no flaking and only negligible electrochemical etching of gold was found, practically unlimited emitter lifetimes may be achieved with fairy-dust coatings. PMID- 11605839 TI - Surfactant chain length effects on the light emission of tris(2,2' bipyridyl)ruthenium(II)/ tripropylamine electrogenerated chemiluminescence. AB - The effects of nonionic surfactant chain length on the properties of tris(2,2' bipyridyl)ruthenium(II) (Ru(bpy)3(2+) where bpy = 2,2'-bipyridine) electrochemiluminescence (ECL) have been investigated. The electrochemistry, photophysics, and ECL of Ru(bpy)3(2+) in the presence of a series of nonionic surfactants are reported (Triton X-100, 114, 165, 405, 305, and 705-70). These surfactants differ in the number of poly(ethylene oxide) units incorporated into the surfactant molecule. The anodic oxidation of Ru(bpy)3(2+) produces ECL in the presence of tri-n-propylamine (TPrA) in aqueous surfactant solution. Increases in ECL efficiency (> or = 5-fold) and TPrA oxidation current (> or = 2-fold) have been observed in surfactant media. Slight decreases in ECL intensity are observed as the chain length of the nonionic surfactant increases. The data supports adsorption of surfactant on the electrode surface, thus facilitating TPrA and Ru(bpy)3(2+) oxidation and leading to higher ECL efficiencies. PMID- 11605838 TI - Electrochemiluminescence of copper(I) bis(2,9-dimethyl-1,10- phenanthroline). AB - The electrochemical and electrochemiluminescence (ECL) properties of Cu[dmp]2+ (dmp = 2,9-dimethyl-1,10-phenanthroline) have been investigated. ECL has been observed for Cu(dmp)2+ in aqueous, nonaqueous, and mixed solvent solutions using tri-n-propylamine as an oxidative-reductive coreactant. The ECL intensity peaks at potential corresponding to oxidation of both the coreactant and Cu(dmp)2+. The peak potential corresponding to maximum ECL emission is approximately 500 mV more anodic than corresponding oxidative peak potentials, indicating that the ECL emission may be due to the formation of either the *Cu(dmp)2+ metal-to-ligand charge-transfer excited state or an excited-state product of Cu(dmp)2+ oxidation. ECL efficiencies (phiecl = photons generated per redox event) are solvent dependent (phiecl (CH3CN) > phiecl (50:50 (v/v) CH3CN:H20) > phiecl (H2O)) and correspond fairly well with photoluminescence efficiencies. Increased ECL efficiencies (> or = 50-fold) are observed in the presence of the nonionic surfactant Triton X-100. PMID- 11605840 TI - Spatial control of cellular measurements with the laser micropipet. AB - Continued progress in understanding cellular physiology requires new strategies for biochemical measurements in solitary cells, multiple cells, and subcompartments of cells. Large spatial gradients in the concentrations of molecules and presumably the activities of enzymes can occur in cells. Consequently, there is a critical need for measurement techniques for mammalian cells with control over the numbers or regions of cells interrogated. In the present work, we developed a strategy to rapidly load the cytoplasmic contents of either multiple cells or a subregion of a single cell into a capillary. A single, focused pulse from a laser created a mechanical shock wave which disrupted a group of cells or a portion of a cell in the path of the shock wave. Simultaneously, the cytoplasm was loaded into a capillary for electrophoretic separation. The size of the region of cellular disruption (and therefore the volume of cytoplasm collected) was controlled by the amount of energy in the laser pulse. Higher energies could be used to sample groups of cells while much lower energies could be utilized to selectively sample the tip of a neuronal process. The feasibility of performing measurements on subcellular compartments was also demonstrated by targeting reporter molecules to these compartments. A reporter localized to the nucleus was detected on the electropherogram following laser-mediated disruption of the cell and the nucleus. Finally, we demonstrate that this method terminated cellular reactions with sufficient rapidity that cellular membrane repair mechanisms were not activated during cytoplasmic collection. The combined ability to preselect a spatial region of a cell or cells and to rapidly load that region into a capillary will greatly enhance the utility of CE in the biochemical analysis of cells. PMID- 11605841 TI - Effect of affinity for droplet surfaces on the fraction of analyte molecules charged during electrospray droplet fission. AB - The effect of uneven fissioning of mass and charge from electrospray droplets on the amount of analyte charged during the electrospray process was explored. A surface selectivity factor (S) was developed to describe the affinity of an analyte for the droplet surface, and both theoretical and experimental response curves were compared for analytes with various S values. The theoretical response curves were generated by calculating the overlap between the charge and analyte spawned from parent droplets to determine the amount of analyte charged. This overlap was then graphed as a function of analyte concentration. Differences in the amount of analyte charged during droplet fission were predicted for analytes of varying surface affinities. The issue of analyte partitioning between the surface and interior phases of the ESI droplet was also included in the discussion. This was accomplished by applying the equilibrium partitioning model to a set of offspring droplets to determine the amount of analyte on their surfaces and then calculating the overlap between fissioning analyte and excess charge. Experimental response curves resembled theoretical ones, and S values predicted from theory were in excellent agreement with those predicted on the basis of the structural characteristics of the analytes. PMID- 11605842 TI - Analysis of trace levels of sulfonamide and tetracycline antimicrobials in groundwater and surface water using solid-phase extraction and liquid chromatography/mass spectrometry. AB - A method has been developed for the trace analysis of two classes of antimicrobials consisting of six sulfonamides (SAs) and five tetracyclines (TCs), which commonly are used for veterinary purposes and agricultural feed additives and are suspected to leach into ground and surface water. The method used solid phase extraction and liquid chromatography/mass spectrometry (LC/MS) with positive ion electrospray. The unique combination of a metal chelation agent (Na2EDTA) with a macroporous copolymer resulted in quantitative recoveries by solid-phase extraction (mean recovery, 98 +/- 12%) at submicrogramper-liter concentrations. An ammonium formate/formic acid buffer with a methanol/water gradient was used to separate the antimicrobials and to optimize the signal intensity. Mass spectral fragmentation and ionization characteristics were determined for each class of compounds for unequivocal identification. For all SAs, a characteristic m/z 156 ion representing the sulfanilyl fragment was identified. TCs exhibited neutral losses of 17 amu resulting from the loss of ammonia and 35 amu from the subsequent loss of water. Unusual matrix effects were seen only for TCs in this first survey of groundwater and surface water samples from sites around the United States, requiring that TCs be quantitated using the method of standard additions. PMID- 11605843 TI - Thermal decomposition of a gaseous multiprotein complex studied by blackbody infrared radiative dissociation. Investigating the origin of the asymmetric dissociation behavior. AB - The blackbody infrared radiative dissociation technique was used to study the thermal decomposition of the gaseous B5 pentamer of the Shiga-like toxin I and its complexes with the Pk trisaccharide and a decavalent Pk-based oligosaccharide ligand (STARFISH, S). Dissociation of the protonated pentamer, (B5 + nH)n+ triple bond B5n+ where n = 11-14, proceeds almost exclusively by the loss of a single subunit (B) with a disproportionately large fraction (30-50%) of the parent ion charge. The degree of charge enrichment of the leaving subunit increases with increasing parent ion charge state. For n = 12-14, a distribution of product ion charge states is observed. The yields of the complementary pairs of product ions are sensitive to the reaction temperature, with higher temperatures favoring greater charge enrichment of the leaving subunit for +13 and +14, and the opposite effect for +12. These results indicate that some of the protons are rapidly exchanged between subunits in the gas phase. Dissociation of B5(14+) x S proceeds exclusively by the loss of one subunit, although the ligand increases the stability of the complex and also reduces the degree of charge enrichment in the ejected monomer. For B5(12+)(Pk)1-3, the loss of neutral Pk competes with loss of a subunit at low temperatures. Linear Arrhenius plots were obtained from the temperature-dependent dissociation rate constants measured for the loss of B from B5n+ and B514+ x S. The magnitude of the Arrhenius parameters is highly dependent on the charge state of the pentamer: Ea = 35 kcal/mol and A = 1,019 s( 1) (+14), 46 kcal/mol and 1,023 S(-1) (+13), 50 kcal/mol and 1026 s(-1) (+12), and 80 kcal/mol and 10(39) (+11). The Ea and A for B5(14+) x S are 59 kcal/mol and 10(30) s(-1), respectively. The reaction pathways leading to greater charge enrichment of the subunit lost from the B5(14+) and B5(13+) ions correspond to higher energy processes, however, these pathways are kinetically preferred at higher temperatures due to their large A factors. A simple electrostatic model, whereby charge enrichment leads to Coulombic repulsion-induced denaturation of the subunits and disruption of the intersubunit interactions, provides an explanation for the magnitude of the Arrhenius parameters and the origin of the asymmetric dissociation behavior of the complexes. PMID- 11605844 TI - Isotope dilution gas chromatography/mass spectrometry method for the determination of methionine sulfoxide in protein. AB - We have developed a new technique for quantifying methionine sulfoxide (MetSO) in protein to assess levels of oxidative stress in physiological systems. In this procedure, samples are hydrolyzed with methanesulfonic acid (MSA) in order to avoid the conversion of MetSO to methionine (Met) that occurs during hydrolysis of protein in HCl. The hydrolysate is fractionated on a cation exchange column to remove the nonvolatile MSA from amino acids, and the amino acids are then derivatized as their trimethylsilyl esters for analysis by selected ion monitoring-gas chromatography/mass spectrometry. The limit of detection of the assay is 200 pmol of MetSO per analysis, and the interassay coefficient of variation is 5.8%. Compared to current methods, the SIM-GC/MS assay avoids the potential for conversion of Met to MetSO during sample preparation, requires less sample preparation time, has lower variability, and uses mass spectrometry for sensitive and specific analyte detection. PMID- 11605846 TI - Kendrick mass defect spectrum: a compact visual analysis for ultrahigh-resolution broadband mass spectra. AB - At currently achievable Fourier transform ion cyclotron resonance broadband mass spectrometry resolving power (m/deltam50% > 350,000 for 200 < m/z < 1,000), it would be necessary to spread out a conventional mass spectrum over approximately 200 m in order to provide visual resolution of the most closely resolved peaks. Fortunately, there are natural gaps in a typical mass spectrum, spaced 1 Da apart, because virtually no commonly encountered elemental compositions yield masses at those values. Thus, it is possible to break a broadband mass spectrum into 1-Da segments, rotate each segment by 90 degrees, scale each segment according to its mass defect (i.e., difference between exact and nominal mass), and then compress the spacing between the segments to yield a compact display. For hydrocarbon systems, conversion from IUPAC mass to "Kendrick" mass (i.e., multiplying each mass by 14.00000/14.01565) further simplifies the display by rectilinearizing the peak patterns. The resulting display preserves not only the "coarse" spacings (e.g., approximately 1 Da between odd and even masses, corresponding to either even vs odd number of nitrogens or 12C(c) vs 12C(c-1)13C1 elemental compositions of the same molecule; approximately 2-Da separations, corresponding to a double bond or ring; approximately 14 Da separations, corresponding to one CH2 group) but also the "fine structure" (i.e., different mass defects for different elemental compositions) across each 1-Da segment. The method is illustrated for experimental electrospray ionization FTICR ultrahigh resolution mass spectra of a petroleum crude oil. Several thousand elemental compositions may be resolved visually in a single one-page two-dimensional display, and various compound families-class (NnOoSs), type (Z in C(c)H2(c+z)NnOoSs), and alkylation series-may be identified visually as well. PMID- 11605845 TI - A portable, high-speed, vacuum-outlet GC vapor analyzer employing air as carrier gas and surface acoustic wave detection. AB - Vacuum-outlet GC with atmospheric-pressure air as the carrier gas is implemented at outlet pressures up to 0.8 atm using a low-dead-volume polymer-coated surface acoustic wave (SAW) detector. Increases in the system outlet pressure from 0.1 to 0.8 atm lead to proportional increases in detector sensitivity and significant increases in column efficiency. The latter effect arises from the fact that optimal carrier gas velocities are lower in air than in more conventional carrier gases such as helium or hydrogen due to the smaller binary diffusion coefficients of vapors in air. A 12-m-long, 0.25-mm-i.d. tandem column ensemble consisting of 4.5-m dimethyl polysiloxane and 7.5-m trifluoropropylmethyl polysiloxane operated at an outlet pressure of 0.5 atm provides up to 4 x 10(4) theoretical plates and a peak capacity of 65 (resolution, 1.5) for a 3-min isothermal analysis. At 30 degrees C, mixtures of vapors ranging in vapor pressure from 8.6 to 76 Torr are separated in this time frame. The SAW detector cell has an internal volume of < 2 microL, which allows the use of higher column outlet pressures with minimal dead time. The sensor response is linear with solute mass over at least 2-3 decades and provides detection limits of 20-50 ng for the vapors tested. The combination of atmospheric-pressure air as carrier gas, modest operating pressures, and SAW sensor detection is well-suited for field instrumentation since it eliminates the need for support gases, permits smaller, low-power pumps to be used, and provides sensitivity to a wide range of vapor analytes. PMID- 11605847 TI - Pressure-driven laminar flow in tangential microchannels: an elastomeric microfluidic switch. AB - This paper describes laminar fluid flow through a three-dimensional elastomeric microstructure formed by two microfluidic channels, fabricated in layers that contact one another face-to-face (typically at a 90 degree angle), with the fluid flows in tangential contact. There are two ways to control fluid flow through these tangentially connected microchannels. First, the flow profiles through the crossings are sensitive to the aspect ratio of the channels; the flow can be controlled by applying external pressure and changing this aspect ratio. Second, the flow direction of an individual laminar stream in multiphase laminar flow depends on the lateral position of the stream within the channel; this position can be controlled by injecting additional streams of fluid into the channel. We describe two microfluidic switches based on these two ways for controlling fluid flow through tangential microchannels and present theoretical arguments that explain the observed dependence of the flow profiles on the aspect ratio of the channels. PMID- 11605848 TI - Microfluidic device for airborne BTEX detection. AB - We fabricated a microfluidic device for the optical detection of airborne benzene, toluene, ethylbenzene and xylenes (BTEX). The device consists of concentration and detection cells formed of 3 cm x 1 cm Pyrex plates. The concentration cell is composed of an adsorbent to concentrate the BTEX gases and a thin-film heater todesorb the concentrated gases from the adsorbent thermally. The collected gases are introduced into the detection cell, which is connected to optical fibers, to measure their absorption spectra. We optimized the device's operating conditions by studying the thermal characteristics of the concentration cell and the time profile of the gas concentration flowing in the detection cell. We used the device under optimized operating conditions to detect toluene gas as a typical example BTEX. The gas concentration amplification rate was approximately 2 orders of magnitude, and we successfully measured parts-per million levels of toluene gas with this device. PMID- 11605849 TI - Two-Dimensional detection in ion chromatography: sequential conductometry after suppression and passive hydroxide introduction. AB - An improved method that uses sequential suppressed and nonsuppressed IC for the sensitive detection of both common anions and very weak acid anions is described. After suppressed conductometric detection of an electrolytically generated hydroxide eluent and an electrolytic suppressor, the eluent is passed into a membrane device where KOH is passively introduced into the eluent stream using Donnan forbidden leakage. A second conductivity detector then measures the conductivity of the stream. The background conductance of the second detector is typically maintained at a relatively low level of 20-30 microS/ cm. The weak acids are converted to potassium salts that are fully ionized and are detected against a low KOH background as negative peaks. The applicability of different commercially available cation exchange membranes was studied. Device configurations investigated include planar, tubular, and a filament-filled annular helical (FFAH) device. The FFAH device provided more effective mixing of the penetrated hydroxide with the eluent stream, resulting in a noise level of < or = 7 nS/cm and a band dispersion value of less than 82 microL. Optimal design and performance data are presented. PMID- 11605850 TI - Evaluation of triterpene glycoside estrogenic activity using LC/MS and immunoaffinity extraction. AB - We present a study on the mass spectral as well as the binding properties of three triterpene glycosides (cimicifugoside, cimiracemoside F, 27-deoxyactein) contained in black cohosh to the ligand binding domain of estrogen receptor beta (ER-beta). Using affinity ultrafiltration and LC/ MS detection, initial experiments using estradiol and the phytoestrogens daidzein and genistein (compounds known to bind ER-beta) were performed to serve as positive controls. The same affinity techniques and LC/MS procedures were then employed to show that neither the triterpene glycosides nor their enzymatically prepared aglycons bound significantly to ER-beta, except for 27-deoxyactein aglycon, which showed weak binding affinity (4%). Additionally, metabolites of the aglycons were prepared by incubation with female human liver microsomes and subjected to binding experiments with ER-beta. No significant binding of the metabolites to the receptor was observed. Further studies are needed to fully characterize whether these triterpene glycosides as well as other components of black cohosh in this plant extract bind to the estrogen receptor alpha (ER-alpha). PMID- 11605851 TI - Microwave digestion of environmental and natural waters for selenium speciation. AB - A microwave preparation procedure is proposed for selenium speciation in natural and drinking waters. Different chemical reagents were tested, and the conditions for Se speciation were optimized. The effect of the different reagents on various oxidation states of selenium under microwave digestion conditions was investigated. Most of the Se(-II) was converted to selenite when digested with HNO3 and <20% to selenate. The digestion with H2O2/H2SO4 can change most Se species into Se(IV). The concentration of Se(IV) in the samples was then determined by HPLC with a fluorescence detector after derivatization with 2,3 diamino-naphthalene (DAN). The microwave preparation procedure allows Se speciation in water samples. Se(IV) was determined after concentrating the sample under nitrogen protection. The amount of Se(IV) and Se(VI) was measured by adding an equal volume of concentrated hydrochloric acid to water sample to reduce Se(VI) to Se(IV). Then the amount of Se(VI) can be calculated by subtraction. The total selenium can be determined after digestion with H2O2/H2SO4, or after digestion with HNO3 followed by reduction with concentrated hydrochloric acid. Selenium (-II, 0) was calculated by subtracting inorganic Se(IV+VI) from the total. Detection limits of 0.0066 ng and 0.0096 ng Se were obtained for HNO3 and H202/H2SO4 as digestion reagents, respectively. The total Se in the four water samples tested range from 0.20 to 0.90 microg L(-1). Among them the dominant form was Se(VI) with the exception of pond waters where Se(-II) predominated. PMID- 11605852 TI - A method for the extraction of ammonium from freshwaters for nitrogen isotope analysis. AB - The measurement of delta15N values of inorganic nitrogen species is an important analytical tool to trace nitrogen species in order to understand nitrogen cycling in aquatic systems. Nitrogen isotope analysis of freshwater ammonium has, however, been hindered by the lack of a simple and reliable technique to measure delta15N values at natural abundance levels. We present a simple and rapid method to concentrate ammonium from freshwater samples for on-line N-isotope ratio determination. Ammonium is collected by adsorption on N-free cation exchange resins. The dried N-loaded exchange resin is then directly combusted to produce N2 gas for subsequent delta15N analysis. The method was evaluated with simulated freshwater solutions containing varying amounts of standard NH4+-N (delta15N = 2.1 per thousand) and potentially interfering inorganic and organic compounds. In general, the cation exchange resin method gives accurate and reproducible delta15N values (sigma1 < 0.3 per thousand; n = 10). Because of adsorption interference, high concentrations of cations in solution may cause ammonium loss but do not result in measurable isotope fractionation. Replicate extractions of the ammonium standard added to water collected from four Swiss lakes demonstrate the good performance of this method when applied to low ionic strength natural water samples with modest concentrations of dissolved organic nitrogen. PMID- 11605853 TI - Sulfur-specific detection of impurities in cimetidine drug substance using liquid chromatography coupled to high resolution inductively coupled plasma mass spectrometry and electrospray mass spectrometry. AB - The use of liquid chromatography coupled to sector field inductively coupled plasma mass spectrometry (SF-ICP-MS) for the specific detection of sulfur containing compounds is described. In the sulfur-containing drug substance cimetidine, structurally related impurities well below the 0.1% mass fraction level relative to the main drug substance could easily be detected. The structure of most of the impurities was confirmed by electrospray mass spectrometry (ESI MS), and thus, the complementarity of the two techniques for drug analysis is shown. The limit of detection by SF-ICP-MS for cimetidine in solution was approximately 4-20 ng x g(-1), but it was blank-limited. PMID- 11605854 TI - Monitoring biogenic volatile compounds emitted by Eucalyptus citriodora using SPME. AB - A procedure to monitor BVOC emitted by living plants using SPME technique is presented. For this purpose, a glass sampling chamber was designed. This device was employed for the characterization of biogenic volatile compounds emitted by leaves of Eucalyptus citriodora. After extraction with SPME fibers coated with PDMS/ DVB, it was possible to identify or detect 33 compounds emitted by this plant. A semiquantitative approach was applied to monitor the behavior of the emitted BVOC during 9 days. Circadian profiles of the variation in the concentration of isoprene were plotted. Using diffusion-based SPME quantitation, a recently introduced analytical approach, with extraction times as short as 15 s, it was possible to quantify subparts-per-billion amounts of isoprene emitted by this plant. PMID- 11605855 TI - Hollow-Fiber flow field-flow fractionation of synthetic polymers in organic solvents. AB - A modified polyacrylonitrile (PAN) hollow-fiber membrane from a commercial source has been applied as the separation channel in flow field-flow fractionation (FFF). With the PAN membrane fiber, the application range of flow FFF could be extended to synthetic polymers that are soluble in a variety of organic solvents. The PAN membrane was shown to be resistant to hydrophobic solvents, such as dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, and methyl ethyl ketone (MEK), as was illustrated by the successful fractionation of different polymer standards in these solvents. The system performance was assessed using polystyrene (PS) standards with ethyl acetate as the solvent. For a 100 kDa PS standard, the average recoverywas 57%, but for standards with a molar mass of 400 kDa and higher, 100% recovery was obtained. A linear relationship between peak area and injected mass was found. The run-to-run and fiber-to-fiber repeatability was determined using 100- and 400 kDa PS standards. The repeatability appeared to be satisfactory, with relative standard deviations < 2% for the retention times and < 5% for the recoveries of the standards. Plate numbers for the 400 kDa standard on different fibers were in the order of 110. From measurements on the fractionation of ferritin aggregates, it is concluded that the instrumental band broadening is negligible. For an accurate determination of diffusion coefficients and molecular sizes based on retention times, calibration of the channel with standards appeared to be necessary. However, it was shown that the FFF system could be coupled to a multiangle light scattering (MALS) detector, thus providing an alternative on-line method for calibration. Expressions for the maximum obtainable plate number per unit of time have been derived for a hollow-fiber flow FFF system. It is shown that an increase in the system performance can be expected from a scaling down of the fiber diameter. PMID- 11605856 TI - Self-assembly on "recordable CDs". AB - Gold substrates for self-assembly were constructed from recordable compact disks (CD-Rs) with simple and straight-forward wet-chemical treatment. In particular, they were made into desired sizes and shapes that satisfy different experimental needs. Self-assembled monolayers (SAMs) of long-chain alkanethiols (e.g., n C18H37SH) adsorbed on gold substrates prepared from CD-Rs have been characterized by wetting measurements, electrochemistry, infrared (IR) spectroscopy, and scanning tunneling microscopy (STM). The results showed that there were no distinct differences in the quality and structure between these monolayers and SAMs formed on standard gold substrates (i.e., prepared from vacuum evaporation of pure gold onto glass slides). The present work demonstrates the applicability of recordable CDs as inexpensive, simple, and versatile gold substrates for self assembly studies. PMID- 11605857 TI - Pulsed electrospray for mass spectrometry. AB - Pulsed electrospray has been developed and been reported for the first time. This new technique is based on the principle of pulsed ion sources, combined with the conventional electrospray. The pulsed ion spray was realized by a homemade pulsed HV circuit and was monitored by a digital microscope and an oscilloscope. Results show that the pulsed ESI device can be operated under proper conditions for a clear on-and-off spray process and that the device was kept in good electric contact for electrospray when pulsed HV was on. A pulsed ion current and pulsed mass spectra can be achieved with this pulsed ESI device. Furthermore, it has been noted that, under the same conditions (i.e., shape and size of sprayer tip, distance from sprayer tip to sampling nozzle, and other parameters for mass spectrometer), stable electrospray could be obtained for lower flow rates with a pulsed spray device. This experimental fact indicates the possible reduction in the total sample consumed could be realized by exploiting this novel design. PMID- 11605858 TI - Academic instrument builders. PMID- 11605859 TI - Internet algorithm tracks microorganisms. PMID- 11605861 TI - GC/MS analyses of chemical vapor deposition precursors. PMID- 11605860 TI - PEBBLEs measure O2 in living cells. PMID- 11605862 TI - Hadamard transform capillary electrophoresis. PMID- 11605863 TI - Better brain imaging with chemometrics. PMID- 11605864 TI - Chiral stationary phases for HPLC. PMID- 11605865 TI - Orthodontic slot size: it's time to retool. PMID- 11605866 TI - The dental follicle in normally and ectopically erupting maxillary canines: a computed tomography study. AB - The subjects in the study were children who were X-rayed because of increased risk for resorption following ectopically erupting maxillary canines. One hundred and seven children 9 to 15 years of age with 156 maxillary canines that were erupting ectopically and 58 normally were investigated by computed tomography (CT) to describe the features of the dental follicles of the erupting maxillary canines. Contiguous, transverse CT scans were exposed through the maxilla in the canine region and the width and shape of the dental follicles were registered scan by scan throughout the extension of the follicle. The width and the shape of the dental follicle of the erupting maxillary canine varied greatly. The range of the maximum width, measured from the crown to the periphery of the follicle, was 0.5-7.0 mm, with a mean of 2.9 mm and a 95% confidence interval of 2.7-3.2 mm for the entire sample. No relationship was found between the width or shape of the follicles and sex, age, stage of eruption, inclination of the canine, or width of the dental arch. However, the location of the maxillary canine vis-a-vis the adjacent incisor was significantly associated with the width of the follicle, which indicated that local anatomic conditions might influence the width and shape of the follicle. The dental follicles of the ectopically erupting canines were, on average, wider than those of the normally erupting canines. The 95% confidence interval for the normally erupting canines was 2.3-2.7 mm; for the buccally erupting canines 2.4-4.1 mm; for the lingually erupting canines 2.6-3.0 mm; and for the apically erupting canines in relation to the lateral incisors 2.9 4.1 mm. Canine follicles that were wide but within normal limits did not cause deviations in adjacent teeth. Cystically degenerated dental follicles were found but were indistinguishable on the CT scans from those that had been widened physiologically. The contributions of the studied variables to the variation in the width of the dental follicle of the maxillary canine were analyzed with regression models. PMID- 11605867 TI - Treatment timing for rapid maxillary expansion. AB - The aim of this study was to evaluate the short-term and long-term treatment effects of rapid maxillary expansion in 2 groups of subjects treated with the Haas appliance. Treatment outcomes were evaluated before and after the peak in skeletal maturation, as assessed by the cervical vertebral maturation (CVM) method, in a sample of 42 patients compared to a control sample of 20 subjects. Posteroanterior cephalograms were analyzed for the treated subjects at T1 (pretreatment), T2 (immediate post-expansion) and T3 (long-term observation), and were available at T1 and at T3 for the controls. The mean age (years: months) at T1 was 11:10 for both the treated and the control groups. The mean ages at T3 also were comparable (20:6 for the treated group and 17:8 for the controls). Following expansion and retention (2 months on average), fixed standard edgewise appliances were placed. The study included transverse measurements on dentoalveolar structures, maxillary and mandibular bases and other craniofacial regions (nasal, zygomatic, orbital, and cranial). Treated and control samples were divided into 2 groups according to individual skeletal maturation. The early treated and early-control groups had not reached the pubertal peak in skeletal growth velocity at T1 (CVM 1 to 3), whereas the late-treated and late-control groups were during or slightly after the peak at T1 (CVM 4 to 6). The group treated before the pubertal peak showed significantly greater short-term increases in the width of the nasal cavities. In the long-term, maxillary skeletal width, maxillary intermolar width, lateronasal width, and lateroorbitale width were significantly greater in the early-treated group. The late-treated group exhibited significant increases in lateronasal width and in maxillary and mandibular intermolar widths. Rapid Maxillary Expansion treatment before the peak in skeletal growth velocity is able to induce more pronounced transverse craniofacial changes at the skeletal level. PMID- 11605868 TI - A comparison of 3 computerized Bolton tooth-size analyses with a commonly used method. AB - Four methods of conducting overall and anterior Bolton tooth-size analyses were compared using 22 (11 pretreatment and 11 posttreatment) sets of models. No more than 3 mm of crowding existed in any of the models, and all were in good condition. An analysis employing vernier calipers was completed 3 times to set a standard. Pearson correlation coefficients revealed a high degree of intra operator reliability with mean R values of 0.930 and 0.843 for the overall and anterior discrepancies, respectively. The mean Vernier caliper results were compared with each of the following computerized methods: QuickCeph, Hamilton Arch Tooth System (HATS), and OrthoCad. No statistically significant error was present for any of the methods using repeated-measures analysis of variance testing and paired t-tests (p < .05). Clinically significant differences (>1.5 mm) were present for each method. Absolute differences were calculated, and linear regression and R values were determined. The HATS analysis had the highest degree of correlation (R = 0.885 for overall and 0.825 for anterior), followed by OrthoCad (R = 0.715, 0.574), and QuickCeph (R = 0.432, 0.439). Each method also was compared based on the time required to complete each analysis. The QuickCeph was the fastest (1.85 minutes) followed by HATS (3.40 minutes), OrthoCad (5.37 minutes), and Vernier caliper (8.06 min). PMID- 11605869 TI - The incisor-lip relationship in Herbst/multibracket appliance treatment of Class II, Division 2 malocclusions. AB - The purpose of this investigation was to examine the effect of Herbst/multibracket appliance treatment on the upper incisor-lower lip relationship in the management of Class II, division 2 malocclusions. The study evaluated 19 successfully treated subjects using lateral head films analyzed at 3 occasions: before (T1) and after (T2) Herbst/multibracket appliance treatment and 1-year posttreatment (T3). The average treatment (T1-T2) changes showed (1) the lower lip overlap on the upper incisors was reduced from 6.0 mm to 4.2 mm (P < .001), (2) the upper incisors were proclined 15.3 degrees (P < .001) and the lower incisors were proclined 9.6 degrees (P < .001), (3) the overbite was reduced from 7.3 mm to 1.7 mm (P < .001), and (4) the sagittal jaw base relationship (Wits) improved from +3.5 to +0.5 mm (P < .001). The average posttreatment (T2-T3) changes showed (1) the upper incisor-lower lip relationship remained stable, (2) the upper (0.6 degrees; P < .001) and lower (2.3 degrees; P < .001) incisors retroclined, (3) the overbite increased (1.2 mm; P < .001), and (4) the sagittal jaw base relationship remained unchanged. In conclusion, it was found that the upper incisor-lower lip relationship was improved by Herbst/multibracket appliance treatment and remained stable during a 1-year posttreatment period in spite of minor relapses of incisor tooth positions and relationships. PMID- 11605870 TI - Frictional resistances of metal-lined ceramic brackets versus conventional stainless steel brackets and development of 3-D friction maps. AB - The frictional resistances of 2 metal-lined ceramic brackets (Luxi and Clarity) were compared with 2 conventional stainless steel brackets (Mini-Taurus and Mini Twin) in vitro. In method 1, we varied the second-order angulation from 0 degrees to 12 degrees while maintaining the normal or ligature force constant at 0.3 kg; in method 2, we varied the ligature force from 0.1 kg to 0.9 kg while maintaining the angulation at theta = 0 degrees or theta = 11 degrees. The hardware simulated a 3-bracket system in which the interbracket distances were always 18 mm. All couples were evaluated at 34 degrees C using the same size stainless steel archwire (19 x 26 mil) and ligature wire (10 mil). In the passive region, the static and kinetic frictional forces and coefficients of friction were key parameters; in the active region, the static and kinetic binding forces and coefficients of binding were critical parameters. From outcomes of methods 1 and 2, the 4 aforementioned parameters, and a knowledge of the critical contact angle for binding, 3-dimensional friction maps were constructed in the dry and wet states from which the frictional resistances could be determined at any ligature force or second-order angulation. Those 3-dimensional maps show that metal-lined ceramic brackets can function comparably to conventional stainless steel brackets and that 18-kt gold inserts appear superior to stainless steel inserts. As the morphologies of metal inserts are improved, these metal-lined ceramic brackets will provide not only good esthetics among ceramic brackets but also minimal friction among conventionally ligated brackets. PMID- 11605871 TI - Nickel and chromium levels in the saliva and serum of patients with fixed orthodontic appliances. AB - The aim of this study was to evaluate the concentrations of nickel and chromium ions in salivary and serum samples from patients treated with fixed orthodontic appliances. A second aim of this study was to determine any significant changes in these concentrations during any period of the treatment time. Saliva and blood samples were collected from 100 patients ranging in age from 12 to 33 years. Twenty samples from each group were obtained. The groups were as follows: In the first group, saliva and blood samples were collected before insertion of the fixed appliances. In the second, third, fourth, and fifth groups, samples were collected at 1 week, 1 month, 1 year, and 2 years after appliance insertion. The serum was prepared by centrifuging the blood samples at 3000 rpm for 10 minutes. The fixed appliances consisted of an average of 4 bands and 20 bonded brackets. No palatal or lingual appliances welded to bands or extraoral auxiliary appliances were used. The spectrophotometric determinations were carried out using electrothermal atomic absorption spectrophotometry. The results indicated certain differences in the amounts of nickel and chromium released from fixed orthodontic appliances during different periods of treatment. The Mann-Whitney U test from the SPSS statistics program was used to analyze the significance of the differences between no-appliance samples and those obtained with the appliances present. In the serum, there were statistically significant increases in ion concentration in the second-year groups. In saliva samples, nickel and chromium reached their highest levels in the first month and decreased to their initial level in the rest of the groups. It can be concluded that fixed orthodontic appliances release measurable amount of nickel and chromium when placed in the mouth, but this increase doesn't reach toxic levels for nickel and chromium in the saliva and serum. PMID- 11605873 TI - The dental arch form revisited. AB - Recently, the beta function has been shown to be an accurate mathematical model of the human dental arch. In this research, we tried to find the equation of a curve that would be similar to the generalized beta function curve and at the same time could represent tapered, ovoid, and square dental arches. A total of 23 sets of naturally well-aligned Class I casts were selected, and the depths and widths of the dental arches were measured at the canine and second molar regions. Using the mean depths and widths, functions in the form of Y = AXm + BXn were calculated that would pass through the central incisors, canines, and second molars. Each function was compared with the generalized beta function with the use of root mean square values. It was shown that the polynomial function Y = AX6 + BX2 was the nearest to the generalized beta function. Then the coordinates of the midincisal edges and buccal cusp tips of each dental arch were measured, and the correlation coefficient of each dental arch with its corresponding sixth order polynomial function was calculated. The results showed that the function Y = AX6 + BX2 could be an accurate substitute for the beta function in less common forms of the human dental arch. PMID- 11605872 TI - Bonded molar tubes--an in vitro evaluation. AB - This study aimed to evaluate the mean shear bond strength of molar tubes with micro-etched bases bonded with either a compomer (Ultra Band-Lok), a resin modified glass ionomer cement (3M Multi-Cure or Fuji Ortho LC), or a light-cured resin adhesive (Transbond). The amount of adhesive remaining on the tooth surface following tube removal was assessed also. Finally, survival time of molar tubes bonded with each bonding agent was assessed following simulated mechanical fatigue in a ball mill. A total of 120 extracted human third molars were collected and randomly divided into 4 test groups. Thirty teeth (20 to assess debonding force and 10 to assess survival time) were bonded with each adhesive according to the manufacturers' instructions. Debonding was carried out using a Nene M3000 testing machine with a crosshead speed of 0.5 mm/min. The mean shear bond strength of tubes bonded with Transbond was significantly less than that of those bonded with 3M Multi-Cure (P = .0036) or Fuji Ortho LC (P < .0001). Tubes bonded with Ultra Band-Lok also had significantly lower mean shear bond strength than those bonded with Fuji Ortho LC (P = .020). Distribution of adhesive remnant index scores only differed significantly between tubes bonded with 3M Multi-Cure or Transbond. Only I molar tube, bonded with Transbond, debonded in the ball mill at 5 hours, but at 50 hours there was no significant difference in the survival time of tubes bonded with any of the bonding agents. Compomer or resin-modified glass ionomer cements appear to be viable alternatives to light-cured resin adhesive for bonding molar tubes. PMID- 11605874 TI - Prediction of the permanent dentition in deciduous anterior crossbite. AB - Early prospective evaluation for self-correction of deciduous anterior crossbite can enable identification of patients who require early treatment as well as those who do not. The purpose of the present study was to generate an algorithm that can be used to predict self-correction in the transitional dentition in 3 year-old subjects. The subjects were divided into 2 groups. One group comprised 22 subjects whose anterior crossbite self-corrected during the transitional stage (hereafter referred to as group N). The other group was comprised of 22 subjects whose anterior crossbite persisted during the transitional dentition (hereafter referred to as group R). All subjects were examined using lateral cephalometric radiography in order to evaluate differences in occlusion. Fifteen measurements were used for the evaluation. For each measurement, the variance ratio and the difference in the population mean between groups N and R were tested and t-values were derived. Based on the Student's t-test results, only measurements that had statistically significant differences (P < .05) were extracted. Predictor variables that had a partial F value of 5 or greater were selected for stepwise discriminant analysis, and the following equation was obtained: deciduous indicator (DI) = -0.58(cranial length anterior) + 1.31(posterior facial height) - 0.76(porion location) - 2.02(Wits appraisal) - 70.28. The lower the DI value (negative), the higher the probability that the crossbite will self-correct at the transitional dentition. On the other hand, a high (positive) discriminant score strongly suggests that the subject requires treatment in the primary dentition. The result of this analysis showed that the apparent error rate was 95.46% and the Maharanobis' generalized distance was 8.99. PMID- 11605875 TI - Effect of head rotation on lateral cephalometric radiographs. AB - The purpose of this study was to identify the potential projection errors of lateral cephalometric radiographs due to head rotation in the vertical Z-axis. For this investigation, 17 human dry skull samples with permanent dentition were collected from the Department of Anatomy in the College of Medicine, Chosun University. They had no gross asymmetry and were well preserved. Each dry skull was rotated from 0 degrees to +/- 15 degrees at 1 degrees intervals. A vertical axis, the Z-axis, was used as a rotational axis to have 527 lateral cephalometric radiographs exposed. The findings were that: (1) angular measurements have fewer projection errors than linear measurements; (2) the greater the number of landmarks on the midsagittal plane that are included in angular measurements, the fewer the projection errors occurring; (3) horizontal linear measurements decrease gradually in length as the rotational angle toward the film increases, whereas a small increase and then decrease of the length occurs as the rotational angle toward the focal spot increases; (4) horizontal linear measurements have more projection errors than vertical linear measurements according to head rotation; and (5) projection errors of vertical linear measurements increase as the distance from the rotational axis increases. In summary, angular measurements of lateral cephalometric radiographs are more useful than linear measurements in minimizing the projection errors associated with head rotation on a vertical axis. PMID- 11605876 TI - A 2-center comparison of orthodontist's perceptions of orthodontic treatment difficulty. AB - The aim of this study was to determine which factors correlate with easy and difficult treatments and to assess the use of the Index of Complexity, Outcome & Need (ICON) as an indicator for treatment difficulty. The study was conducted at 2 centers using a retrospective cross-sectional questionnaire-based design. The participants were specialist orthodontic practitioners in Dresden, Germany and Cardiff, UK. Sixteen specialist orthodontists participated. Each supplied 10 completed cases--5 they regarded as being easy and 5 as being difficult. The specialist orthodontists completed a questionnaire and stated up to 5 reasons why they considered the case easy or difficult. Two examiners were calibrated in the use of the ICON. Logistic regression analysis using a forward conditional systematic model with complexity of case (ie, easy or difficult) as the dependent variable demonstrated statistical significance of the following patient-related factors: pretreatment ICON score, number of appointments, and age. Chi-squared testing demonstrated statistical significance of the following factors: cooperation, extent of overbite, presence of dysfunction, extent of overjet, anchorage, angulation of teeth, presence of crossbite, center-line shift, nonextraction treatment, age at start of treatment, compliance during the course of treatment, oral hygiene level. This study indicates that the main distinguishing factors between easy and difficult cases appear to be pretreatment age, number of appointments, and pretreatment ICON score. However, the odds ratios were not sufficiently high for these factors to be strong predictors of difficulty. PMID- 11605878 TI - Functional appliances. Apical force distribution. PMID- 11605877 TI - Moving an ankylosed central incisor using orthodontics, surgery and distraction osteogenesis. AB - When a dentist replants an avulsed tooth, the repair process sometimes results in the cementum of the root and the alveolar bone fusing together, with the replanted tooth becoming ankylosed. When this occurs, the usual process of tooth movement with bone deposition and bone resorption at the periodontium cannot function. If dental ankylosis occurs in the maxillary incisor of a growing child, the ankylosed tooth also cannot move vertically with the subsequent vertical growth of the alveolar process. This results in the ankylosed tooth leaving the plane of occlusion and often becoming esthetically objectionable. This report describes a 12-year-old female with a central incisor that was replanted 5 years earlier, became ankylosed, and left the occlusal plane following subsequent normal vertical growth of the alveolar process. When growth was judged near completion, the tooth was moved back to the occlusal plane using a combination of orthodontics, surgical block osteotomy, and distraction osteogenesis to reposition the tooth at the proper vertical position in the arch. This approach had the advantage of bringing both the incisal edge and the gingival margin of the clinical crown to the proper height in the arch relative to their antimeres. Previous treatment procedures for ankylosed teeth have often involved the extraction of the affected tooth. When this is done, a vertical defect in the alveolar process results that often requires additional bone surgery to reconstruct the vertical height of the alveolar process. If the tooth is then replaced, the replacement tooth must reach from the final occlusal plane to the deficient ridge. This results in an excessively long clinical crown with a gingival height that does not match the adjacent teeth. PMID- 11605879 TI - Multidrug-resistant tuberculosis and the need for biosocial perspectives. PMID- 11605881 TI - Characteristics of drug resistance and HIV among tuberculosis patients in Mozambique. AB - SETTING: The rate of human immunodeficiency virus (HIV) seroprevalence among tuberculosis patients varies between 2% and 53% in Mozambique, depending on the region. Drug resistance surveillance has been performed in only a few cities in Mozambique. OBJECTIVES: To establish the extent of drug resistance in areas of Mozambique with different levels of HIV prevalence, to estimate the prevalence of HIV among tuberculosis (TB) patients, and to examine the association between drug resistance and HIV infection. DESIGN: All tuberculosis patients diagnosed at randomly selected health facilities over 9 months (September 1998 to June 1999) were enrolled in the study. Sputum was collected, smeared and cultured, and drug susceptibility tests were performed. Blood was tested for HIV in the respective provinces, and patients received pre-test and post-test counselling. RESULTS: Of 709 culture-positive cases, 25.5% were HIV-positive. HIV-positive patients were significantly more likely to have a prior history of treatment (OR 2.2; 95% CI 1.9-3.6) and resistance to both isoniazid and streptomycin (OR 2.3; 95% CI 1.3, 4.5). In patients with no history of prior tuberculosis treatment, the multidrug resistance rate was 3.4% and resistance to isoniazid and streptomycin (HS) was 5.2%. Any drug resistance was significantly more common among those with a history of prior treatment (OR 3.1; 95% CI 2.1-4.7), particularly resistance to HS (OR 4.5; 95% CI 2.6-7.9). CONCLUSIONS: This study demonstrates substantial levels of drug resistance in Mozambique. Differences in drug resistance between high and low HIV prevalence areas may be related to prior treatment. PMID- 11605880 TI - Determinants of drug-resistant tuberculosis: analysis of 11 countries. AB - SETTING: Eleven countries/territories. OBJECTIVES: Global information on the determinants of drug-resistant tuberculosis (TB) based on representative data is not available. We therefore studied the relationship between demographic characteristics, prior TB treatment, and human immunodeficiency virus (HIV) infection with anti-tuberculosis drug resistance. METHODS: Population-based representative data on new and previously treated patients with TB collected within an international drug resistance surveillance network. RESULTS: Of 9,615 patients, 8,222 (85.5%) were new cases of TB and 1,393 (14.5%) were previously treated cases. Compared with new cases, previously treated cases were significantly more likely to have resistance to one (OR = 2.5,95% CI 2.1-3.0; P < 0.001), two (OR = 4.6, 95%CI 3.7-5.6; P < 0.001), three (OR = 11.5, 95%CI 8.6 15.3; P < 0.001), and four (OR = 18.5, 95% CI 12.0-28.5; P < 0.001) drugs. An approximately linear increase in the likelihood of having multidrug-resistant tuberculosis (MDR-TB) was observed as the total time (measured in months) of prior anti-tuberculosis treatment increased (P < 0.001, chi2 for trend). In multivariate analysis, prior TB treatment for 6-11 months (OR = 7.6, 95% CI 2.6, 22.4; P < 0.001) and > or = 12 months (OR 13.7, 95% CI 4.5-41.6; P < 0.001), but not HIV positivity, was associated with MDR-TB. CONCLUSION: This study shows that prior but ineffective treatment is a strong predictor of drug resistance, and that HIV is not an independent risk factor for MDR-TB. The association between length of treatment and drug resistance may reflect longer treatment as a result of treatment failure in patients with drug resistance; it may also reflect irregular prior treatment for TB, leading to drug resistance. PMID- 11605882 TI - Drug resistance trends in M. tuberculosis: Blackburn 1990-1999. AB - SETTING: Blackburn, United Kingdom. OBJECTIVE: To describe the drug resistance data for Mycobacterium tuberculosis in white and Indian Subcontinent (ISC) ethnic patients in a high prevalence district in the United Kingdom (UK) over a 10-year period. DESIGN: Data from a detailed prospective clinical and epidemiological database of all notified patients were examined for the years 1990-1999 inclusive. RESULTS: Primary isoniazid resistance was found in 17/229 (7.4%) of ISC and 3/67 (4.5%) of white isolates. There was no statistical difference in the rates of drug resistance in those of ISC ethnic origin, whether they were ISC or UK born and whether or not they had made return visits to the ISC. CONCLUSION: The rate of primary isoniazid resistance remains between 5-10% in ISC patients in Blackburn, showing no fall from previous surveys. The rate of drug resistance was not lower in those born in the UK, irrespective of whether return visits had been made to the ISC. These data will need to be further monitored. PMID- 11605883 TI - Evaluation of FASTPlaqueTB-RIF, a rapid, manual test for the determination of rifampicin resistance from Mycobacterium tuberculosis cultures. AB - SETTING: Two Mycobacteriology Reference Laboratories in Johannesburg (Laboratory 1) and Cape Town (Laboratory 2), South Africa. OBJECTIVE: To determine the ability of the FASTPlaqueTB-RIF test to correctly identify rifampicin susceptibility on strains of Mycobacterium tuberculosis cultured on solid media. DESIGN: A comparative study of FASTPlaqueTB-RIF and conventional drug susceptibility methods, with selection bias to include sufficient rifampicin resistant strains. RESULTS: Rifampicin susceptibility results were available for 191 strains of M. tuberculosis. Eighty-one strains were found to be rifampicin resistant and 110 strains were rifampicin susceptible by conventional methods. The sensitivity, specificity and overall accuracy for the FASTPlaqueTB-RIF were 100%, 97% and 98% at Laboratory 1, and 100%, 94% and 97% at Laboratory 2. CONCLUSION: FASTPlaqueTB-RIF offers a performance comparable to the gold standard proportion methods of rifampicin susceptibility testing, as well as the advantage of the speed of results that the newer methods deliver, without the need for specialised equipment. This makes FASTPlaqueTB-RIF a rapid test for rifampicin resistance suitable for widespread application. PMID- 11605884 TI - Tuberculosis treatment in nepal: a rapid assessment of government centers using different types of patient supervision. AB - SETTING: Urban and periurban government tuberculosis (TB) treatment clinics in Nepal. OBJECTIVE: To assess TB treatment supervision strategies and outcomes. DESIGN: Three types of treatment centers were selected according to intensity of treatment supervision: Group A-all patients supervised by directly observed therapy (DOT) at the treatment center during the intensive phase; Group B flexible DOT where patient-nominated treatment supervisors include community or family members; Group C-drugs dispensed monthly and no supervised treatment. The cohort studied comprised all new patients starting treatment during a 5-month period in 1996 (n = 759). RESULTS: At group A treatment centers, 100% of patients had daily DOT supervised by treatment center staff during the intensive phase. At group B sites, 75% of nominated supervisors were family or community members and 13% of patients had no supervisor. At group C sites 93% of patients were unsupervised. Bacteriologically confirmed cure rates for smear-positive patients were 91% (95%CI 80.3-97.2) for A sites, 57% (95%CI 48.8-64.0) for B, and 34% (95%CI 25.1-40.4) for C. Treatment centers with the best results had good access to laboratory facilities, uninterrupted drug supply, longer clinic hours, standardized TB case management, and support from a non-governmental organization. CONCLUSION: At government facilities in Nepal, only group A treatment centers achieved World Health Organization global targets for cure. Group B treatment centers showed better outcomes than unsupervised therapy but did not achieve cure targets. Rapid low-cost assessments to collect data that are not routinely reported can improve the evaluation of program aspects such as supervision strategies. PMID- 11605885 TI - High tuberculosis notification and treatment success rates through community participation in central Sulawesi, Republic of Indonesia. AB - SETTING: Central Sulawesi Province, Republic of Indonesia. OBJECTIVE: To increase tuberculosis case notification and maintain high treatment success rates through community participation in a tuberculosis field programme. DESIGN: Comparison of tuberculosis case notification and treatment results in a community based tuberculosis programme (CBTP), before and after introduction of the programme and between areas where the programme was and was not introduced. RESULTS: During 1998, the CBTP was introduced in two of the four rural districts of the Central Sulawesi province, covering 224 (29%) of the 772 villages and 362,700 (33%) of the 1,109,100 population in these districts. In the CBTP villages the notification rate of new smear-positive patients per 100,000 population increased from SI in 1996 and 48 in 1997 to 166 in 1998. In the 548 non-CBTP villages the rates were 62, 60 and 70, respectively. The sputum conversion rate at the end of the first 2 months of the treatment was over 85% in both the CBTP and the non CBTP villages. In the CBTP villages the treatment success rate (cure and treatment completion) was 90.4%, 89.5% and 93.7% in 1996, 1997, and 1998. For the non-CBTP villages these rates were respectively 85.4%, 86.8% and 85.9%. In 1998 the sputum conversion and treatment success rates were significantly higher in the CBTP villages than in the non-CBTP villages. CONCLUSION: Through community participation, the notification of new smear-smear positive patients increased substantially, while sputum conversion and treatment success rates remained high. PMID- 11605886 TI - Incidence of tuberculosis and the importance of treatment of latent tuberculosis infection in a Spanish prison population. AB - OBJECTIVE: To establish the incidence of tuberculosis (TB) in a prison population and its link with latent tuberculosis infection treatment (LTIT). METHODS: From 1991 to 1999 a TB programme was run in a Spanish prison. A cohort study was conducted to know TB incidence and the associated variables. RESULTS: Of 1,050 people studied, 10% were co-infected by the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. Twenty-three cases of TB were detected, an incidence rate of 6.39 per 1,000 person-years of follow-up. Multivariate analysis showed HIV-infected patients (RR 4.07, 95%CI 2.61-6.35), and those infected by M. tuberculosis who did not undergo LTIT (RR 10.15, 95%CI 0.90-50.59) to be at greater risk of developing TB. In TST reactors, those co-infected with HIV (RR 10.15, 95%CI 3.80-27.07) and those who had not undergone LTIT (RR 8.53, 95%CI 1.12-64.86) were shown to be at the greatest risk of developing TB. CONCLUSIONS: The observed incidence of TB is much higher in prisons than in the community at large. HIV-M. tuberculosis co-infection appears as the main risk factor for developing TB, while LTIT significantly reduces incidence. PMID- 11605887 TI - Management of tuberculosis in San Diego County: a survey of physicians' knowledge, attitudes and practices. AB - SETTING: A survey conducted in San Diego County. OBJECTIVE: To assess local physicians' knowledge, attitudes and practices regarding tuberculosis (TB). METHODS: The survey consisted of questions covering diagnosis and treatment of active disease, diagnosis and treatment of latent infection, and infection control. The survey was sent to physicians who reported a TB case or suspect to the local health department in the years 1995-1997. RESULTS: Of the 384 physicians in this group, 150 (39%) returned the survey form. The percentage of physicians whose response conformed to health department guidelines varied widely from question to question (51%-94%, median 83%). Pulmonary medicine and infectious diseases specialists, physicians educated completely in the United States (US), and physicians who treated six or more TB patients in the past 2 years were more likely to give answers in agreement with health department policies. CONCLUSIONS: Because the response rate to the survey was low, these findings may not be completely representative of the targeted group of physicians. Nevertheless, they may indicate that health care provider education about TB management standards is needed. PMID- 11605888 TI - [Study of tuberculosis in health care workers in the public sector of Morocco]. AB - SETTING: Tuberculosis is one of the most important causes of disease in Morocco, with an annual incidence of 100 cases per 100,000 population. There is a permanent risk of tuberculosis for health care workers in contact with bacillary positive tuberculosis patients. OBJECTIVE: To evaluate the risk and incidence of tuberculosis in health care workers and to study its distribution by cohort analysis. METHODS: A questionnaire was sent to all of the provinces and prefectures of the kingdom to gather information on tuberculosis cases notified between 1994 and 1997 in health care workers. RESULTS: Over the 4-year period, 130 new cases of tuberculosis were notified among health care workers in 30 provinces and prefectures: 73 men (56%) and 57 women (44%), with a mean age of 41.3 +/- 8.9 and 38.6 +/- 8.4 years, respectively (P = 0.093). The mean cumulative incidence was 85.3/100 000 health care workers; for doctors in specialist diagnostic centres for tuberculosis it was 1,094.8/100,000. The survey showed no significant difference between the mean annual cumulative incidences for doctors (83.4), nurses (78.5) and administrative staff (94.3). The cohort analysis indicated a mean annual success rate of 89.2%, failure rate of 0.9%, lost to follow-up 0.8%, death 3.8% and transfer out 3.1%. Several studies have shown weaknesses in the conditions of hygiene and security in the health centres (such as lack of gloves and masks, and meals taken within the workplace). CONCLUSION: The risk of tuberculosis is not much higher in health care workers in general than in the general population; however, it is significantly higher in the specialist diagnostic centres for tuberculosis. The recent creation of health units for personnel working in the health centres should result in improvements in working conditions if the recommended preventive measures are respected. PMID- 11605889 TI - Evidence for action? Patterns of clinical and public health research on tuberculosis in South Africa, 1994-1998. AB - OBJECTIVES: To describe patterns of clinical and public health research into tuberculosis in South Africa from 1994-1998, and to assess the quality of studies of diagnostic accuracy and treatment. DESIGN: MEDLINE and the African Health Anthology were searched for journal articles published from 1994-1998 reporting clinical and public health research into tuberculosis in South Africa. Information extracted from the reports included research setting, study design, aspects of the quality of study design and reporting, and evidence of attention to statistical power. RESULTS: One hundred and thirty-five eligible studies were identified; 39 (28.9%) of the studies were case reports or case series. Important methodological flaws were identified in studies of diagnosis and treatment that compromised the validity of the study results. Of the 28 studies assessing interventions, 10 (35.7%) were randomised controlled trials with only one reporting adequate allocation. Of the 34 studies assessing diagnosis, 16 (47.0%) were cross-sectional assessments of diagnostic accuracy, and none reported that comparison of the reference standard was independent or blind. Fifty-four (79.4%) of the analytical studies with statistically non-significant results showed no evidence of consideration of sample size. CONCLUSION: The usefulness of tuberculosis research in South Africa is compromised by the questionable validity of many studies and a lack of attention to sample size. PMID- 11605890 TI - Characterisation of the pncA gene in Mycobacterium tuberculosis isolates from Gauteng, South Africa. AB - SETTING: The use of pyrazinamide (PZA) is important for the treatment of Mycobacterium tuberculosis as it is bactericidal to semi-dormant mycobacteria that are not affected by other drugs. The incidence of resistance to PZA and other drugs used in the treatment of M. tuberculosis is increasing in South Africa. OBJECTIVE: To characterise the pncA gene of M. tuberculosis isolates from Gauteng, South Africa, and to develop a rapid diagnostic method. DESIGN: The pncA gene and the putative regulatory gene were characterised by sequence analysis in a total of six PZA susceptible and 15 resistant isolates. The association with classical PZA susceptibility testing and PZase activity was determined. RESULTS: All PZA-resistant isolates were PZase negative as well as resistant to at least one other anti-tuberculosis drugs. Mutations were identified throughout the length of the pncA gene in 10/15 PZA-resistant isolates. Five lacked PZase activity, but the wild type pncA sequence was present. In all six PZase-positive strains, a PZA-susceptible pattern was obtained on BACTEC and the wild type pncA sequence was present. CONCLUSION: Sequencing is an effective means to identify mutations in the pncA gene in M. tuberculosis and therefore resistance to PZA. The fact that some PZA-resistant M. tuberculosis isolates lack mutations in the pncA gene suggests that alternative mechanisms for drug resistance exist. In PZase negative strains with no genetic changes which are resistant to 100 microg/ml and susceptible to 300 microg/ml, 300 microg/ml may be a more reliable breakpoint. PMID- 11605891 TI - Serological response (Western blot) to fractions of Mycobacterium tuberculosis sonicate antigen in tuberculosis patients and contacts. AB - OBJECTIVE: To assess the serological response to fractions of Mycobacterium tuberculosis sonicate antigen by Western blot analysis in patients with tuberculosis and contacts. METHODS: We studied 71 individuals including 43 patients with active tuberculosis, 16 contacts and 12 healthy blood donors. For Western blot analysis, M. tuberculosis (H37Rv strain) sonicate antigen extract was fractionated by electrophoresis on polyacrylamide gel (SDS-PAGE). RESULTS: We obtained antibody responses directed against four antigenic fractions with molecular weights of 71, 65, 26-38 and 19 kDa. Sixty per cent of pleural tuberculosis and 52.4% of smear-positive pulmonary tuberculosis had whole responses against all four fractions; there were no partial responses in these groups. For patients with smear-negative pulmonary tuberculosis whole responses were 17.6% and partial responses 41.2%. All contacts whose tuberculin tests converted from negative to positive (three cases) reacted exclusively against the 19 kDa fraction. CONCLUSIONS: Western blot-positive results in patients with pleural and smear-positive pulmonary tuberculosis were characterised by a whole pattern against all four antigenic fractions, whereas patients with smear negative pulmonary tuberculosis showed heterogeneous results. The exclusive response against the 19 kDa fraction observed in contacts with tuberculin conversion could help to identify candidates for preventive therapy. PMID- 11605892 TI - The prognosis of respiratory failure in patients with tuberculous destroyed lung. AB - SETTING: The medical intensive care unit of a tertiary referral hospital. OBJECTIVE: To determine the prognosis of patients whose lungs are damaged by previous and/or present tuberculosis infection and who have subsequently been presented with acute respiratory failure requiring mechanical ventilation. DESIGN: A consecutive series of 38 patient cases with retrospective data analysis. RESULTS: Pulmonary function test results for tests performed within the previous year were made available in 21 of the 38 cases (55%). These showed a mean (+/- SD) forced vital capacity (FVC) of 1.52 +/- 0.46 L (41.0 +/- 14.5% predicted), a forced expiratory volume/second (FEV1) of 0.77 +/- 0.18 L (29.3 +/- 13.6% predicted), and an FEV1/FVC ratio of 55.1 +/- 16.2%. The acid-fast bacilli (AFB) positive group had a significantly higher mortality and more severe lung destruction when compared with the AFB-negative group. Patients with positive AFB were significantly more hypocapnic than those with negative AFB (6.4 +/- 2.7 vs. 9.3 +/- 3.9 kPa, P = 0.020). In multivariate analysis, the level of PaCO2 on admission was identified as the only significant prognostic index (OR 0.76, 95%CI 0.60-0.96). CONCLUSION: Patients with positive AFB smears or cultures may have higher mortality rates than those with negative AFB in the tuberculosis destroyed lung patients with acute respiratory failure. A higher PaCO2 measurement could indicate a better survival rate in this group of patients. PMID- 11605893 TI - Antibody detection for the diagnosis of tuberculous pleuritis. AB - SETTING: University Hospital, Bangkok, Thailand. OBJECTIVE: To evaluate the diagnostic value of antibody detection in serum and in pleural effusion as a marker of tuberculous pleuritis (TBP). DESIGN: Cross-sectional study. MATERIALS AND METHODS: One hundred and fifty-five patients with pleural effusion who underwent diagnostic evaluation at Siriraj Hospital between March 1999 and May 2000 were recruited. Samples of pleural fluid were examined biochemically, cytologically and microbiologically. Pathological examination of pleural tissue was also performed. The diagnosis of TBP or other diagnosis was made by either pathological finding or culture result. Immunochromatographic tuberculosis (ICT TB) tests for antibody detection were then performed using the stored serum samples and effusions from those patients with a final definite diagnosis. This test detects antibodies to five secreted antigens of Mycobacterium tuberculosis, including the 38 kDa antigen. RESULTS: We investigated 67 patients with TBP, 44 with malignant pleural effusions, seven with transudates and one with cryptococcal pleuritis. The combined ICT-TB serum and effusion tests were positive in 34/67 TBP and 22/52 non-TBP patients. The sensitivity, specificity, positive predictive value and negative predictive value of the ICT-TB test were 50.7, 57.7, 60.7 and 47.6%, respectively. In 11 TBP patients with human immunodeficiency virus (HIV) co-infection, the sensitivity of the ICT-TB test was 45.6%. There was no correlation between the test positivity and culture result or duration of disease. CONCLUSIONS: The diagnostic value of antibody detection in TBP is modest in an area with intermediate prevalence of tuberculosis, independently of HIV serological status. PMID- 11605894 TI - The Asthma Workshop. Report of a workshop organised by the International Union Against Tuberculosis and Lung Disease, Paris, 15-16 December 2000. PMID- 11605895 TI - Care of HIV complications in patients receiving anti-tuberculosis treatment in hospitals in Malawi. AB - A cross-sectional study was carried out in all 43 hospitals in Malawi that register and treat tuberculosis (TB) patients to determine whether there is care and treatment for human immunodeficiency virus (HIV) complications in TB patients. Of 1,416 adults with TB, 861 (61%) had HIV complications, 627 (44%) patients had received no ward round, and of 1,142 patients who had been on anti tuberculosis treatment for more than 7 days, 294 (26%) had not had a clinical review. Of patients with HIV complications, only 139 (16%) were receiving treatment. There is a lack of regular care and treatment for HIV complications in TB patients in Malawi. PMID- 11605897 TI - Immunological and toxicological implications of short-term studies in animals of pharmaceutical aerosol delivery to the lungs: relevance to humans. AB - The effects of xenobiotics on the lungs have been studied for many years. In the past 50 years, delivery of drugs to the lungs has been adopted to achieve local effects, specifically for the treatment of asthma. Recently, due to the proximity of the circulating blood supply and to their large surface area, the lungs have been proposed as the port of entry for drugs to obtain systemic effects, particularly for macromolecular compounds of biological origin. Numerous studies regarding drug formulation, delivery systems, and related pharmacokinetics have been reported; however, the concurrent effects of pulmonary delivery of drugs on the physiology of the lung has not been evaluated early in the development process. The prospect of using the lungs for the delivery of biological molecules such as proteins, peptides, and nucleic acids raises the question of the local toxicity of these compounds. Therefore, criteria must be established to study the initial impact of pulmonary drug delivery on the physiology of the lungs. This relates particularly to subtle local and systemic implications of those effects on the transport phenomena that may be contrasted with conventional toxicity studies focused on gross effects. PMID- 11605896 TI - Targeted delivery of drugs to the gastrointestinal tract. AB - The oral route is attractive for drug administration because it is associated with patient acceptability, less stringent production conditions, and lower costs. However, gastrointestinal destruction of labile molecules and low levels of absorption generally render oral delivery of peptides and proteins ineffective. Several strategies have the potential to enhance the efficacy of orally administered drugs. Bioadhesion is an approach for increasing interaction between drugs and the mucosae. Bioadhesive systems can be nonspecific, achieving adhesion via mechanical processes or specific systems that recognize receptors on epithelial cells. Lectins are one group of specific bioadhesives with many suitable properties for targeting of cells in the gastrointestinal tract (GIT). This review assesses the potential of lectins in the delivery of drugs and vaccines to the GIT. PMID- 11605898 TI - Antiallodynic effect of intrathecal neostigmine is mediated by spinal nitric oxide in a rat model of diabetic neuropathic pain. AB - BACKGROUND: Intrathecal administration of acetylcholinesterase inhibitors produces antinociception in both animals and humans, but their effect on diabetic neuropathic pain has not been studied. In the current study, we determined the antiallodynic effect of intrathecal injection of an acetylcholinesterase inhibitor, neostigmine, in a rat model of diabetic neuropathic pain. In addition, since acetylcholine can increase release of nitric oxide in the spinal cord, we studied the role of spinal endogenous nitric oxide in the action of intrathecal neostigmine in diabetic neuropathic pain. METHODS: Rats were rendered diabetic with an intraperitoneal 50-mg/kg injection of streptozotocin. Intrathecal catheters were inserted, with tips in the lumbar intrathecal space. Mechanical allodynia was determined by application of von Frey filaments to the hind paw. We first determined the dose-dependent effect of intrathecal neostigmine on allodynia. The role of spinal nitric oxide in the action of intrathecal neostigmine was then examined through intrathecal treatments with a neuronal nitric oxide synthase inhibitor (TRIM), a nitric oxide scavenger (PTIO), L arginine, or D-arginine. RESULTS: The diabetic rats developed a sustained tactile allodynia within 4 weeks after streptozotocin injection. Intrathecal injection of 0.1-0.5 microg neostigmine dose-dependently increased the withdrawal threshold in response to application of von Frey filaments. Intrathecal pretreatment with 30 microg TRIM or 30 microg PTIO abolished the antiallodynic effect of intrathecal neostigmine. Furthermore, the inhibitory effect of TRIM on the action of intrathecal neostigmine was reversed by intrathecal injection of 100 microg L arginine but not D-arginine. CONCLUSIONS: Intrathecal neostigmine produces a profound analgesic effect in a rat model of diabetic neuropathic pain. Spinal endogenous nitric oxide contributes to the analgesic action of intrathecal neostigmine in this rat model of diabetic neuropathic pain. PMID- 11605899 TI - Anesthetic-sensitive 2P domain K+ channels. PMID- 11605900 TI - Extremely prolonged vecuronium clearance in a brain death case. PMID- 11605901 TI - Successful resuscitation of a child after exsanguination due to aortoesophageal fistula from undiagnosed foreign body. PMID- 11605902 TI - Sequential compression devices can cause erroneous cardiac output measurements. PMID- 11605903 TI - Anesthesia for cesarean delivery in a patient with an undiagnosed traumatic diaphragmatic hernia. PMID- 11605904 TI - Spinal-epidural hematoma following epidural anesthesia in the presence of antiplatelet and heparin therapy. PMID- 11605905 TI - Anaphylaxis due to airborne exposure to latex in a primigravida. PMID- 11605906 TI - Complete heart block during anesthetic management in a patient with mucopolysaccharidosis type VII. PMID- 11605907 TI - Acute failure of oxygen delivery. PMID- 11605908 TI - Intramuscular succinylcholine and laryngospasm. PMID- 11605909 TI - The substitute for the intravenous route. PMID- 11605910 TI - Combitube and similar devices should undergo long-term safety evaluation before their routine use in clinical practice. PMID- 11605911 TI - The "sniffing position" facilitates tracheal intubation. PMID- 11605912 TI - Reevaluating the "cornerstone of training in anesthesiology". PMID- 11605913 TI - The "sniffing position" is not an anatomic myth. PMID- 11605914 TI - Another view of the "sniffing position". PMID- 11605915 TI - You can smell the difference. PMID- 11605916 TI - Nitroglycerine and sphincter of Oddi spasm. PMID- 11605917 TI - David Waritier: recipient of the 2001 Excellence in Research Award. PMID- 11605918 TI - Fetuses, fentanyl, and the stress response: signals from the beginnings of pain? PMID- 11605919 TI - Common practice and concepts in anesthesia: time for reassessment: is the sniffing position a "gold standard" for laryngoscopy? PMID- 11605920 TI - Effect of direct fetal opioid analgesia on fetal hormonal and hemodynamic stress response to intrauterine needling. AB - BACKGROUND: Whether the fetus can experience pain remains controversial. During the last half of pregnancy, the neuroanatomic connections for nociception are in place, and the human fetus mounts sizable stress responses to physical insults. Analgesia has been recommended for intrauterine procedures or late termination, but without evidence that it works. The authors investigated whether fentanyl ablates the fetal stress response to needling using the model of delayed interval sampling during intrahepatic vein blood sampling and transfusion in alloimmunized fetuses undergoing intravascular transfusion between 20 and 35 weeks. METHODS: Intravenous fentanyl (10 microg/kg estimated fetal weight x 1.25 placental correction) was given once at intrahepatic vein transfusion in 16 fetuses, and changes (posttransfusion - pretransfusion) in beta endorphin, cortisol, and middle cerebral artery pulsatility index were compared with intrahepatic vein transfusions without fentanyl and with control transfusions at the placental cord insertion. RESULTS: Fentanyl reduced the beta endorphin (mean difference in changes, -70.3 pg/ml; 95% confidence interval, -121 to -19.2; P = 0.02) and middle cerebral artery pulsatility index response (mean difference, 0.65; 95% confidence interval, 0.26-1.04; P = 0.03), but not the cortisol response (mean difference, -10.9 ng/ml, 95% confidence interval, -24.7 to 2.9; P = 0.11) in fetuses who had paired intrahepatic vein transfusions with and without fentanyl. Comparison with control fetuses transfused without fentanyl indicated that the beta endorphin and cerebral Doppler response to intrahepatic vein transfusion with fentanyl approached that of nonstressful placental cord transfusions. CONCLUSIONS: The authors conclude that intravenous fentanyl attenuates the fetal stress response to intrahepatic vein needling. PMID- 11605921 TI - Randomized study comparing the "sniffing position" with simple head extension for laryngoscopic view in elective surgery patients. AB - BACKGROUND: The "sniffing position" is recommended for optimization of glottic visualization under direct laryngoscopy. However, no study to date has confirmed its superiority over simple head extension. In a prospective, randomized study, the authors compared the sniffing position with simple head extension in orotracheal intubation. METHODS: The study included 456 consecutive patients. The sniffing position was obtained by placement of a 7-cm cushion under the head of the patient. The extension position was obtained by simple head extension. The anesthetic procedure included two Laryngoscopies without paralysis: the first was used for topical glottic anesthesia. During the second direct laryngoscopy, intubation of the trachea was performed. The head position was randomized as follows: group A was in the sniffing position during the first Laryngoscopy and the extension position during the second, group B was in the extension position during the first laryngoscopy and the sniffing position during the second. Glottic exposure was assessed by the Cormack scale. RESULTS: The sniffing position improved glottic exposure (decreased the Cormack grade) in 18% of patients and worsened it (increased the Cormack grade) in 11% of patients, in comparison with simple extension. The Cormack grade distribution was not significantly modified between the two groups. Multivariate analysis showed that reduced neck mobility and obesity were independently related to improvement in laryngoscopic view with application of the sniffing position. CONCLUSIONS: Routine use of the sniffing position appears to provide no significant advantage over simple head extension for tracheal intubation in this setting. The sniffing position appears to be advantageous in obese and head extension-limited patients. PMID- 11605922 TI - Changes in plasma creatinine concentration after cardiac anesthesia with isoflurane, propofol, or sevoflurane: a randomized clinical trial. AB - BACKGROUND: Renal impairment often follows cardiac surgery. The authors investigated whether sevoflurane produces greater increases in plasma creatinine concentration than isoflurane or propofol after elective coronary artery surgery. METHODS: As part of maintenance anesthesia, including during cardiopulmonary bypass, patients were randomly allocated to receive one of three agents: isoflurane (n = 118), sevoflurane (n = 118), or propofol (n = 118). Fresh gas flows were 3 l/min. The preoperative plasma creatinine concentration was subtracted from the highest creatinine concentration in the first 3 postoperative days. A median maximum increase greater than 44 microM (0.5 mg/dl) was regarded as clinically important. Data were analyzed on an intention-to-treat basis. Subgroup analyses were performed on per-protocol patients and those with preoperative renal impairment (creatinine concentration > 130 microM [1.47 mg/dl] or urea > 7.7 mM [blood urea nitrogen, 21.6 mg/dl]). RESULTS: The differences between the groups were small, clinically unimportant, and not statistically significant for the primary analysis and subgroups. The proportions of patients with creatinine increases greater than 44 microM were 15% in the isoflurane group, 17% in the sevoflurane group, and 11% in the propofol group (P = 0.45). The median increases were 8 microM in the isoflurane group, 4 microM in the sevoflurane group, and 6 microM in the propofol group. The differences between the three median maximum increases were 1-4 microM (P > 0.45). In the subgroup with preoperative renal impairment, the median increases were 10 microM in the isoflurane group, 15 microM in the sevoflurane group, and 5 microM in the propofol group (P = 0.72). CONCLUSIONS: Sevoflurane did not produce greater increases in creatinine than isoflurane or propofol after elective coronary artery surgery. PMID- 11605923 TI - Changes in blood volume and hematocrit during acute preoperative volume loading with 5% albumin or 6% hetastarch solutions in patients before radical hysterectomy. AB - BACKGROUND: The impact of acute preoperative volume loading with colloids on blood volume has not been investigated sufficiently. METHODS: Before surgery, in 20 patients undergoing major gynecologic procedures, volume loading was performed during anesthesia by infusing approximately 20 ml/kg of colloid at a rate of 90 ml/min (group I: 5% albumin solution; group II: 6% hetastarch solution; n = 10 each). Plasma volume (indocyanine green dilution technique), erythrocyte volume (labeling erythrocytes with fluorescein), hematocrit, total protein, and hetastarch plasma concentrations (group II) were measured before and 30 min after the end of infusion. RESULTS: More than 1,350 ml of colloid (approximately 50% of the baseline plasma volume) were infused within 15 min. Thirty minutes after the infusion had been completed, blood volume was only 524 +/- 328 ml (group I) and 603 +/- 314 ml (group II) higher than before volume loading. The large vessel hematocrit (measured by centrifugation) dropped more than the whole body hematocrit, which was derived from double-label measurements of blood volume. CONCLUSIONS: The double-label measurements of blood volume performed showed that 30 min after the infusion of approximately 20 ml/kg of 5% albumin or 6% hetastarch solution (within 15 min), only mean 38 +/- 21% and 43 +/- 26%, respectively, of the volume applied remained in the intravascular space. Different, i.e., earlier or later, measuring points, different infusion volumes, infusion rates, plasma substitutes, or possibly different tracers for plasma volume measurement might lead to different results concerning the kinetics of fluid or colloid extravasation. PMID- 11605924 TI - Effect of epidural analgesia with ambulation on labor duration. AB - BACKGROUND: Ambulatory epidural analgesia (AEA) is a popular choice for labor analgesia because ambulation reportedly increases maternal comfort, increases the intensity of uterine contractions, avoids inferior vena cava compression, facilitates fetal head descent, and relaxes the pelvic musculature, all of which can shorten labor. However, the preponderance of evidence suggests that ambulation during labor is not associated with these benefits. The purpose of this study is to determine whether ambulation with AEA decreases labor duration from the time of epidural insertion to complete cervical dilatation. METHODS: In this prospective, randomized study, 160 nulliparous women with AFA were randomly assigned to one of two groups: AEA with ambulation and AEA without ambulation. AEA blocks were initiated with 15-20 ml ropivacaine (0.07%) plus 100 microg fentanyl, followed by a continuous infusion of 0.07% ropivacaine plus 2 microg/ml fentanyl at 15-20 ml/h. Maternal measured variables included ambulation time, time from epidural insertion to complete dilatation, stage II duration, pain Visual Analogue Scale scores, and mode of delivery. APGAR scores were recorded at 1 and 5 min. Results are expressed as mean +/- SD or median and analyzed using the t test, chi-square, or the Mann-Whitney test at P < or = 0.05. RESULTS: The ambulatory group walked 25.0 +/- 23.3 min, sat upright 40.3 +/- 29.7 min, or both. Time from epidural insertion to complete dilatation was 240.9 +/- 146.1 min in the ambulatory group and 211.9 +/- 133.9 min in the nonambulatory group (P = 0.206). CONCLUSION: Ambulatory epidural analgesia with walking or sitting does not shorten labor duration from the time of epidural insertion to complete cervical dilatation. PMID- 11605925 TI - Relation between quality of recovery in hospital and quality of life at 3 months after cardiac surgery. AB - BACKGROUND: Improved quality of life (QoL) is a desirable outcome of cardiac surgery. The aim of the current study was to measure the association between quality of recovery 3 days after surgery and QoL measured 3 months later. METHODS: After obtaining ethics committee approval and consent, 120 adult cardiac surgical patients were studied. A 40-item quality of recovery score (QoR-40) was used to measure postoperative health status on days 1-3 and 1 month after surgery. QoL was measured using the short-form health survey (SF-36) at 1 and 3 months after surgery. The effect size (delta mean/SD) was used to define responsiveness, a clinically important difference in health. Associations were measured using correlation and reliability coefficients. RESULTS: There was a significant change in the mean QoR-40 for up to 1 month after surgery (P < 0.0005). QoL was improved at 3 months (P < 0.0005) but not 1 month (P = 0.29) after surgery. There was a moderate correlation between day-3 QoR-40 and 3-month SF-36 (r = 0.39; P < 0.0005). A poor-quality recovery in hospital predicted a poor QoL at 3 months (adjusted odds ratio, 4.20; 95% confidence interval, 1.41 12.5; P = 0.01). CONCLUSIONS: The QoR-40 is a valid measure of quality of recovery after surgery and anesthesia. When compared with the SF-36, it is a better measure of early postoperative recovery. A poor-quality recovery on the days after surgery can predict a poor QoL at 3 months after surgery. This may allow earlier and more effective support strategies while patients are still in the hospital (counseling, home assistance, local doctor notification, cardiac rehabilitation). PMID- 11605926 TI - Comparison of two different temperature maintenance strategies during open abdominal surgery: upper body forced-air warming versus whole body water garment. AB - BACKGROUND: A new system has been developed that circulates warm water through a whole body garment worn by the patient during surgery. In this study the authors compared two different strategies for the maintenance of intraoperative normothermia. One strategy used a new water garment warming system that permitted active warming of both the upper and lower extremities and the back. The other strategy used a single (upper body) forced-air warming system. METHODS: In this prospective, randomized study, 53 adult patients were enrolled in one of two intraoperative temperature management groups during open abdominal surgery with general anesthesia. The water-garment group (n = 25) received warming with a body temperature (rectal) set point of 36.8 degrees C. The forced-air-warmer group (n = 28) received routine warming therapy using upper body forced-air warming system (set on high). The ambient temperature in the operating room was maintained constant at approximately 20 degrees C. Rectal, distal esophageal, tympanic, forearm, and fingertip temperatures were recorded perioperatively and during 2 h after surgery. Extubated patients in both groups were assessed postoperatively for shivering, use of additional warming devices, and subjective thermal comfort. RESULTS: The mean rectal and esophageal temperatures at incision, 1 h after incision, at skin closure, and immediately postoperatively were significantly higher (0.4-0.6 degrees C) in the group that received water-garment warming when compared with the group that received upper body forced-air warming. The calculated 95% confidence intervals for the above differences in core temperatures were 0.7-0.1, 0.8-0.2, 0.8-0.2, and 0.9-0.1, retrospectively. In addition, 14 and 7% of patients in the control upper body forced-air group remained hypothermic (< 35.5 degrees C) 1 and 2 h after surgery, respectively. No core temperature less than 35.5 degrees C was observed perioperatively in any of the patients from the water-garment group. A similar frequency of the thermal stress events (shivering, use of additional warming devices, subjective thermal discomfort) was observed after extubation in both groups during the 2 h after surgery. CONCLUSIONS: The investigated water warming system, by virtue of its ability to deliver heat to a greater percentage of the body, results in better maintenance of intraoperative normothermia that does forced-air warming applied only to the upper extremities, as is common practice. PMID- 11605927 TI - Acute and nonacute complications associated with interscalene block and shoulder surgery: a prospective study. AB - BACKGROUND: The incidence, etiology, and evolution of complications after interscalene brachial plexus block (ISB) are not well-known. The authors prospectively monitored 521 patients for complications during the first 9 months after ISB. METHODS: A total of 521 adults scheduled for elective shoulder surgery performed with an ISB were included in this prospective study. The ISB procedure was standardized for all patients Acute complications were recorded. Patients were observed daily (for 10 days) for paresthesias, dysesthesias, pain not related to surgery, and muscular weakness and were evaluated at 1, 3, 6, and 9 months after surgery. Persistence of paresthesias dysesthesias, pain not related to surgery, or muscular weakness was investigated at 1 or 3 months by means of electroneuromyography. Final evaluation was performed at 9 months. RESULTS: A total of 520 patients completed the study; one was excluded after surgical axillary nerve damage. Two hundred thirty-four patients had an interscalene catheter. Acute complications consisted of one pneumothorax (0.2%) and one episode of central nervous system toxicity (incoherent speech; 0.2%). A 10 days, 74 patients (14%) were symptomatic, and none had muscular weakness. At 1 month, 41 patients (7.9%) had symptoms, and none had muscular weakness. Thirty patients under went electroneuromyography; sulcus ulnaris syndrome (n = 8) carpal tunnel syndrome (n = 2), and complex regional pain syndrome (n = 1) were diagnosed. At 3 months 20 patient (3.9%) were symptomatic, and none had muscular weakness All underwent electroneuromyography; carpal tunnel syndrome (n = 2), complex regional pain syndrome (n = 4), plexus neuropathy (n = 1), and plexus damage (n = 1) were diagnosed. At 6 months, 5 patients (0.9%) were symptomatic. At 9 months 1 patient (0.2%) had persistence of dysesthesia. CONCLUSIONS: Interscalene brachial plexus block performed with a standardized technical approach, material, and drugs is associated with an incidence of short- and severe long-term complications of 0.4%. In case of persistent paresthesia, dysesthesia, or pain not related to surgery after ISB, sulcus ulnaris syndrome, carpal tunnel syndrome, or complex regional pain syndrome should be excluded since specific treatment may be required. PMID- 11605928 TI - Effect of synchronized intermittent mandatory ventilation on respiratory workload in infants after cardiac surgery. AB - BACKGROUND: Synchronized intermittent mandatory ventilation (SIMV) is commonly used in infants and adults. However, few investigations have examined how SIMV reduces respiratory workload in infants. The authors evaluated how infants' changing respiratory patterns when reducing SIMV rate increased respiratory load. The authors also investigated whether SIMV reduces infant respiratory workload in proportion to the rate of mandatory breaths and which rate of SIMV provides respiratory workloads similar to those after tracheal extubation. METHODS: When 11 post-cardiac surgery infants aged 2-11 months were to be weaned with SIMV, the authors randomly applied five levels of mandatory breathing: 0, 5, 10, 15, and 20 breaths/min. All patients underwent ventilation with SIMV mode: pressure control ventilation, 16 cm H2O; inspiratory time, 0.8 s; triggering sensitivity, 0.6 l/min; and positive endexpiratory pressure, 3 cm H2O. After establishing steady state conditions at each SIMV rate, arterial blood gases were analyzed, and esophageal pressure, airway pressure, and airflow were measured. Inspiratory work of breathing, pressure-time products, and the negative deflection of esophageal pressure were calculated separately for assisted breaths, for spontaneous breaths, and for total breaths per minute. Measurements were repeated after extubation. RESULTS: As the SIMV rate decreased, although minute ventilation and arterial carbon dioxide tension were maintained at constant values, spontaneous breathing rate and tidal volume increased. Work of breathing, pressure-time products, and negative deflection of esophageal pressure increased as the SIMV rate decreased. Work of breathing and pressure-time products after extubation were intermediate between those at a SIMV rate of 5 breaths/min and those at 0 breaths/min. CONCLUSION: When the load to breathing was increased progressively by decreasing the SIMV rate in post-cardiac surgery infants, tidal volume and spontaneous respiratory rate both increased. In addition, work of breathing and pressure-time products were increased depending on the SIMV rate. PMID- 11605929 TI - Respiratory sites of action of propofol: absence of depression of peripheral chemoreflex loop by low-dose propofol. AB - BACKGROUND: Propofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol. METHODS: In 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 microg/ml (P(low)), and two studies at a target propofol concentration of 1.5 microg/ml (P(high)) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, carbon dioxide sensitivity, and apneic threshold. Values are mean +/- SD. RESULTS: Plasma propofol concentrations were approximately 0.5 microg/ml for P(low) and approximately 1.3 mg/ml for P(high), Propofol reduced the central carbon dioxide sensitivity from 1.5 +/- 0.4 to 1.2 +/- 0.3 (P(low); P < 0.01 vs. control) and 0.9 +/- 0.1 l x min(-1) x mmHg(-1) (P(high); P < 0.001 vs. control). The peripheral carbon dioxide sensitivity remained unaffected by propofol (control, 0.5 +/- 0.3; P(low), 0.5 +/- 0.2; P(high), 0.5 +/- 0.2 l x min(-1) x mmHg(-1)). The apneic threshold was reduced from 36.3 +/- 2.7 (control) to 35.0 +/- 2.1 (P(low); P < 0.01 vs. control) and to 34.6 +/- 1.9 mmHg (P(high); P < 0.01 vs. control). CONCLUSIONS: Sedative concentrations of propofol have an important effect on the control of breathing, showing depression of the ventilatory response to hypercapnia. The depression is attributed to an exclusive effect within the central chemoreflex loop at the central chemoreceptors. In contrast to low-dose inhalational anesthetics, the peripheral chemoreflex loop, when stimulated with carbon dioxide, remains unaffected by propofol. PMID- 11605930 TI - Drug-induced amnesia is a separate phenomenon from sedation: electrophysiologic evidence. AB - BACKGROUND: Sedative-hypnotic drugs not only increase sedation, but also impair memory as serum concentration increases. These drugs also produce profound changes in the auditory event-related potential (ERP). The ability of various ERP components to predict changes in sedation and memory produced by various drugs was tested. METHODS: Sixty-five healthy volunteers randomly received intravenous placebo, midazolam, propofol, thiopental, fentanyl with ondansetron, or ondansetron alone at five different stable target concentrations (three increasing, two decreasing) using a computer-controlled infusion pump to produce varying degrees of sedation without loss of consciousness. ERPs were recorded while volunteer participants detected a deviant auditory stimulus and made a button-press response to a target tone (standard oddball paradigm, 80:20 ratio, to elicit a P3 response). At each target concentration, volunteers learned a list of 16 words. The predictive probabilities (Pk) of various ERP components were determined for word recognition at the end of the day (memory) and log reaction time to the deviant stimulus (sedation). RESULTS: The N2 latency of the ERP consistently predicted log reaction time in all groups (Pk +/- SE from 0.58 +/- 0.04 to 0.71 +/- 0.04). The N2P3 amplitude of the ERP was the best predictor of memory performance for midazolam (Pk, 0.63 +/- 0.04), propofol (Pk, 0.62 +/- 0.05), and thiopental (Pk, 0.66 +/- 0.04). There was a differential ability to predict memory performance from sedation for midazolam and propofol. CONCLUSIONS: Midazolam and propofol affect memory differentially from their sedative effects, and these are indexed by specific components of the auditory ERP. These components of the ERP are associated with specific, but not necessarily unique, neuroanatomic structures. Thus, these drugs act by additional mechanisms beyond general central nervous system depression to produce the effects of sedation and memory impairment. PMID- 11605931 TI - Effects of rapacuronium on respiratory function during general anesthesia: a comparison with cis-atracurium. AB - BACKGROUND: With its introduction for widespread clinical use, there has been an increase in reports of bronchospasm related to the administration of rapacuronium. As it is commonly used for rapid sequence intubation, it has been suggested that these effects may be related to an inadequate depth of anesthesia. The current study examines the airway effects of rapacuronium in tracheally intubated, anesthetized adults. METHODS: Endotracheal intubation was accomplished without the use of neuromuscular blocking agents. Dynamic compliance, tidal volume, peak inspiratory flow rate, peak expiratory flow rate, and peak inflating pressure were measured after administration of either rapacuronium (1.5 mg/kg) or cis-atracurium (0.2 mg/kg) to 20 adult patients (10 received rapacuronium and 10 received cis-atracurium) anesthetized with propofol-remifentanil. RESULTS: Statistically significant increases in peak inflating pressure (22 +/- 6 to 28 +/ 9 cm H2O, P = 0.0012) and decreases in dynamic compliance (108 +/- 43 to 77 +/- 41 ml/cm H2O, P = 0.0001), peak inspiratory flow rate (0.43 +/- 0.11 to 0.39 +/- 0.09 l/s, P = 0.0062), peak expiratory flow rate (0.67 +/- 0.10 to 0.59 +/- 0.09 l/s, P = 0.0015), and tidal volume (744 +/- 152 to 647 +/- 135 ml, P = 0.0293) occurred after administration of rapacuronium. No changes were seen after administration of cis-atracurium. CONCLUSION: These data demonstrate that rapacuronium, but not cis-atracurium, has significant airway effects in intubated, mechanically ventilated adults. PMID- 11605932 TI - Combined spinal-epidural versus epidural labor analgesia. AB - BACKGROUND: Despite the growing popularity of combined spinal-epidural analgesia in laboring women, the exact role of intrathecal opioids and the needle-through needle technique remains to be determined. The authors hypothesized that anesthetic technique would have little effect on obstetric outcome or anesthetic complications. METHODS: Data were prospectively collected from 2,183 laboring women randomly assigned to have labor analgesia induced with either 10 microg intrathecal sufentanil with or without 2.0 mg bupivacaine (n = 1,071) or 10 microg epidural sufentanil and 12.5-25.0 mg bupivacaine (n = 1,112). Immediately after induction, a continuous epidural infusion of 0.083% bupivacaine plus 0.3 microg/ml sufentanil was begun in all patients and continued until delivery. Labor was managed by nurses, obstetricians, and obstetric residents who were unaware of the anesthetic technique used. RESULTS: Anesthetic technique lacked impact on our primary outcome: mode of delivery or labor duration. Infants whose mothers were allocated to the combined spinal-epidural group had a slightly higher umbilical artery carbon dioxide partial pressure (54.2 +/- 10.4 vs. 53.2 +/- 10.2 mmHg). However, only achieving at least 5 cm cervical dilation before induction of analgesia and having a cesarean delivery were independent risk factors for elevated umbilical artery carbon dioxide partial pressure. The frequencies of accidental dural puncture, failed epidural analgesia, headache, and epidural blood patch were low and similar in the two groups. CONCLUSIONS: Labor progress and outcome are similar among women receiving either combined spinal-epidural or epidural analgesia. The difference in neonatal outcome appears related to the presence of confounding variables. The combined spinal-epidural technique is not associated with an increased frequency of anesthetic complications. Either technique can safely provide effective labor analgesia. PMID- 11605933 TI - Nitrogen at raised pressure interacts with the GABA(A) receptor to produce its narcotic pharmacological effect in the rat. AB - BACKGROUND: Strong evidence supports the concept that conventional anesthetics, including inhalational agents and inert gases, such as xenon and nitrous oxide, interact directly with ion channel neurotransmitter receptors. However, there is no evidence that nitrogen, which only exhibits narcotic potency at increased pressure, may act by a similar mechanism. METHODS: We compared the inhibitory and sedative effects of gamma-aminobutyric acid (GABA) and nitrogen pressure on locomotor activity and striatal dopamine release in freely moving rats and investigated the pharmacologic properties of the GABA-induced and nitrogen pressure-induced narcotic action using the highly selective competitive GABA(A) receptor antagonist bicuculine. RESULTS: Intracerebroventricular GABA infusion up to 60 micromol or exposure to nitrogen pressure up to 3 MPa decreased to a similar extent striatal dopamine release (r2= 0.899, df = 4, P < 0.01) and locomotor activity (r2 = 0.996, df = 28, P < 0.001). However, both agents only showed small effects on striatal dopamine release, reducing dopamine currents by only 12-13% at sedative concentrations. Pretreatment with bicuculline at 0.5, 1, and 2.5 pmol reduced the sedative action of GABA on locomotor activity by 10, 20, and 41%, respectively. Bicuculline in the nanomole range at 1, 2.5, and 5 nmol but not in the picomole range reduced the sedative action of nitrogen pressure by 5, 37, and 73%, respectively. Schild plot analysis is consistent with the fact that bicuculline is a competitive antagonist of both GABA and nitrogen at pressure. CONCLUSIONS: These results suggest (1) that the presynaptic effects of both GABA and nitrogen pressure on striatal dopamine transmission are modest and not mainly involved in their sedative action and (2) that nitrogen at increased pressure may interact directly with the GABA(A) receptor. However, because the antagonistic effect of bicuculline on nitrogen sedation only occurred at much higher bicuculline concentrations than seen with GABA, it is suggested that nitrogen does not compete for the same site as GABA. PMID- 11605934 TI - Ketamine inhibits endotoxin-induced shock in rats. AB - BACKGROUND: Cytokines and nitric oxide are believed to participate importantly in the pathogenesis of endotoxin-induced shock. Several investigators have documented that ketamine attenuates production of cytokines and nitric oxide in endotoxemia, but little is known concerning hemodynamic effects of the drug in this state. The objective of the current study was to assess the potential modifying effects of ketamine in endotoxemia. METHODS: The authors randomly assigned 40 rats to one of four equal groups: endotoxin alone, receiving Escherichia coli endotoxin (15 mg/kg, administered intravenously); saline control, receiving saline only; ketamine alone, receiving ketamine (10 mg x kg( 1) x h(-1), administered intravenously); pretreatment, with ketamine administration initiated before the endotoxin exposure; and posttreatment, with ketamine initiated 2 h after endotoxin. During the 5 h after endotoxin injection, hemodynamics, acid-base status, and plasma concentrations of tumor necrosis factor alpha and interleukin 6 were assessed in each group. RESULTS: Endotoxin injection produced progressive hypotension, metabolic acidosis, and a large increase in the plasma cytokine concentrations. This hemodynamic and cytokine responses to endotoxin were completely abolished in the pretreatment group and modestly suppressed in the posttreatment group. in the absence of endotoxin, ketamine did not modify these responses. CONCLUSION: Ketamine administration inhibited hypotension, metabolic acidosis, and cytokine responses in rats injected with endotoxin. The results suggest that judicious use of ketamine as an anesthetic agent may offer advantages in endotoxemia. PMID- 11605935 TI - Effects of mild hypothermia on blood-brain barrier disruption during isoflurane or pentobarbital anesthesia. AB - BACKGROUND: This study was performed to determine whether mild hypothermia (32 degrees C) could attenuate the degree of blood-brain barrier (BBB) disruption caused by a hyperosmolar solution and whether the degree of disruption would vary depending on anesthetic agents. METHODS: Rats were assigned to one of four groups: normothermic isoflurane, normothermic pentobarbital, hypothermic isoflurane, and hypothermic pentobarbital. During isoflurane (1.4%; normothermic or hypothermic) or pentobarbital (50 mg/kg administered intraperitoneally; normothermic or hypothermic) anesthesia, the external carotid artery and the femoral artery and vein were catheterized. Body temperature was maintained at 37 and 32 degrees C for the normothermic and hypothermic groups, respectively. To open the BBB, 25% mannitol was infused through the right carotid artery at the rate of 0.25 ml x kg(-1) x s(-1) for 30 s. The transfer coefficient of 14C-alpha aminoisobutyric acid was determined. RESULTS: Blood pressure was similar among the four groups of animals. The degree of the BBB disruption by hyperosmolar mannitol was less with isoflurane than pentobarbital anesthesia in the normothermic groups (transfer coefficient: 29.9 +/- 17.1 and 50.4 +/- 17.5 microl x g(-1) x min(-1) for normothermic isoflurane and pentobarbital, respectively; P < 0.05). Mild hypothermia decreased the BBB disruption during anesthesia with both anesthetic agents (hypothermic isoflurane: 9.8 +/- 8.3 microl x g(-1) x min( 1), P < 0.05 vs. normothermic isoflurane; hypothermic pentobarbital: 30.2 +/- 13.9 microl x g(-1) x min(-1), P < 0.05 vs. normothermic pentobarbital), but the disruption was less during isoflurane anesthesia (hypothermic isoflurane vs. hypothermic pentobarbital, P < 0.005). In the contralateral cortex, there were no significant differences among these four experimental groups. CONCLUSIONS: The data demonstrated that hypothermia was effective in attenuating BBB disruption by hyperosmolar mannitol during isoflurane as well as pentobarbital anesthesia. The degree of disruption appeared smaller during isoflurane than during pentobarbital anesthesia in both the normothermic as well as the hypothermic groups. PMID- 11605936 TI - Role of potassium channels in isoflurane- and sevoflurane-induced attenuation of hypoxic pulmonary vasoconstriction in isolated perfused rabbit lungs. AB - BACKGROUND: Although potassium channels are thought to be responsible for the initiation of hypoxic pulmonary vasoconstriction (HPV), their role in the HPV inhibitory effect of volatile anesthetics is unclear. The current study tested if the HPV-inhibitory effect of isoflurane and sevoflurane can be affected by changing the potassium-channel opening status with specific potassium-channel inhibitors in isolated rabbit lungs. METHODS: Isolated rabbit lungs were divided into eight groups (n = 6 each in isoflurane groups and n = 8 in sevoflurane groups): those receiving no inhibitor treatment = control-isoflurane and control sevoflurane groups; those treated with an adenosine triphosphate-sensitive potassium (K(ATP))-channel inhibitor, glibenclamide = glibenclamide-isoflurane and glibenclamide-sevoflurane groups; those treated with a high-conductance calcium-activated potassium (K(Ca))-channel inhibitor, iberiotoxin = iberiotoxin isoflurane and iberiotoxin-sevoflurane groups; and those treated with a voltage sensitive potassium (Kv)-channel inhibitor, 4-aminopyridine = 4-aminopyridine isoflurane and 4-aminopyridine-sevoflurane groups. The effect of anesthetic on HPV was tested by exposure of the lungs to isoflurane at a concentration of 0, 0.5, 1, or 2 minimum alveolar concentration, or to sevoflurane at a concentration of 0, 0.5, 1, or 1.62 minimum alveolar concentration. The relation between anesthetic concentrations and the HPV response was analyzed by the Wagner equation. RESULTS: The inhibition of Kv channels by 4-aminopyridine and K(Ca) channels by iberiotoxin augmented the HPV response. The isoflurane-induced attenuation of HPV was attenuated by voltage-sensitive potassium-channel inhibition with 4-aminopyridine, potentiated by K(Ca)-channel inhibition with iberiotoxin, but not affected by K(ATP)-channel inhibition with glibenclamide. The sevoflurane-induced attenuation of HPV was not affected by any of the potassium-channel inhibitors. CONCLUSIONS: Isoflurane may modulate the HPV response partially through K(Ca) and Kv channels, but sevoflurane may attenuate the HPV response through other pathways rather than through the currently investigated potassium channels in isolated rabbit lungs. PMID- 11605937 TI - Attenuation of lung inflammation by adrenergic agonists in murine acute lung injury. AB - BACKGROUND: Acute lung injury leading to a systemic inflammatory response greatly increases mortality in critically ill patients. Cardiovascular management of these patients frequently involves beta-adrenergic agonists. These agents may alter the inflammatory response. Therefore, the authors tested the hypothesis that beta-adrenergic agonists alter the pulmonary inflammatory response during acute lung injury in mice. METHODS: Five-week-old CD-1 mice received continuous infusions of 10 microg x kg(-1) x min(-1) dobutamine, 6 microg x kg(-1) x min(-1) dopexamine, or vehicle via intraperitoneal mini osmotic pumps, followed immediately by intratracheal instillation of approximately 2 microg/kg endotoxin (or phosphate-buffered saline control). Six hours later the mice were killed, and lung lavage was performed. Interleukin-6 and -10 concentrations in lung homogenates were measured using enzyme-linked immunosorbent assay. Interleukin-6 and macrophage inflammatory protein-2 mRNA was measured using reverse transcription polymerase chain reaction. RESULTS: Interleukin-6 protein and mRNA significantly increased after intratracheal endotoxin (P < 0.001), and the fraction of neutrophils in lung lavage fluid increased in endotoxin-treated (41 +/- 25%) versus control mice (2 +/- 4%, P < 0.05). Treatment of endotoxic mice with dobutamine significantly decreased interleukin-6 protein (P < 0.05) and mRNA (P < 0.05) expression. Dopexamine had similar but less pronounced effects. Dobutamine decreased interleukin-10 expression, whereas dopexamine did not. In endotoxemic mice, both dobutamine and dopexamine decreased induction of macrophage inflammatory protein-2 mRNA (P < 0.05) and reduced the fraction of neutrophils in lung lavage fluid (P < 0.05). CONCLUSIONS: In endotoxin-induced acute lung injury, beta-adrenergic agonists can significantly decrease proinflammatory cytokine expression, decrease induction of chemokine mRNA, and decrease the resultant neutrophil infiltrate in the lung. PMID- 11605938 TI - Interaction of volatile anesthetics with human Kv channels in relation to clinical concentrations. AB - BACKGROUND: Recent evidence shows that inhibition of human Kv3 channels by intravenous anesthetics occurs at clinical concentrations. The effects of volatile anesthetics on these human ion channels are unknown. This study was designed to establish whether minimum alveolar concentrations (MAC) of halothane, enflurane, isoflurane, and desflurane exhibit effects on Kv3 channeLs. To obtain an indication whether these findings may be specific to Kv3 channels, the effects of enflurane and isoflurane on human Kv1.1 channels were also investigated. METHODS: Kv3 channels natively expressed in SH-SY5Y cells and Kv1.1 channels expressed in HEK293 cells were measured with the whole cell patch clamp technique by standard protocols. Concentrations of volatile anesthetics were determined by gas chromatography. RESULTS: Halothane, enflurane, isoflurane, and desflurane reversibly inhibited Kv3 channels in a concentration-dependent manner. Concentrations at half-maximal effect (IC50 values) ranged between 1,800 and 4,600 microM. Hill coefficients were between 1.7 and 2.5. IC50 values for inhibition of Kv1.1 channels were 2,800 and 5,200 microM, and Hill coefficients were 3.9 and 5.6 for enflurane and isoflurane, respectively. CONCLUSION: Volatile anesthetics inhibit human Kv3 channels at clinical concentrations. At 1-3 MAC, inhibition would account on average for 2-12%. Inhibition would be highest with enflurane (between 3% and 22%) and lowest with isoflurane (between 0.2% and 3%). Kv1.1 channels would only be inhibited by enflurane at clinical concentrations (2% at 2 MAC and 8% at 3 MAC). Whether the degree of K channel inhibition by volatile anesthetics may contribute to their clinical action needs further study. PMID- 11605939 TI - Desflurane confers neurologic protection for deep hypothermic circulatory arrest in newborn pigs. AB - BACKGROUND: Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), as used for infant heart surgery, carry a risk of ischemic neurologic injury. Volatile anesthetics have neuroprotective properties against both global and focal ischemia at normothermia. The authors examined the hemodynamic and neuroprotective effects of desflurane in a piglet CPB-DHCA model. METHODS: Twenty piglets aged 5-10 days received a desflurane- (6-9% expired) or fentanyl-based anesthetic before and during CPB (before and after DHCA). DHCA lasted 90 min at 19 degrees C brain. Cardiovascular variables (heart rate, arterial pressure, blood gases, glucose, brain temperature) were monitored. On postoperative day 2, neurologic and histologic outcomes were determined. RESULTS: Cardiovascular variables before, during, and after CPB were physiologically similar between groups. The desflurane group had better neurologic performance (P = 0.023) and greater postoperative weight gain (P = 0.04) than the fentanyl group. In neocortex, the desflurane group had less tissue damage (P = 0.0015) and fewer dead neurons (P = 0.0015) than the fentanyl group. Hippocampal tissue damage was less in the desflurane group (P = 0.05), but overall, neuronal cell counts in the CA1 sector of the right hippocampus were similar to those in the fentanyl group. CONCLUSIONS: Desflurane-based anesthesia yields hemodynamics during CPB with DHCA that are similar to those with fentanyl-based anesthesia. However, desflurane based anesthesia improves neurologic and histologic outcomes of CPB-DHCA in comparison with outcomes with fentanyl-based anesthesia. PMID- 11605941 TI - Adenoviral vector transfection into the pulmonary epithelium after cecal ligation and puncture in rats. AB - BACKGROUND: Adenoviral-targeted gene delivery to respiratory epithelium can augment production of specific proteins. Therefore, it may be valuable in treating the acute respiratory distress syndrome. The authors tested the hypothesis that adenoviral vector uptake after cecal ligation and double puncture in rats, an animal model of the acute respiratory distress syndrome, is higher than that observed in controls that did not undergo operation ("nonoperated") or those that underwent a sham operation ("sham-operated"). METHODS: Adenoviruses expressing green fluorescent protein or Lac-Z were delivered into the lungs of anesthetized rats via tracheal catheter. Animals were killed 24 or 48 h later. Histopathology and green fluorescent protein expression were examined using light of fluorescence microscopy. Cellular localization of Lac-Z was determined with electron microscopy or semithin sectioning. Viral receptor density and localization were determined using imunoblotting and immunohistochemistry. RESULTS: After cecal ligation and double puncture, rats were hypoxic and tachypneic. Alveoli were segmentally consolidated, contained proteinaceous debris and neutrophils, and had thickened septa. Administration of adenoviruses to rats that were sham-operated or underwent cecal ligation and double puncture resulted in high levels of marker protein expression in cells lining alveoli. Use of 3 x 10(11) plaque-forming units instead of 3 x 10(12) plaque-forming units resulted in similar levels of green fluorescent protein expression with negligible viral mediated lymphocytic infiltration. Semithin section and electron microscopy revealed expression primarily localized to type II alveolar cells. Abundance of alpha(v)beta3 integrins and human coxsackie-adenovirus receptor (receptors that modulate viral attachment and internalization) was increased after cecal ligation and double puncture, predominantly in type II pneumocytes. CONCLUSIONS: Cecal ligation and double puncture induces histologic and functional changes consistent with the acute respiratory distress syndrome, increases surface expression of viral receptors, and enhances adenoviral-mediated gene transfer. PMID- 11605940 TI - Pain models display differential sensitivity to Ca2+-permeable non-NMDA glutamate receptor antagonists. AB - BACKGROUND: Ca2+-permeable non-N-methyl-D-aspartate receptors are found in the spinal dorsal horn and represent a presumptive target for glutamatergic transmission in nociceptive processing. This study characterized the analgesic profile associated with the blockade of these spinal receptors by intrathecally delivered agents known to act at these receptors, the spider venom Joro toxin (JST) and philanthotoxin. METHODS: Philanthotoxin (0.5, 2.5, or 5 microg) or JST (5 microg) was given spinally before thermal injury to the paw. JST (5 microg) was also given 10 min before subcutaneous formalin injection, after intraplantar administration of carrageenan, and to rats that were allodynic due to tight ligation of spinal nerves. Lower doses of JST (0.25 and 1.0 microg) were given before formalin injection and testing of thermal latencies. Thermal latencies were measured using a Hargreaves box, mechanical thresholds using von Frey hairs, and formalin response by means of counting flinches. RESULTS: Both agents blocked thermal injury-induced mechanical allodynia. JST (5 microg) given 1 h after carrageenan blocked induction of thermal hyperalgesia and mechanical allodynia. JST (5 microg) had no effect in the formalin test, on allodynia after spinal nerve ligation, or when given 3 h after carrageenan. The lowest dose (0.25 microg JST) at pretreatment intervals of 60-120 min resulted in modest hypoalgesia during phase 1 formalin and thermal testing. CONCLUSIONS: The behavioral effect of intrathecal Ca2+-permeable non-N-methyl-D-aspartate antagonists indicates an important role for this spinal receptor in regulating hyperalgesic states induced by tissue injury and inflammation and reveals an action that is distinct from those observed with other glutamate receptor antagonists. PMID- 11605942 TI - Activation of mu-opioid receptor induces expression of c-fos and junB via mitogen activated protein kinase cascade. AB - BACKGROUND: Opioid-induced long-term functional alterations of the nervous system, such as tolerance, addiction, and dependence, conceivably involve changes in gene expression. The authors have previously reported that opioid receptors are functionally coupled to extracellular signal-regulated kinase, a class of the mitogen-activated protein kinase. To address whether activation of the opioid receptor induces changes in gene expression through the activation of extracellular signal-regulated kinase, the authors examined mu-opioid receptor (MOR)-induced immediate early gene expression. METHODS: Chinese hamster ovary cells stably expressing MOR were used. Cells were stimulated by MOR agonists after 24-h serum starvation. Expression of c-fos and junB genes was analyzed by RNA blot hybridization. To explore the mechanism of MOR-mediated c-fos and junB expression, activity of a transcription factor, Elk-1, was assessed by reporter assay. Furthermore, to investigate the functional consequences of c-fos and junB induction, MOR-mediated formation of the functional transcription factor complex AP-1 was examined by reporter assay and electrophoretic mobility shift assay. RESULTS: Mu-opioid receptor activation induced c-fos and junB messenger RNAs, which were inhibited by pretreatment of the cells with pertussis toxin and PD98059, an inhibitor of extracellular signal-regulated kinase cascade. MOR stimulation elevated Elk-1-mediated transcriptional activity by about 10-fold. AP 1-mediated transcriptional activity was stimulated by MOR agonists by about twofold. Electrophoretic mobility shift assay revealed that AP-1 binding activity in the nuclear extract was elevated by MOR activation and further showed that products of c-fos and junB genes are involved in formation of AP-1 complex. CONCLUSIONS: Mu-opioid receptor activation induces c-fos and junB expression and elevates AP-1-mediated transcriptional activities via the mitogen-activated protein kinase cascade. PMID- 11605943 TI - Role of endothelium in the action of isoflurane on vascular smooth muscle of isolated mesenteric resistance arteries. AB - BACKGROUND: It is believed that isoflurane decreases blood pressure predominantly by decreasing systemic vascular resistance with modest myocardial depression. Nevertheless, little information is available regarding the direct action of isoflurane on systemic resistance arteries. METHODS: With use of the isometric force recording method, the action of isoflurane on contractile response to norepinephrine, a neurotransmitter that plays a central role in sympathetic maintenance of vascular tone in vivo, was investigated in isolated rat small mesenteric arteries. RESULTS: In the endothelium-intact strips, the norepinephrine response was initially enhanced after application of isoflurane (2 5%), but it was subsequently almost normalized to the control level during exposure to isoflurane. However, the norepinephrine response was notably inhibited after washout of isoflurane. In the endothelium-denuded strips, the norepinephrine response was gradually inhibited during exposure to isoflurane (> or = 3%), and the inhibition was prolonged after wash-out of isoflurane. The isoflurane-induced enhancement of norepinephrine response was still observed after inhibitions of the nitric oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase and lipoxygenase pathways, or after blockade of endothelin 1, angiotensin-II, and serotonin receptors; however, it was prevented by superoxide dismutase. CONCLUSIONS: In isolated mesenteric resistance artery, the action of isoflurane on contractile response to norepinephrine consists of two distinct components: an endothelium-dependent enhancing component and an endothelium-independent inhibitory component. During exposure to isoflurane, the former counteracted the latter, preventing the norepinephrine response from being strongly inhibited. However, only the endothelium-independent component persists after washout of isoflurane, causing prolonged inhibition of the norepinephrine response. Superoxide anions may be involved in the enhanced response to norepinephrine. PMID- 11605944 TI - Effects of the anesthetic gases xenon, halothane, and isoflurane on calcium and potassium currents in human atrial cardiomyocytes. AB - BACKGROUND: Negative inotropic and proarrhythmic side effects on the heart are well known for the volatile anesthetics halothane and isoflurane but not for the noble gas xenon. We investigated the effects of halothane, isoflurane, and xenon on calcium and potassium currents in human atrial myocytes to elucidate the cellular and molecular basis of their cardiac actions. METHODS: Atrial myocytes were prepared from the right auricles obtained from patients undergoing heart surgery. Ion currents were measured with the whole cell patch clamp technique during superfusion of the cells with solutions that contained halothane, isoflurane, or xenon at concentrations corresponding to their respective minimum alveolar concentration (MAC); gas concentrations were determined with the head space-gas chromatography/mass spectrometry/selected ion monitoring method. RESULTS: L-type calcium currents were significantly depressed by 31.9 +/- 4.1%, from -1.8 +/- 0.3 to -1.2 +/- 0.4 picoampere (pA)/picofarad (pF) (n = 4; P < 0.05) at 1 MAC halothane and by 21.7 +/- 9.2%, from -1.6 +/- 0.7 to -1.2 +/- 0.6 pA/pF (n = 7; P < 0.05) at 1 MAC isoflurane, but not affected by 70% xenon (1 MAC). Inwardly rectifying potassium currents were not influenced by any anesthetic. Halothane (1 MAC) significantly inhibited the transient as well as the sustained part of voltage-gated potassium outward currents, by 19.4 +/- 6.7%, from 6.7 +/- 2.1 to 5.4 +/- 1.6 pA/pF (n = 8; P < 0.05), and by 8.6 +/- 4.8%, from 5.5 +/- 1.7 to 5.0 +/- 1.5 pA/pF (n = 8; P < 0.05), respectively. Transient K+ outward currents were even more inhibited, by 25.8 +/- 4.8%, from 9.8 +/- 3.1 to 7.3 +/- 2.1 pA/pF (n = 5; P < 0.05) at 1 MAC isoflurane, whereas xenon evoked only a slight (albeit significant) inhibition, by 6.1 +/- 3.7%, from 8.2 +/- 6.0 to 7.7 +/- 5.8 pA/pF (n = 10; P < 0.05). Isoflurane and xenon did not affect sustained potassium currents. All effects of the anesthetics were fully reversible after washout. CONCLUSIONS: Halothane and isoflurane exhibited considerable inhibitory effects on voltage-gated cardiac Ca2+ and K+ currents important for the duration of action potentials and the repolarization. Xenon, in contrast, did not affect Ca2+ currents and only slightly inhibited transient K+ outward currents, in line with the almost absent cardiac side effects of the noble gas. PMID- 11605945 TI - Should children who use cochlear implants wear hearing aids in the opposite ear? AB - OBJECTIVE: The aim of this study was to investigate 1) whether a hearing aid needs to be adjusted differently depending on whether a child wears a cochlear implant or another hearing aid in the contralateral ear; 2) whether the use of a hearing aid and a cochlear implant in opposite ears leads to binaural interference; and 3) whether the use of a hearing aid and a cochlear implant in opposite ears leads to binaural benefits in speech perception, localization, and communicative functioning in real life. DESIGN: Sixteen children participated in this study. All children used a Nucleus 22 or Nucleus 24 cochlear implant system programmed with the SPEAK strategy in one ear. The hearing aid amplification requirements in the nonimplanted ear of these children were determined using two procedures. A paired comparison technique was used to identify the frequency response that was best for speech intelligibility in quiet, and a loudness balancing technique was used to match the loudness of speech in the ear with a hearing aid to that with a cochlear implant. Eleven of the 16 children participated in the investigation of binaural effects. Performance in speech perception, localization, and communicative functioning was assessed under four aided conditions: cochlear implant with hearing aid as worn, cochlear implant alone, hearing aid alone, and cochlear implant with hearing aid adjusted according to individual requirements. RESULTS: Fifteen of the 16 children whose amplification requirements were determined preferred a hearing aid frequency response that was within +/-6 dB/octave of the NAL-RP prescription. On average, the children required 6 dB more gain than prescribed to balance the loudness of the implanted ear for a speech signal presented at 65 dB SPL. For all 11 children whose performance was evaluated for investigating binaural effects, there was no indication of significantly poorer performance under bilaterally aided conditions compared with unilaterally aided conditions. On average, there were significant benefits in speech perception, localization, and aural/oral function when the children used cochlear implants with adjusted hearing aids than when they used cochlear implants alone. All individuals showed benefits in at least one of the measures. CONCLUSIONS: Hearing aids for children who also use cochlear implants can be selected using the NAL-RP prescription. Adjustment of hearing aid gain to match loudness in the implanted ear can facilitate integration of signals from both ears, leading to better speech perception. Given that there are binaural advantages from using cochlear implants with hearing aids in opposite ears, clinicians should advise parents and other professionals about these potential advantages, and facilitate bilateral amplification by adjusting hearing aids after stable cochlear implant MAPs are established. PMID- 11605946 TI - Analysis of narrative ability in children with cochlear implants. AB - PURPOSE: The purposes of this study were to: 1) develop a scoring system to assess narrative ability in children; 2) evaluate the impact of auditory speech perception with a cochlear implant on narrative ability; and 3) evaluate the importance of narrative ability to reading comprehension in deaf children. DESIGN: Narrative productions prompted from an eight-picture sequence story were elicited from 8 and 9 yr olds; 87 who had at least 4 yr of cochlear implant experience and 28 who had normal hearing. The stories were transcribed and a scoring system for narrative ability was developed based on the use of complete narrative structure, conjunctions linking semantic relations, and referents that served to identify and distinguish characters in the narrative. Narrative ability scores of cochlear implant users were examined in relation to their age, IQ, speech perception, language, and reading test scores. In addition, narrative ability scores for children with normal hearing were compared with two groups of cochlear implant users, those with above average speech perception scores and those with below average speech perception scores. RESULTS: Within the sample of hearing-impaired children, narrative ability scores correlated significantly with speech perception, language syntax, and reading test scores. A multiple regression analysis was conducted to predict reading comprehension scores from four predictor variables (age, IQ, language syntax, and narrative ability). Results reflected the independent contribution of discourse-level language skills, as measured by the narrative ability score, as well as sentence-level language skills in predicting reading test scores. Analysis of stories obtained from 8- and 9-yr-old children with normal hearing revealed the classic pattern that included a high point, a resolution, and one or more evaluative statements. Their stories achieved cohesion from correct use of both conjunctions and referents. Deaf children who received above-average speech perception scores with a cochlear implant (i.e., scored above 48% on the Word Intelligibility by Picture Identification speech perception test) told narratives that were similar in structure and use of referents to those of age mates with normal hearing. Although their use of subordinate conjunctions was not as well developed as normal-hearing children, it was significantly above that of deaf children who received less speech perception benefit after a similar period of implant use. These below-average speech perceivers exhibited significantly poorer use of narrative structure and cohesive devices than either normal-hearing age mates or children who achieved above average speech perception with a cochlear implant. CONCLUSIONS: Narrative ability is an important predictor of reading comprehension ability in deaf children above and beyond IQ and syntactic competence. Children who receive a cochlear implant under 5 yr of age and obtain above average speech perception benefit from the device construct narratives that are similar in structure and cohesion to those of their hearing age mates by age 8 to 9. PMID- 11605948 TI - Audio-visual perception of sinewave speech in an adult cochlear implant user: a case study. AB - OBJECTIVE: The purpose of this case study was to investigate multimodal perceptual coherence in speech perception in an exceptionally good postlingually deafened cochlear implant user. His ability to perceive sinewave replicas of spoken sentences, and the extent to which he integrated sensory information from multimodal sources was compared with a group of adult normal-hearing listeners to determine the contribution of natural auditory quality in the use of electrocochlear stimulation. DESIGN: The patient, "Mr. S," transcribed sinewave sentences of natural speech under audio-only (AO), visual-only (VO), and audio visual (A+V) conditions. His performance was compared with the data collected from 25 normal-hearing adults. RESULTS: Although normal-hearing participants performed better than Mr. S for AO sentences (65% versus 53% syllables correct), Mr. S was superior for VO sentences (43% versus 18%). For A+V sentences, Mr. S's performance was comparable with the normal-hearing group (90% versus 86%). An estimate of the amount of visual enhancement, R, obtained from seeing the talker's face showed that Mr. S derived a larger gain from the additional visual information than the normal-hearing controls (78% versus 59%). CONCLUSIONS: The findings from this case study of an exceptionally good cochlear implant user suggest that he is perceiving the sinewave sentences on the basis of coherent variation from multimodal sensory inputs, and not on the basis of lipreading ability alone. Electrocochlear stimulation is evidently useful in multimodal contexts because it preserves dynamic speech-like variation, despite the absence of speech-like auditory qualities. PMID- 11605949 TI - Speech recognition in noise for cochlear implantees with a two-microphone monaural adaptive noise reduction system. AB - OBJECTIVE: In this study the performance of a noise reduction strategy applied to cochlear implants is evaluated. The noise reduction strategy is based on a 2 channel adaptive filtering strategy using two microphones in a single behind-the ear hearing aid. DESIGN: Four adult LAURA cochlear implant users (Peeters et al., 1993) took part in the experiments. The tests included identification of monosyllabic CVC (consonant-vowel-consonant) words and measurements of the speech reception threshold (SRT) of lists of numbers, in background noise presented at 90 degrees relative to the 0 degrees frontal direction of the speech. Percent correct phoneme scores for the CVC words at signal to noise ratios (SNRs) of -5, 0, and +5 dB in steady speech-weighted noise at 60 dB SPL and SRTs for numbers in speech-weighted steady and nonsteady ICRA noise were both obtained in conditions with and without the noise reduction pre-processing. Physical SNR improvements of the noise reduction system are evaluated as well, as a function of the direction of the noise source. RESULTS: Highly significant improvements in speech understanding, corresponding on average to an SNR improvement of about 10 dB, were observed with this 2-channel adaptive filtering noise reduction strategy using both types of speech-noise test materials. These perceptual evaluations agree with physical evaluations and simulations of this noise reduction strategy. Taken together, these data demonstrate that cochlear implantees may increase their speech intelligibility in noisy environments with the use of multimicrophone noise reduction systems. PMID- 11605947 TI - Some measures of verbal and spatial working memory in eight- and nine-year-old hearing-impaired children with cochlear implants. AB - OBJECTIVE: The purpose of this study was to examine working memory for sequences of auditory and visual stimuli in prelingually deafened pediatric cochlear implant users with at least 4 yr of device experience. DESIGN: Two groups of 8- and 9-yr-old children, 45 normal-hearing and 45 hearing-impaired users of cochlear implants, completed a novel working memory task requiring memory for sequences of either visual-spatial cues or visual-spatial cues paired with auditory signals. In each sequence, colored response buttons were illuminated either with or without simultaneous auditory presentation of verbal labels (color names or digit-names). The child was required to reproduce each sequence by pressing the appropriate buttons on the response box. Sequence length was varied and a measure of memory span corresponding to the longest list length correctly reproduced under each set of presentation conditions was recorded. Additional children completed a modified task that eliminated the visual-spatial light cues but that still required reproduction of auditory color-name sequences using the same response box. Data from 37 pediatric cochlear implant users were collected using this modified task. RESULTS: The cochlear implant group obtained shorter span scores on average than the normal-hearing group, regardless of presentation format. The normal-hearing children also demonstrated a larger "redundancy gain" than children in the cochlear implant group-that is, the normal-hearing group displayed better memory for auditory-plus-lights sequences than for the lights only sequences. Although the children with cochlear implants did not use the auditory signals as effectively as normal-hearing children when visual-spatial cues were also available, their performance on the modified memory task using only auditory cues showed that some of the children were capable of encoding auditory-only sequences at a level comparable with normal-hearing children. CONCLUSIONS: The finding of smaller redundancy gains from the addition of auditory cues to visual-spatial sequences in the cochlear implant group as compared with the normal-hearing group demonstrates differences in encoding or rehearsal strategies between these two groups of children. Differences in memory span between the two groups even on a visual-spatial memory task suggests that atypical working memory development irrespective of input modality may be present in this clinical population. PMID- 11605950 TI - Effects of the number of channels and speech-to-noise ratio on rate of connected discourse tracking through a simulated cochlear implant speech processor. AB - OBJECTIVE: To investigate the effects of number of channels and speech-to-noise ratio on connected discourse tracking (CDT) through simulations of cochlear implant speech processing. Previous studies have used citation-form vowel and consonant materials or simple sentences. CDT rates were expected to be less likely to be limited by ceiling effects and more representative of everyday speech communication. DESIGN: Four normal-hearing subjects were presented with speech processed through a real-time sine-excited vocoder having three, four, eight, or 12 channels. Amplitude envelopes extracted from each band modulated sinusoidal carrier signals placed at each band center frequency. Speech-spectrum shaped noise was added to speech before vocoder processing at three signal to noise ratios based on real-time measurements of speech level (+7, +12, +17 dB). RESULTS: CDT rates increased significantly with number of channels up to eight in both quiet and noise, and decreased significantly with each increase in noise level from quiet. CONCLUSIONS: The effects on CDT rates of the number of channels and speech-to-noise ratio are highly correlated with intelligibility measures for Hearing in Noise Test (HINT) sentences, consonants and vowels. However, HINT sentence scores even in noise show ceiling effects that obscure the advantages of processors with eight or more channels. Moderate levels of noise that have only slight effects on other measures significantly affected CDT rate. CDT rates with three or four bands of spectral information were much lower than asymptotic rates, especially in the presence of noise. PMID- 11605951 TI - A comparison of two loudness balancing tasks in cochlear implant subjects using bipolar stimulation. AB - OBJECTIVE: In this study, the accuracy of independent measurement of the loudness of different electrodes in a cochlear implant (the "reference" method) was compared with the accuracy of measurements that depend on the results of previous measurements (the "adjacent" method) by evaluating the similarity between and the slopes of the loudness balance curves, and the variability in the measured loudness balance values. DESIGN: The two methods of loudness balancing differed only in the reference electrode used. In the adjacent method, the loudness of the test electrode was sequentially adjusted to match the loudness of an adjacent reference electrode, whereas in the reference method, the loudness of all test electrodes was adjusted to match that of a common reference electrode. Five subjects implanted with the Nucleus 22 device completed both methods of loudness balancing for all of their functioning electrodes. Each test/reference electrode pair was loudness balanced six times to assess the variability of the two methods. RESULTS: The loudness balance curves for the two methods were statistically correlated (p < 0.001) for all subjects. The slopes of the regression lines for the loudness balance curves were statistically different from zero (p < 0.05) for roughly half of the subjects for each method. A sign test indicated statistically different means for the basal set and apical set of measurements for only one subject for both methods. The variance in the measured values across electrodes for the reference method was significantly greater for three of the five subjects (p < 0.01). CONCLUSIONS: It was hypothesized that because of its dependence on previously measured values, the adjacent method could be susceptible to "drift," i.e., a shift in the overall loudness to which the electrodes are balanced. However, none of the statistical measures employed to test for drift indicated that the adjacent method was more susceptible to drift than the reference method, nor were the responses to the adjacent method more variable. Thus, based on these results, dependent measurements do not seem to be less accurate than independent measurements. The relatively higher variance for the reference method in some subjects may be due to the difficulty of comparing the loudness of stimuli that are far apart in pitch. PMID- 11605952 TI - Activation of an EDS1-mediated R-gene pathway in the snc1 mutant leads to constitutive, NPR1-independent pathogen resistance. AB - The Arabidopsis NPR1 protein is an essential regulatory component of systemic acquired resistance (SAR). Mutations in the NPR1 gene completely block the induction of SAR by signals such as salicylic acid (SA). An Arabidopsis mutant, snc1 (suppressor of npr1-1, constitutive 1), was isolated in a screen for suppressors of npr1-1. In the npr1-1 background, the snc1 mutation resulted in constitutive resistance to Pseudomonas syringae maculicola ES4326 and Peronospora parasitica Noco2. High levels of SA were detected in the mutant and shown to be required for manifestation of the snc1 phenotype. The snc1 mutation was mapped to the RPP5 resistance (R) gene cluster and the eds1 mutation that blocks RPP5 mediated resistance suppressed snc1. These data suggest that a RPP5-related resistance pathway is activated constitutively in snc1. This pathway does not employ NPR1 but requires the signal molecule SA and the function of EDS1. Moreover, in snc1, constitutive resistance is conferred in the absence of cell death, which is often associated with R-gene mediated resistance. PMID- 11605953 TI - A phosphate transporter gene from the extra-radical mycelium of an arbuscular mycorrhizal fungus Glomus intraradices is regulated in response to phosphate in the environment. AB - The majority of vascular flowering plants are able to form symbiotic associations with arbuscular mycorrhizal fungi. These symbioses, termed arbuscular mycorrhizas, are mutually beneficial, and the fungus delivers phosphate to the plant while receiving carbon. In these symbioses, phosphate uptake by the arbuscular mycorrhizal fungus is the first step in the process of phosphate transport to the plant. Previously, we cloned a phosphate transporter gene involved in this process. Here, we analyze the expression and regulation of a phosphate transporter gene (GiPT) in the extra-radical mycelium of the arbuscular mycorrhizal fungus Glomus intraradices during mycorrhizal association with carrot or Medicago truncatula roots. These analyses reveal that GiPT expression is regulated in response to phosphate concentrations in the environment surrounding the extra-radical hyphae and modulated by the overall phosphate status of the mycorrhiza. Phosphate concentrations, typical of those found in the soil solution, result in expression of GiPT. These data imply that G. intraradices can perceive phosphate levels in the external environment but also suggest the presence of an internal phosphate sensing mechanism. PMID- 11605954 TI - Proper regulation of cyclic AMP-dependent protein kinase is required for growth, conidiation, and appressorium function in the anthracnose fungus Colletotrichum lagenarium. AB - Colletotrichum lagenarium, the casual agent of anthracnose of cucumber, forms specialized infection structures, called appressoria, during infection. To evaluate the role of cAMP signaling in C. lagenarium, we isolated and functionally characterized the regulatory subunit gene of the cAMP-dependent protein kinase (PKA). The RPK1 gene encoding the PKA regulatory subunit was isolated from C. lagenarium by polymerase chain reaction-based screening. rpk1 mutants, generated by gene replacement, exhibited high PKA activity during vegetative growth, whereas the wild-type strain had basal level activity. The rpk1 mutants showed significant reduction in vegetative growth and conidiation. Furthermore, the rpk1 mutants were nonpathogenic on cucumber plants, whereas they formed lesions when inoculated through wounds. A suppressor mutant showing restored growth and conidiation was isolated from a rpk1 mutant culture. The rpkl suppressor mutant did not show high PKA activity, unlike the parental rpk1 mutant, suggesting that high PKA activity inhibits normal growth and conidiation. The suppressor mutant, however, was nonpathogenic on cucumber and failed to form lesions, even when inoculated through wounds. The rpk1 and suppressor mutants formed melanized appressoria on the host leaf surface but were unable to generate penetration hyphae. These results suggest that proper regulation of the PKA activity by the RPK1-encoded regulatory subunit is required for growth, conidiation, and appressorium function in C. lagenarium. PMID- 11605955 TI - Cell-to-cell movement of Potato virus X: the role of p12 and p8 encoded by the second and third open reading frames of the triple gene block. AB - Potato virus X (PVX) requires three proteins, p25, p12, and p8, encoded by the triple gene block plus the coat protein (CP) for cell-to-cell movement. When each of these proteins was co-expressed with a cytosolic green fluorescent protein (GFP) in the epidermal cells of Nicotiana benthamiana by the microprojectile bombardment-mediated gene delivery method, only p12 enhanced diffusion of co expressed GFP, indicating an ability to alter plasmodesmal permeability. p25, p12, and CP, expressed transiently in the initially infected cells, transcomplemented the corresponding movement-defective mutants to spread through two or more cell boundaries. Thus, these proteins probably move from cell to cell with the genomic RNA. In contrast, p8 only functioned intracellularly and was not absolutely required for cell-to-cell movement. Since overexpression of p12 overcame the p8 deficiency, p8 appears to facilitate the functioning of p12, presumably by mediating its intracellular trafficking. Considering the likelihood that p12 and p8 are membrane proteins, it is suggested that intercellular as well as intracellular movement of PVX involves a membrane-mediated process. PMID- 11605957 TI - Expression studies of superoxide dismutases in nodules and leaves of transgenic alfalfa reveal abundance of iron-containing isozymes, posttranslational regulation, and compensation of isozyme activities. AB - The composition of antioxidant enzymes, especially superoxide dismutase (SOD), was studied in one nontransgenic and three transgenic lines of nodulated alfalfa plants. Transgenic lines overproduced MnSOD in the mitochondria of nodules and leaves (line 1-10), MnSOD in the chloroplasts (line 4-6), and FeSOD in the chloroplasts (line 10-7). In nodules of line 10-7, the absence of transgene encoded FeSOD activity was due to a lack of mRNA, whereas in nodules of line 4-6 the absence of transgene-encoded MnSOD activity was due to enzyme inactivation or degradation. Transgenic alfalfa showed a novel compensatory effect in the activities of MnSOD (mitochondrial) and FeSOD (plastidic) in the leaves, which was not caused by changes in the mRNA levels. These findings imply that SOD activity in plant tissues and organelles is regulated, at least partially, at the posttranslational level. All four lines had low CuZnSOD activities and an abundant FeSOD isozyme, especially in nodules, indicating that FeSOD performs important antioxidant functions other than the scavenging of superoxide radicals generated in photosynthesis. This was confirmed by the detection of FeSOD cDNAs and proteins in nodules of other legumes such as cowpea, pea, and soybean. The cDNA encoding alfalfa nodule FeSOD was characterized and the deduced protein found to contain a plastid transit peptide. A comparison of sequences and other properties reveals that there are two types of FeSODs in nodules. PMID- 11605956 TI - Overlapping plant signal transduction pathways induced by a parasitic nematode and a rhizobial endosymbiont. AB - Root-knot nematodes and rhizobia establish interactions with roots characterized by the de novo induction of host structures, termed giant cells and nodules, respectively. Two transcription regulators, PHAN and KNOX, required for the establishment of meristems were previously shown to be expressed in tomato giant cells. We isolated the orthologues of PHAN and KNOX (Mt-phan and Mt-knox-1) from the model legume Medicago truncatula, and established the spatial distribution of their expression in situ. We confirmed that Mt-phan and Mt-knox-1 are expressed in lateral root initials and in nematode-induced giant cells and showed that they are expressed in nodules induced by Sinorhizobium meliloti. Expression of both genes becomes spatially restricted as the nodules develop. We further examined nematode feeding sites for the expression of two genes involved in nodule formation, ccs52 (encodes a mitotic inhibitor) and ENOD40 (encodes an early, nodulation mitogen), and found transcripts of both genes to be present in and around giant cells induced in Medicago. Collectively, these results reveal common elements of host responses to mutualistic and parasitic plant endosymbionts and imply that overlapping regulatory pathways lead to giant cells and nodules. We discuss these pathways in the context of phytohormones and parallels between beneficial symbiosis and disease. PMID- 11605958 TI - The antioxidants of legume nodule mitochondria. AB - The mitochondria of legume root nodules are critical to sustain the energy intensive process of nitrogen fixation. They also generate reactive oxygen species at high rates and thus require the protection of antioxidant enzymes and metabolites. We show here that highly purified mitochondria from bean nodules (Phaseolus vulgaris L. cv. Contender x Rhizobium leguminosarum bv. phaseoli strain 3622) contain ascorbate peroxidase primarily in the inner membrane (with lesser amounts detected occasionally in the matrix), guaiacol peroxidases in the outer membrane and matrix, and manganese superoxide dismutase (MnSOD) and an ascorbate-regenerating system in the matrix. This regenerating system relies on homoglutathione (instead of glutathione) and pyridine nucleotides as electron donors and involves the enzymes monodehydroascorbate reductase, dehydroascorbate reductase, and homoglutathione reductase. Homoglutathione is synthesized in the cytosol and taken up by the mitochondria and bacteroids. Although bacteroids synthesize glutathione, it is not exported to the plant in significant amounts. We propose a model for the detoxification of peroxides in nodule mitochondria in which membrane-bound ascorbate peroxidase scavenges the peroxide formed by the electron transport chain using ascorbate provided by L-galactono-1,4-lactone dehydrogenase in the inner membrane. The resulting monodehydroascorbate and dehydroascorbate can be recycled in the matrix or cytosol. In the matrix, the peroxides formed by oxidative reactions and by MnSOD may be scavenged by specific isozymes of guaiacol peroxidase, ascorbate peroxidase, and catalase. PMID- 11605959 TI - Selection of a plant-bacterium pair as a novel tool for rhizostimulation of polycyclic aromatic hydrocarbon-degrading bacteria. AB - We developed a novel procedure for the selection of a microbe-plant pair for the stable and efficient degradation of naphthalene. Based on the rationale that root exudate is the best nutrient source available in soil, the grass (Lolium multiflorum) cultivar Barmultra was selected because of its abilities to produce a highly branched root system, root deeply, and carry a high population of Pseudomonas spp. bacteria on its roots. Starting with a mixture of total rhizobacteria from grass-like vegetation collected from a heavily polluted site and selecting for stable naphthalene degradation as well as for efficient root colonization, Pseudomonas putida strain PCL1444 was isolated. The strain's ability to degrade naphthalene was shown to be stable in the rhizosphere. Moreover, it had superior root-colonizing properties because, after the inoculation of grass seedlings, it appeared to colonize the root tip up to 100 fold better than the efficient root colonizer Pseudomonas fluorescens WCS365. Strain PCL1444 uses root exudate as the dominant nutrient source because the presence of grass seedlings in soil results in up to a 10-fold increase of PCL1444 cells. Moreover, the root colonized by strain PCL1444 was able to penetrate through an agar layer, resulting in the degradation of naphthalene underneath this layer. In addition, the inoculation of grass seeds or seedlings with PCL1444 protected them against naphthalene phytotoxicity. Finally, this plant-microbe combination appeared able to degrade naphthalene from soil that was heavily polluted with a complex mixture of polycyclic aromatic hydrocarbons. To our knowledge, this is the first time that a naturally occurring bacterium has been selected for the combination of the abilities to degrade a pollutant and colonize plant roots. We suggest that the principle described here, to select a bacterium which combines efficient root colonization with a beneficial activity, also can be used to improve the selection of other more efficient plant-bacterium pairs for beneficial purposes such as biocontrol, biofertilization, and phytostimulation. PMID- 11605960 TI - Susceptibility to the sugar beet cyst nematode is modulated by ethylene signal transduction in Arabidopsis thaliana. AB - Previously, we identified Arabidopsis thaliana mutant rhd1-4 as hypersusceptible to the sugar beet cyst nematode Heterodera schachtii. We assessed rhd1-4 as well as two other rhd1 alleles and found that each exhibited, in addition to H. schachtii hypersusceptibility, decreased root length, increased root hair length and density, and deformation of the root epidermal cells compared with wild-type A. thaliana ecotype Columbia (Col-0). Treatment of rhd1-4 and Col-0 with the ethylene inhibitors 2-aminoethoxyvinylglycine and silver nitrate and the ethylene precursor 1-aminocyclopropane-1-carboxylic acid suggests that the rhd1-4 hypersusceptibility and root morphology phenotypes are the result of an increased ethylene response. Assessment of known ethylene mutants further support the finding that ethylene plays a role in mediating A. thaliana susceptibility to H. schachtii because mutants that overproduce ethylene (eto1-1, eto2, and eto3) are hypersusceptible to H. schachtii and mutants that are ethylene-insensitive (etr1 1, ein2-1, ein3-1, eir1-1, and axr2) are less susceptible to H. schachtii. Because the ethylene mutants tested show altered susceptibility and altered root hair density and length, a discrimination between the effects of altered ethylene signal transduction and root hair density on susceptibility was accomplished by analyzing the ttg and gl2 mutants, which produce ectopic root hairs that result in greatly increased root hair densities while maintaining normal ethylene signal transduction. The observed normal susceptibilities to H. schachtii of ttg and g12 indicate that increased root hair density, per se, does not cause hypersusceptibility. Furthermore, the results of nematode attraction assays suggest that the hypersusceptibility of rhd1-4 and the ethylene-overproducing mutant eto3 may be the result of increased attraction of H. schachtii-infective juveniles to root exudates of these plants. Our findings indicate that rhd1 is altered in its ethylene response and that ethylene signal transduction positively influences plant susceptibility to cyst nematodes. PMID- 11605961 TI - Genetic organization of the Pantoea stewartii subsp. stewartii hrp gene cluster and sequence analysis of the hrpA, hrpC, hrpN, and wtsE operons. AB - The hrp/wts gene cluster of Pantoea stewartii subsp. stewartii is required for pathogenicity on sweet corn and the ability to elicit a hypersensitive response (HR) in tobacco. Site-directed transposon mutagenesis and nucleotide sequencing were used to identify hrp/wts genes within the left 20 kb of this cluster. Seventeen open reading frames (ORFs) comprise seven genetic complementation groups. These ORFs share homology with hrp and dsp genes from Erwinia amylovora, Erwinia chrysanthemi, and Pseudomonas syringae pathovars and have been designated, in map order, wtsF, wtsE, hrpN, hrpV, hrpT, hrcC, hrpG, hrpF, hrpE, hrpD, hrcJ, hrpB, hrpA, hrpS, hrpY, hrpX, and hrpL. Putative hrp consensus promoter sequences were identified upstream of hrpA, hrpF, hrpN, and wtsE. Expression of the hrpA, hrpC, and wtsE operons was regulated by HrpS. Transposon mutations in all of the hrp operons abolished pathogenicity and HR elicitation, except for the hrpN and hrpV mutants, which were still pathogenic. hrpS, hrpXY, and hrpL regulatory mutations abolished HrpN synthesis, whereas secretory mutations in the hrpC, hrpA, and hrpJ operons permitted intracellular HrpN synthesis. wtsEF mutants were not pathogenic but still produced HrpN and elicited the HR. wtsE encodes a 201-kDa protein that is similar to DspE in E. amylovora and AvrE in P. syringae pv. tomato, suggesting that this protein is a major virulence factor involved in the elicitation of water-soaked lesions. PMID- 11605962 TI - Biological activity of harpin produced by Pantoea stewartii subsp. stewartii. AB - Pantoea stewartii subsp. stewartii causes Stewart's wilt of sweet corn. A hypersensitive response and pathogenicity (Hrp) secretion system is needed to produce water-soaking and wilting symptoms in corn and to cause a hypersensitive response (HR) in tobacco. Sequencing of the hrp cluster revealed a putative harpin gene, hrpN. The product of this gene was overexpressed in Escherichia coli and shown to elicit the HR in tobacco and systemic resistance in radishes. The protein was designated HrpN(Pnss). Like other harpins, it was heat stable and protease sensitive, although it was three- to fourfold less active biologically than Erwinia amylovora harpin. We used antibodies to purified HrpN(Pnss) to verify that hrpN mutants could not produce harpin. This protein was secreted into the culture supernatant and was produced by strains of P. stewartii subsp. indologenes. In order to determine the importance of HrpN(Pnss) in pathogenesis on sweet corn, three hrpN::Tn5 mutants were compared with the wild-type strain with 50% effective dose, disease severity, response time, and growth rate in planta as parameters. In all tests, HrpN(Pnss) was not required for infection, growth, or virulence in corn or endophytic growth in related grasses. PMID- 11605963 TI - Salicylic acid and NIM1/NPR1-independent gene induction by incompatible Peronospora parasitica in arabidopsis. AB - To identify pathogen-induced genes distinct from those involved in systemic acquired resistance, we used cDNA-amplified fragment length polymorphism to examine RNA levels in Arabidopsis thaliana wild type, nim1-1, and salicylate hydroxylase-expressing plants after inoculation with an incompatible isolate of the downy mildew pathogen Peronospora parasitica. Fifteen genes are described, which define three response profiles on the basis of whether their induction requires salicylic acid (SA) accumulation and NIM1/NPR1 activity, SA alone, or neither. Sequence analysis shows that the genes include a calcium binding protein related to TCH3, a protein containing ankyrin repeats and potential transmembrane domains, three glutathione S-transferase gene family members, and a number of small, putatively secreted proteins. We further characterized this set of genes by assessing their expression patterns in each of the three plant lines after inoculation with a compatible P. parasitica isolate and after treatment with the SA analog 2,6-dichloroisonicotinic acid. Some of the genes within subclasses showed different requirements for SA accumulation and NIM1/NPR1 activity, depending upon which elicitor was used, indicating that those genes were not coordinately regulated and that the regulatory pathways are more complex than simple linear models would indicate. PMID- 11605964 TI - Identification of putative parasitism genes expressed in the esophageal gland cells of the soybean cyst nematode Heterodera glycines. AB - Cloning parasitism genes encoding secretory proteins expressed in the esophageal gland cells is the key to understanding the molecular basis of nematode parasitism of plants. Suppression subtractive hybridization (SSH) with the microaspirated contents from Heterodera glycines esophageal gland cells and intestinal region was used to isolate genes expressed preferentially in the gland cells of parasitic stages. Twenty-three unique cDNA sequences from a SSH cDNA library were identified and hybridized to the genomic DNA of H. glycines in Southern blots. Full-length cDNAs of 21 clones were obtained by screening a gland cell long-distance polymerase chain reaction cDNA library. Deduced proteins of 10 clones were preceded by a signal peptide for secretion, and PSORT II computer analysis predicted eight proteins as extracellular, one as nuclear, and one as plasmalemma localized. In situ hybridization showed that four of the predicted extracellular clones were expressed specifically in the dorsal gland cell, one in the subventral gland cells, and three in the intestine in H. glycines. The predicted nuclear clone and the plasmalemma-localized clone were expressed in the subventral gland cells and the dorsal gland cell, respectively. SSH is an efficient method for cloning putative parasitism genes encoding esophageal gland cell secretory proteins that may have a role in H. glycines parasitism of soybean. PMID- 11605965 TI - Wheat puroindolines enhance fungal disease resistance in transgenic rice. AB - Antimicrobial peptides play a role in the immune systems of animals and plants by limiting pathogen infection and growth. The puroindolines, endosperm-specific proteins involved in wheat seed hardness, are small proteins reported to have in vitro antimicrobial properties. Rice, the most widely used cereal crop worldwide, normally does not contain puroindolines. Transgenic rice plants that constitutively express the puroindoline genes pinA and/or pinB throughout the plants were produced. PIN extracts of leaves from the transgenic plants reduced in vitro growth of Magnaporthe grisea and Rhizoctonia solani, two major fungal pathogens of rice, by 35 to 50%. Transgenic rice expressing pinA and/or pinB showed significantly increased tolerance to M. grisea (rice blast), with a 29 to 54% reduction in symptoms, and R. solani (sheath blight), with an 11 to 22% reduction in symptoms. Puroindolines are effective in vivo in antifungal proteins and could be valuable new tools in the control of a wide range of fungal pathogens of crop plants. PMID- 11605966 TI - Ectopic expression of an Arabidopsis calmodulin-like domain protein kinase enhanced NADPH oxidase activity and oxidative burst in tomato protoplasts. AB - Among plant defense responses to pathogen attack, the release of active oxygen species (AOS), termed the oxidative burst, may affect the attacking pathogen and the host plant cells at the infection site, thereby limiting the spread of the pathogen. Plasma membrane-associated NADPH oxidase represents a key enzyme in mediating the oxidative burst. The mechanisms of NADPH oxidase activation, however, remains unclear. Ectopic expression of AK1-6H, an Arabidopsis calmodulin like domain protein kinase (CDPK) in tomato protoplasts enhanced plasma membrane associated NADPH oxidase activity. Arabidopsis protein phosphatase 2A abolished this enhancement, whereas Arabidopsis dual-specificity protein tyrosine phosphatase 1 or maize protein phosphatase 1 had no effect tMEK2MUT, a constitutively activated, mitogen-activated protein kinase kinase from tomato, did not enhance NADPH oxidase activity when overexpressed. In a cell-free system, AK1-6H moderately stimulated the NADPH oxidase activity on plasma membrane. AK1 6H, but not tMEK2MUT, also enhanced production of AOS in intact protoplasts. Our results show that ectopic expression of a heterologous CDPK can enhance NADPH oxidase activity and stimulate an oxidative burst in tomato protoplasts. PMID- 11605967 TI - Emerging pollutants, and communicating the science of environmental chemistry and mass spectrometry: pharmaceuticals in the environment. AB - While this paper is to a large degree targeted for those not familiar with mass spectrometry, [for an overview of mass spectrometry, a number of excellent websites are available, including http://base peak.wiley.com/links/Resources/Educational_Resources/], the primary focus is on the importance of mass spectrometry in ultimately protecting public health and minimizing risks of chemical exposure. Its other audience is those who practice in this specialized field. Should this subject not interest you, by reading this article you can discover among other things, why elevator rides can be important for your career and for your discipline. Why acetaminophen is used for brown tree snakes, or lipid-lowering drugs for pigeons. PMID- 11605968 TI - Effects of liquid phase composition on salt cluster formation in positive ion mode electrospray mass spectrometry: implications for clustering mechanism in electrospray. AB - Potassium bromate salt clusters, [KBrO3]nKx(x+), formed by electrospray ionization were studied as a function of solution properties. Clusters with up to 4 positive charges were observed. Their abundance, charge state and distribution were shown to vary with the organic solvent in solution. The effects of 7 solvents, including methanol, ethanol, isopropanol, acetonitrile, acetone, pyridine, and 1,4-dioxane, were thoroughly investigated. Solvents with a low dielectric constant and a high viscosity seem to favor clustering in solution but do not systematically allow high charge state ion formation. On the other hand, cluster charge reduction during desolvation was not correlated with solvent cation affinity over the range of solvents examined. However, ion distribution in mass spectra could be rationalized as a combination of these two competing phenomena. Charge state increases with the cluster size but may be reduced during ion desolvation when high cation affinity solvent molecules are actually involved in the ion solvation shell. This assumption could be envisaged in either Iribarne or Dole mechanisms of ion release in the gas phase. However, intensity profiles of multiply charged clusters could only be understood in terms of the ion evaporation mechanism. PMID- 11605969 TI - Stable association complex electrospray mass spectrometry for the determination of cyanuric acid. AB - Cyanuric acid, a suspected gastrointestinal or liver toxicant, has gained interest as a potential degradation product of triazine herbicides, such as simazine and atrazine. This paper investigates the determination of cyanuric acid by stable association complex electrospray mass spectrometry (cESI-MS). The cyanuric acid is extracted from the water through a microscale liquid-liquid extraction. The extract is evaporated to dryness, and an aqueous solution of quaternary ammonium cationic surfactant is added. When injected into the electrospray mass spectrometer, the surfactant and the cyanuric acid form a mass selective stable association complex, which may be used for confident quantification of cyanuric acid. Several extraction solvents and surfactants were investigated. These studies provide insight into the mechanism of electrospray for the formation of these complexes, specifically with regard to the surface activity of the different surfactants and the chemistry of the surfactant cyanuric acid complexes. From an analytical standpoint, the cESI-MS method detection limit for extraction of a 1 mL aqueous solution of cyanuric acid was 130 microg/L based on 3.14sigma(n-1) of seven replicate injections. Standard additions were used for quantification of eight aqueous samples. The cyanuric acid concentrations determined with cESI-MS were not significantly different at the 95% confidence level to those determined by conventional high-performance liquid chromatography (HPLC). A recovery of 100% from a fortified urine sample illustrates the robustness of the technique. PMID- 11605970 TI - The influence of electrostatic interactions on the detection of heme-globin complexes in ESI-MS. AB - The heme-globin complexes of hemoglobin and myoglobin are investigated in positive-ion mode and negative-ion mode using a nano-ESI source coupled to a quadrupole ion trap MS and an orthogonal time-of-flight MS. The extent of dissociation of these noncovalent complexes upon collisional activation and thus their gas-phase stability is strongly dependent on the polarity of the ESI-MS experiment as well as on the charge of the prosthetic group (ferri-heme [Fe3+ heme]+ vs. ferro-heme [Fe2+-heme]+/-0). The results clearly point to the important role of electrostatic interactions on the gas phase stability of noncovalent complexes and therefore the ion signals observed in ESI-MS experiments. PMID- 11605971 TI - Static secondary ion mass spectrometry to monitor solid-phase peptide synthesis. AB - Insights into the direct monitoring of supported peptide synthesis were realized through the design of time of flight static secondary ion mass spectrometry (TOF S-SIMS) experiments. The mass spectrometric method was carried out at the resin bead level and was found reproducible (intra- and inter-day assays), sensitive (femtomol level) and non-destructive (only 0.01% of the peptides were destroyed by the primary ion beam bombardment). The nature of the peptide-resin linkage governed the recovery of ions characterizing the whole peptide sequence. A S-SIMS cleavable bond was thus required solely in that position to achieve the release of the growing structures from the insoluble support into the gas phase without any fragmentation. Results are presented with standard solid-phase resins allowing linkage through an amide or an ester bond. The latter was orthogonally broken upon the bombardment and thus constituted a convenient S-SIMS cleavable bond. PMID- 11605972 TI - Identification of GlcNAcylation sites of peptides and alpha-crystallin using Q TOF mass spectrometry. AB - The addition of a single N-acetylglucosamine residue O-linked to serine and threonine residues of nuclear and cytoplasmic proteins is a widespread modification throughout all eukaryotes. The conventional method for detecting and locating sites of modification is a multi-step radioactivity-based protocol. In this paper we show that using quadrupole time-of-flight (Q-TOF) mass spectrometry, modification sites can be identified at a significantly higher sensitivity than previous approaches. This is the first demonstration that sites of O-GlcNAcylation can be identified directly using mass spectrometry. PMID- 11605973 TI - Formation of molecular radical cations of enkephalin derivatives via collision induced dissociation of electrospray-generated copper (II) complex ions of amines and peptides. AB - Fragmentation of some electrospray-generated complex ions, [63CuII(amine)M].2+, where M is an enkephalin derivative, produces the radical cation of the peptide, M.+. This ion has only been observed when M contains a tyrosyl or tryptophanyl residue plus a basic residue, typically arginyl or lysyl. A typical viable amine is diethylenetriamine. Collision-induced dissociation (CID) of the M.+ ion yields a prominent [M - 106].+ product ion for tyrosine-containing peptides, and a prominent [M - 129].+ ion for a tryptophan-containing peptide. These fragment ions are formed as a result of elimination of the tyrosyl and tryptophanyl side chains. Dissociation of these ions, in turn, produces second generation product ions, many of which are typically absent in the fragmentation of protonated peptide ions. Structures for some of these unusual ions are proposed. PMID- 11605974 TI - Charge exchange ionization in collision cells as a method to detect the presence of long-lived excited electronic states of polyatomic ions. AB - Charge exchange ionization in collision cells installed in a double focusing mass spectrometer with reversed geometry has been used to detect the presence of a long-lived excited electronic state of benzene ion. In particular, the first collision cell located between the ion source and the magnetic sector was modified to serve as an ion source for the reagent ion generated by charge exchange with the primary ion. Strong reagent ion signals were observed when the ionization energies of the reagents (1,3-C4H6, CS2, CH3Cl) were lower than the recombination energy (approximately 11.5 eV) of the excited state benzene ion, while the signals were negligible for reagents (CH3F,CH4) with higher ionization energy. The fact that a strong signal is observable only for electronically exoergic charge exchange is useful for detecting the presence of a long-lived electronically excited state. PMID- 11605976 TI - Electrospray characterization of perrhenate systems. AB - The electrospray negative ion mode (ESI-) mass spectrometry study of freshly prepared perrhenate in the ammonium and alkali metal (Na and K) solutions has been detailed. The cone voltage dependency of the negative ion abundance clearly indicates that the collision-activated dissociation (CAD) process in the cone-to skimmer region is the source for both linear and non-linear cone voltage dependencies. The model also highlights that the [ReO2]- and [ReO3]- ions observed in the ESI- spectra are not present in the bulk, but are due to a dissociative collision, which strips a single oxygen atom from their precursor ions, namely [ReO3]- and [ReO4]- , respectively. PMID- 11605975 TI - Determination of photomodified oligodeoxynucleotides by exonuclease digestion, matrix-assisted laser desorption/ionization and post-source decay mass spectrometry. AB - A fast method to detect and sequence photomodified oligodeoxynucleotides (ODNs) by exonuclease digestion and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) is reported. Upon treatment of modified ODNs with both phosphodiesterase I and phosphodiesterase II, the digestion stops at the sites of photomodification. Post-source decay (PSD) of MALDI-produced ions from two enzymatic digestion end products distinguishes isomers such as 5'-d(T[cis syn]TAAGC) and 5'-d(CGAAT[cis-syn]T), which have symmetrical or identical compositions at the 3' and 5' ends, respectively. Studies have also been done to follow the kinetics for enzyme degradation of photomodified ODNs. The calculated rate constants from a mathematical treatment of the time-dependent MALDI data clearly show that the enzymatic digestion rate slows as the enzyme approaches the modified site. PMID- 11605977 TI - Sjogren's syndrome: challenges to management. PMID- 11605979 TI - Managing dry eyes and dry mouth in Sjogren's syndrome. PMID- 11605978 TI - A review and update of Sjogren's syndrome: manifestations, diagnosis, and treatment. AB - Sjogren's syndrome is an autoimmune disorder that affects approximately 1% of the population. It is a disease that in recent years has not been studied extensively, but for which much study is needed. Diagnosis of this disease is extremely difficult. Until recently no strong consensus on diagnostic criteria has been published. The disease can cause dry eyes, dry mouth, vasculitis, and neurologic disease, and each symptom may be at times correctly attributed to Sjogren's or incorrectly attributed to another disease. Because it affects many different areas, many specialists (rheumatologists, primary care physicians, ophthalmologists, and dentists) have to be educated about Sjogren's syndrome's pathogenesis, manifestations, diagnosis, and treatments to manage this disease and help improve these patients' quality of life. PMID- 11605980 TI - Protein-based inheritance in Saccharomyces cerevisiae: [URE3] as a prion form of the nitrogen regulatory protein Ure2. AB - The [URE3] element of the yeast Saccharomyces cerevisiae results from the presence of an altered form of the nitrogen regulatory protein Ure2. This altered form acts as an infectious protein (prion). Genes affecting [URE3] initiation and propagation should give valuable information about prion diseases as well as other conformational diseases. PMID- 11605981 TI - Bacterial infections of free-living amoebae. AB - Free-living amoebae are a diverse group of ubiquitous unicellular organisms, some of which cause severe central nervous system infections and keratitis. However, the focus of research has shifted from the direct pathogenic effects of free living amoebae towards their role as carriers of pathogenic bacteria. Large outbreaks of legionellosis with numerous fatal cases, both in hospitals and in the community, appear to be the visible tip of the iceberg of complex relationships between amoebae and bacteria in biofilms. The recognition of amoebae as reservoirs and vehicles for bacterial spread leads us to public health issues such as the development of pathogenicity, antibiotic resistance, quality of public water supplies, housing standards, sanitation and decontamination measures. In this review we discuss bacterial infections of free-living amoebae from both a "biological" and general "infection control" point of view. PMID- 11605982 TI - Trends in the use of protozoa in the assessment of wastewater treatment. AB - Increasing environmental pollution and the continuous development of new chemicals and drugs has led to ever growing concern about the potential effects of these compounds directly or indirectly on human health. As concerns water pollution, protozoa seem to be an excellent tool to assess both toxicity and pollution: they are regarded as biological indicators of pollution when their presence or absence can be related to particular environmental conditions, and they are considered test organisms when a species or population is used to evaluate the toxicity of relevant toxic compounds. Thus, an integrated approach is being developed to assess how toxic compounds affect the different biological levels of organisation--from the community level to the species level--of ciliated protozoa. The present paper reports and discusses the current state of the art of this approach. PMID- 11605983 TI - Clinical usefulness of microbiological diagnostic tools in the management of periodontal disease. AB - Periodontal diseases comprises a group of chronic inflammatory conditions affecting tooth supporting structures. It has been known for a long time that pathogenic oral bacteria colonizing the tooth surface are associated with the initiation of the disease process. However, to date, a dozen or so bacterial species have been implicated in the pathogenesis of periodontal disease and no one species by itself is synonymous with disease onset. This multibacterial etiology renders the diagnosis of active periodontal disease based on microbiological data difficult. Numerous studies have attempted to relate the usefulness of microbiological diagnostic aids such as microscopy, bacterial culture, immunological and enzymatic assays. Furthermore, recent technical advances have resulted in the use of nucleic acid probes and amplification techniques for the identification of genetic material belonging to potential periodontal pathogens. Despite the availability of a large number of microbiological testing protocols, identification of the microbial etiological agents remains hampered by the complexity of the microbial challenge during periodontal disease. This review discusses the clinical usefulness of these tests in detection and management of periodontal disease. PMID- 11605984 TI - Characterization of Rhodococcus opacus R7, a strain able to degrade naphthalene and o-xylene isolated from a polycyclic aromatic hydrocarbon-contaminated soil. AB - Rhodococcus opacus R7 was isolated from a soil contaminated with polycyclic aromatic hydrocarbons for its ability to grow on naphthalene. The strain was also able to degrade o-xylene, the isomer of xylenes most recalcitrant to microbial degradation. The catabolic pathways for naphthalene and o-xylene were investigated by identification of metabolites in R. opacus R7 cultures performed with the two hydrocarbons and by evaluation of some enzymes involved in the metabolism of these compounds. 1,2-Dihydro-1,2-dihydroxynaphthalene, salicylic and gentisic acids were identified as metabolites in cultures exposed to naphthalene. This suggests that the degradation occurs through the dioxygenation of the aromatic ring with the formation of 1,2-dihydro-1,2-dihydroxynaphthalene, dehydrogenated to the corresponding 1,2-dihydroxy derivative which is further oxidized to salicylic acid, a key intermediate of naphthalene metabolism; this compound is converted to gentisic acid cleaved by a gentisate 1,2-dioxygenase. From R. opacus R7 cultures supplied with o-xylene, 2,3-dimethylphenol and 3,4 dimethylcatechol were observed. The pathway of o-xylene involves the monooxygenation of the benzene nucleus leading to dimethylphenol which is further metabolised to 3,4-dimethylcatechol, followed by a meta cleavage reaction, catalyzed by the catechol 2,3-dioxygenase. R. opacus R7 is the first strain thus far described both in Gram-negative and Gram-positive bacteria which has the ability to degrade both a polycyclic aromatic hydrocarbon such as naphthalene and a monocyclic aromatic hydrocarbon such as o-xylene. PMID- 11605986 TI - Amount and redox state of cytoplasmic, membrane and periplasmic proteins in Escherichia coli redox mutants. AB - We analyzed the amount and redox state of cytoplasmic, membrane and periplasmic proteins in Escherichia coli mutants deficient in thioredoxin, thioredoxin reductase, glutathione and DsbA, by observing the electrophoretic profile of bacterial extracts after in vivo labelling with monobromobimane. Our results show that these mutations affected not only the amount and the redox state of proteins localized in the same compartment as the deficient oxidoreductase, but also those of the proteins localized in other compartments. These results concord with the hypothesis that there is a link between the redox reactions that occur in the cytoplasm and the periplasm. PMID- 11605985 TI - The arcABC gene cluster encoding the arginine deiminase pathway of Oenococcus oeni, and arginine induction of a CRP-like gene. AB - Oenococcus oeni, the main species which induces malolactic fermentation in wine, uses arginine via the arginine deiminase (ADI) pathway. Using degenerated primers, two specific probes, one for ornithine transcarbamoylase (OTC) and the other for carbamate kinase (CK), were synthesized. These made it possible to clone and sequence a cluster containing genes encoding ADI (arcA), OTC (arcB) and CK (arcC). In addition, sequence analysis upstream of the arcA gene revealed the presence of an open reading frame (orf229) whose 3'-end was only 101 bp-distant from the start codon of the arcA gene and showed similarity with members of the FNR (regulation for fumarate and nitrate reduction) and CRP (cAMP receptor protein) family of transcriptional regulators. Moreover, a putative binding site for such regulators lies in the promoter region of the arcA gene. Induction of the arc cluster by arginine was studied first at the enzymatic level. The activities of the three enzymes strongly increased when cells were grown in the presence of the amino acid. In addition, the influence of arginine on gene transcription was monitored by RT-PCR (reverse transcriptase-polymerase chain reaction). Expression of the three arc genes, and particularly that of arcA, was positively affected by arginine supplementation and thus confirmed the enzymatic results. Moreover, transcription of the putative CRP-like gene orf229 was also stimulated by arginine. These data suggest that the protein encoded by orf229 could be a CRP-like regulator involved in the metabolism of O. oeni. PMID- 11605987 TI - Estimation of the abundance of the cadmium resistance gene cadA in microbial communities in polluted estuary water. AB - We describe herein a molecular method for estimating the abundance of the cadA gene, which encodes a Cd2+/ATPase protein transporter, in bacterial DNA extracted from samples of environmental water. Competitive polymerase chain reaction (cPCR) may be the most appropriate technique for assessing the prevalence of the cadA gene in microbial communities in highly heterogeneous and polluted environments, such as the Seine estuary (France). We describe the development of this method: (i) the choice of two specific primers, based on the sequences encoding the cadmium binding site and the ion channel domains; (ii) the construction of a competitor sequence and assessment of its amplification efficiency; and (iii) the estimation of the copy number of the cadA gene. The cadA content in the bacterial community is expressed as the number of gene copies per ng of total DNA extracted, which is independent of the DNA extraction yield. This molecular procedure was improved to analyze cadA levels in bacterial DNA extracted from estuary water accidentally contaminated with cadmium. Results revealed a subsequent increase in the copy number of the cadA gene in the microbial community. PMID- 11605988 TI - Antioxidant properties of acetaminophen and cardioprotection. AB - The acute administration of acetaminophen to isolated, perfused guinea pig hearts appears to have cardioprotective effects against the injury/mechanical dysfunction caused by global, low-flow, myocardial ischemia and reperfusion. In the current study we selected ischemia/reperfusion and administration of sodium pentobarbital as perturbations of the electrical stability of the myocardium. We investigated their ability to induce ventricular arrhythmias and changes in the characteristics of monophasic action potentials in the absence and presence of acetaminophen (0.35 mmol/l). The numbers of ventricular premature beats and ventricular salvos encountered in the presence of pentobarbital were significantly (P < 0.05) reduced by acetaminophen. The combined frequency of these arrhythmias was 0.14+/-0.06/min vs 0.03+/-0.01/min (P < 0.05) in the absence and presence of acetaminophen, respectively. The incidence of ventricular salvos increased steadily in vehicle-treated hearts after administration of pentobarbital. No such trend was seen with acetaminophen. After 10 min of global, low-flow myocardial ischemia, MAP50 and MAP90 (monophasic action potentials at 50 and 90% repolarization, respectively) decreased without acetaminophen (e.g. MAP50, 31+/-4 ms) but did not change during the same time interval with acetaminophen (e.g. MAP50, 57+/-6 ms)(P < 0.05). During ischemia and reperfusion, acetaminophen attenuated the release of hydroxyl radicals and peroxynitrite. Collectively these data reveal cardioprotective, antioxidant behavior of acetaminophen. Under selected conditions (e.g. those causing release of free radicals and other oxidants) such behavior might also prevent ventricular arrhythmias. PMID- 11605989 TI - Antioxidant changes in the hypertrophied heart due to energy metabolic disorder. AB - Oxidative stress has been implicated in the pathogenesis of both heart hypertrophy and heart failure. Hypertrophied heart, in response to pressure overload, is associated with an increase in antioxidant capacity and a decrease in oxidative stress. However, in the hypertrophied heart due to energy metabolic disorder, antioxidant capacity has not been investigated. Antioxidant changes in juvenile visceral steatosis (JVS) mice, a model of heart hypertrophy due to disorder of fatty-acid oxidation, were examined at 4 weeks (developing hypertrophy stage) and 8 weeks of age (established hypertrophy stage). Superoxide dismutase activity in the JVS mice was higher than that in control mice at 4 weeks of age and was not different from that in the control mice at 8 weeks of age. Glutathione peroxidase activity in the JVS mice at 8 weeks of age was lower than that in the control mice. Catalase activity showed no significant differences between the control and the JVS mice. Lipid peroxidation in the JVS mice was significantly reduced at 4 weeks of age and increased toward control levels at 8 weeks of age. The levels of vitamin E in the heart were increased in the JVS mice at 8 weeks of age. To determine whether antioxidants affect the pathogenesis of hypertrophy in this model, long-term treatments of vitamin E and 2-mercaptopropionyl glycine were performed. Vitamin E treatment partially reduced the heart hypertrophy in these mice. The present study shows that heart hypertrophy in the JVS mice is accompanied with increased antioxidant capacity as indicated in other animal models of heart hypertrophy. The precise mechanism of heart hypertrophy in JVS mice is still unknown, but oxidative stress may play a role in the pathogenesis of heart hypertrophy. PMID- 11605990 TI - T cell-mediated immune response enhances the severity of myocarditis in secondary cardiotropic virus infection in mice. AB - In this report, we showed that a previous enterovirus exposure in ordinary mice with normal T cell function, but not in T cell-deficient mice, can influence development of myocardial inflammation with a second virus exposure. Inoculation of 4-week-old male BALB/c-nu/+ (euthymic and normal T cell function) mice with amyocarditic Coxsackie virus B1 (CB1), followed by inoculation 28 days later with myocarditic variant of Coxsackie virus B3 (CB3-m) resulted in more intense myocardial inflammation and injury than was seen in BALB/c-nu/+ inoculated with CB1, followed by inoculation with non-enterovirus, i.e., encephalomyocarditis virus (EMC) or influenza A virus and in age-matched BALB/c-nu/+ mice secondary inoculated with CB3-m alone. In contrast, this phenomenon of the enhancement of the severity of myocarditis by a secondary CB3-m inoculation was not seen in BALB/c-nu/nu (athymic and T cell- deficient) mice. Interestingly, inoculation of BALB/c-nu/+ mice with CB1, followed by inoculation 28 days later with another amyocarditic variant of Coxsackie virus B3 (CB3-o), resulted in more severe myocarditis than was seen in age-matched BALB/c-nu/+ mice secondary inoculated CB3-o alone. Myocardial-activated T cells and elevated serum interleukin-6 were involved in the exacerbation of the disease during the reinfection. T cell mediated immune responses to a conserved antigenic epitope among the enteroviruses may be involved in the exacerbation of myocardial inflammatory disease during a second enterovirus infection. PMID- 11605992 TI - Limitation of infarct size and attenuation of myeloperoxidase activity by an endothelin A receptor antagonist following ischaemia and reperfusion. AB - It has previously been shown that endothelin (ET) receptor antagonists limit myocardial ischaemia/reperfusion (I/R) injury. The mechanism behind this effect is still unclear. The aim of this study was to elucidate the possible relationship between cardioprotection by an ET(A) receptor antagonist and inhibition of neutrophil accumulation or activation in the myocardium determined as myeloperoxidase (MPO) activity during I/R. Anaesthetised pigs were subjected to 45 min ischaemia by ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Infiltration of MPO-containing cells, presumably neutrophils, into the ischaemic area was confirmed with an immunohistochemical technique using antibodies against porcine MPO. Vehicle (n = 7) or the selective ET(A) receptor antagonist LU 135252 (LU; n = 7) were given into the LAD during the last 10 min of ischaemia and the first 5 min of reperfusion. There were no significant differences in LAD flow, mean arterial pressure, heart rate, or rate pressure product between the groups during I/R. The area at risk was similar in the two groups. LU reduced the final infarct size to 40+/-6% of the area at risk compared to 80+/-6% in the vehicle group (P < 0.001). Endothelin-like immunoreactivity increased 2-fold in the ischaemic area in the vehicle group (P < 0.01), but not in the group given LU. MPO activity was higher (2.5x) in the ischaemic than in the non-ischaemic myocardium of the vehicle group. The MPO activity in the ischaemic myocardium was significantly lower in the group given LU (7.0+/-1.2 units g(-1)) than in the vehicle group (14.2+/-1.9 units g(-1); P < 0.01). There was a significant correlation between the infarct size and MPO activity (P < 0.01, r = 0.68). In conclusion, local administration of the selective ET(A) receptor antagonist LU during the last period of ischaemia and early reperfusion reduces the extent of myocardial necrosis and MPO activity. This suggests that LU may exert its cardioprotective effect by inhibiting neutrophil-mediated injury. PMID- 11605991 TI - Critical timing of mitochondrial K(ATP) channel opening for enhancement of myocardial tolerance against infarction. AB - OBJECTIVE: The present study was designed to assess the relationship between the timing of a mitoK(ATP) channel opener, diazoxide, and its infarct size-limiting effect. METHODS: In isolated rabbit hearts, infarction was induced by 30 min of global ischemia and 2 h of reperfusion, and infarct size was determined by tetrazolium staining and expressed as a percentage of the left ventricle (%IS/LV). Diazoxide, a mitoK(ATP) channel selective opener, and/or 5 hydroxydecanoate (5-HD), a mitoK(ATP) channel blocker, were infused before or after the onset of ischemia. When these agents were infused during the ischemic period, they were dissolved in a hypoxic buffer at concentrations 10-fold higher than those in the pre-ischemic period, and the infusion rate was set at 2% of the pre-ischemic coronary flow. RESULTS: In untreated controls, %IS/LV was 53.2+/-4.1 (SE). Pretreatment with diazoxide (100 microM) with a 10-min washout period reduced %IS/LV to 7.8+/-2.4 and this protection was abolished by co-infusion of 5 HD (50 microM). Pre-ischemic infusion of diazoxide without a washout period reduced %IS/LV to 7.3+/-1.4, and infusion of diazoxide from 10 min after the onset of ischemia also limited %IS/LV to 14.9+/-4.6. However, diazoxide infusion from 25 min after the onset of ischemia failed to reduce infarct size (%IS/LV = 54.5+/-7.2). Furthermore, pretreatment with 5-HD (50 microM) also completely abolished the protection afforded by early post-ischemic diazoxide infusion (%IS/LV = 48.3+/-6.5). Neither infusion of 5-HD nor the anoxic vehicle alone during ischemia modified %IS/LV. CONCLUSION: These findings suggest that opening of mitoK(ATP) channels before ischemia and during early ischemia, but not that upon reperfusion, is important for enhancement of myocardial tolerance against infarction. PMID- 11605993 TI - Fasting limits the increase in intracellular calcium during ischemia in isolated rat hearts. AB - INTRODUCTION: Fasting has been shown to limit ischemic injury and improve functional activity after global ischemia. Because calcium overload is considered a mechanism of ischemic injury, we hypothesized that fasting would limit the accumulation of intracellular calcium [Ca]i during ischemia, potentially due to reduced accumulation of intracellular sodium [Na]i. METHODS: To address this hypothesis, hearts isolated from rats fed either a normal diet or fasted for 24 hours underwent 20 min of global ischemia at 37 degrees. In addition to functional parameters, [Na]i and [Ca]i were measured using 21Na and 19F spectroscopy using thulium-DOTP-5 and 5F-BAPTA, respectively. In vitro measurement of sarcoplasmic reticulum calcium uptake and release, as well as activity of the sarcolemmal Na-Ca exchanger, was performed in hearts from fed and fasted animals under baseline and ischemic conditions. RESULTS: Hearts from fasted animals showed greater recovery of developed pressure (37+/-9 vs. 11+/-6 cm H2O, p < 0.05) and less contracture (end-diastolic pressure 25+/-2 vs. 47+/-2 cm H2O, p < 0.05) by the end of the reperfusion period. [Na]i was similar in the 2 groups during the first half of the ischemic period, albeit with a higher concentration of [Na]i in hearts from fed compared to fasted animals at reperfusion. Fasting markedly limited calcium accumulation during ischemia, with end-ischemic calcium being 419+/-46 nM in the hearts from fasted animals and 858+/-140 nM in the hearts from fed animals (p < 0.01). There was no significant effect of fasting on calcium uptake or release by the SR, nor on sarcolemmal Na Ca exchange activity. CONCLUSIONS: Fasting for 24 hours improves functional recovery and markedly limits [Ca]i accumulation during ischemia and early reperfusion. The mechanism for this phenomenon remains to be elucidated. PMID- 11605994 TI - Transient pleural effusion in norepinephrine-stimulated rats. AB - Transient pleural effusions occurred in rats receiving continuous intravenous infusion of norepinephrine (NE, 0.1 mg/kg/h). We hypothesized that these pleural effusions result from a NE-induced increase in right ventricular systolic pressure (RVSP) and total peripheral resistance (TPR). NE was administered over time intervals between 20 min and 72 h. It induced an immediate doubling in RVSP whereas LVSP remained at the control level. TPR increased with a delay of 6 h. At this time, pleural effusions occurred in NE-treated animals, reached their maximum after 8h and disappeared after 24 h of NE stimulation. Combining NE with the alpha-blocker prazosin normalized TPR and prevented pleural effusions. Therefore, we interpret the pleural effusion as a consequence of pulmonary venous congestion, mainly caused by an increased TPR. LV hypertrophy which developed after 24 h of NE stimulation is considered to compensate for the hemodynamic disturbance due to the NE-induced elevation in TPR. This is reflected in the disappearance of pleural effusion. PMID- 11605995 TI - Effect of radiofrequency ablation on atrial myocardium. AB - OBJECTIVES: Successful RF ablation of atrial fibrillation supposedly requires the creation of continuous linear lesions. This study aimed to determine the potential role of functional modifications of atrial myocardium in the vicinity of anatomic RF lesions. METHODS: In 10 normal beagles (group A), a multiplexer mapping system and an epicardial multi-electrode were used to reconstruct atrial activation patterns during pacing at two cycle lengths before and after attempts to induce two linear right atrial lesions with a standard ablation catheter, respectively. An intercaval "drawback" was repeated 3 times over 5 min at a set temperature of 70 degrees C, followed by a transversal "point-by-point" ablation from the interatrial septum to the right-lateral tricuspid annulus at 70 degrees C/60 s each. Induction of atrial flutter was attempted before and after each ablation. In another 6 beagles (group B), a high-resolution multi-electrode was used to study epicardial functional effects resulting from single endocardial RF lesions on the free right atrial wall. Using three energy settings (60 degrees C/30 s, 60 degrees C/60 s, 70 degrees C/60 s), activation patterns were analyzed at two cycle lengths and local effective refractory periods were measured across the lesion. RESULTS: The lesions induced in group A only marginally affected atrial activation patterns and total activation times. However, as shown in dogs with atrial flutter, regional slow conduction was enhanced and functional conduction blocks were facilitated at high atrial rates, resulting in a significant prolongation in the revolution time of respective reentrant circuits. Apart from inducing anatomic lesions, single endocardial RF lesions (group B) were shown to delay epicardial conduction in adjacent myocardium in an energy- and rate-dependent way. Furthermore, an energy-dependent prolongation of effective refractory periods by far exceeding the size of anatomic lesions was observed. CONCLUSIONS: Continuous linear atrial lesions are hard to achieve with conventional ablation techniques. However, RF lesions induce changes in conduction and refractoriness around the anatomic lesion, which are likely to contribute to the overall effect of respective therapeutic interventions. PMID- 11605996 TI - Protection of IB-MECA against myocardial stunning in conscious rabbits is not mediated by the A1 adenosine receptor. AB - The goal of this study was to determine whether the protective effects of the A3AR agonist N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (IB-MECA) against myocardial stunning are mediated by the A1AR. Six groups of conscious rabbits underwent a sequence of six 4-minute coronary occlusion (O)/4-minute reperfusion (R) cycles for three consecutive days (days 1, 2, and 3). In vehicle-treated rabbits (group I), the recovery of systolic wall thickening (WTh) in the ischemic/reperfused region was markedly depressed on day 1, indicating the presence of severe myocardial stunning. On days 2 and 3, however, the recovery of systolic WTh was markedly accelerated, indicating the presence of late ischemic preconditioning (PC). When rabbits were pretreated with the A1AR agonist 2-chloro N6-cyclopentyladenosine (CCPA, 100 microg/kg i.v.) or with IB-MECA (100 microg/kg i.v.) 10 min prior to the first sequence of O/R cycles on day 1 (group III and V, respectively), the recovery of systolic WTh was markedly accelerated compared to vehicle-treated animals (reflected as an approximately 48% decrease in the total deficit of systolic WTh). The magnitude of the protection afforded by adenosine receptor agonists was equivalent to that provided by late ischemic PC. Pre treating rabbits with the A1AR antagonist N-0861 completely blocked both the hemodynamic and the cardioprotective effects of CCPA (group IV). However, the same dose of N-0861 did not block the cardioprotective actions of IB-MECA (group VI). Importantly, N-0861 did not influence the degree of myocardial stunning in the absence of PC (group II) and it did not block the development of late ischemic PC. Taken together, these results provide conclusive evidence that the cardioprotective effects of IB-MECA are not mediated via the A1AR, supporting the concept that activation of A3ARs prior to an ischemic challenge provides protection against ischemia/reperfusion injury. PMID- 11605997 TI - Nifedipine limits infarct size via NO-dependent mechanisms in dogs. AB - OBJECTIVES: Amlodipine increases NO levels in coronary vessels and aorta via bradykinin-dependent mechanisms in vitro. We have previously reported that nifedipine increases cardiac NO levels in the ischemic canine hearts, suggesting that nifedipine may also have protective effects against ischemia and reperfusion injury, because the enhancement of NO production limits infarct size. We tested whether nifedipine limits infarct size via NO-dependent mechanisms. METHODS: In open chest dogs, the left anterior descending coronary artery was perfused with blood through a bypass tube and occluded for 90 min followed by 6 hours of reperfusion. Infarct size was assessed at 6 hours of reperfusion. Nifedipine of 3 or 6 microg/kg/min was infused into the bypass tube between 10 min prior to the onset of ischemia and 60 min of reperfusion. RESULTS: Neither systemic blood pressure nor heart rate changed during infusion of nifedipine. Infarct size was reduced by the administration of nifedipine (3 or 6 microg/kg/min) compared with the untreated condition (25.6+/-2.6 and 19.1+/-3.5 vs. 43.4+/-5.6%, respectively), which was completely blunted by L-NAME (45.0+/-3.6 and 45.4+/-4.2 vs. 47.9+/-3.9% in the nifedipine (3 or 6 microg/kg/min) with L-NAME groups vs. the L-NAME group). Myeloperoxidase activity of the myocardium increased after 6 hours of reperfusion, which was attenuated by nifedipine. The limitation of infarct size and the attenuation in myeloperoxidase actiivity were completely blunted by L-NAME. There were no significant differences in collateral blood flow at 45 min of ischemia between each group. CONCLUSIONS: We conclude that the Ca channel blocker, nifedipine, limits infarct size via NO-dependent mechanisms. PMID- 11605998 TI - Coronary artery distensibility and compensatory vessel enlargement--a novel parameter influencing vascular remodeling? AB - Vascular remodeling implies the concept of compensatory vessel enlargement to preserve luminal dimensions during atheromatous plaque development. However, negative remodeling, i.e. vessel shrinkage in response to plaque accumulation has also been described. So far, the factors influencing positive or negative remodeling are uncertain. We hypothesized that vascular distensibility, a measure of vessel compliance, is related to compensatory enlargement. In 58 patients undergoing intravascular ultrasound interrogation of a de novo lesion prior to coronary intervention, the cross-sectional vessel area (VA), lumen area (LA) and plaque area (PA = VA minus LA) were measured at end diastole and end systole at the lesion site and at the proximal and distal reference segments. Positive remodeling was defined to be present when the VA at the lesion was > 1.05 times larger than that at the proximal reference (group A), negative remodeling when the VA at the lesion was < 0.95 of the reference site (group C) and in-between was considered to be intermediate (group B). Vessel compliance was measured by calculating vascular distensibility. Results showed a similar LA at the lesion site in all groups (4.18+/-2.18 vs. 4.36+/-1.19 vs. 3.74+/-1.81 mm2, NS) while VA and PA were significantly larger in group A (17.19+/-5.08 vs. 14.22+/-3.66 and 12.45+/-4.82 mm2, p = 0.005 and 13+/-4.55 vs. 9.95+/-3.58 and 8.7+/-3.83, p = 0.003, respectively). Vascular distensibility at the proximal reference segment was significantly greater in group A (3.55+/-2.67 vs. 1.25+/-1.03 and 0.85+/-0.73 mmHg(-1), p < 0.001) with a positive correlation between remodeling and distensibility (R = 0.52, p < 0.001). In a multiple regression model including clinical and lesional factors, distensibility was the only predictor of remodeling. In conclusion, these results suggest that compensatory vessel enlargement occurs to a greater degree in patients with increased coronary artery distensibility, which appears to be a predictor for positive remodeling. PMID- 11605999 TI - Associations between nonshared environment and child problem behaviour. AB - BACKGROUND: Twin studies suggest that environmental effects on the development of child psychopathology largely involve nonshared environmental processes. However, the influence of the nonshared environment may have been overestimated, as the relationship between environment and behaviour may be genetically mediated. A direct measure of the nonshared environment (using the Sibling Inventory of Differential Experience - SIDE) was investigated in relation to child psychopathology, and tested for possible genetic mediation. METHOD: Parent-rated versions of the Child Behaviour Checklist (CBCL) and the SIDE were collected in 760 twin pairs aged 6-17 years. Multilevel regression analysis was used to assess the influence of SIDE scores on CBCL total problem scores, internalising symptoms, externalising symptoms and depressive symptom scores. Genetic mediation was assessed by examining interaction with zygosity in the association between SIDE scores and differences in CBCL scores (absence of interaction indicating no genetic mediation). RESULTS: The results revealed significant associations between SIDE dimensions on the one hand, and degree of internalising, externalising, depression and total symptom scores on the other. However, the effects were non-linear, and especially apparent for the extremes of differential environmental experience within twin pairs. Overall, there was no strong evidence for genetic mediation of associations between nonshared environment and symptoms. CONCLUSIONS: Direct, genetically unconfounded but skewed relationships may exist between nonshared environment on the one hand and behavioural differences on the other, although longitudinal data are necessary to determine the direction of effects. PMID- 11606000 TI - Factors affecting the relation between parental education as well as occupation and problem behaviour in Dutch 5- to 6-year-old children. AB - BACKGROUND: This study investigated whether problem behaviour in 5- to 6-year-old children is related to parental education and occupation. It also analysed the contribution of correlating factors to explain this association. METHOD: The Child Behaviour Checklist was administered to a large community sample of 1317 children who were in the 1st year of normal primary school in the Netherlands. Outcome measures were total problem score, and externalising and internalising scale scores. RESULTS: Results of the logistic regression analyses indicated that higher rates of reported behaviour problems were significantly associated with low parental education and occupation. These associations were mediated by low maternal age at delivery and single-parent families. The number of children in a family and physical illness of the parents did not contribute to these associations. CONCLUSIONS: Parental education and occupation have a large impact on the mental health of young children. Psychosocial and biological factors are possible explanations for this phenomenon. PMID- 11606001 TI - First-episode non-affective psychosis in a total urban population: a 5-year follow-up. AB - BACKGROUND: The aim of this study is to investigate incidence rates, treatment, and outcome of a total in- and outpatient population of 71 patients (of 18-45 years of age) treated for a first-episode psychosis (DSM-IV) in three catchment areas in Stockholm. METHODS: The study is based on the investigation of records and databases and on information by staff members and patients. RESULTS: The incidence rate was 34.8 per 100,000 inhabitants (aged 18-45 years) and 16.5 per 100,000 inhabitants (total population). Sixty percent were diagnosed with schizophrenia syndromes. At 5-year follow-up, 73 % of the patients in the schizophrenia syndromes group versus 47% of the non-schizophrenia group had a sick pension or were on long-term sick leave. Nine percent of the schizophrenia patients and 39% of the non-schizophrenia psychosis patients were rated as not being in need of treatment. Non-compliance of medication was present in one-third of those patients prescribed neuroleptic medication. Seven percent had never received neuroleptic medication, all of whom were rated as ill at the 5-year follow-up. CONCLUSIONS: Incidence of treated first-episode psychosis is higher than has earlier been found, when exclusively outpatient treated individuals are also included. The social outcome is negative, even in the non-schizophrenia group. Non-compliance with medication and insufficient clinical follow-up may have worsened the results. PMID- 11606002 TI - Genetic liability, illicit drug use, life stress and psychotic symptoms: preliminary findings from the Edinburgh study of people at high risk for schizophrenia. AB - BACKGROUND: Studies of groups at high risk of developing schizophrenia have tended to be based on subjects recruited to the study in their infancy. This paper reports on subjects at genetic high risk for schizophrenia assessed as young adults, close to the age when most onsets of schizophrenia occur. METHODS: One hundred and fifty-five young people at elevated risk for the development of schizophrenia and 36 controls not at increased risk were assessed on entry to the Edinburgh High Risk Study. The measures included current psychotic symptoms, past and present cannabis and other drug use, lifetime life events and two aspects of genetic liability to schizophrenia. RESULTS: Cannabis and other illicit drug use were significantly associated with symptoms in both groups. The same held true for the more upsetting life events experienced, but not for less upsetting ones. Within the high-risk group, there was no relationship between symptoms and a measure of genetic loading, but there was some slight evidence of a higher risk of symptoms when affected relatives were on the father's rather than the mother's side of the family. CONCLUSIONS: Cannabis use, use of other illicit substances and upsetting life events may all lead to psychotic symptoms in vulnerable young people. PMID- 11606003 TI - The experience of caregiving for severe mental illness: a comparison between anorexia nervosa and psychosis. AB - BACKGROUND: The aim of this study was to examine the experience of care giving for people with anorexia nervosa and to compare it with the experiences of those people who care for a person with a psychotic illness. METHOD: Carers (parents, siblings and husbands) of people with eating disorders who had experienced an episode of inpatient care for anorexia nervosa (n=71) were given the General Health Questionnaire and the Experience of Caregiving Inventory. A sample of carers (N=68) of people with a psychotic illness from the community were used as a comparison group. A subgroup of the carers (n=20) of people with anorexia nervosa were asked to write about their experiences. RESULTS: The clinical samples had a similar duration of illness, but the patients with anorexia nervosa were significantly younger and a larger proportion were living at home. The general health scores were significantly higher in the carers of anorexia nervosa and they experienced higher levels of difficulties in most areas of caregiving. A variety of variables from the Caregiving Inventory contributed to the level of psychological distress, accounting for 36% of the variance. The themes of guilt and shame were additional dimensions that were addressed in the letters. CONCLUSIONS: Carers of people with anorexia nervosa are challenged by the difficulties their role produces. PMID- 11606004 TI - How are mood and exercise related? Results from the Finnmark study. AB - BACKGROUND: Recreational exercise and mood have frequently been correlated in population studies. Although it is often assumed that recreational exercise improves mood, this has not been consistently demonstrated in population studies. METHOD: The relationship between mood and exercise was studied prospectively in a community sample. A series of synchronous panel models was constructed in two samples (2798 paired observations; sample I = 1219, sample II = 1498) to examine this relationship in the entire population, for women and men separately, for those with sedentary occupations, for those performing physical labour, and for those who initially showed a more dysphoric mood. RESULTS: Although mood and exercise were correlated, the only directional relationship that could be demonstrated was that recreational exercise had an inconsistently positive effect upon mood in those with sedentary occupations. There was no such relationship between doing physical work and mood. Analyses of those who initially showed higher levels of dysphoria did not uncover any directional relationship between mood and exercise. None of the other subgroups showed any directional effects between mood and recreational exercise, nor did the population as a whole. CONCLUSION: The relationship between exercise and mood in this population sample appears to be largely correlational in nature. This result suggests the need to take a cautious view of the role played by exercise in promoting mood in the general population. PMID- 11606005 TI - Attempted suicide rates and trends during a period of severe economic recession in Helsinki, 1989-1997. AB - BACKGROUND: This study investigated attempted suicide trends during a deep economic recession in the 1990s in a well-defined urban catchment area. METHODS: The data covered every suicide attempt treated in health care during sample periods in 1989-1997 in Helsinki, Finland. Annual rates were estimated, 3-year moving averages for trends calculated, and significances tested. RESULTS: The overall attempted suicide rate remained stable over the 9-year study period. Against expectations, male rates decreased significantly (P < 0.01), especially among those aged 15-34. There was a convergence of female and male rates, although male rates remained higher. The proportion of poisonings as method increased (P < 0.01). CONCLUSIONS: Despite the deep economic recession, with rapidly rising unemployment attempted suicide rates remained unexpectedly stable. The total attempted suicide rate did not increase as might have been anticipated, and the male rate even decreased. PMID- 11606006 TI - The relationship between socio-economic inequality and criminal victimisation: a prospective study. AB - BACKGROUND: This study investigates the relationship of socio-economic inequality (SEI) with criminal victimisation. It is hypothesised that disadvantage in terms of SEI is associated with increased risk of being victimised and with increased distress following victimisation. Two concepts of SEI are applied: social class (measured in terms of relation to work) and SES (measured in terms of education). METHOD: A representative sample of the Dutch population, comprising 3446 individuals, was followed up and incident crime victims were identified (n=179). A matched comparison group was recruited from the same sample (n=266). SEI and potential vulnerability measures were taken at baseline. Distress was measured 1 week following victimisation and at 1-month intervals for the following consecutive 3 months. RESULTS: The probability of becoming victimised was significantly higher among the unemployed and (unexpectedly) among persons with higher education. The unemployed also showed an increased vulnerability for distress following victimisation compared to all other class categories. This increased vulnerability could not be explained by differences in style of information processing, locus of control, hardiness, need for affiliation, or social support. CONCLUSION: The limitations of the study are discussed and recommendations with respect to the special attention required for unemployed persons are offered. PMID- 11606007 TI - Effect of tail suspension on haemodynamics in intact and sympathectomized rats. AB - The effect of a 2-week tail suspension on mean arterial pressure (MAP) and pulse interval (PI) was studied in conscious chronically instrumented intact and sympathectomized rats. Sympathectomy was induced by 6-hydroxydopamine (100 mg x kg(-1), i.v.), injected 1 day before, and on days 5 and 10 of suspension. During suspension the intact rats had the same levels of MAP and PI as the intact controls. After release from suspension their MAP did not change: PI decreased (by 9%), but only for 1 h. Sympathectomy augmented the haemodynamic changes after release from suspension: tachycardia (10%) and hypotension (19%) were observed during the entire recording period (2 h). Therefore, in rats, post-suspension hypotension becomes apparent only after elimination of sympathetic influences. In spite of unaltered systemic parameters, intact post-suspension rats showed diminished responses to intravenous administration of tyramine (100 microg x kg( 1)) and phenylephrine (1-2 microg x kg(-1)). In addition, they showed augmented haemodynamic changes associated with natural behaviour. The increase of MAP and the decrease of PI on transition from rest to movement were more pronounced in the intact post-suspension rats than in the control rats (MAP 8.3% vs 4.5%, PI 15% vs 9%). In control rats the spectrum power density of low-frequency (0.0195 0.25 Hz) MAP fluctuations depended only weakly on behavioural activity, whereas in post-suspension intact rats it was profoundly augmented during movements (by 170%). Since the rapid adjustment of haemodynamics to behavioural activity is controlled by the sympathetic nervous system, the unbalanced condition of the cardiovascular system after suspension may reflect an altered sympathetic nerve control of the circulation. PMID- 11606009 TI - No difference in net uptake or disposal of lactate by trained and untrained forearms during incremental sodium lactate infusion. AB - A number of training adaptations in skeletal muscle might be expected to enhance lactate extraction during hyperlactataemia. The aim of the present study was to determine whether resting endurance-trained forearms exhibit an increased net lactate removal during hyperlactataemia. Six racquet-sport players attended the laboratory for two experiments, separated by 2 weeks. In the first experiment incremental handgrip exercise to fatigue was performed to identify trained (TRFA, n = 6) and untrained (UTFA, n = 5) forearms. In the second experiment net forearm lactate exchange was compared between TRFA and UTFA during an incremental infusion of sodium lactate. TRFA performed more work than UTFA during handgrip exercise [mean (SE) TRFA, 66.1 (9.5) J.100 ml(-1); UTFA, 35.1 (2.3) J.100 ml(-1); P = 0.02] and UTFA exhibited a greater increase in net lactate output relative to work load (P = 0.003). During lactate infusion net lactate uptake across the resting forearms increased linearly with the arterial lactate concentration in both groups (TRFA, r = -0.95 (0.03); UTFA, r= -0.92 (0.04); P < 0.02], with no difference in the regression slopes [TRFA, -1.06 (0.13); UTFA, -1.07 (0.27); P = 0.97] or y-intercepts [TRFA, 0.67 (0.20); UTFA, 1.36 (0.67); P = 0.37] between groups. Almost all of the lactate taken up was disposed of by both groups of forearms [TRFA, 99.6 (0.2)%; UTFA, 98.5 (1.0)%; P = 0.37]. It was concluded that the net uptake and removal of lactate by resting skeletal muscle is a function of the concentration of lactate in the blood perfusing the muscle rather than the muscle training status. PMID- 11606008 TI - Force deficits after stretches of activated rat muscle-tendon complex with reduced collagen cross-linking. AB - The forces produced during stretches of passive and activated muscles, and isometric force deficits after stretching of activated muscles were examined in rat plantor flexor muscle-tendon complexes with reduced collagen cross-links (pyridinoline). Female Sprague-Dawley rats (n = 6, age 87 days) were injected twice daily for 43 days with beta-aminopropionitrile (BAPN, 333 mg/kg/day i.p.), an inhibitor of lysyl oxidase, which is responsible for the production of collagen cross-links. The relative weights of the plantar flexor muscles were similar for BAPN and saline-injected (control, C) rats (n = 6). Pyridinoline was lower in the tendon (22.9%), and in the plantaris (17.1%), and soleus (7.4%) muscles (P < 0.05), with no changes observed in collagen content (hydroxyproline), as determined by high-pressure liquid chromatography. At an ankle position of 90 degrees, groups had similar forces at 5, 10, 20, 40, 60 and 80 Hz before stretching. Forces at 40 degrees with stretches of the passive muscles (five times from 90 degrees to 40 degrees) were lower for all stretches in BAPN-injected rats (P < 0.05). Isometric force deficits resulting from stretches of activated muscles (80 Hz, 20 times from 90 degrees to 40 degrees, rest intervals 3 min) followed similar courses for BAPN-injected and C rats, and were 51.1 (2.4)% (C) and 54.7 (4.6)% (BAPN) before the last stretch. After 1 h of rest, isometric force deficits were 26% and 29% larger at 10 Hz and 5 Hz, respectively, in BAPN-treated rats (P < 0.05). The reduction in BAPN-injected collagen cross-linking of the skeletal muscle-tendon complex reduced the forces produced during stretches without muscle stimulation (i.e. passive stretch), and stretching of activated muscles produced larger isometric force deficits only at low stimulation frequencies. PMID- 11606010 TI - Enhanced flow-dependent vasodilatation after bed rest, a possible mechanism for orthostatic intolerance in humans. AB - We investigated the alteration in flow-dependent-dilatation in the orthostatic intolerance occurring after bed-rest deconditioning. Eight men [aged mean (SEM) 32 (2) years] underwent two consecutive periods of 7 days of head-down-tilt (HDT, -6 degrees) during bed rest. A control age and sex matched group [n = 8, 30 (2) years], maintained its usual physical activity. Blood flow velocity (BFV) and diameter (Doppler and echotracking systems) were measured in the brachial artery, under basal conditions and during the post ischaemic hyperaemia following occlusion. The increase in BFV post-ischaemia did not change before, during and after HDT but the relative increase in the diameter was greater on the 7th day of the HDT period than before HDT [+8.8(1.6)% compared to +3.7(1.0)%, P < 0.001]. After HDT, 11 of 16 standing tests (comprising eight subjects in the two HDT periods) had to be stopped because of orthostatic intolerance. The flow-dependent dilatation measured at the end of HDT was negatively correlated with the post-bed rest duration of orthostatic tolerance (r = 0.78, P < 0.01). After the sublingual administration of glyceryl trinitrate, there was no change in the increase in diameter. No significant changes were observed in the control group. Bed-rest deconditioning enhances the flow-dependent vasodilatation of large arteries and might contribute to the orthostatic intolerance observed following bed-rest. PMID- 11606011 TI - Vastus medialis muscle oxygenation trends during a simulated 20-km cycle time trial. AB - In this study we examined the oxygenation trend of the vastus medialis muscle during sustained high-intensity exercise. Ten cyclists performed an incremental cycle ergometer test to voluntary exhaustion [mean (SD) maximum oxygen uptake 4.29 (0.63) l x min(-1); relative to body mass 60.8 (2.4) ml x kg(-1)min(-1)] and a simulated 20-km time trial (20TT) on a wind-loaded roller system using their own bicycle (group time = 23-31 min) in two separate sessions. Cardiorespiratory responses were monitored using an automated metabolic cart and a wireless heart rate monitor. Tissue absorbency, which was used as an index of muscle oxygenation, was recorded simultaneously from the vastus medialis using near infrared spectroscopy. Group mean values for oxygen uptake, ventilation, heart rate, respiratory exchange ratio, power output, and rating of perceived exhaustion were significantly (P < or = 0.05) higher during the incremental test compared to the 20TT [4.29 (0.63) l x min(-1) vs 4.01 (0.55) l x min(-1), 120.4 (26) l x min(-1) vs 97.6 (16.1) l x min(-1), 195 (8) beats x min(-1) vs 177 (9) beats min(-1), 1.15 (0.06) vs 0.93 (0.06), 330.1 (31) W vs 307.2 (24.5) W, and 19 (1.5) vs 16 (1.7), respectively]. Oxygen uptake and heart rate during the 20TT corresponded to 93.5% and 90.7%, respectively, of the maximal values observed during the incremental test. Comparison of the muscle oxygenation trends between the two tests indicated a significantly greater degree of deoxygenation during the 20TT [-699 (250) mV vs 439 (273) mV; P < or = 0.05] and a significant delay in the recovery oxygenation from the 20TT. The mismatching of whole-body oxygen uptake and localised tissue oxygenation between the two tests could be due to differences in muscle temperature, pH, localised blood flow and motor unit recruitment patterns between the two tests. PMID- 11606012 TI - Reproducibility of the parameters of the on-transient cardiopulmonary responses during moderate exercise in patients with chronic obstructive pulmonary disease. AB - To be clinically useful as indices reflective of altered physiological function consequent to interventions in patients with chronic obstructive pulmonary disease (COPD), the time constant (tau) and steady-state amplitude of the kinetic responses for oxygen uptake (VO2) carbon dioxide output (VCO2) ventilation (VE) and heart rate (HR) have to be appropriately differentiable and reproducible. We therefore assessed the reproducibility of tau and steady state amplitude values in 41 patients with severe COPD [mean (SD)] [forced expiratory volume in 1 s = 41 (7)% predicted], aged 64 (5) years. Of the total, 6 of the patients (15%) did not produce breath-by-breath data of sufficient quality to warrant kinetic analysis. The remaining 35 patients completed two moderate-intensity 10 min square-wave exercise tests separated by 2 h, both before and after an endurance training programme. Tests were conducted on an electromagnetically-braked cycle ergometer at an exercise intensity corresponding to 80% of the estimated lactate threshold (thetaLa) or 50% of peak oxygen uptake if thetaLa was insufficiently differentiable. Breath-by-breath measurements of VO2, VCO2, VE and HR were averaged into 10 s bins and the on-transient response kinetics were estimated using a mono-exponential model. Analysing the pre-training and the post-training test 1 and test 2 comparisons together, the test 1- test 2 differences were not significantly different from 0 for either tau or A. The standard deviation of the test 1- test 2 differences allowed us to define the magnitude of change that would reach statistical significance. For tau, this averaged some 8, 10, 11 and 8 s, for VO2, VCO2, VE and HR, respectively, for a one-tailed paired-comparisons test (i.e. appropriate for assessing hypothesised improvements resulting from an intervention); for a two-tailed comparison, the differences were approximately 2 s greater. The corresponding one-tailed values for A were 100 ml x min(-1), 95 ml x min(-1), 2.5 1 x min(-1) and 4 beats x min(-1), respectively; the two-tailed values were 10%-15% greater. We therefore conclude that both tau and A for moderate-intensity exercise can be reproducibly estimated in patients with COPD when the data set provides a sufficiently large amplitude of response and sufficiently low sample variability to allow appropriate parameter estimation. PMID- 11606013 TI - The effect of endurance training on resting heart rate variability in sedentary adult males. AB - Eleven previously sedentary adult males, serving as the experimental (EXP) group [mean (SE) age 36.6 (1.7) years, body mass 87.2 (4.3) kg, body mass index, BMI, 28.4 (1.5) kgm(-2)] participated in a 16-week supervised exercise program (3 days x week(-1), 30 min day(-1), at approximately equal to 80% of heart rate reserve) to determine the temporal effects of a moderate-to-vigorous-intensity exercise program on heart rate variability (HRV). Five sedentary males [mean (SD) age 36.6 (4.2 )years, body mass 83.8 (6.6) kg, BMI 22.8 (1.7) kg x m(-2)] served as non exercising controls (CON). HRV was measured every 4 weeks from a resting electrocardiogram obtained while subjects paced their breathing at 10 breaths x min(-1) (0.167 Hz). The time-domain measures of HRV recorded were the proportion of adjacent intervals differing by more than 50 ms (pNN50), the root mean square of successive differences (rMSSD), and the standard deviation of the resting interbeat interval. The frequency-domain measures recorded were high (HF) and low (LF) frequency oscillations, as determined using the fast Fourier transform technique. Aerobic capacity (i.e., peak oxygen uptake) increased by 13.8% in EXP (P < 0.001), but did not change in CON. Resting heart rate did not change in either EXP or CON. In EXP, pNN50 at week 12 (P<0.01), rMSSD at weeks 12 (P < 0.01) and 16 (P = 0.05), and HF power at weeks 12 (P < 0.01) and 16 (P = 0.05) were elevated above baseline. Time- and frequency-domain measures of HRV remained unchanged in CON. It is concluded that a moderate-to-vigorous-intensity exercise program produces increases in time- and frequency-domain measures of HRV within 12 weeks. PMID- 11606014 TI - Dietary chloride as a possible determinant of the severity of exercise-induced asthma. AB - Dietary sodium chloride (NaCl) has been shown to alter the severity of exercise induced asthma, but it is not known if the sodium and chloride ions have independent effects in this regard. The hypothesis tested in the present study was that both a low sodium, low chloride diet and a high sodium, low chloride diet would improve post-exercise pulmonary function in subjects with exercise induced asthma (EIA) compared to a normal NaCl diet (NSD); but that neither of these diets would have an effect on post-exercise pulmonary function in control (non-EIA) subjects. Eight subjects who suffered from EIA and eight subjects who did not (control) took part in a double-blind crossover study. Pre- and post exercise pulmonary function was assessed after 2 weeks on a NSD, a low NaCl diet (LSD, low sodium, low chloride) or a sodium bicarbonate diet (NaHCO3 diet, high sodium, low chloride). A 1 week washout period occurred between diets. Altering dietary sodium or chloride had no effect on pre-exercise (baseline) pulmonary function in either group or on post-exercise pulmonary function in control subjects. However, both the LSD and the NaHCO3 diet lessened the deterioration in post-exercise pulmonary function in EIA subjects. Comparing results from pre- to post-exercise, forced expiratory volume in 1 s (FEV1) at 15 min post-exercise differed significantly (P < 0.05) between diets [mean (SEM) 7 (4)% on the LSD, 14 (4)% on the NaHCO3 diet, and 19 (2)% on the NSD]. Similar patterns were observed for forced vital capacity (FVC), forced expiratory flow rate at 25%-75% FVC and peak expiratory flow rate. The NaHCO3 diet lessened the deterioration of post exercise pulmonary function, but not to the extent of LSD. These data suggest that both sodium and chloride contribute to the worsening of EIA symptoms seen after consuming a normal or high NaCl diet. PMID- 11606015 TI - Muscle efficiency: the controversial role of elasticity and mechanical energy conversion in stretch-shortening cycles. AB - The analysis of muscle efficiency was performed on a variety of simulated muscle stretch-shortening cycles of in situ rat gastrocnemius muscle. The processes of biochemical energy conversions (phosphorylation and contraction-coupling) and mechanical conversions (internal work to external work) were incorporated in the efficiency calculations. Metabolic cost was determined using a simple linear model. Special attention was drawn to the interacting roles of series elastic compliance and contraction dynamics. The results showed that series elastic compliance affected the efficiency of muscle contraction to a great extent. Stiff muscle was well designed to perform efficient contractions in which muscle merely shortened while active. Compliant muscle performed best in true stretch shortening contractions utilising the storage and release of series elastic energy effectively. However, both stiff and compliant series elastic elements showed similar optimal muscle efficiency values in shortening contractions and stretch-shortening contractions, respectively. The findings indicate that the storage and re-utilisation of series elastic energy does not enhance overall muscle efficiency, but that optimal efficiency is obtained by a proper design of the muscle with regard to the dynamics of the movement task. Furthermore, it was found that although biochemical efficiency determined the feasible range of muscle efficiency, mechanical work conversions had the strongest influence on the exact value of overall muscle efficiency in stretch-shortening contractions. PMID- 11606016 TI - Adaptation to chronic eccentric exercise in humans: the influence of contraction velocity. AB - We compared changes in muscle fibre composition and muscle strength indices following a 10 week isokinetic resistance training programme consisting of fast (3.14 rad x s(-1)) or slow (0.52 rad x s(-1)) velocity eccentric muscle contractions. A group of 20 non-resistance trained subjects were assigned to a FAST (n = 7), SLOW (n = 6) or non-training CONTROL (n = 7) group. A unilateral training protocol targeted the elbow flexor muscle group and consisted of 24 maximal eccentric isokinetic contractions (four sets of six repetitions) performed three times a week for 10 weeks. Muscle biopsy samples were obtained from the belly of the biceps brachii. Isometric torque and concentric and eccentric torque at 0.52 and 3.14 rad x s(-1) were examined at 0, 5 and 10 weeks. After 10 weeks, the FAST group demonstrated significant [mean (SEM)] increases in eccentric [29.6 (6.4)%] and concentric torque [27.4 (7.3)%] at 3.14 rad x s(-1), isometric torque [21.3 (4.3)%] and eccentric torque [25.2 (7.2)%] at 0.52 rad x s(-1). The percentage of type I fibres in the FAST group decreased from [53.8 (6.6)% to 39.1 (4.4)%] while type IIb fibre percentage increased from [5.8 (1.9)% to 12.9 (3.3)%; P < 0.05]. In contrast, the SLOW group did not experience significant changes in muscle fibre type or muscle torque. We conclude that neuromuscular adaptations to eccentric training stimuli may be influenced by differences in the ability to cope with chronic exposure to relatively fast and slow eccentric contraction velocities. Possible mechanisms include greater cumulative damage to contractile tissues or stress induced by slow eccentric muscle contractions. PMID- 11606017 TI - Treadmill and cycle ergometry testing in 5- to 6-year-old children. AB - The primary purpose of this study was to determine the maximal cardiorespiratory responses of 48, 5- to 6-year-old children (24 girls and 24 boys), who were tested on a treadmill (TM) and an electronically braked cycle ergometer (CE). We also examined the percentage of boys and girls who were able to achieve the criteria for reaching maximal oxygen consumption (VO2max) on each testing mode. After an orientation period, each child was tested twice (once on the TM and once on the CE), with an interval of 1 week between tests. VO2max was measured during progressive, all out, continuous TM and CE tests using standardized procedures. A 2 x 2 analysis of variance test (genderxexercise mode) with Bonferroni adjustment revealed the following: (1) there were no gender differences in any of the measured dependent variables, (2) the children produced a significantly higher relative VO2max (ml x kg(-1) x min(-1) and a higher absolute VO2max (l x min(-1)) on the TM than on the CE (P < 0.001), (3) the children produced a higher heart rate on the TM than on the CE (P < 0.001), (4) the CE generated significantly higher values for respiratory exchange ratio (P < 0.001), (5) the criteria necessary to establish a maximal exercise effort were achieved on both the TM and the CE, and (6) all of the children reached two of the criteria associated with a maximal effort, while only 46% of the children reached three criterion measures. There were no significant differences in the attainment of criterion measures between the TM and the CE. The results of this study indicate a lack of gender differences in maximal exercise testing in 5- to 6-year-old children, and that both the CE and the TM are effective modes of maximal cardiorespiratory testing in this age group. PMID- 11606018 TI - Validation of a new ergometer adapted to all types of manual wheelchair. AB - Research concerning the physiological and biomechanical parameters of wheelchair propulsion requires the use of an accurate and reproducible protocol. Although some research comparing different ergometers has been conducted, it is not easy to fulfil the requirements of the realistic simulation of propulsion together with the careful analysis of metabolic and biomechanical parameters of performance. The VP100H ergometer has been validated for this purpose by comparing the values of power output (W) and force exerted to accelerate the wheels (F) with the same measures obtained using a two-dimensional force transducer (platform). The reproducibility of the power was verified during a test re-test procedure. Ten sportsmen performed an incremental exercise. Maximal aerobic power (Waer,max), maximum oxygen uptake (VO2max), maximum heart rate (fcmax), % Waer,max/%VO2max relationship (aV) and %Waer,max/%fcmax relationship (aH) were calculated. Results indicated no significant differences (P > 0.05) in VP100H versus platform measurements for F and W. Errors of measured Fand W ranged from 0.89% to 7.56% and from 0.41% to 6.74%, respectively, depending upon the trunk muscles that participate in the propulsion. This corresponded to a maximum error of 4.9 W for W. No significant differences (P > 0.05) were observed during the test re-test procedure for Waer,max, VO2max, fcmax, aH and aV. The coefficient of variation of these values ranged from 1.4 to 9.5, and the correlation coefficient from 0.68 to 0.98. We conclude that the VP100H is valid for measuring W, and F, and that these values are reproducible (when tested 10 days later). PMID- 11606020 TI - The use of electromyogram biofeedback to reduce Trendelenburg gait. AB - Ten subjects suffering from incomplete spinal cord injuries, clinically diagnosed as walking with Trendelenburg gait, underwent a 2 month therapy program to strengthen their muscles and reduce their gait abnormalities. Therapy involved muscle strengthening and gait training for 2 h a day, 5 days a week in a clinic. Biofeedback was also accomplished for 30 min each training day on all subjects. In addition, five of the subjects wore a two-channel electromyogram (EMG) biofeedback training device at home to see if neuromuscular re-education outside of the clinical setting could speed their recovery. The difference for these five subjects was that they would have continuous biofeedback therapy every time they walked and not biofeedback limited to only 30 min a day. Since weakness of the gluteus medius muscles is the prime contributor to Trendelenburg gait, the device provided warning tones giving feedback of improper gait through bilateral assessment of the use of the gluteus medius muscles. If too little gluteus medius activity was seen on the affected side or the step was too short in duration, the microprocessor provided an audio cue to the subjects alerting them to correct the deficit. Subjects only undergoing clinical therapy showed about a 50% reduction in hip drop due to therapy. However, the group that used the home training device showed almost normal gait after the 2 month period. PMID- 11606019 TI - Endurance training under 2500-m hypoxia does not increase myoglobin content in human skeletal muscle. AB - The present study was carried out to determine whether myoglobin (Mb) concentration ([Mb]) in human skeletal muscle is influenced by 8 weeks of endurance training under normal conditions, and under hypoxic conditions equivalent to an altitude of 2500 m. Fourteen healthy but sedentary male adults who did not participate in any regular exercise program took part in this study. They were divided into two groups according to the training regime to which they were submitted: the N group, who exercised under normobaric conditions, and the H group, who exercised under hypobaric conditions. All subjects performed an incremental cycling exercise at sea level to evaluate their maximal O2 uptake (VO2max) before and after the 8-week endurance training course period. Muscle tissue samples were obtained by needle biopsy from the vastus lateralis muscle for histochemical and biochemical analysis. Training induced an increase in VO2max in both the N and H groups (P < 0.05), although there was no significant difference in these changes between groups. The 8-week training had no effect on [Mb] in either group. Muscle fiber composition was also unaffected by the training course. In contrast, citrate synthase activity in both groups increased by [mean (SD)] 28.2 (33.3)% (N: P < 0.01) and 32.0 (18.2)% (H: P < 0.05) after training, and the number of capillaries (capillary:fiber ratio) increased by 47.7 (33.8)% (N: P < 0.01) and 32.3 (20.6)% (H: P < 0.05). There were no significant differences in these parameters between the N and H groups. These results suggest that significant improvement of aerobic potential as a result of endurance training are not accompanied by increases in [Mb] in human skeletal muscle. In addition, a lower absolute workload may not be sufficient to stimulate Mb synthesis in humans, even where endurance training is carried out under hypoxia. PMID- 11606021 TI - Reproducibility of blood lactate-anchored ratings of perceived exertion. AB - This study investigated the reproducibility of blood lactate-anchored ratings of perceived exertion (RPE) in seven women of average, and seven of above average cardiorespiratory fitness, [moderate and high maximal oxygen uptake (Mod VO2max and High VO2max, respectively)]. The subjects completed a series of four exercise tests, comprising a VO2max assessment and three O-grade, velocity-incremental, treadmill-running RPE estimation trials. The results revealed no significant between-group differences in RPE at the blood lactate concentration threshold (LT), and at reference levels of 2, 2.5 or 4 mmol x l(-1) (RPELT, RPE2, RPE2.5 and RPE4, respectively). The RPELT, RPE2, RPE2.5 and RPE4 were characterised by intra-class correlation coefficients of 0.97, 0.97, 0.97, 0.72 and 0.83, 0.96, 0.96, 0.90, in the High VO2max and Mod VO2max groups, respectively. The SEM% (95% confidence limits computed as a percentage of the group mean score) largely mirrored the trend in reliability with the highest values observed for RPELT in the Mod VO2max group and RPE4 in the High VO2max group. The Spearman-Brown prediction equation indicated that fixed blood lactate concentrations of 2, 2.5 and 4 mmol x l(-1) offer acceptable practical utility as potential perceptual anchor points for both groups, requiring one trial only to achieve a measurement error of less than +/- 6%. PMID- 11606022 TI - 17-beta-estradiol alters Jurkat lymphocyte cell cycling and induces apoptosis through suppression of Bcl-2 and cyclin A. AB - In this investigation, the effects and potential mechanisms of female sex steroid action on proliferation, cell cycling, and apoptosis in Jurkat CD4 + T lymphocytes were examined. 17-beta-Estradiol (estrogen) inhibited Jurkat T cell proliferation, stimulated accumulation of cells in S and G2/M phases of the cell cycle, and induced apoptosis over 72 h in a dose-dependent manner. 4-Pregnene 3,20-dione (progesterone) did not induce redistribution of the cells in the cell cycle but did induce cytostasis and slightly increased apoptosis. Simultaneous staining with anti-BrDU and propidium iodide indicated that estrogen-treated Jurkat T cells proceeded through S phase prior to apoptosis. Progesterone halted cell cycle progression; cells did not progress through S phase or incorporate BrDU. Both hormones decreased the percentage of cells in S or G2/M expressing cyclin A protein, but did not affect cyclin D protein expression. Cyclin A mRNA was markedly decreased by estrogen. Bcl-2 protein and mRNA were also reduced in estrogen but not progesterone-treated Jurkat T lymphocytes. This data shows that high concentrations of estrogen or progesterone significantly suppress lymphoproliferation in association with suppression of cyclin A. Additionally, bcl-2 protein levels were suppressed in association with estrogen-induced apoptosis. These findings demonstrate direct, hormone-specific effects on lymphocytes that may provide insight into their role in immunomodulation or the development of autoimmunity. PMID- 11606023 TI - Modulation of Th2 type cytokine production from human peripheral blood leukocytes by a macrolide antibiotic, roxithromycin, in vitro. AB - The influence of a macrolide antibiotic, roxithromycin (RXM), on Th1 and Th2 cytokine productions from human peripheral blood T cells was examined under stimulation with co-stimulatory molecules. Peripheral blood T cells prepared from both healthy and allergic rhinitis donors were cultured in the presence of RXM on anti-CD3 mAb and anti-CD26 mAb-coated wells, anti-CD3 mAb and anti-CD28 mAb coated wells, and anti-CD3 and PMA. T-cell proliferation, along with the concentration of interleukin (IL)-2, interferon (IFN)-gamma, IL-4 and IL-5 were measured. RXM did not affect T-cell proliferation induced by several ways of co stimulatory activation as assessed by 3H-thymidine incorporation into DNA. RXM also had no effect on IL-2 and IFN-gamma secretion by T cells prepared from both healthy and allergic rhinitis donors. On the other hand, RXM markedly inhibited both IL-4 and IL-5 secretions under each of the co-stimulatory conditions in a dose-dependent manner. These results indicate that RXM inhibits specifically Th2 cytokine secretion from T cells induced by co-stimulatory molecule stimulations. This inhibitory action of RXM may be partially responsible for attenuating effect of the agent on the inflammatory diseases. PMID- 11606024 TI - Regulation of IL-13 production by histamine in cloned murine T helper type 2 cells. AB - Histamine affects the balance of T helper type 1 (Th1) and T helper type 2 (Th2) cytokines by shifting cytokine production from a Th1 to a Th2 pattern. Interleukin-13 (IL-13) is an important autacoid mediator that has been implicated in the development of allergic disease. This study was designed to investigate the mechanisms of regulation of IL-13 by histamine in Th2 cells. D10.G4.1 cells, a murine Th2 cell line, were treated with histamine (10(-8)-10(-4) M) and then activated with PMA (phorbol 12 myristate 13-acetate) plus ionomycin or alphaCD3. Levels of IL-13 production were then measured by enzyme-linked immunosorbent assay (ELISA) and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Cells were pretreated with histamine receptor antagonists pyrilamine, ranitidine, cimetidine and thioperamide to determine the involvement of histamine receptors. Cells were also pretreated with protein kinase A (PKA) inhibitors N-[2-(methylaminoethyl)]-5-isoquinoline-sulfonamide (H-8) and Rp diastereomer of adenosine cyclic 3'5'-phosphorothionate (Rp-cAMPS), and Janus kinase-signal transducer and activator of transcription (Jak-STAT) inhibitor tyrphostin AG490 prior to the addition of histamine. H-8 is an inhibitor of the catalytic subunit of PKA while Rp-cAMPS is an inhibitor of the regulatory subunit of PKA. Tyrphostin is an inhibitor of Jak2, Jak3, STATI, STAT3 and STAT5. Finally, cells were pretreated with IL-12, a monokine known to repress STAT6 DNA binding. We found that histamine dose-dependently enhanced IL-13 secretion and mRNA levels in Th2 cells via H1 and H2 receptors. Pretreatment of cells with H-8, Rp-cAMPS and tyrphostin prevented histamine-induced secretion and transcription of IL-13. Likewise, pretreatment of Th2 cells with IL-12 also reversed histamine's effects on IL-13 secretion from stimulatory to inhibitory. These observations suggest a role for PKA and the Jak-STAT pathway in histamine mediated elevation of IL-13 secretion and transcription. PMID- 11606025 TI - Immunosuppressive effects of vermiculine in vitro and in allotransplantation system in vivo. AB - Vermiculine, a macrocyclic aglycosidic dilactone isolated from Penicillium vermiculatum, has been shown to have immunomodulatory properties. Here, we tested the effects of vermiculine on selected parameters of cell-mediated immunity in vitro and on skin allograft survival in vivo. Vermiculine inhibited in a dose dependent manner the proliferation of mouse spleen cells stimulated with Concanavalin A ((Con A), i.e. T-cell mitogen), bacterial lipopolysaccharide ((LPS), B-cell mitogen) or with irradiated allogeneic cells. In addition, vermiculine dose-dependently inhibited the production of Thl (IL-2, IFN-gamma) and Th2 (IL-4, IL-10) cytokines and suppressed the production of nitric oxide (NO) by activated macrophages. When compared with cyclosporine (CsA), vermiculine was less inhibitory for IL-2 gene expression and IL-2 synthesis, comparably suppressive on IL-10 production and even more inhibitory for NO synthesis. These observations suggest that vermiculine and CsA inhibit immune reactions by different mechanisms. Treatment of graft recipients with vermiculine or CsA prolonged survival of skin allografts in a mouse model. The combination of both drugs enhanced the survival of allografts significantly more than either drug alone. The results thus suggest that vermiculine is a potential immunosuppressive drug acting by a mechanism distinct from that of CsA, and thus it may be used alone or in combination with other drugs for immunoregulatory purposes. PMID- 11606026 TI - The effects of a Chinese herb formula, anti-cancer number one (ACNO), on NK cell activity and tumor metastasis in rats. AB - The effects of anti-cancer number one (ACNO), a 19-herb Chinese formula used to treat cancer patients, were studied in F344 rats. In the first study, the number and activity of circulating NK cells were evaluated following 18 days of oral consumption of 0.1, 0.5, or 2 g/kg/day. The second study assessed the effect of ACNO on resistance to metastasis of the MADB106 tumor line, a syngeneic mammary adenocarcinoma that metastasizes only to the lungs and is highly sensitive to NK activity (NKA) in vivo. Resistance to metastasis was assessed under baseline conditions and following the administration of a beta-adrenergic agonist, metaproterenol (MP). MP was used to simulate sympathetic response to stressful conditions, and was previously shown to suppress resistance to MADB 106 metastasis. The results of the first study indicated a dose-dependent increase in NKA per ml of blood and per NK cell, with no significant changes in blood concentration of NK cells. In the second study, whereas MP caused a 4.5-fold increase in the number of metastases in untreated rats, only a 2.3-fold increase occurred in rats treated with ACNO. No significant improvement in baseline levels of resistance to metastasis was observed. These findings indicate the importance of studying ACNO under stressful conditions in patients with potentially metastasizing tumors. This may prove particularly important during the perioperative period, spanning from the detection of the primary tumor to postoperative treatment. During this critical period, psychological and physiological stress responses are known to cause massive immunosuppression, which was suggested to promote metastatic development. PMID- 11606027 TI - Comparison of cytokine-inducing activity in a lipoteichoic acid-related molecule isolated from a penicillin-killed group A Streptococcus and from untreated bacteria. AB - We previously generated a monoclonal antibody, TS-2, that neutralizes the interferon (IFN)-gamma-inducing activity of OK-432, a penicillin-killed streptococcal preparation [J. Immunother. 13 (1993) 232]. Expression of the TS-2 binding antigen was markedly higher in the cell wall of the penicillin-treated Streptococcus pyogenes (OK-432) than in the untreated bacteria (Su-BBM). We here isolated the antigens from OK-432 and Su-BBM, designated OK-PSA and Su-PSA, respectively. OK-432 markedly induced IFN-gamma and interleukin (IL)-18 as compared with Su-BBM in human peripheral blood mononuclear cells (PBMC). Furthermore, all of the Thl-type and Th1-inducing cytokines tested [IFN-gamma, tumor necrosis factor (TNF)-alpha, IL-12 and IL-18] were secreted by OK-PSA stimulated PBMC far better than by Su-PSA-treated PBMC. In addition, the cytolytic activities of the PBMC were accelerated by the stimulation with OK-432 or OK-PSA far better than by the stimulation with Su-BBM or Su-PSA. These findings strongly suggested that OK-PSA is a highly important molecule of OK-432 and may be a useful immunotherapeutic agent for the patients with malignant diseases as a potent Th inducer. It was also shown that penicillin treatment effectively enhances OK-PSA-induced anti-cancer immunity. PMID- 11606029 TI - Immunoferon, a glycoconjugate of natural origin, inhibits LPS-induced TNF-alpha production and inflammatory responses. AB - We have analyzed the effect of a patented glycoconjugate (GC) of natural origin, Inmunoferon, in the development of the response to endotoxemia induced by administration of LPS in rodents. We have observed that oral treatment with the drug reduced the levels of serum TNF-alpha induced by an intravenous pulse of LPS. The serum of pretreated mice blocked TNF-alpha production by peritoneal macrophages. The drug increased the levels of TNF-alpha regulators such as IL-10 and corticosteroids, whereas it inhibited TNF-alpha-dependent IL-6 production. Further TNF-alpha-dependent responses, such as cell extravasation, was decreased in treated mice. According to these results, Inmunoferon is postulated as an inhibitor of the systemic response to LPS. Correlation of the observations made in mice with a rat model suggests the efficacy of this product in reducing TNF alpha production in a species-independent fashion and opens the possibility of its trial as an adjuvant of antibiotics in treatment against gram-negative bacterial infection. PMID- 11606028 TI - Polysaccharide isolated from the radix of Platycodon grandiflorum selectively activates B cells and macrophages but not T cells. AB - Many polysaccharides isolated from plants are considered to be biological response modifiers and have been shown to enhance various immune responses in vivo and in vitro. Here, we demonstrate that polysaccharide isolated from the radix of Platycodon grandiflorum (PG) has a unique mode of immunostimulation with regard to its cell-type specificity. PG was found to markedly increase polyclonal IgM antibody production and the proliferation of B cells, and to activate iNOS transcription and NO production in macrophages. Moreover, the intraperitoneal administration of PG in mice resulted in increased IgM antibody production in B cells, which were immunized by using T-dependent antigen sheep red blood cells (sRBCs). However, PG did not affect the proliferation of T cells, the IL-2 expression of Th1 cells, or the IL-4 expression of Th2 cells. Although PG and lipopolysaccharide (LPS) had a similar mode of action in B cells and macrophages, they were differentiated by the fact that PG-induced cellular activation was not inhibited by polymyxin B, a specific inhibitor of LPS. Anti-CD19 or anti-CD79b antibody blocked B cell proliferation and anti-CD14 or anti-CD 11b antibody decreased macrophage NO production, indicating the possible cellular binding sites of PG. Our results demonstrate that PG is a specific activator of B cells and macrophages but not of T cells, and suggest that PG is quite distinct from other well-known immunostimulants, such as lentinan and schizophyllan, which mainly act upon macrophages and T cells. PMID- 11606030 TI - Macrophage-oriented cytotoxic activity of novel triterpene saponins extracted from roots of Securidaca inappendiculata. AB - It is recognized that macrophages in peripheral tissues often proliferate under pathological conditions such as tumors, inflammation and atherosclerosis. Because the growth state of macrophages is believed to be a factor regulating the pathological process of the diseases, substances that regulate macrophage growth or survival may be useful for disease control. In this paper, we identified the activity inhibiting macrophage growth in a hot water extract of roots of Securidaca inappendiculata. The extract markedly inhibited macrophage colony stimulating factor (M-CSF/CSF-1)-induced growth of macrophages, whereas it exerted a less potent effect on growth of Concanavalin A (Con A)-stimulated thymocytes or M-CSF-stimulated bone marrow cells. The inhibition of macrophage growth was caused by a cytotoxic effect rather than a cytostatic effect. Cell death was due to the induction of apoptosis, as judged by staining with terminal deoxynucleotidyl transferase-mediated d-UTP nick end labelling (TUNEL). The cytotoxic activity seemed to be specific to peripheral macrophages; it showed a weak effect on the growth and survival of tumor cell lines including a macrophage like cell line, J-774.1. Moreover, the saponin fraction induced apoptotic cell death of macrophages only when they were stimulated by M-CSF; it did not affect the viability of macrophages cultured without M-CSF or with granulocyte/macrophage-CSF. We determined the structures of the two active triterpene saponin compounds in the fraction, named securioside A and securioside B having a 3,4-dimethoxycinnamic group which is essential for the cell death inducing activity. They are believed to be the primary compounds of new drugs for the treatment of pathological states in which macrophage proliferation occurs. PMID- 11606031 TI - Administration of mu-, kappa- or delta2-receptor agonists via osmotic minipumps suppresses murine splenic antibody responses. AB - Previously, our laboratory has shown that morphine given by implantation of a 75 mg slow-release pellet for 48 h suppresses murine splenic antibody responses to sheep red blood cells (SRBCs) in a plaque-forming cell (PFC) assay. However, the use of slow-release pellets for such studies is limited, as these pellets are only available in fixed doses and similar pellets for kappa and delta agonists have not been developed. In the present study, we investigated the feasibility of administering opioids via Alzet osmotic minipumps to assess their immunomodulatory effects. Groups of mice received minipumps dispensing morphine sulfate, which has primary activity at the mu opioid receptor; U50,488H, which is a kappa-selective agonist; deltorphin II, which is a delta2-selective agonist; or DPDPE, which has greater selectivity for delta1 than delta, receptors. Morphine, U50,488H and deltorphin II were all immunosuppressive, with biphasic dose response curves exhibiting maximal (approximately 50%) suppression of the PFC response at doses of 0.5 to 2 mg/kg/day 48 h after pump implantation. Further, immunosuppression by morphine sulfate, U50,488H or deltorphin II was blocked by simultaneous implantation of a minipump administering the opioid receptor selective antagonists CTAP (1 mg/kg/day), nor-binaltorphimine (5 mg/kg/day), or naltriben (3 mg/kg/day), respectively. DPDPE was inactive at doses lower than 10 mg/kg/day. We conclude that osmotic minipumps are a practical and useful way of administering opioids to study their effects on the immune system, and give further evidence that immunosuppression induced in vivo by opioid agonists is mediated not only via mu, but also via kappa and delta2 opioid receptors. PMID- 11606032 TI - Activation of caspases and mitochondria in FTY720-mediated apoptosis in human T cell line Jurkat. AB - FTY720, a novel immunosuppressive drug originally derived from a metabolite from Isaria sinclairii, is known to induce apoptosis in lymphocytes. In this study, we investigated the involvement of caspases and mitochondria in FTY720-mediated apoptosis using Jurkat cells, a human T cell line. Our results indicated that FTY720-induced activation of caspases 2, 3, 6, 8, 9 and 10, whereas caspases 1 and 5 were not activated. We also observed in the FTY720-treated cells a loss of mitochondrial membrane potential, a release of cytochrome c into cytosol and an exposed phosphatidylserine (PS) at the outer surface of the cell membrane. Pretreatment with a peptide inhibitor, benzyloxycarbonyl-Asp-CH2COC-2, 6 dichlorobenzene (Z-Asp-CH2-DCB), prevented apoptosis and externalization of phosphatidylserine, whereas the inhibitor did not prevent the mitochondrial events. This suggests that caspases may play a role downstream of the mitochondrial pathway. Therefore, caspase cascade in FTY720-treated cells may be initiated by activation of mitochondria. PMID- 11606033 TI - Gender-dependent immunosuppression following subacute exposure to fumonisin B1. AB - The effects of fumonisin B1 (FB1), a mycotoxin produced by Fusarium lertcillioides, on the immune system are controversial; FB1 exposure causing immunosuppression in poultry, swine, bovine and rodents species and immunostimulation in rodent species. The current study was conducted to examine the effects of FB1 on the immune system of BALB/c mice and to determine if there is sex specificity. Female and male mice (five per group) received five daily subcutaneous (s.c.) injections of 2.25 mg/kg/day of FB1, on the following day tissues were collected for immunological examinations. FB1 treatment dramatically reduced relative spleen and thymus weights in females, whereas there was no effect on organ weights in males. Exposure to FB1 reduced splenic cellularity and the basal rate of lymphocyte proliferation in females only. In addition, phytohemagglutinin (PHA-P)-induced T-lymphocyte and LPS-induced B-lymphocyte proliferation were reduced in female mice. Splenocytes from female mice exposed to FB1 showed a reduced expression of interleukin-2 mRNA. These changes occurred in the absence of alterations in tumor necrosis factor alpha or interleukin-1beta mRNA expression. Phenotypic analysis indicated that FB treatment caused a relative increase in the T-lymphocyte population in the spleen of female mice only. In contrast, FB1 dramatically reduced the immature CD4+/CD8+ double positive cell population in the thymus of females. No changes were evident in the thymocyte populations of male mice treated with FB1. The results of this study indicate that FB1 is immunosuppressive in mice; the magnitude of FB1-induced immunosuppression is highly dependent on sex, females being more susceptible than males. PMID- 11606034 TI - Interactions of aspirin and salicylic acid with prednisolone for inhibition of lymphocyte proliferation. AB - The anti-inflammatory properties of salicylates and prednisolone were investigated using inhibition of in vitro phytohemagglutinin-stimulated lymphocyte proliferation in human whole blood from healthy male and female subjects. Steroids and salicylates are used in conjunction for the treatment of inflammatory disorders such as rheumatoid arthritis and inhibit the proinflammatory transcription factor, NFKB, by different mechanisms. Data generated using various combinations of these drugs were analyzed using isobolograms and the universal surface response approach based on the Loewe additivity principle. The interaction between aspirin and prednisolone was mildly antagonistic while that between salicylic acid and prednisolone was modestly synergistic at therapeutic concentrations. Further, aspirin was slightly more potent in males, but the nature of the steroid-salicylate interaction was similar across genders. This study helps rationalize part of the beneficial effects of steroids and salicylates in treatment of inflammatory disorders. PMID- 11606035 TI - Effect of contingent hunger state on development of appetite for a novel fruit snack. AB - Eating more fruit can reduce risk of cancer and cardiovascular disease. Understanding barriers to this behaviour is critical for strategies to encourage it. We addressed the question whether the level of hunger at which fruit is eaten would influence the development of appetite for fruit. Half the participants were asked to eat a pair of novel fruit snacks (dried fruit bar; 50 kcal each) exclusively when hungry (at least 3 hours since last eating), and half to eat them exclusively when full (20-30 minutes after a meal), twice a day for one week. Rated appetite for the bars, and ad-libitum intake, were measured when hungry and full, on 2 days prior to, and 2 days after this week. Compliance was assessed from dietary diaries. Thirty participants (22 women, 8 men) completed the study satisfactorily. For the group eating the fruit bars only when hungry (hungry-trained), intake increased after the week, but only when full at the time of testing. Other measures of appetite for this group were unaffected, with the exception of a reduced desire to eat the bars when tested hungry. Ranked preference for the trained flavour increased exclusively among hungry-trained subjects, but only for those who had reported their preferred snack food to be fruit. No change in any measure was found for the group eating the fruit bars exclusively when full. The results suggest the hungry-trained group learnt that the bars lacked strong satiation, thus allowing greater intake when full (learnt desatiation). For the same reason, however, the prospect of eating the bars when mildly hungry lost its appeal. Eating fruit between meals may not encourage snacking on fruit, unless hunger is absent at the time of consumption. PMID- 11606036 TI - Acquisition of texture-cued fasting-anticipatory meal-size change in rats with adequate energy intake. AB - To determine if an increase in intake at a meal before a long fast can be conditioned to food texture cues, male Sprague-Dawley rats were given a high- or low-fat diet in one texture (powder or pellet) for 1 h prior to a 12.5-h fast and in the other texture before a 3-h fast. Each group (N = 9) went through a pseudorandom sequence of four duplicates of each texture-fast pairing over 4 experimental days in each of three training trials, followed by one 4-day trial under extinction, i.e. without the difference in fast lengths between textures. Neither the high-fat group nor the low-fat group as a whole gave a clear indication of a learnt texture-cued increase in meal size before the longer fast relative to the shorter fast. However, the rats trained on the high-fat diet that had the highest intakes on the first 4 days of training showed a relative increase in the amount eaten of the texture predicting the longer fast during the third training trial, and this effect also approached statistical significance in the extinction test. These results provide some support for the conclusion that anticipatory hunger/satiety can be differentially conditioned to dietary texture cues, but only if sufficient food is eaten before a short fast to prevent the rise in hunger during longer fasts that reinforces the discriminative increase in meal size. PMID- 11606037 TI - The role of taste in feeding. PMID- 11606038 TI - Behavioral and biological determinants of leptin resistance. PMID- 11606039 TI - The effects of D1 and D2 receptor blockade on the acquisition and expression of a conditioned appetitive response. PMID- 11606040 TI - Breakfast outcome expectancies modestly predict self-reported diet. PMID- 11606041 TI - Regulatory functions of 3'UTRs. PMID- 11606042 TI - Involvement of phosphorylation of myosin phosphatase by ROCK in trabecular meshwork and ciliary muscle contraction. AB - The control of smooth muscle contraction is an important factor in maintaining normal intraocular pressure. However, the specific factors causing changes in control by phosphorylation/dephosphorylation schemes in the eye are not well defined. The purposes of this experiment were to (i) determine the localization of ROCK (Rho-associated, coiled coil-forming kinase) in monkey and rabbit eye tissues and (ii) measure phosphorylation of ROCK substrate during trabecular meshwork or ciliary muscle contraction induced by carbachol. We found that mRNAs for both ROCK I and II were expressed in most eye tissues from rabbit and monkey. Proteins for ROCK I and II were present in all eye tissues studied except lens. When trabecular meshwork or ciliary muscle were incubated with carbachol to induce contraction, phosphorylation of the myosin-binding subunit (MBS) of myosin phosphatase, a substrate for ROCK, started within 1 min and continued for at least 1 h. This phosphorylation was well correlated with contraction of trabecular meshwork or ciliary muscle. These results suggested that ROCK might regulate contraction of trabecular meshwork or ciliary muscle through phosphorylation of MBS of myosin phosphatase. PMID- 11606043 TI - HIV-1 Tat causes apoptotic death and calcium homeostasis alterations in rat neurons. AB - We investigated the role of the HIV-1 protein Tat in AIDS-associated dementia, by studying its toxicity on rat cortical and hippocampal neurons in vitro. We evaluated the involvement of astroglial cells and of caspase transduction pathway in determining Tat toxicity. Here we report that synthetic Tat(1-86) induced apoptotic death on cultured rat neurons in a time-dependent manner that was not influenced by glial coculture, and that was abolished by blocking caspase transduction pathway. A microfluorimetric analysis on the Tat excitatory properties on neurons, and its effect on intracellular calcium concentrations, revealed that Tat(1-86) induced increase in cytoplasmic free calcium concentrations in rat hippocampal and cortical neurons. This effect required extracellular calcium and was differently reduced by voltage dependent calcium channel blockers and both NMDA and non-NMDA glutamate receptors antagonists. Furthermore, we observed that Tat(1-86)-treated neurons showed increased sensitivity to the glutamate excitotoxicity. Thus, the Tat-induced neuronal injury seems to occur through a direct interaction of the protein with neurons, requires activation of caspases, and is likely to derive from Tat(1-86)-induced calcium loads and disruption of glutamatergic transmission. PMID- 11606044 TI - Clonidine-displacing substance reduces glucagon secretion from mouse pancreatic alpha-cells by K(ATP)-channel-independent inhibition of exocytosis. AB - Clonidine-displacing substance (CDS) is a potent stimulator of insulin release from pancreatic beta-cells and has been suggested to constitute the endogenous ligand for the islet imidazoline-binding site. Here we have explored the effects of CDS on glucagon release from mouse pancreatic alpha-cells. CDS (5 U/ml) produced a 35% inhibition (P < 0.05) of glucagon release from intact islets. This effect was dose-dependent and half-maximal inhibition by CDS was observed at 0.03 U/ml. Inhibition of glucagon release was not associated with a change in whole cell ATP-sensitive K(+)-channel activity in single alpha-cells. However, during intracellular application through the recording pipette, CDS produced a 36% (P < 0.05) decrease in the rate of exocytosis, measured as changes in cell capacitance. The inhibitory effect of CDS on exocytosis resulted from activation of the protein phosphatase calcineurin and was abolished by cyclosporin A. These data provide further evidence for a role of CDS as an endogenous ligand controlling islet hormone secretion. PMID- 11606045 TI - Heterogeneity in the phosphorylation of human death receptors by p42(mapk/erk2). AB - Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation. Therefore, we sought to determine if p42(mapk/erk2) was also capable of phosphorylating additional human death receptors within the TNF receptor superfamily. These studies showed that CD120a and DR3 are significantly phosphorylated by p42(mapk/erk2) but Fas, DR4 and DR5 are not. Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a, and (iv) the p42(mapk/erk2)-dependent phosphorylation of the DR3 cytoplasmic domain occurred exclusively at non-p42/44(mapk/erk2/1) consensus sites. These findings suggest that human death receptors segregate into two groups along lines of phylogeny with respect to Ser/Thr phosphorylation by p42(mapk/erk2). PMID- 11606046 TI - Temperature-sensitive phenotype of Chinese hamster ovary cells defective in PEX5 gene. AB - SK32 mutant cells, which were isolated as peroxisome-deficient Chinese hamster ovary (CHO) cells by an advantage of a visible peroxisome form of green fluorescent protein (GFP), were found to suffer from a functional loss of PEX5 gene encoding for PTS1R. The sequence analysis of cDNA indicated that PEX5 gene encoded for the two isoforms composed of 603 amino acids (PTS1RS) and 640 amino acids (PTS1RL). The mutation changed glycine to arginine at amino acid position 343 of PTS1RL (corresponding to the position 306 of PTS1RS) in SK32 cells. The mutant cells exhibited a temperature-sensitive (TS) phenotype on the peroxisomal localizations of the recombinant GFP and urate oxidase appending a genuine peroxisome targeting signal 1 (PTS1), a tripeptide of Ser-Lys-Leu (SKL) at the C terminus, but did not on that of catalase harboring a divergent PTS1, Lys-Ala-Asn Leu (KANL) sequence. 3-ketoacyl-CoA thiolase (hereafter referred to as thiolase), which harbors an extension sequence (PTS2) at the N-terminus, never appeared to be affected on the peroxisomal localization in the mutant cells. When thiolase was examined on the molecular size in the mutant cells, the enzyme existed as the larger precursor form in the peroxisomes at 37 degrees C and a considerable part (almost half) was converted to the mature size at 30 degrees C. These results indicate that the amino acid substitution, Gly306Arg in PTS1RS and/or Gly343Arg in PTSRL, gives rise to TS phenotype on the peroxisomal translocation of PTS1 proteins and the maturation of PTS2 protein. PMID- 11606048 TI - RANKL induces formation of avian osteoclasts from macrophages but not from macrophage polykaryons. AB - We have shown that chick macrophages express RANK at their surface and human RANKL (hRANKL) triggers the formation of osteoclasts able to degrade dentine. As described for mammalian osteoclasts, hRANKL also stimulates the resorbing activity of chick bone-derived osteoclasts. In other hands, in culture, chick macrophages spontaneously form polykaryons sharing most of the osteoclast markers but unable to resorb bone. Since both bone-resorbing osteoclasts and macrophage polykaryons found in inflammatory tissues are multinucleated cells deriving from the fusion of macrophages, we examined whether macrophage polykaryons could be induced toward bone-resorbing osteoclasts. Long-term exposure of macrophage polykaryons to hRANKL failed to activate any resorbing activity, indicating that although deriving from the same precursors macrophage polykaryons and osteoclasts are independent cell types and polykaryons are not immature osteoclasts. PMID- 11606047 TI - Cloning of the rat IL-5Ralpha gene: analysis of 5'-upstream region and expression by B cells. AB - Although rats are widely used for the analysis of allergic reactions and parasitic infections where IL-5 is involved, nothing is currently known of the expression of IL-5 receptor in this species. In this study, the cDNA sequence, genomic structure and the transcriptional regulation of the rat IL-5Ralpha were analyzed. The rat IL-5Ralpha gene, which we localized to chromosome 4q34-q41, spans more than 25 kb and consists of 12 exons. Promoter activity was seen in different cell lines and analysis by deletion experiments allowed to identify two negative regulatory regions which did not differ when tested either with IL 5Ralpha-negative or positive cells. Finally, the investigation of the expression of IL-5Ralpha showed that it is expressed in lung, spleen, liver, and purified rat B cells from normal rat. This can provide an explanation for the role of rat IL-5 as B-cell growth factor and a relevant model in order to better understand the activity of IL-5 on human B cells. PMID- 11606049 TI - A 30-base-pair element in the first intron of SOX9 acts as an enhancer in ATDC5. AB - SOX9 is a transcription factor that is essential for chondrogenesis and testis differentiation, and haploinsufficiency of SOX9 causes campomelic dysplasia, severe skeletal malformation syndrome with variably penetrant XY sex reversal. Here we demonstrate that in several cell lines that express SOX9, 30-bp element in the first intron of human SOX9 gene act as a potential enhancer in the ATDC5 chondroprogenitor cell line, despite the apparent absence of cell-specific regulatory elements within a 5.5-kb promoter region. Deletion and site-specific mutational analyses reveal that the last 12 bp of the 30-bp element are critical for transcriptional activity, while 5'-half sequences are necessary for full transactivation. Gel retardation assays indicate the possible involvement of several binding factors along the length of this element. These results suggest that functionally interdependent elements in the 30-bp enhancer region of the first intron account for basal expression levels of Sox9 in ATDC5. PMID- 11606051 TI - Coparalogy: physical and functional clusterings in the human genome. AB - Two rounds of large-scale duplications are thought to have occurred in early vertebrate ancestry; this is now known as the "2R hypothesis." They have led to the constitution of subfamilies of paralogous genes. Chromosomal regions that contain present-day paralogs (paralogous regions or paralogons) have been identified in mammals. We show that sets of paralogons (PGs) can be assembled in a tentative "human genome paralogy map" that includes all autosomes and X. A total of 14 PGs, containing more than 1600 genes, were assembled in this paralogy map. Genes that belong to the same PG are coparalogs. We show that identification of coparalogy can be used (i) to broaden data on gene mapping, (ii) to identify physical gene clusters that derive from early cis-duplications, and (iii) to speculate on coevolution and coregulation of genes sharing a common structure or function (functional clusters). Thus, coparalogy analyses should parallel phylogenetic analyses and can help draw hypotheses on gene and genome evolution. PMID- 11606050 TI - Uniaxial cyclic stretch induces focal adhesion kinase (FAK) tyrosine phosphorylation followed by mitogen-activated protein kinase (MAPK) activation. AB - We investigated the role of tyrosine phosphorylation of FAK in the stretch induced MAPKs (extracellular signal-regulated kinase (ERK), p38MAPK) activation in mutant FAK-transfected fibroblasts. In response to uniaxial cyclic stretch (1 Hz, 120% in length), the levels of tyrosine phosphorylation of the Tyr-397 and Tyr-925 of FAK in control cells increased and peaked at 5 min (2.75 +/- 0.51, n = 3), and 20 min (2.98 +/- 0.58, n = 3), respectively, and the activities of MAPKs increased and peaked at approximately 10 min. On the other hand, in the mutant FAK-transfected cells, the stretch-induced MAPKs activation was significantly inhibited. The stretch-induced activation of MAPKs was also significantly abolished by either treatment with Gd(3+) or extracellular Ca(2+) removal which may inhibit intracellular Ca(2+) increase caused by the activation of cation selective (Ca(2+)-permeable) stretch activated (SACatC) channels. These results suggest that the stretch-induced tyrosine-phosphorylation of FAK via SACatC activation is critical for the stretch-induced MAPKs activation. PMID- 11606052 TI - Differential growth regulation in human melanoma cell lines by TIMP-1 and TIMP-2. AB - We investigated the role of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in the growth regulation. Primary (PM-WK and KHm-4), recurrent primary (RPM-EP and RPM-MC), lymph node metastatic (MM-AN, MM-BP and MM-RU), and a visceral metastatic (MM-LH) melanoma cell lines were used. Reverse transcriptase coupled polymerase chain reaction and Western blotting revealed that all expressed and produced TIMP-1 and TIMP-2 except for PM-WK, which neither expressed nor produced TIMP-1. TIMP-1 and TIMP-2 secretion levels were measured by enzyme-linked immunosorbent assay in supernatants of cells. We found that the TIMP-1 production level was correlated with the cell migration rate. Moreover, TIMP-1 enhanced the cell migration of PM-WK. The growth of the primary melanoma cell lines was stimulated by TIMP-1 and inhibited by TIMP-2. In contrast, the growth of the visceral metastatic melanoma cell line was stimulated by TIMP-2. PMID- 11606053 TI - Expression of a novel matrix metalloproteinase gene during Cynops early embryogenesis. AB - Matrix metalloproteinases (MMPs) are thought to play important roles in the gastrulation of Cynops pyrrhogaster embryos. MMP cDNAs were cloned from Cynops pyrrhogaster and we report here a novel MMP called CyMMP, which has strong similarity to MMP-21 (XMMP) in Xenopus. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that CyMMP mRNA was already present in cleavage stage embryos. The amount of the mRNA then gradually decreased, but increased again starting in late gastrula. There were regional differences in the level of CyMMP mRNA expression at late gastrula: the involved archenteron roof was the predominant site of expression of the gene, while there was weak expression in the neuroectoderm and epidermal ectoderm. We also found that the gene was activated in artificially mesodermalized ectoderm. The present findings indicate that CyMMP mRNA expression is activated in differentiating mesoderm during gastrulation, suggesting that CyMMP plays a role in gastrulation-related cell movement. PMID- 11606054 TI - Overexpression of sigma factor, sigma(B), urges Staphylococcus aureus to thicken the cell wall and to resist beta-lactams. AB - Whole genome sequence analysis revealed that Staphylococcus aureus is provided with only a few sigma factors, including the alternative sigma factor, sigma(B), which is thought to regulate some stress responses. Since the sigB knock-out mutant did not show remarkable phenotypic difference, we constructed the over expressed mutant to examine the role of the sigB. Electron microscopic observation revealed that the mutant showed a variety of cell sizes compared with the parent strain which showed almost homogeneous cell sizes. The mutant delivered a thicker cell wall, about 20% thicker than the parent strain. It became resistant to the lytic activity of lysostaphin and also raised MICs to the cell-wall-affecting antibiotics. The yield of carotenoids and transcripts of pbps were also increased in the mutant. The result suggests that sigB plays some important roles in cell wall synthesis and in resistance to antibiotics that perturb the cell wall synthesis. PMID- 11606056 TI - Copy-number fluctuation by unequal crossing-over in the chicken avidin gene family. AB - The chicken avidin gene (AVD) forms a closely clustered gene family together with several avidin-related genes (AVRs). In this study, we used fluorescence in situ hybridization on extended DNA fibers (fiber-FISH) to show that the number of the AVD and AVR genes differs between individuals. Furthermore, the gene copy-number showed wide somatic variation in white blood cells of the individuals. The molecular mechanism underlying the fluctuation is most probably unequal crossing over and/or unequal sister chromatid exchange, as judged by the Gaussian distribution of the gene counts. By definition, an increase in gene number on one locus should be accompanied by a decrease on the other locus in unequal sequence exchange. The results suggest that copy-number lability may be more common among gene families than previously thought. The chicken avidin gene family also provides an excellent model for studying the mechanisms of recombination and gene conversion. PMID- 11606055 TI - Identification of hepatocyte growth factor activator inhibitor type 2 (HAI-2) related small peptide (H2RSP): its nuclear localization and generation of chimeric mRNA transcribed from both HAI-2 and H2RSP genes. AB - A novel small gene, designated hepatocyte growth factor activator inhibitor type 2 (HAI-2)-related small peptide (H2RSP) was cloned and characterized in the process of the search for splicing variant forms of HAI-2 by 3'-rapid amplification of cDNA ends (RACE). The gene consisted of 4 exons spanning approximately 1 kb and was located in 11 kb downstream of HAI-2 gene (19q.13.11). The novel transcript identified by 3'-RACE was thought to be chimerically transcribed from both HAI-2 (exons 1-7) and H2RSP (exons 2-4) genes. Wild-type H2RSP mRNA (0.5 kb) was detected abundantly in various tissues including the gastrointestinal tract, whereas chimeric mRNA (1.5 kb) was found mainly in the kidney, prostate, and placenta by Northern blot analysis. The predicted amino acid sequence of H2RSP contained two unique domains, namely the serine-rich region (exon 3) and the lysine-rich region (exon 4). Transfection of deleted series of H2RSP cDNAs fused to enhanced green fluorescent protein (EGFP) into HeLa cells revealed that H2RSP has nuclear localization signal in the lysine-rich region. Immunohistochemical study using anti-H2RSP polyclonal antibody indeed revealed the nuclear localization of this peptide in vivo. These results suggest that H2RSP and H2RSP/HAI-2 chimeric peptides might function as a transcriptional regulatory peptide at the nucleus. PMID- 11606057 TI - Amida predominantly expressed and developmentally regulated in rat testis. AB - Amida was first isolated from a rat hippocampal cDNA library as an Arc-associated protein. Previous studies showed that Amida is a nuclear protein and overexpression of Amida induces cell apoptosis. In this study, we found that Amida mRNA was expressed predominantly in rat testis by Northern blot analysis. During the development of testis, Amida mRNA was barely detectable until postnatal days 24 to 29 during which it increased to levels found in adults. However, Amida protein was not detected until postnatal day 32. Amida mRNA was found to be enriched in spermatocytes and less in round spermatids, but was undetectable in elongated spermatids by in situ hybridization. In addition, Amida protein was observed in the nucleus of spermatocytes and even in the elongated spermatids by immunohistochemistry. The development and cellular localization differences of Amida mRNA and protein implicates that Amida mRNA may undergo posttranscriptional regulation. Furthermore, Amida mRNA decreased significantly in the 8-day experimental cryptorchid testis when spermatogenesis was disrupted. Taken together, these data suggest that Amida is involved in spermatogenesis and may play an important role in development of testicular germ cells. PMID- 11606058 TI - Retention of multilineage differentiation potential of mesenchymal cells during proliferation in response to FGF. AB - Mesenchymal stem cells (MSC) that can differentiate to various connective tissue cells may be useful for autologous cell transplantation to defects of bone, cartilage, and tendon, if MSC can be expanded in vitro. However, a short life span of MSC and a reduction in their differentiation potential in culture have limited their clinical application. The purpose of this study is to identify a growth factor(s) involved in self-renewal of MSC and the maintenance of their multilineage differentiation potential. Fibroblast growth factor-2 (FGF-2) markedly increased the growth rate and the life span of rabbit, canine, and human bone marrow MSC in monolayer cultures. This effect of FGF-2 was more prominent in low-density cultures than in high-density cultures. In addition, all MSC expanded in vitro with FGF-2, but not without FGF-2, differentiated to chondrocytes in pellet cultures. The FGF+ MSC also retained the osteogenic and adipogenic potential throughout many mitotic divisions. These findings suggest that FGFs play a crucial role in self-renewal of MSC. PMID- 11606059 TI - Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells. AB - Apoptosis-linked gene 2 (ALG-2) is a member of the family of Ca(2+)-binding proteins with penta-EF-hand and is essential for the execution of apoptosis by various signals including Fas activation. We studied the regulation of ALG-2 during Fas-mediated apoptosis in Jurkat cells. The 22-kDa ALG-2 protein is cleaved and becomes a 19-kDa protein after Fas activation. The appearance of 19 kDa ALG-2 protein increases for 4 h after treatment with 200 ng/ml of anti-Fas Ab treatment and gradually degrades afterward. Confocal microscopic analysis showed that ALG-2 translocated from the plasma membrane to the cytosol during Fas mediated apoptosis. Therefore, we examined if ALG-2 interacts with Fas. The protein-protein interaction of ALG-2 with Fas was demonstrated using yeast two hybrid assays as well as in vitro GST pull-down assay. Endogenous ALG-2 was immunoprecipitated with anti-Fas Ab in Jurkat cells without Fas activation. However, the endogenous ALG-2 was no longer immunoprecipitated with anti-Fas Ab 2 h after anti-Fas Ab treatment. This study, for the first time, presents a direct molecular connection of ALG-2 to apoptosis by its direct interaction with Fas, and enlists ALG-2 as a new member of posttranslationally modified proteins during Fas-mediated apoptotic process. PMID- 11606060 TI - Anti-TNF-alpha properties of new 9-benzyladenine derivatives with selective phosphodiesterase-4- inhibiting properties. AB - In inflammatory cells, intracellular cAMP concentration is regulated by cyclic nucleotide phosphodiesterases 4. Therefore, PDE4 inhibition appears as a rational goal for treating acute or chronic inflammatory diseases. Selective PDE4 inhibitors have been developed, but due to unwanted side effects, search for new selective PDE4-inhibitors had to be pursued. Recently, Boichot et al. (J. Pharmacol. Exp. Ther. (2000) 292, 647-653) showed that 9-benzyladenine derivatives are selective PDE4 inhibitors. In vivo data in animals suggested that they may induce fewer side effects (emesis). We examined the effects of new 9 benzyladenines on TNF-alpha, interleukin (IL)-1beta, IL-6 and IL-8 production by lipopolysaccharide-activated peripheral blood mononuclear cells, and compared them to other PDEs inhibitors. Selected potent 9-benzyladenines, strongly inhibited TNF-alpha production. Interleukin-1beta, IL-6, and IL-8 production was not significantly affected. Our results suggest that some of these new adenines (i.e., NCS 675 and NCS 700), may be potential therapeutic candidates for the treatment of inflammatory diseases. PMID- 11606061 TI - Insulin-like growth factor-binding protein-5 inhibits growth and induces differentiation of mouse osteosarcoma cells. AB - The precise role of insulin-like growth factor-binding protein-5 (IGFBP-5) in regulating the growth of tumor cells, especially of bone-derived malignant cells, is not well understood. We have investigated the biological activity of IGFBP-5 by transfecting OS/50-K8 mouse osteosarcoma cells with an expression vector containing the osteocalcin promoter and the complete mouse IGFBP-5 cDNA (OC-IGFBP 5). Overexpression of IGFBP-5 mRNA and secretion of increased amounts of bioactive protein in conditioned media were demonstrated in different clones. For the analysis of cell proliferation, three clones exhibiting high levels of IGFBP 5 expression were selected and compared to a mock clone and to nontransfected parental cells. IGFBP-5-secreting clones displayed reduced proliferation under both anchorage-dependent and -independent conditions (P < 0.05). The increase in proliferation observed in IGFBP-5-secreting clones after addition of exogenous IGF was significantly lower than that observed in mock-transfected or parental cells. A similar result was obtained with long[R3]IGF-I which has a low affinity for all IGFBPs, suggesting that the inhibitory effect of IGFBP-5 is only partially IGF-dependent. OC-IGFBP-5-transfected clones expressed significantly higher amounts of osteocalcin mRNA (P < 0.05) and secreted more osteocalcin protein than a mock clone or parental OS-50/K8 cells. Thus, part of the growth inhibiting effect of IGFBP-5 may be due to an induction of differentiation in these cells. PMID- 11606062 TI - Association between actin and light chains in Chlamydomonas flagellar inner-arm dyneins. AB - Inner dynein arms in cilia and flagella contain actin as a subunit; however, the function of this actin is totally unknown. Here we performed chemical crosslinking experiments to examine the interaction of actin with other subunits. Six of the seven Chlamydomonas inner-arm dynein species separated by anion exchange chromatography contain actin and either one of the two previously identified light chains, p28 and centrin, in a mutually exclusive manner. Western blotting of chemically crosslinked dyneins indicated that actin is directly associated with p28 and centrin but not with the dynein heavy chains (HCs). In contrast, p28 and centrin both appeared to interact directly with the N-terminal half of the HCs. Thus it is likely that actin is associated with the heavy chains through p28/centrin. These light chains may well function in the assembly or targeting of the inner arm to the correct axonemal location. PMID- 11606063 TI - Osteopontin-deficient bone cells are defective in their ability to produce NO in response to pulsatile fluid flow. AB - Osteopontin (OPN) is a noncollagenous component of bone matrix. It mediates cell attachment and activates signal transduction pathways. In this work, bone cells, cultured from fragments of long bones derived from wild-type and OPN-/- ("knock out") mice, were exposed to pulsatile fluid flow (PFF) over a 60-min period. The medium was assayed periodically for nitric oxide (NO) and prostaglandin E(2) (PGE(2)) release. OPN+/+ cells exhibited a peak of NO production 5-10 min after the onset of PFF, decreasing to a stable plateau at 15 min; much less NO was produced by the OPN-/- cells. PFF resulted in reduced PGE(2) release by both cell types, although the reduction was less for the OPN-/- cells in the 15-30 min window. Both cell types exhibited a similar enhancement of cyclooxygenase2 mRNA levels 60 min after initiation of PFF. These results suggest that bone cells require OPN to respond fully to PFF as assessed by increased NO and reduced PGE(2) synthesis. PMID- 11606064 TI - Reconstruction of SEA-B7.1 double signals on human hepatocellular carcinoma cells and analysis of its immunological effect. AB - Since transfection of established tumors with immunostimulatory genes, such as superantigens (SAg), a family of bacterial and viral proteins with strong immunostimulatory properties, can elicit antitumor immunity, direct transfection of tumors with genes of staphylococcal enterotoxin A (SEA) could probably set up a new way of immunological pathway. In our study, human hepatocellular carcinoma (HCC) cell lines stably transduced with SEA and B7.1/SEA fused genes, HHCCSEA and HHCCBS, were obtained by using the method of retroviral mediated gene transduction. The results showed that human HCC cells could express SEA gene. Although a tiny quantity of expression was detected, a robust immune response was promoted. The cytotoxicity of CTL on HHCCBS was the same as that on HHCCSEA. But the K(m) value of the reaction of the former was lower than that of HHCCSEA. Furthermore, the activity assay of T cells by ELISPOT demonstrated that HHCCBS could elicit more CTL activity than HHCCSEA and HHCCB7.1. It suggested that the affinity of T cells to HHCCBS was higher and the maxim velocity of reaction could be attained at an early stage of the reaction. Transduced HCC cells were also analyzed for HLA expression, and it was found that a majority of the cells expressed HLA-I molecules but no HLA-DR molecules. After blocking the HLA-I molecules by HLA-I mAb, the cytotoxicity of T lymphocytes dropped remarkably. The results suggested that SEA were mainly presented by HLA-I molecules, and that B7.1 and SEA could have synergistic action at the early stage of the reaction, but the relationship between them in the consequent process needs to be clarified. PMID- 11606065 TI - Structural insight into human Zn(2+)-bound S100A2 from NMR and homology modeling. AB - The S100 subfamily of EF-hand proteins is distinguished by the binding of Zn(2+) in addition to Ca(2+). In an effort to understand the role of Zn(2+) in modulating the activity of S100 proteins, we have carried out heteronuclear NMR studies of Zn(2+)-bound S100A2 and obtained near complete resonance assignments. This analysis revealed an equilibrium between multiple isoforms due to cis-trans isomerism of proline residues in flexible regions of the protein. The secondary structure of S100A2 has been determined based on the NMR chemical shift index (CSI) technique. The protein is found to possess essentially the same secondary structure found in other S100 proteins such as S100A6 and S100B. Homology models have been built based on the high resolution three-dimensional structures of other S100 proteins. The models predict two Zn(2+) binding clusters, one involving residues His17-Cys21-Cys93 and the other Cys2-His39, and with Cys86 participating in either the N-terminal or the C-terminal binding site. PMID- 11606066 TI - Interaction of syntaxin with alpha-fodrin, a major component of the submembranous cytoskeleton. AB - The soluble N-ethyl maleimide-sensitive factor attachment protein receptor machinery is involved in membrane docking and fusion. In this machinery, the syntaxin family is a central coordinator and participates in multiple protein protein interactions. In this study we have shown that alpha-fodrin, nonerythroid spectrin, is a new binding partner of the syntaxin family. alpha-Fodrin bound to syntaxin-1a, -3, and -4, all of which are localized on the plasma membrane. Syntaxin-3 interacted with alpha-fodrin in dose-dependent and saturable manners but not with alpha-spectrin, erythroid spectrin. Syntaxin-3 interacted with alpha fodrin through its C-terminal coiled-coil region. Binding of Munc18 or SNAP-25 to syntaxin-1a inhibited the interaction of alpha-fodrin with syntaxin-1a. Available evidence indicates that alpha-fodrin is implicated in exocytosis, but a precise mode of action of alpha-fodrin in exocytosis remains unclear. Our results suggest that alpha-fodrin regulates exocytosis through the interaction with members of the syntaxin family. PMID- 11606067 TI - Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein. AB - Grb2-associated binder-1 (Gab1) undergoes tyrosine phosphorylation in response to stimulation by growth factors and hormones including insulin, epidermal growth factor (EGF), nerve growth factor (NGF), and hepatocyte growth factor (HGF). However, the HGF receptor is the only one known to associate directly with Gab1. Herein, we explore the mechanism of Gab1 phosphorylation by other receptor protein-tyrosine kinases unable to bind to Gab1 directly. The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PI3K) regulatory subunit binds Gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of PI3K can mediate the association of Gab1 and receptor protein-tyrosine kinases including the insulin, EGF, and NGF receptors, all of which phosphorylate Gab1. Thus, it appears that the PI3K regulatory subunit acts as an adaptor protein via a phosphotyrosyl-independent SH2 interaction, allowing Gab1 to serve as a substrate for several tyrosine kinases. This is a new role for the PI3K regulatory subunit. PMID- 11606068 TI - The human ABCG4 gene is regulated by oxysterols and retinoids in monocyte-derived macrophages. AB - Here we report the induction of gene expression of ABCG4, a member of the ABC transporter subfamily G, from human macrophages by oxysterols and retinoids, agonists of the nuclear receptors LXR and RXR. The cloned ABCG4 transcript has a size of 3.5 kb and contains an open reading frame which encodes a polypeptide of 646 amino acids. Structurally, the putative ABC transporter protein consists of a nucleotide binding fold followed by a cluster of six transmembrane-spanning domains and thus conforms to the group of half-size ABC transporters. Among the human ABC transporter subfamily G members the novel transporter shows highest protein sequence homology and identity to ABCG1 (84 and 72%, respectively). Analysis of the genomic organization demonstrates that the ABCG4 gene is composed of at least 14 exons which extend across a region of 12.6 kb in size on chromosome 11q23.3. Based on its structural features and an LXR/RXR-responsive regulation similar to the cellular lipid export protein ABCA1, we conclude that ABCG4 may be involved in macrophage lipid homeostasis. PMID- 11606069 TI - Gene expression profile in endometrioid endometrial carcinoma. PMID- 11606070 TI - Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. AB - OBJECTIVE: Endometrioid endometrial carcinoma is caused by a combination of mutational events and hormonal factors. We used large-scale messenger RNA expression analysis to discover genes that distinguish neoplastic transformation and examine the patterns of tumor expression of those genes which are normally regulated during the menstrual cycle. METHODS: Expression of approximately 6000 unique genes was quantified in 4 normal (2 proliferative, 2 secretory) and 10 malignant endometria using Affymetrix Hu6800 GeneChip probe arrays. Expression differences between normal and malignant tissue groups were measured by a test of statistical significance comparing the individual t statistic for each gene to the distribution of maximum t statistics among all genes following 1001 permutations of the tissue group assignments (Permax test). Hormonally responsive genes, selected by comparison of proliferative and secretory subsets of normal endometria using a combination of filters applied to the group means and t test rankings, were then examined in the tumors. RESULTS: Fifty genes with a Permax <0.50 provided excellent discrimination between normal and malignant groups and were predominantly characterized by diminished expression levels in the cancers. We found that 100 genes which are hormonally regulated in normal tissues are expressed in a disordered and heterogeneous fashion in cancers, with tumors resembling proliferative more than secretory endometrium. CONCLUSION: Neoplastic transformation is accompanied by predominant loss of activity of many genes constitutively expressed in normal source tissues and absence of expression profiles which characterize the antitumorigenic progestin response. PMID- 11606071 TI - Strategies for the implementation of cervical and breast cancer screening of women by primary care physicians. AB - OBJECTIVE: While effective screening tests for the prevention and early detection of cervical and breast cancers exist, poor screening rates are evident. The aim of this paper was to determine the most effective strategies for the implementation of breast and cervical cancer screening delivered to women. METHODS: An in-depth search of the literature using Medline and the Cochrane Library was carried out between the years 1966 and 2000. Randomized controlled studies addressing the delivery of both breast and cervical screening were retained for the purposes of this review. Absolute difference (AD) in screening was defined as screening rates in the intervention arm--screening rates in the control arm. Number needed to intervene (NNI) is a new term developed for the purpose of this paper and refers to the number of physicians or physician-patient pairs that must be exposed to the intervention before one screening test is performed. NNI is defined as 1/AD. RESULTS: Strategies for the implementation of screening tests are divided into three categories: physician-only based, physician and patient based, and patient-only based. CONCLUSIONS: Physician-based strategies, especially manual and computer-generated reminders, appear to be the most effective approach in the implementation of breast and cervical cancer delivery to women. Absolute gains in screening rates were as high as 40% with an NNI of 2.5 physicians; therefore, approximately 3 physicians need to be exposed to a reminder notice before 1 physician actually orders the screening tests. PMID- 11606072 TI - Intravenous chemotherapy, early debulking surgery, and consolidation intraperitoneal chemotherapy in advanced ovarian carcinoma. AB - OBJECTIVE: The efficacy of a cisplatin-anthracycline combination, early debulking surgery, and intraperitoneal chemotherapy has been demonstrated through separate studies. We evaluated a multimodal treatment strategy integrating these therapeutic options. METHODS: Women with stage III or IV ovarian carcinoma received six cycles of cisplatin/epirubicin alternating with leucovorin and 5 fluorouracil. Patients with a residual disease (RD) measuring more than 2 cm after the initial laparotomy underwent an early debulking surgery after the first three cycles of chemotherapy. A second-look laparotomy (SLL) was performed after six cycles of intravenous chemotherapy. Intraperitoneal chemotherapy with cisplatin, VP16, and mitoxantrone was then administered in patients with no or RD < 2 cm after SLL. RESULTS: A total of 87 patients were included. After initial laparotomy, 11 patients (12%) had no macroscopic residual disease, 38 (44%) had a RD < or =2 cm, and 38 (44%) had a RD > 2 cm. After early debulking surgery, an additional 18 patients (21%) had a RD < 2 cm. Seventy-five patients were evaluable for response to intravenous chemotherapy: the overall response rate was 80%, and 30 patients achieved a pathological complete response (40%). Eight percent of the patients had stable disease and 12% had a progression. Sixty-eight patients received intraperitoneal chemotherapy after second-look laparotomy. With a 72-month median follow-up, median overall survival and progression-free survival were, respectively, 37 and 19 months. Five-year survival was 41%. CONCLUSION: The prognosis of patients with advanced ovarian carcinoma may be improved by a sequential treatment strategy including intravenous chemotherapy, early debulking surgery, and intraperitoneal chemotherapy. PMID- 11606073 TI - Hepatocyte growth factor/scatter factor is implicated in the mode of stromal invasion of uterine squamous cervical cancer. AB - OBJECTIVE: The purpose of this study was to examine the relationship of hepatocyte growth factor/scatter factor (HGF/SF) to cell motility and invasion in uterine cervical cancer. METHODS: We examined the expression of HGF/SF and its receptor, c-met, in cervical cancer cell lines SKG-IIIa (squamous cell carcinoma) and Hela-S3 (adenocarcinoma) and in stromal cells of the cervical cancer tissue by reverse transcription-polymerase chain reaction. We studied the effect of HGF/SF on invasiveness of SKG-IIIa and Hela-S3 in an invasion model of the modified Boyden chamber method and by electron microscopy. SKG-IIIa cells were also seeded on the thick Matrigel-coated layer to evaluate the invasion patterns in three-dimensional directions. To investigate the mechanism of an inductive effect of HGF/SF on the invasiveness of SKG-IIIa, we examined the effect of HGF/SF on the expression of intercellular adhesion molecule E-cadherin, cell substrate adhesion molecules CD44, alpha2beta1, and alpha6beta1, and intracellular skeleton fiber actin in SKG-IIIa in cell enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining. RESULTS: HGF/SF messenger RNA (mRNA) was detected in stromal cells, and c-met mRNA was detected in SKG-IIIa and Hela-S3. Hela-S3 that initially showed weak intercellular contact freely invaded the Matrigel-coated multiporous membrane without the addition of HGF/SF. In contrast, SKG-IIIa that initially showed strong intercellular adhesion could invade the membrane after the addition of HGF/SF. The same results were represented by an addition of HECD-1, an anti-human E-cadherin antibody. In an experiment with cell culture in a thick Matrigel layer, control SKG-IIIa showed a mirror-ball-like invasion pattern, whereas HGF/SF-stimulated SKG-IIIa spread horizontally over the membrane and migrated through the membrane holes, presenting a tentacular invasion pattern. Migration of SKG-IIIa under the membrane was confirmed by scanning and transmission electron microscopy. The addition of HGF/SF in cell ELISA assay decreased the expression of E-cadherin and actin in SKG-IIIa, but it did not change the expression of CD44, alpha2beta1, and alpha6beta1. Immunofluorescence staining revealed that the expression of E cadherin in cell membrane was disturbed by HGF/SF. CONCLUSIONS: Our data indicate that HGF/SF produced by stromal cells influences the mode of stromal invasion of squamous cervical cancer by selectively decreasing the expression of both E cadherin and actin. PMID- 11606074 TI - Predictors of outcome in small cell carcinoma of the cervix--a case series. AB - OBJECTIVE: The objective of this study was to determine whether clinicopathologic findings or the immunohistochemical presence of molecular markers are predictive of clinical outcome in patients with small cell carcinoma of the cervix (SCCC). METHODS: A retrospective review of cases of carcinoma of the cervix was conducted to identify SCCC. From 1978 to 1999, 16 patients were identified at our institution with the diagnosis of SCCC. Microscopic sections of paraffin-embedded tissue specimens were evaluated for confirmation of diagnosis. Specimens were immunohistochemically stained with antibodies to three neuroendocrine markers: neuron-specific enolase, chromagranin (CGR), and synaptophysin. Specimens were also stained for protein expression of p53, erbB2, proliferating cell nuclear antigen, and c-myc. The relationship between molecular markers and clinical outcome was determined. RESULTS: All 16 cases met the histologic criteria for SCCC. Fourteen of 16 tumors (88%) stained positive for neuroendocrine differentiation. Eleven of 16 patients (69%) died from disease with a median survival of 19 months; there were 3 long-term survivors (greater than 5 years). CGR was positive in 8 (50%) specimens and was found to be highly predictive of death (P = 0.001). Complete loss of p53 protein was seen in 8 patients, 7 of whom died with a median survival of 20 months. CONCLUSION: Immunohistochemistry can be helpful in confirming difficult cases of SCCC. Further studies are necessary to define molecular markers that may be predictive of outcome in patients with SCCC. PMID- 11606075 TI - Are endometrial carcinoma cells disseminated at hysteroscopy functionally viable? AB - OBJECTIVE: The aim of this study was to evaluate the rate of transtubal dissemination of endometrial carcinoma cells by hysteroscopy and the functional viability of disseminated tumor cells by assessing cell adhesion in an in vitro model. METHODS: We studied 24 uteri obtained at TAH+BSO in patients with endometrial carcinoma. Further inclusion criteria were negative peritoneal cytology, no involvement of the uterine serosa or extrauterine disease, and endometrial surface involvement >1 cm in diameter. In vitro fluid hysteroscopy was performed with a 5-mm single-flow rigid hysteroscope. A maximum of 150 ml saline was infused at a maximum pressure of 100 mm Hg for a maximum of 3 min. Fluid running off through the tubes was collected. The cell suspension was enriched by a density gradient centrifugation. The isolated cells had a mean viability of 90% as judged by trypan blue exclusion. Viable cells (5 x 10(4) per 2-cm(2) polyvinyl chloride well plate) were cultured with equal parts of Dulbecco's modified Eagle's minimal essential medium and Ham's F-12 for 24 h. The endpoint of the analysis was the adherence of tumor cells to the polyvinyl chloride well plate, which was taken as a proxy for functional cell viability. Cytological evaluation was performed separately by two cytologists blinded to the source and date of the smears. RESULTS: Transtubal fluid dissemination was seen in 20 of 24 (83%) uteri. Tumor cells were found in 17 specimens (71%). In 10 (42%) specimens the disseminated tumor cells were functionally viable. CONCLUSIONS: Our model suggests that hysteroscopy can cause dissemination of malignant cells into the abdominal cavity from uteri containing endometrial carcinoma and that these cells can be functionally viable and adhere to a matrix. PMID- 11606076 TI - CD44 mediates constitutive type I receptor signaling in cervical carcinoma cells. AB - OBJECTIVE: The CD44 transmembrane glycoprotein family has been implicated in the growth and metastasis of numerous human cancers. CD44 may function in some cells through interactions with type I receptor tyrosine kinases, including erbB2. Here, we tested whether CD44 interacts with erbB2 and another type I receptor, the epidermal growth factor receptor (EGFR), in human cervical carcinoma tissues and cell lines and whether these interactions influence erbB2 signaling. METHODS: CD44, EGFR, and erbB2 colocalization were examined in 36 pT1b-pT2b cervical cancer cases and in the CaSki and SiHa cervical carcinoma cell lines by immunohistochemistry and laser scanning confocal microscopy. The role of CD44 EGFR-erbB2 interactions in erbB2 signaling was examined by immunoprecipitation and using antisense CD44 oligonucleotides. RESULTS: CD44, erbB2, and EGFR coexpression and colocalization were observed in 42% (15/36) of cervical carcinoma cases and in both cervical carcinoma cell lines. Colocalization occurred to an equivalent extent in all tumor grades examined. CD44 coimmunoprecipitated with erbB2 and EGFR in cervical carcinoma cell lysates, indicating that these proteins interact with each other. Reduction of CD44 expression inhibited constitutive erbB2 activity. High CD44 expression was linked to EGFR activity using dominant negative EGFR, suggesting that type I receptors may autoregulate their activity in these cells. CONCLUSIONS: Our data indicate that CD44 can mediate type I receptor function in cervical carcinoma cells that overexpress both CD44 and either erbB2 or EGFR and suggest a novel mechanism by which these proteins may contribute to cervical carcinoma tumor growth and metastasis. PMID- 11606077 TI - Cytokine profile of cervical cancer cells. AB - OBJECTIVE: In patients with cervical carcinoma, the presence of cytokines produced by T(H)2 cells, and the presence of an eosinophilic inflammatory infiltrate, has been associated with a less effective immune response and tumor progression. In the present study, we have investigated the cytokine profile of cervical carcinoma cells. In addition, we have measured whether differences in cytokine profiles between normal and malignant cervical epithelial cells are present. METHODS: For this purpose we have determined the mRNA expression patterns of 20 relevant cytokines by RT-PCR and Southern blotting in 3 normal primary cervical epithelial cell cultures (NPE) and 10 cervical cancer cell lines (CCCL). RESULTS: TGF-beta(1), IL-4, IL-12p35, and IL-15 were produced by all CCCL and NPE. TNF-alpha, IL-10, IL-5, and RANTES were present in most NPE, but not in any of the CCCL. MCP-1 was expressed in all CCCL but in only one NPE. The presence of the anti-inflammatory cytokine TGF-beta(1) in cervical carcinomas was confirmed by RNA in situ hybridization on tissue sections of carcinomas from which the CCCL originated. CONCLUSIONS: Our results suggest that cervical carcinoma cells produce immunomodulatory cytokines and that cytokine expression patterns change after malignant transformation. The implications of locally produced cytokines by cervical cancer cells are further discussed. PMID- 11606078 TI - Downregulation of KAI1 metastasis suppressor protein is associated with a dismal prognosis in epithelial ovarian cancer. AB - OBJECTIVES: The aim of this study was to investigate the impact of downregulation of KAI1 metastasis suppressor protein in epithelial ovarian cancer. In addition, correlation of KAI1 and p53 immunostaining was investigated. METHODS: Expression of KAI1 and p53 was immunohistochemically determined in 107 specimens of epithelial ovarian cancer stages I-IV. Survival of patients was investigated using uni- and multivariate analysis. RESULTS: Strong KAI1 expression was observed in 17.8% of cases, moderate in 27.1%, weak in 21.5%, and complete loss of KAI1 expression in 33.6%. Overexpression of p53 protein was observed in 45.8%. There was correlation of KAI1 expression neither with p53 expression nor with various clinical and histopathological parameters. Serous ovarian cancers showed significantly decreased staining intensity of KAI when compared to other histological types (P = 0.007). Univariate and multivariate analysis revealed that patients with strong or moderate expression of KAI1 had a significantly longer overall (P = 0.0013) and disease-free survival (P = 0.0048) when compared to those with low or absent expression. CONCLUSION: KAI1 downregulation is an independent prognostic factor in epithelial ovarian cancer, indicating dismal prognosis. Our study did not reveal a correlation between p53 status and KAI1 expression, suggesting that p53-independent mechanisms might be involved in the downregulation of KAI1. PMID- 11606079 TI - Expression of cell cycle proteins in ovarian carcinoma cells in serous effusions biological and prognostic implications. AB - OBJECTIVE: The aim of this study was to investigate the expression of cell cycle proteins in ovarian carcinoma cells in serous effusions and respective solid tumors. METHODS: Fifty-five malignant effusions and 38 tumors (20 primary, 18 metastatic) were immunohistochemically stained for cyclin A, p27(kip1), and Ki 67. Staining extent (0-100% cells) and intensity (0-3 scale) were scored. Cyclin A and p27(kip1) expression was additionally studied in 29 malignant effusions using immunoblotting. Immunohistochemistry results in effusions were evaluated for possible association with clinicopathologic parameters. RESULTS: Nuclear immunoreactivity for all markers was detected on carcinoma cells in the majority of effusions using immunohistochemistry. Similarly, immunoblotting showed the presence of cyclin A and p27(kip1) in 29/29 and 25/29 specimens, respectively. Intense (3) immunoreactivity for Ki-67 was detected more often in peritoneal effusions, compared with those of pleural location (P = 0.036). Staining in primary and metastatic lesions was generally comparable to that of tumor cells in effusions. Staining for p27(kip1) was more diffuse in effusion specimens obtained prior to the institution of chemotherapy (P = 0.042). In an analysis of all effusions, an association was observed between the number of cells that were immunoreactive for Ki-67, cyclin A, and p27(kip1) (cyclin A-Ki-67: P = 0.008; p27(kip1)-Ki-67: P = 0.019; cyclin A-p27(kip1): P = 0.032). In survival analysis, the presence of more diffuse (P = 0.042) and intense (P = 0.019) staining for cyclin A correlated with prolonged overall survival. CONCLUSIONS: The expression of the studied cell cycle markers does not differ markedly between ovarian carcinoma cells in the pleural and peritoneal cavity, supporting our previous studies of several metastasis-associated molecules. The presence of cyclin-A positive cell populations is associated with a more favorable disease outcome, possibly due to the targeting of proliferating cells by chemotherapeutic agents. However, the decline in the fraction of p27(kip1)-positive cells in posttreatment specimens may point to additional mechanisms involved in this selection. PMID- 11606080 TI - Improved therapeutic index of lower dose topotecan chemotherapy in recurrent ovarian cancer. AB - OBJECTIVE: Topotecan (1.5 mg/m(2)) administered daily for 5 consecutive days of a 21-day cycle is an established chemotherapeutic regimen in recurrent ovarian cancer. However, noncumulative myelosuppression has limited its use by many clinicians. We sought to determine whether a lower dose of topotecan could provide comparable tumor activity and higher tolerability in pretreated ovarian cancer patients. METHODS: A retrospective chart review was conducted on recurrent ovarian, peritoneal, or fallopian tube cancer patients with measurable disease or elevated cancer antigen 125 levels (evaluable disease). Patients were treated with topotecan (1.0 mg/m(2)) given by 30-min intravenous infusion for 5 consecutive days every 21 days until disease progression or unacceptable toxicity. RESULTS: Treatment records from 37 women who had been treated with a median of 3 courses (range, 1 to 17) of lower dose topotecan were evaluated; all were evaluable for tolerability and 36 were evaluable for response. Patients had received a median of 3 (range, 1 to 6) previous treatments. The overall response rate was 22% (8/36); the response rates for patients with evaluable disease and measurable disease were 35.7 (5/14) and 13.6% (3/22), respectively. An additional 8 patients (22%) achieved stable disease. Grade 4 neutropenia, thrombocytopenia, and anemia occurred in 48.6, 5.4, and 5.4% of patients, respectively. Granulocyte colony-stimulating factor support was used in 37% of patients, including 5 who experienced febrile neutropenia. CONCLUSION: Topotecan at 1.0 mg/m(2) x 5 days every 21 days is active in platinum- and paclitaxel-resistant ovarian cancer, with significant improvements in hematologic toxicity. In heavily pretreated patients-topotecan can be safely given at reduced doses without apparent loss of efficacy. PMID- 11606081 TI - Neoadjuvant chemotherapy for patients younger than 50 years with high-risk squamous cell carcinoma of the cervix. AB - OBJECTIVE: To evaluate the response rate and toxicity and to improve survival, neoadjuvant chemotherapy (NAC) was utilized in patients younger than 50 years with locally advanced cervical squamous cell carcinoma. METHODS: Twenty-one patients were treated with preoperative NAC. Eligibility included patients with previously untreated stage IB or IIA with deep stromal invasion assessed by magnetic resonance imaging or bulky tumor or IIB squamous cell carcinoma who were younger than 50 years. The NAC consisted of cisplatin (60 mg/m(2)) on day 1, vinblastine (4 mg/m(2)/day) on days 1 and 2, and peplomycin (10 mg/day) on days 1, 8, and 15 (PVP). Treatment was repeated every 3 weeks for a total of two cycles. All 21 patients underwent radical hysterectomy following NAC. Postoperative radiotherapy was given to 18 patients. We used 21 patients who underwent radical hysterectomy and postoperative radiation therapy as a nonrandomized control group. RESULTS: The response rate for NAC was 86% (18/21). Two patients required discontinuation of PVP treatment after one administration because of grade 4 neutropenia and thrombocytopenia, and decreased carbon monoxide diffusion capacity, respectively. In the NAC group, stromal invasion was significantly reduced (P = 0.0103), and the incidence of lymph node metastasis was decreased. No patients had positive parametrial and vaginal margins. The overall 5-year survival rate was 84.0% in the NAC group, which was significantly better than that in the control group (58.9%) (P = 0.0434). CONCLUSIONS: NAC for younger patients with locally advanced cervical carcinoma is thought to be safe, well tolerated, effective, and useful for increasing operability, decreasing pathological risk factors, and improving survival. PMID- 11606082 TI - Paclitaxel in the treatment of carcinosarcoma of the uterus: a gynecologic oncology group study. AB - OBJECTIVE: The goal of this study was to estimate the clinical activity of paclitaxel in patients with persistent or recurrent carcinosarcoma of the uterus who have failed other treatments. METHODS: The Gynecologic Oncology Group (GOG) conducted a phase II study of paclitaxel 170 mg/m(2) (135 mg/m(2) in those with prior irradiation) intravenously every 3 weeks in patients with histologic confirmation of carcinoma and measurable disease who had failed appropriate local therapy. RESULTS: A total of 53 patients were entered into the study between September 1994 and January 1997; 44 patients were evaluable for response. The median age of the patients treated was 65 years (range: 38-79). Twenty-six patients had heterologous mixed mesodermal tumors (MMTs) and 18 patients had homologous tumors. A median of three courses were administered (range: 1-18). Fifteen patients had previous radiation therapy and 33 patients had failed prior chemotherapy. Eight patients (18.2%) had a response to paclitaxel: four patients had a complete response and four had a partial response. Neutropenia was the most common toxic effect. CONCLUSIONS: Paclitaxel had moderate activity in patients with carcinosarcoma of the uterus. The GOG is currently studying the combination of paclitaxel and ifosfamide versus ifosfamide alone for patients with advanced or recurrent carcinosarcoma of the uterus. PMID- 11606083 TI - Using a belly board device to reduce the small bowel volume within pelvic radiation fields in women with postoperatively treated cervical carcinoma. AB - OBJECTIVE: The purpose of this study was to attempt to reduce the small bowel volume in cervical cancer patients undergoing radiation therapy using the belly board device and a four-field technique. METHODS: From 1994 through 1997, twenty one patients with cervical cancer were referred to the University of Minnesota Medical Center and underwent surgical staging with or without radical hysterectomy followed by postoperative external beam radiotherapy for various indications including positive nodal disease (n = 11), lymph-vascular space invasion (n = 2), poor histology (n = 3), parametrial disease (n = 4), and positive vaginal margin (n = 1). RESULTS: The median age of the 21 patients was 42 years (25-54 years) and a median external beam pelvic radiation dose of 4775 cGy (range, 4200-5075 cGy) was administered. All patients were evaluated for amount of small bowel in the field in both the supine and prone positions, with and without the belly board device (BBD), using a four-field technique. With a full bladder, abdominal radiographs with contrast were obtained to evaluate the volume of small bowel within the radiation fields. In most patients, the BBD was effective at minimizing the amount of small bowel in the lateral fields, whereas a prone position on the treatment table (without the BBD) spared the most small bowel with the AP/PA fields. Therefore over a 2-day cycle, the most small bowel sparing was obtained with the patients treated prone on the BBD for the lateral fields on Day 1 and prone on the table for the AP/PA fields on Day 2. Patients had FIGO stage IB (n = 18), IA2 (n = 1), and IIA (n = 2). The median follow-up was 37 months (24-65 months). No significant acute gastrointestinal or genitourinary toxicity was experienced and no patients have experienced a bowel obstruction to date. CONCLUSIONS: The BBD may offer a means for positioning the mobile small intestine out of the radiation field and improving the tolerance of radiotherapy. The BBD provides a noninvasive technique for reduction of acute and chronic gastrointestinal morbidity. PMID- 11606084 TI - Intraoperative lymphatic mapping and sentinel node identification with blue dye in patients with vulvar cancer. AB - OBJECTIVE: To determine the effectiveness of intraoperative lymphatic with blue dye alone as a means of localizing sentinel nodes in patients with vulvar cancer. METHODS: All patients undergoing primary surgical treatment for vulvar cancer were eligible for this prospective study. Isosulfan blue dye was injected intradermally at the edge of the primary tumor closest to the adjacent groin. Bilateral dye injections and groin dissections were performed if the tumor was within 2 cm of the midline. RESULTS: Fifty-two patients were enrolled in the study between 1993 and 1999. The median age was 58 years. Eighty-seven percent of the patients had T1 or T2 lesions, and 92% had nonsuspicious lymph nodes on palpation. Sixty-seven percent of the patients had squamous cell carcinoma; the remaining patients had melanoma or adenocarcinoma. The sentinel node was identified in 46 of the 52 patients (88%), comprising 22 of the 25 patients with lateral tumors and 24 of the 27 patients with midline lesions. The sentinel node was successfully identified in 57 of the 76 (75%) dissected groins. Sentinel node identification in the groin was hampered by the effects of prior excisional biopsy vs punch biopsy (11 of 25 vs 8 of 51, P = 0.007) and by the lateral vs midline location of the tumor (22 of 25 groins vs 35 of 51 groins, P = 0.067). During the first 2 years (1993-1994), a sentinel node could not be identified in 4 of the 25 (16%) patients and 13 of the 36 (36%) groins dissected, compared with 2 of the 27 (7%) of patients treated and 6 of the 40 (15%) groins dissected from 1995 through 1999 (P = 0.034). A total of 556 nodes were removed (median, 7 per groin), of which 83 (median, 1 per groin) were sentinel. The sentinel node was not identified in 2 of the 12 groins that proved to have metastatic disease. Both events occurred in the first 2 years of the study. There were no false-negative sentinel nodes. Since 1995, we have successfully identified the sentinel node in 16 of the 16 patients (25 of 25 groins) with T1 or T2 primary lesions, squamous histology, and nonsuspicious groin nodes on physical examination. CONCLUSIONS: Experience and careful patient selection can permit sentinel node identification with blue dye injection alone in more than 95% of patients with vulvar cancer. PMID- 11606085 TI - Potential benefit of lymphadenectomy for the treatment of node-negative locally advanced uterine cancers. AB - OBJECTIVE: The aim of this study was to examine the outcomes in patients with high-risk Stage I endometrial cancers surgically staged by complete pelvic and para-aortic lymphadenectomy, with negative nodes, and treated with postoperative brachytherapy. METHODS: From the database of patients treated for Stage I endometrial cancer, 23 patients were identified with either >50% myometrial invasion or grade 3 histology treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy. All patients had no pathologic evidence of disease in the lymph nodes. These patients were then treated with brachytherapy and followed for treatment and cost outcomes. A comparison was made of the cost of treatment between brachytherapy and external beam radiation. RESULTS: All 23 patients with either grade 3 tumor or greater than 50% myometrial invasion were treated with total abdominal hysterectomy with lymphadenectomy followed by brachytherapy for lesions that did not extend outside the uterine specimen. For all patients in this series, there were no recurrences in the follow-up period (median 25 months). This regimen is more cost efficient and spares the patient from possible complications related to whole pelvic radiation, at an average cost savings of $4100. CONCLUSION: Women undergoing hysterectomy for endometrial adenocarcinoma with high-risk node negative disease confined to the uterus can be safely treated with brachytherapy, at a substantial cost savings, without compromising survival. PMID- 11606086 TI - The effect of bowel resection on survival in advanced epithelial ovarian cancer. AB - OBJECTIVE: FIGO stage III ovarian cancer is further categorized according to the size of tumor, but not according to the organs affected. In this study we evaluated the outcome of patients with and without macroscopic bowel involvement in stage III ovarian cancer. METHODS: This retrospective study analyzed the outcome of 194 ovarian cancer patients with FIGO III with and without bowel involvement who were operated on in our institution between 1985 and 1994. RESULTS: The study demonstrated that maximum tumor reduction without remaining macroscopic cancer offered the best overall survival times in FIGO III ovarian cancer patients. However, whenever the bowel was involved, even maximum bowel resections did not prolong survival compared to patients with remaining tumor after surgery. CONCLUSIONS: This retrospective study demonstrated that bowel involvement in ovarian cancer had a bad prognosis and that survival in these patients could not substantially be prolonged when the affected parts of bowel were resected. To further substantiate these findings, future studies on advanced ovarian cancer should differentiate between patients with and without bowel involvement. PMID- 11606087 TI - Expression and subcellular localization of the cyclin-dependent kinase inhibitor p27(Kip1) in epithelial ovarian cancer. AB - OBJECTIVE: To determine if p27(Kip1) expression was altered in epithelial ovarian cancers as compared to normal ovarian surface epithelial (NOSE) cells and to determine if subcellular localization of p27(Kip1) was an important feature. METHODS: Thirteen tumor samples (1 Stage IC [early] and 12 Stage III/IV [advanced]) from patients with epithelial ovarian cancer and five NOSE samples were evaluated. Samples were surgically dissected to obtain an enriched population (90%) of cancer cells. The level of p27(Kip1) protein expression was determined by Western blot analysis. Actin was used as a loading control, and results were quantified by scanning densitometry using the ratio of the p27(Kip1) signal to the actin signal for comparison. To evaluate the subcellular localization of p27(Kip1), immunocytochemical staining was performed. Clinical pathological parameters were correlated to nuclear p27(Kip1) staining to establish if any association existed. RESULTS: When comparing the expression of p27(Kip1) between NOSE and ovarian cancer samples, only 2 of 13 ovarian cancer samples had altered p27(Kip1) expression. No correlation was found between the expression level of p27(Kip1) on Western blot and clinical pathological correlates. While no correlation between expression level of p27(Kip1) and subcellular localization was found, decreased nuclear staining (1+) was associated with shorter survivals using the log-rank test (P < 0.001). More importantly, in all tumor samples examined under the microscope, no nuclear p27(Kip1) staining was noted in cells that were undergoing mitosis. CONCLUSIONS: p27(Kip1) protein degradation may not be modified in ovarian cancer cells undergoing mitosis. Altered expression of p27(Kip1) is not an overwhelming feature in certain epithelial ovarian cancers. Decreased nuclear staining of p27(Kip1) is associated with poor survival in some epithelial ovarian cancers. PMID- 11606088 TI - Comparison of conventional color Doppler imaging and power doppler imaging for the diagnosis of ovarian cancer: results of a European study. AB - OBJECTIVE: The purpose of this prospective study was to compare the diagnostic accuracy of conventional color Doppler (CCD) imaging and power Doppler (PD) imaging in the diagnosis of ovarian cancer. METHODS: Six hundred fifty-six consecutive women with adnexal masses scheduled for surgery in two European university departments of obstetrics and gynecology underwent preoperative transvaginal ultrasound. The scanning procedure was the same in the two institutions: after B-mode sonography, a CCD/PD imaging scan was performed before pulsed Doppler evaluation. Using both modalities of color Doppler, malignancy was suspected when arterial flow was visualized in an echogenic portion defined as malignant by B-mode. To avoid the risk of bias due to the absence of blindness of the examiner after the first Doppler evaluation, at one institution 328 consecutive women with an adnexal mass were evaluated using only CCD imaging, whereas at the second institution the ultrasonographic evaluation of the same number of masses was performed using PD imaging, and the results were compared prospectively. RESULTS: The age, the rate of postmenopausal women, and the rate of ovarian cancer were similar in the two institutions. The false-positive rate of B-mode imaging was similar in the two institutions (17 versus 18%), while the false-positive rates of CCD and PD imaging were 4.6 and 7.4%, respectively. Although the overall diagnostic accuracy of two techniques seems comparable, with a similar value of K (0.81 versus 0.84), a significantly lower sensitivity in differentiation of benign from malignant ovarian lesions was found using CCD (87 versus 100%). CONCLUSIONS: At least one of the two Doppler techniques should be used in conjunction with B-mode imaging in order to decrease the false-positive rate of B-mode used alone but CCD imaging showed a higher false-negative rate. PMID- 11606089 TI - The effect of radiation therapy on brain metastases from endometrial carcinoma: a retrospective study. AB - OBJECTIVE: The objective of this study was to investigate the effectiveness of radiation therapy as a treatment for brain metastases from endometrial carcinoma. METHODS: Between July 1985 and November 1999, 10 patients with brain metastases from endometrial carcinoma were treated at the Cleveland Clinic. We reviewed the patient and tumor characteristics at the time of the primary diagnosis and the brain metastases diagnosis. For the 8 patients who received radiation therapy with or without surgery, we analyzed the treatment results with regard to survival and local control of the metastases. RESULTS: Brain metastases from endometrial carcinoma were commonly accompanied by uncontrolled local-regional disease and systemic metastases. Multiple brain lesions developed in 7 of 10 patients. Two patients were treated with surgery alone and had a median survival of 2.75 months (4 and 1.5 months) after the brain metastases diagnosis. Three patients were treated with surgery and radiation therapy and lived for a median survival of 15 months (range 11.5 to 15.5 months). The 5 patients who were treated with radiation therapy without surgery had a median survival of 2.4 months (range 0.25 to 6 months). Patients with multiple brain metastases had a shorter survival than patients with a single metastasis. CONCLUSION: Overall survival after brain metastases development in patients with endometrial carcinoma was poor. Although the number of patients was small, radiation therapy alone resulted in poor survival. Combination treatment with surgery and radiation therapy may improve survival for selected patients. PMID- 11606090 TI - 2-[Fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography in the diagnosis of recurrent ovarian cancer. AB - OBJECTIVE: The aim of the study was to investigate the role of 2-[fluorine-18] fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) in the diagnosis of recurrent ovarian cancer. METHODS: One hundred six FDG PET scans performed in 54 patients in the follow-up after cytoreductive surgery and chemotherapy of ovarian cancer were reevaluated. Fifty-eight scans were performed in patients with suspected recurrence and 48 scans in patients who were clinically disease free. Thirty-seven PET scans were validated by histology and 66 studies by a median follow-up of 22 months in disease-free patients or 12 months in patients with recurrent disease. Three scans were validated by concordant positive findings of tumor marker CA125, computed tomography, and FDG PET. RESULTS: FDG PET correctly identified recurrent disease in 73/88 cases. PET ruled out recurrent disease in 15/18 cases. The sensitivity and specificity for PET were 83 and 83%, respectively. In patients with suspected disease, sensitivity was 94% compared to 65% in patients judged clinically disease free. The sensitivity of PET was 96% if suspicion of recurrence was based on a rise of CA125 alone. PET preceded the conventional diagnosis by a median of 6 months in patients judged clinically free of disease. The median relapse-free interval after a negative PET scan was 20 months. CONCLUSION: FDG PET provides the chance to detect recurrent ovarian cancer at an earlier stage during follow-up. Patients with a negative PET scan have a longer relapse-free interval than patients with a positive PET scan. PMID- 11606091 TI - The kinetics of leptin in Meigs' syndrome. AB - OBJECTIVE: The aim of this study was to assess the kinetics and possible role of leptin in the pathophysiology of Meigs' syndrome. METHODS: We report on a 62-year old patient admitted for a large ovarian tumor, hydrothorax, and ascites. The patient underwent abdominal hysterectomy and bilateral adnexectomy revealing a benign ovarian fibroma and no evidence of malignant cells in the pleural or peritoneal fluids. Analysis of serum, peritoneal, and pleural fluids from this patient was performed before, during, and after the operation. RESULTS: Preoperatively, the patient had low levels of leptin in the serum, peritoneal, and pleural fluids. Serum levels increased after removal of the ovarian tumor along with the resolution of ascites and hydrothorax. CONCLUSION: Leptin levels inversely correlate to tumor burden, third space fluid accumulation, and clinical status in Meigs' syndrome. These findings suggest the involvement of leptin in the pathophysiology of this syndrome. PMID- 11606092 TI - Is there a place for a less extensive radical surgery in locally advanced cervical cancer patients? AB - OBJECTIVE: The aim of this study was to assess the association among the pathological status of different lymph node groups and parametrium in a single institutional population of 103 locally advanced cervical cancer (LACC) cases who underwent surgery after a neoadjuvant approach. A series of 29 early cervical cancer patients was also included in the analysis. METHODS: Eighty-two LACC patients with documented clinical response to neoadjuvant treatment and 29 early stage cases underwent radical surgery. The operative technique consisted of a type II-V radical hysterectomy and systematic pelvic lymphadenectomy (median number of lymph nodes removed 46; range 5-140). Sixty-four cases were submitted to para-aortic lymphadenectomy up to the level of the inferior mesenteric artery (median number of lymph nodes removed 13; range 1-37). RESULTS: Two subgroups of lymph nodes were defined: lower pelvic lymph nodes (LPN), including obturator and external iliac nodes, and upper pelvic nodes (UPN) including common iliac, presacral, and internal iliac nodes. Metastatic UPN involvement showed a strict association with LPN involvement: in LACC cases, 6 of 7 (86%) positive UPN cases had tumor disease at the LPN level. The single positive UPN case with negative LPN was intraoperatively identified by palpation and frozen section. Similarly, in early cervical cancer patients, 100% of positive UPN cases showed metastatic involvement at the LPN level. Sixty-three of 70 (90%) LACC patients with negative histological parametrium had negative LPN. Among 12 cases with metastatic involvement of parametrium, 5 cases (41.7%) had positive LPN. In early stage cervical cancer, 23 of 27 (85%) cases with negative parametrium showed no lymph nodal involvement. Intraoperative palpation of the parametrium could identify all cases with parametrial involvement not predicted by LPN status. CONCLUSIONS: These data offer the basis for tailoring the extent of radical surgery in LACC patients, through the selection of those lymph node stations likely to provide reliable information on the pathological status of UPN and parametrium. PMID- 11606093 TI - Expression of serine proteinase inhibitor PP5/TFPI-2/MSPI decreases the invasive potential of human choriocarcinoma cells in vitro and in vivo. AB - OBJECTIVE: PP5/TFPI-2/MSPI is a Kunitz-type serine proteinase inhibitor with broad inhibitory spectra, abundantly produced by placenta and detected in the blood of pregnant women. Expression of PP5/TFPI-2/MSPI is exclusively detected in syncytiotrophoblasts of placenta, but is barely detectable in choriocarcinoma cells, a trophoblast-derived malignant tumor. Chromosome 7, in which the PP5/TFPI 2/MSPI gene is localized, is frequently lost in various types of tumors. We attempted to elucidate the relation between PP5/TFPI-2/MSPI expression and the malignant properties of choriocarcinoma cells. METHODS: Human choriocarcinoma cells, JAR, were transfected with either a human PP5/TFPI-2/MSPI expression vector or an empty vector, and stable clones were obtained. Messenger RNA expression, protein secretion/localization, growth rate, and plating efficiency were evaluated. In vitro migration and invasive activity were determined by transwell chamber experiments. In vivo tumor growth was evaluated by the subcutaneous injection of cells to nude mice and followed by histological examination. RESULTS: Expression of mRNA and protein of PP5/TFPI-2/MSPI were confirmed, and a high producing clone and a low producing clone were chosen for further analysis. The majority of secreted PP5/TFPI-2/MSPI protein was revealed to associate with the extracellular matrix. Expression of PP5/TFPI-2/MSPI did not affect the growth and migration of the tumor cells, but enhanced their plating efficiency. Its expression significantly inhibited invasion through the Matrigel. Invasive growth into the subcutaneous muscle layer was not evident in the nude mouse tumors of the PP5/TFPI-2/MSPI-expressing cells. CONCLUSION: PP5/TFPI-2/MSPI expressing choriocarcinoma cells showed suppressed potential of invasion in vitro and in vivo. It is suggested that loss or suppression of PP5/TFPI-2/MSPI expression may result in the acquisition of invasiveness in choriocarcinoma cells. PMID- 11606095 TI - Novel MUC1 splice variants are expressed in cervical carcinoma. AB - OBJECTIVES: The MUC1 antigen can be used to identify epithelial cells from the background of hemopoietic cells. The present investigation describes patterns of overexpression of two novel MUC1 splice variants in human cervical carcinoma cell lines. METHODS: RT-PCR was carried out to determine MUC1 splice variants in the cervical cancer cell lines C-4 II, C-33A, DoTc 2 4510, C-4 I, SiHa, HT3, Hs 636 T (C4-I), and HeLa. RESULTS: The novel MUC1 splice variant D was expressed in all cell lines and the novel MUC1 splice variant C was expressed in all cell lines but C-33A. Variants A and B were expressed in all (variant A) and all but one (variant B) cell line. MUC1/REP was expressed in all cell lines and MUC1/SEC was positive in all but two cell lines (C-33 A, DoTc 2 4510). All but one cell line (C-33A) expressed MUC1/X and MUC1/Y, and two cell lines (C-33 A, DoTc 2 4510) did not express MUC1/Z, respectively. MUC1 variants A, D, and REP could be demonstrated consistently among all eight cervical carcinoma cell lines we have examined. CONCLUSIONS: The present study describes the feasibility of detecting a large number of MUC1 variants, including MUC1 variants C and D which are described for cervical carcinoma cells for the first time. Further studies will examine the presence of MUC1 splice variants' expression in human cervical carcinoma tissue. PMID- 11606094 TI - Predictive value of the ATP chemosensitivity assay in epithelial ovarian cancer. AB - OBJECTIVE: The aims of this study were to define the specific parameters of the ATP chemosensitivity assay which most accurately predict a patient's clinical response to chemotherapeutic agents in epithelial ovarian cancer and to assess the clinical utility of the ATP assay. METHODS: In our laboratory from 1992 to 1994, fresh tumor specimens from patients with epithelial ovarian carcinomas were assayed with the ATP chemosensitivity assay (ATP-CSA) for their in vitro responses to several chemotherapeutic agents including cisplatin, paclitaxel, and cyclophosphamide. Clinical data on 161 of those patients including all follow-up assessments were then collected, and an investigator blinded to the in vitro assay results determined the patients' responses to chemotherapy. In order to determine which parameter of the assay was the best predictor of clinical response for each drug, receiver-operator characteristic (ROC) curves were constructed for several parameters, including the amount of cell kill at particular dosage levels of drug, the slope of the dose-response curve, and the IC50, or the average concentration of drug at which 50% of the cells were nonviable. RESULTS: The specific parameter of the ATP-CSA which was most predictive of clinical response differed for each drug tested. The resulting positive predictive values for cisplatin, cyclophosphamide, and paclitaxel ranged from 70.0 to 78.3% and negative predictive values from 46.2 to 60.9%, with overall ATP-CSA positive and negative predictive values of 83.0 and 56.5%. Overall, patients whose tumors tested sensitive to an agent in vitro were almost twice as likely (83% versus 43%) to show a clinical response (RR 1.91, 95% CI 1.34-2.71). CONCLUSION: Analysis of the ROC curves in this study shows that different parameters of the ATP-CSA need to be utilized for each drug tested in order to give the best prediction of clinical chemosensitivity. Although the ATP CSA shows predictive ability, routine use of the ATP-CSA for clinical selection of drug therapy in patients with epithelial ovarian cancer would not be warranted without a prospective study comparing chemotherapy treatment based on assay results versus clinician selection of drug. PMID- 11606096 TI - p53 and p21 expression in precancerous lesions and carcinomas of the uterine cervix: overexpression of p53 predicts poor disease outcome. AB - OBJECTIVES: Abnormal expression of the p53 and p21(waf1/cip1) tumor suppressor genes has been observed in a variety of human tumors, but little is known about its expression during cervical tumorigenesis. To identify the potential implications of both genes in the development of cervical carcinoma and explore the clinical importance of changes in gene expression, we assessed the levels of both proteins in precancerous lesions and carcinomas of the cervix. METHODS: In our study, 10 low-grade squamous intraepithelial lesions (LSIL), 35 high-grade squamous intraepithelial lesions (HSIL), 12 microinvasive carcinomas, and 103 invasive carcinomas were evaluated. The expression of p53 and p21 was studied by immunohistochemistry using monoclonal antibodies specific for these proteins. RESULTS: p21 was expressed in all samples of normal epithelium, LSIL, and HSIL, and the mean values of expression were 50.3, 42.5, and 44.5%, respectively. Conversely, the expression of p21 was significantly reduced in microinvasive (30.7%) and invasive carcinomas (9.9%). p53 nuclear staining was not detected in normal epithelium samples or LSILs, while 4 (11.4%) of 35 HSILs, 1 (8.3%) of 12 microinvasive carcinomas, and 38 (36.9%) of 103 invasive carcinomas were positive for p53. Compared with the results of the control group, precancerous lesions, and microinvasive carcinoma, the mean value of p53 expression (4.8%) in invasive carcinoma was significantly higher. Furthermore, p53 overexpression was significantly associated with advanced stage of the tumor (P < 0.001) [16/67 (23.9%) stage I, 15/28 (53.6%) stage II, and 7/8 (87.5%) stage III/IV]. In univariate analysis, p53 overexpression was a significant predictor of poor survival, whereas it had no independent influence on overall survival using the Cox regression method. Our data also revealed that no association between p53 immunostaining and p21 expression was found. CONCLUSIONS: The trend of reduced p21 expression in microinvasive and invasive carcinomas suggests that p21 may play a tumor-suppressor function in neoplastic transformation in cervical epithelium and inactivation of p21 may be an early event in cervical carcinogenesis. Our results indicated that p53 overexpression was a significant predictor of poor disease outcome in univariate analysis. Moreover, significantly increased expression of p53 in advanced-stage cervical carcinoma implies that inactivation of p53 is associated with tumor progression. Finally, this study further supports the notion that induction of p21 expression can be regulated in a p53-independent manner. PMID- 11606097 TI - Simultaneously detected endometrial and ovarian carcinomas--a prospective clinicopathologic study of 74 cases: a gynecologic oncology group study. AB - OBJECTIVES: The coexistence of carcinomas of the endometrium and ovary occurs in about 10% of women with ovarian carcinoma. It is often unclear whether this represents synchronous primary tumors or metastasis from endometrium to ovary, or from ovary to endometrium; consequently, staging, therapy, and expected outcome are uncertain. The Gynecologic Oncology Group sought to study patients with simultaneously detected adenocarcinomas in the endometrium and ovary with disease grossly confined to the pelvis to explore the possible correlation among discrete tumor subsets, natural history, and survival. METHODS: Between 1985 and 1991, 85 patients were prospectively enrolled, of whom 74 were eligible. All were initially treated with total abdominal hysterectomy, bilateral salpingo oophorectomy, and staging laparotomy, with radiation and chemotherapy left to the discretion of the treating physician and patient. Fifteen pathologic variables were examined to identify differences in tumor behavior. RESULTS: Of the 74 patients, 23 (31%) had microscopic spread of tumor in the pelvis or abdomen. Sixty-four (86%) patients had endometrioid carcinomas in both the endometrium and the ovary, and endometriosis was found in the ovary of 23 (31%) patients. There was concordance between the histologic grade of the tumor in the ovary and the uterus in 51 (69%) patients. The estimated probability of recurrence 5 years following staging surgery is 15.1% (95% confidence interval (CI): 8.7-25.2%). The presence of metastasis discriminated two groups of patients that experienced different probabilities of recurrence within 5 years: 10.0% (95% CI: 4.32-21.3%) for those with tumors confined to the uterus and ovary and 27.1% (95% CI: 13.0 48.5%) for those with metastasis (hazard ratio = 4.6, P = 0.006). The histologic grades of ovarian and uterine tumors also distinguished groups of patients with different probabilities of recurrence at 5 years: 8.0% (95% CI: 2.8-21.3%) for those patients with no more than grade 1 disease at either site and 22.4% (95% CI: 11.8-38.4%) for those with a higher grade in either the ovary or the endometrium (hazard ratio = 3.1, P = 0.047). The estimated overall probability of surviving 5 years is 85.9% and that of surviving 10 years is 80.3%. CONCLUSION: The prognosis for women with simultaneously detected carcinomas in the uterus and ovary with gross disease confined to the pelvis is surprisingly good, particularly for those with disease microscopically limited to the uterus and ovary or of low histologic grade. PMID- 11606098 TI - Clinical features and risk of recurrence among patients with vaginal intraepithelial neoplasia. AB - OBJECTIVE: The best treatment modality and factors affecting recurrence among women with vaginal intraepithelial neoplasia (VAIN) are yet to be determined. The aims of the current study were to describe the clinical features, results of treatment, and factors affecting recurrence among patients with VAIN. METHODS: We conducted a retrospective review of 121 women with VAIN after confirming the histologic diagnosis. Patient demographics, clinical features, and results of therapy were recorded. Factors affecting recurrence were assessed using the odds ratio and the 95% confidence intervals among patients who were followed up for 7 months or more and had at least one posttreatment Papanicolaou smear. Significant univariate odds ratios were assessed jointly in a multivariate model with a stratified analysis. RESULTS: The mean age of the patients was 35.0 (+/-17), 41% of the patients smoked, 39% had a history of human papillomavirus infection, 27% had history of sexually transmitted diseases, 22% had history of surgery for cervical intraepithelial neoplasia (CIN), and 23% had total hysterectomy. The upper third of the vagina was the most common site of VAIN and 61% of the lesions were multifocal. Associated cervical and vulvar intraepithelial neoplasia (VIN) were present in 65 and 10%, respectively. Recurrences of VAIN and progression to invasive vaginal cancer occurred in 33 and 2%, respectively. Recurrences following partial vaginectomy, laser, and 5-fluorouracil were 0, 38, and 59%, respectively (P = 0.0001). Multifocality and method of treatment were significant independent predictors of VAIN recurrences (odds ratio 3.3, 95% CI 1.2, 9.2, P = 0.02, and 22.4, 95% CI 1.3, 393.6, P = 0.001, respectively), with no interaction, based on a stratified analysis. CONCLUSIONS: VAIN occurs most often among women with CIN or VIN, commonly involves the upper third of the vagina, and is often multifocal. Partial vaginectomy provides the highest cure rate and multifocality is a risk factor for recurrence. PMID- 11606099 TI - Bax-induced apoptosis as a novel gene therapy approach for carcinoma of the cervix. AB - OBJECTIVE: The transfer of tumor suppressor genes has been shown to revert the malignant phenotype. In this regard, bax is a pro-apoptotic molecule that also functions as a tumor suppressor. The purpose of this study was to evaluate bax as a gene therapeutic in the context of cervical cancer. METHODS: Efficiency of viral transduction in cervical cancer cell lines and primary cervical cancer cells was evaluated with an adenoviral vector encoding green fluorescent protein and luciferase, respectively. We generated a recombinant adenoviral vector that encodes the bax gene under inducible conditions. To this end, expression of this pro-apoptotic gene was controlled by a Cre-LoxP system. Following infection with the recombinant bax adenovirus, the viability of cervical cancer cell lines and primary cervical cancer cells was evaluated using crystal violet staining and FACS analysis. Apoptotic cell death was monitored using annexin V staining. RESULTS: High levels of viral infection were observed in all cervical cancer cell lines (>85%) and primary cervical cancer cells. Significant cytotoxicity was seen in all cervical cancer cells lines and, more importantly, patient-derived primary cervical cancer cells. Moreover, bax-mediated cell death occurred via an apoptotic pathway. CONCLUSIONS: Our results indicate that a bax recombinant adenoviral vector causes cell death mediated via an apoptotic pathway in multiple cervical cancer cell lines and primary cervical cancer cells. These data suggest that bax may be a candidate for human gene therapy in the setting of cervical carcinoma. PMID- 11606100 TI - The implementation of critical pathways in gynecologic oncology in a managed care setting: a cost analysis. AB - OBJECTIVES: The aim of the study is to determine whether critical pathways can be implemented at an academic institution to limit cost, without compromising patient satisfaction and quality of care. PATIENTS AND METHODS: Patients undergoing a hysterectomy with either cervical or endometrial cancer were placed on specific critical pathways consecutively for an 18-month study period. Preoperative teaching was intensified to educate the patient regarding expectations during the postoperative period. All patients were started on early feeding and patients were also placed on separate care pathways addressing pain and deep vein thrombosis prophylaxis. Total direct costs and patient satisfaction were obtained throughout the study period. During the year prior to care pathway implementation, patient data and direct costs were obtained for the preintervention group utilized for comparison. Postintervention groups were summarized every 6 months during the study period. RESULTS: From January 1997 through June 1998, 63 patients with cervical carcinoma undergoing a radical hysterectomy (DRG 353) and 21 patients with endometrial cancer who underwent a hysterectomy and lymph node sampling (DRG 355) were utilized as the preintervention group. During the 18-month study period (July 1998-December 1999), 42 patients (DRG 353) and 25 patients (DRG 355) were accrued. The average length of stay was reduced from 5.2 (DRG 353) and 4.7 days (DRG 355) prior to implementation of pathways to 3.4 days in both groups. In addition, total direct costs were reduced by 29 (DRG 353) and 32% (DRG 355) after implementation of care pathways. Patient satisfaction data recorded during the study did not demonstrate any change throughout the study period nor were there any higher rates of readmission after implementation of the care pathways. CONCLUSIONS: Critical pathways in gynecologic oncology can be implemented in a managed care environment in order to maintain high quality of care, maintain outcomes, and help reduce costs. PMID- 11606101 TI - Germline BRCA1-2 mutations in non-Ashkenazi families with double primary breast and ovarian cancer. AB - OBJECTIVE: Ashkenazi women with double primary breast and ovarian cancer have a high prevalence (57%) of germline Jewish founder mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes. The purpose of this study was to determine the frequency and type of BRCA1-2 mutations in non-Ashkenazi families with at least one member having double primary breast and ovarian cancer. METHODS: Women at increased risk for cancer based upon their family history were enrolled at the University of Texas Southwestern Familial Cancer Registry between 1992 and 2000. Blood samples from patients desiring genetic testing were sent for complete DNA sequencing of the BRCA1 and BRCA2 genes. Families with a member having both breast and ovarian cancer were identified and clinical data were obtained. RESULTS: Sixty-two (7%) of 900 enrolled families were non-Ashkenazi and had at least one member with double primary breast and ovarian cancer. Twenty-one families had members who underwent genetic testing; 41 did not. Thirteen (62%) families had a germline BRCA1 (n = 11) or BRCA2 (n = 2) mutation; only one Jewish founder mutation (185delAG) was detected. Eight (38%) families tested negative. Six (86%) of seven women undergoing genetic testing who themselves had double primary breast and ovarian cancer were BRCA1-2 mutation carriers. CONCLUSIONS: Germline BRCA1-2 mutations are common in non-Ashkenazi families with a member having double primary breast and ovarian cancer. These mutations occurred throughout both genes, emphasizing the need for comprehensive sequencing. One family had the BRCA2 6985delCT mutation, which lies beyond the "ovarian cancer cluster" region. PMID- 11606102 TI - Endometrial cancer in women 40 years old or younger. AB - OBJECTIVE: The aim of this study was to characterize endometrial cancer in women 40 years of age and younger, with special attention toward body-mass index (BMI). METHODS: A retrospective review of women age 40 and under with endometrial cancer was performed. Patients were identified via tumor registry data as well as a search of pathology department diagnoses over the dates 1980-1998. Data were abstracted regarding tumor grade and histology, stage, treatment, smoking, use of oral contraceptives, BMI, medical and family history, parity, and survival. Data were also collected with regard to uterine conservation and pregnancies following endometrial cancer diagnoses. RESULTS: Ninety-five patients were identified. The age range was 24-40 years (median 37) with BMI ranging from 17.5 to 63.6 (median 28.4). Forty-eight patients (52%) were not obese, with BMI < 30. Seventy-six patients (80%) had stage I disease and 60 patients (63%) had grade 1 disease. All but 4 patients had endometrioid histology. Women with BMI < 25 were more likely to have advanced disease (P = 0.04) and more likely to have high-risk histology (P = 0.02). Of the 4 patients with high-risk histology (clear cell or serous papillary), all had BMI < 25. Twelve patients were treated medically rather than surgically, and 4 patients achieved pregnancy, with 5 live births. CONCLUSION: Women under 40 who are not obese are at higher risk of both advanced disease and high-risk histology. Further study at the molecular and genetic level is ongoing in our laboratory to determine whether the mechanism of disease is different in slender woman. PMID- 11606103 TI - A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients. AB - OBJECTIVE: Topotecan is an established topoisomerase I inhibitor for the treatment of relapsed ovarian cancer. Myelotoxicity and suboptimal patient convenience associated with daily topotecan, however, have prompted investigators to explore alternate regimens, including a weekly regimen of topotecan. The objective of this study was to determine the maximum tolerated dose (MTD) of topotecan given as a weekly bolus in previously treated ovarian cancer patients. METHODS: Second- and third-line ovarian cancer patients with measurable disease or elevated cancer antigen 125 received weekly bolus topotecan intravenously starting at 1.5 mg/m(2). Topotecan was escalated in dose increments of 0.5 mg/m(2) every 21 days as tolerability allowed. Dose-limiting toxicity was defined as grade 3/4 neutropenia or thrombocytopenia. RESULTS: Thirty-two of 35 patients were evaluable for safety and tolerability. No notable toxicity was observed with weekly topotecan doses < 4 mg/m(2). Additionally, there was an absence of dose limiting myelotoxicity and thrombocytopenia with weekly topotecan. The MTD of weekly topotecan without the use of granulocyte colony-stimulating factor support was 4 mg/m(2), with grade 2 anemia, chronic fatigue, and grade 2 gastrointestinal toxicity limiting further dose escalation. Weekly topotecan also demonstrated antitumor activity at doses >2 mg/m(2). CONCLUSIONS: The establishment of a well tolerated, weekly regimen of topotecan (4 mg/m(2), with a maximum recommended dose of 6 mg/m(2)) provides the basis for further investigation in phase II studies of single-agent and combination regimens in previously treated ovarian cancer patients. PMID- 11606104 TI - Bone metastasis from a granulosa cell tumor of the ovary. AB - BACKGROUND: Granulosa cell tumors (GCT) of the ovary generally have a good prognosis. Recurrences tend to be late and are usually abdominopelvic. Bone metastases are extremely rare. CASE: A case of recurrent GCT with vertebral metastasis is presented. Radiologic studies were helpful in documenting the presence of an invasive tumor destroying the vertebral body of T7. Bone scintigraphy excluded other metastatic sites. Diagnosis could not be established by CT-scan-directed fine-needle aspiration cytology or trocar biopsies. Since the lesion was isolated and resectable, aggressive surgery with complete tumoral excision was performed followed by local radiation therapy. Megestrol acetate was given as systemic treatment. CONCLUSION: Multiple treatments of GCT may alter the pattern of recurrence. Every symptom should be thoroughly evaluated. Bone metastases may be treated aggressively. PMID- 11606105 TI - Hyalinizing spindle cell tumor with giant rosettes of the broad ligament. AB - BACKGROUND: Hyalinizing spindle cell tumor with giant rosettes (HSTGR) is a rare, recently described tumor that most commonly occurs in the peripheral deep soft tissues. CASE: A 53-year-old woman was operated on because of a mass in the broad ligament which was first noted 17 years previously. The tumor showed typical features of HSTGR. Two years after surgery, the patient is alive with no evidence of disease. CONCLUSIONS: To our knowledge, the present case is the first description of HSTGR occurring in the broad ligament. Despite its bland morphology, HSTGR is a low-grade sarcoma, most probably a variant of low-grade fibromyxoid sarcoma. A wide resection of the tumor and prolonged follow-up are needed because patients may develop late metastases. PMID- 11606106 TI - Villoglandular adenocarcinoma of the vulva. AB - BACKGROUND: Only two previous cases of villoglandular adenocarcinoma of the vulva, an entity morphologically similar to tumors found in the uterine cervix and colorectum, have been reported. This paper communicates the first complete immunohistochemical study in villoglandular adenocarcinoma in order to determine its phenotype and histogenesis. CASE: A 69-year-old woman had a 1.5-cm nodule in the right labium majus. Histologically, it corresponded to a minimally atypical, villoglandular adenocarcinoma with a small microinvasion. Immunohistochemically, it was positive to OC125, CEA, and OC19.9 and coexpressed cytokeratins 7 and 20. Chromogranin, nuclear estrogen, and progesterone receptors were negative. CONCLUSION: Phenotypic expression was more consistent with a papillary mucinous ovarian or cervical neoplasm than of a colonic one. Its behavior was similar to that of its morphologic counterpart in the cervix, since the patient had no recurrence 3 years after a wide local excision. PMID- 11606107 TI - Successful pregnancy after high-dose cyclophosphamide, carboplatinum, and taxol with peripheral blood stem cell transplant in a young woman with ovarian carcinoma. AB - BACKGROUND: Both ovarian carcinoma and high-dose chemotherapy tend to preclude future pregnancies. CASE: We report a case of a young woman with borderline ovarian carcinoma and invasive tumor implants who underwent surgical debulking with preservation of future fertility followed by carboplatinum, paclitaxel (Taxol), and subsequent high-dose chemotherapy with subsequent peripheral blood stem cell rescue as part of a phase I clinical trial. After a brief period of amenorrhea, the patient had a successful pregnancy that was complicated by a spontaneous abortion in the first trimester. Several months later she conceived and delivered a healthy baby at term. CONCLUSIONS: To our knowledge this is the first reported case of pregnancy after high-dose chemotherapy with stem cell transplant in a woman with ovarian carcinoma. PMID- 11606108 TI - Calyceal rupture and perirenal urinoma as a presenting sign of recurrent ovarian cancer. AB - BACKGROUND: Rupture of the urinary collecting system with peripelvic extravasation of urine is an uncommon pathologic condition usually associated with ureteral obstruction from calculi. CASE: We report a patient with calyceal rupture and peripelvic extravasation of urine secondary to distal ureteral obstruction by recurrent ovarian carcinoma. Diagnosis was established with computed tomography and renal scans. Placement of an indwelling ureteral stent via a nephrostomy resolved the urinoma. CONCLUSION: Gynecologic oncologists should be aware that calyceal rupture is a potential complication of gynecologic malignancy. Causes of perirenal urinary extravasation and approaches to diagnosis and management are reviewed. PMID- 11606109 TI - An alpha-fetoprotein-producing hepatoid adenocarcinoma of the endometrium. AB - BACKGROUND: Hepatoid adenocarcinomas are tumors that arise outside the liver but resemble hepatic tissue and produce alpha-fetoprotein. These neoplasms have been described in many locations, including the lung, gastrointestinal tract, and urogenital tract, and have been associated with a poor prognosis. Two previously reported cases of hepatoid adenocarcinoma of the endometrium described aggressive tumors that were unresponsive to multiple forms of therapy. CASE: We report a case of an alpha-fetoprotein-producing hepatoid adenocarcinoma of the endometrium that was successfully treated with surgery and adjuvant chemotherapy. CONCLUSION: Eight years after therapy, the patient is alive with no evidence of disease, suggesting that cytoxan, adriamycin, and cis-platinum are active agents in this unusual entity. PMID- 11606110 TI - Late intracaval and intracardiac leiomyomatosis following hysterectomy for benign myomas treated by surgery and GnRH agonist. AB - BACKGROUND: The aim of this study was to report an exceptional case of a patient presenting with intracaval and intracardiac leiomyomatosis treated by combined surgical and medical treatment. CASE: A 48-year-old presented with intracaval and intracardiac leiomyomatosis (IL) discovered 6 years following a total hysterectomy with ovarian conservation for myomas. Surgical resection of the pelvic myomas and intracaval leiomyomatosis was performed during the same surgical procedure. Given the presence of a small tumor residuum in the pelvic cavity, postoperative medical treatment based on a gonadotropin-releasing hormone (GnRH) agonist was delivered for 1 year. The patient was followed-up using clinical examination and systematic CT scan. Ten months following the end of medical treatment, she is still in good health and the pelvic residuum has stabilized. CONCLUSIONS: Patients with pelvic tumor combined with IL could be treated using a one-stage surgical procedure. In cases of incomplete surgical resection, medical treatment based on GnRH agonist could be successfully delivered. PMID- 11606111 TI - Ovarian conservation in a woman of reproductive age with mullerian adenosarcoma. AB - BACKGROUND: Total abdominal hysterectomy with bilateral salpingo-oophorectomy is generally considered optimal therapy for patients with uterine sarcomas. Local resection of the tumor or hysterectomy with ovarian conservation has been used in only a small number of patients. Recurrence risk in women undergoing ovarian sparing surgery for mullerian adenosarcomas can be difficult to evaluate due to the paucity of literature in this area. We present a reproductive-age woman with a mullerian adenosarcoma and review the literature on conservative surgical management of this class of tumors. CASE: A 25-year-old nulligravida was diagnosed with a uterine adenosarcoma and the question of conservative surgical therapy arose. Following a literature review, discussion with the patient led to the decision for ovarian preservation at the time of hysterectomy. The pelvis and abdomen were grossly free of metastatic disease at laparotomy and all tumor was confined to the uterus on pathologic examination. She is free of disease 36 months postoperatively and is now considering in vitro fertilization using a surrogate. CONCLUSION: Ovarian conservation can probably be offered safely in carefully selected women of reproductive age with mullerian adenosarcomas. PMID- 11606112 TI - Intratumoral sickling in a patient with cervix cancer and sickle trait: effect on blood flow and oxygenation. AB - BACKGROUND: Sickle trait affects approximately 8% of the black population in the United States and up to 40% of individuals in some parts of tropical Africa, but rarely causes clinically significant illness. This report provides the first conclusive evidence that erythrocytes in patients with sickle trait may sickle in the microvasculature of solid tumors, leading to impaired perfusion and hypoxia. CASE: A black woman who was sickle trait positive presented with stage IIIB squamous cell carcinoma of the cervix. A biopsy showed extensive intravascular sickling of erythrocytes. An aspirate of blood obtained directly from the tumor also showed numerous sickled cells. A peripheral blood smear was normal. Direct measurement of oxygen tension using the Eppendorf electrode revealed the tumor to be markedly hypoxic, with 93% of a total of 142 individual oxygen reading <5 mm Hg. CONCLUSIONS: Erythrocytes in patients with sickle trait may sickle in the microvasculature of solid tumors and contribute to reduced blood flow and the development of hypoxia. Hypoxia is a strong independent prognostic factor in patients with cervix cancer, and further study is needed to evaluate the impact of intratumoral sickling on long-term outcome. PMID- 11606113 TI - A noninvasive reporter system to image adenoviral-mediated gene transfer to ovarian cancer xenografts. AB - OBJECTIVE: Gene therapy trials for ovarian cancer would benefit from a noninvasive imaging modality to detect the location and extent of gene transfer. The human type 2 somatostatin receptor gene (hSSTr2) was evaluated as a reporter gene for imaging adenoviral (Ad) gene transfer to ovarian cancer. METHODS: A replication-incompetent Ad vector encoding hSSTr2 (Ad-hSSTr2) was used to infect SKOV3.ip1 cells in vitro and tumors growing in nude mice. Gamma camera imaging detected uptake of 99m-Tc-P2045 (a somatostatin analogue) due to expressed hSSTr2. RESULTS: Specific uptake of 99m-Tc-P2045 was imaged in Ad-hSSTr2-infected cells in vitro. Noninvasive in vivo imaging detected gene transfer to intraperitoneal tumors. Uptake of 99m-Tc-P2045 (percentage dose per gram of tumor) averaged 2.2 and 0.18 for Ad-hSSTr2-injected mice and controls, respectively. CONCLUSION: This study reports the first noninvasive imaging method for imaging gene transfer to ovarian cancer. A human gene therapy trial is planned. PMID- 11606114 TI - Shanxi Province Cervical Cancer Screening Study: a cross-sectional comparative trial of multiple techniques to detect cervical neoplasia. AB - OBJECTIVE: The aim of this study was to design a cervical cancer screening algorithm for the developing world that is highly sensitive for cervical intraepithelial neoplasia (CIN) II, III, and cancer and highly specific for CIN II and III, making it possible to ablate the transformation zone without histologic confirmation. METHODS: In rural Shanxi Province, China, we examined 1997 women ages 35-45. Each subject underwent a self-test for intermediate and high-risk HPV (by HC-II assay), fluorescence spectroscopy, a liquid-based Pap (read manually and by computer and used as a direct test for HPV), a visual inspection (VIA) diagnosis, and colposcopy with multiple cervical biopsies. RESULTS: Mean age was 39.1 +/- 3.16 years, mean number of births was 2.6 +/- 0.93. Based on tests administered, 4.3% subjects had > or =CIN II. All subjects with > or =CIN II had either a ThinPrep Pap (> or =ASCUS) or a positive HPV direct test. The sensitivity and specificity for the detection of > or =CIN II were, respectively, 83 and 86% for the HPV self-test, 95 and 85% for the HPV direct test, 94 and 78% for the ThinPrep Pap (> or =ASCUS), 77 and 98% for the ThinPrep Pap (> or =HGSIL), 94 and 9% for fluorescence spectroscopy, 71 and 74% for VIA, and 81 and 77% for colposcopy. CONCLUSION: Based on these data and the existing healthcare infrastructure in China, we believe that further refinement of primary HPV screening using centralized labs is indicated. Self-testing in the local villages may be effective with improvements in the devices and techniques. PMID- 11606115 TI - Occult cancer in the fallopian tube in patients with a BRCA-1 germline mutation. PMID- 11606116 TI - Prophylactic surgery in patients with inherited risk of ovarian cancer. PMID- 11606118 TI - Rapid enantiomeric quantification of an antiviral nucleoside agent (D,L-FMAU, 2' fluoro-5-methyl-beta,D,L-arabinofurano-syluracil) by mass spectrometry. AB - A novel mass spectrometric method is applied to rapid, accurate (<1%) quantification of chiral Clevudine (L-FMAU, 2'-fluoro-5-methyl-beta,L arabinofuranosyluracil), a potent antiviral nucleoside agent against hepatitis B virus. Transition metal bound complex ions containing the chiral drug are generated by electrospray ionization mass spectrometry and subjected to collision induced dissociation. The ratio of the two competitive dissociation rates is related to the enantiomeric composition of the drug mixture, allowing the determination of enantiomeric contamination in the drug. PMID- 11606119 TI - Aziridinyl quinone antitumor agents based on indoles and cyclopent[b]indoles: structure-activity relationships for cytotoxicity and antitumor activity. AB - A large number of aziridinyl quinones represented by series 1-9 were studied with respect to their DT-diaphorase substrate activity, DNA reductive alkylation, cytostatic/cytotoxic activity, and in vivo activity. As a result, generalizations have been made with respect with respect to the following: DT-diaphorase substrate design, DT-diaphorase-cytotoxicity quantitative structure-activity relationship (QSAR), and DNA reductive alkylating agent design. A saturating relationship exists between the substrate specificity for human recombinant DT diaphorase and the cytotoxicity in the human H460 non-small-cell lung cancer cell line. The interpretation of this relationship is that reductive activation is no longer rate-limiting for substrates with high DT-diaphorase substrate specificities. High DT-diaphorase substrate specificity is not desirable in the indole and cylopent[b]indole systems because of the result is the loss of cancer selectivity along with increased toxicity. We conclude that aziridinyl quinones of this type should possess a substrate specificity (V(max)/K(M)) < 10 x 10(-4) s(-1) for DT-diaphorase in order not to be too toxic or nonselective. While some DNA alkylation was required for cytostatic and cytotoxic activity by series 1-9, too much alkylation results in loss of cancer selectivity as well as increased in vivo toxicity. Indeed, the most lethal compounds are the indole systems with a leaving group in the 3alpha-position (like the antitumor agent EO9). We conclude that relatively poor DNA alkylating agents (according to our assay) show the lowest toxicity with the highest antitumor activity. PMID- 11606120 TI - Measuring molecular similarity and diversity: total pharmacophore diversity. AB - A novel method, total pharmacophore diversity (ToPD), based on known pharmacophore features for numerically defining molecular similarity or diversity is described. The method captures the 3D shape and functionality of molecules by the analysis of relevant intramolecular distances to generate a short and descriptive pharmacophoric fingerprint for each molecule. The ToPD fingerprints can then be used in diversity analysis, clustering, or database searching. Conformational sampling is carried out when needed by the means of molecular dynamics. Our results show that ToPD outperforms a traditional 2D fingerprint technique in all test cases. PMID- 11606121 TI - Toward the quantitative prediction of T-cell epitopes: coMFA and coMSIA studies of peptides with affinity for the class I MHC molecule HLA-A*0201. AB - A set of 102 peptides with affinity for the class I MHC HLA-A0201 molecule was subjected to three-dimensional quantitative structure-affinity relationship (3D QSAR) studies using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). A test set of 50 peptides was used to determine the predictive value of the models. The CoMFA models gave q(2) and r(2)pred below 0.5. The best CoMSIA model has q(2) = 0.542 and r(2)pred = 0.679, and includes hydrophobic, steric, and H-bond donor fields. The hydrophobic interactions play a dominant role in peptide-MHC molecule binding. CoMSIA coefficient contour maps were used to analyze the structural features of the peptides accounting for the affinity in terms of the three positively contributing physicochemical properties: local hydrophobicity, steric bulk and hydrogen-bond-donor ability. PMID- 11606122 TI - Alpha-amino acid phenolic ester derivatives: novel water-soluble general anesthetic agents which allosterically modulate GABA(A) receptors. AB - In the search for a novel water-soluble general anesthetic agent the activity of an alpha-amino acid phenolic ester lead, identified from patent literature, was markedly improved. In addition to improving in vivo activity in mice, good in vitro activity at GABA(A) receptors was also conferred. Within the series of compounds good enantioselectivity for both in vitro and in vivo activity was found, supporting a protein-mediated mechanism of action for anesthesia involving allosteric modulation of GABA(A) receptors. alpha-Amino acid phenolic ester 19, as the hydrobromide salt Org 25435, was selected for clinical evaluation since it retained the best overall anesthetic profile coupled with improved stability and water solubility. In the clinic it proved to be an effective intravenous anesthetic in man with rapid onset of and recovery from anesthesia at doses of 3 and 4 mg/kg. PMID- 11606123 TI - Ligand-protein database: linking protein-ligand complex structures to binding data. AB - In computational structure-based drug design, the scoring functions are the cornerstones to the success of design/discovery. Many approaches have been explored to improve their reliability and accuracy, leading to three families of scoring functions: force-field-based, knowledge-based, and empirical. The last family is the most widely used in association with docking algorithms because of its speed, even though such empirical scoring functions produce far too many false positives to be fully reliable. In this work, we describe a World Wide Web accessible database that gathers the structural information from known complexes of the PDB with experimental binding data. This database, the Ligand-Protein DataBase (LPDB), is designed to allow the selection of complexes based on various properties of receptors and ligands for the design and parametrization of new scoring functions or to assess and improve existing ones. Moreover, for each complex, a continuum of ligand positions ranging from the crystallographic position to points on the surface of the protein receptor allows an assessment of the energetic behavior of particular scoring functions. PMID- 11606124 TI - Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier. AB - The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [(3)H]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2. Amides 3-5 showed no detectable signs of crossing the blood brain barrier, while amide 6 was found in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed in vivo from these amides, was found in significantly smaller amounts (approximately 20 to >5000 times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6 approached that of T138067 and was better tolerated when administered to athymic nude mice bearing MX-1 human mammary tumor xenografts. PMID- 11606125 TI - Synthesis and antitumor activity of conjugates of muramyldipeptide, normuramyldipeptide, and desmuramylpeptides with acridine/acridone derivatives. AB - The synthesis of two groups (Chart 1, types A and B) of conjugates of MDP (muramyldipeptide) and nor-MDP (normuramyldipeptide) with acridine/acridone derivatives and the synthesis of analogues of desmuramylpeptides (Chart 1, types C and D) containing acridine/ acridone derivatives have been described. In type A conjugates, the hydroxyl group at C6 of the sugar moiety was acylated with acridine/acridone N-substituted omega-aminoalkanocarboxylic acids (Scheme 1), whereas the conjugates of type B (Table 2) and three analogues of type C or D (Scheme 2) have an amide bond formed between the carboxylic group of isoglutamine and the amine function of the respective acridine/acridone derivatives. The preliminary screening data indicate that the analogues of groups A, C, and D exhibit small cytotoxic activity, whereas several analogues of type B, 4b, 4c, 4e, 4g, 4h, 4i, and 4l, exhibiting potent in vitro cytotoxic activity against a panel of human cell lines (Table 4), have been selected by the National Cancer Institute (NCI) Evaluation Committee for further testing. Analogues 4b and 4h were active in the in vivo hollow fiber assay (Table 5). Analogue 3a shows an immunostimulating effect on the cytotoxic activity of the NK cells obtained from the spleen of healthy and Ab melanoma bearing animals. PMID- 11606126 TI - Inhibition of cancer cell growth by ruthenium(II) arene complexes. AB - Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(eta(6)-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(eta(6)-p-cymene)Ru(en)Cl]PF(6) (5), [(eta(6)-p cymene)RuCl(2)(isonicotinamide)] (7), and [(eta(6)-biphenyl)Ru(en)Cl]PF(6) (9) are reported. They have "piano stool" geometries with eta(6) coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru-Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial. PMID- 11606127 TI - Synthesis of sulfaphenazole derivatives and their use as inhibitors and tools for comparing the active sites of human liver cytochromes P450 of the 2C subfamily. AB - Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes. These compounds are derived from SPA by replacement of the NH(2) and H (of the SO(2)NH function) substituents of SPA with various R(1) and R(2) groups, respectively. Their inhibitory effects were studied on recombinant CYP 2C8, 2C9, 2C18, and 2C19 expressed in yeast. High affinities for CYP 2C9 (IC(50) < 1 microM) were only observed for SPA derivatives having the SO(2)NH function and a relatively small R(1) substituent (R(1) = NH(2), CH(3)). Any increase in the size of R(1) led to a moderate decrease of the affinity, and the N-alkylation of the SO(2)NH function of SPA to a greater decrease of this affinity. The same structural changes led to opposite effects on molecular recognition by CYP 2C8 and 2C18, which generally exhibited similar behaviors. Thus, contrary to CYP 2C9, CYP 2C8 and 2C18 generally prefer neutral compounds with relatively large R(1) and R(2) substituents. CYP 2C19 showed an even lower affinity for anionic compounds than CYP 2C8 and 2C18. However, as CYP 2C8 and 2C18, CYP 2C19 showed a much better affinity for neutral compounds derived from N-alkylation of SPA and for anionic compounds bearing a larger R(1) substituent. One of the new compounds (R(1) = methyl, R(2) = propyl) inhibited all human CYP 2Cs with IC(50) values between 10 and 20 microM, while another one (R(1) = allyl, R(2) = methyl) inhibited all CYP 2Cs except CYP 2C9, and a third one (R(1) = R(2) = methyl) inhibited all CYP 2Cs except CYP 2C8. Only 2 compounds of the 25 tested derivatives were highly selective toward one human CYP 2C; these are SPA and compound 1 (R(1) = CH(3), R(2) = H), which acted as selective CYP 2C9 inhibitors. However, some SPA derivatives selectively inhibited CYP 2C8 and 2C18. Since CYP 2C18 is hardly detectable in human liver, these derivatives could be interesting molecules to selectively inhibit CYP 2C8 in human liver microsomes. Thus, compound 11 (R(1) = NH(2), R(2) = (CH(2))(2)CH(CH(3))(2)) appears to be particularly interesting for that purpose as its IC(50) value for CYP 2C8 is low (3 microM) and 20-fold smaller than those found for CYP 2C9 and 2C19. PMID- 11606128 TI - Amino acid/spermine conjugates: polyamine amides as potent spermidine uptake inhibitors. AB - In this paper we describe the synthesis and characterization of a series of simple spermine/amino acid conjugates, some of which potently inhibit the uptake of spermidine into MDA-MB-231 breast cancer cells. The presence of an amide in the functionalized polyamine appeared to add to the affinity for the polyamine transporter. The extensive biological characterization of an especially potent analogue from this series, the Lys-Spm conjugate (31), showed this molecule will be an extremely useful tool for use in polyamine research. It was shown that the use of 31 in combination with DFMO led to a cytostatic growth inhibition of a variety of cancer cells, even when used in the presence of an extracellular source of transportable spermidine. It was furthermore shown that this combination effectively reduced the cellular levels of putrescine and spermidine while not affecting the levels of spermine. These facts together with the nontoxic nature of 31 make it a novel lead for further anticancer development. PMID- 11606129 TI - Design, synthesis, and evaluation of a long-acting, potent analogue of gonadotropin-releasing hormone. AB - The design, synthesis, and biological evaluation of a gonadotropin-releasing hormone (GnRH) agonist, [D-Lys(6)(1,3,8-trihydroxy-6-carboxyanthraquinone)]GnRH ([D-Lys(6)(Emo)]GnRH), is described. Synthesis of this analogue was carried out in a homogeneous solution as well as on a polymer support. [D-Lys(6)(Emo)]GnRH was found to bind to rat pituitary GnRH receptors (IC(50) = 0.25 nM), to induce luteinizing hormone (LH) release (ED(50) = 27 pM), and to be devoid of any toxicity. This analogue also proved to be a very potent agonist in vivo and exhibited a prolonged bioactivity. Six hours after its administration to rats, LH levels were substantially higher than those of rats treated with a 10-fold higher dose of the parent peptide. Moreover, chronic treatment of adult male rats with [D-Lys(6)(Emo)]GnRH (0.1 nmol/rat) for one week resulted in a further decrease of the weight of the testes and prostate as compared to those of rats that were treated with a higher dose of [D-Lys(6)]GnRH (1 nmol/rat). The prolonged activity of [D-Lys(6)(Emo)]GnRH may be attributed to its emodic acid moiety, which enhances the binding affinity of the analogue to human serum albumin. Indeed, we found that emodic acid binds to human serum albumin almost completely at the examined range of concentrations. PMID- 11606131 TI - Selective, high affinity peptide antagonists of alpha-melanotropin action at human melanocortin receptor 4: their synthesis and biological evaluation in vitro. AB - Peptide Ac-Nle(4)-cyclo(5beta-->10epsilon)(Asp(5)-His(6)-D-(2')Nal(7)-Arg(8) Trp(9)-Lys(10))-NH(2), compound 1, a cyclic derivative of alpha-melanotropin, is a nonselective high affinity antagonist at human melanocortin receptors 3 and 4, and an agonist at melanocortin receptors 1 and 5. To differentiate between the physiological functions of these receptors, antagonists with improved receptor selectivity are needed. In this study, analogues of compound 1 without Ac-Nle(4) or His(6) and/or the amino group of Asp(5) were prepared and tested in binding assays and in functional assays on CHO cells expressing hMC3-5R. Several of these peptides were to be selective, high affinity hMC-4R antagonists. The most interesting was compound 10, named MBP10, cyclo(6beta-->10epsilon)(succinyl(6)-D (2')Nal(7)-Arg(8)-Trp(9)-Lys(10))-NH(2), an antagonist (IC(50) = 0.5 nM) with 125 fold selectivity over hMC-3R (and of >300-fold selectivity over MC-1RB). This compound had no agonist activity at hMC-3R or hMC-4R and only weak agonist activity at hMC-5R. Examination of the sequences of these new peptides revealed that the D-(2')Nal(7)-Arg(8)-Trp(9) segment of peptide 1 forms the "essential core" required for high affinity and high selectivity of analogues of peptide 1 at hMC-4R, but the "extended core", His(6)-D-(2')Nal(7)-Arg(8)-Trp(9), is necessary for the maximum affinity for hMC-3R and hMC-5R. PMID- 11606130 TI - N-Benzylpolyamines as vectors of boron and fluorine for cancer therapy and imaging: synthesis and biological evaluation. AB - Cancer cells have high-affinity polyamine uptake systems with a low stringency for structural features. Putrescine, spermidine, and spermine have, therefore, been considered as potential vectors for the selective accumulation in tumors of therapeutically or diagnostically useful structures and elements. We envisaged N benzyl derivatives of the polyamines as vectors of (10)B and (18)F for boron neutron capture therapy (BNCT) and tumor imaging by positron emission tomography (PET), respectively. In the present work, the synthesis, transport characteristics, DNA-binding properties, and cytotoxicity of several N-benzyl derivatives of putrescine and spermidine are described. The fluorinated spermidine derivative N-(3-[(4-aminobutyl)amino]propyl)[(4 fluorophenyl)methyl]amine (N(1)-4-Fbz-spd) may be useful for PET because of its high accumulation in cancer cells via the polyamine transport system. Among the boron-containing benzyl polyamines, N-(4-aminobutyl)([4 (dihydroxyboryl)phenyl]methyl)amine (4-Bbz-put) and N-(3-[(4 aminobutyl)amino]propyl)([4-(dihydroxyboryl)phenyl]methyl)amine (N(1)-4-Bbz-spd) should be suitable for BNCT, because their accumulation in B16 melanoma cells was more efficient than that of borocaptate and borophenylalanine, two reference compounds used in BNCT. PMID- 11606132 TI - Investigation of 5-nitrofuran derivatives: synthesis, antibacterial activity, and quantitative structure-activity relationships. AB - Three sets of antibacterial nitrofuran derivatives [set I, 5-R-substituted (Z)-2 (5-nitrofuran-2-ylmethylene)-3(2H)-benzofuranones (R = OCH(3), H, CH(3), C(2)H(5), nC(3)H(7), Cl, Br, CN, and NO(2)) and their 2-hydroxyphenyl and 2 acetoxyphenyl analogues; set II, 5-R-substituted (E)-1-(2-hydroxyphenyl)-3-(5 nitrofuryl)-2-propen-1-ones (R = H, CH(3), C(2)H(5), Cl, and NO(2)); and set III, 5-R-substituted (E)-1-(2-acetoxyphenyl)-3-(5-nitrofuryl)-2-propen-1-ones (R = H, CH(3); C(2)H(5), Cl, and NO(2))] were prepared and tested against a Gram-positive (Staphylococcus aureus, strain ATCC-25923) and a Gram-negative bacterium (Caulobacter crescentus, strain NA 1000). QSAR equations derived for the IC(50) values against both bacteria show negative contributions of two terms: an electronic one, expressed either by sigma, the Hammett substituent constant, or by E, the cyclic voltametric reduction potential. Another term described by an indicator variable, I(abs), is assigned the value of 0 for set I compounds and the value of 1 for sets II and III. No important contribution of the hydrophobic factor was found. For the three sets, the QSAR regressions suggest that the same structural features describe the activities for both bacteria and that, although reduction is a necessary step, it should not be the determining one. These results agree with those found for the QSAR of 5-nitroimidazole analogues. PMID- 11606133 TI - Influence of polyamine architecture on the transport and topoisomerase II inhibitory properties of polyamine DNA-intercalator conjugates. AB - An efficient five-step synthetic method was developed to access a series of spermine derivatives containing appended acridine, anthracene, and 7 chloroquinoline motifs. The derivatives were composed of a spermine fragment covalently tethered at its N4 and N9 positions to an aromatic nucleus via an aliphatic chain (e.g., 8: acridine -[C4 aliphatic tether]-spermine-[C4 aliphatic tether]-acridine). The distance separating the spermine and aromatic nuclei was altered via different tethers composed of four or five methylene units. These bis ligands (8, 9, 12, and 13) were shown to inhibit human DNA topoisomerase II (topo II) activity at 5 microM. Enzymatic activity was assessed as the ability to unknot (decatenate) and cleave kinetoplast DNA (kDNA). Polyamine conjugation did not disrupt the ability of the acridine-spermine conjugates 8 and 9 to inhibit topo II activity as compared with the 9-aminoacridine and 9-(N butyl)aminoacridine controls (at 5 microM). The parent polyamines, spermine (5 microM) and spermidine (10 microM), had little effect on topo II activity. In general, the bis-substituted spermine derivatives (8, 9, 12, and 13) were more efficient topo II inhibitors at 5 microM than their monosubstituted spermidine counterparts (22-25) at 10 microM. Within the bisintercalator spermine series, insertion of an additional methylene unit (i.e., C5 tethers) increased potency 2 fold (8, bis-C4-acridine, 47 h IC(50) = 40 microM; 9, bis-C5-acridine, IC(50) = 17 microM). Comparison of the bis- and monoacridine spermine motifs (8 and 17) revealed a 4-fold increase in potency for the latter architecture (94 h IC(50) for 8, 74 microM; for 17, 17 microM). In general the bisintercalators (8, 9, 12, and 13) behaved as cytostatic agents, while the monosubstituted acridine and anthracene derivatives (22-25) were cytotoxic. Anthracene-containing conjugates were generally more toxic than their acridine counterparts in an L1210 (murine leukemia) cell assay. Of the conjugates tested the (monointercalator)-spermine motif (e.g., 17) had the highest affinity for the L1210 polyamine transporter as revealed by spermidine protection experiments. PMID- 11606134 TI - Synthesis and antitumor activity of ester-modified analogues of bengamide B. AB - Bengamide B, a novel sponge-derived marine natural product with broad spectrum antitumor activity, was not suitable for further preclinical development because of its difficult synthesis and very poor water solubility. Bengamide B produced a 31% T/C at its solubility-limited maximum intravenous dose of 33 micromol/kg in MDA-MB-435 breast carcinoma implanted subcutaneously as a xenograft in nude mice. Compound 8a, a bengamide B analogue with three structural changes (t-Bu alkene substituent, unsubstituted lactam nitrogen, and inverted lactam 5'-myristoyloxy group), was as potent as bengamide B in vitro and more efficacious than bengamide B in vivo. A series of ester-modified analogues based on 8a were synthesized and tested in vitro and in vivo (MDA-MB-435). The cyclohexyl- and phenethyl substituted esters, 8c and 8g, respectively, had in vitro and in vivo activities similar to that of 8a and enhanced water solubility (ca. 1 mg/mL). Consequently, 8c and 8g were tested in the MDA-MB-435 xenograft model at 100 micromol/kg and produced 29% and 57% tumor regression, respectively. PMID- 11606135 TI - Utility of azapeptides as major histocompatibility complex class II protein ligands for T-cell activation. AB - Major histocompatibility complex class II (MHC II) protein binding and antigen specific activation of CD4+ "helper" T cells are demonstrated with peptides composed of the antigenic hen egg ovalbumin 325-339 peptide (OVA) substituted with azaamino acids. AzaAla and azaGly substitutions were made at 10 sequential peptide positions (326Ala-335Asn) that lie in the binding groove. The peptide positions substituted with azaamino acids encompass almost the entire binding groove, including positions where the identity of the amino acid side chain is known to have the most significant effect on MHC binding and the least effect on T-cell recognition. In addition, the T-cell contact 333Glu was substituted with azaGlu to generate a partial agonist ligand for the 3DO-54.8 T-cell hybridoma. Binding to MHC II protein was assayed by measuring the kinetic stability of complexes formed between detergent-solubilized MHC II I-A(d) protein and fluorescein-labeled OVA peptides using a fluorescence-HPLC assay. T-cell activation was also evaluated for aza-substituted peptides with azaamino acid substitutions at the peptide positions known to interact with the MHC II protein. All aza-substituted peptides showed detectable MHC binding, and some were found to show T-cell activation potency equal to the native peptide. Several of these were also found to be weak or partial agonists. Our results demonstrate that azaamino acids substituted into an antigenic peptide cause a subtle, global effect on peptide conformation that can be used to design altered peptide ligands (APL) as T-cell partial agonists. These may have potential as T-cell epitopes for synthetic vaccines and therapeutic agents for autoimmune diseases. PMID- 11606136 TI - Design, synthesis, and biological evaluation of novel nucleoside and nucleotide analogues as agents against DNA viruses and/or retroviruses. AB - A novel strategy was developed for the synthesis of N(7)-purine acyclic nucleosides 9 and 14. The key step involved the reaction between [2-(p methoxyphenyloxy)ethoxy]methyl chloride and N(9)-tritylated nucleobases 6 or 11 followed by concomitant self-detritylation. N(7)-Guanine acyclic nucleoside 9 exhibited antiviral activity, but was phosphorylated by both HSV and Vero cell thymidine kinases. Thus, it showed more potent cellular toxicity than acyclovir (2). N(7)-Adenine acyclic nucleoside 14 was found to be an excellent antiviral agent as well as a good inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows for a greater expression of antiviral activity of antiviral agents, such as N(9)-adenine acyclic nucleoside 1 and ara-A (3). Compound 14 was phosphorylated neither by herpes simplex virus (HSV) thymidine kinase nor by Vero cell thymidine kinase, yet it enhanced the rate constant for the monophosphorylation of acyclovir (2) by HSV thymidine kinase. Consequently, the combination of acyclovir (2) and 14 exhibited greater antiviral activity than acyclovir alone. 7-[2-(Phosphonomethoxy)ethyl]adenine (20) was also synthesized. The key step involved the reaction of 9-(2-cyanoethyl)adenine (15) with methyl iodoacetate in the presence of lithium 2,2,6,6-tetramethylpiperidine in THF. Unlike 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, 4), the N(7)-isomer 20 was not phosphorylated effectively by 5-phosphoribosyl 1-pyrophosphate synthetase (PRPP synthetase). Thus, it did not exhibit pronounced antiviral activity. Dinucleotide 5'-monophosphate 24 and its butenolide ester 25 were also synthesized. Compound 24 showed substrate activity toward PRPP synthetase and exhibited notable activity against DNA viruses. The antiviral activity of the ester derivative 25 was found to be higher than that of the parent molecule 24. Dinucleotide 5' monophosphate 24 is susceptible to degradation by snake venom and spleen phosphodiesterases. However, its respective butenolide ester derivative 25 was completely resistant to snake venom and spleen enzymes. Butenolide ester derivatives 28 and 29 were also synthesized and exhibited notable anti-DNA virus and anti-retrovirus activity in vitro. Compounds 2, 4, 9, 14, 20, 24, 25, and 28 were also evaluated for their inhibitory effect on HSV-1-induced mortality in NMRI mice. N(7)-adenine acyclic nucleoside 14 [LD(50) (intraperitoneal, ip) 950 mg/kg], nucleotide-containing butenolide 25 [LD(50) (ip) 675 mg/kg], and butenolide 28 [LD(50) (ip) 710 mg/kg] were found to be potent anti-HSV-1 agents in vivo. In addition, butenolide 28 efficiently decreased tumor formation induced by Moloney murine sarcoma virus (MSV) in NMRI mice while significantly increasing the survival time of MSV-infected mice. PMID- 11606137 TI - Physicochemical determinants of passive membrane permeability: role of solute hydrogen-bonding potential and volume. AB - The relationship of solute structure with cellular permeability was probed. Two series of dipeptide mimetics consisting of glycine, alanine, valine, leucine, phenylalanine, and cyclohexylalanine with amino acids in the D-configuration were prepared. Partition coefficients for the peptidemimetics were obtained in the octanol/water (log P(octanol/water)), hydrocarbon/octanol (Delta log P), and heptane/ethylene glycol (log P(heptane/glycol)) systems in order to explore the contributions of solute volume, or surface area, and hydrogen-bond potential to the permeability of the solutes. Permeability coefficients were obtained in Caco 2 cell monolayers as a model of the human intestinal mucosa. The results were interpreted in terms of a partition/diffusion model for solute transport where membrane partitioning into the permeability-limiting membrane microdomain is estimated from the solvent partition coefficients. Neither log P(octanol/water) nor Delta log P alone correlated with cellular permeability for all the solutes. In contrast, log P(heptane/glycol) gave a qualitatively better correlation. With regard to solute properties, log P(octanol/water) is predominantly a measure of solute volume, or surface area, and hydrogen-bond acceptor potential, while Delta log P is principally a measure of hydrogen-bond donor strength. Log P(heptane/glycol) contains contributions from all these solute properties. The results demonstrate that both hydrogen-bond potential and volume of the solutes contribute to permeability and suggests that the nature of the permeability limiting microenvironment within the cell depends on the properties of a specific solute. Collectively, these findings support the conclusion that a general model of permeability will require consideration of a number of different solute structural properties. PMID- 11606138 TI - Hydrazinonaphthalene and azonaphthalene thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis. AB - High-throughput screening for the induction of a luciferase reporter gene in a thrombopoietin (TPO)-responsive cell line resulted in the identification of 4 diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC(50) values in the region of 1-20 nM. PMID- 11606139 TI - Synthesis of 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole analogues as novel antiplatelet agents. AB - 1-Benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (28, YC-1) was selected as the lead compound for systemic structural modification. After screening for antiplatelet activity, SARs of YC-1 analogues were established. Among these potent active derivatives, compounds 29, 30, 31, 44, and 45 functioned as potent activators of sGC and inhibitors of PDE5 with potency comparable to that of YC-1. In addition, compound 58 was found to be a selective and potent inhibitor of protease-activated receptor type 4 (PAR4)-dependent platelet activation. PMID- 11606140 TI - N-Succinyl-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin: an extracellularly tumor-activated prodrug devoid of intravenous acute toxicity. AB - Intravenous administration of N-(beta-alanyl-L-leucyl-L-alanyl-L leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped versions of 4 such as the succinyl derivative 5 can be administered by the iv route at more than 10 times the LD(50) of doxorubicin without inducing the acute toxic reaction, and they are active in vivo. PMID- 11606141 TI - Synthesis and cytotoxicity on sensitive and doxorubicin-resistant cell lines of new pyrrolo[2,1-c][1,4]benzodiazepines related to anthramycin. AB - A new 7,8-methylenedioxy analogue (4) of (+)-porothramycin B (2) and its water soluble sodium bisulfite derivative (15) have been synthesized in high yields and have been shown to exhibit high cytotoxic activities against several tumor cell lines. The new pyrrolo[2,1-c][1,4]benzodiazepine 4 was as effective against the resistant cell lines as against the doxorubicin-sensitive cell lines tested. PMID- 11606143 TI - Informed consent in complementary and alternative medicine. PMID- 11606144 TI - Continuous subcutaneous insulin infusion: a comprehensive review of insulin pump therapy. AB - A tremendous amount of data suggest that near-normal glycemic control prevents or delays complications of diabetes, which has led to a dramatic increase in continuous subcutaneous insulin infusion (CSII) or insulin pump use. In this article, the data supporting CSII in type 1 diabetes is reviewed, and the advantages and disadvantages of CSII are analyzed. In addition, CSII use in specific situations is examined, including during childhood and pregnancy and while exercising. The published articles suggest that CSII provides better glycemic control than does conventional therapy and comparable to or slightly better control than multiple daily injections. The use of CSII may be especially indicated during pregnancy or for preconception care and for diabetes presenting in childhood or adolescence. PMID- 11606145 TI - Rigorous new approach to constructing a gold standard for validating new diagnostic criteria, as exemplified by the eosinophilia-myalgia syndrome. AB - BACKGROUND: Constructing diagnostic criteria, a common problem in clinical medicine, is particularly difficult for diseases that lack a pathognomonic "gold standard." To develop an improved strategy for constructing such criteria, we used the eosinophilia-myalgia syndrome as an example. The goal, for research classifications, was to construct validated clinically sensible criteria and to develop improved methods that can be used for other disorders. METHODS: Using a "pattern-based" approach with data from several separate sources, a committee of investigators first prepared and informally tested criteria for the diagnosis of eosinophilia-myalgia syndrome. A gold standard challenge set of reports of cases and noncases was independently generated and separately validated by an external panel of clinical experts. The criteria were then tested using the gold standard set, and interobserver variability and diagnostic accuracy were determined. RESULTS: Interobserver variability showed the following mean proportionate agreements: 98.7% for the presence of specific criteria elements, 99% to 100% for diagnosis, and 97% to 98% for diagnostic pattern. kappa Values were correspondingly high. Diagnostic accuracy showed sensitivity at 88%, specificity at 97%, and overall accuracy at 92%. CONCLUSIONS: The proposed criteria are accurate and reproducible, and can be used in future clinical investigations of the eosinophilia-myalgia syndrome. The new strategy and methods developed for this challenge can be valuable for solving analogous problems in constructing criteria for other clinical disorders. PMID- 11606146 TI - Physical exercise and the prevention of disability in activities of daily living in older persons with osteoarthritis. AB - BACKGROUND: The prevention of disability in activities of daily living (ADL) may prolong older persons' autonomy (older persons are defined in this study as those aged > or =60 years). However, proved preventive strategies for ADL disability are lacking. A sedentary lifestyle is an important cause of disability. This study examines whether an exercise program can prevent ADL disability. METHODS: A 2-center, randomized, single-blind, controlled trial was conducted in which participants were assigned to an aerobic exercise program, a resistance exercise program, or an attention control group. Of the 439 community-dwelling persons aged 60 years or older with knee osteoarthritis originally recruited, the 250 participants initially free of ADL disability were used for this study. Incident ADL disability, defined as developing difficulty in transferring from a bed to a chair, eating, dressing, using the toilet, or bathing, was assessed quarterly during 18 months of follow-up. RESULTS: The cumulative incidence of ADL disability was lower in the exercise groups (37.1%) than in the attention control group (52.5%) (P =.02). After adjustment for demographics and baseline physical function, the relative risk of incident ADL disability for assignment to exercise was 0.57 (95% confidence interval, 0.38-0.85; P =.006). Both exercise programs prevented ADL disability; the relative risks were 0.60 (95% confidence interval, 0.38-0.97; P =.04) for resistance exercise and 0.53 (95% confidence interval, 0.33-0.85; P =.009) for aerobic exercise. The lowest ADL disability risks were found for participants with the highest compliance to exercise. CONCLUSIONS: Aerobic and resistance exercise may reduce the incidence of ADL disability in older persons with knee osteoarthritis. Exercise may be an effective strategy for preventing ADL disability and, consequently, may prolong older persons' autonomy. PMID- 11606147 TI - Drug-related deaths in a department of internal medicine. AB - BACKGROUND: Drug therapy is associated with adverse effects, and fatal adverse drug events (ADEs) have become major hospital problems. Our study assesses the incidence of fatal ADEs in a major medical department and identifies possible patient characteristics signifying fatal ADE risk. METHODS: During a 2-year period, a multidisciplinary study group examined all 732 patients who died--5.2% of the 13992 patients admitted to the Department of Internal Medicine, Central Hospital of Akershus, Nordbyhagen, Norway. Decisions about the presence or absence of fatal ADEs were based on aggregated clinical records, autopsy results, and findings from premortem and postmortem drug analyses. RESULTS: In 18.2% of the patients (133/732) (95% confidence interval, 15.4%-21.0%), deaths were classified as being directly (64 [48.1%] of 133) or indirectly (69 [51.9%] of 133) associated with 1 or more drugs (this equals 9.5 deaths per 1000 hospitalized patients). Those with fatal ADEs (cases) were older, had more diseases, and used more drugs than those without fatal ADEs (noncases). In 75 of the 133 patients with fatal ADEs, autopsy findings and/or drug analysis data were decisive for recognizing the ADEs; in 62 of the remaining 595 patients, similar data proved necessary to exclude the suspicion of a fatal ADE. Major culprit drugs were cardiovascular, antithrombotic, and sympathomimetic agents. CONCLUSIONS: Fatal ADEs represent a major hospital problem, especially in elderly patients with multiple diseases. A higher number of drugs administered was associated with a higher frequency of fatal ADEs, but whether a high number of drugs is an independent risk factor for fatal ADEs is unsettled. Autopsy results and the findings of premortem and postmortem drug analyses were important for recognizing and excluding suspected fatal ADEs. PMID- 11606148 TI - Sustained-release sodium fluoride in the treatment of the elderly with established osteoporosis. AB - BACKGROUND: We ascertained the safety and efficacy of fluoride in augmenting spinal bone mass and reducing spinal fractures in older women with established osteoporosis. We compared a combination of sustained-release sodium fluoride, calcium citrate, and cholecalciferol (SR-NaF group) with calcium and cholecalciferol alone (control group). METHODS: Eighty-five ambulatory women aged 65 years or older with 1 or more nontraumatic vertebral compression fractures were enrolled in a 42-month randomized, double-blind, placebo-controlled trial. Primary outcome measures were vertebral fracture rate, bone mass, and safety. RESULTS: The vertebral fracture rate determined by means of computer assistance in the SR-NaF group was significantly lower than that in the control group (relative risk [RR], 0.32; 95% confidence interval [CI], 0.14-0.73; P =.007). Results of visual adjudicated inspection also confirmed a significant reduction in fracture rate (RR, 0.40; 95% CI, 0.17-0.95; P =.04). Bone mineral density in L2 through L4 increased significantly from baseline in the SR-NaF group by 5.4% (95% CI, 2.7%-8.2%; P<.001), and by 3.2% in the control group (95% CI, 0.8%-5.6%; P =.01). The between-group differences in bone mineral density were not significant. The femoral neck and total hip bone mineral density remained stable in the SR-NaF group and was not significantly different from that of the control group. There were no significant differences in adverse effects between groups. CONCLUSION: The SR-NaF group significantly decreased the risk for vertebral fractures and increased spinal bone mass without reducing bone mass at the femoral neck and total hip. PMID- 11606149 TI - Acute precipitants of congestive heart failure exacerbations. AB - BACKGROUND: Few studies have prospectively and systematically explored the factors that acutely precipitate exacerbation of congestive heart failure (CHF) in patients with left ventricular dysfunction. Knowledge of such factors is important in designing measures to prevent deterioration of clinical status. The objective of this study was to prospectively describe the precipitants associated with exacerbation of CHF status in patients enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study. METHODS: We conducted a 2-stage, multicenter, randomized trial in 768 patients with CHF who had an ejection fraction of less than 40%. Patients were randomly assigned to receive enalapril maleate, candesartan cilexetil, or both for 17 weeks, followed by randomization to receive metoprolol succinate or placebo for 26 weeks. Investigators systematically documented information on clinical presentation, management, and factors associated with the exacerbation for any episode of acute CHF during follow-up. RESULTS: A total of 323 episodes of worsening of CHF occurred in 180 patients during 43 weeks of follow-up; 143 patients required hospitalization, and 5 died. Factors implicated in worsening of CHF status included noncompliance with salt restriction (22%); other noncardiac causes (20%), notably pulmonary infectious processes; study medications (15%); use of antiarrhythmic agents in the past 48 hours (15%); arrhythmias (13%); calcium channel blockers (13%); and inappropriate reductions in CHF therapy (10%). CONCLUSIONS: A variety of factors, many of which are avoidable, are associated with exacerbation of CHF. Attention to these factors and patient education are important in the prevention of CHF deterioration. PMID- 11606151 TI - Variation in routine electrocardiogram use in academic primary care practice. AB - BACKGROUND: Lack of practical consensus regarding routine electrocardiogram (ECG) ordering in primary care led us to hypothesize that nonclinical variations in ordering would exist among primary care providers. METHODS: We used 2 computerized billing systems to measure ECG ordering at visits to providers in 10 internal medicine group practices affiliated with a large, urban teaching hospital from October 1, 1996, to September 30, 1997. To focus on screening or routine ECGs, patients with known cardiac disease or suggestive symptoms were excluded, as were providers with fewer than 200 annual patient visits. Included were 69 921 patients making 190 238 visits to 125 primary care providers. Adjusted rates of ECG ordering accounted for patient age, sex, and 5 key diagnoses. Logistic regression evaluated additional predictors of ECG ordering. RESULTS: Electrocardiograms were ordered in 4.4% of visits to patients without reported cardiac disease. Among the 10 group practices, ECG ordering varied from 0.5% to 9.6% of visits (adjusted rates, 0.8%-8.6%). Variations between individual providers were even more dramatic: adjusted rates ranged from 0.0% to 24% of visits, with an interquartile range of 1.4% to 4.7% and a coefficient of variation of 88%. Significant predictors of ECG use were older patient age, male sex, and the presence of clinical comorbidities. Additional nonclinical predictors included Medicare as a payment source, older male providers, and providers who billed for ECG interpretation. CONCLUSIONS: Variations in ECG ordering are not explained by patient characteristics. The tremendous nonclinical variations in ECG test ordering suggest a need for greater consensus about use of screening ECGs in primary care. PMID- 11606150 TI - Elevated midlife blood pressure increases stroke risk in elderly persons: the Framingham Study. AB - BACKGROUND: Stroke risk predictions are traditionally based on current blood pressure (BP). The potential impact of a subject's past BP experience (antecedent BP) is unknown. We assessed the incremental impact of antecedent BP on the risk of ischemic stroke. METHODS: A total of 5197 stroke-free subjects (2330 men) in the community-based Framingham Study cohort were enrolled from September 29, 1948, to April 25, 1953, and followed up to December 31, 1998. We determined the 10-year risk of completed initial ischemic stroke for 60-, 70-, and 80-year-old subjects as a function of their current BP (at baseline), recent antecedent BP (average of readings at biennial examinations 1-9 years before baseline), and remote antecedent BP (average at biennial examinations 10-19 years earlier), with adjustment for smoking and diabetes mellitus. Models incorporating antecedent BP were also adjusted for baseline BP. The effect of each BP component (systolic BP, diastolic BP, and pulse pressure) was assessed separately. RESULTS: Four hundred ninety-one ischemic strokes (209 in men) were observed in eligible subjects. The antecedent BP influenced the 10-year stroke risk at the age of 60 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.68 [95% confidence interval, 1.25-2.25]; and men, 1.92 [95% confidence interval, 1.39 2.66]) and at the age of 70 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.66 [95% confidence interval, 1.28-2.14]; and men, 1.30 [95% confidence interval, 0.97-1.75]). This effect was evident for recent and remote antecedent BP, consistent in hypertensive and nonhypertensive subjects, and demonstrable for all BP components. CONCLUSIONS: Antecedent BP contributes to the future risk of ischemic stroke. Optimal prevention of late life stroke will likely require control of midlife BP. PMID- 11606152 TI - Reducing infections among women undergoing cesarean section in Colombia by means of continuous quality improvement methods. AB - BACKGROUND: Improving obstetric care in resource-limited countries is a major international health priority. OBJECTIVE: To reduce infection rates after cesarean section by optimizing systems of obstetric care for low-income women in Colombia by means of quality improvement methods. METHODS: Multidisciplinary teams in 2 hospitals used simple methods to improve their systems for prescribing and administering perioperative antibiotic prophylaxis. Process indicators were the percentage of women in whom prophylaxis was administered and the percentage of these women in whom it was administered in a timely fashion. The outcome indicator was the surgical site infection rate. RESULTS: Before improvement, prophylaxis was administered to 71% of women in hospital A; 24% received prophylaxis in a timely fashion. Corresponding figures in hospital B were 36% and 50%. Systems improvements included implementing protocols to administer prophylaxis to all women and increasing the availability of the antibiotic in the operating room. These improvements were associated with increases in overall and timely administration of prophylaxis (P<.001) in both hospitals by time series analysis, with adjustment for volume and case mix. After improvement, overall and timely administration of prophylaxis was 95% and 96% in hospital A and 89% and 96% in hospital B. In hospital A, the surgical site infection rate decreased immediately after the improvements (P<.001). In hospital B, the infection rate began a downward trend before the improvements that continued after their implementation (P =.04). CONCLUSION: Simple quality improvement methods can be used to optimize obstetric services and improve outcomes of care in resource limited settings. PMID- 11606153 TI - Inappropriate use of antibiotics and the risk for delayed admission and masked diagnosis of infectious diseases: a lesson from Taiwan. AB - BACKGROUND: Antibiotic resistance is a serious problem worldwide. It is particularly alarming in Taiwan and other countries of the Pacific Rim, where antimicrobial drugs are used excessively. OBJECTIVE: To determine whether use of antimicrobial drugs before coming to an emergency department was associated with delayed admission or masked or missed diagnoses at a large general hospital in Taiwan. METHODS: Antimicrobial activity in urine (AAU) was determined in all patients seen in the emergency department during a 3-month study. A physician, unaware of the results of the urine tests, reviewed the medical charts of patients who were admitted to the hospital to determine whether admission was delayed for at least 7 days or the diagnosis was masked or missed. RESULTS: Of the 1182 patients, 444 were admitted to the hospital. In 220 patients (49.5%), AAU was detected. There was no significant difference in AAU between patients with or without an infectious disease (53.0% vs 46.3%, respectively; P =.41). For patients with infection, 34.8% of those with AAU had a delayed admission, compared with only 21.6% without AAU (relative risk [RR], 1.61; 95% confidence interval [CI], 1.03-2.52; P =.03). For patients without infection, 36.2% of those with AAU had a delayed admission compared with 31.1% without AAU (RR, 1.16; 95% CI, 0.81-1.68; P =.64). For patients with infection, 48.7% of those with AAU had a masked or missed diagnosis, compared with 25.5% without AAU (RR, 1.91; 95% CI, 1.30-2.80; P<.001). For patients without infection, 27.6% of those with AAU had a masked or missed diagnosis compared with 14.8% without AAU (RR, 1.87; 95% CI, 1.11-3.17; P =.02). CONCLUSION: Use of antimicrobial drugs before coming to an emergency department was associated with a significantly increased risk for delayed and masked or missed diagnoses of infectious diseases and missed diagnosis of noninfectious diseases. PMID- 11606154 TI - Adverse events associated with methicillin-resistant Staphylococcus aureus in a nursing home. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) generates concern in nursing homes. Restrictive isolation precautions may be applied for indefinite periods. Adverse events driving these concerns include transmission and infection. METHODS: The 721-bed Wisconsin Veterans Home in King performs approximately 645 cultures annually. The site, severity, and number of MRSA infections were determined for 69 months. Pulsed-field gel electrophoresis was performed on all initial isolates, followed by a statistical cluster analysis looking for evidence of transmission. RESULTS: Sixty-seven MRSA infections were identified (1.6 per 100 residents per year); many were polymicrobial, and it was difficult to determine the proportionate role of MRSA in morbidity or mortality. There was an episode of rapidly fatal MRSA septicemia in which empiric antibiotic therapy was ineffective. Twenty-one genetic strains were encountered. Statistical analysis identified 13 clusters of genetically identical strains clustered in time and space (P<.05). CONCLUSIONS: Infections with MRSA were identified at relatively low rates; however, the etiology of many serious nursing home infections is not determined, especially pneumonia. Statistical analysis revealed clustering and evidence of transmission. Nursing home practitioners should consider MRSA when applying empiric treatment to serious infections. We recommend a program including (1) judicious use of antibiotics, including topical agents, to reduce selection of resistant organisms; (2) obtaining and tracking cultures of infectious secretions to diagnose MRSA infections and focus antibiotic therapy; (3) universal standard secretion precautions because any resident could be a carrier; and (4) a detailed assessment and care plan for the carrier that maximizes containment of secretions and independence in activities. However, basic hygiene cannot be maintained in communal areas by some residents without restriction of activities of daily living. PMID- 11606155 TI - Pneumonia in long-term care: a prospective case-control study of risk factors and impact on survival. AB - BACKGROUND: Pneumonia is a major cause of morbidity and mortality in long-term care facilities. Prior studies of pneumonia have failed to identify risk factors potentially amenable to intervention. Our objectives were to (1) identify modifiable risk factors for the occurrence of pneumonia and (2) determine the long-term impact of pneumonia on survival. METHODS: We performed a case-control study among residents of a Veterans Affairs long-term care facility. Case patients included all patients developing pneumonia from 2 days to 1 year after admission. Control subjects were matched for admission date, level of nursing care, and dependence in activities of daily living. Patients were followed up for 2 years or until death or discharge from the facility. RESULTS: We identified 104 case-control pairs. Risk factors significantly associated with pneumonia included witnessed aspiration (odds ratio, 13.9; 95% confidence interval, 1.7-111.0; P =.01), sedative medication (odds ratio, 2.6; 95% confidence interval, 1.2-5.4; P =.01), and comorbidity score (odds ratio, 1.2; 95% confidence interval, 1.0-1.4; P =.05). Mortality due to pneumonia was 23% at 14 days. Patients with pneumonia had a significantly higher mortality than did controls at 1 year (75% vs 40%; P<.001); survival curves converged at 2 years. In a Cox proportional hazards regression model, an episode of pneumonia was independently associated with mortality during follow-up (odds ratio, 2.6; 95% confidence interval, 1.7-3.9; P<.001). CONCLUSIONS: Among long-term care patients closely matched for age, level of dependency, and duration of institutionalization, an episode of pneumonia is associated with significant excess mortality that persists for up to 2 years. Two identified risk factors, large-volume aspiration and receipt of sedating medication, are potentially amenable to intervention. PMID- 11606156 TI - Treatment of a bowenoid papulosis of the penis with local applications of cidofovir in a patient with acquired immunodeficiency syndrome. PMID- 11606157 TI - High level of high-density lipoprotein cholesterol (HDL-C) does not attenuate increased risk of elevated triglycerides. PMID- 11606159 TI - Dementia, gastrostomy tubes, and mortality. PMID- 11606161 TI - Urban-rural differences in the quality of care for Medicare patients with acute myocardial infarction. PMID- 11606163 TI - Communications of adverse effects of medications: physician challenges and informatics readiness. PMID- 11606166 TI - Symptoms of hypoglycaemia in people with diabetes. AB - The symptoms of hypoglycaemia are fundamental to the early detection and treatment of this side-effect of insulin and oral hypoglycaemic therapy in people with diabetes. The physiology of normal responses to hypoglycaemia is described and the importance of symptoms of hypoglycaemia is discussed in relation to the treatment of diabetes. The symptoms of hypoglycaemia are described in detail. The classification of symptoms is considered and the usefulness of autonomic and neuroglycopenic symptoms for detecting hypoglycaemia is discussed. The many external and internal factors involved in the perception of symptoms are reviewed, and symptoms of hypoglycaemia experienced by people with Type 2 diabetes are addressed. Age-specific differences in the symptoms of hypoglycaemia have been identified, and are important for clinical and research practice, particularly with respect to the development of acquired hypoglycaemia syndromes in people with Type 1 diabetes that can result in impaired awareness of hypoglycaemia. In addition, the routine assessment of hypoglycaemia symptoms in the diabetic clinic is emphasized as an important part of the regular review of people with diabetes who are treated with insulin. PMID- 11606167 TI - Association of proinsulin and insulin resistance with coronary artery disease in non-diabetic south Indian men. AB - AIMS: To evaluate the association of plasma proinsulin and insulin resistance (IR) with coronary artery disease (CAD) in non-diabetic subjects. METHODS: In this case control study, 41 normoglycaemic men with angiographic evidence of CAD were compared with 41 control men matched for age and glycaemia and with no history or evidence of cardiac diseases. Estimations of plasma glucose, lipids, fasting plasma specific insulin (SI) and proinsulin (PI) were performed. IR was calculated by the homeostasis model assessment (HOMA) method. Multiple logistic regression analysis was performed to test the association of the variables with the prevalence of CAD. RESULTS: Subjects with CAD had a higher body mass index (BMI) (25.4 +/- 4.3 vs. 22.9 +/- 3.2 kg/m2, P = 0.003) and waist to hip ratio (WHR) (0.95 +/- 0.05 vs. 0.89 +/- 0.09, P = 0.001) and a lower high-density lipoprotein (HDL) cholesterol level (0.97 +/- 0.2 vs. 1.1 +/- 0.2 mmol/l, P = 0.002). They also had higher mean SI values (107.5 vs. 62.3 pmol/l, P = 0.002), PI values (19.3 vs. 5.7 pmol/l, P < 0.0001), PI/SI ratios (21.4 vs. 10.3, P < 0.0001) and HOMA IR (4.2 vs. 2.4, P = 0.004) compared with non-CAD subjects. These variables were associated with CAD in the unadjusted multiple regression analysis. In the multiple regression with the forward entry of the variables, WHR and PI only showed independent association with CAD. CONCLUSIONS: Subjects with CAD had higher levels of obesity and WHR. CAD showed an association with low HDL cholesterol, circulating PI, PI/SI ratios and IR. PMID- 11606169 TI - The effect of acute hyperglycaemia on appetite and food intake in Type 1 diabetes mellitus. AB - AIMS: To determine the effects of acute hyperglycaemia on appetite and food intake in Type 1 diabetes mellitus. METHODS: Two separate studies, each involving eight adults with uncomplicated Type 1 diabetes, were performed: one in the fasted state (A) and the other after a nutrient preload (B). In both studies, perceptions of appetite (hunger and fullness) and food intake at a buffet meal were evaluated during euglycaemia (blood glucose, approximately 6 mmol/l) and hyperglycaemia (blood glucose, approximately 14 mmol/l). Both experiments were randomized and single-blind. In study A, appetite was assessed in the fasted state for 90 min before the buffet meal. In study B, a nutrient 'preload' of Ensure and milk containing 13C-octanoic acid was consumed 90 min before the meal. Gastric emptying of the preload was quantified with a radioisotopic breath test technique. RESULTS: There was no significant difference in plasma insulin concentrations between euglycaemia and hyperglycaemia in either study. In study A, there were no differences in hunger, fullness or energy intake between the two treatment days. In study B, subjects were slightly less hungry between the preload and buffet meal during hyperglycaemia than euglycaemia (P = 0.04), and tended to have slower gastric emptying during hyperglycaemia (emptying coefficient, 3.89 +/- 0.16 vs. 3.57 +/- 0.21; P = 0.052), but there was no difference in food intake between hyperglycaemia and euglycaemia. CONCLUSIONS: Acute hyperglycaemia suppresses hunger after a nutrient preload, but not in the fasted state, in patients with uncomplicated Type 1 diabetes. This effect is small and not associated with changes in food intake. PMID- 11606168 TI - Drinking water composition and childhood-onset Type 1 diabetes mellitus in Devon and Cornwall, England. AB - AIMS: Previous studies have reported inconsistent results on the association between some compositions (e.g. nitrate) in domestic water and the risk of childhood-onset Type 1 diabetes mellitus. This study aimed to examine the relationship between nitrate, zinc and magnesium in drinking water and the risk of childhood-onset Type 1 diabetes mellitus. METHODS: The study covers the Cornwall and the former Plymouth Health Authority Regions in the far south-west of England. Five hundred and seventeen children, aged 0-15 years, diagnosed with Type 1 diabetes mellitus between 1975 and 1996, were identified for inclusion in the study. Domestic water data (nitrate, Zn, Mg, Cu, Al, Ca, Fe and Mn) between 1993 and 1997 were provided by South-west Water Plc, UK, for each of the 40 Water Supply Zones in which the subjects had been resident at the time of diagnosis. The standardized incidence ratio (SIR) of the disease was calculated for each Water Supply Zone using the UK 1991 census population data. The relationship between the SIR of the disease and the water quality indicators in thirds (three strata of low, medium and high concentrations) was examined by chi2 test for trend and Poisson regression analysis. RESULTS: The initial analyses by chi2 test for trend on the relation of SIRs and drinking water compositions suggested that copper, magnesium and nitrate might have some protective effects, but Poisson regression analyses showed that only zinc and magnesium were significant factors. The data suggest that the incidence rate of childhood diabetes is significantly lower when the concentrations of zinc and magnesium in the domestic drinking water are in the range 22.27-27.00 microg/l (incidence rate ratio (IRR), 0.76; 95% CI, 0.59-0.97) and greater than 2.61 mg/l (IRR, 0.72; 95% CI, 0.58-0.91), respectively. CONCLUSIONS: Our findings suggest evidence of a possible association between zinc and magnesium in the domestic drinking water and childhood diabetes in the far south-west of England. However, these possible protective effects of zinc and magnesium in domestic drinking water warrant further confirmation. PMID- 11606170 TI - CTLA4 gene polymorphism contributes to the mode of onset of diabetes with antiglutamic acid decarboxylase antibody in Japanese patients: genetic analysis of diabetic patients with antiglutamic acid decarboxylase antibody. AB - AIM: The mode of onset is occasionally similar in Type 1 and Type 2 diabetes mellitus, and some patients with Type 2 diabetes are positive for antiglutamic acid decarboxylase antibody (GAD Ab). We investigated the contribution of Type 1 diabetes susceptibility genes to the progression of the insulin-deficient state and mode of onset of Type 2 diabetes in GAD Ab-positive (GAD-Ab+) patients. We examined the variable number of tandem repeats in the promoter region of the insulin gene (INS-VNTR, insulin-dependent diabetes mellitus (IDDM) 2) and cytotoxic T lymphocyte antigen 4 (CTLA4, IDDM12) as representative of Type 1 diabetes susceptibility genes. METHODS: Patients with Type 2 diabetes who were GAD-Ab+ (n = 51) were selected for this study. In INS-VNTR, the class I allele was classified according to length (1S, 25-38 repeat units; 1M, 39-41 repeat units; 1L, 42-44 repeat units) and the exact class I allele length was analysed by specific polymerase chain reaction (PCR) amplifications. Analyses of classes II and III were performed by Southern blot. CTLA4 gene polymorphism (exon 1 position 49, G/A) was analysed by PCR-restriction fragment length polymorphism. RESULTS: The distribution of INS-VNTR was no different between Type 1 diabetes and Type 2 diabetes with GAD Ab. The allele frequencies of CTLA4 gene polymorphism G and A in Type 2 diabetes/GAD-Ab+ were significantly different from those of Type 1 diabetes/GAD-Ab+ (G: 53%, A: 47% vs. G: 84%, A: 16%; P < 0.0001). CONCLUSIONS: Our data showed that GAD-Ab+ Japanese patients presenting with Type 2 diabetes have shifted A allele while patients with abrupt onset have shifted G allele of CTLA4 gene polymorphism. Our results suggest that immunological function and polymorphism of the CTLA4 gene may contribute to the pathogenesis and progression of Type 1 diabetes. PMID- 11606171 TI - Prevalence of and risk factors for erectile dysfunction in Hong Kong diabetic patients. AB - AIM: To estimate the prevalence of erectile dysfunction (ED) in Chinese diabetic men and to identify its risk factors, we carried out a cross-sectional survey of 500 Chinese diabetic men attending a community hospital diabetic clinic in Hong Kong. METHODS: Patients were interviewed and asked to report on their experience of ED as defined in the National Institutes of Health Consensus Conference 1993. Diabetic complications and patient clinical data were obtained from patients' medical records. RESULTS: Of the 486 patients studied, the prevalence of ED was 63.6% (95% confidence interval 59.3-67.9%). The prevalence of ED increased with age, from 33.3% to 73.8% for diabetic men aged between 21 and 80 years (P = 0.001). Severity of ED also increased with age. Among diabetic men with ED, there was no report of complete ED for diabetic men aged 40 years and below, whereas the proportion of patients with complete ED increased from 7.4% to 71.1% between the ages of 41 and 80 years. ED occurred early in the course of the disease, with a prevalence increasing from 56.0% in men with diabetes mellitus (DM) for < 5 years to 72.0% in those with DM for > 20 years (P = 0.038). Duration of DM was also associated with severity; the proportion of patients with complete ED increased from 30.8% for those with DM for < 5 years to 72.2% for those with DM for > or = 20 years (P < 0.001). Using logistic regression analysis, DM duration, diabetic complications including retinopathy, abnormal albuminuria and sensory neuropathy, and higher level of education were associated with a higher risk of ED. By polychotomous logistic regression, age was the only factor found to be associated with the severity of ED, after adjusting for other variables. CONCLUSIONS: Chinese diabetic patients have a prevalence of self-reported ED that appears to be higher than that of Western populations. This may be due to cultural differences and the association of abnormal albuminuria and hypertension. PMID- 11606173 TI - Change of glycaemic status in Chinese subjects with impaired fasting glycaemia. AB - AIMS: To examine the risk of progression to diabetes in Chinese subjects with impaired fasting glycaemia (IFG) or normal fasting glucose (NFG). METHODS: Between 1988 and 1996, 657 Hong Kong Chinese subjects underwent annual screening, using an oral glucose tolerance test, until they had developed diabetes, or until June 1997, when the data were analysed. All subjects had a risk factor associated with the development of diabetes such as a history of gestational diabetes or a family history of diabetes. The follow-up interval for the subjects ranged from 0.87 to 8.54 years and of the 657, 319 had fasting plasma glucose levels of < 7.0 mmol/L where a fasting glucose level of > or = 7.0 mmol/L was used to diagnose diabetes RESULTS: Of the 319 nondiabetic subjects, 55 had IFG and 264 had NFG. After a median follow-up of 1.12 years (range: 0.87-8.54 years), 27 progressed to diabetes. The Kaplan-Meier analysis of progression to diabetes showed significant differences between subjects with IFG and subjects with NFG. Using Cox regression analysis, IFG (beta = 3.51, SE = 1.63, P = 0.032) and smoking (beta = 3.60, SE = 1.50, P = 0.017) were found to be independently associated with progression to diabetes. CONCLUSIONS: In Hong Kong Chinese with risk factors for glucose intolerance, IFG status is an independent risk factor for progression to diabetes. PMID- 11606172 TI - Use of an alpha-glucosidase inhibitor to maintain glucose homoeostasis during postprandial exercise in intensively treated Type 1 diabetic subjects. AB - AIM: We evaluated the effects of an alpha-glucosidase inhibitor, acarbose, on glucose homoeostasis during postprandial exercise in Type 1 diabetic subjects. METHODS: Seven Type 1 diabetic subjects with good glycaemic control on ultralente regular insulin were randomized in a single blind cross-over study to acarbose 100 mg or placebo taken with a mixed meal (600 kcal, 75 g carbohydrates), followed 90 min later by 30 min of exercise at 50% maximum aerobic capacity. Glucose turnover was measured by tracer (d-[6,6,2H2]glucose) methodology, and intestinal glucose absorption was quantified using carbohydrate polymers labelled with [13C]glucose. RESULTS: Acarbose resulted in a significant decrease in the postprandial glycaemic rise (mean +/- SEM 2.9 +/- 0.6 vs. 5.0 +/- 0.7 mmol/l; P < 0.005) and in the glycaemic nadir during exercise (- 0.8 +/- 0.6 vs. 0.9 +/- 1.3 mmol/l below baseline; P < 0.05). Total glucose appearance increased similarly under the two treatments during the postprandial (27.0 vs. 27.9 micromol per kg per min) and exercise (33.9 vs. 33.5 micromol per kg per min) periods. Mean glucose absorption was significantly delayed by acarbose (7.8 vs. 10.2 micromol per kg per min; P < 0.02), but was compensated by the lack of postprandial suppression of hepatic glucose production (106% of basal hepatic glucose production vs. 81%; P < 0.006). Episodes of hypoglycaemia were no different (three vs. six). CONCLUSION: These results indicate that, in Type 1 diabetic subjects, acarbose results in a better glycaemic profile during postprandial exercise and suggest that it could lead to a lower risk of exercise-induced hypoglycaemia due to delayed glucose absorption and less suppression of hepatic glucose production. PMID- 11606174 TI - Extreme altitude mountaineering and Type 1 diabetes; the Diabetes Federation of Ireland Kilimanjaro Expedition. AB - AIMS: To examine the effects of extreme altitude mountaineering on glycaemic control in Type 1 diabetes, and to establish whether diabetes predisposes to acute mountain sickness (AMS). METHODS: Fifteen people with Type 1 diabetes and 22 nondiabetic controls were studied during the Diabetes Federation of Ireland Expedition to Kilimanjaro. Daily insulin requirements, blood glucose estimations and hypoglycaemic attacks were recorded in diaries by the people with diabetes. The performance of blood glucose meters at altitude was assessed using standard glucose solutions. Symptoms of acute mountain sickness were recorded daily by people with diabetes and by the nondiabetic controls using the Lake Louise Scoring Charts. The expedition medical team recorded the incidence of complications of altitude and of diabetes. The final height attained for each individual was recorded by the expedition medical team and verified by the expedition guides. RESULTS: The final altitude ascended was lower in the diabetic than the nondiabetic group (5187 +/- 514 vs. 5654 +/- 307 m, P = 0.001). The mean daily insulin dose was reduced from 67.1 +/- 28.3-32.9 +/- 11.8 units (P < 0.001), but only 50% of recorded blood glucose readings were within the target range of 6-14 mmol/L. There were few hypoglycaemic attacks after the first two days of climbing. Both blood glucose meters tested showed readings as low as 60% of standard glucose concentrations at high altitude and low temperatures. The Lake Louise questionnaires showed that symptoms of AMS occurred equally in the diabetic and nondiabetic groups. There were two episodes of mild diabetic ketoacidosis; two of the diabetic group and three of the nondiabetic group developed retinal haemorrhages. CONCLUSIONS: People with Type 1 diabetes can participate in extreme altitude mountaineering. However, there are significant risks associated with this activity, including hypoglycaemia, ketoacidosis and retinal haemorrhage, with the additional difficulties in assessing glycaemic control due to meter inaccuracy at high altitude. People with Type 1 diabetes must be carefully counselled before attempting extreme altitude mountaineering. PMID- 11606175 TI - Double-blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients. AB - AIMS: Elevated levels of urinary albumin excretion rate (AER) predict high risk for progressing to end-stage renal disease. In streptozotocin-induced diabetes, supplementation with vitamin C or E reduces albuminuria and glomerular hypertrophy. We tested the hypothesis that supplementation of both vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with persistent micro/macroalbuminuria. METHODS: Thirty Type 2 diabetic patients with AER 30-300 mg/24 h were included in a double-blind randomised, cross-over trial. Patients received vitamin C (1250 mg) and vitamin E (680 IU) per day or matching placebo for 4 weeks with a 3-week wash-out period between treatment periods in random order. RESULTS: Combined treatment with vitamin C and E reduced AER by 19% (95% CI 6-34%) (p = 0.04), geometric mean 197 mg/24 h (95% CI 114-341 mg/24 h) vs. 243 mg/24 h (146-404 mg/24 h). No changes were seen in serum creatinine, haemoglobin A1C or blood pressure. Fasting plasma concentrations of vitamin C and E increased in all patients during active treatment (mean vitamin C 79.4 micromol/L (SD 27.8) vs. 41.9 micromol/L (18.4) and vitamin E 47.0 micromol/L (19.8) vs. 29.5 micromol/L (15.3), P < 0.000001). Except for two patients that started additional blood pressure lowering treatment during the run-in period, no changes in medication, food and exercise habits or in the number of smokers occurred during the study. CONCLUSION: Short-term treatment with vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with micro/macroalbuminuria. Further long-term, large-scale studies of this albuminuria reducing treatment modality are warranted. PMID- 11606176 TI - Reversible amnesia in a Type 1 diabetic patient and bilateral hippocampal lesions on magnetic resonance imaging (MRI). AB - AIMS: Intensive insulin therapy of Type 1 diabetes limits its chronic complications, but is associated with an increased risk of severe hypoglycaemia and its neuroglycopenic consequences. METHODS: Case report. RESULTS: A 24-year old male with 15 years' history of Type 1 diabetes, who was missing for 48 h, was found at home in ketoacidosis coma. Intensive care permitted a rapid improvement revealing an unexpected severe anterograde amnesia, confirmed by neuropsychological testing. MRI performed 4 days after admission showed abnormal bilateral hyperintensity signals on T2-weighted images in the hippocampus. Three months later, the patient had nearly completely recovered and resumed work. MR images and neuropsychological testing returned to normal. CONCLUSIONS: The most likely course of events favours an initial prolonged hypoglycaemic coma following insulin overdose. The hippocampal injury may be a result of hypoglycaemia. Neuropsychological testing and MRI abnormalities were completely reversible. This case underlines the potential risks of intensive insulin therapy. PMID- 11606177 TI - Abrupt onset of diabetes during interferon-alpha therapy in patients with chronic hepatitis C. AB - INTRODUCTION: Interferon-alpha (IFN-alpha) is now widely used in the treatment of chronic hepatitis C. Few patients have been reported as developing impaired glucose tolerance or diabetes mellitus (DM) using this therapy. The explanation for the development of DM in chronic hepatitis C treated with IFN-alpha is unclear. We report two patients who developed an abrupt onset of diabetes during IFN-alpha for chronic hepatitis C. CASE REPORTS: Two male middle-aged patients were admitted to our hospital for an abrupt onset of diabetes, in diabetic ketoacidosis, with a very short duration of hyperglycaemic symptoms. Their clinical course was similar. Case 1 never demonstrated any markers of pancreatic immunogenicity. Case 2 had high levels of decarboxylase glutamic acid autoantibodies (GADAb), before the IFN-alpha treatment that persisted. We compared initial beta-cell function and metabolic control with a group of middle aged patients from our hospital who had recently been diagnosed with Type 1 diabetes mellitus (DM1). In contrast to these, the onset of the disease was particularly severe with beta-cell function substantially impaired and displaying unstable short-term metabolic control. CONCLUSIONS: Type 1 diabetes should be considered as a potential complication if IFN is administered to patients with chronic hepatitis C. Its onset may be severe and result in short-term difficulties in metabolic control. PMID- 11606178 TI - A high prevalence of diabetes mellitus in a municipality of rural Crete, Greece. PMID- 11606179 TI - An unusual case of hypoglycaemia. PMID- 11606180 TI - Comparison of autoantibodies to IA-2 and GAD65 in the rapid- and the slow-onset, adult Type 1 diabetes in Thailand. PMID- 11606181 TI - Assessments of insulin sensitivity in non-obese Japanese Type 2 diabetic patients: comparison of quantitative insulin sensitivity check index with minimal model approach. PMID- 11606182 TI - Prohormone processing and Type 2 diabetes. PMID- 11606184 TI - The biosynthesis of ovothiol A (N-methyl-4-mercaptohistidine). Identification of S-(4'-L-histidyl)-L-cysteine sulfoxide as an intermediate and the products of the sulfoxide lyase reaction. AB - Crude extracts of Crithidia fasciculata catalyse the formation of 4-mercapto-L histidine, an intermediate in the biosynthesis of ovothiol A (N1-methyl-4 mercaptohistidine), in the presence of histidine, cysteine, Fe2+ and pyridoxal phosphate. This activity was present in a 35-55% ammonium sulfate fraction that was shown to produce a transsulfuration intermediate in the absence of pyridoxal phosphate. The transsulfuration intermediate was isolated and identified as S-(4' L-histidyl)-L-cysteine sulfoxide. The synthase activity, partially purified by anion-exchange chromatography, was shown to require oxygen and could be used to synthesize a number of isotopically labeled S-(4'-L-histidyl)-L-cysteine sulfoxides. Sulfoxide lyase activity was partially resolved from the synthase by anion-exchange chromatography. The phenylhydrazone of the product derived from the cysteine moiety of the sulfoxide coeluted with the phenylhydrazone of pyruvate on HPLC, but this assignment could not be confirmed by mass spectral analysis. S-(4'-[14C]L-histidyl)-[U-13C3,15N]L-cysteine sulfoxide was synthesized and converted to products of the lyase reaction in the presence of lactate dehydrogenase and NADH. The 13C-labeled product was identified by 13C-NMR spectroscopy as lactate and the primary product of the lyase reaction is therefore pyruvate. With S-(4'[3H]L-histidyl)-[14C]L-cysteine sulfoxide as the substrate [14C]lactate, [14C]cysteine and [3H]4-mercaptohistidine could be detected as products of the lyase reaction, but the sum of the two thiol species exceeded the amount of sulfoxide substrate used. Evidence is presented that this anomaly was due to the utilization of sulfur from dithiothreitol for the formation of cysteine. PMID- 11606183 TI - Different effects of tert-butylhydroperoxide-induced peroxynitrite-dependent and independent DNA single-strand breakage on PC12 cell poly(ADP-ribose) polymerase activity. AB - The short-chain lipid hydroperoxide analogue tert-butylhydroperoxide induces peroxynitrite-dependent and -independent DNA single strand breakage in PC12 cells. U937 cells that do not express constitutive nitric oxide synthase respond to tert-butylhydroperoxide treatment with peroxynitrite-independent DNA cleavage. Under experimental conditions leading to equivalent strand break frequencies, the analysis of poly(ADP-ribose) polymerase activity showed an increase in PC12 cells but not in U937 cells. The enhanced poly(ADP-ribose) polymerase activity observed in PC12 cells was paralleled by a significant decline in NAD+ content and both events were prevented by treatments suppressing formation of peroxynitrite. Although DNA breaks were rejoined at similar rates in the two cell lines, an inhibitor of poly(ADP-ribose) polymerase delayed DNA repair in PC12 cells but had hardly any effect in U937 cells. The results obtained using the latter cell type were confirmed with an additional cell line (Chinese hamster ovary cells) that does not express nitric oxide synthase. Collectively, our data suggest that tert butylhydroperoxide-induced peroxynitrite-independent DNA strand scission is far less effective than the DNA cleavage generated by endogenous peroxynitrite in stimulating the activity of poly(ADP-ribose) polymerase. PMID- 11606185 TI - Signalling events underlying platelet aggregation induced by the glycoprotein VI agonist convulxin. AB - We have investigated the role of secretion and intracellular signalling events in aggregation induced by the glycoprotein (GP)VI-selective snake venom toxin convulxin and by collagen. We demonstrate that aggregation induced by threshold concentrations of convulxin undergoes synergy with ADP acting via the P2Y12 receptor whereas there is no synergy via the P2Y1 receptor or with thromboxanes. On the other hand, apyrase, the P2Y12 receptor antagonist, AR-C67085, and indomethacin only marginally inhibit aggregation induced by convulxin. In comparison, these inhibitors severely attenuate the response to collagen. In order to investigate whether the weak inhibitory action against convulxin is due to release of agonists other than ADP from dense granules, experiments were performed on murine platelets deficient in this organelle (pearl mice platelets). A slightly greater reduction in aggregation induced by convulxin was observed in pearl platelets than in the presence of inhibitors of ADP, but a maximal response was still attained. Importantly, inhibition of protein kinase C further reduced the response to convulxin in pearl platelets demonstrating a direct role for the kinase in aggregation. Chelation of intracellular Ca2+ with 1,2-bis(2 aminophenoxy)ethane-N,N,N,N',N'-tetraacetic acid (acetoxymethyl)ester (BAPTA-AM) abolished aggregation induced by convulxin under all conditions. Activation of phospholipase C by convulxin was potentiated by ADP acting through the P2Y12 receptor. In conclusion, we show that Ca2+ and protein kinase C, but not release of the secondary agonists ADP and thromboxane A2, are required for full aggregation induced by convulxin, whereas the response induced by collagen shows a much greater dependence on secretion of secondary agonists. PMID- 11606186 TI - The two myostatin genes of Atlantic salmon (Salmo salar) are expressed in a variety of tissues. AB - Two myostatin isoforms were identified in Atlantic salmon (Salmo salar) by RT PCR, and genomic sequences encoding this negative muscle growth factor were for the first time isolated from a nonmammalian species. Salmon myostatin isoform I is transcribed in white skeletal muscle as a 2346-nucleotide mRNA species that encodes a precursor protein of 373 amino acids. Salmon myostatin I shows 93% sequence identity with isoform II which was isolated from white muscle as a partial cDNA sequence of 1409 nucleotides. In contrast to the restricted gene expression of myostatin in mammals, salmon myostatin I and II mRNAs were identified by RT-PCR in multiple tissues, including white muscle, intestine, brain, gills, tongue and eye. In addition, isoform I mRNA was found in red skeletal muscle, heart, spleen, and ovarian tissue. Using polyclonal antibodies against both isoforms, a 55-kDa precursor protein was detected by Western blot analysis in the red and white skeletal muscle, heart, intestine, and brain. Immunoreactive peptides of 35-40 kDa were identified in the gills, tongue, spleen, and head kidney, while the 25-kDa mature myostatin was found in the eye and serum, and in vitro expressed in rabbit reticulocyte lysate. Salmon myostatin was immunohistochemically localized in the sarcoplasma of red and white muscle fibres, in intestinal epithelial cells, at the basis of the branchial primary lamellae, and in odontoblasts and ameloblasts of the tongue teeth. The results indicate that the role of fish myostatin may not be restricted to muscle growth regulation, but may have additional functions similar to the growth/differentiation factor-11 in mammals. PMID- 11606187 TI - Domain-domain interactions of HtpG, an Escherichia coli homologue of eukaryotic HSP90 molecular chaperone. AB - In the present study, we investigated the domain structure and domain-domain interactions of HtpG, an Escherichia coli homologue of eukaryotic HSP90. Limited proteolysis of recombinant HtpG, revealed three major tryptic sites, i.e. Arg7 Gly8, Arg336-Glu337 and Lys552-Leu553, of which the latter two were located at the positions equivalent to the major cleavage sites of human HSP90alpha. A similar pattern was obtained by papain treatment under nondenaturing conditions but not under denaturing conditions. Thus, HtpG consists of three domains, i.e. Domain A, Met1-Arg336; domain B, Glu337-Lys552; and domain C, Leu553-Ser624, as does HSP90. The domains of HtpG were expressed and their interactions were estimated on polyacrylamide gel electrophoresis under nondenaturing conditions. As a result, two kinds of domain-domain interactions were revealed: domain B interaction with domain A of the same polypeptide and domain C of one partner with domain B of the other in the dimer. Domain B could be structurally and functionally divided into two subdomains, the N-terminal two-thirds (subdomain BI) that interacted with domain A and the C-terminal one-third (subdomain BII) that interacted with domain C. The C-terminal two-thirds of domain A, i.e. Asp116 Arg336, were sufficient for the binding to domain B. We finally propose the domain organization of an HtpG dimer. PMID- 11606188 TI - Liberation of the intramolecular interaction as the mechanism of heat-induced activation of HSP90 molecular chaperone. AB - The molecular chaperone function of HSP90 is activated under heat-stress conditions. In the present study, we investigated the role of the interactions in the heat-induced activation of HSP90 molecular chaperone. The preceding paper demonstrated two domain-domain interactions of HtpG, an Escherichia coli homologue of mammalian HSP90, i.e. an intra-molecular interaction between the N terminal and middle domains and an intermolecular one between the middle and C terminal domains. A bacterial two-hybrid system revealed that the two interactions also existed in human HSP90alpha. Partners of the interaction between the N-terminal and middle domains of human HSP90alpha could, but those between the middle and C-terminal domains could not, be replaced by the domains of HtpG. Thus, the interface between the N-terminal and middle domains is essentially unvaried from bacterial to human members of the HSP90-family proteins. The citrate synthase-binding activity of HtpG at an elevated temperature was solely localized in the N-terminal domain, but HSP90alpha possessed two sites in the N-terminal and other domains. The citrate-synthase binding activity of the N-terminal domain was suppressed by the association of the middle domain. The complex between the N-terminal and middle domains is labile at elevated temperatures, but the other is stable even at 70 degrees C. Taken together, we propose the liberation of the N-terminal client-binding domain from the middle suppressor domain is involved in the temperature-dependent activation mechanism of HSP90 molecular chaperone. PMID- 11606189 TI - Structural analysis of the lipopolysaccharide from the nontypable Haemophilus influenzae strain SB 33. AB - The structure of the core region of the lipopolysaccharide (LPS) from the nontypable Haemophilus influenzae strain SB 33 was elucidated. The LPS was subjected to a variety of degradative procedures. The structures of the derived oligosaccharide products were established by monosaccharide and methylation analyses, NMR spectroscopy and mass spectrometry. These analyses revealed a series of related phosphocholine (PCho) containing structures differing in the number of hexose residues. The results pointed to each species containing a conserved phosphoethanolamine (PEtn) substituted heptose-containing trisaccharide inner-core moiety. The major LPS glycoforms were identified as 2-Hex, 3-Hex and 4 Hex species according to the number of hexose residues present. PMID- 11606190 TI - Homocysteine-induced decrease in endothelin-1 production is initiated at the extracellular level and involves oxidative products. AB - The increased cardiovascular risk associated with hyperhomocysteinemia has been partly related to homocysteine (Hcy)-induced endothelial cell dysfunction. However, the intra or extracellular starting point of the interaction between Hcy and endothelial cells, leading to cellular dysfunction, has not yet been identified. We investigated the effects of both intracellular and extracellular Hcy accumulation on endothelin-1 (ET-1) synthesis by cultured human endothelial cells. Incubation of cultures with methionine (1.0 mmol x L(-1)) for 2 h induced a slight increase in cellular Hcy content but no change in ET-1 production. Incubation of cells with Hcy (0.2 mmol x L(-1)) led to a significant fall in ET-1 generation, accompanied by a significant increase in cellular Hcy content. Addition of the amino-acid transport system L substrate 2-amino-2-norbornane carboxylic acid had no effect on the Hcy-induced decrease in ET-1 production but significantly inhibited the Hcy-induced increase in the cellular Hcy content. Incubation of cells with a lower Hcy concentration (0.05 mmol x L(-1)) also reduced ET-1 production without increasing the cellular Hcy content. Co incubation with extracellular free-radical inhibitors (superoxide dismutase, catalase and mannitol) markedly reduced the effect of Hcy on ET-1 production. Thus, it is extracellular Hcy accumulation that triggers the decrease in ET-1 production by endothelial cells through oxidative products. PMID- 11606191 TI - Targeted disruption of a pupal hemocyte protein of Sarcophaga by RNA interference. AB - Previously, we purified a transmembrane protein with a molecular mass of 120 kDa (p120) that is exclusively expressed in pupal hemocytes of Sarcophaga. In this study, we demonstrated that double-stranded RNA (dsRNA) injected into the larval body cavity effectively inhibited the expression of p120 in pupal hemocytes. Thus, RNA interference (RNAi) was found to be a useful technique for creating pupal hemocytes with a loss-of-function of a specific protein. The p120-less pupal hemocytes generated by RNAi were found to have lost the ability to take up acetylated low density lipoprotein, indicating that p120 is a scavenger receptor specifically expressed on the surface of pupal hemocytes. PMID- 11606192 TI - Characterization of the human and mouse genes for the alpha subunit of type II prolyl 4-hydroxylase. Identification of a previously unknown alternatively spliced exon and its expression in various tissues. AB - Prolyl 4-hydroxylase (4-PH) catalyzes the formation of 4-hydroxyproline in -X-Pro Gly- sequences and has a central role in the synthesis of all collagens. We report here on the cloning and characterization of the genes encoding the catalytic alpha(II) subunits of the human and mouse type II 4-PH [alpha(II)]2beta2 tetramers. The human and mouse genes are approximately 34.6 kb and 30.3 kb in size, respectively, and both consist of 16 exons. The translation initiation codons are located in exon 2, and the sizes of the exons consisting entirely of coding sequences are conserved in the two genes, varying from 54 to 240 bp, whereas the exons 1, containing the transcription initiation sites and 5' untranslated sequences, are 546 bp and 293 bp in the human and mouse, respectively. The sizes of the introns vary from 48 to 49 bp to over 8 kb in both genes. The 5' flanking regions contain no TATA box, but they and introns 1 contain several motifs that may act as transcription factor binding sites, including those for Sox9, which regulates chondrocyte-specific expression of collagens II, IX and XI. Unlike the human alpha(I) gene, the alpha(II) genes do not contain an alternatively spliced exon homologous to exon 9. However, a novel mutually exclusively spliced alternative exon 12a was identified in both genes. The nucleotide and amino-acid sequence identities between the 60-bp exon 12a and 66-bp exon 12b are about 35% and 45%, respectively, in both human and mouse genes. PCR analyses showed that both types of exon 12 are expressed in all tissues studied, except for adult leukocytes that expressed only mRNAs containing exon 12b sequences. Insect cell expression studies showed that a recombinant alpha(II) subunit containing amino acids coded by exon 12a associated with the beta subunit to form a fully active enzyme tetramer. PMID- 11606193 TI - Phenylcoumaran benzylic ether and isoflavonoid reductases are a new class of cross-reactive allergens in birch pollen, fruits and vegetables. AB - We investigated the biochemical function of the birch pollen allergen Bet v 6 and its role in the IgE-cross-reactivity between birch pollen and plant foods, and characterized Pyr c 5, a Bet v 6-related food allergen, from pear; the proteins were expressed as His-Tag fusion proteins in Eschershia coli and purified by Ni chelate affinity chromatography under native conditions. Nonfusion proteins were obtained by factor Xa protease treatment. The highest degree of amino-acid sequence identity of Pyr c 5 and Bet v 6 was found with a plant protein related to a defense mechanism, which we have named phenylcoumaran benzylic ether reductase (PCBER) based on its ability to catalyze the NADPH-dependent reduction of 8-5' linked lignans such as dehydrodiconiferyl alcohol to give isodihydrodehydrodiconiferyl alcohol. Enzymatic assays with recombinant Pyr c 5 and Bet v 6 showed PCBER catalytic activity for both recombinant allergens. Both Pyr c 5 and Bet v 6 allergens had similar IgE binding characteristics in immunoblotting and enzyme allergosorbent tests (EAST), and bound IgE from 10 sera of birch-pollen-allergic patients including six pear-allergic subjects. EAST inhibition experiments with Pyr c 5 as the solid phase antigen suggested that homologous allergens may be present in many vegetable foods such as apple, peach, orange, lychee fruit, strawberry, persimmon, zucchini (courgette), and carrot. In extracts of pear, apple, orange, and persimmon, the presence of proteins of approximately 30-35 kDa containing Bet v 6 cross-reactive epitopes was demonstrated with two Bet v 6-specific monoclonal antibodies. Recombinant Pyr c 5 triggered a strong, dose-dependent mediator release from basophils of a pear allergic subject, suggesting that Pyr c 5 has the potential to elicit type I allergic reactions. PMID- 11606194 TI - Physiological and biochemical characteristics of poly gamma-glutamate synthetase complex of Bacillus subtilis. AB - An enzymatic system for poly gamma-glutamate (PGA) synthesis in Bacillus subtilis, the PgsBCA system, was investigated. The gene-disruption experiment showed that the enzymatic system was the sole machinery of PGA synthesis in B. subtilis. We succeeded in achieving the enzymatic synthesis of elongated PGAs with the cell membrane of the Escherichia coli clone producing PgsBCA in the presence of ATP and D-glutamate. The enzyme preparation solubilized from the membrane with 8 mM Chaps catalyzed ADP-forming ATP hydrolysis only in the presence of glutamate; the D-enantiomer was the best cosubstrate, followed by the L-enantiomer. Each component of the system, PgsB, PgsC, and PgsA, was translated in vitro and the glutamate-dependent ATPase reaction was kinetically analyzed. The PGA synthetase complex, PgsBCA, was suggested to be an atypical amide ligase. PMID- 11606195 TI - The C-terminal fragment of the Alzheimer's disease amyloid protein precursor is degraded by a proteasome-dependent mechanism distinct from gamma-secretase. AB - The beta-amyloid protein (Abeta) is derived by proteolytic processing of the amyloid protein precursor (APP). Cleavage of APP by beta-secretase generates a C terminal fragment (APP-CTFbeta), which is subsequently cleaved by gamma-secretase to produce Abeta. The aim of this study was to examine the cleavage of APP CTFbeta by gamma-secretase in primary cortical neurons from transgenic mice engineered to express the human APP-CTFbeta sequence. Neurons were prepared from transgenic mouse cortex and proteins labelled by incubation with [35S]methionine and [35S]cysteine. Labelled APP-CTFbeta and Abeta were then immunoprecipitated with a monoclonal antibody (WO2) specific for the transgene sequences. Approximately 30% of the human APP-CTFbeta (hAPP-CTFbeta) was converted to human Abeta (hAbeta), which was rapidly secreted. The remaining 70% of the hAPP-CTFbeta was degraded by an alternative pathway. The cleavage of hAPP-CTFbeta to produce hAbeta was inhibited by specific gamma-secretase inhibitors. However, treatment with proteasome inhibitors caused an increase in both hAPP-CTFbeta and hAbeta levels, suggesting that the alternative pathway was proteasome-dependent. A preparation of recombinant 20S proteasome was found to cleave a recombinant cytoplasmic domain fragment of APP (APPcyt) directly. The study suggests that in primary cortical neurons, APP-CTFbeta is degraded by two distinct pathways, one involving gamma-secretase, which produces Abeta, and a second major pathway involving direct cleavage of APP-CTFbeta within the cytoplasmic domain by the proteasome. These results raise the possibility that defective proteasome function could lead to an increase in Abeta production in the AD brain. PMID- 11606196 TI - The C-terminal half of Hsp90 is responsible for its cytoplasmic localization. AB - With some exceptions, research so far has shown heat shock protein (Hsp) 90 to be a cytoplasmic protein. Here, we studied the sequence determinants which dictate the subcellular localization of Hsp90. By constructing hybrid molecules between a nuclear protein, progesterone receptor (PR), and parts of Hsp90, we demonstrated that the C-terminal but not the N-terminal half of Hsp90 can prevent nuclear translocation of the PR. Studies with an antibody raised against a region which contains the major nuclear localization signal (NLS) of the PR suggest that the inhibition of nuclear localization is not due to steric hindrance of the NLS of the PR by Hsp90 sequences in hybrid molecules. In order to characterize further the cytoplasmic anchoring of Hsp90 we constructed four chimeric molecules between the C-terminal half of Hsp90 and estrogen receptor (ER) with different numbers of nuclear localization protosignals (proto-NLS). When the C-terminal half of Hsp90 was fused with ER containing no or one proto-NLS, the hybrid molecule was located exclusively in the cytoplasm. When the nuclear translocation signal was strengthened by adding two or three protosignals, the hybrid molecule was exclusively nuclear. These results suggest that the C-terminal half of Hsp90 contains a sequence which is responsible for the cytoplasmic localization of the protein. Further deletions of the molecule suggested that the cytoplasmic anchoring signal is located between amino acids 333 and 664. PMID- 11606197 TI - The human oesophageal squamous epithelium exhibits a novel type of heat shock protein response. AB - The human oesophageal epithelium is subject to damage from thermal stresses and low extracellular pH that can play a role in the cancer progression sequence, thus identifying a physiological model system that can be used to determine how stress responses control carcinogenesis. The classic heat shock protein HSP70 is not induced but rather is down-regulated after thermal injury to squamous epithelium ex vivo; this prompted a longer-term study to address the nature of the heat shock response in this cell type. An ex vivo epithelial culture system was subsequently used to identify three major proteins of 78, 70, and 58 kDa, whose steady-state levels are elevated after heat shock. Two of the three heat shock proteins were identified by mass spectrometric sequencing to be the calcium calmodulin homologue transglutaminase-3 (78 kDa) and a recently cloned oesophageal-specific gene called C1orf10, which encodes a 53-kDa putative calcium binding protein we have named squamous epithelial heat shock protein 53 (SEP53). The 70-kDa heat shock protein (we have named SEP70) was not identifiable by mass spectrometry, but it was purified and studied immunochemically to demonstrate that it is distinct from HSP70 protein. Monoclonal antibodies to SEP70 protein were developed to indicate that: (a) SEP70 is induced by exposure of cultured cells to low pH or glucose starvation, under conditions where HSP70 protein was strikingly down-regulated; and (b) SEP70 protein exhibits variable expression in preneoplastic Barrett's epithelium under conditions where HSP70 protein is not expressed. These results indicate that human oesophageal squamous epithelium exhibits an atypical heat shock protein response, presumably due to the evolutionary adaptation of cells within this organ to survive in an unusual microenvironment exposed to chemical, thermal and acid reflux stresses. PMID- 11606198 TI - Engineering of the protein environment around the redox-active TyrZ in photosystem II. The role of F186 and P162 in the D1 protein of Synechocystis 6803. AB - The photosystem II reaction centre protein D1 is encoded by the psbA gene. By activation of the silent and divergent psbA1 gene in the cyanobacterium Synechocystis 6803, a novel D1 protein, D1', was produced [Salih, G. & Jansson, C. (1997) Plant Cell 9, 869-878]. The D1' protein was found to be fully operational although it deviates from the normal D1 protein in 54 out of 360 amino acids. Two notable amino-acid substitutions in D1' are the replacements of F186 by a leucine and P162 by a serine. The F186 and P162 positions are located in the vicinity of the reaction centre chlorophyll dimer P680 and the redox active Y161 (TyrZ), and F186 has been implicated in the electron transfer between Y161 and P680. The importance of F186 was addressed by construction of engineered D1 proteins in Synechocystis 6803. F186 was replaced by leucine, serine, alanine, tyrosine or tryptophan. Only the leucine replacement yielded a functional D1 protein. Other substitutions did not support photoautotrophic growth and the corresponding mutants showed no or very poor oxygen evolving activity. In the F186Y and F186W mutants, the D1 protein failed to accumulate to appreciable levels in the thylakoid membrane. The F186S mutation severely increased the light sensitivity of the D1 protein, as indicated by the presence of a 16-kDa proteolytic degradation product. We conclude that the hydrophobicity and van der Waals volume are the most important features of the residue at position 186. Exchanging P162 for a serine yielded no observable phenotype. PMID- 11606199 TI - Molecular dynamics simulations of solvated UDP-glucose in interaction with Mg2+ cations. AB - Glycosyltransferases are key enzymes involved in biosynthesis of oligosaccharides. Nucleotide-sugars, the glycosyltransferase substrates, serve as activated donors of sugar residues during the enzymatic reaction Although very little is known about the catalytic mechanism of these enzymes, it appears that the catalytic activity in most glycosyltransferases is dependent upon the presence of a divalent cation, for example Mn2+ or Mg2+. It is not known whether the ion is bound to the enzyme before its interaction with the substrate, or if it binds the substrate before the enzymatic reaction to modify its conformation to fit better the active site of the enzyme. We have inspected the latter possibility by running four 2-ns molecular dynamics trajectories on fully solvated UDP-glucose in the presence of Mg2+ ions. Our results indicate that the divalent cation interacts strongly with the nucleotide-sugar in solution, and that it can alter its conformational behavior. It is also shown that a conformation of the pyrophosphate moiety that results in an eclipsed or almost eclipsed orientation of two of the oxygen atoms, and which is found in protein interacting with a nucleotide di- or tri-phosphate X-ray data, is energetically favored. The results are also discussed in light of existing NMR data, and are found to be in a good agreement with them. PMID- 11606200 TI - Phosphorylation of eukaryotic initiation factor 4E (eIF4E) at Ser209 is not required for protein synthesis in vitro and in vivo. AB - Eukaryotic translation initiation factor 4E (eIF4E) is essential for efficient translation of the vast majority of capped cellular mRNAs; it binds the 5' methylated guanosine cap of mRNA and serves as a nucleation point for the assembly of the 48S preinitiation complex. eIF4E is phosphorylated in vivo at residue 209 of the human sequence. The phosphorylated form is often regarded as the active state of the protein, with ribosome-associated eIF4E enriched for the phosphorylated form and increased phosphorylation often correlated with upregulation of rates of protein synthesis. However, the only reported measured effect attributable to phosphorylation at the physiological site has been a relatively small increase in the affinity of eIF4E for the mRNA m7GTP cap structure. Here, we provide data to suggest that phosphorylation of eIF4E at Ser209 is not required for translation. eIF4E that is modified such that it cannot be phosphorylated (Ser209-->Ala), is unimpaired in its ability to restore translation to an eIF4E-dependent in vitro translation system. In addition, both the wild-type and mutant forms of eIF4E interact equally well with eIF4G, with the phosphorylation of eIF4E not required to effect the change in conformation of eIF4G that is required for efficient cleavage of eIF4G by L-protease. Furthermore, we show that wild-type and phosphorylation-site variants of eIF4E protein are equally able to rescue the lethal phenotype of eIF4E deletion in S. cerevisiae. PMID- 11606201 TI - Analysis of a putative voltage-gated prokaryotic potassium channel. AB - Most of the completely sequenced prokaryotic genomes contain genes of potassium channel homologues, but there is still not much known about the role of these proteins in prokaryotes. Here we describe the large-scale overproduction and purification of a prokaryotic voltage-gated potassium channel homologue, Kch, from Escherichia coli. After successful overproduction of the protein, a specific increase in the potassium permeability of the cells was found. Kch could be purified in large amounts using classical purification methods to prevent aggregation of the protein. The physiological state of the protein was revealed to be a homotetramer and the protein was shown to be localized to the cytoplasmic membrane of the cells. In the course of the localization studies, we found a specific increase in the density of the cytoplasmic membrane on Kch production. This was linked to the observed increase in the protein to lipid ratio in the membranes. Another observed change in the membrane composition was an increase in the cardiolipin to phosphatidylglycerol ratio, which may indicate a specific cardiolipin requirement of Kch. On the basis of some of our results, we discuss a function for Kch in the maintenance of the membrane potential in E. coli. PMID- 11606202 TI - A Drosophila MBD family member is a transcriptional corepressor associated with specific genes. AB - DNA methylation in Drosophila melanogaster is restricted temporally during development and occurs at a significantly lower frequency than in mammals. Thus, the regulatory functions, if any, of this form of DNA modification in Drosophila are unclear. However, the presence of homologs of vertebrate methyl-CpG-binding proteins implies functional consequences for DNA methylation in flies. This work describes the properties of dMBD-like, a Drosophila homolog of vertebrate MBD2 and MBD3. dMBD-like and dMBD-likeDelta (a splice variant) failed to bind model methylated DNA probes, inconsistent with their function as mediators of methyl CpG-directed transcriptional repression. However, the MBD-like proteins exhibit transcriptional and biochemical properties consistent with roles as components of a histone deacetylase-dependent corepressor complex similar to the vertebrate Mi 2 complex. The two proteins are differentially expressed during development, suggesting functional specialization. dMBD-like and/or dMBD-likeDelta is present at the chromocenter on larval polytene chromosomes as well as at discrete bands interspersed along the euchromatic chromosome arms, many of which are coincident with known ecdysone-induced loci. This banding pattern suggests gene-specific regulatory functions for dMBD-like and the Drosophila Mi-2 complex. PMID- 11606203 TI - Isolation and characterization of a novel type of neurotoxic peptide from the venom of the South African scorpion Parabuthus transvaalicus (Buthidae). AB - The venom of the South African scorpion Parabuthus transvaalicus was characterized using a combination of mass spectrometry and RP-HPLC separation and bioassays. The crude venom was initially separated into 10 fractions. A novel, moderately toxic but very high abundance peptide (birtoxin) of 58 amino-acid residues was isolated, identified and characterized. Each purification step was followed by bioassays and mass spectroscopy. First a C4 RP-HPLC column was used, then a C18 RP Microbore column purification resulted in > 95% purity in the case of birtoxin from a starting material of 230 microg of crude venom. About 12-14% of the D214 absorbance of the total venom as observed after the first chromatography step was composed of birtoxin. This peptide was lethal to mice at low microgram quantities and it induced serious symptoms including tremors, which lasted up to 24 h post injection, at submicrogram amounts. At least seven other fractions that showed different activities including one fraction with specificity against blowfly larvae were identified. Identification of potent components is an important step in designing and obtaining effective anti-venom. Antibodies raised against the critical toxic components have the potential to block the toxic effects and reduce the pain associated with the scorpion envenomation. The discovery of birtoxin, a bioactive long chain neurotoxin peptide with only three disulfide bridges, offers new insight into understanding the role of conserved disulfide bridges with respect to scorpion toxin structure and function. PMID- 11606204 TI - The Aspergillus niger D-xylulose kinase gene is co-expressed with genes encoding arabinan degrading enzymes, and is essential for growth on D-xylose and L arabinose. AB - The Aspergillus niger D-xylulose kinase encoding gene has been cloned by complementation of a strain deficient in D-xylulose kinase activity. Expression of xkiA was observed in the presence of L-arabinose, L-arabitol and D-xylose. Expression of xkiA is not mediated by XLNR, the xylose-dependent positively acting xylanolytic regulator. Although the expression of xkiA is subject to carbon catabolite repression, the wide domain regulator CREA is not directly involved. The A. niger D-xylulose kinase was purified to homogeneity, and the molecular mass determined using electrospray ionization mass spectrometry agreed with the calculated molecular mass of 62816.6 Da. The activity of XKIA is highly specific for D-xylulose. Kinetic parameters were determined as Km(D-xylulose) = 0.76 mM and Km(ATP) = 0.061 mM. Increased transcript levels of the genes encoding arabinan and xylan degrading enzymes, observed in the xylulose kinase deficient strain, correlate with increased accumulation of L-arabitol and xylitol, respectively. This result supports the suggestion that L-arabitol may be the specific low molecular mass inducer of the genes involved in arabinan degradation. It also suggests a possible role for xylitol in the induction of xylanolytic genes. Conversely, overproduction of XKIA did not reduce the size of the intracellular arabitol and xylitol pools, and therefore had no effect on expression of genes encoding xylan and arabinan degrading enzymes nor on the activity of the enzymes of the catabolic pathway. PMID- 11606205 TI - Biotinylation of histones in human cells. Effects of cell proliferation. AB - An enzymatic mechanism has been proposed by which biotinidase may catalyze biotinylation of histones. Here, human cells were found to covalently bind biotin to histones H1, H2A, H2B, H3, and H4. Cells respond to proliferation with increased biotinylation of histones; biotinylation increases early in the cell cycle and remains increased during the cycle. Notwithstanding the catalytic role of biotinidase in biotinylation of histones, mRNA encoding biotinidase and biotinidase activity did not parallel the increased biotinylation of histones in proliferating cells. Biotinylation of histones might be regulated by enzymes other than biotinidase or by the rate of histone debiotinylation. PMID- 11606206 TI - Functional expression and characterization of the cytoplasmic aminopeptidase P of Caenorhabditis elegans. AB - Aminopeptidase P (AP-P; X-Pro aminopeptidase; EC 3.4.11.9) cleaves the N-terminal X-Pro bond of peptides and occurs in mammals as both cytosolic and plasma membrane forms, encoded by separate genes. In mammals, the plasma membrane AP-P can function as a kininase, but little is known about the physiological role of the cytosolic enzyme. The C. elegans genome contains a single gene encoding AP-P (W03G9.4), analysis of which predicts regions displaying high levels of amino acid sequence homology between the predicted gene product and mammalian cytoplasmic AP-P, with the absolute conservation of key catalytic residues. The sequence of an EST (yk91g4), comprising the open reading frame of W03G9.4, confirmed the predicted genomic structure of the gene and the prediction that W03G9.4 codes for a nonsecreted protein with a molecular mass of 68 kDa. Nematodes transformed with a promoter reporter construct, W03G9.4:GFP, showed high levels of fluorescence in the intestine of larvae and adult hermaphrodites, indicating that the intestine is a major site of W03G9.4 expression. yk91g4 tagged with a hexahistidine and DLYDDDDK peptide epitope was expressed in Escherichia coli to yield, after affinity purification, a recombinant protein with a molecular mass of 71 kDa. The recombinant W03G9.4 removed the N-terminal amino acid from bradykinin (RPPGFSPFR), a Caenorhabditis elegans neuropeptide (KPSFVRFamide) and Lem Trp 1 (APSGFLGVRamide), but did not display activity towards angiotensin I (NRVYIHPFHL), des-Arg bradykinin and AF1 (KNEFIRFamide). The activity towards bradykinin was inhibited by EDTA and 1, 10 phenanthroline, as expected for a metalloenzyme, and also by apstatin (IC50, 1 microM), a selective inhibitor of mammalian AP-P. A Km of 45 microM and an optimum pH of 7-8 was observed with bradykinin as the substrate. The activity of the nematode AP-P, like its mammalian counterparts, was strongly influenced by metal ions, with Co2+, Mn2+ and Zn2+ all inhibiting the hydrolysis of bradykinin. We conclude that W03G9.4 codes for a cytoplasmic AP-P with very similar enzymatic properties to those of mammalian AP-P, and we suggest that the enzyme has a physiological role in the intracellular hydrolysis of proline-containing peptides absorbed from the lumen of the intestine. PMID- 11606207 TI - Thermal unfolding of monomeric and dimeric beta-lactoglobulins. AB - The thermal stabilities of dimeric bovine beta-lactoglobulin and monomeric equine beta-lactoglobulin were investigated at neutral pH by means of differential scanning calorimetry, circular dichroism, tryptophan fluorescence, and by binding of an hydrophobic probe. Differential scanning calorimetry showed the presence of two structural domains with different thermal stabilities in both proteins. Thermodynamic analysis of the calorimetric signal revealed that the two domains unfold independently according to a mechanism where an equilibrium step is followed by an irreversible transition. The spectroscopic data supported this model and allowed recognition of the structural regions corresponding to the more thermally stable domain. The differences in thermal stability between the two proteins can be primarily ascribed to the properties of the less stable domain. PMID- 11606208 TI - Coupling of endothelin receptors to the ERK/MAP kinase pathway. Roles of palmitoylation and G(alpha)q. AB - Endothelins are potent mitogens that stimulate extracellular signal-regulated kinases (ERK/MAP kinases) through their cognate G-protein-coupled receptors, ET(A) and ET(B). To address the role of post-translational ET receptor modifications such as acylation on ERK activation and to identify relevant downstream effectors coupling the ET receptor to the ERK signaling cascades we have constructed a panel of palmitoylation-deficient ET receptor mutants with differential G(alpha) protein binding capacity. Endothelin-1 stimulation of wild type ET(A) or ET(B) induced a fivefold to sixfold increase in ERK in COS-7 and CHO cells whereas full-length nonpalmitoylated ET(A) and ET(B) mutants failed to stimulate ERK. A truncated ET(B) lacking the C-terminal tail domain including putative phosphorylation and arrestin binding site(s) but retaining the critical palmitoylation site(s) was still able to fully stimulate ERK activation. Using mutated ET receptors with selective G-protein-coupling we found that endothelin induced stimulation of G(alpha)q, but not of G(alpha)i or G(alpha)s, is essential for endothelin-mediated ERK activation. Inhibition of protein kinases A and C or epidermal growth factor receptor kinase failed to prevent ET(A)- and ET(B) mediated ERK activation whereas blockage of phospholipase C-beta completely abrogated endothelin-promoted ERK activation through ET(A) and ET(B) in recombinant COS-7 and native C6 cells. Complex formation of Ca2+ or inhibition of Src family tyrosine kinases prevented ET-1-induced ERK-2 activation in C6-cells. Our results indicate that endothelin-promoted ERK/MAPK activation criticially depends on palmitoylation but not on phosphorylation of ET receptors, and that the G(alpha)q/phospholipase C-beta/Ca2+/Src signaling cascade is necessary for efficient coupling of ET receptors to the ERK/MAPK pathway. PMID- 11606209 TI - Transcriptional regulation of the ovine intestinal Na+/glucose cotransporter SGLT1 gene. Role of HNF-1 in glucose activation of promoter function. AB - Dietary sugars D-glucose and D-galactose are transported across the intestinal brush-border membrane by the Na+/glucose cotransporter, SGLT1. In various species studied, it has been shown that the activity, and expression, of intestinal SGLT1 is regulated by dietary sugars. We report in this paper that regulation of the intestinal SGLT1 gene by lumenal sugar is due, in part, to an increase in transcription. Using deletion analyses of the -66/+21-bp fragment, we have identified the minimal region of the ovine SGLT1 promoter able to support transcription. Site-directed mutagenesis of the hepatic nuclear factor-1 (HNF-1) consensus motif within this domain eliminates basal promoter function. In addition, we show direct evidence for glucose-induced activation of the -66/+21 bp promoter region. There is a co-ordinated decline in the abundance of ovine intestinal HNF-1 and SGLT1 transcripts during transition from preruminant to adult ruminant. This decline is recovered after glucose infusion of adult sheep intestine. Similarly, as shown using DNA mobility-shift assays, the intensity of the HNF-1-binding complex to the target promoter sequence decreases during maturation of the animal; this is restored after intestinal sugar infusion. These data indicate that HNF-1 plays an important role in the glucose responsiveness of the ovine SGLT1 gene. This is the first report of in vitro glucose-induced activation of the intestinal SGLT1 promoter and identification of a glucose responsive region of the ovine SGLT1 promoter. PMID- 11606210 TI - Artificial chaperone mediated refolding of xylanase from an alkalophilic thermophilic Bacillus sp. Implications for in vitro protein renaturation via a folding intermediate. AB - To gain insight into the molecular aspects of unfolding/refolding of enzymes from extremophilic organisms, we have used xylanase from an alkalophilic thermophilic Bacillus as the model system. Kinetics of denaturation/renaturation were monitored using intrinsic fluorescence studies. The protein fluorescence measurements suggested a putative intermediate state present in 0.08 M guanidine hydrochloride with an emission maximum of 345 nm; the far-UV circular dichroism spectra revealed content of secondary structure similar to the native enzyme. Studies with the fluorescent apolar probe 1-anilinonapthalene-8-sulfonate (1,8 ANS) were consistent with the presence of increased hydrophobic surfaces as compared with the native or fully unfolded protein. The refolding of Xyl II, was attempted by a relatively new strategy using an artificial chaperone assisted two step method. The unfolded xylanase was found to bind to the detergent transiently and the subsequent addition of methyl-beta-cyclodextrin helped to strip the detergent and assist in the folding. Our findings suggested that the detergent stabilized a putative intermediate in the folding pathway seemingly equivalent to the folding state described as molten globule. The reactivation of Xyl II was affected by ionic as well as nonionic detergents. However, the cationic detergent cetyltrimethylammonium bromide (CTAB) provided a maximum reactivation (threefold) of the enzyme. The 'delayed detergent addition' experiments revealed that the detergent acts by suppressing the initial aggregate formation and not by dissolving aggregates. The relevance of our findings to the role of artificial chaperones in vivo is discussed. PMID- 11606211 TI - Reaction of hen egg white lysozyme with Fischer-type metallocarbene complexes. Characterization of the conjugates and determination of the metal complex binding sites. AB - The introduction of heavy atoms into protein crystals is sometimes rendered difficult and tedious because of the poor specificity of the available reagents for particular target residues. On the other hand, transition organometallic chemistry offers an almost untouched field for this purpose. In particular, Fischer-type metallocarbene complexes of the general formula (CO)5W=C(OR1)R2 may be attractive reagents because they contain the heavy element tungsten and specifically target amino groups to form stable, covalent aminocarbene adducts. With a small protein such as hen egg white lysozyme (HEWL) with a limited number of potential binding sites, it was possible to form protein-aminocarbene conjugates that have an average of one aminocarbene moiety per protein molecule. RP-HPLC combined with matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MS analysis of the conjugates revealed that they were mixtures of the native protein, monoaminocarbenes and diaminocarbenes. Tryptic proteolysis experiments performed on the protein conjugates combined with MALDI-TOF-MS analysis of the aminocarbenic peptides allowed us to determine that lysines 13, 33, 97 and 116 were involved in the reaction of HEWL with (CO)5W=C(OMe)Me. PMID- 11606212 TI - Insect neuropeptide antagonist. Part II. Synthesis and biological activity of backbone cyclic and precyclic PBAN antagonists. AB - A new approach for the design and synthesis of pheromone biosynthesis activating neuropeptide (PBAN) agonists and antagonists using the backbone cyclization and cycloscan concepts is described. Two backbone cyclic (BBC) libraries were synthesized: library I (Ser library) was based on the active C-terminal hexapeptide sequence Tyr-Phe-Ser-Pro-Arg-Leu-NH2 of PBAN1-33NH2; whereas library II (D-Phe library) was based on the sequence of the PBAN lead linear antagonist Arg-Tyr-Phe-d-Phe-Pro-Arg-Leu-NH2. In both libraries the Pro residue was replaced by the BBC building unit Nalpha-(omega-aminoalkyl) Gly having various lengths of alkyl chain. The peptides of the two libraries were tested for agonistic and antagonistic activity. Four precyclic peptides based on two of the BBC antagonists were also synthesized; their activity revealed that a negative charge at the N-terminus of the peptide abolished antagonistic activity. We also describe the use of the reagent SiCl3I for selective deprotection of the Boc group from the building unit prior to on-resin amino-end to backbone-nitrogen (AE BN) cyclization, during solid-phase synthesis with Fmoc chemistry. PMID- 11606214 TI - Conformation and other biophysical properties of cyclic antimicrobial peptides in aqueous solutions. AB - As a step towards understanding the mechanism of the biological activity of cyclic antimicrobial peptides, the biophysical properties and conformations of four membrane-active cyclic peptide antibiotics, based on gramicidin S (GS), were examined in aqueous environments. These cyclic peptides, GS10 [cyclo(VKLdYP)2], GS12 [cyclo(VKLKdYPKVKLdYP)], GS14 [cyclo(VKLKVdYPLKVKLdYP)] and [d-Lys]4GS14 [cyclo(VKLdKVdYPLKVKLdYP)] (d-amino acid residues are denoted by d and are underlined) had different ring sizes of 10, 12 and 14 residues, were different in structure and amphipathicity, and covered a broad spectrum of hemolytic and antimicrobial activities. GS10, GS12 and [d-Lys]4GS14 were shown to be monomeric in buffer systems with ionic strength biological environments. GS14 was also monomeric at low concentrations, but aggregated at concentrations > 50 microm. The affinity of peptides for self-assembly and interaction with hydrophobic surfaces was related to their free energy of intermolecular interaction. The effects of variations in salt and organic solvent (trifluoroethanol) concentration and temperature on peptide conformation were also examined. Similar to GS, GS10 proved to have a stable and rather rigid conformation in different environments and over a broad range of temperatures, whereas GS12, GS14 and [d Lys]4GS14 had more flexible conformations. Despite its conformational similarity to GS10, GS14 had unique physicochemical properties due to its tendency to aggregate at relatively low concentrations. The biophysical data explain the direct relation between structure, amphipathicity and hydrophobicity of the cyclic peptides and their hemolytic activity. However, this relation with the antimicrobial activity of the peptides is of a more complex nature due to the diversity in membrane structures of microorganisms. PMID- 11606213 TI - Plasmodium falciparum: binding studies of peptide derived from the sporozoite surface protein 2 to Hep G2 cells. AB - Plasmodium falciparum sporozoite surface protein 2 (Pf SSP2), also called thrombospondin related anonymous protein (TRAP), is involved in the process of sporozoite invasion of hepatocytes. Pf SSP2/TRAP possesses two different adhesion domains sharing sequences and structural homology with von Willebrand factor A domains and human repeat I thrombospondin (TSP). Pf SSP2/TRAP has also been implicated in sporozoite mobility and in mosquito salivary gland invasion processes. We tested 15-mer long synthetic peptides having five overlapping residues covering the complete protein Pf SSP2 sequence in binding assays to Hep G2 cells. In these 57 peptides, 21 high-activity binding peptides (HABPs) were identified; five were in the adhesion domains already described and 16 were in two regions toward the protein's carboxy and middle terminal part. Six HABPs showed conserved amino acid sequences: 3243 (21FLVNGRDVQNNIVDE35), 3279 (201FLVGCHPSDGKCNLY215), 3287 (241TASCGVWDEWSPCSV255), 3289 (251SPCSVTCGKGTRSRK265), 3327 (441ERKQSDPQSQDNNGNY455) and 3329 (451DNNGNRHVPNSEDREY465). The HABPs show saturable binding and dissociation constants between 140 and 900 nm with 40 000-855 000 binding sites per cell. The 3279 (201FLVGCHPSDGKCNLY215), 3323 (421NDKSDRYIPYSPLSP435) and 3331 (461SEDRETRPHGRNNENY475) HABPs have B epitopes in their sequences; these have previously been recognized by antibodies partially inhibiting hepatocyte invasion and development of the hepatic state. The 3287 (241TASCGVWDEWSPCSV255) and 3289 (251SPCSVTCGKGTRSRK265) HABPs share common sequences with the Pf SSP2/TRAP region II plus, which is present in a great number of adhesion proteins. Based on this information, six new peptides covering the high binding regions identified previously were synthesized and, using a competition assay, the amino acid involved in the binding were determined. PMID- 11606215 TI - Synthesis, isolation and characterization of Plasmodium falciparum antigenic tetrabranched peptide dendrimers obtained by thiazolidine linkages. AB - Different chemical alternatives were evaluated for obtaining immunogenic polypeptidic macromolecules which could then be used as vaccines. These were based on the ligation reaction between an unprotected immunogenic peptide and an unprotected multifunctional core peptide; polyantigens, designated dendrimers because their form resembles that of dendritic cells, were thus obtained. The antigen-core ligation alternatives, studied by indirect synthesis, were the formation of oxime, hydrazone and thiazolidine linkages, making use of the reaction between a weak base (acting as nucleophile) and an alkyl aldehyde. The other alternative was the formation of a thioether linkage between a sulfydryl and an alkyl halide. Finally, a multiple antigen peptide (MAP) was synthesized by direct synthesis. All reactions were monitored by SEC-HPLC and SDS-PAGE. Dendrimer molecular mass obtained was confirmed by MS MALDI-TOF. Dendrimer purification was first carried out by concentrating crude reaction products with CP-5000 centricons and (using SEC-HPLC) pure tetramers were then obtained. A 20 residue 9376 immunogenic sequence, from Plasmodium falciparum apical merozoite antigen protein (AMA-1), was used to study the best alternative for chemical ligation. It was observed that thiazolidine formation proceeded with greater yield and in less time than the others. A tetramer has been simultaneously synthesized via thiazolidine with the SPf-66 antimalarial vaccine 45-residue monomer, proving the technique's versatility. The 9376 peptide disulfide bound polymer and SPf-66 (as well as their tetrameric thiazolidine dendrimers) were inoculated in rabbits to evaluate their antibody response. It was observed that titers for tetrameric thiazolidine dendrimers were not just greater but were also sustained over time. Western blot for pre-immune and immune sera showed that dendrimer sera recognized specific Plasmodium falciparum proteins as well as disulfide-bound polymers. PMID- 11606217 TI - Synthesis of enantiopure non-natural alpha-amino acids using tert-butyl (2S)-2 [bis-(tert-butoxycarbonyl)amino]-5-oxopentanoate as key-intermediate:the first synthesis of(S)-2-amino-oleic acid. AB - A general method for the synthesis of enantiopure non-natural alpha-amino acids is described. The key intermediate tert-butyl (2S)-2-[bis(tert butoxycarbonyl)amino]-5-oxopentanoate was obtained from l-glutamic acid after suitable protection and selective reduction of the gamma-methyl ester group by DIBALH. Wittig reaction of this chiral aldehyde with various ylides led to a variety of delta,epsilon-unsaturated alpha-amino acids. This methodology was applied to the synthesis of (S)-2-amino-oleic acid. PMID- 11606216 TI - Partial [alphaMe]Aun scan of [l-Leu11-OMe]-trichogin GA IV, a membrane active synthetic precursor of the natural lipopeptaibol. AB - We synthesized using solution-phase methods three analogs of [l-Leu11-OMe] trichogin GA IV, a membrane active synthetic precursor of the lipopeptaibol antibiotic in which the N-terminal n-octanoyl group and each of the three Aib residues in positions 1, 4 and 8 are replaced by an acetyl group and the lipophilic Calpha,alpha-disubstituted glycine l-(alphaMe)Aun, respectively [partial (alphaMe)Aun scan]. FT-IR absorption and CD analyses unequivocally show that the main three-dimensional structural features of [l-Leu11-OMe] trichogin GA IV are preserved in the analogs. Also, [l-Leu11-OMe] trichogin GA IV and the three Nalpha-acetylated l-(alphaMe)Aun analogs exhibit strictly comparable membrane-modifying properties. Taken together, these results strongly favor the conclusion that a shift of the long hydrocarbon moiety from the Nalpha-blocking group to the side-chain of the 1, 4 or 8 residue does not have any significant effect on the conformational properties or the membrane activity of [l-Leu11-OMe] trichogin GA IV and, by extension, of the natural lipopeptaibol. PMID- 11606218 TI - Importance of the C-terminal phenylalanine of gastrin for binding to the human CCK(2) receptor. AB - The importance of the C-terminal Phe of gastrin and structural requirements at position 17 for binding to the human CCK2 receptor were assessed using analogs of [Leu15]G(11-17). The following peptides were synthesized, Ac[Leu15]G(11-17), Ac[Leu15]G(11-16)NH2, [Leu15]G(11-17), [Leu15,Ala17]G(11-17), [Leu15,Abu17]G(11 17), [Leu15,Val17]G(11-17), [Leu15,Leu17]G(11-17), [Leu15,Cha17]G(11-17), [Leu15,Trp17]G(11-17), [Leu15,Tic17]G(11-17), [Leu15, d-Phe17]G(11-17) and [Leu15,p-X-Phe17]G(11-17), where X = F, Cl, Br, I, OH, CH3, NH2 and NO2. Competition binding experiments with [3H]CCK-8 were performed using human CCK2 receptors stably expressed in CHO cells. Phe17 was shown to be important for binding. A hydrophobic side-chain larger than Leu is required at position 17 but aromaticity does not appear to be essential. Constraint of the aromatic side chain either in the g+ or g- conformation, as in the case of Tic, results in a significant decrease in affinity. In addition, the peptide conformation induced by incorporation of d-Phe decreases binding. The size and electron withdrawing/donating properties of the para substituent are not important for interaction with the receptor. The current study shows that the use of des-Phe analogs of gastrin is not a viable strategy for development of antagonists for the human CCK2 receptor. PMID- 11606219 TI - Fast, efficient and selective deprotection of the tert-butoxycarbonyl (Boc) group using HCl/dioxane (4 m). AB - Fast, efficient and selective deprotection of the tert-butoxycarbonyl (Boc) group of various amino acids and peptides was achieved by using hydrogen chloride (4 m) in anhydrous dioxane solution for 30 min at room temperature. In the cases studied in our laboratory, this protocol provided superior selectivity to deprotect Nalpha-Boc groups in the presence of tert-butyl esters and tert-butyl ethers, including thio-tert-butyl ethers, but not phenolic tert-butyl ethers. PMID- 11606220 TI - Identification of the molecular interaction site of amyloid beta peptide by using a fluorescence assay. AB - Beta-amyloid peptides (Abeta) are the main protein components of neuritic plaques and are important in the pathogenesis of Alzheimer's disease. It is reported that Abeta itself is not toxic; however, it becomes toxic to neuronal cells once it has aggregated into amyloid fibrils by peptide-peptide interactions. In this study, to specify the molecular mechanism of aggregation, a novel fluorescence assay was designed. For this purpose, possible partial peptides (38 types of 5 mer) were synthesized on solid-phase. The molecular interactions were examined by a fluorescence probe possessing Lys-Leu-Val-Phe-Phe (KLVFF) as a molecular recognition site. KLVFF is known to be a minimum sequence for formation of the Abeta aggregate. A specific interaction was observed between labeled and immobilized KLVFF. It suggests that the aggregation of Abeta was controlled by the recognition of KLVFF itself by hydrophobic and electrostatic interactions. PMID- 11606221 TI - Calcium regulation in the intraerythrocytic malaria parasite Plasmodium falciparum. AB - The regulation of intracellular Ca(2+) in the intraerythrocytic form of the human malaria parasite, Plasmodium falciparum, was investigated using parasites 'isolated' from their host cells by saponin-permeabilisation of the erythrocyte membrane. The isolated parasites maintained tight control over their resting cytosolic Ca(2+) concentration which ranged from approximately 100 nM in the absence of extracellular Ca(2+) to approximately 700 nM in the presence of 1 mM extracellular Ca(2+). The parasite has two functionally discrete intracellular Ca(2+) stores. One is an 'endoplasmic reticulum (ER)-like' store, the other an 'acidic store'. The ER-like store was discharged by cyclopiazonic acid (CPA), an inhibitor of sarco/endoplasmic reticulum Ca(2+)-ATPases (SERCAs) of animal and plant cells, but not by thapsigargin (TG), a more specific inhibitor of SERCAs of animal cells. The acidic store was discharged by nigericin and by NH(4)(+). The amount of Ca(2+) in the ER-like store increased with increasing extracellular Ca(2+) concentration, whereas the amount of Ca(2+) in the acidic store did not. Ca(2+) released from the ER-like store by CPA was cleared from the parasite cytosol by uptake into the acidic store (over a range of extracellular Ca(2+) concentrations), consistent with the acidic store serving as a Ca(2+) reservoir within the intracellular parasite. PMID- 11606222 TI - Activity of human trypanosome lytic factor in mice. AB - The inability of the cattle pathogen Trypanosoma brucei brucei to infect humans is due to an innate factor in human serum termed Trypanosome Lytic Factor (TLF). Human haptoglobin-related protein is the proposed toxin in TLF and can exist either as a component of a minor subclass of high-density lipoprotein (TLF-1) or as a lipid free, high molecular weight protein complex (TLF-2). The trypanolytic activity of both TLF-1 and TLF-2 has been studied in vitro but their relative contributions to protection against T. b. brucei infection in vivo has not been established. In the present studies we show that treatment of T. b. brucei infected mice with TLF-1 resulted in a dose dependent decrease in parasite numbers but did not affect parasite numbers in mice infected with Trypanosoma brucei rhodesiense, the causative agent of the human sleeping sickness. Similarly, pretreatment of mice with TLF-1 resulted in protection against a challenge by T. b. brucei but had no effect on T. b. rhodesiense challenge. Induction of the acute phase protein haptoglobin, a natural antagonist of TLF-1, diminished but did not abolish the protection against trypanosome challenge. In addition, haptoglobin knockout mice showed higher levels of TLF-1 mediated protection against a T. b. brucei challenge. These results suggest that while TLF 1 is active in vivo, even in the presence of elevated levels of haptoglobin, its activity is modulated in a dose dependent fashion by haptoglobin in the circulation. PMID- 11606223 TI - Analysis of the S(2) subsite specificities of the recombinant cysteine proteinases CPB of Leishmania mexicana, and cruzain of Trypanosoma cruzi, using fluorescent substrates containing non-natural basic amino acids. AB - We have explored the specificity of the S(2) subsite of recombinant cysteine proteinases from Leishmania mexicana (CPB2.8 Delta CTE) and from Trypanosoma cruzi (cruzain) employing a series of fluorogenic substrates based on the peptide Bz-F-R-MCA, in which Bz is the benzoyl group and the Phe residue has been substituted for by Arg, His and non-natural basic amino acids that combine a basic group with an aromatic or hydrophobic group at the side chain: 4 aminomethyl-phenylalanine (Amf), 4-guanidine phenylalanine (Gnf), 4-aminomethyl-N isopropyl-phenylalanine (Iaf), 3-pyridyl-alanine (Pya), 4-piperidinyl-alanine (Ppa), 4-aminomethyl-cyclohexyl-alanine (Ama), and 4-aminocyclohexyl-alanine (Aca). Bz-F-R-MCA was hydrolyzed well by CPB2.8 Delta CTE and cruzain, but all the substitutions of Phe resulted in less susceptible substrates for the two enzymes. CPB2.8 Delta CTE has a restricted specificity to hydrophobic side chains as with cathepsin L. However, the peptides with the residues Amf and Ama presented higher affinity to CPB2.8 Delta CTE, and the latter was an inhibitor of the enzyme. Although, cruzain accepts basic as well as hydrophobic residues at the S(2) subsite, it is more restrictive than cathepsin B and no inhibitor was found amongst the examined peptides. PMID- 11606224 TI - Gene structure of the extracellular glutathione S-transferase from Onchocerca volvulus and its overexpression and promoter analysis in transgenic Caenorhabditis elegans. AB - Two highly similar genes encoding unique extracellular, glycosylated glutathione S-transferases (GSTs) of the human-pathogenic nematode, Onchocerca volvulus (Ov GST1a and Ov-GST1b), have been isolated and characterised. The genes are approximately 3 kb in length and consist of seven exons interrupted by introns of approximately 100 bp in length, with the exception of intron II, which is approximately 1.6 kb in length. Interestingly, exon I and II encode a signal peptide and an N-terminal extension before sequence homology to other GSTs begins. The 5' flanking region was sequenced and analysed for transcription factor binding sites. Consistent with the lack of a TATA box, analysis of the mRNAs by primer extension showed multiple transcription start sites spread over a 60 bp region. To examine the activity and specificity of the Ov-GST1a gene promoter, we have exploited Caenorhabditis elegans as a heterologous transformation system. To analyse whether transgenic C. elegans are able to carry out processing and post-transcriptional modifications of the Ov-GST1a correctly, the protein was ectopically overexpressed in C. elegans. The parasite-derived Ov GST1a gene product was correctly processed in transgenic C. elegans and posttranslational modifications, such as signal peptide cleavage and N glycosylation, were performed successfully. This further demonstrates the potential of C. elegans as a host for expression of candidate vaccine antigens from O. volvulus and affirms the role of C. elegans as a model for parasitic nematodes. PMID- 11606225 TI - Puromycin-N-acetyltransferase as a selectable marker for use in Plasmodium falciparum. AB - The limited number of selectable markers available for malaria transfection has hindered extensive manipulation of the Plasmodium falciparum genome and subsequently thorough genetic analysis of this organism. In this paper, we demonstrate that P. falciparum is highly sensitive to the drug puromycin, but that transgenic expression of the puromycin-N-acetyltransferase (PAC) gene from Streptomyces alboninger confers resistance to this drug with the IC(50) and IC(90) values increasing approximately 3- and 7-fold, respectively in PAC expressing parasites. Despite this relatively low level of resistance, parasite populations transfected with the PAC selectable marker and selected directly on puromycin emerged at the same rate post-transfection as human dihydrofolate reductase (hDHFR)-expressing parasites, selected independently with the anti folate drug WR99210. Transfected parasites generally maintained the PAC expression plasmid episomally at between two and six copies per parasite. We also demonstrate by cycling transfected parasites in the presence and absence of puromycin for several weeks, that the PAC selectable marker can be used for gene targeting. Since the mode of action of puromycin is distinct from other drugs currently used for the stable transfection of P. falciparum, the PAC selectable marker should also have applicability for use in conjunction with other positive selectable markers, thereby increasing the possibilities for more complex functional studies of this organism. PMID- 11606226 TI - Transglutaminase in Plasmodium parasites: activity and putative role in oocysts and blood stages. AB - Transglutaminase was identified in malaria parasites by immunofluorescence microscopy using alpha-transglutaminase antiserum. Functional enzyme was demonstrated in vivo and in vitro using labeled polyamines that become incorporated into protein substrates through TGase activity. In Plasmodium falciparum intraerythrocytic parasites, transglutaminase activity was stage dependent: it was weak in ring-forms but much stronger in trophozoites and schizonts. High levels of activity were detected in P. gallinaceum zygotes and ookinetes and in capsules of oocysts developing on mosquito midguts. Unlike most known transglutaminases, the enzymatic activity in Plasmodium was Ca(2+) independent. Furthermore, levels of activity were similar at 37 and 26 degrees C. Parasite transglutaminase may be responsible for the modification of erythrocytic cytoskeleton in infected cells and it may facilitate the construction of oocyst capsules by cross-linking mosquito-derived basement membrane components with Plasmodium-derived proteins. PMID- 11606227 TI - Cloning and characterization of the metacyclogenin gene, which is specifically expressed during Trypanosoma cruzi metacyclogenesis. AB - We isolated a gene that is differentially expressed during Trypanosoma cruzi metacyclogenesis by the representation of differential expression (RDE) method, using differentiating epimastigotes cultured in chemically defined medium. This gene, the metacyclogenin gene, encodes a 630-nucleotide mRNA that is specifically associated with the polysomes of epimastigotes allowed to differentiate for 24 h. We sequenced and characterized the metacyclogenin gene and found that there were at least three copies of the gene organized into tandem 2.8 kb repeats in the genome of T. cruzi Dm28c. We analyzed the repeats and found that they contained two other genes, one encoding tryparedoxin peroxidase and the other encoding a 0.6 kb mRNA (named associated gene or AG) with sequences showing no significant similarity to those in the GenBank database. Northern blot analysis of polysomal RNA extracted from replicating and differentiating epimastigotes showed that metacyclogenin and AG genes displayed similar patterns of expression. Their products were detected only in differentiating epimastigotes, whereas tryparedoxin peroxidase was detected only in the polysomal RNA fraction of replicating and differentiating epimastigotes. In Northern blots of total RNA from differentiating and replicating epimastigotes, the genes studied were detected in both cell populations. The differential expression of the metacyclogenin gene was confirmed by immunocytochemistry studies showing that the protein is detected only in differentiating (adhered) epimastigote. The results suggest that mRNA mobilization to polysomes is an important mechanism in the regulation of gene expression in T. cruzi. PMID- 11606228 TI - Disruption of the Crithidia fasciculata KAP1 gene results in structural rearrangement of the kinetoplast disc. AB - The mitochondrial DNA (kinetoplast DNA) in trypanosomatids exists as a highly organized nucleoprotein structure with the DNA consisting of thousands of interlocked circles. Four H1 histone-like proteins (KAP1, 2, 3 and 4) are associated with the kinetoplast DNA in the trypanosomatid Crithidia fasciculata. We have disrupted both alleles of the KAP1 gene in this diploid protozoan and shown that expression of the KAP1 protein is eliminated. The mutant strain is viable but has substantial rearrangement of the kinetoplast structure. Expression of the KAP1 protein from an episome restored expression of the KAP1 protein in the mutant strain and also restored a normal kinetoplast structure. These studies provide evidence that the KAP1 protein is involved in kinetoplast DNA organization in vivo but is nonessential for cell viability. PMID- 11606229 TI - Microtubule associated motor proteins of Plasmodium falciparum merozoites. AB - We have studied the occurrence, stage specificity and cellular location of key molecules associated with microtubules in Plasmodium falciparum merozoites. Antibodies to gamma tubulin, conventional kinesin and cytoplasmic dynein were used to determine the polarity of merozoite microtubules (mt), the stage specificity of the motor proteins and their location during merozoite development. We conclude that the minus ends of the mts are located at their apical pole. Kinesin was present throughout the lifecycle, appearing as a distinct crescent at the apex of developing merozoites. The vast majority of cytoplasmic dynein reactivity occurred in late merogony, also appearing at the merozoite apex. Destruction of mt with dinitroanilines did not affect the cellular location of kinesin or dynein. In invasion assays, dynein inhibitors reduced the number of ring stage parasites. Our results show that both conventional kinesin and cytoplasmic dynein are abundant, located at the negative pole of the merozoite mt and, intriguingly, appear there only in very late merogony, prior to merozoite release and invasion. PMID- 11606230 TI - Alpha and beta subunits of pyruvate dehydrogenase E1 from the microsporidian Nosema locustae: mitochondrion-derived carbon metabolism in microsporidia. AB - Microsporidia are highly adapted eukaryotic intracellular parasites that infect a variety of animals. Microsporidia contain no recognisable mitochondrion, but recently have been shown to have evolved from fungi and to possess heat shock protein genes derived from mitochondria. These findings make it clear that microsporidian ancestors were mitochondrial, yet it remains unknown whether they still contain the organelle, and if so what its role in microsporidian metabolism might be. Here we have characterised genes encoding the alpha and beta subunits of pyruvate dehydrogenase complex E1 (PDH, EC 1.2.4.1) from the microsporidian Nosema locustae. All other amitochondriate eukaryotes studied to date have lost the PDH complex and replaced it with pyruvate:ferredoxin oxidoreductase (PFOR). Nevertheless, molecular phylogeny shows that these Nosema enzymes are most closely related to mitochondrial PDH from other eukaryotes, demonstrating that elements of mitochondrial metabolism have been retained in microsporidia, and that PDH has not been wholly lost. However, there is still no evidence for a mitochondrion in microsporidia, and neither PDH subunit is predicted to encode an amino terminal leader sequence that could function as a mitochondrion-targeting transit peptide, raising questions as to whether these proteins function in a relic organelle or in the cytosol. Moreover, it is also unclear whether these proteins remain part of the PDH complex, or whether they have been retained for another purpose. We propose that microsporidia may utilise a unique pyruvate decarboxylation pathway involving PDH, demonstrating once again the diversity of core metabolism in amitochondriate eukaryotes. PMID- 11606231 TI - Expression-site-associated-gene-8 (ESAG8) is not required for regulation of the VSG expression site in Trypanosoma brucei. PMID- 11606232 TI - Sequencing and heterologous expression of a cytosolic-type malate dehydrogenase of Trypanosoma brucei. PMID- 11606233 TI - Drug resistance in Trypanosoma cruzi is not associated with amplification or overexpression of P-glycoprotein (PGP) genes. PMID- 11606235 TI - Epitopes for modified band 3 monoclonal antibody 1C4 are not exposed on the malaria-infected red blood cell surface. PMID- 11606234 TI - Plasmodium vivax: functional analysis of a highly conserved PvRBP-1 protein region. PMID- 11606236 TI - Cloning and characterisation of thrombospondin, a novel multidomain glycoprotein found in association with a host protective gut extract from Haemonchus contortus. PMID- 11606237 TI - A hybrid plasmid for expression of toxic malarial proteins in Escherichia coli. PMID- 11606238 TI - Modelling of catastrophic flashing releases. AB - Several low boiling point materials are stored in closed vessels at ambient temperature, using their own vapour pressure to maintain a liquid state. These materials are often toxic, flammable, or both, and thus any uncontrolled release can have potentially disastrous consequences. There are many ways in which an accidental release can occur, the most severe being due to catastrophic vessel failure. Although not the most common, this mode of failure has the potential to result in an instantaneous loss of the entire vessel inventory in the form of a rapidly expanding, two-phase, vaporising cloud. This paper provides a comprehensive review of the physical processes of existing models and of available experimental and incident data to model such scenarios. Subsequently, this has enabled the development of an improved methodology for the characterisation of the source conditions following catastrophic vessel failures. PMID- 11606239 TI - Effect of malonyl malonanilide dimers on the thermal stability of nitrocellulose. AB - Three malonanilide dimers (MA2-MA4) were prepared by the reaction of ethyl malonate with malonanilide derivatives (M2-M4). These dimers were investigated as new stabilizers for nitrocellulose. The evaluation process has been performed through Bergman-Junk (BJ) test, thermal analysis measurements (TGA and DSC) and kinetic parameters calculations (E(a)). The comparative study between mass spectra and thermal analysis of the new dimers helped in resolving the thermal decomposition mechanisms for the new dimers. It was found that the new dimers especially (MA2 and MA4) showed better stabilizing effect for the nitrocellulose than the centralite 1 (C1) which is the common stabilizer. PMID- 11606240 TI - Vapor-liquid activity coefficients for methanol and ethanol from heat of solution data: application to steam-methane reforming. AB - This paper presents equations and curves to calculate vapor-liquid phase equilibria for methanol and ethanol in dilute aqueous solution as a function of temperature, using activity coefficients at infinite dilution. These thermodynamic functions were originally derived to assess the distribution of by product contaminants in the process condensate and the steam-system deaerator of a hydrogen plant [Paper ENV-00-171 presented at the NPRA 2000 Environmental Conference, San Antonio, TX, 10-12 September 2000], but have general applicability to other systems as well. The functions and calculation method described here are a necessary piece of an overall prediction technique to estimate atmospheric emissions from the deaerator-vent when the process condensate is recycled as boiler feed water (BFW) make-up. Having such an estimation technique is of particular significance at this time because deaerator vent emissions are already coming under regulatory scrutiny in California [Emissions from Hydrogen Plant Process Vents, Adopted 21 January 2000] followed closely elsewhere in the US, and eventually worldwide. The overall technique will enable a permit applicant to estimate environmental emissions to comply with upcoming regulations, and a regulatory agency to evaluate those estimates. It may also be useful to process engineers as a tool to estimate contaminant concentrations and flow rates in internal process streams such as the steam generating system. Metallurgists and corrosion engineers might be able to use the results for materials selection. PMID- 11606241 TI - Stabilization of an elevated heavy metal contaminated site. AB - Heavy metal contamination is a common problem that is encountered at many uncontrolled sites. Immobilization is seen as a promising technology for heavy metal remediation. Here, we report a remediation case study of an elevated and multi-metal contaminated site containing Cd, Cu, Ni, Pb, and Zn. In a laboratory test, when the soil was stabilized with reagent grade stabilizers (CaHPO(4) and CaCO(3)), the toxicity characteristic leaching procedure (TCLP) extractable concentrations of Cd, Cu, Pb, and Zn were reduced by more than 87%. The greatest reduction was shown with Pb (99.8%). In the field, Ca(H(2)PO(4))(2) due to lower cost and higher solubility replaced CaHPO(4). The TCLP results of the field treatment showed that the extractable concentrations of Cd, Cu, Pb, and Zn were significantly reduced after 30 days of stabilization. The reduction ratios were 98% (Cd), 97% (Cu), 99% (Pb), and 96% (Zn). Although, the reduction ratio of Ni was only 65%, the average extractable concentration was still less than 4.0mg/l. The percent reduction can, therefore, be considered reasonable. The significant reduction of extractable metal concentrations showed that the stabilizers, a combination of Ca(H(2)PO(4))(2) and CaCO(3), successfully immobilized heavy metals on the site. PMID- 11606242 TI - Modelling of heavy metal vaporisation from a mineral matrix. AB - This study deals with the fundamental aspects of the volatilisation of heavy metals (HM) during municipal solid waste (MSW) incineration. The thermal treatment of a model waste was theoretically and experimentally studied in a fluid-bed. A mathematical model was developed to predict the fate of metallic species according to the main phenomena controlling the process: heat and mass transfer (transport phenomena), chemical reactions involving HM, and mechanism of vapour metal species sorption inside the porous matrix. The model assumes local thermodynamic equilibrium between the vapour and the metal compound on the substrate in the pores of a particle. This approach permits to predict the extent of HM vaporisation from a mineral porous matrix when its physical properties are known. Experimental data concerning CdCl(2) release from an alumina matrix in a 850 degrees C fluidised bed are in good agreement with theoretical results. PMID- 11606243 TI - Elimination of cutting oil wastes by promoted hydrothermal oxidation. AB - Cutting oils are emulsionable fluids widely used in metalworking processes. Their composition is normally oil, water, and additives (fatty acids, surfactants, biocides, etc.) generating a toxic waste after a long use. Generally, it is a waste too dilute to be incinerated and it is difficult to treat biologically. Other conventional treatment methods currently used are not satisfactory from the environmental point of view. Wet air oxidation (WAO) and supercritical water oxidation (SCWO) are two forms of hydrothermal oxidation that have been proved to be effective processes to treat a wide variety of industrial wastes, but hardly tested for oily wastes. In the case of refractory wastes, WAO process is not efficient enough due to the moderate temperatures used. SCWO is a more powerful process since operating temperatures are usually around 600 degrees C, but the use of severe conditions leads to major disadvantages in the commercialization of the technology. In order to enhance WAO and SCWO efficiency at mild conditions, the use of free radical promoters has been studied in this work. Both normal and promoted hydrothermal oxidation have been tested to treat cutting oil wastes in a continuous flow system operating at 300-500 degrees C. Hydrogen peroxide has been used both as a source of oxygen and as a source of free radicals by introducing it into the reactor with or without previous thermal decomposition, respectively. Organic material is easily oxidized in both cases, obtaining more than 90% TOC reduction in less than 10s at 500 degrees C. At lower temperatures, the use of promoters clearly enhances the oxidation process. Activation energies have been estimated for normal and promoted oxidation processes. PMID- 11606244 TI - Highly crystalline Zeolite-A from flyash of bituminous and lignite coal combustion. AB - Flyash is being generated in voluminous amounts by large scale coal combustion process. It poses a serious threat to thermal power industries specifically, in India, wherein the percent of utilisation of flyash is very poor (3-5%). In view of this problem, newer methods of its disposal and utilisation are being explored. The synthesis of zeolite from flyash appears to be one of the most promising alternatives as it has emphasis on value addition to waste material. Flyashes originating from different sources of coal differ in their characteristics and have implications in this work on Zeolite-A production. These factors have been thoroughly investigated and the conditions favourable for formation of Zeolite-A have been delineated. The reactivity of flyash towards zeolite formation is directly dependent on the SiO(2)/Al(2)O(3) ratio, Fe(2)O(3) and CaO content. Amongst the flyashes investigated, so far the sub-bituminous coal based flyash with SiO(2)/Al(2)O(3) ratio of 3.47 appears to be a suitable substrate for Zeolite-A synthesis. These zeolites have been characterised with respect to XRD crystallinity, calcium binding capacity (CBC) and sorption capacity, wherein the crystallinity ranges from 50 to 100%, the CBC ranges from 290 to 560meq/100g and sorption capacity ranges from 16.6 to 23.8%. PMID- 11606245 TI - Properties of Portland cement--stabilised MSWI fly ashes. AB - In the present paper, the properties of Portland cement mixtures containing fly ashes (FA) collected at four different Italian municipal solid waste incineration (MSWI) plants were investigated. In particular, physical/mechanical characteristics (setting time, unconfined compressive strength (UCS) and shrinkage/expansion), as well as the acid neutralisation behaviour of the solidified products were considered. The FA composition, revealing enrichment in heavy metals, chlorides and sulphates, significantly altered the hydration behaviour of Portland cement. Consequently, for some of the investigated FA the maximum allowable content for the mixtures to achieve appreciable mechanical strength was 20 wt.%. Even at low FA dosages setting of cement was strongly delayed. In order to improve the properties of FA/cement mixtures, the use of additives was tested.Moreover, the acid neutralisation capacity (ANC) of the solidified products was evaluated in order to assess the ability of the matrix to resist acidification, and also to provide information on hydration progression, as well as on heavy metal release under different pH conditions. Comparison of the results from the present work with previous studies carried out on spiked mixtures lead to the conclusion that the mechanical properties of the stabilised FA could not be predicted based on the effect exerted by heavy metals and anions only, even when the dilution effect exerted on cement was taken into account. It was likely that a major role was also played by alkalis, which were present in the FA at much higher concentrations than in cement. PMID- 11606246 TI - Current status of Inherently Safer Design (ISD) use. PMID- 11606249 TI - Germ cell nuclear factor. AB - Germ cell nuclear factor (GCNF) is an orphan nuclear receptor for which a ligand has yet to be identified. However, we do know that GCNF binds to a novel response element as a homodimer and regulates expression of genes, such as the protamines, through this element. In the absence of a ligand, GCNF is a transcriptional repressor that interacts with co-repressors. During embryonic development, GCNF is expressed between the gastrula and neurula stages. Loss of GCNF causes embryonic lethality, disrupts normal somitogenesis, as well as neural tube and axis formation, suggesting that GCNF is a critical factor for normal embryonic development. In adult vertebrates, GCNF expression is predominantly found in the germ cells of gonads. GCNF expression in germ cells suggests that understanding its function in adults will yield greater insight into the regulation of gametogenesis, leading to new contraceptive targets. PMID- 11606250 TI - NKp46. AB - Combating diseases such as cancer and virus infection is one of the major goals of the next millennium. Remarkably, our immune system has developed a unique cell type called Natural Killer (NK) cells, able to kill cancer and virus-infected cells. The nature of the lysis/killer receptors expressed on NK cells, mediating this killing, and their ligands, is only little understood. Four lysis receptors for human NK cells were recently identified, including the NKp30, NKp44, NKp46 and CD16, all of which are capable of mediating direct killing of virus-infected and tumor cells. Among these, the NKp46 receptor is considered to be the major lysis receptor for NK cells. The viral hemagglutinin protein was recently identified as the ligand for the NKp46 receptor. However, the cellular (non viral) ligands recognized by all of the lysis receptors (NKp30, NKp44, NKp46 and CD16) are currently unknown. PMID- 11606251 TI - C-terminal actin-binding sites of smooth muscle caldesmon switch actin between conformational states. AB - Caldesmon is a component of the thin filaments of smooth muscles where it is believed to play an essential role in regulating the thin filaments' interaction with myosin and hence contractility. We studied the effects of caldesmon and two recombinant fragments CaDH1 (residues 506-793) and CaDH2 (residues 683-767) on the structure of actin-tropomyosin by making measurements of the fluorescence polarisation of probes specifically attached to actin. CaDH1, like the parent molecule caldesmon, is an inhibitor of actin-tropomyosin interaction with myosin whilst CaDH2 is an activator. The F-actin in permeabilised and myosin free rabbit skeletal muscle 'ghost' fibres was labelled by tetramethyl rhodamine isothiocyanate (TRITC)-phalloidin or fluorescein-5'-isothiocyanate (FITC) at lysine 61. Fluorescence polarisation measurements were made and the parameters Phi(A), Phi(E), Theta(1/2) and Nu were calculated. Phi(A) and Phi(E) are angles between the fiber axis and the absorption and emission dipoles, respectively; Theta(1/2) is the angle between the F-actin filament axis and the fiber axis; Nu is the relative number of randomly oriented fluorophores. Actin-tropomyosin interaction with myosin subfragment-1 induced changes in the parameters of the polarised fluorescence that are typical of strong binding of myosin to actin and of the 'on' conformational state of actin. Caldesmon and CaDH1 (as well as troponin in the absence of Ca(2+)) diminished the effect of S-1, whereas CaDH2 (as well as troponin in the presence of Ca(2+)) enhanced the effect of S1. Thus the structural evidence correlates with biochemical evidence that C-terminal actin-binding sites of caldesmon can modulate the structural transition of actin monomers between 'off' (caldesmon and CaDH1) and 'on' (S-1 and CaDH2) states in a manner analogous to troponin. PMID- 11606252 TI - Cell death induced by chemical homobifunctional cross-linkers. Cross-linker induced apoptosis. AB - Physical association of proteins that underlies cytotoxic signal induction and transduction suggests a possibility of regulating cell response by modifying protein-protein interactions. For protein complexing, chemical cross-linking agents have been traditionally used. However, the ability of various cross linkers to induce and modify cell responses, cell death in particular, is still obscure. We have undertaken the investigation to test the apoptosis-inducing and modifying properties of the homobifunctional cross-linkers-dimethyl suberimidate (DMS) and 1,5-bis(succinimido-oxycarbonyloxy)pentane (BSOCOP). The functional groups of these cross-linkers are different but both are able to interact with available amino groups. It was shown that bifunctional cross-linkers, unlike their monofunctional analogues, are capable of inducing cell death in transformed cells, thus indicating the crucial role of cross-linking in cell killing. DMS- and BSOCOP-treated cells were shown to undergo cell death by apoptosis, though the signaling pathways were distinct. DMS inhibited bcl-X(L) and bak but not bax gene expression, while BSOCOP potentiated bax mRNA synthesis immediately after application. Cell pre-incubation with DMS, but not with BSOCOP, resulted in an increasing sensitivity to TNF, although activities of anti-Fas cytotoxic antibodies were then inhibited. Thus, this study has demonstrated for the first time that chemical cross-linkers are capable of inducing apoptosis by themselves and modifying the TNF-dependent and Fas-mediated cell death that may have potential therapeutic significance. PMID- 11606253 TI - Cloning and characterization of a novel human TEKTIN1 gene. AB - Tektins comprise a family of filament-forming proteins that are known to be coassembled with tubulins to form ciliary and flagellar microtubules. A new member of the tektin gene family was cloned from the human fetal brain cDNA library. We hence named it the human TEKTIN1 gene. TEKTIN1 cDNA consists of 1375 bp and has a putative open reading frame encoding 418 amino acids. The predicted protein is 48.3 kDa in size, and its amino acid sequence is 82% identical to that of the mouse, rat, and dog. One conserved peptide RPNVELCRD was observed at position number 323-331 of the amino acid sequence, which is a prominent feature of tektins and is likely to represent a functionally important protein domain. TEKTIN1 gene was mapped to the human chromosome 17 by BLAST search, and at least eight exons were found. Northern blot analysis indicated that TEKTIN1 was predominantly expressed in testis. By in-situ hybridization analysis, TEKTIN1 mRNA was localized to spermatocytes and round spermatids in the seminiferous tubules of the mouse testis, indicating that it may play a role in spermatogenesis. PMID- 11606254 TI - Chromatin structure at the 3'-boundary of the human beta-globin locus control region hypersensitive site-2. AB - Chromatin structure was examined at the 3'-boundary region of the human beta globin locus control region hypersensitive site-2 (LCR HS-2) using several footprinting agents. Erythroid K562 cells (possessing HS-2) were damaged by the footprinting agents: hedamycin, bleomycin and four nitrogen mustard analogues. Purified DNA and non-erythroid HeLa cells (lacking HS-2) were also damaged as controls for comparison with K562 cells. The comparison between intact cells and purified DNA showed several protected regions in K562 cells. A large erythroid specific protected region of 135 bp was found at the boundary of HS-2. The length of this protected region (135 bp) was close to that of DNA contained in a nucleosome core (146 bp). Another two protected regions were found upstream of the protected region. A 16-bp erythroid-specific footprint co-localised with a GATA-1 motif-this indicated that the GATA-1 protein could be involved in positioning the nucleosome. Further upstream, a 100-bp footprint coincided with an AT-rich region. Thus our footprinting results suggest that the 3'-boundary of LCR HS-2 is flanked by a positioned nucleosome and that an erythroid-specific protein binds to the sequence adjacent to the nucleosome and acts to position the nucleosome at the boundary of the hypersensitive site. PMID- 11606255 TI - Heparin and chondroitin sulfate inhibit adenine nucleotide hydrolysis in liver and kidney membrane enriched fractions. AB - The inhibition of adenine nucleotide hydrolysis by heparin and chondroitin sulfate (sulfated polysaccharides) was studied in membrane preparations from liver and kidney of adult rats. Hydrolysis was measured by the activity of NTPDase and 5'-nucleotidase. The inhibition of NTPDase by heparin was observed at three different pH values (6.0, 8.0 and 10.0). In liver, the maximal inhibition observed for ATP and ADP hydrolysis was about 80% at pH 8.0 and 70% at pH 6.0 and 10.0. Similarly to the effect observed in liver, heparin caused inhibition of ATP and ADP hydrolysis that reached a maximum of 70% in kidney (pH 8.0). Na(+), K(+) and Rb(+) changed the inhibitory potency of heparin, suggesting that its effects may be related to charge interaction. In addition to heparin, chondroitin sulfate also caused a dose-dependent inhibition in liver and kidney membranes. The maximal inhibition observed for ATP and ADP hydrolysis was about 60 and 50%, respectively. In addition, the hepatic and renal activity of 5'-nucleotidase was inhibited by heparin and chondroitin sulfate, except for kidney membranes where chondroitin sulfate did not alter AMP hydrolysis. On this basis, the findings indicate that glycosaminoglycans have a potential role as inhibitors of adenine nucleotide hydrolysis on the surface of liver and kidney cell membranes in vitro. PMID- 11606256 TI - UGA4 gene encoding the gamma-aminobutyric acid permease in Saccharomyces cerevisiae is an acid-expressed gene. AB - BACKGROUND AND AIMS: biological processes in all organisms are controlled by environmental conditions, however, information concerning the molecular responses to external pH is scarce. In this work we studied the pH response of UGA4 gene encoding delta-aminolevulinic acid and gamma-aminobutyric acid permease in Saccharomyces cerevisiae. METHODS: we analyzed the effect of pH on the expression of UGA4 gene measuring beta-galactosidase activity in cells carrying a UGA4::lacZ fusion gene. RESULTS: results indicate that UGA4 expression is higher at acidic pH. The expression of UGA3 and UGA35 genes, which encode two positive transcription factors, is not regulated by external pH, while the expression of UGA43 gene encoding a repressor of UGA4 transcription is dependent on pH. Using a strain lacking Uga43p we clearly showed that the effect of ambient pH on UGA4 expression is not a secondary effect of the pH regulation on UGA43. We have also demonstrated that the effect of pH can only be detected when UGA4 gene is not subject to a strong repression by Uga43p nor to GABA induction. CONCLUSION: here, we demonstrate that UGA4 is an acid-expressed gene. This regulation is probably mediated by Rim101p through the consensus site 5'-GCCARG-3' at 237 bp preceding the UGA4 coding sequence (201). PMID- 11606257 TI - Photodynamic and light independent action of 8 to 2 carboxylic free porphyrins on some haem-enzymes. AB - BACKGROUNDS AND AIMS: skin lesions in cutaneous porphyrias appear to be determined by the structural properties of the porphyrins accumulated. To better understand the relationship between the structure and physicochemical properties of porphyrins and their specific effect on protein configuration, the action of a whole range of 8 to 2 carboxylic porphyrins has been studied. MATERIALS AMD METHODS: delta-aminolevulinic acid dehydratase (ALA-D) and porphobilinogen deaminase (PBG-D) partially purified from bovine liver, were exposed to 10 microM uroporphyrin (Uro), phyriaporphyrin (Phyria), hexaporphyrin (Hexa), pentaporphyrin (Penta), coproporphyrin (Copro) or protoporphyrin (Proto), either in the dark or under UV light. All experiments were performed in the enzyme solutions after removing the porphyrins. RESULTS: under both illuminating conditions, all porphyrins inactivated the enzymes (20-70% under control values), indicating photodynamic action mediated by oxidative reactions and conformational changes due to direct binding of porphyrins to the protein. Total thiol content in ALA-D was not significantly changed by most porphyrins under UV light, while all porphyrins increase total sulfhydryl groups in PBG-D (23-52% over the control values) indicating changes in the redox status of SH residues. Free amino groups were reduced by all porphyrins in ALA-D (23-56% under controls), instead they were enhanced in PBG-D (23-51% over controls), suggesting protein fragmentation. The formation of molecular aggregates would be the consequence of cross-links between oxidation products, while fragmentation can be attributed to either rupture of disulphur bridges and/or enhancement of free amino groups on the protein enzyme. CONCLUSIONS: the effect of the porphyrins on enzyme activity, total SH groups and free amino groups content, was different for ALA-D and PBG-D, even under the same illuminating conditions. On the basis of these results, no correlation between enzyme alterations and the physico-chemical properties of porphyrins could be established. PMID- 11606258 TI - Dietary cholate increases plasma levels of apolipoprotein B in mice by posttranscriptional mechanisms. AB - To induce atherogenesis in mice, a high fat (HF) diet is supplemented with cholic acid (CA), which increases apoB-containing particles and lower apoA-I-containing particles. HF diet without CA increases levels of both HDL and LDL, suggesting that CA may be responsible for the elevation of LDL and lowering of HDL. The mechanism of dietary CA-induced lowering of apoA-I-containing particles has recently been reported. In this study, we examined the mechanism of CA- and HF induced elevation of apoB-containing lipoproteins in mice. Mice were fed the following four diets: control chow (C), high fat high cholesterol, (HF), control and 0.5% cholate (CA), and HF+CA. Dietary CA increased the plasma levels of apoB containing particles by approximately 2-fold when compared to control; VLDL levels increased 2-fold, and LDL levels increased 1.3-fold. On HF diet, VLDL increased by 1.4-fold, and LDL by 2-fold, suggesting that CA and HF-induced increases of apoB-containing particles occurred by different mechanisms. We investigated the potential mechanisms regulating plasma levels of apoB in CA- and HF-fed mice. Although hepatic apoB mRNA levels did not change on CA diet, apoB 100 mRNA increased relative to B-48 as a result of decreased editing of apoB mRNA. Measurements of hepatic LDL receptor mRNA suggested that CA diet down regulated LDL receptor mRNA, possibly by increasing the levels of hepatic cholesterol. Since plasma and hepatic vitamin E levels did not show significant changes on CA-containing diets, it suggests that dietary CA did not act by increasing the absorption of dietary fat. Hepatic lipase, known to modulate plasma levels of apoB-containing particles, did not show changes in CA- or HF-fed mice. Taken together, these results suggest that dietary CA increased apoB containing particles both in chow-fed and fat-fed mice by enhancing the relative production of apoB-100, and also by reducing LDL receptor-mediated clearance of apoB-containing particles. Thus, dietary cholate modulates plasma levels of apoB primarily by posttranscriptional mechanisms. PMID- 11606259 TI - Growth, protein-turnover rates and nucleic-acid concentrations in the white muscle of rainbow trout during development. AB - We have studied the growth rate, nucleic-acid concentration, protein-accumulation rate (K(G)), and several other parameters relating to protein turnover, such as the protein-synthesis (K(S)), and protein-degradation rates (K(D)), protein synthesis capacity (C(S)), protein-synthesis efficiency (K(RNA)), protein synthesis rate per DNA unit (K(DNA)) and protein-retention efficiency (PRE), in the white muscle of rainbow trout during development. Both growth rate and relative food intake decreased significantly with age and weight, as did the food efficiency ratio (FER) and protein-efficiency ratio (PER). Although absolute RNA and DNA contents increased with age, their relative concentrations decreased. The RNA/DNA ratio increased sharply from 14 to 28 weeks but afterwards decreased towards initial values. Hypertrophy increased rapidly to the 28-week stage but henceforth increased much more slowly. Hyperplasia, on the other hand, continued to increase linearly, resulting in a significant four- to fivefold predominance in this type of growth at the end of the 96-week experimental period. K(G) decreased significantly with age, as did K(S), and C(S), whereas at the 14-week stage, K(D) was significantly lower than at other ages. K(RNA) increased until 28 weeks. K(DNA) increased significantly in juvenile fish compared to both fingerlings and adults, where it showed similar lower values. PRE remained high at all ages. PMID- 11606260 TI - Geometrical properties of gel and fluid clusters in DMPC/DSPC bilayers: Monte Carlo simulation approach using a two-state model. AB - In this paper the geometrical properties of gel and fluid clusters of equimolar dimyristoylphosphatidylcholine/distearoylphosphatidylcholine (DMPC/DSPC) lipid bilayers are calculated by using an Ising-type model (Sugar, I. P., T. E. Thompson, and R. L. Biltonen. 1999. Biophys. J. 76:2099-2110). The model is able to predict the following properties in agreement with the respective experimental data: the excess heat capacity curves, fluorescence recovery after photobleaching (FRAP) threshold temperatures at different mixing ratios, the most frequent center-to-center distance between DSPC clusters, and the fractal dimension of gel clusters. In agreement with the neutron diffraction and fluorescence microscopy data, the simulations show that below the percolation threshold temperature of gel clusters many nanometer-size gel clusters co-exist with one large gel cluster of size comparable with the membrane surface area. With increasing temperature the calculated effective fractal dimension and capacity dimension of gel and fluid clusters decrease and increase, respectively, within the (0, 2) interval. In the region of the gel-to-fluid transition the following geometrical properties are independent from the temperature and the state of the cluster: 1) the cluster perimeter linearly increases with the number of cluster arms at a rate of 8.2 nm/arm; 2) the average number of inner islands in a cluster increases with increasing cluster size, S, according to a power function of 0.00427 x S(1.3); 3) the following exponential function describes the average size of an inner island versus the size of the host cluster, S: 1 + 1.09(1 - e(-0.0072xS)). By means of the equations describing the average geometry of the clusters the process of the association of clusters is investigated. PMID- 11606261 TI - The influence of plasma membrane electrostatic properties on the stability of cell ionic composition. AB - An electro-osmotic model is developed to examine the influence of plasma membrane superficial charges on the regulation of cell ionic composition. Assuming membrane osmotic equilibrium, the ion distribution predicted by Gouy-Chapman Grahame (GCG) theory is introduced into ion transport equations, which include a kinetic model of the Na/K-ATPase based on the stimulation of this ion pump by internal Na(+) ions. The algebro-differential equation system describing dynamics of the cell model has a unique resting state, stable with respect to finite-sized perturbations of various types. Negative charges on the membrane are found to greatly enhance relaxation toward steady state following these perturbations. We show that this heightened stability stems from electrostatic interactions at the inner membrane side that shift resting state coordinates along the sigmoidal activation curve of the sodium pump, thereby increasing the pump sensitivity to internal Na(+) fluctuations. The accuracy of electrostatic potential description with GCG theory is proved using an alternate formalism, based on irreversible thermodynamics, which shows that pressure contribution to ion potential energy is negligible in electrostatic double layers formed at the surfaces of biological membranes. We discuss implications of the results regarding a reliable operation of ionic process coupled to the transmembrane electrochemical gradient of Na(+) ions. PMID- 11606262 TI - Insertion and pore formation driven by adsorption of proteins onto lipid bilayer membrane-water interfaces. AB - We describe the binding of proteins to lipid bilayers in the case for which binding can occur either by adsorption to the lipid bilayer membrane-water interface or by direct insertion into the bilayer itself. We examine in particular the case when the insertion and pore formation are driven by the adsorption process using scaled particle theory. The adsorbed proteins form a two dimensional "surface gas" at the lipid bilayer membrane-water interface that exerts a lateral pressure on the lipid bilayer membrane. Under conditions of strong intrinsic binding and a high degree of interfacial converge, this pressure can become high enough to overcome the energy barrier for protein insertion. Under these conditions, a subtle equilibrium exists between the adsorbed and inserted proteins. We propose that this provides a control mechanism for reversible insertion and pore formation of proteins such as melittin and magainin. Next, we discuss experimental data for the binding isotherms of cytochrome c to charged lipid membranes in the light of our theory and predict that cytochrome c inserts into charged lipid bilayers at low ionic strength. This prediction is supported by titration calorimetry results that are reported here. We were furthermore able to describe the observed binding isotherms of the pore forming peptides endotoxin (alpha 5-helix) and of pardaxin to zwitterionic vesicles from our theory by assuming adsorption/insertion equilibrium. PMID- 11606263 TI - Hierarchical approach to predicting permeation in ion channels. AB - A hierarchical computational strategy combining molecular modeling, electrostatics calculations, molecular dynamics, and Brownian dynamics simulations is developed and implemented to compute electrophysiologically measurable properties of the KcsA potassium channel. Models for a series of channels with different pore sizes are developed from the known x-ray structure, using insights into the gating conformational changes as suggested by a variety of published experiments. Information on the pH dependence of the channel gating is incorporated into the calculation of potential profiles for K(+) ions inside the channel, which are then combined with K(+) ion mobilities inside the channel, as computed by molecular dynamics simulations, to provide inputs into Brownian dynamics simulations for computing ion fluxes. The open model structure has a conductance of approximately 110 pS under symmetric 250 mM K(+) conditions, in reasonable agreement with experiments for the largest conducting substate. The dimensions of this channel are consistent with electrophysiologically determined size dependence of quaternary ammonium ion blocking from the intracellular end of this channel as well as with direct structural evidence that tetrabutylammonium ions can enter into the interior cavity of the channel. Realistic values of Ussing flux ratio exponents, distribution of ions within the channel, and shapes of the current-voltage and current-concentration curves are obtained. The Brownian dynamics calculations suggest passage of ions through the selectivity filter proceeds by a "knock-off" mechanism involving three ions, as has been previously inferred from functional and structural studies of barium ion blocking. These results suggest that the present calculations capture the essential nature of K(+) ion permeation in the KcsA channel and provide a proof of-concept for the integrated microscopic/mesoscopic multitiered approach for predicting ion channel function from structure, which can be applied to other channel structures. PMID- 11606264 TI - Dynamical properties of a hydrated lipid bilayer from a multinanosecond molecular dynamics simulation. AB - A fully hydrated dimiristoylphosphatidylcholine (DMPC) bilayer has been studied by a molecular dynamics simulation. The system, which consisted of 64 DMPC molecules and 1792 water molecules, was run in the NVE ensemble at a temperature of 333 K for a total of 10 ns. The resulting trajectory was used to analyze structural and dynamical quantities. The electron density, bilayer spacing, and order parameters (S(CD)), based on the AMBER forcefield and SPCE water model are in good agreement with previous calculations and experimental data. The simulation reveals evidence for two types of lateral diffusive behavior: cage hopping and that of a two-dimensional liquid. The lateral diffusion coefficient is 8 x 10(-8) cm(2)/s. We characterize the rotational motion, and find that the lipid tail rotation (D(rot_tail) = -0.04 rad(2)/ns) is slower then the head group rotation (D(rot_hg) = 2.2 rad(2)/ns), which is slower than the overall in plane (D(rot) = 3.2 rad(2)/ns) for the lipid molecule. PMID- 11606265 TI - A two-state piezoelectric model for outer hair cell motility. AB - Recent studies have revealed that voltage-dependent length changes of the outer hair cell are based on charge transfer across the membrane. Such a motility can be explained by an "area motor" model, which assumes two states in the motor and that conformational transitions involve transfer of motor charge across the membrane and mechanical displacements of the membrane. Here it is shown that the area motor is piezoelectric and that the hair cell that incorporates such a motor in its lateral membrane is also piezoelectric. Distinctive features of the outer hair cell are its exceptionally large piezoelectric coefficient, which exceeds the best known piezoelectric material by four orders of magnitude, and its prominent nonlinearity due to the discreteness of motor states. PMID- 11606266 TI - Understanding beta-hairpin formation by molecular dynamics simulations of unfolding. AB - We have studied the mechanism of formation of a 16-residue beta-hairpin from the protein GB1 using molecular dynamics simulations in an aqueous environment. The analysis of unfolding trajectories at high temperatures suggests a refolding pathway consisting of several transient intermediates. The changes in the interaction energies of residues are related with the structural changes during the unfolding of the hairpin. The electrostatic energies of the residues in the turn region are found to be responsible for the transition between the folded state and the hydrophobic core state. The van der Waals interaction energies of the residues in the hydrophobic core reflect the behavior of the radius of gyration of the core region. We have examined the opposing influences of the protein-protein (PP) energy, which favors the native state, and the protein solvent (PS) energy, which favors unfolding, in the formation of the beta-hairpin structure. It is found that the behavior of the electrostatic components of PP and PS energies reflects the structural changes associated with the loss of backbone hydrogen bonding. Relative changes in the PP and PS van der Waals interactions are related with the disruption of the hydrophobic core of a protein. The results of the simulations support the hydrophobic collapse mechanism of beta-hairpin folding. PMID- 11606267 TI - Prion diseases: dynamics of the infection and properties of the bistable transition. AB - Prion diseases are thought to result from a pathogenic, conformational change in a cellular protein, the prion protein. The pathogenic isoform seems to convert the normal isoform in an autocatalytic process. In contrast to the conditions used for in vitro studies of enzyme kinetics, the concentration of the catalyst is not much lower than that of the substrate in the course of infection. This feature may endow the system with a time-hierarchy allowing the pathogenic isoform to relax very slowly in the course of infection. This may contribute to the long incubation periods observed in prion diseases. The dynamic process of prion propagation, including turnover of the cellular prion protein, displays bistable properties. Sporadic prion diseases may result from a change in one of the parameters associated with metabolism of the prion protein. The bistable transition observed in sporadic disease is reversible, whereas that observed in cases of exogenous contamination is irreversible. This model is consistent with the occurrence of rare, sporadic forms of prion diseases. It may also explain why only some individuals of a cohort develop a prion disease following transient food contamination. PMID- 11606268 TI - Calculation of rigid-body conformational changes using restraint-driven Cartesian transformations. AB - We present an approach for calculating conformational changes in membrane proteins using limited distance information. The method, named restraint-driven Cartesian transformations, involves 1) the use of relative distance changes; 2) the systematic sampling of rigid body movements in Cartesian space; 3) a penalty evaluation; and 4) model refinement using energy minimization. As a test case, we have analyzed the structural basis of activation gating in the Streptomyces lividans potassium channel (KcsA). A total of 10 pairs of distance restraints derived from site-directed spin labeling and electron paramagnetic resonance (SDSL-EPR) spectra were used to calculate the open conformation of the second transmembrane domains of KcsA (TM2). The SDSL-EPR based structure reveals a gating mechanism consistent with a scissoring-type motion of the TM2 segments that includes a pivot point near middle of the helix. The present approach considerably reduces the amount of time and effort required to establish the overall nature of conformational changes in membrane proteins. It is expected that this approach can be implemented into restrained molecular dynamics protocol to calculate the structure and conformational changes in a variety of membrane protein systems. PMID- 11606269 TI - T-cell activation by soluble MHC oligomers can be described by a two-parameter binding model. AB - T-cell activation is essential for initiation and control of immune system function. T cells are activated by interaction of cell-surface antigen receptors with major histocompatibility complex (MHC) proteins on the surface of other cells. Studies using soluble oligomers of MHC-peptide complexes and other types of receptor cross-linking agents have supported an activation mechanism that involves T cell receptor clustering. Receptor clustering induced by incubation of T cells with MHC-peptide oligomers leads to the induction of T-cell activation processes, including downregulation of engaged receptors and upregulation of the cell-surface proteins CD69 and CD25. Dose-response curves for these T-cell activation markers are bell-shaped, with different maxima and midpoints, depending on the valency of the soluble oligomer used. In this study, we have analyzed the activation behavior using a mathematical model that describes the binding of multivalent ligands to cell-surface receptors. We show that a simple equilibrium binding model accurately describes the activation data for CD4(+) T cells treated with MHC-peptide oligomers of varying valency. The model can be used to predict activation and binding behavior for T cells and MHC oligomers with different properties. PMID- 11606270 TI - The length dependence of translational diffusion, free solution electrophoretic mobility, and electrophoretic tether force of rigid rod-like model duplex DNA. AB - In this work, boundary element modeling is used to study the transport of highly charged rod-like model polyions of various length under a variety of different aqueous salt conditions. Transport properties considered include free solution electrophoretic mobility, translational diffusion, and the components of the "tether force" tensor. The model parameters are chosen to coincide with transport measurements of duplex DNA carried out under six different salt/temperature conditions. The focus of the analysis is on the length dependence of the free solution electrophoretic mobility. In a solution containing 0.04 M Tris-acetate buffer at 25 degrees C, calculated mobilities using straight rod models show a stronger dependence on fragment length than that observed experimentally. By carrying out model studies on curved rod models, it is concluded that the "leveling off" of mobility with fragment length is due, in part at least, to the finite curvature of DNA. Experimental mobilities of long duplex DNA in monovalent alkali salts are reasonably well explained once account is taken of long-range bending and the simplifying assumptions of the model studies. PMID- 11606271 TI - Micron-scale positioning of features influences the rate of polymorphonuclear leukocyte migration. AB - Microfabrication technology was used to create regular arrays of micron-size holes (2 microm x 2 microm x 210 nm) on fused quartz and photosensitive polyimide surfaces. The patterned surfaces, which possessed a basic structural element of a three-dimensional (3-D) network (i.e., spatially separated mechanical edges), were used as a model system for studying the effect of substrate microgeometry on neutrophil migration. The edge-to-edge spacing between features was systematically varied from 6 microm to 14 microm with an increment of 2 microm. In addition, collagen was used to coat the patterned quartz surfaces in an attempt to change the adhesive properties of the surfaces. A radial flow detachment assay revealed that cell adhesion was the strongest on the quartz surface (approximately 50% cell attached), whereas it was relatively weaker on polyimide and collagen-coated quartz (approximately 25% cell attached). Cell adhesion to each substrate was not affected either by the presence of holes or by the spacing between holes. A direct visualization assay showed that neutrophil migration on each patterned surface could be characterized as a persistent random walk; the dependence of the random motility coefficient (mu) as a function of spacing was biphasic with the optimal spacing at approximately 10 microm on each substrate. The presence of evenly distributed holes at the optimal spacing of 10 microm enhanced mu by a factor of 2 on polyimide, a factor of 2.5 on collagen coated quartz, and a factor of 10 on uncoated quartz. The biphasic dependence on the mechanical edges of neutrophil migration on 2-D patterned substrate was strikingly similar to that previously observed during neutrophil migration within 3-D networks, suggesting that microfabricated materials provide relevant models of 3-D structures with precisely defined physical characteristics. In addition, our results demonstrate that the microgeometry of a substrate, when considered separately from adhesion, can play a significant role in cell migration. PMID- 11606272 TI - Calcium protects differentiating neuroblastoma cells during 50 Hz electromagnetic radiation. AB - Despite growing concern about electromagnetic radiation, the interaction between 50- to 60-Hz fields and biological structures remains obscure. Epidemiological studies have failed to prove a significantly correlation between exposure to radiation fields and particular pathologies. We demonstrate that a 50- to 60-Hz magnetic field interacts with cell differentiation through two opposing mechanisms: it antagonizes the shift in cell membrane surface charges that occur during the early phases of differentiation and it modulates hyperpolarizing K channels by increasing intracellular Ca. The simultaneous onset of both mechanisms prevents alterations in cell differentiation. We propose that cells are normally protected against electromagnetic insult. Pathologies may arise, however, if intracellular Ca regulation or K channel activation malfunctions. PMID- 11606273 TI - Activation and propagation of Ca(2+) release during excitation-contraction coupling in atrial myocytes. AB - Fast two-dimensional confocal microscopy and the Ca(2+) indicator fluo-4 were used to study excitation-contraction (E-C) coupling in cat atrial myocytes which lack transverse tubules and contain both subsarcolemmal junctional (j-SR) and central nonjunctional (nj-SR) sarcoplasmic reticulum. Action potentials elicited by field stimulation induced transient increases of intracellular Ca(2+) concentration ([Ca(2+)](i)) that were highly inhomogeneous. Increases started at distinct subsarcolemmal release sites spaced approximately 2 microm apart. The amplitude and the latency of Ca(2+) release from these sites varied from beat to beat. Subsarcolemmal release fused to build a peripheral ring of elevated [Ca(2+)](i), which actively propagated to the center of the cells via Ca(2+) induced Ca(2+) release. Resting myocytes exhibited spontaneous Ca(2+) release events, including Ca(2+) sparks and local (microscopic) or global (macroscopic) [Ca(2+)](i) waves. The microscopic [Ca(2+)](i) waves propagated in a saltatory fashion along the sarcolemma ("coupled" Ca(2+) sparks) revealing the sequential activation of Ca(2+) release sites of the j-SR. Moreover, during global [Ca(2+)](i) waves, Ca(2+) release was evident from individual nj-SR sites. Ca(2+) release sites were arranged in a regular three-dimensional grid as deduced from the functional data and shown by immunostaining of ryanodine receptor Ca(2+) release channels. The longitudinal and transverse distances between individual Ca(2+) release sites were both approximately 2 microm. Furthermore, electron microscopy revealed a continuous sarcotubular network and one peripheral coupling of j-SR with the sarcolemma per sarcomere. The results demonstrate directly that, in cat atrial myocytes, the action potential-induced whole-cell [Ca(2+)](i) transient is the spatio-temporal summation of Ca(2+) release from subsarcolemmal and central sites. First, j-SR sites are activated in a stochastic fashion by the opening of voltage-dependent sarcolemmal Ca(2+) channels. Subsequently, nj-SR sites are activated by Ca(2+)-induced Ca(2+) release propagating from the periphery. PMID- 11606274 TI - Distinct mechanisms of block of Kv1.5 channels by tertiary and quaternary amine clofilium compounds. AB - The quaternary ammonium compound clofilium and its tertiary amine derivative LY97241 were used to analyze mechanisms of block in a voltage-gated potassium channel. Wild-type and mutant Kv1.5 channels expressed in Xenopus oocytes were recorded by two-electrode voltage clamp. Open-channel block to 20% of the control current amplitude was induced reversibly by 50 microM clofilium or 200 microM LY97241, and was seen as an acceleration of the macroscopic current decay. Although blockers remained present after application, channels recovered from block during each interpulse interval. The optimum voltage for recovery (-45 mV at pH 7.3) at the threshold for channel activation indicated that clofilium block and recovery occurred principally through the open channel state. In contrast, LY97241 appeared to exit from the closed state and the open state. In an acid tolerant Kv1.5 mutant channel (H452Q), external pH was used to titrate LY97241. At low pH, which protonates the LY97241 amine group, recovery from block at hyperpolarized potentials was impaired in a manner similar to that seen with clofilium. Recovery from clofilium block was reduced at negative potentials independent of pH, an effect attributed to trapping of the permanently charged compound within the closed channels. PMID- 11606275 TI - Gating charge immobilization caused by the transition between inactivated states in the Kv1.5 channel. AB - Sustained Na(+) or Li(+) conductance is a feature of the inactivated state in wild-type (WT) and nonconducting Shaker and Kv1.5 channels, and has been used here to investigate the cause of off-gating charge immobilization in WT and Kv1.5 W472F nonconducting mutant channels. Off-gating immobilization in response to brief pulses in cells perfused with NMG/NMG is the result of a more negative voltage dependence of charge recovery (V(1/2) is -96 mV) compared with on-gating charge movement (V(1/2) is -6.3 mV). This shift is known to be associated with slow inactivation in Shaker channels and the disparity is reduced by 40 mV, or approximately 50% in the presence of 135 mM Cs. Off-gating charge immobilization is voltage-dependent with a V(1/2) of -12 mV, and correlates well with the development of Na(+) conductance on repolarization through C-type inactivated channels (V(1/2) is -11 mV). As well, the time-dependent development of the inward Na(+) tail current and gating charge immobilization after depolarizing pulses of different durations has the same time constant (tau = 2.7 ms). These results indicate that in Kv1.5 channels the transition to a stable C-type inactivated state takes only 2-3 ms and results in strong charge immobilization in the absence of Group IA metal cations, or even in the presence of Na. Inclusion of low concentrations of Cs delays the appearance of Na(+) tail currents in WT channels, prevents transition to inactivated states in Kv1.5-W472F nonconducting mutant channels, and removes charge immobilization. Higher concentrations of Cs are able to modulate the deactivating transition in Kv1.5 channels and prevent the residual slowing of charge return. PMID- 11606276 TI - Voltage and Ca(2+) dependence of pre-steady-state currents of the Na-Ca exchanger generated by Ca(2+) concentration jumps. AB - The Ca(2+) concentration and voltage dependence of the relaxation kinetics of the Na-Ca exchanger after a Ca(2+) concentration jump was measured in excised giant membrane patches from guinea pig heart. Ca(2+) concentration jumps on the cytoplasmic side were achieved by laser flash-induced photolysis of DM-nitrophen. In the Ca-Ca exchange mode a transient inward current is generated. The amplitude and the decay rate of the current saturate at concentrations >10 microM. The integrated current signal, i.e., the charge moved is fairly independent of the amount of Ca(2+) released. The amount of charge translocated increases at negative membrane potentials, whereas the decay rate constant shows no voltage dependence. It is suggested that Ca(2+) translocation occurs in at least four steps: intra- and extracellular Ca(2+) binding and two intramolecular transport steps. Saturation of the amplitude and of the relaxation of the current can be explained if the charge translocating reaction step is preceded by two nonelectrogenic steps: Ca(2+) binding and one conformational transition. Charge translocation in this mode is assigned to one additional conformational change which determines the equilibrium distribution of states. In the Na-Ca exchange mode, the stationary inward current depends on the cytoplasmic Ca(2+) concentration and voltage. The K(m) for Ca(2+) is 4 microM for guinea pig and 10 microM for rat myocytes. The amplitude of the pre-steady-state current and its relaxation saturate with increasing Ca(2+) concentrations. In this mode the relaxation is voltage dependent. PMID- 11606277 TI - Single-molecule imaging of l-type Ca(2+) channels in live cells. AB - L-type Ca(2+) channels are an important means by which a cell regulates the Ca(2+) influx into the cytosol on electrical stimulation. Their structure and dynamics in the plasma membrane, including their molecular mobility and aggregation, is of key interest for the in-depth understanding of their function. Construction of a fluorescent variant by fusion of the yellow-fluorescent protein to the ion channel and expression in a human cell line allowed us to address its dynamic embedding in the membrane at the level of individual channels in vivo. We report on the observation of individual fluorescence-labeled human cardiac L-type Ca(2+) channels using wide-field fluorescence microscopy in living cells. Our fluorescence and electrophysiological data indicate that L-type Ca(2+) channels tend to form larger aggregates which are mobile in the plasma membrane. PMID- 11606278 TI - I(Ca(TTX)) channels are distinct from those generating the classical cardiac Na(+) current. AB - The Na(+) current component I(Ca(TTX)) is functionally distinct from the main body of Na(+) current, I(Na). It was proposed that I(Ca(TTX)) channels are I(Na) channels that were altered by bathing media containing Ca(2+), but no, or very little, Na(+). It is known that Na(+)-free conditions are not required to demonstrate I(Ca(TTX).) We show here that Ca(2+) is also not required. Whole cell, tetrodotoxin-blockable currents from fresh adult rat ventricular cells in 65 mm Cs(+) and no Ca(2+) were compared to those in 3 mM Ca(2+) and no Cs(+) (i.e., I(Ca(TTX))). I(Ca(TTX)) parameters were shifted to more positive voltages than those for Cs(+). The Cs(+) conductance-voltage curve slope factor (mean, 4.68 mV; range, -3.63 to -5.72 mV, eight cells) is indistinguishable from that reported for I(Ca(TTX)) (mean, -4.49 mV; range, -3.95 to -5.49 mV). Cs(+) current and I(Ca(TTX)) time courses were superimposable after accounting for the voltage shift. Inactivation time constants as functions of potential for the Cs(+) current and I(Ca(TTX)) also superimposed after voltage shifting, as did the inactivation curves. Neither of the proposed conditions for conversion of I(Na) into I(Ca(TTX)) channels is required to demonstrate I(Ca(TTX)). Moreover, we find that cardiac Na(+) (H1) channels expressed heterologously in HEK 293 cells are not converted to I(Ca(TTX)) channels by Na(+)-free, Ca(2+)-containing bathing media. The gating properties of the Na(+) current through H1 and those of Ca(2+) current through H1 are identical. All observations are consistent with two non interconvertable Na(+) channel populations: a larger that expresses little Ca(2+) permeability and a smaller that is appreciably Ca(2+)-permeable. PMID- 11606279 TI - Microscopic kinetics and energetics distinguish GABA(A) receptor agonists from antagonists. AB - Although agonists and competitive antagonists presumably occupy overlapping binding sites on ligand-gated channels, these interactions cannot be identical because agonists cause channel opening whereas antagonists do not. One explanation is that only agonist binding performs enough work on the receptor to cause the conformational changes that lead to gating. This idea is supported by agonist binding rates at GABA(A) and nicotinic acetylcholine receptors that are slower than expected for a diffusion-limited process, suggesting that agonist binding involves an energy-requiring event. This hypothesis predicts that competitive antagonist binding should require less activation energy than agonist binding. To test this idea, we developed a novel deconvolution-based method to compare binding and unbinding kinetics of GABA(A) receptor agonists and antagonists in outside-out patches from rat hippocampal neurons. Agonist and antagonist unbinding rates were steeply correlated with affinity. Unlike the agonists, three of the four antagonists tested had binding rates that were fast, independent of affinity, and could be accounted for by diffusion- and dehydration limited processes. In contrast, agonist binding involved additional energy requiring steps, consistent with the idea that channel gating is initiated by agonist-triggered movements within the ligand binding site. Antagonist binding does not appear to produce such movements, and may in fact prevent them. PMID- 11606280 TI - Intramural multisite recording of transmembrane potential in the heart. AB - Heart surface optical mapping of transmembrane potentials has been widely used in studies of normal and pathological heart rhythms and defibrillation. In these studies, three-dimensional spatio-temporal events can only be inferred from two dimensional surface potential maps. We present a novel optical system that enables high fidelity transmural recording of transmembrane potentials. A probe constructed from optical fibers is used to deliver excitation light and collect fluorescence from seven positions, each 1 mm apart, through the left ventricle wall of the rabbit heart. Excitation is provided by the 488-nm line of a water cooled argon-ion laser. The fluorescence of the voltage-sensitive dye di-4-ANEPPS from each tissue site is split at 600 nm and imaged onto separate photodiodes for later signal ratioing. The optics and electronics are easily expandable to accommodate multiple optical probes. The system is used to record the first simultaneous measurements of transmembrane potential at a number of sites through the intact heart wall. PMID- 11606281 TI - Mapping the energy surface of transmembrane helix-helix interactions. AB - Transmembrane helices are no longer believed to be just hydrophobic segments that exist solely to anchor proteins to a lipid bilayer, but rather they appear to have the capacity to specify function and structure. Specific interactions take place between hydrophobic segments within the lipid bilayer whereby subtle mutations that normally would be considered innocuous can result in dramatic structural differences. That such specificity takes place within the lipid bilayer implies that it may be possible to identify the most favorable interaction surface of transmembrane alpha-helices based on computational methods alone, as shown in this study. Herein, an attempt is made to map the energy surface of several transmembrane helix-helix interactions for several homo oligomerizing proteins, where experimental data regarding their structure exist (glycophorin A, phospholamban, Influenza virus A M2, Influenza virus C CM2, and HIV vpu). It is shown that due to symmetry constraints in homo-oligomers the computational problem can be simplified. The results obtained are mostly consistent with known structural data and may additionally provide a view of possible alternate and intermediate configurations. PMID- 11606282 TI - X-ray diffraction structures of some phosphatidylethanolamine lamellar and inverted hexagonal phases. AB - X-ray diffraction is used to solve the low-resolution structures of fully hydrated aqueous dispersions of seven different diacyl phosphatidylethanolamines (PEs) whose hydrocarbon chains have the same effective chain length but whose structures vary widely. Both the lower-temperature, liquid-crystalline lamellar (L(alpha)) and the higher-temperature, inverted hexagonal (H(II)) phase structures are solved, and the resultant internal dimensions (d-spacing, water layer thickness, average lipid length, and headgroup area at the lipid-water interface) of each phase are determined as a function of temperature. The magnitude of the L(alpha) and H(II) phase d-spacings on either side of the L(alpha)/H(II) phase transition temperature (T(h)) depends significantly on the structure of the PE hydrocarbon chains. The L(alpha) phase d-spacings range from 51.2 to 56.4 A, whereas those of the H(II) phase range from 74.9 to 82.7 A. These new results differ from our earlier measurements of these PEs (Lewis et al., Biochemistry, 28:541-548, 1989), which found near constant d-spacings of 52.5 and 77.0-78.0 A for the L(alpha) and H(II) phases, respectively. In both phases, the d-spacings decrease with increasing temperature independent of chain structure, but, in both phases, the rate of decrease in the L(alpha) phase is smaller than that in the H(II) phase. A detailed molecular description of the L(alpha)/H(II) phase transition in these PEs is also presented. PMID- 11606283 TI - Packing of ganglioside-phospholipid monolayers: an x-ray diffraction and reflectivity study. AB - Using synchrotron grazing-incidence x-ray diffraction (GIXD) and reflectivity, the in-plane and out-of-plane structure of mixed ganglioside-phospholipid monolayers was investigated at the air-water interface. Mixed monolayers of 0, 5, 10, 20, and 100 mol% ganglioside GM(1) and the phospholipid dipalmitoylphosphatidylethanolamine (DPPE) were studied in the solid phase at 23 degrees C and a surface pressure of 45 mN/m. At these concentrations and conditions the two components do not phase-separate and no evidence for domain formation was observed. X-ray scattering measurements reveal that GM(1) is accommodated within the host DPPE monolayer and does not distort the hexagonal in plane unit cell or out-of-plane two-dimensional (2-D) packing compared with a pure DPPE monolayer. The oligosaccharide headgroups were found to extend normally from the monolayer surface, and the incorporation of these glycolipids into DPPE monolayers did not affect hydrocarbon tail packing (fluidization or condensation of the hydrocarbon region). This is in contrast to previous investigations of lipopolymer-lipid mixtures, where the packing structure of phospholipid monolayers was greatly altered by the inclusion of lipids bearing hydrophilic polymer groups. Indeed, the lack of packing disruptions by the oligosaccharide groups indicates that protein-GM(1) interactions, including binding, insertion, chain fluidization, and domain formation (lipid rafts), can be studied in 2-D monolayers using scattering techniques. PMID- 11606284 TI - Osmotically induced shape changes of large unilamellar vesicles measured by dynamic light scattering. AB - Static and dynamic light scattering measurements have been used to characterize the size, size distribution, and shape of extruded vesicles under isotonic conditions. Dynamic light scattering was then used to characterize osmotically induced shape changes by monitoring changes in the hydrodynamic radius (R(h)) of large unilamellar vesicles (LUVs). These changes are compared to those predicted for several shapes that appear in trajectories through the phase diagram of the area difference elasticity (ADE) model (. Phys. Rev. E. 52:6623-6634). Measurements were performed on dioleoylphosphatidylcholine (DOPC) vesicles using two membrane-impermeant osmolytes (NaCl and sucrose) and a membrane-permeant osmolyte (urea). For all conditions, we were able to produce low-polydispersity, nearly spherical vesicles, which are essential for resolving well-defined volume changes and consequent shape changes. Hyper-osmotic dilutions of DOPC vesicles in urea produced no change in R(h), whereas similar dilutions in NaCl or sucrose caused reductions in vesicle volume resulting in observable changes to R(h). Under conditions similar to those of this study, the ADE model predicts an evolution from spherical to prolate then oblate shapes on increasing volume reduction of LUVs. However, we found that DOPC vesicles became oblate at all applied volume reductions. PMID- 11606285 TI - Cholesterol monohydrate nucleation in ultrathin films on water. AB - The growth of a cholesterol crystalline phase, three molecular layers thick at the air-water interface, was monitored by grazing incidence x-ray diffraction and x-ray reflectivity. Upon compression, a cholesterol film transforms from a monolayer of trigonal symmetry and low crystallinity to a trilayer, composed of a highly crystalline bilayer in a rectangular lattice and a disordered top cholesterol layer. This system undergoes a phase transition into a crystalline trilayer incorporating ordered water between the hydroxyl groups of the top and middle sterol layers in an arrangement akin to the triclinic 3-D crystal structure of cholesterol x H(2)O. By comparison, the cholesterol derivative stigmasterol transforms, upon compression, directly into a crystalline trilayer in the rectangular lattice. These results may contribute to an understanding of the onset of cholesterol crystallization in pathological lipid deposits. PMID- 11606286 TI - Lipid membrane reorganization induced by chemical recognition. AB - Nanoscale structural reorganization of a lipid bilayer membrane induced by a chemical recognition event has been imaged using in situ atomic force microscopy (AFM). Supported lipid bilayers, composed of distearylphosphatidylcholine (DSPC) and a synthetic lipid functionalized with a Cu(2+) receptor, phase-separate into nanoscale domains that are distinguishable by the 9 A height difference between the two molecules. Upon binding of Cu(2+) the electrostatic nature of the receptor changes, causing a dispersion of the receptor molecules and subsequent shrinking of the structural features defined by the receptors in the membrane. Complete reversibility of the process was demonstrated through the removal of metal ions with EDTA. PMID- 11606287 TI - Kinetics of membrane adhesion mediated by ligand-receptor interaction studied with a biomimetic system. AB - We report the first measurement of the kinetics of adhesion of a single giant vesicle controlled by the competition between membrane-substrate interaction mediated by ligand-receptor interaction, gravitation, and Helfrich repulsion. To model the cell-tissue interaction, we doped the vesicles with lipid-coupled polymers (mimicking the glycocalix) and the reconstituted ligands selectively recognized by alpha(IIb)beta(3) integrin-mediating specific attraction forces. The integrin was grafted on glass substrates to act as a target cell. The adhesion of the vesicle membrane to the integrin-covered surface starts with the spontaneous formation of a small (approximately 200 nm) domain of tight adhesion, which then gradually grows until the whole adhesion area is in the state of tight adhesion. The time of adhesion varies from few tens of seconds to about one hour depending on the ligand and lipopolymer concentration. At small ligand concentrations, we observed the displacement xi of the front of tight adhesion following the square root law xi approximately t(1/2), whereas, at high concentrations, we found a linear law xi approximately t. We show both experimentally and theoretically that the t(1/2)-regime is dominated by diffusion of ligands, and the xi approximately t-regime by the kinetics of ligands receptors association. PMID- 11606288 TI - Solid-state NMR structure determination of melittin in a lipid environment. AB - Solid-state (13)C NMR spectroscopy was used to investigate the three-dimensional structure of melittin as lyophilized powder and in ditetradecylphosphatidylcholine (DTPC) membranes. The distance between specifically labeled carbons in analogs [1-(13)C]Gly3-[2-(13)C]Ala4, [1 (13)C]Gly3-[2-(13)C]Leu6, [1-(13)C]Leu13-[2-(13)C]Ala15, [2-(13)C]Leu13-[1 (13)C]Ala15, and [1-(13)C]Leu13-[2-(13)C]Leu16 was measured by rotational resonance. As expected, the internuclear distances measured in [1-(13)C]Gly3-[2 (13)C]Ala4 and [1-(13)C]Gly3-[2-(13)C]Leu6 were consistent with alpha-helical structure in the N-terminus irrespective of environment. The internuclear distances measured in [1-(13)C]Leu13-[2-(13)C]Ala15, [2-(13)C]Leu13-[1 (13)C]Ala15, and [1-(13)C]Leu13-[2-(13)C]Leu16 revealed, via molecular modeling, some dependence upon environment for conformation in the region of the bend in helical structure induced by Pro14. A slightly larger interhelical angle between the N- and C-terminal helices was indicated for peptide in dry or hydrated gel state DTPC (139 degrees -145 degrees ) than in lyophilized powder (121 degrees 139 degrees ) or crystals (129 degrees ). The angle, however, is not as great as deduced for melittin in aligned bilayers of DTPC in the liquid-crystalline state (approximately 160 degrees ). The study illustrates the utility of rotational resonance in determining local structure within peptide-lipid complexes. PMID- 11606289 TI - Cholesterol does not induce segregation of liquid-ordered domains in bilayers modeling the inner leaflet of the plasma membrane. AB - A fluorescence-quenching method has been used to assess the potential formation of segregated liquid-ordered domains in lipid bilayers combining cholesterol with mixtures of amino and choline phospholipids like those found in the cytoplasmic leaflet of the mammalian cell plasma membrane. When present in proportions >20-30 mol %, different saturated phospholipids show a strong proclivity to form segregated domains when combined with unsaturated phospholipids and cholesterol, in a manner that is only weakly affected by the nature of the phospholipid headgroups. By contrast, mixtures containing purely unsaturated phospholipids and cholesterol do not exhibit detectable segregation of domains, even in systems whose components differ in headgroup structure, mono- versus polyunsaturation and/or acyl chain heterogeneity. These results indicate that mixtures of phospholipids resembling those found in the inner leaflet of the plasma membrane do not spontaneously form segregated liquid-ordered domains. Instead, our findings suggest that factors extrinsic to the inner-monolayer lipids themselves (e.g., transbilayer penetration of long sphingolipid acyl chains) would be essential to confer a distinctive, more highly ordered organization to the cytoplasmic leaflet of "lipid raft" structures in animal cell membranes. PMID- 11606290 TI - Condensed complexes and the calorimetry of cholesterol-phospholipid bilayers. AB - A recent thermodynamic model describes a reversible reaction between cholesterol (C) and phospholipid (P) to form a condensed complex C(nq)P(np). Here q and p are relatively prime integers used to define the stoichiometric composition, and n is a measure of cooperativity. The present study applies this model to the scanning calorimetry of binary mixtures of cholesterol and saturated phosphatidylcholines, especially work by McElhaney and collaborators. These mixtures generally show two heat capacity peaks, a sharp peak and a broad peak. The sharp heat absorption is largely due to the chain melting transition of pure phospholipid. In the present work the broad heat absorption is attributed to the thermal dissociation of complexes. The best fits of the model to the data require the complex formation to be highly cooperative, with cooperativity n = 12. Detailed comparisons are made between model calculations and calorimetric data. A number of unusual features of the data arise naturally in the model. The principal discrepancy between the calculations and experimental results is a spurious calculated heat absorption peak. This discrepancy is related to the reported relative magnitudes of the integrated broad and sharp heat absorption curves. PMID- 11606291 TI - Theoretical studies of the ATP hydrolysis mechanism of myosin. AB - The ATP hydrolysis mechanism of myosin was studied using quantum chemical (QM) and molecular dynamics calculations. The initial model compound for QM calculations was constructed on the basis of the energy-minimized structure of the myosin(S1dc)-ATP complex, which was determined by molecular mechanics calculations. The result of QM calculations suggested that the ATP hydrolysis mechanism of myosin consists of a single elementary reaction in which a water molecule nucleophilically attacked gamma-phosphorus of ATP. In addition, we performed molecular dynamics simulations of the initial and final states of the ATP hydrolysis reaction, that is, the myosin-ATP and myosin-ADP.Pi complexes. These calculations revealed roles of several amino acid residues (Lys185, Thr186, Ser237, Arg238, and Glu459) in the ATPase pocket. Lys185 maintains the conformation of beta- and gamma-phosphate groups of ATP by forming the hydrogen bonds. Thr186 and Ser237 are coordinated to a Mg(2+) ion, which interacts with the phosphates of ATP and therefore contributes to the stabilization of the ATP structure. Arg238 and Glu459, which consisted of the gate of the ATPase pocket, retain the water molecule acting on the hydrolysis at the appropriate position for initiating the hydrolysis. PMID- 11606292 TI - Hidden-Markov methods for the analysis of single-molecule actomyosin displacement data: the variance-Hidden-Markov method. AB - In single-molecule experiments on the interaction between myosin and actin, mechanical events are embedded in Brownian noise. Methods of detecting events have progressed from simple manual detection of shifts in the position record to threshold-based selection of intermittent periods of reduction in noise. However, none of these methods provides a "best fit" to the data. We have developed a Hidden-Markov algorithm that assumes a simple kinetic model for the actin-myosin interaction and provides automatic, threshold-free, maximum-likelihood detection of events. The method is developed for the case of a weakly trapped actin-bead dumbbell interacting with a stationary myosin molecule (Finer, J. T., R. M. Simmons, and J. A. Spudich. 1994. Nature. 368:113-119). The algorithm operates on the variance of bead position signals in a running window, and is tested using Monte Carlo simulations to formulate ways of determining the optimum window width. The working stroke is derived and corrected for actin-bead link compliance. With experimental data, we find that modulation of myosin binding by the helical structure of the actin filament complicates the determination of the working stroke; however, under conditions that produce a Gaussian distribution of bound levels (cf. Molloy, J. E., J. E. Burns, J. Kendrick-Jones, R. T. Tregear, and D. C. S. White. 1995. Nature. 378:209-212), four experiments gave working strokes in the range 5.4-6.3 nm for rabbit skeletal muscle myosin S1. PMID- 11606293 TI - Purification of native myosin filaments from muscle. AB - Analysis of the structure and function of native thick (myosin-containing) filaments of muscle has been hampered in the past by the difficulty of obtaining a pure preparation. We have developed a simple method for purifying native myosin filaments from muscle filament suspensions. The method involves severing thin (actin-containing) filaments into short segments using a Ca(2+)-insensitive fragment of gelsolin, followed by differential centrifugation to purify the thick filaments. By gel electrophoresis, the purified thick filaments show myosin heavy and light chains together with nonmyosin thick filament components. Contamination with actin is below 3.5%. Electron microscopy demonstrates intact thick filaments, with helical cross-bridge order preserved, and essentially complete removal of thin filaments. The method has been developed for striated muscles but can also be used in a modified form to remove contaminating thin filaments from native smooth muscle myofibrils. Such preparations should be useful for thick filament structural and biochemical studies. PMID- 11606294 TI - Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region. AB - Fifteen percent of the mutations causing familial hypertrophic cardiomyopathy are in the troponin T gene. Most mutations are clustered between residues 79 and 179, a region known to bind to tropomyosin at the C-terminus near the complex between the N- and C-termini. Nine mutations were introduced into a troponin T fragment, Gly-hcTnT(70-170), that is soluble, alpha-helical, binds to tropomyosin, promotes the binding of tropomyosin to actin, and stabilizes an overlap complex of N terminal and C-terminal tropomyosin peptides. Mutations between residues 92 and 110 (Arg92Leu, Arg92Gln, Arg92Trp, Arg94Leu, Ala104Val, and Phe110Ile) impair tropomyosin-dependent functions of troponin T. Except for Ala104Val, these mutants bound less strongly to a tropomyosin affinity column and were less able to stabilize the TM overlap complex, effects that were correlated with increased stability of the troponin T, measured using circular dichroism. All were less effective in promoting the binding of tropomyosin to actin. Mutations within residues 92-110 may cause disease because of altered interaction with tropomyosin at the overlap region, critical for cooperative actin binding and regulatory function. A model for a five-chained coiled-coil for troponin T in the tropomyosin overlap complex is presented. Mutations outside the region (Ile79Asn, Delta 160Glu, and Glu163Lys) functioned normally and must cause disease by another mechanism. PMID- 11606295 TI - Motility of single one-headed kinesin molecules along microtubules. AB - The motility of single one-headed kinesin molecules (K351 and K340), which were truncated fragments of Drosophila two-headed kinesin, has been tested using total internal reflection fluorescence microscopy. One-headed kinesin fragments moved continuously along the microtubules. The maximum distance traveled until the fragments dissociated from the microtubules for both K351 and K340 was approximately 600 nm. This value is considerably larger than the space resolution of the measurement system (SD approximately 30 nm). Although the movements of the fragments fluctuated in forward and backward directions, statistical analysis showed that the average movements for both K340 and K351 were toward the plus end of the microtubules, i.e., forward direction. When BDTC (a 1.3-S subunit of Propionibacterium shermanii transcarboxylase, which binds weakly to a microtubule), was fused to the tail (C-terminus) of K351, its movement was enhanced, smooth, and unidirectional, similar to that of the two-headed kinesin fragment, K411. However, the travel distance and velocity of K351BDTC molecules were approximately 3-fold smaller than that of K411. These observations suggest that a single kinesin head has basal motility, but coordination between the two heads is necessary for stabilizing the basal motility for the normal level of kinesin processivity. PMID- 11606296 TI - Polarized fluorescence microscopy of individual and many kinesin motors bound to axonemal microtubules. AB - Kinesin is a molecular motor that interacts with microtubules and uses the energy of ATP hydrolysis to produce force and movement in cells. To investigate the conformational changes associated with this mechanochemical energy conversion, we developed a fluorescence polarization microscope that allows us to obtain information on the orientation of single as well as many fluorophores. We attached either monofunctional or bifunctional fluorescent probes to the kinesin motor domain. Both types of labeled kinesins show anisotropic fluorescence signals when bound to axonemal microtubules, but the bifunctional probe is less mobile resulting in higher anisotropy. From the polarization experiments with the bifunctional probe, we determined the orientation of kinesin bound to microtubules in the presence of AMP-PNP and found close agreement with previous models derived from cryo-electron microscopy. We also compared the polarization anisotropy of monomeric and dimeric kinesin constructs bound to microtubules in the presence of AMP-PNP. Our results support models of mechanochemistry that require a state in which both motor domains of a kinesin dimer bind simultaneously with similar orientation with respect to the microtubule. PMID- 11606297 TI - A semiflexible polymer model applied to loop formation in DNA hairpins. AB - A statistical mechanical "zipper" model is applied to describe the equilibrium melting of short DNA hairpins with poly(dT) loops ranging from 4 to 12 bases in the loop. The free energy of loop formation is expressed in terms of the persistence length of the chain. This method provides a new measurement of the persistence length of single-stranded DNA, which is found to be approximately 1.4 nm for poly(dT) strands in 100 mM NaCl. The free energy of the hairpin relative to the random coil state is found to scale with the loop size with an apparent exponent of > or = 7, much larger than the exponent of approximately 1.5-1.8 expected from considerations of loop entropy alone. This result indicates a strong dependence of the excess stability of the hairpins, from stacking interactions of the bases within the loop, on the size of the loop. We interpret this excess stability as arising from favorable hydrophobic interactions among the bases in tight loops and which diminish as the loops get larger. Free energy profiles along a generalized reaction coordinate are calculated from the equilibrium zipper model. The transition state for hairpin formation is identified as an ensemble of looped conformations with one basepair closing the loop, and with a lower enthalpy than the random coil state. The equilibrium model predicts apparent activation energy of approximately -11 kcal/mol for the hairpin closing step, in remarkable agreement with the value obtained from kinetics measurements. PMID- 11606298 TI - A simple model for gene targeting. AB - Sequence-specific binding to genomic-size DNA sequences by artificial agents is of major interest for the development of gene-targeting strategies, gene diagnostic applications, and biotechnical tools. The binding of one such agent, peptide nucleic acid (PNA), to a randomized human genome has been modeled with statistical mass action calculations. With the length of the PNA probe, the average per-base binding constant k(0), and the binding affinity loss of a mismatched base pair as main parameters, the specificity was gauged as a "therapeutic ratio" G = maximum safe [PNA](tot)/minimal efficient [PNA](tot). This general, though simple, model suggests that, above a certain threshold length of the PNA, the microscopic binding constant k(0) is the primary determinant for optimal discrimination, and that only a narrow range of rather low k(0) values gives a high therapeutic ratio G. For diagnostic purposes, the value of k(0) could readily be modulated by changing the temperature, due to the substantial Delta H degrees associated with the binding equilibrium. Applied to gene therapy, our results stress the need for appropriate control of the binding constant and added amount of the gene-targeting agent, to meet the varying conditions (ionic strength, presence of competing DNA-binding molecules) found in the cell. PMID- 11606299 TI - Protonation studies and multivariate curve resolution on oligodeoxynucleotides carrying the mutagenic base 2-aminopurine. AB - 2-Aminopurine (P) is a mutagen causing A.T to G.C transitions in prokaryotic systems. To study the base-pairing schemes between P and cytosine (C) or thymine (T), two self-complementary dodecamers containing P paired with either C or T were synthesized, and their protonation equilibria were studied by acid-base titrations and melting experiments. The mismatches were incorporated into the self-complementary sequence d(CGCPCCGGXGCG), where X was C or T. Spectroscopic data obtained from molecular absorption, circular dichroism (CD), and molecular fluorescence spectroscopy were analyzed by a factor-analysis-based method, multivariate curve resolution based on the alternating least squares optimization procedure (MCR-ALS). This procedure allows determination of the number of acid base species or conformations present in an acid-base or melting experiment and the resolution of the concentration profiles and pure spectra for each of them. Acid-base experiments have shown that at pH 7, 150 mM ionic strength, and 37 degrees C, both C and P are deprotonated. At pH near 4, the majority of species shows C protonated and P deprotonated. Finally, at pH values near 3, the majority of species shows both protonated C and P. These results are in agreement with NMR studies showing a wobble geometry for the P x C base pair and a Watson-Crick geometry for the P x T base pair at neutral pH. Melting experiments were carried out to confirm the proposed acid-base distribution profile. For the sequence including the P x T mismatch, only one transition was observed at neutral pH. However, for the sequence including the P x C mismatch, two transitions were detected by CD but only one by molecular absorption. This behavior agrees with that observed by other authors for oligonucleotides of similar sequence and suggests the following sequence of conformational changes during melting: duplex -> hairpin --> random coil. PMID- 11606300 TI - Photoreceptor current and photoorientation in chlamydomonas mediated by 9 demethylchlamyrhodopsin. AB - Green flagellates possess rhodopsin-like photoreceptors involved in control of their behavior via generation of photocurrents across the plasma membrane. Chlamydomonas mutants blocked in retinal biosynthesis are "blind," but they can be rescued by the addition of exogenous retinoids. Photosignaling by chlamyrhodopsin regenerated with 9-demethylretinal was investigated by recording photocurrents from single cells and cell suspensions, and by measuring phototactic orientation. The addition of a saturating concentration of this analog led to reconstitution of all receptor molecules. However, sensitivity of the photoreceptor current in cells reconstituted with the analog was smaller compared with retinal-reconstituted cells, indicating a decreased signaling efficiency of the analog receptor protein. Suppression of the photoreceptor current in double-flash experiments was smaller and its recovery faster with 9 demethylretinal than with retinal, as it would be expected from a decreased PC amplitude in the analog-reconstituted cells. Cells reconstituted with either retinal or the analog displayed negative phototaxis at low light and switched to positive one upon an increase in stimulus intensity, as opposed to the wild type. The reversal of the phototaxis direction in analog-reconstituted cells was shifted to a higher fluence rate compared with cells reconstituted with retinal, which corresponded to the decreased signaling efficiency of 9 demethylchlamyrhodopsin. PMID- 11606301 TI - Calcium-dependent stabilization of the central sequence between Met(76) and Ser(81) in vertebrate calmodulin. AB - Spin-label electron paramagnetic resonance (EPR) provides optimal resolution of dynamic and conformational heterogeneity on the nanosecond time-scale and was used to assess the structure of the sequence between Met(76) and Ser(81) in vertebrate calmodulin (CaM). Previous fluorescence resonance energy transfer and anisotropy measurements indicate that the opposing domains of CaM are structurally coupled and the interconnecting central sequence adopts conformationally distinct structures in the apo-form and following calcium activation. In contrast, NMR data suggest that the opposing domains of CaM undergo independent rotational dynamics and that the sequence between Met(76) and Ser(81) in the central sequence functions as a flexible linker that connects two structurally independent domains. However, these latter measurements also resolve weak internuclear interactions that suggest the formation of transient helical structures that are stable on the nanosecond time-scale within the sequence between Met(76) and Asp(80) in apo-CaM (H. Kuboniwa, N. Tjandra, S. Grzekiek, H. Ren, C. B. Klee, and A. Bax, 1995, Nat. Struct. Biol. 2:768-776). This reported conformational heterogeneity was resolved using site-directed mutagenesis and spin-label EPR, which detects two component spectra for 1-oxyl-2,2,5,5 tetramethylpyrroline-3-methyl)-methanethiosulfonate spin labels (MTSSL) bound to CaM mutants T79C and S81C that include a motionally restricted component. In comparison to MTSSL bound within stable helical regions, the fractional contribution of the immobilized component at these positions is enhanced upon the addition of small amounts of the helicogenic solvent trifluoroethanol (TFE). These results suggest that the immobilized component reflects the formation of stable secondary structures. Similar spectral changes are observed upon calcium activation, suggesting a calcium-dependent stabilization of the secondary structure. No corresponding changes are observed in either the solvent accessibility to molecular oxygen or the maximal hyperfine splitting. In contrast, more complex spectral changes in the line-shape and maximal hyperfine splitting are observed for spin labels bound to sites that undergo tertiary contact interactions. These results suggest that spin labels at solvent-exposed positions within the central sequence are primarily sensitive to backbone fluctuations and that either TFE or calcium binding stabilizes the secondary structure of the sequence between Met(76) and Ser(81) and modulates the structural coupling between the opposing domains of CaM. PMID- 11606302 TI - The effect of water on the rate of conformational change in protein allostery. AB - The influence of solvation on the rate of quaternary structural change is investigated in human hemoglobin, an allosteric protein in which reduced water activity destabilizes the R state relative to T. Nanosecond absorption spectroscopy of the heme Soret band was used to monitor protein relaxation after photodissociation of aqueous HbCO complex under osmotic stress induced by the nonbinding cosolute poly(ethylene glycol) (PEG). Photolysis data were analyzed globally for six exponential time constants and amplitudes as a function of osmotic stress and viscosity. Increases in time constants associated with geminate rebinding, tertiary relaxation, and quaternary relaxation were observed in the presence of PEG, along with a decrease in the fraction of hemes rebinding CO with the slow rate constant characteristic of the T state. An analysis of these results along with those obtained by others for small cosolutes showed that both osmotic stress and solvent viscosity are important determinants of the microscopic R --> T rate constant. The size and direction of the osmotic stress effect suggests that at least nine additional water molecules are required to solvate the allosteric transition state relative to the R-state hydration, implying that the transition state has a greater solvent-exposed area than either end state. PMID- 11606304 TI - Force measurements on single molecular contacts through evanescent wave microscopy. AB - We introduce a new method to apply controlled forces on single molecules. The motion of a micron-sized bead attached to a solid surface through a single molecular contact is tracked by evanescent wave microscopy as a force is exerted through a flow. We report measurements of the streptavidin-biotin bond rupture force obtained with this technique. We also obtain detailed measurements of the balance of forces involved in detaching an adhering bead with a flow. A small lateral force translates into a much bigger normal force on the attachment point. This effect is relevant for the interpretation of common cell adhesion assays. PMID- 11606305 TI - Alignment maps of tissues: I. Microscopic elliptical polarimetry. AB - An automated method for generating a fiber alignment map in tissues, tissue equivalents, and other fibrillar materials exhibiting linear and circular optical properties and scattering is presented. This method consists of interrogating the sample with elliptically polarized light from a rotated quarter-wave plate and an effective circular analyzer, and implementing nonlinear regression techniques to estimate parameters defining the optical properties of the optic train and the sample. Thus, an account is made for imperfect and misaligned optic elements. The optic train was modeled using the Mueller matrix representation and the combined sample properties by an exponential matrix. Because a sample's Mueller matrix does not uniquely determine the linear, circular, or scattering properties, the circular properties and effective scattering are estimated for a matched isotropic sample to determine and correct for the linear birefringence of an aligned sample. The method's utility is demonstrated by generating an alignment map of an arterial media-equivalent, a relevant test case because of its circumferential alignment and thus showing the method's sample orientation independence. PMID- 11606303 TI - Role of native-state topology in the stabilization of intracellular antibodies. AB - The role played by the geometric position of each amino acid in the folding process of the immunoglobulin (Ig) variable domain is identified and measured through molecular dynamics simulations of models based on the topology of its native state. This measure allows identifying the parts of the protein that, for geometrical reasons, when mutated, would result in relevant protein stability changes. Simulations were performed without considering the covalent disulfide bond present in most of the Ig domains. The results are in good agreement with site-directed mutagenesis experiments on the folding of intracellular antibodies in which the disulfide bond does not form. We also found agreement with data on amino acid conservation in the Ig variable domain sequences. This indicates a new way for a rational approach to the design of intracellular antibodies more resistant to the suppression of the disulfide bond that occurs in the cytoplasm. PMID- 11606306 TI - Alignment maps of tissues: II. Fast harmonic analysis for imaging. AB - A methodology for generating polarized light retardation and alignment direction images is presented. A rotated quarter-wave plate changes the linear polarized light to a polarized probe with various degrees of ellipticity by which samples are imaged with the use of a circular analyzer. A harmonic representation of image intensity allows simple analysis, requiring only simple image operations and realizing four orders-of-magnitude computational savings for strongly aligned tissues, where linear birefringence is the dominant optical property. The method is demonstrated for a porcine heart valve leaflet. PMID- 11606307 TI - Progressive rearrangement of subtilisin Carlsberg into orderly and inflexible conformation with Ca(2+) binding. AB - Fluorescence depolarization and decay kinetic profiles, together with differential scanning calorimetric thermograms and circular dichroism spectra, are measured to understand the respective roles of Ca(2+) ions at the strong (Ca1) and weak binding sites (Ca2) of subtilisin Carlsberg (sC). Thermal denaturation temperature decreases considerably with Ca1 removal, whereas it does slightly with Ca2 removal. The fraction of random coil structure increases significantly with Ca2 removal as well as with Ca1 removal. sC shows three fluorescence decay times of 100, 1100, and 3300 ps. Although the fast and the slow do not change noticeably, the medium one decreases progressively with Ca(2+) removal. sC has two fluorescence anisotropic decay components of 340 and 12,000 ps. The fast one arises from the internal rotation of Tyr, whereas the slow results from the global rotation of sC. Although both become significantly faster with Ca2 removal, only the slow one becomes slightly faster with further Ca1 removal. Overall, sC undergoes progressive rearrangement into disorderly and flexible conformation with Ca(2+) removal, indicating that both Ca1 and Ca2 are indispensable for the stable structure of sC. PMID- 11606309 TI - Thrombin-induced platelet endostatin release is blocked by a proteinase activated receptor-4 (PAR4) antagonist. AB - Endostatin is a potent endogenous inhibitor of angiogenesis that was recently shown to be stored in platelets and released in response to thrombin, but not ADP. In the present study, we have tested the hypothesis that thrombin-induced endostatin release from rat platelets is mediated via proteinase-activated receptor-4 (PAR4). Immunoprecipitation and Western blotting confirmed that endostatin is contained within rat platelets. Aggregation and release of endostatin could be elicited by thrombin (0.5 - 1.0 U ml(-1)) or by specific PAR4 agonist (AYPGKF-NH(2); AY-NH(2); 15 - 50 microM). Significant release of endostatin could be induced by a dose of thrombin below that necessary for induction of aggregation. An adenosine diphosphate (ADP) scavenger, apyrase, inhibited the platelet aggregation induced by thrombin, but not the release of endostatin. In contrast, a selective PAR4 antagonist (trans-cinnamoyl-YPGKF NH(2); tcY-NH(2)) prevented endostatin release and aggregation induced by thrombin or by AY-NH(2). We conclude that thrombin-induced endostatin release from rat platelets is PAR4-mediated via an ADP-independent mechanism that can occur independently of platelet aggregation. PMID- 11606308 TI - Comparison of the membrane association of two antimicrobial peptides, magainin 2 and indolicidin. AB - Interactions of two antimicrobial peptides, magainin 2 and indolicidin, with three different model biomembranes, namely, monolayers, large unilamellar vesicles (LUVs), and giant liposomes, were studied. Insertion of both peptides into lipid monolayers was progressively enhanced when the content of an acidic phospholipid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) in a film of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) was increased. Indolicidin and magainin 2 penetrated also into lipid monolayers containing cholesterol (mole fraction, X = 0.1). Membrane association of magainin 2 attenuated lipid lateral diffusion in POPG-containing LUVs as revealed by the decrease in the excimer/monomer fluorescence ratio I(e)/I(m) for the pyrene fatty acid-containing phospholipid derivative 1-palmitoyl-2-[10-(pyren-1-yl) decanoyl] sn-glycero-3-phospho-rac-glycerol (PPDPG). Likewise, an increase in steady-state fluorescence anisotropy of the membrane-incorporated diphenylhexatriene (DPH) was observed, revealing magainin 2 to increase acyl chain order and induce segregation of acidic phospholipids. Similar effects were observed for indolicidin. The topological effects of magainin 2 and indolicidin on phospholipid membranes were investigated using optical microscopy of giant vesicles. Magainin 2 had essentially no influence on either SOPC or SOPC:cholesterol (X = 0.1) giant liposomes. However, effective vesiculation was observed when acidic phospholipid (X(PG) = 0.1) was included in the giant vesicles. Indolicidin caused only a minor shrinkage of giant SOPC vesicles whereas the formation of endocytotic vesicles was observed when the giant liposome contained POPG (X(PG) = 0.1). Interestingly, for indolicidin, vesiculation was also observed for giant vesicles composed of SOPC/cholesterol (X(chol) = 0.1). Possible mechanisms of membrane transformation induced by these two peptides are discussed. PMID- 11606310 TI - Glycosylation and the activation of proteinase-activated receptor 2 (PAR(2)) by human mast cell tryptase. AB - 1. Human mast cell tryptase appears to display considerable variation in activating proteinase-activated receptor 2 (PAR(2)). We found tryptase to be an inefficient activator of wild-type rat-PAR(2) (wt-rPAR(2)) and therefore decided to explore the factors that may influence tryptase activation of PAR(2). 2. Using a 20 mer peptide (P20) corresponding to the cleavage/activation sequence of wt rPAR(2), tryptase was as efficient as trypsin in releasing the receptor activating sequence (SLIGRL.). However, in the presence of either human-PAR(2) or wt-r PAR(2) expressing cells, tryptase could only activate PAR(2) by releasing SLIGRL from the P20 peptide, suggesting that PAR(2) expressed on the cells was protected from tryptase activation. 3. Three approaches were employed to test the hypothesis that PAR(2) receptor glycosylation restricts tryptase activation. (a) pretreatment of wt-rPAR(2) expressing cells or human embryonic kidney cells (HEK293) with vibrio cholerae neuraminidase to remove oligosaccharide sialic acid, unmasked tryptase-mediated PAR(2) activation. (b) Inhibiting receptor glycosylation in HEK293 cells with tunicamycin enabled tryptase-mediated PAR(2) activation. (c) Wt-rPAR(2) devoid of the N-terminal glycosylation sequon (PAR(2)T25(-)), but not rPAR(2) devoid of the glycosylation sequon located on extracellular loop-2 (PAR(2)T224A), was selectively and substantially (>30 fold) more sensitive to tryptase compared with the wt-rPAR(2). 4. Immunocytochemistry using antisera that specifically recognized the N-terminal precleavage sequence of PAR(2) demonstrated that tryptase released the precleavage domain from PAR(2)T25(-) but not from wt-rPAR(2). 5. Heparin : tryptase molar ratios of greater than 2 : 1 abrogated tryptase activation of PAR(2)T25(-). 6. Our results indicate that glycosylation of PAR(2) and heparin-inhibition of PAR(2) activation by tryptase could provide novel mechanisms for regulating receptor activation by tryptase and possibly other proteases. PMID- 11606311 TI - Properties of Ca(2+) release induced by clofibric acid from the sarcoplasmic reticulum of mouse skeletal muscle fibres. AB - 1. To characterize the effect of clofibric acid (Clof) on the Ca(2+) release mechanism in the sarcoplasmic reticulum (SR) of skeletal muscle, we analysed the properties of Clof-induced Ca(2+) release under various conditions using chemically skinned skeletal muscle fibres of the mouse. 2. Clof (>0.5 mM) released Ca(2+) from the SR under Ca(2+)-free conditions buffered with 10 mM EGTA (pCa >8). 3. Co-application of ryanodine and Clof at pCa >8 but not ryanodine alone reduced the Ca(2+) uptake capacity of the SR. Thus, Ca(2+) release induced by Clof at pCa >8 must be a result of the activation of the ryanodine receptor (RyR). 4. At pCa >8, (i) Clof-induced Ca(2+) release was inhibited by adenosine monophosphate (AMP), (ii) the inhibitory effect of Mg(2+) on the Clof-induced Ca(2+) release was saturated at about 1 mM, and (iii) Clof-induced Ca(2+) release was not inhibited by procaine (10 mM). These results indicate that Clof may activate the RyR-Ca(2+) release channels in a manner different from Ca(2+) induced Ca(2+) release (CICR). 5. In addition to this unique mode of opening, Clof also enhanced the CICR mode of opening of RyR-Ca(2+) release channels. 6. Apart from CICR, a high concentration of Ca(2+) might also enhance the unique mode of opening by Clof. 7. These results suggest that some features of Ca(2+) release activated by Clof are similar to those of physiological Ca(2+) release (PCR) in living muscle cells and raise the possibility that Clof may be useful in elucidating the mechanism of PCR in skeletal muscle. PMID- 11606312 TI - Effects of dantrolene and its derivatives on Ca(2+) release from the sarcoplasmic reticulum of mouse skeletal muscle fibres. AB - 1. We analysed the effect of dantrolene (Dan) and five newly synthesized derivatives (GIFs) on Ca(2+) release from the sarcoplasmic reticulum (SR) of mouse skeletal muscle. 2. In intact muscles, GIF-0185 reduced the size of twitch contraction induced by electrical stimulation to the same extent as Dan. GIF 0082, an azido-functionalized Dan derivative, also inhibited twitch contraction, although the extent of inhibition was less than that of Dan and of GIF-0185. 3. In skinned fibres, Dan inhibited Ca(2+)-induced Ca(2+) release (CICR) under Mg(2+)-free conditions at room temperature. In contrast, GIF-0082 and GIF-0185 showed no inhibitory effect on CICR under the same conditions. 4. Dan-induced inhibition of CICR was not affected by the presence of GIF-0082, whereas it was diminished in the presence of GIF-0185. 5. GIF-0082 and GIF-0185 significantly inhibited clofibric acid (Clof)-induced Ca(2+) release, as did Dan. 6. Several Dan derivatives other than GIF-0082 and GIF-0185 showed an inhibitory effect on twitch tension but not on the CICR mechanism. All of these derivatives inhibited Clof-induced Ca(2+) release. 7. The magnitudes of inhibition of Clof-induced Ca(2+) release by all Dan derivatives were well correlated with those of twitch inhibition. This supports the notion that the mode of Clof-induced opening of the RyR-Ca(2+) release channel may be similar to that of physiological Ca(2+) release (PCR). 8. These results indicate that the difference in opening modes of the RyR Ca(2+) release channel is recognized by certain Dan derivatives. PMID- 11606313 TI - Downregulation of vascular soluble guanylate cyclase induced by high salt intake in spontaneously hypertensive rats. AB - 1. Cyclic guanosine monophosphate (cyclic GMP)-mediated mechanism plays an important role in vasodilatation and blood pressure regulation. We investigated the effects of high salt intake on the nitric oxide (NO) - cyclic GMP signal transduction pathway regulating relaxation in aortas of spontaneously hypertensive rats (SHR). 2. Four-week-old SHR and normotensive Wistar-Kyoto rats (WKY) received a normal salt diet (0.3% NaCl) or a high salt diet (8% NaCl) for 4 weeks. 3. In aortic rings from SHR, endothelium-dependent relaxations in response to acetylcholine (ACh), adenosine diphosphate (ADP) and calcium ionophore A23187 were significantly impaired by the high salt intake. The endothelium-independent relaxations in response to sodium nitroprusside (SNP) and nitroglycerin were also impaired, but that to 8-bromo-cyclic GMP remained unchanged. On the other hand, high salt diet had no significant effects on the relaxations of aortic rings from WKY. 4. In aortas from SHR, the release of NO stimulated by ACh was significantly enhanced, whereas the production of cyclic GMP induced by either ACh or SNP was decreased by the high salt intake. 5. Western blot analysis showed that the protein level of endothelial NO synthase (eNOS) was slightly increased, whereas that of soluble guanylate cyclase (sGC) was dramatically reduced by the high salt intake. 6. These results indicate that in SHR, excessive dietary salt can result in downregulation of sGC followed by decreased cyclic GMP production, which leads to impairment of vascular relaxation in responses to NO. It is notable that chronic high salt intake impairs the sGC/cyclic GMP pathway but not the eNOS/NO pathway. PMID- 11606314 TI - Adenosine-mediated hypotension in in vivo guinea-pig: receptors involved and role of NO. AB - 1. Adenosine produced a biphasic lowering of the mean BP with a drastic bradycardic effect at the highest doses. The first phase hypotensive response was significantly reduced by the nitric oxide (NO) synthase inhibitor L-NAME. 2. The A(2a)/A(2b) agonist NECA produced hypotensive and bradycardic responses similar to those elicited by adenosine, which were not significantly modified by the A(2b) antagonist enprofylline. 3. The A(2a) agonist CGS 21680 did not significantly influence basal HR while induced a hypotensive response antagonized by the A(2a) selective antagonist ZM 241385, and reduced by both L-NAME and the guanylate cyclase inhibitor methylene blue. 4. The A(1) agonist R-PIA showed a dose-dependent decrease in BP with a drastic decrease in HR at the highest doses. The A(1) selective antagonist DPCPX significantly reduced the bradycardic activity and also the hypotensive responses obtained with the lowest doses while it increased those obtained with the highest ones. 5. The A(1)/A(3) agonist APNEA, in the presence of the xanthinic non-selective antagonist 8-pSPT, maintained a significant hypotensive, but not bradycardic, activity, not abolished by the histamine antagonist diphenhydramine. 6. The selective A(3) agonist IB-MECA revealed a weak hypotensive and bradycardic effect, but only at the highest doses. 7. In conclusion, in the systemic cardiovascular response to adenosine two major components may be relevant: an A(2a)- and NO-mediated hypotension, and a bradycardic effect with a consequent hypotension, via atypical A(1) receptors. Finally, an 8-pSPT-resistant hypotensive response not attributable to A(3) receptor-stimulation or to release of histamine by mastocytes or other immune cells was observed. PMID- 11606316 TI - alpha(2)-adrenoceptor antagonist properties of OPC-28326, a novel selective peripheral vasodilator. AB - 1. Antagonistic properties of OPC-28326 ([4-(N-methyl-2-phenylethylamino)-1-(3,5 dimethyl-4-propionyl-aminobenzoyl)] piperidine hydrochloride monohydrate), a selective peripheral vasodilator, were investigated by analysing the data from functional studies in various tissues from the rat and binding studies of the drug to alpha(2)-adrenoceptor subtypes. 2. Using a human recombinant receptor and rat kidney cortex, we found that OPC-28326 displays affinities to alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors with K(i) values of 2040, 285, and 55 nM, respectively. The K(i) values of yohimbine for alpha(2A)-, alpha(2B)-, and alpha(2C)-adrenoceptors were 3.0, 2.0 and 11.0 nM, respectively. 3. B-HT 920, an alpha(2)-adrenoceptor agonist, produced a pressor response via peripheral postsynaptic alpha(2)-adrenoceptor stimulation (thought to be an alpha(2B) subtype) in a reserpine-pretreated pithed rat preparation. OPC-28326 (3 - 30 mg kg(-1), i.v.) and yohimbine (0.3 - 3 mg kg(-1), i.v.) caused dose-dependent rightward shift in the pressor dose-response curve induced by B-HT 920. The apparent pA(2) values were 1.55 (0.87 - 2.75, 95% confidence interval) and 0.11 (0.06 - 0.21) mg kg(-1), respectively. The potency of OPC-28326 was about 14 times less than that of yohimbine. 4. Clonidine inhibited the tension developed by electrical stimulation, of the rat vas deferens, by its peripheral presynaptic alpha(2A/D)-adrenoceptor action. OPC-28326 (1 - 100 microM) and yohimbine (10 - 1000 nM) caused a rightward shift in the concentration-response curve of clonidine. The pA(2) values were 5.73 (5.54 - 5.91) and 7.92 (7.84 - 8.01), respectively, providing evidence for a potency of OPC-28326 of about 155 times less than that of yohimbine. 5. Mydriasis was induced by brimonidine via stimulation of central alpha(2A/D)-adrenoceptors in anaesthetized rats. Intravenous OPC-28326 had no effect on this action, even at a very high dose of 10 mg kg(-1) i.v., while yohimbine (0.1 - 0.3 mg kg(-1) i.v.) inhibited mydriasis in a dose-dependent manner, indicating that OPC-28326 was at least 100 times less potent than yohimbine in regard to the anti-mydriatic effect. 6. These data suggest that OPC-28326 preferentially exerts peripheral and postsynaptic antagonistic actions on the alpha(2B)- and alpha(2C)-adrenoceptor subtypes. PMID- 11606315 TI - Pravastatin suppresses the interleukin-8 production induced by thrombin in human aortic endothelial cells cultured with high glucose by inhibiting the p44/42 mitogen activated protein kinase. AB - 1. 3-Hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors (statins) prevent the progression of atherosclerosis by lowering cholesterol. However, the effect of statins on the synthesis of pro-inflammatory cytokines from endothelial cells has not yet been fully investigated. Here, we examined the effect of pravastatin, one of the statins, on IL-8 synthesis induced by thrombin in human aortic endothelial cells (AoEC) cultured with high glucose concentrations. 2. Pravastatin significantly decreased the IL-8 synthesis induced by thrombin. 3. Pravastatin inhibited the p44/42 MAP kinase activity induced by thrombin, but did not inhibit the p38 MAP kinase activity. 4. Translocation of ras protein from the cytosol to plasma membrane was inhibited by pravastatin. 5. Pravastatin inhibit the activator protein-1 activity, but did not inhibit the activation of IkappaB alpha. 6. Dominant negative ras inhibited the p44/42 MAP kinase activity induced by PMA. 7. Our results suggest that pravastatin inhibits IL-8 synthesis by blocking the ras-MAP (p44/42) kinase pathway rather than nuclear factor-kappaB. Pravastatin may prevent atherosclerosis not only by lowering cholesterol levels, but also by suppressing IL-8 synthesis in AoEC through the inhibition of p44/42 MAP kinase, and this may be more beneficial in diabetic patients than in non diabetics. PMID- 11606317 TI - The role of sensory nerve endings in nerve growth factor-induced airway hyperresponsiveness to histamine in guinea-pigs. AB - 1. Nerve growth factor induces an airway hyperresponsiveness in vivo in guinea pigs, as we have shown previously. Since antagonizing the neurokinin-1 (NK(1)) receptor can prevent this NGF-induced airway hyperresponsiveness and since sensory nerves release tachykinins, we investigated the role of sensory nerves in the NGF-induced airway hyperresponsiveness. 2. We used isolated tracheal rings from guinea-pigs to measure tracheal contractility. In these rings sensory nerve endings are present, but these endings lack any contact with their cell bodies. 3. In this in vitro system, NGF dose-dependently induced a tracheal hyperresponsiveness to histamine. The NK(1) receptor antagonist SR140333 could block the induction of tracheal hyperresponsiveness. 4. To further investigate the involvement of sensory nerve endings we used the cannabinoid receptor 1 (CB(1)) agonist R-methanandamide to inhibit excitatory events at the nerve terminal. The CB(1) receptor agonist was capable of blocking the tracheal hyperresponsiveness to NGF in the isolated system, as well as the airway hyperresponsiveness to NGF in vivo. 5. This indicates that NGF can induce an increase in airway responsiveness in the absence of sensory nerve cell bodies. NGF may act by increasing substance P release from sensory nerve endings, without upregulation of substance P in the neurons. Substance P in its turn is responsible for the induction of the NGF-induced airway hyperresponsiveness. PMID- 11606319 TI - Formation of functional alpha3beta4alpha5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach. AB - 1. The alpha5 subunit participates to the formation of native neuronal nicotinic receptors, particularly in autonomic ganglia. Like the related beta3 subunit, alpha5 forms functional recombinant receptors if expressed together with a pair of typical alpha and beta subunits, but its effect on the properties of the resulting alphabetaalpha5 receptor depends on the alpha and beta subunits chosen and on the expression system. We used a reporter mutation approach to test whether alpha5, like beta3, is incorporated as a single copy in human alpha3beta4alpha5 receptors expressed in oocytes. 2. As previously reported, the main indication of the presence of alpha5 in alpha3beta4alpha5(wt) was an increase in apparent receptor desensitization (compared with alpha3beta4 receptors). If the alpha3beta4alpha5 receptor bore a 9'T mutation in the second transmembrane domain of either alpha3 or beta4, alpha5 incorporation produced a decrease in ACh sensitivity (by 4 fold for alpha3(LT)beta4alpha5 vs. alpha3(LT)beta4 and by 40 fold for alpha3beta4(LT)alpha5 vs. alpha3beta4(LT)). The much greater effect observed in alpha3beta4(LT)alpha5 receptors accords with the hypothesis that alpha5 takes the place of a beta subunit in the receptor. 3. Introducing a 9'T mutation in alpha5 had no effect on the agonist sensitivity of alpha3beta4alpha5 receptors, but reduced apparent desensitisation, as judged by the sag in the current response to high agonist concentrations. 4. Introducing the 9'T mutation in alpha3 or beta4 in the triplet receptor reduced the EC(50) for ACh by a similar extent (7 and 9 fold, respectively), suggesting that alpha3beta4alpha5 receptors contain two copies each of alpha and beta and therefore only one copy of alpha5. PMID- 11606318 TI - Nitric oxide (NO) modulation of PAF-induced cardiopulmonary action: interaction between NO synthase and cyclo-oxygenase-2 pathways. AB - 1. To further investigate into the mechanisms of PAF-induced cardiopulmonary actions, we examined the effects of the nitric oxide synthase (NOS) inhibitor L N(omega)-nitro-L-arginine (L-NNA), of the specific cyclooxygenase-2 (COX-2) inhibitor NS 398, and of the combined presence of both COX and NOS inhibitors on the PAF responses in the heart lung preparation of guinea-pig (HLP). 2. In HLPs perfused with homologous blood, dose-response curves for the haemodynamic and bronchial effects of PAF (1 - 32 ng) were carried out in the absence or presence of L-NNA (200 microM). L-NNA caused an increase in the resting pulmonary arterial pressure (PAP) without affecting the other basal values, and strongly potentiated the bronchoconstriction and pulmonary hypertension elicited by PAF. An enhancement of the PAF-induced actions on right atrial pressure (RAP) and cardiac output (CO) was also observed. All the effects of L-NNA were antagonized by L arginine (2 mM). 3. The presence of L-NNA in the perfusing blood of HLPs failed to affect the pulmonary hypertensive and bronchoconstrictor responses induced by the thromboxane A(2) mimetic U46619 (0.05 - 1.6 microg), 5-hydroxytryptamine (0.1 - 1.6 microg), and histamine (0.1 - 1.6 microg), thus suggesting that these PAF secondary mediators are not responsible for the hyper-responsiveness to PAF induced by L-NNA. 4. Blocking COX-2 pathway with NS 398 (15 - 30 microM) did not alter the cardiopulmonary resting variables. However, a reduction of the PAF mediated pulmonary hypertension, but not of bronchoconstriction, was observed. When L-NNA was added to the perfusing medium of HLPs pre-treated with NS 398 or with indomethacin (15 microM), the basal PAP values were enhanced. However, in the combined presence of COX and NOS inhibitors, only a slight increase in the hypertensive responses to the highest doses of PAF was observed, whereas the PAF mediated actions at bronchial and cardiac level were unaffected. 5. This study indicates that (i) the cardiopulmonary actions induced by PAF are specifically modulated by endogenous NO through the NOS pathway, and (ii) COX-2 isoform is involved in the pulmonary hypertensive, but not bronchoconstrictor, effects of PAF. Furthermore, an interaction between PAF stimulated COX, particularly COX-2, and NOS pathways appears to take a functional role at both bronchial and cardiovascular level. PMID- 11606320 TI - Pharmacological comparison of LTB(4)-induced NADPH oxidase activation in adherent and non-adherent guinea-pig eosinophils. AB - 1. Leukotriene B(4) (LTB(4)) stimulation of guinea-pig peritoneal eosinophils, induced a biphasic activation of the NADPH oxidase composed of a rapid (<3 min) phase mediated by non-adherent cells and a sustained (3 - 120 min) phase mediated by CD11b/CD18 adherent eosinophils. Studies were undertaken to compare the intracellular mechanism that mediate these responses. 2. SB 203580 and PP1, inhibitors of p38 mitogen-activated protein (MAP) kinase and the src-family protein tyrosine kinases, respectively caused concentration-dependent attenuation of both the rapid (SB203580: pD(2)=-6.31; PP1: pD(2)=-5.50) and sustained (SB203580: pD(2)=-6.50; PP1: pD(2)=-5.73) phases. Similarly, the MAP kinase kinase-1 inhibitor, PD098059 produced partial inhibition of the both phases of superoxide generation. 3. The protein kinase C (PKC) inhibitors Ro-31 8220, GF 109203X and Go 6976 attenuated the rapid NADPH oxidase response (pD(2)s=-6.10, 6.72, -6.15 respectively) and, to a lesser extent, (pD(2)s=-5.54, -6.02, -6.51 respectively) the sustained phase. 4. An inhibitor of phosphatidylinositol 3 kinase (PtdIns 3-kinase), wortmannin caused concentration dependent attenuation of the sustained (pD(2)=-8.68) but not rapid phase of superoxide generation. In contrast, the syk kinase inhibitor, piceatannol abolished the rapid (pD(2)=-6.43) but not sustained respiratory responses. 5. This study demonstrates that LTB(4) induced superoxide generation from adherent and non-adherent eosinophils is mediated via both common (p38 MAP kinase, MEK-1, PKC and the src kinases) and divergent intracellular pathways (syk kinases and PtdIns 3-kinase). This suggests the possibility of therapeutic intervention to selective attenuate activation of adherent tissue eosinophils. PMID- 11606321 TI - Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping. AB - 1. Since the brain is not a homogenous organ (i.e. the phospholipid pattern and density of lysosomes may vary in its different regions), in the present study we examined the uptake of psychotropic drugs by vertically cut slices of whole brain, grey (cerebral cortex) and white (corpus callosum, internal capsule) matter of the brain and by neuronal and astroglial cell cultures. 2. Moreover, we assessed the contribution of lysosomal trapping to total drug uptake (total uptake=lysosomal trapping+phospholipid binding) by tissue slices or cells conducting experiments in the presence and absence of 'lysosomal inhibitors', i.e., the lysosomotropic compound ammonium chloride (20 mM) or the Na(+)/H(+) ionophore monensin (10 microM), which elevated the internal pH of lysosomes. The initial concentration of psychotropic drug in the incubation medium was 5 microM. 3. Both total uptake and lysosomal trapping of the antidepressants investigated (imipramine, amitriptyline, fluoxetine, sertraline) and neuroleptics (promazine, perazine, thioridazine) were higher in the grey matter and neurones than in the white matter and astrocytes, respectively. Lysosomal trapping of the psychotropics occurred mainly in neurones where thioridazine sertraline and perazine showed the highest degree of lysosomotropism. 4. Distribution interactions between antidepressants and neuroleptics took place in neurones via mutual inhibition of lysosomal trapping of drugs. 5. A differential number of neuronal and glial cells in the brain may mask the lysosomal trapping and the distribution interactions of less potent lysosomotropic drugs in vertically cut brain slices. 6. A reduction (via a distribution interaction) in the concentration of psychotropics in lysosomes (depot), which leads to an increase in their level in membranes and tissue fluids, may intensify the pharmacological action of the combined drugs. PMID- 11606322 TI - Mechanism of trypsin-induced endothelium-dependent vasorelaxation in the porcine coronary artery. AB - 1. To investigate the mechanism underlying the trypsin-induced endothelium dependent relaxation, cytosolic Ca(2+) concentration ([Ca(2+)](i)) and tension development of smooth muscle were simultaneously monitored in the porcine coronary artery, and [Ca(2+)](i) of in situ endothelial cells were monitored in the porcine aortic valvular strips, using fura-2 fluorometry. 2. During the contraction induced by 30 nM U46619, a thromboxane A(2) analogue, 100 nM trypsin induced a rapid transient significant decrease in both [Ca(2+)](i) (from 67.9+/ 5.1 to 15.7+/-4.4%) and tension (from 97.5+/-9.2 to 16.8+/-3.5%) of smooth muscle only in the presence of endothelium (100% level was assigned to the level obtained with the 118 mM K(+)-induced contraction). [Ca(2+)](i) and the tension thus returned to the levels prior to the application of trypsin by 5 and 10 min, respectively. 3. The initial phase of this relaxation was partly inhibited by 100 microM N(omega)-nitro-L-arginine (L-NOARG), and was completely inhibited by L NOARG plus 40 mM K(+) or L-NOARG plus 100 nM charybdotoxin and 100 nM apamin, while the late phase of the relaxation was inhibited by L-NOARG alone. 4. Trypsin induced a transient [Ca(2+)](i) elevation in the endothelial cells mainly due to the Ca(2+) release from the intracellular stores, at the concentrations (1 - 100 nM) similar to those required to induce relaxation. 5. In conclusion, trypsin induced an elevation in [Ca(2+)](i) mainly due to Ca(2+) release in endothelial cells, and thereby caused endothelium-dependent relaxation. The early phase of relaxation was due to nitric oxide and hyperpolarizing factors, while the late phase was mainly due to nitric oxide in the porcine coronary artery. PMID- 11606323 TI - The effects of heparin on the adhesion of human peripheral blood mononuclear cells to human stimulated umbilical vein endothelial cells. AB - 1. The effects of unfractionated heparin (UH) and a selectively O-desulphated derivative of heparin (ODSH), lacking anticoagulant activity, on the adhesion of human peripheral blood mononuclear cells (HPBMNC) to human stimulated umbilical vein endothelial cells (HUVECs), were investigated. 2. For comparison, the effects of poly-L-glutamic acid (PGA), a large polyanionic molecule without sulphate groups and two different molecular weight sulphated dextrans (DS 5 k and DS 10 k) were studied. 3. UH (50 - 1000 u ml(-1)) significantly (P<0.05) inhibited the adhesion of HPBMNC to HUVECs, stimulated with IL-1beta (100 u ml( 1)), TNF-alpha (1000 u ml(-1)) or LPS (100 microg ml(-1)), when the drugs were added together with stimuli to HUVECs and coincubated for 6 h. Such effects on adhesion occurred with limited influence on expression of relevant endothelial adhesion molecules (ICAM-1 and VCAM-1). 4. UH (100 - 1000 u ml(-1)), when added to prestimulated HUVECs, significantly (P<0.05) increased adhesion of mononuclear cells to endothelium at the higher concentrations tested, without any effect on adhesion molecule expression. In contrast, the opposite effect was observed when human polymorphonuclear leucocyte adhesion was examined, under the same experimental conditions, suggesting that the observed potentiation of HPBMNC adhesion is cell specific. 5. The effects of UH on HPBMNC adhesion were shared by the non-anticoagulant ODSH (600 - 6000 microg ml(-1)) but not by sulphated dextrans or PGA (300 - 6000 microg ml(-1)). 6. Heparin affects the adhesion of HPBMNC to stimulated endothelium, in both an inhibitory and potentiating manner, effects which are unrelated to its anticoagulant activity and not solely dependent on molecular charge characteristics. PMID- 11606324 TI - Divergent effects of corticotropin releasing hormone on endothelial cell nitric oxide synthase are associated with different expression of CRH type 1 and 2 receptors. AB - 1. Endothelium is a target for an array of factors involved in inflammation. Endothelial cells express receptors for CRH, a neuropeptide produced during inflammation. We report both the concentration-dependent inhibitory effect of CRH upon cytokine-stimulated nitrite release by H5V murine endothelioma cells, and its stimulatory one in HUVEC cells. 2. Western blot analysis showed that CRH inhibits cytokine-stimulated iNOS protein in H5V cells, and, instead, potentiated it in HUVEC cells. 3. H5V cells expressed both CRH receptors (CRH-R1 and R2) mRNAs, whereas HUVEC cells expressed the CRH-R2 mRNA solely. 4. CRH increased medium nitrites and iNOS protein expression in H5V cells pretreated with the selective CRH-R1 antagonist CP 154,526. However, the selective CRH-R2 antagonist anti-Svg-30 failed to produce similar effects. In fact, anti-Svg-30 inhibited CRH induced increase of nitrite release and iNOS expression in HUVEC cells. 5. Our results confirm the activating role of CRH on endothelial cells, although it suggests its possible inhibitory role in the late phase of the inflammatory response. NO-mediated effects of CRH on endothelial cells could be exploited in therapeutic strategies related to inflammatory and/or degenerative diseases. PMID- 11606325 TI - Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. AB - 1. (-)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). 2. CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy methyl or a carboxyl function and/or the C-5' pentyl group with a di-methyl heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca(2+) concentrations in cells over-expressing human VR1; (b) [(14)C]-AEA uptake by RBL 2H3 cells, which is facilitated by a selective membrane transporter; and (c) [(14)C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. 3. Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC(50)=3.2 - 3.5 microM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 - 70% of the effect obtained with ionomycin (4 microM). CBD (10 microM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. 4. (+)-5'-DMH-CBD and (+)-7-hydroxy-5'-DMH-CBD inhibited [(14)C]-AEA uptake (IC(50)=10.0 and 7.0 microM); the (-)-enantiomers were slightly less active (IC(50)=14.0 and 12.5 microM). 5. CBD and (+)-CBD were also active (IC(50)=22.0 and 17.0 microM). CBD (IC(50)=27.5 microM), (+)-CBD (IC(50)=63.5 microM) and (-) 7-hydroxy-CBD (IC(50)=34 microM), but not the other analogues (IC(50)>100 microM), weakly inhibited [(14)C]-AEA hydrolysis. 6. Only the (+)-isomers exhibited high affinity for CB(1) and/or CB(2) cannabinoid receptors. 7. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB(1) and CB(2) receptors, (-)-5'-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent. PMID- 11606326 TI - Phenanthrolines--a new class of CFTR chloride channel openers. AB - 1. A number of phenanthrolines and benzoquinolines were examined for their ability to activate epithelial chloride secretion by measuring short circuit current (SCC) using the mouse colon epithelium. 1,10 phenanthroline stimulated electrogenic chloride secretion with an EC(50) of 612+/-10 microM and a Hill slope of 4.9+/-0.3. A similar pharmacology was demonstrated by both 1,7 and 4,7 phenanthrolines, 7,8 benzoquinoline and phenanthridine. 2. Evidence that the increase in SCC caused by 1,10 phenanthroline was due to chloride secretion is based upon (a) inhibition of the current by furosemide, (b) failure of cystic fibrosis (CF) colons to respond and (c) an associated net flux of (36)Cl(-). 3. 1,10 Phenanthroline affected neither the generation of cyclic AMP or the concentration of intracellular Ca(2+) in colonic epithelial cells. 4. 1,10 phenanthroline affected the chloride conductance of the apical membrane, as shown by an increase in chloride current in 'apical membrane only' preparations in the presence of an apical to basolateral chloride gradient. The increase in chloride current was inhibited by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and was not present in CF colons. 5. Additionally, 1,10 phenanthroline activated basolateral K(+) channels, both Ca(2+)- and cyclic AMP-sensitive channels, as shown by inhibitor studies with charybdotoxin (ChTX) and XE991, and after the apical membrane was permeabilized with nystatin. 6. The phenanthrolines and benzoquinolines described here, with dual actions affecting CFTR and basolateral K(+) channels, may constitute useful lead compounds for adjunct therapy in CF. PMID- 11606327 TI - Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. AB - 1. We have recently demonstrated that chronic infusion of Angiotensin II into apoE-/- mice promotes the development of abdominal aortic aneurysms. To determine the involvement of specific Angiotensin II receptors in this response, we co infused Angiotensin II (1000 ng kg(-1) min(-1) for 28 days) with losartan (30 mg kg(-1) day(-1)) or PD123319 (3 mg kg(-1) day(-1)) to antagonize AT1 and AT2 receptors, respectively. 2. Infusion of Angiotensin II promoted the development of abdominal aortic aneurysms in 70% of mature female apoE-/- mice. The formation of aortic aneurysms was totally inhibited by co-infusion of Angiotensin II with losartan (30 mg kg(-1) day(-1); P=0.003). In contrast, the co-infusion of Angiotensin II with PD123319 resulted in a marked increase in the incidence and severity of aortic aneurysms. 3. To determine whether AT2 antagonism also promoted Angiotensin II-induced atherosclerosis, Angiotensin II was infused into young female apoE-/- mice that had little spontaneous atherosclerosis. In these mice, co-infusion of PD123319 led to a dramatic increase in the extent of atherosclerosis. This increase was associated with no change in plasma lipid concentrations and only transient and modest increases in blood pressure during co-infusion with PD123319. 4. While antagonism of AT1 receptors totally prevented the formation of aneurysms, antagonism of AT2 receptors promoted a large increase in the severity of Angiotensin II-induced vascular pathology. PMID- 11606328 TI - Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant alpha7 and alpha4beta2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes. AB - 1. Ketamine is a dissociative anaesthetic that is formulated as Ketalar, which contains the preservative benzethonium chloride (BCl). We have studied the effects of pure racemic ketamine, the preservative BCl and the Ketalar mixture on human neuronal nicotinic acetylcholine receptors (nAChRs) composed of the alpha7 subunit or alpha4 and beta2 subunits expressed in Xenopus laevis oocytes. 2. Ketamine inhibited responses to 1 mM acetylcholine (ACh) in both the human alpha7 and alpha4beta2 nAChRs, with IC(50) values of 20 and 50 microM respectively. Inhibition of the alpha7 nAChRs occurred within a clinically relevant concentration range, while inhibition of the alpha4beta2 nAChR was observed only at higher concentrations. The Ketalar formulation inhibited nAChR function more effectively than was expected given its ketamine concentration. The surprising increased inhibitory potency of Ketalar compared with pure ketamine appeared to be due to the activity of BCl, which inhibited both alpha7 (IC(50) value of 122 nM) and alpha4beta2 (IC(50) value of 49 nM) nAChRs at concentrations present in the clinical formulation of Ketalar. 3. Ketamine is a noncompetitive inhibitor at both the alpha7 and alpha4beta2 nAChR. In contrast, BCl causes a parallel shift in the ACh dose-response curve at the alpha7 nAChR suggesting competitive inhibition. Ketamine causes both voltage-dependent and use-dependent inhibition, only in the alpha4beta2 nAChR. 4. Since alpha7 nAChRs are likely to be inhibited during clinical use of Ketalar, the actions of ketamine and BCl on this receptor subtype may play a role in the profound analgesia, amnesia, immobility and/or autonomic modulation produced by this anaesthetic. PMID- 11606329 TI - Methylamine and benzylamine induced hypophagia in mice: modulation by semicarbazide-sensitive benzylamine oxidase inhibitors and aODN towards Kv1.1 channels. AB - 1. In starved mice, the anorectic activity of methylamine (MET) and benzylamine (BZ), both substrates of semicarbazide-sensitive benzylamine oxidases (Bz-SSAO), was compared with that of the potassium channel blocking agents charybdotoxin (ChTX), tetraethylammonium (TEA), gliquidone (GLI), ammonium chloride (NH(4)(+)) and of the anoressants amphetamine (AMPH) and nicotine (NIC). After i.c.v. administration, an approximate ranking order of potency was: ChTX> or =AMPH>NIC=TEA> or =GLI> or =MET>BZ>NH(4)(+). 2. Clorgyline (2.5 mg kg(-1) i.p.) or deprenyl (10 mg kg(-1) i.p.) potentiated the anorectic effect of i.c.v. administered BZ, NIC and AMPH. The effect of TEA was increased only by deprenyl, while MET, NH(4)(+), ChTX and GLI were not affected by either of the inhibitors. 3. The Bz-SSAO inhibitors alpha-aminoguanidine (50 mg kg(-1) i.p.), B24 (100 mg kg(-1) i.p.) and MDL 72274 (2.5 mg kg(-1) i.p.) potentiated the effect of i.p., but not of i.c.v.-administered MET. 4. Antisense oligodeoxyribonucleotides (aODN) to Kv1.1 potassium channels abolished the effect of BZ and TEA, but was ineffective in reducing the activity of MET and other compounds. 5. These results suggest that MET is endowed with peculiar hypophagic effects at dosage levels that are not able to affect gross behaviour in mice. The effect of MET, differently from BZ, seems unrelated to an increase in the central release of monoaminergic mediators, as well as to a Kv1.1 blocking activity. Through a reduction of the endogenous breakdown of MET, Bz-SSAO inhibitors enhance the central pharmacological activity of this amine. PMID- 11606330 TI - Opposing influences of glucocorticoids and interleukin-1beta on the secretion of growth hormone and ACTH in the rat in vivo: role of hypothalamic annexin 1. AB - 1. This study exploited established immunoneutralization protocols and an N terminal annexin 1 peptide (annexin 1(Ac2 - 26)) to advance our knowledge of the role of annexin 1 as a mediator of acute glucocorticoid action in the rat neuroendocrine system in vivo. 2. Rats were treated with corticosterone (500 microg kg(-1), i.p.) or annexin 1(Ac2 - 26) (0.1 - 10 ng rat(-1), i.c.v.) and 75 min later with interleukin 1beta (IL-1beta, 10 ng rat(-1), i.c.v. or 500 microg kg(-1), i.p). Blood was collected 1 h later for hormone immunoassay. Where appropriate, anti-annexin 1 polyclonal antiserum (pAb) was administered subcutaneously or centrally prior to the steroid challenge. 3. Corticosterone did not affect the resting plasma corticotrophin (ACTH) concentration but suppressed the hypersecretion of ACTH induced by IL-1beta (i.p. or i.c.v.). Its actions were quenched by anti-annexin 1 pAb (s.c. or i.c.v) and mimicked by annexin 1(Ac2 - 26). 4. By contrast, corticosterone provoked an increase in serum growth hormone (GH) which was ablated by central but not peripheral administration of anti annexin 1 pAb. IL-1beta (i.c.v. or i.p.) did not affect basal GH but, when given centrally but not peripherally, it abolished the corticosterone-induced hypersecretion of GH. Annexin 1(Ac2 - 26) (i.c.v.) also produced an increase in serum GH which was prevented by central injection of IL-1beta. 5. The results support the hypothesis that the acute regulatory actions of glucocorticoids on hypothalamo-pituitary-adrenocortical function require annexin 1. They also provide novel evidence that the positive influence of the steroids on GH secretion evident within this timeframe is effected centrally via an annexin 1 dependent mechanism which is antagonized by IL-1beta. PMID- 11606331 TI - GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex. AB - 1. GABA (gamma-aminobutyric acid) receptors involved in craniovascular nociceptive pathways were characterised by in vivo microiontophoresis of GABA receptor agonists and antagonists onto neurones in the trigeminocervical complex of the cat. 2. Extracellular recordings were made from neurones in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus, which were subsequently stimulated with L-glutamate. 3. Cell firing evoked by microiontophoretic application of L-glutamate (n=30) was reversibly inhibited by GABA in every cell tested (n=19), the GABA(A) agonist muscimol (n=10) in all cells tested, or both where tested, but not by iontophoresis of either sodium or chloride ions at comparable ejection currents. Inhibited cells received wide dynamic range (WDR) or nociceptive specific input from cutaneous receptive fields on the face or forepaws. 4. The inhibition of trigeminal neurones by GABA or muscimol could be antagonized by the GABA(A) antagonist N-methylbicuculline, 1(S),9(R) in all but two cells tested (n=16), but not by the GABA(B) antagonist 2-hydroxysaclofen (n=11). 5. R(-)-baclofen, a GABA(B) agonist, inhibited the firing of three out of seven cells activated by L glutamate. Where tested, this inhibition could be antagonized by 2 hydroxysaclofen. These baclofen-inhibited cells were characterized as having low threshold mechanoreceptor/WDR input. 6. GABA thus appears to modulate nociceptive input to the trigeminocervical complex mainly through GABA(A) receptors. GABA(A) receptors may therefore provide a target for the development of new therapeutic agents for primary headache disorders. PMID- 11606332 TI - NCX4016 (NO-Aspirin) has multiple inhibitory effects in LPS-stimulated human monocytes. AB - NCX4016 (2 acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester, NicOx S.A., France) is an anti-thrombotic agent, chemically related to acetylsalicylic acid (ASA) and able to release NO. We tested the effects of NCX4016 and ASA on the release of the thromboxane (TX) A(2) metabolite TXB(2), tumour necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), expression and activity of tissue factor (TF) in stimulated, adherent human monocytes. Both ASA and NCX4016 1 - 1000 micromol l( 1) dose-dependently reduced TXB(2) concentration, measured by RIA in the supernatant of 10 microg ml(-1) LPS-stimulated cells. NCX4016 activity was comparable to that of equimolar ASA when incubation lasted 6 h (NCX4016 30 micromol l(-1): -86.0+/-10.1%, NCX4016 300 micromol l(-1): -92.2+/-9.0%, ASA 30 micromol l(-1): -92.3+/-7.5%, ASA 300 micromol l(-1): -97.3+/-1.0%, n=6, M+/ s.d.). Most of the activity of NCX4016 up to 100 micromol l(-1) was prevented by 10 micromol l(-1) ODQ, inhibitor of cyclic GMP. NCX4016 100 - 300 micromol l(-1) reduced TNF-alpha (NCX4016 300 micromol l(-1)=-77.2+/-19.9%, n=6) and IL-6 (NCX4016 300 micromol l(-1): -61.9+/-15.2%, n=6) in LPS stimulated monocytes while ASA had no significant effects. TF activity (NCX4016 300 micromol l(-1): 53.7+/-39.9%, n=4) and immunoreactive TF (NCX4016 300 micromol l(-1): -93.9+/ 7.9%, n=7), measured in the supernatant of stimulated cells, were also dose dependently inhibited by NCX4016 but not by ASA. The present results indicate that NCX4016 inhibits TXA(2) generation as well as cytokine release and TF in human monocytes partly via NO-dependent mechanisms. NCX4016 may have a favourable profile of activities in the clinical setting of athero-thrombosis. PMID- 11606335 TI - Best evidence in anesthetic practice: introducing a new feature in the Canadian Journal of Anesthesia. PMID- 11606333 TI - Dominant role of an endothelium-derived hyperpolarizing factor (EDHF)-like vasodilator in the ciliary vascular bed of the bovine isolated perfused eye. AB - 1. The roles of the endothelium-derived nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor (EDHF) in mediating vasodilator responses to acetylcholine and bradykinin were assessed in the ciliary vascular bed of the bovine isolated perfused eye preparation. 2. Vasodilatation to acetylcholine or bradykinin was unaffected by the nitric oxide synthase inhibitor, L-NAME (100 microM), or the cyclo-oxygenase inhibitor, flurbiprofen (30 microM), but was virtually abolished following treatment with a high concentration of KCl (30 mM), or by damaging the endothelium with the detergent, CHAPS (0.3%, 2 min). 3. Acetylcholine-induced vasodilatation was unaffected by glibenclamide (10 microM), an inhibitor of ATP-sensitive K(+) channels (K(+)(ATP)), but was significantly attenuated by TEA (10 mM), a non-selective inhibitor of K(+) channels. 4. The small conductance calcium-sensitive K(+) channel (SK(+)(Ca)) inhibitor, apamin (100 nM), and the large conductance calcium sensitive K(+) channel (BK(+)(Ca)) inhibitor, iberiotoxin (50 nM), had no significant effect on acetylcholine-induced vasodilatation. In contrast, the intermediate (IK(+)(Ca))/large conductance calcium-sensitive K(+) channel inhibitor, charybdotoxin (50 nM), powerfully blocked these vasodilator responses, and uncovered a vasoconstrictor response. 5. The combination of apamin (100 nM) with a sub-threshold concentration of charybdotoxin (10 nM) significantly attenuated acetylcholine-induced vasodilatation, but the combination of apamin (100 nM) with iberiotoxin (50 nM) had no effect. 6. In conclusion, blockade by a high concentration of KCl, by charybdotoxin, or by the combination of apamin with a sub-threshold concentration of charybdotoxin, strongly suggests that vasodilatation in the bovine isolated perfused eye is mediated by an EDHF. PMID- 11606336 TI - Breathing circuit disconnections: averting catastrophes. PMID- 11606334 TI - Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries. AB - 1. The cannabinoid arachidonyl ethanolamide (anandamide) caused concentration dependent relaxation of 5-HT-precontracted, myograph-mounted, segments of rat left anterior descending coronary artery. 2. This relaxation was endothelium independent, unaffected by the fatty acid amide hydrolase inhibitor, arachidonyl trifluoromethyl ketone (10 microM), and mimicked by the non-hydrolysable anandamide derivative, methanandamide. 3. Relaxations to anandamide were attenuated by the cannabinoid receptor antagonist, SR 141716A (3 microM), but unaffected by AM 251 (1 microM) and AM 630 (1 microM), more selective antagonists of cannabinoid CB(1) and CB(2) receptors respectively. Palmitoylethanolamide, a selective CB(2) receptor agonist, did not relax precontracted coronary arteries. 4. Anandamide relaxations were not affected by inhibition of sensory nerve transmission with capsaicin (10 microM) or blockade of vanilloid VR1 receptors with capsazepine (5 microM). Nevertheless capsaicin relaxed coronary arteries in a concentration-dependent and capsazepine-sensitive manner, confirming functional sensory nerves were present. In contrast, capsazepine and capsaicin did inhibit anandamide relaxations in methoxamine-precontracted rat small mesenteric arteries. 5. Relaxations to anandamide were inhibited by TEA (1 mM) or iberiotoxin (50 nM), blockers of large conductance, Ca(2+)-activated K(+) channels (BK(Ca)). Gap junction inhibition with 18alpha-glycyrrhetinic acid (100 microM) did not affect anandamide relaxations. 6. This study shows anandamide relaxes the rat coronary artery by a novel mechanism. Anandamide-induced relaxations do not involve the endothelium, degradation into active metabolites, or activation of cannabinoid CB(1) or CB(2) receptors, but may involve activation of BK(Ca). Vanilloid receptor activation also has no role in the effects of anandamide in coronary arteries, even though functional sensory nerves are present. PMID- 11606337 TI - Best evidence in anesthetic practice. Prevention: supplemental oxygen reduces the incidence of surgical-wound infection. PMID- 11606338 TI - A breathing circuit disconnection detected by anesthetic agent monitoring. AB - PURPOSE: To describe a case involving a spontaneously breathing patient where a circuit disconnection was detected by a change in monitored anesthetic agent parameters. CLINICAL FEATURES: A patient undergoing shoulder surgery was breathing spontaneously from a circle type anesthesia circuit via a laryngeal mask. A disconnection occurred between the heat and moisture exchanger (HME) and the circle system's Y-piece. As the gas sampling port was integrated into the HME a near normal pattern of CO2 continued to be displayed. The disconnection was noted because of a change in the graphical display of the volatile agent concentration. CONCLUSIONS: Anesthetic circuit disconnection can be difficult to detect, especially in the spontaneously breathing patient. Capnometry may not detect a disconnection on the machine side of the gas sampling port. Changes in oxygen and volatile agent concentrations may provide an early indication of these types of disconnection. PMID- 11606339 TI - Preoperative core temperatures in elective surgical patients show an unexpected skewed distribution. AB - PURPOSE: To document the preoperative core temperature of adult elective surgical patients. METHODS: A prospective audit obtained sublingual temperatures from 446 adult elective surgical patients on arrival in the preoperative holding area. RESULTS: Temperatures ranged from 35.7 degrees C to 37.8 degrees C with a mean of 36.5 degrees C (0.4 SD). The median was 36.4 degrees C and the mode was 36.1 degrees C. There was a skewed distribution with a clustering of values at the lower end of the range. All recordings were within the accepted normothermic range. CONCLUSION: The asymmetric distribution we observed differs from previously published normothermia data which shows a symmetrical distribution of temperatures. This skewed distribution has not previously been documented and we interpret it as being due to the effect of preoperative cooling factors. PMID- 11606340 TI - IM droperidol as premedication attenuates intraoperative hypothermia. AB - PURPOSE: Perioperative hypothermia results largely from core-to-peripheral heat redistribution. Droperidol, which is often used for premedication, promotes vasodilation, and thus may affect redistribution of heat. Accordingly, we tested the hypothesis that preanesthetic droperidol would affect perioperative hypothermia. METHODS: Twenty-three ASA physical status I patients scheduled for arthroscopic ligament reconstruction were randomly assigned to two groups to receive no premedication or im droperidol 0.1 mg x kg(-1) 30 min before anesthesia. Anesthesia was induced and maintained with propofol and fentanyl. We monitored core (tympanic) and peripheral (palm) temperatures, and skin (fingertip) blood flow for two hours after the induction of anesthesia during surgery. RESULTS: Before the induction of anesthesia, patients given droperidol were more deeply sedated than those given no premedication. Core temperature, which was similar in both groups before induction, decreased significantly more in the control than in the droperidol patients (0.75 +/- 0.34 degrees C and 0.37 +/- 0.20 degrees C, respectively, at 75 min after induction; P <0.01). Preinduction peripheral temperature and skin blood flow were lower in the control group than in the droperidol group, but the two variables became similar in both groups after induction. CONCLUSION: The results of the present study confirm our hypothesis that premedication with droperidol affects perioperative hypothermia. Droperidol may prevent core-to-peripheral heat redistribution after the induction of anesthesia. PMID- 11606341 TI - Wavelet transform of heart rate variability to assess autonomic nervous system activity does not predict arousal from general anesthesia. AB - PURPOSE: The relationship between autonomic nervous system (ANS) activity and general anesthesia has been explored. Studies have demonstrated partial recovery of heart rate variability (HRV), representative of ANS activity, in the postoperative period, but the arousal period has not been precisely studied. The goals of this study were to analyze modifications of ANS activity during general anesthesia and, more particularly, around the arousal period, to look for predictors of arousal. METHODS: We analyzed HRV changes using wavelet transform, a time-frequency analysis that, in contrast to Fourier transform, is able to assess abrupt changes of ANS activity. Seventeen patients (mean +/- SD age: 40.9 +/- 16.4 yr) under general anesthesia for hip or knee surgery, were included in the study. The analysis began one hour before anesthesia, focussed on eye opening, and ended three hours after arousal. RESULTS: There was a dramatic decrease in HRV after induction, that extended throughout anesthesia and represented a decrease in global autonomic regulation with, however, a relative predominance of vagal tone. At the moment of eye opening, there was an abrupt change in HRV, representing a sudden shift of ANS balance towards the predominance of sympathetic activity, while none of these indices changed seconds before arousal. CONCLUSIONS: Wavelet analysis of HRV appears to be powerful tool to precisely assess instantaneous changes of HRV during anesthesia. Using this method, there were no identifiable precursory HRV indices of arousal. PMID- 11606342 TI - Information provision, patient involvement, and emotional support: prospective areas for improving anesthetic care. AB - PURPOSE: To explore patients' perceptions of anesthetic care as measured by a patient-centered care survey. Specifically, the survey examined patient views of multiple diverse dimensions of care that are not typically fully addressed among patients receiving anesthesia services, namely opinions on Information Provision, Involvement in Care, Respect Shown, Physical Comfort, and Emotional Support. METHOD: A total of 268 patients responded to a patient-centered care survey, a self-report factor analytically derived instrument designed to measure the aforementioned dimensions of care. RESULTS: Analyses revealed that the highest ratings of care were given to Physical Comfort and Respect. Ratings of Information Provision, Involvement, and Emotional Support were significantly lower. Ratings did not differ as a function of site of service, inpatient vs day surgery, surgical service, type of anesthetic, or anesthesiologist. DISCUSSION: The findings generated from the study are of value in obtaining a broader understanding of anesthesia services from the patient's perspective, and also in directing quality improvement initiatives. Other departments of anesthesiology interested in quality improvement initiatives may similarly benefit from measurement of patient-centered care. PMID- 11606343 TI - Laparoscopic-assisted vaginal hysterectomy and the hyperglycemic response to surgery: an observational study. AB - PURPOSE: To test the hypothesis that laparoscopic-assisted vaginal hysterectomy (LAVH) attenuates the hyperglycemic response to surgery when compared to vaginal hysterectomy (VH). METHODS: Fourteen patients received either LAVH (n=7) or VH (n=7). Whole body glucose production was measured before and three hours after surgery using [6.6-2H2] glucose. Before, during and after the operation, plasma concentrations of glucose, insulin, glucagon, cortisol, epinephrine and norepinephrine were determined. RESULTS: Plasma glucose concentration increased in both groups during and after surgery showing a significantly higher value after VH than after LAVH (VH: 8.3 +/- 1.4 mmol x L(-1); LAVH: 6.6 +/- 0.9 mmol x L(-1), P <0.05). The postoperative increase in glucose production was comparable in both groups. While plasma concentrations of insulin and glucagon remained unchanged, intra- and postoperative plasma cortisol concentrations were significantly higher in the VH group than in the LAVH group. Plasma catecholamine concentrations significantly increased after both types of surgery to the same extent. CONCLUSION: In this observational study, LAVH appears to blunt the hyperglycemic and cortisol response to surgery when compared to VH. PMID- 11606344 TI - Rapid preparation of a patient with pheochromocytoma with labetolol and magnesium sulfate. AB - PURPOSE: To describe the rapid perioperative optimization and control of blood pressure in a young patient who presented with pheochromocytoma. He was non compliant with phenoxybenzamine but insisted on early surgery. He was scheduled for laparoscopic resection of the tumour. CLINICAL FEATURES: This 32-yr-old man presented with uncontrolled hypertension for a few years for which he was treated with nifedipine. He subsequently defaulted follow-up. The patient presented again approximately three months from the day of surgery and was diagnosed to have a pheochromocytoma. The endocrinologist prescribed phenoxybenzamine and propanolol in addition to the nifedipine but the patient stopped taking both drugs six weeks prior to surgery due to their side effects. The patient was admitted the evening before surgery to the intensive care unit for rapid control of his blood pressure. Blood pressure was optimized with an infusion of labetolol and volume expansion titrated under central venous catheter and intraarterial blood pressure guidance throughout the night. On the morning of surgery, a magnesium sulfate infusion was started. The laparoscopic surgery proceeded uneventfully and the patient was hemodynamically stable. There were two transient periods of hypotension after induction and at removal of tumour respectively which were corrected with a brief adrenaline infusion. No adverse outcome was noted. CONCLUSION: This case highlights the possibility of a more rapid perioperative control of pheochromocytoma using high doses of labetolol and a magnesium sulfate infusion to achieve stable intraoperative hemodynamics during laparoscopic resection of pheochromocytoma. PMID- 11606345 TI - Profound postoperative hypoglycemia in a malnourished patient. AB - PURPOSE: To present an unusual case of profound postoperative hypoglycemia resulting in irreversible brain damage in a malnourished patient. CLINICAL FEATURES: A 56-yr-old malnourished woman underwent laparotomy for intestinal obstruction under general anesthesia. Five hours postoperatively she was found to be unresponsive with an immeasureably low blood glucose level. This event was not associated with hyperinsulinemia. Predisposing factors like diabetes mellitus, pheochromocytoma, insulin secreting tumours, adrenal or pitutary deficiency were absent. She was treated with iv dextrose and hydrocortisone with blood glucose levels stabilizing fairly rapidly. However, she unfortunately had sustained irreversible cerebral damage and is left with significant neurological disability. CONCLUSION: Severe postoperative hypoglycemia has several well documented causes. Although hypoglycemia does occur to a moderate degree in malnutrition, it has not been reported to be so severe as to cause cerebral damage in the postoperative setting. PMID- 11606346 TI - Goal oriented general anesthesia for Cesarean section in a parturient with a large intracranial epidermoid cyst. AB - PURPOSE: To illustrate the anesthetic management of a term parturient with a large brain tumour scheduled for Cesarean section. CLINICAL FEATURES: A 26-yr-old woman presented at 33 weeks gestation with a generalized grand mal seizure. Magnetic resonance imaging demonstrated a 5-cm multi-lobulated extra axial mass compatible with an epidermoid cyst, arising from the left temporal lobe associated with shift of the midline structures and compression of the brainstem. She remained stable neurologically until elective Cesarean section at 38 weeks. Immediately prior to induction of general anesthesia, the proposed incision site was infiltrated with lidocaine and the supraglottic structures anesthetized with bilateral superior laryngeal nerve blocks. Remifentanil, thiopentone sodium and succinylcholine were administered in a rapid sequence fashion following voluntary hyperventilation to an endtidal CO2 of 28 mmHg. Anesthesia was maintained with desflurane in oxygen/air and an infusion of remifentanil. Postoperative pain control was achieved using a multi-modal approach which included intraperitoneal deposition of local anesthetic, im ketorolac and rectal acetaminophen prior to emergence followed by regular administration of naproxen and acetaminophen for 72 hr. CONCLUSION: In a parturient with a large intracranial tumour, general anesthesia combined with multi-modal balanced analgesia met the predefined anesthetic management goals and was associated with a favourable outcome. PMID- 11606347 TI - The Trendelenburg position increases the spread and accelerates the onset of epidural anesthesia for Cesarean section. AB - PURPOSE: The effect of position on the spread and the onset time of epidural anesthesia has not been well documented. This study was undertaken to assess the effect of modified Trendelenburg position on the spread of epidural anesthesia for Cesarean section. METHODS: Seven hundred thirty-nine parturients underwent epidural anesthesia for elective or emergent Cesarean section. Patients were divided into two groups in a randomized-controlled study. All patients received 20 mL of 2% lidocaine injected through a 19G epidural needle, a standard technique in our institution. During induction of epidural anesthesia, the first group was placed in 15 Trendelenburg with 10 head-up position and the second in the horizontal position. The onset time and the level of anesthesia, patients' vital signs, and Apgar score were recorded in both groups. RESULTS: There were no significant differences in vital signs, oxygen saturation and Apgar score between the two groups. The results show significant differences in the time of onset (on average four minutes faster in the modified Trendelenburg position group) (P <0.001), and in achieving T5 level sensory blockade (97.5% vs 42.8%) between the modified Trendelenburg and horizontally positioned pregnant women. CONCLUSION: This study demonstrates that the modified Trendelenburg position has a significant effect on the spread and the onset time of single shot epidural anesthesia, and can be used safely in term parturients for emergency or elective Cesarean section. PMID- 11606348 TI - A standardized multidisciplinary approach reduces the use of allogeneic blood products in patients undergoing cardiac surgery. AB - PURPOSE: Individual and institutional practices remain an independent predictor factor for allogeneic blood transfusion. Application of a standardized multidisciplinary transfusion strategy should reduce the use of allogeneic blood transfusion in major surgical patients. METHODS: This prospective non randomized observational study evaluated the effects of a standardized multidisciplinary transfusion strategy on allogeneic blood products exposure in patients undergoing non-emergent cardiac surgery. The developed strategy involved a standardized blood conservation program and a multidisciplinary allogeneic blood transfusion policy based mainly on clinical judgement, not only on a specific hemoglobin concentration. Data obtained in a first group including patients operated from September 1997 to August 1998 (Group pre: n=321), when the transfusion strategy was progressively developed, were compared to those obtained in a second group, including patients operated from September 1998 to August 1999 (Group post: n=315) when the transfusion strategy was applied uniformly. RESULTS: Patient populations and surgical procedures were similar. Patients in Group post underwent acute normovolemic hemodilution more frequently, had a higher core temperature at arrival in the intensive care unit and presented lower postoperative blood losses at day one. Three hundred forty units of packed red blood cells were transfused in 33% of the patients in Group pre whereas 161 units were transfused in 18% of the patients in Group post (P <0.001). Pre- and postoperative hemoglobin concentrations, mortality and morbidity were not different among groups. CONCLUSION: Development of a standardized multidisciplinary transfusion strategy markedly reduced the exposure of cardiac surgery patients to allogeneic blood. PMID- 11606349 TI - [Reproducibility and interchangeability of the Thromboelastograph, Sonoclot and Hemochron activated coagulation time in cardiac surgery]. AB - PURPOSE: Despite their common use in cardiac surgery, few studies have evaluated the reproducibility of the Thromboelastograph (TEG), of the Sonoclot (SCT), and of the activated coagulation time with celite (ACT-C) or kaolin (ACT-K) measured with the Hemochron, in clinical conditions of on-site monitoring of hemostasis. This study determined the reproducibility of those measurements, and evaluated the ability of various devices to substitute for the ACT-C. METHODS: Blood samples collected from 20 volunteers and 21 patients undergoing myocardial revascularization were analyzed in the two channels of the TEG, in two SCT and four Hemochron analyzers. The overall of TEG and SCT coagulation profiles were analyzed by a computerized TEG and an experienced observer respectively. The variation rate (V%) was calculated for each variable. The ability of ACT-K and SCT to substitute for ACT-C under different clinical conditions was evaluated. RESULTS: ACT-C and ACT-K V% ranged between 5.6% and 10.8% and between 6.7% and 12.4% respectively. TEG and SCT V% ranged between 3.1% and 9.5% and between 5.8% and 33.6% respectively, according to different conditions and parameters. In volunteers and non-heparinized patients, the ACT-C and ACT-K were interchangeable. No other test can substitute for the ACT-C when patients are heparinized during cardiopulmonary bypass (CPB). CONCLUSIONS: In the clinical conditions of use, on-site hemostasis monitoring devices providing the most reproducible measurements are, in decreasing order, the TEG, the Hemochron and the SCT. In heparinized patients and during CPB, results from different tests are not interchangeable, stressing the importance of establishing appropriate instrument-specific values for monitoring anticoagulation during cardiac surgery. PMID- 11606350 TI - Improving styletted oral tracheal intubation: rational use of the OTSU. AB - PURPOSE: To introduce an improved method of styletted oral laryngoscopic tracheal intubation. DESCRIPTION OF THE TECHNIQUE: The oral tracheal stylet unit (OTSU) is constructed using a commonly available intubating stylet combined with an ordinary endotracheal tube (ETT). The ETT/stylet is created by a series of specific steps to form an OTSU, each with a standard shape and design that allows the tracheal tube to separate freely from the stylet. After construction, every unit is tested to confirm that the frictional resistance created by the tracheal tube, as it slides along the stationary stylet, is at an absolute minimum. Successful tracheal intubation is based on the following concepts: (a) The j shaped OTSU, when correctly directed through the airway, passes freely from the mouth to the larynx, the laryngoscopic channel; (b) The tip of the ETT must first be placed between the vocal cords with every intubation. The tracheal tube is then launched and advanced into the trachea by sliding along and off a stationary stylette; (c) Only minimal force is required to propel the ETT during intubation; (d) Resistance to placement, launch or advancement means the tip of the OTSU has come into physical contact with the patient's airway; (e) When the epiglottis obscures the larynx, the tip of the OTSU is used to explore the hypopharynx and identify the glottis. The ability to differentiate where the ETT tip is located depends primarily on interpreting the sensations of touch and pressure transmitted from the bevel of the OTSU to the hand. Successful tracheal intubation is accomplished when all criteria for placement, launch, and advancement are met. CONCLUSION: Styletted oral tracheal intubation is well known. However, we describe an improvement of the technique, based on solid physical principles and years of experience, that should prove useful both for routine intubations and unexpected difficult airways. PMID- 11606351 TI - Use of the fibreoptic stylet scope (Styletscope) reduces the hemodynamic response to intubation in normotensive and hypertensive patients. AB - PURPOSE: To compare hemodynamic changes after tracheal intubation when using a new fibreoptic stylet scope (Styletscope) and a conventional laryngoscope in normotensive and hypertensive patients. METHODS: Normotensive (N; n=30) and hypertensive (H; n=30) patients undergoing general anesthesia participated in this study. Each group was divided into two groups. In one group, patients were intubated by using a stylet scope with a laryngoscope as an adjuvant (S; n=15 each), while patients in the other group were intubated using a laryngoscope by the usual technique (L; n=15 each). The time necessary for intubation, hemodynamic changes, and adverse effects were recorded. RESULTS: Patients in the normotensive groups (SN and LN groups) showed significant increases in both systolic and diastolic blood pressures from before induction to one minute after intubation; however, blood pressures in the SN group were significantly lower than those in the LN group. Both systolic and diastolic blood pressures increased after intubation in the LH group, but not in the SH group. Heart rates in all four groups showed significant increases, and there were no differences between heart rates in the stylet scope and laryngoscope groups or between the normotensive and hypertensive groups. The number of patients who complained of sore throat was greater in the laryngoscope groups. CONCLUSIONS: Tracheal intubation with a stylet scope can attenuate hemodynamic changes and reduce the incidence of sore throat in comparison with the conventional laryngoscope technique in both normotensive and hypertensive patients. PMID- 11606353 TI - Web-based examinations come of age. PMID- 11606352 TI - Inhaled prostacyclin (PGI2) is an effective addition to the treatment of pulmonary hypertension and hypoxia in the operating room and intensive care unit. AB - PURPOSE: There is a growing interest in the intraoperative and intensive care use of inhaled epoprostenol (PGI2) for the treatment of pulmonary hypertension (PHT) and hypoxia of cardiac or non-cardiac origin. We report our experience with this form of therapy. METHODS: A retrospective chart review of all patients who received inhaled PGI2 over a one-year period was undertaken. Demographic, hemodynamic, oxygenation status, mode of administration, side effects, duration of hospital stay, and mortality were noted. RESULTS: Thirty-five patients, of which 33 (92%) were in the intensive care unit, received inhaled PGI2. Of the 27 patients whose pulmonary artery pressure (PAP) was monitored, a significant decrease in mean PAP from 34.8 +/- 11.8 mmHg to 32.1 +/- 11.8 mmHg was observed within one hour after the start of therapy (P=0.0017). Selective pulmonary vasodilatation occurred in 77.8% of the patients. Thirty-three patients had arterial blood gases before and after therapy. There was an improvement in the PaO2/FIO2 ratio in 88% of these with a 175% improvement on average. The ratio of PaO2/FIO2 improved from 108 +/- 8 to 138 +/- 105 (P=0.001). Six patients (17%) presented hypotension, two had subsequent pneumothorax, one had bronchospasm and in one patient PGI2 inhalation was stopped because of increasing peak pulmonary pressures from the secondary flow coming from the nebulizer. Mortality of the cohort was 54%. CONCLUSION: Inhaled PGI2 can be useful in the treatment of patients with PHT and severe hypoxia. It can however be associated with systemic side effects. PMID- 11606355 TI - Monitoring of retrohepatic inferior vena caval pressure predicted postoperative hematoma after hepatic surgery. PMID- 11606356 TI - Intubation using the ProSeal laryngeal mask airway and a Cook airway exchange catheter set. PMID- 11606357 TI - Repeat anesthetic management of a patient with Huntington's chorea. PMID- 11606358 TI - Exposure to sevoflurane in otorhinolaryngologic operations. PMID- 11606359 TI - Identification of the thoracic epidural space by the running infusion drip technique. PMID- 11606360 TI - Changes of circulating blood volume in coronary arterial graft surgery with and without cardiopulmonary bypass. PMID- 11606361 TI - Gauging the depth of venipuncture during internal jugular vein cannulation. PMID- 11606362 TI - Bier's first spinal anesthetic and Veress's needle. PMID- 11606363 TI - The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis. PMID- 11606364 TI - A polymorphism in endostatin, an angiogenesis inhibitor, predisposes for the development of prostatic adenocarcinoma. AB - We have performed association studies between a novel coding single nucleotide polymorphism (D104N) in endostatin, one of the most potent inhibitors of angiogenesis, and prostate cancer. We observed that heterozygous N104 individuals have a 2.5 times increased chance of developing prostate cancer as compared with homozygous D104 subjects (odds ratio, 2.4; 95% confidence interval, 1.4-4.16). Modeling of the endostatin mutant showed that the N104 protein is stable. These results together with the observation that residue 104 is evolutionary conserved lead us to propose that: (a) the DNA segment containing this residue might contain a novel interaction site to a yet unknown receptor; and (b) the presence of N104 impairs the function of endostatin. PMID- 11606365 TI - Absence of Msh2 protein expression is associated with alteration in the FHIT locus and Fhit protein expression in colorectal carcinoma. AB - Frequent loss of Fhit expression has been reported in human gastrointestinal tract carcinomas; opinions remain divergent regarding Fhit expression in colorectal carcinoma (CRC) cases. Recent studies have suggested that Fhit inactivation can be a consequence of defects in mismatch repair proteins, particularly Msh2. Immunohistochemical analysis of Msh2 and Fhit protein expression in 62 CRC cases was performed. The same CRCs were examined for allelic loss at three loci within or near FHIT and for FHIT mRNA expression by reverse transcription-PCR amplification. Half of the 62 CRC cases were positive for Fhit protein. Fhit protein loss correlated significantly with the progression of carcinoma (P < 0.01) as well as lymph node metastasis (P < 0.05). Loss of Msh2 protein correlated significantly with loss of Fhit protein (P < 0.05) and FHIT locus alteration (P < 0.05). Loss of Fhit protein expression was observed in 50% of sporadic CRCs and was significantly more frequent in more advanced cancers. Interestingly, alteration of the fragile FHIT locus and loss of Fhit protein expression were significantly more frequent in sporadic CRCs lacking Msh2 protein, suggesting that this mismatch repair protein may be important in maintaining the integrity of the common fragile locus within the FHIT gene. PMID- 11606366 TI - A novel growth suppressor gene on chromosome 17p13.3 with a high frequency of mutation in human hepatocellular carcinoma. AB - Previous studies have shown that there is a high frequency of loss of heterozygosity (LOH) on chromosome 17p13.3 in hepatocellular carcinoma [HCC (M. Fujimori et al., Cancer Res., 51: 89-93, 1991; H. Nagai et al., Oncogene, 14: 2927-2933, 1997; V. Boige et al., Cancer Res., 57: 1986-1990, 1997; Z. Piao et al., Int. J. Cancer, 75: 29-33, 1998; and B. Charroux et al., J. Cell Biol., 148: 1177-1186, 2000)]. The minimum region of LOH on chromosome 17p13.3 in HCC has been defined within the region between D17S643 and D17S1574. Moreover, D17S926 in the minimum region of LOH has the highest frequency of LOH, and its sequencing analysis has been accomplished. In this region, 6 of 13 novel genes have been characterized (X. Zhao, D. Wan, M. He, Yu. Ye, Yi. He, L. Han, M. Guo, Y. Huang, W. Qin, M-W. Wang, W. Chong, J. Chen, L. Zhang, N. Yang, B. Xu, M. Wu, L. Zuo, and J. Gu. A high frequency LOH region on chromosome 17p13.3 in human HCC with densely clustered genes identified, submitted for publication). Here we describe the cloning and characterization of one of these novel genes, designated HCC suppressor 1 (HCCS1), located at this region. HCCS1 had 18 exons, and its full length cDNA was 2.0 kb. The protein expression product of HCCS1 was located in mitochondria. HCCS1 had a high frequency of mutations in HCC samples, whereas no alteration has been found in matched noncancerous liver tissues. Immunohistochemistry revealed a significantly higher expression of HCCS1 in the noncancerous liver tissues (33 of 35 samples) than in the HCC samples (2 of 35 samples). Transfection of HCCS1 cDNA into the HCC cell line remarkably reduced the efficiency of its colony formation and inhibited tumor growth in nude mice. Taken together, these findings strongly suggest a potential role of HCCS1 as a HCC putative suppressor gene. PMID- 11606367 TI - Molecular classification of human carcinomas by use of gene expression signatures. AB - Classification of human tumors according to their primary anatomical site of origin is fundamental for the optimal treatment of patients with cancer. Here we describe the use of large-scale RNA profiling and supervised machine learning algorithms to construct a first-generation molecular classification scheme for carcinomas of the prostate, breast, lung, ovary, colorectum, kidney, liver, pancreas, bladder/ureter, and gastroesophagus, which collectively account for approximately 70% of all cancer-related deaths in the United States. The classification scheme was based on identifying gene subsets whose expression typifies each cancer class, and we quantified the extent to which these genes are characteristic of a specific tumor type by accurately and confidently predicting the anatomical site of tumor origin for 90% of 175 carcinomas, including 9 of 12 metastatic lesions. The predictor gene subsets include those whose expression is typical of specific types of normal epithelial differentiation, as well as other genes whose expression is elevated in cancer. This study demonstrates the feasibility of predicting the tissue origin of a carcinoma in the context of multiple cancer classes. PMID- 11606368 TI - Hypoxia-inducible factor-1alpha is an intrinsic marker for hypoxia in cervical cancer xenografts. AB - The hypoxia-inducible factor 1 (HIF-1) is known to induce the expression of several proteins linked to the maintenance of oxygen homeostasis, cellular energy metabolism, and tumor progression. Its alpha subunit (HIF-1alpha) is stabilized under hypoxic conditions and, therefore, might represent an intrinsic marker for tissue hypoxia. Here we report on the spatial relationship between HIF-1alpha and the nitroimidazole hypoxia marker EF5 in cervical carcinoma xenografts, and on their spatial relationship to tumor blood vessels. EF5 was administered to mice bearing ME180 and SiHa cervical cancer xenografts. Frozen tumor tissue sections, triple-stained for HIF-1alpha, the endothelial cell marker CD31, and EF5, were imaged using wide-field multiparameter immunofluorescence microscopy. Expression levels of EF5 and HIF-1alpha were similar in ME180 xenografts, but the percentage of tumor area stained with EF5 was significantly smaller than the percentage of HIF-1alpha-positive area in SiHa tumors. In both tumor types the EF5-HIF-1alpha overlap was statistically significant, thus confirming their spatial and temporal colocalization. Spatial distribution analysis of EF5 and HIF-1alpha is consistent with different pO2 value "thresholds" for EF5 binding and HIF-1alpha expression. Summarized, our results indicate that HIF-1alpha is a useful intrinsic marker for hypoxia in cervical carcinoma xenografts. PMID- 11606369 TI - DNA polymerase beta mediates protection of mammalian cells against ganciclovir induced cytotoxicity and DNA breakage. AB - The efficacy of suicide herpes simplex virus-1 thymidine kinase (HSVtk)/ganciclovir (GCV) gene therapy is often limited by intrinsic resistance of tumor cells. Here we show that repair of GCV incorporated in DNA is a factor involved in GCV resistance. A protective role of DNA repair in GCV-induced cell killing is supported by the following findings: (a) GCV-exposed Chinese hamster ovary-HSVtk cells exhibited both reduced repair of GCV and cloning efficiency in the presence of a specific polymerase beta (beta-pol) inhibitor, prunasin; (b) DNA beta-pol-deficient mouse fibroblasts were more sensitive to the cytotoxic, apoptosis-inducing, and genotoxic (DNA breakage and chromosomal aberration inducing) effects of GCV as compared with wild-type and beta-pol-complemented cell lines; (c) methoxyamine, an inhibitor of beta-pol-dependent short-patch base excision repair, sensitized wild-type and complemented beta-pol cells to GCV, whereas it had no effect on the sensitivity of beta-pol-null cells to GCV. Because methoxyamine-mediated sensitization of beta-pol wild-type and beta-pol complemented cells to GCV did not reach the level of null cells, we suggest that both beta-pol-dependent short- and long-patch base excision repair are involved in protection of cells to GCV. Some implications for HSVtk/GCV gene therapy are being discussed. PMID- 11606370 TI - Age and TP53 mutation frequency in childhood malignant gliomas: results in a multi-institutional cohort. AB - Malignant astrocytoma is one of the most deadly primary central nervous system tumors. Although significant progress has been made in understanding the molecular pathways that lead to the development of these tumors in adults, comparatively little analysis has been done in childhood astrocytomas, which are less common and have a more favorable prognosis. Our previous studies of an institutional cohort of children with malignant gliomas suggested the existence of distinct molecular pathways of tumorigenesis in younger versus older children, based on the finding of a high frequency of TP53 mutations in tumors from children >3 years of age at diagnosis, compared with those from younger children. In the current study, the association between TP53 mutations and age was examined in greater detail using the multi-institutional group of children enrolled in Children's Cancer Group Study 945, the largest cohort of childhood high-grade gliomas analyzed to date. Seventy-seven tumors with centrally reviewed diagnoses of anaplastic astrocytoma or glioblastoma multiforme had sufficient archival histopathological material for microdissection-based genotyping. Sections were examined histologically, and topographic targets that contained malignant tissue were isolated by microdissection and subjected to PCR-based amplification and sequencing of TP53 exons 5-8. Twenty-six tumors (33.8%) had mutations in those exons. Mutations were observed in 2 of 17 tumors (11.8%) from children <3 years of age at diagnosis versus 24 of 60 tumors (40%) from older children, a difference that was statistically significant (P = 0.04), in agreement with our previous results. Whereas malignant gliomas in older children have a frequency of mutations comparable to tumors that arise in young adults, those from children <3 years old do not. The association between age and frequency of TP53 mutations among pediatric malignant gliomas indicates the probable existence of two distinct pathways of molecular tumorigenesis in younger versus older children. PMID- 11606371 TI - Tyrphostin AG825 triggers p38 mitogen-activated protein kinase-dependent apoptosis in androgen-independent prostate cancer cells C4 and C4-2. AB - Prostate cancer (PCa) progression is aided by abnormal autocrine growth factor loops. We screened for small cell-permeable inhibitors of receptor tyrosine kinases that could block their signaling and trigger cell death in PCa cell lines. We found that the human epidermal growth factor receptor (HER)-2/neu inhibitor tyrphostin AG825 is preferentially toxic to PCa cells that are phenotypically androgen independent. These effects were dose and time dependent in the human LNCaP, C4, and C4-2 cell line models of progression and correlated with the inhibition of HER-2/neu phosphoactivation and its down-regulation. In addition, we show that the inhibition of HER-2/neu signaling with AG825 triggers an imbalance between extracellular signal-regulated kinase 1/2 and p38 mitogen activated protein kinase activation, which leads to p38-dependent apoptosis. Inhibition of HER-1 with Compound 56 had no effect. These findings suggest that the androgen-independent C4 and C4-2 cells can be killed by selectively inhibiting their HER-2/neu signaling pathway and provide insights into the mechanism of action of AG825 in PCa cells. PMID- 11606373 TI - Human Rad17 is phosphorylated upon DNA damage and also overexpressed in primary non-small cell lung cancer tissues. AB - The spRAD17 gene is an essential component of the DNA damage and replication checkpoints in the fission yeast Schizosaccharomyces pombe. Cloning of the human homologue of spRAD17, hRAD17, indicated that it exhibits structural similarity with the replication accessory protein family, which include subunits of the Replication factor C complex. We have analyzed the phosphorylation status of hRad17 in response to DNA damaging agents. Our results showed that phosphorylation of hRad17 occurred immediately after UV and ionizing radiation treatment and reached peak level at approximately 3 h, suggesting that hRad17 may be a component of the DNA damage checkpoint. When primary tumor samples were analyzed, we observed that the majority (74%) of non-small cell lung carcinoma samples exhibited a significantly higher level of hRad17 expression compared with matched normal tissue controls. In contrast, hRad17 protein levels in a panel of primary colon carcinoma samples did not show an elevated level of expression compared with normal colon tissues. This observation suggests that the function of the hRAD17 gene may be involved in lung cancer development and may serve as a potential tumor marker. PMID- 11606372 TI - E1A inhibition of radiation-induced NF-kappaB activity through suppression of IKK activity and IkappaB degradation, independent of Akt activation. AB - Activation of the transcription factor nuclear factor kappaB (NF-kappaB) has been implicated in the protection of cells from apoptosis. We have shown previously that the adenovirus type 5 E1A sensitizes cells to radiation-induced apoptosis by inhibiting NF-kappaB activity. However, the exact mechanism of inhibition is not known. In this study, we compared the activity of inhibitor of nuclear factor kappaB (IkappaB) kinase (IKK) and the degradation of IkappaBalpha in E1A transfectants and parental human cancer cells after ionizing radiation treatment. We found that radiation-induced IKK activity and IkappaBalpha degradation were inhibited in the E1A transfectants. Recently, Akt has been implicated in NF kappaB activation. To test whether Akt is regulated by E1A and is involved in radiation-induced NF-kappaB activity, we examined the phosphorylation status of Akt in the E1A transfectants and parental cells and in irradiated cells. The results indicated that radiation induced Akt phosphorylation and that E1A inhibited basal but not radiation-induced Akt phosphorylation. We additionally examined radiation-induced NF-kappaB activity in cells stably transfected with a dominant-negative, inactive Akt and in parental cancer cells treated with a phosphatidylinositol 3-kinase inhibitor, wortmannin. We found that dominant negative Akt and wortmannin did not block radiation-induced NF-kappaB activity. Thus, our results suggest that inhibition of IKK activity and IkappaB degradation is the predominant mechanism for E1A-mediated inhibition of radiation-induced NF kappaB activity and that radiation-induced Akt activation cannot be inhibited by E1A and is likely independent of radiation-induced NF-kappaB activity. PMID- 11606374 TI - Loss of expression of the metastasis suppressor gene KiSS1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23. AB - KiSS1 is a putative melanoma metastasis suppressor gene, the expression of which may be regulated by another gene(s) mapping to chromosome 6q16.3-q23. To additionally elucidate the role of KiSS1 in the progression of human melanoma in vivo, we examined KiSS1 mRNA expression in 51 melanocytic tumors with various stages of progression by in situ hybridization. We also examined a correlation between loss of KiSS1 mRNA expression and loss of heterozygosity (LOH) of 6q16.3 q23 in 27 melanoma metastases. All of the four nevocellular nevi and eight primary melanomas <4 mm in thickness showed KiSS1 mRNA expression, whereas only 50% (6 of 12) of primary melanomas >4 mm in thickness expressed KiSS1. Loss of KiSS1 mRNA was equally frequent in metastases; 44% (12 of 27) of tumors lost KiSS1 expression. LOH of 6q16.3-q23 was observed in 52% (14 of 27) of metastases. There was a strong association between LOH and loss of KiSS1 expression (P = 0.03); nine metastases with LOH of 6q16.3-q23 lost KiSS1 expression, whereas 10 tumors with no LOH showed positive KiSS1 mRNA expression. The findings in this study show, for the first time, KiSS1 down-regulation during the progression of melanoma in vivo and strongly suggest that inactivation of a tumor suppressor gene(s) mapping to 6q16.3-q23 by deletion or mutation coupled with LOH may lead to the down-regulation of KiSS1. PMID- 11606375 TI - The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. AB - Phosphatidylinositol 3'-kinases (PI3ks) are a family of lipid kinases that play a crucial role in a wide range of important cellular processes associated with malignant behavior including cell growth, migration, and survival. We have used single-strand conformational polymorphism/heteroduplex analysis to demonstrate the presence of somatic mutations in the gene for the p85alpha regulatory subunit of PI3k (PIK3R1) in primary human colon and ovarian tumors and cancer cell lines. All of the mutations lead to deletions in the inter-SH2 region of the molecule proximal to the serine608 autoregulatory site. Expression of a mutant protein with a 23 amino acid deletion leads to constitutive activation of PI3k providing the first direct evidence that p85alpha is a new oncogene involved in human tumorigenesis. PMID- 11606376 TI - Functional significance of XPD polymorphic variants: attenuated apoptosis in human lymphoblastoid cells with the XPD 312 Asp/Asp genotype. AB - Recent molecular epidemiological studies have identified polymorphisms in the XPD gene that are associated with increased risk of brain gliomas and head, neck, lung, and skin cancers. However, the functional significance of these polymorphic variants in altering cell processes such as cell cycle checkpoints, DNA repair, and apoptosis is uncertain. We have cloned the XPD variants Lys751Gln, Asp312Asn, and Lys751Gln-Asp312Asn into a pcDNA-3.1-expression vector. Using these constructs, we did not find any detectable difference in either in vitro binding with wild-type p53 or in DNA repair proficiency as measured by host cell reactivation assay. We then genotyped 34 different lymphoblastoid cell lines from six Centre d'Etude du Polymorphisme Humaine (CEPH)/Utah pedigree families and a CEPH/French pedigree family for polymorphisms at codons 751 and 312 and assessed their apoptotic response after either UV or ionized radiation exposure. The lymphoblastoid cell lines with homozygous or heterozygous Asp at codon 312 have similar apoptotic rates, whereas cell lines with homozygous Asn at codon 312 showed a 2.5-fold increased response to UV (P = 0.005; Student's t test). This is the first report known to us of a functional polymorphism in a gene involved in DNA damage-induced apoptosis. However, the presence of Lys or Gln at codon 751 did not influence the apoptotic response to UV. The diminished apoptotic response of cells containing the 312 Asp allele could both allow the survival and selective clonal expansion of carcinogen-damaged cells and be a mechanistic explanation for the increased risk of cancer at diverse tissue sites. PMID- 11606377 TI - Inducible expression of transforming growth factor beta1 in papillomas causes rapid metastasis. AB - Transforming growth factor beta1 (TGF-beta1) acts as a tumor suppressor at early stages of carcinogenesis, however, it has also been suggested to promote tumor progression at late stages. To determine at which stage and by what mechanisms this functional switch occurs, we have generated gene-switch-TGF-beta1 mice in which TGF-beta1 transgene expression can be induced in skin tumors at specific stages. These mice were exposed to a chemical carcinogenesis protocol, which allows tumorigenesis to develop in progressive stages from benign papillomas to malignant carcinomas. Remarkably, TGF-beta1 transgene induction in papillomas rapidly induced metastasis. This function is in sharp contrast to its tumor suppressive effect when TGF-beta1 transgene expression was induced early in the protocol. Transgenic papillomas exhibited down-regulation of TGF-beta receptors and their signal transducer, the Smads, and loss of the invasion suppressor E cadherin/catenin complex in the cell membrane. These molecules were lost only in malignant carcinomas in control mice at a much later stage. Furthermore, transgenic papillomas exhibited elevated expression of matrix metalloproteinases and increased angiogenesis. Our study suggests that TGF-beta1 overexpression may directly induce tumor metastasis by initiating events necessary for invasion. Down-regulation of TGF-beta signaling components in tumor epithelia selectively abolishes growth inhibition, thus, switching the role of TGF-beta1 to a metastasis promoter. PMID- 11606378 TI - Oxidative stress increases frameshift mutations in human colorectal cancer cells. AB - Chronic inflammation in the gastrointestinal tract increases the risk for development of cancer by an incompletely understood pathway, which may involve microsatellite instability (MSI). Low frequency of MSI referred to as "MSI-L" occurs frequently in chronically inflamed nonneoplastic tissue. In this work, we have tested the hypothesis that oxidative stress may induce the accumulation of frameshift mutations in human microsatellite DNA. Mismatch repair (MMR) proficient HCT116+chr3 and MMR-deficient HCT116 cells were transfected with pCMV (CA)13-EGFP, a plasmid that contains a (CA)13 dinucleotide repeat, which disrupts the reading frame of the downstream enhanced green fluorescent protein gene. A dose-dependent increase in frameshift mutations restoring the enhanced green fluorescent protein reading frame was detected in HCT116 by flow cytometry. At 1 mM H2O2, the mutant fraction was 9-fold higher than that in mock-treated control cells. Although demonstrating stability at lower H2O2 concentrations, MMR proficient HCT116+chr3 cells accumulated mutations at the 1 mM H2O2 level (4.1 fold above mock-treated control). No significant mutations were detected when HCT116 cells were transfected with the pCMV-(N)26-EGFP construct that contains 26 nucleotides in a random sequence. These data indicate that oxidative stress is a potential mutagen leading to accumulation of frameshift mutations and may contribute to MSI in the setting of chronic inflammation. PMID- 11606379 TI - 2-difluoromethylornithine and dehydroepiandrosterone inhibit mammary tumor progression but not mammary or prostate tumor initiation in C3(1)/SV40 T/t antigen transgenic mice. AB - Female transgenic mice that express SV40 T/t antigens under the regulatory control of the rat C3(1) gene spontaneously develop multifocal mammary lesions that predictably evolve into invasive, hormone-independent carcinomas, whereas male mice are prone to develop prostate cancer. Chemopreventive agents were administered to female C3(1)/SV40 large T-antigen mice from 7 to 19 weeks of age, during which time the mammary lesions developed and progressed to invasive carcinomas. No significant differences in the numbers of preinvasive mammary intraepithelial neoplasia lesions (histologically similar to human ductal carcinoma in situ) were observed after 2 or 8 weeks of treatment between mice receiving either vehicle alone, dehydroepiandrosterone (DHEA), or 2 difluoromethylornithine (DFMO). However, a dose-response reduction in invasive carcinoma growth was observed for both DFMO, an inhibitor of ornithine decarboxylase, and DHEA, the primary steroid precursor to both androgens and estrogens in primates. Despite unaltered expression of the transgene, tumor incidence was reduced approximately 20% by DFMO (8000 mg/kg) and 30% by DHEA (4000 mg/kg; P < 0.05). Tumor multiplicity was reduced by approximately 50% by both DFMO and DHEA (P < 0.05). DFMO had a dose-dependent effect on total tumor burden, which was reduced by 25% at low doses (4000 mg/kg) and 70% at high doses (8000 mg/kg). DHEA reduced tumor burden by 50% and 66% at low (2000 mg/kg) and high (4000 mg/kg) doses, respectively. Interestingly, despite its inhibitory effects on tumor development, DHEA caused a dose-dependent increase of serum estradiol levels that we have previously shown to increase mammary tumor formation in this model. No effect on the development of the prostate cancer precursor lesions (prostate intraepithelial neoplasia) was observed when mice were treated with DHEA, DFMO, tocopherol acetate, selenomethionine, or 9-cis retinoic acid, although the effects on late-stage prostate cancer development were not determined. These results demonstrate that despite the expression of the highly transforming C3(1)/SV40 large T-antigen transgene, this transgenic model can be used to study the effects of chemopreventive agents on mammary cancer progression. The tumor-inhibitory effects of DHEA and DFMO on mammary cancer growth appear to occur after the development of preinvasive lesions, suggesting that these agents inhibit tumor progression but not initiation. PMID- 11606380 TI - Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. AB - Trans-3,4',5-trihydroxystilbene (resveratrol), a phytoalexin present in grapes and grape products such as wine, has been identified as a chemopreventive agent. Recent studies performed with MCF-7 human breast cancer cells have demonstrated superestrogenic effects with resveratrol. In contrast, studies performed using estrogen receptor-transfected cell lines have shown that resveratrol acts as a mixed agonist/antagonist. The major objective of this study was to characterize the estrogen-modulatory effects of resveratrol in a variety of in vitro and in vivo mammary models. Thus, the effect of resveratrol alone and in combination with 17beta-estradiol (E2) was assessed with MCF-7, T47D, LY2, and S30 mammary cancer cell lines. With cells transfected with reporter gene systems, the activation of estrogen response element-luciferase was studied, and using Western blot analysis, the expression of E2-responsive progesterone receptor (PR) and presnelin 2 protein was monitored. Furthermore, the effect of resveratrol on formation of preneoplastic lesions (induced by 7,12-dimethylbenz(a)anthracene) and PR expression (with or without E2) was evaluated with mammary glands of BALB/c mice placed in organ culture. Finally, the effect of p.o. administered resveratrol on N-methyl-N-nitrosourea-induced mammary tumors was studied in female Sprague Dawley rats. As a result, in transient transfection studies with MCF-7 cells, resveratrol showed a weak estrogenic response, but when resveratrol was combined with E2 (1 nM), a clear dose-dependent antagonism was observed. Similar mixed estrogenic/antiestrogenic effects were noted with S30 cells, whereas resveratrol functioned as a pure estrogen antagonist with T47D and LY2 cells. Furthermore, in MCF-7 cells, resveratrol induced PR protein expression, but when resveratrol was combined with E2, expression of PR was suppressed. With T47D cells, resveratrol significantly down-regulated steady-state and E2-induced protein levels of PR. With LY2 and S30 cells, resveratrol down-regulated presnelin 2 protein expression. Using the mouse mammary organ culture model, resveratrol induced PR when administered alone, but expression was suppressed in the presence of E2 (1 nM). Furthermore, resveratrol inhibited the formation of estrogen-dependent preneoplastic ductal lesions induced by 7,12 dimethylbenz(a)anthracene in these mammary glands (IC50 = 3.2 microM) and reduced N-methyl-N-nitrosourea-induced mammary tumorigenesis when administered to female Sprague Dawley rats by gavage. Therefore, in the absence of E2, resveratrol exerts mixed estrogen agonist/antagonist activities in some mammary cancer cell lines, but in the presence of E2, resveratrol functions as an antiestrogen. In rodent models, carcinogen-induced preneoplastic lesions and mammary tumors are inhibited. These data suggest that resveratrol may have beneficial effects if used as a chemopreventive agent for breast cancer. PMID- 11606381 TI - A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. AB - CV706 is a prostate-specific antigen (PSA)-selective, replication-competent adenovirus that has been shown to selectively kill human prostate cancer xenografts in preclinical models. To study the safety and activity of intraprostatic delivery of CV706, a Phase I dose-ranging study for the treatment of patients with locally recurrent prostate cancer after radiation therapy was conducted. Twenty patients in five groups were treated with between 1 x 10(11) and 1 x 10(13) viral particles delivered by a real-time, transrectal ultrasound guided transperineal technique using a three-dimensional plan. The primary end point was the determination of treatment-related toxicity. Secondary objectives included evaluation of the antitumor activity of CV706 and monitoring for other correlates of antineoplastic action. In this study, CV706 was found to be safe and was not associated with irreversible grade 3 or any grade 4 toxicity. No grade >1 alterations in liver function tests associated with CV706 administration were observed. Posttreatment prostatic biopsies and detection of a delayed "peak" of circulating copies of virus provided evidence of intraprostatic replication of CV706. The study defined the timing of CV706 shedding into blood and urine as well as the appearance of circulating Ad5 neutralizing antibodies. Finally, this study documents the serum PSA response of treated patients and reveals a dose response showing that all five patients who achieved a > or =50% reduction in PSA were treated with the highest two doses of CV706. This study represents the first clinical translation of a prostate-specific, replication-restricted adenovirus for the treatment of prostate cancer. Taken together, this study documents that intraprostatic delivery of CV706 can be safely administered to patients, even at high doses, and the data also suggest that CV706 possesses enough clinical activity, as reflected by changes in serum PSA, to warrant additional clinical and laboratory investigation. PMID- 11606382 TI - Chemopreventive property of a soybean peptide (lunasin) that binds to deacetylated histones and inhibits acetylation. AB - Lunasin is a unique 43-amino acid soybean peptide that contains at its carboxyl end: (a) nine Asp (D) residues; (b) an Arg-Gly-Asp (RGD) cell adhesion motif; and (c) a predicted helix with structural homology to a conserved region of chromatin binding proteins. We demonstrated previously that transfection of mammalian cells with the lunasin gene arrests mitosis, leading to cell death. Here we show that exogenous application of the lunasin peptide inhibits chemical carcinogen-induced transformation of murine fibroblast cells to cancerous foci. To elucidate its mechanism of action we show that lunasin: (a) internalizes in the cell through the RGD cell adhesion motif; (b) colocalizes with hypoacetylated chromatin; (c) binds preferentially to deacetylated histone H4 in vitro; and (d) inhibits histone H3 and H4 acetylation in vivo in the presence of a histone deacetylase inhibitor. These results suggest a mechanism whereby lunasin selectively induces apoptosis, mostly in cells undergoing transformation, by preventing histone acetylation. In support of this, lunasin selectively induces apoptosis in E1A transfected cells but not in nontransformed cells. Finally, in the SENCAR mouse skin cancer model, dermal application of lunasin (250 microg/week) reduces skin tumor incidence by approximately 70%, decreases tumor yield/mouse, and delays the appearance of tumors by 2 weeks relative to the positive control. These results point to the role of lunasin as a new chemopreventive agent that functions possibly via a chromatin modification mechanism. PMID- 11606383 TI - Enhanced sensitivity of human oral carcinomas to induction of apoptosis by selenium compounds: involvement of mitogen-activated protein kinase and Fas pathways. AB - Prospective studies and recent intervention trials suggest that the risk of some cancers, including respiratory tract cancers, may be inversely related to selenium (SE) intake, and this is supported by strong experimental evidence with chemical-induced animal cancer models. How this cancer-protective effect is mediated is unclear, but interference with the balance of growth/apoptosis during tumor outgrowth is one plausible hypothesis. In general, there is a correlation between the effectiveness of SE compounds as chemopreventive agents in vivo and their ability to inhibit cell growth and induce apoptosis in vitro. This study has investigated the signal transduction pathways affected by SE compounds in biopsies of normal human oral mucosa cells and human oral squamous carcinoma cells (SCCs), using a primary culture system. Two SE compounds were tested: selenodiglutathione (SDG), the primary metabolite of selenite and the most commonly used cancer-protective SE compound in animal models, and the synthetic SE compound, 1,4-phenylenebis(methylene)selenocyanate (p-XSC), one of the most potent chemopreventive pharmacological SE compounds. Three novel findings are reported: (a) SCCs were found to be significantly more sensitive to induction of apo ptosis by SDG than normal human oral mucosa cells, though the differences were marginal with p-XSC; (b) both SE compounds induced the expression of Fas ligand (Fas-L) in oral cells to a degree that correlated with the extent of apoptosis induction; and (c) both SDG and p-XSC induced the stress pathway kinases, Jun NH2-terminal kinase (JNK) and p38 kinase, at concentrations causing apoptosis; p-XSC, and to a lesser extent SDG, also activated extracellular regulated kinases 1&2 (ERKs 1&2) and protein kinase-B or Akt. To test their functional involvement, the effect of inhibiting each of these pathways on induction of apoptosis by SDG and p-XSC was determined in SCCs. Inhibiting the ERKs 1&2 or Akt pathways with specific chemical inhibitors (PD98059 or LY294002, respectively) did not affect the extent of apoptosis induced by SDG or p-XSC (with the exception of LY294002, which actually enhanced the level of induction of apoptosis by SDG). The JNK pathway appeared to be most important for induction of Fas-L and apoptosis because concentrations of SB202190 that inhibited activation of both the JNK and p38 kinase (but not ERKs 1&2) in SCC reduced the extent of induction of Fas-L and apoptosis by SDG and p-XSC, whereas lower concentrations that inhibited activation only of p38 kinase did not. This was confirmed by the fact that exogenous expression of a dominant negative deletion mutant of c-Jun (TAM67) reduced the induction of both apoptosis and Fas-L by SDG. PMID- 11606384 TI - The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells. AB - Many of the major identified risk factors for breast cancer are associated with exposure to endogenous estrogen. In addition to the effects of estrogen as a growth factor, experimental and epidemiological evidence suggest that catechol metabolites of estrogen also contribute to estrogen carcinogenesis by both direct and indirect genotoxic mechanisms. O-Methylation catalyzed by catechol-O methyltransferase (COMT) is a Phase II metabolic inactivation pathway for catechol estrogens. We and others have found that a polymorphism in the COMT gene, which codes for a low activity variant of the COMT enzyme, is associated with an increased risk of developing breast cancer; therefore, the goal of the current study was to investigate the role of decreased COMT activity on estrogen catechol levels and on oxidative DNA damage, as measured by 8-hydroxy-2' deoxyguanosine (8-oxo-dG) levels. MCF-7 cells were pretreated with dioxin as a means to increase estrogen metabolism to catechol estrogens, then treated with estradiol (E2) +/- Ro 41-0960, a COMT-specific inhibitor. After extraction from culture medium, estrogen metabolites were separated using an high-performance liquid chromatography-electrochemical detection method. As expected, dioxin dramatically increased E2 oxidative metabolism, primarily to its 2-OH and 2 methoxy metabolites. The COMT inhibitor blocked 2-methoxy E2 formation. This was associated with increased 2-hydroxy E2 (2-OH E2) and 8-oxo-dG levels. In the presence of COMT inhibition, increased oxidative DNA damage was detected in MCF-7 cells exposed to as low as 0.1 microM E2, whereas in the absence of COMT inhibition, no increase in 8-oxo-dG was detected at E2 concentrations < or =10 microM. This study is the first to show that O-methylation of 2-OH E2 by COMT is protective against oxidative DNA damage caused by 2-OH E2, a major oxidative metabolite of E2. PMID- 11606385 TI - Photosensitization with zinc (II) phthalocyanine as a switch in the decision between apoptosis and necrosis. AB - Photodynamic therapy (PDT) of tumors and other diseases is based on the uptake of a photosensitizing dye in target cells, which are damaged by reactive oxygen intermediates generated on irradiation with light in which the wavelengths match the dye absorption spectrum. PDT can induce cell death by necrosis and apoptosis both in vivo and in vitro, but the factors determining the contribution of either mechanism to the overall process are not completely defined. Our studies on the photosensitization of 4R transformed fibroblasts with the second-generation photosensitizer zinc (II) phthalocyanine (ZnPc) aim at determining the effect of important experimental parameters such as time of cell incubation (2 or 24 h) with ZnPc before irradiation and ZnPc concentration in the incubation medium on cell death. Furthermore, we propose possible correlations between the cell death mechanism and primary photo-damage sites; these are mainly determined by the intracellular localization of the photosensitizer. The mechanism of cell death was determined by both electron microscopy analysis of the morphological alterations induced by photosensitization and measurement of caspase 3 activation. The initial photodamage sites were determined by measuring the activities of several functions typical of mitochondria, lysosomes, Golgi apparatus, cytosol, and plasma membrane. The intracellular localization of ZnPc after 2- or 24-h incubation was determined by fluorescence microscopy. Necrosis, associated with early loss of plasma membrane integrity and complete depletion of intracellular ATP, represents the prevailing mode of death for 4R cells dark incubated for 2 h with ZnPc and irradiated with light doses reducing viability by 99.9%. In contrast, irradiation performed 24 h after ZnPc incubation causes only partial inhibition of plasma membrane activities, and cell death occurs largely by apoptosis. ZnPc is mainly localized in the Golgi apparatus after 2- and 24-h incubation, and in all of the cases this compartment represents a primary target of photodamage. Only after prolonged incubation is mitochondrial localization of ZnPc clearly detected by fluorescence microscopy; this could be a determining factor for promotion of apoptosis. Our data demonstrate that it is possible to modulate the mechanism of cell death by appropriate protocols; this may be relevant for enhancing the therapeutic efficacy of PDT. PMID- 11606386 TI - Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo. AB - This study evaluates the efficacy of the combination of an antiangiogenic drug and conventional chemotherapeutics for the treatment of experimental human gliomas. As an antiangiogenic, we used recombinant human PEX, a fragment of matrix metalloproteinase-2 that we have previously shown to have a significant antimitotic, anti-invasive, and antiangiogenic properties against human glioblastoma in vitro and in vivo. We used carboplatin and etoposide as the two chemotherapeutic drugs routinely used in our institution (Ospedale Maggiore de Milano) for the treatment of malignant gliomas. Conventional chemotherapeutic drugs were administered at high dose or at a low and semicontinuous regimen. Combined treatment of high-dose chemotherapy and PEX did not produce an improvement of survival in comparison with chemotherapy alone, but it was associated with a decrease in tumor volume, vascularity, and proliferative index and an increased apoptosis. All of these animals experienced severe side effects. The longest survival was documented in animals submitted to low and semicontinuous chemotherapy and antiangiogenic treatment. This regimen was associated with no side effects, marked decrease in tumor volume, vascularity, and proliferative index, and an increased apoptosis. Our data suggest that low dose chemotherapy in combination with PEX can be successfully used against human malignant glioma in vivo. PMID- 11606387 TI - Preclinical antitumor activity of BMS-214662, a highly apoptotic and novel farnesyltransferase inhibitor. AB - BMS-214662 is a potent and selective inhibitor of farnesyltransferase (FTI). In rodent fibroblasts transformed by oncogenes, BMS-214662 reversed the H-Ras transformed phenotype but not that of K-Ras or other oncogenes. In soft agar growth assays, BMS-214662 showed good potency in inhibiting H-ras-transformed rodent cells, A2780 human ovarian carcinoma tumor cells, and HCT-116 human colon carcinoma tumor cells. Inhibition of H-Ras processing in HCT-116 human colon tumor cells was more rapid than in H-Ras-transformed rodent fibroblast tumors. BMS-214662 is the most potent apoptotic FTI known and demonstrated broad spectrum yet robust cell-selective cytotoxic activity against a panel of cell lines with diverse histology. The presence of a mutant ras oncogene was not a prerequisite for sensitivity. Athymic and conventional mice were implanted s.c. with different histological types of human and murine tumors, respectively. BMS-214662 was administered both parenterally and p.o. and was active by all these routes. Curative responses were observed in mice bearing staged human tumor xenografts including HCT-116 and HT-29 colon, MiaPaCa pancreatic, Calu-1 lung, and EJ-1 bladder carcinomas. A subline of HCT-116, HCT-116/VM46, resistant to many standard cytotoxic agents by means of a multiple drug resistance mechanism, remained quite susceptible to BMS-214662, and borderline activity was achieved against N-87 human gastric carcinoma. Two murine tumors, Lewis lung carcinoma and M5076 sarcoma, were insensitive to the FTI. In a study performed using Calu-1 tumor-bearing mice, no obvious schedule dependency of BMS-214662 was observed. The FTI, BMS-214662, demonstrated broad spectrum activity against human tumors, but murine tumors were not as sensitive. PMID- 11606388 TI - Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. AB - Hepatocyte growth factor (HGF) is involved in malignant behavior of cancers as a mediator in tumor-stromal interactions through enhancing tumor invasion and metastasis. We found recently that NK4, a four-kringle fragment of HGF, functions as both an HGF-antagonist and an angiogenesis inhibitor. We have now determined whether blockade of the HGF-c-Met/HGF receptor pathway and tumor angiogenesis by administration of recombinant NK4 would inhibit growth, invasion, and metastasis of human pancreatic carcinoma implanted into the pancreas of nude mice. When treatment with NK4 or anti-HGF neutralizing antibody was initiated from the third day after orthotopic injection of SUIT-2 human pancreatic cancer cells, both NK4 and anti-HGF antibody suppressed the conversion of orthotopic pancreatic tumors from carcinoma in situ to aberrantly invading cancers during days 3-14. On the other hand, when the treatment was begun on day 10, a time when cancer cells were already invading surrounding tissues, NK4 but not anti-HGF antibody inhibited tumor growth, peritoneal dissemination, and ascites accumulation at 4 weeks after the inoculation. Antitumor effects of NK4 correlated with decreased microvessel density in pancreatic tumors thereby indicating that the antiangiogenic activity of NK4 may have mainly contributed to its antitumor effects. Moreover, although NK4-treatment was initiated from the end stage (day 24 after tumor inoculation), NK4 prolonged survival time of mice, and the suppression of peritoneal dissemination, ascites accumulation, and invasion of metastasized cancer cells into the peritoneal wall were remarkable. We propose that simultaneous targeting of both tumor angiogenesis and the HGF-mediated invasion-metastasis may prove to be a new approach to treating patients with pancreatic cancer. PMID- 11606389 TI - The farnesyl protein transferase inhibitor SCH66336 is a potent inhibitor of MDR1 product P-glycoprotein. AB - P-glycoprotein (Pgp)-mediated drug efflux is a major factor contributing to the variance of absorption and distribution of many drugs, particularly cancer chemotherapeutics. Multidrug resistance (MDR) is caused largely by the efflux of therapeutics out of the tumor cell by Pgp, resulting in reduced efficacy of chemotherapy. SCH66336, a farnesyl transferase inhibitor in development for cancer therapy, was examined in the present study for its ability to inhibit Pgp. In a test system consisting of a NIH-G185 cell line presenting an overexpressed amount of the human transporter Pgp, known Pgp inhibitors, such as cyclosporin A, paclitaxel, verapamil, tamoxifen, and vinblastine, were demonstrated to inhibit the Pgp-mediated efflux of daunorubicin. SCH66336 significantly inhibited daunorubicin transport with an IC50 of about 3 microM and similarly affected the transport of rhodamine 123 with a potency similar to cyclosporin A. Additionally, by an ATP-hydrolysis assay, SCH66336 was shown to decrease Pgp-mediated ATP hydrolysis by >70% with a Km of 3 microM. This observation indicates that SCH66336 directly interacts with the substrate binding site of Pgp, a quality unique to SCH66336 and its analogues, although not inherent to farnesyl transferase inhibitors in general. Moreover, low concentrations of SCH66336 exhibit synergy with the Pgp substrate/inhibitors paclitaxel, tamoxifen, and vinblastine respectively by significantly potentiating their inhibition of Pgp. Treatment with SCH66336 would be predicted to be synergistic with coadministered cancer therapeutics that are substrates of Pgp. A further benefit of coadministration of SCH66336 could be reduced chemotherapy dosage, hence, lower exposure to normal cells and, therefore, less undesired toxicity. PMID- 11606390 TI - Combined intratumoral injection of bone marrow-derived dendritic cells and systemic chemotherapy to treat pre-existing murine tumors. AB - Dendritic cells (DCs) are attractive candidates for innovative cancer immunotherapy by virtue of their potential to function as professional antigen presenting cells for initiating cellular immune responses. In this study, we evaluated a possible synergy of conventional chemotherapy together with intratumoral injection of syngeneic bone marrow-derived DCs for the treatment of preexisting tumors. Using murine CT26 colon adenocarcinoma cells (parental or modified to express beta-galactosidase as a model tumor antigen) to produce s.c. tumors in syngeneic BALB/c mice, the data demonstrate that direct injections of DCs at the tumor site result in partial eradication of established tumors. Strikingly, the addition of systemic chemotherapy (cyclophosphamide) combined with local intratumoral injection of DCs led to complete tumor regression in the treated animals. The tumor-free mice were able to resist a repeat challenge with the same tumor, suggesting that the animals had acquired long term antitumor immunity. Supporting evidence for the paradigm of systemic chemotherapy and intratumoral administration of DCs was obtained using melanoma B16 syngeneic tumor treated with Adriamycin plus DCs. These novel findings raise the possibility of using this potent strategy of combined intratumoral injections of DCs and systemic chemotherapy for cancer treatment. PMID- 11606391 TI - Levels of phospholipid metabolites in breast cancer cells treated with antimitotic drugs: a 31P-magnetic resonance spectroscopy study. AB - Magnetic resonance spectroscopy (MRS) methods have provided valuable information on cancer cell metabolism. In this study, we characterized the 31P-MR spectra of breast cancer cell lines exhibiting differences in hormonal response, estrogen receptors (positive/negative), and metastatic potential. A correlation was made between the cytotoxic effect of antimitotic drugs and changes in cell metabolism pattern. Because most anticancer drugs are more effective on proliferating cells, our study attempted to elucidate the metabolic profile and specific metabolic changes associated with the effect of anticancer drugs on proliferating breast cancer cell lines. Accordingly, for the 31P-MRS experiments, cells were embedded in Matrigel to preserve their proliferation profile and ability to absorb drugs. The MRS studies of untreated cells indicated that the levels of phosphodiesters and uridine diphosphosugar metabolites were significantly higher in estrogen receptor-positive and low metastatic potential cell lines. 31P-MRS observations revealed a correlation between the mode of action of anticancer drugs and the observed changes in cell metabolic profiles. When cells were treated with antimicrotubule drugs (paclitaxel, vincristine, colchicine, nocodazole), but not with methotrexate and doxorubicin, a profound elevation of intracellular glycerophosphorylcholine (GPC) was recorded that was not associated with changes in phospholipid composition of cell membrane. Remarkably, the rate of elevation of intracellular GPC was much faster in cell population synchronized at G2-M compared with the unsynchronized cells. The steady-state level of GPC for paclitaxel-treated cells was reached after approximately 4 h for synchronized cells and after approximately 24 h (approximate duration of one cell cycle) for the unsynchronized ones. These observations may indicate a correlation between microtubule status and cellular phospholipid metabolism. This study demonstrates that 31P-MRS may have diagnostic value for treatment decisions of breast cancer and reveals new aspects of the mechanism of action of antimicrotubule drugs. PMID- 11606392 TI - Overexpressed androgen receptor linked to p21WAF1 silencing may be responsible for androgen independence and resistance to apoptosis of a prostate cancer cell line. AB - An androgen-independent (AI) prostate cancer cell line, derived recently from an LNCaP cell line maintained in androgen-poor conditions, has properties resembling a subgroup of advanced prostate cancers in that it has an overexpressed androgen receptor (AR), undetectable levels of p21WAF1 and prostate-specific antigen, and is resistant to apoptosis. The loss of prostate-specific antigen expression but not the p21WAF1 is attributable to gene silencing by hypermethylation. The high AR and undetectable p21WAF1 of AI cells, and lower AR but highly expressed p21WAF1 of androgen-dependent parental LNCaP cells, suggest a possibility of a functional link between these two proteins. Therefore, we examined the impact the modulation of AR will have on the expression of p21WAF1. Treatment of androgen dependent cells with an androgen agonist, R1881, increased the AR protein level, whereas it simultaneously reduced the endogenous p21WAF1-protein 8-fold and the activity of a transiently transfected p21-promoter-reporter 10-fold. The down regulation of p21WAF1 promoter appeared to be ARE mediated, dependent on AR, and not cell-type specific. Furthermore, a reduction of the AR level in AI cells by AR-antisense oligonucleotide increased the p21WAF1 promoter-reporter activity by approximately 4-fold, confirming a functional link between these two proteins. A strong, direct induction of p21WAF1 expression achieved by treatment of AI cells with trichostatin A produced a partial reversion of the AI phenotype evidenced by increased sensitivity of these cells to paclitaxel-induced apoptosis. Moreover, a reduction of AR level by antisense treatment, which also increased p21WAF1 expression, partially restored the androgen dependence of AI cells for growth. The functional link between AR dosage and p21WAF1 expression suggests that therapeutic reduction of AR protein in advanced prostate cancers with elevated AR levels may re-establish their hormone dependence and improve therapeutic response to repeated hormonal ablation and/or induction of apoptosis. PMID- 11606393 TI - Cross-resistance to the synthetic retinoid CD437 in a paclitaxel-resistant human ovarian carcinoma cell line is independent of the overexpression of retinoic acid receptor-gamma. AB - Treatment of ovarian carcinomas with the antimitotic antitumor drug paclitaxel is highly efficacious. However, development of drug resistance presents a major obstacle. The common cellular phenotypes associated with paclitaxel resistance are an increased expression of the drug transport protein P-glycoprotein (P-gp), an alteration in the levels of beta-tubulin isotypes, and/or changes in the drug binding affinity of the microtubules. We established two paclitaxel-resistant human ovarian carcinoma cell lines. The 2008/17/4 cells exhibited a "classic" multidrug-resistant phenotype (overexpression of P-gp associated with cross resistance to natural product drugs), whereas the 2008/13/4 cells were an atypical multidrug-resistant subline (no overexpression of P-gp). In addition to being paclitaxel resistant (250-fold), the 2008/13/4 cells were also cross resistant to etoposide (39-fold) and vincristine (460-fold). To identify the alterations in the gene expression profile associated with the development of atypical paclitaxel resistance, we used the Clontech Atlas Human Cancer cDNA Microarray (spotted with 588 genes). The expression of retinoic acid receptor (RAR)-gamma was significantly higher in the paclitaxel-resistant (2008/13/4 and 2008/17/4) cells than in the parental (2008) cells. Northern blotting analysis demonstrated that the expression of RAR-gamma was 7-fold higher in the 2008/13/4 and 2008/17/4 cells than in the 2008 cells, whereas the expression of RAR-alpha and RAR-beta was not observed in any cell line. Whereas the 2008, 2008/13/4, and 2008/17/4 cells were found to resist the antiproliferative effects of all-trans retinoic acid, the paclitaxel-resistant cells were 6- to 7-fold cross-resistant to the antiproliferative effects of CD437 (a synthetic RAR-gamma-selective agonist; 6-[-(1-admantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid) compared with the sensitivity of the parental cells. To further understand the association of paclitaxel and CD437 resistance with the observed RAR-gamma overexpression, we transfected the 2008 cells with a full-length RAR-gamma cDNA construct. Two transfectants with increased expression of the RAR-gamma mRNA and protein were isolated and subjected to growth inhibition assays in the presence of various concentrations of paclitaxel, etoposide, vincristine, and CD437. The sensitivity of the 2008 transfected clones (displaying increased expression of RAR-gamma) to the cytotoxic effects of paclitaxel, etoposide, vincristine, and CD437 was similar to that observed in the parental 2008 cells. These results suggest that the overexpression of RAR-gamma (observed in the 2008/13/4 and 2008/17/4 cells) by itself is not capable of inducing paclitaxel and CD437 resistance (or resistance to etoposide and vincristine). PMID- 11606394 TI - Recombinant CD40 ligand therapy has significant antitumor effects on CD40 positive ovarian tumor xenografts grown in SCID mice and demonstrates an augmented effect with cisplatin. AB - CD40 is a member of the tumor necrosis factor receptor family and was first identified with a monoclonal antibody raised against bladder carcinoma. Recombinant human CD40L has been shown previously to have a direct antitumor effect on an ovarian cancer cell line and ovarian carcinoma cells isolated from ascites fluid. We show here that rhuCD40L inhibits the growth of several ovarian adenocarcinomas derived from surgical specimens and grown as xenografts in severe combined immunodeficient mice. Two 14-day treatment cycles were more effective than one. This effect is apparently not mediated by natural killer cells, because blocking natural killer cell activity by antiasialo GM-1 did not diminish this effect. In addition to suppression of tumor growth, treatment with rhuCD40L resulted in an increased expression of FasL, an increase in apoptosis, and histological changes including increased fibrosis and areas of tumor destruction. Using this model, we examined the efficacy of rhuCD40L in combination with chemotherapeutic agents. The antitumor effect of rhuCD40L in combination with 4 mg/kg cisplatin (CDDP) was increased over the effect of CDDP alone. Furthermore, rhuCD40L increased the efficacy of a suboptimal dose of CDDP (2mg/kg) such that it matched that of high-dose CDDP alone. These data suggest a role for rhuCD40L therapy in combination with platinum based regimens for primary treatment of epithelial ovarian tumors. PMID- 11606395 TI - Administration of interleukin-12 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines in mouse hepatocellular carcinoma. AB - Dendritic cells (DCs) are potent antigen-presenting cells that are capable of priming systemic antitumor immune response. Here, we evaluated the combined effectiveness of tumor lysate-pulsed DC immunization and interleukin (IL)-12 administration on the induction of antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. Mouse DCs were pulsed with lysate of BNL 1ME A.7R.1 (BNL), a BALB/c-derived HCC cell line, and then injected into syngeneic mice in combination with systemic administration of IL-12. Lymphocytes from mice treated with BNL lysate-pulsed DCs and IL-12 showed stronger cytolytic activity and produced higher amounts of IFN-gamma than those from mice treated with BNL lysate pulsed DCs alone. Although immunization with BNL lysate-pulsed DCs alone did not lead to complete regression of established tumors, it significantly inhibited tumor growth compared with vehicle injection. Importantly, the combined therapy of BNL lysate-pulsed DCs and IL-12 resulted in tumor rejection or significant inhibition of tumor growth compared with mice treated with BNL lysate-pulsed DCs alone. In vivo lymphocyte depletion experiments demonstrated that this combination was dependent on both CD8+ and CD4+ T cells, but not natural killer cells. These results demonstrated that IL-12 administration enhanced the therapeutic effect of immunization of tumor lysate-pulsed DCs against HCC in mice. This combination of IL-12 and DCs may be useful for suppressing the growth of residual tumor after primary therapy of human HCC. PMID- 11606396 TI - The infection of human dendritic cells with recombinant avipox vectors expressing a costimulatory molecule transgene (CD80) to enhance the activation of antigen specific cytolytic T cells. AB - Human dendritic cells (DCs) express MHC class I and II molecules and several T cell costimulatory molecules that contribute to their efficiency as antigen presenting cells (APCs). Whereas most human DC populations uniformly express some costimulatory molecules such as B7-2 (CD86), previous studies have shown a wide variation in the expression of B7-1 (CD80) among different human DC preparations. In the studies reported here, we demonstrate that replication-defective avipox vectors expressing B7-1 can be used to rapidly and efficiently infect human DCs and can enhance the efficacy of human DCs to activate specific human T-cell populations. This has been demonstrated both in systems using peptide as a source of signal 1 and in systems using recombinant avipox vector to deliver signal 1. The antigen used in these studies was the tumor-associated human carcinoembryonic antigen (CEA). An immunodominant 9-mer CTL epitope for CEA (designated CAP-1) has been previously characterized (K. Y. Tsang et al., J. Natl. Cancer Inst. (Bethesda), 87: 982-990, 1995). The source of signal 1 used in these studies was (a) the CAP-1 peptide; (b) recombinant avipox-CEA; or (c) the dual transgene recombinant avipox-CEA/B7-1. These studies demonstrate that CEA-specific T cells are more efficiently activated using as APCs peptide-pulsed DCs infected with avipox-B7-1, as compared with peptide-pulsed DCs infected with wild-type vector, or with uninfected peptide-pulsed DCs. Greater activation of CEA-specific T cells was also obtained using as APCs DCs that were infected with avipox-CEA/B7-1 as compared with the use of DCs infected with avipox-CEA. A CEA tetramer was also used to isolate high- and low-tetramer-binding CEA-specific T-cell populations. Although both high- and low-tetramer-binding T cells had the ability to lyse CEA peptide-pulsed targets, only the high-tetramer-binding T cells had the ability to lyse colon carcinoma cells expressing CEA, which suggests the existence of tetramer-binding populations with different T-cell receptor (TCR) affinities. The demonstrated safety of recombinant avipox vectors in humans and the previously demonstrated ability to administer them multiple times without host immune response limitations indicate that these vectors expressing B7-1 have a potential use in enhancing the efficacy of human DC immunotherapy protocols using either peptide or recombinant vector to deliver signal 1. PMID- 11606397 TI - Identification of helper T-cell epitopes that encompass or lie proximal to cytotoxic T-cell epitopes in the gp100 melanoma tumor antigen. AB - The melanocyte-associated antigen gp100 constitutes one of the most attractive targets for T-cell-based immunotherapy against malignant melanoma. Although several MHC class I-restricted epitopes have been identified for CTLs, thus far, only one MHC class II T helper epitope (restricted by HLA-DR4) has been described in the literature. Using an algorithm to identify promiscuous helper T-cell epitopes, here we describe three additional MHC class II-restricted epitopes from gp100. Whereas one T helper epitope, gp100(175-189), was restricted by the HLA DR53 and DQw6 alleles, the T-cell responses to two other epitopes, gp100(74-89) and gp100(576-590), were restricted by HLA-DR7. Most interestingly, the newly identified helper T lymphocyte epitopes encompass or lie proximal to previously described CTL epitopes for this tumor-associated antigen. Together with the previously described HLA-DR4-restricted epitope, these T helper epitopes offer coverage for the majority of the human population. Moreover, the use of peptide vaccines containing both CTLs and T helper epitopes could offer therapeutic advantages over current approaches that focus solely on eliciting antitumor CTL responses. PMID- 11606398 TI - Profiling of cancer cells using protein microarrays: discovery of novel radiation regulated proteins. AB - The advent of DNA microarray technology will likely have a major impact on the molecular classification and understanding of human cancer. Obtaining a global perspective of proteins expressed in cancer cells is considerably more challenging. Here we describe a microarray-based platform that can be used to measure protein levels and activities in a complex biological milieu such as a cellular lysate. Using a protein microarray made up of 1920 elements (146 distinct antibodies) we were able to monitor alterations of protein levels in LoVo colon carcinoma cells treated with ionizing radiation. The protein microarray approach revealed radiation-induced up-regulation of apoptotic regulators including p53, DNA fragmentation factor 40/caspase activated DNase, DNA fragmentation factor 45/inhibitor of caspase activated DNase, tumor necrosis factor-related apoptosis-inducing ligand, death receptor 5, decoy receptor 2, FLICE-like inhibitory protein, signal transducers and activators of transcription 1alpha, and uncoupling protein 2, among others. Consistent with this observation, an increased percentage of apoptosis was observed in irradiated LoVo cells. Interestingly, we also observed radiation-induced down-regulation of carcinoembryonic antigen, a prototypic cancer biomarker. Selected proteins assessed by microarray were validated by traditional immunoblotting. Taken together, our work suggests that protein/antibody microarrays will facilitate high-throughput proteomic studies of human cancer and carcinogenesis. PMID- 11606399 TI - Regulation of human telomerase activity: repression by normal chromosome 3 abolishes nuclear telomerase reverse transcriptase transcripts but does not affect c-Myc activity. AB - Telomerase is required for the complete replication of chromosomal ends. In tumors, the human telomerase reverse transcriptase subunit (hTERT) is up regulated, thereby removing a critical barrier for unlimited cell proliferation. To understand more about hTERT regulation, we measured hTERT RNA levels by quantitative reverse transcription (RT)-PCR. Telomerase-positive cell lines were found to contain between 0.2 and 6 molecules of spliced hTERT RNA per cell, whereas in telomerase-negative cells, the number of molecules was below the sensitivity of the assay (<0.004 molecules/cell). Intron-containing, immature hTERT RNA was observed only in nuclei of telomerase-positive cells, which suggests that hTERT RNA levels are transcriptionally regulated. Microcell transfer of a normal chromosome 3 into the human breast carcinoma cell line (21NT) abolishes telomerase activity and induces senescence. Endogenous hTERT transcripts were undetectable in the nuclei of 21NT-chromosome 3 hybrids, even in cells permanently expressing a transfected hTERT cDNA. However, chromosome 3 transfer did not affect the expression of green fluorescent protein reporter constructs driven by up to 7.4 kb of noncoding DNA flanking the 5' end of the hTERT gene. Because direct up-regulation of hTERT through c-Myc overexpression had previously been reported, we investigated whether chromosome 3 transfer affected c-Myc activity. An at least 30-fold reduction of immature intron containing hTERT RNA was observed after the introduction of a normal chromosome 3, but expression levels of c-Myc, Mad1, and other c-Myc target genes were unchanged. Our results suggest that telomerase is regulated primarily at the level of hTERT transcription by complex mechanisms involving regulatory elements distant from the 5' flanking region, and that the putative hTERT repressor on chromosome 3 does not regulate the expression of hTERT through c-Myc or one of its coregulators. PMID- 11606400 TI - Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair. AB - Loss of DNA mismatch repair (MMR) increases the risk of spontaneous mutations. We sought to determine whether there was an interaction between hypoxia and MMR deficiency that might contribute to the phenomenon of tumor progression. Human colon carcinoma HCT116+ch2 (MMR-deficient) and HCT116+ch3 (MMR-proficient) sublines were exposed for varying periods of time to an environment of <0.1% O2 and pH as low as 6.1. When a population containing 5% MMR-deficient cells and 95% MMR-proficient cells was subjected to hypoxia for 72 h, the MMR-deficient cells were enriched by a factor of 2-fold in the surviving population, whereas no enrichment was detected in cells maintained under aerobic conditions. The potential of hypoxia to destabilize the genome was determined by measuring the frequency of clones in the surviving population resistant to very high concentrations of 6-thioguanine or cisplatin. A 72-h exposure to hypoxia did not increase the frequency of resistant clones in the MMR-proficient cells but produced a 7.8-fold increase in 6-thioguanine-resistant clones and a 2.5-fold increase in cisplatin-resistant clones in the MMR-deficient cells. Loss of MMR increased the frequency of mutations in a reporter vector sensitive to frameshift mutations in a microsatellite sequence. Exposure to hypoxia for a time period as short as 48 h further increased the number of mutations in both cell types, but the absolute number of mutants was higher in the MMR-deficient cells. These results indicate that hypoxia and its accompanying low pH enrich for MMR deficient cells and that loss of MMR renders human colon carcinoma cells hypersensitive to the ability of hypoxia to induce microsatellite instability and generate highly drug-resistant clones in the surviving population. PMID- 11606401 TI - Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. AB - Blood relatives of patients with the inherited disease ataxia telangiectasia (A T) have an increased susceptibility for breast cancer. We therefore looked for sequence alterations of the ATM gene in a large hospital-based series of unselected breast cancer patients. The whole ATM coding sequence was analyzed in genomic DNA samples from a core group of 192 consecutive breast cancer cases to define the spectrum of ATM gene mutations. Common sequence alterations were then screened in the whole series of 1000 breast cancer patients and in 500 random individuals. In the core group, 21 distinct sequence alterations were identified throughout the ATM coding region, and 1 common splicing mutation was uncovered in intron 10. Almost half of the breast cancer patients (46%) were heterozygotes for 1 of 16 different amino acid substitutions, and three patients (1.6%) carried a truncating mutation. These data indicate that approximately 1 in 50 German breast cancer patients is heterozygous for an A-T-causing mutation. In our extended series, the most common A-T mutation 1066-6T-->G was disclosed in 7 of 1000 (0.7%) breast cancer patients. Transcript analyses indicated that the loss of exon 11 in the ATM mRNA was the pathogenic consequence of this splicing mutation, which produced a <10% of full-length ATM mRNA and ATM protein in a homozygous A-T patient. We also found an excess of rare missense substitutions in the breast cancer cohort compared with random individuals (7.9% versus 5.3% of alleles; odds ratio = 1.6; P < 0.01). One missense substitution, S707P in exon 15, was two times more frequent in breast cancer patients (odds ratio = 2.4; 95% confidence interval, 1.0-5.8) and five times more frequent in patients with bilateral disease than in random individuals (P < 0.001). We conclude that a large variety of distinct ATM mutations and variants exist among breast cancer patients, some of which can contribute to the etiology and progression of the malignancy. Screening for frequent A-T mutations such as the 1066-6-->G splice site substitution can be effective to prospectively identify A-T heterozygotes in an unselected cancer patient population. PMID- 11606402 TI - Nontruncating APC germ-line mutations and mismatch repair deficiency play a minor role in APC mutation-negative polyposis. AB - Familial adenomatous polyposis, an autosomal-dominantly inherited colorectal cancer predisposition syndrome, is caused by germ-line mutations in the adenomatous polyposis coli (APC) gene. Despite the use of different screening methods, studies worldwide fail to identify APC mutations in 20-50% of all familial adenomatous polyposis patients (APC mutation-negatives). In this study, missense mutations in the coding region of the APC gene, which would have been missed by the protein truncation test, as well as mutations in the APC promoter and the 3' untranslated region, were determined by the single nucleotide polymorphism discovery assay and direct DNA sequencing in 31 mutation-negative polyposis patients. Seventeen gene alterations were identified, whereof four (12.9%) represent possibly pathogenic germ-line mutations: silent A290T (promoter) and A8822G (3' untranslated region) as well as missense R99W and E1317Q (coding region). The 27 remaining, truly APC mutation-negative polyposis patients displayed a significantly later age at diagnosis compared with APC mutation carriers (46.1 versus 35.2 years; P < 0.01). APC mutation-negative individuals with >100 colonic polyps were more likely to present with extracolonic disease (P < 0.05) than those with <100. Assessment of microsatellite instability (MSI), a hallmark of mismatch repair deficiency, in 68 tumors from 21 truly APC mutation-negative patients, identified 4 (5.9%) unstable tubulo-villous adenomas (3 MSI-High and 1 MSI-Low), stemming from 4 (19%) unrelated individuals and likely to be caused by hMLH1 promoter hypermethylation. In conclusion, only a small proportion of APC germ-line mutation carriers is missed by the protein truncation test, and mismatch repair deficiency does not seem to substantially contribute to tumor development in APC mutation-negative polyposis patients. PMID- 11606403 TI - Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates. AB - To determine the frequency and distribution of mitochondrial DNA mutations in breast cancer, 18 primary breast tumors were analyzed by direct sequencing. Twelve somatic mutations not present in matched lymphocytes and normal breast tissues were detected in 11 of the tumors screened (61%). Of these mutations, five (42%) were deletions or insertions in a homopolymeric C-stretch between nucleotides 303-315 (D310) within the D-loop. The remaining seven mutations (58%) were single-base substitutions in the coding (ND1, ND4, ND5, and cytochrome b genes) or noncoding regions (D-loop) of the mitochondrial genome. In three cases (25%), the mutations detected in coding regions led to amino acid substitutions in the protein sequence. We then screened an additional 46 primary breast tumors with a rapid PCR-based assay to identify poly-C alterations in D310, and we found seven more cancers with alterations. Using D310 mutations as clonal marker, we detected identical changes in five of five matched fine-needle aspirates and in four of four metastases-positive lymph nodes. The high frequency of D310 alterations in primary breast cancer combined with the high sensitivity of the PCR-based assays provides a new molecular tool for cancer detection. PMID- 11606404 TI - Structural fragility of blood vessels and peritoneum in calponin h1-deficient mice, resulting in an increase in hematogenous metastasis and peritoneal dissemination of malignant tumor cells. AB - We have observed weak expression of calponin h1, which stabilizes the actin filament system, in blood vessels within human malignant tumors. This observation suggested that because of a deficiency in stabilization by calponin h1, the structure of blood vessels in malignant tumors is fragile compared with blood vessels in normal tissues. We therefore generated calponin h1-deficient (CN(-/-)) mice to examine the effect of calponin h1 on the integrity of the barrier system in blood vessels against cancer metastasis. The CN(-/-) mice exhibited morphological fragility of the tissues, including the uterus and blood vessels. In particular, we frequently observed bleeding into the surrounding tissue from blood vessels of the ocular fundus in CN(-/-) mice. In addition, mesothelial cells, which usually express calponin h1 in normal (CN(+/+)) mice, were retracted in the CN(-/-) mice. When fluorescein was injected i.v. into mice, the CN(-/-) mice exhibited a greater and more rapid leakage of fluorescein from the blood vessels of the ocular fundus compared with the CN(+/+) mice. In the CN(-/-) mice receiving i.v. inoculations of B16 melanoma cells, significantly more metastatic nodules were formed in the lung than in the CN(+/+) mice. When B16 melanoma cells were injected i.p., the severity of peritonitis carcinomatosa was greater in CN( /-) than in CN(+/+) mice. These results indicate that calponin h1 plays an important role in the regulation of the integrity of the blood vessels and peritoneum, which in turn is an important factor influencing the frequency of cancer metastasis. The CN(-/-) mice, which exhibit fragile blood vessels and peritoneum, could serve as sensitive and useful host models to investigate cancer metastasis. PMID- 11606405 TI - Requirement for Mdm2 in the survival effects of Bcr-Abl and interleukin 3 in hematopoietic cells. AB - The p53/Mdm2 pathway plays an important role in the induction of cell cycle arrest or apoptosis in response to genotoxic stress. Both the oncogene Bcr-Abl and physiological growth factors such as interleukin (IL)-3 can modulate the outcome of cellular exposure to DNA damage. To determine whether Bcr-Abl and growth factors can affect the p53/Mdm2 pathway, we studied the expression of Mdm2 in the IL-3-dependent pre-B cell line BaF3 and its bcr-abl-transfected derivative BaF3p185 after IL-3 deprivation or treatment with the c-Abl tyrosine kinase inhibitor STI571. We found that both growth factor withdrawal and inhibition of Bcr-Abl kinase lead to a down-regulation of Mdm2 preceding the induction of apoptosis. Apoptotic cell death induced by STI571 is partially dependent on p53. The early decrease of Mdm2 protein was not attributable to transcriptional regulation or to caspase-mediated cleavage. On the other hand, it could be completely blocked by the proteasomal inhibitor lactacystin. Targeted down regulation of Mdm2 protein by antisense oligodeoxynucleotides overcame the survival effects of IL-3 and Bcr-Abl and resulted in accelerated apoptosis. Taken together, survival signals provided either by physiological growth factors or by oncogenic Bcr-Abl can positively regulate Mdm2, whereas Mdm2 ablation can reduce cell survival. These findings imply that, similarly to physiological growth factors such as IL-3, Bcr-Abl can promote cell survival through modulating the p53-Mdm2 pathway. PMID- 11606406 TI - HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma. AB - We investigated the role of alterations of HDM2, the human homologue of murine mdm2, in the tumorigenesis and progression of cutaneous melanoma. A well characterized cohort of 172 cases representing different points in the spectrum of melanocyte transformation (16 dysplastic nevi, 11 melanomas in situ, 107 invasive primaries, and 38 metastatic lesions), as well as 11 human melanoma cell lines were examined by immunohistochemistry and Western blotting for HDM2 protein expression, and by either Southern blotting (SB) or fluorescence in situ hybridization for HDM2 gene amplification. HDM2 overexpression, defined as >20% tumor cells showing nuclear immunoreactivity, was observed in 1 of 16 (6%) dysplastic nevi, 3 of 11 (27%) melanomas in situ, and 81 of 145 (56%) invasive primary and metastatic melanomas. Comparable frequencies of HDM2 overexpression were observed among invasive primary cases with differing tumor thicknesses as well as among the metastatic cases: 21 of 40 (53%) at < or =1.5 mm; 31 of 50 (62%) at 1.6-3.9 mm; 10 of 17 (58%) at >4 mm; and 19 of 38 (50%) metastases. HDM2 amplification was observed in 1 of 88 (1%) primary cases using fluorescence in situ hybridization, and in 0 of 12 (0%) metastatic cases that overexpressed HDM2 using SB. Melanoma cell lines expressed HDM2 protein, but there was no evidence of amplification by SB. Our data suggest that HDM2 protein overexpression is common in invasive and metastatic melanoma. Observing HDM2 overexpression in noninvasive melanoma suggests that expression of this oncogene may play an early role in melanocyte transformation. HDM2 amplification occurs infrequently, and other mechanisms that up-regulate HDM2 expression are under investigation. PMID- 11606407 TI - Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. AB - The roles of the protein-serine/threonine kinase, Akt1, in signaling pathways associated with cell motility and extracellular matrix invasion were examined in the immortalized mouse mammary epithelial cell line, COMMA-1D. COMMA-1D cells were engineered to express the avian leukosis subtype A receptor, tv-a, to permit infection by recombinant avian leukosis virus produced by the replication competent avian splice vector, RCAS. COMMA-1D/tv-a cells transduced with RCAS/v akt, but not RCAS/Akt1, formed anchorage-independent colonies in soft agar; however, cells overexpressing either v-akt or Akt1 became highly invasive when grown on the ECM, Matrigel. Zymography of extracellular protease activity shed into the medium by COMMA-1D/Akt1 or COMMA-1D/v-akt cells revealed elevated gelatinase activity that was confirmed to be matrix metalloproteinase-2 (MMP-2; gelatinase A) by Western blotting and immunoprecipitation-zymography. The MMP inhibitor, BB-94, blocked MMP-2 activity and invasion associated with Akt1- and v akt-expressing cells. The proteasome inhibitor, lactacystin, markedly increased MMP-2 levels and invasion in control cells but not in Akt1- and v-akt-expressing cells. These results suggest that the invasive behavior of mammary epithelial cells induced by Akt1 is associated with increased MMP-2 expression that may result from inhibition of MMP-2 degradation by the proteasome pathway. PMID- 11606408 TI - Mobilized human CD34+ hematopoietic stem cells enhance tumor growth in a nonobese diabetic/severe combined immunodeficient mouse model of human non-Hodgkin's lymphoma. AB - Autologous peripheral blood stem cell mobilization is increasingly applied in the treatment of hematological malignancies. Despite the frequent clinical use in a setting of residual disease, it is not known whether mobilization of hematopoietic stem cells might facilitate tumor outgrowth in vivo. In the bone marrow, a bipotential precursor for hematopoietic and endothelial cells called hemangioblast exists. This hemangioblast, characterized by the expression of CD34 and vascular endothelial growth factor receptor (VEGFR)-2, is released from the bone marrow by mobilization and might be able to result in not only the generation of peripheral blood cells but vasculogenesis due to differentiation of the hemangioblast along the endothelial lineage [in addition to VEGFR-2 expression, angiopoietin-2 (ANG-2) expression can also be found in this stage]. New vessel formation in the tumor is critical for tumor growth. A xenotransplant model was established with 10 x 10(6) Daudi cells (non-Hodgkin's lymphoma) s.c. injected in the neck region of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, who were sublethally irradiated with 2 Gy. At day 10 after tumor inoculation, half of the mice were given 0.5 x 10(6) human CD34+ cells i.v., whereas the other half were given PBS i.v. The human CD34+ cells were obtained from leukapheresis samples of myeloma patients undergoing autologous peripheral blood stem cell mobilization. We compared tumor growth and human-specific VEGFR-2 and ANG-2 expression in the two groups. Tumor growth is enhanced 2-fold when mobilized hematopoietic human CD34+ cells are given compared with PBS controls (P = 0.004). In addition, the human-specific VEGFR-2 and ANG-2 reverse transcription PCR was only positive in the tumors of mice i.v. injected with human CD34+ cells. This indicates that the injected human CD34+ cells home to the tumors and differentiate along the endothelial lineage. In the present study, we demonstrate that mobilized human CD34+ hematopoietic cells injected i.v. might facilitate the outgrowth of tumors in the setting of minimal residual disease. Malignant tumors are capable of incorporating human CD34+ hematopoietic cells. This study questions the safety of leukapheresis in patients with (residual) tumor and has important implications for further development of intensive chemotherapy protocols with autologous stem cell rescue. PMID- 11606409 TI - Neither p21WAF1 nor 14-3-3sigma prevents G2 progression to mitotic catastrophe in human colon carcinoma cells after DNA damage, but p21WAF1 induces stable G1 arrest in resulting tetraploid cells. AB - p21WAF1 and 14-3-3sigma, which are both transcriptional products of p53, have been reported to play a role in the G2 DNA damage checkpoint in mammalian cells. Human colon carcinoma cells, isogenic except for the presence or absence of either p21WAF1 or 14-3-3sigma (T. A. Chan et al., Genes Dev., 14: 1584-1588, 2000), are useful models for analysis of the role of these proteins in checkpoint control. Here, we have examined mitotic behavior within a single cell cycle after DNA damage in these cell lines. Our results show that p21WAF1, but not 14-3 3sigma, imposes a significant G2 delay after DNA damage. After G2 delay, we found that all isogenic cells, including those competent for both p21WAF1 and 14-3 3sigma, adapt to the DNA damage checkpoint and progress into mitosis, where they undergo incomplete chromosome segregation and reenter G1 with a tetraploid DNA content. Strikingly, our results show that p21WAF1, but not 14-3-3sigma, activates a checkpoint in response to DNA damage that prevents continued cycling of the tetraploid cells that result from a mitotic catastrophe characterized by failure to complete cell division. These results demonstrate that a tetraploid DNA content is not a reliable criterion to establish that arrest occurs in G2. Also, the DNA damage checkpoint mediated by p53-dependent induction of p21WAF1 assures neither G2 arrest nor DNA repair sufficient to enable accurate chromosome segregation in human colon carcinoma cells. We conclude that p21WAF1, but not 14 3-3sigma, has a unique role in the induction of G1 arrest in tetraploid cells that results from mitotic catastrophe after DNA damage. PMID- 11606410 TI - Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. AB - In the first Phase I clinical trials of endostatin as an antiangiogenic therapy for cancer, the protein was administered as an i.v. bolus for approximately 20-30 min each day. This protocol was based on experimental studies in which animals were treated by s.c. bolus once a day. However, it was not clear in the previous studies whether this schedule could be maximized further. Therefore, we developed experimental models involving continuous administration of endostatin to determine the potency and efficacy of this approach. Endostatin was administered to tumor-bearing mice either s.c. or i.p. in single bolus doses. The efficacy of these regimens was compared with endostatin administered continuously via an i.p. implanted mini-osmotic pump. Our results show that endostatin remains stable and active in mini-osmotic pumps for at least 7 days. We show that endostatin injected i.p. is rapidly cleared within 2 h, whereas endostatin administered continuously via mini-osmotic pump maintains systemic concentrations of 200-300 ng/ml for the duration of administration. Furthermore, continuous i.p. administration of endostatin results in more effective tumor suppression at significantly reduced doses (5-fold), compared with bolus administration. Additional experiments using a human pancreatic cancer model in severe combined immunodeficient mice showed that there was a significant decrease in the microvessel density between the treatment groups and the control group. These data show that continuous administration of human endostatin results in sustained systemic concentrations of the protein leading to: (a) increased efficacy manifested as increased tumor regression; and (b) an 8-10-fold decrease in the dose required to achieve the same antitumor effect as the single daily bolus administration of endostatin. On the basis of this approach, an additional clinical trial has been designed and initiated and is under way in two countries. PMID- 11606411 TI - Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma. AB - Retinoids induce apoptosis and differentiation of hepatocellular carcinoma (HCC) cells and are used clinically in the chemoprevention of HCC. We have shown previously that hepatocarcinogenesis is accompanied by accumulation of full length retinoid X receptor alpha (RXRalpha), although the underlying mechanisms and biological implications have remained unclear. The present studies were based on the finding that the accumulated full-length RXRalpha was phosphorylated at serine/threonine residues both in all human HCC tissues examined and in human HCC derived HuH7 cells. Phosphorylation at serine 260 of RXRalpha, a consensus site of mitogen-activated protein kinase, was closely linked to its retarded degradation, low transactivating activity, and the promotion of cancer cell growth. There was no genomic mutation in the RXRalpha gene, and abrogation of phosphorylation by mitogen-activated protein kinase-specific inhibitors restored the degradation of RXRalpha in an RXR ligand-dependent manner. These results suggest that phosphorylation of RXRalpha may interfere with its metabolism and signaling in human HCC, which could lead to growth promotion of these tumors. PMID- 11606412 TI - Genetic subgroups of anaplastic astrocytomas correlate with patient age and survival. AB - Astrocytomas are brain tumors with variable responses to radiation and chemotherapy. Tumor grade and patient age are important prognostic factors but do not account for the variability in clinical outcome. We hypothesized that genetic subgroups play a role in the outcome of grade III astrocytomas and studied 80 grade III astrocytomas by comparative genomic hybridization. Some chromosomal aberrations (+7p/q, -9p, -10q, -13q, +19q) were related to aberrations that are frequent in grade IV astrocytoma, whereas others (+10p, -11q, +11p, -Xq) were more frequent in grade III astrocytoma. +7p, +19 and -4q were more frequent in tumors from older patients while -11p was more frequent in tumors from younger patients. Finally, gains of 7p and 7q were associated with shorter patient survival, independent of age. Our results indicate that genetic events underlie the well-known effects of age on survival in grade III astrocytoma and demonstrate the importance of molecular classification in astrocytic tumors. PMID- 11606413 TI - Indomethacin-induced radiosensitization and inhibition of ionizing radiation induced NF-kappaB activation in HeLa cells occur via a mechanism involving p38 MAP kinase. AB - Although ionizing radiation (IR) activates multiple cellular factors that vary depending on dose and tissue specificity, the activation of NF-kappaB appears to be a well-conserved response in tumor cells exposed to IR. Recently, it also has been demonstrated that nonsteroidal anti-inflammatory agents inhibit tumor necrosis factor and interleukin-1-induced NF-kappaB activation and act as radiosensitizing agents. These observations reinforce the growing notion that NF kappaB may be a protective cellular factor responding to the cytotoxicity of IR and other damaging stimuli. As such, we addressed the idea and mechanism that NF kappaB is a downstream target of the nonsteroidal anti-inflammatory agent indomethacin and is involved in the process of radiosensitization. In this study, we report that indomethacin inhibited IR-induced activation of NF-kappaB and sensitized HeLa cells to IR-induced cytotoxicity at similar concentrations. Pretreatment of HeLa cells with SB 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (MAPK), abrogated the ability of indomethacin to inhibit IR-induced activation of NF-kappaB and diminished the indomethacin radiosensitizing effect. In addition, the transient genetic activation of p38(MAPK) inhibited IR induction of NF-kappaB gene expression in the absence of indomethacin. Finally, permanently transfected cell lines genetically unable to activate NF-kappaB, because of expression of a dominant negative I-kappaBalpha gene, demonstrated increased sensitivity to IR induced cytotoxicity. Taken together, these results suggest that p38 MAPK is a target involved in indomethacin-induced radiosensitization and that NF-kappaB may be one downstream target in this process. PMID- 11606414 TI - Correspondence re: N. C. Denko and A. J. Giaccia, tumor hypoxia, the physiological link between Trousseau's syndrome (carcinoma-induced coagulopathy) and metastasis. Cancer Res., 61: 795-798, 2001. PMID- 11606415 TI - Correspondence re: Y. Yamada et al., frequent beta-catenin gene mutations and accumulations of the protein in the putative preneoplastic lesions lacking macroscopic aberrant crypt foci appearance, in rat colon carcinogenesis. Cancer Res., 60: 3323-3327, 2000; and sequential analysis of morphological and biological properties of beta-catenin-accumulated crypts, provable premalignant lesions independent of aberrant crypt foci in rat colon carcinogenesis. Cancer Res., 61: 1874-1878, 2001. PMID- 11606416 TI - A Ras subfamily GTPase shows cell cycle-dependent nuclear localization. AB - Previously characterized Ras subfamily proteins have been found to be predominantly associated with the plasma membrane where they function in signal transduction pathways to convey extracellular signals to intracellular targets. Here, we provide evidence that the Dictyostelium Ras subfamily protein RasB has a novel subcellular localization and function. The protein is predominantly localized in the nucleus during most of the cell cycle. Furthermore, during mitosis and cytokinesis RasB assumes a diffuse cellular localization despite the fact that the nuclear membrane stays intact. The linkage between the position of RasB in the cell and division suggests that it may have a role in nuclear division. Consistent with this idea, rasB- cells exhibit severe growth defects and cells overexpressing an activated version of RasB are multinucleate. PMID- 11606417 TI - The cyclin B1 gene is actively transcribed during mitosis in HeLa cells. AB - In mammalian cells, the expression level of the cyclin B1 gene plays a critical role in the progression through mitosis. Here we demonstrate that the transcriptional activity of the human cyclin B1 promoter, as well as the rate of gene transcription, is high during mitosis. Indeed, the cyclin B1 promoter maintains an open chromatin configuration at the mitotic stage. Consistent with this, we show that the cyclin B1 promoter is occupied and bound to NF-Y during mitosis in vivo. Our results provide the first example of RNA polymerase II dependent transcription during mitosis in mammalian cells. PMID- 11606418 TI - A hybrid bacterial replication origin. AB - We constructed a hybrid replication origin that consists of the main part of oriC from Escherichia coli, the DnaA box region and the AT-rich region from Bacillus subtilis oriC. The AT-rich region could be unwound by E. coli DnaA protein, and the DnaB helicase was loaded into the single-stranded bubble. The results show that species specificity, i.e. which DnaA protein can do the unwinding, resides within the DnaA box region of oriC. PMID- 11606419 TI - Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. AB - The p53 protein maintains genomic integrity through its ability to induce cell cycle arrest or apoptosis in response to various forms of stress. Substantial regulation of p53 activity occurs at the level of protein stability, largely determined by the activity of the Mdm2 protein. Mdm2 targets both p53 and itself for ubiquitylation and subsequent proteasomal degradation by acting as an ubiquitin ligase, a function that needs an intact Mdm2 RING finger. For efficient degradation of p53 nuclear export appears to be required. The Mdmx protein, structurally homologous to Mdm2, does not target p53 for degradation, but even stabilizes both p53 and Mdm2, an activity most likely mediated by heterodimerization of the RING fingers of Mdm2 and Mdmx. Here we show that Mdmx expression leads to accumulation of ubiquitylated, nuclear p53 but does not significantly affect the Mdm2-mediated ubiquitylation of p53. In contrast, Mdmx stabilizes Mdm2 by inhibiting its self-ubiquitylation. PMID- 11606421 TI - The cystic fibrosis transmembrane conductance regulator (CFTR) inhibits ENaC through an increase in the intracellular Cl- concentration. AB - Activation of the CFTR Cl- channel inhibits epithelial Na+ channels (ENaC), according to studies on epithelial cells and overexpressing recombinant cells. Here we demonstrate that ENaC is inhibited during stimulation of the cystic fibrosis transmembrance conductance regulator (CFTR) in Xenopus oocytes, independent of the experimental set-up and the magnitude of the whole-cell current. Inhibition of ENaC is augmented at higher CFTR Cl- currents. Similar to CFTR, ClC-0 Cl- currents also inhibit ENaC, as well as high extracellular Na+ and Cl- in partially permeabilized oocytes. Thus, inhibition of ENaC is not specific to CFTR and seems to be mediated by Cl-. PMID- 11606420 TI - Yarrowia lipolytica Pex20p, Saccharomyces cerevisiae Pex18p/Pex21p and mammalian Pex5pL fulfil a common function in the early steps of the peroxisomal PTS2 import pathway. AB - Import of peroxisomal matrix proteins is essential for peroxisome biogenesis. Genetic and biochemical studies using a variety of different model systems have led to the discovery of 23 PEX genes required for this process. Although it is generally believed that, in contrast to mitochondria and chloroplasts, translocation of proteins into peroxisomes involves a receptor cycle, there are reported differences of an evolutionary conservation of this cycle either with respect to the components or the steps involved in different organisms. We show here that the early steps of protein import into peroxisomes exhibit a greater similarity than was thought previously to be the case. Pex20p of Yarrowia lipolytica, Pex18p and Pex21p of Saccharomyces cerevisiae and mammalian Pex5pL fulfil a common function in the PTS2 pathway of their respective organisms. These non-orthologous proteins possess a conserved sequence region that most likely represents a common PTS2-receptor binding site and di-aromatic pentapeptide motifs that could be involved in binding of the putative docking proteins. We propose that not necessarily the same proteins but functional modules of them are conserved in the early steps of peroxisomal protein import. PMID- 11606422 TI - Minireview: aromatase and the regulation of estrogen biosynthesis--some new perspectives. AB - There is a growing awareness that androgens and estrogens have general metabolic roles that are not directly involved in reproductive processes. These include actions on vascular function, lipid and carbohydrate metabolism, as well as bone mineralization and epiphyseal closure, in both sexes. In postmenopausal women, as in men, estrogen is no longer solely an endocrine factor, but instead is produced in a number of extragonadal sites and acts locally at these sites in a paracrine and intracrine fashion. These sites include breast, bone, vasculature, and brain. Within these sites, aromatase action can generate high levels of E2 locally without significantly affecting circulating levels. Circulating C(19) steroid precursors are essential substrates for extragonadal estrogen synthesis. The levels of these androgenic precursors decline markedly with advancing age in women, possibly from the mid to late reproductive years. This may be a fundamental reason why women are at increased risk for bone mineral loss and fracture and possibly decline of cognitive function, compared with men. Aromatase expression in these various sites is under the control of tissue-specific promoters regulated by different cohorts of transcription factors. Thus, in principle, it should be possible to develop selective aromatase modulators that block aromatase expression, for example, in breast, but allow unimpaired estrogen synthesis in other tissues such as bone. PMID- 11606423 TI - Editorial: pulsatile hormone patterns governing transcription factor function. Physiology of episodic GH secretion. PMID- 11606424 TI - Temporal relationship between the sexually dimorphic spontaneous GH secretory profiles and hepatic STAT5 activity. AB - STAT5 transduces transcriptional responses to GH in liver and other tissues and is proposed to mediate the sexually dimorphic effects of plasma GH secretory profiles on rodent liver gene expression. Previous studies have suggested that STAT5 undergoes repeated activation in direct response to successive GH pulses in adult male rats, with STAT5 activation being desensitized in females by their more persistent pattern of GH exposure. These findings, however, were based on in vitro studies or single blood samples analyzed for GH in vivo. In view of the highly pulsatile nature of rat GH secretion, we presently examined these hypotheses by concurrent monitoring of spontaneous GH secretory profiles and hepatic STAT5 activity in conscious, free-moving adult male and female rats. Rats were killed at times associated with spontaneous peaks or troughs of the GH rhythm; livers were removed and analyzed for STAT5 DNA-binding activity. In males, liver STAT5 activity was highest during the initial phase (15-60 min) of a GH secretory episode (mean +/- SE relative STAT5 activity = 86.5 +/- 11.4; plasma GH = 146.7 +/- 22.4 ng/ml) and was significantly lower (P < 0.01) during the downswing of a pulse, 45-75 min after the GH peak (STAT5 = 26.1 +/- 1.7; GH = 33.3 +/- 13.1 ng/ml), consistent with a time-dependent down-regulation of GH signaling to STAT5. The lowest STAT5 activity was observed during the subsequent GH trough period (STAT5 = 3.6 +/- 1.1; GH = 2.6 +/- 0.1 ng/ml). In females, liver STAT5 activity was significantly lower (P < 0.05) than peak male levels during the initial phase of a GH secretory burst (STAT5 = 35.1 +/- 15.9; GH = 68.1 +/- 31.6 ng/ml) although similar to that of males during a plasma GH nadir (STAT5 = 11.0 +/- 2.6; GH = 8.4 +/- 2.2 ng/ml). We conclude that: 1) liver STAT5 is repeatedly activated by successive, spontaneous GH secretory episodes in intact adult male rats at approximately 3- to 3.5-h intervals; 2) time-dependent down regulation of GH signaling to hepatic STAT5 in vivo begins by 45 min after GH peak stimulation; and 3) the lower level of liver STAT5 activation seen in adult female rats, compared with males, is a consequence of the sex-dependent differences in GH secretory patterns that characterize these animals (i.e. lower amplitude GH pulses and lack of prolonged interpulse nadir of GH in the feminine, compared with masculine profile). PMID- 11606425 TI - High neonatal leptin exposure enhances brain GR expression and feedback efficacy on the adrenocortical axis of developing rats. AB - Leptin modifies the activity of the hypothalamic-pituitary-adrenal axis in adult rodents and inhibits the production of glucocorticoids from human and rat adrenals in vitro. During development, high levels of circulating leptin and low levels of corticosterone secretion are observed together with adrenal hyporesponsiveness to stress. As chronic neonatal leptin administration reduced stress-induced corticotropin-releasing factor mRNA expression and ACTH secretion in pups, we determined whether elevated leptin levels enhanced the feedback effect of glucocorticoids on the hypothalamic-pituitary-adrenal axis. In naive pups we found a highly significant inverse relationship between plasma levels of leptin and corticosterone (P < 0.01) during postnatal d 6-20. We tested the ability of dexamethasone (1 or 10 microg/kg BW, ip, -3 h before stress) to suppress ether-induced ACTH secretion in 10-d-old pups that were treated during the neonatal period (d 2-9) with either vehicle or leptin (1 or 3 mg/kg BW, ip, daily). The expressions of brain GR and MR in vehicle- or leptin-treated neonates were determined by in situ hybridization and Western blotting. Chronic leptin treatment enhanced the ability of dexamethasone to suppress ACTH secretion after stress, and the low dose of dexamethasone was discriminant. Leptin treatment increased GR mRNA levels in the hypothalamic paraventricular nucleus (P < 0.05) and in the dentate gyrus of the hippocampus in a dose-dependent fashion. Hippocampal GR protein concentrations were increased by leptin treatment (P < 0.05). Expression of MR mRNA was not modified. Thus, the ability of leptin to enhance glucocorticoid feedback in pups is mediated in part by changes in brain GR. The high circulating leptin concentrations found in developing pups might be critical to regulate glucocorticoid production, GR levels, and stress responses. As leptin levels in pups vary with maternal diet, leptin might represent an important mediator of the maternal environment on the infant. PMID- 11606426 TI - Biosynthesis of the neurosteroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha hp), a specific inhibitor of FSH release. AB - The gonadal steroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP) is a neuroactive steroid with anxiolytic and analgesic actions. In addition, 3 alpha HP has been shown to inhibit GnRH activity on gonadotropes and selectively suppress FSH release from pituitary cells, without an effect on LH. The enzyme 3 alpha-hydroxysteroid dehydrogenase (3 alpha HSD) has been presumed to be the enzyme responsible for the conversion of progesterone to 3 alpha HP, but this has never been confirmed in vitro or in vivo. We have now determined the mechanism of 3 alpha HP synthesis in vivo using specific enzyme inhibitors and in vitro using recombinant proteins. Incubation of [(3)H]progesterone with purified recombinant rat and human 3 alpha HSD isoforms showed that both the rat 3 alpha HSD and the human type 2(brain) 3 alpha HSD converted progesterone to 3 alpha HP. Age dependent 3 alpha HP production was demonstrated in pituitary and cortex. Incubation of both tissues with indomethacin, a known 3 alpha HSD inhibitor, decreased the conversion of progesterone to 3 alpha HP by at least 70%, indicating that 3 alpha HSD was responsible for this conversion. As human type 2 3 alpha HSD is expressed in a region-specific fashion in the brain, 3 alpha HP may only be made in specific regions of the brain. Furthermore, the data suggest that the pituitary has the capacity for 3 alpha HP production, which may provide an additional mechanism for regulation of GnRH action. PMID- 11606427 TI - Novel role of macrophage migration inhibitory factor in angiotensin II regulation of neuromodulation in rat brain. AB - Previously we determined that angiotensin II (Ang II) activates neuronal AT(1) receptors, located in the hypothalamus and the brainstem, to stimulate noradrenergic pathways. To link Ang II to the regulation of norepinephrine metabolism in neurons cultured from newborn rat hypothalamus and brainstem we have used cDNA arrays for high throughput gene expression profiling. Of several genes that were regulated, we focused on macrophage migration inhibitory factor (MIF), which has been associated with the modulation of norepinephrine metabolism. In the presence of the selective AT(2) receptor antagonist PD123,319 (10 microM), incubation of cultures with Ang II (100 nM; 1-24 h) elicited an increase in MIF gene expression. Western immunoblots further revealed that Ang II (100 nM; 1-24 h) increased neuronal MIF protein expression. This effect was inhibited by the AT(1) receptor antagonist losartan (10 microM), the PLC inhibitor U-73122 (10 or 25 microM), the PKC inhibitor chelerythrine (10 microM), and the Ca(2+) chelator 1,2-bis-[2-aminophenoxy]-ethane-N,N,N',N'-tetraacetic acid tetrakis acetoxymethyl ester (10 microM). Taken together with our observation that MIF is expressed in the terminal fields of noradrenergic neurons (hypothalamus) and that Ang II increases the expression of MIF in this region in vivo, our data may suggest a novel role of Ang II in norepinephrine metabolism. PMID- 11606428 TI - Isolation and characterization of a rat nitric oxide synthase type I gene promoter that confers expression and regulation in pituitary gonadotrope cells. AB - Nitric oxide synthase type I (NOS I) is expressed and up-regulated in rat pituitary gonadotrophs. Using rapid amplification of cDNA ends-PCR, 2 major transcripts with 5' ends corresponding to exon 1a but truncated of its first 369 or 384 nucleotides, indicative of two pituitary-specific transcription start sites, were identified. By chromosome walking, we isolated 5'-upstream of this truncated exon termed 1p, a novel -1653/+384-bp genomic region. Transient transfections, using the gonadotrope-derived alpha T3-1 and L beta T2 cell lines and the full-length or 5'-deleted sequences fused to a luciferase reporter gene, demonstrated that cell-specific positive and negative regions were present especially within the -246/-73 region, whereas the +12/+384 region was crucial for transcription. Moreover, in L beta T2 cells, the luciferase activity was increased by GnRH, with the full-length sequence being the most efficient and the -73/+60 region corresponding to the essential zone. The latter region was also crucial for cholera toxin-induced activation. Interestingly, GnRH and cAMP effects were not additive, implying a convergent step in the transduction cascade. These data provide evidence for the presence of several elements controlling NOS I expression in gonadotrophs and demonstrate that GnRH, the prime regulator of gonadotrope function, and cAMP may induce the transcription of NOS I in these cells. PMID- 11606429 TI - Up-regulation of upstream stimulatory factors by protein malnutrition and its possible role in regulation of the IGF-binding protein-1 gene. AB - Protein malnutrition drastically induces the expression of the IGF-binding protein-1 (IGFBP-1) gene. We have previously shown that the region between -77 and -112 bp upstream of the rat IGFBP-1 gene contributes to the response of this gene to amino acid limitation. In an attempt to elucidate the basis of the responsiveness of this putative amino acid response unit (AARU), we searched the nucleus of the rat liver for a trans-acting factor whose binding to AARU was dependent on protein nutrition. Liver nuclear extracts of rats fed a protein-free diet and of those fed a control diet were compared by EMSA using the AARU as probe. One of the protein-probe complexes underwent a drastic increase after dietary protein deprivation. Assays using specific antibodies and several competitor oligonucleotides led to identification of the protein composing the complex as upstream stimulatory factor-1 (USF) and USF-2. The binding site of the USF proteins in the AARU turned out to be a CACGGG sequence that was homologous to the consensus USF-binding sequence (E box; CANNTG). Further, Western blot analyses showed that a protein-free diet caused significant increases in USF-1 and USF-2 levels. Thus, elevated expression of the IGFBP-1 gene under protein malnutrition can be attributable to increased binding of USF to its promoter, which results from increased USF levels. The data suggest that the changes in these ubiquitously distributed transcription factors play an important role in the nutritional regulation of expression of mammalian genes. PMID- 11606430 TI - Unexpected virilization in male mice lacking steroid 5 alpha-reductase enzymes. AB - Mice lacking steroid 5 alpha-reductase 1 and 2 were produced by gene targeting and breeding. Male mice without 5 alpha-reductase 2 or without both enzymes had fully formed internal and external genitalia and were fertile, but had smaller prostates and seminal vesicles than controls. T accumulated to high levels in the reproductive tissues of the mutant mice. DHT administration increased seminal vesicle and coagulating gland weights in mice deficient in 5 alpha-reductase 2 and increased the weights of the prostate, seminal vesicle, and coagulating gland in animals deficient in both enzymes. An inhibitor of both 5 alpha-reductases (GI 208335X) decreased prostate and coagulating gland weights of control mice, but had no effect in those lacking 5 alpha-reductase 1 and 2. Castration reduced the sizes of these tissues in animals of all genotypes. Androgen-dependent gene expression was decreased in the seminal vesicles of mice lacking one or more 5 alpha-reductases and was restored by administration of T or DHT. Female mice missing both enzymes exhibited parturition and fecundity defects similar to those of animals without 5 alpha-reductase 1. We conclude that T is the only androgen required for differentiation of the male urogenital tract in mice and that the synthesis of DHT serves largely as a signal amplification mechanism. PMID- 11606431 TI - Signaling and antiproliferative effects mediated by GnRH receptors after expression in breast cancer cells using recombinant adenovirus. AB - GnRH receptors (GnRH-Rs) are found in human cancers, including those of the breast, and GnRH can inhibit the growth of cell lines derived from such cancers. Although pituitary and extrapituitary GnRH-R transcripts appear identical, their functional characteristics may differ. Most extrapituitary GnRH-Rs have low affinity for GnRH analogs and may not activate PLC or discriminate between agonists and antagonists in the same way as pituitary GnRH-Rs. Here we have assessed whether GnRH-Rs expressed exogenously in breast cancer cells differ from those in gonadotropes. We found no evidence for endogenous GnRH-Rs in MCF7 cells, but after infection with adenovirus expressing the GnRH-R (Ad GnRH-R) at a multiplicity of infection of 10 or greater, at least 80% expressed GnRH-Rs. These had high affinity (K(d) for [(125)I]buserelin, 1.4 nM) and specificity (rank order of potency, buserelin>GnRH>>chicken GnRH-II) and mediated stimulation of [(3)H]IP accumulation. Increasing viral titer [from multiplicity of infection, 3 300] increased receptor number (10,000-225,000 sites/cell) and [(3)H]IP responses. GnRH stimulated ERK2 phosphorylation in Ad GnRH-R-infected cells, and this effect, like stimulation of [(3)H]IP accumulation, was blocked by GnRH-R antagonists. GnRH also inhibited [(3)H]thymidine incorporation into Ad GnRH-R infected cells (but not control cells). This effect was mimicked by agonist analogs and inhibited by two antagonists. Thus, when exogenous GnRH-Rs are expressed at density comparable to that in gonadotropes, they are functionally indistinguishable from the endogenous GnRH-Rs in gonadotropes, and increasing expression of high affinity GnRH-Rs can dramatically enhance the direct antiproliferative effect of GnRH agonists on breast cancer cells. PMID- 11606432 TI - 1-(5-oxohexyl)-3,7-Dimethylxanthine, a phosphodiesterase inhibitor, activates MAPK cascades and promotes osteoblast differentiation by a mechanism independent of PKA activation (pentoxifylline promotes osteoblast differentiation). AB - We have investigated the effect of 1-(5-oxohexyl)-3,7-dimethylxanthine or pentoxifylline (PeTx), a nonselective phosphodiesterase inhibitor, on osteoblastic differentiation in vitro by using two mesenchymal cell lines, C3H10T1/2 and C2C12, which are able to acquire the osteoblastic phenotype in the presence of bone morphogenetic protein-2 (BMP-2). PeTx induced the osteoblastic markers, osteocalcin and Osf2/Cbfa1, in C3H10T1/2 and C2C12 cells and enhanced BMP-2-induced expression of osteocalcin, Osf2/Cbfa1, and alkaline phosphatase. This activity was partially attributed to the fact that PeTx is able to enhance BMP-2-induced Smad1 transcriptional activity. Although PeTx clearly stimulates PKA in these cells, neither pretreatment of cells with the PKA inhibitor H89 nor transfection with the specific PKA inhibitor PKI prevented the induction or enhancement of osteoblast markers by PeTx, demonstrating that these effects were independent of PKA activation. On the other hand, PeTx induced the activation of ERK1/2 and p38 kinase pathways independently of the activation of PKA. Selective inhibitors of these MAPK cascades prevented the induction of osteoblastic markers in cells treated with PeTx, suggesting that the activation of these two pathways plays a role in the effect of PeTx on osteoblastic differentiation. PMID- 11606434 TI - GATA4 mediates activation of the B-type natriuretic peptide gene expression in response to hemodynamic stress. AB - To identify the mechanisms that couple hemodynamic stress to alterations in cardiac gene expression, DNA constructs containing the rat B-type natriuretic peptide (BNP) promoter were injected into the myocardium of rats, which underwent bilateral nephrectomy or were sham-operated. Ventricular BNP mRNA levels were induced about 4-fold; and the BNP reporter construct containing the proximal 2200 bp, 5-fold, in response to 1-d nephrectomy. Deletion of sequences between bp 2200 and -114 did not affect basal or inducible activity of the BNP promoter. An activator protein-1-like site and two tandem GATA elements are located within this 114-bp sequence. Both deletion and mutation of the AP-1-like motif decreased basal activity but did not abolish the response to nephrectomy. In contrast, mutation or deletion of -90 bp GATA-sites abrogated the response to hemodynamic stress. The importance of these GATA elements to BNP promoter activation was further confirmed by the corresponding 38-bp oligonucleotide conferring hemodynamic stress responsiveness to a minimal BNP promoter. In gel mobility shift assays, nephrectomy increased left ventricular BNP GATA4 binding activity significantly. In conclusion, GATA elements are necessary and sufficient to confer transcriptional activation of BNP gene in response to hemodynamic stress. PMID- 11606433 TI - Desensitization of type 1 angiotensin II receptor subtypes in the rat kidney. AB - Differences involving serine residues in the sequence of the carboxyl-terminal tail of type 1 angiotensin II (Ang II) receptor subtypes AT(1A) and AT(1B) suggest differences in desensitization ability. We examined the Ang II-induced homologous desensitization patterns of both receptor subtypes in freshly isolated renal structures: glomerulus (Glom), afferent arteriole, and cortical thick ascending limb (CTAL), whose content in each subtype mRNA is different, by measuring variations in intracellular calcium concentration. A preexposure to a maximal dose of Ang II, followed by a second application of the same concentration, induced: 1) a complete desensitization in Glom, where AT(1A) and AT(1B) mRNAs were expressed in similar proportions, and 2) no or partial desensitization in afferent arteriole and CTAL, where AT(1A) mRNA was predominant. In the absence of nephron structure containing only AT(1B) mRNA, we studied rat anterior pituitary cells that exhibit high content in this subtype and observed that desensitization was not complete. In Glom, CTAL, and pituitary cells, desensitization proceeded in a dose-dependent manner. In Glom and CTAL, desensitization occurred via a PKC-independent mechanism. These results suggest that desensitization does not depend on the nature of Ang II receptor subtype but either on the proportion of each subtype in a given cell and/or on cell specific type. This could allow adaptive biological responses to Ang II appropriate to the specific function of a given cell type. PMID- 11606435 TI - Characterization of muscarinic acetylcholine receptor in rat Sertoli cells. AB - This study was designed to characterize muscarinic acetylcholine receptors (mAChRs) in primary cultured Sertoli cells from 30-d-old rats. RT-PCR was performed, and five PCR products corresponding to m1-m5 mAChR mRNA subtypes were detected in these cells. Ribonuclease protection assay further confirmed the presence of protected products for m1, m2, m3, and m4 mAChR transcripts. Radioligand binding studies and the analysis of changes in intracellular signaling pathways after cell exposure to carbachol were performed to study mAChRs at the protein level. Scatchard analysis revealed one single class of [(3)H]quinuclidinyl benzilate binding sites. Carbachol produced a reduction on forskolin-induced intracellular cAMP accumulation in Sertoli cells. This effect was reversed by atropine, methoctramine, and tropicamide but not by p-fluoro hexahydro-sila-difenidol or pirenzepine. Carbachol also induced an increase on total [(3)H]-inositol phosphates content, an effect antagonized by atropine, p fluoro-hexahydro-sila-difenidol, or pirenzepine but not by methoctramine. Thus, mAChR activation in Sertoli cell is linked to both adenylyl cyclase inhibition and to phosphoinositide hydrolysis. Furthermore, gel shift assays indicated that carbachol also induced a time-dependent stimulation of the activator protein-1 DNA-binding activity, suggesting that activation of mAChRs may play a role in the modulation of gene expression in Sertoli cells. Taken together, these results indicate that mAChRs are present at mRNA and protein level in rat Sertoli cells. PMID- 11606436 TI - Cyclical regulation of GnRH gene expression in GT1-7 GnRH-secreting neurons by melatonin. AB - The pineal hormone melatonin plays an important role in the neuroendocrine control of reproductive physiology, but its effects on hypothalamic GnRH neurons are not yet known. We have found that GT1-7 GnRH-secreting neurons express membrane-bound G protein-coupled melatonin receptors, mt1 (Mel-1a) and MT2 (Mel 1b) as well as the orphan nuclear receptors ROR alpha and RZR beta. Melatonin (1 nM) significantly downregulates GnRH mRNA levels in a 24-h cyclical manner, an effect that is specifically inhibited by the melatonin receptor antagonist luzindole (10 microM). Repression of GnRH gene expression by melatonin appears to occur at the transcriptional level and can be mapped to the GnRH neuron-specific enhancer located within the 5' regulatory region of the GnRH gene. Using transient transfection of GT1-7 cells, downregulation of GnRH gene expression by melatonin was further localized to five specific regions within the GnRH enhancer including -1827/-1819, -1780/-1772, -1746/-1738, -1736/-1728, and -1697/-1689. Interestingly, the region located at -1736/-1728 includes sequences that correspond to two direct repeats of hexameric consensus binding sites for members of the ROR/RZR orphan nuclear receptor family. To begin to dissect the mechanisms involved in the 24-h cyclical regulation of GnRH transcription, we have found that melatonin (10 nM) induces rapid internalization of membrane-bound mt1 receptors through a beta-arrestin 1-mediated mechanism. These results provide the first evidence that melatonin may mediate its neuroendocrine control on reproductive physiology through direct actions on the GnRH neurons of the hypothalamus, both at the level of GnRH gene expression and through the regulation of G protein-coupled melatonin receptors. PMID- 11606437 TI - Development of an ER action indicator mouse for the study of estrogens, selective ER modulators (SERMs), and Xenobiotics. AB - We have developed a transgenic mouse that functions as a reporter of ER activity, termed ER action indicator (ERIN), by incorporating a transgene with an estrogen responsive promoter (three copies of the vitellogenin estrogen response element with a minimal thymidine kinase promoter) linked to the reporter gene beta galactosidase. Evaluation of ER activity in female ERIN mice demonstrated estrogen-inducible expression of the reporter gene in the uterus, pituitary, and hypothalamus; established targets of estrogen action. Importantly, we also identified ER activity in a number of nonclassical estrogen target tissues, including kidney, liver, adrenal, and thyroid gland. ERIN provides a system to measure the same end point (transgene regulation) in different target tissues, permitting separation of the contributions of cell- and promoter-specific factors in determining ER pharmacology. In this regard we observed that on this specific promoter the pituitary gland was 25-fold more sensitive than the uterus to the estrogen diethylstilbestrol, implying the existence of cell-specific factors that influence ligand sensitivity. Our studies also identified considerable difference in the efficacy and potency of ER ligands in the uterus when ER transcriptional activity was assayed vs. uterine weight gain. Specifically, we observed that the environmental estrogen bisphenol A was a potent agonist in stimulating ER transcriptional activity, whereas it exhibited little uterotropic activity. In contrast to bisphenol A, tamoxifen significantly increased uterine weight, but minimally induced ER reporter activity in this tissue. Given the results of these studies, we believe that ERIN will be a useful model to evaluate ER ligand pharmacology and will assist in defining the cellular and molecular mechanisms that determine agonist and antagonist activity. PMID- 11606438 TI - Identification and characterization of two distinct GnRH receptor subtypes in a teleost, the medaka Oryzias latipes. AB - We report the identification and characterization of two distinct GnRH receptor (GnRH-R) subtypes, designated GnRH-R1 and GnRH-R2, in a model teleost, the medaka Oryzias latipes. These seven-transmembrane receptors of the medaka contain a cytoplasmic C-terminal tail, which has been found in all other nonmammalian GnRH Rs cloned to date. The GnRH-R1 gene is composed of three exons separated by two introns, whereas the GnRH-R2 gene has an additional intron and therefore consists of four exons and three introns. The GnRH-R1 and GnRH-R2 genes, both of which exist as single-copy genes in the medaka genome, were mapped to linkage groups 3 and 16, respectively. Inositol phosphate assays using COS-7 cells transfected with GnRH-R1 and GnRH-R2 demonstrated that they had remarkably different ligand sensitivities, although both receptors showed highest preference for chicken-II type GnRH. Phylogenetic analysis showed the presence of three paralogous lineages for vertebrate GnRH-Rs and indicated that neither GnRH-R1 nor GnRH-R2 is the medaka ortholog to mammalian GnRH-Rs that lack a cytoplasmic tail. This, together with an observation that medaka-type GnRH had low affinity for GnRH-R1 and GnRH R2, suggests that a third GnRH-R may exist in the medaka. PMID- 11606439 TI - Thyroid peroxidase autoantibodies obtained from random single chain FV libraries contain the same heavy/light chain combinations as occur in vivo. AB - Three combinatorial libraries were constructed from unpurified, CD19(+), and antithyroid peroxidase (anti-TPO) B cells extracted from thyroid tissue of Graves' disease patients. Fifteen of the 41 randomly derived anti-TPO single chain variable region fragments (scFvs), showed VH1-3/V lambda 1-51 or VH1-69/V lambda 1-40 heavy/light chain pairing similar to that obtained with TPO-specific scFv derived from an in-cell library. One VH1-3/V lambda 1-51 scFv, A16, showed exactly the same nucleotide sequence as in-cell scFv ICB7, demonstrating that in vivo rearrangement can be obtained from a random combinatorial library. The majority of the scFvs used a heavy chain gene derived from the VH1-3 gene segment, whereas the light chain gene segments used were more heterogeneous, with dominance of the V kappa 1-39 and V lambda 1-51 gene segments. The anti-TPO scFvs showed high affinities to TPO, with values between 0.77 and 12.3 nM, and defined seven antigenic regions on the TPO molecule. The anti-TPO fragments, particularly VH1-3/V lambda 1-51 randomly associated scFv B4, which mimic natural H/L pairing, and VH1-3/V lambda 1-40 in-cell-derived scFv ICA5, efficiently displaced the TPO binding of serum autoantibodies from 20 Graves' disease patients. Our study directly demonstrates that antibodies derived from combinatorial libraries are likely to represent in vivo pairing, leading to high affinity antibody fragments mimicking the binding of serum autoantibodies to TPO. PMID- 11606440 TI - Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice. AB - To test the role of gene expression of the classical ER (ER alpha) in the inhibitory effects of E on food intake and body weight, we ovariectomized and administered E2 benzoate (75 pg/d) or vehicle to wild-type (WT) mice and mice with a null mutation of ER alpha (alpha ERKO). Mice were ovariectomized at age 9 wk, at which time there was no significant effect of genotype on food intake or body weight. During an 18-d test after recovery from ovariectomy, vehicle-treated WT mice increased daily food intake and gained more body weight than E2-treated WT mice, whereas food intake and body weight gain were not different in E2- and vehicle-treated alpha ERKO mice. Carcass analysis revealed parallel changes in body lipid content, but not water or protein content. Because an increase in the potency of the peripheral cholecystokinin (CCK) satiation-signaling system mediates part of E2's influence on feeding in rats, the influence of ip injections of 250 microg of the selective CCK(A) receptor antagonist devazepide was then tested. Devazepide increased 3-h food intake in E2-treated WT mice, but was ineffective in both groups of alpha ERKO mice. Furthermore, ip injections of 4 microg/kg CCK-8 increased the number of cells expressing c-Fos immunoreactivity in the nuclei of the solitary tract of E2-treated WT mice more than it did in vehicle-treated WT mice, whereas E2 had no such effect in alpha ERKO mice. Thus, ER alpha is necessary for normal responsivity of food intake, body weight, adiposity, and the peripheral CCK satiation-signaling system to E2 in mice, and ER beta is not sufficient for any of these effects. This is the first demonstration that ER alpha gene expression is involved in the estrogenic control of feeding behavior and weight regulation of female mice. PMID- 11606441 TI - Puberty in female mice is not associated with increases in either body fat or leptin. AB - It has been hypothesized that puberty is triggered when body fat and hence circulating levels of leptin exceed critical thresholds. Four kinds of experiments tested that hypothesis in female mice. When age was the independent variable, body fat and circulating levels of leptin decreased rather than increased before the onset of puberty. When stage of reproductive development was the independent variable, neither body fat nor circulating levels of leptin correlated with the onset of puberty. In sharp contrast, reproductive development was well correlated with body weight. A significant nocturnal peak in circulating levels of leptin was seen before and at all stages of reproductive development, but the highest levels were seen after rather than before the first estrous cycle was initiated. Neither acceleration nor deceleration of puberty by varying the female's social environment had any effect on either body fat or leptin. There is no support in any of these experiments for the hypothesis that an increase in body fat and thus an increase in circulating levels of leptin triggers puberty in female mice. PMID- 11606442 TI - Liver-derived IGF-I regulates GH secretion at the pituitary level in mice. AB - We have reported that liver-specific deletion of IGF-I in mice (LI-IGF-I-/-) results in decreased circulating IGF-I and increased GH levels. In the present study, we determined how elimination of hepatic IGF-I modifies the hypothalamic pituitary GH axis to enhance GH secretion. The pituitary mRNA levels of GH releasing factor (GHRF) receptor and GH secretagogue (GHS) receptor were increased in LI-IGF-I-/- mice, and in line with this, their GH response to ip injections of GHRF and GHS was increased. Expression of mRNA for pituitary somatostatin receptors, hypothalamic GHRF, somatostatin, and neuropeptide Y was not altered in LI-IGF-I-/- mice, whereas hypothalamic IGF-I expression was increased. Changes in hepatic expression of major urinary protein and the PRL receptor in male LI-IGF-I-/- mice indicated an altered GH release pattern most consistent with enhanced GH trough levels. Liver weight was enhanced in LI-IGF-I /- mice of both genders. In conclusion, loss of liver-derived IGF-I enhances GH release by increasing expression of pituitary GHRF and GHS receptors. The enhanced GH release in turn affects several liver parameters, in line with the existence of a pituitary-liver axis. PMID- 11606443 TI - Novel expression of neuropeptide Y (NPY) mRNA in hypothalamic regions during development: region-specific effects of maternal deprivation on NPY and Agouti related protein mRNA. AB - During development there is novel expression of NPY mRNA in the dorsomedial hypothalamic nucleus (DMH) and perifornical region (PFR), in addition to the arcuate nucleus (ARH). Furthermore, NPY mRNA levels peak in all regions on postnatal d 16 (P16) and decrease to adult levels by P30. The purpose of the present study was to determine whether NPY and agouti-related protein (AGRP) mRNA expression in the different hypothalamic regions on P11 and P16 are similarly affected by fasting. An examination of the full rostral to caudal extent of the hypothalamus revealed two additional regions displaying novel NPY mRNA expression, the parvocellular division of the paraventricular nucleus (PVH) and lateral hypothalamus (LH). Maternal deprivation for 36 h, used to bring about a fast, similarly increased (23-29%) NPY and AGRP mRNA expression in the ARH on P11 and P16. In contrast, NPY expression in the DMH and PFR were significantly decreased (19-30% and 48-53%, respectively), whereas NPY mRNA levels in the PVH and LH were not altered by this treatment. The increase in NPY and AGRP mRNA expression in the ARH in response to maternal deprivation suggests that these neuronal populations respond to signals of energy balance. In contrast, NPY expression in the DMH, PFR, PVH, and LH is differentially regulated by maternal deprivation or other factors associated with maternal separation. PMID- 11606444 TI - The effect of chronic exposure to fatty acids on gene expression in clonal insulin-producing cells: studies using high density oligonucleotide microarray. AB - Fatty acids affect insulin secretion of pancreatic beta-cells. Investigating gene expression profiles may help to characterize the underlying mechanism. INS-1 cells were cultured with palmitate (0, 50, and 200 microM) for up to 44 d. Insulin secretion and expressions of 8740 genes were studied. We found that basal insulin secretion increased in cells exposed to palmitate. The response to glucose stimulation declined on d 44 in cells cultured at 200 microM palmitate. In response to 50 and 200 microM palmitate exposure, expression was changed in 11 and 99 genes on d 2 and 134 and in 159 genes on d 44, respectively. Genes involved in fatty acid oxidation were up-regulated, whereas those involved in glycolysis were down-regulated with 200 microM palmitate. A suppression of insulin receptor and insulin receptor substate-2 gene expression was found on d 44 in cells cultured at 200 microM palmitate. In conclusion, chronic exposure to low palmitate alters insulin secretion as well as gene expression. The number of genes that changed expression was palmitate dose and exposure time dependent. Randle's fatty acid-glucose cycle seems to be operative on the gene transcription level. A modification of expression of various genes may contribute to the functional changes. PMID- 11606445 TI - Ceramide inhibits the inwardly rectifying potassium current in GH(3) lactotrophs. AB - The effects of ceramide on ion currents in rat pituitary GH(3) cells were investigated. Hyperpolarization-elicited K(+) currents present in GH(3) cells were studied to determine the effect of ceramide and other related compounds on the inwardly rectifying K(+) current (I(K(IR))). Ceramide (C(2)-ceramide) suppressed the amplitude of I(K(IR)) in a concentration-dependent manner, with an IC(50) value of 5 microM. Ceramide caused a rightward shift in the midpoint for the activation curve of I(K(IR)). Pretreatment with PD-98059 (30 microM) or U 0126 (30 microM) did not prevent ceramide-mediated inhibition of I(K(IR)). However, the magnitude of ceramide-induced inhibition of I(K(IR)) was attenuated in GH(3) cells preincubated with dithiothreitol (10 microM). TNF alpha (100 ng/g) also suppressed I(K(IR)). In the inside-out configuration, application of ceramide (30 microM) to the bath slightly suppressed the activity of large conductance Ca(2+)-activated K(+) channels. Under the current clamp mode, ceramide (10 microM) increased the firing of action potentials. Cells that exhibited an irregular firing pattern were converted to those displaying a regular firing pattern after application of ceramide (10 microM). Ceramide also suppressed I(K(IR)) in neuroblastoma IMR-32 cells. Therefore, ceramide can produce a depressant effect on I(K(IR)). The blockade of this current by ceramide may affect cell function. PMID- 11606446 TI - Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. AB - The mechanisms by which prostate cancer (PCa) cells progress to a hormone refractory state are poorly understood. The progression process under androgen ablation conditions involves the survival of at least a portion of malignant cells and their eventual proliferation in an androgen-independent manner. The goal of this study was to investigate the role of PI3K signaling in such a progression. Using an in vitro model of androgen ablation, we show that after removal of androgen support, the human PCa cell line LNCaP initially arrested in G(1) and trans-differentiated into neuroendocrine-like cells that eventually resumed androgen-independent proliferation. Both acute and chronic androgen ablation resulted in an increase in basal levels of PI3K and Akt activity, which were sustained throughout the progression process. Under these conditions, inhibition of PI3K, pharmacologically or with ectopic expression of PTEN, arrested cell proliferation and blocked progression to the androgen-independent state. In contrast, LNCaP cells in the presence of androgens were marginally sensitive to PI3K inhibition. During the chronic stage of androgen deprivation, androgen-independent proliferation correlated with diminished p27(kip1) protein levels, whereas PI3K and Akt activity remained elevated. At this stage, PI3K inhibition rapidly triggered accumulation of p27(kip1), cell cycle arrest, and cell death. PI3K modulated p27(kip1) levels at least in part by regulating its rate of degradation. Taken together, these data show that androgen ablation alone can increase PI3K-Akt activation, which supports survival after acute androgen ablation and proliferation during chronic androgen deprivation. Successful progression to the androgen-independent state in the LNCaP cell line model requires intact PI3K signaling. PMID- 11606447 TI - High leptin levels acutely inhibit insulin-stimulated glucose uptake without affecting glucose transporter 4 translocation in l6 rat skeletal muscle cells. AB - Obesity is a major risk factor for the development of insulin resistance, characterized by impaired stimulation of glucose disposal into muscle. The mechanisms underlying insulin resistance are unknown. Here we examine the direct effect of leptin, the product of the obesity gene, on insulin-stimulated glucose uptake in cultured rat skeletal muscle cells. Preincubation of L6 myotubes with leptin (2 or 100 nM, 30 min) had no effect on basal glucose uptake but reduced insulin-stimulated glucose uptake. However, leptin had no effect on the insulin induced gain in myc-tagged glucose transporter 4 (GLUT4) appearance at the cell surface of L6 myotubes. Preincubation of cells with leptin also had no effect on insulin-stimulated tyrosine phosphorylation of insulin receptor, IRS-1 and IRS-2, phosphatidylinositol 3-kinase activity, or Akt phosphorylation. We have previously shown that insulin regulates glucose uptake via a signaling pathway sensitive to inhibitors of p38 MAP kinase. Here, leptin pretreatment reduced the extent of insulin-stimulated p38 MAP kinase phosphorylation and phosphorylation of cAMP response element binder, a downstream effector of p38 MAP kinase. These results show that high leptin levels can directly reduce insulin-stimulated glucose uptake in L6 muscle cells despite normal GLUT4 translocation. The mechanism of this effect could involve inhibition of insulin-stimulated p38 MAP kinase and GLUT4 activation. PMID- 11606448 TI - The effect of tibolone on fat mass, fat-free mass, and total body water in postmenopausal women. AB - Changes in body composition occur around the menopausal transition. The major characteristics are a decline in fat-free mass and an increase in body fat as a percentage of body weight. These alterations might be affected by age only or by menopause-related changes in hormone concentration. In this study the effects of tibolone, a tissue-specific compound with favorable effects on bone, vagina, and climacteric symptoms, were determined on body composition using bioelectrical impedance analysis. The focus was especially on fat mass, fat-free mass, and total body water in a group of 85 healthy women (mean +/- SD age, 54.2 +/- 4.7 yr), between 1-15 yr postmenopausal. Participants were randomly assigned to either tibolone (2.5 mg; n = 42) or identically appearing placebo tablets (n = 43) daily for 12 months. All analyses were based on the intent to treat group and last visit. Compared with placebo, tibolone significantly increased fat-free mass by 0.85 kg (P = 0.003) and total body water by 0.78 liter (P = 0.001). No significant difference was observed on the fat mass parameter (P = 0.16). From these results it can be concluded that tibolone may counteract the postmenopausal changes in body composition. PMID- 11606449 TI - Effect of IL-6 on IGF binding protein-3: a study in IL-6 transgenic mice and in patients with systemic juvenile idiopathic arthritis. AB - Stunted growth is a common complication of childhood diseases characterized by chronic inflammation or infections. We previously demonstrated that NSE/hIL-6 transgenic mice, overexpressing the inflammatory cytokine IL-6 since early phase of life, showed a marked growth defect associated with decreased IGF-I levels, suggesting that IL-6 is one of the factors involved in stunted growth complicating chronic inflammation in childhood. Here we show that NSE/hIL-6 mice have normal liver IGF-I production, decreased levels of IGF binding protein-3 (IGFBP-3) and increased serum IGFBP-3 proteolysis. Reduced IGFBP-3 levels results in a marked decrease in the circulating 150-kDa ternary complex, even in the presence of normally functional acid labile subunit. Pharmacokinetic studies showed that NSE/hIL-6 mice have accelerated IGF-I clearance. Patients with systemic juvenile idiopathic arthritis (s-JIA), a chronic inflammatory disease characterized by prominent IL-6 production and complicated by stunted growth associated with low IGF-I levels, have markedly decreased IGFBP-3 levels, increased serum IGFBP-3 proteolysis and normal acid labile subunit levels. Our data show that chronic overproduction of IL-6 causes decreased IGFBP-3 levels, resulting in a decreased association of IGF-I in the 150-kDa complex. Decreased levels of IGF-I appear to be secondary to increased clearance. PMID- 11606450 TI - Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis. AB - To test the hypothesis that leptin secreted from adipose tissue is a mediator linking obesity and pancreatic islet hypertrophy, we examined the effects of leptin on proliferative and apoptotic responses in rat islet cells. Rat pancreatic islets were isolated and incubated with 0, 1, 5, or 75 nM leptin for 24 h under serum-deprived conditions. Cell viability was assessed with 2,5 diphenyltetrazolium bromide and trypan blue dye exclusion tests. Cell proliferation and apoptosis were evaluated with 5-bromo-2'-deoxyuridine incorporation into DNA and DNA ladder formation, respectively. Incubation for 24 h with 1 and 5 nM leptin, the concentrations observed in obese subjects, increased the viability of isolated pancreatic islet cells. Five nanomolar concentrations of leptin did not stimulate 5-bromo-2'-deoxyuridine incorporation into incubated islet cells, indicating no influence on cell proliferation, but did inhibit DNA ladder formation, a hallmark of cell apoptosis. Moreover, 5 nM leptin reduced the triglyceride content and suppressed inducible nitric oxide synthase mRNA expression in incubated islets. These results suggest that leptin increased viable cell numbers via suppression of apoptosis in isolated pancreatic islet cells under these experimental conditions. This mechanism might account at least in part for an obesity-induced increase in pancreatic beta-cell mass. PMID- 11606451 TI - Expression and localization of PPARs in the rat ovary during follicular development and the periovulatory period. AB - PPARs are a family of nuclear hormone receptors involved in various processes that could influence ovarian function. We investigated the cellular localization and expression of PPARs during follicular development in ovarian tissue collected from rats 0, 6, 12, 24, and 48 h post-PMSG. A second group of animals received human CG (hCG) 48 h post-PMSG. Their ovaries were removed 0, 4, 8, 12, and 24 h post-hCG to study the periovulatory period. mRNAs corresponding to the PPAR isotypes (alpha, delta, and gamma) were localized by in situ hybridization. Changes in the levels of mRNA for the PPARs were determined by ribonuclease protection assays. PPAR gamma mRNA was localized primarily to granulosa cells, and levels of expression did not change during follicular development. Four hours post-hCG, levels of mRNA for PPAR gamma decreased (P < 0.05) but not uniformly in all follicles. At 24 h post-hCG, levels of PPAR gamma mRNA were reduced 64%, but some follicles maintained high expression. In contrast, mRNAs for PPAR alpha and delta were located primarily in theca and stroma, and their levels did not change during the intervals studied. To investigate the physiologic significance of PPAR gamma in the ovary, granulosa cells from PMSG-primed rats were cultured for 48 h with prostaglandin J(2) (PGJ(2)) and ciglitazone, PPAR gamma activators. Both compounds increased progesterone and E2 secretion (P < 0.05). These data suggest that PPAR gamma is involved in follicular development, has a negative influence on the luteinization of granulosa cells, and/or regulates the periovulatory shift in steroid production. The more general and steady expression of PPARs alpha and delta indicate that they may play a role in basal ovarian function. PMID- 11606452 TI - alpha(1)-adrenergic receptors mediate LH-releasing hormone secretion through phospholipases C and A(2) in immortalized hypothalamic neurons. AB - Norepinephrine has long been known to stimulate the pulsatile and preovulatory release of LH-releasing hormone (LHRH). In vivo and in vitro studies indicate that these effects are mediated primarily through alpha(1)-adrenergic receptors (alpha(1)-ARs). With the immortalized hypothalamic LHRH neurons, we have found that alpha(1)-adrenergic agents directly stimulate the secretion of LHRH in a dose-dependent manner. Ligand binding and RNA studies demonstrate that the GT1 cells contain both alpha(1A)- and alpha(1B)-ARs. Competition binding experiments show that approximately 75% of the binding is due to alpha(1B)-ARs; the remainder is made up of alpha(1A)-ARs. Receptor activation leads to stimulation of PLC. PLC beta 1 and PLC beta 3 are expressed in GT1 neurons, and these PLCs are probably responsible for the release of diacylglycerol and IP as well as the increase in intracellular calcium. The mobilization of cytoplasmic calcium is sufficient to stimulate cytosolic PLA(2) (cPLA(2)) and release arachidonic acid. A dissection of the contributions of the phospholipases to LHRH secretion suggests that cPLA(2) acts downstream of PLC and that it significantly augments the PLC stimulated LHRH secretory response. Inasmuch as the alpha(1)-ARs are known to play a critical role in LHRH physiology, we propose that both PLC and cPLA(2) are critical in regulating and amplifying LHRH release. PMID- 11606453 TI - Cooperation between low density lipoproteins and IGF-I in the promotion of mitogenesis in vascular smooth muscle cells. AB - Low density lipoproteins (LDL) are an independent risk factor for atherosclerosis and show synergism with some growth factors in vascular smooth muscle cell (VSMC) proliferation. IGF-I has mitogenic actions on VSMC, which, in turn, show enhanced expression of IGF-I and its receptor when exposed to hypercholesterolemic diets in vivo. To investigate the molecular basis of a possible interaction between LDL and the IGF-I signaling system in VSMC, we used A10 cells, where synergism between both factors in DNA synthesis was demonstrated. IGF-I activates phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated MAPK pathways in A10 cells, although insulin receptor substrate-1 (IRS-1) associated PI3 kinase is more closely linked to IGF-I induced proliferation. LDL, in pathophysiological concentrations, affect the IGF-I signaling pathway at multiple levels: 1) they induce phosphorylation of IGF-I receptor beta and IRS-1 in a time- and dose-dependent manner; 2) they up-regulate IRS-1-associated PI3 kinase/Akt activation in response to IGF-I at early times; and 3) they show additive effects with IGF-I on extracellular signal-regulated MAPK 1/2 phosphorylation. These actions are not present in very low density lipoprotein treatments. Taken together, these results indicate specific cooperation between LDL and the IGF-I signaling pathways and may represent a more general mechanism through which proatherogenic lipoproteins modulate VSMC response to growth factors. PMID- 11606455 TI - Molecular regulation of the hypothalamo-pituitary-adrenal axis in streptozotocin induced diabetes: effects of insulin treatment. AB - Increased hypothalamo-pituitary-adrenocortical (HPA) activity in diabetes is likely important in the development of some pathologies associated with the disorder. We hypothesized that central regulation of HPA activity differs among normal, streptozotocin (STZ)-diabetic, and insulin-treated diabetic rats. Blood glucose, ACTH, and corticosterone were elevated, 8 d after inducing diabetes. Insulin treatment normalized these parameters. Plasma norepinephrine was similar in all groups, but epinephrine was lower in STZ-diabetic and higher in insulin treated rats vs. normals. Increased ACTH with diabetes corresponded with increased hypothalamic CRH mRNA, but no change in pituitary POMC mRNA. With insulin-treatment, CRH mRNA remained elevated, and POMC mRNA was unaltered. Hippocampal MR mRNA expression was dramatically increased with diabetes and, moreover, was not normalized by insulin. No differences in GR mRNA were detected between normal and STZ-diabetic rats. However, insulin treatment increased GR mRNA levels in the paraventricular nucleus and pituitary. We postulate that, in STZ-diabetes: 1) increased HPA activity is caused by increased central drive at and/or above the level of the paraventricular nucleus and is associated with decreased epinephrine; and 2) normalized pituitary-adrenal activity with insulin may be caused by the compensatory increase in GR mRNA allowing glucocorticoid mediated suppression of ACTH secretion despite the residual increase in central HPA activity. Thus, insulin apparently restored HPA activity at and below the pituitary but, surprisingly, not above it. PMID- 11606454 TI - Leptin stimulates catecholamine synthesis in a PKC-dependent manner in cultured porcine adrenal medullary chromaffin cells. AB - We have previously shown that murine recombinant leptin directly stimulates catecholamine synthesis through the long form of the leptin receptor (Ob-Rb) expressed in cultured porcine chromaffin cells. Additionally, we found that leptin activates IP3 production after PLC activation. It is well established that activation of PLC elicits IP3 production as well as an increase in diacylglycerol, a compound that stimulates PKC. Therefore, we investigated the involvement of PKC in leptin-induced catecholamine synthesis. Leptin was found to induce significant increases in PKC activity in a dose-dependent manner (1, 10, and 100 nM); chelation of extracellular Ca(2+) by EDTA abolished this PKC stimulatory activity. We also confirmed by Western blot analysis that leptin (at 100 nM) induced significant increases in Ca(2+)-dependent PKC alpha, -beta(I), and -gamma expression. The activity of the rate-limiting enzyme tyrosine hydroxylase (TH) in the biosynthesis of catecholamine is regulated at the transcriptional and posttranscriptional levels. TH enzyme activity and TH mRNA levels induced by 100 nM leptin were significantly inhibited by the PKC inhibitor Ro 32-0432 as well as by EDTA. In addition, increases in TH protein and intracellular catecholamine content stimulated by leptin were completely inhibited by Ro 32-0432. Leptin markedly activated ERKs and, to a lesser extent, JNK; these stimulatory effects on ERKs and JNK were completely inhibited by Ro 32 0432 as well as EDTA. In contrast, leptin did not activate P38 MAPK. Similar to leptin, PMA activated ERK and JNK. Nicardipine and omega-conotoxin GVIA, each at 1 microM, were effective at inhibiting leptin-induced TH enzyme activity, TH mRNA accumulation, PKC activity, and ERK activity. Leptin increased activating protein 1 DNA-binding activity, and this was diminished by Ro 32-0432 as well as EDTA, similar to the reduction of TH mRNA levels. In addition, using supershift analysis, we documented the involvement of c-Fos and, to a lesser extent, c-Jun in leptin-induced activating protein-1 activity. These results indicate that leptin stimulates Ca(2+)-dependent PKC isoform-dependent catecholamine synthesis in porcine chromaffin cells. Previously, we had shown that leptin stimulated cAMP. The present study also showed that H89 (a PKA inhibitor) moderately, but significantly, inhibited leptin-induced ERK and TH mRNA. Consistent with this finding, leptin is shown here to activate novel PKC epsilon, which is assumed to stimulate Raf, upstream of ERKs, via cAMP, supporting the suggestion that Ca(2+) independent novel PKC may also play some physiological role in regulating catecholamine synthesis. PMID- 11606456 TI - PRL receptor-mediated effects in female mouse adipocytes: PRL induces suppressors of cytokine signaling expression and suppresses insulin-induced leptin production in adipocytes in vitro. AB - PRL has been reported to regulate fat metabolism in several species. We recently reported PRL receptor (PRLR) expression in mouse adipocytes and increased levels of PRLR expression in the adipose tissue of lactating and PRL-transgenic mice compared with controls. These results suggest PRLR-mediated effects in adipose tissue. However, to date most studies have been performed in vivo, and it is unclear whether PRL has direct effects on adipocytes. The PRLR belongs to the cytokine receptor family, and a family of suppressors of cytokine signaling (SOCS) was recently identified. The present study was performed to investigate whether PRL has direct effects on adipocytes. The expression of cytokine inducible SH2-domain-containing protein (CIS), SOCS-3, and SOCS-2 mRNA and protein was analyzed using ribonuclease protection assay and immunoblotting, respectively. Ovine PRL induced CIS mRNA expression and a combination of oPRL and insulin induced SOCS-3 mRNA expression in adipocytes cultured in vitro for 0-240 min, demonstrating PRLR-mediated direct effects in these cells. Furthermore, CIS, SOCS-3, and SOCS-2 mRNA and protein were all transiently expressed in adipose tissue obtained from female mice stimulated with oPRL (1 microg/g BW) for 0-24 h. In adipose tissue of female mice with endogenously high PRL levels, PRL transgenic mice, only SOCS-2 expression was increased. The level of SOCS-2 mRNA was also increased in adipose tissue during pregnancy and lactation compared with that in wild-type virgin female mice. A possible reason for increased SOCS-2 expression after prolonged PRL exposure during lactation and in the PRL transgenes could be to restore the sensitivity of adipose tissue to PRL. In addition, the direct effect of PRL on leptin production was investigated in adipocytes cultured in vitro for 6 h. PRL inhibited insulin-induced leptin production in vitro. However, PRL had no effect on leptin production in the absence of insulin. In contrast, serum leptin concentrations were increased in PRL-transgenic females compared with control mice. In conclusion, our results demonstrate functional PRLRs in mouse adipocytes and suggest a role for CIS, SOCS 3, and SOCS-2 in regulating PRL signal transduction in adipose tissue. PMID- 11606457 TI - Anti-Mullerian hormone attenuates the effects of FSH on follicle development in the mouse ovary. AB - Although ovarian follicle growth is under the influence of many growth factors and hormones of which FSH remains one of the most prominent regulators. Therefore, factors affecting the sensitivity of ovarian follicles to FSH are also important for follicle growth. The aim of the present study was to investigate whether anti-Mullerian hormone (AMH) has an inhibitory effect on follicle growth by decreasing the sensitivity of ovarian follicles to FSH. Furthermore, the combined action of AMH and FSH on ovarian follicle development was examined. Three different experiments were performed. Using an in vitro follicle culture system it was shown that FSH-stimulated preantral follicle growth is attenuated in the presence of AMH. This observation was confirmed by an in vivo experiment showing that in immature AMH-deficient females, more follicles start to grow under the influence of exogenous FSH than in their wild-type littermates. In a third experiment, examination of the follicle population of 4-month-old wild type, FSH beta-, AMH-, and AMH-/FSH beta-deficient females revealed that loss of FSH expression has no impact on the number of primordial and preantral follicles, but the loss of inhibitory action of AMH on the recruitment of primordial follicles in AMH-deficient mice is increased in the absence of FSH. In conclusion, these studies show that AMH inhibits FSH-stimulated follicle growth in the mouse, suggesting that AMH is one of the factors determining the sensitivity of ovarian follicles for FSH and that AMH is a dominant regulator of early follicle growth. PMID- 11606458 TI - PTHrP inhibits adipocyte differentiation by down-regulating PPAR gamma activity via a MAPK-dependent pathway. AB - We examined the capacity of PTHrP to modulate the terminal differentiation of the preadipocytic cell line, 3T3-L1. These cells express endogenous PTHrP and its receptor, but expression levels were undetectable after differentiation into mature adipocytes. Cells stably overexpressing PTHrP failed to differentiate when induced to undergo adipogenesis and proliferated at a faster rate. MAPK activity was elevated in PTHrP-transfected 3T3-L1 cells, and treatment with the PKA inhibitor H-8 decreased this activity. Inhibition of MAPK kinase with PD098059 permitted terminal differentiation of PTHrP-transfected 3T3-L1 cells to proceed. Although PPAR gamma gene expression levels remained relatively constant in the PTHrP-transfected cells, PPAR gamma phosphorylation was enhanced. Furthermore, the capacity of PPAR gamma to stimulate transcription in the presence of troglitazone was diminished by PTHrP. Expression of the PPAR gamma-regulated adipocyte specific gene aP2 transiently rose and then fell in PTHrP-transfected cells. These results indicate that PTHrP can increase MAPK activity in 3T3-L1 cells via the PKA pathway, thereby enhancing PPAR gamma phosphorylation. This modification can inactivate the transcriptional enhancing activity of PPAR gamma and diminish the expression of adipocyte-specific genes. These studies therefore demonstrate that PTHrP may inhibit the terminal differentiation of preadipocytes and describe a molecular pathway by which this action can be achieved. PMID- 11606459 TI - Physical and inflammatory stressors elevate circadian clock gene mPer1 mRNA levels in the paraventricular nucleus of the mouse. AB - Stress induces secretion of corticosterone through activation of the hypothalamic pituitary-adrenal axis. This corticosterone secretion is thought to be controlled by a circadian clock in the suprachiasmatic nucleus (SCN). The hypothalamic paraventricular nucleus (PVN) receives convergent information from both stress and the circadian clock. Recent reports demonstrate that mammalian orthologs (Per1, Per2, and Per3) of the Drosophila clock gene Period are expressed in the SCN, PVN, and peripheral tissues. In this experiment, we examined the effect of physical and inflammatory stressors on mPer gene expression in the SCN, PVN, and liver. Forced swimming, immobilization, and lipopolysaccharide injection elevated mPer1 gene expression in the PVN but not in the SCN or liver. A stress-induced increase in mPer1 expression was observed in the corticotropin-releasing factor positive cells of the PVN; however, the stressors used in this study did not affect mPer2 expression in the PVN, SCN, or liver. The present study suggests that a stress-induced disturbance of circadian corticosterone secretion may be associated with the stress-induced expression of mPer1 mRNA in the PVN. PMID- 11606460 TI - Mouse testicular Leydig cells express Klk21, a tissue kallikrein that cleaves fibronectin and IGF-binding protein-3. AB - We have cloned a type of cDNA for a functional glandular kallikrein, designated as mouse Klk21 (mKlk21), from the adult mouse testis cDNA library. mKlk21 was expressed in the kidney, submaxillary glands, and testis of the mouse. In the testis, mKlk21 mRNA was detectable at 4 wk of postnatal development and became more prominent thereafter. The mKlk21 gene was expressed exclusively in the Leydig cells of adult mice. When Leydig cells isolated from 2-wk-old mouse testis were cultured in the presence of T, mKlk21 expression was induced significantly. Active recombinant mKlk21 showed trypsin-like specificity, favorably cleaving Arg X bonds of synthetic peptide substrates. The enzyme activity was strongly inhibited with typical serine protease inhibitors. mKlk21 hydrolyzed casein, gelatin, fibronectin, and IGF-binding protein-3 (IGFBP-3). As in mKlk21, IGF-I and IGFBP-3 were expressed in the Leydig cells of the adult mouse testis, although the transcript of IGFBP-3 was not detected in all of the observed cells. The culture medium of Leydig cells isolated from adult mouse testes contained an mKlk21-like enzyme activity capable of degrading IGFBP-3. These results suggest that mKlk21 plays a role in Leydig cell function in the adult mouse testis. PMID- 11606461 TI - Effect of adrenal and ovarian androgens on type 4 follicles unresponsive to FSH in immature mice. AB - The present study investigates the physiological significance of dehydroepiandrosterone, dehydroepiandrosterone sulfate, T, androstenedione (Delta(4)), dihydrotestosterone (DHT), estrone (E1), and E2 on recombinant human FSH- (rhFSH) resistant type 4 follicles obtained from immature mice. Type 4 follicles of a diameter of 100-120 microm with one or two granulosa cell layers around the oocyte and an intact basal lamina with theca cells were isolated from the ovaries of 11-d-old BDF-1 mice and cultured with medium alone (control) or with dehydroepiandrosterone, dehydroepiandrosterone sulfate, T, Delta(4), DHT, E1, or E2 at concentrations ranging from 1 x 10(-11) to 1 x 10(-7) M for 4 d. We examined the mean diameters of type 4 follicles, levels of immunoreactive (IR) inhibin, and E2 and progesterone in the culture media on day 4. In addition, we evaluated follicular cell proliferation by immunofluorescence staining with 5 bromo-2'-deoxyuridine. All tested androgens significantly increased the diameter of type 4 follicles in a dose-dependent manner without the production of IR inhibin and E2. The nuclei of granulosa cells in type 4 follicles cultured with all tested androgens exhibited intense 5-bromo-2'-deoxyuridine-positive staining, compared with those of controls. In contrast, neither E1 nor E2 had any stimulatory effects. The stimulatory effects of T, Delta(4), or DHT were inhibited by an AR antagonist in a dose-related fashion but not by an aromatase inhibitor. Furthermore, all tested androgens had a synergistic effect with rhFSH on follicular growth and the production of IR-inhibin and E2. These results demonstrated that neither adrenal nor ovarian androgens are arteriogenic but that they stimulate type 4 follicles unresponsive to rhFSH and augment the responsiveness of these follicles to rhFSH. PMID- 11606462 TI - Targeted disruption of the IGF-I receptor gene decreases cellular proliferation in mammary terminal end buds. AB - IGF-I mediates mammary ductal development through stimulation of terminal end bud (TEB) development; however, no published data exist on the mechanism through which this occurs. The mechanism of IGF-I action on the TEB was studied by determining the requirement for the IGF-I receptor (IGF-IR) in IGF-I-dependent ductal development. We hypothesized that loss of the IGF-IR would disrupt mammary ductal development through a combination of decreased proliferation or increased apoptosis. Because IGF-IR null mice die at birth, embryonic mammary gland transplantation was used to study the effects of a disrupted IGF-IR gene. Analyses of grafts after 4 or 8 wk of development demonstrated a limited growth potential of the null mammary epithelium in virgin hosts. Bromodeoxyuridine labeling and terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick-end labeling showed that cell proliferation was significantly decreased in null TEBs, but apoptosis was not. In addition, both the size and number of TEBs were reduced in null outgrowths. In pregnant hosts, null ductal growth was stimulated beyond the level seen in virgin hosts. These findings directly establish a proliferation dependent role for the IGF-IR in the cells of the TEB. Additionally, this study indicates that pregnancy-dependent compensatory mechanisms can stimulate mammary development in the absence of an IGF-IR. PMID- 11606463 TI - Regulation of the hypothalamic-pituitary-adrenocortical system in mice deficient for CRH receptors 1 and 2. AB - Recent investigations in mouse lines either deficient for the CRH receptor 1 (CRHR1) or 2 (CRHR2) suggest that the CRH neuronal system may comprise two separate pathways that can be coordinately and inversely activated in stress induced hypothalamic-pituitary-adrenal (HPA) response and anxiety-like behavior. We generated mice deficient for both CRHR1 (Crhr1(-/-)) and CRHR2 (Crhr2(-/-)) to investigate the HPA system regulation in the absence of known functionally active CRH receptors under basal conditions and in response to different ethologically relevant stressors. To elucidate possible gene dose effects on the action of both CRH receptors, our analysis included heterozygous and homozygous CRHR1- or CRHR2 deficient mice, mutants lacking both CRH receptors, compound mutants with homozygous and heterozygous deficiency for either of the receptors, and their wild-type littermates. Both male and female Crhr1(-/-)Crhr2(-/-) mutants were viable, fertile, and indistinguishable in size from wild-type littermates. We show that the endocrine phenotype of mice lacking both CRHRs is dominated by the functional loss of CRHR1. CRHR2 does not compensate for CRHR1 deficiency, nor does the lack of CRHR2 exacerbate the CRHR1-dependent impairment of the HPA system function. Within the intraadrenal CRH/ACTH system, our data suggest different roles for CRHR1 and CRHR2 in fine-tuning of adrenocortical corticosterone release. PMID- 11606464 TI - Regeneration of pancreatic beta cells from intra-islet precursor cells in an experimental model of diabetes. AB - We previously reported that new beta cells differentiated in pancreatic islets of mice in which diabetes was produced by injection of a high dose of the beta cell toxin streptozotocin (SZ), which produces hyperglycemia due to rapid and massive beta cell death. After SZ-mediated elimination of existing beta cells, a population of insulin containing cells reappeared in islets. However, the number of new beta cells was small, and the animals remained severely hyperglycemic. In the present study, we tested whether restoration of normoglycemia by exogenous administered insulin would enhance beta cell differentiation and maturation. We found that beta cell regeneration improved in SZ-treated mice animals that rapidly attained normoglycemia following insulin administration because the number of beta cells per islet reached near 40% of control values during the first week after restoration of normoglycemia. Two presumptive precursor cell types appeared in regenerating islets. One expressed the glucose transporter-2 (Glut-2), and the other cell type coexpressed insulin and somatostatin. These cells probably generated the monospecific cells containing insulin that repopulated the islets. We conclude that beta cell neogenesis occurred in adult islets and that the outcome of this process was regulated by the insulin-mediated normalization of circulating blood glucose levels. PMID- 11606465 TI - Insulin and IGF-1 induce different patterns of gene expression in mouse fibroblast NIH-3T3 cells: identification by cDNA microarray analysis. AB - The IGF-1 receptor and the related insulin receptor are similar in structure and activate many of the same postreceptor signaling pathways, yet they mediate distinct biological functions. It is still not understood how the specificity of insulin vs. IGF-1 signaling is controlled. In this study, we have used cDNA microarrays to monitor the gene expression patterns that are regulated by insulin and IGF-1. Mouse fibroblast NIH-3T3 cells expressing either the wild-type human IGF receptor or the insulin receptor were stimulated with either IGF-1 or insulin, respectively. Thirty genes, 27 of which were not previously known to be IGF-1 responsive, were up-regulated by IGF-1 but not by insulin. Nine genes, none of which was previously known to be insulin responsive, were up-regulated by insulin but not by IGF-1. The IGF- and insulin-induced regulation of 10 of these genes was confirmed by Northern blot analysis. Interestingly, more than half of the genes up-regulated by IGF-1 are associated with mitogenesis and differentiation, whereas none of the genes specifically up-regulated by insulin are associated with these processes. Our results indicate that under the conditions used in this study, IGF-1 is a more potent activator of the mitogenic pathway than insulin in mouse fibroblast NIH-3T3 cells. PMID- 11606466 TI - Parallel declines in Fos activation of the medial anteroventral periventricular nucleus and LHRH neurons in middle-aged rats. AB - The middle-age decline in reproductive function is manifested by reduced LHRH release, resulting in a decreased magnitude and delay of onset of the LH surge. Earlier studies suggested that the reductions in LHRH neural activation in middle aged rats resulted from deficits in the afferent drive to the LHRH neurons. One critical afferent to the LHRH neurons lies in the anteroventral periventricular preoptic area (AVPv) nucleus. The neurons of the medial AVPv are synchronously activated to express Fos with LHRH neurons at the time of an LH surge in young adult animals. The present study examined whether, in middle age, reductions in the activation of AVPv neurons accompany the reduction in Fos activation in LHRH neurons. Young (3- to 4-month-old) and middle-aged (10- to 12-month-old) spontaneously cycling and ovariectomized steroid-replaced rats were killed during peak and early descending phase of the LH surge, and their brains were examined for Fos in LHRH and AVPv neurons. Young animals had a characteristic increase in Fos expression in both LHRH and AVPv neurons. In middle-aged rats, the proportion of LHRH neurons expressing Fos at the time of an LH surge was reduced by approximately 50%, irrespective of whether surges were spontaneous or induced by exogenous steroids. A similar reduction in the number of Fos+ cells (by approximately 50%) was noted in the medial AVPv. Linear regression analysis of the relationship between the extent of Fos activation in LHRH and AVPv neurons revealed a strong positive correlation (r(2) = 0.66; P < 0.01), suggesting that changes in the AVPv's drive to LHRH neurons underlie the decrease in LHRH activity in middle age. A second series of experiments examined whether decreased input from the AVPv could account for reduced Fos activation in LHRH neurons seen in middle-aged animals. When the medial AVPv was lesioned, LHRH neurons failed to express Fos on the side ipsilateral to the lesion. Animals with lesioned medial AVPv also had significantly lower LH values than animals with an intact medial AVPv. Taken together, these data suggest that a principal deficit in middle-aged rats is the ability of the medial AVPv to stimulate LHRH neurons. PMID- 11606467 TI - PTH regulates fetal blood calcium and skeletal mineralization independently of PTHrP. AB - PTH and PTHrP both act in the regulation of fetal mineral metabolism. PTHrP regulates placental calcium transfer, fetal blood calcium, and differentiation of the cartilaginous growth plate into endochondral bone. PTH has been shown to influence fetal blood calcium, but its role in skeletal formation remains undefined. We compared skeletal morphology, mineralization characteristics, and gene expression in growth plates of fetal mice that lack parathyroids and PTH (Hoxa3 null) with the effects of loss of PTHrP (Pthrp null), loss of PTH/PTHrP receptor (Pthr1 null), and loss of both PTH and PTHrP (Hoxa3 null x Pthrp null). Loss of PTH alone does not affect morphology or gene expression in the skeletal growth plates, but skeletal mineralization and blood calcium are significantly reduced. In double-mutant fetuses (Hoxa3 null/Pthrp null), combined loss of PTH and PTHrP caused fetal growth restriction, limb shortening, greater reduction of fetal blood calcium, and reduced mineralization. These findings suggest that 1) PTH may play a more dominant role than PTHrP in regulating fetal blood calcium; 2) blood calcium and PTH levels are rate-limiting determinants of skeletal mineral accretion; and 3) lack of both PTH and PTHrP will cause fetal growth restriction. PMID- 11606468 TI - Reproductive deficiencies in transgenic mice expressing the rat inhibin alpha subunit gene. AB - Inhibin is an important modulator of reproductive function at both the endocrine level, through its regulation of pituitary FSH biosynthesis, and at the paracrine and autocrine levels, as an intragonadal regulatory factor. To investigate the in vivo actions of inhibin in FSH regulation and gonadal function, transgenic mice that overexpress the rat inhibin alpha-subunit gene were generated. A transgene that includes the mouse metallothionein-I gene promoter (MT-alpha) fused to the rat inhibin alpha-subunit precursor coding sequences was used to produce three lines of transgenic mice. Transgene mRNA is expressed in numerous tissues, including the pituitary, liver, testis, ovary, and kidney. Inhibin alpha-subunit protein was also increased in transgenic pituitary and ovary. Serum inhibin alpha subunit levels are highly increased compared with control mice. Inhibin beta(A)- and beta(B)-subunit protein amounts are lower in transgenic ovaries compared with wild type, although serum levels of activin A are not significantly reduced in transgenic female mice. FSH levels are reduced in both male and female transgenic mice, whereas LH levels are increased in MT-alpha female mice. MT-alpha transgenic females are subfertile and exhibit a 52% reduction in litter size compared with wild-type females. The smaller litter size of MT-alpha female mice was correlated with a reduction in the number of oocytes ovulated during a normal cycle. Treatment of the transgenic females with exogenous gonadotropins resulted in an ovulation rate similar to that of stimulated wild-type animals, suggesting that altered gonadotropin levels may be responsible for the decreased ovulation rates. MT-alpha transgenic male mice are fertile and sire litters of equivalent size to those sired by wild-type males, despite an approximately 50% reduction in sperm numbers. These results indicate that overexpression of the rat inhibin alpha-subunit gene in mice leads to a disruption of the normal inhibin-to-activin ratio and to reproductive deficiencies, and they support the hypothesis that inhibin and activin act to regulate FSH secretion in vivo and are essential for normal gonadal function. PMID- 11606469 TI - Gonadal pathologies in transgenic mice expressing the rat inhibin alpha-subunit. AB - Inhibin and activin are structurally related dimeric peptide hormones and are members of the TGF-beta superfamily of proteins. In the accompanying paper, we describe transgenic mice that overexpress the inhibin alpha-subunit gene from a metallothionein-I promoter (MT-alpha) and examine the effects of the MT-alpha transgene on gonadotropin levels and fertility. To characterize the effects of increased inhibin alpha-subunit on gonadal morphology and function, in this report we investigate gonadal histology, steroid hormone levels, and the basis of ovarian cyst formation in MT-alpha transgenic mice. MT-alpha transgenic female mice develop large fluid-filled ovarian cysts of follicular origin as early as 3 months of age. By 12 months of age, more than 92% of female MT-alpha transgenic mice develop ovarian cysts compared with less than 25% of wild-type littermates. Ovarian cysts form unilaterally or bilaterally, and cystic ovaries often have a greatly expanded bursal sac. Additionally, the ovaries of MT-alpha transgenic mice contain polyovular follicles and have fewer mature antral follicles and corpora lutea. MT-alpha female mice exhibit abnormal steroid hormone production, with increased serum T levels and reductions in serum E with corresponding reductions in uterine mass. In the MT-alpha transgenic males, testis size was decreased by 20-40% compared with control males, and there is a corresponding reduction in seminiferous tubule volume. After a chronic treatment with a GnRH antagonist, MT-alpha female mice continued to develop ovarian cysts and bursal sac expansions, although the cysts were markedly reduced in size. These results indicate that the expression of the rat inhibin alpha-subunit in mice results in significant ovarian pathology, reduced testicular size, and altered ovarian steroidogenesis. The antagonist studies are consistent with a direct ovarian effect of the alpha-subunit transgene product mediated by changes in the inhibin to-activin ratio in these mice. PMID- 11606470 TI - Tissue-specific induction of SOCS gene expression by PRL. AB - The mechanisms whereby tissue sensitivity to PRL is controlled are not well understood. Here we report that expression of mRNA and protein for members of the SOCS/CIS/JAB family of cytokine signaling inhibitors is increased by PRL administration in ovary and adrenal gland of the lactating rat deprived of circulating PRL and pups for 24 h but not in mammary gland. Moreover, suckling increases SOCS mRNA in the ovary but not in the mammary gland of pup-deprived rats. Deprivation of PRL and pups for 48 h allows the mammary gland to induce SOCS genes in response to PRL administration, and this is associated with a decrease in basal SOCS-3 mRNA and protein expression to the level seen in other tissues, suggesting that SOCS-3 induced refractoriness related to filling of the gland. In reporter assays, SOCS-1, SOCS-3, and CIS, but not SOCS-2, are able to inhibit transactivation of the STAT 5-responsive beta-lactoglobulin promoter in transient transfection assays. Moreover, suckling results in loss of ovarian and adrenal responsiveness to PRL administered 2 h after commencement of suckling, as determined by STAT 5 gel shift assay. Immunohistochemistry was used to localize the cellular sites of SOCS-3 and CIS protein expression in the ovary and adrenal gland. We propose that induced SOCS-1, SOCS-3, and CIS are actively involved in the cellular inhibitory feedback response to physiological PRL surges in the corpus luteum and adrenal cortex during lactation, but after pup withdrawal, the mammary gland is rendered unresponsive to PRL by increased levels of SOCS-3. PMID- 11606471 TI - Direct stimulation of arginine vasopressin gene transcription by cAMP in parvocellular neurons of the paraventricular nucleus in organotypic cultures. AB - The regulation of arginine vasopressin (AVP) gene transcription in the paraventricular nucleus (PVN) was studied in rat hypothalamic organotypic cultures using intronic in situ hybridization. While AVP heteronuclear (hn) RNA was not detected in the PVN under basal conditions, a marked induction of AVP hnRNA was observed after 2 and 3 h incubation of slices with forskolin. In contrast to the stimulatory effects of forskolin, phorbol 12-myristate 13-acetate (PMA) was completely ineffective in inducing AVP hnRNA in the PVN at any time examined (1-3 h). Forskolin-induced AVP hnRNA expression was unaffected by blockage of neurotransmission by the sodium channel inhibitor, tetrodotoxin, indicating that forskolin acts directly on AVP cells in the PVN. Dual staining in situ hybridization of forskolin-stimulated hypothalamic sections using both radio labeled AVP hnRNA and digoxigenin-labeled CRH mRNA probes revealed colocalization of both transcripts, indicating AVP hnRNA is expressed in the parvocellular neurons. The data demonstrate that cAMP directly activates AVP gene transcription in parvocellular neurons of the PVN. PMID- 11606472 TI - Intraoperative fluorescence visualization of the parathyroid gland in rats. AB - Bilateral neck exploration is the standard procedure of primary hyperparathyroidism. Preoperative localization is not mandatory. Intraoperative visualization methods help to avoid unsuccessful explorations and to reduce morbidity rates. In our study, the application of 5-Aminolevulinic acid (5-ALA), a precursor in the heme biosynthesis pathway, led to Protoporphyrin IX (PpIX) accumulation within the parathyroid gland (PTG). PpIX, a metabolite of 5-ALA, causes red fluorescence (635 nm) when stimulated by light of a defined wavelength. Largely invisible under conventional illumination, all PTGs were fluorescence positive and detectable after PpIX targeting and blue light excitation (380-440 nm). Point spectrometry to measure fluorescence intensities, showed a fluorescence ratio between PTG and surrounding thyroid gland tissue of 5.7:1 (p < 0.001). Fluorescence guided PTG biopsies showed no false positive findings in histology. 5-ALA induced PpIX fluorescence to detect PTGs suggests to be a highly sensitive intraoperative visualization method. Hence, the performance of minimally invasive video-assisted parathyroidectomy will be facilitated by this innovative technique. PMID- 11606474 TI - Endocrine-related resources from the National Institutes of Health. PMID- 11606473 TI - Inhibition of central amylin signaling increases food intake and body adiposity in rats. AB - Amylin is a 37-amino acid peptide hormone that is co-secreted with insulin by pancreatic beta cells in response to feeding. We recently reported that amylin potently reduces food intake, body weight, and adiposity when delivered into the 3rd cerebral ventricle (i3vt) of rats. We have now infused i3vt a specific antagonist (AC187) to ascertain the physiological relevance of central amylin in the control of energy balance. After establishing the ability of i3vt AC187 to block the anorexic effect of i3vt amylin, we performed an experiment to examine the impact of acute inhibition of central amylin signaling on feeding. Separate groups (n = 7/group) of ad lib-fed male Long Evans rats were given one bolus i3vt infusion of synthetic cerebrospinal fluid vehicle (CSF) or AC187 (250 or 1000 pmol). Acute infusion of AC187 tended to increase 1-h food intake and significantly elevated 4-h intake. Both the 250 and 1000 pmol doses produced significant increases as compared to CSF. In another experiment designed to tonically inhibit central amylin signaling over an extended period, two other groups of rats (n = 6/group) received continuous i3vt infusion of CSF or 100 pmol/h AC187 over 14 days via implantable osmotic pumps. Rats receiving AC187 ate significantly more food over the 14-day infusion period relative to controls (CSF = 322 +/- 6 g, AC187 = 360 +/- 12 g). Although body weight was not significantly affected, body fat was increased by about 30% in the AC187 rats, with no difference in lean tissue between the groups. Additionally, although fasting plasma glucose did not differ between the CSF and AC187 groups after 14 days of infusion, plasma insulin was significantly elevated in the AC187 rats. In summary, the present results document significant increases of food intake and body adiposity resulting from inhibition of central amylin signaling. They are consistent with our hypothesis that CNS actions of endogenous amylin contribute to the long-term regulation of energy balance. PMID- 11606477 TI - COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. AB - The regular use of various nonsteroidal anti-inflammatory drugs (NSAIDs) was shown to decrease the incidence of colorectal cancer. This effect is thought to be caused predominantly by inhibition of cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin synthesis. However, recent studies have suggested that COX-independent pathways may contribute considerably to these antiproliferative effects. To evaluate the involvement of COX-dependent and COX independent mechanisms further, we assessed the effects of celecoxib (selective COX-2 inhibitor) and SC560 (selective COX-1 inhibitor) on cell survival, cell cycle distribution, and apoptosis in three colon cancer cell lines, which differ in their expression of COX-2. Both drugs induced a G0/G1 phase block and reduced cell survival independent of whether or not the cells expressed COX-2. Celecoxib was more potent than SC560. The G0/G1 block caused by celecoxib could be attributed to a decreased expression of cyclin A, cyclin B1, and cyclin-dependent kinase-1 and an increased expression of the cell cycle inhibitory proteins p21Waf1 and p27Kip1. In addition, celecoxib, but not SC560, induced apoptosis, which was also independent of the COX-2 expression of the cells. In vivo, celecoxib as well as SC560 reduced the proliferation of HCT-15 (COX-2 deficient) colon cancer xenografts in nude mice, but both substances had no significant effect on HT-29 tumors, which express COX-2 constitutively. Thus, our in vitro and in vivo data indicate that the antitumor effects of celecoxib probably are mediated through COX-2 independent mechanisms and are not restricted to COX-2 over-expressing tumors. PMID- 11606476 TI - Early impairment of calcium handling and altered expression of junctin in hearts of mice overexpressing the beta1-adrenergic receptor. AB - Chronic stimulation of cardiac beta1-adrenergic receptors contributes to disease progression and mortality in patients and animal models of heart failure. To search for the mechanism of adrenergic impairment of cardiac function in vivo, we studied transgenic mice with cardiac-specific overexpression of beta1-adrenergic receptors. Transgenic mice with cardiac overexpression of beta1-adrenergic receptors showed progressive left ventricular fibrosis starting at 4 months of age. Left ventricular catheterization revealed a modest enhancement of contractility and relaxation at 2 months of age, followed by progressive dysfunction in both parameters and ultimately cardiac failure. When the effects of endogenous catecholamines were blocked by the b-receptor antagonist propranolol, maximal rate of contractility (dp/dtmax) and maximal rate of relaxation (dp/dtmin) were significantly blunted in 2-month-old beta1-receptor transgenic mice. Isolated cardiomyocytes from these animals displayed markedly altered calcium transients with significant prolongation of the intracellular calcium transient compared with nontransgenic littermates. We determined the expression of sarcoplasmic reticulum proteins involved in calcium handling by RNase protection assay and by immunoblotting. Although the expression of calsequestrin, triadin, and phospholamban was not altered, we observed a progressive decrease in junctin abundance in beta1-receptor transgenic mice (Pbeta1-adrenergic receptors. PMID- 11606479 TI - Preservation of motor function by inhibition of CD8+ virus peptide-specific T cells in Theiler's virus infection. AB - Central nervous system-infiltrating CD8+ T cells are potential mediators of neuropathology in models of multiple sclerosis induced by Theiler's murine encephalomyelitis virus (TMEV) infection. C57BL/6 mice mount a vigorous cytotoxic T lymphocyte (CTL) response against the immunodominant virus peptide VP2121-130 and clear TMEV infection. Interferon-g (IFN-g)R-/- mice also mount a strong CTL response against the VP2121-130 epitope, but because of genetic deficiencies in critical IFN-g signaling pathways, they do not clear TMEV infection and develop prominent neurological deficits within 6 wk. This pronounced disease process, coupled with a defined CTL response, provides an ideal model for evaluating the importance of antiviral CTL activity in the development of severe demyelination and loss of motor neuron function. By administering the VP2121-130 peptide before and during TMEV infection, 99% of the VP2121-130-specific CD8+ T cell response was inhibited. No decrease in virus infection was observed. Peptide treatment did result in significantly less motor dysfunction, even when no differences in levels of demyelination were observed. Although most investigators focus on the role of CD4+ T cells in demyelinating disease, these studies are the first to demonstrate a clear contribution of antiviral CD8+ T cells in neurological injury in a chronic-progressive model of multiple sclerosis. PMID- 11606478 TI - Discoidin domain receptor 1 isoform-a (DDR1alpha) promotes migration of leukocytes in three-dimensional collagen lattices. AB - Although integrins are crucial for migration of leukocytes through endothelium, integrin-independent mechanisms appear to take over and mediate the migration of leukocytes through extracellular matrix (ECM) in a three-dimensional tissue microenvironment. Discoidin domain receptor (DDR) 1 is a receptor tyrosine kinase activated by collagen, the most abundant ECM protein. In the present study, we detected that peripheral blood mononuclear cells (PBMC) and polymorphonuclear neutrophils were induced to express DDR1 after incubation in RPMI 1640. The expression level of DDR1 in PBMC was increased further by stimulation with tumor necrosis factor-alpha, interleukin-1beta, granulocyte-macrophage colony stimulating factor, lipopolysaccharide, or phytohemagglutinin, but not with interferon-gamma. In vivo, DDR1 mRNA was detectable in mononuclear leukocytes infiltrating human renal tumor tissue. Among three DDR1 isoforms, DDR1alpha was the major transcript in leukocytes. Functionally, overexpression of either DDR1alpha or DDR1beta in THP-1 cells resulted in increased adherence to collagen coated plates in a beta1-integrin independent manner. However, only DDR1alpha-, but not DDR1beta-, overexpressing cells exhibited marked pseudopod extension and migrated successfully through three-dimensional collagen lattices. Consequently, we propose that the interaction of DDR1alpha with collagen of the ECM results in a requisite intracellular signaling that enables leukocytes to migrate in a tissue microenvironment and participate in host defense. PMID- 11606480 TI - Role of macrophage-expressed adipocyte fatty acid binding protein in the development of accelerated atherosclerosis in hypercholesterolemic mice. AB - Atherosclerosis is an inflammatory disease process associated with elevated levels of plasma cholesterol, especially low-density lipoproteins. The latter become trapped within the arterial wall and are oxidized and taken up by macrophages to form foam cells. This process is an initiating event for atherosclerosis. Fatty acid binding proteins (FABP) are involved in fatty acid metabolism and cellular lipid transport, and adipocyte FABP (aP2) is also expressed in macrophages. We recently generated mice lacking both apolipoprotein (Apo)E and aP2 (ApoE-/-aP2-/-) and found that these mice, compared with ApoE-/- mice, developed markedly smaller atherosclerotic lesions that contained fewer macrophages. Here we investigated the mechanism(s) responsible for this prevention of atherosclerotic lesion formation. Bone marrow transplantations were performed in ApoE-/- mice, receiving cells from either ApoE-/- or ApoE-/-aP2-/- mice. The lack of aP2 in donor marrow cells led to the development of smaller (5.5-fold) atherosclerotic lesions in the recipient mice. No differences were found in plasma cholesterol, glucose, or insulin levels between recipients of bone marrow cells from ApoE-/- or ApoE-/-aP2-/- mice. However, the expression of chemoattractant and inflammatory cytokines was decreased in macrophages from ApoE /-aP2-/- mice compared with ApoE-/- mice, which may contribute to the decrease in atherosclerotic lesion formation. Taken together, we demonstrate the importance of macrophage aP2 in the development of atherosclerotic lesions. PMID- 11606481 TI - A novel contractile phenotype with cardiac transgenic expression of the human P2X4 receptor. AB - The P2X4 receptor is a newly identified receptor expressed in the heart cell. Its function was elucidated with cardiac transgenic (TG) expression of the receptor by using the myocardium-specific a-myosin heavy chain promoter. The presence of the transgene was determined by polymerase chain reaction by using primers specific to the receptor and the vector linker region, by Southern blotting of the genomic DNA, and by immunoblotting and immunohistochemistry of both isolated cardiac myocytes and intact hearts. In intact heart study, the P2X4 receptor TG mouse exhibited significantly elevated basal cardiac contractility with greater rates of contraction and relaxation, left ventricular developed pressure, and cardiac output compared with nontransgenic (NTG) animals but showed no evidence of hypertrophy or heart failure. The TG heart also showed a greater increase of cardiac contractility in response to the P2X receptor agonist 2-methylthioATP, consistent with overexpression of a functional P2X4 receptor with consequent increase in the receptor-mediated response. In isolated cardiac cell study, the TG heart cell showed a similar level of basal contraction amplitude as the NTG heart cell while exhibiting a threefold greater increase in contractility during stimulation by 2-methylthioATP. Thus, an increased responsiveness of the overexpressed P2X4 receptor to endogenous ATP is responsible for the enhanced basal cardiac performance in the intact TG heart. The sustained enhanced contractile function with no associated heart pathology in the P2X4 receptor TG mouse suggests a novel physiologic role of the P2X4 receptor, that of stimulating the cardiac contractility. PMID- 11606482 TI - Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. AB - White adipose tissue and liver are important angiotensinogen (AGT) production sites. Until now, plasma AGT was considered to be a reflection of hepatic production. Because plasma AGT concentration has been reported to correlate with blood pressure, and to be associated with body mass index, we investigated whether adipose AGT is released locally and into the blood stream. For this purpose, we have generated transgenic mice either in which adipose AGT is overexpressed or in which AGT expression is restricted to adipose tissue. This was achieved by the use of the aP2 adipocyte-specific promoter driving the expression of rat agt cDNA in both wild-type and hypotensive AGT-deficient mice. Our results show that in both genotypes, targeted expression of AGT in adipose tissue increases fat mass. Mice whose AGT expression is restricted to adipose tissue have AGT circulating in the blood stream, are normotensive, and exhibit restored renal function compared with AGT-deficient mice. Moreover, mice that overexpress adipose AGT have increased levels of circulating AGT, compared with wild-type mice, and are hypertensive. These animal models demonstrate that AGT produced by adipose tissue plays a role in both local adipose tissue development and in the endocrine system, which supports a role of adipose AGT in hypertensive obese patients. PMID- 11606483 TI - Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression. AB - We identified four new isoforms of human CRH-R1 (e-h) and three of mouse (mCRH R1c, e, and f). In all new forms exon 6 was missing. Human CRH-R1e was characterized by the deletion of exons 3 and 4; exon 12 from CRH-R1f; exon 11, 27 base pairs (bp) of exon 10 and 28 bp of exon 12 from CRH-R1g and CRH-R1h by the addition of a cryptic exon. In mouse CRH-R1c exon 3 was spliced out; in mCRH-R1e exons 3 and 4 and in mCRH-R1f exon 11 were spliced from mRNA. CRH-R1 was expressed in all skin specimens in patterns dependent on the cell type, physiological status, and presence of pathology. CRH-R1a, the most prevalent form, was detected in almost all samples. Ultraviolet radiation (UV) changed the splicing pattern and induced or increased expression of CRH-R1a in cultured skin cells. Continuing UV treatment of succeeding generations of cells resulted in a progressive increase in the number of CRH-R1 isoforms, which suggests that receptor heterogeneity might favor cell survival. TPA (phorbol 12-myristate 13 acetate), forskolin, dbcAMP (N6, 2'-O-dibutyryladenosine 3':5'-cyclic monophospate sodium), and IBMX (3-isobutyl-1-methylxanthine) also changed the splicing pattern. We suggest that a polymorphism of CRH-R1 expression is related to anatomic location, skin physiological or pathologic status, specific cell type, and external stress (UV), and that cAMP-dependent pathways and TPA may regulate CRH-R1. PMID- 11606484 TI - Extinguishing Egr-1-dependent inflammatory and thrombotic cascades after lung transplantation. AB - Hypoxic induction of the early growth response-1 (Egr-1) transcription factor initiates proinflammatory and procoagulant gene expression. Orthotopic/isogeneic rat lung transplantation triggers Egr-1 expression and nuclear DNA binding activity corresponding to Egr-1, which leads to increased expression of downstream target genes such as interleukin-1b, tissue factor, and plasminogen activator inhibitor-1. The devastating functional consequences of Egr-1 up regulation in this setting are prevented by treating donor lungs with a phosphorothioate antisense oligodeoxyribonucleotide directed against the Egr-1 translation initiation site, which blocks expression of Egr-1 and its gene targets. Post-transplant graft leukostasis, inflammation, and thrombosis are consequently diminished, with marked improvement in graft function and recipient survival. Blocking expression of a proximal transcription factor, which activates deleterious inflammatory and coagulant effector mechanisms, is an effective molecular strategy to improve organ preservation. PMID- 11606485 TI - Dissecting hypoxia-dependent and hypoxia-independent steps in the HIF-1alpha activation cascade: implications for HIF-1alpha gene therapy. AB - The heterodimeric hypoxia-inducible factor (HIF)-1 is a master transcriptional regulator of oxygen homeostasis and a possible target for gene therapy of ischemic disease. Although the role of oxygen concentration in HIF-1a protein stabilization is well established, it is less clear whether and how oxygen regulated mechanisms contribute to HIF-1a protein modifications, nuclear translocation, heterodimerization with the b-subunit, recruitment of cofactors, and gene trans-activation. Because the HIF-1a protein is proteolytically degraded under normoxic conditions, we established two HeLa Tet-Off cell lines (HT42 and HT43), which inducibly overexpress high levels of HIF-1a under normoxic conditions, allowing to distinguish hypoxia-dependent from hypoxia-independent activation mechanisms. Using these cells, we found that normoxically induced HIF 1a is localized to the nucleus, binds DNA, and trans-activates reporter and endogenous target genes. The levels of p53 expression remained unaffected. The MAP kinase inhibitor PD98059 attenuated HIF-1a protein modifications and trans activation ability but not protein stabilization and DNA-binding activity. Because overexpressed HIF-1a is fully localized to the nucleus but displays only partial DNA-binding and trans-activation activity, mitogen-activated protein kinase-dependent phosphorylation might be required for full HIF-1 activation. HIF 1a protein was also overexpressed in vivo, following the transplantation of HT42 cells into nude mice, demonstrating the feasibility of HIF-1a gene transfer. PMID- 11606486 TI - 1alpha,25-Dihydroxyvitamin D3 modulates human adipocyte metabolism via nongenomic action. AB - We reported recently that suppression of the renal 1alpha,25-dihyroxyvitamin D3 (1lpha,25-(OH)2-D3) production in aP2-agouti transgenic mice by increasing dietary calcium decreases adipocyte intracellular Ca2+ ([Ca2+]i), stimulates lipolysis, inhibits lipogenesis, and reduces adiposity. However, it was not clear whether this modulation of adipocyte metabolism by dietary calcium is a direct effect of inhibition of 1alpha,25-(OH)2-D3-induced [Ca2+]i. Accordingly, we have now evaluated the direct role of 1alpha,25-(OH)2-D3. Human adipocytes exhibited a 1alpha,25-(OH)2-D3 dose-responsive (1-50 nM) increase in [Ca2+]i (P<0.01). This action was mimicked by 1alpha,25-dihyroxylumisterol3 (1alpha,25-(OH)2 lumisterol3) (P<0.001), a specific agonist for a putative membrane vitamin D receptor (mVDR), and completely prevented by 1b,25-dihydroxyvitamin D3 (1beta,25 (OH)2-D3), a specific antagonist for the mVDR. Similarly, 1alpha,25-(OH)2-D3 (5 nM) caused 50%-100% increases in adipocyte fatty acid synthase (FAS) expression and activity (P<0.02), a 61% increase in glycerol-3-phosphate dehydrogenase (GPDH) activity (P<0.01), and an 80% inhibition of isoproterenol-stimulated lipolysis (P<0.001), whereas 1beta,25-(OH)2-D3 completely blocked all these effects. Notably, 1alpha,25-(OH)2-lumisterol3 exerted more potent effects in modulating adipocyte lipid metabolism, with 2.5- to 3.0-fold increases in FAS expression and activity (P<0.001) and a threefold increase in GPDH activity (P<0.001). Also 1alpha,25-(OH)2-lumisterol3 was approximately twice as potent in inhibiting basal lipolysis (P<0.025), whereas 1beta,25-(OH)2-D3 completely blocked all these effects. These data suggest that 1alpha,25-(OH)2-D3 modulates adipocyte Ca2+ signaling and, consequently, exerts a coordinated control over lipogenesis and lipolysis. Thus, a direct inhibition of 1alpha,25-(OH)2-D3 induced [Ca2+]i may contribute to an anti-obesity effect of dietary calcium, and the mVDR may represent an important target for obesity. PMID- 11606487 TI - Reporting randomized controlled trials in gastroenterology: the CONSORT statement. PMID- 11606488 TI - Neural stem cells express RET, produce nitric oxide, and survive transplantation in the gastrointestinal tract. AB - BACKGROUND & AIMS: Transplantation of neural stem cells (NSC) has been shown to be successful in a variety of experimental models of nongastrointestinal diseases. The aim of this study was to assess the potential of NSC transplantation as a therapeutic strategy for neuronal replacement in disorders of the enteric nervous system. METHODS: Central nervous system-derived NSC (CNS NSC) were obtained from the subventricular zone of rat brain (E17). Expression of RET, GFRalpha1, and neuronal nitric oxide synthase (nNOS) was assessed by Western blot and immunocytochemistry. Nitric oxide (NO) production was assessed using the NO-sensitive fluorescent indicator DAF-2. CNS-NSC (labeled with CM-DiI) were transplanted into the pylorus of mice and fluorescent double-labeling immunostaining for betaIII-tubulin or PGP 9.5 and nNOS was performed at 2, 4, and 8 weeks after transplantation. RESULTS: Our results show that CNS-NSC express both the receptors (RET and GFRalpha1) for the enteric neurotrophin, GDNF; GDNF, in turn, induces expansion of the RET-expressing CNS-NSC population. Furthermore, CNS-NSC express nNOS and produce NO in vitro. When transplanted into the gut, CNS NSC differentiate into neurons, continue to express nNOS and survive at least 8 weeks. CONCLUSIONS: We conclude that transplantation of CNS-NSC bears promise as a potential cellular replacement strategy for enteric neurons. PMID- 11606489 TI - Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. AB - BACKGROUND & AIMS: Marijuana and other cannabinoids are effective anti-emetics. Despite ongoing controversy over their usage, the receptor distribution and the site of the anti-emetic action of these compounds are not known. Our aim was to investigate whether the cannabinoid 1 receptor (CB1r) and endocannabinoids play a role in the anti-emetic action of cannabinoids. METHODS: Ferrets were given an emetic stimulus and the number of episodes of retching and vomiting were observed after administration of CB1r agonists and a CB1r antagonist. CB1r and fatty acid amide hydrolase (FAAH), which degrades endocannabinoids, were localized by immunohistochemistry. RESULTS: CB1r and FAAH were localized in the dorsal vagal complex, consisting of the area postrema, nucleus of the solitary tract, and the dorsal motor nucleus of the vagus in the brainstem. CB1r was found in the myenteric plexus of the stomach and duodenum. Activation of CB1r by the agonists (delta)(9)-tetrahydrocannabinol, WIN 55,212-2, and methanandamide inhibited emesis and their action was reversed by a selective CB1r antagonist, which alone had no effect, but potentiated vomiting in response to an emetic stimulus. CONCLUSIONS: CB1r mediates the anti-emetic action of cannabinoids in the dorsal vagal complex. Endocannabinoids are a novel neuroregulatory system involved in the control of emesis. PMID- 11606490 TI - Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal. AB - BACKGROUND & AIMS: Gastroesophageal reflux typically occurs after meals. During dual gastric and esophageal pH monitoring, we observed that postprandial refluxate was often more acidic than the gastric contents. This study aimed to investigate this phenomenon. METHODS: Dual gastric and esophageal pH tracings were analyzed from 40 dyspeptic patients. Dual pH electrode pull-through studies were performed in healthy volunteers to document regional variation in intragastric pH under both fasting and postprandial conditions. The squamocolumnar junction was identified using radio-opaque endoscopic clips. We also examined in vitro partitioning of gastric juice added to a homogenized fatty meal. RESULTS: The dual pH traces confirmed that esophageal refluxate was frequently more acidic than the body of the stomach after meals but not during fasting. The pull-through studies showed a pocket of acid at the gastroesophageal junction that escaped the buffering effect of meals, remaining highly acidic (median pH 1.6) compared with the body of the stomach (pH 4.7; P < 0.001). This proximal acid pocket extended from the cardia across the squamocolumnar junction 1.8 cm into the distal esophagus. The in vitro studies showed that acidic gastric juice could partition on top of a homogenized fatty meal. CONCLUSIONS: After eating, highly acidic unbuffered gastric juice is present at the gastroesophageal squamocolumnar junction and is likely to contribute to the high prevalence of disease at this site. PMID- 11606491 TI - Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. AB - BACKGROUND & AIMS: Helicobacter pylori may disappear spontaneously with progressing precancerous changes and invalidate serologic studies of its association with gastric cancer. We reestimated the strength of the H. pylori gastric cancer relationship, using both conventional immunoglobulin (Ig) G enzyme linked immunosorbent assay (ELISA) and immunoblot (against cytotoxin-associated antigen A [CagA] antibodies that prevail longer after eradication) to detect past H. pylori exposure more relevant for time at cancer initiation. METHODS: In our population-based case-control study, the seroprevalence among 298 gastric adenocarcinoma cases was 72% (IgG ELISA) and 91% (immunoblot) vs. 55% and 56% among 244 controls frequency-matched for age and gender. RESULTS: Using IgG ELISA only, the adjusted OR for noncardia gastric cancer among H. pylori-positive subjects was 2.2 (95% confidence interval [CI], 1.4-3.6). When ELISA-/CagA+ subjects (odds ratio [OR], 68.0) were removed from the reference, the OR rose to 21.0 (95% CI, 8.3-53.4) and the previous effect modification by age disappeared. ELISA+/CagA- subjects had an OR of 5.0 (95% CI, 1.1-23.6). There were no associations with cardia cancer. CONCLUSIONS: The weaker H. pylori-cancer relationships in studies based on IgG ELISA rather than CagA may be caused by misclassification of relevant exposure. A much stronger relationship emerges with more accurate exposure classification. In the general Swedish population, 71% of noncardia adenocarcinomas were attributable to H. pylori. PMID- 11606492 TI - Recrudescence and reinfection with Helicobacter pylori after eradication therapy in Bangladeshi adults. AB - BACKGROUND & AIMS: In developing countries where Helicobacter pylori infection is widespread, posttherapeutic recurrence rates may be high. Many of the limited studies available have methodological problems and show varied recurrence rates. We determined late recrudescence rates, true reinfection, and ulcer recurrence. METHODS: One hundred five Bangladeshi patients with H. pylori infection and duodenal ulcer disease were treated with a triple therapy. Follow-up included 13C urea breath tests, endoscopy, and biopsy-based tests. In reinfected patients, genomic typing compared pretherapeutic and posttherapeutic strains. RESULTS: Recrudescence, associated with nitroimidazole-based treatment, occurred in 15 of 105 patients (14%) within the first 3 months, but only 8 of 105 patients tested positive 4 weeks after therapy ended. True reinfection was diagnosed in 11 of 105 patients between 3 and 18 months after therapy. The annual reinfection rate was 13%, based on a total follow-up of 84.7 patient years. Ulcer relapse occurred in 2 of 15 (13%) recrudescence cases and in 6 of 11 (55%) reinfection cases, but also in 4 of 73 (5%) H. pylori-negative patients. CONCLUSIONS: In Bangladesh, late recrudescence of H. pylori after eradication therapy occurs within the first 3 months. The reinfection rate is high and might influence cost-benefit analyses for determining diagnostic and therapeutic procedures. PMID- 11606493 TI - Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. AB - BACKGROUND & AIMS: Heredity has been suggested to explain the finding that irritable bowel syndrome (IBS) tends to run in families. Research in this area has been limited. The aim of the present study was to assess the relative contribution of genetic and environmental (social learning) influences on the development of IBS by comparing concordance rates in monozygotic and dizygotic twins to concordance between mothers and their children. METHODS: Questionnaires soliciting information on the occurrence of more than 80 health problems, including IBS, in self and other family members were sent to both members of 11,986 twin pairs. RESULTS: Analysis is based on 10,699 respondents representing 6060 twin pairs. Concordance for IBS was significantly greater (P = 0.030) in monozygotic (17.2%) than in dizygotic (8.4%) twins, supporting a genetic contribution to IBS. However, the proportion of dizygotic twins with IBS who have mothers with IBS (15.2%) was greater than the proportion of dizygotic twins with IBS who have co-twins with IBS (6.7%, P < 0.001), and logistic regression analysis showed that having a mother with IBS and having a father with IBS are independent predictors of irritable bowel status (P < 0.001); both are stronger predictors than having a twin with IBS. Addition of information about the other twin accounted for little additional predictive power. CONCLUSIONS: Heredity contributes to development of IBS, but social learning (what an individual learns from those in his or her environment) has an equal or greater influence. PMID- 11606494 TI - The interleukin 1 receptor antagonist gene allele 2 as a predictor of pouchitis following colectomy and IPAA in ulcerative colitis. AB - BACKGROUND & AIMS: The interleukin 1 receptor antagonist gene allele 2 has been suggested as a determinant of both disease susceptibility and extent in ulcerative colitis. The aim of this study was to assess the allele as a predictor of both the indication for colectomy and the occurrence of pouchitis after ileal pouch-anal anastomosis formation. METHODS: Genotyping for the +2018 single nucleotide polymorphism in the interleukin 1 receptor antagonist gene was performed in 109 patients who had undergone colectomy, including 82 patients who had been followed prospectively after ileal pouch-anal anastomosis formation. RESULTS: Patients with pouchitis had a higher allele 2 carriage rate compared with those without pouchitis (72% vs. 45%) and Kaplan-Meier survival analysis showed that allele 2 carriers had a significantly increased incidence of pouchitis compared with noncarriers (log-rank test, 6.5). After adjustment for confounding covariates in a Cox proportional hazards model, the relative hazard was 3.1 (95% confidence interval [CI], 1.2-7.8; P = 0.02). Although there was a higher allele 2 carriage rate in patients with chronic refractory compared with acute severe ulcerative colitis (63% vs. 48%), this difference was not significant (odds ratio, 1.9; 95% CI, 0.9-4.1; P = 0.1). CONCLUSIONS: The interleukin 1 receptor antagonist gene allele 2 predicts pouchitis after ileal pouch-anal anastomosis in ulcerative colitis. PMID- 11606495 TI - Colonic transit influences deoxycholic acid kinetics. AB - BACKGROUND & AIMS: Prolonged large bowel transit, and an increase in the proportion of deoxycholic acid (DCA), have been implicated in the pathogenesis of cholesterol gallstones-including those developing in acromegalics treated with octreotide. However, there are few data on the effects of intestinal transit on bile acid kinetics. METHODS: We therefore measured the kinetics of DCA and cholic acid (CA) using stable isotopes, serum sampling, and mass spectrometry. The results were related to mouth-to-caecum (MCTT) and large bowel transit times (LBTTs) in 4 groups of 8 individuals: (1) non-acromegalic controls, (2) acromegalics untreated with octreotide, (3) acromegalics on long-term octreotide, and (4) patients with constipation. Paired, before and during octreotide, studies were performed in 5 acromegalics. RESULTS: In the unpaired and paired studies, octreotide significantly prolonged MCTT and LBTT. In the paired studies, the octreotide-induced prolongation of LBTT caused an increase in the DCA input rate (6.4 +/- 2.8 to 12 +/- 2.6 micromol. kg. d, P < 0.05) and pool size (18 +/- 12 to 40 +/- 13 micromol/kg, P < 0.05), and a decrease in CA pool size (45 +/- 15 to 25 +/- 11 micromol/kg, P < 0.05). Furthermore, during octreotide treatment, the mean conversion of 13C-CA to 13C-DCA (micromoles) was greater (P < 0.05) on study days 3, 4, and 5. There were also positive linear relationships between LBTT and DCA input rate (r = 0.78), pool size (r = 0.82, P < 0.001), and a weak (r = -0.49) negative linear relationship between LBTT and CA pool size (P < 0.01). CONCLUSIONS: These data support the hypothesis that, by increasing DCA formation and absorption, prolongation of large bowel transit is a pathogenic factor in the formation of octreotide-induced gallstones. PMID- 11606496 TI - Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. AB - BACKGROUND & AIMS: Interleukin (IL)-1 gene cluster proinflammatory polymorphisms have been associated with development of gastric atrophy and with increased risk of gastric carcinoma. We aimed to determine the association between IL-1 loci polymorphisms and increased risk of gastric carcinoma in samples from a Portuguese population, and to find whether there was any relationship with the histologic types of gastric carcinoma. METHODS: In a case-control study including 220 controls and 152 patients with gastric carcinoma (intestinal, 76; diffuse, 37; and atypical, 39), both the IL-1B-511 biallelic polymorphism and the IL-1RN penta-allelic variable number of tandem repeats were genotyped. RESULTS: We found a significant association between the IL-1 polymorphisms and increased risk for tumor development in patients with intestinal-type gastric carcinoma. A trend towards an increased risk of tumor development was also observed in patients with diffuse-type gastric carcinoma. No significant relationship was observed in patients with atypical carcinoma. Carriers of IL-1B-511T and IL-1RN*2 homozygotes had increased risk for developing intestinal-type gastric carcinoma with odds ratios of 2.7 (95% confidence interval [CI], 1.5-4.9) and 3.1 (95% CI, 1.5-6.5), respectively. Statistical analysis showed an interaction between the 2 loci with the risk conferred by the IL-1B-511T allele substantially increased (odds ratio, 9.0; 95% CI, 3.5-23.0) in individuals homozygous for the IL-1RN*2 allele. CONCLUSIONS: Our results provide further support to the association between IL-1 gene cluster proinflammatory polymorphisms and increased risk of gastric carcinoma. Furthermore, we found evidence pointing to the existence of a synergistic interaction between the IL-1B and IL-1RN polymorphisms. PMID- 11606498 TI - Multicellular gastric cancer spheroids recapitulate growth pattern and differentiation phenotype of human gastric carcinomas. AB - BACKGROUND & AIMS: Advanced gastric cancer has a poor prognosis and is largely unresponsive to currently available chemotherapeutic drugs. The development of more effective therapies would be aided by better preclinical models. METHODS: An in vitro multicellular gastric cancer spheroid model was established using the liquid overlay technique and compared with the corresponding xenografts in immunodeficient mice. RESULTS: Twelve of 17 (71%) gastric cancer cell lines reflected growth characteristics of their parental gastric carcinomas in three dimensional culture. Thus, cell lines derived from peritoneal and pleural carcinomatosis grew as single cells (HSC-39, KATO-II, KATO-III) and cell aggregates (SNU-5, SNU-16). Cell lines representing adenosquamous (MKN-1) and tubular differentiation (MKN-28, MKN-74, N87) formed partly compact multicellular spheroids recapitulating the tumor architecture of the respective original tumor. The differentiated phenotype was lost after subcutaneous implantation of the in vitro spheroids in mice. The degree of morphologic differentiation was reflected by the levels of mucin and constitutive E-cadherin expression. Heterogeneous changes of other adhesion molecules (EpCAM, alpha2beta1, CD44s, Le(x), sLe(x)) were observed. In contrast, cell lines derived from poorly differentiated gastric carcinomas (Hs-746T, RF-1, RF-48) formed fully compact spheroids mimicking the poorly differentiated phenotype, were E-cadherin negative, and showed only CD44s up-regulation. CONCLUSIONS: Recapitulating some complexity of their in vivo counterparts, multicellular gastric cancer spheroids may represent a physiologically valid model for studying the biology of this cancer, and testing new therapeutic strategies. PMID- 11606497 TI - The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. AB - BACKGROUND & AIMS: Estimates of the frequency of hereditary nonpolyposis colon cancer (HNPCC) based on clinical criteria have varied widely. Recent studies of germline mismatch repair gene mutations have suggested that HNPCC accounts for close to 3% of all colon cancer, but this estimate may have been inflated by inclusion of founder effects peculiar to Finland. We therefore determined by genetic criteria the colon cancer burden associated with HNPCC in a population based study of 1066 individuals from Utah and California. METHODS: The coding regions of mismatch repair genes hMSH2 and hMLH1 were sequenced from the germline of those individuals whose tumors exhibited microsatellite instability. RESULTS: Microsatellite instability was present in 16% (171/1066) of tumors. Pathogenic germline mismatch repair gene mutations were identified in 7 individuals, and missense amino acid changes of uncertain significance were identified in another 6 individuals. After adjusting for the availability of sufficient germline DNA for sequencing, the 7 clearly pathogenic mutations accounted for 0.86% of colon cancer at the population level. Individuals with these mutations were significantly younger, more likely to have a family history of colon and endometrial cancer, and more likely to have first-degree relatives with a young age onset of colon cancer than individuals with unstable tumors but without germline mutations (P < 0.01). CONCLUSIONS: We conclude that genetically defined HNPCC accounts for a very small percentage of colon cancer at the population level, a percentage less than that estimated by most previous clinical studies. PMID- 11606499 TI - Immune cell trafficking in uterus and early life is dominated by the mucosal addressin MAdCAM-1 in humans. AB - BACKGROUND & AIMS: In adults, binding of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) to lymphocyte alpha4beta7 integrin directs cell trafficking to gut, whereas interaction of peripheral node addressins (PNAd) with lymphocyte L selectin targets immune cells to peripheral lymph nodes (PLNs). Because nothing is known about these addressins during human development, we studied the expression and function of MAdCAM-1 (and PNAd for comparison) in fetuses and children. METHODS: Series of human tissue samples obtained from fetuses (7-40 weeks), children (2 months-7 years), and adults were immunostained with monoclonal antibodies. The function of the addressins and their lymphocyte counter-receptors was tested in in vitro binding assays on fetal and adult tissues. RESULTS: Unlike in adults, MAdCAM-1 is widely expressed from embryonic week 7 onwards, and it only gradually becomes polarized to mucosal vessels after birth. In utero MAdCAM-1 functionally governs lymphocyte adhesion to vessels both in the gut and PLNs by binding to alpha4beta7 integrin. The later induction of PNAd gradually starts to dominate the binding of lymphocytes to PLNs during childhood. CONCLUSIONS: There are striking age-dependent switches and species specific variation in the molecular mechanisms of lymphocyte migration. In utero and during early childhood, the mucosal addressin MAdCAM-1 plays a dominant role in lymphocyte-endothelial cell adhesion at mucosal and nonmucosal sites. PMID- 11606500 TI - Glutathione S-transferase-pi overexpression is closely associated with K-ras mutation during human colon carcinogenesis. AB - BACKGROUND & AIMS: In colorectal adenoma and carcinoma, glutathione S-transferase pi (GSTP1-1) is highly expressed. K-ras mutation is also known to occur frequently in colorectal adenoma and carcinoma, as well as in the putative precursor of adenoma, aberrant crypt foci (ACF). Further, forced expression of v H-ras in rat liver epithelial cells has been shown to enhance rat pi-class GST expression. The aim of the present study is, therefore, to investigate the causative relationship between GSTP1-1 overexpression and K-ras mutation in these lesions. METHODS: Twenty-seven specimens of colorectal carcinoma, 24 of adenoma, and 28 of ACF were examined in this study. The expression of GSTP1-1 or p21(K ras) was examined by immunohistochemistry. The GSTP1-1 messenger RNA levels were measured by TaqMan reverse-transcription polymerase chain reaction (PCR). K-ras mutation was detected by two-step PCR restriction fragment length polymorphism. v K-ras transfection to RPMI-4788 colon carcinoma cells was carried out by the lipofection method. Activities of GSTP1-1 promoters containing AP-1 and Sp1 responsive elements in the v-K-ras transfectants were measured by a secreted form of human placental alkaline phosphatase (SEAP) assay. Nuclear protein from these transfectants bound to the GSTP1-1 promoter was analyzed by electrophoretic mobility shift assay (EMSA). RESULTS: In human colorectal carcinoma, adenoma, and ACF, close association of increased expression of GSTP1-1 with K-ras mutation was observed. v-K-ras transfectants showed significantly higher SEAP activity than that of mock-transfectant activity. EMSA showed specific interaction of AP-1 with promoter of GSTP1-1. CONCLUSIONS: It is highly plausible that GSTP1-1 overexpression in ACF, colorectal adenoma, and carcinoma is induced by K-ras mutation via AP-1 activation. PMID- 11606501 TI - Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease. AB - BACKGROUND & AIMS: Crohn's disease (CD) is associated with an increased number of infiltrating macrophages, which release a variety of proinflammatory cytokines. Interleukin (IL)-18 has been implicated in the modulation of mucosal CD4(+) T cells towards Th1 responses, which are implicated in the pathogenesis of CD. Here we assess the role of macrophages and of IL-18 in the murine model of intestinal inflammation that mimics the immunologic characteristics of human CD. METHODS: Colitis was induced in C57BL/6 mice immunized with 2,4,6-trinitrobenzene sulfonic acid (TNBS) followed by rectal administration of TNBS in ethanol. Mice were treated with either an antibody directed against macrophages conjugated to the ribosome-inactivating protein saporin (anti-Mac-1-saporin) or with a neutralizing antibody against IL-18. In addition, we assessed whether an identical TNBS immunization/challenge protocol could induce colitis in IL-18(-/-) mice. RESULTS: The colonic mucosa of TNBS-treated mice was marked by infiltration of Mac-1 positive macrophages and up-regulation of IL-18. The administration of the anti Mac-1-saporin antibody or the neutralizing anti-IL-18 antibody resulted in a dramatic attenuation of mucosal inflammation in this model. In addition, TNBS was unable to induce significant colitis in the IL-18(-/-) mice. CONCLUSIONS: Our data underscore the pivotal role of macrophages, and the macrophage-derived IL 18, in the establishment of TNBS-induced colitis in mice. Our results highlight the potential use of therapy directed against IL-18 in the treatment of patients with CD. PMID- 11606502 TI - Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the Apc(Min/+) mouse. AB - BACKGROUND & AIMS: The role of the inducible isoform of nitric oxide synthase (Nos2 or iNOS) in intestinal tumorigenesis is unclear. Conflicting data also exist regarding the ability of Nos2 to modulate expression and/or activity of cyclooxygenase 2 (Cox-2), which promotes intestinal tumorigenesis. Therefore, we determined the effect of a null Nos2 genotype on intestinal tumorigenesis and Cox 2 expression/activity in the Apc(Min/+) mouse model of familial adenomatous polyposis. METHODS: Apc(Min/+)Nos2(-/-) mice were generated by successive crosses between C57BL/6-Apc(Min/+) and C57BL/6-Nos2(tm1Lau) mice. Adenoma characteristics of age-matched Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) mice were compared. The level and cellular localization of Nos2 messenger RNA (mRNA) expression in Apc(Min/+)Nos2(+/+) mouse intestine was determined. Cox-2 expression and activity were measured in both intestinal tissue and bone marrow-derived macrophages in vitro. RESULTS: Apc(Min/+)Nos2(-/-) mice developed significantly more intestinal adenomas than Apc(Min/+)Nos2(+/+) littermates. Epithelial cell Nos2 mRNA expression was decreased in adenomas compared with histologically normal Apc(Min/+)Nos2(+/+) intestine. There was no significant difference in Cox-2 expression or activity in either intestine or bone marrow-derived macrophages from Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) animals. CONCLUSIONS: Nos2 plays an antineoplastic role in the Apc(Min/+) mouse model of familial adenomatous polyposis. Nos2 does not modulate Cox-2 expression or activity in the Apc(Min/+) mouse. PMID- 11606503 TI - A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. AB - BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) is used for the treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) for which it has a positive effect on laboratory values, may delay the development of liver failure and prolong the transplant-free disease period. Standard doses of UDCA (8 15 mg/kg daily) have been shown to be ineffective in the treatment of primary sclerosing cholangitis (PSC). We report on the findings (clinical, biochemical, histological, and cholangiographic) and side effects of a 2-year double-blind placebo-controlled preliminary study of high-dose UDCA in PSC patients. METHODS: Twenty-six patients with PSC were randomized to high-dose (20 mg/kg daily) UDCA or placebo. Cholangiography and liver biopsy were performed at entry and after 2 years. Symptoms, clinical signs, and liver biochemical tests were recorded at 3 monthly intervals. RESULTS: High-dose UDCA did not influence symptoms, but there was a significant improvement in liver biochemistry (serum alkaline phosphatase, P = 0.03; gamma-glutamyl transferase, P = 0.01) and a significant reduction in progression in cholangiographic appearances (P = 0.015) and liver fibrosis as assessed by disease staging (P = 0.05). In the treatment group, a significant increase in total bile acids and saturation with UDCA >70% confirmed patient compliance. No significant side effects were reported. CONCLUSIONS: High-dose UDCA may be of clinical benefit in PSC, but trials with a larger number of participants and of longer duration are required to establish whether the effect of high-dose UDCA on liver biochemistry, histology, and cholangiography in patients with PSC is translated into improved long-term survival. PMID- 11606504 TI - Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive beta-blockers. AB - BACKGROUND & AIMS: Nonselective beta-blockers (beta-blockers) are very effective in preventing first variceal bleeding (FVB) in patients with cirrhosis. However, 15%-25% of patients have contraindications or develop severe side effects precluding its use. The present study evaluates whether isosorbide-5-mononitrate (Is-MN) effectively prevents variceal bleeding in patients with contraindications or who could not tolerate beta-blockers. METHODS: One hundred thirty-three consecutive cirrhotic patients with gastro-esophageal varices and contraindications or intolerance to beta-blockers were included in a multicenter, prospective, double-blind randomized controlled trial. Sixty-seven were randomized to receive Is-MN, and 66 to receive placebo. RESULTS: There were no significant differences in the 1- and 2-year actuarial probability of experiencing a FVB between the 2 treatment groups. Presence of variceal red signs at endoscopy was the only variable independently associated with an increased risk of variceal bleeding on follow-up (relative risk 3.4; P < 0.01). Survival and adverse events were similar in the 2 groups. There were no significant differences in the incidence of ascites or changes in renal function. CONCLUSIONS: Is-MN does not reduce the incidence of FVB in patients with cirrhosis and esophageal varices who cannot be treated with beta-blockers because contraindications or intolerance to these drugs, suggesting that Is-MN has no place in the primary prophylaxis of variceal bleeding. PMID- 11606505 TI - Somatostatin suppresses endothelin-1-induced rat hepatic stellate cell contraction via somatostatin receptor subtype 1. AB - BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are considered therapeutic targets to decrease portal hypertension. To elucidate some of the hemodynamic effects of somatostatin (SST) on portal pressure, the presence and function of SST receptors (SSTRs) on HSCs were investigated. METHODS: SSTR messenger RNA expression, and SSTR presence was investigated using reverse-transcription polymerase chain reaction, real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. The function of SSTRs was studied by examining the effects of SST and specific SSTR agonists on endothelin-1(ET-1) induced HSC contraction. RESULTS: Specific amplicons for SSTR subtypes 1, 2, and 3 were demonstrated in rat liver and in activated HSCs. The presence of SSTR subtypes 1, 2, and 3 was confirmed by Western blotting. With immunohistochemistry, a strong staining of HSCs was obtained for SSTR subtypes 1, 2, and 3 in CCl4-treated rats, but not in normal rat liver. Incubation of HSCs on collagen gels with buffer, 10(-8) mol/L SST, and 2 x 10(-8) mol/L ET-1 resulted in collagen surface area decreases of 5.5% +/- 3.3%, 6.8% +/- 4.4%, and 49.8% +/- 8.3%, respectively. Relative contraction of gels preincubated with 10(-8) mol/L SST followed by 2 x 10(-8) mol/L ET-1 or vice versa as compared with maximal contraction (100%) with 2 x 10(-8) mol/L ET-1 were 72.6% +/- 17.9% and 76.2% +/- 12.6%, respectively (P < 0.05). SSTR agonist 1, but not SSTR agonist 2 or 3, was able to counteract the contractile effect of ET-1. CONCLUSIONA: Activated rat HSCs bear SSTR subtypes 1, 2, and 3. SST causes significant partial inhibition of ET-1-induced contraction of activated HSCs, mainly by stimulation of SSTR subtype 1. PMID- 11606506 TI - Immunotherapy directed against alpha-fetoprotein results in autoimmune liver disease during liver regeneration in mice. AB - BACKGROUND & AIMS: Priming immune responses against alpha-fetoprotein (AFP) highly expressed in the majority of hepatocellular carcinomas results in significant antitumoral T-cell responses. Liver regeneration in humans and mice, however, is also associated with increased AFP expression. Therefore, we evaluated the risk of AFP-directed immunotherapeutic approaches to induce autoimmunity against the regenerating liver. METHODS: Mice were immunized with DNA encoding mouse AFP. For induction of liver regeneration, partial hepatectomy was performed and mice were monitored by serial histopathologic examinations and measurements of serum ALT activities (U/L), and by determination of the kinetics of AFP-specific T-cell responses. RESULTS: Livers of AFP immune mice without partial hepatectomy were characterized by minor lymphocytic infiltrations without transaminase elevations. By contrast, a significant hepatocyte damage was observed in regenerating liver that correlated well with the number of AFP specific CD8(+) T cells, the activity of liver regeneration, and the level of AFP synthesis. Autoimmune liver damage was mediated by CD4(+) T cell-dependent CD8(+) cytotoxic T lymphocytes. CONCLUSIONS: These results show that priming of T-cell responses against shared tumor-specific self antigens may be accompanied by induction of autoimmunity dependent on the level of expression of the self antigen and have important implications for the development of antitumoral vaccines targeted against antigens that are not strictly tumor-specific. PMID- 11606507 TI - Mitogenic effect of gastrin and expression of gastrin receptors in duct-like cells of rat pancreas. AB - BACKGROUND & AIMS: Ductular metaplastic cells are observed during pancreas injury. Growth control by gastrin and expression of gastrin/cholecystokinin (CCK) B receptors were evaluated in these cells. METHODS: Acinoductal transdifferentiation was induced in vitro by culturing of acinar cells, and ductular metaplasia was obtained in vivo by ligation of the pancreatic ducts. Mitogenic effects of gastrin I on ductal complexes in vivo and of tetragastrin, pentagastrin, and gastrin I and II, with or without the CCK-B receptor antagonist L-365,260, on duct-like cells in vitro were analyzed by 5-bromo-2'-deoxyuridine labeling. Immunocytochemistry, Western blotting, and reverse-transcription polymerase chain reaction were applied for detection of the CCK-B receptor. RESULTS: Gastrin analogues induced a mitogenic stimulus in the duct-like cells in vitro and in ductal complexes in duct-ligated rat pancreas. Immunocytochemistry showed expression of CCK-B receptors in these models and in fetal but not normal adult exocrine pancreas. Additionally, up-regulation of CCK-B receptors during ductular metaplasia was shown by Western blotting and reverse-transcription polymerase chain reaction. CONCLUSIONS: Duct-like pancreatic epithelial cells in vitro and ductal complexes in vivo express gastrin/CCK-B receptors and proliferate in response to gastrin. PMID- 11606508 TI - Pancreatic acinar cell dysfunction in CFTR(-/-) mice is associated with impairments in luminal pH and endocytosis. AB - BACKGROUND & AIMS: We have previously shown that endocytosis at the apical plasma membrane in pancreatic acinar cells is coupled to ductal bicarbonate secretion into the lumen. We hypothesized that decreased bicarbonate secretion in cystic fibrosis (CF) inhibits apical endocytosis. The aim of this study was to determine in cftr(-/-) mice (1) if the pH of the pancreatic juice is acidic compared with wild-type (WT) controls, (2) if there is a selective block in endocytosis, and (3) if alkalinization of the luminal fluid reverses this defect. METHODS: Fluid secretion and pH of pancreatic juice were measured. Exocytosis, endocytosis, and morphology were compared in pancreatic lobules from cftr(-/-) and WT mice. RESULTS: Pancreatic juice pH was 8.12 +/- 0.06 in WT mice compared with 6.60 +/- 0.04 in cftr(-/-) mice. Although cholecystokinin-stimulated amylase secretion was not significantly different, endocytosis was markedly inhibited in cftr(-/-) compared with WT mice. Cleavage of GP2, a GPI-anchored protein tightly associated with activation of endocytosis, was also decreased. Incubation of lobules from cftr(-/-) mice at pH 8.3 reversed the luminal dilatation. CONCLUSIONS: These data indicate that apical endocytosis is selectively impaired in cftr(-/-) mice, which explains, in part, the luminal dilatation observed at the apical plasma membrane. In vitro alkalinization of luminal fluid led to reversal of defects in membrane dynamics, restored coupled exocytosis and endocytosis, and abolished the luminal dilatation in this animal model of CF. Acidic pH changes in luminal secretions may play a role in the pancreatic membrane dysfunction observed in CF. PMID- 11606509 TI - Dysfunctional LAD-1 neutrophils and colitis. AB - Leukocyte adhesion deficiency 1 (LAD-1) is characterized by absent or dysfunctional beta2 integrin (CD18), leading to defective chemotaxis, adherence, phagocytosis, and bacterial killing. Colitis, except for rare intestinal necrotizing events, is not a well-recognized feature of this immunodeficiency. A case of nonspecific colitis clinically resembling Crohn's disease in a patient with the severe form of LAD-1 (0.5% < CD18) has been previously reported. We describe an adult patient with the moderate form of LAD-1 and chronic colitis characterized by extensive inflammation and ulceration of the right colon and terminal ileum, leading to adhesions and strictures. The chronic colitis described in this article associated with the dysfunctional neutrophils of LAD-1 represents a distinct pathology from the commonly encountered forms of inflammatory bowel disease (IBD). The existence of active IBD in the presence of dysfunctional CD18/CD11(a-b) intercellular adhesion molecules (ICAM-1) interaction is relevant to the proposed targeting of ICAM-1 for the treatment of Crohn's disease. PMID- 11606510 TI - American Gastroenterological Association policy statement on the precertification of pharmaceuticals. PMID- 11606511 TI - American Gastroenterological Association medical position statement: parenteral nutrition. AB - This document presents the official recommendations of the American Gastroenterological Association (AGA) on Parenteral Nutrition. It was approved by the Clinical Practice and Practice Committee on April 13, 2001 and by the AGA Governing Board on May 18, 2001. PMID- 11606512 TI - AGA technical review on parenteral nutrition. AB - This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Practice Economics Committee. The paper was approved by the Committee on September 13, 2001, and by the AGA Governing Board on May 18, 2001. PMID- 11606513 TI - Gastric cancer and H. pylori: Host genetics open the way. PMID- 11606514 TI - HNPCC: an uncommon but important diagnosis. PMID- 11606515 TI - Adhesion molecules in lymphocyte trafficking and colitis. PMID- 11606516 TI - The role of glutathione S-transferase P1-1 in colorectal cancer: friend or foe? PMID- 11606517 TI - Patients with biliary microlithiasis: Are they a separate breed? PMID- 11606518 TI - Necrotizing enterocolitis: a closer look. PMID- 11606519 TI - Therapy for HCV nonresponders: Is two enough? PMID- 11606520 TI - Antineoplastic and anti-inflammatory effects of PPAR ligands in colitis. PMID- 11606523 TI - George Snell's first foray into the unexplored territory of the major histocompatibility complex. PMID- 11606524 TI - Direct estimate of the mutation rate and the distribution of fitness effects in the yeast Saccharomyces cerevisiae. AB - Estimates of the rate and frequency distribution of deleterious effects were obtained for the first time by direct scoring and characterization of individual mutations. This was achieved by applying tetrad analysis to a large number of yeast clones. The genomic rate of spontaneous mutation deleterious to a basic fitness-related trait, that of growth rate, was U = 1.1 x 10(-3) per diploid cell division. Extrapolated to the fruit fly and humans, the per generation rate would be 0.074 and 0.92, respectively. This is likely to be an underestimate because single mutations with selection coefficients s < 0.01 could not be detected. The distribution of s > or = 0.01 was studied both for spontaneous and induced mutations. The latter were induced by ethyl methanesulfonate (EMS) or resulted from defective mismatch repair. Lethal changes accounted for approximately 30-40% of the scored mutations. The mean s of nonlethal mutations was fairly high, but most frequently its value was between 0.01 and 0.05. Although the rate and distribution of very small effects could not be determined, the joint share of such mutations in decreasing average fitness was probably no larger than approximately 1%. PMID- 11606525 TI - Genes involved in sister chromatid separation and segregation in the budding yeast Saccharomyces cerevisiae. AB - Accurate chromosome segregation requires the precise coordination of events during the cell cycle. Replicated sister chromatids are held together while they are properly attached to and aligned by the mitotic spindle at metaphase. At anaphase, the links between sisters must be promptly dissolved to allow the mitotic spindle to rapidly separate them to opposite poles. To isolate genes involved in chromosome behavior during mitosis, we microscopically screened a temperature-sensitive collection of budding yeast mutants that contain a GFP marked chromosome. Nine LOC (loss of cohesion) complementation groups that do not segregate sister chromatids at anaphase were identified. We cloned the corresponding genes and performed secondary tests to determine their function in chromosome behavior. We determined that three LOC genes, PDS1, ESP1, and YCS4, are required for sister chromatid separation and three other LOC genes, CSE4, IPL1, and SMT3, are required for chromosome segregation. We isolated alleles of two genes involved in splicing, PRP16 and PRP19, which impair alpha-tubulin synthesis thus preventing spindle assembly, as well as an allele of CDC7 that is defective in DNA replication. We also report an initial characterization of phenotypes associated with the SMT3/SUMO gene and the isolation of WSS1, a high copy smt3 suppressor. PMID- 11606526 TI - Characterization of Schizosaccharomyces pombe mcm7(+) and cdc23(+) (MCM10) and interactions with replication checkpoints. AB - MCM proteins are required for the proper regulation of DNA replication. We cloned fission yeast mcm7(+) and showed it is essential for viability; spores lacking mcm7(+) begin S phase later than wild-type cells and arrest with an apparent 2C DNA content. We isolated a novel temperature-sensitive allele, mcm7-98, and also characterized two temperature-sensitive alleles of the fission yeast homolog of MCM10, cdc23(+). mcm7-98 and both cdc23ts alleles arrest with damaged chromosomes and an S phase delay. We find that mcm7-98 is synthetically lethal with the other mcmts mutants but does not interact genetically with either cdc23ts allele. However, cdc23-M36 interacts with mcm4ts. Unlike other mcm mutants or cdc23, mcm7 98 is synthetically lethal with checkpoint mutants Deltacds1, Deltachk1, or Deltarad3, suggesting chromosomal defects even at permissive temperature. Mcm7p is a nuclear protein throughout the cell cycle, and its localization is dependent on the other MCM proteins. Our data suggest that the Mcm3p-Mcm5p dimer interacts with the Mcm4p-Mcm6p-Mcm7p core complex through Mcm7p. PMID- 11606527 TI - Genetic interactions of Spt4-Spt5 and TFIIS with the RNA polymerase II CTD and CTD modifying enzymes in Saccharomyces cerevisiae. AB - Genetic and biochemical studies have identified many factors thought to be important for transcription elongation. We investigated relationships between three classes of these factors: (1) transcription elongation factors Spt4-Spt5, TFIIS, and Spt16; (2) the C-terminal heptapeptide repeat domain (CTD) of RNA polymerase II; and (3) protein kinases that phosphorylate the CTD and a phosphatase that dephosphorylates it. We observe that spt4 and spt5 mutations cause strong synthetic phenotypes in combination with mutations that shorten or alter the composition of the CTD; affect the Kin28, Bur1, or Ctk1 CTD kinases; and affect the CTD phosphatase Fcp1. We show that Spt5 co-immunoprecipitates with RNA polymerase II that has either a hyper- or a hypophosphorylated CTD. Furthermore, mutation of the CTD or of CTD modifying enzymes does not affect the ability of Spt5 to bind RNA polymerase II. We find a similar set of genetic interactions between the CTD, CTD modifying enzymes, and TFIIS. In contrast, an spt16 mutation did not show these interactions. These results suggest that the CTD plays a key role in modulating elongation in vivo and that at least a subset of elongation factors are dependent upon the CTD for their normal function. PMID- 11606528 TI - Development of Saccharomyces cerevisiae as a model pathogen. A system for the genetic identification of gene products required for survival in the mammalian host environment. AB - Saccharomyces cerevisiae, a close relative of the pathogenic Candida species, is an emerging opportunistic pathogen. An isogenic series of S. cerevisiae strains, derived from a human clinical isolate, were used to examine the role of evolutionarily conserved pathways in fungal survival in a mouse host. As is the case for the corresponding Candida albicans and Cryptococcus neoformans mutants, S. cerevisiae purine and pyrimidine auxotrophs were severely deficient in survival, consistent with there being evolutionary conservation of survival traits. Resistance to the antifungal drug 5-fluorocytosine was not deleterious and appeared to be slightly advantageous in vivo. Of mutants in three amino acid biosynthetic pathways, only leu2 mutants were severely deficient in vivo. Unlike the glyoxylate cycle, respiration was very important for survival; however, the mitochondrial genome made a respiration-independent contribution to survival. Mutants deficient in pseudohyphal formation were tested in vivo; flo11Delta mutants were phenotypically neutral while flo8Delta, tec1Delta, and flo8Delta tec1Delta mutants were slightly deficient. Because of its ease of genetic manipulation and the immense S. cerevisiae database, which includes the best annotated eukaryotic genome sequence, S. cerevisiae is a superb model system for the identification of gene products important for fungal survival in the mammalian host environment. PMID- 11606529 TI - The yeast recombinational repair protein Rad59 interacts with Rad52 and stimulates single-strand annealing. AB - The yeast RAD52 gene is essential for homology-dependent repair of DNA double strand breaks. In vitro, Rad52 binds to single- and double-stranded DNA and promotes annealing of complementary single-stranded DNA. Genetic studies indicate that the Rad52 and Rad59 proteins act in the same recombination pathway either as a complex or through overlapping functions. Here we demonstrate physical interaction between Rad52 and Rad59 using the yeast two-hybrid system and co immunoprecipitation from yeast extracts. Purified Rad59 efficiently anneals complementary oligonucleotides and is able to overcome the inhibition to annealing imposed by replication protein A (RPA). Although Rad59 has strand annealing activity by itself in vitro, this activity is insufficient to promote strand annealing in vivo in the absence of Rad52. The rfa1-D288Y allele partially suppresses the in vivo strand-annealing defect of rad52 mutants, but this is independent of RAD59. These results suggest that in vivo Rad59 is unable to compete with RPA for single-stranded DNA and therefore is unable to promote single-strand annealing. Instead, Rad59 appears to augment the activity of Rad52 in strand annealing. PMID- 11606530 TI - Molecular population genetics and evolution of a prion-like protein in Saccharomyces cerevisiae. AB - The prion-like behavior of Sup35p, the eRF3 homolog in the yeast Saccharomyces cerevisiae, mediates the activity of the cytoplasmic nonsense suppressor known as [PSI(+)]. Sup35p is divided into three regions of distinct function. The N terminal and middle (M) regions are required for the induction and propagation of [PSI(+)] but are not necessary for translation termination or cell viability. The C-terminal region encompasses the termination function. The existence of the N terminal region in SUP35 homologs of other fungi has led some to suggest that this region has an adaptive function separate from translation termination. To examine this hypothesis, we sequenced portions of SUP35 in 21 strains of S. cerevisiae, including 13 clinical isolates. We analyzed nucleotide polymorphism within this species and compared it to sequence divergence from a sister species, S. paradoxus. The N domain of Sup35p is highly conserved in amino acid sequence and is highly biased in codon usage toward preferred codons. Amino acid changes are under weak purifying selection based on a quantitative analysis of polymorphism and divergence. We also conclude that the clinical strains of S. cerevisiae are not recently derived and that outcrossing between strains in S. cerevisiae may be relatively rare in nature. PMID- 11606531 TI - Epistatic and synergistic interactions between circadian clock mutations in Neurospora crassa. AB - We identified a series of epistatic and synergistic interactions among the circadian clock mutations of Neurospora crassa that indicate possible physical interactions among the various clock components encoded by these genes. The period-6 (prd-6) mutation, a short-period temperature-sensitive clock mutation, is epistatic to both the prd-2 and prd-3 mutations. The prd-2 and prd-3 long period mutations show a synergistic interaction in that the period length of the double mutant strain is considerably longer than predicted. In addition, the prd 2 prd-3 double mutant strain also exhibits overcompensation to changes in ambient temperature, suggesting a role in the temperature compensation machinery of the clock. The prd-2, prd-3, and prd-6 mutations also show significant interactions with the frq(7) long-period mutation. These results suggest that the gene products of prd-2, prd-3, and prd-6 play an important role in both the timing and temperature compensation mechanisms of the circadian clock and may interact with the FRQ protein. PMID- 11606532 TI - Mutations in mating-type genes of the heterothallic fungus Podospora anserina lead to self-fertility. AB - The heterothallic fungus Podospora anserina has two mating-type alleles termed mat+ and mat-. The mat+ sequence contains one gene, FPR1, while mat- contains three genes: FMR1, SMR1, and SMR2. FPR1 and FMR1 are required for fertilization, which is followed by mitotic divisions of the two parental nuclei inside the female organ. This leads to the formation of plurinucleate cells containing a mixture of parental mat+ and mat- nuclei. Further development requires a recognition between mat+ and mat- nuclei before migration of the mat+/mat- pairs into specialized hyphae in which karyogamy, meiosis, and ascospore formation take place. FPR1, FMR1, and SMR2 control this internuclear recognition step. Initial development of the dikaryotic stage is supposed to require SMR1; disruption of SMR1 results in barren perithecia. In a systematic search for suppressors restoring fertility, we isolated 15 suppressors-all of them mutations in the mating-type genes. These fmr1, smr2, and fpr1 mutants, as well as the strains disrupted for FMR1, SMR2, and FPR1, are weakly self-fertile. They are able to act as the male partner on a strain of the same mating type and give a mixture of biparental and uniparental progeny when crossed with a wild-type strain of opposite mating type. These observations lead us to propose that SMR2, FMR1, and FPR1 act as activators and repressors of fertilization and internuclear recognition functions. PMID- 11606533 TI - The Aspergillus nidulans snt genes are required for the regulation of septum formation and cell cycle checkpoints. AB - In Aspergillus nidulans, germinating conidia undergo multiple rounds of nuclear division before forming a septum. Previous genetic results suggest that the ability to separate nuclear division and septum formation depends upon a threshold level of activity of the cyclin-dependent kinase NIMX(cdk1). Mutations in nimX and nimT, the gene encoding the NIMX(cdk1)-activating phosphatase, have revealed that Tyr-15 phosphorylation is important for determining the timing of the formation of the first septum. Here, we describe a screen for suppressors of nimT23 (snt), designed to identify additional components of the pathway regulating septum formation. We show that a subset of the snt mutants are defective in the temporal regulation of septum formation and in cell cycle checkpoint responses. Molecular characterization of sntA shows that it is allelic to the previously described ankA gene, which encodes the NIMX(cdk1) Tyr-15 kinase. Additional experiments described in this study show that nutritional conditions modulate the timing of septum formation and alter the phenotypes displayed by the snt mutants. A model that suggests that the timing of septum formation is influenced by DNA damage and glucose availability via the sntA and sntB gene products is proposed. PMID- 11606534 TI - Recombination events in Neurospora crassa may cross a translocation breakpoint by a template-switching mechanism. AB - To assist investigation of the effect of sequence heterology on recombination in Neurospora crassa, we inserted the Herpes simplex thymidine kinase gene (TK) as an unselected marker on linkage group I, giving a gene order of Cen-his-3-TK-cog lpl. We show here that in crosses heterozygous for TK, conversion of a his-3 allele on one homolog is accompanied by transfer of the heterologous sequence between cog and his-3 from the other homolog, indicating that recombination is initiated centromere-distal of TK. We have identified a 10-nucleotide motif in the cog region that, although unlikely to be sufficient for hotspot activity, is required for high-frequency recombination and, because conversion of silent sequence markers declines on either side, may be the recombination initiation site. Additionally, we have mapped conversion tracts in His(+) progeny of a translocation heterozygote, in which the translocation breakpoint separates cog from the 5' end of his-3. We present molecular evidence of recombination on both sides of the breakpoint. Because recombination is initiated close to cog and the event must therefore cross the translocation breakpoint, we suggest that template switching occurs in some recombination events, with repair synthesis alternating between use of the homolog and the initiating chromatid as template. PMID- 11606535 TI - Consequences of recombination rate variation on quantitative trait locus mapping studies. Simulations based on the Drosophila melanogaster genome. AB - We examine the effect of variation in gene density per centimorgan on quantitative trait locus (QTL) mapping studies using data from the Drosophila melanogaster genome project and documented regional rates of recombination. There is tremendous variation in gene density per centimorgan across this genome, and we observe that this variation can cause systematic biases in QTL mapping studies. Specifically, in our simulated mapping experiments of 50 equal-effect QTL distributed randomly across the physical genome, very strong QTL are consistently detected near the centromeres of the two major autosomes, and few or no QTL are often detected on the X chromosome. This pattern persisted with varying heritability, marker density, QTL effect sizes, and transgressive segregation. Our results are consistent with empirical data collected from QTL mapping studies of this species and its close relatives, and they explain the "small X-effect" that has been documented in genetic studies of sexual isolation in the D. melanogaster group. Because of the biases resulting from recombination rate variation, results of QTL mapping studies should be taken as hypotheses to be tested by additional genetic methods, particularly in species for which detailed genetic and physical genome maps are not available. PMID- 11606537 TI - Alternative splicing of the Drosophila Dscam pre-mRNA is both temporally and spatially regulated. AB - The Drosophila melanogaster Down syndrome cell adhesion molecule (Dscam) gene encodes an axon guidance receptor that can express 38,016 different mRNAs by virtue of alternative splicing. The Dscam gene contains 95 alternative exons that are organized into four clusters of 12, 48, 33, and 2 exons each. Although numerous Dscam mRNA isoforms can be synthesized, it remains to be determined whether different Dscam isoforms are synthesized at different times in development or in different tissues. We have investigated the alternative splicing of the Dscam exon 4 cluster, which contains 12 mutually exclusive alternative exons, and found that Dscam exon 4 alternative splicing is developmentally regulated. The most highly regulated exon, 4.2, is infrequently used in early embryos but is the predominant exon 4 variant used in adults. Moreover, the developmental regulation of exon 4.2 alternative splicing is conserved in D. yakuba. In addition, different adult tissues express distinct collections of Dscam mRNA isoforms. Given the role of Dscam in neural development, these results suggest that the regulation of alternative splicing plays an important role in determining the specificity of neuronal wiring. In addition, this work provides a framework to determine the mechanisms by which complex alternative splicing events are regulated. PMID- 11606536 TI - The evolutionary analysis of "orphans" from the Drosophila genome identifies rapidly diverging and incorrectly annotated genes. AB - In genome projects of eukaryotic model organisms, a large number of novel genes of unknown function and evolutionary history ("orphans") are being identified. Since many orphans have no known homologs in distant species, it is unclear whether they are restricted to certain taxa or evolve rapidly, either because of a lack of constraints or positive Darwinian selection. Here we use three criteria for the selection of putatively rapidly evolving genes from a single sequence of Drosophila melanogaster. Thirteen candidate genes were chosen from the Adh region on the second chromosome and 1 from the tip of the X chromosome. We succeeded in obtaining sequence from 6 of these in the closely related species D. simulans and D. yakuba. Only 1 of the 6 genes showed a large number of amino acid replacements and in-frame insertions/deletions. A population survey of this gene suggests that its rapid evolution is due to the fixation of many neutral or nearly neutral mutations. Two other genes showed "normal" levels of divergence between species. Four genes had insertions/deletions that destroy the putative reading frame within exons, suggesting that these exons have been incorrectly annotated. The evolutionary analysis of orphan genes in closely related species is useful for the identification of both rapidly evolving and incorrectly annotated genes. PMID- 11606539 TI - The relationship between third-codon position nucleotide content, codon bias, mRNA secondary structure and gene expression in the drosophilid alcohol dehydrogenase genes Adh and Adhr. AB - To gain insights into the relationship between codon bias, mRNA secondary structure, third-codon position nucleotide distribution, and gene expression, we predicted secondary structures in two related drosophilid genes, Adh and Adhr, which differ in degree of codon bias and level of gene expression. Individual structural elements (helices) were inferred using the comparative method. For each gene, four types of randomization simulations were performed to maintain/remove codon bias and/or to maintain or alter third-codon position nucleotide composition (N3). In the weakly expressed, weakly biased gene Adhr, the potential for secondary structure formation was found to be much stronger than in the highly expressed, highly biased gene Adh. This is consistent with the observation of approximately equal G and C percentages in Adhr ( approximately 31% across species), whereas in Adh the N3 distribution is shifted toward C (42% across species). Perturbing the N3 distribution to approximately equal amounts of A, G, C, and T increases the potential for secondary structure formation in Adh, but decreases it in Adhr. On the other hand, simulations that reduce codon bias without changing N3 content indicate that codon bias per se has only a weak effect on the formation of secondary structures. These results suggest that, for these two drosophilid genes, secondary structure is a relatively independent, negative regulator of gene expression. Whereas the degree of codon bias is positively correlated with level of gene expression, strong individual secondary structural elements may be selected for to retard mRNA translation and to decrease gene expression. PMID- 11606538 TI - Ras1 interacts with multiple new signaling and cytoskeletal loci in Drosophila eggshell patterning and morphogenesis. AB - Little is known about the genes that interact with Ras signaling pathways to regulate morphogenesis. The synthesis of dorsal eggshell structures in Drosophila melanogaster requires multiple rounds of Ras signaling followed by dramatic epithelial sheet movements. We took advantage of this process to identify genes that link patterning and morphogenesis; we screened lethal mutations on the second chromosome for those that could enhance a weak Ras1 eggshell phenotype. Of 1618 lethal P-element mutations tested, 13 showed significant enhancement, resulting in forked and fused dorsal appendages. Our genetic and molecular analyses together with information from the Berkeley Drosophila Genome Project reveal that 11 of these lines carry mutations in previously characterized genes. Three mutations disrupt the known Ras1 cell signaling components Star, Egfr, and Blistered, while one mutation disrupts Sec61beta, implicated in ligand secretion. Seven lines represent cell signaling and cytoskeletal components that are new to the Ras1 pathway; these are Chickadee (Profilin), Tec29, Dreadlocks, POSH, Peanut, Smt3, and MESK2, a suppressor of dominant-negative Ksr. A twelfth insertion disrupts two genes, Nrk, a "neurospecific" receptor tyrosine kinase, and Tpp, which encodes a neuropeptidase. These results suggest that Ras1 signaling during oogenesis involves novel components that may be intimately associated with additional signaling processes and with the reorganization of the cytoskeleton. To determine whether these Ras1 Enhancers function upstream or downstream of the Egf receptor, four mutations were tested for their ability to suppress an activated Egfr construct (lambdatop) expressed in oogenesis exclusively in the follicle cells. Mutations in Star and l(2)43Bb had no significant effect upon the lambdatop eggshell defect whereas smt3 and dock alleles significantly suppressed the lambdatop phenotype. PMID- 11606540 TI - Interallelic complementation at the Drosophila melanogaster gastrulation defective locus defines discrete functional domains of the protein. AB - The gastrulation defective (gd) locus encodes a novel serine protease that is involved in specifying the dorsal-ventral axis during embryonic development. Mutant alleles of gd have been classified into three complementation groups, two of which exhibit strong interallelic (intragenic) complementation. To understand the molecular basis of this interallelic complementation, we examined the complementation behavior of additional mutant alleles and sequenced alleles in all complementation groups. The data suggest that there are two discrete functional domains of Gd. A two-domain model of Gd suggesting that it is structurally similar to mammalian complement factors C2 and B has been previously proposed. To test this model we performed SP6 RNA microinjection to assay for activities associated with various domains of Gd. The microinjection data are consistent with the complement factor C2/B-like model. Site-directed mutagenesis suggests that Gd functions as a serine protease. An allele-specific interaction between an autoactivating form of Snake (Snk) and a gd allele altered in the protease domain suggests that Gd directly activates Snk in a protease activation cascade. We propose a model in which Gd is expressed during late oogenesis and bound within the perivitelline space but only becomes catalytically active during embryogenesis. PMID- 11606541 TI - Patterns of DNA sequence variation suggest the recent action of positive selection in the janus-ocnus region of Drosophila simulans. AB - Levels of nucleotide polymorphism in three paralogous Drosophila simulans genes, janusA (janA), janusB (janB), and ocnus (ocn), were surveyed by DNA sequencing. The three genes lie in tandem within a 2.5-kb region of chromosome arm 3R. In a sample of eight alleles from a worldwide distribution we found a significant departure from neutrality by several statistical tests. The most striking feature of this sample was that in a 1.7-kb region containing the janA and janB genes, 30 out of 31 segregating sites contained variants present only once in the sample, and 29 of these unique variants were found in the same allele. A restriction survey of an additional 28 lines of D. simulans revealed strong linkage disequilibrium over the janA-janB region and identified six more alleles matching the rare haplotype. Among the rare alleles, the level of DNA sequence variation was typical for D. simulans autosomal genes and showed no departure from neutrality. In addition, the rare haplotype was more similar to the D. melanogaster sequence, indicating that it was the ancestral form. These results suggest that the derived haplotype has risen to high worldwide frequency relatively recently, most likely as a result of natural selection. PMID- 11606543 TI - Protein variation in Adh and Adh-related in Drosophila pseudoobscura. Linkage disequilibrium between single nucleotide polymorphisms and protein alleles. AB - A 3.5-kb segment of the alcohol dehydrogenase (Adh) region that includes the Adh and Adh-related genes was sequenced in 139 Drosophila pseudoobscura strains collected from 13 populations. The Adh gene encodes four protein alleles and rejects a neutral model of protein evolution with the McDonald-Kreitman test, although the number of segregating synonymous sites is too high to conclude that adaptive selection has operated. The Adh-related gene encodes 18 protein haplotypes and fails to reject an equilibrium neutral model. The populations fail to show significant geographic differentiation of the Adh-related haplotypes. Eight of 404 single nucleotide polymorphisms (SNPs) in the Adh region were in significant linkage disequilibrium with three ADHR protein alleles. Coalescent simulations with and without recombination were used to derive the expected levels of significant linkage disequilibrium between SNPs and 18 protein haplotypes. Maximum levels of linkage disequilibrium are expected for protein alleles at moderate frequencies. In coalescent models without recombination, linkage disequilibrium decays between SNPs and high frequency haplotypes because common alleles mutate to haplotypes that are rare or that reach moderate frequency. The implication of this study is that linkage disequilibrium mapping has the highest probability of success with disease-causing alleles at frequencies of 10%. PMID- 11606542 TI - Evidence for recurrent paralogous gene conversion and exceptional allelic divergence in the Attacin genes of Drosophila melanogaster. AB - Insects produce a limited variety of antibacterial peptides to combat a wide diversity of pathogens. These peptides are often conserved across evolutionarily distant taxa, but little is known about the level and structure of polymorphism within species. We have surveyed naturally occurring genetic variation in the promoter and coding regions of three Attacin antibacterial peptide genes from 12 lines of Drosophila melanogaster. These genes exhibit high levels of silent nucleotide variations (1-3% per nucleotide heterozygosity), but are not excessively polymorphic at the amino acid level. There is extensive variation in the Attacin promoters, some of which may affect transcriptional efficiency, and one line carries a deletion in the Attacin A coding region that renders this gene nonfunctional. Two of the genes, Attacins A and B, are arranged in tandem and show evidence of repeated interlocus gene conversion. Attacin C, more divergent and located 1.3 Mbp upstream of Attacins A and B, does not appear to have been involved in such exchanges. All three genes are characterized by divergent haplotypes, and one Attacin AB allele appears to have recently increased rapidly in frequency in the population. PMID- 11606544 TI - Evidence for a period of directional selection following gene duplication in a neurally expressed locus of triosephosphate isomerase. AB - A striking correlation between neural expression and high net negative charge in some teleost isozymes led to the interesting, yet untested, suggestion that negative charge represents an adaptation (via natural selection) to the neural environment. We examine the evolution of the triosephosphate isomerase (TPI) gene family in fishes for periods of positive selection. Teleost fish express two TPI proteins, including a generally expressed, neutrally charged isozyme and a neurally expressed, negatively charged isozyme; more primitive fish express only a single, generally expressed TPI isozyme. The TPI gene phylogeny constructed from sequences isolated from two teleosts, a single acipenseriform, and other TPI sequences from the databases, supports a single gene duplication event early in the evolution of bony fishes. Comparisons between inferred ancestral TPI sequences indicate that the neural TPI isozyme evolved through a period of positive selection resulting in the biased accumulation of negatively charged amino acids. Further, the number of nucleotide changes required for the observed amino acid substitutions suggests that selection acted on the overall charge of the protein and not on specific key amino acids. PMID- 11606545 TI - Empirical evaluation of genetic clustering methods using multilocus genotypes from 20 chicken breeds. AB - We tested the utility of genetic cluster analysis in ascertaining population structure of a large data set for which population structure was previously known. Each of 600 individuals representing 20 distinct chicken breeds was genotyped for 27 microsatellite loci, and individual multilocus genotypes were used to infer genetic clusters. Individuals from each breed were inferred to belong mostly to the same cluster. The clustering success rate, measuring the fraction of individuals that were properly inferred to belong to their correct breeds, was consistently approximately 98%. When markers of highest expected heterozygosity were used, genotypes that included at least 8-10 highly variable markers from among the 27 markers genotyped also achieved >95% clustering success. When 12-15 highly variable markers and only 15-20 of the 30 individuals per breed were used, clustering success was at least 90%. We suggest that in species for which population structure is of interest, databases of multilocus genotypes at highly variable markers should be compiled. These genotypes could then be used as training samples for genetic cluster analysis and to facilitate assignments of individuals of unknown origin to populations. The clustering algorithm has potential applications in defining the within-species genetic units that are useful in problems of conservation. PMID- 11606546 TI - Reciprocal mouse and human limb phenotypes caused by gain- and loss-of-function mutations affecting Lmbr1. AB - The major locus for dominant preaxial polydactyly in humans has been mapped to 7q36. In mice the dominant Hemimelic extra toes (Hx) and Hammertoe (Hm) mutations map to a homologous chromosomal region and cause similar limb defects. The Lmbr1 gene is entirely within the small critical intervals recently defined for both the mouse and human mutations and is misexpressed at the exact time that the mouse Hx phenotype becomes apparent during limb development. This result suggests that Lmbr1 may underlie preaxial polydactyly in both mice and humans. We have used deletion chromosomes to demonstrate that the dominant mouse and human limb defects arise from gain-of-function mutations and not from haploinsufficiency. Furthermore, we created a loss-of-function mutation in the mouse Lmbr1 gene that causes digit number reduction (oligodactyly) on its own and in trans to a deletion chromosome. The loss of digits that we observed in mice with reduced Lmbr1 activity is in contrast to the gain of digits observed in Hx mice and human polydactyly patients. Our results suggest that the Lmbr1 gene is required for limb formation and that reciprocal changes in levels of Lmbr1 activity can lead to either increases or decreases in the number of digits in the vertebrate limb. PMID- 11606548 TI - DNA dinucleotide evolution in humans: fitting theory to facts. AB - We examine length distributions of approximately 6000 human dinucleotide microsatellite loci, representing chromosomes 1-22, from the GDB database. Under the stepwise mutation model, results from theory and simulation are compared with the empirical data. In both constant and expanding population scenarios, a simple single-step model with parameters chosen to account for the observed variance of microsatellite lengths produces results inconsistent with the observed heterozygosity and the dispersion of length skewness. Complicating the model by allowing a variable mutation rate accounts for the homozygosity, and introducing a small probability of a large mutation step accounts for the dispersion in skewnesses. We discuss these results in light of the long-term evolution of microsatellites. PMID- 11606547 TI - Multiple quantitative trait locus analysis of bovine chromosome 6 in the Israeli Holstein population by a daughter design. AB - Nine Israeli Holstein sire families with 2978 daughters were analyzed for quantitative trait loci effects on chromosome 6 for five milk production traits by a daughter design. All animals were genotyped for 2 markers. The three families with significant effects were genotyped for up to 10 additional markers spanning positions 0-122 cM of BTA6. Two sires were segregating for a locus affecting protein and fat percentage near position 55 cM with an estimated substitution effect of 0.18% protein, which is equivalent to one phenotypic standard deviation. This locus was localized to a confidence interval of 4 cM. One of these sires was also heterozygous for a locus affecting milk, fat, and protein production near the centromere. The hypothesis of two segregating loci was verified by multiple regression analysis. A third sire was heterozygous for a locus affecting milk and protein percentage near the telomeric end of the chromosome. Possible candidates for the major quantitative gene near position 55 cM were determined by comparative mapping. IBSP and SSP1 were used as anchors for the orthologous region on human chromosome 4. Twelve genes were detected within a 2-Mbp sequence. None of these genes have been previously associated with lactogenesis. PMID- 11606549 TI - Recombination in human mitochondrial DNA? AB - The possibility of recombination in human mitochondrial DNA (mtDNA) has been hotly debated over the last few years. In this study, a general model of recombination in circular molecules is developed and applied to a recently published African sample (n = 21) of complete mtDNA sequences. It is shown that the power of correlation measures to detect recombination in circular molecules can be vanishingly small and that the data are consistent with the given model and no recombination only if the overall heterogeneity in mutation rate is <0.09. PMID- 11606550 TI - Are the dominant and recessive plant disease resistance genes similar? A case study of rice R genes and Xanthomonas oryzae pv. oryzae races. AB - The resistance of rice to its bacterial blight pathogen Xanthomonas oryzae pv. oryzae (Xoo) has both qualitative and quantitative components that were investigated using three near-isogenic line sets for four resistance (R) genes (Xa4, xa5, xa13, and Xa21) and 12 Xoo races. Our results indicate that these two resistance components of rice plants were associated with the properties of the R genes. The qualitative component of the R genes was reflected by their large effects against corresponding avirulent Xoo races. The quantitative component of the R genes was their residual effects against corresponding virulent races and their epistatic effects, which together could lead to high-level resistance in a race-specific manner. Our results revealed important differences between the different types of R genes. Two R genes, Xa4 and Xa21, showed complete dominance against the avirulent Xoo races and had large residual effects against virulent ones. They acted independently and cumulatively, suggesting they are involved in different pathways of the rice defensive system. The third R gene, xa5, showed partial dominance or additivity to the avirulent Xoo races and had relatively small but significant residual effects against the virulent races. In contrast, xa13 was completely recessive, had no residual effects against the virulent races, and showed more pronounced race specificity. There was a strong interaction leading to increased resistance between xa13 and xa5 and between either of them and Xa4 or Xa21, suggesting their regulatory roles in the rice defensive pathway(s). Our results indicated that high-level and durable resistance to Xoo should be more efficiently achieved by pyramiding different types of R genes. PMID- 11606551 TI - Gibberellins are not required for normal stem growth in Arabidopsis thaliana in the absence of GAI and RGA. AB - The growth of Arabidopsis thaliana is quantitatively regulated by the phytohormone gibberellin (GA) via two closely related nuclear GA-signaling components, GAI and RGA. Here we test the hypothesis that GAI and RGA function as "GA-derepressible repressors" of plant growth. One prediction of this hypothesis is that plants lacking GAI and RGA do not require GA for normal stem growth. Analysis of GA-deficient mutants lacking GAI and RGA confirms this prediction and suggests that in the absence of GAI and RGA, "growth" rather than "no growth" is the default state of plant stems. The function of the GA-signaling system is thus to act as a control system regulating the amount of this growth. We also demonstrate that the GA dose dependency of hypocotyl elongation is altered in mutants lacking GAI and RGA and propose that increments in GAI/RGA repressor function can explain the quantitative nature of GA responses. PMID- 11606552 TI - Synergistic derepression of gibberellin signaling by removing RGA and GAI function in Arabidopsis thaliana. AB - RGA and GAI are negative regulators of the gibberellin (GA) signal transduction pathway in Arabidopsis thaliana. These genes may have partially redundant functions because they are highly homologous, and plants containing single null mutations at these loci are phenotypically similar to wild type. Previously, rga loss-of-function mutations were shown to partially suppress defects of the GA deficient ga1-3 mutant. Phenotypes rescued include abaxial trichome initiation, rosette radius, flowering time, stem elongation, and apical dominance. Here we present work showing that the rga-24 and gai-t6 null mutations have a synergistic effect on plant growth. Although gai-t6 alone has little effect, when combined with rga-24, they completely rescued the above defects of ga1-3 to wild-type or GA-overdose phenotype. However, seed germination and flower development defects were not restored. Additionally, rga-24 and rga-24/gai-t6 but not gai-t6 alone caused increased feedback inhibition of expression of a GA biosynthetic gene in both the ga1-3 and wild-type backgrounds. These results demonstrate that RGA and GAI have partially redundant functions in maintaining the repressive state of the GA-signaling pathway, but RGA plays a more dominant role than GAI. Removing both RGA and GAI function allows for complete derepression of many aspects of GA signaling. PMID- 11606553 TI - Four mutant alleles elucidate the role of the G2 protein in the development of C(4) and C(3) photosynthesizing maize tissues. AB - Maize leaf blades differentiate dimorphic photosynthetic cell types, the bundle sheath and mesophyll, between which the reactions of C(4) photosynthesis are partitioned. Leaf-like organs of maize such as husk leaves, however, develop a C(3) pattern of differentiation whereby ribulose bisphosphate carboxylase (RuBPCase) accumulates in all photosynthetic cell types. The Golden2 (G2) gene has previously been shown to play a role in bundle sheath cell differentiation in C(4) leaf blades and to play a less well-defined role in C(3) maize tissues. To further analyze G2 gene function in maize, four g2 mutations have been characterized. Three of these mutations were induced by the transposable element Spm. In g2-bsd1-m1 and g2-bsd1-s1, the element is inserted in the second intron and in g2-pg14 the element is inserted in the promoter. In the fourth case, g2-R, four amino acid changes and premature polyadenylation of the G2 transcript are observed. The phenotypes conditioned by these four mutations demonstrate that the primary role of G2 in C(4) leaf blades is to promote bundle sheath cell chloroplast development. C(4) photosynthetic enzymes can accumulate in both bundle sheath and mesophyll cells in the absence of G2. In C(3) tissue, however, G2 influences both chloroplast differentiation and photosynthetic enzyme accumulation patterns. On the basis of the phenotypic data obtained, a model that postulates how G2 acts to facilitate C(4) and C(3) patterns of tissue development is proposed. PMID- 11606554 TI - Anchored reference loci in loblolly pine (Pinus taeda L.) for integrating pine genomics. AB - Anchored reference loci provide a framework for comparative mapping. They are landmarks to denote conserved chromosomal segments, allowing the synthesis of genetic maps from multiple sources. We evaluated 90 expressed sequence tag polymorphisms (ESTPs) from loblolly pine (Pinus taeda L.) for this function. Primer sets were assayed for amplification and polymorphism in six pedigrees, representing two subgenera of Pinus and a distant member of the Pinaceae, Douglas fir (Pseudotsuga menziesii [Mirb.] Franco). On average, 89% of primer sets amplified in four species of subgenus Pinus, 49% in one species of subgenus Strobus, and 22% in Douglas-fir. Polymorphisms were detected for 37-61% of the ESTPs within each pedigree. Comparative mapping in loblolly and slash pine (P. elliottii Englm.) revealed that ESTPs mapped to the same location. Disrupted synteny or significant disruptions in colinearity were not detected. Thirty-five ESTPs met criteria established for anchor loci. The majority of those that did not meet these criteria were excluded when map location was known in only a single species. Anchor loci provide a unifying tool for the community, facilitating the creation of a "generic" pine map and serving as a foundation for studies on genome organization and evolution. PMID- 11606556 TI - Transmission genetics of chromatin from a synthetic amphidiploid to cultivated peanut (Arachis hypogaea L.). broadening the gene pool of a monophyletic polyploid species. AB - Polyploidy creates severe genetic bottlenecks, contributing to the genetic vulnerability of leading crops. Cultivated peanut is thought to be of monophyletic origin, harboring relatively little genetic diversity. To introduce variability from diploid wild species into tetraploid cultivated Arachis hypogaea, a synthetic amphidiploid [[A. batizocoi K9484 x (A. cardenasii GKP10017 x A. diogoi GKP10602)](4x)] was used as donor parent to generate a backcross population of 78 progeny. Three hundred seventy RFLP loci were mapped onto 23 linkage groups, spanning 2210 cM. Chromatin derived from the two A-genome diploid ancestors (A. cardenasii and A. diogoi) comprised mosaic chromosomes, reflecting crossing over in the diploid A-genome interspecific F(1) hybrid. Recombination between chromosomes in the tetraploid progeny was similar to chromosome pairing reported for A. hypogaea, with recombination generally between chromosomes of the same subgenomic affinity. Segregation distortion was observed for 25% of the markers, distributed over 20 linkage groups. Unexpectedly, 68% of the markers deviating from expected segregation showed an excess of the synthetic parent allele. Genetic consequences, relationship to species origins, and significance for comparative genetics are discussed. PMID- 11606555 TI - Intrahaplotype polymorphism at the Brassica S locus. AB - The S locus receptor kinase and the S locus glycoproteins are encoded by genes located at the S locus, which controls the self-incompatibility response in Brassica. In class II self-incompatibility haplotypes, S locus glycoproteins can be encoded by two different genes, SLGA and SLGB. In this study, we analyzed the sequences of these genes in several independently isolated plants, all of which carry the same S haplotype (S(2)). Two groups of S(2) haplotypes could be distinguished depending on whether SRK was associated with SLGA or SLGB. Surprisingly, SRK alleles from the two groups could be distinguished at the sequence level, suggesting that recombination rarely occurs between haplotypes of the two groups. An analysis of the distribution of polymorphisms along the S domain of SRK showed that hypervariable domains I and II tend to be conserved within haplotypes but to be highly variable between haplotypes. This is consistent with these domains playing a role in the determination of haplotype specificity. PMID- 11606557 TI - Dynamics of microsatellite divergence under stepwise mutation and proportional slippage/point mutation models. AB - Recently Kruglyak, Durrett, Schug, and Aquadro showed that microsatellite equilibrium distributions can result from a balance between polymerase slippage and point mutations. Here, we introduce an elaboration of their model that keeps track of all parts of a perfect repeat and a simplification that ignores point mutations. We develop a detailed mathematical theory for these models that exhibits properties of microsatellite distributions, such as positive skewness of allele lengths, that are consistent with data but are inconsistent with the predictions of the stepwise mutation model. We use our theoretical results to analyze the successes and failures of the genetic distances (delta(mu))(2) and D(SW) when used to date four divergences: African vs. non-African human populations, humans vs. chimpanzees, Drosophila melanogaster vs. D. simulans, and sheep vs. cattle. The influence of point mutations explains some of the problems with the last two examples, as does the fact that these genetic distances have large stochastic variance. However, we find that these two features are not enough to explain the problems of dating the human-chimpanzee split. One possible explanation of this phenomenon is that long microsatellites have a mutational bias that favors contractions over expansions. PMID- 11606558 TI - Likelihoods and simulation methods for a class of nonneutral population genetics models. AB - Methods for simulating samples and sample statistics, under mutation-selection drift equilibrium for a class of nonneutral population genetics models, and for evaluating the likelihood surface, in selection and mutation parameters, are developed and applied for observed data. The methods apply to large populations in settings in which selection is weak, in the sense that selection intensities, like mutation rates, are of the order of the inverse of the population size. General diploid selection is allowed, but the approach is currently restricted to models, such as the infinite alleles model and certain K-models, in which the type of a mutant allele does not depend on the type of its progenitor allele. The simulation methods have considerable advantages over available alternatives. No other methods currently seem practicable for approximating likelihood surfaces. PMID- 11606559 TI - A general polyploid model for analyzing gene segregation in outcrossing tetraploid species. AB - Polyploidy has played an important role in higher plant evolution and applied plant breeding. Polyploids are commonly categorized as allopolyploids resulting from the increase of chromosome number through hybridization and subsequent chromosome doubling or autopolyploids due to chromosome doubling of the same genome. Allopolyploids undergo bivalent pairing at meiosis because only homologous chromosomes pair. For autopolyploids, however, all homologous chromosomes can pair at the same time so that multivalents and, therefore, double reductions are formed. In this article, we use a maximum-likelihood method to develop a general polyploid model for estimating gene segregation patterns from molecular markers in a full-sib family derived from an arbitrary polyploid combining meiotic behaviors of both bivalent and multivalent pairings. Two meiotic parameters, one describing the preference of homologous chromosome pairing (expressed as the preferential pairing factor) typical of allopolyploids and the other specifying the degree of double reduction of autopolyploids, are estimated. The type of molecular markers used can be fully informative vs. partially informative or dominant vs. codominant. Simulation studies show that our polyploid model is well suited to estimate the preferential pairing factor and the frequency of double reduction at meiosis, which should help to characterize gene segregation in the progeny of autopolyploids. The implications of this model for linkage mapping, population genetic studies, and polyploid classification are discussed. PMID- 11606560 TI - A genome-wide survey of reproductive barriers in an intraspecific hybrid. AB - Genetic study of the reproductive barriers between related species plays an essential role in understanding the process of speciation. We developed a new method for mapping all possible factors causing deviations from expected Mendelian segregation ratios in F(2) progeny, which substantially contribute to reproductive isolation. A multiresponse nonlinear regression analysis of the allele frequencies of the markers covering an entire genome in the F(2) population was performed to estimate the map position and intensity of the reproductive barriers on each chromosome. In F(2) plants from a cross between a Japonica variety of rice, Nipponbare, and an Indica variety, Kasalath, the deviations of allele frequencies were well explained by 33 reproductive barriers. Of these, 15 reproductive barriers affected the allele transmission rate through the gametophyte and in 9 of these 15 cases, an Indica allele was transmitted at a higher frequency than a Japonica allele. The other 18 reproductive barriers altered the viability of the zygote via its genotype. Two zygotic reproductive barriers showed overdominance and 5 showed underdominance. The most pronounced reproductive barrier, mapped at 62.3 +/- 0.4 cM on chromosome 3, transmitted the Indica allele by 94% through the male gametophyte. The accuracy of the barrier position in the regression analysis was confirmed by progeny analysis. The regression analysis proved to be a powerful tool for detecting and characterizing every reproductive barrier, irrespective of whether it acted on the male or female gametophyte or the zygote. PMID- 11606561 TI - Gene genealogies in a metapopulation. AB - A simple genealogical process is found for samples from a metapopulation, which is a population that is subdivided into a large number of demes, each of which is subject to extinction and recolonization and receives migrants from other demes. As in the migration-only models studied previously, the genealogy of any sample includes two phases: a brief sample-size adjustment followed by a coalescent process that dominates the history. This result will hold for metapopulations that are composed of a large number of demes. It is robust to the details of population structure, as long as the number of possible source demes of migrants and colonists for each deme is large. Analytic predictions about levels of genetic variation are possible, and results for average numbers of pairwise differences within and between demes are given. Further analysis of the expected number of segregating sites in a sample from a single deme illustrates some previously known differences between migration and extinction/recolonization. The ancestral process is also amenable to computer simulation. Simulation results show that migration and extinction/recolonization have very different effects on the site-frequency distribution in a sample from a single deme. Migration can cause a U-shaped site-frequency distribution, which is qualitatively similar to the pattern reported recently for positive selection. Extinction and recolonization, in contrast, can produce a mode in the site-frequency distribution at intermediate frequencies, even in a sample from a single deme. PMID- 11606563 TI - Identification of a conserved archaeal RNA polymerase subunit contacted by the basal transcription factor TFB. AB - Archaea possess two general transcription factors that are required to recruit RNA polymerase (RNAP) to promoters in vitro. These are TBP, the TATA-box-binding protein and TFB, the archaeal homologue of TFIIB. Thus, the archaeal and eucaryal transcription machineries are fundamentally related. In both RNAP II and archaeal transcription systems, direct contacts between TFB/TFIIB and the RNAP have been demonstrated to mediate recruitment of the polymerase to the promoter. However the subunit(s) directly contacted by these factors has not been identified. Using systematic yeast two-hybrid and biochemical analyses we have identified an interaction between the N-terminal domain of TFB and an evolutionarily conserved subunit of the RNA polymerase, RpoK. Intriguingly, homologues of RpoK are found in all three nuclear RNA polymerases (Rpb6) and also in the bacterial RNA polymerase (omega-subunit). PMID- 11606564 TI - Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. AB - Serine phosphorylation of insulin receptor substrate-1 (IRS-1) inhibits insulin signal transduction in a variety of cell backgrounds, which might contribute to peripheral insulin resistance. However, because of the large number of potential phosphorylation sites, the mechanism of inhibition has been difficult to determine. One serine residue located near the phosphotyrosine-binding (PTB) domain in IRS-1 (Ser(307) in rat IRS-1 or Ser(312) in human IRS-1) is phosphorylated via several mechanisms, including insulin-stimulated kinases or stress-activated kinases like JNK1. During a yeast tri-hybrid assay, phosphorylation of Ser(307) by JNK1 disrupted the interaction between the catalytic domain of the insulin receptor and the PTB domain of IRS-1. In 32D myeloid progenitor cells, phosphorylation of Ser(307) inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser(307) (Ser(312) in human IRS-1) might be a general mechanism to regulate insulin signaling. PMID- 11606565 TI - Chaperone suppression of cellular toxicity of huntingtin is independent of polyglutamine aggregation. AB - Polyglutamine protein aggregation is associated with eight inherited neurodegenerative disorders. In Huntington's disease, N-terminal fragments of mutant huntingtin form intracellular aggregates and mediate cellular toxicity. Recent studies have shown that chaperones inhibit polyglutamine-mediated aggregation and cellular toxicity. Because chaperones also inhibit caspase activation to protect cells from death, it remains unclear whether the protective effect of chaperones on polyglutamine-mediated cellular toxicity is dependent on their inhibition of protein aggregation. In this study, we show that several chaperones including HSP 40, HSP 70, and N-ethylmaleimide-sensitive factor can inhibit cellular toxicity caused by N-terminal mutant huntingtin fragments. However, only HSP 40 is able to inhibit huntingtin aggregation. Furthermore, time course study suggests that the protection of chaperones against huntingtin toxicity is not the result of their suppression of huntingtin aggregation. Chaperones inhibit caspase-3 and caspase-9 activation mediated by mutant huntingtin, and this inhibition is independent of huntingtin aggregation. We propose that the inhibition of caspase activity by chaperones is involved in their suppression of polyglutamine toxicity. PMID- 11606566 TI - Phosphatidylinositol 3-kinase c2alpha contains a nuclear localization sequence and associates with nuclear speckles. AB - Phosphoinositide 3-kinase C2alpha (PI3K-C2alpha) belongs to the class II phosphatidylinositol 3-kinases, which are defined by their in vitro usage of phosphatidylinositol and phosphatidylinositol 4-phosphate as substrates. All type II phosphatidylinositol 3-kinases contain at their C terminus a C2-like domain. Here we demonstrate that Homo sapiens phosphoinositide 3-kinase C2alpha (HsPI3K C2alpha) has dual cellular localization present in the cytoplasm and in the nucleus. A distinct nuclear localization signal sequence was identified by expressing HsPI3K-C2alpha-green fluorescent protein fusion proteins in HeLa cells. The nuclear localization signal was mapped to a stretch of 11 amino acids (KRKTKISRKTR) located within C2-like domain of the kinase. In the cytoplasm and the nucleus HsPI3K-C2alpha associates with macromolecular complexes that are resistant to detergent extraction. Indirect immunofluorescence reveals that in the nucleus HsPI3K-C2alpha is enriched at distinct subnuclear domains known as nuclear speckles, which contain pre-mRNA processing factors and are functionally connected to RNA metabolism. Phosphorylation of HsPI3K-C2alpha is induced by inhibition of RNA polymerase II-dependent transcription and coincides with enlargement and rounding up of the nuclear speckles. The results suggest that phosphorylation of HsPI3K-C2alpha is inversely linked to mRNA transcription and supports the importance of phosphoinositides for nuclear activity. PMID- 11606567 TI - Senescence delay of human diploid fibroblast induced by anti-sense p16INK4a expression. AB - p16(INK4a), a tumor suppressor gene that inhibits cyclin-dependent kinase 4 and cyclin-dependent kinase 6, is also implicated in the mechanisms underlying replicative senescence, because its RNA and protein accumulate as cells approach their finite number of population doublings in tissue culture. To further explore the involvement of p16(INK4a) in replicative senescence, we constructed a retroviral vector containing antisense p16(INK4a), pDOR-ASp16, and introduced it into early passages of human diploid fibroblasts. The introduction of this construct significantly suppressed the expression of wild-type p16(INK4a). It also imposed a finite increase in proliferative life span and significant delay of several other cell senescent features, such as cell flattening, cell cycle arrest, and senescence-associated beta-galactosidase positivity. Moreover, telomere shortening and decline in DNA repair capacity, which normally accompany cell senescence, are also postponed by the ASp16 transfection. The life span of fibroblasts was significantly extended, but the onset of replicative senescence could not be totally prevented. Telomerase could not be activated even though telomere shortening was slowed. These observations suggest that the telomere pathway of senescence cannot be bypassed by ASp16 expression. These data not only strongly support a role for p16(INK4a) in replicative senescence but also raise the possibility of using the antisense p16(INK4a) therapeutically. PMID- 11606568 TI - Functional interaction between bovine rhodopsin and G protein transducin. AB - To elucidate the mechanisms of specific coupling of bovine rhodopsin with the G protein transducin (G(t)), we have constructed the bovine rhodopsin mutants whose second or third cytoplasmic loop (loop 2 or 3) was replaced with the corresponding loop of the G(o)-coupled scallop rhodopsin and investigated the difference in the activation abilities for G(t), G(o), and G(i) among these mutants and wild type. We have also prepared the Galpha(i) mutants whose C terminal 11 or 5 amino acids were replaced with those of Galpha(t), Galpha(o), and Galpha(q) to evaluate the role of the C-terminal tail of the alpha-subunit on the specific coupling of bovine rhodopsin with G(t). Replacement of loop 2 of bovine rhodopsin with that of the scallop rhodopsin caused about a 40% loss of G(t) and G(o) activation, whereas that of loop 3 enhanced the G(o) activation four times with a 60% decrease in the G(t) activation. These results indicated that loop 3 of bovine rhodopsin is one of the regions responsible for the specific coupling with G(t). Loop 3 of bovine rhodopsin discriminates the difference of the 6-amino acid sequence (region A) at a position adjacent to the C-terminal 5 amino acids of the G protein, resulting in the different activation efficiency between G(t) and G(o). In addition, the binding of region A to loop 3 of bovine rhodopsin is essential for activation of G(t) but not G(i), even though the sequence of the region A is almost identical between Galpha(t) and Galpha(i). These results suggest that the binding of loop 3 of bovine rhodopsin to region A in Galpha(t) is one of the mechanisms of specific G(t) activation by bovine rhodopsin. PMID- 11606569 TI - Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. AB - The microtubule-associated protein tau is a natively unfolded protein in solution, yet it is able to polymerize into the ordered paired helical filaments (PHF) of Alzheimer's disease. In the splice isoforms lacking exon 10, this process is facilitated by the formation of beta-structure around the hexapeptide motif PHF6 ((306)VQIVYK(311)) encoded by exon 11. We have investigated the structural requirements for PHF polymerization in the context of adult tau isoforms containing four repeats (including exon 10). In addition to the PHF6 motif there exists a related PHF6* motif ((275)VQIINK(280)) in the repeat encoded by the alternatively spliced exon 10. We show that this PHF6* motif also promotes aggregation by the formation of beta-structure and that there is a cross-talk between the two hexapeptide motifs during PHF aggregation. We also show that two of the tau mutations found in hereditary frontotemporal dementias, DeltaK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for beta-structure around the hexapeptide motifs. PMID- 11606571 TI - CpsB is a modulator of capsule-associated tyrosine kinase activity in Streptococcus pneumoniae. AB - Tyrosine phosphorylation is associated with polysaccharide synthesis in a number of Gram-positive and Gram-negative bacteria. In Streptococcus pneumoniae, CpsB, CpsC, and CpsD affect tyrosine phosphorylation and are critical for the production of a mature capsule in vitro. To characterize the interactions between these proteins and the phosphorylation event they modulate, cps2B, cps2C, and cps2D from the capsule type 2 S. pneumoniae D39 were cloned and expressed both individually and in combination in Escherichia coli. Cps2D purified from E. coli was not phosphorylated unless it was co-expressed with its cognate transmembrane domain, Cps2C. Purified phosphorylated Cps2D had tyrosine kinase activity and could phosphorylate both dephosphorylated Cps2D and an exogenous substrate (poly Glu-Tyr) in the absence of ATP. Cps2B exhibited phosphatase activity against both purified phosphorylated Cps2D and p-nitrophenyl phosphate. An additional role for Cps2B as an inhibitor of Cps2D phosphorylation was demonstrated in both co expression experiments in E. coli and in vitro experiments where it blocked the transphosphorylation of Cps2D even in the presence of the phosphatase inhibitor sodium orthovanadate. cps2C and cps2D deletion mutants in S. pneumoniae produced no detectable mature capsule during laboratory culture. Both were avirulent in systemic mouse infections and were unable to colonize the nasopharynx, suggesting that the failure to produce capsule was not dependent on the environment. Based on these results, we propose a model for capsule regulation where CpsB, CpsC, CpsD, and ATP form a stable complex that enhances capsule synthesis. PMID- 11606570 TI - Iron prevents ferritin turnover in hepatic cells. AB - It has long been assumed that iron regulates the turnover of ferritin, but evidence for or against this idea has been lacking. This issue was addressed using rat hepatoma cells with characteristics of hepatocytes subjected to a continuous influx of iron. Iron-pretreated cells were pulsed with [(35)S]Met for 60 min or with (59)Fe overnight and harvested up to 30 h thereafter, during which they were/were not cultured with ferric ammonium citrate (FAC; 180 microm). Radioactivity in ferritin/ferritin subunits of cell heat supernatants was determined by autoradiography of rockets obtained by immunoelectrophoresis or after precipitation with ferritin antibody and SDS-PAGE. Both methods gave similar results. During the +FAC chase, the concentration of ferritin in the cells increased linearly with time. Without FAC, the half-life of (35)S-ferritin was 19-20 h; with FAC there was no turnover. Without FAC, the iron in ferritin had an apparent half-life of 20 h; in the presence of FAC there was no loss of (59)Fe. Without FAC, concentrations of ferritin iron and protein also decreased in parallel. We conclude that a continuous influx of excess iron can completely inhibit the degradation of ferritin protein and that the iron and protein portions of ferritin molecules may be coordinately degraded. PMID- 11606572 TI - Identification of agonistic and antagonistic antibodies against gp190, the leukemia inhibitory factor receptor, reveals distinct roles for its two cytokine binding domains. AB - The receptor for the cytokine leukemia inhibitory factor (LIF) associates the low affinity binding component gp190 and the high affinity converter gp130, both of which are members of the family of hematopoietic receptors characterized by the cytokine receptor homology (CRH) domain. The gp190 is among the very few members of this large family to contain two CRH domains. The membrane-distal one (herein called D1) is followed by an Ig-like domain, a membrane-proximal CRH domain called D2, and three type III fibronectin repeats. We raised a series of monoclonal antibodies specific for the human gp190. Among them was the blocking antibody 1C7, which was directed against the D1Ig region and which impaired the binding of LIF to gp190. Another blocking antibody, called 12D3, was directed against domain D2 and interfered with the reconstitution of the high affinity receptor complex, independently of the interaction between LIF and gp190. The blocking effect of these two antibodies concerned four cytokines known to use gp190, i.e. LIF, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1. Among 23 antibodies tested alone or in combination (two anti-D2 and 21 anti D1Ig), only the mixture of the two anti-D2 antibodies displayed agonistic activity in the absence of the cytokine. Taken together, these results demonstrate that the two CRH domains of gp190 play different functions in ligand binding and receptor activation. PMID- 11606573 TI - A catalytic antibody produces fluorescent tracers of gap junction communication in living cells. AB - The antibody 38C2 efficiently catalyzed a retro-Michael reaction to convert a novel, cell-permeable fluorogenic substrate into fluorescein within living cells. In vitro, the antibody converted the substrate to fluorescein with a k(cat) of 1.7 x 10(-5) s(-1) and a catalytic proficiency (k(cat)/k(uncat)K(m)) of 1.4 x 10(10) m(-1) (K(m) = 7 microm). For hybridoma cells expressing antibody or Chinese Hamster Ovarian (CHO) cells injected with antibody, incubation of the substrate in the extracellular medium resulted in bright intracellular fluorescence distinguishable from autofluorescence or noncatalyzed conversion of substrate. CHO cells loaded with antibody were 12 times brighter than control cells, and more than 85% of injected cells became fluorescent. The fluorescein produced by the antibody traveled into neighboring cells through gap junctions, as demonstrated by blocking dye transfer using the gap junction inhibitor oleamide. The presence of functional gap junctions in CHO cells was confirmed through oleamide inhibition of lucifer yellow transfer. These studies demonstrate the utility of the intracellular antibody reaction, which could generate tracer dyes in specific cells within complex multicellular environments simply by bathing the system in substrate. PMID- 11606574 TI - A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers. AB - The cytoplasmic carboxyl-terminal domain of AE1, the plasma membrane chloride/bicarbonate exchanger of erythrocytes, contains a binding site for carbonic anhydrase II (CAII). To examine the physiological role of the AE1/CAII interaction, anion exchange activity of transfected HEK293 cells was monitored by following the changes in intracellular pH associated with AE1-mediated bicarbonate transport. AE1-mediated chloride/bicarbonate exchange was reduced 50 60% by inhibition of endogenous carbonic anhydrase with acetazolamide, which indicates that CAII activity is required for full anion transport activity. AE1 mutants, unable to bind CAII, had significantly lower transport activity than wild-type AE1 (10% of wild-type activity), suggesting that a direct interaction was required. To determine the effect of displacement of endogenous wild-type CAII from its binding site on AE1, AE1-transfected HEK293 cells were co transfected with cDNA for a functionally inactive CAII mutant, V143Y. AE1 activity was maximally inhibited 61 +/- 4% in the presence of V143Y CAII. A similar effect of V143Y CAII was found for AE2 and AE3cardiac anion exchanger isoforms. We conclude that the binding of CAII to the AE1 carboxyl-terminus potentiates anion transport activity and allows for maximal transport. The interaction of CAII with AE1 forms a transport metabolon, a membrane protein complex involved in regulation of bicarbonate metabolism and transport. PMID- 11606575 TI - Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth. AB - In this study we initially examined the interaction between CD44v3 (a hyaluronan (HA) receptor) and Vav2 (a guanine nucleotide exchange factor) in human ovarian tumor cells (SK-OV-3.ipl cell line). Immunological data indicate that both CD44v3 and Vav2 are expressed in SK-OV-3.ipl cells and that these two proteins are physically linked as a complex in vivo. By using recombinant fragments of Vav2 and in vitro binding assays, we have detected a specific binding interaction between the SH3-SH2-SH3 domain of Vav2 and the cytoplasmic domain of CD44. In addition, we have observed that the binding of HA to CD44v3 activates Vav2 mediated Rac1 signaling leading to ovarian tumor cell migration. Further analyses indicate that the adaptor molecule, growth factor receptor-bound protein 2 (Grb2) that is bound to p185(HER2) (an oncogene product), is also associated with the CD44v3-Vav2 complex. HA binding to SK-OV-3.ipl cells promotes recruitment of both Grb2 and p185(HER2) to the CD44v3-Vav2 complex leading to Ras activation and ovarian tumor cell growth. In order to determine the role of Grb2 in CD44v3 signaling, we have transfected SK-OV-3.ipl cells with Grb2 mutant cDNAs (e.g. Delta N-Grb2 that has a deletion in the amino-terminal SH3 domain or Delta C-Grb2 that has a deletion in the carboxyl-terminal SH3 domain). Our results clearly indicate that the SH3 domain deletion mutants of Grb2 (i.e. the Delta N-Grb2 (and to a lesser extent the Delta C-Grb2) mutant) not only block their association with p185(HER2) but also significantly impair their binding to the CD44v3-Vav2 complex and inhibit HA/CD44v3-induced ovarian tumor cell behaviors. Taken together, these findings strongly suggest that the interaction of CD44v3-Vav2 with Grb2-p185(HER2) plays an important role in the co-activation of both Rac1 and Ras signaling that is required for HA-mediated human ovarian tumor progression. PMID- 11606576 TI - The capsid protein of a plant single-stranded RNA virus is modified by O-linked N acetylglucosamine. AB - Plum pox virus (PPV) is a member of the Potyvirus genus of plant viruses. Labeling with UDP-[3H]galactose and galactosyltransferase indicated that the capsid protein (CP) of PPV is a glycoprotein with N-acetylglucosamine terminal residues. Mass spectrometry analysis of different PPV isolates and mutants revealed O-linked N-acetylglucosamination, a modification barely studied in plant proteins, of serine and/or threonine residues near the amino end of PPV CP. CP of PPV virions is also modified by serine and threonine phosphorylation, as shown by Western blot analysis with anti-phosphoserine and anti-phosphothreonine antibodies. Thus, "yin-yang" glycosylation and phosphorylation may play an important role in the regulation of the different functions in which the potyviral CP is involved. PMID- 11606577 TI - Oxygen-dependent regulation of in vivo replication of simian virus 40 DNA is modulated by glucose. AB - Simian virus 40 (SV40)-infected CV1 cells exposed to hypoxia show an inhibition of viral replication. Reoxygenation after several hours of hypoxia results in new initiations followed by a nearly synchronous round of SV40 replication. In this communication, we examined the effect of glucose on inhibition of viral DNA replication under hypoxia. We found that glucose stimulated SV40 DNA replication under hypoxia in two different ways. First, the rate of DNA synthesis, i.e. the fork propagation rate, increased. This effect seemed to be mediated by inhibition of mitochondrial respiration by glucose (Crabtree effect). Inhibition of mitochondrial respiration probably resulted in a higher intracellular oxygen concentration and an activation of oxygen-dependent ribonucleotide reductase, which provides the precursors for DNA synthesis. This glucose effect was consequently strongly dependent on the strength of hypoxia and the extent of intracellular respiration; hypoxic gassing with 10 ppm instead of 200-400 ppm O(2) or treatment of hypoxic cells with a mitochondrial uncoupler (carbonyl cyanide m-chlorophenylhydrazone) reduced the glucose effect on replication, whereas antimycin A, an inhibitor of respiration, increased it. The second effect of glucose concerned initiation, i.e. stimulation of unwinding of the viral origin. This effect was not influenced by the strength of hypoxia or the extent of cellular respiration and seemed, therefore, not to be mediated through a Crabtree effect. No evidence for a direct correlation between the cellular ATP concentration and the extent of SV40 replication under hypoxia was found. The effect of glucose on replication under hypoxia was not restricted to SV40 infected CV1 cells but was also detectable in HeLa cells. This suggests it to be a mechanism of more general validity. PMID- 11606578 TI - Antagonism of the actions of peroxisome proliferator-activated receptor-alpha by bile acids. AB - The peroxisome proliferator-activated receptor-alpha (PPARalpha) is a ligand activated transcription factor that regulates the expression of a number of genes critical for fatty acid beta-oxidation. Because a number of substrates and intermediates of this metabolic pathway serve as ligand activators of this receptor, homeostatic control of fatty acid metabolism is achieved. Evidence also exists for PPARalpha-dependent regulation of genes encoding critical enzymes of bile acid biosynthesis. To determine whether the primary products of bile acid biosynthesis, cholic acid and chenodeoxycholic acid, were capable of modulating PPARalpha function, a variety of in vivo and in vitro approaches were utilized. Feeding a bile acid-enriched diet significantly reduced the degree of hepatomegaly and induction of target genes encoding enzymes of fatty acid beta oxidation caused by treatment with the potent PPARalpha ligand Wyeth-14,643. Convergent data from mechanistic studies indicate that bile acids interfere with transactivation by PPARalpha at least in part by impairing the recruitment of transcriptional coactivators. The results of this study provide the first evidence in favor of the existence of compounds, normally found within the body, that are capable of antagonizing the physiological actions of PPARalpha. The impact of PPARalpha antagonism by endogenous bile acids is likely to be limited under normal conditions and to have only minimal effects on bile acid homeostasis. However, during certain pathophysiological states where intracellular bile acid concentrations are elevated, meaningful effects on PPARalpha-dependent target gene regulation are possible. PMID- 11606579 TI - Mechanism-based suppression of dideoxynucleotide resistance by K65R human immunodeficiency virus reverse transcriptase using an alpha-boranophosphate nucleoside analogue. AB - The amino acid change K65R in human immunodeficiency virus type 1-reverse transcriptase (RT) confers viral resistance to various 2',3'-dideoxynucleoside drugs in vivo. Using pre-steady state kinetic methods, we found that K65R-reverse transcriptase is 3.2-14-fold resistant to 2',3'-dideoxynucleotides in vitro relative to wild-type reverse transcriptase, in agreement with resistance levels observed in vivo. A decreased catalytic rate constant k(pol) mostly accounts for the lower incorporation efficiency observed for 2',3'-dideoxynucleotides. Examination of the crystal structure of the RT.DNA.dNTP complex suggested that both the charge at position 65 and the 3'-OH of the incoming nucleotide act in synergy during the creation of the phosphodiester bond, resulting in a more pronounced decreased catalytic rate constant for 2',3'-dideoxynucleotides than for dNTPs. This type of intramolecular activation of the leaving phosphate by the 3'-OH group appears to be conserved in several nucleotide phosphotransferases. These data were used to design dideoxynucleotide analogues targeting K65R RT specifically. alpha-Boranophosphate ddATP was found to be a 2-fold better substrate than dATP and inhibited DNA synthesis by K65R RT 153-fold better than ddATP. This complete suppression of drug resistance at the nucleotide level could serve for other reverse transcriptases for which drug resistance is achieved at the catalytic step. PMID- 11606580 TI - Ca2+ pools and cell growth. Evidence for sarcoendoplasmic Ca2+-ATPases 2B involvement in human prostate cancer cell growth control. AB - The present study demonstrates for the first time that intracellular calcium ATPases and calcium pool content are closely associated with prostate cancer LNCaP cell growth. Cell growth was modulated by changing the amount of epidermal growth factor, serum, and androgene in culture media. Using the microspectrofluorimetric method with Fura-2 and Mag Fura-2 as probes, we show that in these cells, the growth rate is correlated with intracellular calcium pool content. Indeed, an increased growth rate is correlated with an increase in the calcium pool filling state, whereas growth-inhibited cells show a reduced calcium pool load. Using Western blotting and immunocytochemistry, we show that endoplasmic reticulum calcium pump expression is closely linked to LNCaP cell growth, and are a common target of physiological stimuli that control cell growth. Moreover, we clearly demonstrate that inhibition of these pumps, using thapsigargin, inhibits LNCaP cell growth and prevents growth factor from stimulating cell proliferation. Our results thus provide evidence for the essential role of functional endoplasmic reticulum calcium pumps and calcium pool in control of prostate cancer LNCaP cell growth, raising the prospect of new targets for the treatment of prostate cancer. PMID- 11606581 TI - Protein kinase A regulates Rac and is required for the growth factor-stimulated migration of carcinoma cells. AB - Members of the Rho family of small GTPases, such as Rho and Rac, are required for actin cytoskeletal reorganization during the migration of carcinoma cells. Phosphodiesterases are necessary for this migration because they alleviate cAMP dependent protein kinase (PKA)-mediated inhibition of RhoA (O'Connor, K. L., Shaw, L. M., and Mercurio, A. M. (1998) J. Cell Biol. 143, 1749-1760; O'Connor K. L., Nguyen, B.-K., and Mercurio, A. M. (2000), J. Cell Biol. 148, 253-258). In this study, we report that the migration of breast and squamous carcinoma cells toward either lysophosphatidic acid or epidermal growth factor involves not only phosphodiesterase activity but also cooperative signaling from PKA. Furthermore, we demonstrate that Rac1 activation in response to chemoattractant or beta(1) integrin clustering is regulated by PKA and that Rac1 is required for this migration. Also, we find that beta(1) integrin signaling stimulates the rapid and transient activation of PKA. A novel implication of these findings is that carcinoma cell migration is controlled by cAMP-dependent as well as cAMP inhibitory signaling mechanisms. PMID- 11606582 TI - NMR spectroscopy reveals the solution dimerization interface of p53 core domains bound to their consensus DNA. AB - The p53 protein is a transcription factor that acts as the major tumor suppressor in mammals. The core DNA-binding domain is mutated in about 50% of all human tumors. The crystal structure of the core domain in complex with DNA illustrated how a single core domain specifically interacts with its DNA consensus site and how it is inactivated by mutation. However, no structural information for the tetrameric full-length p53-DNA complex is available. Here, we present novel experimental insight into the dimerization of two p53 core domains upon cooperative binding to consensus DNA in solution obtained by NMR. The NMR data show that the p53 core domain itself does not appear to undergo major conformational changes upon addition of DNA and elucidate the dimerization interface between two DNA-bound core domains, which includes the short H1 helix. A NMR-based model for the dimeric p53 core-DNA complex incorporates these data and allows the conclusion that the dimerization interface also forms the actual interface in the tetrameric p53-DNA complex. The significance of this interface is further corroborated by the finding that hot spot mutations map to the H1 helix, and by the binding of the putative p53 inhibitor 53BP2 to this region via one of its ankyrin repeats. Based on symmetry considerations it is proposed that tetrameric p53 might link non-contiguous DNA consensus sites in a sandwich-like manner generating DNA loops as observed for transcriptionally active p53 complexes. PMID- 11606583 TI - Alpha(v) integrin, p38 mitogen-activated protein kinase, and urokinase plasminogen activator are functionally linked in invasive breast cancer cells. AB - We reported previously that endogenous p38 MAPK activity is elevated in invasive breast cancer cells and that constitutive p38 MAPK activity is important for overproduction of uPA in these cells (Huang, S., New, L., Pan, Z., Han, J., and Nemerow, G. R. (2000) J. Biol. Chem. 275, 12266-12272). However, it is unclear how elevated endogenous p38 MAPK activity is maintained in invasive breast cancer cells. In the present study, we found that blocking alpha(v) integrin functionality with a function-blocking monoclonal antibody or down-regulating alpha(v) integrin expression with alpha(v)-specific antisense oligonucleotides significantly decreased the levels of active p38 MAPK and inhibited cell associated uPA expression in invasive breast cancer MDA-MB-231 cells. These results suggest a function link between alpha(v) integrin, p38 MAPK activity, and uPA expression in invasive tumor cells. We also found that vitronectin/alpha(v) integrin ligation specifically induced p38 MAPK activation and uPA up-regulation in invasive MDA-MB-231 cells but not in non-invasive MCF7 cells. Finally, using a panel of melanoma cells, we demonstrated that the cytoplasmic tail of alpha(v) integrin subunit is required for alpha(v) integrin ligation-induced p38 MAPK activation. PMID- 11606585 TI - Ligands of peroxisome proliferator-activated receptor-gamma block activation of pancreatic stellate cells. AB - Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Peroxisome proliferator activated receptor gamma (PPAR-gamma) is a ligand-activated transcription factor which controls growth, differentiation, and inflammation in different tissues. Roles of PPAR-gamma activation in PSCs are poorly characterized. Here we examined the effects of PPAR-gamma ligands on the key parameters of PSC activation. PSCs were isolated from rat pancreas tissue, and used in their culture-activated, myofibroblast-like phenotype. Activation of PPAR-gamma was induced with 15-deoxy Delta12,14-prostaglandin J2 (15d-PGJ2) or with troglitazone. Expression of PPAR gamma was predominantly localized in the nuclei, and PPAR-gamma was transcriptionally active after ligand stimulation. PPAR-gamma ligands inhibited platelet-derived growth factor-induced proliferation. This effect was associated with inhibition of cell cycle progression beyond the G1 phase. PPAR-gamma ligands decreased alpha-smooth muscle actin protein expression and alpha1(I) procollagen and prolyl 4-hydroxylase(alpha) mRNA levels. Activation of PPAR-gamma also resulted in the inhibition of inducible monocyte chemoattractant protein-1 expression. 15d-PGJ2, but not troglitazone, inhibited the degradation of IkappaB alpha and consequent NF-kappaB activation. In conclusion, activation of PPAR gamma inhibited profibrogenic and proinflammatory actions in activated PSCs, suggesting a potential application of PPAR-gamma ligands in the treatment of pancreatic fibrosis and inflammation. PMID- 11606584 TI - Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling. AB - Phospholipase Cgamma (PLCgamma) isoforms are regulated through activation of tyrosine kinase-linked receptors. The importance of growth factor-stimulated phosphorylation of specific tyrosine residues has been documented for PLCgamma1; however, despite the critical importance of PLCgamma2 in B-cell signal transduction, neither the tyrosine kinase(s) that directly phosphorylate PLCgamma2 nor the sites in PLCgamma2 that become phosphorylated after stimulation are known. By measuring the ability of human PLCgamma2 to restore calcium responses to the B-cell receptor stimulation or oxidative stress in a B-cell line (DT40) deficient in PLCgamma2, we have demonstrated that two tyrosine residues, Tyr(753) and Tyr(759), were important for the PLCgamma2 signaling function. Furthermore, the double mutation Y753F/Y759F in PLCgamma2 resulted in a loss of tyrosine phosphorylation in stimulated DT40 cells. Of the two kinases that previously have been proposed to phosphorylate PLCgamma2, Btk, and Syk, purified Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK. Using purified proteins to analyze the formation of complexes, we suggest that function of Syk is to phosphorylate BLNK, providing binding sites for PLCgamma2. Further analysis of PLCgamma2 tyrosine residues phosphorylated by Btk and several kinases from the Src family has suggested multiple sites of phosphorylation and, in the context of a peptide incorporating residues Tyr(753) and Tyr(759), shown preferential phosphorylation of Tyr(753). PMID- 11606586 TI - Carboxyl-terminal domain III of the delta' subunit of DNA polymerase III holoenzyme binds DnaX and supports cooperative DnaX complex assembly. AB - The delta' subunit of the DNA polymerase-III holoenzyme is a key component of the DnaX complex; it is required for loading the beta(2) processivity factor onto a primed template. The x-ray crystal structure of delta' indicates a three domain C shaped structure (Guenther, B., Onrust, R., Sali, A., O'Donnell, M., and Kuriyan, J. (1997) Cell 91, 335-345). In this study, we localized the DnaX-binding domain of delta' to its carboxyl-terminal domain III by quantifying protein-protein interactions using a series of delta' fusion proteins lacking specific domains. The fusion protein corresponding to domain III of delta' bound to DnaX with an affinity approaching that of full-length delta'. In contrast, a construct bearing delta' domains I-II did not bind DnaX at detectable levels. The presence of delta and chi psi strengthened the interaction of DnaX with full-length delta' and delta' domain III. Thus, domain III of delta' not only contains the DnaX-binding site, but also contains the elements required for positive cooperative assembly of the DnaX complex. A domain III-specific anti-delta' monoclonal antibody interfered with DnaX complex formation and abolished the replication activity of DNA polymerase III holoenzyme. PMID- 11606587 TI - Presenilin 1 independently regulates beta-catenin stability and transcriptional activity. AB - Presenilin 1 (PS1) regulates beta-catenin stability; however, published data regarding the direction of the effect are contradictory. We examined the effects of wild-type and mutant forms of PS1 on the membrane, cytoplasmic, nuclear, and signaling pools of endogenous and exogenous beta-catenin by immunofluorescence microscopy, subcellular fractionation, and in a transcription assay. We found that PS1 destabilizes the cytoplasmic and nuclear pools of beta-catenin when stabilized by Wnt or Dvl but not when stabilized at lower levels of the Wnt pathway. The PS1 mutants examined were less able to reduce the stability of beta catenin. PS1 also inhibited the transcriptional activity of endogenous beta catenin, and the PS1 mutants were again less inhibitory at the level of Dvl but showed a different pattern of inhibition toward transcription below Dvl. The transcriptional activity of exogenously expressed wild-type beta-catenin and two mutants, DeltaN89beta-catenin and DeltaSTbeta-catenin, were also inhibited by wild-type and mutant PS1. We conclude that PS1 negatively regulates the stability and transcriptional activity of beta-catenin at different levels in the Wnt pathway, that the effect on transcriptional activity appears to be independent of the GSK-3beta mediated degradation of beta-catenin, and that mutations in PS1 differentially affect the stability and transcriptional activity of beta-catenin. PMID- 11606588 TI - Action of recombinant human apoptotic endonuclease G on naked DNA and chromatin substrates: cooperation with exonuclease and DNase I. AB - Endonuclease G (endoG) is released from mitochondria during apoptosis and is in part responsible for internucleosomal DNA cleavage. Here we report the action of the purified human recombinant form of this endonuclease on naked DNA and chromatin substrates. The addition of the protein to isolated nuclei from non apoptotic cells first induces higher order chromatin cleavage into DNA fragments > or = 50 kb in length, followed by inter- and intranucleosomal DNA cleavages with products possessing significant internal single-stranded nicks spaced at nucleosomal ( approximately 190 bases) and subnucleosomal ( approximately 10 bases) periodicities. We demonstrate that both exonucleases and DNase I stimulate the ability of endoG to generate double-stranded DNA cleavage products at physiological ionic strengths, suggesting that these activities work in concert with endoG in apoptotic cells to ensure efficient DNA breakdown. PMID- 11606589 TI - The zinc finger domain of the archaeal minichromosome maintenance protein is required for helicase activity. AB - The minichromosome maintenance (MCM) proteins, a family of six conserved polypeptides found in all eukaryotes, are essential for DNA replication. The archaeon Methanobacterium thermoautotrophicum Delta H contains a single homologue of MCM with biochemical properties similar to those of the eukaryotic enzyme. The amino acid sequence of the archaeal protein contains a putative zinc-binding domain of the CX(2)CX(n)CX(2)C (C(4)) type. In this study, the roles of the zinc finger domain in MCM function were examined using recombinant wild-type and mutant proteins expressed and purified from Escherichia coli. The protein with a mutation in the zinc motif forms a dodecameric complex similar to the wild-type enzyme. The mutant enzyme, however, is impaired in DNA-dependent ATPase activity and single-stranded DNA binding, and it does not possess helicase activity. These results illustrate the importance of the zinc-binding domain for archaeal MCM function and suggest a role for zinc binding in the eukaryotic MCM complex as well, since four out of the six eukaryotic MCM proteins contain a similar zinc binding motif. PMID- 11606590 TI - Molecular mechanism and structural aspects of transporter associated with antigen processing inhibition by the cytomegalovirus protein US6. AB - The human cytomegalovirus (HCMV) has evolved a set of elegant strategies to evade host immunity. The HCMV-encoded type I glycoprotein US6 inhibits peptide trafficking from the cytosol into the endoplasmic reticulum and subsequent peptide loading of major histocompatibility complex I molecules by blocking the transporter associated with antigen processing (TAP). We studied the molecular mechanism of TAP inhibition by US6 in vitro. By using purified US6 and human TAP co-reconstituted in proteoliposomes, we demonstrate that the isolated endoplasmic reticulum (ER)-luminal domain of US6 is essential and sufficient to block TAP dependent peptide transport. Neither the overall amount of bound peptides nor the peptide affinity of TAP is affected by US6. Interestingly, US6 causes a specific arrest of the peptide-stimulated ATPase activity of TAP by preventing binding of ATP but not ADP. The affinity of the US6-TAP interaction was determined to 1 microm. The ER-luminal domain of US6 is monomeric in solution and consists of 19% alpha-helices, 25% beta-sheets, and 27% beta-turns. All eight cysteine residues are involved in forming a stabilizing network of four intramolecular disulfide bridges. Glycosylation of US6 is not required for function. These findings point to fascinating mechanistic and structural properties, by which specific binding of US6 at the ER-luminal loops of TAP signals across the membrane to the nucleotide-binding domains to prevent ATP hydrolysis of TAP. PMID- 11606592 TI - Transcript cleavage by Thermus thermophilus RNA polymerase. Effects of GreA and anti-GreA factors. AB - All known multisubunit RNA polymerases possess the ability to endonucleolytically degrade the nascent RNA transcript. To gain further insight into the conformational changes that govern transcript cleavage, we have examined the effects of certain anions on the intrinsic transcript cleavage activity of Thermus thermophilus RNA polymerase. Our results indicate that the conformational transitions involved in transcript cleavage, and therefore backtracking, are anion-dependent. In addition to characterizing the intrinsic cleavage activity of T. thermophilus RNA polymerase, we have identified, cloned, and expressed a homolog of the prokaryotic transcript cleavage factor GreA from the extreme thermophiles, T. thermophilus and Thermus aquaticus. The thermostable GreA factors contact the 3'-end of RNA, stimulate the intrinsic cleavage activity of T. thermophilus RNA polymerase, and increase the k(app) of the cleavage reaction 25-fold. In addition, we have identified a novel transcription factor in T. thermophilus and T. aquaticus that shares a high degree of sequence similarity with GreA, but has several residues that are not conserved with the N-terminal "basic patch" region of GreA. This protein, Gfh1, functions as an anti-GreA factor in vitro by reducing intrinsic cleavage and competing with GreA for a binding site on the polymerase. PMID- 11606591 TI - Upstream stimulatory factors regulate aortic preferentially expressed gene-1 expression in vascular smooth muscle cells. AB - The phenotypic modulation of vascular smooth muscle cells (VSMC) plays a central role in the pathogenesis of arteriosclerosis. Aortic preferentially expressed gene-1 (APEG-1), a VSMC-specific gene, is expressed highly in differentiated but not in dedifferentiated VSMC. Previously, we identified an E-box element in the mouse APEG-1 proximal promoter, which is essential for VSMC reporter activity. In this study, we investigated the role of upstream stimulatory factors (USF) in the regulation of APEG-1 transcription via this E-box element. By electrophoretic mobility shift assays, recombinant USF1 and USF2 homo- and heterodimers bound specifically to the APEG-1 E-box. Nuclear extracts prepared from primary cultures of rat aortic smooth muscle cells exhibited specific USF1 and USF2 binding to the APEG-1 E-box. To investigate the binding properties of USF during VSMC differentiation, nuclear extracts were prepared from the neural crest cell line, MONC-1, which differentiates into VSMC in culture. Maximal USF1 and USF2 protein levels and binding to the APEG-1 E-box occurred 3 h after the differentiation of MONC-1 cells was initiated. Co-transfection experiments demonstrated that dominant negative USF repressed APEG-1 promoter activity, and USF1, but not USF2, transactivated the APEG-1 promoter. Our studies demonstrate that USF factors contribute to the regulation of APEG-1 expression and may influence the differentiation of VSMC. PMID- 11606594 TI - DNA binding and recognition by the IIs restriction endonuclease MboII. AB - The type IIs restriction endonuclease MboII recognizes nonsymmetrical GAAGA sites, cutting 8 (top strand) and 7 (bottom strand) bases to the right. Gel retardation showed that MboII bound specifically to GAAGA sequences, producing two distinct complexes each containing one MboII and one DNA molecule. Interference analysis indicated that the initial species formed, named complex 1, comprised an interaction between the enzyme and the GAAGA target. Complex 2 involved interaction of the protein with both the GAAGA and the cutting sites. Only in the presence of divalent metal ions such as Ca(2+) is the conversion of complex 1 to 2 rapid. Additionally, a very retarded complex was seen with Ca(2+), possibly a (MboII)(2)-(DNA)(2) complex. Plasmids containing a single GAAGA site were hydrolyzed slowly by MboII. Plasmids containing two sites were cut far more rapidly, suggesting that the enzyme requires two recognition sites in the same DNA molecule for efficient hydrolysis. MboII appears to have a mechanism similar to the best characterized type IIs enzyme, FokI. Both enzymes initially bind DNA as monomers, followed by dimerization to give an (enzyme)(2)-(DNA)(2) complex. Dimerization is efficient only when the two target sites are located in the same DNA molecule and requires divalent metal ions. PMID- 11606593 TI - Very large G protein-coupled receptor-1, the largest known cell surface protein, is highly expressed in the developing central nervous system. AB - We previously identified a member of the G protein-coupled receptor family, very large G protein-coupled receptor-1 (VLGR1). VLGR1 has a large ectodomain containing multiple calcium exchanger beta repeats that resemble regulatory domains of sodium-calcium exchanger proteins. Similar repeats are found in the extracellular aggregation factor of marine sponges, which mediates species specific cell aggregation. We now report that the protein encoded by the originally described human cDNA (now termed VLGR1a) is, in fact, at 1967 amino acids, the smallest of three expressed human isoforms. It is encoded by an alternative transcript that begins within intron 64 of the VLGR1 gene. The longest gene product, VLGR1b, is 6307 amino acids (6298 amino acids in mice) due to a much larger ectodomain containing 35 calcium exchanger beta repeats and a pentraxin homology domain. VLGR1b is apparently the largest known cell surface protein. The VLGR1 gene comprises 90 exons and is >600 kb long. In situ hybridization studies with mouse embryo sections show that high level expression of VLGR1 is restricted to the developing central nervous system and eye. Strong expression in the ventricular zone, home of neural progenitor cells during embryonal neurogenesis, suggests a fundamental role for VLGR1 in the development of the central nervous system. PMID- 11606596 TI - Post-translational modification of the hepatitis C virus core protein by tissue transglutaminase. AB - The hepatitis C virus (HCV) core protein is a structural protein that packages the viral genomic RNA. In this study, we demonstrate that a stable core protein dimer could be produced in liver cells. The production of this protein could be enhanced by calphostin C and serum deprivation. This protein was determined to be the core protein dimer because of its reactivity with the anti-core antibody, its similar electrophoretic mobility compared with that of the core protein dimer generated by cross-linking with glutaraldehyde, and its increase in size by a hemagglutinin tag fused to the core protein sequence. This core protein dimer was highly stable and resistant to SDS and beta-mercaptoethanol. The enzyme that mediated the formation of this stable core protein dimer was determined to be the tissue transglutaminase (tTG) because, first, tTG could be activated by calphostin C and serum deprivation; second, the formation of this dimer was suppressed by monodansylcadaverine, a tTG inhibitor; and third, the core protein could be cross-linked by tTG in vitro. Thus, the HCV core protein represents the first known viral structural protein substrate of tTG. The post-translational modification by tTG reduced the RNA binding activity of the core protein, raising the possibility that tTG may regulate the biological functions of the HCV core protein. PMID- 11606595 TI - Insulin stimulates actin comet tails on intracellular GLUT4-containing compartments in differentiated 3T3L1 adipocytes. AB - Incubation of isolated GLUT4-containing vesicles with Xenopus oocyte extracts resulted in a guanosine 5'-[gamma-thio]triphosphate (GTP gamma S) and sodium orthovanadate stimulation of actin comet tails. The in vitro actin-based GLUT4 vesicle motility was inhibited by both latrunculin B and a dominant-interfering N WASP mutant, N-WASP/Delta VCA. Preparations of gently sheared (broken) 3T3L1 adipocytes also displayed GTP gamma S and sodium orthovanadate stimulation of actin comet tails on GLUT4 intracellular compartments. Furthermore, insulin pretreatment of intact adipocytes prior to gently shearing also resulted in a marked increase in actin polymerization and actin comet tailing on GLUT4 vesicles. In addition, the insulin stimulation of actin comet tails was completely inhibited by Clostridum difficile toxin B, demonstrating a specific role for a Rho family member small GTP-binding protein. Expression of N WASP/Delta VCA in intact cells had little effect on adipocyte cortical actin but partially inhibited insulin-stimulated GLUT4 translocation. Taken together, these data demonstrate that insulin can induce GLUT4 vesicle actin comet tails that are necessary for the efficient translocation of GLUT4 from intracellular storage sites to the plasma membrane. PMID- 11606598 TI - Spread of synaptic potentials through electrical synapses in Retzius neurones of the leech. AB - We studied the spread of excitatory postsynaptic potentials (EPSPs) through electrical synapses in Retzius neurones of the leech Haementeria officinalis. The pair of Retzius neurones in each ganglion is coupled by a non-rectifying electrical synapse. Both neurones displayed synchronous EPSPs of varying amplitudes and rise times. The kinetics of synchronous EPSPs was similar in 79 % of the EPSP pairs. In the remaining 21 %, one EPSP was smaller and slower than the other, suggesting its passive spread from the other neurone. The proportion of these events increased to 75 % in the presence of Mg(2+) in the bathing fluid. This spread of EPSPs from one neurone to another was tested by producing artificial EPSPs by current injection into the soma of one Retzius neurone. The artificial EPSPs were smaller and arrived more slowly at the soma of the coupled neurone. The coupling ratios for the EPSPs were proportional to the coupling ratio for long steady-state pulses in different neuronal pairs. Our results showed that EPSPs spread from one Retzius neurone to the other and support the idea that EPSP spread between electrically coupled neurones may contribute to the integration processes of neurones. PMID- 11606597 TI - Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. AB - To identify human proteins that bind to the Smac and caspase-9 binding pocket on the baculoviral inhibitor of apoptosis protein (IAP) repeat 3 (BIR3) domain of human XIAP, we used BIR3 as an affinity reagent, followed by elution with the BIR3 binding peptide AVPIA, microsequencing, and mass spectrometry. The mature serine protease Omi (also known as HtrA2) was identified as a mitochondrial direct BIR3-binding protein and a caspase activator. Like mature Smac (also known as Diablo), mature Omi contains a conserved IAP-binding motif (AVPS) at its N terminus, which is exposed after processing of its N-terminal mitochondrial targeting sequence upon import into the mitochondria. Mature Omi is released together with mature Smac from the mitochondria into the cytosol upon disruption of the outer mitochondrial membrane during apoptosis. Finally, mature Omi can induce apoptosis in human cells in a caspase-independent manner through its protease activity and in a caspase-dependent manner via its ability to disrupt caspase-IAP interaction. Our results provide clear evidence for the involvement of a mitochondrial serine protease in the apoptotic pathway, emphasizing the critical role of the mitochondria in cell death. PMID- 11606599 TI - Immunochemical analysis of the vacuolar proton-ATPase B-subunit in the gills of a euryhaline stingray (Dasyatis sabina): effects of salinity and relation to Na(+)/K(+)-ATPase. AB - In the gills of freshwater teleost fishes, vacuolar proton-ATPase (V-H(+)-ATPase) is found on the apical membrane of pavement and chloride (Na(+)/K(+)-ATPase-rich) cells, and is an important transporter for energizing Na(+) uptake and H(+) excretion. In the gills of elasmobranch fishes, the V-H(+)-ATPase has not been extensively studied and its expression in freshwater individuals has not been examined. The goals of this study were to examine the effects of environmental salinity on the expression of V-H(+)-ATPase in the gills of an elasmobranch (the Atlantic stingray, Dasyatis sabina) and determine if V-H(+)-ATPase and Na(+)/K(+) ATPase are expressed in the same cells. We found that gills from freshwater stingrays had the highest relative abundance of V-H(+)-ATPase and greatest number of V-H(+)-ATPase-rich cells, using immunoblotting and immunohistochemistry, respectively. When freshwater animals were acclimated to sea water for 1 week, V H(+)-ATPase abundance and the number of V-H(+)-ATPase-rich cells decreased significantly. Atlantic stingrays from seawater environments were characterized by the lowest expression of V-H(+)-ATPase and least number of V-H(+)-ATPase-rich cells. In contrast to teleost fishes, localization of V-H(+)-ATPase in freshwater stingray gills was not found in pavement cells and occurred on the basolateral membrane in cells that are presumably rich in mitochondria. In freshwater stingrays acclimated to sea water and seawater stingrays, V-H(+)-ATPase localization appeared qualitatively to be stronger in the cytoplasm, which may suggest the transporter was stored in vesicles. Using a double-immunolabeling technique, we found that V-H(+)-ATPase and Na(+)/K(+)-ATPase occurred in distinct cells, which suggests there may be two types of mitochondrion-rich cells in the elasmobranch gill epithelium. Based on these findings, we propose a unique model of NaCl and acid-base regulation where the V-H(+)-ATPase-rich cells and Na(+)/K(+)-ATPase-rich cells are the sites of Cl(-) uptake/HCO(3)(-) excretion and Na(+) uptake/H(+) excretion, respectively. PMID- 11606600 TI - Comparative kinematics of the forelimb during swimming in red-eared slider (Trachemys scripta) and spiny softshell (Apalone spinifera) turtles. AB - Softshell turtles (Family Trionychidae) possess extensive webbing between the digits of the manus, suggesting that the forelimb may serve as an effective thrust generator during aquatic locomotion. However, the hindlimb has previously been viewed as the dominant propulsive organ in swimming freshwater turtles. To evaluate the potential role of the forelimb in thrust production during swimming in freshwater turtles, we compared the forelimb morphology and three-dimensional forelimb kinematics of a highly aquatic trionychid turtle, the spiny softshell Apalone spinifera, and a morphologically generalized emydid turtle, the red-eared slider Trachemys scripta. Spiny softshells possess nearly twice as much forelimb surface area as sliders for generating drag-based thrust. In addition, although both species use drag-based propulsion, several aspects of forelimb kinematics differ significantly between these species. During the thrust phase of the forelimb cycle, spiny softshells hold the elbow and wrist joints significantly straighter than sliders, thereby further increasing the surface area of the limb that can move water posteriorly and increasing the velocity of the distal portion of the forelimb. These aspects of swimming kinematics in softshells should increase forelimb thrust production and suggest that the forelimbs make more substantial contributions to forward thrust in softshell turtles than in sliders. Spiny softshells also restrict forelimb movements to a much narrower dorsoventral and anteroposterior range than sliders throughout the stroke, thereby helping to minimize limb movements potentially extraneous to forward thrust production. These comparisons demonstrate considerable diversity in the forelimb kinematics of turtles that swim using rowing motions of the limbs and suggest that the evolution of turtle forelimb mechanics produced a variety of contrasting solutions for aquatic specialization. PMID- 11606601 TI - Standard metabolic rate at the surface and during trained submersions in adult California sea lions (Zalophus californianus). AB - The metabolic rate (MR) of four adult California sea lions (Zalophus californianus), two males and two females, was quantified during trained submersion and stationing behavior in laboratory tanks. MR was measured, at rest and for single submersions of increasing duration (1-7 min), by measuring oxygen consumption using open-circuit, indirect calorimetry. Standard MR was measured under conditions defined for basal MR and was found to be 1.9 to 3 times that predicted for terrestrial animals of similar size. Submersion MRs were calculated from the post-submersion oxygen debt and declined to as little as 47 % of standard MR on the longest submersions. This hypometabolic response was proportional to the duration of submersion and was greatest for the maximum duration submersions. Short submersions produced MRs equivalent to measured standard MR. These data suggest that although California sea lions maintain an elevated metabolism under standard conditions, they are capable of reducing their metabolism in response to the needs of diving. Such metabolic flexibility enables sea lions to moderate their oxygen use during diving and to extend their aerobic diving capability. PMID- 11606602 TI - Speeds and wingbeat frequencies of migrating birds compared with calculated benchmarks. AB - Sixteen species of birds passing Falsterbo in southwest Sweden during the autumn migration season were observed using short-range optical methods. Air speeds and wingbeat frequencies were measured, reduced to sea level, and compared with benchmark values computed by Flight.bas, a published flight performance program based on flight mechanics. The benchmark for air speed was the calculated sea level value of the minimum power speed (V(mp)). The mean speeds of three raptor species that flew by flap-gliding were below V(mp), apparently because the flap glide cycle involved slowing down below V(mp) when gliding and accelerating back up to V(mp) when flapping. The mean speeds of 11 species that flew by continuous flapping were between 0.82V(mp) and 1.27V(mp). Two passerine species that flew by bounding had mean speeds of 1.70V(mp) and 1.96V(mp), but these high mean speeds reflected their ability to fly faster against head winds. These results do not support predictions from optimal migration theory, which suggest that migrating birds 'should' fly faster, relative to V(mp). However, observations were restricted for technical reasons to birds flying below 200 m and may not represent birds that were seriously committed to long-distance migration. The benchmark wingbeat frequency (f(ref)) was derived from dimensional reasoning, not from statistical analysis of observations. Observed wingbeat frequencies ranged from 0.81f(ref) to 1.05f(ref), except in the two bounding species, whose wingbeat frequencies appeared anomalously high. However, the mechanics of bounding with a power fraction q imply that gravity during the flapping phase is increased by a factor 1/q, and when the value of gravity was so adjusted in the expression for f(ref), the wingbeat frequencies of the two bounding species were predicted correctly as a function of the power fraction. In small birds with more muscle power than is required to fly at speeds near V(mp), bounding is an effective method of adjusting the specific work in the muscle fibres, allowing conversion efficiency to be maximised over a wide range of speeds. PMID- 11606603 TI - Light-dependent magnetoreception in birds: the behaviour of European robins, Erithacus rubecula, under monochromatic light of various wavelengths and intensities. AB - To investigate how magnetoreception is affected by the wavelength and intensity of light, we tested European robins, Erithacus rubecula, under monochromatic lights of various wavelengths at two intensities using oriented behaviour as an indicator of whether the birds could derive directional information from the geomagnetic field. At a quantal flux of 7 x 10(15) quanta s(-1) m(-2), the birds were well oriented in their migratory direction east of North under 424 nm blue, 510 nm turquoise and 565 nm green light, whereas they were disoriented under 590 nm yellow light. Increasing the intensity of light at the same wavelengths more than sixfold to 43 x 10(15) quanta s(-1) m(-2) resulted in a change in behaviour: under bright blue and green light, the birds now showed a preference for the East West axis, with the majority of headings at the western end; under bright turquoise light, they oriented unimodally towards a direction slightly west of North. Under bright yellow light, the birds continued to be disoriented. These findings suggest a rather complex relationship between the receptors involved in magnetoreception. Magnetoreception appears to follow rules that are different from those of vision, suggesting that light-dependent magnetoreception may involve receptors and neuronal pathways of its own. PMID- 11606604 TI - Localization of the clock controlling circadian rhythms in the first neuropile of the optic lobe in the housefly. AB - The visual system of a fly expresses several circadian rhythms that have been detected in the photoreceptors of the compound eye and in the first neuropile, the lamina, of the underlying optic lobe. In the lamina, axons of two classes of interneuron, L1 and L2, exhibit cyclical size changes, swelling by day and shrinking by night. These rhythmic size changes may be generated by circadian oscillators located inside and/or outside the optic lobe. To localize such oscillators, we have examined changes in the axonal cross-sectional areas of L1 and L2 within the lamina of the housefly (Musca domestica) under conditions of 12 h of light and 12 h of darkness (LD12:12), constant darkness (DD) or continuous light (LL) 24 h after the medulla was severed from the rest of the brain. After the lesion, the axon size changes of L1 and L2 were maintained only in LD conditions, but were weaker than in control flies. In DD and LL conditions, they were eliminated. This indicates that circadian rhythms in the lamina of a fly are generated central to the lamina and medulla neuropiles of the optic lobe. Cyclical changes of light and darkness in LD conditions are still able, however, to induce a weak daily rhythm in the axon sizes of L1 and L2. PMID- 11606605 TI - Metabolic power, mechanical power and efficiency during wind tunnel flight by the European starling Sturnus vulgaris. AB - We trained two starlings (Sturnus vulgaris) to fly in a wind tunnel whilst wearing respirometry masks. We measured the metabolic power (P(met)) from the rates of oxygen consumption and carbon dioxide production and calculated the mechanical power (P(mech)) from two aerodynamic models using wingbeat kinematics measured by high-speed cinematography. P(met) increased from 10.4 to 14.9 W as flight speed was increased from 6.3 to 14.4 m s(-1) and was compatible with the U shaped power/speed curve predicted by the aerodynamic models. Flight muscle efficiency varied between 0.13 and 0.23 depending upon the bird, the flight speed and the aerodynamic model used to calculate P(mech). P(met) during flight is often estimated by extrapolation from the mechanical power predicted by aerodynamic models by dividing P(mech) by a flight muscle efficiency of 0.23 and adding the costs of basal metabolism, circulation and respiration. This method would underestimate measured P(met) by 15-25 % in our birds. The mean discrepancy between measured and predicted P(met) could be reduced to 0.1+/-1.5 % if flight muscle efficiency was altered to a value of 0.18. A flight muscle efficiency of 0.18 rather than 0.23 should be used to calculate the flight costs of birds in the size range of starlings (approximately 0.1 kg) if P(met) is calculated from P(mech) derived from aerodynamic models. PMID- 11606606 TI - Water acquisition and partitioning in Drosophila melanogaster: effects of selection for desiccation-resistance. AB - We examined physiological features related to water balance in five replicate populations of Drosophila melanogaster that have undergone selection for enhanced resistance to desiccation (D populations) and in five replicate control (C) populations. Adult D flies contain 34 % more water than the control flies. We examined two hypotheses for increased water acquisition in the D flies: (i) that they accumulate more water early in development and (ii) that they have a reduced post-eclosion diuretic water loss. We found no evidence of differential water or dry mass acquisition between the C and D populations prior to adulthood. We also found no evidence of differential post-eclosion diuresis, i.e. both C and D groups showed insignificant changes in water volume in the 4 h period immediately after eclosion. In addition, we quantified water content in the intra- and extracellular compartments of the C and D populations and were able to identify the hemolymph as the primary storage site of the 'extra' water carried by the desiccation-resistant flies. We estimated that 68 % of the increased water volume observed in the D flies was contained in the hemolymph. Desiccation-resistance was strongly correlated with hemolymph volume and only weakly with intracellular water volume. Survival during desiccation was also strongly related to the carbohydrate content of the D flies. It has been presumed that the D flies accumulate carbohydrate primarily as intracellular glycogen, which would result in a significant increase in intracellular water volume. We found that carbohydrate content was weakly correlated with intracellular water volume and more strongly with hemolymph volume. The carbohydrate pool in the D flies may, therefore, be contained in the extracellular compartment as well as in cells. These results are suggestive of the importance of modifications in hemolymph volume and hemolymph solute concentrations in the evolution of enhanced desiccation-tolerance in populations of Drosophila melanogaster. PMID- 11606607 TI - The molecular basis for spectral tuning of rod visual pigments in deep-sea fish. AB - Most species of deep-sea fish possess of a rod-only retina with a pigment that is generally shortwave shifted in lambda(max) towards the blue region of the spectrum. In addition, the lambda(max) values of different species tend to cluster at particular points in the spectrum. In this study, the rod opsin gene sequences from 28 deep-sea fish species drawn from seven different Orders are compared. The lambda(max) values of the rod pigments vary from approximately 520 nm to <470 nm, with the majority lying between 490 nm and 477 nm. The 520 nm pigment in two species of dragon fish is associated with a Phe261Tyr substitution, whereas the shortwave shifts of the pigments in the other 26 species are accountable by substitutions at a further eight sites (83, 122, 124, 132, 208, 292, 299 and 300). Clustering of lambda(max) values does not, however, involve a common subset of these substitutions in the different species. A phylogenetic analysis predicts that the pigment in the ancestral species would have had a lambda(max) of approximately 480 nm. A total of 27 changes is required to generate the pattern of substitutions seen in the different species, with many sites undergoing multiple changes. PMID- 11606608 TI - Sodium and chloride regulation in freshwater and osmoconforming larvae of Culex mosquitoes. AB - In this study, we examined aspects of Na(+) and Cl(-) regulation in mosquito larvae of the genus Culex, a group that includes species that tolerate high salinity as well as other forms that are restricted to fresh water. When the euryhaline osmoconformer C. tarsalis was acutely transferred from 30 % to 50 % sea water, the patterns of hemolymph Na(+) and Cl(-) regulation were similar. The underlying regulatory mechanisms for these two ions have very different characteristics. In C. tarsalis, Na(+) efflux was significantly elevated compared with the rates measured in the freshwater-restricted C. quinquefasciatus, while Cl(-) influx was relatively lower. The modulation of Na(+) efflux and Cl(-) influx allowed C. tarsalis to avoid a potential salt load and ionic disturbance in the hemolymph during an acute increase ( )in salinity. The observed adjustment of NaCl regulation departs from that determined for other euryhaline organisms and is integral to the osmoconforming response. At the other extreme of the salinity spectrum, we observed that C. tarsalis faces difficulties in ion regulation in habitats with low NaCl levels because of its inability to reduce ion efflux and adjust ion absorption rates to maintain hemolymph ion balance. In contrast, C. quinquefasciatus exhibited a reduced ion efflux and the ability to upregulate Na(+) uptake, traits necessary to extend its lower salinity limit. PMID- 11606609 TI - Selective adaptation to noxious foods by a herbivorous insect. AB - When animals repeatedly sample a noxious food over a period of 1-4 days, they can markedly reduce their aversive behavioral response to the diet's unpleasant taste (e.g. 'bitterness') or toxic effects. This long-term adaptation process is selective, however, permitting insects to adapt physiologically to some but not all noxious foods. We hypothesized (i) that the selective nature of this adaptation process stems from the fact that some unpalatable foods are toxic while others are harmless and (ii) that insects have more difficulty adapting to foods that are both unpalatable and toxic. Our model system consisted of Manduca sexta caterpillars and two compounds that taste bitter to humans and elicit an aversive behavioral response in this insect (salicin and aristolochic acid). We found that 2 days of exposure to a salicin diet completely adapted the aversive response of the caterpillars to salicin, but that exposure to an aristolochic acid diet failed to adapt the aversive response to aristolochic acid. We determined that M. sexta could not adapt to the aristolochic acid diet because it lacked mechanisms for reducing the compound's toxicity. In contrast, the salicin diet did not produce any apparent toxic effects, and the caterpillars adapted to its aversive taste within 12 h of exposure. We also found that the salicin adaptation phenomenon (i) was mediated by the central gustatory system, (ii) generalized to salicin concentrations that were twice those in the adapting diet and (iii) offset spontaneously when the caterpillar was transferred to a salicin free diet. We propose that toxicity is a more significant barrier to dietary adaptation than 'bitterness' in this insect. PMID- 11606610 TI - Molecular cloning and characterisation of a novel membrane receptor gene from the lobster Jasus edwardsii. AB - The eyestalk of the lobster, Jasus edwardsii, is an important source for hormones involved in the regulation of growth and reproduction. How these hormones transfer their messages to the cell and nucleus is not known. This paper describes the cloning, characterization and expression analyses of two genes that code for two membrane-associated peptides that may be involved in signal transduction. These genes, peJK2 and peJK3, were isolated from a cDNA library derived from lobster eyestalk mRNAs. The two clones shared 96.6 % sequence homology, and code for putative proteins of 110 and 113 amino acids, respectively. These were likely to be two allelic forms of the same gene. Northern blot analysis using these clones as probes detected the same mRNA from eyestalk, muscle and epithelial extracts, but with greater intensity in the eyestalk extract. In situ hybridisation also indicated the predominant expression of these genes in the eyestalk. Analysis of the putative protein sequences showed that they contained two transmembrane (TM) helices, a short amino acid sequence sharing high homology with the G-protein-coupled receptor (GPCR) motif in the second TM, a signal sequence between the TMs, and a protein kinase phosphorylation site at the C termini. Sequence analyses therefore suggested that the deduced peptides may function in signal transduction. PMID- 11606611 TI - The metabolic cost of birdsong production. AB - The metabolic cost of birdsong production has not been studied in detail but is of importance in our understanding of how selective pressures shape song behavior. We measured rates of oxygen consumption during song in three songbird species, zebra finches (Taeniopygia guttata), Waterslager canaries (Serinus canaria) and European starlings (Sturnus vulgaris). These species sing songs with different acoustic and temporal characteristics: short stereotyped song (zebra finch), long song with high temporal complexity (canary) and long song with high acoustic, but low temporal, complexity (starling). In all three species, song slightly increased the rate of oxygen consumption over pre-song levels (1.02-1.36 fold). In zebra finches, the metabolic cost per song motif averaged 1.2 microl g( 1). This cost per motif did not change over the range of song duration measured for the four individuals. Surprisingly, the metabolic cost of song production in the species with the temporally most complex song, the canary, was no greater than in the other two species. In starlings, a 16 dB increase in sound intensity was accompanied by a 1.16-fold increase in the rate of oxygen consumption. These data indicate that the metabolic cost of song production in the songbird species studied is no higher than that for other types of vocal behavior in various bird groups. Our analysis shows that the metabolic cost of singing is also similar to that of calling in frogs and of human speech production. However, difficulties with measurements on freely behaving birds in a small respirometry chamber limit the depth of analysis that is possible. PMID- 11606613 TI - A new feature for the journal of neuroscience: new directions in neuroscience. PMID- 11606612 TI - Recovery periods restore mechanosensitivity to dynamically loaded bone. AB - Bone cells are capable of sensing and responding to mechanical forces, but mechanosensitivity begins to decline soon after the stimulus is initiated. Under continued stimulation, bone is desensitized to mechanical stimuli. We sought to determine the amount of time required to restore mechanosensitivity to desensitized bone cells in vivo by manipulating the recovery time (0, 0.5, 1, 2, 4 or 8 h) allowed between four identical daily loading bouts. We also investigated the osteogenic effectiveness of shorter-term recovery periods, lasting several seconds (0.5, 3.5, 7 or 14 s), introduced between each of 36 identical daily loading cycles. Using the rat tibia four-point bending model, the right tibia of 144 adult female Sprague-Dawley rats was subjected to bending, sham bending or no loading. In the rats receiving recovery periods between loading bouts, histomorphometric measurements from the endocortical surface of the loaded and nonloaded control (left) tibiae revealed more than 100 % higher relative bone formation rates in the 8 h recovery group than in the 0 and 0.5 h recovery groups. Approximately 8 h of recovery was sufficient to restore full mechanosensitivity to the cells. In the rats allowed time to recover between load cycles, 14 s of recovery resulted in significantly higher (66-190 %) relative bone formation rates compared to any of the three shorter recovery periods. In both experiments, bone formation in the sham-bending animals was similar to that in the nonloaded control group. The results demonstrate the importance of recovery periods for (i) restoring mechanosensitivity to bone cells and (ii) maximizing the osteogenic effects of mechanical loading (exercise) regimens. PMID- 11606614 TI - What does it all mean to you? PMID- 11606615 TI - Open-system approaches to gene expression in the CNS. PMID- 11606616 TI - mRna expression analysis of tissue sections and single cells. PMID- 11606617 TI - Proteomics in neuroscience: from protein to network. AB - Proteomic tools offer a new platform for studies of complex biological functions involving large numbers and networks of proteins. Intracellular networks of proteins perform key functions in neurons and glia. The unicellular eukaryote Saccharomyces cerevisiae has been the prototype for eukaryotic proteomic studies, and when combined with genomics, microarrays, genetics, and pharmacology, new insights into the integrated function of the cell emerge. The anatomical complexity of the nervous system both in cell types and in the vast number of synapses introduces novel technical and biological issues regarding the subcellular organization of protein networks. Here we will discuss the technology of proteomics and its applications to the nervous system. PMID- 11606618 TI - Physiological genomics of antidepressant targets: keeping the periphery in mind. AB - The plasma membrane transporters that clear extracellular serotonin (5-HT) and norepinephrine (NE), serotonin transporters (SERTs) and NE transporters (NETs), have received considerable attention over the past four decades because of their roles in amine neurotransmitter inactivation. In addition, they interact with many centrally active drugs, including multiple classes of antidepressants such as the serotonin-selective reuptake inhibitors, typified by fluoxetine (Prozac), and the more recently developed norepinephrine-selective transporter antagonists, such as reboxetine. The therapeutic utility of these agents supports biogenic amine theories of affective disorders and raises the question as to whether SERT and NET exhibit a functional genetic variation that could influence risk for behavioral disorders. Although evidence exists that a promoter polymorphism in SERT may influence behavioral states, this contention is not without complexity and its mechanism of action remains poorly understood. The identification of coding variants of NETs and SERTs would offer important opportunities to connect genotype to phenotype. However, given the limited frequency of transporter coding variations evident to date in general population surveys or in psychiatric genetic studies, the identification of informative functional variants of transporters will likely require refined phenotypes. In this regard, NET and SERT play critical roles in cardiovascular and gastrointestinal physiology, respectively. This perspective reviews recent human and mouse studies that suggest how peripheral autonomic phenotypes, linked to genetic disruption of NET and SERT function, can aid in the phenotypic segregation needed for advanced theories of biogenic amine dysfunction and pharmacogenetics. PMID- 11606619 TI - Psychogenomics: opportunities for understanding addiction. AB - The term psychogenomics is used here to describe the process of applying the powerful tools of genomics and proteomics to achieve a better understanding of the biological substrates of normal behavior and of diseases of the brain that manifest themselves as behavioral abnormalities. Applying psychogenomics to the study of drug addiction will lead to the identification of genes and their protein products that control the reward pathways of the brain and their adaptations to drugs of abuse, as well as variations in these genes that confer genetic risk for addiction and related disorders. The ultimate goal is to use this information to develop more effective treatments for these disorders as well as objective diagnostic tools, preventive measures, and eventually cures. PMID- 11606620 TI - Neuronal glutamate transporters limit activation of NMDA receptors by neurotransmitter spillover on CA1 pyramidal cells. AB - Glutamate released at synapses in the CA1 region of the hippocampus escapes the synaptic cleft and activates extrasynaptic targets; it also may "spill over" into neighboring synapses and activate receptors there. Glutamate transporters in glial membranes restrict extrasynaptic diffusion, but it is unclear whether neuronal glutamate transporters also limit transmitter diffusion and receptor activation by spillover. I examined the effects of a low-affinity competitive NMDA receptor antagonist on EPSCs in acute hippocampal slices to distinguish receptors activated within active synapses from those activated by spillover. Glutamate spillover is observed between Schaffer collateral fiber synapses onto CA1 pyramidal cells only when transporters in the postsynaptic neuron are inhibited. Because glutamate transporters operate most effectively at negative membrane potentials, these results suggest that activation of NMDA receptors by spillover may depend on postsynaptic activity. PMID- 11606621 TI - Insulin-like growth factor 1 and a cytosolic tyrosine kinase activate chloride outward transport during maturation of hippocampal neurons. AB - The development of hyperpolarizing inhibition is an important step in the maturation of neuronal networks. Hyperpolarizing inhibition requires Cl(-) outward transport that is accomplished by KCC2, a K(+)/Cl(-) cotransporter. We show that cultured hippocampal neurons initially contain an inactive form of the KCC2 protein, which becomes activated during subsequent maturation of the neurons. We also show that this process is accelerated by transient stimulation of IGF-1 receptors. Because the transporter can be rapidly activated by coapplication of IGF-1 and an Src kinase and can be deactivated by membrane permeable protein tyrosine kinase inhibitors, we suggest that activation of K(+)/Cl(-) cotransporter function by endogenous protein tyrosine kinases mediates the developmental switch of GABAergic responses to hyperpolarizing inhibition. PMID- 11606622 TI - Lifespan extension and rescue of spongiform encephalopathy in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase-catalase mimetics. AB - Superoxide is produced as a result of normal energy metabolism within the mitochondria and is scavenged by the mitochondrial form of superoxide dismutase (sod2). Mice with inactivated SOD2 (sod2 nullizygous mice) die prematurely, exhibiting several metabolic and mitochondrial defects and severe tissue pathologies, including a lethal spongiform neurodegenerative disorder (Li et al., 1995; Melov et al., 1998, 1999). We show that treatment of sod2 nullizygous mice with synthetic superoxide dismutase (SOD)-catalase mimetics extends their lifespan by threefold, rescues the spongiform encephalopathy, and attenuates mitochondrial defects. This class of antioxidant compounds has been shown previously to extend lifespan in the nematode Caenorhabditis elegans (Melov et al., 2000). These new findings in mice suggest novel therapeutic approaches to neurodegenerative diseases associated with oxidative stress such as Friedreich ataxia, spongiform encephalopathies, and Alzheimer's and Parkinson's diseases, in which chronic oxidative damage to the brain has been implicated. PMID- 11606623 TI - Demonstration by fluorescence resonance energy transfer of two sites of interaction between the low-density lipoprotein receptor-related protein and the amyloid precursor protein: role of the intracellular adapter protein Fe65. AB - Amyloid-beta, the major constituent of senile plaques in Alzheimer's disease, is derived from the amyloid precursor protein (APP) by proteolysis. Kunitz protease inhibitor (KPI) containing forms of APP (APP751/770) interact with a multifunctional endocytic receptor, the low-density lipoprotein receptor-related protein (LRP), which modulates its proteolytic processing affecting production of amyloid-beta. We used fluorescence resonance energy transfer (FRET) using labeled LRP and APP in H4 cell line to examine the subcellular localization and the molecular domains involved in the APP-LRP interaction. KPI-containing forms of APP (APP770) demonstrated FRET with LRP that was sensitive to the LRP inhibitor receptor-associated protein (RAP), suggesting an interaction between the extracellular domains of APP770 and LRP. APP695 also interacts with LRP to lesser degree (as measured by extracellular domain probes), and this ectodomain interaction is not altered by RAP. By using C-terminally tagged LRP and APP, we demonstrate a second site of interaction between the C termini of both APP695 and APP770 and the C terminus of LRP, and that the interactions at these regions are not sensitive to RAP. We next examined the possibility that the C-termini APP-LRP interaction was mediated by Fe65, an adaptor protein that interacts with the cytoplasmic tails of LRP and APP. FRET studies confirmed a close proximity between the amino Fe65 phosphotyrosine binding (PTB) domain and LRP cytoplasmic domain and between the carboxyl Fe65 PTB domain and the APP cytoplasmic domain. These findings demonstrate that LRP interaction with APP occurs via both extracellular and intracellular protein interaction domains. PMID- 11606624 TI - Paired-pulse plasticity at the single release site level: an experimental and computational study. AB - CA3-CA1 glutamatergic synapses in the hippocampus exhibit a large heterogeneity in release probability (p) and paired-pulse (PP) plasticity, established already in the early neonatal period when the CA3-CA1 connections consist of only a single release site. At such a site two factors decide initial release probability: the number of immediately releasable vesicles (preprimed pool) and the vesicle release probability (P(ves1)). Depletion and replenishment of this pool, an alteration in P(ves), and desensitization of postsynaptic receptors may contribute to PP plasticity. A model based on data from single neonatal CA3-CA1 synapses has been used to address the relative importance of these factors for the heterogeneity in PP plasticity. At a 20 msec PP interval, the PP ratio (P(2)/P(1)) varied from 0.1 to 4.5 among the synapses. At this interval desensitization and replenishment were of little importance. The heterogeneity was explained mostly by the variation in P(ves1), whereas the preprimed pool size was of minor importance. P(ves) altered from the first to the second stimulus such that P(ves2) was rather uniform among the synapses. Its variation thus contributed little to the heterogeneity in PP ratio. The model also shows that the relationship between alterations in release probability and PP ratio is complex. Thus, an increase in release probability can be associated with an increase, a decrease, or no change at all in PP ratio, depending on the original values of P(ves1) and the preprimed pool and on which one of these factors is altered to produce the increase in release probability. PMID- 11606625 TI - The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. AB - Inflammation in Alzheimer's disease (AD) patients is characterized by increased cytokines and activated microglia. Epidemiological studies suggest reduced AD risk associates with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed inflammation and plaque-related pathology in an Alzheimer transgenic APPSw mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is curcumin, derived from the curry spice turmeric. Curcumin has an extensive history as a food additive and herbal medicine in India and is also a potent polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque pathology. Low and high doses of curcumin significantly lowered oxidized proteins and interleukin-1beta, a proinflammatory cytokine elevated in the brains of these mice. With low-dose but not high-dose curcumin treatment, the astrocytic marker GFAP was reduced, and insoluble beta amyloid (Abeta), soluble Abeta, and plaque burden were significantly decreased by 43-50%. However, levels of amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease. PMID- 11606626 TI - Agonist-induced internalization of serotonin-1a receptors in the dorsal raphe nucleus (autoreceptors) but not hippocampus (heteroreceptors). AB - Serotonin-1A (5-HT(1A)) receptors in the CNS are a major target for psychotropic drugs. In nucleus raphe dorsalis (NRD) and hippocampus (CA3), the selective 5 HT(1A) agonist (+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) reduces the firing activity of serotoninergic (5-HT) and pyramidal neurons, respectively. When located on 5-HT (autoreceptors), but not on non-5-HT (heteroreceptors) neurons, 5-HT(1A) receptors are known to be subject to desensitization. Using quantitative electron microscopy after pre-embedding immunogold labeling with specific antibodies, we examined the subcellular distribution of these receptors after acute administration of 8-OH-DPAT (0.5 mg/kg, i.v.). Silver-intensified immunogold particles associated with the plasma membrane or the cytoplasm were counted in somata and dendrites within the NRD, 15 min, 1 hr and 24 hr after 8-OH DPAT injection, and in hippocampal dendrites 1 hr after the same treatment. Significant decrease in the density of membrane labeling and concomitant increase of cytoplasmic labeling were demonstrated in the NRD, 15 min and 1 hr after 8-OH DPAT administration, with a return to baseline level at 24 hr. Internalization was blocked by previous administration of the 5-HT(1A) antagonist N-[2-[4-(2 methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635), which, by itself, was without apparent effect. In hippocampus (CA3), there were no apparent changes in the distribution of the receptor after 8-OH DPAT administration. These findings are in line with earlier results showing a desensitization of 5-HT(1A) autoreceptors but not heteroreceptors after treatment with 5-HT(1A) receptor agonist. They suggest that this desensitization is the result of autoreceptor internalization. PMID- 11606627 TI - Plasma membrane ganglioside sialidase regulates axonal growth and regeneration in hippocampal neurons in culture. AB - It has been long recognized that the ganglioside GM1 plays a role in axonal growth and neuronal differentiation. However, the involvement of plasma membrane GM1 has been difficult to elucidate. This is possible now thanks to the recent cloning of plasma membrane ganglioside sialidase (PMGS), the enzyme responsible for the localized hydrolysis of oligosialogangliosides into GM1. In this work we show that PMGS mRNA and protein levels are high at early developmental stages of the hippocampus and low in adulthood both in vivo and in vitro. We also demonstrate that inhibition of PMGS activity blocks axonal elongation, whereas the increase in PMGS activity dramatically enhances axon growth and accelerates the polarization of cytoskeletal proteins. Finally, we show that axotomy close to the cell body in PMGS overexpressing neurons results in the regrowth of the original axon instead of randomly, as is the case in control neurons. In all, these results imply that PMGS activity through the modulation of GM1 surface levels is an important component of the machinery controlling axonal growth. We hypothesize that increasing PMGS activity in the adult nervous system may be useful to improve regeneration after nerve damage. PMID- 11606628 TI - Odorant feature detection: activity mapping of structure response relationships in the zebrafish olfactory bulb. AB - The structural determinants of an odor molecule necessary and/or sufficient for interaction with the cognate olfactory receptor(s) are not known. Olfactory receptor neurons expressing the same olfactory receptor converge in the olfactory bulb. Thus, optical imaging of neuronal activity in the olfactory bulb can visualize at once the contributions by all the different olfactory receptors responsive to a particular odorant. We have used this technique to derive estimates about the structural requirements and minimal number of different zebrafish olfactory receptors that respond to a series of naturally occurring amino acids and some structurally related compounds. We report that the alpha carboxyl group, the alpha-amino group, and l-conformation of the amino acid are all required for activation of amino acid-responsive receptors. Increasing carbon chain length recruits successively more receptors. With increasing concentrations, the activity patterns induced by a homolog series of amino acids became more similar to each other. At intermediate concentrations patterns were unique across substances and across concentrations. The introduction of a terminal amino group (charged) both recruits additional receptors and prevents binding to some of the receptors that were responsive to the unsubstituted analog. In contrast, the introduction of a beta-hydroxyl group (polar) excluded the odorants from some of the receptors that are capable of binding the unsubstituted analog. Cross-adaptation experiments independently confirmed these results. Thus, odorant detection requires several different receptors even for relatively simple odorants such as amino acids, and individual receptors require the presence of some molecular features, the absence of others, and tolerate still other molecular features. PMID- 11606629 TI - Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy. AB - Lesioned axons within the dorsal roots fail to regenerate through the peripheral nerve transition zone and into the spinal cord. This regenerative failure leads to a persistent loss of sensory function. To induce axonal growth across this barrier, we used recombinant adenovirus to express fibroblast growth factor-2 (FGF2), nerve growth factor (NGF), L1 cell adhesion molecule (L1), or beta galactosidase (LacZ) within the endogenous glia of the dorsal spinal cord 16 d after injury. Expression of either FGF2 or NGF, but not L1 or LacZ, induced robust axonal regeneration into normal as well as ectopic locations within the dorsal spinal cord. This regeneration led to near-normal recovery of thermal sensory function. Functional recovery and the majority of regenerating axons within the dorsal horn disappeared with recutting of the sensory roots. Injections of adenovirus encoding NGF, but not FGF2, also resulted in extensive sprouting of noninjured sensory axons, which we previously demonstrated could cause hyperalgesia and chronic pain. Thus, neurotrophic factor gene therapy administered as late as 16 d after injury may serve as a useful treatment to elicit recovery after dorsal root avulsion; however, the choice of neurotrophin is important to induce selective regeneration of damaged axons. PMID- 11606630 TI - Conditional rescue of olfactory learning and memory defects in mutants of the 14 3-3zeta gene leonardo. AB - Members of the ubiquitous 14-3-3 family of proteins are abundantly expressed in metazoan neurons. The Drosophila 14-3-3zeta gene leonardo is preferentially expressed in adult mushroom bodies, centers of insect learning and memory. Mutants exhibit defects in olfactory learning and memory and physiological neuroplasticity at the neuromuscular junction. Because strong mutations in this gene are lethal, we investigated the nature of the defects that precipitate the learning and memory deficit and the role of the two protein isoforms encoded by leonardo in these processes. We find that the behavioral deficit in the mutants is not caused by aberrant development, LEONARDO protein is acutely required for learning and memory, and both protein isoforms can function equivalently in embryonic development and behavioral neuroplasticity. PMID- 11606631 TI - Distinct roles for the two Rho GDP/GTP exchange factor domains of kalirin in regulation of neurite growth and neuronal morphology. AB - The actin cytoskeleton, essential for neuronal development, is regulated in part by small GTP binding proteins of the Rho subfamily. Kalirin-9, with two Rho subfamily-specific GDP/GTP exchange factor (GEF) domains, localizes to neurites and growth cones of primary cortical neurons. Kalirin-9 overexpression in cultured cortical neurons induces longer neurites and altered neuronal morphology. Expression of the first GEF domain alone results in drastically shortened axons and excessive growth cones, mediated by Rac1. Expression of the second GEF domain alone induces axonal over-elongation and abundant filopodial neurites, mediated by RhoA. Coordination of the actions of the individual GEF domains through their presence in Kalirin-9, with its Sec14p, spectrin, and Src homology domain 3 motifs, is essential for regulating neurite extension and neuronal morphology. PMID- 11606632 TI - Functionally independent columns of rat somatosensory barrel cortex revealed with voltage-sensitive dye imaging. AB - Whisker movement is somatotopically represented in rodent neocortex by electrical activity in clearly defined barrels, which can be visualized in living brain slices. The functional architecture of this part of the cortex can thus be mapped in vitro with respect to its physiological input and compared with its anatomical architecture. The spatial extent of excitation was measured at high temporal resolution by imaging optical signals from voltage-sensitive dye evoked by stimulation of individual barrels in layer 4. The optical signals correlated closely with subthreshold EPSPs recorded simultaneously from excitatory neurons in layer 4 and layer 2/3, respectively. Excitation was initially (<2 msec) limited to the stimulated barrel and subsequently (>3 msec) spread in a columnar manner into layer 2/3 and then subsided in both layers after approximately 50 msec. The lateral extent of the response was limited to the cortical column defined structurally by the barrel in layer 4. Two experimental interventions increased the spread of excitation. First, blocking GABA(A) receptor-mediated synaptic inhibition caused excitation to spread laterally throughout wide regions of layer 2/3 and layer 5 but not into neighboring barrels, suggesting that the local excitatory connections within layer 4 are restricted to single barrels and that inhibitory neurons control spread in supragranular and infragranular layers. Second, NMDA receptor-dependent increase of the spread of excitation was induced by pairing repetitive stimulation of a barrel column with coincident stimulation of layer 2/3 in a neighboring column. Such plasticity in the spatial extent of excitation in a barrel column could underlie changes in cortical map structure induced by alterations of sensory experience. PMID- 11606633 TI - Microglial activation and dopaminergic cell injury: an in vitro model relevant to Parkinson's disease. AB - Microglial activation and oxidative stress are significant components of the pathology of Parkinson's disease (PD), but their exact contributions to disease pathogenesis are unclear. We have developed an in vitro model of nigral injury, in which lipopolysaccharide-induced microglial activation leads to injury of a dopaminergic cell line (MES 23.5 cells) and dopaminergic neurons in primary mesencephalic cell cultures. The microglia are also activated by PD IgGs in the presence of low-dose dopa-quinone- or H(2)O(2)-modified dopaminergic cell membranes but not cholinergic cell membranes. The activation requires the microglial FCgammaR receptor as demonstrated by the lack of activation with PD IgG Fab fragments or microglia from FCgammaR-/- mice. Although microglial activation results in the release of several cytokines and reactive oxygen species, only nitric oxide and H(2)O(2) appear to mediate the microglia-induced dopaminergic cell injury. These studies suggest a significant role for microglia in dopaminergic cell injury and provide a mechanism whereby immune/inflammatory reactions in PD could target oxidative injury relatively specifically to dopaminergic cells. PMID- 11606634 TI - Sodium channel mRNAs at the neuromuscular junction: distinct patterns of accumulation and effects of muscle activity. AB - Voltage-gated sodium channels (VGSCs) are highly concentrated at the neuromuscular junction (NMJ) in mammalian skeletal muscle. Here we test the hypothesis that local upregulation of mRNA contributes to this accumulation. We designed radiolabeled antisense RNA probes, specific for the "adult" Na(V)1.4 and "fetal" Na(V)1.5 isoforms of VGSC in mammalian skeletal muscle, and used them in in situ hybridization studies of rat soleus muscles. Na(V)1.4 mRNA is present throughout normal adult muscles but is highly concentrated at the NMJ, in which the amount per myonucleus is more than eightfold greater than away from the NMJ. Na(V)1.5 mRNA is undetectable in innervated muscles but is dramatically upregulated by denervation. In muscles denervated for 1 week, both Na(V)1.4 and Na(V)1.5 mRNAs are present throughout the muscle, and both are concentrated at the NMJ. No Na(V)1.5 mRNA was detectable in denervated muscles stimulated electrically for 1 week in vivo. Neither denervation nor stimulation had any significant effect on the level or distribution of Na(V)1.4 mRNA. We conclude that factors, probably derived from the nerve, lead to the increased concentration of VGSC mRNAs at the NMJ. In addition, the expression of Na(V)1.5 mRNA is downregulated by muscle activity, both at the NMJ and away from it. PMID- 11606635 TI - Regulation of NMDA receptor activity by F-actin and myosin light chain kinase. AB - The postsynaptic density (PSD) at excitatory dendritic synapses comprises a protein complex of glutamate receptors, scaffolding elements, and signaling enzymes. For example, NMDA receptors (NMDARs) are linked to several proteins in the PSD, such as PSD-95, and are also tethered via binding proteins such as alpha actinin directly to filamentous actin of the cytoskeleton. Depolymerization of the cytoskeleton modulates the activity of NMDARs, and, in turn, strong activation of NMDARs can trigger depolymerization of actin. Myosin, the motor protein of muscular contraction and nonmuscle motility, is also associated with NMDARs and the PSD. We show here that constitutively active myosin light chain kinase (MLCK) enhances NMDAR-mediated whole-cell and synaptic currents in acutely isolated CA1 pyramidal and cultured hippocampal neurons, whereas inhibitors of MLCK depress these currents. This MLCK-dependent regulation was observed in cell attached patches but was lost after excision to inside-out patches. Furthermore, the enhancement induced by constitutively active MLCK and the depression of MLCK inhibitors were eliminated after depolymerization of the cytoskeleton. NMDARs and MLCK did not colocalize in clusters on the dendrites of cultured hippocampal neurons, further indicating that the effects of MLCK are mediated indirectly via actomyosin. Our results suggest that MLCK enhances actomyosin contractility to either increase the membrane tension on NMDARs or to alter physical relationships between the actin cytoskeleton and the linker proteins of NMDARs. PMID- 11606636 TI - Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. AB - Huntington's disease (HD) is characterized by the selective loss of striatal projection neurons. In early stages of HD, neurodegeneration preferentially occurs in the lateral globus pallidus (LGP) and substantia nigra (SN), two regions in which the axons of striatal neurons terminate. Here we report that in mice expressing full-length mutant huntingtin and modeling early stages of HD, neuropil aggregates form preferentially in the LGP and SN. The progressive formation of these neuropil aggregates follows intranuclear accumulation of mutant huntingtin and becomes prominent from 11 to 27 months after birth. Neuropil aggregates, but no intranuclear inclusions, were observed in the LGP and SN, suggesting that huntingtin aggregates are formed in the axons of striatal projection neurons. In the LGP and SN, we observed degenerated axons in which huntingtin aggregates were associated with dark, swollen organelles that resemble degenerated mitochondria. Neuritic aggregates also form in cultured striatal neurons expressing mutant huntingtin, block protein transport in neurites, and cause neuritic degeneration before nuclear DNA fragmentation occurs. These findings suggest that the early neuropathology of HD originates from axonal dysfunction and degeneration associated with huntingtin aggregates. PMID- 11606637 TI - The nonuniform distribution of the GABA(A) receptor alpha 1 subunit influences inhibitory synaptic transmission to motoneurons within a motor nucleus. AB - Using immunohistochemistry we studied the distribution of GABA(A) and glycine receptor alpha1 subunits in the rat hypoglossal nucleus during postnatal development. In the neonate [postnatal day (P) 1-3] and adult nucleus (P28-30), GABA(A) receptor alpha1 subunit labeling was relatively modest. However, in the juvenile nucleus (P9-13), labeling was strong in the ventrolateral region and moderate in the dorsal region. Glycine receptor alpha1 subunit labeling was strong and uniform in the juvenile and adult nucleus and absent in the neonate nucleus. GABA and glycine neurotransmitter labeling was uniform throughout the neonatal and juvenile nucleus. To study the functional consequences of this regional differential GABA(A) receptor alpha1 subunit distribution, we voltage clamped juvenile hypoglossal motoneurons (HMs) from the ventrolateral and dorsal regions and recorded spontaneous miniature IPSCs (mIPSCs). Pure GABAergic events had slower decay times than glycinergic events. Although pure GABAergic and glycinergic decay times did not differ depending on HM location, the decays of mixed mIPSCs from ventrolateral HMs, recorded without GABA(A) and glycine receptor antagonists, had significantly slower decays than mIPSCs from dorsal HMs. Focally applied GABA and glycine onto outside-out patches revealed that the GABAergic to glycinergic peak current amplitude ratio was larger for patches from ventrolateral HMs compared with dorsal HMs. Dual component mIPSCs, presumably caused by co-release of GABA and glycine, were recorded more frequently in the ventrolateral nucleus. These data suggest that the number of synapses using GABA(A) receptor-mediated transmission is greater on ventrolateral HMs than dorsal HMs, demonstrating a nonuniformity of synaptic function within a defined motor nucleus. PMID- 11606638 TI - Dominant-negative synthesis suppression of voltage-gated calcium channel Cav2.2 induced by truncated constructs. AB - Voltage-gated calcium channel alpha1 subunits consist of four domains (I-IV), each with six transmembrane segments. A number of truncated isoforms have been identified to occur as a result of alternative splicing or mutation. We have examined the functional consequences for expression of full-length Ca(v)2.2 (alpha1B) of its coexpression with truncated constructs of Ca(v)2.2. Domains I-II or domains III-IV, when expressed individually, together with the accessory subunits beta1b and alpha2delta-1, did not form functional channels. When they were coexpressed, low-density whole-cell currents and functional channels with properties similar to wild-type channels were observed. However, when domain I II, domain III-IV, or domain I alone were coexpressed with full-length Ca(v)2.2, they markedly suppressed its functional expression, although at the single channel level, when channels were recorded, there were no differences in their biophysical properties. Furthermore, when it was coexpressed with either domain I II or domain I, the fluorescence of green fluorescent protein (GFP)-Ca(v)2.2 and expression of Ca(v)2.2 protein was almost abolished. Suppression does not involve sequestration of the Ca(v)beta subunit, because loss of GFP-Ca(v)2.2 expression also occurred in the absence of beta subunit, and the effect of domain I-II or domain I could not be mimicked by the cytoplasmic I-II loop of Ca(v)2.2. It requires transmembrane segments, because the isolated Ca(v)2.2 N terminus did not have any effect. Our results indicate that the mechanism of suppression of Ca(v)2.2 by truncated constructs containing domain I involves inhibition of channel synthesis, which may represent a role of endogenously expressed truncated Ca(v) isoforms. PMID- 11606639 TI - Phenotypic differentiation during migration of dopaminergic progenitor cells to the olfactory bulb. AB - A possible source for transplantable neurons in Parkinson's disease are adult olfactory bulb (OB) dopamine (DA) progenitors that originate in the anterior subventricular zone and reach the OB through the rostral migratory stream. We used adult transgenic mice expressing a lacZ reporter directed by an 8.9 kb tyrosine hydroxylase (TH) promoter to investigate the course of DAergic differentiation. Parallel transgene and intrinsic TH mRNA expression occurred during migration of DA interneurons through the mitral and superficial granule cell layers before these cells reached their final periglomerular position. Differential transgene and calcium-calmodulin-dependent protein kinase IV expression distinguished two nonoverlapping populations of interneurons. Transgenic mice carrying a TH8.9kb/lacZ construct with a mutant AP-1 site demonstrated that this element confers OB DA-specific TH gene regulation. These results indicate that DA phenotypic determination is specific to a subset of mobile OB progenitors. PMID- 11606640 TI - Potentiation of L-type calcium channels reveals nonsynaptic mechanisms that correlate spontaneous activity in the developing mammalian retina. AB - Although correlated neural activity is a hallmark of many regions of the developing nervous system, the neural events underlying its propagation remain largely unknown. In the developing vertebrate retina, waves of spontaneous, correlated neural activity sweep across the ganglion cell layer. Here, we demonstrate that L-type Ca(2+) channel agonists induce large, frequent, rapidly propagating waves of neural activity in the developing retina. In contrast to retinal waves that have been described previously, these L-type Ca(2+) channel agonist-potentiated waves propagate independent of fast synaptic transmission. Bath application of nicotinic acetylcholine, AMPA, NMDA, glycine, and GABA(A) receptor antagonists does not alter the velocity, frequency, or size of the potentiated waves. Additionally, these antagonists do not alter the frequency or magnitude of spontaneous depolarizations that are recorded in individual retinal ganglion cells. Like normal retinal waves, however, the area over which the potentiated waves propagate is reduced dramatically by 18alpha-glycyrrhetinic acid, a blocker of gap junctions. Additionally, like normal retinal waves, L-type Ca(2+) channel agonist-potentiated waves are abolished by adenosine deaminase, which degrades extracellular adenosine, and by aminophylline, a general adenosine receptor antagonist, indicating that they are dependent on adenosine-mediated signaling. Our study indicates that although the precise spatiotemporal properties of retinal waves are shaped by local synaptic inputs, activity may be propagated through the developing mammalian retina by nonsynaptic pathways. PMID- 11606641 TI - Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. AB - Epilepsy is a common outcome of traumatic brain injury (TBI), but the mechanisms of posttraumatic epileptogenesis are poorly understood. One clue is the occurrence of selective hippocampal cell death after fluid-percussion TBI in rats, consistent with the reported reduction of hippocampal volume bilaterally in humans after TBI and resembling hippocampal sclerosis, a hallmark of temporal lobe epilepsy. Other features of temporal-lobe epilepsy, such as long-term seizure susceptibility, persistent hyperexcitability in the dentate gyrus (DG), and mossy fiber synaptic reorganization, however, have not been examined after TBI. To determine whether TBI induces these changes, we used a well studied model of TBI by weight drop on somatosensory cortex in adult rats. First, we confirmed an early and selective cell loss in the hilus of the DG and area CA3 of hippocampus, ipsilateral to the impact. Second, we found persistently enhanced susceptibility to pentylenetetrazole-induced convulsions 15 weeks after TBI. Third, by applying GABA(A) antagonists during field-potential and optical recordings in hippocampal slices 3 and 15 weeks after TBI, we unmasked a persistent, abnormal APV-sensitive hyperexcitability that was bilateral and localized to the granule cell and molecular layers of the DG. Finally, using Timm histochemistry, we detected progressive sprouting of mossy fibers into the inner molecular layers of the DG bilaterally 2-27 weeks after TBI. These findings are consistent with the development of posttraumatic epilepsy in an animal model of impact head injury, showing a striking similarity to the enduring behavioral, functional, and structural alterations associated with temporal-lobe epilepsy. PMID- 11606642 TI - Semaphorin 3A elicits stage-dependent collapse, turning, and branching in Xenopus retinal growth cones. AB - The semaphorin receptor, neuropilin-1 (NP-1), was first identified in Xenopus as the A5 antigen and is expressed abundantly in developing retinal ganglion cells (RGCs). Here we show that growth cones acquire responsiveness to semaphorin 3A (Sema 3A) with age and that the onset of responsiveness correlates with the appearance of NP-1 immunoreactivity. Growth cones from "old" (stage 35/36) retinal explants collapse rapidly (5-10 min) in response to Sema 3A and turn away from a gradient of Sema 3A, whereas "young" growth cones (stage 24) are insensitive to Sema 3A. Moreover, transfection of full-length NP-1 into young neurons confers premature Sema 3A sensitivity. When young neurons are aged in culture they develop Sema 3A sensitivity in parallel with those in vivo, suggesting that an intrinsic mechanism of NP-1 regulation mediates this age dependent change. Sema 3A-induced collapse is transient, and after recovery approximately 30% of growth cones extend new branches within 1 hr, implicating Sema 3A as a branching factor. Pharmacological inhibitors were used to investigate whether these three Sema 3A-induced behaviors (collapse, turning, and branching) use distinct second messenger signaling pathways. All three behaviors were found to be mediated via cGMP. In situ hybridization shows that Sema 3A is expressed in the tectum and at the anterior boundary of the optic tract where axons bend caudally, suggesting that Sema 3A/NP-1 interactions play a role in guiding axons in the optic tract and in stimulating terminal branching in the tectum. PMID- 11606643 TI - Topographic-specific axon branching controlled by ephrin-As is the critical event in retinotectal map development. AB - The retinotectal projection is the predominant model for studying molecular mechanisms controlling development of topographic axonal connections. Our analyses of topographic mapping of retinal ganglion cell (RGC) axons in chick optic tectum indicate that a primary role for guidance molecules is to regulate topographic branching along RGC axons, a process that imposes unique requirements on the molecular control of map development. We show that topographically appropriate connections are established exclusively by branches that form along the axon shaft. Initially, RGC axons overshoot their appropriate termination zone (TZ) along the anterior-posterior (A-P) tectal axis; temporal axons overshoot the greatest distance and nasal axons the least, which correlates with the nonlinear increasing A-P gradient of ephrin-A repellents. In contrast, branches form along the shaft of RGC axons with substantial A-P topographic specificity. Topography is enhanced through the preferential arborization of appropriately positioned branches and elimination of ectopic branches. Using a membrane stripe assay and time-lapse microscopy, we show that branches form de novo along retinal axons. Temporal axons preferentially branch on their topographically appropriate anterior tectal membranes. After the addition of soluble EphA3-Fc, which blocks ephrin-A function, temporal axons branch equally on anterior and posterior tectal membranes, indicating that the level of ephrin-As in posterior tectum is sufficient to inhibit temporal axon branching and generate branching specificity in vitro. Our findings indicate that topographic branch formation and arborization along RGC axons are critical events in retinotectal mapping. Ephrin As inhibit branching along RGC axons posterior to their correct TZ, but alone cannot account for topographic branching and must cooperate with other molecular activities to generate appropriate mapping along the A-P tectal axis. PMID- 11606644 TI - Activation of synaptic NMDA receptors by action potential-dependent release of transmitter during hypoxia impairs recovery of synaptic transmission on reoxygenation. AB - Increased levels of glutamate and the subsequent activation of NMDA receptors are responsible for neuronal damage that occurs after an ischemic or hypoxic episode. In the present work, we investigated the relative contribution of presynaptic and postsynaptic blockade of synaptic transmission, as well as of blockade of NMDA receptors, for the facilitation of recovery of synaptic transmission in the CA1 area of rat hippocampal slices exposed to prolonged (90 min) hypoxia. During hypoxia, there was a complete inhibition of field EPSPs, which was fully reversible if released adenosine was allowed to act. When adenosine A(1) receptors were blocked with the selective antagonist 1,3-dipropyl-8 cyclopentylxanthine (DPCPX), recovery of synaptic transmission from hypoxia was significantly attenuated, and this impairment could be overcome by preventing synaptic transmission during hypoxia either with tetrodotoxin (TTX) or by switching off the afferent stimulation but not by postsynaptic blockade of transmission with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or selective blockade of adenosine A(2A) receptors. When synaptic transmission was allowed to occur during hypoxia, because of the presence of DPCPX, there was an NMDA receptor-mediated component of the EPSCs recorded in CA1 pyramidal neurons, and blockade of NMDA receptors with AP-5 restored recovery of synaptic transmission from hypoxia. It is concluded that impairment of recovery of synaptic transmission after an hypoxic insult results from activation of synaptic NMDA receptors by synaptically released glutamate and that adenosine by preventing this activation efficiently facilitates recovery. PMID- 11606645 TI - Transforming growth factor beta (TGFbeta) mediates Schwann cell death in vitro and in vivo: examination of c-Jun activation, interactions with survival signals, and the relationship of TGFbeta-mediated death to Schwann cell differentiation. AB - In some situations, cell death in the nervous system is controlled by an interplay between survival factors and negative survival signals that actively induce apoptosis. The present work indicates that the survival of Schwann cells is regulated by such a dual mechanism involving the negative survival signal transforming growth factor beta (TGFbeta), a family of growth factors that is present in the Schwann cells themselves. We analyze the interactions between this putative autocrine death signal and previously defined paracrine and autocrine survival signals and show that expression of a dominant negative c-Jun inhibits TGFbeta-induced apoptosis. This and other findings pinpoint activation of c-Jun as a key downstream event in TGFbeta-induced Schwann cell death. The ability of TGFbeta to kill Schwann cells, like normal Schwann cell death in vivo, is under a strong developmental regulation, and we show that the decreasing ability of TGFbeta to kill older cells is attributable to a decreasing ability of TGFbeta to phosphorylate c-Jun in more differentiated cells. PMID- 11606646 TI - A topographic instructive signal guides the adjustment of the auditory space map in the optic tectum. AB - Maps of auditory space in the midbrain of the barn owl (Tyto alba) are calibrated by visual experience. When owls are raised wearing prismatic spectacles that displace the visual field in azimuth, the auditory receptive fields of neurons in the optic tectum shift to compensate for the optical displacement of the visual field. This shift results primarily from a shift in the tuning of tectal neurons for interaural time difference. The visually based instructive signal that guides this plasticity could be based on a topographic, point-by-point comparison between auditory and visual space maps or on a foveation-dependent visual assessment of the accuracy of auditory orienting responses. To distinguish between these two possibilities, we subjected owls to optical conditions that differed in the center of gaze and the visual periphery. A topographic signal would cause the portions of the space map representing the central and peripheral regions of visual space to adjust differently, according to the optical conditions that exist in each region. In contrast, a foveation-based signal would cause both portions of the map to adjust similarly, according to the optical conditions that exist at the center of gaze. In six of seven experiments, adaptive changes were as predicted by a topographic instructive signal. Although the results do not rule out the possible contribution of a foveation-based signal, they demonstrate that a topographic instructive signal is, indeed, involved in the calibration of the auditory space map in the barn owl optic tectum. PMID- 11606647 TI - Motion processing in the macaque: revisited with functional magnetic resonance imaging. AB - A great deal is known about the response properties of single neurons processing sensory information. In contrast, less is understood about the collective characteristics of networks of neurons that may underlie sensory capacities of animals. We used functional magnetic resonance imaging to study the emergent properties of populations of neurons processing motion across different brain areas. Using a visual adaptation paradigm, we localized a distributed network of visual areas that process information about the direction of motion as expected from single-cell recording studies. However, we found an apparent discrepancy between the directional signals in certain visual areas as measured with blood oxygenation level-dependent imaging compared with an estimate based on the spiking of single neurons. We propose a hypothesis that may account for this difference based on the postulate that neuronal selectivity is a function of the state of adaptation. Consequently, neurons classically thought to lack information about certain attributes of the visual scene may nevertheless receive and process this information. We further hypothesize that this adaptation dependent selectivity may arise from intra- or inter-area cellular connections, such as feedback from higher areas. This network property may be a universal principle the computational goal of which is to enhance the ability of neurons in earlier visual areas to adapt to statistical regularities of the input and therefore increase their sensitivity to detect changes along these stimulus dimensions. PMID- 11606648 TI - Neurotrophin-4 deficient mice have a loss of vagal intraganglionic mechanoreceptors from the small intestine and a disruption of short-term satiety. AB - Intraganglionic laminar endings (IGLEs) and intramuscular arrays (IMAs) are the two putative mechanoreceptors that the vagus nerve supplies to gastrointestinal smooth muscle. To examine whether neurotrophin-4 (NT-4)-deficient mice, which have only 45% of the normal number of nodose ganglion neurons, exhibit selective losses of these endings and potentially provide a model for assessing their functional roles, we inventoried IGLEs and IMAs in the gut wall. Vagal afferents were labeled by nodose ganglion injections of wheat germ agglutinin-horseradish peroxidase, and a standardized sampling protocol was used to map the terminals in the stomach, duodenum, and ileum. NT-4 mutants had a substantial organ-specific reduction of IGLEs; whereas the morphologies and densities of both IGLEs and IMAs in the stomach were similar to wild-type patterns, IGLEs were largely absent in the small intestine (90 and 81% losses in duodenum and ileum, respectively). Meal pattern analyses revealed that NT-4 mutants had increased meal durations with solid food and increased meal sizes with liquid food. However, daily total food intake and body weight remained normal because of compensatory changes in other meal parameters. These findings indicate that NT-4 knock-out mice have a selective vagal afferent loss and suggest that intestinal IGLEs (1) may participate in short-term satiety, probably by conveying feedback about intestinal distension or transit to the brain, (2) are not essential for long term control of feeding and body weight, and (3) play different roles in regulation of solid and liquid diet intake. PMID- 11606649 TI - Microcircuits for night vision in mouse retina. AB - Because the mouse retina has become an important model system, we have begun to identify its specific neuron types and their synaptic connections. Here, based on electron micrographs of serial sections, we report that the wild-type mouse retina expresses the standard rod pathways known in other mammals: (1) rod --> cone (via gap junctions) to inject rod signals into the cone bipolar circuit; and (2) rod --> rod bipolar --> AII amacrine --> cone bipolar --> ganglion cell. The mouse also expresses another rod circuit: a bipolar cell with cone input also receives rod input at symmetrical contacts that express ionotropic glutamate receptors (Hack et al., 1999, 2001). We show that this rod-cone bipolar cell sends an axon to the outer (OFF) strata of the inner plexiform layer to form ribbon synapses with ganglion and amacrine cells. This rod-cone bipolar cell receives direct contacts from only 20% of all rod terminals. However, we also found that rod terminals form gap junctions with each other and thus establish partial syncytia that could pool rod signals for direct chemical transmission to the OFF bipolar cell. This third rod pathway probably explains the rod responses that persist in OFF ganglion cells after the well known rod pathways are blocked (Soucy et al., 1998). PMID- 11606651 TI - Glutamate receptors in the rod pathway of the mammalian retina. AB - Rod bipolar (RB) cells of the mammalian retina release glutamate in a graded, light-dependent fashion from 20 to 40 ribbon synapses (dyads). At the dyads, two classes of amacrine cells, the AI and AII cells, are the postsynaptic partners. We examined the glutamate receptors (GluRs) that are expressed by AI and AII cells using immunocytochemistry with specific antibodies against GluR subunits. Sections of macaque monkey and rabbit retina were examined by confocal microscopy. AII amacrine cells were selectively labeled for calretinin, and AI cells in rabbits were labeled for 5-HT uptake. Thus, double- and triple-labeling for these markers and GluR subunits was possible. Electron microscopy using postembedding immunocytochemistry and double-labeling was applied to show the synaptic expression of GluRs. We also studied the synaptic localization of the two postsynaptic density proteins PSD-95 and glutamate receptor-interacting protein (GRIP). We found that AII amacrine cells express the AMPA receptor subunits GluR2/3 and GluR4 at the RB cell dyads, and they are clustered together with PSD-95. In contrast, AI amacrine cells express the delta1/2 subunits that appear to be associated with kainate receptor subunits and to be clustered together with GRIP. The RB cell dyad is therefore a synapse that initiates two functionally and molecularly distinct pathways: a "through conducting" pathway based on AMPA receptors and a modulatory pathway mediated by a combination of delta1/2 subunits and kainate receptors. PMID- 11606650 TI - A dopamine- and protein kinase A-dependent mechanism for network adaptation in retinal ganglion cells. AB - Vertebrates can detect light intensity changes in vastly different photic environments, in part, because postreceptoral neurons undergo "network adaptation." Previous data implicated dopaminergic, cAMP-dependent inhibition of retinal ganglion cells in this process yet left unclear how this occurs and whether this occurs in darkness versus light. To test for light- and dopamine dependent changes in ganglion cell cAMP levels in situ, we immunostained dark- and light-adapted retinas with anti-cAMP antisera in the presence and absence of various dopamine receptor ligands. To test for direct effects of dopamine receptor ligands and membrane-permeable protein kinase ligands on ganglion cell excitability, we recorded spikes from isolated ganglion cells in perforated-patch whole-cell mode before and during application of these agents by microperfusion. Our immunostainings show that light, endogenous dopamine, and exogenous dopamine elevate ganglion cell cAMP levels in situ by activating D1-type dopamine receptors. Our spike recordings show that D1-type agonists and 8-bromo cAMP reduce spike frequency and curtail sustained spike firing and that these effects entail protein kinase A activation. These effects resemble those of background light on ganglion cell responses to light flashes. Network adaptation could thus be produced, to some extent, by dopaminergic modulation of ganglion cell spike generation, a mechanism distinct from modulation of transmitter release onto ganglion cells or of transmitter-gated currents in ganglion cells. Combining these observations with results obtained in studies of photoreceptor, bipolar, and horizontal cells indicates that all three layers of neurons in the retina are equipped with mechanisms for adaptation to ambient light intensity. PMID- 11606652 TI - Cutaneous vasoconstriction contributes to hyperthermia induced by 3,4 methylenedioxymethamphetamine (ecstasy) in conscious rabbits. AB - 3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy") increases body temperature. This process could be associated with increased cutaneous blood flow, as normally occurs with exercise-induced hyperthermia. Alternatively, an MDMA-induced fall in cutaneous blood flow could contribute to the hyperthermia by diminishing normal heat transfer from the body to the environment. We investigated these possibilities by administering MDMA (1.5-6 mg/kg, i.v.) to conscious freely moving rabbits, determining effects on body temperature, cutaneous blood flow (measured by a Doppler ultrasonic probe that was chronically implanted around the ear pinna artery), and other cardiovascular parameters. MDMA caused a dose dependent increase in body temperature (from 38.3 +/- 0.3 to 41.2 +/- 0.4 degrees C after 6 mg/kg; p < 0.01; n = 5), preceded and accompanied by a dose-dependent cutaneous vasoconstriction (from 29 +/- 6 to 5 +/- 1 cm/sec after 6 mg/kg; p < 0.01; n = 5). MDMA (3 mg/kg) did not change blood flow to the mesenteric vascular bed. Prior unilateral cervical sympathectomy reduced the increase in body temperature elicited by MDMA (6 mg/kg) from 2.0 +/- 0.2 to 1.3 +/- 0.2 degrees C (p < 0.01; n = 5). On the denervated side, ear pinna blood flow after MDMA injection was 13 +/- 3 cm/sec, compared with 3 +/- 1 cm/sec on the sympathetically intact side (p < 0.05; n = 5). Thus, sympathetically mediated cutaneous vasoconstriction is one mechanism whereby MDMA causes hyperthermia. Reversal of cutaneous vasoconstriction by appropriate pharmacological means could be of therapeutic benefit in humans suffering from life-threatening hyperthermia induced by MDMA. PMID- 11606653 TI - The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. AB - The role of limbic-striato-pallidal circuitry in cocaine-induced reinstatement was evaluated. The transient inhibition of brain nuclei associated with motor systems [including the ventral tegmental area (VTA), dorsal prefrontal cortex (dPFC), core of the nucleus accumbens (NAcore), and ventral pallidum (VP)] prevented cocaine-induced reinstatement. However, only the VP proved to be necessary for food reinstatement, suggesting that the identified circuit is specific to drug-related reinstatement. Supporting the possibility that the VTA dPFC-NAcore-VP is a series circuit mediating reinstatement, simultaneous unilateral microinjection of GABA agonists into the dPFC in one hemisphere and into the VP in the contralateral hemisphere abolished cocaine reinstatement. Although dopamine projections from the VTA innervate all three forebrain nuclei, the blockade of dopamine receptors only in the dPFC antagonized cocaine-induced reinstatement. Furthermore, DA administration into the dPFC was sufficient to elicit a reinstatement in drug-related responding. These data demonstrate that dopamine release in the dPFC initiates a dPFC-NAcore-VP series circuit that mediates cocaine-induced drug-seeking behavior. PMID- 11606655 TI - On and off pathways segregated at the auditory thalamus of the guinea pig. AB - ON and OFF auditory responses were examined on the medial geniculate body (MGB) of the guinea pig. Single-unit and multiunit recordings were performed on 13 anesthetized subjects while either noise-burst or pure-tone stimuli were applied to the ear contralateral to the recorded hemisphere. Of 2187 uneven-spaced samples, 1142 were ON neurons, 386 were OFF neurons, and 488 were ON-OFF neurons. Neither ON nor OFF neurons changed their response patterns when the stimulus was changed from a noise burst of 60 dB sound pressure level intensity (expressed in decibels per 20 mPa) to pure tones or noise bursts of other intensities. However, most of the ON-OFF neurons changed to either ON or OFF responses with some stimuli. OFF neurons formed clusters. With anatomical confirmation, we found that OFF neuron clusters are always segregated from ON neuron clusters and form OFF sheets in various divisions of the MGB. In the ventral division of the MGB (MGv), the neurons showed mainly ON responses in its core and OFF responses in its periphery or on its boundary with other divisions. The MGv was partially surrounded by an OFF sheet dorsolaterally at the caudal part and medioventrally at the rostral part and was almost completely surrounded by an OFF sheet at the central level rostrocaudally. PMID- 11606654 TI - Mechanisms underlying developmental changes in the firing patterns of ON and OFF retinal ganglion cells during refinement of their central projections. AB - Patterned neuronal activity is implicated in the refinement of connectivity during development. Calcium-imaging studies of the immature ferret visual system demonstrated previously that functionally separate ON and OFF retinal ganglion cells (RGCs) develop distinct temporal patterns of spontaneous activity as their axonal projections undergo refinement. OFF RGCs become spontaneously more active compared with ON cells, resulting in a decrease in synchronous activity between these cell types. This change in ON and OFF activity patterns is suitable for driving the activity-dependent refinement of their axonal projections. Here, we used whole-cell and perforated-patch recording techniques to elucidate the mechanisms that underlie the developmental alteration in the ON and OFF RGC activity patterns. First, we show that before the refinement period, ON and OFF RGCs have similar spike patterns; however, during the period of segregation, OFF RGCs demonstrate significantly higher spike rates relative to ON cells. With increasing age, OFF cells require less depolarization to reach their action potential threshold and fire more spikes in response to current injection compared with ON cells. In addition, spontaneous postsynaptic currents and potentials are greater in magnitude in OFF cells than ON cells. In contrast, before axonal refinement, there are no differences in the intrinsic excitability or synaptic drive onto ON and OFF cells. Together, our results show that developmental changes in ON and OFF RGC excitability and in the strength of their synaptic drives act together to reshape the spike patterns of these cells in a manner appropriate for the refinement of their connectivity. PMID- 11606656 TI - Altered respiratory motor drive after spinal cord injury: supraspinal and bilateral effects of a unilateral lesion. AB - Because some bulbospinal respiratory premotor neurons have bilateral projections to the phrenic nuclei, we investigated whether changes in contralateral phrenic motoneuron function would occur after unilateral axotomy via C(2) hemisection. Phrenic neurograms were recorded under baseline conditions and during hypercapnic and hypoxic challenge in C(2) hemisected, normal, and sham-operated rats at 1 and 2 months after injury. The rats were anesthetized, vagotomized, and mechanically ventilated. No group differences were seen in contralateral neurograms at 1 month after injury. At 2 months, however, there was a statistically significant decrease in respiratory rate (RR) at normocapnia, an elevated RR during hypoxia, and an attenuated increase in phrenic neurogram amplitude during hypercapnia in the C(2)-hemisected animals. To test whether C(2) hemisection had induced a supraspinal change in respiratory motor drive, we recorded ipsilateral and contralateral hypoglossal neurograms during hypercapnia. As with the phrenic motor function data, no change in hypoglossal output was evident until 2 months had elapsed when hypoglossal amplitudes were significantly decreased bilaterally. Last, the influence of serotonin-containing neurons on the injury-induced change in phrenic motoneuron function was examined in rats treated with the serotonin neurotoxin, 5,7-dihydroxytryptamine. Pretreatment with 5,7-dihydroxytryptamine prevented the effects of C(2) hemisection on contralateral phrenic neurogram amplitude and normalized the change in RR during hypoxia. The results of this study show novel neuroplastic changes in segmental and brainstem respiratory motor output after C(2) hemisection that coincided with the spontaneous recovery of some ipsilateral phrenic function. Some of these effects may be modulated by serotonin-containing neurons. PMID- 11606658 TI - Synchronized periodic Ca2+ pulses define neurosecretory activities in magnocellular vasotocin and isotocin neurons. AB - The electrical activity of magnocellular neurosecretory cells (NSCs) is correlated with the release rates of neurohypophysial hormones. NSCs may control their secretory activity in a cooperative manner by changing their electrical activity in response to changes in the internal milieu. In the present study, we applied confocal Ca(2+) imaging to a sagittally hemisected rainbow trout brain to simultaneously monitor the neuronal activity of a number of NSCs. We found that NSCs in vitro showed synchronized pulsatile elevations of intracellular Ca(2+) levels at regular intervals. Double immunostaining of vasotocin (VT) and isotocin (IT) after the confocal imaging clarified that each of the VT and IT neuronal populations showed a distinct pattern of periodic Ca(2+) pulses. Simultaneous cell-attached patch recordings ensured that individual Ca(2+) pulses were associated with a phasic burst firing. Depolarizing stimuli by increasing the extracellular K(+) concentration from 5 to 7-9 mm reversibly shortened the interpulse intervals in both VT and IT neurons. Interpulse intervals but not durations of pulses were shortened by hypo-osmotic stimuli and prolonged by hyperosmotic stimuli, consistent with the osmoregulatory function of teleost NSCs. We therefore hypothesize that NSCs use intervals of synchronized periodic burst discharges to fit the levels of secretory activity to physiological requirements. PMID- 11606657 TI - The involvement of the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain. AB - The present study investigated the effect of inhibiting the expression of Na(v)1.8 (PN3/SNS) sodium channels by an antisense oligodeoxynucleotide (ODN) on bladder nociceptive responses induced by intravesical acetic acid infusion in rats. Animals were injected intrathecally with either Na(v)1.8 antisense or mismatch ODN. Control cystometrograms under urethane anesthesia during intravesical saline infusion exhibited intercontraction intervals (ICIs) that were significantly longer in antisense-treated rats than in mismatch ODN-treated rats. Intravesical infusion of 0.1% acetic acid induced bladder hyperactivity as reflected by a 68% reduction in ICIs in mismatch ODN-treated rats but did not significantly reduce ICIs in antisense-treated rats. The number of Fos-positive cells after acetic acid administration were significantly reduced in the L6 spinal cord from antisense-treated animals, compared with mismatch ODN-treated animals. In addition, Na(v)1.8 immunoreactivity was reduced in L6 dorsal root ganglion neurons in the antisense-treated rat. In patch-clamp recordings, the conductance density of TTX-resistant sodium currents in dissociated bladder afferent neurons that were labeled by axonal transport of a fluorescent dye, Fast Blue, injected into the bladder wall was also smaller in antisense-treated rats than in mismatch ODN-treated rats, whereas no changes were observed in TTX sensitive currents. These results indicate that the Na(v)1.8 TTX-resistant sodium channels are involved in the activation of afferent nerves after chemical irritation of the bladder. These channels represent a new target for the treatment of inflammatory pain from visceral organs such as the urinary bladder. PMID- 11606659 TI - Morphine induces synchronous oscillatory discharges in the rat locus coeruleus. AB - The noradrenergic locus coeruleus (LC) plays a role in opioid dependence and withdrawal. In the present study, using a multiple-electrode recording technique that allowed several LC neurons to be recorded simultaneously over long time periods, LC neuronal activities were recorded before and after intracerebroventricular injection of morphine (26 nmol) under halothane anesthesia. We found that morphine did not simply decrease firing rates of LC neurons, as reported in earlier studies, but that it induced persistent oscillatory discharges in 49% (87 of 178) of the LC neurons recorded. Cross correlation analysis revealed that almost all LC neurons (86 of 87) that exhibited oscillatory discharges were synchronized with at least one other neuron. When stated in terms of simultaneously recorded neuron pairs, 59% (292 of 492) of the oscillatory neuron pairs discharged synchronously. The morphine induced synchronous oscillation began at approximately 10 min after morphine injection, reached its peak in approximately 20-30 min, persisted throughout the recording periods (up to 110 min after morphine injection, the longest recording time), and were reversed by an opioid receptor antagonist naltrexone. These data suggest that although the overall firing rate of LC neurons was reduced by morphine, the morphine-induced synchronous oscillatory activity may summate temporally and spatially at LC axon terminals and facilitate release of noradrenaline. Noradrenaline is an important neuromodulator and has been shown to induce and facilitate synaptic plasticity at LC target sites. We propose that the morphine-induced long-lasting synchronous oscillatory activity in the LC may be a neuronal signal that could induce synaptic plasticity leading to opioid addiction. PMID- 11606660 TI - Ethanol consumption and behavioral impulsivity are increased in protein kinase Cgamma null mutant mice. AB - Etiological factors influencing the development of alcoholism are complex and, at a minimum, include an interaction between polygenic factors and personality and biological traits. Human and animal studies suggest that some genes may regulate both the traits associated with alcohol abuse, such as decreased sensitivity or anxiety, and vulnerability to alcoholism. The identification of these genes could elucidate neurochemical pathways that are important in the development of alcohol abuse. Results from the present study indicate that the gene encoding the neuronal-specific gamma subtype of protein kinase C (PKCgamma) influences both ethanol consumption and behavioral impulsivity, a personality characteristic associated with Type II alcoholics, in a pleiotropic manner. Mice lacking PKCgamma consume more ethanol in a two-bottle choice paradigm and also demonstrate increased behavioral impulsivity in an appetitive-signaled nosepoke task when compared with wild-type littermate control mice. Therefore, PKCgamma may be an important mechanism within the cell that mediates one or more neurochemical pathways relevant to an increased predisposition to alcoholism. PMID- 11606661 TI - Evidence based medicine: concerns of a clinical neurologist. PMID- 11606662 TI - Getting to the heart of dementia. PMID- 11606663 TI - Videodynamic and sphincter motor unit potential analyses in Parkinson's disease and multiple system atrophy. PMID- 11606665 TI - The Tolosa-Hunt syndrome. PMID- 11606666 TI - A clinical role for [(123)I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer's-type and dementia with Lewy bodies. AB - OBJECTIVE: Scintigraphy with [(123)I]metaiodobenzyl guanidine ([(123)I]MIBG) enables the quantification of postganglionic sympathetic cardiac innervation. Recently, myocardial [(123)I]MIBG scintigraphy has been found to be useful in distinguishing Parkinson's disease, a Lewy body disease, from other akinetic rigid syndromes. Some patients initially diagnosed with dementia of the Alzheimer's type (DAT) are discovered to have an alternative disease such as dementia with Lewy bodies (DLB), despite the application of stringent diagnostic criteria. In the present study, examinations were performed to clarify the usefulness of myocardial [(123)I]MIBG scintigraphy in improving the differential diagnosis between patients with DLB and DAT. METHODS: Fourteen patients with DLB and 14 patients with DAT underwent scintigraphy with [(123)I]MIBG, combined with orthostatic tests and cardiac examinations. RESULTS: In all patients with DLB, the heart to mediastinum (H/M) ratio of MIBG uptake was pathologically impaired in both early and delayed images, independently of the duration of disease and autonomic failure. All patients with DAT had successful MIBG uptake in the heart regardless of duration of disease and autonomic failure. Orthostatic hypotension was seen in four patients with DAT and 13 patients with DLB. CONCLUSIONS: [(123)I]MIBG myocardial scintigraphy might detect early disturbances of the sympathetic nervous system in DLB and might provide useful diagnostic information to discriminate DLB from DAT. The distinction between DLB and DAT may be improved by greater emphasis on cardiac sympathetic disturbances. PMID- 11606667 TI - Effects of a flexible galantamine dose in Alzheimer's disease: a randomised, controlled trial. AB - OBJECTIVE: To assess the efficacy and safety of galantamine in Alzheimer's disease at 3 months using flexible dose escalation. METHODS: A randomised, double blind, placebo controlled trial in 43 centres in the United States, Canada, Great Britain, South Africa, Australia, and New Zealand. Patients with probable Alzheimer's disease (n=386; 171 women) with a score of 11-24 on the mini mental state examination, and a score> or =12 on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog) were randomised to placebo, or galantamine escalated over 4 weeks to a maintenance dose of 24 or 32 mg/day. The primary outcome measures were the change in ADAS-cog score and the clinician's interview based impression of change plus caregiver input (CIBIC-plus) score. Activities of daily living (ADL) and behavioural symptoms were secondary outcomes. To compare the effects of highest levels of dosing, an observed cases (OC) analysis was undertaken, with classic intention to treat (ITT) and ITT with last observation carried forward (LOCF) as confirmatory analyses. RESULTS: At 3 months, galantamine (24-32 mg/day) produced a significantly better outcome on cognitive function than placebo (treatment difference=1.9 points on ADAS-cog, p=0.002) and a significantly better global response than placebo, as measured by CIBIC-plus (deterioration in 21% of patients on galantamine v 37% on placebo; p<0.001). Galantamine produced significant benefits on basic and instrumental ADL. Behavioural symptoms did not change significantly from baseline levels in either group. Adverse events (primarily gastrointestinal) were of mild to moderate intensity. There were no important differences between the OC, ITT, and ITT/LOCF analyses. Most patients (82%) who were maintained on the higher dose of galantamine completed the study. CONCLUSIONS: Patients on galantamine, compared with those on placebo, experienced benefits in cognitive function and instrumental and basic activities of daily living. Flexible dose escalation of galantamine was well tolerated. PMID- 11606668 TI - Quantitative anal sphincter EMG in multisystem atrophy and 100 controls. AB - OBJECTIVE: To evaluate data of quantitative anal sphincter EMG in normal controls and to compare them with patients with multiple system atrophy (MSA). METHODS: Quantitative anal sphincter EMG were performed on 100 normal controls and 11 patients with MSA to characterise EMG data in these two groups. RESULTS: In the normal controls, there was a trend for increased motor unit potential (MUP) amplitude, duration, area, and polyphasicity with advancing age. Patients with MSA exhibited similar MUP size and fibre density. Significant differences were found only in parameters of the recruitment pattern, which were reduced in MSA, with a diminution in the number of active MUPs during rest. CONCLUSIONS: These results may reflect either decreased number of motor cells in Onuf's nucleus without significant consequential reinnervation, or upper motor neuron involvement affecting the anal sphincter in MSA. They further underline the importance of comparative data for age matched controls. PMID- 11606670 TI - Proprioception in Parkinson's disease is acutely depressed by dopaminergic medications. AB - OBJECTIVES: Impaired proprioception has been previously reported in patients with Parkinson's disease. It was hypothesised that dopaminergic medications transiently depress proprioception, with amplification of adventitious movements as a result. This study tested for effects on proprioception of dopaminergic drugs, and for associations between such effects and drug induced dyskinesias. METHODS: In 17 patients with Parkinson's disease, arm proprioception was tested in the practically defined "off" state, and retested 1 hour after taking levodopa or dopamine agonist. Testing consisted of side to side comparison of elbow angle, matching the contralateral elbow angle, and spatial recall of an unrestrained arm. RESULTS: Proprioception deteriorated as hypothesised, reaching significance by one tailed t test for each of the three tasks. The relative deterioration (and the 95% lower confidence bound for estimated deterioration) was 31% (4%) for side to side elbow comparison, was 27% (11%) for accuracy in matching the contralateral elbow angle, and was 11% (0%) for spatial recall. Dyskinetic (n=6) and non-dyskinetic (n=11) patients did not differ significantly in these effects on proprioception. Control subjects (n=6) and untreated parkinsonian subjects (n=5) did not significantly differ from the parkinsonian patients in the off state. CONCLUSIONS: Administration of levodopa and dopamine agonists were associated with a modest acute suppression in central responsiveness to joint position. It is speculated that compensatory exaggerated movement could account in part for the phenomenon of drug induced dyskinesias. PMID- 11606669 TI - Videourodynamic and sphincter motor unit potential analyses in Parkinson's disease and multiple system atrophy. AB - OBJECTIVES: Urinary dysfunction is a prominent autonomic feature in Parkinson's disease (PD) and multiple system atrophy (MSA), which is not only troublesome but also a cause of morbidity in these disorders. Recent advances in investigative uroneurology offer a better insight into the underlying pathophysiology and appropriate management for urinary dysfunction. METHODS: twenty one patients with PD (15 men, six women, mean age 64 (49-76), mean disease duration 4 years (1-8 years), median Hoehn and Yahr grade 3 (1-4), all taking 300 mg/day of levodopa (100-500 mg)) and 15 with MSA (eight men, seven women, mean age 59 (48-72), mean disease duration 3 years (0.5-6 years)) were recruited. Videourodynamic and sphincter motor unit potential analyses in the patients with PD and MSA were carried out, looking for distinguishing hallmarks that might be useful in the differential diagnosis of these two diseases. RESULTS: Urinary symptoms were found in 72% of patients with PD and in 100% with MSA. Filling phase abnormalities in the videourodynamic study included detrusor hyperreflexia in 81% of patients with PD and 56% with MSA, and uninhibited external sphincter relaxation in 33% of patients with PD and 33% of those with MSA. However, open bladder neck at the start of filling was not seen in patients with PD but was present in 53% of those with MSA, suggestive of internal sphincter denervation. Sphincter motor unit potential analysis showed neurogenic motor unit potentials in 5% of patients with PD and in 93% of those with MSA, suggestive of external sphincter denervation. On voiding, detrusor-external sphincter dyssynergia was not seen in patients with PD but was present in 47% of those with MSA. Pressure flow analysis showed that the Abrams-Griffiths number, a grading of urethral obstruction (outflow obstruction >40), in PD (40 in women and 43 in men) was larger than that in MSA (12 in women and 28 in men). Weak detrusor in PD (66% of women and 40% of men) was less common than that in MSA (71% of women and 63% of men). Postmicturition residuals >100 ml were absent in patients with PD but were present in 47% of patients with MSA. CONCLUSION: Patients with PD had less severe urinary dysfunction with little evidence of internal or external sphincter denervation, by contrast with the common findings in MSA. The findings of postmicturition residuals >100 ml, detrusor-external sphincter dyssynergia, open bladder neck at the start of bladder filling, and neurogenic sphincter motor unit potentials are highly suggestive of MSA. PMID- 11606671 TI - Bilateral pallidotomy for treatment of Parkinson's disease induced corticobulbar syndrome and psychic akinesia avoidable by globus pallidus lesion combined with contralateral stimulation. AB - OBJECTIVE: Posteroventral pallidotomy (PVP) has proved to be an effective method for the treatment of Parkinson's disease. However, data on bilateral procedures are still limited. To assess the effects of bilateral globus pallidus (GPi) lesion and to compare it with a combination of unilateral GPi lesion plus contralateral GPi stimulation (PVP+PVS), an open blind randomised trial was designed. METHODS: A prospective series of patients with severe Parkinson's disease refractory to medical treatment, and severe drug induced dyskinesias, were randomised either to simultaneous bilateral PVP or simultaneous PVP+PVS. All patients were assessed with the core assessment programme for intracerebral transplantation (CAPIT), and a comprehensive neuropsychological and neuropsychiatric battery both before surgery and 3 months later. RESULTS: The severe adverse effects found in the first three patients subjected to bilateral PVP led to discontinuation of the protocol. All three patients developed depression and apathy. Speech, salivation, and swallowing, as well as freezing, walking, and falling, dramatically worsened. By contrast, all three patients undergoing PVP+PVS had a significant motor improvement. CONCLUSION: Bilateral simultaneous lesions within the GPi may produce severe motor and psychiatric complications. On the other hand, a combination of PVP+ PVS significantly improves parkinsonian symptoms not associated with the side effects elicited by bilateral lesions. PMID- 11606672 TI - Primary lateral sclerosis: clinical, neurophysiological, and magnetic resonance findings. AB - OBJECTIVE: To describe the clinical, neurophysiological, and MRI findings in 10 patients with primary lateral sclerosis (PLS). RESULTS: The course of the disease was very slowly progressive. Spasticity due to upper motor neuron dysfunction was the most prominent sign, but EMG showed slight lower motor neuron signs, such as a mixed pattern on maximal voluntary contraction and enlarged motor unit potentials. One patient had clinically mild lower motor neuron involvement. Central motor conduction times (CMCT) were more prolonged in PLS than is the case in ALS. Minor sensory signs were found on neurophysiological examination, comparable with those in ALS. In four patients serum creatine kinase activity was raised. On MRI cortical atrophy was seen, most pronounced in the precentral gyrus and expanding into the parietal-occipital region. CONCLUSIONS: PLS is a distinct clinical syndrome, part of the range of motor neuron diseases. Besides pronounced upper motor neuron symptoms, mild lower motor neuron symptoms can also be found, as well as (subclinical) sensory symptoms. PLS can be distinguished from ALS by its slow clinical course, a severely prolonged MEP, and a more extensive focal cortical atrophy. PMID- 11606673 TI - Emil Heinrich Du Bois-Reymond (1818-96). PMID- 11606674 TI - Blood pressure and heart rate variability and baroreflex sensitivity before and after brain death. AB - OBJECTIVES: To evaluate spontaneous blood pressure and heart rate variability and spontaneous baroreflex sensitivity before and after brain death. METHODS: Spontaneous variability of arterial blood pressure and heart rate-estimated by power spectra of systolic (SBP) and diastolic blood pressure (DBP) and pulse interval (PI)-and spontaneous baroreflex sensitivity (BRS)-estimated by the alpha index and the sequence technique-were evaluated in 11 patients twice: shortly before and 1 hour after the onset of brain death. RESULTS: Significant spectral changes occurred after brain death: a general power reduction in PI spectra; a shift of SBP, DBP and PI powers toward the lower frequencies, resulting in a greater slope of the "1/f" spectral trends; and a marked reduction of SBP and DBP powers (-93%) and of SBP-PI coherence (-63%) at 0.1 Hz. The estimated average BRS was relatively high before brain death (around 11 ms/mm Hg), and fell close to 0 or even was not detectable at all after brain death. CONCLUSIONS: Parameters describing spontaneous blood pressure and heart rate variability and indexes reflecting the baroreflex function, which were relatively normal up to a few hours before brain death, underwent marked changes with the onset of brain death. All the changes found are likely to reflect the cessation of activity of the cardiovascular brain stem centres. These findings indicate that techniques of blood pressure and heart rate spectral analysis and of dynamic assessment of baroreflex sensitivity may be useful to complement the diagnosis of brain stem death. PMID- 11606675 TI - The dynamics of drug treatment in epilepsy: an observational study in an unselected population based cohort with newly diagnosed epilepsy followed up prospectively over 11-14 years. AB - OBJECTIVES: To study prospectively long term dynamics and patterns of treatment in a population based cohort of patients with newly diagnosed epilepsy. METHODS: 564 patients with definite epilepsy entered the UK National General Practice Study of Epilepsy (NGPSE), between 1984 and 1987, and were prospectively followed up for between 11-14 years. RESULTS: Treatment was started in 433 (77%) patients. Only 15% of single seizure patients had medication prescribed initially, although due to high seizure recurrence, more than 70% ultimately received antiepileptic medication. 209/564 patients (37%) were on drug therapy for epilepsy at the time of last follow up. 168/564 patients (30%) have stayed continuously on medication and another 41/564 patients (7%) restarted drug therapy because of seizure recurrence, having withdrawn medication. 98/209 (47%) of those on treatment are known to be in 5 year terminal remission. Phenytoin (29%) and carbamazepine (27%) were the most commonly preferred first line drugs followed by valproate (15%). Less than half of treated patients with partial seizures received carbamazepine as a first line drug and less than a third with generalised seizures were prescribed valproate as first choice drug. Nine out of 31 (29%) patients with one or more seizures a week at last follow up had never tried a second drug and only seven (23%) had tried four or more drugs. 11% of all treatment changes involved a new antiepileptic drug. Treatment changes were associated with low terminal remission rates. CONCLUSIONS: Out of 30 000 patients with newly diagnosed epilepsy every year in the United Kingdom, about 6000 have inadequate seizure control in the long term. About a third of the patients in this group have one or more seizures every month. Only two thirds of these patients with frequent seizures are likely to switch medication to try and achieve better seizure control. There is probably still considerable room for improvement in prescribing practice in the United Kingdom. PMID- 11606676 TI - A magnetic resonance study of complicated early childhood convulsion. AB - OBJECTIVES: The relation between complicated early childhood convulsion (ECC) and adult epilepsy is unclear, although a history of complicated ECC is obtainable in half of adults with epilepsy associated with hippocampal sclerosis. It is not known if the ECC is a marker of pre-existing brain damage or is itself harmful to the developing brain. The objective of the study was to assess the extent of structural brain abnormality present soon after a first complicated early childhood convulsion with a view to obtaining data which might contribute to an understanding of whether such abnormalities were likely to be pre-existing or caused by the convulsion. METHODS: Children under the age of 5 years were recruited into the study after their first complicated febrile or non-febrile ECC. None had previously experienced an epileptic seizure. All underwent MRI of the brain within 14 days. Hippocampal volumes and T2 relaxation times were measured. The results were compared with a neurological control group of children without gross structural abnormalities of the neocortex undergoing MRI of the brain for reasons other than epilepsy. RESULTS: Eighteen patients and 10 control subjects were recruited into the study. One patient was subsequently excluded because of EEG and clinical evidence of benign childhood epilepsy. Nine patients had volumetric evidence of significant hippocampal volume asymmetry (3 SD from the mean of the control group), although in only three of these was the asymmetry apparent on visual inspection of the MRI. Three patients had extrahippocampal neuropathology. None of the control subjects had significant hippocampal volume asymmetry (p<0.001). T2 relaxometry showed no evidence that postictal hippocampal oedema contributed to the asymmetry. CONCLUSIONS: There is a high prevalence of structural brain abnormalities in children within 2 weeks of the first complicated early childhood convulsion, including significant hippocampal asymmetry unrelated to oedema. This does not exclude a damaging effect of complicated ECC on the brain, but suggests that in at least some patients the complicated ECC is the result of pre-existing brain abnormalities. PMID- 11606677 TI - The neurobehavioural rating scale-revised: sensitivity and validity in closed head injury assessment. AB - OBJECTIVES: To investigate the factor structure and psychometric properties of the neurobehavioural rating scale-revised (NRS-R) and to determine its usefulness in clinical trials. METHODS: A consecutive series of patients sustaining severe closed head injury were evacuated to one of 11 large regional North American trauma centres and entered into a randomised, phase III, multicentre clinical trial investigating the therapeutic use of moderate hypothermia. Acute care personnel were blinded to outcome and outcome personnel were blinded to treatment condition. The Glasgow outcome scale (GOS) was the primary outcome measure. Secondary outcome measures included the disability rating scale (DRS) and the NRS R. RESULTS: Exploratory factor analysis of NRS-R data collected at 6 months after injury (n=210) resulted in a five factor model including: (1) executive/cognition, (2) positive symptoms, (3) negative symptoms, (4) mood/affect, and (5) oral/motor. These factors showed acceptable internal consistency (0.62 to 0.88), low to moderate interfactor correlations (0.19 to 0.61), and discriminated well between GOS defined groups. Factor validity was demonstrated by significant correlations with specific neuropsychological domains. Significant change was measured from 3 to 6 months after injury for the total score (sum of all 29 item ratings) and all factor scores except mood/affect and positive symptoms. The total score and all factor scores correlated significantly with concurrent GOS and DRS scores. CONCLUSIONS: The NRS-R is well suited as a secondary outcome measure for clinical trials as its completion rate exceeds that of neuropsychological assessment and it provides important neurobehavioural information complementary to that provided by global outcome and neuropsychological measures. PMID- 11606678 TI - Asymmetries of visual attention after circumscribed subcortical vascular lesions. AB - OBJECTIVE: To investigate the role of the basal ganglia and the thalamus for basic processes of visuospatial attention METHODS: Fifteen patients with acute circumscribed vascular lesions (10 with haemorrhage and five with infarction) were included in the study. The lesions were confined exclusively to subcortical structures, such as the basal ganglia, internal capsule, and thalamus, which was confirmed by initial CT on the day of referral and MRI taken 14-28 days after clinical onset. These patients were examined with two computerised attentional tasks (one detection and one search task) measuring spatial visual attention. RESULTS: There was a clear attentional asymmetry in patients with right hemispheric lesions (RHLs) in the visual search task. Seven out of eight patients with RHLs tended to be slower and/or missed significantly more target stimuli in the left sided part of a stimulus array consisting of 25 small squares than in right sided parts, although none of these patients showed signs of visual hemineglect in the visual detection task presenting visual information simultaneously to the right and left visual hemispace. All but one of these patients showed lesions in the posterior limb of the internal capsule and the putamen. On the other hand, patients with left hemispheric lesions were not impaired in the search task with only one patient showing more contralesional omissions of target stimuli than could be expected from the behaviour of normal controls. CONCLUSIONS: The results are in line with previous results showing a dominant role of right hemispheric neuronal structures for spatial attention. Furthermore, the data suggest that even with right hemispheric subcortical lesions without cortical involvement deficits in spatial orienting of attention to the left hemispace can be seen. These asymmetries of visual attention in the absence of neglect symptoms are supposed to be caused (1) by a disruption of the motor corticostriato-pallidothalamo-cortical neuronal circuit or (2) by a (partial) disconnection of relevant parts within the posterior attention network namely, parietal and thalamic structures. PMID- 11606679 TI - Extensive metabolic and neuropsychological abnormalities associated with discrete infarction of the genu of the internal capsule. AB - OBJECTIVE: The clinical presentation of capsular genu infarct varies. Prominent faciolingual weakness and subcortical dementia are the rule, but symptoms depend on the precise location and extension of the lesion beyond the genu. The aim was to characterise the radiographic, electroencephalographic, and neuropsychometric abnormalities in a woman who had a history of recurrent transient memory loss. METHOD: Case report. RESULTS: Magnetic resonance imaging showed an infarct in the genu of the left internal capsule. Positron emission tomography scan demonstrated decreased metabolic activity in the ipsilateral temporal, occipitotemporal, and contralateral cerebellar hemispheres. Electroencephalography showed intermittent rhythmic delta activity in the left frontotemporal region, and findings on neuropsychometric evaluation were consistent with cognitive impairment. Follow up evaluation 7 months after the stroke showed improvement in some areas of the cognitive domain, but residual neuropsychometric and neurophysiological abnormalities persisted. CONCLUSION: This case illustrates that cerebral and cerebellar diaschisis may contribute to the symptomatic presentation and recovery from capsular genu infarct, although its precise role remains elusive. PMID- 11606680 TI - Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation. AB - OBJECTIVE: Adult onset type II citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity. Most of the patients with this disease were reported in Japan and therefore, this disease has not been well recognised outside this country. The detailed clinical pictures of the patients with type II citrullinaemia are reported and their outcomes after liver transplantation referred to. METHODS: Ten patients with this disease were evaluated. Seven of them underwent liver transplants using a graft obtained from a healthy family member. RESULTS: There were six men and four women; the age of onset of encephalopathy ranged from 17 to 51 years. The initial symptom in nine patients was sudden onset disturbance of consciousness, and one patient had long been regarded as having a chronic progressive psychotic illness. High concentrations of plasma citrulline and ammonia were commonly seen on admission. Although brain CT or MRI lacked any consistent findings, the EEG was abnormal in all patients, showing diffuse slow waves. Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. After liver transplantation the metabolic abnormalities, including abnormal plasma concentrations of citrulline and ammonia, were immediately corrected and all neuropsychic symptoms soon disappeared, except for impaired cognitive function in one patient. Six out of these seven patients returned to their previous social lives, including work. CONCLUSIONS: The clinical concept of adult onset type II citrullinaemia coincides well with the range of hepatic encephalopathy, and liver transplantation is a very promising therapeutic approach. PMID- 11606682 TI - Intraoperative values of S-100 protein, myelin basic protein, lactate, and albumin in the CSF and serum of neurosurgical patients. AB - OBJECTIVES: To assess the concentrations of S-100 protein, myelin basic protein (MBP), and lactate, and the (CSF)/serum albumin ratio (Qalb) during intracranial neurosurgical procedures. METHODS: Samples of CSF from 91 patients with various CNS diseases were obtained by aspiration of cisternal CSF at the beginning of surgery (before starting surgical manipulation of the brain) and concentrations of S-100 protein, MBP, and lactate, and Qalb were determined. At the same time blood was sampled for determination of serum S-100 protein concentration. Patients were divided into three groups according to the aetiology of their CNS disease (intracranial haemorrhage, n=11; benign intracranial mass lesion, n=52; malignant neoplastic disease, n=28). Radiological and intraoperative characteristics were documented. RESULTS: In each of these three groups median values of all four CSF variables measured were raised. The occurrence of brain oedema and a midline shift correlated significantly with raised concentrations of MBP and Qalb. Breaching of the arachnoid layer, documented at surgery for benign lesions, correlated with higher concentrations of MBP, lactate, CSF S-100 protein, and Qalb. CONCLUSIONS: Intraoperative values of S-100 protein, MBP, lactate, and Qalb are increased in patients with intracranial haemorrhage, benign intracranial mass lesion, and malignant neoplastic disease. Breaching of the arachnoid layer and oedema is associated with higher concentrations of some of the aforementioned proteins. These biochemical data can serve as a basis for further research into CSF specific proteins. PMID- 11606683 TI - Impaired RNA splicing of 5'-regulatory sequences of the astroglial glutamate transporter EAAT2 in human astrocytoma. AB - A loss of the glutamate transporter EAAT2 has been reported in the neoplastic transformation of astrocytic cells and astrocytoma. The RNA expression of EAAT2 and five 5'-regulatory splice variants was investigated to identify alterations of the post-transcriptional EAAT2 gene regulation in human astrocytic tumours. Three known (EAAT2, HBGTII, and HBGTIIC) and two novel (EAAT2/3 and EAAT2/31) EAAT2 transcripts originating from alternative splicing of 5'-regulatory sequences were subject to an RNA expression analysis using reverse transcription and competitive PCR. Specimens of astrocytoma World Health Organisation (WHO) grade I-IV in 14 patients and control brain tissue obtained from three normal persons were studied. The main EAAT2 RNA was found to be equally expressed in normal human brain and astrocytic tumour samples. By contrast, the expression pattern of four 5'-variants of the transporter transcript was altered in the investigated series of astrocytoma compared with normal brain. HBGTII, HBGTIIC, and EAAT2/3 were amplified from seven and four tumours and one sample, respectively. EAAT2/31 was expressed in none of the tumour specimens studied. In conclusion, in astrocytic tumours of different histopathological grades there was a substantial reduction of RNA splicing events in EAAT2. The impairment of EAAT2 splicing indicates an altered expression which is not primarily involved in the tumorigenesis but may contribute to some biological properties of astrocytoma such as oedema, necrosis, and tumour related seizures. PMID- 11606684 TI - The range of multiple sclerosis associated with neurofibromatosis type 1. AB - Multiple sclerosis associated with neurofibromatosis type 1 (NF1) is a very rare event. Seven patients with multiple sclerosis and NF1 are described in the literature, and all were reported to have the primary progressive form of multiple sclerosis. Three new patients with NF1 that developed multiple sclerosis are described and it is shown that the range of multiple sclerosis associated with NF1 includes the relapsing forms of the disease. The risk of having both NF1 and multiple sclerosis in north east Italy is higher than would be expected based on the prevalence rates of the two diseases. PMID- 11606685 TI - Long term safety and efficacy of unilateral deep brain stimulation of the thalamus for parkinsonian tremor. AB - The objective was to investigate the long term safety and efficacy of unilateral deep brain stimulation (DBS) of the VIM nucleus of the thalamus in Parkinson's disease. Twelve patients with Parkinson's disease underwent unilateral DBS of the thalamus for medication resistant tremor between 1994 and 1997. Patients were evaluated with the motor section of the unified Parkinson's disease rating scale (UPDRS) in the medication on state at baseline, 3 months, 12 months, and yearly thereafter.Three patients were lost to follow up. Nine patients had follow up evaluations greater than 24 months and were included in the analyses. The last postsurgical follow up occurred on average 40.0 (SD 17.2) months after surgery. Tremor scores were significantly improved with stimulation on at the long term follow up compared with baseline. There was no significant change in UPDRS motor scores at long term follow up compared with baseline. There was no significant change in any stimulus parameters from 3 months to the long term follow up. Two patients had asymptomatic intracerebral haemorrhages and one patient had a subcutaneous haematoma over the implantable pulse generator site. Stimulus related adverse reactions were mild and easily controlled with changes in stimulus parameters. Two patients had replacement of the implantable pulse generator due to normal battery depletion, one patient had lead repositioning due to migration, and one patient had the lead extension wire replaced due to erosion. In conclusion, unilateral DBS of the thalamus has long term efficacy for treatment of tremor due to Parkinson's disease. PMID- 11606686 TI - Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports. AB - Parkinson's disease is a nosological entity of unknown origin for which, in some cases, a possible pathogenetic role for mitochondrial dysfunction has been postulated. Two young onset parkinsonian patients with mitochondrial DNA (mtDNA) deletions in skeletal muscle are reported on. Patient 1 also presented with increased blood creatine kinase and lactate concentrations and a family history which included a wide range of phenotypes affecting multiple systems. Patient 2 presented with multiple symmetric lipomatosis. Histopathological investigation showed ragged red fibres and COX negative fibres in muscle biopsies from both patients. The data support the hypothesis that mitochondrial DNA mutations may occur in some cases of parkinsonism, suggesting that a diagnosis of a mitochondrial disorder should be considered in the presence of consistent family history and clinical symptoms. PMID- 11606687 TI - Modality specific neural correlates of auditory and somatic hallucinations. AB - Somatic hallucinations occur in schizophrenia and other psychotic disorders, although auditory hallucinations are more common. Although the neural correlates of auditory hallucinations have been described in several neuroimaging studies, little is known of the pathophysiology of somatic hallucinations. Functional magnetic resonance imaging (fMRI) was used to compare the distribution of brain activity during somatic and auditory verbal hallucinations, occurring at different times in a 36 year old man with schizophrenia. Somatic hallucinations were associated with activation in the primary somatosensory and posterior parietal cortex, areas that normally mediate tactile perception. Auditory hallucinations were associated with activation in the middle and superior temporal cortex, areas involved in processing external speech. Hallucinations in a given modality seem to involve areas that normally process sensory information in that modality. PMID- 11606688 TI - Regression of ventral striatum hypometabolism after calcium/calcitriol therapy in paroxysmal kinesigenic choreoathetosis due to idiopathic primary hypoparathyroidism. AB - A [(18)F]-FDG PET study was performed in a 44 year old man with proximal kinesigenic choreoathetosis (PKC) secondary to idiopathic primary hypoparathyroidism (IPH) before and 1 year after calcium/calcitriol therapy. The [(18)F]-FDG PET performed before the start of the therapy disclosed a significant bilateral hypometabolism in the ventral striatum. One year later, with the patient still under calcium/calcitriol therapy and free of any occurrence of PKC episodes, the [(18)F]-FDG PET did not show the previously detected hypometabolism. The hypometabolism of the ventral striatum secondary to hypocalcaemia seems to play a crucial part in the pathogenesis of paroxysmal kinesigenic choreoathetosis associated with IPH. PMID- 11606690 TI - An unexpected consequence of a roller coaster ride. PMID- 11606689 TI - A 59 year old man with progressive spinal cord and peripheral nerve dysfunction culminating in encephalopathy: Edinburgh advanced clinical neurology course, 1999. PMID- 11606691 TI - Smiling odontoid. PMID- 11606695 TI - NJML+: an extension of the NJML method to handle protein sequence data and computer software implementation. AB - While the maximum-likelihood (ML) method of tree reconstruction is statistically rigorous, it is extremely time-consuming for reconstructing large trees. We previously developed a hybrid method (NJML) that combines the neighbor-joining (NJ) and ML methods and thus is much faster than the ML method and improves the performance of NJ. However, we considered only nucleotide sequence data, so NJML is not suitable for handling amino acid sequence data, which requires even more computer time. NJML+ is an implementation of a further improved method for practical data analyses (including protein sequence data). Our extensive simulations using nucleotide and amino acid sequences showed that NJML+ gave good results in tree reconstruction. Indeed, NJML+ showed substantial improvements over existing methods in terms of both computational times and efficiencies, especially for amino acid sequence data. We also developed a "user-friendly" interface for the NJML+ program, including a simple tree viewer. PMID- 11606696 TI - Mitogenomic exploration of higher teleostean phylogenies: a case study for moderate-scale evolutionary genomics with 38 newly determined complete mitochondrial DNA sequences. AB - Although adequate resolution of higher-level relationships of organisms apparently requires longer DNA sequences than those currently being analyzed, limitations of time and resources present difficulties in obtaining such sequences from many taxa. For fishes, these difficulties have been overcome by the development of a PCR-based approach for sequencing the complete mitochondrial genome (mitogenome), which employs a long PCR technique and many fish-versatile PCR primers. In addition, recent studies have demonstrated that such mitogenomic data are useful and decisive in resolving persistent controversies over higher level relationships of teleosts. As a first step toward resolution of higher teleostean relationships, which have been described as the "(unresolved) bush at the top of the tree," we investigated relationships using mitogenomic data from 48 purposefully chosen teleosts, of which those from 38 were newly determined during the present study (a total of 632,315 bp), using the above method. Maximum parsimony and maximum-likelihood analyses were conducted with the data set that comprised concatenated nucleotide sequences from 12 protein-coding genes (excluding the ND6 gene and third codon positions) and 22 transfer RNA (tRNA) genes (stem regions only) from the 48 species. The resultant two trees from the two methods were well resolved and largely congruent, with many internal branches supported by high statistical values. The tree topologies themselves, however, exhibited considerable variation from the previous morphology-based cladistic hypotheses, with most of the latter being confidently rejected by the mitogenomic data. Such incongruence resulted largely from the phylogenetic positions or limits of long-standing problematic taxa, which were quite unexpected from previous morphological and molecular analyses. We concluded that the present study provided a basis of and guidelines for future investigations of teleostean evolutionary mitogenomics and that purposeful higher-density taxonomic sampling, subsequent sequencing efforts, and phylogenetic analyses of their mitogenomes may be decisive in resolving persistent controversies over higher-level relationships of teleosts, the most diversified group of all vertebrates, comprising over 23,500 extant species. PMID- 11606697 TI - Contrasting levels of nucleotide diversity on the avian Z and W sex chromosomes. AB - Sex chromosomes may provide a context for studying the local effects of mutation rate on molecular evolution, since the two types of sex chromosomes are generally exposed to different mutational environments in male and female germ lines. Importantly, recent studies of some vertebrates have provided evidence for a higher mutation rate among males than among females. Thus, in birds, the Z chromosome, which spends two thirds of its time in the male germ line, is exposed to more mutations than the female-specific W chromosome. We show here that levels of nucleotide diversity are drastically higher on the avian Z chromosome than in paralogous sequences on the W chromosome. In fact, no intraspecific polymorphism whatsoever was seen in about 3.4 kb of CHD1W intron sequence from a total of >150 W chromosome copies of seven different bird species. In contrast, the amount of genetic variability in paralogous sequences on the Z chromosome was significant, with an average pairwise nucleotide diversity (d) of 0.0020 between CHD1Z introns and with 37 segregating sites in a total of 3.8 kb of Z sequence. The contrasting levels of genetic variability on the avian sex chromosomes are thus in a direction predicted from a male-biased mutation rate. However, although a low gene number, as well as some other factors, argues against background selection and/or selective sweeps shaping the genetic variability of the avian W chromosome, we cannot completely exclude selection as a contributor to the low levels of variation on the W chromosome. PMID- 11606698 TI - Evolutionary history of the most speciose mammals: molecular phylogeny of muroid rodents. AB - Phylogenetic relationships between 32 species of rodents representing 14 subfamilies of Muridae and four subfamilies of Dipodidae were studied using sequences of the nuclear protein-coding genes Lecithin Cholesterol Acyl Transferase (LCAT) and von Willebrand Factor (vWF). An examination of some evolutionary properties of each data matrix indicates that the two genes are rather complementary, with lower rates of nonsynonymous substitutions for LCAT. Both markers exhibit a wide range of GC3 percentages (55%-89%), with several taxa above 70% GC3 for vWF, which indicates that those exonic regions might belong to the richest class of isochores. The primary sequence data apparently harbor few saturations, except for transitions on third codon positions for vWF, as indicated by comparisons of observed and expected pairwise values of substitutions. Phylogenetic trees based on 1,962 nucleotidic sites from the two genes indicate that the 14 Muridae subfamilies are organized into five major lineages. An early isolation leads to the clade uniting the fossorial Spalacinae and semifossorial Rhizomyinae with a strong robustness. The second lineage includes a series of African taxa representing nesomyines, dendromurines, cricetomyines, and the sole living member of mystromyines. The third one comprises only the mouselike hamster CALOMYSCUS: The fourth clade represents the cricetines, myospalacines, sigmodontines, and arvicolines, whereas the fifth one comprises four "traditional" subfamilies (Gerbillinae, Murinae, Otomyinae, and Acomyinae). Within these groups, we confirm the monophyly of almost all studied subfamilies, namely, Spalacinae, Rhizomyinae, Nesomyinae, Cricetomyinae, Arvicolinae, Sigmodontinae, Cricetinae, Gerbillinae, Acomyinae, and Murinae. Finally, we present evidence that the sister group of Acomyinae is Gerbillinae, and we confirm a nested position of Myospalacinae within Cricetinae and Otomyinae within Murinae. From a biogeographical point of view, the five main lineages spread and radiated from Asia with different degrees of success: the first three groups are now represented by a limited number of species and genera localized in some regions, whereas the last two groups radiated in a large variety of species and genera dispersed all over the world. PMID- 11606699 TI - Local similarity in evolutionary rates extends over whole chromosomes in human rodent and mouse-rat comparisons: implications for understanding the mechanistic basis of the male mutation bias. AB - The sex chromosomes and autosomes spend different times in the germ line of the two sexes. If cell division is mutagenic and if the sexes differ in number of cell divisions, then we expect that sequences on the X and Y chromosomes and autosomes should mutate at different rates. Tests of this hypothesis for several mammalian species have led to conflicting results. At the same time, recent evidence suggests that the chromosomal location of genes on autosomes affects their rate of evolution at synonymous sites. This suggests a mutagenic source different from germ cell replication. To correctly interpret the previous estimates of male mutation bias, it is crucial to understand the degree and range of this local similarity. With a carefully chosen randomization protocol, local similarity in synonymous rates of evolution can be detected in human-rodent and mouse-rat comparisons. However, the synonymous-site similarity in the mouse-rat comparison remains weak. Simulations suggest that this difference between the mouse-human and the mouse-rat comparisons is not artifactual and that there is therefore a difference between humans and rodents in the local patterns of mutation or selection on synonymous sites (conversely, we show that the previously reported absence of a local similarity in nonsynonymous rates of evolution in the human-rodent comparison was a methodological artifact). We show that linkage effects have a long-range component: not one in a million random genomes shows such levels of autosomal heterogeneity. The heterogeneity is so great that more autosomes than expected by chance have rates of synonymous evolution comparable with that of the X chromosome. As autosomal heterogeneity cannot be owing to different times spent in the germ line, this demonstrates that the dominant determiner of synonymous rates of evolution is not, as has been conjectured, the time spent in the male germ line. PMID- 11606700 TI - Evaluation of methods for determination of a reconstructed history of gene sequence evolution. AB - With whole-genome sequences being completed at an increasing rate, it is important to develop and assess tools to analyze them. Following annotation of the protein content of a genome, one can compare sequences with previously characterized homologous genes to detect novel functions within specific proteins in the evolution of the newly sequenced genome. One common statistical method to detect such changes is to compare the ratios of nonsynonymous (K(a)) to synonymous (K(s)) nucleotide substitution rates. Here, the effects of several parameters that can influence this calculation (sequence reconstruction method, phylogenetic tree branch length weighting, GC content, and codon bias) are examined. Also, two new alternative measures of adaptive evolution, the point accepted mutations (PAM)/neutral evolutionary distance (NED) ratio and the sequence space assessment (SSA) statistic are presented. All of these methods are compared using two sequence families: the recent divergence of leptin orthologs in primates, and the more ancient divergence of the deoxyribonucleoside kinase family. The examination of these and other measures to detect changes of gene function along branches of a phylogenetic tree will become increasingly important in the postgenomic era. PMID- 11606701 TI - A method for distinguishing consanguinity and population substructure using multilocus genotype data. AB - We use the patterns of homozygosity at multiple loci to distinguish between excess homozygosity caused by consanguineous mating and that due to undetected population subdivision (the Wahlund effect). Clarification of the underlying causes of excess homozygosity is of practical importance in explaining the occurrence of recessive genetic disorders and in forensic match probability calculations. We calculated a likelihood surface for two parameters: C, the proportion of the population practicing consanguinity, and theta, the genetic correlation due population subdivision. To illustrate the method, we applied it to multilocus genotypic data of two U.K. Asian populations, one practicing a high frequency of cousin marriage, and another in which caste endogamy was suspected. The method was able to successfully distinguish the different patterns of relatedness. The method also returned accurate estimates of C and theta using simulated data sets. We show how our method can be extended to allow for degrees of inbreeding closer than cousin unions, including selfing. With closer inbreeding, the relatedness of recent ancestors beyond the parents becomes an issue. PMID- 11606702 TI - Phylogenetic relationships and ancient incomplete lineage sorting among cichlid fishes in Lake Tanganyika as revealed by analysis of the insertion of retroposons. AB - Lake Tanganyika harbors numerous endemic species of extremely diverse cichlid fish that have been classified into 12 major taxonomic groups known as tribes. Analysis of short interspersed element (SINE) insertion data has been acknowledged to be a powerful tool for the elucidation of phylogenetic relationships, and we applied this method in an attempt to clarify such relationships among these cichlids. We studied insertion patterns of 38 SINEs in total, 24 of which supported the monophyly of three clades. The other 14 loci revealed extensive incongruence in terms of the patterns of SINE insertions. These incongruencies most likely stem from a period of adaptive radiation. One possible explanation for this phenomenon is the extensive incomplete lineage sorting of alleles for the presence or absence of a SINE during successive speciation events which took place about 5-10 MYA. The present study is the first to report the successful application of the SINE method in demonstrating the existence of such possible "ancient" incomplete lineage sorting. We discuss the possibility that it might potentially be very difficult to resolve the species phylogeny of a group that radiated explosively, even by resolving the genealogies of more than 10 nuclear loci, as a consequence of incomplete lineage sorting during speciation. PMID- 11606703 TI - The DIRS1 group of retrotransposons. AB - Only three retrotransposons of the DIRS1 group have previously been described: DIRS1 from the slime mold Dictyostelium discoideum, PAT from the nematode Panagrellus redivivus, and Prt1 from the zygomycetous fungus Phycomyces blakesleeanus. Analyses of the reverse transcriptase sequences encoded by these elements suggest that they are related to the long terminal repeat (LTR) retroelements, such as the Ty3/gypsy retrotransposons and the vertebrate retroviruses. The DIRS1-group elements, however, have several unusual structural features which distinguish them from typical LTR elements: (1) they lack the capacity to encode DDE-type integrases or aspartic proteases; (2) they have open reading frames (ORFs) of unknown function; (3) they integrate without creating duplications of their target sites; and (4) although they are bordered by terminal repeats, these sequences differ from typical LTRs in that they are either inverted repeats or "split" direct repeats. Because of the small number of DIRS1-like elements described, and the unusual structures of these elements, little is known about their evolution, distribution, and replication mechanisms. Here, we report the identification of several new DIRS1-like retrotransposons, including elements from nematodes, sea urchins, fish, and amphibia. We also present evidence for the existence of DIRS1-like sequences in the human genome. In addition, we show that the lack of DDE-type integrase genes from elements of the DIRS1 group is explained by the finding that the previously uncharacterized ORFs of these elements encode proteins related to the site-specific recombinase of bacteriophage lambda. The presence of lambda-recombinase-like genes in DIRS1 elements also accounts for the lack of target-site duplications for these elements and may be related to the unusual structures of their terminal repeats. PMID- 11606704 TI - Organization of the bovine alpha 2-fucosyltransferase gene cluster suggests that the Sec1 gene might have been shaped through a nonautonomous L1 retrotransposition event within the same locus. AB - By referring to the split coding sequence of the highly conserved alpha 6 fucosyltransferase gene family (assumed to be representative of the common alpha 2 and alpha 6 fucosyltransferase gene ancestor), we have hypothesized that the monoexonic coding sequences of the present alpha 2-fucosyltransferase genes have been shaped in mammals by several events of retrotransposition and/or duplication. In order to test our hypothesis, we determined the structure of the three bovine alpha 2-fucosyltransferase genes (bfut1, bfut2, and sec1) and analyzed their characteristics compared with their human counterparts (FUT1, FUT2, and Sec1). We show that in mammals, a complex nonautonomous L1 retrotransposition event occurred within the locus of the alpha 2 fucosyltransferase ancestor gene itself. A consequence of this event was the processing in Catarrhini of a Sec1 pseudogene via several point mutations. PMID- 11606705 TI - Molecular evolution of the wound-induced serine protease inhibitor wip1 in Zea and related genera. AB - Plant defense mechanisms have been the subject of intensive investigation. However, little is known about their long-term evolutionary dynamics. We investigated the molecular diversity of a wound-induced serine protease inhibitor, wip1, in the genus Zea, as well as the divergence of wip1 among four genera, Zea, Tripsacum, Sorghum, and Oryza, in order to gain insight into the long-term evolution of plant defense. The specific objectives of this study were to determine (1) whether wip1 has a history of positive or balancing selection, as has been shown for genes involved in plant defense against pathogens, and (2) if the evolutionary histories of wip1 inhibitory loops, which come into closest contact with proteases, differ from the evolutionary history of other parts of this gene. The Zea polymorphism data are consistent with a neutral evolutionary history. In contrast, relative-rate tests suggest a nonneutral evolutionary history. This inconsistency may indicate that selection acting on wip1 is episodic or that wip1 evolves in response to selection favoring novel alleles. We also detected significant heterogeneity in the evolutionary rates of the two inhibitory loops of wip1-one inhibitory loop is highly conserved, whereas the second has diverged rapidly. Because these two inhibitory loops are predicted to have very similar biochemical functions, the significantly different evolutionary histories suggest that these loops have different ecological functions. PMID- 11606706 TI - The gene orders on human chromosome 15 and chicken chromosome 10 reveal multiple inter- and intrachromosomal rearrangements. AB - Comparative mapping between the human and chicken genomes has revealed a striking conservation of synteny between the genomes of these two species, but the results have been based on low-resolution comparative maps. To address this conserved synteny in much more detail, a high-resolution human-chicken comparative map was constructed from human chromosome 15. Mapping, sequencing, and ordering of specific chicken bacterial artificial chromosomes has improved the comparative map of chromosome 15 (Hsa15) and the homologous regions in chicken with almost 100 new genes and/or expressed sequence tags. A comparison of Hsa15 with chicken identified seven conserved chromosomal segments between the two species. In chicken, these were on chromosome 1 (Gga1; two segments), Gga5 (two segments), and Gga10 (three segments). Although four conserved segments were also observed between Hsa15 and mouse, only one of the underlying rearrangement breakpoints was located at the same position as in chicken, indicating that the rearrangements generating the other three breakpoints occurred after the divergence of the rodent and the primate lineages. A high-resolution comparison of Gga10 with Hsa15 identified 19 conserved blocks, indicating the presence of at least 16 intrachromosomal rearrangement breakpoints in the bird lineage after the separation of birds and mammals. These results improve our knowledge of the evolution and dynamics of the vertebrate genomes and will aid in the clarification of the mechanisms that underlie the differentiation between the vertebrate species. PMID- 11606707 TI - Rapid evolution of a cyclin A inhibitor gene, roughex, in Drosophila. AB - The recent sequencing of the complete genome of the fruit fly Drosophila melanogaster has yielded about 30% of the predicted genes with no obvious counterparts in other organisms. These rapidly evolving genes remain largely unexplored. Here, we present evidence for a striking variability in an important Drosophila cell cycle regulator encoded by the gene roughex (rux) in closely related fly species. The unusual level of Rux protein variability indicates that there are very low overall constraints on amino acid substitutions. Despite the lack of sequence similarity, certain common features, including the presence of a C-terminal nuclear localization signal and a functionally important N-terminal RXL cyclin-binding motif, exist between Rux and cyclin-dependent kinase inhibitors of the Cip/Kip family. These results indicate that even some genes involved in key regulatory processes in eukaryotes evolve at extremely high rates. PMID- 11606708 TI - A relationship between lengths of microsatellites and nearby substitution rates in mammalian genomes. PMID- 11606709 TI - Nucleotide substitution rate estimation in enterobacteria: approximate and maximum-likelihood methods lead to similar conclusions. PMID- 11606710 TI - Recombination in animal mitochondrial DNA: evidence from published sequences. PMID- 11606711 TI - The correlation between linkage disequilibrium and distance: implications for recombination in hominid mitochondria. PMID- 11606712 TI - Sequence-repeat polymorphisms exhibit the signature of recombination in lodgepole pine chloroplast DNA. PMID- 11606713 TI - Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. AB - Growth of tumors and metastasis are processes known to require neovascularization. To ascertain the participation of the endogenous angiogenic inhibitor thrombospondin-1 (TSP1) in tumor progression, we generated mammary tumor-prone mice that either lack, or specifically overexpress, TSP1 in the mammary gland. Tumor burden and vasculature were significantly increased in TSP1 deficient animals, and capillaries within the tumor appeared distended and sinusoidal. In contrast, TSP1 overexpressors showed delayed tumor growth or lacked frank tumor development (20% of animals); tumor capillaries showed reduced diameter and were less frequent. Interestingly, absence of TSP1 resulted in increased association of vascular endothelial growth factor (VEGF) with its receptor VEGFR2 and higher levels of active matrix metalloproteinase-9 (MMP9), a molecule previously shown to facilitate both angiogenesis and tumor invasion. In vitro, enzymatic activation of proMMP9 was suppressed by TSP1. Together these results argue for a protective role of endogenous inhibitors of angiogenesis in tumor growth and implicate TSP1 in the in vivo regulation of metalloproteinase-9 activation and VEGF signaling. PMID- 11606715 TI - Congruence properties for the partition function. AB - Eighty years ago, Ramanujan conjectured and proved some striking congruences for the partition function modulo powers of 5, 7, and 11. Until recently, only a handful of further such congruences were known. Here we report that such congruences are much more widespread than was previously known, and we describe the theoretical framework that appears to explain every known Ramanujan-type congruence. PMID- 11606714 TI - The tumor-infiltrating B cell response in medullary breast cancer is oligoclonal and directed against the autoantigen actin exposed on the surface of apoptotic cancer cells. AB - Medullary carcinoma of the breast (MCB) is a morphologically and biologically distinct subtype of human breast cancer that, despite cytologically anaplastic features, has a more favorable prognosis than other types of breast cancer at similar stages of differentiation. It has been proposed that the improved clinical outcome is due, at least in part, to the presence of a prominent lymphoplasmacytic cell infiltrate in the tumor stroma. We studied the B lymphoplasmacytic cell infiltrates in MCB to determine the role of the antibody response produced by the local infiltrating cells. Oligoclonal predominance among tumor-infiltrating B cells in a panel of MCB patients was observed, suggesting that certain B cell clones were expanded, possibly in response to specific tumor associated stimuli. IgG antibody phage-display libraries were generated from MCB infiltrating lymphoplasmacytic cells of two patients, and MCB-reactive monoclonal antibodies were retrieved by selection on fresh-frozen MCB tissue sections. Analysis by mass spectrometry revealed that the antigen targeted by the dominant clones in the oligoclonal B lymphoplasmacytic response in both patients was not a cancer-specific antigen but the cytoskeletal protein beta-actin. MCB exhibits an increased rate of apoptosis, and apoptotic MCB cells were shown to expose actin on the cell surface, permitting its recognition by the humoral immune system. Further, actin fragments, similar to those observed after cleavage with the apoptotic protease granzyme B, were observed in MCB tissue. Our results indicate that the major antibody response produced by tumor-infiltrating B lymphoplasmacytic cells are autoimmune in nature and a consequence of the perturbed state of increased MCB apoptosis caused by granzyme B-induced T cell cytotoxicity and/or intrinsic cellular factors of MCB cells. PMID- 11606716 TI - Peptides from the amino terminal mdm-2-binding domain of p53, designed from conformational analysis, are selectively cytotoxic to transformed cells. AB - We have synthesized three peptides from the mdm-2 binding domain of human p53, residues 12-26 (PPLSQETFSDLWKLL), residues 12-20, and 17-26. To enable transport of the peptides across the cell membrane and at the same time to maximize the active mdm-2 binding alpha-helical conformation for these peptides, each was attached at its carboxyl terminus to the penetratin sequence, KKWKMRRNQFWVKVQRG, that contains many positively charged residues that stabilize an alpha-helix when present on its carboxyl terminal end. All three peptides were cytotoxic to human cancer cells in culture, whereas a control, unrelated peptide attached to the same penetratin sequence had no effect on these cell lines. The same three cytotoxic peptides had no effect on the growth of normal cells, including human cord blood-derived stem cells. These peptides were as effective in causing cell death in p53-null cancer cells as in those having mutant or normal p53. Peptide induced cell death is not accompanied by expression of apoptosis-associated proteins such as Bax and waf(p21). Based on these findings, we conclude that the antiproliferative effects of these p53-derived peptides are not completely dependent on p53 activity and may prove useful as general anticancer agents. PMID- 11606717 TI - Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. AB - Cubilin is a 460-kDa protein functioning as an endocytic receptor for intrinsic factor vitamin B(12) complex in the intestine and as a receptor for apolipoprotein A1 and albumin reabsorption in the kidney proximal tubules and the yolk sac. In the present study, we report the identification of cubilin as a novel transferrin (Tf) receptor involved in catabolism of Tf. Consistent with a cubilin-mediated endocytosis of Tf in the kidney, lysosomes of human, dog, and mouse renal proximal tubules strongly accumulate Tf, whereas no Tf is detectable in the endocytic apparatus of the renal tubule epithelium of dogs with deficient surface expression of cubilin. As a consequence, these dogs excrete increased amounts of Tf in the urine. Mice with deficient synthesis of megalin, the putative coreceptor colocalizing with cubilin, also excrete high amounts of Tf and fail to internalize Tf in their proximal tubules. However, in contrast to the dogs with the defective cubilin expression, the megalin-deficient mice accumulate Tf on the luminal cubilin-expressing surface of the proximal tubule epithelium. This observation indicates that megalin deficiency causes failure in internalization of the cubilin-ligand complex. The megalin-dependent, cubilin mediated endocytosis of Tf and the potential of the receptors thereby to facilitate iron uptake were further confirmed by analyzing the uptake of (125)I- and (59)Fe-labeled Tf in cultured yolk sac cells. PMID- 11606718 TI - C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. AB - The transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) is expressed at high levels in liver and adipose tissue. Cell culture studies show that C/EBPalpha is sufficient to trigger differentiation of preadipocytes into mature adipocytes, suggesting a central role for C/EBPalpha in the development of adipose tissue. C/EBPalpha knockout mice die within 7-12 h after birth. Defective gluconeogenesis of the liver and subsequent hypoglycemia contribute to the early death of these animals. This short life span impairs investigation of the development of adipose tissue in these mice. To improve the survival of C/EBPalpha-/- animals, we generated a transgenic line that expresses C/EBPalpha under the control of the albumin enhancer/promoter. This line was bred into the knockout strain to generate animals that express C/EBPalpha in the liver but in no other tissue. The presence of the transgene improved survival of C/EBPalpha-/- animals almost 3-fold. Transgenic C/EBPalpha-/- animals at 7 days of age show an absence of s.c., perirenal, and epididymal white fat despite excess lipid substrate in the serum, whereas brown adipose tissue is somewhat hypertrophied and shows minimal biochemical alterations. Interestingly, mammary gland fat tissue is present and exhibits normal morphology. The absence of white adipose tissue in many depots in the presence of high serum lipid levels shows that C/EBPalpha is required for the in vivo development of this tissue. In contrast, brown adipose tissue differentiation is independent of C/EBPalpha expression. The presence of lipid in brown adipose tissue serves as an internal nutritional control, indicating that neither nutritional intake nor lipoprotein composition is likely responsible for the absence of white fat. PMID- 11606719 TI - THEMATICS: a simple computational predictor of enzyme function from structure. AB - We show that theoretical microscopic titration curves (THEMATICS) can be used to identify active-site residues in proteins of known structure. Results are featured for three enzymes: triosephosphate isomerase (TIM), aldose reductase (AR), and phosphomannose isomerase (PMI). We note that TIM and AR have similar structures but catalyze different kinds of reactions, whereas TIM and PMI have different structures but catalyze similar reactions. Analysis of the theoretical microscopic titration curves for all of the ionizable residues of these proteins shows that a small fraction (3-7%) of the curves possess a flat region where the residue is partially protonated over a wide pH range. The preponderance of residues with such perturbed curves occur in the active site. Additional results are given in summary form to show the success of the method for proteins with a variety of different chemistries and structures. PMID- 11606720 TI - Male mate choice selects for female coloration in a fish. AB - Although sexual selection theory has proved successful in explaining a wide array of male ornaments, the function of ornaments occurring in females is largely unknown. Traditionally, female ornaments have been considered nonfunctional, being merely a genetically correlated response to selection for male ornamentation. However, this hypothesis is only relevant to species in which the ornament is basically the same in the two sexes. Alternatively, female ornaments may be influenced by selection acting directly on the females, either through female-female competition or male choice. We tested the latter hypothesis in mate choice experiments with two-spotted gobies (Gobiusculus flavescens). In this small marine fish, females have bright yellow-orange bellies during the breeding season, a conspicuous trait that is not present in males. We conducted two aquarium experiments to test whether males preferred to mate with more colorful females. In the first experiment, males had a choice between two females that varied in natural coloration (and belly roundness). In the second experiment, we manipulated belly coloration and kept roundness constant. Males spent more time with colorful than with drab females in both experiments and also performed far more courtship displays toward colorful females. Our study provides experimental evidence that males prefer ornamented females in a fish that is not sex-role reversed, supporting the hypothesis that female ornamentation is sexually selected. PMID- 11606721 TI - The kinetic basis of peptide exchange catalysis by HLA-DM. AB - The mechanism by which the peptide exchange factor HLA-DM catalyzes peptide loading onto structurally homologous class II MHC proteins is an outstanding problem in antigen presentation. The peptide-loading reaction of class II MHC proteins is complex and includes conformational changes in both empty and peptide bound forms in addition to a bimolecular binding step. By using a fluorescence energy transfer assay to follow the kinetics of peptide binding to the human class II MHC protein HLA-DR1, we find that HLA-DM catalyzes peptide exchange by facilitating a conformational change in the peptide-bound complex, and not by promoting the bimolecular MHC-peptide reaction or the conversion between peptide receptive and -averse forms of the empty protein. Thus, HLA-DM serves essentially as a protein-folding or conformational catalyst. PMID- 11606722 TI - T7 phage display: a novel genetic selection system for cloning RNA-binding proteins from cDNA libraries. AB - RNA-binding proteins are central to posttranscriptional gene regulation and play an important role in a number of major human diseases. Cloning such proteins is a crucial but often difficult step in elucidating the biological function of RNA regulatory elements. To make it easier to clone proteins that specifically bind RNA elements of interest, we have developed a rapid and broadly applicable in vitro genetic selection method based on T7 phage display. Using hairpin II of U1 small nuclear RNA (U1hpII) or the 3' stem loop of histone mRNA as bait, we could selectively amplify T7 phage that display either the spliceosomal protein U1A or the histone stem loop-binding protein from a lung cDNA phage library containing more than 10(7) independent clones. The use of U1hpII mutants with various affinities for U1A revealed that this method allows the selection even of proteins that bind their cognate RNA targets with relatively weak affinities (K(d) as high as the micromolar range). Experiments with a mixture of recombinant phage displaying U1A or the closely related protein U2B" demonstrated that addition of a competitor RNA can suppress selection of a protein with a higher affinity for a given RNA target, thereby allowing the preferential amplification of a lower affinity protein. Together, these findings suggest that T7 phage display can be used to rapidly and selectively clone virtually any protein that binds a known RNA regulatory element, including those that bind with low affinity or that must compete for binding with other proteins. PMID- 11606723 TI - Genetic characterization of the body attributed to the evangelist Luke. AB - Historical sources indicate that the evangelist Luke was born in Syria, died in Greece, and then his body was transferred to Constantinople, and from there to Padua, Italy. To understand whether there is any biological evidence supporting a Syrian origin of the Padua body traditionally attributed to Luke, or a replacement in Greece or Turkey, the mtDNA was extracted from two teeth and its control region was cloned and typed. The sequence determined in multiple clones is an uncommon variant of a set of alleles that are common in the Mediterranean region. We also collected and typed modern samples from Syria and Greece. By comparison with these population samples, and with samples from Anatolia that were already available in the literature, we could reject the hypothesis that the body belonged to a Greek, rather than a Syrian, individual. However, the probability of an origin in the area of modern Turkey was only insignificantly lower than the probability of a Syrian origin. The genetic evidence is therefore compatible with the possibility that the body comes from Syria, but also with its replacement in Constantinople. PMID- 11606724 TI - A role for frequenin, a Ca2+-binding protein, as a regulator of Kv4 K+-currents. AB - Frequenin, a Ca(2+)-binding protein, has previously been implicated in the regulation of neurotransmission, possibly by affecting ion channel function. Here, we provide direct evidence that frequenin is a potent and specific modulator of Kv4 channels, the principal molecular components of subthreshold activating A-type K(+) currents. Frequenin increases Kv4.2 current amplitudes (partly by enhancing surface expression of Kv4.2 proteins) and it slows the inactivation time course in a Ca(2+)-dependent manner. It also accelerates recovery from inactivation. Closely related Ca(2+)-binding proteins, such as neurocalcin and visinin-like protein (VILIP)-1 have no such effects. Specificity for Kv4 currents is suggested because frequenin does not modulate Kv1.4 or Kv3.4 currents. Frequenin has negligible effects on Kv4.1 current inactivation time course. By using chimeras made from Kv4.2 and Kv4.1 subunits, we determined that the differential effects of frequenin are mediated by means of the Kv4 N terminus. Immunohistochemical analysis demonstrates that frequenin and Kv4.2 channel proteins are coexpressed in similar neuronal populations and have overlapping subcellular localizations in brain. Coimmunoprecipitation experiments demonstrate that a physical interaction occurs between these two proteins in brain membranes. Together, our data provide strong support for the concept that frequenin may be an important Ca(2+)-sensitive regulatory component of native A type K(+) currents. PMID- 11606726 TI - Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors. AB - Naturally occurring variations in maternal licking/grooming influence neural development and are transmitted from mother to female offspring. We found that the induction of maternal behavior in virgin females through constant exposure to pups (pup sensitization) was significantly shorter in the offspring of High compared with Low licking/grooming mothers, suggesting differences in maternal responsivity. In randomly selected females screened for individual differences in maternal responsivity and subsequently mated, there was a significant and negative correlation (r = -0.73) between the latency to exhibit maternal behavior in the pup sensitization paradigm and the frequency of pup licking/grooming during lactation. Females that were more maternally responsive to pups and that showed increased levels of pup licking/grooming also showed significantly higher oxytocin receptor levels in the medial preoptic area, the lateral septum, the central nucleus (n.) of the amygdala, the paraventricular n. of the hypothalamus, and the bed n. of the stria terminalis. Intracerebroventricular administration of an oxytocin receptor antagonist to mothers on postpartum day 3 completely eliminated the differences in pup licking/grooming, suggesting that differences in oxytocin receptor levels are functionally related to maternal behavior. Finally, estrogen treatment of virgin females significantly increased oxytocin receptor binding in the medial preoptic area and lateral septum of female offspring of High, but not Low, licking/grooming mothers. These findings suggest that maternal licking/grooming influences the development of estrogen sensitivity in brain regions that regulate maternal behavior, providing a potential mechanism for the intergenerational transmission of individual differences in maternal behavior. PMID- 11606725 TI - Endostatin regulates branching morphogenesis of renal epithelial cells and ureteric bud. AB - Endostatin (ES) inhibits endothelial cell migration and has been found to bind to glypicans (Gpcs) on both endothelial cells and renal epithelial cells. We examined the possibility that ES might regulate epithelial cell morphogenesis. The addition of ES to cultured epithelial cells causes an inhibition of both hepatocyte growth factor- and epidermal growth factor-dependent process formation and migration. In contrast, ES does not inhibit epidermal growth factor-dependent morphogenesis in renal epithelial cells derived from Gpc-3 -/mice, whereas expression of Gpc-1 in these cells reconstitutes ES responsiveness. Gpc-3 -/mice have been shown to display enhanced ureteric bud (UB) branching early in development, and cultured UB cells release ES into the media, suggesting that ES binding to Gpcs may regulate UB branching. The addition of ES inhibits branching of the explanted UB, whereas a neutralizing Ab to ES enhances UB outgrowth and branching. Thus, local expression of ES at the tips of the UB may play a role in the regulation of UB arborization. PMID- 11606727 TI - Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O6- methylguanine-DNA methyltransferase. AB - O(6)-methylguanine (O(6)mG) is a potent mutagenic and procarcinogenic DNA lesion. Organisms have evolved with a DNA repair mechanism that largely ameliorates the deleterious effects of O(6)mG through a direct reversal mechanism by a protein termed O(6)-methylguanine-DNA methyltransferase (MGMT). However, the contribution of O(6)mG to carcinogenesis, in the absence of known exposure to agents that produce it, has not been defined. Nontransgenic C3HeB male mice have a high frequency of spontaneous liver tumors. Transgenic CeHeB/FeJ mice expressing human MGMT (hMGMT) were generated that had elevated hepatic MGMT activity. The spontaneous development of hepatocellular carcinoma was significantly reduced in those mice expressing hMGMT compared with nontransgenic C3HeB/FeJ male mice. No differences were detected in spontaneous mutant frequencies in lacI transgenes in mice carrying hMGMT compared with that without hMGMT but the proportion of GC to AT transition mutations was lower in the transgenic mice carrying hMGMT as well as lacI. Tumors that arose in C3HeB/FeJ transgenic mice were largely deficient in hMGMT protein as determined by immunohistochemistry with a monoclonal antibody directed against hMGMT. Together these data indicate that spontaneous O(6)mG lesions induced hepatocellular carcinogenesis in C3HeB/FeJ male mice. These transgenic mice represent a rare example of reduced spontaneous carcinogenesis. PMID- 11606729 TI - Phase coupling and synchrony in the spatiotemporal dynamics of muskrat and mink populations across Canada. AB - Population ecologists have traditionally focused on the patterns and causes of population variation in the temporal domain for which a substantial body of practical analytic techniques have been developed. More recently, numerous studies have documented how populations may fluctuate synchronously over large spatial areas; analyses of such spatially extended time-series have started to provide additional clues regarding the causes of these population fluctuations and explanations for their synchronous occurrence. Here, we report on the development of a phase-based method for identifying coupling between temporally coincident but spatially distributed cyclic time-series, which we apply to the numbers of muskrat and mink recorded at 81 locations across Canada. The analysis reveals remarkable parallel clines in the strength of coupling between proximate populations of both species--declining from west to east--together with a corresponding increase in observed synchrony between these populations the further east they are located. PMID- 11606728 TI - FLU: a negative regulator of chlorophyll biosynthesis in Arabidopsis thaliana. AB - Tetrapyrroles such as chlorophylls and bacteriochlorophylls play a fundamental role in the energy absorption and transduction activities of photosynthetic organisms. Because of these molecules, however, photosynthetic organisms are also prone to photooxidative damage. They had to evolve highly efficient strategies to control tetrapyrrole biosynthesis and to prevent the accumulation of free intermediates that potentially are extremely destructive when illuminated. In higher plants, the metabolic flow of tetrapyrrole biosynthesis is regulated at the step of delta-aminolevulinic acid synthesis. This regulation previously has been attributed to feedback control of Glu tRNA reductase, the first enzyme committed to tetrapyrrole biosynthesis, by heme. With the recent discovery of chlorophyll intermediates acting as signals that control both nuclear gene activities and tetrapyrrole biosynthesis, it seems likely that heme is not the only regulator of this pathway. A genetic approach was used to identify additional factors involved in the control of tetrapyrrole biosynthesis. In Arabidopsis thaliana, we have found a negative regulator of tetrapyrrole biosynthesis, FLU, which operates independently of heme and seems to selectively affect only the Mg(2+) branch of tetrapyrrole biosynthesis. The identity of this protein was established by map-based cloning and sequencing the FLU gene. FLU is a nuclear-encoded plastid protein that, after import and processing, becomes tightly associated with plastid membranes. It is unrelated to any of the enzymes known to be involved in tetrapyrrole biosynthesis. Its predicted features suggest that FLU mediates its regulatory effect through interaction with enzymes involved in chlorophyll synthesis. PMID- 11606730 TI - Probing the open state of cytochrome P450cam with ruthenium-linker substrates. AB - Cytochromes P450 play key roles in drug metabolism and disease by oxidizing a wide variety of natural and xenobiotic compounds. High-resolution crystal structures of P450cam bound to ruthenium sensitizer-linked substrates reveal an open conformation of the enzyme that allows substrates to access the active center via a 22-A deep channel. Interactions of alkyl and fluorinated biphenyl linkers with the channel demonstrate the importance of exploiting protein dynamics for specific inhibitor design. Large changes in peripheral enzyme structure (F and G helices) couple to conformational changes in active center residues (I helix) implicated in proton pumping and dioxygen activation. Common conformational states among P450cam and homologous enzymes indicate that static and dynamic variability in the F/G helix region allows the 54 human P450s to oxidize thousands of substrates. PMID- 11606731 TI - Nitrogen cycling by wood decomposing soft-rot fungi in the "King Midas tomb," Gordion, Turkey. AB - Archaeological wood in ancient tombs is found usually with extensive degradation, limiting what can be learned about the diet, environment, health, and cultural practices of the tomb builders and occupants. Within Tumulus Midas Mound at Gordion, Turkey, thought to be the tomb of the Phrygian King Midas of the 8th century B.C., we applied a stable nitrogen isotope test to infer the paleodiet of the king and determine the nitrogen sources for the fungal community that decomposed the wooden tomb, cultural objects, and human remains. Here we show through analysis of the coffin, furniture, and wooden tomb structure that the principal degrader, a soft-rot fungus, mobilized the king's highly (15)N-enriched nutrients, values indicative of a diet rich in meat, to decay wood throughout the tomb. It is also evident from the delta(15)N values of the degraded wood that the nitrogen needed for the decay of many of the artifacts in the tomb came from multiple sources, mobilized at potentially different episodes of decay. The redistribution of nutrients by the fungus was restricted by constraints imposed by the cellular structure of the different wood materials that apparently were used intentionally in the construction to minimize decay. PMID- 11606732 TI - Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate. AB - Protein kinases of the Akt and related serum- and glucocorticoid-regulated kinase (SGK) families are major downstream mediators of phosphatidylinositol (PI) 3 kinase signaling to many cellular processes including metabolic flux, membrane trafficking, and apoptosis. Activation of these kinases is thought to occur at the plasma membrane through their serine and threonine phosphorylation by the phosphoinositide-dependent kinase 1 (PDK1) protein kinase, which interacts with membrane 3'-polyphosphoinositides through its pleckstrin homology (PH) domain. Here, we demonstrate that the SGK family member cytokine-independent survival kinase (CISK) binds strongly and selectively to the monophosphoinositide PI(3)P through its phox homology (PX) domain. Comparing native green fluorescent protein CISK (EGFP-CISK) to a mutant EGFP-CISK (Y51A) that displays attenuated binding to PI(3)P reveals that this interaction is both necessary and sufficient for its localization to early endosome antigen (EEA1)-positive endosomes. Furthermore, early endosome association of expressed epitope-tagged CISK in COS cells directed by binding of its PX domain to PI(3)P is required for activation of the CISK protein kinase by both insulin-like growth factor-1 and epidermal growth factor. Taken together, these results reveal a critical role of endosomal PI(3)P in the signal transmission mechanism whereby this survival kinase is activated in response to PI3-kinase stimulation by growth factors. PMID- 11606733 TI - SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. AB - We describe here the identification and properties of SCH-C (SCH 351125), a small molecule inhibitor of HIV-1 entry via the CCR5 coreceptor. SCH-C, an oxime piperidine compound, is a specific CCR5 antagonist as determined in multiple receptor binding and signal transduction assays. This compound specifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cells but has no effect on infection of CXCR4-expressing cells. SCH-C has broad and potent antiviral activity in vitro against primary HIV-1 isolates that use CCR5 as their entry coreceptor, with mean 50% inhibitory concentrations ranging between 0.4 and 9 nM. Moreover, SCH-C strongly inhibits the replication of an R5-using HIV-1 isolate in SCID-hu Thy/Liv mice. SCH-C has a favorable pharmacokinetic profile in rodents and primates with an oral bioavailability of 50-60% and a serum half-life of 5-6 h. On the basis of its novel mechanism of action, potent antiviral activity, and in vivo pharmacokinetic profile, SCH-C is a promising new candidate for therapeutic intervention of HIV infection. PMID- 11606736 TI - Body patterning. AB - Early patterning of the body during animal development is a fundamental process to subsequent events including cell differentiation, tissue and organ formation, and correct function of the adult body. We focused on two major topics: body segmentation and brain patterning, both of which are essential for conferring a functional complexity to the body, repetition of skeletal elements and complex neural network, respectively. PMID- 11606735 TI - A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell. AB - cAMP, the classical second messenger, regulates many diverse cellular functions. The primary effector of cAMP signals, protein kinase A, differentially phosphorylates hundreds of cellular targets. Little is known, however, about the spatial and temporal nature of cAMP signals and their information content. Thus, it is largely unclear how cAMP, in response to different stimuli, orchestrates such a wide variety of cellular responses. Previously, we presented evidence that cAMP is produced in subcellular compartments near the plasma membrane, and that diffusion of cAMP from these compartments to the bulk cytosol is hindered. Here we report that a uniform extracellular stimulus initiates distinct cAMP signals within different cellular compartments. By using cyclic nucleotide-gated ion channels engineered as cAMP biosensors, we found that prostaglandin E(1) stimulation of human embryonic kidney cells caused a transient increase in cAMP concentration near the membrane. Interestingly, in the same time frame, the total cellular cAMP rose to a steady level. The decline in cAMP levels near the membrane was prevented by pretreatment with phosphodiesterase inhibitors. These data demonstrate that spatially and temporally distinct cAMP signals can coexist within simple cells. PMID- 11606734 TI - Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. AB - The plasma level of NO(x), i.e., the sum of NO(2)- and NO(3)-, is frequently used to assess NO bioavailability in vivo. However, little is known about the kinetics of NO conversion to these metabolites under physiological conditions. Moreover, plasma nitrite recently has been proposed to represent a delivery source for intravascular NO. We therefore sought to investigate in humans whether changes in NO(x) concentration are a reliable marker for endothelial NO production and whether physiological concentrations of nitrite are vasoactive. NO(2)- and NO(3)- concentrations were measured in blood sampled from the antecubital vein and brachial artery of 24 healthy volunteers. No significant arterial-venous gradient was observed for either NO(2)- or NO(3)-. Endothelial NO synthase (eNOS) stimulation with acetylcholine (1-10 microg/min) dose-dependently augmented venous NO(2)- levels by maximally 71%. This effect was paralleled by an almost 4 fold increase in forearm blood flow (FBF), whereas an equieffective dose of papaverine produced no change in venous NO(2)-. Intraarterial infusion of NO(2)- had no effect on FBF. NOS inhibition (N(G)-monomethyl-l-arginine; 4-12 micromol/min) dose-dependently reduced basal NO(2)- and FBF and blunted acetylcholine-induced vasodilation and NO release by more than 80% and 90%, respectively. In contrast, venous NO(3)- and total NO(x) remained unchanged as did systemic arterial NO(2)- and NO(3)- levels during all these interventions. FBF and NO release showed a positive association (r = 0.85; P < 0.001). These results contradict the current paradigm that plasma NO(3)- and/or total NO(x) are generally useful markers of endogenous NO production and demonstrate that only NO(2)- reflects acute changes in regional eNOS activity. Our results further demonstrate that physiological levels of nitrite are vasodilator-inactive. PMID- 11606737 TI - What visual perception tells us about mind and brain. AB - Recent studies of visual perception have begun to reveal the connection between neuronal activity in the brain and conscious visual experience. Transcranial magnetic stimulation of the human occipital lobe disrupts the normal perception of objects in ways suggesting that important aspects of visual perception are based on activity in early visual cortical areas. Recordings made with microelectrodes in animals suggest that the perception of the lightness and depth of visual surfaces develops through computations performed across multiple brain areas. Activity in earlier areas is more tightly correlated with the physical properties of objects whereas neurons in later areas respond in a manner more similar to visual perception. PMID- 11606739 TI - The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P. AB - The surface glycoprotein of the Lassa virus, a member of the arenaviridae family, is synthesized as a 76-kDa precursor (GP-C) that is posttranslationally cleaved into an N-terminal 44-kDa subunit and a C-terminal membrane-anchored 36-kDa subunit. Cleavage occurs at the C-terminal end of the unusual recognition motif R R-L-L. We show here that GP-C is cleaved in the endoplasmic reticulum by the cellular subtilase SKI-1/S1P, an enzyme that has so far been observed to be involved in cholesterol metabolism. Furthermore, we present evidence that only cleaved glycoprotein is incorporated into virions and that this is necessary for the formation of infectious virus. To our knowledge, there have been no previous reports of this type of viral glycoprotein processing, one that may be an interesting target for antiviral therapy. PMID- 11606740 TI - A hallmark of active class switch recombination: transcripts directed by I promoters on looped-out circular DNAs. AB - To specify when and where Ig class switch recombination (CSR) takes place, a good molecular marker closely associated with active CSR is required. CSR is accompanied by deletion of circular DNA from the Ig heavy chain locus. The circular DNA contains a DNA segment between Smu and a target S region including its I promoter, which is driven by specific cytokine stimulation before CSR. We found that the specific I promoter is still active in looped-out circular DNA and directs production of I-Cmu transcripts termed "circle transcripts." Reverse transcription-PCR demonstrated transient induction of specific circle transcripts upon CSR in a murine lymphoma cell line, CH12F3-2A, as well as spleen B cells. Production of the circle transcripts appeared to depend on expression of activation-induced cytidine deaminase (AID), an essential factor for CSR. A comparison of kinetics between circle transcripts and circular DNA showed more rapid disappearance of circle transcripts. Thus, circle transcripts may serve as a hallmark for active CSR in vitro and in vivo. PMID- 11606741 TI - Development of a two-part transcription probe to determine the completeness of temporal and spatial compartmentalization of gene expression during bacterial development. AB - We have developed a two-part test, using the Bacillus subtilis sacB/SacY transcription antitermination system, to evaluate the completeness of temporal and spatial compartmentalization of gene expression during bacterial cell development. Transcription of sacY(1-55) (encoding a constitutively active form of the antiterminator, SacY) is directed by one promoter, whereas transcription of sacB'-'lacZ (the target of SacY action) is directed by the same or another promoter. To obtain beta-galactosidase activity, SacY(1-55) needs to be present when sacB'-'lacZ is being transcribed. We tested the system by analyzing the spatial compartmentalization of the activities of RNA polymerase final sigma factors, which are tightly regulated during sporulation of B. subtilis: final sigma(F) and then final sigma(G) in the prespore, final sigma(E) and then final sigma(K) in the mother cell. We have confirmed that the activities of final sigma(F) and final sigma(E) are spatially compartmentalized. We have demonstrated that there is also sharp temporal compartmentalization, with little or no overlap in the activities of final sigma(F) and final sigma(G) or of final sigma(E) and final sigma(K). In contrast, we found no compartmentalization of the activity of the main vegetative factor, final sigma(A), which continued to be active alongside all of the sporulation-specific final sigma factors. We also found no temporal compartmentalization of expression of loci that are activated during the development of competent cells of B. subtilis, a developmental program distinct from spore formation. A possible mechanism to explain the temporal compartmentalization of final sigma(F) and final sigma(G) activities is that the anti-sigma factor SpoIIAB transfers from final sigma(G) to final sigma(F). PMID- 11606742 TI - An optomechanical transducer in the blue light receptor phototropin from Avena sativa. AB - The PHOT1 (NPH1) gene from Avena sativa specifies the blue light receptor for phototropism, phototropin, which comprises two FMN-binding LOV domains and a serine/threonine protein kinase domain. Light exposure is conducive to autophosphorylation of the protein kinase domain. We have reconstituted a recombinant LOV2 domain of A. sativa phototropin with various (13)C/(15)N-labeled isotopomers of the cofactor, FMN. The reconstituted protein samples were analyzed by NMR spectroscopy under dark and light conditions. Blue light irradiation is shown to result in the addition of a thiol group (cysteine 450) to the 4a position of the FMN chromophore. The adduct reverts spontaneously in the dark by elimination. The light-driven flavin adduct formation results in conformational modification, which was diagnosed by (1)H and (31)P NMR spectroscopy. This conformational change is proposed to initiate the transmission of the light signal via conformational modulation of the protein kinase domain conducive to autophosphorylation of NPH1. PMID- 11606743 TI - Metal ion cooperativity in ribozyme cleavage of RNA. AB - Combinations of chemical and genetic approaches were used to study the function of divalent metal ions in cleavage of RNA by the ribozyme RNase P RNA. We show that different divalent metal ions have differential effects on cleavage site recognition and rescue of cleavage activity by mixing divalent metal ions that do not promote cleavage by themselves. We conclude that efficient and correct cleavage is the result of cooperativity between divalent metal ions bound at different sites in the RNase P RNA-substrate complex. Complementation of a mutant RNase P RNA phenotype as a result of divalent metal ion replacement is demonstrated also. This finding together with other data indicate that one of the metal ions involved in this cooperativity is positioned near the cleavage site. The possibility that the Mg(2+)/Ca(2+) ratio might regulate the activity of biocatalysts that depend on RNA for activity is discussed. PMID- 11606744 TI - Metabolic rate and environmental productivity: well-provisioned animals evolved to run and idle fast. AB - Even among vertebrate species of the same body mass and higher-level taxonomic group, metabolic rates exhibit substantial differences, for which diverse explanatory factors-such as dietary energy content, latitude, altitude, temperature, and rainfall-have been postulated. A unifying underlying factor could be food availability, in turn controlled by net primary productivity (NPP) of the animal's natural environment. We tested this possibility by studying five North American species of Peromyscus mice, all of them similar in diet (generalist omnivores) and in gut morphology but differing by factors of up to 13 in NPP of their habitat of origin. We maintained breeding colonies of all five species in the laboratory under identical conditions and consuming identical diets. Basal metabolic rate (BMR) and daily ad libitum food intake both increased with NPP, which explained 88% and 90% of their variances, respectively. High metabolism mouse species from high-NPP environments were behaviorally more active than were low-metabolism species from low-NPP environments. Intestinal glucose uptake capacity also increased with NPP (and with BMR and food intake), because species of high-NPP environments had larger small intestines and higher uptake rates. For metabolic rates of our five species, the driving environmental variable is environmental productivity itself (and hence food availability), rather than temporal variability of productivity. Thus, species that have evolved in the presence of abundant food run their metabolism "fast," both while active and while idling, as compared with species of less productive environments, even when all species are given access to unlimited food. PMID- 11606745 TI - The nature of the active suppression of responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered by different routes. AB - Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T-cell regulated, antibody-mediated diseases. Peptides p195-212 and p259-271 of the human acetylcholine receptor (AChR) alpha-subunit, were previously shown to be immunodominant T cell epitopes in MG patients as well as in SJL and BALB/c mice, respectively. A dual altered peptide ligand (APL) composed of the two single amino acid analogs of the myasthenogenic peptides was shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthermore, the dual APL was shown to down-regulate the clinical manifestations of an established EAMG in C57BL/6 mice injected with Torpedo AChR (TAChR). In the present study we attempted the elucidation of the mechanism(s) by which the dual APL down regulates EAMG-associated responses. It is shown here that the dual APL acts by actively suppressing, in a specific manner, myasthenogenic T cell responses. The active suppression is mediated, at least partially, by the up-regulation of the secretion of TGF-beta following administration of the dual APL. The up-regulated secretion of TGF-beta is accompanied by down-regulation of IFN-gamma and IL-2 [T helper (Th) 1-type cytokine] secretion and by an up-regulation of IL-10 secretion (Th2-type cytokine). Furthermore, the inhibitory effect of the dual APL could be adoptively transferred to p195-212 or TAChR-immunized mice. The down-regulation of IL-2 secretion and the ability of recombinant IL-2 to rescue lymph node cells of mice treated with the dual APL from a state of unresponsiveness suggests that the dual APL acts also, at least partially, by causing the cells to undergo anergy. PMID- 11606746 TI - Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays. AB - To identify new Drosophila genes involved in the immune response, we monitored the gene expression profile of adult flies in response to microbial infection by using high-density oligonucleotide microarrays encompassing nearly the full Drosophila genome. Of 13,197 genes tested, we have characterized 230 induced and 170 repressed by microbial infection, most of which had not previously been associated with the immune response. Many of these genes can be assigned to specific aspects of the immune response, including recognition, phagocytosis, coagulation, melanization, activation of NF-kappaB transcription factors, synthesis of antimicrobial peptides, production of reactive oxygen species, and regulation of iron metabolism. Additionally, we found a large number of genes with unknown function that may be involved in control and execution of the immune response. Determining the function of these genes represents an important challenge for improving our knowledge of innate immunity. Complete results may be found at http://www.fruitfly.org/expression/immunity/. PMID- 11606747 TI - Formation of supramolecular activation clusters on fresh ex vivo CD8+ T cells after engagement of the T cell antigen receptor and CD8 by antigen-presenting cells. AB - Upon productive interaction of CD4 T cells with antigen-presenting cells (APCs), receptors and intracellular proteins translocate and form spatially segregated supramolecular activation clusters (SMACs). It is not known whether SMACs are required for CD8 T cell activation. CD8 T cells, unlike CD4 T cells, can be activated by a single peptide-MHC molecule, or by purified monovalent recombinant peptide-MHC molecules. We studied, by three-dimensional digital microscopy, cell conjugates of fresh ex vivo CD8 T cells (obtained from OT-1 mice, which are transgenic for T cell antigen receptor reactive with the complex of H-2K(b) and the ovalbumin octapeptide SIINFEKL) and peptide-pulsed APCs. Remarkably, even in T cell:APC conjugates that were formed in the presence of the lowest concentration of peptide that was sufficient to elicit T cell proliferation and IFN-gamma production; the theta isoform of protein kinase C was clustered in a central SMAC, and lymphocyte function-associated antigen 1 and talin were clustered in the peripheral SMAC. Conjugation of T cells to APCs that were pulsed with concentrations of peptide smaller than that required to activate T cells was greatly reduced, and SMACs were not formed at all. APCs expressing mutant H-2K(b) (Lys(227)) molecules that do not bind CD8 were unable to form stable conjugates with these T cells, even at high peptide concentrations. Thus, although CD8 and CD4 T cells may display different sensitivity to the concentration and oligomerization of surface receptors, SMACs are formed and seem to be required functionally in both cell types. However, unlike CD4 T cells, which can form SMACs without CD4, CD8 T cells from OT-1 transgenic mice depend on their coreceptor, CD8, for the proper formation of SMACs. PMID- 11606748 TI - p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis. AB - Full-term pregnancy early in reproductive life is protective against breast cancer in women. Pregnancy also provides protection in animals against carcinogen induced breast cancer, and this protection can be mimicked by using the hormones estrogen and progesterone. The molecular mechanisms that form the basis for this protective effect have not been elucidated. On the basis of our results, we propose a cell-fate hypothesis. At a critical period in adolescence the hormonal milieu of pregnancy affects the developmental fate of a subset of mammary epithelial cells and its progeny, which results in persistent differences in molecular pathways between the epithelial cells of hormone-treated and mature virgin mammary glands. These changes in turn dictate the proliferative response to carcinogen challenge and include a block in carcinogen-induced increase in mammary epithelial cell proliferation and an increased and sustained expression of nuclear p53 in the hormone-treated mammary gland. This hormone-induced nuclear p53 is transcriptionally active as evidenced by increased expression of mdm2 and p21 (CIP1/WAF1). Importantly, exposure to perphenazine, a compound that induces mammary gland differentiation but does not confer protection, does not induce p53 expression, indicating that p53 is not a differentiation marker. The proliferative block and induction of p53 are operative in both rats and mice, results that support the generality of the proposed hypothesis. PMID- 11606749 TI - Oligomerization of the integrin alphaIIbbeta3: roles of the transmembrane and cytoplasmic domains. AB - Integrins are a family of alpha/beta heterodimeric membrane proteins, which mediate cell-cell and cell-matrix interactions. The molecular mechanisms by which integrins are activated and cluster are currently poorly understood. One hypothesis posits that the cytoplasmic tails of the alpha and beta subunits interact strongly with one another in a 1:1 interaction, and that this interaction is modulated in the course of the activation of alphaIIbbeta3 [Hughes, P. E., et al. (1996) J. Biol. Chem. 271, 6571-6574]. To examine the structural basis for this interaction, protein fragments encompassing the transmembrane helix plus cytoplasmic tails of the alpha and beta subunits of alphaIIbbeta3 were expressed and studied in phospholipid micelles at physiological salt concentrations. Analyses of these fragments by analytical ultracentrifugation, NMR, circular dichroism, and electrophoresis indicated that they had very little or no tendency to interact with one another. Instead, they formed homomeric interactions, with the alpha- and beta-fragments forming dimers and trimers, respectively. Thus, these regions of the protein structure may contribute to the clustering of integrins that accompanies cellular adhesion. PMID- 11606750 TI - Deamidation of human proteins. AB - Deamidation of asparaginyl and glutaminyl residues causes time-dependent changes in charge and conformation of peptides and proteins. Quantitative and experimentally verified predictive calculations of the deamidation rates of 1,371 asparaginyl residues in a representative collection of 126 human proteins have been performed. These rates suggest that deamidation is a biologically relevant phenomenon in a remarkably large percentage of human proteins. PMID- 11606751 TI - Gambicin: a novel immune responsive antimicrobial peptide from the malaria vector Anopheles gambiae. AB - A novel mosquito antimicrobial peptide, gambicin, and the corresponding gene were isolated in parallel through differential display-PCR, an expressed sequence tag (EST) project, and characterization of an antimicrobial activity in a mosquito cell line by reverse-phase chromatography. The 616-bp gambicin ORF encodes an 81 residue protein that is processed and secreted as a 61-aa mature peptide containing eight cysteines engaged in four disulfide bridges. Gambicin lacks sequence homology with other known proteins. Like other Anopheles gambiae antimicrobial peptide genes, gambicin is induced by natural or experimental infection in the midgut, fatbody, and hemocyte-like cell lines. Within the midgut, gambicin is predominantly expressed in the anterior part. Both local and systemic gambicin expression is induced during early and late stages of natural malaria infection. In vitro experiments showed that the 6.8-kDa mature peptide can kill both Gram-positive and Gram-negative bacteria, has a morphogenic effect on a filamentous fungus, and is marginally lethal to Plasmodium berghei ookinetes. An oxidized form of gambicin isolated from the cell line medium was more active against bacteria than the nonoxidized form from the same medium. PMID- 11606752 TI - Redundant control of rereplication in fission yeast. AB - The initiation of DNA replication at replication origins in eukaryotic cells is tightly controlled to ensure that the genome is duplicated only once each cell cycle. We present evidence that in fission yeast, independent regulation of two essential components of the initiation complex, Cdc18 and Cdt1, contributes to the prevention of reinitiation of DNA replication. Cdc18 is negatively controlled by cyclin-dependent kinase (CDK) phosphorylation, but low level expression of a mutant form of Cdc18 lacking CDK phosphorylation sites (Cdc18(CDK)) is not sufficient to induce rereplication. Similar to Cdc18, Cdt1 is expressed periodically in the cell cycle, accumulating in the nucleus in G(1) and declining in G(2). When Cdt1 is expressed constitutively from an ectopic promoter, it accumulates in the nucleus throughout the cell cycle but does not promote reinitiation. However, constitutive expression of Cdt1, together with Cdc18(CDK), is sufficient to induce extra rounds of DNA replication in the absence of mitosis. Significantly greater levels of rereplication can be induced by coexpression of Cdc18(CDK) and a Cdt1 mutant lacking a conserved C-terminal motif. In contrast, uncontrolled DNA replication does not occur when either mutant protein is expressed in the absence of the other. Constitutive expression of wild-type or mutant Cdt1 also leads to an increase in the levels of Cdc18(CDK), possibly as a result of increased protein stability. Our data are consistent with the hypothesis that control of rereplication depends on a redundant mechanism in which negative regulation of Cdt1 functions in parallel with the negative regulation of Cdc18. PMID- 11606753 TI - Intermediates in V(D)J recombination: a stable RAG1/2 complex sequesters cleaved RSS ends. AB - Rearrangement of gene segments to generate antigen receptor coding regions depends on the RAG1/2 recombinase, which assembles a synaptic complex between two DNA signal sequences and then cleaves the DNA directly adjacent to the paired signals. After coupled cleavage of complementary signal sequences, virtually all of the cleaved signal ends remained associated with RAG1/2 in stable complexes. These signal end complexes were distinct from various precleavage RAG1/2 signal complexes in that they were resistant to treatment with heparin. A mammalian joining apparatus consisting of purified Ku70/86, XRCC4, and DNA ligase IV proteins was sufficient to join deproteinized cleaved ends, but retention of signal sequences within the signal end complex blocked access to the DNA ends and prevented their joining by these proteins. Sequestration of cleaved ends within the signal end complex would account for the persistence of these ends in the cell after cleavage and may explain why they do not normally activate the DNA damage-dependent cell cycle checkpoint. PMID- 11606754 TI - Water magnetic relaxation dispersion in biological systems: the contribution of proton exchange and implications for the noninvasive detection of cartilage degradation. AB - Magnetic relaxation has been used extensively to study and characterize biological tissues. In particular, spin-lattice relaxation in the rotating frame (T(1rho)) of water in protein solutions has been demonstrated to be sensitive to macromolecular weight and composition. However, the nature of the contribution from low frequency processes to water relaxation remains unclear. We have examined this problem by studying the water T(1rho) dispersion in peptide solutions ((14)N- and (15)N-labeled), glycosaminoglycan solutions, and samples of bovine articular cartilage before and after proteoglycan degradation. We find in model systems and tissue that hydrogen exchange from NH and OH groups to water dominates the low frequency water T(1rho) dispersion, in the context of the model used to interpret the relaxation data. Further, low frequency dispersion changes are correlated with loss of proteoglycan from the extra-cellular matrix of articular cartilage. This finding has significance for the noninvasive detection of matrix degradation. PMID- 11606755 TI - Mechanism of indinavir-induced hyperbilirubinemia. AB - Indinavir is a viral protease inhibitor used for the treatment of HIV infection. Unconjugated hyperbilirubinemia develops in up to 25% of patients receiving indinavir, prompting drug discontinuation and further clinical evaluation in some instances. We postulated that this side-effect is due to indinavir-mediated impairment of bilirubin UDP-glucuronosyltransferase (UGT) activity and would be most pronounced in individuals with reduced hepatic enzyme levels, as occurs in approximately 10% of the population manifesting Gilbert's syndrome. This hypothesis was tested in vitro, in the Gunn rat model of UGT deficiency, and in HIV-infected patients with and without the Gilbert's polymorphism. Indinavir was found to competitively inhibit UGT enzymatic activity (K(I) = 183 microM) while concomitantly inducing hepatic bilirubin UGT mRNA and protein expression. Although oral indinavir increased plasma bilirubin levels in wild-type and heterozygous Gunn rats, the mean rise was significantly greater in the latter group of animals. Similarly, serum bilirubin increased by a mean of 0.34 mg/dl in indinavir-treated HIV patients lacking the Gilbert's polymorphism versus 1.45 mg/dl in those who were either heterozygous or homozygous for the mutant allele. Whereas saquinavir also competitively inhibits UGT activity, this drug has not been associated with hyperbilirubinemia, most likely because of the higher K(I) (360 microM) and substantially lower therapeutic levels as compared with indinavir. Taken together, these findings indicate that elevations in serum unconjugated bilirubin associated with indinavir treatment result from direct inhibition of bilirubin-conjugating activity. PMID- 11606756 TI - Calcineurin controls nerve activity-dependent specification of slow skeletal muscle fibers but not muscle growth. AB - Nerve activity can induce long-lasting, transcription-dependent changes in skeletal muscle fibers and thus affect muscle growth and fiber-type specificity. Calcineurin signaling has been implicated in the transcriptional regulation of slow muscle fiber genes in culture, but the functional role of calcineurin in vivo has not been unambiguously demonstrated. Here, we report that the up regulation of slow myosin heavy chain (MyHC) and a MyHC-slow promoter induced by slow motor neurons in regenerating rat soleus muscle is prevented by the calcineurin inhibitors cyclosporin A (CsA), FK506, and the calcineurin inhibitory protein domain from cain/cabin-1. In contrast, calcineurin inhibitors do not block the increase in fiber size induced by nerve activity in regenerating muscle. The activation of MyHC-slow induced by direct electrostimulation of denervated regenerating muscle with a continuous low frequency impulse pattern is blocked by CsA, showing that calcineurin function in muscle fibers and not in motor neurons is responsible for nerve-dependent specification of slow muscle fibers. Calcineurin is also involved in the maintenance of the slow muscle fiber gene program because in the adult soleus muscle, cain causes a switch from MyHC slow to fast-type MyHC-2X and MyHC-2B gene expression, and the activity of the MyHC-slow promoter is inhibited by CsA and FK506. PMID- 11606757 TI - Viruses from extreme thermal environments. AB - Viruses of extreme thermophiles are of great interest because they serve as model systems for understanding the biochemistry and molecular biology required for life at high temperatures. In this work, we report the discovery, isolation, and preliminary characterization of viruses and virus-like particles from extreme thermal acidic environments (70-92 degrees C, pH 1.0-4.5) found in Yellowstone National Park. Six unique particle morphologies were found in Sulfolobus enrichment cultures. Three of the particle morphologies are similar to viruses previously isolated from Sulfolobus species from Iceland and/or Japan. Sequence analysis of their viral genomes suggests that they are related to the Icelandic and Japanese isolates. In addition, three virus particle morphologies that had not been previously observed from thermal environments were found. These viruses appear to be completely novel in nature. PMID- 11606758 TI - Signal interactions between nitric oxide and reactive oxygen intermediates in the plant hypersensitive disease resistance response. AB - Nitric oxide (NO) and reactive oxygen intermediates (ROIs) play key roles in the activation of disease resistance mechanisms both in animals and plants. In animals NO cooperates with ROIs to kill tumor cells and for macrophage killing of bacteria. Such cytotoxic events occur because unregulated NO levels drive a diffusion-limited reaction with O(2)(-) to generate peroxynitrite (ONOO(-)), a mediator of cellular injury in many biological systems. Here we show that in soybean cells unregulated NO production at the onset of a pathogen-induced hypersensitive response (HR) is not sufficient to activate hypersensitive cell death. The HR is triggered only by balanced production of NO and ROIs. Moreover, hypersensitive cell death is activated after interaction of NO not with O(2)- but with H(2)O(2) generated from O(2)(-) by superoxide dismutase. Increasing the level of O(2)(-) reduces NO-mediated toxicity, and ONOO(-) is not a mediator of hypersensitive cell death. During the HR, superoxide dismutase accelerates O(2)( ) dismutation to H(2)O(2) to minimize the loss of NO by reaction with O(2)(-) and to trigger hypersensitive cell death through NO/H(2)O(2) cooperation. However, O(2)(-) rather than H(2)O(2) is the primary ROI signal for pathogen induction of glutathione S-transferase, and the rates of production and dismutation of O(2)(-) generated during the oxidative burst play a crucial role in the modulation and integration of NO/H(2)O(2) signaling in the HR. Thus although plants and animals use a similar repertoire of signals in disease resistance, ROIs and NO are deployed in strikingly different ways to trigger host cell death. PMID- 11606760 TI - Functional magnetic resonance imaging of reorganization in rat brain after stroke. AB - Functional recovery after stroke has been associated with brain plasticity; however, the exact relationship is unknown. We performed behavioral tests, functional MRI, and histology in a rat stroke model to assess the correlation between temporal changes in sensorimotor function, brain activation patterns, cerebral ischemic damage, and cerebrovascular reactivity. Unilateral stroke induced a large ipsilateral infarct and acute dysfunction of the contralateral forelimb, which significantly recovered at later stages. Forelimb impairment was accompanied by loss of stimulus-induced activation in the ipsilesional sensorimotor cortex; however, local tissue and perfusion were only moderately affected and cerebrovascular reactivity was preserved in this area. At 3 days after stroke, extensive activation-induced responses were detected in the contralesional hemisphere. After 14 days, we found reduced involvement of the contralesional hemisphere, and significant responses in the infarction periphery. Our data suggest that limb dysfunction is related to loss of brain activation in the ipsilesional sensorimotor cortex and that restoration of function is associated with biphasic recruitment of peri- and contralesional functional fields in the brain. PMID- 11606759 TI - Degradation of the kinesin Kip1p at anaphase onset is mediated by the anaphase promoting complex and Cdc20p. AB - Kip1p of Saccharomyces cerevisiae is a bipolar kinesin in the conserved bimC kinesin subfamily that mediates mitotic spindle-pole separation. Here, we show that Kip1p is regulated immediately after anaphase initiation by its rapid degradation. Degradation required the ubiquitin protein ligase called the anaphase-promoting complex, the anaphase-promoting complex activating protein Cdc20, and a unique 43-aa sequence in Kip1p. Degradation also required import of Kip1p into the nucleus, but occurred independently of spindle association. A mutation that stabilized Kip1p impaired anaphase progression. The timing of degradation suggests that Kip1p functions primarily during spindle assembly and metaphase, and that Kip1p degradation facilitates structural changes in the mitotic spindle as anaphase progresses. PMID- 11606761 TI - Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. PMID- 11606762 TI - Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection. AB - In schistosomiasis mansoni, parasite eggs precipitate an intrahepatic granulomatous and fibrosing inflammatory process, which is mediated by, and dependent on, MHC class II-restricted CD4 T helper (Th) lymphocytes specific for schistosome egg antigens (SEA). In the mouse model of the disease, CBA mice develop large granulomas, whereas in C57BL/6 (BL/6) mice these granulomas are significantly smaller. To further investigate how the prevailing cytokine environment influences the development of the egg-induced immunopathology, we immunized the low-pathology BL/6 mice with SEA in complete Freund's adjuvant (CFA) once before, and once again during, the course of a 7-week infection. This immunization caused a pronounced Th1 shift in the SEA-specific CD4 T cell response, which was detected in the mesenteric lymph nodes (MLNs) and spleens, as well as in the granulomatous lesions themselves. The immunized mice displayed a dramatic enhancement of hepatic egg-induced immunopathology manifested by a marked increase in granuloma size and parenchymal inflammation, leading to early death. Control mice immunized with equivalent amounts of SEA or CFA alone displayed the smaller hepatic lesions in a Th2-dominant environment typically seen in the unimmunized BL/6 mice. Analysis of granuloma and MLN lymphocytes from the SEA/CFA-immunized mice revealed that the proportion of CD4 T cells was unchanged in comparison with the control BL/6 groups and remained significantly lower than that seen in the normally high-pathology CBA strain. These results suggest that the shift toward Th1-type cytokine production by a numerically stable population of CD4 T cells correlates with severe exacerbation of immunopathology in schistosomiasis. PMID- 11606763 TI - Comprehensive identification of conditionally essential genes in mycobacteria. AB - An increasing number of microbial genomes have been completely sequenced, and the identified genes are categorized based on their homology to genes of known function. However, the function of a large number of genes cannot be determined on this basis alone. Here, we describe a technique, transposon site hybridization (TraSH), which allows rapid functional characterization by identifying the complete set of genes required for growth under different conditions. TraSH combines high-density insertional mutagenesis with microarray mapping of pools of mutants. We have made large pools of independent transposon mutants in mycobacteria by using a mariner-based transposon and efficient phage transduction. By using TraSH, we have defined the set of genes required for growth of Mycobacterium bovis bacillus Calmette-Guerin on minimal but not rich medium. Genes of both known and unknown functions were identified. Of the genes with known functions, nearly all were involved in amino acid biosynthesis. TraSH is a powerful method for categorizing gene function that should be applicable to a variety of microorganisms. PMID- 11606764 TI - Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory. AB - Activation of central glucocorticoid receptors caused by the stress that is associated with a learning task facilitates storage of the acquired information. The molecular mechanism underlying this phenomenon is entirely unknown. Glucocorticoid receptors can influence transcription both through DNA binding dependent and -independent mechanisms. To assess the importance of these two modes of action for spatial memory, we here used male mutant mice in which homodimerization and DNA binding of the glucocorticoid receptor is largely prevented (GR(dim/dim)) while protein-protein interactions still can take place. These mice showed a selective impairment of spatial memory in the water maze. Locomotion and anxiety-related parameters measured in an open field and a light/dark preference task were comparable for mutant and control mice. Mutant mice released more corticosterone than control mice under basal resting conditions and in response to swimming, which could have influenced memory processes of the mice. However, mimicking the task-related increase in corticosterone by supplementary injection of corticosterone (250 microg/kg, i.p.) in adrenalectomized mice, resulting in equal plasma corticosterone concentrations in both genotypes, improved spatial memory of control mice but had no effect on mutant mice. These findings suggest that task-related facilitating effects of corticosterone on spatial memory indeed depend on DNA binding of the glucocorticoid receptor rather than on protein-protein interactions of the receptor with other transcription factors. Although it cannot be excluded that both processes are involved in a coordinated way, interrupting the DNA-binding capacity of the receptor is sufficient to induce impairment. PMID- 11606765 TI - Paternity and relatedness in wild chimpanzee communities. AB - The genetic structure of three contiguous wild chimpanzee communities in West Africa was examined to determine the extent to which the community, the mixed-sex social unit of chimpanzees, represents a closed reproductive unit. An analysis of paternity for 41 offspring resulted in 34 cases of paternity assignment to an adult male belonging to the same community. Among the 14 offspring for which all potential within-community fathers have been tested, one likely case of extra group paternity (EGP) has been identified, suggesting an incidence of EGP of 7%. This more extensive analysis contradicts a previous genetic study of the Tai chimpanzees that inferred 50% extra-group fathers. We suggest, based on direct comparison of results for 33 individuals at 1 microsatellite locus and direct comparison of paternity assignments for 11 offspring, that the error rate in the previous study was too high to produce accurate genotypes and assignments of paternity and hence caused the false inference of a high rate of EGP. Thus, the community is the primary but not exclusive unit for reproduction in wild chimpanzees, and females do not typically reproduce with outside males. Despite the inferred low level of gene flow from extra-community males, relatedness levels among the community males are not significantly higher than among community females, and the distribution of genetic relationships within the group suggests that, rather than a primarily male-bonded social structure, the group is bonded through relationships between males and females. Kinship may explain cooperative behaviors directed against other communities, but is unlikely to explain the high levels of affiliation and cooperation seen for male within community interactions. PMID- 11606766 TI - A new class of oxidosqualene cyclases directs synthesis of antimicrobial phytoprotectants in monocots. AB - Many plants synthesize antimicrobial secondary metabolites as part of their normal program of growth and development, often sequestering them in tissues where they may protect against microbial attack. These include glycosylated triterpenoids (saponins), natural products that are exploited by man for a variety of purposes including use as drugs [Hostettmann, K. & Marston, A. (1995) Saponins (Cambridge Univ. Press, Cambridge, U.K.)]. Very little is known about the genes required for the synthesis of this important family of secondary metabolites in plants. Here we show the novel oxidosqualene cyclase AsbAS1 catalyzes the first committed step in the synthesis of antifungal triterpenoid saponins that accumulate in oat roots. We also demonstrate that two sodium azide generated saponin-deficient mutants of oat, which define the Sad1 genetic complementation group, are defective in the gene encoding this enzyme and provide molecular genetic evidence indicating a direct link between AsbAS1, triterpenoid saponin biosynthesis, and disease resistance. Orthologs of AsbAS1 are absent from modern cereals and may have been lost during selection, raising the possibility that this gene could be exploited to enhance disease resistance in crop plants. PMID- 11606767 TI - HIV-1 protease cleaves eukaryotic initiation factor 4G and inhibits cap-dependent translation. AB - Several animal viruses inhibit host protein synthesis, but only some members of the picornavirus group are known to do so by cleaving translation initiation factor eIF4G. Here we report that infection of human CD4(+) cells with HIV-1 also leads to proteolysis of eIF4G and profound inhibition of cellular translation. Purified HIV-1 protease directly cleaves eIF4GI at positions 678, 681, and 1086, separating the three domains of this initiation factor. Proteolysis of eIF4GI by HIV-1 protease, as with poliovirus 2A protease, inhibits protein synthesis directed by capped mRNAs but allows internal ribosome entry site-driven translation. These findings indicate that HIV-1, a member of retrovirus group, shares with picornaviruses the capacity to proteolyze eIF4G. PMID- 11606768 TI - Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. AB - We have identified two chemical series of compounds acting as selective positive allosteric modulators (enhancers) of native and recombinant metabotropic glutamate 1 (mGlu1) receptors. These compounds did not directly activate mGlu1 receptors but markedly potentiated agonist-stimulated responses, increasing potency and maximum efficacy. Binding of these compounds increased the affinity of a radiolabeled glutamate-site agonist at its extracellular N-terminal binding site. Chimeric and mutated receptors were used to localize amino acids in the receptor transmembrane region critical for these enhancing properties. Finally, the compounds potentiated synaptically evoked mGlu1 receptor responses in rat brain slices. The discovery of selective positive allosteric modulators of mGlu1 receptors opens up the possibility to develop a similar class of compounds for other family 3 G protein-coupled receptors. PMID- 11606769 TI - Reactivation of proliferin gene expression is associated with increased angiogenesis in a cell culture model of fibrosarcoma tumor progression. AB - Proliferin (PLF) is an angiogenic placental hormone. We now report that PLF gene expression can also occur in a progressive fibrosarcoma mouse tumor cell model. PLF mRNA and protein are detectable at very low levels in cell lines derived from the mild noninvasive stage of tumor development. Expression is greatly augmented in cell lines from the aggressively invasive stage of development, a stage at which the tumor becomes highly angiogenic, and PLF expression remains high in cell lines from the end stage of fibrosarcoma. Activator protein 1 factors present at high levels in the more invasive stages of the tumor may in part allow for increased PLF expression, as cells from the mild stage in which c-jun and junB are stably expressed secrete levels of PLF comparable to that of the advanced stages. Secreted PLF protein is functionally important in tumor cell angiogenic activity, as demonstrated by the reduction of angiogenic activity in fibrosarcoma cell culture medium by immunodepletion of PLF. These results suggest that an extraembryonic genetic program, which has evolved to support fetal growth, may be reactivated in certain tumors and contribute to tumor growth. PMID- 11606770 TI - A genome-wide screen in Saccharomyces cerevisiae for genes affecting UV radiation sensitivity. AB - The recent completion of the deletion of essentially all of the ORFs in yeast is an important new resource for identifying the phenotypes of unknown genes. Each ORF is replaced with a cassette containing unique tag sequences that allow rapid parallel analysis of strains in a pool by using hybridization to a high-density oligonucleotide array. We examined the utility of this system to identify genes conferring resistance to UV irradiation by using a pool of 4,627 individual homozygous deletion strains (representing deletions of all nonessential genes). We identified most of the nonessential genes previously shown to be involved in nucleotide excision repair, in cell cycle checkpoints, in homologous recombination, and in postreplication repair after UV damage. We also identified and individually confirmed, by replacing the genes, three new genes, to our knowledge not previously reported to confer UV sensitivity when deleted. Two of these newly identified genes have human orthologs associated with cancer, demonstrating the potential of this system to uncover human genes affecting sensitivity to DNA-damaging agents and genes potentially involved in cancer formation. PMID- 11606772 TI - Chaos and stability of the solar system. AB - Over the last two decades, there has come about a recognition that chaotic dynamics is pervasive in the solar system. We now understand that the orbits of small members of the solar system-asteroids, comets, and interplanetary dust-are chaotic and undergo large changes on geological time scales. Are the major planets' orbits also chaotic? The answer is not straightforward, and the subtleties have prompted new questions. PMID- 11606773 TI - Multiscale computing. AB - Multiscale computing (MSC) involves the computation, manipulation, and analysis of information at different resolution levels. Widespread use of MSC algorithms and the discovery of important relationships between different approaches to implementation were catalyzed, in part, by the recent interest in wavelets. We present two examples that demonstrate how MSC can help scientists understand complex data. The first is from acoustical signal processing and the second is from computer graphics. PMID- 11606774 TI - Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction. AB - Homocyst(e)ine (Hcy) inhibits the expression of the antioxidant enzyme cellular glutathione peroxidase (GPx-1) in vitro and in vivo, which can lead to an increase in reactive oxygen species that inactivate NO and promote endothelial dysfunction. In this study, we tested the hypothesis that overexpression of GPx-1 can restore the normal endothelial phenotype in hyperhomocyst(e)inemic states. Heterozygous cystathionine beta-synthase-deficient (CBS((-/+))) mice and their wild-type littermates (CBS((+/+))) were crossbred with mice that overexpress GPx 1 [GPx-1((tg+)) mice]. GPx-1 activity was 28% lower in CBS((-/+))/GPx-1((tg-)) compared with CBS((+/+))/GPx-1((tg-)) mice (P < 0.05), and CBS((-/+)) and CBS((+/+)) mice overexpressing GPx-1 had 1.5-fold higher GPx-1 activity compared with GPx-1 nontransgenic mice (P < 0.05). Mesenteric arterioles of CBS((-/+))/GPx 1((tg-)) mice showed vasoconstriction to superfusion with beta-methacholine and bradykinin (P < 0.001 vs. all other groups), whereas nonhyperhomocyst(e)inemic mice [CBS((+/+))/GPx-1((tg-)) and CBS((+/+))/GPx-1((tg+)) mice] demonstrated dose dependent vasodilation in response to both agonists. Overexpression of GPx-1 in hyperhomocyst(e)inemic mice restored the normal endothelium-dependent vasodilator response. Bovine aortic endothelial cells (BAEC) were transiently transfected with GPx-1 and incubated with dl-homocysteine (HcyH) or l-cysteine. HcyH incubation decreased GPx-1 activity in sham-transfected BAEC (P < 0.005) but not in GPx-1-transfected cells. Nitric oxide release from BAEC was significantly decreased by HcyH but not cysteine, and GPx-1 overexpression attenuated this decrease. These findings demonstrate that overexpression of GPx-1 can compensate for the adverse effects of Hcy on endothelial function and suggest that the adverse vascular effects of Hcy are at least partly mediated by oxidative inactivation of NO. PMID- 11606775 TI - Kinetics of duplex formation for individual DNA strands within a single protein nanopore. AB - A single oligonucleotide was covalently attached to a genetically engineered subunit of the heptameric protein pore, alpha-hemolysin, to allow DNA duplex formation inside the pore lumen. Single-channel current recording was used to study the properties of the modified pore. On addition of an oligonucleotide 8 bases in length and with a sequence complementary to the tethered DNA strand, current blockades with durations of hundreds of milliseconds occurred, representing hybridization events of individual oligonucleotides to the tethered DNA strand. Kinetic constants for DNA duplex formation at the single molecule level were derived and found to be consistent with established literature values for macroscopic duplex formation. The resultant equilibrium constant for duplex formation in the nanopore was found to be close to the experimentally derived constant for duplex formation in solution. A good agreement between the equilibrium constants for duplex formation in the nanopore and in solution was also found for two other oligonucleotide pairs. In addition, the nanopore recordings revealed details of the kinetics difficult to obtain by conventional methods, like surface plasmon resonance, which measure ensemble properties. By investigating the temperature dependence of DNA duplex formation at the single molecule level, the standard enthalpy and entropy of the interaction could be obtained. PMID- 11606777 TI - Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals. AB - Oxidation of proteins by reactive oxygen species is associated with aging, oxidative stress, and many diseases. Although free and protein-bound methionine residues are particularly sensitive to oxidation to methionine sulfoxide derivatives, these oxidations are readily repaired by the action of methionine sulfoxide reductase (MsrA). To gain a better understanding of the biological roles of MsrA in metabolism, we have created a strain of mouse that lacks the MsrA gene. Compared with the wild type, this mutant: (i) exhibits enhanced sensitivity to oxidative stress (exposure to 100% oxygen); (ii) has a shorter lifespan under both normal and hyperoxic conditions; (iii) develops an atypical (tip-toe) walking pattern after 6 months of age; (iv) accumulates higher tissue levels of oxidized protein (carbonyl derivatives) under oxidative stress; and (v) is less able to up-regulate expression of thioredoxin reductase under oxidative stress. It thus seems that MsrA may play an important role in aging and neurological disorders. PMID- 11606776 TI - Drosophila MyD88 is an adapter in the Toll signaling pathway. AB - Toll-like receptors comprise a family of cell surface receptors that play a crucial role in the innate immune recognition of both Drosophila and mammals. Previous studies have shown that Drosophila Toll-1 mediates the induction of antifungal peptides during fungal infection of adult flies. Through genetic studies, Tube, Pelle, Cactus, and Dif have been identified as downstream components of the Toll-1 signaling pathway. Here we report characterization of a Drosophila homologue of human MyD88, dMyD88. We show that dMyD88 is an adapter in the Toll signaling pathway that associates with both the Toll receptor and the downstream kinase Pelle. Expression of dMyD88 in S2 cells strongly induced activity of a Drosomycin reporter gene, whereas a dominant-negative version of dMyD88 potently inhibited Toll-mediated signaling. We also show that dMyD88 associates with the death domain-containing adapter Drosophila Fas-associated death domain-containing protein (dFADD), which in turn interacts with the apical caspase Dredd. This pathway links a cell surface receptor to an apical caspase in invertebrate cells and therefore suggests that the Toll-mediated pathway of caspase activation may be the evolutionary ancestor of the death receptor mediated pathway for apoptosis induction in mammals. PMID- 11606778 TI - Transgenic mice produced by retroviral transduction of male germ-line stem cells. AB - Male germ-line stem cells are the only cell type in postnatal mammals that have the capability to self-renew and to contribute genes to the next generation. Genetic modification of these cells would provide an opportunity to study the biology of their complex self-renewal and differentiation processes, as well as enable the generation of transgenic animals in a wide range of species. Although retroviral vectors have been used as an efficient method to introduce genes into a variety of cell types, postnatal male germ-line stem cells have seemed refractory to direct infection by these viruses. In addition, expression of genes transduced into several types of stem cells, such as embryonic or hematopoietic, is often attenuated or silenced. We demonstrate here that in vitro retroviral mediated gene delivery into spermatogonial stem cells of both adult and immature mice results in stable integration and expression of a transgene in 2-20% of stem cells. After transplantation of the transduced stem cells into the testes of infertile recipient mice, approximately 4.5% of progeny from these males are transgenic, and the transgene is transmitted to and expressed in subsequent generations. Therefore, there is no intrinsic barrier to retroviral transduction in this stem cell, and transgene expression is not extinguished after transmission to progeny. PMID- 11606779 TI - IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation. AB - IL-1 beta-converting enzyme (ICE; caspase-1) is the intracellular protease that cleaves the precursors of IL-1 beta and IL-18 into active cytokines. In the present study, the effect of ICE deficiency was evaluated during experimental colitis in mice. In acute dextran sulfate sodium-induced colitis, ICE-deficient (ICE KO) mice exhibited a greater than 50% decrease of the clinical scores weight loss, diarrhea, rectal bleeding, and colon length, whereas daily treatment with IL-1 receptor antagonist revealed a modest reduction in colitis severity. To further characterize the function of ICE and its role in intestinal inflammation, chronic colitis was induced over a 30-day time period. During this chronic time course, ICE KO mice exhibited a near complete protection, as reflected by significantly reduced clinical scores and almost absent histological signs of colitis. Consistently, colon shortening occurred only in dextran sulfate sodium exposed wild-type mice but not in ICE KO mice. Protection was accompanied by reduced spontaneous release of the proinflammatory cytokines IL-18, IL-1 beta, and IFN-gamma from total colon cultures. In addition, flow cytometric analysis of isolated mesenteric lymph node cells revealed evidence of reduced cell activation in ICE KO mice as evaluated by surface expression of CD3 CD69 and CD4 CD25. We conclude that inhibition of ICE represents a novel anti-inflammatory strategy for intestinal inflammation. PMID- 11606781 TI - Engineering salt-tolerant Brassica plants: characterization of yield and seed oil quality in transgenic plants with increased vacuolar sodium accumulation. AB - Transgenic Brassica napus plants overexpressing AtNHX1, a vacuolar Na(+)/H(+) antiport from Arabidopsis thaliana, were able to grow, flower, and produce seeds in the presence of 200 mM sodium chloride. Although the transgenic plants grown in high salinity accumulated sodium up to 6% of their dry weight, growth of the these plants was only marginally affected by the high salt concentration. Moreover, seed yields and the seed oil quality were not affected by the high salinity of the soil. Our results demonstrate the potential use of these transgenic plants for agricultural use in saline soils. Our findings, showing that the modification of a single trait significantly improved the salinity tolerance of this crop plant, suggest that with a combination of breeding and transgenic plants it could be possible to produce salt-tolerant crops with far fewer target traits than had been anticipated. PMID- 11606780 TI - Sequential recruitment of steroid receptor coactivator-1 (SRC-1) and p300 enhances progesterone receptor-dependent initiation and reinitiation of transcription from chromatin. AB - Employing a cell-free chromatin transcription system that recapitulates progesterone receptor (PR)-mediated transcription in vivo, we have investigated further the coactivator functions of steroid receptor coactivator-1 (SRC-1) in terms of its functional domains as well as cooperation with other coactivators in PR transactivation. By analyzing wild-type and mutant SRC-1 with liganded PR in the chromatin transcription system in vitro, the basic helix-loop-helix/Per-Arnt Sim domain, the p300-binding domain, and the carboxyl-terminal region (containing the PR-binding site) of SRC-1 were shown to be important for PR transactivation. Although in context of a synthetic promoter its histone acetyltransferase activity was nonessential for PR-mediated transcription, SRC-1 was observed to act synergistically with p300 to enhance PR transactivation from chromatin. Moreover, SRC-1 and p300 were found to function cooperatively to increase the efficiency of productive transcription initiation and reinitiation. Further analysis of synergism between SRC-1 and p300 revealed an obligatory "sequential" recruitment of SRC-1 and p300 to liganded PR. Efficient recruitment of p300 required the presence of SRC-1. In addition, functional analysis of SRC-2 and SRC 3 coactivators indicated that the SRC family modulated PR transactivation from chromatin by a similar mechanism. PMID- 11606782 TI - Cross-talk between sympathetic neurons and adipocytes in coculture. AB - White adipose tissue plays an integral role in energy metabolism and is governed by endocrine, autocrine, and neural signals. Neural control of adipose metabolism is mediated by sympathetic neurons that innervate the tissue. To investigate the effects of this innervation, an ex vivo system was developed in which 3T3-L1 adipocytes are cocultured with sympathetic neurons isolated from the superior cervical ganglia of newborn rats. In coculture, both adipocytes and neurons exhibit appropriate morphology, express cell-type-specific markers, and modulate key metabolic processes in one another. Lipolysis (stimulated by beta-adrenergic agents) and leptin secretion by adipocytes are down-regulated by neurons in coculture, effects apparently mediated by neuropeptide Y (NPY). Secretion of NPY by neurons is up-regulated dramatically by the presence of adipocytes in coculture and appears to be mediated by an adipocyte-derived soluble factor. Insulin, an antilipolytic agent, down-regulates NPY secretion. Our findings suggest that an adipocyte-derived factor(s) up-regulates the secretion of NPY by sympathetic neurons, which, in turn, attenuates lipolytic energy mobilization by adipocytes. PMID- 11606783 TI - Conformation-family Monte Carlo: a new method for crystal structure prediction. AB - A new global optimization method, Conformation-family Monte Carlo, has been developed recently for searching the conformational space of macromolecules. In the present paper, we adapted this method for prediction of crystal structures of organic molecules without assuming any symmetry constraints except the number of molecules in the unit cell. This method maintains a database of low energy structures that are clustered into families. The structures in this database are improved iteratively by a Metropolis-type Monte Carlo procedure together with energy minimization, in which the search is biased toward the regions of the lowest energy families. The Conformation-family Monte Carlo method is applied to a set of nine rigid and flexible organic molecules by using two popular force fields, AMBER and W99. The method performed well for the rigid molecules and reasonably well for the molecules with torsional degrees of freedom. PMID- 11606784 TI - Identification of sites for exponential translation in living dendrites. AB - Neuronal processes contain mRNAs and membrane structures, and some forms of synaptic plasticity seem to require protein synthesis in dendrites of hippocampal neurons. To quantitate dendritic protein synthesis, we used multiphoton microscopy of green fluorescent protein synthesized in living isolated dendrites. Transfection of dendrites with mRNA encoding green fluorescent protein resulted in fluorescence that exponentially increased on stimulation with a glutamate receptor agonist; a reaction attenuated by the translation inhibitors anisomycin and emetine. Comparable experiments on whole neurons revealed that (RS)-3,5 dihydroxy-phenylglycine 0.5 H(2)O (DHPG)-stimulated fluorescence was linear in cell bodies relative to the exponential increase seen in dendrites. Detailed spatial analysis of the subdendritic distribution of fluorescence revealed "hotspots," sites of dendritic translation that were spatially stable. However, detailed temporal analysis of these hotspots revealed heterogeneous rates of translation. A double-label protocol counterstaining for ribosomes indicated that sites of "fastest" translation correlated with increased ribosome density, consistent with ribosome subunit assembly for initiation, the first step of translation. We propose that dendrites have specific sites specialized for fast translation. PMID- 11606785 TI - The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo. AB - Suppressor of Cytokine Signaling-1 (SOCS-1) is an essential physiological inhibitor of IFN-gamma signaling. Mice lacking this gene die in the early postnatal period from a disease characterized by hyperresponsiveness to endogenous IFN-gamma. The SOCS box is a C-terminal domain shared with over 30 other proteins that links SOCS proteins to an E3 ubiquitin ligase activity and the proteasome, but whether it contributes to inhibition of cytokine signaling is currently disputed. We have deleted only the SOCS box of the SOCS-1 gene in mice and show that such mice have an increased responsiveness to IFN-gamma and slowly develop a fatal inflammatory disease. These results demonstrate that deletion of the SOCS box leads to a partial loss of function of SOCS-1. PMID- 11606786 TI - Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens. AB - Chronic exposure to cocaine causes long-lasting behavioral changes associated with cocaine reinforcement and addiction. An important neural substrate for cocaine addiction is the nucleus accumbens (NAc), which receives dopaminergic input from the ventral tegmental area. Although the neural circuit of the NAc is controlled by several other neurotransmitters, their involvement in cocaine addiction remains elusive. In this investigation, we ablated cholinergic interneurons from the adult NAc with immunotoxin-mediated cell targeting and examined the role of acetylcholine transmitter in adaptive behavioral changes associated with cocaine reinforcement and addiction. Acute exposure to cocaine induced abnormal rotation in unilaterally cholinergic cell-eliminated mice. This abnormal turning was enhanced by repeated exposure of cocaine. In bilaterally cholinergic cell-eliminated mice, chronic cocaine administration induced a prominent and progressive increase in locomotor activity. Moreover, these mice showed robust conditioned place preference with a lower dose of cocaine, compared with wild-type littermates. This investigation demonstrates that acetylcholine in the NAc plays a key role in both acute and chronic actions of cocaine. PMID- 11606788 TI - Position within the host intron is critical for efficient processing of box C/D snoRNAs in mammalian cells. AB - In mammalian cells, all small nucleolar RNAs (snoRNAs) that guide rRNA modification are encoded within the introns of host genes. A database analysis of human box C/D snoRNAs revealed conservation of their intronic location, with a preference for 70-80 nt upstream of the 3' splice site. Transfection experiments showed that synthesis of gas5-encoded U75 and U76 snoRNAs dropped significantly for mutant constructs possessing longer or shorter spacers between the snoRNA and the 3' splice site. However, the position of the snoRNA did not affect splicing of the host intron. Substitution mutations within the spacer indicated that the length, but not the specific sequence, is important. A in vitro system that couples pre-mRNA splicing and processing of U75 has been developed. U75 synthesis in vitro depends on its box C and D sequences and requires an appropriate spacer length. Further mutational analyses both in vivo and in vitro, with subsequent mapping of the branch points, revealed that the critical distance is from the snoRNA coding region to the branch point, suggesting synergy between splicing and snoRNA release. PMID- 11606787 TI - Compared with saturated fatty acids, dietary monounsaturated fatty acids and carbohydrates increase atherosclerosis and VLDL cholesterol levels in LDL receptor-deficient, but not apolipoprotein E-deficient, mice. AB - Heart-healthy dietary recommendations include decreasing the intake of saturated fatty acids (SFA). However, the relative benefit of replacing SFA with monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), or carbohydrates (CARB) is still being debated. We have used two mouse models of atherosclerosis, low density lipoprotein receptor-deficient (LDLRKO) and apolipoprotein E-deficient (apoEKO) mice to measure the effects of four isocaloric diets enriched with either SFA, MUFA, PUFA, or CARB on atherosclerotic lesion area and lipoprotein levels. In LDLRKO mice, compared with the SFA diet, the MUFA and CARB diets significantly increased atherosclerosis in both sexes, but the PUFA diet had no effect. The MUFA and CARB diets also increased very low density lipoprotein-cholesterol (VLDL-C) and LDL-cholesterol (LDL-C) in males and VLDL-C levels in females. Analysis of data from LDLRKO mice on all diets showed that atherosclerotic lesion area correlated positively with VLDL-C levels (males: r = 0.47, P < 0.005; females: r = 0.52, P < 0.001). In contrast, in apoEKO mice there were no significant dietary effects on atherosclerosis in either sex. Compared with the SFA diet, the CARB diet significantly decreased VLDL-C in males and the MUFA, PUFA, and CARB diets decreased VLDL-C and the CARB diet decreased LDL-C in females. In summary, in LDLRKO mice the replacement of dietary SFA by either MUFA or CARB causes a proportionate increase in both atherosclerotic lesion area and VLDL-C. There were no significant dietary effects on atherosclerotic lesion area in apoEKO mice. These results are surprising and suggest that, depending on the underlying genotype, dietary MUFA and CARB can actually increase atherosclerosis susceptibility, probably by raising VLDL-C levels through a non-LDL receptor, apoE-dependent pathway. PMID- 11606789 TI - Invasive melanoma in Cdk4-targeted mice. AB - Many human tumors harbor mutations that result in deregulation of Cdk4 activity. Most of these mutations involve overexpression of D-type cyclins and inactivation of INK4 inhibitors. In addition, a mutation in the Cdk4 protein has been described in patients with familial melanoma (Wolfel, T., Hauer, M., Schneider, J., Serrano, M., Wolfel, C., et al. (1995) Science 269, 1281-1284; Zuo, L., Weger, J., Yang, Q., Goldstein, A. M., Tucker, M. A., et al. (1996) Nat. Genet. 12, 97-99). This mutation, R24C, renders the Cdk4 protein insensitive to inhibition by INK4 proteins including p16(INK4a), a major candidate for the melanoma susceptibility locus. Here we show that knock-in mice expressing a Cdk4 R24C allele are highly susceptible to melanoma development after specific carcinogenic treatments. These tumors do not have mutations in the p19(ARF)/p53 pathway, suggesting a specific involvement of the p16(INK4a)/Cdk4/Rb pathway in melanoma development. Moreover, by using targeted mice deficient for other INK4 inhibitors, we show that deletion of p18(INK4c) but not of p15(INK4b) confers proliferative advantage to melanocytic tumor growth. These results provide an experimental scenario to study the role of Cdk4 regulation in melanoma and to develop novel therapeutic approaches to control melanoma progression. PMID- 11606790 TI - Constructing, verifying, and dissecting the folding transition state of chymotrypsin inhibitor 2 with all-atom simulations. AB - Experimentally, protein engineering and phi-value analysis is the method of choice to characterize the structure in folding transition state ensemble (TSE) of any protein. Combining experimental phi values and computer simulations has led to a deeper understanding of how proteins fold. In this report, we construct the TSE of chymotrypsin inhibitor 2 from published phi values. Importantly, we verify, by means of multiple independent simulations, that the conformations in the TSE have a probability of approximately 0.5 to reach the native state rapidly, so the TSE consists of true transition states. This finding validates the use of transition state theory underlying all phi-value analyses. Also, we present a method to dissect and study the TSE by generating conformations that have a disrupted alpha-helix (alpha-disrupted states) or disordered beta-strands 3 and 4 (beta-disrupted states). Surprisingly, the alpha-disrupted states have a stronger tendency to fold than the beta-disrupted states, despite the higher phi values for the alpha-helix in the TSE. We give a plausible explanation for this result and discuss its implications on protein folding and design. Our study shows that, by using both experiments and computer simulations, we can gain many insights into protein folding. PMID- 11606792 TI - Self-similar intermediate asymptotics for nonlinear degenerate parabolic free boundary problems that occur in image processing. AB - In the boundary layers around the edges of images, basic nonlinear parabolic equations for image intensity used in image processing assume a special degenerate asymptotic form. An asymptotic self-similar solution to this degenerate equation is obtained in an explicit form. The solution reveals a substantially nonlinear effect-the formation of sharp steps at the edges of the images, leading to edge enhancement. Positions of the steps and the time shift parameter cannot be determined by direct construction of a self-similar solution; they depend on the initial condition of the pre-self-similar solution. The free boundary problem is formulated describing the image intensity evolution in the boundary layer. PMID- 11606791 TI - A phylogenetic approach to following West Nile virus in Connecticut. AB - The 1999 outbreak of West Nile (WN) virus in the northeastern United States was the first known natural occurrence of this flavivirus in the Western Hemisphere. In 1999 and 2000, 82 independent Connecticut WN virus isolates were cultured from nine species of birds, five species of mosquitoes, and one striped skunk. Nucleotide sequences obtained from these isolates identified 30 genetic changes, compared with WN-NY99, in a 921-nt region of the viral genome beginning at nucleotide position 205 and ending at 1125. This region encodes portions of the nucleocapsid and envelope proteins and includes the entire coding regions for the premembrane and membrane proteins. Amino acid changes occurred at seven loci in six isolates relative to the WN-NY99 strain. Although 34 of the isolates showed sequences identical to the WN-NY99 isolate, we were able to show geographical based clusters of mutations. In particular, 26 isolates were characterized by mutation of C to T at position 858. This group apparently originated in Stamford, CT and disseminated to sites located as far as 54 miles from Stamford. Sequences of WN virus isolated from both brain and heart tissues from the same avian host were identical in all 14 tested individual birds, suggesting that the mutations we have documented are real and not caused by culture, RNA extraction, or PCR procedures. We conclude that this portion of the viral genome will enable us to follow the geographical and temporal movement of variant WN virus strains as they adapt to North America. PMID- 11606793 TI - Toxicant-induced oxidative stress in cancer. AB - The article highlighted in this issue is "The Role of Oxidative Stress in Indium Phosphide-Induced Lung Carcinogenesis in Rats" by Barbara C. Gottschling, Robert R. Maronpot, James R. Hailey, Shyamal Peddada, Cindy R. Moomaw, James E. Klaunig, and Abraham Nyska (pp. 28-40). The article integrates a traditional pathologic study of toxicant-induced pulmonary carcinogenesis with an immunohistologic assessment of oxidative stress, thereby determining a potential mechanism of action of a toxicant, specifically indium phosphide. PMID- 11606795 TI - A short history of lung cancer. PMID- 11606796 TI - Significant shortcomings of the U.S. Environmental Protection Agency's latest draft risk characterization for dioxin-like compounds. AB - The United States Environmental Protection Agency (U.S. EPA) has concluded that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a human carcinogen, and it has stated that the lifetime all-cancer mortality risk attributable solely to the current background body burden of dioxin-like compounds could be as high as 1.3 per 100. U.S. EPA's most current human cancer risk estimate was obtained from a linear dose-response model fit to the data from three epidemiology studies of TCDD-exposed chemical workers. Herein it is shown that the U.S. EPA model fails to provide an adequate fit to that data, whereas an intercept-only model, having no slope whatsoever, is entirely adequate. Although the epidemiology data used by U.S. EPA are consistent with a significant elevation in all-cancer mortality, by about 32%, among TCDD-exposed workers, this elevation should not be attributed to the workers' TCDD exposure. PMID- 11606797 TI - Alternative models for carcinogenicity testing. AB - The International Conference on Harmonisation Expert Working Group on Safety suggested that under certain circumstances, data from alternative assays could be used in safety evaluation in place of a second bioassay. Several alternatives were discussed. Six of these models were evaluated in a collaborative effort under the auspices of the Health and Environmental Sciences Institute (HESI) branch of the International Life Sciences Institute (ILSI). Standard protocols, pathology review, and statistical evaluations were developed. Twenty-one chemicals were evaluated, including genotoxic, nongenotoxic, carcinogenic, and noncarcinogenic chemicals. The models that were evaluated included the p53(+/-) heterozygous knockout mouse, the rasH2 transgenic mouse, the TgAC transgenic mouse (dermal and oral administration), the homozygous XPA knockout and the XPA/p53 knockout mouse models. Also evaluated were the neonatal mouse models and the Syrian Hamster Embryo (SHE) transformation assay. The results of this comprehensive study suggest that some of these models might be useful in hazard identification if used in conjunction with information from other sources in a weight of evidence, integrated analysis approach to risk assessment. PMID- 11606798 TI - Regulation of rat carboxylesterase expression by 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD): a dose-dependent decrease in mRNA levels but a biphasic change in protein levels and activity. AB - Carboxylesterases play an important role in the metabolism of endogenous lipids and foreign compounds; therefore, xenobiotic regulation of carboxylesterase gene expression has both physiological and pharmacological significance. We previously reported that beta-naphthoflavone and 3-methylcholanthrene, two potent inducers for cytochrome P4501A enzymes, had opposing effects on the expression of hydrolase S, a secretory carboxylesterase. Beta-naphthoflavone caused suppression, whereas 3-methylcholanthrene caused induction of the expression of this enzyme. The aim of the present study was to determine the effects of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), another prototypical cytochrome P4501A inducer, on the expression of this and several other rat carboxylesterases (hydrolases A, B, and C) in liver and extrahepatic tissues. Rats received TCDD treatment at nonlethal (1.0 mM. CONCLUSION: The enhanced lysis of CmPEG-RBCs in ABO-mismatched serum correlated with increased IgM binding and C3a generation and elevated C3b and C9 membrane deposition. While PEG modification effectively blocks non-ABO antigens, these data show that ABO matching is still required. Once ABO-matched, these modified RBCs retain great potential for the prevention of alloimmunization. PMID- 11606821 TI - Generation of reticulated platelets in response to whole blood donation or plateletpheresis. AB - BACKGROUND: There are few reports about thrombopoietic responses in whole blood (WB) and platelet-pheresis donors. This study compares the thrombopoietic responses of such donors and their platelet values. STUDY DESIGN AND METHODS: The effect of WB donation or selective platelet loss (plateletpheresis) was evaluated prospectively. WB and platelet donor samples before donation and for 7 days thereafter were assessed for platelet count, mean platelet volume, and platelet reticulocytes. RESULTS: Reticulated platelets appeared in the circulation of plateletpheresis donors by 24 hours. The proportion of reticulated platelets was highest on Day 2, and above-normal levels of reticulated platelets persisted until Day 7. The mean platelet volume was high on Days 2 and 3, which corresponded with the appearance of reticulated platelets. After plateletpheresis, platelet counts were higher than could be accounted for by new platelets, which suggested the release of sequestered platelets. WB donors manifested no changes in platelet counts but had a peak of circulating platelet reticulocytes 2 days after the donation. CONCLUSION: The thrombopoietic peak in WB and plateletpheresis donors occurs 2 days after donation, and the response level is related to the amount of platelets lost. The impact of platelet loss on the number of circulating platelets is modulated by the release of platelets from the spleen. PMID- 11606822 TI - The effect of hot beverages, cold beverages, and chewing gum on oral temperature. AB - BACKGROUND: A prospective blood donor's oral temperature is affected by external stimuli such as drinking a hot or cold beverage or chewing gum. These stimuli can cause a deferral or an inappropriate acceptance for a certain unknown time. STUDY DESIGN AND METHODS: Ten volunteer subjects were exposed to each of the three stimuli in separate studies. Oral and tympanic membrane temperatures were taken before exposure, immediately after exposure, and at various times until the subject's temperature returned to baseline. RESULTS: The drinking of a hot beverage caused an immediate mean temperature elevation of 2.6 degrees F which would lead to deferral for 7 of 10 subjects. All subjects were acceptable for blood donation (temperature <99.6 degrees F) by 5 minutes. A cold beverage lowered the temperature; the temperature in 6 subjects returned to baseline by 10 minutes and that in 4 did so by 30 minutes. Gum chewing caused minimal temperature elevations; only 1 donor's temperature reached 99.6 degrees F, and it was at acceptable levels for blood donation by 5 minutes. CONCLUSION: Drinking a hot beverage and, to a much lesser degree, gum chewing can lead to a deferral for elevated temperature, but subjects were acceptable by 5 minutes. Cold beverages are of more concern, because they suppress the temperature for a short time and could theoretically lead to acceptance of a febrile, possibly infectious donor. PMID- 11606823 TI - HLA class II antibodies in transfusion-related acute lung injury. AB - BACKGROUND: Transfusion-related acute lung injury (TRALI) is a serious, sometimes fatal, complication of transfusion. Granulocyte and HLA class I antibodies present in blood donors have been associated with TRALI. HLA class II antibodies have recently been described in a few cases of TRALI. STUDY DESIGN AND METHODS: Donors involved in TRALI reactions reported to a blood center over an 18-month period were tested for HLA class I and II antibodies as well as granulocyte antibodies, if HLA antibodies were not identified. RESULTS: HLA class II antibodies were identified, in at least one donor, in 7 (64%) of 11 cases of TRALI. HLA class I antibodies were identified in combination with HLA class II antibodies in 5 of these 7 cases. HLA class I antibodies were exclusively identified in 2 cases. Granulocyte antibodies were identified in 1 case, and no antibodies were identified in another. CONCLUSION: In addition to HLA class I antibodies, HLA class II antibodies are associated with TRALI. Testing of donors for HLA class II antibodies as well as HLA class I and granulocyte antibodies is recommended as part of the investigation of suspected cases of TRALI. PMID- 11606824 TI - Multicenter evaluation of PCR methods for detecting CMV DNA in blood donors. AB - BACKGROUND: CMV DNA screening may be a useful adjunct to serologic tests in distinguishing potentially infectious blood donations from those that are "CMV safe." However, there is currently no consensus on the optimal assay method for accurate detection of CMV DNA in donors. STUDY DESIGN AND METHODS: A blinded multicenter evaluation of seven CMV PCR assays was performed by five laboratories by using coded sets of analytical controls and donor blood samples. RESULTS: Five assays displayed sufficient sensitivity for donor screening, as judged by consistent detection of a minimum of 25 CMV genome equivalents (geq) in analytical controls constructed to contain from 1 to 100 CMV geq in background DNA from 250,000 cells, while the other two assays displayed inadequate sensitivity. Three sensitive assays, two based on nested PCR directed at the UL93 and UL32 regions of the CMV genome and another test (Monitor Assay, Roche), did not detect CMV DNA in samples from any of 20 pedigreed CMV-seronegative, Western blot-negative (S-/WB-) donors. Two other assays based on nested PCR occasionally detected CMV DNA in S-WB- samples, and one sensitive nested PCR assay directed at UL123 detected CMV DNA in a large proportion (85%) of S-WB- samples. CONCLUSION: Seven CMV PCR assays currently used for research and/or diagnostic applications displayed marked variations in sensitivity, specificity, and reproducibility when applied to coded analytical and clinical control samples containing cellular DNA from the equivalent of 250,000 WBCs. These results will be useful in the selection of assays with performance characteristics appropriate to donor screening objectives. They may also help explain discrepant findings from previous studies that used PCR to determine CMV DNA prevalence in seronegative and seropositive blood donors. PMID- 11606825 TI - Comparison of DATs using traditional tube agglutination to gel column and affinity column procedures. AB - BACKGROUND: Detection of immunoglobulin or complement bound to RBCs by using the DAT is valuable in the diagnosis of immune-mediated hemolytic anemia. Traditionally, the DAT has been performed by tube agglutination using anti-IgG or anti-C3d. The purpose of this study was to compare the tube agglutination DAT to gel microcolumn, affinity microcolumn, and flow cytometric DATs on RBCs coated in vitro and on patient RBC samples. STUDY DESIGN AND METHODS: RBCs from 84 patients were assessed by tube agglutination DAT, one gel microcolumn DAT, and two affinity microcolumn DATs. One affinity microcolumn assay was unmodified and one was modified by the addition of polyspecific antiglobulin or anti-IgG as a secondary antibody. RBCs from 15 of the 84 patients underwent analysis by flow cytometry with fluorescence-labeled anti-IgG. The assays were also compared by using D+ RBCs sensitized with serially adjusted concentrations of anti-D. RESULTS: Both tube agglutination and gel microcolumn DATs were positive in 49 patient samples; both assays were negative in 20 samples, and the results were discordant in 15. Gel microcolumn DATs were more likely than were tube agglutination DATs to detect IgG on RBCs. Affinity microcolumn DATs were less likely than gel microcolumn or tube agglutination DATs to detect IgG on RBCs. Flow cytometry results were the same as gel microcolumn results in 12 of 15 patient samples and the same as tube agglutination results in 13 of 15. Tube agglutination and both affinity microcolumn assays reacted with RBCs coated with anti-D that was diluted 1-in-100. The gel microcolumn and flow cytometry assays reacted with RBCs coated with anti-D diluted 1-in-400. There was no correlation between tube agglutination and gel microcolumn DATs in detecting bound C3d. CONCLUSION: Detection of IgG bound to RBCs was not consistent with the methods described. Gel microcolumn DATs were more sensitive than tube agglutination and affinity microcolumn DATs. Given the varied results of these assays, reference laboratories should not rely on a single method for DATs. More comprehensive testing should be performed when the tube agglutination DAT is negative in a patient with suspected immune-mediated hemolytic anemia. Further comparisons are necessary to determine the proficiency of flow cytometric assays. PMID- 11606826 TI - K, Fy(a), and Jk(a) phenotyping of donor RBCs on microplates. AB - BACKGROUND: In many cases, the search for compatible blood for patients with clinically significant RBC alloantibodies is difficult and time-consuming. To date, it has been considered necessary only to phenotype the blood donors for ABO group and D. There has been long experience with automated routine analysis (ABO, C, c, D, E, and e typing and RBC antibody screening), using robotic dispensers and computerized interpretation of microplate results. The purpose of this study was to explore the possibilities of also phenotyping for K, Fy(a), and Jk(a), as antibodies directed against these antigens (together with Rh antigens) are the most common clinically significant alloantibodies in the Swedish population. STUDY DESIGN AND METHODS: One thousand thirty-one EDTA samples from blood donors were phenotyped for K, Fy(a), and Jk(a) by use of an IAT with PEG on microplates. The findings were compared to those using conventional IAT in tube's and the microcolumn gel test (DiaMed-ID, DiaMed). RESULTS: All typing results with the microplate method were correct. All reactions for K and Fy(a) typing could be interpreted by the computer. The results for Jk(a) were indeterminate in 1.4 percent (14/1031) of the samples. CONCLUSION: The PEG-IAT microplate method gave reliable results that were suitable for routine phenotyping, thus making available a stock of phenotyped blood at reasonable cost, ready for delivery when required. PMID- 11606827 TI - Frozen-stored granulocytes can be used for an immunofluorescence test to detect granulocyte antibodies. AB - BACKGROUND: Donor- and/or recipient-derived granulocyte antibodies are considered to be the main cause of transfusion-related acute lung injury (TRALI), neutropenia, and febrile transfusion reactions. Several types of tests are performed to detect antibodies in donated blood and/or the serum of a transfusion recipient. Because granulocytes cannot endure the freezing-thawing process, they cannot be stored in liquid nitrogen (LN2). Therefore, testing is time-consuming, because freshly prepared granulocytes are needed for each testing. An attempt has been made to develop a method that uses granulocytes stored in LN2 for the granulocyte immunofluorescence test (GIFT). STUDY DESIGN AND METHODS: Freshly prepared granulocytes were suspended in a solution of 90-percent fetal bovine serum (FBS) plus 10-percent DMSO and then frozen and stored in LN2. In the case of GIFT, frozen-stored granulocytes were rapidly thawed, washed, and fixed with 1 percent paraformaldehyde (PFA) and then treated with MoAbs or serum containing antibodies that were reactive to granulocytes. After staining of granulocytes with FITC or PE, FACS analysis was performed. RESULTS: A comparison of FACS profiles of freshly prepared granulocytes stained with MoAbs or serum with FACS profiles of frozen-thawed-fixed granulocytes showed that the surface antigen expression was restored. Comparable results from FACS profiles of freshly prepared and frozen-thawed-fixed granulocytes were obtained. CONCLUSION: By being fixed with 1-percent PFA, frozen-stored-thawed granulocytes can be used in the GIFT. With this method, the testing time can be shortened. Moreover, because representative panel granulocytes can be stored in several aliquots, uniform granulocytes can be used as panel cells for each testing. PMID- 11606828 TI - An AQP1 null allele in an Indian woman with Co(a-b-) phenotype and high-titer anti-Co3 associated with mild HDN. AB - BACKGROUND: The Colton blood group system (CO, ISBT 015) is composed of three antigens, of which Co3 (ISBT 015.003) is carried by almost all persons, except those of the extremely rare Co(a-b-) phenotype. The Colton blood group antigens are expressed by the water channel aquaporin 1 (aqp1; also known as channel forming integral protein, CHIP-28), which is a highly conserved RBC integral membrane protein. The two most frequent alleles, CO1 and CO2, encode the antigens Co(a) and Co(b), respectively. Four null alleles have been described for the AQP1 gene to date. CASE REPORT: An Indian woman had an alloimmune antibody to an high frequency antigen associated with mild HDN. Her RBCs were typed Co(a--b-), and the antibody was an anti-Co3. She typed CO1-positive and CO2-negative in a new genotyping method, using PCR with sequence-specific priming, for CO1 and CO2. A method for nucleotide sequencing of the four AQP1 exons from genomic DNA was developed. The patient was shown to be homozygous for a nonfunctional allele AQP1(232delG) that also carried the CO1-specific polymorphism. CONCLUSION: The kindred presented a fifth example of an AQP1 null allele, which was caused by a single nucleotide deletion leading to a shift in the reading frame beyond codon 78. A method of genotyping CO for Co(a) and Co(b) antigen phenotype prediction was presented. PMID- 11606829 TI - Polymorphism and distribution of the Secretor alpha(1,2)-fucosyltransferase gene in various Taiwanese populations. AB - BACKGROUND: The Secretor gene (Se or FUT2), which produces alpha(1,2) fucosyltransferase, exhibits extensive polymorphism. Six Se genes, including the weak Se (Se(w) or Se385) and three nonsecretor alleles (se571, se685, and se849) have been detected in various populations of Taiwan. The distribution of various Lewis phenotypes among the Taiwanese population groups has been shown to vary considerably. STUDY DESIGN AND METHODS: A PCR-RFLP analysis system, which was based on the nucleotide polymorphism variation of the different Se alleles and which can reveal the Se genotype of an individual easily and accurately, was developed. The distribution of the Se alleles among Taiwanese population groups, including the two major populations, Minnan and Hakka Taiwanese, and 11 indigenous groups, was analyzed by the method. RESULTS: Frequencies of the Se alleles among the Taiwanese populations were revealed. The distribution of the nonsecretor alleles, especially se849, showed a marked variation. A good correlation was observed between a person's Se genotype and Lewis phenotype. CONCLUSION: The Se genes have a polymorphic distribution among various Taiwanese populations, and this agrees with previous results for Lewis phenotype distributions. The Se(w) allele and the three se alleles are responsible for the Le(a+b+) and Le(a+b-) phenotypes, respectively. PMID- 11606830 TI - A comparative study of the postoperative allogeneic blood-sparing effects of tranexamic acid and of desmopressin after total knee replacement. AB - BACKGROUND: Tissue hypoxia and reperfusion induce abnormal hemostatic function. Therefore, bleeding after total knee replacement (TKR) may be a result of a tourniquet-induced imbalance of the procoagulant and fibrinolytic systems. Because laboratory confirmation of tourniquet-induced abnormal hemostasis is difficult to obtain, indirect evidence must be sought. STUDY DESIGN AND METHODS: A prospective, single-blind study of 40 patients undergoing TKR was performed. In the tranexamic acid (TA) group, in the 30 minutes before the limb tourniquet was deflated, an IV bolus dose of TA (15 mg/kg) was administered. Thereafter, a constant IV infusion of 10 mg per kg per hour was administered until 12 hours after tourniquet deflation. In the desmopressin group, desmopressin (0.3 mg/kg) and saline were administered by a similar protocol. No blood was administered intraoperatively. A postoperative Hct <27 percent constituted the postoperative transfusion trigger. Patients were examined daily for signs of lower-limb deep vein thrombosis, and they underwent lower-limb Doppler ultrasound on postoperative Day 5. Three months after surgery, the incidence of delayed thromboembolic events was assessed. RESULTS: During the first 12 postoperative hours, blood accumulation in the surgical drain was significantly (p<0.05) lower in the TA group (162 mL +/- 129) than in the desmopressin group (342 mL +/- 169). From the sixth postoperative hour until 3 days postoperatively, Hct levels were significantly lower in the desmopressin group than in the TA group. Significantly more allogeneic blood was transfused in the desmopressin group (11 patients received 16 units) than in the TA group (3 patients each received 1 unit) (p<0.02). There were no clinical signs of deep vein thrombosis or abnormal Doppler ultrasound studies. Three months postoperatively, there were no thromboembolic events among the 37 patients interviewed. CONCLUSION: TA induces better blood sparing than desmopressin. Therefore, a tourniquet-induced increase in fibrinolysis is the likely cause of delayed bleeding after TKR surgery. However, before routine administration, the effect of TA on the incidence of thromboembolic events requires further investigation. PMID- 11606831 TI - Influence of cell-free Hb on local tissue perfusion and oxygenation in acute anemia after isovolemic hemodilution. AB - BACKGROUND: Oxygen-carrying solutions are intended to eliminate the blood transfusion trigger. Their ability to maintain microvascular perfusion and to deliver oxygen to tissue when they replace the RBCs as oxygen carriers has not been directly measured. STUDY DESIGN AND METHODS: Microvascular response to exchange transfusion with a polymerized bovine cell-free Hb (PBH) solution after acute isovolemic hemodilution with a plasma expander was investigated by using the hamster window model. In vivo functional capillary density (FCD), blood flow, and high-resolution oxygen distribution in microvascular networks were measured by noninvasive methods. RESULTS: Exchange transfusion of PBH solution after a 60 percent isovolemic hemodilution with dextran 70 (MW, 70 kDa) resulted in a Hct of 11 percent and a Hb content of 6.7 g per dL. FCD was 0.37 of baseline. Interstitial pO2 was reduced from 21.0 mm Hg to 0.3 mmHg. Arteriolar and venular blood flows were ratios of 0.75 and 0.76 relative to baseline. In a previous study, tissue pO2 after hemodilution to 5.6 g of Hb per dL with dextran 70 was 23.0 mmHg. Hypervolemic injection of PBH solution increased blood pressure and caused vasoconstriction. CONCLUSION: Using PBH solution to replace RBC oxygen carrying capacity during low Hb content conditions (<50%) causes abnormally low tissue oxygenation and FCD, while the same level of hemodilution with dextran maintains normal microvascular conditions. PMID- 11606833 TI - Universal WBC reduction. PMID- 11606832 TI - Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. AB - BACKGROUND: Extracorporeal photochemotherapy (EPC) has recently been proposed for the treatment of adults with either acute or chronic GVHD. However, data on children given this therapy are scarce. A Phase I-II study was carried out on EPC in children experiencing GVHD after allogeneic transplantation of HPCs. STUDY DESIGN AND METHODS: Nine patients with steroid-resistant, grade II-IV acute GVHD and 14 with chronic GVHD, all of whom had been refractory to at least one line of treatment, were enrolled in this study and analyzed. The median age was 10.3 years (range, 5.4-18.1), and the median body weight was 35 kg (range, 17-89). RESULTS: Seven of the nine patients with acute GVHD showed a response to EPC, whereas the disease progressed in the remaining two children (both with skin, gastrointestinal, and liver GVHD), and they died of grade IV acute GVHD. Among the seven children who responded to EPC, it was possible to completely discontinue immunosuppressive treatment in three. In the 14 children with chronic GVHD, 4 and 5 patients experienced complete and partial response to EPC, respectively, whereas the remaining 5 patients, all with extensive chronic GVHD, had stable disease or disease that progressed during EPC. Among these latter 5 patients, 3 died. In 6 of the 9 patients with chronic GVHD responding to EPC, immunosuppressive therapy was discontinued. CONCLUSION: EPC is safe, feasible, and effective in children with either acute or chronic GVHD occurring after an allograft. PMID- 11606834 TI - Evidence-based recommendations for the use of WBC-reduced cellular blood components. PMID- 11606835 TI - Cytokine response after cell salvage in maxillofacial surgery. PMID- 11606836 TI - Prevalence of antibody against West Nile virus in volunteer blood donors living in southeastern France. PMID- 11606839 TI - The active magnetic resonance imaging stent (AMRIS): initial experimental in vivo results with locally amplified MR angiography and flow measurements. AB - RATIONALE AND OBJECTIVES: Magnetic resonance (MR) is limited by artifacts in vessels after stenting. An active MR imaging stent (AMRIS) allows for artifact free imaging with local improvement in signal-to-noise ratio (SNR). In a rabbit model, we evaluated the imaging properties by MR angiography (MRA) and flow measurements. METHODS: The AMRIS was placed in the abdominal aorta of five rabbits. At 1.5 T, MRA (three-dimensional fast low-angle shot) was performed before and after intravenous injection of an iron oxide-based, blood-pool contrast medium (dose, 50 micromol Fe/kg), and flow measurements were performed (electrocardiographically triggered phase-contrast cine gradient-echo sequence). Mean SNRs were calculated and flow volume curves were generated. RESULTS: The SNR was 6.0 +/- 0.6 (outside the stent) versus 12.3 +/- 1.1 (inside the stent, P < 0.05) for plain MRA, 21.2 +/- 0.6 versus 40.6 +/- 5.2 (P < 0.05) for contrast enhanced MRA, and 5.4 +/- 0.4 versus 13.7 +/- 2.1 (P < 0.05) for the magnitude images of flow measurements. Flow volume curves within and distal to the stent were comparable. CONCLUSIONS: By using the AMRIS as a vascular stent, the stented vessel segment can be examined with enhanced signal intensity on MRI. PMID- 11606840 TI - Comparison of gadobenate dimeglumine with gadopentetate dimeglumine for magnetic resonance imaging of liver tumors. AB - RATIONALE AND OBJECTIVES: To compare gadobenate dimeglumine (Gd-BOPTA) with gadopentetate dimeglumine (Gd-DTPA) for magnetic resonance imaging of the liver. METHODS: The contrast agent Gd-BOPTA or Gd-DTPA was administered at a dose of 0.1 mmol/kg to 257 patients suspected of having malignant liver tumors. Dynamic phase images, spin-echo images obtained within 10 minutes of injection, and delayed images obtained 40 to 120 minutes after injection were acquired. All postcontrast images were compared with unenhanced T1-weighted and T2-weighted images obtained immediately before injection. A full safety assessment was performed. RESULTS: The contrast efficacy for dynamic phase imaging was moderately or markedly improved in 90.9% (110/121) and 87.9% (109/124) of patients for Gd-BOPTA and Gd DTPA, respectively. At 40 to 120 minutes after injection, the cor- responding improvements were 21.7% (26/120) and 11.6% (14/121) for spin-echo sequences and 44.5% (53/119) and 19.0% (23/121) for breath-hold gradient-echo sequences, respectively. The differences at 40 to 120 minutes after injection were statistically significant (P < 0.02). Increased information at 40 to 120 minutes after injection compared with information acquired within 10 minutes of injection was available for 24.0% (29/121) of patients with Gd-BOPTA and for 14.5% (18/124) of patients with Gd-DTPA (P < 0.03). Adverse events were seen in 4.7% (6/128) and 1.6% (2/127) of patients receiving Gd-BOPTA and Gd-DTPA, respectively. The difference was not statistically significant. CONCLUSIONS: The efficacy of Gd BOPTA is equivalent to that of Gd-DTPA for liver imaging during the dynamic phase and superior during the delayed (40-120 minutes) phase of contrast enhancement. Both agents are safe for use in magnetic resonance imaging of the liver. PMID- 11606841 TI - Quantification of blood flow in the carotid arteries: comparison of Doppler ultrasound and three different phase-contrast magnetic resonance imaging sequences. AB - RATIONALE AND OBJECTIVES: To compare blood flow velocities in the carotid arteries measured with three different magnetic resonance (MR) phase-contrast imaging techniques and with percutaneous Doppler ultrasound. METHODS: Fourteen healthy male volunteers with a mean age of 33 +/- 3.8 years were studied. Ultrasound and MR phase velocity mapping of both common carotid arteries (n = 28) was performed within 5 hours. A two-dimensional fast low-angle shot sequence with retrospective cardiac gating, a sequence with prospective cardiac triggering, and a breath-hold sequence with prospective cardiac triggering were used. Resistance indexes and pulsatility indexes were calculated for all modalities. RESULTS: The comparison of flow velocities obtained with ultrasound and the different MR techniques led to a moderate correlation of the retrospective gated and prospective triggered MR techniques (eg, r = 0.73 for maximum systolic velocity). The worst correlation was found between the breath-hold technique and retrospective cardiac gating (eg, r = 0.004 for pulsatility index). There was a weak correlation of all three MR sequences compared with ultrasound (r = 0.19 0.60) CONCLUSIONS: A moderate correlation was found between velocities and indexes measured with the prospective cardiac-triggered phase-contrast MR technique and the retrospective cardiac-gated phase-contrast MR technique. A weak correlation was found between the three different MR techniques and ultrasound, as well as between the breath-hold prospective cardiac-triggered MR sequence and both of the other MR sequences. The influence of temporal and spatial resolution on MR phase-contrast velocity mapping was confirmed. PMID- 11606842 TI - Repeatability of lung density measurements with low-dose computed tomography in subjects with alpha-1-antitrypsin deficiency-associated emphysema. AB - RATIONALE AND OBJECTIVES: Multislice computed tomography (MSCT) of the lungs provides a new opportunity for longitudinal assessment of lung densities because of shorter scan duration. The aim of the present study was to assess the intraindividual variation of lung densities measured by MSCT of patients with emphysema. METHODS: Ten patients with emphysema participated in a study in which MSCT was obtained on two occasions, approximately 2 weeks apart. Scanning parameters were 140 kV, 20 mAs, 4 x 2.5-mm collimation, and effective slice thickness of 2.5 mm. Lung density was measured as the 15th percentile point and the relative area below -910 Hounsfield units (HU) by using Pulmo-LKEB software. RESULTS: The mean difference of the 15th percentile point was -1.29 +/- 3.2 HU, and that for the relative area below the -910-HU parameter was -1.02% +/- 3.09%. Intraclass coefficients of variation were 0.96 (0.86-0.99) and 0.94 (0.8-0.98), respectively (95% confidence interval). CONCLUSIONS: Lung density parameters of emphysema derived by MSCT provide an opportunity for analysis of the treatment effects of new drugs on the progression of emphysema. PMID- 11606843 TI - Appearance of vascular stents in computed tomographic angiography: in vitro examination of 14 different stent types. AB - RATIONALE AND OBJECTIVES: To evaluate the appearance of the vessel lumen after implantation of different vascular stents with the use of a computed tomographic (CT) angiography model. METHODS: A vascular phantom was studied with helical CT and different slice thicknesses (2 and 3 mm) and pitch values (1.0, 1.5, and 2.0). Original transverse CT images and coronal reformations were evaluated. Fourteen different stents were analyzed with regard to changes in the stent lumen (attenuation values, noise, and artificial lumen narrowing). RESULTS: Some stents caused artifacts resulting in potential errors during evaluation of their patency. Assessment of the lumen was impaired in two stents (Strecker tantalum and Passager). Increased attenuation values were measured in all stents (increase of 8%-145%). The degree of artificial lumen narrowing was 4.4% to 77.8%. CONCLUSIONS: In most stents, reliable evaluation of the stent lumen seems possible. However, knowledge of the artifacts caused by different stent types is useful for the assessment of stent patency with CT angiography. PMID- 11606844 TI - Functional assessment of canine kidneys after acute vascular occlusion on Gd-DTPA enhanced dynamic echo-planar MR imaging. AB - RATIONALE AND OBJECTIVES: To assess the alteration in renal transit of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) in dog kidneys after acute vascular occlusion on dynamic echo-planar imaging (EPI). METHODS: Dynamic 240-ms EPI series (repetition time/echo time/inversion time [TR/TE/TI] = 3000/42.1/100 ms) of the midcoronal plane of both kidneys of dogs anesthetized by intravenous administration of phenobarbital sodium and ketamine hydrochloride were obtained before and after ligation of the left renal vein (n = 6) or artery (n = 6) for 40 minutes after a 2-second-rate bolus injection of a 0.05 mmol/kg dose of Gd-DTPA. Renal Gd-DTPA transit was analyzed on the time-DeltaR2* curves in each layer of the outer cortex (OC), juxtamedullary cortex and outer zone of the medulla (JMC OM), and the inner zone of the medulla (IM). The results were compared with those in six normal animals and those of a fast gradient-echo T1-weighted dynamic study performed in other vein- (n = 6) or artery- (n = 6) occluded animals and six normal animals. The histopathological basis of the altered Gd-DTPA transit was also evaluated. RESULTS: The dynamic EPI showed rapid Gd-DTPA transit through each of the five concentric layers, with three separate peaks on the time DeltaR2* curves. The vein-occluded kidneys showed immediate swelling, with a significant increase in the cross-sectional area proportion of the JMC-OM layer compared with normals (32% +/- 2% vs 24% +/- 2%, P < 0.0001) and intensely congested capillaries, tubular, obliterated material, and gradual and persistent enhancement of the OC and JMC-OM layers but poor Gd-DTPA migration to the IM layer. The artery-occluded kidneys showed a significant reduction in the entire cross-sectional area compared with normals (1352 +/- 69 vs 1432 +/- 47 mm(2), P < 0.05) and poor enhancement, with significant decreases in the area under the time DeltaR2* curve of the OC and JMC-OM layers compared with the vein-occluded kidneys (79 +/- 50 vs 324 +/- 108 and 82 +/- 42 vs 326 +/- 113, respectively; both P < 0.0001), despite minimal histological damage. In both models, the nonaffected kidneys showed significant increases in the area under the time DeltaR2* curves compared with baseline. The time course of vascular and tubular Gd-DTPA transit was more detailed by the EPI study than by the T1-weighted imaging study. CONCLUSIONS: Echo-planar imaging has an excellent ability to follow the rapid, renal Gd-DTPA transit through the regional anatomy of the canine kidney. After venous occlusion, the JMC-OM layer may be the most affected site, primarily causing renal swelling and interruption of tubular Gd-DTPA transit and concentration. In contrast, an initial block of vascular Gd-DTPA inflow is the primary effect of arterial occlusion. Nonaffected kidneys seem to compensate by increasing excretion of Gd-DTPA. PMID- 11606845 TI - Improved in-stent magnetic resonance angiography with high flip angle excitation. AB - RATIONALE AND OBJECTIVES: To optimize the intraluminal signal intensity of a nitinol stent by performing contrast-enhanced three-dimensional magnetic resonance angiography (CE-MRA) with varying flip angles (FAs). METHODS: Contrast enhanced magnetic resonance angiography at 1.5 T and FAs of 30 degrees, 100 degrees, and 150 degrees was performed on five sheep with 10 iliac nitinol stents (Memotherm-FLEXX). Maximum-intensity projections (MIPs) and composite images of MIPs were performed and compared. RESULTS: Reconstructed MIPs at an FA of 150 degrees showed a slightly disturbed lumen visibility inside the stent accompanied by low-grade lumen visibility outside the stent and vice versa for an FA of 30 degrees. Composite images of a 30 degrees MIP added to a 150 degrees MIP resulted in improved image quality compared with the standard MIP of a single FA. CONCLUSIONS: Signal loss due to radiofrequency shielding inside nitinol stents imaged by CE-MRA can be reduced by applying high FAs. Composite MIP images allow simultaneous visualization of the lumen inside as well as outside the stent. PMID- 11606846 TI - Contrast-enhanced magnetic resonance cholangiography versus heavily T2-weighted magnetic resonance cholangiography. AB - RATIONALE AND OBJECTIVES: To investigate the feasibility of contrast-enhanced magnetic resonance cholangiography (CE-MRC) and compare it with single-shot turbo spin-echo magnetic resonance cholangiography (SSTSE-MRC). METHODS: Fifteen patients with suspected metastatic liver disease (n = 10) or biliary tree abnormalities (n = 5) underwent a magnetic resonance imaging (1.5-T system) examination before and after mangafodipir administration. Contrast-enhanced MRC with a three-dimensional fast low-angle shot sequence after mangafodipir trisodium administration was compared with SSTSE-MRC. Four anatomic segments were evaluated: the intrapancreatic and extrapancreatic common bile duct segments, the cystic duct, and the area of hepatic bifurcation. Contrast-enhanced MRC and SSTSE MRC were separately analyzed on a 5-point grading scale in terms of ductal segment visualization and lumen narrowing or dilatation. RESULTS: There was no difference (P = 0.375) in segment visualization between CE-MRC and SSTSE-MRC; 56 of the 60 segments were visualized by both techniques. In the evaluation of ductal narrowing or dilatation, nonsignificant differences (P = 0.500) were observed. Contrast-enhanced MRC was not influenced by fluid superimposition and provided additional information from background tissues. CONCLUSIONS: Contract enhanced MRC is a feasible technique showing anatomic correlation with SSTSE-MRC, and it can in addition provide functional information. Contrast-enhanced MRC may be used in selected patients when traditional SSTSE-MRC is inconclusive. PMID- 11606848 TI - Postendoscopy syndrome: "the doctor never talked to me". PMID- 11606849 TI - Pharyngeal and upper esophageal sphincter manometry in the evaluation of dysphagia. AB - The use of esophageal manometry seems to be increasing, but the utility of pharyngeal and upper esophageal sphincter (UES) manometry is not widely recognized. This article is intended to clarify this subject. Initially, we review the anatomy and physiology of this area. Most studies indicate that the manometry of the UES and pharynx provides useful information primarily in patients that have symptoms of oropharyngeal dysfunction. Oropharyngeal dysphagia has high morbidity, mortality, and cost. It occurs in one third of all stroke patients and is common in the chronic care setting; up to 60% of nursing home occupants have feeding difficulties, of whom a substantial portion have dysphagia. For patients with oropharyngeal dysphagia, as for those with esophageal dysphagia, barium swallow study and manometry are complimentary. Their combined use permits us to enhance the understanding of the pathophysiologic process that causes the patient's symptoms. Abnormalities have been noted in a variety of diseases, such as Parkinson's disease, oculopharyngeal muscular dystrophy, achalasia, and scleroderma. Thus, it is possible to determine the primary pathology that is causing the patient's dysphagia by analyzing the manometry results. Pharyngeal and UES manometry also has a value in evaluating patients who are candidates for myotomy or dilatation, as it can help identify patients with a prospective good outcome. PMID- 11606850 TI - Clinical applications of magnetic resonance cholangiopancreatography. AB - Magnetic resonance cholangiopancreatography (MRCP) is a novel imaging technique used for noninvasive work-up of patients with pancreaticobiliary disease. Magnetic resonance cholangiopancreatography is useful in the evaluation of a host of pancreaticobiliary disorders, such as congenital disorders, calculus disease, biliary strictures, sclerosing cholangitis, chronic pancreatitis, and cystic pancreatic lesions. It not only provides useful preoperative information to surgeons and gastroenterologists but also serves as a valuable tool in the assessment of postoperative pancreaticobiliary ductal anatomy. Recent refinement of techniques allows faster imaging with superior image resolution. This review summarizes the role of MRCP in clinical practice. PMID- 11606851 TI - Hepatitis C and human immunodeficiency virus coinfections. AB - Hepatitis C virus (HCV) has become a major contributor to morbidity and mortality in patients with human immunodeficiency virus (HIV). It is estimated that 30% to 50% of patients with HIV are coinfected with HCV. Advances in antiretroviral therapy and improved life expectancy of HIV patients have resulted in an emergence of HCV-induced liver disease as a leading cause of significant morbidity and death in this population. Clinically, hepatitis C is a more severe disease in HIV-infected individuals, characterized by rapid progression toward end-stage liver disease. Highly active antiretroviral therapy is the mainstay of current acquired immunodeficiency syndrome management. One of the limiting side effects of combination therapy for HIV is hepatotoxicity, which is more common and often more serious in patients with underlying liver disease. Management of coinfected patients has no strict guidelines, but it is generally accepted that HIV infection needs to be treated before HCV. Hepatitis C in coinfected individuals is probably best treated using combination therapy (interferon alpha and ribavirin). It appears that combination therapy can safely be administered to this population and that previous concerns about ribavirin/zidovudine antagonism are unsubstantiated in clinical practice. Although initial results using only interferon alpha showed poor results in HIV coinfected patients, combination therapy seems to be as effective as in the general population. All HIV-HCV coinfected patients should be vaccinated against hepatitis B and hepatitis A; vaccines are safe and effective. PMID- 11606852 TI - Vigorous achalasia: original description requires minor change. AB - Vigorous achalasia was described in 1957 as a subset of achalasia with a higher contraction amplitude (>37 mm Hg), minimal esophageal dilatation, prominent tertiary contractions, and higher incidence of chest pain. GOALS: Ascertain the existence of a distinct achalasia group based on manometric, radiographic, and clinical grounds. STUDY: The records of 209 idiopathic achalasia patients seen over a 9-year interval were reviewed for duration and frequency of dysphagia, chest pain, heartburn, weight loss, and nocturnal symptoms, as well as for treatment outcome. Manometric tracings were reanalyzed for lower esophageal sphincter pressure (LESP), LES residual pressure, distal esophageal contraction amplitude, and presence of repetitive waves. Patients were subsequently divided into classic (amplitude < or =37 mm Hg) and vigorous (amplitude >37 mm Hg) achalasia groups. Esophagrams were reassessed blindly for esophageal diameter both in the upright and recumbent positions and presence of lumen-occlusive tertiary contractions. RESULTS: One hundred forty-four classic and 65 vigorous achalasia patients were identified. These groups were similar in age and gender, as well as duration of symptoms. Chest pain was equally prevalent in both groups. Lower esophageal sphincter pressure was higher ( p < 0.01) and repetitive waves more common ( p < 0.0001) in the vigorous achalasia group. Upright esophageal diameter was smaller ( p = 0.0003) and tertiary contractions more frequent ( p = 0.0004) in this group. CONCLUSION: The original manometric and radiographic description of vigorous achalasia is accurate. The incidence of chest pain is similar to that of patients with classic achalasia. PMID- 11606853 TI - Esophageal intramural pseudodiverticulosis: review of symptoms including upper gastrointestinal bleeding. AB - BACKGROUND: Esophageal intramural pseudodiverticulosis (EIP) is a rare condition manifested by multiple, flask-shaped outpouchings in the wall of the esophagus, which represent dilated excretory ducts of esophageal mucous glands. STUDY: Five patients with EIP were evaluated with regard to symptoms and concomitant diseases, as well as endoscopic, radiologic, and manometric findings. RESULTS: Primary clinical symptoms reported by the five patients (three men and two women; age range, 59-72 years) were increasing dysphagia ( n = 3), upper gastrointestinal bleeding ( n = 1), and no symptoms ( n = 1). Concomitant diseases were chronic alcoholism ( n = 3), diabetes mellitus ( n = 1), and reflux esophagitis ( n = 1). Primary diagnosis was made endoscopically in all cases. Endoscopic findings other than pseudodiverticula were esophageal webs ( n = 2) and proximal esophageal stenoses ( n = 4). The typical radiologic findings were detectable in two patients, pathologic manometric findings were seen in only one patient. The authors treated the concomitant diseases and performed endoscopic dilatations of esophageal stenoses. One case with initial bleeding from an associated web is described in detail. According to our knowledge, this is the first publication of a case of EIP-associated bleeding. CONCLUSION: Esophageal intramural pseudodiverticulosis is a differential diagnosis in cases of dysphagia and/or esophageal strictures if no other causes are found. The authors think that endoscopy is the method of choice for establishing the diagnosis. PMID- 11606855 TI - Seropositivity against Helicobacter pylori CagA in Turkish gastric cancer patients. AB - BACKGROUND: Increased prevalence of CagA in gastric cancer has been reported; yet, other reports suggest that the cagA gene is not associated with gastric cancer. GOALS: To evaluate the frequency of CagA seropositivity in Turkish patients with gastric cancer. STUDY: Thirty-two patients with gastric adenocarcinoma and 46 patients with nonulcer dyspepsia were examined for Helicobacter pylori status and for antibodies against CagA. RESULTS: H. pylori was positive in 56.3% of patients and in 71.7% of controls. CagA was positive in all patients in the study group, regardless of H. pylori positivity, and in 56.5% of the control group. CagA positivity in H. pylori -positive patients was significantly more frequent in patients with gastric cancer than in those with nonulcer dyspepsia ( p < 0.001). As for H. pylori -negative patients in both groups, CagA positivity was also more frequent in gastric cancer patients ( p < 0.001). CONCLUSION: Testing for H. pylori antibodies without testing for antibodies against CagA will miss patients with either recent or previous infection, which may be a cause of missing the relationship between H. pylori and gastric cancer. The authors think that testing for CagA in patients with dyspepsia can reveal which patients should be followed up for the risk of developing gastric cancer. PMID- 11606854 TI - Interaction between cyclooxygenase-2 and inducible nitric oxide synthase in gastric cancer. AB - BACKGROUND: Chronic expression of cylcooygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) may play an important role in gastric carcinogenesis. Thus, the purpose of our study was to assess the expression of COX-2 and iNOS messenger RNA (mRNA) in gastric cancer and to investigate the correlation between the expression of COX-2 and iNOS mRNA in these patients. STUDY: Twenty-three gastric carcinoma specimens and accompanying adjacent specimens were obtained from surgical resection. The expression of COX-2 and iNOS were examined by comparative reverse transcription polymerase chain reaction. RESULTS: Cylcooygenase-2 and iNOS mRNA were significantly higher in gastric cancer tissues than in adjacent normal tissues. There was significant correlation between the levels of COX-2 and iNOS mRNA in carcinoma tissues. However, there was no significant correlation between the level of COX-2 or iNOS mRNA expression and several clinicopathologic parameters in these patients. CONCLUSION: The expression of COX-2 and iNOS may be one of the factors that contribute to gastric carcinogenesis. PMID- 11606856 TI - Abnormal vitamin levels in patients receiving home total parenteral nutrition. AB - The administration of multivitamins to patients receiving home parenteral nutrition (HPN) was decreased from once daily to three times weekly during the parenteral multivitamin shortage in 1997. Blood vitamin levels were measured to examine whether the decrement in the infused vitamins affected the levels. Six patients with normal renal and liver function, receiving HPN for 6 months to 10 years, were studied 6 months after the institution of 10 mL of multivitamins thrice weekly. Two patients with renal insufficiency who required hemodialysis and HPN were also studied. Multivitamin administration was eliminated in one patient and was reduced to once weekly when elevated pyridoxine levels were found in association with possible neurotoxicity. Five of the six patients with normal renal function had low serum ascorbic acid levels. Serum riboflavin levels were found to be low in one patient, serum pyridoxine was low in one, serum retinoids were low in three, and serum niacin was low in one. There were no clinically obvious untoward effects caused by the vitamin deficiencies. Each of the dialysis patients had elevated serum pyridoxine levels and had some neurologic disturbance (peripheral neuropathy, involuntary movements). The serum pyridoxine levels fell to normal in each after the cessation or decrease of the multivitamin preparation. Ascorbic acid levels were low in one patient and fell into abnormally low levels in the other when the parenteral multivitamins were reduced, but they corrected with the separate administration of intravenous vitamin C. In conclusion, the reduced administration of multivitamins in 1997 resulted in diminished ascorbic acid levels in seven of eight patients receiving total parenteral nutrition. Less often, low levels of retinoids, niacin, pyridoxine, and riboflavin were seen. Patients with chronic renal failure receiving HPN with multivitamins may develop elevated pyridoxine levels, which might result in neurologic sequelae. PMID- 11606857 TI - Close correlation of p53 mutation to microvascular invasion in hepatocellular carcinoma. AB - Mutation of p53 is a poor prognostic indicator of hepatocellular carcinoma (HCC). Although poor histologic differentiation of HCC has been associated with p53 mutations, the exact reasons for unfavorable clinical outcomes in patients with HCC remain to be clarified. In this study, we evaluate the association between p53 mutation and histopathologic features of HCCs, as well as tumor recurrences and survival. We examined 20 HCCs and surrounding liver tissues from patients who underwent surgical resection, and we performed direct sequencing of p53 gene. p53 mutations were found in 9 of 20 HCCs; none were found in the surrounding liver tissue. p53 mutations were frequent in large, multinodular, and poorly differentiated HCCs. Five of 9 with p53 mutation (in contrast, none of 11 with wild-type mutation) showed microvascular invasions. Hepatocellular carcinoma recurred in 6 of 9 with p53 mutation, in contrast to only 2 of 11 with wild-type mutation. The 1-year survival rate with p53 mutation was significantly lower than that with wild-type. In conclusion, it is suggested that p53 mutations tend to be commonly associated with microvascular invasions, which may result in micrometastasis, followed by frequent recurrences. PMID- 11606858 TI - Expression and clinical significance of antinuclear antibody in hepatitis C virus infection. AB - BACKGROUND: The prevalence of antinuclear antibody (ANA) has been documented in patients with hepatitis C virus (HCV) infection. We attempted to determine the titer and to characterize the patterns and clinical significance of ANA in HCV infection. STUDY: Forty-eight consecutive patients with positive anti-HCV antibody and positive HCV RNA were included in this study. Sera from patients were tested for ANA and anti-smooth muscle antibody by indirect immunofluorescence. Serum aminotransferase, alkaline phosphatase, alpha fetoprotein, and cryoglobulin levels also were determined. RESULTS: Eleven (23%) of 48 HCV-infected patients were positive for ANA. Antinuclear antibody revealed speckled pattern in 10 (91%) of the 11 ANA-positive HCV-infected patients. Twenty (54%) of 37 ANA-negative HCV-infected patients had detectable pattern with equivocal titer (titer <1.5). The ANA pattern was speckled in all 20 patients. Hepatitis C virus-infected patients with positive ANA were older than the HCV infected patients with negative ANA (62.90 +/- 11.05 years vs. 56.46 +/- 14.94 years, respectively; p < 0.1). Serum levels of aspartate aminotransferase (39.36 +/- 14.98 IU/L vs. 30.70 +/- 23.15 IU/L, p < 0.05), alkaline phosphatase (189.00 +/- 75.63 IU/L vs. 122.41 +/- 40.88 IU/L, p < 0.01), and alpha-fetoprotein (47.72 +/- 80.47 pg/dL vs. 7.00 +/- 8.28 pg/dL, p < 0.01) were higher in ANA-positive HCV-infected patients than in ANA-negative HCV-infected patients, respectively. There were no significant differences in gender, alanine aminotransferase, anti smooth muscle antibody, or cryoglobulin between the two groups. CONCLUSIONS: Antinuclear antibody was present in 11 (23%) of 48 patients with HCV infection in our study. Speckled pattern is the major expression pattern of ANA in HCV infection. Antinuclear antibody-positive HCV-infected patients have significantly higher serum aspartate aminotransferase, alkaline phosphatase, and alpha fetoprotein levels than ANA-negative HCV-infected patients. PMID- 11606859 TI - Seroprevalence of the antibody to hepatitis C in select groups in the Punjab region of Pakistan. AB - GOALS: Hepatitis C is on the rise in clinics in Pakistan. To estimate the occurrence of hepatitis C in the region and to create awareness about the disease in the general public, two studies were conducted in Punjab, Pakistan. Before this, no such effort has been made in Pakistan. BACKGROUND: Two studies were held in Lahore and Gujranwala of Punjab, Pakistan. These studies were advertised throughout the city, and people who participated were screened for anti-hepatitis C virus (anti-HCV)-positive serology at a concession rate and were surveyed through a questionnaire. In Lahore, there were 488 participants (mean age, 28 years; male-to-female ratio, 1.4 to 1). In Gujranwala, there were 1,922 participants (mean age, 27 years; male-to-female ratio, 1.5 to 1). The patients' blood was tested using an immuno-chromatography to identify the antibody to hepatitis C using Instatest HCV, with very high sensitivity. RESULTS: In Lahore, the occurrence of anti-HCV-positive serology was 15.9%. In Gujranwala, the occurrence of anti-HCV-positive serology was 23.8%. In Lahore, the occurrence was 1.2% in participants 20 years of age and younger and was 23.5% in those who were more than 20 years of age. In Gujranwala, the occurrence of anti-HCV-positive serology was 5.4% in participants 20 years of age and younger and was 34% in those who were more than 20 years of age. CONCLUSION: It can be seen that in those younger than 20 years of age, the occurrence of hepatitis C is almost at par with the rest of the world (0.5-2%). However, those more than 20 years of age had a very high occurrence, as high as 50% in certain age groups. The time-frame of contraction of the HCV for those individuals more than 20 years of age (approximately 20 to 35 years ago) corresponds with that of the smallpox eradication program conducted in Pakistan from 1964 to 1982. This may indicate the likelihood of a relationship between the high rate of hepatitis C and the administration of the smallpox vaccine in Pakistan. PMID- 11606861 TI - Duodenal somatostatinoma presenting with complete somatostatinoma syndrome. AB - Somatostatinomas are the rarest pancreatic endocrine tumors and can arise in the pancreas or duodenum. Duodenal somatostatinomas are less common than, and are distinguished from, their pancreatic counterparts by a frequent association with type I neurofibromatosis, the presence of psammoma bodies, the less frequent presence of metastatic disease, and the absence of somatostatinoma syndrome (diabetes mellitus, steatorrhea, and cholelithiasis). We report a case of somatostatinoma with metastases and psammoma bodies presenting with all three features of the syndrome in a patient with neurofibromatosis. Although several reports have documented portions of the syndrome in patients with duodenal somatostatinomas, to our knowledge, this is the first report of the complete syndrome associated with a duodenal lesion. PMID- 11606860 TI - Jejunal diverticulosis and gastrointestinal bleeding. AB - Occult gastrointestinal bleeding frequently frustrates clinicians' attempts to locate the source. Foci of hemorrhage within the small bowel are often found only at laparotomy and can be attributed to Meckel's diverticula, carcinomas, or less frequently, pulsion-type diverticula. We report our experience with two patients whose jejunal diverticula resulted in recurrent episodes of massive gastrointestinal hemorrhage. PMID- 11606862 TI - Focal nodular hyperplasia of the liver after intraconazole treatment. AB - A 38-year-old woman developed focal nodular hyperplasia of the liver after she had received a 4-month treatment with intraconazole 200 mg/d for a fungal infection of her fingernails. Because the patient underwent yearly liver ultrasound examinations because of the removal of a breast carcinoma, when the tumor was discovered incidentally, it was clear that it had developed within the past year after she had begun receiving intraconazole. Although various chemical agents and drugs have been considered as possible etiologic factors in the development of focal nodular hyperplasia of the liver, cases occurring after intraconazole therapy have not been reported before. Apart from the theoretical considerations with regard to the pathogenesis of nodular hyperplasia of the liver, this case could gain practical importance, as it shows a new adverse effect of a drug that has been used in more than 34 million patients over the past 10 years. Furthermore, this case should draw attention to the possibility of drug-induced benign hepatic tumors, as they may mimic malignant and metastatic disorders, which might be especially alarming in patients undergoing routine examinations after removal of malignant tumors, such as our patient. PMID- 11606863 TI - Acute hepatitis E virus infection presenting as a prolonged cholestatic jaundice. AB - Hepatitis E virus (HEV) is an enteric virus that usually causes a self-resolving hepatitis; although, it may be fatal, especially in pregnant women. Although HEV is endemic in Israel, there have been no recent local outbreaks. We report the case of a 70-year-old man who presented with painless jaundice. Ultrasound and abdominal computed tomography scan revealed gallstones, with no evidence of cholecystitis and no dilatation of the intra-or extrahepatic bile ducts. An open cholecystectomy was performed with intraoperative cholangiography. There was no evidence of choledocholithiasis. A subsequent endoscopic retrograde cholangiopancreatography was normal. His bilirubin level subsequently increased to a maximum of 25 mg/dL, and his gamma-glutamyl-transferase level reached 1,400 U/L. There was no evidence of any autoimmune or metabolic disease, and routine viral serology was normal except for immunoglobulin G to hepatitis A virus. A liver biopsy revealed an acute cholestatic picture. The jaundice resolved slowly after a period of 6 months. Hepatitis E virus RNA was isolated from the acute phase serum and was not detectable in the convalescent serum. This case is a unique example of chronic cholestatic jaundice that we think is caused by acute HEV infection. PMID- 11606864 TI - Endoscopic treatment of a Cameron lesion presenting as life-threatening gastrointestinal hemorrhage. PMID- 11606865 TI - Does Helicobacter pylori always represent a peaceful host of Barrett's esophagus? PMID- 11606866 TI - Interleukin-11 for thrombocytopenia associated with hepatitis C. PMID- 11606867 TI - Interferon alfa-induced pernicious anemia in chronic hepatitis C infection. PMID- 11606868 TI - Going beyond costs when evaluating surgical options for women newly diagnosed with breast cancer. PMID- 11606869 TI - Observation interval for evaluating the costs of surgical interventions for older women with a new diagnosis of breast cancer. AB - OBJECTIVE: To estimate the episodic costs of surgical treatments for breast cancer. METHODS: The surgical treatment period as the 6 weeks following diagnosis is defined. Using a sample of 205 women aged 65 and older and their Medicare claim files, the cost of treatment is estimated and the progression from first to subsequent surgical procedures during the 6-week interval is demonstrated with a decision tree. Two equations are then estimated: the probability of mastectomy versus breast conserving surgery (BCS) as first surgery using Probit regression and the log of total charges using a generalized linear regression model. RESULTS: It was found that only stage predicts the probability of mastectomy versus BCS and that 54% of women receiving BCS undergo a second surgery. Once all treatments in the initial surgical period are accounted, the difference between the adjusted cost of mastectomy alone and BCS followed by a second surgery was not statistically significant. Only a successful first BCS is statistically significantly (P <0.05) less costly than a mastectomy alone ($4,955 vs. $9,049). CONCLUSIONS: By defining a 6-week surgical treatment episode it is shown that BCS followed by subsequent surgeries is the more costly option for initial treatment. Given the high prevalence of second surgeries, previous work may have underestimated the costs of surgical interventions for breast cancer. PMID- 11606870 TI - Access to inpatient or residential substance abuse treatment among homeless adults with alcohol or other drug use disorders. AB - OBJECTIVES: We conducted a theoretically guided study of access to inpatient or residential treatment among a probability sample of homeless adults with alcohol or drug use disorders in Houston, Texas. METHODS: This study used a cross sectional, retrospective design with data collected from a multistage random sample of 797 homeless adults age 18 or older who were living in Houston shelters and streets in 1996. Structured, face-to-face interviews produced screening diagnoses for alcohol and drug use disorders, treatment use data, and candidate predictors of treatment use. Logistic and linear regression analyses were performed on the subset of 326 homeless persons with either alcohol or drug use disorder. RESULTS: 27.5% of persons with substance use disorder had accessed inpatient or residential treatment during the past year. Controlling for additional need factors such as comorbidity, persons having public health insurance and a history of treatment for substance problems had greater odds of receiving at least one night of treatment. Contrary to expectation, contact with other service sectors was not predictive of treatment access. Schizophrenia and having a partner appeared to hinder access. Greater need for treatment was associated with fewer nights of treatment, suggesting retention difficulties. CONCLUSIONS: This study adds to previous findings on access to health care among homeless persons and highlights a pattern of disparities in substance abuse treatment access. Health insurance is important, but enhancing access to care involves more than economic considerations if homeless persons are to receive the treatment they need. Referral relationships across different service sectors may require strengthening. PMID- 11606871 TI - Characteristics of adult primary care patients as predictors of future health services charges. AB - BACKGROUND: Utilization risk assessment is potentially useful for allocation of health care resources, but precise measurement is difficult. OBJECTIVE: Test the hypotheses that health-related quality of life (HRQOL), severity of illness, and diagnoses at a single primary care visit are comparable case-mix predictors of future 1-year charges in all clinical settings within a large health system, and that these predictors are more accurate in combination than alone. RESEARCH DESIGN: Longitudinal observational study in which subjects' characteristics were measured at baseline, and their outpatient clinic visits and charges and their inpatient hospital days and charges were tracked for 1 year. SUBJECTS: Adult primary care patients. MEASURES: Duke Health Profile for HRQOL, Duke Severity of Illness Checklist for severity of illness, and Johns Hopkins Ambulatory Care Groups for diagnostic groups classification. RESULTS: Of 1,202 patients, 84.4% had follow up in the primary care clinic, 63.2% in subspecialty clinics, 14.8% in the emergency room, and 9.6% in the hospital. Of $6,290,775 total charges, $779,037 (12.2%) was for follow-up primary care. The highest accuracy was found for predicting primary care charges, where R2 for predictors ranged from 0.083 for medical record auditor-reported severity of illness to 0.107 for HRQOL. When predictors were combined, the highest R2 of 0.125 was found for the combination of HRQOL and diagnostic groups. CONCLUSIONS: Baseline HRQOL, severity of illness, and diagnoses were comparable predictors of 1-year health services charges in all clinical sites but most predictive for primary care charges, and were more accurate in combination than alone. PMID- 11606872 TI - Shared patient analysis: a method to assess the clinical benefits of patient referrals. AB - BACKGROUND: Referral to specialized physicians or institutions often is deemed necessary in clinical medicine, but no method exists to assess the clinical benefit of such referrals. OBJECTIVES: To describe a method, which is shared patient analysis, to measure the expected improvement in clinical management associated with referrals and to apply that method in the field of abdominal and pelvic oncological radiology. SUBJECTS: All patients referred, during a 4-year period, to surgical oncologists at four academic centers (the referral providers, or RPs) with radiographs performed before referral at a community site (the initial providers, or IPs). Patients (n = 396) for whom both the IP interpretation and a final diagnosis was available were eligible. All IP and RP readings were placed in random order and presented to surgical oncologists, who then recommended a treatment course. MEASUREMENTS: Diagnostic accuracy of the IP and RP readings and the proportion of patients who were assigned to an appropriate treatment by the oncologist were determined. RESULTS: When the indication for imaging was primary diagnosis or staging, the kappa for presence of cancer was 0.70. When the indication was cancer follow-up, the kappa for presence of recurrent/progressing cancer was 0.66. There were disagreements between the IP and RP radiologists over the interpretation of 162 films, with the RP radiologists being correct in 153 (94%). Had the patients been treated using IP readings, there would have been 19 more inappropriate surgeries and 19 more admissions (both P <0.05) than if the oncologists had based their recommendations on RP readings. CONCLUSIONS: The technique of shared patient analysis permits assessment of the clinical benefits associated with referrals. PMID- 11606873 TI - The Medicaid Rx model: pharmacy-based risk adjustment for public programs. AB - BACKGROUND: Risk adjustment models typically use diagnoses from claims or encounter records to assess illness severity. However, concerns about the availability and reliability of diagnostic data raise the potential for alternative methods of risk adjustment. Here, we explore the use of pharmacy data as an alternative or complement to diagnostic data in risk adjustment. OBJECTIVES: To develop and test a pharmacy-based risk adjustment model for SSI and TANF Medicaid populations. RESEARCH DESIGN: Pharmacological review combined with empirical evaluation. We developed the Medicaid Rx model, a system that classifies a subset of the National Drug Codes into categories that can be used for risk-assessment and risk-adjusted payment. SUBJECTS: Subjects consisted of 362,370 persons with disability and 1.5 million AFDC and TANF beneficiaries in California, Colorado, Georgia, and Tennessee during 1990-1999. MEASURES: We compare pharmacy and diagnostic classification for three chronic diseases. We also compare R2 statistics and use simulated health plans to evaluate the performance of alternative models. RESULTS: Pharmacy and diagnostic classification vary in their ability to identify specific chronic disease. Using simulated plans, diagnostic models are better at predicting expenditures than are pharmacy-based models for disabled Medicaid beneficiaries, although the models perform similarly for TANF Medicaid beneficiaries. Models that combine diagnostic and pharmacy data have superior overall performance. CONCLUSIONS: The performance of risk adjustment models using a combination of pharmacy and diagnostic data are superior to that of models using either data source alone, particularly among TANF beneficiaries. Concerns regarding variations in prescribing patterns and the incentives that may follow from linking payment to pharmacy use warrant further research. PMID- 11606874 TI - Understanding patient preferences for the treatment of lupus nephritis with adaptive conjoint analysis. AB - BACKGROUND: Incorporation of patient preferences into treatment decisions is an essential component of medical care. Conjoint analysis is an established method of eliciting consumer preferences in market research and is being increasingly used to study patient preferences for health care. OBJECTIVE: To examine the value of Adaptive Conjoint Analysis (ACA), a unique method of performing conjoint analysis, and to evaluate patient treatment preferences. RESEARCH DESIGN: Interactive computer survey. SUBJECTS: Consecutive women (n = 103) with lupus followed in three community rheumatology practices. MEASURES: ACA was used to assess patients' relative preferences for specific cytotoxic medication characteristics, and to estimate the percentage of women preferring cyclophosphamide over azathioprine for different risk-benefit scenarios. RESULTS: All participants were able to complete the conjoint task in 14 +/-5 minutes. Of the nine medication characteristics studied, efficacy and risk for infection had the greatest impact on preference (each accounting for 20% of the variation in preferences), suggesting that patients consider differences in the risk for infection equally as important as differences in the probability of renal survival. Premenopausal women wanting more children were less likely to choose cyclophosphamide compared with their counterparts (56% vs. 80%, P = 0.04). Modest changes in the probability of renal survival or risk for major toxicity lowered the percentage of women preferring cyclophosphamide by more than 20%, irrespective of their desire for more children. CONCLUSIONS: ACA is a feasible method of assessing how patients consider specific medication characteristics and predicting treatment preferences under different risk-benefit scenarios. ACA may be a valuable tool to incorporate patient preferences into medical decision making. PMID- 11606875 TI - Chronic disease self-management program: 2-year health status and health care utilization outcomes. AB - OBJECTIVES: To assess the 1- and 2-year health status, health care utilization and self-efficacy outcomes for the Chronic Disease Self-Management Program (CDSMP). The major hypothesis is that during the 2-year period CDSMP participants will experience improvements or less deterioration than expected in health status and reductions in health care utilization. DESIGN: Longitudinal design as follow up to a randomized trial. SETTING: Community. PARTICIPANTS: Eight hundred thirty one participants 40 years and older with heart disease, lung disease, stroke, or arthritis participated in the CDSMP. At 1- and 2-year intervals respectively 82% and 76% of eligible participants completed data. MAIN OUTCOME MEASURES: Health status (self-rated health, disability, social/role activities limitations, energy/fatigue, and health distress), health care utilization (ER/outpatient visits, times hospitalized, and days in hospital), and perceived self-efficacy were measured. MAIN RESULTS: Compared with baseline for each of the 2 years, ER/outpatient visits and health distress were reduced (P <0.05). Self-efficacy improved (P <0.05). The rate of increase is that which is expected in 1 year. There were no other significant changes. CONCLUSIONS: A low-cost program for promoting health self-management can improve elements of health status while reducing health care costs in populations with diverse chronic diseases. PMID- 11606876 TI - Breast cancer stage at diagnosis in relation to duration of medicaid enrollment. AB - BACKGROUND: Stage at diagnosis has been used to compare the quality of cancer screening services by health insurance type, using membership at diagnosis or treatment. This study evaluates breast cancer stage among women on Medi-Cal, California's Medicaid program, in relation to duration of coverage to assess the impact of including women with recently acquired benefits in the Medi-Cal group. METHODS: Breast cancers diagnosed in 1993 among women ages 30 to 64 were obtained from the statewide, population-based cancer registry and linked to Medi-Cal enrollment files. Women on Medi-Cal when diagnosed were categorized based on months covered during the 12 months preceding diagnosis (12, 1-11, or none), and compared with all other women with breast cancer. Logistic regression models measured the effect of duration of Medi-Cal coverage on the odds of late-stage disease, controlling for demographic, socioeconomic, health access, and tumor characteristics. RESULTS: Among women with Medi-Cal benefits when diagnosed, 18% were not covered during the year preceding diagnosis, and late-stage disease was common among these women. The odds ratio for late-stage disease among all women on Medi-Cal was 1.67 (95% CI 1.41, 1.97), but was reduced by 42% to 1.39 (95% CI 1.15, 1.67) when women without benefits before diagnosis were excluded from the Medi-Cal group. CONCLUSIONS: Women with Medi-Cal benefits before diagnosis were more likely to be diagnosed with late-stage disease than other women with breast cancer. However, the practice of assigning health insurance status based on enrollment at diagnosis underestimates the effect of access to breast cancer screening through Medicaid. PMID- 11606877 TI - Reducing the cost of frequent hospital admissions for congestive heart failure: a randomized trial of a home telecare intervention. AB - BACKGROUND: The high cost of caring for patients with congestive heart failure (CHF) results primarily from frequent hospital readmissions for exacerbations. Home nurse visits after discharge can reduce readmissions, but the intervention costs are high. OBJECTIVES: To compare the effectiveness of three hospital discharge care models for reducing CHF-related readmission charges: 1) home telecare delivered via a 2-way video-conference device with an integrated electronic stethoscope; 2) nurse telephone calls; and 3) usual outpatient care. RESEARCH DESIGN: One-year randomized trial. SUBJECTS: English-speaking patients 40 years of age and older with a primary hospital admission diagnosis of CHF. MEASURES: Our primary outcome was CHF-related readmission charges during a 6 month period after randomization. Secondary outcomes included all-cause readmissions, emergency department (ED) visits, and associated charges. RESULTS: Thirty-seven subjects were randomized: 13 to home telecare, 12 each telephone care and 12 to usual care. Mean CHF-related readmission charges were 86% lower in the telecare group ($5850, SD $21,094) and 84% lower in the telephone group ($7320, SD $24,440) than in the usual care group ($44,479, SD $121,214). However, the between-group difference was not statistically significant. Both intervention groups had significantly fewer CHF-related ED visits (P = 0.0342) and charges (P = 0.0487) than the usual care group. Trends favoring both interventions were noted for all other utilization outcomes. CONCLUSIONS: Substantial reductions in hospital readmissions, emergency visits, and cost of care for patients with CHF might be achieved by widespread deployment of distance technologies to provide posthospitalization monitoring. Home telecare may not offer incremental benefit beyond telephone follow-up and is more expensive. PMID- 11606878 TI - Can utility-weighted health-related quality-of-life estimates capture health effects of quality improvement for depression? AB - BACKGROUND: Utility methods that are responsive to changes in desirable outcomes are needed for cost-effectiveness (CE) analyses and to help in decisions about resource allocation. OBJECTIVES: Evaluated is the responsiveness of different methods that assign utility weights to subsets of SF-36 items to average improvements in health resulting from quality improvement (QI) interventions for depression. DESIGN: A group level, randomized, control trial in 46 primary care clinics in six managed care organizations. Clinics were randomized to one of two QI interventions or usual care. SUBJECTS: One thousand one hundred thirty-six patients with current depressive symptoms and either 12-month, lifetime, or no depressive disorder identified through screening 27,332 consecutive patients. MEASURES: Utility weighted SF-12 or SF-36 measures, probable depression, and physical and mental health-related quality of life scores. RESULTS: Several utility-weighted measures showed increases in utility values for patients in one of the interventions, relative to usual care, that paralleled the improved health effects for depression and emotional well being. However, QALY gains were small. Directly elicited utility values showed a paradoxical result of lower utility during the first year of the study for intervention patients relative to controls. CONCLUSIONS: The results raise concerns about the use of direct single item utility measures or utility measures derived from generic health status measures in effectiveness studies for depression. Choice of measure may lead to different conclusions about the benefit and CE of treatment. Utility measures that capture the mental health and non-health outcomes associated with treatment for depression are needed. PMID- 11606879 TI - Race and preventive services delivery among black patients and white patients seen in primary care. AB - BACKGROUND: Numerous studies have documented racial disparities in delivery of health care treatment services, but there is little information to determine whether similar disparities exist in the delivery of preventive services. OBJECTIVE: To determine if disparities exist in preventive service delivery to non-Hispanic white patients and black patients in primary care. RESEARCH DESIGN: Multimethod study using direct observation of patient encounters, medical record review, and patient exit questionnaire. SUBJECTS: Four thousand three hundred thirteen outpatients presenting to 138 family physicians. MEASURES: Delivery of 15 screening, 24 health-habit counseling and 11 immunization services recommended by the US Preventive Services Task Force. RESULTS: Using multilevel linear regression analysis, no significant racial differences were found in rates of delivery of screening services or immunizations. However, black patients were more likely to receive preventive health-habit counseling (mean percent of patients up-to-date on all recommended counseling services, adjusted for covariates: 11.6% for black patients, 9.5% for whites, P = 0.003). CONCLUSIONS: Black patients able to access primary care receive preventive services at rates equal to or greater than white patients. This suggests that efforts to increase delivery of preventive care in black patients need to focus on access to primary care. PMID- 11606880 TI - Radioiodine and Graves' ophthalmopathy reconsidered. PMID- 11606881 TI - Hybridization and cell uptake studies with radiolabelled antisense oligonucleotides. AB - BACKGROUND: Radiolabelled antisense oligonucleotides have been proposed as radiopharmaceuticals for imaging changes in the level of gene expression in vivo. This paper describes a study of the uptake of radiolabelled oligonucleotides in cell lines expressing different levels of the target mRNA. METHODS: A 15-mer phosphorodiester deoxyoligonucleotide antisense to c-myc was labelled with 99mTc and 32P. Hybridization and stability studies were performed in vitro. Cell uptake studies were carried out in a c-myc expressing transformed rat embryonic fibroblast cell-line, TGR-1, and a knock-out cell line HO15.19 which does not express c-myc. RESULTS: The oligonucleotides were efficiently labelled with both radionuclides and retained their ability to hybridize with their complementary mRNA when extracted from cell lines. The radiolabelled oligonucleotides were stable for a few hours in human serum. No statistically significant difference was found between the uptake of radioactivity by the two cell lines. CONCLUSIONS: Although able to bind efficiently to their target in cell-free systems, radiolabelled oligonucleotides may be prevented from performing effectively as radiopharmaceutical vectors by the barriers imposed by cell membranes and/or intracellular metabolism. PMID- 11606882 TI - Scatter modelling and correction strategies in fully 3-D PET. AB - PET offers the possibility of quantitative measurements of tracer concentration in vivo. However, there are several issues that must be considered in order to fully realise this potential. Whilst, a correction for a number of background and physical phenomena need to be performed, the two most significant effects are the photon attenuation in the patient and the contribution in the images of events arising from photons scattered in the patient and the gantry. The non-homogeneous distribution of attenuation within the thoracic cavity complicates the interpretation of PET images and precludes the application of simple scatter correction methods developed for homogeneous media. The development of more sophisticated techniques for quantification of PET images are still required. Recent progress in 3D PET instrumentation and image reconstructions has created a need for a concise review of the relevance and accuracy of scatter correction strategies. Improved quantification of PET images remains an area of considerable research interest and several research groups are concentrating their efforts towards the development of more accurate scatter modelling and correction algorithms. PMID- 11606883 TI - Coincidence detection FDG PET in the management of oncological patients: attenuation correction versus non-attenuation correction. AB - The aim of this study was to determine if attenuation correction (AC) in a dual head, coincidence, positron emission tomography imaging system (Co-PET) improved image quality, lesion detection, patient staging and management of various malignant neoplasms, compared to non-attenuation corrected (NAC) images. Thirty patients with known or suspected malignant neoplasms underwent fluorodeoxyglucose (FDG) Co-PET, which was correlated with histopathology, computed tomography (CT) and other conventional imaging modalities and clinical follow-up. The number and location of FDG avid lesions detected on the AC images and NAC Co-PET images were blindly assessed by two independent observers. Semi-quantitative grading of image clarity and lesion-to-background quality was performed. This revealed markedly improved image clarity and lesion-to-background quality in the AC versus NAC Co PET images. AC Co-PET was statistically superior to NAC Co-PET in relation to lesion detection (P<0.01) and tumour staging (P<0.01). NAC Co-PET demonstrated 51 of the 65 lesions (78%) detected by AC Co-PET. AC Co-PET altered tumour staging in five additional patients (16%) compared to NAC Co-PET. Management was altered in two of these five patients. PMID- 11606884 TI - Demonstration of different patterns of musculoskeletal, soft tissue and visceral involvement in melioidosis using 99m Tc stannous colloid white cell scanning. AB - Melioidosis is an infectious disease that can present with multiple foci of disease involvement. Assessment of disease extent can be difficult, especially in musculoskeletal, visceral and soft tissue infection. This study examined the usefulness of white cell scans in this condition. 99mTc stannous colloid white cell scanning was performed in 21 patients with culture-proven melioidosis. Scan results were compared with clinical assessment and correlated with other forms of imaging. White cell scans demonstrated all but one of the clinically apparent sites of musculoskeletal, visceral and other soft tissue infection. Unsuspected disseminated soft tissue lesions were seen in two patients, including femoral node uptake in both, and these patients subsequently presented with relapsing musculoskeletal disease. Unsuspected musculoskeletal disease was found in one patient. Clinically suspected musculoskeletal disease was accurately excluded by white cell scan in another patient. The results of white cell scanning were also examined in disease of other viscera. Renal and prostatic disease were visualized. Unsuspected parotid involvement was found in two patients. Only one of two spinal lesions was visualized. Pulmonary disease was not necessarily associated with abnormal uptake. White cell scanning is a quick and effective way of assessing the extent of musculoskeletal, visceral and soft tissue disease in melioidosis. PMID- 11606885 TI - Diagnosis of bone infection using 99m Tc-HMPAO labelled leukocytes. AB - In order to evaluate the importance of 99mTc-hexamethylpropylene amine oxime (99mTc-HMPAO) leukocyte scintigraphy in the diagnosis of bone infection, we retrospectively reviewed 324 patients. Abnormal findings were seen in 221 patients. In the other 103 cases acute pathological inflammation could be ruled out. The patients with pathological findings were divided into four groups according to the location of the infection. This method showed the localizations of skeletal disorders and its differences to other diagnostic imaging modalities. The underlying abnormalities causing the inflammation were determined. In conclusion, 99mTc-HMPAO leukocyte scintigraphy is still a very sensitive method for either whole body screening or local detection of acute or exacerbated chronic osteomyelitis. The advantages of this method over other diagnostic imaging methods are shown. PMID- 11606886 TI - Quantitative analysis of striatal dopamine D2 receptors with 123 I-iodolisuride SPECT in degenerative extrapyramidal diseases. AB - 123I-Iodolisuride has high specific affinity for binding on dopamine D2 receptors in the striatum and has been used in a few single photon emission computed tomography (SPECT) studies of extrapyramidal disorders. The diagnosis of Parkinson's disease (PD) is very difficult in the first 5 years of evolution, with 15-25% false positive diagnoses. The aim of this study was therefore to determine the value of iodolisuride SPECT in discriminating Parkinson's from the most frequent Parkinson-plus syndromes (PPS). Seventeen patients with an extrapyramidal syndrome had a SPECT examination 1 h after injection of 180-185 MBq of 123I-iodolisuride. They were followed under dopaminergic treatment for at least 2 years. After 2 years, they were separated in two groups according to specific clinical criteria and sensitivity to dopaminergic treatment: nine patients had PD (age = 59.8+/-8.8 years; Hoehn and Yahr = 1.8+/-0.7; evolution = 4.3+/-3 years) and eight had PPS (age = 71.6+/-7.3 years; Hoehn and Yahr = 2.9+/ 2.0; evolution = 4.1+/-1.5 years). The binding potential of iodolisuride in the striatum was assessed by considering the striatum (S)/occipital lobe (O) ratio at the pseudo-equilibrium 1 h after injection. The S/O ratio was statistically different between PD and PPS (1.97+/-0.3 vs. 1.65+/-0.2 (P<0.02)). Iodolisuride SPECT could differentiate both groups with a sensitivity of 88.8% and a specificity of 75%. Iodolisuride is a good specific D2 receptor ligand for SPECT and complements specific clinical criteria for the diagnosis of Parkinson's disease and differentiation between different extrapyramidal disorders. PMID- 11606887 TI - Reproducibility of [11 C]FLB 457 binding in extrastriatal regions. AB - Extrastriatal D2 dopamine receptors represent an important target of research into the pathophysiology and pharmacotherapy of psychiatric disorders. The high affinity radioligand [11C]FLB 457 makes possible the measurement of low concentrations of D2 receptors in extrastriatal regions using positron emission tomography (PET). The aim of this study was to assess the test/retest variability and reliability of [11C]FLB 457 binding using a reference tissue model. Eight healthy male subjects (aged 20-33 years) underwent two [11C]FLB 457 PET examinations. Radioactivity in the cerebellum was used as the reference. The binding potentials (BPs) for five cortical regions of interest (ROIs) were calculated using the reference tissue model. The BP was also calculated for each pixel in the form of parametric images. Reproducibility was assessed both for the ROI method and for the parametric images. The test/retest reproducibility for [11C]FLB 457 binding was good, with a mean variability ranging from 4.5% for the thalamus to 15.5% for the hippocampus. The parametric images also demonstrated good reproducibility. These results support the suitability of using [11C]FLB 457 for the quantitative evaluation of extrastriatal D2 receptors and for protocols requiring repeated measurements in the same individual. PMID- 11606888 TI - Reverse redistribution of 99m Tc-sestamibi after direct percutaneous transluminal coronary angioplasty in acute myocardial infarction: relationship with wall motion and functional response to dobutamine stimulation. AB - Reverse redistribution (RR) of 99mTc-sestamibi is observed after direct percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction (AMI). The purpose of this study was to clarify the functional characteristics of myocardial segments with RR after direct PTCA in AMI. Thirty patients with AMI who had undergone direct PTCA were examined. Myocardial perfusion tomography with 99mTc-sestamibi and low dose dobutamine echocardiography were performed within 2 weeks of the onset. The 99mTc-sestamibi images were obtained 1 and 3 h after tracer administration. The left ventricle was divided into nine segments, and regional 99mTc-sestamibi uptake and clearance were quantitatively evaluated in each segment. RR was defined as a decrease in 99mTc-sestamibi uptake of >10% on 3 h delayed images compared with the 1 h early images. The left ventricle in the echocardiographic images was also divided into nine segments corresponding to the scintigraphic images, and regional wall motion was assessed in the resting condition as the baseline and during dobutamine administration (5-10 microg x kg(-1) x min(-1)). Out of a total of 270 myocardial segments, 111 segments were perfused by the culprit coronary artery and were defined as ischaemic segments. There were 25 segments with RR and 86 segments without RR in the ischaemic myocardium. Enhanced clearance of 99mTc-sestamibi was observed in ischaemic segments with RR (P<0.001). Echocardiography demonstrated that 24 out of 25 segments with RR and 61 out of 86 segments without RR had wall motion abnormalities. Dobutamine infusion improved wall motion in 20 (83%) of the 24 dysfunctional segments with RR and 33 (54%) of the 61 dysfunctional segments without RR (P<0.02). These findings suggest that RR indicates reversible functional abnormalities associated with preserved contractile reserve in response to dobutamine. The early and delayed imaging of 99mTc-sestamibi provides useful information regarding the residual viability of the dysfunctional myocardium in AMI patients. PMID- 11606889 TI - Importance of positioning and frequency of unexpected scintigraphic findings in a high impact sport. AB - Stress-related injuries have been reported for numerous forms of exercise and sport. The patterns of injury and the incremental value of specially developed views were retrospectively reviewed at the end of three successive playing seasons of Australian football. The primary sites of clinical trauma were imaged, as were immediately adjacent bones and joints in order to assess concurrent trauma, and an attempt was made to evaluate the need to extend the area of scanning. Of the injuries detected, 67% of the total occurred at or below the level of the knee. Fifty-five per cent of these injuries occurred in the tibiae, fibulae and bones of the foot in a pattern reflecting the nature of the traumatic insult recurring in this particular sport. An incremental value of 28% was found for the specially developed views. Clinically unsuspected pathology was found in 54% of cases. PMID- 11606890 TI - Occurrence of pulmonary thromboembolism immediately after arthroplasty. AB - INTRODUCTION: Respiratory complications are common after arthroplasty, with pulmonary thromboembolic disease (PTE) and fat emboli being the most serious. A scintigraphic study was designed to assess the occurrence of both diseases. A prospective tomographic study of perfusion was performed within 24 h of arthroplasty. Details of the detection of fat embolism will be presented elsewhere. METHODS: Patients with previous PTE were excluded. Tomographic lung studies were acquired after 99mTc-macroaggregated albumin injection. Pre- and post-operative arterial blood gases (ABGs) and relevant chest radiography/computed tomography scans were obtained. ABGs were analysed as the difference in alveolar-arterial oxygen gradients, pre- and post-operatively (DA a). RESULTS: Forty patients were studied (16F, 24M) with a mean age of 71 years (range 36-88 years). Of these, 16 were hip and 24 knee arthroplasties. PTE was detected in 25 of 38 (66%) patients evaluated. The value of DA-a was significantly different between patients with PTE and without PTE (P>0.05). Administration of prophylactic pre-operative low molecular weight heparin makes no difference to the early onset of PTE. CONCLUSION: There is a high incidence of PTE immediately after arthroplasty. PMID- 11606891 TI - The role of 99m Tc-sestamibi scintimammography and colour Doppler ultrasonography in the evaluation of breast lesions. AB - In the present study we evaluated comparatively the diagnostic value of mammography, of 99mTc-sestamibi scintimammography (sestamibi-SC) and of colour Doppler ultrasonography (CD-US) in 116 breast lesions. Diagnosis was based on histopathological examination. Overall, out of 86 malignant tumours, 80 (93%) and 75 (87%) had a positive sestamibi-SC and positive CD-US, respectively. Out of 30 benign lesions, 25 (83%) and 26 (87%) had a negative sestamibi-SC and negative CD US respectively. The true positive results were similar in palpable and in non palpable lesions for both methods. Out of 19 non-palpable malignant tumours, mammography confirmed malignancy in only one case (5%), which was significantly lower than the results obtained by sestamibi-SC (89%; Px0.0001) and by CD-US (74%; P=0.0001). In palpable malignant tumours, by using mamography, true positive results were obtained in 54/67 (80.5%) patients, which was significantly lower than the results obtained by sestamibi-SC (94%; P=0.03) and marginally different to the results obtained by CD-US (91%; P=0.13). It is concluded that sestamibi-SC and CD-US are useful tools in clarifying the nature of breast lesions in cases with doubtful mammography. The clinical value of these diagnostic procedures in guiding subsequent therapeutic interventions requires further investigation. PMID- 11606892 TI - Different patterns of lymphoscintigraphic findings in patients with intestinal lymphangiectasia. AB - Technetium-99m antimony sulfide colloid lymphoscintigraphy conveniently demonstrates intestinal leakage of lymph in patients with intestinal lymphangiectasia. However, we found no intestinal radioactivity in some patients. We evaluated lymphoscintigraphic findings and compared them with clinical data. Technetium-99m antimony colloid lymphoscintigraphy was performed in 12 patients (age, 8.9+/-6.4 years; male:female=8:4) with histologically proven intestinal lymphangiectasia. After subcutaneous injection of 103.6 MBq of technetium-99m antimony colloid into the webs of both feet, sequential abdominal images were obtained up to 24 h post-injection. Four patients underwent technetium-99m methylene diphosphonate bone scintigraphy. Patients were divided into two groups according to the presence or absence of intestinal radioactivity. Five showed intestinal activity (Group 1), but seven did not (Group 2). No Group 1 patient had a history of ascites, while all Group 2 patients had ascites as the initial manifestation. Serum total protein and albumin levels were significantly lower in Group 1 patients than in Group 2 patients. In three Group 1 patients, technetium 99m methylene diphosphonate bone scintigraphy revealed intestinal radioactivity, while in one Group 2 patient this was not found. We observed two types of lymphoscintigraphic pattern in patients with intestinal lymphangiectasia. To clarify the exact pathophysiology, further study is required. PMID- 11606893 TI - Is deconvolution applicable to renography? AB - The feasibility of deconvolution depends on many factors, but the technique cannot provide accurate results if the maximal transit time (MaxTT) is longer than the duration of the acquisition. This study evaluated whether, on the basis of a 20 min renogram, it is possible to predict in which cases the MaxTT will exceed 20 min. Renograms of various shapes were simulated by convolution of a plasma disappearance curve and various created retention functions with a mean transit time (MTT) ranging from 3 to 23 min. The values of MaxTT were then derived from the created curves and compared to three parameters of transit measured on the renograms: the time to reach the maximum of the curve (Tmax), the output efficiency at 20 min (OE20), and the normalized residual activity at 20 min (NORA20). The proportion of retention functions (n=390) with MaxTT>20 min increased with increasing Tmax (e.g. 9% for 6< or =Tmax<10 min, and 34% for 11< or =Tmax<15 min), increasing NORA20 (e.g. 20% for 1.4< or =NORA20<3.0, and 84% for 3.0< or =NORA20<5.0) and decreasing OE20 (19% for 50% 99%), as estimated by chromatography, and this correlates very well with the minimal or no renal uptake of this compound in patient studies. PMID- 11606895 TI - A collimator with a magnetic personality? AB - We report an unusual technical problem with a gamma camera fitted with a pinhole collimator. An unexpected decrease of approximately 20 keV in the energy of the 99mTc photopeak is seen if the (circular) collimator is rotated relative to the camera head. The centreline of the photopeak varied over the range 118-141 keV depending on the orientation of the collimator. The count rate and photopeak width changed concurrently. Image uniformity was severely degraded for lower peak energies. The reason for this behaviour is that the pinhole collimator had become magnetized. The magnetic field was measured and had maximum values of 1.0 mT at the edge and 0.1 mT near the camera face. The magnetic field strongly influenced the response of the photomultiplier tubes. We conclude that acceptance testing of gamma cameras should include a check for collimator magnetization. PMID- 11606896 TI - Drugs and vaccines for biological weapons. PMID- 11606897 TI - Insulin aspart, a new rapid-acting insulin. PMID- 11606898 TI - Rural life and elder needs. PMID- 11606899 TI - Nursing perspectives on the health care of rural elders. AB - Nurses can play a significant role in providing culturally sensitive, community based health care to rural elders. Health promotion, education, and coordination of care across settings are needed. Unfortunately, rural elders have limited access to nursing care and health care services in general. Inadequate financial support and inflexible reimbursement continue to impede accessibility to health care in those communities. Interdisciplinary collaboration and education models, nurse-managed clinics, and other innovative programs to improve quality and accessibility of health care for rural elders are being explored and evaluated. PMID- 11606901 TI - Home adaptation: helping older people age in place. AB - As people age, decrements in sensory, motor, and cognitive function often jeopardize their ability to manage activities of daily living safely and comfortably in their own homes. The purposes of this article are to discuss common problems faced by many elders who want to remain at home, present information about possible solutions that increase their safety and comfort, and provide resources for additional information on assistive products. PMID- 11606900 TI - Themes of rural health and aging from a program of research. AB - The culture and diversity of rural life and limitations of rural health systems to meet the changing health needs of an aging population lead to problems of obtaining appropriate care in rural America. In a program of nursing research involving three ethnographic studies in rural Colorado, transitions of older adults across differing levels of heath care were explored. The sample totaled 425 participants, of whom 25% were Hispanic. Five major themes emerged: circles of formal and informal care; integration of faith, spirituality, and family with health status; crisis nature of health care transitions; nursing homes as a housing option; and changing spirit of traditional rural nursing. Recommendations for providers included making their practices congruent with rural culture, being fully informed of available resources, facilitating acceptable health care decisions, and integrating physical, mental, and spiritual health care for elders and their families. PMID- 11606903 TI - Telephone screening of older adults using the Orientation-Memory-Concentration test. AB - The inability to efficiently screen the cognitive status of homebound elderly patients can hamper clinicians' ability to plan for safe, appropriate care. In this study, the six-item Orientation-Memory-Concentration (OMC) Test was administered to 12 elderly patients during a routine office visit. That same afternoon, each participant was called at home and the OMC repeated by telephone. Test-retest correlation was excellent (Pearson's correlation =.992). Concurrent validity was supported by complete (100%) agreement between the clinicians' subjective impressions of the patients' mental status and OMC ratings. The outcome implies that telephone screening of cognitive status can be reliable. PMID- 11606902 TI - Home visits after hospitalization: enhancing baccalaureate nursing students' gerontologic clinical experience. AB - This article describes posthospitalization visits by 83 nursing students to 57 older patients and their caregivers discharged from two large academic medical centers and one community hospital. Patient and caregiver interviews in the home focused on the areas of geriatric assessments of cognitive and functional status, patient and caregiver satisfaction with recent hospitalization, ongoing health management, patient teaching, and discharge planning. PMID- 11606904 TI - Health barriers to walking for exercise in elderly primary care. AB - Health status is acknowledged by nursing theory as a factor in the probability of health behavior changes. Yet few studies have addressed the health-related barriers encountered by chronically ill elderly patients in primary care clinics who are trying to increase their physical activity. This study used self- and interviewer-administered instruments to assess potential barriers to physical activity in a sample of 60- to 80-year-old patients entering a walking program. Pain, fatigue, and mobility and sensory impairments were prevalent and could be significant barriers to participation. The authors present specific suggestions for helping patients overcome these barriers. PMID- 11606905 TI - Nurse practitioners in rural settings. Interview by Bernardine Gorek. PMID- 11606906 TI - JoAnn Congdon, PhD, RN, CNS, and Mary Ann Rosswurm, EdD, RN, CS, FAAN: meeting the unique needs of elders in rural settings. AB - In this issue, we salute two of the outstanding teachers, researchers, and geriatric nurse practitioners who have contributed to the understanding of the health issues confronted by rural elders: JoAnn Congdon, PhD, RN, CNS, and Mary Ann Rosswurm, EdD, RN, CS, FAAN. Their personal views and significant thoughts related to this professional propensity are inspiring, In addition to their articles ("Themes of Rural Health and Aging," page 234, and "Nursing Perspectives on the Health Care of Rural Elders," page 231 ), this column features a review of their careers in their own voices. JoAnn relates the roots and progression of her interest in the rural aged with insight and enthusiasm. Her sensitive and thoughtful account emphasizes the consummate importance of mentorship and teamwork in the development of professional direction and sustained interest. Mary Ann, inquisitive as a child, has broad interests and was drawn to the diversity of individuals. Role models and mentors were critical to her development, but circumstance played a large part in her interest in rural elders. Her love of life and new experience shines through in the personal thoughts she presents here. PMID- 11606908 TI - Alzheimer disease and alternative approaches to care a clinical snapshot. PMID- 11606910 TI - Update on statins and other lipid-lowering drugs. PMID- 11606909 TI - Community-based case management for positive outcomes. AB - After identifying high risk patients or high users of costly services, a rural community hospital implemented a community-based case management program that yielded positive results not only in cost containment but also in client-focused outcomes. The implementation of the program is described, as are the results of the outcomes measures affecting cognition, activities of daily living, instrumental activities of daily living, and nutritional risk. Additionally, use of health care resources and associated cost-savings data are discussed. PMID- 11606911 TI - Update on rural health activities: the home health perspective. PMID- 11606912 TI - Meatless diets part 2. PMID- 11606913 TI - Treatment of psoriasis. Part 2. Systemic therapies. AB - The array of systemic medications used in the treatment of psoriasis is rapidly expanding. In the United States, methotrexate, retinoids, and cyclosporine are the only systemic drugs approved by the Food and Drug Administration for the treatment of psoriasis. Monitoring and dosage recommendations for these medications are reviewed. Other drugs that are currently available include tacrolimus, mycophenolate mofetil, hydroxyurea, 6-thioguanine, and sulfasalazine. Experience with these drugs is summarized, and dosage and monitoring recommendations in published literature are presented. Combinations of different treatments are addressed and investigational therapies that are in development are reviewed. PMID- 11606914 TI - The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody. AB - BACKGROUND: Anti-CD11a (hu1124) is a humanized monoclonal antibody directed against the CD11a subunit of LFA-1. This study investigated whether treatment with anti-CD11a antibody provides clinical benefit to patients with moderate to severe plaque psoriasis. METHODS: This was a double-blind, placebo-controlled, phase II, multicenter study. In total, 145 patients with minimum Psoriasis Area and Severity Index scores of 12 and affected body surface area of 10% or more were sequentially enrolled into low-dose (0.1 mg/kg, n = 22) or high-dose (0.3 mg/kg, n = 75) groups. Within groups, patients were randomized to treatment or placebo (n = 48) in a 2:1 ratio. Drug was administered intravenously at weekly intervals for 8 weeks. RESULTS: The percentage of subjects achieving more than 50% improvement in physician's global assessment at day 56 (1 week after final dose) was 15% and 48% for placebo and 0.3 mg/kg of drug, respectively (P =.002). A physician's global assessment of excellent (>75% improvement) was greater in the 0.3 mg/kg group versus placebo (25% vs 2%, P =.0003). Average Psoriasis Area and Severity Index scores at day 56 were 13.9 +/- 7.5 (placebo) and 10.9 +/- 8.4 (0.3 mg/kg) (P <.0001). Epidermal thickness was reduced in the 0.3 mg/kg group compared with the placebo group (37% vs 19%, P =.004). Treatment was well tolerated; mild to moderate flu-like complaints were the most common adverse events. White blood cell counts and lymphocyte counts transiently increased. Depletion of circulating lymphocytes did not occur. CONCLUSIONS: Anti-CD11a antibody administered intravenously in 8 weekly doses of 0.3 mg/kg was well tolerated and induced clinical and histologic improvements in psoriasis. PMID- 11606915 TI - The incidence of erythroderma: a survey among all dermatologists in The Netherlands. AB - BACKGROUND: Erythroderma is a rare skin disorder, and studies on its incidence and causes are lacking. The annual incidence has been estimated to be 1 to 2 patients per 100,000 inhabitants. OBJECTIVE: We investigated the incidence and cause of erythroderma in an unselected population and evaluated the referral pattern of erythrodermic patients by nonacademic dermatologists. METHODS: A survey was performed among all nonacademic dermatologists in The Netherlands, using a mailed questionnaire. Questions dealt with the number of patients diagnosed with erythroderma in the year 1997, the cause of the erythroderma, and whether these patients were referred to a university hospital. A questionnaire was also sent to all university hospitals. RESULTS: Seventy-eight percent of the nonacademic dermatologists answered the questionnaire, and all 8 university hospitals responded. In the year 1997, 141 patients were diagnosed with erythroderma in The Netherlands. The annual incidence of erythroderma based on these figures is 0.9 patients per 100,000 inhabitants. Compared with the university hospitals, erythroderma was more often diagnosed as an exacerbation of preexisting dermatoses (61% vs 51%; P =.37) and less often as idiopathic (14% vs 31%; P =.04) among the nonacademic dermatologists. Cutaneous T-cell lymphoma was rarely the cause, occurring in only 1% of patients diagnosed by the nonacademic dermatologists but in 6% of patients at the university hospitals. Overall, only 37% of nonacademic dermatologists referred patients with erythroderma to a university hospital. CONCLUSIONS: The incidence of erythroderma in The Netherlands is slightly lower than the earlier estimate in the literature. Moreover, the cause of erythroderma is different among patients diagnosed in an academic and a nonacademic setting. The majority of dermatologists in The Netherlands treat patients with erythroderma themselves and do not refer these patients to university hospitals. PMID- 11606916 TI - Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. AB - BACKGROUND: Severe pemphigus vulgaris (PV) is conventionally treated with high dose oral prednisone, usually in combination with an immunosuppressive agent (ISA). Some patients experience significant side effects, which are sometimes fatal, from prolonged immunosuppression. OBJECTIVE: Intravenous immunoglobulin (IVIg) was administered to 21 patients with severe cutaneous and mucosal PV who had not responded to the prolonged use of oral prednisone and multiple ISAs. METHODS: A preliminary dose-determination study tested 7 additional volunteers to ascertain the optimal IVIg dose of 2 g/kg per cycle. Parameters to assess clinical outcome were recorded before and after IVIg therapy. Variables tested were highest dose, total dose, and duration of prednisone and ISAs, their side effects, frequency of recurrence and relapse, duration of IVIg therapy, clinical response, induction and duration of remission, number of hospitalizations, total days of hospital stay, and quality of life. RESULTS: Use of IVIg monotherapy resulted in effective control of disease and produced a sustained remission in the 21 patients. The patients became free of lesions and remained so after finishing IVIg therapy. IVIg had a steroid-sparing effect and produced a high quality of life. Serious side effects from the use of IVIg were not observed. IVIg needs to be gradually withdrawn after achievement of clinical control. CONCLUSION: In patients with PV who do not respond to conventional immunosuppressants, IVIg appears to be an effective treatment alternative. Its early use is of significant benefit in patients who may experience life threatening complications from immunosuppression. IVIg is effective as monotherapy. PMID- 11606917 TI - Linear IgA bullous dermatosis in one of two piroxicam-induced eruptions: a distinct direct immunofluorescence trend revealed by the literature. AB - BACKGROUND: The report focuses first on two patients with piroxicam-induced bullous eruption, one whose disease was diagnosed as linear IgA bullous dermatosis (LABD) and the other with no disease-specific immunologic findings using immunofluorescence methods. A review of the literature points to a distinctive direct immunofluorescence feature of drug-induced LABD cases. OBJECTIVE: Our purposes were to focus on divergent piroxicam reactions and to compare immunofluorescence findings in our and other reported drug-induced LABD cases to randomly occurring LABD cases. METHODS: Direct and indirect immunofluorescence methods were used to study biopsy and serum samples from both cases and biopsy specimens of 40 other LABD cases. RESULTS: Tense blisters developed in two patients medicated with piroxicam. Immunofluorescence studies demonstrated deposits of IgA at the basement membrane zone (BMZ) in case 1 and only non-disease-specific fibrin deposits at the BMZ in case 2. Within 1 month of discontinuation of piroxicam, all lesions were gone in both patients. CONCLUSION: In LABD cases proven by direct immunofluorescence, (1) the index of suspicion of drug induction should be higher in cases with only IgA and no IgG in the BMZ; (2) possibly up to two thirds of all LABD cases may be drug induced; and (3) the negative immunofluorescence findings in case 2 and other cases reported in the literature suggest that LABD is one of several host responses in drug-induced blistering diseases. PMID- 11606918 TI - Medium-dose UVA1 phototherapy in localized scleroderma and its effect in CD34 positive dendritic cells. AB - BACKGROUND: UVA1 radiation seems to be effective in morphea. CD34+ dendritic cells are significantly decreased in lesional skin of morphea patients. OBJECTIVE: We evaluated the therapeutic effectiveness of medium-dose UVA1 phototherapy in localized scleroderma and its effect in the number of dermal CD34+ dendritic cells in skin biopsy specimens of these patients. METHOD: Patients were irradiated with UVA1 (30 J/cm(2)) 30 times. Dermal CD34+ dendritic cells were counted before and after therapy. RESULTS: There was clinical improvement after UVA1 irradiation. Dermal CD34+ dendritic cells significantly increased after UVA1 irradiation. CONCLUSION: Medium-dose UVA1 therapy is effective in the treatment of localized morphea. Effectiveness is associated with an increase in the number of CD34+ dendritic cells in the dermis. PMID- 11606919 TI - A modified staging classification for cutaneous T-cell lymphoma. AB - BACKGROUND: Despite refinements in the diagnosis of cutaneous T-cell lymphoma (CTCL), since 1979 there have been no changes to the staging of CTCL used to classify mycosis fungoides and Sezary syndrome. OBJECTIVE: We reviewed the current staging of CTCL and examined the usefulness of a new staging scheme for mycosis fungoides and Sezary syndrome. METHODS: We determined overall survival of 450 patients with mycosis fungoides and Sezary syndrome using the current and modified staging classifications. RESULTS: There were no significant differences between survival of patients with stage IB (patches/plaques involving greater than 10% body surface area) and IIA (peripheral adenopathy) disease and of patients with stage IIB (tumor) and III (erythroderma) disease. There was a significant difference in survival between patients with extensive patch versus extensive plaque stage disease. Modification of the current classification by splitting T2 into patch versus plaque stage disease and incorporating tumors and erythroderma into stage III proved superior to the current scheme in predicting overall survival. CONCLUSION: Modification of the current staging classification for CTCL yields subgroups useful in the prognostic assessment of CTCL. PMID- 11606920 TI - Are keloids really "gli-loids"?: High-level expression of gli-1 oncogene in keloids. AB - BACKGROUND: Keloids are a common lesion arising from sites of previous trauma and are a considerable source of morbidity because of continued growth of lesions, pruritus, and physical appearance. They consist of mesenchymal cells embedded in a stroma of disordered collagen matrix. Clinically, keloids are distinguished from scars in that keloids demonstrate continued growth over the borders of the original injury. Keloids appear with increased frequency in patients of African and Asian descent. Currently, no entirely satisfactory method of treatment exists for these lesions. Recently, a patient who was enrolled in a clinical trial of topical tacrolimus for atopic dermatitis applied this drug to a keloid and noted clearing. OBJECTIVE: Based on this clinical observation and the observation that rapamycin, a chemically similar compound to tacrolimus, is known to inhibit signaling from the gli-1 oncogene, we examined keloids and scars for expression of Gli-1 protein. METHODS: Skin sections from keloids and scars were examined by immunohistochemical staining for gli-1. To further confirm the presence of gli-1 expression in keloids, reverse transcriptase-polymerase chain reaction was carried out. RESULTS: Expression of gli-1 was strongly elevated in keloids compared with scars. CONCLUSION: These results provide a rationale for the treatment of keloids with topical rapamycin analogs, including tacrolimus. Clinical trials of topical tacrolimus are warranted. PMID- 11606921 TI - Fixed drug eruption induced by trimethoprim-sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype. AB - BACKGROUND: Recent reports indicated a significant association between fixed drug eruption (FDE) and HLA class I antigens. A strong correlation was found between B22 antigen and feprazone-induced FDE. OBJECTIVE: Our aim was to investigate the association between HLA class I antigens and FDE in Turkey, a country where feprazone is not on the market and trimethoprim-sulfamethoxazole is most often the offending drug. METHODS: HLA class I typing was performed by lymphocytotoxicity assay in 67 unrelated patients with FDE, all established by oral provocation. The frequencies are compared with those of 2378 control subjects. RESULTS: Significantly higher (P <.001) frequencies of the A30 antigen and A30 B13 Cw6 haplotype were found in 42 patients with FDE induced by trimethoprim-sulfamethoxazole. HLA-B55 (split of B22) was present exclusively in trimethoprim-sulfamethoxazole-induced FDE, and in higher frequency than in control subjects. CONCLUSION: To our knowledge, ours is the first report indicating a link between A30 B13 Cw6 haplotype and trimethoprim-sulfamethoxazole induced FDE. In addition, HLA-B22 was increased in patients with FDE caused by a drug other than feprazone. PMID- 11606922 TI - Implications of a utility model for ultraviolet exposure behavior. AB - Over the past several decades, the incidence of skin cancer has reached epidemic proportions. Despite numerous efforts to increase public awareness of the risks associated with solar radiation, people continue to sunbathe, use indoor tanning facilities, avoid photoprotective clothing, and fail to use sunscreen. We propose using an economic model, the utility model, to better understand how to reduce tanning behaviors. This model has been widely applied in financial decision making as well as in analysis of risk-taking behaviors such as smoking. The model takes into account both the current perceived benefits of tanning and the future long-term risks. People tend to discount the future; they tend to weigh current benefits more heavily than future risks. As predicted by the model, past prevention efforts that have focused on long-term benefits gained by sun protective behavior have been largely ineffective. In the current social environment, we cannot expect tanning reduction measures based solely on health education to be very effective. Only by changing public perceptions of a tan will efforts to decrease ultraviolet exposure behavior likely be successful. PMID- 11606923 TI - Once-daily topical metronidazole cream formulations in the treatment of the papules and pustules of rosacea. AB - BACKGROUND: The papules and pustules of rosacea can be effectively treated with topical metronidazole. The optimal concentrations of metronidazole and optimum frequencies of application are uncertain. Traditionally, twice-daily applications have been advised, based on the pharmacokinetic profile of metronidazole. Once daily applications may be safer and less expensive, and they may enhance patient compliance. OBJECTIVE: We compared the efficacy and safety of 2 commercially available topical metronidazole formulations (0.75% metronidazole cream formulation and 1.0% metronidazole cream formulation) when both were used in a once-daily regimen. METHODS: A multicenter, randomized, investigator-blind, parallel group trial was conducted at 3 separate clinical sites located in 3 US cities. The study enrolled 72 rosacea patients with at least 8 to 50 inflammatory facial lesions (pustules and papules) and moderately severe facial erythema. Patients were randomly assigned to receive either 0.75% metronidazole cream or 1.0% metronidazole cream and instructed to apply the medication once daily for 12 weeks. Patients' lesions were evaluated at baseline and at weeks 3, 6, 9, and 12. RESULTS: There were no significant differences between treatment groups for any of the efficacy parameters evaluated. The overall median percentage change in lesion count at end point for patients in the 0.75% metronidazole cream treatment group was -62% compared with -60% for the 1.0% metronidazole cream treatment group. The overall percentage change in erythema scores at endpoint for patients in the 0.75% metronidazole cream treatment group was -26% compared with -30% for patients in the 1.0% metronidazole cream treatment group. Regarding physician assessment of global severity, 57% of subjects (20/35) in the 0.75% metronidazole cream group compared with 37% of subjects (13/35) in the 1.0% metronidazole cream group were rated as having a clear to mild condition at end point. Both drugs were well tolerated; there was no significant difference in the number of drug related adverse events between the two agents. CONCLUSION: This controlled trial demonstrates that both 0.75% metronidazole cream and 1.0% metronidazole cream, when used once daily, provide well-tolerated efficacy for moderate to severe rosacea. PMID- 11606924 TI - Treatment of angiofibromas with a scanning carbon dioxide laser: a clinicopathologic study with long-term follow-up. AB - BACKGROUND: Facial angiofibromas in tuberous sclerosis have been managed with various treatment modalities, including carbon dioxide (CO(2)) laser resurfacing. OBJECTIVE: Our purpose was to perform a long-term clinicopathologic assessment of CO(2) laser treatment of angiofibromas. METHODS: This was a retrospective case review of 10 patients treated with a scanning CO(2) laser to flatten lesions. Baseline clinical photographs and those taken at 6, 12, and 24 months after the operation were assessed by a blinded observer. Patients also evaluated outcomes. Biopsy specimens taken immediately and at 4 months after the operation were reviewed. RESULTS: Three groups of patients were identified: the first comprised 2 patients with sustained excellent and good outcomes. A second group (3 patients) had excellent outcomes in the early and medium term but then demonstrated partial deterioration. The last group (5 patients) had a range of early results with invariably poor outcomes at 24 months. In contrast, patients' self-assessment at 24 months was good or excellent in 8 of 10 cases. All biopsy specimens taken immediately after the procedure demonstrated ablation extending into the papillary dermis. Residual angiofibromas were present in 6 biopsy specimens. At 4 months, all biopsy specimens showed a band of superficial dermal fibrosis, but distinguishing between this and adjacent angiofibromas was often difficult. Long-term side effects included 2 cases of subtle hypopigmentation. CONCLUSION: The long-term results of CO(2) laser treatment of angiofibromas are unpredictable. The marked improvement obtained at 6 months is sustained in only a minority of cases at 24 months. Despite this, patient satisfaction appears relatively high. Initial clinical improvement may be the result of a combination of destruction of angiofibromas and their sequestration under postoperative fibrosis. The benefits of therapy should be weighed against both early morbidity and the risks of long-term complications such as scarring and hypopigmentation. PMID- 11606925 TI - Macrolactam immunomodulators for topical treatment of inflammatory skin diseases. AB - The immunomodulatory macrolactams provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Tacrolimus (FK506), as well as the newer ascomycin derivative ASM 981 (pimecrolimus), penetrate the inflamed epidermis and are suitable for topical therapy. Both substances inhibit the transcription of proinflammatory cytokine genes such as interleukin 2, which are dependent on the nuclear factor NF-AT. They block the catalytic function of calcineurin, which leads to the inhibition of the transport of the cytoplasmic component of NF-AT to the cell nucleus. Multicenter, randomized, double-blind clinical trials with topical formulations have shown the efficacy of both substances in moderate to severe atopic dermatitis. A review is presented of the biochemical and cell biologic properties, mode of action, pharmacokinetic data, side effects, results of the clinical trials, and further indications for tacrolimus and ASM 981, along with an overview of the related substances cyclosporine and sirolimus (rapamycin). PMID- 11606926 TI - Neurofibromatosis type 2. PMID- 11606929 TI - Syringocystadenocarcinoma papilliferum: case report and immunohistochemical comparison with its benign counterpart. AB - Syringocystadenocarcinoma papilliferum (SCACP) is the malignant counterpart of syringocystadenoma papilliferum (SCAP), although only a few cases have been reported in the literature and its clinical and histologic characteristics are not well known. We report a case of SCACP that started as an enlarging nodule over 10 years in the perianal area of a 61-year-old man. Macroscopically, the lesion was a black exophytic tumor, 6 cm in diameter, with a granular surface. Histologically, it was an in situ adenocarcinoma, showing cytologic atypia and pagetoid spread in the surrounding epithelia, although the clinicopathologic features were distinct from extramammary Paget's disease. The tumor lacked the typical double-layered pattern of SCAP but had some similar histopathologic features to SCAP. Decapitation secretion was apparent and there was positive immunoreactivity to epithelial membrane antigen and human milk fat globules subclass 2. SCACP is a rare cutaneous tumor but nevertheless represents a specific dermatopathologic entity. PMID- 11606928 TI - Pemphigoid nodularis associated with autoantibodies to the NC16A domain of BP180 and a hyperproliferative integrin profile. AB - Pemphigoid nodularis, a rare variant of bullous pemphigoid, has clinical features resembling prurigo nodularis, with blisters arising from normal-appearing or nodular skin. The fine antigenic epitope of the autoantibodies and the mechanism accounting for the nodular phenotype has not been delineated. We describe a patient with pemphigoid nodularis that fulfilled the criteria of bullous pemphigoid by histopathologic examination and direct and indirect immunofluorescence studies. Immunopathologic examination also revealed in situ deposition and circulating autoantibodies of all IgG subclasses, except IgG3, and both light chains to the patient's skin basement membrane. By immunoblotting, the patient's IgG autoantibodies labeled BP180, BP230, and an unidentified 150-kd epidermal protein and mapped the BP180 epitope to the MCW-1, region 2 of the NC16A domain. The nodular plaque skin showed expression of alpha-6 and beta-1 integrin subunits, mediators of matrix-cell signaling and proliferation, at the basal and the suprabasal epidermis, a pattern found in psoriasis, which is the prototype of hyperproliferative dermatoses. PMID- 11606930 TI - Galli-Galli disease: an unrecognized entity or an acantholytic variant of Dowling Degos disease? AB - Galli-Galli disease is an inherited disease characterized by slowly progressive and disfiguring reticulate hyperpigmentation of the flexures, clinically and histopathologically diagnostic for Dowling-Degos disease, but also associated with suprabasal, nondyskeratotic acantholysis. A few patients exhibiting these features have been described, mainly in the non-English-language literature, which suggests that Galli-Galli disease is not an entity of its own, as originally thought, but is an acantholytic variant of Dowling-Degos disease. We report a typical case of Galli-Galli disease, which supports this concept. PMID- 11606931 TI - Severe predominantly acral variant of angiokeratoma of Mibelli: response to long pulse Nd:YAG (1064 nm) laser treatment. AB - The classification of vascular abnormalities is difficult. We describe a child with a disorder that is best described as angiokeratoma of Mibelli. This unusual, severe, predominantly acral case has been improved by long-wave Nd:YAG laser treatment, but treatment is still ongoing. PMID- 11606932 TI - Pemphigus foliaceus developing after metastasis of cutaneous squamous cell carcinoma to regional lymph nodes. AB - We describe a patient in whom pemphigus foliaceus developed after cutaneous squamous cell carcinoma (SCC) metastasized to regional lymph nodes. Immunologic analysis revealed that production of anti-desmoglein 1 autoantibodies started when SCC metastasized, and the SCC expressed desmoglein 1, suggesting a pathogenic role of metastasized SCC in developing pemphigus foliaceus. PMID- 11606933 TI - Varicella complicated by group A streptococcal facial cellulitis. AB - An increase has been recently noted in the incidence of life-threatening group A beta-hemolytic streptococcal (GABHS) infections in children recovering from varicella. We report our experience with a patient who required pediatric intensive care unit admission because of a serious GABHS infection 1 week after the onset of varicella. Emergency physicians must look for this complication in patients with varicella remaining abnormally febrile and presenting unusual manifestations. PMID- 11606935 TI - Intravenous immune globulin: fighting antibodies with antibodies. PMID- 11606936 TI - The eflornithine story. PMID- 11606937 TI - Minocycline, perinuclear antineutrophilic cytoplasmic antibody, and pigment: the biochemical basis. PMID- 11606938 TI - Mucositis as a treatment-limiting side effect in the use of capecitabine for the treatment of metastatic breast cancer. PMID- 11606939 TI - Tumors arising in nevus sebaceus. PMID- 11606940 TI - Tumors arising in nevus sebaceus: a study of 596 cases. PMID- 11606941 TI - Tumors arising in nevus sebaceus. PMID- 11606942 TI - Tumors arising in nevus sebaceus. PMID- 11606944 TI - Cellular metabolism and actions of 13-cis-retinoic acid. AB - Retinoids (vitamin A and its derivatives) are potent substances for regulating the expression of many different genes within the body. The gene regulatory activities of retinoids are mediated primarily by the all-trans and 9-cis isomers of retinoic acid. Although 13-cis-retinoic acid (isotretinoin) does not have the potent gene regulatory activity of the other two isomers, it is an effective pharmacologic agent for treating a variety of dermatologic conditions. Because 13 cis-retinoic acid is also a naturally occurring retinoid that is present in the circulation, question is raised as to the biochemical mechanism(s) responsible for its pharmacologic efficacy. Some of this efficacy likely arises from the ability of 13-cis-retinoic acid to undergo isomerization to the significantly more active all-trans and 9-cis isomers; however, this does not account for all of the pharmacologic effects observed upon use of this retinoid. Some recent studies suggest that 13-cis-retinoic acid may act by inhibiting the actions of enzymes that are needed to metabolize steroids, while other recent studies indicate that 13-cis-retinoic acid acts through membrane receptors present on the surface of cells. At the present, it is not possible to rule out still other possible biochemical actions of 13-cis-retinoic acid in the body. It is clear, however, that if we are to fully understand the basis for the clinical efficacy of 13-cis-retinoic acid, a better understanding of such biochemical actions is needed. PMID- 11606945 TI - Retinoic acid metabolism. AB - The tissue distribution of retinoic acid (RA) throughout development is highly restricted, defined by the expression patterns of enzymes involved in RA synthesis and catabolism. Presented is a summary of recent research that examines the role of some of the enzymes involved in RA distribution, particularly those involved in RA catabolism (P450RAI). These latter enzymes protect against premature exposure to RA, and the implications of these findings are discussed. PMID- 11606946 TI - Interaction of isotretinoin with endogenous retinoids. AB - Isotretinoin exhibits antiproliferative and antiandrogenic effects on the sebaceous glands by yet unknown mechanisms. This review focuses on a putative mechanism of action of isotretinoin involving the interaction of isotretinoin with the metabolism of endogenous retinoids and androgens. PMID- 11606947 TI - Uses and complications of isotretinoin therapy. AB - Isotretinoin (13-cis-retinoic acid) is a retinoid that has been used over the past 2 decades to treat a wide variety of dermatologic conditions, some with great success. Although it is beneficial in many skin conditions, the side effects and toxicities of oral retinoids require careful monitoring by experienced physicians. The clinical applications of oral retinoids continue to expand both within and beyond the field of dermatology. PMID- 11606948 TI - Regulation of lipid and lipoprotein metabolism by retinoids. AB - Retinoids are small vitamin A-derived lipophilic compounds that influence a wide variety of developmental and metabolic processes. Retinoids exert their action by activating transcription factors belonging to the retinoic acid receptor (RAR) and retinoid X receptor (RXR) subfamilies of nuclear receptors. Therapeutically, retinoids are used for the treatment of dermatological disorders and certain cancers. Dyslipidemia is a common side-effect of therapy with the currently available retinoids. This review summarizes our current understanding of the molecular mechanisms of regulation of lipid and lipoprotein metabolism by retinoids. PMID- 11606949 TI - Suicide, depression, and isotretinoin: is there a causal link? AB - This paper examines the existing literature and MedWatch reports concerning a proposed relationship between isotretinoin and depression and suicide. The authors provide a brief overview of the biology of isotretinoin and depressive disorder and find no basis for a putative molecular mechanism linking the two. They also address the complexities of Substance-Induced Mood Disorder (SIMD) as a psychiatric diagnosis and its relevance to isotretinoin. Based on this review, the authors conclude that there is no evidence to support a causal connection between isotretinoin and major depression or suicide, because reported cases do not meet the established criteria for causality. The authors also conclude, however, that it is important for dermatologists to be aware of the risk factors for suicide and to monitor patients who exhibit depressive symptoms. PMID- 11606950 TI - Isotretinoin effects on bone. AB - Isotretinoin has demonstrated efficacy in a wide range of disorders. The beneficial effects of the drug, however, are limited by its adverse effects on the bone. Children exposed to high doses are at risk for premature epiphyseal closure, while adults on long-term therapy have an increased tendency to develop hyperstosis and other changes of the bone. The knowledge of these effects, in conjunction with continued surveillance, are necessary for expert management and can ensure many years of efficacious treatment with minimal toxicity. PMID- 11606951 TI - Teratogenicity of isotretinoin revisited: species variation and the role of all trans-retinoic acid. AB - This paper reviews the teratogenicity of isotretinoin in regard to aspects of species variation, toxicokinetics, and metabolism. Particular emphasis is given to the hypothesis that most effects of isotretinoin (13-cis-retinoic acid) are mediated by isomerization to the all-trans-retinoic acid. This mechanism of action would provide a basis for the understanding of species differences and the extrapolation of experimental results to the human situation and thus improve drug development. The insensitive species (rat, mouse) eliminate the drug rapidly through detoxification to the beta-glucuronide; also, placental transfer is limited in these species. On the other hand, in sensitive species (primates), the drug is predominantly metabolized to the active 13-cis-4-oxo-retinoic acid; placental transfer is more extensive here. The beta-glucuronides showed limited placental transfer in all species examined; these metabolites exhibited very low, if any, measurable concentrations in the human. The 13-cis-retinoic acid is not appreciably bound to cellular retinoid-binding proteins or nuclear receptors and exhibits low tissue distribution and placental transfer. Its access to the nucleus may be extensive. Because of the long half life of 13-cis-retinoic acid, continuous isomerization results in significant area under the concentration-time curve levels of all-trans-retinoic acid in the mouse, monkey and the human; the all-trans-retinoic acid formed is extensively distributed across the placenta and may be an important factor that contributes to the teratogenic potency of 13-cis retinoic acid. Isomerization cannot explain the teratogenic effects of 13-cis retinoic acid in the rat and rabbit. It is concluded that the high teratogenic activity of isotretinoin in sensitive species (human, monkey) is related to slow elimination of the 13-cis-isomer, to metabolism to the 4-oxo-derivative, to increased placental transfer, to continuous isomerization and significant exposure of the target tissue to all-trans-retinoic acid; and to lack of binding to cytoplasmic retinoid binding proteins that could possibly result in ready access to the nucleus. PMID- 11606952 TI - Analysis of common side effects of isotretinoin. AB - Patients with severe recalcitrant nodular acne that is unresponsive to conventional therapy (including topical and systemic antibiotics) have few alternative effective treatment modalities other than the use of oral isotretinoin (Accutane). The cause of acne vulgaris is multifactorial, but the pathogenesis of this disorder of the pilosebaceous follicles arises mainly from endogenous factors. It is usually, but not always, associated with the onset of puberty. Severe acne, defined by the prevalence of facial and truncal inflammatory lesions, is a disfiguring disease that can often result in significant permanent scarring after the healing of deep inflammatory lesions and other disorders, such as systemic bacterial infections. Topical treatments are considered as the first line of therapy for less severe forms of acne, although systemic treatments such as antibiotics or antiandrogen agents are effective for either mild or moderate forms and sometimes effective for severe acne. However, in many patients with large numbers of nodules, longer treatment periods with these agents are required to reduce the count of inflammatory lesions. It has become increasingly evident that (because topical agents and antibiotic or antiandrogenic therapy have a slow onset of action) even mild or moderate acne that is treated in this way can result in scarring. In addition, the excessive use of systemic antibiotics has led to the detection of increasing numbers of antibiotic-resistant bacteria on the skin of patients with acne.(1) Therefore, because of its relatively rapid onset of action and its high efficacy with reducing more than 90% of the most severe inflammatory lesions, Accutane has a role as an effective treatment in patients with severe acne that is recalcitrant to other therapies. PMID- 11606953 TI - Mounted models needed for proper diagnosis. PMID- 11606954 TI - Most condylar discrepancies not detectable clinically. PMID- 11606955 TI - Timing of twin-block treatment in the United Kingdom. PMID- 11606956 TI - Check out the medical model of board certification. PMID- 11606957 TI - Deciduous canine and permanent lateral incisor differential root resorption. AB - When a permanent maxillary canine erupts apical to the permanent lateral incisor and the deciduous canine, resorption typically takes place only on the deciduous canine root. An understanding of this differential resorption could provide insight into the reasons for excessive iatrogenic root resorption during orthodontic tooth movement. The purpose of the present study was to examine the response of roots of permanent lateral incisors and deciduous canines to simulated resorption, and to acid and enzyme attack, reflecting the physiologic environment of an erupting permanent canine. Groups of maxillary permanent lateral incisor and deciduous canine roots were exposed to 5 combinations of Ten Cate demineralizing solution, Ten Cate demineralizing solution with EDTA, and a Type I collagenase solution. Sections of the roots were examined under a polarized light microscope. Analysis of variation of the resulting root lesions demonstrated that the lesion depths for deciduous canines were greater than those for permanent lateral incisors when averaged across 4 of the conditions (F(1,24) = 7.49, P =.0115). On average, deciduous canine roots demonstrated lesions 10% deeper than did permanent lateral incisor roots. We concluded that when deciduous canine and permanent lateral incisor roots are subjected to acid and enzyme attack, reflecting the physiologic environment of an erupting permanent canine, significantly deeper demineralized lesions are seen in the deciduous roots compared with the permanent roots. This finding may partially explain the differential root resorption during permanent tooth eruption. PMID- 11606958 TI - A comparison of nasopharyngeal endoscopy and lateral cephalometric radiography in the diagnosis of nasopharyngeal airway obstruction. AB - Two auxiliary methods of diagnosing nasopharyngeal airway obstruction were compared. Cephalometric radiography and nasopharyngeal videoendoscopy were evaluated for efficacy in terms of reproducibility and validity. Thirty orthodontic patients (7 to 12 years of age) seeking otorhinolaryngologic treatment for mouth breathing, or mouth and nose breathing, had nasopharyngeal endoscopy and radiographic examinations performed on the same day. Two otorhinolaryngologists analyzed the results. Nasopharyngeal endoscopy was more reliable in identifying all the obstructive nasopharyngeal processes. Endoscopy obtained kappa index scores of almost perfect agreement for diagnosis of posterior nasal septum deviation, of substantial agreement for anterior nasal septum deviation and lower turbinate hypertrophy, and of moderate agreement for middle turbinate hypertrophy. Lateral cephalometric radiography obtained scores of perfect agreement for imaging hypertrophy of the middle turbinate, of almost perfect agreement for imaging hypertrophy of the posterior portion of the inferior turbinate, and of substantial agreement for imaging hypertrophy of the inferior turbinate. Radiographic diagnoses of hypertrophy of the middle and lower turbinates exhibited high sensitivity and low specificity when compared with diagnoses by nasopharyngeal endoscopy. PMID- 11606959 TI - Comparative study of 2 electric and 2 manual toothbrushes in patients with fixed orthodontic appliances. AB - The objective of this prospective single-blind crossover clinical trial was to evaluate the efficacy of 4 toothbrushes in 33 children undergoing fixed appliance orthodontic therapy. The toothbrushes included in this study were the Braun Oral B 3D Plaque Remover (Kronberg, Germany), the Philips-Jordan HP 510 (Philips Domestic Appliances, Groningen, The Netherlands), the Lactona orthodontic toothbrush (Bergen op Zoom, The Netherlands), and the Oral-B Advantage Control Grip (Braun); the first 2 are electric, and the last 2 are manual. Every patient tested each type of toothbrush in a randomly designed sequence. Plaque and gingival scores were recorded at baseline and after every 4-week test period. All patients received professional prophylaxis after each clinical evaluation. The data were analyzed with the Friedman test, which showed no significant differences among the 4 brushes for any of the parameters measured. The Wilcoxon signed rank test, comparing the plaque and the gingival scores between the upper and lower jaw for each brush, indicated that plaque removal was more efficient in the lower jaw than in the upper. PMID- 11606960 TI - Resistance to sliding of self-ligating brackets versus conventional stainless steel twin brackets with second-order angulation in the dry and wet (saliva) states. AB - The frictional properties of conventional stainless steel brackets that were coupled with rectangular stainless steel archwires and ligated with stainless steel ligature wires and the frictional properties of closed self-ligating brackets coupled with the same archwires were compared in terms of second-order angulation. The slides of these self-ligating brackets passively restrained the archwires within the slots. As a control, the frictional properties of the opened self-ligating brackets, which were ligated with stainless steel ligature wires, were measured. The resistance to sliding of the conventional brackets and the opened self-ligating brackets were measured at ligation forces ranging from 200 to 600 cN and at angles from -9 degrees to 9 degrees. The resistances to sliding of the closed self-ligating brackets were measured at the same angles, but no external ligation forces were applied. In the passive configuration, the conventional brackets exhibited similar frictional resistance as the opened self ligating brackets, whereas the closed self-ligating brackets exhibited no friction. In the active configuration, all brackets exhibited increased resistance to sliding as the angulation increased. At all angles, the resistances to sliding of the closed self-ligating brackets were lower than those of the conventional brackets because of the absence of a ligation force when the slide restrained the archwire. PMID- 11606961 TI - Frictional behavior of stainless steel bracket-wire combinations subjected to small oscillating displacements. AB - In orthodontic treatment, sliding is frequently used to cause tooth movement. Inherent to this technique is the generation of a counteracting frictional force. In this pilot study, a fretting test consisting of reciprocating tangential displacements was used to investigate test parameters influencing frictional forces during sliding processes. Tests were run at a normal load of 2 N and a frequency of 1 Hz for tangential displacement strokes of 200 microm. Stainless steel orthodontic wires with cross-sections of .017 x .025 in (W17) and .018 x .025 in (W18), and brackets with slot sizes of .018 in (B18) and .022 in (B22) were used. A specific centered positioning method was developed to achieve a parallel alignment of the wire and the bracket slot. The experimental results indicated the significant role of the centered positioning method on the friction value. Implementation of the centered positioning method resulted in a friction force ranging from 0.89 N to 0.97 N at a 200 microm displacement amplitude and 1 Hz frequency, corresponding to a coefficient of friction ranging from 0.45 to 0.49 for the B18-W17 and the B22-W17 bracket-wire combinations, respectively. When the centered positioning method was not used, significantly higher values for the coefficient of friction were found for both bracket-wire combinations. The slot-filling, bracket-wire combinations (B18-W18 and B22-W22) resulted in an increased coefficient of friction and therefore are not recommended as sliding systems. PMID- 11606962 TI - Force-deflection properties of superelastic nickel-titanium archwires. AB - This in vitro study compared the force-deflection behavior of 8 superelastic nickel-titanium orthodontic wires (0.017 x 0.025 in) under controlled moment and temperature. To simulate leveling a lateral incisor, brackets and first molar tubes without tip and angulation were used. The wires (n = 5) were ligated into stainless steel brackets attached to a plastic jig to simulate a mandibular arch. A testing machine (Instron) applied deflections of 0.2 to 2.0 mm at 35 degrees C in the lateral incisor area. Force-deflection diagrams were determined from the passive position to an activation of 2 mm and then during deactivation. Forces on deactivation at a deflection of 1 mm were compared by analysis of variance. Significant differences (P < .05) in forces were observed among wires. All wires exhibited superelastic behavior, but in stratified loading levels. PMID- 11606963 TI - Metal release from simulated fixed orthodontic appliances. AB - Most orthodontic appliances and archwires are stainless steel or nickel-titanium (NiTi) alloys that can release metal ions, with saliva as the medium. To measure metal released from the fixed orthodontic appliances currently in use, we fabricated simulated fixed orthodontic appliances that corresponded to half of the maxillary arch and soaked them in 50 mL of artificial saliva (pH 6.75 +/- 0.15, 37 degrees C) for 3 months. We used brackets, tubes, and bands made by Tomy (Tokyo, Japan). Four groups were established according to the appliance manufacturer and the type of metal in the .016 x .022-in archwires. Groups A and B were stainless steel archwires from Ormco (Glendora, Calif) and Dentaurum (Ispringen, Germany), respectively, and groups C and D were both NiTi archwires with Ormco's copper NiTi and Tomy's Bioforce sentalloy, respectively. Stainless steel archwires were heat treated in an electric furnace at 500 degrees C for 1 minute and quenched in water. We measured the amount of metal released from each group by immersion time. Our conclusions were as follows: (1) there was no increase in the amount of chromium released after 4 weeks in group A, 2 weeks in group B, 3 weeks in group C, and 8 weeks in group D; (2) there was no increase in the amount of nickel released after 2 weeks in group A, 3 days in group B, 7 days in group C, and 3 weeks in group D; and (3) there was no increase in the amount of iron released after 2 weeks in group A, 3 days in group B, and 1 day in groups C and D. In our 3-month-long investigation, we saw a decrease in metal released as immersion time increased. PMID- 11606964 TI - Fluoride release from new light-cured orthodontic bonding agents. AB - The purpose of this study was to compare the rates of fluoride release with time from 1 nonfluoridated and 3 fluoride-containing orthodontic bonding materials in distilled water and artificial saliva. Materials tested were Assure (Reliance Orthodontic Products, Itasca, Ill), Fuji Ortho LC (GC, Tokyo, Japan), Python (TP Orthodontics, LaPorte, Ind), and Transbond XT (3M Dental Products, Monrovia, Calif). Ten specimens of each material type were stored in distilled water, and 10 of each type were stored in artificial saliva at 37 degrees C. Fluoride release was measured with an ion-specific electrode. Readings were taken periodically for a total time period of 6 months. At day 1, Assure released the most fluoride into distilled water (66.2 microg/cm(2)) and into artificial saliva (65.8 microg/cm(2)), followed by Fuji Ortho LC (25.9 microg/cm(2); 18.8 microg/cm(2)), Python (6.3 microg/cm(2); 4.2 microg/cm(2)), and Transbond (0.1 microg/cm(2); 0.1 microg/cm(2)). The fluoride release rates were highest during the first days of testing, declining to lower but more stable levels. At the end of 6 months, Fuji Ortho LC released the most fluoride (3.8 microg/cm(2); 3.5 microg/cm(2)) followed by Assure (3.1 microg/cm(2); 2.8 microg/cm(2)), Python (2.6 microg/cm(2); 1.7 microg/cm(2)), and Transbond (0.1 microg/cm(2); 0.1 microg/cm(2)). The type of storage medium did not dramatically affect fluoride release. The second part of the study, undertaken after a year of sample storage, tested the 20 samples of Assure for a further 2-week period, after exposure to running and still distilled water. Although fluoride release rates declined with time, they were still higher than the 1.5 microg/cm(2) level that is referenced as inhibiting decalcification of enamel in a clinical environment. Release rates were similar in running and still water at all time points. Throughout the 6 month period, all 3 fluoride-containing materials had rates of fluoride release that could theoretically inhibit decalcification of enamel. PMID- 11606965 TI - A comparison of fluoride release by resin-modified GIC and polyacid-modified composite resin. AB - The objective of this study was to compare the fluoride release of 2 fluoride containing orthodontic adhesives from bracketed teeth and adhesive disks, a resin modified glass ionomer cement (Fuji Ortho LC, encapsulated; GC America Corp, Aslip, Ill) and a polyacid-modified composite resin (Assure; Reliance Orthodontic Products, Itasca, Ill). A composite resin without fluoride (Transbond XT; 3M Unitek, Monrovia, Calif) was used as a reference control. Metal brackets were bonded to the buccal surfaces of 120 human premolars (40 teeth per adhesive), and disks were made from each adhesive. The deionized storage water was changed, and fluoride release was measured at specified intervals up to 28 days for the bracketed teeth and up to 150 days for the disks. Fuji Ortho LC released 75% more accumulated fluoride than Assure (6.61 microg/bracket vs 3.77 microg/bracket) from bracketed teeth over the 28-day observation period. Assure released more fluoride per day than did Fuji Ortho LC from the disks during the first 3 months. For the rest of the 150-day period, Fuji Ortho LC released more fluoride per day than did Assure. The amount of fluoride released by these materials varied dramatically with different water-changing protocols. The large discrepancy between fluoride released from disks compared with that released from bracketed teeth suggests that caution must be used in extrapolating fluoride-release levels of adhesive disks to in vivo treatment conditions. PMID- 11606966 TI - An 18-month clinical study of bond failures with resin-modified glass ionomer cement in orthodontic practice. AB - The purpose of this study was to evaluate, over an 18-month period, the clinical performances of a resin-modified glass ionomer cement for bonding orthodontic brackets and to analyze various factors that influenced their survival and failure rates. Two orthodontists using the edgewise technique participated in this study; 6113 brackets, including 20 molar tubes, were bonded with Fuji Ortho LC (GC, Europe, N.V. Leuven, Belgium) in 135 patients. Ceramic, metal, and resin brackets were tested, and both operators used the same bonding method for the brackets. The survival rate and the failure rate of the brackets were evaluated. The rates were determined by operator, bracket type, tooth position in the dental arch, and age and sex of the patients. Bracket survival rates were estimated using the Kaplan-Meier test. The Cox-Mantel statistical test with a level of significance set at 0.05 was used to compare survival curves. The chi-square test was used at a level of P < .05 to compare failure rates. The overall failure rate for the sample was 7%, and the overall survival rate was equal to 0.918. Age had no significant influence on the failure rate (P = .07); however, it had a significant influence on the survival rate (P < .01). The best survival rates were obtained in the groups aged 16 to 20 years (S[t] = 0.943) and older than 20 years (S[t] = 0.929). The difference between males and females was not statistically significant in terms of failure rate (P = .17). However, the Cox Mantel test showed a higher bracket survival rate for the males (S[t] = 0.924) than for the females (S[t] = 0.839) (P < .00001). The influence of the operator was not statistically significant on the failure rate (P = .08); however, it was significant on the survival rate (P < .0002). Location in the arch had a significant influence on the failure and survival rates. The worst results were obtained in the upper incisors and the canines, and the best results in the lower premolars. Fifteen percent of the molar tubes failed; their survival rate was equal to 0.833. The failure rate was significantly greater for resin brackets than for metal or ceramic brackets (P = .007). The highest survival rate was obtained with ceramic brackets (P = .0001). This in vivo study showed that bonding brackets and molar tubes with Fuji Ortho LC is compatible with clinical orthodontic practice. PMID- 11606967 TI - An assessment of skeletal and dental responses to the functional magnetic system (FMS). AB - Correction of a skeletal Class II malocclusion with functional appliances has been accepted as a viable treatment modality. However, its mechanism of action is still disputed. This retrospective study compared 20 Class II patients treated with the functional magnetic system (FMS) with Class I and Class II groups (the control groups) of 20 untreated subjects each. Dental and skeletal changes were compared using serial lateral cephalograms. The FMS group differed significantly from the control groups in 15 of 24 parameters. The great increase in articulare gnathion distance (3.07 mm) attributed to the attractive magnetic component of the FMS dictates a prolonged propulsion of the mandible. The skeletal:dental response ratio was 1:2 for the anterior region and 1:1 for the posterior region. The dental and skeletal parameters demonstrated a synergistic response in the maxilla and a competitive response in the mandible. This means that greater maxillary molar distal movement and incisor retroclination resulted in a more significant restraint of point A. In contrast, increasing the mandibular molar mesial movement and the incisor proclination accompanied less advancement of the pogonion. Although the skeletal contribution to the resolution of the malocclusion was less than the dental contribution (anteriorly, one third), the functional correction response was found to be regulated by skeletal factors. PMID- 11606968 TI - Magnetic resonance spectroscopy of the masseter muscle in different facial morphological patterns. AB - The aims of this study were (1) to develop a reliable noninvasive method to evaluate the masseter muscle metabolism, by using (31)P-magnetic resonance spectroscopy, and (2) to evaluate the metabolic profile of the masseter muscle in subjects with various facial patterns. The maxillary-mandibular relationship, which varied from hypodivergent to hyperdivergent, was measured on lateral cephalograms of 20 adults, 22 to 35 years of age. (31)P-spectra were acquired from the masseter muscle at rest with a custom-made, single-turn, double-tuned, 3 x 5-cm oblong surface coil. The inorganic phosphate to phosphocreatine (Pi/PCr) ratios were measured and compared in relation to vertical and sagittal cephalometric measurements. A statistically significant (R(2) = 0.65, r = 0.81, P = .001) relationship was found between Pi/PCr ratio and the palatal-to-mandibular plane angle. As the maxillary-to-mandibular divergence increased, the Pi/PCr ratio decreased. This correlation suggests that muscles with a higher Pi/PCr ratio have a higher resting metabolic activity than those with a lower Pi/PCr ratio. Consequently, these muscles may keep bone under more tension and influence its growth in a more horizontal direction. Another possible explanation of the results is that the fiber type composition of the masseter muscle varies with facial morphology. PMID- 11606971 TI - Guidelines for preparing and submitting images for publication. PMID- 11606970 TI - Orthodontic spring guidance of bilateral mandibular distraction in rabbits. AB - Although distraction osteogenesis can lengthen congenitally small mandibles, the distraction procedure can be difficult to control. To study the efficacy and safety of orthodontic spring guidance on bilateral mandibular distraction, an 8 mm anterior open bite was experimentally produced and corrected during bilateral mandibular distraction in rabbits. Orthodontic springs were attached to the anterior maxilla and mandible to redirect an ongoing distraction procedure. Sixteen rabbits underwent mandibular distraction: 6 rabbits received heavy springs (8 oz), 6 rabbits received light force springs (2 oz), and 4 rabbits served as control animals with anterior open bites without spring guidance. Nickel-titanium springs were applied during the last week of osseous distraction and the first week of consolidation. Distractors were left in place throughout a 2-month consolidation period. None of the animals developed fibrous union as a result of spring guidance. The 8-mm open bite did not close in the control group or in the light spring group after 2 weeks of spring wear or during the consolidation period. Heavy springs completely closed the experimental open bites within 2 weeks (P <.01, analysis of variance). Bite corrections did not change during the consolidation period. This study indicated that the addition of an orthodontic spring to a mandibular distraction procedure did not impair bone healing. With the distraction device in place, heavy spring forces redirected an ongoing mandibular distraction procedure and corrected an open bite, distraction side effect. Direct measurements, radiographic measurements, and tissue histologic factors described changes in segment position and shape of the distraction site. PMID- 11606972 TI - Litigation, legislation, and ethics. A disability not disabled. PMID- 11606976 TI - Top-heavy and out of touch? PMID- 11606977 TI - Anti-terrorist agendas. PMID- 11606978 TI - Genetic sleuths rush to identify anthrax strains in mail attacks. PMID- 11606979 TI - Bioweapons treaty under threat. PMID- 11606980 TI - Gaps remain in Japan's biodefences. PMID- 11606981 TI - Scientific leaders respond to US government's call to arms. PMID- 11606982 TI - Plans to centralize biology research set for rough ride. PMID- 11606983 TI - Birds fly in the face of 'green' farming incentive scheme. PMID- 11606984 TI - CERN's head rejects mismanagement claims. PMID- 11606985 TI - Sanger Centre welcomes gene funds with a new name. PMID- 11606986 TI - Chemistry prize reflects tailor-made reactions. PMID- 11606989 TI - The outrageous hypothesis. PMID- 11606987 TI - Bid to end EU's transgenic impasse. PMID- 11606990 TI - It all falls into place... PMID- 11606991 TI - Owen was right, as Darwin's work continues. PMID- 11606992 TI - SPOrt to fill a gap on cosmic maps. PMID- 11606993 TI - Singapore considers institute's future. PMID- 11606994 TI - Peers under review. PMID- 11606995 TI - The best and worst of times. PMID- 11606996 TI - Lessons for the future of journals. PMID- 11607007 TI - In the name of love? PMID- 11607008 TI - An intriguing door. PMID- 11607009 TI - Fat and formation in flight. PMID- 11607010 TI - Mathematics. Where drunkards hang out. PMID- 11607011 TI - Archaeology. Tree trail to Chaco Canyon. PMID- 11607013 TI - Materials science. A magnet made from carbon. PMID- 11607016 TI - Crystallization. Diversity suppresses growth. PMID- 11607014 TI - Huntington's disease. Exploiting expression. PMID- 11607017 TI - Molecular biology. RNA enzymes for RNA splicing. PMID- 11607019 TI - Energy saving in flight formation. AB - Many species of large bird fly together in formation, perhaps because flight power demands and energy expenditure can be reduced when the birds fly at an optimal spacing, or because orientation is improved by communication within groups. We have measured heart rates as an estimate of energy expenditure in imprinted great white pelicans (Pelecanus onocrotalus) trained to fly in 'V' formation, and show that these birds save a significant amount of energy by flying in formation. This advantage is probably a principal reason for the evolution of flight formation in large birds that migrate in groups. PMID- 11607020 TI - Deep-sea ecology. Developmental arrest in vent worm embryos. AB - Temperature is a key factor in controlling the distribution of marine organisms and is particularly important at hydrothermal vents, where steep thermal gradients are present over a scale of centimetres. The thermophilic worm Alvinella pompejana, which is found at the vents of the East Pacific Rise (2,500 m depth), has an unusually broad thermotolerance (20-80 degrees C) as an adult, but we show here that the temperature range required by the developing embryo is very different from that tolerated by adults. Our results indicate that early embryos may disperse through cold abyssal water in a state of developmental arrest, completing their development only when they encounter water that is warm enough for their growth and survival. PMID- 11607021 TI - Geophysics. Longitudinal variation in springtime ozone trends. AB - Satellite measurements indicate that mid-latitude ozone depletion in the Northern Hemisphere spring during 1979-97 was worst over Europe and Russia. Here we show that these longitudinal differences in ozone trends are due to a combination of decadal variations in the circulation and transport of ozone-depleted air from the polar vortex. Any increase in ozone depletion in the polar vortex as a result of future cooling of the stratosphere would therefore be particularly bad over Europe and Russia. PMID- 11607022 TI - Plant genetics. Ancient wild olives in Mediterranean forests. AB - Early domestication and extensive cultivation have meant that staple Mediterranean fruit crops such as olives, grapes and dates exist in wild-looking forms that are secondary derivatives produced by sexual reproduction among cultivated plants (cultivars), which were initially propagated vegetatively. By using genetic markers associated with characters that render plants unsuitable for domestication, we show here that genuinely wild olive trees, which cannot be distinguished morphologically from feral forms, still survive in a few Mediterranean forests. These wild stocks are genetically distinct and more variable than either the crop strains or their derived feral forms, a finding that has important implications for the conservation of these ancient lineages. PMID- 11607023 TI - Splicing-related catalysis by protein-free snRNAs. AB - Removal of intervening sequences from eukaryotic messenger RNA precursors is carried out by the spliceosome, a complex assembly of five small nuclear RNAs (snRNAs) and a large number of proteins. Although it has been suggested that the spliceosome might be an RNA enzyme, direct evidence for this has been lacking, and the identity of the catalytic domain of the spliceosome is unknown. Here we show that a protein-free complex of two snRNAs, U2 and U6, can bind and position a small RNA containing the sequence of the intron branch site, and activate the branch adenosine to attack a catalytically critical domain of U6 in a reaction that is related to the first step of splicing. Our data provide direct evidence for the catalytic potential of spliceosomal snRNAs. PMID- 11607024 TI - Discovery of X-rays from the protostellar outflow object HH2. AB - Herbig-Haro (HH) objects have been known for 50 years to be luminous condensations of gas in star-forming regions, but their underlying physical nature is still being elucidated. Previously suggested models encompass newborn stars, stellar winds clashing with nebular material, dense pockets of interstellar gas excited by shocks from outflows, and interstellar 'bullets' (ref. 6). Recent progress has been made with the jet-induced shock model, in which material streams out of young stellar objects and collides with the surrounding interstellar medium. A clear prediction of this model is that the most energetic Herbig-Haro objects will emit X-rays, although they have not hitherto been detected. Here we report the discovery of X-ray emission from one of the brightest and closest Herbig-Haro objects, HH2, at a level consistent with the model predictions. We conclude that this Herbig-Haro object contains shock heated material located at or near its leading edge with a temperature of about 106 K. PMID- 11607025 TI - Suppression of crystal nucleation in polydisperse colloids due to increase of the surface free energy. AB - The formation of small crystallites is governed by two competing factors: the free energy gained upon transferring constituent atoms, molecules or colloidal particles from the metastable liquid to the more stable solid, and the free energy needed to create the surface area of the crystallite. Because the ratio of surface area to bulk is large for small particles, small crystallites dissolve spontaneously under conditions where larger crystallites are stable and macroscopic crystal growth occurs only if spontaneously formed crystallites exceed a critical minimum size. On theoretical grounds, the probability of forming such critical crystal nuclei is expected to increase rapidly with supersaturation. However, experiments show that the rate of crystal nucleation in many systems goes through a maximum as the supersaturation is increased. It is commonly assumed that the nucleation rate peaks because, even though the probability of forming critical nuclei increases with increasing concentration, the rate of growth of such nuclei decreases. Here we report simulations of crystal nucleation in suspensions of colloidal spheres with varying size distributions that show that the probability that critical nuclei will form itself goes through a maximum as the supersaturation is increased. We find that this effect, which is strongest for systems with the broadest particle size distribution, results from an increase with supersaturation of the solid-liquid interfacial free energy. The magnitude of this effect suggests that vitrification at high supersaturations should yield colloidal glasses that are truly amorphous, rather than nano-crystalline. PMID- 11607026 TI - Self-assembled monolayer organic field-effect transistors. AB - The use of individual molecules as functional electronic devices was proposed in 1974 (ref. 1). Since then, advances in the field of nanotechnology have led to the fabrication of various molecule devices and devices based on monolayer arrays of molecules. Single molecule devices are expected to have interesting electronic properties, but devices based on an array of molecules are easier to fabricate and could potentially be more reliable. However, most of the previous work on array-based devices focused on two-terminal structures: demonstrating, for example, negative differential resistance, rectifiers, and re-configurable switching. It has also been proposed that diode switches containing only a few two-terminal molecules could be used to implement simple molecular electronic computer logic circuits. However, three-terminal devices, that is, transistors, could offer several advantages for logic operations compared to two-terminal switches, the most important of which is 'gain'-the ability to modulate the conductance. Here, we demonstrate gain for electronic transport perpendicular to a single molecular layer ( approximately 10-20 A) by using a third gate electrode. Our experiments with field-effect transistors based on self-assembled monolayers demonstrate conductance modulation of more than five orders of magnitude. In addition, inverter circuits have been prepared that show a gain as high as six. The fabrication of monolayer transistors and inverters might represent an important step towards molecular-scale electronics. PMID- 11607027 TI - Magnetic carbon. AB - The discovery of nanostructured forms of molecular carbon has led to renewed interest in the varied properties of this element. Both graphite and C60 can be electron-doped by alkali metals to become superconducting; transition temperatures of up to 52 K have been attained by field-induced hole-doping of C60 (ref. 2). Recent experiments and theoretical studies have suggested that electronic instabilities in pure graphite may give rise to superconducting and ferromagnetic properties, even at room temperature. Here we report the serendipitous discovery of strong magnetic signals in rhombohedral C60. Our intention was to search for superconductivity in polymerized C60; however, it appears that our high-pressure, high-temperature polymerization process results in a magnetically ordered state. The material exhibits features typical of ferromagnets: saturation magnetization, large hysteresis and attachment to a magnet at room temperature. The temperature dependences of the saturation and remanent magnetization indicate a Curie temperature near 500 K. PMID- 11607029 TI - Agri-environment schemes do not effectively protect biodiversity in Dutch agricultural landscapes. AB - Roughly 20% of the European Union's farmland is under some form of agri environment scheme to counteract the negative impacts of modern agriculture on the environment. The associated costs represent about 4% (1.7 billion euros) of the European Union's total expenditure on the Common Agricultural Policy and are expected to rise to 10% in the near future. Although agri-environment schemes have been implemented in various countries for well over a decade, to date no reliable, sufficiently replicated studies have been performed to test whether such measures have the presumed positive effects on biodiversity. Here we present the results of a study evaluating the contribution of agri-environment schemes to the protection of biodiversity in intensively used Dutch agricultural landscapes. We surveyed plants, birds, hover flies and bees on 78 paired fields that either had agri-environment schemes in the form of management agreements or were managed conventionally. Management agreements were not effective in protecting the species richness of the investigated species groups: no positive effects on plant and bird species diversity were found. The four most common wader species were observed even less frequently on fields with management agreements. By contrast, hover flies and bees showed modest increases in species richness on fields with management agreements. Our results indicate that there is a pressing need for a scientifically sound evaluation of agri-environment schemes. PMID- 11607028 TI - Orbitally induced oscillations in the East Antarctic ice sheet at the Oligocene/Miocene boundary. AB - Between 34 and 15 million years (Myr) ago, when planetary temperatures were 3-4 degrees C warmer than at present and atmospheric CO2 concentrations were twice as high as today, the Antarctic ice sheets may have been unstable. Oxygen isotope records from deep-sea sediment cores suggest that during this time fluctuations in global temperatures and high-latitude continental ice volumes were influenced by orbital cycles. But it has hitherto not been possible to calibrate the inferred changes in ice volume with direct evidence for oscillations of the Antarctic ice sheets. Here we present sediment data from shallow marine cores in the western Ross Sea that exhibit well dated cyclic variations, and which link the extent of the East Antarctic ice sheet directly to orbital cycles during the Oligocene/Miocene transition (24.1-23.7 Myr ago). Three rapidly deposited glacimarine sequences are constrained to a period of less than 450 kyr by our age model, suggesting that orbital influences at the frequencies of obliquity (40 kyr) and eccentricity (125 kyr) controlled the oscillations of the ice margin at that time. An erosional hiatus covering 250 kyr provides direct evidence for a major episode of global cooling and ice-sheet expansion about 23.7 Myr ago, which had previously been inferred from oxygen isotope data (Mi1 event). PMID- 11607030 TI - Endoscopic exploration of Red Sea coral reefs reveals dense populations of cavity dwelling sponges. AB - Framework cavities are the largest but least explored coral reef habitat. Previous dive studies of caverns, spaces below plate corals, rubble and artificial cavities suggest that cavity-dwelling (coelobite) filter-feeders are important in the trophodynamics of reefs. Quantitative community data are lacking, however, as the bulk of the narrow crevices interlacing the reef framework are inaccessible to conventional analysis methods. Here we have developed endoscopic techniques to explore Red Sea framework crevices up to 4 m into the carbonate rock, revealing a large internal surface (2.5-7.4 m2 per projected m2 reef) dominated by encrusting filter-feeders. Sponges alone provided up to 60% of coelobite cover, outweighing epi-reefal filter-feeder biomass by two orders of magnitude. Coelobite community filtration removed more than 60% of the phytoplankton in the course of its less than 5-minute passage through the crevices, corresponding to an uptake of roughly 0.9 g carbon m-2 d-1. Mineralization of the largely allochthonous organic material is a principal source of nutrients supporting coral and algal growth. The supply of new material by coelobites may provide a key to understanding the 'coral reef paradox'-a rich ecosystem thriving in nutrient-poor water. PMID- 11607031 TI - Carrying large fuel loads during sustained bird flight is cheaper than expected. AB - Birds on migration alternate between consuming fuel stores during flights and accumulating fuel stores during stopovers. The optimal timing and length of flights and stopovers for successful migration depend heavily on the extra metabolic power input (fuel use) required to carry the fuel stores during flight. The effect of large fuel loads on metabolic power input has never been empirically determined. We measured the total metabolic power input of a long distance migrant, the red knot (Calidris canutus), flying for 6 to 10 h in a wind tunnel, using the doubly labelled water technique. Here we show that total metabolic power input increased with fuel load, but proportionally less than the predicted mechanical power output from the flight muscles. The most likely explanation is that the efficiency with which metabolic power input is converted into mechanical output by the flight muscles increases with fuel load. This will influence current models of bird flight and bird migration. It may also help to explain why some shorebirds, despite the high metabolic power input required to fly, routinely make nonstop flights of 4,000 km longer. PMID- 11607032 TI - Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. AB - Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses. Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication. Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-kappaB and the production of type I interferons (IFNs). TLR3-deficient (TLR3-/ ) mice showed reduced responses to polyinosine-polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines. MyD88 is an adaptor protein that is shared by all the known TLRs. When activated by poly(I:C), TLR3 induces cytokine production through a signalling pathway dependent on MyD88. Moreover, poly(I:C) can induce activation of NF-kappaB and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature. PMID- 11607034 TI - Forkhead transcription factors contribute to execution of the mitotic programme in mammals. AB - Cell cycle progression is a process that is tightly controlled by internal and external signals. Environmental cues, such as those provided by growth factors, activate early signals that promote cell cycle entry. Cells that have progressed past the restriction point become independent of growth factors, and cell cycle progression is then controlled endogenously. The phosphatidylinositol 3OH kinase (PI(3)K)/protein kinase B (PKB) pathway must be activated in G1 to inactivate forkhead transcription factors (FKH-TFs) and allow cell cycle entry. Here we show that subsequent attenuation of the PI(3)K/PKB pathway is required to allow transcriptional activation of FKH-TF in G2. FKH-TF activity in G2 controls mammalian cell cycle termination, as interference with FKH transcriptional activation by disrupting PI(3)K/PKB downregulation, or by expressing a transcriptionally inactive FKH mutant, induces cell accumulation in G2/M, defective cytokinesis, and delayed transition from M to G1 of the cell cycle. We demonstrate that FKH-TFs regulate expression of mitotic genes such as cyclin B and polo-like kinase (Plk). Our results support the important role of forkhead in the control of mammalian cell cycle completion, and suggest that efficient execution of the mitotic programme depends on downregulation of PI(3)K/PKB and consequent induction of FKH transcriptional activity. PMID- 11607033 TI - Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. AB - Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP. Expression of Httex1p in cultured cells reduces the level of the acetylated histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease. These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms. PMID- 11607035 TI - The bacteriophage straight phi29 portal motor can package DNA against a large internal force. AB - As part of the viral infection cycle, viruses must package their newly replicated genomes for delivery to other host cells. Bacteriophage straight phi29 packages its 6.6-microm long, double-stranded DNA into a 42 x 54 nm capsid by means of a portal complex that hydrolyses ATP. This process is remarkable because entropic, electrostatic and bending energies of the DNA must be overcome to package the DNA to near-crystalline density. Here we use optical tweezers to pull on single DNA molecules as they are packaged, thus demonstrating that the portal complex is a force-generating motor. This motor can work against loads of up to 57 pN on average, making it one of the strongest molecular motors reported to date. Movements of over 5 microm are observed, indicating high processivity. Pauses and slips also occur, particularly at higher forces. We establish the force-velocity relationship of the motor and find that the rate-limiting step of the motor's cycle is force dependent even at low loads. Notably, the packaging rate decreases as the prohead is filled, indicating that an internal force builds up to approximately 50 pN owing to DNA confinement. Our data suggest that this force may be available for initiating the ejection of the DNA from the capsid during infection. PMID- 11607036 TI - Uracil-DNA glycosylase acts by substrate autocatalysis. AB - In humans, uracil appears in DNA at the rate of several hundred bases per cell each day as a result of misincorporation of deoxyuridine (dU) or deamination of cytosine. Four enzymes that catalyse the hydrolysis of the glycosylic bond of dU in DNA to yield an apyridiminic site as the first step in base excision repair have been identified in the human genome. The most efficient and well characterized of these uracil-DNA glycosylases is UDG (also known as UNG and present in almost all known organisms), which excises U from single- or double stranded DNA and is associated with DNA replication forks. We used a hybrid quantum-mechanical/molecular-mechanical (QM/MM) approach to determine the mechanism of catalysis by UDG. In contrast to the concerted associative mechanism proposed initially, we show here that the reaction proceeds in a stepwise dissociative manner. Cleavage of the glycosylic bond yields an intermediate comprising an oxocarbenium cation and a uracilate anion. Subsequent attack by a water molecule and transfer of a proton to D145 result in the products. Surprisingly, the primary contribution to lowering the activation energy comes from the substrate, rather than from the enzyme. This 'autocatalysis' derives from the burial and positioning of four phosphate groups that stabilize the rate determining transition state. The importance of these phosphates explains the residual activity observed for mutants that lack key residues. A corresponding catalytic mechanism could apply to the DNA glycosylases TDG and SMUG1, which belong to the same structural superfamily as UDG. PMID- 11607037 TI - Eplerenone: a selective aldosterone receptor antagonist (SARA). AB - Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT(1)) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels--a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone--the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs)--is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease. PMID- 11607038 TI - An overview of SR121463, a selective non-peptide vasopressin V(2) receptor antagonist. AB - SR121463 is a selective, orally active, non-peptide antagonist of vasopressin (AVP) V(2) receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free-water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V(2) receptors and exhibits a remarkably selective V(2) receptor profile. SR121463 and [(3)H]SR121463 are used, therefore, as selective probes for characterization and labeling of V(2) receptors. In various functional studies in vitro, SR121463 behaves as a potent antagonist. It inhibits AVP-stimulated human renal adenylyl cyclase and dDAVP (1-desamino, 8-D arginine-vasopressin)-induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V(2) receptor mutant. In vitro, SR121463 rescued misfolded V(2) AVP receptor mutants by increasing cell surface expression and restoring V(2) function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose-dependent aquaresis with no major changes in urinary Na+ and K+ excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10-day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V(2) (or V(2)-like) receptors involved in vascular relaxation or clotting factor release in vitro and in vivo. In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V(2) receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V(2) receptors. Pure V(2) receptor antagonists are likely to be therapeutically useful in several water-retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V(2) receptors (e.g., glaucoma). PMID- 11607039 TI - Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall. AB - Ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is widely used in Japan for improving prognosis and relieving symptoms in patients suffering from ischemic stroke or bronchial asthma. These clinical applications are based on the properties of ibudilast that inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The inhibition of platelet aggregation and vasodilatation by ibudilast may be due to synergistic elevation of intracellular cyclic nucleotides and release of nitric oxide (NO) or prostacyclin from endothelium, rather than direct inhibition of PDE5 or PDE3. Another important property of ibudilast is its antiinflammatory activity possibly associated with potent inhibition of PDE4. Combined with its relaxing effects on bronchial smooth muscle, antiinflammatory activity of ibudilast could favorably influence pathophysiology of asthma by antagonizing chemical mediators triggering asthmatic attacks. Ibudilast was also reported to significantly attenuate inflammatory cell infiltration in the lumbar spinal cord in an animal model of encephalomyelitis. Future investigations should include effects of ibudilast on inflammatory reactions between endothelium and blood cells, which may initiate the development of atherosclerosis. PMID- 11607040 TI - Norbormide: a calcium entry blocker with selective vasoconstrictor activity in rat peripheral arteries. AB - Norbormide is a unique vasoactive substance endowed with species- and tissue specific, endothelium independent, vasoconstrictor activity that is restricted to the peripheral arteries of rat. In rat aorta and in all tested arteries of other species norbormide exhibits vasorelaxant property presumably due to the blockade of calcium channels. A calcium entry blocker effect of norbormide has also been described in isolated, perfused guinea pig hearts. In these preparations norbormide produced coronary vasodilator, as well as negative inotropic and dromotropic effects. In single ventricular myocytes of guinea pigs norbormide reduces L-type calcium current. The mechanism underlying the selective vasoconstrictor effect of norbormide is unknown. In rat caudal artery, a vessel contracted by norbormide, the drug activates phospholipase C (PLC) signal cascade which is the biochemical pathway involved in the contractile effect triggered by most receptor-activating vasoactive agents. Therefore, norbormide-induced contraction of rat peripheral vessels is likely to be due to the activation of a PLC-coupled receptor abundantly or selectively expressed in vascular smooth muscle cells. The identification of this putative receptor could facilitate the development of tissue-selective pharmacological agents. PMID- 11607041 TI - Cardiovascular actions of berberine. AB - Berberine, is an alkaloid from Hydrastis canadensis L., Chinese herb Huanglian, and many other plants. It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea. This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8-oxoberberine. Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties. Both derivatives of berberine have antiarrhythmic activity. Some cardiovascular effects of berberine and its derivatives are attributed to the blockade of K+ channels (delayed rectifier and K(ATP)) and stimulation of Na+ -Ca(2+) exchanger. Berberine has been shown to prolong the duration of ventricular action potential. Its vasodilator activity has been attributed to multiple cellular mechanisms. The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure. PMID- 11607042 TI - Gene transfer therapy in vascular diseases. AB - Somatic gene therapy of vascular diseases is a promising new field in modern medicine. Recent advancements in gene transfer technology have greatly evolved our understanding of the pathophysiologic role of candidate disease genes. With this knowledge, the expression of selective gene products provides the means to test the therapeutic use of gene therapy in a multitude of medical conditions. In addition, with the completion of genome sequencing programs, gene transfer can be used also to study the biologic function of novel genes in vivo. Novel genes are delivered to targeted tissue via several different vehicles. These vectors include adenoviruses, retroviruses, plasmids, plasmid/liposomes, and oligonucleotides. However, each one of these vectors has inherent limitations. Further investigations into developing delivery systems that not only allow for efficient, targeted gene transfer, but also are stable and nonimmunogenic, will optimize the clinical application of gene therapy in vascular diseases. This review further discusses the available mode of gene delivery and examines six major areas in vascular gene therapy, namely prevention of restenosis, thrombosis, hypertension, atherosclerosis, peripheral vascular disease in congestive heart failure, and ischemia. Although we highlight some of the recent advances in the use of gene therapy in treating vascular disease discovered primarily during the past two years, many excellent studies published during that period are not included in this review due to space limitations. The following is a selective review of practical uses of gene transfer therapy in vascular diseases. This review primarily covers work performed in the last 2 years. For earlier work, the reader may refer to several excellent review articles. For instance, Belalcazer et al. (6) reviewed general aspects of somatic gene therapy and the different vehicles used for the delivery of therapeutic genes. Gene therapy in restenosis and stimulation of angiogenesis in the cardiac muscle are discussed in reviews by several investigators (13,26,57,74,83). In another review, Meyerson et al. (43) discuss advances in gene therapy for vascular proliferative disorders and chronic peripheral and cardiac ischemia. PMID- 11607043 TI - Pharmacology of the atypical antipsychotic remoxipride, a dopamine D2 receptor antagonist. AB - Remoxipride is a substituted benzamide that acts as a weak but very selective antagonist of dopamine D2 receptors. It was introduced by Astra (Roxiam) at the end of the eighties and was prescribed as an atypical antipsychotic. This article reviews its putative selective effects on mesolimbic versus nigrostriatal dopaminergic systems. In animals, remoxipride has minimal cataleptic effects at doses that block dopamine agonist-induced hyperactivity. These findings are predictive of antipsychotic activity with a low likelihood of extrapyramidal symptoms. Remoxipride also appears to be effective in more recent animal models of schizophrenia, such as latent inhibition or prepulse inhibition. In clinical studies, remoxipride shows a relatively low incidence of extrapyramidal side effects and its effects on prolactin release are short-lasting and generally mild. The clinical efficacy of remoxipride is similar to that of haloperidol or chlorpromazine. Although its clinical use was severely restricted in 1993, due to reports of aplastic anemia in some patients receiving remoxipride, this drug has been found to exhibit relatively high selectivity for dopamine D2 receptors making remoxipride an interesting tool for neurochemical and behavioral studies. PMID- 11607044 TI - Fluvoxamine as an adjunctive agent in schizophrenia. AB - Schizophrenia is a common mental disorder that has an early onset and rates high as a cause of medical disability. Antipsychotic agents are the mainstay of treatment but response is often inadequate. Negative symptoms (disturbances in volition, social interaction and affective functions) are particularly difficult to treat and form a major obstacle to rehabilitation. A promising approach to improve response of negative symptoms has been to add a selective serotonin reuptake inhibitor (SSRI) antidepressant to antipsychotic treatment. This review examines evidence pertaining to the efficacy, tolerability, and safety of the SSRI fluvoxamine, combined with antipsychotic agents, in the treatment of negative symptoms in schizophrenia. Important methodological issues, such as differentiating primary and secondary negative symptoms, are discussed. The balance of available evidence indicates that fluvoxamine can improve primary negative symptoms in chronic schizophrenia patients treated with typical antipsychotics and suggests that it may also do so in some patients treated with clozapine. This combination is generally safe and well tolerated although, as antipsychotic drug concentrations may be elevated, attention to dose and drug monitoring should be considered appropriately. Combination with clozapine may require particular caution because of potential toxicity if serum clozapine levels rise steeply. The fluvoxamine doses effective in augmentation are lower than those usually used to treat depression. Evidence regarding the use of fluvoxamine augmentation to treat phenomena, such as obsessions and aggression, which may be associated with schizophrenia, is also examined. An important goal of future studies will be to define which patient groups can benefit from combined treatment. PMID- 11607045 TI - Adrogolide HCl (ABT-431; DAS-431), a prodrug of the dopamine D1 receptor agonist, A-86929: preclinical pharmacology and clinical data. AB - Adrogolide (ABT-431; DAS-431) is a chemically stable prodrug that is converted rapidly (<1 min) in plasma to A-86929, a full agonist at dopamine D1 receptors. In in vitro functional assays, A-86929 is over 400 times more selective for dopamine D1 than D2 receptors. In rats with a unilateral loss of striatal dopamine, A-86929 produces contralateral rotations that are inhibited by dopamine D1 but not by dopamine D2 receptor antagonists. Adrogolide improves behavioral disability and locomotor activity scores in MPTP-lesioned marmosets, a model of Parkinson's disease (PD), and shows no tolerance upon repeated dosing for 28 days. In PD patients, intravenous (i.v.) adrogolide has antiparkinson efficacy equivalent to that of L-DOPA with a tendency towards a reduced liability to induce dyskinesia. The adverse events associated with its use were of mild-to moderate severity and included injection site reaction, asthenia, headache, nausea, vomiting, postural hypotension, vasodilitation, and dizziness. Adrogolide can also attenuate the ability of cocaine to induce cocaine-seeking behavior and does not itself induce cocaine-seeking behavior in a rodent model of cocaine craving and relapse. In human cocaine abusers, i.v. adrogolide reduces cocaine craving and other cocaine-induced subjective effects. The results of animal abuse liability studies indicate that adrogolide is unlikely to have abuse potential in man. Adrogolide has also been reported to reverse haloperidol-induced cognitive deficits in monkeys, suggesting that it may be an effective treatment for the cognitive dysfunction associated with aging and disease. Adrogolide undergoes a high hepatic "first-pass" metabolism in man after oral dosing and, as a result, has a low oral bioavailability (approximately 4%). This limitation may potentially be circumvented by oral inhalation formulations for intrapulmonary delivery that greatly increase the bioavailability of adrogolide. As the first full dopamine D1 receptor agonist to show efficacy in PD patients and to reduce the craving and subjective effects of cocaine in cocaine abusers, adrogolide represents an important tool in understanding the pharmacotherapeutic potential of dopamine D1 receptor agonists. PMID- 11607046 TI - Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2 propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain. AB - Hundreds of millions of people now die over the age of 80 years primarily due to twentieth century progress in hygiene, chemotherapy, and immunology. With a longer average lifespan, the need to improve quality of life during the latter decades is more compelling. "Aging--The Epidemic of the New Millenium," a recent international conference (Monte Carlo, June 17-18, 2000), showed with peculiar clarity that a safe and efficient drug strategy to slow the age-related decay of brain performance is still missing. This review summarizes the physiologic and pharmacologic arguments in favor of a peculiar lifelong prophylactic medication with reasonable chances to keep in check brain aging and decrease the precipitation of age-related neurological diseases. PMID- 11607047 TI - A review of the pharmacological and clinical profile of mirtazapine. AB - The novel antidepressant mirtazapine has a dual mode of action. It is a noradrenergic and specific serotonergic antidepressant (NaSSA) that acts by antagonizing the adrenergic alpha2-autoreceptors and alpha2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. This dual mode of action may conceivably be responsible for mirtazapine's rapid onset of action. Mirtazapine is extensively metabolized in the liver. The cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4 are mainly responsible for its metabolism. Using once daily dosing, steady-state concentrations are reached after 4 days in adults and 6 days in the elderly. In vitro studies suggest that mirtazapine is unlikely to cause clinically significant drug-drug interactions. Dry mouth, sedation, and increases in appetite and body weight are the most common adverse effects. In contrast to selective serotonin reuptake inhibitors (SSRIs), mirtazapine has no sexual side effects. The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials. In major depression, its efficacy is comparable to that of amitriptyline, clomipramine, doxepin, fluoxetine, paroxetine, citalopram, or venlafaxine. Mirtazapine also appears to be useful in patients suffering from depression comorbid with anxiety symptoms and sleep disturbance. It seems to be safe and effective during long term use. PMID- 11607048 TI - Capelli bitableaux and Z-forms of general linear Lie superalgebras. AB - The combinatorics of the enveloping algebra UQ(pl(L)) of the general linear Lie superalgebra of a finite dimensional Z2-graded Q-vector space is studied. Three non-equivalent Z-forms of UQ(pl(L)) are introduced: one of these Z-forms is a version of the Kostant Z-form and the others are Lie algebra analogs of Rota and Stein's straightening formulae for the supersymmetric algebra Super[L P] and for its dual Super[L* P*]. The method is based on an extension of Capelli's technique of variabili ausiliarie to algebras containing positively and negatively signed elements. PMID- 11607049 TI - Do thylakoids really contain phosphatidylcholine? AB - Isolated intact spinach chloroplasts were incubated with phospholipase C (phosphatidylcholine cholinephosphohydrolase, EC 3.1.4.3) under mild experimental conditions in which only the phosphatidylcholine localized in the cytosolic leaflet of the outer envelope membrane can be hydrolyzed. Thylakoids, which were protected from phospholipase C degradation, were subsequently prepared from the phospholipase C-treated chloroplasts and found to be devoid of phosphatidylcholine. Previously reported occurrences of phosphatidylcholine in thylakoid preparations probably reflect contamination of the thylakoids by envelope membranes. In the present work, contamination of thylakoids by envelope membranes was determined by measuring the 1,2-diacylglycerol 3-beta galactosyltransferase [monogalactosyldiacylglycerol (MGDG) synthase; UDPgalactose: 1,2-diacylglycerol 3-beta-D-galactosyltransferase, EC 2.4.1.46] in the different chloroplast subfractions. We conclude that phosphatidylcholine is not present in highly purified thylakoids. Phosphatidylcholine is also absent from prokaryotic cyanobacterial membranes, and our results are in agreement with the endosymbiotic origin of higher plant chloroplasts. PMID- 11607050 TI - Holomorphic curves in surfaces of general type. AB - This note answers some questions on holomorphic curves and their distribution in an algebraic surface of positive index. More specifically, we exploit the existence of natural negatively curved "pseudo-Finsler" metrics on a surface S of general type whose Chern numbers satisfy c(2)1>2c2 to show that a holomorphic map of a Riemann surface to S whose image is not in any rational or elliptic curve must satisfy a distance decreasing property with respect to these metrics. We show as a consequence that such a map extends over isolated punctures. So assuming that the Riemann surface is obtained from a compact one of genus q by removing a finite number of points, then the map is actually algebraic and defines a compact holomorphic curve in S. Furthermore, the degree of the curve with respect to a fixed polarization is shown to be bounded above by a multiple of q - 1 irrespective of the map. PMID- 11607051 TI - Nonminimum phase non-Gaussian autoregressive processes. AB - The structure of non-Gaussian autoregressive schemes is described. Asymptotically efficient methods for the estimation of the coefficients of the models are described under appropriate conditions, some of which relate to smoothness and positivity of the density function f of the independent random variables generating the process. The principal interest is in nonminimum phase models. PMID- 11607052 TI - Determination of the crystal structure and composition of Li6Be4OH12 by the stochastic method. AB - Because of the failure to find a structure for LiBeH3 with a face-centered unit cube with edge 5.09 A, the x-ray powder pattern has been reindexed for a body centered unit cube with edge 7.24 A. Application of the principles of structural chemistry leads to the formula Li6Be4OH12 and to a structure involving Be4OH12 clusters formed by 4 BeOH3 tetrahedra with their O corner shared, Be--(H,O) bond length 1.59 A, and with the clusters joined to one another by Li with octahedral or rectangular-planar coordination of 6 H or 4 H, Li-H bond lengths about 1.92 A. PMID- 11607053 TI - Bialgebra cohomology, deformations, and quantum groups. AB - We introduce cohomology and deformation theories for a bialgebra A (over a commutative unital ring k) such that the second cohomology group is the space of infinitesimal deformations. Our theory gives a natural identification between the underlying k-modules of the original and the deformed bialgebra. Certain explicit deformation formulas are given for the construction of quantum groups--i.e., Hopf algebras that are neither commutative nor cocommutative (whether or not they arise from quantum Yang-Baxter operators). These formulas yield, in particular, all GLq(n) and SLq(n) as deformations of GL(n) and SL(n). Using a Hodge decomposition of the underlying cochain complex, we compute our cohomology for GL(n). With this, we show that every deformation of GL(n) is equivalent to one in which the comultiplication is unchanged, not merely on elements of degree one but on all elements (settling in the strongest way a decade-old conjecture) and in which the quantum determinant, as an element of the underlying k-module, is identical with the usual one. PMID- 11607055 TI - Inducible morphology, heterochrony, and size hierarchies in a colonial invertebrate monoculture. AB - Conditional or inducible strategies are a powerful tool for analyzing the evolution of aggressive behavior. Structures such as stolons and nematocyst-laden tentacles, induced to deter encroachment by competitors, are proportionately better represented in clonal and colonial marine invertebrates than in aclonal animals. Stolons can be produced by colonies of Membranipora membranacea (Bryozoa) within 48 hr after contact with conspecifics. Absolute size and relative size of interacting colonies determine whether stolons will be produced. Although individual stolons are eventually overgrown by conspecifics, they reduce the size of affected zooids by 27%. Since stolon production is primarily a strategy of large colonies, we suggest that stolons function to limit space occupied by small colonies and may also trigger early and localized reproduction. Thus large colonies can surround multiple small mates and, because they reproduce only locally where induced by contact with small colonies, still maintain high growth rates on free colony perimeters. Stolons appear to be juvenilized zooids and to originate through a process of heterochrony. These induced facultative polymorphisms may be one pathway by which fixed polymorphisms arise in colonial invertebrates. We attribute the unique production of inducible structures against competitors by clonal and colonial invertebrates to both unusually high levels of development plasticity and an energetically favorable architecture for perimeter defense. PMID- 11607056 TI - Helianthus annuus ssp. texanus has chloroplast DNA and nuclear ribosomal RNA genes of Helianthus debilis ssp. cucumerifolius. AB - Heiser [Heiser, C. B. (1951) Evolution 5, 42-51] hypothesized that Helianthus annuus ssp. texanus was derived by the introduction of H. annuus into Texas and subsequent introgression of genes from Helianthus debilis ssp. cucumerifolius into H. annuus. Although often considered to be one of the best cases of introgression in plants, alternative hypotheses to introgression, such as convergence or the joint retention of the ancestral condition, could not be ruled out in the original study. To test for the occurrence of introgression we examined 14 populations of H. annuus ssp. texanus, 14 allopatric populations of H. annuus, and three populations of H. debilis ssp. cucumerifolius with reference to diagnostic chloroplast DNA and nuclear ribosomal DNA markers. Thirteen of the 14 populations of H. annuus ssp. texanus had chloroplast DNA and/or ribosomal DNA markers of H. debilis ssp. cucumerifolius. In contrast, no chloroplast DNA or ribosomal DNA markers of H. debilis ssp. cucumerifolius were found in the 14 allopatric populations of H. annuus. Our findings provide strong support, therefore, for the hypothesized introgressive origin of H. annuus ssp. texanus. PMID- 11607057 TI - Supersymmetric Hilbert space. AB - A generalization is given of the notion of a symmetric bilinear form over a vector space, which includes variables of positive and negative signature ("supersymmetric variables"). It is shown that this structure is substantially isomorphic to the exterior algebra of a vector space. A supersymmetric extension of the second fundamental theorem of invariant theory is obtained as a corollary. The main technique is a supersymmetric extension of the standard basis theorem. As a byproduct, it is shown that supersymmetric Hilbert space and supersymplectic space are in natural duality. PMID- 11607058 TI - Pea leaf mitochondrial pyruvate dehydrogenase complex is inactivated in vivo in a light-dependent manner. AB - We examined the effect of light on the activity of the mitochondrial pyruvate dehydrogenase complex (mt-PDC) by using intact green pea (Pisum sativum) seedlings. Upon illumination there is an initial drop in mtPDC activity followed by oscillations that dampen during the initial period of photosynthesis to a steady-state level of one-fourth or less of the mtPDC activity measured in the dark. The initial light-dependent decrease in mtPDC activity is inhibited by 3 (3,4-dichlorophenyl)-1,1-dimethylurea (an inhibitor of photosystem II of photosynthesis) and does not occur in etiolated seedlings. Therefore, the effect of light is indirect and most likely associated with photosynthesis and/or photorespiration. Conditions that would be unfavorable for photorespiration also inhibited the light-dependent decrease in mtPDC activity. PMID- 11607059 TI - Multiple origins of polyploids in the Glycine tabacina complex inferred from chloroplast DNA polymorphism. AB - The Glycine tabacina polyploid complex has been shown to include a minimum of two morphological and crossing groups, which also differ in chloroplast DNA (cpDNA) restriction map and nuclear ribosomal gene repeat phenotype. These AAB2B2 and BBB2B2 G. tabacina polyploids contain plastomes referable to the A and B diploid plastome groups of subgenus Glycine, respectively. Eight different cpDNA variants were observed among the 65 B-type polyploids studied, six of which were identical for numerous restriction site characters to plastome types found among the highly polymorphic B genome diploid species. It is hypothesized that there have been numerous independent origins of polyploid G. tabacina: at least one AA x B2B2 event and a minimum of five BB x B2B2 events involving different BB types as female progenitor. Low amounts of cpDNA divergence between diploid and polyploid plastomes and among the plastomes of geographically disjunct polyploids suggest that the origin and dispersal of polyploids are relatively recent events. All hypothesized diploid progenitors are native to Australia, while both A- and B type G. tabacina polyploids occur on islands of the Pacific outside the range of diploids. The presence of several different plastome types of polyploid G. tabacina in the Pacific islands suggests that several colonization events have occurred. PMID- 11607060 TI - Juvenile hormone receptors in insect larval epidermis: identification by photoaffinity labeling. AB - Tritiated photoaffinity analogs of the natural lepidopteran juvenile hormones, JH I and II [epoxy[3H]bishomofarnesyl diazoacetate ([3H]EBDA) and epoxy[3H]homofarnesyl diazoacetate ([3H]EHDA)], and of the JH analog methoprene [[3H]methoprene diazoketone ([3H]MDK)] were synthesized and used to identify specific JH binding proteins in the larval epidermis of the tobacco hornworm (Manduca sexta). EBDA and EHDA specifically photolabeled a 29-kDa nuclear protein (pI 5.8). This protein and a second 29-kDa protein (pI 6.0) were labeled by MDK, but excess unlabeled methoprene or MDK only prevented binding to the latter. These 29-kDa proteins are also present in larval fat body but not in epidermis from either wandering stage or allatectomized larvae, which lack high-affinity JH binding sites. A 29-kDa nuclear protein with the same developmental specificity as this JH binder bound the DNA of two larval endocuticle genes. A 38-kDa cytosolic protein was also specifically photolabeled by these photoaffinity analogs. The 29-kDa nuclear protein is likely the high-affinity receptor for JH that mediates its genomic action, whereas the 38-kDa cytosolic protein may serve as an intracellular carrier for these highly lipophilic hormones and hormone analogs. PMID- 11607061 TI - Fractal geometry of music. AB - Music critics have compared Bach's music to the precision of mathematics. What "mathematics" and what "precision" are the questions for a curious scientist. The purpose of this short note is to suggest that the mathematics is, at least in part, Mandelbrot's fractal geometry and the precision is the deviation from a log log linear plot. PMID- 11607062 TI - Differences between pair and bulk hydrophobic interactions. AB - It is now well known that the pair interaction between two hydrocarbon molecules in water has distinctly different properties from the bulk hydrophobic interaction familiar to the biochemist, which is modeled by the transfer of a hydrocarbon from aqueous solutions to pure liquid hydrocarbon. We consider experimental data for pair interactions, which have been fitted by a simple empirical potential function, and point out some of their properties. (i) Surface free energy and cosphere overlap models, of the type considered until now, cannot reproduce correctly both the pair and bulk hydrophobic interactions. (ii) Pair interactions though still attractive are strikingly weaker in aqueous solution than in the gas phase, in contrast to the usual view of hydrophobic interactions. (iii) For pair interactions in water, the solvent-separated configuration is less important than the contact configuration if the hydrocarbon has more than two carbon atoms. PMID- 11607063 TI - Observation of a water-depletion region surrounding loblolly pine roots by magnetic resonance imaging. AB - Magnetic resonance imaging was used to study sand containing various amounts of water and roots of loblolly pine planted into similar sand. Spin-lattice (T1) relaxation times of sand with water contents ranging from 0 to 25% (wt/wt) ranged from 472 to 1265 ms and increased with water content. Spin-spin (T2) relaxation times ranged from 54 to 76 ms and did not change in a discernible pattern with water content. Based on water content and measured T1 and T2 values, the signal intensity of sand/water images was predicted to increase with water content in a linear fashion, with the slope of the lines increasing with the time of acquisition repetition (TR). Measured signal intensity from images of sand with various water contents was found to follow a similar pattern. This allows interpretation of dark images of sand/water to be regions of low water content, and bright images to have comparatively greater water content. Images of loblolly pine seedling roots planted in identical sand showed the formation of a distinct water-depletion region first around the woody taproot and later showed the region extended and expanded around the lateral roots and clusters of mycorrhizal short roots. This observation strongly suggests that water uptake is occurring through the suberized region of the woody taproot. PMID- 11607064 TI - Inhomogeneous basis set of symmetric polynomials defined by tableaux. AB - A basis set of inhomogeneous symmetric polynomials, denoted by tlambda(z), where z = (z1,....,zn) and lambda = [lambda1,...., lambdan] is a partition, is defined in terms of Young-Weyl standard tableaux or, equivalently, in terms of Gel'fand Weyl patterns. A number of significant properties of these polynomials are given (together with outlines of proofs) and compared with properties of the well-known basis set of Schur functions, which are homogeneous polynomials. The basis of the ring of symmetric polynomials defined here is shown to be natural for the expansion of inhomogeneous symmetric functions constructed from rising factorials. PMID- 11607065 TI - Expression of functional replication protein from tomato golden mosaic virus in transgenic tobacco plants. AB - The A component of the bipartite genome of the geminivirus tomato golden mosaic virus (TGMV) encodes the viral protein (AL1) that is required for viral DNA replication. We have constructed transgenic Nicotiana benthamiana plants in which the AL1 open reading frame is transcribed under the control of the cauliflower mosaic virus 35S promoter. The transgenic plants, which were phenotypically normal, produced a single transcript from the 35S-AL1 construct and a 40-kDa protein that cross-reacted with a polyclonal antiserum raised against AL1 protein overproduced in Escherichia coli. Six of nine transgenic lines complemented a TGMV A variant with a mutation in AL1 when coinoculated with the B component of the TGMV genome. Single- and double-stranded forms of the B component were synthesized in leaf discs from a complementing, transgenic line in the absence of TGMV A. These results establish that the transgenic plants express functional AL1 protein and show that this viral protein is not only required, but sufficient, for single- and double-stranded replication of TGMV DNA in the presence of host proteins. These results also show that the AL1 protein is not by itself a determinant of disease or pathogenesis. PMID- 11607066 TI - Grazing in a turbulent environment: behavioral response of a calanoid copepod, Centropages hamatus. AB - Models of marine ecosystem productivity rely on estimates of small-scale interactions, particularly those between copepods and their algal food sources. Rothschild and Osborn [Rothschild, B. J. & Osborn, T. R. (1988) J. Plankton Res. 10, 465-474], hypothesized that small-scale turbulence in aquatic systems increases the perceived abundance of prey to predators. We tested this hypothesis by exposing the planktonic copepod Centropages hamatus to turbulent and nonturbulent environments at different prey concentrations. Our results fell into two main categories. First, the response to turbulence was characterized by an initial period having a high number of escape reactions. This period was followed by one of increased foraging. C. hamatus responded to the higher encounter rates due to turbulence as if it were experiencing altered prey concentrations. Second, the termination of turbulence resulted in an increased foraging response, which was not directly related to the encounter rate. Functional response curves do not adequately explain this foraging response because the time course of the foraging response depends on prior encounter experience and foraging motivation. PMID- 11607067 TI - Grazing in a turbulent environment: energy dissipation, encounter rates, and efficacy of feeding currents in Centropages hamatus. AB - The creation of feeding currents by calanoid copepods increases encounter rates of copepods with their food and provides and advantage in dilute nutritional environments. Small-scale turbulence has also been hypothesized to increase the encounter rate between planktonic predators and their food. Centropages hamatus was exposed to turbulent and nonturbulent environments at two prey concentrations to quantify the influence of turbulence on feeding current efficacy. Turbulent energy dissipation rates used in the experiment were in the range of 0.05-0.15 cm2. sec-3. In the nonturbulent environments, feeding currents increased the encounter rates of C. hamatus 3-5 times that of control encounter areas. In turbulent environments, encounter rates were not increased by feeding currents, yet C. hamatus continued to create feeding currents. Energetic calculations indicate a tradeoff in the value of turbulence to a copepod feeding on phytoplankton. While turbulence is probably beneficial at low food concentrations, it may be deleterious at high food concentrations. PMID- 11607068 TI - Why do polyethylene crystals have sectors? AB - High-resolution (3.7 A in optical diffraction) electron microscope images have been obtained from a series of n-paraffin monolamellar crystals with chain lengths from n-C36H74 to n-C82H166. The higher molecular weight specimens, which do not undergo chain folding, form sectorized crystals and the molecular packing is found to include alternate bands of untilted and tilted chains along <130>. Their widths are consistent with those of Bragg fringe widths in bright-field images obtained at lower magnification. The chain tilt axis is near d*110. Lower molecular weight paraffins form nonsectorized crystals where the chains are generally untilted with occasional small inclinations around nonspecific axes. Surface decoration of the longer alkanes with polyethylene crystallites, first of all, reveals three preferred polyethylene crystal rod orientations ([100] plus two perpendicular to [110]) instead of the two commonly found for the lower alkane. Control studies on solid-solution crystals reveal that the third [100] orientation is a result of slight surface roughness due to unequal chain lengths or surface protrusions of chains; the new decoration is also randomly distributed. For pure n-C60H122 lamellae, however, suggestions of regular bands containing rods along [100], due to surface discontinuities along <130>, can also be seen. In contrast with polyethylene, these data suggest that crystal sectorization may be a function of chain-stem packing alone and that chain folds may play merely a secondary role in the polymer--e.g., by directing the collapse of pyramidal crystals on a flat surface. PMID- 11607069 TI - Laticifer-specific gene expression in Hevea brasiliensis (rubber tree). AB - Natural rubber, cis-1,4-polyisoprene, is obtained from a colloidal fluid called latex, which represents the cytoplasmic content of the laticifers of the rubber tree (Hevea brasiliensis). We have developed a method of extracting translatable mRNA from freshly tapped latex. Analysis of in vitro translation products of latex mRNA showed that the encoded polypeptides are very different from those of leaf mRNA and these differences are visible in the protein profiles of latex and leaf as well. Northern blot analysis demonstrated that laticifer RNA is 20- to 100-fold enriched in transcripts encoding enzymes involved in rubber biosynthesis. Plant defense genes encoding chitinases, pathogenesis-related protein, phenylalanine ammonia-lyase, chalcone synthase, chalcone isomerase, cinnamyl alcohol dehydrogenase, and 5-enolpyruvylshikimate-3-phosphate synthase show a 10- to 50-fold higher expression in laticifers than in leaves, indicating the probable response of rubber trees to tapping and ethylene treatment. Photosynthetic genes encoding ribulose-bisphosphate carboxylase small subunit and chlorophyll a/b-binding protein are not expressed at a detectable level in laticifers. In contrast, genes encoding two hydrolytic enzymes, cellulase and polygalacturonase, are more highly expressed in laticifers than in leaves. Transcripts for the cytoplasmic form of glutamine synthase are preferentially expressed in laticifers, whereas those for the chloroplastic form of the same enzyme are present mainly in leaves. Control experiments demonstrated that beta ATPase, actin, and ubiquitin are equally expressed in laticifers and leaves. Therefore, the differences in specific transcript abundance between laticifers and leaves are due to differential expression of the genes for these transcripts in the laticifers. PMID- 11607070 TI - Antibiotics cause parthenogenetic Trichogramma (Hymenoptera/Trichogrammatidae) to revert to sex. AB - Completely parthenogenetic Trichogramma wasps can be rendered permanently bisexual by treatment with three different antibiotics or high temperatures. The evidence strongly suggests that maternally inherited microorganisms cause parthenogenesis in these wasps. Theories predict female-biased sex ratio in offspring under the influence of maternally inherited symbionts, but extreme sex ratios of 100% females were never considered because the lack of males would prevent the host's reproduction. PMID- 11607071 TI - Discovery of Entomophaga maimaiga in North American gypsy moth, Lymantria dispar. AB - An entomopathogenic fungus, Entomophaga maimaiga, was found causing an extensive epizootic in outbreak populations of the gypsy moth, Lymantria dispar, throughout many forested and residential areas of the northeastern United States. This is the first recognized occurrence of this or any entomophthoralean fungus in North American gypsy moths, and its appearance was coincident with an abnormally wet spring. Most fungal-infected gypsy moth larvae were killed in mass during the fourth and fifth stadium and were characteristically found clinging to the trunks of trees with their heads pointed downward. The fungus produces thick-walled resistant resting spores within dried gypsy moth cadavers and infectious conidia when freshly killed larvae are held in a wet environment. The morphology and development of the fungus are described. The fungus appears to have had its origin in Japan, and the current epizootic may have resulted from the survival and inapparent spread of an early introduction in 1910-1911. PMID- 11607073 TI - Glyoxal oxidase of Phanerochaete chrysosporium: its characterization and activation by lignin peroxidase. AB - Glyoxal oxidase (GLOX) is an extracellular H2O2-generating enzyme produced by ligninolytic cultures of Phanerochaete chrysosporium. The production, purification, and partial characterization of GLOX from agitated cultures are described here. High-oxygen levels are critical for GLOX production as for lignin peroxidase. GLOX purified by anion-exchange chromatography appears homogeneous by NaDod-SO4/PAGE (molecular mass = 68 kDa). However, analysis by isoelectric focusing indicates two major bands (pI 4.7 and 4.9) that stain as glycoproteins as well as for H2O2-producing activity in the presence of methylglyoxal. Purified GLOX shows a marked stimulation in activity when incubated with Cu2+; full activation takes more than 1 hr with 1 mM CuSO4 at pH 6. The steady-state kinetic parameters for the GLOX oxidation of methylglyoxal, glyceraldehyde, dihydroxyacetone, glycolaldehyde, acetaldehyde, glyoxal, glyoxylic acid, and formaldehyde, were determined by using a lignin peroxidase coupled-assay at pH 4.5. Of these substrates, the best is the extracellular metabolite methylglyoxal with a Km of 0.64 mM an apparent rate of catalysis, kcat, of 198 s1 under air saturated conditions. The Km for oxygen is greater than the concentration of oxygen possible at ambient pressure--i.e., >1.3 mM at 25 degrees C. Importantly, oxygen-uptake experiments show that purified GLOX is inactive unless coupled to the peroxidase reaction. With this coupled reaction, for each mol of methylglyoxal, veratryl alcohol (a lignin peroxidase substrate), and oxygen consumed, 1 mol each of pyruvate and veratraldehyde is produced. The importance of these results is discussed in relation to the physiology of lignin biodegradation and possible extracellular regulatory mechanisms for the control of oxidase and peroxidase activities. PMID- 11607074 TI - More cold fusion in metals: corrected calculations and other considerations. AB - A simple model of a metal containing deuterons is considered. The example of palladium is treated in detail. In contrast to a previous calculation, it is shown that the effect of screening of Coulomb fields by conduction electrons is sufficient to allow a deuteron pair to fuse at a rate of 10(-18) sec-1, five powers of 10 larger than some experimental results. It is shown that the Oppenheimer-Phillips process enhances the rate by a factor of 1.77. Difficulties with applying the model to titanium are discussed. PMID- 11607075 TI - Genomic analysis of diploid plants. AB - The numerical analysis of meiosis in the triploid hybrid between an induced autotetraploid and a related diploid provides the basis for investigations of the genomic relationships of diploid species based on chromosome pairing. It is also possible to make legitimate comparisons between different triploid hybrids of this type so that the genomic relationships can be converted into measures of phylogenetic distance for taxa where only diploids are known. PMID- 11607076 TI - Supramolecular arrangement of Rhodospirillum rubrum B880 holochrome as studied by radiation inactivation and electron paramagnetic resonance. AB - Oxidation of the B880 antenna holochrome gives rise to a 3.8-G linewidth electron paramagnetic resonance (EPR) signal that is considerably narrower than the 13-G signal of monomeric bacteriochlorophyll (Bchl) cation. Radiation inactivation was used to verify a model according to which this linewidth narrowing is due to delocalization over several Bchl molecules. Chromatophores of the photoreaction centerless mutant F24 of Rhodospirillum rubrum were subjected to different doses of gamma-radiation. This induced not only a decay of the EPR signal amplitude but also its linewidth broadening. According to target theory, the induced amplitude decay of the EPR signal had a target size of 10.5 kDa. This is attributed to an elementary structure (alpha1beta1Bchl2), whose number in the membrane would limit the rate of encounter with ferricyanide and thus the formation of unpaired spins. We applied Bernoulli statistics to predict, for a given survival probability of the signal, the number of surviving elementary structures in aggregates of (alpha1beta1Bchl2)n where n was varied from 4 to 7. Using an equation that predicted the Bchl special pair in the photo-reaction center, we were able to simulate the observed relationship between the EPR linewidth and the dose of radiation. The best fit was obtained with a hexameric structure alpha1beta1Bchl2)6. PMID- 11607077 TI - Evidence that a distribution of bacterial reaction centers underlies the temperature and detection-wavelength dependence of the rates of the primary electron-transfer reactions. AB - The rates of the primary electron-transfer processes in Rhodobacter sphaeroides reaction centers have been examined in detail by using 150-fs excitation flashes at 870 nm. At room temperature the apparent time constants for both initial charge separation (P* --> P+BPhL-) and subsequent electron transfer (P+BPhL- --> P+QA-) are found to encompass a range of values (approximately 1.3-4 ps and approximately 100-320 ps, respectively), depending on the wavelength at which the kinetics are followed. We suggest this reflects a distribution of reaction centers (or a few conformers), having differences in factors such as distances or orientations between the cofactors, hydrogen bonding, or other pigment-protein interactions. We also suggest that the time constants observed at cryogenic temperatures (approximately 1.3 and approximately 100 ps, respectively, with much smaller or negligible variation with detection wavelength) do not reflect an actual increase in the rates with decreasing temperature but rather derive from a shift in the distribution of reaction centers toward those in which electron transfer inherently occurs with the faster rates. PMID- 11607078 TI - Corn metabolites affect growth and virulence of Agrobacterium tumefaciens. AB - Homogenates of corn seedlings inhibit both growth of Agrobacterium tumefaciens and induction of its Ti plasmid virulence (vir) genes by acetosyringone (AS). The heat-labile inhibitor has been identified as 2,4-dihydroxy-7-methoxy-2H-1,4 benzoxazin-3(4H)-one (DIMBOA), present in 2-week-old seedlings (B73) at a concentration of 1.5 mM or greater. A concentration of 0.3 mM DIMBOA is sufficient to block growth of A. tumefaciens completely for 220 hr. DIMBOA at 0.1 mM concentration completely inhibited vir gene induction by 100 microM AS and reduced growth rate by 50%. Thus, DIMBOA can be expected to have a significant effect on attempts to transform corn by using A. tumefaciens as a vector. PMID- 11607079 TI - Maize sucrose synthase-1 promoter directs phloem cell-specific expression of Gus gene in transgenic tobacco plants. AB - Tobacco plants were transformed by using a chimeric gene construction, in which a corn sucrose synthase-1 gene (Sh) promoter was used to direct expression of the beta-glucuronidase (Gus) reporter gene. Expression of Sh-Gus activity in these plants was found to be cell type specfifc. GUS activity was detected only in the phloem cells but not in any other cell types of vegetative tissues. In addition, Sh-Gus expression was found to be anaerobically inducible in tobacco roots. Sh Gus was also expressed at high levels in the endosperm tissue of maturing tobacco seeds. We thus demonstrated that the corn Sh promoter can direct cell-type specific and inducible expression in a heterologous dicotyledonous plant. PMID- 11607081 TI - Invariant measures for unipotent translations on homogeneous spaces. AB - It is shown that all Borel probability measures invariant under unipotent translations on homogeneous spaces of connected Lie groups are algebraic. PMID- 11607080 TI - Transport of phosphocholine in higher plant cells: 31P nuclear magnetic resonance studies. AB - Phosphocholine (PC) is an abundant primary form of organic phosphate that is transported in plant xylem sap. Addition of PC to the perfusate of compressed Pi starved sycamore cells monitored by 31P NMR spectroscopy resulted in an accumulation of PC and all the other phosphate esters in the cytoplasmic compartment. Addition of hemicholinium-3, an inhibitor of choline uptake, to the perfusate inhibited PC accumulation but not inorganic phosphate (Pi). When the Pi starved cells were perfused with a medium containing either Pi or PC, the resulting Pi distribution in the cell was the same. Addition of choline instead of PC to the perfusate of compressed cells resulted in an accumulation of PC in the cytoplasmic compartment from choline kinase activity. In addition, PC phosphatase activity has been discovered associated with the cell wall. These results indicate that PC was rapidly hydrolyzed outside the cell and that choline and Pi entered the cytosolic compartment where choline kinase re-forms PC. PMID- 11607082 TI - Confirmation of dust condensation in the ejecta of supernova 1987a. AB - Shortly after its outburst, we suggested that supernova 1987a might condense a dust shell of substantial visual optical thickness as many classical novae do and predicted that dust might form within a year after the explosion. A critical examination of recent optical and infrared observations reported by others confirms that dust grains had begun to grow at a temperature of 1000 K after 300 days and that the dust shell had become optically thick by day 600. After day 600, the infrared luminosity closely followed the intrinsic luminosity expected for thermalized 56Co gamma rays, demonstrating that the luminosity is powered by radioactivity and that the dust is outside the radioactivity zone. The infrared luminosity sets an upper limit to the soft intrinsic bolometric luminosity of a pulsar central engine. This upper limit for the pulsar in supernova 1987a is the same luminosity as the Crab pulsar has today 936 years after its formation. It is unlikely that the rotation rate for a pulsar in supernova 1987a can be much higher than approximately 30 revolutions per sec. The relatively long time required for the shell to grow to maximum optical depth as compared with the dust in nova shells may be related to the relatively low outflow velocity of the condensible ejecta. PMID- 11607083 TI - A nontransformable Triticum monococcum monocotyledonous culture produces the potent Agrobacterium vir-inducing compound ethyl ferulate. AB - Exudates of dicotyledonous plants contain specific phenolic signal molecules, such as acetosyringone, which serve as potent inducers for the expression of the virulence (vir) regulon of the phytopathogen Agrobacterium tumefaciens. This induction activates the Agrobacterium T-DNA transfer process to initiate the genetic transformation of target plant cells. Wounded and metabolically active plant cells are particularly susceptible to Agrobacterium infection, and these cells specifically produce vir-inducing molecules. Most monocotyledonous, as opposed to dicotyledonous, species are resistant to Agrobacterium transformation. One hypothesis for this resistance is that nonsusceptible monocotyledonous cells fail to produce vir signal molecules and, thus, are not recognized by Agrobacterium as transformation targets. Here we demonstrate that monocotyledonous cells make such molecules, and, furthermore, we purify the inducer produced by a Triticum monococcum suspension culture that is resistant to Agrobacterium infection. This molecule is shown to correspond to ethyl ferulate [C12H14O4; 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid ethyl ester], to be more active for vir induction at low concentrations than acetosyringone, and to be produced in quantities giving significant levels of induction. Thus, at least for the wheat cell line used in this study, monocotyledonous resistance to Agrobacterium transformation must result from a block to a step of the T-DNA transfer process subsequent to vir induction. PMID- 11607085 TI - Regularities in the sequences of the number of nucleons in the revolving clusters for the ground-state energy bands of the even-even nuclei with neutron number equal to or greater than 126. AB - Values of m, the number of nucleons in the revolving cluster, and of R, the radius of revolution of the cluster about the center of mass of the spherical part of the nucleus, are calculated from the observed values of the energy for the ground-state bands of all nuclei with neutron number N >/= 126 on the basis of the assumptions (i) that both m and R change in a reasonable way with increase in the angular momentum quantum number J and with change in the proton number Z and the neutron number N, (ii) that m is usually an even integer, (iii) that certain clusters are especially stable, and (iv) that there is a special stability of the doubly magic sphere p82n126. PMID- 11607084 TI - Selector genes and the Cambrian radiation of Bilateria. AB - There is a significantly greater post-Cambrian decline in frequency of ordinal origination among serially constructed Bilateria, such as arthropods, than in nonserially constructed Bilateria. Greater decline in arthropod ordinal origination is not predicted by ecologic, diversity-dependent models of decline in the production of higher taxa. Reduction in ordinal origination indicates increased constraint on arthropod body-plan evolution. The dispersal of selector genes in the genomes of arthropods in conjunction with the retention of a simple regulatory hierarchy in development may have caused the increased constraint seen. Increased constraint would not be expected in those organisms that are not serially constructed and presumably have not retained the simple ancestral regulatory hierarchy in development of selector gene differentiation of serial elements. The hypothesis of differential constraint tested against the fossil record in this paper can be further tested by examination of the distribution of selector genes in the genomes of arthropods. PMID- 11607086 TI - Invariants of sets of linear varieties. AB - A minimal set of generators of the ring of invariants for four linear subspaces of dimension n in a vector space of dimension 2n is computed, using the symbolic method introduced by Grosshans et al. [Grosshans, F., Rota, G.-C. & Stein, J. A. (1987) Invariant Theory and Superalgebras (Am. Math. Soc., Providence, RI)]. PMID- 11607087 TI - Coclosure operators and chromatic polynomials. AB - A theorem about closure operators on partially ordered sets is given, and applications to the counting of colorings of graphs according to partition type are derived. PMID- 11607088 TI - Homological properties of rings of functional-analytic type. AB - Strong flatness properties are established for a large class of functional analytic rings including all C*-algebras. This is later used to prove that all those rings satisfy excision in Hochschild and in cyclic homology over almost arbitrary rings of coefficients and that, for stable C*-algebras, the Hochschild and cyclic homology groups defined over an arbitrary coefficient ring k subset C of complex numbers (e.g., k = Z or Q) vanish in all dimensions. PMID- 11607089 TI - Does the maximum entropy method improve sensitivity? AB - Maximum entropy reconstruction has been used in several fields to produce visually striking reconstructions of positive objects (images, densities, spectra) from noisy, indirect measurements. In magnetic resonance spectroscopy, this technique is notable for its apparent noise suppression and its avoidance of the artifacts that affect discrete Fourier transform spectra of short (zero extended) data records. In the general case where the length of the reconstructed spectrum exceeds that of the data record or where a convolution kernel is incorporated in the reconstruction, no known analytical solution to the reconstruction problem exists. Consequently, knowledge of the properties of maximum entropy reconstruction has been mainly anecdotal, based on a small selection of published reconstructions. However, in the limiting case where the lengths of the reconstructed spectrum and the data record are the same and a convolution kernel is not applied, the problem can be solved analytically. The solution has a simple structure that helps explain several commonly observed features of maximum entropy reconstructions--for example, the biases in the recovered intensities and the fact that noise near the baseline is more successfully suppressed than is noise superimposed on broad features in the spectrum. The solution also shows that the noise suppression offered by maximum entropy reconstruction could (in this special case) be equally well obtained by a "cosmetic" device: simply displaying the conventional Fourier transform reconstruction using a certain nonlinear plotting scale for the vertical (y) coordinate. PMID- 11607091 TI - Trophallaxis in a communal halictine bee Lasioglossum (Chilalictus) erythrurum. AB - Food exchange by means of oral trophallaxis was confirmed for a communal halictine bee Lasioglossum (Chilalictus) erythrurum. These results demonstrate an independent evolution of trophallaxis in bees. The occurrence of trophallaxis in a communal species questions the role of trophallaxis in the evolution of sociality. Neutral arena encounters between one fed and one unfed female indicate that food exchange is not associated with familiarity. Donor females fed nestmates and nonnestmates in the same proportion, even when nonnestmates were from a separate nest aggregation located 7 km away. Such universal acceptance is expected if positive fitness benefits accrue from nearly all interactions with conspecifics in nature. PMID- 11607090 TI - Initial electron-transfer in the reaction center from Rhodobacter sphaeroides. AB - The initial electron transfer steps in the photosynthetic reaction center of the purple bacterium Rhodobacter sphaeroides have been investigated by femtosecond time-resolved spectroscopy. The experimental data taken at various wavelengths demonstrate the existence of at least four intermediate states within the first nanosecond. The difference spectra of the intermediates and transient photodichroism data are fully consistent with a sequential four-step model of the primary electron transfer: Light absorption by the special pair P leads to the state P*. From the excited primary donor P*, the electron is transferred within 3.5 +/- 0.4 ps to the accessory bacteriochlorophyll B. State P+B- decays with a time constant of 0.9 +/- 0.3 ps passing the electron to the bacteriopheophytin H. Finally, the electron is transferred from H- to the quinone QA within 220 +/- 40 ps. PMID- 11607092 TI - Distribution and self-organization of photosynthetic pigments in micelles: implication for the assembly of light-harvesting complexes and reaction centers in the photosynthetic membrane. AB - The addition of bacteriochlorophylls and bacteriopheophytins to formamide/water, 3:1 (vol/vol), (or water) containing small spherical micelles of Triton X-100 leads to the reorganization of the detergent into micelles that consist of 5000 40,000 amphiphilic molecules. The pigment distribution within the micelles was determined by modified Poisson statistics taking into consideration the various sizes of micelles. Pigment dimerization occurred in micelles with more than a single occupant and was driven by a free-energy change of -4.5 kcal/mol (1 cal = 4.184 J) for bacteriochlorophyll a in formamide/water, -7.6 kcal/mol for bacteriopheophytin a in formamide/water, and -6.6 kcal/mol for bacteriopheophytin a in water. These values correspond to the room temperature equilibrium constants 2.2 x 10(3) M-1, 3.9 x 10(5) M-1, and 7.5 x 10(4) M-1, respectively. The incorporation of bacteriochlorophylls with attached small formamide polymers and the subsequent dimerization of these pigments in the lipid phase provide a model for studying the synergetic organization of polypeptides and bacteriochlorophyll clusters in the photosynthetic membrane. PMID- 11607093 TI - Method for isolation of auxotrophs in the methanogenic archaebacteria: role of the acetyl-CoA pathway of autotrophic CO2 fixation in Methanococcus maripaludis. AB - A procedure was developed for the enrichment of auxotrophs in the antibiotic insensitive archaebacterium Methanococcus. After mutagenesis with ethyl methanesulfonate, growing cells were selectively killed upon exposure to the base analogs 6-azauracil and 8-azahypoxanthine for 48 hr. Using this method, eight independent acetate autotrophs of Methanococcus maripaludis were isolated. Six of the auxotrophs had an absolute growth requirement for acetate and contained 1-16% of the wild-type levels of CO dehydrogenase. Three of these six also contained 14 29% of the wild-type levels of pyruvate oxidoreductase and 12-30% of the wild type levels of pyruvate synthase. Two spontaneous revertants of these latter auxotrophs regained the ability to grow normally in the absence of acetate and wild-type levels of CO dehydrogenase, acetyl-CoA synthase, pyruvate oxidoreductase, and pyruvate synthase. Likewise, a spontaneous revertant of an auxotroph with reduced levels of CO dehydrogenase and wild-type levels of pyruvate oxidoreductase regained the ability to grow normally in the absence of acetate and wild-type levels of CO dehydrogenase and acetyl-CoA synthase. Two additional auxotrophs grew poorly in the absence of acetate but contained wild type levels of CO dehydrogenase and pyruvate oxidoreductase. These results provide direct genetic evidence for the Ljungdahl-Wood pathway [Ljungdahl, L. G. (1986) Annu. Rev. Microbiol. 40, 415-450; Wood, H. G., Ragsdale, S. W. & Pezacka, E. (1986) Trends Biochem. Sci. 11, 14-18] of autotrophic acetyl-CoA biosynthesis in the methanogenic archaebacteria. Moreover, it suggests that the acetyl-CoA and pyruvate synthases may share a common protein or coenzyme component, be linked genetically, or be regulated by a common system. PMID- 11607094 TI - Fourier-transform Raman spectroscopy applied to photobiological systems. AB - Fluorescence and initiation of photoreactions are problems frequently encountered with resonance Raman spectroscopy of photobiological systems. These problems can be circumvented with Fourier-transform Raman spectroscopy by using the 1064-nm wavelength of a continuous wave neodymium-yttrium/aluminum-garnet laser as the probing beam. This wavelength is far from the absorption band of most pigments. Yet, the spectra of the investigated systems--bacteriorhodopsin, rhodopsin, and phycocyanin--show that these systems are still dominated by the chromophore, or that preresonant Raman scattering is still prevalent. Only for rhodopsin were contributions of the protein and the membrane discernible. The spectra of phycocyanin differ considerably from those obtained by excitation into the UV absorption band. The results show the usefulness of this method and its wide applicability. In addition, analysis of the relative preresonant scattering cross sections may provide a detailed insight into the scattering mechanism. PMID- 11607095 TI - Linear electric field mass analysis: a technique for three-dimensional high mass resolution space plasma composition measurements. AB - A revolutionary type of three-dimensional space plasma composition analyzer has been developed that combines very high-resolution mass composition measurements on a fraction of the incident ions simultaneously with lower mass resolution but high sensitivity measurements of the remaining population in a single compact and robust sensor design. Whereas the lower mass resolution measurements are achieved using conventional energy/charge (E/q) and linear time-of-flight analysis, the high mass resolution measurements are made by timing reflected E/q analyzed ions in a linear electric field (LEF). In a LEF the restoring (reflecting) force that an ion experiences in the direction parallel to the field is proportional to the depth it travels into the LEF region, and its equation of motion in that direction is that of a simple harmonic oscillator. Consequently, an ion's travel time is independent of its initial angle and energy and is simply proportional to the square root of the ion's mass/charge (m/q). The measured m/q resolution, (m/q)/Delta(m/q), for a small LEF-based prototype that we have developed and tested is approximately 20. In addition, our laboratory measurements with the prototype instrument show that characteristic time-of-flight spectra allow the resolution of atomic and molecular species with nearly identical m/q values. The measured response of the prototype is in excellent agreement with computer simulations of the device. Advanced design work using this computer simulation indicates that three-dimensional plasma composition analyzers with m/q resolutions of at least 50 are readily achievable. PMID- 11607096 TI - Disruptive sexual selection in Colias eurytheme butterflies. AB - Sexual selection on male pheromone composition in Colias eurytheme (Pieridae) butterflies has the remarkable effect of increasing the variability of this trait. Sexual selection on important traits is generally thought to have a strong stabilizing effect on intraspecific variation of those characters. In this species, however, the male courtship pheromone is highly variable in the relative proportions of its three chemical constituents. Stabilization and/or canalization of this polygenic character in a population is impeded by the disproportionate mating success of males in one portion of the character distribution with alba (white morph) females, and of those in the opposite portion with orange (colored morph) females. PMID- 11607097 TI - Control of expression of Agrobacterium vir genes by synergistic actions of phenolic signal molecules and monosaccharides. AB - Most virulence (vir) genes of Agrobacterium tumefaciens that are required for the formation of crown gall tumors are expressed in response to such plant signal molecules as acetosyringone and lignin precursors. The phenolic signals are transduced through a receptor VirA protein in the inner membrane of the bacterial cell. The expression of these genes triggers the transfer of a specific DNA segment, called transferred DNA (T-DNA), from the Ti plasmid to plant cells, and its integration into their nuclear DNA. We show here that a group of aldoses (L arabinose, D-xylose, D-lyxose, D-glucose, D-mannose, D-idose, D-galactose, and D talose) can markedly enhance acetosyringone-dependent expression of vir genes when the concentration of acetosyringone is limited (10 microM) but does not enhance the expression of noninducible genes. Likewise, a 2-deoxy-D-glucose, a nonmetabolized sugar, is also effective. When a deletion was introduced into the virA gene in the region encoding the periplasmic portion of the VirA protein, enhancement by glucose disappeared, but vir expression was induced by acetosyringone in this mutant. These results suggest that these sugars directly enhance a signaling process initiated by phenolic inducers that results in an increase in expression of the vir genes. PMID- 11607098 TI - Metal-ion-center assembly of ferredoxin and plastocyanin in isolated chloroplasts. AB - Most chloroplastic proteins are cytosolically synthesized and posttranslationally transported to their proper locations. Two examples of this group of proteins are ferredoxin and plastocyanin, both of which are metal-containing components of the photosynthetic electron-transport chain. The import process for these two proteins includes the insertion of the metal ions to produce the holo forms of the proteins. We show here that in vitro translated precursor proteins of ferredoxin and plastocyanin are synthesized as apo forms and are assembled into their respective holo forms after being imported into isolated chloroplasts. We also provide evidence that only mature-sized proteins are competent to be assembled into holo forms. PMID- 11607099 TI - Transformation of Halobacterium halobium: development of vectors and investigation of gas vesicle synthesis. AB - We developed vector plasmids for the transformation of Halobacterium halobium, using the replicon region from the halobacterial phage H or from the plasmid pHH1 together with a DNA fragment conferring resistance to mevinolin. H. halobium P03, a strain lacking pHH1 as well as the restriction endonuclease activity found in wild-type H. halobium, was used as the recipient strain. All H. halobium fragments tested for autonomous replication as well as the Haloferax volcanii vector pWL102 enabled stable plasmid maintenance in this strain. A frequent loss of all vectors (including pWL102) was observed in Hf. volcanii, where >90% of the mevinolin-resistant colonies obtained after transformation had lost the vector, presumably because of restriction endonuclease activity and concomitant recombination of the mevinolin resistance marker with the chromosome. The expression of gas vesicle-encoding genes (vac) was analyzed by using a 4.5 kilobase-pair (kbp) fragment containing the plasmid-encoded p-vac gene from H. halobium or an 11-kbp fragment containing the mc-vac chromosomal gene from Haloferax mediterranei for transformation experiments with H. halobium and Hf. volcanii. These experiments indicated that the mc-vac fragment contains all information necessary to synthesize gas vesicles, whereas in the case of the smaller p-vac fragment, complementation by other genes was required for a Vac+ phenotype. PMID- 11607100 TI - Allozyme and restriction fragment length polymorphism analyses confirm Entomophaga maimaiga responsible for 1989 epizootics in North American gypsy moth populations. AB - In 1989, populations of North American gypsy moth, Lymantria dispar, in seven contiguous northeastern states were severely reduced by a fungal pathogen. Based on morphology, development, and pathology, this organism appeared to be Entomophaga maimaiga. We have now used allozyme and restriction fragment length polymorphism analyses to confirm this identification. Previously, this mycopathogen had been reported only from gypsy moth populations in Japan. During 1989, E. maimaiga occurred only in areas that had been initially defoliated by gypsy moth >10 years ago. E. maimaiga caused 60-88% mortality in late instar larvae on research sites in central Massachusetts. PMID- 11607101 TI - Phonon representations. AB - The gap between the nonlocalized lattice-phonon description and the localized Einstein oscillator treatment is filled by transforming the phonon Hamiltonian back to the particle variables. The particle-coordinate, normalized, wave function for the phonon vacuum state is exhibited. PMID- 11607102 TI - Extinction and recolonization of local populations on a growing shield volcano. AB - Volcanic action has resulted in the burial of the surfaces of Mauna Loa and Kilauea, Hawaii, by new lava flows at rates as high as 90% per 1000 years. Local populations of organisms on such volcanoes are continually being exterminated; survival of the species requires colonization of younger flows. Certain populations of the endemic Hawaiian species Drosophila silvestris exemplify such events in microcosm. Local populations at the base of an altitudinal cline were destroyed by two explosive eruptions within the last 2100 years. Natural recolonization restored the cline except for one young population that is genetically discordant with altitude. PMID- 11607103 TI - Enhancement of the critical current density in single-crystal Bi2Sr2CaCu2O8 superconductors by chemically induced disorder. AB - The effect of metal substitution on the critical current densities of single crystal PbxBi2-xSr2CaCu2O8 (x = 0 or x = 0.7) superconductors has been investigated. Substitution of lead was found to increase the average critical current density from 1 x 10(5) A/cm2 to 2 x 10(6) A/cm2 at 5 K in an applied magnetic field of 10 kilooersteds (1 oersted = 80 A/m). The order of magnitude increase in the critical current density was observed for temperatures up to the flux vortex lattice melting point; the flux lattice melting point was also found to increase to 30 K (from 22 K) in the lead-substituted materials. Diffraction and microscopy investigations of the structural parameters indicate that the fundamental atomic lattices are virtually the same for both materials. Scanning tunneling microscopy images demonstrate, however, that lead substitution causes significant disorder (or defects) in the one-dimensional superstructure found in Bi2Sr2CaCu2O8. Since crystal defects can increase the critical current density by pinning the motion of flux vortices, it is likely that this lead-induced disorder enhances vortex pinning. The lead-induced disorder is specific to the nonsuperconducting Bi-O layers, and thus our results suggest that chemical substitutions may be utilized to control selectively flux pinning and the critical current density in these materials. PMID- 11607104 TI - Enzymatic and nonenzymatic mechanisms for ferric leghemoglobin reduction in legume root nodules. AB - Evidence is presented for the operation in nodules of at least four systems for restoring functional ferrous leghemoglobin (LB2+) from its inactive, ferric form. (i) Reduction of ferric leghemoglobin (LB3+) by a reductase. The enzyme is a flavoprotein of 100 kDa with two equally sized subunits andexhibits a Km of 9 microM for soybean LB3+ component a and a Km of 51 microM for NADH. NADPH is only 30% (initial velocities) as effective as NADH. LB3+ reductase converts 215 nmol of LB3+ to LB2+.CO (or Lb2+.O2) per mg of protein per min and does not require an exogenous electron carrier. The enzyme shows similar affinity for soybean, bean, and cowpea LB3+, but different Vmax values. The reductase is inactive with LB3+ is bound to nicotinate or NO2-. (ii) Direct reduction of LB3+ by NAD(P)H, ascorbate, and cysteine. Reduction by NAD(P)H is greatly stimulated by trace amounts of metals such as Mn2+. (iii) Reduction of Lb3+ by the flow of electrons from NAD(P)H to free flavins to LB3+. The reaction does not occur via O2.- or H2O2, and thus NAD(P)H-reduced flavins can directly reduce LB3+. The efficiency of the reaction follows the order riboflavin > FMN > FAD. (iv) Reduction of LB3+ by an unknown compound, B, of nodules. B has a molecular mass < 1 kDa and is heat stable. The reaction mediated by B differs from those mediated by flavins and metals in several ways, requires NAD(P)H, and generates O2.-. PMID- 11607105 TI - Adjustments of photosystem stoichiometry in chloroplasts improve the quantum efficiency of photosynthesis. AB - The efficiency of photosynthetic electron transport depends on the coordinated interaction of photosystem II (PSII) and photosystem I (PSI) in the electron transport chain. Each photosystem contains distinct pigment-protein complexes that harvest light from different regions of the visible spectrum. The light energy is utilized in an endergonic electron-transport reaction at each photosystem. Recent evidence has shown a large variability in the PSII/PSI stoichiometry in plants grown under different environmental irradiance conditions. Results in this work are consistent with the notion of a dynamic, rather than static, thylakoid membrane in which the stoichiometry of the two photosystems is adjusted and optimized in response to different light quality conditions. Direct evidence is provided that photosystem stoichiometry adjustments in chloroplasts are a compensation strategy designed to correct unbalanced absorption of light by the two photosystems. Such adjustments allow the plant to maintain a high quantum efficiency of photosynthesis under diverse light quality conditions and constitute acclimation that confers to plants a significant evolutionary advantage over that of a fixed photosystem stoichiometry in thylakoid membranes. PMID- 11607106 TI - Sterol phylogenesis and algal evolution. AB - The stereochemistry of several sterol precursors and end products synthesized by two fungal-like micro-organisms Prototheca wickerhamii (I) and Dictyostelium discoideum (II) have been determined by chromatographic (TLC, GLC, and HPLC) and spectral (UV, MS, and 1H NMR) methods. From I and II the following sterols were isolated from the cells: cycloartenol, cyclolaudenol, 24(28) methylenecycloartanol, ergosterol, protothecasterol, 4alpha-methylergostanol, 4alpha-methylclionastanol, clionastanol, 24beta-ethylcholesta-8,22-enol, and dictyosterol. In addition, the mechanism of C-24 methylation was investigated in both organisms by feeding to I [2-3H]lanosterol, [2-3H]cycloartenol, [24 3H]lanosterol, and [methyl-2H3]methionine and by feeding to II [methyl 2H3]methionine. The results demonstrate that the 24beta configuration is formed by different alkylation routes in I and II. The Delta25(27) route operates in I while the Delta24(28) route operates in II. Based on what is known in the literature regarding sterol distribution and phylogenesis together with our findings that the stereochemical outcome of squalene oxide cyclization leads to the production of cycloartenol rather than lanosterol (characteristic of the fungal genealogy) and the chirality of the C-24 alkyl group is similar in the two nonphotosynthetic microbes (beta oriented), we conclude that Prototheca is an apoplastic Chlorella (i.e., an alga) and that Dictyostelium as well as the other soil amoebae that synthesize cycloartenol evolved from algal rather than fungal ancestors. PMID- 11607107 TI - Interplant communication: airborne methyl jasmonate induces synthesis of proteinase inhibitors in plant leaves. AB - Inducible defensive responses in plants are known to be activated locally and systemically by signaling molecules that are produced at sites of pathogen or insect attacks, but only one chemical signal, ethylene, is known to travel through the atmosphere to activate plant defensive genes. Methyl jasmonate, a common plant secondary compound, when applied to surfaces of tomato plants, induces the synthesis of defensive proteinase inhibitor proteins in the treated plants and in nearby plants as well. The presence of methyl jasmonate in the atmosphere of chambers containing plants from three species of two families, Solanaceae and Fabaceae, results in the accumulation of proteinase inhibitors in leaves of all three species. When sagebrush, Artemisia tridentata, a plant shown to possess methyl jasmonate in leaf surface structures, is incubated in chambers with tomato plants, proteinase inhibitor accumulation is induced in the tomato leaves, demonstrating that interplant communication can occur from leaves of one species of plant to leaves of another species to activate the expression of defensive genes. PMID- 11607108 TI - Evidence from electron micrographs that icosahedral quasicrystals are icosahedral twins of cubic crystals. AB - An analysis of electron micrographs of Al5Mn quasicrystals obtained by rapidly cooling a molten alloy with composition Al17Mn and removing the Al matrix by electrosolution, revealing aggregates of 20 microcrystals at the corners of a pentagonal dodecahedron, supports the proposal that these microcrystals are cubic crystals twinned about an icosahedral seed, with each cubic microcrystal sharing a threefold axis and three symmetry planes with the seed. PMID- 11607109 TI - Superconnections and internal supersymmetry dynamics. AB - In previous papers we proposed a theory of internal supersymmetry using the superalgebra su(n/1) to give rise to a unified structure that included quarks and leptons in 2n-5 generations. In the present paper we suggest that the notion of superconnections as introduced by Quillen provides a natural setting for the dynamics of an internally supersymmetric theory with the Higgs field occurring as the "zero-th order part" of the superconnection. The Higgs mechanism enters quadratically into the curvature of the superconnection and hence quartically into the Lagrangian. The supercovariant derivative gives a coupling of the Higgs field to the matter field similar to that put in "by hand" in the Lagrangian of the Weinberg-Salam theory. PMID- 11607110 TI - Functional expression of the Chlorella hexose transporter in Schizosaccharomyces pombe. AB - Schizosaccharomyces pombe cells were transformed with an S. pombe expression vector containing a full-length cDNA of the Chlorella hexose transporter. The transformed cells accumulated 3-O-methylglucose up to 10-fold, whereas wild-type S. pombe and control transformants could only equilibrate this sugar analogue. In a pH-jump experiment, in which extracellular pH was lowered by 1.9 units, the accumulation ratio was increased in transformed cells but not in control cells. This result indicates that the gene product, Chlorella H+/glucose-symporter protein, and a pH gradient suffice for active sugar uptake. Km values for glucose, 6-deoxyglucose, and 3-O-methylglucose of 1.5 x 10(-5) M, 2.7 x 10(-4) M, and 1.0 x 10(-3) M, respectively, were identical in Chlorella and in S. pombe cells transformed with Chlorella cDNA and approximately 100-fold lower than those of the endogenous transport system of S. pombe. PMID- 11607111 TI - Phonon dynamics. AB - An atomic lattice in its ground state is excited by the rapid displacement and release of an atomic constituent. The time dependence of the energy transfer to other constituents is studied by using a phonon dispersion relation that is linear in frequency and propagation vector components. PMID- 11607112 TI - Stable transformation of plastids in higher plants. AB - Stable genetic transformation of the plastid genome is reported in a higher plant, Nicotiana tabacum. Plastid transformation was obtained after bombardment of leaves with tungsten particles coated with pZS148 plasmid DNA. Plasmid pZS148 (9.6 kilobases) contains a 3.7-kilobase plastid DNA fragment encoding the 16S rRNA. In the 16S rRNA-encoding DNA (rDNA) a spectinomycin resistance mutation is flanked on the 5' side by a streptomycin resistance mutation and on the 3' side by a Pst I site generated by ligating an oligonucleotide in the intergenic region. Transgenic lines were selected by spectinomycin resistance and distinguished from spontaneous mutants by the flanking, cotransformed streptomycin resistance and Pst I markers. Regenerated plants are homoplasmic for the spectinomycin resistance and the Pst I markers and heteroplasmic for the unselected streptomycin resistance trait. Transgenic plastid traits are transmitted to the seed progeny. The transgenic plastid genomes are products of a multistep process, involving DNA recombination, copy correction, and sorting out of plastid DNA copies. PMID- 11607113 TI - Direct structure analysis of a paraffin solid solution. AB - Single microcrystals of a 1:1 solid solution of n-C32H66/n-C36H74 have been grown by epitaxial nucleation on benzoic acid, and 0kl electron diffraction patterns from them can be obtained with a lamellar spacing characteristic of the intermediate n-paraffin n-C34H70. This average structure is also indicated by indices (space group Pca21) for major intensities in this zone. Direct phasing of the intensity data is carried out by combined use of low-dose electron microscope lattice images (to assign values to the "lamellar" reflections) and three-phase structure invariant relationships (to find values for the "polyethylene" reflections). The computed electrostatic potential map closely resembles the crystal structure of n-C34H74, for which all 34 atom positions can be found. It is apparent, however, that lower atomic occupancies at the chain ends correspond to anticipated disorder at the lamellar interface. Structural refinement based on this occupancy results in a good match to the observed intensity data. PMID- 11607114 TI - The left spectrum, the Levitzki radical, and noncommutative schemes. AB - This note contains a brief exposition of the basics of a noncommutative version of affine, quasi-affine, and projective algebraic geometry. In this version, to any associative ring (with unity) a quasi-affine (resp. affine) left scheme is assigned. The notion of the left spectrum of a ring plays the key role. PMID- 11607115 TI - Cold fusion in palladium: a more realistic calculation. AB - The Thomas-Fermi-Mott equation is modified to take account of the fact that conduction electrons in a metal may be considered to have an effective mass at wave-numbers comparable with or less than the inverse Debye screening length, but they should be considered to have the free-electron mass at much larger wavenumbers. This modification allows for a more realistic calculation of the fusion rate of deuteron pairs in palladium, this rate being 10(-23) sec-1, comparable with some experimental results. The Oppenheimer-Phillips process enhances the rate by a factor of 2.262. PMID- 11607116 TI - Microtubule dynamics in living dividing plant cells: confocal imaging of microinjected fluorescent brain tubulin. AB - Carboxyfluorescein-labeled brain tubulin has been microinjected into stamen hair cells of Tradescantia, and its distribution during mitosis and cytokinesis was examined using confocal laser scanning fluorescence microscopy. The results show that brain tubulin incorporates into plant microtubules and is utilized throughout mitosis and cytokinesis. Microtubule structures that incorporate brain tubulin include the preprophase band, the perinuclear sheath at late prophase, the kinetochore fibers during prometaphase, metaphase, and anaphase, the interzone spindle during anaphase, and finally the phragmoplast during late anaphase and telophase. All of these microtubule-containing structures and, notably, their transitions from one to another have been observed in single live cells progressing through mitosis and cytokinesis. PMID- 11607117 TI - Incorporation of Paramecium axonemal tubulin into higher plant cells reveals functional sites of microtubule assembly. AB - Incorporation of Paramecium axonemal tubulin into lysed endosperm cells of the higher plant Haemanthus enabled us to identify sites of microtubule assembly. This exogenous Paramecium tubulin could be traced by specific antibodies that do not stain endogenous plant microtubules. Intracellular copolymerization of protozoan and higher plant tubulins gave rise to hybrid polymers that were visualized by immunofluorescence and by immunoelectron microscopy. The addition of exogenous tubulin revealed many free ends of endogenous microtubules that were competent to assemble ciliate tubulin. The functional roles of the nuclear surface and the equatorial region of the phragmoplast as plant microtubule organizing centers, which were revealed by the intense incorporation of exogenous tubulin, are discussed. These data shed light on the present debate on higher plant microtubule organizing centers. PMID- 11607119 TI - Schur maps, Young tableaux, and supersymmetric algebra. AB - It is shown that the Hopf algebra dual of a supersymmetric Hopf algebra admits two presentations, and a natural isomorphism between them is described. PMID- 11607118 TI - Abnormal plant development and down-regulation of phenylpropanoid biosynthesis in transgenic tobacco containing a heterologous phenylalanine ammonia-lyase gene. AB - Biosynthesis of phenylpropanoid natural products in tobacco was perturbed by introduction of a heterologous (bean) phenylalanine ammonia-lyase (PAL; L phenylalanine ammonia-lyase, EC 4.3.1.5) gene, modified by inclusion of cauliflower mosaic virus 35S enhancer sequences in its promoter. These transgenic plants can exhibit a series of unusual phenotypes including localized fluorescent lesions, altered leaf shape and texture, reduced signification in xylem, stunted growth, reduced pollen viability, and altered flower morphology and pigmentation. Genetic analysis of a transformant with severe symptoms showed that symptom development was inherited as a single, partially dominant trait and cosegregated with reduced levels of PAL activity and soluble phenylpropanoid products. Accumulation of transcripts encoded by the endogenous tobacco PAL genes was suppressed. We conclude that the transgene disrupts PAL regulation and that some of the phenotypes reflect interference with putative signals dependent on phenylpropanoid biosynthesis. PMID- 11607120 TI - Evidence for a biological role in photosynthesis for cytochrome b-559--a component of photosystem II reaction center. AB - Absorbance changes in untreated intact leaf discs, produced upon excitation with high-intensity red light, were shown to be due to the photooxidation of cytochrome b-559. At low intensities (<100 W/m2), photooxidation was almost undetectable. Photooxidation occurred with a half-time of 4.3 sec and an extent of 0.64 mol of cytochrome per 320 mol of chlorophyll. Upon transition to darkness, an additional oxidation occurred that exhibited faster kinetics (t/12 < 100 msec) and 0.32 mol of cytochrome was oxidized per 320 mol of chlorophyll. Photooxidation was inhibited by 3-(3,4-dichlorophenyl)-1,1-dimethylurea and was specifically induced by red light since far-red light did not cause any absorbance decrease. These results suggest that the redox changes of cytochrome b 559 are driven by photosystem II. Photooxidation was increased by 67% and its initial rate was doubled upon incubation of the leaf in carbonylcyanide p trifluoromethoxy-phenylhydrazone. Exposure of the leaf to mild water stress or mild heat stress resulted in an increase in the extent of photooxidation and in a 6-fold decrease in the rate constant. Mild heat stress also induced a large increase of the rate constant for the dark reduction of the cytochrome. The dependence of photooxidation on high-intensity red light, its inhibition criteria, the fast transient dark oxidation, and enhancement of both photooxidation and dark transient oxidation by treatments that affect Z, the primary donor to P680, indicate that cytochrome b-559 in vivo is involved in cyclic electron flow around photosystem II. Its primary role in photosynthesis is to divert excess photons from a linear to a cyclic electron flow at high light intensities for protection of the D1 and D2 proteins against photodamage. Dark oxidation of the cytochrome is suggested to reflect a second role, that of deactivation of the powerful oxidant Z+ in the dark. PMID- 11607121 TI - Reduced coenzyme F420: heterodisulfide oxidoreductase, a proton- translocating redox system in methanogenic bacteria. AB - Washed everted vesicles of the methanogenic bacterium strain Go1 were found to couple the F420H2-dependent heterodisulfide reduction with the transfer of protons across the membrane into the lumen of the everted vesicles. The transmembrane electrochemical potential of protons thereby generated was shown to be competent in driving ATP synthesis from ADP + Pi, exhibiting a stoichiometry of 2 H+ translocated or 0.4 ATP synthesized per F420H2 oxidized. This enzyme system exhibits the phenomenon of coupling and uncoupling and represents a different kind of electron transport chain with the heterodisulfide of 2 mercaptoethanesulfonate and 7-mercaptoheptanoylthreonine phosphate as terminal electron acceptor. The heterodisulfide and methane are formed in the methyl coenzyme M reductase reaction. The reducing equivalents are derived from reduced coenzyme F420, which represents an analogue of NADH + H+ in other respiratory chains. It is assumed that the proton-translocating oxidoreductase discovered in strain Go1 is of principal importance to all methanogenic bacteria not utilizing H2. PMID- 11607122 TI - The Steiner ratio conjecture of Gilbert and Pollak is true. AB - Let P be a set of n points on the euclidean plane. Let Ls(P) and Lm(P) denote the lengths of the Steiner minimum tree and the minimum spanning tree on P, respectively. In 1968, Gilbert and Pollak conjectured that for any P, Ls(P) >/= (radical3/2)Lm(P). We provide an abridged proof for their conjecture in this paper. PMID- 11607123 TI - Desaturation of oleoyl groups in envelope membranes from spinach chloroplasts. AB - Envelope membranes isolated from chloroplasts of spinach (Spinacia oleracea) desaturate oleoyl groups in monogalactosyl diacylglycerol to linoleoyl groups. The desaturation requires NADPH in combination with ferredoxin and is not restricted to monogalactosyl diacylglycerol, since it is also observed in biosynthetic intermediates as, for example, in phosphatidic acid. This indicates a certain degree of unspecificity of the oleate desaturase in isolated envelope membranes. Lipid desaturation is another important function of chloroplast envelopes. PMID- 11607124 TI - Sexual hybridization of Lycopersicon esculentum and Solanum rickii by means of a sesquidiploid bridging hybrid. AB - A sesquidiploid hybrid having two genomes of Lycopersicon esculentum and one of Solanum lycopersicoides served as a pistillate bridging parent in crosses with Solanum rickii to produce L. esculentum x S. rickii hybrid progeny. Of the four progeny obtained, one (GH2754) was diploid and three were aneuploid with extra S. lycopersicoides chromosomes. The hybrids had morphological features of both parents, but attributes of the wild parent dominated. The hybrid nature of the four progeny was confirmed by isozyme, restriction fragment length polymorphism, and cytological analyses. A mean of 9.15 bivalents was observed in pollen mother cells of GH2754. A high level of pollen abortion was seen in all hybrids. Crosses of the hybrids with staminate S. rickii yielded one backcross individual, revealing a very low, but certain level of female fertility. Colchicine treatment of GH2754 generated one promising amphidiploid hybrid, which exhibited strong preferential chromosome pairing (94% of the examined cells had 24 bivalents) and appreciable pollen fertility (43% stainable). Chromosome pairing, isozyme, and restriction fragment length polymorphism data support a very close relationship between the two Solanum spp. and a much greater distance between them and L. esculentum, but the data do not discriminate between them in respect to their distances from the latter. The cytological and molecular observations, previous reports of successful transfer of traits from S. lycopersicoides to L. esculentum, and our hybridization of L. esculentum x S. rickii suggest good prospects for gene transfer from S. rickii to L. esculentum. PMID- 11607130 TI - Excision in algebraic K-theory and Karoubi's conjecture. AB - We prove that the property of excision in algebraic K-theory is for a Q-algebra A equivalent to the H-unitality of the latter. Our excision theorem, in particular, implies Karoubi's conjecture on the equality of algebraic and topological K theory groups of stable C*-algebras. It also allows us to identify the algebraic K-theory of the symbol map in the theory of pseudodifferential operators. PMID- 11607131 TI - Prehistoric extinction of birds on Mangaia, Cook Islands, Polynesia. AB - Mangaia (Cook Islands) consists of a weathered volcanic interior encircled by limestones known as the makatea. Excavations at Tangatatau Rockshelter (site MAN 44), located on the inner cliff of the makatea, produced a stratified sequence of Polynesian artifacts and faunal remains ranging from A.D. 1000-1100 to A.D. 1500 1600. Resident species of birds represented at MAN-44 include nine seabirds (at least three extirpated on Mangaia) and 12 land birds (eight extirpated or extinct). Seven of the extinct/extirpated land birds are confined to the site's four lowest stratigraphic zones, which represent the first 200-300 yr of human occupation at MAN-44. During this time, human exploitation of vertebrates switched from primarily native land birds to almost exclusively small reef fish, domesticates (chickens, pigs), and commensals (rats). Sediment cores from a lake 0.9 km from MAN-44 show clear palynological and stratigraphic signals of human presence on Mangaia, especially forest clearance of the volcanic interior, beginning at 1600 yr B.P. The rugged makatea must have provided a forest refuge for birds during the first 700 yr of human presence, after which Mangaians exploited the previously little used makatea because forest resources (trees, other plants, birds) had been depleted on the now badly eroded volcanic interior. MAN-44 is the oldest archaeological site known on Mangaia. Whether other species of birds were lost in the period of human activity that preceded occupation of MAN-44 remains to be seen. PMID- 11607132 TI - Invasion resistance arises in strongly interacting species-rich model competition communities. AB - I assemble stable multispecies Lotka-Volterra competition communities that differ in resident species number and average strength (and variance) of species interactions. These are then invaded with randomly constructed invaders drawn from the same distribution as the residents. The invasion success rate and the fate of the residents are determined as a function of community-and species-level properties. I show that the probability of colonization success for an invader decreases with community size and the average strength of competition (alpha). Communities composed of many strongly interacting species limit the invasion possibilities of most similar species. These communities, even for a superior invading competitor, set up a sort of "activation barrier" that repels invaders when they invade at low numbers. This "priority effect" for residents is not assumed a priori in my description for the individual population dynamics of these species; rather it emerges because species-rich and strongly interacting species sets have alternative stable states that tend to disfavor species at low densities. These models point to community-level rather than invader-level properties as the strongest determinant of differences in invasion success. The probability of extinction for a resident species increases with community size, and the probability of successful colonization by the invader decreases. Thus an equilibrium community size results wherein the probability of a resident species' extinction just balances the probability of an invader's addition. Given the distribution of alpha it is now possible to predict the equilibrium species number. The results provide a logical framework for an island-biogeographic theory in which species turnover is low even in the face of persistent invasions and for the protection of fragile native species from invading exotics. PMID- 11607133 TI - A general bijective algorithm for trees. AB - Trees are combinatorial structures that arise naturally in diverse applications. They occur in branching decision structures, taxonomy, computer languages, combinatiorial optimization, parsing of sentences, and cluster expansions of statistical mechanics. Intuitively, a tree is a collection of branches connected at nodes. Formally, it can be defined as a connected graph without cycles. Schroder trees, introduced in this paper, are a class of trees for which the set of subtrees at any vertex is endowed with the structure of ordered partitions. An ordered partition is a partition of a set in which the blocks are linearly ordered. Labeled rooted trees and labeled planed trees are both special classes of Schroder trees. The main result gives a bijection between Schroder trees and forests of small trees--namely, rooted trees of height one. Using this bijection, it is easy to encode a Schroder tree by a sequence of integers. Several classical algorithms for trees, including a combinatorial proof of the Lagrange inversion formula, are immediate consequences of this bijection. PMID- 11607134 TI - Variation in repeated nucleotide sequences sheds light on the phylogeny of the wheat B and G genomes. AB - A general method based on variation in repeated nucleotide sequences was developed for the identification of diploid species most closely related to a specific genome of a polyploid species. The utility of this method was demonstrated by showing that Triticum speltoides is the most closely related extant species to both the B and G genomes of tetraploid wheats. PMID- 11607135 TI - Effects of auxin and abscisic acid on cytosolic calcium and pH in plant cells. AB - Dark-grown corn coleoptiles and parsley hypocotyls and their roots were loaded with acetoxymethyl esterified forms of the Ca2+ indicator fluo-3, and the pH indicator 2',7'-bis (2-carboxyethyl)-5(and-6)-carboxyfluorescein. These tissues were treated with the plant growth regulator 2,4-dichlorophenoxyacetic acid (2,4 D), an auxin analogue, or abscisic acid (ABA), and the cytosolic pH (pHcyt) and cytosolic Ca2+ ([Ca2+]cyt) changes were monitored by confocal scanning optical microscopy. Over a period of 4 min pHcyt decreased 0.1-0.2 pH unit and [Ca2+]cyt increased from 280 to 380 nM in response to 2,4-D. ABS, on the other hand, induced cytosolic alkalinization of 0.05-0.1 pH unit with a concomitant increase in [Ca2+]cyt from 240 to 320 nM over a 4-min period. Responses similar to these were observed in all the tissues tested. We suggest that pHcyt profoundly influences signaling by[Ca2+]cyt, possibly by regulating Ca2+-protein binding, and that the divergent effects of auxin and ABA on pHcyt underlie their mutual antagonism. PMID- 11607136 TI - When can ants discriminate the sex of brood? A new aspect of queen-worker conflict. AB - The stage in preimaginal ontogeny at which the sexes can first be distinguished has important implications for queen-worker conflict in social insects. If workers are unable to sex larvae at an early instar, their opportunity to control colony reproductive strategies may be limited. In addition, by concealing the sex of her sons for some portion of development, the queen could protect them from the workers' attempts to substitute their own sons or to skew the numerical sex ratio. In a series of choice experiments, workers of the carpenter ant, Camponotus floridanus, failed to discriminate the sex of several stages of larvae but did retrieve female pupae significantly more rapidly than male pupae. Our results suggest that in this species, sex may not become detectable until pupation, which is consistent with sexual deception as an aspect of queen control. PMID- 11607137 TI - Simultaneous monitoring of light-induced changes in protein side-group protonation, chromophore isomerization, and backbone motion of bacteriorhodopsin by time-resolved Fourier-transform infrared spectroscopy. AB - Absorbance changes in the infrared and visible spectral range were measured in parallel during the photocycle of light-adapted bacteriorhodopsin, which is accompanied by a vectorial proton transfer. A global fit analysis yielded the same rate constants for the chromophore reactions, for protonation changes of protein side groups, and for the backbone motion. From this result we conclude that all reactions in various parts of the protein are synchronized to each other and that no independent cycles exist for different parts. The carbonyl vibration of Asp-85, indicating its protonation, appears with the same rate constant as the Schiff base deprotonation. The carbonyl vibration of Asp-96 disappears, indicating most likely its deprotonation, with the same rate constant as for the Schiff base reprotonation. This result supports the proposed mechanism in which the protonated Schiff base, a deprotonated aspartic acid (Asp-85) on the proton release pathway, and a protonated aspartic acid (Asp-96) on the proton-uptake pathway act as internal catalytic proton-binding sites. PMID- 11607138 TI - Genetic and morphological analysis of a maize-teosinte F2 population: implications for the origin of maize. AB - Genes controlling the dramatic morphological differences between maize and its presumed progenitor (teosinte) were investigated in a maize-teosinte F2 population through the use of molecular markers. Results indicate that the key traits differentiating maize and teosinte are each under multigenic control, although for some traits, such as the number of ranks of cupules, the data are consistent with a mode of inheritance that would involve a single major locus plus several modifiers. For other traits, such as the presence/absence of the pedicellate spikelet, the data indicate multigenic inheritance with no single locus having a dramatically larger effect than the others. Results also indicate that the tunicate locus (Tu) had no major role in the origin of maize, despite previous opinion that it was involved. The major loci affecting the morphological differences between maize and teosinte are located on the first four chromosomes. The data suggest that the differences between teosinte and maize involve, in part, developmental modifications that enable (i) primary lateral inflorescences, which are programmed to develop into tassels (male) in teosinte, to become ears (female) in maize, and (ii) the expression of male secondary sex traits on a female background in maize. Similar changes were likely involved in the origin of maize. PMID- 11607139 TI - A 75-kDa polypeptide, located primarily at the plasma membrane of carrot cell suspension cultures, is photoaffinity labeled by the calcium channel blocker LU 49888. AB - Calcium channel blockers of the phenylalkylamine family bind specifically to membranes and inhibit calcium uptake in carrot protoplast. LU 49888, an azido derivative of phenylalkylamine, behaves as its unmodified homolog in terms of affinity and specificity and therefore allows us to probe the receptor by photoaffinity labeling. Upon UV irradiation, a 75-kDa peptide was specifically labeled. Incubation of microsomes with 3-[(3-cholamidopropyl)dimethylammonio]-1 propanesulfonate, a zwitterionic detergent, led to the solubilization of the LU 49888-binding protein. Electrophoretic analysis under denaturing conditions and gel filtration of the solubilized "receptor-ligand" complex show a 75-kDa peptide mainly located at the plasma membrane. Consequently the LU 49888-binding protein in plants differs significantly from its animal counterpart by its size and may be a primary target for external signal molecules. PMID- 11607140 TI - Cooperative foraging, productivity, and the central limit theorem. AB - The central limit theorem is applied to group foraging to show an automatic and universal benefit to group living. This may explain the paradoxical inverse correlation between group size and per capita brood production in primitively eusocial insects and why only one of the five major lineages of social insects contains species that revert to solitary habit. PMID- 11607141 TI - Expression and subcellular location of the tetrapyrrole synthesis enzyme porphobilinogen deaminase in light-grown Euglena gracilis and three nonchlorophyllous cell lines. AB - The expression and subcellular location of porphobilinogen deaminase (PBGD, also known as hydroxymethylbilane synthase; EC 4.3.1.8), one of the early enzymes of porphyrin synthesis, was investigated in light-grown Euglena and in three cell lines that do not contain chlorophyll: dark-grown Euglena, a streptomycin bleached mutant, and Astasia longa. In wild-type Euglena, immunogold electron microscopy demonstrated that all the immunodetectable enzyme protein was in the chloroplast. PBGD was shown to be photoregulated, and like many other nuclear encoded proteins in Euglena, the regulation was at the posttranscriptional level. In the three nonchlorophyllous cell lines, as in light-grown Euglena, a single protein of 40 kDa was detected with antiserum to PBGD. This same antiserum immunoprecipitated a larger precursor protein from the total translation products of poly(A)+ RNA, and a single transcript, which was large enough to encode the precursor, was detected on Northern blots of all four cell types. Therefore, in cells that make chlorophyll and those that do not (or cannot), PBGD is located in the plastid. No evidence was obtained for another form of the enzyme, which suggests that in Euglena there is only one pathway for the synthesis of the tetrapyrrole moiety of chlorophyll and heme. PMID- 11607142 TI - Scanning tunneling microscopy of a wheat seed storage protein reveals details of an unusual supersecondary structure. AB - Scanning tunneling microscopy has been used to demonstrate that a spiral structure based on beta-reverse turns is adopted by the repeat sequences present in a group of wheat gluten proteins. This structure is similar to the beta-spiral formed by a synthetic polypentapeptide based on a repeat sequence present in elastin. Wheat gluten and elastin are both elastomeric and it is possible that the spiral structure contributes to this property. PMID- 11607143 TI - Additional fossil evidence on the differentiation of the earliest euprimates. AB - Several well-preserved jaws of the rare North American omomyid primate Steinius vespertinus, including the first known antemolar dentitions, have been discovered in 1989 and 1990 in the early Eocene Willwood Formation of the Bighorn Basin, Wyoming. They indicate that its dental formula is as primitive as those in early Eocene Donrussellia (Adapidae) and Teilhardina (Omomyidae)--widely considered to be the most primitive known euprimates--and that in various dental characters Steinius is as primitive or more so than Teilhardina. Therefore, despite its occurrence at least 2 million years later than Teilhardina, S. vespertinus is the most primitive known omomyid and one of the most primitive known euprimates. Its primitive morphology further diminishes the dental distinctions between Omomyidae and Adapidae at the beginning of the euprimate radiation PMID- 11607144 TI - Binding of a single divalent cation directly correlates with the blue-to-purple transition in bacteriorhodopsin. AB - We have characterized a unique divalent cation binding site on bacteriorhodopsin which controls the blue-to-purple transition in the purple membrane of Halobacterium halobium. To identify this site we first showed the correlation between the binding of one Ca2+ per bacteriorhodopsin and the amount of blue membrane converted to purple membrane. When the free Ca2+ was reduced below 1 microM, and the pH was set below 5.0 with 0.5 mM citrate, only binding to this high-affinity site was observed, and we could separate its effect from the effect of other divalent cations binding to the membrane under other conditions. Second, the titration of purple membrane showed that protons are taken up in two distinct steps, about 13 with a pKa of 4-5 and an additional 2 protons with a pKa of 2.75, in 5 mM MgSO4. The latter is identical to the pKa for the purple-to-blue transition in 5 mM MgSO4. Taken together, these observations strongly suggest a direct role for cations in the regulation of the bacteriorhodopsin color under normal conditions. We have also found that the intrinsic pKa for the purple-to blue transition is about 2.05, suggesting this is the pKa of the group or groups that, when protonated, lead to the blue membrane. Previously published data can now be interpreted to suggest that the cation regulates an active site near the retinal chromophore. A binding site for the divalent cation that includes Asp-212 and interactions with the protonated Schiff base, Asp-85, Tyr-57, Tyr-185, and Arg-82 is proposed. PMID- 11607145 TI - Link homotopy. AB - Link homotopy considers systems of pairwise disjoint singular spheres up to deformations through such "link maps." In a large range of higher dimensions the resulting link homotopy groups are determined and described in the language of standard homotopy theory. PMID- 11607146 TI - Stable configurations of confined cold ionic systems. AB - The simple structures formed by charged particles confined in a harmonic potential have been investigated and the configurations of minimum potential energy were identified. For fewer than 12 particles these form polyhedrons centered on the origin. For structures with 13-22 particles one sits in the middle, for 23-26 particles two are in the interior, etc., until a third shell starts forming at 60. When the isotropy of the trap is changed, distortions and discrete phase changes are seen. These structures should correspond to ones formed in ion traps at very low temperatures PMID- 11607147 TI - 2-nitro-3-(p-hydroxyphenyl)propionate and aci-1-nitro-2-(p-hydroxyphenyl)ethane, two intermediates in the biosynthesis of the cyanogenic glucoside dhurrin in Sorghum bicolor (L.) Moench. AB - The biosynthetic pathway for the cyanogenic glucoside dhurrin derived from tyrosine has been studied in vitro by using [18O]oxygen and a microsomal enzyme system obtained from etiolated sorghum seedlings. The products formed were purified by HPLC and TLC, and the incorporation of [18O]oxygen was monitored by mass spectrometry. In the presence of NADPH and [18O]dioxygen, L-tyrosine is converted to (E)- and (Z)-p-hydroxyphenylacetaldehyde oxime with quantitative incorporation of an [18O]oxygen atom into the oxime function. The first step in this conversion is the N-hydroxylation of L-tyrosine to N-hydroxytyrosine. Administration of N-hydroxytyrosine as a substrate results in the production of 1 nitro-2-(p-hydroxyphenyl)ethane in addition to (E)- and (Z)-p hydroxyphenylacetaldehyde oxime, with quantitative incorporation of a single [18O]oxygen atom in all three products. These data demonstrate that the conversion of N-hydroxytyrosine to p-hydroxyphenylacetaldehyde oxime involves additional N-hydroxylation and N-oxidation reactions giving rise to the formation of 2-nitro-3-(p-hydroxyphenyl)propionate, which by decarboxylation produces aci-1 nitro-2-(p-hydroxyphenyl)ethane. Both compounds are additional intermediates in the pathway. The two [18O]oxygen atoms introduced by the N-hydroxylations are enzymatically distinguishable as demonstrated by the specific loss of the oxygen atom introduced by the first N-hydroxylation reaction in the subsequent conversion of aci-1-nitro-2-(p-hydroxyphenyl)ethane to (E)-p hydroxyphenylacetaldehyde oxime. A high flux of intermediates through the microsomal enzyme system is obtained with N-hydroxytyrosine as a substrate. This renders the conversion of the aci-nitro compound rate limiting and results in its release from the active site of the enzyme system and accumulation of the tautomeric nitro compound. PMID- 11607148 TI - Two-dimensionally infinite polyhedra with vertices related by symmetry operations. AB - It is shown that an infinitely extended polyhedron of one sheet composed of plane polygons of finite size, and in which all the vertices are related to one another by symmetry operations, can always be constructed by folding a stiff, unstretchable sheet (such as a piece of paper). It is also shown that only 11 such polyhedra have faces that are regular polygons; these polygons are equilateral triangles and squares. The 4 of these 11 polyhedra that are not known to have been published previously are presented here. PMID- 11607149 TI - Measuring time to the doctorate: reinterpretation of the evidence. AB - There has been increasing concern that the length of time it takes to earn a doctorate in this country has increased dramatically over the last 20 years. The regularly cited evidence--organized by the year in which recipients of doctorates were awarded their degrees--is seriously misleading, however. The application of stable population theory to the problem suggests that the steady fall in the sizes of entering cohorts to graduate school has inflated both the measure of the absolute level of median time to degree and the increase in time to degree. When the same underlying data are reorganized by the year in which recipients of doctorates received their baccalaureate, the statistical bias is eliminated, and the median total time to degree in the humanities is shown to have risen 15-20% rather than the reported 40%. PMID- 11607150 TI - Transition from one revolving cluster to two revolving clusters in the ground state rotational bands of nuclei in the lanthanon region. AB - Whereas 234(92)U142 and other actinon nuclei have ground-state bands that indicate that each nucleus consists of a sphere and a single revolving cluster with constant composition and with only a steady increase in the moment of inertia with increase in J, the angular-momentum quantum number, many of the lanthanon ground-state bands show discontinuities, usually with an initial slightly or strongly curved segment followed by one or two nearly straight segments. The transition to nearly straight segments is interpreted as a change in structure from one revolving cluster to two revolving clusters. The proton neutron compositions of the clusters and the central sphere are assigned, leading to values of the radius of revolution. The approximation of the two-cluster sequences to linearity is attributed to the very small values of the quadrupole polarizability of the central sphere. Values of the nucleon numbers of clusters and spheres, of the radius of revolution, and of promotion energy are discussed. PMID- 11607151 TI - Root communication among desert shrubs. AB - Descriptive and experimental studies of desert shrub distributions have revealed important questions about the mechanisms by which plants interact. For example, do roots interact by mechanisms other than simple competition for limiting resources? We investigated this question using the desert shrubs Ambrosia dumosa and Larrea tridentata grown in chambers that allowed observation of roots during intraplant and intra- and interspecific interplant encounters. Two types of root "communication" were revealed. Ambrosia root systems appear to be capable of detecting and avoiding other Ambrosia root systems, whereas Larrea roots inhibit Larrea and Ambrosia roots in their vicinity. PMID- 11607152 TI - Is the cygnet the quintessential baryon? AB - The apparently new hadron-like particle ("cygnet") indicated by cosmic ray observations on certain neutron stars is predicted to be a spin 1/2 fermion of magnetic moment and charge 0 and lifetime infinity. This derives from the natural identification of the cygnet with the one hitherto unobserved fundamental fermion of chronometric particle theory, the x or "exon", which plays the role of a quintessential baryon. The "partons" are represented by the other fundamental fermions, consisting of e, nue, and numu; e.g., n = x + e+ + e-, p = x + e+ + nue. With further empirical assignments, chronometric theory has a potential for explaining diverse phenomena, such as mixing in the neutral kaon complex and the nature of the higher electrons. Its fundamental fermion and boson fields transform indecomposably under its symmetry group, the conformal group G. Theoretical elementary particles transforming irreducibly under G derive as successive quotients in a maximal chain of invariant subspaces. Mass fixing by Mach's principle breaks the symmetry down to microscopically observed covariance with respect to the Poincare group P0. The resulting representation is normally irreducible, but splits in the case of the K0 into two P0-irreducible components that are mixed by the excess of the chronometric over the relativistic energy ("gravity"), which provides a "superweak" force that may be explanatory of CP violation. PMID- 11607153 TI - Pollen-mediated introgression and hybrid speciation in Louisiana irises. AB - Populations of the "Louisiana iris" species Iris fulva, I. hexagona, and I. nelsonii were examined genetically to test for interspecific gene flow between I. fulva and I. hexagona, for pollen- versus seed-mediated introgression between these species, and for the presumed hybrid origin of I. nelsonii. Genetic markers were identified by using both a polymerase chain reaction-like method that allows the identification of random, nuclear markers and standard polymerase chain reaction experiments involving specific chloroplast DNA (cpDNA) oligonucleotides. Restriction endonuclease digestions of the cpDNA amplification products resolved diagnostic restriction site differences for I. fulva and I. hexagona. The distribution of the species-specific nuclear markers supports a hypothesis of bidirectional introgression between I. fulva and I. hexagona. Thus, individuals analyzed from a contemporary hybrid population demonstrate multilocus genotypes that are indicative of advanced-generation hybrid individuals. Furthermore, several markers from the alternate species were present in low frequency in one allopatric population each of I. fulva and I. hexagona. Data from the nuclear analysis also support the hypothesized hybrid origin of I. nelsonii from the interaction of I. fulva and I. hexagona. Finally, cpDNA data support the hypothesis that the localized and the dispersed introgression are largely due to pollen transfer. In addition to the biological implications, this study demonstrates the power of the polymerase chain reaction methodology for the rapid identification of random and specific genetic markers for testing evolutionary genetic hypotheses. PMID- 11607154 TI - Gene silencing in a polyploid homosporous fern: paleopolyploidy revisited. AB - Because of their high chromosome numbers, homosporous vascular plants were considered paleopolyploids until recent enzyme electrophoretic studies rejected this hypothesis by showing that they express only diploid numbers of isozymes. In polyploid sporophytes of the homosporous fern pelleae rufa, however, progressive diminution of phosphoglucoisomerase activities encoded by one ancestral genome culminates in tetraploid plants exhibiting a completely diploidized electrophoretic phenotype for this enzyme. The demonstration that such gene silencing can make a polyploid fern look isozymically like a diploid questions the validity of isozyme evidence for testing the paleopolyploid hypothesis and supports the proposed role of polyploidization followed by genetic diploidizaton in the evolutionary history of homosporous pteridohytes. PMID- 11607155 TI - Engineering the chloroplast genome: techniques and capabilities for chloroplast transformation in Chlamydomonas reinhardtii. AB - Chloroplast transformation of Chlamydomonas reinhardtii has been accomplished by agitating cell wall-deficient cells in the presence of glass beads and DNA. By using the atpB gene as the selected marker and cells grown in 0.5 mM 5 fluorodeoxyuridine, we have recovered up to 50 transformants per microgram of DNA. This method is easy and does not require specialized equipment, although it is not as efficient as the tungsten particle bombardment method [Boynton, J. E., Gillham, N. W., Harris, E. H., Hosler, J. P., Johnson, A. M., Jones, A. R., Randolph-Anderson, B. L., Robertson, D., Klein, T. M., Shark, K. B. & Sanford, J. C. (1988) Science 240, 1534-1537]. By using particle bombardment, we have developed a cotransformation approach in which spectinomycin-resistant 16S rRNA encoding DNA is the selected marker, and we have demonstrated that cotransformation of an unselected marker on an independent replicon is very efficient. We have used this strategy (i) to recover transformants with partially deleted atpB genes that could not otherwise have been selected since they did not restore photosynthetic capability to a recipient carrying a more extensive atpB deletion and (ii) to generate specific deletion mutations in a wild-type recipient. This methodology should allow the introduction of any desired change into the chloroplast genome, even in the absence of phenotypic selection, and thus a detailed functional analysis of any chloroplast DNA sequence should be possible. PMID- 11607156 TI - Transformation of a partial nopaline synthase gene into tobacco suppresses the expression of a resident wild-type gene. AB - A portion of the nopaline synthase gene under the control of the cauliflower mosaic virus 35S promoter was used to transform a tobacco plant that had previously been transformed with a wild-type nopaline synthase (nos) gene. Unexpectedly, in all nine primary transformants tested the wild-type nos expression was virtually completely suppressed. In contrast, plants transformed with the control vector DNA, which differed only in the absence of the partial nos gene, did not show any inhibition of nos expression. Progeny plants were analyzed for the stability of the gene-silencing phenotype. All of the progeny that carried both the wild-type and partial nos genes had no detectable nopaline synthase activity. In addition, wild-type nos mRNA could not be detected in these plants. In most plants in which the wild-type gene was segregated away from the partial nos gene, wild-type levels of activity were detected. Although DNA methylation has been shown to be correlated with a decrease in promoter activity in plants, none of the progeny appeared to carry a methylated nos promoter. The underlying mechanism causing this gene suppression phenomenon is unclear at this time. PMID- 11607157 TI - Chloroplast DNA evidence for a North American origin of the Hawaiian silversword alliance (Asteraceae). AB - Chloroplast DNA restriction-site comparisons were made among 24 species of the Hawaiian silversword alliance (Argyroxiphium, Dubautia, and Wilkesia) and 7 species of North American perennial tarweeds in Adenothamnus, Madia, Raillardella, and Raillardiopsis (Asteraceae-Madiinae). These data and results from intergeneric hybridization indicated surprisingly close genetic affinity of the monophyletic Hawaiian group to two diploid species of montane perennial herbs in California, Madia bolanderi and Raillardiopsis muirii. Of 117 restriction-site mutations shared among a subset of two or more accessions, more than one-fifth (25 mutations) separated the silversword alliance, M. bolanderi, and Raillardiopsis from Adenothamnus and Raillardella. An additional 10 mutations distinguished the silversword alliance, M. bolanderi, and R. muirii from Adenothamnus, Raillardella, and Raillardiopsis scabrida. Phylogenetic analyses of these data and production of vigorous hybrids of the combinations Dubautia laevigata x R. muirii and (Dubautia knudsenii x Dubautia laxa) x M. bolanderi reinforce and refine Carlquist's hypothesis [Carlquist, S. (1959) Aliso 4, 171 236] that the Hawaiian silversword alliance arose from American tarweeds. Ultimate origin of silversword alliance chloroplast DNA from within the Californian-endemic paraphyletic genus Raillardiopsis was supported with high bootstrap confidence. Geologic considerations and the distribution of sporophytic self-incompatibility among these species demonstrate that the tarweed ancestor of the silverswords overcame (i) a dispersal barrier of at least 3900 km of open ocean and (ii) the breeding barrier of self-incompatibility. PMID- 11607158 TI - Evolution of diabroticite rootworm beetle (Chrysomelidae) receptors for Cucurbita blossom volatiles. AB - The diabroticite rootworm beetles coevolved with plants of the family Cucurbitaceae as demonstrated by their feeding dependence on the tetracyclic triterpenoid cucurbitacins. These beetles also exhibit strong attraction to phenylpropanoid volatile components of Cucurbita blossoms. A mixture of 1,2,4 trimethoxybenzene, indole, and (E)-cinnamaldehyde, all blossom components, is highly attractive to the several species of diabroticite cucumber beetles and corn rootworms and is considered a simplified Cucurbita blossom kairomone odor. The evolutionary divergence in antennal receptor complementarity is best understood by comparing the species-specific responses of several Diabrotica to structural analogues of (E)-cinnamaldehyde, the major attractant for Diabrotica undecimpunctata howardi. Cinnamyl alcohol is a strong attractant for Diabrotica barberi, and 4-methoxycinnamaldehyde is an exceptional attractant for Diabrotica virgifera. The very closely related species D. barberi and Diabrotica cristata are most strongly attracted to 4-methoxyphenethanol, which is unattractive to the other species studied. PMID- 11607159 TI - Nest-mate recognition based on heritable odors in the termite Microcerotermes arboreus. AB - Workers of the Neotropical termite Microcerotermes arboreus distinguish nest mates from other conspecifics by odor. A controlled breeding experiment demonstrated a genetic component to variation in colony odors. Workers were less aggressive toward unfamiliar relatives than toward nonrelatives and distinguished degree of relatedness among unfamiliar workers. Unfamiliar relatives were attacked more often than nest mates, despite similar levels of genetic relatedness; thus, nest-mate recognition is not based solely upon heritable characteristics of individual workers. No difference was detected between the effects of cues inherited through the mother and cues inherited through the father. PMID- 11607160 TI - Biosynthesis of the thiazole moiety of thiamin (vitamin B1) in higher plant chloroplasts. AB - The chloroplast stromal proteins from spinach condense the two heterocyclic moieties of vitamin B1--4-methyl-5-(beta-hydroxyethyl)thiazole and 2-methyl-4 amino-5-hydroxymethylpyrimidine--in the presence of MgATP. We have taken advantage of this observation to study thiazole synthesis. We present data indicating that pyruvate, glyceraldehyde 3-phosphate, tyrosine, cysteine, and MgATP are required for this synthesis and that pyruvate and glyceraldehyde 3 phosphate can be replaced by 1-deoxy-D-threo-2-pentulose. The thiazole synthesis occurs at a sustained, low rate of 140 pmol per mg of protein per hr. PMID- 11607161 TI - Diacylglycerols induce both ion pumping in patch-clamped guard-cell protoplasts and opening of intact stomata. AB - Stomatal guard cells in leaves regulate the apertures of microscopic pores through which photosynthetic gas exchange and water vapor loss occur. Environmental signals, including light, high humidity, and low CO2 concentrations, open stomata by increasing the volume of guard cells. Activation of a plasma membrane H+ pump initiates K+ and Cl- influx, accompanied by malate synthesis, resulting in osmotic water flow into the guard cells, a bowing apart of the guard-cell pair, and consequent stomatal opening. Physiological and electrophysiological techniques were employed to investigate the possibility that a second-messenger lipid, 1,2-diacylglycerol, is involved in the transduction of opening stimuli. The synthetic diacylglycerols 1,2-dihexanoylglycerol and 1,2 dioctanoylglycerol enhanced light-induced stomatal opening in Commelina communis and induced stomatal opening under darkness, whereas an isomer with no known second-messenger role, 1,3-dioctanoylglycerol, did not affect stomatal responses. 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H-7), an inhibitor of protein kinase C, the enzyme typically activated by 1,2-diacylglycerol in animal cells, inhibited light-stimulated stomatal opening and enhanced dark-induced stomatal closure. N-[(2-Methylamino)ethyl]-5-isoquinolinesulfonamide (H-8), which inhibits cyclic nucleotide-dependent protein kinases preferentially over lipid-dependent protein kinases such as protein kinase C, had little effect on stomatal apertures. Whole-cell patch clamping of guard-cell protoplasts of Vicia faba revealed that 1,2-dihexanoylglycerol and 1-oleoyl-2-acetylglycerol activated an ATP-dependent, voltage-independent current, suggesting activation of an electrogenic ion pump such as the H+ pump. Diacylglycerol or functionally similar lipids may act through protein phosphorylation to provide the intracellular signals that mediate H+-ATPase activation and stomatal opening in response to light or other opening stimuli. PMID- 11607162 TI - Einstein's equations with an embedding-dependent energy-momentum tensor for the compactified Minkowski time space and their relationship to the conformal action of SO(4,4) on S3 x S3. AB - For a pseudoriemannian 4-manifold isometrically embedded in a pseudoriemannian 6 manifold an embedding-dependent energy-momentum tensor is proposed, as well as an embedding-dependent cosmological constant. Their behavior is examined under the conformal transformations. It is specialized to the case of S1 x S3 embedded in S3 x S3, where the latter has the metric tensor in the conformal class of the one inherited from sum from 4i=1 (dxi)2 - sum from 8i=5(dxi)2 on R8. Einstein's equations for the restricted metric are shown to be satisfied if and only if the scalar curvature of S3 x S3 vanishes on S1 x S3. PMID- 11607163 TI - Differential scanning calorimetry of plant cell walls. AB - High-sensitivity differential scanning calorimetry has been used to study the phase transition of cell wall preparations of the elongating and mature regions of soybean hypocotyls and of celery epidermis and collenchyma strands. A step like transition believed to be glass transition was observed in walls isolated from the elongating region of soybean hypocotyls at 52.9 degrees C. Addition of 1 mM CaCl2 to the cell wall preparation increased the transition temperature to 60.8 degrees C and greatly reduced the transition magnitude. In walls from the mature region, the transition was small and occurred at a higher temperature (60.1 degrees C). Addition of calcium to the mature region cell wall had little effect on the transition. Based on the known interactions between calcium and pectin, we propose that calcium affects the glass transition by binding to the polygalacturonate backbone of wall pectin, resulting in a more rigid wall with a smaller transition at a higher temperature. The mature region either has more calcium in the wall or has more methyl-esterified pectin, making it less responsive to added calcium. PMID- 11607165 TI - Approximate entropy as a measure of system complexity. AB - Techniques to determine changing system complexity from data are evaluated. Convergence of a frequently used correlation dimension algorithm to a finite value does not necessarily imply an underlying deterministic model or chaos. Analysis of a recently developed family of formulas and statistics, approximate entropy (ApEn), suggests that ApEn can classify complex systems, given at least 1000 data values in diverse settings that include both deterministic chaotic and stochastic processes. The capability to discern changing complexity from such a relatively small amount of data holds promise for applications of ApEn in a variety of contexts. PMID- 11607164 TI - Identification and characterization of nonsedimentable lipid-protein microvesicles. AB - Previously uncharacterized lipid-protein microvesicles have been isolated from young and senescing bean cotyledon tissue. The microvesicles are nonsedimentable and enriched in phospholipid degradation products (free fatty acids, long-chain aldehydes, and long-chain hydrocarbons). They range from 70 to 170 nm (radius) with a mean radius of 132 nm, and it is clear from freeze-fracture electron micrographs that they are bilayered in nature. Nonsedimentable lipid-protein microvesicles containing the same products of phospholipid degradation but smaller were also formed in vitro when smooth microsomal membranes from young cotyledon tissue were treated with Ca2+ to stimulate enzymatic degradation of phospholipids. The data suggest that these microvesicles comprise an intermediate stage of membrane lipid deterioration. They appear to serve as a vehicle for moving phospholipid degradation products out of membranes into the cytosol during senescence and perhaps also during normal membrane lipid turnover. PMID- 11607166 TI - Bergmann's rule near the equator: latitudinal clines in body size of an Andean passerine bird. AB - Critical correlative support for Bergmann's ecogeographic rule is provided by symmetrical patterns of size variation in Diglossa carbonaria, a tropical passerine bird whose geographic range in the Andes Mountains of South America straddles the equator. Body size is positively correlated with latitude both north and south of the equator. Moreover, parapatric taxa that exhibit either partial (north-western Bolivia) or complete (northern Peru) reproductive isolation converge in body size. Relative uniformity in the length of the highly modified flower-piercing bill among populations of D. carbonaria that differ significantly in body size suggests that character displacement or interspecific competition is not responsible for these patterns. These findings support the hypothesis that climate, particularly temperature seasonality, is an important environmental determinant of geographic size variation in homeotherms. In addition they demonstrate that clinal variation correlated with subtle climatic gradients can occur in tropical environments. PMID- 11607167 TI - The second amino acid of alfalfa mosaic virus coat protein is critical for coat protein-mediated protection. AB - Transgenic plants expressing the coat protein (CP) of alfalfa mosaic virus (AIMV) are resistant to infection by AIMV. A mutation was introduced into the second amino acid of the cDNA for the CP of AIMV. Three different transgenic tobacco lines expressing the mutant CP and two different transgenic tobacco lines expressing the wild-type CP at similar levels were challenged with AIMV virions and viral RNA. Whereas the lines expressing the wild-type CP were highly resistant to infection by AIMV virions and viral RNA, the lines expressing the mutant CP were susceptible to infection by both. The binding affinity of the mutant and the wild-type CPs for the 3' terminal protein binding site on AIMV RNAs was similar, as determined by electrophoretic mobility shift assay. A mixture of AIMV genomic RNAs 1-3 was infectious on the plants expressing the mutant CP but not on vector control plants or plants expressing the wild-type CP, indicating that the mutant CP can activate the AIMV genomic RNAs for infection. These results demonstrate that the second amino acid of the AIMV CP is critical for protection from AIMV but not for the initial interaction between the AIMV RNA and CP, suggesting that this initial interaction does not play a major role in CP mediated protection. PMID- 11607168 TI - Assimilate movement dictates remote sites of wound-induced gene expression in poplar leaves. AB - When a single leaf on a young poplar tree is mechanically wounded, wound-induced (win) mRNAs are detected in the unwounded portion of that leaf and in specific leaves that are remote from the wounded leaf. Shortly after wounding (6-8 hr), the remote leaves in which win genes are expressed can be predicted by a knowledge of photoassimilate movement patterns in vivo. When assimilate movement from a wounded leaf is blocked or the direction of assimilate movement is altered by shading, win gene expression in remote leaves is similarly blocked or altered. These data illustrate how the long-distance transduction of wound-induced signals can be manipulated in plants by altering carbon allocation. PMID- 11607169 TI - Gene I, a potential cell-to-cell movement locus of cauliflower mosaic virus, encodes an RNA-binding protein. AB - Cauliflower mosaic virus (CaMV) is a double-stranded DNA (dsDNA) pararetrovirus capable of cell-to-cell movement presumably through intercellular connections, the plasmodesmata, of the infected plant. This movement is likely mediated by a specific viral protein encoded by the gene I locus. Here we report that the purified gene I protein binds RNA and single-stranded DNA (ssDNA) but not dsDNA regardless of nucleotide sequence specificity. The binding is highly cooperative, and the affinity of the gene I protein for RNA is 10-fold higher than for ssDNA. CaMV replicates by reverse transcription of a 358 RNA that is homologous to the entire genome. We propose that the 35S RNA may be involved in cell-to-cell movement of CaMV as an intermediate that is transported through plasmodesmata as an RNA-gene I protein complex. PMID- 11607170 TI - Interspecific gene flow in sympatric oaks. AB - Variation of chloroplast DNA and nuclear ribosomal DNA (DNA encoding ribosomal RNA) was studied for five species of white oak native to the eastern United States. Although these species differ in many morphological characters and have different (though overlapping) geographical ranges and ecological tolerances, they are interfertile and often grow in mixed stands, and hybrids are occasionally found in nature. All individuals studied were morphologically typical members of their respective species-i.e., showed no evidence of recent hybrid ancestry. Restriction site markers in the chloroplast DNA reveal several clear cases of localized gene exchange between species, showing that there is appreciable gene flow between sympatric species in this group. One length variant of the nuclear ribosomal DNA, however, is species specific. The sharp morphological and ecological differences between the species, together with the one ribosomal DNA variant, suggest that nuclear genes may be exchanged less freely between species than are chloroplast genotypes. PMID- 11607171 TI - Protein turnover as a component in the light/dark regulation of phosphoenolpyruvate carboxylase protein-serine kinase activity in C4 plants. AB - Maize leaf phosphoenolpyruvate carboxylase [PEPC; orthophosphate:oxaloacetate carboxy-lyase (phosphorylating), EC 4.1.1.31] protein-serine kinase (PEPC-PK) phosphorylates serine-15 of its target enzyme, thus leading to an increase in catalytic activity and a concomitant decrease in malate sensitivity of this cytoplasmic C4 photosynthesis enzyme in the light. We have recently demonstrated that the PEPC-PK activity in maize leaves is slowly, but strikingly, increased in the light and decreased in darkness. In this report, we provide evidence that cycloheximide, an inhibitor of cytoplasmic protein synthesis, when fed to detached leaves of C4 monocots (maize, sorghum) and dicots (Portulaca oleracea) in the dark or light, completely prevents the in vivo light activation of PEPC-PK activity regardless of whether the protein kinase activity is assessed in vivo or in vitro. In contrast, chloramphenicol, an inhibitor of protein synthesis in chloroplasts, has no effect on the light activation of maize PEPC-PK. Similarly, treatment with cycloheximide did not influence the light activation of other photosynthesis-related enzymes in maize, including cytoplasmic sucrose-phosphate synthase and chloroplast stromal NADPH-malate dehydrogenase and pyruvate, Pi dikinase. These and related results, in which detached maize leaves were treated simultaneously with cycloheximide and microcystin-LR, a potent in vivo and in vitro inhibitor of the PEPC type 2A protein phosphatase, indicate that short-term protein turnover of the PEPC-PK itself or some other essential component(s) (e.g., a putative protein that modifies this kinase activity) is one of the primary levels in the complex and unique regulatory cascade effecting the reversible light activation/seryl phosphorylation of PEPC in the mesophyll cytoplasm of C4 plants. PMID- 11607172 TI - Cortisol rapidly reduces prolactin release and cAMP and 45Ca2+ accumulation in the cichlid fish pituitary in vitro. AB - During in vitro incubation, prolactin release is inhibited in a dose-related manner by cortisol. This action is mimicked by the synthetic glucocorticoid agonist dexamethasone but not by other steroids tested. Perifusion studies indicate that the inhibition of [3H]prolactin release by cortisol occurs within 20 min. Cortisol (50 nM) also inhibits cAMP accumulation and reduces 45Ca2+ accumulation in the tilapia rostral pars distalis within 15 min. Cortisol's action on prolactin release is blocked in the presence of either the Ca2+ ionophore A23187 or a combination of dibutyryl cAMP and 3-isobutyl-1 methylxanthine, which increase intracellular Ca2+ and cAMP, respectively. Taken together, these findings suggest that cortisol may play a physiologically relevant role in the rapid modulation of prolactin secretion in vivo. Our studies also suggest that the inhibition of prolactin release by cortisol is a specific glucocorticoid action that may be mediated, in part, through cortisol's ability to inhibit intracellular cAMP and Ca2+ metabolism. PMID- 11607173 TI - The role of phosphoenolpyruvate carboxykinase in a marine macroalga with C4-like photosynthetic characteristics. AB - Udotea flabellum is a marine, macroscopic green alga with C4-like photosynthetic characteristics, including little O2 inhibition of photosynthesis, a low CO2 compensation point, and minimal photorespiration; but it lacks anatomical features analogous to the Kranz compartmentation of C4 plants, and phosphoenolpyruvate carboxylase [PEPC; orthophosphate:oxaloacetate carboxy-lyase (phosphorylating), EC 4.1.1.31] activity is negligible. Phosphoenolpyruvate carboxykinase (PEPCK) activity (carboxylating) in Udotea extracts was equivalent to that of ribulose-bisphosphate carboxylase [Rubisco; 3-phospho-D-glycerate carboxy-lyase (dimerizing), EC 4.1.1.39]. When PEPCK activity was inhibited in vivo with 3-mercaptopicolinic acid (MPA), thallus photosynthesis decreased by 70% and became sensitive to O2. Codium decorticatum, a related species that lacks C4 like photosynthetic features and PEPCK activity, showed no increase in O2 inhibition upon exposure to MPA. Rubisco and PEPC activities in Udotea were not inhibited by MPA. Labeling of the early photosynthetic products malate and aspartate was reduced 66% by MPA, while intermediates of the photorespiratory carbon oxidation cycle showed a 3-fold increase. Udotea evolved O2 in the light in the absence of inorganic carbon, suggesting it had an endogenous carbon source for photosynthesis. Exogenous malate stimulated this process, while MPA inhibited it. PEPCK was not involved in Crassulacean acid metabolism or dark CO2 fixation. These MPA studies establish a direct link between PEPCK activity and the low O2 inhibition of photosynthesis and low photorespiration in Udotea. The data are consistent with carboxylation by a cytosolic PEPCK providing a C4 acid, such as malate, to the chloroplast for decarboxylation to elevate the CO2 concentration at the Rubisco fixation site. Udotea is to date the most primitive plant with a C4-like form of photosynthesis. PMID- 11607174 TI - Solution of the coupled Einstein-Maxwell equations in oblate spheroidal coordinates. AB - Using Ernst's theory of complex potentials, a solution of the coupled Einstein Maxwell equations in oblate spheroidal coordinates is obtained for a source possessing mass, electric charge, and angular momentum. The density of the electromagnetic energy is evaluated. Explicit expressions are derived for the components of the Ricci tensor Rmunu, and of the electromagnetic energy momentum tensor Emunu, as well as for Enumu. PMID- 11607175 TI - Equilibrium compositions of solutions of biochemical species and heats of biochemical reactions. AB - Equilibrium compositions of solutions of biochemical species can be calculated by use of general equilibrium computer programs that minimize the Gibbs energy. The standard Gibbs energies of formation and standard enthalpies of formation of the species in a biochemical system can be calculated by Gaussian reduction of the augmented transpose of the stoichiometric number matrix for the system. The conservation matrix, which is also needed for the calculation of the equilibrium composition, can be obtained in two ways. The hydrolysis of adenosine 5' triphosphate in solutions containing magnesium ions can be treated by considering 17 species. The equilibrium composition and enthalpy are calculated before and after adding ATPase. This makes it possible to calculate DeltapH, DeltapMg, and the heat of reaction when ATPase is added. PMID- 11607176 TI - Resolution of component proteins in an enzyme complex from Methanosarcina thermophila catalyzing the synthesis or cleavage of acetyl-CoA. AB - An enzyme complex was isolated from acetate-grown Methanosarcina thermophila that oxidized CO and catalyzed the synthesis or cleavage of acetyl-CoA. The complex consisted of five subunits (alpha1beta1gamma1delta1epsilon1) of 89, 71, 60, 58, and 19 kDa. The complex contained nickel, iron, acid-labile sulfide, and cobalt in a corrinoid cofactor. Two components were resolved by anion-exchange chromatography of the complex in the presence of dodecyltrimethylammonium bromide and Triton X-100: a 200-kDa nickel/iron-sulfur protein with the 89- and 19-kDa (alpha2epsilonx) subunits and a 100-kDa corrinoid/iron-sulfur protein with the 60 and 58-kDa subunits (gamma1delta1). The nickel/iron-sulfur component contained 0.21 Ni, 2.7 Zn, 7.7 Fe, and 13.2 acid-labile sulfide (per alpha1epsilon1). The corrinoid/iron-sulfur component contained 0.7 Co, 0.7 factor III [Coalpha-[alpha (5-hydroxybenzimidazolyl)]-Cobeta-cyanocobamide], 3.0 Fe, and 2.9 acid-labile sulfide (gamma1delta1). Both components contained iron-sulfur centers. The nickel/iron-sulfur component oxidized CO and reduced methyl viologen or a ferredoxin isolated from M. thermophila. The nickel/iron-sulfur component also oxidized CO and transferred electrons to the corrinoid/iron-sulfur component, reducing the iron-sulfur and Co centers. UV-visible spectroscopy indicated that the reduced corrinoid/iron-sulfur component could be methylated with CH3I. The results suggest that the enzyme complex from M. thermophila contained at least two enzyme components, each with a specific function. The properties of the component enzymes support a mechanism proposed for acetyl-CoA synthesis (or cleavage) by the enzyme complex. PMID- 11607177 TI - Global and local metric geometry of ligand binding thermodynamics. AB - An abstract metric representation of ligand binding thermodynamics reveals the basic connections between the classical thermodynamic theory of binding and linkage [Wyman, J. (1964) Adv. Protein Chem. 19, 223-286] and its site-specific formulation [Di Cera, E. (1990) Biophys. Chem. 37, 147-164]. These two approaches are limit cases of a general metric formulation of binding and linkage that also includes a number of intermediate "mixed" representations. PMID- 11607178 TI - Self-similarity of the "1/f noise" called music. AB - Suggestions have been made that computer musicians should attempt to compose fractal music, and questions have been raised whether there is such a thing as fractal music. Voss and Clark observed that music is scaling, or 1/f noise, as analyzed on the basis of the amplitude (loudness) of the audio signals; they failed to find a fractal distribution of acoustic frequencies (music notes) in music. Analyzing Bach's and Mozart's compositions, we have shown that the incidence of the frequency intervals, or of the changes of acoustic frequency, has a fractal geometry. Fractal phenomena are characterized by scale independency. The purpose of this investigation is to demonstrate the self similarity of music and to explore its implications. PMID- 11607179 TI - Restriction fragment length polymorphism-mediated targeting of the ml-o resistance locus in barley (Hordeum vulgare). AB - The ml-o locus in barley confers resistance to all known races of the fungus Erysiphe graminis f.sp. hordei. Since the molecular mechanisms underlying ml-o mediated resistance are currently undefined, experiments have been initiated to isolate the gene by means of its map position. A collection of backcross lines containing ml-o alleles derived from six barley genotypes allowed us to identify a set of DNA markers very tightly linked to the resistance locus. These markers span an unexpectedly small segment of 8.6 centimorgans on chromosome 4 that includes the Ml-o locus. Two of the markers cosegregate with the resistance locus on the basis of 44 homozygous resistant plants identified within a segregating F2 population derived from an intravarietal cross. Colinearity of the resistance linked markers was confirmed in an F2 mapping population derived from a wide cross between Hordeum vulgare subsp. vulgare and Hordeum vulgare subsp. spontaneum. The two markers cosegregating with the resistance locus in the former cross define in the latter cross an interval of 2.4 centimorgans within which Ml o is most probably situated. The set of linked markers opens up the possibility of carrying out a bidirectional chromosomal walk or jump to the gene. PMID- 11607180 TI - Two distinct inputs to an avian song nucleus activate different glutamate receptor subtypes on individual neurons. AB - Although neural circuits mediating various simple behaviors have been delineated, those generating more complex behaviors are less well described. The discrete structure of avian song control nuclei promises that circuits controlling complex behaviors, such as birdsong, can also be understood. To this end, we developed an in vitro brain slice preparation containing the robust nucleus of the archistriatum (RA), a forebrain song control nucleus, and its inputs from two other song nuclei, the caudal nucleus of the ventral hyperstriatum (HVc) and the lateral part of the magnocellular nucleus of the anterior neostriatum (L-MAN). Using intracellular recordings, we examined the pharmacological properties of the synapses made on RA neurons by L-MAN and HVc axons. Electrical stimulation of the L-MAN and the HVc fiber tracts evoked excitatory postsynaptic potentials (EPSPs) from >70% of RA neurons when slices were prepared from male birds of 40-90 days of age, suggesting that many individual RA neurons receive excitatory input from L-MAN and HVc axons. The "L-MAN" EPSPs were blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid (D-APV) as well as the broad-spectrum glutamate receptor antagonist kynurenic acid but were relatively unaffected by the non-NMDA receptor blocker 6-cyano-7-nitroquinoxaline 2,3-dione (CNQX). In contrast, "HVc" EP-SPs were relatively insensitive to D-APV but almost completely abolished by CNQX. These experiments suggest that L-MAN and HVc axons provide pharmacologically distinct types of excitatory input to many of the same RA neurons. PMID- 11607181 TI - Analysis of the energy of the first four excited states of the ground- state rotational bands of the even-even lanthanon nuclei (58Ce to 70Yb) with the model of a single cluster of nucleons revolving about a sphere. AB - Analysis of the first four excited energy levels of the ground-state rotational bands of 82 nuclei (isotopes of the seven even-even lanthanons from 58Ce to 70Yb) has provided values of the radius of revolution of a single cluster about a sphere in each nucleus. The number of nucleons m in each cluster is taken to be 2 for neutron number N = 82 in each case for the first excited state, usually increasing by 2 with change in Z or N by +/-2, but sometimes changing by 0 or by 4 or more. The radius of revolution R decreases to a minimum (about 6.7 fm) at N approximately 78, rises sharply at N approximately 86, reaches a maximum (about 7.8 fm) at N approximately 96, and then decreases. PMID- 11607182 TI - Intraspecific variation in population gene diversity and effective population size correlates with the mating system in plants. AB - Published data on allele frequencies at isozyme loci in inbreeding and outbreeding plant species were analyzed to examine intraspecific variation in gene diversity and effective population size (Ne). Compared with outbreeders, inbreeding species showed markedly greater variation among populations in average values of Nei's gene diversity statistic. Effective population size was estimated by assuming that the variation observed at isozyme loci is selectively neutral. Inbreeding species showed greater levels of variation in Ne than did outbreeders, although the upper range of Ne was similar in the two classes of species. The results suggest that there may be considerable genetic variation and potential for evolutionary change in some but not all populations of inbreeders. Moreover, these findings are important with respect to the conservation of genetic resources. In particular, that the amount of intraspecific variation in population genetic diversity and Ne differs between inbreeding and outbreeding species should be taken into account in sampling efforts designed to optimize the diversity of germplasm collections. PMID- 11607186 TI - Localization of xanthine dehydrogenase in cowpea root nodules: implications for the interaction between cellular compartments during ureide biogenesis. AB - Immunocytochemistry was used to assess the location of xanthine dehydrogenase (EC 1.1.1.204) in the infected region of nodules of cowpea (Vigna unguiculata [L.] Walpers cv. Queen Anne Blackeye). Polyclonal antibodies raised against purified cowpea xanthine dehydrogenase were used to localize this enzyme at the electron microscopic level. Sparse nonspecific labeling was observed after treatment of nodule sections with preimmune serum. Although immune serum cross-reacted with the ground cytoplasm of both infected and uninfected cells, significantly more labeling was observed in the uninfected cells. No labeling above background was observed in peroxisomes, mitochondria, proplastids, endoplasmic reticulum, cytoplasmic or peribacteroid membranes, peribacteroid spaces, or bacteroids. The enzyme is soluble and not present in any organelle or membrane. The greater concentration of xanthine dehydrogenase in the uninfected cells suggests that xanthine or a precursor to xanthine, rather than uric acid, is the intermediate that moves from infected to uninfected cells during ureide biogenesis. PMID- 11607187 TI - Chlororespiration: an adaptation to nitrogen deficiency in Chlamydomonas reinhardtii. AB - When grown under nitrogen limitation, pronounced chlororespiratory activity develops together with an altered composition of thylakoid membranes in Chlamydomonas reinhardtii. Relative to control cultures, the flash-inhibited, chlororespiration-dependent O2 consumption signal increases 10-fold. Also augmented is the light-sensitive respiratory activity responsible for the "Kok effect," reflecting competitive inhibition of chlororespiratory electron transport by photosystem I. Fluorescence measurements show that the thylakoid plastoquinone pool is extensively reduced in dark-adapted, N-limited cells. Thylakoids of N-limited cells have reduced amounts of cytochrome b6, cytochrome f, and light-harvesting complexes. However, thylakoid-bound NADH-PQ oxidoreductase, with major subunits of 51 kDa and 17 kDa, is increased 7-fold and two novel cytochromes of 34 and 12.5 kDa are highly abundant. Thus, components of photosynthetic and chlororespiratory electron transport pathways are differentially regulated by N availability. PMID- 11607188 TI - Regulation of movement speed by intracellular pH during Dictyostelium discoideum chemotaxis. AB - Evidence is presented that the chemoattractant-induced cytoplasmic alkalinization in the cellular slime mold Dictyostelium discoideum is essential in regulating locomotion speed during chemotaxis. Intracellular pH was manipulated with weak bases, weak acids, and proton-pump inhibition. Speed of locomotion of individual cells was measured during random and chemotactic movement. We found that (i) an increase of cytoplasmic pH increases the speed of randomly moving cells and (ii) the chemoattractant-induced rise in intracellular pH is essential for the increase in directed locomotion speed upon chemotactic stimulation. In addition, our experiments support the hypothesis that ammonia plays a key role in the thermo- and phototaxis of migrating slugs by increasing the locomotion speed of individual cells through changes in intracellular pH. PMID- 11607189 TI - Structural femtochemistry: experimental methodology. AB - The experimental methodology for structural femtochemistry of reactions is considered. With the extension of femtosecond transition-state spectroscopy to the diffraction regime, it is possible to obtain in a general way the trajectories of chemical reactions (change of internuclear separations with time) on the femtosecond time scale. This method, considered here for simple alkali halide dissociation, promises many applications to more complex reactions and to conformational changes. Alignment on the time scale of the experiments is also discussed. PMID- 11607190 TI - Structure and topological symmetry of the glyphosate target 5 enolpyruvylshikimate-3-phosphate synthase: a distinctive protein fold. AB - 5-enol-Pyruvylshikimate-3-phosphate synthase (EPSP synthase; phosphoenolpyruvate:3-phosphoshikimate 1-carboxyvinyltransferase, EC 2.5.1.19) is an enzyme on the pathway toward the synthesis of aromatic amino acids in plants, fungi, and bacteria and is the target of the broad-spectrum herbicide glyphosate. The three-dimensional structure of the enzyme from Escherichia coli has been determined by crystallographic techniques. The polypeptide backbone chain was traced by examination of an electron density map calculated at 3-A resolution. The two-domain structure has a distinctive fold and appears to be formed by 6 fold replication of a protein folding unit comprising two parallel helices and a four-stranded sheet. Each domain is formed from three of these units, which are related by an approximate threefold symmetry axis; in each domain three of the helices are completely buried by a surface formed from the three beta-sheets and solvent-accessible faces of the other three helices. The domains are related by an approximate dyad, but in the present crystals the molecule does not display pseudo-symmetry related to the symmetry of point group 32 because its approximate threefold axes are almost normal. A possible relation between the three dimensional structure of the protein and the linear sequence of its gene will be described. The topological threefold symmetry and orientation of each of the two observed globular domains may direct the binding of substrates and inhibitors by a helix macrodipole effect and implies that the active site is located near the interdomain crossover segments. The structure also suggests a rationale for the glyphosate tolerance conferred by sequence alterations. PMID- 11607191 TI - Clusters of clusters: self-organization and self-similarity in the intermediate stages of cluster growth of Au-Ag supraclusters. AB - A systematic structural investigation of a new series of high-nuclearity Au-Ag clusters containing 25, 37, 38, and 46 metal atoms led to the description of these clusters as "clusters of clusters" based on vertex-sharing icosahedra as building blocks. Based on the observed structures, a growth sequence is proposed here for the formation of these secondary clusters (clusters of clusters) from a single 13-atom icosahedron to a 127-atom icosahedron of icosahedra via successive additions of vertex-sharing icosahedral units. This cluster-of-clusters growth mechanism parallels the atom-by-atom growth pathway for the primary clusters from a single atom to a 13-atom icosahedron. It is hypothesized that the formation of these clusters of clusters is a manifestation of the spontaneous self organization and self-similarity processes often observed in nature. It is conceivable that the concept of cluster of clusters may be important in the intermediate stages of some cluster growth as exemplified by the polyicosahedral growth of Au-Ag supraclusters. PMID- 11607192 TI - Rice type I phytochrome regulates hypocotyl elongation in transgenic tobacco seedlings. AB - We have examined the biological activity of rice type I phytochrome (PI) in transgenic tobacco seedlings. The progeny of four independent transformants that expressed the rice PI gene segregated 3:1 for shorter hypocotyl length under dim white light (0.04 W/m2). By contrast, this phenotype was not observed either in the dark or under white light at higher intensity (6.0 W/m2). This suggests that the phenotype is dependent not only on light but also on light intensity. The increased light sensitivity cosegregated with the kanamycin-resistance marker as well as with the rice PI polypeptides, indicating that this phenotype is directly related to the expression of the transgene. The transgenic plants showing short hypocotyls exhibited a reduced growth rate throughout the elongation period, and the resulting shorter hypocotyl length was attributable to shorter epidermal cell length but not to reduced cell number. Furthermore, successive pulse irradiations with red light elicited short hypocotyls similar to those obtained under dim white light, and the effect was reversed by immediate far-red light treatment, providing a direct indication that the phenotype is caused by biologically active rice PI. Therefore, the far-red-absorbing form of the introduced rice PI appears to regulate the hypocotyl length of the transgenic tobacco plants through endogenous signal-transduction pathways. This assay system will be a powerful tool for testing the biological activity of introduced phytochrome molecules. PMID- 11607193 TI - Use of a transposon with luciferase as a reporter to identify environmentally responsive genes in a cyanobacterium. AB - Anabaena, a filamentous cyanobacterium, is of developmental interest because, when deprived of fixed nitrogen, it shows patterned differentiation of N2-fixing cells called heterocysts. To help elucidate its early responses to a decrease in nitrogen, we used a derivative of transposon Tn5 to generate transcriptional fusions of promoterless bacterial luciferase genes, luxAB, to the Anabaena genome. Genes that responded to removal of fixed nitrogen or to other environmental shifts by increased or decreased transcription were identified by monitoring the luminescence of colonies from transposon-generated libraries. The Tn5 derivative transposed in Anabaena at ca. 1-4 x 10(-5) per cell and permitted high-resolution mapping of its position and orientation in the genome and facile cloning of contiguous genomic DNA. PMID- 11607195 TI - Electron crystallography of linear polymers: direct structure analysis of poly(epsilon-carprolactone). AB - Three-dimensional electron diffraction intensity data from poly(epsilon caprolactone) are used for an ab initio phase determination based on the probabilistic estimate of three- and four-phase structure invariants in space group P212121. From the initial phase set of 30 reflections (two of which are incorrect) of the 47 in the total data set, computed electrostatic potential maps produce a recognizable structure that can be refined by Fourier techniques and atomic displacement. The final structure (R = 0.21), which is very similar to one found in an earlier fiber x-ray study, shows that the polymer chain must adopt a nonplanar conformation around the ester linkage. PMID- 11607194 TI - Putative receptor for the plant growth hormone auxin identified and characterized by anti-idiotypic antibodies. AB - The molecular mechanism of action of auxins, which are an important class of plant growth regulators, is not known. While they are thought to influence cellular processes such as gene expression and membrane hyperpolarization by binding to specific receptors, no receptor mediating these processes has been unambiguously identified. We describe the identification of a putative auxin receptor by using anti-idiotypic antibodies. We have demonstrated that a 65 kilodalton protein found in a wide range of plants specifically binds auxins. Furthermore, since it is localized to the nucleus, it is a candidate for an auxin receptor that mediates some nuclear process. PMID- 11607197 TI - In vitro assay of the chlorophyll biosynthetic enzyme Mg-chelatase: resolution of the activity into soluble and membrane-bound fractions. AB - The first committed step in chlorophyll synthesis is the Mg-chelatase-catalyzed insertion of magnesium into protoporphyrin IX. Since iron insertion into protoporphyrin leads to heme formation, Mg-chelastase lies at the branch point of heme and chlorophyll synthesis in chloroplasts. Little is known about the enzymology or regulation of Mg-chelatase, as it has been assayed only in intact cucumber chloroplasts. In this report we describe an in vitro assay for Mg chelatase. Mg-chelatase activity in intact pea chloroplasts was 3- to 4-fold higher than in cucumber chloroplasts. This activity survived chloroplast lysis and could be fractionated by centrifugation into supernatant and pellet components. Both of these fractions were required to reconstitute Mg-chelatase activity, and both were inactivated by boiling indicating that the enzyme is composed of soluble and membrane-bound protein(s). The product of the reaction was confirmed fluorometrically as the magnesium chelate of the porphyrin substrate. The specific activity of the reconstituted system was typically 1 nmol of Mg-deuteroporphyrin per h per mg of protein, and activity was linear for at least 60 min under our assay conditions. ATP and magnesium were required for Mg chelatase activity and the enzyme was sensitive to the sulfhydryl reagent N ethylmaleimide (I50, 20 microM). Broken and reconstituted cucumber chloroplasts were unable to maintain Mg-chelatase activity. However, the cucumber supernatant fraction was active when combined with the pellet fraction of peas; the converse was not true, which suggested that the cucumber pellet was the component that lost activity during lysis. PMID- 11607196 TI - Direct transport of ADPglucose by an adenylate translocator is linked to starch biosynthesis in amyloplasts. AB - Starch biosynthesis has been studied by using amyloplasts isolated from cultured cells of sycamore trees (Acer pseudoplatanus L.). Highly purified intact amyloplasts, free from mitochondria and starch granules derived from broken amyloplasts, were isolated from a Percoll step gradient. Subsequently, the double silicone oil layer centrifugation technique was used to study adenylate transport in the amyloplasts. An adenylate-specific carrier was found to be active in the uptake of ATP, ADP, AMP, and most importantly, ADPglucose (ADP-Glc). Kinetic analyses showed that the uptake of these adenylates was mutually competitive with each other. In contrast to the mitochondrial adenylate carrier, in amyloplasts only ATP and ADP-Glc uptake were inhibited by carboxyatractyloside. Evidence is presented that the ADP-Glc transported into the amyloplast stroma can be used in starch synthesis catalyzed by starch synthase (ADP-Glc:1,4-alpha-D-glucan 4-alpha D-glucosyltransferase, EC 2.4.1.21). We propose that starch biosynthesis in amyloplasts is tightly coupled with the direct transport of ADP-Glc synthesized in the cytosol by sucrose synthase (ADP-Glc:D-fructose 2-alpha-D glucosyltransferase, EC 2.4.1.13) PMID- 11607199 TI - Efficient transformation and regeneration of rice small cell groups. AB - Transgenic plants have been regenerated from small cell groups of rice using a simpler, faster, and more efficient method than used previously (e.g., protoplast transformation and regeneration methods). Small cell groups of 50-100 cells were prepared from established suspension cultures of rice cell lines. Transformation of small cell groups with intact cell walls was carried out with a plasmid harboring the beta-glucuronidase gene and was mediated by polyethylene glycol. Assay of beta-glucuronidase activity indicated that the frequency of transformation was about 7%. beta-Glucuronidase activity was detected in the roots and leaves of plants regenerated from transformed calli. One or two copies of the beta-glucuronidase gene per cell were determined to be integrated into the rice chromosomal DNA isolated from transformed calli. This method of transformation and regeneration is widely applicable to both dicotyledonous and monocotyledonous plants, especially those varieties that are resistant to regeneration from protoplasts. PMID- 11607198 TI - Maize oleosin is correctly targeted to seed oil bodies in Brassica napus transformed with the maize oleosin gene. AB - Oleosins are small hydrophobic abundant proteins localized in the oil bodies of plant seeds. An oleosin gene from the monocotyledonous maize (Zea mays L.) was transferred into the dicotyledonous Brassica napus L. using Agrobacterium mediated transformation. The maize oleosin gene was placed under the control of either its own promoter/terminator or the promoter/terminator of a Brassica seed storage protein (napin) gene. Southern blot analyses of individual transformed plants suggested that the oleosin gene from either construct was incorporated into the Brassica chromosomes without appreciable structural alterations. The amount of construct incorporated was from 1 to >10 copies per haploid genome, depending on the individual transformant. Maize oleosin mRNA and protein were detected only in the transformants containing the napin gene promoter/terminator constructs; these transformants were studied further. Northern blot analyses of RNA isolated from different tissues and seeds of different developmental stages indicated that the maize oleosin mRNA was present only in the maturing seed. Approximately 1% of the total protein in mature seed was represented by maize oleosin. Subcellular fractionation of the mature seed revealed that 90% or more of the maize oleosin, as well as the Brassica oleosin, was localized in the oil bodies. The results show that a monocotyledonous oleosin possesses sufficient targeting information for its proper intracellular transport in a dicotyledon and also suggest that the napin gene promoter/terminator of Brassica, or equivalent seed storage protein regulatory elements of other plant species, may be used to express genes for the genetic engineering of seed oils. PMID- 11607200 TI - Phonon Green's function. AB - The concepts of source and quantum action principle are used to produce the phonon Green's function appropriate for an initial phonon vacuum state. An application to the Mossbauer effect is presented. PMID- 11607201 TI - Analysis of pulsed-neutron powder diffraction patterns of the icosahedral quasicrystals Pd3Siu and AlCuLiMg (three alloys) as twinned cubic crystals with large units. AB - The low-Q peaks on three pulsed-neutron powder patterns (total, U differential, and Pd differential) of the icosahedral quasicrystal Pd3SiU have been indexed on the basis of an assumed cubic structure of the crystals that by icosahedral twinning form the quasicrystal. The primitive unit cube is found to have edge length 56.20 A and to contain approximately 12,100 atoms. Similar analyses of pulsed-neutron patterns of Al55Cu10Li35, Al55Cu10Li30Mg5, and Al510Cu125Li235Mg130 give values of the cube edge length 58.3, 58.5, and 58.4 A, respectively, with approximately 11,650 atoms in the unit cube. It is suggested that the unit contains eight complexes in the beta-W positions, plus some small interstitial groups of atoms, with each complex consisting of a centered icosahedron of 13 clusters, each of 116 atoms with the icosahedral structure found in the body-centered cubic crystal Mg32(Al,Zn)49. PMID- 11607202 TI - Ultra-small-angle x-ray-scattering study: preliminary experiments in colloidal suspensions. AB - We report here a multiple-reflection type ultra-small-angle x-ray-scattering apparatus constructed according to the principle proposed by Bonse and Hart. The ultra-small-angle x-ray scattering technique enables us to investigate the distribution of solutes or particles in turbid systems, which could not be studied by the conventional light-scattering and microscopic methods. By this method, the density fluctuation from an order of several thousand angstroms to several micrometers is now detectable. In this paper, the ultra-small-angle x-ray scattering apparatus was calibrated by using well-defined latex particles. PMID- 11607203 TI - N coordination of FeMo cofactor requires His-195 of the MoFe protein alpha subunit and is essential for biological nitrogen fixation. AB - Electron spin echo envelope modulation (ESEEM) spectroscopy, a pulsed electron spin resonance technique, was used to analyze the N coordination of the iron molybdenum (FeMo) cofactor contained within the nitrogenase MoFe protein. Comparison of spectra obtained from whole cells and purified MoFe protein established that the N coordination of the FeMo cofactor provided by the MoFe protein polypeptide matrix can be unambiguously recognized in whole cells. ESEEM spectra of altered MoFe proteins, which were produced in certain mutant strains of Azotobacter vinelandii, showed that the N coordination to FeMo cofactor requires His-195 of the MoFe protein alpha subunit. Moreover, this requirement for His-195 was shown to be essential for biological nitrogen fixation. PMID- 11607204 TI - Induction of soybean vegetative storage proteins and anthocyanins by low-level atmospheric methyl jasmonate. AB - Soybean seedlings were exposed to atmospheric methyl jasmonate (MJ) to determine if low levels of this compound could regulate the expression and accumulation of the vegetative storage proteins (VSPs) in soybeans. Low levels of atmospheric MJ induced the accumulation of three VSPs with molecular masses of 27 kDa, 29 kDa, and 94 kDa (vsp27, vsp29, and vsp94, respectively). Atmospheric MJ caused vsp94 to be accumulated in all above-ground organs of the seedling uniformly after just 3 days of exposure. vsp27 preferentially accumulated in shoot tips and primary leaves, whereas vsp29 preferentially accumulated in the cotyledons. In addition to these effects, MJ also induced the biosynthesis of anthocyanins in light-grown seedlings but inhibited anthocyanin biosynthesis in etiolated seedlings. It is concluded that low levels of atmospheric MJ regulate anthocyanin biosynthesis and the organspecific accumulation of VSPs in developing soybean seedlings. The organ specific differential accumulation may reflect changes in the pattern of nitrogen partitioning between various compounds and/or organs. These results lend substance to the hypothesis that volatile MJ may act as a gaseous messenger or growth regulator in plants. PMID- 11607205 TI - Differential effects of plant sterols on water permeability and on acyl chain ordering of soybean phosphatidylcholine bilayers. AB - To gain some insight into the structural and functional roles of sterols in higher plant cells, various plant sterols have been incorporated into soybean phosphatidylcholine (PtdCho) bilayers and tested for their ability to regulate water permeability and acyl chain ordering. Sitosterol was the most efficient sterol in reducing the water permeability of these vesicles and stigmasterol appeared to have no significant effect. Vesicles containing 24zeta methylcholesterol exhibited an intermediate behavior, similar to that of vesicles containing cholesterol. Cycloartenol, the first cyclic biosynthetic precursor of plant sterols, reduced the water permeability in a very effective way. Of two unusual plant sterols, 24-methylpollinastanol and 14alpha,24zeta-dimethylcholest 8-en-3beta-ol, the former was found to be functionally equivalent to sitosterol and the latter was found to be relatively inefficient. 2H NMR experiments have been performed with oriented bilayers consisting of soybean PtdCho with sitosterol, stigmasterol, or 24-methylpollinastanol. The results provided clear evidence that sitosterol and 24zeta-methylpollinastanol exhibit a high efficiency to order PtdCho acyl chains that closely parallels their ability to reduce water permeability. By contrast, stigmasterol shows a low efficiency for both functions. These results show that sitosterol and stigmasterol, two major 24 ethylsterols differing only by the absence or presence of the Delta22 double bond in the side chain, probably play different roles in regulating plant membrane properties; they also may explain why 9beta,19-cyclopropylsterols behave as good surrogates of sitosterol. PMID- 11607206 TI - Proton NMR investigation into the basis for the relatively high redox potential of lignin peroxidase. AB - Lignin peroxidase shares several structural features with the well-studied horseradish peroxidase and cytochrome c peroxidase but carries a higher redox potential. Here the heme domain of lignin peroxidase and the lignin peroxidase cyanide adduct was examined by 1HNMR spectroscopy, including nuclear Overhauser effect and two-dimensional measurements, and the findings were compared with those for horseradish peroxidase and cytochrome c peroxidase. Structural information was obtained on the orientation of the heme vinyl and propionate groups and the proximal and distal histidines. The shifts of the epsilon1 proton of the proximal histidine were found to be empirically related to the Fe3+/Fe2+ redox potentials. PMID- 11607207 TI - Genetic and acclimatory variation in biophysical properties of insect cuticle lipids. AB - Epicuticular lipids provide the primary barrier to water loss in insects and other terrestrial arthropods. Using Fourier transform infrared spectroscopy, we found that the melting temperatures for these lipids in the grasshopper Melanoplus sanguinipes varied by over 10 degrees C between individuals. The most significant determinant of lipid melting temperature was geographic population, followed by family effects and rearing regime. The width of the phase transition also showed population and family effects. Differences in lipid phase properties were correlated with habitat temperature. Our results provide evidence for genetically based intraspecific variation in epicuticular lipids and have important implications for physiological studies of water balance in arthropods. PMID- 11607208 TI - Dualizing the Poisson summation formula. AB - If f(x) and g(x) are a Fourier cosine transform pair, then the Poisson summation formula can be written as 2sumfrominfinityn = 1g(n) + g(0) = 2sumfrominfinityn = 1f(n) + f(0). The concepts of linear transformation theory lead to the following dual of this classical relation. Let phi(x) and gamma(x) = phi(1/x)/x have absolutely convergent integrals over the positive real line. Let F(x) = sumfrominfinityn = 1phi(n/x)/x - integralinfinity0phi(t)dt and G(x) = sumfrominfinityn = 1gamma (n/x)/x - integralinfinity0 gamma(t)dt. Then F(x) and G(x) are a Fourier cosine transform pair. We term F(x) the "discrepancy" of phi because it is the error in estimating the integral phi of by its Riemann sum with the constant mesh spacing 1/x. PMID- 11607209 TI - The aba mutant of Arabidopsis thaliana is impaired in epoxy-carotenoid biosynthesis. AB - The three mutant alleles of the ABA locus of Arabidopsis thaliana result in plants that are deficient in the plant growth regulator abscisic acid (ABA). We have used 18O2 to label ABA in water-stressed leaves of mutant and wild-type Arabidopsis. Analysis by selected ion monitoring and tandem mass spectrometry of [18O]ABA and its catabolites, phaseic acid and ABA-glucose ester (beta-D glucopyranosyl abscisate), indicates that the aba genotypes are impaired in ABA biosynthesis and have a small ABA precursor pool of compounds that contain oxygens on the ring, presumably oxygenated carotenoids (xanthophylls). Quantitation of the carotenoids from mutant and wild-type leaves establishes that the aba alleles cause a deficiency of the epoxy-carotenoids violaxanthin and neoxanthin and an accumulation of their biosynthetic precursor, zeaxanthin. These results provide evidence that ABA is synthesized by oxidative cleavage of epoxy carotenoids (the "indirect pathway"). Furthermore the carotenoid mutant we describe undergoes normal greening. Thus the aba alleles provide an opportunity to study the physiological roles of epoxy-carotenoids in photosynthesis in a higher plant. PMID- 11607210 TI - Higher-order syzygies for the bracket algebra and for the ring of coordinates of the Grassmanian. AB - A Poincare resolution is given for the supersymmetric ring of brackets over a signed alphabet. As a consequence, a resolution is found for the ring of coordinates of the Grassmanian variety in projective space over any infinite field. PMID- 11607211 TI - Uniformly 13C-labeled algal protein used to determine amino acid essentiality in vivo. AB - The edible alga Spirulina platensis was uniformly labeled with 13C by growth in an atmosphere of pure 13CO2. The labeled biomass was then incorporated into the diet of a laying hen for 27 days. The isotopic enrichment of individual amino acids in egg white and yolk proteins, as well as in various tissues of the hen at the end of the feeding period, was analyzed by negative chemical ionization gas chromatography/mass spectrometry. The amino acids of successive eggs showed one of two exclusive enrichment patterns: complete preservation of the intact carbon skeleton or extensive degradation and resynthesis. The same observation was made in tissue proteins. These patterns were cleanly divided according to known nutritional amino acid essentiality/nonessentiality but revealed differences in labeling among the nonessential amino acids: most notable was that proline accretion was derived entirely from the diet. Feeding uniformly 13C-labeled algal protein and recovering and analyzing de novo-synthesized protein provides a useful method to examine amino acid metabolism and determine conditional amino acid essentially in vivo. PMID- 11607212 TI - Identification of a soluble salicylic acid-binding protein that may function in signal transduction in the plant disease-resistance response. AB - It has recently been demonstrated that salicylic acid (SA) may serve as an endogenous signal molecule in the induction of systemic acquired resistance in tobacco and cucumber. In addition, SA is an endogenous regulator of heat and odor production in the inflorescence of some thermogenic plants. No information, however, is currently available concerning the mode(s) of action of SA in plant signal transduction. In a search for possible cellular factors that directly interact with SA, we have detected and partially characterized a SA-binding protein in tobacco leaves. The SA-binding activity is both SDS and proteinase sensitive and behaves as a soluble protein with an apparent mass of 650 kDa. The protein has an apparent Kd of 14 microM for SA, which is consistent with the range of physiological concentrations of SA observed for the induction of plant resistance responses. Furthermore, the ability of SA analogues to compete with SA for binding to this soluble protein is strictly correlated with their biological activity to induce the expression of genes associated with disease resistance. Biologically active analogues effectively inhibit SA binding while biologically inactive analogues do not. These results collectively indicate that this SA binding protein may play a role in perceiving and transducing the SA signal to appropriate response elements, which ultimately activate one or more of the plant disease-resistance responses. PMID- 11607213 TI - Membrane-bounded nucleoid in the eubacterium Gemmata obscuriglobus. AB - The freshwater budding eubacterium Gemmata obscuriglobus possesses a DNA containing nuclear region that is bounded by two nuclear membranes. The membrane bounded nature of the nucleoid in this bacterium was shown by thin sectioning of chemically fixed cells, thin sectioning of freeze-substituted cells, and freeze fracture/freeze-etch. The fibrillar nucleoid was surrounded by electron-dense granules that were in turn enveloped by two nuclear membranes separated by an electron-transparent space. Immunogold labeling of thin sections of conventionally fixed cells with anti-double-stranded DNA antibody demonstrated double-stranded DNA associated with fibrillar material within the membrane boundary. The occurrence of a membrane-bounded nucleoid in a eubacterial prokaryote is a significant exception to the evidence supporting the prokaryote/eukaryote dichotomous classification of cell structure. PMID- 11607214 TI - A Ricardo model with economies of scale. AB - A model of international trade that resembles the classical Ricardo model but differs from it in admitting economies of scale in production is described. PMID- 11607215 TI - Theory of symmetry classes. AB - Although a great deal of work has gone into construction of the irreducible representations of the symmetric group n (and of the general linear group) a simple, intuitive characterization of the symmetry classes is missing. Relying on a systematic distinction between permutations of variables and permutations of places, we provide two such characterizations, showing that elements belonging to any such symmetry class can be described in one of two ways: (i) as the solutions of explicitly given (though not independent) sets of linear equations or (ii) as linear combinations of "simple" elements of a given symmetry class, a simple element being a generalization to an arbitrary symmetry class of the notion of a decomposable skew-symmetric tensor. PMID- 11607216 TI - Stimulation of pheromone biosynthesis in the moth Helicoverpa zea: action of a brain hormone on pheromone glands involves Ca2+ and cAMP as second messengers. AB - Isolated abdomen and pheromone gland bioassays were utilized to determine the physiological action of the pheromone-biosynthesis-activating neuropeptide (PBAN) in the corn earworm moth Helicoverpa (= Heliothis) zea. An isolated pheromone gland bioassay showed that synthetic PBAN was active at 0.02 pmol, with maximal activity occurring at 0.5 pmol and 60 min of incubation. Second-messenger studies demonstrated that extracellular Ca2+ is necessary for PBAN activity on isolated pheromone glands. The Ca2+ ionophore A23187 stimulated pheromone biosynthesis alone, whereas the Ca2+ channel blockers La3+ and Mn2+ inhibited PBAN activity. However, the organic Ca2+ channel blockers verapamil and nifedipine did not inhibit PBAN activity. Both forskolin and two cAMP analogues stimulated pheromone biosynthesis in the absence of extracellular Ca2+, indicating that Ca2+ may activate an adenylate cyclase. The biogenic amine octopamine did not elicit pheromone production in isolated gland or abdomen bioassays or when injected into intact female moths. Removal of the ventral nerve chord, including the terminal abdominal ganglia in isolated abdomens, did not affect PBAN stimulation of pheromone production. Similar levels of stimulation were found when isolated abdomens were treated with PBAN in scotophase or photophase. PMID- 11607217 TI - Isolation, sequence analysis, and physiological properties of enkephalins in the nervous tissue of the shore crab Carcinus maenas L. AB - [Leu]- and [Met]enkephalin from thoracic ganglia of the shore crab Carcinus maenas have been purified to homogeneity by a reversed-phase HPLC procedure. Automated gas-phase sequencing revealed a primary structure identical with that of enkephalins from vertebrates. The immunoreactive material in different parts of the nervous system of C. maenas was measured by RIA. Isolated crustacean [Leu]enkephalin shows physiological properties identical to synthetic [Leu]enkephalin in our bioassay. The enkephalinergic effect has been monitored by two bioassays: (i) inhibition of release of crustacean hyperglycemic hormone from isolated eyestalks of C. maenas, and (ii) decreased effect on blood glucose level in the fiddler crab Uca pugilator. The decrease in blood sugar level induced by [Leu]enkephalin was antagonized by naloxone, indicating a receptor-mediated process. In sequence analysis, the thoracic ganglion yielded 3 pmol of [Leu]enkephalin and approximately 1 pmol of [Met]enkephalin. The presence of enkephalins in crustaceans shows an earlier phylogenetic origin of opioids than presumed. PMID- 11607218 TI - On the stability of dispensable constituents of the eukaryotic genome: stability of coding sequences versus truly hypervariable sequences in a clonal vertebrate, the amazon molly, Poecilia formosa. AB - In clonal unisexual vertebrates, the genes specifying the males become dispensable. To study the fate of such genes the gynogenetic all-female fish Poecilia formosa was treated with androgens. Phenotypic males were obtained that exhibited the complete set of male characteristics of closely related gonochoristic species, including body proportions, pigmentation, the extremely complex insemination apparatus of poeciliid fish, sexual behavior, and spermatogenesis. The apparent stability of such genic structures, including those involved in androgen regulation, is contrasted by high instability of noncoding sequences. Frequent mutations, their clonal transmission, and at least two truly hypervariable loci leading to individual differences between these otherwise clonal organisms were detected by DNA fingerprinting. These observations substantiate the concept that also in "ameiotic" vertebrates certain compartments of the genome are more prone to mutational alterations than others. PMID- 11607219 TI - Rapid changes of protein phosphorylation are involved in transduction of the elicitor signal in plant cells. AB - Plant cells have an acute sense for pathogen-derived chemical stimuli, so-called elicitors, which induce the plant's defense response. To investigate the molecular basis of chemosensory transduction, elicitor-treated tomato cells were labeled with 1-min pulses of [32P] phosphate. This technique revealed drastic changes in protein phosphorylation in vivo within minutes of stimulation. The protein kinase inhibitors K-252a and staurosporine completely prevented these elicitor-induced changes in protein phosphorylation. They also blocked two early biochemical responses to elicitors, extracellular alkalinization and biosynthesis of ethylene. The ability of K-252a, staurosporine, and benzoylated staurosporine derivatives to inhibit elicitor responses in vivo correlated with their ability to inhibit tomato microsomal protein kinase in vitro. When K-252a was given to elicited cells 1 min after the[32] phosphate, the radioactivity in certain newly labeled phosphoprotein bands disappeared again within minutes. This correlated with an arrest of alkalinization within minutes when K-252a was applied in midcourse of elicitation. These data show that phosphorylation of protein substrates by K-252a-sensitive protein kinases is essential for transduction of elicitor signals in plant cells and that continuous phosphorylation of these proteins is required to maintain the elicited state. PMID- 11607220 TI - Equivariant algebraic vector bundles over representations of reductive groups: theory. AB - Let G be a reductive algebraic group and let B be an affine variety with an algebraic action of G. Everything is defined over the field C of complex numbers. Consider the trivial G-vector bundle B x S = S over B where S is a G-module. From the endomorphism ring R of the G-vector bundle S a construction of G-vector bundles over B is given. The bundles constructed this way have the property that when added to S they are isomorphic to F + S for a fixed G-module F. For such a bundle E an invariant rho(E) is defined that lies in a quotient of R. This invariant allows us to distinguish nonisomorphic G-vector bundles. This is applied to the case where B is a G-module and, in that case, an invariant of the underlying equivariant variety is given too. These constructions and invariants are used to produce families of inequivalent G-vector bundles over G-modules and families of inequivalent G actions on affine spaces for some finite and some connected semisimple groups. PMID- 11607221 TI - Equivariant algebraic vector bundles over representations of reductive groups: applications. AB - Let G be a connected semisimple Lie group over C. In this paper we construct continuous families of nonisomorphic algebraic G-vector bundles in which the base space is a fixed representation of G. The G-vector bundles constructed are all G invariant hypersurfaces in a representation of G. We show that in some cases these vector bundles yield continuous families of distinct G-actions on affine spaces. PMID- 11607222 TI - The structure of K3C60 and the mechanism of superconductivity. AB - Analysis of the interatomic distances in the superconducting substance K3C60 indicates that each of the K atoms in tetrahedral interstices between C60 spheres accepts three electrons from C60, thus becoming quadricovalent; its four bonds resonate among the 24 adjacent carbon atoms to give a strong framework in which the negative charges are localized on these K atoms. The electric current is carried by the motion of positive charges (holes) through the network of C60 spheres and the K atoms in octahedral holes. Superconductivity is favored by the localization of the negative charges on the tetrahedral K atoms and their noninvolvement in valence-bond resonance, decreasing the rate of mutual extinction of electrons and holes. PMID- 11607223 TI - Selective induction of gene expression and second-messenger accumulation in Dictyostelium discoideum by the partial chemotactic antagonist 8-p chlorophenylthioadenosine 3',5'-cyclic monophosphate. AB - During development of the cellular slime mold Dictyostelium discoideum, cAMP induces chemotaxis and expression of different classes of genes by means of interaction with surface cAMP receptors. We describe a cAMP derivative, 8-p chlorophenylthioadenosine 3',5'-cyclic monophosphate (8-CPT-cAMP), which inhibits cAMP-induced chemotaxis at low concentrations but induces chemotaxis at supersaturating concentrations. This compound, moreover, selectively activates expression of aggregative genes but not of postaggregative genes. 8-CPT-cAMP induces normal cGMP and cAMP accumulation but in contrast to cAMP, which increases inositol 1,4,5-trisphosphate levels, 8-CPT-cAMP decreases inositol 1,4,5-trisphosphate levels. The derivative induces reduced activation of guanine nucleotide regulatory proteins, which may cause its defective activation of inositol 1,4,5-trisphosphate production. Our data suggest that disruption of inositolphospholipid signaling impairs chemotaxis and expression of a subclass of cAMP-regulated genes. PMID- 11607224 TI - Solvent reorganizational red-edge effect in intramolecular electron transfer. AB - Polar solvents are characterized by statistical distributions of solute-solvent interaction energies that result in inhomogeneous broadening of the solute electronic spectra. This allows photoselection of the high interaction energy part of the distribution by excitation at the red (long-wavelength) edge of the absorption bands. We observe that intramolecular electron transfer in the bianthryl molecule from the locally excited (LE) to the charge-transfer (CT) state, which requires solvent relaxation and does not occur in vitrified polar solutions, is dramatically facilitated in low-temperature propylene glycol glass by the red-edge excitation. This allows one to obtain spectroscopically the pure CT form and observe its dependence upon the relaxational properties of the solvent. A qualitative potential model of this effect is presented. PMID- 11607225 TI - Nuclear scaffolds and scaffold-attachment regions in higher plants. AB - DNA in the nuclei of eukaryotic organisms undergoes a hierarchy of folding to be packaged into interphase and metaphase chromosomes. The first level of packaging is the 11-nm nucleosome fiber, which is further coiled into a 30-nm fiber. Evidence from fungal and animal systems reveals the existence of higher order packaging consisting of loops of the 30-nm fibers attached to a proteinaceous nuclear scaffold by an interaction between the scaffold and specific DNA sequences called scaffold-attachment regions (SARs). Support for the ubiquitous nature of such higher order packaging of DNA is presented here by our work with plants. We have isolated scaffolds from tobacco nuclei using buffers containing lithium diiodosalicylate to remove histones and then using restriction enzymes to remove the DNA not closely associated with the scaffold. We have used Southern hybridization to show that the DNA remaining bound to the scaffolds after nuclease digestion includes SARs flanking three root-specific tobacco genes. This assay for SARs is termed the endogenous assay because it identifies genomic sequences as SARs by their endogenous association with the scaffold. Another assay, the exogenous assay, depends upon the ability of scaffolds to specifically bind exogenously added DNA fragments containing SARs. The tobacco scaffolds specifically bind a well-characterized yeast SAR, and cloned DNA fragments derived from the 3'-flanking regions of the root-specific genes are confirmed to contain SARs by this exogenous assay. PMID- 11607227 TI - Geonium "K" experiment using spin dependency of cyclotron frequency supports g data of earlier geonium "S" work. AB - By substituting the relativistic spin state dependence of the cyclotron frequency for the continuous Stern-Gerlach effect and running the geonium atom as a microsynchrocyclotron accelerator we have detected spin flips of the individual trapped electron. In our initial efforts we have been able to obtain a simple symmetric spin resonance about 4-fold narrower instead of a complex asymmetric one and also to support but not as yet seriously test the result of the earlier geonium "S" work, g/2 = 1. 001 159 652 185 5(40). PMID- 11607226 TI - Activity of the Agrobacterium T-DNA transfer machinery is affected by virB gene products. AB - The oriT (origin of transfer) sequence and mob (mobilization) genes of plasmid RSF1010 can functionally replace transfer DNA (T-DNA) borders to generate an RSF1010 intermediate transferable to plants through activities of the tumor inducing (Ti)-plasmid virulence (vir) genes of Agrobacterium tumefaciens. Because the Ti plasmid virB gene products are hypothesized to form a membrane-localized T DNA transport apparatus, we investigated whether specific virB genes were needed for RSF1010 transfer. Here we report that transformation of Nicotiana tabacum leaf explants by an RSF1010-derivative plasmid (pJW323) requires the essential virulence genes virB9, virB10, and virB11, consistent with the hypothesis that both the T-DNA and RSF1010 transfer intermediates utilize the same transport machinery. Further, while pJW323 is transferred into plant cells by Agrobacterium strains harboring both pJW323 and pTiA6, the initiation of crown gall tumors (i.e., T-DNA transfer) is greatly suppressed. Coordinate overexpression of the virB9, virB10, and virB11 gene products relieves pJW323-mediated oncogenic suppression and restores tumorigenicity, but does not increase the transfer frequency of pJW323 into plant cells. We propose that the virB9, virB10, and virB11 gene products function coordinately and stoichiometrically to enhance DNA transfer in a fashion specific for the T-DNA intermediate. PMID- 11607228 TI - Phosphate-starvation response in plant cells: de novo synthesis and degradation of acid phosphatases. AB - Induction of phosphatase activity is an important component of the plant cell response to phosphate deficiency. Suspension cell cultures of Brassica nigra contain two major inducible acid phosphatase (APase) isozymes; vacuolar phosphoenolpyruvate (PEP) APase and cell wall nonspecific APase. Polyclonal antibodies raised against purified PEP-APase crossreacted specifically with both isozymes. Furthermore, anti-(PEP-APase) IgG detected proteins from a wide range of higher plants, suggesting that the major plant APase isozymes have diverged from a common ancestral form. Quantification on immunoblots indicated that in B. nigra suspension cells experiencing transition from Pi sufficiency to deficiency or vice versa, the amount of total antigenic APase protein correlated closely with total enzyme activity. This was also shown in intact plant roots. Therefore, the activity was governed by the synthesis and degradation of APases. Increases in the amounts of both major APase isozymes occurred simultaneously following Pi deprivation of B. nigra suspension cells, suggesting the involvement of a common regulatory mechanism. PMID- 11607229 TI - Magnetospheric imaging with low-energy neutral atoms. AB - Global imaging of the magnetospheric charged particle population can be achieved by remote measurement of the neutral atoms produced when magnetospheric ions undergo charge exchange with cold exospheric neutral atoms. Previously suggested energetic neutral atom imagers were only able to measure neutral atoms with energies typically greater than several tens of keV. A laboratory prototype has been built and tested for a different type of space plasma neutral imaging instrument, which allows neutral atoms to be imaged down to <1 keV. Such low energy measurements provide greater sensitivity for imaging the terrestrial magnetosphere and allow the bulk of the magnetospheric ion distribution, typically centered below 10 keV, to be observed rather than just the high-energy tail of the distribution. The low-energy neutral atom measurements are made possible by utilizing charge state modifications that occur when an initially neutral atom passes through an ultrathin carbon foil. Oxygen, for example, is highly electronegative, and for energies of approximately 10-30 keV, the O- yield is approximately 30%, essentially independent of the charge state of the incident oxygen atom. These ions are energy per charge analyzed, and the UV background is rejected by using an electrostatic analyzer. Imaging of other ion species, such as hydrogen, could also be accomplished by using ultrathin foil-induced charge state modifications. The technique described in this paper provides a method for imaging charge exchange neutrals from the terrestrial magnetosphere and would also have applications for similar imaging in other planetary or cometary environs. The Inner Magnetosphere Imaging Mission, which the National Aeronautics and Space Administration is presently considering, would provide a nearly ideal platform for low-energy neutral atom imaging, and such measurements would substantially enhance the scientific yield of this mission. PMID- 11607230 TI - Early tertiary elephant-shrews from Egypt and the origin of the Macroscelidea. AB - Recent expeditions to the Fayum Depression, Egypt, have made possible the discovery of mandibles and a maxilla of a new genus and species of late Eocene elephant-shrew as well as initial evidence of the upper dentition of the early Oligocene taxon Metoldobotes. These fossils demonstrate that macroscelideans underwent a significant radiation in the Early Tertiary of Africa. Two new subfamilies are recognized and described. These Tertiary macroscelideans are the most primitive elephant-shrews known and indicate that previous hypotheses of a close phylogenetic relationship between macroscelideans and either lagomorphs, erinaceotans, or tree-shrews are unlikely. Rather, the dental anatomy of the Fayum macroscelideans provides evidence for a derivation of the order from within the Condylarthra. PMID- 11607231 TI - Spectral kinetics of glutamate-1-semialdehyde aminomutase of Synechococcus. AB - Purified Synechococcus glutamate-1-semialdehyde aminotransferase (GSA-AT; EC 5.4.3.8) has absorption maxima characteristic of vitamin B6-containing enzymes and can be converted to the pyridoxamine 5'-phosphate or pyridoxal 5'-phosphate form by reaction with diaminovalerate or dioxovalerate, respectively, suggesting that these two analogues are intermediates in the conversion of glutamate 1 semialdehyde (GSA) to 5-aminolevulinate (ALA). Values for Km and kmax were calculated for GSA, diaminovalerate, ALA, and gabaculine from absorption change rates during conversion of one coenzyme form of GSA-AT to the other, upon addition of one of these compounds. The substrate specificity (kmax/Km) of diaminovalerate is about 3 orders of magnitude larger than that of dioxovalerate, making the latter an unlikely intermediate in the enzymic conversion of GSA to ALA. GSA reacts with both coenzyme forms, whereas ALA only reacts with the pyridoxamine 5'-phosphate form of the enzyme. However, ALA does form a complex with the pyridoxal 5'-phosphate form of GSA-AT and inhibits reactions between gabaculine and GSA-AT. This relatively stable complex (Ki = 8 M) may have significance in enzyme inhibition. Both L and D enantiomers of GSA react with GSA AT. Spectral changes observed upon addition of DL-GSA are apparently due to reaction with the less reactive D-isomer. L-GSA is converted to ALA prior to major spectral changes induced by the racemic mixture. PMID- 11607232 TI - Analysis of the energy of the first four excited states of the ground-state rotational bands of the even-even nuclei from 6C8 to 56Ba90 with the model of a single cluster of nucleons revolving about a sphere. AB - The results of the analysis of the first four energy levels of the ground-state rotational bands of even-even nuclei from 6C8 to 56Ba90 on the basis of the revolving-cluster model are reported. Values of the nucleon number of the revolving cluster are assigned on the basis in part of the shell model and in part of the expectation that the corresponding values of the radius of revolution would change only slightly from one energy level to an adjacent level or from one nucleus to an adjacent nucleus. The values of the radius of revolution are found to change gradually from about 5 to 6 fm for the lighter nuclei to 7 to 8 fm for the heavier nuclei in the sequence studied. PMID- 11607233 TI - Tensor species and symmetric functions. AB - An equivariant representation of the symmetric group Sn (equivariant representation from here on) is defined as a particular type of tensor species. For any tensor species R the characteristic generating function of R is defined in a way that generalizes the Frobenius characters of representations of the symmetric groups. If R is an equivariant representation, then the characteristic is a homogeneous symmetric function. The combinatorial operations on equivariant representations correspond to formal operations on the respective characteristic functions. In particular, substitution of equivariant representations corresponds to plethysm of symmetric functions. Equivariant representations are constructed that have as characteristic the elementary, complete, and Schur functions. Bijective proofs are given for the formulas that connect them with the monomial symmetric functions. PMID- 11607234 TI - Direct assignment of vitamin K1 as the secondary acceptor A1 in photosystem I. AB - The characteristic electron spin polarized electron paramagnetic resonance (ESP EPR) signal observed in photosystem I (PSI) has been previously assigned to a radical pair composed of the oxidized primary donor and a reduced vitamin K1. Under conditions in which Bottin, H. & Setif, P. [(1991), Biochim. Biophys. Acta 105, 331-336] proposed that A1 is doubly reduced, the ESP EPR signal was not observed. Therefore, the ESP EPR signal can be directly attributed to A-1, and vitamin K1 can be assigned as this PSI acceptor. The ESP EPR signal was partially restored by removal of the chemical reductants. PMID- 11607240 TI - Geometric interpretation of vertex operator algebras. AB - In this paper, Vafa's approach to the formulation of conformal field theories is combined with the formal calculus developed in Frenkel, Lepowsky, and Meurman's work on the vertex operator construction of the Monster to give a geometric definition of vertex operator algebras. The main result announced is the equivalence between this definition and the algebraic one in the sense that the categories determined by these definitions are isomorphic. PMID- 11607241 TI - Post's program and incomplete recursively enumerable sets. AB - A set A of nonnegative integers is recursively enumerable (r.e.) if A can be computably listed. It is shown that there is a first-order property, Q(X), definable in E, the lattice of r.e. sets under inclusion, such that (i) if A is any r.e. set satisfying Q(A) then A is nonrecursive and Turing incomplete and (ii) there exists an r.e. set A satisfying Q(A). This resolves a long open question stemming from Post's program of 1944, and it sheds light on the fundamental problem of the relationship between the algebraic structure of an r.e. set A and the (Turing) degree of information that A encodes. PMID- 11607242 TI - virF, the host-range-determining virulence gene of Agrobacterium tumefaciens, affects T-DNA transfer to Zea mays. AB - The monocotyledonous plant Zea mays does not develop tumors after inoculation with Agrobacterium tumefaciens and is thus defined as nonhost. Agroinfection, Agrobacterium-mediated delivery of maize streak virus, demonstrates that transferred DNA (T-DNA) transfer to the plant does occur. Nopaline-type Agrobacterium strains such as C58 are efficient in the transfer process whereas the octopine-type strain A6 is unable to transfer T-DNA to maize. This phenotypic difference maps to the tumor-inducing (Ti) plasmid but not to the T-DNA. Steps preceding T-DNA transfer, such as attachment and induction of the virulence genes, were shown to take place in the octopine strain. The nopaline-plasmid specific locus tzs and the octopine-plasmid-specific locus pinF (virH) are not involved in the strain specificity. However, mutations in the virF locus rendered the octopine strain agroinfectious on maize, whereas such virF-defective octopine strains, when complemented by virF on a plasmid, completely lost their agroinfectivity. We propose that VirF, known to increase the host range of the bacteria in other systems, acts as an inhibitor of T-DNA transfer to maize. PMID- 11607243 TI - Masculinization of female isopods (Crustacea) correlated with non-Mendelian inheritance of cytoplasmic viruses. AB - When in genetic females external male characters differentiate, the phenomenon is called "male pseudohermaphroditism." This male differentiation occurs in terrestrial isopods (Crustacea, suborder Oniscoidea) and sometimes involves only some epithelial areas (gynandromorphous mosaics). It is not induced by male hormones or by abnormal ovary function. This intersexuality is transmitted maternally (by the intersex females) or paternally (by the brothers of intersex females) to between 30% and 60% of their offspring. Although it occurs at 20 degrees C, the male differentiation disappears when breeding takes place at 27 degrees C. Male characters differentiate in normal females--even in other Oniscoidea species (Porcellio dilatatus, Porcellio laevis, Armadillidium vulgare) -after injection of a 0.22-micron filtered tissue extract. Since an inhibitor of bacterial protein synthesis (gentamycin) does not inhibit this masculinizing effect, we infer that neither organelles nor bacteria are involved. Intersexuality is always correlated with the presence of cytoplasmic viral particles in both intersex-female and transmitter-male tissues. Striking similarities to the Drosophila S virus are noted. A reovirus-like Oniscoidea masculinizing virus, which probably acts only on the epithelial areas sensitive to the male hormones, is most likely the causative agent of this intersexuality. Here we report the conversion of secondary sexual characters putatively caused by a virus. PMID- 11607244 TI - Phytochrome a overexpression inhibits hypocotyl elongation in transgenic Arabidopsis. AB - To develop a model plant system for efficient functional analysis of mutagenized phytochrome polypeptides, we have overexpressed oat phytochrome A in Arabidopsis thaliana. R1 seedlings from selfed primary transformants segregated for hypocotyl length, when grown in the light, with a ratio of 3 short to 1 of normal length. When homozygous lines were established from these two size classes, accumulation of immunologically detectable oat phytochrome cosegregated with the short hypocotyl trait. The short-hypocotyl seedlings contained substantially more spectrally active phytochrome than their normal-sized siblings, indicating that the introduced oat protein was photoreversible. The short-hypocotyl phenotype was strictly light-dependent, since no morphological effects of phytochrome overexpression could be seen in etiolated seedlings. Overexpression of only the chromophore-bearing, N-terminal domain of phytochrome A did not induce short hypocotyls in light-grown seedlings, indicating that additional sequence is essential for photoreceptor function. Similarly, overexpression of a full-length sequence mutated at the chromophore attachment site had no effect on phenotype, indicating the absence of any detectable dominant negative effect of the chromophoreless polypeptide on the activity of endogenous Arabidopsis phytochrome. Thus, the readily scorable short-hypocotyl phenotype of Arabidopsis seedlings overexpressing phytochrome A provides a simple visual assay for rapidly monitoring the biological activity of mutagenized phytochrome A polypeptides. PMID- 11607245 TI - Formation of cage-like particles by poly(amino acid)-based block copolymers in aqueous solution. AB - When dissolved in N,N-dimethylformamide and then dialyzed against phosphate buffered saline, A-B-A block copolymers composed of poly [N5-(2-hydroxyethyl)-L glutamine]-block-poly(gamma-benzyl-L-glutamate)- block-poly [N5-(2-hydroxyethyl) L-glutamine] form particles. The particles are cage-like structures with average diameters of 300 nm (average polydispersity, 0.3-0.5). They are stable in aqueous solution at 4 degrees C for up to 3 weeks, at which time flocculation becomes apparent. Negative staining and freeze-fracture electron microscopy suggest that cage-like particles are formed by selective association of segregated micelle populations. A model of particle formation is presented in which B blocks form micelles in dimethylformamide. On dialysis against an aqueous solution, the extended A blocks then associate intermolecularly to form rod-shaped micelles, which connect the B block micelles. The result is a meshed cage-like particle. The implications of these observations on the aggregation behavior of polymeric surfactants in dilute solution are discussed. PMID- 11607246 TI - Predicting chaos for infinite dimensional dynamical systems: the Kuramoto Sivashinsky equation, a case study. AB - The results of extensive computations are presented to accurately characterize transitions to chaos for the Kuramoto-Sivashinsky equation. In particular we follow the oscillatory dynamics in a window that supports a complete sequence of period doubling bifurcations preceding chaos. As many as 13 period doublings are followed and used to compute the Feigenbaum number for the cascade and so enable an accurate numerical evaluation of the theory of universal behavior of nonlinear systems, for an infinite dimensional dynamical system. Furthermore, the dynamics at the threshold of chaos exhibit a self-similar behavior that is demonstrated and used to compute a universal scaling factor, which arises also from the theory of nonlinear maps and can enable continuation of the solution into a chaotic regime. Aperiodic solutions alternate with periodic ones after chaos sets in, and we show the existence of a period six solution separated by chaotic regions. PMID- 11607247 TI - On the repulsion of energy eigenstates in the time domain. AB - The rate and extent of the exploration of the available phase space of a bound quantum mechanical system are shown to depend on the repulsion of energy eigenstates. Central to the argument is the Fourier transform relating the survival probability (in time) of an initially prepared nonstationary state and the (frequency) autocorrelation function of the excitation spectrum. Strong repulsion of states, as in the Wigner surmise, leads to a rapid dephasing of the initially coherently prepared state. The rate and extent of sampling of phase space depend not only on the spacing distribution but also on the intensity fluctuations. The rate of dephasing is equal to that inferred from the width of the spectral autocorrelation function. PMID- 11607248 TI - An ancient clonal lineage in the fish genus Poeciliopsis (Atheriniformes: Poeciliidae). AB - Genetic diversity in mtDNA was assessed within the unisexual (all female) hybridogenetic fish Poeciliopsis monacha-occidentalis and the two sexual species from which it arose. Results confirm that P. monacha was the maternal ancestor and that paternal leakage of P. occidentalis mtDNA has not occurred. Of particular interest is the high level of de novo mutational divergence within one hybridogenetic lineage that on the basis of independent zoogeographic considerations, protein electrophoretic data, and tissue grafting analysis is of monophyletic (single hybridization) origin. Using a conventional mtDNA clock calibration, we estimate that this unisexual clade might be >100,000 generations old. Contrary to conventional belief, this result shows that some unisexual vertebrate lineages can achieve a substantial evolutionary age. PMID- 11607249 TI - Chemical implementation of finite-state machines. AB - With methods developed in a prior article on the chemical kinetic implementation of a McCulloch-Pitts neuron, connections among neurons, logic gates, and a clocking mechanism, we construct examples of clocked finite-state machines. These machines include a binary decoder, a binary adder, and a stack memory. An example of the operation of the binary adder is given, and the chemical concentrations corresponding to the state of each chemical neuron are followed in time. Using these methods, we can, in principle, construct a universal Turing machine, and these chemical networks inherit the halting problem PMID- 11607250 TI - Regulation of assimilatory nitrate reductase activity in soil by microbial assimilation of ammonium. AB - It is well established that assimilatory nitrate reductase (ANR) activity in soil is inhibited by ammonium (NH4+). To elucidate the mechanism of this inhibition, we studied the effect of L-methionine sulfoximine (MSX), an inhibitor of NH4+ assimilation by microorganisms, on assimilatory reduction of nitrate (NO3-) in aerated soil slurries treated with NH4+. We found that NH4+ strongly inhibited ANR activity in these slurries and that MSX eliminated this inhibition. We also found that MSX induced dissimilatory reduction of NO3- to NH4+ in soil and that the NH4+ thus formed had no effect on the rate of NO-3 reduction. We concluded from these observations that the inhibition of ANR activity by NH4+ is due not to NH4+ per se but to products formed by microbial assimilation of NH4+. This conclusion was supported by a study of the effects of early products of NH4+ assimilation (L amino acids) on ANR activity in soil, because this study showed that the biologically active, L isomers of glutamine and asparagine strongly inhibited ANR activity, whereas the D isomers of these amino acids had little effect on ANR activity. Evidence that ANR activity is regulated by the glutamine formed by NH4+ assimilation was provided by studies showing that inhibitors of glutamine metabolism (azaserine, albizziin, and aminooxyacetate) inhibited ANR activity in soil treated with NO3- but did not do so in the presence of MSX. PMID- 11607251 TI - An auxin-binding protein is localized to the plasma membrane of maize coleoptile cells: identification by photoaffinity labeling and purification of a 23-kda polypeptide. AB - Plasma membrane vesicles were isolated from maize (Zea mays L.) coleoptile tissue by aqueous two-phase partitioning and assayed for homogeneity by the use of membrane-specific enzymatic assays. Using 5-azido-[7-3H]indole-3-acetic acid ([3H]N3IAA), we identified several IAA-binding proteins with molecular masses of 60 kDa (pm60), 58 kDa (pm58), and 23 kDa (pm23). Using Triton X-114, we were able to selectively extract pm23 from the plasma membrane. We show that auxins and functional analogues compete with [3H]N3IAA for binding to pm23. We found that PAB130, a polyclonal antibody raised against auxin-binding protein 1 (ABP-1), recognized ABP-1 as well as pm23. This suggests that pm23 shares common epitopes with ABP-1. In addition, we identified an auxin-binding protein with a molecular mass of 24 kDa (pm24), which was detected in microsomal but not in plasma membrane vesicle preparations. Like pm23 this protein was extracted from membrane vesicles with Triton X-114. We designed a purification scheme allowing simultaneous purification of pm23 and pm24. Homogeneous pm23 and pm24 were obtained from coleoptile extracts after 7000-fold purification. PMID- 11607252 TI - 5'-Azido-[3,6-3H2]-1-napthylphthalamic acid, a photoactivatable probe for naphthylphthalamic acid receptor proteins from higher plants: identification of a 23-kDa protein from maize coleoptile plasma membranes. AB - 1-Naphthylphthalamic acid (NPA) is a specific inhibitor of polar auxin transport that blocks carrier-mediated auxin efflux from plant cells. To allow identification of the NPA receptor thought to be part of the auxin efflux carrier, we have synthesized a tritiated, photolabile NPA analogue, 5'-azido-[3,6 3H2]NPA ([3H2]N3NPA). This analogue was used to identify NPA-binding proteins in fractions highly enriched for plasma membrane vesicles isolated from maize coleoptiles (Zea mays L.). Competition studies showed that binding of [3H2]N3NPA to maize plasma membrane vesicles was blocked by nonradioactive NPA but not by benzoic acid. After incubation of plasma membrane vesicles with [3H2]N3NPA and exposure to UV light, we observed specific photoaffinity labeling of a protein with an apparent molecular mass of 23 kDa. Pretreatment of the plasma membrane vesicles with indole-3-acetic acid or with the auxin-transport inhibitors NPA and 2,3,5-triiodobenzoic acid strongly reduced specific labeling of this protein. This 23-kDa protein was also labeled by addition of 5-azido-[7-3H]indole-3-acetic acid to plasma membranes prior to exposure to UV light. The 23-kDa protein was solubilized from plasma membranes by 1% Triton X-100. The possibility that this 23-kDa polypeptide is part of the auxin efflux carrier system is discussed. PMID- 11607254 TI - Industrial ecology. AB - Industrial ecology addresses issues that will impact future production, use, and disposal technologies; proper use of the concept should reduce significantly the resources devoted to potential remediation in the future. This cradle-to reincarnation production philosophy includes industrial processes that are environmentally sound and products that are environmentally safe during use and economically recyclable after use without adverse impact on the environment or on the net cost to society. This will require an industry-university-government round table to set the strategy and agenda for progress. PMID- 11607253 TI - Industrial ecology: concepts and approaches. AB - Industrial ecology is a new approach to the industrial design of products and processes and the implementation of sustainable manufacturing strategies. It is a concept in which an industrial system is viewed not in isolation from its surrounding systems but in concert with them. Industrial ecology seeks to optimize the total materials cycle from virgin material to finished material, to component, to product, to waste product, and to ultimate disposal. To better characterize the topic, the National Academy of Sciences convened a colloquium from which were derived a number of salient contributions. This paper sets the stage for the contributions that follow and discusses how each fits into the framework of industrial ecology. PMID- 11607255 TI - Industrial ecology: a philosophical introduction. AB - By analogy with natural ecosystems, an industrial ecology system, in addition to minimizing waste production in processes, would maximize the economical use of waste materials and of products at the ends of their lives as inputs to other processes and industries. This possibility can be made real only if a number of potential problems can be solved. These include the design of wastes along with the design of products and processes, the economics of such a system, the internalizing of the costs of waste disposal to the design and choice of processes and products, the effects of regulations intended for other purposes, and problems of responsibility and liability. The various stakeholders in making the effects of industry on the environment more benign will need to adopt some new behaviors if the possibility is to become real. PMID- 11607256 TI - Industry as a metabolic activity. AB - The concept of "industrial economic metabolism" can provide a bridge to better understanding between environmentalists and industry. In nature each individual or species reacts to natural stimuli, competing with others for resources, extending its domain until it loses comparative advantage and comes to equilibrium with an adjacent competitor. Those species that succeed over time flourish; those that do not, diminish or disappear. Nature's rule book has no moral or ethical ingredient beyond self-interest. Corporate metabolisms are remarkably similar to those of nature. They too react to stimuli, collect and use resources, and grow or perish based on how effectively they compete. Corporate management recognizes and responds naturally and efficiently to cost and price signals. Through them it selects resources and converts them into useful products. The efficiency with which this is done is measured by profit, the lifeblood of the corporation and its means of growth. Profit thus provides a discipline on corporate behavior, encouraging efficient performers, and, by its absence, weeding out others. Unfettered by influences other than economics, the path to corporate success is unlikely to be a compassionate one. The dilemma of the manager is that to do what is socially "right" often conflicts with what must be done to survive and prosper. Fortunately, corporations' behavior can be altered by society when their purely economic role comes into conflict with other human values. The environment and the economy are not separate systems but intertwined to form a complex natural and social setting. The human-designed economic system depends on natural resource inputs, and in turn its metabolic wastes can overload the ecological system, threatening the long-term survivability of both. Increasing concern for the environment now gives the farsighted manager new latitude. There are competitive benefits in some pollution prevention. But there are not sufficiently strong forces to correct all current ills. In addition, we must harness the metabolism of the industrial world to the realities of the natural one by recognizing the immense value of depletable natural resources and ecosystems. Considering these resources as "cheap" or "free" encourages their overuse. What is needed are adjustments that price these resources at their true longterm value. Corporations will respond naturally, quickly, and efficiently to such signals. If we can send our metabolic industry the economic signals it can understand, we can retrofit our human economic system to live in harmony with the natural ecosystem of which we are a part. If we do not, nature assuredly will not accommodate our failure by changing its ways. PMID- 11607257 TI - Investigations of the environmental acceptability of fluorocarbon alternatives to chlorofluorocarbons. AB - Chlorofluorocarbons (CFCs) are currently used in systems for preservation of perishable foods and medical supplies, increasing worker productivity and consumer comfort, conserving energy and increasing product reliability. As use of CFCs is phased out due to concerns of ozone depletion, a variety of new chemicals and technologies will be needed to serve these needs. In choosing alternatives, industry must balance concerns over safety and environmental acceptability and still meet the preformance characteristics of the current technology, the only viable alternatives meeting the safety, performance, and environmental requirements for the remaining 40% of demand are fluorocarbons, hydrochlorofluorocarbons (HCFs), and hydrofluorocarbons (HFCs). HCFCs and HFCs possess many of the desirable properties of the CFCs, but because of the, hydrogen, they results in shorter atmospheric lifetimes compared to CFCs and reduces their potential to contribute to stratospheric ozone depletion or global warming; HFCs do not contain chlorine and have no potential to destroy ozone. This paper provides an overview of challenges faced by industry, regulators, and society in general in continuing to meet societal needs and consumer demands while reducing risk to the enviroment without compromising consumer or worker safety. PMID- 11607258 TI - Approaches to eliminating chlorofluorocarbon use in manufacturing. AB - Until quite recently, chlorofluorocarbons (CFCs) had been considered the safest and most benign of industrial chemicals. Their physical and chemical properties made them an integral part of manufacturing processes for electronics products. The recognition that CFCs destroy the stratospheric ozone layer, with consequent enormous consequences to all forms of life on earth, has led to international agreements which will end virtually all possibly before. This impending phaseout of CFCs has caused electronics manufacturers to examine alternative chemicals and processing methods. This manuscript documents the steps AT&T has taken to reach its goal of 100% phaseout of CFCs by years-end 1994. These actions include top down management support with combined bottom-up thrusts, an internal information gathering and dissemination center, internal technology transfer, and external corporate activism. PMID- 11607259 TI - Toxic heavy metals: materials cycle optimization. AB - Long-term ecological sustainability is incompatible with an open materials cycle. The toxic heavy metals (arsenic, cadmium, chromium, copper, lead, mercury, silver, uranium/plutonium, zinc) exemplify the problem. These metals are being mobilized and dispersed into the environment by industrial activity at a rate far higher than by natural processes. Apart from losses to the environment resulting from mine wastes and primary processing, many of these metals are utilized in products that are inherently dissipative. Examples of such uses include fuels, lubricants, solvents, fire retardants, stabilizers, flocculants, pigments, biocides, and preservatives. To close the materials cycle, it will be necessary to accomplish two things. The first is to ban or otherwise discourage (e.g., by means of high severance taxes on virgin materials) dissipative uses of the above type. The second is to increase the efficiency of recycling of those materials that are not replaceable in principle. Here, also, economic instruments (such as returnable deposits) can be effective in some cases. A systems view of the problem is essential to assess the cost and effectiveness of alternative strategies. PMID- 11607260 TI - Alternative starting materials for industrial processes. AB - In the manufacture of chemical feedstocks and subsequent processing into derivatives and materials, the U.S. chemical industry sets the current standard of excellence for technological competitiveness. This world-class leadership is attributed to the innovation and advancement of chemical engineering process technology. Whether this status is sustained over the next decade depends strongly on meeting increasingly demanding challenges stimulated by growing concerns about the safe production and use of chemicals without harmful impacts on the environment. To comply with stringent environmental regulations while remaining economically competitive, industry must exploit alternative benign starting materials and develop environmentally neutral industrial processes. Opportunities are described for development of environmentally compatible alternatives and substitutes for some of the most abundantly produced, potentially hazardous industrial chemicals now labeled as "high-priority toxic chemicals." For several other uniquely important commodity chemicals where no economically competitive, environmentally satisfactory, nontoxic alternative starting material exists, we advocate the development of new dynamic processes for the on-demand generation of toxic chemicals. In this general concept, which obviates mass storage and transportation of chemicals, toxic raw materials are produced in real time, where possible, from less-hazardous starting materials and then chemically transformed immediately into the final product. As a selected example for semiconductor technology, recent progress is reviewed for the on demand production of arsine in turnkey electrochemical generators. Innovation of on-demand chemical generators and alternative processes provide rich areas for environmentally responsive chemical engineering processing research and development for next-generation technology. PMID- 11607261 TI - Efficient energy use in manufacturing. AB - The potential for improved industrial efficiency is great and a substantial part of that potential is being realized in the course of events. With new technology and increasing affluence, the composition of production is changing such that energy and materials consumption is growing more slowly than the economy. Through new technologies and appropriate public policies, the energy intensities of all production processes should also continue to decline. Potential difficulties facing this relatively rosy scenario are also discussed. PMID- 11607262 TI - Pollution prevention as a market-enhancing strategy: a storehouse of economical and environmental opportunities. AB - EPA's (Environmental Protection Agency) Green Lights Program for energy-efficient lighting illustrates the economic benefits and the market-transforming value of a pollution prevention philosophy. Using technologies available today, and assuming current prices, this program is expected to reduce air pollution 5%, while saving the nation's businesses up to 20 billion in electric bills every year. However, these pollution prevention and savings estimates may be low. As Green Lights transforms the market for lighting services by creating a higher demand for better technologies at lower costs, the program will likely achieve even larger pollution reductions and electricity savings. PMID- 11607263 TI - Polymer recycling: opportunities and limitations. AB - The disposal of polymer solid waste by means other than landfilling is necessary. The various approaches-source reduction, incineration, degradation, composting, and recycling-all have their roles and must be employed in an integrated manner. Where appropriate, recycling has ecological advantages, but its application is dependent upon the feasibility of collection, sorting, and/or compatibilization of resulting mixtures to produce economically viable products. The practice should be encouraged by societal or legislative pressure which recognizes that the cost of disposal should be a factor in determining the cost of a product. PMID- 11607264 TI - The ecology of markets. AB - Economies are sometimes viewed as analogous to ecological systems in which "everything is connected to everything else." In complex modern economies, the question arises whether the market mechanism can appropriately coordinate all the interconnections or whether instead some supramarket body is needed to coordinate the vast web of human activities. This study describes how an idealized decentralized competitive market in fact coordinates the different economic organisms in an efficient manner. The problems of pollution and other externalities can undo the efficient outcome unless corrected by appropriate property rights or corrective taxes. But in closing the economic circle, the internalized economy does not actually need to close the natural cycles by linking up all physical flows through recycling. PMID- 11607265 TI - Industrial input-output analysis: implications for industrial ecology. AB - Industrial ecology will need to develop fundamentally new approaches to reducing, reusing, and recycling wastes. Industrial ecology will also require an analytic framework for examining the implications for the economic system as a whole of each potential web of industrial changes. A suitable framework is furnished by structural economics, which situates the economy within the physical world. This approach is based on dynamic analysis rather than static concepts of equilibrium, and optimization assumptions are used selectively rather than as the general solution mechanism. Input-output economics, an important formal model within structural economics, can trace the stocks and flows of energy and other materials from extraction through production and consumption to recycling or disposal. An input-output computation, including wastes, is presented; it illustrates the separate but integrated analysis of physical stocks and flows and of prices and costs. This paper also describes the major advances that have been made in the last decade in the extension of input-output economics to address increasingly complex questions, notably the fully dynamic physical/price/income model and the engineering/input-output data base. Economists need to be able to assess the costs of cleaning up and to develop incentive schemes to increase the likelihood this will happen. To do this, economists need to take on the difficult "how" questions that concern industrial ecologists since the cost, and indeed the wider implications, of cleaning up depends upon how it is done. Structural economics, and modern input-output models and data bases, in particular, can help meet this challenge. PMID- 11607266 TI - Environmental issues and the law. AB - This report first briefly reviews the history and lessons learned from our legislation regarding protection of our environment. Then, these lessons are combined with principles of general jurisprudence to suggest avenues for regulation of industrial ecology. Even though the law has important limitations, it can be used as a tool to identify national goals and to promote their achievement by means of incentives or sanctions. PMID- 11607267 TI - Educating and training industrial ecologists for the 1990s. AB - For industrial ecology to become a reality and flourish, many talents must be integrated into a single system. Basically, there are four types of technologists who must be brought together to create a system: (i) technical specialists-those that can take the state of knowledge to the state of the art and eventually to the state of practice; (ii) technical "generalists"-those that can integrate diverse technologies into a comprehensive solution; (iii) technical managers those that can lead technical efforts to an optimal solution (these people must have management skills in their area); and (iv) program managers-those that can understand and merge the overall efforts of technology, business, schedule, and finance. The initial questions for industrial ecology in the 1990s are: Do these people presently exist in industry? What will be needed to bring new people (recent graduates) into the field of industrial ecology? For this decade, the people who will develop and lead the concept of industrial ecology are presently in industry. However, certainly few, if any, today understand the concept of industrial ecology as a system issue. Training will be needed for these practitioners of the 1990s so that the overall goal and the mechanism for achieving industrial ecology are understood. A three-tiered approach is presented to define the education/training needed, to conduct training on an industry basis, and then to initiate the training to be done within a corporation. The three tiers propose the use of universities, professional societies, and industry groups. Having universities participate in the training of the 1990s industrial ecologists will give universities insight to the development of industrial ecology, and access to industry needs so that curriculum can be initiated to educate the industrial ecologists of the future. PMID- 11607268 TI - Environmental education. AB - The need for a new profession devoted to environmental matters is asserted. The qualities of such a profession are sketched, and it is argued that new initiatives in environmental education are needed in the form of graduate, professional programs with primary emphasis on practice. An example 2-year program is presented. A fundamental requirement is scientific competence; undergraduate preparation in the sciences or engineering is mandatory. The graduate curriculum itself is built on three primary cores: environmental science and engineering, business and management, and public policy. Additionally, an environmental round table is proposed as a focal point for academic, industrial, governmental, and public discussion on environmental matters. The round table would provide oversight for the professional educational program and an affiliated research institute. PMID- 11607269 TI - Education for industrial ecology. AB - The societal issues relevant to the subject of industrial ecology call for the participation of broadly educated engineers who can integrate their technology with the social, political, environmental, and economic aspects of its applications. This increase in the responsibility of traditional engineering to include the end-use, obsolescence, and disposition of technical products signals a new era for engineering education. PMID- 11607270 TI - The transition to a sustainable society. AB - Transitions in dealing with the root causes of environmental problems are advocated to achieve environmental sustainability. These transformations include (i) a demographic transition, (ii) a technology transition that includes the "green" automobile, (iii) an economic transition to one in which prices reflect full environmental costs, (iv) a transition in social equity, and (v) an institutional transition to different arrangements among governments, businesses, and peoples. Businessmen and environmentalists are urged to work together in the next decade to make the environment a personal issue, to call for government action, to recognize the environmental challenges, and to commit to accountability in order to leave a legacy of hope to the twenty-first century. PMID- 11607271 TI - Industrial ecology: an emerging management science. AB - Pollution is a complex equation, compounded by population, rate of consumption, and toxic emissions per unit of resource consumed. This article defines industrial ecology as a management science that focuses a corporation's expertise on the third variable. Thus, industrial ecology is involved with changing the efficiency of machines, not just changing the law or a firm's compliance strategy. This article also explores how this emphasis allows a profoundly different orientation than the end-of-the-pipe regulatory approach of the last 20 yr. PMID- 11607272 TI - Remarks on industrial ecology. PMID- 11607273 TI - Industrial ecology: reflections on a colloquium. AB - Industrial ecology is the network of all industrial processes as they may interact with each other and live off each other, not only in the economic sense, but also in the sense of direct use of each other's material and energy wastes and products. This paper, which reflects upon the papers and discussions at the National Academy of Sciences Colloquium on Industrial Ecology on May 20-21, 1991, is structured around 10 questions. Do sociotechnical systems have long-range environmental goals? How is the concept of industrial ecology useful and timely? What are environmental technologies? Is there a systematic way to choose among alternatives for improving the ecology of technologies? What are ways to measure performance with respect to industrial ecology? What are the sources and rates of innovation in environmental technologies? How is the market economy performing with respect to industrial ecology? What will be the effect of the ecological modernization of the developed nations of the North on the developing countries of the South? How can creative interaction on environmental issues be fostered among diverse social groups? How must research and education change? PMID- 11607274 TI - Friedel-Crafts phenylethylation of benzene and toluene with alpha- and beta phenylethyl chlorides: pi-aryl participation in polarized donor-acceptor beta phenylethylating complexes distinct from phenonium ions (sigma complexes). AB - Friedel-Crafts alpha-phenylethylation of benzene and toluene, compared with beta phenylethylation, shows a low ratio of ortho/para substitution with only 2-3% meta isomer formation, with kT/kB rate ratios between 58 and 76. The data indicate late arenium ion (sigma complex)-like transition states. beta Phenylethylation in contrast gives low kT/kB rate ratios with a substantially higher ortho/para isomer ratio of 17-21% for the meta substituent. Experimental evidence points to thermodynamically controlled isomerizations effecting results. The data also indicate formation of an oriented pi-complex involving phenyl participation (as contrasted with complete phenonium ion formation) in the alkylation intermediates of the beta-phenylethylation reactions. PMID- 11607275 TI - Two levels of alliance formation among male bottlenose dolphins (Tursiops sp.). AB - In Shark Bay, Western Australia, male bottlenose dolphins (Tursiops sp.) cooperate in pairs and triplets to sequester and control the movements of females. We refer to this behavior as "herding" and to the male pairs and triplets as alliances. During a 25-month study (1987-1989) on the social relationships of males, we documented herding in 10 alliances. Males preferentially herded nonpregnant females likely to be in estrus. Alliance members associated with one another consistently when not herding females. Each alliance associated preferentially with one or two other alliances. Occasionally, two alliances combined and took females from another alliance or defended females against such efforts. This study documents multiple-level male alliances within a social group outside of humans. PMID- 11607276 TI - Magic numbers for metallic clusters and the principle of maximum hardness. AB - It is shown that for relatively more stable metallic clusters (those with magic number of atoms) the chemical hardness (I-A) too is relatively larger. Thus the occurrence of magic numbers for metal clusters whose stability is determined by their electronic shell structure can be understood as a manifestation of the principle of maximum hardness. This may also represent a possible way of delineating clusters with stability dominated by their electronic shell structure from those for which the magic numbers occur as a result of their geometric structure. PMID- 11607277 TI - Conserved energy without work or heat. AB - By merely observing the common empirical temperature that two like subsystems in contact reach, as a recordable function of their initial empirical temperatures and specific volumes, we can deduce logically a conserved energy function that depends only on empirical temperature and specific volume. What makes possible this offbeat 18th-century inference, quite free of any 19th-century concepts of "heat" or measurable mechanical work, is the Invariance Law of nature, whereby any four like subsystems must settle down to the same common temperatures regardless of which two-by-two pairings are made-so to speak, an "independence of path" property. Mathematically, the Invariance Law imposes Abel-like functional equations on the admissible functions. Remarkably, recourse to such temperature equalization data renders it impossible to identify one constant in the energy function. By observing how two quite different substances come into equilibrium, or by utilizing "adiabatic slopes" at two points for one substance, or by observing its expansion into a vacuum, we can determine all its unknowns. Much of conventional expositions of the First and Second Laws seems derivable from the equation of state and the First Law's energy function. PMID- 11607278 TI - Calcification in marine molluscs: how costly is it? AB - Although crucial to our understanding of skeletal evolution in marine invertebrates, the cost of calcification has remained elusive for a simple reason: CaCO3 is an inorganic material. Its cost thus derives solely from the metabolic expenses of accumulating, transporting, and precipitating CaCO3 and cannot normally be separated from other metabolic costs. Traditionally, calcification cost has been ignored and total shell cost has been assumed to derive solely from skeletal organic matrix. The cost estimated here was permitted by the substantial natural variation in shell thickness in two rocky-shore gastropods (Nucella lamellosa and Nucella lapillus). In both the field and laboratory, data from three separate experiments revealed that groups of snails producing extra shell material under a particular set of experimental conditions also consumed extra food. The cost of calcification was estimated by computing the extra energy assimilated per unit extra shell produced at a common rate of tissue growth and then subtracting the cost of the organic matrix. At 1-2 J/mg of CaCO3, the calcification cost reported here is roughly 5% of that for the predominantly proteinaceous organic fraction of molluscan shells on a per-gram basis. This may explain why calcareous microstructures high in organic content have become less common evolutionarily. PMID- 11607279 TI - Reversible and irreversible intermediates during photoinhibition of photosystem II: stable reduced QA species promote chlorophyll triplet formation. AB - Photoinhibition of photosynthesis was studied in isolated photosystem II membranes by using chlorophyll fluorescence and electron paramagnetic resonance (EPR) spectroscopy combined with protein analysis. Under anaerobic conditions four sequentially intermediate steps in the photoinhibitory process were identified and characterized. These intermediates show high dark chlorophyll fluorescence (Foi) with typical decay kinetics (fast, semistable, stable, and nondecaying). The fast-decaying state has no bound QB but possesses a single reduced QA species with a 30-s decay half-time in the dark (QB, second quinone acceptor; QA, first quinone acceptor). In the semistable state, Q-A is stabilized for 2-3 min, most likely by protonation, and gives rise to the Q-A Fe2+ EPR signal in the dark. In the stable state, QA has become double reduced and is stabilized for 0.5-2 hr by protonation and a protein conformational change. The final, nondecaying state is likely to represent centers where QA H2 has left its binding site. The first three photoinhibitory states are reversible in the dark through reestablishment of QA to QB electron transfer. Significantly, illumination at 4 K of anaerobically photoinhibited centers trapped in all but the fast state gives rise to a spinpolarized triplet EPR signal from chlorophyll P680 (primary electron donor). When oxygen is introduced during anaerobic illumination, the light-inducible chlorophyll triplet is lost concomitant with induction of D1 protein degradation. The results are integrated into a model for the photoinhibitory process involving initial loss of bound QB followed by stable reduction and subsequent loss of QA facilitating chlorophyll P680 triplet formation. This in turn mediates light-induced formation of highly reactive and damaging singlet oxygen. PMID- 11607280 TI - Practical zero-shift tuning in geonium. AB - Compositeness of the electron may show up in a very small deviation of the measured electron g factor from one calculated for a point electron by quantum electrodynamics. The precision of our g measurements is currently limited by an interaction of the cyclotron motion with standing waves in the trap cavity containing the electron. The important element introduced here is the systematic exploration of the trap cavity modes and the electron's coupling to them by measuring the shifted electron g factor gc = gc(omega e) as a function of the cyclotron frequency omega e. By measuring gc values at five different omega e values and modeling the trap cavity by six lumped LC circuits, the L values for the four most important modes may be determined and finally the unshifted g value may be extracted. Auxiliary experiments are relied upon only for the L values of the two least critical cavity modes. By designing the trap as a high-Q microwave cavity, an electron cyclotron and anomaly resonance linewidth one or even two orders of magnitude narrower than in free space may be approached without introducing appreciable frequency shifts. PMID- 11607281 TI - Changes in cytosolic pH and calcium of guard cells precede stomatal movements. AB - Stomatal opening is induced by indoleacetic acid (IAA), cytokinins, and fusicoccin (FC), whereas stomatal closure is induced by abscisic acid (ABA). To test the effect of these growth regulators on guard cell cytosolic Ca2+ ([Ca2+]cyt) and pH (pHcyt), epidermal strips were taken from the lower side of leaves of the orchid Paphiopedilum tonsum and were loaded with acetomethoxy esterified forms of the Ca2+ indicator fluo-3 or the pH indicator 2',7'-bis(2 carboxyethyl)-5(6)carboxyfluorescein. Basal [Ca2+]cyt ranged from 0.05 to 0.3 M and was 0.22 +/- 0.015 (n = 21). Increases in both [Ca2+]cyt and pHcyt were observed in guard cells after application of 10-100 M ABA to open stomata, and these preceded stomatal closure. The increase in [Ca2+]cyt ranged from 1.5- to 3 fold and was seen in 7 of 10 experiments. Guard cell alkalinization began within 2 min of ABA treatment and continued for the next 8 min. The increase ranged from 0.04 to 0.3 pH unit and was seen in 13 of 14 experiments. Guard cell [Ca2+]cyt increased, whereas pHcyt decreased after treatment of closed stomata with IAA, kinetin, or FC. In response to 50-100 M IAA, [Ca2+]cyt increased 1.5- to 2-fold in all cases, and pHcyt decreased 0.2-0.4 unit within 5 min in 7 experiments. Within 12 min, 10-100 M kinetin caused [Ca2+]cyt to increase in 28 of 34 experiments (1.3- to 2.5-fold) and pHcyt fell 0.1-0.4 unit in 15 of 17 treatments. The response to 10-50 M FC was similar in both time and magnitude. These results show that stomatal opening is accompanied by an increase in [Ca2+]cyt and cytosolic acidification in the guard cells, whereas stomatal closure is preceded by an increase in [Ca2+]cyt and cytosolic alkalinization in the guard cells. The order of these events is still uncertain, but changes in pHcyt are correlated with stomatal movement, and these changes may be an important factor in the regulation of guard cell movement. PMID- 11607282 TI - Caribbean biogeography: molecular evidence for dispersal in West Indian terrestrial vertebrates. AB - The geological association of the Greater Antilles with North and South America in the late Cretaceous led to the hypothesis that the present Antillean biota reflects those ancient land connections. Molecular data from diverse West Indian amphibians and reptiles and their mainland relatives support a more recent derivation of the Antillean vertebrate fauna by overwater dispersal. The catastrophic bolide impact in the Caribbean region at the close of the Cretaceous provides a proximate cause for the absence of an ancient West Indian biota. PMID- 11607283 TI - Involvement of tyrosine residues in the tanning of proteins by 3 hydroxyanthranilic acid. AB - The binding of oxidized phenolic compounds to proteins is of importance in a number of biological systems, including the sclerotization of insect cuticle and the tanning of cocoons. 3-Hydroxyanthranilic acid (3HAA), an aminophenol, is a tryptophan metabolite that undergoes autoxidation readily, and proteins incubated in the presence of 3HAA and oxygen become colored and oxidized. Some moth species are thought to employ this reactivity of 3HAA with proteins for the tanning of cocoons, but the detailed mechanism of this process has not been studied previously. We show that one reaction pathway involves the covalent coupling of 3HAA with tyrosine to form a benzocoumarin derivative, a dibenzo[b,d]pyran-6-one. The stability of the benzocoumarin to conditions of acid hydrolysis normally used for protein digestion has enabled the isolation of the tyrosine adduct from bovine serum albumin that had been incubated with 3HAA. The adduct was also isolated from cocoons of Samia cynthia and Hyalophora gloveri, two species of moths reported to utilize 3HAA for cocoon tanning. These findings indicate that one mechanism of interaction of 3HAA with proteins involves a radical-radical coupling with tyrosine residues. PMID- 11607284 TI - Axial distances in discrete Mobius groups. AB - We describe here new lower bounds for the trace of the commutator of a discrete two-generator group of Mobius transformations. These results lead to sharp estimates for the distance between the axes of elliptics in a discrete group and hence to new bounds for the volume of hyperbolic manifolds and orbifolds that will be discussed elsewhere. PMID- 11607285 TI - Jasmonic acid is a signal transducer in elicitor-induced plant cell cultures. AB - To deter pathogenic microorganisms and herbivores, plants have developed an inducible chemical defense system. It is known that the induced synthesis of low molecular weight compounds can be provoked by exposing cultured cells to fungal cell wall fragments. In this study we show that endogenous jasmonic acid and its methyl ester accumulate rapidly and transiently after treatment of plant cell suspension cultures of Rauvolfia canescens and Eschscholtzia californica with a yeast elicitor. Thirty-six plant species tested in cell suspension culture could be elicited with respect to the accumulation of secondary metabolites by exogenously supplied methyl jasmonate. Addition of methyl jasmonate initiates de novo transcription of genes, such as phenylalanine ammonia lyase, that are known to be involved in the chemical defense mechanisms of plants. These data demonstrate the integral role of jasmonic acid and its derivatives in the intracellular signal cascade that begins with interaction of an elicitor molecule with the plant cell surface and results, ultimately, in the accumulation of secondary compounds. PMID- 11607287 TI - Multiple occurrences of mutualism in the yucca moth lineage. AB - The complex mutualism between yuccas and the moths that pollinate their flowers is regarded as one of the most obvious cases of coevolution. Studies of related genera show that at least two of the critical behavioral and life history traits suggested to have resulted from coevolved mutualism in yucca moths are plesiomorphic to the family. Another trait, oviposition into flowers, has evolved repeatedly within the family. One species with these traits, Greya politella, feeds on and pollinates plants of a different family, but pollination occurs through a different component of the oviposition behavior than in the yucca moths. Major differences compared with yucca moths and their hosts are that G. politella only passively pollinates its host and that copollinators often contribute to pollination. This analysis suggests that evolution of mutualism between yuccas and yucca moths may have required few behavioral and life history changes in the moths. The truly coevolved features of this interaction appear to be the evolution of active pollination by the moths, the associated morphological structures in the moths for carrying pollen, and the exclusion of copollinators by yuccas. PMID- 11607286 TI - Synthesis of the early light-inducible protein is controlled by blue light and related to light stress. AB - The early light-inducible proteins (ELIPs) are expressed in developing plants in the first hours of the greening process. Here we report that strong light causing photoinhibition of photosynthesis also induces ELIP transcription and accumulation of the protein in mature green pea plants. Accumulation of ELIP transcript is induced in plants exposed to light intensities above 500 E/m2.s (E, einstein) and is maximal at approximately 1500 E/m2.s. The ELIP mRNA level increases in correlation with the degree of photoinhibition. The increase in ELIP level in the thylakoid membranes parallels the decrease in the amount of D1 protein of the photosystem II reaction center. Examination of ELIP induction as a function of light quality demonstrates that ELIP transcription is specifically induced by blue (410-480 nm) but not by red or far-red light. The level of blue light-induced ELIP transcript is significantly repressed by low-intensity red light. However, the accumulation of ELIP translation product is related to the total amount of blue and red light energy absorbed. PMID- 11607288 TI - A chemical approach to designing Turing patterns in reaction-diffusion systems. AB - A systematic approach is suggested to design chemical systems capable of displaying stationary, symmetry-breaking reaction diffusion patterns (Turing structures). The technique utilizes the fact that reversible complexation of an activator species to form an unreactive, immobile complex reduces the effective diffusion constant of the activator, thereby facilitating the development of Turing patterns. The chlorine dioxide/iodine/malonic acid reaction is examined as an example, and it is suggested that a similar phenomenon may occur in some biological pattern formation processes. PMID- 11607289 TI - A conjecture of Procesi and the straightening algorithm of Rota. AB - Let R = Q[x1, x2,..., xn] and R* denote the quotient of R by the ideal generated by the elementary symmetric functions. R*, under the action of Sn, yields a graded version of the left regular representation. Procesi asked for a basis of R* consisting of homogeneous polynomials Gamma[S, C] indexed by pairs of tableaux, with S standard and C cocharge, that exhibits the decomposition of R* into its irreducible components. Procesi also suggested a way to construct the Gamma[S, C]. Using Rota's straightening algorithm, I show that certain polynomials [S, C] closely related to the Gamma[S, C] terms yield the desired basis. Parallel to the ring R* there is a family of Sn-modules R that have recently been studied by Garsia and Procesi. These modules have a graded character that is closely related to the q-Kostka-Foulkes polynomials Klambdamu(q). The [S, C] can be shown to yield also a basis when restricted to a given R. Through this connection the work reported here leads to an additional way of proving the charge interpretation for the polynomials Klambdamu(q). PMID- 11607290 TI - Graviton scattering and matter distribution. AB - In this model gravitation results from the emission and absorption of quanta (gravitons) that are scattered a few times in crossing a typical galaxy. Many features of the universe can be explained in terms of this model, although theoretical justification for the scattering of gravitons is lacking. Gravitons follow a random walk and diffuse through the outer regions of a galaxy. As a result the force of attraction follows a 1/R law, matching observed galactic rotation curves and explaining galactic dynamics without the need of dark matter. The model makes predictions regarding early stages in the expansion of the universe and the establishment of the mass distribution. It may be assumed that a nearly uniform expanding cloud of gas was present that was subject to collapse under gravitational forces. The 1/R law of attraction due to graviton diffusion is orders of magnitude more effective for initiation of collapse than the inverse square law, and it applies to blocks of gas larger than the graviton mean free path. Delay in the spread of gravitational attraction by diffusion sets a time dependent range beyond which the attractive force is zero. In the model this causes arrays of matter to collapse locally into zones with a spacing set by the length of the range of the attractive force. An initial examination indicates that under these conditions the background radiation could have been released from a nearly uniform distribution at the time of decoupling of radiation and matter, followed by gravitational collapse into blocks of galactic mass. In the model the diffusion of gravitons continued and collapse became possible on a larger scale, initiating the formation of galactic clusters and still larger structures. The slow rate of diffusion then prevented the largest structures from attracting each other and permitted the formation of the voids on a very large scale. The model predicts that on the largest scale there is a three-dimensional repeated array of structures separated by voids. Ultimately structures larger than galactic clusters outran the diffusion of the gravitons and have since been freely expanding. PMID- 11607291 TI - Casimir energy for dielectrics. AB - A treatment in terms of two scalar fields supplies the electromagnetic energy of attraction between two similar dielectric slabs with parallel plane interfaces. PMID- 11607292 TI - Extension growth of the water mold Achlya: interplay of turgor and wall strength. AB - When hyphae of the water mold Achlya were subjected to osmotic stress, imposed with polyethylene glycol (PEG)-300 or sucrose, turgor pressure fell in proportion to the increase in external osmotic pressure. There was no evidence of turgor regulation, even over a period of days, yet the extension rate was unaffected until turgor was reduced to less than a third of the normal level of 0.6-0.8 MPa (6-8 bars). Measurements of the pressure at which the hyphae burst indicate that they respond to osmotic stress by softening their apical cell walls, sustaining extension growth despite reduced turgor pressure. The effect of osmolytes excluded by the wall was very different; superfusion of growing hyphae with PEG 6000 or dextran-6000 reduced turgor and stopped extension but did not induce wall softening. Furthermore, the hyphae did not resume growth during an hour or more of continuous exposure to these substances. Although the two classes of osmolytes have the same effect on turgor, they may induce different strains within the cell wall; this might then affect the capacity of the organism to detect the drop in turgor or to soften its cell wall. The interplay between turgor and wall strength supports the proposition that turgor supplies the driving force for extension and that production of the standard hyphal form requires a balance between hydrostatic pressure and a resistive cell wall. PMID- 11607293 TI - Approximating Markov chains. AB - A common framework of finite state approximating Markov chains is developed for discrete time deterministic and stochastic processes. Two types of approximating chains are introduced: (i) those based on stationary conditional probabilities (time averaging) and (ii) transient, based on the percentage of the Lebesgue measure of the image of cells intersecting any given cell. For general dynamical systems, stationary measures for both approximating chains converge weakly to stationary measures for the true process as partition width converges to 0. From governing equations, transient chains and resultant approximations of all n-time unit probabilities can be computed analytically, despite typically singular true process stationary measures (no density function). Transition probabilities between cells account explicitly for correlation between successive time increments. For dynamical systems defined by uniformly convergent maps on a compact set (e.g., logistic, Henon maps), there also is weak continuity with a control parameter. Thus all moments are continuous with parameter change, across bifurcations and chaotic regimes. Approximate entropy is seen as the information theoretic rate of entropy for approximating Markov chains and is suggested as a parameter for turbulence; a discontinuity in the Kolmogorov-Sinai entropy implies that in the physical world, some measure of coarse graining in a mixing parameter is required. PMID- 11607294 TI - Sobolev inequalities, the Poisson semigroup, and analysis on the sphere Sn. AB - Hypercontractive estimates are obtained for the Poisson semigroup on Lp(Sn). Such estimates are determined by a sharp logarithmic Sobolev inequality that relates the entropy of a function on Sn to its smoothness. PMID- 11607295 TI - Limit theorems for random trees. AB - This paper is concerned with random rooted trees and studies the distribution of the vertices according to their altitude. If the trees are chosen at random with an increasing number of vertices, then, by a suitable normalization, the distribution function of the number of vertices at a given altitude and the distribution function of the total height approach specific limits. Explicit formulas are given for these limit distribution functions and their moments. PMID- 11607296 TI - Monitoring electron spin by running geonium atom as microaccelerator. AB - Following the classic work of McMillan and of Bohm and Foldy, we have developed a phase equation describing the microsynchrocyclotron acceleration process in geonium. By computer integration of this equation, we are able to confirm that, by making use of the slight relativistic spin dependence of the zero-energy cyclotron frequencies, the acceleration process can be made selective enough to distinguish between spin-up and spin-down states. Quantum effects have been allowed for approximately. PMID- 11607297 TI - Ribosomal gene clusters are uniquely proportioned between open and closed chromatin structures in both tomato leaf cells and exponentially growing suspension cultures. AB - The accessibility of regulatory molecules to specific DNA sequences and chromatin regions in the nucleus is crucial to gene expression. In this study, we examined the chromatin structure in tomato leaf cells and in exponentially growing tomato cell suspension cultures. The structure of ribosomal chromatin was investigated by micrococcal nuclease and psoralen photocrosslinking. We showed that ribosomal genes in tomato are folded into two distinct types of chromatin: an open chromatin conformation and a closed nucleosomecontaining chromatin. In contrast to previous findings in Friend cells, where half of the ribosomal genes were found to be complexed within an inactive chromatin structure, we demonstrated that the canonical nucleosome-containing chromatin is present in the majority (approximately 80%) of the tomato rRNA-encoding DNA clusters. The minor open chromatin population (approximately 20% of the ribosomal genes) could be detected only after analysis following psoralen crosslinking. The relative amounts of the two ribosomal chromatin structures are similar in stationary and exponentially growing cells. This suggests that the proportions of open and closed chromatin structures present in either stationary or exponentially growing tomato cells are not dependent on the transcriptional process. PMID- 11607298 TI - On the relationship between bird and woody plant species diversity in the Uttara Kannada district of south India. AB - Bird species richness is inversely related to woody plant species diversity and vertical stratification in the natural vegetation of Uttara Kannada, the district with the largest contiguous tract of humid tropical forest in peninsular India. This inverse relationship may be explained by the fact that although the peninsular Indian evergreen forests are rich in woody plant species when compared with the drier vegetation, they harbor an impoverished bird fauna due to their smaller overall extent and greater isolation. Much of this impoverishment is accounted for by the absence of many species of understory timaliids characteristic of the humid evergreen forests of the Eastern Himalayas and Southeast Asia. The plantations of Uttara Kannada largely derive their bird fauna from the drier vegetation and exhibit the commoner trend of a positive correlation between bird species richness and vertical stratification of the vegetation. PMID- 11607299 TI - Genetic organization of a repeated DNA sequence family in the rice blast fungus. AB - The fungal rice pathogen Magnaporthe grisea contains repetitive DNA sequences called MGR. We have used a DNA probe, MGR586, derived from these sequences and crosses between rice-pathogenic and non-rice-pathogenic laboratory strains of M. grisea to rapidly map genes in this organism. The rice-pathogenic strain contained 57 EcoRI restriction fragments that hybridize to the MGR586 probe; the other five non-rice-pathogenic parent strains contained a single MGR586 sequence. Genetic analysis of MGR segregation detected eight linkage groups and allowed the mapping of three pigmentation genes (Alb1, Rsy1, and Buf1), the mating type locus (Mat1), the nucleolar organizer (Rdn1), the Smol gene, and two restriction fragment length polymorphisms linked to Smol. Our results indicate that the MGR586 loci are randomly distributed about the M. grisea genome and permit the construction of a well-marked linkage map useful for future studies on genome organization and genetic analysis in M. grisea. PMID- 11607300 TI - Control of excision frequency of maize transposable element Ds in Petunia protoplasts. AB - The complete coding region of maize transposable element Ac and truncated but active derivatives of it were placed under the control of promoters of different strength and tested for the ability to excise transposable element Ds from a beta glucuronidase reporter gene in a cotransfection assay in Petunia protoplasts. The highest excision values (5% of the protoplasts able to express the beta glucuronidase gene in a control experiment) were observed with a truncated version of the Ac coding region under the control of the 2' promoter. The weak Ac promoter is sufficient to give rise to excision values not much lower than those found with much stronger promoters such as the 2' and nos promoters. A decrease in excision frequency was observed when translation of the Ac coding region was hindered by out-of-frame ATG codons in addition to the use of weak promoters. Increasing the level of Ac transposase thus does not seem to be sufficient to raise the level of Ds excision observed in this system and possibly also in maize. Therefore another factor limits the excision of Ds elements. Previously, it was reported that in tobacco cells the deletion of Ds sequence between base pairs 186 and 245 led to a decrease of the Ds excision frequency by the full length but not by the truncated Ac product. In the Petunia assay system, however, deletion of these sequences decreased the excision rate with both the full length and the truncated Ac coding region. A cDNA construct was found similarly active as the corresponding genomic DNA. PMID- 11607302 TI - Constant mean curvature surfaces constructed by fusing Wente tori. AB - Closed smooth surfaces of any genus g >/= 2, immersed in E3 and of constant mean curvature, are constructed, by "fusing" Wente tori. PMID- 11607301 TI - Involvement of a chloroplast HSP70 heat shock protein in the integration of a protein (light-harvesting complex protein precursor) into the thylakoid membrane. AB - Molecular chaperones, including those belonging to the 70-kDa family of heat shock proteins (HSP70), assist both the translocation of proteins across membranes and their assembly into oligomeric complexes. We purified a chloroplast HSP70 (ct-HSP70) and demonstrated that it plays a major role in the insertion of the precursor of the major light-harvesting complex of photosystem II (pLHCP; an integral membrane protein) into the thylakoids (the inner membranes of the chloroplast). Addition of the purified ct-HSP70 is necessary for efficient insertion of pLHCP into isolated thylakoid membranes. This activity of the purified ct-HSP70 is similar to that previously reported for the total stromal extract. When the chloroplast stromal extract is depleted of HSP70, a correlative reduction in the insertion activity of pLHCP is observed. The interaction between the ct-HSP70 and pLHCP involves physical association. The purified HSP70 acts directly on the membrane protein, presumably prevents its refolding, and thereby helps to maintain its competence for insertion into membranes. PMID- 11607303 TI - Inhibition of assimilatory nitrate reductase activity in soil by glutamine and ammonium analogs. AB - Recent work in our laboratory indicated that the inhibitory effect of ammonium (NH4+) on assimilatory nitrate reductase (ANR) activity in soil is not due to NH4+ per se but to glutamine formed by microbial assimilation of NH4+. To test this conclusion, we studied the effects of eight analogs of L-glutamine (L glutamic acid gamma-methyl ester, L-glutamic acid gamma-hydrazide, L-glutamic acid gamma-hydroxamate, L-glutamic acid gamma-ethyl ester, L-glutamic acid dimethyl ester, L-asparagine, L-aspartic acid beta-methyl ester, and L-aspartic acid beta-hydroxamate) and two analogs of ammonium (hydroxylamine and methylamine) on ANR activity in soil slurries. The studies with the L-glutamine analogs showed that all except L-glutamic acid dimethyl ester inhibited ANR activity in soil. The sharp contrast observed between the strong inhibitory effect of L-glutamic acid gamma-methyl ester on ANR activity and the complete lack of an inhibitory effect with the corresponding dimethyl ester suggests that only the free-acid form of glutamine effectively inhibits ANR activity. The studies with hydroxylamine and methylamine showed that both of these ammonium analogs inhibited ANR activity in soil and that this inhibition was dependent upon glutamine synthetase activity. This dependence indicates that inhibition of ANR activity by hydroxylamine and methylamine was due to formation of the glutamine analogs L-glutamic acid gamma-hydroxamate and L-glutamic acid gamma methylamide, respectively. These observations support the conclusion that the inhibitory effect of NH4+ on ANR activity in soil is due to glutamine formed by microbial assimilation of NH4+. PMID- 11607304 TI - Preliminary representation of world population by spherical harmonics. AB - The geographical arrangement of people on the surface of the earth is approximated by a mathematical equation of 361 terms. This is a convenient form for comparison with other distributions and for use in global change studies, and it has other advantages, but it must be considered preliminary because of data limitations. PMID- 11607305 TI - A cyclic peptide synthetase gene required for pathogenicity of the fungus Cochliobolus carbonum on maize. AB - Specificity in many plant-pathogen interactions is determined by single genes in pathogen and host. The single locus for host-selective pathogenicity (TOX2) in the fungus Cochliobolus carbonum governs production of a cyclic tetrapeptide named HC-toxin. We have isolated a chromosomal region, 22 kilobases (kb) long, that contains a 15.7-kb open reading frame (HTS1) encoding a multifunctional cyclic peptide synthetase. The 22-kb chromosomal region is duplicated in toxin producing isolates of the fungus but is completely absent from the genomes of toxin-nonproducing isolates. Mutants of the fungus with disruptions in both copies of HTS1, at either of two different sites within HTS1, were engineered by DNA-mediated transformation. Disruption of both copies at either site resulted in loss of ability to produce HC-toxin and loss of host-selective pathogenicity, but the mutants displayed different biochemical phenotypes depending on the site of disruption. The results demonstrate that TOX2 encodes, at least in part, a large, multifunctional biosynthetic enzyme and that the evolution of host range in C. carbonum involved the insertion or deletion of a large piece of chromosomal DNA. PMID- 11607306 TI - Wood contains a cell-wall structural protein. AB - A pine extensin-like protein (PELP) has been localized in metabolically active cells of differentiating xylem and in mature wood of loblolly pine (Pinus taeda L.). This proline-rich glycosylated protein was purified from cell walls of differentiating xylem by differential solubility and gel electrophoresis. Polyclonal rabbit antibodies were raised against the deglycosylated purified protein (dPELP) and purified antibody was used for immunolocalization. Immunogold and alkaline phosphatase secondary antibody staining both show antigen in secondary cell walls of earlywood and less staining in latewood. Immunoassays of milled dry wood were developed and used to show increased availability of antigen after hydrogen fluoride or cellulase treatment and decreased antigen after chlorite treatment. The specificity of the antigen-antibody reaction was confirmed by competition assays and by preadsorption of antibody to the purified protein. We propose that extensin-like protein is present in xylem cell walls during lignification and that the protein remains as a structural component of cell walls in wood for many years after xylogenesis. We suggest that such structural proteins play important roles in the differentiation of xylem and thereby could affect the properties of wood. PMID- 11607307 TI - Vicariance biogeography in the Pleistocene and speciation in North American wood warblers: a test of Mengel's model. AB - It is widely believed that habitat fragmentation during the Pleistocene initiated speciation events in many songbird genera. One such vicariance model for avian speciation in the Pleistocene was developed by R. M. Mengel for North American birds. This model suggests that the first Pleistocene glacial advance reduced the area of an extensive, eastern North American deciduous forest, forcing adaptation by some species to boreal forest. This, in turn, facilitated the development of transcontinental range expansions during interglacials. Subsequent glacial advances repeatedly fragmented the ranges of these species into eastern and western populations; western isolates speciated to form the multispecies groups observed among various North American birds. We used mtDNA restriction site data to reconstruct the phylogeny of the black-throated green warbler complex-the group that Mengel considered the best fit to his model. Contrary to Mengel's model, the phylogeny indicates that not all western endemics were derived from an eastern ancestor. Instead, our results imply a mix, wherein some western endemics were budded off an eastern source, as Mengel posits, while others probably resulted from intermontane isolations in the west. PMID- 11607308 TI - Comparison of the nitration of polyfluoronitrobenzenes by nitronium salts in superacidic and aprotic media: activation of the nitronium ion by protosolvation. AB - The reactivity of nitronium tetrafluoroborate in the nitration of deactivated di- and trifluoronitrobenzenes is enhanced in superacidic trifluoromethanesulfonic (triflic) acid compared with aprotic methylene chloride and sulfolane solutions. The enhanced reactivity is discussed in terms of better solubility and higher dissociation of the nitronium salts, as well as protosolvation of NO2+ by superacids. PMID- 11607309 TI - Note on the form of the metric for an isolated vortex in general relativity. AB - Calling a metric semidiagonal if it has a single off-diagonal element g t, we show that the stationary interior solution for a cylindrically symmetrical perfect fluid possessing an angular momentum cannot have a semidiagonal metric, unless the motion of the fluid particles is purely rotational around the axis of symmetry. A discussion is given of the relativistic spherical vortex in flat space, with a view of seeking a solution for such an isolated vortex in which gravitation is not neglected. PMID- 11607310 TI - One-step generation of cytoplasmic male sterility by fusion of mitochondrial inactivated tomato protoplasts with nuclear-inactivated Solanum protoplasts. AB - Mesophyll protoplasts of Lycopersicon esculentum were treated with iodoacetamide to inactivate mitochondria, and protoplasts of Solanum acaule and Solanum tuberosum were irradiated with gamma- or x-rays to inactivate nuclei. Mixtures of protoplasts thus modified were treated with Ca2+ and polyethylene glycol to obtain heterologous fusion products. Among the fusion products were some tomato plants that were indistinguishable from the original cultivars with respect to morphology, physiology, and chromosome number (2N = 24) but exhibited various degrees of male sterility (MS): complete lack or malformation of anthers, shrunken pollen, and normal-looking stainable pollen that could not germinate. The MS thus induced in five cultivars of different growth types, including one of subspecies L. esculentum cerasiforme, was inherited maternally over several generations and is, therefore, cytoplasmically determined MS (CMS). Analysis of mitochondrial DNA revealed that the mitochondrial genome of the CMS hybrids does not contain all elements of the mitochondrial DNA of either parent but includes sequences of a recombinational nature not present in either parent. The CMS hybrids, therefore, possess a true hybrid mitochondrial genome. The same procedure applied to fusion of tomato with Solanum lycopersicoides and Nicotiana tabacum cells did not produce CMS phenotypes. The advantages of this method over others for generating MS are as follows: (i) only one step is required; (ii) the nuclear genotype of the cultivar is unaffected; (iii) the prospect that cytoplasmic determination allows generation of 100% CMS progenies. The normal appearing but nonfunctional pollen of certain CMS types might render them attractive to pollinating bumblebees that thus would facilitate production of hybrid seed. PMID- 11607311 TI - Methyl jasmonate inhibition of root growth and induction of a leaf protein are decreased in an Arabidopsis thaliana mutant. AB - Jasmonic acid and its methyl ester, methyl jasmonate (MeJA), are plant signaling molecules that affect plant growth and gene expression. Primary root growth of wild-type Arabidopsis thaliana seedlings was inhibited 50% when seedlings were grown on agar medium containing 0.1 M MeJA. An ethyl methanesulfonate mutant (jar1) with decreased sensitivity to MeJA inhibition of root elongation was isolated and characterized. Genetic data indicated the trait was recessive and controlled by a single Mendelian factor. MeJA-induced polypeptides were detected in Arabidopsis leaves by antiserum to a MeJA-inducible vegetative storage protein from soybean. The induction of these proteins by MeJA in the mutant was at least 4-fold less in jar1 compared to wild type. In contrast, seeds of jar1 plants were more sensitive than wild type to inhibition of germination by abscisic acid. These results suggest that the defect in jar1 affects a general jasmonate response pathway, which may regulate multiple genes in different plant organs. PMID- 11607313 TI - Analysis of gamma-ray energies for 56 excited superdeformed rotational bands of nuclei of lanthanons La to Dy and of Hg, Tl, and Pb on the basis of the two revolving-cluster model, with evaluation of moments of inertia and radii of revolution and assignment of nucleonic compositions to the clusters and the central sphere. AB - Analysis of the gamma-ray energies of 28 excited superdeformed bands of lanthanon nuclei by application of the two-revolving-cluster model yields the result that the central sphere for all 28 has the semimagic-magic composition p40n50, with the range p8n12 to p14n18 for the clusters and the radius of revolution increasing from 7.31 to 7.76 fm. Similar analysis of 28 excited bands of Hg, Tl, and Pb nuclei leads to p56n82 (semimagic-magic) for the central sphere of 24 bands, p64n82 (semimagic-magic) for 2, and p64n90 (doubly semimagic) for 2, with cluster range p8n12 to p14n16 and values of the radius of revolution from 8.70 to 8.92 fm for 26 bands and 9.2 fm for 2. PMID- 11607312 TI - Biochemical complementation of chalcone synthase mutants defines a role for flavonols in functional pollen. AB - Chalcone synthase catalyzes the initial step of that branch of the phenylpropanoid pathway that leads to flavonoids. A lack of chalcone synthase activity has a pleiotropic effect in maize and petunia mutants: pollen fertility as well as flavonoid synthesis is disrupted. Both maize and petunia mutants are self-sterile due to a failure to produce a functional pollen tube. The finding that the mutant pollen is partially functional on wild-type stigmas led to the isolation and identification of kaempferol as a pollen germination-inducing constituent in wild-type petunia stigma extracts. We show that adding micromolar quantities of kaempferol to the germination medium or to the stigma at pollination is sufficient to restore normal pollen germination and tube growth in vitro and full seed set in vivo. Further we show that the rescue ability resides in particular structural features of a single class of compounds, the flavonol aglycones. This finding identifies another constituent of plant reproduction and suggests that addition or removal of the flavonol signal during pollen germination and tube growth provides a feasible way to control plant fertility. PMID- 11607314 TI - The 31S0-33P0 transition in the aluminum isotope ion 26A1+: a potentially superior passive laser frequency standard and spectrum analyzer. AB - The aluminum 26 isotope ion is proposed here as a possible candidate for a superior atomic clock. For this even isotope, the extraordinarily long lifetime of the 33P0 state offers a potential clock transition (31S0-33P0) linewidth of 300 microHz. The mF = 0 --> 0 transition has only a quadratic Zeeman shift approximately 4 x 10(-18) at 0.1 Gauss magnetic field, compared to approximately 10(-8) for the hydrogen maser. Electronic quadrupole moments vanish for both J and J' states and with them shifts due to electric field gradients. All shifts have been estimated and are orders of magnitude less than for Hg+ and Ba+, which are being studied as atomic clock elements. PMID- 11607315 TI - Paleozoic record of morphologica diversity in blastozoan echinoderms. AB - There has been extensive debate about the magnitude and implications of morphological diversity in early Paleozoic animals, with some workers using apparently rapid initial diversification to infer unusual evolutionary processes. Analysis of discrete morphological characters shows that initial morphological diversification in the echinoderm subphylum Blastozoa was so pronounced that morphological diversity relative to taxonomic diversity was greatest in the Cambrian, whereas morphological diversity itself was greatest in the Middle and Upper Ordovician. Thus, a small number of Cambrian taxa sparsely occupied a large range in morphological space, whereas subsequent diversification involved expansion and filling of morphospace. A measure of clade-shape asymmetry and a method for statistical testing of clade shape are used to show that morphological diversity is significantly concentrated early in the history of the Blastozoa. The subphylum represents the highest biologic level at which temporal patterns of morphological diversity have been analyzed. Because this study is based on explicit morphological analysis, not taxonomic proxies for morphological diversity, the results are not artifacts of taxonomic practice. PMID- 11607318 TI - Redox state of a one-electron component controls the rate of photoinhibition of photosystem II. AB - Photosystem II reaction centers in plants, algae, and cyanobacteria are susceptible to damage by excess light that irreversibly impairs activity and eventually results in the proteolytic degradation of at least one of the core proteins. The sequence of events and underlying molecular mechanisms that lead to photoinhibition are poorly understood. Here we present evidence for a one electron redox component that exerts strong control over the rate of photosystem II photoinhibition in isolated thylakoid membranes. Monitoring the impact of various doses of visible light on the rate of water oxidation and on the variable chlorophyll fluorescence, we found that reduction of the redox component increased the rate of photoinhibition >15-fold. Anaerobic potentiometric titrations of the rate of photoinhibition revealed a redox component with a midpoint potential near 20 mV at pH 7.5. The titrations fit a Nernst equation for a one-electron reaction and were nearly pH independent. Although we have not yet identified the chemical species being titrated, a likely candidate is lowpotential cytochrome b-559. We believe this observation reveals an electron transfer pathway in photosystem II that functions to protect the reaction center against excess light energy. PMID- 11607319 TI - Broad-spectrum resistance to Bacillus thuringiensis toxins in Heliothis virescens. AB - Evolution of pest resistance to insecticidal proteins produced by Bacillus thuringiensis (Bt) would decrease our ability to control agricultural pests with genetically engineered crops designed to express genes coding for these proteins. Previous genetic and biochemical analyses of insect strains with resistance to Bt toxins indicate that (i) resistance is restricted to single groups of related Bt toxins, (ii) decreased toxin sensitivity is associated with changes in Bt-toxin binding to sites in brush-border membrane vesicles of the larval midgut, and (iii) resistance is inherited as a partially or fully recessive trait. If these three characteristics were common to all resistant insects, specific crop-variety deployment strategies could significantly diminish problems associated with resistance in field populations of pests. We present data on Bt-toxin resistance in Heliothis virescens, a major agricultural pest targeted for control with Bt toxin-producing crops. A laboratory strain of H. virescens developed resistance in response to selection with the Bt toxin CryIA(c). In contrast to other cases of Bt-toxin resistance, this H. virescens strain exhibits cross-resistance to Bt toxins that differ significantly in structure and activity. Furthermore, the resistance in this strain is not accompanied by significant changes in toxin binding, and resistance is inherited as an additive trait when larvae are treated with high doses of CryIA(c) toxin. These findings have important implications for Bt-toxin-based pest control. PMID- 11607320 TI - Evidence for helical structures in poly(1-olefin sulfones) by transmission electron microscopy. AB - Transmission electron microscope images were obtained of fractions of poly(1 tetradecene sulfone) and poly(cyclohexene sulfone) cast from very dilute solutions (0.007%, wt/vol) and rapidly freeze-dried on a mica surface. The samples were then vertically platinum-carbon (Pt-C) replicated with 9 +/- 0.3-A Pt-C and held together with 128 A of electron-transparent evaporated carbon. The Pt-C coating enlarges the molecular chain diameters by approximately 5 A, so that a single polysulfone chain has an apparent diameter of 9-12 A in the transmission electron microscope. Poly(1-tetradecene sulfone) forms short helical regions that show irregular helical turns of pitch 7-18 A, two to eight turns long with apparent helix diameters of 16-22 A. The n-C12H25 side chains were not obvious on the helices, but a few were visible on extended chain sections. In contrast, poly(cyclohexene sulfone) appears as a collection of Pt-C-coated single chains 10 12 A in diameter with no side-chain projections. The presence and absence of helical regions in these freeze-dried polysulfones thus reflects their solution conformations as long ago inferred on the basis of dielectric measurements. PMID- 11607321 TI - Reactions depending on iron sulfide and linking geochemistry with biochemistry. AB - Iron sulfide gives rise to unusual reducing reactions: some dependent on FeS/H2S synergism [NO-3 --> NH3; HC(three bonds)CH--> H2C=CH2, H3C-CH3; -CH2-CO- --> CH=CH-, -CH2-CH2-; HS-CH2-COOH --> CH3-COOH; others dependent on FeS alone [HS CH2-CH2-X --> CH2=CH2 (where X = OH, SH, or NH2)]. The experimental conditions are geochemically plausible: 100 degrees C, aqueous, nearly neutral, and fastidiously anaerobic. These reactions establish additional facts of soil chemistry, organic geochemistry, and the global nitrogen cycle. Further, they point to the common evolutionary denominator of geochemistry and biochemistry. PMID- 11607322 TI - Rate of evolution of a quantitative character. AB - The rate of change of the mean of a quantitative character is evaluated exactly and also under the hypothesis of linear biparental regression. Generations are discrete and nonoverlapping; the monoecious population mates at random. The genotypic and environmental contributions to the character are additive and stochastically independent. The character is influenced by arbitrarily many multiallelic loci and has constant genotypic values; dominance, epistasis, and the linkage map are also arbitrary. The population is initially in linkage equilibrium, and there is no position effect. If the biparental regression is linear, then the regression coefficient is simply Vgam/V, and hence the single generation change in the mean is deltaZ = (Vgam/V)S, where Vgam and V denote the gametic and total variances in the character and S designates the selection differential. The corresponding exact result is DeltaZ = (C/W) + (B/W2), where C, W and B represent the gametic covariance of the character and fitness, the mean fitness, and a correction term, respectively. If selection is weak, then DeltaZ approximately C/W. Furthermore, deltaZ = C/W if either there is no environmental contribution and the gametic effects are additive or the character is fitness itself. In the latter case, C is the gametic variance in fitness. Thus, even in linkage equilibrium, weakness of selection generally does not suffice to validate the linear-regression result. This conclusion holds even for additive loci. PMID- 11607323 TI - Molecular structure of Ti8C12 and related complexes. AB - Application of valence-bond theory leads to the assignment to the molecule Ti8C12 of a cubic structure, point group Ohm3m, with 8 Ti at the cube corners, +/-(x x x, x, x x [symbol, see text]) where x = 1.78 A, and with 12 C in pairs in the cube faces, +/-(0 y z, [symbol, see text], 0, y z [symbol, see text]) where y = 1.78 A and z = 0.71 A. The Ti-C and C-C bonds have bond number 4/3, corresponding to resonance of single and double bonds in 2:1 ratio. PMID- 11607324 TI - Canonical bases in tensor products. AB - I construct a canonical basis in the tensor product of a simple integrable highest weight module with a simple integrable lowest weight module of a quantized enveloping algebra. This basis is simultaneously compatible with many submodules of the tensor product. As an application, I obtain a construction of a canonical basis of (a modified form of) the quantized enveloping algebra. PMID- 11607325 TI - Systemic release of chemical signals by herbivore-injured corn. AB - Corn seedlings respond to insect herbivore-inflicted injury by releasing relatively large amounts of several characteristic terpenoids and, as a result, become highly attractive to parasitic wasps that attack the herbivores. Chemical evidence showed that the induced emission of volatiles is not limited to the sites of damage but occurs throughout the plant. This evidence was obtained by comparing the release of volatiles from leaves of unharmed (control) seedlings with the release of volatiles from undamaged leaves of seedlings with two injured leaves treated with caterpillar regurgitant. Immediately after injury no differences were measured in the released volatiles, but several hours later the undamaged leaves of injured plants released the terpenoids linalool, (3E)-4,8 dimethyl-1,3,7-nonatriene, and (3E,7E)-4,8,12-trimethyl-1,3,7,11-tridecatetraene in significantly larger amounts than leaves of unharmed plants. Other volatiles that are released by herbivore-injured leaves were detected occasionally only in trace amounts from the undamaged leaves of a damaged seedling. The systemic release of volatiles by injured corn coincided with attractiveness to the parasitoid Cotesia marginiventris; undamaged leaves of injured plants became significantly more attractive than leaves from control seedlings. These findings show conclusively that when a plant is injured by an insect herbivore the whole plant emits chemical signals. PMID- 11607326 TI - Transition metals in legume root nodules: iron-dependent free radical production increases during nodule senescence. AB - The cytosol from root nodules of soybean, bean, and cowpea contained Fe and Cu capable of catalyzing the formation of highly reactive free radicals. Specific and sensitive assays based on free radical-mediated DNA degradation revealed that most catalytic Fe and Cu were present as small chelates (300-600 Da). The involvement of catalytic Fe in free radical production during nodule senescence, which was induced by exposure of plants to continuous darkness for 2-4 days, was investigated. (i) Free heme remained at a constant and low concentration (1-4% of total nodule heme) during senescence, indicating that it is not an important constituent of the catalytic Fe pool of nodules. (ii) Catalytic Fe of nodule cytosol promoted deoxyribose degradation and linolenic acid peroxidation in reaction mixtures containing physiological concentrations of ascorbate and H2O2. Deoxyribose degradation but not lipid peroxidation required hydroxyl radicals to proceed. (iii) The cytosol from senescent nodules, particularly of bean and cowpea, sustained in vitro higher rates of deoxyribose degradation and lipid peroxidation than the cytosol from unstressed nodules. Both degradative processes were inhibited by the Fe chelator desferrioxamine and were correlated with the content of catalytic Fe in the nodule cytosol. (iv) Although other transition metals (Cu, Mn, Mo, and Ni) were present in significant amounts in the low molecular mass fraction (<3 kDa) of the nodule cytosol, Fe is most likely the only metal involved in free radical generation in vivo. (v) By using dimethyl sulfoxide as a molecular probe, formation of significant amounts of hydroxyl radical was observed in vivo during senescence of bean and cowpea nodules. PMID- 11607327 TI - Puzzling questions about excited superdeformed rotational bands of atomic nuclei are answered by the two-revolving-cluster model. AB - The two-revolving-cluster model provides explanations of several questions about excited superdeformed bands: restriction to the lanthanons and the Hg-Tl-Pb region and to the smaller values of the neutron number for each element, truncation of the gamma-ray cascades, differences in shape of the lanthanon and Hg-Tl-Pb bands, alignment of quantified spins, and the existence of pairs of bands with nearly identical gamma-ray sequences. A previously unrecognized kind of pairing (intercalation of gamma-ray values) is also reported and a discussion is given of the values of electric quadrupole moments. PMID- 11607328 TI - Oldest fossil flowers of hamamelidaceous affinity, from the Late Cretaceous of New Jersey. AB - Exceptionally well-preserved staminate inflorescences, pistillate inflorescences, and detached stamens with important phylogenetic and paleoecological implications have been discovered from the Turonian (ca. 88.5-90.4 million years B.P.) Raritan Formation of New Jersey. The fossils have a combination of floral and pollen characters found in various genera of modern entomophilous and anemophilous Hamamelidaceae and anemophilous Platanus (Platanaceae). The floral characters of the fossils, including a sepal cup, staminal tube, and apparently nectariferous staminodes, indicate that this taxon was probably insect pollinated. The juxtaposition of character complexes in an extinct taxon from disparate modern taxa provides an interesting phylogenetic perspective on the origins of Hamamelidaceae and is a striking example of a fossil that is a mosaic of familial level characters relative to modern taxa. Of even broader interest, however, is the occurrence of staminodal nectaries that have structural characters intermediate between the fossil's functional stamens and modern hamamelidaceous petals. This transitional staminode morphology in the context of the other fossil characters suggests a staminodal origin of petals in the hamamelid-rosid lineage. This hypothesis is supported by the apparent staminode position within the fossil flowers where petals are found in modern genera. The character complex of morphologically transitional staminodes, a staminal tube, and sepal cup can be viewed as prehypanthial, lacking only fusion of the staminal tube to the sepal cup. The appearance of the character complex embodied in these flowers during the late mid-Cretaceous may signal the early stages of the relationship between specialized pollinators, such as bees, and the hamamelid-rosid-asterid lineage of angiosperms, arguably one of the most important events in angiosperm radiation. PMID- 11607329 TI - Contrasting leaf phenotypes control seasonal variation in water loss in a tropical forest shrub. AB - Psychotria marginata, a shrub common to humid tropical forests in Central America, produces leaves in two seasonal flushes with contrasting morphology and physiology. Leaf production is bimodal with a major peak at the beginning of the annual wet season and a secondary peak at the end of the wet season. Together these peaks account for 75-87% of annual leaf production. Leaves produced just prior to the dry season have higher specific mass and, during drought, have lower stomatal conductances and higher water-use efficiencies. Plants irrigated during two consecutive dry seasons continued to produce leaves with these morphological and physiological differences, indicating that this feature has been strongly canalized by some factor other than water availability in this highly predictable yet seasonal habitat. The bimodal leaf production results in acclimation to changing conditions through co-occurring leaves that lack the physiological plasticity usually associated with acclimation. Heterophylly of this form suggests that the moderate drought of the dry season has been a significant selective factor for understory plants. PMID- 11607330 TI - Solution of the discrete Plateau problem. AB - We solve a discrete version of the classic Plateau problem, which asks for a minimal surface spanning a given curve. Our algorithm is based on a network-flow formulation that finds minimal slabs, intuitively corresponding to minimal "surfaces" of prescribed thickness. We let the slab thickness approach zero in order to obtain the desired minimal surface. PMID- 11607331 TI - Foraging ability of rufous hummingbirds on hummingbird flowers and hawkmoth flowers. AB - We examine the suitability of ornithophilous flowers and sphingophilous flowers in Ipompsis and Aquilegia for nectar foraging by the hummingbird Selasphorus rufus. In S. rufus, bill length averages 18.9 mm in females and 17.3 mm in males. Maximal tongue extension approximates bill length, suggesting that birds can feed from floral tubes up to 33.5 mm in length. However, their ability to do so is limited by two factors. First, the maximal depth at which S. rufus can extract nectar decreases with the width of the floral tube. Second, feeding time is shortest in short floral tubes and progressively increases as the tubes lengthen because of increased time required for tongue extension and retraction. Hence, nectar foraging occurs with optimal efficiency in moderately broad floral tubes with lengths that do not exceed or only slightly exceed the bill length plus lambda. We extend their result to the more general setting of supersymmetric Young tableaux. Our proof, even in the classical case, has the advantage of providing an explicit combinatorial algorithm for the computation of the coefficients. PMID- 11607355 TI - Crystal structure of lignin peroxidase. AB - The crystal structure of lignin peroxidase (LiP) from the basidiomycete Phanerochaete chrysosporium has been determined to 2.6 A resolution by usine multiple isomorphous replacement methods and simulated annealing refinement. Of the 343 residues, residues 3-335 have been accounted for in the electron density map, including four disulfide bonds. The overall three-dimensional structure is very similar to the only other peroxidase in this group for which a high resolution crystal structure is available, cytochrome c peroxidase, despite the fact that the sequence identity is only approximately 20%, LiP has four disulfide bonds, while cytochrome c peroxidase has none, and LiP is larger (343 vs. 294 residues). The basic helical fold and connectivity defined by 11 helical segments with the heme sandwiched between the distal and proximal helices found in cytochrome c peroxidase is maintained in LiP. Both enzymes have a histidine as a proximal heme ligand, which is hydrogen bonded to a buried aspartic acid side chain. The distal or peroxide binding pocket also is similar, including the distal arginine and histidine. The most striking difference is that, whereas cytochrome c peroxidase has tryptophans contacting the distal and proximal heme surfaces, LiP has phenylalanines. This in part explains why, in the reaction with peroxides, cytochrome c peroxidase forms an amino acid-centered free radical, whereas LiP forms a porphyrin pi cation radical. PMID- 11607356 TI - Solubilized proteins from carrot (Daucus carota L.) membranes bind calcium channel blockers and form calcium-permeable ion channels. AB - Calcium channels have been suggested to play a major role in the initiation of a large number of signal transduction processes in higher plant cells. However, molecular components of higher plant Ca2+ channels remain unidentified to date. Calcium channel blockers of the phenylalkylamine family and bepridil specifically inhibit Ca2+ influx into carrot (Daucus carota L.) cells. By using a phenylalkylamine azido derivative, a 75-kDa carrot membrane protein has been previously identified. Here we have partially purified this Ca2+ channel blocker binding protein by lectin-affinity and ion-exchange chromatographies. The protein fraction containing the 75-kDa binding protein was incorporated into giant liposomes. Single-channel patch-clamp studies on these proteoliposomes showed the presence of Ca2+-permeable channel currents. These Ca2+-permeable channels were not stable. Recordings after durations of 2-10 min showed the appearance of nonselective ion channels with a permeability to calcium and chloride ions. These nonselective Ca2+-permeable ion channels, in contrast, were stable and were recorded for extended durations. The addition of the Ca2+ channel-blocker bepridil (10 M) led to the inhibition of these nonselective Ca2+-permeable channels by reducing the probability of channel opening. These results suggest that the 75-kDa Ca2+ channel blocker-binding protein from carrot cells plays a role in channel sensitivity to Ca2+ channel inhibitors and may constitute one of the components of Ca2+ channels in higher plants. PMID- 11607357 TI - Biogeography of Tongan birds before and after human impact. AB - Bones deposited in caves show that, before the arrival of humans, at least 27 species of land birds lived on the Tongan island of 'Eua, where 13 indigenous species live today. Six of these 13 species were recorded from pre-human strata; three others probably occurred on 'Eua in pre-human times but were not in the fossil sample; and four others probably colonized 'Eua since the arrival of humans approximately 3000 years ago. Of the 23 species of extinct or extirpated land birds recorded from 'Eua, the nearest geographic occurrences of conspecifics or most closely related congeners are from the Solomon Islands (1 species), New Caledonia (2 species), Fiji and/or Samoa (9 species), elsewhere in Tonga (8 species), or unknown (3 species). The avifauna of West Polynesia (Fiji-Tonga Samoa) is more closely related to that of Melanesia than that of East Polynesia. There was little pre-human turnover in Tongan land birds. The arrival of humans has influenced the Tongan avifauna more than any climatic, tectonic, or biological event of the past approximately 100,000 years. PMID- 11607358 TI - Developmental regulation and phytochrome-mediated induction of mRNAs encoding a proline-rich protein, glycine-rich proteins, and hydroxyproline-rich glycoproteins in Phaseolus vulgaris L. AB - We have studied developmental and light regulation of mRNAs encoding a putative cell wall proline-rich protein (PvPRP1), cell wall glycine-rich proteins (GRPs), and cell wall hydroxyproline-rich glycoproteins (HRGPs) in bean (Phaseolus vulgaris). Light increases the levels of these mRNAs 2- to 150-fold in highly spatially regulated patterns during seedling development. These mRNA changes include differential regulation of transcripts derived from the GRP and HRGP multigene families. In 6-day-old light-grown seedlings, the PvPRP1 and GRP1.0 mRNAs were most abundant in the apical region of hypocotyls, epicotyls, and roots. In contrast, several HRGP transcripts were most abundant in the mature region of hypocotyls and roots in light-grown seedlings. When etiolated 6-day-old seedlings were illuminated with white light for 8 hr, maximal accumulation of PvPRP1 and GRP1.0 mRNAs occurred in the apical hook, whereas HRGP and GRP1.8 mRNAs accumulated in the mature region of hypocotyls. Etiolated seedlings subjected to a pulse of red light accumulated PvPRP1, GRP, and HRGP mRNAs in the hypocotyls. Far-red light inhibited red light induction of these mRNAs, indicating a phytochrome-mediated process. The possible roles of PRPs, GRPs, and HRGPs in cell differentiation and photomorphogenesis are discussed. PMID- 11607360 TI - Casimir light: a glimpse. AB - Light emission produced by the reversible collapse of a cavity in a dielectric medium is given an initial, simplified treatment. The agreement between planar and spherical shapes indicates the volume nature of the effect. PMID- 11607359 TI - Cytolocalization of zeatin O-xylosyltransferase in Phaseolus. AB - Zeatin O-xylosyltransferase (EC 2.4.2.-) mediates the formation of O xylosylzeatin from trans-zeatin and UDP-xylose in immature seeds of Phaseolus vulgaris. Tissue printing with a monoclonal antibody specific for the enzyme and a cDNA probe demonstrated that the enzyme was primarily localized and synthesized in the endosperm. Immunolocalization performed on monolayer endosperm at the free nuclei stage and on EM sections demonstrated that the enzyme was associated with the nucleus as well as with the cytoplasm. Immunoanalysis of nuclear fractions revealed that the enzyme was retained in the nuclear pellet. Western analysis also showed that the enzyme was present in the nuclei of cotyledons and endosperm callus. The findings suggest that the enzyme may be involved in the nuclear cytoplasmic transport of cytokinins and related molecules or, possibly, with chromatin of rapidly dividing cells. PMID- 11607361 TI - Effects of hybridization and selection on floral isolation. AB - This paper examines the case of natural hybridization between two angiosperm species (A and B) which are mechanically and ethologically isolated (or florally isolated). What is the effect of hybridization on the pollination system, and conversely, what is the effect of the pollinators on the outcome of the hybridization? The original floral isolation is based on an interspecific differentiation in floral characters, the floral mechanisms of the parental species being specialized for pollination by different types of pollinators with different body forms and behavioral traits. F1 hybrids of A x B have intermediate floral characters and serve as bridges for interspecific cross-pollination. The problem next shifts to the changes in floral characters and mode of pollination that are likely to occur in later generations in the hybrid population. The pollinators of species A and species B exert selective pressures on the hybrid population. If the normal pollinator of A is more abundant, active, and effective in the hybrid population than the pollinator of B, selection is expected to favor a reversion toward the floral characters and pollination system of A. The opposite condition, in which the pollinator of B is predominant, leads to the reciprocal result, reversion toward B. If the two types of pollinators are more or less the same in number of flower visits and pollination effectiveness, their combined selective pressure should produce later-generation derivatives with intermediate floral characters suited for both pollinators. Three western North American plant groups containing florally isolated species that hybridize (Ipomopsis, Diplacus, and Aquilegia) are examined in relation to these predictions. The evidence in the three groups is generally in agreement with the hypothesis. PMID- 11607362 TI - A simple direct method for finding persistence times of populations and application to conservation problems. AB - The computation of persistence times of populations has become a central focus in conservation biology. We describe a simple, direct method for finding the statistics of persistence times by assuming that there is a maximum population size. Thus, even though the population dynamics may be very complex for population sizes below the maximum, it is possible to write a finite set of equations from which the mean and second moment of the persistence time can be found by using simple, algebraic methods. We apply the method to compute the mean and coefficient of variation of persistence times of populations that suffer large decrements (catastrophes). Our results show that in the presence of catastrophes, the increase in mean persistence time with large populations is not nearly as rapid as other theories suggest and that catastrophes occurring at even modest rates can considerably increase the risk of extinction. PMID- 11607365 TI - Modeling the complexation of substituted benzenes by a cyclophane host in water. AB - Monte Carlo statistical mechanics simulations have been used to study the complexation of disubstituted benzenes by Diederich's octamethoxy tetraoxaparacyclophane host. Relative free energies of binding were obtained in water at 25 degrees C for benzene, p-xylene, p-cresol, p-dicyanobenzene, and hydroquinone from statistical perturbation theory. The computed results agree well with experimental data, including the binding affinity of benzene, which was determined after the calculations were completed. The computed structures for the complexes reveal details that are important for understanding the order of binding affinities. It is found that hydroquinone protrudes from one side of the complex and participates in hydrogen bonds between one hydroxyl group and two water molecules and in an intracomplex hydrogen bond between the other hydroxyl group and ether oxygens. The calculations also show a clear preference for binding p-cresol with the hydroxyl group hydrated rather than inside the host's cavity. PMID- 11607363 TI - Mutational analysis of the structure and biogenesis of the photosystem I reaction center in the cyanobacterium Synechocystis sp. PCC 6803. AB - We have utilized the unicellular cyanobacterium Synechocystis sp. PCC 6803 to incorporate site-directed amino acid substitutions into the photosystem I (PSI) reactioncenter protein PsaB. A cysteine residue (position 565 of PsaB) proposed to serve as a ligand to the [4Fe-4S] center Fx was changed to serine, histidine, and aspartate. These three mutants--C565S, C565H, and C565D--all exhibited greatly reduced accumulation of PSI reaction-center proteins and failed to grow autotrophically, indicating that this cysteine most likely does coordinate Fx, which is crucial for PSI biogenesis. Interestingly, the strain C565S accumulated significantly more PSI than the other two cysteine mutants and displayed photoreduction of the [4Fe-4S] terminal electron acceptors FA and FB. Mutations were also introduced into a leucine zipper motif of PsaB, proposed to participate in reaction-center dimerization. The mutants L522V, L536M, and L522V/L536M all exhibited wild-type characteristics and grew autotrophically, whereas the L522P mutation prevented PSI accumulation. These data do not provide support for a major structural role of the leucine zipper in reaction-center dimerization or in assembly of Fx. However, the amino acid substitutions incorporated were conservative and might not have perturbed the leucine zipper. PMID- 11607366 TI - General Gittins index processes in discrete time. AB - We combine the formulation of Mandelbaum [Mandelbaum, A. (1986) Probab. Theory Rel. Fields 71, 129-147] with ideas from Whittle [Whittle, P. (1980) J. R. Stat. Soc. B 42, 143-149] to obtain a simple and constructive proof for the optimality of Gittins index processes in the general, nonmarkovian dynamic allocation (or "multi-armed bandit") problem. Our approach also provides an explicit expression for the value of this problem. PMID- 11607367 TI - Mechanism of superconductivity in K3C60. AB - Using electronic states and phonon states from the first-principles calculations and including both conventional electron-phonon charge coupling and Jahn-Teller coupling, we predict Tc and other superconducting properties. The only adjustable parameter in the theory is the screening length, Rsc. Using Rsc = 0.8-1.0 A, we find excellent agreement with experiment for Tc (16-18 K), pressure dependence of Tc (Delta Tc = -6 to -10 K for 1 GPa), and 12 C to 13 C isotope shift (alphaC = 0.2); experimental values: 19 K, -7 K, and 0.3, respectively. PMID- 11607368 TI - Productivity, consumers, and the structure of a river food chain. AB - We tested models of food chain dynamics in experimentally manipulated channels within a natural river. As light levels increased, primary productivity and the biomass of algae and primary predators increased, but the biomass of grazers remained relatively constant. In the presence of a fourth trophic level, algae and primary predators decreased, but grazers increased. These results match predictions of food chain models based on classical predator-prey theory and suggest that simple models of multitrophic level interactions are sometimes sufficient to predict the responses of natural communities to changes in environmental productivity and predators. PMID- 11607369 TI - Guanine nucleotide binding protein involvement in early steps of phytochrome regulated gene expression. AB - The transmission process of light signals from plant photoreceptors to target cellular events is largely unknown. In the present work, we show that treatment of dark-adapted soybean cells (SB-P) with cholera toxin or pertussis toxin uncouples phytochrome-dependent gene expression. Addition of as little as 10 ng of toxin per ml is sufficient to activate expression of genes encoding the major chlorophyll a/b-binding protein (cab) in the dark. Significant levels of cab transcript accumulation are detected within 0.5 h after addition of the toxins and expression of these genes is desensitized to further light treatments. Treatment of SB-P cells with the calmodulin antagonist N-(6-aminohexyl)-5-chloro 1-naphtha-lenesulfonamide hydrochloride (W-7) prevents induction of the photoregulated gene by phytochrome or bacterial toxins. These results indicate the involvement of guanine nucleotide binding protein(s) in phytochrome-mediated cab gene activation. A likely site of action for this step is between the photoreceptor and a downstream W-7-sensitive effector. PMID- 11607370 TI - T-DNA transfer to maize cells: histochemical investigation of beta-glucuronidase activity in maize tissues. AB - Agrobacterium tumefaciens is routinely used to engineer desirable genes into dicotyledonous plants. However, the economically important graminaceous plant maize is refractory to tumor induction by inoculation with virulent strains of A. tumefaciens. Currently, the only clearcut evidence for transferred DNA (T-DNA) transport from Agrobacterium to maize comes from agroinfection. To study T-DNA transfer from Agrobacterium to maize cells in a virus-free system, we used here the beta-glucuronidase (GUS; EC 3.2.1.31) gene as a marker. GUS expression was observed with high efficiency on shoots of young maize seedlings after cocultivation with Agrobacterium carrying the GUS gene. Agrobacterium virulence mutants, incapable of transferring T-DNA to dicot tissue, were shown to be deficient in eliciting GUS expression in maize. Hence, expression of the T-DNA located GUS gene in maize cells is strictly dependent on Agrobacterium-mediated DNA transfer. Histochemical staining of maize shoots revealed GUS expression located mainly in the leaves and the coleoptile. PMID- 11607371 TI - Pulsed phytoplankton supply to the rocky subtidal zone: influence of internal waves. AB - Hydrographic measurements indicate that the thermocline and the phytoplankton rich chlorophyll maximum layer are vertically displaced over a rocky pinnacle in the central Gulf of Maine by internal waves with maximum amplitudes of 27 m. Such predictable downwelling events are linked to rapid, 2- to 3-fold increases in chlorophyll a, an indicator of phytoplankton concentration, in pulses of warm water recorded 4 cm above the bottom (29-m depth). The 1.5-5.6 degrees C temperature fluctuations had an average period of 10.6 min and were generated on both ebb and flood tides. Local lee waves and the arrival of solitons propagated from Georges Bank are hypothesized to explain the timing of the internal waves. Because internal waves and chlorophyll maxima are pervasive features of stratified temperate seas, this mechanism of food coupling should be common in other rocky subtidal habitats. PMID- 11607372 TI - Oxygen evolution in photosynthesis: from unicycle to bicycle. AB - Flash-induced oxygen evolution in the thylakoids of plants and algae exhibits damped oscillations with period four. These are well described by the S-state model of Kok et al. [Kok, B., Forbush, B. & McGloin, M. (1970) Photochem. Photobiol. 11, 457-475], with damping provided by empirical misses and double hits in the reaction center of photosystem II. Here we apply a mechanistic interpretation of misses as mainly determined by reaction centers that are inactive at the time of the flash due to the presence of either P+ or QA, according to the electron transfer equilibria on the donor and acceptor sides of the reaction center. Calculation of misses on this basis, using known or estimated values of the equilibrium constants for electron transfer between the S states and tyrosine Yz, between Yz and P680, as well as between the acceptor plastoquinones, allows a natural description of the flash number dependence of oxygen evolution. The calculated misses are different for each flash-induced reaction center transition. Identification of this mechanism underlying the miss factor for each transition leads to the recognition of two different reaction sequence cycles of photosystem II, with different transition probabilities, producing an intrinsic heterogeneity of photosystem II activity. PMID- 11607373 TI - Casimir light: the source. AB - The release of Casimir energy in filling a dielectric hole is identified as the source of coherent sonoluminescence. Qualitative agreement with recently acquired data is found for the magnitude and shape of the spectrum. PMID- 11607374 TI - Expression of the functional mature chloroplast triose phosphate translocator in yeast internal membranes and purification of the histidine-tagged protein by a single metal-affinity chromatography step. AB - The mature part of the chloroplast triose phosphate-phosphate translocator was cloned into the yeast expression vector pEVP11. This construct was used to transform cells from both Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. The chloroplast translocator protein was functionally expressed in the transformed yeast cells and represented about 1-2% of the Sch. pombe cell membrane protein. It was localized to mitochondrial membranes and/or membranes of the rough endoplasmic reticulum. In order to purify the recombinant translocator protein, a sequence encoding a C-terminal tag of six histidine residues was introduced into the corresponding cDNA. The expressed histidine tagged translocator protein was purified from the transformed yeast cells under nondenaturing conditions to apparent homogeneity by a single-step affinity chromatography using a Ni2+. nitrilotriacetic acid resin. Both the expressed triose phosphate translocator and the recombinant histidine-tagged protein possess substrate specificities identical to those of the authentic chloroplast protein, providing definitive evidence for its identity as the triose phosphate translocator and further disproving its assignment as the receptor for chloroplast protein import. The yeast expression system in combination with the Ni2+. nitrilotriacetic acid chromatography thus provides a valuable tool for the production of purified membrane proteins in a functional state. PMID- 11607375 TI - Structural biopolymer preservation in Miocene leaf fossils from the Clarkia site, northern Idaho. AB - The 17- to 20-million-year-old locality at Clarkia, northern Idaho, is renowned for yielding amplifiable DNA from a magnolia leaf fossil. In-source pyrolysis mass spectrometry and pyrolysis-gas chromatography/mass spectrometry now reveal that molecular preservation of biomacromolecules is highly selective; structural polysaccharides, cutin polyesters, and proteins were not preserved in detectable quantity in the leaf tissues, whereas both lignin and an aliphatic biopolymer were detected. This study points up the need for improved understanding of the precise modes and extent of preservation of biomacromolecules in fossil materials and sediments. PMID- 11607376 TI - Projective resolutions of Weyl modules. AB - We present a projective resolution of the two-rowed Weyl module, using techniques of supersymmetric algebra. PMID- 11607377 TI - A graded representation model for Macdonald's polynomials. AB - We define doubly graded Sn modules Rmu for which we conjecture that the multiplicities of irreducible representations in various bi-degrees are given by the Macdonald coefficients Klambdamu. Assuming one fundamental conjecture, the modules Rmu can be given several equivalent definitions, which we discuss. We prove the conjectures in various special cases. PMID- 11607378 TI - Global solutions of the equations of elastodynamics of incompressible neo-Hookean materials. AB - I prove that the initial-value problem for the motion of a certain type of elastic body has a solution for all time if the initial data are sufficiently small. The body must fill all of three-space, obey a "neo-Hookean" stress-strain law, and be incompressible. The proof takes advantage of the delayed singularity formation which occurs for solutions of quasilinear hyperbolic equations in more than one space dimension. It turns out that the curl of the displacement of the body obeys such an equation. Thus, using Klainerman's inequality, one derives the necessary estimates to guarantee that solutions persist for all time. PMID- 11607379 TI - Photoreceptor twist: a solution to the false-color problem. AB - In bees and many other insects the majority of photoreceptors are twisted like a corkscrew. Here we show that this structural feature of insect eyes-whose very existence was a source of dispute for several years-is necessary for reliable encoding of information about color. Light reflected from waxy plant surfaces is partially linearly polarized. Moreover, insect photoreceptor membranes are dichroic and thus sensitive to the polarized glare originating from plant surfaces. Taken together, these two phenomena create a serious false-color problem: in the bee's trichromatic color vision system, the color values of a particular part of a plant could be affected not only by the spectral but also by the polarization properties of the reflecting surface. As demonstrated by spectroscopic measurements and optical analyses, the hue of color of a given surface of a plant would change dramatically with the direction of illumination and the bee's line of sight, if the bee possessed straight and thus highly "polarization-sensitive" photoreceptors. However, this false-color problem is overcome completely in photoreceptors that are twisted by exactly the amount we have found to occur in the worker-bee's eye. PMID- 11607380 TI - Casimir light: photon pairs. AB - Expressions are developed for weak single pair emission probability and strong emission average number of pairs. The water transparency cutoff is closely realized, showing that the fundamental time scale is even shorter. PMID- 11607381 TI - Flower-bud formation in explants of photoperiodic and day-neutral Nicotiana biotypes and its bearing on the regulation of flower formation. AB - The capacity to form flower buds in thin-layer explants was studied in flowering plants of several species, cultivars, and lines of Nicotiana differing in their response to photoperiod. This capacity was found in all biotypes examined and could extend into sepals and corolla. It varied greatly, depending on genotype, source tissue and its developmental stage, and composition of the culture medium, particularly the levels of glucose, auxin, and cytokinin. It was greatest in the two day-neutral plants examined, Samsun tobacco and Nicotiana rustica, where it extended from the inflorescence region down the vegetative stem, in a basipetally decreasing gradient; it was least in the two qualitative photoperiodic plants studied, the long-day plant Nicotiana silvestris and the short-day plant Maryland Mammoth tobacco, the quantitative long-day plant Nicotiana alata and the quantitative short-day plant Nicotiana otophora line 38-G-81, where it was limited to the pedicels (and, in some cases, the sepals). Regardless of the photoperiodic response of the source plants, the response was the same in explants cultured under long and short days. The finding that capacity to form flower buds in explants is present in all Nicotiana biotypes studied supports the idea that it is regulated by the same mechanism(s), regardless of the plant's photoperiodic character. However, the source plants were all in the flowering stage, and no flower-bud formation can be obtained in explants from strictly vegetative Nicotiana plants. Hence, flower formation in the explants is not identical with de novo flower formation in a hitherto vegetative plant: it is rather the expression of a floral state already established in the plant, although it can vary widely in extent and spatial distribution. Culture conditions that permit flower-bud formation in an explant are conditions that maintain the floral state and encourage its expression; conditions under which no flower buds are formed reduce this state and/or prevent its expression. PMID- 11607382 TI - Physical cosmology. Introduction to papers presented at a colloquium "Physical Cosmology," March 27-28, 1992, National Academy of Sciences, Irvine, CA. PMID- 11607383 TI - Scientific results from the Cosmic Background Explorer (COBE). AB - The National Aeronautics and Space Administration (NASA) has flown the COBE satellite to observe the Big Bang and the subsequent formation of galaxies and large-scale structure. Data from the Far-Infrared Absolute Spectrophotometer (FIRAS) show that the spectrum of the cosmic microwave background is that of a black body of temperature T = 2.73 +/- 0.06 K, with no deviation from a black body spectrum greater than 0.25% of the peak brightness. The data from the Differential Microwave Radiometers (DMR) show statistically significant cosmic microwave background anisotropy, consistent with a scale-invariant primordial density fluctuation spectrum. Measurements from the Diffuse Infrared Background Experiment (DIRBE) provide new conservative upper limits to the cosmic infrared background. Extensive modeling of solar system and galactic infrared foregrounds is required for further improvement in the cosmic infrared background limits. PMID- 11607384 TI - Preliminary results from the third flight of the Millimeter Anisotropy Experiment (MAX). AB - Preliminary results from the June 1991 flight of MAX are presented. Simultaneous observations were made in bands centered at 6, 9, and 12 cm-1 with a bolometric receiver operating at 300 mK. The experimental sensitivities are the highest reported at angular scales of 0.3 degrees to 1.0 degrees. Interstellar dust is observed to have an emissivity [symbol, see text] nu 1.4+/-0.3 and to correlate with the Infrared Astronomical Satellite (IRAS) 100- map. After removal of emission from interstellar dust, 1.3 hr of integration on a 6 degrees scan yields an upper limit of temperature difference Delta T/T < 2.6 x 10(-5) at a Gaussian autocorrelation function centered at 0.5 degrees. The experiment and data analysis are described. PMID- 11607385 TI - University of california at Santa Barbara Anisotropy Program: degree scale results from the South Pole 1990-1991. AB - We report on the preliminary result of a search for anisotropy in the cosmic background radiation (CBR). Our receiver operates with four equally spaced channels from 25 to 35 GHz with a beam size of approximately 1.5 degrees full width at half maximum. The system operated successfully for 500 hr at the South Pole during 1990-1991 austral summer. The data from one region, representing 25 hr after editing, are presented here. A strong signal is present in the lower frequency channels with a spectrum unlike CBR fluctuations. The highest-frequency channel has the smallest contribution from this signal and has been used to set a 95% confidence level upper limit DeltaT/T = 86 +/- 1 km.sec-1. Mpc-1. PMID- 11607393 TI - Galaxy dynamics and the mass density of the universe. AB - Dynamical evidence accumulated over the past 20 years has convinced astronomers that luminous matter in a spiral galaxy constitutes no more than 10% of the mass of a galaxy. An additional 90% is inferred by its gravitational effect on luminous material. Here I review recent observations concerning the distribution of luminous and nonluminous matter in the Milky Way, in galaxies, and in galaxy clusters. Observations of neutral hydrogen disks, some extending in radius several times the optical disk, confirm that a massive dark halo is a major component of virtually every spiral. A recent surprise has been the discovery that stellar and gas motions in ellipticals are enormously complex. To date, only for a few spheroidal galaxies do the velocities extend far enough to probe the outer mass distribution. But the diverse kinematics of inner cores, peripheral to deducing the overall mass distribution, offer additional evidence that ellipticals have acquired gas-rich systems after initial formation. Dynamical results are consistent with a low-density universe, in which the required dark matter could be baryonic. On smallest scales of galaxies [10 kiloparsec (kpc); Ho = 50 km.sec-1.megaparsec-1] the luminous matter constitutes only 1% of the closure density. On scales greater than binary galaxies (i.e., >/=100 kpc) all systems indicate a density approximately 10% of the closure density, a density consistent with the low baryon density in the universe. If large-scale motions in the universe require a higher mass density, these motions would constitute the first dynamical evidence for nonbaryonic matter in a universe of higher density. PMID- 11607394 TI - Derivation of the cosmological density parameter Omega0 from large-scale flows. AB - Methods for determining the cosmological density parameter 0 from large-scale flows are reviewed. Very consistent results using infrared astronomical satellite (IRAS) data have been obtained by different groups with completely independent methods. The two main methods involve either using maps of the galaxy distribution to predict the peculiar velocity of the Local Group or directly comparing the density field inferred from the IRAS galaxy distribution with the peculiar velocities inferred from optical distance methods. All methods based on IRAS data are consistent with Omega0 = 0.7 +/- 0.1, or if Omega0 = 1, with a bias parameter b = 1.2 +/- 0.1. Various problems associated with the method are discussed, including the issue of which waveband is optimum for such studies, bias, the universality of the luminosity function, and the convergence of the dipole. The lower values of 0 obtained in optical studies may indicate a higher degree of bias toward regions of high total matter-density for elliptical galaxies. A new study using the whole IRAS point source catalog to 0.6 jansky is described, which gives results consistent with other IRAS studies. PMID- 11607395 TI - Dark matter: theoretical perspectives. AB - I both review and make the case for the current theoretical prejudice: a flat Universe whose dominant constituent is nonbaryonic dark matter, emphasizing that this is still a prejudice and not yet fact. The theoretical motivation for nonbaryonic dark matter is discussed in the context of current elementary particle theory, stressing that (i) there are no dark-matter candidates within the "standard model" of particle physics, (ii) there are several compelling candidates within attractive extensions of the standard model of particle physics, and (iii) the motivation for these compelling candidates comes first and foremost from particle physics. The dark-matter problem is now a pressing issue in both cosmology and particle physics, and the detection of particle dark matter would provide evidence for "new physics." The compelling candidates are a very light axion (10(-6)-10(-4) eV), a light neutrino (20-90 eV), and a heavy neutralino (10 GeV-2 TeV). The production of these particles in the early Universe and the prospects for their detection are also discussed. I briefly mention more exotic possibilities for the dark matter, including a nonzero cosmological constant, superheavy magnetic monopoles, and decaying neutrinos. PMID- 11607396 TI - Dissipative processes in galaxy formation. AB - A galaxy commences its life in a diffuse gas cloud that evolves into a predominantly stellar aggregation. Considerable dissipation of gravitational binding energy occurs during this transition. I review here the dissipative processes that determine the critical scales of luminous galaxies and the generation of their morphology. The universal scaling relations for spirals and ellipticals are shown to be sensitive to the history of star formation. Semiphenomenological expressions are given for star-formation rates in protogalaxies and in starbursts. Implications are described for elliptical galaxy formation and for the evolution of disk galaxies. PMID- 11607397 TI - Causes and effects of the first quasars. AB - The light we observe from the most distant known quasars set out when the Universe was about 200 times denser than it is now and less than one-tenth of its present age. The existence of these objects implies that galaxy formation had already, at that early epoch, proceeded to the stage when massive (>10(8)M[symbol, see text]) objects had accumulated in the centers of at least some young galaxies. A specific model is presented to show that the evolution and luminosity function of quasars are compatible with the cold dark matter cosmogony. Most big galaxies probably passed through a quasar phase; the remnant black holes in nearby galaxies may reveal themselves via the flares that occur whenever a star passes too close to them and gets tidally disrupted. The rich absorption spectra of quasars serve as a probe of the intervening medium. The gas responsible for the Lyman alpha absorption lines may be due to primordial gas gravitationally confined in minihalos of dark matter--shallow potential wells whose evolution and relation to dwarf galaxies are briefly discussed. The patchy heat input into the intergalactic medium from early quasars could modulate the environment in which galaxies form, leading to large-scale spatial correlations in the galaxy distribution. This review concludes with general comments on the prospects for a fully quantitative understanding of galaxy formation. PMID- 11607398 TI - Clusters, superclusters, and large-scale structure: a consistent picture. AB - Observations of the large-scale structure in the universe using different tracers and techniques, including the spatial distribution of galaxies, clusters of galaxies, narrow pencil-beam surveys, and quasars, appear to be yielding a consistent picture of the universal structure. A network of large-scale superclusters with scales up to approximately 150h-1 Mpc is suggested (where h approximately 0.5-1 is the Hubble constant in units of 100 km.s-1.Mpc-1; 1 pc = 3.09 x 10(16) m; h = 1 is used throughout this paper). The supercluster network surrounds low-density regions, suggesting a "cellular" structure of the universe. The universal dimensionless cluster correlation function, supported by new data from automated cluster surveys, is consistent with this picture. The "standard" Omega = 1 cold dark matter (CDM) model for the universe appears to be inconsistent with the details of the observed large-scale structure distribution; a low-density, Omega approximately 0.2-0.3, CDM model provides a considerably better fit to the observations. PMID- 11607399 TI - Redshift survey with multiple pencil beams at the galactic poles. AB - Observations of the large-scale structure of the universe suggest inhomogeneities on scales between 100h-1 and 150h-1 Mpc (where h approximately 0.5-1 is the Hubble constant in units of 100 km.s-1.Mpc-1; 1 pc = 3.09 x 10(16) m). A deep redshift survey with a "pencil-beam" geometry of galaxies at the galactic poles indicated strong clustering, with a provocative regularity at 128h-1 Mpc [Broadhurst, T. J., Ellis, R. S., Koo, D. C. & Szalay, A. S. (1990) Nature (London) 343, 726-728]. Using newly acquired data, we demonstrate how multiple deep probes overcome most of the statistical problems associated with single pencil beams. Our results from cross correlations of multiple pencil beams, containing over 1200 galaxies, indicate that the strong peak in the power spectrum results from structures of large transverse size, in agreement with our original conjecture. We also discuss the sensitivity of pencil-beam surveys to the topology of large-scale structures and compare them with sparsely sampled wide-angle local surveys. PMID- 11607400 TI - Galaxy clustering on large scales. AB - I describe some recent observations of large-scale structure in the galaxy distribution. The best constraints come from two-dimensional galaxy surveys and studies of angular correlation functions. Results from galaxy redshift surveys are much less precise but are consistent with the angular correlations, provided the distortions in mapping between real-space and redshift-space are relatively weak. The galaxy two-point correlation function, rich-cluster two-point correlation function, and galaxy-cluster cross-correlation function are all well described on large scales ( greater, similar 20h-1 Mpc, where the Hubble constant, H0 = 100h km.s-1.Mpc; 1 pc = 3.09 x 10(16) m) by the power spectrum of an initially scale-invariant, adiabatic, cold-dark-matter Universe with Gamma = Omegah approximately 0.2. I discuss how this fits in with the Cosmic Background Explorer (COBE) satellite detection of large-scale anisotropies in the microwave background radiation and other measures of large-scale structure in the Universe. PMID- 11607401 TI - Faint galaxy surveys. AB - Various K band galaxy surveys have now established 2.2-m galaxy counts from K = 10 to K = 23. The K band counts rise slightly faster than a Euclidean slope to K = 17, at which point they turn over; beyond this magnitude, galaxies also become much bluer. Spectroscopic samples are available between K = 10 and 20 and show that the conventional distance laws hold rather precisely out to a redshift of about 0.6. Beyond this, galaxies appear fainter than expected. The results appear to favor rapid merging at modest galactic redshifts. PMID- 11607402 TI - Inflation. AB - A short review of inflation is given, starting with a description of the underlying mechanism and the scenario of events. Four variations--old inflation, new inflation, chaotic inflation, and extended inflation--are discussed. It is claimed that the inflationary model provides a plausible explanation for (i) the large number of particles in the universe, (ii) the Hubble expansion, (iii) the large-scale uniformity of the universe, (iv) the nearness of the universe to a critical density, (v) the absence of magnetic monopoles, and (vi) the scale invariant spectrum of microwave background fluctuations observed by COBE (Cosmic Background Explorer). Finally, it is argued that the plausibility of inflation is enhanced by the fact that inflation is eternal. PMID- 11607403 TI - An ancient revisits cosmology. AB - In this after-dinner speech, a somewhat light-hearted attempt is made to view the observational side of physical cosmology as a subdiscipline of astrophysics, still in an early stage of sophistication and in need of more theoretical understanding. The theoretical side of cosmology, in contrast, has its deep base in general relativity. A major result of observational cosmology is that an expansion of the Universe arose from a singularity some 15 billion years ago. This has had an enormous impact on the public's view of both astronomy and theology. It places on cosmologists an extra responsibility for clear thinking and interpretation. Recently, gravitational physics caused another crisis from an unexpected observational result that nonbaryonic matter appears to dominate. Will obtaining information about this massive nonbaryonic component require that astronomers cease to rely on measurement of photons? But 40 years ago after radio astronomical techniques uncovered the high-energy universe, we happily introduced new subfields, with techniques from physics and engineering still tied to photon detection. Another historical example shows how a subfield of cosmology, big bang nucleosynthesis, grew in complexity from its spectroscopic astrophysics beginning 40 years ago. Determination of primordial abundances of lighter nuclei does illuminate conditions in the Big Bang, but the observational results faced and overcame many hurdles on the way. PMID- 11607404 TI - K+-conducting ion channel of the chloroplast inner envelope: functional reconstitution into liposomes. AB - Potassium flux between the chloroplast stroma and cytoplasm is known to be indirectly linked to H+ countertransport and, hence, stromal pH and photosynthetic capacity. The specific molecular mechanism that facilitates K+ flux across the chloroplast envelope is not known and has been a source of controversy for well over a decade. The objective of this study was to elucidate the nature of this envelope protein. To this end, solubilized protein in detergent extracts of purified chloroplast inner envelope vesicles was reconstituted into artificial liposomes, and cation fluxes into these proteoliposomes were measured. Results of inhibitor studies and counterflux experiments indicated that a K+-conducting ion channel was solubilized and functionally reconstituted into the proteoliposomes. This transport protein may be a nonspecific monovalent cation channel. This report represents a direct demonstration of ion channel activity associated with the limiting (inner) membrane of the chloroplast envelope. PMID- 11607405 TI - Self-recognition in helicate self-assembly: spontaneous formation of helical metal complexes from mixtures of ligands and metal ions. AB - On treatment with copper(I) ions, mixtures of the [oligo(2,2')-bipyridine] strands 2-5 yield spontaneously the double helicates 2H(2)-2H(5) without significant crossover. Similarly, when a mixture of the two tris-bypyridine ligands 1 and 3a (containing different substitutions) is allowed to react with copper(I) and nickel(II) ions, only the double helicate 2H(3a) and the triple helicate 3H(1) are formed. Thus, these systems undergo self-assembly of helicates with self-recognition. The process represents a self/nonself-discrimination involving the preferential binding of like metal ions by like ligand strands in a mixture to selectively assemble into the corresponding helicates. In a broader perspective, these results point to a change in paradigm from pure compounds to instructed mixtures--that is from seeking chemical purity to designing programmed systems composed of mixtures of instructed components capable of spontaneously forming well--defined superstructures through self-processes. PMID- 11607406 TI - Calvin cycle multienzyme complexes are bound to chloroplast thylakoid membranes of higher plants in situ. AB - Further evidence is provided that the Calvin cycle enzymes ribose-5-phosphate isomerase (EC 5.3.1.6), ribulose-5-phosphate kinase (Ru-5-P-K, EC 2.7.1.19), ribulose-1,5-bisphosphate carboxylase (RuP2Case, EC 4.1.1.39), glyceraldehyde-3 phosphate dehydrogenase (GAPDH, EC 1.2.1.12), sedoheptulose-1,7-bisphosphatase (Sed-1,7-bPase, EC 3.1.3.37), and electron transport protein ferredoxin-NADP+ reductase (FNR, EC 1.18.1.1) are organized into stable CO2-fixing multienzyme complexes with a molecular mass of 900 kDa. Limited trypsinolysis combined with immunoblotting revealed that all of chloroplast stromal Ru-5-P-K and GAPDH is located in enzyme complexes. The Calvin cycle enzyme complexes remain intact indefinitely at lower ionic strength but dissociate into components at KCl concentrations >250 mM. Immunoelectron microscopy showed that Ru-5-P-K, GAPDH, Sed-1,7-bPase, and FNR are bound to stroma-faced thylakoid membranes in situ, whereas RuP2Case and RuP2Case activase are randomly distributed throughout chloroplasts. The results indicate that membrane-bound enzyme supercomplexes may play an important role in photosynthesis. PMID- 11607407 TI - Analysis of the ground-state band and a closely related intercalated band of 235(92)U143 by the two-revolving-cluster model with consideration of symmetric and antisymmetric resonance of the two dissimilar clusters. AB - The reported ground-state band of 235(92)U143 extending from J = 7/2- to 51/2- is found to be two intercalated bands, one beginning with 7/2- and the other with 9/2-, each with DeltaJ = 2. Analysis by the two-resonating-cluster model leads to 3875 Da.fm2 for the moment of inertia for the first few levels, then increasing by centrifugal stretching. This value is interpreted by the structure p70n112 for the central sphere with clusters p11n16 and p11n15 with radius of revolution R = 8.55 fm. The major principal axis of the Poinsot ellipsoid is taken to be determined by an unquantized number K, with vector intermediate in orientation between L and J. The values of K are found by empirical analysis to equal L + 0.28, with the theory of rotation of the ellipsoid giving L + 0.28 for 7/2-, slowly decreasing to L + 0.251 for 51/2-. The 7/2- band is based on odd values of L (negative parity) and the 9/2- band on even values (positive parity). Negative parity for both bands is achieved by symmetric resonance of the two dissimilar clusters in the 7/2- band and antisymmetric resonance in the 9/2- band. PMID- 11607408 TI - Hopanoid lipids compose the Frankia vesicle envelope, presumptive barrier of oxygen diffusion to nitrogenase. AB - Biological nitrogen fixation in aerobic organisms requires a mechanism for excluding oxygen from the site of nitrogenase activity. Oxygen exclusion in Frankia spp., members of an actinomycetal genus that forms nitrogen-fixing root nodule symbioses in a wide range of woody Angiosperms, is accomplished within specialized structures termed vesicles, where nitrogen fixation is localized. The lipidic vesicle envelope is apparently a functional analogue of the cyanobacterial heterocyst envelope, forming an external gas-diffusion barrier around the nitrogen-fixing cells. We report here that purified vesicle envelopes consist primarily of two hopanoid lipids, rather than of glycolipids, as is the case in cyanobacteria. One envelope hopanoid, bacteriohopanetetrol phenylacetate monoester, is vesicle-specific. The Frankia vesicle envelope thus represents a layer specific to the locus of nitrogen fixation that is biosynthetically uniquely derived. PMID- 11607409 TI - Antisense repression of the chloroplast triose phosphate translocator affects carbon partitioning in transgenic potato plants. AB - The major chloroplast envelope membrane protein E29 is central for the communication between chloroplasts and cytosol. It has been identified as the triose phosphate translocator (TPT) exporting the primary products of the Calvin cycle (i.e., triose phosphates and 3-phosphoglycerate) out of the chloroplast in a strict counter exchange for Pi. To study the in vivo role of the TPT, transgenic potato plants were constructed that have a reduced expression of the TPT at both the RNA and protein level due to antisense inhibition. Chloroplasts isolated from these plants show a 20-30% reduction with respect to their ability to import Pi. The reduced TPT activity leads to a reduction of maximal photosynthesis by 40-60%, to a change in carbon partitioning into starch at the expense of sucrose and amino acids, and to an increase of the leaf starch content by a factor of approximately 3. At early developmental stages the inhibited plants are retarded in growth compared to the wild type. PMID- 11607410 TI - Arabidopsis requires polyunsaturated lipids for low-temperature survival. AB - Mutants of Arabidopsis that contain reduced levels of polyunsaturated fatty acids showed growth characteristics at 22 degrees C that were very similar to wild type. By contrast, at 12 degrees C, the mutants failed to undergo stem elongation during reproductive growth although they produced normal flowers and fertile seeds. After transfer to 6 degrees C, rosette leaves of the mutants gradually died, and the plants were inviable. These different responses of the mutant plants at 12 degrees C and 6 degrees C suggest that distinct functions may be affected at these two temperatures. The gradual development of symptoms at 6 degrees C and other lines of evidence argue against a general collapse of membrane integrity as the cause of the lethal phenotype. Rather, they indicate that the decrease in polyunsaturated membrane lipids may initially have relatively limited effects in disrupting cellular function. PMID- 11607411 TI - The circadian oscillator is regulated by a very low fluence response of phytochrome in wheat. AB - Expression of genes encoding the light-harvesting chlorophyll a/b binding proteins of photosystem II (Cab) in etiolated wheat seedlings is controlled by phytochrome and a circadian clock. Even photoconversion of <1% of phytochrome to its active form, which can be achieved by moonlight, induces the expression of the Cab genes, particularly that of the Cab-1 gene, in circadian fashion. Thus, this reaction shows the characteristics of a low and a very low fluence response. A single far-red light pulse given to an etiolated seedling is sufficient for a persistence of the circadian oscillation of the Cab-1 mRNA level for at least 100 h. Subsequent red (R) or long-wavelength far-red (RG9) light irradiations alter the free running rhythm. These observations indicate a change in sensitivity to phytochrome and/or a control by stable phytochrome. The latter hypothesis is supported by the observation that the level of Cab-1 mRNA is increased or decreased by a second R or RG9 light pulse, respectively. PMID- 11607412 TI - Phytochrome-regulated expression of the genes encoding the small GTP-binding proteins in peas. AB - We examined the effect of light on the mRNA levels of 11 genes (pra1-pra9A, pra9B, and pra9C) encoding the small GTP-binding proteins that belong to the ras superfamily in Pisum sativum. When the dark-grown seedlings were exposed to continuous white light for 24 hr, the levels of several pra mRNAs in the pea buds decreased: pra2 and pra3 mRNAs decreased markedly; pra4, pra6, and pra9A mRNAs decreased slightly; the other 6 pra mRNAs did not decrease. We studied the kinetics of mRNA accumulation for pra2, pra3, and pra9B in detail during white light illumination and compared them with those of the phytochrome gene and the small subunit gene of ribulose bisphosphate carboxylase: mRNA levels of pra2 and pra3 decreased in a manner similar to that of phytochrome while that of the small subunit increased as was expected. The decreases were triggered by a 2-min monochromatic red light (660 nm) irradiation. The effect of red light was reversed by subsequent exposure to far-red light, indicating an involvement of phytochrome as a photoreceptor in this light-regulated event. This work reports negative regulation of mRNA levels of small GTP-binding proteins by light, mediated by phytochrome. PMID- 11607413 TI - Disease risk as a cost of outbreeding in the termite Zootermopsis angusticollis. AB - The effect of the sibship of primary reproductives on mate mortality and the survivorship and growth of incipient colonies was studied in the dampwood termite Zootermopsis angusticollis. Males and females paired with nonsibling mates had higher mortality during the first 10-40 days after pairing, although male and female reproductives showed similar patterns of mortality after colony establishment. The source of mortality appeared to be fungal and/or bacterial pathogens. There were no overall differences in the number of eggs and larvae produced by sibling and nonsibling pairs, and no differences in colony size and biomass 4 years after colony establishment. We therefore could not identify any negative effect of inbreeding in the early phases of colony development. Our results suggest that the risk of exposure to pathogens and the ability of termites to locally adapt to disease could influence the genetic identity of primary reproductives and the extent of inbreeding in termite populations. PMID- 11607414 TI - Circumvention of prey defense by a predator: ant lion vs. ant. AB - The pit-dwelling ant lion Myrmeleon carolinus, although topically sensitive to formic acid, is able to prey on formic acid-spraying ants (Camponotus floridanus). It kills the ants without inducing them to spray, and it sucks out the ant's body contents without puncturing the acid sac. Ordinarily, when Camponotus is attacked it retaliates by simultaneously biting and spraying, but it usually refrains from spraying until it has secured a grip with the mandibles. When Myrmeleon pulls Camponotus into the sand at the bottom of the pit, the ant is seemingly unable to grasp the ant lion and it is killed without being induced to spray. When feeding on the ant, the ant lion sucks up the contents of the nutrient-laden crop. How the ant lion differentiates between crop and acid sac, managing to spare the latter while rupturing the former, remains unknown. PMID- 11607415 TI - Insect pheromone biosynthesis: stereochemical pathway of hydroxydanaidal production from alkaloidal precursors in Creatonotos transiens (Lepidoptera, Arctiidae). AB - The mechanism by which the moth Creatonotos transiens produces its male pheromone, (7R)-hydroxydanaidal, from heliotrine, an alkaloidal precursor of opposite (7S) stereochemistry, was investigated. Specifically deuteriated samples of heliotrine and epiheliotrine were prepared and fed to C. transiens larvae, and the steps in the biosynthetic process were monitored by gas chromatography/mass spectrometry. These analyses indicate that heliotrine is initially epimerized to (7S)-epiheliotrine by oxidation to the corresponding ketone followed by stereospecific reduction. The order of the subsequent steps is (i) aromatization of the dihydropyrrole ring, (ii) ester hydrolysis, and (iii) oxidation of the resulting primary alcohol to the final aldehyde. The ecological implications of this insect's ability (and the inability of another moth, Utetheisa ornatrix) to use representatives of two stereochemical families of alkaloids as pheromone precursors are discussed. PMID- 11607416 TI - Discrete and integral fourier transforms: analytical examples. AB - Analytical examples of the discrete Fourier transform (DFT) help in understanding relations between the DFT and the Fourier integral transform (FIT). Such examples enable one to estimate the errors involved when one transform is approximated by the other, and they suggest how such approximation errors might be reduced. We present mathematical and numerical analyses of the time-to-frequency DFT of the complex exponential function and of the frequency-to-time inverse DFT of the relaxation function. The FITs of these functions are exact inverses, and so they serve to clarify the effects of aliasing and truncation on the DFT. PMID- 11607417 TI - Casimir light: pieces of the action. AB - More realistic dynamics for the collapsing dielectric fluid are introduced in stages by adding contributions to the Lagrangian that forms the action. The elements are kinetic energy, Casimir potential energy, air pressure potential energy, and electromagnetic coupling to the moving dielectric. There are successful tests of partial collapse time and of minimum radius. PMID- 11607418 TI - Gibberellin A1 is required for stem elongation in spinach. AB - The effects of the growth retardants 2'-isopropyl-4'-(trimethylammonium chloride) 5'-methylphenyl piperidine-1-carboxylate (AMO-1618) and calcium 3,5-dioxo-4 propionylcyclohexanecarboxylate (BX-112) on stem elongation were investigated in the rosette plant spinach (Spinacia oleracea L.) under long-day (LD) conditions. Stem growth induced by a LD treatment was prevented by both retardants. The inhibition caused by AMO-1618 was reversed by gibberellin A1 (GA1) and GA20, whereas the effects of BX-112 were reversed by GA1 only. Six GAs (GA53, GA44, GA19, GA20, GA1, and GA8) were quantified by gas chromatography-selected ion monitoring using internal standards. Plants treated with BX-112 had reduced levels of GA1 and GA8 and accumulated GA53, GA44, GA19, and GA20. The relative levels of four additional GAs (3-epi-GA1, GA29, GA60, and GA81) were compared by ion intensities only. Relative to GA81, the level of GA29 was decreased by BX 112, whereas the levels of GA60 and 3-epi-GA1 were increased. Transfer of spinach from short-day conditions to LD conditions caused an increase in all identified GAs of the early 13-hydroxylation pathway with GA20, GA1, and GA8 showing the largest increases. These findings support the position that, of the GAs belonging to the early 13-hydroxylation pathway, GA1 is the primary GA active per se for stem elongation in spinach. The increase in endogenous GA1 in plants in LD conditions is most likely the primary factor for stem elongation. PMID- 11607419 TI - Insight into the relationship of chlorophyll a fluorescence yield to the concentration of its natural quenchers in oxygenic photosynthesis. AB - Fluorescence of chlorophyll a (Chla) is a noninvasive and very sensitive intrinsic probe of photosynthesis. It monitors the composition and organization of the photosystems, the exciton energy transfer, the photochemistry, and the effects of various types of stress on plants. It is the most used as well as the most abused tool in photosynthesis. Thus, an understanding of its relationship to photosynthesis has been of paramount importance. Both the oxidized primary plastoquinone, QA, and the oxidized primary reaction-center Chla, P680+ (for short, P+), are known to be quenchers of Chla fluorescence yield (phi f) of photosystem II. Flash-number dependence of Chla fluorescence yield shows either a period 4, due to the four-step charge-accumulation process of water oxidation (donor side), or period 2 behavior, due to the two-step reduction of the plastoquinone QB (acceptor side) of photosystem II reaction centers. We provide here a further insight into the relationship of variable Chla fluorescence yield (phi f) to the concentration of the two quenchers. The observed time dependence of the ratio of psi f after flash 3 to that after flash 1 (or flash 5) in spinach thylakoids at pH 6 can be explained if we suggest that 1/psi f approximately equals a[PQA] + c, where a, b, and c are constants. From this it follows that the quenching of Chla fluorescence by P680+ after a flash is dependent on QA: for low [QA] (when most reaction centers are closed, [PQA] is low) the quenching of Chla fluorescence by P680+ predominates, while for high [QA] (when most reaction centers are open), the quenching of Chla fluorescence is due predominantly to the increased concentration of the reduced form of P680 ([P+] is low). PMID- 11607420 TI - Signaling in the elicitation process is mediated through the octadecanoid pathway leading to jasmonic acid. AB - Fungal cell walls and fragments thereof (elicitors) induce the formation of low and high molecular weight defense compounds in plant cell suspension cultures. This induced synthesis requires a signal molecule transmitting the message between the elicitor plant cell wall receptor and gene activation. We demonstrate in this study that cis-jasmonic acid is rapidly synthesized in plant cell cultures of diverse taxonomic origin (gymnosperms and mono- and dicotyledonous plants) after challenge with a fungal elicitor preparation. The rapid decline of cis-jasmonic acid in some of these tissues is attributed to rapid metabolism of this pentacyclic acid. The induction of alkaloids by several different molecules provoking the elicitation process is strictly correlated with the synthesis of jasmonates. Elicitation leads to a rapid release of alpha-linolenic acid from the lipid pool of the plant cell. alpha-Linolenic acid and 12-oxophytodienoic acid, the formation of which is also induced, are known to be distant precursors of jasmonic acid. We assume cis-jasmonic acid and its precursors to be the signaling molecules in the elicitation process. PMID- 11607421 TI - Origin of floral isolation between ornithophilous and sphingophilous plant species. AB - Three plant groups in temperate western North America contain closely related ornithophilous and sphingophilous species: the Aquilegia formosa/Aquilegia caerulea group (Ranunculaceae), the Ipomopsis aggregata group (Polemoniaceae), and the Diplacus longiflorus group (Scrophulariaceae). The ornithophilous and sphingophilous species are products of allopatric speciation on the diploid level. Geographical races which are adapted to one class of pollinators in one area where these pollinators are abundant and effective and to another class of pollinators in another geographically isolated area (pollination races) represent a probable intermediate stage in the process of allopatric speciation. Mechanical and ethological isolation (collectively, floral isolation) is a byproduct of the divergence in pollination systems. Selection for reproductive isolation per se has not played any detectable role in the origin of the floral isolation in the three plant groups. PMID- 11607422 TI - Inheritance of freezing resistance in tuber-bearing Solanum species: evidence for independent genetic control of nonacclimated freezing tolerance and cold acclimation capacity. AB - Frost or winter survival is regarded as a complex trait with polygenic inheritance. Two major components of this survival in crop plants are freezing tolerance in the nonacclimated state and cold acclimation capacity. To date researchers have not distinguished the two components as separate heritable traits. The mode of inheritance of these two traits was investigated in F1 and backcross populations of two wild diploid potato species (Solanum commersonii and Solanum cardiophyllum) exhibiting extremes of freezing tolerance and acclimation capacity. Precise assessment of these two traits allowed distinction of small but significant differences among genotypes. The two traits were not correlated in segregating populations, suggesting independent genetic control. Analyses of generation means indicate that all of the variance for acclimation capacity and a major proportion of the variance for the nonacclimated freezing tolerance can be best explained by an additive-dominance model with both traits being partially recessive. Recovery of parental phenotypes in limited populations suggests that both traits are controlled by relatively few genes. To our knowledge this is the first study demonstrating independent genetic control of the two main traits associated with frost or winter survival. Our results show that it should be possible to incorporate these traits from wild germ plasm into cultivated crop plants by independent selection. These results help explain the lack of progress in improving winter survival through field selection. Furthermore, our study demonstrates relative simplicity of the inheritance of cold acclimation, thus providing avenues for understanding the link between biochemical and genetic aspects of low-temperature stress in crop plants. PMID- 11607423 TI - Expression of an antisense prosystemin gene in tomato plants reduces resistance toward Manduca sexta larvae. AB - The growth rates of Manduca sexta (tobacco hornworm) larvae feeding on tomato plants constitutively expressing a prosystemin antisense gene were approximately 3 times higher than growth rates of larvae feeding on nontransformed control plants. The levels of proteinase inhibitor I and inhibitor II proteins in leaves of tomato plants expressing the antisense prosystemin gene remained at undetectable levels until the sixth day of larval feeding and then increased throughout the plants to 100-125 microg/g of leaf tissue after 14 days. In control plants, levels of proteinase inhibitor I and II proteins increased rapidly from the second day of larval feeding and by the eighth day contained levels of 225 microg/g of leaf tissue and 275 microg/g of leaf tissue, respectively, and then increased slowly thereafter. Prosystemin mRNA levels in antisense and control plants after 6 days and 12 days of larval feeding correlated with levels of inhibitor I and II protein levels. These experiments demonstrate that resistance of plants toward an insect pest can be modulated by genetically engineering a gene encoding a component of the inducible systemic signaling system regulating a plant defensive response. PMID- 11607424 TI - Fighting for a harem of queens: physiology of reproduction in Cardiocondyla male ants. AB - Several species of the ant genus Cardiocondyla produce dimorphic males, which exhibit sharply different mating strategies. Winged males typically disperse to mate outside the nest, whereas wingless, ergatoid males stay in the nest and aggressively employ their mandibles against competing ergatoid males to monopolize the virgin queens eclosing in the nest. Such aggressive mating strategy would only be adaptive if the males had unlimited sperm supply. Histological studies showed that, contrary to the rule in the Hymenoptera order, the ergatoid Cardiocondyla males are indeed able to produce sperm during their entire adult life. Winged males, on the other hand, have only a limited sperm supply since spermatogenesis ceases in the late pupal stage. PMID- 11607425 TI - Agricultural soil fumigation as a source of atmospheric methyl bromide. AB - Methyl bromide (MeBr) is used increasingly as a biocidal fumigant, primarily in agricultural soils prior to planting of crops. This usage carries potential for stratospheric ozone reduction due to Br atom catalysis, depending on how much MeBr escapes from fumigated soils to the atmosphere and on details of atmospheric chemical reactions. We present direct field measurements of MeBr escape; 87% of the applied MeBr was emitted within 7 days after a commercial fumigation. Covering the field with plastic sheets retarded MeBr escape somewhat but first day losses were still 40%; thicker sections of sheets were relatively more effective than thin sections. We also measured gaseous MeBr concentrations versus depth in the soil column; these profiles display diffusion-like evolution. In soil, MeBr is partitioned among gas, liquid, and adsorbed solid phases. Calculated soil inventories agreed only roughly with applied amounts, probably due to nonequilibrium partitioning (during the first 30 min) and to uncertainties in partitioning coefficients. Fumigated fields may release less MeBr if they are covered by more gas-tight plastic films, if injection techniques are improved and injection is deeper, and if soil moistures, organic amounts, and densities are greater than in the soil studied here. PMID- 11607426 TI - Randomly amplified polymorphic DNA markers are superior to somatic incompatibility tests for discriminating genotypes in natural populations of the ectomycorrhizal fungus Suillus granulatus. AB - Assessing genetic variation within populations and genetic exchange between populations requires an understanding of the distribution and abundance of individual genotypes within the population. Previous workers have used somatic incompatibility testing to distinguish clones or individuals in natural populations of ectomycorrhizal fungi. However, somatic incompatibility tests performed with isolates of Suillus granulatus from a natural population revealed a lack of transitiveness, which brought into question the validity of this method. Subsequent studies of genetic identity of these isolates, using randomly amplified polymorphic DNA (RAPD) markers, conclusively showed that somatically compatible isolates are not necessarily genetically identical. RAPD marker analysis is more reliable and provides higher resolution of genotype distribution in natural populations than does somatic incompatibility testing. This is of particular importance in populations of organisms such as ectomycorrhizal fungi in which the mating systems are incompletely known. PMID- 11607427 TI - Non-Gaussian autoregressive moving average processes. AB - Non-Gaussian stationary autoregressive moving average sequences are considered. Under conditions concerning smoothness and positivity of the density function of the independent random variables generating the sequence, asymptotically efficient methods for the estimation of unknown coefficients of the model are described. The main interest is in nonminimum-phase models. PMID- 11607428 TI - Poincare resonances and the limits of trajectory dynamics. AB - In previous papers we have shown that the elimination of the resonance divergences in large Poincare systems leads to complex irreducible spectral representations for the Liouville-von Neumann operator. Complex means that time symmetry is broken and irreducibility means that this representation is implementable only by statistical ensembles and not by trajectories. We consider in this paper classical potential scattering. Our theory applies to persistent scattering. Numerical simulations show quantitative agreement with our predictions. PMID- 11607430 TI - Overview of imaging science. AB - The traditional disciplines of science are grounded in the observation and measurement of object properties. Recent advances in digital computer technology have spawned numerous computer-based imaging systems that extend the range of observation and measurement into realms that would otherwise be inaccessible. More importantly, the same set of principles, concepts, strategies, and methods may be used to address the generic issues involved in the production and use of all digitized images. Recognition of this fact is giving rise to the new discipline of imaging science, with its own intellectual agenda. PMID- 11607429 TI - Ethylene induces de novo synthesis of chlorophyllase, a chlorophyll degrading enzyme, in Citrus fruit peel. AB - Chlorophyllase (Chlase; EC 3.1.1.14) was extracted from plastid fractions of ethylene-treated orange fruit peel and purified 400-fold to homogeneity by gel filtration, hydrophobic chromatography, and preparative SDS/PAGE of nonheated protein. SDS/PAGE of nonheated purified enzyme indicated that Chlase activity is associated with a single protein band migrating at an apparent molecular mass of 25 kDa whereas the heated purified enzyme had a molecular mass of 35 kDa. The N terminal sequence of the purified protein was determined. The purified enzyme was used as an immunogen for raising antibodies in rabbits. The antiserum was highly specific and on Western blots recognized both the heated and the nonheated form of Chlase. The antibodies also recognized the solubilized enzyme, as shown by an immunoprecipitation assay and by antigen-antibody capture assays in microtiter plates. Treatment with ethylene, which enhances degreening, increased Chlase activity 12-fold. Immunoblot analyses of crude extracts from ethylene-treated fruit detected a strong signal of the Chlase protein, while only a trace level of the enzyme protein could be detected in air. Gibberellin A3 and N6-benzyladenine partly counteracted the ethylene-induced increase in Chlase activity as well as the immunodetected upsurge of the Chlase protein. Ethylene appears to enhance the degreening of citrus fruit through de novo synthesis of the Chlase protein, which in turn is inhibited by the senescence-delaying regulators, gibberellin A3 and N6 benzyladenine. The Chlase enzyme protein may, therefore, serve as a model system for studying the hormonal molecular regulation of fruit ripening and senescence. PMID- 11607431 TI - Charged-coupled detector sky surveys. AB - Sky surveys have played a fundamental role in advancing our understanding of the cosmos. The current pictures of stellar evolution and structure and kinematics of our Galaxy were made possible by the extensive photographic and spectrographic programs performed in the early part of the 20th century. The Palomar Sky Survey, completed in the 1950s, is still the principal source for many investigations. In the past few decades surveys have been undertaken at radio, millimeter, infrared, and x-ray wavelengths; each has provided insights into new astronomical phenomena (e.g., quasars, pulsars, and the 3 degrees cosmic background radiation). The advent of high quantum efficiency, linear solid-state devices, in particular charged-coupled detectors, has brought about a revolution in optical astronomy. With the recent development of large-format charged-coupled detectors and the rapidly increasing capabilities of data acquisition and processing systems, it is now feasible to employ the full capabilities of electronic detectors in projects that cover an appreciable fraction of the sky. This talk reviews the first "large scale" charged-coupled detector survey. This program, designed to detect very distant quasars, reveals the powers and limitations of charged-coupled detector surveys. PMID- 11607432 TI - Pattern recognition at the Fermilab collider and Superconducting Supercollider. AB - In a colliding beam accelerator such as Fermilab or the Superconducting Supercollider (SSC) protons, or antiprotons, collide at a rate between 10(5) (Fermilab) and 10(8) (SSC) collisions per second. In real time experimentalists have to select those events which are candidates for exploring the limit of known phenomena at a much lower rate, 1-100 per second, for recording on permanent media. The rate of events from new physics sources is expected to be much lower, as low as a few per year. This is a severe problem in pattern recognition: with an input data stream of up to 10(15) potential bits per second in its images, we have to pick out those images that are potentially interesting in real time at a discrimination level of 1 part in 10(6), with a known efficiency. I will describe the overall filtering strategies and the custom hardware to do this event selection (a.k.a. pattern recognition). PMID- 11607433 TI - The intelligent camera: images of computer vision. AB - The field of computer vision is concerned with the problem of deducing properties of object surfaces and the position and orientation of objects in scenes. I illustrate the fundamental difficulty of the problem, describe common approaches taken in the field, and provide representative examples of current solutions. PMID- 11607434 TI - Shape and motion from image streams: a factorization method. AB - Inferring scene geometry and camera motion from a stream of images is possible in principle, but it is an ill-conditioned problem when the objects are distant with respect to their size. We have developed a factorization method that can overcome this difficulty by recovering shape and motion without computing depth as an intermediate step. An image stream can be represented by the 2F x P measurement matrix of the image coordinates of P points tracked through F frames. Under orthographic projection this matrix is of rank 3. Using this observation, the factorization method uses the singular value decomposition technique to factor the measurement matrix into two matrices, which represent object shape and camera motion, respectively. The method can also handle and obtain a full solution from a partially filled-in measurement matrix, which occurs when features appear and disappear in the image sequence due to occlusions or tracking failures. The method gives accurate results and does not introduce smoothing in either shape or motion. We demonstrate this with a series of experiments on laboratory and outdoor image streams, with and without occlusions. PMID- 11607435 TI - UDPglucose: fatty acid transglucosylation and transacylation in triacylglucose biosynthesis. AB - Glandular trichomes of the wild tomato Lycopersicon pennellii Corr. (D'Arcy) secrete large amounts of 2,3,4-tri-O-acylglucoses possessing straight- and branched-chain fatty acids of short to medium chain length (C4-C12). Although previous biosynthetic studies suggested that glucose acylation proceeded via acyl CoA intermediates, repeated attempts to demonstrate isobutyryl-CoA-dependent glucose acylation were unsuccessful. When [14C]isobutyrate is administered to detached L. pennellii leaves, the label is readily converted to 1-O-isobutyryl beta-D-glucose. This is immediately followed by the appearance of di- and triacylated glucose esters. L. pennellii extracts catalyzed the formation of 1-O isobutyryl-beta-D-glucose from isobutyrate and UDPglucose, and detached L. pennellii trichomes catalyzed transfer of the isobutyryl moiety from synthetic 1 O-isobutyryl-beta-D-glucose to D-glucose. Detached L. pennellii trichomes also catalyzed the formation of diacylglucose and triacylglucose via transfer of the isobutyryl moiety from 1-O-[14C]isobutyryl-beta-D-glucose to mono- or diacylglucoses, respectively. These studies suggest a multistep mechanism in which activation of fatty acids to their respective high-energy 1-O-acyl-beta-D glucopyranose derivatives is followed by transfer of the 1-O-acyl moiety to non anomeric positions of other glucose and/or partially acylated glucose molecules. This appears to be the primary mechanism of activation and fatty acid esterification to glucose in L. pennellii trichomes. Cultivated tomato, L. esculentum Mill., also activates free fatty acids to their 1-O-acyl-beta-D glucose derivatives but lacks the acyl transfer mechanism for synthesizing polyacylated sugars. PMID- 11607436 TI - Spinons and holons for the one-dimensional three-band Hubbard models of high temperature superconductors. AB - The one-dimensional three-band Hubbard Hamiltonian is shown to be equivalent to an effective Hamiltonian that has independent spinon and holon quasiparticle excitations plus a weak coupling of the two. The spinon description includes both copper sites and oxygen hole sites leading to a one-dimensional antiferromagnet incommensurate with the copper lattice. The holons are spinless noninteracting fermions in a simple cosine band. Because the oxygen sites are in the Hamiltonian, the quasiparticles are much simpler than in the exact solution of the t-J model for 2t = +/- J. If a similar description is correct for two dimensions, then the holons will attract in a p-wave potential. PMID- 11607437 TI - Sex pheromone for the brownbanded cockroach is an unusual dialkyl-substituted alpha-pyrone. AB - Female brownbanded cockroaches, Supella longipalpa, emit a sex pheromone that attracts males from a distance. This pheromone was isolated and identified as 5 (2,4-dimethylheptanyl)-3-methyl-2H-pyran-2-one (which we refer to as supellapyrone), and its structure was confirmed by synthesis. A racemic blend of the synthetic compound elicited behavioral and electrophysiological responses comparable to the natural pheromone across a range of doses. This compound is not only a very different type of cockroach pheromone but also makes up an additional class of natural products--namely, 3,5-dialkyl-substituted alpha-pyrones. PMID- 11607438 TI - Capelli's theory, Koszul maps, and superalgebras. AB - The straightening laws for the enveloping algebra Ukappa(pl(L)) of the general linear Lie superalgebra of a finite dimensional Z2-graded vector space are investigated. An isomorphism Psi from the supersymmetric algebra Super[L L] of pl(L) to Ukappa(pl(L)) is introduced; the isomorphism Psi maps each bitableau of Super[L L] to the Young-Capelli bitableau of Ukappa(pl(L)) parametrized by the same pair of Young diagrams, both in the permanental case and in the determinantal case. The map Psi is shown to be the inverse of the isomorphism introduced by Koszul [Koszul, J. P. (1981) C.R. Acad. Sci. Paris 292, 139-141]. The set of all costandard determinantal Young-Capelli bitableaux is a basis of Ukappa(pl(L)); this basis acts in a triangular way on the basis of Super[L L]given by the set of all standard permanental bitableaux. PMID- 11607439 TI - Times to extinction for small populations of large birds. AB - A major practical problem in conservation biology is to predict the survival times-"lifetimes"-for small populations under alternative proposed management regimes. Examples in the United States include the 'Alala (Hawaiian Crow; Corvus hawaiiensis) and Northern Spotted Owl (Strix occidentalis caurina). To guide such decisions, we analyze counts of all crow, owl, and hawk species in the most complete available data set: counts of bird breeding pairs on 14 European islands censused for 29-66 consecutive years. The data set yielded 129 records for analysis. We define the population ceiling as the highest number of breeding pairs observed from colonization to extinction, within a consecutive series of counts for a given species on a given island. The resulting distributions of population lifetimes as a function of population size prove to be highly skewed: most small populations disappear quickly, but a few last for a long time. Median (i.e., 50th percentile) lifetimes are calculated as only 1-5 yr for hawk, owl, and crow populations with ceilings of one or two breeding pairs. As expected if demographic accidents are the main cause of extinction for small populations, lifetimes rise by a factor of 3-4 for each additional pair up to three pairs. They rise more slowly thereafter. These observations suggest that lifetimes of the 'Alala (now reduced to about three pairs in the wild), and of populations of Northern Spotted Owl in the smallest forest fragments, will be short unless active management is implemented. PMID- 11607440 TI - Geometric derivation of the chronometric redshift. AB - The chronometric redshift-distance relation z = tan 2(1/2rho), where rho is the distance in radians in the Einstein metric, is derived by an elementary geometric analysis comparable to that in traditional analysis of the expanding universe model. The differential dTt of Einstein time evolution Tt through time t, as applied to the local Minkowski coordinates x, takes the form sec2(1/2t). At the point of observation t = rho, implying that for a sufficiently localized source, observed wave lengths are a factor of sec2(1/2rho) greater than the corresponding emitted wave lengths. PMID- 11607441 TI - An investigation of the interrelationships between linear and nonlinear polarizabilities and bond-length alternation in conjugated organic molecules. AB - A computational method was devised to explore the relationship of charge separation, geometry, molecular dipole moment (mu), polarizability (alpha), and hyperpolariz-abilities (beta, gamma) in conjugated organic molecules. We show that bond-length alternation (the average difference in length between single and double bonds in the molecule) is a key structurally observable parameter that can be correlated with hyperpolarizabilities and is thus relevant to the optimization of molecules and materials. By using this method, the relationship of bond-length alternation, mu, alpha, beta, and gamma for linear conjugated molecules is illustrated, and those molecules with maximized alpha, beta, and gamma are described. PMID- 11607442 TI - Nonequilibrium air clathrate hydrates in Antarctic ice: a paleopiezomdter for polar ice caps. AB - "Craigite," the mixed-air clathrate hydrate found in polar ice caps below the depth of air-bubble stability, is a clathrate mixed crystal of approximate composition (N2O2).6H2O. Recent observations on the Byrd Station Antarctic core show that the air hydrate is present at a depth of 727 m, well above the predicted depth for the onset of hydrate stability. We propose that the air hydrate occurs some 100 m above the equilibrium phase boundary at Byrd Station because of "piezometry"--i.e., that the anomalous depth of hydrate occurrence is a relic of a previous greater equilibrium depth along the flow trajectory, followed by vertical advection of ice through the local phase-boundary depth. Flowline trajectories in the ice based on numerical models show that the required vertical displacement does indeed occur just upstream of Byrd Station. Air hydrate piezometry can thus be used as a general parameter to study the details of ice flow in polar ice caps and the metastable persistence of the clathrate phase in regions of upwelling blue ice. PMID- 11607443 TI - The accessory bacteriochlorophyll: a real electron carrier in primary photosynthesis. AB - The primary electron transfer in reaction centers of Rhodobacter sphaeroides is studied by subpicosecond absorption spectroscopy with polarized light in the spectral range of 920-1040 nm. Here the bacteriochlorophyll anion radical has an absorption band while the other pigments of the reaction center have vanishing ground-state absorption. The transient absorption data exhibit a pronounced 0.9 ps kinetic component which shows a strong dichroism. Evaluation of the data yields an angle between the transition moments of the special pair and the species related with the 0.9-ps kinetic component of 26 +/- 8 degrees. This angle compares favorably with the value of 29 degrees expected for the reduced accessory bacteriochlorophyll. Extensive transient absorbance data are fully consistent with a stepwise electron transfer via the accessory bacteriochlorophyll. PMID- 11607445 TI - Equilibration during mantle melting: a fractal tree model. AB - Many basalts from oceanic islands, ridges, and arcs show strong trace element evidence for melting at great depths, where garnet is a stable phase in mantle peridotites. If partial melts ascend to the surface by porous (intergranular) flow processes, the high-pressure garnet signature will be obliterated by diffusive reequilibration at shallower depths in the mantle. Spiegelman and Kenyon [Spiegelman, M. & Kenyon, P. (1992) Earth Planet Sci. Lett. 109, 611-620] argued that partial melts must therefore be focused into a coarser transport network, for high-speed delivery to the surface. Numerous natural network systems, such as rivers and the human vascular and bronchial systems, have fractal structures that are optimal for minimizing energy expenditure during material transport. I show here that a fractal magma "tree" with these optimal properties provides a network in which magma rapidly loses diffusive chemical "contact" with its host matrix. In this fractal network, magma conduits combine by twos, with the radius and flow velocities scaling as (2)n/3, where n is the generation number. For reasonable values of volume diffusivities, viscosities, and aspect ratios, melts will experience only limited diffusive reequilibration once they have traveled some hundreds of meters from their source. Melts thus represent rather local mantle domains, and there is little problem in delivering melts with deep (<100 km) geochemical signatures to the surface. PMID- 11607444 TI - Primer-mediated in situ detection of the B-hordein gene cluster on barley chromosome 1H. AB - In situ hybridization methods allow the detection of specific DNA sequences on whole chromosomes. The technique has been widely used as a diagnostic and research tool by animal cytogeneticists, for whom detection of unique sequences on mammalian chromosomes is routinely achieved. However, detection of unique sequences on plant chromosomes is less reliable. The recently developed primer induced in situ hybridization (PRINS) technique allows rapid and reliable in situ detection by the hybridization of primers to denatured target DNA, followed by extension with DNA polymerase in the presence of a labeled nucleotide. The use of short oligonucleotide primers could allow improved penetration of debris and highly condensed chromatin common in preparations of plant chromosomes, thus increasing the sensitivity of in situ detection. The feasibility of this approach is demonstrated by the oligonucleotide primer-mediated detection of the B-hordein gene cluster on a barley chromosome. Applications of the PRINS technique for plant cytogeneticists are discussed. PMID- 11607446 TI - Signal efficacy and the evolution of male dimorphism in the jumping spider, Maevia inclemens. AB - An extreme form of male dimorphism occurs in the jumping spider, Maevia inclemens, where two male morphs differ dramatically in both morphology and behavior. We examined the visual signals transmitted to females by the two different morphs during courtship display. Even though the display of each male is different, as a function of behavior and courtship distance, the males present females with images that are almost identical in height and visual target area. By substituting live males with computer-animated sequences of male courtship behavior, the male morphs were superimposed upon each other, and females were determined to have two distinct male-recognition templates. We hypothesize that the dimorphic males of this species evolved through sensory exploitation and selection for alternative male strategies that stimulate different fields of the female visual range. PMID- 11607447 TI - Distortion of area and dimension under quasiconformal mappings in the plane. AB - We find the exact estimates for the distortion of area and Hausdorff dimension under a K-quasiconformal mapping of the complex plane. This solves also the problem of finding the precise bound p(K) of the exponents p such that for each planar K-quasiconformal mapping f the Jacobian Jf is locally p-integrable; it follows that p(K) = 2K/(K - 1). Further consequences include among others the regularity and removability results for quasiregular mappings and sharp estimates for the complex Hilbert transform. PMID- 11607448 TI - Modes and origins of mechanical and ethological isolation in angiosperms. AB - Mechanical and ethological isolation between species is widespread in angiosperms with specialized animal-pollinated flowers, being recorded in 29 species groups belonging to 27 genera and 16 families. Mechanical isolation occurs in two forms. (i) The common type, designated the Salvia type, operates when two or more species of flowers are adapted for different groups of pollinators with different body sizes and shapes. (ii) In the Pedicularis type two flower species have the same species of pollinator but pick up pollen from different parts of the pollinator's body. Four forms of ethological isolation are recognized. (i) In the Aquilegia type, which is widespread, ethological isolation is a side effect of mechanical isolation. (ii) The flower-constancy type, as the name suggests, is based on flower-constant foraging behavior. (iii) In the Ophrys type, floral scents attract male bees or wasps and play a role in their mating behavior; different species of flowers, often orchids, have different scents and attract different sets of hymenopteran species. (iv) The monotropy type occurs in plants pollinated by hymenopterans with species-specific or group-specific flower preferences for nutritive purposes (monotropic and oligotropic bees and fig wasps). Three modes of origin of floral isolation are confirmed by evidence: (i) mechanical and ethological isolation arising as a by-product of allopatric speciation, (ii) ethological isolation developing by selection for reproductive isolation per se, and (iii) mechanical isolation arising as a by-product of character displacement. Mode of origin i accounts for the Salvia and Aquilegia types of isolation in nine known species groups and for the Ophrys type in one group. Mode of origin ii accounts for the flower-constancy type of ethological isolation in two species groups. Mode of origin iii explains mechanical isolation in two groups. Sympatric origin of floral isolation by hybrid speciation and by flower constancy has been proposed, but these modes are undocumented and improbable. PMID- 11607449 TI - The anomaly of silicon in plant biology. AB - Silicon is the second most abundant element in soils, the mineral substrate for most of the world's plant life. The soil water, or the "soil solution," contains silicon, mainly as silicic acid, H4SiO4, at 0.1-0.6 mM--concentrations on the order of those of potassium, calcium, and other major plant nutrients, and well in excess of those of phosphate. Silicon is readily absorbed so that terrestrial plants contain it in appreciable concentrations, ranging from a fraction of 1% of the dry matter to several percent, and in some plants to 10% or even higher. In spite of this prominence of silicon as a mineral constituent of plants, it is not counted among the elements defined as "essential," or nutrients, for any terrestrial higher plants except members of the Equisitaceae. For that reason it is not included in the formulation of any of the commonly used nutrient solutions. The plant physiologist's solution-cultured plants are thus anomalous, containing only what silicon is derived as a contaminant of their environment. Ample evidence is presented that silicon, when readily available to plants, plays a large role in their growth, mineral nutrition, mechanical strength, and resistance to fungal diseases, herbivory, and adverse chemical conditions of the medium. Plants grown in conventional nutrient solutions are thus to an extent experimental artifacts. Omission of silicon from solution cultures may lead to distorted results in experiments on inorganic plant nutrition, growth and development, and responses to environmental stress. PMID- 11607450 TI - Plant hormone ethylene is a Norrish type II product from enzymically generated triplet 1-butanal. AB - The peroxidase-catalyzed aerobic oxidation of a linear aldehyde, leading to the next lower homologue in the triplet state, is accompanied by Norrish type II product ethylene when the substrate is pentanal. This system appears to provide an example of "photobiochemistry without light" because ethylene is a plant hormone and is formed in lipid peroxidation when the recurrent oxidation of linear aldehydes occurs. PMID- 11607451 TI - Light-harvesting chlorophyll c-like pigment in Prochloron. AB - A chlorophyll c-like pigment, similar to magnesium-3,8-divinyl pheoporphyrin a5 monomethyl ester, has been isolated from Prochloron sp. obtained from five species of didemnid ascidians from the Great Barrier Reef, Australia, and from Palau, Micronesia. The pigment represents 4-15% of the total chlorophyll content and is shown to function in a light-harvesting pigment protein complex of Prochloron. The observation that all of the major chlorophylls (a+b+c) function in a light-harvesting role in Prochloron and possibly in other prochlorophytes is discussed in terms of the phylogeny of the prochlorophytes. PMID- 11607452 TI - Atomic force microscopy produces faithful high-resolution images of protein surfaces in an aqueous environment. AB - The atomic force microscope has the potential to monitor structural changes of a biological system in its native environment. To correlate them with the biological function at a molecular level, high lateral and vertical resolution are required. Here we demonstrate that the atomic force microscope is capable of imaging the surface of the hexagonally packed intermediate layer of Deinococcus radiodurans in buffer solution with a lateral resolution of 1 nm and a vertical resolution of 0.1 nm. On average, these topographs differ from those determined by electron microscopy by <0.5 nm. PMID- 11607453 TI - Analysis of a hyperdeformed band of 152(66)Dy86 on the basis of a structure with two revolving clusters, each with a previously unrecognized two-tiered structure. AB - Analysis on the basis of the two-revolving-cluster model has been made of a cascade of 11 gamma-rays constituting a hyperdeformed band of 152(66)Dy86 (or possibly 153Dy) reported by Galindo-Uribarri et al. [Galindo-Uribarri, A., et al. (1993) Phys. Rev. Lett. 73, 231-234], leading to the conclusions that the band extends from values K approximately 82-104 for the angular-momentum quantum number, that the moment of inertia is approximately 5650 Da.fm2, that the composition of the central sphere is p40n50 and that of each of the clusters is p13n18, that each of the clusters consists of two tiers of spherons, and that the radii of revolution of the inner and outer tiers have values of about 8.00 and 11.20 fm, respectively. PMID- 11607454 TI - The protein phosphatase inhibitor calyculin A mimics elicitor action in plant cells and induces rapid hyperphosphorylation of specific proteins as revealed by pulse labeling with [33P]phosphate. AB - Suspension-cultured tomato cells react to microbial signals, so-called elicitors, with rapid alkalinization of the growth medium and increased biosynthesis of the stress hormone ethylene. These responses to elicitors can be blocked by staurosporine and K-252a, two specific inhibitors of protein kinases. Here we show that calyculin A, a potent inhibitor of protein phosphatases, mimics the action of elicitors and, at nanomolar concentrations, induces medium alkalinization as well as a strong increase in the activity of 1 aminocyclopropane-1-carboxylate synthase, the key enzyme of ethylene biosynthesis. Both responses were strongly inhibited by K-252a, and calyculin A induced both responses more rapidly than did a fungal elicitor, xylanase. For example, the lag phase for medium alkalinization was only 0.2-0.4 min for calyculin A, compared with 2 min for xylanase. To study changes in the dynamics of protein phosphorylation, cells were labeled with 30-sec pulses of [33P]orthophosphate. Calyculin A strongly increased phosphorylation of several polypeptide bands within 40 sec of treatment. The same phosphorylated bands also appeared in response to xylanase, but only after a lag phase of 2-3 min. These results show that the protein phosphatase inhibitor calyculin A leads to rapid hyperphosphorylation of specific proteins in cultured cells and indicate that elicitor action could be based on inhibition of a protein phosphatase as well as on activation of a protein kinase. PMID- 11607455 TI - Convergence of quantum electrodynamics in a curved modification of Minkowski space. AB - The interaction and total hamiltonians for quantum electrodynamics, in the interaction representation, are entirely regular self-adjoint operators in Hilbert space, in the universal covering manifold M of the conformal compactification of Minkowski space Mo. (M is conformally equivalent to the Einstein universe E, in which Mo may be canonically imbedded.) In a fixed Lorentz frame this may be expressed as convergence in a spherical space with suitable periodic boundary conditions in time. The traditional relativistic theory is the formal limit of the present variant as the space curvature vanishes. PMID- 11607456 TI - Spectral hole burning and selection of conformational substates in chromoproteins. AB - We investigated spectral holes burnt at 1.5 K into the origins of several tautomeric forms of mesoporphyrin IX-substituted horseradish peroxidase at pH 8 under pressures up to 2 MPa. From the pressure-induced lineshift the compressibility of the apoprotein could be determined. We found that the compressibility changed significantly when measured at different tautomer origins. It was concluded that there must be a correlation between the tautomer configurations of the chromophore and the actual structures of the apoprotein. As a consequence, specific conformational substates of the protein can be selected by optical selection of the associated tautomers. PMID- 11607457 TI - Mechanism of electron transfer in the cytochrome b/f complex of algae: evidence for a semiquinone cycle. AB - The most widely accepted mechanism of electron and proton transfer within the cytochrome (Cyt) b/f complex derives from the Q-cycle hypothesis originally proposed for the mitochondrial Cyt b/c1 complex by Mitchell [Mitchell, P. (1975) FEBS Lett. 57, 135-137]. In chloroplasts, the Cyt b/f complex catalyzes the oxidation of a plastoquinol at a site, Qo (the plastoquinol binding site), close to the inner aqueous phase and the reduction of a quinone at a site, Qi (the plastoquinone binding site), close to the stromal side of the membrane. In an alternative model, the semiquinone cycle [Wikstrom, M. & Krab, K. (1986) J. Bioenerg. Biomembr. 18, 181-193], a charged semiquinone formed at site Qo is transferred to site Qi where it is reduced into quinol. Flash-induced kinetics of the redox changes of Cyt b and of the formation of a transmembrane potential have been measured in Chlorella sorokiniana cells incubated in reducing conditions that induce a full reduction of the plastoquinone pool. The experiments were performed in the presence of an uncoupler that collapses the permanent electrochemical proton gradient and thus accelerates the rate of the electrogenic processes. The results show that the electrogenic reaction driven by the Cyt b/f complex precedes the processes of reduction or oxidation of the b-hemes. This electrogenic process is probably due to a transmembrane movement of a charged semiquinone, in agreement with the semiquinone-cycle hypothesis. This mechanism may represent an adaptation to reducing conditions when no oxidized quinone is available at the Qi site. PMID- 11607459 TI - Vanishing properties of cuspidal local systems. AB - Prehomogeneous vector spaces arising from semisimple groups are considered, and it is shown that certain local systems on the open orbit have the property that their middle extension is zero on the complement of the open orbit. PMID- 11607458 TI - Assessment of genetic diversity of seagrass populations using DNA fingerprinting: implications for population stability and management. AB - Populations of the temperate seagrass, Zostera marina L. (eelgrass), often exist as discontinuous beds in estuaries, harbors, and bays where they can reproduce sexually or vegetatively through clonal propagation. We examined the genetic structure of three geographically and morphologically distinct populations from central California (Elkhorn Slough, Tomales Bay, and Del Monte Beach), using multilocus restriction fragment length polymorphisms (DNA fingerprints). Within population genetic similarity (Sw) values for the three eelgrass populations ranged from 0.44 to 0.68. The Tomales Bay population located in an undisturbed, littoral site possessed a within-population genetic similarity (Sw = 0.44) that was significantly lower than those of the other two populations. Cluster analysis identified genetic substructure in only the undisturbed subtidal population (Del Monte Beach). Between-population similarity values (Sb) for all pairwise comparisons ranged from 0.47 to 0.51. The three eelgrass populations show significantly less between locale genetic similarity than found within populations, indicating that gene flow is restricted between locales even though two of the populations are separated by only 30 km. The study demonstrates that (i) natural populations of Z. marina from both disturbed and undisturbed habitats possess high genetic diversity and are not primarily clonal, (ii) gene flow is restricted even between populations in close proximity, (iii) an intertidal population from a highly disturbed habital shows much lower genetic diversity than an intertidal population from an undisturbed site, and (iv) DNA fingerprinting techniques can be exploited to understand gene flow and population genetic structure in Z. marina, a widespread and ecologically important species, and as such are relevant to the management of this coastal resource. PMID- 11607460 TI - Correlation of song learning and territory establishment strategies in the song sparrow. AB - In a field study, we show that a young song sparrow (i) selects his songs from three or four older birds who have neighboring territories, (ii) preferentially learns song types that these tutor neighbors share, and (iii) ultimately sets up his territory next to, or replaces, one of these tutor neighbors. The consequence of this song learning strategy is that the young bird's song repertoire represents the "logical intersection" of the song repertoires of his tutor neighbors. We argue that this repertoire is optimally designed for mimicry (sounding like your neighbors) and for communication between neighbors (song sparrows address or reply to a neighbor with a song they share with that neighbor). PMID- 11607461 TI - Organization of instabilities in multispecies systems, a test of hierarchy theory. AB - The hierarchy theory predicts that system components functioning at lower levels of hierarchy operate or change at higher rates than the components at the level(s) above. If this prediction is correct, then interpretation of stability in complex ecological systems may be in need of revision. We test the prediction using a model of hierarchical structure of habitat and a coral reef fish community. We found that the variability of ecological range and abundance increases exponentially from habitat generalists (high in hierarchy) to specialists (low in hierarchy), as postulated by the hierarchy theory. Our result suggests that community stability is a composite property and should be evaluated by considering the hierarchical structure of that community. PMID- 11607462 TI - Thermophilic, anaerobic bacteria isolated from a deep borehole in granite in Sweden. AB - A borehole drilled to a total depth of 6779 m in granitic rock in Gravberg, Sweden, was sampled and examined for the presence of anaerobic, thermophilic, fermenting bacteria and sulfate-reducing bacteria. Growth in enrichment cultures was obtained only from water samples collected from a specific sampling depth in the borehole (3500 m). The hole was cased down to a depth of 5278 m and open to the formation below that level. All the water below 2000 m in depth standing in the borehole at the time of sampling must have entered at the 5278-m level or below, during a prior pumping operation. A strong salinity stratification certifies that no major amount of vertical mixing had taken place. The depth from which bacteria could be enriched was that of a pronounced local minimum of salinity. Pure cultures of thermophilic, anaerobic, fermenting bacteria were obtained with the following substrates: glucose, starch, xylan, ethanol, and lactate. The morphology and physiology of the glucose- and starch-degrading strains indicate a relationship to Thermoanaerobacter and Thermoanaerobium species. All but one of the newly isolated strains differ however from those by lacking acetate as a fermentation product. The glucose-degrading strain Gluc1 is phylogenetically related to Clostridium thermohydrosulfuricum, with an evolutionary distance based upon rRNA sequence comparisons of 3%. No sulfate reducing or methanogenic bacteria were found. PMID- 11607463 TI - Osmotin overexpression in potato delays development of disease symptoms. AB - Transgenic potato and tobacco plants carrying the osmotin gene under the control of the cauliflower mosaic virus 35S promoter constitutively overexpressed osmotin to a level of approximately 2% of total cellular protein. Leaves of transgenic potato plants exhibited delayed development of disease symptoms after inoculation with spore suspensions of Phytophthora infestans, which is the cause of late blight disease of potato. In contrast, transgenic tobacco plants did not display any change in the development of disease symptoms when challenged with either spore suspensions or fungal mycelia of Phytophthora parasitica var. nicotianae. Using in vitro assays, purified osmotin was found to be more effective against P. infestans. Some inhibition of P. parasitica also was observed in vitro even though no in vivo effect could be established. PMID- 11607464 TI - Probing toward atomic resolution in molecular topography. PMID- 11607465 TI - Self-incompatibility: how plants avoid illegitimate offspring. AB - In some families of flowering plants, a single self-incompatibility (S) locus prevents the fertilization of flowers by pollen from the same plant. Self incompatibility of this type involves the interaction of molecules produced by the S locus in pollen with those present in the female tissues (pistil). Until recently, the pistil products of the S locus were known in only two families, the Brassicaceae (which includes the cabbages and mustards) and Solanaceae (potatoes and tomatoes). A paper in this issue of the Proceedings describes the molecules associated with self-incompatibility in a third family, the Papaveraceae (poppies). We review current research on self-incompatibility in these three families and discuss the implications of the latest findings in poppy on the likely evolution of self-incompatibility in flowering plants. We also compare research into self-incompatibility with recent progress in understanding the mechanisms by which plants overcome infection by certain pathogens. PMID- 11607466 TI - Lipid-derived signals that discriminate wound- and pathogen-responsive isoprenoid pathways in plants: methyl jasmonate and the fungal elicitor arachidonic acid induce different 3-hydroxy-3-methylglutaryl-coenzyme A reductase genes and antimicrobial isoprenoids in Solanum tuberosum L. AB - Induction of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR; EC 1.1.1.34) is essential for the synthesis of steroid derivatives and sesquiterpenoid phytoalexins in solanaceous plants following mechanical injury or pathogen infection. Gene-specific probes corresponding to different HMGR genes (hmg1 and hmg2) were used to study HMGR expression in potato tissue following treatment with methyl jasmonate, a lipoxygenase product of linolenic acid, or arachidonic acid, an elicitor present in the lipids of the potato late blight fungus Phytophthora infestans. Treatment of potato discs (2.2 cm in diameter) with low concentrations (0.45-45 nmol per disc surface) of methyl jasmonate nearly doubled the wound-induced accumulation of hmg1 transcripts and steroid-glycoalkaloid (SGA) accumulation, reduced the abundance of hmg2 transcripts, and did not induce phytoalexins. High concentrations of methyl jasmonate (2-4.5 mol per disc surface) suppressed hmg1 mRNA and SGA accumulation but did not affect hmg2 mRNA abundance or induce phytoalexins. In contrast, arachidonate treatment strongly suppressed hmg1 and strongly induced hmg2 mRNA in a concentration-dependent manner. There was a corresponding suppression of SGA accumulation and an induction of sesquiterpene phytoalexin accumulation by this elicitor. Lipoxygenase inhibitors reduced the wound-induced accumulation of hmg1 transcripts and suppressed SGA levels, effects that were overcome by exogenous methyl jasmonate (45 nmol per disc surface). The results (i) suggest that methyl jasmonate can function as a signal for hmg1 expression and SGA induction following wounding and (ii) indicate that the arachidonate- and jasmonate response pathways are distinct in relation to HMGR gene expression and isoprenoid product accumulation. The results also are consistent with placement of the HMGR activities encoded by hmg1 and hmg2 within discrete steroid and sesquiterpenoid biosynthetic channels. PMID- 11607467 TI - Minimal representations of E6, E7, and E8 and the generalized Capelli identity. AB - We explicitly construct, in a uniform fashion, the (unique) minimal and spherical representation pi0 of the split real Lie group of exceptional type E6, E7, or E8. We obtain several algebraic and analytic results about pi0. PMID- 11607468 TI - Dynamics and species richness of tropical rain forests. AB - We present a worldwide analysis of humid tropical forest dynamics and tree species richness. New tree mortality, recruitment, and species richness data include the most dynamic and diverse mature tropical forests known. Twenty-five sites show a strong tendency for the most species-rich forests to be dynamic and aseasonal. Mean annual tree mortality and recruitment-turnover-is the most predictive factor of species richness, implying that small-scale disturbance helps regulate tropical forest diversity. Turnover rates are also closely related to the amount of basal area turnover in mature tropical forests. Therefore the contribution of small-scale disturbance to maintaining tropical forest diversity may ultimately be driven by ecosystem productivity. PMID- 11607469 TI - Thorn-like prickles and heterophylly in Cyanea: adaptations to extinct avian browsers on Hawaii? AB - The evolution of thorn-like structures in plants on oceanic islands that lack mammalian and reptilian herbivores is puzzling, as is their tendency toward juvenile-adult leaf dimorphism. We propose that these traits arose in Cyanea (Campanulaceae) on Hawaii as mechanical and visual defenses against herbivory by flightless geese and goose-like ducks that were extirpated by Polynesians within the last 1600 years. A chloroplast DNA phylogeny indicates that thorn-like prickles evolved at least four times and leaf dimorphism at least three times during the last 3.7 million years. The incidence of both traits increases from Oahu eastward toward younger islands, paralleling the distribution of avian species apparently adapted for browsing. The effectiveness of visual defenses against avian browsers (once dominant on many oceanic islands, based on the vagility of their ancestors) may provide a general explanation for insular heterophylly: the other islands on which this previously unexplained phenomenon is marked (New Zealand, New Caledonia, Madagascar, Mascarene Islands) are exactly those on which one or more large flightless avian browsers evolved. PMID- 11607470 TI - A geometric identity for Pappus' theorem. AB - An expression in the exterior algebra of a Peano space yielding Pappus' theorem was originally given by Doubilet, Rota, and Stein [Doubilet, P., Rota, G.-C. & Stein, J. (1974) Stud. Appl. Math. 8, 185-216]. Motivated by an identity of Rota, I give an identity in a Grassmann-Cayley algebra of step 3, involving joins and meets alone, which expresses the theorem of Pappus. PMID- 11607471 TI - A new construction in homological algebra. AB - We present a generalization of the classical bar construction with applications to resolutions of Weyl modules. PMID- 11607472 TI - Contribution of membrane lipids to the ability of the photosynthetic machinery to tolerate temperature stress. AB - The contribution of the unsaturation of membrane lipids to the ability of the photosynthetic machinery to tolerate temperature stress was studied in a transgenic cyanobacterium. Anacystis nidulans R2-SPc was transformed with the desA gene, which encodes the Delta12-desaturase that desaturates the fatty acids of membrane lipids in Synechocystis PCC6803. The transformant acquired the ability to introduce a second double bond into palmitoleic and oleic acids. The transformation enhanced the tolerance of the photosynthetic machinery to chilling stress but it had no detectable effect on the ability to tolerate heat stress. The transformation itself did not have any effect on photosynthetic activity. These results imply that an increase in the unsaturation of membrane lipids enhances the tolerance of the photosynthetic machinery toward chilling stress but not toward heat stress and that such an increase does not affect photosynthesis within the range of physiological temperatures. PMID- 11607473 TI - Ion transport and methane production in Methanobacterium thermoautotrophicum. AB - In Methanobacterium thermoautotrophicum, the protonmotive force for the H+ translocating ATPase consists mainly of a transmembrane electrical gradient (Deltapsi). These cells do not establish a significant transmembrane pH gradient (inside alkaline) and, in fact, if the suspending medium is of pH >/= 7.0, the pH gradient may be reversed-i.e., inside acid with respect to the extracellular pH. These studies show by both 23Na NMR and 22Na+ distribution that Na+ extrusion with the generation of Deltapsi precedes methanogenesis in Mb. thermoautotrophicum. It is calculated that the newly established Na+ gradients increase Deltapsi by approximately 50 mV (inside negative). There is no detectable H+ extrusion during methane synthesis; instead there is a high rate of H+ consumption for methane synthesis and an increase in internal pH. This was supported by 31P NMR experiments, which showed an internal pH shift from 6.8 to 7.6. With the cells maintained at an external pH of 7.2, the initial transmembrane pH gradient of -0.4 (inside acid) at 60 degrees C is equivalent to Deltapsi of + 27 mV (inside positive); after 20 min of incubation, the transmembrane pH gradient is + 0.4 (inside alkaline), which at 60 degrees C is equivalent to Deltapsi of -27 mV (inside negative). Actively respiring cells generated a protonmotive force of -198 mV. It is proposed that energy for CO2 reduction to the level of formaldehyde (the first step in methane synthesis) in Mb. thermoautotrophicum is derived from the Deltapsi generated by electrogenic Na+ extrusion. The protonmotive force required for ATP synthesis consists primarily of Deltapsi and appears to be the result of both an electrogenic Na+ extrusion and a pH gradient (inside alkaline) which develops during methanogenesis. PMID- 11607474 TI - Development of sun compensation by honeybees: how partially experienced bees estimate the sun's course. AB - Honeybees and some other insects, in learning the sun's course, behave as if they can estimate the sun's position at times of day when they have never seen it, but there are competing ideas about the computational mechanisms underlying this ability. In an approach to this problem, we provided incubator-reared bees with opportunities to fly and see the sun only during the late afternoon. Then, on a cloudy day, we allowed bees to fly for the first time during the morning and early afternoon, and we observed how they oriented their waggle dances to indicate their direction of flight relative to the sun's position. The clouds denied the bees a direct view of celestial orientation cues and thus forced them to estimate the sun's position on the basis of their experience on previous evenings. During the test days, experience-restricted bees behaved during the entire morning as if they expected the sun to be in an approximately stationary position about 180 degrees from the average solar azimuth that they had experienced on previous evenings; then from about local noon onward they used the evening azimuth. This pattern suggests that honeybees are innately informed of the general pattern of solar movement, such that they can generate an internal representation that incorporates spatial and temporal features of the sun's course that they have never directly seen. PMID- 11607475 TI - Resource edibility and trophic exploitation in an old-field food web. AB - I tested a food web model that predicts how environmental productivity (nutrient supply) and top carnivores should mediate interactions among herbivores, edible plants, and plants that are resistant to herbivory because they possess anti herbivore defenses. Feeding trials with the dominant grasshopper herbivore at the study site confirmed that certain plant species were resistant to herbivory because of protection by pubescent leaves and stems. Experimental food webs with various numbers of trophic levels composed of edible and resistant plants, grasshoppers, and hunting spiders were assembled in enclosure cages. I randomly assigned half of the cages to a nutrient-enrichment treatment and half remained as a control. Nutrient supply directly enhanced primary productivity and plant and herbivore biomass. Experimentally changing spider abundance caused a classic "trophic cascade" in which herbivore biomass increased and edible plant biomass decreased. Resistant plant biomass increased. These results matched predictions of the model with one exception. A trophic cascade was not observed under enriched conditions. The study nevertheless shows that a simple model attempting to explain heterogeneous interactions in food webs may give considerable insight into the dynamics of natural systems. PMID- 11607476 TI - Reiterative responses to single strands of odor promote sustained upwind flight and odor source location by moths. AB - We characterized single upwind surges of flying male Heliothis virescens moths in response to individual strands of pheromone generated experimentally in a wind tunnel. We then showed how this surge functions in this species as a basic 13.4 cm, 0.38-sec-long building block that is strung together repeatedly during typical male upwind flight in a normal pheromone plume. The template for a single iteration, complete with crosswind casting both before and after the straighter upwind surging portion, was exhibited by males flying upwind to pheromone and experiencing filament contacts just frequently enough to produce successful upwind flight to the source, as hypothesized by an earlier model. Also as predicted, with more frequent filament contact by males, only the straightest upwind portions of the surges were reiterated, producing direct upwind flight with little crosswind casting. Electroantennogram recordings made from males in free flight upwind in a normal point source pheromone plume further support the idea that a high frequency of filaments encountered under the usual pheromone plume conditions promotes only these repeated straight surges. In-flight electroantennogram recordings also showed that when filament contacts cease, the casting, counterturning program begins to be expressed after a latency period of 0.30 sec. Together these results provide a plausible explanation for how male and female moths, and maybe other insects, fly successfully upwind in an odor plume and locate the source of odor, using a surging-casting, phasic-tonic response to the onset and disappearance of each odor strand. PMID- 11607477 TI - A trigonometric sum relevant to the nonrelativistic theory of atoms. AB - We extend Van der Corput's method for exponential sums to study an oscillatory term appearing in the quantum theory of large atoms. We obtain an interpretation in terms of classical dynamics and we produce sharp asymptotic upper and lower bounds for the oscillations. PMID- 11607478 TI - Minimal representations, geometric quantization, and unitarity. AB - In the framework of geometric quantization we explicitly construct, in a uniform fashion, a unitary minimal representation pio of every simply-connected real Lie group Go such that the maximal compact subgroup of Go has finite center and Go admits some minimal representation. We obtain algebraic and analytic results about pio. We give several results on the algebraic and symplectic geometry of the minimal nilpotent orbits and then "quantize" these results to obtain the corresponding representations. We assume (Lie Go)C is simple. PMID- 11607480 TI - Trapped electron cloud bolometer relying on frequency shift. AB - An improved electron cloud bolometer is analyzed. In this device the cloud temperature is read out not via thermal noise induced by the electrons in a coupled LC circuit but via shift in their axial oscillation frequency in the Penning trap confining them. This shift occurs because as the electron cloud expands with increasing temperature, the average restoring force in the slightly anharmonic trap does change perceptibly. The scheme will be useful in exploring the microwave mode structure of the trap cavity and in locating magnetic field values for which the cavity-induced shift in the measured electron g factor disappears. PMID- 11607479 TI - Dynamic reorientation of cortical microtubules, from transverse to longitudinal, in living plant cells. AB - The direction in which plant tissue cells expand is reflected in the alignment of microtubules in the cortical array. When microtubules and coaligned wall microfibrils are arranged transversely around the cell, turgor pressure is chaneled into cell elongation. However, various agents (such as wounding, ethylene, abscisic acid) can cause the microtubules to reorientate by 90 degrees so that they become aligned parallel to the cell's long axis, allowing lateral expansion instead of elongation. The mechanism by which microtubules undergo rapid shifts of alignment is crucial to understanding growth control in plants, but because current models are derived from studies on fixed cells, nothing is known about the dynamics of converting one microtubule alignment to another. Cells tend to have one predominant microtubule alignment--transverse, oblique, or longitudinal--but it is not established whether each represents a stable independent set that only changes by rounds of complete de- and repolymerization, or whether reorientation is a more continuous process involving movement of stable or dynamic microtubules. By microinjecting pea (Pisum sativum) epidermal cells with rhodamine-conjugated brain tubulin and optically sectioning them by confocal laser scanning microscopy, we could follow labeled microtubules for up to 2 hr as they reorientate. Reorientation does not occur by complete depolymerization of microtubules in one orientation followed by polymerization of a new array in another orientation. Instead, increased numbers of discordant microtubules in nontransverse alignment appear in particular locations. Neighboring microtubules then adopt the new alignment, so that there is a stage during which different alignments coexist before the array on the outer tangential cell face finally adopts a uniform steeply oblique/longitudinal configuration. Rapid fluorescence recovery after photobleaching confirms that bundles of cortical microtubules are not stable but exhibit properties consistent with dynamic instability. Dynamic microtubules offer a mechanism for rapid growth responses to a range of physiological stimuli. PMID- 11607481 TI - Casimir light: field pressure. AB - The electromagnetic field is assigned a self-consistent role in which abrupt slowing of the collapse produces radiation and the pressure of the radiation produces abrupt slowing. A simple expression is introduced for the photon spectrum. Conditions for light emission are proposed that imply a high degree of spatial localization. Some numerical checks are satisfied. A study of the mechanical equations of motion suggests an explanation of the very short time scale in terms of oppositely directed field pressures and the speed of light. PMID- 11607482 TI - Expression of an auxin- and cytokinin-regulated gene in cambial region in Zinnia. AB - The expression patterns of a cDNA clone, p48h-10, of an auxin-induced gene were examined in isolated mesophyll cells of Zinnia and in the organs of Zinnia plants. In the isolated mesophyll cells, the mRNA accumulates in 48 hr of culture with 1-naphthaleneacetic acid alone. Because the first cell division occurs before 36 hr of culture, the gene probably is not involved in cell division. Benzyladenine does not induce expression of this gene, but the combination of 1 naphthaleneacetic acid and benzyladenine induces the mRNA accumulation about 24 hr earlier than does 1-naphthaleneacetic acid alone. Tissue print hybridization shows that the mRNA is present predominantly in the cambial region in stems, leaves, and roots and in the vascular bundles in flower buds but does not occur in the apical regions of shoot or root. The characteristics of the gene expression, including auxin- and cytokinin-regulated induction and cambial region localization, encourage us to suggest that the gene is involved in the early process of vascular differentiation. PMID- 11607483 TI - Disruption of hydrogen bonding between plant cell wall polymers by proteins that induce wall extension. AB - Plant cell enlargement is controlled by the ability of the constraining cell wall to expand. This ability has been postulated to be under the control of polysaccharide hydrolases or transferases that weaken or rearrange the loadbearing polymeric networks in the wall. We recently identified a family of wall proteins, called expansins, that catalyze the extension of isolated plant cell walls. Here we report that these proteins mechanically weaken pure cellulose paper in extension assays and stress relaxation assays, without detectable cellulase activity (exo- or endo- type). Because paper derives its mechanical strength from hydrogen bonding between cellulose microfibrils, we conclude that expansins can disrupt hydrogen bonding between cellulose fibers. This conclusion is further supported by experiments in which expansin-mediated wall extension (i) was increased by 2 M urea (which should weaken hydrogen bonding between wall polymers) and (ii) was decreased by replacement of water with deuterated water, which has a stronger hydrogen bond. The temperature sensitivity of expansin mediated wall extension suggests that units of 3 or 4 hydrogen bonds are broken by the action of expansins. In the growing cell wall, expansin action is likely to catalyze slippage between cellulose microfibrils and the polysaccharide matrix, and thereby catalyze wall stress relaxation, followed by wall surface expansion and plant cell enlargement. PMID- 11607484 TI - Timing of fungal invasion using host's ripening hormone as a signal. AB - In many postharvest fruit diseases, fungi remain latent until the fruit ripens. How the fungus times its infection at ripening of the host is not known. We have found that the volatiles produced by the climacteric tomato, avocado, and banana fruits induce germination and appressorium formation in Colletotrichum gloeosporioides and Colletotrichum musae. Exposure of the spores of these fungi to ethylene, the host's ripening hormone, at 99.8%), the procedure also provides C70-enriched fullerene mixture. PMID- 11607496 TI - Fluctuation of the number of particles deposited on a flat surface by a random sequential adsorption mechanism. AB - The problem of the fluctuations of the number n of particles adsorbed on surfaces through a random sequential adsorption process is discussed. Attention is paid, in particular, to the effect of the size of the adsorbing surfaces upon the variance sigma2(n) of this number. On the basis of computer simulations, it is shown that sigma2(n) is not proportional to the area a of the surface but can be written as a sum of three contributions, which are proportional to a, a1/2, and a0. A theoretical estimate based on the relation between the radial distribution function g(r) and the fluctuation is presented and provides a basis for these findings. This analysis is of general validity and can, in particular, also be applied to the equilibrium case (in the absence of a phase transition) and to the ballistic deposition process. PMID- 11607497 TI - Expression of the gene for a small GTP binding protein in transgenic tobacco elevates endogenous cytokinin levels, abnormally induces salicylic acid in response to wounding, and increases resistance to tobacco mosaic virus infection. AB - Tobacco plants transformed with rgp1, a gene encoding a Ras-related small GTP binding protein, were previously shown to exhibit a distinct reduction in apical dominance with increased tillering. These abnormal pheno-types were later found to be associated with elevated levels of endogenous cytokinins (zeatin and zeatin riboside). Analysis of the expression of several genes known to be affected by cytokinins identified a clear increase in the mRNA levels of genes encoding acidic pathogenesis-related proteins in both transgenic plants and their progenies. This increase was directly attributable to elevated levels of the acidic pathogenesis-related protein inducers, salicylic acid (SA) and salicylic acid beta-glucoside, due to an abnormal and sensitive response of the transgenic plants to wounding. In contrast, mRNA levels of the gene for proteinase inhibitor II, which is normally induced by wounding, were generally suppressed in the same wounded plants, probably due to SA overproduction. The changes in SA and pathogenesis-related protein levels in the transgenic plants resulted in a distinct increase in their resistance to tobacco mosaic virus infection. In normal plants, the wound and pathogen-induced signal transduction pathways are considered to function independently. However, the wound induction of SA in the transgenic plants suggests that overexpression of this small GTP binding protein somehow interferes with the normal signal pathways, possibly by affecting cytokinin biosynthesis, and results in cross-signaling between these two transduction systems. PMID- 11607498 TI - Structure of the truncated icosahedron (such as fullerene or viral coatings) and a 60-element conjugacy class in PSl(2, 11). AB - The proper symmetry group of a truncated icosahedron P is the icosahedral group PSl(2, 5). However, knowing the symmetry group is not enough to specify the graph structure (e.g., the carbon bonds for fullerene, C60) of P. The group PSl(2, 5) is a subgroup of the 660-element group PSl(2, 11). The latter contains a 60 element conjugacy class, say M, of elements of order 11. I show here that M exhibits a model for P where the graph structure is expressed group theoretically. For example, the 12 pentagons are the maximal commuting subsets of M. Such a model creates the opportunity of using group-based harmonic analysis (e.g., convolution calculus) to deal with problems concerning the truncated icosahedron. PMID- 11607499 TI - Diurnal cycle of emission of induced volatile terpenoids by herbivore-injured cotton plant. AB - Cotton plants attacked by herbivorous insect pests emit relatively large amounts of characteristic volatile terpenoids that have been implicated in the attraction of natural enemies of the herbivores. However, the composition of the blend of volatile terpenes released by the plants varies remarkably throughout the photoperiod. Some components are emitted in at least 10-fold greater quantities during the photophase than during the scotophase, whereas others are released continuously, without conforming to a pattern, during the entire time that the plants are under herbivore attack. The diurnal pattern of emission of volatile terpenoids was determined by collecting and analyzing the volatile compounds emitted by cotton plants subjected to feeding damage by beet armyworm larvae in situ. The damage was allowed to proceed for 3 days, and volatile emission was monitored continuously. During early stages of damage high levels of lipoxygenase derived volatile compounds [e.g., (Z)-3-hexenal, (Z)-3-hexenyl acetate] and several terpene hydrocarbons [e.g., alpha-pinene, caryophyllene] were emitted. As damage proceeded, high levels of other terpenes, all acyclic [e.g., (E)-beta ocimene, (E)-beta-farnesene], were emitted in a pronounced diurnal fashion; maximal emissions occurred in the afternoon. These acyclic terpenes followed this diurnal pattern of emission, even after removal of the caterpillars, although emission was in somewhat smaller amounts. In contrast, the emission of cyclic terpenes almost ceased after the caterpillars were removed. PMID- 11607500 TI - Four hundred-million-year-old vesicular arbuscular mycorrhizae. AB - The discovery of arbuscules in Aglaophyton major, an Early Devonian land plant, provides unequivocal evidence that mycorrhizae were established >400 million years ago. Nonseptate hyphac and arbuscules occur in a specialized meristematic region of the cortex that continually provided new cells for fungal infection. Arbuscules are morphologically identical to those of living arbuscular mycorrhizae in consisting of a basal trunk and repeatedly branched bush-like tuft within the plant cell. Although interpretations of the evolution of mycorrhizal mutualisms continue to be speculative, the existence of arbuscules in the Early Devonian indicates that nutrient transfer mutualism may have been in existence when plants invaded the land. PMID- 11607501 TI - Ninety-seven million years of angiosperm-insect association: paleobiological insights into the meaning of coevolution. AB - From well preserved leaf damage of the mid-Cretaceous Dakota Flora (97 million years ago), three distinctive, insect-mediated feeding traces have been identified and assigned to two extant genera and one subfamily. These taxa are the leaf miners Stigmella and Ectoedemia of the Nepticulidae and Phyllocnistinae of the Gracillariidae. These fossils indicate that within 25 million years of early angiosperm radiation, the organs of woody dicots already were exploited in intricate and modern ways by insect herbivores. For Ectoedemia and its platanoid host, we document 97 million years of continuity for a plant-insect interaction. The early occurrence during the mid-Cretaceous of diverse and extensive herbivory on woody angiosperms may be associated with the innovation of deciduousness, in which a broadleafed angiosperm provided an efficient, but disposable, photosynthetic organ that with-stood the increased cost of additional insect herbivory. Moreover, the group represented in this study, the leaf-mining Lepidoptera, exhibits a wide range of subordinal taxonomic differentiation and includes the Gracillariidae, a member of the most derived lepidopteran suborder, the Ditrysia. Ditrysian presence during the mid-Cretaceous, in addition to lepidopteran body-fossil evidence from Early Cretaceous and Late Jurassic deposits, suggests that the radiation of major lepidopteran lineages probably occurred during the Late Jurassic on a gymnosperm-dominated flora. PMID- 11607502 TI - Fungal degradation of recalcitrant nonphenolic lignin structures without lignin peroxidase. AB - Lignin peroxidases (LiPs) are likely catalysts of ligninolysis in many white-rot fungi, because they have the unusual ability to depolymerize the major, recalcitrant, non-phenolic structures of lignin. Some white-rot fungi have been reported to lack LiP when grown on defined medium, but it is not clear whether they exhibit full ligninolytic competence under these conditions. To address this problem, we compared the abilities of a known LiP producer, Phanerochaete chrysosporium, with those of a reported nonproducer, Ceriporiopsis subvermispora, to degrade a synthetic lignin with normal phenolic content, a lignin with all phenolic units blocked, and a dimer, 1-(4-ethoxy-3-methoxyphenyl)-2-(2 methoxyphenoxy)propane-1,3-diol, that represents the major nonphenolic structure in lignin. P. chrysosporium mineralized all three models rapidly in defined medium, but C. subvermispora showed appreciable activity only toward the more labile phenolic compound under these conditions. However, in wood, its natural environment, C. subvermispora mineralized all of the models as rapidly as P. chrysosporium did. Defined media therefore fail to elicit a key component of the ligninolytic system in C. subvermispora. A double-labeling experiment with the dimeric model showed that a LiP-dependent pathway was responsible for at least half of dimer mineralization in wood by P. chrysosporium but was responsible for no more than 6-7% of mineralization by C. subvermispora in wood. Therefore, C. subvermispora has mechanisms for degradation of nonphenolic lignin that are as efficient as those in P. chrysosporium but that do not depend on LiP. PMID- 11607503 TI - Plethystic Hopf algebras. AB - The notion of a plethystic algebra associated with a Hopf algebra endowed with a suitable bilinear form is defined. A special case is the Hopf algebra of symmetric functions. PMID- 11607504 TI - Plethystic algebras and vector symmetric functions. AB - An isomorphism is established between the plethystic Hopf algebra Pleth(Super[L]) and the algebra of vector symmetric functions. The Hall inner product of symmetric function theory is extended to the Hopf algebra Pleth(Super[L]). PMID- 11607505 TI - Intracellular Agrobacterium can transfer DNA to the cell nucleus of the host plant. AB - Agrobacterium tumefaciens is a Gram-negative, soil-borne bacterium responsible for the crown gall disease of plants. The galls result from genetic transformation of plant cells by the bacteria. Genes located on the transferred DNA (T-DNA), which is part of the large tumor-inducing (Ti) plasmid of Agrobacterium, are integrated into host plant chromosomes and expressed. This transfer requires virulence (vir) genes that map outside the T-DNA on the Ti plasmid and that encode a series of elaborate functions that appear similar to those of interbacterial plasmid transfer. It remains a major challenge to understand how T-DNA moves from Agrobacterium into the plant cell nucleus, in view of the complexity of obstacles presented by the eukaryotic host cell. Specific anchoring of bacteria to the outer surface of the plant cell seems to be an important prelude to the mobilization of the T-DNA/protein complex from the bacterial cell to the plant cell. However, the precise mode of infection is not clear, although a requirement of wounded cells has been documented. By using a microinjection approach, we show here that the process of T-DNA transfer from the bacteria to the eukaryotic nucleus can occur entirely inside the plant cell. Such transfer is absolutely dependent on induction of vir genes and a functional virB operon. Thus, A. tumefaciens can function as an intracellular infectious agent in plants. PMID- 11607506 TI - Could a nearby supernova explosion have caused a mass extinction? AB - We examine the possibility that a nearby supernova explosion could have caused one or more of the mass extinctions identified by paleontologists. We discuss the possible rate of such events in the light of the recent suggested identification of Geminga as a supernova remnant less than 100 parsec (pc) away and the discovery of a millisecond pulsar about 150 pc away and observations of SN 1987A. The fluxes of gamma-radiation and charged cosmic rays on the Earth are estimated, and their effects on the Earth's ozone layer are discussed. A supernova explosion of the order of 10 pc away could be expected as often as every few hundred million years and could destroy the ozone layer for hundreds of years, letting in potentially lethal solar ultraviolet radiation. In addition to effects on land ecology, this could entail mass destruction of plankton and reef communities, with disastrous consequences for marine life as well. A supernova extinction should be distinguishable from a meteorite impact such as the one that presumably killed the dinosaurs at the "KT boundary." The recent argument that the KT event was exceedingly large and thus quite rare supports the need for other catastrophic events. PMID- 11607507 TI - Forced coalescence phasing: a method for ab initio determination of crystallographic phases. AB - A method has been developed for ab initio determination of crystallographic phases. This technique, called forced coalescence phasing (FCP), is implemented on a computer and uses an automated iterative procedure that combines real space filtering with numerically seeded Fourier transforms to solve the crystallographic phase problem. This approach is fundamentally different from that of traditional direct methods of phasing, which rely on structure invariant probabilistic phase relationships. In FCP, the process begins with an appropriate set of atoms randomly distributed throughout the unit cell. In subsequent cycles of the program, these atoms undergo continual rearrangements ultimately forming the correct molecular structure(s) consistent with the observed x-ray data. In each cycle, the molecular rearrangement is directed by an electron density (Fourier) map calculated using specially formulated numerical seed coefficients that, along with the phase angles for the map, are derived from the arrangement of atoms in the preceding cycle. The method has been tested using actual x-ray data from three organic compounds. For each data set, 100 separate phase determination trials were conducted, each trial beginning with a different set of randomly generated starting phases. Correct phase sets were successfully determined in all of the trials with most trials requiring fewer than 50 cycles of the FCP program. In addition to its effectiveness in small molecule phase determination, FCP offers unexplored potential in the application of real-space methods to ab initio phasing of proteins and other macromolecule structures. PMID- 11607508 TI - Algebraic aspects of the computably enumerable degrees. AB - A set A of nonnegative integers is computably enumerable (c.e.), also called recursively enumerable (r.e.), if there is a computable method to list its elements. The class of sets B which contain the same information as A under Turing computability (/dT ( is the Debye-Waller factor)--is general for glass-forming liquids, including computer-simulated strong and fragile ionic liquids, and is closely correlated with the experimental glass transition temperature. The latter thus originates in strong anharmonicity in certain components of the vibrational density of states, which permits the system to access the multiple minima of its configuration space. The connection between the anharmonicity in these modes, vibrational localization, the Kauzmann temperature, and the fragility of the liquid is proposed as the key problem in glass science. PMID- 11607561 TI - Complexity, contingency, and criticality. AB - Complexity originates from the tendency of large dynamical systems to organize themselves into a critical state, with avalanches or "punctuations" of all sizes. In the critical state, events which would otherwise be uncoupled become correlated. The apparent, historical contingency in many sciences, including geology, biology, and economics, finds a natural interpretation as a self organized critical phenomenon. These ideas are discussed in the context of simple mathematical models of sandpiles and biological evolution. Insights are gained not only from numerical simulations but also from rigorous mathematical analysis. PMID- 11607562 TI - Scaling in geology: landforms and earthquakes. AB - Landforms and earthquakes appear to be extremely complex; yet, there is order in the complexity. Both satisfy fractal statistics in a variety of ways. A basic question is whether the fractal behavior is due to scale invariance or is the signature of a broadly applicable class of physical processes. Both landscape evolution and regional seismicity appear to be examples of self-organized critical phenomena. A variety of statistical models have been proposed to model landforms, including diffusion-limited aggregation, self-avoiding percolation, and cellular automata. Many authors have studied the behavior of multiple slider block models, both in terms of the rupture of a fault to generate an earthquake and in terms of the interactions between faults associated with regional seismicity. The slider-block models exhibit a remarkably rich spectrum of behavior; two slider blocks can exhibit low-order chaotic behavior. Large numbers of slider blocks clearly exhibit self-organized critical behavior. PMID- 11607563 TI - Order and disorder in fluid motion. AB - The development of complex states of fluid motion is illustrated by reviewing a series of experiments, emphasizing film flows, surface waves, and thermal convection. In one dimension, cellular patterns bifurcate to states of spatiotemporal chaos. In two dimensions, even ordered patterns can be surprisingly intricate when quasiperiodic patterns are included. Spatiotemporal chaos is best characterized statistically, and methods for doing so are evolving. Transport and mixing phenomena can also lead to spatial complexity, but the degree depends on the significance of molecular or thermal diffusion. PMID- 11607564 TI - Self-organized criticality: sandpiles, singularities, and scaling. AB - We present an overview of the statistical mechanics of self-organized criticality. We focus on the successes and failures of hydrodynamic description of transport, which consists of singular diffusion equations. When this description applies, it can predict the scaling features associated with these systems. We also identify a hard driving regime where singular diffusion hydrodynamics fails due to fluctuations and give an explicit criterion for when this failure occurs. PMID- 11607565 TI - Finding the missing pieces in the puzzle of plant disease resistance. PMID- 11607566 TI - Two inducers of plant defense responses, 2,6-dichloroisonicotinec acid and salicylic acid, inhibit catalase activity in tobacco. AB - 2,6-Dichloroisonicotinic acid (INA) and salicylic acid (SA) are potent inducers of plant defense responses including the synthesis of pathogenesis-related (PR) proteins and the development of enhanced disease resistance. A soluble SA-binding protein has been purified from tobacco with an affinity and specificity of binding that suggest it is a SA receptor. Recently, this protein has been shown to be a catalase whose enzymatic activity is inhibited by SA binding. We have proposed that the resulting increase in intracellular levels of reactive oxygen species plays a role in the induction of defense responses such as PR protein gene expression. Here we report that INA, like SA, binds the SA-binding protein/catalase and inhibits its enzymatic activity. In fact, the dose-response curves for inhibition of catalase by these two compounds are similar. Furthermore, the ability of both INA analogues and SA derivatives to bind and inhibit tobacco catalase correlates with their biological activity to induce PR-1 gene expression and enhance resistance to tobacco mosaic virus. Comparison of the structures of INA, SA, and their analogues reveals several common features that appear to be important for biological activity. Thus, these results not only suggest that INA and SA share the same mechanism of action that involves binding and inhibition of catalase but also further indicate an important role for reactive oxygen species in the induction of certain plant defense responses. This is supported by the demonstration that INA-mediated PR-1 gene activation is suppressed by antioxidants. PMID- 11607567 TI - Free amino acids exhibit anthozoan "host factor" activity: they induce the release of photosynthate from symbiotic dinoflagellates in vitro. AB - Reef-building corals and other tropical anthozoans harbor endosymbiotic dinoflagellates. It is now recognized that the dinoflagellates are fundamental to the biology of their hosts, and their carbon and nitrogen metabolisms are linked in important ways. Unlike free living species, growth of symbiotic dinoflagellates is unbalanced and a substantial fraction of the carbon fixed daily by symbiont photosynthesis is released and used by the host for respiration and growth. Release of fixed carbon as low molecular weight compounds by freshly isolated symbiotic dinoflagellates is evoked by a factor (i.e., a chemical agent) present in a homogenate of host tissue. We have identified this "host factor" in the Hawaiian coral Pocillopora damicornis as a set of free amino acids. Synthetic amino acid mixtures, based on the measured free amino acid pools of P. damicornis tissues, not only elicit the selective release of 14C-labeled photosynthetic products from isolated symbiotic dinoflagellates but also enhance total 14CO2 fixation. PMID- 11607568 TI - A heme-protein-based oxygen-sensing mechanism controls the expression and suppression of multiple proteins in anoxia-tolerant turtle hepatocytes. AB - The O2 sensitivity of protein expression was assessed in hepatocytes from the western painted turtle. Anoxic cells consistently expressed proteins of 83.0, 70.4, 42.5, 35.3, and 16.1 kDa and suppressed proteins of 63.7, 48.2, 36.9, 29.5, and 17.7 kDa. Except for the 70.4-kDa protein, this pattern was absent during aerobic incubation with 2 mM NaCN, suggesting a specific requirement for O2. Aerobic incubation with Co2+ or Ni2+ increased expression of the 42.5-, 35.3-, and 16.1-kDa protein bands which was diminished with the heme synthesis inhibitor 4,6-dioxoheptanoic acid. Proteins suppressed in anoxia were also suppressed during aerobic incubation with Co2+ or Ni2+ but this was not relieved by 4,6 dioxoheptanoic acid. The anoxia- and Co2+/Ni2+-induced expression of the 42.5-, 35.3-, and 16.1-kDa protein bands was antagonized by 10% CO; however, with the exception of the 17.7-kDa protein, this was not found for any of the O2- or Co2+/Ni2+-suppressed proteins. Anoxia-induced proteins were compared with proteins expressed during heat shock. Heat shock proteins appeared at 90.2, 74.8, 63.4, 25, and 15.5 kDa and were of distinct molecular masses compared with the anoxia-induced proteins. These results suggest that O2-sensing mechanisms are active in the control of protein expression and suppression during anoxia and that, in the case of the 42.5-, 35.3-, 17.7-, and 16.1-kDa proteins, a conformational change in a ferro-heme protein is involved in transducing the O2 signal. PMID- 11607569 TI - Cultural variation in Africa: role of mechanisms of transmission and adaptation. AB - Cultural inheritance can be considered as a mechanism of adaptation made possible by communication, which has reached its greatest development in humans and can allow long-term conservation or rapid change of culturally transmissible traits depending on circumstances and needs. Conservativeness/flexibility is largely modulated by mechanisms of sociocultural transmission. An analysis was carried out by testing the fit of three models to 47 cultural traits (classified in six groups) in 277 African societies. Model A (demic diffusion) is conservation over generations, as shown by correlations of cultural traits with language, used as a measure of historical connection. Model B (environmental adaptation) is measured by correlation to the natural environment. Model C (cultural diffusion) is the spread to neighbors by social contact in an epidemic-like fashion and was tested by measuring the tightness of geographic clustering of the traits. Most traits examined, in particular those affecting family structure and kinship, showed great conservation over generations, as shown by the fit of model A. They are most probably transmitted by family members. This is in agreement with the theoretical demonstration that cultural transmission in the family (vertical) is the most conservative one. Some traits show environmental effects, indicating the importance of adaptation to physical environment. Only a few of the 47 traits showed tight geographic clustering indicating that their spread to nearest neighbors follows model C, as is usually the case for transmission among unrelated people (called horizontal transmission). PMID- 11607570 TI - Significance of bound water to local chain conformations in protein crystals. AB - We examine how the polypeptide chain in protein crystal structures exploits the multivalent hydrogen-bonding potential of bound water molecules. This shows that multiple interactions with a single water molecule tend to occur locally along the chain. A distinctive internal-coordinate representation of the local water binding segments reveals several consensus conformations. The fractional water occupancy of each was found by comparison of the total number of conformations in the database regardless of the presence or absence of bound water. The water molecule appears particularly frequently in type II beta-turn geometries and an N terminal helix feature. This work constitutes a first step into assessing not only the generality but also the significance of specific water binding in globular proteins. PMID- 11607571 TI - Whole-body protochordate regeneration from totipotent blood cells. AB - Cell differentiation, tissue formation, and organogenesis are fundamental patterns during the development of multicellular animals from the dividing cells of fertilized eggs. Hence, the complete morphogenesis of any developing organism of the animal kingdom is based on a complex series of interactions that is always associated with the development of a blastula, a one-layered hollow sphere. Here we document an alternative pathway of differentiation, organogenesis, and morphogenesis occurring in an adult protochordate colonial organism. In this system, any minute fragment of peripheral blood vessel containing a limited number of blood cells isolated from Botrylloides, a colonial sea squirt, has the potential to give rise to a fully functional organism possessing all three embryonic layers. Regeneration probably results from a small number of totipotent stem cells circulating in the blood system. The developmental process starts from disorganized, chaotic masses of blood cells. At first an opaque cell mass is formed. Through intensive cell divisions, a hollow, blastula-like structure results, which may produce a whole organism within a short period of a week. This regenerative power of the protochordates may be compared with some of the characteristics associated with the formation of mammalian embryonal carcinomous bodies. It may also serve as an in vivo model system for studying morphogenesis and differentiation by shedding more light on the controversy of the "stem cell" vs. the "dedifferentiation" theories of regeneration and pattern formation. PMID- 11607573 TI - Evolutionary consequences of food chain length in kelp forest communities. AB - Kelp forests are strongly influenced by macroinvertebrate grazing on fleshy macroalgae. In the North Pacific Ocean, sea otter predation on macroinvertebrates substantially reduces the intensity of herbivory on macroalgae. Temperate Australasia, in contrast, has no known predator of comparable influence. These ecological and biogeographic patterns led us to predict that (i) the intensity of herbivory should be greater in temperate Australasia than in the North Pacific Ocean; thus (ii) Australasian seaweeds have been under stronger selection to evolve chemical defenses and (iii) Australasian herbivores have been more strongly selected to tolerate these compounds. We tested these predictions first by measuring rates of algal tissue loss to herbivory at several locations in Australasian and North Pacific kelp forests. There were significant differences in grazing rates among sea otter-dominated locations in the North Pacific (0-2% day-1), Australasia (5-7% day-1), and a North Pacific location lacking sea otters (80% day-1). The expectations that chronically high rates of herbivory in Australasia have selected for high concentrations of defensive secondary metabolites (phlorotannins) in brown algae and increased tolerance of these defenses in the herbivores also were supported. Phlorotannin concentrations in kelps and fucoids from Australasia were, on average, 5-6 times higher than those in a comparable suite of North Pacific algae, confirming earlier findings. Furthermore, feeding rates of Australasian herbivores were largely unaffected by phlorotannins, regardless of the compounds' regional source. North Pacific herbivores, in contrast, were consistently deterred by phlorotannins from both Australasia and the North Pacific. These findings suggest that top-level consumers, acting through food chains of various lengths, can strongly influence the ecology and evolution of plantherbivore interactions. PMID- 11607572 TI - Light-generated nuclear quantum beats: a signature of photosynthesis. AB - Light-induced radical pairs in deuterated and deuterated plus 15N-substituted Synechococcus lividus cyanobacteria have been studied by transient EPR following pulsed laser excitation. Nuclear quantum beats are observed in the transverse electron magnetization at lower temperatures. Model calculations for the time profiles, evaluated at the high-field emissive maximum of the spectrum, indicate assignment of these coherences to nitrogen nuclei in the primary donor. Thorough investigation of the nuclear modulation patterns can provide detailed information on the electronic structure of the primary donor, providing insight into the mechanism of the primary events of plant photosynthesis. PMID- 11607574 TI - Microevolutionary responses in experimental populations of plants to CO2-enriched environments: parallel results from two model systems. AB - Despite the critical role that terrestrial vegetation plays in the Earth's carbon cycle, very little is known about the potential evolutionary responses of plants to anthropogenically induced increases in concentrations of atmospheric CO2. We present experimental evidence that rising CO2 concentration may have a direct impact on the genetic composition and diversity of plant populations but is unlikely to result in selection favoring genotypes that exhibit increased productivity in a CO2-enriched atmosphere. Experimental populations of an annual plant (Abutilon theophrasti, velvetleaf) and a temperate forest tree (Betula alleghaniensis, yellow birch) displayed responses to increased CO2 that were both strongly density-dependent and genotype-specific. In competitive stands, a higher concentration of CO2 resulted in pronounced shifts in genetic composition, even though overall CO2-induced productivity enhancements were small. For the annual species, quantitative estimates of response to selection under competition were 3 times higher at the elevated CO2 level. However, genotypes that displayed the highest growth responses to CO2 when grown in the absence of competition did not have the highest fitness in competitive stands. We suggest that increased CO2 intensified interplant competition and that selection favored genotypes with a greater ability to compete for resources other than CO2. Thus, while increased CO2 may enhance rates of selection in populations of competing plants, it is unlikely to result in the evolution of increased CO2 responsiveness or to operate as an important feedback in the global carbon cycle. However, the increased intensity of selection and drift driven by rising CO2 levels may have an impact on the genetic diversity in plant populations. PMID- 11607575 TI - Is water structure around hydrophobic groups clathrate-like? AB - The term "clathrate structure" is quantified for solvation of nonpolar groups by enumerating hydrogen-bonded ring sizes both in the solvation shell and through the shell-bulk interface and comparing it to a bulk control using the ST4 water model. For clathrate-like structure to be evident, the distributions along the hydrophobic surface are expected to be dominated by pentagons, with significant depletion of hexagons and larger polygons. While the distribution in this region is indeed distinguished by a large number of pentagons, there are significant contributions from hexagons and larger rings as well. Calculated polygon distributions through the shell-bulk interface indicate that when water structure is highly cooperative along the hydrophobic surface, hydrogen-bonded pathways leading back into bulk are then reduced. These results are qualitatively consistent with the observation that hydrophobicity is proportional to the nonpolar solute surface area. PMID- 11607577 TI - Sequential choice from several populations. AB - We consider the problem of sampling sequentially from two or more populations in such a way as to maximize the expected sum of outcomes in the long run. PMID- 11607576 TI - De novo biosynthesis of the aggregation pheromone components ipsenol and ipsdienol by the pine bark beetles Ips paraconfusus Lanier and Ips pini (Say) (Coleoptera: Scolytidae). AB - The California five-spined ips, Ips paraconfusus Lanier, produces the myrcene derived acyclic monoterpene alcohols ipsenol (2-methyl-6-methylene-7-octen-4-ol) and ipsdienol (2-methyl-6-methylene-2,7-octadien-4-ol) as components of its aggregation pheromone. The pine engraver beetle, Ips pini (Say), produces only ipsdienol. Previous studies have shown that myrcene, a monoterpene in the pines colonized by these beetles, is a direct precursor to these pheromone components. In vivo radiolabeling studies reported here showed that male I. paraconfusus incorporated [1-14C]acetate into ipsenol, ipsdienol, and amitinol (trans-2-methyl 6-methylene-3,7-octadien-2-ol), while male I. pini incorporated [1-14C]acetate into ipsdienol and amitinol. Females of these species produced neither labeled nor unlabeled pheromone components. The purified radiolabeled monoterpene alcohols from-males were identified by comparison of their HPLC and GC retention times with those of unlabeled standards. HPLC-purified fractions containing the individual radiolabeled components were analyzed by GC-MS and were shown to include only the pure alcohols. To further confirm that ipsdienol and ipsenol were radiolabeled, diastereomeric ester derivatives of the isolated alcohols were synthesized and analyzed by HPLC and GC-MS. After derivatization of the radiolabeled alcohols, the HPLC analysis demonstrated expected shifts in retention times with conservation of naturally occurring stereochemistry. The results provide direct evidence for de novo biosynthesis of ipsenol, ipsdienol, and amitinol by bark beetles. PMID- 11607578 TI - Gas-phase nitronium ion affinities. AB - Evaluation of nitronium ion-transfer equilibria, L1NO2+ + L2 = L2NO2+ + L1 (where L1 and L2 are ligands 1 and 2, respectively) by Fourier-transform ion cyclotron resonance mass spectrometry and application of the kinetic method, based on the metastable fragmentation of L1(NO2+)L2 nitronium ion-bound dimers led to a scale of relative gas-phase nitronium ion affinities. This scale, calibrated to a recent literature value for the NO2+ affinity of water, led for 18 ligands, including methanol, ammonia, representative ketones, nitriles, and nitroalkanes, to absolute NO2+ affinities, that fit a reasonably linear general correlation when plotted vs. the corresponding proton affinities (PAs). The slope of the plot depends to a certain extent on the specific nature of the ligands and, hence, the correlations between the NO2+ affinities, and the PAs of a given class of compounds display a better linearity than the general correlation and may afford a useful tool for predicting the NO2+ affinity of a molecule based on its PA. The NO2+ binding energies are considerably lower than the corresponding PAs and well below the binding energies of related polyatomic cations, such as NO+, a trend consistent with the available theoretical results on the structure and the stability of simple NO2+ complexes. The present study reports an example of extension of the kinetic method to dimers, such as L1(NO2+)L2, bound by polyatomic ions, which may considerably widen its scope. Finally, measurement of the NO2+ affinity of ammonia allowed evaluation of the otherwise inaccessible PA of the amino group of nitramide and, hence, direct experimental verification of previous theoretical estimates. PMID- 11607580 TI - Lipid monolayer image dipoles. AB - A simple model is described for calculating the electrostatic energy of lipid domains at the air-water interface, taking account of dipole-dipole repulsions between the lipid molecules themselves, as well as interactions between the molecular dipoles and image dipoles in the subphase. The model assumes that the molecular dipoles within the monolayer arise from the terminal methyl groups of the hydrophobic hydrocarbon chains of the lipid molecules, and that on average they are oriented perpendicular to the plane of the monolayer. With this model the role of the subphase is to enhance rather than suppress the effects of dipole dipole repulsions. PMID- 11607579 TI - Cutting activates a 46-kilodalton protein kinase in plants. AB - Using SDS/polyacrylamide gels that contained myelin basic protein, we identified a 46-kDa protein kinase in tobacco that is transiently activated by cutting. Although the activity of the kinase was rarely detectable in mature leaves, marked activity became apparent within several minutes after isolation of leaf discs and subsided within 30 min. In the presence of cycloheximide (CHX), the kinase activity did not diminish after the isolation over the course of 2 hr, suggesting that protein synthesis was not required for the activation of the kinase. A second cutting of leaf discs between 30 min and 60 min after the isolation failed to activate the kinase, whereas a second cutting given 3 hr after isolation apparently activated the kinase. These results suggest that the 46-kDa protein kinase is desensitized immediately after the first activation, which can be blocked by CHX, but the response ability recovers with time. When protein extracts containing the active kinase were treated with serine/threonine specific or tyrosine-specific protein phosphatase, the kinase activity was abolished. After immunoprecipitation with antibody against phosphotyrosine, activity of the kinase was recovered in the immunoprecipitate. These results suggest that the active form of the kinase is phosphorylated at both serine/threonine and tyrosine residues. It seems likely that the 46-kDa protein kinase can be activated by dual phosphorylation. The activity of a 46-kDa protein kinase was also detected in leaves of a wide variety of plant species including dicotyledonous and monocotyledonous plants. We propose the name PMSAP (plant multisignal-activated protein) kinase for this kinase because the kinase was also activated by various signals other than cutting. PMID- 11607581 TI - Forest losses predict bird extinctions in eastern North America. AB - Claims that there will be a massive loss of species as tropical forests are cleared are based on the relationship between habitat area and the number of species. Few studies calibrate extinction with habitat reduction. Critics raise doubts about this calibration, noting that there has been extensive clearing of the eastern North American forest, yet only 4 of its approximately 200 bird species have gone extinct. We analyze the distribution of bird species and the timing and extent of forest loss. The forest losses were not concurrent across the region. Based on the maximum extent of forest losses, our calculations predict fewer extinctions than the number observed. At most, there are 28 species of birds restricted to the region. Only these species would be at risk even if all the forests were cleared. Far from providing comfort to those who argue that the current rapid rate of tropical deforestation might cause fewer extinctions than often claimed, our results suggest that the losses may be worse. In contrast to eastern North America, small regions of tropical forest often hold hundreds of endemic bird species. PMID- 11607582 TI - Strong regulation of slow anion channels and abscisic acid signaling in guard cells by phosphorylation and dephosphorylation events. AB - Recent evidence suggests that slow anion channels in guard cells need to be activated to trigger stomatal closing and efficiently inactivated during stomatal opening. The patch-clamp technique was employed here to determine mechanisms that produce strong regulation of slow anion channels in guard cells. MgATP in guard cells, serving as a donor for phosphorylation, leads to strong activation of slow anion channels. Slow anion-channel activity was almost completely abolished by removal of cytosolic ATP or by the kinase inhibitors K-252a and H7. Nonhydrolyzable ATP, GTP, and guanosine 5'-[gamma-thio]triphosphate did not replace the ATP requirement for anion-channel activation. In addition, down regulation of slow anion channels by ATP removal was inhibited by the phosphatase inhibitor okadaic acid. Stomatal closures in leaves induced by the plant hormone abscisic acid (ABA) and malate were abolished by kinase inhibitors and/or enhanced by okadaic acid. These data suggest that ABA signal transduction may proceed by activation of protein kinases and inhibition of an okadaic acid sensitive phosphatase. This modulation of ABA-induced stomatal closing correlated to the large dynamic range for up- and down-regulation of slow anion channels by opposing phosphorylation and dephosphorylation events in guard cells. The presented opposing regulation by kinase and phosphatase modulators could provide important mechanisms for signal transduction by ABA and other stimuli during stomatal movements. PMID- 11607584 TI - Pathway of terpene excretion by the appendix of Sauromatum guttatum. AB - Electron microscopy of the cells of the thermogenic appendix of Sauromatum guttatum has revealed a fusion event between pocket-like structures of the rough endoplasmic reticulum (rER) and the plasma membrane. As a result of the fusion event, many regions of the plasma membrane have paired unit membranes (four leaflets instead of two). The fusion allows the transfer of osmiophilic material from the rER pockets to the plasma membrane, where the osmiophilic material is confined to bilayer, pocket-like structures. A clear correlation is found between the presence of the osmiophilic compound and sesquiterpenes. Prior to heat production, the rER- and plasma-membrane pockets are electron dense, and sesquiterpenes are detectable only in tissue extracts. On the day of heat production, electron-translucent pockets are subsequently found and the stored sesquiterpenes are released to the atmosphere. Three sesquiterpenes have been identified by gas chromatography-mass spectrometry as alpha-copaene and beta- and alpha-caryophyllene. PMID- 11607583 TI - Barley telomeres shorten during differentiation but grow in callus culture. AB - Eukaryotic chromosomes terminate with long stretches of short, guanine-rich repeats. These repeats are added de novo by a specialized enzyme, telomerase. In humans telomeres shorten during differentiation, presumably due to the absence of telomerase activity in somatic cells. This phenomenon forms the basis for several models of telomere role in cellular senescence. Barley (Hordeum vulgare L.) telomeres consist of thousands of TTTAGGG repeats, closely resembling other higher eukaryotes. In vivo differentiation and aging resulted in reduction of terminal restriction fragment length paralleled by a decrease of telomere repeat number. Dedifferentiation in callus culture resulted in an increase of the terminal restriction fragment length and in the number of telomere repeats. Long term callus cultures had very long telomeres. Absolute telomere lengths were genotype dependent, but the relative changes due to differentiation, dedifferentiation, and long-term callus culture were consistent among genotypes. A model is presented to describe the potential role of the telomere length in regulation of a cell's mitotic activity and senescence. PMID- 11607585 TI - Etiolated cells of Chlamydomonas reinhardtii: choice material for characterization of mitochondrial membrane polypeptides. AB - We have investigated a light-conditional mutant of Chlamydomonas reinhardtii (J12) that is unable to synthesize chlorophyll in the dark with the aim of characterizing the mitochondrial membrane polypeptides of this alga. A crude membrane fraction derived from etiolated cells was analyzed by gel electrophoresis, immunoblot analysis, and pulse-labeling in the presence of specific protein synthesis inhibitors. This fraction contained both mitochondrial and etioplast membranes, and the latter contained appreciable amounts of subunits of the cytochrome b6f complex. The mitochondria-encoded subunit 1 of cytochrome-c oxidase called COX1 was identified, and its synthesis was detected in this membrane fraction. The redox-difference spectra of mitochondrial cytochromes were studied in whole cells and membrane fractions, in both respiratory-competent and deficient strains. Mitochondrial membranes could be further purified after sucrose gradient centrifugation. The use of etiolated cells and their membrane extracts, in association with appropriate methodologies, opens ways to study the molecular genetics of mitochondria in C. reinhardtii and allows us to address the question of the cooperation established between the three genetic compartments of a plant cell. PMID- 11607586 TI - Sample size determination in combinatorial chemistry. AB - Combinatorial chemistry is gaining wide appeal as a technique for generating molecular diversity. Among the many combinatorial protocols, the split/recombine method is quite popular and particularly efficient at generating large libraries of compounds. In this process, polymer beads are equally divided into a series of pools and each pool is treated with a unique fragment; then the beads are recombined, mixed to uniformity, and redivided equally into a new series of pools for the subsequent couplings. The deviation from the ideal equimolar distribution of the final products is assessed by a special overall relative error, which is shown to be related to the Pearson statistic. Although the split/recombine sampling scheme is quite different from those used in analysis of categorical data, the Pearson statistic is shown to still follow a chi2 distribution. This result allows us to derive the required number of beads such that, with 99% confidence, the overall relative error is controlled to be less than a pregiven tolerable limit L1. In this paper, we also discuss another criterion, which determines the required number of beads so that, with 99% confidence, all individual relative errors are controlled to be less than a pregiven tolerable limit L2 (0 < L2 < 1). PMID- 11607588 TI - The evolution of emergent computation. AB - A simple evolutionary process can discover sophisticated methods for emergent information processing in decentralized spatially extended systems. The mechanisms underlying the resulting emergent computation are explicated by a technique for analyzing particle-based logic embedded in pattern-forming systems. Understanding how globally coordinated computation can emerge in evolution is relevant both for the scientific understanding of natural information processing and for engineering new forms of parallel computing systems. PMID- 11607587 TI - Role of the integument in insect defense: pro-phenol oxidase cascade in the cuticular matrix. AB - The cuticle of the silkworm Bombyx mori was demonstrated to contain pro-phenol oxidase [zymogen of phenol oxidase (monophenol, L-dopa:oxygen oxidoreductase, EC 1.14.18.1)] and its activating cascade. The activating cascade contained at least one serine proteinase zymogen (latent form of pro-phenol oxidase activating enzyme). When the extracted cascade components were incubated with Ca2+, the latent form of pro-phenol oxidase activating enzyme was itself activated and, in turn, converted through a limited proteolysis of pro-phenol oxidase to phenol oxidase. Immuno-gold localization of prophenol oxidase in the cuticle using a cross-reactive hemolymph anti-pro-phenol oxidase antibody revealed a random distribution of this enzyme in the nonlamellate endocuticle and a specific orderly arrayed pattern along the basal border of the laminae in the lamellate endocuticle of the body wall. Furthermore, prophenol oxidase was randomly distributed in the taenidial cushion of the tracheal cuticle. At the time of pro phenol oxidase accumulation in the body wall cuticle, no pro-phenol oxidase mRNA could be detected in the epidermal tissue, whereas free-circulating hemocytes contained numerous transcripts of pro-phenol oxidase. Our results suggest that the pro-phenol oxidase is synthesized in the hemocytes and actively transported into the cuticle via the epidermis. PMID- 11607589 TI - Reproductive cooperation between queens and their mated workers: the complex life history of an ant with a valuable nest. AB - The life history of Harpegnathos saltator is exceptional among ants because both queens and workers reproduce sexually. Recently mated queens start new colonies alone, but later some of the offspring workers also become inseminated and take over the egg-laying role. This alternation seems associated with the existence of very complex underground nests, which are designed to survive floods. Longevity of ponerine queens is low (a consequence of limited caste dimorphism in this "primitive" subfamily), and upon the death of an H. saltator foundress, the nest represents a substantial investment. The queen's progeny should thus be strongly selected to retain the valuable nests. Unlike the flying queens, the workers copulate with males from their own colonies, and, thus, their offspring are expected to be highly related to the foundress. Colony fission appears not to occur because a daughter fragment would lack an adequate nest for protection. Thus, the annual production of queens in colonies with reproductive workers remains essential for the establishment of new colonies. This contrasts with various other ponerine species in which the queens no longer exist. PMID- 11607590 TI - Turbulent diffusion phase transition is due to singular energy spectrum. AB - The phase transition for turbulent diffusion, reported by Avellaneda and Majda [Avellaneda, M. & Majda, A. J. (1994) Philos. Trans. R. Soc. London A 346, 205 233, and several earlier papers], is traced to a modeling assumption in which the energy spectrum of the turbulent fluid is singularly dependent on the viscosity in the inertial range. Phenomenological models of turbulence and intermittency, by contrast, require that the energy spectrum be independent of the viscosity in the inertial range. When the energy spectrum is assumed to be consistent with the phenomenological models, there is no phase transition for turbulent diffusion. PMID- 11607591 TI - The oxygen and carbon dioxide compensation points of C3 plants: possible role in regulating atmospheric oxygen. AB - The O2 and CO2 compensation points (O2 and CO2) of plants in a closed system depend on the ratio of CO2 and O2 concentrations in air and in the chloroplast and the specificities of ribulose bisphosphate carboxylase/oxygenase (Rubisco). The photosynthetic O2 is defined as the atmospheric O2 level, with a given CO2 level and temperature, at which net O2 exchange is zero. In experiments with C3 plants, the O2 with 220 ppm CO2 is 23% O2; O2 increases to 27% with 350 ppm CO2 and to 35% O2 with 700 ppm CO2. At O2 levels below the O2, CO2 uptake and reduction are accompanied by net O2 evolution. At O2 levels above the O2, net O2 uptake occurs with a reduced rate of CO2 fixation, more carbohydrates are oxidized by photorespiration to products of the C2 oxidative photosynthetic carbon cycle, and plants senesce prematurely. The CO2 increases from 50 ppm CO2 with 21% O2 to 220 ppm with 100% O2. At a low CO2/high O2 ratio that inhibits the carboxylase activity of Rubisco, much malate accumulates, which suggests that the oxygen-insensitive phosphoenolpyruvate carboxylase becomes a significant component of the lower CO2 fixation rate. Because of low global levels of CO2 and a Rubisco specificity that favors the carboxylase activity, relatively rapid changes in the atmospheric CO2 level should control the permissive O2 that could lead to slow changes in the immense O2 pool. PMID- 11607592 TI - The challenge of paleoecological stasis: reassessing sources of evolutionary stability. AB - The paleontological record of the lower and middle Paleozoic Appalachian foreland basin demonstrates an unprecedented level of ecological and morphological stability on geological time scales. Some 70-80% of fossil morphospecies within assemblages persist in similar relative abundances in coordinated packages lasting as long as 7 million years despite evidence for environmental change and biotic disturbances. These intervals of stability are separated by much shorter periods of ecological and evolutionary change. This pattern appears widespread in the fossil record. Existing concepts of the evolutionary process are unable to explain this uniquely paleontological observation of faunawide coordinated stasis. A principle of evolutionary stability that arises from the ecosystem is explored here. We propose that hierarchical ecosystem theory, when extended to geological time scales, can explain long-term paleoecological stability as the result of ecosystem organization in response to high-frequency disturbance. The accompanying stability of fossil morphologies results from "ecological locking," in which selection is seen as a high-rate response of populations that is hierarchically constrained by lower-rate ecological processes. When disturbance exceeds the capacity of the system, ecological crashes remove these higher-level constraints, and evolution is free to proceed at high rates of directional selection during the organization of a new stable ecological hierarchy. PMID- 11607593 TI - Quasars and active galactic nuclei: high resolution radio imaging. PMID- 11607594 TI - Very-long-baseline radio interferometry surveys of the compact structure in active galactic nuclei. AB - Very-long-baseline radio interferometry (VLBI) imaging surveys have been undertaken since the late 1970s. The sample sizes were initially limited to a few tens of objects but the snapshot technique has now allowed samples containing almost 200 sources to be studied. The overwhelming majority of powerful compact sources are asymmetric corejects of one form or another, most of which exhibit apparent superluminal motion. However 5-10% of powerful flat-spectrum sources are 100-parsec (pc)-scale compact symmetric objects; these appear to form a continuum with the 1-kpc-scale double-lobed compact steep-spectrum sources, which make up 15-20% of lower frequency samples. It is likely that these sub-galactic-size symmetric sources are the precursors to the large-scale classical double sources. There is a surprising peak around 90 degrees in the histogram of misalignments between the dominant source axes on parsec and kiloparsec scales; this seems to be associated with sources exhibiting a high degree of relativistic beaming. VLBI snapshot surveys have great cosmological potential via measurements of both proper motion and angular size vs. redshift as well as searches for gravitational "millilensing." PMID- 11607595 TI - Morphology of high-luminosity compact radio sources. AB - High-dynamic range imaging and monitoring with very-long-baseline interferometry reveal a rich morphology of luminous flat-spectrum radio sources. One-sided core jet structures abound, and superluminal motion is frequently measured. In a few cases, both distinct moving features and diffuse underlying jet emission can be detected. Superluminal motion seen in such sources is typically complex, on curved trajectories or ridge lines, and with variable component velocities, including stationary features. The curved trajectories seen can be modeled by helical motion within the underlying jet flow. The very-long-baseline interferometry properties of the superluminal features in the jet of 3C 345 and other similar sources can be explained by models invoking the emission from shocks, at least within the vicinity of the compact core. Inverse-Compton calculations, constrained by x-ray observations, yield realistic estimates for the physical conditions in the parsec-scale jet. There is evidence for a transition region in this source beyond which other factors (e.g., plasma interactions and nonsynchrotron radiation processes) may become prominent. Multifrequency and polarization imaging (especially at high frequencies) are emerging as critical tools in testing model predictions. PMID- 11607596 TI - Very-long-baseline radio interferometry observations of low power radio galaxies. AB - The parsec scale properties of low power radio galaxies are reviewed here, using the available data on 12 Fanaroff-Riley type I galaxies. The most frequent radio structure is an asymmetric parsec-scale morphology--i.e., core and one-sided jet. It is shared by 9 (possibly 10) of the 12 mapped radio galaxies. One (possibly 2) of the other galaxies has a two-sided jet emission. Two sources are known from published data to show a proper motion; we present here evidence for proper motion in two more galaxies. Therefore, in the present sample we have 4 radio galaxies with a measured proper motion. One of these has a very symmetric structure and therefore should be in the plane of the sky. The results discussed here are in agreement with the predictions of the unified scheme models. Moreover, the present data indicate that the parsec scale structure in low and high power radio galaxies is essentially the same. PMID- 11607597 TI - Structure and evolution of the compact radio source in NGC 1275. AB - Investigations of the fine-scale structure in the compact nucleus of the radio source 3C 84 in NGC 1275 (New General Catalogue number) are reported. Structural monitoring observations beginning as early as 1976, and continuing to the present, revealed subluminal motions in a jet-like relatively diffuse region extending away from a flat-spectrum core. A counterjet feature was discovered in 1993, and very recent nearly simultaneous studies have detected the same feature at five frequencies ranging from 5 to 43 GHz. The counterjet exhibits a strong low-frequency cutoff, giving this region of the source an inverted spectrum. The observations are consistent with a physical model in which the cutoff arises from free-free absorption in a volume that surrounds the core but obscures only the counterjet feature. If such a model is confirmed, very-long-baseline radio interferometry observations can then be used to probe the accretion region, outside the radio jet, on parsec scales. PMID- 11607598 TI - The parsec-scale jet in M87. AB - We briefly review the observed structure and evolution of the M87 jet on scales less, similar1 parsec (pc; 1 pc = 3.09 x 10(16) m). Filamentary features, limb brightening, and side-to-side oscillation are common characteristics of the pc scale, and kpc-scale jets. The most prominent emission features on both the pc and subpc scales appear stationary (v/c < 0.1). Nonetheless, based on the jet's flux evolution, the presence of kpc-scale superluminal motion, and the absence of a visible counter-jet, we argue for the presence of an underlying relativistic flow, consistent with unified models. The initial jet collimation appears to occur on scales <0.1 pc, thus favoring electromagnetic processes associated with a black hole and accretion disk. PMID- 11607599 TI - Subparsec-scale structure and evolution of Centaurus A (NGC5128). AB - We present a series of 8.4-GHz very-long-baseline radio interferometry images of the nucleus of Centaurus A (NGC5128) made with a Southern Hemisphere array, representing a 3.3-year monitoring effort. The nuclear radio jet is approximately 50 milliarcseconds in extent, or at the 3.5-megaparsec distance of NGC5128, approximately 1 parsec in length. Subluminal motion is seen and structural changes are observed on time scales shorter than 4 months. High-resolution observations at 4.8 and 8.4 GHz made in November 1992 reveal a complex morphology and allow us to unambiguously identify the self-absorbed core located at the southwestern end of the jet. PMID- 11607600 TI - The nuclear jet and counterjet region of the radio galaxy Cygnus A. AB - Very-long-baseline interferometry images of the nuclear region of the radio galaxy Cygnus A reveal a pronounced "core" and a knotty jet and counterjet. The knots are moving away from the core at apparent speeds which are subluminal for h = 1 [h = H0/100 km.s-1.Mpc-1;1 parsec (pc) = 3.09 x 10(16)m] and about c for h = 0.5. The jet is aligned with the outer, kiloparsec-scale jet to within 2 degrees. The counterjet has a total flux density at 5 GHz of about one-fifth of that of the jet. In the context of the twin relativistic jet model for active galactic nuclei, the jet in Cygnus A is oriented at an angle to our line of sight of 35-80 degrees and 55-85 degrees, and the intrinsic velocity of the jet fluid is 0.4 0.6c and 0.6-1c for h = 1 and h = 0.5, respectively. PMID- 11607601 TI - The nuclear region of the spiral galaxy M81. AB - Very-long-baseline radio interferometry images of the nuclear region of the nearby spiral galaxy M81 reveal the most compact galactic core outside the Galaxy of which the size has been determined: 700 x 300 astronomical units (AU). The observations exclude a starburst or supernova interpretation for the core. Instead they favor an active galactic nucleus. There is evidence for a northeastern jet bent by approximately 35 degrees over a length scale from 700 to 4000 AU. The jet is, on average, directed toward an extended emission region, probably a radio lobe, about 1 kiloparsec (kpc) away from the core. A corresponding emission region was found in the southwest at a distance of only 30 pc from the core. The observed jet is extremely stable and likely to be associated with a steady-state channel. There is no detectable motion along the jet beyond the nominal value of -60 +/- 60 km.s-1. The level of activities in the core region of M81 is intermediate between that of SgrA* and that of powerful radio galaxies and quasars. PMID- 11607602 TI - Very-long-baseline radio interferometry (VLBI) observations of gamma-ray blazars: results from millimeter-VLBI observations. AB - VLBI observations of the extremely gamma-bright blazar PKS 0528+134 at 8, 22, 43, and 86 GHz reveal a strongly bent one-sided-core jet structure with at least three moving and two apparently stationary jet components. At the highest observing frequencies the brightest and most compact jet component (the VLBI core) is unresolved with an upper limit to its size of approximately 50 microarcsec corresponding to approximately 0.2 parsec [H0 = 100 km.s-1.Mpc-1 (megaparsec-1), q0 = 0.5, where H0 is Hubble constant and q0 is the deceleration parameter]. Two 86-GHz VLBI observations performed in 1993.3 and 1994.0 reveal a new jet component emerging with superluminal speed from the core. Linear back extrapolation of its motion yields strong evidence that the ejection of this component is related to an outburst in the millimeter regime and a preceding intense flare of the gamma-flux density observed in early 1993. This and the radio/optical "light curves" and VLBI data for two other sources (S5 0836+710 and 3C 454.3) suggest that the observed gamma-radiation might be Doppler-boosted and perhaps is closely related to the physical processes acting near the "base" of the highly relativistic jets observed in quasars. PMID- 11607603 TI - Bidirectional motion observed in the compact symmetric object 1946+708. AB - We present the first direct measurements of bidirectional motions in an extragalactic radio jet. The radio source 1946+708 is a compact symmetric object with striking S-symmetry identified with a galaxy at a redshift of 0.101. From observations 2 years apart we have determined the velocities of four compact components in the jet, the fastest of which has an apparent velocity of 1.09 h 1c. By pairing up the components, assuming they were simultaneously ejected in opposite directions, we derive a 1 lower limit on the Hubble constant, H0 > 42 km.s-1.Mpc-1. PMID- 11607604 TI - Superluminal sources. AB - Predictions for the apparent velocity statistics under simple beaming models are presented and compared to the observations. The potential applications for tests of unification models and for cosmology (source counts, measurements of the Hubble constant H0 and the deceleration parameter q0) are discussed. First results from a large homogeneous survey are presented. The data do not show compelling evidence for the existence of intrinsically different populations of galaxies, BL Lacertae objects, or quasars. Apparent velocities betaapp in the range 1-5 h-1, where h = H0/100 km.s-1.Mpc-1 [1 megaparsec (Mpc) = 3.09 x 10(22) m], occur with roughly equal frequency; higher values, up to betaapp = 10 h-1, are rather more scarce than appeared to be the case from earlier work, which evidently concentrated on sources that are not representative of the general population. The betaapp distribution suggests that there might be a skewed distribution of Lorentz factors over the sample, with a peak at gammab approximately 2 h-1 and a tail up to at least gammab approximately 10 h-1. There appears to be a clearly rising upper envelope to the betaapp distribution when plotted as a function of observed 5-GHz luminosity; a combination of source counts and the apparent velocity statistics in a larger sample could provide much insight into the properties of radio jet sources. PMID- 11607605 TI - Grs 1915+105: a superluminal source in the Galaxy. AB - We present the results of additional observations of the high energy source GRS 1915+105, which produces ejecta with apparent superluminal motions. The observations reported here were carried out with the Very Large Array at 3.5 cm and 20 cm. The 3.5-cm observations made during 1994 May allowed us to continue following the proper motions of the bright 1994 March 19 ejecta, as well as those of a subsequent, fainter ejection. The proper motions of the 1994 March 19 ejecta continued to be ballistic (i.e., constant) over the period of about 75 days where they remained detectable. From the observations in 1994 March-May we have identified three ejections of pairs of plasma clouds moving ballistically in approximately the same direction on the sky with similar proper motions. The 20 cm observations made during 1994 November and December were used to search, yet unsuccessfully, for extended jets or lobes associated with GRS 1915+105. PMID- 11607606 TI - Possible links between BL Lacertae objects and quasars from very long baseline interferometry radio data. AB - Systematic differences in the very long baseline interferometry (VLBI) radio polarization structure and average VLBI component speeds of BL Lacertae objects and quasars support the view that the observational distinction between these classes, based in large part on the strength of their optical line emission, is meaningful; in other words, this distinction reflects significant differences in the physical conditions in these sources. Possible models providing a link between the optical and VLBI properties of BL Lacertae objects and quasars are discussed. Most VLBI polarization observations to date have been global observations made at 6 cm; recent results suggest that the VLBI polarization structure of some sources may change dramatically on scales smaller than those probed by these 6-cm observations. PMID- 11607607 TI - The case for unification. AB - I investigate the issue of whether the various subclasses of radio-loud galaxies are intrinsically the same but have been classified differently mainly due to their being viewed from different directions. Evidence for the two key elements of this popular version of the "unified scheme (US)," relativistic jets and nuclear tori, is updated. The case for the torus opening angle increasing with the radio luminosity of the active galactic nucleus (AGN) is freshly argued. Radio-loud AGN are particularly suited for testing the US, since their structures and polarization properties on different scales, as well as their overall radio sizes, provide useful statistical indicators of the relative orientations of their various subclasses. I summarize recent attempts to bring under a single conceptual framework the USs developed for radio-moderate [Fanaroff-Riley type I (FRI)] and radio-powerful (FRII) AGN. By focusing on FRII radio sources, I critically examine the recent claims of conflict with the US, based on the statistics of radio-size measurements for large, presumably orientation independent, samples with essentially complete optical identifications. Possible ways of reconciling these results, and also the ones based on very-long-baseline radio interferometry polarimetric observations, with the US are pointed out. By incorporating a highly plausible temporal evolution of radio source properties into the US, I outline a scenario that allows the median linear size of quasars to approach, or even exceed, that of radio galaxies, as samples with decreasing radio luminosity are observed. Thus, even though a number of issues remain to be fully resolved, the scope of unified models continues to expand. PMID- 11607608 TI - Difficulties with unification. AB - The difficulties perceived in the orientation-based unified scheme models, when confronted with the observational data, are pointed out. It is shown that in meter-wavelength selected samples, which presumably are largely free of an orientation bias, the observed numbers of quasars versus radio galaxies are not in accordance with the expectations of the unified scheme models. The observed number ratios seem to depend heavily on the redshift, fluxdensity, or radio luminosity levels of the selected sample. This cannot be explained within the simple orientation-based unified scheme with a fixed average value of the half opening angle (c approximately 45 degrees ) for the obscuring torus that supposedly surrounds the nuclear optical continuum and the broad-line regions. Further, the large differences seen between radio galaxies and quasars in their size distributions in the luminosity-redshift plane could not be accommodated even if I were to postulate some suitable cosmological evolution of the opening angle of the torus. Some further implications of these observational results for the recently proposed modified versions of the unified scheme model are pointed out. PMID- 11607609 TI - Unification and large-scale structure. AB - The hypothesis of relativistic flow on parsec scales, coupled with the symmetrical (and therefore subrelativistic) outer structure of extended radio sources, requires that jets decelerate on scales observable with the Very Large Array. The consequences of this idea for the appearances of FRI and FRII radio sources are explored. PMID- 11607610 TI - Compact steep-spectrum sources and the unified scheme. AB - The compact steep-spectrum sources (CSSs) are an interesting class of objects which are of subgalactic dimensions; they occur more frequently in high-frequency surveys because their spectra often turn over at lower frequencies. We have estimated the symmetry parameters of a well-defined sample of CSSs and compared these with the larger 3CR sources of similar luminosity to understand the evolution and the consistency of CSSs with the unified scheme. We suggest that the majority of CSSs are likely to be young sources advancing outward through an asymmetric, inhomogeneous environment to form the larger ones. The radio properties of the CSSs are consistent with the unified scheme, where the axes of the quasars are seen closer to the line of sight while the radio galaxies lie closer to the plane of the sky. We discuss how radio polarization observations may be used to probe whether the physical conditions in the central regions of the CSSs are different from the larger ones. We present a simple scenario where the depolarization and high rotation measures seen in many CSSs can be consistent with the low rotation measures of cores in the more extended quasars and suggest further observations to test this scenario. PMID- 11607611 TI - Optical evidence for the unification of active galactic nuclei and quasi-stellar objects. AB - There is a variety of optical evidence for some unification of different types of active galactic nuclei and quasi-stellar objects (QSOs). The case is very strong for the unification of at least some Seyfert galaxies, where polarization data show that the type assigned to the Seyfert galaxy must depend on viewing direction. It has been proposed that Fanaroff-Riley type 2 (FR2) radio galaxies are quasars seen in a direction from which the quasar is obscured, and there is some limited direct evidence for this picture. The broad absorption line QSOs may be normal QSOs seen from a special direction. Some of the sources observed to have high luminosities in the far infrared could be obscured QSOs and active nuclei. Mergers and interactions are likely to play an important role in nuclear activity, and active galaxies and QSOs could change their apparent types through these encounters followed by subsequent evolution. PMID- 11607612 TI - Probing active galactic nuclei with H2O megamasers. AB - We describe the characteristics of the rapidly rotating molecular disk in the nucleus of the mildly active galaxy NGC4258. The morphology and kinematics of the disk are delineated by the point-like watervapor emission sources at 1.35-cm wavelength. High angular resolution [200 microas where as is arcsec, corresponding to 0.006 parsec (pc) at 6.4 million pc] and high spectral resolution (0.2 km.s-1 or nu/Deltanu = 1.4 x 10(6)) with the Very-Long-Baseline Array allow precise definition of the disk. The disk is very thin, but slightly warped, and is viewed nearly edge-on. The masers show that the disk is in nearly perfect Keplerian rotation within the observable range of radii of 0.13-0.26 pc. The approximately random deviations from the Keplerian rotation curve among the high-velocity masers are approximately 3.5 km.s-1 (rms). These deviations may be due to the masers lying off the midline by about +/-4 degrees or variations in the inclination of the disk by +/-4 degrees. Lack of systematic deviations indicates that the disk has a mass of <4 x 10(6) solar mass (M[symbol: see text]). The gravitational binding mass is 3.5 x 10(7) M[symbol: see text], which must lie within the inner radius of the disk and requires that the mass density be >4 x 10(9) M[symbol: see text].pc-3. If the central mass were in the form of a star cluster with a density distribution such as a Plummer model, then the central mass density would be 4 x 10(12) M[symbol: see text].pc-3. The lifetime of such a cluster would be short with respect to the age of the galaxy [Maoz, E. (1995) Astrophys. J. Lett. 447, L91-L94]. Therefore, the central mass may be a black hole. The disk as traced by the systemic velocity features is unresolved in the vertical direction, indicating that its scale height is <0.0003 pc (hence the ratio of thickness to radius, H/R, is <0.0025). For a disk in hydrostatic equilibrium the quadrature sum of the sound speed and Alfven velocity is <2.5 km.s-1, so that the temperature of the disk must be <1000 K and the toroidal magnetic field component must be <250 mG. If the molecular mass density in the disk is 10(10) cm-3, then the disk mass is approximately 10(4) M[symbol: see text], and the disk is marginally stable as defined by the Toomre stability parameter Q (Q = 6 at the inner edge and 1 at the outer edge). The inward drift velocity is predicted to be <0.007 km.s-1, for a viscosity parameter of 0.1, and the accretion rate is <7 x 10(-5) M[symbol: see text].yr-1. At this value the accretion would be sufficient to power the nuclear x-ray source of 4 x 10(40) ergs-1 (1 erg = 0.1 microJ). The volume of individual maser components may be as large as 10(46) cm3, based on the velocity gradients, which is sufficient to supply the observed luminosity. The pump power undoubtedly comes from the nucleus, perhaps in the form of x-rays. The warp may allow the pump radiation to penetrate the disk obliquely [Neufeld, D. A. & Maloney, P. R. (1995) Astrophys. J. Lett. 447, L17-L19]. A total of 15 H2O megamasers have been identified out of >250 galaxies searched. Galaxy NGC4258 may be the only case where conditions are optimal to reveal a well-defined nuclear disk. Future measurement of proper motions and accelerations for NGC4258 will yield an accurate distance and a more precise definition of the dynamics of the disk PMID- 11607613 TI - Gravitational lensing of active galactic nuclei. AB - Most of the known cases of strong gravitational lensing involve multiple imaging of an active galactic nucleus. The properties of lensed active galactic nuclei make them promising systems for astrophysical applications of gravitational lensing; in particular, they show structure on scales of milliseconds of arc to tens of seconds of arc, they are variable, and they are polarized. More than 20 cases of strong gravitational lenses are now known, and about half of them are radio sources. High-resolution radio imaging is making possible the development of well-constrained lens models. Variability studies at radio and optical wavelengths are beginning to yield results of astrophysical interest, such as an independent measure of the distance scale and limits on source sizes. PMID- 11607614 TI - Probes of the inner jets of blazars. AB - I review models for the "inner jet" in blazars, the section that connects the central engine with the radio jet. I discuss how the structure and physics of the inner jet can be explored using millimeter-wave VLBI (very-long-baseline radio interferometry) as well as multiwaveband observations of blazars. Flares at radio to gamma-ray frequencies should exhibit time delays at different wavebands that can test models for both the high-energy emission mechanisms and the nature of the inner jet in blazars. PMID- 11607615 TI - The acceleration and collimation of jets. AB - I will discuss several issues related to the acceleration, collimation, and propagation of jets from active galactic nuclei. Hydromagnetic stresses provide the best bet for both accelerating relativistic flows and providing a certain amount of initial collimation. However, there are limits to how much "self collimation" can be achieved without the help of an external pressurized medium. Moreover, existing models, which postulate highly organized poloidal flux near the base of the flow, are probably unrealistic. Instead, a large fraction of the magnetic energy may reside in highly disorganized "chaotic" fields. Such a field can also accelerate the flow to relativistic speeds, in some cases with greater efficiency than highly organized fields, but at the expense of self-collimation. The observational interpretation of jet physics is still hampered by a dearth of unambiguous diagnostics. Propagating disturbances in flows, such as the oblique shocks that may constitute the kiloparsec-scale "knots" in the M87 jet, may provide a wide range of untapped diagnostics for jet properties. PMID- 11607616 TI - Evolution of powerful extragalactic radio sources. AB - Observations of complete flux density limited samples of powerful extragalactic radio sources by very-long-baseline interferometry enable us to study the evolution of these objects over the range of linear scales from 1 parsec to 15 kiloparsees (1 parsec = 3.09 x 10(18) cm). The observations are consistent with the unifying hypothesis that compact symmetric objects evolve into compact steep spectrum doubles, which in turn evolve into large-scale Fanaroff-Riley class II objects. It is suggested that this is the primary evolutionary track of powerful extragalactic radio sources. In this case there must be significant luminosity evolution in these objects, but little velocity evolution, as they expand from 1 parsec to several hundred kiloparsecs in overall size. PMID- 11607617 TI - Lipoxygenase-catalyzed oxygenation of storage lipids is implicated in lipid mobilization during germination. AB - The etiolated germination process of oilseed plants is characterized by the mobilization of storage lipids, which serve as a major carbon source for the seedling. We found that during early stages of germination in cucumber, a lipoxygenase (linoleate: oxygen oxidoreductase, EC 1.13.11.12) form is induced that is capable of oxygenating the esterified fatty acids located in the lipid storage organelles, the so-called lipid bodies. Large amounts of esterified (13S) hydroxy-(9Z,11E)-octadecadienoic acid were detected in the lipid bodies, whereas only traces of other oxygenated fatty acid isomers were found. This specific product pattern confirms the in vivo action of this lipoxygenase form during germination. Lipid fractionation studies of lipid bodies indicated the presence of lipoxygenase products both in the storage triacylglycerols and, to a higher extent, in the phospholipids surrounding the lipid stores as a monolayer. The degree of oxygenation of the storage lipids increased drastically during the time course of germination. We show that oxygenated fatty acids are preferentially cleaved from the lipid bodies and are subsequently released into the cytoplasm. We suggest that they may serve as substrate for beta-oxidation. These data suggest that during the etiolated germination, a lipoxygenase initiates the mobilization of storage lipids. The possible mechanisms of this implication are discussed. PMID- 11607618 TI - Plant histochemistry by correlation peak imaging. AB - Using a new NMR correlation-peak imaging technique, we were able to investigate noninvasively the spatial distribution of carbohydrates and amino acids in the hypocotyl of castor bean seedlings. In addition to the expected high sucrose concentration in the phloem area of the vascular bundles, we could also observe high levels of sucrose in the cortex parenchyma, but low levels in the pith parenchyma. In contrast, the glucose concentration was found to be lower in the cortex parenchyma than in the pith parenchyma. Glutamine and/or glutamate was detected in the cortex parenchyma and in the vascular bundles. Lysine and arginine were mainly visible in the vascular bundles, whereas valine was observed in the cortex parenchyma, but not in the vascular bundles. Although the physiological significance of these metabolite distribution patterns is not known, they demonstrate the potential of spectroscopic NMR imaging to study noninvasively the physiology and spatial metabolic heterogeneity of living plants. PMID- 11607619 TI - Pollen selection: a transgenic reconstruction approach. AB - A transgenic reconstruction experiment has been performed to determine the feasibility of male gametophytic selection to enhance transmission of genes to the next sporophytic generation. For tobacco pollen from a transgenic plant containing a single hygromycin-resistance (hygromycin phosphotransferase, hpt-) gene under control of the dc3 promoter, which is active in both sporophytic and gametophytic tissues, 3 days of in vitro maturation in hygromycin-containing medium was sufficient to result in a 50% reduction of germinating pollen, as expected for meiotic segregation of a single locus insert. Pollination of wild type plants with the selected pollen yielded 100% transgenic offspring, as determined by the activity of the linked kanamycin-resistance gene--present within the same transferred T-DNA borders--under control of the nos promoter. This is direct proof that selection acting on male gametophytes can be a means to alter the frequency of genes in the progeny. PMID- 11607620 TI - Relationship between photosynthetic electron transport and pH gradient across the thylakoid membrane in intact leaves. AB - Under conditions (0.2% CO2; 1% O2) that allow high rates of photosynthesis, chlorophyll fluorescence was measured simultaneously with carbon assimilation at various light intensities in spinach (Spinacia oleracea) leaves. Using a stoichiometry of 3 ATP/CO2 and the known relationship between ATP synthesis rate and driving force (Delta pH), we calculated the light-dependent pH gradient (Delta pH) across the thylakoid membrane in intact leaves. These Delta pH values were correlated with the photochemical (qP) and nonphotochemical (qN) quenching of chlorophyll fluorescence and with the quantum yield of photosystem II (phiPSII). At Delta pH > 2.1 all three parameters (qP, qN, and phiPSII) changed very steeply with increasing DeltapH (decreasing pH in the thylakoid). The observed pH dependences followed hexacooperative titration curves with slightly different pKa values. The significance of the steep pH dependences with slightly different pKa values is discussed in relation to the regulation of photosynthetic electron transport in intact leaves. PMID- 11607621 TI - Destruction of a single chlorophyll is correlated with the photoinhibition of photosystem II with a transiently inactive donor side. AB - Pigments destroyed during photoinhibition of water-splitting photosystem II core complexes from the green alga Chlamydomonas reinhardtii were studied. Under conditions of a transiently inactivated donor side, illumination leads to an irreversible inhibition of the electron transfer at the donor side that is paralleled by the destruction of chlorophylls a absorbing maximally around 674 and 682 nm. The observed stochiometry of 1 +/- 0.1 destroyed chlorophyll per inhibited photosystem II suggests that chlorophyll destruction could be the primary photodamage causing the inhibition of photosystem II under these conditions. PMID- 11607622 TI - Temporally and spectrally resolved subpicosecond energy transfer within the peripheral antenna complex (LH2) and from LH2 to the core antenna complex in photosynthetic purple bacteria. AB - We report studies of energy transfer from the 800-nm absorbing pigment (B800) to the 850-nm absorbing pigment (B850) of the LH2 peripheral antenna complex and from LH2 to the core antenna complex (LH1) in Rhodobacter (Rb.) sphaeroides. The B800 to B850 process was studied in membranes from a LH2-reaction center (no LH1) mutant of Rb. sphaeroides and the LH2 to LH1 transfer was studied in both the wild-type species and in LH2 mutants with blue-shifted B850. The measurements were performed by using approximately 100-fs pulses to probe the formation of acceptor excitations in a two-color pump-probe measurement. Our experiments reveal a B800 to B850 transfer time of approximately 0.7 ps at 296 K and energy transfer from LH2 to LH1 is characterized by a time constant of approximately 3 ps at 296 K and approximately 5 ps at 77 K. In the blue-shifted B850 mutants, the transfer time from B850 to LH1 becomes gradually longer with increasing blue shift of the B850 band as a result of the decreasing spectral overlap between the antennae. The results have been used to produce a model for the association between the ring-like structures that are characteristic of both the LH2 and LH1 antennae. PMID- 11607623 TI - Commentary on "From local to global in quasiconformal structures". PMID- 11607624 TI - From local to global in quasiconformal structures. AB - We exhibit a large class of metric spaces whose infinitesimal quasiconformal structure is strong enough to capture the global quasiconformal structure. A sufficient condition for this to happen is described in terms of a Poincare-type inequality. PMID- 11607625 TI - Substructure of the inner core of the Earth. AB - The rationale is disclosed for a substructure within the Earth's inner core, consisting of an actinide subcore at the center of the Earth, surrounded by a subshell composed of the products of nuclear fission and radioactive decay. Estimates are made as to possible densities, physical dimensions, and chemical compositions. The feasibility for self-sustaining nuclear fission within the subcore is demonstrated, and implications bearing on the structure and geodynamic activity of the inner core are discussed. PMID- 11607627 TI - Sodium: a male moth's gift to its offspring. AB - Males of the moth Gluphisia septentrionis acquire sodium by drinking from mud puddles. Analyses of male and female bodies indicate that such "puddling" behavior enables the male to provide his mate with a nuptial gift of sodium, presumably via the spermatophore. This gift (about 10 microg), amounting to more than half of a puddler male's total body sodium, is in large measure apportioned by the female to her eggs. Puddler-sired eggs contain 2 to 4 times more sodium than those control-sired; this difference is already apparent in eggs laid the night after mating. Paternal endowment of offspring with sodium had not previously been demonstrated for an insect to our knowledge. The potential adaptive significance of such chemical bestowal is evident, given that the foliar diet of G. septentrionis larvae is extremely low in sodium content. PMID- 11607626 TI - Recruitment and replacement of hippocampal neurons in young and adult chickadees: an addition to the theory of hippocampal learning. AB - We used [3H]thymidine to document the birth of neurons and their recruitment into the hippocampal complex (HC) of juvenile (4.5 months old) and adult blackcapped chickadees (Parus atricapillus) living in their natural surroundings. Birds received a single dose of [3H]thymidine in August and were recaptured and killed 6 weeks later, in early October. All brains were stained with Cresyl violet, a Nissl stain. The boundaries of the HC were defined by reference to the ventricular wall, the brain surface, or differences in neuronal packing density. The HC of juveniles was as large as or larger than that of adults and packing density of HC neurons was 31% higher in juveniles than in adults. Almost all of the 3H-labeled HC neurons were found in a 350-m-wide layer of tissue adjacent to the lateral ventricle. Within this layer the fraction of 3H-labeled neurons was 50% higher in juveniles than in adults. We conclude that the HC of juvenile chickadees recruits more neurons and has more neurons than that of adults. We speculate that juveniles encounter greater environmental novelty than adults and that the greater number of HC neurons found in juveniles allows them to learn more than adults. At a more general level, we suggest that (i) long-term learning alters HC neurons irreversibly; (ii) sustained hippocampal learning requires the periodic replacement of HC neurons; (iii) memories coded by hippocampal neurons are transferred elsewhere before the neurons are replaced. PMID- 11607628 TI - Self-assembly of a heteroduplex helicate from two different ligand strands and Cu(II) cations. AB - Cu(II) ions have been reacted with a 1/1 mixture of two linear ligands, one containing three 2,2'- bipyridine groups and the other three 2,2':6',2" terpyridine groups. Absorption spectroscopy and fast atom bombardment mass spectrometry indicate the formation of a trinuclear complex containing one ligand of each kind. Determination of the crystal structure of this compound has confirmed that it is indeed a linear trinuclear complex in which two different ligands are wrapped in a helical fashion around the pentacoordinated metal ions. The central coordination geometry is trigonal bipyramidal; the two lateral Cu(II) ions are in a square pyramidal environment. Thus, a heteroduplex helicate is formed by the self-assembly of two different ligand strands and three specific metal ions induced by the coordination number and geometry of the latter. The self-assembly process may be considered to result from the reading of the steric and binding information present in the two ligands by Cu(II) ions through a pentacoordination algorithm. The same ligands have been shown earlier to yield homoduplex helicates from ions of tetrahedral and octahedral coordination geometry and strands of bidentate bipyridines and tridentate terpyridines, respectively. These two types of artificial double helical species may be related on one hand to the natural homoduplex nucleic acids and on the other hand to the DNA:RNA heteroduplex. PMID- 11607629 TI - Quenching of chlorophyll fluorescence in the major light-harvesting complex of photosystem II: a systematic study of the effect of carotenoid structure. AB - The role of carotenoids in quenching of chlorophyll fluorescence in the major light-harvesting complex of photosystem II has been studied with a view to understanding the molecular basis of the control of photoprotective nonradiative energy dissipation by the xanthophyll cycle in vivo. The control of chlorophyll fluorescence quenching in the isolated complex has been investigated in terms of the number of the conjugated double bonds for a series of carotenoids ranging from n = 5-19, giving an estimated first excited singlet state energy from 20,700 cm-1 to 10,120 cm-1. At pH 7.8 the addition of exogenous carotenoids with >=10 conjugated double bonds (including zeaxanthin) stimulated fluorescence quenching relative to the control with no added carotenoid, whereas those with n S1 and S1--> S2 transitions are accompanied by characteristic changes in the shape of the edge, both indicative of Mn oxidation. The edge position shifts very little (0.3 eV) for the S2--> S3 transition, and the edge shape shows only subtle changes. We conclude that probably no direct Mn oxidation is involved in this transition. The proposed Mn oxidation state assignments are as follows: S0 (II, III, IV, IV) or (III, III, III, IV), S1 (III, III, IV, IV), S2 (III, IV, IV, IV), S3 (III, IV, IV, IV). PMID- 11607650 TI - The insect neuropeptide prothoracicotropic hormone is released with a daily rhythm: re-evaluation of its role in development. AB - Prothoracicotropic hormone (PTTH) is the central cerebral neurohormone in insect development. Its release has been believed for decades to be confined to one (or two) critical moments early in each developmental stage at which time it triggers prolonged activation of the prothoracic glands to synthesize and release the steroid molting hormones (ecdysteroids), which elicit developmental responses in target tissues. We used an in vitro assay for PTTH released from excised brains of the bug Rhodnius prolixus and report that release of PTTH does occur at the expected time on day 6, but that this release is merely the first in a daily rhythm of release that continues throughout most of the 21 days of larval-adult development. This finding, together with reports of circadian control of ecdysteroid synthesis and titer throughout this time, raises significant challenges to several features of the current understanding of the hormonal control of insect development. New questions are raised concerning the function(s) of PTTH, its relationship with the prothoracic glands, and the significance of circadian rhythmicity throughout this endocrine axis. The significance of the reported observations derives from the set of entirely new questions they raise concerning the regulation of insect development. PMID- 11607651 TI - Analysis of metabolic pathways by the growth of cells in the presence of organic solvents. AB - A new approach to the analysis of metabolic pathways involving poorly water soluble intermediates is proposed. It relies upon the ability of the hydrophobic intermediates formed by a sequence of intracellular reactions to cross the membrane(s) and partition between aqueous and organic phases, when cells are incubated in the presence of a nonpolar and nontoxic organic solvent. As a result of this thermodynamically driven efflux of the formed intermediates from the cell, they accumulate in the organic medium in sufficient quantities for GC-MS analysis and identification. This enables direct determination of the sequence of chemical reactions involved with no requirement for the isolation of each individual metabolite from a cell-free extract. The feasibility of the proposed methodology has been demonstrated by the elucidation of the biosynthesis of (R) gamma-decalactone from (R)-ricinoleic acid catalyzed by the yeast Sporidiobolus ruinenii grown in the presence of decane. The corresponding 4-hydroxy-acid intermediates, formed in the course of beta-oxidation of (R)-ricinoleic acid, were simultaneously observed in a single experiment on the same chromatogram. Potential applications of this proposed methodology are briefly discussed. PMID- 11607652 TI - Twilight-zone and canopy shade induction of the Athb-2 homeobox gene in green plants. AB - We present evidence that a novel phytochrome (other than phytochromes A and B, PHYA and PHYB) operative in green plants regulates the "twilight-inducible" expression of a plant homeobox gene (Athb-2). Light regulation of the Athb-2 gene is unique in that it is not induced by red (R)-rich daylight or by the light-dark transition but is instead induced by changes in the ratio of R to far-red (FR) light. These changes, which normally occur at dawn and dusk (end-of-day FR), also occur during the daytime under the canopy (shade avoidance). By using pure light sources and phyA/phyB null mutants, we demonstrated that the induction of Athb-2 by changes in the R/FR ratio is mediated for the most part by a novel phytochrome operative in green plants. Furthermore, PHYB plays a negative role in repressing the accumulation of Athb-2 mRNA in the dark and a minor role in the FR response. The strict correlation of Athb-2 expression with FR-induced growth phenomena suggests a role for the Athb-2 gene in mediating cell elongation. This interpretation is supported by the finding that the Athb-2 gene is expressed at high levels in rapidly elongating etiolated seedlings. Furthermore, as either R or FR light inhibits cell elongation in etiolated tissues, they also down regulate the expression of Athb-2 mRNA. Thus, these data support the notion that changes in light quality perceived by a novel phytochrome regulate plant development through the action of the Athb-2 homeobox gene. PMID- 11607653 TI - N2 fixation in marine heterotrophic bacteria: dynamics of environmental and molecular regulation. AB - Molecular and immunological techniques were used to examine N2 fixation in a ubiquitous heterotrophic marine bacterium, the facultative anaerobic Vibrio natriegens. When batch cultures were shifted from aerobic N-replete to anaerobic N-deplete conditions, transcriptional and post-translational regulation of N2 fixation was observed. Levels of nifHDK mRNA encoding the nitrogenase enzyme were highest at 140 min postshift and undetectable between 6 and 9 h later. Immunologically determined levels of nitrogenase enzyme (Fe protein) were highest between 6 and 15 h postshift, and nitrogenase activity peaked between 6 and 9 h postshift, declining by a factor of 2 after 12-15 h. Unlike their regulation in cyanobacteria, Fe protein and nitrogenase activity were present when nifHDK mRNA was absent in V. natriegens, indicating that nitrogenase is stored and stable under anaerobic conditions. Both nifHDK mRNA and Fe protein disappeared within 40 min after cultures were shifted from N2-fixing conditions (anaerobic, N-deplete) to non- N2-fixing conditions (aerobic, N-enriched) but reappeared when shifted to conditions favoring N2 fixation. Thus, unlike other N2-fixing heterotrophic bacteria, nitrogenase must be resynthesized after aerobic exposure in V. natriegens. Immunological detection based on immunoblot (Western) analysis and immunogold labeling correlated positively with nitrogenase activity; no localization of nitrogenase was observed. Because V. natriegens continues to fix N2 for many hours after anaerobic induction, this species may play an important role in providing "new" nitrogen in marine ecosystems. PMID- 11607654 TI - Progress toward chemical accuracy in the computer simulation of condensed phase reactions. AB - We describe a procedure for the generation of chemically accurate computer simulation models to study chemical reactions in the condensed phase. The process involves (i) the use of a coupled semiempirical quantum and classical molecular mechanics method to represent solutes and solvent, respectively; (ii) the optimization of semiempirical quantum mechanics (QM) parameters to produce a computationally efficient and chemically accurate QM model; (iii) the calibration of a quantum/classical microsolvation model using ab initio quantum theory; and (iv) the use of statistical mechanical principles and methods to simulate, on massively parallel computers, the thermodynamic properties of chemical reactions in aqueous solution. The utility of this process is demonstrated by the calculation of the enthalpy of reaction in vacuum and free energy change in aqueous solution for a proton transfer involving methanol, methoxide, imidazole, and imidazolium, which are functional groups involved with proton transfers in many biochemical systems. An optimized semiempirical QM model is produced, which results in the calculation of heats of formation of the above chemical species to within 1.0 kcal/mol (1 kcal = 4.18 kJ) of experimental values. The use of the calibrated QM and microsolvation QM/MM (molecular mechanics) models for the simulation of a proton transfer in aqueous solution gives a calculated free energy that is within 1.0 kcal/mol (12.2 calculated vs. 12.8 experimental) of a value estimated from experimental pKa values of the reacting species. PMID- 11607655 TI - Earthquake prediction: the scientific challenge. PMID- 11607656 TI - Earthquake prediction: the interaction of public policy and science. AB - Earthquake prediction research has searched for both informational phenomena, those that provide information about earthquake hazards useful to the public, and causal phenomena, causally related to the physical processes governing failure on a fault, to improve our understanding of those processes. Neither informational nor causal phenomena are a subset of the other. I propose a classification of potential earthquake predictors of informational, causal, and predictive phenomena, where predictors are causal phenomena that provide more accurate assessments of the earthquake hazard than can be gotten from assuming a random distribution. Achieving higher, more accurate probabilities than a random distribution requires much more information about the precursor than just that it is causally related to the earthquake. PMID- 11607657 TI - Initiation process of earthquakes and its implications for seismic hazard reduction strategy. AB - For the average citizen and the public, "earthquake prediction" means "short-term prediction," a prediction of a specific earthquake on a relatively short time scale. Such prediction must specify the time, place, and magnitude of the earthquake in question with sufficiently high reliability. For this type of prediction, one must rely on some short-term precursors. Examinations of strain changes just before large earthquakes suggest that consistent detection of such precursory strain changes cannot be expected. Other precursory phenomena such as foreshocks and nonseismological anomalies do not occur consistently either. Thus, reliable short-term prediction would be very difficult. Although short-term predictions with large uncertainties could be useful for some areas if their social and economic environments can tolerate false alarms, such predictions would be impractical for most modern industrialized cities. A strategy for effective seismic hazard reduction is to take full advantage of the recent technical advancements in seismology, computers, and communication. In highly industrialized communities, rapid earthquake information is critically important for emergency services agencies, utilities, communications, financial companies, and media to make quick reports and damage estimates and to determine where emergency response is most needed. Long-term forecast, or prognosis, of earthquakes is important for development of realistic building codes, retrofitting existing structures, and land-use planning, but the distinction between short-term and long-term predictions needs to be clearly communicated to the public to avoid misunderstanding. PMID- 11607658 TI - Intermediate- and long-term earthquake prediction. AB - Progress in long- and intermediate-term earthquake prediction is reviewed emphasizing results from California. Earthquake prediction as a scientific discipline is still in its infancy. Probabilistic estimates that segments of several faults in California will be the sites of large shocks in the next 30 years are now generally accepted and widely used. Several examples are presented of changes in rates of moderate-size earthquakes and seismic moment release on time scales of a few to 30 years that occurred prior to large shocks. A distinction is made between large earthquakes that rupture the entire downdip width of the outer brittle part of the earth's crust and small shocks that do not. Large events occur quasi-periodically in time along a fault segment and happen much more often than predicted from the rates of small shocks along that segment. I am moderately optimistic about improving predictions of large events for time scales of a few to 30 years although little work of that type is currently underway in the United States. Precursory effects, like the changes in stress they reflect, should be examined from a tensorial rather than a scalar perspective. A broad pattern of increased numbers of moderate-size shocks in southern California since 1986 resembles the pattern in the 25 years before the great 1906 earthquake. Since it may be a long-term precursor to a great event on the southern San Andreas fault, that area deserves detailed intensified study. PMID- 11607659 TI - Scale dependence in earthquake phenomena and its relevance to earthquake prediction. AB - The recent discovery of a low-velocity, low-Q zone with a width of 50-200 m reaching to the top of the ductile part of the crust, by observations on seismic guided waves trapped in the fault zone of the Landers earthquake of 1992, and its identification with the shear zone inferred from the distribution of tension cracks observed on the surface support the existence of a characteristic scale length of the order of 100 m affecting various earthquake phenomena in southern California, as evidenced earlier by the kink in the magnitude-frequency relation at about M3, the constant corner frequency for earthquakes with M below about 3, and the sourcecontrolled fmax of 5-10 Hz for major earthquakes. The temporal correlation between coda Q-1 and the fractional rate of occurrence of earthquakes in the magnitude range 3-3.5, the geographical similarity of coda Q-1 and seismic velocity at a depth of 20 km, and the simultaneous change of coda Q-1 and conductivity at the lower crust support the hypotheses that coda Q-1 may represent the activity of creep fracture in the ductile part of the lithosphere occurring over cracks with a characteristic size of the order of 100 m. The existence of such a characteristic scale length cannot be consistent with the overall self-similarity of earthquakes unless we postulate a discrete hierarchy of such characteristic scale lengths. The discrete hierarchy of characteristic scale lengths is consistent with recently observed logarithmic periodicity in precursory seismicity. PMID- 11607660 TI - Intermediate-term earthquake prediction. AB - An earthquake of magnitude M and linear source dimension L(M) is preceded within a few years by certain patterns of seismicity in the magnitude range down to about (M - 3) in an area of linear dimension about 5L-10L. Prediction algorithms based on such patterns may allow one to predict approximately 80% of strong earthquakes with alarms occupying altogether 20-30% of the time-space considered. An area of alarm can be narrowed down to 2L-3L when observations include lower magnitudes, down to about (M - 4). In spite of their limited accuracy, such predictions open a possibility to prevent considerable damage. The following findings may provide for further development of prediction methods: (i) long range correlations in fault system dynamics and accordingly large size of the areas over which different observed fields could be averaged and analyzed jointly, (ii) specific symptoms of an approaching strong earthquake, (iii) the partial similarity of these symptoms worldwide, (iv) the fact that some of them are not Earth specific: we probably encountered in seismicity the symptoms of instability common for a wide class of nonlinear systems. PMID- 11607661 TI - A selective phenomenology of the seismicity of Southern California. AB - Predictions of earthquakes that are based on observations of precursory seismicity cannot depend on the average properties of the seismicity, such as the Gutenberg-Richter (G-R) distribution. Instead it must depend on the fluctuations in seismicity. We summarize the observational data of the fluctuations of seismicity in space, in time, and in a coupled space-time regime over the past 60 yr in Southern California, to provide a basis for determining whether these fluctuations are correlated with the times and locations of future strong earthquakes in an appropriate time- and space-scale. The simple extrapolation of the G-R distribution must lead to an overestimate of the risk due to large earthquakes. There may be two classes of earthquakes: the small earthquakes that satisfy the G-R law and the larger and large ones. Most observations of fluctuations of seismicity are of the rate of occurrence of smaller earthquakes. Large earthquakes are observed to be preceded by significant quiescence on the faults on which they occur and by an intensification of activity at distance. It is likely that the fluctuations are due to the nature of fractures on individual faults of the network of faults. There are significant inhomogeneities on these faults, which we assume will have an important influence on the nature of self organization of seismicity. The principal source of the inhomogeneity on the large scale is the influence of geometry--i.e., of the nonplanarity of faults and the system of faults. PMID- 11607662 TI - The repetition of large-earthquake ruptures. AB - This survey of well-documented repeated fault rupture confirms that some faults have exhibited a "characteristic" behavior during repeated large earthquakes- that is, the magnitude, distribution, and style of slip on the fault has repeated during two or more consecutive events. In two cases faults exhibit slip functions that vary little from earthquake to earthquake. In one other well-documented case, however, fault lengths contrast markedly for two consecutive ruptures, but the amount of offset at individual sites was similar. Adjacent individual patches, 10 km or more in length, failed singly during one event and in tandem during the other. More complex cases of repetition may also represent the failure of several distinct patches. The faults of the 1992 Landers earthquake provide an instructive example of such complexity. Together, these examples suggest that large earthquakes commonly result from the failure of one or more patches, each characterized by a slip function that is roughly invariant through consecutive earthquake cycles. The persistence of these slip-patches through two or more large earthquakes indicates that some quasi-invariant physical property controls the pattern and magnitude of slip. These data seem incompatible with theoretical models that produce slip distributions that are highly variable in consecutive large events. PMID- 11607663 TI - Hypothesis testing and earthquake prediction. AB - Requirements for testing include advance specification of the conditional rate density (probability per unit time, area, and magnitude) or, alternatively, probabilities for specified intervals of time, space, and magnitude. Here I consider testing fully specified hypotheses, with no parameter adjustments or arbitrary decisions allowed during the test period. Because it may take decades to validate prediction methods, it is worthwhile to formulate testable hypotheses carefully in advance. Earthquake prediction generally implies that the probability will be temporarily higher than normal. Such a statement requires knowledge of "normal behavior"--that is, it requires a null hypothesis. Hypotheses can be tested in three ways: (i) by comparing the number of actual earth-quakes to the number predicted, (ii) by comparing the likelihood score of actual earthquakes to the predicted distribution, and (iii) by comparing the likelihood ratio to that of a null hypothesis. The first two tests are purely self-consistency tests, while the third is a direct comparison of two hypotheses. Predictions made without a statement of probability are very difficult to test, and any test must be based on the ratio of earthquakes in and out of the forecast regions. PMID- 11607664 TI - What electrical measurements can say about changes in fault systems. AB - Earthquake zones in the upper crust are usually more conductive than the surrounding rocks, and electrical geophysical measurements can be used to map these zones. Magnetotelluric (MT) measurements across fault zones that are parallel to the coast and not too far away can also give some important information about the lower crustal zone. This is because the long-period electric currents coming from the ocean gradually leak into the mantle, but the lower crust is usually very resistive and very little leakage takes place. If a lower crustal zone is less resistive it will be a leakage zone, and this can be seen because the MT phase will change as the ocean currents leave the upper crust. The San Andreas Fault is parallel to the ocean boundary and close enough to have a lot of extra ocean currents crossing the zone. The Loma Prieta zone, after the earthquake, showed a lot of ocean electric current leakage, suggesting that the lower crust under the fault zone was much more conductive than normal. It is hard to believe that water, which is responsible for the conductivity, had time to get into the lower crustal zone, so it was probably always there, but not well connected. If this is true, then the poorly connected water would be at a pressure close to the rock pressure, and it may play a role in modifying the fluid pressure in the upper crust fault zone. We also have telluric measurements across the San Andreas Fault near Palmdale from 1979 to 1990, and beginning in 1985 we saw changes in the telluric signals on the fault zone and east of the fault zone compared with the signals west of the fault zone. These measurements were probably seeing a better connection of the lower crust fluids taking place, and this may result in a fluid flow from the lower crust to the upper crust. This could be a factor in changing the strength of the upper crust fault zone. PMID- 11607665 TI - Geochemical challenge to earthquake prediction. AB - The current status of geochemical and groundwater observations for earthquake prediction in Japan is described. The development of the observations is discussed in relation to the progress of the earthquake prediction program in Japan. Three major findings obtained from our recent studies are outlined. (i) Long-term radon observation data over 18 years at the SKE (Suikoen) well indicate that the anomalous radon change before the 1978 Izu-Oshima-kinkai earthquake can with high probability be attributed to precursory changes. (ii) It is proposed that certain sensitive wells exist which have the potential to detect precursory changes. (iii) The appearance and nonappearance of coseismic radon drops at the KSM (Kashima) well reflect changes in the regional stress state of an observation area. In addition, some preliminary results of chemical changes of groundwater prior to the 1995 Kobe (Hyogo-ken nanbu) earthquake are presented. PMID- 11607666 TI - Implications of fault constitutive properties for earthquake prediction. AB - The rate- and state-dependent constitutive formulation for fault slip characterizes an exceptional variety of materials over a wide range of sliding conditions. This formulation provides a unified representation of diverse sliding phenomena including slip weakening over a characteristic sliding distance Dc, apparent fracture energy at a rupture front, time-dependent healing after rapid slip, and various other transient and slip rate effects. Laboratory observations and theoretical models both indicate that earthquake nucleation is accompanied by long intervals of accelerating slip. Strains from the nucleation process on buried faults generally could not be detected if laboratory values of Dc apply to faults in nature. However, scaling of Dc is presently an open question and the possibility exists that measurable premonitory creep may precede some earthquakes. Earthquake activity is modeled as a sequence of earthquake nucleation events. In this model, earthquake clustering arises from sensitivity of nucleation times to the stress changes induced by prior earthquakes. The model gives the characteristic Omori aftershock decay law and assigns physical interpretation to aftershock parameters. The seismicity formulation predicts large changes of earthquake probabilities result from stress changes. Two mechanisms for foreshocks are proposed that describe observed frequency of occurrence of foreshock-mainshock pairs by time and magnitude. With the first mechanism, foreshocks represent a manifestation of earthquake clustering in which the stress change at the time of the foreshock increases the probability of earthquakes at all magnitudes including the eventual mainshock. With the second model, accelerating fault slip on the mainshock nucleation zone triggers foreshocks. PMID- 11607667 TI - Nonuniformity of the constitutive law parameters for shear rupture and quasistatic nucleation to dynamic rupture: a physical model of earthquake generation processes. AB - Based on the recent high-resolution laboratory experiments on propagating shear rupture, the constitutive law that governs shear rupture processes is discussed in view of the physical principles and constraints, and a specific constitutive law is proposed for shear rupture. It is demonstrated that nonuniform distributions of the constitutive law parameters on the fault are necessary for creating the nucleation process, which consists of two phases: (i) a stable, quasistatic phase, and (ii) the subsequent accelerating phase. Physical models of the breakdown zone and the nucleation zone are presented for shear rupture in the brittle regime. The constitutive law for shear rupture explicitly includes a scaling parameter Dc that enables one to give a common interpretation to both small scale rupture in the laboratory and large scale rupture as earthquake source in the Earth. Both the breakdown zone size Xc and the nucleation zone size L are prescribed and scaled by Dc, which in turn is prescribed by a characteristic length lambda c representing geometrical irregularities of the fault. The models presented here make it possible to understand the earthquake generation process from nucleation to unstable, dynamic rupture propagation in terms of physics. Since the nucleation process itself is an immediate earthquake precursor, deep understanding of the nucleation process in terms of physics is crucial for the short-term (or immediate) earthquake prediction. PMID- 11607668 TI - Rock friction and its implications for earthquake prediction examined via models of Parkfield earthquakes. AB - The friction of rocks in the laboratory is a function of time, velocity of sliding, and displacement. Although the processes responsible for these dependencies are unknown, constitutive equations have been developed that do a reasonable job of describing the laboratory behavior. These constitutive laws have been used to create a model of earthquakes at Parkfield, CA, by using boundary conditions appropriate for the section of the fault that slips in magnitude 6 earthquakes every 20-30 years. The behavior of this model prior to the earthquakes is investigated to determine whether or not the model earthquakes could be predicted in the real world by using realistic instruments and instrument locations. Premonitory slip does occur in the model, but it is relatively restricted in time and space and detecting it from the surface may be difficult. The magnitude of the strain rate at the earth's surface due to this accelerating slip seems lower than the detectability limit of instruments in the presence of earth noise. Although not specifically modeled, microseismicity related to the accelerating creep and to creep events in the model should be detectable. In fact the logarithm of the moment rate on the hypocentral cell of the fault due to slip increases linearly with minus the logarithm of the time to the earthquake. This could conceivably be used to determine when the earthquake was going to occur. An unresolved question is whether this pattern of accelerating slip could be recognized from the microseismicity, given the discrete nature of seismic events. Nevertheless, the model results suggest that the most likely solution to earthquake prediction is to look for a pattern of acceleration in microseismicity and thereby identify the microearthquakes as foreshocks. PMID- 11607669 TI - Slip complexity in earthquake fault models. AB - We summarize studies of earthquake fault models that give rise to slip complexities like those in natural earthquakes. For models of smooth faults between elastically deformable continua, it is critical that the friction laws involve a characteristic distance for slip weakening or evolution of surface state. That results in a finite nucleation size, or coherent slip patch size, h*. Models of smooth faults, using numerical cell size properly small compared to h*, show periodic response or complex and apparently chaotic histories of large events but have not been found to show small event complexity like the self similar (power law) Gutenberg-Richter frequency-size statistics. This conclusion is supported in the present paper by fully inertial elastodynamic modeling of earthquake sequences. In contrast, some models of locally heterogeneous faults with quasi-independent fault segments, represented approximately by simulations with cell size larger than h* so that the model becomes "inherently discrete," do show small event complexity of the Gutenberg-Richter type. Models based on classical friction laws without a weakening length scale or for which the numerical procedure imposes an abrupt strength drop at the onset of slip have h* = 0 and hence always fall into the inherently discrete class. We suggest that the small-event complexity that some such models show will not survive regularization of the constitutive description, by inclusion of an appropriate length scale leading to a finite h*, and a corresponding reduction of numerical grid size. PMID- 11607670 TI - Dynamic friction and the origin of the complexity of earthquake sources. AB - We study a simple antiplane fault of finite length embedded in a homogeneous isotropic elastic solid to understand the origin of seismic source heterogeneity in the presence of nonlinear rate- and state-dependent friction. All the mechanical properties of the medium and friction are assumed homogeneous. Friction includes a characteristic length that is longer than the grid size so that our models have a well-defined continuum limit. Starting from a heterogeneous initial stress distribution, we apply a slowly increasing uniform stress load far from the fault and we simulate the seismicity for a few 1000 events. The style of seismicity produced by this model is determined by a control parameter associated with the degree of rate dependence of friction. For classical friction models with rate-independent friction, no complexity appears and seismicity is perfectly periodic. For weakly rate-dependent friction, large ruptures are still periodic, but small seismicity becomes increasingly nonstationary. When friction is highly rate-dependent, seismicity becomes nonperiodic and ruptures of all sizes occur inside the fault. Highly rate dependent friction destabilizes the healing process producing premature healing of slip and partial stress drop. Partial stress drop produces large variations in the state of stress that in turn produce earthquakes of different sizes. Similar results have been found by other authors using the Burridge and Knopoff model. We conjecture that all models in which static stress drop is only a fraction of the dynamic stress drop produce stress heterogeneity. PMID- 11607671 TI - Slip complexity in dynamic models of earthquake faults. AB - We summarize recent evidence that models of earthquake faults with dynamically unstable friction laws but no externally imposed heterogeneities can exhibit slip complexity. Two models are described here. The first is a one-dimensional model with velocity-weakening stick-slip friction; the second is a two-dimensional elastodynamic model with slip-weakening friction. Both exhibit small-event complexity and chaotic sequences of large characteristic events. The large events in both models are composed of Heaton pulses. We argue that the key ingredients of these models are reasonably accurate representations of the properties of real faults. PMID- 11607672 TI - The organization of seismicity on fault networks. AB - Although models of homogeneous faults develop seismicity that has a Gutenberg Richter distribution, this is only a transient state that is followed by events that are strongly influenced by the nature of the boundaries. Models with geometrical inhomogeneities of fracture thresholds can limit the sizes of earthquakes but now favor the characteristic earthquake model for large earthquakes. The character of the seismicity is extremely sensitive to distributions of inhomogeneities, suggesting that statistical rules for large earthquakes in one region may not be applicable to large earthquakes in another region. Model simulations on simple networks of faults with inhomogeneities of threshold develop episodes of lacunarity on all members of the network. There is no validity to the popular assumption that the average rate of slip on individual faults is a constant. Intermediate term precursory activity such as local quiescence and increases in intermediate-magnitude activity at long range are simulated well by the assumption that strong weakening of faults by injection of fluids and weakening of asperities on inhomogeneous models of fault networks is the dominant process; the heat flow paradox, the orientation of the stress field, and the low average stress drop in some earthquakes are understood in terms of the asperity model of inhomogeneous faulting. PMID- 11607673 TI - Geometric incompatibility in a fault system. AB - Interdependence between geometry of a fault system, its kinematics, and seismicity is investigated. Quantitative measure is introduced for inconsistency between a fixed configuration of faults and the slip rates on each fault. This measure, named geometric incompatibility (G), depicts summarily the instability near the fault junctions: their divergence or convergence ("unlocking" or "locking up") and accumulation of stress and deformations. Accordingly, the changes in G are connected with dynamics of seismicity. Apart from geometric incompatibility, we consider deviation K from well-known Saint Venant condition of kinematic compatibility. This deviation depicts summarily unaccounted stress and strain accumulation in the region and/or internal inconsistencies in a reconstruction of block- and fault system (its geometry and movements). The estimates of G and K provide a useful tool for bringing together the data on different types of movement in a fault system. An analog of Stokes formula is found that allows determination of the total values of G and K in a region from the data on its boundary. The phenomenon of geometric incompatibility implies that nucleation of strong earthquakes is to large extent controlled by processes near fault junctions. The junctions that have been locked up may act as transient asperities, and unlocked junctions may act as transient weakest links. Tentative estimates of K and G are made for each end of the Big Bend of the San Andreas fault system in Southern California. Recent strong earthquakes Landers (1992, M = 7.3) and Northridge (1994, M = 6.7) both reduced K but had opposite impact on G: Landers unlocked the area, whereas Northridge locked it up again. PMID- 11607674 TI - Acridones: a chemically new group of protonophores. AB - Although the interaction of proton-conducting ionophores (protonophores) with photosynthetic electron transport has been extensively studied during the past decade, the mode of action of protonophores remained uncertain. For a better understanding of the molecular mechanism of the action of protonophores, the introduction of chemically new types of molecules will be required. In this work, we demonstrate that acridones (9-azaanthracene-10-ones) completely fulfill this requirement. At low concentrations of acridones, the thermoluminescence bands at +20 degrees C and +10 degrees C were strongly inhibited, while normal electron transport activity was retained. This indicates that the concentrations of S2 and S3 states involved in the generation of these bands are reduced. At higher concentrations, an increased activity of electron transport was observed, which is attributed to the typical uncoupler effect of protonophores. Indeed, acridones accelerate the decay of the electrochromic absorbance change at 515 nm and also inhibit the generation of the transmembrane proton gradient, measured as an absorbance transient of neutral red. Variable fluorescence induction was quenched even at low concentrations of acridones but was restored by either a long-term illumination or high light intensity. Acridones, similarly to other protonophores, promoted the autooxidation of the high-potential form of cytochrome b559 and partially converted it to lower potential forms. These results suggest that acridones, acting as typical protonophores, uncouple electron transport, accelerate the deactivation of the S2 and S3 states on the donor side, and facilitate the oxidation of cytochrome b559 on the acceptor side of photosystem II. PMID- 11607675 TI - Chloroplast DNA evidence of colonization, adaptive radiation, and hybridization in the evolution of the Macaronesian flora. AB - Most evolutionary studies of oceanic islands have focused on the Pacific Ocean. There are very few examples from the Atlantic archipelagos, especially Macaronesia, despite their unusual combination of features, including a close proximity to the continent, a broad range of geological ages, and a biota linked to a source area that existed in the Mediterranean basin before the late Tertiary. A chloroplast DNA (cpDNA) restriction site analysis of Argyranthemum (Asteraceae: Anthemideae), the largest endemic genus of plants of any volcanic archipelago in the Atlantic Ocean, was performed to examine patterns of plant evolution in Macaronesia. cpDNA data indicated that Argyranthemum is a monophyletic group that has speciated recently. The cpDNA tree showed a weak correlation with the current sectional classification and insular distribution. Two major cpDNA lineages were identified. One was restricted to northern archipelagos--e.g., Madeira, Desertas, and Selvagens--and the second comprised taxa endemic to the southern archipelago--e.g., the Canary Islands. The two major radiations identified in the Canaries are correlated with distinct ecological habitats; one is restricted to ecological zones under the influence of the northeastern trade winds and the other to regions that are not affected by these winds. The patterns of phylogenetic relationships in Argyranthemum indicate that interisland colonization between similar ecological zones is the main mechanism for establishing founder populations. This phenomenon, combined with rapid radiation into distinct ecological zones and interspecific hybridization, is the primary explanation for species diversification. PMID- 11607676 TI - Mapping leaf surface landscapes. AB - Leaf surfaces provide the ecologically relevant landscapes to those organisms that encounter or colonize the leaf surface. Leaf surface topography directly affects microhabitat availability for colonizing microbes, microhabitat quality and acceptability for insects, and the efficacy of agricultural spray applications. Prior detailed mechanistic studies that examined particular fungi plant and pollinator-plant interactions have demonstrated the importance of plant surface topography or roughness in determining the outcome of the interactions. Until now, however, it has not been possible to measure accurately the topography -i.e., the three-dimensional structure--of such leaf surfaces or to record precise changes in patterns of leaf surface elevation over time. Using contact mode atomic force microscopy, we measured three-dimensional coordinates of upper leaf surfaces of Vaccinium macrocarpon (cranberry), a perennial plant, on leaves of two age classes. We then produced topographic maps of these leaf surfaces, which revealed striking differences between age classes of leaves: old leaves have much rougher surfaces than those of young leaves. Atomic force microscope measurements were analyzed by lag (1) autocorrelation estimates of leaf surfaces by age class. We suggest that the changes in topography result from removal of epicuticular lipids and that the changes in leaf surface topography influence phylloplane ecology. Visualizing and mapping leaf surfaces permit detailed investigations into leaf surface-mediated phenomena, improving our understanding of phylloplane interactions. PMID- 11607677 TI - Nest predation by cowbirds and its consequences for passerine demography. AB - Brood parasitism by brown-headed cowbirds (Molothrus ater) reduces reproductive success in many passerines that nest in fragmented habitats and ecological edges, where nest predation is also common. We tested the hypothesis that parasitism and predation are often linked because cowbirds depredate nests discovered late in the host's nesting cycle to enhance future opportunities for parasitism. Over a 20-year study period, brood parasitism by cowbirds was a prerequisite to observing marked inter- and intraannual variation in the rate of nest failure in an insular song sparrow (Melospiza melodia) population. Nest failure increased with the arrival and laying rate of cowbirds and declined when cowbirds ceased laying. The absence or removal of cowbirds yielded the lowest nest failure rates recorded in the study. The absence of cowbirds also coincided with the absence of an otherwise strong positive correlation between host numbers and the annual rate of nest failure. Host numbers, cowbird parasitism, and nest failure may be correlated because cowbirds facilitate nest failure rather than cause it directly. However, an experiment mimicking egg ejection by cowbirds did not affect nest failure, and, contrary to the main prediction of the predation facilitation hypothesis, naturally parasitized nests failed less often than unparasitized nests. Higher survival of parasitized nests is expected under the cowbird predation hypothesis when female cowbirds defend access to hosts because cowbirds should often depredate unparasitized nests but should not depredate nests they have laid in. Where female cowbirds have overlapping laying areas, we expect parasitized nests to fail more often than others if different cowbirds often discover the same nests. We suggest that nest predation by cowbirds represents an adaptation for successful parasitism and that cowbirds influence host demography via nest predation. PMID- 11607678 TI - Culture as shared cognitive representations. AB - Culture consists of shared cognitive representations in the minds of individuals. This paper investigates the extent to which English speakers share the "same" semantic structure of English kinship terms. The semantic structure is defined as the arrangement of the terms relative to each other as represented in a metric space in which items judged more similar are placed closer to each other than items judged as less similar. The cognitive representation of the semantic structure, residing in the mind of an individual, is measured by judged similarity tasks involving comparisons among terms. Using six independent measurements, from each of 122 individuals, correspondence analysis represents the data in a common multidimensional spatial representation. Judged by a variety of statistical procedures, the individuals in our sample share virtually identical cognitive representations of the semantic structure of kinship terms. This model of culture accounts for 70-90% of the total variability in these data. We argue that our findings on kinship should generalize to all semantic domains- e.g., animals, emotions, etc. The investigation of semantic domains is important because they may reside in localized functional units in the brain, because they relate to a variety of cognitive processes, and because they have the potential to provide methods for diagnosing individual breakdowns in the structure of cognitive representations typical of such ailments as Alzheimer disease. PMID- 11607679 TI - Ediacaran biota from Sonora, Mexico. AB - The Ediacaran biota is the earliest diverse community of macroscopic animals and protoctists. Body and trace fossils in the Clemente Formation of northwestern Sonora extend downward the geologic range of Ediacaran forms. Taxa present in the Clemente Formation include cf. Cyclomedusa plana, Sekwia sp., an erniettid (bearing an air mattress-like "pneu" body construction), and the trace fossils Lockeia ichnosp. and Palaeophycus tubularis. The trace fossils confirm the presence of sediment-dwelling animals in this shallow marine community. The body fossils are headless, tailless, and appendageless. Some may be body fossils of animals but others may be fossils of large protoctists. These body and trace fossils, recovered from thinly bedded sandstones and siltstones, occur 75 meters lower in the Sonoran stratigraphic section than a distinctive Clemente Formation oolite. The stratigraphic position of the fossils below this oolite permits long distance correlation between fossiliferous Proterozoic strata of Mexico and the United States. Correlations utilizing both the Clemente Formation oolite and a trace fossil (Vermiforma antiqua) confirm the antiquity (600 million years or more) of this body fossil-rich community of macroscopic eukaryotes. The recently discovered body fossils are the oldest known remains of the Ediacaran biota. PMID- 11607680 TI - Why fisheries collapse and what to do about it. AB - With the collapse of fisheries in many parts of the world causing widespread economic harm, attention is focused on a possible cause and remedy of fishery collapse. Economic theory for managing a renewable resource, such as a fishery, leads to an ecologically unstable equilibrium as difficult to maintain as balancing a marble on top of a dome. A fishery should be managed for ecological stability instead--in the analogy, as easy to maintain as keeping a marble near the base of a bowl. The goal of ecological stability is achieved if the target stock is above that producing maximum sustainable yield and harvested at less than the maximum sustainable yield. The cost of managing for ecological stability, termed "natural insurance," is low if the fishery is sufficiently productive. This cost is shown to pay for itself over the long term in a variable and uncertain environment. An ecologically stable target stock may be attained either with annually variable quotas following current practice or, preferably, through a market mechanism whereby fish are taxed at dockside if caught when the stock was below target and are untaxed otherwise. In this regulatory environment, the goal of maximizing short-term revenue coincides with the goal of ecological stability, thereby also maximizing long-term revenue. This new approach to fishery management is illustrated with the recently collapsed Newfoundland fishing industry. The Newfoundland cod fishery is expected to rebuild to an ecologically stable level in about 9 years and thereafter support an annual harvest of about 75% of the 1981-1990 average. PMID- 11607681 TI - Distribution of spontaneous plant hybrids. AB - Natural hybridization is a relatively common feature of vascular plant species and has been demonstrated to have played an important role in their evolution. Nonetheless, it is not clear whether spontaneous hybridization occurs as a general feature of all plant families and genera or whether certain groups are especially prone to spontaneous hybridization. Therefore, we inspected five modern biosystematic floras to survey the frequency and taxonomic distribution of spontaneous hybrids. We found spontaneous hybridization to be nonrandomly distributed among taxa, concentrated in certain families and certain genera, often at a frequency out of proportion to the size of the family or genus. Most of these groups were primarily outcrossing perennials with reproductive modes that stabilized hybridity such as agamospermy, vegetative spread, or permanent odd polyploidy. These data suggest that certain phylogenetic groups are biologically predisposed for the formation and maintenance of hybrids. PMID- 11607682 TI - Successful external fertilization in turbulent environments. AB - Mathematical and experimental simulations predict that external fertilization is unsuccessful in habitats characterized by high water motion. A key assumption of such predictions is that gametes are released in hydrodynamic regimes that quickly dilute gametes. We used fucoid seaweeds to examine whether marine organisms in intertidal and subtidal habitats might achieve high levels of fertilization by restricting their release of gametes to calm intervals. Fucus vesiculosus L. (Baltic Sea) released high numbers of gametes only when maximal water velocities were below ca. 0.2 m/s immediately prior to natural periods of release, which occur in early evening in association with lunar cues. Natural fertilization success measured at two sites was always close to 100%. Laboratory experiments confirmed that (i) high water motion inhibits gamete release by F. vesiculosus and by the intertidal fucoids Fucus distichus L. (Maine) and Pelvetia fastigiata (J. Ag.) DeToni (California), and (ii) showed that photosynthesis is required for high gamete release. These data suggest that chemical changes in the boundary layer surrounding adults during photosynthesis and/or mechanosensitive channels may modulate gamete release in response to changing hydrodynamic conditions. Therefore, sensitivity to environmental factors can lead to successful external fertilization, even for species living in turbulent habitats. PMID- 11607683 TI - A mutation that allows endosperm development without fertilization. AB - The mechanisms that initiate reproductive development after fertilization are not understood. Reproduction in higher plants is unique because it is initiated by two fertilization events in the haploid female gametophyte. One sperm nucleus fertilizes the egg to form the embryo. A second sperm nucleus fertilizes the central cell to form the endosperm, a unique tissue that supports the growth of the embryo. Fertilization also activates maternal tissue differentiation, the ovule integuments form the seed coat, and the ovary forms the fruit. To investigate mechanisms that initiate reproductive development, a female gametophytic mutation termed fie (fertilization-independent endosperm) has been isolated in Arabidopsis. The fie mutation specifically affects the central cell, allowing for replication of the central cell nucleus and endosperm development without fertilization. The fie mutation does not appear to affect the egg cell, suggesting that the processes that control the initiation of embryogenesis and endosperm development are different. FIE/fie seed coat and fruit undergo fertilization-independent differentiation, which shows that the fie female gametophyte is the source of signals that activates sporophytic fruit and seed coat development. The mutant fie allele is not transmitted by the female gametophyte. Inheritance of the mutant fie allele by the female gametophyte results in embryo abortion, even when the pollen bears the wild-type FIE allele. Thus, FIE carries out a novel, essential function for female reproductive development. PMID- 11607684 TI - Congruence of fatty acid methyl ester profiles and morphological characters of arbuscular mycorrhizal fungi in Gigasporaceae. AB - Arbuscular mycorrhizal (AM) fungi (Order Glomales, Class Zygomycetes) are a diverse group of soil fungi that form mutualistic associations with the roots of most species of higher plants. Despite intensive study over the past 25 years, the phylogenetic relationships among AM fungi, and thus many details of evolution of the symbiosis, remain unclear. Cladistic analysis was performed on fatty acid methyl ester (FAME) profiles of 15 species in Gigaspora and Scutellospora (family Gigasporaceae) by using a restricted maximum likelihood approach of continuous character data. Results were compared to a parsimony analysis of spore morphological characters of the same species. Only one tree was generated from each character set. Morphological and developmental data suggest that species with the simplest spore types are ancestral whereas those with complicated inner wall structures are derived. Spores of those species having a complex wall structure pass through stages of development identical to the mature stages of simpler spores, suggesting a pattern of classical Haeckelian recapitulation in evolution of spore characters. Analysis of FAME profiles supported this hypothesis when Glomus leptotichum was used as the outgroup. However, when Glomus etunicatum was chosen as the outgroup, the polarity of the entire tree was reversed. Our results suggest that FAME profiles contain useful information and provide independent criteria for generating phylogenetic hypotheses in AM fungi. The maximum likelihood approach to analyzing FAME profiles also may prove useful for many other groups of organisms in which profiles are empirically shown to be stable and heritable. PMID- 11607685 TI - An endogenous rate of time preference, the Penrose effect, and dynamic optimality of environmental quality. AB - In the present paper, the endogenous theory of time preference is extended to analyze those processes of capital accumulation and changes in environmental quality that are dynamically optimum with respect to the intertemporal preference ordering of the representative individual of the society in question. The analysis is carried out within the conceptual framework of the dynamic analysis of environmental quality, as has been developed by a number of economists for specific cases of the fisheries and forestry commons. The duality principles on intertemporal preference ordering and capital accumulation are extended to the situation where processes of capital accumulation are subject to the Penrose effect, which exhibit the marginal decrease in the effect of investment in private and social overhead capital upon the rate at which capital is accumulated. The dynamically optimum time-path of economic activities is characterized by the proportionality of two systems of imputed, or efficient, prices, one associated with the given intertemporal ordering and another associated with processes of accumulation of private and social overhead capital. It is particularly shown that the dynamically optimality of the processes of capital accumulation involving both private and social overhead capital is characterized by the conditions that are identical with those involving private capital, with the role of social overhead capital only indirectly exhibited. PMID- 11607686 TI - Earliest evolution associated with closure of the Tropical American Seaway. AB - Oceanographic changes caused by the emerging Central American isthmus, which completely severed connections between the Caribbean Sea and tropical Pacific Ocean about 3.5 million years ago, began to stimulate evolution of Caribbean reef corals and benthic foraminifera in the Late Miocene. At that time, first appearances of benthic foraminifera increased, especially those species strongly associated with carbonate-rich substrata; reef corals diversified dramatically; and the carbonate content of southern Caribbean deep-sea sediments increased. We suggest that the changes in marine environments caused by the constricting seaway and resulting in increasing carbonate content of sediments induced accelerated origination in reef corals and carbonate-associated benthic foraminifera. PMID- 11607687 TI - Correlates of the desired family size among Indian communities. AB - The People of India database of the Anthropological Survey of India documents 631 cultural, ecological, and economic traits of the 4635 communities to which the entire Indian population is assigned. Focusing on 1342 communities of South India, we looked for correlates of low (1 or 2 children) and high (4 or more children) desired family size (DFS) reported as the norm for any given community by key informants. We found 10 cultural and 18 economic traits to be significantly correlated to high DFS and 21 cultural and 9 economic traits to low DFS. The economic traits so identified are compatible with high family size being desired by parents who have little capability of investing in quality of offspring, but whose children contribute economically from an early age. In contrast, communities desiring low family size are part of the modern intensive agriculture/organized industry/services sector and invest heavily in educating their children. A composite index based on 27 economic traits (CEI) has a high predictive value with respect to the DFS for the entire set of 4635 Indian communities. The 31 cultural traits highly correlated to high or low DFS constitute 5 clusters that can be identified as characterizing scheduled tribes, scheduled castes, rural and landless lower castes, urban upper castes, and Moslems. Whereas economic traits have similar influence on DFS within each of these ethnic categories, Moslems demonstrate a significantly higher DFS for lower values of CEI. PMID- 11607688 TI - Small viscosity asymptotics for the inertial range of local structure and for the wall region of wall-bounded turbulent shear flow. AB - The small viscosity asymptotics of the inertial range of local structure and of the wall region in wallbounded turbulent shear flow are compared. The comparison leads to a sharpening of the dichotomy between Reynolds number dependent scaling (power-type) laws and the universal Reynolds number independent logarithmic law in wall turbulence. It further leads to a quantitative prediction of an essential difference between them, which is confirmed by the results of a recent experimental investigation. These results lend support to recent work on the zero viscosity limit of the inertial range in turbulence. PMID- 11607689 TI - Natural abundance solid-state carbon NMR studies of photosynthetic reaction centers with photoinduced polarization. AB - Solid-state NMR spectra of natural abundance 13C in reaction centers from photosynthetic bacteria Rhodobacter sphaeroides R-26 was measured. When the quinone acceptors were removed and continuous visible illumination of the sample was provided, exceptionally strong nuclear spin polarization was observed in NMR lines with chemical shifts resembling those of the aromatic carbons in bacteriochlorophyll and bacteriopheophytin. The observation of spin polarized 15N nuclei in bacteriochlorophyll and bacteriopheophytin was previously demonstrated with nonspecifically 15N-labeled reaction centers. Both the carbon and the nitrogen NMR studies indicate that the polarization is developed on species that carry unpaired electrons in the early electron transfer steps, including the bacteriochlorophyll dimer donor P860 and probably the bacteriopheophytin acceptor. I. Both enhanced-absorptive and emissive polarization were seen in the carbon spectrum; most lines were absorptive but the methine carbons of the porphyrin ring (alpha, beta, gamma, ) exhibited emissive polarization. The change in the sign of the hyperfine coupling at these sites indicates the existence of nodes in the spin density distribution on the tetrapyrrole cofactors flanking each methine carbon bridge. PMID- 11607690 TI - Excitation transfer spectroscopy with two metastable 138Ba+ ions in same trap. AB - In the absence of lasers approaching trapped ion clock transitions in sharpness we propose to replace the 12.49 m laser field exciting the D3/2-D5/2 transition of the single Ba+ ion A in D3/2 with the near-field of a close by identical ion B in the excited D5/2 state. We tune the frequency of the near-field by the differential Stark shift generated when the center of mass of the tuned ions is slightly moved out of the trap center by a small bias voltage. We demonstrate that the resultant resonant energy exchange can be made considerably faster than the natural lifetime of either metastable level and show how it might be detected. PMID- 11607691 TI - A mechanism for inducing plant development: the genesis of a specific inhibitor. AB - Parasitic strategies are widely distributed in the plant kingdom and frequently involve coupling parasite organogenesis with cues from the host. In Striga asiatica, for example, the cues that initiate the development of the host attachment organ, the haustorium, originate in the host and trigger the transition from vegetative to parasitic mode in the root meristem. This system therefore offers a unique opportunity to study the signals and mechanisms that control plant cell morphogenesis. Here we establish that the biological activity of structural analogs of the natural inducer displays a marked dependence on redox potential and suggest the existence of a semiquinone intermediate. Building on chemistry that exploits the energetics of such an intermediate, cyclopropyl-p benzoquinone (CPBQ) is shown to be a specific inhibitor of haustorial development. These data are consistent with a model where haustorial development is initiated by the completion of a redox circuit. PMID- 11607692 TI - The best thermoelectric. AB - What electronic structure provides the largest figure of merit for thermoelectric materials? To answer that question, we write the electrical conductivity, thermopower, and thermal conductivity as integrals of a single function, the transport distribution. Then we derive the mathematical function for the transport distribution, which gives the largest figure of merit. A delta-shaped transport distribution is found to maximize the thermoelectric properties. This result indicates that a narrow distribution of the energy of the electrons participating in the transport process is needed for maximum thermoelectric efficiency. Some possible realizations of this idea are discussed. PMID- 11607693 TI - Multicomponent diffusion in polymeric liquids. AB - It is shown how the phase-space kinetic theory of polymeric liquid mixtures leads to a set of extended Maxwell-Stefan equations describing multicomponent diffusion. This expression reduces to standard results for dilute solutions and for undiluted polymers. The polymer molecules are modeled as flexible bead-spring structures. To obtain the Maxwell-Stefan equations, the usual expression for the hydrodynamic drag force on a bead, used in previous kinetic theories, must be replaced by a new expression that accounts explicitly for bead-bead interactions between different molecules. PMID- 11607694 TI - A meta-analysis of the freshwater trophic cascade. AB - The generality of the trophic cascade has been an intensely debated topic among ecologists. We conducted a meta-analysis of 54 separate enclosure and pond experiments that measured the response of the zooplankton and phytoplankton to zooplanktivorous fish treatments. These results provide unequivocal support for the trophic cascade hypothesis in freshwater food webs. Zooplanktivorous fish treatments resulted in reduced zooplankton biomass and increased phytoplankton biomass. The trophic cascade was weakly dampened at the level of the phytoplankton. However, the response of the phytoplankton to the trophic cascade was highly skewed, with very strong responses in slightly more than one-third of the cases and weak responses in the others. PMID- 11607695 TI - Ergodic theorems along sequences and Hardy fields. AB - Let a(x) be a real function with a regular growth as x --> infinity. [The precise technical assumption is that a(x) belongs to a Hardy field.] We establish sufficient growth conditions on a(x) so that the sequence ([a(n)])(infinity)(n=1) is a good averaging sequence in L2 for the pointwise ergodic theorem. A sequence (an) of positive integers is a good averaging sequence in L2 for the pointwise ergodic theorem if in any dynamical system (Omega, Sigma, m, T) for f [symbol, see text] in L2(Omega) the averages [equation, see text] converge for almost every omicron in. Our result implies that sequences like ([ndelta]), where delta > 1 and not an integer, ([n log n]), and ([n2/log n]) are good averaging sequences for L2. In fact, all the sequences we examine will turn out to be good averaging for Lp, p > 1; and even for L log L. We will also establish necessary and sufficient growth conditions on a(x) so that the sequence ([a(n)]) is good averaging for mean convergence. Note that for some a(x) (e.g., a(x) = log2 x), ([a(n)]) may be good for mean convergence without being good for pointwise convergence. PMID- 11607696 TI - Regulation of herbivore growth by the balance of light and nutrients. AB - Experiments using planktonic organisms revealed that the balance of radiant energy and available nutrients regulated herbivore growth rates through their effects on abundance and chemical composition of primary producers. Both algae and herbivores were energy limited at low light/nutrient ratios, but both were nutrient limited at high light/nutrient ratios. Herbivore growth increased with increasing light intensity at low values of the light/nutrient ratio due to increases in algal biomass, but growth decreased with increasing light at a high light/nutrient ratio due to decreases in algal quality. Herbivore production therefore was maximal at intermediate levels of the light/nutrient ratio. The results contribute to an understanding of mass transfer mechanisms in ecosystems and illustrate the importance of integration of energy-based and material-based currencies in ecology. PMID- 11607697 TI - A Carboniferous insect gall: insight into early ecologic history of the Holometabola. AB - Although the prevalence or even occurrence of insect herbivory during the Late Carboniferous (Pennsylvanian) has been questioned, we present the earliest-known ecologic evidence showing that by Late Pennsylvanian times (302 million years ago) a larva of the Holometabola was galling the internal tissue of Psaronius tree-fern fronds. Several diagnostic cellular and histological features of these petiole galls have been preserved in exquisite detail, including an excavated axial lumen filled with fecal pellets and comminuted frass, plant-produced response tissue surrounding the lumen, and specificity by the larval herbivore for a particular host species and tissue type. Whereas most suggestions over whelmingly support the evolution of such intimate and reciprocal plant-insect interactions 175 million years later, we provide documentation that before the demise of Pennsylvanian age coal-swamp forests, a highly stereotyped life cycle was already established between an insect that was consuming internal plant tissue and a vascular plant host responding to that herbivory. This and related discoveries of insect herbivore consumption of Psaronius tissues indicate that modern-style herbivores were established in Late Pennsylvanian coal-swamp forests. PMID- 11607698 TI - Inferring the hydrophobic interaction from the properties of neat water. PMID- 11607699 TI - Quantitative trait loci and metabolic pathways: genetic control of the concentration of maysin, a corn earworm resistance factor, in maize silks. AB - Interpretation of quantitative trait locus (QTL) studies of agronomic traits is limited by lack of knowledge of biochemical pathways leading to trait expression. To more fully elucidate the biological significance of detected QTL, we chose a trait that is the product of a well-characterized pathway, namely the concentration of maysin, a C-glycosyl flavone, in silks of maize, Zea mays L. Maysin is a host-plant resistance factor against the corn earworm, Helicoverpa zea (Boddie). We determined silk maysin concentrations and restriction fragment length polymorphism genotypes at flavonoid pathway loci or linked markers for 285 F2 plants derived from the cross of lines GT114 and GT119. Single-factor analysis of variance indicated that the p1 region on chromosome 1 accounted for 58.0% of the phenotypic variance and showed additive gene action. The p1 locus is a transcription activator for portions of the flavonoid pathway. A second QTL, represented by marker umc 105a near the brown pericarp1 locus on chromosome 9, accounted for 10.8% of the variance. Gene action of this region was dominant for low maysin, but was only expressed in the presence of a functional p1 allele. The model explaining the greatest proportion of phenotypic variance (75.9%) included p1, umc105a, umc166b (chromosome 1), r1 (chromosome 10), and two epistatic interaction terms, p1 x umc105a and p1 x r1. Our results provide evidence that regulatory loci have a central role and that there is a complex interplay among different branches of the flavonoid pathway in the expression of this trait. PMID- 11607700 TI - An information theory model of hydrophobic interactions. AB - A molecular model of poorly understood hydrophobic effects is heuristically developed using the methods of information theory. Because primitive hydrophobic effects can be tied to the probability of observing a molecular-sized cavity in the solvent, the probability distribution of the number of solvent centers in a cavity volume is modeled on the basis of the two moments available from the density and radial distribution of oxygen atoms in liquid water. The modeled distribution then yields the probability that no solvent centers are found in the cavity volume. This model is shown to account quantitatively for the central hydrophobic phenomena of cavity formation and association of inert gas solutes. The connection of information theory to statistical thermodynamics provides a basis for clarification of hydrophobic effects. The simplicity and flexibility of the approach suggest that it should permit applications to conformational equilibria of nonpolar solutes and hydrophobic residues in biopolymers. PMID- 11607701 TI - Auxin as a positional signal in pattern formation in plants. AB - By using a novel, extremely sensitive and specific gas chromatography-mass spectrometry technique we demonstrate in Pinus sylvestris (L.) trees the existence of a steep radial concentration gradient of the endogenous auxin, indole-3-acetic acid, over the lateral meristem responsible for the bulk of plant secondary growth, the vascular cambium. This is the first evidence that plant morphogens, such as indole-3-acetic acid, occur in concentration gradients over developing tissues. This finding gives evidence for a regulatory system in plants based on positional signaling, similar to animal systems. PMID- 11607702 TI - Different sources of reduced carbon contribute to form three classes of terpenoid emitted by Quercus ilex L. leaves. AB - Quercus ilex L. leaves emit terpenes but do not have specialized structures for terpene storage. We exploited this unique feature to investigate terpene biosynthesis in intact leaves of Q. ilex. Light induction allowed us to distinguish three classes of terpenes: (i) a rapidly induced class including alpha-pinene; (ii) a more slowly induced class, including cis-beta-ocimene; and (iii) the most slowly induced class, including 3-methyl-3-buten-1-ol. Using 13C, we found that alpha-pinene and cis-beta-ocimene were labeled quickly and almost completely while there was a delay before label appeared in linalool and 3-methyl 3-buten-1-ol. The acetyl group of 3-methyl-3-buten-1-yl acetate was labeled quickly but label was limited to 20% of the moiety. It is suggested that the ocimene class of monoterpenes is made from one or more terpenes of the alpha pinene class and that both classes are made entirely from reduced carbon pools inside the chloroplasts. Linalool and 3-methyl-3-buten-1-ol are made from a different pool of reduced carbon, possibly in nonphotosynthetic plastids. The acetyl group of the 3-methyl-3-buten-1-yl acetate is derived mostly from carbon that does not participate in photosynthetic reactions. Low humidity and prolonged exposure to light favored ocimenes emission and induced linalool emission. This may indicate conversion between terpene classes. PMID- 11607703 TI - A model of self-thinning through local competition. AB - Explanations of self-thinning in plant populations have focused on plant shape and packing. A dynamic model based on the structure of local interactions successfully reproduces the pattern and can be approximated to identify key parameters and relationships. The approach generates testable new explanations for differences between species and populations, unifies self-thinning with other patterns in plant population dynamics, and indicates why organisms other than plants can follow the law. PMID- 11607704 TI - A modified gambler's ruin model of polyethylene chains in the amorphous region. AB - Polyethylene chains in the amorphous region between two crystalline lamellae M unit apart are modeled as random walks with one-step memory on a cubic lattice between two absorbing boundaries. These walks avoid the two preceding steps, though they are not true self-avoiding walks. Systems of difference equations are introduced to calculate the statistics of the restricted random walks. They yield that the fraction of loops is (2M - 2)/(2M + 1), the fraction of ties 3/(2M + 1), the average length of loops 2M - 0.5, the average length of ties 2/3M2 + 2/3M - 4/3, the average length of walks equals 3M - 3, the variance of the loop length 16/15M3 + O(M2), the variance of the tie length 28/45M4 + O(M3), and the variance of the walk length 2M3 + O(M2). PMID- 11607705 TI - Dendrimer-supported combinatorial chemistry. AB - A new methodology for the construction of combinatorial libraries is described. The approach, termed dendrimer-supported combinatorial chemistry (DCC), centers on the use of dendrimers as soluble supports. Salient features of DCC include solution phase chemistry, homogeneous purification, routine characterization of intermediates, and high support loadings. To demonstrate the feasibility of DCC, single compounds and a small combinatorial library were prepared via the Fischer indole synthesis. Excellent product yields and purities were obtained, and dendrimer-protected intermediates could be routinely analyzed by 1H and 13C NMR and by mass spectrometry. The results indicate that DCC is a general and efficient strategy for the generation of combinatorial libraries. PMID- 11607706 TI - Female mating preference for bold males in the guppy, Poecilia reticulata. AB - Although females prefer to mate with brightly colored males in numerous species, the benefits accruing to such females are virtually unknown. According to one hypothesis of sexual selection theory, if the expression of costly preferred traits in males (such as conspicuous colors) is proportional to the male's overall quality or reveals his quality, a well-developed trait should indicate good condition and/or viability for example. A female choosing such a male would therefore stand to gain direct or indirect fitness benefits, or both. Among potential phenotypic indicators of an individual's quality are the amount and brightness of its carotenoid-based colors and its boldness, as measured by its willingness to risk approaching predators without being killed. Here, we show experimentally that in the Trinidadian guppy (Poecilia reticulata) the visual conspicuousness of the color pattern of males correlates positively with boldness toward, and with escape distance from, a cichlid fish predator. Bold individuals are thus more informed about nearby predators and more likely to survive encounters with them. Mate-choice experiments showed that females prefer colorful males as mates, but prefer bolder males irrespective of their coloration when given the opportunity to observe their behavior toward a potential fish predator. By preferentially mating with colorful males, female guppies are thus choosing on average, relatively bold, and perhaps more viable, individuals. In doing so, and to the extent that viability is heritable, they potentially gain indirect fitness benefits by producing more viable offspring than otherwise. PMID- 11607707 TI - Potassium homeostasis in vacuolate plant cells. AB - Plant cells contain two major pools of K+, one in the vacuole and one in the cytosol. The behavior of K+ concentrations in these pools is fundamental to understanding the way this nutrient affects plant growth. Triple-barreled microelectrodes have been used to obtain the first fully quantitative measurements of the changes in K+ activity (aK) in the vacuole and cytosol of barley (Hordeum vulgare L.) root cells grown in different K+ concentrations. The electrodes incorporate a pH-selective barrel allowing each measurement to be assigned to either the cytosol or vacuole. The measurements revealed that vacuolar aK declined linearly with decreases in tissue K+ concentration, whereas cytosolic aK initially remained constant in both epidermal and cortical cells but then declined at different rates in each cell type. An unexpected finding was that cytoplasmic pH declined in parallel with cytosolic aK, but acidification of the cytosol with butyrate did not reveal any short-term link between these two parameters. These measurements show the very different responses of the vacuolar and cytosolic K+ pools to changes in K+ availability and also show that cytosolic K+ homeostasis differs quantitatively in different cell types. The data have been used in thermodynamic calculations to predict the need for, and likely mechanisms of, active K+ transport into the vacuole and cytosol. The direction of active K+ transport at the vacuolar membrane changes with tissue K+ status. PMID- 11607708 TI - The dwarf-1 (dt) Mutant of Zea mays blocks three steps in the gibberellin biosynthetic pathway. AB - In plants, gibberellin (GA)-responding mutants have been used as tools to identify the genes that control specific steps in the GA-biosynthetic pathway. They have also been used to determine which native GAs are active per se, i.e., further metabolism is not necessary for bioactivity. We present metabolic evidence that the D1 gene of maize (Zea mays L.) controls the three biosynthetic steps: GA20 to GA1, Ga20 to GA5, and GA5 to GA3. We also present evidence that three gibberellins, GA1, GA5, and GA3, have per se activity in stimulating shoot elongation in maize. The metabolic evidence comes from the injection of [17 13C,3H]GA20 and [17-13C,3H]GA5 into seedlings of d1 and controls (normal and d5), followed by isolation and identification of the 13C-labeled metabolites by full scan GC-MS and Kovats retention index. For the controls, GA20 was metabolized to GA1,GA3, and GA5; GA5 was metabolized to GA3. For the d1 mutant, GA20 was not metabolized to GA1, GA3, or to GA5, and GA5 was not metabolized to GA3. The bioassay evidence is based on dosage response curves using d1 seedlings for assay. GA1, GA3, and GA5 had similar bioactivities, and they were 10-times more active than GA20. PMID- 11607709 TI - Immunocytochemical localization of acyl-lipid desaturases in cyanobacterial cells: evidence that both thylakoid membranes and cytoplasmic membranes are sites of lipid desaturation. AB - There are four acyl-lipid desaturases in the cyanobacterium Synechocystis sp. PCC 6803. Each of these desaturases introduces a double bond at a specific position, such as the Delta6, Delta9, Delta12, or omicron3 position, in C18 fatty acids. The localization of the desaturases in cyanobacterial cells was examined immunocytochemically with antibodies raised against synthetic oligopeptides that corresponded to the carboxyl-terminal regions of the desaturases. All four desaturases appeared to be located in the regions of both the cytoplasmic and the thylakoid membranes. These findings suggest that fatty acid desaturation of membrane lipids takes place in the thylakoid membranes as well as in the cytoplasmic membranes. PMID- 11607710 TI - Room-temperature single-electron junction. AB - The design, realization, and test performances of an electronic junction based on single-electron phenomena that works in the air at room temperature are hereby reported. The element consists of an electrochemically etched sharp tungsten stylus over whose tip a nanometer-size crystal was synthesized. Langmuir-Blodgett films of cadmium arachidate were transferred onto the stylus and exposed to a H2S atmosphere to yield CdS nanocrystals (30-50 angstrom in diameter) imbedded into an organic matrix. The stylus, biased with respect to a flat electrode, was brought to the tunnel distance from the film and a constant gap value was maintained by a piezo-electric actuator driven by a feedback circuit fed by the tunneling current. With this set-up, it is possible to measure the behavior of the current flowing through the quantum dot when a bias voltage is applied. Voltage-current characteristics measured in the system displayed single-electron trends such as a Coulomb blockade and Coulomb staircase and revealed capacitance values as small as 10(-19) F. PMID- 11607711 TI - Molecular phylogeny analysis of fiddler crabs: test of the hypothesis of increasing behavioral complexity in evolution. AB - The current phylogenetic hypothesis for the evolution and biogeography of fiddler crabs relies on the assumption that complex behavioral traits are assumed to also be evolutionary derived. Indo-west Pacific fiddler crabs have simpler reproductive social behavior and are more marine and were thought to be ancestral to the more behaviorally complex and more terrestrial American species. It was also hypothesized that the evolution of more complex social and reproductive behavior was associated with the colonization of the higher intertidal zones. Our phylogenetic analysis, based upon a set of independent molecular characters, however, demonstrates how widely entrenched ideas about evolution and biogeography led to a reasonable, but apparently incorrect, conclusion about the evolutionary trends within this pantropical group of crustaceans. Species bearing the set of "derived traits" are phylogenetically ancestral, suggesting an alternative evolutionary scenario: the evolution of reproductive behavioral complexity in fiddler crabs may have arisen multiple times during their evolution. The evolution of behavioral complexity may have arisen by coopting of a series of other adaptations for high intertidal living and antipredator escape. A calibration of rates of molecular evolution from populations on either side of the Isthmus of Panama suggest a sequence divergence rate for 16S rRNA of 0.9% per million years. The divergence between the ancestral clade and derived forms is estimated to be approximately 22 million years ago, whereas the divergence between the American and Indo-west Pacific is estimated to be approximately 17 million years ago. PMID- 11607712 TI - A natural experiment on plant acclimation: lifetime stomatal frequency response of an individual tree to annual atmospheric CO2 increase. AB - Carbon dioxide (CO2) has been increasing in atmospheric concentration since the Industrial Revolution. A decreasing number of stomata on leaves of land plants still provides the only morphological evidence that this man-made increase has already affected the biosphere. The current rate of CO2 responsiveness in individual long-lived species cannot be accurately determined from field studies or by controlled-environment experiments. However, the required long-term data sets can be obtained from continuous records of buried leaves from living trees in wetland ecosystems. Fine-resolution analysis of the lifetime leaf record of an individual birch (Betula pendula) indicates a gradual reduction of stomatal frequency as a phenotypic acclimation to CO2 increase. During the past four decades, CO2 increments of 1 part per million by volume resulted in a stomatal density decline of approximately 0.6%. It may be hypothesized that this plastic stomatal frequency response of deciduous tree species has evolved in conjunction with the overall Cenozoic reduction of atmospheric CO2 concentrations. PMID- 11607714 TI - Mapping the universe in three dimensions. AB - The determination of the three-dimensional layout of galaxies is critical to our understanding of the evolution of galaxies and the structures in which they lie, to our determination of the fundamental parameters of cosmology, and to our understanding of both the past and future histories of the universe at large. The mapping of the large scale structure in the universe via the determination of galaxy red shifts (Doppler shifts) is a rapidly growing industry thanks to technological developments in detectors and spectrometers at radio and optical wavelengths. First-order application of the red shift-distance relation (Hubble's law) allows the analysis of the large-scale distribution of galaxies on scales of hundreds of megaparsecs. Locally, the large-scale structure is very complex but the overall topology is not yet clear. Comparison of the observed red shifts with ones expected on the basis of other distance estimates allows mapping of the gravitational field and the underlying total density distribution. The next decade holds great promise for our understanding of the character of large-scale structure and its origin. PMID- 11607713 TI - A plastid enzyme arrested in the step of precursor translocation in vivo. AB - The key enzyme of chlorophyll biosynthesis in higher plants, NADPH:protochlorophyllide (Pchlide) oxidoreductase (POR, EC 1.3.1.33), accumulates in its precursor form (pPORA) in barley. pPORA is bound to the chloroplasts and is able to interact with the enzyme's substrate, Pchlide, at both the cytosolic as well as the stromal side of the plastid envelope. The interaction with intraplastidic Pchlide, formed in ATP-containing chloroplasts upon feeding with -aminolevulinic acid, drives vectorial translocation of pPORA across the plastid envelope membranes. In contrast, exogenously applied Pchlide causes the release of the envelope-bound precursor protein to the cytosol. Both processes compete with each other if intra- and extraplastidic Pchlide are applied simultaneously. A cytosolic heat shock cognate protein of Mr 70,000 present in wheat germ and barley leaf protein extracts appears to prevent the release of the pPORA to the cytosol in vivo, however. PMID- 11607715 TI - Astrophysical symmetries. AB - Astrophysical objects, ranging from meteorites to the entire universe, can be classified into about a dozen characteristic morphologies, at least as seen by a blurry eye. Some patterns exist over an enormously wide range of distance scales, apparently as a result of similar underlying physics. Bipolar ejection from protostars, binary systems, and active galaxies is perhaps the clearest example. The oral presentation included about 130 astronomical images which cannot be reproduced here. PMID- 11607716 TI - A brief survey of symmetry in mathematics. AB - This paper presents a brief survey of the idea of symmetry in mathematics, as exemplified by some particular developments in algebra, differential equations, topology, and number theory. PMID- 11607717 TI - Convex polytopes and quantization of symplectic manifolds. AB - Quantum mechanics associate to some symplectic manifolds M a quantum model Q(M), which is a Hilbert space. The space Q(M) is the quantum mechanical analogue of the classical phase space M. We discuss here relations between the volume of M and the dimension of the vector space Q(M). Analogues for convex polyhedra are considered. PMID- 11607718 TI - The role of symmetry in fundamental physics. AB - The role of symmetry in fundamental physics is reviewed. PMID- 11607719 TI - Symmetries in geology and geophysics. AB - Symmetries have played an important role in a variety of problems in geology and geophysics. A large fraction of studies in mineralogy are devoted to the symmetry properties of crystals. In this paper, however, the emphasis will be on scale invariant (fractal) symmetries. The earth's topography is an example of both statistically self-similar and self-affine fractals. Landforms are also associated with drainage networks, which are statistical fractal trees. A universal feature of drainage networks and other growth networks is side branching. Deterministic space-filling networks with side-branching symmetries are illustrated. It is shown that naturally occurring drainage networks have symmetries similar to diffusion-limited aggregation clusters. PMID- 11607720 TI - Symmetries throughout the sciences. Concluding talk. PMID- 11607721 TI - Introduction to "From the Academy". PMID- 11607722 TI - Opportunities await. PMID- 11607723 TI - Colleges of agriculture at the land grant universities: public service and public policy. An excerpt from the Executive Summary of the National Research Council Report. PMID- 11607724 TI - Bose-Einstein condensation. PMID- 11607725 TI - The epoch of galaxy formation. PMID- 11607726 TI - Security and privacy in the information economy. PMID- 11607727 TI - Seeking the root of insect resistance to transgenic plants. PMID- 11607729 TI - The age of the universe. PMID- 11607730 TI - Mathematical approaches to comparative linguistics. AB - The inference of the evolutionary history of a set of languages is a complex problem. Although some languages are known to be related through descent from common ancestral languages, for other languages determining whether such a relationship holds is itself a difficult problem. In this paper we report on new methods, developed by linguists Johanna Nichols (University of California, Berkeley), Donald Ringe and Ann Taylor (University of Pennsylvania, Philadelphia), and me, for answering some of the most difficult questions in this domain. These methods and the results of the analyses based on these methods were presented in November 1995 at the Symposium on the Frontiers of Science held by the National Academy of Sciences. PMID- 11607731 TI - The radioactivity of atmospheric krypton in 1949-1950. AB - The chemical element krypton, whose principal source is the atmosphere, had a long-lived radioactive content, in the mid-1940s, of less than 5 dpm per liter of krypton. In the late 1940s, this content had risen to values in the range of 100 dpm per liter. It is now some hundred times higher than the late 1940 values. This radioactivity is the result of the dissolving of nuclear fuel for military and civilian purposes, and the release thereby of the fission product krypton-85 (half-life = 10.71 years, fission yield = 0.2%). The present largest emitter of krypton-85 is the French reprocessing plant at Cap-de-la-Hague. PMID- 11607733 TI - Tribute to Roger Revelle and his contribution to studies of carbon dioxide and climate change. PMID- 11607732 TI - Climate change and carbon dioxide: an introduction. PMID- 11607734 TI - Equilibration of the terrestrial water, nitrogen, and carbon cycles. AB - Recent advances in biologically based ecosystem models of the coupled terrestrial, hydrological, carbon, and nutrient cycles have provided new perspectives on the terrestrial biosphere's behavior globally, over a range of time scales. We used the terrestrial ecosystem model Century to examine relationships between carbon, nitrogen, and water dynamics. The model, run to a quasi-steady-state, shows strong correlations between carbon, water, and nitrogen fluxes that lead to equilibration of water/energy and nitrogen limitation of net primary productivity. This occurs because as the water flux increases, the potentials for carbon uptake (photosynthesis), and inputs and losses of nitrogen, all increase. As the flux of carbon increases, the amount of nitrogen that can be captured into organic matter and then recycled also increases. Because most plant available nitrogen is derived from internal recycling, this latter process is critical to sustaining high productivity in environments where water and energy are plentiful. At steady-state, water/energy and nitrogen limitation "equilibrate," but because the water, carbon, and nitrogen cycles have different response times, inclusion of nitrogen cycling into ecosystem models adds behavior at longer time scales than in purely biophysical models. The tight correlations among nitrogen fluxes with evapotranspiration implies that either climate change or changes to nitrogen inputs (from fertilization or air pollution) will have large and long-lived effects on both productivity and nitrogen losses through hydrological and trace gas pathways. Comprehensive analyses of the role of ecosystems in the carbon cycle must consider mechanisms that arise from the interaction of the hydrological, carbon, and nutrient cycles in ecosystems. PMID- 11607735 TI - Potential responses of soil organic carbon to global environmental change. AB - Recent improvements in our understanding of the dynamics of soil carbon have shown that 20-40% of the approximately 1,500 Pg of C stored as organic matter in the upper meter of soils has turnover times of centuries or less. This fast cycling organic matter is largely comprised of undecomposed plant material and hydrolyzable components associated with mineral surfaces. Turnover times of fast cycling carbon vary with climate and vegetation, and range from <20 years at low latitudes to >60 years at high latitudes. The amount and turnover time of C in passive soil carbon pools (organic matter strongly stabilized on mineral surfaces with turnover times of millennia and longer) depend on factors like soil maturity and mineralogy, which, in turn, reflect long-term climate conditions. Transient sources or sinks in terrestrial carbon pools result from the time lag between photosynthetic uptake of CO2 by plants and the subsequent return of C to the atmosphere through plant, heterotrophic, and microbial respiration. Differential responses of primary production and respiration to climate change or ecosystem fertilization have the potential to cause significant interrannual to decadal imbalances in terrestrial C storage and release. Rates of carbon storage and release in recently disturbed ecosystems can be much larger than rates in more mature ecosystems. Changes in disturbance frequency and regime resulting from future climate change may be more important than equilibrium responses in determining the carbon balance of terrestrial ecosystems. PMID- 11607736 TI - Global air-sea flux of CO2: an estimate based on measurements of sea-air pCO2 difference. AB - Approximately 250,000 measurements made for the pCO2 difference between surface water and the marine atmosphere, DeltapCO2, have been assembled for the global oceans. Observations made in the equatorial Pacific during El Nino events have been excluded from the data set. These observations are mapped on the global 4 degrees x 5 degrees grid for a single virtual calendar year (chosen arbitrarily to be 1990) representing a non-El Nino year. Monthly global distributions of DeltapCO2 have been constructed using an interpolation method based on a lateral advection-diffusion transport equation. The net flux of CO2 across the sea surface has been computed using DeltapCO2 distributions and CO2 gas transfer coefficients across sea surface. The annual net uptake flux of CO2 by the global oceans thus estimated ranges from 0.60 to 1.34 Gt-Cyr-1 depending on different formulations used for wind speed dependence on the gas transfer coefficient. These estimates are subject to an error of up to 75% resulting from the numerical interpolation method used to estimate the distribution of DeltapCO2 over the global oceans. Temperate and polar oceans of the both hemispheres are the major sinks for atmospheric CO2, whereas the equatorial oceans are the major sources for CO2. The Atlantic Ocean is the most important CO2 sink, providing about 60% of the global ocean uptake, while the Pacific Ocean is neutral because of its equatorial source flux being balanced by the sink flux of the temperate oceans. The Indian and Southern Oceans take up about 20% each. PMID- 11607737 TI - Characteristics of the deep ocean carbon system during the past 150,000 years: SigmaCO2 distributions, deep water flow patterns, and abrupt climate change. AB - Studies of carbon isotopes and cadmium in bottom-dwelling foraminifera from ocean sediment cores have advanced our knowledge of ocean chemical distributions during the late Pleistocene. Last Glacial Maximum data are consistent with a persistent high-SigmaCO2 state for eastern Pacific deep water. Both tracers indicate that the mid-depth North and tropical Atlantic Ocean almost always has lower SigmaCO2 levels than those in the Pacific. Upper waters of the Last Glacial Maximum Atlantic are more SigmaCO2-depleted and deep waters are SigmaCO2-enriched compared with the waters of the present. In the northern Indian Ocean, delta13C and Cd data are consistent with upper water SigmaCO2 depletion relative to the present. There is no evident proximate source of this SigmaCO2-depleted water, so I suggest that SigmaCO2-depleted North Atlantic intermediate/deep water turns northward around the southern tip of Africa and moves toward the equator as a western boundary current. At long periods (>15,000 years), Milankovitch cycle variability is evident in paleochemical time series. But rapid millennial-scale variability can be seen in cores from high accumulation rate series. Atlantic deep water chemical properties are seen to change in as little as a few hundred years or less. An extraordinary new 52.7-m-long core from the Bermuda Rise contains a faithful record of climate variability with century-scale resolution. Sediment composition can be linked in detail with the isotope stage 3 interstadials recorded in Greenland ice cores. This new record shows at least 12 major climate fluctuations within marine isotope stage 5 (about 70,000-130,000 years before the present). PMID- 11607738 TI - Direct observation of the oceanic CO2 increase revisited. AB - We show, from recent data obtained at specimen North Pacific stations, that the fossil fuel CO2 signal is strongly present in the upper 400 m, and that we may consider areal extrapolations from geochemical surveys to determine the magnitude of ocean fossil fuel CO2 uptake. The debate surrounding this topic is illustrated by contrasting reports which suggest, based upon atmospheric observations and models, that the oceanic CO2 sink is small at these latitudes; or that the oceanic CO2 sink, based upon oceanic data and models, is large. The difference between these two estimates is at least a factor of two. There are contradictions arising from estimates based on surface partial pressures of CO2 alone, where the signal sought is small compared with regional and seasonal variability; and estimates of the accumulated subsurface burden, which correlates well other oceanic tracers. Ocean surface waters today contain about 45 micromol.kg-1 excess CO2 compared with those of the preindustrial era, and the signal is rising rapidly. What limits should we place on such calculations? The answer lies in the scientific questions to be asked. Recovery of the fossil fuel CO2 contamination signal from analysis of ocean water masses is robust enough to permit reasonable budget estimates. However, because we do not have sufficient data from the preindustrial ocean, the estimation of the required Redfield oxidation ratio in the upper several hundred meters is already blurred by the very fossil fuel CO2 signal we seek to resolve. PMID- 11607739 TI - The observed global warming record: what does it tell us? AB - Global, near-surface temperature data sets and their derivations are discussed, and differences between the Jones and Intergovernmental Panel on Climate Change data sets are explained. Global-mean temperature changes are then interpreted in terms of anthropogenic forcing influences and natural variability. The inclusion of aerosol forcing improves the fit between modeled and observed changes but does not improve the agreement between the implied climate sensitivity value and the standard model-based range of 1.5-4.5 degrees C equilibrium warming for a CO2 doubling. The implied sensitivity goes from below the model-based range of estimates to substantially above this range. The addition of a solar forcing effect further improves the fit and brings the best-fit sensitivity into the middle of the model-based range. Consistency is further improved when internally generated changes are considered. This consistency, however, hides many uncertainties that surround observed data/model comparisons. These uncertainties make it impossible currently to use observed global-scale temperature changes to narrow the uncertainty range in the climate sensitivity below that estimated directly from climate models. PMID- 11607740 TI - Possible forcing of global temperature by the oceanic tides. AB - An approximately decadal periodicity in surface air temperature is discernable in global observations from A.D. 1855 to 1900 and since A.D. 1945, but with a periodicity of only about 6 years during the intervening period. Changes in solar irradiance related to the sunspot cycle have been proposed to account for the former, but cannot account for the latter. To explain both by a single mechanism, we propose that extreme oceanic tides may produce changes in sea surface temperature at repeat periods, which alternate between approximately one-third and one-half of the lunar nodal cycle of 18.6 years. These alternations, recurring at nearly 90-year intervals, reflect varying slight degrees of misalignment and departures from the closest approach of the Earth with the Moon and Sun at times of extreme tide raising forces. Strong forcing, consistent with observed temperature periodicities, occurred at 9-year intervals close to perihelion (solar perigee) for several decades centered on A.D. 1881 and 1974, but at 6-year intervals for several decades centered on A.D. 1923. As a physical explanation for tidal forcing of temperature we propose that the dissipation of extreme tides increases vertical mixing of sea water, thereby causing episodic cooling near the sea surface. If this mechanism correctly explains near-decadal temperature periodicities, it may also apply to variability in temperature and climate on other times-scales, even millennial and longer. PMID- 11607741 TI - Spectrum of 100-kyr glacial cycle: orbital inclination, not eccentricity. AB - Spectral analysis of climate data shows a strong narrow peak with period approximately 100 kyr, attributed by the Milankovitch theory to changes in the eccentricity of the earth's orbit. The narrowness of the peak does suggest an astronomical origin; however the shape of the peak is incompatible with both linear and nonlinear models that attribute the cycle to eccentricity or (equivalently) to the envelope of the precession. In contrast, the orbital inclination parameter gives a good match to both the spectrum and bispectrum of the climate data. Extraterrestrial accretion from meteoroids or interplanetary dust is proposed as a mechanism that could link inclination to climate, and experimental tests are described that could prove or disprove this hypothesis. PMID- 11607742 TI - Can increasing carbon dioxide cause climate change? AB - The realistic physical functioning of the greenhouse effect is reviewed, and the role of dynamic transport and water vapor is identified. Model errors and uncertainties are quantitatively compared with the forcing due to doubling CO2, and they are shown to be too large for reliable model evaluations of climate sensitivities. The possibility of directly measuring climate sensitivity is reviewed. A direct approach using satellite data to relate changes in globally averaged radiative flux changes at the top of the atmosphere to naturally occurring changes in global mean temperature is described. Indirect approaches to evaluating climate sensitivity involving the response to volcanic eruptions and Eocene climate change are also described. Finally, it is explained how, in principle, a climate that is insensitive to gross radiative forcing as produced by doubling CO2 might still be able to undergo major changes of the sort associated with ice ages and equable climates. PMID- 11607743 TI - Gases in ice cores. AB - Air trapped in glacial ice offers a means of reconstructing variations in the concentrations of atmospheric gases over time scales ranging from anthropogenic (last 200 yr) to glacial/interglacial (hundreds of thousands of years). In this paper, we review the glaciological processes by which air is trapped in the ice and discuss processes that fractionate gases in ice cores relative to the contemporaneous atmosphere. We then summarize concentration-time records for CO2 and CH4 over the last 200 yr. Finally, we summarize concentration-time records for CO2 and CH4 during the last two glacial-interglacial cycles, and their relation to records of global climate change. PMID- 11607744 TI - Tree rings, carbon dioxide, and climatic change. AB - Tree rings have been used in various applications to reconstruct past climates as well as to assess the effects of recent climatic and environmental change on tree growth. In this paper we briefly review two ways that tree rings provide information about climate change and CO2: (i) in determining whether recent warming during the period of instrumental observations is unusual relative to prior centuries to millennia, and thus might be related to increasing greenhouse gases; and (ii) in evaluating whether enhanced radial growth has taken place in recent decades that appears to be unexplained by climate and might instead be due to increasing atmospheric CO2 or other nutrient fertilization. It is found that a number of tree-ring studies from temperature-sensitive settings indicate unusual recent warming, although there are also exceptions at certain sites. The present tree-ring evidence for a possible CO2 fertilization effect under natural environmental conditions appears to be very limited. PMID- 11607745 TI - Geochemistry of corals: proxies of past ocean chemistry, ocean circulation, and climate. AB - This paper presents a discussion of the status of the field of coral geochemistry as it relates to the recovery of past records of ocean chemistry, ocean circulation, and climate. The first part is a brief review of coral biology, density banding, and other important factors involved in understanding corals as proxies of environmental variables. The second part is a synthesis of the information available to date on extracting records of the carbon cycle and climate change. It is clear from these proxy records that decade time-scale variability of mixing processes in the oceans is a dominant signal. That Western and Eastern tropical Pacific El Nino-Southern Oscillation (ENSO) records differ is an important piece of the puzzle for understanding regional and global climate change. Input of anthropogenic CO2 to the oceans as observed by 13C and 14C isotopes in corals is partially obscured by natural variability. Nonetheless, the general trend over time toward lower delta18O values at numerous sites in the world's tropical oceans suggests a gradual warming and/or freshening of the surface ocean over the past century. PMID- 11607746 TI - A long marine history of carbon cycle modulation by orbital-climatic changes. AB - Pacing of the marine carbon cycle by orbital forcing during the Pliocene and Pleistocene Ice Ages [past 2.5 million years (Myr)] is well known. As older deep sea sediment records are being studied at greater temporal resolution, it is becoming clear that similar fluctuations in the marine carbon system have occurred throughout the late Mesozoic and Tertiary, despite the absence of large continental ice sheets over much of this time. Variations in both the organic and the calcium carbonate components of the marine carbon system seem to have varied cyclically in response to climate forcing, and carbon and carbonate time series appear to accurately characterize the frequency spectrum of ancient climatic change. For the past 35 Myr, much of the variance in carbonate content carries the "polar" signal of obliquity [41,000 years (41 kyr)] forcing. Over the past 125 Myr, there is evidence from marine sediments of the continued role of precessional (approximately 21 kyr) climatic cycles. Repeat patterns of sedimentation at about 100, 400, and 2,400 kyr, the modulation periods of precession, persistently enter into marine carbon cycle records as well. These patterns suggest a nonlinear response of climate and/or the sedimentation of organic carbon and carbonates to precessional orbital perturbations. Nonlinear responses of the carbon system may help to amplify relatively weak orbital insolation anomalies into more significant climatic perturbations through positive feedback effects. Nonlinearities in the carbon cycle may have transformed orbital-climatic cycles into long-wavelength features on time scales comparable to the residence times of carbon and nutrient elements in the ocean. PMID- 11607747 TI - Dependence of global temperatures on atmospheric CO2 and solar irradiance. AB - Changes in global average temperatures and of the seasonal cycle are strongly coupled to the concentration of atmospheric CO2. I estimate transfer functions from changes in atmospheric CO2 and from changes in solar irradiance to hemispheric temperatures that have been corrected for the effects of precession. They show that changes from CO2 over the last century are about three times larger than those from changes in solar irradiance. The increase in global average temperature during the last century is at least 20 times the SD of the residual temperature series left when the effects of CO2 and changes in solar irradiance are subtracted. PMID- 11607748 TI - The different faces of poly(ethylene glycol). PMID- 11607749 TI - Discussion of evaluation of federal laboratories. PMID- 11607750 TI - Evolution of the Brassica self-incompatibility locus: a look into S-locus gene polymorphisms. PMID- 11607751 TI - Parametrizations of elliptic curves by Shimura curves and by classical modular curves. AB - Fix an isogeny class of semistable elliptic curves over Q. The elements A of have a common conductor N, which is a square-free positive integer. Let D be a divisor of N which is the product of an even number of primes--i.e., the discriminant of an indefinite quaternion algebra over Q. To D we associate a certain Shimura curve X(0)D(N/D), whose Jacobian is isogenous to an abelian subvariety of J0(N). There is a unique A [symbol; see text] A in for which one has a nonconstant map piD : X(0)D(N/D) --> A whose pullback A --> Pic0(X(0)D(N/D)) is injective. The degree of piD is an integer deltaD which depends only on D (and the fixed isogeny class A). We investigate the behavior of deltaD as D varies. PMID- 11607752 TI - Euler characteristics and elliptic curves. AB - Let E be a modular elliptic curve over [symbol, see text], without complex multiplication; let p be a prime number where E has good ordinary reduction; and let Finfinity be the field obtained by adjoining [symbol, see text] to all p power division points on E. Write Ginfinity for the Galois group of Finfinity over [symbol, see text]. Assume that the complex L-series of E over [symbol, see text] does not vanish at s = 1. If p >/= 5, we make a precise conjecture about the value of the Ginfinity-Euler characteristic of the Selmer group of E over Finfinity. If one makes a standard conjecture about the behavior of this Selmer group as a module over the Iwasawa algebra, we are able to prove our conjecture. The crucial local calculations in the proof depend on recent joint work of the first author with R. Greenberg. PMID- 11607753 TI - p-adic L functions and trivial zeroes. AB - The following is adapted from the notes for the lecture. It announces results and conjectures about values of the p-adic L function of the symmetric square of an elliptic curve. PMID- 11607754 TI - Adjoint modular Galois representations and their Selmer groups. AB - In the last 15 years, many class number formulas and main conjectures have been proven. Here, we discuss such formulas on the Selmer groups of the three dimensional adjoint representation ad(phi) of a two-dimensional modular Galois representation phi. We start with the p-adic Galois representation phi0 of a modular elliptic curve E and present a formula expressing in terms of L(1, ad(phi0)) the intersection number of the elliptic curve E and the complementary abelian variety inside the Jacobian of the modular curve. Then we explain how one can deduce a formula for the order of the Selmer group Sel(ad(phi0)) from the proof of Wiles of the Shimura-Taniyama conjecture. After that, we generalize the formula in an Iwasawa theoretic setting of one and two variables. Here the first variable, T, is the weight variable of the universal p-ordinary Hecke algebra, and the second variable is the cyclotomic variable S. In the one-variable case, we let phi denote the p-ordinary Galois representation with values in GL2(Zp[[T]]) lifting phi0, and the characteristic power series of the Selmer group Sel(ad(phi)) is given by a p-adic L-function interpolating L(1, ad(phik)) for weight k + 2 specialization phik of phi. In the two-variable case, we state a main conjecture on the characteristic power series in Zp[[T, S]] of Sel(ad(phi) [symbol, see text] nu-1), where nu is the universal cyclotomic character with values in Zp[[S]]. Finally, we describe our recent results toward the proof of the conjecture and a possible strategy of proving the main conjecture using p adic Siegel modular forms. PMID- 11607755 TI - The structure of Selmer groups. AB - The purpose of this article is to describe certain results and conjectures concerning the structure of Galois cohomology groups and Selmer groups, especially for abelian varieties. These results are analogues of a classical theorem of Iwasawa. We formulate a very general version of the Weak Leopoldt Conjecture. One consequence of this conjecture is the nonexistence of proper Lambda-submodules of finite index in a certain Galois cohomology group. Under certain hypotheses, one can prove the nonexistence of proper Lambda-submodules of finite index in Selmer groups. An example shows that some hypotheses are needed. PMID- 11607756 TI - On the coefficients of the characteristic series of the U-operator. AB - A conceptual proof is given of the fact that the coefficients of the characteristic series of the U-operator acting on families of overconvegent modular forms lie in the Iwasawa algebra. PMID- 11607757 TI - Zeta functions and Eisenstein series on classical groups. AB - We construct an Euler product from the Hecke eigenvalues of an automorphic form on a classical group and prove its analytic continuation to the whole complex plane when the group is a unitary group over a CM field and the eigenform is holomorphic. We also prove analytic continuation of an Eisenstein series on another unitary group, containing the group just mentioned defined with such an eigenform. As an application of our methods, we prove an explicit class number formula for a totally definite hermitian form over a CM field. PMID- 11607758 TI - Deforming semistable Galois representations. AB - Let V be a p-adic representation of Gal(Q/Q). One of the ideas of Wiles's proof of FLT is that, if V is the representation associated to a suitable autromorphic form (a modular form in his case) and if V' is another p-adic representation of Gal(Q/Q) "closed enough" to V, then V' is also associated to an automorphic form. In this paper we discuss which kind of local condition at p one should require on V and V' in order to be able to extend this part of Wiles's methods. PMID- 11607759 TI - Integrality of Tate-cycles. AB - We explain a technical result about p-adic cohomology and apply it to the study of Shimura varieties. The technical result applies to algebraic varieties with torsion-free cohomology, but for simplicity we only treat abelian varieties. PMID- 11607761 TI - On degree 2 Galois representations over F4. AB - We discuss proofs of some new special cases of Serre's conjecture on odd, degree 2 representations of G[symbol, see text]. PMID- 11607760 TI - Congruences between modular forms: raising the level and dropping Euler factors. AB - We discuss the relationship among certain generalizations of results of Hida, Ribet, and Wiles on congruences between modular forms. Hida's result accounts for congruences in terms of the value of an L-function, and Ribet's result is related to the behavior of the period that appears there. Wiles' theory leads to a class number formula relating the value of the L-function to the size of a Galois cohomology group. The behavior of the period is used to deduce that a formula at "nonminimal level" is obtained from one at "minimal level" by dropping Euler factors from the L-function. PMID- 11607763 TI - Colloquium introduction. Links between recombination and replication: vital roles of recombination. PMID- 11607762 TI - Searching for an alien haven in the heavens. PMID- 11607764 TI - Tandem transplantation in lymphoma. AB - The majority of poor-risk lymphoma patients are not cured with conventional chemotherapy. There is evidence for the superiority of single high-dose chemotherapy in such patients, but many still die from recurrent disease. Strategies to improve survival in these poor-risk patients include dose intensification with high-dose chemotherapy and PBPC support, tandem autologous HDC with PBPC support, and autologous followed by non-myeloablative allogeneic transplantation. These more aggressive strategies are feasible and tolerable. Whether tandem transplantation will prove more effective than current single high dose therapy in appropriately selected patients remains to be determined. PMID- 11607766 TI - Allogeneic stem cell transplantation for sickle cell disease. A study of patients' decisions. AB - Allogeneic stem cell transplantation is increasingly considered as a curative though risky treatment option for adults with sickle cell disease. Little is known about attitudes of adult patients and their health care providers regarding the risks and benefits of transplantation. A survey of 100 patients and their health care providers was undertaken. Assessment of risk was by a reference gamble paradigm. Comparison was made of the characteristics of those accepting substantial risk vs those not accepting risk, as well as assessment of agreement on risks recommended by health care providers and accepted by patients. Sixty three of 100 patients were willing to accept some short-term risk of mortality in exchange for the certainty of cure. Fifteen patients were willing to accept more than 35% mortality risk. No differences in patient or disease-related variables were identified between those accepting risk and those not accepting risk. There was no agreement between the recommendations of health care providers and the risk accepted by patients. A substantial proportion of adults with sickle cell disease are interested in curative treatment, at the expense of considerable risk. The decision to accept risk is influenced by individual patient values that cannot be easily quantified and that do not correlate with the assessment of the health care provider. Given the substantial interest in curative therapy, education about and consultation for allogeneic stem cell transplantation in sickle cell patients should be encouraged. PMID- 11607765 TI - Allogeneic peripheral blood stem cell transplantation (PBSCT) from HLA-identical sibling donors in children with hematological diseases: a single center pilot study. AB - Between February 1995 and July 1999 25 pediatric patients (8 months to 14 years old) underwent peripheral blood stem cell transplantation (PBSCT) from an HLA identical sibling donor. Diagnoses included ALL (17), non-ALL (6), and non malignant disease (2). GVHD prophylaxis consisted of cyclosporine plus methotrexate (15), only cyclosporine (8), cyclosporine plus prednisone (1), or nothing (1). All donors (6 months to 41 years old) received G-CSF at 10 microg/kg/day subcutaneously for 4-5 days and on day 5 underwent large volume leukapheresis. Median number of CD34(+) and CD3(+) cells collected and infused was 6.9 x 10(6) (range 2.5-32.8) and 4.5 x 10(8) (0.5-22.1) per kg of recipient body weight respectively. Median time to achieve ANC >0.5 x 10(9)/l and platelets >20 x 10(9)/l was 10 and 12 days, respectively. Acute GVHD grade > or =II developed in 10 of 24 evaluable patients (42%). Probability of acute GVHD was 62%. Median time to discharge was 25 days (range 14-52). Among 20 evaluable patients, five (25%) developed chronic GVHD at day 100. Probability of chronic GVHD was 29% after 1 year post PBSC. At a median follow-up of 558 (9-2071) days, overall survival for the whole group is 68%. Probabilities of event-free survival, overall survival and relapse for patients with malignant hematological diseases are 53%, 59% and 24% at 5 years, respectively. This study has confirmed the feasibility and safety of mobilization and collection of PBSC products and the applicability of this procedure to the pediatric population, both donors and recipients. Studies including larger numbers of pediatric patients undergoing allogeneic PBSCT are warranted to determine the long-term outcomes of such procedures. PMID- 11607767 TI - Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults. AB - Topotecan appears to be relatively unaffected by the most common multidrug resistance mechanisms, may potentiate cytotoxicity of alkylators, has good penetration into the central nervous system, is active against a variety of neoplasms, and has myelosuppression as its paramount toxicity. We present our experience with a myeloablative regimen that includes topotecan. Twenty-one patients with poor-prognosis tumors and intact function of key organs received topotecan 2 mg/m2 by 30-min intravenous (i.v.) infusion on days -8, -7, -6, -5, 4; thiotepa 300 mg/m2 by 3 h i.v. infusion on days -8, -7, -6; and carboplatin by 4 h i.v. infusion on days -5, -4, -3 with a daily dose derived from the pediatric Calvert formula, using a targeted area under the curve of seven mg/ml* min ( approximately 500 mg/m2/day). Stem cell rescue was on day 0. The patients were 1 to 29 (median 4) years old; 18 were in complete remission (CR) and three in partial remission (PR). Early toxicities were severe mucositis and erythema with superficial peeling in all patients and a seizure, hypertension, and renal insufficiency followed by veno-occlusive disease in one patient each. Post transplant treatment included radiotherapy alone (four patients) or plus biological agents (11 patients with neuroblastoma). With a follow-up of 6+ to 32+ (median 11+) months, event-free survivors include 10/11 neuroblastoma patients (first CR), 4/5 brain tumor patients (second PR or CR), 1/3 patients with metastatic Ewing's sarcoma (first or second CR), and a patient transplanted for multiply recurrent immature ovarian teratoma; a patient with desmoplastic small round-cell tumor (second PR) had progressive disease at 8 months. Favorable results for disease control, manageable toxicity, and the antitumor profiles of topotecan, thiotepa, and carboplatin, support use of this three-drug regimen in the treatment of neuroblastoma and brain tumors; applicability to other tumors is still uncertain. PMID- 11607768 TI - Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant. AB - Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin's disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58-1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count >0.5 x 10(9)/l and to platelet count of >20 x 10(9)/l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2-4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9-996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine- and melphalan-based conditioning promotes full donor chimerism, even following HLA mismatched transplants. However, the regimen may be more beneficial when applied to patients undergoing allogeneic HSC transplantation earlier in their disease course. PMID- 11607770 TI - Effect of extended immunosuppressive drug treatment on B cell vs T cell reconstitution in pediatric bone marrow transplant recipients. AB - Allogeneic bone marrow transplantation (BMT) is an effective therapy for a variety of malignancies and blood disorders, but rarely serves as a frontline treatment because of numerous, potential complications. Important and frequent complications relate to the profound immunosuppression that inevitably occurs during the first several months following treatment. To better elucidate and subsequently improve immune reconstitution, we examined T and B cell subsets among 43 pediatric BMT recipients in a retrospective study. We found that the relative numbers of T cells and B cells (T:B ratios) were discordant and highly variable among patients at day approximately 100 after BMT. Further investigation of BMT parameters identified a strong correlation between T:B ratios and immunosuppressive drug treatments, providing an explanation for variable lymphocyte reconstitution profiles. Results suggest that: (1) immunosuppressive therapy inhibits B cell expansion more strongly than T cell expansion following BMT; (2) WBC and absolute lymphocyte counts fail to reveal profound B cell immunodeficiencies in some BMT patients; and (3) routine analyses of T:B ratios serve to identify patients warranting close follow-up and extended supportive immunotherapy. PMID- 11607769 TI - Topotecan-filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells. AB - We compared the efficacy, toxicity, and cost of topotecan-filgrastim and filgrastim alone for mobilizing peripheral blood stem cells (PBSCs) in 24 consecutive pediatric patients with newly diagnosed medulloblastoma. PBSCs were mobilized with an upfront window of topotecan-filgrastim for 11 high-risk patients (residual tumor > or =1.5 cm2 after resection; metastases limited to neuraxis) and with filgrastim alone for 13 average-risk patients. All patients subsequently underwent craniospinal irradiation and four courses of high-dose chemotherapy with stem cell rescue. Target yields of CD34+ cells (> or =8 x 10(6)/kg) were obtained with only one apheresis procedure for each of the 11 patients treated with topotecan-filgrastim, but with a mean of 2.3 apheresis procedures for only six (46%) of the 13 patients treated with filgrastim alone (P = 0.0059). The median peak and median total yield of CD34+ cells were six-fold higher for the topotecan-filgrastim group (328/microl and 21.5 x 10(6)/kg, respectively) than for the filgrastim group (54/microl and 3.7 x 10(6)/kg, respectively). Mean times to neutrophil and platelet engraftment were similar. Myelosuppression was the only grade 4 toxicity associated with topotecan filgrastim mobilization and lasted a median of 5 days. Compared with filgrastim mobilization, topotecan-filgrastim mobilization resulted in a mean cost saving of $3966 per patient. Topotecan-filgrastim is an efficacious, minimally toxic, and cost-saving combination for PBSC mobilization. PMID- 11607771 TI - Immune haemolytic anaemia following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukaemia: association with leukaemic relapse and treatment with donor lymphocyte infusions. AB - Immune haemolytic anaemia (IHA) is a recognised complication after allogeneic stem cell transplantation (SCT) and occurs more frequently if marrow cells have been subjected to T cell depletion (TCD). Among 58 consecutive patients who underwent TCD-allogeneic SCT from volunteer unrelated donors for the treatment of CML at the Hammersmith Hospital during a 3-year period (1 March 1996 to 28 February 1999) we identified nine cases of IHA. All patients had a strongly positive direct and indirect antiglobulin test and in eight patients the serological findings were typical of warm-type haemolysis often with antibody specificities within the Rh system. All nine cases had clinically significant haemolysis and were treated initially with prednisolone and immunoglobulin. The onset of IHA coincided with the occurrence of leukaemic relapse in six cases, and the presence of host haemopoiesis confirmed by lineage-specific chimerism in all four cases studied. Five patients received donor lymphocyte infusions (DLI); in three molecular remission and the restoration of full donor chimerism coincided with resolution of haemolysis. We conclude that in the context of leukaemic relapse, DLI is an effective therapy for IHA following allografts involving TCD. PMID- 11607772 TI - Absence of a CD34- hematopoietic precursor population in recipients of CD34+ stem cell transplantation. AB - The purified CD34(+) cell fraction has been used for hematopoietic stem cell transplantation since they were demonstrated to have long-term reconstituting ability. Therefore, the potential effects of CD34(-) stem cells on the clinical course have been a major concern in recipients of CD34(+)-selected transplantation. To address this concern, we used an in vitro assay to determine whether transplant recipients have CD34(-)precursor population. Lin(-)CD34(-) cells were isolated from bone marrow cells in 11 transplant recipients including four CD34-selected transplantations, six standard bone marrow transplantations, and one T cell-depleted marrow transplantation. The frequency of the Lin(-)CD34( ) population in four CD34-enriched transplantation recipients was not different from those of normal donors or recipients of other modes of transplantation: 0.96 +/- 1.01% (mean +/- s.d., n = 4), 0.45 +/- 0.16% (n = 6), and 0.66 +/- 0.59% (n = 7), respectively. However, the Lin(-)CD34(-)population obtained from the recipients of CD34-enriched transplantation acquired neither CD34 expression nor colony-forming activity after 7 days of culture, whereas the cells from all the normal individuals and standard BMT recipients were able to differentiate into CD34(+) cells accompanied by the emergence of colony-forming activity.We conclude that recipients of CD34-enriched transplantation appear to have defects in their CD34(-) precursor population. The clinical significance of these defects will be determined in a life-long follow-up of these patients. PMID- 11607773 TI - CD34(+) cell collection efficiency does not correlate with the pre-leukapheresis hematocrit. AB - One hundred and seventy-seven large-volume leukapheresis procedures performed on 91 patients over a 15 month period were reviewed to see if the pre-apheresis hematocrit (Hct) affected the CD34(+) cell collection efficiency (CE) of the Fenwal CS 3000 Plus cell separator. The Hct was 0.174-0.461 (median 0.317), and the peripheral blood CD34(+) cell count 2-2487 per microl (median 21). The total CD34(+) cell quantity collected was 3.0-2677.2 x 10(6) (median 113.0). Based on the number of CD34(+)cells contained in the blood volume processed (23.3-37303.2 x 10(6); median 318.0), the CE was 1.7-87.5% (median 30.3). No correlation was found between the Hct and CE (r(2) = 0.0034; P = 0.44) or the total CD34(+) cell quantity collected (r2 = 0.0040; P = 0.40). CEs for Hct <0.25 (median CE 36%), Hct 0.25-0.299 (median CE 30%) and Hct 0.30 (median CE 30%) were comparable. As expected, highly significant correlations were seen between the CD34(+) cell quantities collected and quantities processed (r2 = 0.59; P < 10(-6)) as well as the peripheral blood CD34(+) cell counts (r2= 0.60; P < 10(-6)). We conclude that the minimum acceptable Hct or hemoglobin level for leukapheresis should be dictated by clinical circumstances because it does not affect stem cell collection. PMID- 11607774 TI - Polymorphisms in the coding region of mtDNA and effects on clinical outcome of unrelated bone marrow transplantation. AB - The entire protein-coding region was divided into 45 fragments, separately amplified and analyzed for polymorphism by the PCR-SSCP (single-strand conformation polymorphism) method. The effect of polymorphism mismatching on the clinical outcome of unrelated bone marrow transplantation was studied to clarify whether products from mtDNA become minor antigens. Variability in PCR-SSCP pattern combinations of the 45 fragments suggests that each individual has a different polymorphism combination in the protein-coding region if all the coding regions were compared at the nucleotide sequence level. Nonsynonymous polymorphisms were found at relatively high frequency in MTATP8 and MTND3. Both the polymorphisms with and without substitution matched the peptide-binding motifs of HLA-A*0201. The effects of the polymorphism matching were retrospectively analyzed in 340 recipients transplanted with HLA-A, -B, -DRB1 allele-matched bone marrow from unrelated donors. There were no effects of polymorphism matching on the incidence of acute GVHD and cumulative disease-free survival. These results suggest that polymorphisms which generate peptides, with and without substitutions, that bind the same HLA molecule hardly influence GVHD because the difference between the HLA-peptide complexes is minute. PMID- 11607775 TI - Successful non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) for Waldenstrom's macroglobulinemia with severe pancytopenia. AB - We report a 62-year-old male who underwent non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) because of his life threatening severe pancytopenia due to refractory Waldenstrom's macroglobulinemia. This therapy was performed safely and he made a marked recovery from his cytopenia that had not been improved with any other therapy. Bone marrow aspirates showed post-transplant mixed chimerism during engraftment, and became completely donor-derived after a series of GVHD symptoms, without subsequent donor lymphocyte infusion. Our results suggest that non-myeloablative allogeneic PBSCT could be a good alternative for patients suffering from multi drug resistant Waldenstrom's macroglobulinemia. PMID- 11607776 TI - CMV reactivation induced BK virus-associated late onset hemorrhagic cystitis after peripheral blood stem cell transplantation. AB - Hemorrhagic cystitis (HC) is a known complication of stem cell transplantation. In contrast to early-onset HC that is usually attributed to cyclophosphamide and occurs within a few days of infusion, late onset HC is associated with viral infection. In recent years BK virus has emerged as an important causative agent. We describe two patients who developed late onset HC (38 and 92 days post transplant) associated with BK viruria concomitant with CMV reactivation and suggest a possible role of CMV in the process of BK virus DNA replication. PMID- 11607777 TI - Fatal outcome in a patient developing Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) without measurable disease. AB - A 51-year-old female patient in the first chronic phase of CML received an allogeneic PBSCT from a matched unrelated donor. The transplant was manipulated by CD34+ cell selection. On day +193 after transplantation the patient was readmitted to the hospital with recurrent fever of unknown origin and cough. Clinical, radiographic and sonographic evaluation revealed no characteristic findings besides a mild splenomegaly. Screening for EBV, CMV, RSV and HSV did not indicate an active infection. On day +203 the patient developed generalized seizures, respiratory failure and died within 24 h in multiorgan failure. The macroscopic postmortem was still not enlightening; the histological examination however, demonstrated diffuse organ infiltration by monoclonal lymphoblastoid cells due to EBV-LPD. PMID- 11607778 TI - Ulcerative colitis after autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma. AB - A 54-year-old woman with peripheral T cell lymphoma in second complete remission (CR) received an autologous peripheral blood stem cell transplant (PBSCT). Antibiotic-resistant bloody diarrhea, and fever developed 110 days after transplant. Blood and stool cultures were negative. Skin rash was not observed. Barium enema and colonoscopy showed typical features of pancolonic-type ulcerative colitis (UC). Endoscopic biopsies confirmed the diagnosis of UC. Mesalazine and immunosuppressive therapy improved symptoms dramatically. We detected serum antibodies against synthetic tropomyosin (TM) peptide when UC was diagnosed. We postulate that autoimmunity including autoreactive anti-TM antibodies may be involved in the pathogenesis of UC after autologous PBSCT in this patient. PMID- 11607779 TI - Fatal graft-versus-host disease following HLA-mismatched donor lymphocyte infusion. AB - We report the case of a 10-year-old boy with molecular relapse of CML following unrelated donor BMT who developed fatal grade 4 acute GVHD of the gut and liver following one antigen-mismatched donor lymphocyte infusion. Previous experience of donor lymphocyte infusion in the HLA-mismatched setting is reviewed and the role of adoptive immunotherapy in this situation is discussed. PMID- 11607780 TI - Granulomatous pneumonitis following bone marrow transplantation. AB - We describe the rare occurrence of a granulomatous pneumonitis seen in a patient following allogeneic bone marrow transplantation. Interestingly sarcoidosis was diagnosed in the marrow donor less than a year after donating his bone marrow. PMID- 11607781 TI - Bath PUVA therapy in pediatric patients with drug-resistant cutaneous graft versus-host disease. PMID- 11607782 TI - False-positive results of Aspergillus enzyme-linked immunosorbent assay in a patient with chronic graft-versus-host disease after allogeneic bone marrow transplantation. PMID- 11607783 TI - Rhizopus presenting as an endobronchial obstruction following bone marrow transplant. PMID- 11607784 TI - The role of cytokine polymorphisms in rejection after solid organ transplantation. AB - The importance of cytokines to the immune response is irrefutable. Their role in the biology of solid organ transplantation per se is also assured. Thus it is likely that subtle differences in cytokine composition, particularly at the initiation of an immune response, may have a major effect on the outcome of that response. This may be particularly relevant in solid organ transplantation, where it is possible that genetic polymorphisms which influence cytokine production may determine the outcome of a transplant. Indeed, it has been suggested that immunosuppression may be individualised on the basis of recipient or donor genotype. However, much of the early data regarding the importance of specific cytokine polymorphisms has not been reproduced, and the significance of this field remains controversial. Nonetheless, with the experience gained from earlier studies, some clear patterns for future studies are emerging. PMID- 11607785 TI - NFkappaB polymorphisms and susceptibility to type 1 diabetes. AB - Nuclear factor kappa B (NFkappaB) is an important transcription factor that is involved in the response to oxidative stress and inflammation. Recent studies suggest that it may be involved in the development of diabetic microvascular complications. A highly polymorphic (CA) dinucleotide repeat microsatellite has been identified in the regulatory region of the NFkappaB gene. The aim of this study was to investigate whether this polymorphic region was associated with susceptibility to type 1 diabetes, or its late complications. Genomic DNA was extracted from the peripheral blood of 217 patients with type 1 diabetes mellitus (T1DM) and 111 normal healthy controls. In our population 18 alleles (A1-A18) were identified. There was a highly significant decrease in the frequency of allele 146 bp (A14) in type 1 diabetes (0.03) compared with the normal controls (0.28) (chi(2) = 79.8, Pc = 0.00001). In contrast, the frequency of the allele 138 bp (A10) was significantly increased in patients with type 1 diabetes (0.17) compared with the normal controls (0.02) (chi(2) = 32.8, P < 0.00000). These results demonstrate that the NFkappaB gene may play a role in the susceptibility to type 1 diabetes: individuals with the A10 allele may be more likely to develop diabetes compared with the A14 allele. PMID- 11607786 TI - Dextran sulphate sodium-induced colitis is ameliorated in interleukin 4 deficient mice. AB - The importance of IL-4 and its effects in inflammatory bowel disease (IBD) was studied using the dextran sulphate sodium-induced model of experimental colitis. The model resembles ulcerative colitis in humans. IL-4 deficient mice and IL-4+/+ littermates were used to induce colitis. Activity of disease, extent of tissue damage, immunoglobulin isotypes, IFNgamma and IL-10 production was assessed. Both disease activity index (DAI) and histological scores were consistently lower in the IL-4 deficient mice than in the IL-4+/+ littermates. Furthermore, the lower histological scores reflected the milder inflammatory lesions and decreased ulceration found in the IL-4 deficient mice. Analysis of immunoglobulin subtypes showed that IgG1 was almost absent in the sera of IL-4 deficient mice. IFNgamma contents was much higher in colonic tissues from IL-4 deficient mice. Dextran sulphate sodium-induced colitis is ameliorated in IL-4 deficient mice. IL-4 either directly or through its effects on T and B cells influences its severity. It is unclear if the higher immunoglobulin-producing cells in the colonic tissues of IL-4 deficient mice before colitis was induced could have influenced the outcome of the disease. The high IFNgamma contents in colonic tissues of IL-4 deficient mice argue against the role of this cytokine as a crucial mediator of tissue damage during the acute phase of colitis. PMID- 11607787 TI - Analysis of the association of HLA-DRB1, TNFalpha promoter and TNFR2 (TNFRSF1B) polymorphisms with SLE using transmission disequilibrium test. AB - A number of studies reported associations of HLA-DRB1, TNFalpha (TNF) promoter and TNF receptor II (TNFR2, TNFRSF1B) polymorphisms with systemic lupus erythematosus (SLE), however, the results have often been inconsistent. Such lack of consistency could partly derive from the population admixture involved in the case-control study. To avoid such a problem, polymorphisms in these genes were analyzed using transmission disequilibrium test (TDT) in Caucasian SLE families. Ninety-one Caucasian SLE family samples recruited in southern California were analyzed for the association with HLA-DRB1, TNF promoter positions at -1031, 863, -857 and -308, and TNFR2-196M/R polymorphisms. Significant transmission was observed for HLA-DRB1*1501, but not for HLA-DRB1*0301, nor for TNF haplotype that codes for -308A. Interestingly, TNF haplotype coding for -1031C, -863A, -857C showed a tendency of preferential nontransmission in the patients without lupus nephritis and in those with malar rash. No transmission distortion was observed for TNFR2-196R allele. These findings confirmed the association of HLA-DRB1*1501, but did not replicate that of the HLA-DRB1*0301, TNFA-308A and TNFR2-196R with SLE in this population. In addition, a possible disease-protective role for TNF haplotype coding for -1031C, -863A, -857C was suggested. PMID- 11607788 TI - Mannan-binding lectin (MBL) gene polymorphisms in ulcerative colitis and Crohn's disease. AB - The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC), are complex multifactorial traits involving both environmental and genetic factors. Mannan-binding lectin (MBL) plays an important role in non specific immunity and complement activation. Point mutations in codons 52, 54 and 57 of exon 1 of the MBL gene are associated with decreased MBL plasma concentrations and increased susceptibility to various infectious diseases. If these MBL mutations could lead to susceptibility to putative IBD-etiological microbial agents, or could temper the complement-mediated mucosal damage in IBD, MBL could function as the link between certain microbial, immunological and genetic factors in IBD. In this study, we investigated the presence of the codon 52, 54 and 57 mutations of the MBL gene in 431 unrelated IBD patients, 112 affected and 141 unaffected first-degree relatives, and 308 healthy control individuals. In the group of sporadic IBD patients (n = 340), the frequency of the investigated MBL variants was significantly lower in UC patients when compared with CD patients (P = 0.01) and with controls (P = 0.02). These results suggest that MBL mutations which decrease the formation of functional MBL could protect against the clinical development of sporadic UC, but not of CD. This could be explained by the differential T-helper response in both diseases. PMID- 11607789 TI - A novel, soluble homologue of the human IL-10 receptor with preferential expression in placenta. AB - The cytokine receptor family type 2 (CRF2) comprises receptors for important immunomediators like interferons and interleukin-10 (IL-10). We identified a novel member of this family which represents the first exclusively soluble receptor in this group and was therefore designated as CRF2-soluble 1 (CRF2-s1). The CRF2-s1 gene covers about 28 kb and is located on chromosome 6 in close proximity to the CRF2 members interferon (IFN)-gamma receptor 1 and IL-20 receptor 1. It comprises seven exons and generates two different mRNA splice variants, CRF2-s1-long and CRF2-s1-short. CRF2-s1-long and CRF2-s1-short encode proteins of 263 and 231 amino acids, respectively. A comparison of predicted protein structures led to the postulation that each receptor variants binds a different ligand. Quantitative analysis of human mRNA expression revealed a very restricted pattern for both splice forms. CRF2-s1 turned out to be the first member of this receptor family which was expressed neither in resting nor in stimulated leucocyte populations. CRF2-s1-long was only expressed in placenta, whereas CRF2-s1-short was additionally expressed in human mammary gland and, at a lower level, in skin, spleen, thymus and stomach. The preferential expression of CRF2-s1 in placenta suggests a role for this receptor in establishing and maintaining successful pregnancy. PMID- 11607790 TI - Contrasting evolution of the human leukocyte N-formylpeptide receptor subtypes FPR and FPRL1R. AB - N-formylpeptides are phagocyte chemoattractants that act by binding to two structurally related receptors, FPR (formylpeptide receptor) and FPRL1R (FPR-like 1 receptor), which are encoded by the human genes FPR1 and FPRL1. Single nucleotide polymorphisms (SNPs) in the FPR coding region have been reported and two have been associated with the disease juvenile periodontitis; however, their frequency and linkage relationships are unknown. Here we systematically analyzed polymorphism in the open reading frames of FPR1 and FPRL1 by direct sequencing of cloned alleles from random blood donors from North America. For FPR1 we detected five non-synonymous SNPs and two synonymous SNPs in a sample of 26 chromosomes one each from 17 Caucasian and nine black random blood donors. Although all five non-synonymous SNPs were common in Caucasians, Blacks, and Asians, notable differences in allele frequency were found for each SNP in the different racial groups, suggesting differential selective pressures. We found that the FPR1 polymorphisms are linked in 15 common haplotypes. No polymorphisms were detected in FPRL1 after sampling 44 chromosomes from 36 random blood donors from the same three racial groups. Thus FPR1 and FPRL1, though they originated from a common gene, appear to have undergone markedly different evolutionary events. PMID- 11607791 TI - Nucleotide diversity of the TNF gene region in an African village. AB - The wide variety of disease associations reported at the TNF locus raises the question of how much variation exists within a single population. To address this question, we sequenced the entire TNF gene in 72 chromosomes from healthy residents of a village in The Gambia, West Africa. We found 12 polymorphisms in 4393 nucleotides, of which five have not been previously described, giving an estimated nucleotide diversity (theta) of 5.6 x 10(-4). A significantly higher frequency of polymorphisms was found in the promoter region than in the coding region (8/1256 vs 0/882 nucleotides, P = 0.02). All polymorphisms with the exception of one rare allele were found to be present in Malawi, which is both geographically and genetically distant from The Gambia. Genotyping of 424 Gambian and 121 Malawian adults showed a significant frequency difference between the two populations for eight of the 12 polymorphisms, but the average fixation index across the variable sites was relatively low (F(ST) = 0.007). We conclude that, at the TNF locus, the nucleotide diversity found within a single African village is similar to the global value for human autosomal genes sampled across different continents. PMID- 11607792 TI - IFNs activate toll-like receptor gene expression in viral infections. AB - Toll-like receptors (TLRs) mediate innate immune responses to microbes. TLR2, TLR5, TLR6, and TLR9 have been implicated in responses to bacterial components, and TLR4 is the receptor for Gram-negative bacteria. Recently, TLR4 was described to function in respiratory syncytial virus-induced NF-kappaB activation. Here we have analyzed TLR1-9 mRNA expression in human primary macrophages infected with influenza A and Sendai viruses. TLR1, TLR2, TLR4, TLR6, and TLR8 mRNAs were expressed at basal levels in macrophages. Viral infection enhanced TLR1, TLR2, TLR3, and TLR7 mRNA expression, and neutralizing anti-IFN-alpha/beta antibodies downregulated gene expression of these TLRs. Exogenously added IFN-alpha upregulated TLR1, TLR2, TLR3, and TLR7 mRNA expression in macrophages, as well as TLR3 mRNA expression in epithelial and endothelial cell lines. IFN-gamma enhanced the expression of TLR1 and TLR2 mRNA in macrophages, and TLR3 in epithelial and endothelial cells. The data suggests a novel role for IFNs in the activation of innate immunity. PMID- 11607793 TI - ACE inhibition in aortic stenosis: an intriguing hypothesis, not a proven therapy. PMID- 11607794 TI - ACE inhibition in aortic stenosis: dangerous medicine or golden opportunity? AB - Conventionally angiotensin-converting enzyme (ACE) inhibitors are contraindicated in patients with aortic stenosis. Abundant evidence is now available showing that angiotensin II has a central role in the development of left ventricular hypertrophy (LVH), myocardial contractile failure and diastolic dysfunction in response to pressure overload. In animal models, ACE inhibitors have been shown to attenuate these pathological responses. In humans there is no such evidence available, however uncontrolled studies have shown that these agents are not only tolerated but are associated with acute improvements in haemodynamics and diastolic function. Further studies are merited to assess the possible role of ACE inhibitors in aortic stenosis both before and after valve replacement. Potential benefits may include prevention of LVH, improved diastolic function, reduction of arrhythmias and preservation of left ventricular function. PMID- 11607795 TI - Resistance to antihypertensive medication as predictor of renal artery stenosis: comparison of two drug regimens. AB - BACKGROUND: Renal artery stenosis is among the most common curable causes of hypertension. The definitive diagnosis is made by renal angiography, an invasive and costly procedure. The prevalence of renal artery stenosis is less than 1% in non-selected hypertensive patients but is higher when hypertension is resistant to drugs. OBJECTIVE: To study the usefulness of standardised two-drug regimens for identifying drug-resistant hypertension as a predictor of renal artery stenosis. DESIGN AND SETTING: Prospective cohort study carried out in 26 hospitals in The Netherlands. PATIENTS: Patients had been referred for analysis of possible secondary hypertension or because hypertension was difficult to treat. Patients < or =40 years of age were assigned to either amlodipine 10 mg or enalapril 20 mg, and patients >40 years to either amlodipine 10 mg combined with atenolol 50 mg or to enalapril 20 mg combined with hydrochlorothiazide 25 mg. Renal angiography was performed: (1) if hypertension was drug-resistant, ie if diastolic pressure remained > or =95 mm Hg at three visits 1-3 weeks apart or an extra drug was required, and/or (2) if serum creatinine rose by > or =20 micromol/L (> or =0.23 mg/dL) during ACE inhibitor treatment. RESULTS: Of the 1106 patients with complete follow-up, 1022 had been assigned to either the amlodipine- or enalapril-based regimens, 772 by randomisation. Drug-resistant hypertension, as defined above, was identified in 41% of the patients, and 20% of these had renal artery stenosis. Renal function impairment was observed in 8% of the patients on ACE inhibitor, and this was associated with a 46% prevalence of renal artery stenosis. In the randomised patients, the prevalence of renal artery stenosis did not differ between the amlodipine- and enalapril-based regimens. CONCLUSIONS: In the diagnostic work-up for renovascular hypertension the use of standardised medication regimens of maximally two drugs, to identify patients with drug-resistant hypertension, is a rational first step to increase the a priori chance of renal artery stenosis. Amlodipine- or enalapril-based regimens are equally effective for this purpose. PMID- 11607796 TI - Predictors of sudden cardiac death in never previously treated patients with essential hypertension: long-term follow-up. AB - Increased QT dispersion has been associated with ventricular arrhythmia and sudden death in a variety of cardiac disorders. Left ventricular hypertrophy (LVH) has also been associated with increased incidence of sudden cardiac death in patients with essential hypertension. Furthermore, patients with essential hypertension, particularly those with LVH, are more likely to develop ventricular arrhythmias than are the normal population. The relationship between LVH, QT dispersion, complex ventricular arrhythmia and sudden cardiac death in previously untreated patients over long-term follow-up in hypertension has not been reported before and is the purpose of this study. Fifty-nine adult subjects with essential hypertension, who had never been previously on antihypertensive treatment were followed up for a total of 119.2 +/- 26.2 months. QTc (corrected QT), blood pressure, electrocardiograms, and 24-h Holter ECG recordings were performed in all patients at the time of entry to the study. Ventricular arrhythmias were classified using a modified Lown's scoring system. During the follow-up period death occurred in 12 cases (20%) of which only six (10%) deaths were sudden. The findings of this study indicate that LVH and complex ventricular arrhythmias (Lown's score > or =3) are the only significant predictors of sudden death. Although patients who died suddenly had higher systolic and diastolic blood pressures and greater QTc dispersion compared to surviving patients, this difference was statistically not significant. Similarly, when those who died suddenly were compared to those non-cardiac deaths, LVH and complex ventricular arrhythmias were the only significant predictors of sudden death. In spite of increased QTc dispersion in hypertensive patients, this finding was not associated with increased risk of sudden death and only LVH and high grade ventricular arrhythmias identified hypertensive patients at risk of sudden cardiac death over a 10-year follow-up period. PMID- 11607797 TI - Sphygmomanometers in use in general practice: an overlooked aspect of quality in patient care. AB - OBJECTIVES: To assess the condition, accuracy and safety of mercury and anaeroid sphygmomanometers in use in general practice and to pilot a scheme for sphygmomanometer maintenance within the district. DESIGN: Instruments were checked on site according to set protocols which related to established guidelines and standards and data were entered into a specially designed database. Mercury sphygmomanometers were removed to the laboratory for servicing. Practices received written feedback on the condition of each instrument checked, repairs undertaken and advice, where necessary, for further work required. Participant views on the scheme were sought. MATERIALS AND METHODS: A total of 472 instruments (75.4% mercury) located in 86 general practices (87.8% of practices participated) in a health district in the West Midlands. Instruments were checked against 28 (mercury) and 25 (anaeroid) quality standards and (for mercury instruments) against British Hypertension Society guidelines. RESULTS: 69.1% of mercury and 95.7% of anaeroid instruments checked, had no service records. Of the remainder, only 29 mercury (8.1%) and one anaeroid (0.9%) had a record of a check or service within the previous 12 months. None of the instruments met all of the relevant quality standards and 14 (3.9%) mercury and seven (6.1%) anaeroid instruments met less than half. A large proportion of mercury sphygmomanometers tested had defects likely to affect recommended measurement technique. Only two-thirds were accurate at all pressure levels tested. Only 38.8% of anaeroid instruments were accurate at all test pressure levels. CONCLUSIONS: The level of defects noted could have an impact on diagnosis and monitoring of hypertension. PMID- 11607798 TI - Progressive arterial wall stiffening in patients with increasing diastolic blood pressure. AB - BACKGROUND: Hypertension is an established risk factor for cardiovascular disease. Risk factor patterns for various cardiovascular complications are different. We studied the relationship between increasing diastolic blood pressure and arterial wall dynamics of various peripheral arteries in hypertensives to increase insight in the variability of properties within the arterial tree. METHODS: Eighty-six untreated hypertensives participated in this cross-sectional study. The study-population was divided into quartiles with increasing diastolic office blood pressure. Cross-sectional compliance and distensibility coefficients of the carotid and femoral arteries were determined, using a vessel wall movement detector system (Wall Track System). RESULTS: Diameters of both common carotid arteries enlarged (right: from 7.4 +/- 0.2 to 7.9 +/- 0.2 mm) while cross-sectional compliance (right: from 0.61 +/- 0.04 to 0.42 +/- 0.04 mm(2)/kPa) and distensibility coefficients (right: from 14.2 +/- 1.0 to 9.0 +/- 1.0 10(-3)/kPa) gradually dropped with increasing diastolic blood pressure. Cross-sectional compliance and diameter of the right common femoral artery remained unchanged while distensibility coefficient decreased although less gradually when compared with the carotid arteries. CONCLUSIONS: In untreated hypertensives gradual arterial wall stiffening of the carotid arteries occurred with increasing diastolic blood pressure. Gradual changes were less clear in the common femoral artery which points to the heterogeneity of the arterial tree. PMID- 11607799 TI - Diabetes mellitus and renal failure: effects on large artery stiffness. AB - Diabetes mellitus and end-stage renal disease are two pathologic entities associated with increased cardiovascular risk. Several studies have shown that arterial stiffness is increased in both cases and contributes to the increased risk. In order to determine the effect of diabetes and renal failure on arterial stiffness, we conducted a case-control study. One hundred and twenty-two diabetic patients were compared to 122 non-diabetic patients matched to the study group for sex, age, mean arterial pressure, number and localisation of the atherosclerotic alterations. Arterial stiffness was assessed by automatic measurement of the aortic pulse wave velocity (PWV) and by measuring the peripheral and carotid pulse pressure (PP) and reflected waves through analysis of the pulse wave using the principle of applanation tonometry. Aortic PWV was significantly higher in the diabetic subgroup as well as PP at the peripheral and central levels for the same age and mean arterial pressure. In addition, renal failure was independently associated with an increased aortic PWV but not PP in the general population. Independent of the degree of renal failure, a fall in the glomerular filtration rate was also associated with increased aortic PWV. No interaction was noted between renal failure and diabetes mellitus. In conclusion, this study shows that diabetic patients have higher arterial stiffness compared to non-diabetic ones having one or more cardiovascular risk factors, manifested by increased aortic PWV and PP. In addition, renal failure, irrespective of its degree and independent of diabetes mellitus, is associated with increased aortic PWV but not PP. PMID- 11607800 TI - The association between antihypertensive drug therapies and plasma lipid levels in the general population. AB - OBJECTIVE: To assess the association between different antihypertensive drug regimens and plasma lipid levels in the general population. METHODS: The Monitoring Project on Cardiovascular Risk Factors was conducted from 1987 to 1991 as a cross-sectional study in The Netherlands. Antihypertensive drug-users and untreated hypertensives were selected. After exclusion of users of cholesterol lowering drugs 2997 subjects remained for the analysis. The plasma lipid concentrations of the users and non-users of antihypertensives were compared by multiple linear regression. RESULTS: In the univariate analysis patients using beta-blockers had lower high-density lipoprotein (HDL) concentrations (1.13 mmol/l, P < 0.05) and higher cholesterol ratios (5.74, P < 0.05) than untreated hypertensives (Total cholesterol = 6.07 mmol/l, HDL = 1.20 mmol/l and ratio = 5.44). Patients using diuretics had higher total cholesterol levels (6.34 mmol/l) and higher HDL levels (1.26 mmol/l) compared to untreated hypertensives. After adjustment for possible confounders these differences were smaller and no longer statistically significant. After adjustment we found a significant lower HDL cholesterol (mean difference of -0.10 mmol/l, P < 0.05) for users of a combination of a beta-blocker and a diuretic. CONCLUSIONS: Although randomised, controlled trials have demonstrated that antihypertensive drugs may influence plasma lipid levels we observed no substantial association for single antihypertensive drug therapy in the general population. The combination of a diuretic and a beta-blocker was associated with a worse lipid profile. PMID- 11607801 TI - Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men. AB - As the effects of sildenafil are in part mediated by enhancing the action of nitric oxide and nitrates given acutely markedly reduce early wave reflection, we explored the effects of a single oral dose of sildenafil citrate (50 mg) on blood pressure and arterial wave reflection in treated hypertensive men in a single blind randomised placebo controlled crossover study. Eight men (aged 57-76 years) with well controlled hypertension and erectile dysfunction and no contraindications to the use of sildenafil, were given either sildenafil 50 mg or placebo orally, with the second drug being given 2 weeks later. Blood pressure and heart rate with an automated digital oscillometric device (Omron) HEM-705 CP) and the augmentation index, a measure of arterial wave reflection in the aorta derived using radial applanation tonometry, were measured before and at 15-min intervals for 2 h thereafter. The extent of individual maximum reductions (mm Hg) from baseline in systolic (24 +/- 10 vs. 6 +/- 8, P < 0.05) and diastolic blood pressure (8 +/- 5 vs. 3 +/- 2, P < 0.05) occurred on the sildenafil study day. On average the brachial blood pressure at 75 min following sildenafil was 17/11 mm less than on the placebo day (P < 0.01). Augmentation index was also reduced significantly at 90 min (P < 0.05) suggesting reduced vascular tone in the arteries. The area under the brachial and aortic blood pressure and augmentation index time curve (by the trapezoidal rule corrected for baseline reading) was significantly lower (P < 0.05) on the sildenafil study day. The study shows that the peripheral vasodilatory effects of sildenafil, possibly related to nitric oxide, are accompanied by a fall in systemic blood pressure and reduced arterial wave reflection. PMID- 11607803 TI - The effect of the fast of Ramadan on ambulatory blood pressure in treated hypertensives. AB - Every year, millions of Moslems throughout the world fast from sunrise till sunset daily during the month of Ramadan, that is, experience repeated cycles of fasting-refeeding. Studies in animal models have shown that repeated cycles of fasting-refeeding may cause or exacerbate hypertension. Changes in sleeping patterns as well as changes in medication timing may also influence ambulatory blood pressure. We undertook this study in order to examine the effect of the Ramadan fast on treated hypertensive subjects. Seventeen hypertensive subjects were examined, and 24-h blood pressure monitoring was carried out twice, before and during the last week of the Ramadan. All continued their medications, which were all once-daily preparations. Twenty-four hour mean blood pressure as well as average awake and average asleep blood pressure were compared. There was no difference between mean blood pressure before and during the Ramadan (138.5 +/- 18.5/77.2 +/- 8.1 mm Hg vs 136.4 +/- 20.4/75.7 +/- 5.9 mm Hg, P-nonsignificant). Blood pressure load also did not differ before and during Ramadan (systolic load 49% vs. 44%, diastolic load 21% vs. 18%, P-nonsignificant). Weight was reduced by 1.4 +/- 1.6 kg (P < 0.002). We conclude, that according to our findings, treated, hypertensive patients may be assured that, with continuation of previous medications, traditional fasting during the month of Ramadan can be safely undertaken. PMID- 11607802 TI - Integrated effects of the vasodilating beta-blocker nebivolol on exercise performance, energy metabolism, cardiovascular and neurohormonal parameters in physically active patients with arterial hypertension. AB - OBJECTIVE: The present study was designed to investigate the integrated effects of the beta-1-selective blocker with vasodilator properties, nebivolol, on systemic haemodynamics, neurohormones and energy metabolism as well as oxygen uptake and exercise performance in physically active patients with moderate essential hypertension (EH). DESIGN AND METHODS: Eighteen physically active patients with moderate EH were included: age: 46.9 +/- 2.38 years, weight: 83.9 +/- 2.81 kg, blood pressure (BP): 155.8 +/- 3.90/102.5 +/- 1.86 mm Hg, heart rate: 73.6 +/- 2.98 min(-1). After a 14-day wash-out period a bicycle spiroergometry until exhaustion (WHO) was performed followed by a 45-min submaximal exercise test on the 2.5 mmol/l lactate-level 48 h later. Before, during and directly after exercise testing blood samples were taken. An identical protocol was repeated after a 6-week treatment period with 5 mg nebivolol/day. RESULTS: Nebivolol treatment resulted in a significant (P < 0.01) decrease in systolic and diastolic BP and heart rate at rest and during maximal and submaximal exercise. Maximal physical work performance, blood lactate and rel. oxygen uptake (rel. VO(2)) before and after nebivolol treatment at rest and during maximal and submaximal exercise remained unaltered. Free fatty acid, free glycerol, plasma catecholamines, beta-endorphines and atrial natriuretic peptide (ANP) increased before and after treatment during maximal and submaximal exercise but remained unaltered by nebivolol treatment. In contrast, plasma ANP levels at rest were significantly higher in the presence of nebivolol, endothelin-1 levels were unchanged. CONCLUSIONS: Nebivolol was effective in the control of BP at rest and during exercise in patients with EH. Furthermore, nebivolol did not negatively affect lipid and carbohydrate metabolism and substrate flow. The explanation for the effects on ANP at rest remain elusive. This pharmacodynamic profile of nebivolol is potentially suitable in physically active patients with EH. PMID- 11607805 TI - Geographical variation in prevalence of hypertension within The Gambia. AB - Hypertension has become an important public health problem for sub-Sahara Africa. In a previous nationwide study, we observed a high degree of geographical variation in the prevalence of diastolic hypertension. Geographical variation provides essential background information for the development of community randomised trials could suggest aetiological mechanisms, inform control strategies and prompt further research questions. We designed a follow-up study from the nine high-prevalence communities, and from 18 communities where hypertension was found least prevalent (controls). In each community, 50 households were randomly selected. In each household, an (unrelated) man and woman were enrolled. The risk for hypertension (blood pressure > or =160/95 mm Hg) was higher in the high prevalence communities compared to the control villages (adjusted OR = 1.7, 95% CI 1.3-2.2). The observed coefficient of variation in hypertension prevalence, k, was 0.30. Thus we confirmed significant geographical variation in prevalence of hypertension over time, which has implications for planning of interventions. PMID- 11607804 TI - Educational level and hypertension: how socioeconomic differences condition health care. AB - This is the first European study that has evaluated educational level in a large sample of hypertensive outpatients. We established the educational level of the hypertensive outpatients in our unit, and determined whether the awareness of hypertension and its organ damage was education-related. We analysed data from 812 consecutive outpatients (378 men, mean age 50 +/- 10 years) with essential stage I-II hypertension. Subjects were subdivided into two categories: group A subjects were highly educated; group B subjects had a little education. Data were compared with educational level from the 1991 population census for the Campania region (ISTAT data) and with 200 type 2 diabetes patients (96 men, mean age 51 +/ 9 years) from the nearest diabetes unit. For each hypertensive patient we considered clinical, echocardiographic and biochemical parameters. Data from the last census showed a high percentage (80%) of subjects with low education. The percentage of type 2 diabetic patients with little education was high (190 patients, 95%). Conversely, it is somewhat surprising that most hypertensive patients reached high standards of education and worked at sedentary jobs (group A: 736 patients, 91%; P < 0.0001). Multivariate analysis showed that only diastolic blood pressure (P = 0.03) was independently associated with low educational level. Compared to diabetes, hypertension and its risk factors are relatively unknown to people with little education. Education is associated with greater health care and awareness that may overcome the risk related to low physical activity. Thus, we stress the importance of a sound health policy able to reach out to the uneducated and make them aware of hypertension and the health care services available to them. PMID- 11607806 TI - Transplant renal artery stenosis: hypertension and graft function before and after angioplasty. AB - We present a case, who after 15 years of renal transplantation developed severe deterioration of her hypertension without alteration in renal function. Colour Doppler sonography revealed a 90% stenosis near the anastomosis of the graft artery to iliac artery, which was successfully and uneventfully corrected by percutaneous balloon angioplasty. Following the procedure the blood pressure control dramatically improved and her antihypertensive regimen returned and remained at baseline for the subsequent year of observation. Renal function remained normal and stable before and after angioplasty. PMID- 11607807 TI - Dihydropyridine calcium channel blockers and peripheral side effects. PMID- 11607808 TI - The measurement of diastolic blood pressure in children: K4 or K5? What the journals do. PMID- 11607810 TI - DNA double strand break repair and chromosomal translocation: lessons from animal models. AB - The maintenance of genomic stability is one of the most important defenses against neoplastic transformation. This objective must be accomplished despite a constant barrage of spontaneous DNA double strand breaks. These dangerous lesions are corrected by two primary pathways of double strand break repair; non homologous end joining and homologous recombination. Recent studies employing mouse models have shown that absence of either pathway leads to genomic instability, including potentially oncogenic translocations. Because translocations involve the union of different chromosomes, cellular machinery must exist that creates these structures in the context of unrepaired double strand breaks. Evidence is mounting that the pathways of double strand break repair that are so important for survival may themselves be the culprits that generate potentially fatal translocations. Evidence and models for the dual roles of double strand break repair in both preventing, and generating, oncogenic karyotypic changes are discussed. PMID- 11607811 TI - Mechanisms of chromosomal translocations in B cell lymphomas. AB - Reciprocal chromosomal translocations involving the immunoglobulin (Ig) loci are a hallmark of most mature B cell lymphomas and usually result in dysregulated expression of oncogenes brought under the control of the Ig enhancers. Although the precise mechanisms involved in the development of these translocations remains essentially unknown, a clear relationship has been established with the mechanisms that lead to Ig gene remodeling, including V(D)J recombination, isotype switching and somatic hypermutation. The common denominator of these three processes in the formation of Ig-associated translocations is probably represented by the fact that each of these processes intrinsically generates double-strand DNA breaks. Since isotype switching and somatic hypermutation occur in germinal center (GC) B cells, the origin of a large number of B cell lymphomas from GC B cells is likely closely related to aberrant hypermutation and isotype switching activity in these B cells. PMID- 11607813 TI - Chromosome translocations in multiple myeloma. AB - Multiple myeloma (MM), a malignant tumor of somatically mutated, isotype-switched plasma cells (PC), usually arises from a common benign PC tumor called Monoclonal Gammopathy of Undetermined Significance (MGUS). MM progresses within the bone marrow, and then to an extramedullary stage from which MM cell lines are generated. The incidence of IgH translocations increases with the stage of disease: 50% in MGUS, 60-65% in intramedullarly MM, 70-80% in extramedullary MM, and >90% in MM cell lines. Primary, simple reciprocal IgH translocations, which are present in both MGUS and MM, involve many partners and provide an early immortalizing event. Four chromosomal partners appear to account for the majority of primary IgH translocations: 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf). They are mediated primarily by errors in IgH switch recombination and less often by errors in somatic hypermutation, with the former dissociating the intronic and 3' enhancer(s), so that potential oncogenes can be dysregulated on each derivative chromosome (e.g., FGFR3 on der14 and MMSET on der4). Secondary translocations, which sometimes do not involve Ig loci, are more complex, and are not mediated by errors in B cell specific DNA modification mechanisms. They involve other chromosomal partners, notably 8q24 (c-myc), and are associated with tumor progression. Consistent with MM being the malignant counterpart of a long-lived PC, oncogenes dysregulated by primary IgH translocations in MM do not appear to confer an anti-apoptotic effect, but instead increase proliferation and/or inhibit differentiation. The fact that so many different primary transforming events give rise to tumors with the same phenotype suggests that there is only a single fate available for the transformed cell. PMID- 11607812 TI - Translocations involving c-myc and c-myc function. AB - c-MYC is the prototype for oncogene activation by chromosomal translocation. In contrast to the tightly regulated expression of c-myc in normal cells, c-myc is frequently deregulated in human cancers. Herein, aspects of c-myc gene activation and the function of the c-Myc protein are reviewed. The c-myc gene produces an oncogenic transcription factor that affects diverse cellular processes involved in cell growth, cell proliferation, apoptosis and cellular metabolism. Complete removal of c-myc results in slowed cell growth and proliferation, suggesting that while c-myc is not required for cell proliferation, it acts as an integrator and accelerator of cellular metabolism and proliferation. PMID- 11607814 TI - Translocations involving anaplastic lymphoma kinase (ALK). AB - Anaplastic large-cell lymphoma (ALCL) comprises a group of non-Hodgkin's lymphomas (NHLs) that were first described in 1985 by Stein and co-workers and are characterized by the expression of the CD30/Ki-1 antigen (Stein et al., 1985). Approximately half of these lymphomas are associated with a typical chromosomal translocation, t(2;5)(p23;q35). Much confusion about the exact classification and clinicopathological features of this subgroup of NHL was clarified with the identification of NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) as the oncogene created by the t(2;5) (Morris et al., 1994). With the discovery of NPM-ALK as the specific lymphoma gene mutation, this NHL subtype could be redefined on the molecular level. This achievement was enhanced by the availability of specific antibodies that recognize ALK fusion proteins in paraffin-embedded lymphoma tissues. Several excellent recent reviews have summarized the histopathological and molecular findings of ALCL and their use in the classification of this lymphoma entity (Anagnostopoulos and Stein, 2000; Benharroch et al., 1998; Drexler et al., 2000; Foss et al., 2000; Gogusev and Nezelof, 1998; Kadin and Morris, 1998; Ladanyi, 1997; Morris et al., 2001; Shiota and Mori, 1996; Skinnider et al., 1999; Stein et al., 2000). This review will focus on the molecular function and signal transduction pathways activated by ALK fusion oncogenes, with recent advances and possible clinical implications to be discussed. PMID- 11607815 TI - The role of TCL1 in human T-cell leukemia. AB - The TCL1 locus on human chromosome 14q32.1 is activated in T-cell leukemias by translocations and inversions that juxtapose it to regulatory elements of T-cell receptor genes. We isolated and characterized four genes at this locus, TCL1 and TCL1b (T-cell leukemia/lymphoma 1 and 1b), and TNG1 and TNG2 (TCL neighboring genes 1 and 2) all of which are overexpressed following rearrangements involving 14q32.1. TCL1 and TCL1b show 60% similarity and are represented in the mouse by a cluster of six homologous genes. In humans TCL1 and TCL1b show similar expression patterns: They are expressed mainly in CD4-/CD8- immature T-cells, pre B-cells and virgin B-cells. Expression decreases significantly at more mature stages of B cell development. Activation of TCL1 and/or TCL1b in mature T-cells causes T-cell leukemia in humans. The oncogenic nature of TCL1 was confirmed by the analysis of a transgenic mouse model. Functional analysis of Tcl1 revealed its involvement in a PI3-kinase dependent Akt (PKB) pro-survival pathway through its interaction with the Akt kinase which increases Akt's enzymatic activity and promotes translocation of Akt to the nucleus. PMID- 11607816 TI - Modeling Philadelphia chromosome positive leukemias. AB - The Ph chromosome has been genetically linked to CML and ALL. Its chimeric fusion gene product, BCR-ABL, can generate leukemia in mice. This review will discuss selected model systems developed to study BCR-ABL induced leukemia and focuses on what we have learned about the human disease from these models. Five main experimental approaches will be discussed including: (i) Reconstitution of mice with bone marrow cells retrovirally transduced with BCR-ABL; (ii) Transgenic mice expressing BCR-ABL; (iii) Knock-in mice with BCR-ABL expression driven from the endogenous bcr locus; (iv) Development of CML-like disease in mice with loss of function mutations in heterologous genes; and (v) ES in vitro hematopoietic differentiation coupled with regulated BCR-ABL expression. PMID- 11607817 TI - AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML. PMID- 11607818 TI - Common themes in the pathogenesis of acute myeloid leukemia. AB - The pathogenesis of acute myeloid leukemia is associated with the appearance of oncogenic fusion proteins generated as a consequence of specific chromosome translocations. Of the two components of each fusion protein, one is generally a transcription factor, whereas the other partner is more variable in function, but often involved in the control of cell survival and apoptosis. As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators that interfere with the process of myeloid differentiation, determine a stage specific arrest of maturation and enhance cell survival in a cell-type specific manner. The abnormal regulation of transcriptional networks occurs through common mechanisms that include recruitment of aberrant co-repressor complexes, alterations in chromatin remodeling, and disruption of specific subnuclear compartments. The identification and analysis of common and specific target genes regulated by AML fusion proteins will be of fundamental importance for the full understanding of acute myeloid leukemogenesis and for the implementation of disease-specific drug design. PMID- 11607819 TI - Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. AB - The MLL (Mixed Lineage Leukemia) gene is a common target for chromosomal translocations associated with human acute leukemias. These translocations result in a gain of MLL function by generating novel chimeric proteins containing the amino-terminus of MLL fused in-frame with one of 30 distinct partner proteins. Structure/function studies using an in vitro myeloid progenitor immortalization assay have revealed that at least four nuclear partner proteins contribute transcriptional effector properties to MLL to produce a range of chimeric transcription factors with leukemogenic potential. Mouse models suggest that expression of an MLL fusion protein is necessary but not sufficient for leukemogenesis. Interestingly, whilst all MLL fusion proteins tested so far phenocopy each other with respect to in vitro immortalization, the latency period required for the onset of acute leukemia in vivo is variable and partner protein dependent. We discuss potential mechanisms that may account for the ability of distinct MLL fusion proteins to promote short or long latency leukemogenesis. PMID- 11607820 TI - The role of E2A-PBX1 in leukemogenesis. PMID- 11607821 TI - E2A-HLF usurps control of evolutionarily conserved survival pathways. AB - E2A-HLF, the chimeric fusion protein resulting from the leukemogenic translocation t(17;19), appears to employ evolutionarily conserved signaling cascades for its transforming and antiapoptotic functions. These arise from both impairment of normal E2A function and activation of a survival pathway triggered through the HLF bZip DNA binding and dimerization domain. Recent reports identify wild-type E2A as a tumor suppressor in T lymphocytes. Moreover, E2A-HLF has been shown to activate SLUG, a mammalian homologue of the cell death specification protein CES-1 in Caenorhabditis elegans, which appears to regulate an evolutionarily conserved cell survival program. Recently, several key mouse models have been generated, enabling further elucidation of these pathways on a molecular genetic level in vivo. In this review, we discuss the characteristics of both components of the fusion protein with regard to their contribution to the regulation of cell fate and the oncogenic potential of E2A-HLF. PMID- 11607822 TI - In vivo analysis of the molecular genetics of acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a distinct and paradigmatic subtype of myeloid leukemia associated with reciprocal chromosomal translocations always involving the Retinoic Acid Receptor(alpha) (RARalpha) gene on chromosome 17 and variable partner genes (X genes) on different chromosomes. As a consequence of these translocations X-RARalpha and RARalpha-X fusion genes are generated. RARalpha fuses to the PML gene in the vast majority of APL cases, and in a few cases to the PLZF, NPM, NuMA and STAT5b genes respectively. In the last few years, the functions of these aberrant fusion proteins and of the normal gene products involved in these translocations have been extensively characterized in vivo in transgenic and KO animal models. Here we will review the important conclusions, the novel questions and paradoxes that stem from this analysis. PMID- 11607823 TI - Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. AB - The chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) are characteristic of alveolar rhabdomyosarcoma, a pediatric soft tissue cancer related to the striated muscle lineage. These translocations rearrange PAX3 and PAX7, members of the paired box transcription factor family, and juxtapose these genes with FKHR, a member of the fork head transcription factor family. This juxtaposition generates PAX3-FKHR and PAX7-FKHR chimeric genes that are expressed as chimeric transcripts that encode chimeric proteins. The fusion proteins, which contain the PAX3/PAX7 DNA binding domain and the FKHR transcriptional activation domain, activate transcription from PAX-binding sites with higher potency than the corresponding wild-type PAX proteins. This increased function results from the insensitivity of the FKHR activation domain to inhibitory effects of N terminal PAX3/PAX7 domains. In addition to altered function, the fusion products are expressed in ARMS tumors at higher levels than the corresponding wild-type PAX products due to two distinct mechanisms. The PAX7-FKHR fusion is overexpressed as a result of in vivo amplification while the PAX3-FKHR fusion is overexpressed due to a copy number-independent increase in transcriptional rate. Finally, though FKHR subcellular localization is regulated by an AKT-dependent pathway, the fusion proteins are resistant to these signals and show exclusively nuclear localization. Therefore, these translocations alter biological activity at the levels of protein function, gene expression, and subcellular localization with the cumulative outcome postulated to be aberrant regulation of PAX3/PAX7 target genes. This aberrant gene expression program is then hypothesized to contribute to tumorigenic behavior by impacting on the control of growth, apoptosis, differentiation and motility. PMID- 11607824 TI - Biology of EWS/ETS fusions in Ewing's family tumors. AB - Tumor-associated chromosomal translocations lead to the formation of chimeric fusions between the EWS gene and one of five different ETS transcription factors in Ewing's family tumors (EFTs). The resultant EWS/ETS proteins promote oncogenesis in a dominant fashion in model systems and are necessary for continued growth of EFT cell lines. EWS belongs to a family of genes that encode proteins that may serve as adapters between the RNA polymerase II complex and RNA splicing factors. EWS/ETS fusions have biochemical characteristics of aberrant transcription factors and appear to promote abnormal cellular growth by transcriptionally modulating a network of target genes. Early evidence suggests that EWS/ETS proteins may also impact gene expression through alteration in RNA processing. Elucidation of EWS/ETS target gene networks in the context of other signaling pathways will hopefully lead to biology based therapeutic strategies for EFT. PMID- 11607825 TI - Fusions of the SYT and SSX genes in synovial sarcoma. AB - Synovial sarcomas are high grade spindle cell tumors that are divided into two major histologic subtypes, biphasic and monophasic, according to the respective presence or absence of a well-developed glandular epithelial component. They contain in essentially all cases a t(X;18) representing the fusion of SYT (at 18q11) with either SSX1 or SSX2 (both at Xp11). Neither SYT, nor the SSX proteins contain DNA-binding domains. Instead, they appear to be transcriptional regulators whose actions are mediated primarily through protein-protein interactions, with BRM in the case of SYT, and with Polycomb group repressors in the case of SSX. Ongoing work on the SYT-SSX fusion and synovial sarcoma should yield a variety of data of broader biological interest, in areas such as BRM and Polycomb group function and dysfunction, transcriptional targets of SYT-SSX proteins and their native counterparts, differential gene regulation by SYT-SSX1 and SYT-SSX2, control of glandular morphogenesis, among others. PMID- 11607826 TI - Chromosomal translocation master genes, mouse models and experimental therapeutics. AB - Molecular biologists have elucidated general principles about chromosomal translocations by cloning oncogenes or fusion genes at chromosomal translocation junctions. These genes invariably encode intracellular proteins and in acute cancers, often involve transcription and developmental regulators, which are master regulators of cell fate (e.g. LMO2 which is involved in acute leukaemia). Chromosomal translocations are usually associated with specific cell types. The reason for this close association is under investigation using mouse models. We are trying to emulate the cell-specific consequences of chromosomal translocations in mice using homologous recombination in embryonic stem cells to generate de novo chromosomal translocations or to mimic the consequence of these translocations. In addition, chromosomal translocation genes and their products are important targets for therapy. We have designed new therapeutic strategies which include antigen-specific recruitment of endogenous cellular pathways to affect cellular viability and a novel structured form of antisense to ablate the function of fusion mRNAs. We will evaluate these procedures in the mouse models of chromosomal translocations and the long term aim is to perfect rapid procedures for characterizing patient-specific chromosomal translocations to tailor therapy to individual patients. PMID- 11607828 TI - Adaptor proteins. PMID- 11607829 TI - The transmembrane adapter LAT plays a central role in immune receptor signalling. AB - The transmembrane adapter LAT (linker for activation of T cells) plays a central role in signalling by ITAM bearing receptors expressed on T cells, natural killer cells, mast cells and platelets. Receptor engagement leads to the phosphorylation of tyrosine residues present in the intracellular domain of LAT and formation of a multiprotein complex with other adapter molecules and enzymes including Grb2, Gads/SLP-76 and PLCgamma isoforms. These signalling events predominantly take place in glycolipid-enriched membrane domains. The constitutive presence of LAT in GEMs enables its function as the main scaffolding protein for the organization of GEM-localized signalling. The study of LAT-deficient mice and LAT-deficient cell lines further emphasizes the importance of LAT for these signalling cascades but also defines the existence of LAT-independent events downstream of the Syk family kinase-ITAM complex. PMID- 11607831 TI - The role of the adapter molecule SLP-76 in platelet function. AB - Following vascular injury, one of the most critical initial events is activation of platelets followed by formation of a hemostatic plug. Platelets are capable of responding to a diverse array of agonists resulting in adhesion and granule release. The biochemical events underlying platelet activation are just beginning to be understood. One class of molecules shown to play important roles in this process is adapters. Adapter molecules contain distinct modular domains which mediate protein-protein or protein-lipid interactions giving these proteins the ability to nucleate signal transduction complexes. In this review we will discuss the function of the hematopoietic cell specific adapter molecule, SLP-76 in both platelet activation and hemostasis. Because many parallels exist between signal transduction pathways in platelets and lymphocytes, we will also review the function of SLP-76 in coordinating signal transduction pathways following antigen bind to the T cell receptor. PMID- 11607830 TI - The role of Gads in hematopoietic cell signalling. AB - Gads is a member of the family of SH2 and SH3 domain containing adaptor proteins that is expressed specifically in hematopoietic cells and functions in the coordination of tyrosine kinase mediated signal transduction. Gads plays a critical role in signalling from the T cell receptor by promoting the formation of a complex between SLP-76 and LAT. This complex couples the T cell receptor to Ras through a novel pathway involving PLC-gamma1, Tec family kinases, and RasGRP. Studies with Gads-deficient mice have highlighted its importance for thymocyte proliferation during T cell maturation. Emerging evidence suggests that Gads may also play additional roles in antigen-receptor signalling and receptor tyrosine kinase mediated signalling in other hematopoietic lineages. Gads is a unique member of the Grb2 adaptor family, because its activity can be regulated by caspase cleavage. Gads nucleates multi-protein complexes that are required for tyrosine kinase-dependent signalling in immune cells and may also represent a point of modulation for these pathways through the activation of caspase dependent signalling events. PMID- 11607832 TI - Mitogenesis and endocytosis: What's at the INTERSECTIoN? AB - Endocytosis is a regulated physiological process by which cell surface proteins are internalized along with extracellular factors such as nutrients, pathogens, peptides, toxins, etc. The process begins with the invagination of small regions of the plasma membrane which ultimately form intracellullar vesicles. These internalized vesicles may shuttle back to the plasma membrane to recycle the membrane components or they may be targeted for degradation. One role for endocytosis is in the attenuation of receptor signaling. For example, desensitization of activated membrane bound receptors such as G-protein coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs) occurs, in part, through endocytosis of the activated receptor. However, accumulating evidence suggests that endocytosis also mediates intracellular signaling. In this review, we discuss the experimental data that implicate endocytosis as a critical component in cellular signal transduction, both in the initiation of a signal as well as in the termination of a signal. Furthermore, we focus our attention on a recently described adaptor protein, intersectin (ITSN), which provides a link to both the endocytic and the mitogenic machinery of a cell. Thus, ITSN functions at a crossroad in the biochemical regulation of cell function. PMID- 11607833 TI - Expanding the role of NHERF, a PDZ-domain containing protein adapter, to growth regulation. AB - NHERF (Na+/H+ exchanger regulatory factor or NHERF-1) and E3KARP (NHE3 kinase A regulatory protein or NHERF-2) are structurally related protein adapters that are highly expressed in epithelial tissues. NHERF proteins contain two tandem PDZ domains and a C-terminal sequence that binds several members of the ERM (ezrin radixin-moesin) family of membrane-cytoskeletal adapters. Although identified as a regulator of NHE3, recent evidence points to a broadening role for NHERF in the function, localization and/or turnover of G-protein coupled receptors, platelet derived growth factor receptor and ion transporters such as CFTR, Na/Pi cotransporter, Na/HCO3 cotransporter and Trp (calcium) channels. NHERF also recruits non-membrane proteins such as the c-Yes/YAP-65 complex, members of the phospholipase Cbeta family and the GRK6A protein kinase to apical surface of polarized epithelial cells where they regulate or respond to membrane signals. While two distinct models have been proposed for NHERF's role in signal transduction, the common theme is NHERF's ability to bring together membrane and non-membrane proteins to regulate cell metabolism and growth. NHERF overexpression in human breast cancers and mutations in NHERF targets, such as CFTR and merlin, the product of Neurofibromatosis NF2 tumor suppressor gene, that impair NHERF binding suggest that aberrant NHERF function contributes to human disease. PMID- 11607834 TI - The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions. AB - Grb7 family adaptor molecules consist of Grb7, Grb10 and Grb14, each of which has several splicing variants. Like other adaptor molecules, Grb7 family proteins function to mediate the coupling of multiple cell surface receptors to downstream signaling pathways in the regulation of various cellular functions. They share significant sequence homology with each other and a conserved molecular architecture including an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes a PH domain and shares sequence homology with the Caenorhabditis elegans protein, Mig-10, involved in embryonic migration, and a carboxyl-terminal SH2 domain. Grb7 family proteins are differentially expressed in a variety of tissues. They are phosphorylated on serine/threonine as well as tyrosine residues, although the kinases responsible have not been well characterized. Grb7 family proteins are mainly localized in the cytoplasm, but have been observed at the plasma membrane, focal contacts, or mitochondria under certain conditions. A large number of receptor tyrosine kinases and other signaling molecules can associate with Grb7 family proteins, mostly through the SH2 domains. Various isoforms of Grb10 have been shown to regulate cell proliferation and apoptosis, whereas Grb7 has been found to regulate cell migration and also implicated in tumor progression. Future studies of interests will include identification of potential downstream effectors of Grb7 family proteins as well as understanding of the mechanisms of specificity of the different family members in signal transduction. PMID- 11607836 TI - 14-3-3 proteins; bringing new definitions to scaffolding. AB - The 14-3-3 proteins are a part of an emerging family of proteins and protein domains that bind to serine/threonine-phosphorylated residues in a context specific manner, analogous to the Src homology 2 (SH2) and phospho-tyrosine binding (PTB) domains. 14-3-3 proteins bind and regulate key proteins involved in various physiological processes such as intracellular signaling (e.g. Raf, MLK, MEKK, PI-3 kinase, IRS-1), cell cycling (e.g. Cdc25, Wee1, CDK2, centrosome), apoptosis (e.g. BAD, ASK-1) and transcription regulation (e.g. FKHRL1, DAF-16, p53, TAZ, TLX-2, histone deacetylase). In contrast to SH2 and PTB domains, which serve mainly to mediate protein-protein interactions, 14-3-3 proteins in many cases alter the function of the target protein, thus allowing them to serve as direct regulators of their targets. This review focuses on the various mechanisms employed by the 14-3-3 proteins in the regulation of their diverse targets, the structural basis for 14-3-3-target protein interaction with emphasis on the role of 14-3-3 dimerization in target protein binding and regulation and provides an insight on 14-3-3 regulation itself. PMID- 11607835 TI - Signaling via Shc family adapter proteins. AB - The adapter protein Shc was initially identified as an SH2 containing proto oncogene involved in growth factor signaling. Since then a number of studies in multiple systems have implicated a role for Shc in signaling via many different types of receptors, such as growth factor receptors, antigen receptors, cytokine receptors, G-protein coupled receptors, hormone receptors and integrins. In addition to the ubiquitous ShcA, two other shc gene products, ShcB and ShcC, which are predominantly expressed in neuronal cells, have also been identified. ShcA knockout mice are embryonic lethal and have clearly suggested an important role for ShcA in vivo. Based on dominant negative studies and mouse embryos deficient in ShcA, a clear role for Shc in leading to mitogen activated protein kinase (MAPK) activation has been established. However MAPK activation may not be the sole function of Shc proteins. Although Shc has also been linked to other signaling events such as c-Myc activation and cell survival, the mechanistic understanding of these signaling events remains poorly characterized. Given the apparently central role that Shc plays signaling via many receptors, delineating the precise mechanism(s) of Shc-mediated signaling may be critical to our understanding of the effects mediated through these receptors. PMID- 11607837 TI - Adaptor proteins in protein kinase C-mediated signal transduction. AB - Spatial and temporal organization of signal transduction is essential in determining the speed and precision by which signaling events occur. Adaptor proteins are key to organizing signaling enzymes near their select substrates and away from others in order to optimize precision and speed of response. Here, we describe the role of adaptor proteins in determining the specific function of individual protein kinase C (PKC) isozymes. These isozyme-selective proteins were called collectively RACKs (receptors for activated C-kinase). The role of RACKs in PKC-mediated signaling was determined using isozyme-specific inhibitors and activators of the binding of each isozyme to its respective RACK. In addition to anchoring activated PKC isozymes, RACKs anchor other signaling enzymes. RACK1, the anchoring protein for activated betaIIPKC, binds for example, Src tyrosine kinase, integrin, and phosphodiesterase. RACK2, the epsilonPKC-specific RACK, is a coated-vesicle protein and thus is involved in vesicular release and cell-cell communication. Therefore, RACKs are not only adaptors for PKC, but also serve as adaptor proteins for several other signaling enzymes. Because at least some of the proteins that bind to RACKs, including PKC itself, regulate cell growth, modulating their interactions with RACKs may help elucidate signaling pathways leading to carcinogenesis and could result in the identification of novel therapeutic targets. PMID- 11607838 TI - Crk family adaptors-signalling complex formation and biological roles. AB - Crk family adaptors are widely expressed and mediate the timely formation of signal transduction protein complexes upon a variety of extracellular stimuli, including various growth and differentiation factors. Selective formation of multi-protein complexes by the Crk and Crk-like (CRKL) proteins depends on specific motifs recognized by their SH2 and SH3 domains. In the case of the first SH3 domains [SH3(1)] a P-x-x-P-x-K motif is crucial for highly selective binding, while the SH2 domains prefer motifs which conform to the consensus pY-x-x-P. Crk family proteins are involved in the relocalization and activation of several different effector proteins which include guanine nucleotide releasing proteins like C3G, protein kinases of the Abl- and GCK-families and small GTPases like Rap1 and Rac. Crk-type proteins have been found not only in vertebrates but also in flies and nematodes. Major insight into the function of Crk within organisms came from the genetic model organism C. elegans, where the Crk-homologue CED-2 regulates cell engulfment and phagocytosis. Other biological outcomes of the Crk activated signal transduction cascades include the modulation of cell adhesion, cell migration and immune cell responses. Crk family adaptors also appear to play a role in mediating the action of human oncogenes like the leukaemia-inducing Bcr Abl protein. This review summarizes some key findings and highlights recent insights and open questions. PMID- 11607839 TI - Vav proteins, adaptors and cell signaling. AB - The Vav family is a group of signal transduction molecules with oncogenic potential that play important roles in development and cell signaling. Members of this family are distributed in all animal metazoans but not in unicellular organisms. Recent genomic studies suggest that the function of Vav proteins co evolved with tyrosine kinase pathways, probably to assure the optimal conversion of extracellular signals into biological responses coupled to the cytoskeleton and gene transcription. To date, the best-known function of Vav proteins is their role as GDP/GTP exchange factors for Rho/Rac molecules, a function strictly controlled by tyrosine phosphorylation. Recent publications indicate that this function is highly dependent on the interaction of adaptor proteins that aid in the proper phosphorylation of Vav proteins, their interaction with other signaling molecules, and in modulating the strength of their signal outputs. In addition to the function of Vav proteins as exchange factors, there is increasing evidence suggesting that Vav proteins can mediate other cellular functions independently of their exchange activities, probably by working themselves as adaptor molecules. In this review, we will give a summary of the recent advances in this field, placing special emphasis on the non-catalytic roles of Vav and its interaction with other adaptor molecules. PMID- 11607840 TI - Beyond the RING: CBL proteins as multivalent adapters. AB - Following discovery of c-Cbl, a cellular form of the transforming retroviral protein v-Cbl, multiple Cbl-related proteins have been identified in vertebrate and invertebrate organisms. c-Cbl and its homologues are capable of interacting with numerous proteins involved in cell signaling, including various molecular adapters and protein tyrosine kinases. It appears that Cbl proteins play several functional roles, acting both as multivalent adapters and inhibitors of various protein tyrosine kinases. The latter function is linked, to a substantial extent, to the E3 ubiquitin-ligase activity of Cbl proteins. Experimental evidence for these functions, interrelations between them, and their biological significance are addressed in this review, with the main accent placed on the adapter functions of Cbl proteins. PMID- 11607841 TI - Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton. AB - In response to extracellular signals, cell surface receptors engage in connections with multiple intracellular signaling pathways, leading to the cellular responses such as survival, migration, proliferation and differentiation. The 'pY-->SH2/SH3-->effector' connection is a frequently used scheme by many cell surface receptors, in which SH2/SH3-containing adapters connect protein tyrosine phosphorylation to a variety of downstream effector pathways. Following the initial landmark finding that Grb2 adapter links the receptors to the Ras pathway leading to DNA synthesis, recent studies have revealed that the biological function of the SH2/SH3 adapter Nck/Dock is to link cell surface receptors to the actin cytoskeleton. For example, in the evolutionarily-conserved signaling network, GEF-Rac-Nck-Pak, Nck 'fixes up' the interaction of Pak with its upstream activator, Rac. The activated Pak then regulates the cytoskeletal dynamics. The fact that the majority of the more than 20 Nck-SH3-associated effectors are regulators of the actin cytoskeleton suggests that Nck/Dock regulates, via binding to distinct effectors, various cell type specific motogenic responses. This review focuses on our current understanding of Nck/Dock function. Due to the number and complexity of the terminologies used in this review, a 'Glossary of Terms' is provided to help reduce confusions. PMID- 11607842 TI - Cortactin: coupling membrane dynamics to cortical actin assembly. AB - Exposure of cells to a variety of external signals causes rapid changes in plasma membrane morphology. Plasma membrane dynamics, including membrane ruffle and microspike formation, fusion or fission of intracellular vesicles, and the spatial organization of transmembrane proteins, is directly controlled by the dynamic reorganization of the underlying actin cytoskeleton. Two members of the Rho family of small GTPases, Cdc42 and Rac, have been well established as mediators of extracellular signaling events that impact cortical actin organization. Actin-based signaling through Cdc42 and Rac ultimately results in activation of the actin-related protein (Arp) 2/3 complex, which promotes the formation of branched actin networks. In addition, the activity of both receptor and non-receptor protein tyrosine kinases along with numerous actin binding proteins works in concert with Arp2/3-mediated actin polymerization in regulating the formation of dynamic cortical actin-associated structures. In this review we discuss the structure and role of the cortical actin binding protein cortactin in Rho GTPase and tyrosine kinase signaling events, with the emphasis on the roles cortactin plays in tyrosine phosphorylation-based signal transduction, regulating cortical actin assembly, transmembrane receptor organization and membrane dynamics. We also consider how aberrant regulation of cortactin levels contributes to tumor cell invasion and metastasis. PMID- 11607843 TI - The actin filament-associated protein AFAP-110 is an adaptor protein that modulates changes in actin filament integrity. AB - The actin filament-associated protein of 110 kDa (AFAP-110) was first identified as an SH3/SH2 binding partner for the nonreceptor tyrosine kinase, Src. Subsequent data have demonstrated that AFAP-110 can interact with other Src family members. AFAP-110 contains additional protein binding modules including two pleckstrin homology domains, a leucine zipper motif and a target sequence for serine/threonine phosphorylation. AFAP-110 interacts with actin filaments directly via a carboxy terminal actin-binding domain. Thus AFAP-110 may function as an adaptor protein by linking Src family members and/or other signaling proteins to actin filaments. AFAP-110 also has an intrinsic capability to alter actin filament integrity that can be revealed upon conformational changes associated with phosphorylation or mutagenesis. Recent data has indicated that AFAP-110 may also serve to activate cSrc in response to this conformational change as well. Thus, AFAP-110 may function in several ways by (1) acting as an adaptor protein that links signaling molecules to actin filaments, (2) serving as a platform for the construction of larger signaling complexes, (3) serving as an activator of Src family kinases in response to cellular signals that alter its conformation and (4) directly effecting actin filament organization as an actin filament cross-linking protein. Here, we will review the structure and function of AFAP-110 as well as potential binding partners and effectors of AFAP-110's ability to alter actin filament integrity. PMID- 11607844 TI - Functions of the adapter protein Cas: signal convergence and the determination of cellular responses. AB - Since Cas was first identified as a highly phosphorylated 130 kilodalton protein that associated with the v-Src and v-Crk-oncoproteins, considerable effort has been made to determine its function. Its predicted role as a scaffolding molecule based on its domain structure has been largely confirmed. Through its ability to undergo rapid changes in phosphorylation, subcellular localization and association with heterologous proteins, Cas may spatially and temporally regulate the function of its binding partners. Numerous proteins have been identified that bind to Cas in vitro and/or in vivo, but in only a few cases is there an understanding of how Cas may function in these protein complexes. To date, Cas Crk and Cas-Src complexes have been most frequently implicated in Cas function, particularly in regards to processes involving regulation of the actin cytoskeleton and proliferation. These and other Cas protein complexes contribute to the critical role of Cas in cell adhesion, migration, proliferation and survival of normal cycling cells. However, under conditions in which these processes are deregulated, Cas appears to play a role in oncogenic transformation and perhaps metastasis. Therefore, in its capacity as an adapter protein, Cas serves as a point of convergence for many distinct signaling inputs, ultimately contributing to the generation of specific cellular responses. PMID- 11607845 TI - Paxillin: a focal adhesion-associated adaptor protein. AB - Paxillin is a focal adhesion-associated, phosphotyrosine-containing protein that may play a role in several signaling pathways. Paxillin contains a number of motifs that mediate protein-protein interactions, including LD motifs, LIM domains, an SH3 domain-binding site and SH2 domain-binding sites. These motifs serve as docking sites for cytoskeletal proteins, tyrosine kinases, serine/threonine kinases, GTPase activating proteins and other adaptor proteins that recruit additional enzymes into complex with paxillin. Thus paxillin itself serves as a docking protein to recruit signaling molecules to a specific cellular compartment, the focal adhesions, and/or to recruit specific combinations of signaling molecules into a complex to coordinate downstream signaling. The biological function of paxillin coordinated signaling is likely to regulate cell spreading and motility. PMID- 11607846 TI - The NOD: a signaling module that regulates apoptosis and host defense against pathogens. AB - Nods, a growing family of proteins containing a nucleotide-binding oligomerization domain (NOD), are involved in the regulation of programmed cell death (PCD) and immune responses. Members of the family include Apaf-1, Ced-4, Nod1, Nod2, and the cytosolic products of plant disease resistance genes. The NOD module is homologous to the ATP-binding cassette (ABC) found in a large number of proteins with diverse biological function. The centrally located NOD promotes activation of effector molecules through self-association and induced proximity of binding partners. The C-terminal domain of Nods serves as a sensor for intracellular ligands, whereas the N-terminal domain mediates binding to dowstream effector molecules and activation of diverse signaling pathways. Thus, Nods activate, through the NOD module, diverse signaling pathways involved in the elimination of cells via PCD and the host defense against pathogens. PMID- 11607847 TI - Tumor necrosis factor receptor-associated factors (TRAFs). AB - Tumor necrosis factor receptor-associated factors (TRAFS) were initially discovered as adaptor proteins that couple the tumor necrosis factor receptor family to signaling pathways. More recently they have also been shown to be signal transducers of Toll/interleukin-1 family members. Six members of the TRAF family have been identified. All TRAF proteins share a C-terminal homology region termed the TRAF domain that is capable of binding to the cytoplasmic domain of receptors, and to other TRAF proteins. In addition, TRAFs 2-6 have RING and zinc finger motifs that are important for signaling downstream events. TRAF proteins are thought to be important regulators of cell death and cellular responses to stress, and TRAF2, TRAF5 and TRAF6 have been demonstrated to mediate activation of NF-kappaB and JNK. TRAF proteins are expressed in normal and diseased tissue in a regulated fashion, suggesting that they play an important role in physiological and pathological processes. PMID- 11607848 TI - Immunological tolerance of the human fetus. AB - Why is the fetus not rejected as foreign tissue? The maternal and fetal immune systems temporarily coexist; both are precisely tuned to detect and reject foreign invasion and yet somehow achieve a symbiotic relationship. This mutual state of tolerance is obviously critical for carrying pregnancy to full term. Two active arms of the immune system maintain protection of the host: the first of these involves a humoral immune system in which foreign tissue invokes an antibody response by recognition of antigenic surfaces by the B-cell, the second arm involves cell-mediated immunity in which T-cells and natural killer (NK) cells seek out and destroy foreign tissue. Several mechanisms are thought to invoke the immune tolerance of the fetus. These include: absence of major histocompatibility complex (MHC)-I antigens, presence of unique human lymphocyte antigen (HLA) surface molecules, nonspecific reduction of systemic immunoreactivity, possible role of blocking antibody, expressions of complement regulatory proteins, and factors of locally reduced immunoreactivity. Ultimately, developing regimens to control these elements in the clinical setting may help us overcome preterm labor, infertility, and preeclampsia. Available evidence regarding immune tolerance of the human fetus, integrated into a workable model, and focused at an overview level are systematically reviewed in this article. PMID- 11607849 TI - Interleukin-6 and interleukin-8 in newborn bacterial infection. AB - The objective of this study is to determine the plasma concentrations and diagnostic accuracy of interleukin-6 (IL-6) and interleukin-8 (IL-8) in newborn infection. One hundred and one newborn infants with clinical signs of infection during their primary hospitalization were investigated with the minimum of a blood culture, C-reactive protein (CRP), full blood examination (FBE), and cytokine concentrations (IL-6 and IL-8). Infection in infants was classified without knowledge of cytokine levels into four groups-definite (n = 11), probable (n = 12), uncertain (n = 52), and nil (n = 26). The median concentrations of IL-6 and IL-8 were significantly higher in the definitely infected group compared with the other three groups (p <0.05). At the cut-off concentration of highest accuracy, IL-6 (>175 pg/mL) and IL-8 (>28 pg/mL) had similar sensitivities (80 and 82%, respectively) and specificities (91 and 81%, respectively). Cut-off concentrations could be identified with improved sensitivities (90% for IL-6 and 100% for IL-8) that maintained specificity >50%. However, the confidence intervals were wide for all sensitivities and specificities. IL-6 and IL-8 had little diagnostic accuracy in infants with probable infection. IL-6 and IL-8 concentrations increase early in newborn infants with definite infection. PMID- 11607850 TI - Accuracy of single ultrasound parameters in detection of fetal growth restriction. AB - The objective of this study was to evaluate the diagnostic accuracy of different single ultrasonographic parameters in predicting intrauterine growth-restricted (IUGR) babies as defined by Ponderal index at birth. Study sample composed of two sets of data from Iran and Australia. The Iranian sample consisted of 296 Iranian women. All the study women received prenatal care and delivered at Fatemieh Hospital in Shahrood, Iran. The data from 219 Australian fetuses were obtained from the ultrasound section at the Wollongong Hospital in Australia. Ultrasonographic measurements of biparietal diameter (BPD), femur length (FL), head circumference (HC), abdominal circumference (AC), amniotic fluid index (AFI), and Doppler from umbilical arteries (S/D ratio) were obtained. Only those pregnancies were included in which the estimated date of delivery (EDD) by LMP (last menstrual period) agreed within 14 days with the estimated date of delivery determined by the initial ultrasound examination. Sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) were calculated for single proposed ultrasound parameters in the Iranian and Australian samples. When different variables are compared, with a cut-off point at or below the 10th percentile AC and HC had the highest sensitivities in the Australian sample while AC was the most sensitive parameter for IUGR detection in the Iranian sample. BPD has a reasonably high sensitivity at this threshold. The AFI ratio has the lowest sensitivity in predicting IUGR in the Australian sample. Positive predictive values were low in all of the parameters in both the Iranian and Australian samples. By increasing the cut-off for PI to the 20th percentile, the sensitivity of reduced AC increased in the Australian sample while the sensitivity for an abnormal S/D ratio and reduced AFI to identify IUGR decreased. Our results indicate that reduced AC was the best single parameter in discriminating between IUGR and non-IUGR fetuses with the highest sensitivity among the proposed parameters in the both Iranian and Australian sample. However, the PPV of this parameter is low. This means that a high number of false-positive cases are detected using each parameter, which reduces the usefulness of identification. Other ultrasound obstetrical parameters may also have a reasonable level of sensitivity, however, the PPV of all parameters is low. On the whole, our results show that although the examined ultrasonographic criteria may detect a group of fetuses that need close antepartum surveillance, none of these parameters are appropriate enough to be used in isolation in clinical practice. Using single ultrasound parameters does not have high sensitivity and PPVs in detection of fetal growth restriction. This limits accuracy and utility of these tests in the detection of IUGR fetuses. PMID- 11607851 TI - Concentrations of thrombopoietin and interleukin-11 in the umbilical cord blood of patients with fetal alloimmune thrombocytopenia. AB - The objective of this study is to determine whether the fetus compensates for fetal alloimmune thrombocytopenia (FAITP) by increasing serum concentrations of thrombopoietin (TPO) and interleukin-11 (IL-11). TPO and IL-11 concentrations were measured in cord blood sera of 12 neonates with FAITP, and 35 preterm and 25 term controls. TPO concentrations in the 12 patients (median 129 pg/mL, range 73 to 325 pg/mL) were similar to those of 35 healthy preterm neonates (median 183 pg/mL, range 71 to 290 pg/mL) and the 25 term controls (median 180 pg/mL, range 93 to 302 pg/mL), although the platelet counts were significantly lower in FAITP. TPO concentrations did not correlate with the platelet counts, platelet nadir after birth, or time to recovery of normal platelet count. IL-11 reached detectable concentrations only in four patients with FAITP (median 54 pg/mL). After birth, these patients had a more rapid recovery of the platelet count. Cord blood serum concentrations of TPO are not significantly elevated in FAITP and do not predict the severity of the thrombocytopenia. Elevated IL-11 may signal a more rapid platelet recovery in FAITP. PMID- 11607852 TI - Factors predicting compliance with palivizumab in high-risk infants. AB - Palivizumab must be administered monthly by intramuscular injection throughout the RSV season to maintain the serum concentration at a level sufficient to provide protection against respiratory syncytial virus (RSV). The objective of this study is to determine factors associated with completing all doses of palivizumab. The method was a survey mailed to the families of 385 high-risk children who were eligible to receive palivizumab at Columbus Children's Hospital in 1998-1999. Seventy-eight percent of eligible children received all doses of palivizumab. The strongest predictor of compliance was parents' perception that palivizumab would protect their child from RSV; 67% of parents in the compliant group reported they believed palivizumab protected their child "a great deal" against RSV compared with 48% in the noncompliant group (p = 0.04). Difficulty with transportation was also a barrier to compliance; 85% of parents in the compliant group reported no difficulty with transportation compared with 65% in the non-compliant group (p = 0.004). An interaction between Medicaid status and parental worry showed that parents whose child received Medicaid and who worried a lot (about their child getting RSV) were more likely to be compliant (Odds ratio = 6.62, p = 0.03). Communication with parents that focuses on the benefit of palivizumab in reducing RSV-associated illness and hospitalizations may increase compliance. PMID- 11607853 TI - Ovarian cyst in a premature infant treated with spironolactone. AB - We describe the late occurrence of an ovarian cyst in a premature infant, the second of a set of monochorionic diamnionic twins, during treatment with spironolactone. Spironolactone is commonly used in the management of neonatal chronic lung disease in combination with other diuretics because of its potassium sparing effect. It has progestational activity and has been reported to cause gynecomastia. It is used widely for its antiandrogenic properties in the treatment of female hirsutism and hyperandrogenism and it has a role in the management of familial male-limited precocious puberty. However, the estrogenic influence induced during therapy may significantly alter the hormonal milieu in newborn females, resulting in the formation of ovarian cysts. Simple ovarian lesions <5 cm merit close ultrasonographic surveillance for resolution while larger complex masses may warrant surgical intervention. PMID- 11607854 TI - [Cases of acute poisoning admitted to a medical intensive care unit]. AB - BACKGROUND AND OBJECTIVE: Because of the paucity of information on the epidemiology of acute poisoning requiring intensive medical care, all such patients treated on the medical intensive care unit of the university hospital in Frankfurt am Main, Germany, between January 1993 and December 1999, were retrospectively evaluated. PATIENTS AND METHODS: Of the total of 6211 patients, 147 (80 women, 67 men, mean age 41 years, 2,3 %) were treated for acute intoxication in the intensive care unit. RESULTS: Reasons for admission to the intensive care unit were the need for ventilator treatment or intensive monitoring of vital functions. 52 % of the patients (n = 76) had attempted suicide, most of them using anti-depressive drugs (n = 19), paracetamol (n = 16), or benzodiazepines (n = 9). Two patients (2,6 %) died. 48 % of the patients (n = 71) were admitted because of accidental poisoning. Leading toxic agents in this group were heroin (n = 19), alcohol (n = 18) and digitalis (n = 12). 11 patients had taken herbicides, animal poisons or chemicals used at work or for house cleaning. In this cohort, three i. v. drug abusers (4,2 %) had died. Depending on the agents used, a variety of treatments (charcoal, antidots, extracorporal therapy) were undertaken. CONCLUSION: Due to excellent care in the prehospital phase and in the emergency room the number of patients requiring treatment on the intensive care unit was rather low. The mortality was in the range of other reports. PMID- 11607855 TI - [Out-patient treatment of deep vein thrombosis: management and experience of two vascular care centres in Germany]. AB - BACKGROUND AND OBJECTIVE: In Germany there are still major reservations about using low molecular weight heparin for the treatment of deep vein thrombosis. Based on encouraging international reports, we have been establishing a primarily out-patient management of thrombosis since 1996. In our centres for vascular diseases we tried to evaluate the suitability of such a regimen for the treatment of patients in Germany. PATIENTS AND METHODS: Between January 1996 and October 1999 we evaluated the possibility of an out-patient therapy for all patients with acute deep vein thrombosis who had been referred to our institution. Suitable patients were treated with an initial daily dose of 200 IU Dalteparin per kg body weight in addition to compression therapy. RESULTS: During this time we treated 587 patients with deep vein thrombosis of the lower extremities (41 % men and 59 % woman with a mean age of 60.3 +/- 13.8 years) of whom 105 were hospitalised. Out-patient therapy was without any complications in 94.2 % of the remaining 482 patients. Overall mortality was 0.4 % (2 patients). The deaths occurred without apparent relationship to the kind of therapy. Progressive thrombus extension occurred in five patients, symptomatic pulmonary embolism in one patient and >>recurrent thromboembolic events<< in nine patients. These results correspond with the good efficacy of Dalteparin as expected from the data in the literature. Severe bleedings were not observed. Three patients experienced mild bleeding. CONCLUSIONS: We conclude from our data that, in accordance with international studies, an out-patient thrombosis management with Dalteparin is efficacious and safe. PMID- 11607857 TI - [Telomere and telomerase as starting-points of new forms of treatment in oncology]. PMID- 11607856 TI - [Initial symptoms of hyperthyroidism in a young man with lumbar pain]. PMID- 11607858 TI - [Treatment of the acute respiratory distress syndrome (ARDS)]. PMID- 11607859 TI - [New indications for thalidomide?]. PMID- 11607860 TI - [On the history of the Contergan (thalidomide) catastrophe in the light of drug legislation]. PMID- 11607862 TI - [Advances in surgery -- without advance in medical technology?]. PMID- 11607863 TI - [Statins as a new therapeutic possibility in osteoporosis? Wishful thinking as opposed to data]. PMID- 11607865 TI - [Insurance and genetics - options to prevent undesirable consequences]. AB - The article analyses the different options to prevent or alleviate the undesirable consequences of molecular genetic information in the sphere of insurance. It distinguishes between macro-, meso- and micro-options. The options are examined in respect of their probability to be realised. PMID- 11607866 TI - [Patient self-determination - the beneficiaries of medicine and their rights]. AB - Respect for patient autonomy is one of the major ethical goals of modern medicine. Therefore, it is important to analyse whether the organisational structure of the German health care system impedes the realisation of patient self-determination. It will be shown by means of historical and ethical analysis that the nature of the doctor-patient relationship as well as other factors in the organisation of modern medicine systematically undermine patient autonomy. If individual responsibility in the health care setting is to be strengthened, patients' influence on public health decision-making processes, too, has to be advanced. The paper shows from a patient perspective where this could be the case. PMID- 11607867 TI - [Difficulties in the transfer of drug therapy from inpatient to ambulatory treatment]. AB - The prospective study compares prescribed drugs of 192 primarily cardiological patients at discharge and 7 weeks later in ambulatory care. The data were determined by discharge summaries and by standardized patient-questionnaires. The drug division was made with the ATC-classification according to the recommendations of the World Health Organisation for Drug Utilisation Studies. The intraindividual cost comparison was calculated by current pharmacy sale prices. The findings were changes in hospital discharge medications in ambulatory care in over 2/3 of the cases. The most frequent change was the additional prescribing of drug groups. The average daily tablet number increased in patients with the same or worsened subjective feeling after discharge. Additionally we found in a number of patients a change of drug therapy within the ATC-groups, or in fact, withdrawal of drug therapy all together. The frequency of changes increased with the number of patient/doctor contacts. The observation that the average daily therapeutical cost decreased just slightly could give an indication that cost saving was a minor part of the doctors decision for drug changing. However, the frequency of changes has shown to be dependent upon the specialities of the physician or pharmaceutical group. PMID- 11607868 TI - [Revolving-door case histories as a special problem in psychiatric care in rural regions - results of an innovative project by Lower Saxony statutory health insurance bodies]. AB - OBJECTIVE: We report on experiences from a programme of the AOK (Local Statutory Health Care Fund) in Lower Saxony adapted to mental health care reality in rural regions. The purpose of the programme is the prevention of rehospitalisation of chronically mental ill and socially handicapped patients. On the advice of hospital-based psychiatrists a case manager of the AOK immediately organises outpatient interventions for patients after discharge from clinical treatment. Primary goals are to reduce psychosocial deficits and to activate supporting potentials in the social environment of the patients in respect of long-term stabilisation. RESULTS: Outpatient interventions have proved to be an efficient instrument to reduce rehospitalisation rates; they enable patients to experience more quality of life and they are of considerable importance in reducing costs for individual treatments. DISCUSSION: If we consider the systematics of hospital bed financing, the reduction of individual treatment costs does not imply reduction of AOK total payments for clinical treatment of mentally ill on a short term basis. Hence, maintenance of this kind of outpatient treatment is strongly recommended. PMID- 11607869 TI - [Coordinative treatment and quality of life - a randomised trial of nurses with back pain]. AB - BACKGROUND DATA: The influence of strength training on back conditions has been demonstrated quite well, whereas coordinative training being a major component of physical therapy regarding preventive and rehabilitative treatment of back pain is used only occasionally and has been evaluated even more rarely. One has to consider this fact regarding the still growing number of musculo-skeletal diseases. AIM OF STUDY: The influence of several preventive therapies (coordination training in spacecurl, kinaesthetics/back protective patient transfer) has been investigated with regard to coordination, back pain and quality of life in a randomised controlled study. METHODS: We used an assessment set consisting of a specially devised questionnaire regarding job demands, sports activity and back pain and the WHOQOL-BREF for control of quality of life. These methods were combined with body surface electromyography and posturography. Those methods enabled us to determine parameters such as coordination, back pain and quality of life at 3 different stages (untrained individuals) and 4 points (trained individuals) respectively. RESULTS: Trained individuals showed a significant reduction of back pain frequency (p = 0.016) before and after training. In comparison there was no difference in untrained individuals. Furthermore trained individuals showed an increase in quality of life of 5.4 % (p = 0.028), whereas again there was no difference in untrained individuals. Somatic diagnostics (body surface electromyography, posturography) showed significant changes only in the trained group. CONCLUSION: The used coordination training program is enhancing coordination and reducing back pain whilst having a positive effect upon the quality of life of an individual. PMID- 11607870 TI - [Care and preventive experts lecture in the elementary school programme "Klasse2000" - co-operative teaching]. AB - In the context of the health promotion programme 'Klasse2000', 483 health experts gave specific lessons to pupils from the first to the fourth grade of the elementary school. Following the classes a survey was conducted as to the valuation of the programme, its translation into practice and co-operation between class teachers and health experts. Those questioned considered the programme as really applicable and were absolutely content with the organisation. They regarded direct working with pupils as fairly positive. Co-operation with class teachers was seen as ambivalent. The findings of this survey trigger further optimisation of the programme, especially to enlarge the time spent on efforts by the health experts and to intensify parent co-operation. PMID- 11607871 TI - [Toxicologically determined indoor air guidelines values]. AB - At the Austrian Ministry for Environment (now: Federal Ministry for agriculture and forestry, environment and water management) a working group was established to propose indoor air guideline values. This consists of representatives of different disciplines, such as physicians, toxicologists, engineers and lawyers. Already in the constituent meeting it was decided to employ a set pattern for establishing toxicologically sound guideline values. It was then agreed to use the pattern proposed by the German ad-hoc-working team. The interdisciplinary discussions, however, demonstrated the need for additional clarification, since representatives of different disciplines obviously interpret the various terms and principles differently. In particular, there is a need for discussing in detail the relation between the guideline values for indoor air to other air quality standards (outdoor air and workplace) and to specify their scope and application, especially the need to describe in greater detail what should be done in case either guideline value I or II was exceeded. PMID- 11607872 TI - [Control of low Legionella concentrations in pool water]. AB - The Legionella proof is necessary in pool water according to DIN 19 643 in case of possible aerosol formation. In lab tests it was proven that the direct spatulation of 1 ml water offers high-grade proof with high correlation of the determined concentration to the actual germ content. With very small germ concentrations, however, preceding filtration of larger sample volumes is necessary. During the investigation of routine samples a Legionella proof was possible thereby in individual cases, whereas direct spatulation remained negative. PMID- 11607873 TI - [What do medical students know about cause and epidemiology of the Creutzfeldt Jakob disease in Germany?]. AB - Due to the increase of patients with the variant Creutzfeldt-Jakob disease (vCJD) in Great Britain and the first cases of autochthonous BSE cases in Germany, the study tried to investigate the knowledge of medical students about the epidemiology of CJD in Germany and how they assess the influence of different factors on the etiology of CJD. Altogether 63 first year medical students, 96 third year medical students and 50 nurses were included in an anonymous questionnaire survey. They were asked to estimate the annually incidence of CJD in Germany and to assess, by using analogue-scales, the influence of different factors on the risk of contracting CJD. For the medical students the median was 100 and for the nurses the median was 10 annual CJD cases. All participants, and especially the males, emphasised the influence of "risk behaviour" and "environmental factors" on the risk of contracting CJD, the factor "stress/ emotional strain" was seen as most unimportant. No significant differences between female and male participants in the knowledge about the incidence of CJD in Germany were found. It becomes obvious, that epidemiological knowledge about CJD in medical staff is associated with different and gender-specific views on the etiology. Medical education should consider this to avoid endangering medical staff and patients due to overprotection or insufficient precautions. PMID- 11607874 TI - [Fundamentals of hygiene in old-age and nursing homes. Recommendations for nursing personnel and for hygiene control by German public health offices]. AB - New German legislative ordinances prescribe hygiene control in nursing homes and homes for the aged, e. g. the Law for Protection against Infectious Diseases and in North-Rhine Westphalia the Public Health Law. However, there are as yet no clearly defined standards of hygiene because the special features of nursing homes must be considered when applying the "Guidelines for Hospital Hygiene and Prevention of Infections" issued by the Robert Koch Institute. Hence, specific recommendations are given for hygiene of the hands, disinfection, hygienic treatment care, protective and professional clothing, washing of textiles, central kitchen, disposal of waste, house cleaning and handling of drugs and medicines. PMID- 11607875 TI - Distinct expression of endothelin receptor subtypes A and B in luteinized human granulosa cells. AB - Endothelins (ET) are potent vasoconstrictive peptides originally isolated from vascular endothelial cells. Their biological effects are mediated through two different receptors, the endothelin-1 (ET-1)-selective endothelin receptor subtype ETA and the non-selective receptor subtype ETB. ET-1 protein has been found in human ovarian follicular fluid and ET-1 mRNA expression has been demonstrated in ovarian tissue. These findings indicate that the endothelin system participates in the modulation of ovarian function, probably acting in an autocrine/paracrine manner. In the current study we used freshly aspirated, luteinized human granulosa cells (hGC) representing an in vitro model of the early corpus luteum. By means of RT-PCR and immunocytochemistry we investigated whether luteinized human granulosa cells express ETA and ETB receptors. Specific amplification products of ETA transcripts were detected in all samples investigated. In contrast, only after using a three-fold amount of ETB reverse transcripts we were able to demonstrate specific, but weak amplification products. In addition, immunocytochemical staining for ETA but not for ETB was found in granulosa cell preparations. The present study provides clear evidence that human granulosa cells predominantly express ETA receptor subtype mRNA and protein hinting to its possible role in follicle maturation and corpus luteum formation. PMID- 11607876 TI - Co-administration of etomoxir and RU-486 mitigates insulin resistance in hepatic and muscular tissues of STZ-induced diabetic rats. AB - Insulin resistance is a condition of central importance in a cluster of clinical disorders including diabetes mellitus, hypertension, dyslipidemia, central obesity and coronary heart disease. Despite its association with numerous health problems, the mechanism responsible for the development of this phenomenon remains to be established. A novel theory has proposed that insulin resistance in diabetes stems, at least in part, from enhanced free fatty acid (FFA) oxidation and/or excessive production of glucocorticoids (GCs). Several key predictions of this premise were subjected to experimental testing using streptozotocin (STZ) treated rats as a model for insulin-dependent diabetes mellitus and euglycemic hyperinsulinemic clamp technique for the in vivo measurement of insulin actions. Euglycemic clamp studies with an insulin infusion index of 5 mU/kg/min were used to measure endogenous glucose production (EGP), glucose infusion rate (GIR), glucose disposal rate (GDR) and skeletal muscle glucose utilization index (GUI). Post-absorptive basal EGP and plasma levels of glucose and free fatty acids (FFA) were elevated in the STZ diabetic rats compared to their corresponding control values. In contrast, hypoinsulinemia was evident in these animals. Steady-state GIR and GDR during euglycemic-hyperinsulinemic clamp were markedly decreased in the STZ diabetic rats. Similarly, insulin-mediated suppression of EGP and plasma FFA concentration was also impaired in these animals. GUI, a measure of 2 deoxyglucose (2-DG) uptake, was increased in response to insulin in the order of white gastrocnemus (WG), red gastrocnemus (RG), extensor digitorum longus and soleus muscles. This parallels the percentage of red fibers in these muscles. Diabetes interferes with insulin's ability to increase 2-DG uptake in all of the above muscles with the exception of WG. Nullification of the associated hyperlipidemic and hypercortisolemic states of diabetes with etomoxir (hyperlipidemic) and the glucocorticoid receptor blocker RU-486 (hypercortisolemic) ameliorated the diabetes-related impairment of the in vivo insulin action. Overall these results together with those garnered from the literature support the notion that hypercortisolemia and the enhancement of FFA oxidation are involved, at least in part, in the development of hepatic and skeletal muscle insulin resistance in poorly controlled type I diabetes. PMID- 11607877 TI - Elevated prolactin to cortisol ratio and polyclonal autoimmune activation in Hashimoto's thyroiditis. AB - Cortisol and prolactin, which are considered to have an immunomodulatory effect, and selected autoantibodies were determined in Hashimoto's thyroiditis. 37 patients (8 males and 29 females) (54 +/- 13.8 years) and an equal number of sex- and age-matched normal subjects (52.6 +/- 14.2 years) were studied. None of the 74 subjects suffered from any other immunological, infectious, hepatic, renal or malignant diseases. Patients with Hashimoto's thyroiditis exhibited significantly higher (p < 0.016) prolactin values (14.0 +/- 3.8 ng/ml) than did control subjects (6.5 +/- 1.3 ng/ml). In contrast, cortisol levels were lower in Hashimoto's thyroiditis (13.5 +/- 3.2 microg/dl) vs. normal state (16.0 +/- 1.13 microg/dl), (p < 0.05). The prevalence of anti-TPO and anti-Tg antibodies was 100 % and 43 % in the patients with Hashimoto's disease. In contrast, no subject of the control group was positive for anti-TPO, although 9 subjects (24 %) were positive for anti-Tg autoantibodies. The percentage of positive autoantibodies to nucleus, smooth-muscle, and parietal cells in the patients (36.0, 10.9 and 18.5 %, respectively) was higher than that in healthy group (11.0 and 0 % respectively). Notably, neither group was positive for antibodies against double stranded DNA or mitochondria. In conclusion, our results provide evidence for a polyclonal activity in Hashimoto's thyroiditis, an organ-specific autoimmune disease, associated with an altered prolactin-adrenocortical status. Such information should initiate longitudinal studies to clarify the exact time sequence of these events related to the disease's activity. PMID- 11607878 TI - Cyclosporin a treatment is able to revert the decrease in circulating GH and IGF I and the increase in IGFBPs induced by adjuvant arthritis. AB - The aim of this study was to find out whether cyclosporin A administration is able to revert the decrease in circulating growth hormone (GH) and insulin-like growth factor-I (IGF-I) and the increase in IGF-binding proteins (IGFBPs) levels caused by adjuvant-induced arthritis in rats. Male Sprague-Dawley rats were intradermically injected with Freund's adjuvant or vehicle. Fourteen days later, rats were randomly divided into two groups - one injected with cyclosporin (15 mg/kg) and the other with vehicle from day 16 to 23 after adjuvant injection. Arthritis decreased body weight gain and serum concentrations of GH. Cyclosporin administration to arthritic rats prevented both effects, whereas cyclosporin had no effect in control rats. Arthritis decreased serum concentrations of IGF-I (p < 0.01), but increased IGFBPs. Cyclosporin administration increased circulating IGF I, and there was a negative correlation between circulating IGF-I and arthritis index scores in arthritic rats injected with cyclosporin (p < 0.05). Cyclosporin treatment did not alter serum IGFBPs levels in control rats, whereas cyclosporin administration normalised IGFBPs in arthritic rats. These results indicate that the effects of cyclosporin administration on the GH-IGF-IGFBPs system may partly mediate its beneficial effect on body weight in arthritic rats. PMID- 11607879 TI - Androgen secretion in ectopic ACTH syndrome and in Cushing's disease: modifications before and after surgery. AB - The role of ACTH in the control of adrenal androgen secretion is known, although the possible existence of other regulatory factors has been also suggested. While some data concerning Cushing's disease have been reported, only few studies concerned androgen levels in ectopic ACTH secretion. The aim of this study was to evaluate serum DHEA-S, androstenedione (A) and testosterone (T) levels in 36 women with ACTH-dependent Cushing's syndrome (30 with Cushing's disease and 6 with ectopic ACTH secretion) before and after surgery. Two men with ectopic ACTH production were also studied. In 30 women with Cushing's disease serum DHEA-S (9.6 +/- 0.9 micromol/l), A (15.2 +/- 1.2 nmol/l) and T (4.1 +/- 0.5 nmol/l) were higher than in controls (p < 0.01): elevated DHEA-S, A and T values were found in 8, 18 and 17 cases, respectively. After adenomectomy in 15 apparently cured patients DHEA-S, A and T levels were low at 1 - 3 months and at 6 - 12 months after surgery. At 18 - 24 months, DHEA-S remained low in spite of cortisol normalisation. In ectopic Cushing's syndrome, A levels were significantly higher (23.1 +/- 4.9 nmol/l) than in Cushing's disease (p < 0.05), while no differences were found in DHEA-S and T levels. Two patients had elevated DHEA-S values, 3 women had high T levels and 7 of the 8 patients had very high A concentration that was lowered in 3 operated cases. In conclusion, the pattern of adrenal androgen secretion is rather different in patients with pituitary or with ectopic Cushing's syndrome. While the frequency of DHEA-S and T alterations is similar, androstenedione secretion is greatly increased in the latter condition. It is suggested that in ACTH-secreting non-pituitary tumours, the production of a POMC derived peptide, although unidentified, may lead to preferentially stimulated androstenedione secretion, without affecting other enzymatic pathways. PMID- 11607880 TI - Visceral fat is a determinant of PAI-1 activity in diabetic and non-diabetic overweight and obese women. AB - Plasminogen activator inhibitor type 1 (PAI-1), an inhibitor of fibrinolysis and an important and independent cardiovascular risk factor, has been shown to be elevated in obesity and type 2 diabetes. Recent study results have suggested that adipose tissue--visceral fat in particular--could play an important role in the fibrinolytic process.In order to assess the specific role of this fat distribution, we measured PAI-1 activity (AU/ml) and visceral fat (CT-scan at level L4-L5) in 2 groups of 30 overweight and obese diabetic and overweight and obese non-diabetic women. Subjects were matched for age, weight, body mass index, fat mass and total abdominal fat. Visceral adipose tissue and PAI-1 were significantly higher in diabetic women (p = 0.022 and p = 0.004 respectively) than in non-diabetic patients. Visceral fat correlated significantly with PAI-1 activity, even after correction for insulin and triglycerides (r = 0.28, p = 0.034). Stepwise regression analysis showed visceral fat as the most important determinant factor for PAI-1 in the whole group and in the non-diabetic group. In the diabetic group, fasting insulin was the most important determinant. These results show that visceral fat is more important than BMI or total body fat in the determination of PAI-1 levels. Furthermore, the increased amount of visceral fat in type 2 diabetics may contribute to the increase of PAI-1 activity levels and the subsequent increased risk for thrombovascular disease, regardless of BMI and total fatness. PMID- 11607881 TI - Coadministration of melatonin and estradiol in rats: effects on oxidant status. AB - This study was designed to investigate the effects of melatonin and estradiol (E2) on lipid peroxidation and antioxidant defense enzymes in blood and liver tissue when administered in vivo. Wistar albino rats were divided into three experimental groups and treated with either estradiol (25 mg/kg bw, s.c.), melatonin (i. p.), or melatonin plus E2, whereas control animals had diluent injections only. Melatonin was given 10 mg/kg bw x 2 intraperitoneally 30 min before and 60 min after E2 treatment to the melatonin plus E2 group. Animals were sacrificed three hours after the estradiol injection, and their blood and liver tissues were prepared for biochemical analyses. Tissue malondialdehyde (MDA) levels and antioxidant enzyme activities--superoxide dismutase (SOD) and glutathione peroxidase (GPx)--were determined in the postmitochondrial fraction, and the results were compared. Estradiol injection caused significant increases in both MDA levels and GPx activity in liver. When melatonin was administered in combination with E2, the effect of estradiol on MDA levels was abolished. A significant decrement in SOD activity occurred in melatonin-treated animals. GPx activity in the blood of E2 plus melatonin-injected animals was significantly higher than those in control animals. Melatonin-treated animals exhibited relatively lower levels of SOD activity than those from the control and E2 plus melatonin groups. This indicates that estradiol could exert oxidant action resulting in an increment in tissue malondialdehyde levels. Enhanced activity of GPx in both liver and blood following melatonin injection may indicate the contribution of this neurohormone on the antioxidant defense. PMID- 11607882 TI - Triglyceride-rich lipoprotein cholesterol exceeds low-density lipoprotein cholesterol in hypertriglyceridemia patients. AB - The atherogenicity of triglyceride-rich lipoprotein has been revealed. This study was performed to explore the clinical importance of triglyceride-rich lipoprotein by measuring its cholesterol content and comparing it with other lipoprotein fractions. Blood samples were obtained from 103 patients whose fasting plasma triglyceride concentration exceeded 300 mg/dl. The cholesterol monitor using the technique of high-performance liquid chromatography was used for the measurement of their plasma cholesterol concentrations and the determination of cholesterol distribution among lipoprotein fractions. This monitor showed 4 peaks: large triglyceride-rich lipoprotein, small-triglyceride-rich lipoprotein, low-density lipoprotein, and high-density lipoprotein. Total cholesterol increased with increasing triglyceride. The increment of total cholesterol was nearly equal to that of small-triglyceride-rich lipoprotein cholesterol. Small-triglyceride-rich lipoprotein cholesterol exceeded low-density lipoprotein cholesterol where plasma triglyceride concentration was over 500 mg/dl. In conclusion, triglyceride-rich lipoprotein may be clinically important for hypertriglyceridemic patients as a source of cholesteryl ester in arteriosclerotic plaques, and increased triglyceride-rich lipoprotein cholesterol may be used as a basis for hypertriglyceridemia atherogenicity. Our study suggests that hypertriglyceridemia should be treated to prevent arteriosclerotic disease. PMID- 11607883 TI - Effectiveness of slow-release lanreotide in previously operated and untreated patients with GH-secreting pituitary macroadenoma. AB - The aim of this study was to verify whether treatment with slow-release lanreotide (SRL) before surgery is useful in the management of patients with GH secreting pituitary macroadenoma. Twenty untreated acromegalics were enrolled randomly in two groups. Ten patients (group 1: 2 males and 8 females aged 44.5 +/ 4.3 years) underwent surgery via transsphenoidal access. Only one of them was cured by surgery, whereas the other nine were treated with SRL. In the other ten patients (group 2: 3 males and 7 females aged 43.2 +/- 12.3 years), transsphenoidal surgery followed SRL treatment. Surgery induced the normalization of GH and IGF-1 levels in four group 2 patients - three of them had shown an evident shrinkage of the tumor after SRL treatment. After surgery, group 1 showed a significant decrease of mean IGF-1 (580 +/- 63 vs. 789 +/- 64 ng/ml, p < 0.02), but not of GH values (26.1 +/- 9.8 vs. 44.8 +/- 19.3 ng/ml, NS); the cured patient was excluded from the following evaluations. Group 2 showed an evident, but not significant, decrease of both GH and IGF-1 values compared to values measured at the end of medical treatment (GH: 22.4 +/- 9.7 vs. 7.7 +/- 4.7 ng/ml, NS. IGF-1: 570 +/- 69 vs. 402 +/- 58 ng/ml, NS). Gonadal, thyroid and adrenal impairment was evident in six, four and no patients in group 1 and in three, two and one patients in group 2, respectively. SRL 30 mg was administered every 14 days for three months and then every 10 days until the 6th month. Before SRL treatment, mean GH and IGF-1 levels did not differ significantly in group 1 vs. group 2 (GH: 29.3 +/- 10.5 vs. 43.4 +/- 22.0 ng/ml; IGF-1: 633 +/- 38 vs. 778 +/- 83 ng/ml). In group 1, a significant decrease of serum GH, but not of IGF-1 levels, was achieved at the end of 1st trimester of SRL (GH: 17.6 +/- 5.4 ng/ml, p < 0.05. IGF-1: 540 +/- 48 ng/ml, NS), whereas a significant decrease in both GH and IGF-1 values was evident during the 2nd trimester (GH: 6.1 +/- 3.0 ng/ml, p < 0.05. IGF-1: 433 +/- 74 ng/ml, p < 0.02). Serum GH levels, measured during the 2nd trimester of SRL therapy, were also significantly lower than levels measured at the end of the 1st trimester (p < 0.05). Group 2 serum GH and IGF-1 levels were not significantly decreased at the end of the 1st trimester (GH: 27.2 +/- 12.1 ng/ml, NS. IGF-1: 698 +/- 74 ng/ml, NS), whereas only serum IGF-1 (570 +/- 69 ng/ml, p < 0.05) was significantly reduced during the 2nd trimester of SRL (GH: 22.4 +/- 9.7 ng/ml, NS). Serum GH and IGF-I fell in the normal range in 4 patients in group 1 and one in group 2 at the end of the second trimester of SRL therapy. Independently of the trial applied, the mean clinical score level ameliorated significantly in both groups (group 1: p < 0.0005; group 2: p < 0.0001). In both groups, the proportion of patients complaining of headache and tissue swelling and the score level of headache, tissue swelling and excessive sweating decreased significantly. In group 1 the score level of fatigue and arthralgia also decreased significantly. In conclusion, this study proves that in patients with GH-secreting pituitary macroadenoma: (i) surgery followed by SRL induces a better clinical and biochemical status than SRL alone; (ii) SRL treatment before surgery ameliorates the clinical and biochemical outcome and reduces the prevalence of hypopituitarism due to surgery. PMID- 11607885 TI - Impairment of CYP3A4 capacity in patients receiving danazol therapy: examination on oxidative cortisol metabolism. PMID- 11607884 TI - Validation of endogenous controls for gene expression studies in human adipocytes and preadipocytes. AB - Quantitative gene expression protocols require adequate controls to monitor intersample variation. Quantitative approaches to describe relative changes in gene expression use endogenous controls--"housekeeping" genes. Given the low amounts of mRNA in fat cells, RT-PCR is the method of choice, and housekeeping genes are widely used as endogenous controls. However, literature reports suggest changes in gene expression of typical housekeeping genes (e. g. GAPDH, beta actin, 18S rRNA) upon hormonal stimulation or during adipogenic differentiation. Thus, we tested the influence of 6 hormones and adipogenic differentiation on gene expression levels of 11 commonly used housekeeping genes in primary cultured mature human adipocytes and preadipocytes. Using the TaqMan RT-PCR technique and "Human Endogenous Control Assays" (PE Biosystems), we found several housekeeping genes with at least twice the difference in expression levels between stimulated and unstimulated cells (such as acidic ribosomal protein, beta-actin, beta(2) microglobulin and beta-glucuronidase). Only GAPDH and transferrin receptor gene expression levels did not change under any of the stimuli tested, thus appeared best suited for gene expression studies in human adipose cells across a wide range of experimental settings. PMID- 11607886 TI - [DEGUM-Standards in Prenatal Level II Ultrasound Diagnosis (18-22 weeks of Gestation)]. PMID- 11607887 TI - [Cavitations in biological tissues]. AB - AIM: An important reason for the high popularity of diagnostic ultrasound is its lack of hazardous side effects. However, as described below, the probability of inducing undesirable thermal and mechanical effects in tissue increases with a rise in the output of diagnostic ultrasound machines. METHODS AND RESULTS: The use of increasing negative peak pressures of the applied ultrasound pulse enhances the risk of inducing cavitation inside the body. The potential damage of cavitation results from the dynamic, e. g. wild pulsation, and a collapse of bubbles in the respective sound field. The collapse, especially, releases a high amount of energy, related to secondary effects like shock waves, jet formation and the formation of free radicals. To estimate the likelihood of cavitation and ensuing mechanical biological effects the so-called mechanical index was defined. Nowadays, the mechanical index is displayed in real-time on modern diagnostic ultrasound machines. Echo-contrast agents play an increasing role in sonography. These stabilised gas particles increase the likelihood of cavitation formation and the occurrence of other biological side effects. The potential for mechanically induced side effects of diagnostic ultrasound was tested in many animal studies. As for the use of ultrasound for diagnostic purposes, adverse side effects, like haemorrhage or rupture of capillaries, were only observed in the presence of tissue-gas interfaces - as found in the lung or the intestine - or with high concentrations of contrast media. CONCLUSION: Even though no adverse effects of diagnostic ultrasound have been reported in humans, potentially damaging effect of advanced ultrasound techniques cannot be denied. Various ultrasound organizations, e.g. WFUMB, have therefore formulated recommendations for the safe use of diagnostic ultrasound. PMID- 11607888 TI - Evaluation of first trimester pregnancy in cases of threatened abortion by means of doppler sonography. AB - OBJECTIVE: Threatened abortion is one of the major problems in Obstetrics and applies to (1/3) of all pregnancies. The aim of this study was to establish normal ranges for Doppler indices of the flow velocity waveforms in uterine arteries (S/D, RI, PI) and ss-hCG serum concentrations in a control group in the first trimester of pregnancy. The obtained values were compared with those obtained in pregnancies threatened by abortion (6 - 11 weeks). METHODS: Investigated groups: 55 controls and 47 with symptoms of threatened abortion, 27 of them aborted. Ultrasound examinations were carried out by means of an endovaginal probe. Serum ss-hCG was determined by immunoenzymatic method. The standards for measured values were established based on means from measurements obtained in the control group in the corresponding week of pregnancy. RESULTS: We observed negative correlation between gestational age and RI and negative tendencies for S/D and PI indices in the control group. Positive correlation (p < 0.05) was found between ss-hCG serum concentration and gestational age (up to 9(th) week) and significant differences in ss-hCG concentrations between both examined groups. There were also statistical differences for S/D, RI and PI indices in both analyzed groups for each week of pregnancy. CONCLUSION: We conclude that measurement of the quality parameters of the flow velocity waveforms in uterine arteries and calculation of beta-hCG concentration in serum are useful methods in diagnosis of threatened abortion in the first trimester of pregnancy. PMID- 11607889 TI - [Head circumference in relation to sonographic morphometry of the cerebral ventricles in neonates and infants]. AB - AIM: To determine normal values of sonographic measurements of the brain in neonates and infants. METHOD: Cerebral ultrasonographic examinations were performed in 143 healthy newborns and infants. The size of the ventricles was determined by ascertaining distances as well as performing planimetric measurements of the ventricular area and circumference in standardized planes. RESULTS: Throughout the course of the study we observed a continous increase in size and a strong correlation with head circumference. The middle coronary plane used for the measurements allows the accurate representation of the ventricles and a more objective assessment of size. CONCLUSION: Based on the morphometric data, charts for the determination of ventricular size were developed. PMID- 11607890 TI - [Measurement of skin thickness by high-frequency ultrasound to objectify the effects of hormone replacement therapy in the perimenopause]. AB - AIM: The aim of this study was to show the influence of three different hormone replacement therapy regimes (HRT) by comparing the changes in skin thickness. METHOD: Skin thickness was measured using a high-frequency ultrasound system on the inner side of the left upper arm of perimenopausal women with a low oestradiol level (< 45 pg/ml). The patients were allocated to different groups: Group1 (n = 6) received oestradiol merely transdermally; Group 2 (n = 7) was given transdermal oestradiol as well as progesterone vaginally; Group 3 (n = 8) took oral oestradiol and vaginal progesterone; Group 4 (n = 3) served as the control group without therapy. RESULTS: The median value of skin thickness in all HRT-groups increased highly significantly (0.15 mm) after six months (0.91 mm before therapy versus 1.06 mm after six months of HRT), but there was no significant change in the control group. CONCLUSIONS: The study shows that HRT leads to an increase of skin thickness which can be demonstrated by a high frequency ultrasound. PMID- 11607891 TI - [Quality of praenatal diagnostic ultrasound - comparison of sonographically detected foetal anomalies with diagnostic findings verified post-partum in Switzerland]. AB - AIM: Comparison of all praenatally detected cases of foetal anomalies to actual diagnostic findings post partum during a one year period in Switzerland. METHODS: A retrospective questionnaire-based evaluation including the 5 university hospitals and 6 large hospitals in Switzerland as a population-based study. Analysis of all foetal anomalies detected praenatally by ultrasound in the year of 1995 in these centres. RESULTS: 347 cases have been included in the study. 89 % of cases were detected using screening methods. (2/3) were referred by obstetrical practitioners and GPs. 62 % of the pregnancies were completed and 33 % terminated, while the rest resulted in abortion or stillbirth. In terminated pregnancies there was a 82 % agreement between praenatal and postmortem findings. Sonographic results and clinical/post-mortem diagnosis were in agreement about the presence of major foetal anomalies in 18 % of cases. Additional minor anomalies unperceived by sonography, however, were seen post mortem. There was no false positive case. CONCLUSIONS: Without ultrasound screening almost 90 % of anomalies would have been missed due to the absence of clinical symptoms. The Swiss two-step system for praenatal ultrasound screening, based on screening scans done by the obstetrician and GP in practice, or residents in the public outpatient clinics respectively, and the detailed scan done by a subspecialized perinatologist shows excellent results especially in the subgroup of terminated pregnancies. PMID- 11607892 TI - [Influence of experience on intra- and interindividual variability in assessing peripheral endothelial dysfunction with high resolution ultrasound]. AB - The non-invasive evaluation of endothelial dysfunction with high-resolution ultrasound has become a widely accepted tool in determination of high-risk subjects for early atherosclerosis. Furthermore it is often used as intermediate outcome in intervention studies. AIM: We examined the influence of examiner experience on intra- and inter-individual variability in the measurement of flow associated vasodilation (FAD) independent of automated analysis systems. METHOD: FAD was measured on two occasions in 7 and 8 subjects respectively (mean age 32 +/- 3 years) by two investigators after different prior training procedures with a 13 MHz linear transducer (LA14A, ESAOTE Biomedica). RESULTS: The intra individual variability expressed as median absolute difference in the measurements of FAD was 1.1 % (range from 0.03 % to 3.2 %) for examiner one with an experience of more than 50 FAD measurements through former studies and 2.9 % (range from 1.6 % to 9.2 %) for examiner two with only 10 training examinations under supervision. By a further training period of two months, with an increase of examinations of additional 20 measurements by both examiners, the intra observer variability could be dropped to 0.9 % (range from 0.03 % to 1.3 %) for examiner two (p = 0.0025) with no significant change for examiner one (median 0.6 % with a range from 0.14 % to 3.7 %). As expected, the inter-individual variability was not influenced by this further training (median 1.0 % with a range of 0.5 % to 3.6 % versus a median of 1.6 % with a range from 0.15 % to 7.5 %). CONCLUSION: 30 training measurements of FAD under supervision should be regarded as minimum requirement for valid determination of endothelial function. The reachable result for the intra-observer variability is thereby within the range of computed analysis systems. PMID- 11607893 TI - [Dysphagia without clinically relevant pathological correlation: to exclude tumours of the floor of the mouth and the base of the tongue ultrasound diagnosis is mandatory]. AB - In patients suffering from dysphagia, a tumour of the tongue and its base must be excluded. This is not always possible by means of endoscopy and palpation. In contrast it is possible to visualize deep-seated structures of this region by ultrasound. Unfortunately, this technique is rarely used, as shown in the cases demonstrated. We present five patients suffering from dysphagia for a long period of time (up to 30 years) where ultrasound was not performed and a tumour of the floor of the mouth and the base of the tongue was overlooked. Thus, adequate therapy was delayed, which proved to be especially relevant in three patients suffering from a malignoma. Three patients suffered from a malignant tumour of the base of the tongue. Up to two years passed between the beginning of dysphagia and the necessary surgical treatment. One of these patients even underwent psychological treatment for his symptoms. In two other patients a dermoid cyst and ectopic thyroid tissue were removed. In patients suffering from dysphagia with normal endoscopic findings and normal palpation of the neck ultrasound of the floor of the mouth and the base of the tongue is imperative. Tumours of this area can be detected early with high sensitivity and cost-effectiveness by ultrasound. PMID- 11607894 TI - [Prenatal diagnosis of full, non mosaic trisomy 22 in the third trimester]. AB - A 31-year-old Caucasian women was referred to our department after IUGR was suspected by her gynaecologist at 29 weeks' amenorrhea in her second pregnancy. Multiple anomalies were detected by prenatal ultrasound in the 29th week of gestation. Chordocentesis was performed and revealed a Trisomy 22 in all fetal blood cells. The pregnancy was terminated. Post-mortem investigations excluded chromosomal mosaicism. Prenatal ultrasound findings and post-mortem features are presented. PMID- 11607895 TI - Boneloc bone-cement: experience in hip arthroplasty during a 3-year period. AB - Polymethyl methacrylate (PMMA) bone-cement was introduced in the 1960s for fixation of total hip arthroplasty replacement components. Long-term results of cement fixation for hip and knee arthroplasty have been extremely good. Although the use of PMMA bone-cement has enabled long-term survival of joint arthroplasty implants, there has been concern about aseptic loosening. This concern led to the introduction of Boneloc bone-cement (Biomet, Warsaw, IN) in the early 1990s. It was hoped that with the improved physical and chemical characteristics of Boneloc, there would be less aseptic loosening in the long-term. A clinical trial was conducted to evaluate Boneloc bone-cement in cementing the femoral component of the Bimetric total hip arthroplasty prosthesis in 33 hips in 32 patients. On follow-up, 7 stems (24%) developed definite loosening, and 3 stems (10%) were possibly loose. Of the 7 definite loose stems, 5 (17%) were revised because of increasing pain or progressive loosening. Despite the biologic advantages of Boneloc, this study suggests that the chemicals substituted in Boneloc bone cement led to an alteration in its mechanical properties. These properties proved to be inferior to conventional PMMA bone-cement. There is possible time-dependent deterioration of mechanical properties leading to early aseptic loosening. The conventional PMMA bone-cement has stood the test of time. Research and experimental studies should continue to improve the mechanical properties of Boneloc before further human trials. PMID- 11607896 TI - Radiographic wear measurements in a cementless metal-backed modular cobalt chromium acetabular component. AB - Linear polyethylene wear was measured radiographically and correlated with direct measurements of wear from 21 of 24 liners retrieved at revision. An optical comparator was used to assess linear wear using the shadowgraph technique. Postoperative and prerevision radiographs were reviewed to measure the amount of linear wear radiographically. Seven radiographic methods described in the literature were used: 5 were manual techniques, and 2 techniques used a computer assisted digitizer. Linear regression analysis showed that there was a statistically significant correlation between the radiographic measurements compared with the direct measurement for 4 of the 5 manual techniques but only 1 of the 2 computerized techniques. Based on these results, radiographic wear measurements of cementless, modular components should be considered qualitative rather than quantitative. There is a significant difference in the measurements obtained among various published techniques. The addition of computer digitization to enhance manual methodology does not improve accuracy. PMID- 11607897 TI - Hybrid revision total hip arthroplasty: a 7-year follow-up study. AB - The hybrid method for fixation of total hip arthroplasty (THA) has shown excellent results during the first decade in primary operations. To investigate its role in revision surgery, data on 48 revision THAs in 45 patients that met the inclusion criteria were gathered prospectively, using HGP cementless acetabular components and precoated cemented femoral components inserted with so called second generation femoral cementing technique in each case. For the 48 hips during an average follow-up period of 7.4 years, no acetabular components was loose or had pelvic lysis. One acetabular component was revised for recurrent dislocation; 1 of 48 femoral components was revised for aseptic loosening and 1 for periprosthetic fracture. Three additional femoral stems (6%) were loose. In this small series, the hybrid concept for revision of failed nonseptic THAs has shown excellent results. PMID- 11607898 TI - Patellar tracking in total knee arthroplasty: inset versus onset design. AB - Patellar components come in onset and inset designs. Kinematic differences between these designs were studied in a cadaver model of closed kinetic chain knee extension. Seven frozen knees were implanted with a standard posterior cruciate-retaining design. Each knee first was tested with the inset design, followed by the onset design in the Oxford Knee Rig. Three-dimensional tracking of the femur, tibia, and patella was performed using an electromagnetic system during active knee extension under load. No statistically significant differences were seen in knee kinematics between the 2 designs. The inset patella tended to shift laterally and tilt laterally more than the onset patella. This difference may be clinically significant. PMID- 11607899 TI - Activation of plasma coagulation by retransfusion of unwashed drainage blood after hip joint arthroplasty: a prospective study. AB - Twelve patients undergoing cementless hip joint arthroplasty were retransfused with unwashed drainage blood collected postoperatively. Global coagulation parameters, coagulation factors (factor V:C, factor VIII:C, activated factor XII, and factor XIII) and markers of thrombin generation (F1+2 Fibrin split products, thrombin-antithrombin complexes), fibrin generation (fibrinogen and fibrin degradation products), and fibrinolysis (D-dimers, thrombin degradation products, plasminogen) were determined. High levels of factor XIIa, thrombin and fibrin generation markers, and markers of fibrinolysis were present in the shed blood. After retransfusion (mean, 433 mL), increased levels of these markers together with decreased values for factor XIII and plasminogen were indicative of renewed clot formation and fibrinolysis in the circulation. These changes were highly significant compared with preretransfusion values. The unwashed drainage blood contained high levels of procoagulation material and induced an activation of the plasma coagulation pathway with renewed clot formation and fibrinolysis in the patients. PMID- 11607900 TI - Total joint arthroplasty and incidence of postoperative bacteriuria with an indwelling catheter or intermittent catheterization with one-dose antibiotic prophylaxis: a prospective randomized trial. AB - This study examined the difference in postoperative bacteriuria in total joint arthroplasty after use of either an indwelling catheter or intermittent catheterization. Previous studies showed a preference for an indwelling catheter over intermittent catheterization to resolve postoperative urinary retention in total joint arthroplasty, but these studies generally used 48 hours of antibiotic prophylaxis. Increasing awareness of costs and bacterial resistance to antibiotics have prompted many centers to reduce prophylaxis to only 1 preoperative dose A prospective, randomized, controlled trial was conducted in primary total hip and primary total knee arthroplasty patients. One dose of cefazolin, 1 g, was administered intravenously immediately preoperatively. Five of 13 (38%) men in the indwelling catheter group and 0 of 14 (0%) men in the intermittent catheterization group developed postoperative bacteriuria (P =.016), and 6 of 33 (18%) women in the indwelling catheter group and 3 of 39 (8%) women in the intermittent catheterization group developed postoperative bacteriuria (not significant). A total of 11 (24%) patients in the indwelling catheter group (n = 46) and 3 (6%) patients in the intermittent catheterization group (n = 53) developed postoperative bacteriuria (P =.018). In this setting with 1-dose antibiotic prophylaxis, intermittent catheterization resulted in a lower incidence of postoperative bacteriuria compared with an indwelling catheter. For men, this difference is significant. PMID- 11607901 TI - Reconstruction of the extensor mechanism after proximal tibia endoprosthetic replacement. AB - The proximal tibia is a difficult area in which to perform a wide resection of a bone tumor. This difficulty is due to the intimate relationship of tumor in this location to the nerves and blood vessels of the leg, inadequate soft tissue coverage after endoprosthetic reconstruction, and the need to reconstruct the extensor mechanism. Competence of the extensor mechanism is the major determinant of functional outcome of these patients. Between 1980 and 1997, 55 patients underwent proximal tibia resection with endoprosthetic reconstruction for a variety of malignant and benign-aggressive tumors. Reconstruction of the extensor mechanism included reattachment of the patellar tendon to the prosthesis with a Dacron tape, reinforcement with autologous bone-graft, and attachment of an overlying gastrocnemius flap. All patients were followed for a minimum of 2 years; 6 patients (11%) had a transient peroneal nerve palsy, 4 patients (7.2%) had a fasciocutaneous flap necrosis, and 2 patients (3.6%) had a deep wound infection. Full extension to extension lag of 20 degrees was achieved in 44 patients, and 8 patients required secondary reinforcement of the patellar tendon. Function was estimated to be good to excellent in 48 patients (87%). Reattachment of the patellar tendon to the prosthesis and reinforcement with an autologous bone-graft and a gastrocnemius flap are reliable means to restore extension after proximal tibia endoprosthetic reconstruction. PMID- 11607902 TI - Cementless total hip arthroplasty in young Chinese patients: a comparison of 2 different prostheses. AB - Sixty-one primary cementless total hip arthroplasties were performed in 45 Chinese patients <40 years old. There were 27 Anatomic Medullary Locking (AML, Depuy, Warsaw, IN) prostheses and 34 Porous Coated Anatomic (PCA, Howmedica, Rutherford, NJ) prostheses. The average follow-up was 7.6 years (range, 3-11 years). Ten hips (16%) were reoperated; the reason was polyethylene wear with or without osteolysis in 7 hips. Osteolytic lesion was present in 34 hips (56%). The cumulative successful rate at 10 years was 67% using reoperation for any reason as the endpoint. The cumulative successful rate was 98%, however, if revision for aseptic loosening was used as the endpoint. The 2 prostheses did not show significant differences in most parameters except that the PCA hips had significantly more acetabular loosening (P =.02) and periprosthetic osteolysis (P =.01). PMID- 11607903 TI - Early loosening of the stemmed McMinn cup. AB - The stemmed McMinn cup was used in 26 acetabular reconstructions (median age, 59 [range, 33-85 years]; 21 women) at 5 orthopaedic centers in Sweden between 1995 and 1998. Of the patients, 24 (92%) had severe bone defects (Gustilo-Pasternak grade 3 and 4). At a clinical and radiographic follow-up of median 3 years (range, 1-5 years), 4 (17%) cups were rerevised at 1 (2 cups), 2, and 3 years owing to symptomatic aseptic loosening. Another 8 cups (40%) were radiographically definitely loose and 1 (5%) was probably so. With an overall mechanical failure rate (rerevised plus definitely loose devices) of 43.8% at a minimum 3-year follow-up, the stemmed McMinn cup does not seem to be a reliable solution in acetabular reconstruction. PMID- 11607904 TI - Measurement of perioperative flexion-extension mechanics of the knee joint. AB - Perioperative knee mechanics currently are evaluated Perioperative knee mechanics currently are evaluated by measuring range of motion. This is an incomplete measurement, however, because the torque applied to achieve the motion is not measured. We hypothesized that a custom goniometer and force transducer could measure the torque required to passively flex a knee through its full range of motion. This measurement was done in the operating room immediately before and after surgery in 20 knees having total knee arthroplasty and 9 having surgery on another limb. Surgery changed the mechanics of 8 knees, whereas unoperated knees remained unchanged. This measurement technique is safe, easy, and repeatable. It improves on the current standard of perioperative knee measurement and can be applied to investigate the effects of surgery and rehabilitation on ultimate knee motion. PMID- 11607905 TI - Impregnation of vancomycin, gentamicin, and cefotaxime in a cement spacer for two stage cementless reconstruction in infected total hip arthroplasty. AB - Twenty-two patients with infected total hip arthroplasty were treated with 2 stage arthroplasty, using a cement spacer impregnated with a combination of 3 thermostable antibiotics (vancomycin, gentamicin, and cefotaxime). Initially, implants were removed, and a spacer was inserted. Six to 12 weeks later, the spacer was removed, and the patients underwent reconstruction using cementless components. The patients were followed for an average of 41 months. One patient had a recurrence of infection and was treated with resection arthroplasty. The remaining 21 patients (95%) had no evidence of infection at the final follow-up. We recommend using the combination of these 3 antibiotics in the cement spacer for 2-stage reconstruction in infected hip arthroplasty when the causative organism is not identified in the culture of preoperative aspiration. PMID- 11607906 TI - No relationship between postoperative changes in bone density at the proximal tibia and the migration of the tibial component 2 years after total knee arthroplasty. AB - The relationship between changes in bone mineral density (BMD) in the proximal tibia and fixation of the tibial component during 2 years postoperatively was investigated in 28 knees. BMD was measured using dual-energy x-ray absorptiometry, and fixation was determined using radiostereometric analysis. BMD decreased at 3 months and returned to baseline level at 24 months, but with large variations on an individual basis. Most of the prosthetic migration occurred within the initial 3 months. The results show that the bone remodeling that occurs during the 2 years after operation has no relation to the migration of the tibial component. The early migration seems to be related more to local activities at the interface rather than to changes in BMD assessed below the interface. The changes in BMD during 2 years reflect the bone remodeling caused by the normalization of alignment after operation and are not related to the implant fixation. PMID- 11607907 TI - Hip function in patients >55 years old: population reference values. AB - The purpose of this study was to establish population values for hip function for patients of different ages using the validated WOMAC scoring system and the traditional Harris hip scoring system. A random sample of 184 individuals who had no prior history of hip or knee pain or pathology was evaluated. The average WOMAC scores for pain, function, and stiffness were 0.01, 1.8, and 0.4. The average Harris hip score was 94 +/- 8.2. No significant correlation was noted between the summary WOMAC score, the WOMAC stiffness or pain subscales, or the overall Harris hip score for any of the 3 age groups studied. Patients with complaints in other joints, such as the back and neck, had lower WOMAC and Harris hip scores. Adults who are healthy and do not have a prior history of hip or knee pathology do not show a significant decline in hip function as they grow older. A deterioration in the function of a total hip arthroplasty over time cannot be attributed solely to the aging process. PMID- 11607908 TI - Contamination of polyethylene cups with polymethyl methacrylate particles: an experimental study. AB - The articulating surfaces of 6 ultra-high molecular weight polyethylene cups were exposed to curing polymethyl methacrylate (PMMA) bone-cement and examined with scanning electron microscopy and laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS). Three of the cups were exposed to blood and bone-cement, and the rest were exposed to bone-cement only. After removal of the bone-cement bulk, PMMA particles were found and identified in all 6 cups. The particles were verified by identifying zirconium with energy-dispersive x-ray fluorescence spectroscopy in 5 cups and with LA-ICPMS in 1 cup. The degree of surface contamination was estimated with LA-ICPMS. The number of zirconium-containing particles detected was on average 10 to 20/mm2. PMMA bone-cement left in polyethylene cups during polymerization can contaminate the articulating surface with adherent PMMA particles. PMID- 11607909 TI - The influence of femoral rollback on patellofemoral contact loads in total knee arthroplasty. AB - Increasing femoral rollback in flexion is thought to reduce patellofemoral contact load in total knee arthroplasty (TKA). The objectives of this study were to quantify the dependence of patellar load on rollback and to assess the effectiveness of posterior cruciate ligament (PCL)-retaining, PCL-sacrificing, and PCL-substituting TKA types in generating rollback. Nine cadaver knees were tested in simulated squatting. Six TKAs that were expected to produce varying amounts of femoral rollback were evaluated: PCL-retaining TKA, PCL-sacrificing TKA, a commercially available PCL-substituting TKA, and 3 modified PCL substituting TKAs in which the anteroposterior position of the tibial post was varied. Kinematics, quadriceps loads, and patellofemoral contact loads were recorded. Significant differences in rollback were observed in the 30 degrees to 90 degrees flexion range. PCL-sacrificing TKAs generated the least rollback. PCL retaining TKAs produced greater rollback but had the most variability. PCL substituting TKAs produced the greatest and most reproducible rollback. Moving the tibial post posteriorly further increased rollback. Increased rollback correlated with reduced patellar load (-2.2%/mm). Reductions in patellar load of 17.6% were observed. Quadriceps loads were reduced by increasing rollback but to a smaller degree (-0.9%/mm). Rollback primarily affects patellar load rather than quadriceps load or efficiency. PMID- 11607910 TI - Intraosseous radial nerve entrapment complicating total elbow revision. AB - A 43-year-old man underwent revision of a loose total elbow arthroplasty in 1995. The arthroplasty had been implanted 20 years previously for post-traumatic osteoarthritis after a gunshot wound complicated by permanent ulnar nerve palsy. The patient suffered a minimally displaced periprosthetic fracture 4 years after implantation that was treated closed. The patient subsequently developed severe loosening with bony dilation. During revision surgery, while grasping and removing the periprosthetic membrane from within the humeral medullary canal with a Kerrison rongeur, dorsiflexion of the wrist and hand occurred. Close inspection of the membrane revealed that the radial nerve was encased inside the bone. Although not divided, the traction and contusion of the nerve caused a radial nerve palsy that partially resolved by 4 years of follow-up. PMID- 11607911 TI - Iliopsoas tendinitis after total hip arthroplasty. AB - Determination of the cause of groin pain after total hip arthroplasty can be difficult. The case of a patient with an unusual cause of groin pain after total hip arthroplasty, iliopsoas tendinitis, is presented. The patient failed nonoperative treatment and underwent surgical release of the iliopsoas tendon with complete resolution of symptoms. PMID- 11607912 TI - Fractured Whiteside Ortholoc II knee components. AB - A comprehensive failure analysis was performed on 6 femoral components and 1 tibial component that fractured in service. All were Whiteside Ortholoc II total knee arthroplasty components, manufactured from cast cobalt-chromium-molybdenum alloy and porous coated. Fracture surface analysis revealed fatigue-induced failure in all cases. Most fractures occurred at regions of high stress concentration, such as sharp corners, sintered beads, and thin sections. Metallurgical examination showed significant variation in grain size, interdendritic carbides, and hardness between samples. In some cases, continuous carbide networks and voids were prominent at the bead-substrate interface. Patient weight and surgical placement were identified as contributory factors in component failure. Limitations of cast cobalt-chromium-molybdenum alloy in weight bearing applications must be emphasized, particularly when important determinants, such as design, metallurgy, and specific clinical factors, are less than optimal. PMID- 11607913 TI - Therapeutic embolization of the genicular arteries for recurrent hemarthrosis after total knee arthroplasty. AB - The case of a recurrent hemarthrosis initially presenting 30 months after a total knee arthroplasty in a patient on lifelong warfarin is described. Angiography was used to aid in the diagnosis, and therapeutic selective embolization of the superior genicular arteries was performed with satisfactory clinical results. PMID- 11607914 TI - Destruction of acetabular bone caused by early failure of a constrained acetabular component. AB - Use of a constrained acetabular component is 1 option for the treatment of dislocation after total hip arthroplasty. We report a case of a constrained acetabular component that resulted in postoperative early fixation loss and required revision 12 days after primary surgery. The superoposterior wall of the acetabulum was destroyed by the migrated acetabular component. Sharp ends of screws with a metal shell may have plowed up acetabular bone gradually after fixation loss of the component. This failure illustrates the potential risk of using a constrained acetabular component for total hip arthroplasty. PMID- 11607919 TI - Interactions between the nervous and immune systems. AB - Substantial morphologic and functional evidence exists that supports the reciprocal interactions that occur between the nervous and immune systems. The nervous and immune systems have been increasingly found to use a common chemical language in the form of neuropeptides, cytokines, and hormones. Sophisticated immunologic techniques such as the identification and detection of immune cell surface markers enable researchers to determine the origin and activity of diverse cells in the blood and central nervous system. These techniques have elucidated the activity of immune cells in the central nervous system (CNS) that was previously thought to be privileged from immune surveillance in the presence of an intact blood brain barrier. Immune cells in the CNS play a central role in several degenerative diseases such as Alzheimer's disease, Huntington's disease, Multiple sclerosis, AIDS dementia complex, and nerve destruction associated with trauma. Immune cells also play a role in demyelinating peripheral nerve disorders. Cytokines and neuropeptides secreted by peripheral immune cells have profound effects on behavior that is mediated by the CNS. The close integration between immune and nervous system responses is being increasingly recognized in physiologic and pathologic conditions. PMID- 11607920 TI - Psychosocial-immune relationships in HIV disease. AB - Human immunodeficiency virus (HIV) is now commonly viewed as a chronic disease, which often consists of a wide array of recurrent and sometimes severe psychosocial stressors. An individual's response to these multiple challenges over time may impact their health. In this article, we review research examining the relationship of psychologic factors (eg, depression, stressful life events, coping, social support) with immune system function and disease course. We also explore some of the potential physiologic pathways that may underlie these types of psychosocial-immune relationships, as well as the effects of psychologic interventions, particularly cognitive-behavioral stress management (CBSM), on the psychosocial, neuroendocrine, and immune functioning of people living with HIV. We conclude by suggesting some areas for future research, particularly the study of HIV-positive women. PMID- 11607921 TI - Psychoneuroimmune and endocrine pathways in cancer: effects of stress and support. AB - The bulk of cancer research has productively focused on the pathophysiology of the disease, emphasizing tumor biology, especially tumor characteristics such as DNA ploidy and estrogen/progesterone receptor status as predictors of disease outcome, at the expense of studying the body's psychophysiological reactions to tumor invasion. These reactions are mediated by brain/body mechanisms, including the endocrine, neuroimmune, and autonomic nervous systems. Although a large portion of the variance in any disease outcome is accounted for by the specific local pathophysiology of that disease, some variability must also be explained by 'host resistance' factors, which include the manner of response to the stress of the illness. The evidence of links between social support, stress, emotional state, and immune and endocrine function is growing. Here we examine evidence that 2 especially promising mechanisms, one immune, one endocrine, may mediate the relationship between stress and social support on the one hand and cancer progression on the other. We chose natural killer (NK) cells and cortisol because they are particularly good examples of mediating mechanisms for which there is solid basic and clinical evidence. NK cells are of great interest because they are involved in tumor surveillance, and because their activity can be measured in vitro. PMID- 11607922 TI - Obsessive compulsive disorder: is there an association with childhood streptococcal infections and altered immune function? AB - During the last few years, an increased interest in the possibility of immune mediated pathophysiology of obsessive compulsive disorder (OCD) and related disorders has been seen. In the late 1980s, the National Institute of Mental Health reported an increase of obsessive compulsive symptoms in patients with Sydenham chorea (SC). Subsequently, a precipitating streptococcal infection in children with sudden onset of OCD symptoms but no chorea led to the coining of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus). This association has furthered interest in studying immune parameters in non-PANDAS OCD as well. This article will review the neuropsychiatric findings in OCD and Tourette syndrome (TS) with emphasis placed on PANDAS, and its association with SC, and a review of the existing studies that have assessed immunologic measures in patients with OCD and TS. PMID- 11607923 TI - The neuroimmunology of stress and depression. AB - This article reviews evidence that shows a bidirectional relationship between the brain and the immune system. As a result of this relationship, mental factors such as stress and depression have been shown to affect immune system functioning, with both immunosuppression and immune activation being reported. Stress and depression also have been associated with worse outcomes in immune related disorders including cancer and infectious diseases suggesting that stress/depression effects on the immune system are clinically relevant to disease expression. Conversely, several lines of evidence suggest that immune system activation such as during infectious diseases, cancer, and autoimmune disorders is associated with the development of behavioral symptoms similar to those seen in the context of chronic stress or major depression. These findings implicate a role for the immune system in the cause of behavioral disorders in a wide range of medical illnesses. Finally, a paradigm is proposed in which abnormal functioning of either the hypothalamic-pituitary-adrenal (HPA) axis or the inflammatory response system disrupts feedback regulation of both neuroendocrine and immune systems contributing to the development of neuropsychiatric and immunologic disorders. PMID- 11607924 TI - Neuroimmunologic aspects of sleep and sleep loss. AB - The complex and intimate interactions between the sleep and immune systems have been the focus of study for several years. Immune factors, particularly the interleukins, regulate sleep and in turn are altered by sleep and sleep deprivation. The sleep-wake cycle likewise regulates normal functioning of the immune system. Although a large number of studies have focused on the relationship between the immune system and sleep, relatively few studies have examined the effects of sleep deprivation on immune parameters. Studies of sleep deprivation's effects are important for several reasons. First, in the 21st century, various societal pressures require humans to work longer and sleep less. Sleep deprivation is becoming an occupational hazard in many industries. Second, to garner a greater understanding of the regulatory effects of sleep on the immune system, one must understand the consequences of sleep deprivation on the immune system. Significant detrimental effects on immune functioning can be seen after a few days of total sleep deprivation or even several days of partial sleep deprivation. Interestingly, not all of the changes in immune physiology that occur as a result of sleep deprivation appear to be negative. Numerous medical disorders involving the immune system are associated with changes in the sleep wake physiology--either being caused by sleep dysfunction or being exacerbated by sleep disruption. These disorders include infectious diseases, fibromyalgia, cancers, and major depressive disorder. In this article, we will describe the relationships between sleep physiology and the immune system, in states of health and disease. Interspersed will be proposals for future research that may illuminate the clinical relevance of the relationships between sleeping, sleep loss and immune function in humans. PMID- 11607930 TI - Cyclin-dependent kinase inhibitors for treating cancer. AB - Cyclin dependent kinases (Cdks) are essential enzymes for the control of cell cycle progression. Inhibitors of cyclin-dependent kinases are anticipated to possess therapeutic utility against a wide variety of proliferative diseases, especially cancer. The field of published small molecule Cdk inhibitors is briefly reviewed here as background to a summary of work on a class of pyrido[2,3 d]pyrimidine Cdk inhibitors. Compounds from this class are described that display potency against cyclin D/Cdk4 up to IC(50) = 0.004 microM. Good to moderate selectivity for cyclin D/Cdk4 is also reported for compounds in this structural class. Structure-activity relationship data are presented for substitution at the C2 and N8 positions and these data are interpreted in the context of a binding model that is based on the Cdk2 crystal structure. A representative cyclin D/Cdk4 inhibitor (compound 56) is demonstrated to selectively inhibit the proliferation of an Rb(+) cell line vs. a matched Rb(-) cell line and to produce a distinct G(1) block consistent with cyclin D/Cdk4 inhibition in cells. PMID- 11607931 TI - Tyrosine kinase inhibitors: from rational design to clinical trials. AB - Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors. PMID- 11607932 TI - Chemical genomics: functional analysis of orphan nuclear receptors in the regulation of bile acid metabolism. AB - Chemical genomics is the name we have given to the analysis of gene function through use of small molecule chemical tools. Orphan nuclear receptors are ideally suited to this technique of functional analysis, since their activity as transcription factors is regulated by small hydrophobic ligands. GW4064 is a potent and selective nonsteroidal ligand for the nuclear bile acid receptor FXR (NR1H4). Using GW4064 as a chemical tool, we have identified genes regulated by FXR in the liver, including those involved in bile acid synthesis and transport. We have also discovered that PXR (NR1I2) is a lithocholic acid receptor that controls the biosynthesis and metabolism of bile acids. Together FXR and PXR cooperate to control biliary and urinary bile acid excretion. These functions suggest that potent PXR and FXR ligands may offer a new approach to the treatment of cholestatic liver disease. PMID- 11607933 TI - Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists. AB - The aim of this study is to compare crystal structures of nuclear receptor ligand binding domains in complex with different agonists and partial agonists to achieve a better understanding of the three-dimensional structures and their ligand-induced conformational changes. This led to the identification of structurally conserved "rigid" regions and more flexible parts of the proteins. The analysis was found to be of great value in fitting selected non-steroidal compounds into the human estrogen receptor alpha (hER alpha) ligand binding pocket. The experimentally determined binding affinities for a number of 2-aryl indoles and 2-aryl indenones are in good agreement with the subsequently modeled binding interactions. To date, no crystal structure is published for a complex with a pure antagonist. We therefore used the available structural information on complexes with partial agonists and the crystal structure of a mutant protein in complex with estradiol displaying a similar conformation to predict binding interactions for antagonists. The results are discussed in detail. PMID- 11607934 TI - Peroxisome proliferator-activated receptor (PPAR) modulators: diabetes and beyond. AB - Peroxisome proliferator-activated receptors (PPARs) are a class of ligand modulated transcription factors with a prominent role in the regulation of metabolic processes. This report is intended to provide a limited introduction to the PPAR field, sketched with reference to one early series of PPAR ligands. PMID- 11607935 TI - State funded continuing care for the elderly mentally ill: a legal and ethical solution? PMID- 11607936 TI - The clock drawing test in primary care: sensitivity in dementia detection and specificity against normal and depressed elderly. AB - OBJECTIVES: The aim of this study was to examine the sensitivities and specificities of the clock drawing test (CDT) in the detection of dementia among older people in primary care, with particular emphasis on the effect of depression on CDT specificity. Most previous studies have been sited in specialist settings and few have addressed the issue of specificity against depression. METHODS: Comparison of cohorts identified from community-based screening with GMS-AGECAT. The CDT and the Mini-Mental State Examination (MMSE) were administered to 41 elderly subjects with organic disorder (dementia), 84 elderly subjects with case level depression and 523 normal elderly subjects. Sensitivities and specificities of the CDT were calculated. RESULTS: The sensitivity of the CDT in the detection of dementia in the general community was 76%. The specificities of the CDT against normal elderly and depressed elderly was 81% and 77% respectively. Higher sensitivity and specificity were achieved by the MMSE. CONCLUSIONS: The use of the CDT in the detection of dementia syndromes is likely to be more relevant in the primary care context than in specialist settings. The CDT provides good sensitivity and specificity but may not be as sensitive or specific in the general community as previous studies have suggested, particularly in mild dementia. Community-based late life depression does not appear to alter the specificity of the CDT. PMID- 11607937 TI - Depressive symptoms among poststroke patients in Japan: frequency distribution and factor structure of the GDS. AB - OBJECTIVE: The present study examined the nature, prevalence, and covariates of depressive symptoms among home-dwelling poststroke patients in Japan using the Geriatric Depression Scale Short Form (GDS-1). Poststroke results were compared with those of elderly with affective disorders and with those of healthy nonstroke elderly. METHODS: Poststroke patients (n = 101) who did not also have a diagnosis of Alzheimer's dementia, were identified from patient records at seven randomly selected hospitals with outpatient rehabilitation clinics in a metropolitan area in western Japan and invited to participate in the study. All instruments were interview-administered. RESULTS: GDS scores did not correlate with age, sex, education, functional dependence, aphasia, paralysis or presence of other chronic illnesses. However, GDS scores did correlate significantly with self-rated general health and poststroke duration. Compared with the frequency distribution in a psychiatric sample, poststroke patients had higher positive affect and lower depressed mood but similar social withdrawal scores. The factor structure of the poststroke sample differed from that of nonstroke elderly in that depressed mood items loaded with items for energy loss and memory problems. CONCLUSION: Despite the fact that 62% of subjects scored > or = 6 on the GDS, none were currently receiving assessment and/or treatment for their depressive symptoms. The frequency distribution and factor structure suggest that poststroke GDS scores reflect endorsement of functional losses such as decreased energy and impaired memory and subsequent feelings of helplessness, boredom and social withdrawal rather than decreased positive affect. Treatment should focus on dealing with these issues. PMID- 11607938 TI - Social isolation predicts re-hospitalization in a group of older American veterans enrolled in the UPBEAT Program. Unified Psychogeriatric Biopsychosocial Evaluation and Treatment. AB - OBJECTIVES: Does social isolation predict re-hospitalization in a group of older men enrolled in Unified Psychogeriatric Biopsychosocial Evaluation and Treatment (UPBEAT), a mental health care-coordination project at nine Veterans Affairs Healthcare Centers nationwide? METHODS: The current study examined 123 UPBEAT patients located at West Los Angeles, whose ratings were available on the Lubben Social Network Scale (LSNS), the SF-36 scale, the Cumulative Illness Rating Scale (CIRS) and the Mental Health Index (MHI-38) Depression and Anxiety subscales. Within one year of enrollment, 55% of patients were re-hospitalized. Odds of re hospitalization were calculated using two logistic regression models. Social isolation risk (LSNS) and demographic covariates were included. In addition, Model 1 contained depression and anxiety measures (MHI-38) and physician-rated medical burden (CIRS), while in Model 2, patient-perceived physical (PCS) and mental health (MCS) subscales from the SF-36 were included. RESULTS: The group of patients who were socially isolated or at high or moderate risk for isolation, were 4-5 times more likely to be re-hospitalized within the year, than low isolation risk patients. In both Models 1 (chi-square = 19.86; p = 0.031) and 2 (chi-square = 26.42; p = 0.002) demographic characteristics were not significant predictors of re-hospitalization, but social isolation risk was a significant predictor (Model 1: odds ratio (OR) = 5.31; 95% confidence intervals (CI) = 1.81 15.53; and Model 2: OR = 3.86; 95% CI = 1.39-10.73). In addition, MHI-Anxiety was a significant predictor (OR = 1.22; 95% CI = 1.05-1.43) in Model 1 and in Model 2, patient-perceived physical health significantly predicted re-hospitalization (OR = 0.91; 95% CI = 0.86-0.96). CONCLUSION: When controlling for other covariates, social isolation, physical health and mental health were significant risk factors for re-hospitalization. These findings underline the importance of assessing and addressing lack of social support, along with other factors, in the health care of older male veterans. PMID- 11607939 TI - Depressive symptoms in patients with Alzheimer's disease. AB - OBJECTIVES: A comparison was made between the depressive symptom profiles of thirty patients with Alzheimer's disease (AD) who did not have co-existing depression and thirty patients with major depression who did not have co-existing dementia. The main objective was to identify symptoms common to both disorders and those which may be able to differentiate AD from major depression. METHOD: A sample of patients suffering from either AD (n = 30) or major depression (n = 30) were recruited from a specialist old age psychiatry service. Depressive symptoms were profiled using the Hamilton Depression Rating Scale (HDRS), the Cornell Scale for Depression in Dementia (CSDD) and the Geriatric Depression Scale (GDS). RESULTS: Depressive symptoms were present in AD in the absence of coexistent major depression. Certain depressive symptoms from all the three scales such as sadness, diurnal variation in mood and early or late insomnia were able to differentiate the two disorders with almost 90% accuracy while symptoms such as irritability, retardation and weight loss were common to both and were unable to differentiate the two. CONCLUSION: Depressive symptoms occur in AD when co existing depression is ruled out. Their recognition has implications for the diagnosis of major depression in these patients. PMID- 11607940 TI - Recurrent falls are associated with increased length of stay in elderly psychiatric inpatients. AB - OBJECTIVES: To identify factors which may contribute to prolonged length of stay in an elderly psychiatric inpatient setting. DESIGN: Retrospective case note study. METHODS: A list of all patients over the age of 65 discharged from a private psychiatric hospital over a three-year period excluding those with a length of stay of over 365 days was obtained (n = 1147). A random sample of 150 patients was selected from the study population. A case note study was then performed looking at a number of variables which have been postulated to affect length of stay. The resulting data was analysed using multivariate statistics. RESULTS: There was no statistically significant association found between baseline factors (including age, gender, cognitive impairment, marital status, order of admission and preadmission living arrangement) and length of stay. Having recurrent falls whilst an inpatient was associated with prolonged hospital stay (p = 0.0006). CONCLUSION: Experiencing recurrent falls whilst an inpatient is associated with prolonged length of stay. Recurrent falls in the elderly may be associated with both physical illness and the use of psychotropic medications. A prospective study examining factors contributing to falls would be important in decreasing fall risk and reducing length of stay. PMID- 11607941 TI - Death and dementia. AB - OBJECTIVE: To investigate the last phase of dementia and the causes of death; comparing autopsy and death certificate diagnoses. DESIGN: Prospective, 11-year, longitudinal study of behavioural and psychological changes in dementia, with autopsy follow-up. SETTING: Participants with dementia, living at home with a carer. All lived in Oxfordshire, UK. PARTICIPANTS: Ninety-one people with dementia (Alzheimer's disease and/or vascular dementia) who died during the course of the study. MEASURES: At four-monthly intervals, carers were interviewed about the participants' behaviour using the Present Behavioural Examination. Participants were also assessed cognitively. Causes of death were established from death certificates and, where possible, from post-mortem examination. RESULTS: The main immediate cause of death recorded at autopsy was pneumonia (57%), followed by cardiovascular disease (16%) and pulmonary embolus (14%). This agreed with the immediate cause of death on 53% of death certificates. Pulmonary embolism and bronchopneumonia were under-reported on death certificates. Dementia was mentioned on 73% of death certificates. The dementing illness lasted for a mean of 8.5 years with 58% dying in a debilitated state associated with severe dementia. In the period before death, 35% were unable to walk, 58% were hypophagic, 73% were incontinent of urine, 21% incontinent of faeces and 76% entered an institution permanently for a mean period of 18 months. CONCLUSION: Family and professional carers of people with dementia can be given some information about prognosis to help them plan for the likely outcome of dementia. PMID- 11607942 TI - Depression in the community dwelling elderly: do clinical and sociodemographic factors influence referral to psychiatry? AB - BACKGROUND: Little is known about the reasons why depressed elderly patients are referred to the old age psychiatric services. Reasons for referral of depressed younger patients have been clarified however they may not be generalisable to an older population. OBJECTIVES: The purpose of this study is to examine which clinical and sociodemographic factors influence referral of patients with late life depression from primary care. METHODS: Twenty-eight people were identified with depression in a day hospital referred by their general practitioner. These were compared with fifty-two people with depression in the community who had not been referred to the psychiatric services. RESULTS: Having a more severe depression (p = 0.0016) and having co-morbid anxiety (p = 0.0017) meant you were more likely to be referred to the day hospital. Gender did not appear to influence referral from general practitioners. CONCLUSIONS: It appears that severity of depression and having higher levels of anxiety make it more likely that you will be referred by your general practitioner to the old age psychiatry services. PMID- 11607944 TI - Vitamin B12 in primary health care and geriatrics--attitudes, knowledge and competence. AB - OBJECTIVES: The objective of the study was to test attitudes, knowledge and competence of Swedish general practitioners and geriatricians concerning B12 associated problems in 1998. METHODS: Postal questionnaires were sent to a random sample of 485 GPs and a total sample of 613 geriatricians. The response rates were 70% in the GP group and 69% in the geriatrician group. The questionnaire contained 24 statements to be evaluated by a visuo-analogue scale. RESULTS: There were small numerical differences between the two physician groups. The geriatricians were more aware of risk groups for B12 deficiency. GPs were less categorical concerning low hit rate in the laboratory testing of clinical conclusions. There were statistical differences in both directions for statements on pitfalls in laboratory diagnostics. GPs were somewhat less prone to give risk groups prophylactic B12 therapy. CONCLUSIONS: GPs and geriatricians appeared to be familiar with the current debate on B12-associated problems, suggesting that health care quality will be unaffected by patient transfer from hospital care to primary health care. PMID- 11607943 TI - Psychometric properties of the state part of the Spielberger State-Trait Anxiety Inventory (STAI) in geriatric patients. AB - BACKGROUND: A conspicuously high score on the state part of the State-Trait Anxiety Inventory (STAI) has been observed among geriatric inpatients who are neither demented nor critically ill; 43% of them had a sumscore that, according to Spielberger's criteria, would reflect clinically relevant anxiety symptoms. OBJECTIVES: To explore the reasons for this high score. METHODS: 101 geriatric inpatients and 68 healthy controls of similar age, living at home and recruited through senior citizen centres participated in a controlled cross-sectional study. RESULTS: High item-scores were more frequent on the symptom-negative items than on the symptom-positive items. Multi-group factor analysis produced two factors termed 'well-being' and 'nervousness', which had a moderate correlation (0.61). The intercept was much higher on 'well-being' than on 'nervousness', showing that a lack of well-being contributes significantly to the high score on the STAI. This confounds the sumscore. However, the geriatric inpatients nevertheless had a high score on the factor 'nervousness'. Female controls scored higher than males on both factors, whereas among the geriatric patients neither age nor gender related to them. CONCLUSIONS: The STAI state sumscore is a biased indicator of anxiety in geriatric inpatients owing to confounding by well-being. The most important cause for the observed high score on the STAI state instrument in geriatric patients relates to a reduced well-being. PMID- 11607945 TI - Depression and anxiety disorders among Jews from the former Soviet Union five years after their immigration to Israel. AB - BACKGROUND: Epidemiological studies have shown that the prevalence rates of major depression and anxiety are lower in the elderly than in younger adults. In a recent survey, we found, among immigrants, that the association of age with psychological distress was the reverse. OBJECTIVE: The objective of the present study was to examine, among immigrants, whether the relationship of age with clinically diagnosed depression and anxiety disorders is also reversed. This was done by assessing the age-specific incidence and prevalence of depression and anxiety among immigrants from the former Soviet Union to Israel five years after their immigration. METHODS: A stratified subsample was chosen from a larger random sample of immigrants from the Former Soviet Union who arrived in Israel in 1990. We selected the subsample to include an over-representation of those with a high level of distress in order to increase the probability of finding people suffering from psychopathology. The subjects were interviewed with a diagnostic instrument, the CIDI-S, an abbreviated version of the CIDI. Prevalence and incidence rates of depression and anxiety were calculated separately for two age groups (those below age 65 and those aged 65 and above). RESULTS: Before immigration, incidence rates were lower among the elderly than among younger adults, a finding consistent with the literature. However, after immigration, the reverse was found, with higher prevalence and incidence rates among elderly immigrants. CONCLUSION: The data suggest that immigration contributes to an increase of psychopathology which is particularly pronounced among the elderly. PMID- 11607946 TI - Lithium use in octogenarians. AB - OBJECTIVES: To assess the tolerability and side-effect profile of lithium use in a group of octogenarians attending a specialized lithium clinic. METHODS: This is a cross-sectional study looking at all patients of eighty years and over attending a lithium clinic. Charts were examined to assess renal function, thyroid function and level of side-effects during their course of lithium treatment in order to assess the tolerability of this medication in octogenarians. RESULTS: Twelve patients of 80 years and over (with an average age of 83.6 years) were taking lithium for an average period of 53.7 months. They had a mean serum level of 0.42 mmol/l. No patient had to discontinue lithium therapy because of side-effects, even though some patients did develop transient abnormalities of renal function. One patient developed diabetes insipidus. One female patient developed hypothyroidism. CONCLUSIONS: Lithium was well tolerated and was administered safely to this cohort of octogenarians. Monitoring of serum lithium levels and kidney and thyroid function should preferably be done in the setting of a specialized lithium clinic. PMID- 11607947 TI - Discontinuation of lithium augmentation in an elderly cohort. AB - OBJECTIVES: To observe the effects of gradual discontinuation of lithium augmentation therapy in a group of patients over the age of 65 years and to measure the rate of relapse and to identify any factors which would predict relapse. METHODS: This was a naturalistic study involving 21 patients who were on lithium augmentation and whose lithium was discontinued for a variety of clinical reasons. In most cases lithium was tapered and discontinued over a period of 2-12 weeks. Demographic and other variables were collected at baseline and compared between those who remained well and those that subsequently relapsed. RESULTS: Eleven patients (52.4%) relapsed following discontinuation of lithium augmentation. Those who relapsed had been on lithium for significantly longer than those who remained well off lithium (p = 0.007). There was a trend towards more hospital admissions in the relapse group (p = 0.062). CONCLUSIONS: When lithium augmentation therapy is discontinued in elderly depressives over half of these patients relapse. A longer duration of prediscontinuation lithium treatment and more hospital admissions appear to be associated with increased risk of relapse. PMID- 11607949 TI - Mental health in spouses of patients with gerontopsychiatric disorders. PMID- 11607948 TI - Aromatherapy and behaviour disturbances in dementia: a randomized controlled trial. AB - A random controlled trial of the relaxing effects of an aromatherapy massage on disordered behaviour in dementia was conducted. Twenty-one patients were randomly allocated into one of three conditions, aromatherapy and massage (AM), conversation and aromatherapy (CA) and massage only (M). AM showed the greatest reduction in the frequency of excessive motor behaviour of all three conditions. This reached statistical significance between the hours of three and four pm (p < 0.05). Post hoc analysis suggested that at this time of day the AM consistently reduced motor behaviour when compared with CA (p = 0.05). This provides preliminary evidence of a measurable sedative effect of aromatherapy massage on dementia within a robust scientific paradigm. Further research is recommended with an expanded sample size. PMID- 11607950 TI - Current awareness in geriatric psychiatry. PMID- 11607956 TI - Historical ruminations: rickettsiae and the Rocky Mountain Laboratory. PMID- 11607959 TI - Apologies for interdiction: the homosexual question. PMID- 11607961 TI - Reid and the Cartesian framework. PMID- 11607960 TI - Dominance, leadership, and aggression: animal behavior studies during the Second World War. AB - During the decade surrounding the Second World War, an extensive literature on the biological and psychological basis of aggression surfaced in America, a literature that in general emphasized the significance of learning and environment in the origins of aggressive behavior. Focusing on the animal behavior research of Warder Clyde Allee and John Paul Scott, this paper examines the complex interplay among conceptual, institutional, and societal forces that created and shaped a discourse on the subjects of aggression, dominance, and leadership within the context of World War II. The distinctions made between sexual and social dominance during this period, distinctions accentuated by the threat of totalitarianism abroad, and the varying ways that interpretations of behavior could be negotiated attests to the multiplicity of interactions that influence the development of scientific research. PMID- 11607965 TI - Psychology at Clark University: introduction. PMID- 11607966 TI - Recollections of Clark's G. Stanley Hall. PMID- 11607967 TI - Child study at Clark University: 1894-1904. AB - A first cooperative research program in developmental psychology was established in the Clark questionnaire studies. The program was not meant to be free-standing but to elaborate an evolutionary conception of child development synthesized from findings of several scientific fields. The short-lived program had some serious faults, but an examination of its research papers suggests that it produced some worthwhile work. The child-study researchers gathered information about children's social and emotional reactions in everyday settings; one or two of their studies were replicated; they found pattern and order; they elaborated a meaningful social-biological view of child development. PMID- 11607968 TI - The "magic decade" revisited: Clark psychology in the twenties and thirties. PMID- 11607969 TI - Reshaping psychology at Clark: the Werner era. PMID- 11607976 TI - The wisdom of pain in Chekhov's "Ward number six." PMID- 11607984 TI - The apprenticeship of George Eliot: characterization as case study in "Janet's repentance." PMID- 11607989 TI - Reconciling democracy and the crowd in turn-of-the-century American social psychological thought. PMID- 11607988 TI - Is schizophrenia what it was? A re-analysis of Kraeplin's and Bleuler's population. PMID- 11607991 TI - Legacies of empire for psychology in New Zealand. PMID- 11607995 TI - The origins of plastic surgery in India. PMID- 11607997 TI - Obituary: Margaret W. Menzies Campbell. PMID- 11607999 TI - The origins of military dentistry. PMID- 11608000 TI - John Humphreys, M.A., Ph.D., M.D.S., F.S.A., F.L.S., F.G..S. PMID- 11608001 TI - Dental Historian cover illustration. PMID- 11608002 TI - The Pilleau family: Huguenot goldsmiths in London. PMID- 11608006 TI - [Not Available]. PMID- 11608010 TI - The legend of the Maiden of Kosovo and nursing in Serbia. PMID- 11608015 TI - Queen Victoria and the dentists. PMID- 11608017 TI - [Athenaeum for the History of Medicine in Buenos Aires (the presence of dentists and dental themes in its two eras)]. PMID- 11608018 TI - [Notes on the history of dentistry (continuation): the 17th century, medicine and science]. PMID- 11608019 TI - [Fifty years of dentistry in Argentina (1900-1950)]. PMID- 11608045 TI - From prohibition to regulation: lessons from alcohol policy for drug policy. AB - Like current drug prohibition, alcohol prohibition in the 1920s produced a large criminalized industry. Post-repeal alcohol regulation, which tended to limit overall consumption, suggests that the legal regulated sale of currently illicit substances is technically practical and reasonable. However, no such radical change in drug policy will be politically feasible until well into the twenty first century. Nevertheless, the failures and costs of the War on Drugs make moderate reform a more promising prospect. PMID- 11608048 TI - Irwin Howard Pizer, 1934-1991. PMID- 11608053 TI - Historiography, diagnosis, and poetics. PMID- 11608054 TI - [The society of dentists in Winterthur (VWZ): its foundation and its development]. PMID- 11608058 TI - Dentistry in Europe in the 1790's. PMID- 11608060 TI - Rescuing the reputation of Sir Cyril [Burt]. PMID- 11608064 TI - Colorado and the Medical Library Association 1898-1968. PMID- 11608066 TI - [Not Available]. PMID- 11608072 TI - Beloved illness: transference love as romantic pathology in F. Scott Fitzgerald's Tender is the night. PMID- 11608075 TI - Midwives as providers of prenatal care in Finland--past and present. AB - This study analyzes the role of the midwife in prenatal care by exploring the history of the midwifery profession in Finland and by interviewing midwives. Midwifery education started in Finland in the beginning of the 19th century due to the utilitarian population policy aiming to reduce the high infant mortality rate. Because of a shortage of physicians professional midwives attained an important status in the care of births. With industrialization a state-directed welfare policy with state-subsidized health care developed. After World War II, the midwifery were legally defined as care during pregnancy, delivery, and the postpartum period. In the 1950s, the scope of work of midwifery was further altered because hospital deliveries had become routine. Some midwives provided prenatal care in ambulatory maternity health centers while others worked in hospitals managing normal childbirths. Separate midwifery education ended in 1968 and resumed 1986. Since 1972, public health nurses have increasingly provided prenatal and postnatal care in maternity centers, and specialized nurses have managed normal childbirths. In the future, public health nurses may totally replace midwives in prenatal care, and the role of midwives may return to care of normal deliveries. Midwife interviews revealed the "medicalization" of pregnancy caused both by physicians and midwives' own medical concept of pregnancy and by clients' demands for good care. PMID- 11608076 TI - [Not Available]. PMID- 11608077 TI - [Not Available]. PMID- 11608083 TI - Edmund D. Pellegrino's philosophy of medicine: an overview and an assessment. PMID- 11608084 TI - Mill and Comte on the method of introspection. PMID- 11608086 TI - Dialysis nursing in Wisconsin: 1966-1968. Contributions of Priscilla Scholl. PMID- 11608090 TI - William Isaac Thomas and the Helen Culver Fund for Race Psychology: the beginnings of scientific sociology at the University of Chicago, 1910-1913. PMID- 11608091 TI - Burrhus Frederic Skinner (1904-1990). PMID- 11608093 TI - Peron, Porteus, and the Pacific Islands regiment: the beginnings of cross cultural psychology in Australia. PMID- 11608098 TI - Brilliance and bureaucracy. Nursing and changes in the Rockefeller Foundation, 1915-1930. PMID- 11608119 TI - The angels of Bataan. PMID- 11608121 TI - Anna Wolf's dream: establishment of a collegiate nursing education program. AB - A lifelong dream of Anna D. Wolf was to establish nursing education in a university. Her first step toward this goal occurred in China in 1922 at the Peking Union Medical College (PUMC) which was established by the Rockefeller Foundation to bring the best of scientific Western medicine (and nursing) to China and to make nursing an acceptable occupation for educated Chinese women. PMID- 11608131 TI - Some German dental practitioners of the 1790s. PMID- 11608132 TI - The reputability of sixteenth and seventeenth century toothdrawers. PMID- 11608133 TI - [Not Available]. PMID- 11608150 TI - Marie Elizabeth Zakrzewska 1829-1902. PMID- 11608151 TI - Medical women and social reform--a history of the New York Infirmary for Women and Children. PMID- 11608153 TI - Women-controlled medicine--theory and practice in 19th century Boston. PMID- 11608154 TI - Women-controlled medicine--theory and practice in 19th century Boston. PMID- 11608155 TI - Alice Hamilton 1869-1970. PMID- 11608156 TI - Alice Hamilton 1869-1970. PMID- 11608180 TI - Woman, the anthropologist, meets man, the hunter. [Review of Reiter RR, ed. Toward an anthropology of women. Review Press, 1975]. PMID- 11608165 TI - Florence Nightingale (1820-1910). PMID- 11608183 TI - Royce's community; a dimension missing in Freud and James? AB - Josiah Royce (1855-1916), philosopher of community, taught that social consciousness arises from ego-alter contrasts and is guided by taboos and, before George H. Mead, by reciprocal gestures. A major Roycean contribution was his five conditions for coexperiencing consciousness of genuine community. Related to Freud (via Putnam), Royce did early work on "identification theory" and helped midwife psychotherapy's birth in America. Contrasting with William James's basic differentiation of consciousness according to the quality of its contents (feeling, thought, and conduct), Royce preferred a norm of increasing self-agency (shown in sensitivity, docility, and initiative). The temperaments of James as artist and of Royce as rational interpreter differentiated their approaches to psychology. PMID- 11608188 TI - The philosophical development of the conception of psychology in Germany. PMID- 11608189 TI - Oswald Kulpe and the Wurzburg school. PMID- 11608190 TI - Functionalism at Chicago--memories of a graduate student, 1929-1931. PMID- 11608191 TI - Demonology and the rise of science: an example of the misperception of historical data. PMID- 11608193 TI - Discussion: F. M. Urban and the value of archival material. PMID- 11608207 TI - Asylum psychiatry, neurology, social work, and mental hygiene: an exploratory study in interprofessional history. AB - The author proposes that an adequate appreciation of the American mental health movement will require, ultimately, an appreciation of the concurrent developments in the histories of related professions (e.g., asylum psychiatry, neurology, social work, and public mental health). In this exploratory review, the author demonstrates some reciprocal influences between these professions which were significant determinants for their present positions. Suggestions are offered for other needed interprofessional historical studies in this area. PMID- 11608212 TI - Juan Huarte. The examination of men's wits (1575). PMID- 11608213 TI - Essay review: Robert Copland's art of memory (c.1545). PMID- 11608219 TI - The Renaissance of witchcraft research. PMID- 11608220 TI - G. H. Mead's alleged behaviorism. PMID- 11608222 TI - The role of mental illness in the European witch hunts of the sixteenth and seventeenth centuries. PMID- 11608224 TI - Historical relations of psychology as an object-science and a subject-science: toward psychology as a human science. AB - Textbooks and other teaching of psychology's history oversimplify to the point of presenting it as the evolution of an exclusively object-science--despite general familiarity with integral extrascientistic practices and assumptions. Representative examples are presented, along with an overview of object psychology's cultural/practical routes to dominance. The purpose of highlighting these facets of psychology's development is to call for psychology to take explicit account of humans' subjecthood as well as objectness, on the way rereading our history toward an integrated science. PMID- 11608225 TI - The real F. M. Urban. PMID- 11608228 TI - The history of psychology conceived as social psychology of the past. PMID- 11608231 TI - Charles Spearman and the general factor in intelligence: genesis and interpretation in the light of sociopersonal considerations. PMID- 11608233 TI - The future of an illusion--the illusion of the future: an historic dialogue on the value of religion between Oskar Pfister and Sigmund Freud. PMID- 11608235 TI - Was 1898 a "great date" in the history of experimental social psychology? PMID- 11608236 TI - Mary Whiton Calkins (1863-1930), fourteenth president of the American Psychological Association. PMID- 11608238 TI - [Not Available]. PMID- 11608239 TI - [Not Available]. PMID- 11608240 TI - [Not Available]. PMID- 11608241 TI - [Not Available]. PMID- 11608242 TI - [Not Available]. PMID- 11608243 TI - [Not Available]. PMID- 11608244 TI - [Not Available]. PMID- 11608245 TI - [Not Available]. PMID- 11608246 TI - [Not Available]. PMID- 11608247 TI - [Not Available]. PMID- 11608248 TI - [Not Available]. PMID- 11608250 TI - [Not Available]. PMID- 11608249 TI - [Not Available]. PMID- 11608251 TI - [Not Available]. PMID- 11608252 TI - [Not Available]. PMID- 11608253 TI - [Not Available]. PMID- 11608254 TI - [Not Available]. PMID- 11608255 TI - [Not Available]. PMID- 11608256 TI - [Not Available]. PMID- 11608257 TI - [Not Available]. PMID- 11608258 TI - [Not Available]. PMID- 11608259 TI - [Not Available]. PMID- 11608260 TI - [Not Available]. PMID- 11608261 TI - [Not Available]. PMID- 11608262 TI - [Not Available]. PMID- 11608263 TI - [Not Available]. PMID- 11608264 TI - [Not Available]. PMID- 11608265 TI - [Not Available]. PMID- 11608266 TI - [Not Available]. PMID- 11608268 TI - [Not Available]. PMID- 11608267 TI - [Not Available]. PMID- 11608269 TI - [Not Available]. PMID- 11608272 TI - Ancient dentistry. Teeth without fastenings. PMID- 11608280 TI - The positivist repudiation of Wundt. PMID- 11608281 TI - Wundt and after: psychology's shifting relations with the natural sciences, social sciences, and philosophy. PMID- 11608282 TI - Something old, something new: attention in Wundt and modern cognitive psychology. PMID- 11608284 TI - Objectivity and value judgments in the psychologies of E. L. Thorndike and W. McDougall. PMID- 11608285 TI - A note on the Titchener influence on the first psychology laboratory in the South. PMID- 11608286 TI - An aspect of the early history of the Society for the Psychological Study of Social Issues: psychologists and labor. PMID- 11608288 TI - Early advertising applications of the Gale-Cattell order-of-merit method. PMID- 11608289 TI - G. Stanley Hall and Ashfield's Academy Dinners. PMID- 11608290 TI - [Not Available]. PMID- 11608291 TI - [Not Available]. PMID- 11608292 TI - [Not Available]. PMID- 11608293 TI - [Not Available]. PMID- 11608294 TI - [Not Available]. PMID- 11608295 TI - [Not Available]. PMID- 11608296 TI - [Not Available]. PMID- 11608297 TI - [Not Available]. PMID- 11608298 TI - [Not Available]. PMID- 11608299 TI - [Not Available]. PMID- 11608302 TI - A historical review of treatment modalities for temporomandibular joint dysfunction syndrome. PMID- 11608308 TI - The proletarianization of nursing in the United States. PMID- 11608316 TI - Health and housing: a historical examination of alternative perspectives. AB - The deleterious effect of low-quality housing and related environmental factors on the physical and mental health of its residents is a widely accepted phenomenon. Yet low-quality housing continues to exist, partly because of the nature of housing as a commodity in a capitalist system. This paper defines three political-analytic perspectives within which the housing-health relationship can be seen: individualistic, reformist, and dialectical-materialist. These approaches incorporate perspectives on the nature of the relationship as well as strategic implications arising from them. In this context, the housing-health relationship is examined in fact and interpretation from the 1840s to the present. All three perspectives are illustrated by various popular analyses of changes in urban form and housing as well as the housing-health relationship. The dependence of housing quality on the mode of production is shown, demonstrating the weaknesses of the individualistic and reformist perspectives, which assume housing quality to be independent of the mode of production. The different strategic implications of the three perspectives are illustrated in the conclusion in a discussion of the case of lead paint poisoning. PMID- 11608319 TI - The cervical cap: cap and current experience. PMID- 11608322 TI - Thought-styles, diagnosis, and concepts of disease: commentary on Ludwig Fleck. PMID- 11608323 TI - World 5 and medical knowledge. PMID- 11608325 TI - Consiglio Nazionale delle Ricerche, Rome, Italy. PMID- 11608329 TI - Four decades as nurse and educator: a conversation with Margaret Aiken, RN [interview by Cynthia S. Pomerleau]. PMID- 11608339 TI - The selling of a psychologist: John Broadus Watson and the application of behavioral techniques to advertising. PMID- 11608340 TI - Platonism and penology: James Mill's attempted synthesis. PMID- 11608344 TI - The history course as the capstone of the psychology curriculum. PMID- 11608353 TI - Eliza Maria Mosher, MD (1846-1928). PMID- 11608360 TI - A century of early development and supply of nurses in Nigeria 1850-1950: introduction. PMID- 11608364 TI - Organizing for the kingdom of behavior: academic battles and organizational policies in the twenties. PMID- 11608363 TI - Georgy Chelpanov and the establishment of the Moscow Institute of Psychology. PMID- 11608367 TI - [Not Available]. PMID- 11608374 TI - Medicolegal progress in inquest of felonious deaths: Westminster, 1761-1866. PMID- 11608376 TI - A note on the 1929 International Congress of Psychology. PMID- 11608378 TI - On the difficulty of writing history of ideas: a reply. PMID- 11608379 TI - Ethics, evolution, and the psychology of William James. PMID- 11608381 TI - The trilogy of mind: cognition, affection, and conation. PMID- 11608382 TI - The historical foundation of Herbart's mathematization of psychology. PMID- 11608384 TI - William James and the problem of interests. PMID- 11608390 TI - Dr. High on history. PMID- 11608391 TI - The Loeb-Jennings debate and the science of animal behavior. PMID- 11608392 TI - Psychology's histories: some new ones and a bit about their predecessors--an essay review. PMID- 11608393 TI - A note on an unpublished article by John B. Watson. PMID- 11608396 TI - The durability of scientific reputation. PMID- 11608400 TI - [Not Available]. PMID- 11608421 TI - Wilbur J. Cohen 1913-1987. An ombudsman for America. PMID- 11608434 TI - Touch in nursing practice: a historical perspective. PMID- 11608401 TI - Ob/gyn on the rise: the evolution of professional ideology in the twentieth century. PMID- 11608443 TI - [Not Available]. PMID- 11608442 TI - [Not Available]. PMID- 11608444 TI - [Not Available]. PMID- 11608445 TI - [Not Available]. PMID- 11608447 TI - [Not Available]. PMID- 11608446 TI - [Not Available]. PMID- 11608448 TI - [Not Available]. PMID- 11608449 TI - [Not Available]. PMID- 11608450 TI - [Not Available]. PMID- 11608452 TI - History of convulsive therapy. PMID- 11608456 TI - History of in vivo analysis of brain functions elicited from its inner and outer surfaces. PMID- 11608460 TI - [Not Available]. PMID- 11608458 TI - 'Back to the origins': Erwin Straus--philosopher of medicine, philosopher in medicine. PMID- 11608461 TI - [Not Available]. PMID- 11608462 TI - [Not Available]. PMID- 11608463 TI - [Not Available]. PMID- 11608464 TI - Reproduction: a behavioral and neuroendocrine perspective. In honor of Jay S. Rosenblatt PMID- 11608470 TI - Fitzgerald vs. Fitzgerald: "An Alcoholic Case." PMID- 11608472 TI - Prospero, as a Renaissance therapist. PMID- 11608477 TI - Two pathographies: a study in illness and literature. AB - This study compares two autobiographical descriptions of illness--the seventeenth century John Donne's Devotions Upon Emergent Occasions and the twentieth-century Cornelius and Kathryn Ryan's A Private Battle. I begin by identifying the basic structure in both narratives as parallel to that of the case history, and then show how each individual's experience is shaped by the conditions of illness appropriate to their respective cultures. Lastly, I discuss the way in which both authors understand and represent sickness, as well as their respective therapies, in terms of a particular metaphoric construct: for Donne, it is the analogy between illness of the body and illness of the soul; for Ryan it is the analogy between illness and war. The stance of each towards his illness is conditioned by this metaphoric model: Donne's is one of acceptance, of conforming to the will of God; Ryan's is one of resistance, of fighting heroically until the very end. Thus these metaphors are functional as well as aesthetic: they serve as figural modalities whereby the patient/author hopes to transcend his illness. PMID- 11608481 TI - The consequences of consensus: American health policy in the twentieth century. AB - For most of the twentieth century the central theme in the history of health policy in the United States was the elaboration and implementation of a consensus that health services should be organized in regional hierarchies. This consensus was based on shared beliefs about how medical advances were made and disseminated. Hierarchical regionalism became national health policy in several stages that culminated in the 1960s. Since the 1970s, however, the national policy of hierarchical regionalism has been eroded by the unexpected consequences of its success. PMID- 11608483 TI - [Not Available]. PMID- 11608484 TI - [Not Available]. PMID- 11608485 TI - [Not Available]. PMID- 11608486 TI - [Not Available]. PMID- 11608487 TI - [Not Available]. PMID- 11608489 TI - [Not Available]. PMID- 11608488 TI - [Not Available]. PMID- 11608490 TI - [Not Available]. PMID- 11608491 TI - [Not Available]. PMID- 11608492 TI - [Not Available]. PMID- 11608493 TI - [Not Available]. PMID- 11608495 TI - [Not Available]. PMID- 11608494 TI - [Not Available]. PMID- 11608496 TI - [Not Available]. PMID- 11608497 TI - [Not Available]. PMID- 11608499 TI - [Not Available]. PMID- 11608498 TI - [Not Available]. PMID- 11608501 TI - [Not Available]. PMID- 11608500 TI - [Not Available]. PMID- 11608502 TI - [Not Available]. PMID- 11608503 TI - [Not Available]. PMID- 11608504 TI - [Not Available]. PMID- 11608505 TI - [Not Available]. PMID- 11608506 TI - [Not Available]. PMID- 11608507 TI - [Not Available]. PMID- 11608509 TI - John B. Watson remembered: an interview with James B. Watson. PMID- 11608513 TI - [Not Available]. PMID- 11608514 TI - [Not Available]. PMID- 11608515 TI - [Not Available]. PMID- 11608516 TI - [Not Available]. PMID- 11608517 TI - [Not Available]. PMID- 11608518 TI - [Not Available]. PMID- 11608520 TI - [Not Available]. PMID- 11608519 TI - [Not Available]. PMID- 11608521 TI - [Not Available]. PMID- 11608522 TI - [Not Available]. PMID- 11608523 TI - [Not Available]. PMID- 11608524 TI - [Not Available]. PMID- 11608525 TI - [Not Available]. PMID- 11608526 TI - [Not Available]. PMID- 11608527 TI - Telling likely stories: the rhetoric of the New Psychology, 1880-1920. PMID- 11608528 TI - From separation to division: the origins of two psychological associations in South Africa. PMID- 11608529 TI - [Not Available]. PMID- 11608530 TI - [Not Available]. PMID- 11608531 TI - [Not Available]. PMID- 11608532 TI - [Not Available]. PMID- 11608533 TI - [Not Available]. PMID- 11608534 TI - [Not Available]. PMID- 11608535 TI - [Not Available]. PMID- 11608536 TI - [Not Available]. PMID- 11608537 TI - [Not Available]. PMID- 11608538 TI - [Not Available]. PMID- 11608539 TI - [Not Available]. PMID- 11608543 TI - [Not Available]. PMID- 11608540 TI - [Not Available]. PMID- 11608545 TI - [Not Available]. PMID- 11608544 TI - [Not Available]. PMID- 11608547 TI - [Not Available]. PMID- 11608546 TI - [Not Available]. PMID- 11608548 TI - [Not Available]. PMID- 11608549 TI - [Not Available]. PMID- 11608550 TI - [Not Available]. PMID- 11608551 TI - [Not Available]. PMID- 11608552 TI - [Not Available]. PMID- 11608558 TI - Melancholia and partial insanity. AB - In the medical literature of the eighteenth century melancholia came to be defined as partial insanity. Seventeenth-century English law introduced the term and influenced later forensic concerns about the concept. But the history of melancholia reveals a gradual development of such a concept of limited derangement associated with the delusions usually cited in accounts of this disease. In the early nineteenth century the relationship of melancholia and this concept weakened and was gradually abandoned, the content of the syndrome of melancholia was reduced, and out of this complex process emerged the notion of monomania. PMID- 11608560 TI - Alphonse de Candolle, Francis Galton, and the early history of the nature-nurture controversy. PMID- 11608562 TI - The capture of the invisible. For a (pre)history of psychology in eighteenth century France. PMID- 11608568 TI - [Not Available]. PMID- 11608569 TI - [Not Available]. PMID- 11608570 TI - Psychology at Michigan: the Pillsbury years, 1897-1947. PMID- 11608572 TI - Erik H. Erikson's America: the political implications of ego psychology. PMID- 11608573 TI - Demonology and science during the scientific revolution. PMID- 11608574 TI - Floyd H. Allport and the launching of modern social psychology. PMID- 11608575 TI - Mesmer's failure: sex, politics, personality, and the Zeitgeist. PMID- 11608576 TI - In memoriam: Robert I. Watson, Sr. 1909-1980. PMID- 11608578 TI - Tabula rasa--its origins and implications. PMID- 11608579 TI - Psychology and philosophy: towards a realignment, 1905-1935. PMID- 11608580 TI - Pre-war conformity research in social psychology: the approaches of Floyd H. Allport and Muzafer Sherif. PMID- 11608581 TI - Early developmental theories: a brief review of attempts to organize developmental data prior to 1925. PMID- 11608582 TI - The history of the concept of motivation. PMID- 11608583 TI - The origins of the psychological corporation. PMID- 11608586 TI - The Edison questionnaire. PMID- 11608585 TI - The dream in periodical literature: 1860-1910. PMID- 11608588 TI - The historical roots of contemporary empathy research. PMID- 11608589 TI - The Southern Society for Philosophy and Psychology at midstream. PMID- 11608590 TI - Robert M. Ogden and Gestalt psychology in America. PMID- 11608591 TI - The Kelvin dictum and social science: an excursion into the history of an idea. PMID- 11608597 TI - [Not Available]. PMID- 11608599 TI - [Not Available]. PMID- 11608598 TI - [Not Available]. PMID- 11608600 TI - [Not Available]. PMID- 11608601 TI - [Not Available]. PMID- 11608602 TI - [Not Available]. PMID- 11608604 TI - [Not Available]. PMID- 11608603 TI - [Not Available]. PMID- 11608605 TI - [Not Available]. PMID- 11608606 TI - [Not Available]. PMID- 11608607 TI - [The fortieth anniversary of the creation of the faculty of periodontics]. PMID- 11608608 TI - [A century of dental instruction]. PMID- 11608609 TI - [Historians, bibliographies, and museums: a history of dentistry]. PMID- 11608610 TI - [A faculty and its statutes]. PMID- 11608611 TI - [The function of dentistry in the army (according to the address of an Argentine military physician in 1921)]. PMID- 11608612 TI - [The course program in laboratory techniques- for dentists. Fifty years since its establishment]. PMID- 11608613 TI - [The Pecotche sisters in Argentine dentistry]. PMID- 11608614 TI - [Forensic dentistry as a branch of forensic medicine]. PMID- 11608617 TI - Sex education in Cuba: an interview with Dr. Celestino Alvarez Lajonchere [interview by Elizabeth Fee]. PMID- 11608621 TI - [Not Available]. PMID- 11608623 TI - [Not Available]. PMID- 11608622 TI - [Not Available]. PMID- 11608624 TI - [Not Available]. PMID- 11608625 TI - [Not Available]. PMID- 11608626 TI - [Not Available]. PMID- 11608627 TI - [Not Available]. PMID- 11608628 TI - [Not Available]. PMID- 11608629 TI - [Not Available]. PMID- 11608630 TI - [Not Available]. PMID- 11608634 TI - Medicine, the art of humaneness: on ethics of traditional Chinese medicine. PMID- 11608637 TI - The ethics of impaired physicians: Wolfe's Dr. McGuire and William's Dr. Rivers. PMID- 11608641 TI - The moral vision of The Alchemist: tricks, psychotherapy, and personality traits. PMID- 11608642 TI - Humanism and ethics in Roman medicine: translation and commentary on a text od Scribonius Largus. PMID- 11608646 TI - The changing character of the medical profession. PMID- 11608643 TI - Fictional doctors and the evolution of medical ethics in the United States, 1875 1900. PMID- 11608652 TI - "Hope in another direction": compensation for work-related illness among women, 1900-1960 -- Part I and Part II. PMID- 11608656 TI - Viral oncogenesis and cell differentiation. The contributions of Charlotte Friend PMID- 11608659 TI - Lady Rokujo's ghost: spirit possession, Buddhism, and healing in Japanese literature. PMID- 11608676 TI - The theory of panoptical control: Bentham's panopticon and Orwell's Nineteen eighty-four. PMID- 11608677 TI - Making intelligence functional: Walter Dill Scott and applied psychological testing in World War I. PMID- 11608686 TI - [Robespierre's jaw: thoughts on a historic episode, on the bicentennial of the French Revolution]. PMID- 11608687 TI - [Notes on the history of dentistry]. PMID- 11608692 TI - Forty years of children's dentistry in Northumberland. PMID- 11608689 TI - London dentists 1800-1811: a listing from the trades directories in the Guildhall Library. PMID- 11608693 TI - A history of dentistry and diet in the Falkland Islands. PMID- 11608697 TI - Francis Hay Thomson: a man of art and science. PMID- 11608698 TI - Dental Historian cover illustration. PMID- 11608699 TI - Frederick Breese and the Leigh family. PMID- 11608700 TI - History of dentistry: articles from journals received in the BDA Library September 1988-August 1989 PMID- 11608701 TI - [Notes on the history of dentistry: the 17th century (continued)]. PMID- 11608702 TI - [Dental periodicals in the Argentine Republic]. PMID- 11608703 TI - [Not Available]. PMID- 11608704 TI - [Not Available]. PMID- 11608710 TI - Brunelleschi's trick--a myth. PMID- 11608713 TI - The development of biomedical ethics in the United States. PMID- 11608723 TI - [Not Available]. PMID- 11608724 TI - [Not Available]. PMID- 11608725 TI - [Not Available]. PMID- 11608726 TI - [Not Available]. PMID- 11608727 TI - [Not Available]. PMID- 11608728 TI - [Not Available]. PMID- 11608729 TI - [Not Available]. PMID- 11608730 TI - [Not Available]. PMID- 11608731 TI - [Not Available]. PMID- 11608732 TI - [Not Available]. PMID- 11608733 TI - [Not Available]. PMID- 11608734 TI - [Not Available]. PMID- 11608735 TI - [Not Available]. PMID- 11608736 TI - [Not Available]. PMID- 11608737 TI - [Not Available]. PMID- 11608738 TI - [Not Available]. PMID- 11608740 TI - The historical writings of Lilian Lindsay. PMID- 11608746 TI - [Museums of the history of the health sciences]. PMID- 11608747 TI - [Statutes of the Faculty of Medicine of Buenos Aires]. PMID- 11608748 TI - [Forensic dentistry in the history of catastrophes and well-known homicides]. PMID- 11608749 TI - [Women in dentistry in Argentina: International Day of the Woman: March 8]. PMID- 11608750 TI - [History of dentistry: historians, bibliographies, museums (continued)]. PMID- 11608751 TI - [Dental extraction in China]. PMID- 11608752 TI - [Historical outlines of the training for dental assistants]. PMID- 11608753 TI - [The hardships of Argentine dentistry]. PMID- 11608755 TI - [The Coquets. Tomas Coquet, first dental examiner in 1844, on the centennial of his death (1816-1887)]. PMID- 11608754 TI - [Concrete approaches by the American herbalist to Spanish pharmacology according to the chroniclers of the Indies]. PMID- 11608757 TI - [Not Available]. PMID- 11608756 TI - [Not Available]. PMID- 11608758 TI - [Not Available]. PMID- 11608759 TI - [Not Available]. PMID- 11608760 TI - [Not Available]. PMID- 11608761 TI - The life and career of George Sarton: the father of the history of science. PMID- 11608762 TI - Gabriele Grafin von Wartensleben and the birth of Gestaltpsychologie. PMID- 11608763 TI - Experimental introspection and religious experience: the Dorpat school of religious psychology. PMID- 11608764 TI - Mach's "Psychology of investigation." PMID- 11608769 TI - The 1895 debate on the origins of crowd psychology. PMID- 11608766 TI - Dream dialogue and retrogression: neurolinguistic origins of Freud's "replay hypothesis." AB - At the phenomenological level, Sigmund Freud in the Traumdeutung presents dream speeches that are ubiquitous, and syntactically and pragmatically usually well formed (despite occasional lexical anomalies), while at the generative level Freud maintains that these are playbacks, devoid of linguistic creativity, and as such do not violate the theoretically "primary-process," nondiscursive nature of the dreamwork. Neither anecdotal data nor recent systematic experimental evidence lend the "replay hypothesis" convincing support, however. This hypothesis may (like many other aspects of his dream theory) have its particular antecedents in the theoretical constraints of Freud's protopsychoanalytic "Project for a Scientific Psychology." In fact, the hypothesis can be reconciled with the neurological mechanisms of the "Project," though it cannot be specifically derived from them. Freud utilized the concept of functional retrogression from his still earlier, prepsychoanalytic work On Aphasia, thus effecting the best compromise he could between the constraints of his overall dream theory derived from the "Project" and his own observations on the phenomenology of dream speech. PMID- 11608770 TI - On the origins of Titchener's experimentalists. PMID- 11608771 TI - "I would eagerly leave Neuchatel ..." A 1912 letter by Jean Piaget with an introduction and notes. AB - A 1912 letter from fifteen-year-old Jean Piaget (1896-1980) to the director of the Museum of Natural History of Geneva illustrates Piaget's precocious integration into a community of professional naturalists, and reveals his hitherto unknown plan to study medicine. It is not certain whether he actually intended to realize that plan. An essential biographical fact, however, is that he finally left natural history by turning to philosophy rather than to medicine. PMID- 11608774 TI - Ralph Franklin Hefferline: the Gestalt therapist among the Skinnerians or the Skinnerian among the Gestalt therapists? PMID- 11608775 TI - A note on a Norwegian precursor of Charles Spearman. PMID- 11608776 TI - A note on the historical literacy of first-year graduate students in psychology. PMID- 11608777 TI - The Scottish enlightenment and its mixed bequest. PMID- 11608778 TI - Koffka's Principles after fifty years. PMID- 11608781 TI - Foucault's critique of psychiatric medicine. AB - From his earliest published work, Mental Illness and Personality (1954), to his last project, The History of Sexuality, Foucault was critical of the human sciences as a dubious and dangerous attempt to model a science of human beings on the natural sciences. He therefore preferred existential therapy, which did not attempt to give a causal account of human nature, but rather described the general structure of the human way of being and its possible distortions. Foucault focused his attack on psychiatry, which claimed to have an explanation of normal and abnormal functioning of the personality modeled on medicine. Freud typified for him this deep mistake which he traced first to the Kantian understanding of human beings as transcendental/empirical doubles which must think their own unthought, and then later to the gradually developing confessional practices which lead people in our culture to try unsuccessfully to put all their desires into words so as to conform to the norms of psychoanalysis which in turn are based on an account of sexuality as a cause of personality. Foucault proposed his genealogical account of how our culture arrived at this view of man as sexual being as a form of therapy which was to help us free ourselves from this restrictive self-interpretation. PMID- 11608784 TI - Confession and signification: the systematic inscription of body consciousness. PMID- 11608788 TI - Brunonianism under the bed: an alternative to University Medicine in Edinburgh in the 1780s. PMID- 11608793 TI - The black scholar and intelligence testing: the case of Horace Mann Bond. PMID- 11608794 TI - Deviance and social science: the instructive historical case of Pitirim Sorokin. PMID- 11608795 TI - "Johnny's a gentleman, but Jimmie's a mug": press coverage during the 1930s of Myrtle McGraw's study of Johnny and Jimmy Woods. PMID- 11608812 TI - A personal view of the history of American psychology. PMID- 11608813 TI - Recognition for women: the problem of linkage. PMID- 11608814 TI - The European influence on American psychology: 1892 and 1942. PMID- 11608797 TI - [Not Available]. PMID- 11608815 TI - James McKeen Cattell, the New York Academy of Sciences, and the American Psychological Association, 1891-1902. PMID- 11608816 TI - G. Stanley Hall and Company: observations on the first 100 APA presidents. PMID- 11608817 TI - Sitzfleisch 2: the Platzgeist and cognitive environmental psychology. PMID- 11608818 TI - An epistemological critique of experimentalism in psychology; or, Why G. Stanley Hall waited until William James was out of town to found the American Psychological Association. PMID- 11608819 TI - A history of the New York Branch of the American Psychological Association, 1903 1935. PMID- 11608820 TI - Joseph Jastrow: pioneer psychologist facing the "administrative peril". PMID- 11608823 TI - The neologism ontoi in Broussais's condemnation of medical ontology. AB - This note uses an analysis of Broussais's objection to medical ontology to suggest why Broussais's neologism ontoi is derived not from onta but from a conflation of onta and the plural of ogkos. For Broussais medical ontology, in contrast to philosophical ontology, always refers to abstract entities alleged to explain sensible symptoms, ogkoi, in the sense of indivisible particles in the writings of Lucretius and Epicurus, are such particles; onta are not. PMID- 11608824 TI - "To ask the suffrages of the patrons": Thomas Laycock and the Edinburgh Chair of Medicine, 1855. PMID- 11608825 TI - The new triad: responsibility, solidarity and subsidiarity. PMID- 11608826 TI - Limiting solidarity in the Netherlands: a two-tier system on the way. AB - Health care policy in the Netherlands has long been guided by the values of solidarity and equality. As a result of several forces, particularly the scarcity of resources, the retreat of the Welfare State and the introduction of market forces in health care, both values are increasingly under strain. Next to solidarity and equality, freedom of choice and financial responsibility are playing an important role in Dutch health care. Consequently, there is a growing division in Dutch health care between two tiers, one basic tier giving access to a basic package of services and a luxury tier giving access to a higher quality of care and to services not included in the basic package. The main thesis of the article is that a two-tier system is morally justified on the condition that the basic tier is universally accessible and is based on the value of humanitarian solidarity. PMID- 11608833 TI - (In) equality, (AB) normality, and the Americans with Disabilities Act. AB - The 1990 Americans with Disabilities Act enacted a conceptual shift in the meaning of 'disability.' Rather than defining 'disability' as a disadvantageous physical or mental deficit of persons, it codifies the understanding of 'disability' as a defective state of society which disadvantages these persons. In contrast, the standard medical model incorrectly conceptualizes disabled persons as biologically inferior, and thus confines them to the role of recipients of benevolence or care. Turning to an ethic of caring yields counter intuitive results that conflict with the conceptual apparatus of the ADA. It is argued that in order to liberate social thought from this medical model and thus move the disabled from being socially marginalized to being socially enabled, one must re-conceptualize current practice by adopting the ADA's conceptual framework. PMID- 11608837 TI - From Galen to magnetic resonance: history of medicine in Latin America. AB - Spanish influence in the New World was particularly acute in the areas of medicine and medical education. From the time of Columbus forward prominent medical experts journeyed to Latin America establishing medical schools and research centers. This essay chronicles the history of Latin America with a strong focus on the physicians and scientists who brought modern scientific medicine, as it was then known in Western Europe, to the Americas. PMID- 11608840 TI - Humanistic and social education for physicians: the experience of the Colombian School of Medicine. AB - Medical education at the Colombian School of Medicine has undergone a reconceptualization and reorganization so as to encompasses three fundamental elements of medical practice: 1) development of general abilities and standards necessarky for appropriate professional medical practice; 2) technical education which makes it possible to utilize the bases that science and technology have provided for the development and application of knowledge, and in turn, to expand this base through research and development; and 3) humanistic education to guide students into ethical professional practice. PMID- 11608842 TI - [Not Available]. PMID- 11608843 TI - [Not Available]. PMID- 11608844 TI - [Not Available]. PMID- 11608845 TI - [Not Available]. PMID- 11608852 TI - Museu Salles Cunha. PMID- 11608856 TI - [Remembering E.H. Ackerknecht on the 10th anniversary of his death]. PMID- 11608846 TI - Eloge: Charles Scribner, Jr., 13 July 1921-11 November 1995. PMID- 11608857 TI - [Multiple births in the medical texts of antiquity]. AB - Ancient medical writers and biologists elaborated different theories to explain the phenomenon of multiple births. The earliest extant texts are in the Hippocratic collection and in the physiological treatises of Aristotle. They express opposed ideas: for the Hippocratics multiple births are the result of an ideal conception, for Aristotle they are regarded as anomalies associated with notions of monstrosity and excess. These views shed light on ancient collective imagery. Three themes in particular are found in non-medical literature and iconography: twin birth as a model of ideal fecundity, the ambiguous status of twins of different sexes, and the relation of multiple births to monstrosity and animality, as evidenced by the motif of twins born from one egg. PMID- 11608858 TI - [Witches' ointments and love-potions: a contribution to the cultural history of nightshades]. AB - The nightshades (solanaceae) were used as intoxicants since the ancient civilizations and are still in use today. Their alkaloids, atropine and scopolamine, were the major active substances of the ointments of witches, of medieval "anaesthetics", and of modern poisons for murder. In a medium dose-range the predominant symptoms are hallucinations and illusions. This explains the use of nightshades in fortune-telling and religious rituals. In higher doses the alkaloids produce coma and apnea. Scopolamine enjoyed a particular popularity as a poison for murder. In the 19th century the nightshade alkaloids were also in clinical use. This article focusses on the medical history of the psychosis due to intoxication with solanaceae. PMID- 11608859 TI - [Gottlieb Burckhardt's (1836-1907) contribution to psychosurgery: medicohistorical and ethical aspects]. AB - Psychosurgery is defined as the practice of destroying or removing healthy brain tissue in order to change behaviour. Although the neurologist Egas Moniz (1874 1955) is occasionally said to be the founder of psychosurgery, the first psychosurgical operations were performed by Gottlieb Burckhardt, a Swiss psychiatrist who practised in the late 19th century. In 1891 he reported the results of topectomies on six patients suffering from different psychiatric diseases. The aim of the present article is to illuminate the life of Burckhardt as well as his contribution to psychosurgery. Special attention is paid to the ethical aspects of his operative interventions. First of all, we have to make allowance for the fact that the therapeutic chances in 19th century psychiatry were quite poor. Therefore, Burckhardts topectomies might have been seen as a new and hopeful way of therapy. But by analysing Burckhardt's case reports, it becomes clear that he did not intend to cure his patients but only to ameliorate their disturbing behaviour and their non-compliance. Burckhardt himself tried to justify the immense risk of his operations by referring to the necessity of progress in medicine. Although Burckhardt spoke of promising improvements, his positive appraisal can hardly be maintained. For this and other reasons, his contemporary colleagues mainly declined his methods and reports. PMID- 11608860 TI - [Interpreting cellular inclusions: a contribution to the history of virology]. AB - In the middle of the 19th century cell inclusions were observed with increasing frequency in more and more diseases and were closely scrutinized by researchers working in different fields. Because of their distinct viewpoints, however, the various authors came inevitably to different conclusions. The morphologists interpreted the inclusions as artefacts or degenerative changes, the etiologists, on the other hand, took them for pathogenic protozoa, for cellular lesions inflicted by invisible agents or, conversely - for aggregated products of the cellular defense. Various morphological, parasitological and bacteriological methods have been used to clear up the pros and cons of these hypotheses. It was the rapid progress realized in virology at the middle of the 20th century that finally brought to light their real significance. PMID- 11608870 TI - The tragedy of puerperal fever. PMID- 11608871 TI - Chiropractors -- healers or quacks? Part 1: The 80-year war with science PMID- 11608872 TI - The power of the forceps: a comparative analysis of the midwife--historically and today. PMID- 11608873 TI - A historical perspective on women's health care--female circumcision. PMID- 11608878 TI - Margaret Sanger and the birth control movement. PMID- 11608879 TI - Mercury poisoning and birth defects in Japan. PMID- 11608881 TI - Abortion in early America. PMID- 11608882 TI - The statistical case for elimination of the midwife: fact versus prejudice, 1890 1935 (part 2). PMID- 11608884 TI - The (Woman's) Medical College of Pennsylvania. PMID- 11608886 TI - ADA historical report--dental insurance: how it started and where it is today PMID- 11608885 TI - Scott Adams: A continuing force in the age of discontinuity. PMID- 11608889 TI - Physician awareness of the contents of the Hippocratic Oath. PMID- 11608894 TI - Walker Percy's Thanatos syndrome and the temper of suburban America. PMID- 11608890 TI - Lay midwifery--still an 'illegal' profession AB - This article reviews the process by which a health collective has organized the home birth service. The legal and political problems and ramifications of the Collective's actions are discussed. PMID- 11608895 TI - Florence Nightingale's calling. PMID- 11608896 TI - Hero and heretic: William Osler's interest in Michael Servetus. PMID- 11608897 TI - Dr G Caruana Scicluna, the first Maltese microbiologist. PMID- 11608899 TI - Aldo Castellani FRCP (1877-1971) and the founding of the Ross Institute & Hospital for Tropical Diseases at Putney. PMID- 11608902 TI - An emigre physician: Dr David (Didier) Roth, homoeopath, art collector, and inventor of calculating machines. PMID- 11608911 TI - Andre Gratia (1893-1950): forgotten pioneer of research into antimicrobial agents. PMID- 11608912 TI - Dr. Gustav Nachtigal (1834-1885): a contribution to the history of medicine in mid-nineteenth-century Africa. PMID- 11608915 TI - Physician of Stratford. Dr. John Hall: his life, times and patients. PMID- 11608920 TI - John Snow MD (1813-1858). Part II: becoming a doctor - his medical training and early years of practice. PMID- 11608936 TI - Crossing boundaries: making connectiions. AB - This Presidential address to the International Society for the History of the Neurosciences was given at Lausanne in September 1999. It reviews some of the contributions given at that conference and provides a brief overview of the history of the mind-brain problem in Western neuroscientific thought. PMID- 11608928 TI - Plasticity and neuroplasticity. PMID- 11608937 TI - Proceedings of the Fourth Annual Meeting of the European Association for the History of Psychiatry (EAHP), the European Club for the History of Neurology (ECHN), and the International Society for the History of the History of the Neurosciences (ISHN). September 13-18, 1999 Zurich and Lausanne, Switzerland. PMID- 11608939 TI - The neurophysiological aspects of Pavlov's theory of higher nervous activity: in honor of the 150th anniversary of Pavlov's birth. AB - Whereas Ivan P. Pavlov (1849-1936) is well-known for his work on classical conditioning, his contribution to neuroscience, particularly his interest in the function of neural centers in the central nervous system, is not as widely known. During the last three decades of his life, Pavlov explored cortical processes by salivary reflex conditioning, a method he used to develop his theory of higher nervous activity. This theory outlined the function of the brain in higher organisms in their interaction with the changing environmental contingencies. As early as 1908, Pavlov outlined a neurophysiological theory as the physiological basis of his theory of higher nervous activity. He maintained that the neural processes of excitation and inhibition irradiate and concentrate among the cortical neural centers. Most of all, he emphasized the plasticity of the cortex in higher organisms' in the Darwinian struggle for existence. PMID- 11608940 TI - Five scientists at Johns Hopkins in the modern evolution of neuroscience. AB - Neuroscience's evolution at Johns Hopkins, from neurophysiology to the new field of neurobiology, though unplanned, was rapid and important. Beginning in 1933 when Philip Bard became professor of physiology at Johns Hopkins, members of his department concentrated initially on neuroanatomical control of placing reactions and sexual activity. Vernon Mountcastle, extending available techniques, discovered vertical somato-sensory columns in the 1950's. Stephen Kuffler, who arrived at Hopkins in 1947, was a pioneer in single unit microelectrode recording techniques. He soon attracted scientists from all over the world to his laboratory. Among them, Torsten Wiesel and David Hubel discovered vertical neuronal columns in the visual cortex. During several decades at Johns Hopkins, these five scientists set extremely high scientific standards and established a climate of inquiry in which ideas were shared and young scientists encouraged. They contributed significantly to the emerging discipline of neuroscience. PMID- 11608941 TI - Luigi Luciani and the localization of brain functions: Italian research within the context of European neurophysiology at the end of the nineteenth century. AB - Luigi Luciani, the Italian physiologist who lived during the second half of the nineteenth century and the early years of the twentieth, is generally remembered for his studies on the cerebellum, the physiology of the heart, the respiratory system and on fasting. Less well known is the experimental research he carried out in the field of cerebral localization. It should however be pointed out that, as a result of his work in experimental neurophysiology between the years 1875 and 1885, Luciani was perfectly familiar with the latest findings on the relationship between brain and behavioral functions, but above all he was led by this work to develop an interesting model for the description of brain functions. He refined this model in a close dialectic relationship, of comparison and contrast, with the theories of the leading European neurophysiologists of his time - either those who favored a localizationistic explanation of the brain's functions or those who opposed this view. This paper gives a quick presentation of Luciani's experimental work on the functions of the brain as well as what he thought of the question of cerebral localization. His localizationistic model is compared - both in its general characteristics and in its specific details - with other models which had been proposed during the same years by the outstanding European physiologists of the day like Goltz, Ferrier, and Munk. Luciani's epistemological foundations, as well as his experimental methodology, are analyzed within the context of his wider theoretical ideas about how nervous and psychic activity were linked, with his ideas on physiology, and more in general in relation to his view of man's biological place in the rest of the living world. On the basis of this analysis, the state of the experimental work being done in Italy by Luciani is placed within the European context of neurophysiology in which Luciani was an outstanding figure. PMID- 11608942 TI - Narcolepsy -- cataplexy and psychoanalytic theory of sleep and dreams. AB - Narcolepsy had been documented some twenty years before the psychoanalytic movement, emphasizing the central role of sleep and dreams in the understanding of mental health, offered an entirely novel theory of its aetiology. And when the full range of the behavioral aspects of the condition were documented, it was obvious that intense psychoanalytic interest in it was inevitable. Unfortunately, even mainstream neurology, lacking any rival physiological explanation, for a time tended to entertain a definite role for such beliefs, at least in some cases. However, such a theory involving outre concepts of repressed, guilt-ridden sexual drives as an explanation of the behavioral aspects of narcolepsy cataplexy, of necessity simply added to the burdens of the sufferer. For it became clear that the condition by itself produced enough psycho-social problems without further adding to them. This historical note details the persistence of this misconceived theory up to the later decades of this century, and the burden that it placed upon those who suffered from this condition. PMID- 11608944 TI - Bigger's keratoplasty experiments. PMID- 11608945 TI - The guts of the matter. Infusoria from Ehrenberg to Butschli: 1838-1876. PMID- 11608946 TI - From unit to unity: protozoology, cell theory, and the new concept of life. PMID- 11608947 TI - Protozoa as precursors of metazoa: German cell theory and its critics at the turn of the century. PMID- 11608949 TI - The protozoon and the cell: a brief twentieth-century overview. PMID- 11608950 TI - Health sciences in al-Andalus, Tunisia and Egypt during 10-12th centuries. PMID- 11608951 TI - Persian translation of al-Adwiyah al-Qalbiyah of Ibn Sina. PMID- 11608952 TI - An introduction to the early history of the Caesarean operation and its illustrations. PMID- 11608953 TI - Towards victory in Europe: the battle for Walcheren (part II). PMID- 11608954 TI - A medical student at Leiden and Paris: William Sinclair (1736-38): part III. PMID- 11608955 TI - Andrew Combe (1797-1847): Edinburgh physician and phrenologist. PMID- 11608956 TI - Circumstances surrounding the examination of the skull and brain of George Combe (1788-1858) advocate of phrenology. PMID- 11608957 TI - Marital fertility control among the Qing nobility: implications for two types of preventive check. AB - Demographers, as early as Malthus, have assumed that the preventive checks, delayed marriage and celibacy, were absent in traditional China. In this paper on the Qing (1644-1911) imperial lineage, we demonstrate that, instead, there may have been a different, more 'modern' preventive check: fertility control within marriage. Marital fertility of lineage couples during the eighteenth and nineteenth centuries was low to moderate. Such low fertility was the product of three behavioural mechanisms: late starting, early stopping and, most significantly, long spacing. Couples apparently regulated their fertility according to their economic resources and the sex of their surviving children. Moreover, they did so, we suggest, by regulating their coital frequency. Deliberate fertility control, in other words, was already within the 'calculus of conscious choice' for some Chinese well before this century. the speed of contemporary sinitic fertility transitions may accordingly be attributed to the fact that they did not require a change in attitudes, only the diffusion of new incentives and effective technologies. PMID- 11608958 TI - Urban-rural differentials in infant mortality in Victorian England. AB - This paper examines the magnitude of urban-rural differentials in infant mortality in England during the nineteenth and early twentieth centuries and also compares the timing of decline for a selection of towns of varying size, and their immediate rural hinterlands. Most towns continued to experience short-term fluctuations in infant mortality until the very end of the nineteenth century; however, in some of the adjacent rural communities--where levels of infant mortality were much lower--conditions were sufficiently favourable to allow a continuous decline in infant mortality from at least the 1860s, if not before. The final part of the paper considers the causes of these patterns and their implications for explanations of infant mortality decline. PMID- 11608959 TI - Child mortality in Malaysia: explaining ethnic differences and the recent decline. AB - Infant and child mortality rates have dropped sharply for all ethnic groups in Malaysia between 1950 and 1988, but persistent ethnic differences remain. In this article we assess the contribution of several potential reasons both for the decline and the remaining differences between the Malay and Chinese sub populations. Increased use of health inputs is found to explain a substantial part of the decline, but increased education of mothers, and income growth are also important. Longer spacing between births, and, higher average age at birth as a result of lower fertility and higher age at marriage provide only a marginal direct contribution to the fall in mortality. We find that lower mortality among the Chinese is accounted for by their higher incomes and greater propensty to purchase medical care. We also control for self-selection among users of medical care, and find that those who use health care in Malaysia tend to be subject to higher-than-average risks. PMID- 11608960 TI - Fertility decline in Punjab, India: parallels with historical Europe. AB - Two interesting features emerge from this study of fertility behaviour in Punjab. First, it brings out the common features of peasant life and demographic behaviour found in this developing-country setting and in historical Europe. As in much of Europe, marriage was regulated to adjust to the availability of land and other resources. It is interesting to note that the operation of this 'nuptiality valve' was quite consistent with a system of joint families and partible inheritance. Secondly, the findings suggest that we need to re-define what we understand to be the features of socio-economic development which are crucial for fertility decline. Fertility began to decline steadily in this part of Punjab as early as 1940, at a time when the society was overwhelmingly agrarian, illiterate, and infant mortality was high with no access to modern contraceptive technology, as in historical Europe. The onset of the decline was brought about by development interventions which stabilized fluctuations in crop yields and mortality, thus radically improving stability of people's expectations. This study also points out the inapplicability of Mamdani's theories of fertility behaviour to the people he studies. PMID- 11608961 TI - The 'smooth cool men of science': the feminist and socialist response to vivisection. PMID- 11608962 TI - Freud's Group psychology and the history of the crowd. PMID- 11608963 TI - Pretransition marital fertility variation over time: was there deliberate control in England? AB - An important line of research concerning historical fertility patterns in currently developed countries of Europe has concluded that, prior to the fertility transition, marital fertility was essentially constant over time, and deliberate fertility control was virtually unknown. It has been argued that variations over time in overall fertility were largely the consequence of variations in nuptiality. Other researchers have challenged these views and present evidence for the existence of a significant minority of fertility controllers in pretransition populations. In this article, we find support for this second view and argue that (1) there was significant, non-random variation in marital fertility over time, prior to the transition; (2) in many cases, this variation in marital fertility was large relative to contemporaneous variations in nuptiality; and (3) in a substantial minority of the cases, the variation over time in pretransition marital fertility was so large that it is suggestive of deliberate fertility control. Thus, our findings question the view of fertility transition as an innovation in deliberate marital fertility control. While most of our evidence is based on data from England and Wales, we find corroboration of our key results in other European data. PMID- 11608964 TI - Surgery at the service of theology: postmortem cesarean sections in Puerto Rico and the Royal cedula of 1804. PMID- 11608965 TI - Convict health on Norfolk Island, and mutiny and medicine - an International Conference on the History of Medicine. PMID- 11608966 TI - From a craft to a profession. PMID- 11608967 TI - From penicillin to DNA - a philatelic selection of Nobel Prize winners. PMID- 11608968 TI - Tibb-i Firoz Shahi by Shah Quli. PMID- 11608970 TI - Etiology of diseases in Unani medicine: a critical study. PMID- 11608969 TI - Tibb-i Firoz Shahi by Shah Quli. PMID- 11608973 TI - Physicians and medical sciences in Central Asia: during 15-16 centuries. PMID- 11608974 TI - Unani medicine during the reign of Qutb Shahi dynasty. PMID- 11608975 TI - Unani medicine during the reign of Qutb Shahi dynasty. PMID- 11608976 TI - Rashidud-din Fadlullah, a great Muslim historian and scientist of the early 14th century. PMID- 11608978 TI - Orientalists and the Islamic medicine. PMID- 11608979 TI - Surgical firsts in Arabic medical literature. AB - The contributions to surgery made by physicians writing in Arabic are enumerated and documented. The contributors include the following: Masarjuwayh, al-Razi, Ibn Sina, al-Zahrawi, Ibn Zuhr, al-Shirazi and Ibn al-Dhahabi. Excerpts from the works of most of these authors are given in English translation with references, short biographical notes and a discussion of each contribution. PMID- 11608980 TI - Surgical firsts in Arabic medical literature. PMID- 11608981 TI - Unmasking suffering's masks: reflections on old and new memories of Nazi medicine. PMID- 11608982 TI - The alarmed vision: social suffering and Holocaust atrocity. PMID- 11608983 TI - Motherhood and family health in early Arab medicine. PMID- 11608985 TI - Hakim 'Imaduddin Shirazi. PMID- 11608986 TI - Hakim 'Imaduddin Shirazi. PMID- 11608987 TI - An historical study of Abu Mansur Harawi's Kitab al-abniya. PMID- 11608990 TI - Tibb-i Shahabi: a rare medical treatise of Tughlaq period. PMID- 11608991 TI - Contribution of Hafiz Hasan Efendi to Islamic medical sciences with special reference to his unpublished works preserved in Turkey. PMID- 11608992 TI - Tansukh Nameh-i Ilkhani--a unique Persian work on gemology. PMID- 11608994 TI - The silent partner? The state's role in the formation of the Ontario chiropractic profession's identity. PMID- 11608993 TI - How the discovery of accidental childhood poisoning contributed to the development of environmentalism in the United States. PMID- 11608995 TI - The idea of alcoholism: changing perceptions of alcoholism and treatment in British Columbia, 1870-1988. PMID- 11608996 TI - "They could make their victims dull": genders and genres, fantasies and cures in Colonial Southern Uganda. PMID- 11608997 TI - Penetrating to the bosom of nature: Humphry Davy in the laboratory. PMID- 11608998 TI - Pills, profits and propriety: the early pharmaceutical industry in Britain. PMID- 11608999 TI - Doctors in the Great Famine, 1845-1850. AB - The medical services, like most others in Ireland, were swamped by the massive demands of the Great Famine and its accompanying disruptions, diseases and epidemics. They were not, however, 'drowned', due largely to the fortitude of the individual doctors, the remarkable robustness of many of the medical institutions, and the vigorous if often unpopular steps taken by the central board of health whose most assiduous member was Dominic John Corrigan. There was a heavy price, mortality amongst doctors was very high (in 1847 alone, at least 123 died of 'fever' contracted in the course of duty), and a basic reform--most of the 'medical charities' came to be permanently administered through the Poor Law machinery. PMID- 11609000 TI - Queen's College and Queen's University of Belfast 150th anniversary. PMID- 11609001 TI - Madness and politics: French nineteenth-century alienists' response to revolution. PMID- 11609002 TI - Changing diagnoses in Valkenberg Asylum, Cape Colony, 1891-1920: a longitudinal view. AB - This paper will examine changes made to diagnoses of patients admitted to Valkenberg Asylum, Cape Colony, during the period 1891-1920, in order to illustrate the ambiguous and shifting relationship between psychiatric theory and practice, in this colonial setting. The diagnostic profiles of Valkenberg patients make clear that the distinction between manic-depression and dementia praecox, established in theory by the end of the first decade of this century, was by no means clearly perceived by asylum practitioners. Racial attitudes affected diagnostic practice; these will be outlined. Valkenberg's case records will be used to illustrate interactions between the patient's history, race and gender, classificatory changes, and ambiguous presentation of symptoms. These records add an important diachronic perspective to the synchronic perspective contained in annual reports and lunacy registers. The implications of diagnostic changes for research which attempts retrospective diagnosis will be explored. PMID- 11609003 TI - The anhedonias: a conceptual history. AB - BACKGROUND: The term and concept of 'anhedonia' refer to a group of clinical phenomena whose common denominator is the complaint of a putative incapacity to 'experience pleasure". Linked to disorders such as schizophrenia and depression, anhedonia remains difficult to define and measure. METHOD: This paper explores the historical frames in which anhedonia was originally constructed; and is fully based on primary sources. It makes use of the 'conceptual method', i.e. it differentiates the history of the word from that of the behaviours and concepts involved. RESULTS: Historical analysis shows that the boundaries of 'anhedonia' have been fuzzy since the time of Ribot, and that this has made it conceptually unstable. One reason for this instability pertains to the fact that from the start its definition has been parasitical upon the (itself evolving) concept of 'pleasure'. Another that it is defined negatively, i.e. as a reduction or abolition in a putative unitary function. Yet another, that there is little evidence that anhedonia itself is a unitary phenomenon. CONCLUSIONS: It is concluded that at this stage it might be advisable to refer to the concept in the plural (the anhedonias); that a definition should be formulated that it is less dependent upon the ongoing concept of pleasure; and that far more empirical research is needed to find out whether anhedonia is more than a final common pathway. PMID- 11609004 TI - Notes on the historical vocabulary of neuroanatomy. PMID- 11609005 TI - Notes on the history of psychiatry in Malta. PMID- 11609006 TI - The survival of ancient medicine in modern French psychiatry. AB - Modern French psychiatry was born at the end of the eighteenth century. This medical specialty, which was separating from general medicine, had a foundation in ancient medicine. Ancient theories died slowly but not so surely. These strange theories will be considered useless and even dangerous by the modern reader but they enabled modern psychiatry to understand that madness existed, that it was a disease and a subject for research. So the insane person was no longer considered a criminal or possessed by the devil: he was, at last and at least, a patient. PMID- 11609007 TI - Research strategies in 'slow' infections in psychiatry. AB - The research processes in the elucidation of the causes of general paresis, the first slow infection in psychiatry, and of Kuru, the first slow virus infection in man, were considered. The errors and difficulties encountered may contribute to the formulation of research strategies for contemporary work on possible persistent infections with unknown viruses as a cause of psychiatric disorders. Clinical obsservation, bold hypotheses and methodological advances appear more valuable than diagnostic categorization in etiological research into psychiatric disorders. The low heuristic value of diagnosis is due to the lack of specificity of psychiatric symptoms and syndromes, especially in low grade organic disturbances. PMID- 11609008 TI - The contribution of Thomas Sydenham (1624-1689) to the evolution of psychiatry. PMID- 11609009 TI - The Symbolism of dream (1814) by Gotthilf Heinrich von Schubert: another link in the Aurea Catena. PMID- 11609010 TI - Maurice Dide (1873-1944): a forgotten hero of French psychiatry. PMID- 11609011 TI - The historiography of scientism: a critical review. PMID- 11609012 TI - Curing toothache on the stage? The importance of reading pictures in context. PMID- 11609013 TI - Dualism and the transformation of psychiatric language in the seventeenth and eighteenth centuries. PMID- 11609014 TI - Galvanic disciplines: the boundaries, objects, and identities of experimental science in the era of romanticism. PMID- 11609015 TI - The communications revolution in Italian science. PMID- 11609016 TI - Liberals, the progressive left, and the political economy of postwar American science: the National Science Foundation debate revisited. PMID- 11609017 TI - "New" trends in the history of molecular biology. PMID- 11609018 TI - Mitochondrial structure and the practice of cell biology in the 1950s. PMID- 11609019 TI - Richard Goldschmidt's "heresies" and the evolutionary synthesis. PMID- 11609020 TI - The origins of T. H. Huxley's saltationism: history in Darwin's shadow. PMID- 11609021 TI - A female contribution to early genetics: Tine Tammes and Mendel's laws for continuous characters. PMID- 11609022 TI - Essay review: biology and imperialism. PMID- 11609023 TI - Essay review: The history of scientific illustration. PMID- 11609024 TI - Doubtful sex: the fate of the hermaphrodite in Victorian medicine. PMID- 11609025 TI - The family, love, and suicide in early modern Geneva. AB - Analysis of criminal proceedings and death records for early modern Geneva reveals an explosion in suicides after 1750. New attitudes toward courtship, marriage, and the familly contributed to this dramatic increase, as unprecedented numbers of people took their lives because of family concerns, such as marital breakdown, unhapppy love stories, and deaths of family members. Greater interest in the companionate marriage was central to these changes. After 1750, marriage, even more than parenthood, offered immunity to suicide, as married people were underrepresented among those who took their lives. Although men constituted the large majority of suicides, women and men shared the growing emphasis on conjugal sentiment, which cut across class lines. PMID- 11609026 TI - Avicenna's contribution to the development and progress of medical sciences. AB - Avicenna was born in the village of Belkh near Bukhara in Persia. He was a very famous philosopher, wiseman and an efficient physician. He wrote more than one hundred books on all aspects and sciences known in his time i.e. philosophy, wisdom, religion, mathematics, sophism, literature, poetry and medicine. In medicine, the most celebrated of them is "Al-Qanun fil Tibb", which surpassed other similar books on medicine and considered the biggest medical encyclopaedia of his time. Those orientalists who believe in Greek medicine consider this book as the only textbook on the art of curing and recovery. PMID- 11609027 TI - Development of Unani medicine during Mughal period. AB - Unani medicine was introduced into India in the 7th century A.D. Its progress was not so significant during the reigns of Khiljis, Tughlaqs and Lodhis. Its real development took place during the Mughal period. Apart from the literary works done on the Unani medicine during this period, several hospitals were also established by Mughal emperors and nobles in various parts of the country. Development of Unani medicine in India during the Mughal period was superior both in quantity and quality as compared to the development made during the pre-Mughal period. PMID- 11609028 TI - Medicine through the ages. AB - History of medicine chronologically traces its development from guesswork about the actions of prehistoric man through the centuries to some aspects of the present day. The intellectual and cultural centres of the world have moved over time to time from place to place. In earlier times all knowledge was part of a conglomerate which one polymath might be able to master in a way no longer open to anyone now. The history of medicine through the ages has been presented here under different subdivisions, such as The Past, The Middle Ages, The Twelfth century Renaissance and Medicine and the Renaissance (Newton's century) etc. PMID- 11609029 TI - A journey through memory lane of history of tuberculosis in India. AB - Tuberculosis, an infectious disease has got a special place in the medical bibliography. Its history dates back to 5000 B.C. of neolithic period. Even in modern world with advancement of the knowledge of tuberculosis with specific drugs to treat and programmes for its prevention, this diseasse is top listed on public health problems in all the developing countries. Its sad impact was felt by the human race throughout the world and in all ages. Thus the people of all countries and so also India fought back against this disease. PMID- 11609030 TI - A brief history of Ayurveda in Hyderabad. AB - This article contains a brief history of Ayurveda in Hyderabad. It can be proudly stated that this system is prevailing here since foundation of this city in 1590 A.D. As it is said that the physicians of Ayurveda and Unani both were among the staff of the first general hospital of Hyderabad city 'Darush-shifa' which was constructed in 1595 A.D. After the Qutub Shahi period the rulers of Asafjahi dynasty also patronised this system. The physicians of this period not only run their clinics but they also teach this system to their pupils privately. Due to the efforts of some eminent Ayurvedic physicians, Ayurveda progressed well. The names and the photos of these physicians have been given in this article. Now this system has a good status here with well established college, hospital and research department etc. PMID- 11609031 TI - Dalhana. AB - Dalhana, the celebrated commentator of the Sushruta Samhita, and the author of 'Nibandha Sangraha' is one of the ancient luminaries of the Indian system of medicine. Dalhana perhaps can be counted among the few ancient luminaries who attained the fame and commanded respect from the intellectual circles with just a single work. His contribution to the ancient Indian system of medicine as the author of 'Nibandha Sangraha' is priceless. He belonged to an illustrious family of vaidyas of the 12th century. Patronised by the King Sahajapala Deva. Dalhana made an extensive study of the works of the authors who belonged to the period before him. He has also evidently undertaken extensive tours throughout the country to get himself acquainted with the prevalent traditions and the systems of medicine. PMID- 11609032 TI - Ancient Egyptian roots in the modern medical and pharmaceutical civilisation. AB - The Egyptian civilisation was long before any of the neighbouring countries. Medicine and pharmacy in ancient Egypt were deeply rooted since mellenia of years. The ancient Egyptian medical papyri, discovered more than a century ago, proved that the Egyptians were the first to attain civilisation, which was copied and adopted by all the neighbouring countries and not the reverse as believed by the Europeans that the ancient Greece was the cradle of civilisation. PMID- 11609033 TI - Al-Adwiyah Al-Qalbiyah: introduction and commentary. AB - Avicenna was a great scientist and philosopher of the 10th century A.D. He wrote about 456 books in various fields of learning. Al-Adwiyah Al-Qalbiyah is perhaps the most important work of Avicenna after Al-Qanun fil Tibb or canon of medicine. Like Al-Qanun, it was also very popular in Europe and was translated into Latin. It has also been translated in Turkish, Uzbbek, and later on in Persian and Urdu. PMID- 11609034 TI - Caduceus--an eastern view. AB - The Caduceus--the symbol of medical profession carries with its origin many concepts. The symbol has in its composition, parts totally unconnected to our physical body and yet it represents symbolically the art of healing. On the other hand, the symbol might have been to mean something else, invisible, located within our body which is beneficial for the human as a whole. Charles W. Leadbeater presented the concept of Kundalini as the basis for the symbol Caduceus. PMID- 11609035 TI - Social evolution of hospitals. How is it relevant for health policy? AB - There are different kinds of hospitals. Doctors and nurses are the most prominent and visible components of a hospital. Development of nursing profession and medical technology have been two very significant factors in making hospitals a viable proposition. The hospitals were to start with very much as social institutions. The social basis of hospitals continues to be valid today. In this way, it is tried in this paper to highlight the evolution of different types of hospitals as social and technological institutions with the help of existing literature on history of hospitals and professions associated with it. PMID- 11609037 TI - Medical stamps on stamps. PMID- 11609039 TI - Viewing urology through postage stamps and cancellations. PMID- 11609040 TI - A misleading cachet. PMID- 11609041 TI - Love of animals in veterinary medicine. PMID- 11609042 TI - Some early veterinary therapies. PMID- 11609043 TI - Norman Rockwell's illustration of pet care and veterinary medicine. PMID- 11609044 TI - Alar and apples: newspapers, risk and media responsibility. AB - During 1989, a major environmental and health risk issue, the spraying of Alar on apples, created a furor among the American people. After hearing charges from the Natural Resources Defense Council (NRDC) that eating Alar-laden apples significantly increased a child's risk of developing cancer, numbers of school districts dropped apples from their menus and parents poured apple juice down the drains. Apple sales plummeted. The NRDC's charges, which were disseminated by a well-planned and effective public relations campaign, brought counter-charges from the US environmental Protection Agency, which accused the NRDC of basing its study on poor data, among other things. The core of the dispute was in the risk figures and risk interpretations being used by each organization. PMID- 11609045 TI - Everybody, the historian, and the scientist. PMID- 11609046 TI - Changes in New Zealand pharmacy, 1935-1945. PMID- 11609047 TI - Arthur Cramp: quackery foe. PMID- 11609048 TI - Soldiers on the production line. PMID- 11609049 TI - The mission of social history of medicine: an historical view. AB - This paper analyses the shift in the Society for the Social History of Medicine from public health professionals to full-blooded approaches drawn from social history. The Bulletin of the Society reflected its vigorous interdisciplinary meetings programme: during the 1980s this matured into a fully fledged Journal and a monographs series as the Society took a crucial role in delivering the disciplinary functions of the history of medicicine. PMID- 11609050 TI - The social construction of medical knowledge. AB - The paper examines some of the ways in which a social constructionist perspective may be useful for social historians of medicine. It outlines the streams of thought that, over the last twenty years or so, have contributed to this perspective. Some of the problems and issues raised by social constructionism are considered. The relationships between the history of science and the history of medicine are discussed in order to clarify the extent to which the latter can and should be modeled on the former. I suggest that social constructionism is useful, partly because it gives weight to ideas, and that there is a potentially fruitful alliance to be considered between the social history of medicine and cultural history. PMID- 11609051 TI - The women of the family? Speculations around early modern British physicians. AB - In the extensively explored areas of professionalization, domestic ideology, and the relationships between women and medicine, the debate on the British case has given little consideration to issues of identity arising for the male medical practitioner as a result of family life. For the early modern period, these issues can be seen as among a broad-ranging set of problems posed by the female gender connotations of the medical role. Such problems were most pronounced for the elite physicians who sought membership of the London College of Physicians. Their attitudes and dilemmas are important because of their influence, over the long term, on the criteria for professionalization. Using biographical data, a contrast can be shown between the dynastic ideals of physicians, which stressed the male line, and the high incidence among such physicians of celibacy, childlessness, and small families. Families of origin of physicians, on the other hand, tended to be large. Assumptions about the role of women in medical care, especially in clerical and gentry families, entail a recognition of the possible influence of female relatives on the vocations of male physicians. Given the low status of women's work, physicians developed ambivalences which affected the construction of their identities, their families, and the passing on of their skills. PMID- 11609053 TI - Medicalization and secularization: the Jewish ritual bath as a problem of hygiene (Germany 1820s-1840s). AB - In the 1820s and 1840s the Jewish ritual bath in Germany was criticized on the basis of medical arguments. Associated with this critique were demands for a change in the traditional Jewish way of life in general, especially as concerning the Jewish religion. The new role assigned to religion can be seen as part of a process of 'secularization'. The criticism of the ritual bath was justified by medical arguments and entailed a demand for an extension of the medical sphere of competence, and thus formed part of a development described as 'medicalization'. An historical investigation of the debate on the Jewish ritual bath illuminates the way in which medicalization and secularization were different aspects of the same process of the attribution of complementary circumscribed spheres of medicine and religion. PMID- 11609052 TI - Paracelsus confronts the saints: miracles, healing and the secularization of magic. AB - The sixteenth and seventeenth centuries witnessed an erosion of the role played by the church in healing. Magical practices mediated by the church were replaced by the resources of medicine. This represented an important cultural development and it is often regarded as a manifestation of increasing secularization, the decline of magic and rise of science. This paper examines this issue with special reference to miraculous healing associated with saints, which constituted one of the most important facets of magic controlled by the church. It will be suggested that Paracelsus (Theophrast von Hohenheim, 1493-1541) played an important part in the argument concerning the miraculous powers of saints. Many works by Paracelsus produced at various points in his career were relevant to this issue, but De causis morborum invisibilium, the sequel to his important Opus Paraminum (1531), was especially significant. The question of miraculous healing was therefore important in the first, full presentation of the new system of medicine developed by Paracelsus. Modern commentators have understandably found De causis morborum invisibilium less intelligible and congenial than the more accessible Opus Paramirum. But the former was important to Paracelsus, and it addressed problems that were fundamental to his audience. This case-study shows how conclusions reached by Paracelsus about medical questions were integrally tied up with his theological standpoint and with his wider reaction to the acute crisis of confidence which affected the church and the established social order at the beginning of the sixteenth century. By eliminating the miraculous intervention of saints and promoting the secularization of magic, Paracelsus was contributing to one of the important cultural changes associated with the Reformation. PMID- 11609054 TI - Medical knowledge and medical practice: geriatric medicine in the 1950s. AB - This article examines the development of medical knowledge and practice with regard to sickness in old age in the early years of the National Health Service. It suggests that the creation of a speciality of geriatrics was inspired by the need to prevent hospital beds being blocked by long-stay patients. Thus, the efficient use of hospital provision required the diagnosis, treatment, and rehabilitation of elderly patients. The publication of medical texts on sickness in old age, provided the basis for a more interventionist approach to the care of sick, elderly people, but the development of geriatrics as a separate speciality was hindered by professional disputes over administrative responsibility, funding, private practice, and medical training. One key area of debate was whether sickness in old age was primarily a social rather than a medical problem. This needs to be considered with regard to the relationship between the hospital and the local community and the article examines the contribution of social and medical surveys of elderly people at home to the discourse on sickness and old age. PMID- 11609055 TI - 'A medical El Dorado'? Colonial medical incomes and practice at the Cape. AB - This article focuses on a neglected area--the economics of colonial medicine. It examines medical incomes and practice in the Cape of Good Hope Colony before 1910 in relation to licensed practitioners in private practice. The imperial relationship shaped medical practice, notably in relation to a comparative early regulation of medicine, and an increasingly crowded medical market. The article suggests that Britain was exporting some of its problems--in the form of an oversupply of medical practitioners--to its empire. The opportunities for making a good medical income in the Cape are compared with those in Britain; and the article concludes that, although there were generally better opportunities to make high incomes in the Cape, the risks of professional failure were often greater. PMID- 11609057 TI - Physiological fictions: recent work on medicine and literature. PMID- 11609056 TI - Antenatal care in South Wales 1934-1962. AB - The records of the Special Antenatal Clinics held by the Rhondda Urban District Council between 1934 and 1962 at the Carnegie Welfare Centre in Trealaw, South Wales, were studied. An analysis is presented of structured samples taken from the clinics of one month in each quinquennium from 1934 to 1962. The collected material is then grouped into a period covering the pre-war and wartime years of 1934-1946, and a post-war period from 1950 to 1962. Examination of these sections shows developments in the mid-twentieth century both in the recording of medical histories and in the care of childbirth in this area of Wales. PMID- 11609058 TI - [Not Available]. AB - The article investigates the culture- and socialhistorical background of the origin and early development of sexual pathology in Germany. In its first part it shows how sexual pathology, first known as Psychopathia sexualis, came into being as a special field of psychiatry. Its most important founder, Richard von Krafft Ebing, constructed a system of sexual perverts. After 1869, together with colleagues he developed wholly new concepts of deviant sexuality and how to deal with it. In the second part it is shown which points of Krafft-Ebing's concept of perversity were taken over by his medical successors and which points were modified or even rejected as a result of sharp criticism. Finally the long-term effects of the pathologization of deviant sexual behaviour are depicted, the medicalization of social deviance, the change in understanding of sexuality and other developments. PMID- 11609059 TI - [Not Available]. PMID- 11609060 TI - [Not Available]. AB - In Samuel Hahnemann's French medical diaries, which are owned by the Institute for the History of Medicine of the Robert Bosch Foundation in Stuttgart, 681 prescriptions of Q-potencies, complying with the findings of the 6th edition of the Organon, were identified and listed. The first of these originates in 1838, the last in 1843. This corresponds with Hahnemann's statement that he had gathered four to five years' experience with his "modified, new perfected method" (dynamisation method). According to his data, Hahnemann prescribed sulphur three times more than all other medicines put together, followed by calcarea as the second most prescribed substance. No higher potencies thaan Q8 could be determined. By far the largest number of prescriptions of Q-potenciess are to be found in the as-yet unpublished case-books 13 and 14. PMID- 11609061 TI - [Not Available]. AB - The article describes the social and medical profile of the lay healer Eugen Wenz (1856-1945) during his first period of medical activity as owner of the naturopathic and homoeopathic establishment "Marienbad" in Muhringen in the years 1895-1899. Wenz was severely restricted in his activities: the health insurance schemes did not reimburse him, the medical authorities of Wurttemberg attempted at first to prevent the foundation of the 'Marienbad' and the doctors of the surrounding area interfered several times in his medical treatment. Finally Eugen Wenz appears not to have been accepted by the population of the district (Oberamt), since the Marienbad was very poorly frequented and so unable to provide Wenz with a secure income. A statistic comparison shows that many other lay healers seem to have been confronted with similar problems. The social profile of Eugen Wenz disproves partially the general picture of the profession of German lay healers depicted by research in medical history hitherto. PMID- 11609062 TI - [Not Available]. AB - The rise of allotment gardens at the end of the 19th century is directly connected with radical social changes in society. Industrialization, urbanizatiion and massive migration had serious effects on the way of living of the working class. New forms of industrial labour and miserable living conditions in the urban regions alienated the working class population from nature and natural living conditions. In search of nature and a better living, the proletarians founded allotment gardens to escape from urbanization and unhealthy housing conditions. Soon other allotment movements grew up as middle class movements and civil welfare institutions also became involved in it. They were all aware thaat to be out and moving in the open air and to be working in a garden had positive effects on the state of health and the physical condition. These leisure activities were a cheap and effective part of mental and physical recuperation for the working class members and relieved civil welfare institutions. PMID- 11609063 TI - [Not Available]. AB - The text analyses Koch's microbiology and its rapid success within the context of the intellectual history of Wilhelminian [1888-1918] Germany. Studies of visual and verbal popularisations of microbiology show that scientific theory of microbiology, by communicating in the political language of its age, was followed by an equally specific popular image of the same topic. This included both popularisations of microbiology in militaristic metaphors and the analogous use of microbiological concepts as popularisations of imperialistic and agressive concepts of politics. Thus, the development and success of microbiology is linked to the development of the political language of its age. PMID- 11609064 TI - Police service in Victorian and Edwardian London: a somwhat atypical case of a hazardous occupation. AB - British society in the nineteenth century showed a growing concern with public health issues and with occupational hazards. Police service, which is at the centre of this paper, was not viewed by many as a hazardous occupation. Using the London Metropolitan Police as a case study, the paper suggests that working conditions in the Victorian and Edwardian police had detrimental effects on the health of officers. It is true that medical statistics of the time showed that police officers in London had a lower death rate than the average working man, but this comparison should not obscure the fact that policemen entered the force much healthier than when they retired and that this gap was not merely age related. The paper sets out to answer the following questions: What were the prevalent injuries and illnesses in the Metropolitan Police? What was the work experience of the police officer and what impact did it have on his state of health? In addition to accounting for the deteriorating health of police officers, the paper provides the views of contemporary observers on the subject. PMID- 11609065 TI - [Not Available]. AB - The slogan of an increase in external stimuli is seen as a characteristic of the diverse processes of modernization in the German Empire. A study of Theodor Lessing's "Anti-noise Society" (1908-1914) showed how the individual experienced auditory stimuli andd how these stimuli were understood and digested. Apart from the writings of Lessing, the Society's mouthpiece "Anti-rowdy. The Right to Quietness" was analysed hermeneutically and with respect to questions of social history. The combination of this analysis with the relevant medical results and discussions in specialist literature (question of nervousness; occupational medicine) have shown that the use of an expression like "increase in stimuli" is justified when urban life before World War I is to be characterised. It is, however, only an abstract collective term under which diverse forms of practical knowledge, different ways of giving meaning to this psychosocial phenomenon, and even willful disregard for it as a relevant contemporary issue are subsumed - just as with noise as an environmental problem. PMID- 11609066 TI - [Not Available]. AB - The history of the tradition of medical texts written in the vernacular in the Middle Ages, in particular the strict synchronic study of manuscripts, reveals that we are not dealing with specialized knowledge for experts but with information which was available to anybody who could read. The medical layman and with him the potential patient thus shifted into the centre of interest. The study of these texts illustrated the medieval concept of "knowledge" and the understanding of "reality". It emerged that empiricism in our sense played an important, but not the most important role. Trust in the world order led to the application of principles of analogous magic and faith in the truth of classical Latin tradition and the authority of the ancients went almost unbroken. However, the decisive factor is that the same degree of "reality" was attributed to humoral pathology as is to cellular pathology today. As to the significance of the texts, this means that they conveyed both theoretical intellectual knowledge and concrete practical knowledge from which experts and amateurs were able to benefit in different ways. Whereas ideas are usually developed inductively, medieval argument was conducted deductively, that is, based on natural philosophy not on natural science, and followed therefore the tradition of classical antiquity. In the final analysis it is this factor which, in spite of differing standards, unites learned and popular medicine. PMID- 11609067 TI - [The reproduction of the population in the seventeenth, eighteenth, and nineteenth centuries. Examples from France and Quebec]. AB - This article examines the descendants of four cohorts of couples formed in the seventeenth and eighteenth centuries (two cohorts in two French mountain valleys and one on the Ile-d'Orleans in Quebec). The children are separated into four categories according to their fate (deceased while still unmarried, unknown fate, married but childless, "useful children"). "Useful children", a concept used in population genetics, are those who in turn bear children. In all three places, the useful children represent only from 26 to 31% of births. The study goes on to measure the contributions made by these couples to the next generation. In the mean, each couple gave birth to little over one useful child. But the contributions of couples turns out to be very unequal. Depending on the place, from 36 to 53% of couples left no useful children behind them, while a small minority of couples made an ample contribution to the next generation. The same measure is reproduced in the constitution of the next generation, thereby showing that inequality of couples in terms of reproduction is perpetuated. PMID- 11609068 TI - [Family and population in China from the sixteenth to the eighteenth century in the light of a recent work by Liu Ts'ui-Jung]. AB - Taking as its starting point the huge sample of 260,000 people born in China between the 13th and the 19th century used by Liu Ts'ui-Jung in her recent study on Lineage population, our study aims at assessing the premodern demographic evolution of China. Inasmuch the method of family reconstruction actually limited the scope of her book, Liu Ts'ui-Jung was not able to go beyond the description of a specific demographic regime defined by three elements: 1) universal marriage; 2) a moderate level of masculine fertility; and 3) a life expectation at 15 comprised between 30 and 40. These conditions would not allow the constitution of many extended households, whereas the annual rate of growth would be somewhere around 1%, a situation having little in common with the present day "population explosion". Using data included in the book, but not considered for the demonstration, we have been able to establish a dramatic deterioration of the mortality pattern from the middle of the 18th century onwards. Accordingly, the proportion of widows increases whereas population which would be characterized with a long period of growth followed by a crisis generated by a surge of the mortality rate. PMID- 11609069 TI - Detection without correction: problems in assessing the quality of English ecclesiastical and civil registration. AB - Reliable, good quality source material is required for any demographic study. By selecting specific examples from York during the parish register period and Sheffield during the civil registratiion period deficiencies in both ecclesiastical and civil registration are discussed with reference to how they affect infant and adult mortality calculations. In particular, the extent to which the deaths of very young infants were registered is considered in detail. Bourgeois-Pichat's biometric test, Farr's early life tables and Coale and Demeny's model life tables have all been used to correct inaccuracies within original sources. We consider the limitations of each of these methods and suggest that a reassessment of the quality of vital registration data and the methods used to make corrections is needed in order to make further advances in historical demography possible. PMID- 11609070 TI - [On the importance of anthropometric history]. AB - One can think of the average height at a particular age by individuals in a population as the historical record of their nutritional experience. Medical research has confirmed that nutritional status--and thus physical stature--, is related to food consumption and therefore to real family income, and therefore to wages and to prices and variables. Through anthropometric research one can illuminate the biological well being of some members of a society--women, children, aristocrats, subsistence farmers and slaves--, for whom market wages are seldom available. In additiion, it has been shown that the biological standard of living can diverge from conventional indicators of well being during the early stages of industrialization. These are noteworthy contributions to the frontiers of knowledge in economic and demographic history. PMID- 11609072 TI - ["The main cause of the differences is the crime": An attempt at explaining the excess mortality of illegitimate children in The Hague in the mid-nineteenth century]. AB - During the last quarter of the 19th century, illegitimate children had much higher infant mortality than legitimate children. To investigate which factors played a role in this, we collected information on the household situation and the life course of all illegitimate children, born in the Dutch city of The Hague in the years 1850-1852. Use was made of birth and death certificates and of the population registers of the city. We compared our information with data on a random sample of legitimate children,, born in the same city. After children had reached the age of one month, mortality among illegitimate children became very high, compared to that of our reference group. Proportional hazards analysis showed that this excess mortality was caused by a set of factors, the most important being the age of the mother at birth, regional background, and the socio-economic group to which the notifier of the birth belonged. Aside from those factors, legal status of the child as such had an effect on infant mortality. The unwed mothers most likely to lose their child in its first year of life lived alone with their child and were obliged to resume work to support themselves and their child. The opportunity to breastfeed may have played a key role in this. PMID- 11609071 TI - [Using statistics of tuberculosis clinics and hospitals in the social and epidemiological history of the "white plague" in the late nineteenth and early twentieth centuries]. AB - During the late XIXth and the beginning of the XXth centuries, the struggle against tuberculosis is a strong reason to redefine health as social gaming, and not as individual gaming anymore. Here the number of actors increases on the market of medical cares, involving some tensions. This paper compares (by the means of death causes statistics) people affected and treated in a local hospital, and those treated in the antitubercular health centres from the province of Liege. It studies the respective contribution of hospital records and statistics list of health centres to the historical epidemiology of the "white plague" and to social history of the health. PMID- 11609073 TI - [The premises of a policy of early childhood during the second empire: The association for the care of lying-in women]. AB - As early as the 1830's, the social elite of Mulhouse was aware of the higher infant mortality in the working class. A family policy was adopted only during the Second Empire: the consciousness of the failure of the first philanthropic measures explains why the manufacturers decided to take direct responsibility for the working class family. The demographic preoccupations are directly linked to philanthropy. This paper analises the principles and evaluates the results of the Association for the care of lying-in women. PMID- 11609074 TI - Civilian health during WWI and the causes of German defeat: a reexamination of the winter hypothesis. AB - This paper is a reexamination of the Winter hypothesis, which holds that there was a marked difference in the development of civilian health during the First World War between the central powers and the Western allies. Ultimate success on the battlefield, according to Winter, required balancing the needs of the military with civilian demands; Germany lost because it failed to achieve such a balance. The resulting decline in health standards undermined the war effort and eventually led to defeat. This article proceeds in two steps. First, it demonstrates that Winter's data does not allow him to make a proper comparison between the two camps. Second, I argue that his hypothesis can be refuted once a truly comparable source is used--infant mortality rated. There is as yet no convincing evidence to suggest that the outcome of the First world War was determined by public health policy. PMID- 11609075 TI - The new science and the public sphere in the premodern era. AB - This paper argues that the New Science, which was seen as essentially a public enterprise, was moreover a major constituent of the public sphere in early modern era. In seventeenth- and eighteenth-century Western Europe the sphere of public experimentation, testing, and discussion related to the new science, manifested itself as a highly diversified, contested, and complex social field. Two general problems arose in constructing this cultural public sphere: the selection of participants in the debate and the inclusion of a heterogenous public in the experimental scene. National authorities employed diverse policies but none denied the necessity of public debate for testing the validity of experimentations. The public sphere had to create its own conditions of existence by imposing manifold regulations in order to make these public meetings possible and enjoyable. The regulations emphasized common interest and the moral code as the most basic condition for the sustenance of the public sphere, thus enhancing self-restraint, tolerance, and politeness on the part of both discussants and participants. The more inclusive and heterogenous the public sphere, the more these norms were required. Thus the sphere of public debate constituted by early modern science implied a civilizing process, quite different from and more encompassing than the one analyzed by Norbert Elias. PMID- 11609076 TI - Ecological metaphors as scientific boundary work: innovation and authority in interwar sociology and biology. AB - The development of human ecology during the interwar period was a significant scientific innovation enabled by the sociological use of biological concepts as tropes for social organization. This examination of the connections between biology and sociology illuminates a process whereby new scientific knowledge is generated, new scientific communities are formed, and individuals become scientists. These relationships were arranged around the negotiable boundaries between the social and the natural in 20th-century science. This process is examined through an analysis of scientific texts, metaphor transaction in science, and mentoring practices that reveal the transmission and bounding of knowledge and authority. PMID- 11609077 TI - Book culture and medicine. PMID- 11609078 TI - [Medical books in the possession of Canadian health professionals in the seventeenth and eighteenth centuries]. AB - This study, based on the data found in notarized inventories of the deceased, ex libris or bookplates, and listings of books in institutional libraries, shows clearly that circulation of medical books, generally imported from Europe, was next to non-existent in the general public but growing steadily in the Canadian medical corps during the seventeenth and eighteenth centuries. This growth is proof of the increasing professionalization of the medical corps and institutionalization of medical know-how and expertise during that period. PMID- 11609079 TI - Taste sets the price: Meade, Askew, and the birth of bibliomania in eighteenth century England. AB - Three of the most important libraries sold during the first 100 years of English book auctions belonged to doctors. By examining the contents of these sales and the prices achieved in them, I hope to be able to throw some light on the extent and expertise of English book collecting by physicians to discover the principles that governed book values through this period, and to illustrate how three prominent medical men's libraries fitted into the century's wider cultural development. PMID- 11609080 TI - Promoting good health in the age of reform: the medical publications of Henry H. Porter of Philadelphia, 1829-32. AB - In the early 1830s, the Philadelphia publisher Henry H. Porter rapidly published five journals, six books, and an almanac, works having a particular emphasis on health and personal hygiene. Porter's health publications linked the traditional message about the importance of personal hygiene to health to the messages conveyed by the flourishing American reform movements at the time, and his Journal of Health was among the first American medically oriented periodicals published for the layperson. Yet Porter did not survive in the intensely competitive and financially unstable book trade. This study examines Porter's health publications, attempting to explain why he chose to publish what he did, the message(s) his works contained, the audience(s) he tried to reach, and the failure of his business. PMID- 11609081 TI - Thomsonian medical books and the culture of dissent in Upper Canada. AB - Adherents to American lay healer Samuel Thomson's system of medicine have been viewed in Canada primarily as antagonists of mainstream medicine. Their publishing activities, however, reveal a wide reform impulse. As this discussion illustrates by considering publishers, printers, editors, and compilers of Thomsonian books in Upper Canada, most had links--real and temperamental--to Reform politics and to dissenting Protestant beliefs, especially Methodism. Their publications may thus be viewed as vehicles for social change in a British colony having a strong Tory alliance between church and state. PMID- 11609082 TI - The Osler Club of London, 1928-38: young medical gentlemen, their heroes, liberal education, books, and other matters. AB - This study focuses on the interpretation of the Oslerian legacy reflected in the activities and intellectual emphases of the Osler Club of London during its first 10 years. It argues that the founders and early members of the Club were neophytes in a medical elite, pursuing ideals which were congenial to a subgroup of that elite and in which the Club members had been raised and educated. These ideals may be summed up in the expression "the nineteenth-century, British medical gentleman." Sir William Osler was chosen as patron of the Club because he exemplified important aspects of these ideals. However, in its orientation toward the "British medical gentleman," reflecting the gentility of Osler--including his concern for people, his commitment to teaching, his loyalty to students and medical colleagues, and his interest in the history of medicine, its books, and the broader humanities--the Club missed an important dimension of the Oslerian legacy: an interest in the social institutions and responsibilities of medicine. Finally, this study shows that perhaps the most influential Club founder, A. W. Franklin, in his later life expanded his own vision of medicine to include and even go beyond this latter dimension of the Oslerian legacy. PMID- 11609083 TI - Medical books: for information or learning? Reflections on the books of three Newfoundland physicians, c.1860 to c.1970. AB - This study describes the medical books of three physicians in rural Newfoundland who followed each other chronologically. Spanning the years c.1860 to c.1970, the nearly 300 books prompt a variety of questions about the physicians themselves, their practices, and their reading habits. These enquiries raise further questions about the extent to which medical books are read for factual information or for contemplating more general issues about the nature of disease and the nature of the individual. PMID- 11609084 TI - The library of Thomas Kincaid, a seventeenth-century Scottish surgeon. PMID- 11609086 TI - "Still in process": collaborative authorship in a twentieth-century biomedical textbook. PMID- 11609085 TI - [Directions for curing the disease of Baie St Paul: the first medical publication in Canada]. PMID- 11609087 TI - A search for gold: reconstructing a private library--the case of Dr. Robert Bell. PMID- 11609088 TI - "Who's on first?": Garrison-Morton-Norman at the end of the twentieth century. PMID- 11609089 TI - Early modern English medical wills, book ownership, and book culture. PMID- 11609090 TI - Identifying a family heirloom: The Indian Doctor's Dispensatory. PMID- 11609091 TI - The Medical Profession in Upper Canada reconsidered: politics, medical reform, and law in a colonial Society. AB - This study explores some of the important questions raised but not answered in William Canniff's standard century-old study, The Medical Profession in Upper Canada, 1783-1850. Primarily based on the original medical licenses issued between 1819 and 1841, an array of manuscript material belonging to the Civil Secretary of Upper Canada and the Colonial Office, and documents pertaining to the Medical Board of Upper Canada, this article argues that the disallowance of legislation for the establishment of a colonial College of Physicians and Surgeons in 1839 can only be fully understood in the context of demographic, political, and medical developments which included factors such as ethnicity, tensions between the colony and mother country, and rivalry between medical schools. It explains why the issues of the 1830s continued into the 1840s and undermined any possibility by the profession of forming a single, self regulating, and unified medical body for licensing and educating practitioners. PMID- 11609092 TI - The Canadian revolution in the management of spinal cord injury. AB - During World War II new programs for medical treatment and rehabilitation reduced mortality rates following spinal cord injury from over 80 percent in World War I to below 10 percent by 1946. In Canada a group of physicians, veterans, and civilians developed one of the first comprehensive sets of programs and services to permit the return of veterans with spinal cord injury to independent life in the community, beyond the confines of hospitals or paraplegic colonies. This article reviews the activities of Dr. E. Harry Botterell, Lieutenant John Counsell, and Dr. Al Jousse in the development of a Canadian approach that revolutionized the life experiences and life expectancy of individuals with spinal cord injury. It describes the development of their philosophy of rehabilitation as well as the programs and services they established at the No. 1 Canadian Neurological Hospital in England, and at Christie Street Military Hospital, Lyndhurst Lodge, and the Canadian Paraplegic Association in Canada. PMID- 11609094 TI - "My life in Keg River" by Mary Percy Jackson. PMID- 11609093 TI - [Applying the art of medicine in the study of attitudes]. AB - In 1758, the physician-philosopher Johann-Georg Zimmermann (1728-95) published Vom Nationalstolze. In this treatise, Zimmermann transformed the particulars of medical analysis conceived to examine pathological individuals into an instrument for observing societal mentalities. This article deals with Zimmermann's motivations for writing on national pride and with his observations and reflections on different kinds of national tempers. Zimmermann's descriptions of healthy and unhealthy manifestations of national pride and his prescriptions for preventing its worst effects are expounded through many direct quotes. PMID- 11609095 TI - The portrait of Robert Kerr (d. 1824). AB - The importance of Dr. Robert Kerr in Canadian history is not large, but he played a significant role in the early years of what is now Ontario. Though his Canadian years were spent largely in active military service and, after his discharge, at Kingston and in the Niagara peninsula, nevertheless, in the compact and sparse settlements and posts of the times he was widely known and influential. Moreover, Kerr had a significant connection with one of the founders of Toronto. As this discussion will show, a fateful conjunction of art and medicine lies behind a portrait of Robert Kerr. PMID- 11609096 TI - Charles H. Best, the Canadian Red Cross Society, and Canada's first national blood donation program. AB - This article examines how Canada's first national blood donation program originated during World War II. It focuses on the genesis of Charles H. Best's serum project at the University of Toronto, and the federal government's decision in 1940 to sponsor it as the nation's most viable blood banking option. While Best's personal initiatives were crucial, his project's success was also a result of the larger scientific, political, and institutional circumstances of Canadian medicine. The article also analyzes why the federal government gave responsibility for blood collection to the Canadian Red Cross Society. It shows how the organization's traditional association with military medicine, its more recent involvement with community health services (including blood transfusion), and its flexible national structure suited it for this task. Moreover, Ottawa's willingness to assign this role to a volunteer agency was an indication of the structural deficiencies in Canada's primitive health-care system. The decisions of 1940 flowed from the immediate wartime pressures and individual initiatives. They reflected as well the deeper scientific, institutional, and cultural realities of the time. PMID- 11609097 TI - The rise and fall of anticontagionism in France. AB - This article re-examines the anticontagionist controversy in nineteenth-century France. Erwin Ackerknecht attributed the discrediting of contagion theory to political opposition to quarantines and the rise of social medicine. Later scholars argue that he exaggerated the opposition between contagionists and anticontagionists. I argue that French doctors were genuinely divided on questions of knowledge and practice. Disease by disease, they battled it out. Anticontagionists gained the upper hand in the 1820s and 1830s, only to relinquish it again in the 1840s as contagionists revised their theories to be more progressive and tracked down evidence to which the Academy of Medicine lent its authority. At that point the majority of physicians rallied around to an attenuated theory of transmission and support for quarantines. PMID- 11609098 TI - The 1846 Catalogue of the Halifax Garrison Medical Library. PMID- 11609099 TI - Nineteenth-century narrative case histories: an inquiry into stylistics and history. AB - This study of Canadian nineteenth-century obstetrical and gynaecological case histories enters the current debate about narrative prose and its postulated relation to humanitarianism from a particular point of view. It uses literary analysis to generate new types of evidence to shed light on the development of this medical specialty, and so demonstrates how close textual analysis can be of use to medical historians. The finding that narrative structure played a central role in the development of statistical thinking about disease grants it a highly ambivalent role in relation to humanitarianism. It supports the conclusion that the literary form has no content of its own; narrative appears as a powerful vehicle for creating consensus, but this insight cannot commit one to a view about the subject of the consensus or its social implications. PMID- 11609100 TI - Physiotherapy's quest for professional status in Ontario, 1950-80. AB - Physiotherapy is part of the new female-dominated paramedical occupations which have witnessed considerable growth in Canada since World War II. This article examines the main dimensions of physiotherapy's professionalizing drive in Ontario between 1950 and 1980. It discusses the leadership's continuing efforts to make physiotherapy a self-regulated profession, efforts which will be seriously challenged by the provincial government's growing intervention in the health sector in the 1970s. It also examines physiotherapy's involvement in boundary disputes with the medical profession and chiropractic. Finally, the article explores the influence of gender on physiotherapy's professionalizing efforts, providing insights on the means women health practitioners have used to gain professional status and on the limits and constraints that their gender may have posed to the achievement of their goal. PMID- 11609101 TI - When memory triumphs. PMID- 11609102 TI - Medical authority and memory: considering the patient-professional dichotomy. PMID- 11609103 TI - The Islamic world view and modern science. AB - The author in this article marks various factors that have motivated Muslims to adopt science and technology. In the earlier days the interest of Muslims in science and technology was due to their intellectual necessity to consolidate political independence. But their interest in science has increased today because of its being considered as the most potent means for global domination. Most of the Muslims emulate science without any critical evaluation. They are impervious to the wisdom that science offers and hence increases the depth of understanding of God's sign (ayat) and His art of creation. The author also urged Muslims to realize the devastating consequences caused by the unethical use of modern science. To him such a science that accelerates mass destruction and moral degeneration is opposed to the Islamic science which is based not on reason alone but also on revelation that promotes peace and harmony, and helps mankind to live at peace. The link that has been advocated today between science and ethics by some western writers is most deceptive and incredible, because that link primarily corresponds to a worldview which has been supplanted by that of modern science. Contrary to this the harmony between science and Islam cultivated by Muslims of over a millenium leads to the omnipotence and omniscence of God and guarantees welfare for the whole human kind. PMID- 11609104 TI - Secularism, science and Islam. AB - Western natural science, arising from philosophical secularism, is a potent perpetuator of secularism. Greeks view of reality, was paradoxically strengthened by Christian denigration of nature and reason and by the later, successive European stances of anti-theologism, anti-metaphysicism and scientism. Islam, by seeing the unity of reason-intuition and nature- ghayb posits scientific and spiritual meaning in nature. Western secular science has produced spiritual and natural crises while the holistic, Islamic science resolves them. The desecularisation and Islamisation of society together with the resolution of science-generated crises demands a fundamental criticism of western science and the emergence of a healthier science. PMID- 11609105 TI - Welfare. PMID- 11609106 TI - The great chain of buying: medical advertisement, the bourgeois public sphere, and the origins of the French Revolution. PMID- 11609107 TI - Seeing themselves at work: physicians and the case narrative in the mid nineteenth-century American south. PMID- 11609108 TI - French volunteer nursing and the myth of war experience in World War I. PMID- 11609109 TI - The land-mine disaster: an epidemic of mutilation. PMID- 11609110 TI - Peace and the healing process. PMID- 11609111 TI - [Beginning the Belgian medical exploration of Africa]. PMID- 11609112 TI - [Not Available]. PMID- 11609113 TI - [Not Available]. PMID- 11609114 TI - The pharmaceutical heritage of the Netherlands. AB - For the last 40 years the 'Kring voor de Geschiedenis van de Pharmacie in Benelux' (Society for the History of Pharmacy in Benelux) has been studying the pharmaceutical past, in which the pharmacist, the preparer of medicines from way back, occupies an important place. This historical study supplies some unexpected views of the past and the future. Sarton also pointed this out to us in his 'new humanism' (28). In his own words: "The present without its past is insipid and meaningless; the past without the present is obscure. The life of science, like the life of art, is eternal." His new humanism did not result in narrow specialism, but in what he refers to as a 'double Renaissance', which also incorporates nature, culture and man. In this way an inspiring influence emanates from the past and thus our common pharmaceutical heritage can form a link between our nations. In turn this can contribute to the process of evolution which is necessary to realize harmonization within the framework of the European community. PMID- 11609115 TI - [Not Available]. PMID- 11609116 TI - [Not Available]. PMID- 11609117 TI - [Not Available]. PMID- 11609118 TI - [Not Available]. PMID- 11609119 TI - [Not Available]. PMID- 11609120 TI - [Water and public health during antiquity]. AB - "Thales of Miletus, one of the Seven Wise Men, affirmed that the principle of all things is water; ..." The importance of water for people's health was a widely held opinion of ancient writers. The purpose of the present study was to examine: 1) ideas of the salubrity of water, 2) the organization of water supply in towns, 3) the role of water in agriculture and transport, and 4) the influence of water on public health during antiquity. The written sources indicate that ideas of the salubrity of water are connected with the general scientific level of the society. The quality of water was examined using the senses; taste, smell, appearance and temperature. In addition the health of people and animals using a water source was examined. Tasty, cool, odorless and colourless water was considered best. Stagnant, marshy water was avoided. Settling tanks, sieves, filters and boiling of water were methods used to improve the quality of water during antiquity. The available sources do not permit estimation of the effect of these methods on public health. The relatively extensive urbanization during antiquity may be attributable to the importance dedicated to the transportation of sufficient amounts of water of good quality to the towns, Baths were probably beneficial for public health in towns where an abundance of water was available. In towns where water was scarce the role of baths was probably negative for public health.... PMID- 11609121 TI - [Not Available]. PMID- 11609122 TI - [Four cholera epidemics in nineteenth-century London]. AB - Asiatic cholera originated in India and spread to Europe in the early years of the nineteenth-century. In Britain the first cases were diagnosed late in 1831. The epidemic, reached London in February 1832. The authorities were poorly prepared for the invasion of a new epidemic and the doctors disagreed bitterly on the measures to be taken. There was little co-operation between the authorities, and the fact that the urban poor mistrusted the medical profession did not improve the situation. All this resulted in several cholera riots. These riots were not, however, as violent as those in several other cities in Europe. The 1832-33 cholera epidemic claimed 4,000 to 7,000 victims in London. It seems probable that several isolated cases of cholera occurred in London in 1852. It was not, however, until September 1853 that it was officially announced by the British authorities that a cholera epidemic was claiming victims not only in London but also in other parts of the country. During this epidemic numerous Londoners lodged complaints against nuisances in the metropolis. Yet, in most cases, the fines imposed on offenders were rather slight, since the authorities were extremely reluctant to interfere with anyone's trade or business. It was during this epidemic that John Snow, a London doctor, succeeded in tracing the epidemic to a single water pump on Broad Street in the Golden Square area. Snow did not, however, succeed in convincing the majority of his colleagues regarding the erroneous nature of the miasma theory during the epidemic of 1853/54, which cost the lives of some 12,000 people in the city area.... PMID- 11609123 TI - [Diseases and mortality of crown cattle in south-west Finland in 1556-1563]. AB - No attempts have previously been made to compile statistics on livestock production on the royal domains during the 16th century. Farming was of great importance and in Bishop Peder Mansson's book on farming, cattle-breeding plays an important role and passages are included concerning cattle-diseases and their treatment. The account books of the bailiffs also cover the royal domains. They contain detailed information about all economic transactions and everyday life on the estate. The estates were not just centers for local administration, they also offered the farmers an opportunity to acquaint themselves with new breeds and farming techniques. It is easy to imagine the surprise of the local farmers when the bailiff in 1557 brought two peacocks from Sweden to the estate Ulfsby in Satakunda. In 1560 a serious cattle-disese broke out in Pemar, and on the estate of Nyby one ox, eleven bull calves, four cows, nine heifers, six goats, six lambs and seventy-one pigs died. It is the only time a disease is mentioned in the accounts, but it is possible indirectly to trace serious diseases by comparing the number of slaughtered animals with the total mortality.... PMID- 11609124 TI - Survey on the anthropological collection of the Finnish Nubia Expedition. AB - Thanks to the activity of two field anthropologists the Finnish Nubia Expedition working in the Batn el Hagar area south of the Second Cataract in Upper (Sudanese) Nubia collected human cranial and postcranial remains representing a total of 115 individuals. Two chronological series could be built up, viz. Meroitic/X-Group and Christian Period. Most of the remaining material was chronologically and partly also geographically heterogeneous and covered Mesolithic to New Kingdom times. It was tentatively put together so as to represent the old "Prae-Meroitic" Nubian stock. The material was generally too sparse and too selected to allow a demographic study. However it allowed a comparative anthropometric analysis, focusing on the Meroitic/X-Group and Christian periods. Other aspects of the physical build of the individuals studied could be reconstructed by analysis of descriptive features. The differences observed between the series could be explained by determination of the relative shares of the White and Black anthropological varieties and their blend. The ample collection of pathological findings included rare instances such as two cases of vertebral tuberculosis and one case probably representing fungal osteomyelitis. Detailed data will be published in a monograph under preparation. PMID- 11609125 TI - A historical profile of veterinary pharmacology and therapeutics. PMID- 11609126 TI - "Like a city ablaze": the third sex and the creation of sexuality in Jain religious literature. PMID- 11609127 TI - Gender and male same-sex erotic behavior in British North America in the seventeenth century. PMID- 11609128 TI - Community empowerment and the medicalization of homosexuality: constructing sexual identities in the 1930s. PMID- 11609129 TI - Selections from Elements of controversy: the Atomic Energy Commission and Radiation Safety in nuclear weapons testing, 1947-1974. PMID- 11609130 TI - Friern: a common treasury. PMID- 11609131 TI - 'Pleasure's golden bait': prostitution, poverty and the Magdalen Hospital in eighteenth-century London. PMID- 11609132 TI - Redefining sex in eighteenth-century England. PMID- 11609133 TI - Towards an international bibliographical database in the history of science, technology and medicine. PMID- 11609134 TI - A bibliography of the natural history works printed at New Harmony, Indiana, 1827 1843. PMID- 11609135 TI - Economic swings and demographic changes in the history of Latin America. AB - In this paper we study the effects of short-term fluctuations in indicators of economic well-being on selected demographic response such as births, marriages and deaths at age intervals in eleven Latin American countries between 1910 and 1990. We use conventional distributed lag models to assess the magnitude and direction of effects and test a variety of hypotheses some of which have been posed to hold in Western Europe and others that are more specific and tailored to the Latin American context. We also compare the magnitude and direction of effects obtained among these countries with those obtained for pre-industrial Europe and uncover the existence of broadly similar patterns. PMID- 11609136 TI - Values and fertility change in Japan. AB - This paper analyses how value change and economic and social change have jointly affected fertility in Japan since 1950, and especially since 1973 when fertility resumed declining after some 15 years at near-replacement level. The resumption of fertility decline since 1973 has been driven primarily by underlying economic and social changes. Value change has tended to lag behind fertility change, and this lag has tended to be larger in Japan than in other advanced nations, primarily because underlying economic and social conditions have evolved more rapidly in Japan, and because it takes time for values to adjust to changes in underlying conditions. Because of Japan's high degree of cultural homogeneity, values tend to be widely and quickly shared, so that under certain conditions value change tends to occur in spurts. In Japan, many of the more important value changes affecting fertility in recent decades are bound up with major educational and job gains by women, which have led to greater economic independence and more emphasis on values of individualism and equality between the sexes. PMID- 11609137 TI - Nuptiality, fertility, use of contraception, and family policies in Uzbekistan. AB - With more than 22 million inhabitants, Uzbekistan is the most populous of the Central Asian republics of the former USSR. Using data from a retrospective survey conducted in 1992 among women of reproductive age, the paper examines fertility trends and determinants during the twentieth century. The analysis shows that the absence of a government-supported birth control programme and the strong pro-natalist policies of the Soviet authorities during most of the century did not affect either the onset, nor the progress of the fertility transition. The results indicate, however, that the social development programmes undertaken by the Soviet government did play a very active part in the transition as shown by the impact of education on reproductive behaviour, as well as on the very specific contraceptive mix adopted by the population after the mid-1970s. PMID- 11609138 TI - Fertility decline in Kinshasa. AB - This paper examines key socio-economic changes over the past 40 years in the lives of women in Kinshasa, Zaire, and how those changes relate to observed fertility behaviour. Data from surveys carried out in 1955, 1975, and 1990 are used to highlight the remarkable shift that has taken place in the educational attainment of women: in the 1950s the vast majority of adult women had no formal education, while by 1990 the median woman had been to secondary school. This dramatic shift was accompanied by several related changes, including delays in age at marriage and increased participation in the labour market. Total fertility, which was estimated at 7.5 in the 1950s and had not changed much by 1975, appears to have fallen more recently, by about 1.5 children or more. This decline in fertility appears to be closely linked to the improvements in secondary schooling for women in Kinshasa. PMID- 11609139 TI - Post-Soviet perspectives on Russian psychology. PMID- 11609140 TI - Soviet psychology, perestroika, and the human factor: 1985-1991. PMID- 11609141 TI - Understanding the other order of things. PMID- 11609142 TI - The Institute of Psychology revisited. PMID- 11609143 TI - The American Psychological Association's initiatives in the former Soviet Republic of Russia: where do we go from here? PMID- 11609144 TI - Russian psychology and the "new capitalism". PMID- 11609146 TI - A social history of Russian industrial psychology in the 1920s and 1930s. PMID- 11609145 TI - Comments on the history of psychoanalysis in Russia. PMID- 11609147 TI - Ethnic psychology in Soviet Russia. PMID- 11609148 TI - Is there a comparative psychology in the future of the former member nations of the USSR? PMID- 11609149 TI - Historical background, analytical overview and glossary. PMID- 11609150 TI - Ideological and scientific discourse in Soviet psychological science. PMID- 11609151 TI - Social utopias and knowledge construction in psychology. PMID- 11609152 TI - Societal changes and psychological theory: the Russian case. PMID- 11609153 TI - Is feminism a threat to scientific objectivity? AB - Is there a conflict between women's values and the values of science? Not only do many aspects of science reproduce the ideology of gender, but science itself has been identified as "masculine." The male way of thinking is said to be rational, impersonal, and objective, while the female way of thinking is said to be emotional, personal, and subjective. This paper argues that the distinction between objectivity and subjectivity is built into science at many levels, and is reproduced in the splits between the production of knowledge and its social uses, between knowledge and experience, between expert and nonexpert, between active subject and passive object, and between the forms of our knowledge and the structures of social and economic power in our society. This analysis leads to the question: is there a feminist science? It is argued that, at present, we can only begin to imagine the general form of a feminist science, which in its fully articulated form, could only be produced in a feminist society. This paper offers examples to suggest ways in which an attack on the subjective/objective distinction could lead to a radically transformed science in the future. PMID- 11609154 TI - The Johns Hopkins University: School of Health Services. Humanistic studies in the health associate programs: revisions and new directions. PMID- 11609155 TI - Restaging early traumas in war and social violence. PMID- 11609156 TI - Children in and outside the concentration camp. PMID- 11609157 TI - Can soldiers keep peace? A study of the recent history of the psychological dimensions of the U.S. Army. PMID- 11609158 TI - Dangerous patients: the therapist as "weaponless policeman". PMID- 11609159 TI - [Comparative studies of the tridosha theory in Ayurveda and the theory of the four deranged elements in Buddhist medicine]. AB - It has been said that the tridosha theory in Ayurveda originated from the theory of the three elements of the universe. The names of these three doshas, which are roughly equivalent to humour, are vata (wind), pitta (bile), and Kapha (phlegm), corresponding to the three elements of the universe: air, fire, and water. On the other hand, Buddhist medicine which has a close relation to Ayurveda is based on the theory of the four elements of the universe which includes the earth as well as the three elements mentioned above. Greek medicine on the other hand, is founded on the theory of the four humours, i.e. blood, yellow bile, black bile, and phlegm. Furthermore, even in Ayurveda, like in "Sushruta Samhita", the theory of the four humours can be found: this includes the above-mentioned tridosha plus blood as the fourth humour. "Timaios" by Plato also mentions this. We compared these various theories and pointed out that the tridosha theory had its origin in the theory of the four elements of the universe. The process of the formation of the tridosha theory is considered as follows: (1) "Earth" was segregated from the four elements of the universe owing to its solid properties, and was rearranged into the seven elements of the body called "dhatu"; and the other three elements. "water", "fire", and "air", were integrated as the tridosha theory, namely, the theory of the three humours, owing to their properties of fluid; (2) "Blood", assigned to the element of "earth", was segregated from the tridosha because "blood" was considered to be comprised of the properties of every humour without having its own peculiar properties. Therefore, the diseases caused by deranged "blood" were regarded as an aggregate disease caused by the other three deranged humours. Then the category of the disease, caused by deranged "earth", did not appear. PMID- 11609160 TI - The expedition to Peru and Chile (1777-1788): inventory of scientific production. AB - The aim of this work is to provide an inventory of the scientific corpus produced by the Spanish members of the Expedition to Peru and Chile (1777-1788). This material is divided into six large sections. The first section covers the different versions of the diary of the journey taken by the Expedition. The second section covers the drafts and workbooks used by the Expedition members for the writing of "Flora Peruviana et Chilensis," the manuscripts and published editions of this work, the materials used in the preparation of both the "Prodromus" and the "Systema Vegetabilium," the contributions of the assistants on the Expedition and some monographs of taxonomic interest. The third section is dedicated to quinological studies and other pharmacological works undertaken by Hipolito Ruiz Lopez and Jose Pavon Jimenez. The fourth section includes the writings concerning Ruiz's dispute with Antonio Jose Cavanilles. The fifth section contains texts which set forth the botanical thought of the members of the Expedition. The sixth and final section includes the Expedition members' writings on various subjects, from anthropology and ethnography to others of a purely historical nature. PMID- 11609161 TI - Milestones of pharmaceutical botany: pre-history to 1900. PMID- 11609162 TI - Pharmaceutical botany in the U.S.--1900-1962. PMID- 11609163 TI - Milestones in pharmaceutical botany since 1960. PMID- 11609164 TI - The Philadelphia College of Pharmacy and Science preserves its history. PMID- 11609165 TI - How old legal precedents produce new rules of law: a case study of Jones v. Walgreen. PMID- 11609166 TI - To nurse the young: breastfeeding and infant feeding in late Imperial China. AB - The article concerns breastfeeding and infant feeding in late imperial China, as described in medical texts and family records. Special instructions on nursing appeared in Chinese medical writings from the tenth century on as pediatrics became a medical profession. Instructions changed over time, as did the notion of human milk itself. Advice dealt with how best to select a wetnurse and with how and when to provide solid foods as a complementary and supplementary infant diet. Practical examples from medical case records, and biographical and family documents, reveal people's real experience with breastfeeding and infant feeding. PMID- 11609167 TI - Illegitimate fertility decline in England, 1851-1911. AB - This study attempts to determine the extent to which several hypotheses are able to account for the illegitimate fertility decline in England in the second half of the nineteenth century. The results of a pooled time-series analysis are consistent with the hypothesis that a rise in working-class prosperity accounts for much of the decline. Additional reasons for the decline, which cannot be ruled out with the data used in the analysis, include the diffusion of knowledge and the acceptability of contraceptive methods and a decline in agricultural employment. PMID- 11609168 TI - Drunkenness in turn-of-the-century Newcastle upon Tyne. PMID- 11609169 TI - Frankpledge lists as indices of migration and mortality: some evidence from Essex lists. PMID- 11609170 TI - Seasonality of births and marriages in a seafaring community before the age of steam. PMID- 11609171 TI - Birth, marriage and death in Elizabethan Cumbria. PMID- 11609172 TI - Still-births and the measurement of urban infant mortality rates c.1890-1930. PMID- 11609174 TI - [The 550th anniversary of the creation of the College of Apothecaries of the City of Barcelona]. PMID- 11609173 TI - [The lawsuit of apothecary Lluis Mariner against the College of Apothecaries of Barcelona (1631-1635)]. AB - The author describes the litigation between the "Col-legi d'Apotecaris de Barcelona" and Lluis Mariner, a pharmacist of Barcelona and supplier of the Spanish galleys. Mariner was absolved of the charges, but the author questions himself about the reasons of the Col-legi. PMID- 11609175 TI - [The laboratory of the military pharmacy of Badalona: its historical importance]. PMID- 11609176 TI - [Relations between Spanish and Catalan historians of pharmacy]. PMID- 11609177 TI - [The origin of the names of laboratory pharmaceuticals in use in present day Catalunya]. AB - In this work the author researches about the origin of pharmaceutical laboratories name's (national and foreign) and compiles all the published information about it. He also includes information about recently disappeared or absorbed laboratories. Tables about kinds of names (founder's surname, contractions, acronyms or fantasy names), foundation year, and some curiosities about the names, can be found. PMID- 11609178 TI - [The oldest pharmacy in Lisbon: Sao Vicente de Fora]. AB - This work describe an exposition placed in Lisboa, at the Sao Vicente de Fora monastery during december 1994. The visit of the minster Pharmacy (rebuilded following the pattern of 17th century) was the most interesting thing. We can also remark the two first portuguese pharmacopoeias written by an augustine friar (pharmacist and administrator of this Pharmacy during several years). PMID- 11609179 TI - [Is there a relationship between the retail price to the public of official medicines and the actual costs of the pharmacological agents they contain?]. PMID- 11609180 TI - [A record of the past 50 years since the end of World War II]. PMID- 11609181 TI - Pharmacopoeja Holmiensis Galeno-Chymica. PMID- 11609182 TI - [The founding of the College of Pharmacy of Valencia: approval of the statues (1862-1864)]. PMID- 11609184 TI - Treading on hallowed ground. PMID- 11609186 TI - The Virgil role. AB - The referral of a patient for subspecialty consultation and examination is but one facet of the primary care physician's involvement with his patient. Using examples from my practice, I argue that the term "gatekeeper" is an inadequate term for describing what the primary care physician does, or should do, for his patient. "Virgil Role" is offered as an alternative expression based on a proposed parallel between Dante's passage through the Inferno accompanied by his mentor-guide, Virgil, and a sick person's journey through his personal Hell of illness and the labyrinthine medical care system, guided by his physician. PMID- 11609188 TI - [Roselyne Rey (1951-1995), historian of science in the age of enlightenment]. PMID- 11609189 TI - [Haller and Buffon: apropos of "Reflexions"]. AB - This paper aims to throw light on the controversial issue of A. von Haller's alleged "conversion" from epigenesis to preformation. This "conversion" is usually linked to the reaction of the Swiss scholar to the publication of Buffon's theory of generation (1749). A close study of the texts published by the author of the Physiology on this occasion reveals that, far from having adopted the theory of preformation, he continued to defend epigenesis in a moderate form, a view which was not so different from that held at the same time by Buffon's associate, J. T. Needham. PMID- 11609190 TI - "Les maladies hereditaires:" 18th century disputes in France. AB - This paper describes and analyses the discussions on the subject of hereditary disease that took place between 1748 and 1800 among French physicians. Two essay competitions which set prizes for dissertations on the hereditary transmission of disease (Dijon, 1748; Paris, 1788-1790) prompted several writers to try and specify the peculiarities of hereditary causes. The publication of a sceptical essay written for the first competition by Antoine Louis was a major cause of concern for medics wishing to preserve hereditary influence as a valid etiological category. Louis' analytical denial of even the possibility of the existence of an hereditary cause led both the judges and the best medical writers who took part in the Paris competition to force the situation towards the establishment of clear criteria for isolating the hereditary cause from other pathological influences. The transition from a humoralist to a solidist view of the human constitution (body) provided the frame within which the different criteria for heredity were discussed. The prize essays of the Paris competition shared the position that hereditary influence was characterized by a latent, predisposant kind of causation, which could produce some well known phenomena like atavism (or regression) and homochrony. The solidist causes were thought by most to be better candidates for that role. These developments turned out to be crucial for the emergence and strength of 19th century French (and European) hereditarianism, in medicine and other fields. PMID- 11609193 TI - Explaining Salem: Calvinist psychology and the diagnosis of possession. PMID- 11609191 TI - [Roselyne Rey (1951-1995)]. PMID- 11609194 TI - Dentistry in the Boer Republics. PMID- 11609195 TI - A 19th century report of two royal obstetrical deaths. PMID- 11609196 TI - 6th Annual Leo Schamroth Memorial Lecture, Baragwanath Hospital, 25th May 1995: A matter of the heart. PMID- 11609197 TI - Dr Robert Ainslie Ross, M.B.Ch.B (Edin), F.R.C.S. (Eng.) (1876-1965), "The Sun Doctor". PMID- 11609198 TI - Alchemy and the Society of Jesus in the seventeenth century: strange bedfellows? PMID- 11609199 TI - Adolphe Wurtz and the atomism controversy. PMID- 11609200 TI - Icthyology: some medico-philatelic aspects. PMID- 11609201 TI - Physician eponyms in surgical clamps on stamps. PMID- 11609202 TI - Fermentation and pharmaceuticals. Part I. Alcohol PMID- 11609203 TI - Philipp Franz von Sebold. PMID- 11609204 TI - Archibald Hector McIndoe, plastic surgeon. PMID- 11609205 TI - Hungary; some stamps of medical interest. PMID- 11609206 TI - Medical doctors in Cuban stamps. PMID- 11609207 TI - The stethoscope in historical and philatelic perspective. PMID- 11609208 TI - The endogenous psychoses: a conceptual history. PMID- 11609209 TI - The concept of 'delusion' in Spanish psychiatry. AB - The history of the concept of delusion can be used to explore the general history of psychiatry in Spain and assess the contribution of her most distinguished practitioners. As this paper shows, the latter have not been as creative as their fellow artists or writers. Nonetheless, the ideas on delusions that some of them formulated deserve attention. The history of Spanish psychiatry (qua science) can be divided into four historical periods. (1) The native origins (up to the end of the eighteenth century). (2) The introduction of European psypchiatry (nineteenth century). (3) The period of consolidation (first third of the twentieth century). (4) From the Civil War (1936-39) to the present. These four periods provide a framework within which theories about delusion can be explored. Aspects of these four stages have been dealt with in earlier papers. PMID- 11609210 TI - Misidentification phenomena in German psychiatry: a historical review and comparison with the French/English approach. PMID- 11609211 TI - Pavlov's conceptualization of paranoia within the theory of higher nervous activity. AB - In 1934, I. P. Pavlov conceptualized paranoia within his theory of higher nervous activity. The conceptualization was based on the case study method used in the Psychiatric Clinic where Pavlov observed five cases diagnosed by psychiatrists as paranoid states. Furthermore, experiments with dogs as subjects produced behaviours that appeared analogous to paranoiac characteristics observed in the clinic. Pavlov's paranoia theory did not differ much from Ernst Kretschmer's 1927 explanation of the formation of paranoia. Hereditary predisposition and traumatic life experiences make, according to Pavlov, some centres in the brain more active than nearby areas, which results in preoccupation with certain ideas. Imbalance between neural excitation and inhibition creates a condition where weak external stimuli produce strong reactions, which explains paranoiac overreaction to the feeling of inferiority. Some suggestions as to Pavlov's interest in paranoia are offered. PMID- 11609212 TI - Die Gruppirung der psychischen Krankheiten ... Part III (The classification of mental disorders .. Part III). Translated and with an introduction by G. E. Berrios. PMID- 11609213 TI - Essay review: Sleep, dreams and the symptoms of madness. PMID- 11609214 TI - Some descriptions of schizophrenia-like illness in the German literature of the early nineteenth century. AB - The situation of German psychiatry in the early nineteenth century is of interest as the specialty was developing in a society which was still largely non industrial. Examination of the literature of the time allows, therefore, a testing of hypotheses concerning schizophrenia as a disease of industrial society. This study presents a number of descriptions of illness resembling schizophrenia derived from textbooks on mental illness and psychiatric journals from the period 1790-1830, as well as a fictional account in a novella by George Buchner dating from 1835. These descriptions suggest that schizophrenia did occur not uncommonly in pre-industrial Germany, and that the most detailed descriptions tended to come from non-specialist sources. The implications of this for the non recognition of schizophrenia before Kraepelin's account of 1896 are discussed. PMID- 11609215 TI - Evidence for the existence of schizophrenia in medieval Islamic society. AB - It has been claimed that descriptions of schizophrenia-like disorders were rare before 1800 in the Western world. Historical evidence from medieval Islamic society shows that madness was common in that society. Despite the limitations of the evidence, we propose that medieval Islamic physicians probably diagnosed and treated many cases of schizophrenia. PMID- 11609216 TI - The confinements of Isaac O.: a case of 'acute mania' in colonial Nigeria. PMID- 11609218 TI - Was Darwin really a species nominalist? PMID- 11609217 TI - How did the effects of alcohol on reproduction become scientifically uninteresting? PMID- 11609219 TI - Factors shaping Ernst Mayr's concepts in the history of biology. PMID- 11609221 TI - Vitalism in nineteenth-century scientific thought: a typology and reassessment. PMID- 11609220 TI - The role of the virus in origin-of-life theorizing. PMID- 11609222 TI - Grace Helen Kent. PMID- 11609223 TI - Chauncey Wright's functionalism. PMID- 11609224 TI - Charles S. Peirce (1839-1914): The first American experimental psychologist. PMID- 11609225 TI - George Trumbul Ladd: the great textbook writer. PMID- 11609226 TI - William James, Gustav Fechner, and the question of dogs and cats in the library. PMID- 11609227 TI - Anglo-American criminal insanity-an historical perspective. PMID- 11609228 TI - The case for a revised systematic approach to the history of psychology. PMID- 11609229 TI - Soviet historiography of psychology: IV. History of psychology abroad. PMID- 11609230 TI - Prescriptive dimensions for five schools of psychology. PMID- 11609231 TI - Science in the city: the London Institution, 1819-40. PMID- 11609232 TI - The cobweb or spider's web. The dreamy Stuff of 19th Century Pharmacy and therapeutics. PMID- 11609234 TI - The chondrus industry in New England. PMID- 11609233 TI - The Chair of the History of Pharmacy in the Faculty of Pharmacy, University of Madrid. PMID- 11609235 TI - Trends in 19th century American cholera therapy. PMID- 11609236 TI - The controversy over structure activity relationships in the early twentieth century. PMID- 11609237 TI - Pharmaceutical education in Ontario. 1. Prelude and beginnings. PMID- 11609240 TI - Early books in Welsh on veterinary medicine. PMID- 11609241 TI - Medical history in inscriptions of ancient cave temples of India. PMID- 11609242 TI - Parahita Samhita. A Sanskrit medical treatise of 15th century. A note on the book and the family of famous physicians. PMID- 11609243 TI - Parahita Samhita. English translation of selected verses. PMID- 11609244 TI - Tahqeeq-ul-Buhran (systematic investigation of crisis). PMID- 11609246 TI - Glimpses of medicine in Rajatarangini. Diseases, drugs, physicians and treatments in medieval Kashmir. PMID- 11609245 TI - Siddha medical works attributed to Thiruvalluvar. PMID- 11609247 TI - Qualities or effects of eating meals in vessels of different material or in different leaves. PMID- 11609248 TI - Yusrul Ilaj. (A persian medical manuscript compiled in India by Hekeem Hida etullah, 1731 A. D.) PMID- 11609249 TI - Printed works on medicine by Siddhars. PMID- 11609250 TI - Glimpses of the art of medicine and medical aid in ancient South India. PMID- 11609251 TI - Babu Rajender Lal Dutt (1818-1889). PMID- 11609252 TI - Itrifalat (Unani preparation) through ages. PMID- 11609253 TI - Lord Dhanwantari in Indian literature. PMID- 11609254 TI - Maden-Ush-Shifa Tibbe Sikender Shahi. Compiled in the time of Sultan Sikender Shah Lodi (1488-1518) by his courtier, Behwa bin Qewas Khan. It contains the summary of 13 Ayurvedic books also then existing in India. Chapter 1 Section IX. (Preservation of health and prevention of diseases). PMID- 11609255 TI - Zad-a-Gereeb (Provision for the poor). A medical guide-book for the poor travellers. PMID- 11609256 TI - Medical gleanings from the earliest English travellers in India (1580-1620 A. D.). PMID- 11609258 TI - Select articles on medical history of India. PMID- 11609257 TI - Dr. Whitelaw Ainslie and his contributions to materia medica and history of medicine in India. PMID- 11609259 TI - Selected readings from Todaranandayurvedasaukhya. Chapter XIII (Knowledge of disease). PMID- 11609260 TI - Haramekhala. English translation of selections from Chapter IV. PMID- 11609261 TI - Zia-ul-yuoon. A treatise on ophthalmology by Aynul-Mulk Sheerazi of Akbar's court. PMID- 11609262 TI - Zad-a-Gereeb (Provision for the poor). An Unani medical treatise compiled for the travellers on land and sea, in the time of Mohd. Akbar Shah II, the Emperor of Delhi (1806-1837 A. D.). PMID- 11609263 TI - A short note on history of Siddha medicine. PMID- 11609264 TI - Legends and observations on health and medicine among common people in ancient India. Gleanings from Chinese travellers in India (In V & VI centuries). PMID- 11609265 TI - Popular beliefs and practices relating to health and medicine in VII century A. D. PMID- 11609266 TI - A forgotten chapter in the history of syphilis in India in XVI century. PMID- 11609267 TI - Alfred Adler and the dialectic. PMID- 11609268 TI - Freud and American sociology, 1909-1949. PMID- 11609269 TI - In the shadow of the Enlightenment. PMID- 11609270 TI - Seven psychologies revisited. PMID- 11609271 TI - Some Aristotelian views on learning and memory. PMID- 11609272 TI - Alexander Bain and the classification of knowledge. PMID- 11609273 TI - Classical rhetoric in Vives' psychology. PMID- 11609274 TI - Psychology of religion 1880-1930: the rise and fall of a psychological movement. PMID- 11609275 TI - The influence of psychoanalytic thought on Benjamin Spock's Baby and Child Care. PMID- 11609277 TI - Renaissance and the evolution of medicine. PMID- 11609276 TI - Watsonian behaviorism and the Calvinist conscience. PMID- 11609278 TI - The place of history of medicine in medical education. PMID- 11609279 TI - Serendipity in medicine. PMID- 11609281 TI - Cabanis and the science of man. J PMID- 11609280 TI - The Siddha and Rasa Siddha Schools of Indian medicine. PMID- 11609282 TI - Galileo on primary and secondary qualities. PMID- 11609283 TI - Vocational development theory before 1400. PMID- 11609284 TI - Psychiatric antecedents of psychological testing (before Binet). PMID- 11609285 TI - Soviet historiography of psychology: III. Between philosophy and history. PMID- 11609286 TI - Theory and practice of ability testing in ancient Greece. PMID- 11609287 TI - Karl Jaspers' psychiatry in the light of his basic philosophic position. PMID- 11609288 TI - E. B. Titchener and the case of the missing element. PMID- 11609289 TI - Solomon Stoddard's Safety of appearing and the dissolution of the Puritan faculty psychology. PMID- 11609290 TI - Bibliography of the history of psychology. PMID- 11609291 TI - Reevaluation of Boring on Kantian influence, nineteenth century nativism, Gestalt psychology and Helmholtz. PMID- 11609292 TI - Images of persons in early American sociology. Part III: the social group. PMID- 11609293 TI - Hune's associationist psychology. PMID- 11609294 TI - The current status of the history and systems of psychology courses in American colleges and universities. PMID- 11609295 TI - Freud in the light of classical rhetoric. PMID- 11609296 TI - A factor analysis of ratings of five schools of psychology on prescriptive dimensions. PMID- 11609297 TI - G. T. Fechner: premises toward a general theory of organisms (1823). PMID- 11609298 TI - Bibliography [of the history of psychology, 1974]. PMID- 11609299 TI - From mechanism to vitalism in eighteenth century English physiology. PMID- 11609300 TI - The place of man in the development of Darwin's theory of transmutation. PMID- 11609301 TI - The rise and fall of Darwin's first theory of transmutation. PMID- 11609302 TI - The initial reactions of French biologists to Darwin's Origin of species. PMID- 11609304 TI - Transvestites in the Middle Ages. PMID- 11609303 TI - Charles Darwin's debt to Malthus and Edward Blyth. PMID- 11609305 TI - Unfouling the public's nest: Chicago's sanitary diversion of Lake Michigan water. PMID- 11609306 TI - Cadaveric supply for anatomical dissections--a historical review. PMID- 11609307 TI - The period of Indian society as reflected in Caraka-Samhita. PMID- 11609308 TI - Professional ethics in ancient Indian medicine. PMID- 11609310 TI - Aspect philosophique du developpement de la biologie moleculaire. (En japonais). PMID- 11609309 TI - Homeostasis - some ancient Indian concepts. PMID- 11609312 TI - Die kranken Sklaven auf der Tiberinsel nach dem Edikt des Claudius. PMID- 11609311 TI - Dr. med. August de Bary und sein standesartztliches Wirken. PMID- 11609313 TI - Der kindliche Schwachsinn als diagnostisches, therapeutisches und soziales Problem im 19. Jahrhundert. PMID- 11609314 TI - Die Anfange der toxikologischen Fremdstoffbeurteilung in der Lebensmittelwissenschaft. PMID- 11609315 TI - August de Bary und die Geschichte der Medizin. PMID- 11609316 TI - Prosopography as a research tool in history of science: the British scientific community 1700-1900. PMID- 11609317 TI - Swedish science in the eighteenth century. PMID- 11609318 TI - The Darwin industry--a critical evalution. PMID- 11609319 TI - Greek medicine dissected. PMID- 11609320 TI - The history of mineral terminology. PMID- 11609321 TI - Introductory statement: the objectives and history of birth planning. PMID- 11609322 TI - The development of population policy in Britain. PMID- 11609323 TI - Carucarya, a medieval sanskrit treatise on personal hygiene. PMID- 11609324 TI - Al-Hawi (Liber continens) of Ar-Razi, Abu Bakr Muhammed Bin Zakariyya: synopsis of the eleventh volume. PMID- 11609325 TI - A Dutch traveller of 16th century on "Social conditions, drugs, diseases, physicians and hospitals in India". PMID- 11609326 TI - Indian goddesses of epidemic diseases. PMID- 11609327 TI - What a modern seer said 25 years ago. The need for an institute of the history of medicine in India. PMID- 11609328 TI - Anandakandam (Root of Bliss). A medieval medical treatise of South India. PMID- 11609329 TI - Manuscripts and psychohistory. PMID- 11609330 TI - Socio-cultural contours of disease. PMID- 11609331 TI - Evolution of obstetrics, gynaecology and family planning in India. PMID- 11609332 TI - A history of western medicine in India. PMID- 11609333 TI - Nineteenth century educational finance: the literary and philosophical societies. PMID- 11609334 TI - A note on "Hara Mekhala". A work in Prakrit, containing many prescriptions of interest to health and medicine. PMID- 11609335 TI - Tibb-a-Giyasia. Unani manuscript on hygiene. (Compiled by HK. Shemsuddeen bin Nooruddeen, during the reign of Jehangir, 1605-1628 A.D.) PMID- 11609336 TI - The medical heritage of India. PMID- 11609337 TI - Ancient Indian medicine. Philosophical and ethical basis, educational and scientific methodology. PMID- 11609339 TI - History of medicine and the Indian universities. PMID- 11609338 TI - A rare manuscript of Madhava's Dravyaguna. PMID- 11609340 TI - What ought to be and what was: Women's sexuality in the nineteenth century. PMID- 11609341 TI - Science, medicine and the universities of early modern England: background and sources, part 2. PMID- 11609342 TI - Centre and periphery in the International Scientific Community: Germany, France and Great Britain in the 19th century. PMID- 11609343 TI - Dialektik und Medizin in der Antike. PMID- 11609344 TI - Melancholie in Ludwig Tiecks "William Lovell". PMID- 11609345 TI - "Die Freigabe der Vernichtung lebensunwerten Lebens"; eine Untersuchung zu der Schrift von Karl Binding und Alfred Hoche. PMID- 11609346 TI - Die Aerzteheiligen Kosman und Damian; ihre Wunderheilungen im Lichte alter und neuer Medizin. Nach einem nachgelassenen Manuskript bearbeitet von Walter Artelt und Werner Friedrich Kummel. PMID- 11609347 TI - Das Instrumentarium von G. A. Brambilla (1785) in Florenz und seine Wiederherstellung nach der Arno-Uberschwemmung im Jahre 1966. PMID- 11609348 TI - Das Portrat des Neuroanatomen Ludwig Edinger von Lovis Corinth (1909). PMID- 11609349 TI - Newton and the demonic furies: some current problems and approaches in history of science. PMID- 11609350 TI - The quest for archives of British men of science. PMID- 11609351 TI - Der Marinearzt Louis Rouppe und sein Beitrag zur Medicina Nautica. PMID- 11609352 TI - Patient und Arzt: die Welt des Kranken im Alten Testament. PMID- 11609353 TI - Recent literature concerning the history of science in the Netherlands. PMID- 11609354 TI - Johann Hartmann Degner und Maximilian Jakob de Man. Ein Beitrag zur Geschichte des Physikats der Stadt Nijmegen im 18. Jahrhundert. PMID- 11609355 TI - Die Krebserkrankung der Byzantinischen Kaiserin Theodora (ein Beitrag zur Geschichte der Syphilis). PMID- 11609356 TI - Antoinette Bourignon's first letter to Jan Swammerdam. A contribution to his biography. PMID- 11609357 TI - Zum Umfallen geboren. Die Kategorien des Pathologischen im Weltbild des Paracelsus. PMID- 11609358 TI - Edelsteine als Antidota. Ein Kapital aus dem Giftbuch des ibn al-Mubarak. PMID- 11609359 TI - Soma, in the light of comparative pharmacology, etymology and archeology. PMID- 11609360 TI - Makers of jewel lenses in Scotland in the early nineteenth century. PMID- 11609361 TI - American and English attitudes to scientific education during the nineteenth century. PMID- 11609363 TI - Logic of discovery and justification in regulatory genetics. PMID- 11609362 TI - The background of physiological psychology in natural philosophy. PMID- 11609364 TI - History of the New York Laryngological Society 1873-1973. PMID- 11609365 TI - A Nightingale letter. PMID- 11609366 TI - A unique addition to the Mortimer and Anna L. Neinken collection: Compasso, Gio. Bartolomeo. Compendi de gli ordini, e decreti dell'Illmo. Magto. di Sanita fatti in ocasione del Contaggio di Milano...l'anno 1629...Milan, 1667. PMID- 11609367 TI - Sir Charles Bell, F.R.C.S.E. (1774-1842): anatomy of expression. PMID- 11609368 TI - Science and philosophy in Aristotle's Generation of animals. PMID- 11609369 TI - Towards a synthesis: population concepts in Russian evolutionary thoutht, 1925 1935. PMID- 11609370 TI - The history of the naming of the Loblolly Bay. PMID- 11609371 TI - The history of embryology as intellectual history. [Essay review]. PMID- 11609372 TI - Descartes' physiological method: position, principles, examples. PMID- 11609373 TI - Harvey and Fludd: The irrational factor in the rational science of the seventeenth century. PMID- 11609374 TI - The medical teaching of demonology in the 17th and 18 centuries. PMID- 11609375 TI - Perkinism vs. mesmerism. PMID- 11609376 TI - A summer institute on the history of psychology: part II. PMID- 11609377 TI - A reappraisal of faculty psychology. PMID- 11609378 TI - Jose Ingenieros, psychologist. PMID- 11609379 TI - Historical aspects of free choice. PMID- 11609380 TI - Whatever happened to the will in American psychology. PMID- 11609381 TI - Values move will: the problem of conceptualization. PMID- 11609382 TI - The reflex model in psychology: origins and evolution. PMID- 11609383 TI - Changes of emphasis in the sociology of W. I. Thomas. PMID- 11609386 TI - The care and use of medicinal leeches in 19th century pharmacy and therapeutics. PMID- 11609387 TI - Magnesia alba before Black. PMID- 11609388 TI - Cornell--a short-lived school of pharmacy. PMID- 11609389 TI - Drug adulteration: Detection and control in Canada. I. Beginnings: The Inland Revenue Act of 1875. PMID- 11609391 TI - Factors leading to the formation of the Chicago College of Pharmacy. PMID- 11609390 TI - American concern over marihuana in the 1930's. PMID- 11609392 TI - Die Entwicklung der Zahn-, Mund- und Kieferheilkunde im europaischen Mittelalter. PMID- 11609393 TI - Die Grafin von Mansfeld als arztliche Ratgeberin Luthers. PMID- 11609394 TI - Die Lehre von der Spatgestose (Eklampsie) im Spiegel der allgemeinen Medizingeschichte. PMID- 11609395 TI - Zur Entwicklung der Irrenfursorge im Donauraum. PMID- 11609396 TI - Ueber den Einfluss der Chenotschen Seuchenordnung auf Siebenburgen. PMID- 11609397 TI - Die Pharmakopoe, ein Spiegel ihrer Zeit (Tschirch)? PMID- 11609398 TI - Ein bisher unveroffentlichter Brief Wilhelm Griesingers an Carl August Wunderlich. PMID- 11609399 TI - Ein zahnmedizinischer Bericht von 1867 aus Stavanger. PMID- 11609400 TI - Zur Osteoarchaologie der mittelalterlichen Lepra. Ergebnis einer Probegrabung im Melaten bei Aachen. PMID- 11609401 TI - Statilios Attalos. Ein Beitrag zur medizinhistorischen Numismatik der Antike. PMID- 11609402 TI - Yuhanna ibn Sarabiyun. Untersuchungen zur Ueberlieferungsgeschichte seiner Werke. PMID- 11609403 TI - L. J. Henderson and the theory of buffer action. PMID- 11609404 TI - Aus meinem Leben--Ruckschau und Ausblicke. PMID- 11609405 TI - [Not Available]. PMID- 11609407 TI - History: The Muse and her doctors. PMID- 11609408 TI - As others saw us: notes on the reputation of the American Philosophical Society. PMID- 11609409 TI - The story of "Anna O": a critical review with new data. PMID- 11609410 TI - The causal issue in empirical psychology from Hume to the present, with emphasis upon the work of Michotte. PMID- 11609411 TI - Aristotle's opinion on perception in general. PMID- 11609412 TI - Who originated the term "psychology"? PMID- 11609413 TI - Sebastien Le Clerc on retinal disparity. PMID- 11609414 TI - Bibliography [of history of behavioral sciences]. PMID- 11609415 TI - A prescriptive analysis of Descartes' psychological views. PMID- 11609416 TI - William James on the will. PMID- 11609418 TI - George Combe: a portrait of a heretofore generally unknown behaviorist. PMID- 11609417 TI - Henri Pieron and French psychology: a comment on Professor Fraisse's note. PMID- 11609419 TI - Did Titchener commit the stimulus error? The problem of meaning in structural psychology. PMID- 11609420 TI - The Journal of American Psychology: a pioneering psychological journal. PMID- 11609421 TI - Bibliography [of the History of Psychology]. PMID- 11609422 TI - Preformation and pre-existence in the seventeenth century: a brief analysis. PMID- 11609423 TI - The iatromechanical background of Lagrange's theory of animal heat. PMID- 11609424 TI - Measuring man's needs. PMID- 11609425 TI - Concepts of nerve fiber development, 1839-1930. PMID- 11609426 TI - Sir William Lawrence (1783-1867); a study of pre-Darwinian ideas on heredity and variation. PMID- 11609427 TI - Fontenelle and the problem of generation in the eighteenth century. PMID- 11609428 TI - Lamarck's science of living bodies. PMID- 11609429 TI - Organic synthesis and the unification of chemistry--a reappraisal. PMID- 11609430 TI - Conflict of concepts in early vitamin studies. PMID- 11609431 TI - Notes on source materials: the L. J. Henderson papers at Harvard. PMID- 11609432 TI - Schrodinger's problem: What is life? PMID- 11609433 TI - An unacknowledged founding of molecular biology: H. J. Muller's contributions to gene theory, 1910-1936. PMID- 11609434 TI - Haldane and Huxley: the first appraisals. Essay review. PMID- 11609435 TI - USSR: current activities in the history of physiology and psychology. PMID- 11609436 TI - Darwin, Malthus, and selection. PMID- 11609437 TI - The background to Eduard Buchner's discovery of cell-free fermentation. PMID- 11609438 TI - Organismic and holistic concepts in the thought of L. J. Henderson. PMID- 11609439 TI - Muckraking and consumer protection. The case of the 1938 Food, Drug and Cosmetic Act. PMID- 11609440 TI - The development of drug standards in Latin America. PMID- 11609442 TI - Reception of the germ theory of disease in the American Journal of Pharmacy. PMID- 11609441 TI - Gnosticism, drugs, and alchemy in late Roman Egypt. PMID- 11609443 TI - Samson of the materia medica: medical theory and the use and abuse of calomel in nineteenth century America. PMID- 11609444 TI - Structure-activity relationships--the early mirage. PMID- 11609445 TI - Hans von Gersdorff and some anonymous Strassburg apothecaries. PMID- 11609446 TI - My dear Professor Kremers: the Ebert letters. PMID- 11609447 TI - Facts about artifacts. PMID- 11609448 TI - Education and sex: the medical case against higher education for women in England, 1870-1900. PMID- 11609449 TI - On the apparent size of projected after-image: Emmert's or Castelli's law? A case of 242 years anticipation. PMID- 11609450 TI - Helvetius and Jefferson: studies of human nature and government in the eighteenth century. PMID- 11609451 TI - Models of mind and mental illness in ancient Greece: II. The platonic model. PMID- 11609452 TI - The incorporation of action into associationism: the psychology of Alexander Bain. PMID- 11609453 TI - The old Greek concept of "relative" health. PMID- 11609454 TI - The short history of projective techniques. PMID- 11609455 TI - The professionalization of American psychology, 1870-1917. PMID- 11609456 TI - Information, redundancy and gestalt psychology: an historical note and translation. PMID- 11609457 TI - Development of the third party payment concept for medical and pharmaceutical services. PMID- 11609458 TI - Blumberg collection Auctioned. PMID- 11609459 TI - A salute to Glenn Sonnedecker. PMID- 11609460 TI - The Seminary for the history of pharmacy at the Technical University in Braunschweig. PMID- 11609462 TI - Amber in ancient pharmacy. The transmission of information about a single drug. PMID- 11609461 TI - Innovation, confrontation, and perseverance-Albert B. Prescott's legacy to pharmaceutical education in America. PMID- 11609463 TI - Marcellus of Bordeaux and the beginnings of medieval materia medica. PMID- 11609464 TI - From these ashes. PMID- 11609465 TI - The pharmaceutical poster. PMID- 11609466 TI - The Pharmaceutical Museum of the Central Pharmaceutical Scientific-Research Institute (Moscow). PMID- 11609467 TI - Growth of scientific medicine in France from Renaissance to second World War. PMID- 11609468 TI - Public medical service and the growth of hospitals in India. PMID- 11609469 TI - History of depression--some aspects. PMID- 11609470 TI - A note on cobras and cure of blindness. PMID- 11609471 TI - A note on Charcot (1825-1893). PMID- 11609472 TI - The Davenport papers. PMID- 11609473 TI - DNA and reductionism. PMID- 11609474 TI - ["The plant wizard" and the geneticist]. PMID- 11609475 TI - Animal chemists and urinary stone. PMID- 11609476 TI - The Annales de Chimie, 1789-1815. PMID- 11609478 TI - [Not Available]. PMID- 11609477 TI - Some comments on the contemporary Helmontian renaissance [Essay review]. PMID- 11609479 TI - [Not Available]. PMID- 11609480 TI - [Not Available]. PMID- 11609481 TI - [Not Available]. PMID- 11609482 TI - Problems of a new medical and pharmaceutical print collection. PMID- 11609483 TI - [Not Available]. PMID- 11609484 TI - [Not Available]. PMID- 11609485 TI - [Not Available]. PMID- 11609486 TI - [Not Available]. PMID- 11609487 TI - [Not Available]. PMID- 11609488 TI - [Not Available]. PMID- 11609489 TI - [Not Available]. PMID- 11609490 TI - [Not Available]. PMID- 11609491 TI - [Not Available]. PMID- 11609492 TI - [Not Available]. PMID- 11609493 TI - [Not Available]. PMID- 11609494 TI - [Not Available]. PMID- 11609495 TI - Home medication on the American frontier (1804). PMID- 11609496 TI - [Not Available]. PMID- 11609497 TI - [Not Available]. PMID- 11609498 TI - [Not Available]. PMID- 11609499 TI - Jan Evangelista Purkyne's contribution to the study of drugs. PMID- 11609500 TI - [Not Available]. PMID- 11609501 TI - [Not Available]. PMID- 11609502 TI - The standardisation of galenical medicines in 19th century British pharmacy. PMID- 11609503 TI - [Not Available]. PMID- 11609504 TI - [Not Available]. PMID- 11609505 TI - [Not Available]. PMID- 11609506 TI - [Not Available]. PMID- 11609508 TI - Governmental regulation of the use of human subjects in medical research; The approach of two federal agencies. PMID- 11609507 TI - Scarce resources and medical advancement. PMID- 11609509 TI - The brass age of psychology. [Exhibit review]. PMID- 11609510 TI - The intellectual development of Walter Charleton. PMID- 11609511 TI - The history of chemistry and the history of science. PMID- 11609513 TI - Historical demography. PMID- 11609512 TI - French Stahlism and chemical studies of air, 1750-1770. PMID- 11609514 TI - Economic development and the fertility transition. PMID- 11609515 TI - Marriage and marital fertility. PMID- 11609516 TI - Early fertility decline in Austria-Hungary: a lesson in demographic transition. PMID- 11609517 TI - Fertility and population growth in Spain in the eighteenth and nineteenth centuries. PMID- 11609518 TI - Certain demographic characteristics of the plague epidemic in France, 1720-22. PMID- 11609519 TI - Mortality in pre-industrial England: the example of Colyton, Devon, over three centuries. PMID- 11609520 TI - Notes on the demography of London at the end of the seventeenth century. PMID- 11609521 TI - Legitimate fecundity and infant mortality in France during the eighteenth century: a comparison. PMID- 11609523 TI - Prescriptions as operative in the history of psychology. PMID- 11609522 TI - Underlying themes in the witchcraft of seventeenth-century New England. PMID- 11609524 TI - Gestation of the instinct concept. PMID- 11609525 TI - Alfred Adler and G. Stanley Hall: correspondence and general relationship. PMID- 11609526 TI - Allport, Murray, and Lewin on personality theory: Notes on a confrontation. PMID- 11609527 TI - "Sigmund Freud as a Jew": A study in ambivalence and courage. PMID- 11609528 TI - Binet on perceptual-cognitive development or Piaget-come-lately. PMID- 11609529 TI - Aristotle's dynamic approach to sensing and some current implications. PMID- 11609530 TI - Some significant aspects of the origin and development of medicine in ancient India. [Abridged]. PMID- 11609531 TI - Human anatomy according to the Agni Purana. PMID- 11609532 TI - Biology in ancient and medieval India. PMID- 11609533 TI - Contribution of Susruta to the fundamentals of orthopaedic surgery. PMID- 11609534 TI - Family relations of some plants in the Atharvaveda. PMID- 11609535 TI - Susruta's contributions to the fundamentals of surgery. PMID- 11609536 TI - Methodology for experimental research in ancient India. PMID- 11609537 TI - Medical science and dispensaries in ancient South India as gleaned from epigraphy. PMID- 11609538 TI - The Brahmanas on medicine and biological sciences. PMID- 11609539 TI - Medicine--as it evolved in ancient and mediaeval India. PMID- 11609540 TI - French origins of the psychology of behavior: the contribution of Henri Pieron. PMID- 11609541 TI - Morton Prince and the dissociation of a personality. PMID- 11609542 TI - Gestalt theory: early history and reminiscences. PMID- 11609543 TI - Landmarks in the history of Latin American psychology. PMID- 11609546 TI - An historical note: J Stanley Gray's "behavior modification," 1932. PMID- 11609545 TI - Goethe as behavior therapist. PMID- 11609544 TI - An application of the concept of identification for the historian. PMID- 11609547 TI - A note on a seventeenth-century distinction between feral man and manlike apes. PMID- 11609549 TI - An historical look at ethology: a shot in the arm for comparative psychology. PMID- 11609548 TI - Hartmann's relationship to Freud: a reappraisal. PMID- 11609550 TI - The formation of the medical and surgical professorial units in the London teaching hospitals. PMID- 11609551 TI - Aztec science and technology. PMID- 11609552 TI - The history of optical instruments. A brief survey of sources and modern studies. PMID- 11609553 TI - Medicine in ancient Mesopotamia. PMID- 11609554 TI - War-horse of dosimetry. PMID- 11609555 TI - Florentius Schuyl und seine Bedeutung fur die Verbreitung des Cartesianismus in den Niederlanden. PMID- 11609556 TI - Wer waren Georg Grubler und Karl Hollborn? PMID- 11609558 TI - "Volpone" as the source of the sickroom scheme in Middleton's "Mad World". PMID- 11609557 TI - Johann Marcus Marci writes to Athanasius Kircher. PMID- 11609559 TI - Primary care in the industrial areas of Britain. Evolution and current problems. PMID- 11609560 TI - Harvard's new collection in the history of radiology. PMID- 11609562 TI - The problem of animate motion in the seventeenth century. PMID- 11609564 TI - The X Club: fraternity of Victorian scientists. PMID- 11609563 TI - The idea of chemical warfare in modern times. PMID- 11609565 TI - Ueber die Sorgfaltspflicht der Aerzte von Kos. PMID- 11609566 TI - Die reale Stadt und die Krankheit im 17. Jahrhundert. PMID- 11609567 TI - Ueber die Einflusse der Jesuitenmission des 17. und 18. Jahrhunderts auf die Medizin in China. PMID- 11609568 TI - Das Isolierungsprinzip in der Pestbekampfung des 17. Jahrhunderts. PMID- 11609569 TI - Ernst Georg Pringsheim (geb. 26. 10. 1881). Eine autobiographische Skizze. PMID- 11609570 TI - Unser Bild. PMID- 11609571 TI - Zu Begriffsgeschichte und Bedeutungswandel von vis und virtus im Paracelsistenstreit. PMID- 11609572 TI - Dura mater, Pia mater. Die Geschichte zweier anatomischer Termini. Dem Andenken Hermann Lehmanns gewidmet. PMID- 11609574 TI - Die Anfaange der wissenschaftlichen Nekroskopie in Russland. PMID- 11609573 TI - Hypothesen zur ursprunglich geplanten Ordnung der hippokratischen Schriften De fracturis and De articulis. PMID- 11609575 TI - Hygiene in utopischen Entwurfen des 16. und 17. Jahrhunderts. PMID- 11609576 TI - "Soe-Quaest-Huuset" das Marinespital zu Kopenhagen und seine Funktion 1788-1791. PMID- 11609577 TI - Schadeltrepanationen in Afrika. (Eine Erganzung zu dem Beitrag von A. M. Dauer und L. v. Karolyi: "Maganga--ein wissenschaftlicher Film?" In: Med. Hist. J. 5 (1970), S. 138-144). PMID- 11609578 TI - Rudolf Virchow als Gast im Hause meines Grossvaters; eingeleitet von Valeriu L. Bologa. PMID- 11609579 TI - Konturen der medizinhistorischen Arbeit in der DDR. PMID- 11609580 TI - [J. Chr. G. Jorg]. PMID- 11609581 TI - Klinische Beschreibung des Barre-Lieou-Syndroms in De Arthritide anomala sive interna von G. Musgrave. PMID- 11609582 TI - Die Militarspitaler wahrend der napoleonischen Kriege in Mahren. PMID- 11609583 TI - Zur Geschichte der Anatomischen Institute von Kassel und Mainz. PMID- 11609584 TI - Albrecht von Graefe (geb. 1828) zum 100. Todestag am 20.7. 1970. PMID- 11609585 TI - Deutsche Aerzte uber den sudlichen Himmel und das Land Brasilien 1500-1650. PMID- 11609586 TI - Gemeinschaft und Absonderung der Kranken als antagonistische Faktoren historischer Hospitaler (1500-1900). PMID- 11609587 TI - Das Elisabeth-Hospital zu Marburg an der Lahn. Ein bau- und medizingeschichtliches Denkmal aus der Nach-Stauferzeit. PMID- 11609588 TI - Zur Arbeit von Hans-Theodor Koch, Dr. Wilhelm Reil-Bey (1820-1880). Ein abtrunniger "Homoopath als Balneologe in Aegypten". In: "Medizinhistorisches Journal", 1968, Bd. 3, Heft 2, S. 101-113. PMID- 11609589 TI - Dr. Wilhelm Reil-Bey (1820-1880), ein abtrunniger Homoopath! (Erwiderung auf die Diskussionsbemerkung von Hein Henne). PMID- 11609590 TI - Numismatische Darstellungen der Arztheiligen Kosmas und Damian. PMID- 11609591 TI - Henry E. Sigerist--ein enttauschter Amerikaner? PMID- 11609592 TI - Arzt und Krankheit in einigen Gedichten des arabischen Lyrikers al-Mutanabbi. PMID- 11609593 TI - The New York study of physical constitution and psychotic pattern. PMID- 11609594 TI - Early history of perceptual illusions. PMID- 11609595 TI - A note on the Koffka papers. PMID- 11609596 TI - Hume's contribution to behavioral science. PMID- 11609597 TI - The contents of children's minds: a partial replication. PMID- 11609598 TI - Degeneration, disinhibition, and genius. PMID- 11609599 TI - A reply to Thornton's: "Socrates and the history of psychology". PMID- 11609600 TI - Citation analysis as a tool in historical study, a case study based on F.C. Donders and mental reaction times. PMID- 11609601 TI - Early experimental psychology in New Zealand: the Hunter-Titchener letters. PMID- 11609602 TI - On the pitfalls of biographical writing (on Paul Roazen's Brother animal--the story of Freud and Tausk) [Essay review]. PMID- 11609603 TI - Edward Bradford Titchener: a pioneer in perception. PMID- 11609604 TI - The Biblical conception of psychopathy: the law of the stubborn and rebellious son. PMID- 11609605 TI - The legacies of Koffka's Principles. PMID- 11609607 TI - The neurological origin of Freud's dream theory. PMID- 11609606 TI - Greek theories of imagination. PMID- 11609608 TI - The relations between history and history of science. PMID- 11609610 TI - Relations and rivalry: Interactions between Britain and the Netherlands in eighteenth-century science and technology. PMID- 11609609 TI - William Harvey revisited. PMID- 11609611 TI - The psychohistorical origins of the Nazi youth cohort. PMID- 11609612 TI - The use and abuse of psychology in history. PMID- 11609613 TI - Presidency General Hospital, Calcutta: Treatment of fever and dysentery cases during 1797-1850. PMID- 11609614 TI - The outline of the history of the Unani medical literature. Part II. PMID- 11609615 TI - Historical errors in neuroblastoma literature. PMID- 11609616 TI - [History of science in Japan]. (Jpn) PMID- 11609617 TI - The archives of the history of American psychology. PMID- 11609618 TI - A short history of public health in India. PMID- 11609619 TI - The concept of Rasayana therapy in Indian medicine and a comprehensive approach to its evaluation. PMID- 11609620 TI - Alchemy: origin or origins? PMID- 11609621 TI - The Hartlib papers and seventeenth century chemistry. Pt. II. PMID- 11609623 TI - The date of Dhanwantari nighantu. PMID- 11609622 TI - The growth of Greco-Arabian medicine in medieval India. PMID- 11609624 TI - Ideas of scientific measurement in basic principles of Ayurveda with special reference to somatometry. PMID- 11609625 TI - The revolution in English social thought 1880-1914. PMID- 11609626 TI - Psychology at Victorian Cambridge-the unoffical laboratory of 1887-1888. PMID- 11609627 TI - The newer antivivisectionists. PMID- 11609628 TI - The Animadversiones of Ippolito Francesco Albertini (1748) on cardiac and precordial diseases which cause dyspnea. PMID- 11609630 TI - The Pharmacopeia and America--150 years of service. An address presented on the occasion of the sesquicentennial convention of the USP, April 8-10, 1970. PMID- 11609629 TI - The philanthropic contributions of Chicago's first pharmacist-Philo Carpenter (1805-1886). PMID- 11609631 TI - A note on embalming procedures of al-Razi. PMID- 11609632 TI - Lithotherapy in the Middle Ages... lapidaries considered as medical texts. PMID- 11609633 TI - The persistence of theriac in France. PMID- 11609634 TI - Caspar Neumann, an early teacher of pharmaceutical chemistry. PMID- 11609635 TI - Josiah Kirby Lilly, Sr., the man (1861-1948). PMID- 11609636 TI - The original text of the Latin Morienus. PMID- 11609637 TI - The "Macbridean doctrine" of air: and eighteenth-century explanation of some biochemical processes, including photosynthesis. PMID- 11609638 TI - Autobiographic notes on the identity crisis. PMID- 11609639 TI - The continuity of genetics. PMID- 11609640 TI - DNA. PMID- 11609641 TI - Fifty years of progress in structural chemistry and molecular biology. PMID- 11609642 TI - Nineteenth century ventures in Liverpool's scientific education. PMID- 11609643 TI - The later Victorians and scientific and technical education. PMID- 11609644 TI - A note on Vaidyasastra Sivanubhava, an Ayurvedic manuscript of XVII. Century A.D. PMID- 11609645 TI - Anandakandam; nineteenth ullasa. PMID- 11609646 TI - Tohofetul-mulook (a gift for the kings). PMID- 11609647 TI - Mayarul-atibba. (a standard book for the physicians). PMID- 11609648 TI - Health, disease, physician and medicine in Thirukkural. PMID- 11609649 TI - 150 year old bibliography of Siddha medical literature. PMID- 11609650 TI - Tuberculosis in ancient India. PMID- 11609652 TI - Action propre and action commune: the localization of cerebral function. PMID- 11609651 TI - Dollo on Dollo's law: irreversibility and the status of evolutionary laws. PMID- 11609653 TI - Electricity and the nervous fluid. PMID- 11609654 TI - Darwin and the physiologists, or the Medusa and modern cardiology. PMID- 11609655 TI - Lamarck, evolution and the politics of science. PMID- 11609656 TI - Humboldt, Darwin, and population. PMID- 11609657 TI - Preventive psychotherapy-some Indian concepts. PMID- 11609658 TI - G. Stanley Hall and John B. Watson as child psychologists. PMID- 11609659 TI - Leibniz, Freud and Kabbala. PMID- 11609660 TI - Freud's visit to America: newspaper coverage. PMID- 11609661 TI - Is phrenology foolish? A rejoinder. PMID- 11609662 TI - A note on an eighteenth century anticipation of Freud's theory of dreams. PMID- 11609664 TI - Social welfare in Calvin's Geneva. PMID- 11609665 TI - Gymnastics and sports in fin-de-siecle France: opium of the classes? PMID- 11609666 TI - Joseph Priestley, natural philosopher. PMID- 11609667 TI - English medical reformers of the Puritan Revolution: a background to the "Society of Chymical Physitians". PMID- 11609668 TI - The history of biological researches IV. The historical consideration on the karyological studies in yeasts. PMID- 11609672 TI - A note on Harita Samhita. PMID- 11609674 TI - Siddhars, their attainments and their role in medicine. PMID- 11609673 TI - Establishment of Unani hospitals in Islamic countries. PMID- 11609675 TI - About entry of homoeopathy into India. PMID- 11609677 TI - Select articles of medical history of India in journals of Indian systems of medicine. PMID- 11609676 TI - John Forbes Royle, botanist, medical historian, teacher, and benefactor of British Empire. PMID- 11609681 TI - Rattlesnakes and hummingbirds: Philadelphia's resources for the history of science. PMID- 11609682 TI - The origins of health insurance for the aged. PMID- 11609683 TI - Dress, ornaments and daily physical care in Caraka and Susruta. PMID- 11609684 TI - History of mycetoma. PMID- 11609685 TI - An analysis of the Ayurvedic concept of the anatomy and physiology of urinary tract in the light of modern science. PMID- 11609686 TI - Dracontiasis--a historical review. PMID- 11609687 TI - Bringing the history of personality theories up to date: German theories of personality stratification. PMID- 11609688 TI - The pre-Chicago association of the early functionalists. PMID- 11609689 TI - Puritans and the passions: the faculty psychology in American Puritanism. PMID- 11609690 TI - G. Stanley Hall and the boys' club: conservative applications of recapitulation theory. PMID- 11609691 TI - An historical note on Descartes' psychophysical dualism. PMID- 11609692 TI - Bibliography [of history of behavioral sciences]. PMID- 11609693 TI - Second Summer Institute on the History of Psychology. PMID- 11609695 TI - Acupuncture. PMID- 11609696 TI - Alexander Crum Brown and his doctoral thesis of 1861. PMID- 11609697 TI - The London Chemical Society 1824. PMID- 11609698 TI - Johann Conrad Barchusen (1666-1723)--contemporary and rival of Boerhaave. PMID- 11609699 TI - La typologie d'Albrecht Durer. PMID- 11609700 TI - Ancient trepanning instruments (extract). PMID- 11609701 TI - On the early history of tattooing. PMID- 11609702 TI - Steno in Amsterdam. PMID- 11609703 TI - The correspondence of Hugo de Vries and Charles Darwin. PMID- 11609704 TI - Die Palpation in Corpus Hippocraticum. Ein Beitrag zur Geschichte der antiken Diagnostik. PMID- 11609706 TI - Basic terms of Greek alchemy in historical perspective. PMID- 11609705 TI - Barchusen and Boerhaave. PMID- 11609707 TI - Un polyptyque Breton inedit des saints Come et Damien. PMID- 11609708 TI - History and the learned journal. PMID- 11609709 TI - Aristotle and modern biology. PMID- 11609710 TI - Thorndike's puzzle boxes. PMID- 11609712 TI - Precursors of psychology in ancient Egypt. PMID- 11609711 TI - E. B. Titchener and his lost system. PMID- 11609713 TI - The self-psychology of Mary Whiton Calkins. PMID- 11609715 TI - Spinoza's influence on the rise of scientific psychology a neglected chapter in the history of psychology. PMID- 11609714 TI - The German university and the development of experimental psychology. PMID- 11609716 TI - Format of publication and election to the presidency of the American Psychological Association. PMID- 11609717 TI - Behaviourism and positivism. PMID- 11609718 TI - Kant's view on the nature of empirical psychology. PMID- 11609719 TI - To test or not to test: trends in the Soviet views. PMID- 11609720 TI - The background to Otto Warburg's conception of the Atmungsferment. PMID- 11609721 TI - The re-examination of Spallanzani's interpretation of the role of the spermatic animalcules in fertilization. PMID- 11609722 TI - The historical context of natural selection: The case of Patrick Matthew. PMID- 11609723 TI - Bonnet and Buffon: Theories of Generation and the problem of species. PMID- 11609724 TI - The biometric defense of Darwinism. PMID- 11609725 TI - Six recent additions to the history of physiology in the USSR. PMID- 11609726 TI - Ernst Cassirer's psychology. PMID- 11609727 TI - Soviet historiography of psychology. PMID- 11609728 TI - Discussion: The influence of Whitehead's organism upon Murray's personology. PMID- 11609730 TI - Some problems and sources in the foundations of modern physiology in Great Britain. PMID- 11609729 TI - Galton's "Law of ancestral heredity": Its influence on the early development of human genetics. PMID- 11609731 TI - The psychology and physiology of behaviour: some recent Soviet writings on their history. PMID- 11609732 TI - William Bateson, Mendelism and biometry. PMID- 11609733 TI - The recent historiography of genetics. [essay review]. PMID- 11609734 TI - Mr. Darwin' critics. old and new. [essay review]. PMID- 11609735 TI - Spermatozoan biology from Leeuwenhoek to Spallanzani. PMID- 11609736 TI - "Notes for Mr. Darwin": Letters to Charles Darwin from Edward Blyth at Calcutta: a study in the process of discovery. PMID- 11609737 TI - Problems of variation and heredity in Russian biology in the late nineteenth century. PMID- 11609738 TI - History of sciences in India: Pali sources. PMID- 11609739 TI - Sivadasa Sen--a scholar commentator on Indian medicine of later medieval period (15th cent. A.D.). PMID- 11609740 TI - Trimalla Bhatta: his dates and work with special reference to his Materia Medica in one hundred verses. PMID- 11609741 TI - Notices of thirteen MSS. in Prakrt with special reference to their scientific and technological contents. PMID- 11609743 TI - OE "Hors-ome". PMID- 11609742 TI - John Addington Symond's share in "Sexual inversion". PMID- 11609744 TI - Sources for the history of science in the Harvard University Archives. PMID- 11609745 TI - From amateurs to professionals in American science: the controversy over the proceedings of an 1853 scientific meeting. PMID- 11609746 TI - An early 18th-century artist looks at medicine. [Abridged]. PMID- 11609747 TI - Murder and medicine. [Abridged]. PMID- 11609748 TI - Medical education in 18th century hospitals. PMID- 11609749 TI - Sir Alexander Ogston. PMID- 11609750 TI - [Japanese herbals mentioned in Thunberg's books]. (Jpn) PMID- 11609751 TI - Annual bibliography for 1969. PMID- 11609752 TI - The seat of mind - some ancient concepts. PMID- 11609753 TI - The place of history of medicine in medical education. PMID- 11609754 TI - Panch Karma therapy in Indian medicine. PMID- 11609755 TI - Historical review of carcinoma of the gallbladder. PMID- 11609756 TI - Thirty-five years with Freud. In honour of the hundredth anniversary of Paul Federn, M.D., PMID- 11609757 TI - Phenomenology of willing in historical view. PMID- 11609758 TI - The debt of Leibniz to Pardies. PMID- 11609759 TI - What can we learn from the history of psychology? PMID- 11609760 TI - America's first major psychologist Laurens Perseus Hickok. PMID- 11609761 TI - Mary Whiton Calkins: A discussion. PMID- 11609762 TI - Social research in America before the Civil War. PMID- 11609763 TI - Schools and systems: The mutual isolation of operant and non-operant psychology as a case study. PMID- 11609764 TI - Wolfgang Talhauser zu Leben und Werk eines Augsburger Stadtarztes und seinen Beziehungen zu Paracelsus und Schwenckfeld. PMID- 11609766 TI - Ein Corpus Medicorum Syriacorum. PMID- 11609765 TI - Eine spatmittelalterliche Darstellung des Mongolismus-Syndroms auf dem Aachener Passionsaltar. PMID- 11609767 TI - Experimentelle Pharmakologie an der Universitat Gottingen im 18. Jahrhundert. PMID- 11609768 TI - Johann Beckmanns Berichte uber Linne und Hammarby. PMID- 11609769 TI - Johann Andreas Murray als Lehrer der Kinderheilkunde in Gottingen. PMID- 11609770 TI - Der Generationswechsel. Die Geschichte eines biologischen Problems. PMID- 11609771 TI - Rudolf Virchow und Gustav Wegscheider in der Erinnerung Alfred Kortes. PMID- 11609772 TI - Jugenderinnerungen an das alte Senckenbergianum. PMID- 11609773 TI - Eine Schlusselbeinbeschadigung aus der Wikingerzeit--Folge einer Folterung? PMID- 11609774 TI - Altes Neues zu Philipp Bozzini (1773-1809). PMID- 11609775 TI - Der Frankfurter Arzt Philipp Bozzini, der Erfinder des Lichleiters, 1773-1809. PMID- 11609776 TI - Zum Plan eines Corpus Medicorum Syriacorum. PMID- 11609777 TI - Alchemie und Aufklarung. Ein Beitrag zur Naturwissenschaftsgeschichtsschreibung der Aufklarung. PMID- 11609779 TI - Idiosynkrisie und therapeutischer Nihilismus. PMID- 11609778 TI - Das Steinbuch des Xenokrates von Ephesos. PMID- 11609780 TI - Die Ikonographie des Steinschneiders Jacques Beaulieu (1651-1714). PMID- 11609781 TI - William Prout, M.D., F.R.S. physician and chemist (1785-1850). PMID- 11609782 TI - William Prout and barometry. PMID- 11609783 TI - Thomas Thomson's activities in Edinburgh, 1791-1811. PMID- 11609784 TI - The X-Club a social network of science in late-Victorian England. PMID- 11609785 TI - Some botanical activities of Herman Boerhaave, professor of botany and director of the botanic garden at Leiden. PMID- 11609786 TI - Einige Beitrage zur Geschichte der Krebskrankheit in Byzanz (die Aerzte-der Kaiser-die Prinzessin). PMID- 11609787 TI - Colloidal gold as an alchemical preparation. PMID- 11609788 TI - The impact of Descartes on seventeenth century medical thought in the Netherlands. PMID- 11609789 TI - Newtonian and Darwinian conceptions of man; and some alternatives. PMID- 11609790 TI - Erik Erikson on William James's dream: a note of correction. PMID- 11609791 TI - Eminent psychologists: corrections and additions. PMID- 11609792 TI - Science and Scottish University reform: Edinburgh in 1826. PMID- 11609798 TI - Eroticism and gastrosophy. PMID- 11609799 TI - Medical manuscripts in Middle English. PMID- 11609800 TI - Toward a psychoanalytic interpretation of Bismarck. PMID- 11609801 TI - Between science and art [Essay review]. PMID- 11609802 TI - John Locke, John Ray, and the problem of the natural system. PMID- 11609803 TI - The universal gestation of nature: Chambers' Vestiges and explanations. PMID- 11609804 TI - Wallace, Darwin, and Edward Blyth: further notes on the development of evolution theory. PMID- 11609805 TI - The endurance of the mechanism-vitalism controversy. PMID- 11609806 TI - Harvey redux [Essay review]. PMID- 11609807 TI - Lamarck revisited. PMID- 11609808 TI - The spontaneous generation controversy (1700-1860): The origin of parasitic worms. PMID- 11609809 TI - Verbal charms in British folk medicine. PMID- 11609810 TI - Modern psychology and the interpretation of medieval texts. PMID- 11609811 TI - Robert Burton, Jonathan Swift, and the tradition of anti-Puritan invective. PMID- 11609812 TI - Body, soul, and the marriage relationship: the history of an analogy. PMID- 11609813 TI - Western natural philosophy published in late Ming China. PMID- 11609815 TI - Scientific works in Sanskrit, translated into foreign languages and vice-versa in the 18th and 19th century A.D. PMID- 11609814 TI - Botany in the Vedas (part I). PMID- 11609816 TI - Female emancipation, birth control, and fertility in European history. PMID- 11609817 TI - Death and dying in Puritan New England. PMID- 11609818 TI - Pharmacy in a Castle. PMID- 11609819 TI - Helmholtz's "Popular lectures on vision." PMID- 11609820 TI - Erwin A. Esper 1895-1972. PMID- 11609821 TI - Is man no more than this?: Evaluative bias in interspecies comparison. PMID- 11609822 TI - D'Assigny and the art of memory. PMID- 11609823 TI - The humanization of the American child: Benjamin Spock as a popularizer of psychoanalytic thought. PMID- 11609824 TI - Irons in the fire: Introduction to a symposium on archival research. PMID- 11609825 TI - Retrieval of primary sources. PMID- 11609826 TI - Design questions in archival research. PMID- 11609827 TI - Unique values of archival research. PMID- 11609828 TI - Some values and limitations of oral histories. PMID- 11609829 TI - Frustrations and joys of archival research. PMID- 11609830 TI - The influence of Jung on the work of Claude Levi-Strauss. PMID- 11609831 TI - Perversions ancient and modern: I. Agalmatophilia, the statue syndrome. PMID- 11609832 TI - The history of psychology as a specialty: A personal view of its first 15 years. PMID- 11609833 TI - The doctrine of "pure experience": the evolution of a concept from Mach to James to Tolman. PMID- 11609834 TI - The history of the relationship between environment and culture in ethnological thought: an overview. PMID- 11609835 TI - The almost forgotten Feuchtersleben: poet, essayist, popular philosopher and psychiatrist. PMID- 11609836 TI - A note on Sumerian Ki-Ag and territoriality. PMID- 11609837 TI - Models of power: past and present. PMID- 11609838 TI - In honor of Robert Brodie Macleod: psychological phenomenology face to face with the persistent problems of psychology. PMID- 11609839 TI - The 1774 ordinance for the hospitalization of the mentally ill in Tuscany: a reassessment. PMID- 11609840 TI - Harvey on the soul: a unique episode in the history of psychophysiological thought. PMID- 11609841 TI - A national inventory of historic psychological apparatus. PMID- 11609842 TI - Wilhelm Wundt 1832-1920: a brief biographical sketch. PMID- 11609843 TI - Christian science and mind cure in America: a review article. PMID- 11609844 TI - Medicine and pharmacy in French political prints. PMID- 11609845 TI - Lest we forget... Address of the president. PMID- 11609846 TI - Edmund Burke Delabarre and the petroglyphs of southeastern New England. PMID- 11609847 TI - The interpretation of dreams: early reception by the educated German public. PMID- 11609848 TI - The early Nebraska psychology laboratory, 1889-1930: Nursery for presidents of the American Psychological Association. PMID- 11609849 TI - Case studies in nineteenth century scientific rejection: Mesmerism, perkinism, and acupuncture. PMID- 11609850 TI - The historiography of scientific psychology: A critical study. PMID- 11609852 TI - Die Entwicklung der Impfgesetzgebung in Hessen. PMID- 11609851 TI - Bibliography [of the History of Psychology, 1974]. PMID- 11609853 TI - Jakob von Uexkull und Houston Stewart Chamberlain. Ein Briefwechsel in Auszugen. PMID- 11609854 TI - Alte Medizin in Darmstadt. PMID- 11609855 TI - Die Bedeutung Lorenz Heisters in der Hasenschartenchirurgie. PMID- 11609856 TI - Razis Gutachten uber Rosenschnupfen. PMID- 11609857 TI - History of science in Durham Libraries. PMID- 11609858 TI - The Edinburgh phrenology debate: 1803-1828. PMID- 11609859 TI - Phrenological knowledge and the social structure of early nineteenth-century Edinburgh. PMID- 11609860 TI - A critique of Shapin's social interpretation of the Edinburgh phrenology debate. PMID- 11609861 TI - From farriery to veterinary medicine. PMID- 11609862 TI - Roman cavalry rations: A calculation of the daily ration of barley issued to the troop horse. PMID- 11609863 TI - The early history of horse shoeing. PMID- 11609864 TI - The iconography of the laboratory. PMID- 11609865 TI - The attitude of Agrippe von Nettesheim (1486-1535) towards alchemy. PMID- 11609866 TI - The "Venable Collection" in the history of chemistry at the University of North Carolina. PMID- 11609867 TI - A word about Descartes' mechanistic conception of life. PMID- 11609868 TI - The purpose of immunity: Landsteiner's interpretation of the human isoantibodies. PMID- 11609869 TI - The transformation of the science of nutrition. PMID- 11609870 TI - Biology and philosophy: the methodological foundations of biometry. PMID- 11609871 TI - Were the opium poppy and opium known in the ancient Near East? PMID- 11609873 TI - Lyman Spalding and the U.S. Pharmacopoeia. PMID- 11609872 TI - Studies on the history of rickets. II. The roles of cod liver oil and light. PMID- 11609874 TI - Medical views on narcotics and their effects in the mid-1890's. PMID- 11609876 TI - A history of the psychological interpretation of alchemy. PMID- 11609877 TI - Collection of treatises on plague regimen and remedies published in the German Duchy of Swabia in the XVIIth century. PMID- 11609878 TI - The origins of the British Association for the Advancement of Science. PMID- 11609879 TI - Alfred Russel Wallace: Philosophy of nature and man. PMID- 11609880 TI - The drug lore of Asclepiades of Bithynia. PMID- 11609881 TI - The first national organization for employee-pharmacists 1910-1934. PMID- 11609882 TI - Barton's unpublished Materia Medica. PMID- 11609883 TI - Property, patronage, and the politics of science. The founding of the Royal Society of Edinburgh. PMID- 11609884 TI - A microscopic incident in a monumental struggle: Huxley and antibiosis in 1875. PMID- 11609885 TI - Bhattara Haricandra. PMID- 11609886 TI - Brief biographies of eminent Unani Hekeems of India. Based on Nuz-Hatul-Khwatir (Pleasure of hearts) by Allama-Abdul-Hayy. PMID- 11609887 TI - History of the army medical corps. PMID- 11609888 TI - Professor Henry E. Sigerist, medical humanist, visionary and friend of India. PMID- 11609889 TI - Recent Indian medical historiography, bibliography for 1971. PMID- 11609890 TI - Theories of perception and the physiology of mind in the late eighteenth century. PMID- 11609891 TI - Arthur Cushny, optical isomerism, and the mechanism of drug action. PMID- 11609892 TI - The development of Albrecht von Haller's views on embryology. PMID- 11609893 TI - An early Darwin manuscript: the "Outline and Draft of 1839". PMID- 11609894 TI - Charles Darwin's theory of evolution: an analysis. PMID- 11609895 TI - Reflections on the progress of Darwin studies. PMID- 11609896 TI - The history of biochemistry: a survey. PMID- 11609897 TI - Euripus; or, the ebb and flow of the blood. PMID- 11609898 TI - Abstracts of select medico-historical articles in Hindi. PMID- 11609899 TI - Indian knowledge of blood circulation. PMID- 11609900 TI - Swami Kumara. PMID- 11609901 TI - Biography of an eminent Unani Hakeem called Abu Sayeed Sinan Bin Sabit Bin Qurra. PMID- 11609902 TI - Descriptive catalogue of Arabic manuscripts preserved in the Indian Institute of History of Medicine. PMID- 11609903 TI - Health hazards, diseases, hospitals & physicians in East Indies and Ceylon, in XVII century. Based on travels of Christopher Schweitzer. PMID- 11609904 TI - The pseudo-harita samhita. PMID- 11609905 TI - The proper object of vision. PMID- 11609906 TI - Bleeding through the ages. Blood-letting, barber-surgeons and bleeding bowls: some lessons for today. PMID- 11609907 TI - Development of radiopharmacy education in America--a brief survey. PMID- 11609908 TI - Drug adulteration: detection and control in Canada. A step forward: the Adulteration Act of 1884. PMID- 11609909 TI - On the transmission of Indian pharmaceutical knowledge to physicians. PMID- 11609910 TI - The pharmacy and materia medica of al-Biruni and al-Ghafiqi--a comparison. PMID- 11609911 TI - The education of an English midwife in the eighteenth century. PMID- 11609912 TI - Wine: history's special medicament. PMID- 11609913 TI - Phrenology: the provocation of progress. PMID- 11609914 TI - Some sources and procedures for editing a Medieval Arabic surgical tract. PMID- 11609915 TI - The "Industrial Revolution" in the home: household technology and social change in the 20th century. PMID- 11609916 TI - The award of the Copley medal to Charles Darwin. PMID- 11609918 TI - Sir Henry Dale (1875-1968), some letters and papers. PMID- 11609919 TI - Ancient medical conscience and the life of children. PMID- 11609920 TI - Nineteenth century family planning practices. PMID- 11609921 TI - Psychistorical approaches to the study of Nazism. PMID- 11609922 TI - The latest Freud research. PMID- 11609923 TI - The metaphor of organization: an historiographical perspective on the bio-medical sciences of the early nineteenth century. PMID- 11609924 TI - The herbal in the healing arts. PMID- 11609925 TI - A Luso-African formulary of the late eighteenth century; some notes on Angolan contributions to European knowledge of materia medica. PMID- 11609926 TI - Arabic glass seals on early eighth-century containers for materia medica. PMID- 11609927 TI - The last stage: historical adulthood and old age. PMID- 11609928 TI - Robert Hooke on memory, association and time perception. PMID- 11609929 TI - A note on the background to, and refereeing of, R. A. Fisher's 1918 paper 'On the correlation between relatives on the supposition of Mendelian inheritance'. PMID- 11609930 TI - The social basis and changing fortunes of an early scientific institution: an anlysis of the membership of the Royal Society, 1660-1685. PMID- 11609931 TI - Seventeenth century science and religion: the state of the argument. PMID- 11609933 TI - The vital flame. PMID- 11609932 TI - The Henrys of Manchester: William Henry: contagion and cholera; the textbook. PMID- 11609934 TI - Roger Bacon's place in the history of alchemy. PMID- 11609935 TI - The Confucian Perception of Adulthood. PMID- 11609936 TI - Rajput adulthood: reflections on the Amar Singh diary. PMID- 11609937 TI - Adulthood refracted: Russia and Leo Tolstoi. PMID- 11609938 TI - Adulthood in Islam: religious maturity in the Islamic tradition. PMID- 11609939 TI - Sex and socialism: the opposition of the French Left to birth control in the nineteenth century. PMID- 11609940 TI - Christian Mentzel und der Hof des Grossen Kurfursten als Mittelpunkt weltweiter Forschung. PMID- 11609941 TI - Johann Kunckel, Geheimer Kammerdiener des Grossen Kurfursten, und sein Glaslaboratorium auf der Pfaueninsel in Berlin. PMID- 11609942 TI - Medizin und Naturwissenschaft in Brasilien zur Zeit der Verwaltung des Grafen Johann Moritz von Nassau-Siegen. PMID- 11609943 TI - Christian Mentzel, die Leopoldina und der ferne Osten. PMID- 11609944 TI - A history of magnesia alba. PMID- 11609945 TI - On the nature of the physician's understanding. PMID- 11609946 TI - Philosophy of Medicine: problematic and potential. PMID- 11609947 TI - "Philosophical" medicine in nineteenth-century Germany: an episode in the relations between philosophy and medicine. PMID- 11609948 TI - Renaissance humanism and botany. PMID- 11609949 TI - John Case on art and nature. PMID- 11609950 TI - A little great awakening: an episode in the American Enlightenment. PMID- 11609951 TI - Malthus, Darwin, and the concept of struggle. PMID- 11609952 TI - The music of pulse in the writings of Italian academic physicians (fourteenth and fifteenth centuries). PMID- 11609953 TI - From city to farm: urban wastes and the American farmer. PMID- 11609954 TI - The image of alchemy in nineteenth and twentieth century histories of chemistry. PMID- 11609955 TI - What forced by fire: concerning some influences of chemical thought and practice upon English poetry. PMID- 11609956 TI - Techniques of ancient skull surgery. PMID- 11609957 TI - The diagnosis, care and treatment of leprosy in Wales and the border in the Middle Ages. PMID- 11609958 TI - Thomas Baskerville, Elizabethan apothecary of Exeter. PMID- 11609959 TI - The nature of the early Royal Society. Part II. PMID- 11609960 TI - Eyeglasses and concave lenses in fifteenth-century Florence and Milan: new documents. PMID- 11609961 TI - Action and reaction before Newton. PMID- 11609962 TI - Isvarasena. PMID- 11609963 TI - The geographical data in the Susruta Samhita. PMID- 11609964 TI - History of diabetes from remote to recent times. PMID- 11609965 TI - Brief biographies of eminent Unani Hekeems of India. Based on Nuz-Hatul-Khwatir (Pleasure of hearts) written in Arabic by Allama Abdul Hayy of Lucknow. PMID- 11609966 TI - Recent Indian medical historiography bibliography for 1974. PMID- 11609967 TI - Psychiatry and the children's movement. PMID- 11609968 TI - The evolution of childhood reconsidered. PMID- 11609969 TI - Images of the family: portrait paintings as indices of American family culture, structure and behavior, 1730-1860. PMID- 11609970 TI - The idea of childhood and child care in medical writings of the Middle Ages. PMID- 11609971 TI - Arthur Lee: a life history in the American Revolution. PMID- 11609972 TI - The transmission of science. PMID- 11609973 TI - The transmission of two new scientific disciplines from Europe to North America in the late nineteenth century. PMID- 11609974 TI - Twenty-five years of the National Science Foundation. PMID- 11609975 TI - The gene as catalyst; the gene as organism. PMID- 11609976 TI - Nature and nurture: the interplay of biology and politics in the work of Francis Galton. PMID- 11609977 TI - A review of Francois Jacob, The logic of life, a history of heredity. Trans. Betty E. Spillmann. New York. Pantheon Books. 1973. viii, 348 pp. PMID- 11609978 TI - Experiment and explanation in the physiology of Bichat and Magendie. PMID- 11609979 TI - Diseases and doctors, drugs and cures. A very preliminary list of passages of medical interest in a number of traditional Chinese novels and related plays. PMID- 11609980 TI - The William Bateson papers. PMID- 11609981 TI - Naturphilosophie: the Bayrische Staatsbibliothek, Munchen. PMID- 11609982 TI - Sources in the study of eugenics, 1: inventory of the American Eugenics Society papers. PMID- 11609983 TI - Evolutionism in the Enlightenment. PMID- 11609984 TI - Queries, answers and unsolved problems in eighteenth century biology. PMID- 11609985 TI - Recent Paracelsian Studies. PMID- 11609986 TI - On biological and social determinism. PMID- 11609987 TI - Experimentation with poisons. PMID- 11609988 TI - The great chain of being after forty years: an appraisal. PMID- 11609989 TI - Contemporary West European historiography of psychology. PMID- 11609990 TI - The origins and development of the Scottish scientific community, 1680-1760. PMID- 11609991 TI - History of science in the Federal Republic of Germany. PMID- 11609993 TI - The audience for science in eighteenth century Edinburgh. PMID- 11609994 TI - The chemical philosophers: chemical medicine from Paracelsus to Van Helmont. PMID- 11609992 TI - Reflections on the history of Scottish science. PMID- 11609996 TI - Early New York medicine. PMID- 11609995 TI - Science and society in nineteenth century anthropology. PMID- 11609997 TI - Repression and change in the sexual life of young people in medieval and early modern times. PMID- 11609998 TI - The end of the wet-nursing business in France, 1874-1914. PMID- 11609999 TI - Biochemistry and the historian. PMID- 11610000 TI - The history of Galenism. PMID- 11610001 TI - The "claim" of Cesalpino and the first and second editions of his "Peripatetic Questions". PMID- 11610002 TI - Albert Einstein and Max Wertheimer: a Gestalt psychologist's view of the genesis of special relativity theory. PMID- 11610003 TI - Chuma v Manchjurii. The plague in Manchuria in the years 1910-11. PMID- 11610004 TI - Medicine in colonial America. PMID- 11610005 TI - Bakulakara. PMID- 11610007 TI - Al-Hawi (liber continens) of Ar-Razi, Abu Bakr Muhammed Bin Zakariya; synopsis of the fourteenth volume (Part I). PMID- 11610006 TI - Astangahrdayadipika of Udayaditya. PMID- 11610008 TI - Genesis of Charaka Club, New York, and gleanings related to Hindu medicine from the proceedings. PMID- 11610009 TI - A note on the ancient knowledge about the prevention of water borne epidemics. PMID- 11610010 TI - Early history of the theory of probability. PMID- 11610011 TI - A single path to the double helix? PMID- 11610012 TI - The John Sealy Hospital: a study of late nineteenth century hospital design. PMID- 11610013 TI - The hero as madman. PMID- 11610014 TI - The origins of Titchener's doctrine of meaning. PMID- 11610016 TI - Scientists and sectarians: the case of psychoanalysis. PMID- 11610015 TI - Forgotten mnemonists. PMID- 11610017 TI - The authenticity of the Freud Memorial Collection. PMID- 11610018 TI - Encounter of behavioral sciences with new machine-organism analogies in the 1940's. PMID- 11610019 TI - Anticipation of dream psychology in the Talmud. PMID- 11610020 TI - The untranslated content of Wundt's Grundzuge der physiologischen Psychologie. PMID- 11610021 TI - [Bibliography of the History of the Behavioral Sciences, 1975]. PMID- 11610022 TI - Explorations toward a logic of empirical discovery: a case study in clinical medicine. PMID- 11610023 TI - Causality and medicine. PMID- 11610024 TI - Ancient and modern conceptions of health and medicine. PMID- 11610025 TI - Causal thinking in Erewhon and elsewhere. PMID- 11610027 TI - The making of the modern family. PMID- 11610026 TI - Genetics, eugenics and society: internalists and externalists in contemporary history of science. PMID- 11610028 TI - Marital timing in women's life patterns. PMID- 11610029 TI - Marriage patterns in Victorian Britain: an analysis based on registration district data for England and Wales 1861. PMID- 11610030 TI - Household dynamics in a Belgian village, 1847-1866. PMID- 11610031 TI - Darwinism, Soviet genetics, and Marxism-Leninism. PMID- 11610032 TI - "The survival of the fittest is our doctrine": history or histrionics? PMID- 11610033 TI - The dream that gave pharmacy its colorful great moments. PMID- 11610034 TI - Johann Christian Senckenbergs Tagebucher als historische Quelle. PMID- 11610036 TI - Goethe und die Chemie. PMID- 11610035 TI - Senckenbergs Stiftung und die Frankfurter Republik der Aerzte im 19. Jahrhundert. PMID- 11610037 TI - Der Einfluss von Botanik und Pharmakognosie auf die Arzneimittelkontrolle in den Pharmakopoen des 19. Jahrhunderts. PMID- 11610038 TI - "Aesculapius veterinarius". Zu einer unbekannten Munze aus Parion an der Propontis. PMID- 11610039 TI - Medizinhistorischer Unterricht in der Sowjetunion. PMID- 11610040 TI - Medicina electrica -Titelkupfer- aus: Johann Gottlieb Schaffer, Die electrische Medicin oder die Kraft und Wirkung der Electricitat in dem menschlichen Korper und dessen Krankheiten besonders bey gelahmten Gliedern aus Vernunftsgrunden erlautert und durch Erfahrungen bestatigt. 2. Auflage. Regensburg 1766. [1. Auflage Regensburg 1752.]. PMID- 11610041 TI - Die Bedingungen des Wissenschaftsprogresses im Bewusstsein der Naturforscher des 18. Jahrhunderts. PMID- 11610042 TI - Das Leibesinnere nach den altagyptischen medizinischen Texten. PMID- 11610043 TI - Paracelsus Arabus. Eine Studie zur "alchemistischen Medizin" im Orient. PMID- 11610044 TI - Behandlungsmethoden in einem norwegischen Leprakrankenhaus 1861-1870. PMID- 11610045 TI - Der Frankfurter Lichtleiter. Neues uber Phillipp Bozzini und sein Endoskop. PMID- 11610046 TI - Der "Hydriot" Nikolai Kleinenberg oder: Spekulation und Beobachtung. PMID- 11610048 TI - Die sichtbaren Warmezeichen und die Warmeformen im Innern des Korpers in der altagyptischen Medizin. PMID- 11610047 TI - Zwei Briefe von Johannes Muller, an Francois-Louis Guisan und Eduard Rene Claparede PMID- 11610049 TI - Bearbeitungen von Schriften des Iatrosophisten Palladius unter den Namen des Johannes, Stephanus und Theophilus. PMID- 11610050 TI - Zur Osteoarchaologie der mittelalterlichen Lepra (II). PMID- 11610051 TI - Der Kariesbefund und die Abrasion der Zahne der frankischen Bevolkerung aus dem Siedlungsraum Eltville, Rheingaukreis, zwischen 500 und 800 n. Chr. PMID- 11610052 TI - Alte volksmedizinische Gegenstande im Nationalmuseum von Reykjavik, Island. PMID- 11610053 TI - Zum Begriff des "Pathologischen" bei Goethe. PMID- 11610054 TI - Das Krankenhaus des 19. Jahrhunderts im Spiegel der zeitgenossischen Kunst. PMID- 11610055 TI - Welchen Wert haben Sammlungen fur die Wissenschaftsgeschichte? PMID- 11610056 TI - Der ingolstadter Lorenz Gruber (1803-1975), ein typischer Vertreter der Laienorthopadie des 19. Jahrhunderts. PMID- 11610057 TI - Ein Kreislaufmodell um 1850. PMID- 11610058 TI - Geschichte der Sammlung naturwissenschaftlicher und technischer Objekte in Ungarn. PMID- 11610059 TI - Chymische Pflanzen in der deutschen Literatur. PMID- 11610060 TI - Warme bei Fieber und Entzundung in den altagyptischen medizinischen Texten (smm und srf). PMID- 11610061 TI - "Schwarzliche" Organe im fruhgriechischen Denken. PMID- 11610062 TI - Neues zum Steinbuch des Xenokrates. PMID- 11610063 TI - Ein Fall von Tuberkulose aus Nordnorwegen in der Merowingerzeit. PMID- 11610064 TI - Vom Ingolstadter Anatomischen Theater zum Deutschen Medizinhistorischen Museum. PMID- 11610065 TI - Aristotle and woman. PMID- 11610066 TI - Freud before Oedipus: race and heredity in the origins of psychoanalysis. PMID- 11610067 TI - Organotherapy, British physiology, and discovery of the internal secretions. PMID- 11610068 TI - The critic and the advocate: contrasting British views on the state of endocrinology in the early 1920s. PMID- 11610069 TI - On the diffusion of a new specialty: Maranon and the "Crisis" of endocrinology in Spain. PMID- 11610070 TI - "The die is cast"--"I am going home": the appointment of Herbert McLean Evans as head of anatomy at Berkeley. PMID- 11610072 TI - Avesta und Medizin. Ein literaturgeschichtlicher Beitrag zur Heilkunde im alten Persien. PMID- 11610071 TI - Niederlandische Leopoldina-Mitglieder des 17. und 18. Jahrhunderts und ihre Korrespondenz mit dem Akademieprasidium. PMID- 11610073 TI - A summer institute on the history of psychology: part I. PMID- 11610074 TI - Masters and pupils among French psychologists. PMID- 11610075 TI - Socrates and the history of psychology. PMID- 11610076 TI - Self: the history of a concept. PMID- 11610077 TI - Galen -- on mental disorders. PMID- 11610078 TI - The orientation of the cerebral image in Descartes' theory of visual perception. PMID- 11610079 TI - Order and control: the scientific method in China and the United States. PMID- 11610080 TI - Controversy and conflict in science: a case study--the English biometric school and Mendel's laws. PMID- 11610081 TI - The formation of Soviet research institutes: a combination of revolutionary innovation and international borrowing. PMID- 11610083 TI - Apprenticeship records. An examination of Inland Revenue apprenticeship records between the years 1710 and 1811 with particular reference to medicine and pharmacy. PMID- 11610082 TI - The advisers of the United States National Science Foundation. PMID- 11610084 TI - Some eminent Cambridge apothecaries. PMID- 11610085 TI - The nonnaturals: a paradox in the Western concept of health. PMID- 11610086 TI - William McDougall and the problem of purpose. PMID- 11610087 TI - Seventeenth century French "connectionism": La Forge, Dilly, and Regis. PMID- 11610088 TI - Gustav Fechner, Dr. Mises, and the comparative anatomy of angels. PMID- 11610089 TI - Falconry: neglected aspect of the history of psychology. PMID- 11610090 TI - "The birds are rather big for ducks." criterion and material in history. PMID- 11610091 TI - The long neglect of genetic discoveries and the criterion of prematurity. PMID- 11610092 TI - The peripherality of reductionism in the development of molecular biology. PMID- 11610093 TI - The double-edged effect of Sir Francis Galton: a search for the motives in the biometrician-Mendelian debate. PMID- 11610094 TI - The Drosophila group: the transition from the Mendelian unit to the individual gene. PMID- 11610095 TI - Opposition to the Mendelian-chromosome theory: the physiological and developmental genetics of Richard Goldschmidt. PMID- 11610097 TI - The origins of molecular genetics. PMID- 11610098 TI - Science and the Franco-Prussian war. PMID- 11610096 TI - William Johannsen and the genotype concept. PMID- 11610099 TI - Harward's Electuarium... earliest drug treatise published by an American colonist? PMID- 11610100 TI - Nicander's toxicology. I:snakes. PMID- 11610101 TI - "The drug store cabaret:" pharmacy and vaudeville in 1920. PMID- 11610102 TI - Fertility, marriage, and occupation in the Pennsylvania anthracite region, 1850 1880. PMID- 11610103 TI - Automatic family reconstitution: the French-Canadian seventeenth-century experience. PMID- 11610104 TI - The formation of the American personality through psychospeciation. PMID- 11610105 TI - The contemporary "crisis" of the American family: the perspective of a family historian and psychohistorian. PMID- 11610106 TI - Children in early medieval art: ninth through twelfth centuries. PMID- 11610107 TI - Psycho-sexual aspects of the fascism of Drieu La Rochelle. PMID- 11610108 TI - The psychogenic theory of history. PMID- 11610109 TI - Psychohistory in the university. PMID- 11610110 TI - Die alte Mainzer medizinische Fakultat und die Wissenschaft ihrer Zeit. PMID- 11610111 TI - Die Grundung des Mainzer Accouchements unter Johann Peter Weidmann im Jahre 1784. PMID- 11610112 TI - Archivalien, Instrumente und Kapitalien der Mainzer medizinischen Fakultat im 17. und 18. Jahrhundert. PMID- 11610113 TI - Das kurmainzer Medizinalreformprojekt von Anton Maria Marchand aus dem Jahre 1790. PMID- 11610114 TI - "Die schone Mainzerin" Samuel Thomas Soemmerrings. PMID- 11610116 TI - Schinderhannes, Galvanismus und die experimentelle Medizin in Mainz um 1800. PMID- 11610115 TI - Funfhundert Jahre Medizin in Mainz. PMID- 11610117 TI - Fertility, infant mortality and breast-feeding in the seventeenth century. PMID- 11610118 TI - Ye cow-pock, Gillray and social medicine--a note on Gillray's caricature of Jenner and the 'New inoculation'. PMID- 11610119 TI - Dispensaries in the nineteenth-century: a short bibliography. PMID- 11610120 TI - Obstetrics in the 17th and 18th centuries and its implication for maternal and infant mortality. PMID- 11610121 TI - Blood and hemoglobin: the evolution of knowledge of functional adaptation in a biochemical system, part I: The adaptation of chemical structure to function in hemoglobin. PMID- 11610122 TI - The spontaneous generation controversy (1859-1880): British and German reactions to the problem of abiogenesis. PMID- 11610123 TI - Instinct theory and the German reaction to Weismannism. PMID- 11610124 TI - The reception of Eduard Buchner's discovery of cell-free fermentation. PMID- 11610125 TI - Models for cardiac structure and function in Aristotle. PMID- 11610126 TI - Francis Galton's contribution to genetics. PMID- 11610127 TI - The inspiration of Lamarck's belief in evolution. PMID- 11610129 TI - Historical demography as social history: possibilities in Germany PMID- 11610128 TI - Family history and the life course. PMID- 11610130 TI - The American scientist in antebellum society: a quantitative view. PMID- 11610131 TI - The family entity and famine among the nineteenth-century Akamba of Kenya: social responses to environmental stress. PMID- 11610132 TI - A new perspective on the twentieth-century American fertility swing. PMID- 11610133 TI - The study of the European fertility decline. PMID- 11610134 TI - Black fertility and family structure in the U.S., 1880--1940. PMID- 11610135 TI - Sources and problems in the history of drug commerce in late medieval Europe. PMID- 11610136 TI - Therapeutic mule: the use of arsenic in the nineteenth century materia medica. PMID- 11610137 TI - Les chirurgiens de la peste a Mons au XVIe siecle. PMID- 11610138 TI - J. L. C. Pompe van Meerdervoort and his "Vijf Jaren in Japan". PMID- 11610139 TI - Le medionat--une tache moins connue du barbier-chirurgien lors d'une execution. PMID- 11610140 TI - Le jardin botanique d'Anvers 1797-1926. PMID- 11610141 TI - The "scientific" study of nature reflected in the composition of the vegetation in late-medieval paintings. PMID- 11610142 TI - Pierre Fauchard et la morphologie de la denture au dix-huitieme siecle. PMID- 11610143 TI - Carolus Clusius and the beginning of botany in Leiden University. PMID- 11610144 TI - History of modern biology. PMID- 11610145 TI - On the process of establishment of the DNA. PMID- 11610146 TI - Science and values: the eugenics movement in Germany and Russia in the 1920s. PMID- 11610147 TI - Witchcraft trials in seventeenth-century Russia. PMID- 11610148 TI - Zur Stellung der Naturwissenschaften im absolutistischen Staat. PMID- 11610149 TI - Naturwissenschaftlich-biologische Grundlagenforschung in der Medizin des 17. Jahrhunderts. PMID- 11610150 TI - Staatsidee, aufgeklarter Absolutismus und Wissenschaft bei Abrecht von Haller. PMID- 11610151 TI - Albrecht Hallers Aufenthalt in Paris im Lichte eines unbekannten Tagebuchs Johannes Gessners. PMID- 11610152 TI - Arzt und medizinische Wissenschaft im franzosischen Absolutismus. PMID- 11610153 TI - L'emergence de la medecine scientifique en France sous le regne de Louis XIV. PMID- 11610155 TI - Der naturwissenschaftliche Unterricht an der Hohen Karlsschule. PMID- 11610154 TI - Die Strassburger Anatomie und Museologie im 18. Jahrhundert und die Einflusse der Stadtverwaltung. PMID- 11610156 TI - Bezoars. PMID- 11610157 TI - Entwicklungsstufen der neuzeitlichen Hamatologie. PMID- 11610158 TI - The emergence of Binet's conceptions and measurement of intelligence: a case history of the creative process. Part II. PMID- 11610159 TI - The beginnings of psychotherapy. PMID- 11610160 TI - A longitudinal study of the research methodology in The Journal of Abnormal and Social Psychology, The Journal of Nervous and Mental Disease, and The American Journal of Psychiatry. PMID- 11610161 TI - The "Zeitgeist" and American psychology. PMID- 11610162 TI - "Proofreader's syndrome" and scientific method. PMID- 11610163 TI - The mark of the beast. PMID- 11610164 TI - Studies on the history of rickets. I. Recognition of rickets as a deficiency disease. PMID- 11610165 TI - Henry C. Lawrence, 1820-1862, mentor of Eli Lilly. PMID- 11610166 TI - An historic pharmacy, Central City, Colorado. PMID- 11610167 TI - [On the process of establishment of the DNA model and the central dogma (I)] (Jpn). PMID- 11610168 TI - [Philosophical aspect of the development of molecular biology] (Jpn). PMID- 11610169 TI - Feminism, philanthropy and science in the development of the oral contraceptive pill. PMID- 11610170 TI - The papers of Rufus Ashley Lyman. PMID- 11610171 TI - The concept of species in retrospect and perspective. PMID- 11610172 TI - Some new data concerning the publication of 'L'Homme machine' and 'L'Homme plus que machine'. PMID- 11610173 TI - Medical aspects of Rembrandt's anatomy lesson of Doctor Tulp. PMID- 11610175 TI - Contribution a l'etude de l'histoire de l'atrophie musculaire spinale progressive (Duchenne-Aran) et de la cellule motrice de la corne anterieure de la moelle epiniere. PMID- 11610174 TI - Microcosm and macrocosm according to some Jewish medieval works up to the 12th century. PMID- 11610176 TI - Caspar Pelletier. Ein Botaniker in den Anfangen des 17. Jahrhunderts. PMID- 11610177 TI - Zur "Secreta Mulierum" -Forschung. PMID- 11610178 TI - Steno in Leiden. PMID- 11610179 TI - Der Puls und das Problem der Zeitmessung in der Geschichte der Medizin. PMID- 11610180 TI - Neues zu den diatetischen Schriften des Rufus von Ephesos. PMID- 11610181 TI - Schamanistische Zuge der chinesischen Volksmedizin. Zur Bewertung unorthodoxer Heilmethoden im traditionellen China. PMID- 11610182 TI - Carl Friedrich Heusinger (1792-1883). Ein Beitrag zur Geschichte der Marburger Medizin. PMID- 11610183 TI - Johann Georg Heinrich Zeder (1764-1837). PMID- 11610184 TI - Robert Brodie MacLeod (1907-1972). PMID- 11610185 TI - Karl Philipp Moritz's Magazin zur Erfahrungsseelenkunde (Magazine for empirical psychology) 1783-1793. PMID- 11610186 TI - From looking to listening. PMID- 11610187 TI - Neglected American philosophers in the history of symbolic interactionism. PMID- 11610188 TI - Freud and the birth of child psychiatry. PMID- 11610189 TI - The faculty psychology of Benjamin Rush. PMID- 11610190 TI - On plagiarism: Buffon, Condillac, Porterfield, Schopenhauer. PMID- 11610191 TI - The emergence of Binet's conception and measurement of intelligence: a case history of the creative process. PMID- 11610192 TI - The comparative anatomy of angels (1). A sketch by Dr. Mises: 1825, translated by Hildegard Corbet and Marilyn E. Marshall (2). PMID- 11610193 TI - Psychology in recent American historical thought. PMID- 11610194 TI - Notes on Alfred C. Kinsey's pre-sexual scientific work and the transition. PMID- 11610195 TI - Edwin Garrigues Boring: 1886-1968. PMID- 11610196 TI - Eugenics in Britain. PMID- 11610197 TI - Alchemy, with the egg as its symbol. PMID- 11610199 TI - The Liebig-Mulder controversy. On the methodology of physiological chemistry. PMID- 11610198 TI - Nicholas Bidloo and his unknown drawings. PMID- 11610200 TI - Medicinal plants in Tsarist Russia. PMID- 11610201 TI - Moleschott in Heidelberg. Die Entwicklung seiner allgemeinen Auffassungen. PMID- 11610202 TI - Kamala--the national flower of India--its ancient history and uses in Indian medicine. PMID- 11610203 TI - [History of occupational hygiene] (Jpn). PMID- 11610204 TI - Recent literature concerning the history of science in the Netherlands. PMID- 11610205 TI - A select bibliography of Soviet publications on Al-Biruni. PMID- 11610206 TI - Die Schrift des Rufus "De infantium curatione" und das Problem der Autorenlemmata in den "Collectiones medicae" des Oreibasios. PMID- 11610207 TI - Die Wandlung embryologischer Forschung von der deskriptiven zur experimentellen Phase unter dem Einfluss der Zoologischen Station in Neapel. PMID- 11610209 TI - [History of medicine] (Jpn). PMID- 11610208 TI - Zur Biographie und Charakteristik Joseph von Mohrenheims. PMID- 11610210 TI - [Seventeenth century biology.] (Jpn). PMID- 11610211 TI - [Human genetics and eugenics in Japan: a case study of three geneticists -- T. Komai, R. Kawakami and T. Furuhata] (Jpn). PMID- 11610212 TI - The quest for "useful knowledge" in eighteenth-century America. PMID- 11610213 TI - Sources for a history of plant sciences in India. II. The RG Vedic Soma plant. PMID- 11610214 TI - Sources for a history of plant sciences in India. III. The maritime trade of ancient Tamils in plant products--a critique. PMID- 11610215 TI - Ayurvedic concept of the psychosomatic basis of health and disease. PMID- 11610216 TI - I remember when... PMID- 11610218 TI - [The origin of the male and female symbols in biology] (Jpn). PMID- 11610217 TI - [Nineteenth century biology.] (Jpn). PMID- 11610219 TI - The earliest European descriptions of Japan's flora. PMID- 11610220 TI - [Asajiro Oka: Biology and the impermanence of life.] (Jpn). PMID- 11610221 TI - Astrology and science in seventeenth-century England. PMID- 11610222 TI - Berkeley's "proper object of vision". PMID- 11610223 TI - Victorian science and the "genius" of woman. PMID- 11610224 TI - The relationships of particular trace elements to various bone pathologies in the Dickson Mounds skeletal population. PMID- 11610225 TI - A prehistoric achondroplastic dwarf from California: a preliminary note. PMID- 11610226 TI - Microradiography for anthropologists: a survey of current research. PMID- 11610227 TI - Demonstration of erythrocytes and hemoglobin products in mummified tissue. PMID- 11610228 TI - Preservation of proteins in mummified tissue. PMID- 11610229 TI - Preparation of the dead in Pre-Columbian coastal Peru. PMID- 11610230 TI - The British Government: skeletons in the closet. PMID- 11610231 TI - Gonorrhoea in the ancient world. PMID- 11610233 TI - The development of veterinary education in the east of Scotland. PMID- 11610234 TI - Rabies: some glimpses into the past. PMID- 11610232 TI - The influence of plants on medicinal chemistry. PMID- 11610235 TI - Amino acid dating. PMID- 11610236 TI - Medicaments in practice 50 years ago. PMID- 11610237 TI - The Bardsley plan and the early 19th century controversy on rabies. PMID- 11610238 TI - The days of the farriers. PMID- 11610240 TI - Origin of the "British Veterinary Codex". PMID- 11610239 TI - From pestle and mortar to pharmacopoeia. PMID- 11610241 TI - Zum sogenannten Symposionrelief von Kos. PMID- 11610242 TI - Brotgeruch als Todes-Hemmer; zur Geschichte einer volkstumlichen Anschauung. PMID- 11610243 TI - Biologie und Geschichte; Ansatze und Versuche zur biologistischen Theorie der Geschichte im 19. und beginnenden 20. Jahrhundert. PMID- 11610244 TI - Zur Darstellung des Heiltanzes in der Malerei um 1500. PMID- 11610246 TI - Charles Darwin and artificial selection. PMID- 11610245 TI - The treatment of animals. PMID- 11610247 TI - The changing meaning of "evolution". PMID- 11610248 TI - Anal and genital warts in the ancient world. PMID- 11610249 TI - Histology and electron microscopy. PMID- 11610250 TI - Some thoughts on the definition of human paleopathology. PMID- 11610251 TI - Philip Guide, Huguenot refugee doctor of medicine (ca.1640-1716). PMID- 11610252 TI - [Not Available]. PMID- 11610253 TI - [Not Available]. PMID- 11610254 TI - [Not Available]. PMID- 11610255 TI - [Not Available]. PMID- 11610256 TI - A Franco-American pharmacist: John T. G. F. de Milhau (1795-1874). In: Die Vortrage der Hauptversammlung in Paris gehalten wahrend des Pharmaziegeschichtlichen Kongresses der Internationalen Gesellschaft fur Geschichte der Pharmazie e. V. in Paris vom 24.-29. September 1973. PMID- 11610257 TI - [Not Available]. PMID- 11610258 TI - [Not Available]. PMID- 11610259 TI - [Not Available]. PMID- 11610260 TI - French pharmacy in Louisiana in the late 18th and early 19th centuries. PMID- 11610261 TI - [Not Available]. PMID- 11610262 TI - [Not Available]. PMID- 11610263 TI - [Not Available]. PMID- 11610264 TI - [Not Available]. PMID- 11610265 TI - [Not Available]. PMID- 11610266 TI - [Not Available]. PMID- 11610267 TI - [Not Available]. PMID- 11610268 TI - The poisoning of the sick at Jaffa. PMID- 11610269 TI - [Not Available]. PMID- 11610270 TI - Paupers or patients? the Poor Law infirmaries 1890-1929. PMID- 11610271 TI - Social roots of medical ideas: disease and civilization in the 19th century. PMID- 11610272 TI - The Victorian medical profession, the family, and social mobility. PMID- 11610274 TI - Social and cultural contradictions: women and medicine in the 19th century. PMID- 11610273 TI - Working wives or healthy homes: the late Victorian controversy. PMID- 11610275 TI - Nature and culture in the late nineteenth century: some comments on the emergence of the sociobiological tradition. PMID- 11610276 TI - The 1858 Medical Act: the origins and the aftermath. PMID- 11610277 TI - Medical professionalism and maternity hospitals in eighteenth century London: a sociological interpretation. PMID- 11610279 TI - The influence of medical missions on the health services of Africa. PMID- 11610278 TI - The Manson-Ross controversy: tropical medicine and imperialism. PMID- 11610280 TI - The nineteenth century British mortality statistics: towards an assessment of their accuracy. PMID- 11610281 TI - Pathology of French paleolithic man. PMID- 11610282 TI - Death and disease in ancient Egypt; a two-day symposium, February 1st and 2nd, 1973. PMID- 11610283 TI - Temporal bone findings in Peruvian mummies. PMID- 11610284 TI - Temporal variation and sex differences in the incidence of cranial porotic hyperostosis in Peru. PMID- 11610285 TI - [Paleopathology in Peru]. PMID- 11610286 TI - Early Holocene funeral bundles from the Central Andes. PMID- 11610287 TI - Ultrastructural findings on peripheral blood elements from Pum-III. PMID- 11610288 TI - Cervical ribs related to disuse atrophy in an archaic skeleton (490 B.C.): a preliminary report. PMID- 11610289 TI - Age at first marriage in Europe before 1850: a summary of family reconstitution data. PMID- 11610290 TI - Household structure in urban and rural areas: the case of Rhode Island, 1774 1800. PMID- 11610291 TI - Marriage patterns in midnineteenth-century New York State: a multivariate analysis. PMID- 11610292 TI - Marriage and family in a Tudor elite: familial patterns of Elizabethan bishops. PMID- 11610293 TI - The Methodist parish chest. PMID- 11610294 TI - The English provincial veterinarian and his practice. PMID- 11610295 TI - The stimulus for the statutory control of animal diseases in Great Britain in the 19th century. PMID- 11610296 TI - William Moorcroft, the first European veterinarian to visit Lahore. PMID- 11610297 TI - The history of comparative endocarditis. PMID- 11610298 TI - Harvey on the hart. (sic) PMID- 11610299 TI - The development of veterinary education in the west of Scotland. PMID- 11610300 TI - Some examples of natural mummies. PMID- 11610301 TI - Women and abortion in Victorian and Edwardian England. PMID- 11610302 TI - Women's work and regulation of family size: the question of abortion in the nineteenth century. PMID- 11610303 TI - Middle ear disease in a prehistoric Iranian population. PMID- 11610304 TI - Arterio - sclerotic change in the carotid artery of a mummy of New Kingdom date. PMID- 11610305 TI - Analysis of Pum - II mummy fluid. PMID- 11610306 TI - Computerized axial tomography in medical archeology. PMID- 11610307 TI - The paleopathology program at the Smithsonian Institution. PMID- 11610308 TI - Bone changes in sickle cell disease. PMID- 11610309 TI - Trace element analysis of tissue and resin from the egyptian mummy Pum-II. PMID- 11610310 TI - Syphilis in the ancient world. PMID- 11610311 TI - Syphilis: where did it come from? PMID- 11610312 TI - Paleopathology symposium: presented at the annual meeting of the American Association of Physical Anthropologists, April 11th, 1974. PMID- 11610313 TI - Charles E. Bessey: the impact of the "New" botany on American agriculture, 1880 1910. PMID- 11610314 TI - History of chemistry with special reference to Muslim contribution. PMID- 11610315 TI - Zwei spatantike Kommentare zu der hippokratischen Schrift "De morbis muliebribus". PMID- 11610316 TI - Zur Bedeutung medizinischer Bemuhungen im Wirken Gerhard Tersteegens. PMID- 11610317 TI - "Les saints guerisseurs" von Notre-Dame-du-Haut; religiose Volksmedizin in der Bretagne. PMID- 11610319 TI - 'Sins and diseases': some notes on homosexuality in the nineteenth century. PMID- 11610318 TI - Air pollution and fuel crises in predindustrial London, 1250-1650. PMID- 11610320 TI - Torus mandibularis in early Scottish cemetery. PMID- 11610321 TI - Biology and the social sciences. PMID- 11610322 TI - Johann David Schoepf (1752-1800); a German physician as a botanist and zoologist in North America. PMID- 11610324 TI - Progress report on a biobibliographic project in the history of pharmacology. PMID- 11610325 TI - Pharmaceutical and medical valentines. PMID- 11610323 TI - New light on Circa instans. PMID- 11610326 TI - American impressions of a Swiss pharmacist (1894); an unpublished letter of F.A. Fluckiger to A. Tschirch. PMID- 11610327 TI - Opium over the counter in nineteenth century England. PMID- 11610328 TI - The doctor of medicine degree--1839. PMID- 11610329 TI - Interest in air pollution among early Fellows of the Royal Society. PMID- 11610330 TI - A collection of some observations on bills of mortality & parish registers: an unpublished manuscript by Stephen Hales, F.R.S. (1677-1761). PMID- 11610331 TI - Medical teaching at the University of Paris, 1600-1720. PMID- 11610332 TI - Edward Frankland and the Cheapside chemists of Lancaster: an early Victorian pharmaceutical apprenticeship. PMID- 11610333 TI - The position of the glycosidic bond in purine nucleosides: the conservative influence of a convention of chemical nomenclature. PMID- 11610334 TI - Comments on Baumrin's analysis of Shute and Aristotle. PMID- 11610335 TI - Gestalt psychology and Gestalt therapy. PMID- 11610336 TI - Editorial statement. PMID- 11610337 TI - Psychotherapy in the Third Reich: a research note. PMID- 11610338 TI - An American analyst in Vienna during the Anschluss, 1936-1938. PMID- 11610340 TI - The structure of psychological revolutions. PMID- 11610339 TI - Historical research: an observation. PMID- 11610341 TI - Droysen and the idea of Verstehen. PMID- 11610342 TI - The philosopher and society: John Locke and the English revolution. PMID- 11610343 TI - Evolution of medieval mentalities: a cognitive-structural approach. PMID- 11610344 TI - The character of Erasmus. PMID- 11610345 TI - Ritualistic acts and compulsive behavior: the pattern of Tudor martyrdom. PMID- 11610346 TI - Temporal bone disease in pre-Columbian America. PMID- 11610347 TI - Malaria in pre-Columbian America? PMID- 11610348 TI - Trace elements in paleopathology. PMID- 11610349 TI - Western scientific manuscripts before 1600: a checklist of published catalogues. PMID- 11610350 TI - From homme machine to homme sensible: changing eighteenth-century models of man's image. PMID- 11610351 TI - Papers and exhibits on paleopathology presented at the annual meeting of the Paleopathology Association. PMID- 11610352 TI - Palaeopathology in the British Museum (natural history) human osteology collection. PMID- 11610353 TI - Paul F. Lazarsfeld and the history of empirical social research. PMID- 11610354 TI - Efficient causality in Boring's work and thought: a case of one-sided determinism. PMID- 11610355 TI - Kurt Lewin in retrospect--a psychiatrist's view. PMID- 11610356 TI - Looking back on Kurt Lewin: from field theory to action research. PMID- 11610357 TI - Kurt Lewin as metatheorist. PMID- 11610358 TI - Kurt Lewin and social change. PMID- 11610359 TI - Has "field theory" been "tried and found wanting"? PMID- 11610360 TI - From "race psychology" to "studies in prejudice": some observations on the thematic reversal in social psychology. PMID- 11610361 TI - Victorian opium eating: responses to opiate use in nineteenth century society. PMID- 11610362 TI - The social history of malaria in Europe. PMID- 11610364 TI - Theory and practice in psychiatry: the case of James Cowles Prichard, M.D., F.R.S. (1786-1848). PMID- 11610363 TI - The work and theories of Paracelsus. PMID- 11610365 TI - A note on recent work on the archives of the incorporated Liverpool School of Tropical Medicine. PMID- 11610366 TI - Some psychological consequences of English individualism, 1400-1700. PMID- 11610367 TI - The attitude of the medical profession to sexuality in the 19th century. PMID- 11610368 TI - [Not Available]. PMID- 11610370 TI - [Not Available]. PMID- 11610369 TI - [Not Available]. PMID- 11610371 TI - [Not Available]. PMID- 11610372 TI - [Not Available]. PMID- 11610373 TI - The role of German immigrants on the health of early settlers of Milwaukee. PMID- 11610374 TI - [Not Available]. PMID- 11610375 TI - [Not Available]. PMID- 11610376 TI - [Not Available]. PMID- 11610377 TI - Medicine and pharmacy in French political prints--the Franco-Prussian war and the Commune. PMID- 11610378 TI - [Not Available]. PMID- 11610379 TI - Vegetable gums and resins in medieval recipe literature. PMID- 11610380 TI - A Spanish secret remedy of the XVIth century: "The holy Oil of the Biscayan." PMID- 11610381 TI - [Not Available]. PMID- 11610382 TI - [Not Available]. PMID- 11610383 TI - [Not Available]. PMID- 11610384 TI - [Not Available]. PMID- 11610385 TI - Historical studies of medical instruments. PMID- 11610387 TI - Chemistry, pharmacy and cosmology: a Renaissance union. PMID- 11610386 TI - Cos versus Cnidus and the historians: part 2. PMID- 11610388 TI - Science as a guide in regulating technology: the case of DDT in the United States. PMID- 11610389 TI - Saints in medical history. PMID- 11610390 TI - The "Liber Monstrorum": an unpublished manuscript and some reconsiderations. PMID- 11610391 TI - Notes on the age of maternity, population growth and family structure in the past. PMID- 11610392 TI - Black fertility and the black family in nineteenth century: a reexamination of the past. PMID- 11610393 TI - Physics and chemistry in the Netherlands in the period 1750-1850. PMID- 11610394 TI - Surgeons and physicians in seventeenth century Amsterdam. PMID- 11610395 TI - Concepts of disease and the physician in the early Middle Ages. PMID- 11610396 TI - A newly discovered "Oeconomia animalis", by Pieter Muis of Rotterdam (c. 1645 1721). PMID- 11610398 TI - International influences on the development of natural history in the Netherlands and its East Indian colonies between 1750 and 1850. PMID- 11610397 TI - Die Medizin zur Zeit der Regierung des Konigs Wilhelm I in den Niederlanden (1813 1840). PMID- 11610399 TI - The Milislav Demerec papers. PMID- 11610401 TI - The Knights of Saint John and the hospitals of the Latin West. PMID- 11610400 TI - Sources in the study of eugenics, no.2: The Bureau of Social Hygiene papers. PMID- 11610402 TI - On suicide. PMID- 11610403 TI - Sexual mores in the eighteenth century: Robert Wallace's "Of venery". PMID- 11610404 TI - Joseph Leconte's evolutional idealism: a Lamarckian view of cultural history. PMID- 11610405 TI - Science, scientism and anti-science in Hellenic Athens: a new Whig interpretation. PMID- 11610406 TI - Reappraisals in Renaissance science. PMID- 11610407 TI - The historiography of the Claude Bernard industry. PMID- 11610408 TI - Medical components in Cabanis's science of man. PMID- 11610409 TI - The role of mathematical population geneticists in the evolutionary synthesis of the 1930s and 1940s. PMID- 11610410 TI - Reinterpretation or rehabilitation: an excercise in contemporary Marxist history of science. PMID- 11610411 TI - Perfect adaptation and teleological explanation: approaches to the problem of the history of life in the mid-nineteenth century. PMID- 11610412 TI - Louis Pasteur and molecular dissymmetry, 1844-1857. PMID- 11610413 TI - Nicander's toxicology; I: spiders, scorpions, insects and myriapods. PMID- 11610414 TI - Drug therapy at a frontier fort hospital; Fort Laramie, Wyoming territory, 1870 1889. PMID- 11610415 TI - Ephraim Eliot; first president of the Massachusetts College of Pharmacy. PMID- 11610416 TI - Zacharias Sylvius (1608-1664), author of the Praefatio to the first Rotterdam edition (1648) of Harvey's De Motu Cordis. PMID- 11610417 TI - Plants of Russian folk medicine. PMID- 11610418 TI - Bemerkungen zur "Physiologia" des Niederlanders Daniel Voet (1630-1660). PMID- 11610419 TI - Hellenistische Offenbarungsmotive und das Buch "Geheimnis der Schopfung". PMID- 11610420 TI - Essay review; the history of molecular biology. PMID- 11610421 TI - History of science journals: 'to be useful, and to the living'? PMID- 11610422 TI - Beichte und Heilung. PMID- 11610423 TI - Von der medizinischen Volksbelehrung zur Popularisierung der medizinischen Wissenschaft; Ideen einer "demokratischen Medicin" um 1848. PMID- 11610424 TI - Der sogenannte Frenulumspanner. PMID- 11610425 TI - Die Schule von Salerno. PMID- 11610426 TI - Studien zur Wirkungsgeschichte biologischer Motive in den Pseudo-Klementinen. PMID- 11610427 TI - Brief M. V. Lomonosovs an I. I. Suvalov: "Von der Vermehrung und Erhaltung des russischen Volkes" (1761). PMID- 11610428 TI - Zur Charakterisierung des Briefes: "Von der Vermehrung und Erhaltung des russischen Volkes" von M. V. Lomonosov. PMID- 11610429 TI - Die Sammlungen des gelehrten Superintendenten Johann Samuel Schroter (1735-1808). PMID- 11610430 TI - Neue Quellen zur Biographie des Mainzer Anatomen Franz Georg Ittner und seiner Familie sowie zum Maler seines Portrats. PMID- 11610431 TI - The interplay between socio-economic factors and medical science: yellow fever research, Cuba and the United States. PMID- 11610432 TI - Strategy in American cancer research after World War II. PMID- 11610433 TI - The rise and fall of the Limits to growth debate. PMID- 11610435 TI - From Candolle to Croizat: comments on the history of biogeography. PMID- 11610434 TI - Charles Darwin, the origin of consciousness, and panpsychism. PMID- 11610436 TI - The embryological origins of the gene theory. PMID- 11610437 TI - Theophrastus on herbals and herbal remedies. PMID- 11610438 TI - The J.H.B. archive report: the Alexander Forbes papers. PMID- 11610439 TI - Methodology and the emergence of physiological chemistry. PMID- 11610440 TI - Societies for the improvement of medical and chirurgical knowledge. PMID- 11610441 TI - Animal models of human malformation--a Hunterian concept. PMID- 11610442 TI - John Hunter--myth or legend? PMID- 11610443 TI - In a paper I once wrote . . . PMID- 11610444 TI - The entry of women into medicine in America: education and obstacles 1847-1910. PMID- 11610446 TI - Medical allusions in the inscriptions of Andhra Pradesh. PMID- 11610445 TI - Vapyacandra. PMID- 11610447 TI - Virechana Karma in Indian literature. PMID- 11610448 TI - Arabian physicians and medical science. PMID- 11610449 TI - Military medicine in Ancient India. PMID- 11610450 TI - In memorium: Dr. Douglas Guthrie. PMID- 11610451 TI - Need for a section of History of Medicine in the important medical libraries of India. PMID- 11610452 TI - Common plants of the 6th cent. A.D. as described in the Brhat Samhita of Varahamihira (505-587 A.D.). PMID- 11610459 TI - Reflections on the Neo-Romantic critique of science. PMID- 11610460 TI - Endless frontier or bureaucratic morass? PMID- 11610461 TI - Academic freedom and scientific freedom. PMID- 11610462 TI - The Gertrude Tuckwell collection (Trades Union Congress, Gt. Russell St., London, W.C.l.). PMID- 11610463 TI - Imperialism and motherhood. PMID- 11610464 TI - Sukira--Sudhira. PMID- 11610465 TI - Medicine and health in the Srishtikhanda of Padmapurana. PMID- 11610466 TI - Medical knowledge of Vemana. PMID- 11610467 TI - Biographies of Unani physicians found in Al-Hawi of Rhazes. PMID- 11610468 TI - A short historical review on Satar--an Unani drug. PMID- 11610469 TI - Reflections from the life of Dr. Karl Julius Aegidi, the founder of the first Paediatric Homeopathic Hospital. PMID- 11610470 TI - Plants in the works of the three sages of Sanskrit grammar. PMID- 11610471 TI - Edward Bach; a medico-historical study of his contributions to homeopathy. PMID- 11610472 TI - Personal reminiscences of Dr. P. Kutumbaiah. PMID- 11610473 TI - XXV International Congress of the History of Medicine; participating institutions and delegates--impressions, reflections and suggestions. PMID- 11610474 TI - Abstracts of medico-historical articles in Hindi journals. PMID- 11610476 TI - History of Guggulu based on Ayurvedic literature. PMID- 11610475 TI - Indian medical historiography; bibliography for 1965. PMID- 11610477 TI - Some saint physicians of Deccan. PMID- 11610478 TI - Brief biographies of eminent Unani Hekeems of India. PMID- 11610479 TI - An Indian scientist in America: the story of Dr. Yellapragada Subba Row. PMID- 11610480 TI - Kartikakunda. PMID- 11610481 TI - Medical lore in the works of Srinatha. PMID- 11610482 TI - Gayadasa. PMID- 11610483 TI - Daily regimen in Yashastilakachampu of Somadeva. PMID- 11610484 TI - Kaviraj Purushottam Dev Multani: an early Arabian author on the Indian system of medicine. PMID- 11610485 TI - Epigraphical allusion to surgery in Ayurveda. PMID- 11610486 TI - Al-Hawi (liber continens) of Ar-Razi, Abu Bakr Muhammed Bin Zakariya; synopsis of the fourteenth volume. Part II. PMID- 11610488 TI - A list of Unani medical printed books in Arabic language preserved in different libraries of Hyderabad. PMID- 11610487 TI - Rasheed Uddin Ahmad: critical appreciation of Avicenna's theories and terminology of drugs for general and cardiac ailments in Kitab-Ul-Adviyah-Qalbiyah. PMID- 11610489 TI - Unani medicine during Nizam dynasty. PMID- 11610490 TI - Nand Raj: Hahnemann's knowledge of bacteriology. PMID- 11610491 TI - Nand Raj: the medium system of Honigberger. PMID- 11610492 TI - History of cholera and its influence on the formation of W.H.O. PMID- 11610493 TI - Elixirs of mineral origin in Greek alchemy. PMID- 11610494 TI - The chemical library of Thomas Britton (1654-1714). PMID- 11610495 TI - Religion and science in the thought of Liebig. PMID- 11610496 TI - Medicine and the waning of professional sovereignty. PMID- 11610497 TI - "Let each man pass his days in that wherein his skill is greatest". PMID- 11610498 TI - The Ricettario Fiorentino. 1567. The origin of the art of the apothecary and the Florentine Pharmacopoeias. PMID- 11610499 TI - Concepts of existence: Greek origins of generational thought. PMID- 11610500 TI - Bringing up the father question. PMID- 11610501 TI - Generational difference: the history of an idea. PMID- 11610502 TI - The transcendent vitamin: efflorescence of Lang-kan. PMID- 11610503 TI - Current research on the history of science in the People's Republic of China. PMID- 11610504 TI - [Directory of historians of Chinese science]. PMID- 11610505 TI - Why Sirhan killed Kennedy: psychoanalytic speculations on an assassination. PMID- 11610506 TI - Philobatism and American culture. PMID- 11610507 TI - Images of childhood in early Byzantine hagiography. PMID- 11610508 TI - A history of health center in the 60's. (Jpn) PMID- 11610509 TI - Health technologists in the 60's. (Jpn) PMID- 11610510 TI - Ryoji Tazawa as tuberculosis specialist. (Jpn) PMID- 11610511 TI - Medicine and pharmacy in history. (East-Asia. 2) (Jpn) PMID- 11610512 TI - Rise of school health technologist and school nurse in Tokyo. (Jpn) PMID- 11610513 TI - Wissenschaft und Politik im Schicksal der Zoologischen Station in Neapel. PMID- 11610514 TI - Rassenhygiene im Dritten Reich. Krise und Wende. PMID- 11610515 TI - Herzskarabaus. PMID- 11610516 TI - Unser Bild. Melchior Adam Weikard, Kupferstichsilhouette, H. 23,8 cm, B. 18,2 cm. Kunstler und Stecher sind unbekannt. Das Original befindet sich im Stadtarchiv Mainz. PMID- 11610517 TI - Minutor ministerialis. Zur sozialen Mobilitat von Heilhilfspersonen in Klostern des Hochmittelalters. PMID- 11610518 TI - Die Unschatzbarkeit arztlicher Leistung und das Honorarproblem. PMID- 11610519 TI - Wissenschaft und Oeffentlichkeit im Spiegel der deutschen Arzneibuchliteratur. Zum deutsch-lateinischen Sprachenstreit in der Medizin des 16. und 17. Jahrhunderts. PMID- 11610520 TI - Die Pocken in Mainz im Jahre 1766. Ein Beitrag zur Epidemiologie aus historisch demographischer Sicht. PMID- 11610521 TI - Karl Friedrich Kielmeyer, ein Wegbereiter neuer Ideen. Der Einfluss seiner Methode des Vergleichens auf die Biologie der Zeit. PMID- 11610522 TI - Malleus Maleficarum or the hammer of witches. PMID- 11610523 TI - The notion of animal electricity: a phase in the history of physiology. PMID- 11610524 TI - The historical significance and future value of the Ashbel Smith Building--"Old Red." PMID- 11610525 TI - Construction and architecture of the Ashbel Smith Building. PMID- 11610526 TI - Magic, astrology, and the early American religious heritage, 1600-1760. PMID- 11610527 TI - A composing the chronological table of post-war medical technology. (Jpn) PMID- 11610528 TI - Periodization of activities and opinions of the Japan Medical Association after the war. (Jpn) PMID- 11610530 TI - A history of post war medicine viewed from patients' movements. (Jpn) PMID- 11610529 TI - Steps of medical social works. (Jpn) PMID- 11610531 TI - Around the Kampo (Chinese originated traditional) medicine. (Jpn) PMID- 11610532 TI - Nature and problems of the post war history of medical technology. (Jpn) PMID- 11610533 TI - [Psychiatrist Shuzo Kure and his relations with Ogai Mori and with Bunso Kure]. (Jpn). PMID- 11610534 TI - Controversy on division of medicine and pharmacy--a historical reflexion. (Jpn) PMID- 11610535 TI - Population and fertility in London, 1580-1650. PMID- 11610536 TI - From the empty nest to family dissolution: life course transitions into old age. PMID- 11610537 TI - Primitive physick: John Wesley's receipts. PMID- 11610538 TI - Domestic medicine chests: microcosms of 18th and 19th century medical practice. PMID- 11610539 TI - On the local government's health policy in the Meiji period. (Jpn) PMID- 11610540 TI - Early activities of the Japanese Association of Insurance Medicine. (Jpn) PMID- 11610541 TI - Research on Japanese foods. (Jpn) PMID- 11610542 TI - Glauber's salt and nitre. (Jpn) PMID- 11610543 TI - Ando Shoeki's thought on medicine. PMID- 11610544 TI - A short history of clioquinol, especially of its early toxicity. (Jpn) PMID- 11610545 TI - Health centers in the 30's. (Jpn) PMID- 11610546 TI - Activities of visiting nurse in the 30's. (Jpn) PMID- 11610547 TI - Contemporary evaluation of the Sanitary Association. (Jpn) PMID- 11610548 TI - Hireling nurses in the Meiji period. (Jpn) PMID- 11610549 TI - Hireling nurses in the Taisho period. (Jpn) PMID- 11610550 TI - A facet of governmental drug administration in Japan. (Jpn) PMID- 11610551 TI - A history of quarantine in 1945-1954. (Jpn) PMID- 11610552 TI - A history of medical technologist in medical and health care. (Jpn) PMID- 11610553 TI - A note on the modern medical history in Germany. (Jpn) PMID- 11610554 TI - Nursing education in 1945-1954. (Jpn) PMID- 11610555 TI - Strikes of nurses before the war (1). (Jpn) PMID- 11610556 TI - Nursing textbooks in Japan (the Meiji period). (Jpn) PMID- 11610557 TI - A comment on the medical history of ancient Japan. (Jpn) PMID- 11610558 TI - Nazi's doctors thereafter. (Jpn) PMID- 11610559 TI - Psychosomatic medicine and Buddhism (especially with regard to the Yuishiki- Kishin Ron). (Jpn) PMID- 11610560 TI - Antikamnia; the story of a pseudo-ethical pharmaceutical. PMID- 11610561 TI - Nicander's toxicology II: spiders, scorpions, insects and myriapods. PMID- 11610563 TI - Alteration of medical institution after the war; what is ongoing behind so-called "prosperity of private medical institutions". (Jpn) PMID- 11610562 TI - [Hara Sakae, a tuberculosis doctor]. (Jpn). PMID- 11610565 TI - Report of the Mori Ogai Society: Tohoku University, Medical School, 1937-1938. PMID- 11610564 TI - [W. Anderson, employed in the Japanese naval hospital]. (Jpn). PMID- 11610566 TI - In defence of biography: the use of biography in the history of science. PMID- 11610567 TI - Where does Schroedinger's "What is life?" belong in the history of molecular biology? PMID- 11610568 TI - Advancement of surgical technics in the Taisho period. (Jpn) PMID- 11610569 TI - Nature and role of infant care activities. (Jpn) PMID- 11610570 TI - Psychiatry in the Taisho Period. (Jpn) PMID- 11610571 TI - Notes on the history of Japanese drug manufacture. Part II. Introduction of the Western medicine and new development of drug manufacture. (Jpn) PMID- 11610573 TI - A comparative history of Eastern medicine. (Jpn) PMID- 11610572 TI - [The theory of primary infection of tuberculosis - works of Harumichi Oka]. (Jpn). PMID- 11610574 TI - Teido Kunisaki in memory. (Jpn) PMID- 11610575 TI - Around the surgery of the '60s. (Jpn) PMID- 11610576 TI - Note on the history of Japanese drug manufacture--introduction of medicinal culture from Asian continent and rise of drug manufacture. (Jpn) PMID- 11610577 TI - A note on keshiyaki (baked poppy). (Jpn) PMID- 11610579 TI - Health and medicine in the 1960's--summary. (Jpn) PMID- 11610578 TI - The beneficiary function of Tekko Kumiai (Iron Workers' Union) of the Rodo Kumiai Kiseikai) (Part III). (Jpn) PMID- 11610580 TI - Nursing in the 60's--through focusing on Junio nurse. (Jpn) PMID- 11610581 TI - Controversy of nursing education in the 60's--particularly on movements of the Japanese Association of Nurse. (Jpn) PMID- 11610582 TI - Some problems on professional establishment of pharmacist in Japan. (Jpn) PMID- 11610583 TI - A dento-historical study on an unusually shaped dental extractor; contnd. (Jpn) PMID- 11610584 TI - The beneficiary function of Tekko Kumiai (The iron worker's union of the Rodo Kumiai Kiseikai). Part 1: a historical study of social medicine in Japan. (Jpn) PMID- 11610585 TI - A short history of medicine in Muroran. (Jpn) PMID- 11610586 TI - F. Bacon's idea of health. (Jpn) PMID- 11610587 TI - Note on the history of medical economics. (Jpn) PMID- 11610588 TI - [Publication of Teido Kunizaki's letters]. PMID- 11610589 TI - A note on the ancient history of Japanese medicine. (Jpn) PMID- 11610590 TI - A commentary on the herbal terminology. (Jpn) PMID- 11610591 TI - On the final report of the C.C.M.C. (Jpn) PMID- 11610592 TI - Harvard mummies: a preliminary report. PMID- 11610593 TI - Head lice from an Aleutian mummy. PMID- 11610594 TI - Annotated bibliography [of paleopathology]. PMID- 11610595 TI - A golden age of pharmacy, 1877-1977. PMID- 11610596 TI - A question in the modern Japanese history of medical education. (Jpn) PMID- 11610597 TI - A short history of anti-malarial drug development. (Jpn) PMID- 11610598 TI - On measures against pneumosilicosis among metal miners after enacting the Keihai Tokubet Su Hogo Ho (pneumosilicosis prevention law). (Jpn) PMID- 11610599 TI - Testimonies of a generation (Part I). PMID- 11610600 TI - [Dawson's report; interim report on the future provision on medical and allied sciences, 1920]. (Jpn). PMID- 11610601 TI - A cholera epidemic of 1886 in a local district. (Jpn) PMID- 11610602 TI - Patient and physician written by Robert Gersney. (Jpn). PMID- 11610603 TI - An interpretation of Dattashank etc. in Susruta Samhita. (Jpn) PMID- 11610605 TI - A history of public health nurses after the war, especially their group activities. (Jpn) PMID- 11610606 TI - Controversy of division of medicine and pharmacy, a historical reflexion. Part. 2. (Jpn) PMID- 11610604 TI - Training of public health nurses before enactment of the regulation. (Jpn) PMID- 11610607 TI - Anatomical knowledge in Buddhism. (Jpn) PMID- 11610608 TI - The beneficiary function of the Tekko Kumiai (iron worker's union) of the Rodo Kumiai Kiseikai). (Part II). (Jpn) PMID- 11610609 TI - Annotated bibliography [of paleopathology]. PMID- 11610610 TI - Rheumatoid arthritis. PMID- 11610611 TI - Note on the history of Japanese drug manufacture (Part II) II. Transmission of the Western medicine and new development of drug manufacture. (Jpn) PMID- 11610612 TI - [The theory of primary infection of tuberculosis; works of M. Oka]. (Jpn). PMID- 11610613 TI - Change of fee system regulation in dental practice. (Jpn) PMID- 11610615 TI - The epidemic of 994 and rumors. (Jpn) PMID- 11610614 TI - Poisons of Faust. (Jpn) PMID- 11610616 TI - Conception of living body in the Indian medicine. (Jpn) PMID- 11610617 TI - Papers on paleopathology presented at the annual meeting of the Paleopathology Association. PMID- 11610618 TI - Frontier municipal baths and social interaction in thirteenth-century Spain. PMID- 11610619 TI - Influence of sensationalist tradition on early theories of the evolution of behavior. PMID- 11610620 TI - The achievement of Pompe van Meedervoolt. (Jpn) PMID- 11610621 TI - Medicine and pharmacy in the history. (Jpn) PMID- 11610622 TI - Montaigne and Moore, their conception of health. (Jpn) PMID- 11610623 TI - Social medicine as historical science. (Jpn) PMID- 11610624 TI - O'gai, Pettenkofer and army. (Jpn) PMID- 11610625 TI - Japanese pioneers in the vaccination. (Jpn) PMID- 11610626 TI - Modernity and tradition in the context of Arab medicine. PMID- 11610627 TI - Nephrology in ancient Indian system of medicine. PMID- 11610628 TI - Triphala and its Arabic and Chinese synonyms. PMID- 11610629 TI - Medical world of madness, morality, and number. PMID- 11610630 TI - The specter of progressive medicine. PMID- 11610631 TI - As in a looking-glass: perceptual acquaintance in eighteenth-century Britain. PMID- 11610632 TI - Science policy advisory councils in France, the Netherlands and the United States, 1957-77: a comparative analysis. PMID- 11610633 TI - Quantitative measures of communication in science: a critical review. PMID- 11610634 TI - Gesellschaft, Wirtschaft und arztlicher Stand im fruhen und hohen Mittelalter. PMID- 11610635 TI - Ueber die Termini "Pharmacognosis" und "Pharmacographia", ein Beitrag zur Geschichte der pharmazeutischen Wissenschaften. PMID- 11610636 TI - Henry E. Sigerist: the years in America. PMID- 11610637 TI - Der Respirator oder Lungenschutzer. PMID- 11610638 TI - The imagery of death in anatomical illustrations. PMID- 11610639 TI - Mercury poisoning: a probable cause of Isaac Newton's physical and mental ills. PMID- 11610640 TI - Newton's 'Derangement of the intellect'; new light on an old problem. PMID- 11610641 TI - The contemporary scientific archives centre. PMID- 11610642 TI - British and American views of the German menace in World War I. PMID- 11610643 TI - Annotated bibliography [of paleopathology]. PMID- 11610644 TI - The postmortem on Crow Creek. PMID- 11610645 TI - Lead ingestion in ancient times. PMID- 11610646 TI - Childlessness and its correlates in historical perspective: a research note. PMID- 11610647 TI - The social relations of science: The British Association for the Advancement of Science, 1931-1946. PMID- 11610649 TI - On the science and technology of medicine. PMID- 11610648 TI - Institutional organization, incentives, and change. PMID- 11610650 TI - Development and alteration of the medical system in the Ritsuryo Code Regimen. (Jpn) PMID- 11610651 TI - Favorinus' disorder: Reifenstein's syndrome in Antiquity? PMID- 11610652 TI - The movement for euthanasia, 1875-1975. PMID- 11610653 TI - Carl Ludwig Blume and the Netherlands East Indies. PMID- 11610654 TI - Herman Boerhaave und die Entwicklung der Medizinwissenschaft in Ungarn. PMID- 11610655 TI - Historical group-fantasies. PMID- 11610656 TI - Children and violence in Chaucer's Canterbury Tales. PMID- 11610657 TI - Darwin after Malthus. PMID- 11610658 TI - The lessened locus of feelings: a transformation in French physiology in the early nineteenth century. PMID- 11610659 TI - Some reflections on the protean nature of the scientific precursor. PMID- 11610660 TI - Vin Mariani. PMID- 11610661 TI - The German apothecary societies of New York. PMID- 11610663 TI - Randlords and rotgut 1886-1903. PMID- 11610662 TI - The Rockefeller Foundation and the development of scientific medicine in Great Britain. PMID- 11610664 TI - Non-psychoanalytic approaches to national socialism. PMID- 11610665 TI - Critical bibliography [of psychohistory]. PMID- 11610666 TI - Is psychohistory really history? PMID- 11610667 TI - Hot beverages and the enterprising spirit in 18th-century Europe. PMID- 11610668 TI - Sons of the ante-bellum gentry: Olmsted and his contemporaries. PMID- 11610669 TI - New developments in applied psychoanalysis. PMID- 11610670 TI - Reconstruction in psychoanalytic biography: understanding Thomas Jefferson. PMID- 11610671 TI - Father and sons: notes on "new light" and "new left" young people as a historical comparison. PMID- 11610672 TI - Autonomy and affection: parents and children in eighteenth-century Chesapeake families. PMID- 11610673 TI - "From the cradle to the coffin": parental bereavement and the shadow of infant damnation in Puritan society. PMID- 11610674 TI - The cradle of true patriots. PMID- 11610675 TI - John Humphrey Noyes and the Oneida Community: a 19th-century American father and his family. PMID- 11610676 TI - Adolescent peer group morality: its origins and functions in the United States. PMID- 11610677 TI - The priests of the body and masturbatory insanity in the late nineteenth century. PMID- 11610678 TI - History as mythology: the "Punjab Style" in British India. PMID- 11610679 TI - Notes toward an interpretation of antebellum childrearing. PMID- 11610680 TI - Belinskii and Bakunin: a psychoanalytic study of adolescence in nineteenth century Russia. PMID- 11610681 TI - Evaluating psychohistorical explanations. PMID- 11610682 TI - Die Zusammenarbeit der Sozialhygieniker Alfred Grotjahn und Alfons Fischer. PMID- 11610683 TI - Zur Titelgestaltung medizinischer Fachbucheditionen des 17. Jahrhunderts. PMID- 11610684 TI - Kritisches zu den "Urkunden zur Hochschulpolitik der romischen Kaiser." PMID- 11610685 TI - Some thoughts on the psychohistorical study of women. PMID- 11610687 TI - Garrisonian abolitionism and the Boston Clique: a psychosocial inquiry. PMID- 11610686 TI - 1866: Bismarck's gamble. PMID- 11610688 TI - The methodology of psychohistory: an annotated bibliography. PMID- 11610689 TI - The child in American historiography: accomplishments and prospect. PMID- 11610690 TI - Biron's execution: a note on the psychology of dying in early modern France. PMID- 11610691 TI - Clio, Eros, and Psyche: separation, divorce, or marriage? PMID- 11610692 TI - Ayurveda and the Indian State. PMID- 11610693 TI - [Medicine in the Sanskrit tradition]. PMID- 11610694 TI - The transference model in psychohistory: a critique. PMID- 11610695 TI - Reflections on the state of psychohistory. PMID- 11610696 TI - Why America loved Theodore Roosevelt: or charisma is in the eyes of the beholders. PMID- 11610697 TI - Grandiosity and violence in the Kennedy family. PMID- 11610698 TI - A note on the adaptation of the psychoanalytic method to the study of historical personalities: psychoanalysts on Schreber. PMID- 11610699 TI - The "touchiness" of the gentleman planter: the sense of esteem and continuity in the ante-bellum South. PMID- 11610700 TI - Human values and the market: the case of life insurance and death in 19th-century America. PMID- 11610702 TI - Vaidyasastrasivanubhava. Translation of selected passages. PMID- 11610701 TI - Haritaki. A comparative study of literature in Ayurveda and Tibetan medicine. PMID- 11610703 TI - Muheet-a-Azam. (A great Unani pharmacopeia.) A short note on the author and the book. PMID- 11610704 TI - Brief biographies of eminent Unani Hekeems of India based on nuz-hatul-khwatir (pleasure of hearts). PMID- 11610705 TI - Dr. Mahendra Lal Sircar. The first eminent allopath to practise and propagate homoeopathy. PMID- 11610706 TI - Netradarpanam. ("Mirror of the Eye"). A treatise in Telugu on eye diseases. An account of the author and the book. PMID- 11610707 TI - Survey of sources for the history of biochemistry and molecular biology: an introductory report. PMID- 11610708 TI - The role of "Archives d'Anthropologie Criminelles" in the interrelations between society, medicine and law. PMID- 11610709 TI - Psychology in New England: a retrospective look -- a woman's point of view. PMID- 11610710 TI - Quantification in ethnology and its appearance in regional culture trait distribution studies (1888 to 1939). PMID- 11610711 TI - The history of introspection reconsidered. PMID- 11610712 TI - A methodological note on the research use of the Syntopicon. PMID- 11610713 TI - Innovation in the Malinowskian mode: an essay review of long-term field research in social anthropology. PMID- 11610714 TI - Women sanitary inspectors. PMID- 11610715 TI - Nineteenth century pharmaceutical research into plants of the southwestern deserts. PMID- 11610716 TI - Liberal arts and pharmacy education: where do we now stand? PMID- 11610717 TI - The checkered history of lithium in medicine. PMID- 11610718 TI - "The past recaptured"...five North Carolina pharmacies. PMID- 11610719 TI - This sea of simples; the materia medica in three early English receipt books. PMID- 11610720 TI - The octocentenary of the Pepperers' Gild. PMID- 11610721 TI - The records of the American Association of Colleges of Pharmacy. PMID- 11610722 TI - Historical pharmaceutical exhibits at PCP&S. PMID- 11610723 TI - Facts about artifacts [in the history of pharmacy]. PMID- 11610724 TI - The eclectic "concentrations" and American pharmacy (1847-1861). PMID- 11610725 TI - A demographic and social analysis of widowhood and remarriage: the example of the castellany of Thoissey-en-Dombes, 1670-1840. PMID- 11610726 TI - Old women: some historical observations. PMID- 11610727 TI - The life cycle of American families: an expanded analysis. PMID- 11610728 TI - Female longevity and diet in the Middle Ages. PMID- 11610729 TI - Joseph LeConte and the development of the physiology and psychology of vision in the United States. PMID- 11610730 TI - Early research on the biological effects of microwave radiation: 1940-1960. PMID- 11610731 TI - The origins of Soviet genetics and the struggle with Lamarckism, 1922-1929. PMID- 11610732 TI - Essay review; early Victorian science: science in culture. PMID- 11610733 TI - Essay review; Horace Judson and the molecular biologists. PMID- 11610734 TI - Darwin's botanical arithmetic and the "principle of divergence," 1854-1858. PMID- 11610735 TI - Geographical distribution and the origin of life: the development of early nineteenth-century British explanations. PMID- 11610736 TI - The movement for smoke abatement in 19th-century Britain. PMID- 11610737 TI - Preferences for the sex of offspring and demographic behavior in eighteenth and nineteenth-century Germany: an examination of evidence from village genealogies. PMID- 11610738 TI - The female life cycle in a Belgian commune: La Hulpe, 1847-1866. PMID- 11610739 TI - History, philosophy and sociology of biology: a family romance. PMID- 11610740 TI - Palingenesis, alchemy and metempsychosis in Renaissance medicine. PMID- 11610741 TI - A survey of the paleopathology of the Vidor site, Guanacaste Province, Costa Rica. PMID- 11610742 TI - 'Skinny bones' from the Dakhleh Oasis. PMID- 11610743 TI - A ninth century account of diets and Dies Aegyptiaci. PMID- 11610744 TI - Another look at Prospero and Caliban: magic and magical thinking in British India. PMID- 11610745 TI - The unstrung Orpheus: Flaubert's youth and the psycho-social origins of art for art's sake. PMID- 11610746 TI - Human values and the market: the case of life insurance and death in 19th-century America. PMID- 11610747 TI - Oxyurid infestations in small animals from 9,000 B.P. in Brazil. PMID- 11610748 TI - The paleopathology of the human remains from Nebwenenef's tomb--the 1979 season. PMID- 11610749 TI - Annotated bibliography [of Paleopathology]. PMID- 11610750 TI - From prizes to grants in the support of scientific research in France in the nineteenth century: the Montyon legacy. PMID- 11610751 TI - The redistribution of authority in national laboratories in Western Germany. PMID- 11610752 TI - Gerrit Arie Lindeboom and the history of medicine in the Netherlands. PMID- 11610753 TI - Lambertus Bicker (1732-1801). An early adherent of Lavoisier in the Netherlands. PMID- 11610754 TI - Jan Ingen-Housz (1730-1799): some new evidence about his life and work. PMID- 11610755 TI - Samuel Musgrave's attack upon Stahl's and Boerhaave's doctrines in 1763. PMID- 11610756 TI - Jaspers und Van Gogh--oder uber Krankheit und Kunst. PMID- 11610757 TI - Decora Merenti. Glory, merit and science. Haller spellbound by the Newtonian star. PMID- 11610759 TI - The final illness of Gotthold Ephraim Lessing. PMID- 11610758 TI - A. W. van Renterghem und Frederik van Eeden, zwei hollandische Aerzte als Bahnbrecher auf dem Gebiete der psychischen Therapie. PMID- 11610760 TI - The revival of the anatomico-clinical method in Padua: the fundamental contribution of F. S. Verson (1805-1849) from Trieste, a disciple of the Vienna School of Medicine. PMID- 11610761 TI - "Dictata" zu den Werken von Johannes de Gorter (1689-1762), professor in Harderwijk: medicinae compendium, praxis medicae systema und chirurgia repurgata. PMID- 11610763 TI - Medicina Historica. Zum Selbstverstandnis der historischen Medizin. PMID- 11610762 TI - Leeuwenhoek's Sehversuch am zusammengesetzten Auge und die entsprechende Beobachtung Boll's an der Stabchenschicht der Netzhaut. PMID- 11610764 TI - The life course of women: age and age consciousness, 1865-1915. PMID- 11610765 TI - Short-term trends in bastardy in Taiwan. PMID- 11610766 TI - Death and the family. PMID- 11610767 TI - Reflections on the history of pharmacology. PMID- 11610768 TI - Concepts of illness in ancient China: the case of demonological medicine. PMID- 11610769 TI - Medical theory and demographic concerns in early industrial England. PMID- 11610770 TI - The passions according to Adam Smith and Pierre-Jean-Georges-Cabanis. Two sciences of man(1). PMID- 11610771 TI - Medicine and the Enlightenment in Eighteenth century England. PMID- 11610772 TI - The Scottish dimension of Enlightenment medicine; the political economy of health. PMID- 11610773 TI - The Enlightenment and infant care. PMID- 11610774 TI - Public medicine and medical careers in France during the reign of Louis XV. PMID- 11610775 TI - [The need to preserve medical history records]: Evidence presented to the Public Records Committee. PMID- 11610776 TI - Bologna and the Royal Society in the seventeenth century. PMID- 11610777 TI - Marshall Hall, F.R.S. (1790-1857); a conspectus of his life and work. PMID- 11610778 TI - W. T. Astbury and Ross G. Harrison: the search for the molecular determination of form in the developing embryo. PMID- 11610779 TI - The circulation and use of medical manuscipts in ARabic in 16th century Spain. PMID- 11610780 TI - Publishing the Dictionary of Scientific Biography. PMID- 11610781 TI - Palaeoecology of Tsetse flies and sleeping sickness in Africa. PMID- 11610782 TI - The rise and fall of public opposition in specific social movements. PMID- 11610783 TI - The brain drain re-emergent: foreign medical graduates in American medical schools. PMID- 11610784 TI - Hierarchy and peripherality: the organisation of a Mexican research institute. PMID- 11610785 TI - Politics and vocation: French science, 1793-1830. PMID- 11610786 TI - Romantic science? Michelet, morals, and nature. PMID- 11610787 TI - Papers on Paleopathology presented at the Third European Members Meeting of the Paleopathology Association. 1980, Sept. 26-28. Caen, France. PMID- 11610788 TI - Variations in shape and size of the lumbar spinal canal. PMID- 11610789 TI - Paleopathology in Peru. PMID- 11610790 TI - Health of farm children in the South, 1900-1950. PMID- 11610791 TI - Will medical history join the American mainstream? PMID- 11610792 TI - The statistical case for elimination of the midwife: fact versus prejudice, 1890 1935. PMID- 11610793 TI - Together but not equal: amateurs and professionals in early American scientific societies. PMID- 11610794 TI - Man amuck. PMID- 11610795 TI - Decrease and stultify: contraception and abortion in American society. PMID- 11610796 TI - Writing public health history: the need for a social scaffolding. PMID- 11610797 TI - From creeds to therapies: Philip Rieff's work in perspective. PMID- 11610798 TI - Women in the medical profession: why were there so few? PMID- 11610799 TI - Infanticide, illegitimacy and the medical profession in nineteenth century England. PMID- 11610800 TI - Social concepts in anatomy: theories of the cell state of Oscar Hertwig (1849 1922) and Wilhelm Waldeyer (1836-1921). PMID- 11610801 TI - Suicide in Victorian London; an urban view. PMID- 11610802 TI - Deviants in death? Plebeian secularists and spiritualists c. 1860-1910. PMID- 11610803 TI - The dance of Death. An iconographic interpretation of the popular theme of death through five centuries. PMID- 11610804 TI - A dissection of the Anatomy Act. PMID- 11610805 TI - The medical practice of the East India Company. PMID- 11610806 TI - From physician to scientist: changing styles of thought in late Victorian physiology. PMID- 11610807 TI - Technology the dehumanizer. PMID- 11610808 TI - The historian as policy analyst: the challenge of HEW. PMID- 11610809 TI - The economic effects of cattle disease in Britain and its containment, 1850-1900. PMID- 11610810 TI - Carcinogenic risk assessment in the United States and Great Britain: the case of Aldrin/Dieldrin. PMID- 11610811 TI - Aconite and its antidote in Arabic writings. PMID- 11610812 TI - Arabic manuscripts of the National Library of Medicine, Washington, D.C. PMID- 11610813 TI - The changing environments of science. PMID- 11610814 TI - The appearance of scientific naturalism in Syria and Egypt. PMID- 11610815 TI - Sarton (1884-1956) and the Arabic-Islamic legacy. PMID- 11610816 TI - The origins of the American Scientific debate over fallout hazards. PMID- 11610817 TI - From avocation to job: the changing nature of scientific practice. PMID- 11610818 TI - Urban pollution: historical perspective needed. PMID- 11610819 TI - Politics and science in the laetrile controversy. PMID- 11610820 TI - Dutch immigrant demography, 1820-1880. PMID- 11610821 TI - Slave marriage and the family. PMID- 11610822 TI - Science and sedition: how effective were the acts licensing lectures and meetings, 1795-1819? PMID- 11610823 TI - E. V. McCollum: pathfinder in nutrition investigations and world agriculture. PMID- 11610825 TI - Science and politics in the war on cattle diseases: the Kansas experience, 1900 1940. PMID- 11610824 TI - Pesticide use in early twentieth century animal disease control. PMID- 11610826 TI - The radical sociology of medicine. PMID- 11610827 TI - [The history of physiology:] essay review PMID- 11610828 TI - Problems of individual development: descriptive embryological morphology in America at the turn of the century. PMID- 11610830 TI - In search of the new biology: an epilogue. PMID- 11610829 TI - Morphology and twentieth-century biology: a response. PMID- 11610831 TI - Pseudo-Dioscorides' Ex herbis femininis and early medieval medical botany. PMID- 11610832 TI - Shifting assumptions in American biology: embryology, 1890-1910. PMID- 11610833 TI - Essay review: life science in the twentieth century. PMID- 11610834 TI - The American drinking tradition. PMID- 11610835 TI - Mad and bad in California. PMID- 11610836 TI - Consanguinity and noble marriages in the tenth and eleventh centuries. PMID- 11610837 TI - Anatomical illustrations with superimposed flaps. PMID- 11610839 TI - The psychohistory of history: a symposium. PMID- 11610841 TI - Oral history and psychohistory. PMID- 11610840 TI - Content analysis in psychohistory: a study of three lieutenants in the Indian mutiny, 1857-58. PMID- 11610842 TI - Alchemists, critics and psychohistorians. PMID- 11610843 TI - The histology of ancient mammoth tissue. PMID- 11610844 TI - A small skeletal sample from northern Ghana. PMID- 11610845 TI - Stafne defect: a histological approach. PMID- 11610846 TI - Palaeodontology of the Nile Valley. PMID- 11610847 TI - A brief note on rubber technology and contraception: the diaphragm and the condom. PMID- 11610848 TI - Utopian and pragmatic rationalism: the political context of scientific advice. PMID- 11610849 TI - Hippocrates and the biomedical scientist: the problems of controlling the dangers of science. PMID- 11610850 TI - The early institutional establishment of social science research: the local community research committee at the University of Chicago, 1923-30. PMID- 11610851 TI - Dragon bones and drugstores: the interaction of pharmacy and paleontology in the search for early man in China. PMID- 11610852 TI - Henry Hurd Rusby: scientific explorer, societal crusader, scholastic innovator. PMID- 11610853 TI - Ancient medical recipes and the computer: the Theorema project. PMID- 11610854 TI - Heart transplantation---1979. PMID- 11610855 TI - Dr. Brown-Sequard in space and time. PMID- 11610856 TI - The route back to Methusaleh. PMID- 11610857 TI - Belle-Ile and the secret expedition. PMID- 11610858 TI - From Concorde to the cosmos. PMID- 11610859 TI - Development of modern neonatal surgery. PMID- 11610860 TI - "Mony a mickle..." PMID- 11610861 TI - John Hunter: a man of his age. PMID- 11610862 TI - Pharmacy in the time of John Hunter (1728-1793). PMID- 11610863 TI - [Phosphor-poisoning in match factories and the Salvation Army General Booth] (Jpn). PMID- 11610864 TI - [An interpretation of a syndrome depicted in Buddhist cannon [sic] through Susruta Samhita] (Jpn). PMID- 11610865 TI - [Nurse's images in the Taisho period; nurses described in women's magazines] (Jpn). PMID- 11610866 TI - [Background of Rintaro Mori's debates on statistics] (Jpn). PMID- 11610867 TI - [Chukichi Kubokawa and industrial Hygiene] (Jpn). PMID- 11610868 TI - [Psychiatry in the early 19th century Japan] (Jpn). PMID- 11610870 TI - [Development and alteration of medical system in the Ritsuryo code regimen] (Jpn). PMID- 11610869 TI - [Visiting nurse after the World War II] (Jpn). PMID- 11610871 TI - [Formation of the medical system in the Ritsyryo code regimen] (Jpn). PMID- 11610872 TI - [Visiting nursing in 1926-1945] (Jpn). PMID- 11610874 TI - [The Osaka Charity Hospital and private practitioner] (Jpn). PMID- 11610873 TI - [A chronological table on district nurse (Hokenfu) in after the war. Part I] (Jpn). PMID- 11610875 TI - Scientific change, emerging specialties, and research schools. PMID- 11610876 TI - The fine structure of scientific creativity. PMID- 11610877 TI - Possible treponematosis in fourteenth century Dakota territory: a progress report. PMID- 11610878 TI - Aseptic bone necrosis found in the skeletal material from the Merovingian cemetery of Kleinlangheim, Southern Germany. PMID- 11610879 TI - Papers on paleopathology: presented at the Annual Meeting of the Paleopathology Association, 22 April, 1981. [Supplement to Paleopathology Newsletter, No. 34, June 1981]. PMID- 11610880 TI - The pharmacy in comic postcards. PMID- 11610882 TI - [My way of medical history study]. PMID- 11610881 TI - "Thialion!!!" Anatomy of a pseudo-ethical proprietary. PMID- 11610883 TI - [Medical history in the medical education] (Jpn). PMID- 11610884 TI - [A historical study on formation of policy for "Nambyo" (intractable diseases)] (Jpn). PMID- 11610885 TI - [Development of the concept on open system hospital in Japan] (Jpn). PMID- 11610886 TI - Brain stimulation and affective behavior: a note on an early demonstration of a "reward center". PMID- 11610887 TI - Freud's confrontation with the telic mind. PMID- 11610888 TI - A note on the role of Karl Christian Wolfart (1778-1832) in the study of animal magnetism. PMID- 11610889 TI - From psychotherapy to psychoanalysis: Frederik van Eeden and Albert Willem van Renterghem. PMID- 11610890 TI - Arthur F. Bentley and the foundations of behavioral science. PMID- 11610891 TI - Pavlov's contributions to physiology before 1900. PMID- 11610894 TI - War, revolution, and psychoanalysis: Freudian thought begins to grapple with social reality. PMID- 11610892 TI - Pavlov's influence on psychology in America. PMID- 11610893 TI - Pavlov and psychiatry. PMID- 11610895 TI - A note on the history of psychology in magazines. PMID- 11610896 TI - The mistaken mirror: on Wundt's and Titchener's psychologies. PMID- 11610897 TI - Quantification and Chicago social science in the 1920s: a neglected tradition. PMID- 11610898 TI - Freud and the problem of sexuality. PMID- 11610899 TI - The rise and fall of moral algebra: Frances Hutcheson and the mathematization of psychology. PMID- 11610900 TI - Interpretations of Freud's Jewishness, 1924-1974. PMID- 11610901 TI - Psychology, progress and the problem of reflexivity: a study in the epistemological foundations of psychology. PMID- 11610902 TI - "Visible colleges" and archives in Europe: first impressions. PMID- 11610903 TI - [Madness described in essays during the Edo period] (Jpn). PMID- 11610904 TI - [A study on Shimpei Goto/Part II & III. His basic idea on central and rural health organization] (Jpn). PMID- 11610905 TI - [A historical study on expansive use of chloroquine] (Jpn). PMID- 11610906 TI - The people of Tuscany and their families in the fifteenth century: Medieval or Mediterranean? PMID- 11610907 TI - Marriage, migration, and urban demographic structure: a case from France in the Belle Epoque. PMID- 11610909 TI - Bureaucracy, liberalism and the body in post-revolutionary France: Bichat's physiology and the Paris school of medicine. PMID- 11610908 TI - Birth control and the fertility of the U. S. Black population, 1880 to 1980. PMID- 11610911 TI - [Posthumous manuscripts: medicine and people in Britain] (Jpn). PMID- 11610910 TI - Mother nature and the scientific revolution. PMID- 11610912 TI - ["Eisei-Shinpen"--Ogai Mori as a physician (II)]. PMID- 11610913 TI - [Interim report on the future provision on medical and allied services, 1920 (I)] (Jpn). PMID- 11610914 TI - [Papers on Chinese medicine and on the study of medical history in China.] (Chi) PMID- 11610915 TI - Vom Giessener pharmakologischen Institut unter Rudolf Buchheim und Karl Gaehtgens (1867-1898). PMID- 11610916 TI - Synopsis zur neueren Medizingeschichte Russlands. PMID- 11610917 TI - Deutsche Uebersetzungen englischer humanmedizinischer Werke 1680-1810. Eine vorlaufige Bibliographie. PMID- 11610918 TI - Richard Hermann Koch (1882-1949): Arzt, Medizinhistoriker, Medizinphilosoph (Biographisches, Ergographisches). 1. Teil. Zur Biographie. PMID- 11610919 TI - Die Infektionskrankheit im erzahlerischen Werk Thomas Manns. PMID- 11610920 TI - Das Biogenetische Grundgesetz--Vorgeschichte und Folgerungen. PMID- 11610921 TI - Popularisierungstendenzen in der mittelalterlichen Fachliteratur. PMID- 11610922 TI - A hidden chapter of German eugenics between the two world wars. PMID- 11610923 TI - Wie ich aus Deutschland vertrieben wurde: Dokumente mit Kommentaren. PMID- 11610924 TI - Moritz Schiffs gescheiterter Habilitationsversuch an der Universitat Gottingen im Jahre 1855. PMID- 11610925 TI - Homoopathische Fernbehandlung durch Samuel Hahnemann. PMID- 11610926 TI - Das Kausalitatsproblem in der Evolutionslehre. Ein Beitrag zur Strukturgeschichte der Biologie. PMID- 11610927 TI - Ein romisches Arztgrab des 3. Jahrhunderts n. Chr. aus Kleinasien. PMID- 11610928 TI - Samuel Thomas von Soemmerring (1755-1830), Aquarell, gemalt 1794 von seiner Frau Margarethe Elisabeth, geb. Grunelius (1768-1802), Grosse des Bildovals 12,8 cm (Hohe): 11,5 cm (Breite) (Privatbesitz). PMID- 11610930 TI - Sauerbruch und der Nationalsozialismus. PMID- 11610929 TI - [Not Available]. PMID- 11610932 TI - The mechanism of mortality change in Germany, 1750-1850. PMID- 11610931 TI - Richard Hermann Koch (1882-1949). PMID- 11610933 TI - Ernst Haeckel und der Darwinismus: Popularisierung, Propaganda und Ideologisierung. PMID- 11610934 TI - Polemik und Kontroversen um Haeckel. PMID- 11610935 TI - Die Haeckel-Rezeption durch die Botanik. PMID- 11610936 TI - The Third International Eugenics Congress, 1932. PMID- 11610937 TI - Reconstructing restoration science: styles of leadership and social composition of the early Royal Society. PMID- 11610938 TI - The first Latin treatise on horse medicine and its author Pelagonius Saloninus. PMID- 11610939 TI - Ibn Quaiyim al-Gauziya uber die Methoden der Embryologie. PMID- 11610940 TI - Georg August Bertele (1767-1818) und die Arzneimittellehre der romantischen Naturphilosophie. PMID- 11610941 TI - Die Fleckfieber-Epidemie in Kulmbach im Jahre 1793. PMID- 11610942 TI - [Not Available]. PMID- 11610943 TI - Neil Arnott, F.R.S., reformer, innovator and popularizer of science, 1788-1874. PMID- 11610944 TI - The classical period in chemical genetics; recollections of Muriel Wheldale Onslow, Robert and Gertrude Robinson and J. B. S. Haldane. PMID- 11610945 TI - The van Leeuwenhoek specimens. PMID- 11610946 TI - A letter from Sydney Parkinson in Batavia to Dr. John Fothergill. PMID- 11610947 TI - John Macculloch, M.D., F.R.S., and his geological map of Scotland: his years in the Ordnance. 1795-1826. PMID- 11610948 TI - The physiology of mind, the unity of nature, and the moral order in Victorian thought. PMID- 11610949 TI - The Philosophical Society of Edinburgh 1748-1768. PMID- 11610950 TI - The problem of ventilation through the ages. PMID- 11610951 TI - Convergent themes in the history of science, medicine, and technology. PMID- 11610952 TI - Chekhov's doctors. PMID- 11610953 TI - Eunuchs and eunuchism--an historical discourse. PMID- 11610954 TI - C. Louis Leipoldt--medical student extraordinary. PMID- 11610955 TI - Instinct and intelligence in British natural theology: some contributions to Darwin's theory of the evolution of behavior. PMID- 11610956 TI - Darwin's data: his reading of natural history journals, 1837-1842. PMID- 11610957 TI - The problem of the organic individual: Ernst Haeckel and the development of the biogenetic law. PMID- 11610959 TI - Embryology in Talmudic and Midrashic literature. PMID- 11610958 TI - George Henry Lewes: a man of his time. PMID- 11610961 TI - Absent the incentive: an example of contemporary history. PMID- 11610960 TI - The J.H.B. Archive report: the papers of Harry Hamilton Laughlin, eugenicist. PMID- 11610962 TI - The doctors' dilemma: sin, salvation, and the menstrual cycle in medieval thought. PMID- 11610963 TI - Zur Erforschung archaisch-griechischer "Zeugungslehren". PMID- 11610964 TI - Krote und Igel in schwankhafter Literatur des spaten Mittelalters. PMID- 11610965 TI - Probleme der Arzneipreisgestaltung im 19. Jahrhundert. PMID- 11610966 TI - Haminkristalle--Ludwik Teichmanns Blutnachweis. PMID- 11610967 TI - Santiago Ramon y Cajal und die Typologie des Wissenschaftlers. PMID- 11610968 TI - Die Bemuhungen zur Schaffung eines Reichsgesundheitsministeriums in der ersten Phase der Weimarer Republik 1918-1922. PMID- 11610969 TI - Die Augenanomalie an einem romischen Bildnis. PMID- 11610970 TI - "Klinisches Ambulatorium" von Andor Dudits, 1890. PMID- 11610971 TI - Prostitution and the medical profession in the nineteenth century. PMID- 11610972 TI - Love for hire: the regulation of the wet-nursing business in eighteenth-century Hamburg. PMID- 11610973 TI - The decision to institutionalize: families with exceptional children in 1900. PMID- 11610974 TI - Scarcity and prosperity in postwar childbearing: explorations from a life course perspective. PMID- 11610975 TI - Philippe Aries, historian of the family. PMID- 11610976 TI - Giochi, scommesse sulla vita, tabelle di mortalita, nascita del calcolo probabilistico, statistica e teoria delle popolazioni. PMID- 11610977 TI - Reflections on the historiography of molecular biology. PMID- 11610978 TI - The pre-history of an academic discipline: the study of the history of science in the United States, 1891-1941. PMID- 11610979 TI - Superlative achievement and comparative neglect: Alexandrian medical science and modern historical research. PMID- 11610980 TI - Liebigiana: old and new perspectives. PMID- 11610981 TI - Coadaptation and the inadequacy of natural selection. PMID- 11610983 TI - Closing the door on Lord Morton's mare: the rise and fall of telegony. PMID- 11610982 TI - Library and archive resources in the history of science and medicine at the University of Leeds. PMID- 11610984 TI - Sex and the single organism: biological theories of sexuality in mid-nineteenth century. PMID- 11610985 TI - Naturalists and experimentalists: the genotype and the phenotype. PMID- 11610986 TI - Francis B. Sumner and the evolutionary synthesis. PMID- 11610987 TI - Geographic isolation in Darwin's thinking: the vicissitudes of a crucial idea. PMID- 11610988 TI - From "Gene Fund" to "Gene Pool": on the evolution of evolutionarylanguage. PMID- 11610989 TI - Bergmann's rule: animal heat as a biological phenomenon. PMID- 11610990 TI - Louis Agassiz and the species question. PMID- 11610991 TI - The rise of the vitamin-medicinal as illustrated by vitamin D. PMID- 11610992 TI - Drug supply systems in West Africa; a historical overview with particular reference to Nigeria. PMID- 11610993 TI - The anatomy of a pharmacist. PMID- 11610994 TI - Health and mortality in London 1580-1650. PMID- 11610995 TI - The provincial practitioner and his services to the poor, 1750-1800. PMID- 11610997 TI - Femina sexualis: medico-legal control in Victoriana. PMID- 11610996 TI - Barbers and barber-surgeons: an occupational group in an English provincial town, 1550-1640. PMID- 11610998 TI - All that summer she was mad: Virginia Woolf and her doctors. PMID- 11610999 TI - Ignorant midwives--a persistent stereotype. PMID- 11611001 TI - How socially distinctive is cognitive deviance in an emergent science? The case of parapsychology. PMID- 11611000 TI - The expulsion of the Neanderthals from human ancestry: Marcellin Boule and the social context of scientific research. PMID- 11611002 TI - An early psychologist of the unconscious. PMID- 11611003 TI - The place of laughter in Hobbes's theory of emotions. PMID- 11611004 TI - Theodicy and social policy in Malthus' thought. PMID- 11611006 TI - The myth of altruism: a psychohistory of public agency social work. PMID- 11611005 TI - Science and social passion: the case of seventeenth-century England. PMID- 11611007 TI - The history of childhood through German literature: a psychogenic model. PMID- 11611008 TI - John Hunter, the animal oeconomy, and late eighteenth-century physiological discourse. PMID- 11611009 TI - The Gottingen School and the development of transcendental Naturphilosophie in the Romantic Era. PMID- 11611010 TI - Russian and Central European family structures: a comparative view. PMID- 11611012 TI - The large and fragile community of scientists in India. PMID- 11611011 TI - Making governmental policy under conditions of scientific uncertainty: a century of controversy about saccharin in Congress and the laboratory. PMID- 11611013 TI - Brucellosis: a case report dating from 650-700 A.D. PMID- 11611014 TI - Public policy and drug innovation. PMID- 11611015 TI - An unpublished letter from Eugene Soubeiran to Antoine Portal, June 3, 1828. PMID- 11611016 TI - Zur Geschichte der Meeresheilkunde: Georg Christoph Lichtenberg und das Seebad Cuxhaven. PMID- 11611017 TI - Hermann Helmholtz und Franz Boll. PMID- 11611018 TI - Simon Baruch (1840-1921) und die offentliche Gesundheitspflege in New York. PMID- 11611019 TI - Schriftenverzeichnis Hans-Heinz Eulner (19. 4. 1925 - 17. 10. 1980). PMID- 11611020 TI - Hermann Andreas Reimer und seine 1855 eroffnete "Heilanstalt fur Epileptische" in Gorlitz. PMID- 11611021 TI - Auf der Suche nach einer adaquaten Methode fur die Geschichte und Theorie der Medizin. Auseinandersetzung mit Ludwik Flecks "Entstehung und Entwicklung einer wissenschaftlichen Tatsache". PMID- 11611022 TI - Descartes und das mechanistische Menschenbild. PMID- 11611023 TI - Struktur des Arguments als Struktur der Geschichte?--oder: Paradigm lost! PMID- 11611024 TI - Medizin, Naturwissenschaft und Technik im Mittelalter, Kontinuitat und Wandel in Darstellung und Deutung: Die arabisch-islamische Welt. PMID- 11611025 TI - Zur Ikonographie der Blutschau. PMID- 11611026 TI - Ein besonderer Eid fur die judischen Arzte und Wundarzte in Preussen. Ein Beitrag zur Geschichte der judischen Arzte in Deutschland. PMID- 11611027 TI - Die Medikalisierung der franzosischen Gesellschaft am Ende des Ancien Regime: die Bretagne als Beispiel. PMID- 11611028 TI - African population: reproduction for whom? PMID- 11611029 TI - The technocratic image and the theory of technocracy. PMID- 11611030 TI - A Greek alchemical formula. PMID- 11611031 TI - Arabic-Islamic alchemy--three intertwined stages. PMID- 11611032 TI - Chemistry in a provincial context: the Montpellier Societe Royale des Sciences in the eighteenth century. PMID- 11611033 TI - Science in provincial society: the case of Liverpool in the early nineteenth century. PMID- 11611034 TI - Daniel David Palmer: rediscovering the frontier years, 1845-1887. PMID- 11611036 TI - The struggle for accreditation in chiropractic: a unique history of educational bootstrapping. PMID- 11611035 TI - Solon Massey Langworthy: keeper of the flame during the 'lost years' of chiropractic. PMID- 11611037 TI - The structural approach to chiropractic: from Willard Carver to present practice. PMID- 11611038 TI - The roots of cranial manipulation: Nephi Cottam and 'craniopathy'. PMID- 11611039 TI - Manipulative therapy of the spine: the development of 'manual medicine' in Germany and Europe. PMID- 11611040 TI - In tribute to a living pioneer: Dr. Lyndon Edmund Lee. PMID- 11611041 TI - Discovering and recording chiropractic history: for a systematic program in the profession. PMID- 11611042 TI - Evolution and the problem of mind: part II. John Hughlings Jackson. PMID- 11611043 TI - Essay review: new developments in Darwins studies? PMID- 11611044 TI - Essay review: how scientists view their heroes: some remarks on the mechanism of myth construction. PMID- 11611045 TI - The debate on spontaneous generation and the birth of microbiology. PMID- 11611046 TI - The cure of Rachel Baker's "Devotional Somnium" (Sleep-preaching). PMID- 11611047 TI - National Health Dental Services 1948-1955. PMID- 11611048 TI - Medical politics and the state: the part played by the medical profession in the development of the National Health Service. PMID- 11611049 TI - Dr. Christopher Addison and social reform. PMID- 11611050 TI - Democratic epistemology: mid-19th-century plebeian medicine. PMID- 11611052 TI - Interpreting the fringe. PMID- 11611051 TI - The creation of the medical fringe 1500-1700. PMID- 11611053 TI - Para-medical provision in the West Riding. PMID- 11611054 TI - The emergence of a medical strategy in the Labour Movement 1906-1919. PMID- 11611055 TI - The reorganisation of the National Health Service in 1974. PMID- 11611056 TI - Herbal medicines and the midwife. PMID- 11611058 TI - Reports by Louis Pasteur and Claude Bernard on the organization of scientific teaching and research. PMID- 11611057 TI - Portrait of Dorothy Hodgkin, O.M., F.R.S. PMID- 11611059 TI - The Royal Society and Italy 1667-1795. PMID- 11611060 TI - Relief of the poor in Bristol from late Elizabethan times until the Restoration era. PMID- 11611061 TI - Patterns of colonial science in India. PMID- 11611062 TI - Unani medicine in India during the Delhi Sultanate. PMID- 11611063 TI - Jaina alchemy. PMID- 11611064 TI - Medical trends in Kashmir during Zain-ul-Abidin's reign. PMID- 11611065 TI - Renaissance Latin Aristotle commentaries: authors So-Z. PMID- 11611066 TI - The influence of Lamarckism on the development of Freud's psychoanalytic theory. PMID- 11611067 TI - Vagbhata on medicinal uses of gems. PMID- 11611068 TI - An occurrence of cinnabar in Rasarnavakalpa. PMID- 11611069 TI - Robert I. Watson and the development of the history of psychology: a symposium PMID- 11611070 TI - Recollections of Clark's G. Stanley Hall. PMID- 11611071 TI - Psychology at Cornell after Titchener: Madison Bentley to Robert Macleod, 1928 1948. PMID- 11611072 TI - Roman pharmacy and the eastern drug trade. PMID- 11611073 TI - On the history of medical statistics. PMID- 11611074 TI - Prolific immigrants and dwindling natives?: fertility patterns in western Massachusetts, 1850 and 1880. PMID- 11611075 TI - The discourse of physical power and biological knowledge in the 1930s: a reappraisal of the Rockefeller Foundation's 'policy' in molecular biology. PMID- 11611076 TI - Warranting scientific belief. PMID- 11611077 TI - Reconstructing restoration science: problems and pitfalls in institutional history. PMID- 11611078 TI - Shutting people up. PMID- 11611079 TI - Penal reform and progressive ideology. PMID- 11611080 TI - History of medical instrumentation. PMID- 11611081 TI - John Sealy Hospital Training School for Nurses. PMID- 11611082 TI - Moving the Wellcome Collection to the Science Museum. PMID- 11611083 TI - The development of veterinary education in Nigeria. PMID- 11611084 TI - Brogarden in Skaba - the cradle of Swedish veterinary medicine PMID- 11611086 TI - The emergence of evolutionary biology of behaviour in the early nineteenth century. PMID- 11611085 TI - The early history of the library of the Royal Veterinary College. PMID- 11611087 TI - Library resources for the history of science in Newcastle upon Tyne. PMID- 11611088 TI - Wilhelm Wundt resurrected. PMID- 11611089 TI - Science and the arts in the Renaissance: the search for truth and certainty, old and new. PMID- 11611091 TI - Michel Foucault and the history of psychoanalysis. PMID- 11611090 TI - The Enlightenment and the sciences of man. PMID- 11611092 TI - A note on public health in early Galveston. PMID- 11611093 TI - On the consciousness of holocaust. PMID- 11611094 TI - "The fust official psychologist in the wurrld": aspects of the professionalization of psychology in early twentieth century Britain. PMID- 11611095 TI - The great plague of Athens. PMID- 11611096 TI - The Piltdown Hippocrates. PMID- 11611097 TI - Dictionaries and the history of science. PMID- 11611098 TI - Atypical toothwear in fossil man. PMID- 11611099 TI - Identification of insects associated with Peruvian mummy bundles by using scanning electron microscopy. PMID- 11611100 TI - Who invented the modern hospital and who should tell the story? PMID- 11611101 TI - A history of biochemistry. PMID- 11611103 TI - Heretics as physicians in the thirteenth century. PMID- 11611102 TI - Healthy animals and civic life: Sylvester Graham's physiology of subsistence. PMID- 11611104 TI - Historians and psychologists, pluralism and professionalism: a review essay. PMID- 11611105 TI - The price and value of children: the case of children's insurance. PMID- 11611106 TI - Spiritualist perspectives on antebellum experience. PMID- 11611107 TI - [The caricature of the teacher]. PMID- 11611108 TI - Fort Wayne College of Medicine. Includes The practice of medicine in the Fort Wayne area written in 1889 by B. S. Woodworth. PMID- 11611110 TI - National celebrities brought cheer to young patients at Riley Hospital (I. U. Medical Center) in the 1930's. PMID- 11611109 TI - Daniel Drake: the Ohio Valley's man for all season. PMID- 11611111 TI - The spreading of the word: new directions in the historiography of chemistry 1600 1800. PMID- 11611112 TI - The American private philanthropic foundation and the public sphere 1890-1930. PMID- 11611113 TI - Remarks on the history of foundations and their role in the promotion of learning. PMID- 11611115 TI - The decade preceding the B.S.A.V.A. PMID- 11611114 TI - Book values and the book market; some hints for collectors. PMID- 11611116 TI - The crusade against drink. PMID- 11611117 TI - A difficult pill to swallow. PMID- 11611118 TI - Highlights of the Adler Museum collections. PMID- 11611119 TI - Biblical inscriptions on Hebrew medical amulets. PMID- 11611120 TI - Eunuchs and eunuchism - an historical discourse. Part II - Civil law. PMID- 11611121 TI - The death of the Duchesse de Nemours. PMID- 11611122 TI - View from the Rive Gauche: a comment on Annales Historiography. PMID- 11611123 TI - Heinz Kohut and the historical imagination. PMID- 11611124 TI - Natural mummies in central Italy: a preliminary survey. PMID- 11611125 TI - The prince of El Plomo. PMID- 11611126 TI - Medical ethics in Medieval Islam. PMID- 11611127 TI - Body and soul. PMID- 11611128 TI - Attemperament in medicine. PMID- 11611129 TI - Greco-Arabic and modern Western Medicine: conflict or symbiosis? PMID- 11611130 TI - The theory and practice of science according to Ibn Sina and al-Biruni. PMID- 11611131 TI - Central State Hospital. Part 2. PMID- 11611132 TI - The deliberate extinction of a species. PMID- 11611133 TI - The invisible monster. Investigations into the 1833 cholera epidemic in Southern Indiana. PMID- 11611135 TI - Leaf in a storm: Jayaprakash Narayan as politician and as saint. PMID- 11611134 TI - Indiana medical history--the medical school at LaPorte. PMID- 11611137 TI - History, science and psychohistory. PMID- 11611136 TI - The next "next assignment": leader and led, individual and group. PMID- 11611138 TI - The psychology of women. PMID- 11611139 TI - The influence of Leiden on botany in Dublin in the early eighteenth century. PMID- 11611140 TI - Marriage, family size, and inheritance among Hessian nobles, 1650-1900. PMID- 11611141 TI - [Grave robbing]. PMID- 11611142 TI - "The free mothers": pronatalism and working women in industry at the end of the last war in Britain. PMID- 11611143 TI - Ontogeny and phylogeny. PMID- 11611144 TI - Joseph Eastman, M.D., LL.D; citizen, soldier, surgeon and medical educator. PMID- 11611145 TI - "We war perplext by a disease cald milksick"; the story of the pioneers' most dreaded plague. PMID- 11611146 TI - Guide to the botanical records and papers in the archives of the Hunt Institute. PMID- 11611147 TI - Health and pleasure seekers at the springs of Indiana: pamphlet literature in the Library of Congress. PMID- 11611148 TI - The Indiana Medical History Museum. PMID- 11611149 TI - The old pathology building (The Pathological Department of the Central Indiana Hospital for the Insane) PMID- 11611150 TI - Ginseng and the Royal Society. PMID- 11611151 TI - Explicit qualifications as a criterion for membership of the Royal Society: a historical review. PMID- 11611152 TI - Frederick Hughes Scott and his contribution to the early history of the transmitter concept. PMID- 11611153 TI - Chauvinism and internationalism in science: The International Research Council, 1919-1926. PMID- 11611154 TI - Eggs of Diphyllobothrium pacificum in precolumbian human coprolites. PMID- 11611155 TI - Disease in art: a case for carcinoma of the breast in Michelangelo's La notte. PMID- 11611156 TI - Damiana - history of a herbal hoax. PMID- 11611157 TI - Quinine pills, manufactured on the Missouri frontier (1832-1862). PMID- 11611158 TI - History of Pharmacy at the University of Granada PMID- 11611159 TI - Facts about artifacts; drugstore perfumes in the 1890s. PMID- 11611160 TI - Picture postcards; a resource for social history of pharmacy. PMID- 11611161 TI - Pharmacy ruins from 1600's excavated in Stockholm. PMID- 11611162 TI - Vials and bottles for peppermint and other essences. PMID- 11611163 TI - Development of Pharmacology in American Schools of Pharmacy. PMID- 11611164 TI - Love, death, and continuity in Darwin's thinking. PMID- 11611165 TI - Charles Darwin and the human sciences. Special issue. PMID- 11611167 TI - History and creative work: from the most ordinary to the most exalted. PMID- 11611166 TI - Anxiety and interchange: Daniel Deronda and the implications of Darwin's writing. PMID- 11611168 TI - Why Darwin delayed, or interesting problems and models in the history of science. PMID- 11611169 TI - Beyond anthropocentrism. PMID- 11611170 TI - Darwin, instinct, and ethology. PMID- 11611171 TI - Darwinism and developmental psychology. PMID- 11611172 TI - Reminiscences of a state mental hospital attendant. PMID- 11611173 TI - Mental health care in early twentieth century Indiana and the limits of reform. PMID- 11611174 TI - Press coverage of Central State Hospital: alarms and excursions. PMID- 11611175 TI - Biological roots of violence. PMID- 11611176 TI - Medicine in literature: theses; a survey of secondary sources. PMID- 11611178 TI - Librarians in the history of the health sciences: challenges and opportunities in the 80's. PMID- 11611177 TI - The regulations of patent medicines in the United States and France. PMID- 11611179 TI - Natural philosophy and public spectacle in the eighteenth century. PMID- 11611181 TI - Images of John Hunter in the nineteenth century. PMID- 11611180 TI - On Whiggism. PMID- 11611182 TI - The American Breeders' Association: genetics and eugenics in an agricultural context, 1903-13. PMID- 11611183 TI - Sir Dominic Corrigan (1802-1880). PMID- 11611184 TI - Corrigan and the Charitable Infirmary. PMID- 11611185 TI - Corrigan and The House of Industry Hospital. PMID- 11611186 TI - Corrigan on cardiac disease. PMID- 11611187 TI - Corrigan's disease. PMID- 11611188 TI - Corrigan on pulmonary disease. PMID- 11611189 TI - Corrigan on abdominal disease. PMID- 11611190 TI - Corrigan on fever. PMID- 11611191 TI - The fevers of the Great Famine. PMID- 11611192 TI - Corrigan bibliography. PMID- 11611193 TI - Memorabilia and letters of Dominic Corrigan: catalogue of an exhibition. PMID- 11611194 TI - [Case report on paleopathology]. PMID- 11611195 TI - The paleopathology of the human remains from Nebwenenef's tomb. Part II: The histologic findings. PMID- 11611196 TI - Enterobiasis in precolumbian America. PMID- 11611197 TI - The family in Reformation Germany: the bearing and rearing of children. PMID- 11611198 TI - The voyage of the challenger. PMID- 11611199 TI - The search for synthetic penicillin during World War II. PMID- 11611200 TI - The Fort Wayne Medical Schools 1876-1905 and the Union with Purdue University. PMID- 11611201 TI - "From the waters of Sion to Liffeyside". The Jewish contribution: medical and cultural. PMID- 11611202 TI - The relationship between medical and veterinary surgeons from Sumer to the present. PMID- 11611203 TI - A veterinary student's experience of the general strike. PMID- 11611204 TI - The centenary of the Lincolnshire Veterinary Medical Society. PMID- 11611205 TI - Livestock at Garton Slack 2000 years ago. PMID- 11611206 TI - Chiropractic in American history: the ins and outs of museums. PMID- 11611207 TI - W. A. Budden: the transition through proprietary education, 1924-1954. PMID- 11611208 TI - Forgotten parameters of general practice: the chiropractic obstetrician. PMID- 11611209 TI - Schism and suppression: the elimination of medical protest schools, 1846-1939. PMID- 11611210 TI - B. J. Palmer and the 'German issue:' the crisis in postwar European chiropractic. PMID- 11611211 TI - The troubled legacy of Harvey Lillard: the black experience in chiropractic. PMID- 11611212 TI - The cutting edge of chiropractic recognition: prosecution and legislation in Massachusetts. PMID- 11611213 TI - The social anthropology of chiropractic in Washington, D.C.: project DC/DC. PMID- 11611214 TI - The disciplinary stake: the case of chronobiology. PMID- 11611215 TI - Naturwissenschaft und Sozialismus: Tendenzen der Naturwissenschafts-Rezeption in der deutschen Arbeiterbewegung des 19. Jahrhunderts. PMID- 11611216 TI - The IQ in history. PMID- 11611217 TI - Paul Julius Mobius (1853-1907). PMID- 11611218 TI - Die Stadt als Krankheitsfaktor; eine Analyse arztlicher Auffassungen im 19. Jahrhundert. PMID- 11611219 TI - Das Buch "Der Arzt" (1906) stammt nicht von Ernst Schweninger! PMID- 11611220 TI - Die Spezifitatslehre Robert Kochs; 100 Jahre Entdeckung der Tuberkelbakterien. PMID- 11611221 TI - "Kognitive" Leistungen des Immunsystems. PMID- 11611223 TI - Eine imaginare Krankheit: der Polyp des Herzens. PMID- 11611222 TI - Bewitched or intoxicated? The etiology of witch persecution in early modern England. PMID- 11611224 TI - Goethes Morphologie in ihrer Beziehung zum darwinistischen Evolutionsdenken. PMID- 11611225 TI - Phrenologische Schnupftabakdosen; ein Beitrag zur Wirkung Franz Joseph Galls bei seiner Ankunft in Paris. PMID- 11611226 TI - Central control and the approved societies: access to social support under the interwar health insurance scheme. PMID- 11611227 TI - The BMA-TUC alliance and the Beveridge report. PMID- 11611228 TI - General practice under the panel - the last phase. PMID- 11611229 TI - The hospitals of later medieval London. PMID- 11611230 TI - Medical practice in the early modern period: trade or profession? PMID- 11611231 TI - Urban health in the French Enlightenment. PMID- 11611232 TI - The politics of brain: phrenology in Birmingham. PMID- 11611233 TI - Public health and civic administration in nineteenth-century Glasgow. PMID- 11611234 TI - The Domesday Book of British hospitals. PMID- 11611235 TI - Ignorant midwives - a rejoinder. PMID- 11611236 TI - The Stopes collection in the Contemporary Medical Archives Centre at the Wellcome Institute for the History of Medicine. PMID- 11611237 TI - Images and ideas: Leeuwenhoek's perception of the spermatozoa. PMID- 11611238 TI - The history of ecology: achievements and opportunities, part one. PMID- 11611239 TI - Das alchemistische Bildgedicht vom 'Nackten Weib' in seiner bisher altesten Uberlieferung. PMID- 11611240 TI - A doctor's fifty year perspective. PMID- 11611242 TI - The true inventors of the keratoscope and photo-keratoscope. PMID- 11611243 TI - The Indianapolis City Hospital, 1833-1866. PMID- 11611241 TI - Natural knowledge in a traditional culture: problems in the study of the history of Chinese science. PMID- 11611244 TI - Public health in the South. PMID- 11611246 TI - Pierre Louis Moreau de Maupertuis - a precursor of Mendel? PMID- 11611245 TI - A war on two fronts: J. B. S. Haldane and the response to lysenkoism in Britain. PMID- 11611247 TI - From creation to evolution: Sir William Dawson and The idea of design in the nineteenth century. PMID- 11611248 TI - Konrad Lorenz's ethological theory: explanation and ideology, 1938-1943. PMID- 11611249 TI - John Goodsir and the making of cellular reality. PMID- 11611250 TI - The Leiden Anatomy Theatre as a source for Davenant's 'Cabinet of death' in Gondibert. PMID- 11611251 TI - Infants, infant care, and attitudes toward infancy in the medieval Lives of Saints. PMID- 11611252 TI - On the history of the statistical method in biology. PMID- 11611253 TI - Witches, witchcraft, and Allegany Seneca medicine. PMID- 11611254 TI - Industrialization, proletarianization, and marriage: a reconsideration. PMID- 11611255 TI - California besieged: the foot-and-mouth epidemic of 1924. PMID- 11611256 TI - Evolutionary biology and psychoanalysis: a review essay on Frank J. Sulloway's Freud: biologist of the mind. PMID- 11611257 TI - The "crisis" of William James: a revisionist view. PMID- 11611258 TI - Implicit ideology in the psychoanalytic study of culture. PMID- 11611259 TI - Archives and manuscripts in the Moody Medical Library. PMID- 11611261 TI - Husband's participation in childbirth: a nineteenth-century phenomenon. PMID- 11611260 TI - American gravestones and attitudes toward death: a brief history. PMID- 11611262 TI - Alaska's great sickness, 1900: an epidemic of measles and influenza in a virgin soil population. PMID- 11611263 TI - Techniques for extraction of foreign bodies from war wounds in medieval India. PMID- 11611264 TI - Unani medicine in India. PMID- 11611265 TI - Two eminent physicians (of Unani medicine) during Shah Jahan's reign. PMID- 11611266 TI - Contributions of Sarngadhara in the field of materia medica and pharmacy. PMID- 11611267 TI - Medicinal use of opium and cannabis in Medieval India. PMID- 11611268 TI - Ideas of integration as a process of evolution of Indian system of medicine in the Medieval period. PMID- 11611269 TI - Contribution of Unani materia medicas to the identification of Vedic plants with special reference to Usana. PMID- 11611270 TI - An Arabic source for the History of Ancient Indian medicine. PMID- 11611271 TI - Poisons and antidotes in Unani system of medicine. PMID- 11611272 TI - The origin and development of pulse examination in Medieval India. PMID- 11611274 TI - Humoral theory of Unani Tibb. PMID- 11611273 TI - Contribution of Madanapala Nighantu to the knowledge of Indian materia medica with particular reference to fig [Anjira]. PMID- 11611275 TI - Contribution of Medieval India to Ayurvedic Materia Medica. PMID- 11611276 TI - The treatment of Lamarckism as found in forty-one college textbooks. PMID- 11611277 TI - VIII Genitus homo as a nomen sacrum in a twelfth-century Anglo-Latin fever charm. PMID- 11611278 TI - Analytical studies in the evidences regarding chemico-culture in the history of Indian medicine in ancient period-allium series. PMID- 11611279 TI - Some spiritual alchemies of seventeenth-century England. PMID- 11611281 TI - Healthy or hungry thirties? PMID- 11611280 TI - Feeding England during the Industrial Revolution: a view from the Celtic fringe. PMID- 11611282 TI - Children in history: a personal review of the past decade's published research. PMID- 11611283 TI - Psychohistory and histoire des mentalites. PMID- 11611284 TI - The late conceptualization of the self in psychoanalysis: the German language and Jewish identity. PMID- 11611285 TI - The 1918 influenza epidemic. PMID- 11611286 TI - A history of bloodletting. PMID- 11611287 TI - Eshmun, healing of God of Sidon. PMID- 11611288 TI - Doctor "Ribbebene" - cobbler, lumberman, dentist, politician and researcher. PMID- 11611290 TI - A surgeon's view of Cape Town in 1787. PMID- 11611289 TI - Two pioneer paediatricians in Palestine under the Turks. PMID- 11611291 TI - Fertility of southern black farmers in 1900: evidence and speculation. PMID- 11611292 TI - The value of children during industrialization: sex ratios in childhood in nineteenth-century America. PMID- 11611293 TI - "Sisters worthy of respect": family dynamics and women's roles in the Blackwell family. PMID- 11611294 TI - Serf diet in nineteenth-century Russia. PMID- 11611295 TI - Theory or practice? The eighteenth-century debate on the scientific status of chemistry. PMID- 11611296 TI - William Harvey and the 'Way of the Anatomists'. PMID- 11611297 TI - The ordeal of vocation: the Paris Academy of Sciences and the Terror, 1793-95. PMID- 11611298 TI - Mendel and methodology. PMID- 11611299 TI - Medical police and public health: problems of practice and ideology. PMID- 11611300 TI - Ferriar's fever and Kay's cholera: disease and social structure in Cottonopolis. PMID- 11611301 TI - Healthy or hungry thirties? PMID- 11611302 TI - Disease in the 19th century urban economy: the medical officer of health and the community. PMID- 11611303 TI - Sydenham and social history. PMID- 11611304 TI - The school medical officer 1880-1914. PMID- 11611305 TI - The invention of the normal child. PMID- 11611306 TI - The history of medical photography. PMID- 11611307 TI - Lunacy and the Industrial Revolution. Programme notes. PMID- 11611308 TI - A century of dental myths and messages. PMID- 11611309 TI - Infant mortality and social policy: the eugenists and the social ameliorators, 1900-1914. PMID- 11611310 TI - Mass-observation. PMID- 11611311 TI - The birth of an NHS practice. PMID- 11611312 TI - The origin of the Royal College of General Practitioners. PMID- 11611313 TI - The crisis in general practice--1965. PMID- 11611314 TI - Re-thinking general practice: some issues of policy and practice in the 1970s illustrated by case study. PMID- 11611315 TI - Ordinary medicine for ordinary people: illness and its treatment in the East Midlands, 1600-1630. PMID- 11611316 TI - Health and illness in traditional rural France in the 18th and 19th centuries: the example of wet-nurses. PMID- 11611317 TI - What is an accident? PMID- 11611318 TI - Workmen's compensation in British law, society and politics, 1897-1946. PMID- 11611319 TI - Workers' insurance versus protection of the workers. Remarks on state social policy in the early Kaiserreich. PMID- 11611320 TI - Workers' health protection as an issue of industrial hygiene and occupational medical science in the early Kaiserreich (1871-84). PMID- 11611321 TI - Disease, labour migration and technological change: the case of the Cornish miners. PMID- 11611322 TI - Two thousand medical men in 1847. PMID- 11611323 TI - TNT poisoning among women workers in the First World War. PMID- 11611324 TI - Industrial health and rationalisation in an Italian light engineering firm: the Magneti Marelli in the Fascist period. PMID- 11611325 TI - Coronary heart disease: a disease of affluence or a disease of industry? PMID- 11611326 TI - Recent trends in the social history of occupational medicine in the Federal Republic of Germany. PMID- 11611327 TI - From workers' diseases to occupational diseases: the causality of experts' evidence on liability in the development of social medicine. PMID- 11611328 TI - Occupational health statistics in Germany and in the Federal Republic of Germany: a patient in need of care. Some contributions to the history of reporting of industrial pathology. PMID- 11611329 TI - The Peckham key: ideal project and terrifying dream. PMID- 11611330 TI - Simpson's Tempo and Mode in Evolution revisited. PMID- 11611331 TI - Evolution and special creation: historical aspects of the controversy. PMID- 11611332 TI - Dame Agatha's dispensary. PMID- 11611333 TI - Colored glass in pharmacy. PMID- 11611334 TI - The regulation of health quackery. PMID- 11611335 TI - The allegory of Christ in a pharmacy. PMID- 11611336 TI - Antique pharmacy bottles: sources and pricing. PMID- 11611337 TI - Tuberculosis, silicosis, and the slate industry in North Wales: Medical examinations of the high tuberculosis death rates in the North Wales slate mining and quarrying districts, 1927-1939. PMID- 11611338 TI - The influenza epidemic of 1918 and its effects on the military. PMID- 11611339 TI - "I don't know only what we hear": the soldiers' view of the 1918 influenza epidemic. PMID- 11611340 TI - Indiana and the influenza pandemic of 1918. PMID- 11611341 TI - [A study of the ancient medical manuscript "Tsu-pei-shih-i-mo-chiu-ching" recently found in Ma-wang-t'ui, China.] (Jpn). PMID- 11611342 TI - [Tezuka Ryosen, army doctor-in-chief of the infantry regiment.] (Jpn). PMID- 11611343 TI - [Josen Morii and his medicine.] (Jpn). PMID- 11611344 TI - [Erwin von Baelz as a pioneer in obstetrical anaesthesia in Japan.] (Jpn). PMID- 11611346 TI - [The scientific revolution in 18th century Japanese medicine - the ideal premise for the development of Dutch learning.] (Jpn). PMID- 11611345 TI - [Prevalence of scurvy among soldiers of the Hirosake feudal clan in Yezo area.] (Jpn). PMID- 11611347 TI - Theory and practice in British psychiatry from J. C. Prichard (1785-1848) to Henry Maudsley (1835-1918). PMID- 11611348 TI - The place of the 'core-set' in modern science: social contingency with methodological propriety in science. PMID- 11611349 TI - Ibn al-Nafis's Perfected book on ophthalmology and his treatment of trachoma and its sequelae. PMID- 11611350 TI - Avicenna on the division of the sciences in the "Isagoge" of his "Shifa". PMID- 11611351 TI - A hitherto unknown eighth-century commentary on Avicenna's "Kulliyyat". PMID- 11611352 TI - Three medical recipes in Codex Biblioteca Medicea-Laurenziana Or. 215. PMID- 11611353 TI - The importance of the Cairo Genizah for the history of medicine. PMID- 11611355 TI - Ibn Sina und die Medizin des arabisch-islamischen Mittelalters - Alte und neue Urteile und Vorurteile. PMID- 11611354 TI - Vegetarianism and the argument from marginal cases in Porphyry. PMID- 11611356 TI - Entbindungswissenschaft und Entbindungskunst bei Friedrich Benjamin Osiander. PMID- 11611357 TI - Pockenschutz in Hohenlohe. PMID- 11611358 TI - Ein Briefwechsel zweier Kieler Professoren aus dem Jahre 1931 und sein zeitgeschichtlicher Hintergrund. PMID- 11611360 TI - Gunter Mann: Neovitalismus. PMID- 11611359 TI - Die "Gesundheitsfuhrung" des Deutschen Volkes. PMID- 11611361 TI - A group of Roman surgical and medical instruments from Cramond, Scotland. PMID- 11611362 TI - Chemophysiologie zwischen vitalistischer und mechanistischer Biologie im 19. Jahrhundert. PMID- 11611363 TI - Zur Typologie des Botanikers in der ersten Halfte des 19. Jahrhunderts: Christian Friedrich Hornschuch. PMID- 11611364 TI - Naudin, Darwin, Nageli: Bemerkungen zu den Vererbungsvorstellungen des 19. Jahrhunderts. PMID- 11611365 TI - Die Bewertung des Suizides im Laufe der Geschichte. PMID- 11611366 TI - Die Entdeckung der Mastzellen durch den Freiburger Medizinstudenten Paul Ehrlich. PMID- 11611367 TI - Der Arzt und Dichter Laurentius Span (1530-1575). PMID- 11611368 TI - Drei Bilder eines Arztes des 16. Jahrhunderts. PMID- 11611369 TI - Neues uber die Krankheit Wallensteins. PMID- 11611371 TI - Buffon, organic alterations, and man. PMID- 11611370 TI - Ein hundertjahriger Medizinstudenten-Stock. PMID- 11611372 TI - Principles of general physiology: the comparative dimension to British neuroscience in the 1830s and 1840s. PMID- 11611373 TI - Evolution of the concept of Astavarga. PMID- 11611374 TI - Breast-feeding habits and their relation to infant mortality and marital fertility. PMID- 11611375 TI - Agricultural variation and human fertility in antebellum Pennsylvania. PMID- 11611376 TI - Malleus and podagra: lead poisoning in horse and man. PMID- 11611377 TI - Zoonoses in South Wales, 1875-1915. PMID- 11611378 TI - A Hunterian account of human rabies. PMID- 11611379 TI - Veterinary cross-currents in ideas on infectious diseases since Aristotle. PMID- 11611380 TI - Napoleon and Lamarck. PMID- 11611381 TI - A comparative study of the early system of Indian cosmology and the tridosa humoral doctrine. PMID- 11611382 TI - Growing up female in eighteenth-century Germany. PMID- 11611383 TI - Reflections on the psychohistory of France, 1919-1940. PMID- 11611384 TI - Emotional factors in America's Western Pacific policy: Wood and Stimson in the Philippines. PMID- 11611385 TI - Moshe Dyan: the infantile roots of political action. PMID- 11611386 TI - Insects, food, and hunger: the paradox of plenty for U. S. entomology, 1920-1970. PMID- 11611387 TI - The Anglo-Boer War of 1899-1902:enteric fever and Captain Maxwell Louis Hughes. PMID- 11611388 TI - From Malkowal to Calcutta: an historical appreciation of Haffkine's victorious struggle. PMID- 11611389 TI - The cock as a symbol of medicine. PMID- 11611390 TI - The study of fossils in the Romantic philosophy of history and nature. PMID- 11611391 TI - Scientific studies at Oxford and Cambridge in the seventeenth century - a research review. PMID- 11611392 TI - The well-principled savage, or the child of the Scottish enlightenment. PMID- 11611394 TI - The Amsterdam pharmacist Willem van Barneveld (1747-1826) and the discovery of photosynthesis (1778). PMID- 11611393 TI - The Renaissance pater familias - "Be ye perfect". PMID- 11611395 TI - Christiaan Huygens & the development of the air pump. PMID- 11611396 TI - The two medicines: some ecclesiastical concepts of disease and the physician in the high Middle Ages. PMID- 11611397 TI - On the microscopes of Antoni van Leeuwenhoek. PMID- 11611398 TI - Huygens' microscopical researches. PMID- 11611399 TI - Huygens' pulse models as a bridge between phenomena and Huygens' mechanical foundations. PMID- 11611400 TI - The struggle for authority in the field of heredity, 1900-1932: new perspectives on the rise of genetics. PMID- 11611401 TI - Theories of osteogenesis in the eighteenth century. PMID- 11611402 TI - Further remarks on Darwin's spelling habits and the dating of Beagle voyage manuscripts. PMID- 11611403 TI - Aristotle's statement on the reproduction of sharks. PMID- 11611404 TI - The concepts of dormancy, latency, and dominance in nineteenth-century biology. PMID- 11611405 TI - Essay review: Spanish science and the New World. PMID- 11611406 TI - Prophecy and madness: women visionaries during the Puritan Revolution. PMID- 11611407 TI - [Scientific revolution in 18th century Japanese medicine: intellectual preconditions for the development of the Dutch school of medicine (Rampo).] (Jpn). PMID- 11611408 TI - [The incidence of Kakke-disease (beriberi) in pre-war mental hospitals] (Jpn). PMID- 11611409 TI - [Studies on the history of the anthropology of the Ainu skulls.] (Jpn). PMID- 11611410 TI - Aphrodisiacs - a psychosocial perspective. PMID- 11611411 TI - Diseases due to deficiencies of vital principles in the body. PMID- 11611412 TI - Unani medicine in India 1524 to 1605 A.D. PMID- 11611413 TI - Two eminent physicians (of Unani medicine) during Shah Jahan's reign. PMID- 11611414 TI - Alchemy and its fundamental terms in Greek, Arabic, Sanskrit and Chinese. PMID- 11611415 TI - The family: historical function, dysfunction, lack of function, and schizophrenia. PMID- 11611416 TI - Le origini storiche dell'elettroencefalografia. PMID- 11611417 TI - Informazioni bibliografiche. PMID- 11611418 TI - Introduzione a Piaget. PMID- 11611419 TI - Cooperation, legitimation and some aspects of the history of social psychology. PMID- 11611420 TI - Darwin e la psicologia. PMID- 11611421 TI - Phirangiroga (syphillis) and its management as described in Vaidyaka Samgraka, an old Gujarati manuscript of an unknown author (18th century A.D.). PMID- 11611422 TI - The state of Ayurvada in the eighteenth and nineteenth centuries. PMID- 11611423 TI - Medicine in Arabia Deserta. PMID- 11611424 TI - A-Z in South African medical history. V. The Versveld family. PMID- 11611425 TI - Rene Theophile Hyacinthe Laennec (1781-1826), inventor of the stethoscope. PMID- 11611426 TI - Hebrew medical amulets. PMID- 11611427 TI - [The influence of "Pen tsao kang mu" in Japan]. PMID- 11611428 TI - [An introduction to ancient Roman medicine] (Chi). PMID- 11611430 TI - [Examples of special literary problems of ancient medical classics]. PMID- 11611429 TI - [Textual research on "Xiao pin (short and miscellaneous) prescriptions"]. PMID- 11611431 TI - [Translation, interpretation and textual research of medical works unearthed in Ma Wang Dui]. PMID- 11611432 TI - [Knowledge of the human body displayed in inscriptions on bone and tortoise shell]. PMID- 11611433 TI - [Life and chronology of Xue Lizhai]. PMID- 11611434 TI - [Advanced medical education in north-east China before the Liberation] (Chi). PMID- 11611435 TI - Bao Gu, the distinguished woman physician of the Jin Dynasty. PMID- 11611437 TI - [Textual research - on records of ancient Chinese medical history]. PMID- 11611436 TI - [Textual research on some ancient medical figures]. PMID- 11611438 TI - [Notions about gerontism, longevity and life span in ancient China]. PMID- 11611439 TI - [Exploration of the relationship between defeating Cao Cao in Chibi and schistosomiasis]. PMID- 11611440 TI - [A sketch of the life of Lu Liuliang]. PMID- 11611441 TI - [Ly Yanshi, life and medical achievements]. PMID- 11611442 TI - [On the medicine of the Tai Ping Heavenly Kingdom]. PMID- 11611443 TI - Dangerous dust. PMID- 11611444 TI - Carlos J. Finlay and the conception of contagion. PMID- 11611445 TI - Bakula, a reputed drug of Ayurveda, its history, uses in Indian medicine. PMID- 11611446 TI - Techniques of venupuncture (siravedha) in India in 18th century. PMID- 11611448 TI - Unser Bild. - Das "Licht der Natur" [A. Tschinkel, 1964]. PMID- 11611447 TI - On the identity and economico-medicinal uses of hastikarnapalasa (Leea macrophylla Roxb., family: Ampelidaceae) as evinced in the ancient (Sanskrit) texts and traditions. PMID- 11611449 TI - Hilde Mangold, co-discoverer of the organizer. PMID- 11611450 TI - Darwin's use of the analogy between artificial and natural selection. PMID- 11611451 TI - The romantic programme and the reception of cell theory in Britain. PMID- 11611452 TI - Essay review: the roots of biological determinism. PMID- 11611453 TI - The Galenic and Hippocratic challenges to Aristotle's conception theory. PMID- 11611454 TI - A look at covered mortars and pestles. PMID- 11611455 TI - Electronic therapeutics of Albert Abrams, M.D. PMID- 11611456 TI - Highlights of the International Congress for the History of Pharmacy. PMID- 11611457 TI - Pharmacy and freedom. PMID- 11611458 TI - History with a purpose: the fate of Paracelsus. PMID- 11611459 TI - Practical Pharmacy by Mohr, Redwood, and Procter: an international pharmacy textbook. PMID- 11611460 TI - Expositio and oblatio: the abandonment of children and the ancient and medieval family. PMID- 11611461 TI - Man - a musical instrument: models of the brain and mental functioning before the computer. PMID- 11611462 TI - The definition of molecular biology and the definition of policy: the role of the Rockefeller Foundation's policy for molecular biology. PMID- 11611463 TI - The Rockefeller Foundation's funding policy for molecular biology: success or failure? PMID- 11611464 TI - The sheriff and the cowboys: or Weaver's support of Astbury and Pauling. PMID- 11611465 TI - Scepticism about the centrality of technology transfer in the Rockefeller Foundation programme in molecular biology. PMID- 11611466 TI - Beyond deterministic sociology and apologetic history: reassessing the impact of research policy upon new scientific disciplines (Reply to Fuerst, Bartels, Olby and Yoxen). PMID- 11611468 TI - America's only school of pharmacy for women. PMID- 11611467 TI - Derek John de Solla Price: an appreciation. PMID- 11611469 TI - The penicillin mystique and the popular press (1935-1950). PMID- 11611470 TI - The Museum of Materia Medica of Paris. PMID- 11611472 TI - Pharmacy graduates in use from 1880 to 1920. PMID- 11611471 TI - Three proprietaries and their claim as American "Indian" remedies. PMID- 11611473 TI - Pharmacy in Hartford's Historical Museum of Medicine and Dentistry. PMID- 11611474 TI - J. B. Van Mons' essai sur les principes de la chimie antiphlogistique: a mystery solved. PMID- 11611476 TI - Fruhe Formen der Antipsychiatrie und die Reaktion der Psychiatrie. PMID- 11611477 TI - Arzteemigration nach 1933 in die USA: der Fall New York. PMID- 11611475 TI - The preparation and uses of artificial mineral waters (ca. 1680-1825). PMID- 11611478 TI - Mensch und Gesundheit in der Geschichte der Neuzeit. PMID- 11611479 TI - The reception of Morgan's chromosome theory in Germany: inter-war debate over cytoplasmic inheritance. PMID- 11611480 TI - Die historische Pathologie, Nosologie und Epidemiologie im 19. Jahrhundert. PMID- 11611481 TI - Benedict Stillings (1810-1879) Untersuchungen uber das Ruckenmark--ein Wendepunkt in der neuroanatomischen Forschung. PMID- 11611482 TI - The leper in medieval Islamic society. PMID- 11611483 TI - Arcana disclosed: the advent of printing, the books of secrets tradition and the development of experimental science in the sixteenth century. PMID- 11611484 TI - The first person: Descartes, Locke and mind-body dualism. PMID- 11611485 TI - Enterobius vermicularis eggs in preColumbian human coprolites from Chile. PMID- 11611486 TI - [A brief textual research on the life of Wang Shixiong, a renowned physician of Qing Dynasty]. PMID- 11611487 TI - [History of the prevention and treatment of rabies by acupuncture and moxibustion, a review and prospect] (Chi). PMID- 11611488 TI - [An appraisal on Zhang Xichun's thought of amalgamating traditional Chinese medicine with western medicine] (Chi). PMID- 11611489 TI - [The discovery of paragonimiasis in Fujian Province] (Chi). PMID- 11611491 TI - [Ancient Sino-Iraian medical exchanges as seen in Tanksuq-nameh] (Chi). PMID- 11611490 TI - [Research on the history of medicine and hygiene of Mohe, an ancient Chinese minority nationality] (Chi). PMID- 11611492 TI - [On Li Shizhen's contributions to the method of systematization of Chinese herbology] (Chi). PMID- 11611493 TI - [10 kinds of symptom and sign of the pharynx and throat in ancient Chinese historical materials] (Chi). PMID- 11611494 TI - [On the characteristics and contents of Dian Nan Ben Tsao: an extant work of materia medica featuring traditional medicine of both Chinese (Han) nationality and local minority nationalities] (Chi). PMID- 11611495 TI - [My new opinion on the date of writing of the "Seven Grand Chapters" in Internal Classics of Yellow Emperor: exploration based on the origin and evolution of the historical materials of ancient records on astronomy, classical music and calendar] (Chi). PMID- 11611496 TI - [Xue Shengbai's life and his scholarly method] (Chi). PMID- 11611497 TI - Science in the Low Countries during the sixteenth century. A survey. PMID- 11611498 TI - Some historical aspects of Parkinson's disease. The progression of insights in the period 1817-1868. PMID- 11611499 TI - [On "Chindoku" a toxicant in the oriental tradition] (Jpn). PMID- 11611500 TI - [Pharmacognostical studies on the molluscan drugs (14). Historical and herbological investigations on "Tianluo" and "Luosi"] (Jpn). PMID- 11611501 TI - [Development of natural crude drug resources from Taiwan (I). Pharmacognostical studies on the Chinese crude drug "Han-lian-cao (1). The herbological studies] (Jpn). PMID- 11611502 TI - [On the ancient manuscript named "A Togoku-ohayashi-ninjin"] (Jpn). PMID- 11611503 TI - [A history of pharmaceutical education in Okayama (I). Private Okayama pharmaceutical school (primary)] (Jpn). PMID- 11611504 TI - Conference Report. Social history of nineteenth- and twentieth-century German medicine. PMID- 11611505 TI - The study of illegitimacy from kirk session records: two eighteenth-century Perthshire parishes. PMID- 11611506 TI - Modes of production and demographic patterns in nineteenth-century France. PMID- 11611507 TI - Medical philately: Robert Koch (1843-1910) the man, his germ and history. PMID- 11611508 TI - British colonial administration in the Fiji Islands during the 1875 measles epidemic. PMID- 11611509 TI - Dr. Harvey Pirie: versatile man of science and pioneer explorer of sub-antarctic regions eighty years ago. PMID- 11611510 TI - Depopulation, nationalism, and feminism in fin-de-siecle France. PMID- 11611511 TI - Gender and revolution: Rosa Luxemburg and the female revolutionary personality. PMID- 11611512 TI - Comparative psychohistory: snake-handling in Hellenistic Greece and the American South. PMID- 11611513 TI - Sittin' tight and bustin' loose: contradiction and conflict in midwestern masculinity and the psychohistory of America. PMID- 11611514 TI - Towards a psychobiography of Charles I. PMID- 11611516 TI - Water and wastes: a retrospective assessment of wastewater technology in the United States, 1800-1932. PMID- 11611515 TI - Presidential children: abandonment, hysteria and suicide. PMID- 11611517 TI - Infant birth weight and nutrition in industrializing Montreal. PMID- 11611518 TI - Ladygina-Kots and Soviet comparative psychology. PMID- 11611519 TI - Un tema ricorrente nello Zibaldone: la memoria. PMID- 11611520 TI - La riabilitazione dell'inconscio in Unione Sovietica: il Convegno internazionale di Tbilisi. PMID- 11611521 TI - Psychoanalysis, romanticism and biology. PMID- 11611522 TI - Locating sources in the history of medicine and health care: a guide for students and faculty at UTMB. PMID- 11611523 TI - [A history of the discovery of cholera pathogen] (Chi). PMID- 11611524 TI - [Ancient medical classic - the Papyrus Ebers] (Chi). PMID- 11611525 TI - [Preliminary exploration on the materia medica from the localities inhabited by ancient China's minority nationalities] (Chi). PMID- 11611526 TI - [An introduction to the pharmaceutical administration of ancient Chinese feudal dynasties] (Chi). PMID- 11611528 TI - [On the formation and development of the Meng He School of Jiangsu Province in traditional Chinese medicine] (Chi). PMID- 11611527 TI - [Research on You Ke Lei Cui (Classified Collections in Pediatrics): a rare edition of pediatrics printed in the Ming dynasty] (Chi). PMID- 11611529 TI - [The therapeutic custom handed down from the Meng He School] (Chi). PMID- 11611530 TI - [Talks on the historical materials of medicine in Fujian Province] (Chi). PMID- 11611531 TI - [Textual research on the date of birth and death of Chunyu Yi and his appointment] (Chi). PMID- 11611532 TI - [Exploration on the date of birth and death of Chunyu Yi] (Chi). PMID- 11611533 TI - [Discussion on the time of formation of the theoretical system of Ziwuliuzhu (Selection of acupoint for treatment varied with the circadian changes of vital energy and blood flow in the channels and collaterals relevant to heavenly stem and earthly branches)] (Chi). PMID- 11611534 TI - [The historical materials of modern medical education in Nantong city: an early medical school solely established by Chinese] (Chi). PMID- 11611535 TI - The ideology of science during the Nixon years: 1970-76. PMID- 11611536 TI - Three models of policymaking: expert advice in the control of environmental lead. PMID- 11611537 TI - The mummies of the Abbey of Saint Domenico Maggiore in Naples. PMID- 11611538 TI - Annotated bibliography [of paleopathology]. PMID- 11611539 TI - The burials from King Henry VIII's ship, the Mary Rose: an interim statement. PMID- 11611540 TI - Historiography of psychology in West Germany: approaches from social history. A review of the past ten years. PMID- 11611541 TI - Craik e la psicologia meccanicistica. PMID- 11611542 TI - Klaus F. Riegel and dialectical psychology: in search for the changing individual in a changing society. PMID- 11611543 TI - Umana o artificiale, purche sia intelligenza. PMID- 11611544 TI - Pinel e il magnetismo animale. PMID- 11611545 TI - The history of genetics in Germany. PMID- 11611546 TI - Alexander Hollaender Papers (1898- ). PMID- 11611547 TI - The housewife doctor. PMID- 11611548 TI - Highlights of the Adler Museum collections: the Jenner letter. PMID- 11611549 TI - The Caledon baths. PMID- 11611550 TI - A history of the Medical Branch of the Royal Air Force, part 1. PMID- 11611551 TI - Dr. Charles Porter. PMID- 11611552 TI - Illusions and counter-illusions or aesthetic effects in Greek temples? PMID- 11611553 TI - Considerazioni psicologiche su alcuni fenomeni della visione descritti nei trattati di prospettiva dei secoli XV-XVII. PMID- 11611554 TI - La percezione della numerosita. PMID- 11611555 TI - Le illusioni ottiche nell'Ottocento tra fenomenologia e neurofisiologia. PMID- 11611556 TI - The psychology of Jakob Friedrich Fries (1773-1843): its context, nature, and historical significance. PMID- 11611558 TI - Panpsichismo e psicologia nel pensiero di Ernst H. Haeckel. PMID- 11611557 TI - La psicologia del pensiero dalla polemica di Wundt alla Entwicklungspsychologie di Buhler. PMID- 11611559 TI - L'uomo senza facolta: modelli del comportamento in Musil. PMID- 11611561 TI - The Archives of the History of American Psychology. PMID- 11611560 TI - Il mito jacksoniano. PMID- 11611562 TI - L'effetto Baldwin. PMID- 11611563 TI - With a spoonful of sugar. The art of prescription writing in the late 19th and early 20th century. PMID- 11611564 TI - The Richtmann Archive at Auburn University. PMID- 11611565 TI - Eighteenth-century poison phials. PMID- 11611566 TI - Entrepreneurial scientists and entrepreneurial universities in American academic science. PMID- 11611568 TI - Causes and consequences of the American medical system. PMID- 11611567 TI - The slow and uneven growth of sociology in Great Britain. PMID- 11611569 TI - Was social medicine revolutionary? Rudolf Virchow and the revolutions of 1848. PMID- 11611570 TI - Doctors and the Revolution in Russia. PMID- 11611571 TI - States and epidemic threats. PMID- 11611572 TI - Death camps in the Congo: administrative responses to sleeping sickness 1903 1911. PMID- 11611573 TI - Epidemics and social control in twentieth-century South Africa. PMID- 11611574 TI - The structured dependency of the elderly: a twentieth-century creation? PMID- 11611575 TI - Medicine and the Puritan Revolution. PMID- 11611576 TI - Old people and poverty in early modern towns. PMID- 11611577 TI - Old people's attitudes to death in the twentieth century. PMID- 11611578 TI - The perception and experience of old age 1945-1965. PMID- 11611579 TI - The French Revolution, hospitals, and the medical profession. PMID- 11611580 TI - Analogy and technology in Darwin's vision of nature. PMID- 11611582 TI - The appearance of academic biology in late nineteenth-century America. PMID- 11611581 TI - Darwin's experimental natural history. PMID- 11611584 TI - L'esprit de la science anglaise et les Francais au XIXeme siecle. PMID- 11611583 TI - E. S. Russell and J. H. Woodger: the failure of two twentieth-century opponents of mechanistic biology. PMID- 11611585 TI - James Sterling Wilkie: 1906-1982. PMID- 11611586 TI - The group-fantasy origins of AIDS. PMID- 11611587 TI - The making of a fearful leader: "Where's the rest of me?" PMID- 11611589 TI - A historical overview of British and European chiropractic. PMID- 11611588 TI - [History of Dutch learning in Tokugawa Japan] (Jpn). PMID- 11611590 TI - Chiropractic lyceums: the colorful origins of chiropractic continuing education. PMID- 11611591 TI - The sweetheart of the PSC--Mabel Heath Palmer: the early years. PMID- 11611592 TI - Anatomist, scholar and gentleman: Arthur V. Nilsson-a legend in his own time. PMID- 11611593 TI - Broadsides, epigrams, and testimonials: the evolution of chiropractic advertising. PMID- 11611594 TI - The origins of chiropractic physiological therapeutics: Howard, Forester and Schulze. PMID- 11611595 TI - Rebels among dissenters: a local history of chiropractic in Provo, Utah. PMID- 11611596 TI - D. D.'s first book. PMID- 11611597 TI - The evolution of our understanding of the cell: a study in the dynamics of scientific progress. PMID- 11611598 TI - Gedanken zur Archivierung medizinischen Schriftguts. PMID- 11611599 TI - Zur Rolle histochemischer Phanomene bei der Erforschung und Systematisierung des chromaffinen Gewebes. PMID- 11611600 TI - "Medicus Politicus" oder "Machiavellus Medicus"? Wechselwirkungen von Ideal und Realitat des Arzttypus im 17. Jahrhundert. PMID- 11611601 TI - Ein Manuskript von Georg Meister, dem Kunst- und Lustgartner, in der British Library. PMID- 11611602 TI - Le docteur Gall a Cynthere. PMID- 11611604 TI - Ernst Schweninger (1850-1924). Zu seinem Leben und Wirken. Erganzungen, Korrekturen. PMID- 11611603 TI - Linne, Gedner und die biologische Kontrolle. PMID- 11611605 TI - Stimme und Konstitution im Werk Gregorio Maranons. PMID- 11611606 TI - Die Fallhaube: eine Erfindung des 16. Jahrhunderts? PMID- 11611607 TI - Ein unbekanntes Portrat des Hirnforschers Oskar Vogt (1870-1959). PMID- 11611608 TI - Deutsche Uebersetzungen englischer humanmedizinischer Werke 1680-1810. PMID- 11611609 TI - The Mayos: a historical vignette. PMID- 11611610 TI - A history of the medical branch of the Royal Air Force: part II aviation medicine. PMID- 11611611 TI - Highlights of the Adler Museum collections. PMID- 11611612 TI - Centenary: Barberton Hospital. PMID- 11611613 TI - Studies of the rickettsial diseases at the South African Institute for Medical Research: epidemic louse-borne typhus fever. PMID- 11611614 TI - The relationship between human and animal health in nineteenth century Dublin. PMID- 11611615 TI - Veterinary life in the Boer War 1899-1902. Correspondence of James William Hall Masheter M.R.C.V.S. PMID- 11611616 TI - The skeleton of Eclipse. PMID- 11611618 TI - Lesions in a prehistoric bear: differential diagnosis. PMID- 11611617 TI - The movement of younger scientists into and out of the United States from 1967 to 1980: some aspects of the international movement of scientific knowledge. PMID- 11611620 TI - Eugenics and the Left. PMID- 11611619 TI - Hume and the relation of science to religion among certain members of the Royal Society. PMID- 11611621 TI - Rather never than late: celibacy and age at marriage in English cohort fertility, 1541-1871. PMID- 11611622 TI - Perceptions of health and environment in the settlement of North America in the early seventeenth century. PMID- 11611623 TI - Religious and professional interests in northern spa literature, 1625-1775. PMID- 11611624 TI - The rise and fall of the Bath waters. PMID- 11611625 TI - The physiology of air: eighteenth-century fever therapy in the advice literature. PMID- 11611626 TI - Cleaning up the Great Wen: public health and eighteenth-century London. PMID- 11611627 TI - Medical topography and the rebuilding of Le Mans. PMID- 11611628 TI - A 'quiet revolution': the coming of pure water to contemporary France. PMID- 11611629 TI - Cholera and public health reform in nineteenth-century England and Wales: interpreting the geographical patterns. PMID- 11611630 TI - Medical topography. PMID- 11611631 TI - Disease and dirty water in West Somerset in the late nineteenth century. PMID- 11611632 TI - Environmental factors in infant and early childhood mortality decline in England and Wales, 1895 to 1910. PMID- 11611633 TI - The development of the sanatorium treatment for consumption in Britain, 1880 1914. PMID- 11611634 TI - Open-air therapy and the rise of open-air hospitals. PMID- 11611635 TI - The pioneer health centre at Peckham. PMID- 11611636 TI - Guide to sources and writings on the history of medicine in Bristol, 1600-1900. PMID- 11611637 TI - The 'biographical memoirs' of the Bristol Infirmary. PMID- 11611638 TI - Social history of medicine and the geographers--a bibliography. PMID- 11611639 TI - The ESRC Data Archive. PMID- 11611641 TI - Environments of disease and mortality in the New World and the Old World. PMID- 11611640 TI - Printed advertisements for women medical practitioners in London, 1670-1710. PMID- 11611642 TI - Scientists' libraries: a handlist of printed sources. PMID- 11611643 TI - Religious opposition to obstetric anaesthesia: a myth? PMID- 11611644 TI - Dalla filosofia alla psicologia sociale. Una "lettura" di Carlo Cattaneo. PMID- 11611645 TI - Holzkamp's critical psychology and the functional-historical method: a critical appraisal. PMID- 11611646 TI - Wilhelm Wundt's publication record: a re-examination. PMID- 11611647 TI - Dal comportamentismo alla simulazione del comportamento. PMID- 11611648 TI - La storia della psichiatria nell'Ottocento: i contributi italiani nell'ultimo decennio (1968-1978). PMID- 11611649 TI - Biographical genre and biographical archetype: five studies of Gustav Theodor Fechner. PMID- 11611650 TI - Isaac Newton's two uses of hypothetical reasoning: dual influences on the history of psychology. PMID- 11611651 TI - Il manifesto della scuola storico-culturale. PMID- 11611652 TI - La polemica tra Henning e Buhler. PMID- 11611653 TI - Trends in Soviet cognitive psychology. PMID- 11611654 TI - Wundt e il linguaggio dei gesti. PMID- 11611655 TI - De Sanctis e la psicologia italiana. PMID- 11611656 TI - Fisica ingenua a teoria cartesiana degli urti. PMID- 11611657 TI - Il concetto di adattamento nella psicologia evoluzionistica di K. Lorenz e nell'epistemologia genetica di J. Piaget. PMID- 11611658 TI - Il bilancio e le prospettive della psicoanalisi francese nella riflessione critica di alcuni protagonisti (1970-1980). PMID- 11611659 TI - Wilhelm Reich nel dibattito psicoanalitico degli anni Trenta. PMID- 11611660 TI - From the north to Red Lion Court: the creation and early years of the Annals of Natural History. PMID- 11611661 TI - The rise and fall of the American establishment. PMID- 11611662 TI - Between autonomy and planning: the Chinese Academy of Sciences in transition. PMID- 11611663 TI - The journalists and technology: reporting about Love Canal and Three Mile Island. PMID- 11611664 TI - Ferriar's fever to Kay's cholera: disease and social structure in cottonopolis. PMID- 11611665 TI - Science, scientists and history of science. PMID- 11611666 TI - Alchemy and eschatology in seventeenth-century poetry. PMID- 11611667 TI - The structure of mythos: on the cultural stability of alchemy. PMID- 11611668 TI - Alchemy in Newton's library. PMID- 11611669 TI - Child health on postage stamps. PMID- 11611670 TI - UTMB: eighty years ago. PMID- 11611671 TI - The earliest Egyptian medical texts. PMID- 11611672 TI - Ottoman and European diet in the fifteenth century PMID- 11611673 TI - The physician in nineteenth-century English and American literature. PMID- 11611674 TI - Books by physician travelers. PMID- 11611675 TI - An analytical and comparative study of Indian and Chinese cosmologies. PMID- 11611676 TI - Bath in Ayurveda, Yoga and Dharmashastra. PMID- 11611677 TI - The Ayurvedic system of medicine: its fate in medieval India. PMID- 11611678 TI - The meaning of prajna-aparadha and karma in Ayurveda. PMID- 11611679 TI - A note on Goraksanatha and his work Yogadipika. PMID- 11611680 TI - Ilajul Atfal: a treatise on pediatrics by Fezl-e-Ali-Shifa-ee Khan. PMID- 11611681 TI - Abstracts of medico-historical articles in Hindi journals. PMID- 11611683 TI - Major General S. L. Bhatia (1891-1982). PMID- 11611682 TI - Prof. Jean Filliozat (1906-1981). PMID- 11611684 TI - Prelude to upgraded Department of History of Medicine, Hyderabad. PMID- 11611685 TI - Esquisse; a technological history of heating, air- and environmental-conditioning in European and American architecture, before 19th century. PMID- 11611686 TI - Traffic in corpses: some evidence from Barming, Kent (1788-1812). PMID- 11611687 TI - Committed history and philosophy of the social sciences in the two Germanies. PMID- 11611688 TI - Themes, genres and orders of legitimation in the consolidation of new scientific disciplines: deconstructing the historiography of molecular biology. PMID- 11611689 TI - Guide to the botanical records and papers in the archives of the Hunt Institute. PMID- 11611690 TI - Historical milestones. PMID- 11611691 TI - Spice dishes and spice plates. PMID- 11611692 TI - Alexander Dalmahoy. PMID- 11611693 TI - [The transition of morphine hydrochloride preparations as opium alkaloid in Japanese pharmacopoeia between 1886 (J.P.I.) and 1981 (J.P.X.)] (Jpn). PMID- 11611694 TI - [The transition of digitalis preparations as cardiac glycoside in Japanese pharmacopoeia between 1886 (J.P.I.) and 1981 (J.P.X.)] (Jpn). PMID- 11611695 TI - [A history of pharmaceutical education in Okayama (IV) Private Okayama Pharmaceutical School (secondary)] (Jpn). PMID- 11611696 TI - [On the ancient manuscript named "San'emon Imai's Application"] (Jpn). PMID- 11611697 TI - [Discrepancy in the "Biography of N. Nagai" written by S. Kanao] (Jpn). PMID- 11611698 TI - ["Shokokusanbutsurei" a writ of an inquisition about the domestic products] (Jpn). PMID- 11611699 TI - [Historical research study on why there can be no separation between pharmacy and medicine in Japan (I)] (Jpn). PMID- 11611700 TI - Aleen Cust - first woman veterinary surgeon in Britain - early influences. PMID- 11611701 TI - Animal health and ecological disaster in nineteenth century Australia. PMID- 11611702 TI - Hippocrates and veterinary medicine. PMID- 11611703 TI - British veterinarians in the veterinary service of Palestine. PMID- 11611704 TI - Books and articles on veterinary history PMID- 11611705 TI - American morphology in the late nineteenth century: the biology department at Johns Hopkins University. PMID- 11611707 TI - James Keill, George Cheyne, and Newtonian physiology, 1690-1740. PMID- 11611706 TI - Conceptual models and analytical tools: the biology of physicist Max Delbruck. PMID- 11611708 TI - "Such monstrous births": a neglected aspect of the Antinomian controversy. PMID- 11611709 TI - Medical knowledge and urban planning in tropical Africa. PMID- 11611710 TI - [A talk on homologous organ therapy in traditional Chinese medicine: from the textual research on the Chinese character yan] (Chi). PMID- 11611711 TI - [The Chinese characters ji and bing: on the origin and development of medical characters] (Chi). PMID- 11611712 TI - [A chronology of Wang Mengying] (Chi). PMID- 11611713 TI - [A brief textual research on Zhu Danxi's disciples] (Chi). PMID- 11611715 TI - [A talk on the date of writing of the theory of doctrine on five element's motion and six kinds of natural factors in Internal Classics of Yellow Emperor] (Chi). PMID- 11611714 TI - [Exploration on the medical life of Bian Que, a renowned physician in ancient China] (Chi). PMID- 11611716 TI - [Health care of the Chinese Worker's and Peasant's Red Army in the Second Revolutionary Civil War period] (Chi). PMID- 11611717 TI - [A general survey of practitioners of traditional Chinese medicine in the town district of Wuxi City in modern period] (Chi). PMID- 11611718 TI - [Uygharian medical handbook on the therapy of sundry diseases, its significance in medical history] (Chi). PMID- 11611719 TI - [Study on Chen Yaodao's Differentiation of zheng in Exogenous Feberile Diseases] (Chi). PMID- 11611720 TI - Healing cults in antiquity: the dream cures of Asclepius of Epidaurus. PMID- 11611721 TI - Psychohistory: expanding the parameters of historical causality. PMID- 11611722 TI - The anti-Freudian crusade continues. PMID- 11611723 TI - Medicine's humble humbug: four periods in the understanding of the placebo. PMID- 11611724 TI - Friedrich Wilhelm Serturner and the discovery of morphine. PMID- 11611725 TI - Cosmas and Damian in the Near East: earliest extant monument. PMID- 11611726 TI - Burkhard Reber: a pharmacist-collector and his collection. PMID- 11611727 TI - Vapo-cresolene lamp and bottles. PMID- 11611728 TI - The marketing of patent medicines in Lincoln's Springfield. PMID- 11611730 TI - Die Rolle der Heilkulte in der romischen Republik: Eine Einfuhrung zu ihrer politischen Funktion. PMID- 11611729 TI - Annotated bibliography [of paleopathology]. PMID- 11611731 TI - Studien zum Gesundheitswesen bei den Wikingern. PMID- 11611732 TI - Josef Skoda's relation to the work of Ignaz Semmelweis. PMID- 11611733 TI - Die Evolution der Organismen im Denken des Palaontologen Oswald Heer (1809-1883). PMID- 11611734 TI - Der Arzte-Anteil in der fruhen NS-Bewegung: ein soziologisch-soziographisches Problem. PMID- 11611735 TI - Das Pathologisch-anatomische Bundesmuseum in Wien. PMID- 11611736 TI - Karl Mathias Ernst (1758-1830) als illustrator medizinischer Werke. PMID- 11611737 TI - Expertise and causal attribution in deciding between crime and mental disorder. PMID- 11611738 TI - English marriage patterns revisited. PMID- 11611739 TI - Tabernacles for waiting spirits: monogamous and polygamous fertility in a Mormon town. PMID- 11611740 TI - Scholastic philosophy and Renaissance magic in the De vita of Marsilio Ficino. PMID- 11611741 TI - Some current trends in the study of Renaissance medicine. PMID- 11611742 TI - The short and simple annals of the poor: foundation funding for the humanities, 1900-1983. PMID- 11611743 TI - Philanthropy and science. PMID- 11611744 TI - Philanthropy and the social sciences. PMID- 11611745 TI - The history of ecology: achievements and opportunities, part two. PMID- 11611746 TI - Organotherapy and the emergence of reproductive endocrinology. PMID- 11611747 TI - Ernst Mayr on the history of biology. PMID- 11611748 TI - E. G. Conklin on evolution: the popular writings of an embryologist. PMID- 11611749 TI - Socio-economic characteristics and life expectancies in nineteenth-century England: a district analysis. PMID- 11611750 TI - Social class inequality in mortality from 1921 to 1972 in England and Wales. PMID- 11611751 TI - Age at first marriage and age at death in the Lincolnshire fenland, 1252-1478. PMID- 11611752 TI - The seeming paradox of increasing mortality in a highly industrialized nation: the example of the Soviet Union. PMID- 11611753 TI - The doctors of Auschwitz: the biomedical vision. PMID- 11611754 TI - Shattered alternatives in medicine. PMID- 11611755 TI - Pride and prejudice: ladies and nurses in the Crimean War. PMID- 11611756 TI - The history of American medicine: a field in ferment. PMID- 11611757 TI - Clio as physicist and machinist. PMID- 11611758 TI - The Black Death and Western European eschatological mentalities. PMID- 11611759 TI - The Gestalt psychologists in behaviorist America. PMID- 11611760 TI - The surgical mask in literature. PMID- 11611761 TI - The discovery of insulin and control of diabetes mellitus. PMID- 11611762 TI - L'authenticite et l'origine des deux traites de toxicologie attribues a Dioscoride: I. Historique de la question II. Apport de l'histoire du texte Grec. PMID- 11611763 TI - Notes towards the history of anorexia nervosa. PMID- 11611765 TI - The two medicines: some ecclesiastical concepts of disease and the physician in the high Middle Ages. PMID- 11611764 TI - The Amsterdam pharmacist Willem van Barneveld (1747-1826) and the discovery of photosynthesis (1778). PMID- 11611766 TI - On the microscopes of Antoni van Leeuwenhoek. PMID- 11611767 TI - Huygens' microscopical researches. PMID- 11611768 TI - Philosophy of biology versus philosophy of physics. PMID- 11611769 TI - Analytical studies in the evidences regarding chemico-culture in the history of Indian medicine in ancient period--allium series. PMID- 11611770 TI - A comparative study of the early system of Indian cosmology and the tridosa humoral doctrine. PMID- 11611771 TI - Aphrodisiacs--a psychosocial perspective. PMID- 11611772 TI - Diseases due to deficiencies of vital principles in the body. PMID- 11611773 TI - Techniques for extraction of foreign bodies from war wounds in medieval India. PMID- 11611774 TI - Contribution of medieval India to Ayurvedic Materia Medica. PMID- 11611775 TI - Unani medicine in India. PMID- 11611776 TI - Contributions of Sarngadhara in the field of materia medica and pharmacy. PMID- 11611777 TI - Medicinal use of opium and cannabis in medieval India. PMID- 11611778 TI - Ideas of integration as a process of evolution of Indian system of medicine in the medieval period. PMID- 11611779 TI - Contribution of Unani Materia Medicas to the identification of vedic plants with special reference to Usana. PMID- 11611780 TI - An Arabic source for the history of ancient Indian medicine. PMID- 11611781 TI - Poisons and antidotes in Unani system of medicine. PMID- 11611782 TI - Alchemy and its fundamental terms in Greek, Arabic, Sanskrit and Chinese. PMID- 11611783 TI - The origin and development of pulse examination in medieval India. PMID- 11611784 TI - Contribution of Madanapala Nighantu to the knowledge of Indian materia medica with particular reference to fig (anjira). PMID- 11611785 TI - Humoral theory of Unani Tibb. PMID- 11611786 TI - A survey of the concepts and measures developed by the Greco-Arab physicians related with the prevention and treatment of the infections and epidemic diseases. PMID- 11611787 TI - Interaction in chemistry and medicine between India and Europe in 18th-19th century. PMID- 11611788 TI - Bakula--a reputed drug of Ayurveda, its history, uses in Indian medicine. PMID- 11611789 TI - Intoxicants in Mughal India. PMID- 11611790 TI - On the identity and economico-medicinal uses of Hastikarnapalasa (Leea macrophylla Roxb., Family: Ampelidaceae) as evinced in the ancient (Sanskrit) texts and traditions. PMID- 11611791 TI - Parisrut the earliest distilled liquor of Vedic times or of about 1500 B.C. PMID- 11611792 TI - Childlessness in a transitional population: the United States at the turn of the century. PMID- 11611793 TI - Breast-feeding habits and their relation to infant mortality and marital fertility. PMID- 11611794 TI - Agricultural variation and human fertility in antebellum Pennsylvania. PMID- 11611795 TI - An "epidemic" of adolescent pregnancy? Some historical considerations. PMID- 11611796 TI - Rumanian research in historical demography: a note. PMID- 11611797 TI - Husbands' participation in childbirth: a nineteenth-century phenomenon. PMID- 11611798 TI - Factors affecting the fecundity and fertility of historical populations: a review. PMID- 11611799 TI - Russian historical demography and family history. PMID- 11611801 TI - Sex of offspring and fertility in South Asia: demographic variance and decision procedures in "joint family" households. PMID- 11611800 TI - Demographic transitions in a Sicilian rural town. PMID- 11611802 TI - On doctors and bonesetters in the 16th and 17th centuries. PMID- 11611803 TI - Seeking the rational alternative: the National College of Chiropractic from 1906 to 1982. PMID- 11611804 TI - The search for the first 15 'disciples'. PMID- 11611805 TI - Perspectives on chiropractic education in medical literature, 1910-1933. PMID- 11611806 TI - The New Zealand Commission of Inquiry: its significance in chiropractic history. PMID- 11611807 TI - Chiropractic observed: thirty years of changing sociological perspectives. PMID- 11611808 TI - Chiropractors as interns, residents and staff: the hospital experience, 1910 1960. PMID- 11611809 TI - Women in chiropractic: exploring a tradition of equity in healing. PMID- 11611811 TI - Pioneering mental health: institutional psychiatric care in chiropractic. PMID- 11611810 TI - Almeda Haldeman, Canada's first chiropractor: pioneering the prairie provinces, 1907-1917. PMID- 11611812 TI - Lincoln College and the 'Big Four': a chiropractic protest, 1926-1962, PMID- 11611813 TI - Correspondence of William Heberden, F.R.S. with the Reverend Stephen Hales and Sir Charles Blagden. PMID- 11611814 TI - American colonial scientists who published in the Philosophical Transactions of the Royal Society. PMID- 11611815 TI - Murders and the detection of arsenic. PMID- 11611816 TI - The relic of Dr. John Oglander. PMID- 11611817 TI - Surgeon-apothecaries in Edinburgh in 17th and early 18th centuries. PMID- 11611818 TI - A history of herbal medicine. PMID- 11611819 TI - Pharmaceutical connections: the Maw's family. PMID- 11611820 TI - [Textual research on the origin and development of crocus sativus L., a Chinese medicinal herb] (Chi). PMID- 11611821 TI - [An introduction to Shen Zhiwen's works, Jie wei yuan sou, and his contributions to leprology] (Chi). PMID- 11611822 TI - [Kou Zongshi and his Amplification of classics of Shen Nong's Herbal] (Chi). PMID- 11611823 TI - [Textual research on the invention of decoction by Yi Yin, a renowned high ranking official of the Shang Dynasty] (Chi). PMID- 11611824 TI - [A brief history of Korean medicine]. PMID- 11611825 TI - [From human-pox vaccination to cowpox vaccination] (Chi). PMID- 11611826 TI - [On the development and application of tools for grinding crude drugs in ancient China] (Chi). PMID- 11611827 TI - [Medical thought in Lu shi chenqiu, an ancient Chinese work] (Chi). PMID- 11611828 TI - [A brief history of ancient Chinese dietotherapy]. PMID- 11611829 TI - [Texture research on Zhu Na, the native place of the renowned acupuncturist Huangfu Mi] (Chi). PMID- 11611830 TI - [Trade on Chinese medical herb: a brief history of jianchang gang]. PMID- 11611831 TI - [The public hospital in the capital of the Qing Dynasty] (Chi). PMID- 11611832 TI - [On the Taoists' thought in traditional Chinese medicine] (Chi). PMID- 11611833 TI - [The spreading of jiuhuang ben tsao (herbology for relieving famine)] (Chi). PMID- 11611834 TI - Pharmacy in pre-Soviet Russia. PMID- 11611835 TI - A pharmacist in Tsarist Russia--a reminiscence, 1892-1909, by Isaiah Ginzburg. PMID- 11611836 TI - Literary reflections of pharmacy--III: Dona Flor and her two husbands. PMID- 11611837 TI - German-American links in 19th-century pharmacy. PMID- 11611838 TI - Of battleships and battlegrounds. PMID- 11611839 TI - Patent ring jars. PMID- 11611840 TI - John Armstrong: poet and physician. PMID- 11611841 TI - Rietfontein Hospital. PMID- 11611842 TI - Medical philately: failures and feuds among famous physicians. PMID- 11611843 TI - The history of plastic surgery in South Africa. PMID- 11611844 TI - Nuptiality and age at marriage in nineteenth-century England. PMID- 11611845 TI - Trends and regional differences in breastfeeding in Germany from 1871 to 1937. PMID- 11611846 TI - In tema di hypertrichosis universalis congenita: contributo storico-medico. PMID- 11611847 TI - Adaptations to sedentism and food production: the Paloma Project. PMID- 11611848 TI - Annotated bibliography [of Paleopathology]. PMID- 11611849 TI - Aidan Cockburn (1912-1981): a memorial. PMID- 11611850 TI - Pathological anatomy and electron microscopy of prehistoric human skeletons of the southeastern coast and Lagoa Santa region of Brazil. PMID- 11611851 TI - Adaptations to sedentism and food production: the Paloma Project (cont'd). PMID- 11611852 TI - Spondylolysis and spondylolisthesis in two Anglo-Saxon skeletons. PMID- 11611853 TI - Transcending cultural barriers: the european reception of medicinal plants from the Americas. PMID- 11611854 TI - The history of curare research. PMID- 11611855 TI - The impact of the materia medica of the North American Indians on professional practice. PMID- 11611856 TI - Traditional medicine in Southern Appalachia and some thoughts for the history of medicinal plants. PMID- 11611857 TI - The aztec herbal of 1552. Martin de la Cruz' "Libellus de medicinalibus indorum herbis"; context of the sources on nahualt materia medica. PMID- 11611858 TI - The George Stubbs exhibition. PMID- 11611859 TI - George Stubbs and his l8th century patrons. PMID- 11611862 TI - Books and articles on veterinary history. PMID- 11611860 TI - The St. Bel plan. PMID- 11611861 TI - J.-P. Megnin. PMID- 11611863 TI - The aging society. PMID- 11611864 TI - Drugless healing in the 1920s: the therapeutic cult of sanipractic. PMID- 11611865 TI - Ann Petry: from pharmacist to novelist. PMID- 11611866 TI - Insulin: a case study in the emergence of collaborative pharmacomedical research. PMID- 11611867 TI - The celebrated glass label. PMID- 11611868 TI - The showglobe--a beacon through time. PMID- 11611869 TI - Historical images of the drug market--IX. PMID- 11611870 TI - "A digression of the animal spirits": the changes of the concept of 'spirit' in the seventeenth-century science (I). PMID- 11611871 TI - The theory of life in the early 20th century--in Japan and in Europe. PMID- 11611872 TI - On the formation of Helmholtz' view of life processes in his studies of fermentation and muscle action--in relation to his discovery of the law of conservation of energy. PMID- 11611873 TI - The history of science in the non-Western world--an inventarisation of some important works during the 20th century. PMID- 11611874 TI - Fruhe christliche Missionshospitaler in China im 19. Jahrhundert. PMID- 11611875 TI - Some matters in the study of von Siebold from the past to the present and new materials found in relation to Siebold and his works. PMID- 11611876 TI - The 'treatment of choice': breast cancer surgery 1860-1985. PMID- 11611877 TI - Records recently selected for permanent preservation from central government sources. PMID- 11611878 TI - The social structure of medicine in medieval Islam. PMID- 11611879 TI - Dorothy McLaren. PMID- 11611880 TI - Astrology and medicine in the Middle Ages. PMID- 11611881 TI - The medieval hospital of St Thomas the Martyr in Southwark. PMID- 11611882 TI - John Mirfield and the Breviarium Bartholomei: the medical writings of a clerk at St Bartholomew's Hospital in the later fourteenth century. PMID- 11611883 TI - The profits of practice: the wealth and social status of medical men in later medieval England. PMID- 11611885 TI - Science and medicine in the nineteenth century: changing conceptions of medical practice. PMID- 11611884 TI - Early medical chemistry at Guy's Hospital, 1800-1850. PMID- 11611886 TI - Medicine and science in Denmark in 1859. PMID- 11611887 TI - Explanations of disease and the technology of hygiene in Parkes's Manual, 1864 1873. PMID- 11611888 TI - Science in the service of medicine: germ theory, bacteriology and English public health, 1860-1914. PMID- 11611889 TI - Pure science and applied medicine: the relationship between bacteriology and biochemistry in England after 1880. PMID- 11611890 TI - Clinical research: the case of St Mark's Hospital, London, and colo-rectal surgery. PMID- 11611892 TI - The image of medicine at war. PMID- 11611891 TI - The First World War and British cardiology: a case of soldier's hearts. PMID- 11611893 TI - The politics of cancer research: Walter Morley Fletcher and the origins of the British Empire cancer campaign. PMID- 11611895 TI - The Byzantine welfare state: image and reality. PMID- 11611894 TI - Tuberculosis and the Medical Research Council, 1911-1939. PMID- 11611896 TI - Resources for radiobiology: medical support for research into the biological effects of radiation in inter-war Britain. PMID- 11611897 TI - The Medical Research Council's inter-war dietary surveys. PMID- 11611898 TI - Exploring 'clinical research': academic medicine and the clinicians in early twentiety-century Britain. PMID- 11611899 TI - The British success with penicillin. PMID- 11611900 TI - The role of bioassay in therapeutic advancement. PMID- 11611901 TI - Brain death and brainstem death. PMID- 11611902 TI - Seeing with sound: the development of ultrasound equipment in medicine. PMID- 11611903 TI - Physicians at work: self- and public images, 1890-1930. PMID- 11611904 TI - The New Deal's Federal Theatre Project. PMID- 11611905 TI - A fifteenth-century papal brief on human dissection. PMID- 11611906 TI - The anatomical models of Dr. Auzoux. PMID- 11611907 TI - The medicine doll with bound feet. PMID- 11611908 TI - Christian Scientists and the medical profession: a historical perspective. PMID- 11611909 TI - Federal funding and sudden infant death research, 1945-80. PMID- 11611910 TI - On conservative and adventurous styles of scientific research. PMID- 11611911 TI - Is the psychogenic theory scientific? PMID- 11611912 TI - "Beyond one's control": life course and the tragedy of class, Boston, 1800 to 1900. PMID- 11611913 TI - Institutional efforts: popularization of science in the mid 19th century. PMID- 11611914 TI - From the secrets of nature to public knowledge: the origins of the concept of openness in science. PMID- 11611915 TI - The place of private foundations in the support of research in the Federal Republic of Germany. PMID- 11611916 TI - Voluntary science in nineteenth century Cambridge University to the 1850's. PMID- 11611917 TI - Context, image and function: a preliminary enquiry into the architecture of scientific societies. PMID- 11611918 TI - Reflections on recent levels and trends of fertility and mortality in Egypt. PMID- 11611919 TI - Relative trends in mortality from related respiratory and airborne infectious diseases. PMID- 11611920 TI - How change in age-specific mortality affects life expectancy. PMID- 11611921 TI - The demographic revolution in England: a re-examination. PMID- 11611923 TI - The polygyny-fertility hypothesis: a re-evaluation. PMID- 11611922 TI - Polygyny among Arabs. PMID- 11611924 TI - Demographic changes in East Malaysia and their relationship with those in the Peninsula 1960-80. PMID- 11611925 TI - Zwischen Antike und europaischem Mittelalter. Die arabisch-islamische Medizin in ihrer klassischen Epoche. PMID- 11611926 TI - The effect of canonical prohibitions on the Faculty of Medicine at the University of Paris in the Middle Ages. PMID- 11611927 TI - Sopono, Pocken und Pockengottkult der Yoruba. Erster Teil. PMID- 11611929 TI - Zwei bemalte griechische Arztegrabstelen aus Chersones. PMID- 11611928 TI - "Uber Natur und Kunst in der Arzneiwissenschaft]. Karl Wenzel (1769-1827) als Lehrer und Kritiker der Geburtshilfe seiner Zeit. PMID- 11611930 TI - Geneticists embattled: their stand against rampant eugenics and racism in America during the 1920s and 1930s. PMID- 11611931 TI - Portraits of doctors by Rembrandt and Rubens. PMID- 11611932 TI - Collecting medical history: the ingenuity of the addict. PMID- 11611933 TI - Formalizing a hobby: the bibliography of medical philately. PMID- 11611934 TI - Collecting Ex libris: the lure of the medical bookplate. PMID- 11611935 TI - The early medical libraries of Edinburgh and Glasgow. PMID- 11611936 TI - 'The healer's art': a fascination for centuries. PMID- 11611937 TI - The historical collections: past, present, and future. PMID- 11611938 TI - Privilege, communication, and chemiatry: the hermetic-alchemical circle of Moritz of Hessen-Kassel. PMID- 11611939 TI - Alchemy and melancholy in medieval and renaissance thought: a query into the mystical basis of their relationship. PMID- 11611940 TI - Vicente de Seabra and the chemical revolution in Portugal. PMID- 11611941 TI - Atrocious misery: the African origins of famine in northern Somalia, 1839-1884. PMID- 11611942 TI - Anglo-Indian medical theory and the origins of segregation in West Africa. PMID- 11611943 TI - Psychohistory as history. PMID- 11611944 TI - The early years: the medical world in which Walsh McDermott trained. PMID- 11611945 TI - The problems of cost, access, and distribution of medical care. PMID- 11611946 TI - America's romance with medicine and medical science. PMID- 11611947 TI - Reaching out to the community: responses by medicine. PMID- 11611948 TI - Cross-cultural medicine: the Navajo Indians as case exemplar. PMID- 11611949 TI - The changing concept of the ideal physician. PMID- 11611950 TI - Ideas in conflict: the rise and fall (and rise and fall) of new views of disease. PMID- 11611951 TI - Where have we been? Where are we going? PMID- 11611952 TI - The emergence of the physician-basic scientist in America. PMID- 11611954 TI - The changing role model, and the shift in power. PMID- 11611953 TI - Medical education at the peak of the era of experimental medicine. PMID- 11611955 TI - Medical schools and research: is the tail wagging the dog? PMID- 11611956 TI - Indigenous systems of medicine in India. Early history, literature and special features. PMID- 11611957 TI - Ayurvedic material in A. P. O. M. L. & R. Institute Hyderabad. PMID- 11611958 TI - Buddha's discourses on medicament treatment and nursing. PMID- 11611959 TI - List of medical manuscripts in two colleges in Pune. PMID- 11611960 TI - Medicine in north India. PMID- 11611961 TI - Research in allopathic medicine in India during the last 100 years: investigations and investigators. PMID- 11611962 TI - The social demography of Hungarian villages in the eighteenth and nineteenth centuries (with special attention to Sarpilis, 1792-1804). PMID- 11611963 TI - Annotated bibliography [of paleopathology]. PMID- 11611964 TI - Anomalous tooth-neck wear in North African mesolithic populations. PMID- 11611966 TI - Extending the senses: the graphic method. PMID- 11611968 TI - Patients and enemies: medics and POWs in the Korean War. PMID- 11611967 TI - Diego Rivera's Detroit Industries. PMID- 11611969 TI - Visual rhetoric: Navajo art and curing. PMID- 11611970 TI - The Venetian plague of 1630-1631: assessment of a human disaster. PMID- 11611971 TI - The pursuit of the artificial heart. PMID- 11611973 TI - Highlights of the Adler Museum collections: Cambridge electrocardiograph machine. PMID- 11611972 TI - Medical philately: "A very special juice". A bloody tale on stamps. PMID- 11611974 TI - St. Giles, St. Francis et al.: medical patron saints. PMID- 11611975 TI - African sleeping sickness--African trypanosomiasis. The story of its conquest. PMID- 11611976 TI - Archives and special collections on women in medicine, Medical College of Pennsylvania. PMID- 11611977 TI - William Smellie (1697-1763): the father of scientific obstetrics. PMID- 11611978 TI - Medicine as seen through art. PMID- 11611979 TI - All the colours of the Rimbaud. PMID- 11611980 TI - Vesalius' Icones anatomicae: design binding by Michael Wilcox. PMID- 11611981 TI - Medieval iatrochemists and the search for quintessence. PMID- 11611982 TI - Public pharmacology: modes of action of nineteenth-century "patent" medicines. PMID- 11611983 TI - The Merck Manual. PMID- 11611984 TI - Psychohistorians discuss psychohistory. PMID- 11611985 TI - [A historical reexamination on the investigations of atomic radiation effects in Hiroshima and Nagasaki: underestimations of acute radiation effects]. PMID- 11611986 TI - Reason in the Zeitgeist. PMID- 11611987 TI - The Gregor Mendel controversy: early issues of goodness-of-fit and recent issues of genetic linkage. PMID- 11611988 TI - Between ecology and evolutionary biology. PMID- 11611989 TI - Evolution into ecology? The strategy of Warming's ecological plant geography. PMID- 11611990 TI - Advantage, adaptiveness, and evolutionary ecology. PMID- 11611991 TI - Mathematical figments, biological facts: population ecology in the thirties. PMID- 11611993 TI - On fitness and adaptedness and their role in evolutionary explanation. PMID- 11611992 TI - Evolutionary ecology and the use of natural selection in ecological theory. PMID- 11611994 TI - Reflections on reflections: ecology and evolutionary biology. PMID- 11611995 TI - [Not Available]. PMID- 11611996 TI - Functionaries and seekers in Latin America: missionary diffusion of the exact sciences, 1850-1930. PMID- 11611997 TI - [Not Available]. PMID- 11611998 TI - [Not Available]. PMID- 11611999 TI - [Not Available]. PMID- 11612000 TI - [Not Available]. PMID- 11612001 TI - [Not Available]. PMID- 11612002 TI - [The influence of scientific thought of traditional Chinese medicine on the treatment of surgical operation]. PMID- 11612003 TI - [Materials related to preventive medicine of the pre-Spring-Autumn and Spring Autumn periods]. PMID- 11612004 TI - [In commemoration of the centenary anniversary of the passing away of Paul Bert, one of the founders of aero-medicine and diving medicine]. PMID- 11612005 TI - [Traumatic surgery in rGyud-bZhi (the four tantras), a Tibetan medical classic]. PMID- 11612006 TI - [The medical work of the PLA Fourth Field Army in China's War of Liberation]. PMID- 11612007 TI - [Maternity and child hygiene work in the Shaanxi-Gansu-Ningxia border region]. PMID- 11612008 TI - [An inquiry on ma fei san (an anaesthetic formula) and re-discussion on Hua Tuo's nationality]. PMID- 11612010 TI - Experimental science and the rational artist in early modern Europe. PMID- 11612009 TI - Freud in three frames: a cognitive-scientific approach to creativity. PMID- 11612012 TI - Medicine in the Scottish enlightenment: stocktaking time? PMID- 11612011 TI - Family economy and the black american fertility transition. PMID- 11612013 TI - Edinburgh's infirmary in the eighteenth century: the birth of the clinic? PMID- 11612014 TI - Jews in the Scottish universities in the age of enlightenment. PMID- 11612015 TI - Malnutrition in Scotland since 1700, and its social consequences. PMID- 11612016 TI - St Kilda: emigrants and disease. PMID- 11612017 TI - The parochial medical service in nineteenth-century Scotland. PMID- 11612018 TI - Scotland's 'museums of madness': the origins and early growth of an organisation of insanity in nineteenth-century Scotland. PMID- 11612019 TI - The mad, the bad, and the sad: psychiatric care in the Royal Edinburgh Asylum, Morningside, 1813-1894. PMID- 11612020 TI - The miasmatic theory and public health: administration in Edinburgh and Leith, 1830-1879. PMID- 11612021 TI - Medical teaching and the rise of the professional medical officer of health in Scotland. PMID- 11612022 TI - The evolution of community medicine teaching in Edinburgh, 1815-1955. PMID- 11612023 TI - Sanitising social space in the twentieth century. PMID- 11612024 TI - What was social medicine? A historiography of the concept (or, George Rosen revisited). PMID- 11612025 TI - The origins of social medicine in Britain. PMID- 11612026 TI - The roots of community medicine. PMID- 11612027 TI - The decline of crisis mortality: what part did the poor law play? PMID- 11612028 TI - Poverty and lunacy: some thoughts on directions for future research. PMID- 11612029 TI - 'I'd rather have been a parish surgeon than a union one'. PMID- 11612030 TI - William Cullen and Edinburgh medicine: a reappraisal. PMID- 11612031 TI - Medicine and the end of the poor law. PMID- 11612032 TI - Problems in assessing nutritional status in historical studies. PMID- 11612033 TI - All trivial fond records: medical archives in Scotland. PMID- 11612034 TI - [The doctor through history]. PMID- 11612035 TI - [On the extraction of lateral incisor and deformative operation of the skull: surgical operation in new Stone Age]. PMID- 11612036 TI - [Textual research on medicine in oracle inscriptions of the Shang (Yin) period (c 16th-11th century B.C.)]. PMID- 11612037 TI - [Hygiene work in the Second Front Army of the Chinese Workers' and Peasants' Red Army]. PMID- 11612039 TI - [A sketch of the hygiene and antiepidemic work of Yanbian Chaoxian minority autonomous prefecture]. PMID- 11612038 TI - [Yang Zemin's life and his opinion on the standardization of nomenclature of diseases in traditional Chinese medicine]. PMID- 11612040 TI - [A short history of pharmacology]. PMID- 11612041 TI - [Medicine of the western Xia Regime (1038-1227) as viewed from Wen Hai, a semantic dictionary of western Xia nationality]. PMID- 11612042 TI - [Pharmaceutical education in the period from the end of Qing Dynasty to pre liberation]. PMID- 11612043 TI - [A brief history of the dentistry in the revolutionary base, Yanan (1939-1948)]. PMID- 11612044 TI - [A sketch of the Coptis Chinensis]. PMID- 11612045 TI - [On Zhang Xichun's thought of amalgamating traditional Chinese medicine with western medicine]. PMID- 11612046 TI - [On the native place of Wang Shuhe, a renowned physician of Jin Dynasty]. PMID- 11612047 TI - [The Sino-Foreign medical exchanges in Sui-Tang Period]. PMID- 11612048 TI - Ptah, the dwarf god of ancient Egypt. PMID- 11612049 TI - British medical administration during the East African campaign 1914-1918. PMID- 11612050 TI - Highlights of the Adler Museum collections. Dr Greathead's consulting room. PMID- 11612051 TI - Pioneer dentists in Johannesburg. The Kincaid-Smith saga. PMID- 11612052 TI - Medical nemesis? PMID- 11612053 TI - Madness and healing in nineteenth century America. PMID- 11612054 TI - Foundations and ruling class elites. PMID- 11612055 TI - The creation of a company culture: Cadburys, 1861-1931. PMID- 11612056 TI - Period parity progression ratios and birth intervals in England and Wales, 1941 1971: a synthetic life table analysis. PMID- 11612057 TI - Johann Peter Sussmilch: a German prophet in foreign countries. PMID- 11612058 TI - Mortality and metropolis: the case of London 1675-1825. PMID- 11612059 TI - Period parity progression measures of fertility in China. PMID- 11612060 TI - [Stressing the uniqueness of traditional Chinese medicine and developing external treatment, in commemoration of the 100 anniversary of Wu Shangxian's death] (Chi). PMID- 11612061 TI - [An account of gynecology and obstetrics in the Tang Dynasty] (Chi). PMID- 11612062 TI - [A brief account of the surgical achievement in the Ming Dynasty] (Chi). PMID- 11612063 TI - [Western medical education in Guangdong Province in modern China]. PMID- 11612064 TI - [Public health work of the Chinese Medical Association] (Chi). PMID- 11612065 TI - [A brief history of dermatoglyphics in China] (Chi). PMID- 11612066 TI - [Parasitic diseases in Fujian Province, past and present] (Chi). PMID- 11612067 TI - [Wu pu ben cao in the developmental history of Chinese herbology] (Chi). PMID- 11612068 TI - Collecting and writing United States surgical history. PMID- 11612069 TI - 'A shoemaker who sticks to his last'. PMID- 11612070 TI - Early women medical writers: a descriptive handlist. PMID- 11612071 TI - Libraries of physicians: a review of the literature. PMID- 11612072 TI - 21st International Symposion on the History of Veterinary Medicine. September 2nd to 6th, 1986; Szekesfehervar (Hungary). Abstracts of the lectures PMID- 11612073 TI - [Studies on the Hamada-ko, a hereditary plaster] (Jpn). PMID- 11612074 TI - [On the herb garden of the fief of Sagara at Hitoyoshi] (Jpn). PMID- 11612075 TI - [The transitions of clove and clove oil in Japanese pharmacopoeia (between JPI and JP XI)]. PMID- 11612077 TI - [On the ninjin produced in the Sendai-han at the end of the Tokugawa era] (Jpn). PMID- 11612076 TI - [On the herbal collection list of Neo district by Yokusai Iinuma] (Jpn). PMID- 11612078 TI - An enquiry into mortality in some mid-Wharfedale parishes in 1623. PMID- 11612079 TI - Death in fifteenth-century Tottenham. PMID- 11612080 TI - Life expectancy and 'age of first appearance' in medieval manorial court rolls. PMID- 11612081 TI - The Lancashire population crisis of 1623--further comment. PMID- 11612082 TI - The Japanese experience with pollution and controls. PMID- 11612083 TI - Dying of a sweat: Falstaff and Oldcastle. PMID- 11612084 TI - The rationalization of sexual behavior: the institutionalization of eugenic thought in Germany. PMID- 11612085 TI - A critical appreciation of the exposition of alchemy by Ibn Khaldun. PMID- 11612086 TI - Abstracts of medico historical articles in Hindi journals. PMID- 11612087 TI - Historical significance of contraception. PMID- 11612088 TI - The Madanadi Nighantu of Candranandana in the light of a new manuscript. PMID- 11612089 TI - Physicians of Hyderabad during Nizam IV, V & VI. PMID- 11612090 TI - Medicine in North India (from Islami Tibb). PMID- 11612091 TI - The green pharmacists. PMID- 11612092 TI - Irish pharmacy's struggle for identity. Part one. PMID- 11612093 TI - Annotated bibliography [of paleopathology]. PMID- 11612094 TI - A compound composite odontoma in a fourteenth century Scottish skull. PMID- 11612095 TI - An 18th century theory on the nature of syphilis and its best cure. PMID- 11612096 TI - [Not Available]. PMID- 11612098 TI - [Not Available]. PMID- 11612097 TI - [Not Available]. PMID- 11612099 TI - [Not Available]. PMID- 11612100 TI - Ancient Egyptian pharmacy. PMID- 11612101 TI - [Not Available]. PMID- 11612102 TI - [Not Available]. PMID- 11612103 TI - [Not Available]. PMID- 11612104 TI - The Society for the History of Pharmacy in South Africa. PMID- 11612105 TI - [Not Available]. PMID- 11612106 TI - The Society's first fifty years: part I--Ambix. PMID- 11612107 TI - "Chemical translation" and the role of impurities in alchemy: examples from Basil Valentine's Triumph-Wagen. PMID- 11612108 TI - Moses Stringer (fl. 1695-1713): iatrochemist and mineral master general. PMID- 11612109 TI - Democritus and the beginnings of Greek alchemy. PMID- 11612110 TI - Biting the hand: medical courtesy, quackery, and the antebellum clergy. PMID- 11612111 TI - [Not Available]. PMID- 11612112 TI - [Not Available]. PMID- 11612113 TI - [Not Available]. PMID- 11612114 TI - [Not Available]. PMID- 11612115 TI - [Not Available]. PMID- 11612116 TI - [Not Available]. PMID- 11612117 TI - [Not Available]. PMID- 11612118 TI - [Not Available]. PMID- 11612119 TI - The controversy on the nature of filterable viruses (1935-1956). PMID- 11612120 TI - [Not Available]. PMID- 11612121 TI - [Not Available]. PMID- 11612122 TI - [Not Available]. PMID- 11612123 TI - [Not Available]. PMID- 11612124 TI - "The Healing Arts in Early America"--Fraunces Tavern Museum, New York. PMID- 11612125 TI - Botanical explorations and discoveries in colonial Maryland, 1688 to 1753. PMID- 11612126 TI - A 1698 Maryland florula by the London apothecary James Petiver (ca. 1663-1718). PMID- 11612127 TI - "Early" fertility decline in America: a problem in family history. PMID- 11612128 TI - The social meanings of illness. PMID- 11612129 TI - Traditions of health in Western culture. PMID- 11612130 TI - Religious insanity; history of a diagnosis. PMID- 11612131 TI - Medicine, modernization, and religion in the People's Republic of China. PMID- 11612132 TI - [The American doctor, D. B. Simmons--especially his achievement at Japan Hospital (Yokohama) and his relation to Yukichi Fukuzawa] (Jpn). PMID- 11612133 TI - [A study of malaria in "Meigetsuki"] (Jpn). PMID- 11612134 TI - [Supplement on historical of ameurinase-bacilli] (Jpn). PMID- 11612135 TI - [The significance of item no. 478 of Maspero's documents on Sir Aurel Stein's Kharakhoto excavation] (Jpn). PMID- 11612136 TI - [First general anesthesia by Dohryu Mikami in Tsugaru] (Jpn). PMID- 11612137 TI - [A study of sui in Wu-shih-erh-ping-fang] (Jpn). PMID- 11612138 TI - [A newly found copy of the "Ranto Kotohajime" and Kosai Nagasaki] (Jpn). PMID- 11612139 TI - Aspirin in Germany: the pharmaceutical industry and the pharmaceutical profession. PMID- 11612140 TI - Pharmacy in l'imagerie populaire. PMID- 11612141 TI - Texts and sources in ancient pharmacy (continued). PMID- 11612142 TI - Implicit fever theory in Epidemics 5 and 7. PMID- 11612143 TI - Medical science, medical practice, and the emerging concept of typhus in mid eighteenth-century Britain. PMID- 11612144 TI - Cullen and the study of fevers in Britain, 1760-1820. PMID- 11612145 TI - Fever pathology in the sixteenth century: tradition and innovation. PMID- 11612146 TI - Thomas Willis and the fevers literature of the seventeenth century. PMID- 11612148 TI - Fevers and other fundamentals: Dutch and German medical explanations c. 1680 to 1730. PMID- 11612147 TI - Sydenham versus Newton: the Edinburgh fever dispute of the 1690s between Andrew Brown and Archibald Pitcairne. PMID- 11612149 TI - Food policy in the early modern period: medical practitioners and others. PMID- 11612150 TI - The influence of nutrition upon achievement in maritime history. PMID- 11612151 TI - The problem of land scurvy, 1820-1910. PMID- 11612152 TI - The 'discovery' of colonial malnutrition. PMID- 11612153 TI - 'Venturing on to the borderline': Audrey Richards's ethnographic contribution to the 'hungry thirties' debate in Africa, 1927-1942. PMID- 11612154 TI - School meals and the problem of malnutrition in England and Wales 1900-1939. PMID- 11612155 TI - Food, poverty and growth: the application of nutrition science, 1918-1939. PMID- 11612156 TI - Physicians' scepticism towards vitamins: the issue of negative causality. PMID- 11612157 TI - Paton, Cathcard and Findlay: a conservative stance in Scottish nutrition. PMID- 11612158 TI - The use of old records in current research on dietary causes of cancer. PMID- 11612159 TI - The licensing of health professions: medical or ministry control? PMID- 11612160 TI - The Nuffield Report and the community pharmacist: an historical perspective. PMID- 11612161 TI - Ministering to the departed: post-mortem technicians and the development of mortuary work as a skilled occupation, 1900-1980. PMID- 11612162 TI - Masseuse to physiotherapist: a study of growth by acquisition. PMID- 11612163 TI - Occupational therapy and tuberculosis. PMID- 11612164 TI - The control of medical X-rays, 1895-1917: Why scientists as paramedics not medics as parascientists? PMID- 11612165 TI - State registration and the shortage of radiographers in the National Health Service 1948-1960. PMID- 11612166 TI - The economy of famine in early modern England. PMID- 11612167 TI - Taking the waters in early modern France: some thoughts on a commercial racket. PMID- 11612168 TI - The medecins du roi at the end of the ancien regime and in the French Revolution. PMID- 11612170 TI - The politics of medicine in restoration France. PMID- 11612169 TI - Medical politics and the study of mind in France 1815-1835. PMID- 11612171 TI - 'Risk', law and hygiene in late nineteenth-century France. PMID- 11612172 TI - Inequalities in retrospect. PMID- 11612174 TI - "I am the poison dripping dragon": iguanas and their symbolism in the alchemical and occult paintings of David Teniers the Younger. PMID- 11612173 TI - The society's first fifty years: part II--members and meetings. PMID- 11612175 TI - Instrument makers in the London guilds. PMID- 11612177 TI - Irish pharmacy's struggle for identity. Part two. PMID- 11612176 TI - 18th century drugs for the Royal Navy. PMID- 11612178 TI - [Views on the study of the history of medicine in China as seen from the Chinese Journal of Medical History] (Chi). PMID- 11612179 TI - [Life and works of Xu Shuwei, a renowned physician of the Song Dynasty] (Chi). PMID- 11612180 TI - [New research on the dates of Tong Zonghai's birth and death] (Chi). PMID- 11612181 TI - [Liu Baoyi's life and his medical contributions] (Chi). PMID- 11612182 TI - [A chronicle of life of Zhang Shanlei, with textual research] (Chi). PMID- 11612183 TI - [Medical thoughts in Ben Cao Gang Mu (Compendium of materia medica)] (Chi). PMID- 11612184 TI - [A list of medical works of Dunhuang Caves] (Chi). PMID- 11612185 TI - [An account of medical history of the Khitan nationality in the Liao period] (Chi). PMID- 11612186 TI - [Characteristics of the military medical organizations in the Ming Dynasty] (Chi). PMID- 11612187 TI - [A brief history of medical works of Guizhou Province during the war of resistance against Japan (1937-1945)] (Chi). PMID- 11612188 TI - [On the study of Chinese materia medica by Chinese scholars in 1920s-1940s] (Chi). PMID- 11612189 TI - [On the formation and development of Tibetan medicine] (Chi). PMID- 11612190 TI - [A brief textual research on Hui hui prescription] (Chi). PMID- 11612191 TI - [Opinions on the adoption of remained contents of the lost Canon of materia medica collected from various sources] (Chi). PMID- 11612192 TI - [Research on the archaic pronunciation of Ma Bi San for Ma Fei San, a well-known anaesthetic proposed by Hua Tuo of Han Dynasty] (Chi). PMID- 11612193 TI - [On nature human-being relationship vs Yellow emperor's classics of internal medicine] (Chi). PMID- 11612194 TI - [Opinions on the methods of medical history research] (Chi). PMID- 11612195 TI - [Preliminary investigation on former residence of Ye Tianshi, a renowned physician of Qing Dynasty] (Chi). PMID- 11612196 TI - [Wu Zhiwang's life and investigation of his relics] (Chi). PMID- 11612197 TI - Migration and the generation of new scientific ideas. PMID- 11612198 TI - Groping towards science policy in the United States in the 1930s. PMID- 11612200 TI - The public health of Rhazes. PMID- 11612199 TI - [Not Available]. PMID- 11612201 TI - [Not Available]. PMID- 11612202 TI - The decline of plague in Egypt in the nineteenth century. PMID- 11612203 TI - [Not Available]. PMID- 11612204 TI - The cholera epidemic in America 1832-1833. PMID- 11612205 TI - [Not Available]. PMID- 11612206 TI - [Not Available]. PMID- 11612207 TI - [Not Available]. PMID- 11612208 TI - [Not Available]. PMID- 11612210 TI - [Not Available]. PMID- 11612209 TI - [Not Available]. PMID- 11612211 TI - [Not Available]. PMID- 11612212 TI - Medecine in Zante from the 16th till middle of the 19th century. PMID- 11612213 TI - [Not Available]. PMID- 11612214 TI - A sketch of the health conditions and diseases in the hellenic area after the fall of the Byzantine empire (1453) until the Greek revolution (1821). PMID- 11612215 TI - [Not Available]. PMID- 11612216 TI - [Not Available]. PMID- 11612217 TI - Contribution of Russian factory inspectors to social hygiene and public health (the 2nd half of the 19th century). PMID- 11612218 TI - Development of public medical service in Ukraine. PMID- 11612219 TI - Healthy elements in Bulgarian spring folk customs. PMID- 11612220 TI - [Not Available]. PMID- 11612221 TI - [Not Available]. PMID- 11612222 TI - [Not Available]. PMID- 11612223 TI - 125 years old is the Hungarian medical weekly: Orvosi Hetilap. PMID- 11612224 TI - [Not Available]. PMID- 11612225 TI - [Not Available]. PMID- 11612226 TI - Language, nationality, medecine. A paper on the history of the Finnish Medical Society "Duodecim". PMID- 11612227 TI - The natural history of the 19th century Canadian medical periodicals. PMID- 11612228 TI - [Not Available]. PMID- 11612230 TI - [Not Available]. PMID- 11612229 TI - Mass communication and public health: the 1905 campaign against yellow fever in New Orleans. PMID- 11612231 TI - [Not Available]. PMID- 11612232 TI - The Hebrew "Book of Medecines" attributed to Asaf the physician: an early mediaeval encyclopaedia of Greek medicine based on an Indian model. PMID- 11612233 TI - [Not Available]. PMID- 11612234 TI - [Not Available]. PMID- 11612235 TI - [Not Available]. PMID- 11612236 TI - [Not Available]. PMID- 11612237 TI - A Vesalian speculation. PMID- 11612239 TI - [Not Available]. PMID- 11612238 TI - Moses of Palermo, translator from the Arabic at the Court of Charles of Anjou. PMID- 11612240 TI - [Not Available]. PMID- 11612241 TI - [Not Available]. PMID- 11612242 TI - [Not Available]. PMID- 11612243 TI - [Not Available]. PMID- 11612244 TI - [Not Available]. PMID- 11612245 TI - The influence of French biomedical theory on nineteenth-century Canadian neuropsychiatry: Bichat and Comte in the work of R. M. Bucke. PMID- 11612246 TI - [Not Available]. PMID- 11612247 TI - Mater puerorum, the history of a term. PMID- 11612248 TI - [Not Available]. PMID- 11612249 TI - The contribution of John Wesley (1703-1791) to medical literature. PMID- 11612250 TI - [Not Available]. PMID- 11612251 TI - [Not Available]. PMID- 11612252 TI - [Not Available]. PMID- 11612253 TI - [Not Available]. PMID- 11612254 TI - [Not Available]. PMID- 11612255 TI - The early nineteenth century French public health movement. PMID- 11612256 TI - [Not Available]. PMID- 11612257 TI - [Not Available]. PMID- 11612258 TI - [Not Available]. PMID- 11612259 TI - Early pediatric literature: (a problem of communication), from the author to the reader, through the book's preface. PMID- 11612260 TI - The standard of living in Montreal, Canada 1850-1900. PMID- 11612261 TI - Medical malpractice law and the public's health in the United States during the 19th century. PMID- 11612262 TI - [Not Available]. PMID- 11612263 TI - [Not Available]. PMID- 11612265 TI - [Not Available]. PMID- 11612266 TI - [Not Available]. PMID- 11612264 TI - [Not Available]. PMID- 11612267 TI - [Not Available]. PMID- 11612268 TI - Letter exchange as vehicle of communication in the history of medecine. PMID- 11612269 TI - The early reception of Harvey's theory on blood circulation in the Netherlands. PMID- 11612270 TI - Social structure and medicine, medical education and medical students in France and the United States (1820-1861). PMID- 11612271 TI - Jane C. Rider and her somnambulistic vision. PMID- 11612272 TI - [Not Available]. PMID- 11612273 TI - [Not Available]. PMID- 11612274 TI - Andreas Vesalius and anatomy: a re-evaluation of his efforts. PMID- 11612275 TI - A revealing examination paper: Ralph Bathurst and the Oxford Circle in the mid seventeenth century. PMID- 11612276 TI - De medicina statica: Archbishop Thomas Secker, a forgotten English iatromechanist. PMID- 11612278 TI - The first Nobel Prize for medicine to the Nordic countries (Niels Ryberg Finsen 1903). PMID- 11612277 TI - The scientific papers of Augustus Volney Waller (1816-1870). PMID- 11612279 TI - [Not Available]. PMID- 11612280 TI - [Not Available]. PMID- 11612281 TI - [Not Available]. PMID- 11612282 TI - [Not Available]. PMID- 11612284 TI - The formative years of Sir William Bowman, F. R. S. PMID- 11612283 TI - [Not Available]. PMID- 11612285 TI - The gallstone disease of two poets and one painter. PMID- 11612286 TI - Distinguished doctors--famous musicians 18th-19th centuries. PMID- 11612287 TI - Kohl along history in medicine and cosmetics. PMID- 11612288 TI - Death and suicide in Finnish mythology and folklore. PMID- 11612289 TI - [Not Available]. PMID- 11612290 TI - Fungi and ancient medicine. PMID- 11612291 TI - [Not Available]. PMID- 11612292 TI - [Not Available]. PMID- 11612293 TI - [Not Available]. PMID- 11612294 TI - The Scythian lamb. PMID- 11612295 TI - [Not Available]. PMID- 11612296 TI - [Not Available]. PMID- 11612297 TI - [Not Available]. PMID- 11612299 TI - The regulation of patent medicines in the United States and France. PMID- 11612298 TI - [Not Available]. PMID- 11612300 TI - [Not Available]. PMID- 11612301 TI - Medical history in James Joyce's Ulysses. PMID- 11612303 TI - The history of hyoscine. PMID- 11612302 TI - [Not Available]. PMID- 11612304 TI - The early history of radiotherapy. PMID- 11612305 TI - The regulation of remedies in eighteenth century France. PMID- 11612306 TI - [Not Available]. PMID- 11612307 TI - The medical care of old people during the ancient and Byzantine period. PMID- 11612308 TI - The legislation concerning psychiatric patients and their treatment during the Byzantine period. PMID- 11612309 TI - Some original patterns about the folklore treatment of diabetes mellitus in Turkey. PMID- 11612310 TI - Palaeolithic medicine, with particular reference to children of Australian aborigines. PMID- 11612311 TI - [Not Available]. PMID- 11612312 TI - The materia medica of Thomas Phaire (1510?-1560). PMID- 11612313 TI - [Not Available]. PMID- 11612314 TI - [Not Available]. PMID- 11612315 TI - Three decades of antihypertensive therapy. PMID- 11612316 TI - The cataract operation in ancient Greece. PMID- 11612317 TI - The first successful total gastrectomy in America. PMID- 11612319 TI - Exposition sur l'angiographie; exhibition on angiography history from 1896 till 1952. PMID- 11612318 TI - Urinary stones their cause and treatment as described in the sushrutasamhita. PMID- 11612320 TI - Bronchial asthma in medical literature of Greek antiquity. PMID- 11612321 TI - [Not Available]. PMID- 11612322 TI - Alchemy, magic and miracles in the Neapolitan medical culture in the Aragonise age (1442-1502). PMID- 11612323 TI - The popular blood letting man, a survival of a medieval tradition. PMID- 11612324 TI - [Not Available]. PMID- 11612325 TI - [Not Available]. PMID- 11612326 TI - [Not Available]. PMID- 11612328 TI - [Not Available]. PMID- 11612327 TI - [Not Available]. PMID- 11612329 TI - [Not Available]. PMID- 11612330 TI - [Not Available]. PMID- 11612331 TI - [Not Available]. PMID- 11612332 TI - [Not Available]. PMID- 11612333 TI - Aging in colonial Philadelphia. PMID- 11612334 TI - Demographic perspectives on the long-lived society. PMID- 11612335 TI - Asylums, families and the state. PMID- 11612336 TI - "Here is adhesiveness": from friendship to homosexuality. PMID- 11612337 TI - Public gardens and social action in late Victorian London. PMID- 11612338 TI - Anatomy, physiology, and surgery: physiology teaching in early nineteenth-century London. PMID- 11612339 TI - [Not Available]. PMID- 11612340 TI - Juan Luis Vives: the De subventione pauperum. PMID- 11612341 TI - The medical and demographic importance of wet-nursing. PMID- 11612342 TI - Gender and insanity as characteristics of the insane: a nineteenth-century case. PMID- 11612343 TI - William Bateson's introduction of Mendelism to England: a reassessment. PMID- 11612344 TI - Screen memories: towards a history of psychiatry and psychoanalysis in the movies. PMID- 11612345 TI - Morbidity in historical plague epidemics. PMID- 11612346 TI - Factors associated with the Finnish fertility decline since 1776. PMID- 11612347 TI - The decline of fertility in Los Angeles, California, 1880-1900. PMID- 11612348 TI - Neurology in ancient India: Muladhara cakra--a physiological reality. PMID- 11612349 TI - Evolution of Kusta. PMID- 11612350 TI - Women pharmacists in nineteenth- and early twentieth-century Russia. PMID- 11612351 TI - The development of a pharmaceutical profession in Ireland. PMID- 11612352 TI - The novels of the American pharmacist, John Uri Lloyd. PMID- 11612353 TI - The heyday of drugstores in Alabama. PMID- 11612354 TI - History of pharmacy: what is it? or how should AIHP develop its policies? PMID- 11612355 TI - Annotated bibliography: doctoral dissertations [on paleopathology] 1976-1986. PMID- 11612356 TI - The mummy from mummy cave: preliminary reports. PMID- 11612357 TI - Experimenting with humans. Part I: History and context. PMID- 11612358 TI - [On the theory of movement of Vaisesika system in ancient India (II)--the movement of human body] (Jpn). PMID- 11612359 TI - Medical and biological constraints: early research on variation in bacteriology. PMID- 11612360 TI - Renaissance sexuality and the Florentine Archives: an exchange. The "lesbian" nun of Judith Brown: a different conclusion. PMID- 11612361 TI - Problems and challenges in the history of Canadian science and technology revisited: the making of a bibliography. PMID- 11612362 TI - Problems and challenges in the history of Canadian science and technology revisited: the making of a bibliography. PMID- 11612363 TI - [Not Available]. PMID- 11612364 TI - The infrastructure of an emerging field. PMID- 11612365 TI - "Know thyself": a phrenological character reading. PMID- 11612366 TI - Claude O. Watkins: pioneer advocate for clinical scientific chiropractic. PMID- 11612367 TI - The anatomy of a policy reversal: the A.P.H.A. and chiropractic, 1969 to 1983. PMID- 11612368 TI - Before the Palmers: an overview of chiropractic's antecedents. PMID- 11612369 TI - From workbench to high tech: the evolution of the adjustment table. PMID- 11612371 TI - The postwar rise and decline of American fertility: the pace of transition to motherhood among 1950-1969 marital cohorts of white women. PMID- 11612370 TI - Clinton, Iowa c. 1906(?): 'the old doctor' vs. 'old dad chiro'. PMID- 11612372 TI - Technology for the prevention of "Les maladies produites par la masturbation." PMID- 11612373 TI - The strange object of biology. PMID- 11612374 TI - Islamic ethics and values in medical sciences and practice. PMID- 11612375 TI - Margaret Altmann: a rugged pioneer in rugged fields. PMID- 11612376 TI - A psychologist in Idaho and New Mexico in the 1930s: some recollections. PMID- 11612377 TI - Early psychological assessments of Mexican-American children. PMID- 11612378 TI - Anne Roe: the making of a scientist. PMID- 11612379 TI - The legendary beauty of the Rocky Mountain region: is it more than skin deep? PMID- 11612380 TI - From Mormon academy to four-year state college: psychology at Weber State College. PMID- 11612381 TI - Psychology among the saints: the development of behavioral science at Brigham Young University. PMID- 11612382 TI - Psychology at the University of Deseret (Utah): a century of progressive struggle. PMID- 11612383 TI - Mirror of New England: the early years of psychology at Colorado College. PMID- 11612384 TI - From soul to psyche and frontier to mainstream: a history of psychology at the University of Denver to 1960. PMID- 11612385 TI - Unplanned birth: psychology at the University of Arizona. PMID- 11612386 TI - Nature and necessity in the land grant context: history of psychology at Colorado State University. PMID- 11612387 TI - Natural science, functionalism, and psychology at the University of New Mexico, 1889-1964. PMID- 11612388 TI - Psychology at the University of Nevada-Reno: a retrospective account. PMID- 11612389 TI - The Boulder model: a history of psychology at the University of Colorado. PMID- 11612390 TI - Graduate days revisited. PMID- 11612391 TI - Camaraderie across distance and diversity: a history of the Rocky Mountain Psychological Association. PMID- 11612392 TI - Press coverage of psychology in the Rocky Mountains: 1885-1956. PMID- 11612393 TI - [The life and achievements of Sahachiro Hata] (Jpn). PMID- 11612394 TI - [The acceptance of Koplik's spot in the Japanese medical world] (Jpn). PMID- 11612395 TI - [An inquiry into mikka-yami (three-day disease) which appeared in medieval Japan] (Jpn). PMID- 11612396 TI - [The lists of "Igakushi", graduates of Faculty of Medicine, University of Tokyo, in early Meiji era (1)] (Jpn). PMID- 11612397 TI - [On the cultivation of Panax Shinseng by the Nagoya (Owari) clan in the Edo era]. PMID- 11612398 TI - [Some aspects of contemporary medicine from the viewpoint of a historian] (Jpn). PMID- 11612399 TI - [Correcting three life stories of ancient Japanese physicians]. PMID- 11612400 TI - [A (provisional) chronicle of the printed books of physiology from Edo Era to early Meiji Era] (Jpn). PMID- 11612401 TI - [An index of the reference documents in the "Honzo-Wamyo"] (Jpn). PMID- 11612402 TI - [Ishinho vol. 13 Kongoji Temple copied in the 13th century] (Jpn). PMID- 11612403 TI - Maggot therapy--a backwater in the fight against bacterial infection. PMID- 11612404 TI - Research note on Spanish-American drug trade. PMID- 11612405 TI - The pharmacology of nineteenth-century patent medicines. PMID- 11612406 TI - Pharmaco-historical resources in Madison, Wisconsin. I. An introduction. PMID- 11612407 TI - Museum of Pharmacy at the Medical Academy of Cracow. PMID- 11612408 TI - A receipt guaranteed to cure hungar pangs, inspired by A. A. Parmentier. PMID- 11612409 TI - Relations of literature and science 1984-85. PMID- 11612410 TI - [Wang Jimin: dedication to the study of medical history for fifty years](Chi). PMID- 11612411 TI - [Characteristics of development of obstetrical thought in traditional Chinese medicine as viewed from Fu Qing Zhu Nu Ke, a book on obstetrics and gynecology] (Chi). PMID- 11612412 TI - [The effect of Confucianism on the development of traditional Chinese medicine] (Chi). PMID- 11612413 TI - [Cremation, a hygienic custom of the Chinese people from antiquity] (Chi). PMID- 11612414 TI - [Bao Jian Yao She and Wei Sheng He Zuo She, two medical cooperative institutions at the Shaanxi-Gansu-Ningxia border region in pre-liberation period] (Chi). PMID- 11612415 TI - [On the examination system for the traditional medical practitioner proposed by Kuomintang's government during 1946-1948] (Chi). PMID- 11612416 TI - [A sketch of medical and hygienic work in Taiwan before 1945] (Chi). PMID- 11612417 TI - [Preliminary investigation on the medicine of the Lisu nationality in Sichuan Province] (Chi). PMID- 11612418 TI - Medico historical information from non-medical sources. PMID- 11612419 TI - Health and hygiene in medieval Andhra and the remonstration by Vemana. PMID- 11612420 TI - Medicine in the Deccan. PMID- 11612422 TI - Brockedon's press. PMID- 11612421 TI - Bibliography of the articles [on Indian medical history]. PMID- 11612423 TI - Nicolas Cabry, master-apothecary of Paris. PMID- 11612424 TI - The Channel Islands during the German occupation. PMID- 11612425 TI - A history of mustard in pharmacy and medicine. PMID- 11612426 TI - Asthma cures: ancient and modern. PMID- 11612427 TI - Gran angelica. Patrick Anderson and the true Scots Pills. PMID- 11612428 TI - An 18th century controversy. PMID- 11612429 TI - Paleopathology and the health status of the American Indian. PMID- 11612430 TI - Saints, drugs, and surgery: Byzantine therapeutics for breast diseases. PMID- 11612431 TI - Samuel Thomson and his effect on the American health care system. PMID- 11612432 TI - Nineteenth-century green glass prescription vials. PMID- 11612433 TI - The path to full accreditation: CMCC and its governors, 1945-86. PMID- 11612434 TI - D. D. Palmer and the metaphysical movement in the 19th century. PMID- 11612435 TI - The search for the subluxation: an investigation of medical literature to 1985. PMID- 11612436 TI - Diversified chiropractic: Northwestern College and John B. Wolfe, 1941-1984. PMID- 11612438 TI - Paleopathology in the Canary Islands. PMID- 11612437 TI - Assessing the oracle at the fountain head: B. J. Palmer and his times, 1902-1961. PMID- 11612439 TI - Case reports on paleopathology. PMID- 11612440 TI - Sex discrimination and admission to medical school, 1929-1984. PMID- 11612441 TI - Suicide in America: a test of Durkheim's theory of religious and family integration, 1933-1980. PMID- 11612442 TI - Oaks and cacti. PMID- 11612443 TI - Deconstructing disease. PMID- 11612444 TI - Industrial wastes in southeast Chicago: production and disposal, 1870-1970. PMID- 11612445 TI - [A sketch of Chinese traditional medicine in Shanxi Province during 1912-1949] (Chi). PMID- 11612446 TI - [Is Wang Qingren a scholar belonging to the sect of Amalgamating traditional Chinese with Western medicine?] (Chi). PMID- 11612448 TI - [A brief history of traditional Chinese medical case record] (Chi). PMID- 11612447 TI - [Journal of acupuncture and moxibustion, the earliest periodical on acupuncture and moxibustion in modern China] (Chi). PMID- 11612449 TI - [A short history of tibetan medicine] (Chi). PMID- 11612450 TI - [Textural research on the history of the spreading of tobacco into China and its medical use] (Chi). PMID- 11612451 TI - [An analytical study on the seven chapters on five elements' motion and six kinds of natural factors in Internal classics of Yellow Emperor] (Chi). PMID- 11612452 TI - [On comprehensive prescriptions of native herbs and its reference books cited] (Chi). PMID- 11612453 TI - [Prelimary study on Zu Bi Shi Yi Mai Jiu Jing, the silk writing unearthed in Ma Wang Dui] (Chi). PMID- 11612454 TI - The president's report [on ancient medicine and pharmacy]. PMID- 11612456 TI - An ecological perspective on the origins of industrialization. PMID- 11612457 TI - Biotic change in nineteenth-century New Zealand. PMID- 11612458 TI - Historical writing on American science. PMID- 11612459 TI - Lawrence Herbert Wells (1908-1980) and the Wits anatomy department with some glimpses of his role in australopithecine unravelling. PMID- 11612460 TI - The mandrake legend. PMID- 11612461 TI - History of Lennon Limited. PMID- 11612462 TI - The first organ transplant operation in the Johannesburg Hospital and subsequent studies in the laboratories of the Poliomyelitis Research Foundation. PMID- 11612463 TI - Reform or cooptation: the creation of the modern American medical school. PMID- 11612464 TI - What is an epidemic? AIDS in historical perspective. PMID- 11612465 TI - The power of professionalism: policies for AIDS in Britain, Sweden, and the United States. PMID- 11612466 TI - Chemical physiology versus biochemistry, the clinic versus the laboratory. The Glaswegian opposition to Edward Mellanby's theory of rickets. PMID- 11612467 TI - The Jews in medicine in Scotland. PMID- 11612469 TI - The first Polish women pharmacists. PMID- 11612468 TI - Pictures from an exhibition. PMID- 11612470 TI - Three Atlanta pharmacists. PMID- 11612471 TI - The Florilegio medicinal: source of Southwest ethnomedicine. PMID- 11612472 TI - Quantification and medical motivation: factors in the interpretation of early modern chemistry. PMID- 11612473 TI - [The development of otorhinolaryngology in the northern Song dynasty]. PMID- 11612474 TI - [The medical work of the Second Field Army in the period of China's war of liberation] (Chi). PMID- 11612475 TI - [Textural research on the life of Ran Xue-feng, a renowned physician in modern China] (Chi). PMID- 11612476 TI - [Study on adoption of remained contents of the lost Xiao Er Yi Fang Miao Xuan (the excellent selection of children's recipes)] (Chi). PMID- 11612477 TI - [Literature research on the use of medicinal thread in some ulcerous diseases in TCM] (Chi). PMID- 11612478 TI - [Study on the monographs about Jin Kui Yao Lue (synopsis of prescriptions of the Golden Chamber) in the past dynasties] (Chi). PMID- 11612479 TI - [The achievements on the science of moxibustion in the Qin and Han dynasties] (Chi). PMID- 11612480 TI - [An investigation on the medicine of the Oroqen nationality, inhabited in Heilongjiang Province] (Chi). PMID- 11612481 TI - [In commemoration of the 140 anniversary of William Osler's birthday] (Chi). PMID- 11612482 TI - [A brief history of psychosomatic medicine] (Chi). PMID- 11612483 TI - [Reminiscence of the Central China Medical College in the period of war of resistance against Japan (1937-1945)] (Chi). PMID- 11612484 TI - The gospel and science of health: hygenic ideology in America, 1830-1920. PMID- 11612485 TI - The first world war: healthy or hungry? PMID- 11612486 TI - Patients and practitioners: virtues and vices of the new social history of medicine. PMID- 11612487 TI - Institutionalized ambiguity: conflict and continuity in the American hospital. PMID- 11612488 TI - Uncovering the hidden history of people with disabilities. PMID- 11612490 TI - The firing of man and animals. PMID- 11612489 TI - A burning issue. PMID- 11612492 TI - Sons of Thomond. PMID- 11612491 TI - Farriers and other veterinary workers in the London trades directories, Group II, 1800-1811. PMID- 11612493 TI - Gerald Grob's The state and the mentally ill: a turning point in the study of the American mental hospital. PMID- 11612494 TI - The ethics of using Nazi medical data. A Jewish perspective. PMID- 11612495 TI - Losing patients: culture, consumption and popular ideas about science and medicine. PMID- 11612496 TI - Making medical institutions. PMID- 11612497 TI - Exploring the dangerous trades. PMID- 11612498 TI - Relations of literature and science 1987-88; general studies, antiquity, Middle Ages, Renaissance, seventeenth and eighteenth centuries, nineteenth century, twentieth century. PMID- 11612499 TI - Editorial - Leslie T. Morton. PMID- 11612500 TI - Leslie Morton and the US. PMID- 11612501 TI - The future of the "Garrison-Morton" bibliography. PMID- 11612502 TI - The history of 'Garrison-Morton': a personal account. PMID- 11612503 TI - The importance of the study of the history of medicine. PMID- 11612504 TI - F. C. Pybus: the man and his books. PMID- 11612505 TI - The people their own physicians: 2000 years of patient information. PMID- 11612506 TI - Medical tradition and medical libraries in Japan. PMID- 11612507 TI - The NHS Regional Librarians Group. PMID- 11612508 TI - "The wilful communication of a loathsome disease": marital conflict and venereal disease in Victorian England. PMID- 11612509 TI - Benjamin Rush and the humane treatment of animals. PMID- 11612510 TI - The history of veterinary medicine in Alabama, 1892-1952. PMID- 11612511 TI - Bibliographic briefs on Hermann M. Biggs, M.D., and three other physicians--all honorary members of the American Veterinary Medical Association. PMID- 11612512 TI - A survey of veterinary medical history instruction in United States and Canadian schools. PMID- 11612513 TI - Why document veterinary medical history and collect and preserve the materials? PMID- 11612514 TI - Pepys on pox. PMID- 11612515 TI - The heroes in white. PMID- 11612516 TI - Changing concepts of lactose maldigestion. PMID- 11612517 TI - Highlights of medical research at the South African Institute for Medical Research. PMID- 11612518 TI - [Problems in theory of industrial health technology. (1) Points of the controversy (1962) between K. Kogi and J. Hashimoto] (Jpn). PMID- 11612519 TI - Into the whirlwind of suffering: resistance and transformation. PMID- 11612520 TI - The death and dying movement: psychologies and the formation of culture. PMID- 11612521 TI - Plague, piety, and policy. PMID- 11612522 TI - The campaign against odors: sanitarians and the genesis of public health in Charlottetown, Prince Edward Island (1855-1900). PMID- 11612523 TI - Sustained effects of the 1974-75 famine on infant and child mortality in a rural area of Bangladesh. PMID- 11612524 TI - Rapid estimations of maternal mortality in countries with defective data. An application to Bamako (1974-85) and other developing countries. PMID- 11612525 TI - Structural change in life cycle fertility during the fertility transition: France before and after the Revolution of 1789. PMID- 11612526 TI - Fertility decline in Czechoslovakia during the last two centuries. PMID- 11612528 TI - Cultural and historical factors in the population decline of the Parsis of India. PMID- 11612527 TI - On the origins of the United States Government's international population policy. PMID- 11612529 TI - Matters of life and death: the social and cultural conditions of the rise of anatomical theatres, with special reference to seventeenth century Holland. PMID- 11612530 TI - Pus, sewage, beer and milk: microbiology in Britain, 1870-1940. PMID- 11612532 TI - The establishment of basic medical science departments in the School of Dentistry, University of the Witwatersrand, Johannesburg. PMID- 11612531 TI - Luke, alone, is with me. PMID- 11612533 TI - Joseph Lister and antisepsis in midwifery. PMID- 11612534 TI - Doctor Arthur Conan Doyle's South African adventures. PMID- 11612535 TI - [On the origin and development of pulsological techniques in the pre-Han period] (Chi). PMID- 11612536 TI - [On Danxi's theory and the medical thinkings of the early Ming dynasty] (Chi). PMID- 11612537 TI - [The origin and development of heated-needling] (Chi). PMID- 11612538 TI - [A historical review of patriotic health campaign in China] (Chi). PMID- 11612539 TI - [The establishment of epidemic prevention bureau in Shaanxi and its main contributions] (Chi). PMID- 11612540 TI - [The first educational institution of acupuncture-moxibustion in China] (Chi). PMID- 11612541 TI - [The medicine of ancient Yue-people] (Chi). PMID- 11612542 TI - [sDe-rid Sangs-rgyas rGya-mtsho, a Tibetan medical historian] (Chi). PMID- 11612543 TI - [Exploration on herbology of Kai-Bao period (Kai Bao Bin Cao)] (Chi). PMID- 11612544 TI - Francis Kolar and chromotherapy. PMID- 11612545 TI - Major Bertrand De Jarnette: six decades of sacro occipital research, 1924-1984. PMID- 11612546 TI - National Institute of Chiropractic Research (NICR). Titles and abstracts of historical articles in critically reviewed periodicals, 1989-90. PMID- 11612547 TI - Joy Loban and Andrew P. Davis: itinerant healers and "schoolmen," 1910-1923. PMID- 11612548 TI - The genius of D. D. Palmer: an exploration of the origin of chiropractic in his time. PMID- 11612549 TI - A history of the Delta Sigma Chi fraternity of chiropractic. PMID- 11612550 TI - Fred Rubel: the first black chiropractor? PMID- 11612551 TI - From culture as organism to organism as cell: historical origins of bacterial genetics. PMID- 11612552 TI - Stabilizing instability: the controversy over cyclogenic theories of bacterial variation during the interwar period. PMID- 11612553 TI - The problem of natural antibodies, 1894-1905. PMID- 11612554 TI - Black death and the silver lining: meaning, continuity, and revolutionary change in histories of medieval plague. PMID- 11612555 TI - Aristotle's cardiocentric model of animal locomotion. PMID- 11612556 TI - Essay review: gender and the scientific "civilizing process". PMID- 11612557 TI - Book Review Issue. PMID- 11612558 TI - A survey of Bengali writings on science and technology, 1800-1950. PMID- 11612559 TI - S'riyantra--the ancient instrument to control the psychophysiological state of man. PMID- 11612560 TI - A comparative study of Chinese cosmology-cum-humorology with eight elements. PMID- 11612561 TI - Rasa ratna samuccaya. Sixth chapter, Sanskrit text, English translation, notes. PMID- 11612563 TI - The five souls of Indian medicine. PMID- 11612562 TI - Chemical research in India during nineteenth century. PMID- 11612564 TI - Three phases of magic squares of three. PMID- 11612565 TI - Ali ibn Rabban at-tabari, a ninth century Arab physician, on the ayurveda. PMID- 11612566 TI - Some reflections on the history of medicine. PMID- 11612567 TI - The Ergebnisse der allgemeinen Pathologie: a forgotten chapter in the literature of veterinary pathology. PMID- 11612568 TI - Pioneers in animal reproduction - I. PMID- 11612569 TI - Karl Ernst von Baer (1792-1876). Kurze Ubersicht seines Lebens. PMID- 11612570 TI - Infanticide, its judicial resolution, and criminal code revision in early Pennsylvania. PMID- 11612571 TI - The word Kkohala in Susruta and term alcool-vini of Paracelsus. PMID- 11612572 TI - Minerals and gems in Indian alchemy. PMID- 11612573 TI - Ayurvedasara or virabhattiya of Revanasiddha. PMID- 11612574 TI - Egyptian medical papyri. PMID- 11612575 TI - Medical manuscripts of Qutub Shahi period in the libraries of Hyderabad. PMID- 11612576 TI - Selected articles on medical history from Hindi journals, 1984-1989. PMID- 11612577 TI - Bibliography of the articles in Bulletin of the Indian Institute of History of Medicine (1986-89). PMID- 11612578 TI - History of medicine and the contribution of Hahnemann. PMID- 11612579 TI - The Calcutta Collection of the Wellcome Institute for the History of Medicine. PMID- 11612580 TI - Growth of the hospital system in Hyderabad - historical and demographic aspects: 1880's-1950's. PMID- 11612581 TI - Medicine under the royal patronage of Asafia kings. PMID- 11612583 TI - Salient features of Dhanvantari, a less-known Ayurvedic treatise. PMID- 11612582 TI - Ayurveda in the eighteenth and nineteenth centuries. PMID- 11612585 TI - Edward's patent feeding bottle. PMID- 11612586 TI - General practice pharmacy in the 1840s. (Part two). PMID- 11612588 TI - The social biases of environmental change in Gary, Indiana, 1945-1980. PMID- 11612589 TI - Makeshift technology: water and politics in 19th-century Philadelphia. PMID- 11612590 TI - Dietary modernization. PMID- 11612591 TI - Charities or businesses? American hospitals in the twentieth century. PMID- 11612592 TI - Environmental, safety and health issues at U.S. nuclear weapons production facilities, 1946-1988. PMID- 11612594 TI - Tragic figures: thoughts on the visual arts and anatomy. PMID- 11612595 TI - Family planning services: a history of U.S. federal legislation. PMID- 11612596 TI - Family contexts of fertility and infant survival in nineteenth-century Montreal. PMID- 11612598 TI - Pearl Harbor and the Emperor's physiologists. PMID- 11612597 TI - Five discourses on desire: sexuality and gender in northern France around 1200. PMID- 11612599 TI - The smoking gun of eugenics. PMID- 11612600 TI - The victory of psychiatry over demonology: the origin of the nineteenth-century myth. PMID- 11612601 TI - J. Chr. A. Heinroth (1773-1843): a psychiatrist of the German romantic era. PMID- 11612602 TI - Thomas Laycock and the cerebral reflex: a function arising from and pointing to the unity of nature. PMID- 11612604 TI - Hidden philosophy and theology in Morel's theory of degeneration and nosology. PMID- 11612603 TI - De Clerambault's concept of erotomania and its place in his thought. PMID- 11612605 TI - Amok in nineteenth-century British Malaya history. PMID- 11612606 TI - Lunacy in seventeenth- and eighteenth-century England: analysis of Quarter Sessions records. Part I. PMID- 11612608 TI - Essential requirements of the [Americans with Liabilities] Act: a short history and overview. PMID- 11612607 TI - Historical-critical presentation of the theories on the nature and seat of mental diseases. PMID- 11612610 TI - Correspondence [on the teaching of medical history]. PMID- 11612609 TI - The dominance of traits in genetic analysis. PMID- 11612611 TI - The celebrated abortion trial of Dr. Emily Stowe, Toronto, 1879. PMID- 11612612 TI - "Keep your seats and face facts": western Canadian women's discussion of birth control in the 1920s. PMID- 11612613 TI - Advice to parents: the Blue Books, Helen MacMurchy, MD, and the federal Department of Health, 1920-34. PMID- 11612614 TI - Making a difference: the history of Canada's nurses. PMID- 11612615 TI - Abraham Groves (1847-1935): a pioneer Ontario surgeon, sufficient unto himself. PMID- 11612616 TI - A guide to historical records in hospitals in London, England and Ontario, Canada, c. 1800-c. 1950. Part 1: An overview of the continuities and changes in the content and the forms of records. PMID- 11612618 TI - Public health and progressive dairying in Illinois. PMID- 11612617 TI - Groves' amputation knife. PMID- 11612619 TI - The 1891 census and local population studies. PMID- 11612620 TI - A philosophical perspective on the mind-body problem or, why neuroscientists and psychologists should care about philosophy. PMID- 11612621 TI - William Bosworth Castle (October 21, 1897-August 9, 1990). PMID- 11612622 TI - Alexander Ludwig von Muralt (August 19, 1903-May 28, 1990). PMID- 11612623 TI - Social insurance and public assistance: the influence of gender in welfare thought in the United States, 1890-1935. PMID- 11612624 TI - Exporting scientific instruments around 1700: the Musschenbroek documents in Marburg. PMID- 11612625 TI - Introduction: the GRO and the historians. PMID- 11612626 TI - Statistics and the science of society in early Victorian Britain; an intellectual context for the General Register Office. PMID- 11612627 TI - The GRO and the Public Health movement in Britain, 1837-1914. PMID- 11612628 TI - Disease, febrile poisons, and statistics: the census as a medical survey, 1841 1911. PMID- 11612629 TI - The GRO and the provinces in the nineteenth century. PMID- 11612630 TI - The US Bureau of the Census in the nineteenth century. PMID- 11612631 TI - Official statistics and medicine in nineteenth-century France: the SGF as a case study. PMID- 11612632 TI - The 150th anniversary of the Edinburgh Medical Missionary Society. PMID- 11612633 TI - Hogarth and the art of alcohol abuse. PMID- 11612634 TI - Seventeenth century Edinburgh surgeons: trade or profession? PMID- 11612635 TI - The restoration of number 8 Queen Street. PMID- 11612636 TI - The pharmaceutical writings of Gilbertus Anglicus. PMID- 11612638 TI - Pharmacists and physicians: an uneasy relationship. PMID- 11612637 TI - Occupational inheritance in American pharmacy. PMID- 11612639 TI - Aconitum: genus of powerful and sensational plants. PMID- 11612640 TI - Italian renaissance drug jars in southern collections. PMID- 11612641 TI - Robert Wooffendale, chemist, druggist and dentist: the making a reputation. PMID- 11612642 TI - Pharmacy in the 1840s: the wholesale chemists and druggists. PMID- 11612645 TI - Jewish apothecaries and surgeons in eighteenth century London. PMID- 11612646 TI - It never dies: assessing the Nazi analogy in bioethics. PMID- 11612647 TI - Vincent: is this madness? PMID- 11612648 TI - Medical and neuropsychiatric aspects of lycanthropy. PMID- 11612649 TI - London's mortality in the "long eighteenth century": a family reconstitution study. PMID- 11612650 TI - Health and housing in Victorian London. PMID- 11612651 TI - New urban demands in early modern London. PMID- 11612652 TI - Caring for the sick poor in St Bartholomew's Exchange: 1580-1676. PMID- 11612653 TI - Cleaning up the Great Wen: public health in eighteenth-century London. PMID- 11612654 TI - Parish pump to private pipes: London's water supply in the nineteenth century. PMID- 11612655 TI - Cholera, nuisances and environmental management in Islington, 1830-55. PMID- 11612656 TI - Ideological currents and the interpretation of demographic trends: the case of Francis Amasa Walker. PMID- 11612657 TI - Carl Jung and Max Wertheimer on a priority issue. PMID- 11612658 TI - Skirting the abyss: a history of experimental explorations of automatic writing in psychology. PMID- 11612659 TI - Some features of the Anatomy Department, University of the Witwatersrand 1923 1928. PMID- 11612660 TI - "The Lancet" and the South African War: the first period October 1899-June 1900. PMID- 11612661 TI - Plague in the twentieth century with special reference to southern Africa. PMID- 11612662 TI - The Piltdown skull forgery and Taung: rejection and acceptance in science - and new revelations on the identity of the forger (part I). PMID- 11612664 TI - Psychological concepts and psychiatric symptomatology in some ancient Chinese medical texts. PMID- 11612663 TI - The life and work of Professor Werner Janzarik. PMID- 11612665 TI - Lunacy in seventeenth- and eighteenth-century England: analysis of Quarter Sessions records. Part II. PMID- 11612666 TI - Eighteenth-century madhouse practice: the Prouds of Bilston. PMID- 11612667 TI - 100 years of Heidelberg psychiatry. PMID- 11612668 TI - Karl Ludwig Kahlbaum (1828-1899) and the emergence of psychopathological and nosological research in German psychiatry. PMID- 11612669 TI - A certain archway: autoscopy and its companions seen in Western writing. PMID- 11612670 TI - A comparison of symptoms recorded from the same patients by an asylum doctor and 'a Constant Observer' in 1823. The implications for theories about psychiatric illness in history. PMID- 11612671 TI - Karl Philipp Moritz and the Journal of Empirical Psychology: an introductory note and a series of psychiatric case reports. PMID- 11612672 TI - The market for rare and antiquarian medical books. PMID- 11612673 TI - Practicing medicine along the Indiana frontier. PMID- 11612675 TI - The history of resistant rickets: a model for understanding the growth of biomedical knowledge. PMID- 11612674 TI - The "moral anatomy" of Robert Knox: the interplay between biological and social thought in Victorian scientific naturalism. PMID- 11612676 TI - Essay review: Race hygiene and Nazi medicine. PMID- 11612677 TI - Mortality and socio-economic status in two eighteenth-century Dutch vilages. PMID- 11612678 TI - Fertility in England: a long-term perspective. PMID- 11612679 TI - Two centuries of mortality change in central Japan: the evidence from a temple death register. PMID- 11612680 TI - The prevalence of chronic diseases during mortality increase: Hungary in the 1980s. PMID- 11612681 TI - Intentional age-misreporting, age-heaping, and the 1908 Old Age Pensions Act in Ireland. PMID- 11612682 TI - Journalists, broadcasters, scientific experts and public opinion. PMID- 11612683 TI - Speech and the chest in old English poetry: orality or pectorality? PMID- 11612684 TI - History, novelty, and progress in scholastic medicine. PMID- 11612685 TI - Theory, everyday practice, and three fifteenth-century physicians. PMID- 11612686 TI - The medical meaning of physica. PMID- 11612687 TI - Giovanni Argenterio and sixteenth-century medical innovation: between princely patronage and academic controversy. PMID- 11612688 TI - Girolamo Mercuriale's De modo studendi. PMID- 11612689 TI - The reception of Fracastoro's Theory of contagion: the seed that fell among thorns? PMID- 11612691 TI - The nature and limits of medical certitude at early fourteenth-century Montpellier. PMID- 11612690 TI - The construction of a philosophical medicine: exegesis and argument in Salernitan teaching on the soul. PMID- 11612692 TI - Jewish appreciation of fourteenth-century scholastic medicine. PMID- 11612693 TI - [Uber das Leben des Dejima-Faktoreiarztes Caspar Schamberger] (Jpn). PMID- 11612695 TI - [The lists of "Igakushi", graduates of Faculty of Medicine, University of Tokyo, in early Meiji era (2)] (Jpn). PMID- 11612694 TI - [The Royal Infirmary of Edinburgh and Agnes Vetch] (Jpn). PMID- 11612696 TI - ["A transcript of Dutch medicine" including prescriptions of F. von Siebold] (Jpn). PMID- 11612697 TI - [Historical materials on the medical system of Edo Shogunate (3)] (Jpn). PMID- 11612698 TI - [Not Available]. PMID- 11612699 TI - [On the relationship between the development of Buddhism and the spread and treatment of diseases] (Jpn). PMID- 11612700 TI - [Physicians during the Tempo-period in Nagoya] (Jpn). PMID- 11612701 TI - [Tezuka Ryosen, army doctor-in-chief of infantry regiments and his family] (Jpn). PMID- 11612702 TI - [Historical materials on the medical system of Edo Shogunate (4)] (Jpn). PMID- 11612703 TI - [A chronological table of Chinese medical books reprinted in Japan up to Edo period] (Jpn). PMID- 11612704 TI - On the making of sex hormones: research materials and the production of knowledge. PMID- 11612705 TI - The Rockefeller Foundation's medical policy and scientific research in Latin America: the case of physiology. PMID- 11612706 TI - Ecological theory and pest control practice: a study of the institutional and conceptual dimensions of a scientific debate. PMID- 11612707 TI - [A sketch on the pre-modern and modern history of pharmaceutical science and technology in the east and the west. II. The introduction of the pre-modern and modern pharmaceutical science and technology into Japan and the social background] (Jpn). PMID- 11612708 TI - [Studies on the crud drug "woniu". (II) On the original mollusks of "Yauansangluo"] (Jpn). PMID- 11612709 TI - [Studies on the spiders as folk medicines. (I) Medicinal spiders in China] (Jpn). PMID- 11612710 TI - [The transition of psychotropic drug in Japanese pharmacopoeia (JP). (Part 1) The transition of the standards and the testmethods of potassium bromide between JP I (1886) and JP V (1932) and the comparison with USP and BP] (Jpn). PMID- 11612711 TI - [The development of modern Japan's pharmaceutical industry. (Part 2) The circumstances of medical science and pharmacology viewed historically from the early Meiji era till the 19th year of Meiji (1886) when the pharmacopoeia of Japan was established] (Jpn). PMID- 11612712 TI - [History of opium poppy cultivation in Okayama prefecture] (Jpn). PMID- 11612713 TI - [The study of OTC-drugs estimation standing a point of health care (5) A signification of Hippocrates' medicine in the light of the present from view point of regulatory integration for physiological function and ecological adaptation for environment] (Jpn). PMID- 11612714 TI - [Yokusai Iinuma's herbarium of "sabina called in market"]. PMID- 11612715 TI - [The transition of psychotropic drugs in Japanese pharmacopoeia (JP) (Part 2) The transition of the standards and the testmethods of potassium bromide on JP V (1932) and JP VI (1951) and the comparison with USP XIV (1950) and BP VIII (1953)] (Jpn). PMID- 11612716 TI - [Historical review of insulin and its preparations in pharmacopoeia (I) Biological assays] (Jpn). PMID- 11612717 TI - [Ibuki-moxa and the culture in Edo era] (Jpn). PMID- 11612718 TI - [Uiroh tochinkoh and the culture of the Muromachi period and the Edo era] (Jpn). PMID- 11612720 TI - [Introduction and development of hygiene as one of the basic parts in the pharmaceutical sciences of Japan. 1. Meiji era] (Jpn). PMID- 11612719 TI - [The historic places of the herbal gardens at Yabe, Kumamoto] (Jpn). PMID- 11612721 TI - About history of pharmacy in Holland: an international story. PMID- 11612722 TI - [A consideration on the import of Chinese crude drugs for general use in the Meiji era (5) especially on the change of the exports of rhubarb from China to our country in the first to second half of the Meiji era] (Jpn). PMID- 11612723 TI - [The way for carrying medicine and its containers (II) The origin of inro] (Jpn). PMID- 11612724 TI - Transforming the work of the pharmacist: the need for historical perspective. PMID- 11612725 TI - The elusive history of High John the Conqueror Root. PMID- 11612726 TI - The personal papers of Donald E. Francke (1919-1978). PMID- 11612727 TI - Tomato pills will cure all your ills. PMID- 11612729 TI - The medical botany of John Bartram. PMID- 11612728 TI - Pharmaceutical museum in Bratislava. PMID- 11612730 TI - Animal-disease crisis in Peoria: actinomycosis; and meat inspection. PMID- 11612731 TI - Equine colic: from curse to cure. PMID- 11612732 TI - The origins of private social insurance: public policy and fringe benefits in America, 1920-1950. PMID- 11612733 TI - [Not Available]. PMID- 11612734 TI - [Not Available]. PMID- 11612735 TI - [Not Available]. PMID- 11612736 TI - [Not Available]. PMID- 11612737 TI - [Not Available]. PMID- 11612738 TI - [Not Available]. PMID- 11612740 TI - Causes of disease and death in the Babylonian Talmud. PMID- 11612739 TI - [Not Available]. PMID- 11612741 TI - Essay review: Science and politics in the nineteenth century. PMID- 11612742 TI - The acceptance of scientific theories and images of masculinity and femininity: 1959-1985. PMID- 11612743 TI - Reevaluating progressive eugenics: Herbert Spencer Jennings and the 1924 immigration legislation. PMID- 11612744 TI - Diseases associated with man and pig in the ancient Near East. PMID- 11612745 TI - A veterinary pathologist in two world wars. PMID- 11612746 TI - American Medical Association's Historical Health Fraud and Alternative Medicine Collection: an integrated approach to automated collection description. PMID- 11612747 TI - ['Mal de siment' in 16th-century Valencia: images of 'morbo gallico' (syphilis) in a Mediterranean European city]. PMID- 11612749 TI - [History of disease: new approaches and problems: a presentation]. PMID- 11612748 TI - [Medical testimony on the life and work conditions of miners in Almaden in the second half of the 18th century: the prologue of The catastrophic illness of the mercury mines of the village of Almaden del Azogue (1778) by Jose Pares y Franques (+1798)]. PMID- 11612750 TI - [From "mal de la rosa" to the "enfermedad de la miseria": the social etiology of pelagra in Asturian medical bibliography in the 18th and 19th centuries]. PMID- 11612752 TI - [Alcoholism as a social disease in Spain during the Restoration: problems of definition]. PMID- 11612753 TI - [Transformation of the Plague: the laboratory and the identification of infectious diseases]. PMID- 11612751 TI - [Venereal diseases in Spain in the last third of the 19th century: an approximation of the moral foundations of hygiene]. PMID- 11612754 TI - [Leprosy and society in Spain in the first half of the 20th century: the Colonia Sanatorio de Fontilles (1908-1932) and the process of intervention by the Second Republic]. PMID- 11612755 TI - [Exams for the white death: new trends in the historiography of tuberculosis. A review essay]. PMID- 11612756 TI - [But, for what disease is he being treated? The current state of studies on health and healing in Africa]. PMID- 11612757 TI - Anthropological identification and paleopathological study of a skeleton, probably pertaining to the Roman doctor from the I-II century B.C., Tiberius Claudius Apollinaris (Tarragona, Spain). PMID- 11612758 TI - On leaving the mine: historiographic resource exhaustion in antibiotics history. PMID- 11612759 TI - [Three unpublished manuscripts of Ignacio Maria de Luzuriaga (1763-1822) on naval hygiene]. PMID- 11612760 TI - [The Black Plague of 1348: the origins of its construction as a disease and a social calamity]. PMID- 11612761 TI - [In commemoration of the 90th anniversary of the medical historian Prof. Li Tao's birthday]. PMID- 11612762 TI - [Anti-malarial history in Hainan island] (Chi). PMID- 11612763 TI - [The important action off cultural exchange from central China on zhuang medicine] (Chi). PMID- 11612764 TI - [The history of ophthalmoscope] (Chi). PMID- 11612765 TI - [Traditional medicine in Europe] (Chi). PMID- 11612766 TI - [Personal opinion on the formation of Chinese medicine] (Chi). PMID- 11612767 TI - [A review on the medical scientists of Xujiang] (Chi). PMID- 11612768 TI - [Achievements in the anti-epidemic works in the Shaanxi-Gansu-Ningxia border region] (Chi). PMID- 11612769 TI - [Traditional Chinese medicine in the Soviet area of western Fujing] (Chi). PMID- 11612770 TI - [Profile of a Mongolian classical work Zheduiningzhur (selections of Mongolian medicine and materia medica)] (Chi). PMID- 11612771 TI - [A brief account of the achievements in acupuncture and moxibustion in the Tang dynasty] (Chi). PMID- 11612772 TI - Dearth and social policy in early modern England. PMID- 11612773 TI - John Bradmore and his book Philomena. PMID- 11612775 TI - Thistle on the Delaware: Edinburgh medical education and Philadelphia practics, 1800-1825. PMID- 11612774 TI - Contracting cancer? The politics of commissioned histories. PMID- 11612776 TI - Predisposing causes and public health in early nineteenth-century medical thought. PMID- 11612777 TI - Death in its season: class, environment and the mortality of infants in nineteenth-century Sheffield. PMID- 11612779 TI - After Binet: French intelligence testing, 1900-1950. PMID- 11612778 TI - Medicine, VD and prostitution in pre-Revolutionary China. PMID- 11612780 TI - Minds and machines in Renaissance Spain: Gomez Pereira's theory of animal behavior. PMID- 11612782 TI - Climates of opinion: acclimatization in nineteenth-century France and England. PMID- 11612781 TI - Orphans and family disintegration in Chile: the mortality of abandoned children, 1750-1930. PMID- 11612783 TI - The U.S. Public Health Service Commissioned Corps pharmacist: the evolution of professional practice. PMID- 11612784 TI - "Shaker-made" remedies. PMID- 11612785 TI - A panel discussion: the historical literature of American pharmacy PMID- 11612786 TI - Agatha Christie's drugs and disease. PMID- 11612787 TI - Magnetic healing, spiritualism and chiropractic: Palmer's union of methodologies, 1886-1895. PMID- 11612788 TI - The roots of Western States Chiropractic College 1904-1932. PMID- 11612789 TI - T. F. Ratledge, the missionary of straight chiropractic in California. PMID- 11612790 TI - [Physician historians and the pathology of leaders]. PMID- 11612791 TI - [Not Available]. PMID- 11612792 TI - The first chemist shops in Russia. PMID- 11612793 TI - Obstetric forceps and vectis: the roots. PMID- 11612794 TI - Health service prescription stamps. PMID- 11612795 TI - Introduction in pharmacy. PMID- 11612796 TI - The pharmaceutical industry: the true perspective. PMID- 11612797 TI - The pharmaceutical industry: the true perspective. PMID- 11612798 TI - Italian influences on Antoni van Leeuwenhoek. PMID- 11612800 TI - Contacts between Italian and Dutch scientists between 1750-1789. PMID- 11612799 TI - The editorial fortune of Bolognese scientists in Holland (1669-1726). PMID- 11612801 TI - The elegant anatomist. The Italian medical connections of Eduard Sandifort (1742 1814). PMID- 11612802 TI - Italian and Dutch universities in the sixteenth and seventeenth centuries. PMID- 11612803 TI - Religious healing in first-century Christianity. PMID- 11612804 TI - [Problems in theory of industrial health technology. (2) Basic categories of industrial health technology] (Jpn). PMID- 11612805 TI - [Not Available]. PMID- 11612806 TI - [Not Available]. PMID- 11612807 TI - [Not Available]. PMID- 11612808 TI - Signs and signboards of the pharmacy. PMID- 11612809 TI - [Not Available]. PMID- 11612810 TI - [Not Available]. PMID- 11612811 TI - [The medical materials which Dioscorides called metallic]. PMID- 11612812 TI - [Some memorable pharmaceutical personalities from the region of Charleroi]. PMID- 11612813 TI - [Not Available]. PMID- 11612814 TI - [Not Available]. PMID- 11612815 TI - [Not Available]. PMID- 11612816 TI - The changing role of the English apothecary. PMID- 11612817 TI - The state of the art of farriery in 1791. PMID- 11612818 TI - The 1937 study tour in Germany by students of the Royal Veterinary College, London. A personal introduction to foot and mouth disease research. PMID- 11612819 TI - Rabies and the Governor-General of Canada. PMID- 11612820 TI - Dr George Fussell. PMID- 11612821 TI - Thomas Burgess of Odiham and veterinary science. PMID- 11612823 TI - The absence of psychology in the eighteenth century: a linguistic perspective. PMID- 11612822 TI - Radiological weapons and radioactive waste in the United States: insiders' and outsiders' views, 1941-55. PMID- 11612824 TI - Experiment, difference, and writing: I. Tracing protein synthesis. PMID- 11612825 TI - Danger on the home front: motherhood, sexuality, and disabled veterans in American postwar films. PMID- 11612826 TI - "Lost manhood" found: male sexual impotence and Victorian culture in the United States. PMID- 11612827 TI - Of genes and men. PMID- 11612828 TI - The Leslie Matthews Medal. PMID- 11612830 TI - Pharmacy in the mid-nineteenth century. PMID- 11612833 TI - Guaranteed to cure: inventions for healing. PMID- 11612834 TI - The problems of teaching nursing history - twelve years on: a personal view of the progress. PMID- 11612838 TI - Shortages of nurses 1928-1935: was nursing going - or was nursing going on? PMID- 11612836 TI - Poor law nursing in Northamptonshire: from pauper to professional. PMID- 11612840 TI - Eva Charlotte Luckes: pioneer or reactionary? (1854-1919). PMID- 11612842 TI - Mahlon William Locke: "toe-twister." PMID- 11612843 TI - [About Zimmermann's medical experience]. PMID- 11612844 TI - Patent medicines in Imperial Germany. PMID- 11612845 TI - "Ignorant of any rational method": European assessments of indigenous healing practices in the North American Arctic. PMID- 11612846 TI - A guide to historical records in hospitals in London, England and Ontario, Canada c. 1800-c. 1950. Part 2: A consolidated list of records. PMID- 11612847 TI - From metals to human beings: medical aspects of European alchemy. PMID- 11612848 TI - Henna and psoriasis. PMID- 11612849 TI - Medicine under the royal patronage of Asafia kings. PMID- 11612852 TI - In defense of joy: C. S. Lewis and psychoanalysis. PMID- 11612850 TI - Principles, methods and importance of literary research in the history of Ayurveda. PMID- 11612851 TI - Treatment of anaemia with special reference to iron in ancient Indian medicine Ayurveda: a historical perspective. PMID- 11612854 TI - Narasimhapandita. PMID- 11612853 TI - Fifteen years after "animal liberation": Has the animal rights movement achieved philosophical legitimacy? PMID- 11612855 TI - The Bengali context. PMID- 11612856 TI - The term tria prima of Paracelsus explained and justified. PMID- 11612857 TI - Medical manuscripts of Qutub Shahi period in the libraries of Hyderabad. PMID- 11612858 TI - The Greek factor in Muslim pharmacy: a survey. PMID- 11612859 TI - The materia medica of Christopher Columbus PMID- 11612860 TI - Portraits of American pharmacy in German pharmacy journals from 1880 to 1950. PMID- 11612861 TI - Papers of the American Institute of the History of Pharmacy. PMID- 11612862 TI - Garlic--the pungent panacea. PMID- 11612863 TI - Roy Anderson Bowers, 1913-1992. PMID- 11612864 TI - New exposition in the Museum of Pharmacy at the Medical Academy of Cracow. PMID- 11612865 TI - [The miserable life of the Antwerp physician Jean Carolus (1), friend of C. Brockx and Ch. Daremberg: the canonical truth and the private version]. PMID- 11612866 TI - History of obstetrical forceps from 1750 to the present era. PMID- 11612867 TI - [The role of pharmaceuticals in the etiology of mental illness around 1850]. PMID- 11612869 TI - Almost forgotten, never told: the Griqualand West Medical Society (1882). PMID- 11612868 TI - [Not Available]. PMID- 11612870 TI - Luke and haemathidrosis. PMID- 11612871 TI - Academic medicine in South Africa: past, present and future. PMID- 11612874 TI - Psychoanalysis in historical writing. PMID- 11612872 TI - Men in nursing and the Royal College of Nursing. PMID- 11612875 TI - "Conceived in sins, born in delights": stories of procreation from early Ireland. PMID- 11612876 TI - "The word made flesh": language, authority, and sexual desire in late nineteenth century America. PMID- 11612877 TI - Demanding subjectivity: transsexualism, medicine, and the technologies of gender. PMID- 11612878 TI - What is the history of psychiatry? PMID- 11612879 TI - Phenomenology, psychopathology and Jaspers: a conceptual history. PMID- 11612880 TI - Eduard Hitzig, neurophysiologist and psychiatrist. PMID- 11612881 TI - The missing link: Schreber and his doctors. PMID- 11612882 TI - On periodic or intermittent mania. PMID- 11612883 TI - Caribbean psychiatry yesterday, today and tomorrow. PMID- 11612884 TI - Foundations, universities, and trends in support for the physical and biological sciences, 1900-1992. PMID- 11612885 TI - Anatomical wax modelling and the Northumberland Museum of the Royal College of Surgeons in Ireland. PMID- 11612886 TI - Patent medicine muckraking: influences on American pharmacy, social reform, and foreign authors. PMID- 11612887 TI - Old English patent medicines in America. PMID- 11612888 TI - [Modern Sino-Japanese exchanges in TCM] (Chi). PMID- 11612889 TI - [The lunar king of medicine (sMan-dpyad Zia-ba'i rGyal-po) and the extreme plainness of yellow emperor] (Chi). PMID- 11612890 TI - [Institutions of medical history in the period of the Republic of China (1912 1949)] (Chi). PMID- 11612892 TI - [Golden mirror of orthodoxy of medicine: its compilation and achievements] (Chi). PMID- 11612891 TI - [Investigation on some problems from Tao Hongjing's work on herbology] (Chi). PMID- 11612893 TI - [Contribution of the great compendium of Chinese materia medica to stomatology] (Chi). PMID- 11612894 TI - [The discerning of Zhang Zhongling's Methods of pulse feeling, on febrile and miscellaneous diseases] (Chi). PMID- 11612895 TI - The reasoning of the strongest: the polemics of skill and science in medical diagnosis. PMID- 11612896 TI - Science, sexuality, and gender in the fin de siecle: Otto Weininger as Baedeker. PMID- 11612897 TI - "The power of imagination": psychological explanations in mid-seventeenth-century England. PMID- 11612898 TI - Speaking of "science and religion"--then and now. PMID- 11612899 TI - Trends in numbers and mortality at high ages in England and Wales. PMID- 11612900 TI - Famine mortality in nineteenth-century Japan: the evidence from a temple death register. PMID- 11612901 TI - Migration, marriage, and mortality: correcting sources of bias in English family reconstitutions. PMID- 11612902 TI - Louis Henry (1911-1991). PMID- 11612903 TI - "Exploiting a wonderful opportunity": the patronage of scientific research at Stanford University, 1937-1965. PMID- 11612904 TI - Science and technology after Mao. PMID- 11612905 TI - Natural knowledge as cultural property: disputes over the 'ownership' of natural history in late eighteenth-century Edinburgh. PMID- 11612906 TI - The British Medical Journal and Koch's secret remedy. PMID- 11612907 TI - Pursued by genetics: an autobiographical disclosure. PMID- 11612908 TI - The history of psychoanalysis in France. PMID- 11612909 TI - New lives: differential receptions of psychobiographical writing by twentieth century historians. PMID- 11612910 TI - The Bishops' Census of 1563: its significance and accuracy. PMID- 11612911 TI - Childhood and sexual identity under slavery. PMID- 11612912 TI - Science and popular education in the 1830s: the role of the Bridgewater Treatises. PMID- 11612913 TI - Madness and degeneration, Part I. From 'fallen angel' to mentally ill. PMID- 11612914 TI - Schizophrenia as a permanent problem. Some aspects of historical evidence in the recency (new disease) hypothesis. PMID- 11612915 TI - Historical continuities and discontinuities between religious and medical interpretations of extreme fasting. The background to Giovanni Brugnoli's description of two cases of anorexia nervosa in 1875. PMID- 11612916 TI - The psychodynamic approach in American psychiatry: a case study in ethnomedicine. PMID- 11612918 TI - Introductory remarks on the translation of Emil Kraepelin's paper Die Erscheinungsformen des Irreseins (1920). PMID- 11612919 TI - Constructing histories of twentieth-century experimental life science: the promise and perils of archives. PMID- 11612920 TI - Sources in the history of American biology at the archives of the Stazione Zoologica "Anton Dohrn". PMID- 11612921 TI - [Medical historian Ernst Nachmanson and some notices on medical history instruction at our medical faculties in the past and the present]. PMID- 11612922 TI - [Gothenburg's Florence Nightingale--on nurse Emma Klingberg at the General and Sahlgrenska hospital]. PMID- 11612923 TI - [The history of the artificial eye]. PMID- 11612925 TI - [Biology research in Uppsala during the 1940's]. PMID- 11612924 TI - [The Satra Brunn spa--from ritual water healing to modern rehabilitation]. PMID- 11612926 TI - Pathogenic life-styles, morbid cravings and euphorophilia: a case for historians and futurologists. PMID- 11612927 TI - [Carl Sandstedt--a biography]. PMID- 11612928 TI - [Dental care is recognized as a social right in 1920's Sweden]. PMID- 11612929 TI - [The Eastman Institute. An institution for children's dental health]. PMID- 11612930 TI - ["Putting medicine back in its right and natural state." Why did Boerhaave have such great influence in Sweden during the first half of the 18th century?]. PMID- 11612931 TI - [On the milieus of our oldest hospitals]. PMID- 11612932 TI - [On Antoni van Leeuwenhoek, and on the production of and work with small lenses]. PMID- 11612933 TI - [Mysteries surrounding Gregor Mendel and his research]. PMID- 11612934 TI - [Wilhelm Conrad Rontgen]. PMID- 11612935 TI - [Radiology's contribution to the progress of medicine]. PMID- 11612936 TI - Illness and the origin of caring. AB - In recent years, many in medical education have examined the question of how best to reinvigorate the doctor-patient relationship, given the increasing technological distance that has emerged between them in modern medicine. In this paper it is argued that "humanism" and caring in medicine reflect the quality of transitional relatedness in the illness condition, a significant separation attachment phase of life. By improving our understanding of the origin of caring, educational strategies for physicians in training may improve as might our abilities to provide care. PMID- 11612937 TI - Aristotle's biology and the transplantation of organs. PMID- 11612938 TI - Essay review: the eugenics industry--growth or restructuring? PMID- 11612939 TI - From enlightenment to Naturphilosophie: Marcus Herz, Johann Christian Reil, and the problem of border crossings. PMID- 11612941 TI - The origin of DNA:RNA hybridization. PMID- 11612940 TI - Redrawing the boundaries of molecular biology: the case of photosynthesis. PMID- 11612942 TI - Histories of the sciences and their uses: a review to 1913. PMID- 11612943 TI - Controlling the experiment: rhetoric, court patronage and the experimental method of Francesco Redi. PMID- 11612944 TI - Hustlers and patrons of science. PMID- 11612945 TI - Child abuse and creativity: a new look at Sherwood Anderson's breakdown. PMID- 11612946 TI - Indian medicine wheels and placentas: how the tree of life and the circle of life are related. PMID- 11612947 TI - Of 'science and liberty': the scientific instruments of King's College and eighteenth century Columbia College in New York. PMID- 11612948 TI - Madness and degeneration, II. Alcoholism and degeneration. PMID- 11612949 TI - To cure those afflicted with the disease of insanity: Thomas Bakewell and Spring Vale Asylum. PMID- 11612950 TI - The dissolution of dementia praecox. PMID- 11612951 TI - The seduction theory. PMID- 11612952 TI - War and psychiatry: examining the diffusion theory in light of the insanity defence in post-World War I Britain. PMID- 11612953 TI - Sleep as a cure for schizophrenia: a historical episode. PMID- 11612954 TI - County of Lancaster Asylum, Rainhill: 100 years ago and now. PMID- 11612955 TI - Gleanings from Sukla Yajurveda. PMID- 11612956 TI - Some views based on the survey of medical manuscripts and practitioners. PMID- 11612957 TI - Roots of Andalusian Islamic medicine in the European civilisation. PMID- 11612958 TI - Hakim Ziyauddin Nakshabi's contribution to Unani medicine during 14th century in India. PMID- 11612959 TI - Medical manuscripts of Qutub Shahi period in the libraries of Hyderabad. PMID- 11612960 TI - Cakrapanidatta. PMID- 11612961 TI - History of cataract surgery. PMID- 11612962 TI - Therapy and medicaments by Ibn al-Nafis. PMID- 11612963 TI - Razi's treatise Bar-us-sa'ah on first aid and some medicinal plants used to assist such conditions. PMID- 11612964 TI - History of Ayurveda in 'Islami Tibb'. PMID- 11612965 TI - Introduction to Madhavanidana. PMID- 11612966 TI - Child-birth and child-care in medieval Andhra society. PMID- 11612967 TI - The 1850 Harvard Medical School dispute and the admission of African American students. PMID- 11612968 TI - [Development and historical background of China's modern orthopedics] (Chi). PMID- 11612969 TI - [Discovery of filariasis in Fujian Province and its basic eradication] (Chi). PMID- 11612970 TI - [Organization of public health in Jiangxi Province (1934-1949)] (Chi). PMID- 11612971 TI - [A short biography of Huang Kuan] (Chi). PMID- 11612972 TI - [A new evidence for the writing date of Master Lei's essay on drug processing] (Chi). PMID- 11612973 TI - [Some idea on Chen Cang-qi's Supplementary herbology and its level in natural sciences]. PMID- 11612974 TI - [On the significance of Dunhuangological medicine] (Chi). PMID- 11612975 TI - [On the conceptual history of TCM] (Chi). PMID- 11612976 TI - [The developmental process of the 12-channel theory as viewed from Inner Canon of Yellow Emperor] (Chi). PMID- 11612977 TI - [Ponderation aroused from the medical suit case of Renzong and Yingzong emperors of the Northern Song dynasty] (Chi). PMID- 11612979 TI - [Medical exchange between the Tang dynasty and Tubo dynasty] (Chi). PMID- 11612978 TI - [Gain and loss of medical development in the Ming dynasty] (Chi). PMID- 11612980 TI - [General interpretation of the transliteration of Book of Channels and Book of Stretching, the bamboo slips unearthed in Zhangjia Shan's Han tomb] (Chi). PMID- 11612981 TI - [Textual study on Xu Zhicai's Medical couplet] (Chi). PMID- 11612983 TI - [Ruins of underground water supply project in Yangcheng in Warring States showing the stress of drinking sanitation] (Chi). PMID- 11612982 TI - [Two evidences for the creation of "Shiji" (ten forms of recipes) by Chen Cangqi] (Chi). PMID- 11612984 TI - [The influence of social factors on literatures of Chinese pharmacology] (Chi). PMID- 11612985 TI - Biography of Lu Gwei-Djen. PMID- 11612986 TI - [On the shifting of stress point in the study of history of medicine] (Chi). PMID- 11612987 TI - [Central Hospital of Yan'an during the period of anti-Japanese War] (Chi). PMID- 11612988 TI - [Chronicle of modern physiology in China] (Chi). PMID- 11612989 TI - [Ding Fubao and Sino-Japanese medical exchanges of traditional medicine] (Chi). PMID- 11612990 TI - [Brief history of laboratory technique on the examination of helicobacter pylori] (Chi). PMID- 11612991 TI - [History of study on electroretinography] (Chi). PMID- 11612992 TI - [Application of white sugar in Tibetan and Mongolian therapies] (Chi). PMID- 11612993 TI - 'The witnesses' in Davenport: was Brady and Third chiropractic's Dealey Plaza in August 1913? PMID- 11612994 TI - Sylva L. Ashworth, D.C., the "Grand old lady of chiropractic." PMID- 11612995 TI - Chiropractor's struggle for legal recognition: balancing rights and protections. PMID- 11612996 TI - Pseudo-chiropractors: the correspondence school experience, 1912-1935. PMID- 11612997 TI - Merging with honor: a history of the Missouri Chiropractic College, 1920-64. PMID- 11612998 TI - Old Dad Chiro and extravertebral manipulation. PMID- 11612999 TI - The Royal College of Physicians and Irish medicine. PMID- 11613000 TI - Irish students at Leiden and the renaissance of medicine in Dublin. PMID- 11613001 TI - Botany and medicine; Dublin and Leiden. PMID- 11613002 TI - Robert Boyle: a major contributor to European science. PMID- 11613003 TI - John Locke and the college charter. PMID- 11613004 TI - Doc Painter and the mighty New York Yankees ... Ruth, DiMagio and Gehrig were his patients. PMID- 11613005 TI - 'Mom & Pop' chiropractic schools in Kansas. PMID- 11613006 TI - 'The great backward state': the 50-year struggle in New York, 1913-1963. PMID- 11613008 TI - Lost technology: the rise and fall of chiropractic instrumentation. PMID- 11613007 TI - Legalizing chiropractic by initiative petition and referendum, 1918-1922. PMID- 11613009 TI - The evolution of higher education in chiropractic: a survey 1906-74. PMID- 11613010 TI - More baseball: 'another coat of Painter'. PMID- 11613012 TI - Recollections of a mental hospital dentist. PMID- 11613011 TI - The Chapple amendment: parliamentary intervention and the General Nursing Council. PMID- 11613013 TI - A village school perspective. PMID- 11613015 TI - The late Miss G.E. Treble - Winchester nursing sister: portrait of a nurse in the inter war period PMID- 11613016 TI - The Lonsdale affair: a nineteenth century struggle for nurse power. PMID- 11613017 TI - Yellow fever, folio, and the new public health. PMID- 11613018 TI - The therapeutic state as "humane nurse": the evolution off discourse, policies, and services. PMID- 11613019 TI - Decline and fall. PMID- 11613020 TI - When is mortality risk determined? Historical insights into a current debate. PMID- 11613021 TI - "General practice' in seventeenth-century Edinburgh: evidence from the Burcgh Court. PMID- 11613022 TI - The archives of the British Red Cross. PMID- 11613023 TI - A pioneer in infant welfare: the Huddersfield scheme 1903-1920. PMID- 11613024 TI - Museums of Madness revisited. PMID- 11613025 TI - Mothers, babies, and the mothers and babies movement: Australia through depression and war. PMID- 11613026 TI - Smallpox, subfecundity, and sterility: a case study from a nineteenth-century Dutch municipality. PMID- 11613027 TI - Early stages of human development in the light of the Quran, Hadith andscience. PMID- 11613028 TI - Psychiatry: an Islamic approach. PMID- 11613029 TI - The concept of quackery in early nineteenth century British medical periodicals. PMID- 11613030 TI - The relationships of science and religion. PMID- 11613031 TI - Annotated bibliography. PMID- 11613032 TI - Veterinary specimens of congenital malformations of the Vrolik Collection. PMID- 11613033 TI - A symbol in veterinary medicine: centaurs or Chiron? PMID- 11613034 TI - Pioneers in animal reproduction III. PMID- 11613035 TI - [Not Available]. PMID- 11613036 TI - Aberdonians, insulin and marine biology: the pelagic connections. PMID- 11613037 TI - Practitioners versus legislators: the shaping of the Scottish vaccination act. PMID- 11613039 TI - Sigmund Freud: neurologist. PMID- 11613038 TI - Did Christopher Douglas provide the first description of coeliac disease in 1793? PMID- 11613040 TI - Rheumatoid arthritis: a link with Columbus? PMID- 11613041 TI - Mobile hospitals and Sherman's Atlanta campaign. PMID- 11613042 TI - Spinal manipulation in the 11th century Middle East. PMID- 11613044 TI - Minnesota, 1905: who killed the first chiropractic legislation? PMID- 11613043 TI - The legitimation of chiropractic: the first thirty years, 1900-1935. PMID- 11613045 TI - Joseph W. Howe: A pioneer in the evolution of chiropractic radiology. PMID- 11613046 TI - The limits of medicine: a social history of chiropractic, 1895-1930. PMID- 11613047 TI - Biography, culture, and science: the formative years of Robert Boyle. PMID- 11613048 TI - Patients and healers in late Imperial China: evidence from the Jinpingmei. PMID- 11613049 TI - Pasteur on lactic acid yeast: a partial semiotic analysis. PMID- 11613050 TI - Spiderwoman and the chaste tree: the semantics of matter. PMID- 11613051 TI - J. J. R. Macleod: the co-discoverer of insulin. PMID- 11613052 TI - The first four consulting physicians of Leith Hospital. PMID- 11613053 TI - J. D. Comrie--Archangel journal: part II. PMID- 11613054 TI - Time was when youth grew pale, and spectre thin, and died. PMID- 11613055 TI - On the historical relationship between infant and adult mortality. PMID- 11613056 TI - The contraceptive pill and women's employment as factors in fertility change in Britain 1963-1980: a challenge to the conventional view. PMID- 11613057 TI - The modern shift to below-replacement fertility: has Israel's population joined the process? PMID- 11613059 TI - The creation of postdoctoral fellowships and the siting of American scientific research. PMID- 11613058 TI - High fertility, high emigration, low nuptiality: adjustment processes in Scotland's demographic experience, 1861-1914, Part II. PMID- 11613060 TI - Sanitarians, engineers and public science in the gilded age. PMID- 11613061 TI - Landmarks in the historical development of fluorescein angiography. PMID- 11613064 TI - The German Hospital--a unique story. PMID- 11613062 TI - Gartnavel Royal Hospital, Glasgow: its foundation and early history. PMID- 11613067 TI - Recollections of nursing in the 1930s. PMID- 11613071 TI - Tuberculosis amongst New Zealand nurses, 1940-1950. PMID- 11613068 TI - The servant, the poet and the doctor: an example of 18th century psychiatric care. PMID- 11613072 TI - [The cause of health care established by overseas Chinese of Fujian Province in modern age] (Chi). PMID- 11613073 TI - [Spreading of western medicine into Weifang region of Shandong Province] (Chi). PMID- 11613075 TI - [Time features of the Medical theory in classic of questioning (Nanjing)] (Chi). PMID- 11613074 TI - [Textual research on Bian Que (Qin Yueren)'s native place] (Chi). PMID- 11613076 TI - [A review on the writing date of Extreme plainness of inner canon ofyellow emperor] (Chi). PMID- 11613077 TI - [Fujianese folklore and hygienic charitable undertakings] (Chi). PMID- 11613078 TI - [Exploration on the average life span of prehistoric Chinese] (Chi). PMID- 11613079 TI - [Abolishment, persistence and rehabilitation of kampo medicine during Meiji reform and its influence on China] (Chi). PMID- 11613080 TI - [Characteristics of medicine of Yao minority and its modalities of heritage] (Chi). PMID- 11613081 TI - [Study on Cui Hao's Classic of food in the northern Wei Dynasty] (Chi). PMID- 11613082 TI - [Sex education in schools in the period of late Qing Dynasty to early Republic]. (Chi). PMID- 11613083 TI - [Quantitative analysis of herbal classic at the time of its compilation] (Chi). PMID- 11613084 TI - Medical history: today's perspectives. PMID- 11613085 TI - Typhoid fever: the stimulation and delaying factors in the reform of the government hospital system in Western Australia. PMID- 11613087 TI - Harvey House and the West Australian Medical Museum. PMID- 11613086 TI - The New Zealand hospital system 1876-1910. PMID- 11613088 TI - St John Ambulance and the Western Australian State Ambulance Service. PMID- 11613089 TI - Designing premises for general practitioners, 1945-1960. PMID- 11613090 TI - E. G. Saint--professor of medicine, University of Western Australia. PMID- 11613091 TI - Spinal man--the historical years for spinal cord injury in Western Australia, 1947-1955. PMID- 11613092 TI - The hospice and pallitive care movement in Western Australia. PMID- 11613093 TI - Naval surgeons in Western Australia. PMID- 11613094 TI - Wilson Inlet and Denmark River, Western Australia--the linked Australian memorials and lives of two Royal Naval surgeons. PMID- 11613095 TI - Dr Thomas Braidwood Wilson R. N. surgeon explorer in Australia. PMID- 11613096 TI - Agent orange: its Australian aftermath. PMID- 11613097 TI - The Camp Hospital for Venereal Diseases, Langwarrin, Victoria. PMID- 11613098 TI - Malaria in the nineteenth century military settlements of the Northern Territory. PMID- 11613099 TI - Julius Wagner-Jauregg: a forgotten benefactor. PMID- 11613100 TI - The aetiology of malaria: the race for the prize. PMID- 11613101 TI - The origins of school medicine in New Zealand. PMID- 11613102 TI - From Gumnut babies to Koorie kids. PMID- 11613103 TI - Frederic Wood Jones. His impact on Australian medicine and scientific thought. PMID- 11613104 TI - Tuberculosis and the Maori, 1900-1960. PMID- 11613105 TI - The contribution of surgeon Gaimard to the record of French maritime exploration. PMID- 11613106 TI - Reflections of paediatric morbidity in Western Australia. PMID- 11613107 TI - Pioneer medical men in Western Australia: 1829-1900. PMID- 11613108 TI - Development of paediatrics. PMID- 11613109 TI - The Islamic personality and Jihad in history. PMID- 11613110 TI - Teaching history to health care workers. PMID- 11613111 TI - Scurvy, lemon juice and naval discipline. PMID- 11613112 TI - Succour and supply--the role of the amity in Australian exploration. PMID- 11613113 TI - Amity, Albany and Surgeon Superintendent Thomas Braidwood Wilson. PMID- 11613114 TI - Dr Alexander Collie - colonial surgeon and administrator. PMID- 11613115 TI - Australian native plants used medicinally by Europeans. PMID- 11613116 TI - The laws response to intellectual disability in Western Australia 1829-1990. PMID- 11613117 TI - Colonial self-care. PMID- 11613119 TI - The "RSI" syndrome in historical perspective. PMID- 11613118 TI - Exercise and massage in health care through the ages. PMID- 11613120 TI - Hygeia or panacea? French and first nation encounters. PMID- 11613121 TI - Plague? PMID- 11613122 TI - Mokare's people. PMID- 11613123 TI - The old homeopathy box. PMID- 11613124 TI - Voluntary health insurance: lessons from the past. PMID- 11613125 TI - The teratogenic aspects of diabetes in pregnancy. PMID- 11613126 TI - Historical aspects of the fabrication of dentures. PMID- 11613127 TI - Mr Alfred Kaufman and the Metropolitain Dental Company. PMID- 11613128 TI - Women in New Zealand medicine up to 1930. PMID- 11613129 TI - From gold bars to bumper bars: the history of metals in dentistry. PMID- 11613130 TI - A brief history of dentistry in Western Australia. PMID- 11613131 TI - [Preliminary exploration on the silk scroll, Wang of pulse feeling, sphygmology] (Chi). PMID- 11613132 TI - [Differentiation of the falsehood of Danxi's book] (Chi). PMID- 11613133 TI - [Anecdote and lineage of dispensary of Yue's family line] (Chi). PMID- 11613134 TI - [Herbological research on chrysanthemum, a traditional Chinese drug] (Chi). PMID- 11613135 TI - [History of exploitation of medicinal resources in Inner Mongolia] (Chi). PMID- 11613136 TI - [Query on the article entitled "Ling Shu plus Su Wen unequal to Huang Di's Inner canon, written in eastern Han Dynasty"] (Chi). PMID- 11613138 TI - [On the relationship between medicine and Confucianism] (Chi). PMID- 11613137 TI - [Fang Yizhi's idea and his medical discourses] (Chi). PMID- 11613139 TI - [Shang Congshan, a famous physician of the Yuan Dynasty] (Chi). PMID- 11613140 TI - [A study on the physician Yanshang Xingweng] (Chi). PMID- 11613141 TI - [Medical institutions in juyan bamboo slips of the Han Dynasty] (Chi). PMID- 11613142 TI - [General view on the evolution of ancient needles] (Chi). PMID- 11613144 TI - [Hygiene work in Soviet region of Western Fujian province (1929-1934)] (Chi). PMID- 11613143 TI - [Research on the origin of the term mapifeng and its differences and similarities with bronchiolitis] (Chi). PMID- 11613145 TI - [A brief history of cardioangiography] (Chi). PMID- 11613146 TI - [A brief history of interventional radiology] (Chi). PMID- 11613147 TI - [Abu al-Qasim al-Zahrawi (Abulcasis): Arab pioneer of surgery]. PMID- 11613148 TI - Sclerema neonatorum: a renewed examination of primary sources regarding the early history of the disease. PMID- 11613150 TI - [Not Available]. PMID- 11613149 TI - [Not Available]. PMID- 11613151 TI - Vienna dermatology and its historical roots. PMID- 11613152 TI - [Not Available]. PMID- 11613153 TI - [Not Available]. PMID- 11613154 TI - [Not Available]. PMID- 11613155 TI - Representing AIDS. PMID- 11613156 TI - Medicine in the divine comedy and early commentaries. PMID- 11613157 TI - [Modern development of TCM diagnosticis] (Chi). PMID- 11613158 TI - [Quarantine service in Xiamen (Amoy) in the period of post anti-Japanese War] (Chi). PMID- 11613159 TI - [The stomatological contributions of pathogenesis and manifestations of all diseases] (Chi). PMID- 11613160 TI - [Sun Simiao and critical care medicine] (Chi). PMID- 11613161 TI - [Preliminary exploration on the only extant edition of Xuke's medical talks] (Chi). PMID- 11613162 TI - [Inquiry on the problem of "Wan's secretly handed-down mastery of external diseases". NOT written by Wan Quan] (Chi). PMID- 11613163 TI - [An inquiry into the fact of Sanki Tashira learning medicine from Yu Tuan's grandson] (Chi). PMID- 11613164 TI - [Study on carved recipes preserved in the Cave of Recipes] (Chi). PMID- 11613165 TI - Inventing electrocution. PMID- 11613166 TI - Technique, task definition, and the transition from genetics to molecular genetics: aspects of the work on protein synthesis in the laboratories of J. Monod and P. Zamecnik. PMID- 11613167 TI - Renato Dulbecco and the new animal virology: medicine, methods, and molecules. PMID- 11613168 TI - Experiment and orientation: early systems of in vitro protein synthesis. PMID- 11613169 TI - Molecular biology in the French tradition? Redefining local traditions and disciplinary patterns. PMID- 11613170 TI - Building a science in Japan: the formative decades of molecular biology. PMID- 11613171 TI - The survival of basic biological research in National Socialist Germany. PMID- 11613172 TI - Thomas Huxley: fossils, persistence, and the argument from design. PMID- 11613173 TI - Viewing bodies: medicine, public order, and English inquest practice. PMID- 11613174 TI - Scientific controversy as farce: the Benveniste-Maddox counter trials. PMID- 11613175 TI - Expertise lost: an early case of technology assessment. PMID- 11613177 TI - The founding period of the U. S. Pharmacopoeia. PMID- 11613176 TI - The design of American pharmacies, 1865-1885. PMID- 11613178 TI - [The dissection of human bodies and its justifications in antiquity]. PMID- 11613179 TI - Physicians, abortions, and the law in early twentieth-century Ontario. PMID- 11613180 TI - [Joseph-Albert Baudoin (1875-1962): professor of hygiene]. PMID- 11613181 TI - Western medicine in Palestine, 1860-1940: the Edinburgh Medical Missionary Society and its hospital. PMID- 11613182 TI - American medicine in the gilded age: the first technological era. PMID- 11613183 TI - In the clinic: framing disease at the Paris Hospital. PMID- 11613184 TI - The strategy of biological research programmes: reassessing the "Dark Age" of biochemistry, 1910-1930. PMID- 11613185 TI - The comparative history of sleeping sickness in east and central Africa. PMID- 11613186 TI - [Origin, development and characteristics of Taoist art of health-preserving] (Chi). PMID- 11613187 TI - [On the history of visceral manifestation in traditional Chinese medicine] (Chi). PMID- 11613188 TI - [Is "Collection of discourses of Wu physicians" a consecutive publication] (Chi). PMID- 11613189 TI - [On the printing and handed-down edition of Jin gui Yu Han Jing and its value"] (Chi). PMID- 11613190 TI - [Some investigation on the 7 chapters about yunqi] (Chi). PMID- 11613191 TI - [A brief textual reesearch on Tianbao's Medicinal illustration of single recipes] (Chi). PMID- 11613192 TI - [Lost text of "Time for collection" of drugs in Shen Nong's Herbology] (Chi). PMID- 11613193 TI - [Oversea spread of Chinese drugs in both Song dynasties] (Chi). PMID- 11613195 TI - [Research and explanation on medical books from Han Tomb in Mawangdui] (Chi). PMID- 11613194 TI - [The medical materials collected from Secret history of Mongolia] (Chi). PMID- 11613196 TI - [Achievements of physicians of communicating traditional Chinese and Western medicine, its proper recognition and appraisal] (Chi). PMID- 11613197 TI - Nutrition, sanitation, hygiene, and the likelihood of death: the British Army in India c. 1870-1920. PMID- 11613198 TI - The diffusion of fertility control in Taiwan: evidence from pooled cross-section time-series models. PMID- 11613199 TI - Otto Diederich Lutken--40 years before Malthus? PMID- 11613200 TI - Histories of demography: a review article. PMID- 11613201 TI - Responses to possession and insanity in the earlier Byzantine world. PMID- 11613202 TI - Family care and hospital care: the 'sick poor' in nineteenth-century Glasgow. PMID- 11613203 TI - 'A scourge to be firmly gripped': the campaign for VD controls in interwar Scotland. PMID- 11613204 TI - An honourable calling or a despised occupation: licensed midwifery and its relationship to distric nursing in England and Wales before 1948. PMID- 11613205 TI - Health and illness in German workers': autobiographies from the nineteenth and early twentieth centuries. PMID- 11613206 TI - Spectacles improved to perfection and approved of by the Royal Society. AB - The letter sent by the Royal Society to the London optician, John Marshall, in 1694, commending his new method of grinding, has been reprinted, and referred to, in recent years. However, there has been no comprehensive analysis of the method itself, the letter and the circumstances in which it was written, nor the consequences for trade practices. The significance of the approval by the Royal Society of this innovation and the use of that approbation by John Marshall and other practitioners are examined. Gaps in existing accounts of Marshall's method are partly remedied by supplementing surviving written materials with accounts of contemporary, and present-day, trade practices based on his method. The reasons why Marshall and his contemporaries failed to record his method and specify his improvements are discussed. The reactions of the Spectacle Makers' Company and its more prominent members, both to the innovation itself and to the Royal Society's letter, are analysed. The impact of the new technique on contemporary and later opticians is described. PMID- 11613208 TI - Science at the periphery: an interpretation of Australian scientific and technological dependency and development prior to 1914. PMID- 11613209 TI - Achievements in cancer therapy. PMID- 11613210 TI - R. W. Innes-Smith: a man to study. PMID- 11613211 TI - Cholera in Fife: the great sanitary reformers. PMID- 11613212 TI - A radiotherapist looks back. PMID- 11613213 TI - Experiment, difference, and writing: II. The laboratory production of transfer RNA. PMID- 11613214 TI - Emil Kraepelin: psychiatry and public affairs in Wilhelmine Germany. PMID- 11613215 TI - The development of modern psychiatric services in China 1891-1949. PMID- 11613216 TI - Psychiatry and social control in the nineteenth and twentieth centuries. PMID- 11613217 TI - Carl Wernicke's localization theory and its significance for the development of scientific psychiatry. PMID- 11613218 TI - Argentinian alienism from 1852-1918. PMID- 11613219 TI - Phrenitis: inflammation of the mind and the body. PMID- 11613221 TI - Bartolome Llopis (1906-1964). PMID- 11613220 TI - Dissertation on acute mania. PMID- 11613222 TI - Essay review [on psychiatry]. PMID- 11613223 TI - Psychiatry and its historians. PMID- 11613224 TI - Historiography and history of psychiatry in Austria. PMID- 11613225 TI - The historiography of psychiatry in Belgium. PMID- 11613226 TI - History of psychiatry in Britain. PMID- 11613227 TI - The historiography of Dutch psychiatry and mental health care. PMID- 11613228 TI - The history of psychiatry in Italy. PMID- 11613229 TI - The history of psychiatry in Spain. PMID- 11613230 TI - History of psychiatry in Sweden. PMID- 11613231 TI - History of psychiatry in Switzerland. PMID- 11613232 TI - The significance of symptom complexes in psychiatry. PMID- 11613233 TI - Chemical librarianship: a kind of 'women's work' in America. PMID- 11613234 TI - So long as they both shall live: marital dissolution and the decline of domestic homicide in France, 1852-1909. AB - This article suggests that the growth of European states, the decline of familism, and the rise of individualism generated the institutionalization of judicial separation and divorce. Time-series analyses of France (1852-1908) reveal a persistent negative association between separation/divorce and domestic homicide, especially among males. Neither indicators of economic change nor trends in the wider pattern of violent crime account for the relationship. Although marital dissolution is a negative correlate of premeditated domestic homicide, the rate of separation/divorce is directly associated with spontaneous domestic homicide, for both females and males and may indicate that abandoned spouses can become homicidal. PMID- 11613235 TI - Experimental paleoparasitology: identification of Trypanosoma cruzi DNA in desiccated mouse tissue. AB - The polymerase chain reaction (PCR) has been used for clinical diagnosis of infectious disease and to research ancient animal and microbiological DNA from a wide range of tissues. PCR was used to study the possibility of Trypanosoma cruzi kinetoplast DNA (kDNA) extraction from experimentally desiccated mouse tissue (heart, skeletal muscle, liver, spleen, and pancreas). The results obtained suggest the application of this technique to T. cruzi detection in archaeological material. PMID- 11613236 TI - [Exploration on conception of preventive medicine in Dong nationality]. AB - On the basis of materials of folk medicine and traditional medical experience collected on the spot, the preventive methods in Dong nationality and its national customs and habits are analysed and systemitized preliminary exploration is made on its preventive conception, thus providing a valuable basis for systematizing the medical system of Dong medicine. PMID- 11613237 TI - [Chen Haifeng and his history of health care in China]. PMID- 11613238 TI - [Life of Wan Quan and some of his anecdotes]. AB - By investigating the literatures and medical arts written by Wan Quan so as to probing the formation and development of his medical art, this paper deals with the experience in Confucianism, clinical practice, his disciples and childrens. It points out that there are three essential conditions of Wan's academic basis, viz., achievements in Confucianism, family heritage and his own rich clinical experience. PMID- 11613239 TI - [Danxi Xinfa and Zhu Danxi's correlated works]. AB - Investigations are made on the study of serial works of Danxi Zhengzhi Xinfa carried out by later scholars. It is claimed that the background works of this is Jin Gui Gou Xuan. Danxi xinfa Benji being the Shanxi edition of Xinfa, while Chen Chong's Anhui edition of Danxi Xinfa is the representative works of Xin fa, Lu he's Danxi Zuanyao, Fang Guang's Danxi Xinfa Fuyu, Gao Zizheng's Danxi Xiansheng Zhi Fa Xin Yao also have their own uniqueness. Mai Yin Zheng Zhi and Danxi Shoujing are apocryp has of Huang Jizhi's Ben Cao Quan Du of the Ming Dynasty and should be, of course, excluded from the series. PMID- 11613240 TI - [My personal idea on authorship of Nanjing (Classic of Questioning)]. AB - It has been a matter of dispute on the authorship, date of writing of Nanjing (Classic of Questioning). This paper mentions 2 evidences based on the Classic's academic idea and its developmental history and 3 collateral evidences from literatures of the Han Dynasty, claiming that Nanjing was written in the period of Warrings States by Qin Yueren. This is of significance in the assessment of the position and influence of Nanjing in the history of TCM. PMID- 11613241 TI - [Medicine of first half of nineteenth century]. PMID- 11613242 TI - [Early missionary medicine in Taiwan]. AB - Taiwan, as mainland China, first received modern medicine from Christian missionaries. Although Western medicine was introduced by the Dutch in the 17th century, it disappeared after their expulsion by Zheng Chenggong. It was not until 1865 when the British Presbyterian Church sent Dr. James Laidlow Maxwell to Taiwan to engage in medical and missionary work that Western medicine was able to take root in Taiwan. The last three decades of the 19th century were a key period in the development of modern medicine in Taiwan. This paper discusses three major figures in early missionary medicine in Taiwan, Dr. James Laidlow Maxwell, Rev. George Leslie Mackay, and Dr. David Landsborough and their contributions to the development of modern medicine in Taiwan. PMID- 11613244 TI - [One hundred twenty years of China's health quarantine service]. AB - China's health quarantine service, initiated in 1873, has experienced a long way of 120 years. This article focuses on the rapid development of all aspects in the quarantine construction of organization, profession and ideology, especially in P. R. China's period of reform. The number of quarantine service has increased from 17 seaport services to 192 services, including seaport, airport and land frontier services (up to the end of 1992). The professional quarantine works has expanded from simple quarantine inspection to comprehensive surveillance of communicable diseases, vector control, imported foodstuff supervision and examination etc. Significant contributions have been made to the prevention of the transmission of communicable diseases into the territory, the improvement of the sanitary condition of frontier ports and means of transportation. Frontier health quarantine is one of the strongest lookout posts of sanitation door of the country. It has become one of the major branches of preventive medicine and one of the key links of international health care cooperation. Health quarantine is being developing and strengthening for new and greater success for the realizatiion of the socialist modernization of our country. PMID- 11613243 TI - [A brief history of clinical application of bismuth]. AB - Brief discourse is given on the application history of bismuth in clinical therapy, diagnosis and other subsidiary departments. It also deals with its present status at home and abroad. PMID- 11613245 TI - [An outline of spreading of Western mediciine into Yantai in modern age]. AB - At the turn of the last century, side by side with the infiltration of religious culture from Western countries, western medicine spread into Yantai. The religious force, headed by American Presbyterian Mission, carried out charitable activities in the process of preaching and laid down the foundation for western medicine rooted in Yantai by establishing schools, education and training followers. They cultivated local physicians by first setting up clinics which had later transformed into hospitals. These are their major measures for building bases for spreading Christianity by foreigners. The Temple Hill Hospital set up by the American physician Oscar F. Hills in Yantai was a successful example of mutual promotion of missionary and medical activities which pushed forward the spreading and development of western medicine in Yantai. PMID- 11613246 TI - [The founding of Baoding Medical College]. AB - Baoding Medical College, an earlier institution of combining western and traditional Chinese medicine, played an active role in the development of combined medicine. This paper introduces its historical background, regulations for teaching program and student management. This might be helpful to contemporary educational reform. PMID- 11613247 TI - [On historical stages of studies on the science of Shang Han Lun]. AB - Based on the inherent rule and historical characteristics, the history of studies on Shang Han Lun can be divided into 5 stages, viz. (1) Formation (Pre-Qin period - 219 AD); (2) Copying (219 - 1065); (3) Stressing clinical application (1065 - 1144); (4) Stressing both theory and practice (1140 - 1894); (5) Comprehensive study (1894 -). Brief descriptions are given to each stage. PMID- 11613248 TI - [Studies on Shang Han Lun in Ming Dynasty and its influence]. AB - This paper points out, on the basis of systemic investigation on works of Shang Han Lun in the Ming Dynasty, that the manifestation of its influence on later ages is the promotion of gradual maturation of the theory of Wen Bing (seasonal febrile diseases). The resystematization of Ming edition of Shang Han Lun provides a multifarious approach for its study, while the contention deepens the study in later ages. It serves as a period linking the past and the future concerning studies on the science of Shang Han Lun. It also sets up a model for Qing Dynasty and modern age to follow in this aspect. PMID- 11613249 TI - [Examination for medical officials and its question examples in Qing Dynasty]. AB - Following some of the systemic regulations of the Song Dynasty, the Ming Dynasty set up a complete system for examination and medical education of its own. Successively, the Imperical Medical Academy set up Department of Learning, Bureau of Medicine for teaching and examination and selection of right personnels to be promoted to the positions of medical officials. The compulsory subjects for exam included Su Wen, Herbology, and Pulsolgy. It also includes topics from major texts of relevant disciplines. This paper offers example questions for exams selected from two books of Draft for Examination in Qing Imperial Medical Academy. PMID- 11613250 TI - [Study on Bian Que's tomb and temple]. AB - The historical archives and records and the existed Bian Que's tombs and temples in over a dozen of locations, including Hebei, Shandong, Henan, Shanxi, have aroused controversies as to which is the authentic one. So far, no conclusion can be drawn. By combining the burial and offering customs and rituals at the end of Spring-Autumn period, analyses are made on Bian Que's tombs, temples, former residence, Bian Que Village, Bian Que town, historical remains of Prince Guo and legends on location of Bian Que's activity for making immortal pills etc., it is claimed by the authors that, besides a few places related to Bian Que's life, all the others are tombs and temples built by local people where Bian Que's visited for his memory, and his merits, reflecting the historical facts about Bian Que's activities. All these historical and cultural remains are precious evidences for the historic appraisal of Bian Que by modern scholars. PMID- 11613251 TI - [A brief history of epidemiology of rabies]. PMID- 11613252 TI - [History of knowledge on hepatitis virus]. PMID- 11613253 TI - [A textual research on drinking disease and antidrinking remedies]. AB - This subject is investigated through three aspects, viz., definition of drinking disease, its manifestations and treatment, and recipes and drug for antidrinking. The term "drinking disease" (Jiu Bing) was first recorded in Wang Shuhe's Canon of Pulsology, while abnormal drinking (Jiu Bo) was mentioned in Miraculous Pivot (Ling Shu). On Pathogenesis Manifestation of all diseases (Zhu Bing Yuan Hou Lun) gives the pathology and etiology. Great influence was exerted from Jin-yuan dynasties concerning its treatment. Zhang Jiebin expounded the comatous syndrome due to drinking (Jiu Jue). The earliest antidrinking drug was recorded in Shen Nong's Classic of Herbology. Through investigation, the commonly applied drug for relieving drunk include Flos Puerariae, Fructus Hovenariae, while the famous recipe for relieving drunk is Anti-tipsy Decoction of Flos Puerariae. PMID- 11613254 TI - [Contributions of On Pathogenesis and Manifestations of All Diseases to the development of Chinese ancient psychiatry]. AB - Playing an important role in the developmental history of China's medicine, On the etiology and manifestations of all diseases makes great contributions in many aspects. This paper deals exclusively with its psychiatric aspect under six subheadings. By applying the theory of Qi and blood, it develops the pathogenetic theory and syndrome typing; rationalizes the classification of ancient mental diseases by categorizing on the basis of clinical features under internal medicine, external, gynecological and pediatrical diseases. It also makes remarkable progress in the recognition of diseases falling under the category of modern mental disorders. For instance, mental disturbances induced by taking stone-materials and alcoholism are discussed in detail; mental disturbances due of beriberi are also mentioned systematically. PMID- 11613255 TI - [History of kidney transplantation and progress in realizing the mechanism of immunology]. PMID- 11613256 TI - [Modern TCM education in Shanghai]. AB - Shanghai is a main base of the education of Chinese medicine (TCM) in modern time. A good many of famous TCM doctors, as well as TCM colleges or schools may be found in Shanghai. Many specialists and scholars of TCM gathered in Shanghai. The conditions of running TCM schools on Shanghai during 1840-1948 was introduced briefly, especially for the course and characteristic of the foundation of Shanghai Specialized School of TCM, the Chinese Medical College, the Shanghai Medicine College, the New China College of TCM and four private schools of TCM. In addition, the conditions of the correspondence schools of Shanghai in modern time were also introduced. PMID- 11613258 TI - [Historical and hygienic materials of medicine in Taiwan (1898-1945)]. PMID- 11613257 TI - [The origin of channel syndromes]. AB - Originally, "Shi Dong" disease, one of the Channel Syndromes, first appeared in Moxibustion Canon of Eleven-channels of Yin-yang System is a manifestation in pulse diagnosis. The two pulse-syncope (mai jue) syndromes in On Syncope of Plain Question are also the summary from different scholars far pulse manifestation. On the other hand, the "Suo Sheng" disease is the summary of ancient scholar on the lesions at the superficial running courses of channels and the disease condition of its underlying viscera, which would also be changed with the changes of channels and viscera. PMID- 11613259 TI - [Fragmentary materials of history of Yi-nationality medicine]. AB - Early in the matriarchal society 4000 years ago, medical activities of the Yi nationality had already begun. Through long process of struggle against diseases, the ancestor of Yi-nationality accumulated a huge wealth of medical knowledge, including acupuncture, medicinal wine and herbs, from which the theory of "Ba Fang" (eight-direction) "Ba Jiao" (eight-corner) and Yin-Yang system were formed, and became the core of rationale of Yi-medicine. Due to geographical reasons, Yi medicine was isolated and scarcely communicated with the outside world. Hence, so far it preserves much of its own features and thus, it offers excellent materials for the studies on the provenance and development of the medicine of Chinese minorities. PMID- 11613261 TI - [A study on the authorship of Yang Xing Yan Ming Lu]. PMID- 11613260 TI - [Fu Lianzhang and hygiene-prevention]. PMID- 11613262 TI - [A collection of 23 supplemented lost entries of Canon of Herbology collected by Huang Shi]. PMID- 11613263 TI - [Military medicine of the Song dynasty]. PMID- 11613264 TI - [A brief investigation on history of recognition of dreams in TCM]. PMID- 11613265 TI - [Medicine of seventeenth century]. PMID- 11613266 TI - Physician, heal thyself: the health and mortality of Victorian doctors. AB - Since the work of Dr William Ogle in 1886 the health and mortality of members of the Victorian medical profession has been a relatively neglected subject. 'Physicians, surgeons and general practitioners' represents probably the only occupation whose mortality experience--both in terms of age and cause of death- may be traced continuously since the 1860s. Ogle's work, together with that based on the Registrar General's Decennial Supplements, shows how vulnerable especially young doctors were to high mortality risks. Their use in conjunction with data compiled by the Friendly Societies also suggests that before the twentieth century members of the medical profession may have experienced substantial periods of work-preventing illness which would certainly have affected their ability to make a satisfactory living. It is also clear that among members of the medical profession there were substantial variations in life chances; that Fellows of the Royal colleges fared far better than their less well-placed colleagues, but that among Fellows the surgeons and physicians shared similar experiences. PMID- 11613267 TI - The papers of Cicely Williams (1893-1992) in the Contemporary Medical Archives Centre at the Wellcome Institute. AB - The papers of Cicely Williams were given to the Contemporary Medical Archives Centre in 1993, and subsequently catalogued. They cover most aspects of her work in the field of maternal and child health, as practitioner, teacher and consultant, 1929-1989, especially in the developing world. The collection includes correspondence, reports, lectures, publications, photographs and sound recordings, and is of relevance to a wide range of issues related to maternal and child health and the development of appropriate local health care systems. In particular, it is of interest in relation to Williams' pioneering work on the identification of the childhood malnutrition disease kwashiorkor. The Cicely Williams papers complement many other collections held by the Contemporary Medical Archives Centre. This article focuses on two pre-war reports of her work in the Gold Coast and Singapore, which show the early development of ideas which are echoed throughout the rest of her papers. PMID- 11613268 TI - Should smallpox virus be destroyed? The relevance of the origins of vaccinia virus. AB - The fate of surviving stocks of smallpox virus is still uncertain, and it is important that arguments in favour of retention or destruction should present balanced evidence. This article balances the view, probably incorrect and possibly alarmist presented earlier in this Journal by Peter Razzell, that vaccinia and cowpox viruses were derived from smallpox virus. The generally accepted alternative view that all three viruses are independent species and that smallpox virus could not emerge through simple mutation of the other two is presented, together with appropriate literature citations. PMID- 11613270 TI - The Dutch health services before compulsory health insurance, 1900-1941. AB - By 1930, almost all the Dutch population had access to basic medical care encompassing general and specialized medical services, hospital care and community services. The system by which this had been accomplished was determined by the fact that central government was unwilling to accept responsibility for health care by stimulating public services or regulating health insurance. In general, the poor were cared for out of municipal medical relief funds while the rest of the working classes were able to participate in voluntary sickness fund insurance schemes. The middle and upper classes had to rely on private practice, yet they found it increasingly difficult to pay for expensive hospital admissions. Moreover, the financial limitations of voluntary insurance, as well as the dominant position of the medical profession vis-a-vis sickness funds, meant that most funds did not cover hospital care or community services. The actual delivery of these services was often in the hands of private organizations but the municipal authorities paid most of the costs, either through direct payment or through subsidies. Before the introduction of compulsory health insurance in 1941, the highly independent Dutch municipalities did not only care for the poor; they also provided hospital care and community services for almost the entire population. This brought about wide geographical variations in the Dutch health services. PMID- 11613269 TI - Physical education and the School Medical Service in England and Wales, 1907 1939. AB - Historians who have examined physical education (PE) have rarely related PE to its wider social context. This article considers the development of PE in elementary schools in England and Wales between 1907 and 1939, and locates PE within the wider history of the School Medical Service. From 1907, local authorities appointed specialist staff, acquired playing fields, and sent their teachers on short vacation courses, while at a policy level the Chief Medical Officer, Sir George Newman, came to regard PE as a component of preventive medicine. In the interwar period, PE was greatly influenced by voluntary organizations, and by the physical training schemes set up by the continental dictatorships, and this culminated in the Physical Training and Recreation Act of 1937. However PE also illustrated many of the weaknesses of the School Medical Service, including striking regional variations in its provisions, and in the 1930s the emphasis on PE contrasted with the relative neglect of malnutrition. The article concludes by suggesting that the contrast between Sir George Newman's ambitious plans for PE as a branch of preventive medicine, and provision in most local authorities, illustrated the great gulf that could exist between rhetoric and reality. PMID- 11613271 TI - Children's health camps in New Zealand: the making of a movement, 1919-1940. AB - The children's health camp movement in New Zealand was the product of early twentieth century concerns about national efficiency and racial strength. Inspired by open-air schools in Europe and the United States, the movement shows how overseas models were translated into a distinctive New Zealand institution, based on a national appeal for funds, and combining voluntary effort with solid government support. Although health camps had a strong socialization function, it was easier for doctors and laypersons to intervene in children's lives in the name of health, than under any other rubric. In the space of 20 years health camps changed from informal summer events held under canvas, into substantial institutions operating on a year-round basis. By 1940 their symbolic status was more important than any demonstrated achievement in improving child health. PMID- 11613272 TI - Interactions between public health nurses and clients on American Indian reservations during the 1930s. AB - This essay examines the encounters between clients and public health nurses hired by the Office of Indian Affairs to work on American Indian reservations during the 1930s. It relies on two different types of sources. The first are the accounts of the nurses, including letters, memoirs, and above all their monthly and annual reports to Washington. The second are oral histories conducted by the authors with elderly residents of two Sioux reservations in South Dakota during August 1993. One of the key missions of the public health nurses was to inculcate Euro-American beliefs. They assumed that American Indians would follow a linear progression from understanding the 'rules of health' to the eradication of all traditional practices. That model left no room for ambiguity or syncretism. The Sioux viewed the nurses as resources to be used strategically and selectively. Those who accepted the nurses' services did so because the services addressed specific needs the Sioux themselves defined as important. Most disregarded the health education programme insofar as it assumed the superiority of Euro-American values. PMID- 11613273 TI - Resurrecting the body: Has portmodernism had any effect on biology? AB - While postmodernism has had very little influence in biology (for reasons discussed in the paper), it can provide a framework for discussing the context in which biology is done. Here, four biological views of the body/self are contrasted: the neural, immunological, genetic, and phenotypic bodies. Each physical view of the body extrapolates into a different model of the body politic, and each posits a different relationship between bodies of knowledge. The neural view of the body models a body politic wherein society is defined by its culture and laws. The genetic view privileges views of polities based on ethnicity and race. The immune body extrapolates into polities that can defend themselves against other such polities. The phenotypic view of the body politic stands in opposition to these three major perspectives and integrates them without giving any predominance. The view of science as a "neural" body of knowledge contends that science is aperspectival and objective. The perspective of the "immune" body is that science exists to defend the interests of its creataors. The genetic view of science is that science is the basis of all culture. The extrapolation of the phenotypic body to science insists upon the utilitarian rationale for scientific interprises. In all instances, the genetic view of the body/body politic/body of science is presently in ascendance. PMID- 11613274 TI - Postmodernism and immune selfhood. AB - Two research traditions in immunology, supposedly centered on the same issue of immune identification, have followed different theoretical goals and originated from competing philosophical foundations. These may be labelled modernist and postmodernist, respectively, thereby applying cultural and philosophical categories to immunology in order to articulate potential scientific resonances with the broader culture. To accept that exercise an important caveat is imposed, namely, this translation is most appropriately discussed at the level of metaphor. In other words, I will structure my treatment of these issues as expressed in the metaphorical language of the discipline, and thus the bulk of this discussion will focus on how the language and modeling of the science draws from the culture-at-large. Scientists seek images from their everyday lives to describe phenomena that may be poorly articulated in their technical discourse; such is the utility and importance of metaphors generally, and thus it is not surprising that we might discern echoes of a postmodernist sentiment in the metaphors borrowed from post-World War II culture. I will also discuss, to a more limited extent, how postmodernists have sought support for their own ideological arguments in immunology. This last topic serves only to illustrate the bidirectionality of scientific discourse with the society in which it is embedded. PMID- 11613275 TI - Who wrote the book of life? Information and the transformation of molecular biology, 1945-55. AB - This paper focuses on the opening of a discursive space: the emergence of informational and scriptural representations of life and hereditiy and their self negating consequences for the construction of biological meaning. It probes the notion of writing and the book of life and shows how molecular biology's claims to a status of language and texuality undermines its own objective of control. These textual significations were historically contingent. The informational representations of heredity and life were not an outcome of the internal cognitive momentum of molecular biology; they were not a logical necessity of the unravelling of the base-pairing of the DNA double-helix. They were transported into molecular biology still within the protein paradigm of the gene in the 1940s and permeated nearly every discipline in the life and social sciences. These information-based models, metaphors, linguistic, and semiotic tools which were central to the formulation of the genetic code were transported into molecular biology from cybernetics, information theory, electronic computing, and control and communication systems--technosciences that were deeply embedded with the military experiences of World War II and the Cold War. The information discourse thus became fixed in molecular biology not because it worked in the narrow epistemic sense (it did not), but because it positioned molecular biology within postwar discourse and culture, perhaps within the transition to a post-modern information-based society. PMID- 11613276 TI - [Medicine in Taiwan during the period of Japanese occupation]. AB - During this period, malaria, pneumonia, dysentery and enteritis, and acute infectious diseases, including plague, typhoid fever, dysentery, cholera, smallpox, infectious epidemic meningitis, malaria, tsutsugamushi and endemic diseases such as goitre were the important causes of death. In parasitology, the most important discovery was lung fluke, followed by research achievement in clinical and basic sciences. In Taiwan, studies on poisonous snake were proceeded rather early. The special medical system in this period included the Gynecological Hospital and medical insurance system. In the medical staff, not a few Japanese were included. Dr. Du Congming, who made great contributions to medicine in Taiwan, may be viewed as the father of medicine in Taiwan. A Journal of Taiwan Medical Association was published in Taiwan by the said Association. PMID- 11613278 TI - [A brief history of hygiene in modern Shanghai concessions]. AB - Medical activities in modern Shanghai concessions have their own specialties in fives aspects, including medical administration, hospitals, pharmaceuticals in traditional and western drugs, epidemic prevention and environmental sanitation. Most hygienic measures carried out in the concessions are helpful to the development of modern western medical cause in China. PMID- 11613277 TI - [A brief history of functional rhinoscopic operation]. PMID- 11613279 TI - [A brief history of western hospital in modern Shanghai]. AB - This paper introduces the brief history of western hospital in modern Shanghai. It deals with this problem under the following three headings: missionary western hospital, public western hospital and private western hospital. PMID- 11613280 TI - [Brief introduction to modern TCM professional schools in Hubei]. AB - Established in 1933, the Hubei Professional TCM School gathered the famous TCM contemporary professionals and personnels from all medical disciplines of Wuhan Region. Among them, there were educationists, famous at home and abroad. Under the School, there were the Principle, Board of Directors are administrative organ for staff members. There was also a simple Regulations, including the objective, curricular installation, method of exams. Several hundreds of TCM Professionals were cultivated. PMID- 11613281 TI - [Time frame and reasons of Kangxi Emperor adopted variolation]. AB - This paper is concerned with the time frame and the reasons why the Kangxi Emperor adopted variolation in the Qing Imperial family. The Manchus, especially the Qing Imperial family, lived in the fear of contracting smallpox. They took various strategies to protect themselves from smallpox. One of the most conspicuous methods was adopting variolation in royal family in the Kangxi reign. The purpose of this important action was to maintain the superiority of the Manchu minority and to reduce the mortality rate of smallpox in the Imperial family. In this paper, I would like to point out the time when the Kangxi Emperor intended to use variolation was earlier than we had known through the previous studies. The Emperor's decision of variolation was mainly stimulated by his personal experiences and his practical character. PMID- 11613282 TI - [A brief history of studies on anti-tumor remedies in China]. AB - This paper gives a general introduction to the studies on the formulation and invention of anti-tumor remedies from 1950s-1980s. Beginning from 50s, antitumor antibiotics were investigated. New alkylicompoun and antibiotics were found in the 60s, while more new natural compounds were found in the 70s. Researches were proceeded in the 80s based on the former achievements. Through the process of about 30 years, nearly 80 new species were produced, many anti-tumor pharmaceutical corporations established, and a contigent of high level research workers was formed. However, there still exist a rather large gap between the urgent clinical needs for clinical chemotherapeutics and the actual status. Based on some 30 years of experience in China, the following points were summarized, i.e., shifting from merely imitation to invention, developing the spirit of massive cooperation, investigating the thesaurus of TCM, developing China's plant resources, and traditional Chinese preventive idea, so that the stress point for research be laid on the invention of preventive anti-tumor remedies. PMID- 11613283 TI - [Preliminary research of Astangahrdayasamhita]. AB - Astangahrdayasamhita, transmitted into the region of Tibet and Mongolia as Buddist Scripture, is a classical work of ancient Indian medicine. It has had an important influence on the formation of the theoretical system of Tibetan medicine and Mongolian medicine. Divided into six parts, eight branches and 120 chapters, Astangahrdayasamhita describes systematically physiology, pathology, diagnosis and treatment of diseases. This article describes Astangahrdayasamhita in four aspects, including the author and dating of its writing: the main contents; its position in Ayur-vedic medicine; the influence on Tibetan and Mongolian medicine. PMID- 11613284 TI - [Medical exchanges among China and Asiana countries]. AB - Among the issues of medical exchanges, medicaments are more often encountered than medical issues, based on ancient Chinese literatures, early in the Han-Jin Dynasties, Thailand, Malaysia, Indonesia, and Brunei had exchanges with China, also in Sui-Tang Dynasties. In the Song-Yuan Dynasties, ancient Singapore and the Philippines also incorporated in exchanges of medicament and goods. In the Ming Qing dynasties, these 6 Asian countries had even more close contact with China, especially in trades and medical exchanges among the masses, carried out in a large scale thus, promoting the advent and development of TCM in Asiana Regions. PMID- 11613285 TI - [On the military physician Cui and his academic achievements]. AB - Based on the 385 pieces of recipes and its discourses quoted from Cui's by Wai Tai Mi Yao (Medical secret of an official), this author discusses the brief biography of Cui Zhiti, a military physician of the Tang Dynasty and his achievements on field epidemics, field internal medicine, field surgery and comes to a conclusion that Cui Zhiti and his "Cui's Collected Essential Recipes" is of significance in China's military medical history. PMID- 11613286 TI - [Differentiation of Ziyi Bencao as an apocrypha]. AB - It is generally believed that Ziyi Bencao is a book of the pre-Qin period. By studies on several aspects, including ancient bibliographical records, relics unearthed in Mawangdui Han tombs, nomenclature of ancient book titles, the date of appearance of ancient classics, contradictions between the time of activities of Bian Que and Ziyi, it is concluded that, in the pre-Qin period, there were no classic of herbology of any kind, even less Ziyi Bencao. The books entitled Ziyi Bencao recorded in bibliographies after Han Dynasty are all apocryphas made by Han authors. PMID- 11613287 TI - [Textual research on Dan Fang Jing Yuan (Mirror origin from alchemical chambre), an alchemical herbology]. AB - Having made a textual research on the relation between the two editions of Dan Fang Jing Yuan of Zheng Tong Dao Zang and Zheng Lei Ben Cao, we consider the materials quoted by the latter to be derived from the three-volume Dan Fang Jian Yuan of Dao Zang, while the Dan Fang Jing Yuan from the fourth volume of Qian Gong Jia Geng Zhi Bao Ji Cheng is in fact an apocrypha of Zheng Lei Ben Cao by Song people. The dating of the two books are also studied. PMID- 11613288 TI - The Marine Biological Station on Puffin Island (Ynys Seiriol) and the work of the Liverpool Marine Biology Committee (1887-1892). PMID- 11613289 TI - The Naturalists' Directory and the evolution of communication among American naturalists. AB - From the colonial period through the civil war period, naturalists in America were scattered over an extensive area, much of which was still sparsely settled, and all of which was very distant from the intellectual centers of Europe. Developing a network of contacts with like-minded naturalists took many years of correspondence. To facilitate communication among these naturalists, the Naturalists' Directory was compiled and first published in 1865. It has gone through more than 46 editions and is still being published. The role of the directory in the ever-changing communication process that has occurred in America from 1865 to the present is reviewed, as are the directories themselves: the early Frederic W. Putnam editions (which were published in association with the Proceedings of the Essex Institute, 1865-1866, the Samuel E. Cassino editions (editions 1-30, 1877-1936), and the post-Cassino editions (with various publishers, editions 31-46, 1938-1993). PMID- 11613290 TI - Universal health care and self-help: paying for district nursing before the National Health Service. PMID- 11613291 TI - Organizing integrity: American science and the creation of public interest organizations, 1955-1975. AB - The power and prestige of science is typically thought to be grounded in the ability of scientists to draw strong distinctions between scientific and nonscientific interests. This article shows that it is also grounded in a contradictory act: the demonstration of the compatibility between scientific and nonscientific interests. Between 1955 and 1975, American political protest forced scientists to find ways to reconcile these contradictions. One way in which this reconciliation was accomplished was through the formation of public interest science organizations, which permitted the preservation of organizational representations of pure, unified science, while simultaneously assuming responsibilities to serve the public good. PMID- 11613292 TI - Racial differences in marriage and childbearing: oral history evidence from the South in the early twentieth century. AB - Using oral histories collected in 1938 and 1939 in the Southern United States, this article examines how African-Americans and whites viewed marriage and nonmarital childbearing. The authors document distinct racial differences in family norms and the sanctions that supported those norms. Giving birth outside a marital relationship was clearly not the stigmatizing event for African-Americans that it was for whites. The authors also found that African-Americans were more likely than whites to end marriages under similar conditions. These results suggest that debates about contemporary racial differences need to take into account the historical background, both cultural and demographic, of diverse groups. PMID- 11613294 TI - The plague fighter: Wu Lien-teh and the beginning of the Chinese public health system. AB - At the end of 1910, when the Qing dynasty was on the verge of collapse and the whole Chinese empire in a process of transformation, North Manchuria was devastated by a large pneumonic plague epidemic. The Russian and Japanese governments wanted to use the outbreak of the disease as a pretext to invade north-east China, making plague an issue of international politics. At this dramatic moment the empire relied on the skills of the young Chinese doctor Wu Lien-teh, the first Chinese medical graduate from Cambridge. Wu investigated the disease on the spot, chaired an international plague conference in Shenyang (Manchuria) in April 1911, and, later on, became the figurehead of fundamental public health reforms in Republican China. Highly ambitious, striving for personal fame and international renown for China, supported by an excellent network of personal connections, and equipped with a medical training considered the best in the world at the time, he launched on a startling career as one of China's key medical reformers and international representatives. His history is an example of the inseparable links between personal fate and historical events, and between the interests of scientists, medical men, politicians, and businessmen on the national and international stages. PMID- 11613293 TI - Medical representations of the body in Japan: gender, class, and discourse in the eighteenth century. AB - This paper examines the introduction of European anatomy to Japan via translated medical texts in the eighteenth century. It argues how detailed illustrations of the body found in the texts presented a new discourse by which to objectify and control the body, and new metaphors and analogies by which to view society. Inspection of bodily parts through dissection and the reading of anatomical texts marked a transition to Western forms of science, to 'reliable' knowledge which was certified by the social status of the author. By looking at one important text, the Kaitai shinsho [A New Book of Anatomy] (1774), it will be shown that changes in representations of the body reflect the social construction of gender. PMID- 11613295 TI - The 'culture' of science and colonial culture, India 1820-1920. PMID- 11613296 TI - The evolution of U. S. food color standards, 1913-1919. PMID- 11613297 TI - History of dental education in Indiana. PMID- 11613298 TI - [The sleeping girl from Okno]. AB - The peninsula of Okno is located on the Baltic in Southern Sweden. It was here a 14 year-old girl "fell asleep" around Christmas time in the year 1875 - she woke up on April 3rd, 1908. She was then 46 years of age and had slept for 32 years. Except for numerous newspaper articles this unusual case has been described by the Swedish psychiatrist Harald Froderstrom in 1912. The present article is based on his review and the investigation of the medical records at the hospital of the city of Oskarshamn where the woman in question was hospitalized for one month in 1892. At the city hospital she was given the diagnosis dementia paralytica - a diagnosis which was obviously wrong. When the woman woke up in 1908 she assumed a normal life and remained healthy until she died in 1950 through a brain hemorrhage. Froderstrom, who except for an article written in French, wrote several extensive articles for Swedish newspapers about the sleeping girl. These articles are here reviewed from a modern psychiatric point of view. PMID- 11613299 TI - Reflections on medical history - its development, function and implementation. PMID- 11613300 TI - [Hans Bendz - pathologist and humanitarian]. PMID- 11613301 TI - [Coping with sickness: perspectives on health and health care, past and present]. PMID- 11613302 TI - [Diseases and health care at Oland - from the past to the present]. PMID- 11613303 TI - [Seldinger - the method. Recollections and reflections]. AB - The author relates the commercial/technical events preceding and following the conception of "The Seldinger Technique" in 1951 by Dr Sven-Ivan Seldinger, Stockholm. The "PE-tubing", developed in 1950 by Clay-Adams Inc., New York, N.Y. was then presented to the Swedish medical profession by AB Stille-Werner (Stille) in Stockholm. PE-tubing with its suitable properties for arterial catheterization was at the time the only industrially produced tubing with degrees of tolerances to render possible the development of the Seldinger "guide wires". Technical development was undertaken by Mr Elof Tornros, chief engineer of the Stille Experimental Workshop, in accordance with the special wishes of Seldinger. The guide wires were produced in two sizes to be used with PE-tubing PE-160 and PE 205 of the Clay-Adams catalogue. Seldinger, radiologist in the X-Ray department of the Karolinska University Hospital in Stockholm, conceived "The Seldinger Technique", which historically proven resulted in vast numbers of "spin-off" catheters. Not only for angiography and intervention radiology but also for a great number of other vascular catheterization procedures as well as for intravenous infusions by the use of "over-the-needle" "soft" infusion needles. PMID- 11613304 TI - [Ligamentum denticulatum s. serratum]. PMID- 11613305 TI - [Some recollections of Gustaf Petren and the surgical clinic at Lund in the early 1930's]. PMID- 11613306 TI - [Health, disease and society: new historical perspectives]. PMID- 11613307 TI - [Ars bene moriendi]. PMID- 11613308 TI - [The murders at Malmo eastern hospital]. PMID- 11613309 TI - [What can we learn from medicine in Greek antiquity? On the notion of the art of healing]. PMID- 11613310 TI - [The Petrens - a remarkable group of siblings in turn-of-the-century Lund, as described by the sister Louise Petren-Overton]. PMID- 11613311 TI - [A report from the 15th Nordic congress on the history of medicine in Iceland]. PMID- 11613312 TI - [From infirmary to university clinic]. PMID- 11613314 TI - Mathematical theories versus biological facts: a debate on mathematical population dynamics in the 1930s. PMID- 11613313 TI - Drosophila embryos as transitional objects: the work of Donald Poulson and Christiane Nusslein-Volhard. PMID- 11613315 TI - Making a machine instrumental: RCA and the wartime origins of biological electron microscopy in America, 1940-1945. PMID- 11613316 TI - Goethe's Archetype and the romantic concept of the self. AB - This paper attempts to illuminate Goethe's concept of an archetype by setting it alongside the concept of the self that was being articulated at the same time, also by writers of the Romantic movement. The Romantic concept of the self expresses a new concept of the self as a 'core' plus an expression of the core: and it is the same 'core plus expression' idea that is embodied in the Goethean archetype. Goethe's archetype is not simply a 'plan'. It is a kind of agent at the heart of a thing, striving for self expression, and to this end driving the thing's development. Both Romantic self and archetype reflect the wider attempt to reinstate the concept of action in our understanding of things and happenings in general. The root idea of there being at the heart of a living thing an agent pursuing a goal remains in the modern concept of the organism. PMID- 11613317 TI - Generalizations in biology. [Review of: Schaffner, K. F. Discovery and explanation in biology and medicine. University of Chicago Press, 1993]. PMID- 11613318 TI - From floating brothels to surburban semirespectability: two centuries of nonmarital pregnancy in Australia. AB - The sexual revolution that through the 1950s and 1960s saw nonmarital fertility and marital childbearing following premarital conception rise rapidly in Australia, especially among women in their teens and early twenties, received considerable research attention. Now, in the mid-1990s, childbearing following nonmarital pregnancy has assumed a very different character. The pregnant teenaged bride is almost a thing of the past, and nonmarital births occur mainly at normative reproductive ages within consensual unions. Similar trends have occurred in other developed countries, but Australia boasts an unusual precedent for this new phase, in that during its early years of colonial settlement, convictism also gave rise to widespread childbearing within consensual unions. This precedent and the distinctive circumstances that produced it are explored in the context of tracing the full and varied history of fertility associated with nonmarital coitus in Australia. PMID- 11613319 TI - The rhetoric of reproduction and the reconfiguration of womanhood in the French birth control movement, 1890-1920. AB - Birth control movements that emerged in Europe and the United States during the last third of the nineteenth century lost their emancipatory and feminist potential in the twentieth century as they succumbed to control by the medical profession, eugenicists, and institutionalized goals of planned parenthood. The neo-Malthusian movement in France, however, retained a radical character and became a focal point for the convergence of libertarian, feminist, and anarchist concerns. By emancipating women from their "biological destiny" and separating sexuality and reproduction, neo-Malthusian rhetoric reconfigured womanhood and established the basis for women's development as full individuals and citizens. PMID- 11613320 TI - Wood engraving and American medical publishing in the early nineteenth century. PMID- 11613321 TI - Learning disability nursing in the post war period. AB - This paper considers the place of learning disability nursing within the profession in the 1940's and 1950's. A number of sources are discussed, which throw light on the problem of recruitment to this branch of nursing as well as its future as seen at the time. Comparisons are drawn between it and other types of nursing and conclusions are drawn about the extent to which it was a valued part of the profession. PMID- 11613322 TI - The London County Council Nursing Service 1929-48: the significance of the nursing leadership. AB - 'On the vesting day of the National Health Service, the LCC handed over to the NHS the largest and most comprehensive hospital system under a single authority that existed in the world' (1). The careers of the Matrons-in Chief, Dorothy Bannon and subsequently Rosalie Dreyer, demonstrate that the LCC had been able to attract nursing leaders from the voluntary hospitals. Both were able to use their new position within the LCC hierarchy to promote the interests of nursing. They took this opportunity to develop a nursing service which became a model to rival the hegemony of the voluntary hospitals. PMID- 11613323 TI - The lecture notes of two pupil nurses of the preliminary training school at Glasgow Royal Infirmary. AB - The Preliminary Training School (PTS) for nurses which opened at Glasgow Royal Infirmary in 1893 was the first attempt to provide a theoretical pre-clinical course for 'pupil' nurses. The notebooks of two pupils are reviewed in terms of the contemporary medical and nursing knowledge and provide indications of subject matter that pupil nurses were taught. PMID- 11613324 TI - The dregs of society? Occupational patterns of male asylum attendants in Victorian England. AB - This paper presents the results of a database study of male attendants hired at two Surrey asylums between 1868 and 1881. It challenges the widely held assumption that attending was an 'occupation of last resort' and places asylum work within the wider context of a rapidly changing labour market in Victorian England. PMID- 11613325 TI - The war and nursing in Germany. PMID- 11613326 TI - A short outline of the history of nursing training in Poland. PMID- 11613327 TI - We are strongly individual - and together we are even stronger. PMID- 11613328 TI - Towards a history of nursing. PMID- 11613329 TI - Population, technology, and the human environment: a thread through time. PMID- 11613331 TI - A "second front" in Soviet genetics: the international dimension of the Lysenko controversy, 1944-1947. PMID- 11613330 TI - The beginnings of the "Delft tradition" revisited: Martinus W. Beijerinck and the genetics of microorganisms. PMID- 11613332 TI - Psychobiology, progressivism, and the anti-progressive tradition. PMID- 11613333 TI - Proximate determinants of birth seasonality and conception failure in Nepal. PMID- 11613334 TI - From inoculation to vaccination: smallpox in Sweden in the eighteenth and nineteenth centuries. PMID- 11613336 TI - Life writing in medical history. PMID- 11613335 TI - [The experimental counter-proof in the office of Claude Bernard: the case of the destruction of a pancreas]. AB - Claude Bernard attributed a fundamental role in experimental medicine to the "contre-epreuve." He believed that a phenomenon fails to appear if its cause is eliminated (contre-epreuve). Therefore, the relation "preuve-contre-epreuve" emerges as the best criterion of experimental truth. In 1848 Claude Bernard discovered that pancreatic secretion could emulsify and saponify fatty substances. This article, based on his original manuscripts, shows that Bernard demonstrated in 1851 that the absence of pancreatic juice resulted in the arrest of fat digestion. Using the "contre-epreuve," he destroyed the pancreas in dogs as another way to prove his theory of the pancreatic digestion of fat. PMID- 11613337 TI - "Very truly and undisturbedly yours": Joseph Workman and a verdict of malpractice against John Galbraith Hyde. PMID- 11613338 TI - Pharmacy records at the Archives of Ontario: their form, content, and value for research. PMID- 11613339 TI - Medical students at the University of Toronto, 1910-40: a profile. AB - This article is intended to contribute to the small but growing literature on university students in nineteenth- and twentieth-century Canada--in this case, to add to our knowledge about medical students at the University of Toronto between 1910 and 1940. Aside from crude estimates of total numbers, we know very little about medical students before the early twentieth century because the kinds of records required to probe further have rarely survived. Beginning in 1910, however, all of the applications for entry to the Universitiy of Toronto medical faculty have been preserved, as have the academic record cards of many graduates. Using these and other sources, this article focuses on the academic standards students had to meet to get into medical school; on the socio-economic composition of the student body, and how that changed over time; and on some key features of students' progress through the program of studies. PMID- 11613340 TI - [Women and the practice of health in the "Register of counsels' speeches in the Parlement of Paris, 1346-1427"]. AB - The study of women in medieval medical practice is a recent area of research plagued by method, sources, and interpretation problems. The main obstacle is probably the paucity of the documentation, the underrepresentation of women in the sources. Studying the judiciary sources of fourteenth- and fifteenth-century Paris reveals women tried by the highest court of justice in France for illicit practice of medicine. Of 34 trials pertaining to health in the "Registre des plaidoiries du Parlement de Paris 1364-1427," eight cases involve women. Two of these trials are particularly instructive because they give many details on certain aspects of women's practice in the Middle Ages. Perette la Petone is brought to justice by the "corporation des chirurgiens de Paris" for illicit practice of surgery and Jeanne Pouquelin is tried by the "communaute des barbiers de la ville de Paris" for illicit practice of "barbery." This article includes a transcript of the unpublished sources used for the study of these two cases. They shed some light on questions such as: What is the place and role of women in the medical guilds? How do they acquire the expertise required for these crafts? How are they perceived by their peers and society in general? And what is the extent of their medical knowledge? PMID- 11613341 TI - For "the honor and dignity of the profession": organized medicine in colonial New Brunswick, 1793-1860. AB - This article discusses the several attempts to organize and regulate the medical profession in New Brunswick, Canada, between 1793 and 1860. It examines medical legislation during the colonial era, culminating in the creation of the Medical Faculty of New Brunswick in 1859. Also, it explores the desire within the profession itself for increased protection and recognition. This desire inspired the formation of several medical societies in the years following 1827. A central figure in professional organization was Robert Bayard (1788-1868), who graduated from Edinburgh in 1809. The article examines his relationship with his colleagues, notably Thomas Paddock, John Boyd, and Alexander Boyle, to identify personal tensions affecting the development of the medical profession. The article concludes that the medical profession acquired a significant degree of authority in New Brunswick only following the enlistment of legislative support. The search for greater authority stemmed from the advent of sectarian doctors in the province. Although sectarian practitioners never flourished in New Brunswick, the law of 1859 gave the province's regular doctors a sense of identitiy that facilitated the establishment of medical societies and the province's first general public hospital, in Saint John. PMID- 11613342 TI - [Dashengbian (thesis on longevity) and its author]. AB - Dashengbian was a very popular obstetric book in the 18th century. It once had a significant influence in history not only because it fairly well sumed up predecessors' experiences and filled in the gaps in the field of obstetrics, but also because it had an easy-reading, concise and practical contents. As for the author of the book, although many blockprinted editions were signed by Lay Buddhist Ji Zhai, his real name was unknown. This article holds that the book had been circulated for some time before it came out in the 54th year of Kang Xi reign which is in line with the manuscripts of Qian Long reign of the Qing dynasty and the names carried in its case records. According to other relevant data, the article believes that Lay Buddhist Ji Zhai was most likely to be Zhang Zhao, a scholar of the early Qing dynasty. PMID- 11613343 TI - [Study on the original title and number of volumes of Variorum of Herbological Canons]. AB - Though there are a few studies on this Variorum, there still leave much to be desired on the studies of its original title, number of volume. Through careful study, based on materials newly found in Sui Book, Hua Yang Pu, and Daozang, it is claimed that the original name of the book was Ben Cao (Herbals), containing 3 volumes in which the 2nd is subdivided into 7 subvolumes, which may bear the title of Annotation of Herbological Canons. PMID- 11613344 TI - [Contention on reform of teaching of medical history in TCM College and University]. PMID- 11613345 TI - [Medicine in first half of 20th century]. PMID- 11613346 TI - [Comments on several questions about TCM as described in Laufer's Sino-Iranica]. PMID- 11613347 TI - [Probing the origin of Chinese medical kings and temples of medical kings of successive ages]. PMID- 11613348 TI - [Formation and shifting of TCM center]. AB - Analysis is made on the so-called "Yuasa Phenomenon" in the history of Chinese medicine, which holds that, in the development of medical history, there exists a center of medical theory and practice representing the peak of development and orientation. Since the Song-Yuan dynasties, there was a process of constant changes and formation of medical center. This period had seen three separate TCM centers in Henan, Hebei and South of Yangtze River, discerning four stages, viz., inheritance, invention, renewal and unprecedented flourishing. This is a phenomenon not only reflecting the internal laws of medical development, but also deeply embodying the profound influence of social economy and culture on medicine. PMID- 11613349 TI - [A brief history of osteo-traumatology of the pre-Qin period]. AB - Historical materials from oracle inscriptions to Mawangdui Ancient Books are summarized. Research is made on four aspects, including recognition on bone, wounds to bone, and bone diseases, osteological treatment by drugs, acu moxibustion, massage and Daoyin, traumatological medical jurisprudence and prevention of such diseases. This fills the gap left out in the developmental history of osteo-traumatology. PMID- 11613350 TI - [Preliminary exploration on knockout drops (Meng Han Agents)]. AB - This author points out, based on relevant materials, that knockout drops were vertigo powder. Due to homophonic reasons in Chinese language, the term "mingxuan" was transliterated into the former Chinese term (menghan). Knockout drops for medicinal use were merely made up of compound recipes containing stramonium flowers. The knockout drops in old fictions and opera books were powder of stramonium flower. The ingredients and application of such recipes are discussed here, the anti-remedies for such recipes are also mentioned. PMID- 11613351 TI - [Comparison between Chinese and Tibetan pulsology]. AB - There is considerably close relationship in the origins of pulse feeling between Chinese and Tibetan medicine. Pulsology of both systems were mutually infiltrated, hence, there are many similarities, and with its own uniqueness in clinical application at the same time. This paper deals with the problem under the subheadings of preparation before taking the pulse and the optimal time for taking the pulse, etc. PMID- 11613352 TI - [In memory of Dr. Lien-teh Wu]. AB - Based on materials dealing with early medical activities of Mr. Lien-teh Wu, this paper gives a description to his contribution to modern medical course in China. For examples, he inaugurated the Chinese Medical Journal both in Chinese and English within the same issue, which is the first of its kind in the history of Chinese journals. Moreover, Mr. Wu was also the first to establish modern hospital, port quarantine, banning drug abuse, and many others. He also advocated medical education, gave special attention to traditional medical morality and mottoes. He made substantial medical writing as well. He was a great contributor to the development of China's medicine. PMID- 11613353 TI - [Textual research on Ji Jiu Xian Fang (Excellent recipes for emergent cases)]. AB - In medical subsection of the third part (zi part) of A complete book in four parts, there is a 6-volume Ji Jiu Xian Fang. Based on the author's study, the currently circulated Ji Jiu Xian Fang from Daozang Collections is no longer an original but an apocrypha with interpolations imposed when it was revised during the Zhengtong reign of the Ming dynasty. Only its 8th and 9th volumes are of original ones. Whereas the copy from the A complete book in four parts still preserves the original pages of the said book. The contents of this book is not restricted to external diseases but a comprehensive medical book for emergent and practical use compiled by Song authors. PMID- 11613354 TI - [Research on origin and evolution of Wan Mizhai's Medical Encyclopedia]. AB - This encyclopedia was lost early in the Ming dynasty. The current edition was blockprinted by Wan's fifth generation grandson in 1654-1659, then comes the next edition of Zhang Tanyi Shilu Tang of Hanyang edition blockprinted in 1712. Next comes Hu Leuqing Wei Tang of Jinxi's edition blockprinted in 1724, which was interpolatedly reprinted by Fuwentang, Tongrentang. The latter was entitled Wan Mizhai's Medical Encyclopedia when blockprinted in 1741. After 1778, there was also a Zhongxintang edition with unknown printed time. The modern printed edition of Luotian revised edition was printed in 1981-1986. The above editions are verified by textual research and material books by describing their printing, edition features and mutual relationship between its origin and development. Errors of printing of some editions are also dealt with. PMID- 11613355 TI - Australian medical students in 19th century Scotland. PMID- 11613356 TI - Thales to Galen: a brief journey through rational medical philosophy in ancient Greece. Part III: Galenic medicine. PMID- 11613357 TI - Memories of a surgeon-lieutenancy Edinburgh 1941-43: part IV. PMID- 11613358 TI - Guide to veterinary museums of the world. PMID- 11613359 TI - The phenotype/genotype distinction and the disappearance of the body. PMID- 11613360 TI - Physiology's evolution: reassessment of the morphological tradition. Transformation of a research field between 1870 and 1890. PMID- 11613361 TI - "Dark as a dungeon": environment and coal miners' health and safety in nineteenth century America. PMID- 11613362 TI - The contribution of Polish physicians and scientists to world medicine. PMID- 11613363 TI - Cultural relations between England and Poland with special focus on medicine. PMID- 11613364 TI - [Fifty years of the Polish School of Medicine at the University of Edinburgh (1941-1991)]. AB - The Polish School of Medicine at the University of Edinburgh started in 1941 on the initiative of the University. It was destined for soldier-students in the Polish Forces in Great Britain. This academic institution, unique in the history of universities, was a joint Scottish-Polish enterprise. An Agreement was concluded between the Polish Government in London and the University of Edinburgh. The School was an independent Polish academic institution and, at the same time, an integral part of the University of Edinburgh. The students matriculated at the University. The University provided all the laboratory and clinical facilities necessary for teaching. Due to a lack of Polish professors for some chairs a few of them were held by Scottish professors. Attached to them were Polish lecturers but the examinations were then held in English. The diploma, originally valid only in Poland, became recognised in Great Britain following an Act of Parliament in 1947. There were 337 students, a number of them women. 227 obtained the degree M.B., Ch.B. The war ended in 1945. The School continued up till 1949. Poland was not free. The Nazi occupation of Poland was replaced by Soviet domination which was to last for over 40 years. Only 22 of the graduates returned home, about 100 settled in G. Britain, another 100 dispersed world wide. The "magnanimous gesture" of the University of Edinburgh was thereafter remembered with gratitude by the members of the Polish School. In 1961, on the occasion of the 20th anniversary of the School, the first reunion of the graduates was organised in Birmingham for those settled in Gr. Britain. The success of the reunion prompted decision on organising annual "English" gatherings of the Polish graduates in Gr. Britain. The first world reunion of the graduates took place in Edinburgh in 1966, attracting a large number of participants on this occasion of the 25th anniversary of the School. That immensely successful anniversary of the Polish School which was celebrated by the University, influenced the participants to organise regular quinquennial world reunions in Edinburgh. A later, particularly memorable event, was the world reunion in 1976 on the occasion of the 250th anniversary of the Medical Faculty of the University; it was celebrated jointly, as it coincided with the 35th anniversary of the Polish School. The 45th anniversary of the School in 1986 was marked by the opening of the "Polish School of Medicine Historical Collection" in the Polish Room of the Erskine Medical Library of the University of Edinburgh. Also a Polish School of Medicine Memorial Fund, founded on contributions from the graduates, was inaugurated at the University of Edinburgh to provide scholarships for research workers from Poland. Another venture was the "Professor Antoni Jurasz Lectureship" for professors of the Edinburgh Medical Faculty to promote contact with Medical Schools in Poland by delivering lectures. An ardent desire was expressed by the original organisers of the School to continue into the future the academic links in medicine between the University and Poland. Political and ideological factors which devided the post-war Europe did not favor such a fulfillment of this plan. The members of the School who remained in the West, maintained links with the University and prepared funds to put the plans of co-operation into action. With the end of the political division of Europe the future of a productive Scottish-Polish collaboration can be viewed with hope and confidence. PMID- 11613365 TI - [Scottish professors in the Polish School of Medicine in Edinburgh]. AB - In 1941, on the initiative of the University of Edinburgh, a Polish School of Medicine was founded at that University for soldier-students in the Polish Forces in Gr. Britain. It was a joint Scottish-Polish academic enterprise, unique in the history of universities. The Polish school of Medicine became an integral part of the University. As only 7 Polish professors were available (apart from associate professors and senior lecturers), a number insufficient to start a Medical School, a similar number of Scottish professors filled the vacant Polish chairs. Such an arrangement had been agreed by the organisers of the School and was included in the Agreement, negotiated between the University of Edinburgh and the Polish Government in London. According to the agreement the Scottish professors were proposed by the University authorities. A special invitation was sent to them by the Polish Government in London. The Scottish professors of the Polish School of Medicine were: Lt col. F.A.E. Crew honorary professor of the Polish School. L.S.P. Davidson (medicine), A.M. Drennan (pathology), D.M. Dunlop (co examiner to prof. L.S.P. Davidson), R. W. Johnstone (obstetrics/gynaecology), T.J. Mackie (bacteriology), G.F. Marrion (chemistry/biochemistry), C. McNeil (paediatrics) and Sydney Smith (forensic medicine). Replacement due to retirement: R.J. Kellar, R.W.B. Ellis, Sir James Learmonth. Polish lecturers were attached to all the Scottish professors who held the Polish chairs. Thus the instruction in the above-mentioned subjects was given in Polish but the examination was conducted in English by the Scottish professors. But in some subject, both the instruction and the examination, were in English. The students had to learn English quickly as the language was essential for their reading of English textbooks and dealing with Scottish patients in the wards. A typical picture at that time in the wards of the Royal Infirmary was of a group of Scottish students being instructed by their professor at patient's bedside, and at another bed, a group of Polish soldier-students in battledress, being taught in Polish by their lecturer. The co-operation worked very well indeed. Seemingly impossible things can be successfully accomplished in exceptional circumstances for instance in warfare. A total of 227 students obtained the diploma M.B., Ch.B. It was valid only in Poland. By an Act of Parliament the diploma was made valid also in Gr. Britain. The diploma was in two versions: a Latin text of the diploma of the University of Edinburgh, and a Polish text of the Polish universities. In recognition of the invaluable help extended by the University of Edinburgh to Polish science and learning, a bronze plaque was unveiled in 1949 in the Quadrangle of the Medical Faculty. PMID- 11613366 TI - [Teaching department of the Polish Paderewski Hospital in Edinburgh]. AB - An agreement was concluded on 24.02.1941 between the University of Edinburgh and the Polish Government in Exile in London that brought into being the Polish School of Medicine at the University of Edinburgh. The School was intended for soldier-students in the Polish Forces in Gr. Britain. This agreement was meant for the time of war. With the end of the war a number of medical student-soldiers liberated from the German prisoner of war camps, applied to the Polish Medical School at the University of Edinburgh. In accord with the agreement the University discontinued the official admission of new students to the Polish School in Edinburgh. The students, numbering 37, who could not be admitted as regular students, were given facilities by Professor Jurasz, the Dean of the Polish School, to carry on their studies at the Polish Paderewski Hospital in Edinburgh (at the Western General Hospital). Thus there came into being two Schools: one regular, authorized Polish School of Medicine within the University, and the other, an unofficial School at the Paderewski Hospital, undertaking the teaching of students but with no power to grant a medical qualification. The teachers attached to the official Polish Medical School in Edinburg co-operated in the instruction of the students of the unofficial School. Nearly 20 of the 4th and 5th year students finished their courses and passed their examinations. Each of them was given a certificate that he had concluded his medical studies and had passed all the examinations which were necessary in Poland to obtain a medical diploma. A number of those who obtained the certificate applied to the Conjoint Examining Board in London and succeeded in obtaining the diploma L.R.C.P. London and M.R.C.S. England, and the licence to practice from the General Medical Council. A few third year students studied and obtained the degree at the Universities of England, Ireland and Canada; and some returned to Poland. A few settled in the U.S.A. and in South America. The unofficial School was active for two years. PMID- 11613367 TI - [The life of Polish students at the Polish School of Medicine at the University of Edinburgh]. AB - The article has been written by a former student of the Polish School of Medicine at the University of Edinburgh, a member of the Polish Forces in Britain. The reminiscences concentrate on day to day life of others, like himself, seconded from the Forces to continue their medical studies. Statistical data concerning the activities of Polish School of Medicine are presented and analysed. Detailed mention is made of various routes by which Polish students reached Great Britain from the time of defeat and partition of Poland between Germany and Soviet Union. The various phases of relationship and attitudes between Polish Armed Forces and the body of students are described and illustrated by extracts from personal memoirs. The number of other topics is presented and discussed: The difficulties and problems encountered in living and studying amongst people, who although sympathetic, but whose language, culture and customs were completely foreign to the Poles. The ways in which individuals and groups of students tried and in many instances managed to overcome these obstacles, forging links with their Scottish colleagues and population at large. The participation in various joint activities like Settlement Day, work in agricultural camps, sports, Scottish students Unions and Representative Councils etc. are described. "Inner life" of Polish students concentrated in "Bursa" (an equivalent of University Residence) is presented in a light-hearted way. Large detachments of a foreign army, living, amongst albeit friendly population, are bound to cause, sometimes serious, friction. Very much in relation to this problem the role of Polish students as ambassadors of Poland and Polish Causes are presented and their value assessed. PMID- 11613368 TI - Clandestine medical education in Poland 1939-1945. PMID- 11613369 TI - [The Polish Medical Association, Londyn]. AB - The Polish Medical Association, founded in 1944 in London and celebrating its Golden Jubilee in 1944, is a unique organisation of doctors brought together by the shared experience of serving in the Polish armed forces on the fronts of the II World War. Preparing themselves for the return to a free Poland and later facing the realities of the emigre existence, they formed an association based on an identity with patriotic ideals and espousing a loyalty to the national cause, solidarity with the aspirations and goals of the expatriate community and commitment to the integrity in the performance of their professional duties. It was created against a background of the already existing Polish Medical Faculty at the University of Edinburgh and supported by strong lobbying on the part of the Polish Government and the favourable political climate. The need for a professional body of Polish doctors became evident. During the first few years the Association, originally called the Polish Medical Association in the British Empire, numbered over 700 doctors and achieved notable succeses for its members. The most significant were the endeavours which contributed to the inclusion of the so-called Clause 5 of the Polish Resettlement Act 1947, which in practice allowed Polish doctors serving in the Polish forces under British command to obtain full medical registration. Almost 800 doctors benefitted from this legislature and by coincidence, with the introduction of the National Health Service, they constituted the single most significant injection of non-British doctors into the British health care system. Throughout the years the Association, which originally comprised doctors with an Army background acquired more and more civilian members. The second generation followed, smaller waves of post-war emigration brought in new members from Poland. With time the administrative structure of the Association--initially comprising ten divisions in the UK and overseas--has changed; the second generation--those already born and educated in the UK--joined the professional ranks, and later achieved the highest positions. The return of democracy to Poland, so eagerly awaited, has brought a new dimension to the Association's activities. Its original character, however--identity with the national ideals of dignity, honour, integrity- naturally, remains unchanged and deeply ingrained in the collective and individual consciousness of this unique group. The Association maintains active contacts with Poland's leading medical institutions and academic establishments and is the initiator of the ideal of integrated effort of the Polish emigre medical milieu and medicine in Poland--the ultimate goal is the long-term commitment to the health of the Polish nation. PMID- 11613370 TI - Polish medical journals published in exile during the Second World War. PMID- 11613371 TI - [Polish doctors graves at the cemeteries in Edinburgh]. AB - The first part of the text reviews the cultural links between Poland and Scotland. These links were originated in the 14th century and were created by scottish students travelling to Poland to seek learning in the then polish centre of excellence Jagiellonian University in Cracow. There were also some learned Scots who ventured to Poland, seeking work. Some of them achieved positions of distinction. The first Polish medical men attended the University of Edinburgh in the 18th century. In the 19th century, following the suppression of the polish uprising against Russia, there were a small group of Poles seeking asylum in Scotland. A few of them enlisted at the University of Edinburgh at the medical faculty. The above history is described in detail in Annotations. In the second part of the paper all the polish medical and veterinary doctors whose graves are located in various cemeteries in Edinburgh are listed in chronological order of their deaths. As full as possible personal data, the kind of medical work, and location of their graves are given. Greater details, whenever obtainable, are dealt with in Annotations. The total of thirty deceased between 1942 and 1993 are described. PMID- 11613372 TI - History of medicine in Poland, its past, present and future. PMID- 11613373 TI - Esther and Arthur Mork: a "chiropractic love story." AB - Drs. Esther and Arthur Mork were arrested in Wisconsin for practicing chiropractic without a license. At that time, Wisconsin had a medically controlled basic science examination that was required before chiropractors could sit for their own licensing board. Their case was to be a test case for basic science examinations. Although the appeal was dropped and the Morks paid the fine, the story of their introduction into chiropractic, Esther's experiences at Palmer and their battle with the medical profession serves as a case study of chiropractic's experiences with the basic science boards in the thirties and forties. Esther's lively narration is set against the hard, cold facts of source documents. PMID- 11613374 TI - Birth of the "chiropractic angel": a Caduceus counterpoint. AB - Use of the winged angel with raised hands as a chiropractic emblem began circa 1928. Although often attributed to the National Chiropractic Association (NCA), the emblem was created prior to the NCA's formation, and was initially "copyrighted ... for the exclusive use of members of the American Society of Chiropractors." The emblem appeared as part of the ASC's advertising in popular national magazines, including American Legion Monthly, Cosmopolitan, Liberty, and Physical Culture. First use of the chiropractic angel to represent the NCA and its ally, the Internatonal Chiropractic Congress (ICC), took place at the NCA and ICC joint national convention in Denver in 1933. The emblem was formally adopted by the NCA at its 1934 convention in Pittsburgh. This paper reviews some of the early history of the emblem and its use by the ASC and the NCA. PMID- 11613375 TI - Mainstreaming chiropractic: tracing the American Chiropractic Association. AB - The American Chiropractic Association (ACA) as it is known today was formed by a series of amalgamations. Starting with the Universal Chiropractic Association (UCA) of 1906 and the original American Chiropractic Association (ACA) of 1922, the two associations merged to form the National Chiropractic Association (NCA) in 1930. This Association merged with the New American Chiropractic Association (ACA) formed by non-NCA Association members and a splinter group from the International Chiropractors Association (ICA) in 1963. The total merger including all of NCA's assets, facilities, resources, personnel and membership was completed by 1964. PMID- 11613376 TI - Old Dad Chiro comes to Portland: rediscovering DD in Oregon, 1908-10. AB - This paper sketches Palmer's Portland period, and relies upon five issues of DD's periodical, the Chiropractor's Adjuster, to supplement traditional sources. The early activities of the D.D. Palmer College of Chiropractic are reviewed, and Palmer's travels throughout the region are noted. Old Dad Chiro's widespread influence in the profession is apparent from the diverse correspondence reprinted in his magazine, including letters from chiropractors in at least 22 states. During his Portland years his intent to "adjust" the "mistaken" ideas of chiropractors and his anger at son BJ became plainly and painfully evident. The founder's activities in Portland gave impetus to chiropractic education in the Northwest, and his schools' successor, the Oregon Peerless College of Chiropractic & Neuropathy, continued to operate for several years until its merger with another forerunner of today's Western States Chiropractic College. Most importantly, Palmer's stay in Oregon saw perhaps the first publication of his final theories of chiropractic, and gave rise to his classic text, The Chiropractor's Adjuster: the Science, Art and Philosophy of Chiropractic. PMID- 11613377 TI - BJ in 1906: predictions and personal reflections. PMID- 11613378 TI - Beyond the "Jim Crow" experience: blacks in chiropractic education. AB - Although the first chiropractic adjustment was given by D.D. Palmer to a black man in 1895, within two decades attendance at the Palmer School of Chiropractic was forbidden to blacks. Not until mid-century were blacks allowed entrance into the oldest and largest chiropractic college in the United states. Denied entry at the Palmer School, most blacks who entered chirporactic studied in "Jim Crow" schools run by white practitioners in the North. This paper explores the social, historicl and economic factors influencing the exclusion of blacks from medical education, and concludes that chirpractic education is at the stage medical education was twenty-five years ago in its attempts to recruit black students. The author recommends that the Association of Chiropractic Colleges establish a task force on minoritiy recruitment to expand the educational opportunities in chiropractic for blacks and other minorities. PMID- 11613379 TI - "Quo warranto": only in California--challenging early chiropractic law. AB - In California from 1907-1925 two writs of quo warranto were filed against the first two chiropractic boards. Thirteen of the fifty original medical practice acts and at least eleven original chiropractic acts contained an eligibility requirement for first appointed board members, a stipulated pre-practice period. Twenty-three of these combined boards suffered no legal challenges by practicing colleagues, the attorney general or the courts, for what appeared to be unlicensed practice. Only in California were the first two boards so challenged. In California, there were other unique forces at work that no chiropractor suspected would prematurely expunge the first appointed board. These legal quagmires delayed the systematic licensing for many months. Only in California did this unique history take place. PMID- 11613380 TI - "With malice aforethought": revisiting the BJ Palmer "patricide" controversy. AB - For over eight decades of chiropractic's existence, one of the myths associated with Founder Daniel David Palmer was the unsupported and largely surreptitious allegation that his son, B.J. Palmer, was somehow respondible for his death; What became known as the Palmer "patricide controversy" involved many of the players in early chiropractic and became little more than a sordid melodrama involving rival schools, chiropractic politicians and lawyers. It involved three Iowa grand juries and lawsuits and brought out the worst passions and actions of a family that had never really understood the father or the son. This study will review the original events, the allegations by those who sought to indict B.J. Palmer for the wrongful death of his father and the ultimate disposition of the incident, which still finds credence today among some who see conspiracy theories within the evolution of chiropractic. PMID- 11613381 TI - Where is the fountain head of chiropractic? PMID- 11613382 TI - Willard Carver, LL.B., 1866-1943: doctor, lawyer, Indian chief, prisoner and more. AB - Willard Carver was a pioneer in chiropractic education who founded seven schools, and ardent legislative leader in Oklahoma, who later suffered indignation from authorities that brought him to the Senate's bar of justice, was convicted and sent to jail. How this episode fostered defeat by a referendum petition of a proposed medical practice act at the polls, laying groundwork for passage of Oklahoma's Chiropractic Act in 1921, is recalled in this paper. Carver became a prolific author of textbooks, a life-long antagonist to Dr. B.J. Palmer, both invested as Indian chiefs, loved and hated by equal numbers of tribesmen and a remarkable chiropractic pioneer of great proportion. PMID- 11613383 TI - Gloom or boom for chiropractic in its second century? A comparison of the demise of alternative healing professions. AB - As Americans suffered through the heroic medicine of the 1800s, many medical alternatives, known as sects, evolved in the United States. Examination of the developments and problems encountered of medical sects, namely Thomsonism, homeopathy, osteopathy, naturopathy and chiropractic, reveals many similarities among them. While some sects have either dissolved or been absorbed by other professions, chiropractic has survived as a separate and distinct healing art. As chiropractic approaches its centennial celebration, it continues to demonstrate specific sectarian characteristics that may hinder progression into the future. This paper examines parallels among the developments of chiropractic and other alternatives. A review of some historic and contemporary scholars' predictions for the future of chiropractic is presented as well as potential solutions. PMID- 11613384 TI - Chiropractic goes to Washington: with Dr. Emmett J. Murphy, 1938-1964. AB - Articulate, urbane, naturally companionable, and always prepared, Dr. Emmett J. Murphy was perfectly suited to the office he created as chiropractic's first full time national lobbyist. As labor relations director of the National Chiropractic Association from 1938 to 1964, he worked diligently to increase awareness of chiropractic among legislators, the federal bureaucracy, veterans organizations, labor and other groups equally concerned about the affairs of government. Many of his accomplishments, especially for chiropractic students, were pioneering efforts. PMID- 11613385 TI - Oakley Smith's schism of 1908: the rise and decline of naprapathy. AB - The year 1908 through circumstance and perhaps inevitable progression of new healing concepts, proved to be one of historical moment for two of the first followers of Daniel David Palmer. Oakley Smith, who graduated under "Old Chiro" in 1899, and John F. A. Howard, who was in the Class of 1906, would find themselvles in Chicago, each heading new schools. Smith, a one-time Iowa medical student who had investigated Andrew Still's osteopathy in Kirksville, Missouri before going to Davenport, was to take another path. In the strict sense, it was not dissent but schism. For Smith, who would in time reject the Palmer concept of vertebral subluxation, it was to be a total departure as to the "doctrine of disease," and he was to announce his own concept, which was "the connective tissue doctrine." PMID- 11613386 TI - Universal College, 1910-1944: only a third of chiropractic, but with a deep and rich legacy. PMID- 11613387 TI - In the eye of the storm: Dossa Dixon Evins and the neurocalometer debacle. AB - Dossa Dixon Evins, one of the lesser known figures in chiropractic history, played a prominent role in the 1920s, yet we know little about him. He was a vaudeville entertainer with his wife Billie, an inventor, electrical engineer, and a radio operator for the Secret Service during World War I. He is also the person who best weathered the hurricane which his most famous invention stirred in the chiropractic profession. What sort of man was he? The author seeks to answer that question in this paper as well as delving into the Neurocalometer Incident. PMID- 11613388 TI - Price of dissension: the private wars of Dr. Leo L Spears, 1921-1956. AB - Anathema to the Denver medical community, favorite of the 1950s-era sensationalist press, Leo Spears and his hospital represented the complexities of chiropratic. A dynamic achiever in the face of adversity, this 1921 Palmer School graduate built the profession's first large hospital complex and had plans for an institution that would have been among the largest healthcare facilities in existence. PMID- 11613389 TI - The establishment and development of chiropractic in Tennessee, 1910-1994. AB - Tennessee was to see the first practitioners of the new alternative school of chiropractic within the second decade of chiropractic. This paper deals with the earliest recorded roots of the profession by individual chiropractors and the major legislative issues and organizational evolution in the state. Consideration is given to the influence of the Nashville College of Chiropractic, the longest continuous early school in the South (1936-1947). PMID- 11613390 TI - As ever, B.J.": The Palmer-Stoke correspondence of 1926-1952. AB - John H. Stoke was a 1920 graduate of the Palmer School and a loyalist among the admirers of B.J. Palmer during the turbulent 1920s in which Palmer leadership was questioned and the Neurocalometer debacle had eroded his following. Stoke, however, was a critical B.J. advocate, and engaged in sometimes detailed analysis of Palmer-Stoke correspondence and the issues which confronted the profession in those difficult times in the early years of this century. PMID- 11613391 TI - D.D. Palmer: a new look at an old visionary. PMID- 11613392 TI - "Jailing ideas": a 1921 populist critique. PMID- 11613393 TI - African Americans, chiropractic and social change, 1895-1945. AB - African Americans have had a long and interesting relationship with chiropractic. Although few in actual numbers, black chiropractors as well as lay persons have made significant contributions while often suffering the double edged sword of professional isolation and racial oppression. This account traces their first half century. PMID- 11613394 TI - D.D. Palmer and the origin of "tone": a centennial critique. PMID- 11613395 TI - Thirty years after "Bonesetting, Chiropractic & Cultism": confessions of a chiropractic heretic. AB - Bonesetting, Chiropractic and Cultism, a controversial critique on chiropractic written by a chiropractor and published in 1963, was initially ignored by the chiropractic profession. In recent years, however, there has been renewed interest in the book, and it has received favorable reviews thirty years after its publication. PMID- 11613396 TI - Daniel David Palmer: alchemy in the creation of chiropractic. AB - D.D. Palmer has been a much ignored man in the discipline he founded. The same applies to several early concepts he used to develop from a mere healer's background: D.D. Palmer invested them with an entirely different meaning. When considered, they help to understand the inner logic that allowed for chiropractic survival. There was an alchemy in the creation of chiropractic and the senior Palmer was the alchemist. He has not been recognized even within his own profession for the self-taught scholar and clinician that he was, knowledgeable about the various medical and scientific theories of his time. PMID- 11613397 TI - Bartlett Joshua Palmer: toward an understanding of the man, 1881-1961. AB - B.J. Palmer was clearly the most colorful of chiropractic's personalities and he exerted a powerful influence over the profession for many years and was perceived in a variety of ways. At the age of 18, his father abandoned the ownership and responsibility for the PSC and the profession was effectively transferred to him. From this point B.J.'s successes and his diplomatic failures evolved simultaneously. B.J.'s near-obsessive reductionistic traits appear to derive from his father's school teacher emphasis on reducing complex systems to simple explanations. B.J. and his father were at odds through life, yet B.J. remained respectful through his adult years until D.D. died in 1913. He was greatly influenced by his father's attitudes and admonitions and by his father's assumption that the Palmer family had a proprietary role in chiropractic. PMID- 11613398 TI - David Daniel Palmer: "The Educator" as the legacy of the third generation. AB - David Daniel Palmer was born into the crucible of chiropractic formulation. He would be raised in the environment of BJ Palmer's leadership and school domination and the acquisition of the broadcasting empire that shaped the profession and its ultimate acceptance. With the investiture of David D. Palmer as the third president of the Palmer School, a new era of academic and professional growth took place at the Palmer institutions. During his presidency, transition of the school from proprietary to a non-profit status was achieved, as was full accreditation. The Palmer Junior College and a new relationship with the Davenport community was initiated. Reorganization of the Palmer faculty, new admissions procedures, a strong alumni association and improved facilities were accomplished under the Palmer known as "The Educator." PMID- 11613399 TI - Kansas coconuts: legalizing chiropractic in the first state, 1910-1915. AB - When the Kansas Supreme Court averred that, under existing law, chiropractic was the practice of medicine, the matter was settled. The beleaguered chiropractic profession of that state had two choices: it could risk continued harassment by the medical establishment or seek legislation. In a small frontier town in western Kansas, a benchmark trial would clearly demonstrate the public's feeling about chiropractic's right to exist on its own merits, separate and distinct from medicine. That coveted goal seemed to have been achieved by passage of the Chiropractic Act of 1913, the world's first such law. However, a board of examiners could not be legally seated. It would be a combination of brilliant legal strategy on the part of the chiropractors and the medical board's own negligence that would end the dilemma, allowing licensure in Kansas by 1915. PMID- 11613400 TI - The neurocalometer: watershed in the evolution of a new profession. AB - The Neurocalometer and its companion devices opened the way for a Pandora's box of instruments that often beguiled the chiropractor. Straight Palmerites were disheartened and confused by B.J.'s emphasis on machines; the definition of "pure" chiropractic was blurred. Some tried to recapture an ultrastraight chiropractic by following D.D.'s admonition that no electrical appliance should enter the adjusting room, while many with mixer tendencies moved toward pan therapy, choosing from an array of instruments parading before them. Determining the efficacy of any particular one presented a daunting task and helped flame the fires of schism. PMID- 11613401 TI - The Chiropractic Centennial Historic Exhibit: marking the ten decades of chiropractic history. AB - The Chiropractic Centennial Historic Display was exhibited at the Chiropractic Centennial celebrations in Washington, DC, July 6-9 and Davenport, IA September 14-17, and proved to be the visual centerpiece for the year's historic commemorations. The Association for the History of Chiropractic coordinated the display through the Chiropractic Centennial Foundation. PMID- 11613402 TI - Daniel David Palmer's medical library: the founder was "into the literature." AB - Although initially dismissed as an "unlearned healer," D.D. Palmer has proven to be a literate if self-taught writer, editor, author and teacher, who utilized the medical literature of his day in a surprising manner in his many publications. An examination of his work in The Chiropractor's Adjustor demonstrated the exactness of his thought. Very few medical practitioners at his time in America could claim to be so well read as was Palmer. He was competent in the use of medical literature, and not at all the uneducated healer he was alleged to be. A project, related to this study, is underway to reassemble DD's library to permit further examination of Palmer's scholarship. PMID- 11613403 TI - "Heat by nerves and not by blood": the first major reduction in chiropractic theory, 1903. AB - Recalled as the demarcation between D.D. Palmer's magnetic healing and chiropractic, the Harvey Lillard case holds a special place in the history of the profession and its healing art. Less familiar to chiropractors today, but of considerable significance in the subsequent development of chiropractic theories, was Old Dad Chiro's 1903 "discovery" that thermoregulation was a neural rather than a circulatory phenomenon. This Santa Barbara incident established the first major alteration in D.D. Palmer's chiropractic concepts, and would set the stage for the earliest known acquittal of a DC for unlicensed practice four years later, which in turn created strong incentive for subsequent differentiation between "neural supremacy" and the osteopathic "rule of the artery." The nature of the 1903 insight and some of the reasons why it is not more widely remembered among chiropractors today are discussed. PMID- 11613404 TI - Buckeye chiropractic: turbulence in a limited branch of medicine, 1915-1975. AB - In Ohio in 1915, the Platt-Ellis Law was enacted, a compromise between medical and chiropractic forces that defined chiropractic as a "limited branch of medicine or surgery." Practitioners of chiropractic, naprapathy, spondylotherapy, mechanotherapy, magnetic healing, and other "minor" healing arts excluding osteopathy and midwifery were all examined by the State Medical Board. The two disparate definitions created six decades of turmoil for chiropractic in Ohio. The 1920's were marked by the civil disobedience employed successfully in other states, with hundreds of unlicensed chiropractors choosing jail over fines. Multiple state organizations were formed, representing "straights, mixers, straight-mixers, mixing straights, minglers" and every other possible combination. The public accepted licensed and unlicensed practitioners, and doctors included their licensing status in their advertisements. PMID- 11613405 TI - A review and critique of Chiropractic History. PMID- 11613407 TI - Burton's Anatomy of Melancholy: Philosophically, Medically and Historically: part 1. PMID- 11613406 TI - The evolution of chiropractic orthopedists: a bootstrapping of clinical skills. AB - Spanning half of the chiropractic century, the development of the American Board of Chiropractic Orthopedists (ABCO) is a story of an educational bootstrapping that originated from the concerns of practicing field chirporactors. In the post World War II era, a need was determined to develop various principles and procedures of orthopedics in relation to chiropractic practice. Innovative chiropractors sought to promote greater levels of diagnostic precision within the profession by creating a post graduate program to teach advanced methods of physical and neuromusculoskeletal examination and treatment. Various specialty societies emerging after the 1947 creation of the professionally owned, non profit Los Angeles College of Chiropractic provided a humble beginning for the task. Eventually, with its roots in the National Chiropractic Association, the ABCO and its predecessors were successful in enhancing the education of practicing doctors, instituting similar programs in chiropractic college curricula, contributing papers to chiropractic literature and providing groundwork for early chiropractic research pertaining to musculoskeletal disorders. PMID- 11613408 TI - Quality of life and medicine: a historical note. AB - This paper analyses the historical origins of the concepts of welfare as a positive right and of quality of life. The latter has historical antecedents but has become important in the latter half of the twentieth century, owing to the conflict between consumer demands for medicine and constraints upon spending. It is argued that, beyond the immediate economic and utilitarian contexts, the concept of quality of life has the potential to promote individual liberty and a more subjectively-based approach to medicine. PMID- 11613409 TI - The dichotomies: psychosis/neurosis and functional/organic: a historical perspective. AB - Psychosis and neurosis have formed one of the crucial dichotomies in psychiatric classification. This has not always been the case, and indeed the distinction is again being blurred (Cooper 1989). This article will show how the dichotomy arose and how it was strengthened during the first fifty years after the introduction of the term psychosis. The relationship between psychosis and neurosis has not been examined historically, except briefly by Berrios (1987). Lopez Pinero (1983) has dealt with the origins of the concept of neurosis, but his study does not address later issues. The term psychosis was coined in 1845 (Feuchtersleben 1845) to denote 'mental disorder which affected the personality as a whole' and was a subcategory of the then much wider category of the neuroses. The latter were described by Cullen (1784) in the late eighteenth century to denote all the diseases of the nerves and muscles. In 1800, therefore, the neuroses were seen as diseases with a physical cause. The insanities, by contrast, were viewed as diseases of the mind and not generally of physical origin. By about 1900 this situation had been reversed. Most psychiatrists believed that the insanities were of organic aetiology, while the neuroses were of psychological origin, although at that time some psychiatrists and neurologists still believed that the neuroses were caused by organic changes, albeit ones which were not detectable by currently available means, and ones which were therefore referred to as 'functional disorders'. The historical contrast between the so-called functional and the organic disorders will be addressed in this article, as will its relationship to historical and contemporary issues regarding the psychosis neurosis dichotomy. PMID- 11613410 TI - Simon Browne: the soul-murdered theologian. PMID- 11613411 TI - The limits of medicalization: Jewish lunatics and nineteenth-century Germany. PMID- 11613412 TI - Madness, race and moral treatment: Robben Island Lunatic Asylum, Cape Colony, 1846-1890. PMID- 11613413 TI - Jurists versus doctors: the birth of legal medicine in the United States. AB - This paper considers some of the problems that attended the birth of legal medicine in the USA. The historical study of relations between American medicine and jurisprudence and ethics should identify some of the philosophical assumptions that inspire their views of anomalous behaviour. PMID- 11613414 TI - Introduction to 'On the pathology of the consciousness of the self'. PMID- 11613415 TI - The founding of the University of Wisconsin School of Pharmacy. PMID- 11613416 TI - The public image of the American pharmacist in the popular press. PMID- 11613417 TI - Systems of drug supply in German hospitals: the Nuremberg example. PMID- 11613418 TI - Superstition and medical knowledge in an Italian herbal. PMID- 11613420 TI - Pharmacy museums in old Czechoslovakia. PMID- 11613419 TI - Snakestones and experiment. PMID- 11613421 TI - Wet-nursing, onanism, and the breast in eighteenth-century Germany. PMID- 11613422 TI - Anne Lister's construction of lesbian identity. PMID- 11613424 TI - Magdeleine des Aymards: demonism or child abuse in early modern France? PMID- 11613423 TI - Women ovulate, men spermate: Elizabeth Blackwell as a feminist physiologist. PMID- 11613425 TI - Through the looking glass: reflections of Soviet psychology and the Russian psyche. PMID- 11613426 TI - "Bystanders at the banquet": Dickens and the psychopathology of consumption in Victorian England. PMID- 11613427 TI - Introduction: instruments in the history of science. PMID- 11613428 TI - Helmholtz and the materialities of communication. PMID- 11613429 TI - Instruments, nerve action, and the all-or-none principle. PMID- 11613430 TI - [Not Available]. PMID- 11613431 TI - [Not Available]. PMID- 11613432 TI - [Not Available]. PMID- 11613433 TI - [Not Available]. PMID- 11613434 TI - [Not Available]. PMID- 11613435 TI - Stone "Sarcophagi" and ancient hospitals in Sri Lanka. PMID- 11613436 TI - [Not Available]. PMID- 11613437 TI - [Not Available]. PMID- 11613438 TI - Otto Stader veterinary orthopedist. PMID- 11613439 TI - Sources of new information for the veterinarian. PMID- 11613440 TI - Blisters, beetles, and beliefs. PMID- 11613441 TI - Why did the infants and toddlers die? Shifts in Americans' ideas of responsibility for accidents -- from blaming Mom to engineering. PMID- 11613442 TI - Preventing "the needless peril of the coal mine": the Bureau of Mines and the campaign against coal mine explosions, 1910-1940. PMID- 11613443 TI - Pacing the heart: growth and redefinition of a medical technology, 1952-1975. PMID- 11613444 TI - Humor in science. PMID- 11613445 TI - 'Religious fanaticism' and wrongful confinement in Victorian England: the affair of Louisa Nottidge. AB - Louisa Nottidge was kidnapped and committed to a private asylum in 1846 by her family because she had joined a millenarian sect of which they disapproved. After eighteen months the Commissioners in Lunacy were pressurised into ordering her release. Subsequently, she successfully sued her brother and brother-in-law for wrongful imprisonment. The judge's criticisms of the medical profession led to an acrimonious public debate about the nature of mental illness and its treatment, a debate that involved some of the leading 'mad doctors' of the day including Dr. John Conolly. The complex history of this case, frequently referred to in recent scholarly work, but never discussed in detail, is examined together with its implications for our understanding of Victorian psychiatry, and its attitude to mental illnesses involving religious matters. PMID- 11613446 TI - Making medicine scientific: empiricism, rationality, and quackery in mid Victorian Britain. AB - This paper discusses the strategies used to construct scientific medicine in mid Victorian Britain. An opening section considers why it was thought desirable to create a properly scientific medicine, and outlines the empirical and rational bases of the medical establishment's projects for this. The bulk of the paper concerns an alternative approach to making medicine scientific--that put forward by certain advocates of homoeopathy--and how this approach was excluded from those arenas where scientific medicine was being created, and thereby made unscientific. This process is illustrated by the clash between homoeopathy and establishment medicine that occurred in mid-Victorian Cambridge. The final section briefly considers the complementary process of educating the public in what was properly scientific medicine, and what was not, and suggests that the processes of building boundaries to exclude competing practitioners, while keeping patients inside, created the space in which modern scientific medicine has flourished so successfully. PMID- 11613447 TI - 'Searching for Mary, Glasgow': contact tracing for sexually transmitted diseases in twentieth-century Scotland. AB - Social historians of medicine and sexuality have focused in recent years upon various strands of public health policy towards sexually transmitted diseases. However, despite the fact that, from the 1930s, contact tracing became one of the primary weapons with which British government sought to contain the incidence of STDs, its history in twentieth-century Britain has been largely ignored. Based on a range of governmental and private archives, supplemented by interviews with former practitioners, this paper examines the development of contact tracing in Scotland from its origins in the interwar period, through its expansion under Defence Regulation 33B during the period 1942-7, to its postwar development within the National Health Service. Particular attention is paid to the discriminatory aspects of wartime controls and to the professional, resource, and legal constraints shaping contact tracing in postwar Scotland. PMID- 11613448 TI - Accountability, entitlement, and control issues and voluntary hospital funding c1860-1939. AB - New income sources, revised organizational principles, treatment charges and a broader social range of patients featured in late nineteenth- and twentieth century voluntary hospitals. Participation in service organization and patient entitlement are neglected themes in discussion of the voluntary hospital system. They complicate presentations of popular support or ideological commitment to voluntarism, or oppositional advocacy of municipal or state services. Utilizing contemporary publications relating to hospital management, publicity, and contributory schemes, tension and conflict within voluntary effort are examined. Financial assistance did not signify full endorsement of voluntarism or deference to established hospital or medical authority, and later support for the NHS may not reflect a sea change in popular opinion concerning healthcare. PMID- 11613450 TI - 'Not always one and the same thing': the registration of tuberculosis deaths in Britain, 1900-1950. PMID- 11613449 TI - Invisible labours: mill work and motherhood in the American South. AB - With an almost total lack of access to contraceptive information before the mid 1930s, a high percentage of married women working in the textile mills of the American south were or rapidly became mothers. Without the financial resources to provide their families with wholesome food, medical care, and adult supervision, these women, who bore many children and shouldered most domestic duties in addition to their mill jobs, presumably had particular health care needs. This essay intially questions the usefulness of traditional categories that label physical ailments and accidents as either job-related or lifestyle-related. A group of female physicians in Greenville and Spartanburg Counties in South Carolina, all of them southern natives, worked during the 1930s to address some of the most immediate medical needs of the region's working women. These physicians had no appreciable effect, however, on workplace conditions and did not question the social and economic relationships that led so many working mothers to depend on their services. This essay also provides a partial analysis of public health services available to working mothers in Carolina mill villages during the Depression decade and explores reasons why the region's female medical professionals failed to challenge a form of social organization that left working mothers' particular health care needs unaddressed. PMID- 11613451 TI - The medicalization of war--the militarization of medicine. AB - After many years of relative neglect, the military and militaristic aspects of medical practice are again beginning to receive historical attention. This review indicated some of the themes emerging from recent scholarship on medicine and war, and indicates some further areas for investigation. The two most fundamental issues arising from this scholarship relate to what might be termed, respectively, 'the militarization of medicine' and the 'medicalization of war'. The former raises the question of to what extent modern medicine was affected by the militarization of many advanced industrial societies from the late nineteenth century, and by the experience of two World Wars. The latter draws attention to the gradual incorporation of medicine within the armed forces, and the growing influence therein of medical experts; a process arguably essential to the prosecution of 'modern' mass warfare. PMID- 11613453 TI - To die or not to dye. Poisoning from arsenical pigments in the 19th century. PMID- 11613454 TI - Opium smoking. PMID- 11613455 TI - Gender and nursing in colonial Victoria, 1840-1870. AB - The role of the nurse in health care has been the subject of a debate over time which engages with the ambiguity about the role of the nurse, the boundaries of nursing work, and the question of the status of women and men within the profession. In this paper we report on a historical analysis of the nature of nursing work in colonial Victoria, Australia, which was undertaken in order to understand how the nursing role evolved and was socially constructed in early Australia. A significant absence of accounts of nurses between 1840 and 1870, and a lack of comparative analysis of male and female roles in nursing care in this period, suggested a need to reveal some of the social, political and economic influences on the delineation of nursing work and the relevance of these factors to the relationships between hospital staff. The study adopted three strategies or methods. First, the scattered and diffuse references to the origin and development of the role and function of the nurse in this were collated, particularly identifying nursing duties and the existing division of labour. Following this, hospital administrative structures were analysed. Finally, an interpretive methodology of textual analysis was employed and the portrayal of nursing in a number of texts, including hospital histories, annual reports and contemporary literature were examined. This provided us with a socio-cultural and historical perspective on the nature of nursing work in early Victoria. PMID- 11613456 TI - Terms used in Byzantium for nursing personnel. AB - It has been long recognised that Byzantium was the cradle of hospital care. Most of the hospitals, called Xenones, were annexed to monasteries. The nursing staff were either volunteers or paid personnel. Professional nursing personnel were used for the first time in Byzantium hospitals. Many terms were used to describe the personnel in these hospitals and this paper identifies these nursing personnel from Byzantine sources and provides definitions of their duties: deaconesses (diakonisses), ministers (ypourgoi) and ministresses (ypourgisses), nurses (nosokomoi-nosileftes), auxiliary nurses (paranosokomoi), hoteliers (xenodochoi), excubitors (exkoubitores), phlebotomists (phlebotomoi), parabolani (parabolaneis or parabalaneis), scribones and deputati (skrivones and depotatoi), and midwives (maies). The paper further demonstrates that for the first time hospital personnel were divided into categories; hospital administration was exercised by specialist personnel, the nosokomoi. PMID- 11613457 TI - Nazism and nursing: a comment on relevance. AB - This paper suggest that it is crucial at the present time to look back and consider the role of nurses and the health-care system in the development of Nazi Germany. The paper points out that medical involvement in the Holocaust was extensive and underwritten by the subversion of science to political ends. Evidence is amassed which points to dangerous trends in the conduct of contemporary medicine and to the continuing capacity for institutionally endorsed abuses of human rights. It is suggested that nursing examine its role in the implementation of Nazi policies, so that its continuing susceptibility to political subversion can be recognised, evaluated and neutralised. PMID- 11613458 TI - Nurse recruitment and retention in the 19th century London teaching hospitals. AB - 'One of the greatest difficulties which occurs in completing the arrangements of a hospital is the procuring of proper persons to act as nurses; since as much perhaps depends on the humane endeavours of a kind and attentive female as upon the ability of the medical attendant', Benjamin Golding wrote in 1819. He had just qualified as a doctor at St Thomas' and was impressed by the way a skilful nurse could often secure a patient's recovery when the doctor had given up all hope. This article addresses the problem which Golding identified, the recruitment and retention of nurses in the London teaching hospitals during the 19th century. The recruitment and retention of sisters and matrons was much less difficult, and I therefore confine my discussion to the problems involved in finding what Golding called 'proper persons to act as nurses'. PMID- 11613459 TI - Performance practice: music, medicine and natural philosophy in Interregnum Oxford. PMID- 11613460 TI - Discovering the invisible Puerto Rican slave family: demographic evidence from the eighteenth century. AB - Traditional notions that family life among slaves during the pre-plantation period in the non-Hispanic Caribbean was necessarily unstable are fading in light of new research. Although marriage among this segment of the population in Caguas, Cayey, San German, and Yauco--rural parishes in Puerto Rico--involved only a fraction of the overall number of marriages in these communities, the marriage of slaves was much more frequent than previously assumed. Family life among the eighteenth-century Puerto Rican slave population appears to have been quite stable, as shown by the reconstruction of birth intervals for both married and unmarried mothers. Married and unmarried mothers exhibited similar reproductive behavior. These results strongly suggest that a majority of the unmarried slave mothers lived in unions that were not institutionally recognized, but that were nevertheless stable, as indicated by the high percentage of their children born at intervals comparable to those of married mothers. If unmarried mothers were living in stable consensual unions, then our understanding of these slave family units during the colonial period must be reassessed not only for Puerto Rico but possibly for the rest of the Caribbean and Latin America. PMID- 11613461 TI - "A sudden and terrible revelation": motherhood and infant mortality in France, 1858-1874. AB - In 1874, legislators in France passed a law regulating the wet-nursing industry. Citing recent medical research into the causes and social costs of high infant mortality, the law's supporters met little opposition, despite the fact that the law challenged the tradition of paternal authority and familial autonomy that had been inscribed in French law since the promulgation of the Civil Code of 1804. Extending state power into the familial realm required a concerted effort by reformers, who concentrated on two issues: maternal responsibility for newborn infants and the social costs of early death. Because working women in urban areas used wet-nurses to preserve their wage-earning capacity, reformers capitalized on widespread opposition to women's labor outside the home. The law met little opposition in part because the issues of paternal authority had already been thoroughly debated several months earlier in the child labor law of 1874. PMID- 11613462 TI - Children's cemeteries: early Christianity, not disease. PMID- 11613463 TI - Annotated bibliography. PMID- 11613464 TI - The use of natron in Egyptian mummification: preliminary report. PMID- 11613465 TI - aDNA analysis in paleopathology: mini-review and prospects. AB - The epidemiology of human diseases is a major indicator of living conditions. Cardiovascular diseases are said to be a phenomenon of modern industrial societies, but infectious diseases have always been an indicative determinant in historic and prehistoric human populations. The spread of infectious agents is closely related to socioeconomic factors, e.g., nutritional status, population density, and hygienic conditions. Gathering more paleoepidemiological data on infectious diseases would also be helpful in studying human adaptivity and the evolutionary capability of pathogenic microorganisms. Until now, the collection of paleoepidemiological data was restricted to those human diseases that left traces on the skeletal remains, e.g., the terminal stages of syphilis, tuberculosis, and leprosy, or degenerative disorders of the joints. With modern molecular techniques, the spectrum of detectable infectious and heritable human diseases will foreseeably be enlarged. By detecting the infectious agent, or analysing the genetic codes, it will be possible to focus systematically on those diseases that either lead to sudden death or do not affect the skeleton because of their specific course. PMID- 11613466 TI - An unusual paleopathological finding: a possible 'ciclicium' in a XV century natural mummy from central Italy. PMID- 11613467 TI - Cranial tumors from an early Christian tomb. PMID- 11613468 TI - Islamic medicine in philatelic perspective. PMID- 11613469 TI - Pestilence and postage. PMID- 11613470 TI - Remembering early anesthesia. PMID- 11613472 TI - My view of veterinary medicine in the early nineteen thirties at Belmond, Iowa. PMID- 11613471 TI - Historical height samples with shortfall: a computational approach. AB - Research in economic history frequently uses human height as a proxy for net nutrition. This anthropometric method enables historians to measure time trends and differences in nutritional status. However, the most widely used data sources for historical heights, military mustering registers, cannot be regarded as random samples of the underlying population. The lower side of the otherwise normal distribution is eroded by a phenomenon called shortfall, because shorter individuals are under-represented below a certain threshold (truncation point). This paper reviews two widely used methods for analyzing historical height samples with shortfall - the Quantile Bend Estimator (QBE) and the Reduced Sample Maximum Likelihood Estimator (RSMLE). Because of the drawbacks of these procedures, a new computational approach for identifying the truncation point of height samples with shortfall, using density estimation techniques, is proposed and illustrated on an Austrian dataset. Finally, this procedure, combined with a truncated regression model, is compared to the QBE to estimate the mean and the standard deviation. The results demonstrate the deficiencies of the QBE again and cast a good light on the new method. PMID- 11613473 TI - A brief history of the School of Veterinary Medicine at Tuskegee University. PMID- 11613474 TI - The Blue Cross veterinary emblem. PMID- 11613475 TI - A historical survey of vivisection from antiquity to the present. PMID- 11613476 TI - The development of an international business information service for the pharmaceutical industry. PMID- 11613478 TI - The early years of British pharmaceutical journalism. PMID- 11613477 TI - The Dutch pharmacist in the mid-nineteenth century. PMID- 11613479 TI - The history of pharmaceutical associations. PMID- 11613480 TI - The Derbyshire General Infirmary. PMID- 11613481 TI - Medical fiction and pharmaceutical facts about theriac. PMID- 11613482 TI - Medicine from animals: from mysticism to science. PMID- 11613483 TI - Some early London physic gardens. PMID- 11613484 TI - George Edward Trease (1902-1986) - a man of his time. PMID- 11613485 TI - FDA and the practice of pharmacy: prescription drug regulation before the Durham Humphrey Amendment of 1951. PMID- 11613488 TI - Formal and informal training in pharmacy, Ontario, Canada, 1917-1927. PMID- 11613489 TI - Immigrant pharmacists in Minnesota 1885-1910. PMID- 11613492 TI - The founding period of the U.S. Pharmacopeia. III. The First Edition. PMID- 11613494 TI - Pharmacology and public health: the Jamaica ginger paralysis episode of the 1930s. PMID- 11613496 TI - Anna Karenina and opiate addiction. PMID- 11613497 TI - [On a circular notice about herbs in Kisodani of mid-Edo period]. AB - There is a circular notice about the gathering of herbs in Kiso-dani of Mid-Edo Period, and this notice is stocked at T. Simada's house in Nakatsugawa City. Thirty-two herb names and the prices are recorded in this notice, and some of them have the precise description of collection, medical parts, processing, general treatment, etc. Doeki Mimura contributed greatly to the development of Kiso Yakushu (crude drug), however, we cannot pass over the activity of Saiyaku shi (medical officer) as well. PMID- 11613498 TI - [Historical and herbalogical studies on coloring crude drug (Part 3) "Shu wei cao"]. AB - The usage of Shu wei cao as a coloring matter was described for the first time in Er Ya as the name of Jing shu wei. But, in modern Chinese and Japanese literature, few papers reported the use of Shu wei cao as a dye. As a herbal medicine, it seems that it was first described in Ming Yi Bie Lu. In this study, we found that in Chinese and Japanese literature, there is much confusion about the origin of Shu wei cao. It is likely that the original plant of Shu wei cao is to be Salvia japonica Thunb. In Japan, it is feasible that Shu wei cao is to be recognized as Aki-no-tamura-so, while some suggested that misohagi (Lythrum anceps Makino) was identical to Shu wei cao. PMID- 11613499 TI - [The proposal for community pharmacist activity from a viewpoint of science history]. AB - Community pharmacists have many kinds of problems for demonstrating their ability and activity. One of them is to realize the professional activity. At present, I am afraid that such community professional activities might be for now confined to legal extension. I would therefore like to discuss the aspect of professional centrifugal practice in community health care system under the pharmaceutical law system. Secondly, the role of pharmacists in drug sale comprises advising and controlling medication that we call "Application Pharmacy" in which individual pharmacokinetics and susceptivities have to be considered. The Application Pharmacy will be established in the community medical health care system for new pharmacist's activity. The Application Pharmacy should be a requirement for community pharmacists and lead to a notion of "Community Pharmacy Therapeutics."]. PMID- 11613500 TI - [The development of modern Japanese pharmaceutical industry (Part 4). From 1906 to 1920, coinciding with the era between the institution and issue of Japanese Pharmacopoeia Third Edition with Fourth Edition (JP III-JP IV)]. AB - The publishing of the Third Edition of Japanese Pharmacopoeia was performed after Russo-Japanese War, on July 2, 1906. In those times, the military and economical power of Japan advanced toward East Asia, and thus gradually, Japan had become one of the powerful force in the world, partly because due to the unexpected victory in the War. Thereafter, in the second decade of the twentieth century, Japan was involved in the World War I, from July, 1914 to November, 1918, which ceased the fire by the defeat of Germanic Allied Countries. In Japan, the next revise of the pharmacopoeia was performed and the Fourth Edition of it was published on December 15, 1920. The Japanese pharmaceutical industry developed remarkably in those times, during the big war and confusion in the market, by accompanying with the suitable and tentative pharmaceutical legislations by the government and the supportive aids to the civilian enterprises in the productions, supplies and distributions of the materials and medicinal products. PMID- 11613501 TI - [Review of the pharmaceutical exhibitions in the Meiji Era (Supplement)]. AB - The author described (Jpn. J. History Pharm. 16(1), 9-20 (1981) the Review of the Pharmaceutical Exhibitions in the Meiji era. But afterwards the author found there were omissions of three exhibitions. These are the Nagaoka, the Osaka, and the Akita Exhibitions. The Nagaoka Exhibition was organized by the Nagaoka Pharmacists Association in June, 1890. The Osaka Exhibition opened on Jan. 18, 1891 by Osaka Branch of the Pharmaceutical Society of Japan. The Akita Pharmaceutical Exhibition was held on Sept. 24-26, 1892, as the chief event of the opening ceremony of the Akita Drug-Trader Association, united pharmacists, druggists, and drug-manufacturers throughout Akita Prefecture. It is the most large-scaled of the three. The exhibits were 1,419, and the visitors were above 8,830. The planning originated with a young pharmacist Masayasu Hanyu. PMID- 11613502 TI - [C.P. Thunberg and his voyage to Japan (4). Mercury water therapy for syphilis introduced into Japan by Thunberg]. AB - During his 16-month stay in Japan from August 1775 to December 1776, Thunberg taught mercury water therapy to Japanese medical doctors and interpreters in order to help them treat syphilis, which was prevalent in Japan at that time. Kohgyu Yoshio, a Japanese-Dutch interpreter who was taught this therapy by Thunberg, recorded Thunberg's teaching in his "Kohmoh Hijiki." According to this book, the mercury water therapy that Thunberg introduced to Japan had been tested successfully by van Swieten, a Dutch doctor, about 20 years previously in Europe and used corrosive sublimate (mercuric chloride), the active ingredient, dissolved in distilled water with honey. The formula is described, in measurement units used in Europe at that time, in a letter addressed by van Swieten to a doctor in Rotterdam in 1755. The formula recorded in "Kohmoh Hijiki" in measurement units used in Japan at that time gives a content of the active ingredient equivalent to that mentioned in van Swieten's letter. This fact indicates that van Swieten's formula introduced by Thunberg was correctly accepted by Japanese doctors and interpreters, who had acquired basic medical knowledge since the publication of "Kaitai Shinsho" in 1774. PMID- 11613503 TI - [C.P. Thunberg and his voyage to Japan (5). Mercury water therapy fpr syphilis (continued)]. AB - The formula for the mercury water therapy introduced into Japan by Thunberg for the treatment of syphilis was received in 1742 by van Swieten, a Dutch medical doctor who studied under Boerhaave and who later became a professor at Vienna Univ., from Sanchez, a Russian medical doctor. After trying it personally for the treatment of the sexual disease for 12 years, van Swieten tested it in 128 patients at St. Marx's Hospital in 1754. It spread throughout Europe when it was published by van Swieten after confirming its safety in these patients. The formula was listed in Pharmacopoeia of different countries from the 1830's to the 1930's under name "van Swieten Liquid." In Japan, it spread widely through Kohgyu Yoshio, a Japanese-Dutch interpreter who was taught it by Thunberg, and his pupils. The first (1886) through 5th (1932) edition of the Japanese Pharmacopoeia listed corrosive sublimate as an oral drug for syphilis. The indicated dosage is within the range of van Swieten's original formula. PMID- 11613504 TI - [The transition of psychotropic drugs in Japanese Pharmacopoeia (JP) (Part 7). The study for cultivation of Valeriannae Radix in Hokkaido area]. AB - Japanese Valerianae (J.V) was widely cultured all over Japan until the second World War (War II). J. V contained more volatile oil than European Valerianae. Therefore, J.V was exported mainly to Germany until the War II and was highly evaluated by foreign countries. After the War II, the food situation in Japan was bad. Then the increase of foodstuff production had priority over the herb growth. Therfore, J.V was not widely cultured all over Japan as before the War II. After the War II, J.V was cultured only in Hokkaido. Valerianae Radix cultured in Hokkaido was changed to Hokkai-Kisso from J. V after the War II. The beginning of Hokkai-Kisso could not be confirmed completely yet by this study. The operation of Valerianae is easy and safe. So it is thought that Valerianae Radix may be used for raw materials of general drugs and will remain in the general drug market mainly in the future too. PMID- 11613506 TI - [The historical change of the German pharmacy symbol "Apotheken-A"]. PMID- 11613505 TI - [Japanese medicines studied by Hepburn, an American missionary, in 1860s]. AB - In the last days of the Tokugawa shogunate when Japan was opened its door to trade, J.C. Hepburn came to Japan, and he contributed to the modernization of Japan as a missionary, a doctor and an instructor. His great academic achievement was publishing a Japanese-English and English-Japanese dictionary. The dictionary contained words which were generally used in those days. It is said that it was way of living and culture in Japan as seen by an American. Words about medicine show the conditions of the business of medicine in those days. Until 1889 a pharmacist was not professionalized yet, nor was the separation of dispensary from medical practice effective. As most of doctors were Chinese herb doctors, there was not the word "MD." As Chinese doctors were the leading ones, lots of words about herb were mentioned. We can find only a few words about chemicals. The common people used patent medicine such as Daranisuke, Mankintan. Less than 100 years, sorts of medicine in Japan have changed to those of medicine in Western countries. PMID- 11613507 TI - [The essays of Keizou Tanba and Ougai Mori about separation of dispensary from medical practice]. AB - Keizou Tanba wrote an article on separation of dispensary in Chugai-iji-shinpo in June, the year 23 of Meji Era. It was said that separation of dispensary had to be carried out and it brought many advantages. First, a pharmacist can examine the prescription and correct it if there are any mistakes. He will be able to give an advice to a doctor that the side effects will perhaps occur due to preparation of medicine. Secondly, a pharmacist can superintend whether unnecessary medicine is prescribed or not. He will check surplus prescription in such a case that a patients will be cured by observing dietary or exercise. According to Tanba's opinion, if we will get people to know what separation of dispensary is, it is easy to be carried out. Ougai Mori wrote an essay separation of dispensary in the same period. His opinion was opposite, basically. It caused to impose a burden on a patient. As the number of pharmacist were not enough, it was impossible to carry it out. A conflict of opinion also remains among people related to medicine at present. The circumstances on separation of dispensary have not been changing during one hundred years. PMID- 11613508 TI - [Memoirs of historical review for research of tetrodotoxin]. PMID- 11613509 TI - [Historical review on chemical and medical studies of globefish toxin before World War II]. AB - "Fugu," a species of globefish has eaten by Japanese people for a long time, so globefish poisoning in Japan has been prevalent. Figures are shown in the Annual Food Poisoning Report collected and issued by health service authorities of Japanese Government since 1879. These reports prompted Dr. Yoshizumi Tahara, National Institute of Hygienic Sciences to conduct a chemical investigation of the toxic substance of globefish in 1884. However, the analysis was very difficult and his report of investigation was delayed. Before publication of the report of Dr. Tahara, pharmacological and toxicological studies of globefish poisoning were reported by three research groups from the Facultly of Medicine, University of Tokyo in 1889. These reports concluded that globefish poison has curare-like activity and its distribution was limited to specific organs such as the ovaries and the liver. Dr. Tahara successfully isolated the poison from aqueaous extract of ovaries of globefish by precipitation with lead acetate in the presence of ammonia. He presented the results at the monthly meeting of the Pharmaceutical Society of Japan in July 1894. He continued the studies and established an improved method for extraction and purification suitable for large scale production. Finally, he confirmed that globefish contains only one toxic substance and named it Tetrodotoxin (TTX) in 1909. He elucidated the chemical nature of TTX as follows: 1) TTX is an amorphous hygroscopic powder and its character is neither alkaloid nor protein. 2) The possibility of TTX being a protamine was excluded by chemical analysis. Before the discovery ot TTX, according to folklore, globefish was regarded as medicine for leprosy because flesh of globefish contaminated with a sublethal dose of toxic substance alleviated the neuralgia of patients affected with leprosy. The clinical effect of TTX prepared by Tahara's method to suppress severe neuralgia due to leprosy and to reduce muscle spasms due to tetanus were reported by dermatologists in 1911. TTX was also given to patients with rheumatoid arthritis due to its analgesic effect. Thus, injectable TTX was manufactured and distributed by Sankyo Co., Ltd. from 1913. In terms of purity, the TTX preparation manufactured by Tahara's method seemed to be much more crude than the crystalline TTX obtained by Professor Tsuda and Dr. Kawamura in 1952. According to their report, the LD50 of the preparation for clinical use manufactured by Tahara's method was 4-5 mg/kg mouse compared to 4-6 microg/kg mouse of crystalline TTX. PMID- 11613510 TI - [Studies on Fugu (globefish) tetrodotoxin over one century]. AB - One century has passed since fugu toxin was first named tetrodotoxin by Tahara. Chemical problems such as crystallization of tetrodotoxin, followed by structure determination by the research groups headed by Tsuda, Hirata, Woodward, and Mosher, and its subsequent synthesis by Kishi have been solved. In the last 10 years, research on the distribution of tetrodotoxin in nature has shown that tetrodotoxin is not produced by fugu fish, but rather is formed by sea bacteria such as Vibrio, Alteromonas, Photobacterium, and Aeomonas. However, it remains unclear why tetrodotoxin accumulates at a high concentration only in fugu. PMID- 11613511 TI - [Pharmacology of tetrodotoxin and molecular structure of sodium channel as its target molecule]. AB - Since Dr. Y. Tawara started investigation of the lethal paralytic toxin (tetrodotoxin) from globefish just 100 years ago, Japanese researchers have contributed greatly at every stage of its chemical and pharmacological analysis as well as to the molecular studies which led to the discovery of the sodium channel as its target. On this special ocasion, I briefly review the pharmacology of tetrodotoxin and the molecular structure of the sodium channel. PMID- 11613512 TI - [A history of a hundred years of pharmaceutical education in Japan]. AB - The history of a hundred years of pharmaceutical education in Japan is divided into six periods for the purposes of discussion. 1. Founding period of the pharmaceutical education in the Meiji era (1873-1879) The Department of Manufacturing Pharmacy, Faculty of Medicine, University of Tokyo was established in 1873 (now, Faculty of Pharmaceutical Sciences, the University of Tokyo). The purpose of this school was for professional training to accommodate growing imported Western drugs. 2. Building period of the pharmaceutical education in the Meiji era. (1880-1911) The Pharmaceutical society of Japan (academic) was established in 1880, and then 13 years later (1893) the Japan Pharmaceutical Association (professional) was established. The order of establishments, first academic and then professional, was opposite of the history in European countries. Twenty-nine schools of pharmacy were built in the Meiji era, however 20 schools of pharmacy have been closed. 3. Developing period the pharmaceutical education in the Taisho era and half of the Showa era (1912-1944) Seventeen pharmaceutical colleges were built in these periods. Pharmaceutical chemistry, pharmacognosy, hygenic chemistry, and manufacturing chemistry were mainly taught in these schools of pharmacy, however pharmacology, bacteriology, and biochemistry were not taught in these schools. 4. Reform of pharmaceutical education system after the World War II (1945-1960) In 1949, the Japanese education system was reformed, and then 46 colleges and universities of pharmacy were built. Then, the number of students doubled to 8,000. Graduates from pharmaceutical colleges and universities, pharmaceutical departments were eligible to take the national pharmacists licence examination which was conducted by the Ministry of Health and Welfare. The standard of the pharmaceutical education system was revised in 1656, recommending that the single pharmaceutical departments at the colleges of pharmacy by replaced by three departments, pharmacy, manufacturing pharmacy and biological pharmacy. 5. Improvement and developement of pharmaceutical education (1961-1985) Many universities and colleges were founded, and there are currently 46 universities and colleges. Every year, some 8,000 people who study pharmacy at 14 national, 3 public and 29 private universities enter the profession on graduation. About 60 percent found jobs in the pharmaceutical industry, and the remainder work as pharmacists in hospitals and pharmacies. 6. Recent movements toward reform in pharmaceutical education (1986-present) Two amendments to the Medical Services Law in 1986 and 1992 have specified clearly the role to be played by pharmacists and pharmacies within their local medical service and has sharpened the distinction between medicine and pharmacy. Thus, in 1994, the period required for graduation is proposed by a committee of the Ministry of Health and Welfare, supplementing of the current 4-year undergraduate pharmacy course with a 2-year postgraduate master's degree course or a 6-year new pharmaceutical education system including practical training in a medical institution for a period of at least 6 months. PMID- 11613513 TI - [Studies on the medicinal plants in the "Sambutsu-cho" of Merayama, belonging to Kuma province, Higo]. AB - The Sambutsu-cho, a list of the natural products, of Merayama, belonging to Kuma Province, Higo was dedicated to the Tokugawa shogunate ca. 1735. This book did not contain so many names, but there were various names of plants, animals and minerals. In the plant kingdom, there were the names of the wild and cultivated plants, such as cereals, vegetables, fruits, trees, bamboos, herbs and mushrooms. The part on trees had 61 names and the other part, on herbs, had 76 names. In this report, I studied the species of the trees and herbs which were listed by their local and standard names. I identified them and found 56 and 63 species, respectively. Among the 56 species of trees, 39 were medicinal plants. Also, 48 medicinal plants were found among the 63 species of herbs. The ratio of medicinal plants to trees and herbs was 70 and 76%. This Sambutsu-cho contained color illustrations of the herbs, trees, animals, birds and insects. These pictures were not always accurate but very much useful to identify the local names in the Edo-period to match them with their scientific names. One of the most interesting samples was "Miso-ushinai." This was identified as Lyonia ovalifolia var. elliptica, Ericaceae. PMID- 11613514 TI - [Siebold's mydriatic eyedrops]. AB - I discovered two prescriptions of mydriatic eye drops that seemed to be written by Von Siebold. One prescription (prescription 1) belongs to the Siebold Memorial Hall in Nagasaki City, and the other (prescription 2) to the Municipal Museum in Ohzu City in Ehime Prefecture. Prescription 2 does not bear Siebold's signature but can be considered to have been written by him based on handwriting analysis. The major drugs in these prescriptions are Ex Belladonna and Ex Hyoscyamus. However, both prescriptions seem to have been written not only for mydriasis but also for antiphlogistic, analgesic and anticonvulsant effects in patients with eye disease. Based on the notes of the JP III and JP V, the mydriatics used by Siebold in operations such as for cataract were Ex Belladonna and Ex Hyoscyamus at a concentration of about 1%. Prescription 1. For a male with eye disease. Ex Belladonna 0.65 g; Laudanum 20 drops; Barium chloride 1.3 g; Rose water or chamomile water 124.4 g. Administer 3 times/day. Von Siebold (signature). Prescription 2. For Soya's daughter in Narutaki. Ex Hyoscyamus 0.39 g; Rose water 62.2 g. Administer some drops twice/day. PMID- 11613515 TI - [The medicine chest handed down in the Takaya family, doctors of Sendai-han]. AB - There is a medicine chest with design of Chrysanthemums in Makie made for Edo-era and handed down in the Takaya family, doctors of Sendai-han. Many kinds of crude drugs, named by one Chinese character, are kept in this chest. They were classified into three types, namely, [Japanese characters]. Identification of these crude drugs was carried out and the meaning of the classification was brought up as a question. PMID- 11613516 TI - [History of professionalization of modern clinical pharmacist (3). The birth of clinical medicine and clinical pharmacy]. AB - At the end of eighteenth century and the beginning of the nineteenth century clinical medical and clinical pharmaceutical teaching was organized according to the reformation of the medical system in French Republic. Michel Foucault said in the book "Naissance de la clinique." -- "To all appearance, it was simply reviving, as the only possible way of salvation, the clinical trandition that had been developed in the 18-century. But it was fundamental experience, because, unlike the 18-century clinic, it is not a question of an encounter, after the event, of a previously formed experience and an ignorance to be dissipated. It is a question, in the absence of any previous structure, of a domain in which truth teaches itself, and, in exactly the same way, offers itself to the gaze of both the experienced observer and the naive apprentice; for both, there is only one language: the hospital, in which the series of patients examined is itself a school."--(M. Foucault, 1963) Clinical pharmaceutical teaching started in the central pharmacy and in the hospital pharmacies in Paris with the rule of 4. ventose in year X. This was the birth of Clinical Pharmacy Practice as a new fundamental experience in France. PMID- 11613517 TI - [A review on the development of Kallikrein (Kallidinogenase)]. AB - This article briefly summarizes the historical events particularly these in Japan, in the kallikrein-kinin research and progress of the development of kallidinogenase (INN), enzyme with circulatory action. In 1926, E. K. Frey observed a drop in blood pressure in dogs following intravenous injection of the urine of human and other mammals into dogs. Intensive research showed that the urine contained a high-molecular active substance which dilated the peripheral arterial vessels. The substance was later called kallikrein after the Greek synonym for pancreas, as it occurred there at such a high concentration (Kraut et al., 1930) that this gland was thought to be its cite of origin. In 1930, kallikrein was commercially available as Padutin from Bayer, Germany. The product was introduced into Japan a few years later under the trade name of Kallikrein and was used for the treatment of circulatory disorders even during the Second World War. Kallikrein was again imported by Yoshitomi Pharmaceutical Industries, Ltd. in 1952. However, Kallikrein introduced after the War did not contain substance derived from the urine but from porcine pancreatic kallikrein as the active ingredient. It grew rapidly with its active promotion of the product in such fields as internal medicine, ophthalmology, otology etc. Domestic manufacturers increasingly entered this market and the number of the manufacturing license holders of similar products reached 26 in 1975 when kallidinogenase preparations were designated to undergo drug re-evaluation by the health authorities. Since June 1988 when the re-evaluation for kallidinogenase preparations was completed, all the relevant manufacturers have supplied new formulations containing higher quality substances and labeling their potencies expressed in International Units based on the kallidinogenase reference standards which had since been established. PMID- 11613518 TI - [Historical sketch of modern pharmaceutical science and technology (Part 3). From the second half of the 19th century to World War II]. AB - The history of modern pharmaceutical science and technology, from the second half of the 19th century to the end of World War II, is divided into nine sections for the purpose of discussion. 1. The European medical and pharmaceutical science and technology at the end of the 19th century is reviewed. Pharmacology, bacteriology and biochemistry were built in this period. 2. The Meiji Government accepted Western medicine and medical law and regulations in 1883. Consequently, the Japanese physician changed from Eastern (Kanpooi) to Western (Seiyooi). 3. Modern scientific and engineering education had been accepted in America, England, Germany, and France etc. Foreign scientists and engineers (Oyatoi-gai-kokujin) were educated by practice and theory. The Faculty of Engineering was established in the universities in Japan. This fact is one of the differences in the history of universities in Europe and America. 4. Pharmaceutical education in the Meiji period (1873-1911). Twenty-nine schools of pharmacy were built in this period. However, 20 schools of pharmacy had been closed. Pharmacy and pharmaceutical industry was not established in the Meiji era. 5. The profession of pharmacist in 1873-1944. The policy of medicine was changed by the Meiji Government in 1889, when Western physicians were allowed to prepare medicines for patients, and this practice continues today. Political and technological power of Japanese pharmacists was weak, so their role was not estimated. 6. Consequences of world War I, and the establishment of the pharmaceutical industry. The Sino-Japanese War (1894-95) and Russo-Japanese War (1904-05) were won fortunately. The first pharmaceutical company was established in 1885. At this times, many pharmaceutical manufacturing companies, which were converted from whole sale merchants, were built. Then started the manufacturing of commercial drugs. 7. Hygienic chemistry and some problems of public hygiene. The causes of diseses unique to Japan, such as beriberi (Katuke), were searched for in medical and agricultural laboratories. Dr. Suzuki discovered olizanine from rice bran, which was effective for deficiency of vitamin B1 disease. However, pharmaceutical scientists did not participate in this research. Hygienic and forensic chemistry were included in pharmaceutical departments. 8. Pharmaceutical scientific studies in Europe and Japan in the first half of the 20th century. The discovery of a drug for the treatment of syphilis by Ehrlich-Hata (1889), then chemotherapeutics were started. Adrenalin, the first isolated hormone, by Takamine (1900), after this time many hormones were discovered. The first Japanese pharmacists who studied abroad studied in Germany and came back to Japan. Then, they built the pharmaceutical sciences. Studies on natural products by chemistry and organic chemistry were started. 9. Pharmaceutical scientific and technology during 15 Years of War (1931-45). Since 1930, theoretical organic chemistry was developed in England and America. The discovery of chemotherapeutics and antibiotics (sulfonamides and penicillin) and studies on some vitamins and hormones proceeded during the 15 years of war (1931-45) at Tokyo and Kyoto Universities, and some institutes in China and Manchuria. Studies on anti-maralia, sulfonamides and penicillins were carried out. PMID- 11613519 TI - [Differences in the development of pharmacy in Europe, Japan and the U.S. -- Historical review and outlook]. PMID- 11613520 TI - [Study of "Bishu Yakuen Ransho-Roku (the origin of herb garden in Owari Clan)]. AB - "Bishu Yakuen Ransho-Roku (The origin of herb garden in Owari Clan)" is in the possession of the Institution of Tokugawa Rinseishi in Tokyo. This paper was written about the origin of the herb garden established by Mr. Shinken Mimura, an herbalist in the Owari clan between 1735 and 1746. Mr. Shinken Mimura cultivated ginseng by according to the guide issued by the shogunate, but he found the methods unsuitable. Therefore, he made efforts to improve the cultivation of ginseng. As a result, he succeeded in the cultivation of good ginseng. He had contributed to the development of the production of ginseng in the Owari clan. He write this document so that his methods could be handed down for posterity. This document has two parts: one is the growth of ginseng in the form of a diary and the other is the conditions of cultivation as to seeding, fertilization, the counter-measures for damage due to blight and insects, and so on. PMID- 11613521 TI - [The historic study on the health drink-especially on the origin of health drink and the formation of its market-]. AB - The health drink is oral liquids which are classified as elixirs or limonades and so on, which are peculiar to Japan and differ from other liquids to glass a dose of drug. It has mainly been divided into two classes by glassed volume (dosage) in the bottle. One class is the drink tonic which is the capacity of 100 ml and another is the mini-drink tonic which is 50 ml and less. In addition, oral liquid glassed with an ampule is called the ampule tonic. Such drugs were thought to appear after World War II and have been widely known since 1960. However, tonics which had consisted of recipies like the present health drink were shown to exist before World War II. Thus, it was considerable that such prescription formulas were also applied to the ampule tonic and drink tonic. On the other hand, one of the important problems with health drugs was how to make their taking easy in its development. Further, it was necessary to add to acid antiseptic and high content of sugar etc., because the liquids generally had been putrescible. It might be one of the reason for their appearances that it was allowed to produced a liquid which was stabler and made its taking easier to be released from the above limit by the introduction of a dose-glassed liquid. In 1960, the ampule tonic quickly became popular and the drink tonic followed. It was probably caused by changes on the standard and style of living involved the enhancements of the labor time, purchasing power and sense on the health and active propaganda of the manufacturers. In this way, the market has satisfactorily expanded. However, because such medicines liked beverages appeared, it was difficult to distinguish their differences since 1965. Therefore, the Ministry of Health and Welfare has performed some administrative guidances. In 1978, it regulated new approval of the production of 100 ml drink tonics, which led to the appearance of the mini drink tonic. Its market rapidly expanded since 1985. In 1991, its scale reached about 200 billion yen on both drink tonics and the sale volume was 20% at drug stores in Japan. The health drink is supporting the economic foundation of drug stores at present. PMID- 11613522 TI - [The transition of psychotropic drugs in Japanese Pharmacopoeia (JP) (Part 8). The adoptiion of barbiturates, hypnotics and sedatives in Japanese Pharmacopoeia (JP) and transition of the standards and the test methods]. AB - This is the study on the transition of the standards and test methods for barbiturates drugs (Bar-d) between JP IV (1920) and JP XII (1991). The results are as follows: Many new Bar-d appeared between JP VI (1951) and JP VIII (1971). Then many kinds of test methods for Bar-d were studied between JP VII (1961) and JP VIII (1971) and common and precise test methods were established. It is thought that Bar-d were used widely as hypnotics and sedatives in the 1960's in Japan, but some Bar-d were eliminated since JP IX (1976). The test methods for Bar-d were never revised after JP VIII (1971). It is thought that the first choice drugs for hypnotics and sedatives in Japan have transferred from Bromides and Bar-d to Benzodiazepines and the demand of Bar-d as hypnotics and sedatives has declined. PMID- 11613523 TI - [Studies on the crude drugs used for the folk medicine described in "mimi bukuro"]. AB - "Mimi-bukuro" is a book written by Moriyasu Negishi in the Edo period. M. Negishi (1737-1815) was a magistrate in the town of Edo. He was very much interested in listening and recording many kinds of stories, which were told by the various kinds of people, such as public officers, samurais, merchants, doctors, etc. Among the stories of this book, some stories were found concerning folk medicine, medicinal substance and charms. In this report, I studied the medicines which were used in these stories. The medicines originated from zoological, botanical and mineral substances. As the results of my studies, there were zoological, botanical and mineral medicines were 13, 36 and 4 species, respectively. The examples of such medicines were as follows. Zoological samples: Felis catus, Gallus gallus domesticus, Anguilla japonica and Rapana venosa. Botanical samples: Artemisia princeps, Nicotiana tabacum, Panax ginseng, Terminaria chebula and Piper nigrum. PMID- 11613524 TI - [The medical and pharmacy history museums in Hungary]. PMID- 11613525 TI - [Von Siebold's prescriptions (1)]. AB - I interpreted and explained von Siebold's prescriptions kept at the Siebold's Memorial Museum, Nagasaki City. The prescriptions kept at the Municipal Museum of Ohzu City will be analyzed in the next paper. Classifications and statistical analyses of his prescriptions according to the name of drug, dosage forms, drug efficacy, and the name of disease will be provided in the next paper entitled von Siebold's Prescriptions (2). PMID- 11613526 TI - [The classification and therapeutical methods of cataract on Chinese medicine in the modern times]. AB - We investigated cataract-related description on the medical literatures written at China in modern times. In those days, the cataract was classified by the shapes of clouds on the crystalline lens. In present Chinese medicine, it has been interpreted that the senilecataract was showed Eneinaisyo. Hyoei-naisyo, Katsuei-naisyo, Zyuei-naisyo, Sanei-naysyo, Fuei-naisyo, Tinei-naisyo, Ohei naisyo, Engetsuei-naisyo, Soukaei-naisyo, Hakueiohsin-naisyo and Kokusuigyoei naisyo; these words were old names for cataract. We separately rethought about their symptoms from the description in the original literatures; however, they showed some symptoms which generally were not found on the senilecataract. On the other hand, the therapeutic methods mainly existed pharmacotherapy, surgical methods and treatments with acupuncture and moxibustion and their applications were each different according to the shapes of the clouds. PMID- 11613527 TI - [Advertisements in newspapers and magazines about patent medicines in the Meji era (The first dissertation) (Part 1)]. AB - In February 1869, the government first permitted newspapers to be published. The Yokohama-mainichi, the Tokyo-nichi-nichi, the Nisshin-shinjishi and so on were published. The traders of medicine quickly turned their attention to the newspapers. Jihei Morita put an advertisement about "Houtan" in the newspaper issued in July in the 4th year of the Meiji era (1871) and Ginko Kishida put an advertisement about "Seikisui" in the Mainichi in Yokohama dated August 18th in the 4th year of the Meiji era. After that, the traders of medicine advertised in newspapers one after another, and the contents of advertisements were expressly the efficacy of medicine. As Yukichi Fukuzawa doubted if the trend was really desirable, he carried his comment against the trend in the Katei Sodan published by Keio-Gijuku, but the contents of advertisements were not changed. Advertisements emphasising the efficacy of medicine were prominent. PMID- 11613528 TI - [Advertisements in newspapers and magazines about patent medicines in the Meiji era (The first dissertation) (Part 2)]. AB - On January 20th of the 10th year of the Meiji era (1877) the government enforced the laws regulating patent medicines. Since then patent medicines were frequently attacked in the newspapers. Abuses of patent medicines became the target of criticism. Yukichi Fukuzawa had carried his comments against abusing patent medicines in "Minkanzasshi" for 4 days from March 24th in the 11th year of the Meiji era. Abuses of patent medicines prevented medical science from progressing. He pointed out the responsibility of newspapers which printed advertisement of ineffective patent medicines. "The kanayomi" which was a small newspaper company refuted his comments. Jihei Morita published the magazine "Houtan" in person, and he ran many advertisements about patent medicines. In October in the 15th year of the Meiji era, the law, which imposed a tax on patent medicines was enacted. In addition to the censure against patent medicines were an account in the newspaper successively. However, at the same time, these accounts had serious consequences the traders of medicine and they went to law by the reason which they led to serious interference with their business. PMID- 11613529 TI - [Advertisements in newspapers and magazines about patent medicines in the Meiji era (the first dissertation) (Part 3)]. AB - After the conclusion of the trial was carried out on december 25th in the 18th year of the Meiji era, write-ups decreased graduallly. Under these circumstances, the traders of medicine began their own publication at their convenience and they put advertisements in them. "Eisei-tebako" by "Kishida ginko" and "Houtan keikenroku" by "Morita Jihei" were the typical of them. While patent medicines were extremely popular, pharmacists at that time never denied the necessity of patent medicines. Junichiro Shimoyama and Keizo Tanba, who were representatives of pharmacists in Japan, suggested that pharmacists had ought to manage patent medicines and pointed out that excessive write-ups exacerbated the situation. PMID- 11613530 TI - [Shen Nong, why not Nong Shen?]. AB - In the Chinese language, the word order of 'modifier+modifiee' indicates a Northern origin whereas the order of 'modifiee+modifier' reflects Southern dialects. Shen Nong, a Chinese mythical diety, is known as an originator of herbal medicines as well as of agriculture, and his name ('modifiee+modifier') clearly suggests a Southern type. This linguistic feature can be related to depiction of Shen Nong's life which implies a Southern origin. Shen Nong must have already been so named in the era of Shang dynasty which preceeded the Xia culture of Southern origin. The myth of Shen Nong may be ethnically of the people of the South. PMID- 11613531 TI - [The patent drugs that have been inherited in Daiyuzan Saijyouji temple]. AB - Mysterious medicines being left at temples founded toward the middle of Edo era, the contents and origins of which are pursued. The mode of medicine sales, peculiar to Japan, is elucidated. PMID- 11613532 TI - [The progress in radiopharmaceuticals in Japan--In connection with the 100-year anniversary after Prof. Rontgen discovered X-ray in 1895]. AB - This year is the 100-year anniversary after Prof. W.K. Rontgen discovered X-rays in 1895. In connection with this point, I studied the history of radiopharmaceuticals (RP) in Japan. In 1937, the first cyclotoron was established by Dr. Yoshio Nishina in Tokyo and researches for radioisotope (RI) were started in the medical field in Japan. After the Second World War, RI research in the medical field started again using imported RI from U.S.A. in 1950. The National Institute of Radiological Sciences was established by the Japanese Government in Chiba-city in 1957 and the RP law was enacted by the Ministry of Health and Welfare of Japan. Twenty-five nuclear elements were regulated as RP by the Pharmaceutical Law in 1959. Five RP products were included for the first time in the Japanese Pharmacopoeia (JP), 7th Edition, in 1961. The Japan Radioisotope Association (JRIA) was established in 1951 for the purpose of importing and distributing RI, technical training for safety operation, collecting the RI wastes and so on. The JRIA is playing an important role in the progress of RP. Now, RP were separated officially for in vivo use and in vitro use in Japan. PMID- 11613533 TI - [A short history of patient package insert in the EU]. AB - In recent years the Japanese general public has become increasingly aware of health matters, and many people wish to know more about the medicines they receive from doctors. This means that Japanese patients have not been given medicinal product information fully by medical professionals, whereas many European countries have already introduced patient package inserts (PPIs) with near full disclosure leaflets in understandable language in all packages of dispensed medications. This article describes a short history of PPIs in European countries, centering on the development of PPIs in Germany and Belgium. It is expected that these European experiences contribute to our country in terms of providing patients with pharmaceutical information. PMID- 11613534 TI - [Analytical chemistry]. PMID- 11613535 TI - [Pharmaceutical information activities]. AB - This paper reviewed the progress of the pharmaceutical information activities after the war during fifty years. Activities of the pharmaceutical information organizations, progress of pharmaceutical information tools and techniques, the pharmaceutical information education in universities are described. PMID- 11613536 TI - [Historical sketch of modern pharmaceutical science and technology (Part 4). Post World War II 50 years]. AB - A short history of the pharmaceutical science and technology, postwar 50 years is divided into nine sections for the purpose of discussion. 1. Japan's postwar rehabilitation, Japanese pharmaceutical industries and newly developed pharmaceutical sciences and technologies. In 1945, the Japanese pharmaceutical industry was reconstructed. Production of penicillin was carried out with the strong support of the U.S. Occupation Forces. New sciences in pharmacy (biochemistry, biopharmacy, pharmacology, microbiology, physical chemistry, etc.) were introduced in this period. 2. Introduction age of foreign new drugs and technology (1951 to 1960s). Japan gained independence in 1951. Japanese pharmaceutical companies imported many new drugs and new pharmaceutical technologies from the U.S.A. and European countries in this period. Then, these companies were reconstruction rapidly. However, consequently Japanese pharmaceutical companies were formed as an imitation industry. 3. Rapid economic growth period for pharmaceutical companies (1956 to 1970s). In this period, many Japanese pharmaceutical companies grew rapidly at an annual rate of 15-20% over a period of 15 years, especially with regard to the production of active vitamin B1 analog drugs and some OTC (public health drugs). Some major companies made large profits, which were used to construct research facilities. 4. Problems for the harmful effects of medicines and its ethical responsibility. In the 1970s, many public toxic and harmful effects of medicines were caused, especially SMON's disease. In this time, many pharmaceutical companies changed to its security got development of ethical drugs. 5. Self development of new drugs and administration of pharmaceutical rules (1970s). During the 1970s, many pharmaceutical laws (GLP, GCP, GMP, GPMSP etc.) were enacted by the Ministry of Health and Welfare. In 1976, the Japanese Pharmaceutical Affairs Law was revised, which set forth standards regarding the efficacy and safety of ethical drugs and re-evaluation of drugs. Many facilities were built for the purpose of ensuring efficacy and safety, as shwon in Table 1. 6. Problems of Intellectual Property and followed the revisionist line of research and development for new ethical drugs. In 1976, Japanese pharmaceutical companies ceased to be an imitation industry, and increased research for the development of new drugs. 7. Pharmaceutical science and technology innovation (After 1985). Many of the pharmaceutical innovations during this period were as follows: 7.1) Technology innovation for evaluation of drug efficacy; 7.2) 1st to 3rd medical diagnostic technology innovations; 7.3) medical analytical methods and spectrometry technologies; 7.4) Computer-aided drug-design technology and drug information technology innovation; and 7.5) Drug delivery system and treatment drugs. 8. Recent research and development of new ethical drugs in Japan (1970 to 1995). Cephalosporine type beta-lactams (cefazolin, cefametazole, furomoxef, cefdinir), new quinolones (norfloxcin, ofloxacin, tosfloxcin), H1-Blockers (famotidine), Ca-antagonists (diltiazem, nicardipine), and other new drugs (pravastatine, taclolimus, leuprine) etc. came onto the market. 9. International Harmonization Age and Review toward 21 century. The rapid development and globalization of the pharmaceutical market has promoted international harmonization and rationalization of pharmaceutical regulatory affairs. In 1990, the Japan Pharmaceutical Manufacturers Association published a report toward 21 century, which described practical plans. PMID- 11613537 TI - [Memorandum on the origin of Rx, the signal be employed to the heading in the prescription]. AB - The symbol variously written Rp. Rx. or R. is still employed by physicians to head their prescriptions. In our country, we have learned and believe that the origin of the symbol is an abbreviation of the Latin word for "recipe." In Europe, another suggestion of the origin of the symbol appears to represent the astronomical sign of the planet Jupiter. There is, however, no evidence to support this suggestion. As regards the Jupiter symbol it is probably that printer may have used the sign as the nearest approach he had in type to the abbreviated sign for recipe. It is believed that the confusion between the two symbols is due to a mere typographical coincidence. A careful examination of the various styles of writing the symbol, clearly shows that the sign was originally adopted as an abbreviation of the word "recipe." Recently, it has been suggested that the symbol originates in "the eye of Horus," but, as regards the eye of Horus symbol, much more still remains to be examined. Thus, I will suspend judgement until the facts of the matter become clear, and expect further researches in future. PMID- 11613538 TI - [The names of drugs in the cassia-bark family in China prior to the 11th century- On the standardization as Guizhi by Ling Yi and other scholars of cassia-bark family drug names appearing in the medical works written by Zhongjing]. AB - The Chinese medical classics Shangham Lun, Jingui Yaolue and Jingui Yuhanjing are regarded as having been written by Zahn Zhongjing in the early part of the third century A.d. However, all current editions of the three works are based on the northern Song edition revised by Lin Yi and other scholars that was first published in 1065 and 1066. Guizhi appears in prescriptions in all three books as an important medicine. Yet whereas in the Chinese Pharmacopoeia (C.P.) Guizhi is defined as the Cinnamomi Ramulus (the whole twig), in the Japanese Pharmacopoeia (J.P.) it is defined as the Cinnamomi Cortex (the bark). The reasons for this difference between China and Japan has not been studied before. The author conducted a historical analysis of the terms and materials used for cinnamomic medicine in China from the third century B.C. to the year 1066, and the following results were obtained. (1) Until the Han period, the drug name Gui was commonly used for products made from the bark (the cork from the bark being removed) of cinnamomic plant. Such products have been excavated from a tomb where they were interred in the second century B.C., and the drug name Guixin was commonly used for them until the Tang period. (2) The terms Gui, Qin, Mugui, Mugui, guirou, Rougui, Guixin, and Guizhi found in medical texts up to the tenth century were all used for the products made from the bark. The Tang government's pharmacopoeia of 659, the Xinxiu Bencao, designates their material plant as either C. cassia or C. obtusifolium. This product primarily corresponds to Cinnamomi cortex, being Keihi in J.P. or Rougui in C.P. (3) The term Jungui was used from the third century B.C. for products in the shape of a bamboo pipe which were made from the bark of cinnamomic plant twig that had been repeatedly rolled up, and which were used as dietary foods or spices. The Xinxiu Bencao designates the material plant as C. burmanni, and the product corresponds to the cinnamon sticks now in use. (4) As to use Guizhi as decoction, we cannot deny the possibility that in the original medical works of Zhongjing there was a prescription by the name of Guizhi Tang. However, there are no examples of the drug name Guizhi until the sixth century, and most prescriptions of Zhongjing that were used around the Tang period employ Guixin or Gui. Because of this, in some prescriptions there has arisen a contradiction in the terminology; for example in Guizhi Tang, Guizhi might be prescribed instead of Guixin. Further, there are also prescriptions named Guixin... Tang. On the other hand, no evidence has been found that the whole twig of cinnamomic plant was used as a drug prior to the eleventh century. Consequently, this indicates an extremely small likelihood that in the time of Zhongjing the drug name Gizhi was employed, or that the whole cinnamomic twig was employed as a drug. (5) In the Taiping Shenghifang which was published in the early part of northern Song period there is, among the prescriptions for Guizhi, and example drawn from the prescriptions of Zhonjing, of the use of a drug named Guizhi, which has the same meaning as Guixin. However, at the time Gixin was a commonly used term. PMID- 11613539 TI - Numismatics and medicine at the Academy. PMID- 11613540 TI - Medicine: the first step on the road to holiness? AB - The connections of Medicine and Religion are thoroughly documented in the primitive societies, and it comes as no surprise to see them together. Here we describe the true story of a Portuguese physician of the late 19th century whose image today is venerated in such a way as to compare him to a saint and to bestow upon him miraculous powers of healing. We propose that modern day physicians can learn from the example of this man that the role of doctor encompasses not only scientific and technical mastery but, most of all, piety, humanity and compassion. PMID- 11613541 TI - Women in nineteenth century homeopathic medicine. PMID- 11613543 TI - Infiltrating the curriculum: an integrative approach to history for medical students. AB - I believe that the purpose of history in a medical school can be related to two simple goals: first, to make students a bit skeptical about everything else they are to be taught in the other lectures--skepticism fosters humility and life-long learning; second, to make them aware that medical history is a research discipline as compelling as any of the basic and clinical sciences they are traditionally taught. In the fall of 1988, I was given an opportunity to build a "course" in history for medical students--a course with no fixed time slot, no fixed syllabus, and no fixed content. I wanted to teach history of anatomy during anatomy sessions, history of pathology during pathology, history of obstetrics during obstetrics, and so on. I hoped to end each session with a disciplinary controversy that extended into present practice. The ultimate manifestation of infiltration would be to have one question on every exam that the students would write during their medical school experience. This is the story of how my medical history teaching moved from nothing to a program integrated throughout four years of medical studies, complete with goals and objectives and two questions of every exam. The content, advantages, and problems of the approach in the Queen's University experience will be presented. PMID- 11613544 TI - Fear of reproduction and desire for replication in Dracula. PMID- 11613545 TI - Health in ancient societies. PMID- 11613546 TI - Germ fighters of the 19th century. PMID- 11613547 TI - Reflection in Chalcedon: Herophilus of Alexandria (c. 300 B.C.). PMID- 11613548 TI - Robert Graves (1796-1853): clinician and teacher. PMID- 11613549 TI - Highlights from the Adler Museum - hearing aids. PMID- 11613551 TI - Centenary of the death of Alfred Nobel (1833-1896): the man and his prizes. PMID- 11613550 TI - Medical numismatics. PMID- 11613552 TI - AIDS history San Francisco: archival documentation and oral history. PMID- 11613553 TI - The New Jersey AIDS oral history project and AIDS collection. PMID- 11613554 TI - The NIH AIDS Oral History Project: documenting the NIH response to AIDS (1981 1991). PMID- 11613555 TI - Ethical issues for the archivist: the Brown and Williamson Collection and beyond. PMID- 11613556 TI - Some recent German stamps of medical interest. PMID- 11613557 TI - US Hospital Ships. PMID- 11613558 TI - Medical philately - the Scots. PMID- 11613559 TI - [Modern history of gynecology in China]. AB - Dealing with the modern history (1850-1949) of the establishment and development of Gynecology in China, this paper claims that the sprouting period covers the time prior to 1899. After 1991 Gynecology developed steadily due to the advancement of surgery, pathology, bacteriology and anesthesiology. During this period, there were definite improvements in Gynecology diagnosis, treatment of pelvic inflammation and gynecological endocrinology. PMID- 11613560 TI - [Medical activities and Chinese postal articles]. AB - Based on the postal articles relevant to medicine printed and distributed in modern age before and after 1949, it can be seen that the developmental course of Chinese health care and benevolence from retardation to flourishing were all closely related to its historical background, political status and contemporary government policy. Though it only reflects a unilateral view in modern medical history, the postal articles connected with medical materials definitely are testimonies of the history of civilization, providing an approach to the study of medicine and is also helpful to the study of history of medicine. PMID- 11613561 TI - [Variolation, pioneer of modern immunology]. AB - Smallpox spread into China at the end of the Han Dynasty. Therapeutic remedies were first recorded in Ge Hong's Zhou Hou Jiu Zu Fang in the Jin Dynasty. It is possible that variolation made its first appearance in the Northern Song Dynasty. It can be sure that there was a variolation centre in Taiping County of Ningguo District in Anhui. The Kangxi Emperor of the Qing Dynasty advocated and encouraged the popularization of the art which was then spread outside China. Edward Jenner, the English physician who practised variolation, modified variolation into vaccination, which eventually lead to the formation of modern immunology and the declaration of eradication of smallpox on the Earth by WHO in 1980. The article describes the historical process of variolation to vaccination and points out that the modified variolation was safe and reliable. Unfortunately, the westerners only followed the simple smallpox-juice method which was relatively more dangerous. PMID- 11613562 TI - [History of cholelithiasis]. PMID- 11613563 TI - [Medicine of Liao Dynasty]. AB - The Taizhu Emperor of Liao Dynasty forced the popularization of medical knowledge by imitating that of the Tang Dynasty. After entering the Capital Bian, Taizong Emperor, seized the medical men of Jin to the North, while Jingzong Emperor treasured medicine. All the above had pushed the development of Liao's medicine in Northern China to its mature stage. Special administration institutions for medicine were established. Autopsy and anatomy were advocated. Therapeutic modalities were mainly TCM, traditional materia medica and acu-moxibustion. Zhilugu and Yeludilu were among the famous physicians. However, viewing from an overall standpoints, Liao medicin was rather backward. Due to its small territory, religious superstition and special humanities and geographical conditions, the development was rather limited. PMID- 11613564 TI - [The historical personages pushing two acu-moxibustion tides in France]. AB - By textural investigation and on-the-spot visits, this author introduces the main facts of the historical personages who twice applied the art of acu-moxibustion in France in 17th century. The materials presented were exact, clear and comprehensive, thus, offering valuable first-hand materials for the study of spreading of TCM and acu-moxibustion in France as well as Europe in modern age. PMID- 11613565 TI - [Medical history as an academic subject in German medical schools, historical background and contemporary]. PMID- 11613566 TI - [The mourning for Dr. Joseph Needham, the man bridging culture between east and west]. PMID- 11613567 TI - [Cherish the memory of Dr. Joseph Needham]. PMID- 11613568 TI - [Textual research on genealogy and related problems of Xu Lingtai]. AB - This paper deals with Xu Lingtai's genealogy from his grand-grand father down to six generations with the short biographical acounts of each generation. From these, one can learn the origin, development of the literary and medical aspects of Xu's family. It also discusses the name, nickname, other names, dates of birth and death, tombs of Xu Lingtain by studies on relics and literatures, intending to solve the puzzles and errors of the above problems. PMID- 11613569 TI - [Study on Gong Dingguo]. AB - It is proved through textual researches that Gong Dingguo, the author of Neifu Michuan Jingyan Nuke, was the son of gong Tingxian, a famous physician of the late Ming Dynasty. PMID- 11613571 TI - [Textual research on Newly Carved sun Zhenren's Qian jin fang]. AB - As one of the ancient edition of Qian jin fang, this Newly Carved Sun Zhenren's Qian Jin Fang is far more authentic in the structure of its contents and its text, as compared to those editions of the Song Dynasty, and is, of course, closer to its original form and more reliable with textual significance. This article explores the distribution, characters of the edition and time of carving. PMID- 11613570 TI - [Study on Xu Shuwei's Zhongjing's 36 kinds of maifatu]. AB - The extant book titled Maifa Weizhi copied in the Ming Dynasty, is, in fact, an edition of the lost book of Zhongjing's 36 kinds of Maifatu written by Xu Shuwei of the Southern Song Dynasty. This is one of the earliest illustrative books on pulsolgy some one hundred years earlier than Shi Fa's Chabing Zhinan. PMID- 11613572 TI - [Answers to queries on absence of "heart related to fire" theory in the western Han Dynasty]. AB - This paper claims that all the materials, including the first chapter of Lu's Chun Qiu Shi Er Ji, the theory of Heart Related to Fire in Huai Nan Zi Di Xing Xun, and "Chi Di Zi kills Bai Di Zi" are all later interpolations and are, therefore, unconvincing. The author offers ten questions conflicting with the old sayings. PMID- 11613573 TI - [Medicine of second half of nineteenth century]. PMID- 11613574 TI - [The law of ancient states in Asia Minor and forensic medicine]. AB - The relevant materials to forensic medicine in ancient law of Asia Minor countries, including Sumerian Law, Hammurabi's code, Hittite Code, Assyrian Law, and Mosaic Law, are reported comprehensively in this paper. The earliest materials can be traced back to 21 century B.C. It indicates that these materials described in ancient law in the world belongs to Asia Minor countries. The author considered that those materials are very important for tracing the source of forensic medicine, especially clinical forensic medicine and compensation medinine. PMID- 11613575 TI - [Textual research on diagnosis by lingual vessels]. AB - Being a unique Chinese diagnostic measure, this method focussing its observation on the ventral vessels of the tongue, is first recorded in Neijing, saying that it is indicated when the vessels are varicose by puncturing for bloodletting in malaria, mad, and sadness. Ge Hong and Cao Yuanfan applied it for juandice, also for prognosis. Yimenfang predicts by this method the diagnosis for prognosis of the mother and foetus in difficult delivery, while Chen Zhiming popularized it in his Chan Nan sheng Si Jue. Inherited from the theory of Collateral Vessel Diagnosis, this approach pays attention to the observation of the forms and colors of collateral vessel, claiming that dark green color and congestion have bad diagnosis. Though not well developed, it was applied as extra-acupoints for swelling tongue, sore throat and jaundice. While Zhou Xuehai elaborated Liu Shouzhen's idea and put forward a theory of minute-vessel-stasis which is wonderfully conincided with modern microciroulation theory. In 1964, Zhang Zanchen again advocated its diagnostic value in tumor, hepatopathy and cor pulmonale. PMID- 11613576 TI - [History of modern obstetrics in western medicine in china]. AB - This paper deals with the developmental history of western medicine in China. Due to the hindrance of feudal conception, modern obstetrics began rather late. The first Chinese obstetrical ward was established in Fujian Province in 1911. Before 1930, the Chinese maternal and neonatal mortality rates were 4-5 times higher than that of European and American countries. After 1930, "Education of Midwives" commenced, including the founding of midwifery school, antenatal care, pelvie measurements, improvements of the diagnosis for pathological pregnancy, management of complications during pregnancy. All these have improved modern obstetrics in China and laid down the foundation for its development after 1949. PMID- 11613577 TI - [Spreading of Christianity and western medicine into Henan Province]. AB - After the Opium war, the aggressors, under the mask of missionaries, came to China by making use of western medicine as its tool for cultural invasion. This paper gives a description on the activities of all sects of Christianity and the institutions set up by them. Hospitals run by Christian Missions became the therapeutic institutions at all levels and made contributions to the prevention and treatment of diseases for local people. PMID- 11613578 TI - [Application of toxic substances in ancient Chinese Army]. AB - Application of toxic substances as a weapon began in the Spring-Autumn Period. In 677 B.C. the people of Sui dropped poisons into water to expel army from Qi State. During the period of cold weapon in addition to toxic fumigation, poisons were also spread on spears, swords and arrows. Recipes for anti-toxic arrows were recorded in Chen Yanzhi's Xiao-pin-fang of the Western Jin Dynasty, Liu Juan-zi's Gui-Yi-fang of the Liu-Song Dynasty, Jin-chuang-mi-chuan-jin-fang of the Yuan Dynasty. As a rule, toxication through natural sources were emphasized as described in Tai-bai-yin-jing of the Tang Dynasty, etc, including selection of camping sites, quality of water supply. It was also mentioned that the general of an army should despatch order for antitoxicity during travelling. PMID- 11613579 TI - [Medicine in Taiwan during the period of Japanese occupation]. AB - During the period of 1894-1945, hygienic administration institutions were established in the central and local levels, responsible for general hygienic affairs, including prevention of infectious diseases, public health, anti-opium smoking and drug inspection. Medical education and research unit were also set up, such as Taibei Hospital, Taiwan Viceroy Medical School and Taibei Imperial University. From these institutions, not a few medical professionals were cultivated. PMID- 11613580 TI - [Historical records of 110 years of People's Hospital of Hainan]. PMID- 11613581 TI - [Introduction of Indian medicine into China in the Wei-Jin-Southern-Northern dynasties as interpreted by beriberi]. AB - Since the sea route between China and all countries in the Western Region was unimpeded, many Buddhist monks came to China. Some of them settled in Lingnan Region. With them, Indian medicine was imported which greatly expanded the coverage of TCM. Some of the Northerners moved southward into Lingnan Region and contracted beriberi which were cured by Indian monks. The author explores the importation of Indian medcine through analysis of beriberi as an example. PMID- 11613582 TI - [Origin of gestation theory in Tibetan medicine]. AB - Generally, it is claimed that gestation theory was originated locally in Tibet, with only a single origin. This author proves that there are two sources, both derived from India. One is a combination of gestation theory from rGyud-bzhi, i.e. Astangahrdayasamhita, and the Great Ratnakuta, and the other, from Somaradza, also derived from the Great Ratnakuta. The dates of writing of modern edition of Somaradza and rGyud-bzhi are still uncertain yet. Based on the linguistic features, this author claims that Somaradza was written before the Tibetan version of Great Ratnakuta (9 century), while rGyud-bzhi, after the translation of Astangahrdayasamhita (10-11 century). PMID- 11613583 TI - [Zhang Taiyan, leader of TCM transform]. AB - Being an influential figure of old democratic revolutionalist, thinker and scholar, Mr. Zhang Taiyan is also a medical man. He lived in a period of modern turbulence with introduction of western medicine into China, while TCM was confronting the challenge. He advocated the mutual absorption so as to be benefitted from both TCM and western medicine. By adopting some of his discourses of over one hendred pieces on Shang Han Lun, poet, essays, condolescent poet to form a thesis, it can be shown that his medical undertakings was but a part of his whole career. PMID- 11613584 TI - [Western medical books translated by J. Dudgeon]. AB - John Dudgeon (1837-1901) was a famous medical missionary in Modern China. He not only translated traditional Chinese medicine, arts of Chinese healing and Chinese culture and introduced them to European, but also translated Western medicine, science and technique and introduced them to Chinese. Dudgeon had introduced Western anatomy, physiology and clinical experience. This author claimed that Dudgeon transfered a new kind of mankind concept and methodology during his translative career, and the later was even more important for Chinese scholars and Chinese academic circles. PMID- 11613585 TI - [On the source of 4-syndrome 8-symptom-sign in convulsion]. PMID- 11613586 TI - Possessed by the devil? A very public dispute in Utrecht. PMID- 11613587 TI - Death and memory in modern Russia. PMID- 11613588 TI - Colonial bodies, hygiene and abolitionist politics in eighteenth-century France. PMID- 11613589 TI - Dope girls 1918-1995, and other stories. PMID- 11613590 TI - Making Irish famine history in 1995. PMID- 11613591 TI - The official opening of the Osler Library, May 29, 1929. PMID- 11613592 TI - Odontodysplasia leprosa in Danish mediaeval skeletons. In: PMID- 11613593 TI - History of the Medical Service Corps. PMID- 11613594 TI - The esculentist movement in mediaeval Chinese botany; studies on wild (emergency) food plants. PMID- 11613595 TI - [Care for foundlings]. PMID- 11613596 TI - Spondylosis cervicalis. Thesis--summary in English and Danish. Copenhagen, 1969. PMID- 11613597 TI - [On Rontgen and the discovery of the x-rays]. PMID- 11613598 TI - An unusual case of tuberculosis in a medieval leper. PMID- 11613599 TI - [The craving for tobacco]. PMID- 11613600 TI - [Herman Boerhaave (1668-1738)]. PMID- 11613601 TI - [Not Available]. PMID- 11613603 TI - A bibliography of the Dutch medical books translated into Japanese. PMID- 11613602 TI - [Some thoughts about Semmelweis and his doctrine]. PMID- 11613604 TI - Lupton of Levenshulme. PMID- 11613605 TI - A pharmaceutical museum. PMID- 11613606 TI - Fifty years of the New Jersey Journal of Pharmacy. PMID- 11613608 TI - Education of a provincial apothecary. PMID- 11613607 TI - A reminiscence: pharmacy in the first half of the 20th century. PMID- 11613609 TI - Some midland apothecaries. PMID- 11613610 TI - The city of York's first spicers, grocers and apothecaries. PMID- 11613611 TI - Pharmacy in Stamford a century ago. PMID- 11613612 TI - Archives: the 'memory of man.' PMID- 11613614 TI - Medical allusions in some inscriptions of Andhra Pradesh. PMID- 11613613 TI - Gadadhara. PMID- 11613615 TI - Apurva Vaidya of Vagbhata. PMID- 11613616 TI - Jalinoos [Galen] the famous physician of Yunan (Greece). PMID- 11613617 TI - The first Indian War of Independence and military surgery. PMID- 11613618 TI - Abstracts of select medico-historical articles in Hindi [1974]. PMID- 11613619 TI - Recent Indian medical historiography; bibliography for 1973. PMID- 11613620 TI - Apothecaries' memorials. PMID- 11613621 TI - Local history and the pharmacist. PMID- 11613623 TI - Surgical treatment of Fistula-in-Ano. Historical evolution of a technique. PMID- 11613622 TI - Abhidhanaratnamala; a work with a new classification of Dravyas. PMID- 11613624 TI - Tamil medical manuscripts in Oriental Research Institute, S.V. University, Tirupati. PMID- 11613625 TI - History of Siddha medicine; need for further detailed studies. PMID- 11613626 TI - Sculpture of fasting Buddha; artist's knowledge of anatomy in ancient India. PMID- 11613627 TI - Glimpses of medicine in Rajatarangini; diseases, drugs, physicians and treatments in medieval Kashmir. PMID- 11613628 TI - Yusrul Ilaj; a Persian medical manuscript compiled in India by Hakeem Hidaetullah, in 1731 A.D. PMID- 11613629 TI - Development of dravyaguna in India. PMID- 11613630 TI - A note on ancient Indian medicine. PMID- 11613631 TI - Origin and slow progress of study of anatomy in ancient times. PMID- 11613632 TI - Biography of the Unani physician Arestu. PMID- 11613634 TI - The homoeopathic treatment of cholera; a historical study. PMID- 11613633 TI - Original observations of Filippo Pacini on vibrio cholera. PMID- 11613635 TI - Concept of disease and folk therapy in a village of Andhra Pradesh. PMID- 11613637 TI - Recent Indian medical historiography: bibliography for 1975. PMID- 11613636 TI - Abstracts of medico historical articles in Hindi journals. PMID- 11613638 TI - Contribution of Andhra to ayurveda in Sanskrit. PMID- 11613639 TI - Chapters of "Huang-ti-nei-ching-su-wen" derived from "Yin-yang-shih-i-mo-chiu ching". (Jpn) PMID- 11613640 TI - The Leprosy Museum of Bergen. PMID- 11613641 TI - Additional material in Astanga Sangraha. PMID- 11613642 TI - Abstracts of medico historical articles in Hindi journals. PMID- 11613643 TI - References to Ayurveda in the commentaries of Mallinatha. PMID- 11613644 TI - The evolution and chronology of ancient Indian medical sciences. PMID- 11613645 TI - Dalhana's version of the Susruta Samhita. PMID- 11613646 TI - A 19th century manuscript on traditional medicine. PMID- 11613647 TI - A brief introduction of Siddha system of medicine. PMID- 11613648 TI - Development of naturopathy in Andhra Pradesh. PMID- 11613650 TI - Hakim Nizamuddin Ahmed Geelani; a physician of Qutub Shahi period. PMID- 11613649 TI - Single drugs mentioned by Avicenna for cardiac ailments in his canon and Kitab-Ul Adwiyyah Qalbiyyah. PMID- 11613651 TI - Hatharatnavali of Srinivasabhatta, a late medieval treatise on yoga and tantra. PMID- 11613652 TI - The fortunes of economic reform legislation: the case of the Drug Amendments Act of 1962. PMID- 11613653 TI - 1839 advertisements. PMID- 11613654 TI - Winchester in the 18th century. PMID- 11613656 TI - [Brief history of consumption-thirst syndrome (diabetes mellitus)]. PMID- 11613655 TI - Physick in Bolton in 1779. PMID- 11613657 TI - [Army medical organization of Qing Dynasty after the Opium War]. PMID- 11613658 TI - [Galen's thought, physiology and anatomy as taught by him]. PMID- 11613659 TI - [Origin and development of cytobilogy]. PMID- 11613660 TI - [On pulverizing instruments for Chinese herbal drugs and their evolution in ancient China]. PMID- 11613661 TI - [Yang Tianhui and his "Records on Radix aconitinum"]. PMID- 11613662 TI - [On the origin of medicine ... from sorcery]. PMID- 11613663 TI - [Two questions about the Tian Sheng bronze statue for acupuncture of the Sung dynasty]. PMID- 11613664 TI - Colonialism and the truncation of science in Ireland and French Canada during the nineteenth century. PMID- 11613665 TI - Medical professionalization: pitfalls and promise in the historiography. PMID- 11613666 TI - The historical collections of the Pharmacist Institute of New Jersey. PMID- 11613667 TI - Opium and oral history. PMID- 11613668 TI - Explaining the postwar baby boom. PMID- 11613669 TI - Tying the knot - secundum artem. PMID- 11613670 TI - Food and famine in China. PMID- 11613672 TI - The development of the office of a permanent medical health officer for St. John's, Newfoundland, 1826-1905. PMID- 11613673 TI - Water and usahpana in ayurvedic literature. PMID- 11613671 TI - [Not Available]. PMID- 11613674 TI - Outline of history of Yoga. PMID- 11613675 TI - Additional material in Astanga sangraha. PMID- 11613676 TI - The doctrine of Karma and Ayurveda. PMID- 11613677 TI - Physicians of Hyderabad during Nizam II & III. PMID- 11613678 TI - Urine in ancient ayurvedic literature. PMID- 11613679 TI - Human experimentation of Drugs. PMID- 11613680 TI - The eminence of Lakshmipathi. PMID- 11613681 TI - A note on Kriya Yoga. PMID- 11613682 TI - A note on the New Edition of Bhela Samhita. PMID- 11613683 TI - Bhishagratna Achanta Lakshmipathi, his dedicated service to Ayurveda. PMID- 11613684 TI - Health habits of South Indians as recorded by Abbe J. A. Dubois. PMID- 11613685 TI - History of Medicine in India. PMID- 11613686 TI - Vindication of the doctor's decisions. PMID- 11613687 TI - Skull trepanation in Eastern Africa. PMID- 11613688 TI - The development of hematology. PMID- 11613689 TI - Ottoman medicine viewed through Western eyes. PMID- 11613691 TI - Mortality among the Puerto Rican born in New York City. PMID- 11613690 TI - Occupational health and safety legislation in Ontario: an analysis of its origins and content. PMID- 11613692 TI - The power of Paracelsus. PMID- 11613693 TI - Crime and anaesthesia -- robbery. PMID- 11613694 TI - [Not Available]. PMID- 11613695 TI - Highlights of medical history PMID- 11613696 TI - Asthma -- a note on its history. PMID- 11613698 TI - Royal pseudocyesis. PMID- 11613697 TI - "Amadeus" was Mozart poisoned? PMID- 11613699 TI - Osler and Kipling. PMID- 11613700 TI - An enquiry into 'the ague' in Scotland. PMID- 11613701 TI - Murder by morphine. PMID- 11613702 TI - Medical statues: the Bernard Appel Hall of Medicine, Boston University School of Medicine. PMID- 11613703 TI - Osteochondritis dissecans from the Great Plains of North America. PMID- 11613704 TI - The Graham site: a McKean cremation from southern Saskatchewan. PMID- 11613705 TI - Generational differences in fertility among Mexican Americans: implications for assessing the effects of immigration. PMID- 11613706 TI - Fertility expectations and behavior among Mexican Americans in Los Angeles, 1973 82. PMID- 11613707 TI - Ancient osteopathology from the Caddoan burials at the Kaufman-Williams site, Texas. PMID- 11613708 TI - "Bullet hole" in an ancient South Dakota skull, or a trephination? PMID- 11613709 TI - Salmon and malnutrition on the Northwest Coast. PMID- 11613710 TI - Economic and other determinants of annual change in U.S. fertility: 1917-1976. PMID- 11613711 TI - Gender and parenthood. PMID- 11613713 TI - Science and technology in the 1980s. PMID- 11613712 TI - Dismantling the community-based service system. PMID- 11613714 TI - Centenaries. PMID- 11613715 TI - Human adaptation: health and disease. PMID- 11613716 TI - The pilgrim's progress, the BAAS, and research in Canada: from Montreal to Toronto. PMID- 11613718 TI - Cultural patterns in Trukese suicide. PMID- 11613717 TI - Fine tuning well-being: food stamp use and nutritional adequacy of children's diets. PMID- 11613719 TI - Medicine wheels, sun circles, and the magic of world center shrines. PMID- 11613720 TI - Public opinion and the legalization of abortion. PMID- 11613721 TI - Heritage map of medical London. PMID- 11613722 TI - The legacy of Henry Wellcome. PMID- 11613723 TI - Paul Bert and the flight of the Zenith. PMID- 11613725 TI - A note on healing and ignorance in the Bible. PMID- 11613724 TI - The moment of death in Aggadic literature. PMID- 11613726 TI - Markus Herz, a biographical study. PMID- 11613727 TI - Fertility in Jewish tradition (ethno-medical and folkloric aspects). PMID- 11613728 TI - A brief anthropological analysis of connections between 'impurity', 'zara'at' and slander in Jewish culture. PMID- 11613729 TI - Water supply and public baths: a chapter in Talmudic public hygiene. PMID- 11613730 TI - A mediaeval Hebrew presage of the circulation of the blood, based on biblical and Talmudic concepts. PMID- 11613731 TI - The child in the first two chapters of the Gospel of Luke. A contribution to the understanding of generation, birth and child development in the first century of Christianity. PMID- 11613732 TI - Anointing with oil--an hygienic procedure in the Bible and in the Talmud. PMID- 11613733 TI - Common baldness in the Old Testament. PMID- 11613734 TI - Remarks on Tobit's blindness. PMID- 11613735 TI - The illness of King Hezekiah and "The Book of Remedies" which he hid. PMID- 11613736 TI - The medical topoi in the Bible. PMID- 11613738 TI - Toxicology and the Bible. PMID- 11613739 TI - Normal and abnormal gestation periods in humans: a survey of ancient opinion (Greek, Roman and rabbinic). PMID- 11613740 TI - Alcohol and drunkenness in the Bible and in the Talmud. PMID- 11613741 TI - Leprosy in the Byzantine monasteries of the Judean Desert. PMID- 11613742 TI - Pestilence in Bible and Talmud. Some aspects related to public health. PMID- 11613743 TI - Talmudic medicine and Greek sources. PMID- 11613744 TI - The contribution of rabbinic law to the understanding of Talmudic medical data. PMID- 11613746 TI - Observations on the pathology of the Jewish population in Israel (100 B.C. to 600 C.E.). PMID- 11613745 TI - Concepts of disease in the Talmud. PMID- 11613747 TI - Psoriasis, leprosy and the Dead Sea Valley. PMID- 11613748 TI - An illustration of the religious foundations of Talmudic medicine: tractate megillah fol. 27b-28a. PMID- 11613749 TI - Aspects of medicine in the Hebrew Bible. PMID- 11613751 TI - The birthright-story of Esau and Jacob (from medical, legalistic and psychological point of view). PMID- 11613750 TI - A comparison of the oaths of Hippocrates and Asaph. PMID- 11613752 TI - General hygiene in the works of Flavius Josephus. PMID- 11613754 TI - Imaging of hydrocephalus--a historical review. PMID- 11613753 TI - Manuscripts of Moses Ben Maimon's Pirke Moshe in Hebrew translation. PMID- 11613755 TI - Romano-Ward syndrome in a Biblic/Talmudic family? PMID- 11613756 TI - Genetics and the Terah-Abraham genealogy in Genesis. PMID- 11613757 TI - Mechanistic views on nutrition in the XVIIIth century. PMID- 11613758 TI - Medical aspects of the Torah and rabbinic literature. PMID- 11613759 TI - Ruminations of a medical exlibrist. PMID- 11613760 TI - Markus Moses' doctoral dissertation or who remembers Butzow. PMID- 11613762 TI - Are we really measuring the quality of life? Well-being has subjective dimensions, as well as objective ones. PMID- 11613761 TI - A concise history of histology and microscopical science. PMID- 11613763 TI - Sir Victor Horsley. A centennial recognition of his impact on neuroscience and on neurological surgery. PMID- 11613764 TI - History of neuroanesthesia. PMID- 11613765 TI - Trigeminal neuralgia: historical background, etiology, and treatment. PMID- 11613766 TI - [Not Available]. PMID- 11613767 TI - [Not Available]. PMID- 11613768 TI - [Not Available]. PMID- 11613769 TI - [Not Available]. PMID- 11613770 TI - [Not Available]. PMID- 11613771 TI - [Not Available]. PMID- 11613772 TI - [Not Available]. PMID- 11613773 TI - A Low German tract on the virtues of herbs. PMID- 11613774 TI - [Not Available]. PMID- 11613775 TI - [Not Available]. PMID- 11613776 TI - [Not Available]. PMID- 11613777 TI - [Not Available]. PMID- 11613778 TI - [Not Available]. PMID- 11613779 TI - [Not Available]. PMID- 11613780 TI - [Not Available]. PMID- 11613781 TI - [Not Available]. PMID- 11613782 TI - [Not Available]. PMID- 11613783 TI - [Not Available]. PMID- 11613785 TI - Selections from medieval herbals and related medical texts. PMID- 11613784 TI - [Not Available]. PMID- 11613786 TI - [Not Available]. PMID- 11613787 TI - [Not Available]. PMID- 11613788 TI - [Not Available]. PMID- 11613789 TI - [Not Available]. PMID- 11613790 TI - [Not Available]. PMID- 11613791 TI - [Not Available]. PMID- 11613793 TI - [Not Available]. PMID- 11613792 TI - [Not Available]. PMID- 11613795 TI - [Not Available]. PMID- 11613794 TI - [Not Available]. PMID- 11613796 TI - [Not Available]. PMID- 11613797 TI - [Not Available]. PMID- 11613798 TI - Analytic philosophy, psycho-analytic theory and formalism. PMID- 11613800 TI - On children and childhood in ancient Jewish sources. PMID- 11613801 TI - The dissemination of medical knowledge in early modern Europe. PMID- 11613799 TI - Dietary standards in the 19th century. PMID- 11613802 TI - The place of medicine in the Talmud. PMID- 11613804 TI - Forensic sexual cases in the Old Testament. PMID- 11613803 TI - Mycotoxins, the flood, and human lifespan in the Bible. PMID- 11613805 TI - Milk and cheese in classic Jewish sources. PMID- 11613806 TI - Perspectives on "pain" in the Bible. PMID- 11613807 TI - A heritage map of medical London. PMID- 11613809 TI - The birthplace of radiology: reborn from the ashes. PMID- 11613808 TI - A gestational history of radiology. PMID- 11613810 TI - The workings of a living fossil. PMID- 11613811 TI - Late archaic mortuary practices of the lower Pecos River region, southwest Texas. PMID- 11613812 TI - Love, sex, and madness in eighteenth-century England. PMID- 11613813 TI - The clitoridectomy craze. PMID- 11613814 TI - Women and madness in Tudor and Stuart England. PMID- 11613815 TI - The true story of Anna O. PMID- 11613816 TI - Female sexuality and madness in Russian culture: traditional values and psychiatric theory. PMID- 11613817 TI - On putting two and two together: osmosis and cholera. PMID- 11613819 TI - 150 years in a country practice. PMID- 11613818 TI - Society and medical education. PMID- 11613820 TI - Anglo-Saxon dermatology. PMID- 11613821 TI - Harold Ridley--surgeon and visionary. PMID- 11613822 TI - Boerhaave's syndrome? PMID- 11613823 TI - A century of endocrinology. PMID- 11613825 TI - Nursing history from artefacts. PMID- 11613824 TI - 200 years of obstetrics: the General Lying-in Hospital, York Road, Lambeth. PMID- 11613826 TI - A Canadian historical view of nurses and health care: the traditional area of "female expertise". PMID- 11613827 TI - Nursing in New Zealand (Part 1): the development of formal nursing in New Zealand, 1840-1900. PMID- 11613828 TI - Nursing research and nursing history meet in New Zealand. PMID- 11613829 TI - Tile pictures in hospitals. PMID- 11613830 TI - Some nursing memories of 1935-1939 and 1940-1946. PMID- 11613831 TI - A heritage map of medical London. [continued]. PMID- 11613832 TI - The first Jewish hospital in Jerusalem. PMID- 11613833 TI - Bern Dibner and the Burndy Library. PMID- 11613834 TI - [Not Available]. PMID- 11613835 TI - [Not Available]. PMID- 11613836 TI - [Not Available]. PMID- 11613837 TI - [Not Available]. PMID- 11613838 TI - [Not Available]. PMID- 11613839 TI - Medieval hepatic therapy and some folk medical survivals. PMID- 11613840 TI - [Not Available]. PMID- 11613841 TI - [Not Available]. PMID- 11613842 TI - [Not Available]. PMID- 11613843 TI - [Not Available]. PMID- 11613844 TI - [Not Available]. PMID- 11613845 TI - [Not Available]. PMID- 11613846 TI - [Not Available]. PMID- 11613848 TI - [Not Available]. PMID- 11613847 TI - Biographical note: Friedrich Arnold (1803-1890). PMID- 11613849 TI - [Not Available]. PMID- 11613850 TI - [Not Available]. PMID- 11613853 TI - Royal porphyria. PMID- 11613852 TI - [Not Available]. PMID- 11613854 TI - Immigration of engineers, scientists, and physicians and the U. S. high technology renaissance. PMID- 11613855 TI - Mrs Bedford Fenwick and Project 2000: the politics of reforming nursing education. PMID- 11613851 TI - [Not Available]. PMID- 11613856 TI - Not all dull and gloomy. PMID- 11613857 TI - The railroad stewardess-nurse: a step toward autonomy in nursing practice. PMID- 11613858 TI - A hospital nurse: 1935-1940. PMID- 11613859 TI - The London hospitals: principles and problems. PMID- 11613860 TI - Health, history and tin openers - a further comment on domestic practice. PMID- 11613862 TI - Memories of a war nurse: Princess Mary's R.A.F. Nursing Service in Europe. PMID- 11613861 TI - The development of psychiatric care in Ireland. PMID- 11613863 TI - Mexican fertility and the revolution of 1910-1920. PMID- 11613864 TI - The Miao and poison: interactions on China's southwest frontier. PMID- 11613866 TI - 'A very special juice': some thoughts on the origins of blood transfusion. PMID- 11613867 TI - Third international symposium on medicine in Bible and Talmud: Jerusalem, December 7-9, 1987. PMID- 11613868 TI - Psychiatry and self in Bible and Talmud: the example of posttraumatic stress disorder and enemy herem. PMID- 11613869 TI - The curse of water pollution in Israel and in the ancient Near East. PMID- 11613870 TI - "He looked in the liver" (Ezekiel 21:26): the medical origins of liver divination. PMID- 11613871 TI - Philosophical observations on Maimonides' critique of Galen. PMID- 11613872 TI - Rav Huna's views on medicine and public health. PMID- 11613873 TI - Childbirth in the Bible. PMID- 11613875 TI - The roots of Jewish sobriety. Alcoholism in the first century C.E PMID- 11613874 TI - Mental health: biblical and talmudic directives. PMID- 11613876 TI - G. Groddeck (1866-1934) on Genesis. PMID- 11613877 TI - New light on Graunt. PMID- 11613878 TI - Burial seasonality and causes of death in London, 1670-1819. PMID- 11613879 TI - The causes of rapid infant mortality decline in England and Wales, 1861-1921, Part I. PMID- 11613880 TI - American Catholicism and the international family planning movement. PMID- 11613882 TI - The NHS and the history of nurses' pay. PMID- 11613881 TI - Ethel Manson and Henry Burdett: two great minds not thinking alike. PMID- 11613883 TI - A tuberculosis ward in the early 1940s: amended extracts of a descriptive article. PMID- 11613884 TI - Recollections of the Nation's Fund for Nurses in 1927. PMID- 11613885 TI - Reclaiming our artefacts: graduation pins from the schools of nursing of British Columbia, 1891-1987. PMID- 11613886 TI - Celebrities and suicide: a taxonomy and analysis, 1948-1983. PMID- 11613887 TI - The continuing significance of race: a study of race, class, and quality of life in America, 1972-1985. PMID- 11613888 TI - The decline of black marital fertility in the rural South. PMID- 11613889 TI - Causes and empiricism: a problem in the interpretation of later Greek medical method. PMID- 11613890 TI - Major epidemics of the 20th century: from coronary thrombosis to AIDS. PMID- 11613891 TI - S. Y. Agnon's T'mol Shilshom as a medical record. PMID- 11613893 TI - Jewish Nobel Prize-winners in medicine and physiology. PMID- 11613892 TI - Remarks on Talmudic medical terminology. PMID- 11613894 TI - Medical treatises by Moses b. Isaac Ibn Waqar. PMID- 11613895 TI - The neoplatonic movement in 14th century Jewish literature and its relationship to theoretical and practical medicine. PMID- 11613896 TI - Yakov Zahalon and the Jewish attitude towards medicine. PMID- 11613897 TI - Problems of techno-scientific manuscripts from the Arabic legacy. PMID- 11613898 TI - Medicine and pharmacy under the Fatimids. PMID- 11613899 TI - A Canadian retrospective on AIDS: implications for future policy, economics, behaviour modification, and research. PMID- 11613900 TI - The origin and antiquity of syphilis: paleopathological diagnosis and interpretation. PMID- 11613902 TI - Fur trader and Indian office obstruction to smallpox vaccination in the St. Louis Indian superintendency, 1831-1834. PMID- 11613903 TI - Infectious disease and the northern Plains horticulturists: a human behavior model. PMID- 11613904 TI - Differential reproduction rates and Osage population change, 1877-1907. PMID- 11613905 TI - The ecology of malaria and changes in settlement pattern on the Cheyenne and Arapaho Reservation, Indian Territory. PMID- 11613906 TI - The epidemiological consequences of forced removal: the northern Cheyenne in Indian territory. PMID- 11613907 TI - Moral reform and the anti-abortion movement. PMID- 11613908 TI - Commission on bibliography of the International Union of the History and Philosophy of Science. PMID- 11613909 TI - Acculturation and health in the Highlands of Papua New Guinea: dissent on diversity, diets, and development. PMID- 11613910 TI - Female quacks in the consumer society. PMID- 11613911 TI - John Conolly's attendants at the Hanwell Asylum 1839-1852. PMID- 11613912 TI - Sister Diana Mary: England's gift to American nursing, 1857-1928. PMID- 11613913 TI - Victorian values: the Plaistow Nurses' Home, 1889 PMID- 11613914 TI - Lees, Florence Sarah (Mrs Dacre Craven) 1840-1922 PMID- 11613915 TI - The medical history of Shakespeare's Sir John Falstaff. PMID- 11613916 TI - George Owen Rees (1813-1889): champion of medical chemistry. PMID- 11613917 TI - Healthy livestock--wholesome meat: a short history of the Bureau of Animal Industry. PMID- 11613918 TI - The transmission of Greek medical literature from antiquity to the Renaissance. PMID- 11613919 TI - Jesse William Lazear: the successful experimental transmission of yellow fever by the mosquito. PMID- 11613920 TI - Second sight: the microscope in medicine. PMID- 11613921 TI - Healers and patients in Moliere's theatre. PMID- 11613922 TI - German romantic psychiatry: Part I. PMID- 11613923 TI - Hysteria in seventeenth-century case records and unpublished manuscripts. PMID- 11613924 TI - Concerning a hitherto unknown disease resembling pseudosclerosis. PMID- 11613925 TI - The early history of the Vienna Psychiatric Clinic. PMID- 11613926 TI - [Not Available]. PMID- 11613927 TI - [Not Available]. PMID- 11613928 TI - A treatise on planetary herbs found by Alexius Africus in the tomb of Kyranos. PMID- 11613929 TI - [Not Available]. PMID- 11613930 TI - [Not Available]. PMID- 11613931 TI - [Not Available]. PMID- 11613932 TI - Ellenbogiana. PMID- 11613933 TI - [Not Available]. PMID- 11613935 TI - [Not Available]. PMID- 11613934 TI - [Not Available]. PMID- 11613936 TI - [Not Available]. PMID- 11613937 TI - [Not Available]. PMID- 11613938 TI - [Not Available]. PMID- 11613939 TI - [Not Available]. PMID- 11613941 TI - [Not Available]. PMID- 11613940 TI - [Not Available]. PMID- 11613942 TI - [Not Available]. PMID- 11613943 TI - [Not Available]. PMID- 11613944 TI - [Not Available]. PMID- 11613945 TI - [Not Available]. PMID- 11613946 TI - [Not Available]. PMID- 11613947 TI - [Not Available]. PMID- 11613948 TI - [Not Available]. PMID- 11613949 TI - [Not Available]. PMID- 11613950 TI - Comments on cosmetic surgery in the ancient Near East. PMID- 11613951 TI - [Not Available]. PMID- 11613953 TI - Columbia's overseas venture: the School of Tropical Medicine at the University of Puerto Rico. PMID- 11613952 TI - Cyril Adler (1903-1988) and the Adler Museum of the History of Medicine. PMID- 11613954 TI - A heritage map of medical London. PMID- 11613955 TI - Roses from the south: the Reynolds Historical Library and its founder, Lawrence Reynolds, M.D. PMID- 11613956 TI - A gestational history of radiology. Part III. PMID- 11613957 TI - Beauperthuy's place in the history of tropical epidemiology. PMID- 11613958 TI - A heritage map of medical London. PMID- 11613959 TI - Brighton medical worthies: a miscellany. PMID- 11613960 TI - The anatomy museum of Leiden; a curious collection. PMID- 11613961 TI - A gestational history of radiology. PMID- 11613962 TI - History of modern dermatology: the Vienna-London-Paris-Vienna circuit. PMID- 11613966 TI - Who was Alice Fisher? PMID- 11613967 TI - From probationer to student-1919-Briggs. PMID- 11613969 TI - Reforming highway safety in New York State: an evaluation of alternative policy interventions. PMID- 11613970 TI - [Not Available]. PMID- 11613971 TI - [Not Available]. PMID- 11613972 TI - [Not Available]. PMID- 11613973 TI - [Not Available]. PMID- 11613974 TI - [Not Available]. PMID- 11613975 TI - [Not Available]. PMID- 11613976 TI - [Not Available]. PMID- 11613977 TI - [Not Available]. PMID- 11613978 TI - Das einstige "Collegium Saxonicum" der ehemaligen Universitat Erfurt im Bild. PMID- 11613979 TI - Jabir's 'Elucidation' in alchemy: a critical essay. PMID- 11613980 TI - Some folk remedies used in Central Anatolia Region of Turkey. PMID- 11613981 TI - Jabir's magic square as the symbol of Venus which was the eight cornered star. PMID- 11613982 TI - Momordica charantia--a review. PMID- 11613983 TI - Some controversial drugs from Avicenna's Canon of medicine--an appraisal. PMID- 11613984 TI - A botanical and pharmacognostic account of Hui hui yao fang, the Islamic formulary. PMID- 11613985 TI - Heat stress and illness patterns among engine room personnel on board warships of the Imperial German Navy (1871-1918). PMID- 11613986 TI - Salvadora persica, Linn. (siwak)--its position and heritage in Islamic dentistry. PMID- 11613987 TI - Islamic contribution to dentistry. PMID- 11613988 TI - Desription of emaciation by Bu Ali Sina. PMID- 11613989 TI - Spot-light on al-mashayekh coptic medical papyrus (Chassinat papyrus). PMID- 11613990 TI - Leprosy in India. PMID- 11613992 TI - Medical literature on Yemen (north and south). A bibliographic survey from 1841 1978. PMID- 11613991 TI - The influence of traditional medicine upon modern medicine. PMID- 11613993 TI - The use of micro-organisms in ancient Egypt. PMID- 11613994 TI - Introduction to Arag-Islamic alchemy. PMID- 11613996 TI - Medical literature on Bahrain. A bibliographic survey from 1906-1979. PMID- 11613995 TI - Ibn Sina's cardiac drug zarnab. PMID- 11613997 TI - Vistas of Arabic healing arts in theory and practice. PMID- 11613998 TI - Pharmacy and medicine education in ancient Egypt. PMID- 11613999 TI - Chemical therapy in tenth century Arabic medicine. PMID- 11614000 TI - The influence of Islamic surgeons on the development of oral surgery in early medieval Europe. PMID- 11614001 TI - Medical parasitology of the Arabian peninsula. A bibliographic survey from 1904 1979. PMID- 11614002 TI - Al-Zahrawi's al-tasrif, commemorating its millenary appearance. PMID- 11614003 TI - Aromatherapy throughout history. PMID- 11614004 TI - Alchemy--lessons from the history. PMID- 11614005 TI - The six plants considered as sacred. PMID- 11614006 TI - The zigzag line as the symbol of life and the cross as symbol of soul PMID- 11614007 TI - Jordan's memorial of medicine and pharmacy (A.D. 533). PMID- 11614008 TI - Famous Egyptian physicians throughout the ages. PMID- 11614009 TI - Nutritions and dietetics in Ibn al-Quff al-Karaki's writings. PMID- 11614010 TI - Arab-Muslim legacy to psychotherapy. PMID- 11614011 TI - The growth of medicine during the Abbasid period. PMID- 11614012 TI - The magic square of three as implicitly containing the symbol of heaven and earth. PMID- 11614013 TI - Alchemy: Jabir ibn Hayyan (702-765) and chemistry. PMID- 11614014 TI - The magic square of three compared with the Chinese symbol of cosmogony, yin yang, pa-kua. Part II. PMID- 11614016 TI - Neuropsychiatry in Islamic medicine. PMID- 11614015 TI - Ibn al-Quff's contributions to Arab-Islamic medical sciences. PMID- 11614017 TI - Two Japanese historians of pharmacy. PMID- 11614018 TI - The Chinese cult of longevity and the making of alchemy. PMID- 11614019 TI - Extraction of volatile oils throughout history. PMID- 11614021 TI - Kept well and working: the Royal College of Nursing and Occupational Health Nursing. PMID- 11614022 TI - Mediaeval London: care of the sick. A selective view of the literature. PMID- 11614024 TI - Famous nursing leaders: Dame Muriel Powell (1914-1978). PMID- 11614027 TI - Cheltenham Dispensary: its beginnings. PMID- 11614029 TI - Fifty years of reform (1948-1979). PMID- 11614030 TI - Rani at the castle: the reminiscences of a V.A.D. in the First World War. PMID- 11614033 TI - Sister Elizabeth Kenny's trial by Royal Commission. PMID- 11614034 TI - The beginnings of the University of Leiden, an 'Asylum for the Muses' in a country in revolt. PMID- 11614035 TI - Harvey, Goulston and Galen. PMID- 11614036 TI - Galen's dissection of the elephant. PMID- 11614037 TI - Franz Kuhn--the inaugurator of "peroral intubation." PMID- 11614038 TI - William Osler and Thomas Browne, a friendship of fifty-two years; Sir Thomas pervades Sir William's library. PMID- 11614039 TI - On value judgements in the teaching of the history of medicine. PMID- 11614040 TI - [Not Available]. PMID- 11614041 TI - Hospital administrators in the French Revolution. PMID- 11614042 TI - Medieval Hebrew anatomical names: a contribution to their history. PMID- 11614043 TI - Dr. Isac Lampronti of Ferrara. PMID- 11614045 TI - Embalming and cremation in Judaism. PMID- 11614044 TI - Charles and Dorothea Singer's aid to Nazi victims. PMID- 11614046 TI - [Not Available]. PMID- 11614047 TI - [Not Available]. PMID- 11614048 TI - [Not Available]. PMID- 11614050 TI - Professor Joshua O. Leibowitz. PMID- 11614049 TI - [Not Available]. PMID- 11614051 TI - Heralds of science. PMID- 11614052 TI - The first recorded aeromedical evacuation in the British Army--the true story. PMID- 11614053 TI - Johannes Muller and Justus Liebig on nutrition. PMID- 11614054 TI - The evolution of wound healing by first intention (a short history of wound treatment). PMID- 11614055 TI - Three pioneers in Swedish military medicine: Carolus Linnaeus, Pehr Zetzell and Arvid Faxe. PMID- 11614056 TI - [Not Available]. PMID- 11614057 TI - [Not Available]. PMID- 11614058 TI - The early practice of medicine and the formation of medical libraries. PMID- 11614059 TI - [Not Available]. PMID- 11614061 TI - [Not Available]. PMID- 11614062 TI - Four mnemonic distichs in Bodleian Library MS. Ashmole 342. PMID- 11614060 TI - [Not Available]. PMID- 11614063 TI - [Not Available]. PMID- 11614064 TI - [Not Available]. PMID- 11614065 TI - [Not Available]. PMID- 11614066 TI - [Not Available]. PMID- 11614067 TI - [Not Available]. PMID- 11614068 TI - [Not Available]. PMID- 11614069 TI - [Not Available]. PMID- 11614070 TI - [Not Available]. PMID- 11614071 TI - [Not Available]. PMID- 11614072 TI - [Not Available]. PMID- 11614073 TI - [Not Available]. PMID- 11614074 TI - [Not Available]. PMID- 11614075 TI - [Not Available]. PMID- 11614076 TI - [Not Available]. PMID- 11614077 TI - [Not Available]. PMID- 11614078 TI - [Not Available]. PMID- 11614079 TI - [Not Available]. PMID- 11614080 TI - [Not Available]. PMID- 11614081 TI - [Not Available]. PMID- 11614082 TI - [Not Available]. PMID- 11614083 TI - [Not Available]. PMID- 11614085 TI - [Science, worldview, and metaphysical pathos in inter-war Sweden]. PMID- 11614084 TI - [Not Available]. PMID- 11614086 TI - [A paternal rod and the corporeal punishment of children: on approaches to the plague and the fight against it in spiritual literature during the ages of reformation and empire]. PMID- 11614087 TI - [Traveling students during 600 years]. PMID- 11614088 TI - The influence of medieval Christian ideology on Western hospitals. PMID- 11614089 TI - Pathfinders of clinical chemistry. PMID- 11614090 TI - A death knell: the final months of the Medical Department of the University of Alabama in Mobile. PMID- 11614092 TI - Nineteenth century neurology/psychiatry. PMID- 11614091 TI - Harry Tutwiler Inge, M.D.; Mobile, Alabama surgeon 1915-1921. PMID- 11614093 TI - The evolution of neurophysiology and electrodiagnostics. PMID- 11614094 TI - The development of family practice: the 20th specialty. PMID- 11614095 TI - Ayurveda and its influence on western medicine. PMID- 11614096 TI - Monte Leroy Moorer. PMID- 11614097 TI - James F. Heustis, assistant surgeon United States Navy. PMID- 11614101 TI - The Bethlem Royal Hospital Museum. PMID- 11614104 TI - Flying high: aeromedical evacuation takes off in World War II. PMID- 11614105 TI - [Sixty years of study on Chinese medical history]. AB - The sixty years of Chinese Society of Medical History since its establishment is an important period of from young to maturity, experiencing vicissitude of its indepth development. Overcoming numerous difficulties, the Chinese Journal of Medical History has been recognized by scholars, domestic and foreign, as a journal of high academic level with new messages and materials. In the field of theoretical study, all relevant problems, including origin of medicine, division of historical periods, appraisal of medical figures, relationship between the inner law of medical development and cultural background, have been explored actively, profoundly and objectively. Study on general medical history has been more popularized and comprehensive. The studies on the history of diseases, history of medical disciplines, modern history , excavation and systematization in the fields of archeology and medical literatures, laid down a basis for further development of research work. PMID- 11614106 TI - [Sixty years of society of medical history, Chinese Medical Association]. AB - Being the earliest special Society under the CMA, the Society of Medical History was founded in 1935. The history of the 60 years since its establishment can be divided into 4 stages: the stage of foundation (1935-1952) in which solid works on academic exchanges, publications of monographs and Journal of Medical History, founding of museum and library, laid down the foundation for the later stages; the stage of continuous development (1952-1965) saw the moving of th Society office from Shanghai to Peking. The works in the 2 branch Societies in Peking and Shanghai were very active, with only little activity carried out at the national level; the third stage (1966-1979) was a stage of stagnation; the last stage (1979-1995) is a stage of rejuvenation and development. During this last stage, 8 national conferences, 1 international congress were sponsored, 16 local branches established, 500 members were included. Under the Society, there is a Head Group, under which there are 3 academic titles, viz. Society of Medical History, CMA, Group Membership of Chinese Association for History of Science and Technology, and Socieity of History of Chinese Medicine under the China Association of Traditional Chinese and Pharmacy. PMID- 11614107 TI - [Sixty years of study on history of special medical disciplines]. AB - By history of special medical disciplines, it refers to history of many subjects in special medicine, basic medicine, clinical medicine, and preventive medicine. Being an important field in the research of medical history, it made its first appearance around 1911. For the period beginning from 1930's-1960's, it passes through 3 stages, viz. the beginning, the flourishing and the profound development. The first period includes the publication of over 400 papers, the 2nd period, over 440 articles, and that in the 3rd period, over 1300 papers. It has been estimated that over one hundred journals and newspapers published articles in this special field. PMID- 11614108 TI - [Sixty years of study on history of diseases]. AB - The study of history of diseases includes research on archeology, ancient medical works and systematic study on the history of diseases. By reviewing the process of 60 years, the paper points out that the process includes two approaches. On the one hand, it is defined by modern disease titles, offering historical background to cosmopolitan medicine and integrated Chinese and western medicine, and retifying the positive role of Chinese ancient medical workers' contribution to mankind. On the other hand, it also defined by traditional Chinese disease syndrome titles, offering experiences for the development of Chinese medical academy and realization of modernization of Chinese medicine. Both approaches are mutually promoted, infiltrated, thus stimulated the deeper development for the study of history of diseases. PMID- 11614109 TI - [Sixty years of study on ancient medical history]. AB - The paper includes ten parts, viz. origin of medicine, division of historical periods in Chinese medicine, medical institution, history of preventive medicine, history of medicl disciplines and diseases, history of exchanges among China and foreign countries, history of medical education, history of minority medicine, studies on medical figures, works on Chinese medical history. It summarizes the brilliant achievements in the study of ancient Chinese medical history. PMID- 11614110 TI - [Sixty years of study on history of chinese medical education]. AB - This paper deals with the general study on ancient and modern Chinese medical education, namely the history of institution, history of medical thinking, regional medical education, minority medical education. The summary showed that there are certain achievements in this field of research. However, generally speaking, the basis is rather weak and the progress is sluggish. Many fields, including summary and systematization on heritage, developmental law of Chinese medical education, need to be further explored. The study on the contemporary part of the history of Chinese medical education should also be strengthened. Some suggestions are given in the summary of this paper. PMID- 11614111 TI - [Sixty years of study on Chinese military medicine]. AB - Before Liberation, the study on Chinese military medicine is a virgin land. Since 1949, preliminary investigation has been made in ancient military medicine in China. Unfortunately, the study is rather superficial in the definition, scope and division of historical period of the ancient military medicine. PLA used to pay attention to the investigation and systematization and many reminescences, original articles and monographs have been published. In view of the lack of systematization in this field, the Ministry of Health of General Logistics Department, PLA, organized, in 1988, experts and professors of military medicine, together with administrators, scientific cadres, to compile Chinese History of Military Medicine which was completed in 1994, to be published soon. PMID- 11614112 TI - [Sixty years of studies on history of Chinese pharmacy]. AB - This paper is presented in studies on the following subtopics: 1. General history of Chinese pharmacy; 2. Study and systematization of ancient herbological works; 3. History of individual drugs; 4. History of commercial and industrial aspects of Chinese and Western drugs; 5. Unearthed historical materials of pharmacy; 6. History of pharmacy of national minority; 7. Education on pharmacy; 8. History of special subjects in pharmacy; 9. Figures of pharmacy. PMID- 11614113 TI - German politics of genetic engineering and its deconstruction. AB - Policy-making, as exemplified by biotechnology policy, can be understood as an attempt to manage a field of discursivity, to construct regularity in a dispersed multitude of combinable elements. Following this perspective of politics as a textual process, the paper interprets the politicization of genetic engineering in Germany as a defence of the political as a regime of heterogeneity, as a field of 'dissensus' rather than 'consensus', and a rejection of the idea that the framing of technological transformation is an autonomous process. From its beginning in the early 1970s, genetic engineering was symbolically entrenched as a key technology of the future, and as an integral element of the German politics of modernization. Attempts by new social movements and the Green Party to displace the egalitarian imaginary of democratic discourse into the politics of genetic engineering were construed by the political elites as an attack on the political order of post-World War II Germany. The 1990 Genetic Engineering Law attempted a closure of this controversy. But it is precisely the homogenizing idiom of this 'settlement' which continues to nourish the social movements and their radical challenge to the definitions and codings of the politics of genetic engineering. PMID- 11614114 TI - [The revival of Linnean ideas in nineteenth-century France]. AB - During the first half of the 19th century, and notably during the Restoration, many French naturalists gathered into some new natural history Societies, called Linnean Societies. They tried to remove the chaos of the zoological and botanical nomenclature, and decided to fight against the generalization of the natural method. They worshipped Linnaeus' memory, his artificial system of classification of plants and animals, and his binomial nomenclature. This worshipping, ignored by the official scientific institution, opened up the way to an international critical approach aiming at the stabilization and universalization of zoological, botanical and geological nomenclatures. At the end of the century this approach caused the writing of the International codes of nomenclature currently in use today. The starting points of these codes were Linnaeus' 10th edition of Systema naturae (1758), 1st edition of Species plantarum (1753) and 5th edition of Genera plantarum (1754). PMID- 11614115 TI - [Not Available]. AB - The correspondence between the physicist Laura Bassi (1711-1778) from Bologna and the physician and scientist Giovanni Bianchi (1693-1775) from Rimini comprehends altogether 17 letters from 1733 to 1745. Concerning Bassi, these letters are one of the few sources from a period which was decisive for her personal and scientific development; as to Bianchi, they confirm in many details the traditional picture of his person. The estimation, in which Bassi was held by Bianchi, her scientific training and her marriage are important subjects of the correspondence. Furthermore, Bianchi often sent her copies of his publications. PMID- 11614116 TI - Workshop on bibliographic control of sources for the history of science, technology, and medicine: new directions and opportunities, Trento, Italy, 23-25 September 1992. PMID- 11614118 TI - [Not Available]. AB - A review of the inaugural addresses held during half a century in Italy makes clear the image that the University professors of medicine wanted to present about themselves and their activities. They sang a hymn to science, the only admittable authority, by which useful and astonishing prodigies were performed. The annual addresses deliberately stressed those particular themes which would better illustrate past and present progress: surgical improvements, achievements in hygiene and dictates of preventive medicine, bacteriological 'revolution' etc. More and more the medical professors were claiming competences which should enlarge their field; they promised the just unified Italian nation that they would bring about a gradual but whole physical, moral and social "redemption". PMID- 11614117 TI - Sources and resources for history of science to 1600: a survey of computer assisted catalogues for original sources in manuscript. AB - Two reports of the Commission on bibliography are published. The first, by Henry Lowood, concerns the Workshop on bibliographic control of sources for the history of science, technology, and medicine held in Trento in September 1992; the second, by Wesley M. Stevens, is a survey of computer-assisted catalogues of pre 1600 manuscripts. PMID- 11614119 TI - [Recent research on Hippocrates and the Hippocratic corpus]. PMID- 11614120 TI - Species, rules and meaning: the politics of language and the ends of definitions in 19th century natural history. PMID- 11614122 TI - Thales to Galen: a brief journey through rational medical philosophy in ancient Greece. Part I: pre-Hippocratic medicine. PMID- 11614123 TI - Memories of a surgeon-lieutenancy, Edinburgh 1941-43: Part II. PMID- 11614121 TI - The medical history of Martin Luther. PMID- 11614125 TI - Sir James Paget (1814-99): surgical Osler? PMID- 11614124 TI - Monro Secundus and 18th century lymphangiography. PMID- 11614126 TI - The place of Darwin and his theory within history studies. PMID- 11614128 TI - De bevolking van Duiven, 1665-1795. Een historisch-demografische studie. PMID- 11614127 TI - The Royal Medical Society and medical women. PMID- 11614129 TI - Repertorium medico-historicum Aquense II. Ein Beitrag zur medizinhistorischen Topographie. PMID- 11614130 TI - Antiche illustrazioni mediche. PMID- 11614132 TI - Riga als Zentrum der Wissenschaft. PMID- 11614133 TI - The anatomy of plants and its contribution to the origin of cellular theory in the early 19th century. PMID- 11614131 TI - The oldest herbal in Hungarian. PMID- 11614134 TI - Biochemical journals and their profile in 1840-1930. PMID- 11614135 TI - From physiological chemistry to biochemistry. PMID- 11614136 TI - The social structure of nutrition: a case. PMID- 11614137 TI - The unintended consequences of policy change: the effect of a restrictive abortion policy. PMID- 11614138 TI - Flying hospital wards. PMID- 11614139 TI - The "Ayars", the surgeons and the orthopedic surgeons of Khorasan at the end of the ninth century of Hejira. PMID- 11614141 TI - Man and cannabis in Africa: a study of diffusion. PMID- 11614142 TI - The social and economic effects of sleeping sickness in Mweru-Luapula 1906-1922. PMID- 11614143 TI - Recent developments in the healing concepts and activities of the Aladura churches. PMID- 11614144 TI - Economic consequenses of long-distance trade in East-Africa: the disease factor. PMID- 11614145 TI - Prayers, amulets and charms: health and social control. PMID- 11614146 TI - Alabama public health campaign, 1900-1919. PMID- 11614147 TI - Health and welfare of freedmen in reconstruction Alabama. PMID- 11614148 TI - Mobile v. Birmingham: the Alabama Medical College controversy, 1912-1920. PMID- 11614149 TI - Smallpox strikes the Aleuts. PMID- 11614150 TI - Intrepid nurses faced the challenges. PMID- 11614151 TI - Sexual deviance and disaster during the Napoleonic wars. PMID- 11614153 TI - Opposition to the Contagious Diseases Act, 1864-1886. PMID- 11614152 TI - Neo-Malthusians, eugenists, and the declining birth-rate in England, 1900-1918. PMID- 11614154 TI - Medical opinion and the first year of national health insurance in Britain. PMID- 11614155 TI - Masturbation and insanity: Henry Maudsley and the ideology of sexual repression. PMID- 11614156 TI - Nursing education and change. PMID- 11614157 TI - A preliminary evaluation of tooth tartar among the preconquest Maya of the Tayasal area, El Peten, Guatemala. PMID- 11614158 TI - The rarest of all revolutions: G. K. Chesterton on the relation of human life to Christian doctrine. PMID- 11614159 TI - The acceptance of chaplains in mental hospitals. PMID- 11614160 TI - Recombinant DNA: history of the controversy. PMID- 11614162 TI - Health insurance and cost-containment policies: the experience abroad. PMID- 11614161 TI - Fertility and child mortalilty over the llfe cycle: aggregate and additional evidence. PMID- 11614163 TI - Regulation and the choice of prescription drugs. PMID- 11614164 TI - A bulwark against mighty woes: the hundredth anniversary of the American Red Cross. PMID- 11614165 TI - The healing art. PMID- 11614166 TI - The Mosher report. PMID- 11614167 TI - A medic in the Normandy invasion. PMID- 11614168 TI - "A disease called milksick." PMID- 11614169 TI - Out of sight, out of mind. PMID- 11614170 TI - "Step right up, ladies and gentlemen...": Patent medicines in 19th-century America. PMID- 11614171 TI - A horse on the street is a rare sight. PMID- 11614172 TI - Medicine in the Revolution. PMID- 11614173 TI - The first energy crisis: the great epizootic. PMID- 11614174 TI - Burial as a disposition mechanism for Navajo jish or medicine bundles. PMID- 11614175 TI - Changes in Navajo mortuary practices and beliefs. PMID- 11614176 TI - An ethnography of the Navajo reproductive cycle. PMID- 11614177 TI - Who or what's a witch: Iroquois persons of power. PMID- 11614178 TI - Tuuhikya: the Hopi healer. PMID- 11614179 TI - Implementing a permissive policy: hospital abortion services after Roe V. Wade. PMID- 11614180 TI - Jewish deaths included in the vital records of American cities, 1821-1829. PMID- 11614181 TI - A quarantine quandary; ship fever and yellow fever in Providence, Rhode Island, 1797. PMID- 11614182 TI - The design of reform: the public bath movement in America. PMID- 11614183 TI - The conservative connection: the chairman of the board took LSD before Timothy Leary. PMID- 11614184 TI - National history through local social evils and the origin of municipal services in Cincinnati. PMID- 11614185 TI - "A great black book": East of Eden and Gunn's New family physician. PMID- 11614186 TI - The ghetto of the mind: notes on the historical psychology of Chinese America. PMID- 11614187 TI - Sikh family patterns and ethnic adaptation in Vancouver. PMID- 11614188 TI - Tobacco: that pernicious habit. PMID- 11614189 TI - Insalubrious California. PMID- 11614190 TI - The Australian fever tree in California: eucalypts and malaria prophylaxis. PMID- 11614191 TI - Native population decline in Totonicapan, Guatemala. PMID- 11614192 TI - Disease and ethnicity in an urban environment. PMID- 11614193 TI - The first rural public hospital. PMID- 11614194 TI - Excavated surgical instruments from old Cairo, Egypt. PMID- 11614196 TI - Renaissance science and professionalisation. PMID- 11614195 TI - Excavated surgical instruments from Old Cairo, Egypt. PMID- 11614197 TI - Ptolemaic baths of Kom Ganady. PMID- 11614198 TI - The persistence and spread of some obstetric concepts held in ancient Egypt. PMID- 11614199 TI - Further evidence of dental prothesis in ancient Egypt. PMID- 11614200 TI - Probable trephination of five early Saxon skulls. PMID- 11614201 TI - Romano-British pathology. PMID- 11614202 TI - Rabies archaeologorum. PMID- 11614203 TI - "Nature's law": the venereal disease debate, Melbourne 1918-19. PMID- 11614205 TI - A question of policy: is provision of special schools for defectives to be undertaken by this department? PMID- 11614206 TI - Aspects of the interrelations of medicine, magic and philosophy in ancient Greece. PMID- 11614207 TI - The naive empiricism of an ancient medicine. PMID- 11614209 TI - Why Europe responded to the Muslims' medical achievements in the Middle Ages. PMID- 11614208 TI - Why Islam permitted birth control. PMID- 11614211 TI - Tod, Totentanz, Jenseits. PMID- 11614212 TI - The supply of water to Newcastle upon Tyne and Gateshead, 1680-1837. PMID- 11614214 TI - Gynecological operations on the insane. PMID- 11614215 TI - War amputations in Upper Canada. PMID- 11614213 TI - Classical prosthetics. PMID- 11614216 TI - Biomedical techniques for influencing human reproduction in the fourth century B.C. PMID- 11614218 TI - Biomedical techniques for influencing human reproduction in the fourth century B.C. PMID- 11614217 TI - Selected bibliography on psychoanalysis and classical studies. PMID- 11614219 TI - The black death in Chinatown; plague and politics in San Francisco 1900-1904. PMID- 11614220 TI - Doctors, druggists and dentists in the Oklahoma Territory, 1889-1907. PMID- 11614221 TI - Beans, bacon, and galantine truffles: the food of the Western miners. PMID- 11614222 TI - Analysis of human skeletal remains from the Montgomery farm, Barry County, Missouri. PMID- 11614223 TI - The evolution of mental health care in Arkansas. PMID- 11614224 TI - The failure of relief during the Arkansas drought of 1930-1931. PMID- 11614225 TI - The introduction of prepayment medicine to Arkansas: the Trinity Hospital experience. PMID- 11614227 TI - Thr Turkish genocide of the Armenians: a premeditated and official assault. PMID- 11614226 TI - It happened in 1915: the massacre of the Armenians in the Ottoman empire. PMID- 11614228 TI - The science of the soldier's food. PMID- 11614229 TI - Passage of the lines. PMID- 11614230 TI - The specialty of oral surgery in retrospect and in prospect. PMID- 11614231 TI - The first dental hospital in Chalmers St., Sydney. PMID- 11614232 TI - China, Europe and the origins of modern science. PMID- 11614233 TI - Medical education in the People's Republic of China. PMID- 11614234 TI - Sitala: the small-pox goddess of India. PMID- 11614235 TI - The origin of Chinese folk medicine. PMID- 11614236 TI - Chinese folk medicine: a study of the Shan-hai Ching. PMID- 11614237 TI - An application of dental anthropological analysis to the human dentition of two early metal age sites, Palawan, Philippines. PMID- 11614238 TI - Early phases of homoeopathy in India. PMID- 11614239 TI - Initiating a population revolution in Thailand: politics, bureaucracy, and social change. PMID- 11614240 TI - Historical attitudes toward women and childbirth. PMID- 11614241 TI - The inadequacy of health care of women. PMID- 11614242 TI - The politics of abortion: trends in Canadian fertility policy. PMID- 11614244 TI - Alchemists and antiquaries in Enlightenment France. PMID- 11614243 TI - Aspects of Australian fertility, 1861-1901. PMID- 11614245 TI - Fertility trends and prospects in Australia and other industrialised countries. PMID- 11614246 TI - Educational expansion, curriculum reform and psychological theory: Australia in the 1930s. PMID- 11614247 TI - The public doesn't want health and isn't going to get it unless.... PMID- 11614248 TI - Health costs and health policy. PMID- 11614249 TI - A sociodemographic profile of Hispanic physicians in three United States metropolitan areas. PMID- 11614250 TI - Health care: the dilemma of delivery. PMID- 11614251 TI - Health care beliefs and practices among Mexican Americans: a review of the literature. PMID- 11614253 TI - Sanitary condition of Melbourne, 1888-1891: a study. PMID- 11614254 TI - The history of Southern Baptist medical missions. PMID- 11614255 TI - Southern Baptist convention resolutions on the family. PMID- 11614256 TI - Asylum at lower Fort Garry, 1874-1886. PMID- 11614257 TI - Bella Coola: Indian and European medicines. PMID- 11614258 TI - Belizean nursing education in the 19th century. PMID- 11614261 TI - Cult banks from Hatra. PMID- 11614259 TI - The emergence of the prototype of the modern hospital in medieval Islam. PMID- 11614260 TI - The origins of "the Pusa experiment": the East India Company and horse-breeding in Bengal, 1793-1808. PMID- 11614262 TI - Wissenschaftliche Bibliotheken in Madrid. PMID- 11614263 TI - Psychological processes in preparing contemporary biography. PMID- 11614264 TI - Explorations in character: Gamaliel Bradford and Henry Murray as psychobiographers. PMID- 11614265 TI - The Contestations between the Paris College of Surgery and the Faculty of Medicine (1743-1750). PMID- 11614266 TI - On the authorship of an astrologico-medical calendar for 1474. (Pol) PMID- 11614267 TI - The mental health status of older black Americans: a national study. PMID- 11614268 TI - Death rates of aged blacks and whites, United States, 1964-1978. PMID- 11614269 TI - Psychosocial competence characteristics of black and white women: the constraining effects of "triple jeopardy". PMID- 11614270 TI - Demographic performance of two slave populations of the Dutch speaking Caribbean. PMID- 11614271 TI - An epidemic among the Kgatla: the influenza of 1918. PMID- 11614272 TI - The role of dingaka tsa setswana from the 19th century to the present. PMID- 11614273 TI - History of the Botswana veterinary services--1905-66. PMID- 11614274 TI - Notes on the history of sleeping sickness. PMID- 11614275 TI - British books on tropical medicine. PMID- 11614277 TI - The mental health review tribunal: a question of imbalance. PMID- 11614276 TI - The age of specialisation. PMID- 11614278 TI - Science, law and safety standards: a case study of industrial disease. PMID- 11614279 TI - Psychology and the law: a critical review of research and practice. PMID- 11614280 TI - Does spending on defence cut spending on health? A time-series analysis of the U. S. economy 1929-74. PMID- 11614281 TI - Some notes on seventeenth-century continental hospitals. PMID- 11614282 TI - A pictorial essay, medicine and the arts. PMID- 11614283 TI - "Nine children were born": a historical problem from the Sugar Creek episode. PMID- 11614284 TI - A Roman veterinary physician from the Thames Valley. PMID- 11614285 TI - Famosa pestis and Britain in the fifth century. PMID- 11614286 TI - The story of Farnborough Hospital. PMID- 11614287 TI - The British Red Cross in the Bromley area 1910-1919. PMID- 11614288 TI - A history of Orpington Hospital. PMID- 11614290 TI - Modern and traditional medicine: rivals or friends? Some solutions attempted by India, China, Japan and Tibetans in exile. PMID- 11614289 TI - James Scott, the famous surgeon of Bromley, 1770-1848. PMID- 11614291 TI - The impact of Arabic science on western civilisation in the Middle Ages. PMID- 11614292 TI - Indian medicine and the state. PMID- 11614293 TI - The impact of western medicine on Muslim physicians and their writings in the 17th century. PMID- 11614294 TI - Catologue des manuscrits alchimiques. Acad R Belg. PMID- 11614296 TI - Notes on nine physicians of ancient Egypt, five hitherto unknown. PMID- 11614295 TI - Environmental science in early Georgia. PMID- 11614297 TI - Some historical problems connected with the study of Egyptian mummies. PMID- 11614298 TI - A confraternity document of St. Mary Magdalene's Hospital, Liskeard. PMID- 11614299 TI - The "Faithful Brethren" of Edinburgh: the acceptable face of Protestantism. PMID- 11614300 TI - The social and economic structure of an early modern suburb: the Tything at Worcester. PMID- 11614301 TI - The Prior of Butley and the lepers of West Somerton. PMID- 11614302 TI - Some correspondence in the John Rylands University Library of Manchester concerning John Lewis Burckhardt and Lady Hester Stanhope's physician. PMID- 11614303 TI - Man and nature--the ecological controversy and the Old Testament. PMID- 11614304 TI - Catalogue of Ethiopian manuscripts of the Wellcome Institute of the History of Medicine in London. PMID- 11614305 TI - Hariti and the chronology of the Kusanas. PMID- 11614306 TI - Contributions to the study of the "Jivaka-pustaka". PMID- 11614307 TI - The Egyptian plagues in the Palaea Historica. PMID- 11614308 TI - Shipping patterns and mortality in the African slave trade to Rio de Janeiro, 1825-1830. PMID- 11614309 TI - Historical perspectives on penicillamine. PMID- 11614310 TI - Medical professionals and public health in "Doldrums" Russia (1725-62). PMID- 11614311 TI - Communicable disease, anti-epidemic policies, and the role of medical professionals in Russia, 1725-62. PMID- 11614312 TI - Plague and the Russian countryside: monastic estates in the late fourteenth and fifteenth centuries. PMID- 11614313 TI - NRC: where science fiction often comes true. PMID- 11614314 TI - Birth control and abortion in Canada, 1870-1920. PMID- 11614315 TI - "From social reform to social service": the changing role of volunteers: the anti tuberculosis campaign, 1900-30. PMID- 11614316 TI - Venereal disease and public health reform in Canada. PMID- 11614317 TI - The development and distribution of health care services in Ethiopia: a preliminary review. PMID- 11614318 TI - Plague, population and ecology in early modern England. PMID- 11614319 TI - Femininity first, sport and physical education for Ontario girls, 1890-1930. PMID- 11614321 TI - Environmental politics in the Soviet Union: the Baikal controversy. PMID- 11614320 TI - Medicare is not the health charter for Canadians. PMID- 11614322 TI - Dissent, law and psychiatry in the Soviet Union. PMID- 11614323 TI - Chemistry and numismatics. PMID- 11614324 TI - "To supply the sick poor". PMID- 11614325 TI - Academic politics in the history of science: experimental psychology in Germany, 1879-1941. PMID- 11614326 TI - The fight for female physicians in Imperial Germany. PMID- 11614327 TI - The anguish of the veterans. PMID- 11614328 TI - On mass inoculation, who should be heard? PMID- 11614329 TI - The artificial heart program. PMID- 11614330 TI - Changing concepts of mental abnormality. PMID- 11614331 TI - Medicine in the Middle Ages: the theory of a profession. PMID- 11614332 TI - The English romantics and modern psychology. PMID- 11614333 TI - The creation of Chicago's sanitary district and construction of the Sanitary and Ship Canal. PMID- 11614334 TI - When cholera scourged Chicago. PMID- 11614335 TI - Performance and the Chinese political system: a preliminary assessment of education and health policies. PMID- 11614336 TI - Changing medical models in China: organizational options or obstacles? PMID- 11614337 TI - The Chinese food-grain crisis: 1959-61--some explanations. PMID- 11614338 TI - Birth control and planned parenthood in China. PMID- 11614339 TI - The "House of life" of Bubastis. PMID- 11614340 TI - Indian territory forts: charnel houses of the frontier, 1839-1865. PMID- 11614341 TI - Stress and death in the settlement of Indian territory. PMID- 11614342 TI - Medical practices and health in the Choctaw Nation. 1831-1885. PMID- 11614343 TI - Ordeal of the Oklahoma coal miners: coal mine disasters in the Sooner state, 1886 1945. PMID- 11614344 TI - A study of the use of madstones in Oklahoma. PMID- 11614345 TI - Medical libraries in Cincinnati. PMID- 11614346 TI - Patrons and proteges: Cincinnati's first generation of women doctors 1875-1910. PMID- 11614347 TI - Civil War anthropometry: the making of a racial ideology. PMID- 11614348 TI - Pity the poor surgeon. PMID- 11614349 TI - Politics in medicine: the Georgia Freedmen's Bureau and the organization of health care, 1865-1866. PMID- 11614350 TI - Romans and physicians. PMID- 11614351 TI - The problem of female infanticide in the Greco-Roman world. PMID- 11614352 TI - Nicander: Theriaca 811. PMID- 11614353 TI - Aristotle's De anima 3.2: how do we perceive that we see and hear? PMID- 11614354 TI - The plague of Athens, 430-428 B.C.: epidemic and epizootic. PMID- 11614355 TI - Psychoanalytic writings on Greek and Latin authors, 1911-1960. PMID- 11614356 TI - Relations of literature and science: a bibliography of scholarship, 1978-79. PMID- 11614357 TI - You were there--back in 1850. Dental journal provides rare glimpse into Mint's gold refining technique. PMID- 11614358 TI - Confines, wards, and dungeons. PMID- 11614360 TI - The drug habit in nineteenth-century Colorado. PMID- 11614359 TI - The death cart: it's place among the Santos of New Mexico. PMID- 11614361 TI - A typhoid fever epidemic and the power of the press in Denver in 1879. PMID- 11614362 TI - A history of the Nordrach Ranch: Colorado's first sanatorium of the open air. PMID- 11614363 TI - Ayurveda and mental illness. PMID- 11614364 TI - Contraception and the working classes: the social ideology of the English birth control movement in its early years. PMID- 11614365 TI - Premarital sexual permissiveness and illegitimacy in the Nordic countries. PMID- 11614366 TI - The glut of doctors in mid-nineteenth century France. PMID- 11614367 TI - The historiography of scientific medicine: an invitation to the human sciences. PMID- 11614368 TI - Rationality and control in French eighteenth-century medical views of the peasantry. PMID- 11614369 TI - Nineteenth-century Asante medical practices. PMID- 11614370 TI - A prehistory of the social sciences: phrenology in France. PMID- 11614371 TI - A century and one-half of American epitaphs (1660-1813): toward the study of collective attitudes about death. PMID- 11614372 TI - The naked science: psychoanalysis in Spain. PMID- 11614373 TI - Psychoanalysis in the Netherlands. PMID- 11614374 TI - The acceptance of psychoanalysis in Western cultures: an afterword on its comparative history. PMID- 11614375 TI - The Lutheran Sanitarium at Wheat Ridge. PMID- 11614376 TI - Catch-22 in the nineteenth century: the evolution of the therapeutic confinement for the criminally insane in Canada, 1840-1900. PMID- 11614377 TI - Literary interpretation and three phases of psychoanalysis. PMID- 11614378 TI - [Population and plague of Vallalon 16-17 centuries] (Spa). PMID- 11614379 TI - Cuban food policy and popular nutritional levels. PMID- 11614380 TI - Modernization and suicide in Japan: a comparative approach. PMID- 11614381 TI - Disease and public health in Tunisia: 1882-1970. PMID- 11614382 TI - Two cholera ships in Halifax. PMID- 11614383 TI - Psychomythology: A phenomenological critique of psychohistory. PMID- 11614384 TI - Nursing history in undergraduate curriculum: renewal and relevance. PMID- 11614385 TI - From mission to hospital: the Detroit Florence Crittenton Organization, 1897 1930. PMID- 11614386 TI - Epidemics in Devon, 1538-1837. PMID- 11614387 TI - Observations upon the distribution and spread of the English sweating sickness (sudar anglicus) in Devon in 1551. PMID- 11614388 TI - Birth, marriage and death in East Budleigh, 1555-1810. PMID- 11614389 TI - Mormon sexuality and American culture. PMID- 11614390 TI - Mormon sexuality in cross-cultural perspective. PMID- 11614391 TI - Mormon sex standards on college campuses: or deal us out of the sexual revolution! PMID- 11614392 TI - Shall the youth of Zion falter? Mormon youth and sex: a two-city comparison. PMID- 11614393 TI - Polygamous eyes: a note on Mormon physiognomy. PMID- 11614395 TI - The imperfect science. Brigham Young on medical doctors. PMID- 11614394 TI - Medicine and the Mormons: a historical perspective. PMID- 11614396 TI - Herbal remedies: God's medicine? PMID- 11614397 TI - His chastening rod: cholera epidemics and the Mormons. PMID- 11614398 TI - A peculiar people: "the physiological aspects of Mormonism 1850-1975." PMID- 11614399 TI - Mormon health. PMID- 11614400 TI - His chastening rod: cholera epidemics and the Mormons. PMID- 11614401 TI - The word of wisdom in early nineteenth-century perspective. PMID- 11614402 TI - Did the word of wisdom become a commandment in 1851? PMID- 11614403 TI - The word of wisdom: from principle to requirement. PMID- 11614404 TI - Medicaid fraud reconsidered: how the hospitals got on welfare. PMID- 11614405 TI - The corruptions of science. PMID- 11614406 TI - The life of the homeless. PMID- 11614407 TI - Poverty, pigs and pestilence in medieval Dublin. PMID- 11614408 TI - A note on the hoard of Roman equipment buried at Cambridge. PMID- 11614409 TI - Chemistry, physiology and materialism in the romantic period. PMID- 11614410 TI - Early medicine in the north country. PMID- 11614411 TI - An early American sex manuel, or Aristotle who? PMID- 11614412 TI - A preliminary catalog of the scientific and technical societies of Antebellum East Tennessee. PMID- 11614413 TI - Medicine nineteenth-century style. PMID- 11614414 TI - Some new aspects on Swedish population growth. PMID- 11614415 TI - Disease or famine? Mortality in Cumberland and Westmorland 1580-1640. PMID- 11614416 TI - The black death. PMID- 11614417 TI - Marriage rates and population pressure: Ireland, 1871 and 1911. PMID- 11614418 TI - 'Famine, mortality, and epidemic disease in the process of modernization'. PMID- 11614419 TI - The impact of the first world war on civilian health in Britain. PMID- 11614420 TI - Famine, mortality, and epidemic disease: a comment. PMID- 11614421 TI - Age, region and marriage in post-famine Ireland: an empirical examination. PMID- 11614422 TI - Family limitation in pre-industrial England: a reappraisal. PMID- 11614423 TI - Marital fertility in seventeenth century Colyton. PMID- 11614424 TI - The disappearance of plague: a continuing puzzle. PMID- 11614425 TI - The demographic impact of the old poor law: more reflexions on Malthus. PMID- 11614426 TI - The trend of mortality in Carlisle between the 1780s and the 1840s: a demographic contribution to the standard of living debate. PMID- 11614428 TI - Changes in the asylum: the case of York, 1777-1815. PMID- 11614427 TI - The disappearance of plague: an alternative view. PMID- 11614429 TI - Health education and the demand for tobacco in Ireland, 1953-76: a note. PMID- 11614431 TI - The male labour force participation decision: health, reported health and economic incentives. PMID- 11614430 TI - Birth under-registration in the Republic of Ireland during the twentieth century. PMID- 11614432 TI - Ephebi, Epigoni, and Fornacalia: some meditations on the contemporary historiography of the eighteenth century. PMID- 11614433 TI - Aspects of infant feeding in 18th-century France. PMID- 11614435 TI - A moral spectacle: American relief and the famine, 1845-1849. PMID- 11614434 TI - Irish-American scientists. PMID- 11614436 TI - Gilding the anemometer: Irish science of the past. PMID- 11614437 TI - Significant events in the first decade of Medicare. PMID- 11614438 TI - The horse disease in Kansas, 1912-1913. PMID- 11614439 TI - The Walcheren Expedition and the New Army Medical Board: A reconsideration. PMID- 11614441 TI - Some new Medici in the Roman Empire. PMID- 11614440 TI - The doctors of the Roman navy. PMID- 11614442 TI - The eugenics movement in America. PMID- 11614443 TI - Family demography and the published records: an analysis of the vital statistics of Salem, Massachusetts. PMID- 11614444 TI - Salem's great inoculation controversy, 1773-74. PMID- 11614445 TI - The medical history of Ethiopia during the Italian fascist invasion and occupation. PMID- 11614446 TI - Ethnicity, fraternalism, social and mental health. PMID- 11614447 TI - Demographic characteristics affecting living arrangements among young currently unmarried Puerto Rican, non-Spanish black, and non-Spanish white mothers. PMID- 11614448 TI - Another look at the "fever and ague" of western Oregon. PMID- 11614449 TI - Aboriginal Micmac population: a review of the evidence. PMID- 11614450 TI - Epidemics and Indian middlemen: rethinking The Wars of the Iroquois, 1609-1653. PMID- 11614451 TI - Entomological considerations in Southeastern aboriginal demography. PMID- 11614453 TI - A native American adaptation to drought: the Kumeyaay as seen in the San Diego Mission records, 1770-1798. PMID- 11614452 TI - The rural demography of medieval England. PMID- 11614454 TI - Volcanism as a factor in human ecology: the Aleutian case. PMID- 11614455 TI - Delivery in the XVIIIth century: traditional customs and medical control. (Fre). PMID- 11614456 TI - A medicine-man's implements and plants in a Tiahuanacoid Tomb in Highland Bolivia. PMID- 11614457 TI - Towards the light? Science, politics and the enlightenment. PMID- 11614458 TI - The incidence of lead in late Shang and early Chou ritual vessels. PMID- 11614459 TI - Health, work, and leisure before the industrial revolution. PMID- 11614461 TI - Interrelations of population density, urbanization, literacy, and fertility. PMID- 11614460 TI - Enclosure and population growth in eighteenth-century England. PMID- 11614462 TI - Fecundity, infanticide, and food consumption in Japan. PMID- 11614463 TI - Slave height profiles from coastwise manifests. PMID- 11614464 TI - Cycles and trends of mortality in 18 large American cities, 1871-1900. PMID- 11614465 TI - The determinants of slave mortality rates on the middle passage. PMID- 11614466 TI - The disease horse. PMID- 11614467 TI - Doctor in the house: medicine and private morality in France, 1800-1850. PMID- 11614468 TI - The history and politics of birth control: a review essay. PMID- 11614469 TI - Care or cure? Childbirth practices in 19th-century America. PMID- 11614470 TI - A brief history of women workers and hazards in the workplace. PMID- 11614471 TI - Implementing safety and health regulations for women in the workplace. PMID- 11614473 TI - Asiatic cholera: Kentucky's first public health instructor. PMID- 11614472 TI - Occupational hazards to reproduction: a review essay and annotated bibliography. PMID- 11614474 TI - Asiatic cholera's first visit to Kentucky: a study in panic and fear. PMID- 11614475 TI - The agricultural experiment station and food and drug control: another look at Kentucky progressivism, 1898-1916. PMID- 11614477 TI - The Psychology Department at the University of Louisville, 1907-1953. PMID- 11614476 TI - The "Spanish Lady" in Kentucky 1918-1919. PMID- 11614478 TI - The Louisville Medical Institute: a case history in American medical education. PMID- 11614479 TI - The witchcraft craze of the sixteenth and seventeenth centuries. PMID- 11614480 TI - Flintknapping and silicosis. PMID- 11614481 TI - A persistent paradox. PMID- 11614482 TI - The element of witchcraft in "The scarlet letter." PMID- 11614483 TI - Turkish and Mongol shamanism in the Middle Ages. PMID- 11614484 TI - Spices in the medieval diet: a new approach. PMID- 11614485 TI - A role for algae as human food in antiquity. PMID- 11614487 TI - Socio-economic development and fertility change in rural Africa. PMID- 11614486 TI - Food shortage, nutrition, and epidemic disease in the subsistence crises of preindustrial Europe. PMID- 11614488 TI - Gene wars. PMID- 11614489 TI - Mothers, madness, and the middle class in The bell jar and Les mots pour le dire. PMID- 11614490 TI - Abortion in France: women and the regulation of family size 1800-1914. PMID- 11614491 TI - Abortion in nineteenth-century France. PMID- 11614492 TI - The social functions of the hospital in 18th-century France: the case of the Hotel-Dieu of Nimes. PMID- 11614493 TI - The Paris morgue as a social institution in the nineteenth century. PMID- 11614494 TI - Who's testing black children and youth in the public schools? PMID- 11614495 TI - Community control, Cuban style. PMID- 11614496 TI - A personal history of Bexar County medicine. PMID- 11614497 TI - Sexism in women's medical care. PMID- 11614498 TI - The cradle of sexual politics. PMID- 11614499 TI - Using oral history to chart the course of illegal abortions in Montana. PMID- 11614500 TI - Public health in Atlanta: The formative years, 1865-1879. PMID- 11614501 TI - Letters and papers of Dr. Daniel Turner: a Rhode Islander in South Georgia. PMID- 11614502 TI - Medical assistance for the sick poor in ante-bellum Savannah. PMID- 11614503 TI - Colonial medicine in Georgia and South Carolina. PMID- 11614504 TI - Medicine and slavery: an essay review. PMID- 11614506 TI - The trustees' garden at Savannah. PMID- 11614505 TI - "The seasoning": disease and death among the first colonists of Georgia. PMID- 11614508 TI - Legacy of bitterness: poison gas and atrocities in the Italo-Ethiopian War 1935 1936. PMID- 11614507 TI - Pollution: not a new problem for Missourians. PMID- 11614509 TI - The diffusion of cholera in the United States in the nineteenth century. PMID- 11614510 TI - Medical promotion and the consumptive immigrant to Australia. PMID- 11614511 TI - Geophagy in Central America. PMID- 11614512 TI - Malaria in Bangladesh. PMID- 11614513 TI - Modern population growth in historical perspective. PMID- 11614514 TI - The doctor in the late medieval 'Arztspiel'. PMID- 11614515 TI - The fate of mixed blood children. PMID- 11614516 TI - The use of gold in dentistry: an historical overview. PMID- 11614518 TI - Power and responsibility in the upbringing of the nineteenth-century tsars. PMID- 11614517 TI - Gold in medicine: a review of its use in the West before 1900. PMID- 11614519 TI - The graduate years: what kind of journey? PMID- 11614520 TI - A rationale for teaching psychohistory. PMID- 11614521 TI - Culture and character: some perspectives from psychological anthropology for psychohistorians. PMID- 11614522 TI - The new woman and the psycho-historian: a modest proposal. PMID- 11614523 TI - Media resources available for teaching psychohistory. PMID- 11614524 TI - Springfield uber alles: role playing and the teaching of psychohistory. PMID- 11614525 TI - Psychohistory in religious studies. PMID- 11614526 TI - Medical services for the island of Guam until World War Two. PMID- 11614527 TI - Aspects of population history in the London parish of St. Olave, Old Jewry, 1645 1667. PMID- 11614528 TI - The rediscovery of the need for a feminist medical education. PMID- 11614529 TI - Anesthesia and photography. PMID- 11614530 TI - The ghost of Yellow Jack. PMID- 11614531 TI - Notes on some Cypriote priests wearing bull-masks. PMID- 11614533 TI - Chinese herbal medicine. PMID- 11614532 TI - Herbs and spices through the ages. 5. PMID- 11614534 TI - Childhood history and decisions of State: The Case of Louis XIII. PMID- 11614535 TI - Growing up in new China: a twist in the circle of filial piety. PMID- 11614536 TI - Child-abuse and self-abuse: Two Victorian cases. PMID- 11614537 TI - Story of an English cotton mill lad. PMID- 11614538 TI - Parents and children in eighteenth century Europe. PMID- 11614539 TI - Bismarck's childhood: A psychohistorical study. PMID- 11614540 TI - Further notes on the history of infanticide. PMID- 11614541 TI - Justification without joy: Psychohistorical reflections on John Wesley's childhood and conversion. PMID- 11614542 TI - The abolition of corporal punishment in New Jersey schools. PMID- 11614543 TI - Freud and the discovery of child sexuality. PMID- 11614544 TI - James Otis, Jr.: an ambivalent revolutionary. PMID- 11614545 TI - Clio and Psyche. [Essay review]. PMID- 11614546 TI - Adults and children: against evil or against each other. [Essay review]. PMID- 11614547 TI - A transcendentalist father: the child-rearing practices of Bronson Alcott. PMID- 11614548 TI - Paranoia or persecution: the case of Schreber. PMID- 11614549 TI - Fears of sexual license during the English Reformation. PMID- 11614550 TI - Infanticide in Florence: new sources and first results. PMID- 11614551 TI - Psychohistorians discuss psychohistory. A forum for ideas. PMID- 11614552 TI - Bartholomaeus Anglicus on child-rearing. PMID- 11614553 TI - Hitler looks east. PMID- 11614554 TI - The independence of psychohistory. With comments by B. Tuchman, R. B. Lyman, P. P. Dunn, F. I. Greenstein, F. Leboyer, E. E. Hagen. PMID- 11614555 TI - Adolescence in eighteenth-century America. PMID- 11614556 TI - The early years of Theodore Roosevelt: A study in character formation. PMID- 11614557 TI - Religion and the conception of youth in seventeenth-century England. PMID- 11614558 TI - A bibliography of psychohistory. PMID- 11614559 TI - Hitler as the bound delegate of his mother. PMID- 11614560 TI - Social reform and the movement to organize children's play during the Progressive Era. PMID- 11614562 TI - The psychologies of presidents. PMID- 11614561 TI - Archetypal psychology as a key for understanding prehistoric art forms. PMID- 11614563 TI - Janusz Korczak: the making of a martyr. PMID- 11614564 TI - Infanticide: a historical survey. PMID- 11614566 TI - The English Puritans and pregnancy, delivery and breast feeding. PMID- 11614565 TI - Infanticide in England in the later Middle Ages. PMID- 11614567 TI - Mesmer and his followers: the beginnings of sympathetic treatment of childhood emotional disorders. PMID- 11614568 TI - Infanticide in Florence: new sources and first results. PMID- 11614569 TI - The open air school movement in Sheffield. PMID- 11614570 TI - Rockefeller philanthropy and the British Empire: the creation of the London School of Hygiene and Tropical Medicine. PMID- 11614571 TI - Fathers and daughters: reflections on women, science, and Victorian Cambridge. PMID- 11614573 TI - Issue at stake: the biosocial background. PMID- 11614572 TI - The development of school biology, 1918-1945. PMID- 11614575 TI - Educational psychology and social reform in the Progressive Era. PMID- 11614574 TI - Eugenics and the feeble-minded: the Parliamentary debates of 1912-14. PMID- 11614576 TI - The collapse and revival of medical education in France: A consequence of revolution and war, 1789-1795. PMID- 11614577 TI - Education and professional life styles: law and medicine in the nineteenth century. PMID- 11614578 TI - Psychologists and the war: the meaning of intelligene in the alpha and beta tests. PMID- 11614579 TI - Ideas of the early sex education movement in America, 1890-1920. PMID- 11614581 TI - Hallmarks of reform: social change and the new education in Canada. PMID- 11614580 TI - "To create a strong and healthy race": school children in the public health movement, 1880-1914. PMID- 11614582 TI - Declaring the glory of God. PMID- 11614583 TI - On the psychohistory of childhood. PMID- 11614584 TI - From trade to profession: surgical education in eighteenth-century Spain. PMID- 11614585 TI - The mental hygiene movement, the development of personality and the school: the medicalization of American education. PMID- 11614586 TI - Eugenics and progressive thought: a study in ideological affinity. PMID- 11614587 TI - Population change, family structure and the good of counting. PMID- 11614588 TI - Family responsibility and state responsibility in Britain before the welfare state. PMID- 11614589 TI - The completeness of 1900 mortality data collected by registration and enumeration for rural and urban parts of states: estimates using the Chandra Sekar-Deming technique. PMID- 11614591 TI - Statistical and mathematical methods for historians: an annotated bibliography of selected books and articles. PMID- 11614590 TI - Linkage of the 1880-81 Philadelphia death register to the 1880 manuscript census: a comparison of hand and machine-record linkage techniques. PMID- 11614593 TI - Can a historian or social scientist learn anything from sociobiology? An attempt at an answer. PMID- 11614592 TI - Adapting methods to needs: studying fertility and nuptiality in seventeenth- and eighteenth-century Belgium. PMID- 11614594 TI - Recent developments in historical demography: a review of the European fertility project with some comparisons from Japan. PMID- 11614595 TI - Sources and methods for the study of historical nutrition in Latin America. PMID- 11614596 TI - Nutrition and fertility: a review essay. PMID- 11614597 TI - Psychohistory: Clio on the couch - or off? PMID- 11614598 TI - Own-child estimates of U. S. white fertility, 1886-1899. PMID- 11614599 TI - Height and per capita income. PMID- 11614600 TI - The Mormon historical demography project. PMID- 11614601 TI - A community-based sample of the older population from the 1880 and 1900 United States manuscript census. PMID- 11614602 TI - The economics of mortality in North America, 1650-1910: a description of a research project. PMID- 11614603 TI - A description and evaluation of mortality data in the federal census: 1850-1900. PMID- 11614604 TI - The estimates of early American historical demographers: two steps forward, one step back, what steps in the future? PMID- 11614605 TI - The analysis of eighteenth-century causes: some methodological considerations. PMID- 11614606 TI - Student views of the medical institution at Dartmouth in 1813 and 1814. PMID- 11614607 TI - Canadian doctors and the cholera. PMID- 11614608 TI - The impact of epidemic influenza, Canada, 1918-1919. PMID- 11614609 TI - Further reflections to witchcraft and European folk religion. PMID- 11614610 TI - The human body as microcosm in India, Greek cosmology, and sixteenth-century Europe. PMID- 11614611 TI - The establishment of the Australian department of health: its background and significance. PMID- 11614612 TI - Theories of differential fertility and the Australian experience, 1891-1911. PMID- 11614613 TI - Ethics and disease in the later nineteenth century: the Contagious Diseases Acts. PMID- 11614615 TI - The pastoral interest and Sydney's public health. PMID- 11614614 TI - Whose reality?: The Irish famine in history and literature. PMID- 11614616 TI - The struggle against pulmonary tuberculosis in Australia, 1788-1950. PMID- 11614617 TI - Smallpox in aboriginal Australia, 1829-31. PMID- 11614618 TI - The history of science in a history department. PMID- 11614619 TI - The history of science at Cornell University. PMID- 11614620 TI - 'Yellow Jack': Caribbean fever. PMID- 11614622 TI - Medieval hospitals of England. PMID- 11614621 TI - "Yellow Jack", Caribbean fever. PMID- 11614623 TI - The prospects of life, 1951-71. PMID- 11614624 TI - Bart's Hospital, from its refoundation by Henry VIII. PMID- 11614625 TI - The plague in England. PMID- 11614626 TI - Age in old England. PMID- 11614628 TI - Psychohistory: an Australian perspective. PMID- 11614627 TI - Being mad in Georgian England. PMID- 11614629 TI - Spas: pleasure of penance? PMID- 11614630 TI - Bombay: City of gold. PMID- 11614631 TI - Holy dying: evangelical attitudes to death. PMID- 11614632 TI - Death and the Danse Macabre. PMID- 11614634 TI - Noise. PMID- 11614633 TI - Lepers, Jews and Moslems: the plot to overthrow Christendom in 1321. PMID- 11614635 TI - Genius and intemperance. PMID- 11614636 TI - Pestilence and progress: health reform in Galveston and Houston during the nineteenth century. PMID- 11614638 TI - Mortality differentials within large American cities in 1890. PMID- 11614639 TI - Scholarship in psychology. PMID- 11614640 TI - The sanitary pottery industries of South Debbyshire, 1840-1914. PMID- 11614637 TI - "Overlaying" in 19th-century England: infant mortality in infanticide? PMID- 11614641 TI - Some Indian sources for the study of the history of medicine. PMID- 11614643 TI - The disease complaint at Bosque Redondo (1864-68). PMID- 11614642 TI - Health conditions of native Americans in the 20th century. PMID- 11614644 TI - Genocide of the California Indians, with a comparative study of other minorities. PMID- 11614645 TI - Selected aspects of sex life in ancient Greece. PMID- 11614646 TI - Marriage: a twentieth century social problem. PMID- 11614647 TI - The runaway patient: a legend in oral circulation and the media. PMID- 11614648 TI - History, medicine, and culture: history for science students. PMID- 11614649 TI - Persistence and change in traditional medical practice in Ghana. PMID- 11614650 TI - Sociological theory and the social position of the aged. PMID- 11614651 TI - The demographic transition in the Middle East and North Africa. PMID- 11614652 TI - The regional equalization of health care and education in Syria since the Ba'thi revolution. PMID- 11614653 TI - Colonialism, ethnic personality, and psychiatry. PMID- 11614654 TI - The historical development of medical education in Africa and the place of medical library and information services. PMID- 11614655 TI - The challenge of medical librarianship in Nigeria. PMID- 11614656 TI - Salvation and healing in the community: the Old Testament understanding. PMID- 11614657 TI - French workers and the temperance movement. PMID- 11614658 TI - Studies in the politics of environmental protection: the historical roots of the British Clean Air Act, 1956: III. The ripening of public opinion, 1898-1952. PMID- 11614659 TI - Illegitimacy and pre-nuptial pregnancy in Ireland before 1864: the evidence of some Catholic parish registers. PMID- 11614660 TI - The "blessed turf": cholera and popular panic in Ireland, June 1832. PMID- 11614661 TI - A review of history of biological and related sciences in the Middle East during the 9th to 13th centuries. PMID- 11614662 TI - Maristan (Hospitals) in Medieval Spain. PMID- 11614663 TI - Maimonides' "four perfections". PMID- 11614664 TI - Notes on the position of Jewish physicians in mediaeval Muslim countries. PMID- 11614665 TI - [Not Available]. PMID- 11614666 TI - The economic and political significance of Chinese Communist production and exportation of dangerous drugs. PMID- 11614667 TI - A demographic estimate of Chinese Communism's cost to human life. PMID- 11614669 TI - Medical health work in rural areas. PMID- 11614668 TI - Communist China's population problem in the 1980's. PMID- 11614670 TI - The birth control movement on the Chinese mainland. PMID- 11614671 TI - The Maoist "health revolution." PMID- 11614672 TI - The Maoist production of narcotics and their intrigue to poison the world. PMID- 11614673 TI - Barefoot doctors in mainland China: a unique medical corps. PMID- 11614674 TI - Communist China's food: still a long way to go. PMID- 11614675 TI - The museum of the history of medicine. PMID- 11614676 TI - Admission of foreign medical graduates to the U.S. PMID- 11614677 TI - The 1889-97 rinderpest epidemic and the rise of British and German colonialism in eastern and southern Africa. PMID- 11614678 TI - Location of mortality schedules of the United States decennial censuses, 1850 1900. PMID- 11614679 TI - Records of the Sellers Funeral Home, Chambersburg, Pennsylvania, relating to the black families of Franklin County, 1866-1933. PMID- 11614680 TI - Nostrum advertising and the image of woman as invalid in late Victorian America. PMID- 11614681 TI - Woodrow Wilson's neurological illness. PMID- 11614682 TI - Anti-evolution sentiment and behavior: the case of Arkansas. PMID- 11614684 TI - Compulsory health insurance: "the next great step in social legislation." PMID- 11614683 TI - The female animal: medical and biological views of woman and her role in nineteenth century America. PMID- 11614685 TI - To engineer the metropolis: sewers, sanitation, and city planning in late nineteenth-century America. PMID- 11614686 TI - Apathy and death in early Jamestown. PMID- 11614687 TI - Professionalism, feminism, and gender roles: a comparative study of nineteenth century medical therapeutics. PMID- 11614688 TI - The unstable world of Benjamin Spock: social engineering in a democratic culture, 1917-1950. PMID- 11614689 TI - Temperance and intemperance as historical problems. PMID- 11614690 TI - "Science" enters the birthing room: obstetrics in America since the eighteenth century. PMID- 11614691 TI - Conditions in the Volga region 1919-1922. PMID- 11614692 TI - Consanguineous marriage in Pali literature. PMID- 11614693 TI - The introduction of Greek medicine into Tibet in the seventh and eighth centuries. PMID- 11614694 TI - Forensic medicine in pre-imperial China. PMID- 11614695 TI - American attitudes to death. PMID- 11614696 TI - Climate, health and black labor in the English Americas. PMID- 11614697 TI - New evidence for the antiquity of leprosy in early Britain. PMID- 11614698 TI - Osteological evidence of the use of a surgical modiolus in a Romano-British population: an aspect of primitive technology. PMID- 11614699 TI - Radiocarbon dates and the history of treponematoses in man. PMID- 11614700 TI - Animal palaeopathology: possibilities and problems. PMID- 11614701 TI - Continuity and change in cannabis use by Africans in South Africa. PMID- 11614702 TI - Death in India, 1871-1921. PMID- 11614703 TI - Crisis mortality in the nineteenth century Philippines: data from parish records. PMID- 11614704 TI - The goddess Sitala and epidemic smallpox in Bengal. PMID- 11614705 TI - Soma, an attempt to classify the plant and the drug. PMID- 11614706 TI - Chemehuevi shamanism, sorcery, and charms. PMID- 11614707 TI - A possible shamans's cache from CA-RIV-102, Hemet, California. PMID- 11614708 TI - Science policy in Canada. PMID- 11614710 TI - A Greek doctor at Chester. PMID- 11614709 TI - Cherokee theory and practice of medicine. PMID- 11614711 TI - Introduction of opium cultivation to China. PMID- 11614712 TI - Church versus state: family planning in Colombia, 1966-1972. PMID- 11614714 TI - Unnatural selection: creationism and evolutionism. PMID- 11614713 TI - Religion, medicine, and the state: reflections on some contemporary issues. PMID- 11614715 TI - Pressure groups and the Australian political process: the case of the Australian Medical Association. PMID- 11614716 TI - Bacteriological warfare. PMID- 11614718 TI - Struggles over health care in the People's Republic of China. PMID- 11614720 TI - Military fitness and civilian health in Britain during the first World War. PMID- 11614719 TI - Politics of the poppy: The Society for the Suppression of the Opium Trade, 1874 1916. PMID- 11614721 TI - The history of childhood sexuality. PMID- 11614722 TI - The Workingmen's Samaritan Federation (Arbeiter-Samariter-Bund) 1888-1933. PMID- 11614723 TI - Perspectives in development: the problem of nurses and nursing in Zambia. AB - The training of indigenous women in hospital nursing is directly modelled on western services. Hence training does not address social problems attendant on implicit cultural conflict between indigenous and western healing systems and conceptualisations of illness. Because these problems are not faced in the curriculum, nurses are imperfectly socialised into the modern health care setting. They, and the public, continue to accept the efficacy of both health care systems, assuming complementarity when in fact in many respects they conflict. The involvement of young women in healing, a radical innovation, became institutionalized. Because of the high visibility of the nurse and a radical change in the role of young women as healers, and because of the vulnerability of the patients, conflict in treatment systems focused on nurses who became scapegoats in hospitals, which came to be called 'houses of death'. PMID- 11614724 TI - The history and traditional treatment of smallpox in the Sudan. PMID- 11614725 TI - The second plague pandemic and its recurrences in the Middle East: 1347-1894. PMID- 11614726 TI - Sex, marriage and family: an update from Amsterdam. PMID- 11614727 TI - A technique for the oral examination of a mummy. PMID- 11614729 TI - Papyrus Carlsberg 67: A healing-prayer from the Fayum. PMID- 11614730 TI - Observations on a collection of crania from the mastabas of the reign of Cheops at Giza. PMID- 11614728 TI - Teeth and bread in ancient Egypt. PMID- 11614731 TI - The problem of brain removal during embalming by the ancient Egyptians. PMID- 11614732 TI - The history of Hamot Medical Center. PMID- 11614733 TI - Some factors influencing the health of traditional Ethiopia. PMID- 11614734 TI - The history of famine and pestilence in Ethiopia prior to the founding of Gondar. PMID- 11614735 TI - Scientific attitudes toward Indian mixed-bloods in early nineteenth century America. PMID- 11614736 TI - Learned helplessness: the need for self-determination among the Chinese American elderly. PMID- 11614737 TI - Race, class, and medicine: "Bad Blood" in twentieth-century America. PMID- 11614738 TI - The plague and the pre-Malthus Malthusians. PMID- 11614739 TI - The stabilisation of mortality in preindustrial Western Europe. PMID- 11614741 TI - Science, medicine and the Puritan society. PMID- 11614740 TI - Plague in Europe and the Mediterranean countries. PMID- 11614742 TI - Infant mortality, maternal mortality and public health in Britain in the 1930's. PMID- 11614743 TI - Aspects of the impact of the first world war on infant mortality in Britain. PMID- 11614744 TI - The Irish Tontine (1777) and fifty Genevans: an essay on comparative mortality. PMID- 11614745 TI - Attitudes to witchcraft and demonic possession in France during the 18th century. PMID- 11614746 TI - Plague writing: from Boccaccio to Camus. PMID- 11614747 TI - Hungarian spa glasses of the early 19th century. PMID- 11614748 TI - German idealism and the development of psychology in the nineteenth century. PMID- 11614749 TI - Captive surgeon in Hong Kong: the story of the British Military Hospital, Hong Kong 1942-1945. PMID- 11614750 TI - The great plague of Hong Kong. PMID- 11614752 TI - Economics of scale in sewage purification and disposal. PMID- 11614753 TI - The cultural background of Sinhalese medicine. PMID- 11614751 TI - The British Medical Association and its overseas branches: a short history. PMID- 11614754 TI - The span of life. PMID- 11614755 TI - The improving accuracy of the basic data and the exposed-to-risk of the English life tables. PMID- 11614756 TI - St. Albans Medical Club. PMID- 11614757 TI - Health and environmental problems: the role of the border in El Paso-Ciudad Juarez coordination. PMID- 11614758 TI - Population growth and crisis: Leon, 1720-1860. PMID- 11614759 TI - Survival of Indian communities in nineteenth-century Bolivia: a regional comparison. PMID- 11614760 TI - The origin of compulsory drug prescriptions. PMID- 11614761 TI - Estimating the effects of regulation on innovation: an international comparative analysis of the pharmaceutical industry. PMID- 11614762 TI - Medical schools: producers of what? sellers to whom? PMID- 11614763 TI - Effects of regulation on hospital costs and input use. PMID- 11614764 TI - Competing for professional control: professional mix in the eyeglass industry. PMID- 11614765 TI - A positive theory of environmental quality regulation. PMID- 11614766 TI - Of graver importance than history: psychiatry in fiction. PMID- 11614767 TI - Medicine and the crimination of sin: "self-abuse" in the 19th century America. PMID- 11614769 TI - The lying truths of psychiatry. PMID- 11614768 TI - The early development of medical licensing laws in the United States, 1875-1900. PMID- 11614770 TI - Education and attitudes of early medical librarians to their work: a discussion based on the oral history project of the Medical Library Association. PMID- 11614771 TI - Scientific societies and exchange: a facet of the history of scientific communication. PMID- 11614772 TI - Brooklyn's health and sanitation, 1834-1855. PMID- 11614773 TI - The self and madness in Marlowe's "Edward II" and Webster's "The Duchess of Malfi". PMID- 11614774 TI - Melancholy and the divine frenzies in the French Pleiade: their conflicting roles in the art of "beaux exercices spirituels." PMID- 11614776 TI - The disappearance of Bronze John in Mississippi. PMID- 11614775 TI - Mississippi and the yellow fever epidemics of 1878-1879. PMID- 11614777 TI - Gulfport's and Biloxi's hospitals: their first fifty years. PMID- 11614778 TI - Chemical regulation in Mississippi: the State Laboratory (1882- ). PMID- 11614779 TI - U. S. population policies, development, and the rural poor of Africa. PMID- 11614780 TI - The coming crisis in psychohistory. PMID- 11614781 TI - From Mayerling to Sarajevo. PMID- 11614782 TI - The road to Ypres: the beginnings of gas warfare in World War I. PMID- 11614783 TI - The hysteria diagnosis and the politics of anticlericalism in late nineteenth century France. PMID- 11614784 TI - Toward the improvement of the human race: the history of eugenics in France. PMID- 11614786 TI - Black and white child self-esteem in social science: an overview. PMID- 11614785 TI - Medical commentaries from Nippur PMID- 11614787 TI - Black Americans and the medical profession, 1930-1970. PMID- 11614788 TI - Summer program in medical school environment for undergraduate students: an evaluation. PMID- 11614789 TI - From hospital to college: black nurse leaders and the rise of collegiate nursing schools. PMID- 11614790 TI - The Mercy Hospital controversy among Cleveland's Afro-American civic leaders, 1927. PMID- 11614791 TI - White cannibals, black martyrs: fear, depression, and religious faith as causes of suicide among new slaves. PMID- 11614792 TI - Aging and slavery: gerontological perspective. PMID- 11614793 TI - The Pacific islander hospitals in colonial Queensland: the failure of liberal principles. PMID- 11614794 TI - The introduction of venereal disease into Tahiti: a re-examination. PMID- 11614795 TI - Coping with Samoan restistance after the 1918 influenza epidemic: Colonel Tate's problems and perplexities. PMID- 11614796 TI - Research communication: war as a human endeavor: the high-fatality wars of the twentieth century. PMID- 11614797 TI - Popular dream-interpretation in ancient Greece and Freudian psychoanalysis. PMID- 11614799 TI - Chiropractic in America: the historical conflicts of cultism and science. PMID- 11614798 TI - The changing life of Mickey Finn: some notes on chloral hydrate down through the ages. PMID- 11614800 TI - Ideologies in stone: meanings in Victorian gravestones. PMID- 11614801 TI - American sportswomen in the 19th century. PMID- 11614802 TI - Human remains from Gortnacargy, Co. Cavan. PMID- 11614803 TI - A personal struggle with religion: significant fact in the lives and work of the first psychologists. PMID- 11614804 TI - Saltwater and ashes: instruments of curing among some Zulu zionists. PMID- 11614805 TI - The founding of San Diego's Red Cross. PMID- 11614806 TI - San Diego's early years as a health resort. PMID- 11614807 TI - Personal faith and the fear of death among divergent religious populations. PMID- 11614808 TI - Religion, ideal family size, and abortion: extending Renzi's hypothesis. PMID- 11614809 TI - The effect of the decline in institutionalized religion on suicide, 1954-1978. PMID- 11614810 TI - Medical arts at Wat Phra Chetuphon: various Rishi statues. PMID- 11614811 TI - Another demographic use of inquisitions post mortem. PMID- 11614812 TI - The Crimean War and the formation of the medical staff corps. PMID- 11614813 TI - The destruction of the British Army in the West Indies, 1793-1815: a medical history. PMID- 11614814 TI - Bullet wounds and X-Rays in Britain's little wars. PMID- 11614815 TI - Three southern food and drug cases. PMID- 11614816 TI - The hidden epidemic: opiate addiction and cocaine use in the South, 1860-1920. PMID- 11614818 TI - "Embodied selves": the rise and development of concern for physical education, active games and recreation for American women, 1776-1865. PMID- 11614817 TI - The attitudes of leading New England transcendentalists toward healthful exercise, active recreation and proper care of the body: 1830-1860. PMID- 11614819 TI - Muscular vegetarianism: the debate over diet and athletic performance in the progressive era. PMID- 11614820 TI - "Athlete's heart": the medical debate over athleticism, 1870-1920. PMID- 11614821 TI - Managing change through organization structure. PMID- 11614822 TI - Death in Odessa: a study of population movements in a nineteenth-century city. PMID- 11614823 TI - Professional revolution and reform in the Progressive era: Cincinnati physicians and the city elections of 1897 and 1900. PMID- 11614824 TI - The separate vs. combined sewer problem: a case study in urban technology design choice. PMID- 11614826 TI - An ecology of family decisions: suburbanization, schooling, and fertility in Philadelphia, 1880-1920. PMID- 11614825 TI - The strange career of municipal health initiatives: Cincinnati and city government in the early nineteenth century. PMID- 11614827 TI - New York's public baths: a case study in urban progressive reform. PMID- 11614828 TI - A new look at "Melencolia I". PMID- 11614829 TI - Leon Battista Alberti's system of human proportions. PMID- 11614830 TI - Health in southern California, 1850-1900. PMID- 11614831 TI - Son-of-a-gun to pate de foie gras: chow on early great plains ranches. PMID- 11614832 TI - Make Milwaukee safe for babies: the Child Welfare Commission and the development of urban health centers, 1911-1912. PMID- 11614834 TI - Pioneer medicines: doctors, nostrums, and folk cures. PMID- 11614833 TI - Soldiering, suffering, and dying in the Mexican War. PMID- 11614835 TI - Opiate addiction in the American West, 1850-1920. PMID- 11614836 TI - "Medicine in the West"--an introduction. PMID- 11614837 TI - Medicine in the Indian-fighting army, 1866-1890. PMID- 11614838 TI - Medical education in the Far West. PMID- 11614839 TI - Chasing the cure--a history of healthseekers to Albuquerque, 1902-1940. PMID- 11614840 TI - Medicine in the West: an historical overview. PMID- 11614841 TI - Photography in medicine. PMID- 11614843 TI - Legitimacy and "likpieza de sangre" in the practice of medicine in the Spanish Empire. PMID- 11614842 TI - Native American women in medicine and the military. PMID- 11614844 TI - Diamond jubilee of the Vincentian Sisters of Charity. PMID- 11614845 TI - Psychosomatics, hermetic medicine, and dream interpretation in the Qumran literature. PMID- 11614846 TI - Jewish physicians in Southern France during the thirteenth and fourteenth centuries. PMID- 11614848 TI - Some demographic characteristics of the Jewish population in Russia at the end of the nineteenth century. PMID- 11614847 TI - Survival and guilt feelings of Jewish concentration camp victims. PMID- 11614849 TI - Jewish fertility trends and differentials: an examination of the evidence from the census of 1970. PMID- 11614850 TI - Some involuntary conversion techniques. PMID- 11614852 TI - The Pottawatomies and alcohol: an illustration of the illegal trade. PMID- 11614851 TI - Science news of controversy: the case of marijuana. PMID- 11614853 TI - The folklore of teething. PMID- 11614854 TI - The passing of the Arkansas granny midwife. PMID- 11614855 TI - Tennesse's Tyree Springs: the most celebrated watering place in the State. PMID- 11614856 TI - "The lumberjack and the deaf tree": images of the deaf in folk narrative. PMID- 11614858 TI - Health and wealth: goals of the New Orleans public health movement, 1879-84. PMID- 11614859 TI - The yellow fever panic of 1897 in Louisiana. PMID- 11614857 TI - The power of not thinking: a jocular toothache cure. PMID- 11614860 TI - Lepers, anachronisms, and the Progressives: a study in stigma, 1889-1920. PMID- 11614861 TI - Cultural aspects of the Industrial Revolution: Lynn, Massachusetts, shoemakers and industrial morality. PMID- 11614862 TI - Tragedy at Bellevue: anatomy of a mine disaster. PMID- 11614863 TI - Battling pollution in the Progressive era. PMID- 11614864 TI - Southern spas: source of the American resort tradition. PMID- 11614865 TI - Health planning in Latin America: review and evaluation. PMID- 11614866 TI - Chilean social and demographic history: sources, issues, and methods. PMID- 11614867 TI - Sources for studies of historical demography in Uruguay (1728-1860). PMID- 11614868 TI - Health care financing in Central America and the Andean Region: a workshop report. PMID- 11614869 TI - Involuntary commitment for mental disorder: the application of California's Lanterman-Petris-Short Act. PMID- 11614870 TI - The new Dutch and German drug laws: social and political conditions for criminalization and decriminalization. PMID- 11614871 TI - The impact of changes in judicial doctrine: the abrogation of charitable immunity. PMID- 11614872 TI - Liberia's population figures. PMID- 11614873 TI - Doctors in literature. PMID- 11614874 TI - Introductory lectures in nineteenth century American chemistry courses. PMID- 11614875 TI - Patient libraries in hospitals for the insane in the United States, 1810-1861. PMID- 11614876 TI - London scientific libraries in the nineteenth century. I: The springs of action. PMID- 11614877 TI - Historical collections in psychiatry and psychoanalysis. PMID- 11614878 TI - Sources for urban history: a nineteenth century dispensary at work. PMID- 11614879 TI - Life and death in an Oxfordshire churchyard. PMID- 11614880 TI - Clergymen's return to the 1831 census. PMID- 11614881 TI - Public health and local history. PMID- 11614882 TI - The local study of plague. PMID- 11614883 TI - A Roman burial group from Bow, with a report on the skeletal remains. PMID- 11614884 TI - A pair of late medieval spectacles from the Trig Lane site. PMID- 11614885 TI - Bodysnatchers and Benthamites: the implications of the Dead Body Bill for the London Schools of Anatomy, 1820-42. PMID- 11614886 TI - Free water: the public drinking fountain movement and Victorian London. PMID- 11614887 TI - East End opium dens and narcotic use in Britain. PMID- 11614888 TI - Doctors learned from slaves. PMID- 11614889 TI - The Charlottesville General Hospital 1861-1865. PMID- 11614890 TI - Midway Hospital: 1861-1863. The diary of Miss Clarke of South Carolina. PMID- 11614891 TI - The Libri morales in the Faculty of Arts and Medicine at Bologna: Bartolomeo da Varignana and the Pseudo-Aristotelian Economics. PMID- 11614892 TI - Scholasticism in compendia of practical medicine, 1250-1450. PMID- 11614893 TI - Two Montpellier recipe collections. PMID- 11614894 TI - The teaching of astronomy in medieval universities, principally at Paris in the forteenth century. PMID- 11614895 TI - Pearl Kibre: bio-bibliography. In Siraisi NG, Demaitre L, ed: Science, medicine and the university, 1200-1550. Essays in honor of Pearl Kibre. Part II. PMID- 11614896 TI - The development of the archives of the history of American psychology. PMID- 11614897 TI - Battalion surgeon on Iwo Jima. PMID- 11614898 TI - The thread of a concept. PMID- 11614899 TI - The Customs Quarantine Service. PMID- 11614900 TI - The politics of birth control. PMID- 11614901 TI - Time, sugar and sweetness. PMID- 11614902 TI - A note on Marxism and psychoanalysis. PMID- 11614903 TI - Psychohistory, theory and practice. PMID- 11614904 TI - Curanderismo: the folk healer in the Spanish-speaking community. PMID- 11614905 TI - An early California document. PMID- 11614907 TI - Revolutionary doctors of Anne Arundel County PMID- 11614906 TI - Science education in the 19th century: The Natural History Society of Montreal, 1827-1925. PMID- 11614908 TI - The history of women in medicine. PMID- 11614911 TI - When the old Mercy Hospital was new. PMID- 11614909 TI - Occupational health and the developing class consciousness of southern textile workers: the case of the Brown Lung Association. PMID- 11614913 TI - Green Mount: the introduction of the rural cemetry into Baltimore. PMID- 11614914 TI - Practicing medicine at the Baltimore Almshouse, 1828-1850. PMID- 11614918 TI - When folk medicine flourished in the shadows of Grady Hospital. PMID- 11614916 TI - Death and class in Baltimore: the yellow fever epidemic of 1800. PMID- 11614919 TI - Signs of death in Middle English. PMID- 11614920 TI - The medieval cartulary tradition and the survival of archival material as reflected in the English Hospitaller Cartulary of 1442. PMID- 11614921 TI - The French prayer for the sick in the Hospital of the Knights of Saint John of Jerusalem at Acre. PMID- 11614922 TI - Graduation speeches of Gentile da Foligno. PMID- 11614923 TI - The effects and extent of the Black Death of 1348: new evidence for clerical mortality in Barcelona. PMID- 11614924 TI - A leper cemetery at South Acre, Norfolk. PMID- 11614926 TI - A history of the Mennonite medical work in the Muria Mountain area of Java, Indonesia, 1894-1971. PMID- 11614925 TI - On the history of early entomology, chiefly Greek and Roman, with a preliminary bibliography. PMID- 11614927 TI - The role of a Braucher-chiropractor in an Amish community. PMID- 11614928 TI - The Mennonite mental health story. PMID- 11614929 TI - Influences on the origin and development of Mennonite mental health centers. PMID- 11614930 TI - Sigmund Freud, Carl Jung and religion. PMID- 11614931 TI - Experiences in mental hospitals in World War II. PMID- 11614932 TI - John P. Richmond, M. D., first Methodist minister assigned to the present State of Washington. PMID- 11614933 TI - Methodist Hospital of Brooklyn. PMID- 11614934 TI - A medical geography of tuberculosis in Michigan: an alternative framework for health care organization. PMID- 11614935 TI - Our botanical forbears in Michigan. PMID- 11614936 TI - Body snatching in the Midwest. PMID- 11614937 TI - The doctors' war in the Michigan legislature, 1835-1851. PMID- 11614938 TI - Body snatching in the Midwest. PMID- 11614939 TI - The doctors' war in the Michigan legislature, 1835-1861. PMID- 11614940 TI - Celebrated celery city quacks. PMID- 11614941 TI - Don't go to Michigan, that land of ills. PMID- 11614942 TI - Notes on the University Hospital: the early decades. PMID- 11614943 TI - Bankrobbers, burkers and bodysnatchers. PMID- 11614944 TI - Presidential address: [Microscopy in 19th century England]. PMID- 11614945 TI - The Hiroshima maidens and American benevolence in the 1950's. PMID- 11614946 TI - Epidemic disease in the postcontact southeast: a reappraisal. PMID- 11614947 TI - Some demographic indicators for Khartoum Conurbation, Sudan. PMID- 11614949 TI - A Warwickshire market town in adversity: Stratford-upon-Avon in the sixteenth and seventeenth centuries. PMID- 11614948 TI - Food shortages in the Middle East. PMID- 11614950 TI - The American Jewish population erosion. PMID- 11614951 TI - How, though Jewish, I did not become a doctor. PMID- 11614952 TI - A psychiatrist in Youth Aliah (1956-57). PMID- 11614953 TI - Nazi sexual demonology. PMID- 11614954 TI - Psychobiography: case history of life history? PMID- 11614955 TI - Science and secular idealism. PMID- 11614957 TI - Indo-Chinese refugees: a national mental health need assessment. PMID- 11614958 TI - Cholera and the army in the West: treatment and control in 1866 and 1867. PMID- 11614959 TI - The mobilization of American psychologists, 1938-1941. PMID- 11614960 TI - Morality legislation and British troops in late nineteenth century India. PMID- 11614961 TI - "The case of the miraculous bullet" revisited. PMID- 11614962 TI - The unused weapon. PMID- 11614963 TI - Fort Concho, 1868-1872: the medical officers observations [ed. by Stephen Schmidt]. PMID- 11614964 TI - The St. Louis Cholera epidemic of 1849. PMID- 11614965 TI - The 1918 Kansas City influenza epidemic. PMID- 11614966 TI - Bernarr MacFadden. PMID- 11614968 TI - Of sugar and salt and things in the cellar and sun: food preservation in Jackson County in the 1850's. PMID- 11614967 TI - Base hospital 21 and the Great War. PMID- 11614969 TI - Indian famines and peasant victims: the case of Bengal in 1943-44. PMID- 11614970 TI - Germ warfare and "plausible denial": the Korean war, 1952-1953. PMID- 11614971 TI - Literary diseases: From pathology to ontology. PMID- 11614972 TI - Brother Andrew's problems: a sick soul of the sixth century. PMID- 11614973 TI - Tularemia in Montana. PMID- 11614974 TI - Rocky mountain spotted fever: the sickness and the triumph. PMID- 11614975 TI - Darwinism in the Arab world: the Lewis affair at the Syrian Protestant College. PMID- 11614976 TI - Death in the Chesapeake: two life tables for men in early colonial Maryland. PMID- 11614978 TI - New England and the medicine men and witch doctors. PMID- 11614979 TI - Aging in seventeenth-century New England. PMID- 11614980 TI - New England mill casualties: 1890-1910. PMID- 11614981 TI - Newark and the great polio epidemic of 1916. PMID- 11614982 TI - The Passaic Valley trunk sewer. PMID- 11614983 TI - New Jersey's Reaction to the Tennesse evolution trial. PMID- 11614985 TI - A dark and terrible moment: the Spanish flu epidemic of 1918 in New Mexico. PMID- 11614984 TI - New Mexico: salubrious El Dorado. PMID- 11614986 TI - Healing, imagination, and New Mexico. PMID- 11614987 TI - In the wake of Willowbrook. Home health care: fragments and layers. PMID- 11614988 TI - Indispensable facilities: in defense of municipal hospitals. PMID- 11614989 TI - Solid waste: the end of the bottomless pit. PMID- 11614991 TI - Institutional retreat. PMID- 11614990 TI - Health care: no time for placebos. PMID- 11614992 TI - Folk obstetrics, gynecology, and pediatrics in Utica, New York. PMID- 11614993 TI - Some implications of urban witchcraft beliefs. PMID- 11614994 TI - Divine providence or miasma? The yellow fever epidemic of 1822. PMID- 11614995 TI - Sex in utopia: a review essay. PMID- 11614996 TI - Military medicine in northern New York, 1776-1777. PMID- 11614998 TI - A municipal hospital system: myths and realities. PMID- 11614997 TI - They did not leave the valley. PMID- 11614999 TI - Public health nuisances in Omaha, 1870-1900. PMID- 11615000 TI - 19th century army doctors on the frontier and in Nebraska. PMID- 11615001 TI - Plains Caddoan relationships: the view from craniometry and mortuary analysis. PMID- 11615002 TI - Medieval multiple birth. PMID- 11615003 TI - Nevada's treatment of the mentally ill, 1882-1961. PMID- 11615004 TI - Millay's "Ungrafted tree"; the problem of the artist as woman. PMID- 11615005 TI - Impact of the new child care allowances. PMID- 11615007 TI - Famous Hungarian doctors. PMID- 11615006 TI - Birth control, abortion and public opinion. PMID- 11615008 TI - Freud in Hungary. An interview with Imre Hermann, the psychoanalyst. PMID- 11615009 TI - Strike at Charleston. PMID- 11615010 TI - Newport's revolutionary physicians. PMID- 11615011 TI - Fifty years of dental education in India. PMID- 11615013 TI - Health care facilities at Buffalo in 1846. PMID- 11615012 TI - History of dental education in India. PMID- 11615014 TI - Nigerian pioneer doctors and early West African politics. PMID- 11615015 TI - The rural cemetery. PMID- 11615016 TI - [Not Available]. PMID- 11615017 TI - The society of physicians and naturalists of Jassy. PMID- 11615018 TI - Epidemics in Tudor York. PMID- 11615019 TI - Northwestern Ohio's cholera years: 1849-1854. PMID- 11615020 TI - Concerning the origin and formation of Korean shamanism. PMID- 11615021 TI - North Carolina popular beliefs and superstitions. (Section on Human body and folk medicine). PMID- 11615022 TI - Passing through: A folk remedy. PMID- 11615024 TI - An ounce of prevention, and grandma tried them all. PMID- 11615023 TI - Madstones in North Carolina. PMID- 11615025 TI - The lady with the snake in her. PMID- 11615026 TI - Medical education in the 1890's: an Ohio woman's memories. PMID- 11615027 TI - Doctors and diseases on the Ohio frontier. PMID- 11615028 TI - Homeopathy and sexual equality: the controversy over coeducation at Cincinnati's Pulte Medical College, 1873-1879. PMID- 11615029 TI - British Library, Cotton Vitellius C. III, f. 82. PMID- 11615030 TI - British Library, Royal 12 D. XVII, f. 30v. PMID- 11615031 TI - Why so doleful? The funereal poetry of the early Midwest. PMID- 11615032 TI - Cholera in Upper Canada, 1832. PMID- 11615033 TI - Ontario medical periodicals as mirrors of change. PMID- 11615034 TI - "In charge of the loons": a portrait of the London, Ontario, Asylum for the Insane in the nineteenth century. PMID- 11615035 TI - The case of the missing midwives: a history of midwifery in Ontario from 1795 1900. PMID- 11615036 TI - Childbirth in Ontario: the transition from home to hospital in the early twentieth century. PMID- 11615037 TI - Motherhood issues during the late nineteenth and early twentieth centuries: some recent viewpoints. PMID- 11615038 TI - Methodology in the study of women in history: a case study of Helen MacMurchy, M.D. PMID- 11615039 TI - The Hamilton birth control clinic of the 1930's. PMID- 11615040 TI - A note on fertility rates among married women in Toronto, 1871. PMID- 11615041 TI - Preservation of health mineral water spas of nineteenth century Ontario. PMID- 11615042 TI - In those days... Tillamook County. PMID- 11615043 TI - The old Goschenhoppen Lutheran burial register: 1752-1772. PMID- 11615044 TI - American army hospitals in Pennsylvania during the Revolutionary War. PMID- 11615045 TI - "My unhappy son": a narrative of drinking in federalist Pennsylvania. PMID- 11615047 TI - The 'Industrious poor' and the founding of the Pennsylvania Hospital. PMID- 11615046 TI - The ante-bellum drug trade: Troth and Company of Philadelphia. PMID- 11615049 TI - Homeopathy in the Lehigh Valley, 1881-1920. PMID- 11615048 TI - Social response to epidemic disease in Pittsburgh, 1872-1895. PMID- 11615050 TI - Powwowing: folk medicine or white magic? PMID- 11615051 TI - American confrontation with opium traffic in the Philippines. PMID- 11615052 TI - The Robinson affair. PMID- 11615053 TI - Did early Spokane have a medical school? PMID- 11615054 TI - Science in Russian America, 1741 to 1865. PMID- 11615055 TI - The treatment of the mentally ill in Alaska, 1884-1912. PMID- 11615057 TI - A new disease in Southeast Asia: man's creation of dengue haemorrhagic fever. PMID- 11615056 TI - Mental health policy in Washington territory, 1853-1875. PMID- 11615058 TI - Out of the valley of the shadow of death via Cader Idris: a study of disease and drains, health and hygiene in Victorian public and preparatory schools. PMID- 11615059 TI - Psychoanalysis and childhood education: A historical review. PMID- 11615060 TI - Psychoanalysis and childhood education: a historical review. PMID- 11615061 TI - [Not Available]. PMID- 11615062 TI - Disease and death among the Anasazi: some notes on Southwestern paleoepidemiology. PMID- 11615064 TI - Witchcraft in New Mexico. PMID- 11615063 TI - Mortuary practices of the Mojave Indians. PMID- 11615065 TI - Witchcraft along the Rio Grande. PMID- 11615066 TI - Botany and witchcraft. PMID- 11615067 TI - Witchcraft and black magic: an interpretive view. PMID- 11615068 TI - A selected bibliography [on witchcraft]. PMID- 11615069 TI - The hazards of the trail. PMID- 11615070 TI - Tradition in Arabic medicine. PMID- 11615071 TI - Epidemic! Iowa battles the Spanish influenza. PMID- 11615072 TI - Health care planning in Slovenia. PMID- 11615073 TI - Of battle and disease: the East African Campaign of 1914-18. PMID- 11615074 TI - The self-image of effeteness: physical education and nationalism in nineteenth century Bengal. PMID- 11615075 TI - Did suicide increase with industrialization in Victorian England? PMID- 11615076 TI - The self-image of effeteness: physical education and nationalism in nineteenth century Bengal. PMID- 11615078 TI - Alcohol abuse in Alaska. PMID- 11615077 TI - Attitudes to menstruation in seventeenth-century England. PMID- 11615079 TI - Empiricism versus rationalism in American medicine 1650-1950. PMID- 11615080 TI - Scientists and politicians: hospital reform in Paris on the eve of the French Revolution. PMID- 11615081 TI - "Scientific eating": New Englanders prepare and promote a reform, 1873-1907. PMID- 11615082 TI - Venereal disease: the AEF's experience. PMID- 11615083 TI - Cleansing the nation: the war on prostitution, 1917-21. PMID- 11615084 TI - Ingredients of famine analysis: availability and entitlements. PMID- 11615085 TI - The Canadian contribution to the China convoy. PMID- 11615086 TI - The politics of population: birth control and the eugenics movement. PMID- 11615087 TI - We walk the line: the struggle at preterm. PMID- 11615088 TI - The long struggle for reproductive rights. PMID- 11615089 TI - Movements of affirmation: sexual meanings and homosexual identities. PMID- 11615090 TI - Sexual matters: on conceptualizing sexuality in history. PMID- 11615091 TI - The historical construction of homosexuality. PMID- 11615092 TI - Sexuality in 19th and 20th century America: the sources and their problems. PMID- 11615093 TI - Social control and social service: the changing use of space in charity hospitals. PMID- 11615094 TI - Ideology and reality: sexuality and women's status in the Oneida community. PMID- 11615096 TI - Happy families. PMID- 11615095 TI - The biological enterprise: sex, mind, and profit from human engineering to sociobiology. PMID- 11615098 TI - Portrait of William Norris. Broadside, 1815, with etched portrait (1814) entitled 'William Norris: confined in this manner in Bethlem Hospital'; George Arnald, A.R.A., artist, etcher, and publisher. PMID- 11615099 TI - Dr. Erasmus Darwin consults with another physician. PMID- 11615097 TI - The historical denial of lesbianism. PMID- 11615100 TI - Rethinking "the family". PMID- 11615101 TI - Imperialism, culture and resistance. PMID- 11615102 TI - Rockefeller's draconian drug law. PMID- 11615103 TI - Psychiatry's sacred cow. PMID- 11615104 TI - The dirty little secret behind our drug laws. PMID- 11615105 TI - Handicapping an innovator. PMID- 11615106 TI - Louisiana health and the Civil Works Administration. PMID- 11615107 TI - Early attitudes toward alcoholic beverages in the South. PMID- 11615108 TI - From cramps to consumption: women's health in Owensboro, Ky. during the Civil War. PMID- 11615109 TI - The conditions for science in the academic department of Transylvania University, 1799-1857. PMID- 11615110 TI - Books of materia medica in Toronto libraries: the Renaissance publications of a traditional character. PMID- 11615111 TI - A note on the pharmaceutical, medical and agricultural books in the Forbes Collection. PMID- 11615112 TI - The contribution of humanism to the birth of modern science. PMID- 11615113 TI - Contagion theory and contagion practice in fifteenth-century Milan. PMID- 11615114 TI - Recent work in Renaissance studies: psychology: did madness have a Renaissance? PMID- 11615115 TI - In dispraise of the muckrakers: United States occupational mortality, 1890-1910. PMID- 11615117 TI - High fertility in mid-nineteenth century France: a multivariate analysis of fertility patterns in the arrondissement of Lille. PMID- 11615118 TI - An economic history of urban location and sanitation. PMID- 11615119 TI - Population issues in American economic history: a survey and critique. PMID- 11615120 TI - The fertility of American slaves. PMID- 11615121 TI - A decade in Soviet genetics. PMID- 11615122 TI - Renaissance Europe and the population of America. PMID- 11615124 TI - Medical physics in Poland, research in the 25 years of People's Poland. PMID- 11615123 TI - The state and development of Polish parasitology over the 25 years of People's Poland. PMID- 11615125 TI - The problems of human ecology during the 25 years of the Polish People's Republic. PMID- 11615126 TI - The Section of Biological Science of the Polish Academy of Sciences over the last 25 years. PMID- 11615127 TI - Polish contribution to the development of biomedical science. PMID- 11615129 TI - The work of the Committee on Biochemistry and Biophysics during twenty five years of the Polish Academy of Sciences. PMID- 11615128 TI - The section of biological science of the Polish Academy of Sciences over the last 25 years. PMID- 11615130 TI - The twenty-fifth anniversary of the Polish Academy of Sciences and the twentieth anniversary of its medical science section. PMID- 11615131 TI - Sixty years of the Nencki Institute of Experimental Biology. PMID- 11615132 TI - Scientists and scholars of Polish origin and Polish men of learning active abroad: their share in the development of science. PMID- 11615133 TI - Developmental tendencies of Polish 19th- and 20th century science against the background of world science. PMID- 11615134 TI - The political economy of rural health care in China. PMID- 11615135 TI - The political ecology of disease. PMID- 11615136 TI - Malaria, the politics of public health and the international crisis. PMID- 11615137 TI - Abortion clinics and the organization of work: a case study of Charles Circle. PMID- 11615139 TI - Medical practitioners of Bulawayo in the mid 1920's. PMID- 11615138 TI - Biology and sociology and economics: an historical analysis. PMID- 11615140 TI - Marriage and death notices from the City Gazette, 1827. PMID- 11615141 TI - Schamanismus bei den Eskimos. PMID- 11615142 TI - Slave demography of the Danish West Indian Islands. PMID- 11615143 TI - The origin of newborn screening. PMID- 11615144 TI - Substance abuse serials: the neverending narcotics story. PMID- 11615145 TI - A history of the birth control movement. PMID- 11615146 TI - Chlorosis and chronic disease in nineteenth-century Britain: the social constitution of somatic illness in a capitalist society. PMID- 11615147 TI - Illustrative material in the Wellcome Institute for the social history of medicine. PMID- 11615148 TI - Politics in the service of knowledge: the debate over the administration of medicine and welfare in late eighteenth-century France. PMID- 11615149 TI - Death and the social historians: some recent books in French and English. PMID- 11615150 TI - Bio-ethique et techniques biomedicales. PMID- 11615151 TI - L'interpretation historique des archives du Comite Nobel de Medecine, 1901-1920. PMID- 11615152 TI - Pratiques alimentaires et dietetique medicale en milieu tibetain. PMID- 11615153 TI - Cause-structure of post-transitional mortality decline: the case of Utah. PMID- 11615154 TI - Professional power and social change at the community level: the case of three prepaid health care programs. PMID- 11615155 TI - Mexican-American ethnicity, socioeconomic status, and infant mortality: a county level analysis. PMID- 11615156 TI - Health research on undocumented Mexicans. PMID- 11615157 TI - Recruitment and retention of federal physicians on the Navajo Reservation. PMID- 11615159 TI - Education, working conditions, and worker's health. PMID- 11615158 TI - Infant mortality of the Spanish surname population. PMID- 11615160 TI - The politics of aging. PMID- 11615161 TI - Suicide and the city. PMID- 11615162 TI - Shrinking households. PMID- 11615163 TI - Reconciling risk and regulation. PMID- 11615165 TI - Paternalism and public policy. PMID- 11615166 TI - Marijuana policy and drug mythology. PMID- 11615164 TI - Medicine and the market place. PMID- 11615167 TI - Silent knife: Cesarean section in the United States. PMID- 11615169 TI - Psychiatric abuse in the Soviet Union. PMID- 11615168 TI - Crisis administration of the hospitalized. PMID- 11615170 TI - Sunbelt, frostbelt and public health. PMID- 11615171 TI - The flea and the elephant: infant formula controversy. PMID- 11615172 TI - Mad tales from the Raj. PMID- 11615173 TI - Past is prologue. PMID- 11615174 TI - Upheaval and adaptation. PMID- 11615175 TI - The business of childbirth. PMID- 11615176 TI - Local plants in folk remedies in the Mammoth Cave region. PMID- 11615178 TI - Les remedes du vieux temps: remedies and cures of the Kaplan area in southwestern Louisiana. PMID- 11615177 TI - Was there a witch craze in Muscovite Russia? PMID- 11615180 TI - Swallow it or rub it on: more mammoth cave remedies. PMID- 11615179 TI - Folklore from the printed sources of Essex County, Massachusetts. PMID- 11615181 TI - [A description of demographic cognition during the Ch'ing Dynasty]. PMID- 11615182 TI - [Demographic methodology and its application to studies of historical populations]. PMID- 11615183 TI - Immigrants, cholera and the Saint John Sisters of Charity, 1854-64. PMID- 11615184 TI - [Not Available]. PMID- 11615185 TI - Understandable but mistaken: law, morality and the Canadian Catholic Church 1966 1969. PMID- 11615186 TI - Grangethorpe Hospital, Rusholme, 1917-20. PMID- 11615187 TI - A few faulty railway statistics. PMID- 11615188 TI - The great famine in Ukraine: a journalist's eyewitness account PMID- 11615189 TI - Parish registers and urban structure: the example of late-eighteenth century Liverpool. PMID- 11615190 TI - Patent license restrictions in the prescription drug industry. PMID- 11615191 TI - Doctors and daguerrotypes. Contributions of medical men to the history of photography. PMID- 11615192 TI - Specialist journals and professional rivalries in Victorian medicine. PMID- 11615193 TI - Victorian women and menstruation. PMID- 11615194 TI - Brain fever in 19th century literature: fact and fiction. PMID- 11615196 TI - Abortion in England, 1890-1914. PMID- 11615195 TI - Reforming the commonwealth of thieves: British phrenologists and Australia. PMID- 11615197 TI - Victorian opium eating: response to opiate use in nineteenth century England. PMID- 11615198 TI - Victorian women and insanity. PMID- 11615199 TI - The heroine of irregular features: physiognomy and conventions of heroine description. PMID- 11615200 TI - Unenglish and unmanly: Anglo-Catholicism and homosexuality. PMID- 11615201 TI - The Victorian Royal commission on contagious bovine pleuropneumonia of 1863-64 and the essay prizes of 1864-65. PMID- 11615202 TI - La transcription des manuscrits sur soie des traites medicaux decouverts dans la tombe han no. 3 a Mawangtui (Changsha). (Chi) PMID- 11615203 TI - "Ants, muskeetoes, flies and stinking chints": the British battle against disease in India. PMID- 11615204 TI - Health in America. PMID- 11615205 TI - The doctors. PMID- 11615206 TI - The right track. PMID- 11615208 TI - A tyranny of experts. PMID- 11615207 TI - America and world hunger. PMID- 11615209 TI - Psychiatry in America. PMID- 11615210 TI - Rheumatoid arthritis: clinicohistorical review. PMID- 11615211 TI - The Health Sciences Library Medical museum collection. PMID- 11615212 TI - Saddlebags and the medical conquest of the west. PMID- 11615213 TI - Curiosity and exploration in medicine. PMID- 11615214 TI - In the shadow of Daniel Drake. PMID- 11615215 TI - The influence of literary legends on medicine. PMID- 11615216 TI - [Not Available]. PMID- 11615217 TI - On outstanding achievements of Soviet general psychology. PMID- 11615218 TI - The basic concept of psychical development in Soviet psychology and several of its variants. PMID- 11615219 TI - The development of psychology in Hungary between 1945 and 1970. PMID- 11615220 TI - [Customs, habits and medical culture in the Qin-Han Periods]. AB - The unity of Qin-Han feudal dynasties improves the development of society, flourishes the economy and creates a good environment for friendly communication and fusion of customs among all nationalities, exerting positive and active influence on medicine. Analyses are made on the relation between customs and habits, and medical culture. it is stressed that not all customs are in line with science. Some of them might even be superstitious or anti-scientific. However, in some sense, it is the soil for the advent of medical and health care issues. PMID- 11615221 TI - [The uniformity of medical terms in early period: a review on the work of China Medical Missionary Association]. AB - Translation in medical terminology was a subject the medical missionaries encountered in China. The medical missionaries had done a lot of useful work in standardizing medical terms. Their work impelled the spread and development of Western medicine in China. It also laid a foundation for the uniformity of medical nomenclature. Unfortunately, this complex task was far beyond the reach of medical missionaries and had to leave it to those Chinese physicians who were well educated in modern medicine. PMID- 11615222 TI - [Formation of popular medical books in Sichuan Province in late Qing Dynasty and its influence]. AB - Among the traditional Chinese medical works in the Qing Dynasty is Sichuan province, popular ones occupied the major part. This author investigates its causes from the angles of economics, population and characteristics of physicians in this province. He also discusses the abridgement or re-compilation on the basis of those authors by their own clinical experience, who either imitated the stkyle, recompiled, or even attached their own work to Chen Xiuyuan's medical books. The influence, significance and role of these medical books are also mentioned. PMID- 11615223 TI - [Analysis on the causes of death of inhabitants at the inner and outer cities of Peking in late Qing Dynasty]. AB - Reports were made on the causes of death of Peking people inhabited in inner and outer cities within 2 days in 1908. Analysis showed that over 50% of the deaths were due to infectious diseases. The first 8 causes accounted for 70% of the total deaths, while the average expectancy of life at birth was 40.16 years of age. PMID- 11615224 TI - [Comparability of dai and thai traditional medicines]. AB - Through a preliminary comparison between traditional medicines of Dai and Thai, this article claims that these two traditional medical systems are of identical nature. They are comparable because their basic theories are of the same type. Further comparative research of them is one of the main approaches for the study and improvement of traditional medicines of Dai and Thai. PMID- 11615225 TI - [P. Meniere and Meniere's disease]. PMID- 11615226 TI - [Connections between Henry Sigerist and Chinese medical scholars and its influence]. PMID- 11615227 TI - [Differential analyses on the historical relationship between Zhenglei bencao (herbology of classified syndromes) and Mingyi Bie Lu (appendant records of famous physicians)]. AB - This author claims that, by using the approach of "inclusion of all canons", Tao Hongjing incorporated the 365 kinds of drugs from the earliest canon "Shen Nong's Herbological Canon" with another 365 kinds of "subordinated drugs from famous physicians", including Wu Pu and Li Dangzhi etc. to compile his 7-volume "Collected variorum of herbological canon". Owing to the changes and modifications made on the term "subordinated drugs from famous physicians" by the prefaces of herbological works of successive ages, the misunderstandings that the other 365 appendant kinds of drug were derived from an available Ming Yi Bie Lu and that the preface by Tao Yinju of the Liang Dynasty in Zhenglei Bencao was the preface of the book Mingyi Bielu were thuw formed. PMID- 11615228 TI - [Problems regarding the compilation of the ancient volume of "A general Chinese medical history"]. AB - This article deals with all aspects during the compilation of the book. These include the style, division of historical periods, origin of medicine, structural form of ancient Chinese medicines, Chinese ancient medicine and humanistic geography, cultural tradition, appraisal of medical figures, medical historical materials, etc. PMID- 11615229 TI - [Sprouting of forensic medicine]. AB - Since there are materials relevant to medical jurisprudence in Qin Lu (law of Qin Dynasty), Feng Zhen Shi (sealed pattern of investigation) and Huangdi Neijing (inner canon of Yellow Emperor), and the examining system of Warring States Period include procedures, personnel and reports on examination of medical jurisprudence, it can be concluded that the pre-Qin Period saw the sprouting period of Chinese medical jurisprudence. PMID- 11615230 TI - [Study on healing art among the aboriginals of Taiwan]. AB - The aboriginals of Taiwan who settled the island prior to the Han nationally can be divided into two groups, sinified plain people and less sinified mountain dwellers. The mountain dwellers fall into different groups; the Atayal, Saisiat, Bunun, Tsou, Rukai, Paiwan, Puyuma, Ami, and Yami. Before modern medicine penetrated the lives of the aboriginal, disease was treated by sorcery or by empirically applied herbal medicines. We visited various townships in Taiwan, including Chenggong, Daren, Haiduan, Puyuma, Changbin, and Yanping of Taidong County, Taidong City, and the offshore island of Lanyu; Mudan, Pindong County; and Fuxing, Taoyiuan County. We thereby covered the Ami, Paiwan,, Bunun, Puyuma, Yami, and Atayal groups. Although the aboriginals of Taiwan belong to the Malayo Poly-nesian cultural system, there are nevertheless major differences among them. The aboriginals of Taiwan believe disease to be a punishment of the gods or the malicious interference of evil spirits. The various groups have distinct shamanistic rituals. This paper discusses the practices of sorcery in the Paiway, bunun, and describes the herbal remedies used by them. PMID- 11615231 TI - [Characteristics of ancient medical administration in China and its contemporary enliytenment]. AB - This paper deals with the common characteristies, general rules and elementary clues for ancient medical administration before the Opium War. It also discusses the esternal influencing factors, background of its gain and loss. It mentions 7 aspects for the enlightment of modern administration, viz.; establishment of a united administrative system, setting up of medical curriculum, medical exchanges and medical development, establishment of patent drugs of individual materia medica, standardization of measurement system, the long-standing task of medical literature, prevention and treatment of epidemic through the effort of the mass. PMID- 11615232 TI - [Materials of history of TCM in Hainan]. AB - TCM therapy began in the Song Dynasty in Hainan. Medical instructor (Xun dao) was first established in the Ming Dynasty, with a total of thirty physicians. In the early Qing Dynasty, monastery of medical kings, Pujitang were built while Hui Ai Yi Ju and Aiseng Hospital were established in late Qing Dynasty. The development of TCM medical exchanges and planting southern herbs during the 20th century are also discussed. PMID- 11615233 TI - [Zur-mkhar bLo-gros rGyal-po, A distinguished physician of Tibet]. AB - The unity of Qin-Han feudal dynasties improves the development of society, flourished the economy and creates a good environment for friendly communication and fusion of customs among all nationalities, exerting positive and active influence on medicine. Analyses are made on the relation between customs and habits, and medical culture. It is stressed that not all customs are in line with science. Some of them might even be superstitious or anti-scientific. However, in some sense, it is the soil for the advent of medical and health care issues. PMID- 11615234 TI - [History of medicine in medieval period]. PMID- 11615235 TI - [A widespread historical book of gynecology]. PMID- 11615236 TI - [Research on Atlas of Viscera]. AB - Chinese ancient visceral atlas, or anatomical illustrations were derived from Taoist and medical schools through observation in cadavers. During the period from Five-Dynasties to Song, there were several works on visceral atlas, including Yanluo illustration, Atlas of Ou Xifan's visceral atlas of fidelity, Li Jung's Atlas. Among them, there exist relations of transmission-heredity, with gradual improvement. It seems likely that the visceral illustrations in Japanese Wan'an Prescription is the extant illustration of Ou's. After the advent of Atlas of Fidelity visceral atlas was differentiated into 3 different kinds of illustrations, as the Inner Picture (Neijing) of Mingtang Atlas; Neizhao Picture in pulsological works and visceral picture in physical Shenxing picture. Chinese visceral atlas was transmitted to Japan, Korea, Persia, and Europe and exerted some influence on cosmopolitan medicine. PMID- 11615237 TI - [Analysis on various deduction patterns of Yunqi theory in the Seven Major Discourses in suwen (plain questions)]. AB - It is pointed out that in the Seven Major Discourses, there are different patterns of deducing Yunqi theory. The design and method of deduction are then dealt with. In the light of the fact that there was physician in the staff of astronomical organization in the Eastern Han Dynasty as well as the cultural background as a whole, it is concluded that the KYunqi theory was proposed at the turn of middle and later period of Eastern Han Dynasty. PMID- 11615239 TI - [A brief history of cardiologoy in Western medicine]. PMID- 11615238 TI - [Fang Yizhi, beginner of thinking of confluence and western medicine]. AB - As a famous scholar of late Ming and early Qing Dynasties, Fang Yizhi's academic achievements have been highly praised. However, little was known about his advocation of confluence of Chinese and Western medicine. Through the author's study, it is evident that Fang Yizhi introduced new ideas on human anatomy and physiology spread by western missionaries. His records that "brain is responsible for memory", "brain governs movement and sensation" embodies the description of confluence of Chinese and Western medicine and is the earliest of its kind of his contemporaries. His summary of "zhiche", "tonji" on the art of Chinese and western knowledge is a conclusion in principle and universally accepted in the academic field. The so-called "superior-inferior-spring-autumn", "configuation nature and Qihua" conception from main exponents of confluence school, Wang Xuequan, Tang Roagehuan, Zhuk Peiwen is derived from Fan's idea. PMID- 11615240 TI - [Emergence and evolution of pharmaceutical chemistry]. PMID- 11615242 TI - The politics of macromolecules: molecular biologists, biochemists, and rhetoric. PMID- 11615243 TI - Science, politics, and the renegotiation of expertise at EPA. PMID- 11615244 TI - Setting federal salaries in the space age. PMID- 11615245 TI - Science, universities, and national defense, 1945-1970. PMID- 11615247 TI - Documenting recent science: progress and needs. PMID- 11615248 TI - Big science: Price to the present. PMID- 11615251 TI - Big science in the last years of the big Soviet Union. PMID- 11615252 TI - Plants as intellectual property: American practice, law, and policy in world context. PMID- 11615253 TI - Sir William Kynsey and the development of health care in Sri Lanka. PMID- 11615254 TI - Julius Wagner-Jauregg (1857-1940). PMID- 11615255 TI - Jaques-Louis Reverdin (1842-1929) and his cousin Auguste (1848-1908) of Geneva; or how surgical clinical practice prevailed over experimental physioloy. Part I. PMID- 11615256 TI - Sir Richard Owen (1804-1892): comparative anatomist and palaeontologist. PMID- 11615257 TI - Dr W G Grace: cricketer and general practitioner. PMID- 11615258 TI - Frederick Delius: the man, the composer, the patient. PMID- 11615259 TI - "The Doctor". PMID- 11615260 TI - Pott and his fracture; with a note on the surgical ambience of the age. PMID- 11615262 TI - Argyll Robertson--a breadth of vision. PMID- 11615261 TI - James IV of Scotland: monarchy and medicine. PMID- 11615263 TI - John Elliotson (1791-1868): a bitter enemy of legitimate medicine? Part II: The mesmeric scandal and later years. PMID- 11615264 TI - Semmelweis: a rereading of Die aetiologie ... Part I: Puerperal sepsis before 1845; Die aetiologie. PMID- 11615265 TI - Sheffield Medical School: origins and influences. PMID- 11615266 TI - Doctor David Livingstone FRS (1813-1873): "the fever" and other medical problems of mid-nineteenth century Africa. PMID- 11615267 TI - Mozart's last months and controversial death. PMID- 11615268 TI - Saints Cosmas and Damian: patron saints of medicine. A story from prayers and pictures? PMID- 11615269 TI - Mozart's Indian: Dr. Ferdinand Dejean. PMID- 11615270 TI - Theodore Howard Somervell OBE FRCS: surgeon, missionary, mountaineer, painter, musician. PMID- 11615271 TI - Rasprave o nacinu dijagnosticiranja u kolegiju, prognoziranju i lijecenju groznica kao i o ljudskoj sreci i napokon o morskoj plimi i oseci netom objavljene godine 1528. PMID- 11615272 TI - Ernest Skinner, Henry James, and the death of Stephen Crane: a Cora Crane inscription. PMID- 11615273 TI - Toward a rational history of medical science. [Review of W. F. Bynum, Science and the practice of medicine in the nineteenth century, Cambridge University Press, 1994, and A. S. Evans, Causation and disease: a chronological journey, Plenum Medical Book Company, 1993]. PMID- 11615274 TI - Ramanujan's illness. PMID- 11615275 TI - John Hill and the Royal Society in the eighteenth century. PMID- 11615276 TI - Portraits of Dr Erasmus Darwin, F.R.S., by Joseph Wright, James Rawlinson and William Coffee. PMID- 11615277 TI - R. A. Fisher on Karl Pearson. PMID- 11615278 TI - Pioneers of genetics: a comparison of the attitudes of William Bateson and Erwin Baur to eugenics. PMID- 11615279 TI - J.B.S. Haldane and R.A. Fisher's draft life of Karl Pearson. PMID- 11615280 TI - A provincial man of science at work: Martin Lister, F.R.S., and his illustrators 1670-1683. PMID- 11615281 TI - Erasmus Darwin's life at Lichfield: fresh evidence. PMID- 11615282 TI - Ibn al-Nafis and his work, Kitab Mujiz al-Qanun. PMID- 11615283 TI - Riyad-i 'Alamgiri--a medical manuscript. PMID- 11615284 TI - Riyad-i 'Alamgiri--a medical manuscript. PMID- 11615285 TI - Tadhkira-i Sharifi--a study. PMID- 11615286 TI - Tadhkiri-i Sharifi--a study. PMID- 11615287 TI - Qarabadayn: a new source for botanical information concerning the utilization of some plants in medieval India. PMID- 11615288 TI - A new manuscript on prophet's medicine by Jalal al-Din al-Suyuti. PMID- 11615289 TI - A new manuscript on Prophet's medicine by Jalal al-Din al-Suyoti. PMID- 11615290 TI - [The scientific conceptualization of the female being. Metaphoric use in Galen's writings]. AB - This article, a gender study of the writings of Galen, aims to investigate the reasons for the sustained claims of the inferiority of feminine nature with respect to masculine nature. We offer a reconstruction of the social values held by Galen, which conferred to him an androcentric model of knowledge that differed from the other scientific forms in existence at that time. We show that descriptions of the female organism are assiduously associated with maleness or nature, which we interpret as a metaphorical and exemplifying use for the transmission of ethical norms, and the credibility of the doctrine. PMID- 11615291 TI - [The role of nursing in the development of public health in Spain (1923-1935): the public health nurse]. AB - In this research we analyze the process of institutionalization of Public Health Nursing in Spain during the period 1923-1935. Socialization programs are first studied, within the framework of the National School of Child Care (1926) and the National School of Health (1933), as well as the agreement on postgraduate training abroad signed with the Rockefeller Foundation (1931). Secondly, we analyze the professional activities carried out by these nurses, and the organizational efforts of this collective, which led specifically to the foundation of the Public Health Nursing Association in 1934. Our findings bring to light the process of sociological definition, as a specialized sector within nursing practice, attained by the professional activity of public health nursing, and illustrate the influence of this profession on the improvement of public health in Spain. PMID- 11615292 TI - [Childhood as a value and a problem in the campaigns for health at the beginning of the twentieth century in Spain]. AB - The paper explores how, through a process that began in the last decades of the nineteenth century and continued during the first part of the present century, especially in the 1920's infancy and infant health were regarded as objects of great value and as a social problem. The child's body was studied and analyzed by doctors, a situation that had important repercussions in other spheres of social life. Children were considered to have a series of characteristics which formed, as a whole, an ideal model within the family and home setting. Care, protection and intervention are the three components underlying the sanitary reform process that supported the health and welfare of children in Spain during this period. PMID- 11615293 TI - [Medicine and scientific method in the Roman world. Introduction]. PMID- 11615294 TI - Galen ad multos annos. AB - This paper focuses on demonstrating the weakness of the traditional date for Galen's death. It shows that there are good grounds from both within the Galenic Corpus and outside it for thinking that he lived at least until he was eighty. Information from Byzantine and Arab scholars from the sixth century onwards suggests that he had died in the reign of Caracalla, perhaps in 216. PMID- 11615295 TI - Method in Galen. AB - I have discussed the four methods of ancient philosophy namely demonstration, division, resolution, and composition. But first, I glance at logic, which "discovers the principles of medical treatment". Method in pathology discovers "the affected parts of the body" and nosology, "the symptoms of diseases and their causes". In therapeutics, method "discovers drugs appropriate to specific diseases". The leader in all things pertaining to method is Hippocrates. PMID- 11615296 TI - [Elements for the construction of case histories in Galen]. AB - This note calls attention to Galen's use of different, nonrational elements of Hellenic culture and society in the construction of his case histories. PMID- 11615297 TI - [Galen and the refounding of medicine]. AB - The writings of Galen discussed in this article present an outline of the project he devoted his life to. Firstly, the reconstruction of a higher model of medical knowledge, in terms of its epistemological legitimization and its cultural and social role. Galen's refoundation of the epistemological statute of medicine involved increased emphasis on axiomatization, albeit not without disregard to data obtained through experience as a final guarantee. Secondly, the construction of a lay morality, independent of the ties to power or religious constraints. Through anatomy and physiology, Galen was attempting to comprehend the providential notion that governed nature: a powerful ideology set against the uncertainty of philosophers and the propagation of irrationalist religions. From this extreme position, the galenic physician demanded that medicine be not only a general task of ideological and cultural orientation, but also a source of real, particular power over the control of moral behavior and social deviation. PMID- 11615298 TI - [Not Available]. PMID- 11615299 TI - [Not Available]. PMID- 11615300 TI - [Not Available]. PMID- 11615301 TI - [Not Available]. PMID- 11615302 TI - [Not Available]. PMID- 11615303 TI - [Not Available]. PMID- 11615304 TI - [Not Available]. PMID- 11615305 TI - [Not Available]. PMID- 11615306 TI - [Not Available]. PMID- 11615307 TI - [Not Available]. PMID- 11615308 TI - [Not Available]. PMID- 11615309 TI - [Not Available]. PMID- 11615310 TI - [Not Available]. PMID- 11615311 TI - [Not Available]. PMID- 11615312 TI - The Grazer school of thought on the Sprachapparat and Otto Gross' theory of a 'non-organic aphasia' (mind split). PMID- 11615313 TI - [Not Available]. PMID- 11615314 TI - [Not Available]. PMID- 11615315 TI - [Not Available]. PMID- 11615316 TI - [Not Available]. PMID- 11615317 TI - [Not Available]. PMID- 11615318 TI - [Not Available]. PMID- 11615319 TI - [Not Available]. PMID- 11615320 TI - [Not Available]. PMID- 11615321 TI - [Not Available]. PMID- 11615322 TI - [Not Available]. PMID- 11615323 TI - [Not Available]. PMID- 11615324 TI - [Not Available]. PMID- 11615325 TI - [Not Available]. PMID- 11615326 TI - [Not Available]. PMID- 11615327 TI - [Not Available]. PMID- 11615328 TI - Frank Menzies Cameron Forster, 1923-1995. PMID- 11615329 TI - Pe-ru-na: a catarrh cure from Columbus. PMID- 11615330 TI - Walle J. H. Nauta (8 June 1916-24 March 1994). PMID- 11615331 TI - Howard M. Temin (10 December 1934-9 February 1994). PMID- 11615332 TI - [How infectious diseases were taken over at the end of the XIXth century: The Saint-Denis Hospital example]. AB - In 1881, the Saint-Denis hospital equipped itself with a real infectious diseases department which was conceived in respect to the rules of hygiene, cleanliness and prophylaxis. On the one hand, this department had an isolation purpose for the people who suffered from epidemic infections favoured by the environment. On the other hand, it was realized to deal with the common infectious diseases known at this time. The analysis of these diseases shows that the first anti-rabic vaccination attempt by Pasteur carried out at the Saint-Denis Hospital. PMID- 11615333 TI - [Hippocrates' heritage from Lyons]. AB - Hippocrates' influence is known in Lyons as soon as the time of the Renaissance, after the discovery of printing. Symphorien Champier and later chiefly Rabelais translated texts of the Cos master and had them edited by the first printers. Hippocrates' influence is moreover evident in Rabelais' work. In the XIXth century, surgeon major Petrequin published the first book devoted to Hippocrates's surgery. More recently, Professor Pierre Delore has been a convinced supporter of neo-hippocratic medicine of which he developed the chief principles in his works. PMID- 11615334 TI - La variole avant Jenner (XVIIe-XVIIIe siecles). PMID- 11615335 TI - [G. W. Leibniz: medicine and the sciences of life. Ist part: Leibniz as a "medical practioner]. AB - A universal thinker, Leibniz always expressed a marked interest for matters of life. A reader and a correspondent of the most famous physicians of his time, he exhorted them - with some results - to found their theories on the ground of detailed comparative observations and of verified experiments, firmly distinguishing scientific and metaphysic points of view. He worked out a primal organismic theory, but devoted himself mostly to set up a coherent medical training programme and a requiring health policy. Nevertheless, beyond anecdote, Leibniz never pretended to be a medical practioner, but thought he was a "medically-minded" philosopher. PMID- 11615336 TI - [Philippe Pinel in 1784. A "foreign" physician in front of the Paris Faculty of Medicine]. AB - Philippe Pinel (1745-1826), the most famous French alienist was forbidden to practice medicine in Paris during the "Ancien Regime" as he had obtained his doctorate from a provincial faculty. Having been twice an unfortunate candidate to a competition which would have allowed him to resume his studies, he was also rejected in 1784 for functions at Court. The circumstances of these failures are reinvestigated here in the light of various documents some of which unpublished. PMID- 11615337 TI - [Ambroise Pare in French literature]. AB - The 16th century by its passionate side has been the favourite one of authors of historical novels in which among the heroes of "cloak and dagger stories" appears sometime Ambroise Pare. Alexandre Dumas (the father) has shown him at the court of Charles IX in La Reine Margot (1845) where he does not however play a great role. On the contrary, Balzac in Le Martyr calviniste (1842) has given him a capital part close to the dying Francois II, whom he intended to trepanize but had to give up this idea as a consequence of the opposition of the queen-mother Catherine de Medicis. In the present century, Robert Merle in Paris ma bonne ville (Fortune de France, 3, 1980) shows Pare at the time of the Saint Barthelemy. PMID- 11615338 TI - [Health services, morbidity and mortality in the regiment of the Papal Zouaves in Italy (1861-1870)]. AB - The regiment of the Zouaves pontificaux was formed by young Catholic volunteers, chiefly French, Dutch and Belgian, who enrolled for the defence of the Pontifical State from 1861 to 1870 against the scheme of the United Italy planned by King Victor-Emmanuel II and Garibaldi. For ten years fights were scarce. They only took place in 1867 principally in Mentana and in September 1870 when the papal state was invaded and Rome taken. At first the military medical service in the regiment as in the whole army was rather inadequate except for the central hospital. The ambulances system was based largely upon benevolent people. But the organization improved in 1870. On the whole amongst more than 9,000 enlisted volunteers, 476 died (5%). The causes of death were more often diseases (78%) than injuries. As in all the armies of that time, cholera, smallpox, typhoid fever made a lot of victims. Malaria which still reigned in the Latium was responsible of a large morbidity. PMID- 11615339 TI - [Ludwig van Beethoven: an autoimmune deafness?]. AB - The author reminds us of the great moments of Beethoven's life and of the different stages of his deafness onset, until to last instants. The post-mortem examination, performed by doctor Wagner, and the scientific studies of the remains, during the exhumations, are reported. Beethoven's deafness was clearly a sensorineural impairment and the previously suggested prevalent hypotheses are discussed. A new theory is emphasized, based on modern studies about autoimmune sensorineural hearing losses in relation with chronic inflammatory bowel ailment. Conclusion is that Beethoven's deafness was probably owing to a primary autoimmune degeneration of the organ of Corti, giving rise to atrophy of the auditory nerve. PMID- 11615340 TI - Under pressure. PMID- 11615341 TI - Samuel Sharp and the Operations of Surgery, 1739. PMID- 11615342 TI - Roger Reid's early contribution to the study of penicillin. PMID- 11615343 TI - Francis Brett Young, Mercia and the Birmingham Medical School. PMID- 11615344 TI - Hector Berlioz, medical student and commposer, with a note on his medical teachers. PMID- 11615345 TI - The course of Heinrich Heine's illness: diagnostic considerations. PMID- 11615346 TI - An unexpected circumstance: the ailments and death of John Constable RA. PMID- 11615347 TI - Visiting Lister and his Scottish friends. PMID- 11615348 TI - Arnold Meadowcroft Muirhead (1900-1988) and the story of the Lady Osler memoir. PMID- 11615349 TI - The Reverend Doctor Samuel Bernard: Doctor William Harvey prescribes again. PMID- 11615350 TI - Interview with Dr David Cohen. PMID- 11615351 TI - Julia Bell (1879-1979). Steamboat Lady, statistician and geneticist. PMID- 11615352 TI - Fergus William Campbell - 30 January 1924--3 May 1993. PMID- 11615353 TI - David Guthrie Catcheside - 31 May 1907--1 June 1994. PMID- 11615354 TI - Ragnar Granit - 30 October 1900--11 March 1991. PMID- 11615355 TI - Charlotte Auerbach - 14 May 1899--17 March 1994. PMID- 11615356 TI - Sir Harold Percival Himsworth, K.C.B. - 19 May 1905--1 November 1993. PMID- 11615357 TI - Robert Alexander McCance - 9 December 1898--5 March 1993. PMID- 11615358 TI - Sir John McMichael - 25 July 1904--3 March 1993. PMID- 11615359 TI - Malcolm Milne - 22 May 1915--3 April 1991. PMID- 11615360 TI - Shosaku Numa - 7 February 1929--15 February 1992. PMID- 11615361 TI - George Wells Beadle - 23 October 1903--9 June 1989. PMID- 11615362 TI - Howard M. Temin - 10 December 1934--9 February 1994. PMID- 11615363 TI - Dame Janet Maria Vaughan, D.B.E. - 18 October 1899--9 January 1993. PMID- 11615364 TI - Frank Yates - 12 May 1902--17 June 1994. PMID- 11615365 TI - Solly Zuckerman, Baron Zuckerman, of Burnham Thorpe. O.M.,K.C.B. - 30 May 1904--1 April 1993. PMID- 11615366 TI - Denis Parsons Burkitt - 28 February 1911--23 March 1993. PMID- 11615367 TI - Karl Pearson's Gresham lectures: W. F. R. Weldon, speciation and the origins of Pearsonian statistics. PMID- 11615368 TI - Genetics in Germany. [Review of: Harwood J, Styles of scientific thought: the German genetics community, 1900-1933. Chicago: University of Chicago Press, 1993]. PMID- 11615369 TI - George Grubler and Karl Hollborn: two founders of the biological stain industry. AB - The aniline dye industry was created in 1856 when the Englishman William Perkin prepared the color mauve from aniline. Dye industries were then formed in several European countries, and each year thousands of new colors and shades were tested on fabrics. Scientists of that period used these new dyes to study the structures of plant and animal tissues. Starting in 1880 George Grubler, a German pharmacist, sold biological stains to scientists around the world. Grubler stains earned a reputation for reliability, and many of the staining methods, developed at that time stiuplated the use of Grubler's dyes, even after the firm was sold to Karl Hollborn who continued Grubler's work and devised new staining methods. The Grubler company continued to prosper until World War I. The Chroma Gesellschaft-Schmid GMBH Company in Germany is a successor of the Grubler company. The interrupted supply of Grubler stains during World War I prompted the start of the American biological stain industry and subsequently the Biological Stain Commission was formed. PMID- 11615370 TI - James Augustine Shannon (9 August 1904-20 May 1994). PMID- 11615371 TI - Science at home: the space between Henrietta Heathorn and Thomas Huxley. PMID- 11615372 TI - The neoterics and political power in Spanish Italy: Giovanni Alfonso Borelli and his circle. PMID- 11615373 TI - Blake, Donne, and death. PMID- 11615374 TI - The science of human worth. [Review of: Larson EJ. Sex, race, and science: eugenics in the deep South. Johns Hopkins University Press, 1995]. PMID- 11615375 TI - Correspondence of Freud and Ferenczi. [Review of: Brabant E, et. al., eds. Sigmund Freud and Sandor Ferenczi, Briefwechsel, Vol.I/1 (1908-1911). Bohlau Verlag, 1993]. PMID- 11615376 TI - [Not Available]. PMID- 11615377 TI - A closer look. Herbert Watkins-Pitchford, CMG, FRCVS, FRSE. Paradoxical veterinary surgeon: a reappraisal of his work in Natal on rinderpest. PMID- 11615378 TI - [Not Available]. PMID- 11615379 TI - University College Hospital physicians on stamps. PMID- 11615380 TI - Medical persecution with special reference to Garcia da Orta. PMID- 11615381 TI - Nobel prize winners: a stamp, a cover, and a souvenir sheet of medical interest. PMID- 11615382 TI - Charlotte Friend: March 11, 1921-January 13, 1987. PMID- 11615383 TI - James Jerome Gibson: January 27, 1904-December 11, 1979. PMID- 11615384 TI - Albert Baird Hastings: November 20, 1895-September 24, 1987. PMID- 11615385 TI - Nathan Oram Kaplan: June 25, 1917-April 15, 1986. PMID- 11615386 TI - Wilton Marion Krogman: June 28, 1903-November 4, 1987. PMID- 11615387 TI - Thomas Addis: July 17, 1881-June 4, 1949. PMID- 11615388 TI - Philip Levine: August 10, 1900-October 18, 1987. PMID- 11615389 TI - John Howard Northrop: July 5, 1891-May 27, 1987. PMID- 11615390 TI - Howard A. Schneiderman: February 9, 1927-December 5, 1990. PMID- 11615391 TI - Reconstruction of the facial features of George Buchanan: tutor of James VI and founder of the 'Tounis College of Edinburgh'. PMID- 11615392 TI - Rhododendrons, doctors and India, 1780-1860. PMID- 11615393 TI - Two men and a bug: one hundred years of tuberculosis in Edinburgh. PMID- 11615394 TI - Thales to Galen: a brief journey through rational medical philosophy in ancient Greece. Part II: Hippocratic medicine. PMID- 11615395 TI - Matthew Arnold: a forgotten verse impromptu. PMID- 11615396 TI - L'art d'observer au XVIIIe siecle: Jean Senebier et Charles Bonnet. PMID- 11615397 TI - Markus Elieser Blochs und Johann August Ephraim Goezes Beitrage zur Erforschung der Eingeweidewurmer. PMID- 11615400 TI - A rare sanskrit medical manuscript of early period of Vijayanagar kingdom. Vaidyavallabha by Lakshmana Pandita, Pranacharya of King Bukka II (1404-1406 A.D.). PMID- 11615401 TI - Ferdinand Cohn. PMID- 11615402 TI - The first English pediatricians and Tudor attitudes toward childhood. PMID- 11615403 TI - "The mesmeric mania": the early Victorians and animal magnetism. PMID- 11615404 TI - Physical, human and divine attraction in the life and thought of George Cheyne. PMID- 11615405 TI - Herman Boerhaave and the element-instrument concept of fire. PMID- 11615406 TI - Studies in the natural philosophy of Sir Kenelm Digby. Part II. Digby and alchemy. PMID- 11615407 TI - The conception of alchemy as expressed in the Pretiosa Margarita Novella of Petrus Bonus of Ferrara. PMID- 11615408 TI - Studies in the natural philosophy of Sir Kenelm Digby. Part III. Digby's experimental alchemy-the book of secrets. PMID- 11615409 TI - The Henrys of Manchester. Part I: Thomas Henry (1734-1816). PMID- 11615410 TI - Some bibliographical puzzles concerning George Starkey. PMID- 11615411 TI - The Henrys of Manchester, Part 2. Thomas Henry's sons: Thomas, Peter, and William. PMID- 11615412 TI - The Henrys of Manchester, Part 3. William Henry and John Dalton. PMID- 11615413 TI - The higher elements and prime matter in Renaissance naturalism in Paracelsus. PMID- 11615414 TI - The Robert L. Levy collection of William Harvey and the cardiac classics. PMID- 11615415 TI - Mount Auburn cemetery: a proper Boston institution. PMID- 11615416 TI - Liebig on Francis Bacon and the utility of science. PMID- 11615417 TI - The Flexner Report by Abraham Flexner. PMID- 11615418 TI - The interpretation of dreams by Sigmund Freud. PMID- 11615419 TI - Albrecht von Haller on the future of science. PMID- 11615421 TI - James Morison and his pills. A study of the nineteenth century pharmaceutical market. PMID- 11615420 TI - The contacts between Karl Marx and Charles Darwin. PMID- 11615422 TI - Dr. James's Fever Powder. PMID- 11615423 TI - Renaissance Latin Aristotle Commentaries: authors A-B. PMID- 11615424 TI - Pourquoi Descartes soutint-il les oeuvres de Harvey? (En japonais). PMID- 11615425 TI - William Blomfild, Elizabethan alchemist. PMID- 11615426 TI - Howard Walter Florey, Baron Florey of Adelaide and Marston 1898-1968. PMID- 11615427 TI - William Ogilvy Kermack 1898-1970. PMID- 11615428 TI - Alfred Alexander Peter Kleczkowski 1908-1970. PMID- 11615429 TI - William Kershaw Slater 1893-1970. PMID- 11615430 TI - Alexander Robertson 1896-1970. PMID- 11615431 TI - Francis Peyton Rous 1879-1970. PMID- 11615432 TI - Leonard Colebrook, 1883-1967. PMID- 11615433 TI - Ioannes Marcus Marci (1595-1667). PMID- 11615434 TI - Goldschmidt Papers, University of California, Berkeley. PMID- 11615435 TI - Fechner's panpsychism: a scientific solution to the mind-body problem. PMID- 11615436 TI - How do you spell Pawloff?: a note. PMID- 11615437 TI - Models of mind and mental illness in Ancient Greece: I. The platonic model. PMID- 11615438 TI - Goethe is different things to different people: a note. PMID- 11615439 TI - Psychological terminology in the Tusculans. PMID- 11615440 TI - A Hampton marries a Halsted. PMID- 11615441 TI - Addition to the Rufus Cole collection. PMID- 11615442 TI - Gandhi; a psychoanalytic view. [Essay review of Erik H. Erikson, Gandhi's truth]. PMID- 11615443 TI - Doctor Francois Rabelais: Pantagruel and health. PMID- 11615444 TI - Henry Brougham and the Scottish methodological tradition. PMID- 11615445 TI - Friendship and influence: Martinus van Marum, F.R.S. PMID- 11615446 TI - Richard Bradley's relationship with Sir Hans Sloane. PMID- 11615447 TI - Thomas Young's lectures at the Royal Institution. PMID- 11615448 TI - Ernest William Goodpasture, October 17, 1886-September 20, 1960. PMID- 11615449 TI - Frank Charles Mann, September 11, 1887-September 30, 1962. PMID- 11615450 TI - Henry Wieghorst Nissen, February 5, 1901-April 27, 1958. PMID- 11615451 TI - John Thomas Patterson, November 3, 1878-December 4, 1960. PMID- 11615452 TI - Thomas Milton Rivers, September 3, 1888-May 12, 1962. PMID- 11615453 TI - Charles Thom, November 11, 1872-May 24, 1956. PMID- 11615454 TI - William Ernest Castle, October 25, 1867--June 3, 1962. PMID- 11615455 TI - Robert Mearns Yerkes, May 26, 1876--February 3, 1956. PMID- 11615456 TI - Surgical principles in the Sutrasthanam of the Susruta samhita. Management of retained foreign bodies. PMID- 11615457 TI - Caraka and Susruta on sleep. PMID- 11615458 TI - Susruta recommends golden and jewelled vessels for eating and drinking. PMID- 11615459 TI - Milislav Demerec, January 11, 1895-April 12, 1966. PMID- 11615460 TI - Kenneth Fuller Maxcy, July 27, 1889--December 12, 1966. PMID- 11615461 TI - Gregory Goodwin Pincus, April 9, 1903-August 22, 1967. PMID- 11615462 TI - Alfred Newton Richards, March 22, 1876-March 24, 1966. PMID- 11615463 TI - Alphonse Raymond Dochez, April 21, 1882-June 30, 1964. PMID- 11615464 TI - Oswald Hope Robertson, June 2, 1886=March 23, 1966. PMID- 11615465 TI - Bateson and chromosomes: conservative thought in science. PMID- 11615466 TI - Prout's hypothesis: a reconsideration. PMID- 11615467 TI - Die Untersuchungen von Niels Stensen uber die Haut. Versuch einer kritischen Betrachtung. PMID- 11615468 TI - Was the university of Christian III a twopenny university, or was the salary demanded by Leonhart Fuchs unreasonable? The professors' pay in the 16th century. PMID- 11615469 TI - Current Mendel research. PMID- 11615470 TI - Rubens Paele's experiments with mesmerism. PMID- 11615471 TI - Benjamin Rush, David Hartley, and the revolutionary uses of psychology. PMID- 11615472 TI - Huxley in America. PMID- 11615473 TI - Frederic Charles Bartlett, 1886-1969. PMID- 11615474 TI - Samuel Phillips Bedson, 1886-1969. PMID- 11615475 TI - Charles Arthur Lovatt Evans, 1884-1968. PMID- 11615476 TI - David Willis Wilson Henderson, 1903-1968. PMID- 11615477 TI - Arthur St George Joseph McCarthy Huggett, 1897-1968. PMID- 11615478 TI - Robert Thomson Leiper, 1881-1969. PMID- 11615479 TI - Ernest Basil Verney, 1894-1967. PMID- 11615480 TI - Henry Hallett Dale, 1875-1968. PMID- 11615481 TI - Joseph Erlanger, January 5, 1874-December 5, 1965. PMID- 11615482 TI - Arnold Kent Balls, April 2, 1891-May 25, 1966. PMID- 11615483 TI - Maimonides as a physician. PMID- 11615484 TI - Medical men and medicine in the correspondence of Athanasius Kircher (1602-80). PMID- 11615485 TI - Glauber und die Weltanschauung der Rosenkreuzer. PMID- 11615486 TI - Studies in the natural philosophy of Sir Kenelm Digby. PMID- 11615487 TI - A reconsideration of Roger Bacon's theory of pinhole images. PMID- 11615488 TI - Metaphysical derivations of a law of refraction: Damianos and Grosseteste. PMID- 11615489 TI - [Not Available]. PMID- 11615490 TI - Priestley's library of scientific books: a new list. PMID- 11615492 TI - Open problems of Darwin research. [Essay review]. PMID- 11615491 TI - Refutation and conjecture: Darwin's response to Sedgwick's attack on Chambers. [Essay review]. PMID- 11615493 TI - Darwin's method or methods? [Essay review]. PMID- 11615494 TI - The phenomenology of William James. PMID- 11615495 TI - The understanding of sickness in Donne's Devotions. PMID- 11615496 TI - Thomas Thomson: professor of chemistry and university reformer. PMID- 11615498 TI - Erasmus Darwin's view of evolution. PMID- 11615497 TI - Who was the Beagle's naturalist? PMID- 11615499 TI - Ernst Haeckel's monistic religion. PMID- 11615500 TI - Copernicus' attitude toward the common people. PMID- 11615501 TI - George William Bartelmez. PMID- 11615502 TI - David Wright Wilson. PMID- 11615503 TI - Edwin Bidwell Wilson. PMID- 11615504 TI - Edwin Garrigues Boring. PMID- 11615505 TI - Charles Judson Herrick. PMID- 11615506 TI - Lines of influence in thirteenth century optics: Bacon, Witelo, and Pecham. PMID- 11615507 TI - A right frvtefvll and approoved treatise, for the artificiall cure of that malady called in Latin struma, and English, the evill, cured by kinges and queenes of England. Very necessary for all young practizers of Chyrurgery. [Essay review]. PMID- 11615508 TI - Tributes to Gertrude L. Annan. PMID- 11615509 TI - A hidden Zionist theme in Freud's "My son, the Myops..." dream. PMID- 11615510 TI - John Locke and the changing ideal of scientific knowledge. PMID- 11615511 TI - The principle of population as political theory: Godwin's Of population and the Malthusian controversy. PMID- 11615512 TI - Coleridge's manuscript essay On the passions. PMID- 11615514 TI - Robert Burton and Ramist method. PMID- 11615513 TI - James, Dewey, and the reflex arc. PMID- 11615515 TI - The theater of cruelty and alchemy: Artaud and le grand oeuvre. PMID- 11615516 TI - Darwinism and social Darwinism. PMID- 11615517 TI - "To charm thy curious eye": Erasmus Darwin's poetry at the vestibule of knowledge. PMID- 11615518 TI - Natural selection in The origin of species. PMID- 11615519 TI - Newton and the classical theory of probability. PMID- 11615520 TI - All's well that ends well and the Galenico-Paracelsian controversy. PMID- 11615521 TI - Leyden and the "fortuna" of Apicius. PMID- 11615522 TI - William James and the twice-born sick soul. PMID- 11615523 TI - Henry Power's experimental philosophy PMID- 11615524 TI - William Brockedon, F.R.S. (1787-1854). PMID- 11615525 TI - Some sources of Herman Boerhaave's concept of fire. PMID- 11615526 TI - Further thoughts on the identity of "Eirenaeus Philalethes". PMID- 11615527 TI - Further thoughts on the identity of "Eirenaeus Philalethes". PMID- 11615528 TI - Anatomy the teacher: on the impact of Leonardo's anatomical research on his musical and other machines. PMID- 11615529 TI - A letter of George H. Shull to Wilhelm Ludwig Johannsen, 1908 (In the Library of the American Philosophical Society). PMID- 11615530 TI - A little known early seventeenth century treatise on vision: Benedetto Castelli's Discorso sopra la vista (1639-1669). Translation and critical comments. PMID- 11615531 TI - Beethoven's deafness and the saga of the stapes. PMID- 11615533 TI - Lyell and evolution: an account of Lyell's response to the prospect of an evolutionary ancestry for man. PMID- 11615534 TI - The Mattei cancer cure: a Victorian nostrum. PMID- 11615535 TI - A study of Parentalia, with two unpublished letters of Sir Christopher Wren. PMID- 11615536 TI - E. H. J. Schuster (1897-1969). PMID- 11615537 TI - Henry Bence-Jones, M.D., F.R.S. (1813-1873). PMID- 11615538 TI - Sleeping sickness. The Castellani-Bruce controversy. PMID- 11615539 TI - The influence of Brueghel's print The Alchemist. PMID- 11615540 TI - Mediaeval empiricism: the case of Grosseteste's optics. PMID- 11615541 TI - Mendels dichterischer Versuch aus seinen Studentenjahren. PMID- 11615542 TI - Zur Begegnung von Mendel mit dem bekannten Bienenzuchter Dathe. PMID- 11615543 TI - Die Publizitat der klassischen Arbeit Gregor Mendels vor der Wiederentdeckung im Jahre 1900. PMID- 11615544 TI - Benjamin Franklin, F.R.S., Sir Joshua Reynolds, F.R.S., P.R.A., Benjamin West, P.R.A. and the invention of bifocals. PMID- 11615545 TI - The versatile Nehemiah Grew. PMID- 11615546 TI - The anatomical and physiological bibliography of George E. Day (1815-1872). PMID- 11615547 TI - Boyle's conception of nature. PMID- 11615548 TI - Benjamin Rush on government and the harmony and derangement of the mind. PMID- 11615549 TI - The knowledge of Aristotle's Lapidary during the Latin Middle Ages. PMID- 11615550 TI - William James MacNeven and early laboratory instruction in the United States. PMID- 11615551 TI - The chemist breeders: the research schools of Liebig and Thomas Thomson. PMID- 11615552 TI - The youth of John Quincy Adams. PMID- 11615553 TI - Wer war Jacob von Landsberg? PMID- 11615554 TI - Drei Briefe uber Reine Linien von Galton, de Vries und Yule an Wilhelm Johannsen in 1903 geschrieben. PMID- 11615555 TI - Two little known copies of Black's lecture notes. PMID- 11615556 TI - Opponents of classical learning in America during the Revolutionary period. PMID- 11615557 TI - The European education of an American chemist and its influence in 19th-century America: Eben Norton Horsford. PMID- 11615558 TI - The "founder" of modern plastic surgery: Carl Ferdinand von Graefe (1787-1840). PMID- 11615559 TI - Descartes and the method of English science. PMID- 11615560 TI - Suicide and Brutus' philosophy in Julius Caesar. PMID- 11615561 TI - Rowland G. Hazard (1801-88) on freedom in willing. PMID- 11615562 TI - The evolution of Akenside's The Pleasures of the Imagination: the missing link established. PMID- 11615563 TI - An eighteenth-century best seller. PMID- 11615564 TI - An Arabic translation solves some problems in Galen. PMID- 11615565 TI - Politics and patricide in Freud's interpretation of dreams. PMID- 11615566 TI - Hitler and psychohistory. PMID- 11615567 TI - Bonham's case reviewed. PMID- 11615568 TI - Aemilius Macer, Alexipharmaca? PMID- 11615569 TI - Natural science in Japan. I. Before 1830. PMID- 11615570 TI - Walter Charleton's early life 1620-1659, and relationship to natural philosophy in mid-seventeenth century England. PMID- 11615571 TI - Science and theology at Groningen University (1698-1702). PMID- 11615572 TI - The manuscripts of Platina "De honesta volupte..." and its source, Martino. PMID- 11615573 TI - Newly found additions to the Hunter-Baillie MSS. PMID- 11615574 TI - The Hunter-Baillie MSS. Pt. 2. PMID- 11615575 TI - Petrarch and the Black Death: from fear to monuments. PMID- 11615576 TI - Die statistische Auswertung der meteorologischen Daten eines Monates durch J. G. Mendel als Beispiel seiner Arbeitsweise, dargestellt an Hand der auf zwei Foliobogen erhalten gebliebenen Rechnungen. PMID- 11615577 TI - I. Minis Hays, secretary, librarian, and benefactor of the American Philosophical Society. PMID- 11615578 TI - Sir G. B. Airy, F.R.S. (1801-1892) and the symptomatology of migraine. PMID- 11615579 TI - The Darwin letters at Shrewsbury School. PMID- 11615581 TI - Jewels in my acquaintance with C. S. Sherrington, F.R.S. PMID- 11615580 TI - Charles Scott Sherrington (1857-1952). PMID- 11615582 TI - Letters from C. S. Sherrington, F.R.S., to Angelo Ruffini between 1896 and 1903. PMID- 11615583 TI - Samuel Johnson's "Wonderful" remission of dropsy. PMID- 11615584 TI - Character and physiognomy: Bocchi on Donatello's St. George, a Renaissance text on expression in art. PMID- 11615585 TI - Joseph Priestley: an addition to Hartley's observations. PMID- 11615586 TI - The Hurst collection of genetical letters. PMID- 11615587 TI - Walt Whitman on marriage. PMID- 11615588 TI - T. Willis' and Lower's physiology, with special reference to the theory of heart movement. PMID- 11615589 TI - A late medieval arbor scientiarum. PMID- 11615590 TI - Purkyne and Valentin on ciliary motion: an early investigation in morphological physiology. PMID- 11615591 TI - Darwin's debt to philosophy: an examination of the influence of the philosophical ideas of John F. W. Herschel and William Whewell on the development of Charles Darwin's theory of evolution. PMID- 11615592 TI - L.C. Dunn papers. PMID- 11615593 TI - Reasoning in scientific change: Charles Darwin, Hugo de Vries, and the discovery of segregation. PMID- 11615594 TI - Enrique IV and Gregorio Maranon. PMID- 11615595 TI - New evidence about Burton's melancholy? PMID- 11615596 TI - Drug therapy at the Massachusetts Leper Colony 1905-1921. PMID- 11615597 TI - The medieval herbal tradition of Macer Floridus. PMID- 11615598 TI - The physician's tale: Geoffrey Chaucer and Fray Juan Garcia de Castrojeriz. PMID- 11615599 TI - Food, laxatives and catharsis in Chaucer's "Nun's priest's tale". PMID- 11615600 TI - An unnoticed explanation of enzyme action: the view of G.J. Mulder (1843). PMID- 11615602 TI - Early terms for Elixir hitherto unrecognized in Greek alchemy. PMID- 11615601 TI - "Nature itself is all arcanum": the scientific outlook of John Adams. PMID- 11615603 TI - The German model of chemical education in America: Ira Remsen at Johns Hopkins (1876-1913). PMID- 11615604 TI - Dryden's cave of sleep and Garth's "Dispensary". PMID- 11615605 TI - The Thrales of Streatham Park. PMID- 11615606 TI - Chaucer's Troilus and the ruby. PMID- 11615608 TI - The portraits of Tobias Smollett. PMID- 11615607 TI - Les versions latines du "Regime" pseudohippocratique. PMID- 11615609 TI - Albrecht von Haller on academies and the advancement of science: the case of Gottingen. PMID- 11615610 TI - Relations between alchemy and poetics in the Renaissance and seventeenth century, with special glances at Donne and Milton. PMID- 11615611 TI - Arthur Dee and Johannes Banfi Hunyades: further information on their alchemical and professional activities. PMID- 11615612 TI - Dr William Brownrigg, F.R.S.: physician, chemist and country gentleman. PMID- 11615613 TI - Blood: a seventeenth-century perspective. PMID- 11615614 TI - Elizabethan psychology and Burton's Anatomy of melancholy. PMID- 11615615 TI - Berkeley, George. PMID- 11615616 TI - The Henrys of Manchester. Part 6. William Charles Henry: the magnesia factory. PMID- 11615617 TI - Alchemical imagery in John Donne's "A nocturnall upon S. Lucies Day". PMID- 11615618 TI - Anatomy of a fraud: Harry Price and the medium Rudi Schneider. PMID- 11615619 TI - A note on Thomas Graham, surgeon, author of botanical lectures delivered at the Royal Polytechnic Institution, London. PMID- 11615620 TI - An unpublished letter of Alexander Pope to Dr. Oliver. PMID- 11615621 TI - Ernest Harms. PMID- 11615622 TI - Dr. Thomas Beddoes and the establishment of his pneumatic institution: a tale of three presidents. PMID- 11615623 TI - Giovanni Battista Della Porta. ca. 1536-1615. Natural Magick...in twenty books...London:1658. PMID- 11615624 TI - Sir Winston Churchill. PMID- 11615625 TI - Herbert Spencer Jennings. PMID- 11615626 TI - Edward C. Kendall. PMID- 11615627 TI - Eugene Lindsay Opie. PMID- 11615628 TI - John Rodman Paul. PMID- 11615629 TI - Jack Schultz. PMID- 11615630 TI - Stanley Smith Stevens. PMID- 11615631 TI - The influence of Karl Ernst von Baer's embryology, 1828-1859: a reappraisal in light of Richard Owen's and William B. Carpenter's "palaeontological application of 'Von Baer's Law". PMID- 11615632 TI - Two Darwins: history versus criticism. PMID- 11615633 TI - Edmund B. Wilson as a preformationist: some reasons for his acceptance of the chromosome theory. PMID- 11615634 TI - Critical teleology: Immanuel Kant and Claude Bernard on the limitations of experimental biology. PMID- 11615635 TI - Darwin as a social evolutionist. PMID- 11615636 TI - The Darwin reading notebooks (1838-1860). PMID- 11615637 TI - Darwinism and the argument from design: suggestions for a reevaluation. PMID- 11615638 TI - Galen's criticism of Aristotle's conception theory. PMID- 11615639 TI - William Bateson and the promise of Mendelism. PMID- 11615640 TI - Charles Haskell Danforth. PMID- 11615641 TI - Howard Bishop Lewis. PMID- 11615642 TI - Edward Arthur Steinhaus. PMID- 11615643 TI - Chester Hamlin Werkman. PMID- 11615644 TI - Thomas Francis, Jr. PMID- 11615645 TI - La Mettrie: the robot and the automaton. PMID- 11615647 TI - Herbert McLean Evans. PMID- 11615646 TI - Swift on medical extremism. PMID- 11615648 TI - Elmer Verner McCollum. PMID- 11615649 TI - George Richards Minot. PMID- 11615650 TI - Carl Richard Moore. PMID- 11615651 TI - Astrology, magic, and optics: facets of John Dee's early natural philosophy. PMID- 11615652 TI - Jefferson, Rush, and the limits of philosophical friendship. PMID- 11615653 TI - Dr. Zuriel Waterman: an itinerant surgeon in the Revolutionary era. PMID- 11615655 TI - Evarts Ambrose Graham. PMID- 11615654 TI - Medicine, science, and moral philosophy: David Hartley's attempt at reconciliation. PMID- 11615656 TI - Georg von Bekesy. PMID- 11615657 TI - Francis Peyton Rous. PMID- 11615658 TI - Fuller Albright. PMID- 11615659 TI - Donald Dexter van Slyke. PMID- 11615660 TI - Carl John Wiggers. PMID- 11615661 TI - John Aubrey, F.R.S., John Lydall, and science at Commonwealth Oxford. PMID- 11615662 TI - Ernest Lyman Scott's work with insulin, a reappraisal. PMID- 11615663 TI - Reconstruction of an 1884 American pharmacy. PMID- 11615664 TI - The place of man in the development of Darwin's theory of transmutation. PMID- 11615665 TI - The origin of the Origin revisited. PMID- 11615666 TI - La medecine dans Homere, une bibliographie. PMID- 11615667 TI - Unveroffentlichte Briefe V.A. Subbotins an Max von Pettenkofer. PMID- 11615668 TI - [Sokichi Hashimoto (1763-1836), pioneer pharmacologist.] (Jpn). PMID- 11615669 TI - [Why did Descartes support Harvey's works?] (Jpn). PMID- 11615670 TI - Mendeleev and the scientific claims of spiritualism. PMID- 11615671 TI - Clarence Cook Little. PMID- 11615672 TI - Cyril Norman Hugh Long. PMID- 11615673 TI - Hans Thacher Clarke. PMID- 11615674 TI - Henry Clapp Sherman. PMID- 11615675 TI - Clarence Henry Graham. PMID- 11615676 TI - [Jitsuri and Jitsuyo in Rangaku -- The medical thought of Sugita Genpaku--] (Jpn). PMID- 11615677 TI - The development of the Blalock-Taussig operation and its results twenty years later. PMID- 11615678 TI - "Why not try the experiment?" The scientific education of Edward Jenner. PMID- 11615679 TI - Matthew Guthrie (1743-1807): an eighteenth-century gemmologist. PMID- 11615680 TI - Other men's shoulders. PMID- 11615681 TI - Catherine II, bubonic plaque, and the problem of industry in Moscow. PMID- 11615682 TI - The Gamgees--medical and veterinary. PMID- 11615683 TI - The management of science: the experience of Warren Weaver and the Rockefeller Foundation programme in molecular biology. PMID- 11615684 TI - Descartes, the sceptics, and the rejection of vitalism in seventeenth-century physiology. PMID- 11615685 TI - Hugo De Vries and Thomas Hunt Morgan: the mutation theory and the spirit of Darwinism. PMID- 11615686 TI - The Pasteur collection at UTMB Library. PMID- 11615687 TI - William Harvey. PMID- 11615688 TI - The A. H. Sturtevant papers. PMID- 11615689 TI - Ralph Cleland letters at Bloomington, Indiana. PMID- 11615690 TI - A fresh comparison of "The Idiot Boy" and "The Idiot". PMID- 11615691 TI - Joseph Priestley, "Aerial philosopher": metaphysics and methodology in Priestley's chemical thought, from 1772 to 1781, part I. PMID- 11615692 TI - Bernhard Tollens and his influence on research into carbohydrates in Russia. PMID- 11615693 TI - The inter-relations between social, biological, and medical thought, 1750-1850: Saint-Simon and Comte. PMID- 11615694 TI - Locating Dutrochet. PMID- 11615695 TI - Thomas Young's "Autobiographical sketch". PMID- 11615696 TI - Cos versus Cnidus and the historians: part I. PMID- 11615697 TI - Karl Pearson and statistics: the social origins of scientific innovation. PMID- 11615698 TI - Statistical theory and social interests: a case-study. PMID- 11615699 TI - The life and afterlife of Elmer J. McCurdy, a melodrama in two acts with a prologue by Theodore A. Reyman. PMID- 11615700 TI - Charles Bonnet's taxonomy and chain of being. PMID- 11615701 TI - Robert Fludd's "Declaratio brevis" to James I. PMID- 11615702 TI - Joseph Priestley, "Aerial philosopher": metaphysics and methodology in Priestley's chemical thought, from 1772 to 1781. Part II. PMID- 11615703 TI - The conflicting microscopic worlds of Berkeley's Three Dialogues. PMID- 11615704 TI - Ann Fothergill: the mistress of Harpur Street. PMID- 11615705 TI - Cadwallader Colden's attempt to advance natural philosophy beyond the eighteenth century mechanistic paradigm. PMID- 11615706 TI - Joseph Priestley, "Aerial philosopher": metaphysics and methodology in Priestley's chemical thought, from 1772 to 1781. Part III. PMID- 11615707 TI - James Hutton, Joseph Black and the chemical theory of heat. PMID- 11615708 TI - The discovery of saccharin: a centennial retrospect. PMID- 11615709 TI - John Hunter--the Scotsman in London. PMID- 11615710 TI - Hunter's contribution to the surgery of trauma. PMID- 11615711 TI - Detlev Wulf Bronk, 13 August 1897--17 November 1975. PMID- 11615712 TI - Julian Sorell Huxley, 22 June 1887--14 February 1975. PMID- 11615713 TI - Harry Raymond Ing, 31 July 1899--23 September 1974. PMID- 11615714 TI - Max Rudolf Lemberg, 19 October 1896--10 April 1975. PMID- 11615715 TI - Cyril Leslie Oakley, 20 June 1907--27 March 1975. PMID- 11615716 TI - Edgar Stedman, 12 July 1890--8 May 1975. PMID- 11615717 TI - Ivan de Burgh Daly, 14 April 1893--8 February 1974. PMID- 11615718 TI - Edward Charles Dodds, 13 October 1899--16 December 1973. PMID- 11615719 TI - Emmeline Jean Hanson, 14 November 1919--10 August 1973. PMID- 11615720 TI - Francis Gerald William Knowles, 9 March 1915--13 Jul 1974. PMID- 11615721 TI - Carl Hamilton Browning, 1881-1972. PMID- 11615722 TI - Frederick Charles Bawden, 1908-1972. PMID- 11615723 TI - Wilfrid Edward Le Gros Clark, 1895-1971. PMID- 11615724 TI - James Bertram Collip, 1892-1965. PMID- 11615725 TI - James Norman Davidson, 1911-1972. PMID- 11615726 TI - Paul Gordon Fildes, 1882-1971. PMID- 11615727 TI - Cyril Norman Hinshelwood, 1897-1967. PMID- 11615728 TI - Lionel Sharples Penrose, 1898-1972. PMID- 11615729 TI - Francis John Worsley Roughton, 1899-1972. PMID- 11615730 TI - William Robin Thompson, 1887-1972. PMID- 11615732 TI - Hamilton Hartridge, 7 May 1886--13 January 1976. PMID- 11615731 TI - Alexander Haddow, 18 January 1907--21 January 1976. PMID- 11615733 TI - Herbert Davenport Kay, 9 September 1893--24 November 1976. PMID- 11615734 TI - Montague Maizels, 30 September 1899--10 February 1976. PMID- 11615735 TI - Jacques Lucien Monod, 9 February 1910--31 May 1976. PMID- 11615736 TI - Philip Macdonald Sheppard, 27 July 1921--17 October 1976. PMID- 11615737 TI - Conrad Hal Waddington, 8 November 1905--26 September 1975. PMID- 11615738 TI - Theodosius Grigorievich Dobzhansky, 25 January 1900--18 December 1975. PMID- 11615739 TI - Lancelot Thomas Hogben, 9 December 1895--22 August 1975. PMID- 11615740 TI - Paul Karrer, 21 April 1889--18 June 1971. PMID- 11615741 TI - Richard Alan Morton, 22 September 1899--21 January 1977. PMID- 11615742 TI - Wilder Graves Penfield, 26 January 1891--5 April 1976. PMID- 11615743 TI - Archibald Vivian Hill, 26 September 1886--3 Jun 1977. PMID- 11615744 TI - Renaissance Latin Aristotle commentaries. (The first part of this inventory appeared in Stud Renaiss, 21:228-89, 1974). PMID- 11615745 TI - Renaissance Latin Aristotle Commentaries: authors N-Ph. PMID- 11615746 TI - Elements pour la constitution de l'experience en physiologie au XVIIIe siecle: 1752. PMID- 11615747 TI - The Ohm-Seebeck dispute, Hermann von Helmholtz, and the origins of physiological acoustics. PMID- 11615748 TI - Charles Robert Harington, 1897-1972. PMID- 11615749 TI - Geoffrey Wingfield Harris, 1913-1971. PMID- 11615750 TI - Leslie William Mapson, 1907-1970. PMID- 11615751 TI - John Boyd Orr, Baron Boyd Orr of Brechin Mearns, 1880-1971. PMID- 11615752 TI - Harold Raistrick, 1890-1971. PMID- 11615753 TI - David Alymer Scott, 1892-1971. PMID- 11615754 TI - Otto Heinrich Warburg, 1883-1970. PMID- 11615756 TI - Francis Albert Eley Crew, 1886-1973. PMID- 11615755 TI - Herbert McLean Evans, 1882-1971. PMID- 11615758 TI - Bernardo Alberto Houssay, 1887-1971. PMID- 11615757 TI - Edward Hindle, 1886-1973. PMID- 11615759 TI - Muriel Robertson, 1883-1973. PMID- 11615760 TI - Max Leonard Rosenheim, Baron Rosenheim of Camden, 1908-1972. PMID- 11615761 TI - Trevor Ian Shaw, 1928-1972. PMID- 11615762 TI - Arne Tiselius, 1902-1971. PMID- 11615763 TI - George Lindor Brown, 1903-1971. PMID- 11615764 TI - Francis Martin Rouse Walshe, 1885-1973. PMID- 11615765 TI - Some of Arthur Dee's associations before visiting Russia clarified, including two letters from Sir Theodore Mayerne. PMID- 11615766 TI - Fourcroy and the Journal de la Societe des Pharmaciens de Paris. PMID- 11615767 TI - J. Krizenecky papers in the Mendelianum (Brno, Czechoslovakia). PMID- 11615768 TI - Sources in the study of eugenics, No. 3. The papers of Harry Hamilton Laughlin. PMID- 11615769 TI - Francis Bacon and his medical utopia. PMID- 11615770 TI - Two ghost editions of Marsilio Ficino's De vita inanes esse figuras suspicor (op. 559). PMID- 11615771 TI - Rationalism and embryology: Caspar Friedrich Wolff's theory of epigenesis. PMID- 11615773 TI - The young Darwin. PMID- 11615774 TI - The Joseph Erlanger collection at Washington University School of Medicine, St. Louis. PMID- 11615775 TI - The Vesalian movement in sixteenth-century Spain. PMID- 11615776 TI - Was Aristotle's biology sexist? PMID- 11615777 TI - Between the Italian Renaissance and the French Enlightenment: Gabriel Naude as an editor. PMID- 11615778 TI - Malthus and the theology of scarcity. PMID- 11615779 TI - Humanists, scientists, and Pliny: changing approaches to a classical author. PMID- 11615780 TI - Chaucer's physician: an uncollected allusion 1611. PMID- 11615781 TI - A footnote to the publication of Peter Smith's Indian Doctor's Dispensatory (Cincinnati, 1813). PMID- 11615782 TI - A mediaeval compendium of Arabic medicine: Abu Sahl al-Masihi's "Book of the Hundred." PMID- 11615783 TI - Moll's fate: "Mother Midnight" and Moll Flanders. PMID- 11615784 TI - Book reviews, lectures, and marginal notes; three previously unknown sixteenth century contributors to pharmacy, medicine and botany: Ioannes Manardus, Franciscus Frigimelica, and Melchior Guilandinus. PMID- 11615785 TI - Eugenics movement in Japan; R. Ikeda and his "Yusei Undo (eugenics movement)." [Jpn]. PMID- 11615786 TI - "Mother Emancipator:" the meaning of Jane Addams' sickness and cure. PMID- 11615787 TI - Good bodies: Horace Mann and the physiology of morals. PMID- 11615788 TI - The society for the perpetuation of Gmelin: The Cavendish Society, 1846-1872. PMID- 11615789 TI - A decisive example of the influence of psychological doctrines in Islamic science and culture: some relationships between Ibn Sina's psychology, other branches of his thought, and Islamic teachings. PMID- 11615790 TI - Edgar Douglas Adrian, Baron Adrian of Cambridge, 30 November 1889 - 4 August 1977. PMID- 11615791 TI - John Alfred Valentine Butler, 14 February 1899 - 16 July 1977. PMID- 11615792 TI - Samuel Rickard Christophers, 27 November 1873 - 19 February 1978. PMID- 11615793 TI - James Craigie, 25 June 1899 - 26 August 1978. PMID- 11615794 TI - Pehr Victor Edman, 14 April 1916 - 19 March 1977. PMID- 11615795 TI - James Walter McLeod, 2 January 1887 - 11 March 1978. PMID- 11615796 TI - Some problematic features of Erik H. Erikson's psychohistory. PMID- 11615797 TI - Disciplined subjectivity and the psychohistorian: a critical look at the work of Erik H. Erikson. PMID- 11615798 TI - Erik H. Erikson's post-Freudianism. PMID- 11615799 TI - Revisiting Erikson's contributions to the psychology of religion. PMID- 11615800 TI - On teaching Erikson. PMID- 11615801 TI - The writings of Erik H. Erikson. PMID- 11615803 TI - William James's eyes: the thought behind the man. PMID- 11615802 TI - An interview with Leon Edel on the James Family. PMID- 11615805 TI - An exchange of letters between William and Alice James. PMID- 11615804 TI - Henry James's dream of the Louvre, "The Jolly Corner," and psychological interpretation. PMID- 11615806 TI - Notes on the theology of Henry James Sr. PMID- 11615807 TI - In search of Mary James. PMID- 11615808 TI - Dr. Weinstein's interpretation of Woodrow Wilson: some preliminary observations. PMID- 11615809 TI - The mind of Maurice Bardeche. PMID- 11615810 TI - Benjamin Nelson's contribution to psychosocial perspectives. PMID- 11615811 TI - The fatal illness of the antiquary William Burton (1609-57). PMID- 11615812 TI - Thomas Cogan on studying. PMID- 11615813 TI - Botanist Carl Theimer (1823--1870) in the cultural context of Brno during the period of Mendel's research. PMID- 11615814 TI - Locke's Tabula Rasa and Freud's "Mystic writing pad." PMID- 11615815 TI - Theodosius Dobzhansky Papers. PMID- 11615816 TI - The Henry Fairfield Osborn Papers at the American Museum of Natural History. PMID- 11615817 TI - 'Problems A': the solution to Wilfred Owen's 'The Imbecile.' PMID- 11615818 TI - Darwin, Wallace, and the origin of sexual dimorphism. PMID- 11615819 TI - Christian Wolff's prolegomena to empirical and rational psychology: translation and commentary. PMID- 11615820 TI - On Shakespeare's death, funeral, and burial. PMID- 11615821 TI - Death, dung, the devil, and worldly delights: a metaphysical conceit in Harington, Donne, and Herbert. PMID- 11615822 TI - Biographia Literaria and the language of science. PMID- 11615823 TI - Thomas Sherley's philosophical essay (1672): Helmontian mechanism as the basis of a new philosophy. PMID- 11615824 TI - Newton's illness of 1692-3. PMID- 11615825 TI - Some 'philosophical scribbles' attributed to Robert Hooke. PMID- 11615826 TI - Homerus Herbarius. PMID- 11615827 TI - A letter from Herman Boerhaave to Johan Philip Burggraaf jr. PMID- 11615828 TI - The instrument-collection of Peter Vink, a chapter in the development of the surgical profession in the Netherlands during the 18th century. PMID- 11615829 TI - Background to the reflex controversy: William Alison and the doctrine of sympathy before Hall. PMID- 11615830 TI - Theories to work by: rejected theories, reproduction, and Darwin's path to natural selection. PMID- 11615831 TI - Moorcroft's life in England; some new evidence. PMID- 11615832 TI - Griffith Evans (1835-1935) and his trypanosome. PMID- 11615833 TI - Professor Gamgee and the farmers. PMID- 11615834 TI - Hippocratic problems. PMID- 11615835 TI - Aristotle's de Motu Animalium. PMID- 11615836 TI - Aldous Huxley and the Sheldonian hypothesis. PMID- 11615837 TI - E. V. McCollum: "lamplighter" in public and professional understanding of nutrition. PMID- 11615838 TI - Henryson's "Sum Practysis of Medecyne". PMID- 11615839 TI - Feriis Festisque Diebus: the salutatory oration of Elisha Cooke, Jr., 7 July 1697. PMID- 11615840 TI - Childhood and death: a reading of John Skelton's Phillip Sparrow. PMID- 11615841 TI - Apotheosis to ignominy: the martyrdom of Marshal Petain. PMID- 11615842 TI - Politics and emotion in the thought of John Stuart Mill. PMID- 11615843 TI - Herbert Hoover and David Copperfield: a tale of two childhoods. PMID- 11615844 TI - Getting back---and down---to basics. PMID- 11615845 TI - Face-painting scenes in Ben Jonson's plays. PMID- 11615846 TI - Morelli, Freud and Sherlock Holmes: clues and scientific method. PMID- 11615847 TI - Is there a doctor in the house? or for the house? PMID- 11615848 TI - God and natural selection: the Darwinian idea of design. PMID- 11615849 TI - Darwin and the political economists: divergence of character. PMID- 11615850 TI - J. J. Gibson and the ecological approach to perception. PMID- 11615851 TI - Schriftauslegung und Schriftverstandnis bei Paracelsus. PMID- 11615852 TI - Paracelsian magic and theology; a case study of the Matthew commentaries. PMID- 11615853 TI - Nature et philosophie. PMID- 11615854 TI - Arzneirezepte von Paracelsus. PMID- 11615855 TI - Paracelsus-Lexikographie in vier Jahrhunderten. PMID- 11615856 TI - Hohenheims Bergsuchtmonographie. PMID- 11615857 TI - Ulrich Gyger, sin diener. Versuch einer biographischen Rekonstruktion. PMID- 11615858 TI - The Paracelsian Elias Artista and the alchemical tradition. PMID- 11615859 TI - The anthropological roots of Paracelsus' psychiatry. PMID- 11615860 TI - Die Schreibart des Paracelsus im Urteil deutscher Fachschriftsteller des 16. und 17. Jarhunderts. PMID- 11615861 TI - "My life"; an important Ellis manuscript. PMID- 11615862 TI - Was it yellow fever? PMID- 11615863 TI - The Paracelsians in eighteenth century France: a Renaissance tradition in the age of the Enlightenment. PMID- 11615864 TI - Aristotle on the function of sense perception. PMID- 11615865 TI - Harvard's first science professor: a sketch of Isaac Greenwood's life and work. PMID- 11615866 TI - Dr. Thomas Beddoes at Oxford: radical politics in 1788-1793 and the fate of the Regius Chair in Chemistry. PMID- 11615867 TI - Wilhelm Weinberg's contribution to quantitative genetics. PMID- 11615868 TI - The first report of the harvesting of Asafetida in Iran. PMID- 11615869 TI - William Bateson's pilgrimages to Brno. Cesty Williama Batesona do Brna. PMID- 11615870 TI - Christiaan Huygens's contribution to the development of a calculus of probabilities. PMID- 11615871 TI - Shelley, Hawthorne, and Wells: images of medicine in early science fiction. PMID- 11615872 TI - The library of Gay-Lussac. PMID- 11615873 TI - Wedgwood's ceramic wares for chemical use, production and supply from 1779-1794. PMID- 11615874 TI - The Carl Correns papers. PMID- 11615875 TI - Thomas Hunt Morgan papers at the American Philosophical Society. PMID- 11615876 TI - Early problems in professionalizing scientific research: Nehemiah Grew (1641 1712) and the Royal Society with an unpublished letter to Henry Oldenburg. PMID- 11615877 TI - "The other" John Hunter, M.D., F.R.S. (1754-1809): his contributions to the medical literature, and to the introduction of animal experiments into infectious disease research. PMID- 11615878 TI - Robert Angus Smith, F.R.S., and 'Chemical climatology'. PMID- 11615879 TI - The Galveston smallpox quarantine camp in 1899. PMID- 11615880 TI - Voltaire's relation to the discipline of medicine. PMID- 11615881 TI - The Edward Lawrie Tatum papers. PMID- 11615882 TI - Contradicting the doctor: Billy Hancock and the problem of baloma. PMID- 11615883 TI - Bibliography of the publications of George Urdang on his birth centenary. PMID- 11615884 TI - The John Jacob Abel papers--primary sources for the history of American pharmacology. PMID- 11615885 TI - James Bell Heyl, Bermuda's pharmacist-photographer. PMID- 11615886 TI - Peoria's pioneer druggists, the Farrells, and Farrell's Arabian liniment. PMID- 11615887 TI - Maupertuis and the eighteenth-century critique of preexistence. PMID- 11615888 TI - The J. H. B. Archive report; the Edward Lawrie Tatum papers at the Rockefeller University Archives. PMID- 11615889 TI - Evolution and the problem of mind: part I. Herbert Spencer. PMID- 11615890 TI - The digestive and "circulatory" systems in Aristotle's biology. PMID- 11615891 TI - Honoring the founder in his country: conception and struggle for Canada's Memorial College. PMID- 11615892 TI - A William James renaissance: four essays by young scholars. PMID- 11615893 TI - "The worst kind of melancholy": William James in 1869. PMID- 11615894 TI - The personal equation in science: William James's psychological and moral uses of Darwinian theory. PMID- 11615895 TI - Making the world: William James and the life of the mind. PMID- 11615896 TI - William James on psychopathology: the 1896 Lowell lectures on "Exceptional mental states". PMID- 11615897 TI - Two refugee chemists in the United States, 1794: how we see them. PMID- 11615898 TI - Erich Lindemann: the humanist and the era of community mental health. PMID- 11615899 TI - Darwin's conversion: the Beagle voyage and its aftermath. PMID- 11615900 TI - The dinosaur connection: a reinterpretation of T. H. Huxley's evolutionary view. PMID- 11615901 TI - New light on The foundations of the origin of species: A reconstruction of the archival record. PMID- 11615902 TI - Why Lamarck did not discover the principle of natural selection. PMID- 11615903 TI - Sigmund Freud, his Jewishness, and scientific method: the seen and the unseen as evidence. PMID- 11615904 TI - Bergson and Jung. PMID- 11615905 TI - An exchange of letters between William and Alice James. PMID- 11615906 TI - The use and abuse of illness in the James family circle: a view of neurasthenia as a social phenomenon. PMID- 11615907 TI - Thomas Vaughan as an interpreter of Agrippa von Nettesheim. PMID- 11615908 TI - A reluctant catalyst: Joseph Black and the Edinburgh reception of Lavoisier's chemistry. PMID- 11615909 TI - Maria the Jewess--founding mother of alchemy. PMID- 11615910 TI - [Goethe Link. Includes text of two of his talks]. PMID- 11615911 TI - [Willis Dew Gatch. Includes reprints of three of his articles]. PMID- 11615912 TI - An epoch of medical education. PMID- 11615913 TI - Harvey Washington Wiley; a famous Hoosier and "The father of pure food". PMID- 11615914 TI - The Lindsay-Stipp debate. PMID- 11615915 TI - [John S. Bobbs]. PMID- 11615916 TI - Ernst Mach und das Mechanismusproblem in der Biologie. PMID- 11615917 TI - Die Mitteilung des Lebensfeuers. Zum therapeutischen Konzept von Franz Anton Mesmer (1734-1815). PMID- 11615918 TI - Johann Christoph Gatterers 'Linnaeismus graphicus'. Klassifikation und Universalismus im 18. Jahrhundert. PMID- 11615920 TI - A concordance of abbreviations used in references to reviews in botanical bibliographies by Cobres (1782), Bohmer (1787), and Militz (1829). PMID- 11615919 TI - The medical activities in eighteenth century Ethiopia of James Bruce the explorer. PMID- 11615921 TI - The date of the Linnaean index in John Martyn's Historia plantarum rariorum. PMID- 11615922 TI - "One bold incision": Dr. William A. Lindsay's radical cure. PMID- 11615923 TI - Dr. William A. Lindsay, innovator, physician, enterpreneur. PMID- 11615924 TI - Surgery in early nineteenth century Indiana. PMID- 11615925 TI - Women and medicine in early nineteenth century Indiana. PMID- 11615927 TI - Edwin Walker, M.D., Evansville, Indiana. PMID- 11615926 TI - Charles Darwin and group selection. PMID- 11615928 TI - One hundred years medicine: Indianapolis, 1820-1920. PMID- 11615929 TI - A preliminary examination of John Wesley's "Primitive physick". PMID- 11615930 TI - William Bateson's rejection and eventual acceptance of chromosome theory. PMID- 11615931 TI - 'That impudent fellow Hill'. PMID- 11615932 TI - Sigmund Freud, John Hughlings Jackson, and speech. PMID- 11615933 TI - Theological voluntarism and biological analogies in Newton's physical thought. PMID- 11615934 TI - T. Schwann's three preliminary articles on "Cell theory". PMID- 11615935 TI - Whewell and Mill on the relation between philosophy of science and history of science. PMID- 11615936 TI - Jean Filliozat (1906-1982). PMID- 11615937 TI - Photography, advertising, and the history of medicine: notes on the medico historical art of Lejaren a Hiller. PMID- 11615938 TI - Francis Galton's African ethnography and its role in the development of his psychology. PMID- 11615939 TI - Sir William B. O'Shaughnessy, pioneer chemical educator in India. PMID- 11615940 TI - The mystery of Stephen H. Emmens: successful alchemist or ingenious swindler?. PMID- 11615941 TI - Lavoisier's memoirs on the nature of water and their place in the chemical revolution. PMID- 11615942 TI - Priestley in London. PMID- 11615943 TI - William Dobinson Halliburton, F.R.S. (1860-1931) - pioneer of British biochemistry? PMID- 11615944 TI - 'No ordinary case of a village apothecary': the doctor as hero in Harriet Martineaus's Deerbrook. PMID- 11615946 TI - Louisa May Alcott: a study in persona and idealization. PMID- 11615945 TI - Kant and the stoics on suicide. PMID- 11615947 TI - Helmont, Glisson, and the doctrine of the common reservoir in the seventeenth century revolution in physiology. PMID- 11615948 TI - An unnoticed copy of Hippocrates' prognosticon. PMID- 11615949 TI - The Alfred E. Mirsky papers at the Rockefeller University Archives. PMID- 11615950 TI - "William Keith Brooks (1848-1908): primary resource material". PMID- 11615951 TI - Gavin De Beer and the Neo-Lamarckians. PMID- 11615952 TI - George Gaylord Simpson and Lamarck. PMID- 11615953 TI - George Henslow: true Darwinist. PMID- 11615954 TI - Christian Gottfried Ehrenberg: Founder of micropaleontology. PMID- 11615955 TI - The historical work of William Dosite Postell, Sr. PMID- 11615956 TI - In quest of the psychohistorical Lincoln. PMID- 11615957 TI - Un fragment d'un manuscrit disparu d'Oribase, C. L. A. 116 (Vatican, Urb. lat. 293, ff. 95-96, VIIIe siecle). PMID- 11615958 TI - Mendel's rejection of the concept of blending inheritance. PMID- 11615959 TI - Christiaan Huygens' theory of research. PMID- 11615960 TI - D. J. A. McBride, MRCVS, 1843?-1889, itinerant professor extraordinary. PMID- 11615961 TI - The science of anthropology: an essay on the very old Marx. PMID- 11615962 TI - The chronology of Robert Grosseteste's writings on nature and natural philosophy. PMID- 11615963 TI - Banks papers in the Kent Archives Offices, including notebooks by Joseph Banks and Francis Bauer. PMID- 11615964 TI - Derek J. de Solla Price (1922-1983). PMID- 11615965 TI - The Royal Society in Thomas Henry Huxley's time. PMID- 11615966 TI - The life and works of Sir Alexander Crichton, F.R.S. (1763-1856): a Scottish physician to the Imperial Russian Court. PMID- 11615967 TI - Dr. Thomas Beddoes (1750-1808): science and medicine in politics and society. PMID- 11615968 TI - The caloric theory of S. L. Metcalfe. PMID- 11615970 TI - La double nature de l'immunologie: histoire de la transplantation renale. PMID- 11615969 TI - Published primary sources to Gregor Mendel's biography. Mendelianum of the Moravian Museum, Brno. PMID- 11615971 TI - Schrodinger et la biologie moleculaire. PMID- 11615972 TI - "I have the itch of botany, of chemistry, of mathematics ... strong upon me": the science of Benjamin Henry Latrobe. PMID- 11615973 TI - Joseph Priestley, scientist, philosopher and divine. PMID- 11615974 TI - John Calvin's anxiety. PMID- 11615975 TI - E. W. MacBride's Lamarckian eugenics and its implications for the social construction of scientific knowledge. PMID- 11615977 TI - An alchemical ghost: the Rasaratnakara by Nagarjuna. PMID- 11615976 TI - Richard Knight (1768-1844): a forgotten chemist and apparatus designer. PMID- 11615978 TI - Ernst Heinrich Haeckel as an intermediary in the transmutation of an idea. PMID- 11615979 TI - Fresh light on John Dalton. PMID- 11615980 TI - Sir William Brooke O'Shaughnessy, F.R.S. (1809-1889), Anglo-Indian forensic chemist. PMID- 11615981 TI - Sherrington and industrial fatigue. PMID- 11615982 TI - Venel, Lavoisier, Fourcroy, Cabanis and the idea of scientific revolution: the French political context and the general patterns of conceptualization of scientific change. PMID- 11615983 TI - Luther and the family. PMID- 11615984 TI - [Betrachtungen uber die fruhesten physiologischen Arbeiten Hermann von Helmholtz, die zu seiner Entdeckung des Gesetzes von der Erhaltung der Energie fuhren] (Jpn). PMID- 11615985 TI - The dreams of Alexander the Great. PMID- 11615986 TI - The establishment of Wilhelm Wundt's Leipzig laboratory. PMID- 11615987 TI - Freud and Lindner on pleasure sucking. PMID- 11615988 TI - Wundt, Titchener e la psicologia americana. PMID- 11615989 TI - Teoria e politica nella psicosociologia di E. Mayo. PMID- 11615990 TI - Lacan: un ritorno a Freud? PMID- 11615991 TI - Koffka e la psicologia sovietica. PMID- 11615993 TI - The introduction of the Natural System of classification of plants to nineteenth century American students. PMID- 11615992 TI - Robert Erskine--Scottish pioneer of Russian natural history. PMID- 11615994 TI - The emblematic title-page to Stirpium Adversaria nova by Petro Pena and Mathias de L'Obel (1570). PMID- 11615995 TI - The life, work, and geological collections of Richard Bright, M.D. (1789-1858); with a note on the collections of other members of the family. PMID- 11615996 TI - Marginalia to Andrea Cesalpino's work on botany. PMID- 11615997 TI - The date of birth of Sir John Hill (1714-1775). PMID- 11615998 TI - "Rhubarb" Mounsey and the Surinam toad--a Scottish physician--naturalist in Russia. PMID- 11615999 TI - L'oeuvre scientifique de Jacques Monod. PMID- 11616000 TI - G. Mendel and the foundation of genetics. PMID- 11616001 TI - The care of the insane in Texas. PMID- 11616002 TI - John Charnley: 29 August 1911-5 August 1982. PMID- 11616003 TI - Hans Gruneberg: 26 May 1907-23 October 1982. PMID- 11616004 TI - Charles Skinner Hallpike: 19 July 1900-26 September 1979. PMID- 11616005 TI - Hans Adolf Krebs: 25 August 1900-22 November 1981. PMID- 11616006 TI - Joshua Harold Burn: 6 March 1892-13 July 1981. PMID- 11616007 TI - Alfred Spinks: 25 February 1917-11 February 1982. PMID- 11616008 TI - Colin Munro MacLeod: January 28, 1909-February 11, 1972. PMID- 11616009 TI - Samuel Marion McElvain: December 9, 1897-April 11, 1973. PMID- 11616010 TI - Walter Joseph Meek: August 15, 1878-February 15, 1963. PMID- 11616011 TI - William Hay Taliaferro: February 10, 1895-December 21, 1973. PMID- 11616012 TI - Antedatings and additions for OED from the vertuose boke of Distyllacyon of the waters of all maner of herbes (1527). PMID- 11616013 TI - Isaac Beeckman and his diary-notes on William Harvey's theory on blood circulation (1633-1634). PMID- 11616014 TI - Organic theories of art: the importance of embryology. PMID- 11616015 TI - Quelques considerations sur les etudes de Spallanzani a propos de la respiration, par rapport a ses manuscrits inedits. PMID- 11616016 TI - Reading Gauguin. Experiments in interpretation. PMID- 11616017 TI - Medical incunabula. PMID- 11616018 TI - Alfred Nobel and his legacy to medicine. PMID- 11616019 TI - Paul Ehrlich and the introduction of Salvarsan. PMID- 11616020 TI - Microscopes. PMID- 11616021 TI - The yellow fever story. PMID- 11616022 TI - Sir Jonathan Hutchinson, 1828-1913. PMID- 11616023 TI - Doctor Arthur Conan Doyle's patients in fact and fiction. PMID- 11616024 TI - Presidents' health and history. PMID- 11616025 TI - The private Benjamin Rush. PMID- 11616026 TI - Aging in Western medicine and iconography. PMID- 11616027 TI - When Americans called for Dr. Kildare: images of physicians and nurses in the Dr. Kildare and Dr. Gillespie movies, 1937-1947. PMID- 11616028 TI - The discovery and early development of penicillin. PMID- 11616029 TI - Collecting rare medical books: a dealer's perspective. PMID- 11616030 TI - Disraeli, Freud, and Jewish conspiracy theories. PMID- 11616031 TI - Imputing intentionality: Popper, demarcation and Darwin, Freud and Marx. PMID- 11616032 TI - John Caius and the Eton Galen: medical philology in the Renaissance. PMID- 11616033 TI - Bemerkungen zum Hippokratischen Eid. PMID- 11616034 TI - Ein weiteres spatantikes Zeugnis fur die Zahnzahl der Eunuchen. PMID- 11616035 TI - Die traditionelle chinesische Medizin im 20. Jahrhundert. Uberlebenskampf und Legitimationsstrategien. PMID- 11616036 TI - "Die Verlangung zu seelischen Storungen." Ferdinand Albert Kehrer und die heutige Psychiatrie. PMID- 11616037 TI - Eine unveroffentlichte Notiz Cajals zu den Cajalschen Zellen von Retzius. PMID- 11616038 TI - Karl Baas, Gesundheitspflege im mittelalterlichen Sudwestdeutschland. PMID- 11616039 TI - C. Koizumi: as a promoter of the Ministry of Health and Welfare and an originator of the BCW research program. PMID- 11616040 TI - James J. Gibson's revolution in perceptual psychology: a case study of the transformation of scientific ideas. PMID- 11616041 TI - Reid's direct approach to perception. PMID- 11616042 TI - William Osler's historiography: a rhetorical analysis. PMID- 11616043 TI - [Not Available]. PMID- 11616044 TI - [Not Available]. PMID- 11616045 TI - [Not Available]. PMID- 11616046 TI - [Not Available]. PMID- 11616047 TI - [Not Available]. PMID- 11616048 TI - [Not Available]. PMID- 11616049 TI - [Not Available]. PMID- 11616050 TI - [Not Available]. PMID- 11616051 TI - [Not Available]. PMID- 11616052 TI - [Not Available]. PMID- 11616053 TI - [Not Available]. PMID- 11616054 TI - Dr. Lydgate: the literary characterization of the doctor at a historical turning point. PMID- 11616055 TI - [Not Available]. PMID- 11616056 TI - [Not Available]. PMID- 11616057 TI - [Not Available]. PMID- 11616058 TI - [Not Available]. PMID- 11616059 TI - Mead, Bateson, and 'Hitler's peculiar psychological makeup'--applying anthropology in the era of appeasement. PMID- 11616060 TI - On creativity of eye and ear: a commentary on the career of T. W. Engelmann. PMID- 11616061 TI - An interpretation of the Fama Fraternitatis with respect to Dee's Monas Hieroglyphica. PMID- 11616062 TI - Charles Loudon Bloxam--a Victorian university and military academy chemistry teacher. PMID- 11616063 TI - The British Association Committee on Chemical Symbols 1834: Edward Turner's letter to British chemists and a reply by William Prout. PMID- 11616064 TI - [Medicine in the Azuchi-Momoyama era as seen in the Japanese-Portuguese Dictionary (I) medical instruments] (Jpn). PMID- 11616065 TI - [Erwin Baelz and typhus] (Jpn). PMID- 11616066 TI - [Hans Gierke and Joseph Disse; foreign teachers of anatomy at Tokyo University early in the Meiji Era (part I)] (Jpn). PMID- 11616067 TI - [The Dutch doctors who worked in Japan around the Meiji Restoration (1857-1894). Introduction: the Bauduin clan] (Jpn). PMID- 11616068 TI - [Amputations and prosthesis in the Russo-Japanese War, and an artificial arm which was designed by General Nogi] (Jpn). PMID- 11616069 TI - [On "so"] (Jpn). PMID- 11616070 TI - [Cesarean section during the Meiji period in Hokkaido] (Jpn). PMID- 11616071 TI - [A medico-historical study on unearthed remains in ancient capitals of Japan] (Jpn). PMID- 11616072 TI - [Motoyasu Taki and his "Yezo-chi Ishitsu ko"] (Jpn). PMID- 11616073 TI - [The date of birth of Dr. Antonius Franciscus Bauduin] (Jpn). PMID- 11616074 TI - Two legacies of the later Alexandrian school: the preliminary questions in commentaries; the theory/practice division of medicine. PMID- 11616075 TI - Chemical fallout: Rachel Carson's Silent Spring, radioactive fallout and the environmental movement. PMID- 11616076 TI - The Norwich Quakers: some links with pharmacy and medicine. PMID- 11616077 TI - No better float through posterity. PMID- 11616078 TI - A note concerning 'Dr.' Bateman and his drops PMID- 11616079 TI - Robert Keith Cannan: April 18, 1894-May 24, 1971. PMID- 11616080 TI - Theodosius Dobzhansky: January 25, 1900-December 18, 1975. PMID- 11616081 TI - Edwin Broun Fred: March 22, 1887-January 16, 1981. PMID- 11616082 TI - Edwin Bennett Astwood: December 29, 1909-February 17, 1976. PMID- 11616084 TI - Philip Handler: August 13, 1917 - December 29, 1981. PMID- 11616085 TI - Walter Richard Miles: March 29, 1885-May 15, 1978. PMID- 11616086 TI - George Holman Bishop: June 27, 1889-October 11, 1973. PMID- 11616087 TI - Hubert Bradford Vickery: February 28, 1893-September 27, 1978. PMID- 11616088 TI - Abraham White: March 8, 1908-February 14, 1980. PMID- 11616089 TI - The Julian Sorell Huxley Papers, Rice University Library, Houston, Texas. PMID- 11616090 TI - On new book of anatomy of horse (Kaiba Shinsho) by Tosui Kikuchi in Japan. PMID- 11616091 TI - Perenc as historian of veterinary science in Poland. PMID- 11616092 TI - [Not Available]. PMID- 11616093 TI - Emblems in the Anatomy of Melancholy. PMID- 11616094 TI - The Leeuwenhoekiana of Clifford Dobell (1886-1949). PMID- 11616095 TI - Medicine in the shadow of the Principia. PMID- 11616096 TI - Reminiscences about Sir John McFadyean and Tom Hare. PMID- 11616097 TI - New evidence for Dr. Arbuthnot's authorship of "The rabbit-man-midwife." PMID- 11616098 TI - The 1699 diary of Gershom Bulkeley of Wethersfield, Connecticut. PMID- 11616099 TI - Alchemy and the world of science: an intellectual biography of Frank Sherwood Taylor. PMID- 11616101 TI - Ibn Sina as a scientist. PMID- 11616100 TI - The life and teachings of Ibn Sina. PMID- 11616102 TI - Ibn Sina and Indian science. PMID- 11616103 TI - De morbo gallico cum aliis: another incunabular edition of Gaspar Torrella's Tractatus cum consiliis contra pudendagram seu morbum gallicum (1497). PMID- 11616104 TI - A source for Peacock's satire of spiritualism in Gryll Grange. PMID- 11616105 TI - J. A. Froude, the Good Templars, and drink. PMID- 11616107 TI - [Sokei-en, a country place of medical doctor Murais, Higo]. PMID- 11616106 TI - [The pharmaceutical education in the Chugoku region in the Meiji era] (Jpn). PMID- 11616108 TI - [A consideration on the imports of Chinese crude drugs of China-grown for general use in Meiji era] (Jpn). PMID- 11616109 TI - [Comparison between the Royal Dutch medical law (1865) and "the law of state medical supervision and pharmaceutical practicing in Holland" stored in the Yamazaki Library (II)] (Jpn). PMID- 11616110 TI - [About the travel diary of Yoshinari Taguchi, who looked for the methods of the cultivation for panax ginseng in Edo era] (Jpn). PMID- 11616111 TI - Franz Bergel: 13 February 1900-1 January 1987. PMID- 11616112 TI - John Leonard Jinks: 21 October 1929-6 June 1987. PMID- 11616113 TI - Hermann Lehmann: 8 July 1910-13 July 1985. PMID- 11616114 TI - Joseph Stanley Mitchell: 22 July 1909-22 February 1987. PMID- 11616115 TI - John Guest Phillips: 13 June 1933-14 March 1987. PMID- 11616116 TI - Henry Edward Shortt: 15 April 1887-9 November 1987. PMID- 11616117 TI - Herbert Williams Smith: 3 May 1919-16 June 1987. PMID- 11616118 TI - Walter Stanley Stiles: 15 June 1901-15 December 1985. PMID- 11616119 TI - Graham Selby Wilson: 10 September 1895-5 April 1987. PMID- 11616120 TI - Malcolm Dixon: 18 April 1899-7 December 1985. PMID- 11616121 TI - Grand illusions. PMID- 11616122 TI - Mona Edgecombe Going. PMID- 11616123 TI - Standards, guidelines and so on ... PMID- 11616124 TI - The psychology of reading: an essay in honour of Mona Going. PMID- 11616125 TI - The Sheila Moore Award: twenty-five years on. PMID- 11616126 TI - Sir Henry Marsh, Bart (1790-1860). PMID- 11616127 TI - Avoiding the subject: a Foucaultian itinerary. PMID- 11616128 TI - John Boswell: part II. PMID- 11616129 TI - A Treatise on poisons. PMID- 11616131 TI - The memoirs of Dame Elizabeth Cockayne. PMID- 11616133 TI - Highlights of early medical research in South Africa. PMID- 11616132 TI - Special issue: The Menninger School of Psychiatry. PMID- 11616134 TI - Risus sardonicus. PMID- 11616135 TI - Leander Starr Jameson: as others saw him and as he saw the medical profession. PMID- 11616136 TI - Percival Willughby, "obstetrician", and obstetrics in seventeenth century England. PMID- 11616137 TI - Kenneth Bryan Raper: July 11, 1908-January 15, 1987. PMID- 11616138 TI - Joseph Hall Bodine: September 19, 1895-July 23, 1954. PMID- 11616139 TI - George Gaylord Simpson: June 16, 1902-October 6, 1984. PMID- 11616140 TI - Owen Harding Wangensteen: September 21, 1898-January 13, 1981. PMID- 11616141 TI - John Franklin Enders: February 10, 1897-September 8, 1985. PMID- 11616142 TI - Selig Hecht: February 8, 1892-September 18, 1947. PMID- 11616143 TI - Popular medical guides and the study of women's history. PMID- 11616144 TI - Two German translations of Benjamin Rush. PMID- 11616145 TI - Rene Jules Dubos: February 20, 1901-February 20, 1982. PMID- 11616146 TI - Arie Jan Haagen-Smit: December 22, 1900-March 18, 1977. PMID- 11616147 TI - Harry Frederick Harlow: October 31, 1905-December 6, 1981. PMID- 11616148 TI - Charles Heidelberger: December 23, 1920-January 18, 1983. PMID- 11616149 TI - Percival Bailey: May 9, 1892-August 10, 1973. PMID- 11616151 TI - David Nachmansohn: March 17, 1899-November 2, 1983. PMID- 11616150 TI - Moses Kunitz: December 19, 1887-April 20, 1978. PMID- 11616152 TI - Dickinson Woodruff Richards: October 30, 1895-February 23, 1973. PMID- 11616153 TI - Eric Glendinning Ball: July 12, 1904-September 4, 1979. PMID- 11616154 TI - William Christopher Stadie: June 15, 1886-September 12, 1959. PMID- 11616155 TI - Gertrude Mary Cox: January 13, 1900-October 17, 1978. PMID- 11616156 TI - Conrad Arnold Elvehjem: May 27, 1901-July 27, 1962. PMID- 11616157 TI - Gottfried Samuel Fraenkel: April 23, 1901-October 26, 1984. PMID- 11616158 TI - Haldan Keffer Hartline: December 22, 1903-March 18, 1983. PMID- 11616159 TI - Manfred Martin Mayer: June 15, 1916-September 18, 1984. PMID- 11616160 TI - George Wells Beadle: October 22, 1903-June 9, 1989. PMID- 11616161 TI - Walsh McDermott: October 14, 1909-October 17, 1981. PMID- 11616162 TI - Frederic C. Bartter: September 10, 1914-May 5, 1983. PMID- 11616163 TI - Theophilus Shickel Painter: August 22, 1889-October 5, 1969. PMID- 11616164 TI - Edward Lawrie Tatum: December 14, 1909-November 7, 1975. PMID- 11616165 TI - Cornelis Bernardus van Niel: November 4, 1897-March 10, 1985. PMID- 11616166 TI - Maxwell Myer Wintrobe: October 27, 1901-December 9, 1986. PMID- 11616167 TI - Solomon A. Berson: April 22, 1918-April 11, 1972. PMID- 11616169 TI - "To know, to fly, to conjure": situating Baconian science at the juncture of early modern modes of reading. PMID- 11616168 TI - Proceedings of the workshop: Jan Evangelista Purkyne and the origin of the cell theory, Mikulov, Sept. 1-3, 1987. Contributions by D. von Engelhardt, J. Louzil, J. Sekerak, J. Sajner, J. Jakrlova, F. Di Trocchio, V. J. Novak, E. Krausse, R. J. Wood, J. Janko, J. Obermajer, A. Svoboda, J. Farley, S. Nakazawa, N. Priestland, J. Siegelova, S. PMID- 11616170 TI - William Harvey and art misplaced. PMID- 11616171 TI - 'Out of sight, out of mind?': the Daniel Turner-James Blondel dispute over the power of the maternal imagination. PMID- 11616173 TI - Ivan Pavlov on Communist dogmatism and the autonomy of science in the Soviet Union in the early 1920s. PMID- 11616172 TI - True to their natures: Sir Joshua Reynolds and Dr William Hunter at the Royal Academy of Arts. PMID- 11616174 TI - Robert Courrier: 6 October 1895-14 March 1986. PMID- 11616175 TI - John Herbert Humphrey: 16 December 1915-25 December 1987. PMID- 11616177 TI - Alan Robertson: 21 February 1920-25 April 1989. PMID- 11616176 TI - Juda Hirsch Quastel: 2 October 1899-15 October 1987. PMID- 11616178 TI - Francis Leslie Rose: 27 June 1909-3 March 1988. PMID- 11616179 TI - Sewall Wright: 21 December 1889-3 March 1988. PMID- 11616180 TI - Frank George Young: 25 March 1908-20 September 1988. PMID- 11616181 TI - Jean Brachet: 19 March 1909-10 August 1988. PMID- 11616182 TI - Mythology as code: Lapo de Castiglionchio's view of homosexuality and materialism at the Curia. PMID- 11616183 TI - The razor king. PMID- 11616184 TI - Regulating what we eat: Mary Engle Pennington and the Food Research Laboratory. In Marcus AI, Lowitt R, ed: The United States Department of Agriculture in historical perspective. PMID- 11616185 TI - Forbes in Hibernia: the narrative of a Scottish physician's visit to Ireland in 1852. PMID- 11616186 TI - Charles Lucas' letter (1736) to Sir Hans Sloane about the natural history of The Burren, County Clare. PMID- 11616187 TI - Joseph J. Spengler (November 19, 1902-January 2, 1991). PMID- 11616188 TI - Apollo mathematicus: a story of resistance to quantification in the seventeenth century. PMID- 11616189 TI - Burrhus Frederic Skinner (March 20, 1904-August 18, 1990). PMID- 11616190 TI - The rise and fall of Bruno Bettelheim. PMID- 11616191 TI - Through a Kohutian lens: William James and Josiah Royce. PMID- 11616192 TI - Bombshell in Beltsville: the USDA and the challenge of "Silent spring." PMID- 11616193 TI - Foucault's clinic. PMID- 11616194 TI - Does Williams' do the right thing? A disagreement between female and male medical students over "The use of force." PMID- 11616195 TI - The mishaps of peripheral science: the life and work of Manoel Joaquim Henriques de Paiva, Luso-Brazilian chemist and physician of the late eighteenth century. PMID- 11616196 TI - [Not Available]. PMID- 11616197 TI - [Not Available]. PMID- 11616198 TI - [Not Available]. PMID- 11616199 TI - [Not Available]. PMID- 11616200 TI - [Not Available]. PMID- 11616201 TI - [Not Available]. PMID- 11616202 TI - Race and class in Fritz Lenz's eugenics. PMID- 11616203 TI - [Not Available]. PMID- 11616204 TI - [Not Available]. PMID- 11616205 TI - [Not Available]. PMID- 11616206 TI - Edwin Chadwick and the engineers, 1842-1854: systems and antisystems in the pipe and-brick sewers war. PMID- 11616207 TI - The controversy between John H. Northrop and Max Delbruck on the formation of bacteriophage: bacterial synthesis or autonomous multiplication? PMID- 11616208 TI - Herman Boerhaave and John Clerk of Penicuik: friendship and musical collaboration. PMID- 11616209 TI - Medicine and art: diagnosis and medical treatment. PMID- 11616210 TI - David M. Moir: cholera papers. PMID- 11616211 TI - The price of the pox in 1527: Johannes Sinapius and the guaiac cure. PMID- 11616212 TI - Georgius Agricola as humanist. PMID- 11616213 TI - Would our physician forebear Sir William Osler have liked a jazz funeral New Orleans style? PMID- 11616214 TI - Henricus Gerardus Jacobus Maria Kuypers: 9 September 1925-26 September 1989. PMID- 11616215 TI - Konrad Zacharias Lorenz: 7 November 1903-27 February 1989. PMID- 11616216 TI - Kenneth Mather: 22 June 1911-20 March 1990. PMID- 11616217 TI - Ann Bishop: 19 December 1899-7 May 1990. PMID- 11616218 TI - John Alexander Fraser Roberts: 8 September 1899-15 January 1987. PMID- 11616220 TI - Kenneth Stewart Cole: 10 July 1900-18 April 1984. PMID- 11616219 TI - Edith Bulbring: 27 December 1903-5 July 1990. PMID- 11616221 TI - Gerty Theresa Cori: August 8, 1896-October 26, 1957. PMID- 11616222 TI - John Holmes Dingle: November 24, 1908-September 15, 1973. PMID- 11616223 TI - Harvey Fletcher: September 11, 1884-July 23, 1981. PMID- 11616224 TI - Dwight Joyce Ingle: September 4, 1907-July 28, 1978. PMID- 11616225 TI - Arthur Weever Melton: August 13, 1906-November 5, 1978. PMID- 11616226 TI - Perry William Wilson: November 25, 1902-August 17, 1981. PMID- 11616227 TI - Clyde Hamilton Coombs: July 22, 1912-February 4, 1988. PMID- 11616228 TI - Carl Ferdinand Cori: December 5, 1896-October 19, 1984. PMID- 11616229 TI - "Victims of vaccination?": opposition to compulsory immunization in Ontario, 1900 90. PMID- 11616230 TI - The Nagler case: a revealing moment in Red Cross history. PMID- 11616231 TI - The Guru and the godfather: Henry Sigerist, Hugh MacLean, and the politics of health care reform in 1940s Canada. PMID- 11616232 TI - [Medicine and its origins]. PMID- 11616233 TI - [Causes of death in Quebec in the nineteenth century: the problem of sources]. PMID- 11616234 TI - [The medical records of the quarantine of the federal department of agriculture in the Canadian national archives, 1867-1918]. PMID- 11616235 TI - Medical bibliography, publishing, and libraries. PMID- 11616236 TI - The Jesuit and the general: Sherman's private war. PMID- 11616237 TI - Freud's devaluation of Nietzsche. PMID- 11616238 TI - Reaping the benefits of collaboration while avoiding pitfalls: Marie Curie's rise to scientific prominence. PMID- 11616239 TI - Giuseppe Montalenti (13 December 1904-2 July 1990). PMID- 11616240 TI - Freund's adjuvant and the realization of questions in postwar immunology. PMID- 11616241 TI - [The changes of pharmaceutical administration in Japan after World War II] (Jpn). PMID- 11616242 TI - [Von Siebold's prescriptions] (Jpn). PMID- 11616243 TI - [A consideration on the import of Chinese crude drugs of general use in the first half of Taisho era especially on the change of import volume and price of rhubarb] (Jpn). PMID- 11616244 TI - [The way for carrying medicine and its containers. Moisture absorption from the viewpoint of drug preservation--concept and measures in the Edo era] (Jpn). PMID- 11616245 TI - [Historical review of insulin and its preparations in pharmacopoeia. Development of new technology for analysis of insulin] (Jpn). PMID- 11616246 TI - [Medicinal plants in "nogyo zensho". (I) On the plants cultivated for medical use] (Jpn). PMID- 11616247 TI - [Medicinal plants in "nogyo zensho". (II) On the medical use of the cultivated plants] (Jpn). PMID- 11616248 TI - [The way for carrying medicine and its containers] (Jpn). PMID- 11616249 TI - Navel battles: interpreting Renaissance gynecological manuals. PMID- 11616250 TI - Prayers for the Queen in travail. PMID- 11616251 TI - Prayers for the Queen in travail. PMID- 11616252 TI - How nobody invented anesthesia. PMID- 11616253 TI - Herman Moritz Kalckar - March 26, 1908-May 17, 1991. PMID- 11616255 TI - Hermann Rahn - July 5, 1912-June 23, 1990. PMID- 11616254 TI - Israel Michael Lerner - May 14, 1910-June 12, 1977. PMID- 11616256 TI - Albert Hewett Coons - June 28, 1912-September 30, 1978. PMID- 11616257 TI - Eliot Stellar - November 1, 1919-October 12, 1993. PMID- 11616258 TI - Harland Goff Wood - September 2, 1907-September 12, 1991. PMID- 11616259 TI - Susumu Hagiwara - November 6, 1922-April 1, 1989. PMID- 11616260 TI - Numerus, figura, proportio, situs; Linnaeus's definitory attributes. PMID- 11616261 TI - Dr William Hamilton (ca 1783-1856), botanist, of Donegal and Plymouth. PMID- 11616262 TI - Who was Dr Lydgate? PMID- 11616263 TI - Chekhov after Sakhalin Island. PMID- 11616264 TI - The medical health of Napoleon Bonaparte. PMID- 11616265 TI - Dead man's chest: a clinical reappraisal of Robert Louis Stevenson. PMID- 11616266 TI - Edward Jenner (1749-1823): naturalist, scientist, country doctor, benefactor to mankind. PMID- 11616267 TI - Dr William Woodville (1752-1805) and the St Pancras Smallpox Hospital. PMID- 11616268 TI - Ralph Pemberton MD (1877-1949), pioneer rheumatologist. PMID- 11616269 TI - George Gushue-Taylor and the medical missions of Formosa. PMID- 11616270 TI - Henry Graves Bull (1818-1885): a provincial polymath. PMID- 11616271 TI - An Orsett census enumerator. AB - Given the wide use of Victorian census enumerators' books (CEBs), it is surprising that so little is known about the background and ability of the enumerators who compiled them. For the most part they are anonymous persons with difficult handwriting and strange spelling. One such enumerator was the current author's grandfather, William Woollings of Orsett, Essex, who compiled the censuses of 1851, 1861 and 1871 for one of the enumeration districts in the parish in which he lived. This article examines his qualifications for the task of census enumerator and attempts to find if his knowledge of and social standing in the local community affected the way in which he completed the census returns. Secondly, by comparing the three censuses that he compiled an overall assessment is made of the accuracy of his returns in the light of the difficulties that he experienced, and the improvements that were made over time. PMID- 11616272 TI - Elizaabeth Latimer Shrimpton, M.D. (1875-1955): unsung heroine of medical librarianship. PMID- 11616273 TI - Resistance to medical ethics reform in the nineteenth century. PMID- 11616274 TI - Alistair Cameron Crombie (1915-1996). PMID- 11616275 TI - Fermentation and pharmaceuticals - Part II. PMID- 11616276 TI - Three pioneers of Cuban medicine in the XIX century. PMID- 11616277 TI - Two cheers for orphanages. [Reviews of: Zmora, N. Orphanages reconsidered: child care institutions in progressive era Baltimore, (Philadelphia, 1994); Friedman, R.S. These are our children: Jewish orphanages in the United States, 1880-1925, (1994); Cmiel, K. A home of another kind: one Chicago orphanage and the tangle of child welfare, (1995)]. PMID- 11616278 TI - Jeanne Fery: a sixteenth-century case of dissociative identity disorder. PMID- 11616279 TI - Psychological purposes served by war: three perspectives. PMID- 11616280 TI - The coming of the electronic age to the Cambridge Physiological Laboratory: E.D. Adrian's valve amplifier in 1921. AB - E.D. Adrian, F.R.S. (1889-1975) was one of Britain's most distinguished neurophysiologists, who, during a long and productive lifetime, achieved most honours and distinctions available to a scientific man. These included the 1932 Nobel Prize for Physiology or Medicine, shared with Sir Charles Sherrington, F.R.S., the Order of Merit (1942), and Presidency of the Royal Society (1950-55). His interest in the nervous system started at the beginning of his undergraduate career, much influenced by his Director of Studies, Keith Lucas, F.R.S. (1879 1916). Lucas, a skilled and imaginative neurophysiologist, was particularly renowned for his technical ability to design and build new equipment. In turn, his pupil's work on recording and analysing the electrical impulses in nervous tissue was also facilitated by the development of appropriate, sensitive instrumentation. This paper will describe Adrian's first use of valve amplifiers to enlarge the extremely small electrical signals then obtainable in the physiological laboratory, a development that epitomized the beginning of the electronic revolution in life sciences' laboratories. PMID- 11616281 TI - Paracelsus, religion, and dissent: the case of Philipp Homagius and Georg Zimmermann. PMID- 11616282 TI - [Not Available]. AB - This text is the description of an investigation. At the same time it is an interpretative essay and detailed description of still unexplored archival material, currently being catalogued. It also describes photographs, scientific instruments and books, all belonging to one of the oldest and most important institutions for childhood. The focus is on the nineteenth and twentieth centuries, a decisive and yet too little studied period at the origins of pediatrics. During this period the Istituto degli Innocenti experienced an extraordinary transformation from being a place of charity to being a centre for maternity and infant care in the modern sense, where pioneering activities took place relating to scientific research, sanitary care, medical experimentation and training, as well as to specialised nursing, prevention and divulgation. PMID- 11616283 TI - [Historical drug research: reflections on an epistemology of research on the history of ancient medicaments]. PMID- 11616284 TI - Science and culture in mid-Victorian Britain: the reviews, and William Crookes' Quarterly Journal of Science. AB - Charles Darwin's Origin of Species was published in 1859, and we are often disposed to see it as marking an epoch in the struggle between religion and science. Recent analyses especially of the part played by T. H. Huxley, 'Darwin's bulldog', emphasise instead (or as well) Huxley's aim to exclude affable 'gentlemen of science' from what was becoming a profession for experts. Evidence from the Reviews of the period show that science accounted for some 10% of the articles; but also that demand for this very general literature was falling, as science and humanities indeed grew apart into what C.P. Snow later called 'two cultures'. PMID- 11616285 TI - [Not Available]. AB - This article starts with the description of a medical case: the removal of a brain tumor carried out in 1886 in London at the National Hospital for the Paralysed and Epileptic. This medical case is recorded in the Casebooks that today can be found in the archive of the hospital. Firstly, there is the description of the patient's state of health and of the intracranical surgery performed by Victor Horsley who referred himself to David Ferrier's cortical maps. Secondly, there is the reconstruction of the theoretical path that led Ferrier, in the 1870s, to prove on an experimental basis the existence of different localised cerebral functions in specific cortical areas. These cerebral localizations are then compared with the model that, at the beginning of the century, contained their first theoretical seed: the Organology of Franz Joseph Gall. PMID- 11616286 TI - Consuming Freud in consumer culture: historicizing the empty self. PMID- 11616287 TI - Twentieth-century persons: experts and clients. PMID- 11616288 TI - The problem of the relation of "self" and "society" in writing the history of psychotherapy. PMID- 11616289 TI - From the empty self to the communal self: reactions to the journey. PMID- 11616290 TI - Nymphomania and the Freudians. PMID- 11616291 TI - Clara Schumann: 'A woman's love and life': a psychoanalytic interpretation. AB - This study was undertaken to demonstrate how psychoanalysis can shed new light on a much studied life history. Clara's emotional life knew a sequence of losses and "prohibited" intimate relationships that created grave loyalty, identity, and identificatory conflicts for her. Since her early childhood, when her father forced her to give up her mother, she had been forced into a choice between the love objects most dear to her and the one on whom she depended for her emotional survival. This resulted in her later repetition compulsion to maneuver herself into the same conflict of loyalty and in her hesitation to decide when choosing one object meant losing the other. Clara had never known a normal separation, only loss and abandonment. She strove to combine the incompatible and succeeded in remaining loyal not only to her mother and father, but also to Robert Schumann, and eventually to Johannes Brahms. Clara Schumann's ideals were conflicted not only because she was educated by two men who were fighting each other, but also because her father, as well as Robert, had internally inconsistent and ambiguous ideas about women. Clara not only had to be obedient and creative, but self-sufficient at the same time. She was partially able to satisfy her own and her partner's needs and solve her deficiencies by projective identification, choosing taciturn men, more maternal than she. PMID- 11616292 TI - The burden of a great name: Robert M. La Follette, Jr. PMID- 11616293 TI - Cherchez la femme: religion and gender in Daniel Paul Schreber's Memoirs of my nervous illness. PMID- 11616295 TI - Keynes' vision: a psychological interpretation. PMID- 11616294 TI - Nurturing: attachment theory and Fanny Burney's Evelina and Cecilia. PMID- 11616296 TI - Psychoanalytic anti-Semitism. PMID- 11616297 TI - The politics of psychoanalytic memory in Germany. PMID- 11616298 TI - Impure epistemology and the search for the nervous agent: a case study in seventeenth- and eighteenth-century neurophysics. AB - In this contribution, I argue for epistemological impurity as the key to the historical reconstruction of the proto-biological sciences of the eighteenth century. The traditional approaches to the more or less complex and more or less stratified past of science either focus on the ideal content of that which has in the meantime been recognized as standard biological knowledge (transmitted from generation to generation by textbooks) or otherwise try to uncover the implicit cognitive principles at work in order to reveal their shortcomings (as measured against today's accepted criteria = epistemological presentism). A closer look at the breakdown of the classical models of mechanistic explanation and the detailed analysis of the new empirico-experimental research in the neurophysiology of the eighteenth century shows, however, that eclectic procedures of various kinds have dominated the field. This eclecticism (the principle of epistemological impurity) supported, and was in turn supported by, what has recently become known as "thinking with one's hand." The paper illustrates this specific kind of thinking (and experimental acting) with reference to the case of Nicolas Le Cat's microphysics of nervous activity. PMID- 11616299 TI - The Lentaigne manuscript: an account by John of Arderne of his treatment of fistula-in-ano. PMID- 11616300 TI - Weimar culture and biological theory: a study of Richard Woltereck (1877-1944). PMID- 11616302 TI - Leo Schamroth (1924-1988): his life and work. PMID- 11616301 TI - With certain reservations: the American veterinary community's reception of Pasteur's work on rabies. PMID- 11616303 TI - Lady Mary Wortley Montagu and the Reverend Cotton Mather: their campaigns for smallpox inoculation. PMID- 11616304 TI - Dr Robert Greenhill Cochrane CMG MD FRCP DTM&H: leprologist par excellence. AB - Dr Robert Cochrane devoted his entire working life to the study and control of leprosy. Most of his working life was spent in India, with interludes in Britain and East Africa. He initiated epidemiological surveys of leprosy, was instrumental in the introduction of sulphones for the definitive therapy of the disease, and contributed significantly to the development of rehabilitation programmes for sufferers from the disease. He campaigned actively for altering social attitudes to leprosy and latterly was in favour of replacing the often pejorative term with that of Hansen's disease. A devout Christian, he believed strongly in setting an example for others as an important means of introducing them to Christianity. At the same time, he was not a taciturn individual and had a well developed sense of humour. PMID- 11616305 TI - The life and death of Alexander Bogdanov, physician. AB - It was early in April in 1928 when the word went out in Moscow that Alexander Bogdanov had died. He was a controversial figure, an old Bolshevik who had left that party long before the 1917 revolution and never returned. All the same, he had had Lenin's respect as a scientist (as long as he stayed out of politics). More recently, he also had the support of the new party strong man, Stalin. Bogdanov opposed the growing despotism of the "dictatorship of the proletariat", under which slogan Communist autocracy was being developed. But he was respected as a tireless propagandist for the socialist cause, an enthusiastic teacher of the proletariat, and a writer of arcane science and philosophy. Bogdanov was held in such respect that Communist bigwigs spoke glowingly at the funeral, praising his intellect, courage, and dedication to science and humanity. They did not fail to point out that he had split with his one-time friend, Lenin, and had succumbed to ideological "errors". Indeed, he had powerful enemies in the early Soviet state. Bogdanov was a physician, economist, philosopher, natural scientist, writer of utopian science fiction, poet, teacher, politician (unsuccesful), lifelong revolutionary, forerunner of what we now call cybernetics and organizational science, and founder of the world's first institution devoted entirely to the field of blood transfusion. You could call him a Renaissance man. Although he clearly fitted the category of the late-nineteenth-century Russian intellectual revolutionary, Bogdanov differed from most of them in being no dilettante. More than just a theorist, he was an active scientist and physician. As a teacher, he firmly believed that education and indoctrination could alter people's ways of thinking and behaving, and that humanity could be perfected under socialism. Like many revolutionaries, Bogdanov tried to keep ahead of the Tsar's police by using a variety of pseudonyms, among them Riadavoy, Werner, Maximov, and Bogdanov. After the revolution, he kept the name Bogdanov. PMID- 11616306 TI - Stephen Mannington Caffyn: a colonial literary life. PMID- 11616307 TI - Anton Chekhov, writer and physician: wedded to medicine. PMID- 11616308 TI - Sun Yat-Sen (1866-1925), a man to cure patients and the nation - his early years and medical career. AB - "The top physician cures the nation first, and then the people." This is a saying recorded in the Guo Yu, the ancient Chinese book of history. Another saying is that one may choose "To be either a good prime minister or a good doctor", by Fan Zhong-Yan (989-1052), a high official. Such sayings reflect the aspirations of many Chinese literary men in the past. This aspiration to high office had been particularly popular among the Confucian physicians since the eleventh century AD, underlining the point of view that the curing of patients by a good physician was just like a good prime minister administering a nation. Hence, many Confucian scholars and men of letters took medicine either as a career or as a charitable exercise as well as a way to fulfil filial piety for preserving themselves and their families, especially if they had failed to be a candidate for an official position. Quite a few officials also followed suit, especially when they experienced difficulties in their posts, like being demoted, or sacked. However, none of them had ever become head of the nation, or a revolutionary, or exerted so profound an influence upon the history of China as Sun Yat-Sen, who started his career as a physician, became a democratic revolutionary and overthrew the Qing monarchy and founded the republic, is not only unique in the history of China, but in the history of medicine as well. The year 1996 is the hundred and thirtieth anniversary of his birth. This article marks this occasion. PMID- 11616309 TI - The photographic collection of Charles John Bond (1856-1939. AB - During the history of the Leicester Royal Infirmary from its foundation in 1771, Charles John Bond (1856-1939) emerges as one of the most distinguished members of the medical staff. He was born at Bittesby House in Leicestershire and brought up on his father's farm, where his early interest in natural history was fostered, and was further developed when he want to Repton school, nearby. His medical career began in February 1875, when he was apprenticed to Dr C M Sidley, a general practitioner of Welford Road, Leicester. For a short time he was an "outdoor" pupil at Leicester Infirmary before proceeding to University College London in the following October. He gained gold medals in physiology and anatomy and silver medals in surgery, midwifery, and medical jurisprudence, qualified in 1879 and was appointed house surgeon to Bedford General Infirmary. He returned to London in 1882 to study for the FRCS and shared rooms in Charlotte Street with his lifelong friend Victor Horsley, who in that year was appointed Assistant Professor of Pathology at University College Hospital. In the same year Charles Bond returned to Leicester and became house surgeon to Sir Charles Marriott. He did much to extend the use of Lister's recently introduced antiseptic methods. In the short period of four years he was appointed full surgeon at the Infirmary, and in 1893, because of his distingugished career and wide interests, he was offered the opportunity of joining the staff of University College Hospital. However, he preferred to stay in Leicester in spite of the limited opportunities for scientific investigation and research. In 1890 he married Edith, daughter of George Simpson, a justice of the peace in Derbyshire, and in 1910 they moved to a large Victorian house, Fernshaw, in Springfield Road on the then outskirts of Leicester, where various animals and birds could be kept for use in his experimental work. In this year he took the unusual step of giving up his large private practice to devote more time to study and to his research interests. three years later, at the age of 57, he retired from the staff of the Infirmary, and the governing body made him an honorary consultant surgeon and also elected him a vice president, the only doctor to be so honoured. Thus he retained a close association with his hospital until his death in 1939. PMID- 11616310 TI - Schubert and syphilis. PMID- 11616311 TI - John Forbes and Daniel O'Connell: the meeting of a Scottish physician with an Irish nationalist in 1841. AB - Last year was the 150th anniversary of the failure of the potato crop in Ireland, which initiated the famine years of 1845-9. The consequences for agricultural communities dependent on this source of food for survival were disastrous in terms of mortality and emigration, although it was not the sole cause for the emergency of an Irish "diaspora". Within two years the Irish people suffered a further blow with the death of their parliamentary champion, O'Connell. Daniel O'Connell (1775-1847) was popularly known in Ireland as the "Liberator", as he promoted the cause of Catholic emancipation together with repeal of the Act of Union between Great Britain and Ireland of 1801. He was skilled as a barrister and politician, and remarkable in that he advocated non-violent means to achieve his aims. His family were fairly well-to-do landowners in County Kerry, in the south-west. In contrast, John Forbes came from a humbler background of tenant farmers in the north-east of Scotland. It may be of interest to outline the circumstances leading to his meeting with O'Connell in 1841. PMID- 11616312 TI - Iodine and pharmaceutical history. PMID- 11616313 TI - Mr Humphrey's inhaler. PMID- 11616314 TI - Marion Merrell Dow - historical perspective of a "merging" company. PMID- 11616315 TI - Next to Godliness. [Review of: Hoy, S. Chasing dirt: the American pursuit of cleanliness. Oxford University Press, 1995; Williams, M.T. Washing "the great unwashed": public baths in urban America, 1840-1920. Ohio State University Press, 1991]. PMID- 11616316 TI - The Arabic origin of Jabir's Latin works. PMID- 11616318 TI - Ibn Zuhr's contributions to surgery. PMID- 11616319 TI - The giver of oxygen: Hercules Sanche and the Oxydonor. AB - During the late nineteenth and early twentieth centuries, gas-pipes were among the most popular therapeutic devices available to an unhealthy public. Spurred on by the explosion of print advertising, mail-order gas-pipes were questionable remedies promoted for such diverse conditions as pneumonia and neurasthenia. Though they are an interesting part of the social history of questionable therapeutics, no historian has recently looked in depth at these devices. This paper examines the clinical, social, and economic environment that facilitated the success of the most ubiquitous gas-pipe, the Oxydonor, and its proprietor, Hercules Sanche. PMID- 11616320 TI - Fictional women physicians in the nineteenth century: the struggle for self identity. AB - By the late nineteenth century, there were large numbers of women physicians in the United States. Three Realist novels of the time, Dr. Breen's Practice, by William Dean Howells, Dr. Zay, by Elizabeth Stuart Phelps and A Country Doctor, by Sarah Orne Jewett, feature women doctors as protagonists. The issues in these novels mirrored current issues in medicine and society. By contrasting the lives of these fictional women doctors to their historical counterparts, it is seen that, while the novels are good attempts to be truthful treatments of women physicians' struggles, in certain areas they do not accurately address the concerns of women physicians. PMID- 11616321 TI - Denying the body? Memory and the dilemmas of history in Descartes. PMID- 11616322 TI - Historiography of chemistry in the eighteenth century: Hermann Boerhaave and William Cullen. PMID- 11616323 TI - Robert Edward Gross - July 2, 1905-October 11, 1988. PMID- 11616324 TI - Harry Grundfest - January 10, 1904-October 10, 1983. PMID- 11616325 TI - Daniel Sanford Lehrman - June 1, 1919-August 27, 1972. PMID- 11616326 TI - Kenneth Wartinbee Spence - May 6, 1907-January 12, 1967. PMID- 11616327 TI - Max Tishler - October 30, 1906-March 18, 1989. PMID- 11616328 TI - George Hoyt Whipple - August 28, 1878-February 2, 1976. PMID- 11616329 TI - Felix Haurowitz - March 1, 1896-December 2, 1987. PMID- 11616330 TI - Eugene Markley Landis - April 4, 1901-February 14, 1987. PMID- 11616331 TI - Carl Vernon Moore - August 21, 1908-August 13, 1972. PMID- 11616332 TI - Theodore Mead Newcomb - July 24, 1903-December 28, 1984. PMID- 11616333 TI - Charles H. Rammelkamp, Jr. - May 24, 1911-December 5, 1981. PMID- 11616334 TI - Hermann Irving Schlesinger - October 11, 1882-October 3, 1960. PMID- 11616335 TI - Calvin Perry Stone - February 28, 1892-December 28, 1954. PMID- 11616336 TI - Sewall Wright - December 21, 1889-March 3, 1988. PMID- 11616337 TI - Leon Festinger - May 8, 1919-February 11, 1989. PMID- 11616338 TI - David P. C. Lloyd - September 23, 1911-April 20, 1985. PMID- 11616339 TI - Hans Popper - November 24, 1903-May 6, 1988. PMID- 11616340 TI - Curt P. Richter - February 20, 1894-December 21, 1988. PMID- 11616341 TI - Albert Joyce Riker - April 3, 1894-February 21, 1982. PMID- 11616342 TI - Cecil James Watson - May 31, 1901-April 11, 1983. PMID- 11616343 TI - George Washington Corner - December 12, 1889-September 28, 1981. PMID- 11616344 TI - Gilbert Dalldorf - March 12, 1900-December 21, 1979. PMID- 11616345 TI - Herbert Spencer Gasser - July 5, 1888-May 11, 1963. PMID- 11616346 TI - William B. Castle - October 21, 1897-August 9, 1990. PMID- 11616347 TI - Robert Kyle Burns - July 26, 1896-June 26, 1982. PMID- 11616348 TI - Burrhus Frederic Skinner - March 20, 1904-August 18, 1990. PMID- 11616349 TI - Andre Frederic Cournand - September 24, 1895-February 19, 1988. PMID- 11616350 TI - Barbara McClintock - June 16, 1902-September 2, 1992. PMID- 11616351 TI - Irvine Heinly Page - January 7, 1901-June 10, 1991. PMID- 11616352 TI - William Cumming Rose - April 4, 1887-September 25, 1985. PMID- 11616353 TI - Carl Frederic Schmidt - July 29, 1893-April 4, 1988. PMID- 11616354 TI - John Clark Sheehan - September 23, 1915-March 21, 1992. PMID- 11616355 TI - George Streisinger - December 27, 1927-September 5, 1984. PMID- 11616356 TI - Carroll Milton Williams - December 2, 1916-October 11, 1991. PMID- 11616357 TI - Min Chueh Chang - October 10, 1908-June 5, 1991. PMID- 11616358 TI - George Constantin Cotzias - June 16, 1918-June 13, 1977. PMID- 11616359 TI - Sir Henry Thompson: the first British urologist (1820-1904). PMID- 11616360 TI - Pierre Francois Olive Rayer (1793-1867). AB - Pierre Francois Olive Rayer is an important figure in French medicine and medical biology of the second half of the nineteenth century, although he is scarcely recognized as such even in his own country. PMID- 11616361 TI - Desmond Bernal and his role in the biological exploitation of X-ray crystallography. PMID- 11616362 TI - Pioneers of the transition from antiseptic to aseptic surgery. PMID- 11616363 TI - Alexander Porfir'yevich Borodin (1833-1887): composer, chemist, physician and social reformer. PMID- 11616364 TI - Australia's three leading wine doctors. PMID- 11616365 TI - A short history of C F Palmer (London) Ltd, physiological instrument makers. PMID- 11616366 TI - Schubert and syphilis. PMID- 11616367 TI - The illness of Dr George Turnavine Budd and its influence on the literary career of Sir Arthur Conan Doyle. PMID- 11616368 TI - Gustave Flaubert and the Museum of Medical History, Rouen. PMID- 11616369 TI - The discovery of nerves in the placenta and the human umbilical cord by Sir Everard Home (1824). PMID- 11616370 TI - Seeing and doing. [Review of: Wilson C. The Invisible world: early modern philosophy and the invention of the microscope. Princeton University Press, 1995]. PMID- 11616372 TI - Chickenpox: an error in diagnosis by Hermann Boerhaave? PMID- 11616373 TI - The discovery of drugs. PMID- 11616374 TI - Robert Graves and neurology: a bicentenary tribute. AB - Armand Trousseau of Paris praised The Clinical Lectures of Robert James Graves (1796-1853). The Dublin physician's book never left Trousseau's study; he valued particularly 'the lectures which treat of paralysis'. These, he said, 'contain a complete doctrine', enlarging concepts introduced by Whytt and Prochaska. Gowers (1902) and Kinnier Wilson (1954) credited Graves with an early account of peripheral neuritis; more recently Lawrence C. McHenry (1969) referred to him as the first to recognise that disease processes may affect the peripheral nerves. This and other contributions of Robert Graves to neurology are discussed against the contemporary framework appropriate to the bicentenary year. PMID- 11616375 TI - Marat: his science and the French Revolution. PMID- 11616377 TI - Tempest in the academy. Jean-Baptiste Le Roy, the Paris Academy of Sciences and the project of a new Hotel-Dieu. PMID- 11616378 TI - [On Samuel David Gross]. PMID- 11616379 TI - Jajjata. PMID- 11616381 TI - Bukhrat (Hippocrates): the most famous physician of Yunan (Greece). PMID- 11616380 TI - Rasapradipika; a Sanskrit medical work attributed to Bharadvaja. PMID- 11616382 TI - Hortus Indicus Malabaricus (Garden of Malabar of India). PMID- 11616384 TI - Influence on Ibn Sina on Unani medicine in subsequent ages. PMID- 11616383 TI - Wilhem Ten Rhyne (Rhijne) and his Treatise on Asiatic Leprosy; a medical classic by a Dutch physician in Java in the last quarter of 17th century. PMID- 11616385 TI - Cosmetics according to Avicenna. PMID- 11616386 TI - Contribution of Avicenna in therapeutics reflecting on modern medicine. PMID- 11616387 TI - Avicenna as a physician and medical writer. PMID- 11616388 TI - 'Shaik -al - Rais' Abu Ali Ibn Sina (Avicenna) and his contribution to the science and art of medicine. PMID- 11616389 TI - Contribution of Avicenna to medicine. PMID- 11616390 TI - Anatomy of eye and the mechanism of vision according to Avicenna. PMID- 11616391 TI - A critical analysis of Avicenna's contribution to physiology. PMID- 11616392 TI - Avicenna on digestion of food. PMID- 11616393 TI - Avicenna's thoughts and concepts of the pulse (sphygmology). PMID- 11616394 TI - Avicenna, a physician and his approach to medicine. PMID- 11616395 TI - Avicenna on ear, nose and throat diseases. PMID- 11616396 TI - Avicenna's description of tuberculosis. PMID- 11616397 TI - Avicenna as a clinician. PMID- 11616398 TI - Avicenna's contribution to the understanding of anatomy and pathology of heart. PMID- 11616399 TI - Avicenna's principles of dietetics. PMID- 11616400 TI - Avicenna's influence on European medicine. PMID- 11616402 TI - A commentary on the last illness of Sir William Osler. PMID- 11616401 TI - Robert P. Fischelis 1891-1981. PMID- 11616403 TI - Walter B. Cannon and homeostasis. PMID- 11616404 TI - Max Delbruck and the birth of molecular biology. PMID- 11616405 TI - Atoms, molecules, and Linus Pauling. PMID- 11616406 TI - Thomas Hunt Morgan: materialism and experimentalism in the development of modern genetics. PMID- 11616407 TI - H. J. Muller: the role of scientist in creating and applying knowledge. PMID- 11616408 TI - We are all aspects of one single being: an introduction to Erwin Schrodinger. PMID- 11616409 TI - [Not Available]. PMID- 11616410 TI - The scientific legacy of Marie Curie. PMID- 11616411 TI - The provenance of some of the incunables in the Osler Library. PMID- 11616412 TI - A. D. Waller and Jimmie: a centenary contribution. PMID- 11616413 TI - A. D. Waller: a biographical note. PMID- 11616414 TI - William Osler at work: reading John Richard Green-introduction. PMID- 11616415 TI - Finding Osler's letters in the Osler Library: a preliminary report and some discoveries. PMID- 11616416 TI - [Not Available]. PMID- 11616417 TI - [Not Available]. PMID- 11616419 TI - Sir John Russell Reynolds: 1828-1896. PMID- 11616418 TI - Human embryology in Zakariya al-Qazwini's The Marvels of Creation. PMID- 11616420 TI - William Heberden the elder (1710-1801): physician of the enlightenment. PMID- 11616421 TI - Nelson's wounds. PMID- 11616422 TI - Order and disorder in Freud's Vienna. PMID- 11616423 TI - The busts of Sir William Osler. PMID- 11616424 TI - Osler's brain again. PMID- 11616425 TI - Perspectives of the Jabirian Alchemical Corpus. PMID- 11616426 TI - Durkheim, suicide, and religion: toward a network theory of suicide. PMID- 11616427 TI - In praise of remarkable men, microscopes, and chicken salad. PMID- 11616428 TI - The Osler-Bucke relationship and the Whitman clutter. PMID- 11616429 TI - Jacob Henle's views on disease causation. PMID- 11616430 TI - [Not Available]. PMID- 11616431 TI - Anatomy teaching at the University of Tartu. PMID- 11616432 TI - Karl Ernst von Baer's challenge to future research. PMID- 11616433 TI - Pharmaceutical legislation in the Baltic Republics. PMID- 11616434 TI - The development of research in the field of chemistry at Tartu University and the problems of genealogy of science. PMID- 11616436 TI - A general dispensary practice 150 years ago. PMID- 11616435 TI - Arthur Boettcher, Karl Bogislaus Reichert and Ernst Reissner: 19th century pioneers in inner ear research at the Tartu University in Estonia. PMID- 11616438 TI - Orthodox medicine and the health reform movement in the Maritimes, 1850-1885. PMID- 11616437 TI - Health, education, economy: philanthropic foundations in the Atlantic region in the 1920's and 1930's. PMID- 11616439 TI - "Marked for slaughter": the Halifax Medical College and the wrong kind of reform, 1868-1910. PMID- 11616440 TI - Volunteers in action: the establishment of government health care on Prince Edward Island, 1900-1931. PMID- 11616441 TI - Primum non nocere: philological commentaries on a medical aphorism. PMID- 11616442 TI - Infections, diseases, and health services in Delta Amacuro, Venezuela. PMID- 11616444 TI - [Not Available]. PMID- 11616445 TI - Physiology at the crossroads of biology, chemistry and physics: the contradictory development of a scientific discipline. PMID- 11616446 TI - Establishment of instruction and research centres for biochemistry in the years 1850-1930. PMID- 11616447 TI - Strategy of biochemistry in the 20th century. PMID- 11616448 TI - Biotechnology and the revolution in biology. PMID- 11616449 TI - Physiology of senses and revolutionary changes in life sciences at the turn of the 19th and 20th centuries. PMID- 11616450 TI - Biologic research in Slovakia. PMID- 11616451 TI - The CME School of Medicine: its struggle for recognition and status, 1905-1915. . PMID- 11616452 TI - Niels Bjorn Jorgensen: painless dentist. PMID- 11616453 TI - Clinique "La Ligniere": the first seventy years of Seventh-day Adventist medical work in Switzerland, 1896-1966. PMID- 11616454 TI - An alumnus of distinction: Sir Maui Pomare, K.B.E., C.M.G., M.D., M.P. PMID- 11616457 TI - Nigeria 1956-65: a medical memoir. PMID- 11616456 TI - Kwic-bru, granose, granola and the gospel. PMID- 11616458 TI - Cutting down trees: women, nutrition and agricultural change in the northern province of Zambia, 1920-1986. PMID- 11616459 TI - Spirit possession and healing in modern Zambia: an analysis of letters to Archbishop Milingo. PMID- 11616460 TI - The Bridgman family in medical and missionary work in southern Africa 1860-1946. PMID- 11616461 TI - Struggles for control: the social roots of health and healing in modern Africa. PMID- 11616462 TI - The social history of Africa in the future: medical-related issues. PMID- 11616463 TI - Urban development planning and environmental pollution in Africa: the case of Calabar Municipality, Nigeria. PMID- 11616464 TI - Susan McKinney Steward: New York State's first African-American woman physician. PMID- 11616465 TI - Some of the incidents in the life of Mark De Mortie. PMID- 11616466 TI - The black-white mortality differential in New York State, 1900-1950: a socio historical reconsideration. PMID- 11616467 TI - "A fiendish outrage?" A study of animal maiming in East Anglia: 1830-1870. PMID- 11616468 TI - The size and weight of cattle and sheep in early modern Scotland. PMID- 11616469 TI - Anatomical manikins and diagnostic dolls. PMID- 11616470 TI - My father: Dr. Luther Leonidas Hill. PMID- 11616472 TI - Slaves as guinea pigs: Georgia and Alabama episodes. PMID- 11616471 TI - The Alabama Academy of Science and the maturing of a profession. PMID- 11616473 TI - A desperate and dangerous man: Captain Michael A. Healy's Arctic cruise of 1900. PMID- 11616474 TI - Curing crippled prospectors: the wonderful waters of Chena Hot Springs. PMID- 11616475 TI - Surviving Denali: accidents on the highest, coldest mountain in North America. PMID- 11616476 TI - Dr. Goddard's medicinal hot springs: building a sanitarium at Goddard Hot Springs. PMID- 11616477 TI - Alaska's greatest disaster: the 1918 Spanish influenza epidemic. PMID- 11616478 TI - The serum dash to Nome, 1925: the making of Alaskan heroes. PMID- 11616479 TI - The time of my life: a frontier doctor in Alaska. PMID- 11616480 TI - Doctor in the Coal Branch. PMID- 11616481 TI - Growing up in Alberta. PMID- 11616483 TI - The National Association for the Promotion of Social Science: its contribution to Victorian health reform, 1857-1886. PMID- 11616482 TI - Charles Masterman and National Health Insurance. PMID- 11616484 TI - Dental evidence for prehistoric dietary change on the northern Channel Islands, California. PMID- 11616485 TI - John Rowzee Peyton and the myth of the mound builders. PMID- 11616486 TI - "Thomas Cole is no more" A letter from John Falconer to Jasper Cropsey, February 24, 1848. PMID- 11616487 TI - Art and deception: Ralph Blakelock and his guardian. PMID- 11616489 TI - Spiritual sickness in the physician's and pardoner's tales: thematic unity in fragment VI of the Canterbury Tales. PMID- 11616488 TI - Spiritual sickness in the physician's and pardoner's tales: thematic unity in fragment VI of the Canterbury Tales. PMID- 11616490 TI - Those deceptively simple postulates of Professor Robert Koch. PMID- 11616491 TI - Medical bibliophiles and historical scholarship. PMID- 11616493 TI - The health and earnings of rejected disability insurance applicants. PMID- 11616492 TI - The lulling effect: the impact of child-resistant packaging on aspirin and analgesic ingestions. PMID- 11616494 TI - Fertility and the personal exemption: implicit pronatalist policy in the United States. PMID- 11616495 TI - Military medicine. PMID- 11616496 TI - The oddest of characters. PMID- 11616498 TI - What happened off Devon? PMID- 11616497 TI - Why we didn't use poison gas in World War II. PMID- 11616499 TI - Appendicitis at 100. PMID- 11616500 TI - Bellevue: no one was ever turned away. PMID- 11616501 TI - The first chapter of children's rights. PMID- 11616502 TI - William T. Sherman. PMID- 11616503 TI - America's "turbulent spirit": Dr. Benjamin Rush. PMID- 11616504 TI - General Grant's calico colonel. PMID- 11616505 TI - A Red Cross nurse in Belgrade: Mary Gladwin saw World War I from the inside of a hospital. Her battles were no easier than those of the soldiers. PMID- 11616506 TI - A persistent rebel. PMID- 11616507 TI - Dr. Beaumont's miracle. PMID- 11616508 TI - Clara Barton: founder of the American Red Cross. PMID- 11616509 TI - "Stamping" out tuberculosis: the story of Christman seals. PMID- 11616510 TI - Crosscultural contacts: changes in the diet and nutrition of the Navajo Indians. PMID- 11616511 TI - Medicine for the Rosebuds: health care at the Cherokee Female Seminary, 1876 1909. PMID- 11616512 TI - Liminality and incorporation in the art of the Tlingit shaman. PMID- 11616513 TI - Firewater labels and methodologies. PMID- 11616514 TI - Nursing care and beliefs of expectant Navajo women (part 1). PMID- 11616515 TI - Against common right and reason: the College of Physicians versus Dr. Thomas Bonham. PMID- 11616517 TI - Galen and the Antonine plague. PMID- 11616518 TI - Galen's Platonism. PMID- 11616516 TI - Slaves as fellow servants: ideology, law, and industrialization. PMID- 11616519 TI - Plato and the female physician ("Republic", 454d 2). PMID- 11616520 TI - The war-weariness hypothesis: an empirical test. PMID- 11616521 TI - Reminiscences of early Denver. PMID- 11616522 TI - Notes on an early Virginia physician. PMID- 11616523 TI - Amelia Greenwald: the Jewish Florence Nightingale. PMID- 11616524 TI - Dr. Samuel James Meltzer: physiologist of the Rockefeller Institute. PMID- 11616525 TI - Health and the eastern European Jewish immigrant. PMID- 11616526 TI - Powdered tin and rose petals: Myer Myers, Goldsmith, and Peter Middleton, physician. PMID- 11616527 TI - Transcendentalism and psychotherapy: another look at Emerson. PMID- 11616528 TI - More on Pound's prison experience. PMID- 11616529 TI - Cummings and Freud. PMID- 11616530 TI - Hemingway's home: depression and suicide. PMID- 11616531 TI - Faulkner's last days. PMID- 11616532 TI - The poet as neurotic: the official biography of Robert Frost. PMID- 11616534 TI - Respect for civilian authority: the tragic career of Captain Angus. PMID- 11616533 TI - Mary Gove Nichols' Mary Lyndon: a forgotten reform novel. PMID- 11616535 TI - The Searsport "thirty-six": seafaring wives of a Maine community in 1880. PMID- 11616536 TI - Edwin Garrigues Boring (1886-1968). PMID- 11616537 TI - Gaining ground: the impact of Medicaid and WIC on infant mortality. PMID- 11616538 TI - Principals, bureaucrats, and responsiveness in clean air enforcements. PMID- 11616539 TI - Republican schoolmaster: the U.S. Supreme Court, public opinion and abortion. PMID- 11616540 TI - Presbyterians and prayers for the sick: changing patterns of pastoral ministry. PMID- 11616541 TI - The trial of Thomas Blackwood: Presbyterians, public morals, and the politics of medicine on the Michigan frontier. PMID- 11616543 TI - Law, sex, cruelty, and divorce in Victorian America, 1840-1900. PMID- 11616542 TI - A century of PCUS medical mission, 1881-1983. PMID- 11616544 TI - "Through the cracked and fragmented self": William James and the Turn of the screw. PMID- 11616547 TI - Victorians abed: William Graham Sumner on the family, women and sex. PMID- 11616546 TI - "A certain restless ambition": women physicians and World War I. PMID- 11616548 TI - United States versus American Medical Association et al. The medical antitrust case of 1938-1943. PMID- 11616549 TI - Pulse on San Francisco's Chinatown: health service utilization and health status. PMID- 11616550 TI - Demographic change in northwestern New Spain. PMID- 11616551 TI - Dialectic and health in Plato's Gorgias: presuppositions and implications. PMID- 11616552 TI - Soren Kierkegaard's final illness and death. PMID- 11616553 TI - Anglo-Saxon medicine and magic. PMID- 11616554 TI - Deinstitutionalization and welfare policies. PMID- 11616556 TI - The insanity defense in England and Wales since 1843. PMID- 11616555 TI - The insanity defense before 1800. PMID- 11616557 TI - Empirical research on the insanity defense. PMID- 11616558 TI - Why the experts disagree: variations in the psychiatric evaluation of criminal insanity. PMID- 11616559 TI - Population dynamics and policy in the People's Republic of China. PMID- 11616560 TI - Birth planning and fertility transition. PMID- 11616561 TI - A review of research on the insanity defense. PMID- 11616562 TI - Care and treatment of the mentally ill in the United States: historical developments and reforms. PMID- 11616563 TI - Civil commitment of the mentally ill: an overview. PMID- 11616564 TI - Legal intervention in civil commitment: the impact of broadened commitment criteria. PMID- 11616565 TI - How did Tarasoff affect clinical practice? PMID- 11616566 TI - Oregon's Psychiatric Security Review Board: a comprehensive system for managing insanity acquittees. PMID- 11616568 TI - Recent changes in American fertility, marriage, and divorce. PMID- 11616569 TI - Chinese apothecary in frontier Idaho. PMID- 11616571 TI - Johann Peter Frank and social medicine. PMID- 11616570 TI - Chinese medical recipes from frontier Seattle. PMID- 11616572 TI - Manuscript collections: The Jeannette Dean-Throckmorton papers. PMID- 11616573 TI - The Flexner investigation of the University of Iowa Medical School. PMID- 11616574 TI - The life and works of Giovanni Fontana. PMID- 11616575 TI - New light on Paolo dell'Abbaco. PMID- 11616576 TI - [Not Available]. PMID- 11616577 TI - Divini and Campani: a forgotten chapter in the history of the Academia del Cimento. PMID- 11616578 TI - Derek J. DeSolla Price. PMID- 11616579 TI - [Not Available]. PMID- 11616580 TI - Some unpublished correspondence of Giovanni Alfonso Borelli. PMID- 11616581 TI - Prints commemorating the Rome, 1656 plague epidemic. PMID- 11616582 TI - Medical incidents in the life of Dr. John H. Finfrock. PMID- 11616584 TI - Coal mine explosions at Almy, Wyoming: their influence on Wyoming's first coal mining safety laws. PMID- 11616583 TI - John C. Davis Sr.: portrait of a Rocky Mountain drug wholesaling pioneer. PMID- 11616585 TI - A bibliography of writings concerning the Big Horn Medicine Wheel, Big Horn National Forest. PMID- 11616586 TI - Dr. William Sabin Bennett: the rise and fall of a pioneer doctor. PMID- 11616587 TI - Troilus: a medieval psychoanalysis. PMID- 11616588 TI - Empedocles' sexual theory: a note on fragment B 63. PMID- 11616589 TI - [Not Available]. PMID- 11616590 TI - Lydia Pinkham understood what it took to promote cures. PMID- 11616591 TI - Death of sheep. PMID- 11616593 TI - A note on the anatomical and philosophical claims of Diogenes of Apollonia. PMID- 11616594 TI - Aristotle and the functionalist debate. PMID- 11616595 TI - Aristotle the first cognitivist? PMID- 11616596 TI - The "theology" of the Hippocratic treatise on the sacred disease. PMID- 11616597 TI - Doctrines of the mean and the debate concerning skills in fourth-century medicine, rhetoric and ethics. PMID- 11616598 TI - Empiricism and ontology in ancient medicine. PMID- 11616599 TI - Health and safety versus profits in the coal industry: the Gateway case and class struggle. PMID- 11616600 TI - Ibn Al-Haytham's theory of knowledge and its significance for later science. PMID- 11616602 TI - Some assumptions behind medicine for the poor during the reign of Louis XIV. PMID- 11616603 TI - Development of medical education among the Arabic-speaking peoples. PMID- 11616601 TI - Gentile da Foligno and the Via medicorum. PMID- 11616604 TI - A retrospect on the historiography of the life sciences. PMID- 11616605 TI - On the friendship between a Tajik poet and a Czech doctor in Bukhara in 1918 1920. PMID- 11616606 TI - Brotherhood thanatology. PMID- 11616607 TI - Archival sources for New Zealand's medical history. PMID- 11616608 TI - Hospital records and record-keeping c.1850-c.1950. Part II. PMID- 11616610 TI - Toronto's public health photography. PMID- 11616609 TI - Hospital records and record-keeping c.1850-c.1950. Part I. PMID- 11616611 TI - Researching public health services in Ontario, 1882-1930. PMID- 11616612 TI - Records of tuberculosis in Calgary. PMID- 11616613 TI - The picture of health. PMID- 11616614 TI - Frobisher's Eskimos in England. PMID- 11616615 TI - The new social history of medicine: some implications for research. PMID- 11616616 TI - The medical practice of George Chalmers, M.D. PMID- 11616617 TI - The archives of the Inclusa. PMID- 11616618 TI - "Allmost as bad as Ireland": Saint John, 1847. PMID- 11616619 TI - "Architecture as therapy." PMID- 11616620 TI - The early years of public health: the Department of Agriculture, 1867-1918. PMID- 11616622 TI - Lancets of stone: traditional methods of surgery among the Alaska natives. PMID- 11616621 TI - Fitness and amateur sport: a partner in excellence. PMID- 11616623 TI - Memory eternal: orthodox Christianity and the Tlingit mortuary complex. PMID- 11616625 TI - The aftermath of Prairie Grove: Union letters from Fayetteville. PMID- 11616624 TI - Plague on the homefront: Arkansas and the great influenza epidemic of 1918. PMID- 11616626 TI - "That troublesome old cocklebur": John R. Brinkley and the medical profession of Arkansas, 1937-1942. PMID- 11616627 TI - From quackery to qualification: Arkansas medical and drug legislation, 1881-1909. PMID- 11616628 TI - Culture, ceremonialism, and stress: American Indian veterans and the Vietnam War. PMID- 11616629 TI - Alcohol abuse and the Soviet military. PMID- 11616630 TI - Vietnam veterans and the agent orange controversy. PMID- 11616631 TI - "Race problems" and the Armenian genocide: the State Department file. PMID- 11616633 TI - Armenian healers and their metier. PMID- 11616632 TI - Coping with massive stressful life event: the impact of the Armenian genocide of 1915 on the present day health and morale of a group of women survivors. PMID- 11616634 TI - Chemical warfare: 1983. PMID- 11616635 TI - Pollock as Jungian illustrator: the limits of psychological criticism. PMID- 11616636 TI - Mortal themes: Winslow Homer. PMID- 11616637 TI - Michelangelo's mutilation of the Florence Pieta: a psychoanalytic inquiry. PMID- 11616638 TI - Madness and folly: Peter Bruegel the elder's Dulle Griet. PMID- 11616639 TI - The artist as anthropologist in mid-Victorian England: Frith's Derby Day, the Railway Station and the new science of mankind. PMID- 11616640 TI - "Le vieux marcheur" and "Les deux risques": Picasso, prostitution, venereal disease, and maternity, 1899-1907. PMID- 11616641 TI - Michelangelo and the human form: his knowledge and use of anatomy. PMID- 11616642 TI - The population of Egypt in the nineteenth century. PMID- 11616644 TI - Food policy in China: recent efforts to balance supplies and consumption requirements. PMID- 11616643 TI - "Fatalism"? Indian responses to plague and other crises. PMID- 11616645 TI - Thirty years of family planning in India. PMID- 11616646 TI - Health policy and politics in Sri Lanka: developments in the south Asian welfare state. PMID- 11616647 TI - Islam and birth control in Muslim minority areas of China. PMID- 11616648 TI - Review article: the "yellow rain" controversy. PMID- 11616649 TI - Cascade Springs: an Atlanta urban spa. PMID- 11616650 TI - The early life of a University of Georgia professor: Malthus A. Ward, M.D., 1794 1831. PMID- 11616651 TI - Notes and documents: Warm Springs recollections from the Graham Jackson papers. PMID- 11616652 TI - Modern nerves, nervous moderns: notes on male neurasthenia. PMID- 11616653 TI - Yo, ho, ho and many bottles of rum? PMID- 11616654 TI - The medical profession in New South Wales, 1788-1850. PMID- 11616655 TI - Fertility decline in New South Wales: the MacKellar Royal Commission reconsidered. PMID- 11616657 TI - The rise of the therapeutic state: psychiatry and the system of criminal jurisdiction in New South Wales, 1890-1940. PMID- 11616658 TI - Taylorism in the home: the medical profession, the infant welfare movement and the deskilling of women. PMID- 11616659 TI - Recent developments in Canadian health services: lessons for Australia. PMID- 11616660 TI - Psychoanalytic practice in Austria. PMID- 11616662 TI - [Not Available]. PMID- 11616661 TI - [Not Available]. PMID- 11616663 TI - [Not Available]. PMID- 11616665 TI - [Not Available]. PMID- 11616664 TI - Psychoanalysis: science, literature, art? PMID- 11616666 TI - [Not Available]. PMID- 11616667 TI - [Not Available]. PMID- 11616669 TI - Pioneers in respiratory care: William F. Miller, MD. PMID- 11616668 TI - The dead child. PMID- 11616670 TI - Anne Steele's health: a modern diagnosis. PMID- 11616672 TI - Mary Percy Jackson: pioneer doctor. PMID- 11616671 TI - Benjamin Smith Barton's influence on Trans-Allegheny natural history. PMID- 11616673 TI - To the rebellion in a folding canoe. PMID- 11616674 TI - 1757--year of failure and tragedy. PMID- 11616675 TI - Disease and the conquest of America. PMID- 11616676 TI - Cromwell's personality: the problems and promises of a psychohistorical approach. PMID- 11616677 TI - Concealment and disclosure in Sir Leslie Stephen's mausoleum book. PMID- 11616678 TI - "Our good friend Mr. Stevenson". PMID- 11616679 TI - A case of mistaken identity: djugashvili-Stalin. PMID- 11616680 TI - Early psychobiography, 1900-1930: some reconsiderations. PMID- 11616681 TI - Jefferson and Erikson, politics and the life cycle. PMID- 11616682 TI - Personality, pathology, and the act of creation: the case of Alfred Hitchcock. PMID- 11616683 TI - Congenial associates: the biographical essays of William Osler. PMID- 11616684 TI - Strategic irony and Lytton Strachey's contribution to biography. PMID- 11616685 TI - Eugene O'Neill in mourning. PMID- 11616687 TI - Myth in the lives of leaders of social movements: the case of the family planning movement. PMID- 11616688 TI - The early use of the stethoscope in Scotland: William Stokes' contributions as a medical student. PMID- 11616689 TI - William Blake and eighteenth-century medicine. PMID- 11616690 TI - The authenticity of Robert Boyle's anonymous writings on reason. PMID- 11616691 TI - Myles Blomefylde, Elizabethan physician, alchemist and book collector: a sketch of a life. PMID- 11616692 TI - Aspects of automation in a major science library. PMID- 11616693 TI - Manuel Pantoja. PMID- 11616695 TI - Brunfelsia in ethnomedicine. PMID- 11616697 TI - A note on the fertility of the Mbanderu women. PMID- 11616696 TI - Ruiz as an ethnopharmacologist in Peru and Chile. PMID- 11616698 TI - Insulin. PMID- 11616699 TI - The years of reform. PMID- 11616700 TI - The city of Bath. PMID- 11616701 TI - Gardener's delight. PMID- 11616703 TI - Strong minds and weak bodies: sports, gymnastics and the medicalization of women's education. PMID- 11616702 TI - Politics and psychoanalysis: the sources of Hitler's political behavior. PMID- 11616704 TI - Sport, recreation and physical education: the evolution of a national policy of regeneration in Eire, 1926-48. PMID- 11616705 TI - The 'Sloane Group': related scientific and medical manuscripts from the fifteenth century in the Sloane Collection. PMID- 11616706 TI - A checklist of medical journals published in England during the seventeenth, eighteenth and nineteenth centuries. PMID- 11616707 TI - Nathan Smith (1762-1828): surgical consultant to Joseph Smith. PMID- 11616708 TI - Joseph Smith's boyhood operation: an 1813 surgical success. PMID- 11616709 TI - Saints and the San Francisco earthquake. PMID- 11616710 TI - William Farr, M.D., R.R.S., D.C.L., C.B., 1807-1883. PMID- 11616712 TI - Penicillin and its successors: a personal view. PMID- 11616711 TI - Physiognomy, phrenology and characterisation in the novels of Charlotte Bronte. PMID- 11616713 TI - What is happening to our health care system? PMID- 11616714 TI - Traditional Chinese medicine and the United States: past, present, and future. PMID- 11616715 TI - The history of antibiotics: a critical bibliography. PMID- 11616716 TI - Hypnotic and mesmeric themes and motifs in selected English-language novels, short stories, plays and poems, 1820-83. PMID- 11616717 TI - Freud, Osler, and the Norman Collection. PMID- 11616718 TI - Darwin's "Notebooks on transmutation of species". Pt. 6. Pages excised by Darwin. PMID- 11616719 TI - Lu-mu-ssu ti ch'e-ti ching-yen lun. PMID- 11616721 TI - A pioneer in information science. PMID- 11616720 TI - Richard Harrison Shryock (1893-1972). PMID- 11616723 TI - The effects of life assurance and pension funds on other savings: the postwar UK experience. PMID- 11616722 TI - Indian medecine in Sri Lanka. PMID- 11616724 TI - Courage, compassion, and providence: Woodbury 1793. PMID- 11616725 TI - Alchemy in the reign of Edward VI: an episode in the careers of Richard Whalley and Richard Eden. PMID- 11616726 TI - Probate valuations and the death duty registers. PMID- 11616727 TI - Occupation interval and mortality rate: a methodological approach. PMID- 11616728 TI - Differential mortuary treatment of Seneca women: some social inferences. PMID- 11616729 TI - Journal of a plague year: Arthur Helps, Stephen Spring-Rice, John Simon and the health fund for London, 1853-54. PMID- 11616730 TI - Samuel Johnson and "The Life of Dr. Richard Mead". PMID- 11616731 TI - Pre-1700 medical books in the Rylands Library. PMID- 11616732 TI - Demography, disease and medical care in Caribbean slave societies. PMID- 11616733 TI - [Not Available]. PMID- 11616735 TI - Demographic transition in Korea. PMID- 11616734 TI - Refugee physicians in Italy and Switzerland from 1933 to 1946. PMID- 11616737 TI - The 1904 epidemic of cholera in Persia: some aspects of Qaja society. PMID- 11616738 TI - The 1904 epidemic of cholera in Persia: some aspects of Qajar society. PMID- 11616736 TI - Paltiel: a note. PMID- 11616740 TI - Industrial R & D in pharmaceutical firms in the early twentieth century. PMID- 11616739 TI - [Pigalle's bust of Dr. Maloet acquired by Fitzwilliam Museum, Cambridge, 1979]. PMID- 11616741 TI - Herbert Hoover, the U. S. Food Administration, and the dairy industry, 1917-1918. PMID- 11616742 TI - The strategic use of public policy: business support for the 1906 Food and Drug Act. PMID- 11616743 TI - The male midwife. PMID- 11616744 TI - The Hospital of the Holy Trinity, Aylesford. PMID- 11616746 TI - The confinement of women: childbirth and hospitalization in Vancouver. PMID- 11616745 TI - Styliane. PMID- 11616748 TI - Sequah, a quack in nineteenth century Cape Town. PMID- 11616750 TI - Comte's theory of mental development. PMID- 11616749 TI - Coca in, coca out. PMID- 11616751 TI - Thomas Starr King and the mercy million. PMID- 11616747 TI - From self-segregation to integration: the vicissitudes of Victoria's Chinese hospital. PMID- 11616752 TI - 100 years on a killer's trail: the California disease. PMID- 11616753 TI - Plague in Russia and Danilo Samoilovich: An historiographical comment and research note. PMID- 11616754 TI - AH Robins and the Dalkon Shield: an update. PMID- 11616755 TI - The work environment board: next stage in occupational health and safety. PMID- 11616756 TI - Psychologists' perceptions of the Canadian immigrant before World War II. PMID- 11616758 TI - Sadlermiut mystery. PMID- 11616757 TI - Doctors and deports: the role of the medical profession in Canadian deportation, 1900-20. PMID- 11616759 TI - A Canadian hero of the 1920s: Dr. Frederick G. Banting. PMID- 11616760 TI - Ontario's civil registration of vital statistics, 1869-1926: the evolution of an administrative system. PMID- 11616762 TI - The creation of a haven for "human thoroughbreds": the sterilization of the feeble-minded and the mentally ill in British Columbia. PMID- 11616761 TI - The letters of Francis Codd from Pembroke, Canada West, 1847-8. PMID- 11616763 TI - Canada's first doctor's strike: medical relief in Winnipeg, 1932-4. PMID- 11616764 TI - For "patients of moderate means": the transformation of Ontario's public general hospitals, 1880-1950. PMID- 11616765 TI - Pharmaceutical policy processes in Sierra Leone. PMID- 11616766 TI - The Emin Pasha Relief Expedition (1887-1889): some comments on disease and hygiene. PMID- 11616767 TI - Sleeping sickness in the history of northeast Congo (Zaire). PMID- 11616768 TI - Cocaine use and problems in North America. PMID- 11616769 TI - Professional preparation concerns of the normal college of the American Gymnastic Union (1866-1919). PMID- 11616770 TI - To breast a storm: Nathaniel Topliff Allen and the demise of military drill as the physical education ethic in the public schools of Massachusetts, 1860-1870. PMID- 11616772 TI - Elfrida K. Berzins: world record holder, olympic athlete, concert soloist, author, and pioneer physical educator. PMID- 11616771 TI - School athletic organizations and professional associations for physical educators: a retrospect on interfacing (1900-1986). PMID- 11616773 TI - Frederick Rand Rogers: educational provocateur (1894-1972). PMID- 11616774 TI - The sport and physical education heritage of Poland: a study of medieval and renaissance periods. PMID- 11616775 TI - Federal programmes of physical recreation and fitness: the contributions of Ian Eisenhardt and BC's Pro-Rec. PMID- 11616776 TI - God, science and the market place: the bases for exercise prescriptions for females in nineteenth century North America. PMID- 11616777 TI - Pirandello's personal experience with madness. PMID- 11616778 TI - The impact of resource development on the health of native people in the northwest territories. PMID- 11616779 TI - Tragedy at work and at home: three histories of occupational and environmental health in America. PMID- 11616780 TI - Doctors or professors? Late Victorian physicians and the culture(s) of professionalism. PMID- 11616782 TI - Lenin and the problems of psychohistory. PMID- 11616783 TI - Tolstoy's depiction of death in the context of recent studies of the "experience of dying." PMID- 11616784 TI - Lifestyle risks: smoking and drinking in Canada. PMID- 11616785 TI - Increased life expectancy, 1921 to 1981. PMID- 11616786 TI - Therapeutic abortion in Canada. PMID- 11616787 TI - AIDS in Canada. PMID- 11616788 TI - Trends in cancer since 1970. PMID- 11616789 TI - Trends in suicide. PMID- 11616790 TI - Cardiovascular disease, cancer and life expectancy. PMID- 11616791 TI - Edward T. Fristoe: Confederate colonel, president of CSW. PMID- 11616792 TI - Jerome Henry Kidder. PMID- 11616793 TI - Frederick Hall, Washington's first teacher of mineralogy. PMID- 11616794 TI - Lewis Henry Steiner. PMID- 11616795 TI - Chemist Jones, superintendent of the patent Office. PMID- 11616796 TI - Swine fever ironies: the slaughter of the Haitian black pig. PMID- 11616797 TI - Did Fidel fudge the figures? Literacy and health: the Cuban model. PMID- 11616798 TI - How to figure out Cuba: development, ideology and mortality. PMID- 11616799 TI - David Daniel Davis, M.D., F.R.C.P. (1777-1841). PMID- 11616800 TI - Johann Bapt. Michael Sagar (1732-1813). PMID- 11616801 TI - The safety and efficacy of new drug approval. PMID- 11616802 TI - Toward the psychological drama of high politics: the case of Bismarck. PMID- 11616803 TI - The debate about foundling hospitals in enlightenment Germany: infanticide, illegitimacy, and infant mortality rates. PMID- 11616804 TI - Doctor Leonardo Conti and his nemesis: the failure of centralized medicine in the Third Reich. PMID- 11616805 TI - Chaucer's idea of the pardoner. PMID- 11616806 TI - Chesterton's attack on the proto-Nazis: new light on the Black Legend. PMID- 11616807 TI - "No job for a woman." PMID- 11616808 TI - C. P. "Doc" Wickmiller: boomer with a "hatful of pills." PMID- 11616809 TI - Warren Felt Evans and mental healing: romantic idealism and practical mysticism in nineteenth-century America. PMID- 11616810 TI - Physic and metaphysic in nineteenth-century America: medical sectarians and religious healing. PMID- 11616811 TI - The ritual of happy dying among early American Methodists. PMID- 11616812 TI - Daniel Drake: the Ohio Valley's Benjamin Franklin. PMID- 11616813 TI - The S. S. Daniel Drake. PMID- 11616814 TI - Miss Cora Dow. PMID- 11616815 TI - Thomas J. Jackson and the idea of health: a new approach to the social history of medicine. PMID- 11616816 TI - On the duties of the surgeon in action: Surgeon Richard Vickery. PMID- 11616817 TI - "Glorious war": the diary of Westwood James, 16th Alabama. PMID- 11616818 TI - Surgeon General William Hammond. PMID- 11616820 TI - Chimborazo Hospital: "That charnal house of living sufferers." PMID- 11616819 TI - The man who played doctor. PMID- 11616821 TI - Amazing Mary: awarded the Medal of Honor. PMID- 11616823 TI - A southern nurse and a northern patient. PMID- 11616822 TI - The left-armed corps: rehabilitation for the veteran. PMID- 11616824 TI - The enemy among us: venereal disease among Union soldiers in the far West, 1861 1865. PMID- 11616825 TI - A tale of two cities: the hidden battle against venereal disease in Civil War Nashville and Memphis. PMID- 11616826 TI - Lincoln finds a surgeon general: William A. Hammond and the transformation of the Union Army medical library. PMID- 11616827 TI - Lucretius on the inefficiency of the medical arts: 6.1179 and 6.1226-38. PMID- 11616828 TI - The Hippocratic physician and his drugs: a reinterpretation of "aporeisthai" and "diamartanein" in Chapter 2 of Peri aeron, hydaton, topon. PMID- 11616829 TI - The theoretical possibility of extensive infanticide in the Graeco-Roman world. PMID- 11616831 TI - Thucydides and the plague: a footnote. PMID- 11616832 TI - Pleasure, tragedy and Aristotelian psychology. PMID- 11616833 TI - The medical theory and the text at Lactantius, Mort. persec. 33.7 and Pelagonius 347. PMID- 11616834 TI - The mediocrity of Celsus. PMID- 11616835 TI - Lucretius, epilepsy, and the Hippocratic on breaths. PMID- 11616836 TI - Prudentius, Shakespeare, and the seven ages of man: a note. PMID- 11616837 TI - L. Gellius Maximus, physician and procurator. PMID- 11616838 TI - The Hippocratic question. PMID- 11616839 TI - The semantics of Bramble's hypochondria: a connection between illness and style in the eighteenth century. PMID- 11616840 TI - Incarnations of evil: changing perspectives on the European witch craze. PMID- 11616841 TI - Some psychological shortcomings of historians' explanations of human behavior. PMID- 11616842 TI - Scientific art: the interpretation of dreams. PMID- 11616843 TI - The art of the healer: women in the fiction of Sarah Orne Jewett. PMID- 11616844 TI - Forms of insanity and insane characters in Moby Dick. PMID- 11616845 TI - Kate Campbell Hurd-Mead (1867-1941) and the medical women's struggle for history. PMID- 11616846 TI - "The battalion of life": medical women, the American women's hospitals, and war service in the First World War. PMID- 11616847 TI - Dress reform and the constraints of clothing on women physicians at the Woman's Medical College of Pennsylvania, 1850-1900. PMID- 11616848 TI - Colorado's first physicians: a look at medicine from before the gold rush to the gilded age. PMID- 11616849 TI - Frontier dentist: the letters of Walthus Jewell Watkins. PMID- 11616850 TI - Freud's Jewish problem. PMID- 11616851 TI - The curious history of Waldemar Haffkine. PMID- 11616852 TI - A placebo for the doctor. PMID- 11616853 TI - The famine the "Times" couldn't find. PMID- 11616854 TI - Infanticide, child abandonment, and female honour in nineteenth-century Corsica. PMID- 11616855 TI - Frieda M. Damm: Red Cross Nurse--1917-1919. PMID- 11616856 TI - Doctor Samuel Broadbent (1759-1828), itinerant limner. PMID- 11616857 TI - "Mon oncle de Marienbad: sociobiology comes to the land of the structuralists. PMID- 11616858 TI - Lacans's ambiguous impact on French psychoanalysis. PMID- 11616859 TI - Biochemical warfare: deterrence vs. arms control. PMID- 11616860 TI - Warnock--the next stage. PMID- 11616861 TI - Sickness in an early modern workplace. PMID- 11616862 TI - The rise of suicide verdicts in southeast England, 1530-1590: the legal process. PMID- 11616863 TI - Sex-specific mortality and economic opportunities: Massachusetts, 1860-1899. PMID- 11616864 TI - The historical case against abortion. PMID- 11616866 TI - Infanticide in European history. PMID- 11616865 TI - Public administration in Pilgrims Rest, 1915-1969. PMID- 11616867 TI - Unpublished by Freud to Fliess: restoring an oscillation. PMID- 11616868 TI - History and psychoanalysis. PMID- 11616869 TI - How to do the history of psychoanalysis: a reading of Freud's Three essays on the theory of sexuality. PMID- 11616870 TI - The secret of psychoanalysis: history reads theory. PMID- 11616871 TI - The struggle of psychiatry with psychoanalysis: who won? PMID- 11616872 TI - Sex and the emergence of sexuality. PMID- 11616873 TI - Black bodies, white bodies: toward an iconography of female sexuality in late 19th-century art, medicine, and literature. PMID- 11616874 TI - In the company of the century. PMID- 11616875 TI - A 17th century Florence Nightingale. PMID- 11616876 TI - [Dr. Matias Nieto y Serrano and Romantic medicine in Spain.] (Spa) PMID- 11616877 TI - Man alive: D. H. Lawrence and tuberculosis. PMID- 11616878 TI - Jonson's elegies of the plague years. PMID- 11616879 TI - Doctor Pierre Didier and early industrial medicine. PMID- 11616880 TI - John Vaughan's "Wilmington Medical Register for 1803". PMID- 11616881 TI - "Let every reader form his own conclusions": Dr. James A. Tilton's case report of a Delaware woman cured of rabies. PMID- 11616882 TI - Demographic transition theory and developing countries: a case study of India. PMID- 11616883 TI - Henry Fitzbutler: Detroit's first black medical student. PMID- 11616885 TI - China's new population policies: rationale and some implications. PMID- 11616884 TI - From slave to physician: Robert J. Boland (1850-1918). PMID- 11616886 TI - Ethical issues in reproductive medicine: a Mormon perspective. PMID- 11616887 TI - Charles Dickens and "The Sanatorium": an unpublished letter and manuscript. PMID- 11616888 TI - Freud versus feminism. PMID- 11616889 TI - Freud, male homosexuality, and the Americans. PMID- 11616890 TI - Bread and roses, crusts and thorns: the troubled story of 1199. PMID- 11616892 TI - Will we save the children? New York City as child abuser. PMID- 11616891 TI - Toward adequate health care. PMID- 11616893 TI - Paracelsian medicine in Volpone. PMID- 11616894 TI - Mary Breckinridge and the frontier nursing service. PMID- 11616896 TI - Cotton Mather's pharmacy. PMID- 11616895 TI - Yellow fever and Charles Brockden Brown: the contest of the emerging novelist. PMID- 11616897 TI - Early medical dissertation research on Tennessee geology. PMID- 11616898 TI - The Slovak enigma: a reassessment of the halt to the deportations. PMID- 11616899 TI - Changing styles of drinking; alcohol use in the Balkans. PMID- 11616900 TI - Alcohol consumption--an indicator of system malfunction in contemporary Poland. PMID- 11616901 TI - Drinking up: alcohol, class, and social change in rural Romania. PMID- 11616902 TI - Viennese wine gardens and their magic. PMID- 11616903 TI - [Nurses and nursing in China in the 1940's: Yunan]. PMID- 11616904 TI - Richard Owen Currey, a little known intellectual figure of antebellum Tennessee. PMID- 11616905 TI - Substitution in public spending: who pays for Canadian National Health Insurance? PMID- 11616906 TI - Discrimination on nonwage margins: safety in the West Virginia coal industry, 1906-1925. PMID- 11616907 TI - Physician licensure: a new approach to examining the role of professional interests. PMID- 11616908 TI - Malthus, the Poor Law, and population in early nineteenth-century England. PMID- 11616909 TI - Speculations on the European mortality decline. PMID- 11616910 TI - Mortality in the fifteenth century: some new evidence. PMID- 11616911 TI - Counting the cost: sickness and disability among working people in an era of industrial recession, 1920-39. PMID- 11616912 TI - Doctors and patients in an era of national health insurance and private practice, 1913-1938. PMID- 11616913 TI - That your widows may be rich: providing for widowhood in old regime Europe. PMID- 11616914 TI - Whose enlightenment? Not man's: the case of Michel Foucault. [Essay review]. PMID- 11616915 TI - Albrecht von Haller's Botany and "Die Alpen." PMID- 11616916 TI - The pregnant Pamela: characterizations and popular medical attitudes in the 18th century. PMID- 11616917 TI - The ferment of knowledge: the historiography of eighteenth-century science. PMID- 11616918 TI - Hypochondria and hysteria: sensibility and the physicians. PMID- 11616919 TI - Cheat and impostor: debate following the case of the rabbit breeder. PMID- 11616920 TI - Psychoanalytic criticism and Swift: the history of a failure. PMID- 11616921 TI - Berkeley's Siris and the "whiskey patriots." PMID- 11616922 TI - [An Irish poem in honor of Sylvester O'Halloran, 1728-1807]. PMID- 11616923 TI - Jacques Necker and the reform of the Paris hospitals before the French Revolution. PMID- 11616924 TI - "The secrets of generation display'd": Aristotle's Master-piece in eighteenth century England. PMID- 11616926 TI - Disease and ventilation in the Royal Navy: the woodenship years. PMID- 11616927 TI - Aspects of infant feeding in eighteenth-century France. PMID- 11616925 TI - Sexual imagination as revealed in the Traite des superstitions of Abbe Jean Baptiste Thiers. PMID- 11616928 TI - Forum: the perils of relying on Thomas Kuhn. PMID- 11616929 TI - The problem of soul in the "little machines" of Reaumur and Charles Bonnet. PMID- 11616930 TI - Valentine Greatrakes, a seventeenth-century "touch-doctor". PMID- 11616932 TI - Asylums and other "total institutions" in Ireland: recent studies. PMID- 11616933 TI - Health quackery: an historian's advice. PMID- 11616931 TI - Mindful of the body: medical allusions in Beckett's Murphy. PMID- 11616934 TI - Leprosy or syphilis in Henryson's "Testament of Cresseid?" PMID- 11616936 TI - The saving hand of God: the significance of the emblematic frontispiece of the Religio medici. PMID- 11616938 TI - Sir Thomas Browne and the Republic of Letters: Introduction. PMID- 11616940 TI - Public health and the medical profession in nineteenth century Canada: a historical sociology. PMID- 11616941 TI - "The anatomy of melancholy" of R. Burton and its era. (Gre). PMID- 11616942 TI - Salem witchcraft and De Forest's "Witching Times". PMID- 11616943 TI - James Thacher's American Medical Biography: the sketch of Dr. Joseph Orne of Salem and Beverly, Massachusetts. PMID- 11616944 TI - The impact of evolutionary theories on the Salem group of Agassiz zoologists (Morse, Hyatt, Packard, Putnam). PMID- 11616945 TI - The work cure at Devereux Mansion. PMID- 11616946 TI - Salem's physician-meteorologist: Dr. Edward A. Holyoke. PMID- 11616947 TI - Benjamin Rush on savagism and progress. PMID- 11616948 TI - The Florilegio Medicinal: source of Southwest ethnomedicine. PMID- 11616950 TI - Colonial policy and native depopulation in California and New South Wales, 1770 1840. PMID- 11616949 TI - The explorer as ethnologist: James Mackay's "Indian Tribes" manuscript with a test of his comments on the native mortuary customs of the Trans-Mississippi west. PMID- 11616951 TI - Cherokee population losses during the Trail of Tears: a new perspective and a new estimate. PMID- 11616952 TI - A further note on Iroquois suicide. PMID- 11616954 TI - Planning full-size life careers. Consequences of the increase in the length and certainty of our life spans over the last three hundred years. PMID- 11616953 TI - Primary source by primary source? On the role of epidemics in new world depopulation. PMID- 11616955 TI - Popular diet in Norway and natural science during the 19th century. The porridge feud 1864-66. PMID- 11616956 TI - D. H. Lawrence's "blood consciousness" and the work of Xavier Bichat and Marshall Hall. PMID- 11616957 TI - A survey of some recent population trends in Greenland. PMID- 11616958 TI - Towards a new perspective on Netjilik Inuit female infanticide. PMID- 11616959 TI - Aging and body image in the sixteenth century: Hermann Weinsberg's (1518-97) perception of the aging body. PMID- 11616960 TI - Svevo, Trieste and the Vienna Circle: Zeno's analyst analysed. PMID- 11616961 TI - Edward Franklin Meeker (1943-1980). PMID- 11616962 TI - The eighteenth-century English diet and economic change. PMID- 11616963 TI - Birth weights and infant mortality among American slaves. PMID- 11616964 TI - Essays in exploration: new demographic history of the late 19th-century United States. PMID- 11616965 TI - Factory fatalities and regulation in Britain, 1878-1913. PMID- 11616966 TI - Population census in China PMID- 11616967 TI - Freud's Dora, Dora's hysteria: the negation of a woman's rebellion. PMID- 11616968 TI - "A new generation of women": progressive psychiatrists and the hypersexual female. PMID- 11616969 TI - John Croghan [1790-1849]: an enterprising Kentucky physician. PMID- 11616970 TI - A great purging--cholera or calomel? PMID- 11616971 TI - Crusader extraordinary: Thomas Duche Mitchell, 1791-1865. PMID- 11616972 TI - There is no Sunday in the army: Civil War letters of Lunsford P. Yandell, 1861 62. PMID- 11616973 TI - Editing Rafinesque's holographs: the case of the short letters. PMID- 11616974 TI - Frederick Herman Verhoeff, M. D. PMID- 11616975 TI - Dr. Anthony Hunn: from storm and stress to tempest and sunshine. PMID- 11616976 TI - Kentucky biographical notebook: Dr. Frederick Ridgely, 1757-1824. PMID- 11616977 TI - Heroic medicine in Kentucky in 1825: Dr. John R. Henry's care of Peyton Short. PMID- 11616978 TI - Camp Nelson, Kentucky, during the Civil War: cradle of liberty or refugee death camp? PMID- 11616979 TI - Standards of nutrition in a St. Augustine hospital, 1783-1821. PMID- 11616980 TI - Exhuming Trotula, sapiens matrona of Salerno. PMID- 11616981 TI - Contributions of 'Ali al-Tabari to ninth-century Arabic culture. PMID- 11616982 TI - Margaret Ridley Charlton, medical librarian and historian: on evaluation of her career. PMID- 11616983 TI - [History of the Fort Concho hospital]. PMID- 11616984 TI - The excavation of the Fort Concho Post Hospital or How to fool an archeologist in one easy lesson. PMID- 11616985 TI - Military Medicine on the frontier: Charles M. Gandy in Texas, 1886-1890. PMID- 11616986 TI - Philippe Aries and the French way of death. PMID- 11616987 TI - The social functions of the hospital in eighteenth-century France: the case of the Hotel-Dieu of Nimes. PMID- 11616988 TI - Rimbaud's "Poetique sensationniste" and some nineteenth-century medical writing. PMID- 11616989 TI - Sartre and Freud. PMID- 11616990 TI - Yellow clover: Katharine Lee Bates and Katharine Coman. PMID- 11616991 TI - Who is frightened of reproductive freedom for women and why? Some historical answers. PMID- 11616992 TI - Joseph Jones and the confederate medical history. PMID- 11616993 TI - A new letter by Thomas Holley Chivers. PMID- 11616994 TI - Dr. Thomas Jarram Wray (1781-1851): pioneer botanist of Augusta, Georgia. PMID- 11616996 TI - Dirty water and clean toilets: medical aspects of the 1904 Louisiana Purchase Exposition. PMID- 11616995 TI - The death of a president, April 12, 1945: an account from Warm Springs. PMID- 11616998 TI - The defrocking of Tom Dooley: a biographical sketch. PMID- 11616997 TI - From lay practitioner to doctor of medicine: woman physicians in St. Louis, 1860 1920. PMID- 11616999 TI - Beyond sympathy: the St. Louis Ladies' Union Aid Society and the Civil War. PMID- 11617000 TI - Inside the sentimental: the psychological work of The Wide Wide World. PMID- 11617001 TI - David Livingstone 1813-1873: a centenary assessment. PMID- 11617002 TI - When malaria was an English disease. PMID- 11617003 TI - Patterns of American rice consumption in 1955 and 1980. PMID- 11617004 TI - Need and demand for mental health care: Massachusetts 1854. PMID- 11617005 TI - The growth of world food output and population. PMID- 11617006 TI - Professionals and national socialism: the case histories of a small-town lawyer and physician, 1918-1945. PMID- 11617007 TI - Medical men of Glamorgan: Dr. Donald Rose Paterson (1862-1939). PMID- 11617008 TI - The publication date of the first Irish flora: Caleb Threlkeld's Synopsis Stirpium Hibernicarum, 1726. PMID- 11617009 TI - Lexicographical notes on Galen's writings. PMID- 11617011 TI - Sources for ancient India literature on veterinary science. PMID- 11617010 TI - A brief history of the National Eye Institute. PMID- 11617012 TI - Pharmacy in ancient India. PMID- 11617013 TI - Nutritional and managerial practices of animals in ancient India. PMID- 11617014 TI - Possibilities of relating modern veterinary science literature to the growth of relevant knowledge in ancient India. PMID- 11617015 TI - Historical background and analysis of scientific content of ancient Indian literature on practices for the treatment of diseases of domestic animals. PMID- 11617016 TI - Antimicrobial agents used in ancient India. PMID- 11617017 TI - Importance of studying veterinary science literature in ancient India. PMID- 11617018 TI - Scope of study of veterinary science literature in ancient India. PMID- 11617019 TI - Plato and the method of Hippocrates. PMID- 11617020 TI - Epicurean emotions. PMID- 11617021 TI - The life and death of John Lambe. PMID- 11617022 TI - Public health nurses in Mississippi: good work in hard times. PMID- 11617023 TI - A letter from Fort Gaines. PMID- 11617024 TI - Camille: the Mississippi Gulf Coast in the coils of the snake. PMID- 11617025 TI - Brains over muscles: the meaning of intelligence and race in American history. PMID- 11617026 TI - Freud under siege. PMID- 11617027 TI - Curing, poisoning, and sorcery: earlier and later European interpretations of Malay belief and ritual. PMID- 11617028 TI - Surgeon Hans Kierstede of New Amsterdam. PMID- 11617029 TI - Tibb and tibbi institutions in Turkey: a historical survey. PMID- 11617030 TI - Hampshire man [Wilfred Buckley] and the quest for clean milk. PMID- 11617031 TI - To make the spirit whole. PMID- 11617032 TI - Famine's foes in Ch'ing China. PMID- 11617034 TI - The text of Aristotle's "De motu animalium". PMID- 11617033 TI - Dr. Warren's possessions. PMID- 11617035 TI - Guilt and martyrdom: the case of John Bradford. PMID- 11617036 TI - Horses, pigeons, and the therapy of conversion: a psychological reading of Jonathan Edwards's theology. PMID- 11617037 TI - The graduation ceremony of the medical school in "Le malade imaginaire": Moliere's use of Latin and its rendering in the Hebrew translation by N. Altermann. (Heb). PMID- 11617038 TI - Two centuries of eye care in Hawaii. PMID- 11617039 TI - The "battle of Kalahau," as reported in the newspaper Kuokoa. PMID- 11617040 TI - Catastrophic mortality in Hawaii: an update. PMID- 11617041 TI - The nuisance factor in early Honolulu. PMID- 11617042 TI - Darwin revisited. PMID- 11617043 TI - The doctor and the doctor's friend: Logan Clendening and Ernest Hemmingway. PMID- 11617044 TI - The Marion Central Relief Committee and the Soviet famine of 1921-23. PMID- 11617045 TI - The history of the Indaba Tree and Nurses' Memorial, Penhalonga. PMID- 11617046 TI - A new letter by Berkeley on tar-water. PMID- 11617047 TI - Malthus and the pre-famine economy. PMID- 11617048 TI - David Smyth Torrens: physiologist and horologist. PMID- 11617049 TI - [Not Available]. PMID- 11617050 TI - On the botanical excursus in "De natura pueri", 22-27. PMID- 11617051 TI - A new testimonium about Polybus. PMID- 11617052 TI - [A tribute to Hans Diller]. PMID- 11617053 TI - A spurious correlation of r=.70: or historiodemographe, modere tes transports! PMID- 11617055 TI - Burials from the Santa Barbara Presidio chapel. PMID- 11617054 TI - The Bengal famine, 1943 and the brown spot of rice--an inquiry into their relations. PMID- 11617056 TI - Mental testing: origins, evolution and present status. PMID- 11617057 TI - Huxley as educator: a reappraisal. PMID- 11617058 TI - In praise of great men. PMID- 11617059 TI - The new historiography of American medical education. PMID- 11617060 TI - The socialist popularization of science in America, 1901 to the First World War. PMID- 11617061 TI - Approaches to the history of psychological testing. PMID- 11617062 TI - Primary education and the fight against alcoholism in Belgium at the turn of the century. PMID- 11617063 TI - The new historiography of American medical education. PMID- 11617064 TI - Continuity and discontinuity in the history of childhood and family: a reappraisal. PMID- 11617065 TI - Child-saving. PMID- 11617066 TI - [Not Available]. PMID- 11617067 TI - Thought, affect, drive and pathogenesis in Spinoza and Freud. PMID- 11617068 TI - The political self: Auguste Comte and phrenology. PMID- 11617069 TI - Human rights issues affecting women in Napoleonic legal medicine textbooks. PMID- 11617070 TI - Calculable minds and manageable individuals. PMID- 11617071 TI - From free associations: a new radicalization of psychoanalysis. PMID- 11617073 TI - The origins of British "social science": political economy, natural science and statistics, 1830-1835. PMID- 11617072 TI - Wilberforce and Huxley: a legendary encounter. PMID- 11617074 TI - The cost of Pitt's Caribbean campaigns, 1793-1798. PMID- 11617076 TI - The "disappearance" of France, 1896-1940: French politics and the birth rate. PMID- 11617075 TI - Eugenics and ideology. PMID- 11617077 TI - The origins of the Australian Army Nursing Service and its involvement in the First World War. PMID- 11617078 TI - The world of Alexander Johnston: the creolization of ambition, 1762-1787. PMID- 11617079 TI - Medicine, property and the law in Britain, 1800-1914. PMID- 11617080 TI - Medical practice in the Connecticut River Valley, 1650-1750. PMID- 11617081 TI - David Griffith--chaplain, surgeon, patriot. PMID- 11617082 TI - A salve for a sicke Man: William Perkins' contribution to the ars moriendi. PMID- 11617083 TI - James Moore Hickson and spiritual healing in the American Episcopal church. PMID- 11617084 TI - The children shall lead us: the relationship between the U.S. birthrate and Episcopal Church membership. PMID- 11617085 TI - Methodological issues in the use of population registers for fertility analysis. PMID- 11617086 TI - Estimating mortality from annuities, insurance, and other life contingent contracts. PMID- 11617087 TI - Estimating levels of adult mortality in eighteenth-century Spain. PMID- 11617088 TI - Availability of kin and the demography of historical family structure. PMID- 11617089 TI - The life expectancies of colonial Maryland legislators. PMID- 11617090 TI - Regional mortality tables for Spain in the 1860s. PMID- 11617091 TI - Doctor Amos Twitchell: pioneer surgeon. PMID- 11617092 TI - Dr. Samuel Bemis: renaissance yankee. PMID- 11617093 TI - Back from the gates of hell: the deadly campaign of the drafted militia. PMID- 11617094 TI - New Zealanders and the Spanish Civil War. PMID- 11617095 TI - Crisis in a country town: the 1918 epidemic in Temuka. PMID- 11617096 TI - Healthy, wealthy and wise: the urge toward health insurance in New Zealand and the United States. PMID- 11617097 TI - Deviant anonymous: single mothers at the Hopital de la Misericorde in Montreal, 1929-1939. PMID- 11617098 TI - Women and drink in Edwardian England. PMID- 11617099 TI - [Not Available]. PMID- 11617100 TI - On Malthus's population principle and social reform. PMID- 11617101 TI - On the political rhetoric of Freud's individual psychology. PMID- 11617102 TI - Population and ideology. PMID- 11617103 TI - Bibliography of the history of Australian science, no. 3, 1982. PMID- 11617104 TI - Sir Harry Allen and the Foundation of the Walter and Eliza Hall Institute of Medical Research. PMID- 11617105 TI - Lionel Bately Bull 1889-1978. PMID- 11617106 TI - The Kanematsu Memorial Institute of Pathology: the Inglis era, 1933-60. PMID- 11617107 TI - Science in the "pastoral age": veterinary responses to the New South Wales catarrh epizootics of the 1830s. PMID- 11617108 TI - Walter Victor Macfarlane, 1913-82. PMID- 11617109 TI - Robert John Walsh, 1917-83. PMID- 11617110 TI - Robert Ford Whelan, 1922-1984. PMID- 11617111 TI - Alfred Edmund Finckh, 1866-1961: leader the 1898 Coral Reef Boring expedition to Funafuti. PMID- 11617112 TI - The road to fat city: an interpretation of the development of weight consciousness in Western society. PMID- 11617113 TI - Social psychology as political ideology: the case of Wilfred Trotter and William McDougall. PMID- 11617115 TI - Patterns and prosecution of suicide in eighteenth-century Paris. PMID- 11617114 TI - Medicine and medical imagery in Bacon's Great Instauration. PMID- 11617117 TI - When did John Hopton become blind? PMID- 11617118 TI - Body and soul: Bible nurses and the poor in Victorian London. PMID- 11617120 TI - "The question of the poor" in the nineteenth century city. PMID- 11617119 TI - Smallpox in aboriginal Australia, 1829-31. PMID- 11617121 TI - Subtle poison: the puerperal fever controversy in Victorian Britain. PMID- 11617122 TI - The struggle against pulmonary tuberculosis in Australia 1788-1950. PMID- 11617124 TI - Macassans and aboriginal smallpox: the "1789" and "1829" epidemics. PMID- 11617123 TI - Environment, economy and Australian biology, 1890-1939. PMID- 11617125 TI - Smallpox in aboriginal Australia: the early 1830s. PMID- 11617126 TI - Sir Charles Mackellar: psychiatry, eugenics and child welfare in New South Wales, 1900-1914. PMID- 11617128 TI - Craniometry and eugenics in Australia: R. J. A. Berry and the quest for social efficiency. PMID- 11617130 TI - Francis Galton and eugenics. PMID- 11617129 TI - Ego psychology and the historian. PMID- 11617131 TI - The sanitary idea and a Victorian novelist. PMID- 11617132 TI - Sir James McGrigor and the Army Medical Corps. PMID- 11617133 TI - Baikie's exploration of the Niger and his use of quinine. PMID- 11617134 TI - The plague and the fire: reminiscences. PMID- 11617135 TI - The "new treatment" of the insane in Paris: the formation of the lunatic asylum under the French Revolution. PMID- 11617137 TI - The descent of genius: Charles Darwin's brilliant career. PMID- 11617136 TI - Henry Moule and cholera in Dorset: nineteenth-century sanitary reform. PMID- 11617138 TI - A tall story? The standard of living debate. PMID- 11617139 TI - William Hunter, surgeon. PMID- 11617140 TI - Images of the nineteenth-century nurse. PMID- 11617141 TI - "Mad all my life": the dark side of Samuel Johnson. PMID- 11617142 TI - "France in peril": the French fear of denatalite. PMID- 11617144 TI - Before the fringe: quack medicine in Georgian England. PMID- 11617143 TI - Under the influence: Mesmerism in England. PMID- 11617145 TI - Luther: sex, marriage and motherhood. PMID- 11617146 TI - Pox and paranoia in renaissance Europe. PMID- 11617147 TI - Ministering angels. PMID- 11617148 TI - Man and body in the history of the modern age. PMID- 11617149 TI - The medical personnel at the court of Queen Anne. PMID- 11617150 TI - "Nawghtye mallenchollye": some faces of madness in Tudor England. PMID- 11617153 TI - Holocaust and genocide: the essential dialectic. PMID- 11617151 TI - Sick people, health and doctors in Georgian England. PMID- 11617154 TI - The role of Turkish physicians in the World War I genocide of Ottoman Armenians. PMID- 11617155 TI - Essay: On the place of the Holocaust in history. In honour of Franklin H. Littell. AB - The Holocaust was a human event, perpetrated for human reasons which can be historically explained. As an event within history, it is unique in terms of the murderers'S motivation: a mission to rescue Germany, Europe and the world from their supreme enemy, the Jews. Other events, such as that which seems to most closely parallel the Holocaust, the Armenian massacres by the Turks in World War I, bear certain similarities to the Holocaust. Yet. In its attempt at total physical annihilation of all Jews everywhere, the Holocaust is unique. It stands at the extreme end of a continuum of human brutality, extending from mass murder, which has become commonplace, to genocide, and to Holocaust. PMID- 11617156 TI - "Rollbahn mord": the early activities of Einsatzgruppe C. AB - Einsatzgruppe C was active in the Ukraine and became responsible for the murder of Jews, including the Babi-Yar massacre at Kiev. At first, men only were murdered, but after a number of weeks, women and children became victims, too. The Einsatzgruppe was assisted in its task by the Wehrmacht, the German police, other units of the SS and by both individuals and organized groups of local Ukrainians and Germans. Though no clear orders regarding the scope of the Final Solution seem to have been given, Einsatzgruppe C relentlessly continued pursuing its victims until the act of murder itself became routine. PMID- 11617157 TI - Sajmiste--an extermination camp in Serbia. AB - German army reprisals against the local Serbian population's resistance to the Occupation, between August and December 1941, were used by the army as an excuse to murder the Jewish men of Serbia. Jewish women and children (8000-9000) were then interned in Sajmiste, a concentration camp established at the site of an abandoned exhibition ground on the outskirts of Belgrade After seeking RSHA aid to deal with these Jews, the local German administration received a gas van with which it murdered the Jews, from March to May 1942 This is the only known instance of on-the-spot gassing outside of Eastern Europe. PMID- 11617158 TI - Kommandostab Reichsfuhrer-SS: Himmler's personal murder brigades in 1941. PMID- 11617160 TI - Hydroelectric development and dietary delocalization in northern Manitoba, Canada. PMID- 11617161 TI - The forced sterilization program under the Indian emergency: results in one settlement. PMID- 11617162 TI - The politics of health in the fourth world: a northern Canadian example. PMID- 11617163 TI - Socialist development and primary health care: the case of Tanzania. PMID- 11617164 TI - Primary health care in the People's Republic of China: a march backward? PMID- 11617165 TI - Native American suicide in New Mexico, 1957-1979: a comparative study. PMID- 11617166 TI - Psycho-social stress and the construction of a flood-control dam in Santa Catarina, Brazil. PMID- 11617167 TI - Truk suicide epidemic and social change. PMID- 11617168 TI - The theme of suicide in the work of Thomas Mann. [Tr. by B. Jager]. PMID- 11617169 TI - Suicide as communication: Adler's concept and current applications. PMID- 11617170 TI - The impact of Hungarian scientists on the development of biochemistry. PMID- 11617171 TI - Medicine and religion in 18th-century England: a case of conflict? PMID- 11617172 TI - Descartes' mathematisation of medicine. PMID- 11617174 TI - Some early Italian epidemiological maps. PMID- 11617175 TI - United States steerage legislation: the protection of the emigrants en route to America. AB - The immigrant experience of travelling to America was fraught with discomfort and often with danger. Legislation regarding minimum standards of comfort and safety by the late nineteenth century related mainly to sailing ships: by this time, most immigrants travelled under steam power. This article charts the concerns and responses of the US government over the conditions of the immigrants en route. Legal decisions, Congress investigations and reports from other interested bodies all played a part in producing legislation to further regulate and improve the passage to America in the period 1880-1924. PMID- 11617176 TI - When the rains failed: famine, relief and mortality in British India. PMID- 11617178 TI - The 1918-1919 influenza pandemic--the Indian experience. PMID- 11617181 TI - Fertility and Fiji's Indian grants, 1879-1919. PMID- 11617183 TI - Rural health care in the Madras Presidency: 1919-39. PMID- 11617185 TI - Infant mortality and Fiji's Indian migrants, 1879-1919. PMID- 11617187 TI - The autobiography of Dr. Edward A. Rumely. PMID- 11617188 TI - It was not smallpox: the Miami deaths of 1732 reexamined. PMID- 11617186 TI - William James and I. A. Richards. PMID- 11617189 TI - A Hoosier nurse in France: the World War I diary of Maude Frances Essig. PMID- 11617190 TI - Public health and sanitation in an Indiana community: the garbage disposer and Jasper. PMID- 11617191 TI - A Hoosier country doctor: Dr. Harry K. Engleman's medical ledger, 1911-1917. PMID- 11617192 TI - Two Hoosiers and the two food laws of 1906. PMID- 11617193 TI - Crime and mental illness in Middletown, 1870-1910: a study in social control. PMID- 11617194 TI - They had to go out, but the Dobbins Boat brought them back. PMID- 11617195 TI - Marine casualties on the Great Lakes 1863-1873: an analysis. PMID- 11617196 TI - Reflecting upon a decade of disasters: the evolving response of the international community. PMID- 11617198 TI - The evolution of Japanese images of the environment. PMID- 11617197 TI - Disarmament and other options for western policy-making on chemical warfare. PMID- 11617199 TI - [Not Available]. PMID- 11617201 TI - Family planning, fertility decline, and family size preference in Hong Kong: some general observations. PMID- 11617200 TI - [Not Available]. PMID- 11617203 TI - Medical practitioners of African descent in colonial Ghana. PMID- 11617202 TI - Anglo-American rivalry and the establishment of a medical research institute in Egypt, 1942-1948. PMID- 11617204 TI - Rwanda and Burundi, 1889-1930: chronology of a slow assassination. PMID- 11617205 TI - Twentieth century reflections on death in Zanzibar. PMID- 11617206 TI - The 1920s anti-yaws campaigns and colonial medical policy in Kenya. PMID- 11617207 TI - "Le bebe en brousse": European women, African birth spacing and colonial intervention in breast feeding in the Belgian Congo. PMID- 11617208 TI - Epidemics, famines, and population in the Cape Verde Islands, 1580-1900. PMID- 11617210 TI - War, famine, and pestilence in late precolonial Tanzania: a case for a heightened mortality. PMID- 11617211 TI - Fertility, mortality, and migration in the Cape Colony, 1891-1904. PMID- 11617212 TI - Colonialism, class and African medicine in West Africa. PMID- 11617213 TI - Sieg heil to the most glorious era of German sport: continuity and change in the modern German sports movement. PMID- 11617214 TI - The robust woman and the muscular Christian: Catharine Beecher, Thomas Higginson, and their vision of American society, health and physical activities. PMID- 11617215 TI - [Not Available]. AB - Some ideas, whether right or wrong, seem never to die, whatever might be the general evolution of knowledge, of science, or simply of good common sense. This is exactly the case with physical education or sports. For centuries, and especially since the middle of the nineteenth century, its advocates have fought for recognition of its all-round virtues, taken as a concept. But to attain a high level of recognition, not only in society but in official government circles, certain conditions were necessary. Education as a whole, around the middle of the nineteenth century, had to be strict and similar to military drill to be considered efficient, although the French middle classes and bourgeoisie had very little taste for the military. Although they admired physical prowess they had a horror of regimentation. But later on, when the Prussians so easily defeated Austria, feelings of doubt in French superiority began to spread, and a handful of theoreticians of physical exercise tried to show that to combat the so called degeneration of the race, it was essential to impose a system of education in which physical exercise, coupled with military drill, still had an important place. As scientific arguments they referred to the theories of evolution and its then accepted principle, according to Lamarck, or the transmission of acquired properties and character. Darwin was still unknown in France at that time. These zealous advocates succeeded in convincing the Minister of Public Education, Victor Duruy, to include gymnastics in the normal course of studies in all schools, and by 1869 one can say that a craze for all types of physical exercise and sport had spread into many levels of society. That was the start of a never ending movement which has passed through various stages of evolution corresponding to the changes in society itself. It has therefore changed its methods, its ways, its forms, but the overall principle remains the same, in spite of the improved understanding of human physiology for instance. Huge amounts of energy and money were spent on realizing this theory: politicians, educators, the military, religious authorities, men of distinction, all fought for the best possible application of this miraculous principle which was believed to cure all ills in this world. Was it really worthwhile? Was it possible to expect objectively measurable results on a national scale if the social factors - such as standards of living, hygiene, working hours, urban conditions - were not taken into account? The history of this element requires a deep understanding of the evolution of most of the factors which make up real life in a country such as France, which experienced various stages in a industrial revolution as well as many political changes. In spite of this evolution, one must acknowledge that false beliefs survived well into the 1940s, and furthermore, physical exercise, whatever its form, still belongs in many ways to hedonism and is therefore difficult to impose as a universal solution to political problems. As a democracy, France could not accept militarization. PMID- 11617216 TI - Historical demography. PMID- 11617217 TI - Jamaican women in the US health industry: caring, cooking and cleaning. PMID- 11617218 TI - The role of the sensible species in St. Thomas' epistemology: a comparison with contemporary perception theory. PMID- 11617220 TI - American and British pharmaceutical industries. PMID- 11617219 TI - Chemical weapons and deterrence: the World War II experience. PMID- 11617221 TI - Dr. Thomas Beddoes: the interaction of pneumatic and preventive medicine with chemistry. PMID- 11617222 TI - NJAA: food shortages and famines in Tanzania between the wars. PMID- 11617223 TI - The visit of Frederick Forbes to the Somali coast in 1833. PMID- 11617224 TI - Sir William Petty: his Irish estates and Irish population. PMID- 11617225 TI - Premature mortality in the Republic of Ireland. AB - Regional variations in the incidence of premature deaths between 1971 and 1981 arc examined by mapping standardised mortality ratios for deaths under the age of 65. Premature mortality is also examined with regards to the number of years of normal life lost by those who die prematurely, using a specially defined unfulfilled life index. Unfulfilled life and premature deaths arc found to have a higher incidence in the major urban areas and a lower incidence in western counties, although there are some interesting differences in their spatial distributions. Differences with regard to sex. age at death and cause of death are also examined. PMID- 11617226 TI - Historical revision XXII: John White (c. 1756-1832), surgeon-general of New South Wales: biographical notes on his Irish origins. PMID- 11617227 TI - Henderson Wightman, R. N., 1810-16. PMID- 11617228 TI - Assistant surgeon William Bradshaw, V.C. PMID- 11617229 TI - Cows and convalescents: government house as health and education centre, 1917 1924. PMID- 11617230 TI - Physicians, quacks & opium eaters: the professionalization of medicine in the 19th century. PMID- 11617231 TI - The spiritual medicine of early Muslims. PMID- 11617232 TI - Muslim sources of Albert's contribution to optics. PMID- 11617233 TI - Family planning programs and fertility decline in Taiwan and mainland China: a comparison. PMID- 11617234 TI - Maize, cattle and mosquitoes: the political economy of malaria epidemics in colonial Swaziland. PMID- 11617235 TI - From "death camps" to cordon sanitaire: the development of sleeping sickness policy in the Uele district of the Belgian Congo, 1903-1914. PMID- 11617236 TI - Judge William Henry Hastie and military hemophobia, 1940-1943. PMID- 11617237 TI - Rituals of exclusion and the Jonestown dead. PMID- 11617238 TI - Cleaning up Newport: the U.S. Navy's persecution of homosexuals after World War I. PMID- 11617239 TI - What is a health fad? The posture movement as an example. PMID- 11617240 TI - Gynecological instruments and surgical decisions at a hospistal in late 19th century America. PMID- 11617241 TI - Casting bread on troubled waters: Grahamism and the west. PMID- 11617242 TI - The changing nature of American medicine. PMID- 11617243 TI - Interpreting nineteenth-century pharmacy practice: the Ohio experience. PMID- 11617244 TI - Wisconsin's midwives as working women: immigrant midwives and the limits of a traditional occupation, 1870-1920. PMID- 11617245 TI - Woodrow Wilson and the case for psychohistory. PMID- 11617246 TI - Jonathan Edwards's religious psychology. PMID- 11617247 TI - "Best for babies" or "preventable infanticide"? The controversy over artificial feeding of infants in America, 1880-1920. PMID- 11617248 TI - The Rockefeller Foundation, China, and cultural change. PMID- 11617249 TI - Power, conflict, and identity in mid-nineteenth-century American medicine: therapeutic change at the Commercial Hospital in Cincinnati. PMID- 11617250 TI - "Uncontrolled desires": the response to the sexual psychopath, 1920-1960. PMID- 11617251 TI - The Fort Pillow massacre: a statistical note. PMID- 11617252 TI - Health care practices in the life of Katherine Schrag Kaufman. PMID- 11617253 TI - Medical and dental services in early Mennonite communities. PMID- 11617254 TI - Health care beliefs and practices of the Hutterites of Forest River community, North Dakota. PMID- 11617255 TI - The evolution of anatomical knowledge in ancient India, with special reference to cross-cultural influences. PMID- 11617256 TI - Medicine and immortality in T'ang China. PMID- 11617257 TI - The americanization of Sigmund Freud: Adaptations of psychoanalysis before 1917. PMID- 11617258 TI - The psychological context of three tales by Poe. PMID- 11617259 TI - History, politics, and health in early American thought: the case of David Ramsay. PMID- 11617260 TI - Elizabeth Packard: nineteenth-century crusader for the rights of mental patients. PMID- 11617261 TI - No legal impediment: access to abortion in the United States. PMID- 11617262 TI - Terror on the Hassayampa: the Walnut Grove Dam disaster of 1890. PMID- 11617263 TI - Bigelow's "American medical botany". PMID- 11617264 TI - Transition from natural to semi-controlled birth rate in India. PMID- 11617265 TI - Trends in birth and death rates in Goa, 1820-1910: some evidence gathered from the baptism and burial records of a parish. PMID- 11617266 TI - Suicide and internal migration in Sri Lanka. PMID- 11617267 TI - The spiral of suicide and social change in Sri Lanka. PMID- 11617268 TI - Health, fertility, and society in India: microstudies and macrostudies--a review article. PMID- 11617269 TI - Science and medicine in Imperial China--the state of the field. PMID- 11617270 TI - The demographic transition in the Baltic Provinces and Finland: prospects for a comparative study. PMID- 11617271 TI - The economic demise of blacks in America: a prelude to genocide? PMID- 11617272 TI - The impact of region on racial differences in attitudes toward legal abortion. PMID- 11617273 TI - The Royal College of Physicians of London and its support of the parliamentary cause in the English Civil War. PMID- 11617274 TI - A shaman's "sucking tube" from San Diego County, California. PMID- 11617275 TI - Disease and demographic patterns at Santa Cruz Mission, Alta California. PMID- 11617276 TI - Demographic patterns in the missions of central Baja California. PMID- 11617277 TI - From purification to celebration: the history of the service for women after childbirth. PMID- 11617278 TI - Rural protest and medical professionalism in turn-of-the-century Ontario. PMID- 11617280 TI - Health care financing and the Canada Health Act. PMID- 11617279 TI - The social effects of demographic change: Canada 1851-1981. PMID- 11617281 TI - Hysteria and insanity in women: a nineteenth-century Canadian perspective. PMID- 11617282 TI - Mortality and labour on the Codrington Estates, Barbados. PMID- 11617283 TI - John Alcindor and James Jackson Brown--Afro-Caribbean doctors in London 1899 1953. PMID- 11617284 TI - Political theology: the role of organized religion in the anti-abortion movement. PMID- 11617286 TI - TV articulates abortion in America: competition and the production in cultural repertoire. PMID- 11617285 TI - Africanus Horton as a constitution-maker. PMID- 11617287 TI - The question of judgment: intelligence and medicine. PMID- 11617288 TI - The enclosure of the body: on the historical relativity of "health", "nature" and the environment of sport. PMID- 11617289 TI - Incommunicable knowledge: science, technology and the clinical art in Britain 1850-1914. PMID- 11617290 TI - The wandering Jew and the problem of psychiatric anti-Semitism in fin-de-siecle France. PMID- 11617291 TI - "Somehow very distasteful": doctors, men and sexual problems between the wars. PMID- 11617292 TI - The mad man as artist: medicine, history and degenerate art. PMID- 11617293 TI - Doctors, workers and the scientific cosmology of the industrial world: the social construction of "health" and the "homo hygienicus." PMID- 11617294 TI - The history of smallpox vaccination in Germany: a first step in the medicalization of the general public. PMID- 11617296 TI - The bio-medical origins of urban sociology. PMID- 11617295 TI - Professional medicine and the working classes in Germany. PMID- 11617297 TI - Professionalization and socialization of physicians in Wilhelmine and Weimar Germany. PMID- 11617298 TI - The salpetriere in the age of Charcot: an institutional perspective on medical history in the late nineteenth century. PMID- 11617299 TI - Gullible's travails: tuberculosis and quackery 1890-1930. PMID- 11617300 TI - Schweninger's seminar. PMID- 11617301 TI - The enclosure of the body--on the historical relativity of "health," "nature" and the environment of sport. PMID- 11617302 TI - Excess deaths and industrialization: a realist theory of Stalinist economic development in the 1930s. PMID- 11617303 TI - A dedicated medical student: Solomon Mordecai, 1819-1822. PMID- 11617304 TI - Sir Robert Malory, Prior of the Hospital of St. John of Jerusalem in England (1432-1439/40.) PMID- 11617305 TI - Religion and magic in Elizabethan Wales: Robert Holland's dialogue on witchcraft. PMID- 11617306 TI - Income, public works, and mortality in early twentieth-century American cities. PMID- 11617307 TI - Mold poisoning and population growth in England and France, 1750-1850. PMID- 11617308 TI - Inequality and childhood mortality: a comparison of England and Wales, 1911, and the United States, 1900. PMID- 11617309 TI - A peculiar population: the nutrition, health, and mortality of American slaves from childhood to maturity. PMID- 11617310 TI - New evidence on the causes of slave and crew mortality in the Atlantic slave trade. PMID- 11617311 TI - The effects of population redistribution on the level of mortality in nineteenth century England and Wales. PMID- 11617312 TI - Deaths of slaves in the middle passage. PMID- 11617313 TI - The quality of services in company towns: sanitation in coal towns during the 1920s. PMID- 11617314 TI - Biological consequences of segregation and economic deprivation: a post-slavery population from southwest Arkansas. PMID- 11617315 TI - Taxation, health insurance, and market failure in the medical economy. PMID- 11617316 TI - The political economy of the pharmaceutical industry. PMID- 11617317 TI - Mary Dendy, 1855-1933, pioneer of residential schools for the feeble minded. PMID- 11617319 TI - Eugenics and the education of women in the United States. PMID- 11617318 TI - The First World War, sex education, and the American Social Hygiene Association's campaign against venereal disease. PMID- 11617320 TI - Ethnic doctors in Los Angeles's Chinatown. PMID- 11617321 TI - American Indians and drunkenness. PMID- 11617322 TI - Ecological inequities and the new South: black communities under siege. PMID- 11617323 TI - Spreading carnal knowledge or selling dirt cheap? Nicolas Venette's Tableau de l'amour conjugal in eighteenth century England. PMID- 11617324 TI - "Every material of the best quality": the foundation of Bloomfield Hospital, Dublin. PMID- 11617326 TI - The evolution of the Anglo-American rural cemetery: landscape architecture as social and cultural history. PMID- 11617327 TI - The botanical garden of Padua: the first hundred years. PMID- 11617325 TI - The design of the early British cemeteries. PMID- 11617328 TI - Plant effluvia. Changing notions of the effects of plant exhalations on human health in the eighteenth and nineteenth centuries. PMID- 11617329 TI - Hortus auriaci: the Gardens of Orange and their place in late 17th-century botany and horticulture. PMID- 11617330 TI - The psychotherapy scence in Euripides' Bacchae. PMID- 11617331 TI - The effect of a simile: Empedocles' theories of seeing and breathing. PMID- 11617332 TI - Two buildings in sanctuaries of Asklepio. PMID- 11617333 TI - Physiology and medicine in a Greek novel: Achilles Tatius' Leucippe and Clitophon. PMID- 11617335 TI - "Fit localities for an asylum": the historical geography of the nineteenth century "mad business" in England as viewed through the pages of the asylum journal. PMID- 11617334 TI - Mortality, weather and prices in London 1675-1825: a study of short-term fluctuations. PMID- 11617336 TI - Uneven zenith: towards a geography of the high period of municipal medicine in England and Wales. PMID- 11617337 TI - Alessandro Achillini (1463-1512) and Ockhamism at Bologna (1490-1500). PMID- 11617338 TI - Teleology, chance, and Aristotle's theory of spontaneous generation. PMID- 11617341 TI - What was social medicine? An historiographical essay. PMID- 11617339 TI - Did Descartes have a philosophical theory of sense perception? PMID- 11617342 TI - Governments and radical oppositions: the psychologies of system-supporting and system-challenging behavior. PMID- 11617343 TI - Malnutrition, public policy, and agrarian change in Guatemala. PMID- 11617344 TI - Infection, hidden hunger, and history. PMID- 11617345 TI - The nutrition-mortality link in past times: a comment. PMID- 11617346 TI - Famines, epidemics, and population growth in India. PMID- 11617347 TI - Nutrition in African history. PMID- 11617348 TI - Secular changes in American and British stature and nutrition. PMID- 11617349 TI - Secular changes in American and British stature and nutrition. PMID- 11617350 TI - Diet and delocalization: dietary changes since 1750. PMID- 11617351 TI - The value of contemporary food and nutrition studies for historians. PMID- 11617352 TI - Seasonal aspects of infant and childhood mortality: Philadelphia, 1865-1920. PMID- 11617353 TI - Differential mortality in the United States before 1900. PMID- 11617354 TI - Work, pregnancy, and infant mortality among southern slaves. PMID- 11617355 TI - Plantation slave life in Barbados: a physical anthropological analysis. PMID- 11617356 TI - Biochemistry, suicide, and history: possibilities and problems. PMID- 11617357 TI - Hard choices: supplying water to New England towns. PMID- 11617359 TI - Immigration, mortality, and population growth in Boston, 1840-1880. PMID- 11617358 TI - The case for birth control before 1850: Nantucket reexamined. PMID- 11617360 TI - Iron in two seventeenth-century plague epidemics. PMID- 11617361 TI - Climatic variability and the European mortality wave of the early 1740's. PMID- 11617362 TI - Escaping from constraints: the industrial revolution in a Malthusian context. PMID- 11617363 TI - Death in London, 1750-1909. PMID- 11617364 TI - Voice change in human biological development. PMID- 11617365 TI - Fertility, nutrition, and pellagra: Italy during the vital revolution. PMID- 11617366 TI - Morbidity and mortality on the North Atlantic passage: eighteenth-century German immigration. PMID- 11617367 TI - Urban sanitation in preindustrial Japan. PMID- 11617368 TI - Mortality in Victorian England: models and patterns. PMID- 11617369 TI - Out of Africa: the slave trade and the transmission of smallpox to Brazil, 1560 1831. PMID- 11617370 TI - Diagnosis, death, and diet: the case of London, 1750-1909. PMID- 11617371 TI - Breastfeeding and maternal sexuality in colonial America. PMID- 11617373 TI - Birth weight and standards of living in Vienna, 1865-1930. PMID- 11617374 TI - Epidemiology and the Pacific labor trade. PMID- 11617375 TI - Environment, health, and medicine in the old regime. PMID- 11617376 TI - American immigration, fertility, and race suicide at the turn of the century. PMID- 11617377 TI - Medieval dynastic decisions: evolutionary biology and historical explanation. PMID- 11617378 TI - Harriet Lane Johnston: pioneer advocate of special care for children with chronic diseases. PMID- 11617379 TI - Matters of life and death: a demographic analysis of eighteenth century Lancaster Reformed Church records. PMID- 11617380 TI - The education of a physician in early nineteenth century. PMID- 11617381 TI - Medical doctor, popular saint: the syncretic symbolism of Ricardo Moreno Canas and Jose Gregorio Hernandez. PMID- 11617382 TI - Cholera and race in the Caribbean. PMID- 11617383 TI - The frequency and severity of medical malpractice claims. PMID- 11617384 TI - Direct and indirect effects of regulation: a new look at OSHA's impact. PMID- 11617385 TI - The effect of commercial practice restrictions: the case of optometry. PMID- 11617386 TI - The economic consequences of the OSHA cotton dust standards: an analysis of stock price behavior. PMID- 11617387 TI - The effects of fuel economy standards on automobile safety. PMID- 11617388 TI - Consent, coercion and consortium: the sexual politics of sterilisation. PMID- 11617389 TI - Contemporary social historical perspectives on mental health reform. PMID- 11617390 TI - The criminal sanction as it relates to human reproduction: the genesis of the statutory prohibition of abortion. PMID- 11617391 TI - Thomas Wakley--an enemy of injustice. PMID- 11617392 TI - The right of women to graduate in medicine--Scottish judicial attitudes in the nineteenth century. PMID- 11617393 TI - Stanley Hall: a priestly prophet of a new dispensation. PMID- 11617394 TI - Book collector, bibliographer, and benefactor of libraries: Sir William Osler. PMID- 11617396 TI - Dead or alive? The holy man as healer in East and West in the late 6th century. PMID- 11617395 TI - The search for the cause of beriberi in the Malay Peninsula: the contribution of Dr. W. L. Braddon. PMID- 11617397 TI - Western society and alchemy from 1200-1500. PMID- 11617398 TI - The theme of folly in Rabelais and Ariosto. PMID- 11617399 TI - Shakespeare's metaphors of health: food, sport, and life-preserving rest. PMID- 11617400 TI - The dance of the madmen in the Duchess of Malfi. PMID- 11617401 TI - The U. S. Army medical department and the attack on Pearl Harbor. PMID- 11617402 TI - Stripping away the veneer: P. O. W. survival in the Far East as an index of cultural atavism. PMID- 11617403 TI - U.S. Army medical preparations and the outbreak of war: the Philippines, 1941-6 May 1942. PMID- 11617404 TI - Medicine in antebellum Mississippi. PMID- 11617405 TI - Jefferson Davis and his health, Part I: June 1808-December, 1860. PMID- 11617406 TI - Jefferson Davis and his health. Part II: January, 1861-December, 1889. PMID- 11617407 TI - "To be, to do, and to suffer": responses to illness and death in the nineteenth century central South. PMID- 11617408 TI - The political economy of food production and nutrition in southern Africa in historical perspective. PMID- 11617409 TI - Freud, marriage, and late Viennese liberalism: a commentary from 1905. PMID- 11617410 TI - Hitler's early doctors: Nazi physicians in predepression Germany. PMID- 11617411 TI - Irreconcilable differences: David H. Smith's relationship with the muse of Mormon history. PMID- 11617413 TI - That elusive rhubarb: some botanical and horticultural aspects before the twentieth century. PMID- 11617415 TI - Healthy livestock--wholesome meat: a short history. PMID- 11617416 TI - Animal parasitology in the United States Department of Agriculture: 1886-1984. PMID- 11617418 TI - Meat and poultry inspection in the United States Department of Agriculture. PMID- 11617420 TI - Veterinary medicine in the United States Department of Agriculture. PMID- 11617423 TI - Animal husbandry--animal science. PMID- 11617424 TI - The educational system and black mental health. PMID- 11617425 TI - Document: letters of James Durham to Benjamin Rush. PMID- 11617426 TI - Women in medicine. PMID- 11617427 TI - The roots of the LSU School of Medicine in Shreveport. PMID- 11617428 TI - Medicine in early North Louisiana. PMID- 11617429 TI - Civil War medicine in North Louisiana. PMID- 11617430 TI - Yellow fever: the Shreveport epidemic of 1873. PMID- 11617431 TI - Dr. James Cronin Egan. PMID- 11617432 TI - Child health care and pediatrics. PMID- 11617434 TI - Yellow fever: the Shreveport epidemic of 1873. PMID- 11617433 TI - The roots of the LSU School of Medicine in Shreveport. PMID- 11617435 TI - History of medicine in Shreveport: the black experience. PMID- 11617437 TI - A bomb or a bullet or the bloody flux? Population change in the Aitape inland, Papua New Guinea, 1941-1945. PMID- 11617436 TI - Cane River physician: the practice and letters of Dr. J. A. Leveque, 1832-1893. PMID- 11617438 TI - A dysentery epidemic in New Guinea and its mortality. PMID- 11617439 TI - Veil of dishonour: sexual jealousy and suicide on Fiji plantations. PMID- 11617440 TI - Mortality and the Pacific labour trade. PMID- 11617441 TI - The psychohistory of warfare: the coevolution of culture, psyche and enemy. PMID- 11617442 TI - An airing of the Clean Air Act. PMID- 11617443 TI - State implementation effort and federal regulatory policy: the case of occupational safety and health. PMID- 11617444 TI - Health politics in the 1980s. PMID- 11617445 TI - Male labor force participation and the social security disability program. PMID- 11617446 TI - Changing world prices, women's wages, and the fertility transition: Sweden, 1860 1910. PMID- 11617447 TI - Accounting for changes in tastes. PMID- 11617448 TI - Malthus was right after all: poor relief and birth rates in southeastern England. PMID- 11617449 TI - A model of the demand for longevity and the value of life extension. PMID- 11617450 TI - Water policy decision-making and implementation in the Johnson administration. PMID- 11617451 TI - Leprosy in New Zealand. PMID- 11617452 TI - On calculating the crude death rates in the Pacific labour trade. PMID- 11617453 TI - Madness and society in the street ballads of early modern England. PMID- 11617454 TI - George E. Cannon: Black churchman, physician, and Republican politician. PMID- 11617455 TI - Bright delusion: Presbyterians and African colonization. PMID- 11617456 TI - Religio medici: Karl A. Menninger, Calvinism and the Presbyterian Church. PMID- 11617457 TI - Anton T. Boisen and the study of "living human documents." PMID- 11617458 TI - Primary medical care and the friendly societies in nineteenth and early twentieth century Victoria. PMID- 11617459 TI - The beginning of a quarantine system at the Quarantine Station, North Head, Port Jackson. PMID- 11617460 TI - Charles Evans Reeves: saint or rogue? PMID- 11617461 TI - David Laseron: a clergyman in the Rookwood Asylum. PMID- 11617462 TI - The "Mutumwa" churches of Zambia: an indigenous African religious healing movement. PMID- 11617463 TI - The Mutumwa Church of Peter Mulenga (part 1). PMID- 11617464 TI - "Exchanging earth for heaven": death in the Papuan mission fields. PMID- 11617466 TI - "Working for the good of the community": Rest Haven Preventorium for children. PMID- 11617465 TI - The Waksman Institute of Microbiology 1954 to 1984. PMID- 11617467 TI - Religious influence and congressional voting on abortion. PMID- 11617468 TI - Sociology's one law: religion and suicide in the urban context. PMID- 11617469 TI - Class and the treatment of the insane in mid-nineteenth century Scotland. PMID- 11617470 TI - Thai traditional medicine: ancient thought and practice in a Thai context. PMID- 11617471 TI - Wirral Hospital records. PMID- 11617472 TI - The British Army and the Caribbean expeditions of the war against revolutionary France 1793-1801. PMID- 11617473 TI - The journal of Patrick Sinclair Laing, Assistant Surgeon, 86th Regiment, 1842 1848. PMID- 11617474 TI - Witchcraft, healing and historians' crazes. PMID- 11617475 TI - The moral message of child guidance. PMID- 11617476 TI - Immigrant suicide in the United States: toward a psycho-social history. PMID- 11617477 TI - Historical notes on the doctors' work ethic. PMID- 11617479 TI - History and health policy: an autobiographical note on the decline of historicism. PMID- 11617480 TI - Research or advocacy: federal occupational safety and health policies during the New Deal. PMID- 11617478 TI - Prostitution and charity: the Magdalen Hospital, a case study. PMID- 11617481 TI - Public policy on human reproduction and the historian. PMID- 11617482 TI - American physicians and birth control, 1936-1947. PMID- 11617483 TI - Why not the best? Some reasons and examples of child health and rural hospitals. PMID- 11617484 TI - Government actions in times of crisis: lessons from the history of drug regulation. PMID- 11617485 TI - The nature and style of practice of immigrant midwives in early twentieth century Massachusetts. PMID- 11617486 TI - Paralysis: the rise and fall of a "hysterical" symptom. PMID- 11617487 TI - Empirics and charlatans in early modern France: the genesis of the classification of the "other" in medical practice. PMID- 11617489 TI - The evolution of the doctrine of mental cruelty in Victorian American divorce, 1790-1900. PMID- 11617488 TI - Submerged sensuality: technology and perceptions of bathing. PMID- 11617490 TI - The prevention of diphtheria in Canada and Britain 1914-1945. PMID- 11617491 TI - Madness in early American history: insanity in Massachusetts from 1700 to 1820. PMID- 11617492 TI - The myths of social control and custodial oppression: patterns of psychiatric medicine in late nineteenth-century institutions. PMID- 11617493 TI - The right to be sick: American physicians and nervous patients, 1885-1910. PMID- 11617494 TI - "Civilizing Rio de Janeiro": the public health campaign and the riot of 1904. PMID- 11617495 TI - Modern obstetrics and working-class women: the New York Midwifery Dispensary, 1890-1920. PMID- 11617496 TI - The contemporary historiography of AIDS. PMID- 11617497 TI - Issues in the political economy of health in Southern Africa. PMID- 11617498 TI - Tuberculosis and the development of industrial health policies on the Witwatersrand, 1902-1932. PMID- 11617499 TI - The local state and public health reform in South Africa: Bloemfontein and the consequences of the Spanish 'flu epidemic of 1918. PMID- 11617500 TI - Doctors or medical aids--the debate over the training of black medical personnel for the rural black population in South Africa in the 1920s and 1930s. PMID- 11617501 TI - Facing the "black peril": the politics of population control in South Africa. PMID- 11617502 TI - Work and health in Namibia: preliminary notes. PMID- 11617503 TI - Mother's sacred duty: breast-feeding patterns among middle- and upper-class women in the antebellum South. PMID- 11617505 TI - Cows, ticks, and disease: a medical interpretation of the Southern cattle industry. PMID- 11617504 TI - Yellow fever and black policemen in Memphis: a post-reconstruction anomaly. PMID- 11617506 TI - Pyotr Franzevich Lesgaft (1837-1909): the founder of Russian physical education. PMID- 11617507 TI - Sexual equality and the legacy of Catharine Beecher. PMID- 11617508 TI - "It pays": John H. Patterson and industrial recreation at the National Cash Register Company. PMID- 11617509 TI - The health reformers: George Barker Windship and Boston's strength seekers. PMID- 11617510 TI - Sport in a middle-class Utopia: Asbury Park, New Jersey, 1871-1895. PMID- 11617511 TI - Edward M. Hartwell and physical training at the Johns Hopkins University, 1879 1890. PMID- 11617512 TI - Physiologists, physicians, and physical educators: nineteenth century biology and exercise, hygienic and educative. PMID- 11617513 TI - Bernarr Macfadden: reformer of feminine form. PMID- 11617514 TI - Exercise, physical capability, and the eternally wounded woman in late nineteenth century North America. PMID- 11617515 TI - The scientific quest for physical culture and the persistent appeal of quackery. PMID- 11617516 TI - Anabolic steroids: the gremlins of sport. PMID- 11617517 TI - Feminist Charlotte Perkins Gilman's pursuit of health and physical fitness as a strategy for emancipation. PMID- 11617518 TI - Plato: on death and dying. PMID- 11617520 TI - Medicine comes to town: medicine and social structure in urban Britain, 1780 1870. PMID- 11617519 TI - The emergence of bureaucracy: the Vancouver health department, 1886-1914. PMID- 11617521 TI - Dissection and divinity in Leonardo's late anatomies. PMID- 11617522 TI - Doctor Parma's medicinal macaronic: poem by Bartolotti, pictures by Giorgione and Titian. [Wellcome MS 461]. PMID- 11617524 TI - Pioneer medicines: doctors, nostrums, and folk cures. PMID- 11617525 TI - Opiate addiction in the American West, 1850-1920. PMID- 11617523 TI - Bishop Bradwardine on the artificial memory. PMID- 11617526 TI - Medicine in the Indian-fighting army, 1866-1890. PMID- 11617527 TI - Medical education in the Far West. PMID- 11617528 TI - Chasing the cure--a history of healthseekers to Albuquerque, 1902-1940. PMID- 11617529 TI - Medicine in the West: an historical overview. PMID- 11617530 TI - Photography in medicine. PMID- 11617531 TI - John Luke Poett: a pioneer veterinarian in western Canada. PMID- 11617532 TI - Animal health in the west. PMID- 11617533 TI - Veterinary medicine in the west: introduction: an overview. PMID- 11617534 TI - The farmer thought it might be bluetongue. PMID- 11617535 TI - George Wilkins Kendall and early efforts to control scabies in western range sheep. PMID- 11617536 TI - Mark Francis and veterinary medicine in Texas, 1880-1936. PMID- 11617537 TI - Professionalization of veterinary medicine: the Oklahoma experience. PMID- 11617538 TI - The care of captive animals: a historical perspective. PMID- 11617539 TI - Doc. PMID- 11617540 TI - "That by means of which people live": Indians and their horses' health. PMID- 11617542 TI - The woman's experience of childbirth on the western frontier. PMID- 11617541 TI - Westward to health: gentlemen health-seekers on the Santa Fe Trail. PMID- 11617543 TI - Infanticide in pre-Petrine Russia. PMID- 11617544 TI - Reconsiderations on plague in early modern Russia, 1500-1800. PMID- 11617545 TI - Cinchona: "the nearest place to heaven." PMID- 11617546 TI - Robert Jackson, M.D., 1750-1827: sometime doctor in Jamaica and a bold crusader of his day. PMID- 11617547 TI - The medical profession in Jamaica in the post-emancipation period. PMID- 11617549 TI - Newspapers and medicine in Jamaica a century ago. PMID- 11617550 TI - Joyce and embryology: Giulio Valenti's "Lezioni elementari di embriologia" as a source for "Oxen of the Sun." PMID- 11617551 TI - A scurrilous anecdote concerning Maimonides. PMID- 11617552 TI - Andries Salomonsz, a converted "Rabbi and Doctor" in Leiden (1553-1561). PMID- 11617553 TI - Early Caribbean Jewry: a demographical perspective. PMID- 11617554 TI - The burial grounds controversy between Anglo-Jewry and the Victorian Board of Health, 1850. PMID- 11617555 TI - A view of the press in the twenties. PMID- 11617556 TI - For the "poor mute mothers"? Margaret Sanger and the woman rebel. PMID- 11617557 TI - Advertising abortion during the 1830s and 1840s: Madame Restell builds a business. PMID- 11617558 TI - Opposing abortion clinics: a New York Times 1871 crusade. PMID- 11617560 TI - Maimonides as a physician. PMID- 11617559 TI - A citizen's forum: 15 years against pollution. PMID- 11617561 TI - A protohistoric Piman burial and a consideration of Piman burial practices. PMID- 11617562 TI - Central-European surgery in the "fin de siecle." PMID- 11617563 TI - Book review essay: A surgeon's surgeon. PMID- 11617564 TI - [Not Available]. PMID- 11617565 TI - Remembering J. E. Purkyne. PMID- 11617566 TI - Bringing water to the crescent city: Benjamin Latrobe and the New Orleans waterworks system. PMID- 11617567 TI - Benevolent societies of New Orleans blacks during the late nineteenth and early twentieth centuries. PMID- 11617568 TI - Mass communication and public health: the 1905 campaign against yellow fever in New Orleans. PMID- 11617570 TI - The popular defence of Chidley. PMID- 11617571 TI - The western dilemma: miners, silicosis, and compensation. PMID- 11617569 TI - A death at Deer Lake: catalyst of a forgotten Newfoundland work stoppage, 1924. PMID- 11617572 TI - The 1918 strike of the medical profession against the friendly societies in Victoria. PMID- 11617573 TI - Medicine and the labour movement in New South Wales, 1788-1850. PMID- 11617574 TI - The study of occupational health in Australia. PMID- 11617576 TI - "Once a drunkard always a drunkard": social reform and the problem of "habitual drunkenness" in Australia, 1880-1914. PMID- 11617577 TI - Rethinking the circle of poison: the politics of pesticide poisoning among Mexican farm workers. PMID- 11617578 TI - White slavery, public health, and the socialist position on legalized prostitution in Argentina, 1913-1936. PMID- 11617579 TI - Organized medicine in Mingqing China: state and private medical institutions in the lower Yangzi region. PMID- 11617580 TI - A case for Confucian sexuality: the eighteenth-century novel Yesou Puyan. PMID- 11617581 TI - Practitioner fraud and abuse in medical benefit programs: government regulation and professional white-collar crime. PMID- 11617583 TI - Comparing Justice and Labor Department lawyers: ten years of occupational safety and health litigation. PMID- 11617584 TI - The dilemmas of legal mobilization: ideologies and strategies of mental patient liberation groups. PMID- 11617582 TI - Regulation, risk assessment, and the Supreme Court: the case of OSHA's cancer policy. PMID- 11617585 TI - Assessing the consequences of corporate discretion on regulatory compliance: the case of motor vehicle safety in Canada. PMID- 11617586 TI - Compensating victims for harms caused by pollution and other hazardous substances: a comparison of American and Japanese policies. PMID- 11617587 TI - Representing respondents under new civil commitment statutes: an analysis of counsel's role in and out of the courtroom. PMID- 11617588 TI - The catalytic effect of a federal court decision on a state legislature. PMID- 11617589 TI - The origin of insanity as a special verdict: the trial for treason of James Hadfield (1800). PMID- 11617591 TI - The first blood transfusion to man, infusion experiments, physiological problems, and some curiosities of medicine reported in a letter from J. Bruynestein to W. van Liebergen (1668). PMID- 11617592 TI - Darwin, Coleridge and the theory of unconscious creation. PMID- 11617593 TI - The sexual politics of illness in turn of the century libraries. PMID- 11617594 TI - Books as disease carriers, 1880-1920. PMID- 11617595 TI - Foiling the pirates: the preparation and publication of Andreas Vesalius's De humani corporis fabrica. PMID- 11617596 TI - The kaleidoscopic mind of Peter Mark Roget. PMID- 11617597 TI - The Bernhold Apicius. PMID- 11617598 TI - An alchemical poem: authorship and manuscripts. PMID- 11617599 TI - Richard Haydocke: translator, engraver, physician. PMID- 11617600 TI - The books of Myles Blomefylde. PMID- 11617601 TI - Walsingham's copy of Bailey's brief discourse. PMID- 11617602 TI - John Gerard, the herbalist. PMID- 11617603 TI - The invention of spectacles and the advent of printing. PMID- 11617605 TI - Death and the Australian colonial family. PMID- 11617604 TI - The woman rebel: feminism and Margaret Sanger in 1914. PMID- 11617606 TI - the concealment of birth in nineteenth-century Victoria. PMID- 11617607 TI - Recovering the past for the present: the history of Victorian calisthenics. PMID- 11617608 TI - A study of Louis J. Weichmann. PMID- 11617609 TI - The accident-prone John Wilkes Booth. PMID- 11617610 TI - The United States General Hospital at Cleveland, Ohio, 1862-1865. PMID- 11617611 TI - Linnaeus's medical career. PMID- 11617612 TI - Chuantong di jiazu rentong xinli tanxi. PMID- 11617613 TI - The debate about historical culture and the status of the history of science. PMID- 11617614 TI - Lithuanian physicians--"Ausrinikai". 1. Editors of Ausra. PMID- 11617615 TI - Lithuanian physicians--"ausrininkai." PMID- 11617616 TI - Lithuanian physicians affiliated with U.S. and Canadian universities (Part II). PMID- 11617617 TI - The evolution of psychiatry in a clinician's lifetime (Frederick Hopkins Memorial Lecture). PMID- 11617618 TI - The smoke abatement campaign in Salt Lake City, 1890-1925. PMID- 11617619 TI - The National Health Service in London: a review of the impact of NHS policy since 1976. PMID- 11617620 TI - Post voluptatem misericordia: the rise and fall of the London Lock Hospitals. PMID- 11617621 TI - AIDS on Long Island: the regional history of an epidemic 1981-1988. PMID- 11617622 TI - AIDS on Long Island:the regional history of an epidemic 1981-1988. PMID- 11617623 TI - A medical student of the 1830s: excerpt from the diary of Ethelbert Algernon Coleman, 23 October 1831-29 April 1832. PMID- 11617624 TI - Memories of Blue Ridge Sanitarium: two cases, 1926 and 1930. PMID- 11617625 TI - Portraits of Benjamin Rush, M.D., by his contemporaries. PMID- 11617626 TI - Bartram's Garden in Philadelphia. PMID- 11617627 TI - Influenza 1918: a Maine perspective. PMID- 11617628 TI - Diary of a nurse. PMID- 11617629 TI - Diabetes in the early days of the Manchester Royal Infirmary. PMID- 11617630 TI - Tyrocaesar: a manual for Sir Walter Mildmay. PMID- 11617631 TI - A new look at a manuscript containing the old English translation of the Herbarium Apulei. PMID- 11617632 TI - Science, medicine and the university: 1200-1550. Essays in honor of Pearl Kibre. 2 parts. PMID- 11617633 TI - The threat of chemical warfare. PMID- 11617634 TI - Cook and scurvy. PMID- 11617635 TI - British whaling surgeons in the South Seas, 1823-1843. PMID- 11617636 TI - The funerary monuments and burial patterns of colonial Tidewater Virginia, 1607 1776. PMID- 11617637 TI - Henry Furbush Howe. PMID- 11617638 TI - Freud: the psycho-archeology of civilizations. PMID- 11617639 TI - Freud and the twenties. PMID- 11617640 TI - The silverplated ice water pitcher: an image of changing America, 1850-1900. PMID- 11617642 TI - The bottles of Northrop & Lyman, a Canadian drug firm. PMID- 11617641 TI - Earth closets and the dry earth systems of sanitation in Victorian America. PMID- 11617643 TI - "Canadian ways": an introduction to comparative studies of housework, stoves, and diet in Great Britain and Canada. PMID- 11617644 TI - Beautifying the boneyard: the changing image of the cemetery in nineteenth century Ontario. PMID- 11617645 TI - An introductory bibliography on cultural studies relating to death and dying in Canada. PMID- 11617646 TI - [Not Available]. PMID- 11617647 TI - Feeding the nineteenth-century baby: implications for museum collections. PMID- 11617648 TI - Mother and child: history of mothering from 1600 to the present. PMID- 11617649 TI - Famine in Bunyoro (Kitara) 1900-1939. PMID- 11617650 TI - The impact of migratory labour on health. PMID- 11617651 TI - Unravelling the strands of time. PMID- 11617652 TI - Marketing the unmentionable: Wallace Meyer and the introduction of Kotex. PMID- 11617654 TI - A tale of ratiocination: the death and burial of Edgar Allan Poe. PMID- 11617655 TI - Medical education for an African colonist. PMID- 11617657 TI - The Baltimore theater and the yellow fever epidemic. PMID- 11617660 TI - The tribulations of Mrs. Turner: an episode after Guilford Court House. PMID- 11617661 TI - Eminent chemists of Maryland. PMID- 11617663 TI - On the drama of dying in early nineteenth century Baltimore. PMID- 11617665 TI - Baltimore's burial practices, mortuary art and notions of grief and bereavement, 1780-1900. PMID- 11617667 TI - The practice of Dr. Andrew Scott of Maryland and North Carolina. PMID- 11617670 TI - A memorable trial in seventeenth-century Maryland. PMID- 11617671 TI - Materia medica in ms London B.L. Add. 10289. PMID- 11617672 TI - Structures with actors: an approach to the historical experience of the street in Melbourne. PMID- 11617673 TI - The history of science today. PMID- 11617674 TI - Childbirth, disease and death among the Mennonites in nineteenth-century Russia. PMID- 11617675 TI - John Wesley on health: a word for sensible regimen. PMID- 11617676 TI - Fyodor Mikhailovich Dostoievsky (1821-1881), great existentialist-psychiatrist. PMID- 11617677 TI - The daily register of Dr. Cyrus Bacon, Jr.: care of the wounded at the battle of Gettysburg. PMID- 11617678 TI - "Better living through heredity": Michael F. Guyer and the American eugenics movement. PMID- 11617680 TI - Caroline Bartlett Crane and urban reform. PMID- 11617679 TI - Health, law and rituals of the Spanish Morisco in BN Aljamaido Ms 4987. PMID- 11617681 TI - Died in the mines. PMID- 11617682 TI - An airing of reputations. PMID- 11617683 TI - The WCTU discovers science: the Women's Christian Temperance Union, plus teachers, doctors and scientific temperance. PMID- 11617684 TI - Join the Army and become a doctor. PMID- 11617685 TI - Dr. Upjohn's company. PMID- 11617686 TI - Thomas Blackwood, frontier physician. PMID- 11617687 TI - Douglas Houghton. PMID- 11617688 TI - Michigan medics in action: the 107th Medical Battalion in World War II. PMID- 11617689 TI - The magnetic mineral springs of St. Louis, Michigan. PMID- 11617690 TI - Angels of mercy: Michigan's midwives. PMID- 11617691 TI - "Every child is worthy of kindness and care": the founding and early development of the Children's Hospital of Michigan, 1886-1922. PMID- 11617692 TI - Fertility change on the Michigan frontier: Saginaw County, 1840-1850. PMID- 11617693 TI - Tending their flock: diet, hygiene, and health for 19th century reformatory children. PMID- 11617694 TI - Dr. Louis Jacob Hirshman. PMID- 11617695 TI - Harry Stocker, M.D.: his life and times (1897-1953). PMID- 11617696 TI - Alternative psychological interpretations of Woodrow Wilson. PMID- 11617697 TI - Milk to motherhood: the New York Milk Committee and the beginning of well-child programs. PMID- 11617698 TI - Love Canal: a historical review. PMID- 11617699 TI - Visiting the rural community: a public health education program in the 1930's. PMID- 11617700 TI - Two letters from Erzerum. PMID- 11617701 TI - The beatification of Wilhelm Reich. PMID- 11617702 TI - Freud and Herzl. PMID- 11617703 TI - Why did Hitler hate the Jews? PMID- 11617704 TI - Was the Pied Piper of Hameln Jewish? PMID- 11617705 TI - Social security at fifty years: a preface toward choices. PMID- 11617706 TI - National Migrant Referral Project: facilitating migrant health care for 15 years. PMID- 11617708 TI - An overview of the growth and development of the U.S. Migrant Health Program. PMID- 11617707 TI - Culture, health care and the new Caribbean immigrants: implications for new health policy and planning. PMID- 11617709 TI - The health of the Union military in the District of Columbia, 1861-1865. PMID- 11617710 TI - Wounds without scars: treatment of battle fatigue in the U.S. Armed Forces in the Second World War. PMID- 11617711 TI - The development of segregation in U.S. Army hospitals, 1940-1942. PMID- 11617712 TI - The development of British military medicine. PMID- 11617713 TI - Race, sex and war: the impact of race and sex on morale and health services for the Indian Corps on the Western front, 1914. PMID- 11617714 TI - United States Army remount depots: the Oklahoma experience, 1908-1947. PMID- 11617715 TI - The perils of unpreparedness: the American Expeditionary Forces and chemical warfare. PMID- 11617716 TI - Doctor William Thornton Parker: enigmatic physician-soldier. PMID- 11617717 TI - Militia medicine in New York, 1812. PMID- 11617718 TI - The 1878 ambulance board: part 2, field use in the west, 1878. PMID- 11617719 TI - The 1878 ambulance board, Part I. PMID- 11617720 TI - A short history of some U.S. Army medical insignia. PMID- 11617721 TI - Individual first aid equipment in the U. S. service. PMID- 11617722 TI - Uniforms and equipment of the Ambulance Corps, Massachusetts Volunteer Militia, 1890-1900. PMID- 11617723 TI - Men and authority: the Union Army nurse and the problem of power. PMID- 11617724 TI - The soldiers' nurse: Colonel Florence A Blanchfield. PMID- 11617725 TI - The eugenics crusade of Charles Fremont Dight. PMID- 11617726 TI - Of cadavers, chases, and colleges: newspaper coverage, 1885. PMID- 11617727 TI - All the names of death: Walker Percy and Hemingway. PMID- 11617728 TI - Patients, politics and physicians: the struggle for control of state lunatic asylum no. 1, Fulton, Missouri. PMID- 11617731 TI - Urban development and death: Bombay City, 1870-1914. PMID- 11617730 TI - Colonialism and sanitary medicine: the development of preventive health policy in the Punjab, 1860 to 1900. PMID- 11617729 TI - A "pill-grimage": the life and times of John Richie Ferguson, 1842-1929. PMID- 11617732 TI - Plague, policy and popular unrest in British India. PMID- 11617733 TI - Madness and racial theory in I. J. Singer's The family Carnovsky. PMID- 11617734 TI - That dog again: melancholia canina and Chaucer's Book of the Duchess. PMID- 11617735 TI - The prince of physicians on the nature of man. PMID- 11617736 TI - AIDS and capitalist medicine. PMID- 11617737 TI - George Armstrong Custer: a psychoanalytic approach. PMID- 11617738 TI - A psychoanalytical approach to Custer: some reflections. PMID- 11617739 TI - Lewis and Clark: Westering physicians. PMID- 11617740 TI - Bitterroot enigma: Howard Taylor Ricketts and the early struggle against spotted fever. PMID- 11617741 TI - "An El Dorado of ease and elegance": taking the waters at White Sulphur Springs, 1866-1904. PMID- 11617742 TI - The perils of working in the Butte underground: industrial fatalities in the copper mines, 1880-1920. PMID- 11617743 TI - Montanans and "the most peculiar disease": the influenza epidemic and public health, 1918-1919. PMID- 11617744 TI - Buffalo and bacteria. PMID- 11617745 TI - Michinaga's maladies, a medical report on Fujiwara no Michinaga. PMID- 11617746 TI - A study of al-Samarqandi's medical writings. PMID- 11617748 TI - Christian missionary penetration of the Nigerian emirates, with special reference to the medical missions approach. PMID- 11617747 TI - Ivor Gurney's mental illness. PMID- 11617749 TI - Hans Froelicher, Jr.: civic educator. PMID- 11617751 TI - A half-century of health care: Raleigh's Rex Hospital, 1894-1944. PMID- 11617752 TI - The development of health care systems in Bismarck, 1872-1937. PMID- 11617753 TI - Some medical aspects of the Lewis and Clark Expedition. PMID- 11617754 TI - Herbal treatments using plants found on the Northern Plains: pioneer remedies and folk medicines. PMID- 11617755 TI - Nehemiah Kenison: New England's pioneer podiatrist. PMID- 11617756 TI - Florence Nightingale's cap. PMID- 11617757 TI - A record of deaths in Rhode Island and Massachusetts, 1813-1852. PMID- 11617758 TI - The Down East screamer. PMID- 11617759 TI - Jonathan Edwards and melancholy. PMID- 11617760 TI - Parkman's crack-up: a Bostonian on the Oregon Trail. PMID- 11617761 TI - James Jackson Putnam: an American perspective on the social uses of psychoanalysis, 1895-1918. PMID- 11617762 TI - Leonard Wood, William Muldoon and the medical profession: public health and universal military training. PMID- 11617764 TI - Sound minds and unsound bodies: Massachusetts schools and mandatory physical training. PMID- 11617763 TI - "Eyes be blind, heart be still": a new perspective on Emily Dickinson's eye problem. PMID- 11617765 TI - The death of Silas Deane: another opinion. PMID- 11617766 TI - "Here among soldiers in hospital": an unpublished letter from Walt Whitman to Lucia Jane Russell Briggs. PMID- 11617767 TI - Cotton Mather's "most unhappy wife": reflections on the uses of historical evidence. PMID- 11617768 TI - Samuel Willard and the spectres of God's wrathful lion. PMID- 11617769 TI - Laboratories on the New England shore: the "somewhat different direction" of American marine biology. PMID- 11617770 TI - Walter G. Alexander: a physician in civil rights and public service. PMID- 11617772 TI - "An army of tubercular invalids": New Mexico and the birth of a tuberculosis industry. PMID- 11617771 TI - 1918 influenza in Morris County. PMID- 11617773 TI - John Weinzirl: a personal search for the conquest of tuberculosis. PMID- 11617774 TI - A Tory-loyalist doctor's prescription for Nova Scotia, 1784. PMID- 11617775 TI - Unnatural mothers: infanticide in Halifax, 1850-1875. PMID- 11617776 TI - Health care in New York City: a system in flux. PMID- 11617777 TI - Accident narratives: self protection in the workplace. PMID- 11617778 TI - Edward H. Dixon and medical education in New York. PMID- 11617779 TI - James W. Wadsworth, Sr. and the meat inspection act of 1906. PMID- 11617780 TI - Ethyl in Manhattan: a note on the science and politics of leaded gasoline. PMID- 11617781 TI - The trial of John Hendrickson, Jr.: medical jurisprudence at mid-century. PMID- 11617782 TI - Christchurch in the 1918 influenze epidemic: a preliminary study. PMID- 11617783 TI - Truby King in Australia: a revisionist view of reduced infant mortality. PMID- 11617784 TI - The making of New Zealand's 1920 Health Act. PMID- 11617787 TI - A subtle containment: women in New Zealand medicine, 1893-1941. PMID- 11617788 TI - Fighting the "red plague": observations on the response to venereal disease in New Zealand, 1910-1945. PMID- 11617790 TI - Maori mortality in the 1918 influenza epidemic. PMID- 11617791 TI - Sensation and explanation: the problem of consciousness in Descartes. PMID- 11617792 TI - Black water, red tape: anatomy of a border problem. PMID- 11617793 TI - The American Red Cross: a century of service. PMID- 11617794 TI - Surgeon at Fort Sidney: Captain Walter Reed's experiences at a Nebraska military post, 1883-1884. PMID- 11617795 TI - Hog cholera, Texas fever, and Frank S. Billings: an episode in Nebraska veterinary science. PMID- 11617796 TI - Pioneer pharmacist J. Walter Moyer's notes on Crawford and Fort Robinson in the 1890's. PMID- 11617797 TI - Susan La Flesche Picotte: Nebraska's Indian physician, 1865-1915. PMID- 11617798 TI - Nebraska's oral law of 1911 and the deaf community. PMID- 11617799 TI - The McCook, Nebraska, letters of Dr. Byron B. Davis, 1885-1887. PMID- 11617800 TI - Dr. Olga Stastny, her service to Nebraska and the world. PMID- 11617801 TI - Robert and Roderick Badger, pioneer Georgia dentists. PMID- 11617803 TI - "Our cursed natures": sexuality and the Puritan conscience. PMID- 11617802 TI - Regulating public health in Nevada: the pioneering efforts of Dr. Simeon Lemuel Lee. PMID- 11617804 TI - "A bold plunge into the sea of values": the career of Dr. Richard Cabot. PMID- 11617805 TI - From seduction theory to Oedipus complex: a historical analysis. PMID- 11617806 TI - The theory and therapy of Balint, Ferenczi, Hermann, and Szondi. PMID- 11617807 TI - Sandor Ferenczi the man. PMID- 11617808 TI - The health of the young. PMID- 11617809 TI - The Nietzsche murder case. PMID- 11617810 TI - Swedenborg, psychology, and the cerebellum. PMID- 11617811 TI - Sensing and the sensitive mean in Aristotle. PMID- 11617812 TI - Combatting the invisible enemy: health and hospital care in the army of New Spain, 1760-1810. PMID- 11617813 TI - Reflections: Freud and the Soul [as perceived in America]. PMID- 11617814 TI - Mollie Fancher . . . 'The Brooklyn Enigma'. The psychological marvel of the 19th century. PMID- 11617816 TI - Medicine's great journey. One hundred years of healing PMID- 11617815 TI - An eighteenth century summer visitor to Newport. PMID- 11617817 TI - A physician's journey through Western New York and Upper Canada in 1815. PMID- 11617818 TI - The Francis E. Fronczak Collection. PMID- 11617819 TI - Local government and the development of health services in a Nigerian area (IMO state, 1914-1966). PMID- 11617820 TI - The medical community of the last century. PMID- 11617821 TI - Dickens and the passions. PMID- 11617822 TI - The challenge of cholera: the last epidemic at Newcastle upon Tyne. PMID- 11617823 TI - Mortality and economic change in the diocese of York, 1390-1514. PMID- 11617824 TI - Northern Virginia life expectancies: a comparison of Fairfax County and Alexandria City (1800-1880). PMID- 11617826 TI - Medical aid to Ethiopia, 1950-1970. PMID- 11617825 TI - Don Wilkins and the building of Fairfax Hospital. PMID- 11617827 TI - Anna May: eighty-two years in New England. PMID- 11617828 TI - The early life of a pioneer Ohio physician: Dr. Horatio Conant, 1785-1816. PMID- 11617829 TI - George Chauncey Jameson, M.D., 1865-1948. From bloodletting to antibiotics. PMID- 11617830 TI - Myth, allegory, and scientific truth: an alchemical tradition in the period of the scientific revolution. PMID- 11617831 TI - Vanderbilt's influence on world nutrition PMID- 11617832 TI - The beginnings of the Nutrition Section of WHO, 1949-1951. PMID- 11617833 TI - Nutrition research at the Lister Institute: recollections. PMID- 11617834 TI - What Americans ate in 1787. PMID- 11617835 TI - The origin of nutrition history notes. PMID- 11617836 TI - Random notes on nutrition interests of some founding fathers. PMID- 11617837 TI - Folk medicine in colonial North Carolina as found in Dr. John Brickell's Natural History. PMID- 11617838 TI - Free love in Ohio: Jacob Beilhardt and the Spirit Fruit Colony. PMID- 11617839 TI - Doctors and diseases on the Ohio frontier. PMID- 11617841 TI - Winifred Howells and the economy of pain. PMID- 11617840 TI - "Go and sin no more": maternity homes in Cleveland, 1869-1936. PMID- 11617842 TI - Bucke, pioneer psychiatrist, practical mystic. PMID- 11617843 TI - R. M. Bucke: a Victorian asylum superintendent. PMID- 11617844 TI - State medicine in transition: battling smallpox in Ontario, 1882-1885. PMID- 11617845 TI - The health reformers versus the common Canadian: the controversy over compulsory vaccination against smallpox in Toronto and Ontario, 1900-1920. PMID- 11617846 TI - Public health services and limited prospects: epidemic and conflagration in Cobalt. PMID- 11617847 TI - The aristocratic vice: the medical treatment of drug addiction at the Homewood Retreat, 1883-1900. PMID- 11617848 TI - Jenny Kidd Trout and the founding of the women's medical colleges at Kingston and Toronto. PMID- 11617849 TI - Chemical weapons: restoring the taboo. PMID- 11617850 TI - The decimation of a people. PMID- 11617851 TI - Bellinis Tod in Paris. PMID- 11617852 TI - "This worry I have": Mary Herren journal. PMID- 11617853 TI - Susan Haines Clayton, American lady, 1851-1948. PMID- 11617854 TI - Goethe, Rousseau, and the "Hyp". PMID- 11617855 TI - Doctor Bernard Connor: physician to King Jan III Sobieski and author of the History of Poland (1698). PMID- 11617856 TI - Doctor Christopher Reitinger and a seal of Tsar Boris Godunov. PMID- 11617857 TI - Dental caries and horticulture in prehistoric Ohio. PMID- 11617858 TI - Ann Preston: pioneer of medical education and women's rights. PMID- 11617859 TI - "Little Doc": architect of modern nursing. PMID- 11617860 TI - Most deadly business. PMID- 11617862 TI - The College of Physicians of Philadelphia: "not for oneself, but for all." PMID- 11617861 TI - Behind the Battle of Gettysburg: American nursing is born. PMID- 11617863 TI - Charles Sumner, Doctor Jackson and the mountain. PMID- 11617864 TI - A stick to break our heads with: Elizabeth Blackwell and Philadelphia medicine. PMID- 11617865 TI - Institutional imperialism and the sick poor in late eighteenth-century Philadelphia: the House of Employment vs. the Pennsylvania Hospital. PMID- 11617866 TI - Benjamin Franklin and Princess Czartoryska: an unknown therapeutic encounter. PMID- 11617868 TI - Mine safety and social control in the anthracite industry. PMID- 11617867 TI - Eugenics, crime and ideology: the case of progressive Pennsylvania. PMID- 11617869 TI - The history of Pennsylvania's workmen's compensation, 1900-1916. PMID- 11617870 TI - The Philadelphia Pediatric Society and its Milk Commission, 1896-1917: an aspect of urban progressive reform. PMID- 11617871 TI - The community, the hospital, and the working-class patient: the multiple uses of asylum in nineteenth-century America. PMID- 11617872 TI - "A Philadelphia surgeon on a slaving voyage to Africa, 1749-1751". PMID- 11617873 TI - Dr. James Durham, mysterious eighteenth-century black physician: man or myth? PMID- 11617874 TI - The Kirkbride-Langenheim collaboration: early use of photography in psychiatric treatment in Philadelphia. PMID- 11617875 TI - The domesticated madman: changing concepts of insanity at the Pennsylvania Hospital, 1780-1830. PMID- 11617876 TI - Guarding against alien impurities: the Philadelphia Lazaretto, 1854-1893. PMID- 11617877 TI - The decline in mortality in Philadelphia from 1870 to 1930: the role of municipal services. PMID- 11617878 TI - The proper place of homeopathy: Hahnemann Medical College and Hospital in an age of scientific medicine. PMID- 11617879 TI - "A very diffused disposition": dissecting schools in Philadelphia 1823-1825. PMID- 11617880 TI - The diary of Mary Theodora McGavran. PMID- 11617881 TI - St. Joseph's and St. Mary's: the origins of Catholic hospitals in Philadelphia. PMID- 11617882 TI - China's fertility transition: the one-child campaign. PMID- 11617883 TI - The dueling doctors of Stockton. PMID- 11617884 TI - John Muir's enlightenment. PMID- 11617885 TI - John Marsh. PMID- 11617886 TI - Philip King Brown and the Arequipa Sanatorium. PMID- 11617887 TI - Sherburne Friend Cook: rebel-revisionist (1896-1974). PMID- 11617888 TI - Medical censorship in occupied Japan, 1945-8. PMID- 11617889 TI - Until God knows when: smallpox in the late-colonial Philippines. PMID- 11617890 TI - Angel of mercy for 172 islands. PMID- 11617891 TI - Early Idaho panhandle doctor reached patients on horseback, boats and rails. PMID- 11617892 TI - When the plague hit Spokane. PMID- 11617893 TI - Bob Bartlett and the Alaska Mental Health Act. PMID- 11617894 TI - "In gauze we trust": public health and Spanish influenza on the home front, Seattle, 1918-1919. PMID- 11617895 TI - Changes in Rarotongan attitudes toward health and disease: historical factors in the development of a mid-twentieth-century understanding. PMID- 11617896 TI - Francis Schlatter: a fool for God. PMID- 11617897 TI - Fort Burgwin's hospital. PMID- 11617898 TI - Memoirs of a Council Bluffs druggist. PMID- 11617899 TI - Thomas MacBride's dream: Iowa Lakeside Laboratory. PMID- 11617900 TI - The Okoboji Lakeside Laboratory. PMID- 11617901 TI - "My life is not quite useless": the 1866 diary of an asylum bookkeeper. PMID- 11617902 TI - Death and dying on the southern Great Plains around 1900. PMID- 11617903 TI - Psychoanalysis in Vienna. PMID- 11617904 TI - The secularization of suicide in England, 1660-1800. PMID- 11617905 TI - Health, welfare and unemployment during the Depression. PMID- 11617906 TI - Cholera and colonialism in British India. PMID- 11617907 TI - Public anatomy lessons and the carnival: the anatomy theatre of Bologna. PMID- 11617908 TI - Epidemics and revolutions: cholera in nineteenth-century Europe. PMID- 11617910 TI - Debate: the secularization of suicide in England 1660-1800. PMID- 11617911 TI - The changing face of hunger in southern African history, 1880-1980. PMID- 11617913 TI - Care of the dead (and lack of it) at 19th century posts. PMID- 11617912 TI - Smallpox and peasants. PMID- 11617914 TI - Medical Center Hospital. PMID- 11617915 TI - The necklace of a whore. PMID- 11617916 TI - The life of Don Pedro Jaramillo: benefactor of humanity. PMID- 11617917 TI - The status of studies in folk medicine in the Philippines. PMID- 11617918 TI - Psychology in the Philippines: history and current trends. PMID- 11617919 TI - Kepler, Hobbes and medieval optics. PMID- 11617920 TI - 1953 and all that: a tale of two sciences. PMID- 11617921 TI - Increasing sex mortality differentials among black Americans, 1950-1978. PMID- 11617922 TI - Death timing among deceased married couples in a southern cemetery. PMID- 11617923 TI - Feliks Pawel Wierzbicki in California. PMID- 11617924 TI - Who discovered vitamins? PMID- 11617925 TI - Nicholas Copernicus' Italian studies: their chronology and scope. PMID- 11617926 TI - Psychological service in the Polish armed forces in the second world war. PMID- 11617927 TI - Tuberculosis in western Alaska 1900-1950. PMID- 11617928 TI - The impact of citizen participation on hazardous waste policy implementation: the case of Clermont County, Ohio. PMID- 11617929 TI - Human rights and institutional process: abortion policy in six nations. PMID- 11617930 TI - State enforcement of federal regulatory policy: the lessons of OSHA. PMID- 11617931 TI - Correlates of consumer participation in health planning agencies: findings and implications from a national survey. PMID- 11617932 TI - Social problem-solving in a revolutionary setting: Nicaragua's pesticide policy reforms. PMID- 11617933 TI - The changing context of academic science: university-industry relations in biotechnology and the public policy implications. PMID- 11617934 TI - The Reagan administration's welfare retrenchment policy: terminating social security benefits for the disabled. PMID- 11617935 TI - Water pollution control in democratic societies: a cross-national analysis of sources of public beliefs in Japan and in the United States. PMID- 11617936 TI - The termination of Medibank. PMID- 11617937 TI - The political anatomy of community health policy in Australia, 1972-1982. PMID- 11617938 TI - The review and discussion of changes in China's population policy during the early years of the People's Republic. PMID- 11617939 TI - Congressional liaison operations during the Johnson administration: the case of Medicare. PMID- 11617940 TI - Franklin D. Roosevelt and water pollution control policy. PMID- 11617941 TI - Dr. Benjamin Rush in Princeton:1777-78. PMID- 11617942 TI - Princeton plagues: the epidemics of 1832, 1880 and 1918-19. PMID- 11617943 TI - The genial Dr. Howell: Princeton medicine in the 1820's-1830's. PMID- 11617944 TI - Louis-Jean Deprez. PMID- 11617945 TI - Compensating workplace toxic torts. PMID- 11617946 TI - Authority, autonomy, and radical commitment: Stephen and Abby Kelley Foster. PMID- 11617947 TI - Did the Mathers disagree about the Salem witchcraft trials? PMID- 11617948 TI - The French national public health bureaucracy and the bacteriological revolution. PMID- 11617949 TI - The French temperance movement and problem of rural alcoholism. PMID- 11617950 TI - The French temperance movement and the problem of rural alcoholism. PMID- 11617951 TI - Medical thought on aging in eighteenth-century France. PMID- 11617952 TI - The birth of a revolutionary: Robespierre in Artois. PMID- 11617954 TI - The hospital of Mantes-La Jolie in the first half of the nineteenth century. PMID- 11617953 TI - Two cultures, one profession: the surgeons of France in the eighteenth century. PMID- 11617955 TI - Jacques Necker's enquete of the Paris hospital (1777). PMID- 11617956 TI - "La cendrillon des sciences": toward the professionalization of veterinary medicine in 18th- and 19th-century France. PMID- 11617957 TI - Dorset apothecaries' tokens and their issuers. PMID- 11617958 TI - The demography of Carrick-on-Suir, 1799. PMID- 11617959 TI - The health of blacks in the District of Columbia, 1860-1865. PMID- 11617960 TI - A new look at medicine in England in the sixteenth century. PMID- 11617961 TI - "Primitive physic": an interesting association copy. PMID- 11617962 TI - Jarvis revisited: distance decay in service areas of mid-19th century asylums. PMID- 11617963 TI - Thomas Lawson, second Surgeon General of the U. S. Army: a character sketch. PMID- 11617965 TI - A heavy sea running: the formation of the U.S. Life-saving Service, 1846-1878. PMID- 11617964 TI - Herbert Hoover: the orphan as children's friend. PMID- 11617967 TI - Medical therapies and the body politic. PMID- 11617966 TI - Huxley's rhetoric and the mind-matter debate: 1868-1874. PMID- 11617968 TI - The lonely crowd in Minnesota: a psychometric approach to the study of the modern American character. PMID- 11617969 TI - Putting the past under grass: history as death and cemetery commemoration. PMID- 11617970 TI - American psychiatry: an ambivalent specialty. PMID- 11617971 TI - "Intervals of tranquility": the language of health in antebellum America. PMID- 11617973 TI - Searching for hunger in America. PMID- 11617972 TI - The relationship of the women's rights movement to women's sport and physical education in the United States 1848-1920. PMID- 11617974 TI - The French population debate. PMID- 11617975 TI - The social security explosion. PMID- 11617976 TI - Between profession and vocation: the case of public health. PMID- 11617977 TI - Violent death, violent states, and American youth. PMID- 11617978 TI - Cleaning up Superfund. PMID- 11617979 TI - Alcoholism: the mythical disease. PMID- 11617980 TI - The Medicare debate in Canada: the politics of new federalism. PMID- 11617981 TI - The changing role of the federal and state courts in safeguarding the rights of the mentally disabled. PMID- 11617983 TI - Changing politics of federal health insurance programs. PMID- 11617982 TI - Some extinct black hospitals of Little Rock and Pulaski County. PMID- 11617984 TI - The medical works in the Dessinian Collection. PMID- 11617985 TI - Pieter Heinrich Polemann (1779-1839)--a prominent Cape Town pharmacist. PMID- 11617986 TI - A reformulation of the economic theory of fertility. PMID- 11617987 TI - Recent acquisitions of the manuscript division PMID- 11617988 TI - Shakespeare and witchcraft. PMID- 11617989 TI - Cost convergence between for-profit and not-for-profit nursing homes: does competition matter? PMID- 11617990 TI - A hitherto unknown edition of W.H. Ryff's "Tabulae decem", Antwerp, Cornelis Bos, c. 1542. PMID- 11617991 TI - Enthusiasm and madness: anti-Quakerism in the seventeenth century. PMID- 11617993 TI - The Cincinnati cholera epidemic of 1849. PMID- 11617992 TI - Mary Dyer and the "monster" story. PMID- 11617994 TI - The birth of pediatrics: Children's Hospital in its first five decades. PMID- 11617995 TI - A new profession for women: the art and science of nursing in Cincinnati, 1889 1940. PMID- 11617996 TI - Daniel Drake and his influence on medical journal literature in Cincinnati. PMID- 11617997 TI - From trade to profession--the rise of mortuary science in Cincinnati. PMID- 11617998 TI - A psychoanalytic geronimo. PMID- 11617999 TI - The career and legacy of Jean Piaget. PMID- 11618000 TI - Historical perspectives on AIDS: society, culture, and STDS. PMID- 11618001 TI - Men, women, and the liberal ideal: an historian's reflections on the Morgentaler case. PMID- 11618002 TI - The good die young: tragedy and the jazz life. PMID- 11618006 TI - The medicine of history. PMID- 11618003 TI - Asylums, psychiatry and the history of madness. PMID- 11618007 TI - Alchemy and iatrochemistry: persistent traditions in the 17th and 18th centuries. PMID- 11618009 TI - Queen of the Bolsheviks: the hidden history of Dr. Marie Equi. PMID- 11618008 TI - The early years of the Rhode Island Birth Control League. PMID- 11618010 TI - The psychology of work: work and mental health in historical perspective. PMID- 11618011 TI - American inquisition: the FDA's persecution of Wilhelm Reich. PMID- 11618012 TI - Saccharin: sweet truth. PMID- 11618013 TI - It's effective--but is it safe? PMID- 11618014 TI - A view from Oklahoma, 1866-1868: the diary and letters of Dr. James Reagles, Jr., Assistant Surgeon, U. S. Army. PMID- 11618015 TI - History of Mammoth Cave, emphasizing tourist development and medical experimentation under Dr. John Croghan. PMID- 11618016 TI - Joseph Nash McDowell, M.D., parts II and III. PMID- 11618017 TI - A Union surgeon views the war from Kentucky, 1862. PMID- 11618018 TI - Mary Breckinridge and the Frontier Nursing Service. PMID- 11618019 TI - Mary Breckinridge and the American Committee for Devastated France: the foundations of the Frontier Nursing Service. PMID- 11618020 TI - The anatomy of melancholy and Richard Whitlock's Zootomia. PMID- 11618021 TI - Renaissance exempla of schizophrenia: the cure by charity in Luther and Cervantes. PMID- 11618022 TI - The lover's body: the somatogenesis of love in Renaissance medical treatises. PMID- 11618024 TI - Trials of a depression era doctor. PMID- 11618023 TI - [Not Available]. PMID- 11618025 TI - The Budds of North Tawton: a medical family of the 19th century. PMID- 11618026 TI - The changing face of the English sweating sickness in the epidemic of August, 1551, in Devonshire: a shift towards endemicity? PMID- 11618027 TI - Bodies, death, and pauper funerals. PMID- 11618028 TI - "Scenes of an indelicate character": the medical "treatment" of Victorian women. PMID- 11618029 TI - Morality and the wooden spoon: Russian doctors view syphilis, social class, and sexual behavior, 1890-1905. PMID- 11618030 TI - Commercial sexuality in nineteenth-century France: a system of images and regulations. PMID- 11618031 TI - The body versus the social body in the works of Thomas Malthus and Henry Mayhew. PMID- 11618032 TI - A metaphor for social exchange: the Florentine plague of 1630. PMID- 11618033 TI - Law and sacrifice: Bataille, Lacan, and the critique of the subject. PMID- 11618034 TI - Writing the unspeakable: Fanny Burney's mastectomy and the fictive body. PMID- 11618035 TI - Andreas Vesalius and the anatomy of antique sculpture. PMID- 11618036 TI - William Harvey's Prelectiones: the performance of the body in the Renaissance theatre of anatomy. PMID- 11618037 TI - Suicide and the rise of the popular press in England. Comments by R. E. Zelnik, p. 55-9. PMID- 11618038 TI - La rage and the bourgeoisie: the cultural context of rabies in the French 19th century. PMID- 11618039 TI - Adolf Hitler and the psychohistorians. PMID- 11618040 TI - Daniel Paul Schreber: a case study of private fate as public possibility. PMID- 11618041 TI - The impact of development programs on women and fertility in three developing countries. PMID- 11618042 TI - Foreign aid birth control campaigns: the disability connection. PMID- 11618043 TI - Social dimensions of disability: women with MS. PMID- 11618044 TI - Agnes Higgins, nutritionist, 1911-1985, and the Montreal diet dispensary. PMID- 11618045 TI - The abortion struggle in Quebec: fifteen years in view. PMID- 11618046 TI - Gheorhe Stupa [The first Roumanian pharmacist of Arad] (Rom). PMID- 11618047 TI - Magical and medical texts: further joins and duplicates. PMID- 11618048 TI - Indigenous populations of the Sao Paulo-Rio de Janeiro coast: trade, aldeamento, slavery and extinction. PMID- 11618049 TI - Colonial enthusiasts and plague in Tunis 1818-1819. PMID- 11618050 TI - [Not Available]. PMID- 11618051 TI - [Not Available]. PMID- 11618052 TI - Titchener and American experimental psychology. PMID- 11618053 TI - Europeans psychology as represented in the Archives of the History of American Psychology. PMID- 11618054 TI - History of psychology and history of science: reflections on two subdisciplines, their relationship, and their convergence. PMID- 11618055 TI - William James on psychopathology: an archival memoir. PMID- 11618056 TI - The visibility of Josef Brozek's work. PMID- 11618057 TI - Aid to emigre psychologists in the United States, 1933-1943: a research note. PMID- 11618058 TI - Henry Rutgers Marshall--the forgotten American Psychological Association president. PMID- 11618060 TI - [Not Available]. PMID- 11618061 TI - [Not Available]. PMID- 11618059 TI - The historical development of psychology in Scandinavia: a study on the history of science. PMID- 11618062 TI - [Not Available]. PMID- 11618064 TI - Pierre Borel (1620?-1671). PMID- 11618063 TI - [Not Available]. PMID- 11618065 TI - Descartes' corporeal ideas hypothesis and the origin of scientific psychology. PMID- 11618066 TI - Native America: the economics of radioactive colonization. PMID- 11618067 TI - Ecumenism and abortion: a case study of pluralism, privatization and the public conscience. PMID- 11618068 TI - Some conflicting sources of hippocratic theory. PMID- 11618069 TI - Arresting puberty. PMID- 11618070 TI - Microscopes and medicine in the U.S., 1840-1860. PMID- 11618071 TI - Life and death in nineteenth century Rochester. PMID- 11618073 TI - Revolution and psychosis: the mixing of science and politics in Russian psychiatric medicine, 1905-1913. PMID- 11618072 TI - Drugs and revolution: Moscow pharmacists in the first Russian Revolution. PMID- 11618074 TI - A medical trade token of Oakham. PMID- 11618075 TI - Missionary doctors and African healers in mid-Victorian South Africa. PMID- 11618076 TI - The effects of climate and disease on African farming in Natal 1895-1905. PMID- 11618077 TI - Death in early Charleston: an estimate of the crude death rate for the white population of Charleston, 1722-1732. PMID- 11618078 TI - The Waring Historical Library Manuscript Guide. PMID- 11618079 TI - South Dakota spa: a history of the Hot Springs Health Resort, 1882-1915. PMID- 11618081 TI - Opportunity and fulfillment: sex, race, and class in health care education. PMID- 11618082 TI - The health status of black women in the U.S.: implications for health psychology and behavioral medicine. PMID- 11618084 TI - Despite poor health: Olivia Davidson Washington's story. PMID- 11618085 TI - Unburying the statue: the lives of Virginia Woolf. PMID- 11618086 TI - Reminiscences of Dr. Charles McKenzie. PMID- 11618087 TI - Horse-trading and health insurance: Saskatchewan and dominion-provincial relations, 1937-1947. PMID- 11618088 TI - Food, fare and nutrition. Some reflections on the historical development of food consumption. PMID- 11618090 TI - Are children poor men's riches? PMID- 11618089 TI - Public infrastructure, its indispensability for economic growth: the case of Norwegian public health measures 1850-1940. PMID- 11618091 TI - The Riksdag, the state bureaucracy and the administration of hospitals in eighteenth-century Sweden. PMID- 11618092 TI - The boundaries of femininity: the Danish experience, 1880-1980. PMID- 11618093 TI - Konrad Gessner (1516-1565). PMID- 11618094 TI - Safety and health on the job as a class issue: the Worker's Health Bureau of America in the 1920s. PMID- 11618095 TI - The reversal of federal policy toward worker safety and health. PMID- 11618096 TI - Regulation and development times in the U.K. pharmaceutical industry. PMID- 11618097 TI - Access to U. S. Government periodicals in health sciences libraries: an overview. PMID- 11618098 TI - Midwives versus doctors: the case of Louise Bourgeois. PMID- 11618100 TI - The veiled woman in Freud's "Das unheimliche". PMID- 11618101 TI - Women and suicide in historical perspective. PMID- 11618102 TI - Helene Deutsch: a new look. PMID- 11618103 TI - Merchandising the sanitary napkin: Lillian Gilbreth's 1927 survey. PMID- 11618104 TI - Women's medical practice and health care in medieval Europe. PMID- 11618105 TI - Pressing at the limits: the challenge of the Hebrew Committee of National Liberation to chemical warfare policy. PMID- 11618106 TI - The forgotten part of the "final solution": the liquidation of the ghettos. PMID- 11618107 TI - "Doctor" Bruno's solar medicine. PMID- 11618108 TI - "Woful childe of parents rage": suicide of children and adolescents in early modern England, 1507-1710. PMID- 11618110 TI - Remarks on the diffusion of Byzantine scientific and pseudo-scientific literature among the Orthodox Slavs. PMID- 11618109 TI - Erotic love and the Inquisition: Jacques Ferrand and the Tribunal of Toulouse, 1620. PMID- 11618111 TI - Slave birth, death and disease on Golden Grove Plantation, Jamaica, 1765-1810. PMID- 11618112 TI - The maroons of Jamaica, 1730-1830: livelihood, demography and health. PMID- 11618113 TI - Fertility differentials on three slave plantations in Suriname. PMID- 11618114 TI - Climate, crops, and natural increase in rural Russia, 1861-1913. PMID- 11618115 TI - Freudian theory under Bolshevik rule: the theoretical controversy during the 1920's. PMID- 11618116 TI - Freud's ideas in the Soviet setting: a meeting with Aleksandr Luriia. PMID- 11618117 TI - Labor violence and regime brutality in Tsarist Russia: the Iuzovka cholera riots of 1892. PMID- 11618118 TI - Where there's fire there is smoke--and usually a "chimney." PMID- 11618119 TI - The wretched life and death of an "American Van Gogh." PMID- 11618120 TI - In the 1900s, antismoking was a burning issue. PMID- 11618121 TI - When 20 million tons of water flooded Johnstown. PMID- 11618122 TI - "Opposed to pain": a history of the Antikamnia Chemical Company. PMID- 11618123 TI - Society receives Indianapolis Industrial Clinic collection PMID- 11618124 TI - Towards a social history of institutionalization. PMID- 11618125 TI - The emergence of the modern life cycle in Britain. PMID- 11618126 TI - Suicide in pre-industrial England. PMID- 11618127 TI - Birth and history. PMID- 11618128 TI - Orphans, idiots, lunatics, and historians: recent approaches to the history of child welfare in Canada. PMID- 11618129 TI - The great Canadian peritonitis debate--1844-1847. PMID- 11618130 TI - [Not Available]. PMID- 11618131 TI - The geographical origins and destinations of medical graduates in Quebec, 1834 1939. PMID- 11618132 TI - Marital fertility in Kingston, 1861-1881: a study of socio-economic differentials. PMID- 11618134 TI - Central African experiences. PMID- 11618133 TI - Additional note on the herbalist associations. PMID- 11618135 TI - A survey of recent literature on the biological past of the black. PMID- 11618136 TI - Future Studies of the biological past of the black. PMID- 11618137 TI - African health at home and abroad. PMID- 11618138 TI - Lead contact and poisoning in Barbados slaves: historical, chemical, and biological evidence. PMID- 11618139 TI - A dreadful childhood: the excess mortality of American slaves. PMID- 11618140 TI - The new "black death": cholera in Brazil, 1855-1856. PMID- 11618141 TI - Africa, Afro-Americans, and hypertension: an hypothesis. PMID- 11618142 TI - Major cities and disease crises: a comparative perspective. PMID- 11618143 TI - Silent travelers: germs, genes, and American efficiency, 1890-1924. PMID- 11618144 TI - The earliest American epidemic. The influenza of 1493. PMID- 11618145 TI - Letters of thanks from hell. PMID- 11618146 TI - The psychotherapy subculture: practice and ideology. PMID- 11618147 TI - The socioeconomic status of deaf workers: a minority group perspective. PMID- 11618148 TI - The economics of the implementation of social policy: searching for the missing link. PMID- 11618149 TI - Race differences in long-term disability: middle-aged and older American Indians, blacks and whites in Oklahoma. PMID- 11618151 TI - Medical priorities and practice in nineteenth-century British India. PMID- 11618150 TI - A sociological profile of August B. Hollingshead. PMID- 11618152 TI - Temperance reform in the antebellum South: social control and urban order. PMID- 11618153 TI - Life history, psychoanalysis, and social science: the example of John Dollard. PMID- 11618154 TI - Diagnostic technologies: X-rays, electrocardiograms, and CAT scans. PMID- 11618155 TI - Dr. Levi Cooper Lane: Civil War medical examiner. PMID- 11618156 TI - The Los Angeles Clinical Laboratory Medical Group: the early years. PMID- 11618157 TI - Modifying the public school curriculum to accommodate mentally retarded students: Los Angeles in the 1920s. PMID- 11618158 TI - Skins, rum & ruin: the impact of the colonial deerskin trade on the southern tribes, 1708-1782. PMID- 11618159 TI - Ernest Everett Just: marine biologist, man extraordinaire. PMID- 11618160 TI - "I know something awful is going to happen": abortion in early twentieth century Alabama. PMID- 11618161 TI - Kentish agues and American distempers: the transmission of malaria from England to Virginia in the seventeenth century. PMID- 11618162 TI - The wellsprings of a populist: Dr. C. W. Macune before 1886. PMID- 11618163 TI - The development of hospitals in Galveston during the nineteenth century. PMID- 11618165 TI - Why is most psychohistory so bad? PMID- 11618166 TI - Soviet immigrant physicians in Israel. PMID- 11618167 TI - Incriminating evidence: excess deaths and forced labour under Stalin: a final reply to critics. PMID- 11618168 TI - The activity of D. S. Samoilovich in the Ukraine. PMID- 11618169 TI - The quarantine service and anti-epidemic measures in the Ukraine in the eighteenth century. PMID- 11618170 TI - Introduction. PMID- 11618171 TI - The history of the plague epidemic in the Ukraine in 1770-74. PMID- 11618172 TI - The Moscow uprising of September 1771. PMID- 11618173 TI - Notes of an eyewitness of the plague riot in Moscow in 1771. PMID- 11618174 TI - I. A. Poletika--an outstanding Ukrainian physician and scholar of the eighteenth century. PMID- 11618175 TI - The exiles of Penikese Island: politics prejudice and the public health. PMID- 11618176 TI - Black children in America. PMID- 11618177 TI - Emerson and phrenology. PMID- 11618178 TI - Dr. Johnson's practice: the medical context for Rasselas. PMID- 11618179 TI - Nature, art, and imitation: the Wild Boy of Aveyeron as a pivotal case in the history of psychology. PMID- 11618181 TI - Medical men of Bath. PMID- 11618182 TI - Trembley, Bonnet, and Reaumur and the issue of biological continuity. PMID- 11618183 TI - Medicine as a key to defining Enlightenment issues: the case of Julien Offray de La Mettrie. PMID- 11618184 TI - Madness and society in England: the historiography reconsidered. PMID- 11618185 TI - Arabic plague chronologies and treatises: social and historical factors in the formation of a literary genre. PMID- 11618186 TI - Iran and the great plague, 1830-1831. PMID- 11618187 TI - Order and progress for some--death and disease for others: living conditions of non-whites in Rio de Janeiro, 1890-1940. PMID- 11618189 TI - Problems of psychology in the works of Karl Marx. PMID- 11618188 TI - The "Matlazahuatl" of 1737-1738 in some villages in the Guadalajara region. PMID- 11618190 TI - Psychiatry and the Soviet state. PMID- 11618191 TI - Sanitary conditions in Poland. PMID- 11618192 TI - The supply of medicines in Poland. PMID- 11618193 TI - Social and economic rights in Eastern Europe. PMID- 11618194 TI - Chemical weapons and the Third World. PMID- 11618196 TI - "A sneaky, cowardly enemy": Tampa's yellow fever epidemic of 1887-88. PMID- 11618195 TI - Religious mass suicide before Jonestown: the Russian Old Believers. PMID- 11618197 TI - A symbol of the sixties: the Florida Mental Health Institute. PMID- 11618198 TI - Education policy and biological science: genetics, eugenics, and the college textbook, c. 1908-1931. PMID- 11618199 TI - Resistance in school and society: public and pedagogical debates about eugenics, 1900-1947. PMID- 11618200 TI - The history of science today. PMID- 11618201 TI - An introduction to alchemical apparatus in the late Middle Ages. PMID- 11618202 TI - Military hospitals in Memphis, 1861-1865. PMID- 11618203 TI - Surgical operation on James K. Polk by Ephraim McDowell, or the search for Polk's gallstone. PMID- 11618204 TI - Deaths and disabilities in the Provisional Army of Tennessee. PMID- 11618205 TI - The Memphis sewer experiment. PMID- 11618206 TI - Introducing a classic: Gunn's Domestic medicine. PMID- 11618207 TI - Nicholson Springs Resort Hotel: a nineteenth century spa. PMID- 11618208 TI - Spanish diet in the Atlantic crossing, the 1570s. PMID- 11618209 TI - Abortion clinic violence as terrorism. PMID- 11618210 TI - The popularization of medicine: Tissot on onanism. PMID- 11618211 TI - Garrick's King Lear and the English malady. PMID- 11618212 TI - The patient's view: doing medical history from below. PMID- 11618213 TI - The poison squad. PMID- 11618214 TI - The specter of the deadly woodlands. PMID- 11618215 TI - Out of the glass house: Robert Todd Lincoln's crucial decade. PMID- 11618216 TI - AIDS in historical perspective. PMID- 11618217 TI - Plagues and peoples, William H. McNeill. PMID- 11618218 TI - Plague: the creative response. PMID- 11618219 TI - Michael Boym's Medicus sinicus. PMID- 11618220 TI - Eroticism in late Ming, early Qing fiction: the beauteous realm and the sexual battlefield. PMID- 11618221 TI - Medicine as science in the early commentaries of "Johannitius". PMID- 11618222 TI - Classical poetry in the Systema naturae of Linnaeus. PMID- 11618223 TI - A wall-painting of the arms of the Apothecaries Company from Stow-on-the-Wold. PMID- 11618224 TI - Malaria in medieval Gloucestershire: an essay in epidemiology. PMID- 11618225 TI - Thomas Lorkyn's dissections, 1564/5 and 1566/7. PMID- 11618226 TI - Chicago scientists who promoted bacteriology in the early 1880's. PMID- 11618227 TI - Doctors, public service and profit: general practitioners and the National Health Service. PMID- 11618228 TI - Medical care of infants in the United States: a review of recent historical work. PMID- 11618229 TI - The marriage of Asclepius and Clio: recent studies in the health sciences of early America. PMID- 11618230 TI - The history of birth control in the United States. PMID- 11618231 TI - The Ukrainian holocaust. PMID- 11618232 TI - Punishment by hunger. PMID- 11618233 TI - The great man-made famine in Ukraine 1932-32: political, social and economic reasons for the famine. PMID- 11618234 TI - A victim's account of his internment in Dnipropetrovsk SPH. PMID- 11618235 TI - Mortality patterns and public health in Hamilton, Canada. PMID- 11618236 TI - An urban middle-class calling: women and the emergence of modern nursing education at the Toronto General Hospital, 1881-1914. PMID- 11618237 TI - The black infant mortality rate: an unequal chance for life. PMID- 11618238 TI - Hospital/health facilities and the Hill-Burton obligations: a secret from the black community. PMID- 11618239 TI - On assessing black health status: a historical overview. PMID- 11618240 TI - The once and present urban crisis. PMID- 11618241 TI - Cosimo Noto's The Ideal City (1903): New Orleans as medical utopia. PMID- 11618242 TI - "If it had been God's will": Dr. James M. M. Ambler and the Jeannette expedition. PMID- 11618245 TI - The most common rush or vilest weed: some unpublished letters of James Petiver to William Byrd II. PMID- 11618246 TI - "Trip to the Virginia spring": an extract from the diary of Blair Bolling, 1838. PMID- 11618249 TI - The sex lives of the James family. PMID- 11618247 TI - The paradox of Eleanor Roosevelt: alcoholism's child. PMID- 11618251 TI - Birth control in Australia. Henry Keylock Rusden and Knowlton's "Fruits of philosophy". PMID- 11618252 TI - Dr. M. L. Verso: the society's new president. PMID- 11618254 TI - Dr. de'Prati: a note and a query. PMID- 11618253 TI - Wilkie Collins' Heart and science and the vivisection controversy. PMID- 11618255 TI - The significance of "The maiden tribute of modern Babylon". PMID- 11618256 TI - Miss Clough, Miss Nightingale and the Highland Brigade. PMID- 11618257 TI - Mary Cowden Clarke, "The girlhood of Shakespeare's heroines", and the sex education of Victorian women. PMID- 11618258 TI - Miss Nightingale and Miss Clough: letters from the Crimea. PMID- 11618259 TI - T. H. Huxley's "Evolution and Ethics": the politics of evolution and the evolution of politics. PMID- 11618260 TI - A brilliant career? John Conolly and Victorian psychiatry. PMID- 11618261 TI - Sir Francis Galton: pioneer in gifted education. PMID- 11618262 TI - Psychoanalysis and progressive eduction: Margaret Naumburg at the Walden School. PMID- 11618263 TI - The modern psychology of Thomas Reid. PMID- 11618264 TI - Lillian Wald: social force in America. PMID- 11618265 TI - Green Mountain diaspora: Indian population movements in Vermont, c. 1600-1800. PMID- 11618266 TI - Samuel Thomson's botanic system: alternative medicine in early nineteenth century Vermont. PMID- 11618268 TI - Castleton Old Chapel-Medical building. PMID- 11618269 TI - The pathology of a profession: death in the United States Navy Officer Corps, 1797-1815. PMID- 11618270 TI - Aircrew and "lack of moral fibre" in the Second World War. PMID- 11618271 TI - Swimming in the atomic lagoon. PMID- 11618272 TI - Operation bacterium: testing germs on the A train. PMID- 11618273 TI - Life and death in the emergency room. PMID- 11618274 TI - Vietnam 1975-1982: the cruel peace. PMID- 11618275 TI - Biological warfare, genetic engineering, and the treaty that failed. PMID- 11618276 TI - Haverfordwest and the plague, 1652. PMID- 11618277 TI - Work and death in the South Wales coalfield, 1874-1914. PMID- 11618278 TI - Folk medicine and intra-cultural diversity among West Texas Americans. PMID- 11618279 TI - Ste. Anne de Beaupre: Roman Catholic pilgrimage and healing. PMID- 11618280 TI - Customary observances in modern medicine. PMID- 11618281 TI - To die in Goldfield: mortality in the last boomtown on the mining frontier. PMID- 11618282 TI - Death at Mormon Nauvoo, 1843-1845. PMID- 11618283 TI - Pittsburgh in the great epidemic of 1918. PMID- 11618284 TI - Judicial decision making and biological fact: Roe v. Wade and the unresolved question of fetal viability. PMID- 11618285 TI - Beginnings of the Jewish Consumptive Relief Association (City of Hope). PMID- 11618286 TI - Marx and Alex Lesem of San Diego: father and son in the health field. PMID- 11618287 TI - In search of the history of the Texas patriot Moses A. Levy: part I. PMID- 11618288 TI - Herman Sugarman, M.D., a pioneer Jewish physician of Los Angeles. PMID- 11618289 TI - A dentist in a gold rush town. PMID- 11618290 TI - The first triplets born in the west--1867. PMID- 11618291 TI - The "new" woman in an old role: maternal-child care in Memphis. PMID- 11618292 TI - Bovine tuberculosis and the battle for pure milk in Memphis, 1910-1911. PMID- 11618293 TI - Annie Cook: "the Mary Magdalene of Memphis." PMID- 11618294 TI - Medical conditions at West Texas military posts in the 1850s. PMID- 11618295 TI - Cyrus N. Ray: the Abilene man. PMID- 11618296 TI - Dr. Peterson E. Harrison: pioneer traiblazer for mental health in West Texas. PMID- 11618297 TI - A comfortable subsistence: the changing composition of diet in rural New England, 1620-1840. PMID- 11618298 TI - Weaning among West Indian slaves: historical and bioanthropological evidence from Barbados. PMID- 11618299 TI - The political psychology of the Federalist. PMID- 11618301 TI - Charles Darwin and the Beagle. PMID- 11618300 TI - 'On the importance of the obstrick art': changing customs of childbirth in America, 1760-1825. PMID- 11618302 TI - Stitching a safety net. PMID- 11618303 TI - Stretching the span. PMID- 11618304 TI - The death and life of Samuel Johnson. PMID- 11618305 TI - In sickness and in health. PMID- 11618306 TI - William James. PMID- 11618307 TI - Airborne toxins and the American house, 1865-1895. PMID- 11618308 TI - The health of central Wisconsin residents in 1880: a new view of midwestern rural life. PMID- 11618309 TI - Psychology of women: feminist therapy. PMID- 11618311 TI - Creation and healing: an empowering relationship for women artists. PMID- 11618310 TI - Speaking out against the "talking cure": unmarried women in Freud's early case studies. PMID- 11618312 TI - Domineering mothers in the 1950s: image and reality. PMID- 11618313 TI - Go to Switzerland, young women, if you want to study medicine. PMID- 11618314 TI - Folk medicine practices: women as keepers and carriers of knowledge. PMID- 11618315 TI - Chronicles of confinement: reactions to childbirth in British women's diaries. PMID- 11618316 TI - Feminism and the "eroticization" of the middle-class woman: the intersection of class and gender attitudes. PMID- 11618317 TI - The Irish traditional lament and the grieving process. PMID- 11618319 TI - Life in the XY corral. PMID- 11618318 TI - The silencing of women in childbirth or let's hear it from Bartholomew and the boys. PMID- 11618320 TI - The Robert Mearns Yerkes papers. PMID- 11618321 TI - The Beaumont letters. PMID- 11618322 TI - Chicago's Turners: inspired leadership in the promotion of public physical education, 1860-90. PMID- 11618323 TI - Towards the notion of health in the Vedic phase of Indian medicine. PMID- 11618324 TI - Early Anglo-Norman recipes; MS. London, B.I., Royal 12 C XIX. PMID- 11618325 TI - Early Anglo-Norman recipes in ms London, B.L. Royal 12 C XIX. PMID- 11618326 TI - An unknown manuscript of the book of epidemics of Hippocrates. PMID- 11618327 TI - Is psychoanalysis a pseudoscience? Karl Popper versus Sigmund Freud. PMID- 11618328 TI - The "Novele chirurgerie" in ms London, British Library, Harley 2558. PMID- 11618329 TI - All for health. PMID- 11618330 TI - The letters between Adolphe Quetelet and William Farr 1852-1874. PMID- 11618331 TI - Has psychohistory come of age? PMID- 11618332 TI - [Not Available]. PMID- 11618333 TI - [Not Available]. PMID- 11618335 TI - Epilogue. PMID- 11618334 TI - [Not Available]. PMID- 11618337 TI - The psychological tasks of the immigrant: psychoanalytic, linguistic, and literary perspectives. PMID- 11618338 TI - The question of Jung and racism reconsidered. PMID- 11618340 TI - Veterinary practice in Walsall, circa 1870 onwards. PMID- 11618341 TI - The history of leather making in Walsall with particular reference to saddlery. PMID- 11618342 TI - The Mayers of Newcastle-under-Lyme and their place in the emerging veterinary profession. PMID- 11618343 TI - The history of rabies. PMID- 11618344 TI - Sodomy and the Knights Templar. PMID- 11618345 TI - [Medical history of Hokkaido in the context of Russo-Japanese relations]. PMID- 11618346 TI - [A study on the papers and biographies of Edward Jenner from the standpoint of modern virology]. PMID- 11618347 TI - [Medical affairs under the Kaitakushi (Hokkaido Colonial Office), 1869-82]. PMID- 11618348 TI - Burton's Anatomy of melancholy: philosophically, medically and historically: part 2. PMID- 11618349 TI - Idiocy in the nineteenth century. PMID- 11618350 TI - Metaphors of madness: Iain Crichton Smith's journey through the inferno. PMID- 11618351 TI - 'An erroneous bias': the mental illness of Jean-Francois Berger. PMID- 11618352 TI - Les Alienes voyageurs: how fugue became a medical entity. AB - Dissociative fugue was first treated as a distinct psychiatric illness in Bordeaux in 1887, and was taken up by Charcot as automatisme ambulatoire in 1888. Charcot held that fugue episodes were caused by latent epilepsy; his opponents maintained an hysterical origin. The diagnosis flourished in France for more than a decade but, like the superordinate diagnosis of hysteria, had faded by 1910, although it was exported to Italy, Germany and Russia (but not the anglophone world). It was closely associated with vagrancy as a social problem, and military doctors tried to define the illness in order to protect deserters from punishment. Fugue was a companion to multiple personality, especially in respect of gender - most multiples were women, most fugueurs were men. Dissociative fugue provides a cameo illustration of how a psychiatric entity comes into being and then disappears. PMID- 11618353 TI - Un cas de depersonnalisation. Introduction by M. Sierra and G. E. Berrios. PMID- 11618354 TI - The history of science and the sciences of medicine. PMID- 11618355 TI - The experimental life sciences in the twentieth century. PMID- 11618356 TI - Historiography of chemistry in the eighteenth century: Hermann Booerhave and William Cullen. PMID- 11618358 TI - 1st. September 1932 - an important day for pharmacy. PMID- 11618357 TI - "Mr sweet pea himself": Bernard Rees Jones. PMID- 11618359 TI - A Bradord-on-Avon pharmacy: prescription books, 1863-1918. PMID- 11618360 TI - Commercial drug cultivation in England. PMID- 11618361 TI - Wendell Stanley's dream of a free-standing Biochemistry Department at the University of California, Berkeley. PMID- 11618362 TI - Sequences, conformation, information: biochemists and molecular biologists in the 1950s. PMID- 11618364 TI - Molecular biologists, biochemists, and messenger RNA: the birth of a scientific network. PMID- 11618363 TI - Comparing experimental systems: protein synthesis in microbes and in animal tissue at Cambridge (Ernest F. Gale) and at the Massachusetts General Hospital (Paul C. Zamecnik), 1945-1960. PMID- 11618365 TI - "Biochemists and molecular biologists: laboratories, networks, disciplines": comments. PMID- 11618366 TI - "The tools of the discipline: biochemists and molecular biologists": a comment. PMID- 11618368 TI - George Bennett, the plagiarist. PMID- 11618367 TI - Two little-known nineteenth century collectors: Dr Thomas Dowler and John Keast Lord, Esq., F.Z.S. AB - Neither Dowler nor Lord seems personally to have left any record in the entomological literature, but both made or obtained significant collections of insects in areas which at the time, and for a considerable period subsequently, were entomological terrae incognitae. Their collections were drawn on extensively by contemporary describers, for example, by Frederick Smith and Francis Walker, and what remains of their material is concentrated in the collections of The Natural History Museum, London. There is no entry for Dowler in D.N.B., and no entries for either in Horn and Kahle (1935-37), Gilbert (1977) or Horn, Kahle, Friese and Gaedike (1990), and an appeal for information published in Newsletter 51 (January 1995) of the Society for the History of Natural History elicited no response. The present note, which is written with particular reference to their Hymenoptera, is published with the intention of drawing attention to their material and in the hope that the wider circulation of the Archives may bring further biographical detail to light. PMID- 11618369 TI - "Passionate Intensity" in Wells's The Island of Doctor Moreau and Yeats's "The Second Coming": constructing an echo. PMID- 11618370 TI - The first fifty years - A tribute to E. Grebenik. PMID- 11618371 TI - Editor's note. PMID- 11618372 TI - Demography and social science. PMID- 11618373 TI - Population growth, development and the environment. AB - When Population Studies was founded in 1946 a main preoccupation of demographers and of the public was the prospective decline of the British population, and the falling off of its quality because on the average a poor family had more children than a better-off one. Over the course of the 50 years interests have shifted to the aging of populations as births decline and mortality improves; immigration, immigrants being welcomed for the decades after the war, and subsequently facing hostile political pressures; environmental degradation and the spread of new diseases. The fall in the birth rate, required both for development and for protection of the environment, is spreading from the original industrialized countries of Europe and America to Asia, somewhat more slowly to Latin America, slowest of all to Africa. PMID- 11618374 TI - Demographic transition theory. AB - Demography is a science short on theory, rich in quantification. Nevertheless, demography has produced one of the best documented generalizations in the social sciences: the demographic transition. What is the demographic transition? Stripped to its essentials it is the theory that societies progress from a pre modern regime of high fertility and high mortality to a post-modern regime of low fertility and low mortality. The cause of the transition has been sought in the reduction of the death rate by controlling epidemic and contagious diseases. Then, with modernization, children become more costly. Cultural changes weaken the importance of children. The increasing empowerment of women to make their own reproductive decisions leads to smaller families. Thus there is a change in values, emphasizing the quality of children rather than their quantity. In short, the fertility transition is becoming universal phenomenon, in which every country may be placed on a continuum of progress in the transition. PMID- 11618375 TI - Anchored narratives: the story and findings of half a century of research into the determinants of fertility. AB - This paper reviews half a century of research into the determinants of fertility. It is argued that the quest for the determinants of fertility behaviour and change during that period can best be interpreted as the development of a series of sub-narratives from different disciplinary perspectives and orientations. These are normally based upon the initial narrative of the demographic transition and usually take the form of a verbal theory illustrated by a 'box and arrow' diagram. On occasions formalization has been attempted. Different parts of the initial narrative have been highlighted at different times depending on policy interest, improvements in technical skills, availability of data, changes in social setting, and the degree of satisfaction with the dominant sub-narrative of the day. There is every reason to believe that the research process identified will continue and will lead to a further accumulation of knowledge. In fact, all important variables have probably already been identified. That it will, ultimately, lead to a single, consolidated narrative fully satisfactory for all settings and for all time is, however, highly unlikely. PMID- 11618376 TI - Demographic data collection in less developed countries 1946-1996. AB - This evolution over the last 50 years of data collection systems in less developed countries is assessed. The progress made by civil registration systems has been extremely disappointing. Except in Central and South America, their role in providing vital rate estimates is still very limited. In contrast, the promulgation of regular population censuses has been a success, particularly in Africa. The relative merits and demerits of different types of demographic surveys are described. To some extent multi-round designs have given way to single-round surveys, such as the Demographic and Health Surveys (DHS). DHS-style enquiries are particularly suitable for evaluation of interventions but are less appropriate if the main aim is to measure vital rates. PMID- 11618377 TI - The development and use of demographic models. AB - In this review, we first examine two classical demographic models - conventional life tables and stable populations - and a modern generalization of stable population theory; we then discuss mathematical models of conception and birth. These models involve purely mathematical relations in formal demography as opposed to empirical regularities. Next we consider model age schedules of mortality, nuptialitiy, marital fertility, fertility, and migration that are explicitly based on such empirical patterns. We close this empirical section with a discussion of model stable populations, which are based on model life tables. We next examine the use of demographic models in forecasting future mortality, nuptiality, and fertility and in population projection. Following a discussion of microsimulation models, which gives us the opportunity to mention model age schedules of post partum amenorrhoea and of sterility, we close with observations about the purposes and uses of demographic models. PMID- 11618378 TI - Fertility in England and Wales: a fifty-year perspective. AB - This paper provides a detailed account of fertility levels and trends in England and Wales since 1938, with a briefer coverage of a much longer time-span. The paper is concerned both with the measurement of fertility and with understanding the observed fertility behaviour. We lament and correct the failure of demographers to apply measurement tools available since the 1950s to the analysis of fertility in England and Wales, with a particular emphasis on adjustment of period measures and period parity progression ratios and show how some of the grosser errors of analysis and interpretation might have been avoided by earlier use of these approaches. We also relate these estimates to more recent ones. Once a clearer account of trends has been established, the paper goes on to reinterpret and explain the baby boom and baby bust. The conclusion looks at future prospects for fertility. PMID- 11618379 TI - Population studies of mortality. AB - Population Studies has become the principal outlet for demographic research on mortality. Many of the advances in the measurement of mortality in data-poor countries were reported in its pages. It has also published most of the influential articles which attempted to make a broad-scale assessment of the sources of mortality change. These include special attention to developments in England and Wales and Sri Lanka. Capitalizing on the widespread availability of demographic surveys, articles in the 1980s featured careful analyses of the demographic correlates of child mortality. Such studies have passed the point of diminishing returns, and declines in child mortality have focused increased attention on conditions among adults. Unfortunately, demography has not developed the means for measuring and analysing adult mortality in underdeveloped countries that are equivalent in their power to methods for studying child mortality. PMID- 11618380 TI - Historical demography: achievements and prospects. AB - Historical demography as a separate discipline came into existence when family reconstruction was first developed for the analysis of a pre-transition population. This paper assesses the significant achievements made in this field of population studies since then. Attention is also paid to equally significant findings obtained from aggregative analysis based on back projection, and to a large body of research results for the period of the demographic transition. In the last part of the paper, new research directions are discussed. Data issues as well as methodological ones are raised. Special attention is given to newly emerging Asian historical demography where different source materials require different methods and techniques, which in turn are expected to broaden the scope of the so far disproportionality fertility-oriented field. Finally, discussions are extended to economic, cultural and institutional aspects of the subject, with a plea not to isolate demographic analysis from other branches of historical research. PMID- 11618381 TI - Annotated bibliography. PMID- 11618382 TI - Case Report No. 19: Early inflammatory change in leprosy affecting the rhinomaxillary region. PMID- 11618384 TI - Early days in pharmacy. PMID- 11618383 TI - Proprietary Articles Trade Association. PMID- 11618385 TI - Pharmacists and the introduction of gas lighting. PMID- 11618386 TI - A little-known emperor-physician: Manuel I Comnenus of Byzantium (1143-1180). PMID- 11618387 TI - The surgical legacy of Arris and Gale. PMID- 11618388 TI - Arthur Wellesley Edis (1840-1893): obstetrician and gynaecologist. PMID- 11618389 TI - Jane Elizabeth Waterston - Southern Africa's first woman doctor. PMID- 11618390 TI - Undercover doctors. PMID- 11618391 TI - A Crabbe with four limbs. PMID- 11618392 TI - The "back-room boys of state medicine": David Stark Murray and Bevan's National Health Service. PMID- 11618393 TI - Sigmund Freud (1856-1939): life and work. PMID- 11618395 TI - Blood transfusion in Edinburgh. PMID- 11618394 TI - Mouldy case notes on penicillin. PMID- 11618396 TI - The Lawson Memorial Hospital. PMID- 11618397 TI - Who put the George in George Eliot? PMID- 11618399 TI - The house and lineage of David. PMID- 11618398 TI - The life and times of A. E. Maylard, first surgeon to the Victoria Infirmary, Glasgow. PMID- 11618401 TI - Animals in the history of medicine. PMID- 11618400 TI - Royal physicians in Scotland. PMID- 11618402 TI - Robert Fergusson's illness revisited. PMID- 11618403 TI - William MacGillivray and his association with John James Audubon. PMID- 11618404 TI - Theodore Billroth - a short biography. PMID- 11618405 TI - Yellow fever in Europe in the early 19th century - Cadiz 1819. PMID- 11618406 TI - A backward look at 43 years of hospital medicine. PMID- 11618407 TI - James Maxwell Adams, (1817-1899), physician, forensic scientist and engineer. PMID- 11618408 TI - Storming the Citadel: the international campaign for women doctors. PMID- 11618409 TI - The first Haldane Tait lecture: John de Medina and the surgeons. PMID- 11618410 TI - The Kozhevnikov circle: clinical neurology in Moscow during the late nineteenth century. PMID- 11618411 TI - Carl Wernicke and Sergei Korsakoff: fin de siecle innovators in neuropsychiatry. PMID- 11618412 TI - Changing nineteenth century views on the origins of cerebral palsy: W. J. Little and Sigmund Freud. PMID- 11618413 TI - The history of the neurological examination. Part 1: ancient and pre-modern history--3000 BC to AD 1850. AB - Every time a physician conducts a neurological examination the process continues a biomedical search for understanding the nervous system which is as ancient as the earliest civilizations in human history. Most of the modern neurological examination evolved in a short time span, between 1850 and 1914, but the origins of neurology as a medical quest for knowledge date to the first evolution of urban life, in the valleys of the Euphrates and the Nile. This paper reviews this history in two chronological segments: part 1 up to 1850 and part 2 the subsequent period. PMID- 11618414 TI - The man behind the syndrome: Jean-Martin Charcot. PMID- 11618415 TI - Charcot-Marie-Tooth disease from first description to genetic localization of mutations. AB - Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy first described in 1886. Our increasing knowledge of this disease correlates well with the development of methods used in neurology over the past 100 years. Although its physiopathology and treatment is still not fully understood, current developments in techniques are opening the way to future discoveries. We have divided its history into three theoretical periods: the first from 1886 to 1956, which was devoted to clinical and pathological study of the disease; the second from 1956 to 1982, which saw the development of electromyography in the investigation of neuromuscular diseases; and the last and current period based upon genetic research, using the methods of molecular biology. PMID- 11618416 TI - Amyotrophic lateral sclerosis--the Edinburgh disease? PMID- 11618417 TI - Neurofibromatosis: why not Smith's disease? PMID- 11618418 TI - On some arthropathies apparently related to a lesion of the brain or spinal cord, by Dr. J.-M. Charcot, January 1868. PMID- 11618419 TI - The discovery of anti-epileptic drugs. AB - The general history of epilepsy is well documented, there being detailed accounts from ancient times in Babylonia (Wilson et al., 1990), ancient India (Bharucha & Bharucha, 1989), and China (Lai & Lai, 1991), up until the end of the 19th century (Tempkin, 1971). But relatively little has been written about its medical treatment, (Melville, 1982). The subject of this article is the history of potassium bromide, phenobarbitone and phenytoin, how their use in epilepsy was discovered, and in particular the surprisingly large part played by chance, luck and serendipity, in their introduction to the pharmacopaeia. The advance in this field has been one of sudden leaps forward, followed by periods of apparent inactivity, until the next discovery emerged, a pattern repeated many times, since medical treatment of epilepsy began with potassium bromide in 1857, until the introduction of vigabatrin in 1990. PMID- 11618420 TI - Antiepileptic therapy with bromides--historical and actual importance. PMID- 11618421 TI - Two mid-18th century descriptions of probable cluster headache. PMID- 11618422 TI - Phrenology as clinical neuroscience: how American academic physicians in the 1820s and 1830s used phrenological theory to understand neurological symptoms. PMID- 11618423 TI - The man behind the syndrome: Guillaume Duchenne. PMID- 11618424 TI - Vincent van Gogh's malady: a test case for the relationship between temporal lobe dysfunction and epilepsy? PMID- 11618425 TI - Schilder's or Stohr's disease? PMID- 11618426 TI - Considerations on "the sacred disease" by Hippocrates. PMID- 11618427 TI - "The moon" and "the blood": two emblematic symbols in headache and epilepsy according to scientific traditions of the Salerno Medical school and popular medicine in southern Italy. AB - Before describing the state of knowledge on headache and epilepsy at the Salerno Medical School (SMS), we will briefly summarize in the first part its history through the centuries until the "golden period" of the 12th century when it reached its peak by outshining all others in teaching, studies and research. In the second part we will refer to Saint Donato, healer of epileptics in the south of Italy, whose worship is still alive today. The finding of common symbols in conceptions of headache and epilepsy, both in the scientific tradition of the School and in popular medicine, represents a link which is explicable by the wide dissemination of the school's doctrines. PMID- 11618428 TI - The distinction between Alzheimer's disease and senile dementia: historical considerations. PMID- 11618429 TI - Isaac Van Deen and Benedikt Stilling: a controversy on the function of the spinal cord in the 19th century. PMID- 11618430 TI - A century of cortical architectonics. PMID- 11618431 TI - A traveller in neuroanatomy--Stensen, 1664-1670. PMID- 11618432 TI - The Galenic tradition and migraine. PMID- 11618434 TI - Art and reality. PMID- 11618433 TI - The man behind the syndrome: Friedrich Horner. AB - Although oculosympathetic lesions were described in the early 18th century in animal experiments, detailed description in humans, with the well-known triad of miosis, ptosis and enophthalmos comprising Horner's syndrome, is accredited to the Swiss ophthalmologist Friedrich Horner (1831-1886). This paper briefly reviews the symptoms and localization of the lesion with currently available diagnostic aids, and sketches the eponymous life behind Horner's syndrome. PMID- 11618435 TI - Early studies on the biological effects of high-intensity magnetic fields. AB - In 1892, Frederick Peterson described the experiences of humans exposed to magnetic fields of strength comparable to those currently used in magnetic resonance imaging. These investigations were conducted in the Edison Laboratory. None of the subjects exposed to constant and to time-variable magnetic fields suffered any ill effects. Peterson concluded that the human organism was in no way appreciably affected by the most powerful magnets known to nineteenth-century science. Peterson can be credited with the first truly scientific assessment of the biological effects of high-intensity magnetic fields. His experiments on humans, done one century ago with great cogency and skill, provide a source of inspiration to modern studies on magnetic resonance imaging. PMID- 11618436 TI - The man behind the syndrome: Sigvald Refsum. PMID- 11618437 TI - The history of hydrocephalus. PMID- 11618438 TI - Danish neurological theses: a bibliography. PMID- 11618439 TI - Trephination of the skull in pre-Columbian cultures. PMID- 11618440 TI - Effectiveness and historical merit of trephination. PMID- 11618441 TI - Neuroscience in the English-speaking world prior to 1500. PMID- 11618442 TI - European neurology from its beginnings until the 15th century: an overview. PMID- 11618443 TI - Neurology in Islamic Spain: a call for further research. PMID- 11618444 TI - Pre-Columbian neurology in ancient Ecuador. PMID- 11618445 TI - The Abbe Nollet (1700-1770): the beginnings of electrotherapy. PMID- 11618446 TI - Hughlings Jackson's rejection of the unconscious. PMID- 11618447 TI - How Thudichum came to study the brain. PMID- 11618448 TI - The history of narcolepsy and other sleep disorders. PMID- 11618449 TI - The first neurological research center: Turner's Lane Hospital during the American Civil War. PMID- 11618450 TI - The man behind the syndrome: S.A. Kinnier Wilson. PMID- 11618451 TI - The British contribution to the treatment of spinal injuries. PMID- 11618452 TI - The recent origins of paediatric neurology in the UK. PMID- 11618453 TI - The development of electromyography and neurography for diagnosis. PMID- 11618454 TI - Steno on hydrocephalus. Introduction to Niels Stensen's letter 'On a calf with hydrocephalus', with a short biography. PMID- 11618455 TI - 'On a calf with hydrocephalus'. A scientific letter dated June 1669 to Ferdinand II, Grand Duke of Tuscany. By Niels Stensen, Royal Anatomist. PMID- 11618456 TI - The history of Spanish clinical neurology in Barcelona 1881-1949. PMID- 11618457 TI - Doctor Justinus C.A. Kerner (1786-1862), and his own case of juvenile hyperemesis. PMID- 11618459 TI - Detecting feigned illness during the American Civil War. AB - The problem of feigned illness was a common one in the Civil War, afflicting both Northern and Southern military forces. The diagnostic approach of the Civil War doctor involved the initial dichotomous classification of each patient; he either suffered from physical illness (what today would be called an organic illness) or he purposely devised symptoms to avoid military service. The modern concept of the unconscious mind was totally absent from the diagnostic thinking of the Civil War physician. PMID- 11618458 TI - Neuropsychiatric treatments in medieval Rome. PMID- 11618460 TI - A note on the use of wax for bone hemostasis. Henri-Ferdinand Dolbeau (1840-77). PMID- 11618461 TI - William Osler, Sigmund Freud and the evolution of ideas concerning cerebral palsy. PMID- 11618462 TI - The use and abuse of metaphors in the history of brain science. PMID- 11618463 TI - On Dalton's cat: the history of the cervical sympathetic syndrome. PMID- 11618464 TI - The demonstration of the visual area by means of the atrophic degeneration method in the work of Bartolomeo Panizza (1855). PMID- 11618465 TI - Neurology: past achievements and future developments. A tribute to J.M. Charcot (1825-93). PMID- 11618466 TI - [An appendicitis in Beirut one hundred years ago]. PMID- 11618467 TI - [When quinine arrived to Lebanon]. PMID- 11618468 TI - [Health and social hygiene at Mount Lebanon in 1914 (about a manuscript by doctor Georges Baz)]. PMID- 11618469 TI - [Recollections from sixty-three years of medical practice]. PMID- 11618470 TI - 5 generations de medecins en 160 ans. PMID- 11618471 TI - Constructing South Kensington: the buildings and politics of T. H. Huxley's working environments. PMID- 11618472 TI - The social construction of illness: illness and medical knowledge in past and present. PMID- 11618474 TI - The social construction of illness in the early modern period. PMID- 11618476 TI - Medicine and the history of the body: the lady of the court. PMID- 11618478 TI - The doctor, his audience, and the meaning of illness. The drama of medical practice in the late 18th and early 19th centuries. PMID- 11618480 TI - The local space of medical discourse: disease, illness and hospital architecture. PMID- 11618482 TI - The social construction of health: from early modern times to the beginnings of the industrialization. PMID- 11618483 TI - Towards an externalist history of Islamic science. AB - The author sets out to propose a methodology for the study of the history of Islamic science. He chooses the externalist, rather than the internalist method for his discussion. The internalist method of science follows a rational course, while the externalist methodology studies many factors that influence the direction of sciences and may not be rational. He argues that narrative history and the logic of discovery are not adequate when one is trying to identify those key factors that have influenced the tradition of Islamic science. If Islamic science is unique, we should be able to explain how and when, it branched off from the ancient sciences. Only external history, involving a study of cultural and sociological influences on the development of science and the roles of various socioeconomic and political institutions can explain how Islamic science developed as a unique tradition and why it could not be sustained. PMID- 11618484 TI - Do horses gallop in their sleep? Consciousness, evolution, and the problem of animal minds. PMID- 11618485 TI - The trouble with welfare. [Reviews of: Coll BD. Safety net: welfare and social security, 1929-1979. Rutgers Univeristy Press, 1995. Mink G. The wages of motherhood: inequality in the welfare state, 1917-1942. Cornell University press, 1995]. PMID- 11618486 TI - Human guinea pigs: medical experimentation before World War II. [Review of: Lederer SE. Subjected to science: human experimentation in America before the Second World War. Johns Hopkins University Press, 1995]. PMID- 11618487 TI - The frontier thesis. [Review of: Achenbaum WA. Crossing frontiers: gerontology emerges as a science. Cambridge University Press, 1995]. PMID- 11618488 TI - Soul sisters: the St. John and Raynard nurses in nineteenth century London. AB - This paper uses the archives of the St John's training institution for nurses and the Raynard Mission to determine the extent to which cultural images and specialised space defined and drove the nursing profession in nineteenth and early twentieth century London. Emphasis is placed upon image and rhetoric, both sacred and secular, and the way the two combined to define the 'ideal' Victorian woman and nursing in the nineteenth and early twentieth centuries, and the understanding and treatment of illness. Research to date suggests that through a process of rationalisation of biblical and socio-cultural rhetoric, a specialisation of space, symbolic and literal, abstract and real was created; this enabled women to work in a gendered enclave, the organisational structure and rhetoric of which paralleled that of nunneries or convents. And even as the 'secular' became dominant in medical attitudes and treatment, the 'sacred'aspect of nursing and the emphasis placed upon it as being a vocation remained strong. PMID- 11618489 TI - Method and theory in the practice of nursing history. AB - This paper examines two main issues connected to the writing of history and ipso facto the history of nursing. In the first section, the issue pertaining to the difficulties involved in writing an account of past events is addressed. Light is shed on how the historian goes about interpreting the past in order to render an accurate and reliable account of the phenomenon under investigation. This issue inevitably incorporates the relevant observations of other historians hence highlighting the diversity of views and the underlying assumptions to the methodological approach. In the second section, the issue relating to the thorny problem of the role of social theory in historical writing and the challenge this presents to the historian receive attention. In this analysis about method and theory in the practice of history attention is only directed to the written word as the documentary sources constitute the bulk of the surviving records about the past. PMID- 11618490 TI - Letters from a Nightingale nurse. AB - Mary Cadbury was one of six daughters in a wealthy Birmingham family, all of whom took up professional or unpaid philanthropic work. In 1873 Mary began nurse training at the Nightingale School, St Thomas's Hospital, and regularly sent letters to family and friends, which provide a graphic account of the experience of a nurse in the latter half of the nineteenth century. PMID- 11618491 TI - First aid in the history of occupational health nursing. AB - The history of occupational health nursing has been bedevilled with a vision of nurses who sit in treatment rooms providing first aid and nothing else. This paper provides a preliminary review of some of the literature available in the UK in an attempt to offer an explanatiion concerning the association of occupational health nursing with first aid. The argument suggests that female first aiders were known as nurses prior to 1919 and the legacy of this post-1919, with first aiders inappropriately and probably illegally using the title 'sister', has led to the ambiguity surrounding the role today. PMID- 11618492 TI - History of 'tropical nursing' in East London: the Dreadnought experience. AB - In the latter years of the nineteenth century, the 'Dreadnought' Seamen's Hospital (previously the Infirmary of the Greenwich Hospital) became London's centre of excellence for the healthcare of 'seamen of all nations' (many had 'tropical' and/or sexually-transmitted diseases); this followed a 50-year period (1821-1870) during which three successive hospital ships (anchored on Greenwich Reach) had been used for this purpose' (1). Numerous mariners 'afloat and ashore' therefore owed their lives (and good health) to the skill of the physicians and surgeons based there, but equally (and perhaps more) important was the care and devotion of the nursing staff (2). PMID- 11618493 TI - A brand new beginning. PMID- 11618494 TI - A response to Angela Cushing. PMID- 11618495 TI - A brief historical note on the use of restraint and seclusion of the mentally disordered. PMID- 11618496 TI - The history of medicine on bank-notes. PMID- 11618497 TI - Airthrey Castle Maternity Hospital 1939-1948. PMID- 11618498 TI - Airthrey Castle Maternity Hospital 1948-1969. PMID- 11618499 TI - The Glasgow University Physic Garden 1704-1803. PMID- 11618500 TI - Sir William Fergusson, Bart. (1808-1877). PMID- 11618501 TI - The Bramwells. PMID- 11618502 TI - Cowane's Hospital - a Stirling almshouse. PMID- 11618503 TI - Medical care in Arkansas: an introduction. PMID- 11618505 TI - From home to hospital: changing work settings of Arkansas nurses, 1910-1954. PMID- 11618507 TI - Plague on the homefront: Arkansas and the great influenza epidemic of 1918. PMID- 11618509 TI - Health and death in early Arkansas, 1541-1803. PMID- 11618512 TI - Obstetrics in antebellum Arkansas: women and doctors in a new state. PMID- 11618514 TI - "Dug up from the hitherto dark, unfathomed recesses of nature:" abortion and the modernization of Arkansas medicine, 1875-1920. PMID- 11618515 TI - Infant mortality among New Mexican Hispanics, Anglos, and Indians. PMID- 11618516 TI - The Osler Collection of Myron Prinzmetal at McMaster University. PMID- 11618517 TI - Managing biomedical news. PMID- 11618518 TI - An apology for commemorative history: an essay review. PMID- 11618519 TI - Science at Harvard University, 1846-47: a case study of the character and functions of written documents. AB - This paper explores surviving documentation and what it reveals about the underlying social structure and relations in a historic time and place. The mid nineteenth century is chosen as a period prior to modern bureaucracies so that documents are not found in defining filing systems. Some six hundred documents are studied individually and characterized collectively. They are examined not to tell a story, however, but for evidence of their creation and maintenance and of their physical types, functional characteristics, and relations between authors and recipients. The study reveals the fruitfulness of such an orientation to documents, which complements traditional historical uses that emphasize document content. PMID- 11618520 TI - Prostitutes in the archives: problems and possibilities in documenting the history of sexuality. AB - In the past decade, the study of sexuality has proven to be one of the most dynamic academic enterprises. Among the most popular topics has been the history of prostitution. Archivists have been invaluable but largely unsung allies in the explosive growth of a new revisionist literature. Through the preservation of long-ignored and often-discarded records and manuscripts, archivists provided the means enabling historians to answer many new questions, not only about prostitution but about the history of sexuality. Yet some of these sources raise provocative and controversial problems for historians and archivists documenting the history of sexuality. The author acknowledges and thanks Loyola University of Chicago, the National Endowment for the Humanities, and the Newberry Library in Chicago for providing financial support to complete this article. His appreciation also extends to Mary Rose Alexander, Kenneth Cobb, Phillip Costello, and the anonymous referees of The American Archivist for their criticism and helpful comments on earlier drafts. PMID- 11618521 TI - Longevity and achievement in eighteenth century Scotland. PMID- 11618522 TI - Ethics of death and dying: historical perspective. PMID- 11618523 TI - The emergence of American medicine in the nineteenth century. PMID- 11618524 TI - The Harry Price Library in the University of London Library. PMID- 11618525 TI - Naval medicine and modern sea power. PMID- 11618526 TI - The water cure at "the San." PMID- 11618527 TI - Opposition to state medicine and state education: an historical analogy. PMID- 11618528 TI - Washington's first medical journal: Duff Green's Register and Library of Medical and Chirurgical Science, 1833-1836. PMID- 11618529 TI - Father of clinical neurology and pioneer in psychiatry (Jean Martin Charcot). PMID- 11618530 TI - [Christian ideals in the history of medical care]. AB - Probably because the Renaissance period tended to be overglorified, people have even come to equate the "Middle Ages" with the "Dark Ages". But some writings have recently expressed positive views on the "Middle Ages" in history. The Christian teachings from the Middle Ages concerning the sick and the poor have undoubtedly contributed to forming the ideals of modern medical care. Today's medical facilities run especially by churches are expected to continue their services based on a biopsychosociomedical model rather than on a biomedical model. PMID- 11618531 TI - [The development of I. P. Pavlov's conditioned reflex theory]. AB - This paper deals with the theory of Ivan Petrovich Pavlov (1849-1936), a Russian physiologist who presented for the first time the systematic theory of the function of the brain that controls the whole behavior of animals, i.e. higher nervous activity through experimental studies. This paper, principally based on Lectures on Conditioned Reflexes (1928), investigates the development of conditioned reflex theory from its beginning by dividing it into three periods. First, during the period from 1898 to 1906, the fundamental concept of conditioned reflex was established and the study of conditioned reflex became an independent discipline. From 1907 to 1916, the second period, Pavlov theorized on higher nervous activity on the basis of extensive data from his laboratory experiments of conditioned reflex. And Pavlov complemented conditioned reflex theory, during the third period from 1916 to 1928, and extended the boundaries of it through applications of conditioned reflex theory to psychopathology and typology. The study contributes to the understanding that conditioned reflex theory was historically developed, and not presented as a complete form from the beginning, and that Pavlov intended to study the higher nervous activity through the method of neurophysiology. PMID- 11618532 TI - [The beginning of western medical education]. AB - Our country had quite an advanced system of medical education during the era of the Koryo Kingdom, and during the Choson Dynasty, the Kyong Guk Dae Jon, in which a systematized medical education was clearly described, was compiled in the era of King Sejong. However, the educational system was not for Western medicine. Western medicine was first introduced to our country in the 9th year of King Injo (1631) when Chong Du Won, Yi Yong Jun, etc. returned from Yon Gyong (Beiuin) with Chik Bang Oe Gi. Knowledge of Western medicine was disseminated by Shil Hak (practical learning) scholars who read a translation in Chinese characters, of Chik Bang Oe Gi. Yi Ik (Song Ho), Yi Gyu Gyong (O ju), Choe Han Gi (Hye Gang), Chong Yak Yong (Ta San), etc., read books of Western medicine and introduced in writing the excellent theory of Western medicine. In addition, Yu Hyong Won (Pan Gye), Pak Ji Won (Yon Am), Pak Je Ga (Cho Jong), etc., showed much interest in Western medicine, but no writings by them about western medicine can be found. With the establishment of a treaty of amity with Japan in the 13th year of King Kojong (1876), followed by the succession of amity treaties with Western powers, foreigners including medical doctors were permitted to flow into this country. At that time, doctors Horace N. Allen, W. B. Scranton, John W. Heron, Rosetta Sherwood (Rosetta S. Hall), etc., came to Korea and inaugurated hospitals, where they taught Western medicine to Korean students. Dr. Horace N. Allen, with the permission of king Kojong, established Che Jung Won in April 1885, and in March 1886, he began at the hospital to provide education of Western medicine to Korean students who were recrutied by the Korean Government. However, the education was not conduted on a regular basis, only training them for work as assistants. This is considered to be the pioneer case of Western medical education in this country. Before that time, Japanese medical doctors came to Korea, but there are no records showing they conducted medical education. There is a documont showing that Chi Sok Yong, who not a medical doctor, accompanied a diplomatic mission to Japan in 1880, and returned with the technique of vaccination. As a Korean, he was the first to learn and introduce western medicine to this country. PMID- 11618533 TI - [On Hansung Physicians Association]. AB - Hansung Physicians Association was organized in Dec. 1915. Its members were medical practitioners residing in Kyungsung (Seoul). It was apposed to Kyungsung Physicians Association, of which members were Japanese. After the foundation of Hansung Physicians Association some other local physicians associations were begining to be founded. Hansung Physicians Association's social activities were fee-free round practice and improving sanitary conditions. It was basically gathering-meeting or interest group for doctors, which is reflected in the fact that Hansung Physicians Association limited its members as medical practitioners. It is contrasted with the Chosun Medical Association which was founded in 1930. Chosun Medical Association differs from Hansung Physicians Association in that it was a academic association. The first issue of Bulletin of Hansung Physicians Association was published in August 1933. But it came to be the last issue. Hansung Physicians Association was disorganized compulsarilly in 1941 by Japanese Government-General of Korea. PMID- 11618534 TI - [Division and specialization of the Western European physiology]. AB - The 19th century has been thought to be the turning point that the experimental method began to take strong root as the core to solve many physiological subjects, and the discipline of physiology got firmly fixed as the specialized one in the western Europe. Authors found the following characteristics in the process of the division and specialization of the 19th century western physiology. 1) It was the process of its separation from the discipline of anatomy that was necessary in the development of physiology as the independent, specialized division. Newly grown ideas, that there were working functions specialized study, were the important background and basis of the development of physiology as the specialized discipline. 2) It was not until the force and influence of the metaphysical concept on the living things (vitalism) grew weak that physiology could become the specialized discipline. The new materialistic concept about living things made it possible for the researchers of that time to apply the physico-chemical method in the study of physiological problems. 3) Institutionalization of the physiological research and education accelerated its development and specialization. The followings appeared in the mid-19th century: specialized professorship, division as the separated subject in the undergraduated medical school curriculum, laboratory settings for the purpose of physiological study, establishment of independent academic societies and publication of their own journals. Two main factors, namely, both the settlement of the new physiological thought and method of the very scientific nature and the institutionalization within the academic and medical societies, exerted influences on each other in the ground of the 19th century western Europe. Through that process, the discipline of physiology took root deep as the independent specialized division in the societies of science and medicine. PMID- 11618535 TI - [Study on the transition of intestinal parasites in Korea from 1913 to 1989]. AB - This study was performed to review the transition of infection rate and major factor in decreasing pattern of intestinal parasites infection in Korea. The results of this review study are as follows: 1) The first study on the intestinal parasites of Korean was performed by Muta (1913): he reported egg positive rate of A.lumbricoides 80%; that of T.trichiura 93%; that of Hook worm 65%. 2) After then the egg positive rates of A.lumbricoides among Korean people has been higher than 80% until and after Korean war. Owing to the biannual mass chemotherapy for 20 years by K.A.P.E. (Korea Association for Parasite Eradication), a decreasing pattern was recognized after 1960's. 3) The nationwide egg positive rate A.lumbricoides was estimated by M.H.S.A. (Ministry of Health and Social Affairs) and K.A.P.E. (1971, 1976, 1981, 1986) to be 54.89%, 41.0%, 13.0%, 2.1%. 4) The causal ageants in decreasing pattern of intestinal parasites in Korea are multifactorial such as mass chemotherapy, environmental sanitation, public education, improvement in socio-economic status, development in antihelminths, increase in use of chemical fertilizer, acceleration in national industrialization and so forth. 5) The infection rate of Korea is still higher than that of Japan and Taiwan but lower than any other countries in Southeast Asia. Nevertheless it is apparent that the present situation is not satisfactory and in this sense more effective and efficient control program is desirable. PMID- 11618536 TI - [Kyongsong Imperial University Medical College]. AB - Japan annexed Korea in 1910 and with the promulgation of the Chosen Kyoyuk Ryong (the Korea Education Decree) in 1911, it began to conduct education for the Korean people. However, this was only a matter of formality and a policy for liquidating the spirit of the Korean people. It finally resulted in the uprising of March 1, 1919 of the Korean people that has a cultural tradition of a high level. This event served as a cause of widely spread censure among the Korean people as well as the people of the whole world. Even in Japan voice of criticism rose high. Such being the situation, Japan amended the Korean educational law under the pretext of shifting to a so-called civil-rule policy. The Japanese authorities adopted the same educational system as was practiced in Japan proper, for primary and middle school education. As for higher education, they placed under a strict control the educational facilities already established by Korean people and foreign missionaries, suppressing even minor expansions of existing facilities. However, the movement by some Korean educators to establish a private university and efforts by some missionaries to integrate the existing educational organizations into a university made it inevitable for the Japanese authorities to set up a university of their own in Korea. Thus, they hurriedly established the Kyonsong Imperial University in which was included a medical college that was an indispensable organization for colonial education. They professed that the medical college was established for the purpose of providing equal opportunities and privileges to Korean and Japanese students, but, on the contrary, the operation of the college was done strictly under their colonial policy. The system of the Kyongsong Imperial University was enforced acording to the Japanese Imperial University Law, and all the faculty members and the administratial officials were Japanese. As for Koreans, a few graduates of the university was named nonpaid deputy assistants, and graduates of other colleges were employed as nonpaid subdeputy assistants. In most cases, Koreans, finally handicapped compared with Japanese, could not continue their study and research. A few of them who could conduct continued study and research were placed under strict restraints and, accordingly, their opportunities to achieve academic and social promotion were quite limited. During the history of 20 years of the Kyongsong Imperial University Medical College Yun Il Son and Ko Yong Sun served as assistant professors for 13 months and three days respectively. In addition, there were 12 Koreans who worked as temporary assistants, the periods of their service varying from two days to 10 years. The rate of graduates for Koreans was less than 30% and the rate for Koreans who received a degree of doctor of medical science was only 25%. From 1940, the course of the medical college was shortened to three years and same months under the war-time system, and with Japan's unconditional surrender to the Allied Forces on August 15, 1945, the entire faculty of the medical college was discharged by the U.S. Military Government on November 5, 1945. PMID- 11618537 TI - [An analytic study of medical records in Sam-Kuk-Sa-Ki]. AB - In Sam-Kuk-Sa-Ki there are several types of records which are associated with medicine. They are of the plagues, delivery of twins, drugs in use of the time, religious healing and names of some diseases. Records of plagues are most frequently described and they are described associated with climate and natural disasters. Those who delivered twins were awarded by the nation. Because at that time when population was not so large, the population was the power of the nation. As Buddhism was the ruling religion of the time, records of religious healing were mostly associated with the Buddhism. Medical records in Sam-Kuk-Sa Ki gives us valuable clues to the understanding of the medicine of the time, the ancient Koreans' concept of diseases and the way how they confronted them. PMID- 11618538 TI - [Dr. Choi Myung-Hak, the first modern Korean anatomist]. AB - Though it is known that the concept of anatomy was introduced in the age of Three Kingdoms, anatomy in modern sense meaning was introduced in late Chosun Dynasty by western missionary doctors. From that time on the lecture of anatomy was not given by anatomists until early 1910s. The first Korean anatomist of medical school graduates was Choi Myung Hak, graduated from Severance Union Medical College (SUMC) in 1926. He was born in 1898 at Ham Heung (Ham Gyung Nam Do Province), and entered SUMC in 1922 and graduated in 1926. He was in charge of anatomy for two years after graduation, and then he went to Kyoto Imperial University Medical College (KIUMC) and reserched under the direction of Dr. Ogawa in the field of experimental embryology and histology. He returned to Korea in 1930 and then became a lecturer in January 1931. His Doctorial thesis was recepted by KIUMC on April 18th 1932. So he became the first Korean Doctor of anatomy. He promoted to professor in February 1922. His publications can be seen in Folia anatomica Japonica. In 1934 he became a councillor of the Japanese Association of Anatomist. He resigned SUMC because of some kind of problem of the school. From that time on Chung, Il-Chun who was appointed as a lecturer in 1934 was in charge of department of anatomy. PMID- 11618539 TI - [Studies on the history of psychiatric diagnosis of the western and the eastern medicine with special reference to the papers presented at the 16th Taniguchi Symposium on the Comparative History of Medicine East and West]. AB - Scientific papers on the history of psychiatric diagnosis presented at the 16th International Taniguchi Symposium for Comparative History of Medicine-East and West which was held in 1991 in Japan were briefly reviewed and discussions and comments interchanged in this meeting were introuduced with some personal appreciation that the meeting was excellently organized and enormously successful. Particularly, the papers of medical historians and the expert in specific area like Indian medicine from North America and Europe were highly instructive. The informal gathering in the evening had offered a fascinating original report such as an old documentary film about Imu, a Japanese culture bound syndrome. One very important point was raised in this review that the comparisons between the Medicine-East and the West, particularly the translation of the Eastern medical descriptions of mental illness into the modern Western pschiatric terms should be very cautiously carried out, because by the crude identification of one medical system with the other system the uniqueness of the illness in a specific time and in a specific place might easily be overlooked. For both Japanese and Korean traditional medicine share with Chinese traditional medicine and yet they preserve their uniqueness, a small group study for comparative East Asian medicine was suggested for the more elaborated clarification of medical terms. PMID- 11618540 TI - [The anatomist Guillaume Desnoues (1650-1735), cartesianism and facial embryology]. PMID- 11618541 TI - John Hunter's surgical instruments and operative procedures. AB - Whereas John Hunter (1728-93) the anatomist, zoologist, physiologist, pathologist and museum collector receives unceasing eulogy, his work as a practising surgeon is curiously neglected. As far as can be determined, there are no studies devoted to his instruments and operative technique before a personal investigation in 1991, perhaps for the good reason that these would prove inconclusive. Nevertheless, the writer believes sufficient evidence is available to justify further communication. PMID- 11618542 TI - [On the right employment of a replica: reflections based on the identification of an embalming instrument from ancient Egypt]. PMID- 11618543 TI - [Poem in honor of Vesalius]. PMID- 11618544 TI - Public health and children's well-being and health during antiquity. AB - The health and well-being of children depends on many factors. These factors may include: 1) geographic location, 2) genetic composition of the population, 3) existence of parasites and their hosts, 4) previous history of diseases (e.g. immunity) and 5) socio-economic structure (Grmek 1989). During the last two centuries, industrialized societies have successfully manipulated several of these factors for the benefit of children. But what were the possibilities in pre industrial societies to improve public health and to promote the health of children? The aim of this study was to examine the relationship between public health and the health and well-being of children during Antiquity (roughly 500 B.C.-500 A.D.). To realize this aim, both written and archeological evidence was considered. Unfortunately both types of sources are biased, their data being defective with regard to children. Public health was not a major topic of interest for ancient authors (medical or others). There are few archaeological studies which have concentrated on public health aspects (e.g. water supply, sewers, housing conditions) of ancient societies. PMID- 11618545 TI - Places the medical historian should visit: London's museums of health and medicine. PMID- 11618546 TI - A Dublin observer of the Lisbon yellow fever epidemic. AB - The history of yellow fever is discussed with relevance to the Lisbon epidemic of 1857. Robert S.D. Lyons, professor of medicine at the Catholic University Medical School in Dublin, was given leave by the rector to investigate its pathology and set off for Portugal in November. He performed autopsies and studied possible environmental factors, with negative results. The professor's "prolonged absence" began to worry the rector in January but, before long, Dr Lyons returned to his duties and published a report. PMID- 11618547 TI - Perceptions of amputation before and after gunpowder. AB - Woodall's remark on limb amputation, in 1617, that "it is no small presumption to Dismember the Image of God", reflected lingering doubts attributable to widespread ancient beliefs or taboos which, at least during the early historic period, shunned elective amputations completely. Death was preferred to operative destruction of the body's integrity, even when societies were aware of traumatic, disease-induced and legal amputations, eventually to be accepted and managed rationally. Deep-rooted resistance to planned dismemberment became unbalanced by the malevolent wounds of gunshot missiles which contrasted vividly with cold steel and blunt injuries of earlier warfare. Massive soft tissue destruction, bone comminution and, above all, embedded missiles and clothing posed perplexing complications for both patients and surgeons, often causing gangrene and death. Finally despite resultant deformity, amputation was recognised as a means of preserving life. It is maintained the philosophical perception, believing it is better to live with three limbs than to die with four, gained acceptance due to the persuasive influence of gunpowder on battlefields and in battle-ships. Notwithstanding, until carbolised catgut ligatures were employed amputation remained a hazardous procedurep it persists as a repugnant operation of last resort. PMID- 11618548 TI - [A Belgian surgical team at the Battle of Normandie in 1944]. AB - During the year 1992, the main episodes of the battle of Normandy (1944) were commemorated with solemnity and dignity. The workmen of the victory, in what was called the greatest Battle of History, were essentially the American, British and Canadian troops. But, units composed of men from some European countries, particularly Frenchmen, Poles, Dutchmen and Belgians were also involved. Some of these units were engaged in action only at the beginning of August 1944, as soon as the whole peninsula of Cotentin, from Cael to Avranches, was firmly held by the Allied Forces and an offensive war through the Continent was considered. Apparently, the Allied Supreme Command had decided to preserve a reduced effective force of these units, during the most bloody phase of the battle for the conquest of a strong bridgehead. So they were kept in a position to participate in the liberation of their respective countries. In this paper, the author evokes a Belgian medical participation in the campaign of Normandy. PMID- 11618549 TI - Mondino's book and the human body. AB - The assertion that Mondino da Luzzi, the 14th Century Bolognese anatomist, was the first genuine human anatomist is questioned. Mondino's work is examined and his findings shown to be less than original. The investigations of surgeons, who conducted post mortem examinations during the 13th Century are highlighted, their contributions to anatomical science underscored, and their knowledge of human structure reexamined and evaluated. PMID- 11618550 TI - Contraception and abortion in the Greco-Roman world. AB - The author discusses the validity of the claim that, in Antiquity, effective contraceptives and abortifacients were available, were widely used, and their use was responsible for the decline of population in certain periods. After reviewing the maneuvers and drugs used for those purposes, the author concludes that ancient physicians did not have at their disposal effective contraceptives and abortifacients other than those that acted mechanically. In view of the danger associated with the mechanical induction of abortion, the ineffectiveness of pharmacological agents, and the limitations of mechanical contraceptives, it is concluded that drugs and other means of inducing abortion and contraception had a very limited impact on population in Antiquity. PMID- 11618551 TI - [Places the medical historian should visit: medical museums and historic hospitals of Paris]. PMID- 11618552 TI - Studies in the history of animal chemistry and its relation to physiology. PMID- 11618553 TI - "Decknamen or pseudochemical language"? Eirenaeus Philalethes and Carl Jung. AB - It is impossible to investigate the historiography of alchemy without encountering the ideas of the "father of analytical psychology", Carl Jung. Jung argued that alchemy, viewed as a diachronic, trans-cultural entity, was concerned more with psychological states occurring in the mind of the practitioner than with real chemical processes. In the course of elucidating this idea, Jung draws on a number of alchemical authors from the early modern period. One of these is Eirenaeus Philalethes, the pen name of George Starkey (1628-1665), a native of Bermuda who was educated at Harvard College, and who later immigrated to London. A careful analysis of Starkey's work shows, however, that Jung was entirely wrong in his assessment of this important representative of seventeenth-century alchemy. This finding casts serious doubt on the Jungian interpretation of alchemy as a whole. PMID- 11618554 TI - [The alkahest, universal dissolvent or when theory turns an impossible practice into the imaginable]. AB - Using again a term coined by Paracelsus, Van Helmont calls Alkahest the universal solvent able to reduce any body in its prime matter. The search for Alkahest takes up a great part of the chemical works of the second half of the seventeenth century. Simple corrosive product for some, "Philosophers' Mercury" for others, Alkahest withstands objections in spite of its absurd properties, by means of the persistence of alchemical theories in the field of chemistry. PMID- 11618555 TI - Moses Montefiore, a Hebrew prayer book, and medicine in the Holy Land. PMID- 11618556 TI - J. Liebig and the controversy over the source of muscle power. PMID- 11618558 TI - A short history of the Jewish neurological school in Russia. PMID- 11618557 TI - Napoleon's physicians in Palestine. PMID- 11618559 TI - More on ritual murder trials: the ritual murder charge of Orkut, greater Hungary, 1764. PMID- 11618561 TI - Benvenutus Grapheus of Jerusalem, an oculist in the era of the crusades. PMID- 11618560 TI - A document from a mid-nineteenth century Mohelbuch. PMID- 11618562 TI - Review essay. [Review of: Van den Bussche, H. Im Dienste der "Volksgemeinschaft": Studienreform im National-sozialismus am Beispiel der aerztlichen Ausbildung. Dietrich Reimer Verlag, 1989]. PMID- 11618563 TI - The medical work of Hunayn Ben Ishaq (Johannitius) in Hebrew translation. PMID- 11618564 TI - Orthodoxy and reform: differing medical practices in a Glasgow Jewish Victorian family. AB - Medical botanists formed a major and growing element in the delivery of medical care in Victorian Britain, supplementing the provision made by qualified physicians. Medical reform, introduced into Britain from the United States in the middle of the nineteenth century, combined botanical treatment, including a strong emphasis on the use of lobelia, with physiotherapy. The Levenston family in Glasgow was represented among both qualified orthodox medical practitioners and unqualified practitioners of medical botany. Samuel Levenston graduated M.D. at the University of Glasgow in 1859 and had a long career in medical practice in Glasgow after years of work as an unqualified practitioner. His father and brothers were active in medical botany in Glasgow, Edinburgh and Dublin, often posing as doctors but without appropriate qualifications. This paper examines the history of the Levenstons and contrasts the practices of the different members of the family, showing the relationships between a university-trained physician and medical chemists. The surviving Glasgow pharmacopeia of Solomon (Alexander) Levenston illustrates the style of his medical treatments, setting the practice of his medical botany into context. PMID- 11618565 TI - Alexis Carrel and the Jews at the Rockefeller Institute. PMID- 11618566 TI - Dr. Max Meyerhof, F.I.C.S.: a tribute. PMID- 11618568 TI - [Jews and pharmacy during the middle ages and the renaissance in southern Europe]. PMID- 11618569 TI - Life expectations of the widows and orphans of freemen in London 1375-1399. PMID- 11618570 TI - Age at baptism in rural Hampshire in the second half of the nineteenth century. PMID- 11618567 TI - Dam Himud--blood of desire. PMID- 11618571 TI - Home medicine: the Newfoundland experience. PMID- 11618572 TI - The evolution of mycobacterial disease in human populations: a reevaluation. PMID- 11618573 TI - The origin of Chinese folk medicine. PMID- 11618574 TI - Abortions in Byzantine times (325-1453 AD). AB - The legislation and the texts of the most important medical writers of Byzantine times have been studied with reference to abortions, the ethical aspect of this social and medico-legal problem, the theological and the scientific approach. The theoretical basis of the permanent and absolute condemnation of all kinds of abortions except those permitted for medical reasons, is greatly influenced by the spirit of Christianity. In fact, religion supported the view that the reception of the seed in the uterus and the conception of the embryo means the beginning of life and accepted that the foetus is already a living creature. All legislation of Byzantium from the earliest times also condemned abortions. Consequently, foeticide was considered equal to murder and infanticide and the result was severe punishments for all persons who participated in an abortive technique reliant on drugs or other methods. The punishments could extend to exile, confiscation of property and death. The physicians followed the tradition of Ancient Greece, incorporated in the Hippocratic Oath, representative of the ideas of previous philosophers. According to this famous document, it is forbidden them to give a woman "an abortive suppository". The Orthodox faith reinforced this attitute, protective of every human life. On the other hand, the Church and the State accepted selective abortion based on medical data, such as prevention of dangerous conditions in pregnancy or anatomical difficulties involved. In conclusion, science, church and legislation had a common attitude to matters concerning abortion and this fact reveals an effort to apply a fair policy for the rights of the embryo and the protection of human life in Byzantine society. PMID- 11618575 TI - [Alphonse LeRoy and the birth of pedicatrics from the begining of the 19th century]. AB - Although pediatrics as a specialty was not founded before the end of the 19th century, physicians showed a growing interest in childhood about a century earlier. Alphonse LeRoy (1742-1816), an obstetrician in Paris, was one of them, and little has been written on him in this context. We have endeavored to show that his work entitled "La Medecine Maternelle" (1803) is in no way less representative of this period than the much more celebrated works of the English authors Underwood or Buchan, and those of the German scholars Hecker or Hufeland. PMID- 11618576 TI - Medicine and law. AB - This paper covers the period where medicine and law have come into contact over the past two or three hundred years. From the time of the Scottish Enlightenment, doctors and lawyers met philosophers and scientists in a sharing of intellectual activity. A later example in the nineteenth century, did not reflect well on an anatomist Dr Knox, who appeared in the criminal trial of Burke and Hare. His misdemeanours resulted in a change of the law on dissection. The increasing use of medical evidence with the growth of medical science led to the development of forensic medicine. Differences between legal and medical thinking led to the need for definitions of mental illness in relation to criminal responsibility. The law has also needed to protect public interest in distinguishing between medical negligence and misadventure. The history of both professions helps an understanding of the problems. PMID- 11618577 TI - Classical Greek attitudes to illness. AB - The history of Greek attitudes to illness is characterised throughout by two oppositions. One concerns aetiology (divine intervention or the operation of fully explicable natural forces) and treatment (by science or by magic). The other opposition concerns the role of the sick or disabled individual in the community: a liability, to be rejected as such, or a fellow-human deserving compassion. PMID- 11618578 TI - The Ripley Scroll of the Royal College of Physicians of Edinburgh. AB - Alchemical scrolls associated with George Ripley are unusual documents which illustrate the pursuit of the Philosophers Stone. Scrolls vary from about 5 feet in length by 5 inches wide to over 20 feet long and about 3 feet wide. There are 16 scrolls in libraries in the UK and 4 in the USA. Ripley whose name is attached to the scrolls was a Canon of Bridlington in Yorkshire and lived from about 1415 to 1495. He is renowned as an alchemist and author of alchemical works in rhyme, and his verses are used on the scrolls. Some of the scrolls were produced in the 16th century, in Lubeck, probably at the request of John Dee the Elizabethan polymath. A Ripley scroll is in the library of the Royal College of Physicians of Edinburgh to which it was presented in 1707. The only published description of this scroll appeared in 1876, and it has not apparently been studied since. Interest in Ripley scrolls has grown in recent years and there have been a number of publications describing them since 1990. The Edinburgh scroll is described and is compared with the other scrolls which have been seen personally or for which detailed descriptions have been published. The origin, significance and use of Ripley Scrolls are discussed in an attempt to define their contemporary role. PMID- 11618579 TI - [Places the medical historian should visit]. PMID- 11618580 TI - Ancient medicine in E. German libraries. PMID- 11618581 TI - Greek medical manuscripts: a bibliography. PMID- 11618582 TI - Report of the 16th annual meeting of the Society for Ancient Medicine and Pharmacy, December 28, 1990 San Francisco, California. PMID- 11618583 TI - Supplements to Helmut Leitner, Bibliography to the Ancient Medical Authors. PMID- 11618584 TI - [Medicine in Phoenicia]. PMID- 11618585 TI - [Seventeenth-century ideas on making babies]. PMID- 11618586 TI - The development of thoracic surgery in Lebanon. PMID- 11618587 TI - [Yemenite monks, Maronite college, and present-day cafe]. PMID- 11618588 TI - La medecine dans les pays arabes, au Liban et en Syrie a l'epoque ottomane (en arabe). PMID- 11618589 TI - [Greatness and difficulties in Byzantine medicine]. PMID- 11618590 TI - [The struggle against pain]. PMID- 11618592 TI - The beginnings of ophthalmology in Lebanon. PMID- 11618591 TI - [Lebanese physicians in the Arab world]. PMID- 11618593 TI - Histoire de la tuberculose au Liban (en arabe). PMID- 11618594 TI - [Ibn Nafis and the discovery of the cardiovascular system]. PMID- 11618595 TI - [Medical education in the days of the first Lebanese doctors of medicine]. PMID- 11618596 TI - [Medical advertising in Beirut in the first half of the twentieth century]. PMID- 11618597 TI - Abortion and Islam. PMID- 11618598 TI - The evolution of the cataract operation. PMID- 11618599 TI - L'avortement en Islam (en arabe). PMID- 11618601 TI - [The history of the Lebanese-French society of medicine]. PMID- 11618600 TI - [Recollections from 63 years of medical practice]. PMID- 11618602 TI - [The Lebanese medical society before 1947]. PMID- 11618603 TI - [A history of forensic medicine]. PMID- 11618604 TI - La medecine au Liban de 1871 a 1914 (en arabe). PMID- 11618605 TI - The outcomes movement and its influence on the future of pharmacy practice and research. PMID- 11618606 TI - [Five centuries of hospital pharmacy in France]. PMID- 11618607 TI - [History of the Hospital of Saint Andrew, its pharmacy, and its apothecaries from Bordeaux]. PMID- 11618608 TI - [1515 or 1995? The applicable regulations for a pharmacist at the Hospital of Strasbourg]. PMID- 11618609 TI - [The work of the Misericorde of Montpellier: its history and that of its apothecary]. PMID- 11618610 TI - [Pharmacies in hospitals of Nancy other than those of the Central University Hospital System]. PMID- 11618611 TI - [The atypical management of the workers' foreman at the Hotel-Dieu of Rouen from 1696 to the Revolution]. PMID- 11618612 TI - [The apothecary sisters in France in the 17th and 18th centuries]. PMID- 11618613 TI - [The central apothecary shop of the Indies Company at the port of the Orient]. PMID- 11618614 TI - [Concerning la Charite de Vineuil at the hospice in Conde, Chantilly]. PMID- 11618615 TI - [The health of hospitals after the Revolution]. PMID- 11618616 TI - [History of the professionalization of modern clinical pharmacy]. PMID- 11618618 TI - [The hospital of the Cloister of Mount Athos around 1870]. PMID- 11618617 TI - [Pharmacy practice in the General Hospital of the American Army in Europe during World War II]. PMID- 11618619 TI - [Not Available]. PMID- 11618621 TI - [Apothecary shops of two old hospitals in Genoa, Italy]. PMID- 11618620 TI - [The old apothecary shop of the Hospital of the Holy Spirit in Saxia, Rome]. PMID- 11618622 TI - [The apothecary shop Ca Granda, founded in 1470]. PMID- 11618623 TI - [History of the hospital pharmacy in Wilanow]. PMID- 11618624 TI - [Considerations on hospital pharmacy in Romania]. PMID- 11618626 TI - [Hospitals and hospital pharmacies in Transylvania at the end of the 19th century]. PMID- 11618627 TI - [History of the pharmacies of the university clinics of Cluj]. PMID- 11618625 TI - [Drugs and pharmaceutical forms used in the "Bolnitza" of the monastery of Cernica]. PMID- 11618628 TI - The history of the Swedish hospital pharmacy. PMID- 11618629 TI - [The first Swedish pharmacy in a hospital and its jars]. PMID- 11618630 TI - [A tax on drugs of 1815 at the hospital in Berne]. PMID- 11618631 TI - [The pharmacy of the hospital of Sivas]. PMID- 11618632 TI - [Pharmacies of the hospitals of Istanbul during the Ottoman era]. PMID- 11618633 TI - [The pharmacy of the hospital of the Palace of Yildiz]. PMID- 11618634 TI - [Not Available]. PMID- 11618635 TI - Pharmaceutical services in North Africa hospitals during 18th century. PMID- 11618636 TI - [Al-Bimaristan (hospital)]. PMID- 11618637 TI - [Evolution and history of pharmacy in Portugal]. PMID- 11618638 TI - Norwegian pharmacy 400 years. A brief presentation of the oldest pharmacies. PMID- 11618639 TI - [Pharmaceutical societies in Istanbul under the Ottoman Empire]. PMID- 11618640 TI - Drug supply in German hospitals in the nineteenth century. PMID- 11618641 TI - [Pharmaceutical publicity in Greece in the 1920s: the example of Thessalonica]. PMID- 11618642 TI - [Not Available]. PMID- 11618643 TI - [Not Available]. PMID- 11618644 TI - [A reflection on the history of pharmacy]. PMID- 11618645 TI - [Johann Moritz Kunckel and his years of service of pharmacy during the French Revolution]. PMID- 11618647 TI - The structure of pharmacy and materia medica according to early university teaching in Germany at the beginning of the 19th century. PMID- 11618646 TI - [Historical study of Galenic pharmacy in pharmaceutical licensing in Grenada]. PMID- 11618648 TI - [Not Available]. PMID- 11618649 TI - [The evolution of the chemical disciplines in pharmaceutical teaching in Romania]. PMID- 11618650 TI - [Not Available]. PMID- 11618651 TI - History of a hundred years of pharmaceutical education in Japan. PMID- 11618652 TI - [Study of the pharmacy chest of the Barcelona apothecary Ignacio Francisco Ameller (1777)]. PMID- 11618653 TI - [Pharmaceutical industry, public hygiene, and health at the turn of the century]. PMID- 11618654 TI - [The repercussions of pharmaceutical forms of French origin at the dawn of pharmaceutical industrialization in Spain]. PMID- 11618655 TI - [The sterilization of injecting ampules in the autoclave. An adaptation technique proposed by the pharmacist Saturnino Cambronero (1915)]. PMID- 11618656 TI - [Platearius and the Antidotary Nicolas]. PMID- 11618657 TI - [The editors of the first formulary of drugs of the Hotel-Dieu (1739)]. PMID- 11618658 TI - [The influence of celebrated Parisian physician Jacques Dubois on the dispensary of Nuremburg]. PMID- 11618659 TI - [Not Available]. PMID- 11618661 TI - [French language pharmaceutical periodicals of the Ottoman Empire]. PMID- 11618662 TI - [Not Available]. PMID- 11618660 TI - [Two pharmaceutical inventories belonging to Brasov (1576) and Targu-Mures (1789)]. PMID- 11618663 TI - [The translation into Turkish of the Pharmacopee francaise of 1866]. PMID- 11618664 TI - [Greek astrobotany and pharmacology in the first centuries of our era]. PMID- 11618665 TI - A spectrum of Ayurvedic pharmaceutical preparations. PMID- 11618666 TI - [Medications sanctioned by Theophanes Nonnos in gynecology]. PMID- 11618667 TI - [In the middle ages, Saint Jacques Hagiotherapeute]. PMID- 11618668 TI - The incidence of scurvy at sea and its treatment. PMID- 11618669 TI - [History of the treatment of syphilis with mercury: five centuries of uncertainty and toxicity]. PMID- 11618670 TI - [Treatment of psoriasis with pine-tar, past and present]. PMID- 11618671 TI - [The General Hospital of Valencia and the treatment of dermatomycotic illnesses]. PMID- 11618672 TI - The importance of anise (Fructus anisi vulgaris) from the point of view of Turkish medical history and its place in the traditional treatments in Turkey. PMID- 11618673 TI - First hospital experiences with cinchona ordered by Spanish court (ca. 1770). PMID- 11618674 TI - [The act of the council of state of the King of 17 march 1731, instituting the commission of specific remedies]. PMID- 11618675 TI - [The pharmacy of the old hospital of La Santa Creu of Barcelona, pioneer of European hospital pharmacy]. PMID- 11618676 TI - [Assistance to drowned persons in the city of Paris, 1772-1831. The composition of boxes in terms of utensils and medications]. PMID- 11618678 TI - "Uluus"-the first medicine with a western-styled name in Japan. PMID- 11618677 TI - [Drugs of the Court: a chronology, placed in humanitarian work and results]. PMID- 11618679 TI - Historical review of medical and chemical research on globefish toxin, tetrodotoxin. PMID- 11618680 TI - The purgative plan of James Hamilton, Senior: drug therapy and pharmaceutical philosophy in the early nineteenth century. PMID- 11618681 TI - [European pharmaceutical patent medicines delivered by the dispensaries of Istanbul, Turkey in 1850]. PMID- 11618682 TI - [On the leech: a therapy that doesn't bite. Its use in Paris from the 18th to the 20th century]. PMID- 11618683 TI - [The course of pharmaceutical residencies in the 19th century, revealing the problem of opium]. PMID- 11618684 TI - The pharmacy of the King of Burgos Hospital. PMID- 11618685 TI - [The use of opioids in Polish hospitals in the second half of the 19th century]. PMID- 11618686 TI - [Not Available]. PMID- 11618687 TI - [Not Available]. PMID- 11618688 TI - [Golden chloride: concerning some chemical and histochemical studies of Sigmund Freud]. PMID- 11618689 TI - Sulfones and the miracle at Carville. PMID- 11618690 TI - [The history of cyclosporin]. PMID- 11618691 TI - [Hospital pharmacy in Valencia in the 13th, 14th, and 15th centuries]. PMID- 11618692 TI - [What are fire and air made of?]. PMID- 11618693 TI - [Influence of the work of the Catalan chemist and naturalist Antonio de Marti Franques (1750-1832) in European scientific circles]. PMID- 11618694 TI - [Two personalities of the pharmacy world in the Ottoman Empire]. PMID- 11618695 TI - [Edouard Grimaux: from the pharmacy of the Marines to higher learning, then to the Academy of Sciences]. PMID- 11618696 TI - [Not Available]. PMID- 11618697 TI - [1780-1980: two centuries of work by Parisian pharmacists on the chemistry and biochemistry of glucides]. PMID- 11618698 TI - [Louis Pasteur and the Societe de pharmacie de Paris]. PMID- 11618699 TI - [Fr. Al. Ionescu-Matiu and his relations with the Institut Pasteur in Paris]. PMID- 11618700 TI - Heptoses--from curiosities to biochemical importance--with some help from pharmacists. PMID- 11618701 TI - [Historical reflections on pharmacy at the Hospital "Sant Pau i Santa Tecla" of Tarragona]. PMID- 11618702 TI - [Joaquin Mas-Guindal (1875-1945): a military pharmacist in the Spanish protectorate of Morocco]. PMID- 11618703 TI - [A multidisciplinary pharmacist: Fr. Leon Launoy (1876-1971)]. PMID- 11618704 TI - [Not Available]. PMID- 11618705 TI - [The creation of the Institut de chimie des substances naturelles at Gif-sur Yvette by Mr. M. Janot]. PMID- 11618706 TI - Pharmacist's dispensaires in Denmark from baroque to art nouveau a culture historical research. PMID- 11618707 TI - [Hospitals and their patrimony: cultural identities and strategic stakes]. PMID- 11618708 TI - The pharmacy in the Trinity Hospital in Salamanca. PMID- 11618709 TI - [Transplantation of the black leg by the Saints Cosmos and Damien: a fresco from the 15th century]. PMID- 11618710 TI - [Saints Cosma and Damien from medicine to pharmacy]. PMID- 11618711 TI - [The pharmacy of Saint Hopital de la Passion de Ciudad Rodrigo (Salamanca)]. PMID- 11618712 TI - Yakushi Nyorai (the Buddha of healing) statue with medicinal pot in Japan. PMID- 11618713 TI - [Pharmacy in Swedish art]. PMID- 11618714 TI - [Purple digitalis in the two portraits of Dr. Gachet painted by Can Gogh at Auvers in 1890: symbol or sign of its use?]. PMID- 11618715 TI - [The separation of pharmacy from medicine]. PMID- 11618716 TI - [The parmacy of the Hopital de Saint Augustin of "El Burgo de Osma" (Soria)]. PMID- 11618717 TI - [History of the pharmacy of the Hospital of Santa Cristina in Madrid]. PMID- 11618718 TI - [The Lazaretto of Barcelona (1709-1823)]. PMID- 11618719 TI - The ladies infirmary. A health centre in the spanish court (17th century). PMID- 11618720 TI - [Hospital pharmacy in Sevilla in the 18th century]. PMID- 11618721 TI - [Study of medicines used in the pharmacy of the "Hospital of the Five Wounds" in Sevilla (1776-1836)]. PMID- 11618722 TI - [Pharmaceutical support in the hospitals of Jerez de la Frontera (16th-19th centuries)]. PMID- 11618724 TI - Community pharmacy in Colorado from 1800 to 1920. PMID- 11618723 TI - The American Society of Health-System Pharmacists: a historical perspective. PMID- 11618725 TI - 'Identities ascertained': British ophthalmology in the first half of the nineteenth century. AB - The paper takes its cue from the work on specialization and American ophthalmology by George Rosen (1944). Where Rosen's account was inspired by sociology, this paper gives a non-teleological account of medical specialization through a cultural history of ophthalmology. The cultural nature of the ophthalmic epidemics motivated practitioners to study the eye in earnest. These practitioners had to surmount obstacles intrinsic to the medical culture: the division between physicians and surgeons, hostility to specialisms, and the association with quackery. Practitioners justified their interests through the management of history, the association with philanthropy, and the construction of a father-figure. New interest in the eye was partly legitimated by the use of existing discourses, both philosophical and religious, that offered practitioners motivating languages to describe their practice. Specialization was effected through varying combinations of elements: emotional and intellectual investment in the eye, the advocacy of further research, and the explicit prosecution of specialties. The process depended upon generalist enthusiasm for the eye, and specialists' championing of generalist medicine. Specialization is a continual cultural process in a constant balancing act with the generalist tendency in medicine. PMID- 11618726 TI - The New Poor Law and the County Pauper Lunatic Asylum--the Devon experience 1834 1884. AB - In this article we examine the impact of the policies and practices of the Guardians of the New Poor Law Unions on the management of pauper lunatics in four Devon Poor Law Unions in the critical period 1834-84. The central role of the Victorian Poor Law in provision made for the insane has only recently been recognized in the research literature. Scholars have been much more concerned with the activities of professionalizing physicians and the general project of state management than they have with the micro-politics of the local Poor Law and the magistracy who were responsible for the legal disposition of the insane. In this paper we argue that not only were the Guardians of the Poor Law Unions central in the determination of the lunatic's journey through the institutional systems provided in the mid-nineteenth century, but also that there were significant variations within the Poor Law system which made for contrasting systems of disposal of lunatics as between the Unions themselves. These variations in disposal of lunatics in Devon raise important questions of ideology, policy, and practice which, if repeated elsewhere, point to a need to refine significantly our assumptions regarding the disposal of pauper lunatics in England and Wales in the fifty years following the 1834 Poor Law Amendment Act. PMID- 11618727 TI - European madness and gender in nineteenth-century British India. AB - The aim of this article is to explore whether gender was a linchpin in the construction of Europeans' mental health in nineteenth-century British India. A relational model of gender will be employed which places emphasis on the complementarity of men's and women's mental problems within the socio-economic, political and cultural confines of nineteenth-century colonialism. The postulate of a 'female malady' which has been promulgated in recent accounts of women's mental health will be shown to be inapplicable in the context of the raj. Instead a reading of the history of mental health in nineteenth-century British India will be suggested which sees different kinds of 'madness' coexisting alongside each other, merely incorporating assumptions about gender relations rather than exemplifying any one exclusively female construct of 'madness'. The primary sources will be female and male patients' case stories and statistics produced in European lunatic asylums in India and England. PMID- 11618728 TI - Back to the future: Valentin Magnan, French psychiatry, and the classification of mental diseases, 1885-1925. AB - To this day one of the most curious gaps in the historiography of French psychiatry is the era between the fin-de-siecle and the 1920s, years that overlapped the life and career of Valentin Magnan (1835-1916), a pivotal figure in the historical classification of mental diseases. This paper seeks to address this shortcoming as well as contribute to the growing scholarly interest in the history of clinical psychiatry. It argues that Magnan was in many ways a tragic figure, someone who lived and worked at a time when circumstances conspired against him and his efforts to reform psychiatric classification. Essentially Magnan had the misfortune to practise psychiatry when Emil Kraepelin's influence began to spread beyond Germany's borders, sparking a nationalist reaction that penalized both French Kraepelinians and Magnan whose theories shared similarities with Kraepelin's. But Magnan's stature also suffered because of the intense internecine quarrels that arose in late nineteenth-century French psychiatry. Magnan was no helpless victim, though, and there is reason to believe that some of the criticism directed at him was based on documented personal failings. Ultimately, Magnan's theory of psychiatric classification was overtaken by these and other events in French psychiatry, culminating by the interwar period in the emergence of a new national, nosological pardigm that has dominated French psychiatry for most of the twentieth century. Thus Magnan was in many respects a pariah within French psychiatry by the early twentieth century. An examination of his career casts light on this crucial turning-point in the history of French psychiatry and indicates why and how the new model of classification was more to the tastes of his medical colleagues. PMID- 11618729 TI - The statistical big bang of 1911: ideology, technological innovation and the production of medical statistics. AB - This paper examines the relationship between intellectual debate, technologies for analysing information, and the production of statistics in the General Register Office (GRO) in London in the early twentieth century. It argues that controversy between eugenicists and public health officials respecting the cause and effect of class-specific variations in fertility led to the introduction of questions in the 1911 census on marital fertility. The increasing complexity of the census necessitated a shift from manual to mechanised forms of data processing within the GRO. The subsequent increase in processing power allowed the GRO to make important changes to the medical and demographic statistics it published in the annual Reports of the Registrar General. These included substituting administrative sanitary districts for registration districts as units of analysis, consistently transferring deaths in institutions back to place of residence, and abstracting deaths according to the International List of Causes of Death. PMID- 11618730 TI - The National Institute of Hygiene and public health in Poland 1918-1939. AB - As the largest country of the former Eastern bloc, Poland presents an interesting case study for the evolution of public health in Eastern Europe in the twentieth century. This article looks more specifically at the interwar period when an epidemiological institute--created to deal with the epidemic aftermath of the First World War--developed into the National Institute of Hygiene (NIH), still Poland's first and foremost public health institution today. It considers the origins of the Polish hygiene movement, the influence of foreign models on Polish health structures as well as the specificities of the political and economic context of the 1920s and 1930s in relation to health issues. The foundations laid in those years seem to have played a more important role in the improvement of post war health than is commonly believed. PMID- 11618731 TI - In search of the 'problem family': public health and social work in England and Wales 1940-70. AB - Recent attempts to explain the decline of public health in England and Wales after 1948 have suggested that services had developed steadily but haphazardly in the interwar period, and that the lack of an underlying philosophy left Medical Officers of Health and their empires vulnerable to a range of forces that included the decline of infectious disease, the rise of hospital medicine, the growth of general practice, and the increasing professionalism of social work. Yet the argument that public health practitioners lagged behind contemporary thinking on social work in the 1950s deserves closer examination, and this article uses the rise and decline of the concept of the 'problem family' to examine the changing relationship between the two professional groups. It traces the emergence of the concept of the 'social problem group' in the 1930s, and considers why and how Medical Officers of Health and the Eugenics Society took up the idea of the 'problem family' after the Second world War. It charts how the Ministry of Health encouraged local authorities to use home helps and health visitors to tackle the 'problem family', and contrasts this medical approach with the casework methods developed by voluntary organizations and subsequently adopted by the social work profession. The article concludes that in revealing how Medical Officers of Health were out of touch with contemporary research and practice in social work, the issue of the 'problem family' helps to explain the decline of public health under the early National Health Service. PMID- 11618732 TI - The morbidity of medical practitioners. AB - In Volume 9, Number 1 of Social History of Medicine Robert Woods provides estimates for the mortality of Victorian doctors, showing that younger doctors and less well placed practitioners fared poorly. In part of that essay he attempts also to estimate the morbidity that doctors experienced, assuming a fixed relationship between mortality and morbidity risk. This comment explains why that assumption should not be made. Further, Woods relies on an objection Jacques Bertillon raised to infer that sickness time in Britain did not increase between the 1860s and the 1890s. This comment reviews the comparison that Bertillon made between British and continental friendly societies and explains the misunderstandings that nullify Bertillon's objection. PMID- 11618733 TI - [Not Available]. AB - To the bougeoisie in the last quarter of the 19th century, the housing problem seemed to be the key problem regarding the "social issue" (Soziale Frage). This was the background on which a number of Swiss cities undertook extensive surveys of the living conditions towards the end of the century. These surveys, which were methodologically based on the quantifying and therefore objective instruments of statistics, also attracted attention in other European states. Scientific hygiene supplied its values as the seemingly objective material criteria for the surveys. These values consisted among others of the limiting value "Luftkubus" (air volume), the natural human need for air expressed in exact numbers, as well as the rules for social behaviour in connection with this value. Together they justified "sanitary living", which a closer examination reveals as being a scientifically constructed bourgeois reality. This reality was guarded by sanitary officials, who were under the municipal sanitary authorities' supervision. These officials disposed of the means of criminal law in their struggle against "unsanitary living". The obligation to maintain health mandated by the public authorities ultimately aimed at integrating the workers into the Swiss bourgeois state and ensuring and increasing national power in modern industrial society. PMID- 11618734 TI - [Not Available]. AB - The processes leading to doctors becomming professional were not until recently compared on an international scale. There is, however, still no such comparison for doctors practicing alternative medicine. The national homoeopathic doctors' association of Germany and that of the United states of America are taken here as examples to examine the similarities and differences on the road to recognition and influence. The respective institutional frameworks of these two medical markets have a considerable effect on the possibilities of homeopathy and for those practicing homeopathy to organize themselves as a recognized profession. PMID- 11618735 TI - [Not Available]. AB - This article traces the relatively early and successful establishment, institutionalization and professionalization of homoeopathy in the kingdom of Bavaria. Prevailing antirationalist and antimaterialist tendencies in "romantic" Bavaria made homoeopathy a particularly attractive option among parts of the clerical-conservative and aristocratic ruling elites. Building upon their support in the administration and in Parliament, Bavarian homoeopaths were largely able to ward off the legal restrictions advocated by their allopathic opponents. The first (honorary) German professorship for homoeopathy was established in Munich and a homoeopathic hospital prospered. In contrast to other German states, however, a homoeopathic mass movement failed to develop, presumably due to the relative weakness of bourgeois culture and to the enduring predominance of traditional "folk"-medicine as the major alternative to academic medicine among wide sectors of the population. PMID- 11618736 TI - [Not Available]. AB - This work presents a series of homeopathical doctors who were associated with the lay doctor Clemens von Bonninghausen (1785-1864) in the area Westfalen and introduces "Vereinigung homoopathischer Aerzte Rheinlands und Westphalens" which was founded in 1849. This is followed by biographical sketches of the chairmen until 1921. PMID- 11618737 TI - [Not Available]. PMID- 11618738 TI - Pathology and the case-history in Giambattista Morgagni's "On the seats and causes of diseases investigated through anatomy" (1761). PMID- 11618739 TI - [Not Available]. AB - In Germany a new type of hospital pharmacist with new tasks and new professional aims developed from the formation of modern hospitals in the 19th century, the pharmacists' organization however was not able to successfully prevent the hospital pharmacists from becoming independent. The strategy of ostracism, however, pursued by the German Apothecaries Association (DAV) and the Association of German Apothecaries (VdA/VkA) led inevitably to the formation of a new profession with its own characteristic features - a profession within their own profession, defined by the foundation of a professional association and by the aim to monopolize hospital drug supplies and thereby displace the competing group of dispensary nurses. PMID- 11618740 TI - [Not Available]. AB - Many pioneers of the developing medical specialties in the 19th century were Jewish physicians. This phenomenon is explained by the difficulties Jews had in obtaining academic careers and therefore the necessity to cultivate the periphery of science. The development of "physical medicine" seems to be a good example to investigate this thesis. A quantitative analysis of the rise of institutes and departments for physical medicine in Vienna shows that this special field was first established in the private sector between 1890 and 1914. At the same time 75 per cent of the "Dozenten" of the University of Vienna, who worked in the field of physical medicine, were Jewish doctors. This affinity can be explained by the scientific appeal of physical medicine on the one hand and the chance to work independently of public institutions on the other. The result indicates that the development of physical medicine as a specialised part of modern medicine was predominantly due to the work of Jewish physicians. PMID- 11618741 TI - [Not Available]. AB - Due to an exceptional source it is possible to reconstruct the medical history of King Asarhaddon who reigned in Assyria between 681 and 669 BC. It makes it possible to diagnose that the king suffered from lupus erythematodus disseminatus, first announced in 672 and which led in 670 to a full outbreak of the condition. It also gives us an insight into the limits of medicine of that time in the treatment of various symptoms, and the interaction with magic which was typical of the times. We are able to observe the behaviour of the court officials including that of the personal physician towards the respectible and exceedingly sensitive and depressive patient. PMID- 11618742 TI - The discovery of REM sleep. AB - The impetus to pursue the study of ocular motility in sleeping adults was derived from a previous study conducted by the author on infants. He noted through visual observation alone that there was an approximate twenty minute interlude of complete ocular quiescence during each hour of sleep. This period of quiescence was termed 'No Eye Movement Period' or 'N.E.M. Period', and it was the intent of the author to ascertain what effect age would have on the distribution of N.E.M. periods during sleep. In the latter part of 1951, the first continuous all-night recording of ocular motility in sleep using a combined EEG and EOG technique was conducted on the author's eight year old son. Instead of N.E.M. Periods, what he found were aproximately twenty minute periods of vigorous ocular activity including saccadic-like eye movements. Although he ultimately termed these epochs as 'REM Periods', his initial intent was to name them 'Jerky Eye Movement Periods' or "JEM Periods'. Ironically, some three decades later he found that a mathematical measure of jerkiness was a better discriminator than velocity in distinguishing REMs from waking saccades. Kleitman, who was the thesis advisor, played the role of skeptic during the REM discovery and demanded unassailable proof of the existence of REM. His feelings had to be ambivalent inasmuch as the REM state, with its concurrent activated cerebral cortex, negated his own theory that sleep was a completely passive phenomenon. PMID- 11618743 TI - Gustave Dax and his fight for recognition: an overlooked chapter in the early history of cerebral dominance. AB - The year 1865 was revolutionary in neuroscience. In this year, three papers were published on the topic of cerebral dominance for speech. These papers were authored by Paul Broca, Marc Dax, and Gustave Dax, and they contributed to a priority debate that cannot be easily resolved. Gustave Dax claimed that his long dead father had written a memoir and presented it orally in Montpellier in 1836, thus making him the first person to write about cerebral dominance. He also claimed that he was the second person to write on the subject, the first to support his father's claims, and the first to try to localize the center for speech in just one part the left hemisphere, the middle (temporal) lobe. Paul Broca, however, was now getting much of the credit for these discoveries. To set the record straight, Gustave published several letters. This paper presents translations of Gustave's letters of 1866, 1875, and 1877, as well as the historical note written by Raymond Caizergues in 1879, and recreates the events that triggered the younger Dax's anger. PMID- 11618744 TI - On Morel's 'epilepsie larvee: the first Danish epileptologist Frederik Hallager's opposition in 1884 against Morel's psychical epileptic equivalents. AB - In 1860 B. A. Morel published some cases of masked epilepsy, i.e., paroxysmal behaviour disturbances or "epileptic equivalents". The majority behaved criminally. Hughlings Jackson opposed and Hallager showed that all the cases related later as epilepsie larvee could be explained as postepileptic attacks, general paralysis, paradoxical normalization, schizophrenia, mania and otherwise. True criminal behaviour was exceptional. The present author agreed. There is no need for epilepsie larvee. It is discussed whether Blumer's recent "Paroxystic neurobehaviour disorder" will revive "Morel's disorder". PMID- 11618745 TI - Light and enlightenment: Cabanis, ideology, and the role of phosphorus in the brain. AB - When Georges Cabanis presented his views to the National Institute of France in 1797 on the physiological basis of human psychology, he introduced the concept that phosphorus was of special importance in the workings of the brain. The presence of phosphorus in that organ had only recently been described by A F Fourcroy, a finding that impressed Cabanis because of the association of light (phosphorescence) and heat (evolved during oxidation) with the element. Furthermore, he hypothesised that the electrical activity of the brain represented a parallel and interacting system with that of phosphorus. Cabanis was one of the leading exponents of "ideology", the principal school of philosophy at the time of the French Revolution. Ideology promoted the systematisation of knowledge in every sphere--social, scientific and medical, for example-- and Cabanis's views about cerebral phosphorus evolved from those teachings. PMID- 11618746 TI - From Morvan's fibrillary chorea to the "mal des ardents". AB - The authors present a case of Morvan's fibrillary chorea. We compare this observation with cases in the past such as the "mal des ardents", the plague of Athens, acrodynia and the epidemic of Pont St Esprit which were all characterized clinically by pain, burning sensations, hallucinations and insomnia. Since aetiological aspects remain uncertain, the similarity in clinical observations establishes a close relationship between the "mal des ardents" and the clinical features of our patient. PMID- 11618747 TI - Georg Friedrich Handel's strokes. AB - Although there is no definite proof, it seems most likely that Georg Friedrich Handel suffered from cerebrovascular disease, which caused two or three minor strokes and weakness of his eyesight in his last years. His etiologically important risk factors and the symptoms of Handel's strokes are presented and evaluated by primary sources; various diagnoses are discussed. In Handel's musical work, no direct impact from his illness can be found, but there are some indirect outflows of Handel's pathography on his compositions, especially the Messiah. PMID- 11618748 TI - The first career of William Alexander Hammond. AB - Neurology in its modern sense was first studied in the well-known neurological institutions of France and England. In America, however, this new field of medicine was developed by a physician in a private practice, Dr. William Alexander Hammond. This article addresses the question how Hammond was able to limit his practice to neurology. It is argued that Hammond was a famous military physician before becoming the first practitioner of clinical neurology in America. This fame translated into a large referral base. PMID- 11618749 TI - Robert Wartenberg: stormy petrel of neurology; rebel of book reviewers. AB - This "Sherlock Holmes" in the discipline of neurology, always searching for truth accuracy and dependability of researcher, clinician or writer, advanced his endowment into book reviewing. His acrid criticism was accurate, for the succeeding edition always embodied all recommendations, but at all times everyone benefited from the Wartenberg warmth, for he never made enemies with his microscopic scrutiny of facts in his unique but complete review of a tome. PMID- 11618750 TI - Frantz Fanon 1925-1961. PMID- 11618751 TI - The life and psychiatric work of Frantz Fanon. PMID- 11618752 TI - Frantz Fanon and political psychiatry. PMID- 11618753 TI - French psychiatry in Algeria (1830-1962): from colonial to transcultural. PMID- 11618754 TI - Care of the insane in Algeria since the nineteenth century. PMID- 11618755 TI - Koro in ancient Chinese history. PMID- 11618756 TI - Pakistan's microcephalic chuas of Shah Daulah: cursed, clamped or cherished. PMID- 11618757 TI - Moral insanity, science and religion in nineteenth-century America: the Gray-Ray debate. PMID- 11618758 TI - Theodor Meynert (1833-1892): his life and poetry. PMID- 11618760 TI - "Moldy Mary" and the Illinois Fruit and Vegetable Company. PMID- 11618759 TI - The purgative plan of James Hamilton, Senior: therapeutic philosophy in the early nineteenth century. PMID- 11618761 TI - Pharmacy Museum opens in the U.S. Virgin Islands. PMID- 11618762 TI - Historical images of the drug market- LII PMID- 11618763 TI - Willughby's observations in midwifery: the Dutch translation. AB - The Dutch translation of the manuscript of "Observations in Midwifery" (ca. 1672) by the English man-midwife Percival Willughby (1596-1685) - pupil and friend of William Harvey - was printed in The Netherlands in 1754 and antedated the English edition (1863) by more than a century. This delay may explain why this valuable 17th-century text had no impact on obstetrical practice in Willughby's native country. PMID- 11618764 TI - [The phobia of being buried alive from Michael Ranft (1728) to Eugene Bouchut (1849)]. AB - In the XVIII and XIXth centuries, a real morbid fear of premature burial raged all over Europe. Though this question is lost in the mists of time, the publication of Michael Ranft's book (1728) on the one hand, and the awarding of the Manni Prize to Eugene Bouchut (1849) on the other hand, are two key-dates, between which the amount of researches on the diagnosis of death show the need of reassuring answers to an anxious population. This paper summarizes the bibliography on premature burial, and its results on the diagnosis of death from 1728 till 1849. PMID- 11618765 TI - The Highlands and Islands Medical Service: precursor of a state funded medical care system? AB - The Highlands and Islands of Scotland cover a large area of the country and are sparsely populated. A series of man-made and natural disasters ensured that, early in the nineteenth century, they were also poverty stricken. It was gradually recognised that the degree of social deprivation was too severe for self-help and could only be alleviated from outside the area. This paper traces the use of State funds to support a medical service, from the first payments under the new Poor Law until the outbreak of war in 1939. Improvement was at first very slow but a turning point came with the establishment in 1913 of the Highlands and Islands Medical Service Committee. The committee was given a free hand to expand or retain its annual grant as it saw fit; the way in which the money was used to develop first a comprehensive primary care service and then the nucleus of an integrated hospital service is revealed in the annual reports. The success of this local scheme may have made easier the later introduction of a national health service. PMID- 11618766 TI - [The literary impact of the propaganda campaign against veneral disease at the turn of the century]. AB - The literary perception of venereal diseases in the XIXth century was radically modified by the big prophylactic campaign that began at its end. After writers presented a romantic vision of syphilis associated initially with pride and exaltation, came a generation distressed by the obsession and the phobia that the antivenereal reaction then generated. The moving elements of this campaign, were the extreme attention to overvalued statistics and excessive consideration of indirect transmission; but also such mythical concepts as parasyphilis, syphilitic diathesis, "le genie syphilitique" and especially "heredosyphilis". This antivenereal campaign, appearing as a sanitary prophylaxis invented by the syphiligraphes, rapidly changed to a moral prophylaxis, using intensively dissuasive methods and generating among others a true propaganda literature. After World War I, the fear of a degeneration of the race, weakened by depopulation, caused an intensification of the propaganda. Its protectionist, xenophobic and intolerant nature then grew considerably in the militant literature to merge into the themes that have characterized the political speech of the Hitlerian period. The Allies and penicillin fortunately put an end to this delirious rhetoric. PMID- 11618767 TI - Places the medical historian should visit: Jerusalem. PMID- 11618768 TI - Galenicae Quaestiones Disputatae Duae: rete mirabile and pulmonary circulation. AB - The author discusses two points of Galenic medicine that have long interested medical historians: why did Galen describe a non-existent arterial rete mirabile at the base of the human brain and was Galen the first to discover the pulmonary circulation. After reviewing the evidence, it is concluded that Galen mistook the venous rete mirabile at the base of the human brain for an arterial one and that he indeed described the passage of blood from the right to the left ventricle although he did not discover the pulmonary circulation. PMID- 11618769 TI - [The disgrace of Antoine Daquin, first physician of Louis XIV (1693)]. AB - Antoine Daquin, Principal Physician of Louis XIV and Earl of Jouy-en-Josas, was born in Paris. He was the son of Louis-Henri Daquin, Physician to Queen Marie de Medicis; his paternal grandfather, born in the Jewish religion, became converted to catholicism at Aquino, in Italy, whence his name d'Aquin, then Daquin. A. Daquin studied to be a doctor at Montpellier and graduated on 18 May 1648. He married Marguerite Gayant, Antoine Vallot's niece, Antoine Vallot being the Principal Physician of Louis XIV. This relationship permitted him to get the position of Principal Physician of the Queen, then, after Vallot's death, to succeed him, on 18 April 1672, as Principal Physician of the King. The kindliness of the King's mistress, Mme de Montespan, helped him in that appointment. Daquin was a good doctor, he turned out awkward: "great courtier, but rich, miser, grasping, wanting to establish his family anyway" said the Duc de Saint-Simon. He dared ask the King for the Archbishopric of Tours for his son: "it was the rock on which he broke up" said again Saint-Simon. On 2 November 1693, the comte de Pontchartrain came to his home by order of the King, to tell him, he was ordered to retire from Court without delay. It was forbidden him to come back or to write to the King. Guy-Crescent Fagon was designated "Premier Medecin" instead of him; but Fagon had worked at the undoing of Daquin, with a view to robbing him of his position, with the complicity of the King's new mistress, Mme de Maintenon. After his disgrace, Daquin retired probably to Moulins; he died obscurely in Vichy, on 17 May 1696. Today, Daquin is regarded as a victim of intrigues of Court, which explains his celebrity. PMID- 11618770 TI - The wet nurse: a study in ancient medicine and Greek papyri. AB - This paper examines Greek medical recommendations concerning the selection of the wet-nurse, her regimen, and her duties towards the child (in particular feeding, and later weaning) in comparison with some contemporary Greek papyri concerning wet-nursing which come from Roman Egypt. It also measures the degree of medical awareness among the laity presented in the papyri. This paper demonstrates that these medical recommendations, though they were perhaps insinuated by social needs, were not necessarily always followed either by the nurse of those who selected her. Greek contracts which correspond in points with medical recommendations differ in adding more prohibitions. Yet it seems hard to prove that they were either respected or supervised. They were meant to be a deterrent to ensure the nurse's well behaviour and every possible care for the child. PMID- 11618771 TI - [Phrenitis in the Hippocratic Corpus: a philological and medical study]. AB - Phrenitis has a history, from Hippocrates to Pinel. This study is owed to two scholars of different disciplines; the first is a classicist, the other a psychiatrist. It only concerns "phrenitis" in the Hippocratic Corpus. The authors have come to the conclusion that phrenitis has a pathology similar to the organic delirium. PMID- 11618772 TI - The third sex: the idea of the hermaphrodite in twelfth-century Europe. PMID- 11618773 TI - Female fraud: counterfeit maidenheads in the eighteenth century. PMID- 11618774 TI - The way of all flesh: degeneration, eugenics, and the gospel of free love. PMID- 11618775 TI - It's a scrapbook life: using ephemera to reconstruct the everyday of medical practice. PMID- 11618776 TI - The importance of impermanence. PMID- 11618777 TI - The sociophilosophy of folk psychology. PMID- 11618778 TI - Shaping a new biological factor, 'the interferon', in room 215 of the National Institute for Medical Research, 1956/57. PMID- 11618780 TI - [A bibliographical review of the history of eugenics (III). Eugenics and the eugenics movement in U.S.A. and Japan]. PMID- 11618781 TI - Darwin's illness and systemic lupus erythematosus. PMID- 11618779 TI - [Reconsideration of the "conversion theory" from the primacy of the heart to the primacy of the blood--William Harvey's observation, logic and the construction of the exercitatio]. AB - In De Motu Cordis, W. Harvey sometimes waxes lyrical on the primacy of the heart. In his another treatise, De Generatione, however, he insists on the primacy of the blood. The "conversion theory" explained this discrepancy with Harvey's conversion as caused by his discovery of the antiquity of the blood. But Whitterridge showed that Harvey had already described the antiquity of the blood in his earliest notebook, Prelectiones. As shown in this article, Harvey's observation was not a mere accidental discovery; based on the "classic questions", it was continuously and persistently conducted until he was assured of having seen the blood to exist prior to the pulse and movement to occur in the blood. While this crucial observation was not yet made in Prelectiones and De Motu Cordis, it was described as crucial evidence of the theory of the primacy of the blood in De Generatione, in which this new theory was introduced as an independent topic of the exercitatio. The topic of the order of the generation was a crucial issue in the theoretical medicine of Harvey's days. That is, the Aristotelian primacy of the heart had been seriously challenged by the Galenic tripartite theory which pursued the antiquity of three organs. Harvey's theory, or the primacy of the blood, seems to consists with Aristotle's premise, in that it asserts the existence of the only source of all functions in living animals. Harvey's theory, however, was confronted, on the other hand, with Aristotle's another inconsistency, namely, the issue of two definitions about anima. We must consider the construction and strategy of the exercitatio in Harvey's days to understand the exact meaning of the primacy of the heart in De Motu Cordis. In De Motu Cordis, Harvey did not use the primacy of the heart in a central part of the exercitatio, namely, in confirming his unprecedented theory, the circulation of the blood, but he settled this Aristotelian premise in a marginal part, namely, in ratiocinating the final cause of the circulation and supporting his new theory from the sidelines. PMID- 11618782 TI - Medicine and the management of modern warfare. PMID- 11618784 TI - With reluctant feet - the story of FDR's struggle with polio. PMID- 11618783 TI - People, institutions, and ideas: American and British geneticists at the Cold Spring Harbor symposium on quantitative biology, June 1955. PMID- 11618785 TI - Circe in crinoline: domestic poisonings in Victorian England. PMID- 11618786 TI - How & why? PMID- 11618787 TI - Health and disease in the parishes of Edinburgh and Lothian 200 years ago. PMID- 11618788 TI - The success of vaccination in tropical countries. PMID- 11618789 TI - Edward Jenner: benefactor to mankind. PMID- 11618790 TI - Another look at Burke and Hare: the last day of Mary Paterson - a medical cover up? PMID- 11618791 TI - Occult resemblances: magic and medicine in the age of William Harvey. PMID- 11618792 TI - The sartorial hermaphrodite. PMID- 11618793 TI - [Study on history of cosmopolitan medicine in China]. AB - Roughly, three stages may be differentiated in the studies on the history of cosmopolitan medicine in China. The first stage (1907-1949) is mainly focussed on the translation of articles on medical history from abroad, mostly for popularization of the knowledge on medical history. The second stage (1950-1979), like the first stage, is a stage of translation of papers on medical history from foreign countries, mainly the USSR and Eastern European countries. The third stage (1980-1995) deals with, in addition to translation, studies on special topics with increasing coverage for investigation. PMID- 11618794 TI - [Fifty year's career of Chinese Journal of Medical History]. AB - The Journal of Medical History, the antecedent of the now Chinese Journal of Medical History, was inaugurated in March 1947. This paper divides the whole course of publication and compilation of this Journal into 3 stages, namely, Stage of Initiation and Growth (1947-1948), Stage of Tortuous Progressing (1951 1959), Stage of Flourishing and developing (1980-). Altogether 25 volumes, 95 issues have been published in 953 millon Chinese characters and 1684 original articles. Being a highly effective major journal of medical history, this Journal satisfies nearly 40% of the information in this subject and has been indexed by major medical cataloging tool books, both domestic and foreign. Experience and prospects are also mentioned here. PMID- 11618795 TI - [Sixty years of study on modern Chinese medical history]. AB - This author gives a general description to the study of modern Chinese medical history in the last six decades, which is divided into 3 stages of Initiation, Accumulation and Development, introducing representative works from all stages with emphasis laid on the achievements attained in the last stage. PMID- 11618796 TI - [Sixty years of study on medical philosophy in China]. AB - This article includes three aspects, viz. philosophical problems on the background of medical development, philosophy in TCM, and philosophy in integrated medicine and comparative study. It also gives a prospect on the basic problems in the future development of medical philosophpy based on a philosophical standpoint. These includes the study on the law of medical development, analytical study on the basic idea and theoretical struture of medicine, and study on health soft science relevant to philosophy. PMID- 11618797 TI - [Sixty years of study on history of medicine of Chinese minorities]. AB - This paper is divided into three parts for the description of history of minority medicine: 1. Liberal period (before 1980), only a few papers were published, mostly individual study. 2. Foundation period (1980-1987), more papers were published, dealing with all aspects of the subject in an organized basis. 3. Flourishing period (1988-1995), an unprecedented and comprehensive development, both quantitatively and qualitatively. An independent branch of the science, History of Minority Medicine, is formed during this period. PMID- 11618798 TI - [Sixty years of museum for history of Chinese medicine]. AB - The developmental course of museum for history of Chinese medicine can be divided into 4 stages, namely, Period of Initiation (1937-1949), Period of Development (1950-1965), Period of Stagnation (1966-1976) and Period of Rejuvenation (1977-). The article introduces the dovelopmental course of museum for history of Chinese medicine period by period, supported with plenty of historical facts. PMID- 11618799 TI - [Sixty years of study on history of Chinese legal medicine]. AB - The paper introduces all aspects of history of Chinese legal medicine, including brief history of legal medicine, comments on ancient methods of inspection, bibliography, books on criminalislics, figures, special subjects, division of historical periods, re-printed ancient works and its foreign versions, and international academic exchanges. PMID- 11618800 TI - [Old dispensaries of Chinese materia medica in the Qing Dynasty]. AB - Beginning from the pre-Qin Dynasty, there were commercial activities in medical field. Since then, it developed steadily to a certain scale until the Qing Dynasty. There was not a few dispensaris for Chinese materia medica, some of which are still existing and running to day. This author gives a brief account on these old traditional dispensaries in the Qing Dynasty. Analysis for the reasons of its prolonged existence is also given. PMID- 11618801 TI - [Preliminary exploration on Zhang Jingyue's thinking of Chinese psychiatry]. AB - As a great medical scholar of the Ming Dynasty with great achievements, Zhang Jingyue made great contributions to the course of TCM, both clinical and theoretical. This paper explores his achievements in psychiatry from the following points: 1. Expounding of etiology and pathogenesis of depressive psychoses; 2. Recognition on etiology and pathogenesis of Mania; 3. Recognition of some special psychoses; 4. Recognition of epilepsy; 5. Recognition of dementia; 6. Recognition of depression; 7. Diagnosis of feign disorders. PMID- 11618802 TI - [In commemoration of the 200th anniversary of E. Jenner's invention of vaccination]. PMID- 11618803 TI - Reanimating the face: early writings by Duchenne and Darwin on the neurology of facial emotion expression. PMID- 11618804 TI - The Neuron Doctrine 1891. PMID- 11618805 TI - The man behind the technique: in the steps of Christian Doppler. PMID- 11618806 TI - Baron Larrey's description of traumatic aphasia. PMID- 11618807 TI - The case against ataxia. PMID- 11618808 TI - The man behind the syndrome: Argyll Robertson, Scotland's ambassador extraordinary in the realm of ophthalmology. PMID- 11618809 TI - Historical anatomical aspects of stroke. PMID- 11618810 TI - The history of vascular dementia. PMID- 11618811 TI - Clinical developments in cerebrovascular disease. PMID- 11618812 TI - An historic survey of electroencephalography in cerebrovascular disease during the period 1950-1990. PMID- 11618813 TI - The history of neuro-sonology. PMID- 11618814 TI - Images of Parkinson's disease, past and present. PMID- 11618815 TI - The woman behind the syndrome: Frey's syndrome--the untold story. PMID- 11618816 TI - Reconstructing a doctrine: Galen on apoplexy. PMID- 11618817 TI - Hughlings Jackson's theory of cerebral localization. PMID- 11618818 TI - Hughlings Jackson, concomitance, and mental evolution. PMID- 11618819 TI - Eugenio Tanzi (1856-1934) and the beginnings of European neurology. PMID- 11618820 TI - Contributions by Bartolomeo Panizza to the anatomy and physiology of some cranial nerves. PMID- 11618821 TI - The origins of neuropsychiatric renewal in Milan. PMID- 11618822 TI - A reappraisal of the controversy of Dax and Broca. AB - Paul Broca is unanimously recognized as the founder of neuropsychology. Helis development of the scientific method to map mental functions onto brain topographpy has been enormously influential. Nevertheless, Dax's paper on the left hemisphere dominance for speech was written and published before Broca explicitely proposed the same theory. Probably, Broca was aware of the paper prior to 1865, but he never acknowledged Dax's original theoretical contribution. On the contrary, he always claimed to be the first to espouse the theory of left hemisphere dominance for language and never quoted Marc Dax (Broca, 1877 p 536), 'I do not like dealing with the questions of priority concerning myself. That is the reason why I did not mention the name of Dax in my paper'. In our opinion, the weight of evidence reported here suggests that the theory of the left hemisphere dominance for speech must be attributed equally to Dax and Broca, and henceforth should be called 'the theory of Dax-Broca'. PMID- 11618823 TI - Sherlock Holmes, Conan Doyle and cocaine. PMID- 11618824 TI - Epilepsy and the ancient world: from the magic beliefs of the Babylonians to the Hippocratic scientific thinking. PMID- 11618825 TI - The neurology of ancient Greece--an overview. PMID- 11618826 TI - Somatic motor nerve and function as conceived by Alcmaeon of Croton. PMID- 11618827 TI - Galen's ideas on neurological function. AB - Galen was the leading physician of the Roman empire during the last half of the second century. Unlike some of his predecessors, Galen concluded that the brain controlled cognition and willed action. The initial evidence for this doctrine was that the brain was the site of termination of all of the five senses: touch, taste, smell, sight, and hearing. Galen presumed that the information from these five senses was organized by a part of the brain that generated a concept of an object common to all senses; this part of the brain he considered to be the area of common sense. Galen thought that he could differentiate sensory from motor nerves (not nerve fibers) by palpation. Sensory nerves were soft because they needed to be impressed with the essence of the object seen, heard, felt, smelled, or tasted. Motor nerve fibers were very hard because they needed to carry the force of the will from the brain to the muscles. Strong willed people had especially firm motor nerve fibers; hence, the modern term that a person with great bravery has 'nerves of steel'. Galen considered that common sense, cognition, and memory were functions of the brain. Personality and emotion were not generated by the brain, but rather by the body as a whole (or perhaps by the heart and liver). Galen's studies of respiration and of the recurrent laryngeal nerve solidified the knowledge that the brain, not the chest, was the site of the rational power that guides human behavior. This doctrine has continued from Galen's time to the present. PMID- 11618828 TI - Historical biography of medicinal plants. AB - Medicinal plants, have been the chief source of drugs used in treatment of various ailments. It is observed that the position of medicinal plants is not the same as in Samhitas. There is a lot of addition of new synonyms and also recording of new observations in terms of actions and uses. Thus, it would be interesting to study such developments in case of each drug historically and scientifically under the heading of 'The Historical Biography', covering the entire life of a medicinal plant along with various changes taking place from time to time. PMID- 11618829 TI - Medical science in ancient Indian culture with special reference to Atharvaveda. AB - A high quality of Medical Knowledge was prevalent in ancient India. The present day Archaeological evidences of Mohenjo-daro and Harappa imparts the high civilization in matters of sanitation and hygiene. An analysis of the material in the Vedas reveals that, all the four Vedas replete the references regarding various aspects of medicine. The Atharva Veda is deemed to be an encyclopaedia for medicine "Interalia", and Ayurveda (the science of life) is considered as Upa Veda (supplementary subject) of the Atharva Veda. A few glimpses of medical Science as prevalent in the ancient India have been presented here. PMID- 11618830 TI - Eminent ayurvedic physicians of Nizam dynasty. AB - It is a biographical work which sheds light on the lives and works of some of the Ayurvedic Physicians flourished during Nizam dynasty. The credit for development of Ayurveda in Hyderabad goes to the eminent Ayurvedic Physicians, mentioned in this articles who taught Ayurveda in their private clinics, rendered their services during the outbreak of epidemics, organised conferences, compiled very useful works on Ayurveda and established an Ayurvedic school on a grand scale which was recognised by the government. PMID- 11618831 TI - Humoral classification of diseases in Siddha system of medicine. AB - In siddha system of medicine the total number of diseases are said to be 4448, but the subclassification methodology and enumeration differ from one source to another. However, classification of the majority of these diesases is either based on clinical symptoms or vitiation of humor. Futher they have been sub classified on the basis of the predominent symptoms, affected organs and aetiological factors. This study may help to understand the diseases classified under humors very well and would trigger interest in scholars to correlate the diseases in Siddha system with those in modern medicine. PMID- 11618832 TI - Ibn-Sina's concept of cardiovascular diseases. AB - Ibn-Sina's description of cardiac diseases has been logically and scientifically presented perhaps for the first time in the history of medicine through a classified description of cardiac diseases. The terminology employed by him is basically Greco-Arabic. Ibn-Sina with his logical mind, classified drugs according to their potency of overcoming malhumours. He is the first physician to correlate the diseases of the heart with the temperament and psychic make up of an individual. PMID- 11618833 TI - Rhazes contribution to the development and progress of medical sciences. AB - Rhazes was fond of music since his childhood, then studied philosophy and wrote several books about it. Later on he indulged himself in the study of chemistry and medicine. After finishing his studies, Rhazes went back to his home town and practised medicine and soon became very famous. He wrote more than 224 books on various subjects. His most important work is the medical encyclopaedia "continens" (Al-Hawi) which greatly effected the human civilization specially in Europe. PMID- 11618834 TI - Ethical aspects of the Hippocratic Oath and its relevance to contemporary medicine. AB - For centuries the Hippocratic Oath was the example of medical etiquette and as such, determined the professional attitude of physicians in modern medicine. This essay includes a short biographical account of Hippocrates, throws some light on the origin of the oath, cites the text of the oath (in English) and gives an ethical interpretation of the oath. Analysis of the past very often offers creative guidance to the present and also to the future, and the Hippocratic oath is no exception. PMID- 11618835 TI - Jahangir's interest in public health and medicine. AB - Jahangir, after his accession on the 24th October, 1605 A.D. passed twelve orders, as we learn from his Memoirs (Tuzuk-e-Jahangiri). According to fifth order manufacturing and sale of Rice-Spirit and any kind of intoxicating drug were forbidded. The tenth order was for the foundation of free hospitals and appointment of physicians in all the great cities of the empire. We learn from Edward Terry who was in India from 1615-18 A.D. that the common diseases of the time included the venereal disease, which was possibly syphilis. In the twelfth year of his reign Jahangir passed orders prohibiting smoking tobacco. In Tuzuk we find that in the third year of his reign a doe was brought to Jahangir, it was milked. Here Jahangir says that the milk of a she-antelope was believed to be a remedy for asthma. In the eighth year of his reign he tried to test the milk of a tigress which was brought to his court. He, however, failed to get the milk of the tigress. Here he says that, it was heard from philosophers that the milk of a tigress was highly useful for brightening eyes. Jahangir's belief in spiritual help in curing diseases is reflected in the fact that in the ninth year of his reign when he fell ill, he took a vow that after recovery he would make holes in his ears to declare that he owed his very existence to Khawaja Muinu-ddin and so he was Khawaja's ear-bored slave. After recovery he did accordingly and wore a pearl in each of his ears. Shaykh Hasan or Hassu whose father and grand father were surgeions of Akbar's times was a surgeon and a childhood friend of Jahangir. Jahangir after his accession made him governor of Gujarat and gave him the title of Mukarrab Khan. Another physician Hakim Ali whome Akbar had once sent as ambassador to Bijapur and was made a commander of 700 on his return, was made commander of 2,000 by Jahangir. PMID- 11618836 TI - Development of Unani system of medicine during Asafjahi period. AB - During Asafjahi dynasty Unani system of medicine was used extensively. Works of the Persian and Arabian physicians were studied. The medical works were translated in Persian and subsequently in Urdu. Commentaries were written on them and therapeutic investigations of drugs were undertaken. This period produced an enormous number of highly experienced physicians and surgeons. Various Unani Institutions including directorate, hospitals, dispensaries, college and drug stores were established giving tremendous encouragement to this system of medicine. PMID- 11618837 TI - Moalejat-E-Hindi. AB - It is an introductory note on a rare and important medical manuscript, which were compiled in Persian language by the order of the 3rd Nizam of Hyderabad. It contains a number of Ayurvedic formulations, found very effective by him. These preparations were prepared and preserved by the Nizam in his royal store-house. The Sanskrit shiokas found in it are in transliterated form, written in beautiful script. PMID- 11618838 TI - Glimpses of the advancement of medical science as depicted in the Mahabharata. AB - The Mahabharata of Vedavyasa is an encyclopaedic work, which has got some importance from the standpoint of Indian medical science also. According to it Ayurveda was a compulsory subject which was taught to everybody. Perhaps, Mahabharata is the first epic which presents the term Ayurveda. The fundamentals of Ayurveda are discussed in it very well. Circulations of blood described here reminds us the same of sushruta samhita. Three types of poisons and a number of metals and jewels have also been given in Mahabharata. PMID- 11618839 TI - Medical aspects of the late European alchemy. AB - Medical trends in European alchemy are discussed. There existed a direction that in curing illnesses made use of various substances known to alchemists. The origin can be traced back to the 14th century and further development of this trend has later led to iatrochemistry. Beside this, there existed all the time the second direction called alchemical medicine. It searched for miraculous universal medicine using for this purpose approaches known from attempts in metal transmutation. Several examples of the confused world of alchemical medicine are brought. PMID- 11618840 TI - Historical introduction of acupuncture in India. AB - Acupuncture, though originated in oriental countries in the ancient times but, its philosophical understanding is amazingly wide open to the modern medical science. Historically, records are there regarding its Indian origin. However, acupuncture practised today in Indian sub-continent mainly shows Chinese origin and its introduction to India was pioneered by Dr. B.K. Basu, the first Indian who learned Chinese acupuncture from mainland China during 1959. It is interesting enough to note that though acupuncture is successfully practised in India in a rejuvenated form for the last few decades but due to lack of proper Governmental support this thereby suffers from under utilization and under development. While WHO suggested for its wider application and development through concerted Governmental efforts. PMID- 11618841 TI - Filariasis (Shlipada). AB - Filariasis is known to medical science over many centuries. It is a disease of tropical countries due to the presence of microfilaria. The effected areas are large and elephantoid in appearance, so it is called 'Elephantiasis'. A non parasitic form of Elephantiasis occurs when the lymphatics are blocked. In Ayurveda this disease is termed as Shlipada. PMID- 11618842 TI - Therapeutic potential of Satvavajaya therapy in the management of Amavata. AB - Amavata which is popularly correlated with Rheumatoid disease, is characterised by its eternal course, uncertain progression and unpredictable series of exacerbations and remissions. In Ayurveda the impact of the Amavata over psychological setup of the patient is well recognised. Satvavajaya therapy of Ayurveda may be considered as a kind of patient education in rheumatology but with much broader base and much better applicability. PMID- 11618843 TI - Theory of colors according to ancient Indians. AB - The theory of colors according to the ancient Indians was rooted clear and comprehensively in the Sankhya-Patanjali system. As was known then, the theory was essentially metaphysical in concept and based on then prevalent basics of natural philosophy. What appears striking is that there has been a total failure to understand the role of the eye in the different perceptions. The attempt cannot also be summarily dismissed as it runs parallel to information processing approach in the metaphysical plane. PMID- 11618844 TI - Galaxy of health hazards in various socio-cultural scenario. AB - The word 'Health' has enjoyed an enormous popularity with writers during the past quarter century. It was only during the second world war, the term 'social medicine' came into wider use. The concept of social medicine has given a new orientation of medicine to the changing needs of man and society. The vast majority of the population of the world still have no access to decent health care. PMID- 11618845 TI - History of drugs with special reference to Indian contribution. AB - The Knowledge of drugs is as old as man himself. The methods used by him to find remedies against different ailments rested to a great extent on Psychical effects and certain simple procedures like blood letting and cupping. However, attempts were also made to obtain efficient cure by drugs mainly by the vegetable and to some degree from animal and mineral kingdoms. Thus, on the basis of the historical evidences it can be said that, the history of drugs is spread over a long period and also the contribution made by the Indian physicians in this regard is not less than that of the physicians of other countries. PMID- 11618846 TI - Food, dietetics and nutrition in ancient India. AB - In pre-agricultural era, entire mankind consumed meat as early man was a hunter. Possibly he ate from plants sources which grew in the wilderness. With the advent of agriculture as an outcome of civilization, man acquired the ability to cultivate what he wanted, as by now he was influenced to some extent by the selection of the food that he wanted to eat. All this ultimately led to him taking to vegeterianism, which probably did not occur until approximately 1500 B.C. It is tried in this study to examine the concept of nutrition, balanced diet, appetite, food etiquette, food sanitation and food poisoning etc. in ancient India. PMID- 11618847 TI - The medical practice of John Hall, Shakespeare's son-in-law. PMID- 11618848 TI - The formulary of a West Yorkshire pharmacy 1885-1927. PMID- 11618849 TI - Sir James Spence Kt MC MD LLD Durham Hon DSc FRCP, Professor of Child Health (1928-1954). PMID- 11618850 TI - Walter Bradford Cannon (1871-1945): early and late aftermath of contrast radiography. PMID- 11618851 TI - Philosophical aspects of John Hughlings Jackson's ideas on speech disorders and the nervous system. PMID- 11618852 TI - Purkyne's Austria Polyglotta: an historical note for our times. PMID- 11618853 TI - Why Samuel Pepys stopped writing his diary: his dimming eyesight and ill-health. PMID- 11618854 TI - Leopold Mozart: a patient in eighteenth-century London. PMID- 11618855 TI - The pathology collection of John Hunter--a spectrum of disease in the eighteenth century. PMID- 11618856 TI - The Thackray Medical Museum. PMID- 11618857 TI - Maurice R Raynaud and his protean disease. PMID- 11618858 TI - Interview with Sir William Trethowan. PMID- 11618859 TI - Henry Souttar and surgery of the mitral valve. Part I: the surgeon and his patient. PMID- 11618860 TI - [Life history of people in Hida--a study of Kakocho of Ogenji temple]. PMID- 11618861 TI - [People who lived the world of the Ema family documents]. PMID- 11618862 TI - [Historical profile of hematology and transfusion medicine in Japan]. PMID- 11618863 TI - [A medical history of the Edo era in the Owari clan]. PMID- 11618864 TI - [Dr. Toraakira Okuyama, a higher medical officer of the Japanese navy in Meiji era]. AB - Toraakira Okuyama was born in Nagasaki in 1840. His father, Genchu Okuyama, was the Dutch learning doctor of the Kaminoyama clan and one of the founders of the Otamagaike Vaccination Center. During Tokugawa period T. Okkuyama, who had a title "Gensei", was appointed as medical officer in the infantry regiments in 1863 and then was promoted to vice-director. He was appointed as doctor of the national hospital (Daibyoin) and then as assistant professor in the new epoch of Meiji was transferred to become a naval medical officer in 1871. He was advanced to Dai-ikan, the highest rank of medical officer in the Japanese navy. He worked for the establishment of naval medical systematization and gave students education at the naval medical school (Kaigun-Guni-Ryo-Gakusha) with William Anderson and Edwin Wheeler. He resigned his post in 1876 and died in 1926, until which time he continued the life of a practitioner. PMID- 11618865 TI - [Manase Dosan (the Elder) and leprosy]. AB - The aim of this paper is to describe the main features of Manase Dosan's (1507 1594) study and treatment of leprosy. Contrary to general medical opinion in the Middle Ages that leprosy was the result of divine retribution. Dosan viewed leprosy as simply another disease and treated it accordingly from a medical perspective. Furthermore, the commonly held belief from the latter half of the 17th century onwards amongst Early Modern era doctors and also the general populace that leprosy was a hereditary disease, was not considered by Dosan. The foregoing two points can be explained by his rational approach to medicine, plus the fact that leprosy at the time was widely prevalent amongst all areas of society, not just restricted to particular households. It is thus fair to say that Dosan's medical philosophy reflected the state of Japanese society during the transition from medieval to the Early Modern period. It should be noted, however, that Dosan's view that leprosy was caused by meat-eating and overindulgence in sex gave rise to a new, negative image of the disease, and in so doing tied in with the Early Modern era prejudices against "lust", "intemperance" and "laziness." PMID- 11618866 TI - [A historical survey of diphtheria in Europe, China and Japan. Part I: ancient and medieval age]. AB - The history of diphtheria has not yet been fully studied. The author presents two cases of diphtheria from the Hippocratic collection. It is presumed that a tracheotomy was performed in one of them. The author presents the ancient Chinese names of diphtheria, Houbi (Kohi) which means "laryngeal obstruction", Mengju (Moso) which means "fulminant carbuncle" and Yaoju (Yoso) which means "children killing carbuncle", from Chinese medical classics, and suggests that Shaoyinbing (Shoinbyo) which means "small negative disease", in Shanghanlun (Shokanron) is possible to be diphtheria. In the Medieval Age (6-15c.), so many records and commentaries are found in Chinese medical books, which describe diphtheria by many different names, such as Mabi (Bahi), Chanhoufeng (Tenkofu), Datoubing (Daitobyo) and so on. Mabi means fulminant diphtheria. Chanhoufeng means strangling disease, which coincides with the old Spanish name of diphtheria "Garrotillo." Datoubing means "big head disease" which represents the swelling of face and neck in malignant diphtheria, and which coincides with the English vulgar name "Bull-neck." Japan also has some descriptions about diphtheria in medical books and chronicles of the Kamakura-Muromachi Age (13-15c.), which use the words Houbi (Kohi), Houzhong (Koshu) etc. for diphtheria. PMID- 11618867 TI - [Treatise on Kankeru (cancer) written in the book "Komo Ijutsu Monsho" by Goda Daisuke]. AB - "Komo Ijutsu Monsho" (Book on Dutch Style Medicine) was written by Goda Daisuke (1738-1795), who was a physician in Sanuki (Kagawa Prefecture) and younger brother of the author of "Komo Igen" (Introductory Note on Dutch Internal Medicine) Goda Kyugo, by listening to the Japanese interpreters Yoshio Kogyu and Rofu of Nagasaki, around the 1760's. In this book, he noted the nature of Kankeru (cancer), especially of the breast, and also referred to the fact that the disease is curable when it was removed in its early stage. Later on, this information led to the success of surgical resection of breast cancer by Hanaoka Seishu in 1805 by the use of general anesthesia, which he invented. This article introduces the pioneering work of Goda Daisuke. PMID- 11618868 TI - [On the medical staff of the Dutch factories in Hirado and Nagasaki during the 17th century]. PMID- 11618869 TI - [The background of the hardships of Moabit Hospital; an aspect of German medicine under the National-Socialistic rule]. AB - Under the National-Socialistic (Nazi) rule, Moabit Hospital (City Hospital of Berlin at Moabit) met various hardships. In the present communication, their sufferings and backgrounds are described as an aspect of German medicine during the Nazi regime. 1. Around April 1st, 1933, the day of an anti-Jewish boycott, the Jewish doctors, co-medical and non-medical personnel were banned from the hospital. 2. At the hospital, they were forced to perform involuntary sterilization on psychiatric patients and patients with hereditary disease, by an inhuman law. 3. Dr. Georg Groscurth, a chief physician of the hospital, was executed because of his anti-Nazi activity. His act came from his patriotism and righteous indignation against the cruelty of Nazism. 4. In comparison with the inhumanity of the Nazis and in relation to the origin of the name of the area, Moabit, the author comments on "the Prussian tolerance" realized by Elector Friedlich Wilhelm of Brandenburg. The author believes this tolerance was one of the important causes of the flourishing of German medicine in the ninteenth century. PMID- 11618870 TI - [Teiho Shimamura (1830-1881), his life and work]. AB - The author reported on the career and work of Teiho Shimamura, a last Dutch scholar in Japan. He was born in Okakyama, 1830 as the second son of Koan Tsuge and was adopted into the Shimamura family at age four. When he was 23 years of age, he started to study Dutch learning at Teki-Juku. Later he went to Edo and engaged in translation of Dutch books into Japanese. In 1866, he translated D. Lubach's book of physiology and S.D. Gross's book of surgery and published them with favorable criticism. In 1868, he was appointed as a professor of Higasi-ko, the predecessor of Tokyo University and the lectures of Dr. Wilson and Dr. Bauduin were edited and published as [Japanese word] in 1869 and 1870 respectively. These owe much to Teiho's effort as a person in charge, from his preface. At the early years of Meiji, many English books were also translated into Japanese and these were mostly proof read and corrected by Teiho because of his Chinese knowledge. In his later years, he was sickly and died at the age of 52 in 1881. PMID- 11618871 TI - [Strike of doctors in the Uwajima clan (a quarrel among physicians)]. AB - The following article tells about an incident from the history of the Uwajima clan, which occurred in 1816. Bokuan Kako, one of the private doctors of the clan often quarreled with the other doctors about usual medicines for a young lord. The clan authorities' support for Bokuan's claim made the other doctors feel dissatisfied. Then, on the day when they were supposed to go up to Edo for an alternate-year residence, the other doctors resorted to the tactics of absenteeism owing to illness. In spite of their insolent doings, they went unpunished just to avoid medical confusion in the clan. PMID- 11618873 TI - [Decipherment of an old medical manuscript named "Iyaku Chozai Kosho" preserved in the Horyuji temple]. PMID- 11618872 TI - [Discord between the Department of Defense and Toko on the foundation of the Bureau of the Army Doctors]. AB - The relation between the Department of Defense and Toko was not intimate before the Bureau of Army Doctors, his relation to Toko was also not smooth. and then he had to employ the army doctors from the organization other than Toko. I pointed out that the transfer of the higher army doctors to the Bureau of the Army Doctors was done not just after its foundation, as it was said before, but in 1874, after the normalization of the relationship of the two. PMID- 11618874 TI - [The historical materials about the medical system of the Edo Shogunate]. PMID- 11618875 TI - [Dr. Torafumi Okuyama, naval medical officer and the author of the dictionaries of medical terms]. AB - Dr. Genryo Torafumi Okuyama, the second son of Dr. Genchu Okuyama of the Kaminoyama clan, was born on Dec. 4th, 1847. His elder brother Dr. Toraakira Okuyama was promoted to Dai Ikan (Senior Captain), the highest rank of medical officer in the Japanese Navy, and rendered distinguished services in the establishment of the naval medical systematization in the early Meiji era. Dr. Trafumi Okuyama, who was appointed as medical officer of the Yokohama army Hospital and transferred to Daibyoin in Edo, was engaged in medical treatment of injured soldiers during the Boshin-war in 1868. He went to Kagoshima with William Willis and as one of the founders of the Kagoshima Medical school, gave students education there. He resigned his naval position in 1874, when he was Dai Gun I (Senior Leutenant) and died at the age of 41 in April 16th 1887. Dr. Torafumi Okuyama compiled A medical vocabulary in English and Japanese ("Igo Ruizyu") and Deutsch-Japanisches Hand-Worterbuch fur Medizin ("Dokuwa Igaku Ziten) and published "Koen Hikki", the translation of the lectures by Dr. Edwin Wheeler. PMID- 11618876 TI - [How did Japanese psychiatrists receive conceptions of dementia praecox and schizophrenia?]. AB - Before the introduction of Emil Kraepelin's system of classification of mental illness, several systems coexisted in Japanese psychiatry and the terminology of mental illness was unclear. Shuzo Kure, after his study under Kraepelin in Heidelberg, came back to Japan in 1901. The next year Kure and Kinnosuke Miura (neurologist) founded the Japanese Society of Neurology (now, the Japanese Society of Psychiatry and Neurology). Kure introduced Kraepelin's system of classification. It took about a decade for most Japanese psychiatrists to accept Kraepelin's system. Only a few psychiatrists criticized Kraepelin's conception of dementia praecox. Eugen Bleuler's conception of schizophrenia was accepted with little discussion. As for translation, three different words were used for "schizophrenia". It was in 1937 that the Japanese Society of Pspychiatry and Neurology determined the Japanese equivalent of "seishin(mind)-bunretsu (splitting)-byo(disease)" for schizophrenia. PMID- 11618877 TI - [Marcello Malpighi's theory of medicine]. AB - Marcello Malpighi (1628-94) was the most important anatomist of Seventeenth Century Italy. He investigated chiefly the minute structures of living things with the microscope, as his discovery of the capillary vessels of the lung, and his description of the Malpighi-corpuscle of the kidney has showed. Malpighi discusses the role of anatomy in medicine in the "Risposta" to G.G. Sbaraglia's "De recentiorum medicorum" in which it was insisted that anatomical study with the microscope makes no contribution to practical cure. Malpighi's argument for the anatomical study is based on the mechanistic view of nature. He considers living things analogous to machines made up of minute parts, and believes that the cure of diseases must be done as the repair of broken machines. He insists that by the dissection of the bodies of dead patients we should get knowledge of the relation between the change of tissues and the symptom of disease. Naturally it is impossible to explain the cause of disease only by the mechanistic explanation as Malpighi insisted, but his mechanistic view largely influenced the methodology of Morgagni, the father of modern pathological anatomy in the eighteenth century. PMID- 11618878 TI - [Analysis of old surgical operation records of the Drs. Ishin Fuwa who graduated from Hanaoka School of Medicine]. AB - Ninety-five surgical records prepared by Dr. Ishin Rensai Fuwa from 1826 to 1859, and by his son, Dr. Ishin Kyousai Fuwa, from 1860 to 1871, were analyzed. These two surgeons lived in Fuwaishiki Village in the Mino area and performed many surgical operations under general anesthesia more than a century ago. The former was one of the trainees of Dr. Seishu Hanaoka who had performed the first operation under general anesthesia by Mafutsusan in 1804. Forty-eight patients were from the Mino area, and thirty-one from the Owari area; the others were from the Ise, Mikawa and Oomi areas. Seventy-three of 95 operations were for breast cancer, four for neck tumor, four for facial tumor, three for cleft palate and so on. The ages of breast cancer patients ranged from 15 to 68 years (mean 44 years), and 27% of 73 patients had an operation for breast cancer with removal of axillary nodes. Even at that time, informed consent for surgery seemed to have been obtained when a cancer was at the advanced stage and recurrence was suspected. These records clarify the medical situation, especially with regard to surgery, in one district of the Mino area at the end of the Edo era before Western medicine had been introduced to Japan. PMID- 11618879 TI - [An examination of the Cunzhen Huan Zhong Tu]. AB - A human dissection autopsy was performed in China in 1045, resulting in the production of the Ou Xi-fang Wu Zang Tu. Subsequently, between 1102 and 1106, Yang Jie augmented this with the Cun Zhen Tu. Both of these have not been preserved. The author has re-examined these on the basis of materials (preserved in Japan) left by the 16th century figure Gen'un. 1. The material used by Gen'un was the Cun Zhen Huanzhong Tu, and he did not cite directly from the Ou Xi-fang Wu Zang Tu. 2. The drawing of internal viscera cited by Gen'un is the same as that cited in the Ton'isho. 3. Cun Zhen Huanzhong Tu is comprised of two sections; the drawings and explanations in the Cun zhen Tu deal with internal viscera, and those of the Huanzhong Tu with meridians and acupoints. 4. The explanatory text in the Cun Zhen Tu cited by Gen'un accords with the citation in the extant text of the Xinke Hua Tuo Neizhao Tu. 5. Kozo Watanabe has argued that the Ton'isho cited the Cun Zhen Huanzhong Tu in its entirety, but this is incorrect. Rather, the citation is only a partial one. PMID- 11618880 TI - [The historical materials about the medical system of the Edo Shogunate (7)]. PMID- 11618881 TI - Museums and the establishment of the history of science at Oxford and Cambridge. PMID- 11618882 TI - History of science and the Science Museum. PMID- 11618883 TI - Charles Singer and the early years of the British Society for the History of Science. PMID- 11618884 TI - Moralizing science: the uses of science's past in national education in the 1920s. PMID- 11618885 TI - Joseph Needham (1900-95). PMID- 11618886 TI - The irrelevance of contemporary orthopedic pathology to specimens from antiquity. PMID- 11618887 TI - Herbert Evans and the collecting of medicine and science. PMID- 11618888 TI - The life and times of John Uri Lloyd: a view from the archives of the Lloyd Library. PMID- 11618889 TI - A survey of chemical medicine in the 17th century: spanning court, classroom, and cultures. PMID- 11618890 TI - Carl Binz (1832-1913): an early pioneer of pharmacology and chemotherapy. PMID- 11618891 TI - The national quinine pool: when quinine went to war. PMID- 11618892 TI - C.C. Little and the Jackson Laboratory Archives: some notes on the intersecting histories of eugenics, mammalian genetics, and cancer research. PMID- 11618893 TI - Eugenic science in California: the papers of E. S. Gosney and the Human Betterment Foundation. PMID- 11618894 TI - Genetics collections now available for research at the A.P.S. Library. PMID- 11618895 TI - Refraction and reflexivity in the history of genetics: the Tracy M. Sonneborn Papers at the Lilly Library. PMID- 11618896 TI - The rehabilitation of wretched subjects. PMID- 11618897 TI - Ramsay MacDonald, the Labour Party, and child welfare, 1900-1914. PMID- 11618898 TI - Essay Review: democracy and health care. PMID- 11618899 TI - Against generality: meaning in genetics and philosophy. PMID- 11618900 TI - Between American history and history of science. PMID- 11618901 TI - Cellular and theoretical chimeras: piecing together how cells process energy. PMID- 11618902 TI - Essay review: the instrument trade in Britain. PMID- 11618903 TI - Galen's method of healing. (Proceedings of the 1982 Galen Symposium) PMID- 11618904 TI - Style and context in the Method of healing. PMID- 11618905 TI - 'Endeixis' as a scientific term? A) Galen's usage of the word (in medicine and logic). PMID- 11618906 TI - 'Endeixis' as a scientific term: B) 'Endeixis' in authors other than Galen and its Medieval Latin equivalents. PMID- 11618907 TI - A brief note on Arabic equivalents to Galen's 'Endeixis'. PMID- 11618908 TI - A list of Latin manuscripts containing medieval versions of the Methodus Medendi. PMID- 11618910 TI - The Method of healing in Middle English. PMID- 11618909 TI - [Not Available]. PMID- 11618911 TI - Teaching Methodus Medendi in the Renaissance. PMID- 11618912 TI - [Not Available]. PMID- 11618913 TI - [Not Available]. PMID- 11618914 TI - Galen on logic and therapy. PMID- 11618915 TI - Atomism, Lynceus, and the fate of seventeenth-century microscopy. AB - Recent scholarship, focusing on the rapid decline of microscopy after the late 1680's, has shown that the limitations of microscopy and the ambivalent meaning of its findings led to a wide-spread sense of frustration with the new instrument. The present article tries to connect this fall from favor with the microscope's equally surprising but hitherto little noticed late rise to prominence. The crucial point is that when the microscope, more than a decade after the telescope, finally managed to arouse the interest of natural philosophers, it did so as a corpuscularian tool, and as such it came to share the difficult fate of seventeenth-century corpuscularianism. The essay ends with the claim that the fall of microscopy was not only due to the failure of microscopy to corroborate corpuscularianism, but also to the changing definition of natural philosophy in the late seventeenth and early eighteenth centuries and to the separation of the domains of living matter (to which the microscope found itself confined) from a physica whose recent mathematical framework excluded the organic world. PMID- 11618916 TI - Confession-building, long-distance networks, and the organization of Jesuit science. AB - The ability of the Society of Jesus to engage in a broad and enduring tradition of scientific activity is here addressed in terms of its programmatic commitment to the consolidation and extension of the Catholic confession (i.e., to a multipronged program of confession-building) and its mastery of the administrative apparatus necessary to operate long-distance networks. The Society's early move into two major apostolates, one in education and the other in the overseas missions, brought Jesuits into regular contact with the educated elites of Europe and at the same time placed the society's missionaries in remote parts of the natural world. The modes of organization of travel and communication required by the Society's long-distance networks (i.e., the training and deployment of reliable agents willing to work under direction in remote locations and capable of providing trustworthy reports and observations to their superiors through regular exchange of correspondence) not only facilitated scientific communication and collaboration within the order, it also provided Jesuits with the resources they needed to engage successfully in 'ministries among the learned'. Evidence of a sustained attempt by Jesuit authors to assume the role of Kulturtrager is found in the several genres of scientific publications that dominate the society's scientific corpus. Thus the society's early recognition of the "apostolic value" of scientific publications in recruiting friends and allies among Europe's intellectual elites, I argue, allowed a robust interest in natural knowledge to emerge as a legitimate part of the Jesuit vocation. PMID- 11618917 TI - [Reform of the medical education in the early 20th century America and the Flexner Report of 1910]. AB - Reform of the medical education in the early 20th century America caused many consequences in the various aspects of the medical fields as well as the improvement of the medical education itself such as the reinforcement of the laboratory training in the basic science courses and hospital instruction in the clinical courses. The reform brought about the direct or indirect elimination of the irregular sectarian practitioners and the minority groups such as black and women from the medical market place, established the concrete position of the regular physicians in the American society, reinforced the biomedical aspects which would become the general tendency in the 20th century Western medicine. And the author stressed that the reform was neither initiated nor invoked but just accelerated by the so-called Flexner Report of 1910, rather it had been performed through the processes of the interaction and struggle between the various contradictory trends, tendencies, and forces such as american Medical Association (AMA), some leading medical educators and scientists, medical colleges, and philanthropic foundations in the socio-cultural millieu gradually moving to favor the "science". PMID- 11618918 TI - [The development of German social medicine in the nineteenth century]. AB - In his influential treatise System einer vollstandigen medizinischen Polizey, Johann Peter Frank (1745-1821) made significant contributions to the establishment of the concept of medical police, which has been understood as the forerunner of social medicine. Cameralism, the German version of mercantilism, became the very basis on which Frank and other German writers developed the framework of medical police. 'Medical reform' was the catchword of German medical men in the 1840s. The medical reform movement of 1848 was partially caused by a deep political, economic, and social crisis. Although Industrial Revolution began in Germany later than in England and France during the first half of the nineteenth century, by 1848 the formation of German industrial working-class made medical reformers recognize the causal relationships between social and health problems. The outstanding figures in the German medical reform movement of this period were Rudolf Virchow (1821-1902), Solomon Neumann and Rudolf Leubuscher. In his famous Report on the Typhus Epidemic in Upper Silesia, Virchow proposed several radical measures that could be used against the epidemic: the absolute separation of the schools from the church, the establishment of self-government in the state and community, unlimited democracy, road building, and the improvement of agriculture and horticulture. ... PMID- 11618919 TI - [The mode of medical inference in the history of medicine]. AB - In the primitive ages the system of thought about health and disease was a closed system of thought which had the premise of witchcraft. In the ancient and middle ages the problems of health and disease had been dealt with within logical thinking but the phenomena of human life had been explained metaphysically and the medical problems had been inferred from deductive logic. The abnormalities of health problems which were inferred from deductive logic had not been substantiated because anatomy, physiology and technology had not been advanced far enough. In the Renaissance and modern ages the knowledge of anatomy, physiology and pathology of living body have begun to increase. The human body could be explained in the terms of structure and function of the body as a machine. Approaching this way the disease has been understood as the abnormality of structure or function of the body and the problems of health and disease are inferred from inductive logic. ... PMID- 11618921 TI - [Textbooks of western medicine in the early modernization period]. AB - The first modern hospital, royal Kwang-Hye-Won (House of Extended Grace) was established in April of 1885, whose name was changed into royal Che-Jung-Won (House of Helpfulness) in several days. Private (not royal) Je-Jung-Won opened its Medical School in 1899. And the teachers composed of western missionaries taught some Korean student-assistants the Western medicine with English textbooks in English. With very low effectiveness of teaching due to language barrier, Dr. Avison, the principal of that school decided to write medical textbooks in Korean. At first he tried to translate Henry Gray's Anatomy of 1859. In the effort he referred some Chinese and Japanese medical books. With that reason, we can find many Japanese style medical terms in some medical books of his. On the other hand, Eui-Hak-Kyo (the Medical School) was established by the Government of Dae-Han Empire in 1899. The teaching staff of the school published medical textbooks in Korean, some of which were written by Japanese doctors. After the Japanese annexation of Korea in 1910, Japanese government forced teachers of the school to teach with Japanese medical books and to speak Japanese in teaching. ... PMID- 11618920 TI - [Some tentative cases of the holistic approach to health care]. AB - Some observers have insisted that modern medicine should be restored to the holistic nature in the face of the limitations of the current mechanistic modern medicine. Four medical doctors trained in modern medicine, Simonton, Chopra, Kohda and Takeguma are showing the creative models of medicine based on the holistic philosophies and methodologies. It will be meaningful to investigate what the sociocultural backgrounds of their thinkings and practices are, and how much these are socially acceptable and useful. PMID- 11618922 TI - [Analysis of services of medical missionaries during the late Yi-Dynasty and the era of the Japanese occupation of Korea]. AB - Authors investigated the services of medical missionaries during the late Yi Dynasty and the era of the Japanese Occupation in Korea. The information and materials were got from the following primary sources: The Searching Report on the European and American Residents in Korea (1907-1942); The Korean Mission Field, Vol 1 (1905.11)-Vol 37 (1941.11); Christian Newspapers, No 1 (1915.2)-No 1128 (1937.7). Through this study we found that 280 medical missionaries came to Korea to do the medical services during the period from 1884 to 1941. Among them were 133 medical doctors, 5 dentists, 6 pharmacists and 136 nurses. And it was found that 71 medical missionaries (25%) belonged to US Northern Presbyterian Church, 50 (18%) to US Northern Methodist Church, 38 (14%) to US Southern Presbyterian Church, each 32 (11%) to US Southern Methodist Church and Society for the Proppagation of the Gospel (Anglican Church), 20 (7%) to Canadian Presbyterian Church, each 12 (4%) to Australian Presbyterian Church and Catholic Church, 9 (3%) to Seventh Day Adventist Church, and 31 Western medical personnels without connection to any missionary society. ... PMID- 11618923 TI - [Modernization process of the medical education in Korea]. AB - In Korea, there had been the public educational system of the traditional medicine since Shilla Kingdom of 7th century, and Koryo government had the Selection System of the medical doctors for the public services from the reign of King Kwangjong (AD 958). These traditional system had been maintained until King Kojong of Chosun Kingdom (AD 1885), when the traditional hospital with medical school Hye-Min-Seo was replaced by Che-Jung-Won, the first modern hospital in Korea, where the Western medical service for people and practical medical education were performed by western missionary doctors. But the medical education in Che-Jung-Won did not last long because people and government at that time did not recognize the value of the Western medicine, in addition to the personal difficulties some medical missionaries had. After the reformation of 1894 when the health administration and service based upon Western medicine were planned, the government of Chosun Kingdom needed the personnel who could practice the Western medicine. So government began by establishing the short-term (one month) Vaccinator's Training Center in 1897, and founded the first public medical school named Eui-Hak-Kyo Medical school of three-year course for educating the medical students in 1899. ... PMID- 11618924 TI - [A medico-historical review on biomedicine and its limitations and problems]. AB - Biomedicine is a conceptualized technical term for current medicine in a historical perspective. Physics, chemistry and biology are considered to be the sciences basic to biomedicine. This medical model depends essentially on a mechanistic approach based on understanding of the structure and function or the body. The biomedical model assumes that illness can be explained in terms of morphological, physiological and biochemical derangements or dysfunctions (a reductionist concept of disease). As medicine of primitive ages and ancient times can be conceptualized in terms of witch-philosophical medicine, medicine of the Middle Ages can be conceptualized in terms of religious medicine. The early steps by which modern medical sciences have been gradually built up appeared in the 10th and 17th century. In those ages direction and methodology forward scientific medicine were established. Medicine of Renaissance ages can be conceptualized in terms of mechanical medicine. Remarkable progress has been made in biomedicine in the last three centuries. ... PMID- 11618925 TI - [The early history of national education of western medicine in Korea]. AB - On the record 1995 is the 100th anniversary of Western medical education in our country which began with the opening of the Vaccinators' Training Center, but the actual history of Korea's Western medical education is 97 years old. To become vaccinators the students underwent training for a month including the manufacturing of vaccine and the practicing of vaccination. These vaccinators were the first vaccination specialists trained in Western medicine in our country. Their service included vaccination as well as education. These professionals of Western medicine, in spite of a short period of their training, saved countless human lives, contributing greatly to the welfare of society. In the years 1897-1898, there were quite a number of foreign missionary medical doctors in Korea, who were providing Western medical education each according to their own need. Some of the examples were Wells and Follwell in Pyongyang, Johnson in Taegu, and Scranton, Avison and Rosstta Hall in Seoul. They were all medical doctors who received regular medical education and were engaged in clinical medicine. ... PMID- 11618927 TI - [The transition of medical terms in Korea between 1935 and 1985]. AB - Korean modern medicine was imported from American missionaries in the late 19th century. At the beginning of the 20th century, Japanese medicine, which was influenced by German medicine, was imported along with the Japanese invasion. After the liberation of Korea, however, American medicine influenced the Korean Medicine in a broad spectrum: for example, medical science, medical instruments, and health care system. Not only an unstable social environment but also the rapid development of medical science changed medical terms. In order to investigate the 50-year transition of medical terms in Korea, we compare the names of diseases in 'Cho-Son-Eu-Bo' published in 1934, 1935 and 1936 with those in the 'Journal of the Korean Medical Association' published in 1985. The names of diseases were classified according to number 17 classification method of ICD-9 (International Classification of Disease). The proportionate ratio of the number of names of diseases between 1935 and 1985 was 3.2 in neoplasms, 3.1 in diseases of the circulatory system, and 2.7 in mental disorders. The causes of the transition of the names of diseases were three. The first was the simple change of the rules of spelling, the second was the change of the concept of disease, and the third was the subdivision of diseases. 26.1% (N=37) of the names of diseases in 1935 (N=142) were changed by 1985. PMID- 11618926 TI - [Smallpox epidemics and folk's responses in the late Choson period]. AB - Smallpox was one of the most dreadful epidemic diseases in Korea until the early twentieth century. In the Choson period, smallpox came to prevail more frequently and vigorously, and many people died of the disease. To cope with smallpox, the society of Choson had various modes of measures, though they were not always effective, which included the government's rituals, medical men's prescriptions, and folk's recipes. Among various responses to smallpox, the recipes of folklore seem to be very interesting. While attitude toward other contagious diseases (e.g., typhoid fever, or malaria) mainly consisted of exorcism, smallpox was believed to be the passage of the smallpox deity. Sonnim (which means guest), through the body of patient for certain time span, and gods of smallpox were treated hospitably. This attitude toward smallpox was deeply rooted in Korean shamanism, and partly in the natural history of the disease. From 1876 smallpox vaccination was reintroduced and practiced. There were, however, a lot of difficulties in practice of vaccination due to distrust and prejudice. and traditional dealings with smallpox, in spite of vaccination, didn't disappear even after the Japanese compulsory occupation. PMID- 11618928 TI - [The medical philosophy of Choe Han-Ki]. AB - Choe Han-Ki was a philosopher of the 19th century who resided in Seoul. He accumulated vast amount of knowledge of Western science and on the basis of them he built his own philosophical system different from those of the philosophers before him. Not only has he wrote books on philosophy, but many books on science as well. Among them Shin-Ki-Chon-Hum is a very unique medical book which reveals his original medical philosophy. He acquired medical knowledge through the medical books put into Chinese by missionary doctor Hobson and on the basis of them he criticized traditional medicine. He criticized traditional medicine because it explained vital phenomenon through the reductionist theory, such as Oh Haeng (theory of five phases). And he also criticized it because it lacked in exact anatomical knowledge and that the exact origin of the disease was not known and it had limitations on treatment. He also criticized Western Medicine because it supposed God as a creator. He saw the possibility of communication between Western Medicine and traditional medicine. He didn't regard medicine as concerning disease and health only, but it included everything in it. His philosophy of medicine is just a part of his original system of science, Ki-Hak. PMID- 11618929 TI - [Women's Medical Training Institute 1928 to 1938]. AB - Historical development of Women's Medical Training Institute in Seoul, Korea, between 1928 to 1938, which had been elevated to the Kyongsong Women's Medical College in Seoul, Korea, under the Japanese Imperial Government, will be presented. The College after few changes of its policies, finally became as Medical College of the Korea University in 1971. Dr. Rosetta Sherwood Hall, a medical missionary from New York who had spent for 44 years in Korea, witnessed the necessity of having woman doctors in Korea in order to save those shy Korean ladies silently suffering from sickness. As an initial step to implement women's medical education, Dr. R.S. Hall together with Drs. Kil Chung-Hee and Kim Tak-Won founded the Choson Women's Medical Training Institute in 1928, with a purpose to eventually elevate it to a Women's Medical School. The Institute had a five-years course of curriculum with one year of pre-medical and four years of medical education. In 1933, Dr. Hall, at the age of 66, had to retire and return to America. Therefore, the management of the Institute had been transferred to Drs. Kim T.W. and Kil C.H., but under a new name of Kyongsong Women's Medical Training Institute, upon the request from Japanese Government. The Institute had moved to a new location and continued to expand its curriculum, and furthermore, a hospital had been annexed. ... PMID- 11618930 TI - [The early history of private education of western medicine for women]. AB - As early as in the 6th year of King Taejo of the Choson Dynasty (1406), there emerged a medical training organization which turned out women doctors who would engage in the treatment of diseases for women and conduct the service of midwifery. Of course the healing art those women doctors adopted at that time was Oriental medicine, and due to the strict Confucian prejudice against women, the medical treatment for women did not go beyond the limit of home treatment. Such being the situation, from the viewpoint of Western medicine, it is hard to say that there existed women doctors in Korea before the advent of the Kyongsong Women's Medical Training Institute. Such social situations and the customs peculiar to the Korean women badly required the existence of women doctors. However, the Choson Government-General which was the ruler of the Korean Peninsula at that time, was quite indifferent to the urgent need. ... PMID- 11618931 TI - [Parasitic diseases in Dong-Eui-Bo-Kam]. AB - Dong-Eui-Bo-Kam is a medical book of Korean traditional medicine, which is of encyclopedic characteristics. Its contents imply almost every field of medicine. There are also descriptions of human parasites in this book under the title of 'Worms'. Worms described in the book are Sam-Shi-Choong, Ku-Choong (nine worms) and Oh-Jang-Choong (worms of five organs). Among these Sam-Shi-Choong are not real worms, but quite mythological ones which have been mentioned in the religious Taoism. It is well-known that Dong-Eui-Bo-Kam has Taoistic characteristics. We can verify this characteristics by the fact that it mentions Sam-Shi-Choong on the top of the title 'Worms'. Dominant pathologic theory in the traditional medicine is a kind of balance theory, which defines the healthy state as the harmonious equilibrium of body elements. On the contrary parasitic diseases suppose real agents as the causes of diseases. This point of view appeares to be quite different from traditional pathologic view. PMID- 11618932 TI - [The history of small pox prevention in Korea]. AB - The first record of small pox epidemics in Korea claims that the malignant pestilence came from China around the 4th-5th century. Records have been found indicating that this pestilence attacked Korea every few years and that the havoc it caused was beyond description. China was the first country in the orient to use Jenner's vaccine, 10 years after its invention in 1796. The effect of the vaccine had been widely recognized and it was introduced to Korea through Japan. Mr. Sok-Yong Chi, an educator who was much interested in modern medical science, with the cooperation of the public, introduced wide usage of the vaccine in December 1879. Through continued effort with vaccination by 1959 this pestilence had completely disappeared from this country. Before the introduction of vaccinations, the variolation method, which came from China was also practiced here. Its effect was not recognized by the public and the method did not become popular. In addition, a few other methods to prevent this pestilence were introduced. Methods such as inhalation of pox-liquid and insertion of scar-pills (a chinese style of intranasal inoculation) were also practiced. ... PMID- 11618933 TI - [Medical education in Pyongyang (1890-1945)]. AB - As early as the reign of King Taejo, the Choson Dynasty started medical education in Pyongyang by establishing a medical school under "uikwa" which was an independent governmental organization of the 10 bu. Toward the end of the Dynasty, a local medical organization called "uihakwon", which was independent of the "Hyeminso" and comparatively large as a local medical organization, was established in Pyongyang under the control of "Pusa" and "Chick chang". This educational organization was staffed by one professor and had an enrolment of 16 students. Around 1894, when the Sino-Japanese War broke out, American missionaries, medical and non-medical, chose Pyongyang as the base of their missionary activities and started medical and educational work. William James Hall, of the Northern Methodist Church, started medical work, sometime later, Rossetta S. Hall, who accompanied her husband to Pyongyang, opened a hospital for women. In the meantime, J. Hunter Wells, of the Northern Presbyterian Church, inaugurated the "Chejungwon" and launched medical service in Pyoungyang. These medical activities naturally needed trained medical assistants and missionary doctors came to embrace an idea of educating regular medical doctors in Korea where there were no Korean medical doctors. This occasioned Dr. Hall and Dr. Wells to launch medical education. Their medical education which began in 1897 1899 was a pioneer work for Western medical education in Pyoungyang. ... PMID- 11618934 TI - [Medical education in Taegu (1890-1945)]. AB - In Taegu, the Yaknyongshi was established as early as the 9th year of King Hyojong (1658) of the Chosen Dynasty, and in the 10th year of King Hyojong (1659) the "Tonguibogam" was published as a Yongyongbon edition by the Kyongsang Provincial Government. In fact, it may not be an exaggeration to say that Taegu was the base of the traditional medicine in Korea. In the meantime the general public began to become aware of the importance of Western medicine when Fr. Woodbridge O Johnson of the Northern Presbyerian Church introduced Western medicine by opening the "Miguk Yakpang" (American dispensary) and began to teach Western medicine to Korean youths. At that time, while constructing the Kyong for a war against Russia, Japanese began to establish hospitals in several majar cities and towns along the railway line and mobilized Tonginhae doctors. However, those medical facilities were solely for the benefit of Japanese people residing in Korea and had nothing to do with ordinary Koreans. The attached medical school of the Taegu Tonginuiwon failed, contrary to expectation, to turn out even a single Korean medical doctor. This hospital was later reorganized into Taegu Chahyeuiwon and was soon closed according to the policy of educational unification of the Government General Korea. ... PMID- 11618935 TI - [Introduction and establishment of pathology in Korea (1910-1960)]. AB - The concept of modern pathology had not been present in Korea until it was introduced through the Japanese pathologists who came to Korea to work as staff pathologists at [Korean] Hospital in 1913. Two prominent Japanese pathologists at that time were Dr. Inamoto and Dr. Tokumitzu who taught pathology at Hospital affiliated Medical Institute. Department of Pathology was established at Keijo Medical College in 1916 and at Keijo Imperial University Faculty of Medicine in 1926. In the private medical school, Severance Union Medical School, the pathology was taught by Japanese and American Physicians until Dr. Il Sun Yun established Department of Pathology in 1929. Papers on histopathological description of disease started to appear in the medical literature, Chosen Medical Journal that was first issued just after Japanese occupation of Korea in 1910. Many diseases of Koreans had been scientifically documented in medical literature since 1911 by the leading role of faculty pathologists of Keijo Medical College and Keijo Imperial University Faculty of Medicine until 1940. ... PMID- 11618936 TI - [Oriental medical doctors and the oriental medicine training institute during the era of enlightenment]. AB - The medical system of the Koryo Kingdom was maintained by the Choson Dynasty without much change. In the meantime, with the tide of enlightenment surging into the Korean Peninsula, Western medicine was introduced into this land and began to be recognized as a reliable, new healing art. At that time, Western medicine was highly valued by court officials and some upper-class people. However, the greater part of the general public preferred Oriental medicine on account of their long tradition and failed to understand the importance of Western medicine. With the Kabo-Kyongjang (Reformation), Korea, in imitation of Japan, began pursuing the policy of enlightenment. Meanwhile, Japan drove China out of Korea and later succeeded in Russia's encroachment upon the Korean Peninsula. By so doing, Japan actively began interfering in Korea's national affairs, politically, diplomatically and militarily. Japan applied to Korea the same, even harsher, method that it used at the time of the Meiji Restoration and began to encroach upon Korea's sovereinty. ... PMID- 11618937 TI - [Vitalism and mechanism: their meanings in the milieu of the 17th and 18th centuries]. AB - The views on the life in the early modern period (the 17th and 18th centuries) with their socio-cultural backgrounds and their meanings at that time were discussed in this paper. Those views discussed here were the dualistic, mechanistic one of Rene Descartes (1596-1650), the animistic, vitalistic one of Georg Ernst Stahl (1660-1734), and the monistic, mechanistic one of Julien Offray de la Mettrie (1709-1751). Author stressed that the processes of their view formation were influenced by the wide range of the various political and religious factors as well as the scientific, medical facts and opinions at that time, and that not only the contents of the views but also their historical contexts should be pursued in the study on the medical thoughts. PMID- 11618938 TI - [Psychiatric care and its change under the Japanese government in Korea with the special reference to the clinical activities at the Colonial Government Hospital: 'Chosun-Chong-Dok-Bu Ui-Won' (1913-1927)]. AB - The purpose of this is to elucidate the ways of introduction of modern psychiatric care into Korea and to demonstrate the changing patterns of psychiatric care during the time between 1913 and 1927. The study was focused on the clinical activities of the colonial governmental hospital on the basis of the annual reports of the hospital from 1912 to 1928. The investigation has revealed the fact that the first special institution for the care of the mentally ill patients was founded in 1911 in Seoul by the colonial government which was called "Che Saeng Won". It was also confirmed that the first clinical department of the psychiatry in Korea was established in 1913 at the colonial governmental hospital, "Chong-dok-bu Ui-won" which has taken over the role of psychiatric care from Che Saeng Won. The first chairman of the department of pspychiatry was Misuzu Nobuharu and his assistant was Shim Ho-Sub, the first Korean psychiatrist who became assistant professor of psychiatry at Kyongsung medical college in 1916 1917 but moved to Severance hospital and changed his speciality to neurology of internal medicine. The department had two physicians and 4 care persons at the beginning stage and 22 beds for the mentally ill patients in the hospital which had total 330 beds. Later, the department has developed to 54 bed clinic with 4 staff physicians. ... PMID- 11618939 TI - [The Korean doctors who studied medicine abroad]. AB - Chi Seok-Young was the first Korean to go abroad to study the Western medicine. In Japan, he studied it for approximately 4 months from May to September 1880. He did not go through the curriculum in its entirity but was able to bring back knowledge in the Western medicine nevertheless. Seo Jae-Pil, who exiled to the United States as the result of Kapsin coup failure in December 1884, was the next to study the medicine abroad. He enrolled at the Columbian University School of Medicine in 1889 and completed requirements in March 1892, becoming the first Korean doctor in the Western medicine. In 1896, Kim Ik-Nam enrolled Jikeikai Hospital Medical School in Japan after passing 1895 government-sponsored qualification examination to study abroad in Japan. He graduated in November 1899 and received a license to practice medicine from the Ministry of Education in Japan. And in 1902, Ahn Sang-Ho also graduated from Jikeikai Hospital Medical school. ... PMID- 11618940 TI - [A comparative analysis of two historical approaches to the formation of the modern clinical medicine]. AB - From the perspective of research methodology, it may be said to exist two kinds of different historical approaches with regards to the formation of modern clinical medicine at the turn of the nineteenth century. One is to explain this in terms of the agency or structure that is associated with research topic. This historical view assumes that the Western scientific rationalism is characterized by the unity of Western tradition and its evolution as continuity. Its main focus is given either on how French revolution and war affected the growth of clinical medicine and the hospital reform movement or on how Paris Clinical School contributed to the birth of modern clinical medicine. The other is, according to Michel Foucault, to analyze how medical discourses are related to social (institutional) practices. Following Canguilhem's history of concepts, Foucault traces the historical development of the concept of disease. Elizabeth A Williams, another proponent of this method, conceptualizes the eighteenth-century medicine as three different medical discourses--anthropology, physiology and philosophical medicine, and analyzes how their structural fragmentation were transformed into the modern establishment of clinical medicine in the nineteenth century. ... PMID- 11618941 TI - [A historical study on the introduction and development of anatomy in Japan]. AB - Japan received the Western medicine through Portuguese, Spanish and Netherlanders. Especially Netherlanders established House of Trade in Nagasaki, where doctors from their homeland stayed for several years for the health care of their tradesmen, and taught Japanese Western medicine (mainly surgery). By them Anatomy books written in western languages were introduced into Japan and some Japanese had the eager to identify the real structures of human body. At last Yamawaki Toyo became the first dissector of human body in Japan (1754) and he made his own dissection records. In 1774 Sukita Kenpaku translated the Anatomy book of Kulmus into the classic Chinese. From that time on Japanese translated a lot of Anatomy books in western languages and they themselves wrote Anatomy books of their own. PMID- 11618942 TI - [The philosophy & medicinal thought of Dong Mu Lee Jae-Ma]. AB - In this paper, the philosophy and the content of medicinal philosophy of Lee Jae Ma were illuminated through the history and philosophy of the late Choseon times from 1837 to 1900. Some conclusions were as follows: 1) Lee Jae-Ma was a philosopher as well as a physician, and his philosophical background was well appeared in the book of (Kogchigo). 2) Although the philosophy of Lee Jae-Ma and its terms were derived from the Kyunghakseol of Confucianism, the concept of these terms was different from the Neo-Confucianism of Song Dynasty in China. 3) The four phases of the philosophy of Lee Jae-Ma was originated from the four important trigrams, however, he did not take the meanings of the changes and development of the trigrams in , but also took the four components of construction of cosmos similar to the Western theory of four component. ... PMID- 11618943 TI - [A study on background of doctrine for seasonal febrile diseases in Qing Dynasty]. AB - The seasonal febrile diseases had been studied before Qing dynasty, but it was accomplished in Qing dynasty because of high incidence of the epidemics in those days. I studied and analyzed epidemics in Zai Yi Zhi of Qing Shi Gao on the reasons and patterns as yearly, regional, and seasonal parameters. Based on these analyses, I want to report how the doctrine of seasonal febrile diseases could be established in Qing dynasty. The incidence of epidemics was very high during the regimes of Kang Xi (1662-1722), Yong Zheng (1723-1735), and Qian Long (1736-1795) Emperors, the most advanced period in Qing dynasty. The diseases occurred at least once per two years, although, sometimes twice or 5 times per a year. Once it was developed and then smashed through the whole China, especially in Jiang Nan. It was the main reason why the four greatest scholars in the doctrine of seasonal febrile diseases came out from Jiang Nan. These diseases appeared most highly and worst in summer as pestilence. These resulted in the development of the studies of epidemics in those days. Based on the clinical studies of fever related diseases, the scholars of seasonal febrile diseases tried to cure them with endless and continuous efforts. Finally, they could complete the doctrine of seasonal febrile diseases in Qing dynasty. PMID- 11618944 TI - [Infectious diseases and medical institutions in the late Chosen dynasty]. AB - There were severe outbreaks of cholera and syphilis in the late Chosen Dynasty. In this article, I examine how these diseases spreaded and which preventive and curative measures were used against them. There were five times of cholera epidemic in Chosen Dynasty. Oriental medicine was initially adopted for the prevention and cure of the disease, but it did not produce remarkable results. Disinfection center and Cholera Clinic, the first special institution for the patients suffering from epidemic diseases, were established in Jeol-yung island, but could not be run properly at first. As preventive measures came to be more westernized, the popular awareness of understanding of the disese was improved. Temporary quarantine stations were established, and Korean government announced several rules against cholera. Contemporary Korean physicians had not known well about syphilis. Syphilis began to spread after the 1905 Protectorate Treaty was contracted and the Japanese migrated to Korea in large numbers. Syphilis had already spreaded widely among the Japanese prostitutes, and special clinic was established from relatively early times. ... PMID- 11618945 TI - [Tong-In Club's medical education movement]. AB - During the Japanese imperialism, and attempt for colonial education in the Korean peninsula was to put operation of a medical education movement. This plan was set up by the Tong-in club in 1907 and the foundations were laid in Pyong-yang and Tae-gu Tong-in hospitals. This report is a review acheiving the approach that was underplotted with the intention of the colonial education policy. Also, this report centralizes on the objectives of the Tong-in club establishment and the details of the medical education movement in the Korean paninsula. On June 16th, 1902, the Tong-a Don-mun club, Tong-a-mun club, Tong-mun medical club were established under the management of Mr. Irizawa Tatchkiji. The objectives of these clubs were to spread and popularize medical science into the Qing-Dynasty, Choson Dynasty and other countries. Tong-in club practiced modern medicine in the Korean peninsula. ... PMID- 11618946 TI - The institutionalization of public hygiene in Korea, 1876-1910. AB - On the whole, the major impetus for the institutionalization of public hygiene in Korea came from two directions. On one hand, the self-enlightened intellectuals had introduced a variety of Western ideas and theories on public hygiene since the mid-eighteenth century. On the other hand, Japan strongly influenced the modern systems of Korean health care and medical education, especially through Japanese efforts at the sanitary control of infectious diseses such as smallpox and cholera. The institutionalization of Korea's public hygiene in this period corresponded not to the high ideas of the progressive intellectuals but to the larger social and institutional changes caused by the major political events. Ideas of public hygiene were institutionalized as a powerful strategy of linking the imperial capital and colonial domains. PMID- 11618947 TI - [The pathologic theory of the oriental medicine]. AB - The oriental medicine differs from the western medicine in many aspects. Especially they show great differences in their understanding of diseases as the object of medical science. But their differences were often exaggerated and accentuated. In this article I would like to reveal various aspects of oriental medicine which have often been ignored by schematic comparison with the western medicine. They are as follows. 1) The pathologic theory of the oriental medicine has changed as the time has gone by. 2) The pathologic theory of the oriental medicine is not based on single paradigm. 3) Nosologic problems in oriental and western medicine. PMID- 11618948 TI - [A study on the Korean traditional medical literatures before Koryo dynasty]. AB - So far, the research has not been actively carried out on the oriental medical books of traditional Korean origin, published before Koryo Dynasty. It was attempted in this study for better understanding of current and pre-Koryo Dynasty oriental medicine by introducing and translating those medical books originated from pre-Koryo Dynasty. However the medical formularies of pre-Koryo Dynasty were written and handed down up to the present rather by Chinese and Japanese medical books. And this study was performed based on these books. It was assumed that Koryonosabang was written by an old master of oriental medicine. Backjaesinjibbang was written by a person who lived in the same period and Shillabubsabang, Shillabubsayugwanbimilyosulbang, Shillabubsabimilbang by a monk doctor during Kokuryo, Backjae and the Unified Silla Dynasty, respectively. ... PMID- 11618949 TI - [On the objectives and the contents of the course: "Introduction to medicine" - a literature investigation]. AB - The education of Introduction to Medicine for the medical students can be traced back to the Hippocratic medicine in ancient Greece, when regarded some essays on the nature of medical care in Corpus Hippocraticum. However, its modern precurser may be the medical historian, Henry Sigerist who published the book: Einfuhrung in die Medizin (Introduction to medicine) in 1931 on the basis of his lecture at Leipzig University. Influenced probably by the German medical tradition the education of the Introduction to Medicine has been flourished in the medical schools in Japan since 1941. In Korea the course has been introduced in 1971 and only few universities have adopted it as the regular course for medical students, while the education of behavioral science in the medical schools became more popular since 1970. The objectives and the contents of the education of the Intorduction to Medicine seem to be different according to the organizer of this course. This study deals with the questions about the objectives and contents of the Introduction to Medicine. Fourteen books by twelve authors entitled with either the Introduction to Medicine or the relevant one which were published in Japan, except for the above mentioned book of Sigerist since 1945 were under the investigation. The motivations and the purposes of the authors for the publications of the books and their contents were compared each other in which the guidelines for the education of Introduction to Medicine were indirectly reflected. ... PMID- 11618950 TI - [On the education of the history of medicine in the Korean medical schools]. AB - Authors got the following information on the present state of the education on the history of medicine in the Korean medical schools through analyzing the responses of the medical schools to the questionnaires that we sent and the related parts of The Present State of Medical Education in Medical Schools, 1994 (published by the Committee of Deans of Korean Medical Schools). In 1994, 27 of 32 medical schools (except Kon-kuk, Pusan, Yonsei, Inje and Chungnam Medical Schools) offered 41 lectures of the related subjects, of which 'History of Medicine' and 'Introduction to Medicine' were offered mainly to the premedical students, and 'Medical Ethics' largely to junior or senior students. And we found that the lectures varied widely in lecture-hours, credits, the specialties of instructors (most of the lectures were not conducted by medical historians), and so on. In the latter part of this paper (based on the discussions at the 1st Workshop for the Improvement of the Education on the History of Medicine held on the 9th of February 1995) which was focused on the goals and objectives of the lectures, credits and lecture-hours of the course, ideal style and method of the course operation, contents of the lecture, authors stressed the topic-oriented lecture and the voluntary participation of the students in the courses. PMID- 11618951 TI - [The ideal and practice of Greek medical ethics]. AB - This paper is concerned not with medical theories, but with practices of Greek physicians, and I have addressed the subject of medical ethics as related to the Hippocratic tradition. And I have attempted a synthetic account of Greek physicians' actual practice and its ideals in the Hippocratic tradition. My understanding of the tradition succeeds the revelations in the first chapter of my doctoral dissertation, one of them is the fact that Hippocratic tradition is amalgamation of ethical code with rational or scientific medical theory. In the first chapter of this paper, I have attempted a social history of Greek physicians by analyzing Hippocratic writings. The Hippocratic collections, Corpus Hippocraticum, throw light not only on the origins and early development of classical medicine, but on its place in Greek Society. In the second chapter, I aim at understanding of the medical morality in its practice by analyzing the Corpus. Particularly the Oath shall be examined. Some questions, above all, such as "Was it ever a reality or merely a 'counsel of perfection'?" can not be answered. But by the way of the examination of the deontological treatises, the characters of the ethics of Greek physicians become clear. It was the result of outward performance in the relation of inner intention. In the result Greek physicians were the first to attempt to establish a code of behavior for the medical profession and to define the doctor's obligations to the society. PMID- 11618952 TI - [Understanding American health care reform, 1910-1932: toward an interpretive history of health policy]. AB - The purpose of this article is to analyze the two early health care reform groups: the American Association for Labor Legislation (AALL), the first organization to try to initiate compulsory health insurance in the U.S., and the Committee on the Costs of Medical Care (CCMC), a self-formed committee to study the economics of medical care. By viewing health policy from a historical perspective, we can find a variety of possible alternatives that would have been implemented in different place and time. Unlike positivistic studies on health policy whose only concern is with successful programs, the history of health policy is interested not only in success but also in failure of policy. Reformers from the late 1910s through early 1930s recognized health insurance as a medical issue not as a welfare issue. As long as health insurance belonged to medical domain, policy on health insurance remained separate from public policy. If so, who analyzed and decided the policy? This article argues that social reformers in this period should have tried to launch health insurance not from the front of medical care but in the field of public welfare. This shift in the direction of health care reform would inevitably have caused changes in the strategies accepted. PMID- 11618953 TI - [An aspect of Buddhistic medicine in ancient Korea: Wonhyo and medicine]. AB - Lack of historical records causes some difficulties in the historical studies of ancient Korea. It is the same case as that of the history of medicine. We imagine what the situation of medicine was like in ancient Korea with a bit of historical records. In ancient times, medicine had very close relation with religions. In ancient Korea, it had very close relation with Buddhism. According to Sam Kuk Sa Ki and Sam Kuk Yu Sa buddhist monks treated patients with the religious rituals. In this article, the authors would like to present a record which had been unnoticed until now. It is the commentary of Wonhyo on a certain Buddhistic cannon called Kum Kwang Myung Kyung. A chapter (Je Byung Poom) of this cannon is on the theory of medicine, causes of diseases and treatments. We can presume Wonhyo's knowledge of medicine at that time through his commentary on this chapter. PMID- 11618954 TI - [Infectious diseases and medical institutions in the late Chosen dynasty]. AB - The first Korean record on the smallpox can be found in the Hyangyak-Kukupbang compiled during the period of late Koryo dynasty. The record told on the cause, symptom, preventive and curative method of the disease but it did not touch upon its infectivity. Jeong Yak-Yong and Lee Jong-In of late 18th and early 19th centuries recognized first that the disease is infectious and it can be prevented by the vaccination method. But the vaccination against smallpox had not been carried out in public until 1880. From 1879 Chi Suk-Young began to try it privately to his relatives and neighbors. For sometime the smallpox vaccination was considered foreign and heretical by many people and some officers, so the trial of Chi and his colleagues had to go through an ordeal until the Reform of 1894. In 1895 the government first proclaimed an Ordinance on the Smallpox Vaccination in October and an Ordinance on the Training Center for Smallpox Vaccination in November. And two years later, in 1897 to bring up the vaccination doctors the government established the Training Center for Smallpox Vaccination, which was in 1899 integrated into the Medical school, the first modern and westernized medical school run by Korean government. Many of the vaccination doctors were posted at the newly established Office of Smallpox Vaccination by the government to perform their activities there until 1907. PMID- 11618955 TI - [Medical books published in North Korea]. AB - In those days, commercial and cultural exchanges between South Korea and North Korea become more active than before. But in medicine, there has been no activities of exchange and we don't know much about medicine in North Korea. We have some information on medical systems in the North, but we know little about how the medical activities are, what achievements they have made and what kind of medical books have been published. The authors classified 575 books according to their specialties and publishing years and analysed the characteristics and tendencies of medical books publishing in North Korea. PMID- 11618956 TI - [Western medical theory introduced first to Korea]. AB - Western Medical Theory, subject of this thesis, was derived from physiological theory of western medical science which was inserted in the translation of Jesuit doctrine by Adam Schall, German, who had arrived in 1622 at Peiking, China, as Jesuit missionary. This was reproduced by Lee Ik (1682-1763) in his book titled "Sungho Saisul". Through the contents of this medical theory, therefore, one is able to test to what extend the physiological knowledge of western medical science was in 1622, that is the beginning of 17th century, and, moreover, one can tell what effect the introduction of this medical theory had upon practical use of medical art in our country. Historical investigation of the contents of this medical theory concludes as follows: ... PMID- 11618957 TI - Sammy Tubbs and Dr. Hubbs: anatomical dissection, minstrelsy, and the technology of self-making in postbellum America. PMID- 11618958 TI - [Origin and development of treatment of Guzhang syndrome (ascitis and abdominal distention) in TCM]. AB - The theory and treatment of Guzhang syndrome was continuously developing as time went on. From Spring and Autumn, Warring States to the Han-Jin period, Neijin and Shang Han Lun laid down the foundation for the development of later ages. During the Tang-Song-Jin-Yuan periods, there were breakthrough and inventions in the recognition theory and treatment, particularly the contention between Gong (purgation) and Bu (reinforce) schools, thus further promoting the development of research on Guzhang syndrome. During Ming-Qing dynasties, based on summing up the experiences of forerunners, new implication or the causes, pathomechanism, diagnosis and treatment appeared with even greater progress. After inheriting and developing the available experiences, modern and contemporary doctors paid attention to combining TCM with modern medicine so that the theory and practice can be more perfected. PMID- 11618959 TI - [The changing vasculo-cardiology in the midst of revolution of modern science and technology]. AB - Modern revolution of science and technology exerts profound and overall influences on the basic research, diagnosis and treatment of cardiovascular diseases. The application of molecular biology has been revealing the nature of cause, pathogenic mechanism, physiology and pathology of cardiovascular diseases, while gene therapy is expected to yield a radical cure of these diseases. The products of modern technology including computerized tomography, computer enhanced digital angiography, magnetic resonance imaging, ultrasonic cardiography, positron emission tomography, single photon emission computerized tomography, percutaneous transluminal coronary angioplasty and other techniques, laser, artificial pacemaker, artificial heart etc. have greatly improved the capacity of diagnosis and therapy of cardiovascular diseases. Now the studies probe not only the levels of organ and cell, but also the levels of protein, nucleic acid and gene. The diagnosis of cardiovascular diseases is focussed on, besides the traditional "four diagnostic methods", i.e. inspection, palpation, percussion and auscultation, precise diagnosis with the help of various advanced medical equipments. As to the treatment, in addition to traditional drugs and surgical operations, new therapeutic methods such as gene therapy and interventional measures are also applied. PMID- 11618960 TI - [Historical materials of Chinese food hygiene (1927-1949)]. AB - The author discusses the situation on the work of food hygiene from 1928 to 1949 in China. During this period, the Health and Epidemic Prevention Bureau under the Ministry of Health were all in charge of food hygiene work. They formulated a series of standards, laws and rules on food hygiene which were carried out by hygienic policemen of the Bureau of Public Security. There were two ways for the education of food hygiene: Short-term course teaching class for food hygiene in medical college. The inspection and research work of food hygiene were performed by the Central Testing House of Hygiene, The Central Experimental Office of Hygienic Facilities and the Central Office of Epidemic Prevention and Nutritional Institute of the Health Office. After anti-Japanese war was broken out in 1937, food hygiene work were carried out mainly in the service in the war. PMID- 11618961 TI - [The authenticity of the case record of Wang Zhongxuan diagnosed by Zhang Zohngjing and its value]. AB - Query on the authenticity of the case record of Wang Zhogxuan's case diagnosed by Zhang Zhongjing mentioned in Huangfu Mi's Zhen-Ju-Jia-Yi-Jing of the Jin dynasty was raised in the 1950s. It was believed that Huangfu Mi's idea was "subjective" "exaggerated" "fabricated" story which should be discarded. The truthfulness of the case record is undeniable, since Huangfu Mi's work was reliable, and there was possibility of meeting between Wang and Zhang, and also the facts that "leprosy is incurable twenty years later". This is of significance to the recognition of some special type of leprosy and the understanding of Zhang's life. PMID- 11618962 TI - [An outline history of ancient application and development of cardio-pulmonary resuscitation (CPR)]. AB - Through analysing the ancient medical literatures, the author sums up the brief history of CPR in ancient China and claims that, the use of CPR in China was over one thousand years earlier than that of the Western countries, and it stimulates the birth of modern CPR technique. PMID- 11618964 TI - [Unearathed ancient pulsological books and theoroy of "three parts with nine palpation sites"]. AB - Textual research is made on the evolution of the theory of "three parts with nine palpation sites" in TCM. It is concluded that the theory, having received the influence of ancient astrology and arithmatics, was sprouted in the Eastern Han Dynasty and still is valid today. It further points out that the arrangement of channel order, and selection of channel title were all influenced by the theory of "Three Parts with Nine Palpation Sites". PMID- 11618963 TI - [A brief discussion on ancient Chinese Infectious Hospital and setting down for the patients with infectious diseases]. AB - The medical care and treatment of patients with infectious diseases began in the Yin-Sang dynasty is the earliest in Chinese character, indicating an idea of patients with infectious diseases kept in isolation ward. This character was found in Bronze inscriptious dated 3350 years ago. In the Spring and Autumn period, isolation ward for infectious disease patients was mentioned in Lun Yu. In the Qin dynasty, isolation ward for leprosy patients was mentioned by Qinjian from Yunmeng (Cloudy Dreams of Sleeping Tiger) in Hubei provice, which was called Liqiansuo. In the Eastern Han dynasty, infectious army hospital was set up - Yanlu. From the Six dynasties period to the Sui-Tang dynasties, clinical wards in the temples, and after the song dynasty--An Le Fang, An Ji Fang, Bao Shou Cui He Guan, Jiang Li Yuan, Yang Ji Yuan, Fu Tian Yuan etc, though not specifically set up for infectious diseases patients, all played an important role for the isolation, setting down and treatment of infectious diseases patients. PMID- 11618965 TI - [An outline medical history of Taiwan (I): the period of folklore medicine and witch doctor]. AB - The paper makes a correlated analysis on the origin of health folklore between Chinese in mainland and Taiwan island. After quoting literatures written by authors living in the Qing dynasty in Taiwan, this paper analyses health condition among aboriginals of Taiwan during the witchcraft age. Along with the increasing immigration from China mainland to Taiwan island, health of folklore and gods from China mainland were introduced into Taiwan, hence the period of witch doctor in Taiwan, featuring the correlation of both. Though modern medicine in Taiwan is so advanced, yet there are still witch doctors elsewhere. PMID- 11618966 TI - [Guan-bu-za-bu, A Mongolian physician]. AB - Guan-bu-za-bu was a famous figure in academic circle living in Inner Mongolian and Beijing regions from Kangxi to Qianlong age of Qing dynasty. He mastered four languages, viz. Mongolian, Tibetan, Chinese and Manchurian, and had great achievements in Mongolian philology, historiology and made great contribution to Mongolian Medicine. His blockprinted Name of Tibet, Mongolian, Chinese Medicament and Prescription played an important role in the history of Mongol medicine. Especially the former book was even called the handbook of medical name because its name of Mongolian materia medica were written in Tibetan and Chinese. It was printed again and again and played a historical role for morn than 250 years since its publication. PMID- 11618969 TI - [A brief history of development of intelligence-sharpening acu-moxatherapy in ancient China]. AB - Through monographical investigation on various ancient literatures on intelligence-sharpening acu-moxatherapy, considering the scholastic background and combining with the historical quantitative analysis, this composition has tracked down it origin and explored its development history. It is found that intelligence-sharpening acu-moxatherapy laid its foundation in the Qin-Han periods and developed in the Jin-Tang period, fluorished in the Song-Yuan period and widely applied in the Ming-Qing period. This paper clarifies the developing process of intelligence-sharpening Acu-moxatherapy in China. PMID- 11618967 TI - [Textual research on Wei Yuhuang's life]. AB - Wei was not only a noted doctor, but also a poet, who made friends with contemporary famous scholars. Based on these scholar's writings, this author maintains that Wei's sobriquet was not "Yuhuang", but rather "Yuheng"; and his date of birth was 1719, not in 1722; He had lived a life of 54 years old, not 50. Wei was born in Guangdong, later came to Hangzhou at 12 years old. His life was full of frustrations. The article makes a textural research into his tracks, means of making a living, to his places of activities especially in Hangzhou. PMID- 11618968 TI - [Yu Jinghe's Chronicle]. AB - The life and origin of medical learning from family of Yu Jinghe, renowned doctor of the Qing Dynasty, are described here in the form of chronicle. He was born in Yixing, Jiangsu. His parent died when he was a boy and he joined the Taiping Army for 5 years with difficult experiences. Later, he moved to Menghe and learned pharmacology from his elder brother. His works include Yu's Annotation on Shanghanlun Yi, Collection of Case Records on External Diseases, Collection After Practising Hour etc. Moreover, Yu's descendents and his close relationship with other modern celebrated doctors such as Ding Ganren and his son Ding Zhongying, and Yun Tieqiao are also mentioned. PMID- 11618970 TI - A medical practice in the upper reaches of the White River Valley, 1882-1903. A reminiscence prepared in 1940. PMID- 11618972 TI - Medical and dental diploma mills in Vermont in the 1880's and 1890's. PMID- 11618971 TI - Folk medicine in the writings of Rowland Robinson. PMID- 11618973 TI - The influence of Florence Nightingale's image on Liverpool nurses 1945-1995. AB - Images of Florence Nightingale have been crystallised over time so that an iconoclastic image is frequently presented. Using oral history as a research method, a convenience sample of Liverpool nurses, spanning the period 1945-1995 discussed how this image had a bearing on them as nurses and on their practice. It would appear that during their training, lectures were about Florence Nightingale as a person and students were expected to emulate her. The influence of the image led to a rigorous attention to detail in the work and their persona. Over time, this influence has diminnished through the many changes experienced in the delivery of healthcare. However, it is contended that if attention was paid to Nightingale's works rather than her image, there could have been a resurgence of interest which might have influenced practice. PMID- 11618974 TI - Daily life in a 20th century psychiatric hospital: an oral history of Prestwich Hospital. AB - Twenty-five loosely structured interviews were conducted with subjects who had been associated with Prestwich Hospital for varying lengths of time between 1922 and 1975. The information which these subjects provided was significant for two reasons. Firstly, it provides an account of what life was like in one large psychiatric institution during the middle years of the twentieth century. Secondly, these accounts revealed that even within one institution there were huge variations in the standard of nursing practice. Furthermore, at the lower end of the continuum of quality of care there was little change in nursing practice until the final quarter of the twentieth century. PMID- 11618975 TI - We were proud to be nurses: the socialisation of women as student nurses 1946 1961. AB - Radical changes have taken place in the National Health Service (NHS) during the 1990s, both in relation to management and the training of student nurses. These changes have sometimes highlighted and sometimes obscured that earlier fundamental change - that of the inception of the NHS itself - which had similar far reaching consequences. In this study, the changes brought about by the introduction of the NHS are explored through the experiences of two provincial hospitals, one a former voluntary hospital - Hospital A - and the other a former municipal hospital - Hospital B. PMID- 11618976 TI - Uncommon entrance? The recruitment of probationers to Merseyside hospitals 1919 1938. AB - That voluntary and municipal hospitals in inter-war Britain enjoyed different levels of prestige is well known. This article explores ways in which the status of hospitals was reflected in the recruitment of probationer nurses on Merseyside and argues that there were overlapping hierarchies between and within the two sectors. PMID- 11618977 TI - Strachey on Nightingale. (An extract from Florence Nightingale by Lytton Strachey published by Penguin, 1996) PMID- 11618978 TI - From the regulatory vision of cancer to the oncogene paradigm, 1975-1985. PMID- 11618979 TI - Galen's critique of rationalist and empiricist anatomy. PMID- 11618980 TI - Converging images: techniques of intervention and forms of representation of sodium-channel proteins in nerve cell membranes. PMID- 11618982 TI - Annual bibliography of scholarship in social welfare history. PMID- 11618981 TI - Heterotrophic CO2-fixation, mentors, and students: the Wood-Werkman ReactionS. PMID- 11618983 TI - Blood - a clinical and historical philatelic review. PMID- 11618984 TI - Studies in the history of medicine concerning toxicology after 1970. PMID- 11618985 TI - The effect of divorce on child survival in a rural area of Bangladesh. AB - The data for this study come from Matlab, a rural area of Bangladesh, where a continuous registration of demographic events has been maintained by the International Centre for Diarrhoeal Disease Research, Bangladesh since 1966. A total of 11,951 first marriages of Muslims that took place in the area between 1975 and 1987 were followed until the end of 1989, to examine the relationship between parental marriage breakdown and survival of first live-born children. The impact of divorce on survival of children during infancy and childhood was examined, using hazard analysis. Other independent variables included age of mother at birth, and mother's education, year of birth, sex of children, and residence at the time of childbirth. It is shown that the net odds of death among children of divorced mothers in infancy and childhood were respectively 3.2 and 1.4 times higher than those of mothers whose marriages continued. The paper also discussed the possible mechanisms which link divorce and child survival. PMID- 11618986 TI - The economic theory of fertility over three decades. AB - After a promising start some three decades ago, the application of micro-economic analysis to fertility studies has proved disappointing. It has not led to an increased understanding of fertility decisions nor to the policy insights which had been expected. This paper considers the reasons for this disappointment. It reviews briefly the development of the now dominant version of the economic approach to fertility analysis, the so-called "Chicago Model". It concludes that several basic conceptual and theoretical weaknesses of this approach have led it up a blind alley. The paper concludes with suggestions for new assumptions and approaches which may make the theory more relevant for policy programmes. PMID- 11618987 TI - Fertility levels and differentials in Beirut during wartime: an indirect estimation based on maternity registers. AB - In this paper, total fertility estimates for Greater Beirut in the mid-eighties and early nineties are presented, and changes in socio-religious differentials of fertility across time are explored. The baseline information was recorded from registration details for all maternities in Beirut and its inner suburbs in 1984 and 1991: age of mother, number of children ever-born, hospital class, and religion of newborn. An indirect method was used to estimate total fertility from the joint distribution of mothers by age and parity, and, using hospital class as a proxy for social class, differentials in fertility were investigated by Poisson regression. The estimates of total fertility for Beirut shifted from 2.60 in 1984 to 2.52 in 1991, and were higher for Muslims than for Christians in the two periods. The regression analysis showed that: (1) the difference between the two religious groups persisted after control for social class, and in fact applied to the lower social class; (2) fertility dropped between the two dates in the lower social class, and more so for Muslims than for Christians. In comparison with other countries of the region, the decline in Beirut was found to be relatively modest. If the trends assessed in this study were to continue, the religious based fertility differentials would taper off progressively in the capital city of Lebanon. PMID- 11618988 TI - Mortality in Quebec during the nineteenth century: from the state to the cities. AB - The aim of this paper is to explore mortality in Quebec during the nineteenth century from a demographic perspective. During the nineteenth century, there was excess urban mortality in various countries; in order to identify such mortality differentials, we compared mortality indicators for the province of Quebec and then for the urban areas of Montreal and Quebec City. Using data from various studies, we produced life tables and compared life expectancies. We show that at different times during the nineteenth century, spatial variations in mortality levels across the province of Quebec and its urban areas were significant. According to the data we analyzed, mortality is undoubtedly higher in urban areas even though a convergence in trends took place towards the end of the century, resulting in an overall reduction in mortality. Also, exploring life expectancies within a cohort approach at times of fast-changing mortality patterns has proved to be instructive. Life expectancy estimates based on a cross-sectional approach were systematically lower than those resulting from a cohort-specific one. Trends diverged to a greater extent beginning with the 1870 cohort, reflecting the improvements made from that point on to World War II. Since current mortality levels are substantially determined by the cumulative effects of past behaviour specific to each generation, it is quite obvious that mortality analysis will reveal its true meaning only with the help of cohort life tables. PMID- 11618989 TI - Amputations in Civil War necessary to save lives. PMID- 11618990 TI - Edward Horton Bensley, 1906-1995. PMID- 11618991 TI - In memoriam - Ellen Baker Wells. PMID- 11618992 TI - Origins of a tragedy: Joseph Stalin's cycle of abuse. PMID- 11618993 TI - The history of German childhood through autobiographies. PMID- 11618994 TI - Scientific organizations in Spain (1950-1970): social isolation and international legitimation of biochemists and molecular biologists on the periphery. AB - Through a study of Spanish scientific organizations and the involvement of Spanish scientists in international ones, the beginnings of biochemistry and molecular biology in Spain are explored. The centre-periphery dichotomy is useful in explaining the progress of the establishment of these disciplines, together with the political context, both national and international, in which such establishment took place. It is suggested that international ties and national support are both necessary, but not sufficient conditions to overcome the distance between the Spanish scientific community and the centres of development and productivity in biochemistry and molecular biology. The interplay between both national and international factors has proved to be crucial. As a tool to study the whole scientific community of biochemists and molecular biologists, scientific societies allow us to analyze the role of that interplay in Spanish scientific development. PMID- 11618995 TI - Joseph Rogers and the reform of workhouse medicine. PMID- 11618996 TI - Science in the early Athenaeum: a mirror of crystallization. AB - The Athenaeum, one of the most influential weekly magazines of Victorian Britain, was launched in 1828, towards the end of the period which saw the crystallization of science out of eighteenth-century natural philosophy and the differentiation of the individual sciences one from another. We examine the magazine's coverage of specific scientific areas in the year from May 1828 to April 1829, looking at what it defined as science and how it arrived at its definitions. The picture that emerges is complex, influenzed by editorial preferences as well as more clearly discernible objective criteria. But, at this stage, The Athenaeum appears to be opposed to opening up a gulf between the scientifically literate and the rest of its readership, reminding science of its debt to earlier endeavours. PMID- 11618997 TI - Edward Stabler in Alexandria, 1792-1796. PMID- 11618998 TI - Pioneering work on crude oil processing in pharmacies before Ignacy Lukasiewicz. PMID- 11618999 TI - Some notes on history of pharmacy in Portugal. PMID- 11619000 TI - The library of a Virginia apothecary, 1792-1852. PMID- 11619001 TI - The Swan Pharmacy in Lund. PMID- 11619002 TI - The making of a European chiropractor: Fred Illi and the Universal College, 1925 1927. AB - Fred W. H. Illi (1901-1983) was one of the most prominent pioneer chiropractic researchers of the first half of this century, developing theories on the role of spinal biomechanics in the human body. With practical work in chiropractic radiology and later special work in human dissection in Chicago in the 1930-40 decades, and later at his Institute for the Study of the Statics & Dynamics of the Human Body in Geneva, Illi produced a massive volume of documentation in both written and visual format. The education of this researcher was a difficut and, at times, seemingly hopeless experience of self-determination and grit in pre depression America. Illi's biographer traces his American interlude and the influence of the Universal Chiropractic College in his chosen work, an unusual marriage of his first career choice of engineering, the use of the Xray in chiropractic and the sound, if limited training he received in the critical years from 1925 to 1927. PMID- 11619004 TI - Morris Fishbein, M.D.: the "medical Mussolini" and chiropractic. AB - Morris Fishbein, M.D. is the most important non-chiropractor to influence the chiropractic profession. From his post as editor and secretary of the American Medical Association, his anti-chiropractic writings, speeches and political activities had a profound effect on the profession's development. Because he was not only the foremost medical politician of the time, but also perceived as a multi-faceted author on public health issues, his credibility was high across large sections of the population and in most social institutions. His tactics and stature undoubtedly helped keep the profession limited to caring for a small percentage of the population. Because of him, chiropractors devised survival strategies that continue to influence the profession even today. PMID- 11619003 TI - Chiropractic in Australia: the first forty years (1905-1945). AB - The history of chiropractic in Australia is traced from the first grateful patient who also attended a course of instruction at the Palmer School and Infirmary of Chiropractic under D.D. Palmer and B.J. Palmer and brought chiropractic to Australia. The influence of Henry Otterholt--a U.S.-born Palmer graduate who was recruited by an untrained manipulator to take over his practice in order to study chiropractic at Palmer--on the early development of chiropractic in Australia and New Zealand is noted. He actively recruited students to the Palmer school, who upon graduation not only spread chiropractic in New Zealand, but also in the various states of Australia. The first twenty years saw the establishment of chiropractic practices in the capital cities of most states, but it would take more years before chiropractic was established in the capital cities. By this time country circuits had been established to serve patients in provincial centers. The advent of World War II brought further development to a standstill. This early period saw the emergence of the first group of what is considered today as the second stream in chiropractic in Australia, practitioners who would later be registered as chiropractors in the various Australian jurisdictions under grandfather clauses. PMID- 11619005 TI - The short life & enduring influence of the American Chiropractic Association, 1922-1930. AB - The American Chiropractic Association (ACA) of the 1920s is an ancestor of today's ACA. Established in 1922 as an alternative to B.J. Palmer's protective society, the Universal Chiropractors' Association (UCA), the ACA floundered under its first administration, but found its way when Frank R. Margetts, D.D., LL.D., D.C. was elected its second president in 1923. A skilled orator, Margetts toured the nation to rally support for the new society's policies and programs: independence from any school, higher educational standards, opposition to basic science legislation, national publicity, a clinical research program, and malpractice insurance and legal aid for its members. The ACA accepted straight and mixing chiropractors, but rejected applicants with only correspondence school diplomas. The ranks of the ACA grew after Palmer's 1924 introduction of the neurocalometer and the consequent decline in UCA membership. Following BJ's ouster from the UCA, the two societies commenced the lengthy negotiations for amalgamation which produced the National Chiropractic Association (NCA) in 1930. The NCA became today's ACA in 1963; the enduring influences of the 1920s ACA upon the present day ACA are considered. PMID- 11619006 TI - The sixteen major events in chiropractic history. AB - A centennial is the time for chiropractic to take stock, review its past, and plan for the future. "Major events" are those that define what chiropractic has become, turning points or obstacles overcome, without which chiropractic would not be what it is today. I identify what I consider the sixteen most important events in the chiropractic history, note relevant names and dates, place each event in its historical context, and discuss its significance. I discuss the events chronologically rather than in order of their importance. PMID- 11619007 TI - Chiropractic's tension with the germ theory of disease. AB - After briefly reviewing the development of the germ theory of disease, the author delineates the opposition that the germ theory met from many practitioners, especially chiropractors. This paper explores the evolution of chiropractic's position regarding the germ theory of disease and its dominance in medicine's approach to prophylactic therapy by surveying the chiropractic literature. If the number of monograph and journal publications is indicative of the degree of chiropractic sentiment against the germ theory, the opposition to the theory was heaviest in the 1940's, trailing off to only the occasional monograph or journal article in the 1970's and beyond. Although the development of penicillin and the Salk vaccine may be tied to the demise of most published chiropractic opposition to the germ theory of disease, the basic differences between medicine's approach and chiropractic's approach to disease still remain. Although the differences may be ones of degree, the approaches taken as to whether disease is caused and cured from within the body or from outside the body remains a very real philosophical distinction between the two methods of health care. PMID- 11619008 TI - ALHHS oral history interview. PMID- 11619009 TI - [Reconsideration of the "conversion theory" from the primacy of the heart to the primacy of the blood--William Harvey's observation, logic and the construction of the exercitatio]. AB - In De motu cordis, W. Harvey sometimes waxes lyrical on the primacy of the heart. In his another treatise, De generatione, however, he insists on the primacy of the blood. The "conversion theory" explained this discrepancy with Harvey's conversion as caused by his discovery of the antiquity of the blood. But Whitterridge showed that Harvey had already described the antiquity of the blood in his earliest notebook, Prelectiones. As shown in this article, Harvey's observation was not a mere accidental discovery; based on the "classic questions", it was continuously and persistently conducted until he was assured of having seen the blood to exist prior to the pulse and movement to occur in the blood. While this crucial observation was not yet made in Prelectiones and De motu cordis, it was described as crucial evidence of the theory of the primacy of the blood in De generatione, in which this new theory was introduced as an independent topic of the exercitatio. The topic of the order of the generation was a crucial issue in the theoretical medicine of Harvey's days. That is, the Aristotelian primacy of the heart had been seriously challenged by the Galenic tripartite theory which pursued the antiquity of three organs. Harvey's theory, or the primacy of the blood, seems to consists with Aristotle's premise, in that it asserts the existance of the only source of all functions in living animals. Harvey's theory, however, was confronted, on the other hand, with Aristotle's another inconsistency, namely, the issue of two definitions about anima. We must consider the construction and strategy of the exercitatio in Harvey's days to understand the exact meaning of the primacy of the heart in De motu cordis. In De motu cordis, Harvey did not use the primacy of the heart in a central part of the exercitatio, namely, in confirming his unprecedented theory, the circulation of the blood, but he settled this Aristotelian premise in a marginal part, namely, in ratiocinating the final cause of the circulation and supporting his new theory from the sidelines. PMID- 11619010 TI - [A bibliographical review of the history of eugenics (III). Eugenics and the eugenics movement in U.S.A. and Japan]. PMID- 11619011 TI - History of paediatric neurology: a brief review. PMID- 11619013 TI - Historical aspects of the neonatal neurological examination: why child neurologists are not 'little' adult neurologists. AB - The origins of the neonatal neurological examination are described with their common basis attributable to evolutionary theory, the classical neurosciences, clinical neurology, and developmental psychology. It is shown that not only have the techniques of the bedside examination changed over the past half century but the purpose of the examination has also evolved; initially the examination was used to assess maturation of the developing infant, now it is used to determine whether cerebral pathology may be present and whether examination abnormalities are helpful in outcome assessment. The development of several of the current neonatal neuroogical examinations are reviewed and their cllinical and scientific basis examined. PMID- 11619012 TI - John Cheyne's classic monographs. AB - John Cheyne (1777-1836), a Scotsman born in Leith, graduated at Edinburgh University but spent most of his career in Dublin. He was professor of medicine (1813-19) at the Royal College of Surgeons in Ireland, physician to the House of Industry Hospitals and co-founder of the Dublin Hospital Reports in which his celebrated account of a patient with irregular breathing was described in 1818. His Essay on hydrocephalus acutus (1808) and Cases of apoplexy and lethargy (1812), important nineteenth-century contributions to neuropathology are considered here in detail. Towards the end of his life he was afflicted by depression and his posthumously-published Essays on the partial derangement of the mind (1843) was written as a therapeutic exercise. PMID- 11619014 TI - The protagon phoenix. AB - From 1865 to about 1910 studies of the chemistry of the brain were afflicted by the hypothesis that cerebral lipid matter consisted of a giant molecule from which all the simpler lipids were derived as breakdown products. In successive periods the main proponents of this 'protagon' theory were Oscar Liebreich, Arthur Gamgee and William Cramer. The theory was disproved by the careful and detailed studies of JLW Thudichum whose work on the brain was described in many papers, government reports, and two outstanding monographs. The controversy involved rough moments, generated by both sides, but by 1910, a few years after his death, Thudichum was fully vindicated in his opposition to the protagon concept and his classification of brain lipids became the accepted standard for biochemistry as a whole. PMID- 11619015 TI - Occupational neurotoxicity and movement disorders: a historical perspective. AB - It is shown that while metal toxicity has been known to be associated with risks to the health of miners and other workers for over a thousand years generally little was done before the 19th century to enquire into the relationship between lead, mercury, and manganese and neurological movement disorders. Reasons for this are suggested. PMID- 11619016 TI - What did the Greeks mean? AB - By tracing in the work of medical authorities, some of whom are not widely quoted, the changing meaning of three neurological terms used in ancient Greece - poplexia, epilepsia and cephalalgia - the development of Greek ideas about neurological science may be appreciated. It may be concluded that the achievement of the schools of Greek medicine was in keeping with the level attained by the ancient Greeks in philosophy and other aspects of civilization. PMID- 11619017 TI - Charcot and Les nevroses traumatiques: scientific and historical reflections. AB - Between 1878 and 1893, Jean-Martin Charcot published over twenty detailed case histories dealing with what he termed 'traumatic hysteria' and what today would be labelled the psychoneurology of trauma. Charcot's cases record a highly diverse clinique tableau of symptoms. Etiologically, Charcot posited a dual model of a hereditary diathese, or constitutional predilection to nervous degeneration, and an environmental agent provocateur. Increasingly during the 1880s, he emphasized the role of 'psychical shock'. These writings of Charcot also exhibit many of the same, superb clinical qualities that distinguish his work on other medical topics. Charcot isolated several hystero-traumatic formations and provided outstanding clinical depictions of subgenres of the disorder, most notably brachial monoplegias. His clinical demonstrations of the differential diagnosis of organic and functional post-traumatic pathologies represent Charcot the virtuoso neurologist at his finest. Taken together, these writings offer a penetrating exploration of the complex and elaborate functional sequelae of minor bodily injury and the phenomenon of traumatic psychogenic somatic symptom formation. The revival today of medical interest in psycho-traumatic pathology, including the traumatic origins of certain dissociative states, provides an important context for the renewed appreciation of Charcot's work in this area. PMID- 11619018 TI - The history of vascular dementia. PMID- 11619019 TI - Historical aspects of cerebrotendinous xanthomatosis (CTX). PMID- 11619020 TI - Sutherland's syphilis hypothesis of Down's syndrome. PMID- 11619021 TI - Contributions of the founders of Craig Colony to epileptology and public care of epileptics: 1890-1915. AB - Craig Colony in Sonyea, New York, was America's first comprehensive public epilepsy center. The background to its establishment (the first patients were admitted in 1896) and its role as a model for other institutions is described. The history of the first 25 years of the Colony is recounted and the contributions to epileptology, and the legacy to health care, of the founders- William Pryor Letchworth, Frederick Peterson, Roswell Park, William P. Spratling and Frederick Munson--are assessed. PMID- 11619022 TI - Experimental and clinical studies of localisation before Flourens. AB - Experimental studies in the localisation of brain function did not begin with Flourens, nor did clinical studies with the phrenologists or physicians like Auburtin, Bouillaud, or Dax, shortly afterward. Although the pre-1820 literature is moderate, some of it is worth examining because of the problems associated with interpreting it. There are three separate but related problems: philosophical, methodological, and conceptual. Philosophically, whether one saw the brain as the main organ of sensibility, as did the Hippocratic writers and Galen, or the heart, as did Aristotle, determined the attention given to the brain. The methodological problems arose from the gross structure of the brain not being immediately obvious and the dominant technique of dissecting the brain in transverse sections revealing the ventricles and their immediately associated structures more readily than other structures. Conceptually, the ventricles were seen as the sites through which sensations were transferred to the muscles. Observations relevant to localisation were thus related to the ventricles or to structures lying outside the cerebrum. What are now considered major structural landmarks were not discovered until late: the Sylvian fissure in about 1640 and the fissure of Rolando in 1829, the former being dependent on new methods of dissection. In general, it was not until the first half of the nineteenth century that the cerebral structures were properly differentiated. Consequently, calls for comparative clinical studies of the effects of lesions in different parts of the brain inevitably fell on ears tuned to a framework which could not incorporate them. So, did the results of the earlier experimental studies. PMID- 11619023 TI - Pineal gland, perennial puzzle. AB - Since antiquity this tiny intracranial appendicular organ has aroused sexual connotations and denials. Controversial and enigmatic, it played a significant part in the development of endocrinology and even neurosurgery. What was its histology, what was its role as a gland so intimately attached to the brain? What did comparative anatomists make of it in the light of its function as a 'third eye?' Mysticism and the famous Cartesian apothegm placed it in the center of Eastern and Western approaches to the mind-body problem and to mental disorders. The latter were connected with the common calcifications, so helpful in the radiological diagnosis of brain shifts due to mass lesions. Undefeated, even spurred by continuing uncertainties, researchers keep looking into this 'photo neuro-endocrine transducer.' PMID- 11619024 TI - Descartes and the pineal gland in animals: a frequent misinterpretation. AB - Rene Descartes presented a number of reasons for his choice of the pineal gland as a logical place for the soul to interact with the physical machinery of the body. It is often stated that one of his reasons was that he believed animals do not have pineal glands, whereas humans alone possess a soul and this small structure. This is a misinterpretation of Descartes. The philosopher knew that barnyard and other animals possess pineal glands, having seen this with his own eyes. His point was that the pineal is unique in humans only because of a special function - acting as the seat for the rational soul. PMID- 11619025 TI - Seventeenth- and eighteenth-century commentators on the chemical composition of the brain. AB - The period between 1600 and 1800 was one of great change in the history of science, generally, and in the history of chemistry, specifically. It opened with Francis Bacon's visionary recognition of the benefits to mankind that would accrue from the expansion of scientia and closed with the overthrow of the phlogiston hypothesis. New chemical knowledge resulted from the efforts of the alchemists, especially in Paracelsians, and of the phlogistic philosophers, some of it recorded by writers of magic books (Thorndike, 1958; Camporesi, 1989). The authors of these works reflected 'the general mentality ... imbued with magic, occult beliefs, unreal suggestions, 'voices', and 'rumours', ... 'errors' and 'prejudices'. In respect to brain chemistry there appeared, beside the fantastic, elements of fact that characterise this period as embracing the 'pre-history' of neurochemistry. PMID- 11619026 TI - Neural integration at the mesoscopic level: the advent of some ideas in the last half century. AB - History seen by a professional historian, based only on the documented record, always incomplete and liable to bias, can be unreliable. Modern history seen by a protagonist must surely be among the most unreliable. Yet, I must try, in a limited scope, to show the human drama as well as the flood on which we are floating, unable to dump the baggage of past biases. Our points of view, priorities, and positions on all the controversial issues and even the well established, noncontroversial ones, are not as rational as we would like to think but are strongly conditioned by where we came from. I wil depend on selected vignettes of the way things looked when I was a student, a young postdoctoral fellow and an Assistant Professor, to compare with the way they look now, in each of half a dozen mesoscopic domains--those in between the most basic subcellular or molecular and the higher levels of learning and cognition. The half dozen constitute, of course, anything but a representative fraction of neuroscience. But they add up to a nontrivial segment of the big picture with respect to the integrative aspects of our science. Most of the fronts that grew into today's popular branches are not represented, but a small set of particular interest and probability of further surprises. PMID- 11619027 TI - Spitzka and Spitzka on the brains of the assassins of presidents. AB - Although four American Presidents have been assassinated (Lincoln, Garfield, McKinley, Kennedy), only the assassins of Garfield (Charles Julius Guiteau) and McKinley (Leon Franz Czolgosz) were tried, convicted, and executed for their crime. In 1882 Edward Charles Spitzka, a young New York neurologist with a growing reputation as an alienist, testified at the trial of Guiteau. He was the only expert witness who was asked, based on his personal examination of the prisoner, a direct question concerning the mental state of Guiteau. Spitzka maintained the unpopular view that Guiteau was insane. In spite of aggressive and spirited testimony on Spitzka's part, Guiteau was convicted and hanged. However, even before the execution it was acknowledged, by some experts, that Spitzka was undoubtedly right. About 20 years later, in 1901, Edward Anthony Spitzka, the son of Edward Charles Spitzka, was invited to conduct the autopsy on Czologsz, the assassin of McKinley. At the time Spitzka the younger, who had just published a detailed series of papers on the human brain, was in the fourth year of his medical training. It was an unusual series of fortuitous events that presumably led to Edward A. Spitzka conducting the autopsy on the assassin of the President of the United States while still a medical student. This, in light of the fact that other experts were available. Each Spitzka went on to a career of note and each made a number of contributions in their respective fields. It is however, their participation in the 'neurology', as broadly defined, of the assassins of Presidents Garfield and McKinley that remains unique in neuroscience history. Not only were father and son participants in these important events, but these were the only times that assassins of US Presidents were tried and executed. PMID- 11619028 TI - Representation and identity - convergence of brain research and mind-brain philosophy. AB - The localization or representation of mental abilities in the brain have always been considered as key questions for understanding the organization of the human nervous system. Particularly with the advent of modern electrophysiological and imaging techniques that provide maps of electromagnetic fields and metabolic processes on the living central nervous system, the representation theory is experiencing a scientific renaissance in neurology, but is only one theory, however, in the succession of a long philosophical tradition dealing with the possible identification of mental phenomena and brain processes. This dichotomy was formulated at the latest in the Cartesian dualism of res cogitans and res extensa of the mind-body problem. Nowadays philosophical discussion, on the contrary, is dominated by monistic concepts that attempt to explain the mental realm on an organic foundation in order not to succumb to the problem of a psychophysical dualism. Of these, the identity theory offers a philosophically plausible concept postulating that the identity of brain conditions and mental phenomena is based on organic foundations. In this theory, the efforts of brain research converge on the representations of mental phenomena in the human nervous system. In a comprehensive approach, both concepts could complement each other. PMID- 11619029 TI - Brown-Sequard and his syndrome. AB - The contributions of Charles Edouard Brown-Sequard (1817-1894) to the advancement of medical science included his emphasis on functional processes in the integrative action of the nervous system, his discovery of the vasomotor nerves, his experimental demonstration that the adrenal glands are esential to life, and his pioneering work on hormone replacement therapy. He is best remembered, however, for his work in delineating the sensory pathways in the spinal cord. His later work on the sensory function of the cord emphasized dynamic spinal mechanisms that may well have major implications for the rehabilitation of patients with cord injuries. PMID- 11619030 TI - Brown-Sequard and the discovery of the vasoconstrictor nerves. AB - In August 1852, Brown-Sequard who had left Paris for Philadelphia at the beginning of the same year published in the Medical Examiner a description of the effects he observed in various animals after electrical stimulation of the distal part of severed cervical sympathetic chains. The blood vessels of the face and ear contracted and the temperature of the tissues decreased. After stimulation ceased, all the phenomena observed by Claude Bernard after sectioning the chain reappeared, especially vasodilation and hyperthermia. Brown-Sequard concluded that the sympathetic chain sends motor nerve fibres to many of the blood vessels of the head and that vasodilation followed by hyperthermia resulted from the section of these fibres. This view was challenged by Claude Bernard who had assumed the presence of "calorific" fibres in the sympathetic chain. The controversy between the two physiologists is related in the article. PMID- 11619031 TI - Brown-Sequard and cerebral localization as illustrated by his ideas on aphasia. AB - Brown-Sequard's concept of localization was built on the phenomena of inhibition and dynamogenesis, constituting a dynamic system in which reflex mechanisms, that played a part not only in the spinal cord but in the brain as well, were considered of particular importance. The use of this concept is considered in Brown-Sequard's discussion of the subject of cerebral localization, and especially of aphasia. The origin and development of Brown-Sequard's ideas on aphasia from 1861 onwards are discussed, as is the part he possibly played in the transfer of knowledge from Paris to London (Broca and Jackson). In the 1870's Brown-Sequard debated on cerebral localization with Charcot before the Societe de Biologie. Opposing the cluster theory of localization, Brown-Sequard developed the theory of "reseau de cellules anastomosees", a kind of network theory in which scattered cells subserving the same function are connected by nerve fibers. This was to him a plausible theory, with which he was able to explain the fact that damage in several locations may produce the same effect, and, to account for observations that some functions remain unimpaired despite extensive brain injury. Although Brown-Sequard's arguments were not always valid, because they were based on imprecise observations, his dynamic model, nowadays, seems valuable. He influenced "anti-localizers" such as Goltz, but also Jackson and probably Von Monakow and Sherrington. PMID- 11619032 TI - Brown-Sequard's theory of recovery. AB - Charles Edouard Brown-Sequard used observation of recovered patients and experimental animals to support his theory of cerebral localization. Recovery theories assume that the nervous system is composed of one organ or many, and that each organ has one function or many. From his own studies as well as others, Brown-Sequard concluded that the brain contained at least nine separate organs, each with a single distinct function, and that each organ is organized, not as a geographically isolated cluster of neurons, but as a widely disseminated network. According to his view, function is not uniformly distributed in an organ. Focal necrosis of part of an organ temporarily inhibits the action of distant, undamaged parts; resolution of this inhibition results in recovery. Using this theory of cerebral localization and recovery, Brown-Sequard practiced an early form of scientific neurology. PMID- 11619033 TI - Sherrington's legacy: evolution of the synapse concept, 1890s-1990s. AB - The history of the synapse concept is traced from its inception in the 1890s to the present day. Three major periods are highlighted: the 1890s, the mid twentieth century and modern times. The dependence of progress on the development of techniques is emphasised. The significance of the external context, the metaphors and general theory within which work proceeds, is also stressed. The development of the synapse concept can be seen to depend on a complex interplay between these internal and external factors. The reticularist/neuronist controversy provides a continuing leitmotiv. PMID- 11619034 TI - Phineas Gage's contribution to brain surgery. AB - In much contemporary literature the Phineas Gage case is described as contributing to the development of lobotomy and leucotomy but the historical evidence shows this to be an almost completely erroneous view. His case was, however, important in the development of brain surgery itself. I begin this paper by briefly mentioning four early cases of brain surgery and describing the Gage case. I then set out the context of the localisation debate, concentrating particularly on Broca's clinical observations, because Macewen planned the first operation on the brain in the light of Broca's findings. I then turn to that context as it was developed through Jackson's observations and Ferrier's experiments, because Bennett and Godlee used it in planning the first operation for the removal of a brain tumour. It was also in the localisation context that Starr first drew attention to the significance of the changes in Gage for localising frontal tumours. By the turn of the century, several operations had been performed on the frontal lobes and various difficulties with Starr's criteria had become apparent. The reasons for the difficulties will be brought out and I conclude with a brief discussion of the relation between the Gage case and the operations performed by Burckhardt, Moniz, and Freeman. PMID- 11619036 TI - Obituary: Renato Boeri. PMID- 11619035 TI - Dr. C.E. Brown-Sequard, M.D., F.R.C.P., F.R.S., London: the casting of the die. AB - In 1858 Dr. Brown-Sequard arrived in London. During his stay there, he was appointed physician at the National Hospital for the Paralysed and Epileptic (now the National Hospital), and was elected Fellow of the Royal College of Physician's of London, as well as Fellow of the Royal society. During this time he also published his 'Course of Lectures on the Physiology and Pathology of the Central Nervous System' an early exposition of what is now know as 'his' syndrome. During his time in London, Dr. Brown-Sequard made many well-known acquaintances, amongst others Charles Darwin, T.H. Huxley, and Louis Pasteur. Three years after his appointment as physician at the National Hospital, he left London. Increasingly, he was to abondon fashionable practice to concentrate on his study of what are now known as the endocrinal glands. In this way, he became a pioneer of the study of endocrinology. PMID- 11619037 TI - Willis and Steno on muscles: rediscovery of a 17th-century biological theory. AB - Niels Stensen in 1667 in the first systematic analysis of muscle fibre contraction described the unipennate actuator of skeletal muscles, now applied in computer programs simulating muscular action. Three years later Thomas Willis partially approved Stensen's description and brought an exact anatomical illustration from an ox, probably drawn by Christopher Wren. This new concept and theory was, however, refuted by Mayow, Borelli, Johann Bernoulli, Boerhaave and von Haller and became almost forgotten until the anatomical rediscovery in 1981. PMID- 11619038 TI - Charcot and aphasia. AB - Whereas the beginning part of Charcot's career was occupied with a rigorous and unerring devotion to the anatomo-clinical method, his later career shared attention with physiologic and psychological analyses of hysteria. The seeming paradox between these differing approaches to neurologic study can be better understood by an analysis of Charcot's work on aphasia. This area of study grew out of Charcot's larger research effort on cerebral localization, but was not well known, because most of his lectures on aphasia were never widely published or distributed in either French or English. In analyzing aphasia, Charcot began with anatomic lesions, but gradually incorporated cases of hysterical aphasia, as evidence of dynamic lesions of the same brain areas. Although aphasia never represented a prominent area of study for Charcot, it held a particularly important place in his career first because it provided this transition between anatomic and physiologic approaches to neurologic research, and second because it permitted a natural two-way passage between the topics of cerebral localization and hysteria. PMID- 11619039 TI - Freud's impact on aphasiology--aphasiology's impact on Freud. AB - In 1891, Sigmund Freud published a book on aphasia. Although Freud's contribution to aphasiology could have been important in retrospect, it was hardly acknowledged for three quarters of a century. It may have had an impact on psychoanalytic theory, but this was not acknowledged by Freud. If there are neurological roots in psychoanalysis, they are buried by paradigmatic shifts in Freud's theory. PMID- 11619040 TI - 'On mind-blindness (optic agnosia)', a classical clinico-pathological report, and its author Wilhelm von Stauffenberg (1879-1918). AB - Two photographs from the beginning of our century still instructively illustrate the phenomenon of visual agnosia: the perplexed face of an old lady confronted with objects clears after touching them. This patient with bilateral posterior cerebral infarction was followed for seven years at the Munich Medicine Department of Friedrich von Muller (1858-1941) who had a strong interest in neurology. His assistant Wilhelm von Stauffenberg (1879-1918) reported the case in great detail, including anatomical analysis performed under Constantin von Monakow (1853-1930). Promoted to "Privatdozent" in 1913 on the basis of this report, Stauffenberg's work included several additional, similarly extensive clinico-anatomical case studies but was not limited to problems of cerebral localisation. Under the influence of the Burgholzli group in Zurich he started to practice psychotherapy. Stauffenberg, deeply interested also in the arts and in literature, was the physician of the poet Rainer Maria Rilke (1875-1926) from 1914. He succumbed to pneumonia in 1918. PMID- 11619041 TI - Albert Wilmarth's nineteenth century study of Down's syndrome in America: the work of a neuropathologist, asylum superintendent and eugenicist. AB - Albert Wilmarth was an influential physician in nineteenth century America. His works in asylum management, eugenics and neuropathology were intimately interrelated, and his conception of people with Down's syndrome and how they should be treated were largely a product of these relationships. While many of his activities may be perceived in a negative way today, he should be credited with having discovered vasculitis in the brains of people with Down's syndrome during his pathological studies, a condition which is now perceived as autoimmune. PMID- 11619042 TI - Neurology in Tulp's Observationes medicae. AB - The beginning of the seventeenth century marked the start of a scientific revolution, which had consequences for medicine. Vesalius in anatomy, and Harvey in physiology, were important figures who gave the Hippocratic and Galenic traditions new impulses. In this period of change in medical thought, Nicolaas Tulp (1593-1674) wrote his 'Observationes Medicae' (Tulp, 1641). A controversy existed in The Netherlands, concerning the circulation, with many doctors still adhering to the Galenic tradition. The following analysis discusses some of the neurologic cases from Tulp's book, seen in the light of modern medical thought. PMID- 11619043 TI - Neurology and the soul: from the origins until 1500. AB - The mind-brain dichotomy recalls the soul-body duality and the tendency to individualize in the nervous system a location for the soul. In this paper, the author analyses some of the principal theories which attribute the soul to a cerebral location, from the origins until the year 1500. PMID- 11619044 TI - Ottorino Rossi and the medical tradition of Pavia. AB - Ottorino Rossi was a remarkable Italian neurologist of the first half of this century. He made important contributions to many fields of clinical neurology, neurophysiopathology and neuroanatomy. Among these are: the identification of glucose as the reducing agent of the cerebrospinal fluid, the demonstration that fibres from the spinal ganglia pass into the dorsal branch of the spinal roots, and the description of the cerebellar symptom which he termed "the primary asymmetries of positions". Moreover, he conducted important studies on the immunopathology of the nervous system, on the serodiagnosis of neurosyphilis and on the regeneration of the nervous system. He studied pathological anatomy under Camillo Golgi and clinical neurology under Casimiro Mondino and completed his clinical preparation in Florence with Eugenio Tanzi, and in Munich at the Institute directed by Emil Kraepelin. Ottorino Rossi taught at the Universities of Siena, Sassari and Pavia; in the last town he was made Dean of the University and managed to have the buildings of the new San Matteo Polyclinic completed. Ottorino Rossi was one of Camillo Golgi's most illustrious pupils as well as one of the most eminent descendants of Pavia's medico-biological tradition. PMID- 11619045 TI - The history of the tic douloureux: autopathograph of an Italian lawyer who suffered from trigeminal neuralgia from 1803 to 1824. AB - In the years from 1803 to 1824 an Italian lawyer suffered from paroxysmal facial pain that resembled essential trigeminal neuralgia. He kept a diary of his disease from its onset until 1823 when he was admitted to the old Arcispedale S. Anna in Ferrara (St. Anna's Hospital), Italy. The diary was recently discovered in the library of the Arcispedale S. Anna where it was probably put when the patient died. The patient was a man of notable culture and was able to describe with great diligence not only the course of his disease but also the most accredited treatments of that age. Some of the most famous Italian physicians of the period (A.G. Testa, V.L. Brera, G.A. Tommasini, A. Scarpa) examined and treated the patient. Letters of theirs were attached to the manuscript as well as notes on several treatments for trigeminal neuralgia drawn from medical magazines of that age. A copy of the patient's autopsy was enclosed: it ruled out the possibility of secondary neuralgia. This manuscript gives us information on the clinical and pathogenetic theories about trigeminal neuralgia and the state of diagnostic and therpeutics in the first years of the nineteenth century. PMID- 11619046 TI - Winslow's contribution to our understanding of the cervical portion of the sympathetic nervous system. AB - Jacques Benigne Winslow (1669-1760) was one of the most brilliant anatomists of the XVIIIth century. Though having Danish origins, he spent most of his life in Paris where he held the chair of anatomy of the Jardin du Roy between 1742 and 1758. Among his numerous contributions in the field of human anatomy, the "Exposition anatomique de la structure du corps humain" (1732) had a great influence on anatomical literature for over a century. Winslow's description of the sympathetic nervous system had a significant importance to the understanding of this controversial part of the nervous system. The structure and distribution of the cervical part of the sympathetic nervous system, as described in his textbook (edition of 1752), were analyzed in the light of our current knowledge. It appears that Winslow not only modified the terminology by replacing the term "intercostal nerve" by that of the "great sympathetic nerve", but also knew, with a few exceptions, the systematization of the cervical ganglia and their branches. The name of Winslow is therefore undissociable from the history of the sympathetic nervous system. PMID- 11619048 TI - Evolution of concepts and definitions of Parkinson's disease since 1817. AB - In the first half of the nineteenth century many patients suffering from multiple sclerosis, amyotrophic lateral sclerosis, tabes dorsalis, neuropathy and myopathy were in general described as a paralysis, paralysis agitans, and used 'lessened muscular power' to characterize the disorder. In this article we will review various definitions of Parkinson's disease, which appeared in textbooks since the original description and demonstrate that the number of symptoms as well as the selection of the symptoms in those definitions varied, although the different definitions clearly referred to the same disease. PMID- 11619047 TI - A note on the treatment of drummer Bock: an early Danish account of multiple sclerosis? AB - Multiple sclerosis (MS) was first presented in a clinical setting in 1838. In this paper the presentation and treatment of a transient hemiparesis in a drummer in 1789 is discussed. This may have been an early case of MS and presents evidence against the theory that MS is an infectious disease beginning in the 19th century. PMID- 11619050 TI - Domus Willisi: a neuro-architectural tour. AB - Fifteen sites in England today can be identified with Dr. Thomas Willis, the Oxford physician and anatomist, who was the founder of neurology. Four of these were domiciles; Beam Hall, where Willis and his colleagues met to study the brain and nerves, can be claimed as the first Neurological Institute. The last dwelling place of Willis is Westminster Abbey, where in 1961 his memorial stone was renewed by neurologists and neurosurgeons. Part of this original stone marks the new Brain Imaging Centre at the Montreal Neurological Institute, where the name of Thomas Willis shares a place in the Hall of Neurological Fame. PMID- 11619049 TI - Webb Haymaker: operation 'stratomouse'. PMID- 11619051 TI - A place for chiropractic historians: the workshop to develop a chiropractic research agenda. AB - After a century of existence, the chiropractic profession has entered a new age of acceptance and accountability. With these privleges given by society have also come an increased responsibility in demonstrating cost effectiveness, validity and treatment effectiveness. The profession has taken this challenge seriously, creating a research agenda for the profession. Chiropractic historians, and in particular the Association for the History of Chiropractic, have a true role to play in the future of chiropractic by acting as consultants to research planners. PMID- 11619052 TI - The search for Alma Arnold: chiropractic's forgotten woman pioneer, 1903-1938. AB - Alma Cusian Arnold (1871-19??) was one of the first woman chiropractors, having graduated from Langsworthy's American School in 1903. Within the next decade, she would establish dual practices in Washington and New York with a patient constituency which included members of Congress, a Vice President and Clara Barton, the founder of the American Red Cross. She authored a book, was president of two schools of chiropractic and was arrested and imprisoned for her advocacy of the new profession. Engaging in critical dialogue over her technique with both Palmers, Arnold would establish a "Healtharium" with Terrance V. Powderly, the most prominent labor leader of the late 19th century and later Commissioner of Immigration. Her story is a personification of the exceptional men and women who formulated early chiropractic. PMID- 11619054 TI - An Australian perspective on chiropractic spinography. AB - Daniel David Palmer and Wilhelm Conrad Roentgen were born in the same year, and each of them, at the age of fifty, made the discovery for which he came to be best known. Both of them built upon earlier theories and discoveries. Roentgen's discovery, x-ray, was to become an indispensable diagnostic tool for the profession which grew out of Palmer's discovery, chiropractic. This paper traces some of the developments which led to the discovery of x-ray, early milestones in applied radiography, and the emergence of spinography in chiropractic. Special emphasis is given to chiropractic innovations in roentgenography and the use of spinography by chiropractors practising in Australia. PMID- 11619053 TI - The role of the encyclopedic Howard System in the professionalization of chiropractic National College, 1906-1981. AB - D.D. Palmer, chiropractic's discoverer and nomenclator, lost his Palmer School to his son, B.J., in 1906. That same year, a Palmer graduate, John Fitz Alan Howard, founded the National School of Chiropractic in the Ryan Building in Davenport. In 1908, he moved National to Chicago to secure the clinical, laboratory, dissection, hospital, facilities, licensure and other advantages in Illinois. Within two years, Howard's commonsensical, science-based lectures encompassed virtually every major characteristic of the chiropractic profession as it stands today. Dr. Howard called it the "Howard System" of Chiropractic. National's presidents (Dr.s. Schulze and Janse) led faculty who continued to raise educational standards. Gradually, other surviving colleges embraced most of NCC's first seventy-five years of philosophic, scientific and artistic educational innovations, and thus the profession emerged. PMID- 11619055 TI - Advertising in chiropractic, 1939-1944: an introspective look at the early years of the Chirogram. AB - The Chirogram was a popular and widespread chiropractic journal that was reborn in 1939 and lasted for 40 years. With 8,000 copies circulated for the debut May 1939 issue, the journal grew steadily to 11,000 copies per month by December 1944. As one of the largest journals of its time, the Chirogram was well supported by vendors that supplied chiropractors with products and services. By reviewing the advertisements, one can see through the eyes of early doctors; they saw the trends, fads, common remedies and popular treatments of the time. A manual search was conducted through the Chirogram from May 1939 to December 1944, and the advertisements were organized into categories. Each of the vendors were recorded and tallied for the year and month that they appeared. This quantitative study utilizes frequency counts and graphs of the data to provide insight into trends in advertising and practice styles of chiropractors in the early 1940s and relate them to then current events in the United States. PMID- 11619056 TI - The chiropractic heritage of Paul Caster: magnetic healer. AB - Magnetic healers were a phenomenon in America's heartland, from Iowa, Kansas, Missouri in Illinois in the late 1860s. Three noted magnetics in this region were Paul Caster, Andrew Still and Daniel Palmer; the first and third would have a chiropractic legacy, while Dr. Andrew Taylor Still would found osteopathy. This is the story of the chiropractic heritage from Paul Caster via his son, Jacob, to his grandson, Charles E. Caster, D.C. Magnetic healing in this family was considered by Paul to be a divine gift, while Still and Palmer would be rejected by the clergy and believed their skills could be learned, thus passed on. PMID- 11619057 TI - Remembering Dr. Lyle Wheeler Sherman. AB - Lyle Wheeler Sherman was a chiropractor with a passion for chiropractic. He brought dignity to the chiropractor; but most profoundly, he brought dignity to the chiropractic profession. He rendered a quality professional service and helped his fellow chiropractor do the same. He was a published author and co developer of various chiropractic instruments. A renowned teacher, former assistant director and chief of staff of the B.J. Palmer Chiropractic Research Clinic in Davenport, Iowa, he was a sought-after speaker at both state and national chiropractic conventions. Dr. Sherman was a man of knowledge and wisdom. Local chiropractors sought his technical advice and assistance which he provided at no charge. Both laymen and chiropractors recognized him as a chiropractic authority. He regularly received letters from patients who had traveled both the medical route and the chiropractic route and were seeking the more specific care offered by Dr. Sherman. He always attempted to accommodate them. His gentle personality and sense of humor, coupled with his exactness in chiropractic analysis and adjustment procedures, won the respect of students, colleagues and patients. His expertise was recognized by his appointment to many state and national offices and by the many awards he received. His greatest and most lasting award was the chiropractic college that bears his name: Sherman College of Straight Chiropractic in Spartanburg, South Carolina--the first chiropractic college in the southeast. PMID- 11619059 TI - Epigramania revisited. PMID- 11619058 TI - Hole in one: a history of its founding. AB - Following closely upon the controversial introduction of the Neurocalometer in 1924, the announcement of the Hole-In-One (HIO) theory created yet another significant stir in the chiropractic profession in the early 1930s. Surprisingly, no one has ever tried to trace the history of HIO using primary reference material. Today, numerous spin-off techniques from HIO exist. Some claim that B.J. Palmer invented HIO while others say it was Aleck August Wernsing, D.C., from California. Was it really B.J. Palmer's idea, or did he get it from Wernsing? In this paper the authors have attempted to trace the origins of HIO theory. PMID- 11619060 TI - Worth remembering: the process and products of oral history. AB - This paper documents the process of an oral history study that involved interviews with 18 women who graduated from the Illinois Training School near the turn of the century. It described oral history as a methodology, the process of data collection as it related to working with a specific population, the significance of the findings as they relate to self care, and a summary of the efforts with recommendations for future endeavours. PMID- 11619061 TI - A history of transplantation. AB - This paper provides a brief historical overview of the development of transplantation by highlighting some of the key developments in both physiological knowledge and surgical technique which enabled progress to be made towards the present day situation. PMID- 11619062 TI - The anomaly of autonomy: space and status in early nursing reform. AB - As the focus of care begins to shift from the hospital to the community, it is perhaps timely to look back at the contrasting trend which established the hospital as the dominant locus for nursing care and the space within which nursing skill would be reformed during the middle of the nineteenth century. This paper argues that one of the paradoxical consequences of nursing's shift into the hospital was the loss of a level of autonomy which nurses have struggled to achieve ever since, and considers the campaign which sought to squeeze the ostensibly more autonomous and skilful domiciliary nurse out of the healthcare market and replace her with a more professional and pliant hospital counterpart. PMID- 11619063 TI - Infant welfare in inter-war Oxford. AB - State provision of welfare increased in the 1930s in Great Britain, especially the welfare of mothers and babies. The national picture hid many local nuances and practices concerned with the implementation of policies. Using Oxford and Oxfordshire as a case study, this paper examines the ways in which local authorities chose to interpret national policies and to insist on a mixture of personal responsibility, public philanthropy and professional involvement. PMID- 11619064 TI - An historical note on the relationship between nursing and nursing history. PMID- 11619065 TI - My dear Harry: a life of Henry Bonham-Carter. AB - Henry Bonham-Carter was both a relative and the 'workhorse' of Florence Nightingale. His administrative skills contributed much to the development of nursing yet he is less well-known than his cousin. This article describes a recent exhibition in London to celebrate his life and involvement in nursing. PMID- 11619067 TI - Midwifery in England and Wales before 1936: handywomen and doctors. AB - The social history of medicine incorporates a respectable body of research on maternity care in Britain, but illegal midwifery in the 1920s and 1930s remains inadequately understood. Midwives' statutory regulation began with the Midwives Act of 1902, which was implemented over the eight years to 1910. The licensing body for England and Wales was the Central Midwives Board, which enrolled midwives with approved qualifications and, initially, others who were untrained but who were accepted as having been in 'bona fide' practice before the legislation. Its effect was to prohibit midwifery by the untrained 'handywomen' on whom many poorer women had formerly relied (1). The 'bona fide' enrolments covered some such practice, but it otherwise became illegal. PMID- 11619066 TI - The personal experiences of a nurse in England, 1938-1974. AB - These recollections trace the experiences of a school nurse working in the East End of London from 1938 to 1974. They include a brief history of Stepney and the Docklands, the ethnic mix and the social and economic conditions before the war. They describe the effects of World War II with the bombing and its devastation and the evacuation of children to the country, their return and forced re evacuation, and the effect on the children. After the war the recollections recount the continuing struggle with health education as a health visitor and something of the post-war reconstruction. PMID- 11619068 TI - Oral history and content analysis using Ethnograph. AB - The oral testimony is a well-established tool for the historian of the recent past and there is a considerable body of literature on the techniques for collecting oral testimony, the pitfalls to be avoided, as well as the conceptual issues involved. There is, however, little to guide the researcher on the analysis of oral testimony and this paper presents a computer-based technique for analysing taped recollections. It uses one example to demonstrate how Ethnograph can assist in a more rapid, but nevertheless equally valid, analysis of oral testimony. PMID- 11619069 TI - The role of women in mental health care in 19th century England. AB - The history of women's role in the care of mentally ill people is relatively unchartered territory. Women were involved in mental health care in a variety of ways and at the beginning of the 19th century they could operate in capacities equal in status to those of men. Social policies which gave legal backing to medical authority; the rise of medical professionalism, which until the last quarter of the century excluded women; the Victorian ideology which fixed women in a subservient role, all served to ensure that their contribution to the care of mentally ill people was subordinate to that of men. This was reflected in the duties they undertook and their rates of pay, which were always less than those of men. PMID- 11619070 TI - Conflict and consensus in the International Council of Nurses. AB - In this article we argue that the International Council of Nurses' (ICN) identity changed in response to external pressure that took the form of particular moments of crisis. We address one of these crises, the expulsion of the South African Nurses' Association (SANA), as a case study in the politics of identity and consider its implications for the historical evolution of the ICN as an international organisation more generally. PMID- 11619071 TI - War and peace. AB - The Dame Kathleen Raven Lecture is an annual lecture in recognition of the contribution of Dame Kathleen Raven to nurse education and nursing practice. Each year, distinguished speakers are encouraged, in front of an invited and eminent audience, to range far and wide and reflect on nursing, education and patient care. Uniquely, in 1995, Dame Kathleen herself gave the lecture. The following comprised the substantial part of her important speech to the assembled guests. PMID- 11619072 TI - A brief history of the Royal College of Nursing History of Nursing Society and its journal, 1983-1994. Part I - the early years. AB - In this two-part overview of the history of the History of Nursing Society and its journal, Monica Baly traces some of the key issues, personalities and events in the life of the longest-running history of nursing group in the world. Part 1 covers the early years and the struggle to construct a workable constitution within the Royal College of Nursing, to recruit members and to publish original research. PMID- 11619073 TI - War diary reminiscences. AB - In Part 1 of her war diary, Brenda MacDuff, a nurse with the Colonial Nursing Service in Malaya, tells of her early experiences in the country at the outbreak of war in the East and of her subsequent capture by the Japanese Army. PMID- 11619074 TI - District nursing associations and doctors: aspects of interprofessional relationships, 1902-1914. AB - District nursing associations' midwifery was the key to their early twentieth century growth, which would have been impossible without doctors' co-operation. Yet doctors were reportedly hostile to district nurses in this period, and had particular reasons for resisting their midwifery. Here it is argued that the Queen's Institute's co-ordination of the associations' work, and its conduct of negotiations with the British Medical Association, promoted arrangements under which doctors were likely to gain more than they feared losing by accepting district nurses' midwifery. PMID- 11619075 TI - Nursing leadership as a legacy of the Second World War. AB - In an overview of British nursing history from 1939 onwards, this paper challenes the view that professional stagnation in the post war period resulted from a lack of nurse leadership. Instead the paper argues that strong dynamic leaders did exist, but they failed to gain the support of rank and file nurses. PMID- 11619076 TI - Cheltenham women and provincial medical care in the early nineteenth century. AB - The focus of the history of Cheltenham has been primarily upon the rich, while little recognition given to the suffering poor. Both categories co-existed and the former were often there to help the latter. In the early nineteenth century there was the initiation of a range of charitable institutions and domiciliary care in which the rich played a prominent role, most giving generously of their time and money. This paper highlights some of the women associated with the fledgling institutions, those who played a quasi-medical role, during the period in which the medical profession slowly gained recognition. PMID- 11619077 TI - The great divide. AB - In November 1937, a group of masked nurses marched through London's streets, carrying placards proclaiming their demand for improved pay and conditions. The campaign they and like-minded nurses fought was to have far reaching consequences. Trade unionism was established elsewhere in nursing, but this was to be an important first step in breaking down the hegemony of the professional associations in general nursing as well as the service's dominant culture of subordination and loyalty to a mythic but compelling vocational ideal. PMID- 11619078 TI - War diary reminiscences: part two. AB - In the concluding part of her war diary, Brenda MacDuff, a nurse with the Colonial Nursing Service in Malaya, tells of her final incarceration, eventual freedom and reunion with her husband. PMID- 11619079 TI - A history of the Royal College of Nursing History of Nursing Society: Part II. AB - In the concluding part of her article, Monica Baly traces the history of the RCN History of Nursing Society from 1989 to the present day. PMID- 11619080 TI - Doctors who climbed mountains. PMID- 11619081 TI - Women Nobel Laureates in science. PMID- 11619082 TI - Cuban Tainos and pre-Columbian medicine. PMID- 11619083 TI - Christopher Wren and the Wren Building - a cancellation. PMID- 11619084 TI - The Hagyard, Davidson and McGee practice, a cornerstone in the development of Kentucky's racehorse-breeding industry. PMID- 11619085 TI - A personal history of veterinary public health. PMID- 11619086 TI - The Red Star goes to war. PMID- 11619087 TI - Vaccination trials against cattle plague in Hungary in 1838. PMID- 11619088 TI - Elmer A. Woelffer, DVM, 1897-1995. PMID- 11619089 TI - Rabies treatments and preventives through the ages. PMID- 11619090 TI - Doctors' autobiographies. PMID- 11619091 TI - A Japanese artist in the West London Hospital (1907): Yoshio Markino in London (1897-1942). PMID- 11619092 TI - Werner Forssmann (1904-1979), auto-experimenter/medical martyr. The original cardiac catheterization. PMID- 11619093 TI - Henry Souttar and surgery of the mitral valve. Part II: the operation and its aftermath. PMID- 11619094 TI - Ignac Langer (1819-1895), pioneer of American-Hungarian medical relations. PMID- 11619095 TI - Dr Ralph Barnes Grindrod, the medical apostle of temperance. PMID- 11619096 TI - Frederick Everard Hunt MRCS (Eng) LRCP (Edin) (1840-1900): an early general practitioner in Christchurch, New Zealand. PMID- 11619097 TI - George Busk FRS (1807-1886), nineteenth-century polymath: surgeon, parasitologist, zoologist and palaeontologist. PMID- 11619098 TI - [Radiochemistry]. PMID- 11619099 TI - [Chemical evaluation and consideration on the traditional drug "ULUUS" (2)]. AB - Traditional patent medicine named "ULUUS" has been regarded to be the first Dutch precipitation with a western name in Japan. It was found that this drug consists of Rhubarb mainly, and it contained high amounts of effective compounds as for the traditional sample that has been stored for more than 100 years. In fact, a dose of this medicine was supposed to cause a laxative effect. PMID- 11619100 TI - [Advanced medical pharmacy]. AB - This paper reviews the progress of Medical Pharmacy for about the past 30 years. Nowadays, Medical Pharmacy is becoming an important and essential part of pharmacist's business and pharmaceutical education. PMID- 11619102 TI - [Comparative studies on saccharated preparations in traditional medicine]. AB - We studied the descriptions of saccharated preparations found in traditional medical books and reported the following points. 1. Among the preparations described in medical books in Uigurian traditional medicine, the most numerous are saccharated preparations. These are often used to ripen and detoxicate malignant body fluids. 2. The contents of ancient writings found in Turfan in Uiguru relate not only to Greek medicine but also to Ayurvedic and Tibetan medicine. The application of saccharated preparations described in these writings is similar to that mentioned above. 3. The most important book of Tibetan medicines, "Sibu Yidian (The Four Medical Tantras)" describes saccharated preparations as making viscous body fluids ripe and improving their passage. The same book also regards them as mitigative. 4. "Caraka samnita" and "Sushruta samhita" show that honey and sugar are used separately in most cases of Ayurvedic medicine and that they expel malignant body fluids. 5. According to books of Greek medicine, honey is often added to extracts of herbal medicine at the time of taking it, and is used to ripen, detoxicate, and expel malignant body fluids. 6. The origin of saccharated preparations seems to be related to similary humoral theories in Greek, Arab, Indian, and Tibetan medicine. PMID- 11619101 TI - [Chronological table of Mr. and Mrs. Curie and Mr. and Mrs. Joliot-Curie--in connection with the 100-year anniversary since Dr. H. Becquerel discovered radial ray in 1896]. AB - This year (1996) is the 100th year since Dr. Henri Becquerel discovered radial rays in 1896 in France. In 1897, Dr. Pierre Curie and Marie Curie preliminarily reported the existence of polonium and radium which have radioactivity. H. Becquerel, Pierre and Marie Curie were awarded the Nobel Chemical Prize for discovering artificial radioactivity in 1935. I report herein the chronological table of Mr. and Mrs. Curie and Mr. and Mrs. Joliot-Curie spanning about one century. PMID- 11619103 TI - [The transition of psychotropic drugs in Japanese pharmacopoeia (JP) (Part 9). The transition of valerianae radix drugs in the books]. AB - Valerianae Radix (V.R.) has been written about in every kind of books concerning the vegetable drugs and medicinal plants, published between the Meiji period and the Heisei period. Between the Meiji period and the middle of the Showa period, V.R. was introduced as a drugs for the cure of mental disease. However, recently V.R. was not included in almost all medical books and was not used in clinical fields. On the other hand, the action of V.R. is gentle and very easy to preparing OTC general drugs. Therefore, it is thought that V.R. will be revaluated for use in the treatment of the elderly. PMID- 11619104 TI - [ULUUS, the first Japanese medicine with a western name]. AB - "ULUUS" is a patent medicine which was put on sale when the Japanese started to adopt Western Medicine brought in from Holland. It is regarded as the first medicine to have a Western-style name in Japan. In those days, ULUUS was thought be a useful medicine for patients with diseases called Tan, Ryuin and Shakki, causing the excretion of phlegm and bad accumulations in the body through expectoration, urine of feces. We recently obtained an ULUUS medication which was made in around 1870. It contains 15 tablets pressed neatly onto a sheet and has an inner wrapper, middle wrapper and outer wrapper made from 3 kinds of Japanese paper... PMID- 11619105 TI - [Von Siebold's prescriptions (2)]. AB - I have interpreted and explained 20 of von Siebold's prescriptions 4 times. Of the 20 prescriptions, 6 were stored at the Siebold's Memorial Museum (questionable 1 was excluded) and 14 at the Municipal Museum of Ohzu City, Ehime Prefecture. The 20 prescriptions used 39 types of drugs (different forms of the same drug such as crude glycyrrhiza, glycyrrhiza extract, and glycyrrhiza powder were regarded as 3 types). The prescriptions were classified according to the drug form: powders, 6 prescriptions; pills, 3; decoctions 2; confections, 2; eye drops, 2; drugs for internal and external use, 2; applications, 1; solutions (?), 1; and unknown 1. There were 2 prescriptions that use oil-sugars as correctives. The classification of the prescriptions according to drug efficacy and disease was difficult because one drug had various effects, or some diseases could be considered depending on symptoms. However, the following classification was done: digestives, 4 prescriptions; drugs for syphilis-suppuration, 3; drugs for eye diseases, 3; cathartics, 2; alteractives and resolvents, 2; drugs for scrofula, 1; drugs for scabies, 1; antitussives and expectorants, 1; rubefacients, 1; diuretics-antiphlogistic-laxative (niter), 1; and unknown, 1. Siebold's medical activities were performed mainly in the last days of the Tokugawa shogunate in Japan. Therefore, there may be only a few prescriptions remaining in other countries. Such important cultural heritage should be carefully stored. PMID- 11619106 TI - [Simejigahara, a place noted for moxa]. AB - Shimejigahara is a place-name often used in old Waka (Japanese poems). It was reputed in the past to be a site rich in the plants moxa and mugwort. A study of this placed carried out. Shimejigahara, as mentioned in the literature of the Heian to Kamakura eras, seems to have been located at the site of the current Tochigi City. During the Edo era, however, Senjogahara in Nikko came to be referred to as Shimejigahara. In addition, some other places in what is now called Utsunomiya City, on Ibuki Mountain in Shiga Prefecture, and in Chiba City were referred to as Shimejigahara during the Edo era. When the types of wild mugwort seen in these various sites called "Shimejigahara" were searched for, Artemisia princeps P. was found in the cities of Tochigi, Utsunomiya and Chiba, while A. montana P. was seen in Senjogahara and on Ibuki Mountain. Papers published during the Edo era suggest that moxa, gathered in the Shimejigahara, was on the market during that period. It is, however, doubtful that the moxa produced from Shimejigahara was really commercialized, like the well-known "Ibuki moxa." PMID- 11619108 TI - [Pharmaceutics]. PMID- 11619107 TI - [The transition of psychotropic drugs in Japanese pharmacopoeia (JP) (Part 10). The study for transition of cultivation of valerianae radix]. AB - Valerianae Radix (V.R.) had a large advantage throughout domestic and foreign markets before the Second World War. After the Second World War, many kinds of psychotropic pharmaceutics were imported from foreign countries. Therefore, the production of V. R. declined greatly in Japan. Now, V. R. are grown only in the Hokkaido area for the purpose of preserving the species. In spite of this situation, it is thought that V. R. may be useful as a sedative drug for aging society by its gentle action. Therefore, the cultivation of V. R. and its quality improvement in Japan may be research subjects in the near future. PMID- 11619109 TI - [History of Wirow in Japan (1-3)]. AB - 1. History in Japan of Wirow, the oldest drug available to the general public, is described. The focus is placed on the manufacture's family, the Kyoto headquarters, and their descendants. 2. There are two different views of the history of the first immigrants to Japan, namely Chen Shun Zu or Chen Yan You. In this article, however, these two persons are assumed to be brothers. 3. The brilliant social activities of Chin Soden, the forefather of the resurrection of wirow, as a medical doctor and a man of culture have been verified philologically. 4. It has also been verified that Wirow Ukon, the 9th generation of wirow, was exiled to a remote place. This was because he played kyokumari, violating the rules of kemari imposed by the Asukai family, kemari's supreme ruler. 5. It has been suggested that the wirow family changed their occupation to operating drug stores in their final days, although they started their carreers as medical doctors. PMID- 11619110 TI - [Chemical evaluation and consideration on the traditional drug "ULUUS" (1)]. AB - Traditional medicine named "ULUUS" is regarded to be the first Dutch precipation with a western name in Japan. It was found that this drug consists of Rhubarb (originated from Rheum sp.). Although it is still uncertain whether it was made only of Rhubarb by being kneaded hard into the monotonous square form, we could not find out any other ingredients except Rhubarb, on the bases of our chemical analysis. PMID- 11619111 TI - [Historical investigation on herbal and medical literatures of processing and effect of Rehmanniae Radix]. AB - The radix of Rehmannia glutinosa has been applied to medicinal use since ancient times, and has been called Kiou in the Han dynasty and has been classified by prepared methods, with each preparation given a different name. There were Syoujiou, Kanjiou and Zyukujiou etc. The first was introduced in the Sinnou honzoukyou and the first and second had been used to prepare some prescriptions contained in the Kinki-youryaku and so on. The third began to appear on the medical and herbal literatures from the Tang period to the early Song. The Rehmanniae Radix has been used as the main material of Hokyoyouketu prescriptions, and by the use of Zyukujiou, their efficacy was regarded to be particularly stronger than the others. The preparation of Hatimigan recorded in the Kinki-youryaku had been used in Kanjiou but was later replaced with Zyukujiou. We should rethink about the quality and process of Chinese herbs on the pharmacy of Kampo medicine. PMID- 11619112 TI - Contributions to social history by some Georgia physicians. PMID- 11619113 TI - The evolution of American medical education, institutional histories, and the Medical College of Georgia. PMID- 11619114 TI - Business leadership in Memphis public health reform, 1880-1900. PMID- 11619115 TI - Impotence, biography, and the Froude-Carlyle controversy: "Revelations on ticklish topics." PMID- 11619116 TI - [On femininity, masculinity and biology at the turn of the century 1800]. AB - This study examines the constructions of sex/gender present in medical manuals on sexuality and marriage, published in Sweden 1790-1830. The findings confirms Thomas Laqueur's thesis that a "one-sex-model" shaped the understanding of the human body until the eighteenth century. The ancient medical tradition is evident in the instructions on how to achieve health, and the reproduction-theories are influenced by the Hippocratian/Galenian tradition as well as the Aristotelian tradition. According to the manuals, sexualality should be connected to love and marriage, for the sake of both the young couple in love and of their future children. The parents' "fluids" and emotions at the moment of conception are believed to be crucial for the quality of the offspring. Children are also believed to inherit acquired characteristics, which makes the behaviour of the parents-to-be very important. The norms for proper conduct can be related to a bourgeois ideology of the relations between the sexes in which femininity and masculinity are defined as complementary categories. Furthermore, male domination and female subordination are inherent in "womanliness", manliness", romantic love and sexual attraction. "Nature" is--in contrast to civilisation--a normative ideal. The "natural" active male and passive female behaviour are not, however, legitimised by biological theories. Women and men are both regarded as "natural" sexual beings and the female orgasm is considered crucial for conception, although women who shows lustful feelings are considered despicable and "unnatural". ... PMID- 11619117 TI - An institute for the history of science. PMID- 11619118 TI - [Not Available]. PMID- 11619119 TI - The founding of the Methodist School. AB - In an attempt to clarify the quaestio disputata concerning the identify of the founder of the Methodist School and the chronology of its foundation, the author reviews the pertinent primary and secondary literature. In spite of the acceptance on the part of some of Edelstein's opinion that the School was founded by Thessalus of tralles during the first century A.D., it is concluded that the traditional view, that it was founded by Themison of Laodicea toward the end of the Republic, is correct. PMID- 11619120 TI - [Not Available]. PMID- 11619121 TI - [Not Available]. PMID- 11619122 TI - [Not Available]. PMID- 11619123 TI - Telling tales out of school--portrayals of the medical student experience by physician-novelists. AB - Changes in medical and medical ethics education are being considered with little attention to the experience of the medical students involved. This study attempts to characterize and highlight certain aspects of that experience from a literary perspective. After a brief review of the history of traditional academic studies in the field, eight novels, written by physician-writers and featuring medical student protagonists, are analyzed. Several common themes of the student experience are identified in the novels, and are contrasted with themes found in the medical literature. A plea is made to acknowledge literary as well as scientific interpretations of the medical student experience when considering changes in medical education. PMID- 11619125 TI - William Farr (1807-1883) and the "human unit". PMID- 11619124 TI - Descartes's demon and the madness of Don Quixote. PMID- 11619126 TI - Contagious bovine pleuropneumonia in Victoria 1858-61: fate or folly? PMID- 11619127 TI - Graham Mitchell, F.R.C.V.S., c1831-88. PMID- 11619128 TI - [Not Available]. PMID- 11619129 TI - [Not Available]. PMID- 11619130 TI - [Not Available]. PMID- 11619131 TI - [Not Available]. PMID- 11619132 TI - [Not Available]. PMID- 11619133 TI - [Not Available]. PMID- 11619134 TI - [Not Available]. PMID- 11619135 TI - [Not Available]. PMID- 11619136 TI - [Not Available]. PMID- 11619137 TI - [Not Available]. PMID- 11619138 TI - [Not Available]. PMID- 11619139 TI - Medical parody and medical practice in medieval German. PMID- 11619140 TI - [Not Available]. PMID- 11619141 TI - [Not Available]. PMID- 11619142 TI - [Not Available]. PMID- 11619143 TI - [Not Available]. PMID- 11619144 TI - [Not Available]. PMID- 11619145 TI - [Not Available]. PMID- 11619146 TI - [Not Available]. PMID- 11619147 TI - [Not Available]. PMID- 11619148 TI - [Not Available]. PMID- 11619149 TI - [Not Available]. PMID- 11619150 TI - [Not Available]. PMID- 11619151 TI - [Not Available]. PMID- 11619152 TI - [Not Available]. PMID- 11619153 TI - [Not Available]. PMID- 11619155 TI - [Not Available]. PMID- 11619154 TI - [Not Available]. PMID- 11619156 TI - [Not Available]. PMID- 11619157 TI - [Not Available]. PMID- 11619158 TI - [Not Available]. PMID- 11619159 TI - [Not Available]. PMID- 11619160 TI - [Not Available]. PMID- 11619162 TI - [Not Available]. PMID- 11619161 TI - Stadelmann's Psychotherapeut: marking the beginning of modern psychotherapy? PMID- 11619163 TI - [Not Available]. PMID- 11619164 TI - [Not Available]. PMID- 11619165 TI - [Not Available]. PMID- 11619166 TI - [Not Available]. PMID- 11619167 TI - [Not Available]. PMID- 11619168 TI - The use of sedatives in the medical treatment of insanity in France from 1800 to 1870. PMID- 11619169 TI - Fathering and the British Mother's Magazine, 1845-1864. PMID- 11619170 TI - [Development of infectious diseases treatment in Szczecin following the World War Two through the prism of infectious diseases ward]. AB - The epidemiological situation of Szczecin following the liberation was both difficult and dangerous. Numerous cases of typhus, diphteria ague, venereal diseases, typhoid and dysentery were noted and an urgent need of dealing with them was necessary. Thus an infectious diseases ward was opened in 1945 at 4 Arkonska Str. Its organiser was dr Elzbieta Buk. Despite of lack of both medical staff and equipment as well as medicines in its first month of operation the ward had 160 patients. Mostly they suffered from typhus, diphtheria, dysentery and typhoid. Mortality was high: 37 patients died. Till the end of 1945 674 patients were treated, most in September. The patients were mostly Germans, Poles, Russians, Ukranians, Belorussians and occasionally French. The most frequent was typhus though there were cases of malaria and rabies. Typhoid TB, dysentery and diphtheria were also observed. In 1946/47 more wards were opened dealing with lung, skin, venereal and children's diseases. The last one directed by Dr Krystyna Stawiarska hod its scarlet fever and diphtheria sections and simultaneously an analytical and a bacteriological labs were set up and due to Dr Stanislae Swierczysski determination they enabled basic diagnostics. Slowly post war epidemics were contained and both infections mortality and admissions grew smaller. PMID- 11619171 TI - [Reflection of hygenic and anti-epidemic problems at international hygenic exhibitions in Dresden in 1911 and 1930]. AB - Ist International Hygenic Exhibition took place in Dresden in 1911 and it was dedicated to communicable diseases. In period of three months when it was opened it was seen by 5 million people. Next, the second - in 1930, was including also the problems connected with neoplastic and psychic diseases, and also with diseases of circulatory system. Sections dedicated to different problems, have had a similar didactic plan. They have been presenting a disease prevalence in the world; how to recognize it and what the course of it is; how it comes to infection and how it is transmitted; what present medicine can do about its treatment; what everybody should do to prevent becoming ill. Exhibitions were one of the elements of communicable diseases prevention, and of health education propagation; they played a significant part in this field. PMID- 11619172 TI - [Laws concerning prevention and fight against infectious diseases issued by the Military Sanitary Council between 1919-1921]. AB - Military Sanitary Council situated at Ujazdowski Hospital in Warsaw was set up in April 1919. Its members were representatives of a number of branches of medicine among others colonels professors Rudolf Weigl and Odo Bujawid. The foremost task of the council was prevention and fight against infections diseases in the Polish Army. Between 1919 and 1921 the council members prepared over 100 drafts of regulations, sanitary instructions and others dealing with the above. A number of drafts was published as directives or military orders at the time and later. MSC provided legal grounds and conditions for prevention and fight against infections diseases and it also improved the health care system in the Polish Army. PMID- 11619173 TI - [The Chief Special Commission for Epidemics in the fight against infection diseases 1920-1923]. PMID- 11619174 TI - [German studies in tropical medicine after the Ist World War]. AB - German Studies in tropical medicine come down from two sources. One of them is a pioneer activity of Koch and his disciples, especially after cholera epidemic in Hamburg in 1882; the other one--an activity of pharmaceutic industry, in particular of Bayer company. In article there are presented the scientists engaged upon the succeeding preparations against malaria and the ways leading to synthesis of them. There is also presented the progress of studies on schistosomatosis. Among the particularly meritorious in this field there are the Institut in Hamburg and similar institutions in Tubingen and Munich. Significant part in development of research was played by Germany Society for Tropical Medicine. PMID- 11619175 TI - [Short history of Polish and German relations in field on the history of medicine]. AB - The beginnings of regular contacts between historians of medicine from Germany goes back to 1977. The initiators of them were: from German side Prof. Georg Harig, from Polish side Prof. Tadeusz Brzezinski. Since then 4 conferences have taken place: two in German, and two in Poland. Another flow of contacts there became a cooperation on the grounds of Societe Internationale d'Historie de la Medecine. It has brougt the fruits of contacts mainly between Szczecin centre and Professors Hans Schadewaldt and Heinz Goerke, and also between other Polish and German Departments of Medical History. The idea of revival of the conferences was born at the Congress of Medical History in Glasgow and a present conference is the fruit of it. PMID- 11619176 TI - [Gustaw Giemsa (1867-1948)--his universal method of microscopic dying and his contribution for tropical medicine and chemotherapy]. AB - Giemsa was born on 20th November 1867 as a son of a foundry worker in Blachownia Slaska near Slawiecice in Upper Silesia ("Blechhammer bei Slawentzits"). His baptism certificate was found in "Taufbuch der Pfarrkirche Slawentzitz 1865-1875, Fol. 278, No.236." All the data collected indicate he was true to his land of Opole. He studied in Leipzig, later in Berlin. Between 1895-1898 he worked in South East Africa, at the time the German colony. From 1900 till 1933 Giemsa was a head of the Chemical ward of the Tropical and Maritime Diseases Institute in Hamburg with which he was connected all his life. He also travelled much and spent some time at Instituto Oswaldo Cruz in Rio de Janeiro in Brazil. Giemsa's most important achievement was his method of dying. It is an important development of Romanowski's method and became important itself in research of tropical diseases of blood. Gustaw Giemsa accurately labelled dyes that appear at so-called ripening of methyl blue. He worked out technical details of obtaining asure-eozine mixture. The formulae for fying could be applied in swabs of a thick blood drop and in everyday procedures. Giemsa also recognised the walue of water PH used for dying and means for closing microscope preparations under a covering glass. Giemsa's dying method turned out to be applicable in protozoology, parasitology, haematology and cytology. In oncological cytology Giemsa's dying method is becoming more and more popular due to its technical simplicity. ... PMID- 11619177 TI - [Paul Ehrlich (1854-1915) and his contacts with East European physicians at the time of testing the first chemioterapeutics]. AB - Among numerous scientific contacts which Paul Ehrlich had with foreign scientists information about his contacts with East European scientists is very limited. The communique will deal with some of the particulars concerning Ehrlich's co operation with physicians from East Europe directly before the practical application of the chemioterapeutics among others he was in touch with the Russians: Georgi N. Gabryczewski, Alexander A. Wladimirow and a Finn Julius Iversen. The contacts originated during Robert Koch bacteriological courses at the Institute of Hygiene in Berlin. Only between 1885-1988 at least 11% of participants came from the countries of Eastern Europe. Ehrlich and Gabryczewski correspondence indicates that such a co-operation had already existed in the 90 ties, at the time of the research of a therapeutic influence of aniline dyes like diacetylparaaminophenol and triasid at spirillioza (recurrens). Iversen, a chief physician of Obuchow Hospital in St. Petersburg, was one of the first who after initial tests (Atoxyl, Arsazetin), at Ehrlich's request successfully used 606 preparation in case of spirochaeta infections. PMID- 11619178 TI - [Roentgenology and tuberculosis in the early part of XXth century]. AB - The author presented the ways the method of radiological examination had developed from inventing it to the wide use of it is diagnostics of tuberculosis. He has proved, that this method, in addition to therapeutic methods, contributed to decrease of a death rate because of tuberculosis, which in 1900 was 150/100,000 inhabitants of Europe and USA, in 1940-only 70 already, and in 1950 5. PMID- 11619179 TI - [1901 Slawiecice Lung Hospital and Goetsch and Robert Koch testing on tuberculine]. AB - In 1884 count Hohenlohe August Hospital at Slawiecice (Slawentzitz) was opened. The first head of the hospital was privy councellor dr Goetsch. Basically the hospital was of a general nature yet its patients came mainly from the staff of Hohenlohe-Oehringen estate. However Goetsch was interested first of all in TP the tuberculine testing. His research made the Slawiecice hospital famous. In the early 90-ties of the 19 c. he succeeded in getting Robert Koch to cooperate. A number of tuberculin inoculations took place at Slawiecice. Testing done on Duke Hohenlohe-Oehringen's cattle aroused considerable interest at home and abroad. Tuberculine testing fame influenced the Duke who donated a special centre for consumptive people (Lugenheilanstalt). Naturally it meant TB at the time was one of the very serious diseases of circulatory system. The centre remained an integral part of the Duke's hospital. The newly built centre, had special areas for deck chairs, climatic treatment and isolation of the sick. The surrounding woodlands drew the patients and helped the development of the lung centre. The Centre for Treatment of Lung Diseases at Slawiecice was one of the earliest of its kind within the borders of the then Prussia--Germany and all over the world. The scientific co-operation of Goetsch and Koch lasted till 1903 that is the former's death. An agreeable situation, the Duke's donations, the illness of his family member, the fame of Koch and the interest and tests of Goetsch all added up to setting up the hospital which has survived the two world wars and silesian uprisings. It took a century to change a panorama of lung diseases: in the first half of the 20 c. it was TB at present it is lung cancer, immunological diseases and anthracosis. PMID- 11619180 TI - [The construction of epidemic station in Leipzig until the beginning of the present century]. AB - Among three large medieval foundations: St George's Hospital (opened in 1212 as a shelter for the homeless and terminally sick), St John's Hospital (first mentioned as a leprosarium in 1278) and St James' Hospital (probably opened at the end of 15 c. as a shelter for the terminally sick) only St George's and St James' survived the changeable fortunes of Leipzig (though the latter was at a number of occasions destroyed and rebuilt at a different site). Particularly at the times of war and epidemics they were used as field hospitals. E.G. St James' since 1566 was used as a quarantine for the plaque victims. At the end of 19 c. Leipzig hospitals had practically no isolation wards. In 1871 as a result of small-pox, temporary building were constructed for infections patients moved later to St James'. The particular status of Leipzig as a trade, fair and transportation centre influenced a number of decisions concerning the prevention of epidemics whose introduction coincided with the state and land regulations dealing with observation of people suspected to be ill, isolating them and desinfecting objects of contact. The town archives disclose talks concering the construction of isolation stations at St James', in 1913 St George's was reopened. It had kept two buildings for the sick, mostly TB patients. PMID- 11619181 TI - [Spanish 'flu in Leipzig 1918-1920]. AB - Town archives enable reconstruction of an outbreak of a flu epidemic and its consequences for Leipzig in 1918 in 1919. First news of the 'Spanish disease' reaching Leipzig appeared in local press on 1st July 1918. The danger was on purpose underestimated not to upset the public and weaken its 'moral resistance'. Eventually because of parents' protests schools were closed at the end of October. The statistics and resources of the archives indicate 1409 persons dying between July 1918 and March 1919. Naturally the youngest and the oldest suffered most fatalities. The disease caused also interference in public life when a theatre and a number of public institutions were closed and public gatherings forbidden. PMID- 11619182 TI - [The fight against dysentery, typhus and typhoid by Polish underground between 1941-1944]. AB - Between 1941 and 1944 the Polish Home Army sanitary service was well prepared for the fight against infections diseases. The underground in so called General Government was both well organised and unimerous (nearly 350,000). The medical staff consisted of army doctors not taken prisoner, and civilians who as reserve officers were sworn to serve in the Home Army. Students from both elementary and secondary schools acted as undercover nurses having been prepared for the job by girl guides organisation. The main infections diseases were dysentery typhus and typhoid. Other diseases were rather rare during the World War Two. Since majority of population had been inoculated, the partisans needed only boosters. The typhoid spread in winters of 1941-42 and 1942-43 to the cast of the Vistula. Infections centres were isolated yet only the German part of population was inoculated by Weigl method. Since the vaccine was both expensive and hard to get only the Polish a staff officers of the Home Army and some doctors were inoculated. The epidemics of dysentery was particularly dangerous in August and September 1944 in the Kampinos Group during the Warsaw Uprising. In the barns of six villages in Kampinos there were 1190 sick partisans. Small amounts of medicines were parachuted by Polish Air Force from Italy. Therefor the chief medical officer recommended each patient drink a glass of bovine blood daily. This decreased mortality to nearly a zero. PMID- 11619183 TI - [Professor Dr Rudolf Weigl (1883-1957) and the activity of his typhus institute in Lvov between 1939 and 1944]. AB - Rudolf Weigl started his study on typhus fever still in time of the Ist World War, and developed them in 1920 as the member of Military Sanitary committee. The study has been carried out for all period of 20 years between the world Wars. As the greatest achievement of Weigl in field of microbiology there should be recognized the use for the first time a bacterial culture in a living organism, and then production of efficient typhus fever vaccine. Of great importance there was a production of vaccine for succeeding armies occupying Lvov; Soviet and German. Weigl's Institute was a harbour for numerous crowds of educated Poles, who--thanks to being employed at the institute--were protected against repressive measures from German invader. Occasionally the institut was supplying also Polish population with vaccines. PMID- 11619184 TI - [Little known activity of the Czestochowa typhus Institute in 1943 and 1944]. AB - In 1921 Prof. Rudolf Weigl started manufacturing on an industrial scale a typhus vaccine. Until the beginning of World War Two he organised five companies called Weigl Institute. During the Soviet occupation the Lvov plant became the Lvov Sanitary and Bacteriological Institute and after the town was taken over by the German Army on 1st July 1941, Prof. Weigl became a head of research of the Military Typhus Institute. It consisted of four sections for manufacturing the vaccine. All the produce was mainly despatched to the Russian front and only very little reached the civilians. In November and December 1943 the plant was moved to Czestochowa into a main building in Wilsona str. and two four storey others in Jasnogorska str. Its head became a German doctor Mozer (witness test). It is difficult to state numbers the plant employed there being no data left but according to employees still alive there must have been about a hundred lab. staff and two hundred feeders. The plant was divided into "breeding", "preparatory" and "liofilisation" sections. "The breeding" was for feeders and breeding lice. Cages containing about 30,000 lice were fastened to voluntary feeders for each feeding. Next "loaders" covered a so-called key board with 20 insects and infectors introduced and pressurised solution containing live rickets into a louse intestine. After a six or seven day passage, lice ware dried and their intestines prepared to produce liofilizeate all the staff and their families were inoculated. ... PMID- 11619185 TI - [Epidemiologic problems of Szczecin between 1945 and 1948]. PMID- 11619186 TI - Blood transfusion in peace and war, 1900-1918. AB - The practice of blood transfusion became commonplace in the first half of the twentieth century, a time that coincided with the practice of war on a hitherto unprecedented scale. A close examination of the process reveals that it was not a simple one of war acting as a stimulus to scientific and medical discovery. Most innovations had their origins in the United States before the war, whose main effect was to diffuse and perfect transfusion through greatly increased use of the technique. The result was that in less than twenty years blood transfusion changed from being a medical curiosity and procedure of last resort to a practical and relatively simple treatment that demonstrated its value in saving thousands of lives. PMID- 11619187 TI - Chasing the ambulance. The emerging crisis in the preservation of modern health records. AB - In this brief essay we argue that the best efforts of archivists, scholars, and practitioners within the National Health Service have not prevented the wholesale destruction of the bulk of patient records created during the twentieth century. This is a matter of vital concern not merely for historians of modern medicine. Important clinical work has frequently been undertaken on materials which have survived, usually by chance or by the foresight of physicians, matrons, and administrators. Even the significant fragments of historical documents which remain in the hands of the health authorities have been threatened by the continuing drive to reduce storage and maintenance costs within hospitals. Archivists and academics have struggled to address the problems of sampling, storage, and access which the enormous bulk of modern records present. In this essay we suggest that the first step must be to raise awareness amongst professionals and the public of the extent to which any future history of the medical services and of patient care will depend on a reasonable rate of survival of these records. The second step must be to confront the problem of resources and the inevitable task of selection which must form the foundations of any long term policy of preservation. An initial survey of archival materials in Devon indicates that the records of community health care form a substantial and potentially invaluable research source for future historians, though their relevance has rarely been recognized within the academic community. PMID- 11619188 TI - Getting out of the asylum: understanding the confinement of the insane in the nineteenth century. AB - This paper critically re-examines our assumptions about the social rule of asylums in the nineteenth century by separating the history of the confinement from the history of psychiatry. Rather than medical superintendents being central to the admission of patients, this paper will argue that control over confinement was predicated upon the desires of families to care for and control dependent and violent relatives. The confinement of the insane can thus be seen not as a consequence of a professionalizing psychiatric elite, but rather as a strategic response of households to the stresses of industrialization. The second part of this paper surveys changing approaches to the social history of the asylum and directs these techniques to a combination of institutional and non-institutional sources which will shed new light on the dynamic between informal patterns of family caring 'in the community' and formal medical treatment in purpose-built institutions. Having set out the methodological possibilities of using new types of admission records, the last section of this paper explores different approaches to the history of the family and applies them to the question of why the insane were confined. This will provide an analytical framework for understanding the interface between the family and the formal medical institution. Throughout, this paper draws on more than three dozen international studies to illuminate some comparative aspects of confinement in different national contexts. PMID- 11619189 TI - 'Sickness is a baffling matter'. A reply to James C. Riley. AB - This paper replies to the comments made by James C. Riley. It provides a defence of the assumptions adopted in 'Physician, heal thyself' (Social History of Medicine, 9(1996), 1-30) to estimate the average duration of work-preventing sickness experienced by members of the medical profession in England in the 1860s as well as offering some new estimates. It also provides further criticisms of Riley's contention that although the rate of mortality declined in England between the 1860s and 1890s that of morbidity increased, which is based on surveys of friendly society members. In doing so it reiterates the warning given by Jacques Bertillon in 1892 concerning the use of friendly society surveys for the measurement of variations and trends in morbidity patterns by age. PMID- 11619190 TI - Cape Town and 'country' doctors in the Cape Colony during the first half of the nineteenth century. AB - This paper argues that during the 'golden' age of medical reform in the first half of the nineteenth century in the Cape Colony there was significant differentiation within the medical profession which contributed to a slow and uneven process of professionalization in spite of comprehensive and early legal regulation under one licensing body. Differences in permitted practice, settlement patterns, economic and organizational opportunities gave doctors in Cape Town, the colony's biggest and most important city, greater incentives and more scope to develop professional regulation and organization than those in the rest of the colony. A government Ordinance passed in 1807 gave regularly-trained medical practitioners a legal monopoly over medical practice, but did not initially prevent those practising outside Cape Town from selling both medicines and medical advice. Cape Town doctors thus enjoyed greater social differentiation from tradesmen and better legal control over competition from druggists and 'irregulars' than country practitioners. The difference between practitioners in Cape Town and elsewhere remained important even after new regulations removed legal distinctions in 1830. While country practitioners now sought tighter regulation over permitted practice they could not easily make common cause with the more powerful professional medical elite in Cape Town. This elite group had vested social and economic interests in maintaining their privileged status within the Cape profession, especially when threatened by local recession and political and economic competition from Eastern Cape doctors in the 1850s. PMID- 11619191 TI - Dying with style: infant death and its context in a rural industrial township 1650-1830. AB - The literature on the demographic impact of rural industrialization in England has lagged somewhat behind continental inspired historiography. Nowhere is this more apparent than in the sphere of infant mortality, where commentators have failed to balance the effects of rural industry on health and welfare--such as higher earnings and the existance of more dense kinship networks--with the negative effects--proximity of rural industrial areas to rapidly growing towns, poor public health and rapidly increasing population density. Using the results from a very detailed analysis of a proto-industrial township in the West Riding of Yorkshire between 1650 and 1830, this article contends that rural industrial areas had a distinctive experience of infant mortality. In line with much of the existing literature on England, rates of infant mortality in this township were modest. However, concentration on bald figures without wider contextualization, masks the fact that infant mortalitiy visited itself most intensely on a narrow range of families and a narrow range of spatial areas. Those most susceptible were in-migrants living on common land, and the wider linkage of family reconstitution data to poor law evidence suggests that the defining characteristic of concentrated infant mortality was recurrent parental illness, leading to inadequate child care and breast-feeding. PMID- 11619192 TI - Professionalization in public health and the measurement of sanitary progress in nineteenth-century England and Wales. AB - During the course of the nineteenth century, the Registrar-General's Office in England and Wales used crude mortality rates as a demographic barometer of the environmental conditions of towns and cities. The local authorities in places with comparatively high rates were exhorted to improve them through more and better public health reforms. This technique of public coercion was often criticized, especially by a selection of Medical Officers of Health, who argued that crude death rates were an inaccurate measure of changing mortality levels and thus the success of preventive medicine. The debate over sanitary progress created no little tension between staff at the General Register Office and the Medical Officers, as well as between the Medical Officers themselves, at a time when public health doctors were seeking to properly establish themselves as a legitimate, professionalized branch within medicine. Despite this, the collection and dissemination of local mortality statistics became an indispensable component for the nineteenth century campaign to improve the nation's health. PMID- 11619193 TI - Other than healing: medical practitioners and the business of life assurance during the nineteenth and early twentieth centuries. AB - The purpose of this paper is to explore briefly the nature, development and implications of the relationship between medical practitioners and life assurance companies. The aim is to elucidate the development both of the medical profession and the life insurance business--two important aspects of economic and social change in the nineteenth and early twentieth centuries which are usually treated separately. The focus is primarily, though not exclusively, on Scottish companies as they carried out a disproportionately large amount of the UK life assurance business by the mid-nineteenth century. The insurance industry's increasing, and increasingly systematic, tapping of medical expertise enabled it to raise profits by reducing losses on standard policies and by venturing out into types of business previously thought too risky. While nineteenth-century medical therapeutics may have left much to be desired, medical involvement in insurance suggests that medical practitioners were by no means ineffective. At the same time, a substantial proportion of the medical profession gained valuable part time appointments which helped to alter the diagnostic techniques of the profession more generally. Thus insurance turns out to be an especially important element in the 'non-healing' aspects of medicine, with spin-offs for the healing side as well. PMID- 11619194 TI - David Hartley's psychobiological associationism and the legacy of Aristotle. AB - The idea that there are certain "laws" of learning (similarity, contrast, contiguity) can be traced to Aristotle. He maintained that external stimuli cause small movements in the vessels to the dominant heart, the vestiges of which can be linked to one another. Aristotle's laws of learning were incorporated into the writings of Hobbes, Locke, and Berkeley, men who said nothing about the physiological correlates of mental associations. This left the door open for David Hartley to combine mental associationism with the Newtonian idea that sensations can cause minute particle vibrations in the nerves. Hartley's amalgam of psychology, philosophy, and neurology was first presented in 1746, as a "trial balloon" at the end a little-known monograph on a treatment for kidney stones. It was repeated three years later in his better-known Observations on Man. In many ways, modern psychobiological connectionism can be traced back to Hartley's Conjectures of 1746, in which Aristotle's original thoughts were modified with then current ideas about functions of the mind and the nervous system. PMID- 11619195 TI - The legacy of the Wernicke-Lichtheim model. AB - Wernicke established an integrated model of the relation between higher cognitive functions and neurophysiological structure of the human brain in 1874. The previous Bouillaud/Broca view envisaged a mosiac map of centres for specific functions, each of which had no clear inter-relation with other centres or with input/output pathways, and with no theoretical explanation of how each centre operated in relation to more basic neural elements. Wernicke's model overcame these objections, and, with Lichtheim's systematization in 1885, the "Wernicke Lichtheim model" became the standard neuropsychological theory. In this model, each normal higher function is explained in terms of an underlying neural pathway that includes the input/output systems, related functions employ portions of the pathways used for other functions, pathological syndromes are explained by reference to where in the pathway damage occurred, and previously unobserved pathological syndromes can be predicted. Development of the model at the hands of Lissauer, Dejerine, Liepmann, Geschwind, Heilman, and Ellis and Young is traced. PMID- 11619196 TI - George III: a revised view of the royal malady. AB - George III of England's episodic psychotic illness is described. The data has previously been used to substantiate the diagnosis of an unlikely hereditary metabolic disease, porphyria. A scientific perspective, aimed at removing psychiatric diagnosis from dependence on subjective evaluations, is corrected by the diagnosis of a mood disorder. His unipolar mania of late onset is a syndrome, the sine qua non of bipolar disorder, in this instance complicated by the toxicity of quinine, antimony, and purgatives. PMID- 11619197 TI - George Sigerson: Charcot's translator. AB - Senator George Sigerson (1836-1925), Dublin's first neurologist, was also a significant contributor to Anglo-Irish literature. His medical career and literary accomplishments are outlined, the focus of the article being Sigerson's friendly relationship with Charcot (with whom he corresponded), and whose Lecons sur les maladies du systeme nerveux he translated. PMID- 11619198 TI - Does bromide cause conversion of epilepsy to psychosis? AB - The aim of this study is to find out whether bromide was able to cause conversion of epilepsy to psychosis i.e., so-called paradoxical normalization such as has been seen in treatment with modern antiepileptic drugs. Spontaneous conversion has been known for three hundred years. Locock introduced bromide in the treatment of epilepsy in 1857. Belgrave wrote in 1868 on its effect on epileptic attacks and concommitant insanity. In 1868 Holm observed reduction of the frequency of seizures at the same time as psychotic symptoms or just dysphoria. In 1875 Voisin described a dose-dependent intoxication with psychosis and/or neurological signs. Stark in 1875 and Bannister in 1881 were the first to clearly describe the antagonism between epileptic seizures and psychotic symptoms, an antagonism or conversion described by many authors, both in cases with high and low dosage, and with and without intoxication. Thus, the title of this paper should be answered in the affirmative. Bromide has been used as a sedative and has rarely caused intoxication. Thus the presence of epilepsy is not a condition for the development of bromide intoxication. A case with epilepsy and fatal massive bromide intoxication is reported. It is discussed whether the pathological findings give support to Wolf's hypothesis of latent epileptic activity in subcortical pathways during "normalization". PMID- 11619199 TI - Neurological concepts in archaic Greece: what did Homer know? AB - There are few written records which tell us about Archaic Greek thought and certainly no medical writings. The earliest notions about neurologic matters can be found, however, in the Homeric epics. The attitudes and information which made up the culture of the Archaic Greeks were the starting point from which the later Greek medical literature grew. Although the Odyssey and Iliad are not medical texts, they contain many neurologic descriptions which can be analyzed to reveal the knowledge and concepts which were held by the people in Archaic Greece. By knowing the beginnings of the ancient medical traditions one is better equipped to understand the later works written specifically about medical matters. PMID- 11619200 TI - Neurosurgical treatment for tetanus. AB - Soon after the discovery of the tetanus antitoxin, animal experiments led to the conclusion that intracerebral injection of the antitoxin would be useful in the treatment of tetanus. The French surgeon Quenu carried out the first injection and gave a description of the neurosurgical technique required. The method was applied in other European countries until it was declared to be less efficient than simple subcutaneous or intravenous injections. Outside Europe, intracerebral injections of tetanus antitoxin were reported and photographed in Montevideo, Uruguay, in 1901. PMID- 11619201 TI - A neolithic case of Down syndrome. AB - The aim of the study is to draw attention to the existence of a Neolithic figurine from Greece with characteristics compatible with Down syndrome. We have reviewed the relevant medical and archaeological literature, and we have compared photographs of the figurine with photographs of a patient with typical Down syndrome (DS). From the above data we conclude that the 7000 years old artefact may well be the most ancient representation of the disease in Western civilisation. PMID- 11619202 TI - The place of clinical trials in the development of psychopharmacology. PMID- 11619203 TI - The scientific origins of electroconvulsive therapy: a conceptual history. PMID- 11619204 TI - The American Psychiatric Association, 1844-1994: international perspectives. PMID- 11619205 TI - On the symptomatology of left-sided temporal lobe atrophy. Classic Text No. 29. (Translated and annotated by D.M. Girling and G.E. Berrios.) PMID- 11619206 TI - The survival of the ritualistic over the 'scientific' element of hydrotherapy in Greece. AB - In this paper we present some elements of the history of 'scientific' psychiatric hydrotherapy and, moreover, of a particular form of the water-purifying ritual- that is, foot washing--among the populations living in Greece and in Orthodox communities in the Balkans. We speculate on the reasons that caused the virtual disappearance of the former, while the latter still flourishes. PMID- 11619207 TI - The psychological treatment of insanity in France in the first part of the nineteenth century. PMID- 11619208 TI - Psychosurgery and the child prodigy: the mental illness of violin virtuoso Josef Hassid. PMID- 11619209 TI - The origins of psychosurgery: Shaw, Burckhardt and Moniz. AB - The concepts and techniques involved in the origins of psychosurgery during the late nineteenth century are analyzed, particularly in the work of Claye Shaw and Gottlieb Burckhardt. It is shown that their views and therapeutic behaviour were guided by scientific, ethical and social warrants not dissimilar from those of today. The debate that followed their work can thus be considered as a trial run to that elicited by the work of Moniz. This paper focuses on the work of Shaw, Cripps, Tuke and Duncan for, until now, it has not featured in any history of psychosurgery. From the point of view of the history of science, their work is important, for it relates to the debate on brain localization, neuronal circuits and the neurobiological representation of mental illness that took place at the dawn of the twentieth century. Nothing is said on the history of psychosurgery subsequent to the work of Moniz. PMID- 11619210 TI - Use of physical restraints in a nineteenth-century state hospital. AB - Archival records of physical restraint usage at the St. Louis Insane Asylum (now the St. Louis State Hospital) were examined from January through June 1885. The demographics of restrained patients were determined from archival admission records. In the 6-month (181-day) sample period, 53 patients accounted for the total of 2,537 incidents of night restraint. Sixty percent of the restrained patients were women and 53% were immigrants. By far most (98.5%) of the incidents of restraint were brought on by violent behaviour (fighting, destroying property, injury to self) while most incidents in modern hospitals result from verbal threats or shouting. When these records were combined with day restraint records from the same 6-month period in 1889, an overall incidence rate of 9.7% per month was estimated. This is similar to rates reported from modern psychiatric hospitals. Possible reasons for the discrepancies and similarities in the types of patients restrained and the activities which brought on restraint in the nineteenth and twentieth centuries are discussed. PMID- 11619211 TI - [Galen, the solitary master]. PMID- 11619212 TI - [Malaria and car accident at Beit-Mery]. PMID- 11619213 TI - [A description of false croup]. PMID- 11619214 TI - Arab contribution to medicine. PMID- 11619216 TI - [Histoire de la greffe de la cornee]. PMID- 11619215 TI - [Laveran, or the origin of parasitology]. PMID- 11619217 TI - [Breast cancer surgery]. PMID- 11619218 TI - [Amputation is the only treatment for joint wounds]. PMID- 11619219 TI - Phoenicia and the alphabet. PMID- 11619220 TI - [Pere Cattin's diploma]. PMID- 11619221 TI - [Pierre-Paul Emile Guigues, professor at the faculty of medicine in Beirut (1868 1930)]. PMID- 11619222 TI - [Al-Zahrawi]. PMID- 11619223 TI - [Cauterization: a therapeutic weapon which is forgotten today]. PMID- 11619224 TI - [Hippollyte de Brun, professor at the French faculty of medicine in Beirut (1885 1931)]. PMID- 11619225 TI - [The history of constipation and the constipated]. PMID- 11619226 TI - [The clinical chart for whooping cough]. PMID- 11619227 TI - Pioneers of Arabian medicine. PMID- 11619228 TI - [Les debuts de la medecine au Liban]. PMID- 11619229 TI - [The scientific works of Henri Chaoul (1887-1964)]. PMID- 11619230 TI - Henri Chaoul, from Deir-el-Kamar to the University of Berlin. PMID- 11619231 TI - [Theriac: a panacea]. PMID- 11619232 TI - [Georges Mauric, professor at the faculty of medicine in Beirut]. PMID- 11619233 TI - [The first description of an occupational cancer in 1777 (scrotal cancer, cancer of chimney sweeps)]. PMID- 11619234 TI - The humoral doctrine. PMID- 11619235 TI - [Rescuers in the seventeenth century and respiratory resuscitation]. PMID- 11619236 TI - [Students of medicine during the renaissance]. PMID- 11619237 TI - [A letter: Apropos of "Malaria and car accidents in Beit Mery"]. PMID- 11619238 TI - [An animal that moves inside a woman's body]. PMID- 11619239 TI - [Histoire de l'ophtalmologie]. PMID- 11619240 TI - The golden era of Arab medicine. PMID- 11619241 TI - [Intimate care among renaissance ladies]. PMID- 11619243 TI - [La medecine a Beyrouth a l'epoque ottomane]. PMID- 11619242 TI - [A displaced liver is not a serious matter]. PMID- 11619244 TI - [Family medicine, 1850-1950]. PMID- 11619245 TI - [The story of the mummy, or the adventures of the heart of Louis XIV]. PMID- 11619246 TI - [Jean Senac, father of cardiology]. PMID- 11619247 TI - [A history of hemorrhoids]. PMID- 11619248 TI - [To those good at dictation]. PMID- 11619249 TI - [L'operation de la cataracte]. PMID- 11619251 TI - [Women in medicine]. PMID- 11619250 TI - [The Kennedy assassination: doubts and certainties around an autopsy]. PMID- 11619252 TI - [The treatment of a pneumonia 100 years ago]. PMID- 11619253 TI - [The history of eyeglasses and contact lenses]. PMID- 11619254 TI - Coming to grips with the limitations of science: infertility and heredity in American history. [Reviews of: Marsh M; Ronner W. The empty cradle: infertility in America from colonial times to the present. Johns Hopkins University Press, 1996; and Paul DB. Controlling human heredity: 1865 to the present. Humanities Press, 1995]. PMID- 11619255 TI - The defining historical divide. [Review of Markowitz G and Rosner D, Children, Race, and Power; University Press of Virginia, 1996]. PMID- 11619256 TI - Kuhn--the conservative and radical interpretations: are some Mertonians 'Kuhnians' and some Kuhnians 'Mertonians'? PMID- 11619257 TI - Thomas S. Kuhn (18 July 1922-17 June 1996). PMID- 11619258 TI - The mortality crisis of 1623 in north-west England. PMID- 11619259 TI - Computerising the 1861 census abstracts and vital registration statistics. PMID- 11619260 TI - American ecologists: a biographical bibliography. AB - This paper includes sources of published biographical information on about 575 identified ecologists. There are over 2,400 references cited, providing a wealth of material covering the lives and work of ecological practitioners. Entries range from very short notices of death to somewhat longer obituaries and "Resolutions of Respect" to book-length biographies and autobiographies. The bibliography is alphabetical by individual, while referenced sources are alphabetical and thence chronological. It should be useful to historians, ecologists and historians of science, including biographers, as an entry into the voluminous literature on the development of ecological science. PMID- 11619261 TI - X-rays; a chance observation. PMID- 11619262 TI - 28th International Congress on the History of Veterinary Medicine, Vienna/Austria, October 16th-19th, 1996. PMID- 11619263 TI - Leslie G. Matthews. 30.11.1897 - 24.2.1997. An appreciation. PMID- 11619264 TI - The laboratory and stocks of the Society of Apothecaries: the making of medicine over 250 years. PMID- 11619265 TI - In service of economy and science: hospital pharmacy in Heidelberg throughout history. PMID- 11619266 TI - [Public health and medical corps in transition: the case of Crete at the beginning of the 20th century]. AB - This article deals with the transformation of the public health system in Crete at the turn of the century, when the island was placed under the protection of the European Powers. Cretan archives, especially those from the town of Rethimno, provide a wealth of information on this subject. They show that the new ruling powers, with the declared objective of safeguarding their soldiers, required local authorities to keep a close watch over epidemics, indeed to lock up populations considered dangerous for public health, such as lepers and prostitutes--who did not fail to put up a strong resistance. While providing equipment for hospital facilities, which were still primitive, the Powers also introduced legislation concerning the practice of medicine, from which Muslim Cretans were gradually excluded. The rate at which medical care was provided increased markedly at the beginning of the twentieth century, in particular in the principal towns. The Rethimno notarial archives reveal that this new and well qualified medical corps belonged to the world of prominent citizens, and while ministering to the town's health needs, they held considerable political and economic power. PMID- 11619267 TI - [Bernard Lepetit (1948-1996): a eulogy]. PMID- 11619268 TI - Population decline and plague in late medieval Norway. AB - Norwegian scholars have engaged in considerable research over the last half century in an attempt to assess the impact of the Black Plague of 1349 on population and society in Norway. Evidence has been put forward relating the incidence of plague to a continuance of population decline over the two centuries following its initial introduction. Estimates of population decline in Norway between 1350 and 1550 indicate a reduction by as much as 65%. Two directions of study have emerged, one concentrating on land abandonment known as the "Odegard Project." The other is represented by the recent works of Ole Jorgen Benedictow presenting epidemiological and osteo-archaeological research. An examination of the available literature raises questions concerning the degree to which plague, and its recurrence, directly affected population decline in Norway during the Late Middle Ages. While evidence of the virulence of the plague and the degree of farm abandonment is compelling, a direct relationship to population decline may not be as great as implied by the research. Other explanatory factors, especially social and economic responses to plague, have been given limited attention. PMID- 11619269 TI - Population increase policy after the 1783 great famine in northeastern Tokugawa Japan. AB - During the Tokugawa Period, northeastern Japan has been thought one of the poorest region in the country for the population had been decreasing for over 100 years as early as the 18th century. In particular, farmers had been severely affected by several famines, especially in 1783. I have reevaluated the social and economic situation after 1783 by investigating the details of the in migration plan. The in-migration plan in the study area was not a kind of welfare policy to relieve farmers affected by the 1783 great famine, but evidence shows the beginning of a proto-industrialization. The demand for female labor to produce hemp cloths increased rapidly from the beginning of the 19th century. Women who were good at weaving were invited as brides. PMID- 11619270 TI - Mexico's other wars: epidemics, disease, and public health in Guanajuato, Mexico, 1810-1867. AB - "Mexico's Other Wars" refers to the fight against disease, particularly epidemic disease, during the period when Mexico gained its independence and was involved in the very conflictive process of nation-building, from 1810-1867. Controlling and eradicating disease was an integral part of that process. In this period, fighting disease assumed the crucial political purpose of making all people healthier as one means of building an economically productive civil society. To attain this goal, early nineteenth-century local policy makers organized an increasingly secular and integrated public health system governed by municipal and state officials who legislated local public health regulations. While disease was not eradicated, the incidence and severity of epidemics decreased and likely contributed, as one of many factors, to population increase. This process was evident in the city and state of Guanajuato, the focus of this paper, for Guanajuato's population almost doubled in this period despite war and intermittent armed conflict. PMID- 11619271 TI - [Public health statistics in the Soviet Union in the 1920s: international cooperation and national tradition in a post-revolutionary framework]. AB - In October 1929, a two-man delegation (a social hygienist and a sanitary statistician) went to Paris to participate in the meeting of the International Institute of Statistics called to consider revisions of the Bertillon classification of the causes of illness and death. The Soviet delegates were demonstrably eager to be considered part of the international scene in public health statistics. But they came to Paris with a radical proposal to replace the locationist system of classification with one that gave clear primacy to the principle of social etiology. This paper examines the assumptions about public health statistics, about the international area, and about their own indigenous tradition in public health, that underlay the Soviet proposal. On the basis of this particular case, the paper raises questions about the factors that favor the adoption of one system of statistical classification as opposed to others and about the general problem of studying "internationalism" in public health. PMID- 11619272 TI - Germs of disaster: the impact of epidemics on Japanese military campaigns in Taiwan, 1874 and 1895. AB - This essay highlights the ways in which epidemics shaped Japanese military campaigns in Taiwan in 1874 and again in 1895, as well as subsequent colonial policy after 1895. I have focused on these particular campaigns because a vast body of source materials exists which allows us not only to understand the diseases which ravaged the Japanese forces, but also to determine their effects on particular battles and subsequent Japanese military, foreign and colonial policy. For example, during the 1874 campaign in the southern tip of Taiwan, of the approximately 5,990 men at risk, only 4 soldiers were killed in battle, while 20 succumbed to battle wounds and other injuries. In contrast, 547 men died of disease, particularly malaria. During the 1895 campaign, the Japanese force of just over 50,000 men suffered horrific losses due to epidemics, with 4,642 soldiers dying of diseses as opposed to 164 killed in battle and 515 wounded or injured. Although the Japanese quickly won the war against the resistance forces, their battle against Taiwan's epidemics had only just begun, as thousands of Japanese soldiers and civilians perished during the first ears of the Japanese Occupation era (1895-1945). The Japanese soon realized that they would have to solve Taiwan's public health problems if they were to have any hope of effectively governing their new colony. As a result some of the first regulations of the colonial government concerned sanitation and quarantine measures. All in all, Japanese colonial policy and its colonial modernization of Taiwan appear to have been significantly shaped by fear of the island's epidemics and the need to bring them under control. PMID- 11619273 TI - [Mortality in Galicia, 1600-1850]. AB - The author's goal is to determine the influence of the death rate on the demography of Galicia, a region located in the north-west of the Iberian peninsula, during the Ancien Regime. From this viewpoint, he examines the general characteristics of mortality as well as the chronology, intensity and nature of the different waves of mortality from 1600 to 1850. He also presents a rough outline of the fall in Galicia's death rate, by comparing the results obtained at various levels with those from other regions of Spain as well as Europe. This paper is meant to complement the efforts of all researchers interested in the "geography of death" in modern Europe. PMID- 11619274 TI - [Differences between town and country and evolution of mortality in Germany during industrialization]. AB - Traditionally cities and towns in historical Europe were perceived as being particularly unhealthy. Terms like 'le handicap urbain' or 'urban penalty' have been introduced in order to emphasize the high death rates in the fast-growing industrial towns of nineteenth century Europe, which significantly exceeded the average rates for rural areas or the whole country. A rising population density was ideal for the transmission of the prevailing infectious diseases. This paper assesses urban and rural mortality change in Imperial Germany, when the country was going through a process of accelerated industrialization and urbanization. It provides an analysis of changes in age-, sex- and disease-specific mortality in urban and rural Prussia. In general, urban mortality in Germany reached its peak after the middle of the century, thereafter urban mortality improved substantially in relative as well as in absolute terms, the gap between urban and rural mortality narrowed and finally disappeared entirely. The largest cities registered the strongest decline in mortality. Obviously they had the potential to overcome the threats of disease or death, and became forerunners of improved health conditions in modern industrialized societies. An analysis of the mechanisms of mortality change in an urban environment during industrialization in the late nineteenth and early twentieth centuries can therefore serve as a paradigm for conditions in highly urbanized industrial societies. PMID- 11619275 TI - [Spatial and ethnic differentiations of infant mortality: Quebec 1885-1971]. AB - The aim of this paper is to present an overview of the evolution of Infant Mortality in Montreal and in the whole Province of Quebec, from 1885 to 1971, and to highlight factors which may have determined the differential decline during this period. Based on civil registers, quality and fiability of the results are first discussed. Compiling statistics on infant mortality was of great importance in so far as it enabled hygienists to justify baby welfare clinics and county health units. In Montreal, cultural context showed a powerful influence on infant mortality: more French Canadian infants died in their first year than in British and the Jews. Between 1920 and 1930, infant mortality rates in the Canadian metropolitan area declined in rural areas of the Province. After this period, these rates have declined even more rapidly. PMID- 11619276 TI - [Saugrain's censuses: genesis of a hypothesis]. AB - Many historians of population have tried to determine the origins of the population statistics published in the Denombrement du Royaume (1709) and in the Nouveau Denombrement du Royaume (1720) by Claude Saugrain. J. Hussenet provides new developments; his main document is a manuscript kept in the Senate arkivs listing, at the time of Regency, more than 38,000 french settlements classified. The Dictionnaire geographique du Royaume de France seems to be the copy of a much older book commissioned by the Controle general des Finances. Claude Saugrain may have used it for his publication of 1709 and to a smaller extent for the one of 1720. A close examination of this document shows that the Controle general concern was to evaluate rather count the population. PMID- 11619277 TI - [Understanding migratory phenomena: mobility within a village in Herault from 1836 to 1962]. AB - Using a previous reconstitution of families living in the village of Puechabon (Herault) and twenty-three lists of its inhabitants from 1836 to 1962 as a base, the author has analyzed the migrations of the villagers according to sex, marital status and age group while distinguishing two types of migration: actual departures and entries (permanent or long-term departures, and entries by newcomers or those returning after prolonged absences), and short-term absences and subsequent returns. Using this typology, he brings out three periods of migration for the village residents: before the War of 1870, there were traditional movements; between 1870 and World War II, a pronounced rural exodus occurred; and since then, there has been a less striking but more regular decline in population. PMID- 11619278 TI - [The fecundity of immigrants to Argentina, the French of Tandil, 1860-1914]. AB - Based on the reconstitution of families of French immigrants who settled in Tandil (Buenos Aires) during the great wave of immigration, this article examines the migrants' fertility. Legitimate births, descendants, proto and intergenesiacal intervals as well as the maternal ages at the final delivery are successively analyzed. The results are then compared with data gathered in the French regime from which the immigrants came. The application of the method perfected by Louis Henry makes possible a micro-discussion of certain hypotheses connecting the demographic transition in Argentina with the arrival of European immigrants. The article's main findings are that there was no voluntary birth control among the immigrants and the determination of their birthrate, which was midway between that existing in their native regions in France and that of the local population in Argentina. PMID- 11619279 TI - [History and demographic systems]. AB - Is it possible to describe the past evolution of populations by using the notion of system? This article shows that three obstacles arise: the disciplinary stricture, that is, the artificial isolation of demographic phenomena cut off from the political and economic phenomena on which they depend; the spatial stricture, that is, the delimitation of a given zone, quite often a village or small town, which means excluding readjustments, by migration; and, finally, the confusion of scales, that is, the passing from an individual level ("micro") to a collective one ("macro"). Given these obstacles, the few systems proposed are severely limited. An example of this limitation is given with the model called self-regulating, which is disturbed when mortality diminishes. Hence, we propose a more modest vision of demographic systems. PMID- 11619280 TI - [Regionalization of the total mortality of young girls in Belgium between 1890 and 1910]. AB - In this article we describe the evolution of mortality and differential mortality between the sexes in Belgium from birth till the 20th birthday during the period 1890-1910. Excess female mortality occurred especially between the ages of 5 and 20 and had a favourable development during the period of observation: in 1910 the phenomenon was not as general as in 1890, but it still existed in 21 of the 41 districts, with variable intensity. Excess female mortality declined more rapidly in the South than in the North of the country. We noted on the other hand that the intensity of the phenomenon was not related to the level of mortality: tuberculosis, a related cause to excess female mortality, dropped clearly during this period, consequence of better working conditions and a better standard of living. The analysis of excess female mortality in areas with a different system of production showed the importance of the position of girls (and boys) in the production process towards the explanation of the spatial variation of excess female mortality. The female disadvantage was most important in rural and textile areas due to the intensity and the nature of the labour of girls in these regions. PMID- 11619281 TI - [Territorial jurisdiction of sanitary risk and demographic statistics: the "tuberculous buildings" of the unhealthy block of Saint-Gervais (1894-1930)]. AB - The assumption of contagion is often employed as an argument for the demarcation of areas considered dangerous to public health. This article examines how it was used in the case of the insalubrious district of Saint Gervais (Paris). The district was identified thanks to statistics available from the health records of Parisian apartment houses, which have been kept since 1894. The author's main concern is the existence of "maisons meurtrieres (deathtraps) denounced by contemporary documents although deaths from tuberculosis were progressively decreasing. The examination of statistics giving the number of inhabitants and fatalities from tuberculosis in each apartment building shows that, with the exception of those with furnished rooms, only a small proportion of these dwellings actually had a high death rate from tuberculosis between 1894 and 1930. It also shows that the delimitation of the insalubrious area was based on the idea that the illness was irreversible, allowing the "deathtraps" discovered in earlier stages to be added to those found in each subsequent check. This method made it possible to designate "infected districts" and to justify a policy of city planning. PMID- 11619282 TI - [The legend of 150,000 deceased from tuberculosis per year]. AB - This article analyzes the stages by which it was concluded that there were 150,000 deaths from tuberculosis in France at the end of the nineteenth century. The calculations made by Brouardel are broken down and the inappropriate nature of some of his choices is pointed out. In addition to these oddities in calculation, the contemporary social and political factors warrant our attention. The estimation can also be explained by the growing fears regarding demographic and social perils. Did not tuberculosis and the falling birth rate jeopardize all hope of taking revenge on Germany? In fact, the "enemy" had decided to undertake a vast program for the construction of sanatoriums, thus tempting the French public health authorities to use the figures to mobilize the attention of the public and politicians. In the collective imagination, tuberculosis and its 150,000 fatalities replaced the great epidemic of the nineteenth century, cholera, whose most destructive appearance in 1854 killed precisely 150,000 persons. In spite of the more probable estimation from the statistical services (fewer than 100,000 deaths), this figure of 150,000 deaths from tuberculosis was revived in the period between the World Wars and again in the last decade by certain historians, which proves that it became engraved in memory. However, from the turn of the century, and especially between 1918 and 1940, the proponents of these numbers have admitted that they used them to influence opinion. Here we have an excellent example of a dual language: depending on where he was speaking, the same scientist of political authority could simply double the estimations of mortality from tuberculosis. PMID- 11619283 TI - [The evolutionary threshhold of age from old age: comparative approaches in France and Sweden]. AB - The major criticism to be made concerning studies of ageing populations is that the threshold chosen as the entry into old age has remained fixed. However, in recent years, the realities of the age at which one becomes elderly have changed so much that persons in the category "over 60", for example, no longer occupy the same place in the succession of generations, the same economic and social roles as their not so distant forefathers. In particular, they no longer have the same life expectancy or the same state of health. Therefore, how are we to understand and interpret the growing proportion of older persons in our populations? To get out of this impasse, this article presents one possibility for determining an evolutionary threshold--it is one of the conditions of the comparison-- for entry into old age. It depends on the state of health of the persons concerned at each stage. This synthetic indicator has been applied in the French and Swedish populations since the mid-nineteenth century. The results underline the extent of the changes that have occurred, especially in the twentieth century, the closeness of the thresholds between the two countries at the beginning and end of the period, as well as the differences in the progress of masculine life expectancy. Although the proposed indicator can certainly be improved, it emerges strengthened by this comparative approach. PMID- 11619284 TI - [Evolution of the curves of total survivorship, without chronic illness and without incapacity in France from 1981 to 1991: the application of an OMS model]. AB - In 1984, World Health Organisation (WHO) has proposed a demo-epidemiological model which allows the assessment of the possible consequences of the lengthening of life on the level of health. This model is represented in a graphic form by three curves: the observed survival curve, the hypothetical survival curve without chronic diseases and the hypothetical survival curve without disability; thus, as life expectancy at any age is calculated from the survival curve, this model allows the computation of life expectancy without chronic diseases and life expectancy without disability. The relationships between the three curves, can be used to illustrate the numerous theories dealing with the evolution of the populations' health which enliven debates in public health since several decades. Application of the model to French data on mortality, morbidity and disability also allows to enlighten the evolution of the health status of the French population over the last decade. PMID- 11619285 TI - Royal charters and veterinary statutes. PMID- 11619286 TI - The deadly bite of ancient animals: written evidence for rabies, or the lack thereof, in the ancient Egyptian and Mesopotamian texts. PMID- 11619287 TI - The development of a livestock industry in Kenya. PMID- 11619288 TI - The struggle for the charter of the Royal College of Veterinary Surgeons, 1844. PMID- 11619289 TI - The death of William Youatt. PMID- 11619290 TI - [The origin and development of the herbal gardens of the Owari clan]. AB - The early herbal garden of the Owari Clan was called Ofuke-Oyakuen. By careful reading of the "Illustration of the Honorable Herb Garden (OYakuen no Zu), it is pointed out that this garden might have been opened around 1562 when 39 species of herbs granted by Shogun Iemitsu were planted. This garden was enlarged in about 1684. We found that the well-known "Honorable Illustration of Former Herb Garden (Moto-oyakuen On-ezu)" was a drawing of a part of this enlarged herbal garden. On the other hand, in 1735 a new herbal garden, Oshitayashiki-oyakuen was opened for cultivation of Panax Shinseng. While this garden produced fair results at Panax cultivation, it was closed in 1869 at the Meiji Restoration. In the last days of the Tokugawa regime, herbalists of this garden had made original advances in natural history. PMID- 11619291 TI - [Caspar Schamberger und die 'Caspar-Chirurgie' (2)]. PMID- 11619292 TI - [The disputes in the Nippon Medical School Foundation and the coming into being of the Tokyo Medical School]. AB - The Nippon Medical School Foundation was an institution that developed after the closing of the Saiseigakusha Medical School, inheriting the spirit of the latter. During the period extending from 1912 to May 1916, the Ministry of education remained reluctant to approve of the Foundation as a Ministry-designated institution. Actively lobbying the Ministry were people such as Tatsukichi Irisawa, a member of the "Meiji Society of Medicine", a partisan clique of the University of Tokyo Medical School. Meanwhile within the Foundation itself, an internal strife took place between the Directors Kenzo Isobe and Taketaro Takizawa, which brought about its disintegration and collapse from within. Some four hundred and fifty students lodged their petition for official approval, sealed with blood, to the School authorities and to the Ministry. Having their petition for approval rejected, all these four hundred and fifty odd students withdrew from the School and founded within the building of the Tokyo Physics School a 'Tokyo Medical Training School'. Some forty students who did not withdraw, in collaboration with members of the teaching staff, re-established the Nippon Medical School Foundation. PMID- 11619293 TI - [Medical and pharmaceutical tales recorded in "Genroku- Sekenbanashi-Fubunshu"]. AB - "Genroku-Sekenbanashi-Fubunshu" consists of eleven volumes and was written from 1694 to 1703, in the Edo Period. The original book was kept at the Faculty of Literature, Tokyo University. In 1994, this book was first published as one of the Iwanami-Bunko Series. I studied the tales recorded in this book and found that twenty-seven of them were concerned with medical and pharmaceutial sciences. In these medical and pharmaceutical tales, there were several kinds, relating to such matters as spells to cure or prevent illness, curious sicknesses, episodes regarding the origin of remedies, medicinal plants and crude drugs, medical books, doctors and surgeons, persons who lived long, and so forth. It was difficult to explain about the spells which were thought effective to cure illness, but I could gain an understanding that Japanese people lived such lives in the old days. PMID- 11619294 TI - [The village of a fable on cinchona, chinchon and the Countess of Chinchon]. PMID- 11619295 TI - [The historical materials about the medical system of the Edo Shogunate (8)]. PMID- 11619296 TI - A short history of the British army veterinary services. PMID- 11619297 TI - Lieutenant-General Sir Frederick W J Fitzwygram Bart MP JP FRCVS. PMID- 11619298 TI - Some memories of service with the RAVC 1944-1947. PMID- 11619299 TI - A history of the Royal Army Veterinary Corps 1961 to 1996: some thoughts and an appeal. PMID- 11619300 TI - An introduction to veterinary militaria of the British Empire. PMID- 11619301 TI - Milton and two Italian humanists: some hitherto unnoticed neo-Latin echoes in In obitum procancellarii medici and In obitum praesulis eliensis. PMID- 11619302 TI - Sterne and The history of cold-bathing. PMID- 11619303 TI - Swine fever in Cricklade, 1888. PMID- 11619304 TI - A closer look--Herbert Watkins-Pitchford, CMG, FRCVS, FRSE. Paradoxical veterinary surgeon. PMID- 11619305 TI - Remarks on the history of demodecid mites. PMID- 11619306 TI - The Weybridge Veterinary Laboratory during the Second World War. PMID- 11619307 TI - The Marti Pumarola's notebook: a clinical and pharmacological approach to 19th century veterinary activity. PMID- 11619308 TI - Tropical zoonoses, veterinary zoonoses, and evolutionary patterns of disease. PMID- 11619309 TI - [Spread of Hanaoka's method of general anesthesia with Mafutsu-san: a discussion of surgical operations by Sanai Hashimoto]. AB - It had been generally accepted that Hanoaka's secretiveness was the most contributory factor in preventing his method of general anesthesia with Mafutsusan from becoming wide spread in Japan. However, the author found several cases of the use of general anesthetic according to his method in various areas in Japan. For instance, Doryu Mikami, a surgeon of the Tsugaru feudal clan entered Hanaoka's school to study his medicine for several years and came back to Tsugaru to perform an amputation of the nose of a young lady with syphilis in about 1864. Hanaoka's method of general anesthesia was also practised safely in the Saga area of Kyushu even in the year of about 1900. The author studied in detail two cases of surgical operation under general anesthesia performed by Sanai Hashimoto, a physician of the Fukui feudal clan. One case was an amputation of the penis but no further detailed information was given to us. The other was an excision of the breast cancer of Toko Yoshida's wife. Yoshida was Hashimoto's teacher of Chinese literature. The operation was successful and the patient was reported to have survived three years after the operation. These facts strongly suggest that the method had been transmitted and practised in many districts in Japan by many disciples of his school. However, such cases have not been reported in detail. Thus the widely rumoured evaluation of Hanaoka's secretiveness is incorrect. PMID- 11619312 TI - [The disputes in the Nippon Medical School Foundation and the coming into being of the Tokyo Medical School (1)]. PMID- 11619313 TI - Caspar Schamberger und die Caspar Chirurgie (1). PMID- 11619316 TI - [A study on "Kyo gige" or "Jing Yijie" mentioned in the Ishinpo]. AB - The Ishinpo written in 984 is the oldest extant medical work in Japan. In this work a unique sequence of characters, [Japanese characters] (Kyo gige in Japanese, Jing Yijie in Chinese) followed by the character [Japanese character], which usually indicates a citation, can be found only once in vol. 25 of the Nakarai-MA [Japanese character]. That is why it has been regarded as a cited book title until now. However, there were no books with the title [Japanese characters] before the time of the Ishinpo. The authors therefore tried to make a historical investigation into this phrase. The following results could be found: (1) The phrase in question has to be seen as one unit together with the last character of the former line [Japanese character] and should be read as [Japanese characters] (Myakukyo Gige in Japanese, Maijing Yijie in Chinese). (2) There are no books extant with the title [Japanese characters], and we see no possibility that such a book might have been written before the time of the Ishinpo. (3) The most possible reason why the phrase [Japanese characters], which is not a book title is given only here is miscopy and mispagination. Originally, there must have been two separate citations, one from [Japanese characters], an annotated book to the Maijing [Japanese characters], and the other from [Japanese characters], a shortened name of the Ryo-no Gige [Japanese characters]. As a result of miscopy and omissions, [Japanese characters] were finally combined to [Japanese characters]. (4) The sentence [Japanese characters] which follows the phrase [Japanese characters] may be a missing part of the [Japanese characters]. (5) There is a possibility that the [Japanese characters] might have been the Maijing Yinyi written in China, or any other unknown book written in Japan. PMID- 11619318 TI - [A historical survey of diphtheria in the Western World, China and Japan. Part II: Modern age (from sixteenth century to the beginning of nineteenth century)]. AB - In Europe and North America, literatures on diphtheritic diseases was increasing from sixteenth to eighteenth century. In New England of North America, diphtheria and scarlet fever occurred epidemically in mingled form from 1735 to the succeeding year. Thereafter, many physicians in Europe and America treated patients of diphtheria and had different opinions about the nature of croup and diphtheria. In China, its own clinical medicine progressed extraordinarily during the modern age. Laryngeal specialists appeared and wrote special monographs about the pharynx and larynx. A physician wrote about "epidemic exanthem", which the author presumes to be a complicated form of scarlet fever and diphtheria. In Japan, diphtheria occurred in sporadic form usually, and in epidemic form occasionally. Japanese physicians studied medicine from China since the ancient age, and also introduced European medicine through the Netherlands in the eighteenth century. So Japanese physicians learned knowledge about throat diseases and diphtheria from Chinese and European medicine. PMID- 11619320 TI - [The statue, tomb and Hebrew name of Moses Maimonides]. PMID- 11619321 TI - Robert Paul Hanson: May 14, 1918 - July 27, 1987. PMID- 11619322 TI - Federick Seymour Hulse: February 11, 1906 - May 16, 1990. PMID- 11619323 TI - Leon Orris Jacobson: December 16, 1911 - September 20, 1992. PMID- 11619324 TI - Choh Hao Li: April 21, 1913 - November 28, 1987. PMID- 11619325 TI - Kenneth Stewart Cole: July 10, 1900 - April 18, 1984. PMID- 11619326 TI - Efraim Racker: June 28, 1913 - September 9, 1991. PMID- 11619327 TI - Harry Lionel Shapiro: March 19, 1902 - January 7, 1990. PMID- 11619328 TI - Alfred Gilman: February 5, 1908 - January 13, 1984. PMID- 11619329 TI - Keith Dalziel: 24 August 1921 - 7 January 1994. PMID- 11619330 TI - Harry Harris: 30 September 1919 - 17 July 1994. PMID- 11619331 TI - William Hayes: 18 January 1913 - 7 January 1994. PMID- 11619332 TI - Donald Olding Hebb: 22 July 1904 - 20 August 1985. PMID- 11619333 TI - Sir William Drumond Macdonald Paton, C.B.E.: 5 May 1917 - 17 October 1993. PMID- 11619334 TI - Linus Carl Pauling: 28 February 1901 - 19 August 1994. PMID- 11619335 TI - Charles Garrett Phillips: 13 October 1916 - 9 September 1994. PMID- 11619336 TI - Claude Rimington: 17 November 1902 - 8 August 1993. PMID- 11619337 TI - Salimuzzaman Siddiqui, M.B.E.: 19 October 1897 - 14 April 1994. PMID- 11619338 TI - Hugh Blaschko: 4 January 1900 - 18 April 1993. PMID- 11619339 TI - Patrick Christopher Steptoe, C.B.E.: 9 June 1913 - 22 March 1988. PMID- 11619340 TI - Richard Laurence Millington Synge: 28 October 1914 - 18 August 1994. PMID- 11619341 TI - David Whitteridge: 22 June 1912 - 15 June 1994. PMID- 11619342 TI - From victim to witness: the solution of a medieval medical mystery. PMID- 11619343 TI - Selections from the case-books and diaries of Dr J B S Greathead MB MC (Edin.) MRCS (Eng.) Part II. PMID- 11619344 TI - Philatelic history of diabetes. PMID- 11619345 TI - Sanatorium of the south? Public health reform in Tasmania 1880 to 1914. PMID- 11619346 TI - An oral history (O-H) study of the development of the health service in the ACT over the last forty years, via its retirees. PMID- 11619347 TI - The early history of Canberra Hospital (1914-30). PMID- 11619348 TI - The Cumpston years in Western Australia. PMID- 11619349 TI - The introduction of insulin to Australia. PMID- 11619350 TI - Keeping in touch. PMID- 11619351 TI - 'From the other side: the patient experience of outpost medicine in New Guinea during WWII.' PMID- 11619352 TI - Towards a new historiography of psychiatry. PMID- 11619353 TI - A sharp distinction between mind and body: the debate over neurophysiological implications of guillotining in late eighteenth century France. PMID- 11619354 TI - Dr William Ernest Jones, psychiatrist. PMID- 11619355 TI - "The 'Arab' contribution to the history of psychiatry". PMID- 11619356 TI - Edinburgh medical notebooks of a Castlemaine general practitioner. PMID- 11619357 TI - Outpost pharmacy. PMID- 11619358 TI - Find the founder. PMID- 11619359 TI - 'The history of the present': nursing and critical historiography. PMID- 11619360 TI - Nursing in the outposts: resources for a historian of nursing. PMID- 11619361 TI - What is scientific evidence?: Sister Kenny, American doctors and polio therapy, 1940-1952. PMID- 11619362 TI - In defence of an outpost of Empire: Sister Radcliff goes to Gallipoli. PMID- 11619363 TI - The life and times of Dr Charles Thelander (1883-1959). PMID- 11619364 TI - John William Springthorpe - a remarkable physician. PMID- 11619365 TI - Thomas Young Cotter - colonial surgeon - South Australia - success or failure? PMID- 11619366 TI - Dr John Coverdale (1814-1896): the last civil commandant and medical officer of the convict settlement of Port Arthur (1873-1877). PMID- 11619367 TI - A century of infant feeding in the United States and New Zealand. PMID- 11619368 TI - Metaphorical dimensions of childhood autism. PMID- 11619369 TI - An obstetric and gynaecological historical resource in Sydney - the Benevolent Society Gordon Bradley Lowe Collection. PMID- 11619370 TI - Rhesus rescue - three successful pioneering attempts to save infants with haemolytic disease of the newborn. PMID- 11619371 TI - Chiron and chirurgery: the sympolism of the centaur in medicine. PMID- 11619372 TI - The other side of the coin. PMID- 11619373 TI - A question of diligence: the first ten years of death registration in Darwin. PMID- 11619374 TI - Plevna Ryan - a Melbourne surgeon to the Turks. PMID- 11619375 TI - Medical men in Tasmania 1803-1870. PMID- 11619376 TI - The Asclepian tradition in ancient Greek medicine. PMID- 11619377 TI - Dr T.P. Lucas and the papaw - "The most wonderful tree in the world". PMID- 11619378 TI - A rare oral source of early c17th century domestic herbal medicine. PMID- 11619379 TI - Antisepsis crosses the Tasman, both ways. PMID- 11619380 TI - The Chinese and public health in Bendigo 1854-1916. PMID- 11619381 TI - Outpost medicine in the mining industry. PMID- 11619382 TI - "Oral history" - memorials to three pioneer Australian dentists. PMID- 11619383 TI - Blood clots: the nineteenth-century debate over the substance and means of transfusion in Britain. AB - Historians have devoted little attention to blood transfusion in the nineteenth century. In part, this neglect reflects the presentist assumption that, before Karl Landsteiner's discovery of blood types, this practice would have failed too often to gain currency. Yet, transfusion was in fact the subject of much debate, and was actively practised, primarily by obstetricians on haemorrhaging women. Examining this practice through the conceptual lens of 'blood clots', both as noun and as observation, I follow transfusors' assumptions about the nature of the blood and the problem of its coagulation. Tracing the medicalization of ideas about blood by the century's end, I map this shift onto changing notions about why transfusion was performed, what substance was best employed, and what instrument best fitted that substance's movement into the circulation. In this way, 'Blood Clots' reconstructs the discourse surrounding transfusion, extending that discourse to material culture in order to illuminate the rationale that guided transfusion's practice in nineteenth-century Britain. PMID- 11619384 TI - Frederick Pavy (1829-1911) and his opposition to the glycogenic theory of Claude Bernard. AB - For more than 50 years the Guy's Hospital physician Frederick Pavy (1829-1911) attempted to discredit the theory of his erstwhile teacher, Claude Bernard, that liver glycogen was broken down to supply sugar to the systemic circulation. His opposition was driven by his clinical perceptions and was based on two assumptions: the first was that the kidney was a simple filter through which small molecules would diffuse, so that sugar had to be prevented from reaching the systemic circulation. For Pavy, the liver was the barrier. The second was teleological: he could not believe that nature would operate in what he saw as a defective way, i.e. converting sugar into glycogen and then back again. At the beginning of his long working life Pavy regarded himself as a physiologist and was critical of the stagnancy of English physiology which was kept afloat by amateurs like himself in whatever time they could spare from busy private practice. At the end he came to see his own view of carbohydrate metabolism as symbolic of the schism between responsible clinicians (himself) and irresponsible daydreaming physiologists (his opponents). PMID- 11619385 TI - Hot heads and cold brains. Aristotle, Galen and the "radiator theory". AB - The Author examines two similar theories about the functioning of human brain as a refrigerator: Falk's and Fialkowski's (1990) and Aristotle's (IVth century b.C.). There are surprising, although fortuitous, convergences between the two, with the remarkable difference, however, that Artistotle's doctrine (later severely criticized by Galen) thinks of the brain merely as an organ for the cooling of the body's (the heart's) heat, while according to the modern radiator theory the human brain developed starting as a refrigerator of itself. PMID- 11619386 TI - [Not Available]. PMID- 11619387 TI - [Not Available]. PMID- 11619388 TI - [Not Available]. PMID- 11619389 TI - Pollution in Poullaouen. PMID- 11619390 TI - Atmospheric pollution and the British copper industry, 1690-1920. PMID- 11619391 TI - A medico-historical review of Arjuna AB - Ancient Indian Medical knowledge known as Ayurveda goes back to a immemorial past. The Vedas and Puranas refer various materials of medical importance including herbs, plants and trees etc. The ancient medical scientists have mentioned the properties of the Arjuna, and recommended mainly for the management of Hirta/Rudhira vikaras, Vrana, Prameha, Visa Vikaras, Asrugdhara, Kshetriya/Shukra dosha etc. The modern medical/Botanical scientists have also carried out so many researches on Arjuna and do not find any difference with the ancestery knowledge. PMID- 11619392 TI - Using sociological concepts in the study of Indian medical systems: medical system, role & profession. AB - Now-a-days there is renewed interest all over the world in the medical systems other than modern medicine, identified as 'alternative' or 'conplementary' medicine. Research on these medical systems of India, as well as of other Asian societies continues to thrive. In this study, efforts has been made to place these systems in a frame work using the tolls of sociology. The research undertaken encompassed more than this, private clinics and the government hospitals of these systems in Hyderabad and miscellaneous, clinics, such as bone setters also. PMID- 11619393 TI - A brief history of Indian alchemy covering transitional and tantric periods (circa 800 A.D.-1300 A.D.). AB - A brief history of Indian alchemy covering the pre-vedic, vedic and Ayurvedic periods (Circa 4000 B.C. to 800 A.D.) was given in one of the previous issues of this Bulletin, i.e. Volume 23, NO.2, July, 1993, pp. 151-166. In continuation of the same, this article is presented here, giving an account of the development of the chemical knowledge in India during transitional and tantric periods (circa 800 A.D. to 1300 A.D.). PMID- 11619394 TI - One hundred fifty years of Osmania Medical College (1846-1996). AB - The Hyderabad Medical School which came into existence in 1846 A.D. was the fore runner of Osmania Medical College. The medium of instruction was Urdu the degree was Hakeem. Last two decades of nineteenth century was the glorious period of this school. Seventh and the last Nizam of Hyderabad Nawab Mir Osman Ali Khan established Osmania University in 1919 A.d. and in the following year the Hyderabad Medical College. In 1957 A.D. Hyderabad became the Capital of enlarged Andhra Pradesh. Tremendous zeal and enthusiasm was evident to achieve alround progress in medical education. PMID- 11619395 TI - Khadira (Acasia Catechu Linn.) - A medico-historical review. AB - Indigenous Medical wisdom in India known as Ayurveda goes back to a hoary past. We find references in Vedas not only to medical science but to various drugs also. The medico-historical review of Khadira (Acasia Catechu linn.) including the historical perspectives, identity, varieties, formulae and therapeutic usage etc. is presented here, based on the classical treatises, medical lexicons, commentaries and other compilations, covering the from Vedic period to present times. PMID- 11619396 TI - Lesser known Ayurvedic physicians of India from an Urdu book- "Rumoozul Atibba". AB - In early 20th century some Urdu scholars tried to enrich urdu literature with medical history. They started compiling and publishing the biographies of the contemporary physicians along with their achievements. One of such works "Rumoozul Atibba" a rare book compiled by Hakim Fairozuddin in Urdu, published by 'Darul Kutub Rafiqul Atibba' and printed in 'Rifah-e-Aam Press' at Lahore in the year 1913 A.D. has been taken here. It contains about 150 short biographies of Ayurvedic and Unani physicians, out of which all the twenty biographies of Ayurvedic physicians given in it, have been presented in this article. PMID- 11619397 TI - Preparation of ethereal oils (Al-Duhoun) by Ibn Al-Quff (13th century A.D.). AB - Ibn Al-Quff was born in Damascus. He learned medicine from Ibn Abi Usaibia. Ibn Al-Quff was excelled in medicine as well as in Surgery. He wrote several books, of which was "Al-Qumdah" (The Authority on Surgery). Another book was "Al-Shafi" (The Healer) on medicine. In the book "The Authority on Surgery", Ibn Al-Quff has devoted a special chapter, on the preparation of ethereal oils, which was commonly known as Al-Duhoun. He has described about 34 different oils together with their medical action. PMID- 11619398 TI - Abul Fatah - a commentator of "Al-Qanoon". AB - The Commentator of "Al-Qanoon" (Canon of Avicenna) Abul Fatah known as "Maseehuddin" also was a native of Gilan. He migrated to India during Akbar's period (1556-1605 A.D.). The emperor honoured him by confering Sadarat of Delhi, Malwa and Gujarat and bestowed upon him the title of Hasht Sadi. His commentary on the Canon is known as "Fatahi", in which he explained various problems elaborately. He was well versed in anatomy and connoisseur of Prose and Poetry. He had made a good change in Huble-Buble and he was the first who had made the inhailing of smoke less harmful. He died on 20th June, 1580 A.D. PMID- 11619399 TI - Hunain bin Ishaq on opthalmic surgery. AB - Hunain Ibn Ishaq was a doyen in the field of medicine during the Arab era of Unani medicine, and made significant contributions in ophthalmic surgery by adding new therapeutic uses and techniques. He established the opthalmic surgery on sound systemic footing. His earliest work on the subject may not be ignored by historians. PMID- 11619400 TI - Aristotle's ethical theory & modern health care. AB - The Greek physician of antiquity - Hippocrates (460-356 B.C.) is called the Father of Modern Medicine and the Hippocratic Oath to which doctors of modern medicine traditionally and formally express their allegiance, forms the basic foundation of medical ethics. The tradition of Western ethical philosophy began with the ancient Greeks. From Socrates (469-399 B.C.) and his immediate successors, Plato (427-347 B.C.) and Aristotle (384-322 B.C.), there is a clear line of continuity, through Hellenistic period (from the death of Alexander the Great (323 B.C.) to the end of Ptolemic dynasty (30 B.C.) and the Roman annexation of Egypt - broadly post-Aristotelian and medieval thought to the present day. But the society has qualitatively and quantitatively changed since the Industrial Revolution in the late 18th and 19th centuries. Society, today, is just a collection of discrete individuals, each with his or her own purposes and interests. Hence it has become almost imperative to apply the principle of autonomy to issues in the ethics of health care. The aim of this short essay is, therefore, an attempt to explore the relevance, if any, of Aristotelian ethical theory to the modern health care. PMID- 11619401 TI - Skin diseases - management with reference to Ranbir Prakash. AB - A reliable estimate is that one in twenty people has a skin disease. The quest for health which started with the advent of man on the horizon of this universe is still continuing. Such an attempt was also made during the reign of Maharaja Ranbir Singh of Jammu & Kashmir, when "Ranbir Prakash" a compendium of different. Ayurvedic texts came into existence. In the present paper it is tried to bring forth the different therapeutic regimens for the management of different skin afflictions described under Kushtha roga in the "Ranbir Prakash". PMID- 11619402 TI - Embryology in Holy Bible. AB - The knowledge of Embryology and its existence dates back to the remote antiquity of mankind. The theory of maternal impressions on Embryo has its sanction in the Holy Bible. Apart from this it is remarkable to find artificial incubation of the eggs of birds practised 'probably' as far back as about 3000 B.C. Other than these, the existence of midwives, cases of premature births, deliveries of the women of advanced age and the obstetric chair etc. are the expositions of the science of medicine in the Holy Bible. PMID- 11619403 TI - Dr. Edward Lawrie's remarks on the findings of Hyderabad chloroform commissions in his annual report of 1303 Fasli. AB - This article is a re-presentation of the important remarks of Dr. Edward Lawrie with regard to the Chloroform Commissions as found in the administrative report of the Nizam's Government for 1893-94. It seems that these remarks might have been presented by Dr. Lawrie to the Nizam's Government in the form of an annual report in 1303 Fasli. Though these findings were later proved to be wrong, but the value of Dr. Lawrie efforts will remain as a landmark in the history of medicine. PMID- 11619404 TI - Eugenics and rural development: the Vermont Commission on Country Life's program for the future. PMID- 11619405 TI - Long-term mortality patterns in Chinese history: evidence from a recorded clan population. AB - Human populations have lived on the earth for millions of years, yet the study of population history only began to be established in the mid-twentieth century. In spite of the considerable progress in the study of historical demography which has since been made, there have been hardly any detailed studies of fertility and mortality before the sixteenth century. This study, by analysing a set of Chinese genealogies, examines long-term mortality patterns in a selected clan population over a period of more than 1000 years. The result shows that, in this selected population, mortality fluctuated around a relatively high level and showed no secular change over the very long period studied. The study also provides a comparison between the mortality patterns found in the selected population and those observed in a much larger Chinese lineage population, as well as those recorded among the British elites born between the sixteenth and the early nineteenth century. Based on the findings of this research, the paper presents some tentative suggestions about long-term mortality changes in Chinese history. PMID- 11619406 TI - Remarks on Raphael's Transfiguration. PMID- 11619407 TI - Chimo: an unusual form of tobacco in Venezuela. PMID- 11619408 TI - Medical attendance in Vancouver, 1886-1920. PMID- 11619409 TI - Stereotypes and Scottish witchcraft. PMID- 11619410 TI - Notes on GW 272 and 273. PMID- 11619411 TI - An inter-disciplinary approach to African-American medicinal and health practices in colonial America. PMID- 11619412 TI - Experiences and voices of eugenics field-workers: 'women's work' in biology. AB - Experiences and ideas of eugenic 'field-workers' offer a new historical perspective on American eugenics, while highlighting terms of women's early twentieth-century scientific education and research employment. To advance knowledge of heredity, the US Eugenics Record Office (ERO), between 1910 and 1924, trained 258 students (85% of them women) to collect information about individuals, families and communities. Though some historians have dismissed eugenic field-workers as careless or uncritical, many had scientific or medical backgrounds, and took research seriously. While gendered expectations and other obstacles limited women's hopes for professional advance, the female field workers created a strong community and culture of their own. Comparing notes, some recognized that their results did not support eugenic assumptions, and cautioned against letting enthusiasm overwhelm scientific integrity. These women field-workers raised serious questions about methodology and ethics, but the situation of eugenics work at the time undermined chances for such criticism to be acknowledged. After World War I, military-related research and political manoeuvring dominated eugenics, further marginalizing field-workers. Ironically, while ERO head Charles Davenport had wanted students to promote eugenics, some demonstrated more fundamental commitment to scientific ideals--but to little avail. PMID- 11619413 TI - Leonhart Fuchs on the importance of pictures. PMID- 11619414 TI - Descartes on love and/as error. PMID- 11619415 TI - Kaleidoscoping public understanding of science on hygiene, health and plague: a survey in the aftermath of a plague epidemic in India. AB - In September 1994 a plague epidemic hit a number of cities in India. Though the spread of the disease was controlled within a short period of about one month, its influences on various channels of information, on the functioning of government departments (especially health and sanitation), on the scientific community and on people's scientific information level were remarkable. This paper analyzes the responses of 1127 individuals interviewed in December 1994. The data indicates high levels of informedness about health, hygiene and plague, with little reference to extra-scientific explanations of the causes of the epidemic. Respondents expressed a high degree of confidence in the modern system of medicine. From this analysis we also infer that the public could not be described as 'superstitious', 'unscientific' or 'unhygienic': only when denied access to information and civic amenities did they show extra-scientific thinking or 'unhygienic' behaviour. PMID- 11619416 TI - Skirts in the lab: Madame Curie and the image of the woman scientist in the feature film. AB - Recent research has appropriately emphasized the significant role played by feature films in the creation (as well as the reflection) of popular stereotypes of the scientist. However, no particular study has yet been devoted to the depiction of women scientists in the cinema, even though it is quite clear that this presents its own distinctive features. Taking the influential Madame Curie (Mervyn LeRoy, 1943) as a starting point, this paper attempts to give a first overview of the subject. PMID- 11619417 TI - [Two unedited letters from Baron Louis Suetin: their significance in the biography of a surgeon (1816-1817)]. AB - The author reveals and comments two letters written by the surgeon Louis Seutin and discovered in 1994. They were sent in February 181 6 and July 1817 to lieutenant Ferdinand Doignon, a native from Tournai. Circumstances which created Seutin's friendship for lieutenant Doignon in 1813, during the campaign of Saxony of the Great Army, are described. These two letters are different by their tone. Consideration is given to the periods and places in which they were written. Their significance in Seutin's biography is enlightened through explanatory comments. PMID- 11619418 TI - Goiters in the Renaissance. AB - Enlargements of the thyroid gland known as goiters appear in artworks and artifacts of many cultures. They are represented in sculptures, bas-reliefs, masks, waxes, mosaics, bronzes, stained glass windows, paintings and drawings of the last two millennia. These are described in several monographs and in Merke's scholarly History and Iconography of Endemic Goitre and Cretinism (Barbieri 1993, Gianpalmo and Fulcheri 1988, Gianpalmo 1992, Medvei 1982, Merke 1984). Most numerous among these works are the portrayals of goiters in paintings and drawings of the Renaissance. This essay lists eleven additional Renaissance artworks in which goiters are represented, as well as reviewing reasons for this occurrence and examines the unusual case of Piero della Francesca. PMID- 11619419 TI - Pieter Van Foreest, the Dutch Hippocrates. AB - This year, 1997, marks the 400th anniversary of the death of Pieter Van Foreest (1521-1597) in his native town of Alkmaar. This 16th century physician trained at the universities of Leuven, Padua, Bologna, and Paris. He was town physician in Alkmaar for 12 years and then in Delft for 40 years. The Prince of Orange was one of his patients. On 8 February 1575 he was present, as Professor of Medicine, at the opening of the University of Leiden. His international reputation was based on his Observationes, a large collection of annotated medical case histories. In his therapeutic approach to patients, Van Foreest showed himself to be a typical 'Hippocratic' physician. PMID- 11619420 TI - [Anselme Boece De Boodt (1550-1632), gem cutter and physician to Rudolph II]. AB - Anselme-Boetius De Boodt was born in Bruges. He had already finished his studies of the law, when he became interested in medicine and later was appointed physician to the Emperor Rudolf II. He was the author of a treatise on mineralogy: Gemmarum et lapidum Historia (1609) in which he still expressed his belief that gems have therapeutic as well as other marvellous virtues. He felt he had personal proof as "the turquoise he wore on his finger preserved him several times from injury." PMID- 11619421 TI - 250 years of military dermatology: the British Army experience. AB - The British Army has encountered significant morbidity due to skin disease from the eighteenth century to the present time. The young age and pre-deployment screening of soldiers coupled with adverse environmental conditions produce a predominance of infective and eczematous conditions. The dermatologist still has a significant contribution to make in keeping the individual soldier healthy. PMID- 11619422 TI - Chemical dissection and the ethics of preclinical science. AB - It is my contention in this paper that the bioethical landscape is closely linked to the model of health and disease with which we work, as scientists or as medical practitioners. The Human Genome Project is the logical extension of the dissection process, which has constituted the history of medical science. It is already revealing an ethical minefield which may result in harming the very people we need to serve. Adoption of more holistic models of health and disease would counter the reductionist drift into eugenics, and would place the practice of medical science more humbly within a wider context, as the servant of the patient, rather than as the sole arbiter of health and social aceptability. PMID- 11619423 TI - The case of E. O. Brown. PMID- 11619424 TI - Premarital pregnancy in America, 1640-1971. PMID- 11619425 TI - Elizabethan birth control and Puritan attitudes. PMID- 11619426 TI - The origins of the birth control movement in England in the early nineteenth century. PMID- 11619427 TI - Coding categories for the study of child-rearing from historical sources. PMID- 11619428 TI - An economic model of family planning and fertility. PMID- 11619429 TI - Infant mortality trends and capitalist development in Brazil: the case of Sao Paulo and Belo Horizonte. PMID- 11619430 TI - Puerto Rico: a case study of population control. PMID- 11619431 TI - "Perish Judah": Nazi Extermination Propaganda 1920-1945. PMID- 11619432 TI - The long Victorian sunset: anthropology, eugenics and race in Britain, c1900-48. PMID- 11619433 TI - Dr. Med. Friedrich Ludwig Liesching. PMID- 11619434 TI - Edward Stone (1702-1768) and Edmund Stone (1700-1768): confused identities resolved. PMID- 11619435 TI - The miracle of vaccination. PMID- 11619436 TI - On the usefulness of the history of science for scientific education. PMID- 11619437 TI - Emotion as an explanatory principle in early evolutionary theory. PMID- 11619438 TI - A failure to flourish? David Yellowlees and the Glasgow School of Psychiatry: Part 1. PMID- 11619439 TI - Depersonalization: a conceptual history. AB - As with other clinical phenomena, the historical analysis of the term, concepts and behaviours involved in the construction of 'depersonalization' should provide researchers with an essential frame for its empirical study. Before the term was coined in 1898, and under a variety of names, behaviours typical of 'depersonalization' were reported by Esquirol, Zeller, Billod, and Griesinger. The word 'depersonnalisation, derived from a usage in Amiel's Journal intime, was first used in a technical sense by Ludovic Dugas. The new disorder has since been explained as resulting from pathological changes in the sensory system, memory, affect, body image and self-experience. During the 1930s, evolutionary views became popular, particularly in the work of Mayer-Gross. The unclear conceptual boundaries of depersonalization still invite confusion and often enough fragments of what used to be its core-behaviour are used to diagnose the disorder. Depersonalization has of late become subsumed under the dissociative disorders. The definitional instability of the latter, however, has caused further complications to the study of depersonalization. It is recommended that the term is used to refer only to the original core-behaviour as this has shown adequate stability. PMID- 11619440 TI - Norway: water and class in nineteenth-century psychiatry. AB - Water has long been considered an effective means of therapy for mental disorders. Its use, however, was divided along class lines during the nineteenth century. After presenting a brief background of the general conditions of the insane in Norway around the mid-nineteenth century when modern psychiatry entered the scene, I will present some examples of developments in hydrotherapy- fashionable bath resorts for the rich, and the use of prolonged baths as coercive treatment for asylum paupers. PMID- 11619441 TI - The development of institutional care for 'idiots and imbeciles' in Scotland. PMID- 11619442 TI - French psychiatrists on the causes of madness, 1800-1870: an ambiguous attitude before an epistemological obstacle. AB - Modern psychiatry was born in the late eighteenth and early nineteenth centuries. At that time French psychiatrists had much to learn. One of their interests was in recognizing the causes of madness which they divided into physical and moral. This article aims to describe this moment in the history of medicine and to demonstrate how ancient ideas were reworked by these alienists. Above all it is argued that alienists struggled with a kind of disease that was regarded as unacceptable at the time. PMID- 11619443 TI - Charles Blondel and La conscience morbide. PMID- 11619444 TI - Bewitched, bothered, and deluded: a maddening pursuit of the insanity defence. [Review of: Robinson DN. Wild beasts and idle humours: the insanity defense from antiquity to the present. Harvard University Press, 1996]. PMID- 11619445 TI - The Cross of Lorraine and TB stamps. PMID- 11619446 TI - Beecham, Bonnington, Mcbean Stewart and advertisement stamps. PMID- 11619447 TI - Suicide amongst the agricultural sector in Ireland; 1982-1994. AB - A large number of suicides (20%) which occur in Ireland are amongst the agricultural sector. Statistical records were examined and suicide fatalities amongst the agricultural sector identified and collated. Significant differences (X2, p=0.01) were found between the marital status, methods employed and age profiles of both men and women involved within the agricultural sector as compared with suicides as a whole over the same time period. Such information may be relevant to future suicide prevention strategies. PMID- 11619448 TI - Picking up Galen: James Joyce in Cecilia Street. AB - James Joyce (1882-1941) registered as a student of the Catholic University Medical School, Cecilia Street, in 1902. His attendance in November was brief; by early December, Joyce was in Paris. A recently-acquired Guide for Medical Students, a booklet compiled by Ambrose Birmingham, dean of the Cecilia Street school, sheds light on this hitherto obscure episode. PMID- 11619449 TI - The source of the bile: the legacy of Mathias Mockel. PMID- 11619450 TI - The halakhic definition of death in light of medical history. PMID- 11619451 TI - The rabbinic conception of conception: an exercise in fertility. PMID- 11619452 TI - David Patey, surgeon and academic: a memoir. PMID- 11619453 TI - Joseph Everett Dutton (1874-1905): pioneer in elucidating the aetiology of west African trypanosomiasis. PMID- 11619454 TI - William Gilbert (1544-1603): physician and founder of electricity. PMID- 11619455 TI - Thomas Jefferson and medicine. PMID- 11619456 TI - Worms, diabetes and King Herod the Great. PMID- 11619457 TI - The Museum of the History of Medicine, Paris. PMID- 11619458 TI - Steps in the career of A V Waller. PMID- 11619459 TI - The mythical "arms" of John Hunter. PMID- 11619460 TI - Sir William MacGregor - a frustrated doctor? The correspondence of Sir William MacGregor with Sir Ronald Ross. PMID- 11619461 TI - "La cendrillon des sciences": toward the professionalization of veterinary medicine in eighteenth- and nineteenth-century france. PMID- 11619462 TI - The emergence of veterinary instruction in the German language area; a preliminary typological study. PMID- 11619463 TI - Cultural roots and socio-political climate of the Italian veterinary schools from their origins (1769) to the Italian unification (1861). PMID- 11619464 TI - Foundation of the danish veterinary school in Copenhagen in 1773 and a short history of its development until 1851. PMID- 11619466 TI - The beginnings of veterinary education in the Ukraine. PMID- 11619465 TI - The beginnings of the veterinary schools in Spain. PMID- 11619467 TI - The incubation and the foundation period of the veterinary school at Utrecht, The Netherlands, 1796-1821. PMID- 11619468 TI - An attempt to summarize and to compare. PMID- 11619469 TI - Lyon, the cradle of veterinary training and of veterinary sciences. PMID- 11619470 TI - Elias Metschnikoff, Anton Dohrn, and the Metazoan common ancestor. PMID- 11619471 TI - Wilhelm Roux: visionary with a blind spot. PMID- 11619472 TI - The exclusion of minor malformations in the study of mutation in the offspring of survivors of atomic bombs: methodological, not sociopolitical, rationale. PMID- 11619473 TI - The implausibility of Mendel's theory before 1900. AB - Attention is paid to the category of the plausibility of Mendel's terminology in formulating the research problem, in describing experimental model and research method and in explaining his theory in the historical context of the long lasting enigma of generation, hybridization and heredity. The new research problem of heredity derived from the enigma of generation was plausible for the sheep breeders in Brno in 1836-1837 who also formulated the research question: what and how is inherited? But they did not find an approach to the experimental investigation. Later in 1852 the research problem of heredity was formulated by the physiologist of the Gottingen University, R. Wagner, who also outlined the method of crossing animals or artifical fertilization of plants for the investigation of the enigma of generation and heredity. But he could not carry out the recommended experiments at the University. His proposal remained without echo. Mendel first mentioned the motivation for his research arising from plant breeding experience and then from the experiments with plant crossing by botanists. He delivered his lectures in Brno to the community of naturalists, who paid attention to the appearance of hybrids in nature, but were not interested in plant breeding. After describing research model and experimental method Mendel presented the sequence of hypotheses proved in experiments and explained the origin and development of hybrids and at the same time also the mechanism of fertilization and of transmission of traits, what was heredity without using the term. The listeners of his lectures and later the readers of his paper did not understand his explanation. ... PMID- 11619474 TI - The Czech cytologists F. Vejdovsky, B. Nemec and V. Ruzicka, and Mendelism in the Czech Republic. AB - Czech scientists accepted Mendelism mostly without great excitement and casually. More important discussions were connected with the cytological foundations of heredity. Worth mentioning is the contribution of three leading Czech cytologists at the turn of 19th and 20th centuries: the zoologist F. Vejdovsky, botanist B. Nemec and physician V. Ruzicka. PMID- 11619475 TI - The propagation of Mendelism in Bulgaria. AB - The rise of genetics in Bulgaria is connected with the work of M. Popoff from the Sofia University that was a center of Bulgarian studies into heredity and variation. M. Popoff's studies in Drosophila and D. Kostoff's research into Nicotiana were threatened by the conflict with Lysenkoist teaching on the inheritance of acquired characters. PMID- 11619476 TI - Bioethics and the problem of natural teleology. AB - In this paper it is argued that a re-evaluation of a teleological philosophy of nature is necessary because, first, the acceptance of natural theology would be in more accordance with the position of (teological) (wo)man as a natural product of a natural evolutionary process and, second, it seems to be a prerequisite for the formulation of an adequate bio- und eco-ethics which stresses the "intrinsic value" of nature. PMID- 11619477 TI - Nurses and physiotherapists: issues in the professionalization of health care occupations during and after World War I. PMID- 11619478 TI - In tribute to Malcolm Gordon Taylor, 1915-1994. PMID- 11619479 TI - Jewish mysticism in romantic medicine? Indirect incorporation of Kabbalistic elements in the work of Gotthilf Heinrich Schubert. AB - This paper attempts a first outline of an analysis of the connection between the Kabbalah, the tradition of Jewish mysticism, and medicine in the Romantic age. The physician and natural philosopher Gotthilf Heinrich Schubert (1780-1860), a friend and pupil of the philosopher Friedrich Wilhelm Joseph Schelling, is chosen as a representative of the era. The political, institutional, and philosophical background at the beginning of the 19th century is outlined to make intelligible the contemporary disposition for mystical ideas. The historical lines of connection between the Kabbalistic tradition and Romantic medical thought as represented by Schubert are investigated, and examples are given for some correspondences of ideas and topics. The specific combination of these topoi, and a multitude of historical lines of connection, primarily through the work of Schelling and the theologian Friedrich Christoph Oetinger, support the hypothesis that Schubert was indirectly influenced by ideas from the Kabbalah. Finally, the history of the reception of Romantic medicine is sketched, with special regard to those strands that are likely to have incorporated elements from the Jewish mystical tradition. PMID- 11619480 TI - The mid-century biophysics bubble: Hiroshima and the biological revolution in America, revisited. PMID- 11619481 TI - The unique decline of mortality in revolutionary France. AB - This article seeks to draw historians' attention to a neglected reconstruction of the French population and its mortality rates developed by the Institut National d'Etudes Demographiques in the 1970s. The reconstruction shows a sharp decline in French mortality rates, beginning in the 1790s and continuing through the 1820s. This conflicts with recent historiography stressing the negative effects of the Revolution. This article contends that the reconstruction is plausible and that the French mortality decline was unique in Europe in this period. In turn, this suggests that the Revolution had a much more favorable impact than many historians would have us believe. PMID- 11619482 TI - Genital mutilation: some curiosities. PMID- 11619483 TI - Thomas Wakley (1795-1862): medical journalist and parliamentarian. PMID- 11619484 TI - Psychiatry in traditional song: catatonic schizophrenia. PMID- 11619485 TI - Overlooked Nobel laureates. PMID- 11619486 TI - The history of the neurology section of the National Institute for Personnel Research. PMID- 11619487 TI - Dr Ludwig L Zamenhof & Esperanto, an international language. PMID- 11619488 TI - From crippledom to orthopaedic nursing: Pyrford 1908-1945. AB - This study is based on the records of the institution which finally became known as the Rowley Bristow Orthopaedic Hospital, Pyrford, Surrey. The hospital began as a home for crippled children run by a Church of England charity called the Waifs and Strays' Society. The arrival of a leading practitioner of the new discipline of orthopaedic surgery resulted in the transition from a social model of care to a medical one. One part of this process was the redefining of the role of most of the nurses as the recipients of nursing education, with a view to making orthopaedic nursing more attractive as an occupation. However, this educational strategy resulted in a progressive lowering of the entry age and the recruitment of large numbers of probationers who failed to complete the course. PMID- 11619489 TI - The Ladies Committee of the Women's Hospital, Castlegate, Nottingham, 1880-1900. AB - This study co*siders the management of a small provincial and specialist hospital, the Women's Hospital, Castlegate, Nottingham, during the closing two decades of the 19th century. The unusual administration of such an institution by the Ladies committee is examined and the resulting conflict between female authority and the male medical hegemony is described. It is contended that the growing confidence of these women throughout these years in administration and organisation culminated in their renewed constitutional demand for suffrage in 1909. PMID- 11619490 TI - Yarmouth, Nova Scotia: the rise and fall of Miss Watson. AB - In this paper, we discuss the rise to power of Miss Mary Watson, first superintendent of a small hospital and school of nursing at the beginning of the century in a town in southwestern Nova Scotia, Canada. The data were retrieved from first-hand documents still preserved in the hospital. They consisted of student records written in her own hand, minutes of medical meetings which she attended, newspaper clippings and oral histories of nurses who worked in the Yarmouth Hospital in the 1920s and 1930s. We trace her professional career in that town and document how she lost control and eventually left the province of Nova Scotia. PMID- 11619491 TI - Family visitors or social workers? Health visiting and public health in England and Wales 1890-1974. AB - This article examines health visiting from its origins in the late 19th century to the 1974 National Health Service reorganisation. It looks at the successes and failures of health visiting in England and Wales as a whole, and compares this with a case study of provision in the Midlands city of Leicester. PMID- 11619492 TI - Method and theory in the practice of nursing history. PMID- 11619493 TI - What is colonial about colonial medicine? And what has happened to imperialism and health? PMID- 11619494 TI - Scientific rhetoric in the consolidation of a therapeutic monopoly. Medical discourses of Spanish radiotherapists, 1895-1936. AB - This paper analyses the medical discourses produced by the pioneers of Spanish radiotherapy in order to market their new therapy and to establish their monopoly. Social negotiation (persuasion and consensus) involved radiologists arguing against surgeons, gynaecologists, dermatologists and otorhinolaryngologists (ENT specialists). The arguments revolved around the scientific foundations of radiotherapy, the ability to control the doses, and the value of doctors' clinical experience. Radiotherapists argued that the difficulties of their practice necessitated special expertise; they negotiated over the range of use of radiotherapy, beginning with palliative applications, and going on to establish wider claims of advantage over existing treatments. PMID- 11619495 TI - Neglected roots of regionalism? The Commissioners for the special areas and grants to hospital services in the 1930s. AB - The inter-war years in the UK were notable for debates about the extent to which an extension of state intervention in hospital provision was desirable and necessary, and about the limits to and future of the voluntary hospital system which relied largely on various forms of private charity. These themes were intertwined in the UK's 'Special Areas', locations recognized as having suffered adversely from the inter-war depression, with consequent effects on their ability to finance desirable investments in social infrastructures. Grant aid was offered to hospitals in these locations under the terms of the Special Areas legislation of 1934, but there were extensive debates about the principle and practice of such subsidies to hospital development. This paper reviews these debates and considers whether the measures taken by the Commissioners can be seen as neglected antecedents of the regionalism detected in British hospital policy by several commentators. PMID- 11619496 TI - An 'anthropathology' of the 'American Negro': anthropology, genetics, and the new racial science, 1940-1952. AB - This essay documents how, in the 1940s and early 1950s, one scientifically discredited racialist assumption, namely the notion that 'hybridity', embodied by the 'American Negro', and linked to degeneration and disease, was re-authorized, again by science, through the discursive fusion of anthropology, medicine and genetics in the context of a particular disease--sickle cell anaemia. More specifically, I am concerned with the construction of what came to be called an 'anthropathology' of the 'American Negro', the discourse networks that situated it, its conditions of possibility and its consequences. PMID- 11619497 TI - The rise and fall of pink disease. AB - This paper explores the social and medical history and context of pink disease (acrodynia), a serious disease of infants and young children that baffled the medical world during the first half of the twentieth century until it was shown to be caused by mercury poisoning. In the English-speaking world the commonest source of the mercury was teething powders, which were widely available and advertised with increasing sophistication. Efforts to control them (such as the BMJ's campaign against 'Secret Remedies') were as yet unsuccessful. The article discusses the social conditions that influenced the existence and recognition of pink disease, the delay in finding its cause, the way in which it was explained as a virus infection or nutritional deficiency and why it seldom occurred outside the teething period. It discusses both professional and lay attitudes to health and diseases during the early twentieth century and provides a model of how the disease developed in a specific social setting and how the medical profession attempted to deal with it within the limitations of contemporary professional thought. The resistance to the evidence of mercury poisoning is typical of resistance to new medical knowledge and declined only when the opponents and sceptics grew old and disappeared from the scene. Meanwhile, the cause having been identified and accepted, pink disease disappeared, but its consequences emerged much later, in an unexpected quarter, as a cause of male infertility. PMID- 11619498 TI - Finding and using inter-war maternity records. AB - This paper describes the results of a search for the obstetric records of a cohort of over 5,000 children who participated in surveys of childhood diet and growth during the late 1930s and early 1940s conducted by the Rowett Research Institute in Aberdeen. The surveys were conducted at sixteen centres throughout England and Scotland. Birth-weight data were found in hospitals, health authority archives and local authority record offices for approximately 10 per cent of these children. The sources and methods used to find the records are described and their representativeness is evaluated. It is anticipated that this report will be of some interest to medical historians and epidemiologists conducting retrospective studies. PMID- 11619499 TI - 'I remember it well': oral history in the history of pharmacy. AB - The reminiscences and personal testimony of retired pharmaceutical chemists provide a rich and valuable source of historical material, which can be used not only in tracing the history of the practice of pharmacy, but also for illuminating the social, political and economic context in which health care has been delivered during the course of the twentieth century. A wide range of accounts of the lives and work activities of pharmaceutical chemists now exists. Some of these are written, others have been recorded, and extracts from a number of these recordings have been published. The purpose of this paper is to describe and review the material currently available in relation to pharmacy in Great Britain. PMID- 11619500 TI - The psychogenic theory of history. PMID- 11619501 TI - Habeas corpus: death in nineteenth-century America. [Review of: Laderman, G. The sacred remains: American attitudes toward death, 1799-1883. Yale University Press, 1996]. PMID- 11619502 TI - Coming to grips with the limitations of science: infertility and heredity in American history. [Review of: Marsh, M; Ronner, W. The empty cradle: infertilitiy in America from colonial times to the present. Johns Hopkins University Press, 1996; Paul, DB. Controlling human heredity: 1865 to the present. Humanities Press, 1995]. PMID- 11619503 TI - Getting under your skin: X-rays as social history. [Review of: Howell, J. Technology in the hospital: transforming patient care in the early twentieth century. Johns Hopkins University Press, 1995]. PMID- 11619504 TI - Defining health care reform. [Review of: Hacker, JS. The road to nowhere: the genesis of President Clinton's plan for health security. Princeton University Press, 1997]. PMID- 11619505 TI - Inoculating the urban poor in the late eighteenth century. AB - Historical accounts of the practice of smallpox inoculation in the late eighteenth century invariably made a distinction between the widespread general inoculations carried out within small rural parishes and the partial inoculations in urban centres such as London, Manchester, Newcastle and Leeds. This distinction, moreover, is generally reinforced by concluding that the rural inoculation programmes were 'highly effective' or 'successful' in contrast with the urban inoculation schemes, which are often seen as 'marginally effective' or indeed 'failing'. Success or failure tends to be judged by the impact which inoculation had upon reducing mortality from smallpox, but as a result of this demographic focus the motives behind the implementation of urban inoculation have been overlooked. My paper readjusts this balance by looking more closely at motives and by judging success in relation to aims. To achieve this I have taken a new approach towards the history of smallpox inoculation as a whole, and portray the basic idea of giving a person smallpox in order to confer subsequent immunity as being modified in the hands of different people throughout the course of the century. Hence it is possible to trace the development of inoculation from a folk practice carried out within the home with the aim of protecting individuals, to large-scale general inoculation of an entire community, which aimed to eradicate the disease altogether. PMID- 11619506 TI - Repetitive order and the human walking apparatus: Prussian military science versus the Webers' locomotion research. AB - The addition of 'fire' to the European battle repertoire resulted in the close order drill for manoeuvres of the line. Begun in late sixteenth-century Netherlands and perfected in eighteenth-century Prussia under Frederick the Great, the drill's precision marching evolved into a military science which conceived what infantry acquired through rigorous training as a lawful 'second nature' of men. In contrast, the liberal Webers' 1836 locomotion research orientation was, as was that of French skirmishing, one of natural self regulation. Later Prussian military science, restored in Imperial Germany, was merged into locomotion science. PMID- 11619507 TI - Why can't we make prohibition work better? Some consequences of ignoring the unattractive. PMID- 11619508 TI - A tale of two worksites. PMID- 11619509 TI - Impure science: AIDS, activism, and the politics of knowledge. PMID- 11619510 TI - Botanical taxonomy and buggery in Browning's "Soliloquy of the Spanish Cloister". PMID- 11619511 TI - Activism, drug regulation, and the politics of therapeutic evaluation in the AIDS era: a case study of ddC and the 'surrogate markers' debate. AB - This paper presents an extended case study to demonstrate that the interpretation of clinical trials of antiviral AIDS drugs is significantly shaped by a widely dispersed allocation of scientific credibility. Specifically, the participation of AIDS activists in claims-making about AIDS trials and AIDS drugs complicates the politics of therapeutic evaluation, even as it challenges the monopolization of credibility by credentialed researchers. The paper tracks the social construction of belief about the efficacy of the combination therapy of AZT and ddC, between 1990 and 1995 in the United States. By intervening simultaneously in interpretative debates about the results of the clinical trials of this therapy and in methodological debates about how efficacy might best be measured in such trials, activists have helped to shape what is believed to be known about these drugs. PMID- 11619512 TI - Social worlds, actor-networks and controversy: the case of cholesterol, dietary fat and heart disease. AB - Knowledge which links dietary fat and cholesterol to coronary heart disease (CHD) has been controversial for more than forty years. While policies advocating fat and cholesterol restriction are now deeply ingrained in affluent western societies, the scientific 'facts' on which they are supposedly based are highly contested. Applying concepts from actor-network theory and the symbolic interactionist social worlds approach, I argue that knowledge and dietary recommendations relating to cholesterol, fat and CHD are the outcome of complex social negotiations which can only be understood in their cultural, commercial and political contexts. Policies were framed in the 1960s before 'proof' of their efficacy was available. Since then, ambiguous experimental results have been shaped to support the policies. I argue that, despite its many attractive features, actor-network theory cannot adequately deal with protracted controversies. Social worlds theory provides a much more useful framework for investigating long debates in which the 'facts' remain elusive. PMID- 11619513 TI - Science policy reforms: the New Zealand experience. AB - Changes in science policy are taking place in industrialized democracies throughout the world. This paper is concerned with the implications of these changes for the content and conduct of publicly-funded science and research. We start from the view that science policy changes are related to wider changes in the role of government, and in the structure, organization and management of the public sector. New Zealand has attracted international attention in this context because of its commitment to a radical programme of public sector reforms. While this reflects similar developments and concerns elsewhere, the New Zealand experience is especially interesting because of the rigour with which policy has been implemented, the radical nature of the changes made, and the relatively short time-span involved. Thus, in focusing on New Zealand, we hope to present material of interest both there and to a wider audience. PMID- 11619514 TI - Interdisciplinary history: Visions of empire, dreams of youth. [Review of: Miller DP and Reill PH, eds. Visions of empire: voyages, botany and representations of nature. Cambridge University Press, 1996]. PMID- 11619515 TI - Medieval neuroanatomy: the text of Mondino dei Luzzi and the plates of Guido da Vigevano. AB - The Italian anatomists Mondino dei Luzzi (c. 1275-1326) and Guido da Vigevano (c. 1280-1349) must be regarded as pivotal figures in the history of medieval anatomy. Mondino's book (written in 1316 and published in 1478) was the first treatise of anatomy based on the dissection of human cadavers, whereas the plates of Vigevano's manuscript (1345) marked the beginning of a new trend which became increasingly widespread during the following centuries: the use of anatomical illustration in textbooks. Though their neuroanatomical descriptions are rather simple and somewhat difficult to correlate with current descriptions, analysis of these works sheds new light on the knowledge of brain and spinal cord anatomy in the Middle Ages (Olry, 1996). Vigevano's contribution to neuroanatomy, however, appears more important than that of Mondino dei Luzzi, probably because his anatomical illustrations often compelled the draftsman to break free from Galen's dominating influence. PMID- 11619516 TI - Domenico Cotugno, a pioneer in neurosciences. AB - Dominico Cotugno was born in Ruvo Pugliese on January 29, 1736. In 1756, he graduated in Medicine from the Medical School in Salerno. In 1761, Cotugno published the "Aquaeductibus auris humanae internae anatomica dissertatio" ("Anatomical dissertation on acqueducts of the human inner ear") in which he provided the first detailed description of aqueducts of the vestibule and cochlea and formulated the theory of resonance subsequently resumed by Helmholtz. Cotugno gave also the first description of the naso-palatine nerve and of its role in sneezing. In 1764, he published "Commentarius de ischiade nervosa" ("Remarks on nervous ischialgia") advancing the hypothesis that some acrid fluid might penetrate the sheaths of the sciatic nerve. In 1766, he was appointed Professor of Anatomy at the University of Naples. In 1769, he published "De sedibus variolarum syntagma" ("Investigation on the localization of variola pustules"). Furthermore, he discovered albuminuria about a half century before Bright and was also one of the first scientists to identify urea in human urine. He died at the age of 86 in 1822. PMID- 11619517 TI - A memoir of olfaction. AB - Osphreiology, though beginning with Aristotle, and the title of a classical monograph from 1819 by Cloquet, has, like the human sense of smell itself, played a relatively modest role, compared to other sensory functions. The anatomical and physiological connections of the nose to the brain proved to be more complex than those of sight, hearing and even touch, and were therefore poorly understood before the second half of the 19th century. Moreover, the close association between smell and taste gave rise to much controversy regarding the respective roles of the first and the fifth cranial nerves. Next, came the unfolding of the evolutionary influence of cerebral structure and function--viz Broca's "limbic" concept, and the "olfactory desert" in the brains of "anosmatic" animals, Jackson's "uncinate" seizures featuring olfactory hallucinations brought the hippocampal formation into focus. Finally, there were the clinical manifestations of hyposmia and hyperosmia, from "coryza", the common cold, to injury or neoplasms causing hyposmia, as well as some endocrine alterations causing hyperosmia. (And let us not forget Charles Huysman's "Against the Grain" and Marcel Proust's evocative fragrant madeleine.). PMID- 11619518 TI - The first lumbar puncture. AB - In this article it is argued that Heinrich Irenaus Quincke who should be credited with the discovery of lumbar puncture. Although some authors mention the names of James Leonard Corning and Walter Essex Wynter as well, it is demonstrated, by comparing the relevant publications, that the discovery, the application for diagnostic purposes and the introduction in clinical practice of the lumbar puncture were done by Quincke. At first, the purposes for performing a lumbar puncture were purely therapeutic, for instance CSF-drainage in hydrocephalus and meningitis. But, soon after, it was applied for diagnostic aims as well. PMID- 11619519 TI - The history of head injuries: an overview. AB - The history of cerebral trauma is a large subject and this overview is an attempt to summarise the main trends of understanding and management over the millenia. Although beginning with anthropological evidence, papyrology and Homeric times, the main impetus for its scientific study began with Hippocrates, but little progress was made until the Salernitan period. Because the ancients believed it was the fractured bone and not the underlying neurological status that mattered, and determined whether an operation was to be performed, the classification of head injuries was based on the types of skull fracture and not the underlying neurological damage. Only in recent centuries was it realised that it was not skull fractures that were important but the brain lesion. Further improvement in management occurred during warring periods but the lessons learned were not passed on, although mortality from military wounds has steadily declined. Since only a small percentage of head injuries require surgery, consideration should be given to reserve the time and skills of the neurosurgeon to those cases requiring his expertise; this would require that the preliminary care should be undertaken by physicians with a specific interest in this field. PMID- 11619520 TI - Georges Ungar and memory transfer. AB - The idea that memories could be transferred from one organism to another by administration of a "trained" donor brain to a naive recipient seized both scientific and public attention in the 1960's and early 1970's. Georges Ungar was one of the earliest and strongest proponents of this idea, and he provided it extensive theoretical and experimental support. This paper reviews Ungar's work on memory transfer (and in particular on the scotophobin molecule), with an analysis of its successes and failures. PMID- 11619521 TI - Heinrich Kluver and the temporal lobe syndrome. AB - Heinrich Kluver and Paul Bucy described a constellation of symptoms in monkeys following large resections of the temporal lobe that they termed the "temporal lobe syndrome"; now commonly referred to as the Kluver-Bucy syndrome. The aim of this paper is threefold: (1) to review Heinrich Kluver's behavioral studies on monkeys that led up to his temporal lobe experiments with Paul Bucy; (2) to understand why Brown and Schafer dismissed the behavioral changes in temporal lobe monkeys they had observed fifty years prior to the studies of Kluver and Bucy; and (3) to show that Kluver's phenomenologically motivated conceptual paradigm helped to unify both neuropsychological and neuroanatomical theories regarding the visual and emotive functions of the non-human primate temporal lobe. PMID- 11619523 TI - Victorian Order of Nurses for Canada (VONC). PMID- 11619522 TI - The Social Service Department Archives: Peking Union Medical College 1928-1951. AB - The case records in the Social Service Department Archives of the Peking Union Medical College not only provide information on medical practices in China between 1928 and 1951, but also a wealth of information on the social and economic conditions in China at that time, particularly for women and families. The records also provide information on the philanthropic work of the Rockefeller Foundation, which provided vast amounts of grant funds for the Peking Union Medical College. Research in the archives is limited, however, by the large number of files and the lack of finding aids, as well as the ever-changing attitude of the hospital administration toward researchers' use of the archives. PMID- 11619524 TI - "An apple a day ..." PMID- 11619525 TI - The ambulance - Larrey's legacy. PMID- 11619526 TI - Medical botany (Contd.). PMID- 11619527 TI - The UCLA history of pain collection: a work in progress. PMID- 11619528 TI - A short history of HISTLINE. PMID- 11619529 TI - Jewish thought and scientific discovery in early modern Europe. PMID- 11619530 TI - Thai research on male homosexuality and transgenderism and the cultural limits of Foucaultian analysis. PMID- 11619531 TI - "All they needed": AIDS, consumption, and the politics of class. PMID- 11619532 TI - Horror autotoxicus in the Red Night trilogy: ironic fruits of Burroughs's terminal vision. PMID- 11619533 TI - Cybernetics, information, life: the emergence of scriptural representations of heredity. PMID- 11619534 TI - Outburst! A chilling true story about emerging-virus narratives and pandemic social change. PMID- 11619535 TI - Mechanism and teleology in Aristotle's biology. PMID- 11619536 TI - The Iowa State Psychopathic Hospital. PMID- 11619537 TI - American hospital units in France in World War I. PMID- 11619538 TI - Galen on the elements of olfactory sensation. PMID- 11619539 TI - [Not Available]. PMID- 11619540 TI - [Not Available]. PMID- 11619541 TI - [Not Available]. PMID- 11619542 TI - [Not Available]. PMID- 11619543 TI - [Not Available]. PMID- 11619544 TI - [Not Available]. PMID- 11619545 TI - [Not Available]. PMID- 11619546 TI - [Not Available]. PMID- 11619547 TI - The Soviet legalization of abortion in German medical discourse: a study of the use of selective perceptions in cross-cultural scientific relations. PMID- 11619548 TI - [Not Available]. PMID- 11619549 TI - [Not Available]. PMID- 11619550 TI - [Not Available]. PMID- 11619551 TI - Wilhelm C. Hueper: pioneer of environmental carcinogenesis. PMID- 11619552 TI - [Not Available]. PMID- 11619553 TI - [Not Available]. PMID- 11619554 TI - [Not Available]. PMID- 11619555 TI - [Not Available]. PMID- 11619556 TI - [Not Available]. PMID- 11619557 TI - [Not Available]. PMID- 11619558 TI - [Not Available]. PMID- 11619559 TI - [Not Available]. PMID- 11619560 TI - [Not Available]. PMID- 11619561 TI - [Not Available]. PMID- 11619562 TI - [Not Available]. PMID- 11619563 TI - [Not Available]. PMID- 11619564 TI - [Not Available]. PMID- 11619565 TI - [Not Available]. PMID- 11619566 TI - [Not Available]. PMID- 11619567 TI - [Public health seen through the Talmud: principles of collective hygiene]. PMID- 11619568 TI - [Not Available]. PMID- 11619569 TI - [Not Available]. PMID- 11619570 TI - [Not Available]. PMID- 11619571 TI - Barbara McClintock and the transposition concept. AB - Barbara McClintock was awarded Nobel Prize in Physiology or Medicine in 1983 for the discovery and characterization of jumping genes or transposons. In 1948 she described for the first time maize controlling elements. She proposed 'transposition' as a mechanism that relates phenotypic characteristics with the presence of unstable genes. This discovery was 'ignored' even though she was recognized as a brilliant cytogeneticist. In this paper I approach the matter of the maize research groups within which McClintock developed all of her work, and the problem of variegation in relation to unstable genes and transposition. PMID- 11619572 TI - [Georges Canguilhem, 1904-1995]. PMID- 11619574 TI - Insects and parasites found in ancient bodies. PMID- 11619573 TI - [Alistair Cameron Crombie, 1915-1996]. PMID- 11619575 TI - Does the body matter? PMID- 11619576 TI - Socrates' and Callicles': settlement--or, the invention of the impossible body politic. PMID- 11619578 TI - Decentering the natural body: making difference matter. PMID- 11619577 TI - The posthuman body: inscription and incorporation in Galatea 2.2 and Snow Crash. PMID- 11619579 TI - Profitable pursuits? Rural industry and mortality in the proto-industrial West Riding 1650-1830. PMID- 11619580 TI - Is there anything wrong with Hitler these days? Ethics in a postmodern world. PMID- 11619581 TI - Joshua Bierer: striving for power. PMID- 11619582 TI - A failure to flourish? David Yellowlees and the Glasgow School of Psychiatry: Part 2. PMID- 11619583 TI - The concept of consciousness in the history of neuropsychiatry. PMID- 11619584 TI - Kraepelin's 'diagnostic cards': the confluence of clinical research and preconceived categories. PMID- 11619585 TI - 'By cowntynaunce it is not wist': Thomas Hoccleve's Complaint and the spectacularity of madness in the Middle Ages. PMID- 11619586 TI - Suicide - a traveller's tale: a study of the adoption of the word 'suicide' into the main romance languages. PMID- 11619587 TI - Forging the 'missing link': the significance of the Mental After Care Association archive. PMID- 11619588 TI - Charles Dickens's 'The Signalman': a case of partial insanity? PMID- 11619589 TI - Seignot's paper on the treatment of Tourette's syndrome with haloperidol. Classic Text No. 31 AB - The paper of Seignot in 1961 is the first clinical description of the use of haloperidol to treat the symptoms of Gilles de la Tourette syndrome (GTS). It is widely quoted in literature about GTS. However, it is not widely known that the single case involved had been subject to a frontal lobectomy prior to treatment with haloperidol. We present a translation of that paper and a discussion of its significance. PMID- 11619590 TI - The centenary of the surgical glove. AB - It is customary to attribute the introduction of gloves into surgical practice to William Stewart Halsted [1852-1922] of Johns Hopkins Hospital, but it was his assistant, Joseph Colt Bloodgood [1867-1935] who, from February 1897 onwards, was the first to equip the whole theatre staff with rubber gloves. In Ireland, as elsewhere, the introduction of the revolutionary adjunct to aseptic technique was not without controversy or bizarre interpretation, before its eventual adoption. PMID- 11619591 TI - The International Council of Nurses is almost 100 years old. PMID- 11619592 TI - The inner limits. PMID- 11619593 TI - The Massachusetts veterinary profession, 1882-1904: a case study. PMID- 11619594 TI - Prime Minister D. G. Monrad: manic-depressive disorder and political leadership. PMID- 11619595 TI - The use of medicines: historical trends and international comparisons. PMID- 11619596 TI - A collection of home remedies: Susanna Weinbach Hoffman, 1742-1803. PMID- 11619597 TI - Tycho Brahe's Elixier. PMID- 11619598 TI - Das Arzneibuch Johannes Schoners und seine mittelhochdeutschen Quellen. PMID- 11619599 TI - Droogeryen Honzo. PMID- 11619600 TI - Arthritis in ancient Indian literature. PMID- 11619601 TI - Foods or medicines? A study in the relationship between foodstuffs and materia medica from the sixteenth to the nineteenth century. PMID- 11619602 TI - Jejjata (9th century A.D.) and his informations about Indian drugs. PMID- 11619603 TI - Asoka (Saraca Indica Linn)-a cultural and scientific evaluation. PMID- 11619604 TI - American Reactions to international narcotic traffic. PMID- 11619605 TI - Smallpox vaccination in the nineteenth century. PMID- 11619606 TI - Smallpox: a scourge of the past. PMID- 11619608 TI - Reshaping technology in wartime: the effect of military goals on entomological research and insect-control practices. PMID- 11619607 TI - Fear and loathing in addicted America. PMID- 11619609 TI - The embryology of Yuhanna ibn Masawaith. PMID- 11619610 TI - Memories from the street: oral histories of elderly methadone patients. PMID- 11619611 TI - The identity and critical appraisal of the basis of nomenclature and ancient socio-cultural and geographico-historical reflections evinced with the Paninian perfume-plant/plant-part 'Kisara' (Panini IV. IV. 53). PMID- 11619612 TI - On the identity of and Indo-Greek relation reflected in the plant-names and uses evinced in the Kautiliya Arthasastra with particular reference to 'Kiratatikta' of 'Katuvarga' (group of spices). PMID- 11619613 TI - Spinach is an alchemical antidote to heavy metal poisoning. PMID- 11619614 TI - Galen on the astronomers and astrologers. PMID- 11619615 TI - Galen PMID- 11619616 TI - The medicine stamp acts of Great Britain. PMID- 11619617 TI - Placental passage of drugs: pre-20th century evidence. PMID- 11619618 TI - Thabit ibn Qurra's Epitome of Galen's Book on Seven-Month Children. PMID- 11619619 TI - [Ibn al-Nafis and the discovery of the pulmonary circulation]. PMID- 11619621 TI - [The relationship between medical arabism and the medical school in Montpellier across the centuries]. PMID- 11619620 TI - Nutrition and dietetics in Ibn al-Quff al Karaki's writings. PMID- 11619622 TI - [Taqwim al-Sihha (Tacuinum Sanitatis) by Ibn Butlan: the history of the text]. PMID- 11619623 TI - [Arabic medicine in the Southern Netherlands from the fifteenth to the seventeenth century]. PMID- 11619624 TI - The Vedic gods Agni, Indra and Soma as interrelated: a study of Soma. PMID- 11619625 TI - The Medicean dukes of Florence and Friar Lawrence's 'distilling liquor' (Romeo and Juliet IV.i.94). PMID- 11619626 TI - Seeing the wood for the trees--the early papers of Denis Burkitt. AB - Denis Burkitt's was a remarkable career. A surgeon in the Colonial Medical Service in Uganda, his keen observation of the incidence of jaw tumours in children led him to describe a new form of lymphatic cancer. He confirmed, for the first time in man, that a cancer was caused by a virus and, most remarkable of all, he discovered a cure--low-dose chemotherapy. The condition was named after him--Burkitt's lymphoma--and with this came membership of a select group of eponymous Irishmen, including Graves, Colles and Corrigan. His ability to link the incidence of disease with geographical distribution brought him, first to question and then to champion Peter Cleave's theory that lack of dietary fibre contributed to many of the diseases common in western civilisation. In the process, he changed the dietary habits of the Western world. Yet Denis Burkitt's early career in Trinity College, Dublin was not auspicious for, as a Junior Freshman engineer in 1929, his tutor despaired of him, writing to his father 'Don't blame me if he gets stuck'. A happy irony then, that the College made him an Honorary Fellow half a century later. PMID- 11619628 TI - Recent studies on Goroji Nakagawa, pioneer of vaccination in Japan. On the bicentenary of his birth. PMID- 11619627 TI - Mental handicap in Indian history: cross-cultural action research & communication. PMID- 11619629 TI - The mass inoculation of the poor in South Hampshire, 1773-1783. PMID- 11619630 TI - Chrysippus and the Placita. PMID- 11619631 TI - The career of Oribasius. PMID- 11619632 TI - William James, Theodore Dreiser and the "anaesthetic revolution." PMID- 11619633 TI - The great Salk vaccine mess. PMID- 11619635 TI - The pox upon her. PMID- 11619634 TI - Linus Pauling: the scientist as crusader. PMID- 11619636 TI - Drug abuse in the East Los Angeles Health District. PMID- 11619637 TI - A legend of the heart. PMID- 11619638 TI - A neglected Mayan galactagogue, Ixbut (Euphorbia lancifolia). PMID- 11619639 TI - Another fragment from the autograph of Ibn Al-Tilmidh's "Marginal commentary on Ibn Sina's Canon of medicine". PMID- 11619640 TI - The religious therapeutic functions of the cemetery for the Kongo of Zaire. PMID- 11619641 TI - "Give up that filthy habit--cocaine." PMID- 11619642 TI - Opiate addiction as a consequence of the Civil War. PMID- 11619643 TI - Juxtaposed medical traditions: Pliny HN 27, 131. PMID- 11619644 TI - Critical notes on Galen's "De venae sectione adversus Erasistrateos Romae degentes". PMID- 11619645 TI - Thucydides and the plague of Athens. PMID- 11619646 TI - The life and death of Asclepiades of Bithynia. PMID- 11619647 TI - The illness of Caligula: PMID- 11619648 TI - Caligula's illness again. PMID- 11619649 TI - De Quincey's opium experiences. PMID- 11619650 TI - The limits of absolutism: Joseph II and the Allgemeines Krankenhaus. PMID- 11619651 TI - The female opiate addict in 19th-century America. PMID- 11619652 TI - Richard III's disfigurement: a medical postscript. PMID- 11619653 TI - American health quackery: an historical view. PMID- 11619654 TI - Medicine and spices, with special reference to medieval monastic accounts. PMID- 11619655 TI - Galen and Stoic rhetoric. PMID- 11619656 TI - The Revolta contra vacina of 1904: the revolt against "modernization" in belle epoque Rio de Janeiro. PMID- 11619657 TI - The introduction of smallpox vaccine in 1803 and the adoption of immunization as a government function in Puerto Rico. PMID- 11619658 TI - Elixirs, nerve tonics and panaceas: the medicine trade in nineteenth-century New Hampshire. PMID- 11619659 TI - Frank Macfarlane Burnet 1899-1985. PMID- 11619660 TI - Bede Morris 1927-1988. PMID- 11619661 TI - Repeat performance: a psychohistorical study of Leopold III and Belgian neutrality. PMID- 11619662 TI - Did Victorian medicine crush Olive Schreiner's creativity? PMID- 11619663 TI - Ibn Sina's treatise on drugs for the treatment of cardiac diseases. PMID- 11619664 TI - "Right and left in the sexual theories of Parmenides". PMID- 11619665 TI - The Arabic version of Galen's "Ars parva". PMID- 11619666 TI - The experimenta of Arnald of Villanova. PMID- 11619667 TI - The Experimenta of Arnald of Villanova. PMID- 11619668 TI - Cosmas and Damian in the New Sacristy [Medici Chapel of San Lorenzo, Florence]. PMID- 11619669 TI - The author of a Renaissance commentary on Pliny: Rivius, Trithemius or Aquaeus. PMID- 11619670 TI - The Boston inoculation controversy: a revisionist interpretation. PMID- 11619671 TI - Mohave Indian gathering of wild plants. PMID- 11619672 TI - "Tacuini sanitatis". A little-known edition of 1531. PMID- 11619674 TI - Gods flesh and other pre-Columbian phantastica. PMID- 11619675 TI - Smallpox inoculation in the American colonies, 1763-1783. PMID- 11619676 TI - "Liber de visu": the Greco-Latin translation of Euclid's "Optics". PMID- 11619677 TI - The medical history of Menilek II, Emperor of Ethiopia (1844-1913): a case of medical diplomacy. PMID- 11619678 TI - A thirteenth-century Jewish physician in Jerusalem (a Geniza portrait). PMID- 11619680 TI - The colonial surgeon's rise to prominence: Dr. Silvester Gardiner (1707-1786) and the practice of lithotomy in New England. PMID- 11619679 TI - Plants used by Indians in the Missouri River area. PMID- 11619681 TI - A reconsideration of the inoculation controversy. PMID- 11619682 TI - The medicinal herbs of our forefathers. PMID- 11619683 TI - Between ancients and moderns: Tommaso Cornelio's medical teaching and unpublished comment by him on the Galenic "Ars parva". PMID- 11619684 TI - The mysterious death of Mrs. Leland Stanford. PMID- 11619685 TI - Devils drugs, and doctors. PMID- 11619686 TI - "Safe levels, acceptable risks": the accident at Seveso. PMID- 11619687 TI - Whatever happened to human body glue? PMID- 11619688 TI - Endless sacks: soldiers' desire in Tamburlaine. PMID- 11619689 TI - Egyptian mumia: the sixteenth century experience and debate. PMID- 11619690 TI - The decline of small pox and the demographic revolution of the eighteenth century. PMID- 11619691 TI - Alfred H. Isham: a gilded age entrepreneur in San Diego County. PMID- 11619692 TI - Drug use: special implications for black America. PMID- 11619693 TI - The life and work of Dr. Carroll Gideon Bull: pioneer in medicine. PMID- 11619694 TI - Burgundio of Pisa's translation os Galen's Peri ton peponthoton topon: 'De interioribus'. PMID- 11619695 TI - The Athenian plague. Smallpox. PMID- 11619696 TI - The big sleazy: Love Canal ten years later. PMID- 11619697 TI - America's first cocaine epidemic. PMID- 11619698 TI - From population control politics to chemicals: the WHO as an intermediary organization in contraceptive development. AB - Studies of laboratory work have rarely focused on the role of intermediary organizations in developing R&D activities. Most studies focus on a single university-based research laboratory or an industrial R&D unit. Moreover the rejection by social constructivist scholars of universalistic, deterministic explanations of the development of science and technology has led to an overemphasis on the local features of scientific and technological work. Based on a case study of the role of the World Health Organization (WHO) in contraceptive R&D, this paper suggests that an analysis of the role of intermediary organizations enables us to go beyond a too-narrow focus on the micro sociological dynamics of laboratory work, to include the macro- and meso sociological dimensions of science and technology. First, a focus on intermediary organizations enables us to learn more about the manner in which locally specific laboratory cultures are transformed into translocal research practices. This paper shows how literary technologies, and to an even greater extent material technologies, are important tools in accomplishing standardization of local laboratory cultures. Second, a focus on intermediary organizations enables us to study how concerns that go beyond the laboratory--in this case, population control policies and the agenda of the WHO--help to shape laboratory practices. PMID- 11619699 TI - 'Speaking scars': the tattoo in popular practice and medico-legal debate in nineteenth-century Europe. PMID- 11619700 TI - Prosthetic reconstructions: making the industry, re-making the body, modelling the nation. PMID- 11619701 TI - Cannibalism and witchcraft in early modern Europe: reading the visual images. PMID- 11619703 TI - A second look at nursing history. PMID- 11619702 TI - Uniform and nursing reform. AB - Uniforms for nurses have been of prevailing significance since the inception of nurse training in this country. Indeed the uniform may be considered a metaphor for the reform that was instituted, both of care-givers and care provision for the sick and disabled of colonial Australia and subsequently. There are nuances and ambiguities in references to nursing and nursing attire, and historical research and historiography has begun to explicate such complexities. PMID- 11619704 TI - The rise and demise of fever nursing. AB - This important branch of nursing history has been virtually ignored, and yet, as will be seen, it could offer lessons for the future. This paper relies mainly on primary sources. It also demonstrates the value of a nursing journal as a vehicle for records, in this case, those of the Fever Nurses' Association. This original study illustrates how fever nursing arose and declined in an endeavour to serve the needs of society. PMID- 11619705 TI - The great nursing dispute of Guy's Hospital 1879-1880. PMID- 11619706 TI - Recollections of specialty nursing in war-time Lancashire. PMID- 11619707 TI - Some details of the administration and functioning of the Byzantine hospitals. PMID- 11619708 TI - Dieting for an emperor. A translation of Books 1 and 4 of Oribasius' Medical Compilations with an introduction and commentary. PMID- 11619709 TI - Dr John Roberts, pilgrim from the Meirion hills. PMID- 11619710 TI - William Laidlaw Purves MD (1842-1917): aurist, oculist and golfer. PMID- 11619711 TI - On the centenary of Sir Ronald Ross's discovery of the role of the mosquito in the life cycle of the malaria parasite. PMID- 11619712 TI - George Duncan Gibb (1821-1876): London's foremost laryngologist. PMID- 11619713 TI - Untamed editor: F Knight Hunt MRCS (1814-1854). PMID- 11619714 TI - The cancer of the German Emperor and King of Prussia, Frederick III. PMID- 11619715 TI - Dr Charles Thomas Jackson's aphasia. PMID- 11619716 TI - The physiological researches of A V Waller. PMID- 11619717 TI - Ancient medicine review. PMID- 11619718 TI - [Not Available]. PMID- 11619719 TI - [Not Available]. PMID- 11619720 TI - Child poverty in ancient Rome: the 'Alimenta Italiae' of the "Good Emperors." PMID- 11619721 TI - Medicine at the German universities, 1348-1500; a preliminary sketch. PMID- 11619722 TI - [Not Available]. PMID- 11619723 TI - [Not Available]. PMID- 11619724 TI - [Not Available]. PMID- 11619725 TI - [Not Available]. PMID- 11619726 TI - [Not Available]. PMID- 11619728 TI - [Not Available]. PMID- 11619727 TI - [Not Available]. PMID- 11619729 TI - [Not Available]. PMID- 11619730 TI - [Not Available]. PMID- 11619731 TI - [Not Available]. PMID- 11619732 TI - [Not Available]. PMID- 11619733 TI - [Not Available]. PMID- 11619734 TI - [Not Available]. PMID- 11619735 TI - [Not Available]. PMID- 11619736 TI - [Not Available]. PMID- 11619737 TI - [Not Available]. PMID- 11619738 TI - [Not Available]. PMID- 11619739 TI - [Not Available]. PMID- 11619740 TI - [Not Available]. PMID- 11619741 TI - [Not Available]. PMID- 11619742 TI - [Not Available]. PMID- 11619743 TI - [Not Available]. PMID- 11619744 TI - [Not Available]. PMID- 11619745 TI - [Not Available]. PMID- 11619747 TI - Genius, mysticism, and madness. PMID- 11619746 TI - From couch to culture. PMID- 11619748 TI - Edinburgh medicine in Simpson's time. PMID- 11619750 TI - In search of sources: observations on a watercolour painting of an anatomical subject. PMID- 11619749 TI - The rise and fall of chloroform anaesthesia. PMID- 11619751 TI - A history of the St John Ophthalmic Hospital, Jerusalem. PMID- 11619752 TI - The Purple Cross aid for wounded and sick Army horses. PMID- 11619754 TI - Animals and the veterinarian in ancient Rome. PMID- 11619753 TI - Hocus pocus: a pharmacologic look at patent medicine colic cures. PMID- 11619755 TI - Francis Glisson 1597-1677. PMID- 11619756 TI - Additional philatelic errors of medical interest. PMID- 11619757 TI - Organ transplants on stamps. PMID- 11619758 TI - Bloodletting in veterinary medicine. PMID- 11619759 TI - The history of zoos and the emergence of zoo veterinarians. PMID- 11619760 TI - The spread of European veterinary education to some early American schools. PMID- 11619761 TI - Parker Ranch: Pacific pioneer in animal health. PMID- 11619762 TI - Development of equine veterinary medicine in the United States. PMID- 11619763 TI - The modern horse doctor. PMID- 11619764 TI - A personal history of veterinary public health. PMID- 11619765 TI - Tuberculosis and 19th and 20th century painters. PMID- 11619766 TI - Medical students in the first World War: the Edinburgh experience. PMID- 11619767 TI - Venereal disease in eighteenth-century Scotland: evidence from the divorce courts. PMID- 11619768 TI - The plague of Athens. PMID- 11619769 TI - The York Factory medical journals, 1846-52. AB - The York Factory medical journals are the only surviving medical ledgers in the 200-year history of the Hudson's Bay Company, written by two physicians posted at one of the Company's largest and pre-eminent posts, York Factory. The daily journals offer us a unique glimpse, albeit for a seven-year span from 1846 to 1852, into the incidence and prevalence, duration, severity, treatment, outcomes, and seasonality of illness and disease. Occupations are noted, as are age and gender, in many of the entries. There are a total of 1,653 cases seen by the two physicians over the time period, 5 percent of which are Native. Several women were seen by the physicians, primarily for gynecological disorders. Gastro intestinal disorders were a major source of morbidity at this time and place. PMID- 11619770 TI - Diary notes on a trip to West Africa in relation to a yellow fever expedition under the auspices of the Rockefeller Foundation, 1926, by Oskar Klotz. PMID- 11619771 TI - Cruel knives? Vivisection and biomedical research in Victorian English Canada. AB - This discussion shows how the use of animals in biomedical research in Canada evolved during the latter half of the nineteenth century from simple demonstrations to more sophisticated series of experiments. More important, however, is the argument advanced that Anglo-Canadian society's response to vivisection and the use of animals in research centred on issues such as cruelty, exploitation, and broader notions of religion, power, and gender. This exploration of vivisection in Victorian Canada, then, reveals that it was, as elsewhere, a complex debate involving more than the use of animals for biomedical research purposes. PMID- 11619772 TI - [Thomas J. W. Burgess and the administration of the Verdun Protestant Hospital for the Insane (1890-1916)]. AB - This article examines the administration of the Verdun asylum in Quebec and the central role played by Dr. Burgess from the asylum's opening in 1890 until World War I. It focuses first on the marked difference between the democratic approach to management actively employed at Verdun and the more rigid proprietorial control that characterized francophone asylums. It then outlines methods for organizing the daily routine of patients; achievements arising from the systematic application of moral treatment and the importance that Dr. Burgess gave to this form of treatment; and the problems encountered in medical superintendence of the asylum during these difficult years. The discussion concludes by considering how Burgess and his colleagues contributed both to the development of the psychiatric profession in Quebec and to medical research into mental illness. PMID- 11619773 TI - Accounts of abuse of patients at the Toronto Hospital for the Insane 1883-1937. AB - In an effort to uncover the experiences and perspectives of patients about abuse in institutions, this article will present the writings of asylum inmates and third-party observers, including relatives and staff, on this topic. These documents consist almost entirely of material from the Toronto Hospital for the Insane, from the late nineteenth and early twentieth centuries. References include physical, verbal, and sexual abuse. Methodological challenges when coming across this evidence will be addressed, most notably the problem of verification when charges of abuse are denied or are met with silence by hospital officials. Furthermore, this topic will include a discussion of inmates abusing other patients in an effort to compare how these episodes were reported in contrast to incidents that involved staff. PMID- 11619774 TI - [Alsatian chemists in Paris in the 19th century: a network, a school?]. AB - During the nineteenth century French chemistry was marked by an outstanding number of Alsatian chemists whose scientific contributions cannot be ignored. Especially following the Franco-Prussian War, their regional origin was given a particular importance as a means of affirming their singularity on the French scientific scene. However, some questions may be raised: can we distinguish the Alsatians from other French chemists before 1870? Were they a homogeneous group sharing a common origin? The aim of this article therefore, is, to show that by their theoretical options within chemistry, their personal and professional relationships, as well as by their participation in various common initiatives, they organized themselves both formally and informally within the Parisian scientific community. Amongst these forms of organization the research school of Charles Adolphe Wurtz (1817-84) emerges as the nucleus of what we may envisage as a network of Alsatian chemists working in Paris, in the second half of the nineteenth century. PMID- 11619775 TI - First cure for diphtheria by antitoxin as early as 1891. PMID- 11619776 TI - Hidden persuaders: medical indexing and the gendered professionalism of American medicine, 1880-1932. PMID- 11619777 TI - Developmental biology as a feminist cause? PMID- 11619778 TI - Gender and "modern" botany in Victorian England. PMID- 11619779 TI - The women, gender, and science question: What do research on women in science and research on gender and science have to do with each other? PMID- 11619780 TI - Medicine and science as masculine "fields of honor". PMID- 11619781 TI - [Anthrax: a malady of animals and of man which hides in the earth]. AB - Anthrax is an infectious disease of herbivores, especially sheep and cattle, but also of horses, of pigs, of dogs, of wild animals and of humans. Bacillus anthracis causes the disease. This bacterium needs plenty of oxygen to procreate and to produce resistant spores, which remains viable in the soil during 3.5 years, at times during 15-20 years. The author tries to follow step by step the evolution of the ideas concerning the origin and the pathology as well as of the veterinarians measures against this disease during the 19th and 20th centuries. Many studies of the endemic anthrax were made from the beginning of the second half of the 19th century. Thanks to Louis Pasteur (1822-1895) in France and Robert Koch (1843-1910) in Germany, the anthrax could be identified with a soil disease between 1870 and 1880. The statistics concerning the anthrax in the Grand Duchy of Luxembourg compared to the geological and pedological structures of the soil, have fully confirmed the scientific findings at the end of the 19th century. Nowadays the anthrax has disappeared from our landscape thanks to the preventive inoculation and to the industrial use of the animal cadavers. PMID- 11619782 TI - Personality and policy in the Gold Coast. Some incidents in the history of the colonial veterinary services, 1945-1948. PMID- 11619783 TI - Petrus Camper on the origin and color of blacks. PMID- 11619784 TI - Introduction: historiographic issues. PMID- 11619785 TI - Debating humoral immunity and epistemology: the rivalry of the immunochemists Jules Bordet and Paul Ehrlich. PMID- 11619786 TI - Romana's sign. PMID- 11619787 TI - Technology, clinical studies, and control in the field of organ transplantation. PMID- 11619788 TI - Helpers and suppressors: on fictional characters in immunology. PMID- 11619789 TI - Epidemiology, immunology, and yellow fever: the Rockefeller Foundation in Brazil, 1923-1939. PMID- 11619790 TI - Historical and philosophical perspectives concerning immune cognition. PMID- 11619791 TI - Should they have got the Nobel Prize? PMID- 11619792 TI - Silphion. PMID- 11619793 TI - 100 years ago - birth centenary - Hugh Cairns (1896-1952): pioneer neurosurgeon. PMID- 11619794 TI - Selections from the case-books and diaries of Dr J B S Greathead MB MC (Edin.) MRCS (Eng.) Part 1. PMID- 11619795 TI - The rhetoric of a health technology: the microprocessor patient card. PMID- 11619796 TI - The many Galens of the medieval commentators on vision. AB - It is my aim in this paper to discuss some aspects of the relationship between medieval medical authors and classical authorities. Historians of medicine have stressed the academic activities of medical masters as those of conciliation and explanation of authority. I will rather suggest that the explanation of classical authority was not the main aim of the medical masters but, in fact, its very construction. I would like to develop this possibility by analysing the nature of the approach to visual perception in academic medical circles at the end of the thirteenth century and the beginning of the fourteenth century. PMID- 11619797 TI - [The concept of intensity in Charles Bonnet's psychology]. AB - The concepts of intensity and vivacity are studied in the psychological texts of Charles Bonnet (1720-1793). In 1854, intensity measured physical movements of the nerves, and vivacity pertained to psychical order. In 1760, however, the two scales were confused. This development, based on an imaginary of measure justified by methodological considerations, led to a research field whose apparent goal was to measure the soul's faculties. Moreover, intensity--which had been quantified in Bouguer's work at that time (1760)--was abandoned and was transferred to the notion of energy, not yet quantified. Consequently, Bonnet's apparent dualism seems, in fact, to have been grounded on a monistic foundation, assuring an unmeasurable place to the soul, corresponding to freedom. PMID- 11619798 TI - [The rebirth of Rudolf Virchow's biological thought, in the work of Ludwig Aschoff]. AB - Rudolf Virchow's teaching was challenged by German physicians in the 1920s. Scientific medicine, they argued, did not provide sufficient tools for patient care. They held Virchow responsible for this state of things. According to Ludolf von Krehl, Gustav von Bergmann or Ferdinand Sauerbruch, Virchow fostered a mechanistic trend in medicine which neglected the human dimension in medical practice. These clinicians claimed that scientific medicine should therefore be complemented at the bedside by a teleological approach, taking into account the purposiveness of vital processes. This was the methodological core of the reform that they intended to promote. Many pathologists alike were preoccupied with the reformatory trend launched by the physicians. Ludwig Aschoff, Paul Ernst, Max Borst and Walter Pagel endeavoured to reform the theoretical foundations of their discipline. However, they did not agree with the physicians' view of Virchow's teaching. Aschoff especially showed that Virchow's initial writings provided in fact an epistemological basis supporting the clinicians' endeavour. In this paper, I examine Aschoff's argumentation. I hope thereby to improve our knowledge of one of the components of the medical reform which took place in Germany during the Weimar period. PMID- 11619799 TI - [The introduction in France, between the two World Wars, of the ideas of American scientific ecology]. AB - From the early XIXth century, studies of plant associations in relation to their different environments arose in geobotany, next to classical studies of species distribution. This trend in research was perpetuated and may explain some characteristics of the reception in France of American scientific ecology. Thus, during the interwar years, the Zurich-Montpellier school of phytosociology made possible important progress in bringing to the fore the discontinuities in vegetation. However, it hindered ecological research from the approach of plant associations dynamics, hence to ideas in systems ecology, while works on these subjects were successfully carried out at the same time in the USA. Nevertheless, several researchers (geobotanists, microbiologists or biocoenologists) worked within a conceptual framework that was in harmony with American studies on biotic communities. PMID- 11619800 TI - Conceptions of dynamic accommodation in vertebrate eyes: from the 17th to the early 20th century and the relation to current views. A historical essay. PMID- 11619801 TI - Psychiatric expansionism and social control: the intersectioin of community care and state policy. AB - Informed by the theories of political economy and professional interests, this research argues that psychiatric commitments to community care and to scientific categorization have contributed to expanding control of the mentally ill, and that these ideological commitments run parallel to and are exacerbated by state responses to macro-economic conditions. Time series analysis of the period from 1932 to 1975 is used to assess the relative impact of deinstitutionalization, medical entrenchment, and state fiscal policy on psychiatric expansionism. The findings demonstrate that a professional interests explanation (indicated by a commitment to community and to science) provides a significant contribution to a materialist-based explanation of expanding psychiatric control. PMID- 11619802 TI - Pasteur: an underestimated hero of science: an essay review. [Review of: Geison GL. The private science of Louis Pasteur. Princeton University Press, 1995]. PMID- 11619803 TI - The history of child abuse. PMID- 11619804 TI - Transformations of Eros: sexuality and the family in Russia. PMID- 11619805 TI - Just before Nature: The purposes of science and the purposes of popularization in some english popular science journals of the 1860s. AB - Popular science journalism flourished in the 1860s in England, with many new journals being projected. The time was ripe, Victorian men of science believed, for an 'organ of science' to provide a means of communication between specialties, and between men of science and the public. New formats were tried as new purposes emerged. Popular science journalism became less recreational and educational. Editorial commentary and reviewing the progress of science became more important. The analysis here emphasizes those aspects of popular science which have been identified by Frank Turner as 'public science' and by Thomas Gieryn as 'boundary-work'. the religious, intellectual, and utilitarian values claimed for science by editors and contributors in their tasks of persuading the public to support science and of distinguishing science from what they often called 'applied science' are discussed. These values are shown to vary among editors and, for the editors examined here, Shirley Hibberd, Henry Slack, James Samuelson, William Crookes, and Henry Lawson, to differ significantly from those of T. H. Huxley, John Tyndall, and Norman Lockyer, on whom much study of the popularization of science in the 1860s has focused. PMID- 11619806 TI - Karl Pearson's mathematization of inheritance: from ancestral heredity to Mendelian genetics (1895-1909). AB - Long-standing claims have been made for nearly the entire twentieth century that the biometrician, Karl Pearson, and colleague, W. F. R. Weldon, rejected Mendelism as a theory of inheritance. It is shown that at the end of the nineteenth century Pearson considered various theories of inheritance (including Francis Galton's law of ancestral heredity for characters underpinned by continuous variation), and by 1904 he 'accepted the fundamental idea of Mendel' as a theory of inheritance for discontinuous variation. Moreover, in 1909, he suggested a synthesis of biometry and Mendelism. Despite the many attempts made by a number of geneticists (including R. A. Fisher in 1936) to use Pearson's chi square (X2, P) goodness-of-fit test on Mendel's data, which produced results that were 'too good to be true', Weldon reached the same conclusion in 1902, but his results were never acknowledged. The geneticist and arch-rival of the biometricians, Williams Bateson, was instead exceptionally critical of this work and interpreted this as Weldon's rejection of Mendelism. Whilst scholarship on Mendel, by historians of science in the last 18 years, has led to a balanced perspective of Mendel, it is suggested that a better balanced and more rounded view of the hereditarian-statistical work of Pearson, Weldon, and the biometricians is long overdue. PMID- 11619807 TI - Anglo-Saxon midwives. PMID- 11619808 TI - Winecraft and chemistry in 18th-century France: Chaptal and the invention of Chaptalization. PMID- 11619809 TI - Meeting the mother man: rediscovering Walt Whitman, writer and nurse. AB - Despite a long history of men working as nurses, there is a dearth of prominent male role models in nursing history. This article reevaluates the legacy left for nursing by Walt Whitman, the famous American writer who spent three years visiting hospitals and doing voluntary nursing work during the American Civil War. Whitman's nursing practice and beliefs are examined in historical context. His motivation is also explored and related to current perspectives on males in nursing. Whitman emerges as a singular man with a talent for caring and communicating its value. He is posited as a significant figure in the history of males in nursing, whose status as a gay archetype required further research. His writings comprise a substantial legacy for the whole nursing community. PMID- 11619810 TI - Life as a nun -- possibilities and limitations. PMID- 11619811 TI - Fever nurses' perceptions of their fever nurse training 1921-1971. AB - This paper is based on evidence from 118 ex-fever nurses. The method used, postal questionnaires, is rarely mentioned by oral historians, yet it proved invaluable in such a scattered target population. It shows the importance of collecting evidence before it is too late. This study gave the respondents a welcome opportunity to recall, analyse and reflect on their fever nursing practice. It complements the previous paper, 'The rise and demise of fever nursing' and confirms its findings. PMID- 11619812 TI - Memories of orthopaedic nursing training. PMID- 11619813 TI - Tales of the tenements: midwifery training in Glasgow. PMID- 11619814 TI - Nights on the women's medical ward, 1952. PMID- 11619815 TI - Nursing leaders and feminist issues: Susan McGahey and the New South Wales experience, 1890-1910. AB - Susal Bell McGahey was arguably the most prominent nurse leader and reformer in New South Wales, Australia between the years 1890 and 1910. While McGahey was influenced in her ideas about ways of organising and reforming nursing by international nurse leaders, especially Ethel Bedford Fenwick and Lavinia Dock, she never shared their commitment to feminist issues. This paper considers why this was the case. PMID- 11619816 TI - Science and democracy: historical reflections on present discontents. PMID- 11619817 TI - Theodule Ribot and the reception of evolutionary ideas in France. AB - Although the French scientific community was reluctant to honour Darwin for his work, the eminent psychologist Theodule Ribot used an evolutionary framework for his thesis on heredity. The publication of L'Heredite psychologique in 1873 was intended for lay readers at a period in French history when many scientific topics were popular. As a result French readers were introduced to the Darwinian and Spencerian ideas that Ribot included -- as an analysis of L'Heredite shows. This work was important for French psychology and psychiatry: it extended the domain of the former, and by endorsing degeneracy theory provided alienists with a scientific explanation of mental pathology which a somatic approach had failed to discover. L'Heredite is a synthesis of biology, exolutionary ideas and the features of heredity, addressed and related to social concerns of the last three decades of nineteenth-century France. PMID- 11619818 TI - Towards defining the Freudian unconscious: seduction, sexology and the negative of perversion (1896-1905). PMID- 11619819 TI - Chloroform-induced insanity defence confounds lawyer Lincoln. AB - During an 1857 trial, the defence claimed that the accused should be absolved of wilful murder because an overdose of chloroform during surgery induced insanity. In a rare appearance as a prosecutor, Abraham Lincoln tried the case for the State of Illinois. Expert medical witnesses testified about the side effects of chloroform and chloroform-induced insanity. Significantly, Lincoln was not knowledgeable about medical jurisprudence and overlooked potential sources of evidence and expert witnesses. Defence lawyers presented an impressive array of physicians to testify about insanity, about chloroform and about the results of an overdosage during anaesthesia. Considering the state of scientific knowledge at the time, the trial was notable. PMID- 11619820 TI - Mad, not bad: crime, mental disorder and gender in nineteenth-century Ireland. PMID- 11619821 TI - The pauper insane of Leicester in 1844. AB - In 1844 the Poor Law Commissioners followed up a dispute with the Guardians of Leicester Union regarding the care of Pauper Lunatics by appointing Dr Samuel Hitch, an Assistant Poor Law Commissioner, to survey the treatment and condition of the pauper insane in Leicester and Birmingham Workhouses. At Leicester he exceeded his brief and surveyed the 13 insane on outdoor relief, 29 in the workhouse and 23 in the asylum. As such it is one of the earliest surveys of an area. This paper describes the dispute, the report and considers its aftermath. PMID- 11619822 TI - The Willis family and George III. PMID- 11619823 TI - 'Concerning memory deceptions'. Translated and with an introduction by I.S. Markova. PMID- 11619824 TI - Race, culture, and the colonization of childbirth in northern Canada. AB - This paper traces the history, in northern Canada, of what childbirth has been made to stand for in the relationship between aboriginal women and the agents of colonization. During the early centuries of contact, European impressions of aboriginal women were dominated by associations with animal nature and the myth of painless childbirth, with the result that the culture of childbirth and the role of the midwife were overlooked. During the nineteenth century, the emphasis upon racial difference was reinforced by evolutionary theory, and the myth of the 'savage' woman's 'parturition without pain' was put to rhetorical use by health reformers, physicians, and feminists in Europe and North America. Meanwhile, the realities surrounding childbirth in aboriginal communities received little attention from colonial authorities until high infant and maternal death rates began to arouse official concern in the early twentieth century, when they were blamed on aboriginal women's ignorance of healthy child-bearing practices. As part of its 'civilizing mission', the Canadian government adopted an interventionist policy which led, in recent decades, to the practice of evacuating pregnant women to distant hospitals. This policy has had serious social consequences, and resistance on the part of aboriginal women includes the attempt to legitimize a traditional culture of childbirth disregarded throughout the colonization process. PMID- 11619826 TI - Shaping institution-based specialism: early twentieth-century economic organization of medicine. AB - This paper focuses on structural development of institution-based medical specialism in the USA in the first third of the twentieth century. It examines organizational ideas of key reformers and specialty leaders and it examines corresponding characteristics of the institutions they built. The structural characteristics which they incorporated into medical care embodied forms of economic organization of the time. Leaders (variously) explained their reform activities in terms of scientific, professional, and/or economic development of medicine. The first section describes a form of specialization within academic medical centres as a vertical functional division of labour which divided medical work into procedures performed by a range of personnel. This division of labour and its required management changed the work of doctors and nurses and required a multiplication of 'auxiliary' hospital staff, as shown in the second section. The final section demonstrates how the departmental structure within academic medical centres provided a necessary institutional framework for vertical specialism. The literature has emphasized the fact that an industrial model was only partly implemented in medical care at the time. Nevertheless, the (industrial) characteristics identified had a significant impact on fundamental structures of twentieth-century medicine. PMID- 11619825 TI - The issue of never-married motherhood in Britain, 1920-70. AB - This article examines shifts in attitudes and changes in provision with regard to never-married mothers within three broad chronological periods. The first section considers attitudes towards these mothers in the period 1918-45, when the issue was conceptualized as one of public health and moral welfare. Second, the article examines the period between 1945 and 1970, when the dominant professional view of never-married mothers focused on identifying individual pathology, but when significant continuities in treatment can nevertheless be found. Third, the article looks briefly at the substantial change in policy and provision for what were then called 'one-parent families' during the 1970s. In conclusion it argues that while there were substantial changes in terms of the way in which unmarried motherhood was defined, from the point of view of the unmarried mothers themselves the continuities have been more striking. Unmarried mothers have been persistently singled out and labelled a social problem and, in all but a brief period during the late 1960s and 1970s, also as a moral problem. PMID- 11619827 TI - 'My beloved chloroform'. Attitudes to childbearing in colonial Queensland: a case study. AB - In 1847 the anaesthetic and analgesic properties of chloroform were discovered. This technology generated a new era for midwifery: mothers could be relieved of pain in childbirth. The introduction of chloroform for childbirth saw increasing medical dominance in obstetrics, traditionally in the hands of the midwife. At the same time the use of chloroform sparked a medical and moral controversy which lasted for several decades. On the one hand women were destined by the 'curse of Eve' to experience pain during childbirth; on the other, medical humanitarians and practitioners believed that there were technical and moral reasons for alleviating pain in childbirth. In concentrating on the debate historians have largely ignored the reactions of mothers to the introduction of the technology. This paper explores changing attitudes to childbearing within the context of colonial Queensland society, 1860-90, by examining the correspondence of an upper class mother. Her education and liberal outlook, and a certain ambivalence towards motherhood, all influenced her attitude to the use of chloroform and the process of childbirth. PMID- 11619828 TI - Fear and envy: sexual difference and the economies of feminist critique in psychoanalytic discourse. AB - This essay examines Freud's construction of a mythical moment during early childhood, in which differences between male and female sexual identities are said to originate. It focuses on the way in which Freud divides fear and envy between the sexes, allocating the emotion of (castration) fear to men, and that of (penis) envy to women. On the one hand, the problems of this construction are pointed out, but on the other hand, it is shown that even a much-maligned myth may still provide food for thought. Then, four critiques of Freud which have been articulated by prominent feminist psychoanalysts -- Karen Horney, Nancy Chodorow, Luce Irigaray, and Jessica Benjamin -- are presented, as well as the alternative visions of sexual identities which these thinkers have developed. The basic metaphors or economies guiding these visions of sexual difference are appraised in terms of their breadth and depth, with particular reference to their ability to acknowledge and integrate the presence of fear and envy as passions which are evoked but also repressed in the face of sexual difference. ... PMID- 11619829 TI - Physicians and gumshoes: prescription for bad medicine, or the man who didn't like doctors. AB - Raymond Chandler, the creator of legendary detective Philip Marlowe and the recipient of increasing literary admiration over the past 40 years, used numerous physicians as minor characters in his novels and short stories. The presence of physicians as minor characters in Chandler's work, though unnoticed by previous critics, is illustrative both of the writer's personal antipathy towards medical doctors and larger societal forces which left medical charlatans free to open "clinics." Chandler's own chronic health problems and those of his wife Cissy may have contributed to the writer's negative attitude toward medicine and health care, though little is known of Chandler's personal interactions with physicians prior to his death in 1959. PMID- 11619830 TI - Consilience among the great branches of learning. PMID- 11619831 TI - Peter of Spain, Albert the Great and the Quaestiones de animalibus. PMID- 11619832 TI - [Not Available]. AB - In the Lombard-Veneto Kingdom, founded in 1815 under Austrian rule in the northwestern regions of Italy, the mineral waters were the object of a special attention by the political authorities, often with the direct intervention by the Archduke Ranieri. Chemical researches on the properties, composition, transportation and conservation of the water from different sources in the area of Recoaro, near Vicenza, were carried out by Girolamo Melandri Contessi (professor of chemistry at Padua University). In his work, carried out for ten years and more, he developed a new analytical procedure by following the suggestions made by J. Murray, a Scottish physician who applied the stoichiometric relations to the quantitative determination of salt content. The gas content was exactly measured with the Lavoisier's gasometer, improved by a device for the fine gauge. Melandri also built an apparatus for bottling water with carbon dioxide to avoid contamination by atmospheric oxygen. PMID- 11619833 TI - [Not Available]. PMID- 11619834 TI - T. B. in transition - a personal perspective. PMID- 11619835 TI - C Louis Leipoldt (1880-1947). PMID- 11619836 TI - Recollections of the Class of '50. PMID- 11619837 TI - The medical school of the University of Witwatersrand - a brief history. PMID- 11619839 TI - Text and illustration: the digitisation of a medieval manuscript. AB - This paper considers the choice of the medieval Aberdeen Bestiary as the first project in Aberdeen University Library's digitisation programme, and discusses some of the unusual features of the manuscript itself. Attention is given to the content and depth of the accompanying commentaries, and particular notice is paid to the nature and extent of the textual apparatus (translation and transcription). The factors influencing the choice of (a) PhotoCD as the image capture method, and (b) JPEG as the image format for transmission of the page images across the World Wide Web are examined. The importance of the Web design to the effectiveness of the overall resource is emphasised. PMID- 11619838 TI - Roentgen - Arrhenius correspondence. PMID- 11619840 TI - "Now the all-engrossing subject". PMID- 11619841 TI - Pharmacy and education, 1841-1899. PMID- 11619842 TI - Charles Elliot and Spilsbury's antiscorbutic drops. PMID- 11619843 TI - English apothecaries and probate inventories: their use in pharmaceutical history. PMID- 11619844 TI - Charles Loomis Dana: a guide to the Academy's holdings. PMID- 11619845 TI - Digitizing patient information and laboratory research data for archival reference and research. PMID- 11619846 TI - Did "undesirable" immigrants carry a special gene for uncontrollable Wanderlust? PMID- 11619847 TI - Pharmaceutical wholesale distribution in the United Kingdom - its development to 1950. PMID- 11619848 TI - Hubert Harrington Warner, the patent medicine "king". PMID- 11619849 TI - Tops of the pots II: a unique West Australian collection. PMID- 11619850 TI - A tale of two stones: the impact of medical history on contemporary medical Halakhah. AB - The advances in modern medicine have spawned a myriad of ethical and halakhic dilemmas. Modern day poskim (rabbinic authorities) address these issues by relying heavily on the works of their predecessors, works that often refer to contemporaneous medical theories and practice. While the principles of Halakhah have remained unchanged since the giving of the Torah, the principles of medical theory and practice have changed radically over the centuries. Therefore, when approaching any pre-20th-century medical halakhic text, it is imperative to realize that the medical theories and practices discussed therein can only be understood in their proper historical context. This essay analyzes two rabbinic sources from the 18th century which discuss a particular disease and its treatment. The contemporaneous history of this disease is presented for the purpose of clarifying the ambiguities of the text and preventing possible anachronistic interpretations and halakhic misapplications. PMID- 11619851 TI - The sexual behavior of American GIs during the early years of the occupation of Germany. PMID- 11619853 TI - Some observations on writers and suicide. PMID- 11619852 TI - An expanding service: municipal acute medicine in the 1930s. PMID- 11619854 TI - From physicians' enquiry to Dewar report: a survey of medical services in the West Highlands and Islands of Scotland, 1852-1912: Part I. PMID- 11619855 TI - The development of the clinical thermometer. PMID- 11619856 TI - The last illness of Lord Byron. PMID- 11619857 TI - The medical history of John Knox. PMID- 11619858 TI - Biologizing social facts: an early 20th century debate on Kraepelin's concepts of culture, neurasthenia, and degeneration. AB - This paper uses an historical approach to elucidate two alternative modes of conceptualizing the relation between social factors and psychological phenomena perceived as pathological. The core features of Neo-Kraepelinian psychiatric nosology associated with the introduction of DSM-III in 1980 were also at the center of a debate in early 20th century Germany. The protagonists were Emil Kraepelin and Oswald Bumke. Kraepelin's empirical research selectively focused on somatic factors as independent variables, such as alcohol, syphilitic infection, and heredity. The ensuing nosology marginalised social factors which might contribute to the etiology and symptom formation of psychiatric conditions. For Bumke, the disorders in question (including the category of neurasthenia) did not represent qualitative deviations from normal psychological states, but quantitative variations of ubiquitous psychological functions caused by a multitude of somatic, psychological, and social factors. The main arguments of the historical debate are reconstructed, with special regard to the professional and political context. The paper illustrates the importance of context-bound pre 'scientific' decisions for the process of formulating theoretical concepts in psychiatry and related disciplines. PMID- 11619860 TI - Galen and the ventricular system. AB - This paper examines the anatomy and physiology, together with the pathophysiology, of the ventricular system of the brain, as it was understood by arguably its greatest exponent in Western Antiquity, Galen. According to him, the purpose of the ventricles was to elaborate, store and distribute psychic pneuma, the motive force of Galenic neurology, throughout the nervous system. However, impressive as the delineation of the ventricular system is, the details of this distribution are not forthcoming from Galen. Finally, I discuss the ventricles as the site of intellect, a notion only tentatively advanced by Galen, but cast into dogma by his successors. For all the mistakes Galen made in anatomy and physiology, the study of the ventricular system reveals a mind not dissimilar to our own. PMID- 11619859 TI - Edwin Sisterson Clarke (1919-1996). PMID- 11619861 TI - Albert the Great's interpretation of neuropsychiatric symptoms in the context of scholastic psychology and physiology. AB - Albert the Great (ca. 1193-1280) serves as an example to show how the Latin West successfully integrated Greco-Arabian psychology with Galenic physiology. He divised a model of perceptive, cognitive and mnestic powers located in different areas of the "brain cells" and interacting with the immaterial and man-specific intellect. He managed to describe anmesis, epileptic seizures and psychotic states as results of disturbed brain fuction. Finally, further aspects of Scholastic theorizing on mental disorders are discussed. PMID- 11619862 TI - William A. Hammond, the dynamograph, and bogus neurologic testimony in old New York. AB - April 25, 1870, court of General Sessions, New York City, Doctor William A. Hammond, neurologist and former Surgeon General of the United States Army, testified at the trial of his patient Daniel McFarland. McFarland had fatally wounded famous journalist Albert Richardson in November of 1869. Dr. Hammond said McFarland suffered from temporary insanity due to cerebral congestion from over use of the brain. Hammond told the jury he had, "devoted the last five years of his professional life exclusively to the study of the mind", and opined that the evidence of cerebral congestion was profound: McFarland's head was hot, and his carotid throbbed. The proof came from the test with the dynamograph machine: McFarland could not keep a pencil still to trace a straight line in the center of a moving piece of paper. The dynamograph, Dr. Hammond assured the jury, measured the power of a man over his will and thus provided "full and decided evidence" there can be no doubt that McFarland "could not control his will". What were the motivations behind the testimony of this famous expert witness? Did bogus neurologic testimony exist in old New York over a century before our time? PMID- 11619863 TI - Theodor Meynert (1833-1892), pioneer and visionary of brain research. AB - Theodor Meynert (1833-1892) was the first scientist to perceive brain research as an interdisciplinary project, documented by his own fundamental contributions as a selfstanding enterprise and presented with comprehensive objectives of research. Meynert was born in Dresden and lived in Vienna from the age of 8. In a steep career, he reached high professional recognition: Aged 37, he took charge of the management of the 1st Psychiatric Clinic, established especially for him; he exerted competent influence in the so-called 2nd Viennese School of Medicine and at international level. The focal points of his scientific work have been anatomy and histology of cerebrum and brainstem, topography and functional relations of the main connecting fiber systems, also demonstrated by precisely interpreted clinipathological obaservations. Among his timely findings should be stressed: the stratified texture, cellular architecture and regional differentiation of the cerebral cortex as a basis of present cytoarchitectonics and of cortical localisation theory, e.g., regarding speech defects. Intending to establish psychiatry as an exact science on the basis of brain pathology, Meynert formulated a program which anticipates the targets designed by today's biological psychiatry. The vital and psychic dynamics of the brain he interpreted in critical speculation along the lines of the contemporary philosophy of nature. Meynert combined his ingenious exact findings with results of the upcoming neurophysiology, neurochemistry and neuropsychology into a prodigious coherent system representing the complexity of the human brain-world relationship. These achievements reveal Meynert as the founder of scientific brain research. PMID- 11619864 TI - Jean-Martin Charcot and the epilepsy/hysteria relationship. AB - Research from many perspectives has been made on the work of the French neurologist, J.-M. Charcot (1825-1893) with particular reference to his fame for his studies and "construction" of hysteria. What has not been demonstrated so far is the extent to which Charcot's construction can be explained by the perceived relationship between hysteria and epilepsy and Charcot's access to epileptic patients at La Salpetriere. From the confusion that reigned concerning hysteria and epilepsy, both separately and in relation to each other, Charcot claimed to have isolated hysteria as a distinctive and universal pathology. This claim was partly based on the "grande attaque", representing the most intense degree of hysteria. A comparison with Gowers, the contemporary English neurologist suggests that diagnosis was the function of the practitioners' preferences; and a linguistic analysis pinpoints Charcot's problems in describing an isolated pathology in terms of its relation to its neighbour, epilepsy. PMID- 11619865 TI - From DOPA to Parkinson's disease: the early history of dopamine research. AB - Dopamine is among the most well-researched neurotransmitters at the present time. For the first half-century of neurotransmitter research, however, interest in dopamine was minimal, and only a few scattered groups of researchers studied it. It was their research that stimulated current interest, and provided the background for our present understanding of this important substance. By the late 1950s, it was clear to these individuals that dopamine served an important physiological role in mammalian brains, and that its role was most likely that of a central nervous system agonist. Soon after this, dopamine, or more specifically the depletion of dopamine, was clearly implicated in Parkinson's disease. This paper looks at the early history of the physiological roles of this intriguing compound. PMID- 11619866 TI - Cognition and multiple sclerosis: a historical analysis of medical perceptions. AB - The earliest descriptions of multiple sclerosis (MS) rarely distinguished cognitive impairment from the general category of "mental symptoms", which also encompassed a broad range of affective disorders. Case-study methods led to disputes about the extent and nature of these symptoms, exacerbated by different national medical traditions. Appropriate scientific methods were only used to investigate cognitive performance in a modest number of studies up to the 1960s, and it was being argued as late as the mid 1970s that affective processes rather than cognitive processes were the key to understanding the psychological aspects of MS. However, the early 1980s, saw major developments in test procedures for the detection of subtle and selective cognitive changes, in the use of brain imaging techniques, and in collaboration between neurologists and neuropsychologists. Pressure to use research findings to improve patients' daily lives suggests a need to reconsider the connection between affective and cognitive processes in MS. PMID- 11619867 TI - Three head injuries: the Biblical account of the deaths of Sisera, Abimelech and Goliath. AB - Three head injuries are described in the Bible: the death of Sisera at the hands of Jael, the skull fractures inflicted on Abimelech near the walls of Thebez, and the slaying of Goliath by David. The various attempts to understand the mechanisms of these head injuries are reviewed. We shall try to identify the site of the mortal blow on Sisera's head, to understand why Abimelech, still conscious, asked to die, and to clarify whether the Philistine giant from Gat was a rugged warrior or just an endocrinological cripple. PMID- 11619868 TI - Newborn infants with yellow brains: the discovery of kernicterus in Germany, 1875 1908. AB - Kernicterus, described in the period just before Kinnier Wilson's publication of his study of hepatolenticular degeneration, served him as a model of liver dysfunction associated with neurological disorder. The work of the early investigators of kernicterus, especially their descriptions of the pathological changes in the brain, led Wilson to postulate that a hepatotoxin was responsible for the neurological entity that he elucidated. PMID- 11619869 TI - Edward Meryon (1807-1880): his life and Huguenot background. PMID- 11619870 TI - Bernhard Bardenheuer's (1839-1913) contribution to the development of modern urology. PMID- 11619872 TI - That the blind may read: the legacy of Valentin Hauy, Charles Barbier, Louis Braille and William Moon. PMID- 11619871 TI - Henry Head: man of culture, compassion and science. PMID- 11619873 TI - G E Morrison: an Australian in China. PMID- 11619874 TI - Leonard Wood: the physician who was almost President of the United States. PMID- 11619875 TI - Extinction of the speckled monster celebrated in 1996. PMID- 11619876 TI - Anne Boleyn, the sweating sickness, and the hantavirus: a review of an old disease with a modern interpretation. PMID- 11619877 TI - Vincent van Gogh and Felix Ray MD: the whereabouts of half an ear. PMID- 11619878 TI - Henry Bence Jones and his protein. PMID- 11619879 TI - [The French Revolution and mental troubles 1789-1799]. AB - Are wars and political strife factors in the cause of mental diseases? For instance what do we know about the French Revolution? Contemporary writers of memoirs are untrustworthy, whether opponents or supporters. We have neither morbiditiy nor mortality statistics nor accurate diagnostics, for the patients in public hospitals or private mental homes. A few cases are described for some mystical or political lunatic women, and some Jacobin leaders. The "psychiatrists" of that time have not noticed any increasing of insanity: a revolution is not enough to provoke mental disease, but it may reveal it. PMID- 11619880 TI - An early reader of Vesalius' Fabrica. AB - Hieronymus Gemusaeus (1505-1544), Professor of Medicine at Basle, is the earliest known reader of Vesalius' "Fabrica", commenting on it in a preface dated 1 August 1543. PMID- 11619881 TI - Brief history of medicine in Slovenia. AB - Slovenes have lived in the territory of today's Slovenia for more than 14 centuries, whilst the history of its medical culture goes back for 2000 years. The advent of Christianity in Slovenia in the eighth century AD marked an important turning point in the development of its medicine. The 500 years of the Habsburg monarchy was later to have a further impact on the development of new medical ideas. During the Renaissance, the names of the Slovene doctors Mattioli, Paracelsus, Scopoli and Hacquet, who worked among Slovenians, were to become known all over Europe. Others of Slovene origin were Perlach, Santorio, Gerbezius, Carbonarius, Plenciz, and Sagar, whose work influenced European medical culture, especially in German speaking countries. However their Slovene nationality was not acknowledged until the second half of the 19th century. PMID- 11619882 TI - [Near relations of Georges Mareschal, first surgeon of Louis XIV and Louis XV (1658-1736)]. AB - Georges Mareschal, First Surgeon to Louis XIV and then to Louis XV, exercised a great influence on some near relations of his, who, like him, became excellent surgeons. A nephew of his, Martin Guerin, probably Marie Roger's sister's son, Mareschal's wife, distinguished himself as a surgeon. His uncle made him Ordinary Surgeon of the "hopital de la Charite" in Paris. His hand was "swift and skilful". He gave treatment to Colonel de Fenelon, a French archbishop's great nephew, war wounded in 1713. And he operated on James Edward Stuart of England for "fistula", the "Old Pretender" or the "Chevalier de Saint-Georges", in Avignon, in 1716. Martin Guerin's eldest son, Georges Guerin, was also a highly esteemed surgeon. On and after 1733, he was successively a surgical departmental head of the Italian Army, a chief-surgeon of the "Hopital de la Charite" in Paris, a surgical officer of the second Musketeer Company. He was ennobled by Louis XV and received the ribbon of the "Ordre de Saint-Michel". One of Georges Guerin's sisters married the surgeon Sauveur-Francois Morand, who achieved celebrity for the diversity of his operations and his works. He delivered a funeral oration in praise of Georges Mareschal, at the meeting of the "Academie royale de chirurgie" on June 18th 1737. His son, a medical doctor, Clement Morand, and his son-in-law, the surgeon Sabatier, were not second to him as far as talent is concerned. Mareschal's fourth near relative, an anatomist, got himself talked about in connection with an autopsy. He was the husband of one of Elisabeth du Brun's daughters, Mareschal's sister. PMID- 11619883 TI - Medical honoraria in the 17th century. AB - Paolo Zacchias (1584-1659), the physician of the Pope, in his main work, "Quaestiones medico-legales" (Rome, 1621-1625) provides answers to hundreds of important practical and theoretical questions. On the following pages the author tries to summarize Zacchias's opinion concerning the problem of honorarium and fee, hoping that this short extract will prove to be useful for the modern physician as well. PMID- 11619884 TI - The devil's apples. AB - The magic of the Mandrake grew with the passage of time. Elusive in its origins, where its associations lay with the age-long mysteries of love, its potency lingers on through the medicine of the Middle Ages, then beyond the Renaissance to find an historical mention even in the mid twentieth century physicians' vade mecum, Martindale's Extra Pharmacopoeia. But before it is stripped of its more dramatic pretensions to stand revealed, there are romantic byways to explore, where it has played a role as powerful as its pharmacological properties; and these are real enough. Its nature is of the essence of mediaeval medicine. Its first secrets were those of love and fecundity and sleep. Sterile marriages were anathema to the Jews. What better authority to search for the means of their correction could be found than in The Bible itself, which records the success of the Mandrake in promoting fertility, when every other subterfuge had been exhausted. PMID- 11619885 TI - [Military surgery in the years of the Great Patriotic War. (Recollections of a surgeon)]. PMID- 11619886 TI - The inside story of medicines: a symposium. PMID- 11619887 TI - The discovery of M & B 693 (sulfapyridine) PMID- 11619888 TI - The introduction of the thiazides: a case study in twentieth-century therapeutics. PMID- 11619889 TI - Planning and serendipity in the search for a nonaddicting opiate analagesic. PMID- 11619890 TI - Old drugs, old and new history. PMID- 11619891 TI - The recent history of pharmacognosy. PMID- 11619892 TI - Pharmacology: current and future trends. PMID- 11619893 TI - Current and future trends in medicinal chemistry. PMID- 11619894 TI - Recent trends and the future of pharmaceutics. PMID- 11619895 TI - Clinical trials: new developments and old problems. PMID- 11619896 TI - Recent trends in drug development. PMID- 11619897 TI - Sure cure: public policy on drug efficacy before 1962. PMID- 11619898 TI - Historical perspectives on the marketing of medicines. PMID- 11619899 TI - The therapeutic crisis of the eighteenth century. PMID- 11619900 TI - Medicines in American society--a personal view. PMID- 11619901 TI - The road to twentieth-century therapeutics: shifting perspectives and approaches. PMID- 11619902 TI - Alkaloids to arsenicals: systematic drug discovery before the first world war. PMID- 11619903 TI - The discovery of insulin: the inside story. PMID- 11619904 TI - [Military officers of Ukraine - leaders of military-medical service during the years of the Great Patriotic War of 1941-1945]. PMID- 11619905 TI - [History of the Kiev military hospital during the Great Patriotic War]. PMID- 11619906 TI - [A tale of Nachsanarm Boiko and his comrades]. PMID- 11619907 TI - [Moorings of the hope (recollections of a medical officer)]. PMID- 11619908 TI - [In memory of Wilhelm von Hebra (On the 50th anniversarky of his tragic death)]. PMID- 11619909 TI - [On specification of some facts from the history of Ukrainian medicine]. PMID- 11619910 TI - [On the 150th anniversary of the Department of Faculty Therapy of Academy A.A. Bogomolets Ukrainian Medical University]. PMID- 11619911 TI - [Ukrainian medical scientists - victims of Stalin's repressions]. PMID- 11619912 TI - [Chernobyl aftereffects]. PMID- 11619913 TI - [Contribution of Kiev pathologist and therapeutist Yu.I. Matson to scientific development of the method of thorax percussion]. PMID- 11619914 TI - [Theodor Billroth and his school of surgery]. PMID- 11619915 TI - [The invention of X-rays belongs to Professor Ivan Pulyui]. PMID- 11619916 TI - [Medicine in the context of history and culture of Ukraine]. PMID- 11619917 TI - [The library of the college of physicians of Philadelphia and its Russian collection]. PMID- 11619918 TI - [Medical security system in Bulgaria: retrospections and prospects]. PMID- 11619919 TI - Paradox and persuasion: negotiating the place of molecular evolution within evolutionary biology. PMID- 11619920 TI - German women in chemistry, 1895-1925 (Part I). AB - The paper traces the entrance of German women into the chemistry profession from the 1890s to 1925, examining how they first overcame social and cultural conservatism to obtain access to opportunities for a chemical education during the later Kaiserreich, then began to seek academic and industrial careers and to establish a professional organization in the face of resistance from the established Verein Deutscher Chemiker. The paper examines the effect of World War I and the advent of the Weimar Republic in completing the process whereby German women achieved a small but significant role in the profession of chemistry, in science as well as industry. Finally, it discusses the considerable limitations on women's full and equal participation that still remained by 1925. PMID- 11619922 TI - George Urdang Medal remarks. PMID- 11619921 TI - [Not Available]. AB - The euthanasia action in Nazi Germany during 1940/41 ("Aktion T4") belongs to the most horrible chapters in history of medicine. The article describes the life of Horst Schumann, who was involved in the murder of more than 15 000 people and after that did cruel sterilization experiments in Auschwitz. It will be depicted the personal characteristics to show, why he was susceptible to this development. The critical look at these events shall warn us not to push away mental patients and mentally handicapped people from our society. The personal rights of this group of patients must not be questioned. PMID- 11619923 TI - The letters of Dr. William Brown to Andrew Craigie. PMID- 11619924 TI - Pharmaceutical impact on cost reduction in German hospitals prior to World War II. PMID- 11619925 TI - The history of optometry in America: information waiting to be found. PMID- 11619926 TI - Reappraising Foucault. [Review of: Davidson AI, ed. Foucault and his interlocutors. University of Chicago Press, 1997; Foucault M. "Il faut defendre la sociee: Cours au College de France, 1976. Paris, 1997]. PMID- 11619927 TI - The most select and the most democratic: a century of science in the Royal Society of Canada. AB - This paper is a history of the Science Academy of the Royal Society of Canada, from its foundation in 1882 until the early 1990s. The RSC has always had an honorific role, but it has sought a more substantive one in scientific publication (a role that it has largely lost to the National Research Council and to other scientific societies and journals), in educating the public, in reperesenting Canada internationally, and in undertaking scientific inquiries of public import, for example in assessing the risks associated with nuclear winter, or in the Canadian Global Change Program. Often, Fellows of the RSC have individually achieved more in science than the Society has achieved institutionally but as this narrative shows, the dynamic between science, government, the RSC, and the Canadian public, has been important in Canadian science and in Canadian history. PMID- 11619928 TI - Patronage and power: the College of Physicians and the Jacobean court. PMID- 11619929 TI - The Ram's Horn: the commonplace book of Dr. Earle Parkhill Scarlett. AB - Dr. Earle Scarlett (1896-1982) was "a man for all sasons:" he was a flourishing internist in Calgary, Alta., and a proud, self-confessed "medical truant." One of his greatest accomplishments was his written work; he published over 500 articles in several journals. His passion for books and reading gave rise to his commonplace book, The Ram's Horn. He used this collection of poems, prose, quotations, thoughts, and ideas as a source for his articles, most of which focused on historical and philosophical matters, and were rich in references to literary figures, mythology, and the Bible. The Ram's Horn contains writings that he deemed to be worthwhile and enjoyed reading over again. This book gives insight into the writings and interests of Scarlett, and in his words. "sound[s] a full-blooded compliment to [his] life." PMID- 11619930 TI - "Che" Guevara, the final chapter. PMID- 11619931 TI - Dr. Hastings Kamuzu Banda. PMID- 11619932 TI - A Japanese cancellation. PMID- 11619933 TI - Asklepios or not- that is the question. PMID- 11619934 TI - The Richard Benedict Goldschmidt papers. PMID- 11619935 TI - The Wistar Institute Archives: rats (not mice) and history. PMID- 11619936 TI - Sources for the study of biology at the Scripps Institution of Oceanography. PMID- 11619937 TI - Controversy and the state: lord ARPA and intelligent computing. AB - This is a study of a well-known controversy in computer science, between artificial intelligence and neural networks researchers. It examines claims made by participants in the field that the controversy was triggered, shaped and finally resolved in connection to activities of state research agencies, particularly the US Department of Defense Advanced Research Projects Agency (ARPA). In contrast to these claims, this account concludes that, although ARPA's relations to the controversy among researchers were important, they were indirect. This study thus beings the analytical resources of studies of scientific controversy to bear on a domain which has so far gone largely unexamined in studies of 20th-century controversies - namely, state research policy and management. The account is based on contemporary documents, historical literatuare, and interviews with researchers and ARPA officials. PMID- 11619938 TI - Recombination, rationality, reductionism and romantic reactions: culture, computers, and the genetic algorithm. AB - The genetic algorithm (GA) is a computational procedure that 'evolves' solutions to optimization problems by generating populations of possible solutions, and then by treating these solutions metaphorically as individuals that can 'mate' and 'compete' to 'survive' and 'reproduce'. In this paper, I explore how culturally specific notions of evolution, population, reproduction, sex/gender, and kinship inflect the ways GAs are assembled and understood. Combining the results of fieldwork among GA workers with analysis of GA texts, I contend that the picture of 'nature' embedded in GAs is resonant with the values of secularized Judeo-Christian white middle-class US-American and European heterosexual culture. I also maintain that GA formulations are accented by languages inherited from sociobiology. I argue that examining GAs can help us track how dominant meanings of 'nature' are being stabilized and refigured in an age in which exchanges of metaphor between biology and computer science are increasingly common. PMID- 11619939 TI - Sir William Brooke O'Shaughnessy, M.D., F.R.S., F.R.C.S., F.S.A.: a biographical appreciation by an electrical engineer. PMID- 11619940 TI - Lionel Penrose, F.R.S. (1898-1972) and eugenics: part one. PMID- 11619941 TI - The 1997 Wilkins lecture: Erasmus Darwin, the lunaticks and evolution. PMID- 11619943 TI - Fertility decline in Scotland, England and Wales, and Ireland: comparisons from the 1911 census of fertility. AB - Data on family size by year of marriage, age at marriage, and duration of marriage, from the 1911 Fertility Census, are compared between Scotland, England and Wales, Irish county boroughs, and the rest of Ireland. While means show significant inter-country differences, from the 1880s marked similarities are found across all the countries in the pattern of fertility decline, strongly suggesting significant fertility limitation in rural Ireland well before 1911. Noting the implications for the use of rural Ireland as a natural fertility population, the data are instead compared with the Coale-Trussell and Hinde-Woods schedules. The former provides more plausible results, which imply strong period rather than cohort effects in the fertility decline. Except in rural Ireland, little evidence is found for significant fertility limitation early in marriage among younger marrying couples, but many older marrying couples appear to have stopped childbearing at very low parities from an early date. PMID- 11619942 TI - Uncovering the Arundel Library at the Royal Society: changing meanings of science and the fate of the Norfolk donation. PMID- 11619944 TI - Relationships between nuptiality and fertility: a case study on the Spanish Province of Navarre, 1786-1991. AB - In this article we analyse the influence of age at marriage and percentage of definitive celibacy on marital and total fertility over the past two hundred years in the Spanish province of Navarre. A considerable percentage of the fall in marital fertility in the first half of the twentieth century in rural Navarre was due to the postponement in women's age at marriage. On the other hand, Navarre offers many exceptions to the scenario often endorsed by researchers that sees marriage as the prime mechanism for regulating reproduction in traditional societies. While in the northern part of the province this mechanism did bring about the reduction of total fertility, in the southern part the fall was primarily a consequence of a fall in marital fertility. PMID- 11619945 TI - 'Between one and three million': towards the demographic reconstruction of a decade of Cambodian history (1970-79). AB - Estimates of mortality in Camabodia during the Khmer Rouge regime (1975-79) range from 20,000 deaths according to former Khmer Rouge sources, to over three million victims according to Vietnamese government sources. This paper uses an unusual data source - the 1992 electoral lists registered by the United Nations - to estimate the population size after the Khmer Rouge regime and the extent of "excess" mortality in the 1970s. These data also provide the first breakdown of population by single year of age, which allows analysis of the age structure of "excess" mortality and inference of the relative importance of violence as a cause of death in that period. The estimates derived here are more comparable with the higher estimates made in the past. In addition, the analysis of likely causes of death that could have generated the age pattern of "excess" mortality clearly shows a larger contribution of direct or violent mortality than has been previously recognized. PMID- 11619946 TI - The adoption of fertility control on Mykonos, 1879-1959: stopping, spacing or both? AB - This abstract examines the timing and means of the fertility transition on the Greek island of Mykonos in the period 1879 to 1959. By combining the results of family reconstitution with oral evidence, an unusual insight into the pathways of the fertility transition of this island population is offered. The paper concludes by outlining a model of the adoption of fertility control, a model which sees the transition from high to low fertility as a transition from spacing to stopping, and from innovation of methods to innovation of ideas. PMID- 11619948 TI - The Civil Veterinary Service in the former Dutch East Indies. PMID- 11619947 TI - Western veterinary medicine in colonial Africa: a survey, 1902-1963. PMID- 11619949 TI - [Not Available]. PMID- 11619950 TI - [Not Available]. PMID- 11619951 TI - [Not Available]. PMID- 11619952 TI - Holy anorexia revisited: the reputation of fasting in the case of Maria Janis. PMID- 11619953 TI - Otto Fenichel - historian of the psychoanalytic movement. PMID- 11619954 TI - Seneca, ethics, and the body: the treatment of cruelty in medieval thought. PMID- 11619955 TI - Medical profession changes between religion, science, skill, ethics, law and economics. AB - How has the medical profession changed during the centuries? How has the evolution of the profession been influenced by the balance of different issues, e.g. magic, religion, philosophy, science, technology, ethics, law and/or economics? One needs to examine many historical changes leading from the hierarchized medicine of Ancient Egypt to the Asklepiadic and Hippocratic medicine at the time of Plato, from the newly organized medicine of the Renaissance to the emerging social medicine of the XIX century, from the nosological medicine centered on the evaluation of the symptoms to the medicine which explores the human body through technologies. Furthermore, an overview from the past to the future should analyze the new doctor-patient relationship in a health system of managed care, between market and solidarity, between the efficientistic guidelines of the providers (hospitals, physicians, etc.) and an anthropocentric view of the rights of the citizen-customers. These problems are presented and discussed by many Authors in three issues of Medicina nei Secoli (II/III.1997-I, 1998) as an aid to understanding what it means to be a physician today, from the past to the future. PMID- 11619956 TI - [Physicians in the Pharaonic Ages' Egyptian society]. AB - Egyptian tombstones and funerary stelae dating to the ancient Empire well testify the hierarchies existing in the Egyptian medical society. This article deals with both formal and practical aspects of the medical profession, and with the deeper meaning connected to the most interesting medical titles. PMID- 11619957 TI - [The doctor and his relationship with patients in Greece in the fifth and fourth centuries B.C]. AB - Ever since the fifth century B.C. Greek doctors were well aware of the importance and implications of the doctor/patient relationship. In the fifth and fourth centuries B.C. two contrasting views developed. The first is set out in various treatises of the corpus Hippocraticum, especially in those in which the genuine hippocratic spirit seems to be present, with significant echoes in Platonic thought. According to this, the doctor should carry on a continuous informative and persuasive dialogue with the patient. Under the alternative view, which is explained most clearly in another treatise of the Corpus entitled The Art, the medical practitioner, as the only person possessing scientific knowledge, acts only to convey instructions to ill people, without trying in any way to instal an exchange of information with them. This second model of the doctor/patient relationship has undoubtedly dominated throughout the history of western medicine, until this century in fact. Only recently has the need to involve the patient more directly in treatment been realised, as part of a humanistic approach to medicine. PMID- 11619958 TI - Medical instruments in the Roman world. AB - By the beginning of the 1st century AD Roman medical instruments had begun to acquire the distinctive forms which they were to retain, more or less unchanged, for the next half millennium. They were carefully-designed, highly-crafted precision tools well-adapted to the range of surgical interventions and operations described in the contemporary medical texts. Their versatility and multiplicity of function is discussed, as also is the evidence derived from apparently complete instrumentaria, which sheds light on the form of medical practise undertaken by the people who used them. PMID- 11619959 TI - [Galen and his bad female patients]. AB - Why is the relationship between Galen and his female patients particularly difficult? PMID- 11619960 TI - [The mad man and his doctor]. AB - There weren't specialist physicians for mental diseases in Antiquity, but mad men were usually attended to by doctors from the time of Hippocrates to Late Antiquity. The therapies were generally physical (pharmaceutical and dietetic), but some schools of medicine (Asclepiades, Celsus, Caelius Aurelianus) took into consideration the psychological behaviour and experimented with a sort of relational therapy of madness. PMID- 11619961 TI - Phanostrate, Metrodora, Lais and the others. Women in the medical profession. AB - This article offers a historical view of the women in the medical profession from the Homeric epics to Soranus and Galen until the early Middle Ages, in both the Eastern and Western Mediterranean areas. Recent important medical-historical papers well claify the contribution of women in health care in both the Greek and the Roman world. PMID- 11619962 TI - [Eustress and therapeutic success]. AB - Kamlanie is a particular spell used by the Siberian medicine-man to heal a patient, by invoking animal and human spirits. This article proposes to explain the healing capability of the medicine-man not only through the hypnotic suggestion: the healing messages, in the same moment when they arrive to the patient, would become special sound signals, directly reaching the immune system. PMID- 11619963 TI - [The physician in the Talmudic period: between technie and halakhah]. AB - The Talmud is a vast corpus in which medicine is no more than an artifact. We can nevertheless, in the light of the extant data, gain some idea of the status of physicians in biblical and talmudic times. After some brief considerations on the biblical period, particularly on the relationship of priests and prophets to medicine, we shall focus on the talmudic data. Several Sages of note were knoledgeable in medical lore, mostly of popular origin, but in some cases of scientific origin as well. The most impressive case is that of Mar Samuel. A report of an experimentation in the field of embryology allegedly performed in Alexandria will be described. In all these cases, data pertaining to the healing art (techne) are recorded with the only aim of establishing the law (halakkah). We shall then detail what is known of the medical profession then and there, i.e., licensing, liability and fees. Some data on ethics and etiquette will close this overview of the practice of medicine in ancient Jewish lore. PMID- 11619964 TI - [The physician in Italy between late antiquity to early middle age. Social typologies and forms of cultural representation]. AB - The imperial legislation of Theodosian and Justinian codes pays attention above all to the archiatri sacri palatii and to the Roman archiatri. Her lexicon is ambiguous and it is difficult to understand by the legislation what the term archiater really means in Late Antiquity. Prosopographical analysis allows to outline various social figures of medical doctors: archiatri of the sacred palace, iatrosophistai, civic physicians, statal physicians, military physicians, ecclesiastical physicians. By some epitaphs of the 5th century emerges that physicians were conscious of the social role of medicine, and they were proud of it. Medicine was thought in contemporary culture as ars honesta; this fact implies that, on the average, her practitioners were placed on the same level of craftsmen and tradesmen (i.e. viri honesti). In spite of the christian thought increased her attention on medical assistance of the poors, the physician's position lost his own visibility in our sources between the 5th to the 7th century. This fact is due to the change in thinking the concept of sickness: in christian world, sickness is not only a physical deficiency but becomes also a spiritual deficiency. Consequently the saint, and not the physician, becomes the symbolic figure whom people entrusts his own anxiety of salvation. PMID- 11619965 TI - [Court physicians and universities]. AB - Medicine in the setting of the royal courts of Europe from Renaissance to the Enlightment has been recently discussed, but Italian court medicine has been so far very largely neglected. In this article central problems are the relations between court medicine and academic medicine and the social status of the court physician in the fourteenth century. Both problems are investigated in two Italian courts: the Visconti court in Milan and Pavia and the Aragonese court in Sicily. the list of the Visconti physicians and astrologers attests that they had all been celebrated university professors and that their condition as personal physicians to Galeazzo and Gian Galeazzo was far superior to the academic one in honour and salaries. Their role could also be representative and political. This was expecially the case of Ruggero de Camma, who was chosen as personal physician to the Aragonese king Martino II and appointed by him as first protomedico for political reasons. PMID- 11619966 TI - [Medical deontology in Islam]. AB - Our knowledge of medical practice in medieval Islam is still scanty. It is mostly derived from normative sources, textbooks and deontological texts, which rather depict an ambitious ideal to be followed than the social reality of the average physician. Moreover, deontological regulations in Arabic medical literature are to a large degree shaped by traditional conceptions. The present article, which is based on three so-called mirrors for physicians dating from the 9th to the 12th century AD, attempts to give a provisional outline of possible Greek sources beyond the well-known Hippocratic writings on medical ethics and deontology and a first assessment of topics which seem to be original with the Arabic authors. PMID- 11619967 TI - [Ethical medicine in Paracelsus]. AB - The last decades have been an increasing interest in medical ethics. Paracelsus occupies an important place in the development of ethics in medicine in the crucial cultural passage between Middle Ages and Renaissance. Paracelsus' biography is in itself connected with ethical choices and theories. In his medical doctrines ethics is rooted in the belief in a strict correspondence between micro- and macrocosmos. Love is the basis on which a correct doctor patient relationship can be built. Ilnesses are but episodes in the human life, and care for both spiritual and bodily health should dominate the entire life, and not ony the crucial moments of birth, sickness and death. PMID- 11619968 TI - John Gregory (1724-1773) and his lectures on the duties and qualifications of a physician establishing modern medical ethics on the base of the moral philosophy and the theory of science of the empiric British Enlightenment. AB - In 1769/70 the Scottish physician and philosopher John Gregory (1724-1773) published Lectures On the Duties and Qualifications of a Physician. Gregory developed a truely ethical - in the sense of (moral) philosophically based - system of conduct in a physician. His concept of practising and teaching ethics in medicine and science is established on a very broad footing: combining Bacon's (1561-1626) general philosophy of nature and science with both, the general, likewise empirically based moral philosophy of his personal friend David Hume (1711-1776), and with the principles upheld by the so-called Common-Sense Philosophy. His Lectures had - particularly via the famous Code of Medical Ethics of Thomas Percival (1740-1804) - a decisive influence on our contemporary concepts of ethics in medicine and science. John Gregory is, without doubt, one of the most important and certainly the most comprehensive among the founders of what is known today as modern Bioethics. PMID- 11619969 TI - [For an history of hospitals in Italy. The tipology and evolution of hospitals in XIX century]. AB - In XIX century the modern hospital develops because of and by means of the scientific revolution in medicine, and, in particular, in clinics. In the new hospital the hippocratic praxis and the models of experimental medicine combine, together with mechanistic epistemology and the new general theory of illness, health and disease. The new medicine, founding on an anthropological view of life and death, links with a renewed political attention towards social events; the new idea of health proposes a new model for hospitalization in which doctores and manuales (specialists in surgery) meet. In Italy, the evolution of the hospital tipology develops through the century. PMID- 11619970 TI - Dinner goes to war: the long battle for edible combat rations is finally being won. PMID- 11619971 TI - Worlds in collision: Owen and Huxley on the brain. PMID- 11619972 TI - Rhetorical strategies in the presentation of ethology and comparative psychology in magazines after world war II. PMID- 11619973 TI - Richard Hume Adrian, D.L., 2nd Baron Adrian of Cambridge, 16 October 1927-4 April 1995. PMID- 11619974 TI - Wilhelm Siegmund Feldberg, C.B.E., 19 November 1900-23 October 1993. PMID- 11619975 TI - Percy Cyril Claude Garnham, C.M.G. 15 January 1901-25 December 1994. PMID- 11619976 TI - Benjamin Arthur Hems, 29 June 1912-2 July 1995. PMID- 11619977 TI - Niels Kaj Jerne, 23 December 1911-7 October 1994. PMID- 11619978 TI - Motoo Kimura, 13 November 1924-13 November 1994. PMID- 11619979 TI - Murray Llewellyn Barr, O.C.,20 June 1908-4 May 1995. PMID- 11619980 TI - Severo Ochoa, 24 September 1905-1 November 1993. PMID- 11619981 TI - Thomas Philip Stroud Powell, 13 July 1923-8 February 1996. PMID- 11619982 TI - Roger Wolcott Sperry, 20 August 1913-17 April 1994. PMID- 11619983 TI - Maurice Stacey, C.B.E., 8 April 1907-9 October 1994. PMID- 11619984 TI - The nature of nature in early modern Europe. PMID- 11619985 TI - Between carnival and lent: the scientific revolution at the margins of culture. PMID- 11619986 TI - Travellers on a hidden river. PMID- 11619987 TI - Horatio Nelson never was blind: his woundings and his frequent ill-health. PMID- 11619988 TI - "All that glisters is not gold." Sir John Forbes (1787-1861): a West Indian enigma. PMID- 11619989 TI - Arthur Dickson Wright (1897-1976): surgeon, wit and eccentric. PMID- 11619990 TI - Derek E Denny-Brown (1901-1981): his life and influence on American neurology. PMID- 11619991 TI - Thomas Orme Dudfield: the model medical officer of health. PMID- 11619992 TI - Robert Donaldson (1887-1933); pioneer of the biological treatment of infected wounds. PMID- 11619993 TI - The giant little woman: Dr. Elizabeth Blackwell, the first woman US medical graduate. PMID- 11619994 TI - Erasmus Wilson - philanthropic polymath: an enigmatic personality. PMID- 11619995 TI - German women in chemistry, 1925-1945 (Part II). AB - The paper traces the role of German women into the chemistry profession from 1925 to 1945, examining their relative numbers and experience in higher education, in academic and industrial careers as well as in professional organizations such as the Verein Deutscher Chemikerinnen. The paper examines the effect of the 1930s Depression, National Socialism, and World War II on women chemists, considering both general trends as well as the experiences and achievements of several individual women in a variety of situations. Finally, it considers the longterm consequences of these developments, such as the Nazi expulsion of Jewish women, destruction of women's organizations and devaluing of women's achievements, in limiting the recognition and participation of German women chemists after 1945. PMID- 11619996 TI - [Not Available]. AB - The significance of Warburg's work for the transformation of concepts in the investigation of vitamins is stressed, and the different investigative approaches of the competing groups are made clear. The grounds for the controversy carried out in their scientific publications, between Paul Karrer and Warburg on the one side, and Richard Kuhn on the other side, are fully examined, using the example of vitamin B2. A second level of discussion that remained hidden from behind the public scienfific debate is analysed; the priority dispute between the savants was connected with the interests of the chemical industry. PMID- 11619997 TI - The NHS in context: notes from the Ministry of Health. AB - The National Health Service, which started on 5th July, 1948, is an agreed Service from the point of view of politics. All three of the major political parties have accepted it and played their part in its planning, and it is therefore wrong to refer to it as "Socialised Medicine" as though it were a feature of one party only. All three parties are committed to it, and it is not expected that a change of Government would make any serious difference to the scheme as a whole, although details might be altered. In order to understand the National Health Service and to realize why it has taken the shape it has it is necessary to know something of how the different health services in this country developed. PMID- 11619998 TI - NHS hospitals and specialist services. PMID- 11619999 TI - The early problems of the NHS. AB - Sir Thomas commenced his address [delivered in 1960] with a brief description of the long history of medicine and hospitals and gave examples from old records dating back as far as the Babylonian empire and a code laid down in 2,000 BC. He then dealt with developments through the ages culminating in the milestone of the introduction of the Health Service in 1948. PMID- 11620000 TI - Nursing and the early crisis of the NHS. PMID- 11620001 TI - NHS thoughts from home and abroad. PMID- 11620002 TI - The Northern Ireland health services: 1948-1988: nursing - midwifery - health. PMID- 11620003 TI - The life of Jadwiga Maria Kaniewska-Izycka. PMID- 11620004 TI - Freud and the diagnosis of Gilles de la Tourette's illness. AB - A number of observers recently have taken Freud to task for failing to have diagnosed both Frau Emmy von N.'s (1888-9) involuntary ticcing and vocalizations and Daniel Paul Schreber's (1911) coprolalia and convulsive tics as Tourette's syndrome. None of Freud's critics, however, has placed Freud's understanding of motor and vocal tics in historical context. None seems aware of the contests over the classification of tic symptoms in the 1880's and 1890's, nor do they appreciate the extent to which Charcot and Gilles de la Tourette had conceded that motor and vocal tics, as well as coprolalia, could also appear as symptoms of hysteria. By 1893 (when Freud first wrote out his case of Frau Emmy von N.), both Gilles de la Tourette and Charcot had defended themselves against Guinon's claim that conculsive tics were always a symptom of hysteria by distinguishing those tic symptoms that should be classified as "maladie des tics" from those that accompanied hysteria. Yet Charcot and Gilles de la Tourette had agreed by 1890 that tic symptoms were possible outcomes of either maladie des tics or of hysteria. What separated those afflicted with "hysteria", were particular inherited factors and whether or not the patient could be cured of tics and vocalizations. Thus, within Charcotian terms, Freud was hardly obligated to conclude that his ticcing and cursing patients should have been diagnosed with maladie des tics de Gilles de la Tourette. PMID- 11620005 TI - Professor William Llywelyn Parry-Jones (22 June 1935 - 20 July 1997). PMID- 11620006 TI - Henry Hutchinson Stewart (1798-1879): from page to philanthropist. AB - Henry Hutchinson Stewart [1798-1879] began life as a page to the Vice-Reine and came to the study of medicine rather belatedly. After some years in general practice he was appointed Governor to the Hospitals of the Houses of Industry in Dublin. In 1856 he was responsible for the removal of forgotten, friendless mental patients from the Houses of Industry to a disused hotel at Lucan outside the city. Later on, when a committee proposed to provide a training institution for the menatlly handicapped, he handed over his premises in Lucan to them with its annual income in addition to a donation. In his will he bequeathed further substantial sums to the Institution which still bears his name, and money was also made available to the Irish Universities to found valuable scholarships. PMID- 11620007 TI - Hospital care of madness in the Turk sixteenth century according to the witness of G.A. Menavino from Genoa. AB - Early in the sixteenth century G.A. Menavino from genoa, a twelve-year-old, became a slave at the Court of Constantinople. His observations on the customs of the Turks, published in Nenice in 1548 and in Florence in 1551, discuss some of the city's public buildings, including Timerahane which was devoted to the care and punishment of the mentally ill. In Menavino's description, mad people were taken to Timerahane in chains and shackled to the beds, in the care of warders who punished or rewarded them, and also exhibited them for the amusement of the public. Menavino also mentions drugs and other aspects of their treatment but with little detail. PMID- 11620008 TI - Art for psychiatry's sake: an interview with Dr E. Cunningham Dax. PMID- 11620009 TI - Mental health and psychiatric care in the Second Spanish Republic. PMID- 11620010 TI - Begging the question of idiocy: the definition and socio-cultural meaning of idiocy in early modern Britain: Part 1. PMID- 11620011 TI - Study of a nervous disorder characterized by motor incoordination with echolalia and coprolalia (The introduction and case studies of Gilles de la Tourette's 1885 paper). PMID- 11620012 TI - An introduction to Thomas Browne (1605-1682) and his connections with Winchester College. PMID- 11620013 TI - Research bibliography: a union list of publications from Michigan's mineral springs, mineral wells, and mineral baths. AB - Although no more than a few dozen mineral wells and springs existed in Michigan at any one time, since their discovery over 125 years ago nearly two hundred firms have operated watering places for the suffering in this state. The publications produced by this industry were collectively quite numerous, but scarcely a hundred or so examples of this genre can be located today. On those rare occasions when materials of this nature can be found in out-of-print book stores or antiquarian dealers'catalogs, it is not uncommon for the asking price to approach $100 per piece. Now that this union list has revealed how scarce and valuable these publication are, persons and institutions possessing such items should take precautions to ensure the security of their holdings. PMID- 11620014 TI - Destination unforeseen: the birth of the research-intensive pharmaceutical industry PMID- 11620015 TI - From mustard gas to medicines: the history of modern cancer chemotherapy. PMID- 11620016 TI - Mary Keith, R.N., energy personified. PMID- 11620017 TI - Societal integration and age-standardized suicide rates in 21 developed countries, 1955-1989. AB - Gender-specific age-standardized suicide rates for 21 developed countries over seven 5-year periods (1955-59...1985-89) form the two dependent variables. Durkheim's theory of societal integration is the framework used to generate the independent variables, although several recent theories are also examined. The results from a MGLS multiple regression analysis of both male and female rates provide overwhelming support for a multidimensional theory of societal integration and suicide, as first suggested by Durkheim. PMID- 11620018 TI - Signs, marks, and private parts: doctors, legal discourses, and evidence of rape in the United States, 1823-1930. PMID- 11620019 TI - Divine sex, happy marriage, regenerated nation: Marie Stopes's marital manual Married Love and the making of a best-seller, 1918-1955. PMID- 11620020 TI - Visual representation and post-constructivist history of science. PMID- 11620021 TI - Learning from an adversary? Warburg against Wieland. PMID- 11620022 TI - Antimony in medicine. PMID- 11620023 TI - Traditional Chinese herbal medicine PMID- 11620024 TI - Samuel Johnson, his health and the doctors. PMID- 11620025 TI - The anatomy of the mermaid. AB - Investigation of the anatomy of the mermaid and of mermaid lore has revealed a tangled web of stories, sightings and specimens of the most diverse nature, extending worldwide into the realms of folklore and legend, zoology and cryptozoology, anatomy, physiology, radiography and folk medicine, ethnography, social history and the history of science. The stereotype we know as the mermaid is surely a fit subject for further serious study PMID- 11620026 TI - The history of medicine represented in heraldry. PMID- 11620027 TI - Sir Charles Bell (1774-1842) and the portraiture of beauty. PMID- 11620028 TI - Professor Cathcart's military physiology and nutrition. PMID- 11620029 TI - The popularisation of milk as a beverage during the 1930's. PMID- 11620030 TI - Was Harvey's historic study of Hugh Montgomery's living heart carried out in Edinburgh? PMID- 11620031 TI - Medical visitors to 18th century New Zealand. PMID- 11620032 TI - Philatelic list of persons and their contributions to genetics. PMID- 11620033 TI - Archibald Philip Bard: October 25, 1898-April 5, 1977. PMID- 11620034 TI - Emil Thomas Kaiser: February 15, 1938-July 18, 1988. PMID- 11620035 TI - Paul Alfred Weiss: March 21, 1898-September 8, 1989. PMID- 11620036 TI - Robert Brainard Corey: August 19, 1897-April 23, 1971. PMID- 11620037 TI - Albert Dorfman: July 6, 1916-July 27, 1982. PMID- 11620038 TI - Louis Barkhouse Flexner: January 7, 1902-March 29, 1996. PMID- 11620039 TI - Johannes Holtfreter: January 9, 1901-November 13, 1992. PMID- 11620040 TI - Carl Iver Hovland: June 12, 1912-April 16, 1961. PMID- 11620041 TI - Heinrich Kluver: May 25, 1897-February 8, 1979. PMID- 11620042 TI - Lewis Gibson Longsworth: November 16, 1904-August 8, 1981. PMID- 11620043 TI - Alfred Ezra Mirsky: October 17, 1900-June 19, 1974. PMID- 11620044 TI - Alfred Henry Sturtevant: November 21, 1891-April 5, 1970. PMID- 11620045 TI - Frank Ambrose Beach: April 13,1911-June 15, 1988. PMID- 11620046 TI - Veterinary medicine in the medieval period: The Christian kingdoms in Spain. PMID- 11620047 TI - From Captain Ludgate to the Queen Caroline affair, or how a dedicated collector of medical prints became an expert on a British royal divorce. PMID- 11620048 TI - Old Hungarian books in the special book collection of veterinary history: 1574 1850. PMID- 11620049 TI - The early years of chiropractic in California: the people versus C.D. Greenall. AB - During the dawning years of the chiropractic profession, many of our brethren ventured forth to the fertile land of California to establish thriving practices and schools. These early pioneers practiced outside the laws of California, and many became subject to persecution by the authorities. With these persecutions came counter-attacks which shaped the future battles to be waged. Some of these counter-attacks were successful; most were not. These early laws and challenges influence our practice rights through the present and will continue to do so. C.D. Greenall, D.C., stood up to the medical authorities and won his case at the California Supreme Court fifteen years before the California electorate approved the Chiropractic Initiative Act in 1922. PMID- 11620050 TI - Arthur Emanuel Lundh, Norway's first chiropractor - the years between the wars. AB - These days, chiropractic is progressing worldwide as a recognized health discipline. Most of today's chiropractors, however, have graduated in the last fifteen years. Do they recognize the principle that one must know one's past in order to form one's future? Do they know what it took, what sacrifices that were made in order for them to become members of a respected health profession? This paper is an attempt to demonstrate the character of one of the pioneers who laid down the fundament of today's chiropractic. It took special people with an extraordinary character to give today's chiropractors today's opportunities. PMID- 11620051 TI - Did D.D. Palmer visit A.T. Still in Kirksville? AB - It has been claimed that prior to the discovery of chiropractic in 1895, D.D. Palmer, the discoverer of chiropractic, visted A.T. Still, the founder of osteopathy, in Kirksville, Missouri, where Still started the first school of osteopathy. Palmer's signature supposedly can be found in A.T. Still's guestbook. Palmer denied ever being in Kirksville, as did his son B.J. This article explores the evidence on both sides of the question. PMID- 11620052 TI - Early Canadian chiropractic colleges. AB - Chiropractic education arrived in Canada, principally in Ontario, in 1909 with Robbins Chiropractic Institute, (RIC) in Sault Ste. Marie, Ontario. After the RIC's closure in 1913, the Canadian Chiropractic College (CCC) Hamilton, Ontario, held its first classes in 1914 under Dr. Ernest Du Val, 1911 Palmer School of Chiropractic graduate. It was during this period that the Hodgins Commission on Ontario Medical Education held public sessions with presentations from all health professions including chiropractic. It was the outcome of this Commissions Report that dealt a devastating blow to chiropractic. The CCC, which moved to Toronto in 1919, remained the only chiropractic college in Canada until 1920 with the opening of the Toronto Chiropractic College (TCC). The CCC closed in 1923; and the TCC, in 1926. Although all three colleges taught a "straight" program, the "mixers," largely from American schools, became the dominant political force in the province, particularly on the Board of Regents for the enforcement of the 1925 Drugless Practitioners Act, a mixed Board of chiropractors, osteopaths and drugless therapists. PMID- 11620053 TI - Ohio legal entanglement: A.W. Lensgraf, D.C.: 1927-1935. AB - The purpose of this paper is to illustrate the legal frustration of the early practice life during the late 1920s and 1930s in Ohio of Arthur William Lensgraf, D.C., a rank-and-file practicing Palmer graduate who, early on in his career, was an ardent supporter of B.J. Palmer and "the good ole P.S.C." At this time, B.J.'s influence on the profession was at an all time high; and he did not refrain from exerting it in Ohio. Attention will be paid to the arrest and constant threat of imprisonment since, during this time, the licensing laws present in Ohio were ambiguous at best. The Platt-Ellis law that was passed in 1915 and enacted in 1916 compromised medical and chiropractic forces into defining chiropractic as a "limited branch of medicine and surgery" placing it directly under the thumb of the Ohio state medical board. PMID- 11620054 TI - Perspectives in chiropractic history. PMID- 11620055 TI - [Francois-Joseph Gall (1758-1828), Vesalius of the brain, founder of phrenology: Phrenonolgical report of an engraver in Bruges (1837)]. PMID- 11620056 TI - [Corneille De Baersdorp (1486-1565), chief physician of Charles V and commentator of Galen]. PMID- 11620057 TI - [Not Available]. PMID- 11620059 TI - Oral and dental diseases in ancient Egypt. PMID- 11620058 TI - [The evolution of the concept of the transitive cortex: between Yin and Yang]. PMID- 11620060 TI - [A tribute to Robert Joly, Belgian follower of the Hippocratic system]. PMID- 11620061 TI - [Not Available]. PMID- 11620063 TI - Henry Charles Lea: historian and medical publisher. PMID- 11620062 TI - [Not Available]. PMID- 11620064 TI - Kurt Lewin and the first attempts to establish a department of psychology at the Hebrew University. PMID- 11620066 TI - Life writing versus biography. PMID- 11620065 TI - Gazing down a well: medical biography and the narrator. PMID- 11620067 TI - Value of biography to the history of medicine. PMID- 11620068 TI - Value of biography to history of medicine. PMID- 11620070 TI - The value of biography for medical history. PMID- 11620069 TI - Why historians of medicine are wary of biography. PMID- 11620071 TI - Invasion of privacy? Writing the biography of Mona Wilson. PMID- 11620072 TI - Novelization. PMID- 11620073 TI - Crusading for the forgotten: Dr. Peter Bryce, public health, and prairie native residential schools. AB - This article examines the rise of the public health movement and its impact on native affairs in Canada at the turn of the century. It focuses on the efforts of Peter Bryce, Chief Medical Officer for the Departments of the Interior and Indian Affairs, to improve conditions in native schools and on reserves. In 1907 Bryce released his controversial Report on the Indian Schools of Manitoba and the North West Territories, revealing that 24 percent of all native residential school students had died of tuberculosis. Believing firmly that the state was responsible for promoting the health and welfare of its people, Bryce insisted that the federal government address this high death rate. His tireless crusade on behalf of the native population demonstrated the extent to which native affairs were influenced by the broader social, political, and economic agendas of the day, and anticipated the federal government's changing role in social services following World War I. PMID- 11620074 TI - Publishing the works of Nicholas Culpeper, astrological herbalist and translator of Latin medical works in seventeenth-century London. AB - This investigation attempts primarily to untangle the complex publishing history of the works of Nicholas Culpeper (1616-54), astrological herbalist and translator of Latin medical works. It therefore identifies those works published in seventeenth-century London: the study indicates that London stationers capitalized on the reputation of Nicholas Culpeper to build the widest possible market for his original astrological/herbal medical works and his translations from continental authors. PMID- 11620075 TI - The middle-class plague: epidemic polio and the Canadian state, 1936-37. AB - During the pre-Salk era, paralytic poliomyelitis was one of the most feared diseases of twentieth-century North America. This perception, held most strongly by the middle class-- polio's principal target--shaped a unique Canadian response to it based on comprehensive, standardized, and unconditional programs of "state medicine" at the provincial level. Of Canada's four major waves of provincial polio epidemics, the second struck Ontario to an unprecedented degree in 1937, generating a similarly unprecedented response from the Ontario government in its control, treatment, hospitalization, and aftercare measures. As this article discusses, the severity of this epidemic led the provincial, and other Canadian public health authorities, to face a central question: How far should governments be compelled to go to ensure the advantages of modern treatment for their people? This article helps place the social impact of, and political and scientific response to, epidemic polio within the context of Canada's evolving public health and state medicine infrastructure at the time. PMID- 11620076 TI - [An iatrochemist in Lower Canada: Francois Blanchet and his Research on medicine, or application of chemistry in medicine]. AB - Francois Blanchet holds a central place in the history of medicine in Lower Canada (now Quebec): a prime mover in the professionalization of French-Canadian physicians, Blanchet was also one of the first Canadians to have studied outside of Canada. While he was in New York, where he studied medicine at Columbia College, he published a book entitled Recherches sur la medecine ou application de la chimie a la medicine. The historiography of Canadian medicine frequently cites this book and presents it as one of the first Canadian medical publications but has not always explored its scientific content. This article therefore examines the medico-chemical aspects of Blanchet's work. Influenced by the Lavoisian revolution in chemistry, Blanchet elaborated a system where etiology and therapy rested on two new elements of nomenclature put forward by French chemists--oxygen and caloric. After examining Blanchet's iatrochemical system, this article compared Recherches sur la medecine with contemporaneous American and European publications in medicine which were themselves inspired by the pneumatic theory of French chemists. PMID- 11620077 TI - Colonial care: medical attendance among the Mikmaq in Nova Scotia. AB - In Nova Scotia before Confederation, medical care for native peoples formed an integral part of the fledgling Indian administration. As the colonial authorities became more involved in all aspects of native life, an opportunity for self advancement was presented to doctors. Practioners among the Mikmaq came from the emerging medical elite. This article argues that their service to the Mikmaq was part of a broader and widespread reform effort. Doctors not only delivered care to the Mikmaq, but they also served the needs of a colonial administration actively seeking to settle natives in reserve communities. The activities of doctors, however, did not go uncontested. This study illustrates the complex interaction among the native administration, the Mikmaq population, and a medical community struggling to organize. PMID- 11620078 TI - Jane Marion Oppenheimer (19 September 1911-19 March 1996). PMID- 11620079 TI - Theodor Hermann Felix Wieland (5 June 1913-24 November 1995). PMID- 11620080 TI - Hazardous history: researching the dangerous trades. [Review of: Sellers CC. Hazards of the Job, University of North Carolina Press, 1997]. PMID- 11620081 TI - The Atomic Bomb Casualty Commission: science constrained by culture or by nature? [Review of: Lindee SM. Suffering made real. University of Chicago Press, 1994]. PMID- 11620082 TI - On embryos and ancestors. PMID- 11620083 TI - America's first medical breakthrough: how popular excitement about a French rabies cure in 1885 raised new expectations for medical progress. PMID- 11620084 TI - Groundwater and the law: records v. recollections. PMID- 11620085 TI - Making the Pap smear into the "right tool" for the job. AB - Despite being a rather recalcitrant tool, the "Pap smear" is today the major cancer screening technology in the world. This paper examines how and why hetrogeneous actors chose to advocate the Pap smear as a screen for cervical cancer in the late 1940's, and to tinker both in and far beyond the diagnostic laboratory for over 50 years to make the Pap smear "fit" as a screening and clinical technology. Tinkerings included gendering the division of labour, attempting to automate reading of smears, juggling costs, exploring alternative screening technologies, pushing for regulation of laboratories, and settling for locally-negotiated orders of clinical accuracy instead of global standardization, still elusive today. PMID- 11620086 TI - Psychoanalysis in Britain in the early twentieth century: an introductory note. PMID- 11620087 TI - The Stracheys and psychoanalysis. PMID- 11620088 TI - Anxiety at a time of crisis. PMID- 11620089 TI - Bombs away. PMID- 11620090 TI - Historical imagination/psychoanalytic. PMID- 11620092 TI - Apparatus of bygone days. PMID- 11620091 TI - Hysterical cures: hypnosis, gender and performance in World War I and Weimar Germany. PMID- 11620093 TI - British chemists & druggists in pursuit of pharmaceutical science in the nineteenth century. PMID- 11620094 TI - Prescriptions on stamped paper - an eighteenth century suggestion. PMID- 11620095 TI - William Walter Stoddart, Ph.C.: the first public analyst for the city of Bristol. PMID- 11620097 TI - Infant survival chances, unmarried motherhood and domestic arrangements in rural Scotland, 1845-1945. PMID- 11620096 TI - From poor law to nation health service. PMID- 11620099 TI - An American perspective on British historiography of science. PMID- 11620100 TI - Discovering the insulin documents: an archival adventure. PMID- 11620101 TI - The concept of creative illness in the works of N.N. Bazhenov. PMID- 11620103 TI - Begging the question of idiocy: the definition and socio-cultural meaning of idiocy in early modern Britian. Part 2. PMID- 11620102 TI - The first casualty: the war over psychoanalysis and the poverty of historiography. AB - Many recent discussions of the early history of psychoanalysis have claimed that Freud's work was methodologically (and hence scientifically) flawed. It is suggested that such criticisms are often based on studies that are deficient in the way they approach historiography. The work of Adolf Grunbaum and Frederick Crews (as, respectively, specialist and populist) is used to illustrate both this and the consequent theses that dehistoricized approaches to Freud lead to anachronistic blunders and that anti-Freudian tendentiousness clothed in the illusion of historiographical expertise is no substitute for scholarly rigour. It is concluded that when criticizing Freud it is often a good idea to read him first, but no optimism is entertained about the prospects of raising the standard of debate about psychoanalysis and its orgins. PMID- 11620104 TI - Alcoholism and medicine in Spain in the second half of the nineteenth century. PMID- 11620105 TI - Asylum in the community: managing the insane in antebellum America. PMID- 11620106 TI - Jaspers, Kurt Schneider and the Heidelberg school of psychiatry. AB - The psychiatric tradition of Heidelberg goes back to Kraepelin. Its psychopathological orientation was established by Jaspers and developed by K. Schneider. The relationship between these two men is explored through an analysis of their correspondence, which lasted for more than fifty years. PMID- 11620107 TI - Demographic transition in the Netherlands: a statisticsl analysis of regional differences in the level and development of the birth rate and of fertility, 1850 1890. PMID- 11620108 TI - The history of midwifery in Aberdeen. PMID- 11620109 TI - Reform and the monopolistic impulse: the professionalization of medicine in the Maritimes. PMID- 11620111 TI - The campaign against malaria and the expansion of scientific, medical, and sanitary services in British West Africa, 1898-1910. PMID- 11620110 TI - Committee on food chemistry and technology. PMID- 11620112 TI - The heyday of drugstores in Alabama. PMID- 11620113 TI - British chemistry and the concept of science in the eighteenth century. PMID- 11620114 TI - Hopkins pioneers in nursing: Isabel Hamptom Robb and M. Adelaide Nutting. PMID- 11620115 TI - Mortuary art of the Alaskan Eskimos. PMID- 11620116 TI - Ars gratia cultus: Ovid as beautician. PMID- 11620117 TI - Adolphus S. Solomons and Clara Barton: A forgotten chapter in the early years of the American Red Cross. PMID- 11620118 TI - Pathological images in the Quebec novel. PMID- 11620119 TI - Psychic epidemics and American literary history: literature, neurosis, and cultural change. PMID- 11620120 TI - Pretext or prophylaxis? Racial segregation and malarial mosquitos in a British tropical colony: Sierra Leone. PMID- 11620121 TI - Rattus rattus: the introduction of the black rat into Britain. PMID- 11620122 TI - The early development of the scientific movement in Australian education - child study. PMID- 11620123 TI - Records of tuberculosis in Calgary. PMID- 11620124 TI - [Not Available]. PMID- 11620125 TI - Painters "born under Saturn": the physiological explanation. PMID- 11620126 TI - The natural theologians and Darwin: a case of divergent evolution in the history of ideas. PMID- 11620127 TI - The historical role of Australian medical libraries. PMID- 11620128 TI - Silvano Arieti. PMID- 11620129 TI - The Mental Health Act 1959: rethinking an old problem. PMID- 11620130 TI - Hieronymus Mercurialis "De arte gymnastica": classification and dogma in the sixteenth century. PMID- 11620131 TI - A short history of the libraries and list of manuscripts and original drawings in the British Museum (Natural History). PMID- 11620132 TI - The studies of yellow-fever by Noah Webster and John Conrad Otto at Red Bank, New Jersey. PMID- 11620133 TI - Segregation in British West Africa. PMID- 11620135 TI - The "Enlightenment" in Spain: expressed concern for physical education in Spanish educational thought, 1765-1810. PMID- 11620134 TI - The flat-tired, flat--tired--people. PMID- 11620136 TI - Indian mortality. PMID- 11620137 TI - Horticultural biographies; challenges and opportunities. PMID- 11620138 TI - John Lambert Richmond, M.D. "The first Caesarian section in America". PMID- 11620139 TI - Worms and the death of kings: a cautionary note on disease and history. PMID- 11620140 TI - A history of medicine in Nova Scotia, 1784-1854. PMID- 11620141 TI - Condorcet's Memoire sur les hopitaux (1786): an English translation. PMID- 11620142 TI - Psychology and mathematical method: a capsule history and a modern view. PMID- 11620143 TI - Scurvy and the ventilation of ships in the Royal Navy: Samuel Sutton's contribution. PMID- 11620144 TI - Science in the Virginia Gazette, 1736-1780. PMID- 11620145 TI - Dr. Leo Davidoff: "a tree for posterity". PMID- 11620147 TI - The improving health of the United States, 1850-1915. PMID- 11620146 TI - Mortality in rural America, 1870-1920: estimates and conjectures. PMID- 11620148 TI - Workplace safety during the Progressive era: fatal accidents in bituminous coal mining, 1912-1923. PMID- 11620149 TI - "Woman is perfect": H. D.'s debate with Freud. PMID- 11620150 TI - History of public health-history in public health: looking back and looking forward. AB - The history of public health is a given aspect of general (cultural, social and political) history. It is subject to conditions and quality standards given in general history. History in public health is-in contrast to a history of public health-guided by the relevance of its questions and issues for present-day problems of general decision-making in public health care. The task of history in public health is the background analysis of social changes in public health. History in public health clarifies the actual field of public health with respect to its open and hidden lines and factors of development. PMID- 11620151 TI - The orgins of vaccinia virus-a brief rejoinder. PMID- 11620152 TI - Abortion policy and politics on the Lane Committee of Enquiry, 1971-1974. AB - The 1967 Abortion Act did not quell public discussion on therapeutic abortions in Britain. Criticism of the way the Act was working began almost as soon as the legislation came into force. After only three years, a committee of enquiry, chaired by Justice Elizabeth Lane, studied the working of the Act. This Committee caused some surprise on all sides of the abortion debate by offering unanimous support for the Act in its original form. Understanding how the Lane Committee arrived at its unexpected recommendations is important not only because the Report has proved to be an enduring endorsement of the Act but also because the Lane Committee provides a case study of the process of policy formulation at the level of a committee of enquiry. The Lane Committee appears to have achieved consensus incrementally. First a majority and then the whole Committee supported the Act as a humane measure requiring regulatory and not legislative solutions to the problems of its working. Using both written and oral sources, I will argue that consensus evolved through the compelling leadership of several key members of the majority group with particular influence by the most psychosocially oriented members of the Committee. PMID- 11620153 TI - Explaining the modern mortality decline: what can we learn from sea voyages. AB - During the past two decades, scholars have attempted to quanify the mortality at sea of a large number of seaborne populations. We now have estimates of death rates associated with over 13,000 voyages between 1497 and the First World War. These include voyages of Portuguese and Dutch travellers to Asian destinations; African slaves, European convicts, and free emigrants to the Americas; British convicts to Australia; British government-assisted emigrants to South Africa and Australia; and African, Indian, Chinese, and Pacific Islander indentured labourers to various destinations in the Atlantic, Indian, and Pacific Ocean regions. Whereas the death rate on slave voyages did not decline over time, the death rate of young adults and older children on non-slave voyages plummeted in the early-to-middle nineteenth century, preceding the modern mortality decline on land. Yet, the infant death rate of babies who embarked, or who were born at sea, although steadily declining, remained very much higher than infant mortality on land. The reduction in infant maritime mortality, which lagged well behind that of voyaging adults and children, thus mirrors the difficulty in reducing infant death rates on land. This paper surveys the recent literature on mortality at sea, drawing implications for our understanding of the modern mortality decline on land. PMID- 11620154 TI - Vaccination policy against smallpox, 1835-1914: a comparison of England with Prussia and Imperial Germany. AB - There are three identifiable phases in comparing vaccination policy in England, Prussia and Imperial Germany. (1) Prior to the 1870's the tradition of medical police in Prussia resulted in the vaccination of the population being treated as a State responsibility earlier than in England and provided an appropriate administrative framework. The administrative pressure that could be exerted persuaded the Prussian authorities that legislation to make vaccination compulsory was unnecessary. In contrast, England and Wales lacked both the tradition and administrative structures of a medical police. Legislation (1840, 1853) for free and universal infant vaccination was followed by radical ideological and administrative innovation. (2) From 1875 to 1889 both countries provided free and compulsory vaccination for all. In England this was limited to infants; in Germany including Prussia, it included the re-vaccination of children. (3) After 1889 England and Germany began to diverge more sharply. In England vaccination rates fell and after 1898 conscientious objectors were excused from having to have their children vaccinated. Germany retained compulsory vaccination and rates in the two countries increasingly diverged. England came to rely on the local public health administration for the surveillance and containment of smallpox, including selective vaccination of contacts. Despite these differences smallpox mortality dropped sharply in both countries, although in Germany somewhat earlier. The English reliance on surveillance and containment prefigures that of the WHO in the eradication of smallpox in the Third World. It suggests that the emphasis on the importance of high levels of mass vaccination in the German literature should perhaps be revised. PMID- 11620155 TI - Health reform in Israel: some aspects of seventy years of struggle (1925-1995). AB - This work traces attempts to bring about the passage of a compulsory health insurance law in Israel-from initial efforts in 1925 to the actual passage of such legislation in 1995. It examines the course of events in historical perspective, documenting positions adopted by various bodies-governmental, political, quasi-political, professional, and other-at various stages, clarifying why early initiatives failed. Most of this work is founded on historical archival documents found in London and Israel. PMID- 11620156 TI - Beggars, metaphors, and stigma: a missing link in the social history of leprosy. AB - Students of leprosy stigma are at odds over its sources, intensity, and current presistence. On the basis of a study of leprosy in Thailand that combined an archival survey with anthropological field-work, the present article offers a different thesis on these issues from those that have been proposed thus far. The thesis suggests that prior to the discovery of a cure for the disease, its sufferers encountered ambivalent rather than severly stigmatizing reactions. Yet the public's selective exposure-mainly to beggars with the disease-paved the way to the perception of leprosy as the epitome of stigmatization and to its transformation into a metaphor for degradation. Progress in the medical treatment of the disease significantly improved patients' social acceptance but also allowed them to keep their illness a secret. Their consequent disappearance from the public eye turned the figurative use of leprosy in the spoken language into the main source of shaping its image. This development contributed to the irrefutability and perpetuation of the negative image, and even to its intensification to the extent of utter divorce from concrete reality. After expounding this thesis, the paper discusses its potential contribution to resolving the disputes over the roots, severity, and persistence of leprosy stigma on the international level. PMID- 11620157 TI - Changes in the medical profession in Great Britain in the xix century. AB - The nineteenth century was important for medicine in Britain because the foundations of a united medical profession were laid by the Medical Act of 1858. This established the General Medical Council which had the responsibility of maintaining a list of qualified medical practitioners. This not only protected the public from unknowingly using unqualified medical practitioners, but also created a monopoly of medical practice which was protected by law. In the second half of the century, women started to qualify and be registered. The century also saw the development of effective anaesthetics and the idea that the health of the public could be preserved by legislation. The notion of prevention was born, even though after a further one hundred years, the profession is still dominated by the idea that its responsibility is to cure. PMID- 11620158 TI - An exile in my own country: the confinement of leprosy patients at the United States National Leprosarium. AB - Leprosy is a disease which has long been stigmatized and persons afflicted with it have frequently been segregated from the rest of society. This paper focuses on the evolution of policies concerning the confinement of patients at the national leprosarium operated by the United States Public Health Service (PHS) at Carville, Louisiana. After a brief review of the origins of the Lousiana Leper Home, which eventually became the national leprosarium, the paper traces changing attitudes and policies at Carville from 1921, when the PHS took control of the facility, to the 1950s. PMID- 11620159 TI - The future of the medical profession between bioethics and the market: a final comment. AB - For a variety of historical and professional reasons the field of bioethics has paid little attention to the market. It has tended to treat the market with suspicion or hostility. Now, however, the market must be taken seriously. It has become a world-wide force in health care, and there is every reason to believe it will remain strong in the future. For that reason, it is wise to see what can be taken from the market, rather than simply dismiss it altogether. The market has various aspects: a theory of human nature, a view of human behavior, and an ideological aspect, with proponents stressing the necessary connection between political and market freedom. This article argues that only its view of human behavior should be accepted, particularly the possibility of using incentives, positive and negative, to change behavior. That can be helpful in health care, whereas the market's view of human nature should be rejected. PMID- 11620160 TI - [Medical deontology and medical ethics]. PMID- 11620161 TI - [A more objective medical responsibility]. AB - The present severe forensic interpretation about professional responsibility of physicians has two effects, the first inducing an extreme caution in the strategic choice and a loss in the decisional autonomy of the doctor, the second changing the general architecture of the criminal law, because the principle of the objective liability is threatening to be a general principle. PMID- 11620162 TI - The future of the doctor-patient relationship in a world of managed care. AB - Today, the doctor-patient relationship is strictly linked with the larger context of the medical profession and the managed care revolution. This article focuses on three important questions: 1. In the U.S., how did we arrive at the current situation where the DPR is under sustained assault and is now being used increasingly as a mechanism of cost control? 2. What approaches will be used in the managed care setting to limit and control the decision-making freedom of patients and doctors within the doctor-patient relationship? 3. Will the doctor patient relationship, as we know it, survive the managed care revolution? PMID- 11620163 TI - The idea of physician as a bioethical topic. AB - The model of the physician as a caregiver and as a researcher has been given extensive attention in the bioethical debate. There has been a transition in the last decades from the traditional idea of a physician inserted in the hippocratic ethos to a more technical and contractarian model; we contend that the latter fails to capture the essential features of the clinical encounter, in that its presuppositions are abstract and lead to unintended results. Other models have been proposed (beneficence, covenant, care) which seem to better fit the reality of the clinical encounter. In the experimental setting there is a particularly illuminating example of the type of relationship which we find more convincing. PMID- 11620164 TI - Canadian physicians: the struggle with health reform. AB - The Canadian health system is now in an era of significant change. Decentralization, the changing role of government consumer movement and new views on health greatly affect physicians' relationships with patients, consumers and other health professionals, and will determine the governance and mandate of medical associations. While the Canada Health Act requires coverage of all medically necessary health services provided by hospitals and medical practiitioners, the understanding of the term medically necessary appears to be changing to include issues related to financial sustainability and scientific appropriateness. As goverments become interventionist in the health care system as a reaction to fiscal imperatives, their traditional role as funder and planner is changing as they begin in a more explicit manner, to manage the health care system and to engage in directly influencing patient management decision-making. These new directions will have a major influence on the practice of medicine in the 21st century. PMID- 11620165 TI - The heartbeat in the White House. PMID- 11620166 TI - Battling the Red Death. PMID- 11620167 TI - Alas, Memphis! PMID- 11620168 TI - "My God, sir, I think the president is doomed!" [Grover Cleveland's cancer surgery]. PMID- 11620169 TI - Physicians and abortion reform in the nineteenth century: social control as the new orthodoxy. PMID- 11620170 TI - Thomas Hunt Morgan: family influences in the making of a great scientist. PMID- 11620171 TI - The medical market place. PMID- 11620172 TI - Harriet Hosmer's sojourn in St. Louis. PMID- 11620173 TI - Diffusion of diseases in the western interior of Canada, 1830-1850. PMID- 11620174 TI - Kainji twenty years on: human health developments arising from the damming of one of Africa's major rivers. PMID- 11620175 TI - Medicine and medical practice in later medieval London. PMID- 11620177 TI - A history of the university chemical laboratory, Trinity College, Dublin. PMID- 11620176 TI - Delicacy and propriety: the acceptance of the woman physician in Victorian America. PMID- 11620178 TI - Disease and medicine in African history: a bibliographical essay. PMID- 11620180 TI - Eugenicists, doctors and the quest for national efficiency: an educational crusade, 1900-1939. PMID- 11620179 TI - Medical practices in the French West Indies: master and slave in the 17th and 18th centuries. PMID- 11620181 TI - Robbins and the reproductive ratio: a note on the fall in the birth-rate after 1964. PMID- 11620182 TI - Prosecutions for sodomy in England at the beginning of the nineteenth century. PMID- 11620183 TI - Providence, prayer and cholera: the English general fast of 1832. PMID- 11620184 TI - Local and regional studies in historical demography. PMID- 11620185 TI - Event sequence and event duration: colligation and measurement [in medicine]. PMID- 11620186 TI - Historical demography in Germany: a research note. PMID- 11620187 TI - Eliminating the yahoo--eugenics, social Darwinism and five Fabians. PMID- 11620188 TI - Suggestions on writing the history of psychological data. PMID- 11620189 TI - Sea bathing at Margate. PMID- 11620191 TI - Friendship in history. (Translated from the original Dutch version by Bernd Jager). PMID- 11620192 TI - The first English printing of Galen: the formation of the company of barber surgeons. PMID- 11620193 TI - International control of narcotics and dangerous drugs: a synopsis. PMID- 11620194 TI - Canadian food aid: surplus and hunger. PMID- 11620195 TI - Demographic trends and policies in developed countries. PMID- 11620196 TI - Social thought and social statistics in the early nineteenth century: the case of sanitary statistics in England. PMID- 11620197 TI - The Dr. Charles R. Drew stamp. PMID- 11620198 TI - Ronald Reagan and "Operation Coffeecup": a hidden episode in American political history. PMID- 11620199 TI - The art of bloodletting: as practiced by my father. PMID- 11620200 TI - The gift of healing. PMID- 11620201 TI - Technocrats and the generalist mystique: physicians, engineers, and the administrative system of Pakistan. PMID- 11620202 TI - Food supply and population growth in southwest China, 1250-1850. PMID- 11620203 TI - Implications of nutritional potential of anadromous fish resources of the western Snake River plain. PMID- 11620204 TI - St. Luke's Home, Vancouver, 1888-1936: a transitional hospital. PMID- 11620205 TI - Federalism, interest groups, and parliamentary government: the Canadian Medical Association. PMID- 11620206 TI - Sons of the fathers: temperance reformers and the legacy of the American Revolution. PMID- 11620207 TI - An Ethiopian medical text book written by Gerazmac Gabrawald Aragahan Daga Damot. PMID- 11620208 TI - Climate as a factor affecting the human environment in the Middle Ages. PMID- 11620209 TI - A time series study of fertility in England and Wales, 1877-1938. PMID- 11620210 TI - Attitudes to homosexuality in eighteenth century France. PMID- 11620211 TI - Freud: instinctivist or behaviorist? The mirages of American sociology. PMID- 11620212 TI - Transactions of the China Medico-Chirurgical Society, 1845-6. PMID- 11620213 TI - Beware the deadly books: a forgotten episode in library history. PMID- 11620214 TI - Health and the Mexican Americans in Los Angeles, 1850-1887. PMID- 11620215 TI - Sex and revolution: an examination of literary and statistical data on the mores of Soviet students in the 1920s. PMID- 11620216 TI - Bias and alternatives in psychological testing. PMID- 11620217 TI - Witchcraft and healing in an African church. PMID- 11620218 TI - Medicinal and economic plants of the Musaeum Zeylanicum of Paul Hermann. PMID- 11620219 TI - Pioneer in oral surgery: Simon P. Hullihen. PMID- 11620220 TI - Iconographical notes towards a definition of the medieval fool. PMID- 11620221 TI - A general syllogy of Maya medicine. PMID- 11620222 TI - The madstone: its origins and application in Barlow, Ballard County, Kentucky. PMID- 11620223 TI - An accumulation of misery? PMID- 11620224 TI - Continence for a nation: seminal loss and national vigour. PMID- 11620225 TI - Lobotomy--it's coming back. PMID- 11620227 TI - The medicine man of the Apache. PMID- 11620226 TI - Bibliography and insanity: Smollett and the mad-business. PMID- 11620228 TI - Charitable bequests and their recipients. PMID- 11620229 TI - The politics of London water. PMID- 11620230 TI - Medical science and superstition: a report on a unique medical scroll of the eleventh-twelfth century. PMID- 11620231 TI - Surgeons of the Mary Rose: the practice of surgery in Tudor England. PMID- 11620233 TI - Magister Iodocus: "Regule phisonomie". PMID- 11620232 TI - Fighting the invisible enemy and enhancing the United States image in Venezuela, 1941-1945. PMID- 11620235 TI - Medieval scientific and medical views of sexuality: questions of propriety. PMID- 11620234 TI - [Not Available]. PMID- 11620236 TI - Some contributions of Robert Bentley Todd. AB - A Dubliner by birth and education, Robert Bentley Todd (1809-1860) settled in London, achieving success as physician and educator. He was professor of anatomy and physiology at King's College, and a founder of King's College Hospital. His publications were numerous; he edited a Cyclopaedia of Anatomy and Physiology in which he introduced the terms afferent and efferent and pointed to the location of the major lesion of tabes dorsalis. He described postictal paralysis in his Lumleian Lectures (1849); the features of "Todd's paralysis" are discussed. He appeared for the prosecution at the Smethurst murder trial (1859). He prescribed wine and brandy copiously for fevers. PMID- 11620237 TI - Thomas Laycock and a trophic nervous system. AB - A short introduction is given to Thomas Laycock (1812-1876), and attention drawn to the development of neurological understanding in the nineteenth century. The main text describes a postulated part of the nervous system, the trophic, which was thought to govern nutritive functions of the body. Thomas Laycock appears as a lone figure in British medicine in giving serious consideration to a trophic nervous system. His discussions are based on clinical observations but his theories are speculative. He devised an instrument (an aesthesiometer) which he hoped would identify abnormalities of the trophic nervous system. The demise of a trophic nervous system is described with quotations from Charcot and Gowers and the use of the word trophic in current practice is mentioned. PMID- 11620238 TI - Early contributions to the reflex chain hypothesis. AB - The reflex chain hypothesis was developed to explain the observation that successive movements could be linked together into a contiguous sequence. From the established principles of reflex physiology and association psychology, scientists in the last half of the 19th century began to develop the notion that each of a series of movements may be linked through the sensory results of prior movements. In addition, the same basic principles were applied to mental actions, thus providing a credible explanation for all behavior. The wide applicability of this hpothesis made it an important influence on the scientific thought in the early 20th century. PMID- 11620239 TI - Cajal's views on the Nobel Prize for physiology and medicine (October 1904). AB - In this report we present and discuss an unpublished letter written by Santiago Ramon y Cajal in October 1904 in relation to his possible nomination for the Nobel Prize for Physiology and Medicine. This letter shows that Cajal was aware of his previous nominations for the Prize. He was convinced that these nominations had not been successful because neither anatomy nor histology were among the sciences included in the Nobel Statutes' definition of Physiology or Medicine. He gives a list of the merits he thought might be used for a new nomination, which included only works concluded during the previous five years. PMID- 11620240 TI - Cases of stroke on the throne of Byzantium. AB - The authors describe the fatal illnesses of three Byzantine emperors, Alexander, Michael IX Palaeologus and Manuel II Palaeologus, who may have died of a stroke. From the texts of Byzantine historians and the indications of chroniclers, it was found that Alexander died of a stroke (possibly cerebral hemorrhage); Michael IX Palaeologus died of what seems to have been the same disease and the the last of these emperors, Manuel II Palaeologus, of hemiplegia. This paper provides the opportunity to see how the non-medical texts of historians and chroniclers adopt and express the scientific Byzantine terminology of the medical writers of the period, which is used differently today. PMID- 11620241 TI - Herman Boerhaave. PMID- 11620242 TI - Jacobus Schroeder van der Kolk: 1797-1997. PMID- 11620243 TI - John C. Eccles (1903-1997): neurophysiologist and neurophilosopher. PMID- 11620244 TI - A medieval scientific encyclopedia "renewed by goodly printing"; Wynkyn de Worde's English De proprietatibus rerum. AB - Wynkyn de Worde published c. 1495 the first printed edition of John Trevisa's English translation of an influential work of science composed by Bartholomew the Englishman in Latin in the thirteenth century, De Proprietatibus Rerum (DPR). The design of the Worde's book, the use of Latin in the rubrics, and the visual vocabulary of the illustrations bring readers of English into the circle of learning. First, the plan of organization of Bartholomew's encyclopedic work is analyzed and both that structure and the expository style of the work are related to memorial reading and use as a textbook. Next, the widespread use of DPR in Latin and vernacular languages is reviewed, the suggestion that certain of its books seem to have been used more than others is made, and the reliance of English readers, such as Roger Thorney, who commissioned de Worde's edition, on de Worde for learned books printed in their provincial tongue is pointed out. Finally, through comparison with certain manuscript and other printed editions, the methods de Worde used to make the book readable are explained, the layout is shown to support the idea of system, and the function of the pictures as visual texts carrying scientific ideas is demonstrated. PMID- 11620245 TI - Vernacularisation of medical writing in English: a corpus-based study of scholasticism. AB - This article proposes a model for linguistic analysis of scientific thought styles, combining quantitative and qualitative analyses in the variationist frame and focusing on writings of the scholastic period. The first part of the article considers factors that led to the vernacularisation of scientific writings in fifteenth-century England and the sources, underlying traditions and audiences of these writings. The empirical part focuses on two features typical of scholasticism: references to authorities and the use of prescriptive phrases. The results show statistical differences between varieties of writing. A close semantic analysis reveals a pattern which is related to the underlying layers of tradition and to the sociohistorical background of the texts. The material comes from a computer-readable Corpus of Early English Medical Writing 1375-1750, which the authors are compiling at the University of Helsinki. PMID- 11620247 TI - Medical writing in transition: between ars and vulgus. PMID- 11620246 TI - The vernacularization of science, medicine, and technology in late medieval Europe: introduction. PMID- 11620248 TI - Charles Dickens, The Royal Veterinary College and the veterinary profession. PMID- 11620249 TI - To the pillory for putrid poultry: meat hygiene and the medieval London butchers, poulterers and fishmongers companies. PMID- 11620250 TI - British veterinary surgeons, the Australian Agricultural Company and the early years of the Indian horse trade. PMID- 11620251 TI - Dr. Henry Bracken of Lancaster. PMID- 11620252 TI - Retrodiction and the histories of bioethics. PMID- 11620253 TI - Holocaust hospital in the forests of White Russia. PMID- 11620254 TI - The chemical revolution and pharmacy: a disciplinary perspective. PMID- 11620255 TI - Drugs and chemicals. PMID- 11620256 TI - Pharmacy in Soviet Russia before the great patriotic war (1941-45). PMID- 11620257 TI - Homeopathic journals of the United States. PMID- 11620258 TI - Frederick Albert Cook, a medical polar explorer. PMID- 11620259 TI - A new look at Harvey Cushing as a radiologic pioneer. PMID- 11620261 TI - The Gratiot County landfill: one of Michigan's foremost toxic waste sites. PMID- 11620260 TI - Mind over medicines. PMID- 11620262 TI - Childbearing patterns in 1850 rural America. Fertility differentials in an agricultural society: Saginaw County, Michigan, in 1850. PMID- 11620263 TI - Robert C. Kedzie: Michigan's nineteenth century consumer activist. PMID- 11620264 TI - The impact of European diseases in the sixteenth-century southeast: a case study. PMID- 11620265 TI - Psychology and colonialism: some observations. PMID- 11620266 TI - Phrenology: getting your head together in ante-bellum America. PMID- 11620267 TI - Dr. Brydon's report of the Kabul disaster and the documentation of history. PMID- 11620268 TI - Not Available. PMID- 11620269 TI - Something in excess? Priapea 50, 2. PMID- 11620270 TI - [Not Available]. PMID- 11620271 TI - Recognizing India's doctors: the institutionalization of medical dependency, 1918 1939. PMID- 11620272 TI - Bubonic plague in nineteenth-century China. PMID- 11620273 TI - The troubled course of medical research. PMID- 11620274 TI - Psychology and Quaker mysticism: the legacy of William James and Rufus Jones. PMID- 11620276 TI - The birth-baptism interval and the estimate of English population in the eighteenth century. PMID- 11620275 TI - Jokes of nature and jokes of knowledge: the playfulness of scientific discourse in early modern Europe. PMID- 11620277 TI - Identification of the plants described by Albertus Magnus. PMID- 11620278 TI - Public death in the eighteenth century. PMID- 11620279 TI - One hundred medical recipes in Judeo-Spanish of ca. 1600. PMID- 11620280 TI - Achievements in microbiology in Poland in the period 1945-1970. PMID- 11620281 TI - Immunology in Poland in the years 1971-1975. PMID- 11620282 TI - The scruples of a chemist. PMID- 11620283 TI - Obethio's owl. PMID- 11620284 TI - A history of first aid in Australia: the evolution of pre-hospital care. PMID- 11620285 TI - Medieval guilds, passions and abuse. PMID- 11620286 TI - Medieval crime, violence and superstition: symptomatic dysfunction. PMID- 11620287 TI - [Not Available]. PMID- 11620288 TI - The transportation of mules from South America to the West Indies in the 1860s. PMID- 11620289 TI - [Not Available]. PMID- 11620290 TI - The influence of medicine on science education in England, 1892-1911. PMID- 11620291 TI - Medicine in ancient Rome. PMID- 11620292 TI - Meals on the mess deck: from canteen messing to professional catering. PMID- 11620293 TI - The Smoke Abatement Exhibition of 1881. PMID- 11620294 TI - Mary Ellen Umberger, D.C.: an oral history. PMID- 11620295 TI - The American Council of Women Chiropractors from 1935 to 1960. AB - Equal rights for women have been a never ending battle in the professional world. Even though many women influenced the chiropractic profession, these same battles could not be avoided. For this reason, several students from the Lincoln Chiropractic College worked to form the American Council of Women Chiropractors (ACWC), a council of the American Chiropractic Association (ACA). From 1935 to 1960, the organization was represented in the House of Counselors of the NCA, had a monthly section in the Journal of the National Chiropractic Association to publish information about the council along with scholarly work by their members, and formed a Scholarship Foundation for Women Chiropractic Students. Perhaps one of the most important roles the ACWC played was in its support of women chiropractors. Through annual meetings and personal contacts, the members were able to endure many difficulties that existed both inside and outside chiropractic. PMID- 11620296 TI - Dr. Millie Cleveland: chiropractic achiever. AB - Dr. Mildred Genoa Allison-Cleveland, affectionately known as "Dr. Millie," was an important part of life at Cleveland Chiropractic College for over thirty years, serving first as a clerical assistant, then instructor, administrative assistant, and trusted right hand of her husband, Dr. Carl Cleveland, Jr. Yet Mildred Cleveland, like many other women who have helped the profession grow and survive over the years, has never been the subject of an article in print. In this paper, the author will strive to outline Dr. Mildred Cleveland's accomplishments, as well as to give the reader as clear a picture as possible of the woman who was the wife of one chiropractic pioneer and mother of another. PMID- 11620297 TI - The resurrection of the B.J. Palmer Clinic research: a personal view. AB - This article discusses the history of the B.J. Palmer Clinic research files, and describes a long-term project to archive these files for use in chiropractic case studies and descriptive research. The methods used in this project, and examples of published works from the B.J. Palmer research will be given. In additon, a researcher's view of B.J. Palmer's important historical role in the chiropractic profession will be offered. PMID- 11620298 TI - Ted L. Shrader, D.C., F.I.C.C.: a gentle force for improvement in chiropractic. 1998 Lee-Homewood Chiropractic Heritage Award recipient. AB - Long before technology assessment and continuous quality improvement were in vogue in chiropractic, Ted L. Shrader, D.C., F.I.C.C., was working toward these goals in the profession. Convinced that chiropractic must change from within for the benefit of society, Dr. Shrader has made a career-long commitment to evaluating chiropractic procedures and establishing consensus statements regarding chiropractic principle. Determined in mind, moral by nature, and unobtrusive in manner, Dr. Shrader has been decidedly effective in his endeavors. He has encouraged in chiropractic a mind for critical thinking. The fruits of his labor can be seen today in chiropractic publication, among chiropractic scholars, within the American Chiropractic Association Council on Technique, in conference proceedings, and in our institutions. PMID- 11620299 TI - Jailed chiropractors: those who blazed the trail. AB - When the iron doors of the Scott County Jail shut on D.D. Palmer in the spring of 1906 he was destined to be the first of hundreds of chiropractors who would "go to jail for chiropractic" through most of three quarters of the century. This study recalls the significant jailing and the commitment of many who sustained multiple trials, convictions and imprisonment. By, far Ohio was the harshest jurisdiction in the country, jailing better than a third of those imprisoned. An extensive appendix of those D.C.s who served time, by states, is included in this contribution. PMID- 11620300 TI - Pacific States Chiropractic College: the legacy of George Emmet Anderson, D.C. AB - Established in 1976, Pacific States Chiropractic College (PSCC) was the first such institution in Northern California since the 1950s. Its founder, Dr. George E. Anderson, was himself a 1954 graduate of an earlier school, Claifornia Chiropractic College at Oakland. His vision was of a strong, professionally-owned institution founded on a balance of science, art and traditional chiropractic principles. It was to be a fitful start for the new school as two administrators would be discharged for malfeasance; lawsuits filed against them by Dr. Anderson and his founding associate, Dr. George Wentland. A newly-structured PSCC reopened in September 1978 at its present location in San Lorenzo and with its master plan intact. In the early 1980s, after three interim administrations and a long search Pacific States was merged with Life Chiropractic College of Marietta, GA. Dr. Gerard W. Clum was named president. Fully accredited, Life Chiropractic College West today the largest chiropractic institution on the West Coast and carries on the dream of Dr. George Anderson. PMID- 11620301 TI - Highly restricted fertility: very small families in the British fertility decline. AB - From the earliest stages of the British fertility decline, falling mean family size was accompanied by marked rises in the proportion of married women who remained childless or who bore only a single child. This paper summarises those changes, their impact on average family size, and the implications for estimates of the proportions of couples who attempted to space their children in the early years of marriage. The explanatory power of some commonly cited interpretations of the general decline in marital fertility is then considered in the context of this growth in number of families of highly restricted fertility. The paper highlights a need for more emphasis on descriptive and analytical approaches that are sensitive to distributions within populations. Also emphasized is the importance of developing interpretations that allow for the possibility that different factors may operate on different sub-sets of families at different points in time. PMID- 11620302 TI - Beyond infant mortality: gender and stillbirth in reproductive mortality before the twentieth century. AB - Though it has been the largest component of reproductive mortality since its statutory registration in 1928, stillbirth has received little attention from historical demographers, who have relied on the more orthodox indicator of early human survival changes - "infant mortality". The exclusion of stillbirth hampers demographic analysis, underestimates progress in newborn vitality, and over privileges post-natal causes in theoretical explanation. A case is made for estimating stillbirth before 1928 as a ratio of early neonatal death, and for employing perinatal mortality as an historical indicator of female health status. The long-run trend of reproductive mortality (encompassing mature foetal and live born infant death during the first eleven months) reveals a substantial decline in perinatal causes in the first industrial century (1750-1850), implying a major concurrent improvement in the nutritional status of child bearers. Reproductive mortality is a more complete indicator of death in infancy. It offers demographers a means of fracturing the fertility versus mortality dualism and a potential purchase on gender as a demographic variable, while re-opening the case on mortality in the demographic dynamic of the world we have lost. PMID- 11620303 TI - Emile Zuckerkandl, Linus Pauling, and the molecular evolutionary clock, 1959 1965. PMID- 11620304 TI - To be an invalid, redux. PMID- 11620305 TI - The role of the Vilmorin Comapny in the promotion and diffusion of the experimental science of heredity in France, 1840-1920. PMID- 11620306 TI - The limits of heredity: nature and nurture in American eugenics before 1915. PMID- 11620307 TI - Essay review: cancer and science: the Hundred Years War. PMID- 11620308 TI - Erasmus Darwin, (1731-1802): a great eighteenth century English physician. PMID- 11620309 TI - Who was "Lily the Pink"? the story of an American proprietary medicine. PMID- 11620310 TI - Duncan and Flockhart: the story of two men and a pharmacy. AB - The history of Duncan, Flockhart and Company and its manufacturing activities has been previously recorded in some detail. This paper looks at the two men John Duncan and William Flockhart, who gave their name to a major pharmaceutical manufacturer, and also at their pharmacy the parent of the company. PMID- 11620312 TI - Population change in Kericho District, Kenya: an example of fertility increase in Africa. PMID- 11620313 TI - Cattle plague in eighteenth-century England. PMID- 11620314 TI - The linguistic repudiation of Wundt. AB - Wilhelm Wundt's influence on the development of linguistics and psychology was pervasive. The foundations for this web of influence on the sciences of mind and language were laid down in Wundt's own research program, which was quite different from other attempts at founding a new psychology, as it was deeply rooted in German philosophy. This resulted in certain gaps in Wundt's conception of mind and language. These gaps provoked a double repudiation of Wundt's theories, by linguists and psychologists. The psychological repudiation has been studied by historians of psychology, and the linguistic repudiation has been studied by historians of linguistics. The intent of this article is to bring the linguistic repudiation to the attention of historians of psychology, especially the one outlined by two important figures in the history of psychology: Karl Buhler and George Mead. PMID- 11620315 TI - Early applied psychology between essentialism and pragmatism; the dynamics of theory, tools, and clients. AB - The indebtedness of applied psychology to classical laboratory psychology is much greater than is usually assumed. It manifests itself both in the initial use of laboratory apparatus and diagnostic tools and in the conception of vocational fitness as a matter of the same elementary mental functions as those measured in the laboratory. In America this psychological essentialism soon gave way to a more pragmatic approach, aimed at prediction of success. As the history of the psychotechnical movement shows, this transition occurred on the European continent much later. The disparity is explained by differences in the primary audience of the pioneers of practice at both sides of the Atlantic. The development of occupational psychology is used as a case of transition in investigative style in general. PMID- 11620316 TI - Klaus Holzkamp and the rise and decline of German critical psychology. AB - The history of German Critical Psychology focuses on the works of its most significant representative, Klaus Holzkamp (1927-1995), and reconstructs the development of his ideas, critiques, and results. For historical-systematic reasons his work is divided into a precritical period (until 1968), a critical emancipatory period (1968-1972), a critical-conceptual period (1973-1983), and a subject-scientific period (1984-1995). Social movements and internal problems of traditional psychology are identified as factors in the rise of his psychology, whereas the decline of Critical Psychology in the 1980s and 1990s is attributed to social development, limitations of a systematic-foundational framework, and the emergence of alternative critical approaches. Despite these problems the article shows that Holzkamp is an eminent theoretical psychologist who has made significant contributions to psychological knowledge. PMID- 11620317 TI - Wolfgang Kohler and Gestalt theory: an English translation of Kohler's Introduction to die physischen Gestalten for Philosophers and Biologists. AB - This article presents an English translation (from the German) of one of gestalt psychology's most significant documents, first published in 1920 in Wolfgang Kohler's Die physischen Gestalten in Ruhe und im stationdren Zustand (The Physical Gestalten at Rest and in a Stationary State). The book it introduces both embodies Kohler's extension of gestalt theory into new domains and did much to ensure the broad impact of these ideas and approaches. This introduction itself well illustrates Kohler's own thought processes both as his ideas emerged and as he sought to convince his readers of their value. Despite the fact that they are more than 70 years old, Kohler's words have many implications for late 20th century discussions of the relationships among psychology, physiology, and physics. PMID- 11620318 TI - "The defects of his race": E.G. Boring and antisemitism in American psychology, 1923-1953. AB - From the 1920s to the 1950s, Edwin G. Boring wrote letters of reference for Jewish students and colleagues in which he followed the common practice of identifying them as Jews and assessing whether they showed "objectionable traits" thought to characterize Jews. These practices are discussed in relation to the increasing antisemitism of the interwar period, with specific reference to Abraham A. Roback and Kurt Lewin. In Roback's case, the "defect" of Jewishness was thought to explain his undesirable personality: with Lewin, personal charm mitigated the "defect" of Jewishness. Boring's unsuccessful attempts to place Jewish students, his subsequent pessimism, and his postwar discussions of Jewish identity are examined in relation to the general issue of antisemitism in the history of academic psychology. PMID- 11620319 TI - On History of Psychology's launch. PMID- 11620320 TI - Gordon Allport, character, and the "culture of personality," 1897-1937. AB - This article examines the cultural context of early American personality psychology through a consideration of the early career of Gordon Allport. Between 1921 and 1937, Allport was among the leading figures in the movement to establish personality as a research category in American psychology. Far from being a strictly scientific concern, Allport's project was deeply embedded in the cultural politics of the age. Of particular importance was the gradual erosion of the language of character and the self-sacrificing, morally grounded self that it supported. Allport's "psychology of personality" helped fuel this trend while simultaneously attempting to resist it. His experience illustrates the elasticity and moral ambiguity of the newly emerging category of personality. PMID- 11620322 TI - The thoroughly modern Aristotle: was he really a functionalist? AB - In recent years a debate has developed over whether Aristotle's theory of the psuche is properly characterized as having been "functionalist" in the sense that contemporary computational cognitive scientists claim to be adherents of that position. It is argued here that there are indeed some similarities between Aristotle's theory and that of contemporary functionalists but that the differences between them make it misleading, at best, for functionalists to look to Aristotle for ancient support. In particular, it is argued that Aristotle would not have--indeed, specifically did not--support the claim, central to functionalism, that the mind can in principle be transported from one body to another simply by instantiating in the new body some set of organizational properties that were instantiated in the old. PMID- 11620321 TI - The Lashley-Hull debate revisited. AB - N. Weidman (1994) claimed that "Karl Lashley and Clark Hull had a long and unresolved controversy about the structure and function of the brain, its relationship to the mind, and the use of machine metaphors to explain intelligence" (p. 162). The record contained in published articles and unpublished correspondence indicates otherwise. The clash was explicitly about continuity versus noncontinuity in discrimination learning, stimulus generalization, and the development of quantitative and mathematical psychological theory and its relation to neurophysiological data. Weidman also contended that the subtext of the debate was whether heredity or environment was more important in determining intelligence and behavior. This is doubtful. It is more probable that the debate stemmed from Lashley's career-long opposition to connectionism. PMID- 11620323 TI - Theta H. Wolf (1904-1997). PMID- 11620324 TI - Virginia Staudt Sexton (1916-1997). PMID- 11620325 TI - Marie C. Stopes and the popularization of birth control technology. PMID- 11620326 TI - The enigma of early lens use. PMID- 11620327 TI - Cannibalism and contagion: framing syphilis in counter-reformation Italy. AB - The outbreak of syphilis in Europe elicited a variety of responses concerning the disease's origins and cure. In this essay, I examine the theory of the origins of syphilis advanced by the 16th-century Italian surgeon Leonardo Fioravanti. According to Fioravanti, syphilis was not new but had always existed, although it was unknown to the ancients. The syphilis epidemic, he argued, was caused by cannibalism among the French and Italian armies during the siege of Naples in 1494. Fioravanti's strange and novel theory is connected with his view of disease as corruption of the body caused by eating improper foods. His theory of bodily pollution, a metaphor for the corruption of society, coincided with Counter Reformation concepts about sin and the social order. PMID- 11620328 TI - Alchemy vs. chemistry: the etymological origins of a historiographic mistake. AB - The parallel usage of the two terms "alchemy" and "chemistry" by seventeenth century writers has engendered considerable confusion among historians of science. Many historians have succumbed to the temptation of assuming that the early modern term "chemistry" referred to something like the modern discipline, while supposing that "alchemy" pertained to a different set of practices and beliefs, predominantly the art of transmuting base metals into gold. This paper provides the first exhaustive analysis of the two terms and their interlinguistic cognates in the seventeenth century. It demonstrates that the intentional partition of the two terms with the restriction of alchemy to the sense of metallic transmutation was not widely accepted until the end of the seventeenth century, if even then. The major figure in the restriction of meaning, Nicholas Lemery, built on a spurious interpretation of the Arabic definite article al, which he inherited from earlier sources in the chemical textbook tradition. In order to curtail the tradition of anachronism and distortion engendered by the selective use of the terms "alchemy" and "chemistry" by historians, the authors conclude by suggesting a return to seventeenth-century terminology for discussing the different aspects of the early modern discipline "chymistry." PMID- 11620329 TI - The truth about truth. [Review of : Shapin, S. A social history of truth: civility and science in seventeenth-century England. University of Chicago Press, 1994]. PMID- 11620330 TI - Doctor Erasmus Darwin's death in 1802. PMID- 11620331 TI - Illustrating a revolution: an unrecognized contribution to the golden era of cerebral localization. AB - The late 19th century witnessed a remarkable growth of knowledge concerning the functions of the brain. The excitability of the cerebral cortex was first reported by Gustav Fritsch (1838-1927) and Eduard Hitzig (1838-1907) in 1870, followed by the classical investigation of cerebral localization by David Ferrier (1843-1928). Ferrier's identification of cerebral motor centres based on a series of cortical stimulations and ablations was central to the physiological and clinical achievements of cerebral localization in the late 19th century. Cerebral illustrations were an important component of Ferrier's physiological research, synthesizing a great deal of experimental data and suggesting precise locations and boundaries of sensory and motor areas. Surprisingly, little attention has been paid to the construction of cerebral maps and their role in establishing the utility and veracity of the doctrine of cerebral localization. Two illustrations of the macaque brain based on Ferrier's experimental work were particularly influential. These and other important illustration accompanied Ferrier's manuscript, "the localisation of functions in the brain", submitted to the Royal Society in early 1874, but were not produced by Ferrier himself. Rather, they were sketched by E.A. Waterlow (1850-1919), a young painter and acquaintance of Ferrier's who--undoubtedly under Ferrier's guidance--synthesized the experimental data of more than a dozen experiments in these diagrams. Unfortunately, during contentious review, abstraction and fragmentation of Ferrier's manuscript, Waterlow's monogrammed insignia was omitted from reproductions of his sketches and Ferrier's acknowledgement to him was not published in subsequent works. PMID- 11620332 TI - Lionel Penrose, F.R.S. (1898-1972) and eugenics. Part two. PMID- 11620333 TI - [A new studie of embalment in ancient Egypt]. AB - The instruments of the Embalmer Priest. Studies on the practice of embalming in ancient Egypt have mostly neglected the instruments used by embalmers to make their activity easier. Only three embalmer's caches contained embalmers' instruments, but some further objects have been found in museum collections. We have created bronze reproductions of these tools which then used on a corpse at the Faculty of Medicine of Paris VII. PMID- 11620334 TI - Saint Sebastian and the Black Death. AB - The martyrdom of Saint Sebastian is one of the most enduring themes in Western religious art. The execution scene so often portrayed - with the Saint transfixed with arrows - is based on the legend about his life and death during the reign of the Roman emperor, Diocletian. However, it is the symbolic association of arrows with the Black Death - during the Middle Ages and during the Renaissance - which identifies Sebastian as the patron saint of plague victims. After more than four centuries of recurrent epidemics, the plague died out in Europe; but the image of St. Sebastian continued to inspire artists until the end of the 19th century. PMID- 11620335 TI - Ibn Al Jazzar and the Kairouan medical school of the tenth century AD. AB - This brief account of the Tunisian physician Ibn Al Jazzar heralds the Congress of the International Society for the History of Medicine to be held in his native country in September 1998. His life work reveals him as a pioneer in distinguishing the art of medicine and pharmacy. PMID- 11620336 TI - [Andres Piquer and the Hippocratic tradition in 18th-century Spain]. AB - Andres Piquer (1711-1772) was the most important medical philosopher of the Spanish Enlightenment. He was also the first who translated Hippocratic works into Spanish. In the following pages, the authors summarize Andres Piquer's opinions concerning the problem of the relationship between philosophical methods and understanding medicine. PMID- 11620337 TI - Medecine a la Moliere. AB - Of Moliere's thirty six plays, seven deal, to a greater or lesser extent, with medicine; the medicine as practiced in Paris during the reign of Louis XIV. In these days, Moliere satirises the recalcitrant conservatism of the Paris medical faculty. It is, however, an informed satirisation. This paper explores Moliere's motives and attempts to place Moliere's medical plays against a broad canvas of his other works. The ultimate purpose is to assess to what extent Moliere's philosophical persuasions and how he balanced them against the needs of contemporary, commercial theatre. PMID- 11620338 TI - Medical declarations on temperance. AB - As early as 1736, the Royal College of Physicians submitted to Parliament a representation concerning the excessive consumption of spirituous liquors. No further authoritative statement was made for nearly a century, by which time the first Temperance and Total Abstinence societies had been formed. Many medical men were happy to support the call for moderation and a number of societies issued declarations signed by local practitioners; however, fear of losing patients meant that few doctors supported total abstinence. In addition, alcohol was widely used as a therapeutic agent. In spite of this, declarations were issued in 1839 and in 1847 which were essentially "teetotal" in tone. Most of the declarations were reported only in the temperance journals. That of 1871 was entirely different; it was circulated to every doctor on the medical register and publicised in full in all the national newspapers. It was signed by the Presidents of the Royal Colleges and by 233 others; it condemns the "inconsiderate prescription" of alcohol and questions its value as a food or as a medicine. The therapeutic arguments and the impact of the volte face of the medical establishment in supporting the declaration are examined, as is the reaction of the lay press. PMID- 11620339 TI - The diagnosis of disease from ancient coins. PMID- 11620340 TI - Health care in Norman England. PMID- 11620341 TI - When sense and life begin: background for a remark in Aristotle's Politics [1335b24]. PMID- 11620342 TI - A chapter from the Rgyud-Bzi. PMID- 11620343 TI - The age and sex composition of Chinese-Americans: recent trends. PMID- 11620344 TI - The fur traders: their diet and drugs. PMID- 11620345 TI - "Nirkit": good food. PMID- 11620346 TI - Psychohistory and its discontents. PMID- 11620347 TI - From faceless chronicler to self-creator: the diary of Louisa Galton, 1830-1896. PMID- 11620348 TI - Frantz Fanon: his work in historical perspective. PMID- 11620349 TI - American assassins: an alternative typology. PMID- 11620351 TI - Chemical warfare and arms control crisis and concern. PMID- 11620350 TI - The Roman baths at Bath: the excavations 1969-75. PMID- 11620352 TI - The early expansion of the Norwich Union Life Insurance Society, 1808-37. PMID- 11620353 TI - The double bind of the double standard: VD control and CWAC in World War II. PMID- 11620354 TI - Losing touch: criminal insanity. PMID- 11620355 TI - Remember the nurses: Michael Reese Hospital School of Nursing, 1890-1981. PMID- 11620356 TI - Birth control in China: local data and their reliability. PMID- 11620357 TI - Reginald Scot and his Discoverie of witchcraft: religion and science in the opposition to European witch craze. PMID- 11620358 TI - Spotsylvania: reflections. How men die in battle. PMID- 11620359 TI - A note on Alexander's death. PMID- 11620360 TI - The nature of Sappho's seizure in fr. 31 LP as evidence of her inversion. PMID- 11620361 TI - Genetics and communism. PMID- 11620362 TI - Working class birth control in Wilhelmine Germany. PMID- 11620363 TI - The reception of psychoanalysis in Germany. PMID- 11620364 TI - Homosexuality in France. PMID- 11620365 TI - Out of the fiscal shadow: carceral trends in Canada and the United States. PMID- 11620366 TI - Robert Lowry Sibbet (1826-1898), a medical reformer. PMID- 11620367 TI - Pioneer medicine in Indiana. PMID- 11620368 TI - Sharing more than marble palaces. PMID- 11620369 TI - Bohemia during the medieval Black Death: a pocket of immunity. PMID- 11620370 TI - Family limitation in pre-industrial England. PMID- 11620371 TI - "The monster nuisance of all": landowners, alkali manufacturers, and air pollution, 1828-64. PMID- 11620373 TI - Pre-famine Irish population: the evidence from the Trinity College estates. PMID- 11620372 TI - Reflections on Galen. PMID- 11620374 TI - A case study of population change over two centuries: Blaris, Lisburn 1661-1848. PMID- 11620375 TI - Schistosomiasis control in Red China. PMID- 11620376 TI - The paradox of prudence: mental health in the gilded age. PMID- 11620377 TI - Stable force in a storm: Harry J. Anslinger and United States narcotic foreign policy, 1930-1962. PMID- 11620378 TI - Degeneracy and race in the nineteenth century: the impact of clinical medicine. PMID- 11620379 TI - Brigham Young in life and death: a medical overview. PMID- 11620380 TI - The Ethel Jones Report: black women in the nursing profession, 1925. PMID- 11620381 TI - Health and health care for the Palestinians of the West Bank and Gaza Strip. PMID- 11620382 TI - "Working for the good of the community": Rest Haven Preventorium for Children. PMID- 11620383 TI - Folk memories of the decline of Angkor in nineteenth-century Cambodia: the legend of the leper king. PMID- 11620384 TI - The incident. PMID- 11620385 TI - Tender loving care: a study of the doctors, their medicines and medical treatment during the American Civil War era. PMID- 11620386 TI - Abstinence and moderation: mixing Mennonite drinking norms. PMID- 11620387 TI - "At the time of our misfortune": relief efforts following the 1918 Cloquet fire. PMID- 11620388 TI - An untarnished youth in the gilded age: Theodore Schroeder of Wisconsin and Dakota territory. PMID- 11620389 TI - The buffalo disaster of 1882. PMID- 11620390 TI - Witchcraft and superstitions of Torrance County. PMID- 11620391 TI - Francis Schlatter: the healer of the southwest. PMID- 11620392 TI - Epidemics and mortality in Nova Scotia, 1749-1799. PMID- 11620393 TI - Medical aspects of the Lewis and Clark expedition. PMID- 11620394 TI - The Nebraska Asylum for the Insane, 1870-1886. PMID- 11620395 TI - George Springmeyer and the quarantine rebellion of 1902: student revolt reaches the University of Nevada. PMID- 11620396 TI - The curious trial of "the Durham boy." PMID- 11620397 TI - Medical crisis at Fort Niagara, 1779-80. PMID- 11620398 TI - A demographic outline for the development of Soviet society: some recent trends and prospects for the future. PMID- 11620399 TI - Doctors, paupers, and landowners. The evolution of primary medical care in Orkney. PMID- 11620400 TI - Dating Howells' adolescent breakdown. PMID- 11620401 TI - The Trinity Medical College. PMID- 11620403 TI - Food supply and starvation: a study of famines with reference to the Indian sub continent. PMID- 11620402 TI - My medical school (1890-1894). PMID- 11620404 TI - Against all odds: Chevalier Jackson, physician and painter. PMID- 11620405 TI - Crisis in the capital: the cultural significance of Philadelphia's great yellow fever epidemic. PMID- 11620406 TI - Unsung partner against crime: Harry J. Anslinger and the Federal Bureau of Narcotics, 1930-1962. PMID- 11620407 TI - Training for a prophet: the west coast missions of John Alexander Dowie, 1888 1890. PMID- 11620408 TI - West Coast medicine in 1776. PMID- 11620409 TI - Detaining the insane: detention hospitals, mental health, and frontier politics in Alaska, 1910-1915. PMID- 11620411 TI - The medical school of Velia. PMID- 11620412 TI - [Not Available]. PMID- 11620410 TI - Ancient Jerusalem: its water supply and population. PMID- 11620413 TI - [Not Available]. PMID- 11620414 TI - Analysis terminable and interminable. PMID- 11620415 TI - Unnatural conceptions: the study of monsters in sixteenth- and seventeenth century France and England. PMID- 11620416 TI - Birth-control in the west in the thirteenth and early fourteenth centuries. PMID- 11620417 TI - Oral contraceptives and early-term abortifacients during classical antiquity and the Middle Ages. PMID- 11620418 TI - Review article: But what was the disease? The present state of health and healing in African studies. PMID- 11620419 TI - Neuroanniversaries 1998. PMID- 11620420 TI - Cerebral mythology: a skull stuffed with gods. (Neurowords 3) PMID- 11620421 TI - The effects of mental health legislation 1890-1990. AB - This investigation sought to examine mental health legislation between 1890-1990 and to appraise their effects on the care and social control of the mentally ill. The research activities included the study and analysis of archival documents, Hansard, newspapers and professional journals. The findings show that those who cared for the mentally ill were subjected to the changes brought in by successive mental health legislation. These changes affected the working condition of the "mental nurse", and the social control and rights of the mentally ill person. PMID- 11620422 TI - The changing focus of nursing practice in Brazil. AB - Using a historical-social perspective, the authors aim at understanding and analysing the vision of supervision and leadership in the history of Brazilian nursing from 1930 to 1995. The empirical material comprised journal articles, books, theses and proceedings. In the first period (1930-1949), preliminary expressions of the organization and control of nursing work were found. In the second (1950-1969), the concept of human relations at work emerged in the third period (1970-1979) evidence was found for concern about staffing structures following changes in the health sector. In the most recent period (1980-1995), a new perspective is established, emphasising nursing as a social practice related to supervision rather than leadership. Based on this historical search, and linked with views of health practice and change in Brazilian society, supervision and leadership can be located within management ideas and practice. These concepts are understood, generally, within a theoretical critique that should demonstrate a close relationship with control of workers or the work process and its effects in the health sector, especially in nursing. PMID- 11620423 TI - The role and rewards of asylum attendants in Victorian England. AB - This paper reports on a study of the role and rewards of asylum attendants at a West Yorkshire asylum in the period 1852-1889. The role aspect was analysed with reference to the Regulations and Orders of the institution concerned and the rewards aspects with reference to the staff records. It emerged that attendants were the most poorly paid group of staff within the institution and the drop-out rate was high in the early years of service, though a number did give long service. PMID- 11620424 TI - Capturing nursing memories. AB - This paper describes how the history of a group of nurses who trained and worked in the Queen Elizabeth Hospital, Birmingham during the period 1938-1957 was captured and published (Clifford 1997). The time span of the book reflected the existence of the Queen Elizabeth Hospital Nurse Training School before it merged with other schools to become the Queen Elizabeth School of Nursing. PMID- 11620425 TI - "We picked the wrong one to sterilise": the role of nursing in the eugenics movement in Alberta, 1920-1940. AB - The opening decades of the twentieth century were years in which the Canadian government actively recruited immigrants from the United Kingdom, Europe and the United States to assist in the settlement of western Canada. The immigration waves that followed contained large numbers of non-English speaking people of eastern European heritage. As these numbers increased, the white Anglo-Saxon minority feared a "multiplication of the inferior". Alberta's solution was the passage of the Sterilization Act in 1928 and the creation of the Eugenics Board. The Act remained law until 1972 and its repercussions are facing Alberta courts today. The Act was supported by many prominent first-wave feminists such as Nellie McClung and Emily Murphy. Nurses too supported the Act and the philosophical ideology on which the need for sterilization was based- "an available means for racial improvement." The role nurses played in promoting eugenics in Alberta through referrals to the Eugenics Board and the promotion of birth control material will be explored in the presentation. Contributions made by public health nurses will be included since much of their work was devoted to the socialization of new immigrants to Canada. Class, gender and ethnicity are central themes to this discussion because the majority of individuals who were sterilized were unemployed, female immigrants from eastern Europe. These two decades represent a time in nursing history when the nurse's duty to care was complicated by the attitudes and values of the society in which she existed. Primary sources used include the personal collection of one of Alberta's early birth control nurses, Canadian Journal of Public Health, Canadian Nurse, and Alberta newspapers. PMID- 11620426 TI - Motherhood, milk, and money: infant mortality in pre-industrial Finland. AB - This article presents an analysis of the levels, trends and determinants of infant mortality in various regions of Finland between the late seventeenth and early twentieth centuries. Nursing habits were of critical importance as were diet and hygiene. It is suggested that there were differences in the frequency of breastfeeding with the landless being more and the farmers being less likely to breastfeed their children. In areas where cows milk was readily available as a substitute for breast milk other influences on infant mortality were the contamination of drinking water and the water in which feeding utensils were washed. At the end of the eighteenth century, in the south-west of Finland, the introduction of the potato created a suitable food for women and children and lowered the mortality rate of infants aged 3-6 months. By contrast, in the regions where the first solid food given to infants was chewed by the mothers, infant mortality remained high. In the part of Finland adjacent to St Petersburg infant mortality actually increased as local mothers were engaged as wet-nurses by the city's foundling hospital. PMID- 11620427 TI - Physical puritanism and religious dissent: the case of John Young (1820-1904), Sunderland chemist and druggist and Methodist lay preacher. AB - "Physical puritanism", the name given to the popular medical reform movements of early Victorian Britain by the Edinburgh academic Samuel Brown, nicely evokes their links with religious dissent. While historians have examined the formal organization, leadership, and membership of several of these movements, we know very little about the ways of thinking of their ordinary adherents. The diary of John Young (1820-1904), a Sunderland chemist and druggist and local preacher of the Wesleyan Methodist Association, affords unrivalled insights into the mind of one "physical puritan". In particular, Young's reading of the Edinburgh physician and phrenologist Andrew Combe's influential work Principles of Physiology (1834) can be examined in detail. Virginia Smith has argued that such advice books are valuable in providing access to lay ideas about health. Their readership, however, has not been studied. This article offers a case study which calls into question Smith's assertion that the new utilitarian popular physiology of the 1830s and 1840s was valued principally for the physical benefits offered by its therapies, so distinguishing it from its more spiritually-oriented eighteenth century antecedents. I argue that the natural theology which marks Combe's work was important in helping dissenters like Young to appropriate new ideas (in particular ideas derived from the popular science of phrenology) not only to promote physical health, but also to assist in attaining spiritual goals. For some of their readers, Combe and Wesley were not so far apart. PMID- 11620428 TI - The Romanian privilege in French medicine and anti-Semitism. AB - This paper reviews a special privilege given to Romanian medical students over other foreign medical students coming to study in France from the 1850s to the 1930s. It shows how, because of changing circumstances in Romania itself, this privilege evolved from benefiting small numbers of Christian students, who generally returned home after their studies, to benefiting large numbers of Jewish students, many of whom remained in France to practise medicine. It also shows how this evolution fed into medical anti-Semitism in France which discriminated specifically against these Romanian students as Jews, a phenomenon which was distinct from the French medical xenophobia directed against all foreign students. PMID- 11620429 TI - Building the French Muscular Dystrophy Association: the role of doctor/patient interactions. AB - The process of creating the French Muscular Dystrophy Association (AFM) is analysed through the interactions between the medico-scientific community on the one hand, and patients and their families on the other, from the 1950s to 1986. Each stage of its development was characterized by a particular mode of co operation between lay people and doctors. Starting in 1958, the Association built a close relationship with a single partner, Jean Demos, a paediatrician and biochemist who developed a new vasodilation therapy based on his controversial vascular theory of muscular dystrophy. Around 1966, some AFM members, disappointed by Demos' treatment, decided to collaborate with other specialists, primarily neurologists, but channelled most of their resources in social action. Two other organizations were then created around Dr. Demos: the first (Union de Myopathes de France (UMF) acted as a "grass-roots organization" for maintaining "therapeutic orthodoxy" among patients and supporting his research through political lobbying; the other, composed of a handful of wealthy individuals, raised private funds for his laboratory. In the late 1970s, some UMF members questioned Demos' approach. They united with AFM to form a single association and created a Scientific Council representing all French groups interested in neuromuscular diseases. The co-operation established between these two collective partners proved to be most fruitful for both parties. PMID- 11620430 TI - Case notes, case histories, and the patient's experience of insanity at Gartnavel Royal Asylum, Glasgow, in the nineteenth century. AB - This article is concerned primarily with questions as to how and why case notes were produced and utilized, and how they may (or may not) be used by historians. More specifically, it discusses how the Glasgow Royal Asylum's case notes may be deployed to access patients' experiences of madness and confinement. The deficiencies and biases of the case record are also explored. So too is the relationship of case notes with other asylum based records, including reception order questionnaires, with a separate section on patient writings as part of the case history corpus. This leads into an analysis of how the Asylum's case notes became case histories and for what purposes. These subjects are related to changes and continuities in medical ideologies about insanity, social attitudes to the insane and the nature of medical practice in asylums. Some fundamental shifts in emphasis in the use of the case note and case history occurred in this period. These shifts were associated with an increased emphasis on organic interpretations of mental disease and on clinical approaches to insanity; with the medicalization of asylum records and the wider discourse on insanity, and with declining deference to the public at large in the presentation of cases. The survey concludes by analysing the changing place of patient testimony within the case record. PMID- 11620431 TI - Women and abortion in 1930s Britain: a survey and its data. AB - This paper examines over 3,000 questionnaires on abortion that were distributed through the National Birthday Trust Fund, a non-governmental orrganization, to working-class women in municipal hospitals in 1930s Britain. The aim of the survey was to "discover the proportion of induced to spontaneous abortions". Although the study was abandoned due to weaknesses in its design, the collected data contain a mass of detailed information about the lives and reproductive history of working-class women in this period. The background to the survey is discussed, setting it within the development of research on poverty and women's health, as well as contemporary debate on the issue of abortion. The survey data, which are both qualitative and quantitative, are analysed and presented in figures with accompanying commentary. Issues covered include the impact of poverty, overcrowding, reasons for avoiding pregnancy, and contraception. PMID- 11620432 TI - Above all, do no harm. PMID- 11620433 TI - Richard Brocklesby FRS FRCP (1722-1797): physician and friend. PMID- 11620434 TI - Sir Harold Stiles (1863-1946). PMID- 11620435 TI - John Simon as surgeon and scientist. PMID- 11620436 TI - Queen Alexandra, Niels Finsen and the London Hospital: enlightened links. PMID- 11620437 TI - Grandfather's choice - psychiatry in mid-Victorian Ireland. PMID- 11620438 TI - The case of professor Presbury: a literary digression on the controversial birth of endocrinology. PMID- 11620439 TI - Pioneers of music therapy. PMID- 11620440 TI - A west country polymath: William Musgrave MD FRS FRCP, of Exeter (1655-1721). PMID- 11620441 TI - The cause of death of the Byzantine emperor John I Tzimisces (969-976). Poisoning or typhoid fever? PMID- 11620442 TI - The pathography of composers: modest Mussorgsky. PMID- 11620444 TI - Modern malaria PMID- 11620445 TI - The Irish famine: a century and a half on. PMID- 11620443 TI - George Budd FRS (1808-1882): pioneer gastroenterologist and hepatologist. PMID- 11620446 TI - Camphor, cabbage leaves and vaccination: the career of Johnie "Notions" Williamson, of Hamnavoe, Eshaness, Shetland. PMID- 11620448 TI - A triennial review (1994-7) by the retiring president. PMID- 11620447 TI - Matthew Hay's lectures on materia medica given at Aberdeen University 1886-1887. PMID- 11620449 TI - To ban or not to ban? - that is the question. PMID- 11620450 TI - Creutzfeldt-Jakob Disease - the story so far. PMID- 11620451 TI - Some reflections on the case of Dr. Pritchard. PMID- 11620452 TI - Rabies: false, forgotten and fresh findings. PMID- 11620453 TI - From physicians' enquiry to Dewar Report: a survey of medical services in the West Highlands and islands of Scotland, 1852-1912: part II. PMID- 11620454 TI - Edinburgh Medical College at the end of the eighteenth century and the training of North American doctors. PMID- 11620455 TI - "... But our patrols are out": medical and military brinkmanship at the Normandy bridgehead and a royal rescue. PMID- 11620456 TI - Closing the circle: how Harvey and his contemporaries played the game of truth, Part 2. PMID- 11620457 TI - Rational artistry. [Review of: Crombie A. Styles of scientific thinking in the European tradition: the history of argument and explanation especially in the mathematical and biomedical sciences and arts. London, Gerald Duckworth, 1994]. PMID- 11620458 TI - (Ad)ministering angels: colonial nursing and the extension of empire in Africa. AB - This essay reviews recent feminist scholarship, autobiographical narrative and fiction which explores nurses' engagement with empire in Africa and elsewhere in this century. Such literature suggests that while nursing work may have improved native health in colonized regions, it also contributed significantly to the establishment and stabilization of the racialized order of colonial rule. Of particular significance was colonial nursing's intervention into the reproductive practices of native women, resulting in the loss of local knowledges and autonomy, the disruption of complex social links and indigenous health strategies, and the expansion of markets for western capitalism. PMID- 11620459 TI - Medicalizing malignancy: the uneasy origins of Ontario's cancer program, 1929-34. AB - In the late 1020s, cancer was characterized as a public health problem for which urgent government attention was needed. Initially reluctant to become involved in cancer treatment, the government of Ontario was prompted by initiatives in other parts of Canada to establish a Royal Commission on the Use of X-Rays and Radium in 1931. The Commission recommended the purchase of radium and the establishment of a network of cancer clinics which became the framework of today's cancer system. This study explores the factors leading to the decision by the Ontario government to become involved in cancer and focuses on the role of the medical profession in shaping official response to the cancer problem. Despite the wish of the government to keep the Commission free from medical domination, the formulation of cancer policy became a struggle between two groups of doctors: specialists who believed in centralization and the organized medical profession which saw the state's involvement in cancer as a threat to its independence. This struggle resulted in a more fragmented and dispersed system than the comprehensive, centrally coordinated cancer system envisaged by the Commission. PMID- 11620460 TI - The development of the day treatment centre for emotionally disturbed children at the West End Creche, Toronto. AB - This article describes the interplay of various interests in centre-based child care from the 1930s to the late 1960s, through an examination of the development of a treatment centre for children with autism at the West End Creche in Toronto. The impact of the attention to child care during World War II in North America is described in relation to the postwar trend to reorient child care away from a service for wage-earning mothers and towards an educational-therapeutic service for children and families. The role of local and international welfare associations, as well as the influence of the interrelated professions of child psychiatry, social work, and nursery education, is reviewed. Finally, implications for current developments in the field of early childhood education are discussed. PMID- 11620461 TI - [Genesis of a profession: pharmacists in Quebec in the 19th century]. AB - Before pharmacy was legally recognized as an autonomous profession and before pharmacists were sufficiently numerous and organized to represent their own interests, some "underground" developments marked the appearance of this group in the field of health care. The purpose of this article is to identify and analyze some of the events which led to the emergence in Quebec of pharmacy as a distinct medical profession and the restructuring of the medical community with advances in commercial and industrial activity in the pharmaceutical field. These developments are important to understand the particular orientation of pharmacy in Quebec and also to demonstrate the importance of pharmaceuticals in the health profession. PMID- 11620462 TI - "Its baneful influences are too well known": debates over drug use in Canada, 1867-1908. AB - This article examines the debates about drug addiction, as presented by medical and non-medical reformers in Victorian Canada, to explain the emergence of anti narcotic legislation in the early twentieth century. Most of the studies of drug prohibition in Canada emphasize the anti-Chinese issues surrounding the drafting of the 1908 Opium Act. This study asserts that in order to understand why parliament unanimously accepted this legislation, we must look beyond the issue of anti-Chinese sentiment. It explores the discussions of drug addiction rhetoric. It concludes that the concern over both addiction in Canada and the Chinese in Canada drew upon parallel issues of freedom versus slavery, racial purity, and the need to protect the integrity of a moral and strong nation. PMID- 11620463 TI - What research tools do historians of Canadian medicine currently use? what do they need and want for the future? report and analysis of a survey, 1995-96. PMID- 11620464 TI - Dr. Jimenez Diaz (1898-1967). PMID- 11620465 TI - Two neurologists on a cancel. PMID- 11620466 TI - The Caesars - Julius, Augustus and Claudius, a medical evaluation. PMID- 11620467 TI - Angel Arturo Aballi Arellano. PMID- 11620468 TI - Medicines from the farmyard. PMID- 11620469 TI - Brig. Gen. Adolfo del Castillo Sanchez. PMID- 11620471 TI - Pricing trends in science and technology books. PMID- 11620470 TI - The Glycon snake. PMID- 11620472 TI - Possible efficacy of a Creek folk medicine through skin absorption: an object lesson in ethnopharmacology. PMID- 11620473 TI - Incest: frequency, predisposing factors, and effect in a Brazilian population. PMID- 11620474 TI - Pollution, promiscuity, and the pox: English venereology and the early modern medical discourse on social and sexual danger. PMID- 11620475 TI - The great masturbation panic and the discourses of moral regulation in nineteenth and early twentiety-century Britain. PMID- 11620476 TI - "Only the real, the true, the masculine held its value": Ernst Rohm, masculinity, and male homosexuality. PMID- 11620477 TI - Contemporary lesbian, gay, bisexual, transgender, queer theories, and their politics (review essay). PMID- 11620478 TI - "Refusal to treat under six conditions", the earliest medical and ethical code in ancient China. AB - In the paper the principle of physician's "Refusal to treat under six cases" was reviewed. It was the first ethical code for physician in ancient China. The emergence of ethical code for physician was the result of medical professionalism and the formation of the professional groups. The principle proposed by the famous physician Bian-Que in ancient China, like Hippocratic Oath, was an ethics of outer achievement rather than one of inner intention. It provided a framework of medical behavior, and emerges as a powerful tool seeking to safeguard the reputation of the profession for its own sake rather than, in main, seeking to promote the patients' good. PMID- 11620479 TI - Textual research on Pang Anshi's case record of acupuncture treatment for difficult labor. AB - Ancient works on women's diseases of successive ages were studied on the question Pang Anshi's acupuncturing the point "Hukou" at the dorsal aspect between the thumb and index finger to cure a case of difficult labor. Query is put forward on the absence of such case report in all those books through deliberated investigation of relevant medical literatures. It is concluded that Pang's case report is convincing and is worthy of attention. PMID- 11620481 TI - An Investigation on Dow Hospital in Beijing (Peking). AB - Dow Hospital is one of the western medical hospitals and the earliest established by American Presbyterian Mission in 1885 in downtown Beijing. It is good at Obstetrics and Gynecology and Pediatrics. It had been playing the role of spreading advanced western medical science. It is a pioneer of transmitting new method of delivery in Beijing and was changed to Beijing Sixth Municipal Hospital since 1949. PMID- 11620480 TI - My personal idea on "seven reduction and eight boost" in plain question of inner canon. AB - Although ancient and contemporary scholars fail to reach an agreement on the explanation about "Qi-Sun and Ba-Yi", the following is the most acceptable. According to the medical books found in Ma-wang-dui Tombs, scholars, domestic and abroad, take the Taoist school as love-making and theory of Laozi as pornographic writings. Combining the Taoist theory with my own medical practics. I argue that "Qi-Sun and Ba-Yi" have a different meaning. Most explanations about "Qi-Sun and Ba-Yi" centre on "Qi"--seven and "Ba"--eight, the two numbers, instead of "Sun" and "Yi". Plain Questions points out the southern red colour connecting with the "heart" numbers 7--"Qi", while the "heart" is the most important organ. Once the heart was healthy, the body is at ease, thus, one can live longer. The eastern black colour connecting with the liver number 8--"Ba", so "Ba-Yi" means to strengthen the liver and kidney. PMID- 11620482 TI - A brief history of printing of lithographic medical books in modern times. AB - A large number of lithographic medical books came out within about 100 years after the introduction of lithography technique from the west. There are about 1000 extant lithographic medical books among which 500 still extant as lithographic edition in our country. The development of lithographic medical book could be divided into three stages: the embryonic stage, the prosperous stage and the devlined stage. In spite of the shortcomings that the printing was not exquisite and the textual proofreading was not precise, the value of these lithographic medical books could not be underrated in preserving the medical documents, spreading the medical knowledge and promoting the confluence of TCM and western medicine. PMID- 11620483 TI - A brief history of diagnostic cytology. AB - Being a discipline specialized for diagnosis of tumors, diagnostic cytology has a history of over 100 years. By exploring the origin, development and its formative process, valuable and special information which are helpful to the general investigation of tumor cases and screening of such patients can be provided. PMID- 11620484 TI - Erosive-throat with rash (scarlet fever), an investigation on its brief history. AB - Being a kind of epidemic contagious disease in modern time, erosive-throat with rash was a fatal disease causing numerous victims. High attention was paid to by traditional medical professionals through various fields, theoretical and clinical. A correct conclusion was reached claiming that TCM did make contributions to its prevention and treatment before effective treatment in western medicine appeared in China. PMID- 11620485 TI - Study on the difference between Shennong's drug nature quoted by Wu Puu and by Shennong's drug in material medical in classified syndromes (Zheng). AB - Several questions were mentioned through the analysis and comparison of "Shennong's drug nature" (DN) as quoted by Wu Pu's Meteria Madica (WP) and Materia Medica of Classified Syndrome (Zheng) (ZL). These include: (1) The DN in ZL are incomplete, the "toxic nontoxic" terms were absent here; (2) There were different editions of ancient "Shennong's Canon of Materia Medica", carrying different numbers of drugs, including 365 kinds, 595, 441, 319 kinds respectively; (3) some of the drugs indicated as DN were, strangely, indicated as "drugs of supplemented Records" in ZL. PMID- 11620486 TI - Modern medicine in Taiwan (II). AB - Taiwan's population has undergone rapid growth. From 3000000 in 1906. It had grown to 6000000 by 1941. By the end of 1996 the total population has reached 21500000. This large population is served by over 120000 health professionals. For every 10000 people there are 12.91 doctors (including 11.52 Western medical doctors and 1.39 Chinese medical doctors), 3.37 dentists and 9.36 pharmacists. There has been a huge change in causes of mortality. Under the Japanese occupation, the main causes of death were malaria, pneumonia, dysentery, enteritis, and pulmonary tuberculosis. After the return to Chinese control, the main causes were acute contagious diseases and digestive tract disease. At present, malignant tumors, cerebrovascular accident, heart disease, and diabetes are the main causes of death. With the development of the health-care system, infectious diseases have been controlled or eliminated. Malaria was eradicated from the island in 1956. PMID- 11620487 TI - Yin Duanmo, the person in medical history. AB - Yin Duanmo (Weijie) was graduated from Beiyang Medical College and worked in Canton Hospital as a doctor during the Late Qing Dynasty period. He was the first Chinese doctor to edit medical journals and to translate English medical works into Chinese independently. He and Dr. Sun Yatsen served in the same private clinic. He supported democratic revolution led by Sun Yatsen consistently. He was the first one graduated in China medical school and became a practitioner in Hong Kong. PMID- 11620488 TI - The puzzle of Wang Bing's life story. AB - Since Wang Bing made great contributions to the development of TCM, exploration on Wang Bing's life story is helpful to the analysis on the intention of his medical works. There are controversies on Wang's life story, some of which are still in debate. Through the elucidation of Wang's name, other names, sobriquet, dates of birth and death, official positons and scholarly lineage, this author holds that more relevant historical materials are needed so that the puzzle of his life story can be eventually revealed and uncovered. PMID- 11620489 TI - Research on medical texts quoted by "a new book of pediatrics". AB - "A New Book of Pediatrics" (hereinafter referred to as "the Book") is a pediatric monumental work written in the Song Dynasty. The Book quoted 141 medical texts with 10096 items totally. Relying on the Book, many lost and important ancient pediatrical works, to a great extent, are preserved up to now. Also, the Book collects a large number of never-published prescriptions applied among the people or handed down on the family from generation to generation secretly. As the source of all quoted literatures are indicated, the original shapes of many literatures can thus be resumed by conclusion and collating. Therefore, the Book has important research significance to collating literatures as well as of great reference value to medical practice. PMID- 11620490 TI - Chu Cheng and Chu's bequeathed book. AB - Chu Cheng, a native of Yangzhai county in Henan Province, was born in the Nanqi Dynasty. His "Chu's Bequeathed Book" has more than 2200 Chinese characters, was divided into ten verses, reflecting the secrets of Qi-Blood-Yin-Yang. This author tries to introduce and study Chu Cheng's life, his story and his academic views, not only on embryogensis, pulse taking and Five Ti, but also on Yin-Ying-Jing Xue, obstetrical hygiene and infectious disease and the usage of medicine, etc. PMID- 11620491 TI - Spreading of Hua Shou's medical books in Japan. AB - The paper inquired into the situation of spread and influence of a distinguished physician of the Yuan dynasty, Hua Shou's medical books in Japan. Nippon editions of Hua Shou's medical books had been investigated. The conditions that Hua Shou's medical books were translated, annotated, studied by Japanese medical workers before Meiji, and the role of Hua Shou's medical books played on the medical education in Japan was also discussed. PMID- 11620492 TI - Cloister medicine in Rus. PMID- 11620493 TI - They healed both princes and beggars. PMID- 11620494 TI - Academician G.E. Rein, medicine reformer, herald of state health care. PMID- 11620496 TI - Louis Pasteur. PMID- 11620495 TI - Viktor Andriyovych Subbotin, the first Ukrainian professor of hygiene. PMID- 11620497 TI - Estimation of the effect of the accident at Chernobyl NPP on the state of health in Ukraine population. PMID- 11620498 TI - Physician, an outstanding public figure, Yevgen Ozarkevych. PMID- 11620499 TI - On the history of life prolongation problem. PMID- 11620500 TI - On the history of the fight with tuberculosis in Dnipropetrovsk region. PMID- 11620502 TI - Modern computer technologies in forensic medical identification of remain of historical individuals. PMID- 11620501 TI - Philanthropic activity of Doctor G. Bykhovsky. PMID- 11620504 TI - From the history of cholera epidemics in Kyiv in 1847. PMID- 11620503 TI - Two letters of V.P. Filatov to V.F. Voino-Yasenetsky. PMID- 11620505 TI - The first in Ukraine Kherson sanitary organization of zemstvo. PMID- 11620506 TI - Robert Koch. PMID- 11620507 TI - Will we come back to the saint doctor? PMID- 11620508 TI - John Howard, a friend of people. PMID- 11620509 TI - Ukrainian neurohistologist Olexander Chernyakhivsky. PMID- 11620510 TI - S. Kh. Khotovytsky, medical scientist: pediatrist and hygienist. PMID- 11620511 TI - Phisician and patriot K.G. Solukha. PMID- 11620512 TI - On priority of introduction of one clinical diagnosis. PMID- 11620513 TI - Blood groups: the history of discovery, importance for science and practice. PMID- 11620514 TI - Problems of dementia: the history of formation of the ideas about the nature of Alzheimer's disease. PMID- 11620515 TI - Nurse service in the Crimean campaign of 1854-1856. PMID- 11620516 TI - The world celebrity, unknown in his homeland. PMID- 11620517 TI - Pavlo Pundiy--a historiographer of the Ukrainian national medicine. PMID- 11620518 TI - Main stages of pharmaceutics development in Galitsia (the 13th--early 20th centuries). PMID- 11620519 TI - The eighteenth century pharmacy at 60, High Street, Tenterden, Kent. PMID- 11620520 TI - The rauwolfia story: ancient herbal medicine - 20th century tranquilliser - 21st century reject? PMID- 11620521 TI - You are what you read: food texts as historical documents. PMID- 11620522 TI - Women's dreams in ancient Greece. PMID- 11620523 TI - Autopsy practises for brain dissections and Rembrandt's anatomy lesson of Dr. Deyman. AB - Illustrations, previous to the 19th century, provide evidence that brain dissections were executed on an isolated head, contrary to Rembrandt's anatomy lesson of Dr. Deyman. This paradox seems to be explained by clever biased composition. PMID- 11620525 TI - Roots and routes of Russian neurosurgery (from surgical neurology towards neurological surgery). AB - Regular and purposeful neurosurgical interventions started at the end of the nineteenth century. Both surgical and neurological roots of the emerging speciality could be traced. The surgical roots of neurosurgery were the invention of anaesthesia, aseptics and antiseptics which made brain operations relatively safe and markedly reduced postoperative mortality. The neurological roots were the improvement of topical diagnosis in neurology and the understanding of the anatomy and physiology of the nervous system. The first operating room at the neurology department of the Russian Military Medical Academy was established in 1897 by the famous Russian neurologist and psychiatrist Vladimir Bekhterev (1857 1927). According to Bekhterev, neurology should become a surgical speciality like gynaecology or opthalmology and "neurologists will take a knife in their hands and do what they should do". Bekhterev's pupil Ludwig Puusepp (1875-1942) became the first full-time Russian neurosurgeon ("surgical neurologist"). He headed the first university course in surgical neurology in the world organised in 1909 at Bekhterev's Psychoneurological Institutte in St. Petersburg and bacame professor of surgical neurology in 1910. The role of neurologist might be illustrated by the development of a sterotactic instrument named "encephalometer" designed by D. Zernov in 1889 and improved by G. Rossolimo in 1907. The idea was to map cerebral structures in degrees of latitude and longitude similar to mapping the terrestrial globe in order to localise the brain lesion and enhance its minimally invasive removal.... PMID- 11620524 TI - An element of thought: phosphorus and mental philosophy in the nineteenth century. AB - Georges Cabanis (1757-1808), through his writings on the relation of the physical and moral, or psychological, aspects of man, left a legacy that made the study of mental activity a part of physiology. His views on the importance of phosphorus to the function of the brain thrust that element into a prominent stream of research that involved many investigators in several countries. Although that particular stream eventually dried up, its influence remained: by the beginning of the twentieth century basic medical science had become well set on studies of the mind-body relationship. PMID- 11620526 TI - Capablanca's stroke: an early case of neurogenic heart disease. Cuban-world champion of chess 1921-1927. AB - The great chess master Jose Raul Capablanca died of a stroke in New York city in 1942. An analysis of his death is instructive in the discussion of cardiac repercussions of hypertensive cerebral hemorrhage, particularly regarding the close relationship between subendocardial hemorrhage and its probable source - sympathetic activation - caused by stroke. PMID- 11620527 TI - Beyond social construction: toward new histories of psychiatry (review essay). AB - Focusing on symptom classification and on the outcome of somatic interventions, Berrios and Shorter challenge the social constructionist and anti-psychiatry tendencies that have framed the writing of the history of psychiatry for the past quarter-century. Contextualizing clinical interventions, these studies point out the value of examining the proposition that practitioners were motivated as much about curing distress as they were about eliminating nonconformity. Such examinations require an understanding of the strengths and limits of medical science that often have been trivialized or ignored by some social constructionists. Together the studies under review open the possibility that recent biological interventions may have transformed psychiatry in such fundamental ways that they call into question the assumptions that have underlay in an almost two-century-old classification system. Ironically, adherence to the scientific method (falsification) reveals that the biological revolution in psychiatry fits post-modern claims about the tentative nature of knowledge claims, while it simultaneously undercuts the particular historical interpretations of post-modern scholarship. PMID- 11620528 TI - Descartes' visit to the town library, or how Augustinian is Descartes' neurophysiology? AB - Rene Descartes was early accused of taking his central philosophical proposition from St Augustine. Did he also take his central neurophysiological concept from the same source? This is the question which this paper sets out to answer. It is concluded that the foundational neurophysiology propounded in L'Homme does indeed show strong and interesting resemblences to Augustine's largely Erasistratean version. Descartes, however, working within the new paradigm of seventeenth century physical science, introduced a new principle: whereas Augustine's neurophysiology is pervaded throughout by a vital factor, the pneuma, Descartes' theory involved only inanimate material forces. It is concluded, further, that in spite of the interesting similarities between Augustinian and Cartesian neurophysiology there is no evidence for any direct plagiarism. It seems more likely that Augustine's influence was filtered through the Galenical physiologists of Descartes' own time and of the preceding century. PMID- 11620529 TI - William Lawless: an Irish and French revolutionary. AB - William Lawless, professor of anatomy and physiology (1794-98) at the Royal College of Surgeons in Ireland (RCSI), and a member of the United Irishmen, fled to France to avoid arrest and was expelled retrospectively by the College authorities. His subsequent career was that of a combatant officer in Napoleon's armies. He died on 27 December 1824 and was buried in Paris in the cemetery of Pere Lachaise. His name has recently been restored to the College rolls. PMID- 11620530 TI - The historiography of medicine in America. AB - What is the state of medical historiography in America? This discipline is now asking new questions, branching new directions and speaking to new audiences. The social and cultural contexts in which medicine moved and moves needs to be an effective integral part of approaching the historical studies. There is today, in the U.S.A., a new history of medicine more problem-oriented and interested in the culture of medicine and in the meaning of medicine to cultural history. This new interdisciplinary field of interest deals with the study of epidemics, seen as causative agents in historical developments and as a means of studying changing ideas; it deals also with the history of women, of their medical professionalization and of their diseases. American medical history, over the last thirty years, has reconstructed the medical practices of the past by using clinical records; between other fields of research, the history of psychiatry has become a particularly fertile field of scholarship, especially in its studies about hysteria and neurasthenia; finally, medical anthropology and the history of ancient and medieval medicine, has flourished and contribute today in a high significant way to the critical reconstruction of a cultural past of medicine, quite far away from the mere biographical historiographical researches. PMID- 11620531 TI - [Phases and positions of the historiography of medicine in Germany]. AB - Already in 1941, A. Pazzini underlined the importance of the links connecting German and Italian schools of History of Medicine. Today, medical ethics is seen, all over the world, as a necessary integration of ethics in all the phases of the medical curriculum is provided by law. I.e. at the Medical Faculty of Lubecca, three different phases are scheduled: i. Phase 1: a basic course during the pre clinical training: history and practice, two hours a week ii. Phase 2: a seminar with the patients during the clinical training: ethics at the bed of the patient iii. Phase 3: a studying day for all the students, together with the medical and paramedical staff. Obviously, an ethical training does not produce automatically an ethical behaviour, but it helps the students to better understand the relationship with their patients. In this sense, ethics is an important part of the teaching of history of medicine, because ethics, as well as an historical consciousness and the historiography of medicine concerns the modern development of the relationship between medicine, science and history. PMID- 11620532 TI - [The marriage between the physician and philology]. AB - The day before yesterday: the physician-philologist. The times of the first appearance of printed books and of the re-discovery of ancient texts are also the times of syphilis. The physician, more than a philosopher as Galen suggested, is also a philologist. A very interesting example is fournished by Antonio Benivieni (+1502) and by his book De causis abditis (1506). Yesterday: the philologist physician. Charles Daremberg (1816-1872) is our example. In 1841, he wrote his medical thesis Exposition des connaissances de Galien sur l'anatomie, la physiologie et la pathologie du systeme nerveux (faculte de medecine de Paris, n 222). Today: a necessary couple, the physician and the philologist. Greek and Latin are no more subjects of teaching in school, and the philologists seem to be strange, dusty and dirty people. Is the physician-philologist still alive or not? To be useful to the daily practice of medicine, history of medicine will be also a philological matter, as philology is the complete study of ancient, modern and contemporary texts. It teaches to read well, to understand all that has been written and, as a consequence, all that the patients tell today to their physicians. The problem is not teaching something more (new facts, new notions...) but teaching to know well; in a word, teaching the famous continuous learning, which is still a difficult reality. PMID- 11620533 TI - Studying and teaching the history of medicine in Greece: the National University of Athens experience (1837-1997). AB - In medical education, little interest is shown in medical history. However, the history of medicine is one vital pathway to the proper study of the evolution of medicine, from ancient to modern times, and it should be a requisite of the medical curriculum. The value of medical history in the understanding of the present and in creating the medicine of the future, is enormous. Our experience has indicated that medical students and younger physicians who ignore the mistakes of their forefathers are destined to repeat them. Furthermore, the history of medicine is needed not only to broaden the students' horizon, it is also necessary in order to prevent the physicians of the 21st century from becoming dehumanized by their bio-technological training. The history of medicine, therefore, is the best antidote to overconcentration on, and overspecification in medical technology and it is the most useful stimulus to more humane professional behaviour and optimal medical education. The new history of medicine does not consist only of the accumulation of dates, events and names; it is a discipline needed for life and action. Tomorrow's historians will view the last years of the second millennium as an eventful and critical period for the medical education of the future. PMID- 11620534 TI - The historiography of medicine in the U.K. AB - The practice of the history of medicine in Britain is characterized by a health pluralism and diversity. Thirty years ago, history of medicine in Britain was generally considered a space of no particular relevance to history at large; today, public attitudes towards scientific medicine and the medical profession have grown critical, and the history of medicine has itself been problematized, commanding widespread scholarly attention. This article deals with some of the historiographical fields thanks to which the discipline has been energized over the last thirty years: the history of health, analyzing the healthiness of populations, the length of their lives and the causes of death; the history of the body, which has been considered as a biological and as a sociological entity; the history of sexuality and sexual behaviour; the demographic and epidemiological history, both ocnnected with the environmental history; the history of death and corpses; the history of mental disorders; the historical role of the hospital in the reformation of popular health care. PMID- 11620535 TI - [Teaching humanities to the students of the medical faculties, reasons and why]. AB - There are many reasons to include a programme of human sciences, literature and art in the undergraduate medical curriculum. In the present text, the implications of three reasons are described, namely the increasing demand of health by a rapidly changing society, the need for practising whole person medicine and for improving the doctor the rational and moral awareness of his/her clinical objectives. The possible ways of introducing humanities in the medical curriculum, some international experiences and the role of Medical faculites in interacting with other University disciplines are discussed. PMID- 11620536 TI - [Education of history of medicine at the Spanish University. project PB96-0631 C03-01 (DGES)]. AB - The following article aims to show the place of History of Medicine and related subjects, in the instruction of Medicine at the Spanish Universities. The present situation is very complex, as at this moment a new program of studies is being implemented, at a different path in each univeristy. In the new curriculum History of Medicine is placed in the core curriculum as introduction to medicine and scientific methodology and as mandatory teaching as history of clinics, bioethics, medical anthropology, etc. Choice of optional teachings and post graduate courses (at Ph.D. level) are also described. In any case, the subjects with historic and medical contents are well represented. The text provides detailed information about the subjects instructed at the main universities. PMID- 11620538 TI - Commemoration of A.M. Pazzini on the centenary of his birth. PMID- 11620537 TI - [Philosophical and historical values of medicine]. AB - History of Medicine has pointed its higher attention on both great physicians and relevant medical schools. The hieratic person of the physician has been pre eminent and conditioning the relationship between patients and doctor, the latter in a paternalistic dominant position. Changes occurred in medicine during the last century, mainly related to the technological advancements and a new ethiopatogenetic view. Better social conditions, improvement of diagnostic procedures and the discovery of effective therapeutic drugs (e.g. antibiotics, etc.) has produced advancements in general life conditions (measured by parameters such as aging, reduction of newborn mortality etc.), but also an increase in the cost of the social medical system. So, the new frontier of History of Medicine is the analysis of changes occurred in medicine (new epistemological rules, pressure of new technologies, more sophisticated citizens patients) to deepen the values of medicine in an anthropological view of managed care. PMID- 11620539 TI - [Scientific work of Adalberto M. Pazzini]. PMID- 11620540 TI - The certification of insanity in nineteenth-century England and Wales. PMID- 11620541 TI - Alienists' wives: the unusual case of Mrs John Conolly. PMID- 11620542 TI - "Searching for the soul": religious factors in Leendert Bouman's development of a 'psychological psychiatry'. PMID- 11620543 TI - Obsessional neurosis: a nosographic innovation by Freud. AB - Freud refers in a paper published in 1895 to the phobias of obsessional neurosis. James Strachey, the editor of the Standard Edition of Freud's works, comments on this as follows: The term obsessional neurosis (Zwangsneurose) makes its first published appearance in this sentence...Lowenfeld... attributed the origin of both the term and the concept to Freud. Freud himself gave no indication at this point that he was introducing a new term. It was not until 1896 that he described obsessional neurosis as his nosographic innovation. The following questions are examined in the paper: Is it true that Freud coined the term obsessional neurosis? If so why is this fact so little known? What were the views of German language neuropathology and psychiatry in the period around 1895 concerning the symptoms subsumed by Freud under obsessional neurosis, and in what respects did Freud's contribution differ from that of his colleagues? This paper is concerned exclusively with German-language psychiatry and neuropathology; it makes only isolated reference to their French counterparts. Furthermore, it focuses solely on the symptom that Freud placed at the core of obsessional neurosis, namely obsessional ideas. PMID- 11620544 TI - Psychiatry as craft. AB - A number of essays published in History of Psychiatry are examined which concern the general character of the historiography of psychiatry, and the professional relations between psychiatrist-historians and professional historians. An alternative is offered to the various positions advanced in these essays in which psychiatry is understood as a craft. This conception draws attention to ways in which psychiatric theory is acquired through clinical experience rather than text based formal education. It is suggested that this creates difficulties of interpretation for the historian of psychiatry, but that these difficulties can be inappropriately exploited by critical historians, who rely on the ambiguity of psychiatric terms to argue that psychiatry has historically been a primarily normative and political enterprise, or at least an intellectually weak and professionally greedy one. A more tentative approach to the interpretation of textual sources from the history of psychiatry is suggested. This approach may lead to a less adversarial relationship between psychiatrist-historians and critical professional historians of psychiatry. PMID- 11620546 TI - The Royal Flying Doctor Service of Australia. PMID- 11620545 TI - Folie a deux - a mad family. (Classic Text No.35, with introduction by G.E. Berrios). PMID- 11620548 TI - Hysteria, psychoanalysis, and feminism: the case of Anna O. PMID- 11620549 TI - Hysteria, psychoanlysis, and feminism: the case of Anna O. PMID- 11620550 TI - The cosmology of 'Hippocrates', De Hebdomadibus. PMID- 11620551 TI - Phrenes as an anatomical organ in the works of Homer. PMID- 11620552 TI - Infanticide in an eleventh-century old English homily. PMID- 11620553 TI - Morphew, leprosy, and the date of Marston's Antonio and Mellida. PMID- 11620554 TI - Science, scientific management, and the transformation of medicine in Britain c. 1870-1950. PMID- 11620555 TI - Holistic theories of mind in early twentieth-century Germany. [Essay review of: Harrington, A., Reenchanted Science: Holism in German culture from Wilhelm II to Hitler. Princeton University Press, 1996 and Ash, M.G. Gestalt Psychology in German culture, 1890--1967: holism and the quest for objectivity. Cambridge University Press, 1995]. PMID- 11620556 TI - Leibniz on the unicorn and various other curiosities. AB - I discuss some of Leibniz's pronouncements about fringe phenomena--various monsters; talking dogs; genies and prophets; unicorns, glossopetrae, and other games of nature--in order to understand better Leibniz's views on science and the role these curiosities play in his plans for scientific academies and societies. However, given that Leibniz's sincerity has been called into question in twentieth-century secondary literature, I begin with a few historiographical remarks so as to situate these pronouncements within the Leibnizian corpus. What emerges is an image of Leibniz as a sober, cautious interpreter, a skeptic one might say but one who is prepared to concede the possibility of many strange phenomena. Leibniz expects these fringe phenomena to take their place among the natural curiosities catalogued as part of a hoped for empirical database intended as means toward the perfection of the sciences. PMID- 11620557 TI - [The palaestrae of Jean de Spello: scholarly exercises of a master physician at Perouse in the 14th century]. PMID- 11620558 TI - Subterranean Fire. Changing theories of the earth during the Renaissance. AB - Aristotle described the earth as a cold and dry body and paid no attention to the phenomenon of terrestrial heat. Renaissance physicians, by contrast, when seeking to understand the origin of hot springs in the context of their balneological studies, came to defend a theory of subterranean fires. This tradition, which started in Italy, became widely known through the works of Georgius Agricola. But although it had implications for the explanation of further natural phenomena, it remained almost exclusively confined to medical circles. As far as physics as an academic discipline was concerned, the ideas concerning subterranean fire were hardly taken note of. Only with the collapse of Aristotelian philosophy in the seventeenth century could these by then "old innovations" obtain a wider significance. PMID- 11620559 TI - Felice Fontana. 1730-1805. Eleven false attributions. PMID- 11620560 TI - Memoir: early years of Hospital insurance in British Columbia. PMID- 11620561 TI - A meeting with Maimonides. PMID- 11620562 TI - On parallel lines: natural history and biology from the late Victorian period. PMID- 11620563 TI - [Regenerationist Usage of Water's Symbology Between Decaying Spa Resorts Movement and Kneippist Morals]. AB - At the end of the 19th century coexisted in Spain several therapies based on the use of water. Some of them were considered orthodox therapies, some were applied as unorthodox medicines, but all of them relied on the symbolism of water to obtain patients. From the point of view of the orthodoxy, the discourse of medical hydrology, thalassotherapy and hydrotherapy tended to exclude unscientific values. The naturist and kneippist movements, on the other hand, frequently used images of water (especially cold water) as a support for their regenerational projects, using both the material and the moral aspects. Therefore, Kneipp's therapy became a kind of Spanish interpretation of the social catholic reforming attitude. PMID- 11620565 TI - [Degenerate Children: mental medicine and "regenerationism" in Spain at the end of the 19th century]. AB - The aim of this paper is to analyse some aspects of the psychiatric and medical social discourse on the relationship between childhood and insanity in Spain at the end of nineteenth century and during the first third of the twentieth century. We study the principal theories about degenerate children (delinquent childhood and anormal childhood) based on two of the most paradigmatic works of the Spanish medical literature: Estudio medico-social del nino golfo by Jose Sanchis Banus and Los ninos mentalmente anormales by Gonzalo Rodriguez Lafora. PMID- 11620564 TI - [Re-establishing the health of the state: medicine and national regeneration explained through a criminal trial at the turn of the 19th century]. AB - This article aims to show how the discussions of a criminal trial at the turn of the nineteenth century suffice to shed light on the opinions of the Spanish people on the model of society that they wanted. Specifically, one of the principal aims of the essay is to enquire into the ideas that prevailed at that time on the role of science in the organization of society. Analysis of the discussion which came out of the trial helps to highlight the ways in which various factors influenced the development of medicine, in particular forensic medicine. As a result, the article also hopes to contribute to our understanding of how the discourse on criminality has functioned and changed in Spain. PMID- 11620566 TI - [The health of a city: Seville in the turn-of-the-century crisis]. AB - In this article we analyze three projects for urban reform in Seville in which health constitutes a primary element. These three projects are framed within the dialectic process of degeneration-regeneration which characterized the last decade of the nineteenth century in Spain, and which was a basic aspect of the collective way of thinking. Healthiness became an argument used by groups and individuals with the objective of defending their interests, in this case, those related to the use of urban space. PMID- 11620567 TI - [The idea of a healthy city and the advertising of Malaga]. AB - Malaga was advertised as a therapeutic place for tuberculosis since the central years of the 19th century. However, this offering of Malaga as a health resort was opposed by certain foreign authors, who pointed to its exceedingly poor sanitary conditions and its high mortality rates. The need for urban hygiene became stronger due to the social variety of the urban structure and the economic turn-of-the-century failure, and helped to the triumph of the idea of social regeneration through the implementation of sanitation. PMID- 11620568 TI - [Spanish medicine and the 1898 crisis. An introduction]. PMID- 11620569 TI - [Amazing health rates in turn-of-the-century Majorca]. AB - Majorca's mortality rates in the turn of the century were the lowest of Spain and nearer to those of the northern European countries than to Mediterranean ones and therefore their amazing quality. This paper seeks to contribute to solve that riddle and, as a first step, it reviews the island's demographic conditions and its economic, political and social and cultural context, including the analysis of the development of medical sciences and the sanitary reform of the city of Palma proposed by Eusebio Estada. PMID- 11620570 TI - [Health and primary education in the regenerationist ideology at the open educational institution]. AB - The objective of this work is to reconstruct the discourse of the authors who published about issues establishing links between health and primary education in the Boletin de la Institucion Libre de Ensenanza at the time of the Spanish colonial crisis in 1898. This source has been chosen due to its relevance to Spanish pedagogical renovation. Physical education was taken as a model for analysis for two reasons: firstly, it is the aspect that received the most attention; secondly, it became the engine for change in the renovation programme. In addition, its holistic nature was intended to lead to the new citizen that was needed by the country after the loss of the colonies. PMID- 11620571 TI - [Health education of the clergy. The case of the Conciliar Seminary of Seville in the 1898 crisis]. AB - The objective of the present article is to study health education that Sevillian seminarians (apprentice priests) received in the third part of the nineteenth century. The introduction in the seminary of courses on Natural History, Physiology and Health (courses intended to inculcate a moral-hygienic conscience and reinforce the Catholic doctrine, antidarwinism, etc.) was preceded by increasing social awareness of the concept of health. These circumstances, together with the Church's perception of the crisis of the end of the century, conditioned the particular interpretation of that crisis. PMID- 11620572 TI - [The question of health regenerationism and its debate during the second republic: elements of class and ideology]. AB - This study analyzes the consensus and conflicts with regard to the criteria for what constituted the health problem in Spain and its possible solutions. We start from the assumption that the general idea of change, implicit in the regenerationist project of the end of the nineteenth century, constituted one of the active elements in the proclamation of the Second Republic. We consider three aspects: the critque of a situation in which living conditions had a negative influence on issues of health and disease; the role of technicians or experts--in this case physicians--; and the role of educational aspects. As sources we used the labor press, the general press associated with certain ideological options and social groups, and the Diario de Sesiones de las Cortes. We found that different strategies and concrete choices in health issues, and hence diverse practical interests reflecting differences in class, political affiliation and ideology, could be manifested under apparently identical expressions, eg, those related with the action of regeneration. PMID- 11620573 TI - [The role of the Junta Suprema de Sanidad (Supreme Board of Health) in Spanish health policy in the 18th century]. AB - The Supreme Board of Health was the first Spanish health institution that took responsibility for health throughout the entire territory of the Crown. Established in 1720 at the behest of Felipe V, the Board was endowed of wide prerogatives from the political and administrative point of view, and was characterized by a rational, centralist stance. In practice, however, its function was limited in essence to the preservation of the Kingdom and the protection of the people's health against catastrophic diseases. It adopted measures of a defensive nature in the face of the various epidemics that occurred within the outside of Spain during the eighteenth century. PMID- 11620574 TI - [Regulation of health care in the Spanish Habsburg Court (1515-1700)]. AB - This article tries to reconstruct the composition of the royal health care system during the government of the Spanish kings in the sixteenth and seventeenth centuries. The health professions during this period comprised five institutions: Royal Physicians, responsible for the health of the king, his family and all the staff of the Royal House; the Royal Apothecary, responsible for the preparation, dispensation and storage of medicines; the Royal Distillery Laboratories; the Ladies Infirmary, responsible for the medical care of all the ladies who directly served the queen; and the Royal Chemistry Laboratory, founded for the dispensation of chemical drugs, commonly used in the seventeenth century. PMID- 11620575 TI - [Giuseppe Cervi, Guillaume Jacobe and the relations between the Royal Society of Medicine and other sciences of Seville and the Royal Society of London in 1736]. AB - The eighteenth century was the century of scientific institutions. Spain did not remain apart from this process, and among the earliest institutions was the Regia Sociedad de Medicina y demas Ciencias de Sevilla, which, although founded at the beginning of the century, really came into its own in the decade of the thirties. In this reappearance of the Sevillian Society Giuseppe Cervi, first court physician to Felipe V and one of the most relevant personages of the Spanish medical panorama of the era, played a key role. This article aims to study the circumstances that surrounded the election of Cervi as a member of the Royal Society of London--thanks to the efforts by the French physician Guillaume Jacobe, hired by the Regia Sociedad, undertaken during a stay in Paris in 1735. The career of this physician and his services to the Spanish medical institution are also further examined. PMID- 11620576 TI - [The impact of germ theory in the genesis of cancer. Consequences for surgical treatment in the victorian era]. AB - We use texts by preeminent figures in Victorian surgery at the end of the nineteenth century and information about their role in disseminating the germ theory to analyse the impact of this new etiologic element in the genesis of cancer. We trace the career of William Watson Cheyne (1852-1932), a disciple of Lister, and of many other surgeons of his generation, to outline the changes in the approach to treatment for cancer, the theoretical basis for these changes, and the role of a new conceptualization of cancer in the light of the microbial theory. This theory, among many other better-known factors, helped establish the foundation for radical surgery which became widespread in oncological treatment during the final decade of the nineteenth century. PMID- 11620577 TI - The role of insurance in the prevention of work-related accidents in France in the first half of the 20th century. AB - Insurance has played a role in the develoment of prevention of work-related accidents in several ways in France since the industrical revolution. The first attempts at prevention were taken at the initiative of manufacturers' associations, but it remained a matter of goodwill for manufacturers. The 1898 law gave systematic, if partial, financial responsability for occupational hazards to employers, who turned to insurance companies to carry the risks. As a result a new branch of insurance (assurance-loi) appeared, which accounted for 40% of general accident revenue for companies at the time of World War II. But the new law made no mention of prevention and even had a negative impact, since compensation was taken care of by insurance. However, after World War I, insurance companies created an association for the prevention of work-related accidents and illnesses and started to adjust rates according to the prevention efforts of corporations. When social insurance was generalized in 1946, insurance of occupational hazards went under state control and became compulsory. But the experience accumulated in the field of prevention by insurance companies was put to use in this new context, both on the technical side and the financial side. PMID- 11620578 TI - In search of the plague. The Greek peninsula faces the black death, 14th to 19th centuries. AB - Histories of the plague are based on the belief that we can locate epidemics in the related sources and classify them according to present-day medical categories. This article rests upon the assumption that present day medical discourse which is based upon laboratory observation is totally incompatible with history which lacks analogous techniques in constructing its own discourse. It explores the possibilities and the limits of a history of the plague based upon the phenomenology of the disease as recorded in the sources that concern the period of the second pandemic of the plague. PMID- 11620579 TI - [Translation of the prologue to the Libro de medicamentos simples by Abu-l-Salt of Denia]. AB - This article offers the Spanish translation of the theoretical introduction that Abu-l-Salt of Denia (1068-1134) placed at the beginning of his treatise on simple drugs. In his introduction he explained the reasons for preparing compound drugs, and how to prepare them. Although the rest of the book was translated from Arabic into Latin by Arnau de Vilanova (c. 1283) this introduction is not found in any of the extant Latin manuscripts and therefore does not appear in the critical edition of the works of Arnau. PMID- 11620580 TI - [Biochemistry in the School of Medicine at the University of Granada. A contribution to the article by J.M. Cano Pavon, "Chemistry Research in Granada during the 20th century, 1900-1975"]. PMID- 11620581 TI - [Jose Luis Goti Iturriaga (1923-1998)]. PMID- 11620582 TI - [Delfin Garcia Guerra (1933-1998)]. PMID- 11620583 TI - [Theses on the history of medicine and science presented in Spanish universities, 1997-1998]. PMID- 11620584 TI - [The 1898 crisis and the new scientific institutions: the creation of Ramon y Cajal's biological research laboratory]. AB - The neglect of science was considered to be one of the causes of the 1898 crisis and therefore the production of science was regarded at the end of the last century as one of the principal measures to achieve national regeneration. The creation of research institutions, especially for outstanding researchers like Cajal, became a national goal. The press contributed greatly to bring about this goal, and in the case of Cajal, was not only the reporter but also the instigator of the campaign to provide him with his own research centre: the Biological Research Laboratory. This paper analyses the start, development and culmination of this campaign. PMID- 11620585 TI - [The antecedents and creation of the Alfonso XIII Institute of Serotherapy, Inoculation and Bacteriology]. AB - This article studies the establishment of the Alfonso XIII Institute of Serotherapy, Inoculation and Bacteriology in 1899, using the general press and the professional-scientific, medical and pharmaceutical press as its prime source, It aims to highlight the principal factors which led to its gestation and later development, as well as the circumstances which led to its creation, by analyzing the antecedents and orgins of the aforementioned institution. PMID- 11620586 TI - Noel David Richards 1937-1998. PMID- 11620587 TI - [Not Available]. AB - The philosophical interpretation of nature around 1800 exercised a deep influence on the natural sciences and medical disciplines, especially in regard to organisms, diseases and the relationship between nature and culture. Natural scientists and speculative philosophers in the Romantic era, a special phase between the 18th and 19th century, criticized the science of their time, but they in no way challenged the value and justification of an empirical approach to nature, though they rejected the absolutizing aspect of its positivistic perspective and pleaded for the unity of natural phenomena, the responsibility of man for nature, the concept of medicine as science and art. PMID- 11620588 TI - [Methodological problems in Maurizio Bufalini's thought]. AB - Maurizio Bufalini's methodology represented a particularly interesting example of an opposition to current medical thought in an age dominated by few systems, such as Browns's. Bufalini made a strongly critical examination of Brown's thinking. Through a new interpretation and a critical analysis of some passages from his fundamental works, the most important topics of Bufalini's thought processes are stressed, and his methodology for medical sciences is emphasized, i.e. the search for true causes of diseases by a progressive exclusion of unconvincing causes. PMID- 11620589 TI - [Rasori, Borda and the theory of stimolo and contrastimolo]. AB - Brown's thought represented one of the most successful medical systems which arose in the XVIIIth century, as a consequence of vitalism and as a reaction to the inadequacy of Hippocratic-Galenic medicine. Giovanni Rasori was a strong supporter of Brown's theories in Italy and creator of the scientific movement which was, then, called Rasorism. A fundamental point of Rasori's therapeutic thought was represented by the dynamic action of drugs, so that a pharmacological experimentation became necessary, for medical practice. Siro Borda, who was a follower and personal friend of Rasori, made experiments on 150 substances to identify their dynamic action and, finally, he classified them in three groups: stimolanti, controstimolanti, eterocliti. This last class comprehended all the pharmacological substances of uncertain or not yet determined nature. PMID- 11620590 TI - [Samuel Hahnemann: a mystical empiricist. A study of the origin and development of the homeopathic medical system]. AB - Homeopathy is the product of the time of its birth and systematization and its founder's cultural background. From the beginning, homeopathy looked in two directions at the same time. On the one hand, it looked towards scientific enquiry and empirical proof and, on the other, towards religion, metaphysics and mysticism. The origin of this lies in the double orientation of Hahnemann's work: while affirming a rational system of therapeutics based on observation, he also developed a metaphysical theory of illness as well as of the action of medicines. PMID- 11620591 TI - [Giacomo Andrea Diacomini, the medical systems and the origins of experimental pharmacology]. AB - Giacomo Andrea Ciacomini was Professor of Physiology, Pathology and General Therapeutics in the University of Padua (1824-1849); follower of systematic medicine, he followed vitalistic theories. For him diagnosis-identification of diseases and therapy are closely related and diseases are due to an excess or a loss of stimulations. About quinine, generally administered in fevers at high doses as a tonic-stimulant drug, Giacomini believed that it has a depressant activity, an action verified by him on rabbits, an early example of exerimental pharmacology in Italy (1840). Thus, Giacomini performed empirical studies, and the real differences between systematic and scientific medicine are in the different approach to the relationship between empirical observations and theoretical hypotheses. PMID- 11620592 TI - [Not Available]. AB - The chemical revolution which arose between XVIIIth and XIXth centuries, had a special influence on the studies about living organisms and medicine. The idea was that the laboratory's discoveries could be applied to all the chemical transformation occurring in the human body. This point of view allowed the development of exerimental physiology and led to the birth of physiological chemistry; it influenced also a new theoretical discussion in medicine, by suggesting possible application to diagnostic and therapy. Paradoxically, in consideration of the importance of iatrochemistry in last centuries, the chemical revolution had a really small influence on medical systems. PMID- 11620593 TI - Camillo Golgi as clinical pathologist: epicritical reading of Golgi's works on malaria. AB - Camillo Golgi confirmed, in 1885, Marchiafava's and Celli's discoveries about malaria, following a clinical-pathologic research pattern and studying the patient directly. In 1889 he associated the naturalistic-biological point of view and the clinical-pathologic one so that he made possible a differential diagnosis between tertian and quartan fever, independently from the clinical observation; he supplied useful laboratory data for clinical diagnosis and, in doing so, he created the new figure of the clinical pathologist; he distinguished three different kinds of intermittent fevers and, in 1888, he specified the useful time for quinine administration. The article analyzes, also, his methodological and scientific principles. PMID- 11620594 TI - Some aspects of Camillo Golgi's parliamentary activity. AB - The authors present some considerations about the senatorial activity of Camillo Golgi. His presence in Parliament confirms definite and not negligible interest in political affairs, especially those concerning health and universities. PMID- 11620595 TI - [History and criticism of systematic medicine in the works of Augusto Murri and his school]. AB - Augusto Murri's last book entitled Nosologia e Psicologia was published in 1924; in the same year his follower Antonio Gnudi delivered a very important commemorative speech for the 100th anniversary of the Societa Medica Chirurgica of Bologna. Both works have great value for the understanding of both the history and the theories of so-called systematic medicine as well as the criticisms that led, through Maurizio Bufalini's ideas and the teaching of Augusto Murri and his school, to the birth, at Bologna, of scientific medicine. PMID- 11620596 TI - Eine Freiburger medizinische Glossensammlung aus dem 15. Jahrhundert. PMID- 11620598 TI - Classification of diseases. PMID- 11620597 TI - Problems of translation and modernisation of ancient Chinese technical terms. Manfred Porkert's interpretations of terms in ancient and medieval Chinese natural and medical philosophy. PMID- 11620599 TI - Foucault & the history of classification theory. PMID- 11620600 TI - Erasmus' prescription for Henry VIII: logotherapy. PMID- 11620601 TI - Abortion attitudes of black women. PMID- 11620602 TI - An alternative science, Linnaean natural history in Germany, 1770-1790. PMID- 11620603 TI - Myth and the reconciliation of opposites: Jung and Levi-Strauss. PMID- 11620604 TI - Additions to OED from John Cotta's Ignorant Practisers of Physicke, 1612. PMID- 11620606 TI - Maternal politics: the principles and practice of maternity care in eighteenth century Hamburg. PMID- 11620605 TI - Macquer's Dictionnaire de Chymie: a bibliographical study. PMID- 11620607 TI - Darwin's language and logic. PMID- 11620608 TI - A question of style? PMID- 11620609 TI - From Galen's theory to William Harvey's theory: a case study in the rationality of scientific theory change. PMID- 11620610 TI - Neo-Darwinism and survival through fitness in Reagan's America. PMID- 11620611 TI - [Hideo Kikkawa's works on eye pigment] (Jpn). PMID- 11620612 TI - The Ross Granville Harrison papers. PMID- 11620613 TI - Rona Hurst (1897-1980); Gregory Bateson (1904-1980). PMID- 11620614 TI - The Emil Hermann Fischer papers. PMID- 11620615 TI - Age reporting by the elderly and the nineteenth century census. PMID- 11620616 TI - Depopulation and changing household structure in the mining communities of West Cornwall, 1851-71. PMID- 11620617 TI - A survey of East Anglian medical practitioners 1500-1640. PMID- 11620618 TI - Leeuwenhoek and the campaign against spontaneous generation. PMID- 11620619 TI - Die mechanistische Deutung des Lebens und ihre Grenzen. PMID- 11620620 TI - Das Arzneibuch der Landgrafin Eleonore von Hessen-Darmstadt. Ein Beitrag zum Phanomen medizinischer caritas nach der Reformation. PMID- 11620621 TI - Anton Storck und seine Bedeutung fur die Altere Wiener Schule. Zum 250. Geburtstag eines grossen Gelehrten und Klinikers. PMID- 11620622 TI - Blumenbach und der Bildungstrieb. Zum Verhaltnis von epigenetischer Embryologie und typologischem Artbegriff. PMID- 11620623 TI - [Not Available]. PMID- 11620624 TI - Die Gemme eines Arztes. PMID- 11620625 TI - The fetal origins of history. PMID- 11620626 TI - Transcendental school journals in nineteenth century America. PMID- 11620627 TI - Towards a psychological understanding of the relationship between Whittaker Chambers and Malcolm Cowley. PMID- 11620628 TI - Guilt, martyrdom and monasticism. PMID- 11620629 TI - The psychohistorian's childhood and the history of childhood. PMID- 11620631 TI - Thoughts concerning some objections to group-fantasy analysis. PMID- 11620630 TI - Trashing the sixties: defensive reactions within psychoanalysis. PMID- 11620632 TI - Anton Chekhov's tales. The physician-patient encounter. PMID- 11620633 TI - Carl Manchot, plastic surgery's missed opportunity. PMID- 11620634 TI - Sporting with life. Frankenstein and the responsibility of medical research. PMID- 11620635 TI - The theoretical bases of medieval herbalism. PMID- 11620636 TI - The strange case of Mary Toft (who was delivered of sixteen rabbits and a tabby cat in 1726). PMID- 11620637 TI - Mission Micronesia. PMID- 11620638 TI - St. Anthony's Fire. PMID- 11620639 TI - Hermann Joseph Muller. PMID- 11620640 TI - Uses and misuses of digitalis. PMID- 11620641 TI - Ignaz Philipp Semmelweis. PMID- 11620642 TI - Huxley, Hutton and the 'white rage': a debate on vivisection at the Metaphysical Society. PMID- 11620643 TI - Huxley's botanist brother-in-law. PMID- 11620644 TI - The Flexner Report: revised or revisited? PMID- 11620645 TI - MASH vs M*A*S*H: the Mobile Army Surgical Hospital. PMID- 11620647 TI - Immortal quackery. PMID- 11620646 TI - George Washington and the doctors: treating America's first superhero. PMID- 11620649 TI - Physician portraiture. PMID- 11620648 TI - Osler gives Cushing a word to the wise. PMID- 11620650 TI - Caricatures in Vanity Fair. PMID- 11620651 TI - The swine flu immunization program. PMID- 11620652 TI - Sixteenth-century Renaissance art and anatomy: Andreas Vesalius and his great book--a new view. PMID- 11620653 TI - Sir Astley Paston Cooper: a pioneer of arterial surgery. PMID- 11620654 TI - Durer's image of perfect health before the Fall. PMID- 11620655 TI - Collecting rare medical books: a dealer's perspective. PMID- 11620656 TI - Selman A. Waksman. PMID- 11620657 TI - The Cross of Lorraine. PMID- 11620658 TI - Blood and sexuality in medieval leprosy. PMID- 11620659 TI - In memoriam: Frans Verdoorn, bryologist, publisher and biohistorian. PMID- 11620660 TI - Pharmacy and the pharmaceutical profession in the Aztec culture. PMID- 11620661 TI - [Forerunners of molecular genetics in Japan] (Jpn). PMID- 11620662 TI - [Succession and distribution of an ancient Chinese veterinary text book in old time Japan] (Jpn). PMID- 11620663 TI - Ancient psychotherapy. PMID- 11620664 TI - Inverse projection and back projection: a critical appraisal, and comparative results for England, 1539 to 1871. PMID- 11620665 TI - Smallpox and epidemiological-demographic change in Europe: the role of vaccination. PMID- 11620666 TI - Marx and Malthus in north-east Brazil: a note on the world's largest class difference in fertility and its recent trends. PMID- 11620667 TI - "Gouge and bite, pull hair and scratch": the social significance of fighting in the southern backcountry. PMID- 11620668 TI - Voltaire versus Needham: atheism, materialism, and the generation of life. PMID- 11620669 TI - Industrial research comes of age: the American pharmaceutical industry, 1920 1940. PMID- 11620670 TI - George Frederick Payne and the Atlanta College of Pharmacy. PMID- 11620671 TI - Scientific ambitions: the pharmaceutical industry, 1900-1920. PMID- 11620673 TI - Pain relief--a new sub-specialty? PMID- 11620672 TI - Annotated bibliography [on paleopathology]. PMID- 11620674 TI - Pain, addiction, and traditional therapy in Southeast Asia. PMID- 11620675 TI - Medical electricians - benefactors or quacks? PMID- 11620676 TI - Medicine as a commodity: hydropathy in Matlock. PMID- 11620677 TI - An imponderable liberator: J. J. Garth Wilkinson. PMID- 11620678 TI - Deaths in childbed from the late eighteenth century to 1935. PMID- 11620679 TI - 'The life of a human football'? Women and madness in the era of the new woman. PMID- 11620680 TI - Hospital gynaecology 1842-1890. PMID- 11620682 TI - Health and medicine in modern German social history. PMID- 11620681 TI - Women's work and women's health in the munitions industry in World War I. PMID- 11620683 TI - Health and unemployment. PMID- 11620684 TI - Problems and methods in the history of medicine. PMID- 11620685 TI - Two-hundredth anniversary of the 1784 report on fever at Radcliffe Mill. PMID- 11620686 TI - Perceptions of pain in seventeenth-century England. PMID- 11620687 TI - Research by wire: a historian's guide to online information services. PMID- 11620688 TI - Museums of health and medicine: Liberpool, Bristol, and London. PMID- 11620689 TI - Charles Lindbergh's artificial heart. PMID- 11620690 TI - The skeletal remains of Ramon Llull (Raymond Lully). PMID- 11620691 TI - Annotated bibliography [of paleopathology]. PMID- 11620692 TI - The experimental approach to paleoparasitology: desiccation of Trichuris Trichiura eggs. PMID- 11620693 TI - The roots of 'Michurinism': transformist biology and acclimatization as currents in the Russian life sciences. PMID- 11620694 TI - A new perspective on Lysenko? PMID- 11620695 TI - Geneticists and the evolutionary synthesis in interwar Germany. PMID- 11620696 TI - Weimar eugenics: the Kaiser Wilhelm Institute for Anthropology, human heredity and eugenics in social context. PMID- 11620697 TI - Schooling and the discovery of latency in nineteenth-century America. PMID- 11620699 TI - The strange history of female adolescence in the United States. PMID- 11620698 TI - Cotton Mather and his female children: notes on the relationship between private experience and public thought. PMID- 11620700 TI - Changing the history of childhood: a modest proposal. PMID- 11620701 TI - An idol of the market-place: Baconianism in nineteenth century Britain. PMID- 11620702 TI - Revisions of science and magic. PMID- 11620703 TI - Balthasar Bekker and the decline of the witch-craze: the old demonology and the new philosophy. PMID- 11620704 TI - Wolfgang von Buddenbrock (1884-1964), der Zoologe und Physiologe. PMID- 11620705 TI - Wolfgang von Buddenbrock und die Begrundung der vergleichenden Physiologie. PMID- 11620706 TI - Medizinische Menschenversuche gegen Ende des 19. Jahrhunderts und der Fall Neisser. PMID- 11620707 TI - Deutsche Arzte-Emigration und gesundheitspolitische Entwicklungen in "Eretz Israel" (1933-1948). PMID- 11620708 TI - Zur Korrektur des Darwin-Bildes: Eine Nachlese auf das Jubilaumsjahr 1982. PMID- 11620709 TI - Franz Amling: Impftag auf dem Lande. PMID- 11620710 TI - Judische Arzte im Romischen Reich. PMID- 11620711 TI - Athanasius Kircher: Seine Mikroskopie, die Animalcula und die Pestwurmer. PMID- 11620712 TI - [Not Available]. PMID- 11620713 TI - Theorie und Praxis der Kinderheilkunde bei Johann Heinrich Ferdinand von Autenrieth (1772-1835). PMID- 11620714 TI - Die Phrenologie als publizistisches Ereignis Galls Schadellehre in der Tagespublizistik des 19. Jahrhunderts. PMID- 11620715 TI - Venereal disease in nineteenth-century children. PMID- 11620716 TI - The maternal Christ as redeemer: speech and gender in the thought of Martin Luther. PMID- 11620717 TI - Expunctum est Mithridatium. PMID- 11620718 TI - The Salerno regimen and its influence in England. PMID- 11620719 TI - Bristol Apprentice Books: the status of apothecary apprentices' fathers. PMID- 11620720 TI - Emperor Claudius: a medical paradox. PMID- 11620721 TI - Leipoldt's European journey. PMID- 11620722 TI - Kleine-Koch-Orenstein: the German connection with medical research in South Africa. PMID- 11620723 TI - Medical philately: failures and feuds amongst famous physicians. PMID- 11620724 TI - The frog pregnancy test: the first of its kind in the world. PMID- 11620725 TI - Science and philanthropy: Wickliffe Rose and the International Education Board. PMID- 11620726 TI - Weismann and evolution. PMID- 11620727 TI - From Galen's ureters to Harvey's veins. PMID- 11620728 TI - Optics in Philadelphia during the nineteenth century. PMID- 11620729 TI - Evidence from trade cards for the scientific instrument industry. PMID- 11620730 TI - Emotionology: clarifying the history of emotions and emotional standards. PMID- 11620731 TI - Engels, Marx, Malthus, and the machine. PMID- 11620732 TI - Ephemera of the American medicine show. PMID- 11620733 TI - Growth pattern of community pharmacies: Michigan, 1877-1973. PMID- 11620735 TI - Memories of sixty years in Florida pharmacy. PMID- 11620734 TI - Literary reflections of pharmacy--IV: the novels of Tobias Smollett, M.D. PMID- 11620736 TI - The president's address: A strategy for the future. PMID- 11620737 TI - The influenza epidemic of 1918 and its effects on the military. PMID- 11620738 TI - "I don't know only what we hear": the soldiers' view of the 1918 influenza epidemic. PMID- 11620739 TI - Indiana and the influenza pandemic of 1918. PMID- 11620740 TI - A profile of Richard Q. Peavey. PMID- 11620741 TI - Evolution of pharmaceutical oral dosage forms. PMID- 11620742 TI - Beginning of a pharmacist. PMID- 11620743 TI - The George-Deen Act of 1936 and the "Wisconsin Plan". PMID- 11620744 TI - Frontier druggists of Westport, Missouri during the westward migration, 1848 1861. PMID- 11620745 TI - The day book of a New York physician-pharmacist, 1743. PMID- 11620746 TI - Foucault and the unconscious of history. PMID- 11620747 TI - Posttraumatic stress disorders in veterans of early American wars. PMID- 11620748 TI - Neurasthenia and vocational crisis in post-Civil War. PMID- 11620749 TI - Mary Wollstonecraft's depression and diagnosis: the relation between sensibility and women's susceptibility to nervous disorders. PMID- 11620750 TI - Due scritti inediti di Spallanzani sugli animaletti delle infusioni. PMID- 11620751 TI - Science and technology museums, and problems in scientific education. PMID- 11620752 TI - Conrad Gessner to Leonhart Fuchs, October 18, 1556. PMID- 11620753 TI - Spongy hyperostosis and cribra orbitalia in a Maya subadult temple. PMID- 11620754 TI - Trichuris trichiura infection in colonial Brazil. PMID- 11620755 TI - Two examples of erosive arthropathy in skeletal material. PMID- 11620756 TI - Paleopathology of the skull. PMID- 11620757 TI - Health and sanitation in Southampton at the end of the 19th century. PMID- 11620758 TI - Apothecaries and the development of sea bathing. PMID- 11620760 TI - Pharmacopoeias--national and international. Whence and whither? PMID- 11620759 TI - A history of counterprescribing. PMID- 11620761 TI - Apothecaries and the development of sea bathing. (II) PMID- 11620762 TI - Science advisers and scientific advisers. PMID- 11620763 TI - The development of pneumococcal vaccine. PMID- 11620764 TI - Dental pathology and nutritional patterns of South Asian megalith-builders: the evidence from Iron Age Mahurjhari. PMID- 11620765 TI - Nettie Maria Stevens (1861-1912): her life and contributions to cytogenetics. PMID- 11620766 TI - Alaska's great sickness, 1900: an epidemic of measles and influenza in a virgin soil population. PMID- 11620767 TI - La recherche d'un code moleculaire de la memoire. PMID- 11620768 TI - Epidemics of measles in a seventeenth-century English town. PMID- 11620769 TI - Scientific work and uncertainty. PMID- 11620771 TI - Annual variations in deaths by age, deaths by cause, prices, and weather in London 1670 to 1830. PMID- 11620770 TI - Gregory King, Robert Malthus and the origins of English social realism. PMID- 11620774 TI - Rationality at risk: science against pseudoscience. PMID- 11620773 TI - Policies for responding to allegations of fraud in research. PMID- 11620775 TI - Academic self-regulation and the chemical profession in Imperial Germany. PMID- 11620776 TI - The morality of scientists. PMID- 11620777 TI - Literature on the history of botany and botanic gardens 1730-1840: a bibliography. PMID- 11620778 TI - Popular science periodicals in Paris and London: the emergence of a low scientific culture, 1820-1875. PMID- 11620779 TI - The William Bateson letters at the John Innes Institute. PMID- 11620780 TI - Walter Abraham Jacobs: December 14, 1883-July 12, 1967. PMID- 11620781 TI - Leonard Carmichael: November 9, 1898-September 16, 1973. PMID- 11620782 TI - Robert Kho-Seng Lim: October 15, 1897-July 8, 1969. PMID- 11620783 TI - William Barry Wood, Jr.: May 4, 1910-March 9, 1971. PMID- 11620784 TI - Lemuel Roscoe Cleveland: November 14, 1892-February 12, 1969. PMID- 11620785 TI - Lester Reynold Dragstedt: October 2, 1893-July 16, 1975. PMID- 11620786 TI - Luigi Gorini: November 13, 1903-August 13, 1976. PMID- 11620787 TI - Karl Friedrich Meyer: May 19, 1884-April 27, 1974. PMID- 11620788 TI - Theodore Shedlovsky: October 29, 1898-November 5, 1976. PMID- 11620789 TI - Wilson Stuart Stone: October 6, 1907-February 28, 1968. PMID- 11620790 TI - Lorande Loss Woodruff: July 14, 1879-June 23, 1947. PMID- 11620791 TI - William David Coolidge: October 23, 1873-February 3, 1975. PMID- 11620792 TI - Ralph Waldo Gerard: October 7, 1900-February 17, 1974. PMID- 11620793 TI - John Heysham Gibbon, Jr.: September 29, 1903-February 5, 1973. PMID- 11620794 TI - Richard Baldwin Turner: October 7, 1916-December 22, 1971. PMID- 11620795 TI - Alfred Blalock: April 5, 1899-September 15, 1964. PMID- 11620796 TI - The garbage disposer, the public health, and the good life. PMID- 11620797 TI - Historical and subgroup variations in the association between marriage and first childbirth: a life-course perspective. PMID- 11620798 TI - Lodovick Bryskett and renaissance attitudes to suicide. PMID- 11620799 TI - The Philosophical Society of Edinburgh 1768-1783. PMID- 11620800 TI - The Russification of the St. Petersburg Academy of Sciences and Arts in the eighteenth century. PMID- 11620801 TI - Bernard John Norton: 1945-1984. PMID- 11620802 TI - Un recueil grec de pharmacologie du Xe siecle illustre au XIVe siecle: le Vaticanus gr. 284. PMID- 11620803 TI - Paracelsus, the stars and medicine. PMID- 11620804 TI - Leipoldt's European journey. Part II. PMID- 11620805 TI - A forgotten giant: Dr Max Marcuse, one of the founders of the science of sexology. PMID- 11620806 TI - Medical missionary's medicine chests. PMID- 11620807 TI - The recent wave of interest in the history of anaesthesia. PMID- 11620809 TI - Excavations at an Egyptian burial site. PMID- 11620808 TI - St Bees man. PMID- 11620810 TI - Committee on the preservation of human remains. PMID- 11620811 TI - The Knights Hospitallers of England as undertakers. PMID- 11620812 TI - Thomas Mayer, Thomas Walton Mayer and the veterinary surgeons charter of 1844. PMID- 11620813 TI - Mayer House, 6-8 Queen Street, Newcastle-under-Lyme. PMID- 11620814 TI - The veterinary profession and the horse 1882-1983. PMID- 11620815 TI - Herbert Spencer's epigenetic epistemology. PMID- 11620816 TI - Bio-science between experiment and ideology, 1835-50. PMID- 11620817 TI - [Historical and herbological studies in the molluscan drugs (3): on the Japanese name of "wen-ge"] (Jpn). PMID- 11620818 TI - [On the arrangement of the drugs contained in "shen nong ben cao jing" (2): botanical drugs] (Jpn). PMID- 11620819 TI - [Concerning with wild atractylodes lancea DC. found in Sado Island of Niigata] (Jpn). PMID- 11620820 TI - [On Gendo Ooi, who first translated pharmacognosy into Japanese expression "shoyaku-gaku"] (Jpn). PMID- 11620821 TI - [Review of the pharmaceutical exhibitions in the Meiji era] (Jpn). PMID- 11620822 TI - [Consideration for the relation between a book of prescriptions of Chinese traditional medicine "he ji ju fang" and pharmacopoeia] (Jpn). PMID- 11620823 TI - [The official travel gathering the medicinal plants in Edo period] (Jpn). PMID- 11620824 TI - [Concerning with the studies on cultivation of panax schinseng nees in Sado Island, Niigata in Edo era] (Jpn). PMID- 11620825 TI - [Historical and herbological studies on the molluscan drugs (5): on "dancai"] (Jpn). PMID- 11620826 TI - [Historical and herbological studies on the traditional Japanese and Chinese crude drugs (7), on "gouteng"] (Jpn). PMID- 11620827 TI - [View on the history of the medicinal plants garden of Japan in modern times. (III)] (Jpn). PMID- 11620828 TI - [Medical, pharmaceutical and natural historical spots and monuments in Kumamoto City] (Jpn). PMID- 11620829 TI - [Studies on the transitions of salicylic acid and its preparations in Japanese pharmacopoeia] (Jpn). PMID- 11620830 TI - [The poison took by Kusuko Huziwara. (Concerning antique poisons.)] (Jpn). PMID- 11620831 TI - [Recollections of a century after Dr. A.J.C. Geerts' death] (Jpn). PMID- 11620832 TI - [Concerning the garden for medical herbs of Sado Magistrate's Office and the places where panax schinseng nees was transplanted for the first time] (Jpn). PMID- 11620833 TI - [The transition of salicylic acid as antimicrobials in Japanese sake] (Jpn). PMID- 11620834 TI - [Historical analysis of crude drug and prescriptions of Chinese traditional medicine (4): studies on "lianqiao"] (Jpn). PMID- 11620835 TI - [The points at issue in "The centennial history of the Pharmaceutical Society of Japan"] (Jpn). PMID- 11620836 TI - [View on history of the medicinal plants garden of Japan in modern times (IV)] (Jpn). PMID- 11620837 TI - [The transitions of the standards and the test-methods of the medicines in Japanese pharmacopoeia between 1886 (J.P.I) and 1981 (J.P.X)] (Jpn). PMID- 11620839 TI - [Investigations on the plants painted on the ceiling of the ship "Naminashi maru"] (Jpn). PMID- 11620838 TI - [A history of pharmaceutical education in Okayama (II): the rise and fall of pharmaceutical course of the medical faculty in the Third Senior Middle School] (Jpn). PMID- 11620840 TI - Ralph Papworth Hougham (1785-1837), surgeon of Brookland, Kent. PMID- 11620841 TI - Dr. William Johnston (1846-1900) of Leicester: an unknown Victorian general practitioner. PMID- 11620842 TI - The early history of general practice, 1700-1850: sources and methods. PMID- 11620844 TI - How to curb the fertility of the Edwardian unfit. PMID- 11620843 TI - The careers of those who were apprenticed to surgeon-apothecaries in Suffolk 1815 1858. PMID- 11620845 TI - Inmates, institutions and social historians. PMID- 11620846 TI - Eugenics, mental deficiency, and Fabian socialism between the wars. PMID- 11620847 TI - The Brookland Maid--wraith or reality? PMID- 11620848 TI - The origins and functions of Section 47 of the National Assistance Act 1948. PMID- 11620849 TI - The Peckham Health Centre: 'an inquiry into the nature of living'. PMID- 11620850 TI - A rural outbreak of smallpox in 1823--a cameo of the early post-Jenner era. PMID- 11620851 TI - A demographic crisis in Aylesbury 1742. PMID- 11620853 TI - Materials in the French Revolutionary tracts of the British Library relating to medicine, hospitals and poor relief. PMID- 11620852 TI - Paracelsus and Paracelsianism: basic data. PMID- 11620854 TI - The G.P. and infant welfare in the interwar years. PMID- 11620855 TI - The double helix and the warped zipper--an exemplary tale. PMID- 11620856 TI - The role of reductionism in the development of molecular biology: peripheral or central? PMID- 11620857 TI - A unique surgical operation on the horns of African bulls in ancient and modern times. PMID- 11620858 TI - Bibliography of recent archeological discoveries bearing on the history of science and technology. PMID- 11620859 TI - Archeological sources for the history of science, technology, and medicine. Some supplementary references. PMID- 11620860 TI - Notes on studies in the history of science in the People's Republic of China. PMID- 11620861 TI - Why the scientific revolution did not take place in China--or didn't it? PMID- 11620862 TI - A directory of scholars in East Asia engaged in research on traditional Chinese science. PMID- 11620863 TI - Chinese researches in the history of science and technology, 1982. PMID- 11620864 TI - Charles Turner Thackrah and preventive medicine. PMID- 11620865 TI - Apprenticeship gleanings. PMID- 11620866 TI - Pharmacy and medicine in the University of Leeds. PMID- 11620867 TI - Contributions of American veterinary medicine to human welfare: the conquest of tuberculosis. PMID- 11620868 TI - Dr. Langdon Frothingham, Nebraska's first football coach - a premier pioneer veterinary pathologist. PMID- 11620869 TI - October. PMID- 11620870 TI - A tale of two surgeons. PMID- 11620871 TI - The tubercular patient in art and in life. PMID- 11620872 TI - Painting for patients: Grunewald's Isenheim Altarpiece PMID- 11620873 TI - The universal drug: theriac through the ages. PMID- 11620874 TI - Collecting rare medical books: a dealer's perspective. PMID- 11620875 TI - Pre-antiseptic surgery. PMID- 11620876 TI - 'Hands off chiropractic': organized medicine's attempts to restrict chiropractic in Ontario, 1900-1925. PMID- 11620877 TI - Chiropractic education in Canada: the early decades PMID- 11620878 TI - The attitude of organized medicine toward chiropractic: a sociohistorical perspective. PMID- 11620879 TI - Trial by fire: Canadian Royal commissions investigate chiropractic. PMID- 11620880 TI - Brief guide for chiropractic oral history research. PMID- 11620881 TI - Chiropractic's Abraham Flexner: the lonely journey of John J. Nugent, 1935-1963. PMID- 11620882 TI - 'Hands-on practice': an examination of the evolution of clinical chiropractic. PMID- 11620883 TI - A clinical reformation in chiropractic: the research of Dr. Fred Illi. PMID- 11620884 TI - Evolution of chiropractic theories of practice and spinal adjustment, 1900-1950. PMID- 11620885 TI - Counting heads and jobs: science as an occupation in the Victorian census. PMID- 11620886 TI - Scientific records in the British Public Record Office. PMID- 11620887 TI - Scientific enterprise and the colonial 'model': observations on Australian experience in historical context. PMID- 11620888 TI - The cabinet of Bonnier de la Mosson (1702-1744). PMID- 11620889 TI - The letters and papers of Sir John Hill, 1714-75. PMID- 11620890 TI - Jean de Thevenot and burials in Lilliput. PMID- 11620891 TI - Child-killing and child-selling once again: a new source for Swift's A Modest Proposal. PMID- 11620892 TI - The medical recipes in MS Royal 5 E.vi. PMID- 11620893 TI - Sir Samuel Garth, F.R.S.: the dispensary poet. PMID- 11620894 TI - Humphrey Jackson, F.R.S., 1717-1801: a pioneering chemist. PMID- 11620895 TI - Conan Doyle's 'Challenger' unchampioned: William Rutherford, F.R.S. (1839-99), and the origins of practical physiology in Britain. PMID- 11620896 TI - [Not Available]. PMID- 11620897 TI - [Not Available]. PMID- 11620898 TI - [Not Available]. PMID- 11620900 TI - [Not Available]. PMID- 11620899 TI - [Not Available]. PMID- 11620901 TI - 150.000 missing Filipinos: a demographic crisis in Batangas, 1887-1903. PMID- 11620902 TI - [Not Available]. PMID- 11620903 TI - [Not Available]. PMID- 11620904 TI - [Not Available]. PMID- 11620905 TI - [Not Available]. PMID- 11620906 TI - [Not Available]. PMID- 11620907 TI - "Singuliere anomalie sociale." The hippophagy debate in 19th century France. PMID- 11620908 TI - The British veterinary service in the Abyssinian war of 1868. PMID- 11620909 TI - Historical images of the drug market. PMID- 11620910 TI - Insulin: a case study in the emergence of collaborative pharmacomedical research. PMID- 11620911 TI - The pharmacy in the popular arts. PMID- 11620912 TI - Franciscus pill coater. PMID- 11620913 TI - The Kodak and the drugstore. PMID- 11620914 TI - The strange lore of leeches. PMID- 11620915 TI - The research guarded by military secrecy--the isolation of the E.H.F. virus in Japanese biological warfare unit. PMID- 11620916 TI - William Harvey and the primacy of the blood. PMID- 11620918 TI - Biology and society in the age of enlightenment. PMID- 11620917 TI - A note on the proposed amalgamation of the Lister Institute of Preventive Medicine and the Medical Research Committee: philanthropy and state support of medical research, 1914. PMID- 11620919 TI - Claude Bernard's prophecies and the historical relation of science to literature. PMID- 11620920 TI - Neurology in ancient India--some evidences. PMID- 11620921 TI - What is a gene? PMID- 11620922 TI - Triangulating clinical and basic research: British localizationists, 1870-1906. PMID- 11620923 TI - Towards Solomon's house: rival strategies for reforming the early Royal Society. PMID- 11620924 TI - Cyril Bowdler Henry FDS MRCS RCS Eng., LRCP, LDS and his notes on dentistry. PMID- 11620925 TI - The life of James Robinson, Britain's first anaesthetist. PMID- 11620927 TI - Carl Koller--the man and the drug. PMID- 11620928 TI - When did Bartholomew Ruspini come to England? PMID- 11620929 TI - The Museum of the School of Dental Surgery, University of Liverpool. PMID- 11620931 TI - 19th century toothbrushes. PMID- 11620932 TI - Lobbying for registration laws: letters from the past. PMID- 11620933 TI - Glimpses of Mary Eliza Mahoney (7 May 1845-4 January 1926). PMID- 11620934 TI - Nineteenth-century philosophic influences on Nightingale's concept of the person. PMID- 11620935 TI - Ladies' Aid Societies and the nurses of Lincoln's army. PMID- 11620936 TI - Early nursing textbooks. PMID- 11620937 TI - Occult muddles. PMID- 11620938 TI - Professionalism and the nineteenth-century American pharmacist. PMID- 11620939 TI - Women in Ontario pharmacy, 1867-1927. In commemoration of the centenary of the first admission of women to the University of Toronto, 1984-85. PMID- 11620940 TI - The History of Health Sciences Library and Museum of the University of Cincinnati Medical Center. PMID- 11620941 TI - Pharmaceutical education in Central Europe: a historical review. PMID- 11620942 TI - Twentieth-century literary perceptions of pharmacists from James Joyce to Kurt Vonnegut. PMID- 11620944 TI - Completely molded graduates. PMID- 11620943 TI - Historical images of the drug market. PMID- 11620945 TI - Mesomelic dwarfism in a Romano-British skeleton. PMID- 11620947 TI - An exciting find: Thomas Hunt Morgan letters. PMID- 11620946 TI - David Starr Jordan (1851-1931). Papers at Stanford University archives. PMID- 11620948 TI - Philosophical issues and the founding of Division 24, American Psychological Association. PMID- 11620949 TI - Henry H. Goddard and the immigrants, 1910-1917: the studies and their social context. PMID- 11620950 TI - A tribute to Eugenia Hanfmann, 1905-1983. PMID- 11620951 TI - A list of drugs. PMID- 11620952 TI - Diet and leprosy in the medieval west: the noble leper. PMID- 11620953 TI - Helius Eobanus Hessus' Bonae valetudinis conservandae rationes aliquot: an inquiry into its sources. PMID- 11620954 TI - Felix von Oefele and Babylonian medicine. PMID- 11620955 TI - Pederasty, the Scantinian Law, and the Roman army. PMID- 11620956 TI - Paleopathology at Inamgaon: a post-Harappan agrarian village in western India. PMID- 11620958 TI - The welfare of livestock and work animals in ancient Greece and Rome. PMID- 11620957 TI - Cooper Curtice: soldier on the quiet frontier. PMID- 11620959 TI - William Osler and Arthur Conan Doyle versus the antivivisectionists: some lessons from history for today. PMID- 11620960 TI - Veterinary homeopathy. PMID- 11620961 TI - Bloodletting in the horse: a therapeutic modality in the early to mid-nineteenth century. PMID- 11620963 TI - Classics of equine veterinary medicine. PMID- 11620965 TI - [A medico-historical study on unearthed remains in ancient capitals of Japan (Part 1) on mokkan or wooden tablets] (Jpn). PMID- 11620964 TI - Frank Schofield (1889-1970) and anticoagulant therapy. PMID- 11620962 TI - The domestic cat: man's friend and foe. PMID- 11620966 TI - [The first encounter of Dr. Kure Shuzo and Dr. Fujikawa Yu--searching the beginning of full-fledged study of medical history in Japan] (Jpn). PMID- 11620968 TI - [An early history of gall-bladder surgery in Japan] (Jpn). PMID- 11620967 TI - [Supplement to a biography of Dr. Tatsuya Inoue, pioneer of Japanese ophthalmology (1848-1895)] (Jpn). PMID- 11620969 TI - Man as machine and man as microcosm: a comparison of western and traditional Japanese approaches to patient care. PMID- 11620970 TI - [On the story of Jenner's cowpox experiment on his son which is believed in Japan] (Jpn). PMID- 11620971 TI - [On the sphere and form of medical examination and treatment of public doctors in ancient countries in Japan] (Jpn). PMID- 11620972 TI - [Various conditions before German medicine was adopted in the University of Tokyo at the beginning of the Meiji Era 1869 A.D.] (Jpn). PMID- 11620973 TI - [The first Cesarean section in Aomori prefecture by Dr. Tazawa] (Jpn). PMID- 11620974 TI - [Medical aspect on 1902's winter march of the 8th Division of Japan Imperial Army] (Jpn). PMID- 11620975 TI - Competition among healing paradigms: an aspect of the professionalization of medicine in America. PMID- 11620976 TI - [On some changes in the situation of the doctor among the people in ancient times] (Jpn). PMID- 11620977 TI - [Medicines in Ssu-min-yueh-ling] (Jpn). PMID- 11620978 TI - [Sanei Koseki and internal medicine] (Jpn). PMID- 11620979 TI - [One hundred years of Matsuzawa Hospital, as described in literary works] (Jpn). PMID- 11620980 TI - [On the story of Jenner's experiment on inoculation of his son with swine pox matter] (Jpn). PMID- 11620981 TI - [A historical study on the San Sze-miao and his Chien Ching Fang] (Jpn). PMID- 11620982 TI - [Chodo Inoue's works in a history of Chinese medicine in Tokushima prefecture in the Meiji era] (Jpn). PMID- 11620983 TI - [Shotetsu Kiriyama, a physician of the Hirosaki feudal clan and the exhibition of natural history in Saiju-kan] (Jpn). PMID- 11620984 TI - Scientization of medicine. PMID- 11620985 TI - [The rod and serpent of Asklepios, symbol of medicine, dentistry and pharmacy] (Jpn). PMID- 11620986 TI - [Ancient dentistry in China] (Jpn). PMID- 11620987 TI - [On Hase-dera Kenki, its cases of religious healing] (Jpn). PMID- 11620988 TI - [Huang Ti and medicine--on the formation of Huang-ti-nei-ching] (Jpn). PMID- 11620989 TI - [On "Yojo-Shogen" written by Toshikatsu Fujita] (Jpn). PMID- 11620990 TI - [On the foundation of Otamagaike Vaccination Infirmary part 2: Toshiakira Kawaji and Genzo Saito] (Jpn). PMID- 11620991 TI - [Wilhelm Donitz: one of the pioneers of anatomy, forensic medicine and hygiene in Japan (part 2)] (Jpn). PMID- 11620992 TI - Evolution of the ideas about the nature of the psychotherapeutic process of the western world. PMID- 11620993 TI - [Prof. Kure's life and works] (Jpn). PMID- 11620994 TI - [Contemporary significance of the investigation on home confinements of the mental disorder in Japan] (Jpn). PMID- 11620995 TI - [List of articles deposited by Prof. Kure Shuzo in the treasures house of medicine] (Jpn). PMID- 11620996 TI - [Not Available]. PMID- 11620997 TI - [Siebold and his influence on the Japanese culture] (Jpn). PMID- 11620998 TI - [On the medical service idea in old Japanese festivals] (Jpn). PMID- 11620999 TI - [The source of medicine in Kyoto] (Jpn). PMID- 11621000 TI - [Historical consideration of the medical ethics in Kyoto in the Edo-era] (Jpn). PMID- 11621001 TI - [Was the vaccinia virus, which was introduced into Japan by Dr. Otto G. J. Mohnike, used for vaccination in Japan] (Jpn). PMID- 11621002 TI - Prescriptions written at the time of the Han Dynasty. PMID- 11621003 TI - [On the "Hasso-setsu" written by Risshi Mori--questioning the number of volumes of the Su wen] (Jpn). PMID- 11621004 TI - [Dr. Hiizu Miyake's diary, 1888-1938] (Jpn). PMID- 11621005 TI - [A name list of British physicians who resided in Japan during a period from 1862 to 1900] (Jpn). PMID- 11621006 TI - The history of acupuncture in the west: exoticism, esoterism and opposition to Cartesian rationalism, complementarity to the Occidental medical system. PMID- 11621007 TI - [A study on the pediatric chapter in the "Man-anpo"] (Jpn). PMID- 11621008 TI - [Historical notes on the study of fox-possession--Erwin Baelz, Shimamura Shun ichi and Kure Shuzo] (Jpn). PMID- 11621009 TI - [The first fatal case from chloroform anesthesia--the case of Hannah Greener] (Jpn). PMID- 11621010 TI - [The medical magazine called Meishichi Zasshi which was published in 1876 at Takamatsu] (Jpn). PMID- 11621011 TI - [Gentaku Otsuki and Seihein-Taigo] (Jpn). PMID- 11621012 TI - [Kensai Ikeda] (Jpn). PMID- 11621013 TI - [Dr. Genkuro-Fujino in the lineage of western study by the Dutch language (Ran Gaku)] (Jpn). PMID- 11621014 TI - [Arrival of the Iranian physician, Way-yarid in Japan in 554 A.D.] (Jpn). PMID- 11621015 TI - [Medical contributions of Dr. Shochu Sato] (Jpn). PMID- 11621016 TI - [Notes on Leopold Muller and Theodor E. Hoffmann, founders of the medical school of Tokyo in the early Meiji Era] (Jpn). PMID- 11621017 TI - [The early stages of traditional pediatrics in Japan] (Jpn). PMID- 11621018 TI - [Etymological study of "masui"] (Jpn). PMID- 11621019 TI - Contribution of Shibasaburo Kitasato to the improvement of smallpox vaccine in Japan. PMID- 11621020 TI - [Medical history in Kanagawa] (Jpn). PMID- 11621021 TI - [Parasites in Japanese medical history] (Jpn). PMID- 11621022 TI - ["Medicine" in Chinese history] (Jpn). PMID- 11621023 TI - [Keicho Mission and early Christian medicine] (Jpn). PMID- 11621024 TI - [Concerning the experiment of the spontaneous generation of rats--the incident in the scientific experiment was a hoax] (Jpn). PMID- 11621025 TI - [The most northern area of cholera prevalence in the Ansei period (1858-1859)] (Jpn). PMID- 11621026 TI - [Studies on G. Nakagawa's vaccination--new evidence of Nakagawa's vaccination] (Jpn). PMID- 11621027 TI - [Ernst Tiegel, a leader in physiology and hygiene for the Japanese in the early Meiji Era (2)] (Jpn). PMID- 11621028 TI - [Medicine in the Azuchi-Momoyama Era as seen in the Japanese-Portuguese Dictionary (2) medicines (herbs, folk remedies, patent medicines and so forth)] (Jpn). PMID- 11621029 TI - Smallpox mortality in a mountainous district in Japan where neither variolation nor vaccination had been performed. PMID- 11621030 TI - [The examination in psychiatry in the Edo Medical School (the 1st report)] (Jpn). PMID- 11621031 TI - [Sanei Mochizuki's viewpoint on Dutch medicine and Japanese medicine] (Jpn). PMID- 11621032 TI - [Contemporary trends in the academic career and times of Dr. Genkuro Fujino] (Jpn). PMID- 11621033 TI - [Chusai Shibue and Tsugaru-Ichiryu-Kintan] (Jpn). PMID- 11621034 TI - [On the history of the skull brought to Japan by Pompe van Meerdervoort] (Jpn). PMID- 11621035 TI - [On the trip to Nagasaki by Kokan Shiba] (Jpn). PMID- 11621036 TI - [Japanese animals collected by Pompe van Meerdervoort] (Jpn). PMID- 11621038 TI - [History of remedies--investigation into their real values in use] (Jpn). PMID- 11621037 TI - [The letters of Dr. Pompe van Meerdervoort concerning the Japanese animal specimens] (Jpn). PMID- 11621039 TI - [Tatewaki Nakajo and the obstetrics of Nakajo-Ryu (Nakajo school)] (Jpn). PMID- 11621040 TI - [News in Javasche Courant, dated January 5th, 1850, which reported the successful introduction of a cowpox strain into Japan] (Jpn). PMID- 11621041 TI - [The influence of Buddhism on meat-eating and vegetarianism in Japan] (Jpn). PMID- 11621042 TI - [The system of Aisei-kan] (Jpn). PMID- 11621043 TI - [On an epidemic "osharaku" that occurred at Sakata in 1722] (Jpn). PMID- 11621044 TI - An English translation of the Latin preface of Brunner's 'Experimenta nova circa pancreas' (1683). PMID- 11621045 TI - [E. Baelz's "Uber Besessenheit und verwandte Zustande"] (Jpn). PMID- 11621047 TI - [A short study on Choshuku Yoshida] (Jpn). PMID- 11621046 TI - [On footnotes of the "Ontleedkundige tafelen"] (Jpn). PMID- 11621048 TI - [Medical service in the Roman army in the Republic] (Jpn). PMID- 11621049 TI - John Hunter: the founder of pathological anatomy and experimental surgery. PMID- 11621050 TI - [The graveyard of the Hitomi clan in Kawasaki] (Jpn). PMID- 11621051 TI - [The system of Aisei-kan] (Jpn). PMID- 11621052 TI - [The manuscript "Togoku-Ohayashi-Ninjin" and the scholar Kunzan Matsudaira] (Jpn). PMID- 11621053 TI - [The introduction of the 'Anatomie clastique' to Japan] (Jpn). PMID- 11621054 TI - [Propaganda bills for vaccination distributed during the Kaei Period in Japan] (Jpn). PMID- 11621055 TI - [On the Jinmensozusetsu by Katsuragawa Hoken--Holdings of the National Museum of Ethnology, Leiden] (Jpn). PMID- 11621056 TI - [History of poppy cultivation in Japan] (Jpn). PMID- 11621057 TI - [An introductory study on the "Xiao pin fang" with reference to a recently discovered old manuscript] (Jpn). PMID- 11621058 TI - The present status of medical history in medical education in Germany. PMID- 11621059 TI - [A historical approach to the study of "kakke-kin (beriberi strain) in Japan] (Jpn). PMID- 11621060 TI - [The field hospital in the Sino-Japanese War] (Jpn). PMID- 11621061 TI - [Kensai Ikeda, supplement] (Jpn). PMID- 11621062 TI - [Fifty five years of Chinese medical history] (Jpn). PMID- 11621063 TI - [What we can learn from Prof. Shuzo Kure--association of helpers of the mentally ill] (Jpn). PMID- 11621064 TI - [Yu Fujikawa and Hiroshima] (Jpn). PMID- 11621065 TI - [Three anatomists of Pavia University in Italy] (Jpn). PMID- 11621066 TI - Rather never than late: celibacy and age at marriage in English cohort fertility, 1541-1871. PMID- 11621067 TI - The earliest printed herbals and evolution of pharmacy. PMID- 11621068 TI - Imperialism and professionalization: Dominion registration and Canadian physicians during the Boer War. PMID- 11621069 TI - Traffic in corpses: some evidence from Barming, Kent (1788-1812). PMID- 11621070 TI - Extracts from the parish registers of Barming, Kent. PMID- 11621071 TI - Insects and the European mortality decline. PMID- 11621073 TI - 50 years in research of anthropozoonoses. PMID- 11621072 TI - Food for the body and food for the mind: the regulation of freshwater fisheries in the 1870s. PMID- 11621074 TI - A short history of echinococcosis control in Cyprus. PMID- 11621075 TI - [Not Available]. PMID- 11621076 TI - Suicide in America: a test of Durkheim's theory of religious and family integration, 1933-1980. PMID- 11621077 TI - Fertility and cultural change among families in Italy and America. PMID- 11621078 TI - Annotated bibliography [of paleopathology]. PMID- 11621079 TI - Intact smallpox virus particles in an Italian mummy of the XVI century: an immuno electron microscope study. PMID- 11621080 TI - Isaac Starr and the ballistocardiograph. PMID- 11621081 TI - Using the Rockefeller archives for research on modern Chinese natural science. PMID- 11621082 TI - Blood, body and gender: medical images of the female condition in China: 1600 1850. PMID- 11621083 TI - Not quite gentlemen? Doctors in Sung and Yuan. PMID- 11621084 TI - Pasteur's theory of fermentation: a "virtual tautology"? PMID- 11621085 TI - The "social chemists": English chemical societies in the eighteenth and early nineteenth century. PMID- 11621086 TI - The impact of Mendel's work on the development of genetics in Finland. PMID- 11621087 TI - The introduction of Mendelism to Spain. PMID- 11621088 TI - Editing Darwin. PMID- 11621089 TI - Medicinal liquor in the United States. PMID- 11621090 TI - Drug therapy of eye diseases in seventeenth-century Islamic medicine. The influence of the "New chemistry" of the Paracelsians. PMID- 11621091 TI - Medicine labels of Russia 1908-1919. PMID- 11621092 TI - Remembering a pharmaceutical baron--Jesse Boot. PMID- 11621093 TI - 18th century apothecary apprenticeship premiums. PMID- 11621095 TI - Medicine and health in early Johannesburg: the first 25 years (1886-1911). PMID- 11621094 TI - Medicine in Palestine following the flight of Jewish physicians from Nazi Germany. PMID- 11621096 TI - This history of medicine through art. PMID- 11621097 TI - [Newly-found Kamakura period manuscripts of the "Ishinho" Vol. 13 in the Kongo Temple] (Jpn). PMID- 11621098 TI - [A study on measles and variola in the present texts of "Daidoruishuho"] (Jpn). PMID- 11621099 TI - [A study of the secret pill "Tsugaru-ichiryu-kintan"] (Jpn). PMID- 11621100 TI - [New information on Russian physicians to the Russian Consul General in Hakodate] (Jpn). PMID- 11621101 TI - [Not Available]. PMID- 11621102 TI - [Gout and podagra]. PMID- 11621103 TI - Ancient Chinese medical history. PMID- 11621104 TI - [Wilhelm Conrad Rontgen]. PMID- 11621105 TI - [Henri Becquerel and the discovery of natural radioactivity]. PMID- 11621107 TI - [Spas around Lund]. PMID- 11621106 TI - [When brain surgery in Sweden and Norway was still in its infancy]. PMID- 11621109 TI - [Standpoints through the times on difficult dentition (dentitio difficilis) in the deciduous set of teeth]. PMID- 11621108 TI - [Adolphe Quetelet and relative body weight]. PMID- 11621110 TI - [Experiences of Swedish internal medicine during the twentieth century]. PMID- 11621111 TI - [The history of a family of healers]. PMID- 11621112 TI - [The interplay between immunology and genetics in a historical light with aspects of Lund]. PMID- 11621113 TI - [The infancy of ultrasound diagnostics--a recollection from the horizon of Lund]. PMID- 11621114 TI - [The plague epidemic in Malmo in 1712]. PMID- 11621115 TI - Prince Gustav of Vasa in Moravia: healthways, hygiene and hedonism in the Highlands. PMID- 11621116 TI - [On the bed in our hospitals. Historical glimpses]. PMID- 11621117 TI - [Quarrels over precedence within otorhinolaryngology during the nineteenth century]. PMID- 11621118 TI - [Karl Petter Dahlgren and his trepanation forceps]. PMID- 11621119 TI - [Fritz Bauer--prominent surgeon and army surgeon general]. PMID- 11621120 TI - [The development of gastrointestinal endoscopy]. PMID- 11621121 TI - [Manic depression as source of creativity for famous authors]. PMID- 11621122 TI - [Magical remedy--from schamans and sorcery to priests and placebo]. PMID- 11621123 TI - [On animals and animal mummies in pharaonic Egypt--from the viewpoint of medical history]. PMID- 11621124 TI - [Egill Skallagrimsson's disease]. PMID- 11621125 TI - [From Pharmacopoeja Holmiensis 1686 to the pharmacopoeia of the Swedish medical products agency]. PMID- 11621126 TI - [How did the dentists become dentists?]. PMID- 11621127 TI - [Personal physician Casten Ronnow--remarkable expatriate Swede and donor]. PMID- 11621128 TI - [The physician as scientist]. PMID- 11621129 TI - Drawing the life-blood of physiology: vivisection and the physiologists' dilemma, 1870-1900. PMID- 11621130 TI - Alhazen, Leonardo, and the late-medieval speculation on the inversion of images in the eye. PMID- 11621131 TI - The reception of Foucault by historians. PMID- 11621132 TI - [Not Available]. PMID- 11621133 TI - [Not Available]. PMID- 11621134 TI - [Not Available]. PMID- 11621135 TI - [Not Available]. PMID- 11621136 TI - [Not Available]. PMID- 11621137 TI - [Not Available]. PMID- 11621138 TI - [Not Available]. PMID- 11621139 TI - [Not Available]. PMID- 11621140 TI - Antonio Machado Nunez and Antonio Machado Alvarez: a family of progressive nineteenth century intellectuals. PMID- 11621141 TI - [Not Available]. PMID- 11621142 TI - [Not Available]. PMID- 11621143 TI - [Not Available]. PMID- 11621144 TI - [Not Available]. PMID- 11621145 TI - [Not Available]. PMID- 11621146 TI - [Not Available]. PMID- 11621147 TI - [Not Available]. PMID- 11621148 TI - [Not Available]. PMID- 11621149 TI - [Not Available]. PMID- 11621150 TI - History of science in Scandinavia PMID- 11621151 TI - Historical outlook among medical practitioners in India. PMID- 11621152 TI - Unani physicians in Hyderabad State during Nizam IV, V and VI. PMID- 11621153 TI - A chronological probe into Siddha system. PMID- 11621154 TI - Rasasiddhas of Alampur. PMID- 11621155 TI - Influence of nathayogis on Telugu literature. PMID- 11621156 TI - List of medical manuscripts in Visakhapatnam & Kakinada. PMID- 11621157 TI - Body fluids according to Avicenna. PMID- 11621158 TI - Abstracts of medico-historical articles in Hindi journals. PMID- 11621159 TI - [The ancient harbours in Fujian Province and Sino-foreign medical exchanges] (Chi). PMID- 11621160 TI - [Textual research on several drugs in The recipes for 52 kinds of disease] (Chi). PMID- 11621161 TI - [Contribution of physicians of the Xinan District to traditional Chinese medicine and its standing in the Chinese medical history] (Chi). PMID- 11621162 TI - [The establishment of military medical hospitals in ancient China] (Chi). PMID- 11621163 TI - [Medical psychology thought in traditional Chinese medicine] (Chi). PMID- 11621164 TI - [A sketch of the sweating therapy] (Chi). PMID- 11621165 TI - [A brief history on the development of the science of seasonal febril diseases] (Chi). PMID- 11621166 TI - [Ding Fubao: a scholar of the modern period] (Chi). PMID- 11621167 TI - [The set up of medical officials in the early days of the Taiping Heavenly Kingdom] (Chi). PMID- 11621168 TI - [A brief history of the invention of microscope] (Chi). PMID- 11621169 TI - [Li Zhenxiang: an organizer of first-aid treatment for the rescue of the wounded in East-China Field Army during the China's liberation war] (Chi). PMID- 11621170 TI - [Traditional Chinese medicine and medical geography] (Chi). PMID- 11621171 TI - [A sketch of the history of wind-stroke syndrome] (Chi). PMID- 11621172 TI - [A brief developmental history of psychiatry in traditional Chinese medicine] (Chi). PMID- 11621173 TI - [The medical work of New Fourth Army in Southern Anhui Province] (Chi). PMID- 11621174 TI - [Medical materials of Changshu County, Jiangsu Province, in modern period] (Chi). PMID- 11621175 TI - [A perspective on the mutual infiltration of correlated sciences as viewed from the developmental history of visual science] (Chi). PMID- 11621176 TI - [A discussion on Xian Yao Jing of the Yi nationality] (Chi). PMID- 11621177 TI - [Discrimination on the origin of the so-called divine recipes in Huatuo Shen Yi Mi Chuan] (Chi). PMID- 11621178 TI - [A short introduction on Zhi Zhen Quan Shu (A complete book on treatment of rash diseases)] (Chi). PMID- 11621180 TI - A unique ancient Egyptian mummified head, demonstrating removal of the brain from the foramen magnum. PMID- 11621179 TI - Biologists and the promotion of birth control research, 1918-1938. PMID- 11621181 TI - Annotated bibliography [on paleopathology]. PMID- 11621182 TI - The Berkeley primate skeletal collection: a new resource for studies in paleopathology. PMID- 11621183 TI - Making it legal 'down under': the struggle for recognition in Australia. PMID- 11621184 TI - Still and Palmer: the impact of the first osteopath and the first chiropractor. PMID- 11621185 TI - Oakley Smith's five lost years in chiropractic PMID- 11621186 TI - Thirteen years after Roentgen: the origins of chiropractic radiology. PMID- 11621187 TI - D. D. Palmer and innate intelligence: development, division and derision. PMID- 11621188 TI - The public bootstrapping of physical therapy to a provider profession, 1919-86. PMID- 11621189 TI - Legally defensible: chiropractic in the courtroom and after, 1907. PMID- 11621190 TI - 'Bees in his bonnet': D. D. Palmer's students and their early impact. PMID- 11621191 TI - A bibliography of the Palmer green books in print, 1906-1985. PMID- 11621192 TI - A profession for 'Bohemian chiropractic': Oakley Smith and the evolution of naprapathy. PMID- 11621193 TI - Paradigms and productivity: the case of physiological optics, 1840-94. PMID- 11621194 TI - The British success with penicillin. PMID- 11621195 TI - The medical elite in France in the early nineteenth century. PMID- 11621196 TI - The impact of medical practice on biomedical research: the case of human leucocyte antigens studies. PMID- 11621197 TI - The statistician's role in society: the institutional establishment of statistics in France. PMID- 11621198 TI - John Hunter and St. George's Hospital. PMID- 11621199 TI - The Hunterian Society's collection & its curators. PMID- 11621200 TI - Some Hibernian connections. PMID- 11621201 TI - Contrasts in scientific style. Emil Fischer and Franz Hofmeister: their research groups and their theory of protein structure. PMID- 11621202 TI - Isidor Traube: physical chemist, biochemist, colloid chemist and controversialist. PMID- 11621203 TI - Ulf Svante von Euler: 7 February 1905-10 March 1983. PMID- 11621204 TI - David Gwynne Evans : 6 September 1909-13 June 1984. PMID- 11621205 TI - Haldan Keffer Hartline: 22 December 1903-18 March 1983. PMID- 11621206 TI - Cecil Arthur Hoare PMID- 11621207 TI - Robert Russell Race: 28 November 1907-15 April 1984. PMID- 11621208 TI - Esmond R. Long: June 16, 1890-November 11, 1979. PMID- 11621209 TI - Eli Kennerly Marshall: May 2, 1889-January 10, 1966. PMID- 11621210 TI - Per Fredrik Thorkelsson Scholander: November 29, 1905-June 13, 1980. PMID- 11621211 TI - William H. Stein: June 25, 1911-February 2, 1980. PMID- 11621212 TI - Curt Stern: August 30, 1902-October 23, 1981. PMID- 11621213 TI - Merton Franklin Utter: March 23, 1917-November 28, 1980. PMID- 11621214 TI - Vincent du Vigneaud: May 18, 1901-December 11, 1978. PMID- 11621215 TI - The politics of public health reform: Felix J. Underwood and the Mississippi State Board of Health, 1924-58. PMID- 11621216 TI - [Dr. T. Shimizu, man and his works] (Jpn). PMID- 11621217 TI - [Japanese pharmacopoeia and Dr. Shimizu] (Jpn). PMID- 11621218 TI - [Museum of pharmaceutical science and Dr. T. Shimizu] (Jpn). PMID- 11621219 TI - [Chinese medicine and Dr. Shimizu] (Jpn). PMID- 11621220 TI - [How did Japanese herbalists think about "Canton ginseng"?] (Jpn). PMID- 11621221 TI - [Preventive foods for diseases inscribed in the "Roadside Stone Monument of Kinka zan"] (Jpn). PMID- 11621222 TI - [Shokei Shibata and Nagajoshi Nagai--the opinion of the pioneers of pharmacy on the development of Japan pharmacy] (Jpn). PMID- 11621223 TI - [Studies on the crude drugs in "Yufuyakubutsukai-mokuroku" (II) on seventy-two guest drugs in this country] (Jpn). PMID- 11621224 TI - [A basic research on the vol. 30 of the "Ishinho on historical and herbological value] (Jpn). PMID- 11621225 TI - [The transition of arsenic trioxide and its preparations in Japanese pharmacopoeia (between JPI and JPXI)] (Jpn). PMID- 11621227 TI - [Investigations on the plants painted on the ceiling of the ship "Naminashi-maru" (Supplement)] (Jpn). PMID- 11621226 TI - [Contribution of Prof. Totaro Shimizu on dispensing pharmacy] (Jpn). PMID- 11621228 TI - [Studies on the crude drugs in "Yufuyakubutsukai-mokuroku" (I). On thirty main drugs] (Jpn). PMID- 11621229 TI - [Transition of glycyrrhizae radix and cinnamomi cortex as crude drug preparations between 1886 (J.P.I) and 1981 (J.P.X)] (Jpn). PMID- 11621230 TI - [Concerning the colored illustration of domestic products of Sado Island, "Sasyuzu, the first volume"] (Jpn). PMID- 11621231 TI - [A Japanese literature titled "the law of state medical supervision and pharmaceutical practicing in Holland," stored in the Yamazaki Library and its source] (Jpn). PMID- 11621232 TI - [Historical and herbological studies on the traditional Japanese and Chinese crude drugs. On the "Shan-ci-gu"] (Jpn). PMID- 11621233 TI - [Pharmacognostical studies on the molluscan drugs. Historical and herbological investigations on "Xishishe"] (Jpn). PMID- 11621234 TI - [Chen Bangxian, a renowned Chinese medical historian] (Chi). PMID- 11621235 TI - [Review on the North China College of Traditional Chinese Medicine on the history of higher education of TCM in Beijing during 1912-1949] (Chi). PMID- 11621236 TI - [A sketch of the origination of the Yi Jie Chun Qiu She (a society of physicians at TCM) in Shanghai] (Chi). PMID- 11621237 TI - [On the legal medicine since 1911] (Chi). PMID- 11621238 TI - [The significance of successful experimental limb replantation in China] (Chi). PMID- 11621239 TI - [Argumentation about the theories of Internal Classics of Yellow Emperor in the last fifty years] (Chi). PMID- 11621241 TI - [A study on the Somaratza, a Tibetan medical classic, and Huang Di Nei Jing Tai Su (comprehensive notes to the Internal Classics of Yellow Emperor] (Chi). PMID- 11621240 TI - [Archives from the Imperial Palace of the Qing Dynasty and history of Tong Ren Tan (a well-known traditional Chinese herbs shop), Beijing] (Chi). PMID- 11621242 TI - [A brief history of opium] (Chi). PMID- 11621243 TI - [Infering the date of writing of the Recipes for 52 kinds of disease by the archaic linguistics of the Book of Song] (Chi). PMID- 11621244 TI - [Investigation on a stone inscription about Chinese herb in Northern Song Imperial Mausoleum] (Chi). PMID- 11621245 TI - The universities, scientific research and the national interest in Latin America. PMID- 11621246 TI - Assessment by peers in nineteenth-century France: the manuscript reports on candidates for election to the Academie des Sciences. PMID- 11621247 TI - In search of improvement: the reorganization of higher education in Turkey. PMID- 11621248 TI - Disability insurance and the limits of American history. PMID- 11621249 TI - [Not Available]. PMID- 11621250 TI - Early colonial science in North America and Mexico. PMID- 11621251 TI - [Not Available]. PMID- 11621252 TI - [Not Available]. PMID- 11621253 TI - William Pitcairn, MD (1712-1791)--a biographical sketch. PMID- 11621255 TI - Ephedra as soma meaning hemp fibres with soma later misidentified as the hemp plant itself. PMID- 11621254 TI - Robert Hardwicke (1822-1875), publisher of biological and medical books. PMID- 11621256 TI - James Frederic Danielli: 13 November 1911-22 April 1984. PMID- 11621257 TI - William Rushton: 8 December 1901-21 June 1980. PMID- 11621259 TI - Roger Yate Stanier: 22 October 1916-29 January 1982. PMID- 11621258 TI - George Gaylord Simpson: 16 June 1902-6 October 1984. PMID- 11621260 TI - Carl Ferdinand Cori: 5 December 1986-20 October 1984. PMID- 11621261 TI - The biotheoretical gathering, trans-disciplinary authority and the incipient legitimation of molecular biology in the 1930s: new perspective on the historical sociology of science. PMID- 11621262 TI - Courting the cerebellum: early organological and phrenological views of sexuality. PMID- 11621263 TI - Of what is history of psychology a history? PMID- 11621264 TI - The politics of reproduction: medieval Norwegian kingship. PMID- 11621265 TI - Annotated bibliography [of paleopathology]. PMID- 11621266 TI - The torus auditivus: a reappraisal. PMID- 11621267 TI - Providence and putrefaction: Victorian sanitarians and the natural theology of health and disease. PMID- 11621268 TI - The Canadian birth control movement: two approaches to the dissemination of contraceptive technology. PMID- 11621269 TI - Medical perceptions of female sexuality: a late 19th-century case. PMID- 11621270 TI - Gynaecology, pornography, and the antivivisection movement. PMID- 11621271 TI - A brilliant career? John Conolly and Victorian psychiatry. PMID- 11621272 TI - Three medical illustrators: the Fabers of Philadelphia. PMID- 11621273 TI - The professional legacy of John Attfield. PMID- 11621274 TI - Taste and quality in 15th- and 16th-century Galenic pharmacology. PMID- 11621275 TI - A store mixt, various, universal. PMID- 11621276 TI - Texts and sources in ancient pharmacy. PMID- 11621277 TI - Dr. John S. Pemberton: originator of Coca-Cola. PMID- 11621278 TI - The Liber de heros morbo of Johannes Afflacius and its implications for medieval love conventions. PMID- 11621279 TI - [Not Available]. PMID- 11621280 TI - [Not Available]. PMID- 11621281 TI - [Not Available]. PMID- 11621282 TI - Bilan de la recherche en demographie historique dans les pays scandinaves. PMID- 11621283 TI - [Not Available]. PMID- 11621284 TI - [Not Available]. PMID- 11621285 TI - [Not Available]. PMID- 11621286 TI - [Not Available]. PMID- 11621287 TI - [Not Available]. PMID- 11621288 TI - Quelques remarques complementaires sur la contribution de Jozsef Korosy au developpement de la demographie. PMID- 11621289 TI - [Not Available]. PMID- 11621290 TI - [An aspect of psychiatry in the romantic era--a contribution on the 200th birthday of Justinus Kerner (1786-1862), poet, doctor and spiritualist] (Jpn). PMID- 11621292 TI - [Not Available]. PMID- 11621291 TI - [Mental illness and its treatment as seen in medical texts on Sui-T'ang] (Jpn). PMID- 11621293 TI - The voyage of Captain George Vancouver 1791-95: the interplay of physical and psychological pressures. PMID- 11621294 TI - Juan Luis Vives: a humanistic medical educator. PMID- 11621295 TI - Beyond the asylum: professionalization and the mental hygiene movement in Canada, 1914-1928. PMID- 11621296 TI - John Hunter (b 13 February 1728 d 16 October 1793). PMID- 11621297 TI - South Africa's role in the story of military plastic surgery. PMID- 11621298 TI - Frere Hospital--East London. PMID- 11621299 TI - The history of the Bridgman Memorial Hospital. PMID- 11621300 TI - Dental health and the chocolate factory. PMID- 11621301 TI - Common roots. PMID- 11621302 TI - Notes on Mouton's Essay D'Odontotechnie of 1746. PMID- 11621303 TI - Lost teeth and mind over matter. PMID- 11621304 TI - Historical aspects of the use of fluorides. PMID- 11621305 TI - London dentists in the 18th century: a listing from the trades directories in the Guildhall Library. PMID- 11621306 TI - [Not Available]. PMID- 11621307 TI - [Not Available]. PMID- 11621308 TI - [Not Available]. PMID- 11621309 TI - [Not Available]. PMID- 11621310 TI - [Not Available]. PMID- 11621311 TI - [Not Available]. PMID- 11621312 TI - [Not Available]. PMID- 11621313 TI - [Not Available]. PMID- 11621314 TI - [Not Available]. PMID- 11621315 TI - [Not Available]. PMID- 11621316 TI - [Not Available]. PMID- 11621317 TI - [Not Available]. PMID- 11621318 TI - Pharmacists and their contribution to British political life. PMID- 11621319 TI - The dawning of a national scientific community in Canada, 1878-1896. PMID- 11621322 TI - Science and scientists in government, 1878-1896 -- Part II. PMID- 11621321 TI - Science and scientists in government, 1878-1896 -- Part I. PMID- 11621320 TI - Henry Hunt Stabb and the establishment of a lunatic asylum in St. John's, Newfoundland, 1836-1855. PMID- 11621323 TI - [Not Available]. PMID- 11621324 TI - The terminal illness of Franz Schubert and the treatment of syphilis in Vienna in the eighteen hundred and twenties. PMID- 11621325 TI - Keats as a student at Guy's Hospital. PMID- 11621326 TI - [Not Available]. PMID- 11621327 TI - Medical technology in Victorian Canada. PMID- 11621328 TI - Russian physicians and medical politics in the Revolution of 1917. PMID- 11621329 TI - [Not Available]. PMID- 11621330 TI - In defense of the King's domain: disease prevention and health care in the Spanish Maritime Expeditions to the North Pacific, 1774-1795. PMID- 11621331 TI - The medical view of women: the case of the late nineteenth century Canada. PMID- 11621332 TI - An English-language bibliography of classical Greek medicine. PMID- 11621333 TI - [Not Available]. PMID- 11621334 TI - Beyond the book: Charles Singer and Anglo-Saxon medicine revisited. PMID- 11621335 TI - History of science today, 2. History of science in the Netherlands. PMID- 11621336 TI - The post-demographic transition in East and South East Asia: similarities and contrasts with Europe. PMID- 11621337 TI - Exposure, resistance and life expectancy: disease and death during the economic development of Japan, 1900-1960. PMID- 11621338 TI - Malthus and the development of demographic analysis. PMID- 11621339 TI - Approaches to the fertility transition in Victorian England. PMID- 11621340 TI - Southern initiative in public health nursing: the founding of the Nurses' Settlement and Instructive Visiting Nurse Association of Richmond, Virginia, 1900 1910. PMID- 11621342 TI - Men in nursing: their contributions to the mainstream nursing literature, 1955 1985. PMID- 11621341 TI - From "bu" to "won": the influence of the United States in Korea and the professionalization of Korean nursing, 1945-1948. PMID- 11621343 TI - A Benedictine's contribution to health care: the ministry of Sister Mary Olivia Gowan, OSB, R.N. PMID- 11621344 TI - Lavinia L. Dock: calling nurses to support women's rights, 1907-1923. PMID- 11621345 TI - Veterinary history society proposed in 1938. PMID- 11621346 TI - London farriers and other veterinary workers in the 18th century. PMID- 11621347 TI - Reminiscences about professors James MacQueen and Bernard Gorton. PMID- 11621348 TI - Recollections on the development of veterinary pharmacology. PMID- 11621349 TI - Witchcraft, medicine and the Inquisition in sixteenth-century Venice: II. Fear death by water: Girolamo Donzellini and the Venetian Inquisition. PMID- 11621350 TI - 3D history: the recreation of a surgery at the Ironbridge Gorge Museum. PMID- 11621351 TI - Hospital record surveys: from listings to paper archaeology. PMID- 11621352 TI - 'The demoniacke worlde': possession, exorcism and eschatology in early modern Europe. PMID- 11621353 TI - Medicine, witchcraft and uncertainty in early modern England. PMID- 11621354 TI - Evil humours: witchcraft, illness and healing in early modern England. PMID- 11621355 TI - Medicine and the decline of magic. PMID- 11621356 TI - Medical education in the provinces in eighteenth-century England. PMID- 11621357 TI - Walking the wards: physicians', surgeons' and apothecaries' pupils at the London hospitals, 1715-1815. PMID- 11621358 TI - Medical student life and practice: the Weekes family letters. PMID- 11621359 TI - Clinical education in nineteenth-century Germany: a theatre of knowledge. PMID- 11621360 TI - Medical education: between Kultur and professional expertise. PMID- 11621362 TI - The education policy of the General Nursing Council for England and Wales 1919 1939. PMID- 11621361 TI - Women's access to medical education in Great Britain, 1877-1900: an overview. PMID- 11621363 TI - Medicine and economic incentives in the early modern period. PMID- 11621364 TI - The origins of the English pharmaceutical industry: Thomas Corbyn. PMID- 11621365 TI - Prosperity and poverty in general practice 1750-1850. PMID- 11621366 TI - Witchcraft, medicine and the Inquisition in sixteenth-century Venice: I. Elena Draga and popular healing. PMID- 11621367 TI - The financial attractions of being a dentist in the early nineteenth century. PMID- 11621368 TI - West Riding medical practice from nineteenth-century census data: a view of the region and selected towns. PMID- 11621369 TI - The Medical Research Council and the pharmaceutical industry. PMID- 11621371 TI - Working-class primary medical care before the NHS. Are there any lessons? PMID- 11621370 TI - Profit and loss and the new hospital nurse. PMID- 11621372 TI - Technology and the structure of the UK radiological equipment industry since 1945. PMID- 11621373 TI - The history of legal medicine (University of Lancaster, 9-11 April 1987). PMID- 11621374 TI - Boccaccio as therapist: plague literature and the soul of the city. PMID- 11621375 TI - Personality in the political career of Chateaubriand. PMID- 11621376 TI - Hermann Hesse: narcissism and mother-complex. PMID- 11621377 TI - Caesar and his barren relationship with Rome. PMID- 11621378 TI - Historical questions in hazardous waste management. PMID- 11621379 TI - Turning from the dual empire to the inner world: Freud's creation of psychoanalysis. PMID- 11621381 TI - Visual surface and visual symbol: the microscope and the occult in early modern science. PMID- 11621382 TI - Sir Robert Sibbald, Kt, the Royal Society of Scotland and the origins of the Scottish Enlightenment. PMID- 11621383 TI - Epidemics in Tudor England. PMID- 11621384 TI - Medical reputation and literary creation: an essay on Arthur Conan Doyle versus Sherlock Holmes 1887-1987. PMID- 11621385 TI - "De venarum osteolis." PMID- 11621386 TI - Early milestones in school hygiene. PMID- 11621387 TI - The medical martyrdom of Martin Luther. PMID- 11621388 TI - Twenty-five years of The Adler museum of the history of medicine. PMID- 11621389 TI - Reflections after a 50-year interest in the history of modern surgical anaesthesia. PMID- 11621390 TI - The prescription sign; the crossed R. PMID- 11621391 TI - The concept of disease and the birth of modern medicine. PMID- 11621392 TI - Early medical works in the Grey collection, South African Library, Cape Town. PMID- 11621393 TI - A nesting place for the Caladrius. A short history of Medunsa , the Medical University of Southern Africa. PMID- 11621394 TI - Medical philately: medical martyrs. PMID- 11621395 TI - The oath of Asaph. PMID- 11621396 TI - Yellow fever--the story of its conquest. PMID- 11621397 TI - Dr. Acton's enemy: medicine, sex and society in Victorian England. PMID- 11621398 TI - Fertility and nuptiality in the Netherlands, 1850-1960. PMID- 11621399 TI - Socio-economic factors in infant and child mortality: a cross-national comparison. PMID- 11621400 TI - A noted on the origin of the net reproduction ratio. PMID- 11621402 TI - A pandemic (panzootic) of pleuro-pneumonia, 1840-1860. PMID- 11621401 TI - Doing harm: the DES tragedy and modern American medicine. PMID- 11621403 TI - Utility and audience in eighteenth-century chemistry: case studies of William Cullen and Joseph Priestley. PMID- 11621404 TI - The Scottish Enlightenment and the end of the Philosophical Society of Edinburgh. PMID- 11621405 TI - Towards a history of biology in the twentieth century: directed autobiographies as historical sources. PMID- 11621406 TI - Oral history and geriatric mental health: distortions of testimony produced by psychopathology. PMID- 11621407 TI - Rinderpest in 19th century Russia: an account by two Danish veterinarians. PMID- 11621408 TI - [Not Available]. PMID- 11621409 TI - National Veterinary Research Institute in Vom at 60. PMID- 11621410 TI - Milton Geiger--writer and pharmacist. PMID- 11621411 TI - John Channing: eighteenth-century apothecary and Arabist. PMID- 11621412 TI - Caleb Taylor, Philadelphia druggist, 1812-1820: a preliminary analysis. PMID- 11621413 TI - The muhtasib of Valencia and pharmacy in Aragon. PMID- 11621414 TI - Drug jars from Sweden's first hospital pharmacy. PMID- 11621415 TI - Pharmaco-historical resources in Madison, Wisconsin. II. Periodical literature. PMID- 11621416 TI - [Vladimir Bechterev--neuro-pioneer and teller of truths]. PMID- 11621417 TI - [Medical-historical collections at Lund]. PMID- 11621418 TI - [Islamic medicine--its days of glory, decline and revival]. PMID- 11621419 TI - [The plague epidemic in Stockholm 1710-1711]. PMID- 11621420 TI - [Bibliotheca Rostiana medica]. PMID- 11621421 TI - [The manuscript collection of KIBIC. A goldmine for medical historians]. PMID- 11621422 TI - [Traces of ancient medicine in contemporary Swedish]. PMID- 11621424 TI - [Obstetrics at Lund 1940-1979]. PMID- 11621423 TI - [Odontological terms in the mirror of history]. PMID- 11621425 TI - [The crofter and the doctor. Some reflections on the history of ideas of care giving]. PMID- 11621426 TI - [Inro and netsuke in Japanese medicine]. PMID- 11621427 TI - [Spontaneous combustion of the human body]. PMID- 11621428 TI - When did Alexander I of Russia die? PMID- 11621429 TI - The reception of Leibniz's philosophy in the writings of Charles Bonnet (1720 1793). PMID- 11621430 TI - Jeffries Wyman, philosophical anatomy, and the scientific reception of Darwin in America. PMID- 11621431 TI - Neo-Lamarckism and technique: Hans Spemann and the development of experimental embryology. PMID- 11621432 TI - Frank Macfarlane Burnet: 3 September 1899-31 August 1985. PMID- 11621433 TI - Frank Dickens: 15 December 1899-25 June 1986. PMID- 11621434 TI - John Franklin Enders: 10 February 1897-8 September 1985. PMID- 11621435 TI - Honor Bridget Fell: 22 May 1900-22 April 1986. PMID- 11621436 TI - Rodney Robert Porter: 8 October 1917-6 September 1985. PMID- 11621437 TI - John Turton Randall: 23 March 1905-16 June 1984. PMID- 11621438 TI - William Homan Thorpe: 1 April 1902-7 April 1986. PMID- 11621439 TI - The Maynard family of apothecaries. PMID- 11621440 TI - John Nicholson, 1685: the first chemist and druggist? PMID- 11621441 TI - Leslie T. Morton and his 'spare-time hobby'. PMID- 11621442 TI - (Almost) everything you ever wanted to know about informed consent. [Review of: Faden, RR and Beauchamp, TL. A history and theory of informed concsent. New York and Oxford: Oxford University Press, 1986]. PMID- 11621443 TI - Richardson's "nerves": the physiology of sensibility in Clarissa. PMID- 11621445 TI - The Peabody family and the Jones Very "insanity": two letters of Mary Peabody. PMID- 11621444 TI - The Liebig Research Group--a reappraisal. PMID- 11621446 TI - Stature and nutrition in the Habsburg monarchy: the standard of living and economic development in the eighteenth century. PMID- 11621447 TI - Suffering and sentimentality. A thematic essay on literature and medicine. PMID- 11621448 TI - "Take me to the river": the water-cure in America. PMID- 11621449 TI - The interventionist imperative. PMID- 11621450 TI - Killing in the name of healing. PMID- 11621452 TI - A scientific use of their humanity. PMID- 11621451 TI - Childbirth and conspiracy. PMID- 11621453 TI - Comparing health policies. PMID- 11621454 TI - Ancient living legacies. PMID- 11621455 TI - History and public policy. PMID- 11621456 TI - Literary portrayals of hard drinking. PMID- 11621457 TI - Otto Krayer: October 22, 1899-March 18, 1982. PMID- 11621459 TI - J. George Harrar: December 2, 1906-April 18, 1982. PMID- 11621458 TI - Rebecca Craighill Lancefield: January 5, 1895-March 3, 1981. PMID- 11621460 TI - John Howard Mueller: June 13, 1891-February 16, 1954. PMID- 11621461 TI - Robert Franklin Pitts: October 24, 1908-June 6, 1977. PMID- 11621462 TI - Gerhard Schmidt: December 26,1901-April 30, 1981. PMID- 11621463 TI - Hans-Lukas Teuber: August 7, 1916-January 4, 1977. PMID- 11621464 TI - Warren Weaver: July 17, 1894-November 24, 1978. PMID- 11621465 TI - [A sketch of history of malarial epidemiology in China] (Chi). PMID- 11621466 TI - [Preliminary study on the history of occupational diseases] (Chi). PMID- 11621467 TI - [An account on the gynecology and obstetrics in the Jin dynasty] (Chi). PMID- 11621468 TI - [Chen Shiduo's life and his medical works] (Chi). PMID- 11621469 TI - [Modern medical education in Hubei province] (Chi). PMID- 11621470 TI - [Dr Wu Lien-teh and the National Maritime Quaritine Service of China in 1930s] (Chi). PMID- 11621471 TI - [Achievements in the study of Treatise on feberile disease caused by cold in the Song dynasty] (Chi). PMID- 11621472 TI - [Personal opinion on the date of writing of the Internal classics of Yellow Emperor] (Chi). PMID- 11621473 TI - [The massotherapy in the Recipes for 52 kinds of disease] (Chi). PMID- 11621474 TI - [Medicine in the murals of Taoist Yongle Temple in Shanxi province] (Chi). PMID- 11621475 TI - [A brief medical history of Hainan Island, China] (Chi). PMID- 11621476 TI - [Rudolf Lehmann and the beginning of pharmacy in Kyoto under his influence] (Jpn). PMID- 11621478 TI - [Transitional history of the apothecary officers in the Japanese navy] (Jpn). PMID- 11621477 TI - [Lists of the pharmaco-historical relics in Kyoto] (Jpn). PMID- 11621479 TI - [The transition of zinc oxide and its preparations in Japanese pharmacopoeia (between JP I and JP XI)] (Jpn). PMID- 11621480 TI - [Studies on the illustrated list of products of Sado Island called "Sadoshima Saiyakufu"] (Jpn). PMID- 11621481 TI - [C. P. Thunberg and his voyage to Japan (I): the background to his voyage] (Jpn). PMID- 11621482 TI - [The pharmacy and the civil life in Kyoto in the medieval ages] (Jpn). PMID- 11621483 TI - [Histological and herbological studies on "Xian"--pharmacognostical studies on the molluscan drugs (XVII)] (Jpn). PMID- 11621484 TI - [The domestic production of santonin at Kyoto--a review on H. Ichinose's works] (Jpn). PMID- 11621485 TI - A history of veterinary education in Quebec. PMID- 11621486 TI - How important was Upton Sinclair's The Jungle to federal meat inspection reform? PMID- 11621487 TI - Veterinary medical service of the Army in the Spanish-American War, 1898 (With notes on the "embalmed beef" scandal). PMID- 11621488 TI - The history of scabies in veterinary and human medicine from biblical to modern times. PMID- 11621489 TI - The heritage of American Indian horse doctors. PMID- 11621490 TI - Constitution and bylaws of the United States Veterinary Medical Association, 1863: officers, meetings, committees, new-member qualification, and code of ethics. PMID- 11621491 TI - Clifford H. Eby, D.V.M.: the man: his works: his legacy. PMID- 11621492 TI - Veterinarians challenge Dr. Robert Koch regarding bovine tuberculosis and public health: a chronology of events. PMID- 11621493 TI - A veterinarian's notes on the Civil War. PMID- 11621494 TI - Memoirs of veterinary practice and veterinarians of southwest Louisiana beginning in 1933. PMID- 11621496 TI - Human acclimatization: perspectives on a contested field of inquiry in science, medicine and geography. PMID- 11621495 TI - Medical science and moral science: the cultural relations of physiology in restoration France. PMID- 11621497 TI - Autobiographical reflections on The Psychohistory Review. PMID- 11621498 TI - The economic status of the practice of Dr. Harmaunus Smith in Wentworth County, Ontario, 1826-67. PMID- 11621499 TI - A rural practice in nineteenth-century Ontario: the continuing medical education of James Miles Langstaff. PMID- 11621500 TI - Body-snatching in Ontario. PMID- 11621501 TI - Form and function: early efforts to relate chemical structure and pharmacological activity. PMID- 11621502 TI - Moses and monotheism and the psychoanalytic study of early Christian mythology. PMID- 11621503 TI - Male menstruation in history and anthropology. PMID- 11621504 TI - The portrayals of Freud as the counterfeit redeemer. PMID- 11621505 TI - Darwin's psychological theorizing: triangulating on habit. PMID- 11621506 TI - Fertility, nuptiality, and family limitation among the Wends of Serbin, Texas, 1854 to 1920. PMID- 11621507 TI - Erasmus Darwin, man of ideas and inventor of words. PMID- 11621508 TI - Thomas Henry Huxley's lecture tour of the United States, 1876. PMID- 11621509 TI - [Not Available]. PMID- 11621510 TI - [Not Available]. PMID- 11621511 TI - [Not Available]. PMID- 11621512 TI - Differential diagnosis of facial skin ulcerations in an Egyptian mummy. PMID- 11621513 TI - [Not Available]. PMID- 11621514 TI - [Not Available]. PMID- 11621515 TI - [Not Available]. PMID- 11621516 TI - [Not Available]. PMID- 11621517 TI - [Not Available]. PMID- 11621518 TI - [Not Available]. PMID- 11621519 TI - [Not Available]. PMID- 11621520 TI - A veterinary triumph: the fight against hog cholera in Wiregrass Alabama. PMID- 11621521 TI - Annotated bibliography [of paleopathology]. PMID- 11621522 TI - Recent finds of trichuris and ascaris ova from Britain. PMID- 11621523 TI - The use of a statistical test for the identification of helminth eggs in coprolites. PMID- 11621524 TI - Anthropology and paleopathology research in Greece. PMID- 11621526 TI - Experiences of an honorary librarian. PMID- 11621525 TI - Nursing in Philadelphia. PMID- 11621527 TI - The psychiatrist's contribution to the relief of pain. PMID- 11621528 TI - One hundred years of the co-ordinated service for tuberculosis. PMID- 11621529 TI - The health divide in perspective. PMID- 11621530 TI - The last illness of David Hume. PMID- 11621531 TI - An investigation of medieval medical treatments: Soutra Hospital Archaeoethnopharmacological Research Project (SHARP). PMID- 11621532 TI - From the librarian's desk. PMID- 11621533 TI - Scepticism in medicine--200 years ago and today. PMID- 11621534 TI - Introductory lectures--200 years ago and today. PMID- 11621535 TI - The Sydney A. Smith collection. PMID- 11621536 TI - The education of a professional woman, 1915-1925. PMID- 11621537 TI - The diagnosis of Oliver Cromwell's fatal illness. PMID- 11621538 TI - The Richard Poole collection. PMID- 11621540 TI - [The Mongolian medical schools and its exponents] (Chi). PMID- 11621539 TI - The first twenty years of the Medico-Pharmaceutical Forum. PMID- 11621541 TI - [Yi-nationality's viewpoint on disease in Liang Shan Yi nationality autonomous prefecture] (Chi). PMID- 11621542 TI - [Textual research on Ji Yin Gang Mu (a book on gynecology)] (Chi). PMID- 11621543 TI - [Preliminary research on the medical works of Xu Ling-tai. A renowned physician in the Qing dynasty] (Chi). PMID- 11621544 TI - [Study on Bian Que's sphygmology] (Chi). PMID- 11621545 TI - [On the medical organizations in the Qin and Han dynasties] (Chi). PMID- 11621546 TI - [A brief history of ophthalmology in the pre-Qin period] (Chi). PMID- 11621547 TI - [Introduction to first-aid for war wounded in the PLA North China Army during the China's liberation war] (Chi). PMID- 11621548 TI - [A sketch of the history of navigation health care in China] (Chi). PMID- 11621549 TI - [The history of the Jiangxi traditional Chinese medical school] (Chi). PMID- 11621551 TI - From home to hospital: changing work settings of Arkansas nurses, 1910-1954. PMID- 11621552 TI - Early development of formal nurse education in Peking, China: 1915-1925. PMID- 11621550 TI - A sketch of Emily Haines Harrison: Civil War nurse, spy, and nurse on the Kansas prairie. PMID- 11621553 TI - Bertha Harmer and McGill University nurses fight to forestall closure of the School for Graduate Nurses during the depression. PMID- 11621555 TI - Cultural enterprise: science, steam intellect and social class in Rochdale circa 1833-1900. PMID- 11621556 TI - Analyzing the fluoridation controversy: resources and structures. PMID- 11621557 TI - The order of (non)eating. PMID- 11621558 TI - American nursing's plight. PMID- 11621560 TI - The nurse perceived and projected. PMID- 11621559 TI - Of nurses, women, and the devaluation of caring. PMID- 11621561 TI - A cultural history of cancer. PMID- 11621562 TI - John Bull's physicians. PMID- 11621563 TI - The assessment of interdisciplinary research in the 1930s: the Rockefeller Foundation and physico-chemical morphology. PMID- 11621564 TI - Great Britain and allied scientific information: 1939-1945. PMID- 11621565 TI - Plantation slave mortality in Trinidad. PMID- 11621567 TI - From Flexner to Elliott: the educational survey movement and the health professions. PMID- 11621566 TI - Basic patterns in annual variations in fertility, nuptiality, mortality, and prices in pre-industrial Europe. PMID- 11621569 TI - The continuing influence of the survey during the 1960s, 70s, and early 80s--a personal look. PMID- 11621568 TI - The pharmaceutical survey revisited. PMID- 11621570 TI - An assay of coca wine: an eyewitness account. PMID- 11621572 TI - The saga of Betty Brown, Ph.G. PMID- 11621571 TI - Pharmaco-historical resources in Madison, Wisconsin. III. Kremers reference files. PMID- 11621573 TI - The three Lieschings and their contribution to medical history at the Cape 1800 1843. PMID- 11621574 TI - Blood transfusion in Johannesburg; pre-South African blood transfusion service. PMID- 11621575 TI - The history of para-aminosalicylic acid (pas), the first tuberculosis anti microbial agent, and streptomycin (sm): a comparative study. PMID- 11621576 TI - Civil registration and baptism; popular perceptions of the 1836 act for registering births, deaths and marriages. PMID- 11621577 TI - Mortality crises in sixteenth-century Dorking. PMID- 11621578 TI - A study of nurse children, 1550-1750. PMID- 11621579 TI - Norwegian College of Veterinary Medicine: 50 years 1935-1985. PMID- 11621580 TI - The history of veterinary anaesthesia. PMID- 11621582 TI - Contribution of Siddhabhesajamanimala, a treatise of 19th century. PMID- 11621581 TI - Philipp Lorenz Geiger and Justus Liebig. PMID- 11621583 TI - Medical conditions in Goa of 16th and 17th centuries: a study of foreign travelogues. PMID- 11621584 TI - Abstracts of medico-historical articles in Hindi journals. PMID- 11621585 TI - Psychosomatic illness in history: the "green sickness" among nineteenth-century adolescent girls. PMID- 11621586 TI - The mind of Stalin on the eve of Hitler's invasion of the Soviet Union. PMID- 11621587 TI - Freud, seduction and his father. PMID- 11621588 TI - [History of occupational and environmental health] (Jpn). PMID- 11621589 TI - The Colombian mummy project. PMID- 11621590 TI - Two possible cases of infantile cortical hyperostosis. PMID- 11621591 TI - The eugenics record office at Cold Spring Harbor, 1910-1940: an essay in institutional history. PMID- 11621592 TI - Recombinant DNA technology and its social transformation, 1972-1982. PMID- 11621593 TI - Introduction of Western science into colonial India: role of the Calcutta Medical College. PMID- 11621594 TI - Harry Stenberg (1910-1981): pionier in the veterinary history of Finland. PMID- 11621596 TI - The Ph.C. degree: an affirmation of chiropractic philosophy, 1908-1968. PMID- 11621595 TI - [Not Available]. PMID- 11621597 TI - Defining the debate: an exploration of the factors that influenced chiropractic's founder. PMID- 11621598 TI - One profession--one oath? A survey of the disparity of the chiropractic oath. PMID- 11621599 TI - How many chiropractic schools? An analysis of institutions that offered the D.C. degree. PMID- 11621600 TI - Edward Tennyson in York: 1832-1833. PMID- 11621601 TI - Egnatio Danti's Optics. Cinquecento Aristotelianism and the medieval tradition. PMID- 11621602 TI - [Not Available]. PMID- 11621603 TI - The idea of the primary unity of elements in the microscopic structure of animals and plants. J. E. Purkyne and Th. Schwann. PMID- 11621604 TI - [Not Available]. PMID- 11621605 TI - [Not Available]. PMID- 11621606 TI - The enigma of generation in connection with heredity in the teaching of J. E. Purkyne (1787-1869). PMID- 11621607 TI - [Not Available]. PMID- 11621608 TI - [Not Available]. PMID- 11621609 TI - [Not Available]. PMID- 11621610 TI - [Not Available]. PMID- 11621611 TI - Freud's Case studies and the Locus of psychoanalytic knowledge. PMID- 11621612 TI - [Not Available]. PMID- 11621614 TI - [Not Available]. PMID- 11621615 TI - [The professional doctor in Andalucia: the distribution of doctors in the province of Granada (1901-1981)]. PMID- 11621616 TI - [Not Available]. PMID- 11621617 TI - [Not Available]. PMID- 11621618 TI - Further documents for the biography of Arnau de Vilanova. PMID- 11621619 TI - [Not Available]. PMID- 11621620 TI - [Not Available]. PMID- 11621621 TI - [Not Available]. PMID- 11621622 TI - Biology as social theory: John Scott Haldane and physiological regulation. PMID- 11621623 TI - Jane Eyre: the madwoman as Hyena. PMID- 11621624 TI - Dr. James Latham (c. 1734-1799): pioneer inoculator in Canada. PMID- 11621626 TI - On the medicare crisis. PMID- 11621625 TI - Earle Parkhill Scarlett of Calgary: 1896-1982. PMID- 11621628 TI - The origins of the asylum in Upper Canada, 1830-1839. PMID- 11621627 TI - [Not Available]. PMID- 11621629 TI - Saturnism at Hudson's Bay: the York Factory complaint of 1833-1836. PMID- 11621630 TI - Medicinal leeching--the golden age. PMID- 11621631 TI - The invisible lady: Sir John A. MacDonald's first wife. PMID- 11621632 TI - Public health at the Fair. PMID- 11621633 TI - Relationships between synthetic dyes and drug entities. PMID- 11621634 TI - Malaria in the 18th and 19th centuries in Ontario. PMID- 11621635 TI - [Not Available]. PMID- 11621636 TI - The myth of a Canadian Boswell: Dr. R. M. Bucke and Walt Whitman. PMID- 11621637 TI - [Not Available]. PMID- 11621638 TI - Illustrations in a sixteenth-century book on obstetrics. PMID- 11621639 TI - "Because there is pain": alcoholism, temperance and the Victorian physician. PMID- 11621640 TI - Foucault plus twenty: on writing the history of Canadian psychiatry in the 1980s. PMID- 11621642 TI - Sir James Alexander Grant, 1831-1920: physician and politician. PMID- 11621641 TI - Some high points of the medical history of Provence. PMID- 11621643 TI - [Not Available]. PMID- 11621644 TI - The new Marxist orthodoxy. PMID- 11621645 TI - Smallpox management on Prince Edward Island, 1820-1940: from neglect to fulfilment. PMID- 11621646 TI - [Not Available]. PMID- 11621647 TI - Herbert Spencer's influence on the genesis of Sherrington's concept of the integrative action of the nervous system. PMID- 11621648 TI - Sir William Osler and medical hypnosis. PMID- 11621649 TI - [Not Available]. PMID- 11621650 TI - [Not Available]. PMID- 11621651 TI - The Utopia of human relations: the conflict-free family in American social thought, 1930-1960. PMID- 11621652 TI - Crawford, Willis, and Anthropologie abstracted: some early English uses of psychology. PMID- 11621653 TI - The genesis of Hull's Principles of behavior. PMID- 11621654 TI - From the population to society: the cooperative metaphors of W. C. Allee and A. E. Emerson. PMID- 11621655 TI - Technocratic optimism, H. T. Odum, and the partial transformation of ecological metaphor after World War II. PMID- 11621656 TI - Ecology and evolutionary biology in the war and post-war years: questions and comments. PMID- 11621657 TI - Science, foundations, and American universities in the 1920s. PMID- 11621659 TI - The race hygiene movement in Germany. PMID- 11621658 TI - Walter B. Cannon, L. J. Henderson, and the organic analogy. PMID- 11621660 TI - History of biology. PMID- 11621661 TI - History of the social sciences. PMID- 11621662 TI - Science in medicine. PMID- 11621663 TI - The "Geber" tradition in western alchemy and chemistry. PMID- 11621664 TI - Sex and power in the book and in America. PMID- 11621665 TI - Feminist revisionist psychobiography: a new interpretation of Mary Todd Lincoln. PMID- 11621666 TI - Freud's baby and ours: notes toward a psychohistory of psychoanalysis. PMID- 11621667 TI - Finding a policy for mapping and sequencing the human genome: lessons from the history of particle physics. PMID- 11621668 TI - American foundations and academic social science, 1945-1960. PMID- 11621669 TI - Science policy in the Soviet Union, 1917-1927. PMID- 11621670 TI - Demographic transitions and the life course: lessons from Japanese and American comparisons. PMID- 11621671 TI - Birth control in Britain during the interwar years: evidence from the Stopes correspondence. PMID- 11621672 TI - Paleoparasitological analyses of fecal material from Amerindian (or New World) mummies: evaluation of saprophytic arthropod remains. PMID- 11621673 TI - The beginnings of pharmacology in the federal government. PMID- 11621674 TI - Literary reflections of pharmacy-XI: thallium as "an untraceable poison". PMID- 11621675 TI - Pharmaco-historical resources in Madison, Wisconsin. IV. Manuscript collections. PMID- 11621676 TI - Jerry Stannard: 1926-1988. PMID- 11621677 TI - [Not Available]. PMID- 11621678 TI - [Not Available]. PMID- 11621679 TI - Military radiology: historical notes with a Belgian point of view!. PMID- 11621680 TI - [Not Available]. PMID- 11621681 TI - [Not Available]. PMID- 11621682 TI - [Not Available]. PMID- 11621683 TI - [Not Available]. PMID- 11621684 TI - [Not Available]. PMID- 11621685 TI - [Not Available]. PMID- 11621686 TI - Explaining John Freind's history of physick. PMID- 11621687 TI - Oswald Avery and the origin of molecular biology. PMID- 11621688 TI - The history of science of Canada. PMID- 11621689 TI - Observations on the history of science in Italy. PMID- 11621690 TI - Anatomy in Alexandria in the third century B.C. PMID- 11621691 TI - History of science and technology resources at the Linnean Society of London. PMID- 11621692 TI - Chloral hydrate: medicine and poison? PMID- 11621693 TI - John Channing: Arabist and apothecary. PMID- 11621694 TI - Pharmacy in the Australian colonies - the British influence. PMID- 11621695 TI - 19th century origins of the American Veterinary Medical Association (formerly the United States Veterinary Medical Association), with special reference to education. PMID- 11621696 TI - John Hunter (1728-1793) and veterinary medicine. PMID- 11621697 TI - [Tibetan medicine]. PMID- 11621698 TI - [Trained nurses and nurse training at Lund hospital in the early twentieth century]. PMID- 11621699 TI - [When Aeneas was seriously injured during the Trojan war]. PMID- 11621700 TI - [The medical history society of southern Sweden - 25 years]. PMID- 11621701 TI - [Schiller's skull in fact and fiction]. PMID- 11621702 TI - [Contagion and miasma at the plague of Karlskrona 1788-90]. PMID- 11621703 TI - [Magnus Blix on the flight of birds and men]. PMID- 11621704 TI - [The history of the incubator. From ancient times to the 1940's]. PMID- 11621705 TI - History of Western medicine in Japan from the European discovery to the Meiji restoration (1542-1868). PMID- 11621706 TI - [The departments of Johns Hopkins in Baltimore]. PMID- 11621707 TI - An early Swedish-American research collaboration: William Beaumont and Jons J Berzelius. PMID- 11621708 TI - [A sketch of history of collation on the Chinese traditional medical ancient books] (Chi). PMID- 11621710 TI - [My opinions on the division of periods in Chinese medical history] (Chi). PMID- 11621709 TI - [The knowledge of blood vessels in Lun Heng (written by Wang Chong in the Han Dynasty) and its significance in medical history] (Chi). PMID- 11621711 TI - [A brief biography of Song Xiang-yuan] (Chi). PMID- 11621712 TI - [On the formation and development of the characteristic of the Chinese traditional surgical treatment] (Chi). PMID- 11621713 TI - [The formation and development of basic theories as an independent discipline in Chinese traditional medicine] (Chi). PMID- 11621714 TI - [A brief history of medical education in the central Soviet area (established during the Second Revolutionary Civil War period, 1927-1937)] (Chi). PMID- 11621715 TI - [The achievements of the botany for medical use in Tu Jing Ben Cao (a collection of herb illustration, by Su Song in the Song Dynasty)] (Chi). PMID- 11621716 TI - [A renowned Uygur nationality's physician Maula Aiwaiz Hotaini and his Acksalai in the Qing Dynasty] (Chi). PMID- 11621717 TI - [A summary of the Lahu nationality's traditional medicine] (Chi). PMID- 11621718 TI - The Indian and Nepalese collections of the Wellcome Institute for the History of Medicine. PMID- 11621719 TI - A history of the Tibetan medical system. PMID- 11621720 TI - Glimpses into the practice and principles of medicine in Buddhistic India in the 7th century A.D. PMID- 11621721 TI - Medicine and allied sciences in Sivatattvaratnakara. PMID- 11621722 TI - The rise of the European lunatic asylum in colonial India (1750-1858). PMID- 11621723 TI - The singular fate of genetics in the history of French biology, 1900-1940. PMID- 11621724 TI - Charles Darwin on man in the first edition of the Origin of species. PMID- 11621725 TI - The selection of the "survival of the fittest." PMID- 11621727 TI - Scurvy in Ireland during the Great Famine. PMID- 11621726 TI - Centers and peripheries: the development of British physiology, 1870-1914. PMID- 11621728 TI - Behind closed doors; lunatic asylum keepers, 1800-60. PMID- 11621729 TI - The impact of female labour conditions on infant mortality: a case study of the parishes of Nedertornea and Jokkmokk, 1800-96. PMID- 11621730 TI - A discipline of relevance: the historiography of the later medieval hospital. PMID- 11621731 TI - Racial hygiene: the pseudo-science of Nazi medicine. PMID- 11621732 TI - Pathfinder: historical views of medicine and American culture. PMID- 11621733 TI - The plague of the alchemist. PMID- 11621734 TI - The mathematician Rehuel Lobatto advocates life insurances in the Netherlands in the period 1830-1860. PMID- 11621735 TI - [Not Available]. PMID- 11621736 TI - [Not Available]. PMID- 11621737 TI - [Not Available]. PMID- 11621738 TI - [Not Available]. PMID- 11621739 TI - [Not Available]. PMID- 11621740 TI - [Not Available]. PMID- 11621741 TI - The Netherlands: birthplace of F. I. P. PMID- 11621742 TI - Willmaking on the deathbed. PMID- 11621743 TI - Science and technology policy in France: 1981-1986. PMID- 11621744 TI - Thirteenth century material pantheism in the pseudo-Lullian 's'-circle of the powers of the soul. PMID- 11621745 TI - Medical chemistry at Guy's Hospital (1770-1850). PMID- 11621746 TI - Declining mortality in the United States in the late nineteenth and early twentieth centuries. PMID- 11621747 TI - Protoindustrialization and marriage ages in eastern Belgium. PMID- 11621748 TI - [Not Available]. PMID- 11621749 TI - [Not Available]. PMID- 11621750 TI - [Not Available]. PMID- 11621751 TI - [Not Available]. PMID- 11621752 TI - [Not Available]. PMID- 11621753 TI - [Not Available]. PMID- 11621754 TI - [Not Available]. PMID- 11621755 TI - [Not Available]. PMID- 11621756 TI - [Not Available]. PMID- 11621758 TI - "An ideal librarian": Charles Perry Fisher PMID- 11621757 TI - Exploring the borderlands of neurology: the Spiegels of Philadelphia. PMID- 11621759 TI - William Tyson Kendall 1851-1936. PMID- 11621760 TI - A history of veterinary education in Quebec. PMID- 11621761 TI - John Weiss and the spring fleam. PMID- 11621762 TI - History of veterinary dentistry. PMID- 11621763 TI - Professor Josip Ubl; author of the first veterinary textbooks in Croatia. PMID- 11621764 TI - The infiltration of animal diseases through war and commercial products into Finland. PMID- 11621765 TI - The Pasteur Institute in Paris. PMID- 11621766 TI - The interview as inquiry for psychiatrists and oral historians: convergence and divergence in skills and goals. PMID- 11621767 TI - Greek homosexuality, Greek narcissism, Greek culture: the invention of Apollo. PMID- 11621768 TI - Resources for the history of nursing. PMID- 11621769 TI - An aristocratic surgeon Thomas Gery Cullum, (1741-1831). PMID- 11621770 TI - Pharmacy in the Australian colonies - the British influence. PMID- 11621771 TI - Islamic scientific history: where to next? PMID- 11621772 TI - Project documents the versatile William Thornton PMID- 11621773 TI - An ethnohistorical perspective on Cheyenne demography. PMID- 11621774 TI - Migration and fertility: behavioral change on the American frontier. PMID- 11621776 TI - Operationism in psychology: a discussion of contextual antecedents and an historical interpretation of its longevity. PMID- 11621775 TI - Mill and Comte on psychology. PMID- 11621777 TI - Thomas Reid and the Aberdeen years: common sense at the Wise Club. PMID- 11621778 TI - A note on Freud's idea that Moses was an Egyptian as scriptural and traditional. PMID- 11621780 TI - Venezuelan equine encephalitis. PMID- 11621779 TI - Dr. Mark Francis: the man and the legend. PMID- 11621782 TI - [Not Available]. PMID- 11621781 TI - [Not Available]. PMID- 11621783 TI - Dutch contributions to induction of labor. PMID- 11621784 TI - [Not Available]. PMID- 11621785 TI - Medical and pharmaceutical poster art. PMID- 11621786 TI - Guardians, ferrets and defilers of the treasure: the Masson-Freudians controversy. PMID- 11621787 TI - "That familiar proverb": folly as the elixir of youth in Erasmus's Moriae encomium. PMID- 11621788 TI - Ibn Sina's medical works. PMID- 11621789 TI - The section on cardiac diseases and their treatment in the Qanun of Ibn Sina. PMID- 11621790 TI - Ibn Sina on materia medica. PMID- 11621791 TI - Impact of Ibn Sina on pulse examination and materia medica of medieval period of Ayurveda. PMID- 11621792 TI - Physiological approach of Ibn Sina towards the science of behaviour. PMID- 11621793 TI - Ibn Sina on speech articulation. PMID- 11621794 TI - German-Soviet co-operation in science: the case of the laboratory for racial research, 1931-1938. PMID- 11621795 TI - German-Soviet cooperation in science: the case of the Laboratory for Racial Research, 1931-1938. PMID- 11621797 TI - A note on the entries catalempsi and goute festre in the Middle English Dictionary. PMID- 11621796 TI - Publication and referencing patterns in a Mexican research institute. PMID- 11621798 TI - The 'bed's feet' in Donne's 'A Nocturnal upon St. Lucy's day'. PMID- 11621799 TI - The National Science Foundation and curriculum reform: a problem of stewardship. PMID- 11621800 TI - A short historical presentation of the central veterinary institutions in Slovenia. PMID- 11621801 TI - [Not Available]. PMID- 11621802 TI - [Not Available]. PMID- 11621804 TI - From family helpmeet to independent professional: women in American pharmacy, 1870-1940. PMID- 11621803 TI - The pharmacist in British political prints. PMID- 11621805 TI - Why did Sherlock Holmes use cocaine? PMID- 11621806 TI - The pomander. PMID- 11621807 TI - Research note: genes on chromosomes: the conversion of Thomas Hunt Morgan. PMID- 11621808 TI - Selling pure science in wartime: the biochemical genetics of G. W. Beadle. PMID- 11621809 TI - Ernst Kjellberg: his influence on chiropractic in Queensland, Australia. PMID- 11621810 TI - The development of chiropractic in New Zealand, 1910-1980. PMID- 11621811 TI - Early legislation affecting chiropractic in South and Western Australia: 1940 1970. PMID- 11621812 TI - History of the Australian Chiropractors' Association: the first twenty-five years. PMID- 11621813 TI - Tracking 'Old Dad Chiro' to the West Coast: was he in Portland, Oregon in 1903? PMID- 11621815 TI - [Not Available]. PMID- 11621814 TI - Kenneth Clark and the "mechanistic tendency of modern psychology". PMID- 11621816 TI - "Forgotten and lost": some reactions to autonomous science in the seventeenth century. PMID- 11621817 TI - Charcot's response to Freud's rebellion. PMID- 11621818 TI - Guide to the botanical records and papers in the archives of the Hunt Institute. Part 3. PMID- 11621819 TI - Manuscript resources in the history of chemistry at the National Library of Medicine. PMID- 11621821 TI - Policing the health of London: the College of Physicians and the early Stuart monarchy. PMID- 11621820 TI - Fruhe Falle der "Verwendung" von Analogien in der altgriechischen Medizin. PMID- 11621822 TI - The 'sick and drooping poor' in eighteenth-century Bristol and its Region. PMID- 11621823 TI - Hospitals, housing, and tuberculosis in Glasgow, 1911-51. PMID- 11621824 TI - Annie Goodrich's psychiatric nursing program. PMID- 11621825 TI - Siamese twins: double trouble. PMID- 11621826 TI - A short history of dissection. PMID- 11621827 TI - Burial seasonality and causes of death in London 1670-1819. PMID- 11621828 TI - Ernest Sandford Jackson: pioneer surgeon, early medical historian and champion of public health in Australia. PMID- 11621829 TI - The limits of industrial hygiene: commonwealth government initiatives in occupational health, 1921-1948. PMID- 11621830 TI - Henry Byam Ellerton - Caesar of lunacy. PMID- 11621831 TI - Microbes and madness: the exclusions policy of Ballarat District Hospital, 1856 to 1876. PMID- 11621832 TI - Dr F. W. E. Hare and the cold bath treatment of typhoid fever. PMID- 11621833 TI - A history of trophoblastic tumours in the 19th century. Terminological and taxonomic problems with colonial references. PMID- 11621834 TI - A brief history of the Adelaide Children's Hospital. PMID- 11621835 TI - Michael Kelly, MD (Adel.): pioneer Australian rheumatologist. PMID- 11621836 TI - Changing patterns of disease in a new colony. PMID- 11621837 TI - A country practice. PMID- 11621838 TI - Was Tratford ill? PMID- 11621839 TI - No. 3 A. G. H. in 1915 and 1918. PMID- 11621840 TI - Sir Constantine Trent Champion de Crespigny as medical administrator. PMID- 11621841 TI - Frederic Wood Jones: his activities during the Boer War, the First World War and World War II: and his attitude to war. PMID- 11621842 TI - The Queen Victoria Homes for Consumptives Fund: a history of its origins, functions, and achievements. PMID- 11621843 TI - Sunstroke and insanity in nineteenth century Australia. PMID- 11621844 TI - Ferments, zymes and the west wind: adapting disease theories and therapies in New South Wales, 1860-1880. PMID- 11621845 TI - Wounds of the head: from Vesalius to Cairns. PMID- 11621846 TI - The discovery of the Bairnsdale ulcer and the source of the Nile. PMID- 11621847 TI - Lilian Avice Foster, OBE: a volunteer hospital worker in the Great War and the Russian civil war, 1914-21. PMID- 11621848 TI - Doctors and the training of nurses in south Australia 1880-1920. PMID- 11621849 TI - The 'beame of diuinity': animal suffering in the early thought of Robert Boyle. PMID- 11621850 TI - Perceiving health and experiencing illness. PMID- 11621851 TI - Rembrandt's painting of the Anatomy lesson of Dr Tulp. PMID- 11621852 TI - A note on the letters of C. G. Jung. PMID- 11621853 TI - The significance of chemical history. PMID- 11621854 TI - Chinese and western alchemy: the link through definition. PMID- 11621855 TI - Agricola, Paracelsus, and "chymia." PMID- 11621856 TI - Raymund de Tarrega--marrano, heretic, alchemist. PMID- 11621857 TI - Psychologists and the dream accounts of August Kekule. PMID- 11621858 TI - [Not Available]. PMID- 11621859 TI - [Not Available]. PMID- 11621860 TI - [Not Available]. PMID- 11621861 TI - A contribution to the history of intrauterine contraception. PMID- 11621862 TI - Baunscheidtism. PMID- 11621864 TI - Early pharmaceutical education in Edinburgh. PMID- 11621863 TI - The Pharmaceutical Society in Scotland. PMID- 11621866 TI - [Not Available]. PMID- 11621865 TI - [Not Available]. PMID- 11621867 TI - The discovery and rediscovery of the treatment of vitiligo with psoralens. PMID- 11621871 TI - The changing shape of Soviet mortality, 1958-1985: an evaluation of old and new evidence. PMID- 11621869 TI - [Not Available]. PMID- 11621868 TI - [Not Available]. PMID- 11621872 TI - Social class differentials during fertility decline: England and Wales revisited. PMID- 11621873 TI - Duration of marriage, fertility and women's employment opportunities in England and Wales in 1911. PMID- 11621874 TI - [Not Available]. PMID- 11621875 TI - A history of ticks and tick-borne diseases of cattle in Rhodesia. PMID- 11621876 TI - [Not Available]. PMID- 11621878 TI - [Not Available]. PMID- 11621877 TI - The development of the military hospitals in the Netherlands Army Medical Service. PMID- 11621879 TI - Biomedical research and government support: the case of drug development. PMID- 11621880 TI - Literary reflections of pharmacy--XII: the toxicity of nicotine. PMID- 11621881 TI - A case unresolved: Mrs. George vs. Dr. Hand and his colic cure. PMID- 11621882 TI - The Nubian people of the Nile Valley: past and present. PMID- 11621883 TI - 'Biology' in the life sciences: a historiographical contribution. PMID- 11621884 TI - The progress of eugenics: growth of knowledge and change in ideology. PMID- 11621885 TI - The self-made mandarin: the Eloges of the French Academy of Medicine, 1824-47. PMID- 11621886 TI - Science and the origins and concerns of the Scottish Enlightenment. PMID- 11621887 TI - Scientific theory choice and social structure: the case of Joseph Lister's antisepsis, humoral theory and asepsis. PMID- 11621888 TI - Presocratic philosophy and Hippocratic medicine. PMID- 11621889 TI - The archive of the Society for the Protection of Science and Learning. PMID- 11621890 TI - Carlill v. Carbolic Smoke Ball Company: influenza, quackery, and the unilateral contract. PMID- 11621891 TI - The Howell theory of blood coagulation: a record of the pernicious effects of a false theory. PMID- 11621892 TI - Moral treatment to monolith: the institutional treatment of the insane in Manitoba, 1871-1919. PMID- 11621893 TI - "The infant soldier": the Great War and the medical campaign for child welfare. PMID- 11621894 TI - James Jamieson and the ladies. PMID- 11621895 TI - Some outstanding medical personalities associated with the Australian Medical Association (1859-1869) and its benevolent fund. PMID- 11621896 TI - Papua New Guinea's barefoot doctors, the Aid Post Orderly and his predecessor the medical tultul: an historical account from colonisation to independence. PMID- 11621897 TI - Health officers of the city of Melbourne. PMID- 11621898 TI - Germ theory: practical implications for medicine in Victoria. PMID- 11621899 TI - The library of Dr John Maund. PMID- 11621900 TI - Revelations of 19th century medicine culled from the Victorian Supreme Court records. PMID- 11621901 TI - Render unto Caesar: three generations of income tax returns from general practice. PMID- 11621903 TI - A plague on whose house? Ballarat and the Spanish influenza of 1919. PMID- 11621902 TI - Dr. Richard Arthur and the defence of hypnotism in late nineteenth century Australia. PMID- 11621904 TI - Continuity in Australian psychiatry. PMID- 11621905 TI - The effect of war on the theory and practice of psychiatry in Australia. PMID- 11621906 TI - Pioneering in geriatrics: the Newcastle experience. PMID- 11621907 TI - A dead whale or a stove boat. PMID- 11621908 TI - 'Non paulatim sed multum'--a century of service. PMID- 11621909 TI - Alfred Jefferis Turner--a man before his time. PMID- 11621910 TI - American dentistry of the past--G. V. Black. PMID- 11621911 TI - The Great Western Railway dental service. PMID- 11621912 TI - The school dental service in wartime: the city of Nottingham 1939-1945. PMID- 11621913 TI - Using the 18th century London trades directories from the Guildhall Library. PMID- 11621914 TI - Life expectancy of the gentry in eighteenth and nineteenth-century Philadelphia. PMID- 11621915 TI - Demography in early Philadelphia, 1690-1860. PMID- 11621916 TI - "Is this the promised end?" Death and dying in King Lear. PMID- 11621917 TI - A study of the Navanitaka: the Bower manuscript. PMID- 11621919 TI - Importance of and difficulties in the study of manuscripts. PMID- 11621918 TI - Tibb and tibbi institutions in Turkey. PMID- 11621920 TI - [On the formation of the Yin Yan theory in Internal classics of Yellow Emperor] (Chi). PMID- 11621921 TI - [The role of Song government in the development of contemporary medicine] (Chi). PMID- 11621922 TI - [Some ear manifestations as described in ancient China historical materials] (Chi). PMID- 11621923 TI - [Preliminary research on Sino-foreign medical exchanges in the Yuan dynasty] (Chi). PMID- 11621924 TI - [The evolution of the theory of febrile diseases caused by cold in ancient China] (Chi). PMID- 11621925 TI - [On the wax and wane of taking stone drugs and alchemy in ancient China] (Chi). PMID- 11621926 TI - [Discussion on the medical policy of the government in the northern Song dynasty] (Chi). PMID- 11621927 TI - [Research on the diseases of oral mucosa in ancient China] (Chi). PMID- 11621928 TI - [A brief history of Zi Wu Liu Zhu (midnight-noon flow, an ancient theory of selecting acupuncture points) and Ling Qui Fei Teng (extraordinary turtle flying, an ancient method of selecting points)] (Chi). PMID- 11621929 TI - [A short history of four-state theory of Korean medicine in China] (Chi). PMID- 11621930 TI - Sphagnum moss in World War I: the making of surgical dressings by volunteers in Toronto, Canada, 1917-1918. PMID- 11621931 TI - [Not Available]. PMID- 11621932 TI - The Ontario Vaccine Farm, 1885-1916. PMID- 11621933 TI - A student's ode to Osler's text republished with notes. PMID- 11621934 TI - The technology of medicine. PMID- 11621935 TI - Numismatic tokens of veterinary history in Hungary. PMID- 11621936 TI - Mayor for a day: Edward Taylor of Rochdale. PMID- 11621937 TI - Edward Robinson Squibb--the man and his company. PMID- 11621938 TI - La Mettrie's Institutions de medecine: a reinterpretation of the Boerhaavian legacy. PMID- 11621940 TI - From Berggasse XIX to Central Park West: the Americanization of psychoanalysis, 1919-1940. PMID- 11621939 TI - [Development of low temperature sterilization in Japan] (Jpn). PMID- 11621941 TI - The army intelligence tests and Walter Lippmann. PMID- 11621943 TI - Mind-body concepts in the Middle Ages. Part I. PMID- 11621942 TI - Does James's criticism of Helmholtz really involve a contradiction? PMID- 11621944 TI - George Herbert Mead and social reform: his work and writings. PMID- 11621945 TI - Child health as a social value in early modern England. PMID- 11621946 TI - Women health workers: the case of the first women factory inspectors in Britain. PMID- 11621947 TI - Maternal mortality: 1880-1950. Some regional and international comparisons. PMID- 11621948 TI - The complementarity of teaching and research in Liebig's laboratory. PMID- 11621949 TI - Kant, Schelling, and the administration of science in the Romantic era. PMID- 11621950 TI - German eugenics between science and politics. PMID- 11621951 TI - Science in Germany. PMID- 11621952 TI - University reform in medical thought at the end of the eighteenth century. PMID- 11621953 TI - The rise and decline of the Bonn natural sciences seminar. PMID- 11621954 TI - Raising "good vigorous animals": medical interest in children's health in Ontario, 1890-1930. PMID- 11621955 TI - [Not Available]. PMID- 11621956 TI - [Not Available]. PMID- 11621957 TI - [Not Available]. PMID- 11621958 TI - Contribution of Dr. Odon Bujwid to the development of Esperanto. PMID- 11621959 TI - [Not Available]. PMID- 11621960 TI - [Not Available]. PMID- 11621961 TI - [Not Available]. PMID- 11621962 TI - [Not Available]. PMID- 11621963 TI - Self-curing animals. PMID- 11621964 TI - [Not Available]. PMID- 11621965 TI - [Not Available]. PMID- 11621966 TI - [Not Available]. PMID- 11621967 TI - [Not Available]. PMID- 11621968 TI - [Not Available]. PMID- 11621969 TI - 200 years of the digitalis in medical history. PMID- 11621970 TI - [Not Available]. PMID- 11621972 TI - [Not Available]. PMID- 11621971 TI - [Not Available]. PMID- 11621973 TI - [Not Available]. PMID- 11621974 TI - [Not Available]. PMID- 11621975 TI - Leonhart Fuchs and his Commentaries on Galen. PMID- 11621976 TI - [Not Available]. PMID- 11621977 TI - [Not Available]. PMID- 11621978 TI - [Not Available]. PMID- 11621980 TI - Generation and the Origin of Species (1837-1937): a historiographical suggestion. PMID- 11621979 TI - Genetics, eugenics and evolution. PMID- 11621981 TI - Development and adaptation: evolutionary concepts in British morphology, 1870 1914. PMID- 11621982 TI - The dimensions of scientific controversy: the biometric--Mendelian debate. PMID- 11621983 TI - The 'Sonderweg' of German eugenics: nationalism and scientific internationalism. PMID- 11621984 TI - Geneticists and the eugenics movement in Scandinavia. PMID- 11621985 TI - The biology of stupidity: genetics, eugenics and mental deficiency in the inter war years. PMID- 11621986 TI - An error in classical Essential pentosuria with a discussion on its origin. PMID- 11621987 TI - The development of paediatric education in Johannesburg 1917-1968. PMID- 11621988 TI - Medical philately: Louis Pasteur and his Institute--a century of progress. PMID- 11621989 TI - Charles Porter, Jan Christian Smuts and the establishment of the Medical School of the University of the Witwatersrand. PMID- 11621990 TI - [Not Available]. PMID- 11621991 TI - [Not Available]. PMID- 11621992 TI - Puerperal fever: the epic of a great killer. PMID- 11621993 TI - Tuberculous cattle problem in the United States. PMID- 11621994 TI - "My Dear Mr Bell"--the background. PMID- 11621996 TI - History of Reckitt & Colman Pharmaceutical Division. PMID- 11621997 TI - The Hull Pharmacists Association (part 1). PMID- 11621995 TI - The professionalisation of British pharmacy. PMID- 11621998 TI - Thomas N. R. Morson: an eminent chemist. PMID- 11621999 TI - The Hull Pharmacists Association (part 2). PMID- 11622000 TI - Pestle & forceps. The pharmaceutical dentist after the 19th century. PMID- 11622001 TI - William Hunter: anatomist and obstetrician supreme. PMID- 11622002 TI - John Hunter--rheumatologist "sufferer." PMID- 11622004 TI - [Not Available]. PMID- 11622003 TI - [Not Available]. PMID- 11622005 TI - [Not Available]. PMID- 11622006 TI - [Not Available]. PMID- 11622007 TI - [Not Available]. PMID- 11622008 TI - [Not Available]. PMID- 11622010 TI - [Not Available]. PMID- 11622009 TI - In memoriam Johannes Sambucus. PMID- 11622011 TI - [Not Available]. PMID- 11622012 TI - Medical and scientific manuscripts of the Corvinian Library. PMID- 11622013 TI - [Not Available]. PMID- 11622014 TI - [Not Available]. PMID- 11622015 TI - [Not Available]. PMID- 11622016 TI - [Not Available]. PMID- 11622017 TI - [Not Available]. PMID- 11622018 TI - [Not Available]. PMID- 11622019 TI - Some myths about Aristotle's biological motivation. PMID- 11622020 TI - The glorious revolution and medicine in Britain and the Netherlands. PMID- 11622021 TI - Leeuwenhoek and other Dutch correspondents of the Royal Society. PMID- 11622022 TI - On some aspects of the life and work of John Burdon Sanderson Haldane, F.R.S., in India. PMID- 11622023 TI - The causes of rapid infant mortality decline in England and Wales, 1861-1921. Part II. PMID- 11622025 TI - Frailty, sickness, and death: models of morbidity and mortality in historical populations. PMID- 11622024 TI - Age, period, cohort and early mortality: an analysis of adult mortality in Italy. PMID- 11622027 TI - The art of memory reconceived: from rhetoric to psychoanalysis. PMID- 11622026 TI - Smallpox and its eradication in Finland: implications for disease control. PMID- 11622028 TI - Platonic trends in Renaissance medicine. PMID- 11622029 TI - Patrick Moloney, MB (Melbourne), 1843-1904. PMID- 11622030 TI - The Sydney Hospital archive. PMID- 11622031 TI - 30 years on. Medical History Society, 1953-83. PMID- 11622032 TI - Reminiscences: Changi 1942-5. PMID- 11622033 TI - The Sir Edward Stirling Memorial Lecture. PMID- 11622034 TI - Doctors, midwives, puerperal infection and the problem of maternal mortality in late nineteenth and early twentieth century Sydney. PMID- 11622035 TI - Samuel Solomon and the Cordial Balm of Gilead. PMID- 11622036 TI - "Oh, Mama, I smell the business!" The growing up years of Eli Lilly, 1885-1907. PMID- 11622037 TI - The personal papers of Francis E. Stewart (1853-1941). PMID- 11622038 TI - Ignacy Lukasiewicz (1822-1882). PMID- 11622039 TI - The Ortho Museum on the history of contraception. PMID- 11622040 TI - [Ernst Tiegel, a leader in physiology and hygiene for the Japanese in the early Meiji era] (Jpn). PMID- 11622041 TI - "Psychiatry" of Paracelsus. PMID- 11622042 TI - Concepts of psychiatric interest in Chinese traditional medicine. PMID- 11622043 TI - [The bacillus isolated from whooping cough patients by Henry Koplik] (Jpn). PMID- 11622044 TI - [A study on Shinpei Goto's "Mei-ka theory"] (Jpn). PMID- 11622045 TI - [Notes on Leopold Muller and Theodor E. Hoffmann, founders of the Medical School of Tokyo in the early Meiji era] (Jpn). PMID- 11622046 TI - [On the consistency of Shinpei Goto's theories of sanitary administration]. PMID- 11622047 TI - [The Kessei Yakuin, Serum Institute of the Imperial government of Japan] (Jpn). PMID- 11622048 TI - [A bibliographical study of the "Jingui Yaolue" (the 1st. report)--The "Xinbian Jingui Fanglun" published by Deng Zhen in the Yuan dynasty] (Jpn). PMID- 11622050 TI - [The field hospital in the Russo-Japanese War] (Jpn). PMID- 11622049 TI - [A study of malaria in "Meigetsuki"--supplementary report] (Jpn). PMID- 11622051 TI - [Genesis of multiphasic health testing--supplementary notes] (Jpn). PMID- 11622052 TI - [On Kan'en Iwasaki's manuscripts which have relation to P. F. von Siebold] (Jpn). PMID- 11622053 TI - [History of security against miners' phthisis and pneumoconiosis by Tomoko Union and labour union] (Jpn). PMID- 11622054 TI - [A licence scroll to practice Dutch surgery] (Jpn). PMID- 11622055 TI - [The A. J. Bauduin letters] (Jpn). PMID- 11622056 TI - [A short history of dissection in Hokuriku] (Jpn). PMID- 11622057 TI - [A list of Unju Taki's pupils] (Jpn). PMID- 11622058 TI - [On the "Kosai Iwa" written by Kosai Nagasaki] (Jpn). PMID- 11622060 TI - [Development of Dutch study (Rangaku) in the Yodo feudal clan] (Jpn). PMID- 11622059 TI - [E. Baelz and Tsutsugamushi-disease] (Jpn). PMID- 11622061 TI - [Illness and treatment in "The Diary of Bakin"] (Jpn). PMID- 11622062 TI - [The rod of Asklepios, symbol of medicine: its reception in Japan] (Jpn). PMID- 11622063 TI - [On the use of moulages in Japan] (Jpn). PMID- 11622064 TI - [Career and writings of Dr. Misao Nakano] (Jpn). PMID- 11622065 TI - Legal aspects of medicine. PMID- 11622066 TI - [Masturbation, excessive venery and psychoses: the history of a theory in psychiatry] (Jpn). PMID- 11622067 TI - [Translations of western child care books in the early Meiji period (1780s)] (Jpn). PMID- 11622068 TI - [The intermittent fever in the Totomi area at the beginning of the Meiji period] (Jpn). PMID- 11622069 TI - [The family tree and the life of Dr. Yoshiharu Tsuboi, pediatrician for the son of Lu Xun] (Jpn). PMID- 11622070 TI - [The study of some anatomical illustrations: the change in visualizations from Anatomia (by Cowper) to Kaibo-Sonsinzu] (Jpn). PMID- 11622071 TI - [An inquiry into the translation process of Ogata Koan's "Hu-Shi Keiken Ikun (Enchiridion medicam by Hufeland)"] (Jpn). PMID- 11622072 TI - [Schmid's medical activities at Nagasaki at the end of the Tokugawa Shogunate] (Jpn). PMID- 11622073 TI - [The topics concerning the history of beriberi in Meiji period] (Jpn). PMID- 11622074 TI - [The historical materials about the medical system of Edo Shogunate] (Jpn). PMID- 11622075 TI - [Research on the Ikeda documents (1) ... working group for the study of the Ikeda documents] (Jpn) PMID- 11622076 TI - the sources and developments of the Japanese medical thought. PMID- 11622077 TI - Western Americana: tracking frontier medicine. PMID- 11622079 TI - Annotated bibliography [of Paleopathology], cont'd. PMID- 11622078 TI - Essentials of college education for nursing--a past and current perspective. PMID- 11622080 TI - Analysis of pulmonary tissue from a natural mummy of the XIII century (Saint Zita, Lucca, Tuscany, Italy) by FT-IR microspectroscopy. PMID- 11622081 TI - [Not Available]. PMID- 11622082 TI - [Not Available]. PMID- 11622083 TI - [Not Available]. PMID- 11622085 TI - The Golden Staph: medicine's response to the challenge of the resistant staphylococci in the mid-twentieth century. PMID- 11622084 TI - [Not Available]. PMID- 11622086 TI - [Not Available]. PMID- 11622087 TI - [Not Available]. PMID- 11622088 TI - [Not Available]. PMID- 11622089 TI - [Not Available]. PMID- 11622091 TI - Medical books in early public libraries. PMID- 11622090 TI - The popularisation of medical knowledge: the case of cosmetics. PMID- 11622092 TI - From Self-Preservation to Love Without Fear: medical and law writers of sex advice from William Acton to Eustace Chesser. PMID- 11622093 TI - Popularising competitiveness: the double helix. PMID- 11622094 TI - Psychiatry and colonialism: lunatic asylums in British India 1800-1858. PMID- 11622095 TI - Smallpox and colonial medicine in India. PMID- 11622097 TI - The influenza pandemic in Southern Rhodesia: a crisis of comprehension. PMID- 11622096 TI - Nineteenth-century medical attitudes to the Maori population of New Zealand. PMID- 11622098 TI - Sleeping sickness and public health in the Belgian Congo, 1903-1930. PMID- 11622100 TI - Paediatrics and nationalism in Imperial Germany. PMID- 11622101 TI - Medical debates on woman's 'nature' in England around 1700. PMID- 11622099 TI - The transition from public health to community medicine: the evolution and execution of a policy for occupational transformation. PMID- 11622102 TI - More than the dust: personal reflections on paleopathology and medical history. PMID- 11622103 TI - The archives of Tower Hamlets Health Authority. PMID- 11622104 TI - Psychiatric hospital archives at risk. PMID- 11622105 TI - [Pharmacotherapy according to Chinese hygienic concepts--as seen in the "Xiao Pin Fang" of medieval China] (Jpn). PMID- 11622106 TI - [A pathography of Tamon-in Eishun--a case of syphilis in the 16th century Japan] (Jpn). PMID- 11622107 TI - [Japanese medical students studying in Europe from 1868-1886] (Jpn). PMID- 11622108 TI - [The charity society for the mentally ill] (Jpn). PMID- 11622109 TI - [Establishment of National Institute of Health of Japan and reorganization of the Institute for Infectious Diseases, Imperial University of Tokyo] (Jpn). PMID- 11622110 TI - [War and physician: in the case of Hiroshima] (Jpn). PMID- 11622111 TI - [The secret anesthetic used in the repair of a hare-lip performed by Tokumei Takamine in Ryukyu] (Jpn). PMID- 11622112 TI - [Tezuka Ryosai, Army Infantry Regiment Chief Medical Officer (further report)] (Jpn). PMID- 11622113 TI - [Relics and a brief history of William Smellie] (Jpn). PMID- 11622114 TI - [A newly found old manuscript of the "Ishinho"] (Jpn). PMID- 11622115 TI - [Notes on the origin of the word "hi-gaku"] (Jpn). PMID- 11622116 TI - [A letter of Miura Baien, a philosopher-doctor (2)] (Jpn). PMID- 11622117 TI - [The development of medicine in Japan] (Jpn). PMID- 11622118 TI - [The faithful copy of the "Ishinho" by the staff of the Yedo=Igaku Medical Academy] (Jpn). PMID- 11622119 TI - [Ancient Chinese medicine and the "Ishinho"] (Jpn). PMID- 11622121 TI - [Medical officers in the infantry regiments] (Jpn). PMID- 11622120 TI - [Preliminary research in to the ancient medical documents as presented in the Ishinho] (Jpn). PMID- 11622122 TI - [A study on secret in the "Tsugaru-Ichiryu-Kintan"] (Jpn). PMID- 11622123 TI - [Genesis of multiphasic health testing: London, California and Tokyo] (Jpn). PMID- 11622124 TI - On medical history instruction in West Germany. PMID- 11622125 TI - [Procedures used for the preparation of decoctions, ointments and plasters in Wu shih-erh-ping-fang] (Jpn). PMID- 11622126 TI - [Genesis of multiphasic health testing: London, California and Tokyo (1)] (Jpn). PMID- 11622127 TI - [On the Taohsing chih-chi fang or the Taohsing's treatment, written in the sixth century, China] (Jpn). PMID- 11622128 TI - [Tannawa's scroll on anatomy] (Jpn). PMID- 11622129 TI - ["Ryumachi shinron", the first translated and published monograph on rheumatic diseases in Japan, and short biographical sketches of the author of the original book, Austin Flint (1812-1886), and of the translator, Toshio Yasugi (1847-1883)] (Jpn). PMID- 11622130 TI - [Hazama Sogen, author of "Roba-shinsho" and Sugimoto Ryo] (Jpn). PMID- 11622131 TI - [Physicians described in the "Tennojiya-Kaiki"] (Jpn). PMID- 11622132 TI - [Traduction de francais en japonais d'oeuvres d'Ambroise Pare] (Jpn). PMID- 11622133 TI - [The development of psychiatric services in pre-war Japan] (Jpn). PMID- 11622134 TI - [A historical observation on the wrapping form of medicine in Japan] (Jpn). PMID- 11622135 TI - [On the herb garden, located at Chawan-yama, of the fief of Hosokawa, Higo district] (Jpn). PMID- 11622136 TI - [The transition of camphor and its preparations in Japanese pharmacopoeia (between JP I and JP XI)] (Jpn). PMID- 11622137 TI - [Comparison between the Royal Dutch medical law (1865) and the "law of state medical supervision and pharmaceutical practicing in Hollandnd" stored in the Yamazaki Library (I)] (Jpn). PMID- 11622139 TI - [Comparison between the Royal Dutch medical law (1865) and "the law of state medical supervision and pharmaceutical practicing in Holland" stored in the Yamazaki Library (III)] (Jpn). PMID- 11622138 TI - [Study on the opium war from the pharmaceutical point of view] (Jpn). PMID- 11622140 TI - [Problems in the modern Japanese pharmacy and the drug trade: bases for the acceptance of the European pharmacy] (Jpn). PMID- 11622141 TI - [The transition of tannic acid and its preparations in Japanese pharmacopoeia (between JP I and JP XI)] (Jpn). PMID- 11622142 TI - [Study on the situation of the introduction of the modern pharmacy into Japan] (Jpn). PMID- 11622143 TI - [The development of modern Japanese pharmaceutical industry, Part I. Histories of foreign trade and domestic distribution of drugs and 'baiyaku' (medicine peddling) before the Meiji era] (Jpn). PMID- 11622144 TI - [The analects of Hajime Hoshi (no. I)] (Jpn). PMID- 11622145 TI - The experiment of Psammetichus: fact, fiction, and model to follow. PMID- 11622146 TI - Centers of medical publishing before l64l. PMID- 11622147 TI - Nature in the new world. PMID- 11622148 TI - [Our first smallpox vaccinator]. PMID- 11622149 TI - [Music and orthopedics--Franz Berwald in Berlin 1829-1841]. PMID- 11622150 TI - [The development of diagnostics and therapy within Swedish neurology during 100 years]. PMID- 11622151 TI - [The initial stages of neurology in Finland]. PMID- 11622152 TI - [Pioneers in oral x-ray diagnostics in Europe and the United States]. PMID- 11622153 TI - [Radiumhemmet and the history of Swedish radio therapy]. PMID- 11622154 TI - [Doctors' recollections of the Korean war]. PMID- 11622155 TI - The last lepra patient in Iceland. PMID- 11622156 TI - [Feed, prevent and purge--the difficult choice then and now]. PMID- 11622157 TI - [Woman in pharaonic Egypt--some medical and social notices]. PMID- 11622158 TI - [The earliest physicians in Sweden known by name and profession?]. PMID- 11622159 TI - [Andreas Vesalius's "Tabulae anatomicae sex."]. PMID- 11622160 TI - [The history of portal hypertension]. PMID- 11622162 TI - [Leg prostheses in olden times]. PMID- 11622161 TI - [The history of appendicitis during 400 years--1521-1921]. PMID- 11622163 TI - Fairs, festivals and fertility in Alkmaar, North Holland, 1650-1810. PMID- 11622164 TI - Childbirth deaths in Shipton-under-Wychwood, 1565-1665. PMID- 11622165 TI - The early medieval 'Medicus', the saint--and the enchanter. PMID- 11622166 TI - Eugenics and the campaign for voluntary sterilization in Britain between the wars. PMID- 11622167 TI - 'Some of them gets lead poisoned': occupational lead exposure in women, 1880 1914. PMID- 11622168 TI - Medicine in industrial Britain: the uses of local studies. PMID- 11622169 TI - Our daily bread. PMID- 11622170 TI - Nuclear power and the environment: the Atomic Energy Commission and thermal pollution, 1965-1971. PMID- 11622171 TI - The hog cholera battle and veterinary professionalism. In Danbom DB, ed: Publicly sponsored agricultural research in the United States: past, present, and future. PMID- 11622172 TI - The last days of B. J. Palmer: revolutionary confronts reality. PMID- 11622174 TI - Titles and abstracts of historical articles in critically reviewed periodicals PMID- 11622173 TI - Dansk kiropraktor kursus: an historical perspective and overview of the Danish Chiropractors' School. PMID- 11622175 TI - A question of diagnosis: the acceptance of chiropractic analysis in New York State, 1963. PMID- 11622176 TI - The ancient philosophic roots of chiropractic in literature. PMID- 11622177 TI - C. O. Watkins, D.C.: a photo history. PMID- 11622178 TI - John Hunter (1728-1793) and rabies. PMID- 11622179 TI - An American veterinary historian: a biography, Ulysses Grant Houck (1866-1934). PMID- 11622180 TI - Twilight of the cavalry: Colonel E. L. Nye remembered. PMID- 11622181 TI - Henry Bickersteth of the Bickersteth medical dynasty. PMID- 11622182 TI - The first year medical class of 1917 of the South African School of Mines and Technology. PMID- 11622183 TI - Samuel Pepys's materia medica. PMID- 11622184 TI - The earliest occurrence of "tumeric." PMID- 11622186 TI - Unorthodox medicine. PMID- 11622185 TI - Freudian slip. PMID- 11622187 TI - Medicine, politics, and madness. PMID- 11622188 TI - The chameleon enterprise: American voluntary hospitals. PMID- 11622189 TI - [Textual research of various versions of Ben Cao Pin Hui Jing Yao (Essentials of materia medica)] (Chi). PMID- 11622190 TI - [An introduction to medical literature in Tai Pin Yu Lan] (Chi). PMID- 11622191 TI - [A restricted view of massage in Yin Dynasty] (Chi). PMID- 11622192 TI - [A historical review of biyuan (nasal sinusitis)] (Chi). PMID- 11622193 TI - [Renowned physicians of traditional Chinese medicine in Taiwan in the Qing Dynasty] (Chi). PMID- 11622194 TI - [Textual research on the history of epidemic in Dandong trading port area, Liaoning Provice] (Chi). PMID- 11622196 TI - [On the formation and development of virology] (Chi). PMID- 11622195 TI - [Development of Chinese drug property theory in the Song, and Jin and Yuan Dynasties] (Chi). PMID- 11622197 TI - [Exploration of Mongolian translation of The Four medical tantras (rGyud-bzhi)] (Chi). PMID- 11622198 TI - Harveiana in the historical collections of the library. PMID- 11622199 TI - "At heart, I am a collector": the papers of Samuel X. Radbill. PMID- 11622200 TI - The application of computer assisted tomography in a mummy bundle from Colombia. PMID- 11622201 TI - Recent finds of parasitic evidence in coprolites. PMID- 11622202 TI - Models and instruments in the development of electrophysiology, 1845-1912. PMID- 11622203 TI - The intake-output method of quantification in physiology. PMID- 11622204 TI - Some impressions of recent work on eighteenth-century science. PMID- 11622205 TI - Managing cooperative research and borderland science in the National Research Council, 1922-1942. PMID- 11622206 TI - Text, context, and quicksand: method and understanding in studying the Nobel science prizes. PMID- 11622207 TI - The life and work of Luis Nee, botanist of the Malaspina expedition. PMID- 11622208 TI - From xylography to holography: five centuries of natural history illustration. PMID- 11622209 TI - Antoni Gaymans (ca 1630-1680) and his herbaria. PMID- 11622210 TI - Hysteria and its historiography: a review of past and present writings (I). PMID- 11622211 TI - Hysteria and its historiography: a review of past and present writings (II). PMID- 11622212 TI - What is the good of history of science? PMID- 11622213 TI - [The development of the facial prosthesis during the last 100 years]. PMID- 11622214 TI - [Pasteur's personality illustrated by events in his life]. PMID- 11622215 TI - [The history of periodontology]. PMID- 11622216 TI - [Fredrik Wilhelm Djurberg--historian of medicine and museum pioneer]. PMID- 11622217 TI - [Albert Schweitzer's hospital in Lambarene. Modern medical service or old fashioned charity?]. PMID- 11622218 TI - [Glimpses from the history of sports medicine]. PMID- 11622219 TI - [The physician's role as reflected in feature film]. PMID- 11622220 TI - [The Swedish academy of pharmaceutical sciences and its pharmaceutical history museum in Stockholm]. PMID- 11622221 TI - A probable diagnosis of the Roman Emperor Claudius. PMID- 11622222 TI - [On and from the history of Tibetan medicine]. PMID- 11622223 TI - [Petrus Kirstenius--a remarkable professor of medicine in seventeenth-century Uppsala]. PMID- 11622224 TI - [On older studies of human gait]. PMID- 11622225 TI - [Mother Kisa]. PMID- 11622226 TI - [John Forssman--a biography]. PMID- 11622227 TI - [The early history of Forssman's antigen and the controversy between Bang Forssman and the school of Ehrlich]. PMID- 11622228 TI - [The department of bacteriology at Lund in the shadow of world war II]. PMID- 11622229 TI - [Carl August Ljunggren--pioneer of tissue culture]. PMID- 11622230 TI - Wilhelm Wagner (1848-1900): a centennial commemoration of a forgotten pioneer neurosurgeon. PMID- 11622231 TI - William Osler and Harvey Cushing. PMID- 11622232 TI - [Medicine and physicians during the French revolution]. PMID- 11622234 TI - [Medical Latin]. PMID- 11622233 TI - [Jean Paul Marat. Physician and revolutionary]. PMID- 11622235 TI - [The dreadful louse disease]. PMID- 11622236 TI - [Doctoral questions at the medical conferment ceremonies at Lund]. PMID- 11622237 TI - [Carl-Jacob Ask and Maison Charriere]. PMID- 11622238 TI - [The development of coronary angiography]. PMID- 11622239 TI - [Artificial respiration and resuscitation in historical perspective]. PMID- 11622241 TI - [The foundation of the medical history museums at Lund and Helsingborg]. PMID- 11622240 TI - [Not Available]. PMID- 11622242 TI - [Medical microbiology in Lund. The first documents and practitioners]. PMID- 11622243 TI - [Third symposium: Spanish Society for the History of Medicine: defending the documentary heritage of the history of medicine in Spain]. PMID- 11622244 TI - [Intellectual relations between the Crown of Aragon and Italy (1470-1520): Valencian medicine students in general studies in Siena, Pisa, Ferrara, and Padua]. PMID- 11622245 TI - [Micro-iconographic embryology in the Traite de la structure du coeur, de son action et de ses maladies, by Jean Baptiste Senac (1693-1770)]. PMID- 11622246 TI - [The Medical History Museum of Barcelona]. PMID- 11622247 TI - [Social scientific problems of anticholera vaccination in Seville (1885): the reports of Rafael Tunon and Leopoldo Murga]. PMID- 11622248 TI - [Tuberculosis as a social disease in Spanish epidemiological studies before the Civil War]. PMID- 11622249 TI - [The Medical History Library and Museum of Valencia]. PMID- 11622250 TI - [Laboratories for genetic testing belonging to the Junta para la Ampliacion de Estudios]. PMID- 11622251 TI - In memoriam: Iain Malcolm Lonie (1932-1988). PMID- 11622252 TI - [In memoriam: Georg Harig (1935-1989)]. PMID- 11622253 TI - [Medieval archives]. PMID- 11622254 TI - [General historical archives: the General Archive of Simancas]. PMID- 11622255 TI - [Contemporary administrative archives]. PMID- 11622256 TI - [The program: Guide to sources for the study of infectious diseases]. PMID- 11622257 TI - Rheumatology: yesterday, today and tomorrow. PMID- 11622258 TI - A little known engraving of Lord Lister. PMID- 11622259 TI - John Boswell. PMID- 11622260 TI - Lessons from history on attempts to control the spread of sexually transmitted diseases. PMID- 11622261 TI - The journal of John Boswell: Part I. PMID- 11622263 TI - Surgery in a new nation: America in 1800. PMID- 11622262 TI - A neurologist looks back. PMID- 11622265 TI - [Not Available]. PMID- 11622264 TI - [Not Available]. PMID- 11622266 TI - [Not Available]. PMID- 11622267 TI - [Not Available]. PMID- 11622268 TI - [Not Available]. PMID- 11622269 TI - [Not Available]. PMID- 11622270 TI - [Not Available]. PMID- 11622271 TI - [Not Available]. PMID- 11622272 TI - [Not Available]. PMID- 11622274 TI - [Not Available]. PMID- 11622273 TI - [Not Available]. PMID- 11622275 TI - [Not Available]. PMID- 11622276 TI - Eighteenth-century England: surgical education in a commercial society. PMID- 11622277 TI - Luis Federico Leloir: 6 September 1906-3 December 1987. PMID- 11622278 TI - Robert Gwyn Macfarlane: 26 June 1907-26 March 1987. PMID- 11622279 TI - Bryan Harold Cabot Matthews: 14 June 1906-23 July 1986. PMID- 11622280 TI - Peter Brian Medawar: 28 February 1915-2 October 1987. PMID- 11622281 TI - Peter Frederick Baker: 11 March 1939-10 March 1987. PMID- 11622282 TI - Arnold Ashley Miles: 20 March 1904-11 February 1988. PMID- 11622283 TI - Albert Charles Chibnall: 28 January 1894-10 January 1988. PMID- 11622285 TI - Annotated bibliography [of paleopathology]. PMID- 11622284 TI - Allan Watt Downie: September 1901-26 January 1988. PMID- 11622287 TI - The professional liability insurance crisis in the U.S.A. PMID- 11622286 TI - Samuel Beckett at Saint-Lo--'Humanity. PMID- 11622288 TI - Anaesthesia--its coming of age and the road not yet taken. PMID- 11622289 TI - David Smyth Torrens: a Leonard Abrahamson Dublin contemporary. PMID- 11622290 TI - Medical facets in Verdi's operas. PMID- 11622291 TI - The Hippocratic tradition in medical education. PMID- 11622292 TI - Reminisences of my student days at the Royal College of Surgeons Dublin, Ireland. PMID- 11622293 TI - Medicine and the masters of Italian opera. PMID- 11622294 TI - Electric delight--the road to the scans. PMID- 11622295 TI - William Doolin: humanist and surgeon. PMID- 11622296 TI - Congenital heart disease 1958-1988: a personal perspective. PMID- 11622298 TI - Irish naval surgeons. PMID- 11622297 TI - The Dublin bills of mortality. PMID- 11622299 TI - John Mallet Purser: medicine under the microscope. PMID- 11622300 TI - History of radium therapy in Ireland: the 'Dublin method' and the Irish Radium Institute. PMID- 11622301 TI - The external statuary of the Royal College of Surgeons in Ireland. PMID- 11622302 TI - The human eye from The Light of the Eye and Compendium of the Arts by Abu Zakariya Yahya ibn Abi' l-Raja PMID- 11622303 TI - Arabic medical literature in Dublin libraries: a bibliographic study. PMID- 11622304 TI - The Royal College of Physicians on Kildare Street. PMID- 11622305 TI - Richard Carmichael and parotid surgery. PMID- 11622306 TI - Dr. Steevens' Hospital. PMID- 11622307 TI - The development of the Scottish Poor Law medical service 1845-1914. PMID- 11622308 TI - The Oyster Club. PMID- 11622310 TI - The nephrologist's tale. PMID- 11622309 TI - Ancient Egyptian dwarfs. PMID- 11622312 TI - Women in pharmacy. PMID- 11622311 TI - Manufacturing drugs in the early consumer society: the case of Corbyns. PMID- 11622313 TI - Sir William Osler: book collector par excellence. PMID- 11622314 TI - Physicians and books: some early medical libraries. PMID- 11622315 TI - Quantification in science and cognition circa 1937. A newly discovered text of Ludwik Fleck. PMID- 11622316 TI - Endocrinologists and the conceptualization of sex, 1920-1940. PMID- 11622318 TI - The Fish Commission Laboratory and its influence on the founding of the Marine Biological Laboratory. PMID- 11622317 TI - The idea of immunity: Metchnikoff's metaphysics and science. PMID- 11622319 TI - The privy and the pump: the Matthewman & Johnson excavating office. PMID- 11622320 TI - Western fertility in mid-transition: fertility and nuptiality in the United States and selected nations at the turn of the century. PMID- 11622321 TI - What can we learn about fertility transitions from the New York State census of 1865? PMID- 11622322 TI - Household composition, extended kinship, and reproduction in Taiwan: 1965-1985. PMID- 11622323 TI - Effects of reproductive behaviour on infant mortality of French-Canadians during the seventeenth and eighteenth centuries. PMID- 11622324 TI - Scientific imagery in Proust. PMID- 11622325 TI - [Not Available]. PMID- 11622326 TI - [Not Available]. PMID- 11622327 TI - [Not Available]. PMID- 11622328 TI - [Not Available]. PMID- 11622329 TI - An illuminated titlepage to the Venice, 1502 Galen. PMID- 11622330 TI - [Not Available]. PMID- 11622331 TI - [Not Available]. PMID- 11622332 TI - [Not Available]. PMID- 11622333 TI - [Not Available]. PMID- 11622334 TI - [Not Available]. PMID- 11622335 TI - New light on ancient Indian anatomy. PMID- 11622336 TI - A note on Mualejat-e-nebevi. PMID- 11622337 TI - Ancient history of ocular photo-coagulation. PMID- 11622338 TI - Rasayana in the light of Chinese alchemy. PMID- 11622340 TI - Origin and development of medical libraries with special reference to India (upto 18 c). PMID- 11622339 TI - History of anaesthesia and Hyderabad Chloroform Commissions. PMID- 11622341 TI - Politics, congress, and outpatient prescription drug coverage under Medicare: a historical review, 1965-1989. PMID- 11622342 TI - Literary reflections of pharmacy--XIV. A nineteenth-century French fantasy. PMID- 11622343 TI - Phu: valerian and other anti-hysterics in European and American medicine (1733 1936). PMID- 11622344 TI - Historical images of the drug market. PMID- 11622345 TI - The testimony of our senses: William Heberden's lectures upon materia medica of 1743. PMID- 11622346 TI - AAHN: in the beginning. PMID- 11622347 TI - A survey of chiropractic college archives in the United States and Canada. PMID- 11622348 TI - William H. Werner and the American Bureau of Chiropractic: organizing a lay constituency. PMID- 11622349 TI - An historical overview of foreign students in chiropractic: 1900-1988. PMID- 11622350 TI - The history of child assault. PMID- 11622351 TI - A respectable mad-doctor? Dr. Richard Hale, F.R.S. (1670-1728). PMID- 11622352 TI - George Eliot's support for physiology: the George Henry Lewes Trust, 1879-1939. PMID- 11622353 TI - Salmonella typhi and the Crown of Spain. PMID- 11622354 TI - How can university presses publish Canadian medical history? PMID- 11622355 TI - The McGill experience of Robert A. Cleghorn, MD: recollections of D. Ewen Cameron. PMID- 11622356 TI - Rheumatoid arthritis: an example of ecological succession? PMID- 11622358 TI - Hospital history in Canada and the United States. PMID- 11622357 TI - In view of the body of Job Broom: a glimpse of the medical knowledge and practice of John Rolph. PMID- 11622359 TI - [Not Available]. PMID- 11622360 TI - [Not Available]. PMID- 11622361 TI - [Not Available]. PMID- 11622362 TI - [Not Available]. PMID- 11622363 TI - [Not Available]. PMID- 11622364 TI - [Not Available]. PMID- 11622365 TI - The epidemiologic transition and morbidity. PMID- 11622366 TI - [Not Available]. PMID- 11622367 TI - Women's position, family and fertility decline in Parral (Mexico) 1777-1930. PMID- 11622368 TI - Breast feeding and sexual intercourse in medieval Norway. PMID- 11622369 TI - [Not Available]. PMID- 11622370 TI - [Not Available]. PMID- 11622371 TI - [Not Available]. PMID- 11622373 TI - Food and drug regulation under the USDA, 1906-1940. PMID- 11622372 TI - The eleventh commandment: sex and spirit in Wollstonecraft and Malthus. PMID- 11622374 TI - Sir John Colbatch and Augustan medicine: exerimentalism, character and entrepreneurialism. PMID- 11622375 TI - The foundation of the first modern chemical laboratories in Yugoslav countries. PMID- 11622376 TI - The development of biology in Russia in the first half of the 19th century. PMID- 11622377 TI - Specificity in the era of Koch and Ehrlich: a generalized interpretation of Ludwik Fleck's 'serological' thought style. PMID- 11622378 TI - Empty signs: Reading the book of nature in Renaissance science. PMID- 11622379 TI - Letters from abroad to Professor dr. med. Bernhard Bang, Copenhagen. PMID- 11622380 TI - [Not Available]. PMID- 11622381 TI - [Dr. Manuel Martinez Solorzano, life and works]. PMID- 11622382 TI - On social history of psychology in Brazil. PMID- 11622383 TI - The historic photographs collection of the Royal Pharmaceutical Society of Great Britain. PMID- 11622384 TI - T. N. R. Morson and his scientific friends. PMID- 11622385 TI - [Albert Claude and the early stages of modern cell biology]. PMID- 11622386 TI - Art and spine. PMID- 11622387 TI - [Not Available]. PMID- 11622388 TI - [Who was Herophilos?]. PMID- 11622389 TI - [Not Available]. PMID- 11622390 TI - [A cesarean in 1869: twenty days to die]. PMID- 11622391 TI - [Not Available]. PMID- 11622392 TI - The visionary experiences of John Humphrey Noyes. PMID- 11622393 TI - A non-oedipal Rex in early modern France. PMID- 11622394 TI - Historical questions in hazardous waste management. PMID- 11622395 TI - 'In her vapours ... [or] indeed in her madness'? Mrs Clerke's case: an early eighteenth century psychiatric controversy. PMID- 11622396 TI - A theory of hallucinations. PMID- 11622397 TI - Mania, hysteria and gender in Lower Austria, 1891-1905. PMID- 11622399 TI - "The Snow Man": nausea or numin? PMID- 11622398 TI - Hysteria and its historiography: the future perspective. PMID- 11622400 TI - Roundtable: historians and the Webster case. PMID- 11622401 TI - Archibald Menzies MD, FLS (1754-1842), aspects of his life, travels and collections. PMID- 11622402 TI - St Petersburg to Edinburgh--Matthew Guthrie's introduction of medicinal plants in the context of Scottish-Russian natural history exchange. PMID- 11622403 TI - Philip Miller's resignation from the Chelsea physic garden. PMID- 11622404 TI - Enterprise in botany: Van Reede and his Hortus malabaricus--Part l. PMID- 11622405 TI - A letter of Andrea Cesalpino. PMID- 11622407 TI - Enterprise in botany: Van Reede and his Hortus malabaricus--part II. PMID- 11622408 TI - How to "grow" a natural history museum: the building of colonial collections, 1850-1900. PMID- 11622406 TI - The natural history society in Britain through the years. PMID- 11622410 TI - Medicine in context: a review essay of the history of medicine. PMID- 11622409 TI - Socialist institutions and family wealth flows reversal: an assessment of post revolutionary Chinese rural fertility. PMID- 11622411 TI - Conflict and consensus: explaining the British Health Service. PMID- 11622412 TI - Cohort parity analysis and fertility transition dynamics: reconstructing historical trends in fertility control from a single census. PMID- 11622413 TI - The case of the crippled blockholer: miners, managers, and talk about early twentieth-century industrial accidents. PMID- 11622415 TI - Medical manuscripts of Qutub Shahi period in the libraries of Hyderabad. PMID- 11622414 TI - The patron-gods of health and of longevity, Chinese, Greek and Indian. PMID- 11622416 TI - Heart disease in Ayurveda III: a historical perspective. PMID- 11622417 TI - [Not Available]. PMID- 11622418 TI - [Not Available]. PMID- 11622419 TI - [Not Available]. PMID- 11622420 TI - [Not Available]. PMID- 11622421 TI - [Not Available]. PMID- 11622422 TI - [Not Available]. PMID- 11622423 TI - [Not Available]. PMID- 11622424 TI - [Not Available]. PMID- 11622425 TI - Occupational illnesses to be compensated, or worker's diseases to be eradicated? PMID- 11622426 TI - [Not Available]. PMID- 11622427 TI - [Not Available]. PMID- 11622428 TI - [Not Available]. PMID- 11622429 TI - [Not Available]. PMID- 11622430 TI - [Not Available]. PMID- 11622431 TI - [Not Available]. PMID- 11622432 TI - [Not Available]. PMID- 11622433 TI - [Not Available]. PMID- 11622434 TI - [Not Available]. PMID- 11622435 TI - Reform and the languages of renaissance theoretical medicine: Harvey versus Fernel. PMID- 11622436 TI - Physics and the emergence of molecular biology: a history of cognitive and political synergy. PMID- 11622437 TI - Charles Darwin PMID- 11622438 TI - Essay review: Russian Darwinism. PMID- 11622439 TI - A redefinition of Boyle's chemistry and corpuscular philosophy. PMID- 11622440 TI - W. T. Astbury, Rosie Franklin, and DNA: a memoir. PMID- 11622441 TI - The philosophy of Islamic medicine and its relevance to the modern world. PMID- 11622442 TI - Islam and the philosophy of science. PMID- 11622443 TI - On the discovery of leukaemia, or should it be leucocythaemia? PMID- 11622444 TI - The neglect of female children and childhood sex ratios in nineteenth-century America: a review of the evidence. PMID- 11622445 TI - Lewis Henry Morgan and the prohibition of cousin marriage in the United States. PMID- 11622446 TI - Out of wedlock childbearing in an ante-bellum southern county. PMID- 11622447 TI - St. Augustine: "common man" or "intuitive psychologist"? PMID- 11622448 TI - Unnatural child death among Christians and Jews in medieval England. PMID- 11622449 TI - Variances in meaning in discovery accounts: the case of contemporary biology. PMID- 11622450 TI - From neurosis to narrative: the private life of the nerves in Villette and Daniel Deronda. PMID- 11622451 TI - Graphic understanding: instruments and interpretation in Robert Hooke's Micrographia. PMID- 11622452 TI - Mechanical and "organical" models in seventeenth-century explanations of biological reproduction. PMID- 11622453 TI - Science as receptor of technology: Paul Ehrlich and the synthetic dyestuffs industry. PMID- 11622454 TI - Chinese intellectuals and science: a history of the Chinese Academy of Sciences (CAS). PMID- 11622455 TI - Alfred Maury and the politics of the unconscious in nineteenth-century France. PMID- 11622456 TI - Wagner-Jauregg's contribution to the study of cretinism. PMID- 11622457 TI - Edinburgh's poet laureate: Robert Fergusson's illness reconsidered. PMID- 11622458 TI - The nuclear symptom of schizophrenia and the praecoxfeeling. PMID- 11622459 TI - John Hunter, Everard Home and the establishment of the London Veterinary College. PMID- 11622460 TI - C. O. Jensen, March 18th 1864-September 3rd 1934: a biography. PMID- 11622461 TI - [Not Available]. PMID- 11622462 TI - Hadassah and the nursing connection: early days. PMID- 11622463 TI - Hermann von Helmholtz: the problem of Kantian influence. PMID- 11622464 TI - The 'Glasgow School' of Paton, Findlay and Cathcart: conservative thought in chemical physiology, nutrition and public health. PMID- 11622465 TI - The interface of natural theology and science in the ethology of W. H. Thorpe. PMID- 11622466 TI - Darwin, Wallace, and Huxley, and Vestiges of the natural history of creation. PMID- 11622467 TI - The interaction of science and world view in Sir Julian Huxley's Evolutionary biology. PMID- 11622468 TI - Sewall Wright's place in twentieth-century biology. PMID- 11622469 TI - Isaac Sprague, "Delineator and naturalist." PMID- 11622470 TI - Pierre-Joseph Macquer. PMID- 11622471 TI - Receptarum sinensium liber of Michael Boym. PMID- 11622473 TI - Sources for ancient Indian literature on veterinary sciences. PMID- 11622472 TI - The venetian plague. PMID- 11622474 TI - Rural folk prescriptions: plea for search of scientific content. PMID- 11622475 TI - Pharmacy in ancient India. PMID- 11622476 TI - Breeding practices and selection criteria for domestication of animals. PMID- 11622477 TI - Administrative recommendation in regard to upkeeping, health, and management of animals in ancient India. PMID- 11622478 TI - Possibilities of relating modern veterinary science literature to the growth of relevant knowledge in ancient India. PMID- 11622479 TI - Historical background and analysis of scientific content of ancient Indian literature on practices for the treatment of diseases of domestic animals. PMID- 11622480 TI - Antimicrobial agents used in ancient India. PMID- 11622481 TI - Scope of study of veterinary science literature in ancient India. PMID- 11622482 TI - Method of science used in past India and its relevance to present day context. PMID- 11622483 TI - Medieval transmission of alchemical and chemical ideas between India and China. PMID- 11622484 TI - History of cinnabar as drug, the natural substance and the synthetic product. PMID- 11622485 TI - Perfumery in ancient India. PMID- 11622486 TI - Introducing the history of emotion. PMID- 11622487 TI - Some comments on the history of emotion. PMID- 11622488 TI - Cultural history, the construction of subjectivity and Freudian theory: a critique of Carol and Peter Stearns' proposal for a new history of the emotions. PMID- 11622489 TI - Sexual underworlds: Eros, lust, and love in the Enlightenment. PMID- 11622490 TI - Public institution and private relationship: marriage and marriage guidance, 1920 1968. PMID- 11622491 TI - William Hammond and his enemies. PMID- 11622492 TI - The arthritis of Peter Paul Rubens as a perspective of his time. PMID- 11622493 TI - The syringe. PMID- 11622494 TI - Moses Maimonides the physician. PMID- 11622495 TI - Black health on the plantation: masters, slaves, and physicians. PMID- 11622496 TI - The Lensgraf chiropractors: three generations of practitioners. PMID- 11622497 TI - Following D. D. Palmer to the West Coast: the Pasadena connection, 1902. PMID- 11622498 TI - Rationalism and empericism vs. the philosophy of science in chiropractic. PMID- 11622500 TI - [A sketch on the pre-modern and modern history of pharmaceutical science and technology in the East and the West. I.] (Jpn). PMID- 11622499 TI - The man, the book, the lessons: the chiropractor's adjuster, 1910. PMID- 11622501 TI - [A consideration on the imports of Chinese crude drugs of China grown for general use in the Meiji era 3. Especially on the transition of rhubarb import in the third period: its quality and price] (Jpn). PMID- 11622502 TI - [The analects of Hajime Hoshi (No. 2)] (Jpn). PMID- 11622503 TI - [Early European influences on Japanese pharmacy-as example, the reception of a textbook written by Joh. Barth. Trommsdorff] (Jpn). PMID- 11622504 TI - [Evidence of the ginseng culture at Sakanashi, Aso] (Jpn). PMID- 11622506 TI - [A study on newly found Chinese materia medica (ben-cao) of the "Xiaopin Fang" (Vol. 11)--on its original style and herbological value] (Jpn). PMID- 11622505 TI - [Studies on the crude drug "woniu" (I) Historical and herbological studies and investigations on the specimens on Dongbei Market, China] (Jpn). PMID- 11622507 TI - [Ginkou Kishida who devoted himself to medical world early in Meiji era] (Jpn). PMID- 11622508 TI - [The seikisui was eyewater in Japan in the Meiji era] (Jpn). PMID- 11622509 TI - [Ceiling painting of plants in shrines and temples in Okayama Prefecture (Part 2) Painting of coffering in Nishinobo and Shorenji] (Jpn). PMID- 11622510 TI - [Progress of pharmaceutics in the textbooks] (Jpn). PMID- 11622512 TI - [The transition of iodine and its preparations in Japanese pharmacopoeia (between JP I and JP XI)] (Jpn). PMID- 11622511 TI - [A consideration on the pharmacy in ancient Greece--concerning IX book of Theophrastus' Historia plantarum] (Jpn). PMID- 11622513 TI - [History of dispensing pharmacy in the Showa Age (1926-1989)] (Jpn). PMID- 11622514 TI - [A consideration on the imports of Chinese crude drugs of China grown for general use in the Meiji era. 2. Especially on the transition of rhubarb import in the second period: its quality and price] (Jpn). PMID- 11622515 TI - [The life of Ryoonzenzi who made "kintaien"] (Jpn). PMID- 11622516 TI - [The advertisement of "seikisui" and discussion about the patent medicine"] (Jpn). PMID- 11622517 TI - [The discovery of tuberculin--a talk of the beginning] (Jpn). PMID- 11622518 TI - [The way for carrying medicine and its containers (i) "Inro"] (Jpn). PMID- 11622519 TI - [Philological studies on the history of the separation of medical practice and drug dispensing in Japan (I) Study on the historical change of activity of the separation of medical practice and drug dispensing] (Jpn). PMID- 11622520 TI - [Philological studies on the history of the separation of medical practice and drug dispensing in Japan (II) The bibliographic items and contents of the books related to the separation of medical practice and drug dispensing] (Jpn). PMID- 11622521 TI - [A consideration on the import of Chinese crude drugs of China grown for general use in the Mejii era (4) Especially on the transition of rhubarb import in the fourth period: its quality and price] (Jpn). PMID- 11622522 TI - [On the tablet of "Ban-ji-en," the herbal garden of the fief of Hosokawa, Higo] (Jpn). PMID- 11622523 TI - A few facts of historical interest relating to diabetes mellitus. PMID- 11622524 TI - Milgram's shocking experiments; a case in the social construction of 'science'. PMID- 11622525 TI - [Not Available]. PMID- 11622526 TI - [Music and medicine: F. X. Cid and his "tarantismo observado en Espana" (1787)]. PMID- 11622527 TI - Measurement for a votive candle: a rite of healing. PMID- 11622528 TI - [Not Available]. PMID- 11622529 TI - The sickness experience of the Josselins' children. PMID- 11622530 TI - John Leyden, physician, poet and linguist. PMID- 11622531 TI - William Pulteney Alison. PMID- 11622532 TI - The Jews in medicine in Scotland, Part II. PMID- 11622534 TI - Infants, children and death in medieval Muslim society. PMID- 11622533 TI - The Skeleton and the rhinoceros. PMID- 11622535 TI - Eighteenth-century medical practice: a case study of Bradford Wilmer, surgeon of Coventry, 1737-1813. PMID- 11622536 TI - An inexact science: the statistics of tuberculosis in late nineteenth-century France. PMID- 11622537 TI - The limits of government patronage of science: social hygiene and the Soviet state, 1920-1930. PMID- 11622538 TI - The social history of health in France: a survey of recent developments. PMID- 11622539 TI - Public virtues and private vices?: some recent literature on health care systems. PMID- 11622540 TI - The movement of scientific knowledge from and to Germany under national Socialism. PMID- 11622541 TI - The culture of effective science: Japan and the United States. PMID- 11622542 TI - Ideas on heredity in Greek and Roman antiquity. PMID- 11622543 TI - [Not Available]. PMID- 11622545 TI - Stephanus of Alexandria: pharmaceutical notions and cosmology in his alchemical work. PMID- 11622544 TI - Christoph Bergner: the last Prague alchemist. PMID- 11622546 TI - Canadian university presses and the publishing of history of medicine PMID- 11622547 TI - Military surgical practice and the advent of gunpowder weaponry. PMID- 11622548 TI - Medicine and the goodness of war. PMID- 11622549 TI - Scurvy and Canadian exploration. PMID- 11622550 TI - Ancient texts and the historian. PMID- 11622551 TI - Bovell's obstetrical set. PMID- 11622553 TI - Lunatics and the state in Georgian England. PMID- 11622552 TI - Mortality gradients and disease exchanges: comparisons from old England and colonial America. PMID- 11622554 TI - Medicine and religion in pre-Revolutionary France: introduction. PMID- 11622555 TI - The Brothers of Charity and the mentally ill in pre-Revolutionary France. PMID- 11622556 TI - Sisters of Charity and the ailing poor. PMID- 11622557 TI - Sex and the historians: some recent literature on the construction and policing of sexuality. PMID- 11622558 TI - Rethinking the politics of child abuse. PMID- 11622559 TI - The teaching of medical history and education for change. PMID- 11622560 TI - AIDS and the historian. PMID- 11622561 TI - Alfonso Cossa (1833-1902), a self-taught Italian chemist. PMID- 11622562 TI - Alchemy, magic, poisons and the virtues of stones in the old Russian Secretum secretorum. PMID- 11622563 TI - Sex and gestation, the union of opposites in European and Chinese alchemy. PMID- 11622564 TI - Ideology and experience: public health nursing and the Ontario Rural Child Welfare Project, 1920-25. PMID- 11622565 TI - Social class and health care in a community institution: the case of Hamilton City Hospital. PMID- 11622566 TI - The Magic mountain--a time capsule of tuberculosis treatment in the early twentieth century. PMID- 11622567 TI - [Not Available]. PMID- 11622568 TI - Rural medical practice in the smelter West, 1898-1923: a case-study comparison. PMID- 11622569 TI - Joseph Janse: the formative years of a chiropractic educator, 1897-1930. PMID- 11622570 TI - Merger almost: ICA unity efforts and formation of the American Chiropractic Association. PMID- 11622571 TI - Selling the "big idea": B. J. Palmer ushers in the Golden Age, 1906-1920. PMID- 11622572 TI - The limits of medical dominance: pre-World War II chiropractic in Utah. PMID- 11622574 TI - Age patterns of mortality in London during the 'long eighteenth century': a test of the 'high potential' model of metropolitan mortality. PMID- 11622573 TI - Historians as demonologists: the myth of the midwife-witch. PMID- 11622575 TI - 'Dear old mother Levy's': the Jewish maternity home and Sick Room Helps Society, 1895-1939. PMID- 11622576 TI - Medicine and visual culture. PMID- 11622577 TI - Private clinics in Central Europe 1850-1933. PMID- 11622578 TI - The Contagious Diseases Act reconsidered. PMID- 11622579 TI - The early discovery of Freud by the British general educated public, 1912-1919. PMID- 11622581 TI - Historical development of the hospital system in Germany. PMID- 11622580 TI - Medical practitioners in medieval England. PMID- 11622582 TI - Abstracts of medico-historical articles in Hindi journals. PMID- 11622583 TI - Mukhzan-e-Ayurveda. PMID- 11622584 TI - Medicine under the royal patronage of Asafia kings. PMID- 11622585 TI - Waters and spas in the classical world. PMID- 11622586 TI - Spas and sensibilities: Darwin at Malvern. PMID- 11622587 TI - Arthur Stanley Wohlmann, the first government balneologist in New Zealand. PMID- 11622588 TI - The contradictions of specialization: rheumatism and the decline of the spa in inter-war Britain. PMID- 11622589 TI - "In this our lightye and learned tyme": Italian baths in the era of the Renaissance. PMID- 11622590 TI - The development of the spa in seventeenth-century France. PMID- 11622592 TI - Physicians, chemists, and the analysis of mineral waters: "The most difficult part of chemistry." PMID- 11622591 TI - A sword in a madman's hand: professional opposition to popular consumption in the waters literature of southern England and the Midlands, 1570-1870. PMID- 11622593 TI - Chemistry, medicine, and the legitimization of English spas, 1740-1840. PMID- 11622594 TI - A trial of the Bath Waters: the treatment of lead poisoning. PMID- 11622595 TI - Interacting with other worlds: a review of books from the Park Ridge Center. PMID- 11622597 TI - Annotated bibliography. PMID- 11622596 TI - Pharmacy in Manchester pre the Pharmaceutical Society. PMID- 11622598 TI - Isolated erosions in antiquity: the hole truth. PMID- 11622599 TI - The rehydration of coprolites using trisodium phosphate solution: color reaction and smell. PMID- 11622600 TI - Medicine, genetics and art. PMID- 11622601 TI - The Alexander Blackhall-Morison Collection. PMID- 11622602 TI - Iron in the soul. PMID- 11622603 TI - Expectation, modelling and assent in the history of optics: part I. Alhazen and the medieval tradition. PMID- 11622604 TI - On the identity of Jacques du Moulin, F.R.S. 1667. PMID- 11622605 TI - E. G. Boring's review of Brigham's A study of American intelligence: a case-study in the politics of reviews. PMID- 11622606 TI - Levers and counterweights: a laboratory that failed to raise the world. PMID- 11622607 TI - Dublin's demography in the early nineteenth century: evidence from the Rotunda. PMID- 11622608 TI - Regional inequalities in infant mortality in Britain, 1861-1971: patterns and hypotheses. PMID- 11622609 TI - Canada balsam. PMID- 11622610 TI - History of science and technology today in Spain. PMID- 11622612 TI - The museum of the Royal Pharmaceutical Society of Great Britain. PMID- 11622611 TI - The role of fear: transitions in American emotional standards for children, 1850 1950. PMID- 11622613 TI - The chaste tree: Vitex agnus castus. PMID- 11622614 TI - Emblems of Polish pharmacies. PMID- 11622615 TI - Illicit price of cocaine in two eras: 1908-14 and 1982-89. PMID- 11622616 TI - Historical images of the drug market--XXIX (continued periodically). PMID- 11622617 TI - Agatha Christie's helpful and harmful health providers: writings on physicians and pharmacists. PMID- 11622619 TI - [The enlightenment of history of modern Chinese pharmaceutics] (Chi). PMID- 11622618 TI - Cachous: their containers and promotion (accompanied by a catalogue of known embossed cachou boxes). PMID- 11622620 TI - [Medical application of meloe and mylabn's in ancient China with textual research] (Chi). PMID- 11622621 TI - [A primary study on the history of ancient West-Asia and Egypt's pharmacy] (Chi). PMID- 11622622 TI - [A short history of pharmaceutical ethics in foreign countries] (Chi). PMID- 11622623 TI - [Study on Internal classics of yellow emperor by the Qing Confucians and its influence on medical professional in China and Japan] (Chi). PMID- 11622624 TI - [A brief history of keeping health and longevity in China in the period 1367 1946] (Chi). PMID- 11622625 TI - [On the laws of Sun Simiao's medical thought] (Chi). PMID- 11622626 TI - [The Public Health Organization of the Republic of China in 1912-1949] (Chi). PMID- 11622627 TI - [A sketch of the history of Red Army's Hospital in the Minxi Soviet area (established during the Second Revolutionary Civil War period in western Fujian Province, 1929-1934)] (Chi). PMID- 11622628 TI - [The establishment of TCM Study Society in the Harbin, China] (Chi). PMID- 11622629 TI - [The brief biography of Gong Naiquan, a brilliant physician in modern China] (Chi). PMID- 11622631 TI - [A historical review of medical and health work in Liaoning Province (1881-1949)] (Chi). PMID- 11622630 TI - [The historical material of plague epidemic in northern Hainan Island, China] (Chi). PMID- 11622632 TI - [The medical and health organization in Shaanxi Province (1931-1949) (Chi)]. PMID- 11622633 TI - [Research on certain problems of nursing in China in the early period of its development] (Chi). PMID- 11622634 TI - [On Yang Ze-ming's philosophical study of Canon of medicine] (Chi). PMID- 11622635 TI - [Chen Lian-fang, a famous physician of traditional Chinese medicine in modern times] (Chi). PMID- 11622636 TI - [Some doubts about Liu Kui as a great scholar who expounded plague] (Chi). PMID- 11622637 TI - [A preliminary study of acupuncture in The four medical tantras (rGyud-bzhi)] (Chi). PMID- 11622638 TI - [A study of Zambaldorz, a celebrated Mongolian physician and pharmacist in the Qing Dynasty] (Chi). PMID- 11622639 TI - [On the medical theories of the book Chashira circulating among Yi nationality in Yunnan Province] (Chi). PMID- 11622640 TI - [Medical books printed in Anhui during the Ming and Qing Dynasties and their medical historical value] (Chi). PMID- 11622641 TI - [Textual research on illustration for hiding afterbirth, the silk writing unearthed in Mawangdui] (Chi). PMID- 11622642 TI - [Chen Bangxian and Chinese historiography] (Chi). PMID- 11622643 TI - [Health and disease prevention work in the Army of North China during the liberation war (1946-49)] (Chi). PMID- 11622644 TI - [The struggle for regaining the right of quarantine] (Chi). PMID- 11622645 TI - [A preliminary investigation into the factors influencing the outbreak and spread of epidemics in ancient China] (Chi). PMID- 11622646 TI - [A historical review of fontanel diagnosis] (Chi). PMID- 11622647 TI - [On the academic contention of representative physicians of the Jin-Yuan period] (Chi). PMID- 11622648 TI - [On Huang Zunxian's research in Japanese medical history] (Chi). PMID- 11622649 TI - [The history of march hemoglobinuria] (Chi). PMID- 11622650 TI - [A survey of traditional medicine of the She nationality in Eastern Fujian] (Chi). PMID- 11622651 TI - [Ancient Roman pharmacy and its contribution] (Chi). PMID- 11622652 TI - [A review of development of surgery in German-speaking area, Europe] (Chi). PMID- 11622653 TI - [Preliminary research on the extant literatures of massage and tuina] (Chi). PMID- 11622654 TI - [Secret recipes for wounds and fractures bequeathed by deity, a monograph not written in the Tang Dynasty] (Chi). PMID- 11622656 TI - ["Sise" disease in medicine of Yi nationality] (Chi). PMID- 11622655 TI - [A brief biography of mKhyenrab Norbu, the great master of Tibetan medicine and astronomic-mathematics] (Chi). PMID- 11622657 TI - [Application and development of first-aid techniques in battle injuries of the PLA during the period of liberation war] (Chi). PMID- 11622658 TI - [China's education on medical laboratory during 1949-1987] (Chi). PMID- 11622660 TI - [On Lu Yuaniei's academic thinkings] (Chi). PMID- 11622659 TI - [The "Medical Pursuits Society" in Guangdong] (Chi). PMID- 11622661 TI - [Exploration on the chrono-medical thoughts in medical books unearthed in Mawangdui] (Chi). PMID- 11622663 TI - The career of John Watts, apothecary. PMID- 11622664 TI - Early advertising and media (Part one). PMID- 11622665 TI - Early advertising and media. PMID- 11622666 TI - [Not Available]. PMID- 11622667 TI - The epidemic or pandemic of influenza in 1708-1709. PMID- 11622668 TI - [Not Available]. PMID- 11622669 TI - [Not Available]. PMID- 11622670 TI - [Not Available]. PMID- 11622671 TI - [Not Available]. PMID- 11622672 TI - [Not Available]. PMID- 11622673 TI - [Not Available]. PMID- 11622674 TI - [Not Available]. PMID- 11622675 TI - [Not Available]. PMID- 11622676 TI - [Not Available]. PMID- 11622677 TI - [Not Available]. PMID- 11622678 TI - [Not Available]. PMID- 11622679 TI - [Not Available]. PMID- 11622680 TI - [Not Available]. PMID- 11622681 TI - [Not Available]. PMID- 11622682 TI - [Not Available]. PMID- 11622683 TI - [Not Available]. PMID- 11622684 TI - [Not Available]. PMID- 11622685 TI - [Not Available]. PMID- 11622687 TI - [Not Available]. PMID- 11622686 TI - [Not Available]. PMID- 11622688 TI - [Not Available]. PMID- 11622689 TI - [Not Available]. PMID- 11622690 TI - [Not Available]. PMID- 11622691 TI - Edwin Klebs' criteria for disease causality. PMID- 11622692 TI - [Not Available]. PMID- 11622693 TI - Ancient veterinary medicine. A survey of Greek and Latin sources and some recent scholarship. PMID- 11622694 TI - The innate heat in Galen. PMID- 11622695 TI - [The Arab author of the Liber de Coitu and the mode of working of Constantine the African]. PMID- 11622696 TI - [Not Available]. PMID- 11622697 TI - [Not Available]. PMID- 11622698 TI - [Not Available]. PMID- 11622699 TI - [Not Available]. PMID- 11622701 TI - [Not Available]. PMID- 11622700 TI - [Not Available]. PMID- 11622702 TI - [Not Available]. PMID- 11622703 TI - [Not Available]. PMID- 11622704 TI - [Not Available]. PMID- 11622705 TI - Newsletter. PMID- 11622706 TI - Whewell's developmental psychologism: a Victorian account of scientific progress. PMID- 11622707 TI - The germs of a new enlightenment. PMID- 11622708 TI - The eighteenth Brumaire of Bruno Latour. PMID- 11622710 TI - [Not Available]. PMID- 11622709 TI - Expectation, modelling and assent in the history of optics--II. Kepler and Descartes. PMID- 11622711 TI - Animal wealth and health in ancient Egypt. PMID- 11622712 TI - The manufacture and marketing of veterinary products from 1850-1914. PMID- 11622714 TI - Slaughtering methods and equipment. PMID- 11622713 TI - The veterinary profession and the RSPCA. The first fifty years. PMID- 11622715 TI - Notes on balling guns. PMID- 11622716 TI - The origins of virus research at Pirbright. PMID- 11622717 TI - Hunting vets. PMID- 11622718 TI - [The Institute for Infectious Diseases under the jurisdiction of the Ministry of Home Affairs] (Jpn). PMID- 11622720 TI - [History of studies on the motility of alimentary tracts] (Jpn). PMID- 11622719 TI - [A bibliographical study of the "Jingui Yaolue" (2)--The "Xinbian Jingui Yaolue Fanglum" published by an anonymous person in the Ming dynasty and its related editions] (Jpn). PMID- 11622721 TI - [On the actual conditions of medical care during the Nara Era] (Jpn). PMID- 11622722 TI - [Use of phonetic equivalents in medical history] (Jpn). PMID- 11622723 TI - [Historical materials on the medical system of Edo Shogunate (2)] (Jpn). PMID- 11622724 TI - Signs and signboards of the pharmacy. PMID- 11622725 TI - Pharmacy and radio: 1935-1960. PMID- 11622726 TI - The history of pharmacy and estates of science: institutional frameworks for drug research in America. PMID- 11622727 TI - From liquid scent to oxygen pillows: a rare specimen from Rorstrand. PMID- 11622728 TI - Domestic medical guides and the drug trade in nineteenth-century America. PMID- 11622729 TI - Medieval apothecary weights and measures: the principal units of England and France. PMID- 11622730 TI - Experiments on the identity of chiu shi (autumn mineral) in medieval Chinese pharmacopeias. PMID- 11622731 TI - Literary reflections of pharmacy--XIII: the death of a pharmacist. PMID- 11622732 TI - Early pharmaceutical glassware in New Zealand--the American influence. PMID- 11622734 TI - How to adulterate volatile oils. PMID- 11622733 TI - Golden seal in early American medical botany. PMID- 11622735 TI - St. John's wort--ancient herbal protector. PMID- 11622736 TI - Three royal medicine chests. PMID- 11622737 TI - [A childless marriage in the seventeenth century]. PMID- 11622738 TI - ["The concept of contagion" during the time immediately before bacteriology]. PMID- 11622739 TI - Two Swedish pioneering achievements in radiotherapy. PMID- 11622740 TI - [Ernst Westerlund--the doctor of Enkoping, in his time the most consulted physician in Sweden]. PMID- 11622741 TI - [From the history of oral surgery]. PMID- 11622742 TI - [The history of Crede's prophylaxis in Sweden]. PMID- 11622743 TI - [Orthodontics as specialty, an historical overview]. PMID- 11622744 TI - [Bananas and hurricanes--a fruitful medical history]. PMID- 11622745 TI - Bibliotherapy in the history of medicine and book culture. PMID- 11622746 TI - [Form and function--from Babylonian liver divination to liver surgery of today]. PMID- 11622747 TI - [On the oldest care institutions in Sweden]. PMID- 11622748 TI - [Military surgeons and body guards in the army of Charles XII, and prescriptions for their ailments]. PMID- 11622749 TI - [The first anatomical textbook in Swedish]. PMID- 11622750 TI - [Swedenborg, Linnaeus and brain research]. PMID- 11622751 TI - [Not Available]. PMID- 11622752 TI - Itinerant medical practitioners in the Dutch Republic: the case of Groningen. PMID- 11622753 TI - The book of nature: Jan Swammerdam's microscopical investigations. PMID- 11622754 TI - History of biology in the Netherlands: a historical sketch. PMID- 11622755 TI - Medical innovation or medical malpractice? Or, a Dutch physician in London: Joannes Groenevelt, 1694-1700. PMID- 11622756 TI - "Othered" matters: reconceptualizing dominance and difference in the history of sexuality in America. PMID- 11622757 TI - AIDS and the burdens of historians. PMID- 11622758 TI - Holy Harlots: prostitute saints in medieval legend. PMID- 11622759 TI - Mollies or men of mode? Sodomy and the eighteenth-century London stage. PMID- 11622760 TI - Sexual politics and public order in late eighteenth-century France: the Memoires secrets and the Correspondance secrete. PMID- 11622762 TI - Early modern syphilis. PMID- 11622761 TI - Representing the "unspeakable": William Godwin and the politics of homophobia. PMID- 11622763 TI - Saint Teresa, hysteria and Middlemarch. PMID- 11622764 TI - Nazis and drifters: the containment of radical (sexual) knowledge in two Italian neorealist films. PMID- 11622765 TI - Rubber wars: struggles over the condom in the United States. PMID- 11622766 TI - Is there a modern sexual culture in the West; or, did England never change between 1500 and 1900? PMID- 11622767 TI - The illicit love visit: an archaeology of old Norse sexuality. PMID- 11622768 TI - Peasants against nature: crossing the boundaries between man and animal in seventeenth- and eighteenth-century Sweden. PMID- 11622769 TI - Tribades on trial: female same-sex offenders in late eighteenth-century Amsterdam. PMID- 11622770 TI - The "bird in the cage" in the history of sexuality: Sir John Everett Millais and William Holman Hunt. PMID- 11622771 TI - Representations of homosexuality: an essay on cultural ontology and historical comparison. Part I. PMID- 11622772 TI - Literary fat rabbis: on the historical origins of the grotesque body. PMID- 11622773 TI - A debate on the American home: the antipolygamy controversy, 1880-1890. PMID- 11622774 TI - Representations of homosexuality: an essay on cultural ontology and historical comparison. Part II. PMID- 11622775 TI - Etching patriarchal rule: ritual dye, erotic potency, and the Moroccan monarchy. PMID- 11622776 TI - Infanticide and the juries in France, 1825-1913. PMID- 11622777 TI - Highlights of the Adler Museum collections. PMID- 11622778 TI - Medical truants - a philatelic selection. PMID- 11622779 TI - The gulf between medical practice and medical education in the Transvaal, South Africa in the 1920s-1960s. PMID- 11622780 TI - The Adelaide Hospital and the churches. PMID- 11622781 TI - [The history of forensic medicine in the Republic of China (1912-1949)] (Chi). PMID- 11622782 TI - [Research on the appelation of "doctor"] (Chi). PMID- 11622783 TI - [Exploration on east and west anatomical activities in early period] (Chi). PMID- 11622784 TI - [The developmental survey of bacteriology in Meiji period of Japan] (Chi). PMID- 11622785 TI - [Investigation on the medicine of Dong nationality in southeast Guizhou] (Chi). PMID- 11622786 TI - [Yan Chunxi and his Mastery of obstetrics] (Chi). PMID- 11622787 TI - [Textual research on Zhang Wenzhong's Prescription as cited in Secret essence of an official] (Chi). PMID- 11622788 TI - The Bloomsbury Dispensary--then and now. PMID- 11622789 TI - A book of recipes. PMID- 11622790 TI - Corollary development of the professions of veterinary medicine and human medicine in the United States. PMID- 11622791 TI - The zoocomium, or an eighteenth-century veterinary hospital. PMID- 11622792 TI - The value of history instruction in veterinary medical education. PMID- 11622793 TI - [Not Available]. PMID- 11622794 TI - The classification of mental diseases in the Ottoman medical manuscripts. PMID- 11622795 TI - [Not Available]. PMID- 11622797 TI - [Not Available]. PMID- 11622796 TI - [Not Available]. PMID- 11622798 TI - [Not Available]. PMID- 11622800 TI - [Not Available]. PMID- 11622799 TI - [Not Available]. PMID- 11622801 TI - [Not Available]. PMID- 11622802 TI - [Not Available]. PMID- 11622803 TI - [Not Available]. PMID- 11622804 TI - [Not Available]. PMID- 11622805 TI - A view on the dealers with health in the Turkish medical history. PMID- 11622806 TI - [Not Available]. PMID- 11622807 TI - [Not Available]. PMID- 11622808 TI - [Not Available]. PMID- 11622809 TI - [Not Available]. PMID- 11622810 TI - [Not Available]. PMID- 11622812 TI - [Not Available]. PMID- 11622811 TI - [Not Available]. PMID- 11622813 TI - [Not Available]. PMID- 11622814 TI - [Not Available]. PMID- 11622815 TI - A look at the topic "Ziynet" in the Canon of Ibn Sina. PMID- 11622816 TI - [Not Available]. PMID- 11622817 TI - [Not Available]. PMID- 11622818 TI - [Not Available]. PMID- 11622819 TI - [Not Available]. PMID- 11622820 TI - Dr. William Cullen and Mr. Adam Smith: a case of hypochondriasis? PMID- 11622821 TI - A life of devotion to industrial health: a tribute to one of America's great physicians--Dr. Alice Hamilton (1869-1970). PMID- 11622823 TI - Red-hair medicine: Dutch-Japanese medical relations. PMID- 11622822 TI - Contrast in the care of VIPs: the death of a president's baby and the survival of a president. PMID- 11622825 TI - Bibliography of Japanese-Netherlands medical relations by Dutch authors. PMID- 11622826 TI - "Ontleedinge" (anatomy) as underlying principle of western medicine in Japan. PMID- 11622829 TI - Dutch surgery in Japan. PMID- 11622831 TI - The introduction of acupuncture into western medicine: the influence of Japanese and Dutch physicians. PMID- 11622833 TI - The fight against smallpox in Japan. The value of western medicine proved. PMID- 11622835 TI - The influence of the Dutch on Japanese ophthalmology in the 19th century. PMID- 11622837 TI - From God to apostate: medicine in Japan before the Caspar school. PMID- 11622838 TI - JHR J.L.C. Pompe van Meerdervoort. PMID- 11622840 TI - German romantic psychiatry. Part 2. PMID- 11622839 TI - JHR J.L.C. Pompe van Meerdervoort. PMID- 11622841 TI - Some observations on the writings of Felix Platter (1536-1614) in relation to mental handicap. PMID- 11622842 TI - Chronic pain in nineteenth-century British medical writings. PMID- 11622843 TI - The story of Helene Preiswerk: a critical study with new documents. PMID- 11622844 TI - James Tilly Matthews in London and Paris 1793: his first peace mission--in his own words. PMID- 11622846 TI - The beginning of American pharmaceutical journalism. PMID- 11622845 TI - On certain peculiar diseases of old age. PMID- 11622847 TI - Jacob Bell and his trial of chloric ether at the Middlesex Hospital. PMID- 11622848 TI - The homeopathic drugstore of Riga. PMID- 11622849 TI - A pharmacy in New Zealand. PMID- 11622850 TI - "In old California"--John Wayne as a pharmacist. PMID- 11622851 TI - Ethereal epidemic: mesmerism and the introduction of inhalation anaesthesia to early Victorian London. PMID- 11622852 TI - Surveys of developments in the social history of medicine: II. Italian scholars and the social history of medicine, 1960-1990. PMID- 11622853 TI - The Jewish Maternity Home and Sick Room Helps Society, 1895-1939: a reply to Lara Marks. PMID- 11622854 TI - Ethnicity, religion and health care. PMID- 11622855 TI - AIDS and the relevance of history. PMID- 11622856 TI - The healthy city and the ecological idea. PMID- 11622857 TI - On maternal and infant mortality, 1900-1960. PMID- 11622859 TI - The people's choice: the medical schools of Belfast 'Inst' (1835-1849) and the Catholic University (1855-1908) compared. PMID- 11622858 TI - Cancer policy and the health system in France: "big medicine" challenges the conception and organization of medical practice. PMID- 11622860 TI - Annotated bibliography [of paleopathology]. PMID- 11622861 TI - Case reports on paleopathology. PMID- 11622862 TI - Galen on Archimedes: burning mirror or burning pitch? PMID- 11622863 TI - "Underground Manchester" at the greater Manchester Museum of Science and Industry. PMID- 11622864 TI - "Enemies of the race": biologism, environmentalism, and public health in Edwardian England. PMID- 11622865 TI - Science in the American South through the eyes of four natural historians, 1750 1850. PMID- 11622866 TI - A newly discovered Guy de Chauliac manuscript. PMID- 11622867 TI - The John Abercrombie Collection. PMID- 11622868 TI - The Scottish Women's Hospital at the French Abbey of Royaumont. PMID- 11622869 TI - Reminiscences of a physician in southern Africa. PMID- 11622870 TI - [Not Available]. PMID- 11622871 TI - The determinants of local variations in fertility in Bas-Languedoc and Roussillon during the mid-nineteenth century. PMID- 11622872 TI - [Not Available]. PMID- 11622873 TI - [Not Available]. PMID- 11622874 TI - [Not Available]. PMID- 11622875 TI - [Not Available]. PMID- 11622876 TI - [Not Available]. PMID- 11622877 TI - Demographic history and the political economy of war in western Europe, 1914 1918. PMID- 11622878 TI - [Not Available]. PMID- 11622879 TI - [Not Available]. PMID- 11622880 TI - [Not Available]. PMID- 11622882 TI - [Not Available]. PMID- 11622881 TI - [Not Available]. PMID- 11622883 TI - [Not Available]. PMID- 11622884 TI - General practice pharmacy in the 1840's. PMID- 11622886 TI - Early advertising and media. PMID- 11622888 TI - A page from a counter day book dated 1821. PMID- 11622887 TI - Early advertising and media. (Part two). PMID- 11622889 TI - A page from a counter day book dated 1821. PMID- 11622890 TI - The evolution of child health care in far northern Australia. PMID- 11622891 TI - Domestic medicine in colonial Queensland. PMID- 11622892 TI - Dr L. L. Smith's entrepreneurial medical practice in Victorian Melbourne. PMID- 11622893 TI - Death and the man midwife in eighteenth-century Britain. PMID- 11622894 TI - The Emperor's physician. PMID- 11622896 TI - Insights and experiments in development of neurophysiological thought. PMID- 11622895 TI - Interpreting the medical culture. PMID- 11622897 TI - BCG vaccination: comparative perspectives. PMID- 11622898 TI - Sir Neil Hamilton Fairley, drug resistant malaria and the myth of massive infection in Malaya 1947-63. PMID- 11622899 TI - Some stages in the understanding of the relationship between body, brain and mind. PMID- 11622900 TI - The enigma of 'Bea' Miles. PMID- 11622901 TI - Body 'music': an essay on the medical semiology of sounds. PMID- 11622902 TI - The Kanematsu Institute 1933-1982. PMID- 11622903 TI - Thomas Fiaschi and Listerian antisepsis in Sydney 1880-1900. PMID- 11622904 TI - Inert and blundering practitioners? A Scottish approach to quantitative history. PMID- 11622905 TI - Vocational medical colleges in Australia and New Zealand: a latter-day phenomenon. PMID- 11622906 TI - Quarantine during the smallpox epidemic in Sydney, 1881-82. PMID- 11622907 TI - Semmelweis: a reappraisal. PMID- 11622908 TI - Bubonic plague in Australia after 1900--enzootic foci or non-indigenous intrusion. PMID- 11622909 TI - The politics of medical administration II: Frederic Truby King and the Seacliff Asylum. PMID- 11622910 TI - Epidemics and power: Weil's disease in North Queensland, 1929-39. PMID- 11622911 TI - Australia and New Zealand in the 1918-19 influenza pandemic. PMID- 11622912 TI - Historiographical trends in the history of medicine: an editor's perspective. PMID- 11622913 TI - Mortality on convict voyages 1787-1820: whose responsibility? PMID- 11622914 TI - Infant survival and the baby health movement. PMID- 11622916 TI - Nietzsche and Freud: two voices from the underground. PMID- 11622915 TI - Realism and simplicity in the Castle-East debate on the stability of the hereditary units: rhetorical devices versus substantive methodology. PMID- 11622917 TI - Disclosure and secrecy among gay men in the United States and Canada: a shift in views. PMID- 11622919 TI - The condom in modern and postmodern culture. PMID- 11622920 TI - Trends, age patterns and differentials in childhood mortality in Haiti (1960 1987). PMID- 11622921 TI - The centenarian question: old-age mortality in the Soviet Union, 1897 to 1970. PMID- 11622922 TI - On the demography of south Asian famines. Part II. PMID- 11622923 TI - Alfred Sauvy: statistician, economist, demographer and iconoclast (1898-1990). PMID- 11622924 TI - From Pasteur to parity violation: cosmic dissymmetry and the origins of biomolecular handedness. PMID- 11622925 TI - Famine and mortality crises in mid-Sussex, 1606-1640. PMID- 11622926 TI - Die Embryologie im Spannungsfeld zwischen Tradition und Empirie. PMID- 11622927 TI - Neurology in ancient India: ajna cakra-a physiological reality. PMID- 11622928 TI - Why did the scientific revolution take place in Europe and not elsewhere? PMID- 11622929 TI - Science and divine philosophy in the seventeenth century Europe. PMID- 11622930 TI - The development of the Draize test for eye toxicity. PMID- 11622931 TI - European influence on American pharmacy: Frederick Hoffman (1832-1904). PMID- 11622932 TI - Women in early twentieth-century pharmacy. PMID- 11622933 TI - Gentian--a bitter pill to swallow. PMID- 11622934 TI - Polygynous fertility: sexual competition versus progeny. PMID- 11622935 TI - A faraway look. Herbert Watkins-Pitchford and Rinderpest 1896-1912. PMID- 11622936 TI - Veterinary history on stamps. PMID- 11622937 TI - Youatt and Brunel. PMID- 11622938 TI - Situation frightful but not necessarily fatal. Rabies in eighteenth century England. PMID- 11622939 TI - Andrew Snape (1644-1708) and the beginning of veterinary anatomical instruction in England. PMID- 11622940 TI - [The fate of Ibn al-Haitham's optics: the book De aspectibus (Kitab al-Manazir) in medieval Latin]. PMID- 11622941 TI - Biotechnology in the twentieth century. PMID- 11622942 TI - Origins of the second golden age of Dutch science after 1860: intended and unintended consequences of educational reform. PMID- 11622943 TI - British women of the nineteenth and early twentieth centuries who contributed to research in the chemical sciences. PMID- 11622944 TI - 'Nature' in the laboratory: domestication and discipline with the microscope in Victorian life science. PMID- 11622945 TI - From Aldrovandi to Algarotti: the contours of science in early modern Italy. PMID- 11622946 TI - Offense against family order: infanticide in Belgium from the fifteenth through the early twentieth centuries. PMID- 11622947 TI - Sex, gender, and sexual identity in modern culture: male sodomy and female prostitution in enlightenment London. PMID- 11622948 TI - Colonizing the breast: sexuality and maternity in eighteenth-century England. PMID- 11622949 TI - Incest or survival strategy? Plebeian marriage within the prohibited degrees in Somerset, 1730-1835. PMID- 11622950 TI - Homosexual behavior in the nineteenth-century Dutch army. PMID- 11622951 TI - A tale of two fishes: magical objects in natural history from antiquity through the scientific revolution. PMID- 11622953 TI - Cash and Conscience: financing the General Hospital at Bath 1738-1750. PMID- 11622952 TI - Cooking (with) Clio and Cleo: eloquence and experiment in seventeenth-century Florence. PMID- 11622954 TI - Morbidity and mortality among early nineteenth century engineering workers. PMID- 11622955 TI - The role of medical societies in the rise of the Scottish medical profession 1730 1939. PMID- 11622956 TI - The influenza epidemic of 1918-1919 in France: contemporary concepts of aetiology, therapy, and prevention. PMID- 11622957 TI - A social health service without social doctors. PMID- 11622959 TI - Scientific instruments in Russia from the Middle Ages to Peter the Great. PMID- 11622960 TI - [Not Available]. PMID- 11622961 TI - [Who was Erasistratus?]. PMID- 11622962 TI - [Not Available]. PMID- 11622964 TI - Ibn Zuhr (Avenzoar) (1091-1162). PMID- 11622963 TI - [The dance of death and medical professions]. PMID- 11622965 TI - Dentistry in the Anglo-Boer War (1899-1902). PMID- 11622966 TI - Some aspects of Elizabethan psychiatry in two of Shakespeare's plays. PMID- 11622968 TI - Ibn Sina's psychology and Dante's Divine Comedy. PMID- 11622969 TI - The peculiarities of the Americans or Are there national styles in the sciences? PMID- 11622967 TI - Mainaduc, magic, and madness: George Cumberland and the Blake connection. PMID- 11622970 TI - The history of sexuality in context: national sexological traditions. PMID- 11622971 TI - Epistemic styles in German and American embryology. PMID- 11622972 TI - Interwar "German" psychobiology: between nationalism and the irrational. PMID- 11622973 TI - John Franklin Enders: (February 10, 1897-September 8, 1985). PMID- 11622974 TI - Medical and related museums, historic sites, and exhibits in Ontario: an annotated guide and review PMID- 11622975 TI - Cameron's search for a cure. PMID- 11622976 TI - The embodied soul in seventeenth-century French medicine. PMID- 11622977 TI - Professional aspirations and the limits of occupational autonomy: the case of pharmacy in nineteenth-century Ontario. PMID- 11622978 TI - A Hempelian explanatory shift in neuropathology: a study in the history and logic of medicine. PMID- 11622979 TI - Crisis and controversy: historical patterns in breast cancer surgery. PMID- 11622980 TI - Planning and presenting a medical exhibit: Fanshawe Pioneer Village and the Dr. William Anson Jones collection. PMID- 11622981 TI - Canada honours its first licensed woman doctor: Jeannie (Jenny) Kidd Trout (1841 1921). PMID- 11622982 TI - Somnambulism, vampirism and suicide: the life of Dr John Polidori. PMID- 11622983 TI - Lady Tarbat and the physicians: 1699. PMID- 11622984 TI - William Henry Lowe 1815-1900: 74th president of the college 1873-1875. PMID- 11622985 TI - Late nineteenth- and early twentieth-century childlessness. PMID- 11622986 TI - John Hunter--a man of his time. PMID- 11622987 TI - Wellcome and Hunter--men and museums. PMID- 11622988 TI - Cancer, cancerphobia, and culture: reflections on attitudes in the United States and Great Britain. PMID- 11622989 TI - AIDS in the UK: contemporary history and the study of policy. PMID- 11622990 TI - The sexual molestation of children: historical perspectives. PMID- 11622992 TI - Civil War nurses: our nursing heritage. PMID- 11622991 TI - Plants collected by Gedeon Bonivert (1651-1703) in the garden of Johan Stickers (1630-1701). PMID- 11622993 TI - Annotated bibliography [of Paleopathology]. PMID- 11622994 TI - Cultivating a killer virus. PMID- 11622995 TI - Children in hospital: the past and the future. PMID- 11622996 TI - Myxoedema: three early cases of interest from Dublin (1886-1893). PMID- 11622997 TI - Down a steep place into the sea: suicide in Stephen Crane's Maggie. PMID- 11622998 TI - Tomatoes as "love apples" in Ulysses. PMID- 11622999 TI - Drosophila and evolutionary genetics: the moral economy of scientific practice. PMID- 11623000 TI - Alienists on trial: conflict and convergence between psychiatry and law (1876 1913). PMID- 11623001 TI - The discourse of race and the medicalization of public and private space in modern China (1895-1949). PMID- 11623002 TI - Definition and control: Alexander Walker's trilogy on woman. PMID- 11623003 TI - Forbidden by God, despised by men: masturbation, medical warnings, moral panic, and manhood in Great Britain, 1850-1950. PMID- 11623004 TI - Sexual politics in Wilhelmine Germany: the male gender crisis, moral purity, and homophobia. PMID- 11623007 TI - The birth of the speciality of orthodontics. Part II. PMID- 11623006 TI - Discourses on and of AIDS in West Germany, 1986-90. PMID- 11623008 TI - Pathology of the temporomandibular joint and its treatment in the first half of the 19th century. Part II. PMID- 11623009 TI - Dental aspects of the Spitalfields exhumations. PMID- 11623010 TI - What is a virus? The case of tobacco mosaic disease. PMID- 11623012 TI - The treatment of war wounds by Islamic surgeons. PMID- 11623011 TI - Of mice and mastodons: contributions to the literature of mammalogy by officers and men of the United States Army in the nineteenth century. PMID- 11623013 TI - Food and drug regulation under the USDA, 1906-1940. PMID- 11623014 TI - Girolamo Cardano and the art of medical narrative. PMID- 11623015 TI - Early illustrated botanical books. PMID- 11623016 TI - Chinese versus western medicine: a history of their relations in the twentieth century. PMID- 11623017 TI - Anatometrics in ancient China. PMID- 11623018 TI - Over the borders: technical history, philosophy, and the social sciences. PMID- 11623019 TI - How adequate was hospital provision before the NHS? An examination of the 1945 South Wales hospital survey. PMID- 11623020 TI - Seasonal variation patterns in baptisms and burials for Ruislip, Middlesex. PMID- 11623021 TI - Changing disciplines: John Ryle and the making of social medicine in Britain in the 1940s. PMID- 11623022 TI - Squibs and snobs: science in humorous British undergraduate magazines around 1830. PMID- 11623023 TI - "Nothing in nature that is not useful". The anti-vaccination crusade and the idea of 'harmonia naturae' in Alfred Russel Wallace. PMID- 11623024 TI - [Not Available]. PMID- 11623025 TI - The Pomar Codex (ca, 1590): plants and animals of the old world and from the Hernandez expedition to America. PMID- 11623026 TI - [Not Available]. PMID- 11623027 TI - Shelley and science. PMID- 11623028 TI - The development of the hysterical personality. PMID- 11623029 TI - Psychiatry in ancient Indian texts: a review. PMID- 11623030 TI - The history of psychiatry in the United States: historiographic and theoretical considerations. PMID- 11623031 TI - The cult of curability and the doctrine of perfectibility: social context of the nineteenth-century American asylum movement. PMID- 11623032 TI - Insulin treatment in psychiatry. PMID- 11623033 TI - Proving the somaticist position: J. B. Friedreich on the nature and seat of mental disease. PMID- 11623034 TI - Psychiatric observations on contemporary issues. PMID- 11623035 TI - George Mora. PMID- 11623036 TI - Economic models of fertility in post-war Britain--a conceptual and statistical re interpretation. PMID- 11623037 TI - Recent mortality trends in the three Baltic republics. PMID- 11623038 TI - The medical history of John Calvin. PMID- 11623040 TI - Transplantation and cancer control: a lifetime of research. PMID- 11623039 TI - Thomas Laycock. PMID- 11623041 TI - Between fact and technique: the beginnings of hybridoma technology. PMID- 11623042 TI - What is a mutation? Identifying heritable change in the offspring of survivors at Hiroshima and Nagasaki. PMID- 11623043 TI - From Aristotle to Darwin: reflections on Ernst Mayr's interpretation in The Growth of biological thought. PMID- 11623044 TI - Charles Darwin's health problems: the allergy hypothesis. PMID- 11623045 TI - In memoriam: Louis Henry 1911-1991. PMID- 11623046 TI - William James and the noun brainstorm. PMID- 11623047 TI - Muddling in bumbledom: on the enormity of large sanitary improvements in four British towns, 1855-1885. PMID- 11623048 TI - John Gerard and his herbal. PMID- 11623052 TI - [Not Available]. PMID- 11623051 TI - Domestic medicine chests: home pharmacy in the nineteenth century. PMID- 11623053 TI - [Medicine and the symbolism of the room of the segnatura]. PMID- 11623054 TI - [From "the man with the calf's head" to "Elephant man", or the avatars of fame: a contribution to the history of neurofibromatosis]. PMID- 11623055 TI - [Not Available]. PMID- 11623056 TI - [The miserable life of the Antwerp physician Jean Carolus, friend of C. Broeckx and Ch. Daremberg: the canonical truth and the private version]. PMID- 11623057 TI - Episiotomy repair according to Shute. PMID- 11623058 TI - Tropical medicine in nineteenth-century India. PMID- 11623060 TI - Passion as "confused" perception or thought in Descartes, Malebranche, and Hutcheson. PMID- 11623059 TI - Descartes' dreams and their address for philosophy. PMID- 11623062 TI - From antigens to ultrasound: glimpses from the history of the medical faculty in Lund. PMID- 11623061 TI - [Philosophy, medicine, and Immanuel Kant]. PMID- 11623063 TI - Diabolic hiccups. PMID- 11623064 TI - [When dysentery raged in Malmo 1880-1882]. PMID- 11623065 TI - [Ura-Kaipa's skull-hole lid: Magic or therapy]. PMID- 11623066 TI - [Peter Hernquist: disciple of Linnaeus and medical doctor]. PMID- 11623067 TI - [Starvation and creativity]. PMID- 11623068 TI - [Francisco Goya: the deaf artist]. PMID- 11623070 TI - [The development of anesthesia into a medical specialty at Lund hospital]. PMID- 11623069 TI - P. Stradins museum of the history of medicine. PMID- 11623071 TI - [The plan of the abbey of St. Gall and its medical facilities (820-830 A.D.). An ideal Carolingian monastery]. PMID- 11623072 TI - [Not Available]. PMID- 11623073 TI - [Robert Schumann: his life, musical creation, and diseases]. PMID- 11623074 TI - [The snake--a powerful and paradoxical symbol]. PMID- 11623075 TI - [The auditorium of Malmo university clinics--an anatomical theater]. PMID- 11623076 TI - A select few: women and the National Research Council of Canada, 1916-1991. PMID- 11623077 TI - The NRC Postdoctorate Fellowships, 1948-1978. PMID- 11623078 TI - The National Research Council of Canada: its historiography, its chronology, its bibliography. PMID- 11623079 TI - The origins of organized Canadian medical research: the National Research Council's Associate Committee on Tuberculosis Research, 1924-1938. PMID- 11623080 TI - The associate committees on medical research of the National Research Council and the Second World War. PMID- 11623081 TI - Expansion and consolidation: the Associate Committee and the Division of Medical Research of the NRC, 1938-1959. PMID- 11623082 TI - Sir Peter Brian Medawar (28 February 1915-2 October 1987). PMID- 11623084 TI - The historical demography of the scientific community, 1450-1900. PMID- 11623085 TI - Reconstructing clinical activities: patient records in medical history. PMID- 11623086 TI - White poison? The social consequences of milk consumption, 1850-1930. PMID- 11623087 TI - Religion and health: Catholicism and regional mortality differences in nineteenth century Netherlands. PMID- 11623089 TI - The rise or fall of tuberculosis in belle-epoque France: a reply to Allan Mitchell. PMID- 11623088 TI - Marie Stopes in Ireland--the Mother's Clinic in Belfast, 1936-47. PMID- 11623090 TI - Tuberculosis statistics and the McKeown thesis: a rebuttal to David Barnes. PMID- 11623091 TI - A doctor's petition for a salaried post in Saladin's hospital. PMID- 11623092 TI - Health and medicine in the twentieth century: contemporary history and health policy. PMID- 11623093 TI - Shaping the child's personality: medical advice on child-rearing from the late eighteenth to the early twentieth century in Germany. PMID- 11623094 TI - Letters from abroad to Professor dr. med. Bernhard Bang, Copenhagen. PMID- 11623095 TI - Squares and diopters: the drawing system of a famous anatomical atlas. PMID- 11623096 TI - The programme devised in 1791 by Fourcroy for the establishment of clinical laboratories. PMID- 11623097 TI - [Not Available]. PMID- 11623098 TI - Francis Buchanan (Hamilton): physician, botanist and surveyor. PMID- 11623099 TI - Norman Henry Bethune: Canadian doctor and Chinese hero. PMID- 11623101 TI - John Dixon Comrie: his lectures and journal. PMID- 11623100 TI - The possible influence of climate on historical outbreaks of malaria in Scotland. PMID- 11623102 TI - [Not Available]. PMID- 11623103 TI - [Not Available]. PMID- 11623104 TI - [Not Available]. PMID- 11623105 TI - [Not Available]. PMID- 11623106 TI - Official medicine and customary medicine in early modern Wurttemberg: the career of Christoph Friedrich Pichler. PMID- 11623107 TI - [Not Available]. PMID- 11623108 TI - [Not Available]. PMID- 11623109 TI - [Not Available]. PMID- 11623110 TI - [Not Available]. PMID- 11623111 TI - Pietism and medical care in colonial Georgia. PMID- 11623113 TI - Rickets and the rest: child-care, diet and the infectious children's diseases, 1850-1914. PMID- 11623114 TI - Takling the 'hideous scourge': the creation of the venereal disease treatment centres in early twentieth-century Britain. PMID- 11623116 TI - Beyond National Health Insurance. The voluntary hospitals and hospital contributory schemes: a regional study. PMID- 11623115 TI - The failure of expertise: public health policy in Britain during the 1918-19 influenza epidemic. PMID- 11623117 TI - Hospital provision before the National Health Service: a geographical study of the 1945 hospital surveys. PMID- 11623118 TI - Principle versus expediency: a rejoinder to F. B. Smith. PMID- 11623119 TI - Surveys of developments in the social history of medicine: IV. The history of public health and prevention: current Swedish research. PMID- 11623120 TI - [Who are the amateurs?]. PMID- 11623121 TI - [Saviors of mothers]. PMID- 11623122 TI - Quandoque bonus dormitat Hippocrates: induced abortion and embryos' age in the Hippocratic Corpus. PMID- 11623124 TI - An outline of the infectious exchange of 1492. PMID- 11623123 TI - [Not Available]. PMID- 11623125 TI - Annotated bibliography. PMID- 11623126 TI - The mummies of the church of S. Maria della Grazia in Comiso, Sicily (18th-19th century). PMID- 11623127 TI - Dioscoride Vitali and Carlo Erba - two key figures in nineteenth century Italian pharmacy. PMID- 11623129 TI - William Stukeley (M.D.Cantab.) and the apothecaries. PMID- 11623131 TI - Wages, secondary workers, and fertility: a working-class perspective of the fertility transition in England and Wales. PMID- 11623132 TI - The first medicalization: the taxonomy and etiology of queerness in classical Indian medicine. PMID- 11623133 TI - [Not Available]. PMID- 11623134 TI - [Not Available]. PMID- 11623136 TI - [Not Available]. PMID- 11623135 TI - [Not Available]. PMID- 11623137 TI - Medals of Nobel laureates in the medal cabinet of the Semmelweis Museum of History of Medicine. PMID- 11623138 TI - [Not Available]. PMID- 11623139 TI - [Not Available]. PMID- 11623140 TI - [Not Available]. PMID- 11623141 TI - [Not Available]. PMID- 11623142 TI - [Not Available]. PMID- 11623143 TI - [Not Available]. PMID- 11623145 TI - [Not Available]. PMID- 11623144 TI - [Not Available]. PMID- 11623146 TI - Following the trend into medical history. PMID- 11623148 TI - Artists and anatomists in Renaissance Europe. PMID- 11623147 TI - Prolegomena to the psychological dimension of early modern European history. PMID- 11623149 TI - Diseases revisited, or anthrax and bovine spongiform encephalopathy. PMID- 11623150 TI - Why mammals are called mammals: gender politics in eighteenth-century natural history. PMID- 11623151 TI - [Not Available]. PMID- 11623152 TI - [Hematuria in Egypt during the pharaonic era]. PMID- 11623153 TI - The river of destiny or the near drowning of the father of American urology. PMID- 11623154 TI - [The first anesthesias in Belgium]. PMID- 11623155 TI - [Not Available]. PMID- 11623156 TI - Ankylosing spondylitis 1992: from Connor to transgenes. PMID- 11623157 TI - Graphical method and discipline: self-recording instruments in nineteenth-century physiology. PMID- 11623158 TI - Veterinary medicine in philately. PMID- 11623159 TI - OVATOOMB: other viruses and the origins of molecular biology. PMID- 11623160 TI - How bacteriophage came to be used by the Phage Group. PMID- 11623161 TI - The "light" organism for the job: green algae and photosynthesis research. PMID- 11623162 TI - Drosophila: a life in the laboratory. PMID- 11623163 TI - The old martyr of science: the frog in experimental physiology. PMID- 11623164 TI - The Wistar Rat as a right choice: establishing mammalian standards and the ideal of a standardized mammal. PMID- 11623165 TI - How the choice of experimental organism matters: epistemological reflections on an aspect of biological practice. PMID- 11623166 TI - The Dolan Brothers' prescription book: a late nineteenth-century treasury. PMID- 11623167 TI - The Herbarius of Paracelsus. PMID- 11623168 TI - Godfrey's cordial again. PMID- 11623170 TI - Cookworthy - chemist and potter. PMID- 11623171 TI - Cookworthy-chemist and potter. PMID- 11623173 TI - The history of A. H. Cox & Co. Ltd. PMID- 11623175 TI - The Edinburgh District Chemists' Trade Association: a centenary review. PMID- 11623176 TI - George H. Dadd, veterinary reformer: the Boston connection. PMID- 11623177 TI - A catalogue of English, French, Italian and German scientific instruments makers from 1750 to 1900. PMID- 11623178 TI - [Not Available]. PMID- 11623179 TI - History of science: problems and practices. History of science(s), history of mentalities, micro-history. PMID- 11623180 TI - [Not Available]. PMID- 11623181 TI - Medical philately: Nobel Prize winners between the wars. PMID- 11623182 TI - Now and then - a dental miscellany. PMID- 11623183 TI - A well-thumbed Gray's Anatomy - from father to son. PMID- 11623185 TI - Baragwanath Hospital - the beginning. PMID- 11623184 TI - 50 years ago: the discovery of streptomycin. PMID- 11623186 TI - A cornucopia of reference works for the history of Chinese medicine. PMID- 11623187 TI - Halley the Londoner. PMID- 11623188 TI - The Royal Society specimens from the Chelsea Physic Garden 1722-1799. PMID- 11623189 TI - Thomas Henry Huxley's address at the opening of the Johns Hopkins University in September 1876. PMID- 11623190 TI - The historiography of chemistry in the eighteenth century: a preliminary survey and bibliography. PMID- 11623191 TI - Case Report No. 17: Oxycephalia: an extreme case of craniosynostosis; Specimen number: 2625, Museo de Ciencias Naturales de Caracas. PMID- 11623192 TI - Livingstone's 'alternative hypothesis'. PMID- 11623193 TI - An unusual find: an ancestral variant (processus paramastoideus) in the human cranium. PMID- 11623194 TI - The chemists go to war: the mobilization of civilian chemists and the British war effort, 1914-1918. PMID- 11623195 TI - Famine, maternal nutrition and infant mortality: a re-examination of the Dutch hunger winter. PMID- 11623196 TI - The decline of mortality in England and Wales 1861 to 1964: decomposition by cause of death and component of mortality. PMID- 11623197 TI - High fertility, high emigration, low nuptiality: adjustment processes in Scotland's demographic experience, 1861-1914, Part I. PMID- 11623198 TI - Unifying biology: the evolutionary synthesis and evolutionary biology. PMID- 11623200 TI - Essay review: portraying molecular biology. PMID- 11623199 TI - Darwin on man in the Origin of Species: further factors considered. PMID- 11623201 TI - The Rockefeller Foundation and spectroscopy research: the programs at Chicago and Utrecht. PMID- 11623202 TI - Public health and political stabilisation: the Rockefeller Foundation in central and eastern Europe between the two World Wars. PMID- 11623203 TI - Biomedical research in a period of scarcity: the United States and Great Britain. PMID- 11623204 TI - "Scientists versus scholars": the prelude to Communist takeover in Hungarian science, 1945-1947. PMID- 11623207 TI - A unique ceremony in pharmaceutical history. PMID- 11623205 TI - Our great cordiall. PMID- 11623208 TI - C.R.S.: pharmacist and archaeologist. PMID- 11623210 TI - [Etiological studies on A Discourse of pathogenesis and manifestations of all diseases] (Chi). PMID- 11623209 TI - C.R.S.: pharmacist and archeologist. PMID- 11623211 TI - [Research on the Chart for acupuncture] (Chi). PMID- 11623212 TI - [On Paradigm of Shanghan, Zhang Zhongjing and Wang Shuhe] (Chi). PMID- 11623213 TI - [The Inner canon of yellow Emperor doesn't equate with Plain questions plus miraculous pivot] (Chi). PMID- 11623214 TI - [Li Shizhen's comprehensive treatment of the entry "hama" from Herbology of classified syndromes] (Chi). PMID- 11623215 TI - [The contribution of Zhang Zhongjing to iatrogenic diseases] (Chi). PMID- 11623216 TI - [Exploration on the history of Chinese free medical service system] (Chi). PMID- 11623217 TI - [The health work of allied anti-Japanese army in northeast] (Chi). PMID- 11623218 TI - [A brief history of western medical education in modern Shanghai] (Chi). PMID- 11623219 TI - [The medical contents of the ancient book of Yi nationality, On Cosmos and humanity] (Chi). PMID- 11623220 TI - [Retroactive records on medical informations of Li nationality] (Chi). PMID- 11623221 TI - [Exploration on and retrospect of the objectives and tasks of research on Chinese medical history] (Chi). PMID- 11623222 TI - [The first discovery of a Tang manuscript from Dunhuang, A scroll of simple and effective prescriptions for emergency, collected in the British Library] (Chi). PMID- 11623223 TI - [Study of the first record on the bulb of tendril-leaf fritillary] (Chi). PMID- 11623224 TI - [On the provenance and evolution of medicine in Pukui] (Chi). PMID- 11623225 TI - [A textual research on the origin and development of feigned disease] (Chi). PMID- 11623226 TI - [The life and academic thinking of Yun Tieqiao] (Chi). PMID- 11623227 TI - [A brief introduction of medical periodicals of Shaanxi] (Chi). PMID- 11623230 TI - [Progress of the study of medical history in Kyoto] (Jpn). PMID- 11623229 TI - [An introduction to the study of medical history in the provinces] (Jpn). PMID- 11623228 TI - [Medical workers in Taiwan during the period of Japanese colony] (Chi). PMID- 11623231 TI - [The first vaccination by cowpox in Inaba and Hoki] (Jpn). PMID- 11623232 TI - [Medical education and Murai family of doctors in Higo] (Jpn). PMID- 11623233 TI - [Hoshu Tsuboi in the Satsuma clan] (Jpn). PMID- 11623234 TI - [Genseiko as the starting point of medical modernization in southern Totomi area] (Jpn). PMID- 11623235 TI - [The European academic circle of medical history] (Jpn). PMID- 11623236 TI - [Caspar Schambergers "Leichenpredigt"]. PMID- 11623237 TI - [A contribution to the history of psychiatric nursing in prewar Japan] (Jpn). PMID- 11623238 TI - [Soseki Natsume's stomach trouble and his literature--with priority given to the "serious condition at Shuzenji"] (Jpn). PMID- 11623239 TI - [D. B. Simmons, an American doctor--Dr. Simmons in the U.S.A. as seen from the letters of Yukichi Fukuzawa] (Jpn). PMID- 11623240 TI - [A chonological table of Chinese medical books reprinted in Japan up to Edo period: title index] (Jpn). PMID- 11623241 TI - [Historical materials on the medical system of Edo Shogunate] (Jpn). PMID- 11623242 TI - [Research on the Ideda documents--working group for the study of the Ikeda Documents] (Jpn) PMID- 11623243 TI - [On the history of meridian and meridian points in old Chinese medicine] (Jpn). PMID- 11623244 TI - [An aspect of Japanese medical history from the view of transmission of "Ishimpo"] (Jpn). PMID- 11623245 TI - [Dr. Fujikawa Yu and Dr. Kure Shuzo: their friendship and the study of medical history] (Jpn). PMID- 11623246 TI - [Fifty years after his death, Dr. Fujikawa Yu's native place, Hiroshima, still remembers him] (Jpn). PMID- 11623247 TI - [Fujikawa Yu and Dohi Keizo] (Jpn). PMID- 11623248 TI - [Fujikawa Yu and Zeitschrift] (Jpn). PMID- 11623249 TI - [A newly found leaf of the "Ishinho" in the Ninnaji temple] (Jpn). PMID- 11623250 TI - [Albin Lenhardtson--union politician, health educator, and tooth paste manufacturer]. PMID- 11623251 TI - [From the dance of Saint Vitus to "20th-century disease". Psychogenic epidemics- historical and current perspectives]. PMID- 11623252 TI - [Patrik Haglund--the renaissance man who became Scandinavia's first professor of orthopedics.] ]. PMID- 11623254 TI - [The history of appendicitis, part 2--1921-1991]. PMID- 11623253 TI - [Jorgen Lehmann--one of our great medical researchers]. PMID- 11623255 TI - [The medical history museums' collaborative associations in Sweden and abroad]. PMID- 11623256 TI - [Medicine's divine protection in antiquity]. PMID- 11623257 TI - [Sven Broms--leading physician and mill owner in 17th century Sweden]. PMID- 11623258 TI - [Military surgeons throughout history from the point of view of a dentist]. PMID- 11623259 TI - [Adolph Murray's chairmanship lecture in 1794, "A dissertation on the progress of anatomy in recent times"]. PMID- 11623261 TI - [Kitta in the Saghus valley. A Swedish 19th century quack and sex adviser]. PMID- 11623260 TI - [Doctors' memories from Swedish study tours in 19th century Europe]. PMID- 11623262 TI - On the history of cystic fibrosis PMID- 11623263 TI - [From the history of children's dental care, especially in Sweden]. PMID- 11623264 TI - Roup revelations. PMID- 11623265 TI - Louis Pasteur, Alexandre Liautard, and the Riverdale dog case. PMID- 11623266 TI - [A commentary on modern history of traditional Chinese medicine] (Chi). PMID- 11623267 TI - [On Huang Zhuzhai's research work on the theory of Zhang Zhongjing] (Chi). PMID- 11623268 TI - [Huang Zhuzhai and the archaic edition of On febrile and miscellaneous diseases] (Chi). PMID- 11623269 TI - [Sir Patrick Manson and the initiative of quarantine service of Xiamen (Amoy) customs] (Chi). PMID- 11623270 TI - [Liu's selected case records of four scholars and Weng Tonghe's unpublished preface] (Chi). PMID- 11623271 TI - [Introduction to prescriptions of health preserving] (Chi). PMID- 11623272 TI - [The author and writing date of Random talks of outer canon] (Chi). PMID- 11623273 TI - [Cui Jinyan's Xiyuan School of Pulsology and its academic achievements] (Chi). PMID- 11623274 TI - [An introduction to modern studies in Mongolian medical history] (Chi). PMID- 11623275 TI - [Medical art of Huns as interpreted by the first-aid technique performed on the case of Su Wu's suicide] (Chi). PMID- 11623276 TI - [On the introduction of western medicine into Fujian Province] (Chi). PMID- 11623278 TI - [Church bells in folk medicine]. PMID- 11623277 TI - Black Athena, Afro-centrism, and the history of science. PMID- 11623279 TI - [A new medical history museum in Lund]. PMID- 11623280 TI - [On false beliefs]. PMID- 11623281 TI - [Not Available]. PMID- 11623282 TI - [The development of urology in Sweden]. PMID- 11623283 TI - [Not Available]. PMID- 11623284 TI - [Ridiculous doctors--ridiculous lawyers]. PMID- 11623285 TI - [Girolamo Fracastoro and the poem Syphilis sive morbus gallicus]. PMID- 11623286 TI - The eleventh century School of Salerno. PMID- 11623287 TI - [The obstetrician--from shaman to epidemiologist]. PMID- 11623288 TI - Carnap's Philosophy of mind. PMID- 11623289 TI - Making mistakes in science: Eduard Pfluger, his scientific and professional concept of physiology, and his unsuccessful theory of diabetes (1903-1910). PMID- 11623290 TI - Effects of government intervention on population growth in Imperial China. PMID- 11623291 TI - [Not Available]. PMID- 11623292 TI - Case histories in nineteenth-century hospitals--What do they tell the historian? Some methodological considerations with special reference to McKeown's criticism of medicine. PMID- 11623293 TI - [Not Available]. PMID- 11623294 TI - [Not Available]. PMID- 11623295 TI - [Not Available]. PMID- 11623296 TI - [Not Available]. PMID- 11623297 TI - Medical thought in ancient India and Greece. A comparative perspective on the relation between social structure and modes of medical reasoning. PMID- 11623298 TI - [Not Available]. PMID- 11623299 TI - [Not Available]. PMID- 11623300 TI - [A consideration on the import of Chinese crude drugs of general use in the 2nd half of Taisho era (7): especially on the change of import volume and price of rhubarb]. AB - Since most of the crude drug rhubarb was imported in the Taisho era, similarly to the Meiji era, it was possible to refer to the government statistic data by investigating and elucidating the import volume of the same in the treaty ports at that time. Upon examining the import status in the period from the late part of the Taisho era to the early part of Showa era (around 1920 to 1930), the following transitions were observed. 1) In 1923 (Taisho 12), the Kantoh earthquake happened and it attacked Yokohama where the function as main trade port was almost totally destroyed. ... 2) The earthquake happened just at the time when the tariff protectionism was increasingly promoted in every country. ... 3) Since the port of Yokohama, as trade port, was damaged by the earthquake at that time and the government import statistic data were limited to a partial summing-up, our investigation was referred to the statistic data at the ports of Osaka and Kobe. ... PMID- 11623301 TI - [A consideration on the import of Chinese crude drugs of general use in the 2nd half of Taisho era. Especially on the change of import volume and price of rhubarb] (Jpn). PMID- 11623302 TI - [Dr. Hideyo Noguchi and Hajime Hoshi]. AB - Hajime Hoshi is a founder of Hoshi Pharmaceutical Company and of Hoshi University. He became acquainted with Dr. Hideyo Noguchi in the United States in 1901 during his study abroad. Hoshi often stayed overnight at Noguchi's apartment in Philadelphia. Hoshi and Noguchi were both from Fukushima, Japan, and Hoshi was three years older than Noguchi. Both persons had been good friends until Hoguchi died in 1928. Hoshi and Noguchi together had met Hirobumo Ito and Thomas Edison. In 1906, Hoshi came back to Japan after a 12-year stay in the United States. The financial support by Hoshi enabled the only and one temporary returning of Noguchi to Japan in 1915. In this paper, the friendship between the famous two persons is described in detail. PMID- 11623303 TI - [Dr. Hideyo Noguchi and Hajime Hoshi] (Jpn). PMID- 11623304 TI - [The recollections of "vitacampher" development]. PMID- 11623305 TI - [The recollections of "vitacampher" development] (Jpn). PMID- 11623307 TI - [The way for carrying medicine and its containers. "Packaging material--paper] (Jpn). PMID- 11623306 TI - [The way for carrying medicine and its containers (V). "Packaging material- paper"]. AB - In the Edo era, paper was useful as the most suitable packaging materials for carrying medicines. It was considered that the wrapping paper protected medicines from an imaginary gaseous medium "ki", which meant atmospheric moisture in this case. Also brand name and indications of medicines were printed on the wrapping paper for taking a medicine correctly. In the 18th century, wrapping paper for medicine was produced. It was specially processed for wrapping medicines only, and it was called "yakutaishi" in Japanese. PMID- 11623309 TI - [The transition of the standards and the test-methods of ethanol between JP I (1886) and JP XII (1991)] (Jpn). PMID- 11623308 TI - [The transition of the standards and the test-methods of ethanol between JP I (1886) and JP XII (1991)]. AB - Ethanol was listed as a "Spiritus" in Japanese pharmacopoeia (JP), which was issued officially in Japan in 1886 for the first time. Then, its name was changed to alcohol in JP V (1932). "Ethanol-Aethanolum" for alcohol was listed in JP VII (1961). The specification related to ethanol was very simple at that time of 1886. However, since JP IV (1920), the specification for products listed in JP became more in detail gradually and came to those which we can see today. For example, the items of confirmation test, purity test and the other tests were established in JP VII of 1961. Ethanol will be still useful in future because of its low price and stable supply. PMID- 11623310 TI - [The way for carrying medicines and its containers (VI) "Packaging material- glass bottle"]. AB - Production of glass ware, though it was only used for ornaments, was performed in Japan from ancient times. We can find them in relics of the ancient. But it was only two hundred years ago that glass bottles were applied to medicines. The bottles and a method of making a glass bottle were introduced in the Edo period by studying science in the Dutch language. It instructed us that the glass bottle could be applied to containers for medicines, and that the glass bottle was useful for the containers to protect medicines from light and moisture. PMID- 11623311 TI - [The way for carrying medicines and its containers. "Packaging material--glass bottle"] (Jpn). PMID- 11623312 TI - [The transition of psychotropic drugs in Japanese pharmacopoeia (JP) (Part 3). The transition of the standards and the test methods of potassium bromide between JP VI (1951) and JP XII (1991) and the comparison with BP XIV (1988)]. AB - This is the study on the transition of the standards and test-methods for potassium bromide between JP VI (1951) and JP XII (1991), and the study on the comparison with BP XIV (1988). The results were as follows: the standards and test-methods for potassium bromide have gotten originality gradually by a suitable revision of JP VII (1961)--JP XII (1991) and have become accurate standards in practice for the parties concerned with medicine of our country. They are different from BP XIV (1988) on methodology but have established the effective standards for quality maintenance. PMID- 11623313 TI - [The transition of psychotropic drugs in Japanese pharmacopoeia (JP). (Part 3) The transition of the standards and the testmethods of potassium bromide between JP VI (1951) and JP XII (1991) and the comparison with BP XIV (1988)] (Jpn). PMID- 11623314 TI - [C. P. Thunberg and his voyage to Japan (2): medical studies conducted before arrival in Japan]. AB - C. P. Thunberg (1743-1828) stayed in Japan for about 16 months as a doctor attached to the Dutch trading post. He taught medicine, pharmaceutical science and natural history to Japanese doctors and interpreters during his stay. In order to determine his educational, mainly medical, background, I made inquiries to the university and other facilities where he studied, as well as programs he followed. ... PMID- 11623315 TI - [C. P. Thunberg and his voyage to Japan. (2) Medical studies conducted before arrival in Japan] (Jpn). PMID- 11623316 TI - [C. P. Thunberg and his voyage to Japan (3): medical articles written before arrival in Japan]. AB - Three medical articles written by Thunberg before his visit to Japan were reviewed. "De venis resorbentibus" is an article on the lumph duct written in Latin under the guidance of Professer Linne. ... "De ischiade" is a thesis written in Latin under the guidance of Prof. Sidren. This thesis, examined in public on June 28, 1770, lists 8 major causes of lumbago and explains therapies for lumbago in each cause. ... "Handelse, at Blybvitt af forseende blif vit brukadt i mat" is a short article published in the Kungliga Vetenskaps Academiens Handlingar, 1773. It relates his own experience of acute lead poisoning during his travel from Holland to South Africa by ship in January 1772. ... PMID- 11623317 TI - [C. P. Thunberg and his voyage to Japan. (3) Medical articles written before arrival in Japan] (Jpn). PMID- 11623318 TI - Rheumatoid arthritis--rare findings from Scanian skeletal remains from Viking and medieval times. PMID- 11623320 TI - Evidence of rheumatoid arthritis in an icelandic textbook from 1782. PMID- 11623319 TI - Archbishop Andreas Sunesson and his illness. Leprosy or arthritis? PMID- 11623321 TI - Joint and muscular pain and the struggle against it in rheumatoid arthritis. PMID- 11623322 TI - History and memoirs of the 1950 Nobel Prize-winning discovery of the anti inflammatory effects of adrenocortical extract. PMID- 11623323 TI - Introductory remarks to the History of chronic joint diseases. PMID- 11623324 TI - Anatomy in the Corpus Hippocraticum. PMID- 11623325 TI - [From Hippocrates to Galen]. PMID- 11623326 TI - [Not Available]. PMID- 11623327 TI - [The explanation of the School of Athens]. PMID- 11623328 TI - The legacy of Jehan Yperman (circa 1260/1280-circa 1331/1334) to plastic surgery. PMID- 11623329 TI - Henry Sigerist in South Africa PMID- 11623330 TI - The gentle communicator: a tribute to Rose Melzer. PMID- 11623331 TI - The Beals: a father and son devoted to pharmacy. PMID- 11623333 TI - Conical graduates with replaceable bodies or bases. PMID- 11623332 TI - The phenolphthalein follies: purgation and the pleasure principle in the early twentieth century. PMID- 11623334 TI - Fact, fiction and pharmaceutical history. PMID- 11623335 TI - Fact, fiction and pharmaceutical history. PMID- 11623337 TI - Pharmaceutical wholesaling--an historical perspective. PMID- 11623339 TI - The two Johns: Channing and Pringle. PMID- 11623341 TI - Sex fraud. PMID- 11623340 TI - "Taking the waters" in Indiana. PMID- 11623342 TI - LSD at 50: Albert Hofmann and his discovery. PMID- 11623343 TI - A chronicle of anesthesia discovery in New England. PMID- 11623344 TI - The personal papers of Robert P. Fischelis. PMID- 11623345 TI - Adenocarcinoma in the mummy of Ferrante I of Aragon, King of Naples (1431-1494). PMID- 11623347 TI - The newest knowledge of nutrition: Wise Burroughs, DES, and modern meat. PMID- 11623348 TI - Medieval Jewish aesthetics: Maimonides, body, and scripture in Profiat Duran. PMID- 11623349 TI - [A lecture "The animal hygiene (1901)" by a German veterinarian J. L. Janson] (Jpn). PMID- 11623350 TI - Der Arzt Polybos De natura hominis und die hippokratische Arzteschule--Eine geistesgeschichtliche Voruntersuchung zur griechischen Medizin. PMID- 11623351 TI - [A bibliographical review of the history of eugenics. Eugenics and the eugenics movement in Britain] (Jpn). PMID- 11623352 TI - [The development of contemporary medicine in relation to biology] (Jpn). PMID- 11623353 TI - The Athenian state poison. PMID- 11623354 TI - Samuel Johnson, his health and the doctors. PMID- 11623355 TI - J. D. comrie--archangel journal: part III PMID- 11623356 TI - Botanists of the Mexican-United States boundary survey. PMID- 11623357 TI - Some aspects of research at Baragwanath Hospital in its early years. PMID- 11623358 TI - The South Africa Orthopaedic Association: 50 years--1942-1992. PMID- 11623359 TI - 1543 - the year of Vesalius. PMID- 11623361 TI - A struggle for water. PMID- 11623360 TI - The American academia and the private sector. PMID- 11623362 TI - [The position of the history of medicine]. PMID- 11623363 TI - Medical historiography in English Canada. PMID- 11623364 TI - The founding period of the U.S. Pharmacopeia. PMID- 11623365 TI - A history of pharmacy: future opportunities. PMID- 11623366 TI - Erik H. Erikson as a teacher. PMID- 11623367 TI - "Is it really so terrible her?": Karl Menninger's pursuit of Erik Erikson. PMID- 11623368 TI - Beyond rumor and reductionism: a textual dialogue with Erik H. Erikson. PMID- 11623369 TI - Erikson on Hitler: the origins of 'Hitler's imagery and German youth'. PMID- 11623370 TI - Taking Erikson's identity seriously: psychoanalyzing the psychohistorian. PMID- 11623372 TI - The death of Rosa: sexuality in rural America. PMID- 11623374 TI - "Minds the dead have ravished": shell shock, history, and the ecology of disease systems. PMID- 11623371 TI - Erikson on Luther. PMID- 11623375 TI - "One face, one voice, one habit, and two persons!" The survival of twins in early modern society. PMID- 11623376 TI - [A retrospective: demographic policy in Romania, 1945-1989]. PMID- 11623377 TI - [A demography of the jews in Metz (1740-1789)]. PMID- 11623378 TI - English population statistics for the first half of the Nineteenth Century: a new answer to old questions. PMID- 11623379 TI - [French influences on Brazilian ideas: race, nation, and population (1890-1930)]. PMID- 11623380 TI - [An ignored aspect of urban demography during the great war: the tragedy of the elderly in Berlin, London, and Paris]. PMID- 11623381 TI - The impact of the great war on infant mortality in London. PMID- 11623382 TI - [The celebration of the thirtieth anniversary of the society for historical demography]. PMID- 11623383 TI - [Social history and historical demography]. PMID- 11623384 TI - [Historical genetics and demography]. PMID- 11623385 TI - [American Indian inhabitants in Saint Lawrence Valley, 1608-1765]. PMID- 11623386 TI - [Between ethnology and demography: lying-in women and newborn babies in traditional Bulgarian society]. PMID- 11623387 TI - [The families of Curitiba (Brazil) in the eighteenth century: Approaching fertility]. PMID- 11623388 TI - [The urban penalty and the decline in mortality in England and Wales, 1851-1900]. PMID- 11623389 TI - Archie as I remember him. PMID- 11623390 TI - The first sixty years of the Racquet Court practice. PMID- 11623391 TI - J. A. Donaldson, 1914-1993. PMID- 11623392 TI - Scientific models in optics: from metaphor to metonymy and back. PMID- 11623393 TI - [Psychiatry and pharmaceutical practices: the evolution of dosage forms for psychiatric use]. PMID- 11623394 TI - [Not Available]. PMID- 11623396 TI - The limbic terminology: natural history of semantic fluctuations. PMID- 11623395 TI - [An episode in the life of surgeon Louis Seutin of the Grande Armee]. PMID- 11623397 TI - [Isidore Geoffroy Saint-Hilaire (1805-1861)]. PMID- 11623398 TI - [Not Available]. PMID- 11623399 TI - The Waterhouse clock. PMID- 11623401 TI - The emergence of biomathematics and the case of population dynamics: a revival of mechanical reductionism and Darwinism. PMID- 11623400 TI - From pneumonia to DNA: the research career of Oswald T. Avery. PMID- 11623402 TI - Standardizing the subject: experimental psychologists, introspection, and the quest for a technoscientific ideal. PMID- 11623403 TI - Losing touch: the controversy over the introduction of blood pressure instruments into medicine. PMID- 11623404 TI - Chiropractic and the social context of medical technology, 1895-1925. PMID- 11623405 TI - Engineering behavior: Project Pigeon, World War II, and the conditioning of B. F. Skinner. PMID- 11623406 TI - In the image of science? Negotiating the development of diagnostic ultrasound in the cultures of surgery and radiology. PMID- 11623407 TI - Reflections on a medical innovation: transcutaneous oxygen monitoring in neonatal intensive care. PMID- 11623408 TI - Sexuality, reproduction, contraception, and abortion: a review of recent literature. PMID- 11623409 TI - Doctors and dying declarations: the role of the state in abortion regulation in British Columbia, 1917-37. AB - In Canada, the history of state regulation of abortion is underexamined, leaving the general impression that the state played a secondary role to that of the medical profession in attempting to enforce the federal anti-abortion law. Studies have focused on "regular" physicians as a regulator of abortion to such an extent that the state's involvement in this process has been largely neglected or obscured. In contrast, this study highlights the actions taken by lower-level state agencies, namely, the Coroner's Inquisition and municipal and provincial police, to enforce the federal abortion law in British Columbia. The study examines the records of the inquests held into the deaths of 34 women from illegal abortion and offers three main observations. First, state agencies consistently sought information about abortionists and the circumstances surrounding the abortions from the women in hospital, their families, lovers, and doctors. Especially important is how authorities routinely attempted to extract dying declarations from the ill women. Second, while it is clear doctors participated in the investigative process, the records suggest they were often ambivalent or reluctant to do so. Finally, this study concludes that many of the actors involved in these events resisted the authorities' attempts to enforce the law, some successfully, thereby effectively undermining state regulatory practices as a result. PMID- 11623410 TI - [Bayt al-hikmah and the cultural policy of the caliph al-Ma'mun]. AB - The Bayt al-hikmah, which begins to operate under this name during the kingdom of Harun al-Rasid, develops especially under al-Ma'mun. It was a library and one of the places in which the IX century translations were carried out. It does not seem to have been a development center of the Su'ubiyyah, but it contributed to the discussions which took place before the proclamation of the mu'tazilite policy of al-Ma'mun. It was one of the elements of a cultural integration in the Moslem world, and it reached mathematicians and astrologers more than doctors, because of their strong tie with Christian traditions. PMID- 11623411 TI - [The role of Hunayn, physician and translator]. AB - Hunayn ibn Ishaq is one of the most important translators of scientific and medical texts in the 'abbasid era. He played a fundamental role in the transmission of Greek medical science to the Arab world, because of his deep knowledge of the Syriac, Arabic and Persian languages. He translated about 300 texts, especially medical ones, and he founded a school in which many disciples were instructed in the art of translation, like his son Ishaq and his nephew Hubays. Hunayn composed a lexicon of scientific terminology, using a new method of translation which represents his great innovation. PMID- 11623412 TI - [The work of Hunayn ibn Ishaq in the Arabic manuscripts of Escurialense Library]. AB - After a short historical introduction about Hunayn's life and about the foundation and development of the Escurialense Library, the article deals with the Arabic collection which is kept in it. Hunayn is the author of some work in the Escurialense codices, and the translator of some others. Particularly, three codices containing original medical works by Hunayn are listed here and commented on in detail, together with twenty-five containing Hunayn's translations of Hippocratic and Galenic texts. Some astrological texts are also treated. PMID- 11623413 TI - [Not Available]. AB - This paper is concerned with the Arabic translation of the Alexandrian Summaries of Galen's works, and in particular with one of them. These summaries were compiled during the VI-VII centuries by medical professors, iatrosophistae, whose names are variously related. The most elaborate and extensive of these summaries is that of Galen's Ad Glauconem; it is in fact not merely a resume of its model but an ample paraphrasis with a rich commentary within it. This summary is strictly akin to the Alexandrian commentary on the same Galenic work by Stephanus of Athens and the Latin commentary by Agnellus of Ravenna. PMID- 11623414 TI - The Ibn Buhtisu' bestiary tradition. The text and its sources. AB - The Ibn Buhtisu' Book on the usefulness of Animals is extant in several copies, five of them illustrated. After giving an account of the text, the Author of the article investigates its sources, finding that they are two-folded: partly coming from a Greek tradition ultimately related to Aristotle's Zoology, and partly coming from Ibn Buhtisu' medical writings, which seem to stem from the lengthy tradition of the famous School of Gondesapur. A profile of the main representatives of the Ibn Buhtisu' family, for the first time translated here from the Arabic sources, is also given. PMID- 11623415 TI - [The Epistle of Conceiving in the Encyclopedia of the Ihwan al-Safa']. AB - This study illustrates the physiology of the embryo as it is described in the Conception Letter of the Ihwan al-Safa'. The Author compares this text with Hippocratic and Galenic writings, to underline all the points in which the Ihwan detach themselves from the classical tradition. Here, as elsewhere, the originality of these Authors seems to be connected to the religious and sapiential features of their production. PMID- 11623416 TI - Abu Bakr Muhammad al-Razi's (Rhazes) medical works. AB - A-Razi (Rhazes, with variants, in Medieval Latin), Abu Bakr Muhammad ibn Zakariyya' (al-Rayy, close to modern Teheran, Iran, A.D. 865-925), is rightly considered one of the greatest medical practitioners and writers in the period between Galen and the renaissance reemergence of medicine as an empirical discipline (apart from his ranking as one of the most original and independent minded philosophers of Islam). The following biobibliographical survey - in the format of an encyclopaedia article - will focus on those of his medical works which either had the greatest impact on posterity and/or attest most solidly to al-Razi's outstanding combination of textual scholarship and clinical observation, outstanding at least with reference to the horizon of his culture. PMID- 11623417 TI - [Ibn Sina or the control of medical reasoning]. AB - This article analyses the context in which Ibn Sina produced his works and the terminologic and conceptual material used by him to write his medical and philosophical texts and to become generally acknowledged as a sage or learned scholar. Between the prince and the theologian, he is a physician-philosopher who uses reason to create his own space. The Qanun fi'l-tibb is the consequent expression of medical reasoning typical of the early XI century; if, on one hand, it is indebted to objective conditions, we remark also that it is structured around an epistemological project which organizes its expression and transmits its knowledge in a technical, codified language. PMID- 11623418 TI - [The generalities of the Averroes' medicine]. AB - The most important medical work of Averroe, known in Medieval times as the main commentator of Aristotle, is the Kitab al-kulliyat fi' l-tibb. It is a work composed of 7 books, concerning: 1. Anatomy, 2. Physiology 3. Pathology 4. Symptomatology 5. Pharmacology 6. Hygiene 7. Therapeutics. The book was employed in its Latin translation - the Colliget, made in Padua in the second half of the XIII century - as a scholastic book for European Universities, where it introduced the Aristotelian medical doctrines. Averroes, in fact, exposed the general features of medical science, trying to establish its theoretical basis through Aristotle's philosophy. PMID- 11623419 TI - [The iconography of consumption in the ancient world]. AB - There is in Delphi a votive statue - representing a man affected with phtisis - which is said to have been dedicated by Hippocrates himself. A little bronze found in Soissons could refer to the legend of Perdiccas' love sickness. We draw a parallel between Perdiccas' bronze and a mosaique in Lambiridi. Others representations (portraits, coins, statues of rickety children and iconographies of the Old Age) of weak and thin bodies are here studied following a medical approach. PMID- 11623420 TI - [Another satyriasis. Ancient medicine, philology and art history]. AB - The author explains that several ancient diseases bear the name of satyriasis. One of them is a form of lepra. An ancient terra-cotta mask of a satyre helps understanding why it is so. PMID- 11623421 TI - Uterine amulets and Greek uterine medicine. AB - This article publishes for the first time a hematite uterine amulet in the author's possession. After a brief look at this amulet I offer a summary of previous scholarship on uterine amulets, and then focus on three specific aspects -the amulets' relation to Greek medical texts on gynecological topics; evidence for the use of perishable and non-perishable amulets by Greek women prior to the proliferation of the hematite examples in the Roman period (ca. II CE). I conclude with a discussion of the derivation and meaning of ororiouth, based on my correspondence with Dr. Roy Kotansky. PMID- 11623422 TI - [Twins in the Greco-Roman world: medical theories and iconographpy]. AB - The phenomenon of multiple births aroused very ambivalent feelings in the ancient classical world. This article endeavours to define how this ambivalence was expressed, on the one hand in ancient medical theories, through associations with concepts of monstrosity and excess, on the other hand in art, through a selection of mythological themes and iconographic conventions. PMID- 11623423 TI - [Women and motherhood in funerary reliefs from Attica]. AB - Interest increasing about woman in Athens of classical period is closely linked to the social importance of motherhood. Pregnancy and childbirth bear remarkable risks both for the mother and the unborn child. There are large number of funerary reliefs erected in attica to commemorate the death in childbirth of young women. PMID- 11623424 TI - [Antique and medieval representations of foetus in utero]. AB - Until Renaissance, human foetus had never been drawn, except in an obstetrical manuscript from Moschion. He wrote towards the VIth century A.D. a little work in Latin extracted from Soranos' Gynecia for the instruction of midwives. He reviews the different cases of foetal presentations during delivery, and gives advice on the best method to adopt for each case. PMID- 11623425 TI - [Tooth pastes and oral hygiene in the Roman world]. AB - The trial against Apuleius frames historically and socially the subject of oral hygiene, which hides behind the semiotic paradigm full of magic, superstition, and all of the roman cultural background which stems from the ancient greek tradition. After reading carefull the latin odontic prescription written by Scribonius Largus, Celsus, Plinius, Marcellus etc., we don't want to stop at a precise list of tooth paste ingredients but we have tried to interpret the ideological procedures and practices which guided the greek and latin therapeutic practices and daily hygiene. PMID- 11623426 TI - [Votive offering in Etrurian-Italic area]. AB - A large quantity of votive offering representing parts of human bodies has been found in Etruria, Lazio and Campania. An archaelogical, methodological and cultural exam throw light on the links existing between magic, religion and ancient medicine. Votive offerings, being far from an anatomically correct description, reflect only popular and religious traditions. PMID- 11623427 TI - The literary styles of Sir William Osler. PMID- 11623428 TI - An historical note on Ethiopian terminology for syphilis. PMID- 11623430 TI - Tripping out from San Francisco. PMID- 11623429 TI - Miltiades. Aratus and compound fractures. PMID- 11623431 TI - The language of bodybuilding. PMID- 11623432 TI - The empirical element in the methods of early Greek medical writers and Herodotus: a shared epistemological response. PMID- 11623433 TI - Military heroism: an occupational definition. PMID- 11623434 TI - Medical Latin in 1644 A.D. PMID- 11623435 TI - Maternal health care policy: Britain and the United States. PMID- 11623436 TI - A note on some Middle English medical terms. PMID- 11623437 TI - Under the shadow of maternity: American women's responses to death and debility fears in nineteenth-century childbirth. PMID- 11623438 TI - Protecting infants: the French campaign for maternity leaves, 1890s-1913. PMID- 11623439 TI - "Three lexicographical notes." PMID- 11623440 TI - Lexicographical notes on Galen's writings (part II). PMID- 11623441 TI - Lexicographical notes on Galen's pharmacological writings. PMID- 11623442 TI - Prepositional idiom in Galen. PMID- 11623443 TI - Addenda Lexicis, primarily from Aetius of Amida and Paul of Aegina. PMID- 11623444 TI - Unnoticed medical language in Demosthenes. PMID- 11623445 TI - [Not Available]. PMID- 11623446 TI - Premium weaving in the 19th century parish of Natra: women, production and reproduction. PMID- 11623447 TI - Early multilingual and multiscript indexes in herbals. PMID- 11623449 TI - The Indian mines maternity benefit question, 1919-47. PMID- 11623450 TI - Esperanto and trans-national identity: the case of Dr. Zamenhof. PMID- 11623451 TI - Church-state relations and the development of Irish health policy: the mother-and child scheme, 1944-53. PMID- 11623452 TI - The soma of the Rig Veda: what was it? PMID- 11623453 TI - Concepts of pregnancy, childbirth, and infancy in Ch'ing Dynasty China. PMID- 11623454 TI - Healing eloquence: Petrarch, Salutati, and the physicians. PMID- 11623455 TI - Anatomical and pathological terms in Akkadian. PMID- 11623456 TI - Maimonides in Muscovy: medical texts and terminology. PMID- 11623457 TI - Classificatory thinking from Kinner to Wilkins: classification and thesaurus construction, 1645-1668. PMID- 11623458 TI - Medieval Iberian vernacular versions of the herbal called Macer floridus. PMID- 11623459 TI - Johnson, James, and the Medicinal Dictionary. PMID- 11623460 TI - The reading public, the medical profession, and the use of English for medical books in the 16th and 17th centuries. PMID- 11623461 TI - Sixteenth century medical nomenclature and "The birth of mankind". PMID- 11623462 TI - (R)evolutionary scenes: the body politic and the political body in Henry Maudsley's nosology of "masturbatory insanity." PMID- 11623463 TI - The nature of biblical "leprosy" and the use of alternative medical terms in modern translations of the Bible. PMID- 11623464 TI - Chinese scientific terminology. PMID- 11623466 TI - [Illness in the arts of late antiquity: some aspects of a Christian iconographic programme]. AB - Nowadays concepts of Art are quite different from those of Antiquity. For instance, the healing ex votos which were sculpted in wood and dedicated to Sequana in the IIIrd century were undoubtedly seen as crude works: today, they are considered as expressions of popular arts, just like african statues. If art is defined by an esthetic purpose, and not only pragmatic, we can see no trace of sicks in the arts of Late Antiquity. There are only some examples in christian art, where Jesus' healing miracles are illustrated. Their iconographic representation doesn't dissociate illness from healing. This fact is highly representative of a christian iconographic programme, linking illness to carnal condition and healing to salvation. So, the arts of Late Antiquity teach us almost anything about disease, but very much about the perception of it and its pastoral use. PMID- 11623465 TI - The rhetoric of dehumanization: an analysis of medical reports of the Tuskegee syphilis project. PMID- 11623467 TI - [Deaths and death in Italian medieval painting]. AB - The role played by great epidemics in the composition of the Triumphs of Death and the Dances of the Deaths in Italy from XIVth to XVth century has been recently well discussed by historiographical licterature. The human body has been linked to the idea of frialty and decomposition already before XIVth century; ascetical and penitential ideals have been joined together with critical economical, social and sanitary conditions. European medieval populations were mown down by endemic illnesses and it certainly is possible that these catastrophic events influenced the composition of Triumphs and Dances. PMID- 11623468 TI - [Testimonies of an autochthonous illness on the anthropomorphic pottery in ancient Peru]. AB - The vases belonging to the Mochica civilization of the Precolombian period in Peru represent images that strongly recall pain and illness. In particular the anthropomorphic vessels show in a very realistic fashion severe facial lesions probably associated with different diseases such as cutaneous Leishmaniasis. The different types of leishmaniasis may, in fact, produce asymptomatic visceral, cutaneous, or muco-cutaneous infections, the latter causing remarkable facial deformities like those represented in the vascular production. PMID- 11623469 TI - [The Hebrew manuscript of Avicenna's Canon]. AB - The Hebrew manuscript of Avicenna's Canon, today in the University Library of Bologna (Ms 2197) dates from about the middle of the XVth century; it contains six full-page illuminations which have probably been performed by Northern Italian artists. The study of the pictures may help modern comprehension of the relationships between medieval men, illnesses and ages of life, and it clarifies the profound ethical links correlating physicians with patients and their entourage. The text, written in Hebrew square capitals and Rashi italics, clearly shows how, on the threshold of Italian Renaissance, Hebrew was still considered, as Greek and Latin, one of the classical languages. PMID- 11623471 TI - [The iconography of illness in the Middle Ages: two Swabian documents]. AB - Two herbaria, dating at the end of XIII century and now in Firenze and Vienna, offer an interesting documentation about the history of medicine and pharmacy in Italian Southern Italy during Federico II's age. Their inluminures allow to paint a faithful picture of the medioeval attitude towards illness and pain. PMID- 11623470 TI - [On the Gravissima malattia agli occhi of Francesco d'Assisi in Greccio]. PMID- 11623472 TI - [The conjoined twins born in Valdarno al Terraio]. AB - Surgical pre and post-operative problems involving the separation of conjoined twins of ischiopagus type make actual the interpretation of a relief coming from the Hospital of Santa Maria della Scala in Florence and dating probably from XIVth century. The work has been sculptured after the death of a couple of ischiopagus twins in the same Hospital in 1316. Their birth is registered in Giovanni Villani's Cronaca and in Petrarca's Rerum Memorandarum Libri. PMID- 11623473 TI - Illustrations as abstracts: the illustrative programme in a Montpellier manuscript of Roger Frugardi's Chirurgia. AB - Illustrated manuscripts of Roger Frugardi's Chirurgia (c. 1180) form but a small proportion of extant manuscripts in Latin or in any of the medieval vernaculars. We study the single de luxe illustrated Latin manuscript of the work which is notable for its extensive programme of over 100 medical illustrations. We suggest that both the length of the cycle and the integration of the illustrations into the text is linked to the absence of rubrics and that the cycle was conceived to act as a form of visual rubric. We show that this function had a determining influence on the iconography and examine the methods used to represent the text visually. PMID- 11623474 TI - [The endemic goitre in figurative arts]. AB - For the past fifteen years the author has been collecting photografic documentation of works of figurative arts (graffiti, mosiac, engravings, paintings and sculptures) made at different times and places, in which he found mostly unintentional display of diseases or deformities that would be clearly identified in nosography in the light of today's knowledge. In this study the author intends to illustrate briefly different cases on endemic goitre - whose representation is particularly frequent in figurative arts - in chronological order, beginning with the most ancient ones and focussing on Italian portraying of the Nativity and the Passion of Christ, where the most striking infirmities and disabilities were mirrored and commonly accepted. This study whose interest lies between a scientific and a humanistic one has also importance in the field of art, and especially in relevant philological research which is of particular importance to us pathologists. At last it contribute to establish the epidemiology of some diseases and the knowledge of historical and geographical pathology. PMID- 11623475 TI - Operational practice and the emergence of modern chemical concepts. AB - Both "early chemistry" and "modern concepts" are imprecise. The earliest references to the materials involved in metallurgy, painting, ceramics, and the like, reveal an awareness that one group of materials were called "salts" because of their similarities. I consider this a chemical "concept." Seeking another example I claim to have found it is the so-called "mineral acids." The evidence for the existence of this concept is cumulative during the period just before the emergence of "modern chemistry," of which it may be considered a cause. That evidence is particularly found in the literature of pharmacy and of medicine, both of which belong to the practical arts. PMID- 11623476 TI - [Medicine as ars in the Roman world. Its advance from sacral to secular approach, its trading and public diffusion: socio-political considerations and their legal consequences]. AB - The close linkage between empiric knowledge and its magic religious background in the archaic period appears clearly as a main feature characterizing the medical ars at its beginning, at least till it advances to a full secular approach during the fifth and fourth century B.C. The medical knowledge, which had been a privileged inheritance of the ruling class underwent a rapid transformation with the rise of the Roman Empire and its hegemonic politics that reached its climax during the Punic wars. As it was spread to all social classes it achieved an ever increasing importance leading to its specialisation and trading. This socio political change had repercussions on the legal field: indeed conventiones concerning medical service came into effect. As far as action was concerned, doctors were permitted to avail themselves of the cognitio extra ordinem in order to get the rewards they were entitled to. The application of the legal tool cognition was however a device embedded in a set of other remedies aiming at granting rewards and incentives i.e. privilegia and salarium. Their development over the period of the Roman Empire was linked with a growing monopoly run by the supreme authority. PMID- 11623477 TI - [Environment and political institutions between antiquity and contemporary medicine]. AB - In both myth and Genesis (by God) the creation of the world begins with the separation of water, sky/air and ground; later appear the life and the man and from Olympic divinities (or God) derive health and disease and remedies. When Milesian philosophers distinguished between nature (to be observed) and speculation, a parallel revision has been made in the medicine, from theurgical to rational one. Thus, Hippocratic medicine pointed attention on air waters and places as natural environmental elements, to be observed, as method to understand the probable diseases of a city, also with a role of political institutions, says the Hippocratic treatise De aere. Centuries later, only in the 19th century has been rediscovered the importance of environment in the health's policy, a concept full developed in the last time (i.e. health and pollution, health and quality of life). PMID- 11623478 TI - [Hippocratic medicine and the treatise Airs, waters and places. A short history of the beginnings and influence of a scientific error]. AB - The hippocratic treatise Airs, waters and places is a book for travelling practitioners, explaining them all they have to check when they arrive in a new unknown place. According to the author of this manual, one of the most frequent causes of diseases is the bad quality of environmental air. Admitting this theory, the medical man could not imagine that diseases might be transmitted by contagion. Yet vets had always known about contagion among herds and flocks. Christian literature which used so frequently the metaphor of the good sheperd and the sick sheep might have drawn doctors' attention and parallelized the situation among animals and that among human beings. The authority of the so called father of medicine was so powerful that this did not happen and that contagionists and anticontagionists would quarrel for ages. PMID- 11623479 TI - [Archaelogical documentation of the atmospheric pollution in antiquity]. AB - Authors examines the paleopathologic evidences of the atmosferic pollution in ancient time, point out the attention on two principal findings: pulmonar anthracosis and lead exposure. Pulmonar anthracosis is present in many mummified bodies and was due to the deposition on the pulmonar alveoli of carbon particles coming from the combustion of oils or vegetables for illumination, cooking or heating. Lead atmosferic pollution was very high between V century B.C. and III century A.D. in the North emisphere, in consequence to the impressive quantity of lead produced by Greek and Roman metallurgic technology (perhaps 80,000 metric tons per year around the start of I century AD). Cumulative lead fallout to the Greenland Ice Sheet during these eight centuries was as high as 15 percent of that caused by the massive use of lead alkyl additives in gasoline since the 1930s. Finally, the high atmosferic lead concentration caused a high exposure of humans to the lead: in fact paleopathologists, have clarely demonstrated a high quantity of lead concentration in the human bone dated to the period between III century B.C. and VI century AD circa. PMID- 11623480 TI - Outdoor air pollution and health. AB - Outdoor air pollution has been recognized as a relevant factor for health. Studies on exposure of both workers and normal population due to accidental contaminations of environment have been performed. Energy production, winter heating, vehicle exhausts and industrial activities can act acutely or chronically. Epidemiological studies should be corrected for disturbing factors, so that the result are useful to suggest new rules about total good quality of environment (outdoor and indoor). PMID- 11623481 TI - [The use of water as indication of the presence of life: technical ways of employment in the archaelogical documentation]. AB - Ancient urbanization often is strictly connected with rivers and sources. In the ancient world, the usage of water is also linked with the idea of sacrum and with specific religious cults (i.e. the King's Numa mith or the legend of the nymph Egeria). A complex technique of rain water preservation has been elaborated in Rome by building structures of water supplying: the exemples of Segni's colony and Ventotene's imperial island are here examined. Due to the general absence of water supply directly in the houses, public fountains were largely present in the public ways. PMID- 11623482 TI - [Thermalism in ancient world]. AB - The importance of water was well known in Prehistory and in ancient World. There are, in Homeric poems, several descriptions of cold and warm baths, a witness of their utilization in ancient Greek civilization. But the sources of water were always linked with the divinities of the Earth, and the temples dedicated to Asklepios had also thermal baths. The Romans, heirs of Etruscan culture, made the baths a social and public matter, and in Rome the Thermate reached a high degree of perfection. PMID- 11623483 TI - [Drinking water: use, consume and biological hazard]. AB - The Authors drew the attention to the rising danger of water crisis also in countries usually immune from this problem. The most important causes of these crisis are presented along with some of the most important laws concerning civil use of water. The Authors underline the biological risk induced by new aetiologycal agents (i.e. aeromonas hydrophyla, Criptococcus, Escherichia coli (O:127 H7) found in drinking water too. Some of the health problems correlated to the civil use of water are also presented: water supply of hospitals, schools and hotels. The Authors conclude underlining that the answer to this problem must be found in a good management of water sources which requires efficient monitoring systems. PMID- 11623484 TI - [Not Available]. AB - The quality of drinking water is known to have positive or negative influences on human health. At present, in the industrialized countries microbiological contaminants in public water supplies are under control, due to the widespread introduction of effective disinfection and potabilization systems. However, of special interest are other public health problems linked with the presence of many water components or contaminants. Since the beginning of this century, fluoride showed to have beneficial effects on dental caries and the practice of adding fluoride to drinking water has been widely followed in many countries for reduction of dental caries. More recently, a large body of scientific information indicates that various characteristics related to water hardness are correlated with incidence of cardiovascular disease. Moreover, the discovery of the presence in drinking water of inorganic and organic contaminants with mutagenic/carcinogenic properties gives rise to public health concern. PMID- 11623485 TI - [Italian medical hydrology and contemporary medicine. Scientific features and usefulness in therapeutics]. AB - The scientific features of our better medical Termalism from the first Convention of Italian Medical Association of Hydroclimatology, Bologna 1888 are here briefly illustrated. In the thirthies of this century, the Hydrological doctrine and studies about it are subjected to sistematically rigorous researches performed by Mariano Messini, his medical school and others. The matter is seen as Therapeutics branch. The Italian Medical Hydrology is well known in the world for his studies about physiopathology and therapeutic usefulness in some gastroenterological, rheumatological and respiratory diseases. PMID- 11623486 TI - [An archaelogical contribution to hygienical principles in the Roman town planning]. AB - Greek and Roman ancient medical writers suggest hygienical rules which are strictly dependent on the orientation of towns, the direction of winds and the quality of waters. According to Vitruvius, architects and builders should have some medical knowledge, together with a strong new interest towards the improvement of enviromental conditions. Norba, a little city never built up again after the Sillan distruction in 81 B.C., and Civitas Artena, quitted in the first century B.C., have been studied as significant exemples of this architectural behaviour. The construction of Villae - big country houses nearby the city - was conditioned by economics, easily available water, sunshine light and proximity to fruitful soils. PMID- 11623487 TI - [Indoor pollution]. AB - The Author reports more important phases from the beginning of housing to now: the indoor pollution time. Shelter is a basic need; humans require protection against the elements, somewhere to store and prepare the food, and a secure place to raise offspring; but indoor environment is not always safe. It has been known since Hippocrates' time that housing conditions affect health. Today situation starts from the enormous growth of urbanization. At 1888 in Italy first legislation on health, including healthy building, has been issued. The prevention policies were based on local hygiene regulations. At present housing programmes of who stress the problem in consideration too of the great part of time that, in industrialized Countries, we all pass at home, in the indoor environment. Following the general introduction the Author relates on the features of indoor climate, that may be identical that out of doors, or may be modified by heating, cooling, humidification and ventilation. Larger commentaries are reported on indoor pollution and its increasing by modern technology producing several new hazards. Physical, chemical and biological indoor air pollutants, with their principal sources and health damages associated, are analyzed. In conclusion the author shows some data from a research on indoor pollution in the houses of Rome. PMID- 11623488 TI - [The places of Mal'aria and the causes of malaria]. AB - According to the Hippocratic medicine remittent and intermittent fevers were caused by bad air (mal'aria) and bad water of marshes, which produced miasmata affecting people living near these environments. This wrong theory was remarkably stable and persistent until the end of the last century, being in fact quite adequate to decribe the epidemiology of malaria in Mediterranean areas, where the transmission of the parasite depended on mosquitoes breeding mainly in marsh ecosystems. The theory was even reinforced with the spreading of severe malaria due to Plasmodium falciparum (more closely associated with warm marshy areas) and when a specific remedy, quinine, came into the picture, improving the distinction of malaria from other fever diseases. After the discovery of the true causes of malaria infection and transmission, scientific medicine developed completely new definitions of malarious environments based on their stratification in terms of transmission risk and several parameters were introduced which provide a measure of the vectorial capacity. This paper focus on the most relevant historical events that have brought to the present knowledge of malarious environments, examining at the same time the effectiveness and limits of the Hippocratic view on the etiology of malaria. PMID- 11623489 TI - [Public health in the XXI century]. AB - To understand what will happen in the future one must draw on the experience of those from the past who have tried to predict what is happening now. The paper develops a taxonomy of visionaries of futurologist; the advocates of historical determinism, who come from both the left, such as Marx, and the right, such as Toffler and Fukuyama; the scientist, ranging from Leonardo da Vinci to Arthur C. Clarke, and the pragmatists, who seek to learn from evidence and the experience of others. These will be examined in turn and the frequent failings of the first three will be illustrated. Drawing on experience in a variety of European countries it will be concluded that our best hope is to learn from each other and from empirical evidence. The article will conclude with a review of some of the challenges which are either predictable but being ignored or totally unpredictable. PMID- 11623490 TI - [Law and nature in the Hippocratic treatise De aere]. AB - The treatise can be considered as one of the first and most important writings of the ancient ethnology. Its most outstanding character consists in an interrelated analysis of the influence both of natural environment and of the political and social conditions on pathology and on the different ways of life. If the natural and climatic aspects of the human habitat play a basic role in determining the health conditions as well as the psychic characters of different populations, it is also true that the political institutions can counteract on these environmental factors. In particular, freedom and democracy may improve the moral and intellectual attitudes of men, while dispotic forms of power make them unwilling to fight and to exercise autonomous judgement. The psychological and intellectual superiority of the Greeks should be traced back to their democratic institutions, that could apply to other people as well. PMID- 11623491 TI - [Etnography between Herodotus and Hippocrates: the case of warrior women]. AB - According to Herodotus, which tells the myth of their origin, Sauromatides are the daughters of Amazons and of Scitian men; they live as warrior women adapting theirselves on a male model from the childhood until the old age. Hippocrates, corretting the herodotean heritage, says that Sauromatides change their roles with male ones, but only until the age of their marriage. Ephoros says that Sauromatides are a people dominated by women; Plato assignes them a special role in his social roject of Laws. PMID- 11623492 TI - The concept of quality of life in relation to health. AB - This paper will discuss the broadening of the concept of health to include social and psychological concepts, as well as physical health, and the movement away from narrow conceptions of health and disease. In Europe and in USA, some specialties, particularly in psychiatry and cancer, have made considerable progress in the development of broader measurements of outcome in relation to health related quality of life. Others, such as cardiology and rheumatology have been more limited (concentrating on role functioning or return to work at most). Across all specialties, however, there has been an increasing interest in measuring outcome of health care in relation to the patient's quality of life. PMID- 11623493 TI - [Health and health services]. AB - The state of health of the world population has costantly improved in recent years. However, quality of life and life expectancy show huge variations in the different demografic regions of the world. To explain such differences three main factors can be considered: 1 - patterns of disease, which are largely determined by geography and climate; 2 - human behaviour; 3 - health services funding, organization and management. The paper develops a discussion on these issues, focusing on correlation between health systems methods of funding and management and state of health of the world population. PMID- 11623494 TI - Experimental techniques and laboratory apparatus in ancient Greece: drug and perfume preparation. AB - Ancient greek laboratory experts - phycisians, drogists or perfumers - may be accredited with the evolution of rather sophisticated techniques for the isolat ion of plant ingredients and the preparation of medicines and fragnances. Mainly based on literary sources, from linear B tablets to Galen or the alchemic corpus, the present paper presents these procedures and describes the apparatus use. PMID- 11623495 TI - [An outline of odontoiatry and odontology in the ancient world]. AB - Dentistry was surely practiced in ancient Egypt, Mesopotamia, Phoenicia, Etruria, Greece and Rome, but odontology arose only with the dawn of Greek science. One may find the first references to a rational odontology only in the fragments of the Pre-socratic philosophers and in the Corpus Hippocraticum. Aristotle was the first to treat odontology under a comparative anatomo-physiological point of view. Celsus and Scribonius Largus got their matter from Hippocrates, Aristotle, the Hellenistic anatomists as well as from folk-traditions, but payed attention rather to dentistry than to odontology. Finally Galen gathered all the knowledge about odontology and dentistry from Hippocrates up to the Hellenistic anatomists and organized all the matter in his monumental teleologic and theological system, that was inherited by both the so called iatrosophists and the Byzantine physicians. PMID- 11623496 TI - Stephanus of Alexandria; on the structure and date of his alchemical work. AB - On the authorship of Stephanus' of Alexandria On the great and sacred art of making gold many questions have arisen, and many scholars have in my estimation misunderstood and undervaluated it. As a commentary on selected passages of earlier alchemical texts it in fact offered an opportunity to its author to demonstrate wide rhetorical prowess, extensive learning, and significant breadth of philosophical understanding. In this article we present additional arguments in favour of Stephanus' authorship of the work; demonstrate that what was its concluding portion has been lost; indicate how two of the original lectures it contained have each been divided into two other lectures; and attempt to pin point its exact date of composition on the basis of astronomical information it contains. PMID- 11623497 TI - [Giovanni Battista Bonagente, a Venetian physician in Cairo]. AB - Giovanni Battista Bonagente from Vicenza was a physician attached to the Venetian consulate in Cairo from 1634 to 1641. Though he did not leave a diary, he partially narrated his Egyptian experience in the letters he sent to his uncle, Giambattista Benasutti. The unpublished correspondance between Bonagente and Benasutti is investigated by the present paper. PMID- 11623498 TI - Society, the state, and abortion in East Germany, 1950-1972. PMID- 11623499 TI - Studies in Linnaean method and nomenclature. PMID- 11623500 TI - Gleanings about dentistry from the world of literature. PMID- 11623501 TI - Charles Fowler (1799-1858), surgeon of Cheltenham, and his contemporaries. PMID- 11623502 TI - Two Norwegian neurological giants: Georg H Monrad-Krohn and Sigvald Refsum. PMID- 11623503 TI - Ludo Van Bogaert (1897-1989). PMID- 11623504 TI - James Young and the "cancer germ". PMID- 11623505 TI - Jonathan Pereira (1804-1853), the father of pharmacology. PMID- 11623506 TI - Dr. Edwyn Andrew's contribution to the Eye, Ear and Throat Institute for Shropshire and Wales. PMID- 11623507 TI - John Desmond Gimlette: "one of God's own". PMID- 11623508 TI - Hypermanic traits behind a Byzantine princess's creativity. PMID- 11623509 TI - Brunel's Crimean War hospital - Renkioi revisited. PMID- 11623510 TI - Sylvester Graham: partly right, mostly for the wrong reasons. PMID- 11623511 TI - The origins of learning disability nursing. AB - Learning disability nursing has always had an ambivalent relationship with the rest of the nursing profession. This article examines the origins of the discipline in the early part of the twentieth century and argues that its development was closely tied to changes in service provision, loose definitions of nursing work and the emerging speciality of mental deficiency within psychiatry. PMID- 11623512 TI - Marketing the municipal model: the London County Council Nursing Service recruitment strategies 1930-45. AB - Municipally administered, with its origins in the Poor Laws, the LCC Nursing Service could be said to have been a Cinderella Service in comparison with the prestigious London voluntary hospitals. This paper analyses the recruitment strategies of the London County Council Nursing Service within the context of the overall national situation during the 1930s and the Second World War. These can be categorised as cosmetic, reactive, innovative and pragmatic. An astute nursing leadership could use the resources of a large municipal authority to challenge the voluntary hospitals in the nursing labour market in the area of acute hospital care. The image of the acute hospitals could be favourably projected; however, local as well as national difficulty persisted in the recruitment of candidates to Cinderella services such as tuberculosis sanatoria. PMID- 11623513 TI - The acute sick versus the chronic sick: the takeover of Fairmile House by the NHS. AB - This study investigates the changes the introduction of the National Health Service (NHS) brought to a former workhouse. The take-over by the NHS changed this workhouse from an infirmary mainly caring for the aged and chronic sick to a hospital mostly caring for acutely ill people. As a consequence, nursing at this institution probably lost some of the expertise it possessed in caring for the aged and the chronic sick. PMID- 11623514 TI - Working conditions and duties of nurses in Byzantium. AB - From the beginning of the Christian Era, nurses in Byzantium were female and belonged to the Church. These women were called deaconesses and received no payment. Later on, there were professional nurses; the men were called hypourgoi and the women hypourgisses. Their main duties were: Psychological support of patients, everyday care of patients' bodily needs and elementary comfort, cleaning of patients and providing them with proper food, the administration of medicines according to a doctor's instructions, supervising wards when the physicians were not present, the performance of enemas, cuppings and bloodletting, the main therapeutic means used at that time, the placing of patients on the operating table and the performance of minor operations. In the present study details are also given about woking hours and the nourishment and payment of nurses. PMID- 11623515 TI - Midwifery in the Belfast City Hospital. AB - The process of improving midwifery services for poor women in Belfast was a slow one. Traditional midwives were gradually supplanted by midwives who were trained and controlled by the medical profession, but it was many years before the problems of puerperal infection were brought under control in the new institutions. PMID- 11623516 TI - Hanwell Lunatic Asylum 1831-1844: the golden years. AB - The achievements at Hanwell Lunatic Asylum were widely praised in their time. The ideals of the physicians were dependent on the attendants for their success. A variety of documentation, including patient case-books, manuals of staff duties, matron's daily report books and visitors reports, are examined to assess the reality behind the public image. PMID- 11623517 TI - Missionary nursing in Nyasaland. AB - This article is an extract from the booklet The Tale of Two Sisters, by the Harvey Twins (Elsie Neave and Isabel Quincey) and is published here by kind permission of Sarah Duncan, Kettering General Hospital, UK PMID- 11623518 TI - The National Health Service Consultants' Distinction Award Scheme - history and personal critique. PMID- 11623519 TI - Therapies for mental ailments in eighteenth-century Scotland. PMID- 11623520 TI - The yew tree (taxus baccata) in mythology and medicine. PMID- 11623522 TI - An exhibition of 50 years of surgery: the Royal College of Surgeons of Edinburgh. PMID- 11623521 TI - The NHS revolution: before and after. A personal view. PMID- 11623523 TI - The role of contraceptive supply and demand in Mexican fertility decline: evidence from a microdemographic study. AB - This paper uses retrospective life history data to assess the impact of family planning services on contraceptive use in a rural Mexican township. Between 1960 and 1990 contraceptive use rose and fertility declined dramatically. Both contraceptive supply and demand factors were influential in these trends. The start of the government-sponsored family planning programme in the late 1970s was associated with a sharp rise in female sterilization and use of the IUD. However, once we controlled for the changing socio-economic and demographic characteristics of the sample, the presence of family planning services had no significant effect on the likelihood that women used modern reversible methods compared to traditional methods. Men and women expressed concerns about the safety of modern methods such as the pill and the IUD. Efforts to increase modern contraceptive use should place greater emphasis on communicating the safety of these methods and improving the quality of services. PMID- 11623524 TI - Fertility and son preference in Korea. AB - In Korea, total fertility declined from 6.0 in 1960 to 1.6 in 1990, in spite of a strong preference for male offspring. This paper addresses the notion that son preference hinders fertility decline, and examines the effects of patriarchal relations and modernization on fertility using the 1991 Korea National Fertility and Family Health Survey. It was found that women who have a son are less likely to have another child, and that women with a son who do progress to have another child, take longer to conceive the subsequent child. This pattern prevailed for women of parity one, two, and three, and became more pronounced with higher parity. A multivariate analysis showed that preference for male offspring, patriarchy, and modernization are all strong predictors of second, third, and fourth conceptions. PMID- 11623525 TI - Famine, disease, and mortality patterns in the parish of Borshevka, Russia, 1830 1912. AB - Scholars have projected a dismal image of nineteenth-century, rural Russia as a society repeatedly punctuated by crop failures, famine, starvation, and epidemics of famine-related diseases. But there has been no rigorous attempt, using appropriate methods, to assess the nature of demographic crises in Russia and their contribution to overall mortality and population growth. The pattern of mortality evident in the parish under examination is distinguished by an extremely high incidence of infant, diarrhoeal diseases and childhood, infectious diseases. This unfavourable disease environment and resulting high rates of infant and early childhood mortality were more closely related to fertility levels, household size, housing conditions, and weaning practices than to annual or seasonal food availablity and the nutritional status of the population. In a disease-driven society, the susceptibility to infection and the force of infection can, to a considerable extent, be determined by demographic factors, familial norms, and climatic constraints. PMID- 11623526 TI - Medieval theories of mental representation. AB - Throughout most of the Middle ages, it was generally held that stored mental representations of perceived objects or events preserved the forms or species of such objects. This belief was consistent with a metaphor used by Plato. It was also consistent with the medieval belief that a number of cognitive processes took place in the ventricles of the brain and with the phenomenology of afterimages and imagination itself. In the 14th century, William of Ockham challenged this belief by claiming that mental representations are not stored but instead constructed in the basis of past learned experiences. PMID- 11623527 TI - Popularizing American psychotherapy: the Emmanuel Movement, 1906-1910. AB - As late as 1907 Americans knew little of psychotherapy. The word itself was virtually nowhere to be found in either professional or popular literature. Talking cures were not talked about. Despite growing medical and cultural awareness of mental suffering, few physicians made any effort to treat such states by appealing to mind. Indeed, for more than 3 decades, American physicians -particularly those who specialized in the treatment of nervous and mental disorders--had scoffed at anything even remotely resembling mental therapeutics. By 1910 this situation changed dramatically. Whereas decades of vigorous internal professional debates had failed to generate a consensus among American physicians and academic psychologists regarding the scientific legitimacy and clinical efficacy of mental therapeuitcs, in 2 short years the Emmanuel Church Healing Movement had forced both physicians and psychologists to confront squarely and publicly a subject that they had long avoided. Lasting from 1906 to 1910, this popular mevement was the primary agent responsibile for the efflorescence of psychotherapy in the United States. PMID- 11623528 TI - Graduate education and postdoctoral training opportunities in history of psychology at North American universities and colleges. AB - The four reports that follow embody the second installment of a series designed both to provide an orienting overview of education in the history of psychology to prospective students in the field and to characterize one highly significant aspect of the state of the discipline as the century ends. Like those included in the first series, each of these reports effectively conveys an awareness of a program's (or an individual professor's) goals and emphases and (in a number of cases) also provides a sense of how the particular program evolved since its creation. Such historically oriented self-presentations seem especially appropriate for a journal that focuses on psychology's past. Unlike the reports in the previous installment, however, these have had to be condensed, at times significantly, and one or two refer readers to their authors for specific additonal information. A final series of reports will appear in History of Psychology's next issue or (as I noted in the last issue), they will if those invited to submit them meet the journal's deadline. PMID- 11623529 TI - Chen Li: China's elder psychologist. AB - Chen Li is one of a small group of psychologists in China who trained abroad early in their careers, returned to teach and do research, and continued doing so into later life beyond normal retirement age. His contacts with a number of prominent psychologists in England and Germany in the 1930s, and his inadvertent position at the center of a political row in China in the 1960s, leading to the shutting down of psychology for 10 years, made him historically important. Known for his work in organizational psychology and education, he is a distinguished psychologist and educational leader. Although trained as an experimentalist, he now embraces a broader view of psychology but remains emphatic it should be applied to real-life problems. PMID- 11623530 TI - The concept of individuality in Canguilhem's philosophy of biology. PMID- 11623531 TI - "The Mouse People": Murine genetics work at the Bussey Institution, 1909-1936 PMID- 11623532 TI - Monsters as evidence: the uses of the abnormal body during the early eighteenth century. PMID- 11623533 TI - Metagons in killer paramecia: problems of reproducibility and alternative hypotheses. PMID- 11623534 TI - Oh give me a home? Disabled civil war veterans and the welfare state. [Review of: Kelly, PJ. Creating a national home: building the veteran's welfare state, 1860 1900. Harvard University Press, 1997]. PMID- 11623535 TI - Victorian vice. [Review of: Beisel, N. Imperiled innocents: Anthony Comstock and family reproduction in Victorian American. Princeton University Press, 1997]. PMID- 11623536 TI - Public visions of genetics. [Review of: Dijck, JV. Imagenation: popular images of genetics. Macmillan, 1998. Mawer, S. Mendel's dwarf. Doubleday, 1997]. PMID- 11623537 TI - The Blue Cross veterinary emblem. PMID- 11623538 TI - Antony van Leeuwenhoek (1632-1723). PMID- 11623539 TI - [Not Available]. PMID- 11623540 TI - Radium girls, corporate boys. [Review of: Clark, C., Radium girls: women and industrial health reform, 1910-1935. University of North Carolina Press, 1997]. PMID- 11623541 TI - Revealing America's welfare state. [Review of: Howard, C., The hidden welfare state: tax expenditures and social policy in the United States. Princeton University Press, 1997]. PMID- 11623542 TI - "Hippocrates coitum comitiali morbo similem iudicavit": a note on Marsilio Ficino, De Vita I, 7. PMID- 11623543 TI - [Diseases of the pericardium in Avenzoar's Kitab al-Taysir (c.1095-1162)]. AB - Avenzoar has been credited as the author of the first description of inflammation of the pericardium in medical historical literature. Our study shows that although Avenzoar authored a study of diseases of the pericardium with emphasis on pathologies, his epistemological framework was similar to that used by Galen and Avicenna, authors who constituted the source of knowledge for Islamic medicine. We show that the approach used by Avenzoar appears to derive from the absence of anatomical and physiological information, and from a detailed description of the indications and treatments, which distinguish his work from earlier writings. PMID- 11623544 TI - [The golden panacea. Alchemy and distillation in the court of Philip II (1527 1598)]. AB - This study analyzes the relationships between Philip II and the two main goals of Alchemy: obtaining or forging alchemical gold, and preparing chemical drugs, liquors and perfumes. The first part of the study shows that throughout his reign Philip II maintained contacts with alchemists of several nationalities (Flemish, German, Italian, English and Spanish) in the Low Countries and Spain who were determined to obtain gold and silver. Their activities were overseen by high level bureaucrats. Despite the disapproval of the Church and intense repression by the Holy Office, the alchemists had no difficulties during his reign, although their situation changed markedly after his death. In relation with distillation, Philip II ordered stills to be installed in all his gardens in Madrid, Aranjuez and the Escorial. He hired a corps of Flemish distillers who worked at all three sites in the preparation of chemical drugs, liquors and perfumes for the royal household. Their activities, and records conserved at the library of the Escorial, bear witness to a new route for the introduction of Paracelsism in Spain. Philip II organized the distillers' activities and brought them under the oversight of his apothecaries and protophysicians. The distillers' activities were later regulated by the by-laws fo the Royal Apothecary, inaugurated in 1594. PMID- 11623545 TI - [Physicians and surgeons in Saragossa during the modern age. Number, social and family structure]. AB - Documentation at the College of Physicians and Surgeons of Saragossa, scattered throughout many archives, made it possible to trace the evolution of the number of physicians and surgeons in the city of Saragossa in the Modern Age with regard to the number of inhabitants of this city. Also studied are the possible causes of increases or decreases in their numbers, and the proportions of physicians and surgeons to inhabitants are compared with figures from other Spanish regions. By studying a 1723 census, the social and family structures of the different health professions in Saragossa are analyzed. Comparisons of these figures to the structures of other professions made it possible to determine the different social level of each structure. The social level of physicians was the same as that of apothecaries, whereas it was higher than that of surgeons and veterinarians and lower than that of legal professionals, notaries and jurists. PMID- 11623546 TI - [The problem of knowledge among enlightened landowners and merchants in the province of Caracas, Venezuela (1793-1810)]. AB - Part of the native elite of the province of Caracas, consisting of landowners and merchants, were slow to become aware of the importance of knowledge and technique for the development of the colony. Awareness came from the moment when they began to participate in the government of the recently unified Tierra Firme provinces (currently Venezuela), through the operation of the Real Consulado de Caracas (1789). Although the consulate had mercantile court functions, it was also responsible for stimulating the development of agriculture and trade in the provinces. The Consuls were concerned with the lack of scientific knowledge and technical personnel needed to improve and increase agricultural productivity, and also with the colony's trade infrastructure. This was a powerful reason for the Consulate to sponsor the project of a Mathematics Academy in Caracas. However, this led to a conflict with another sector of the native elite: academicians at the university. Although influenced by Enlightment ideas, they did not understand the need to instruct young persons in mathematics as applied to the practical crafts. PMID- 11623547 TI - [Population history, medical and health history: fifty years of shared experiences]. AB - The history of epidemics and health has been completely revised in France as a result of studies done by the Annales School and on the basis of the results of historical demographic research of the nineteen fifties and nineteen sixties. The discovery of peaks in mortality in long-term death rates and the construction of a model for the mortality crisis of the Ancien regime have led to the study of past epidemics and their relation with malnutrition. Effects related with the development of historical anthropology and the publications of Michel Foucault have also had an influence. This article notes the important place of the history of the eighteenth and nineteenth centuries in efforts to understand the marked decrease in mortality in developed countries, the disappearance of large epidemics, and the increase in endemics. Methods developed by population historians have made it possible to refine the analyses of this decrease despite variations in nosology. In addition, this article suggests especially promising avenues for future research. PMID- 11623548 TI - Natural and deliberate health: coping with health in German autobiographies from the 18th and 19 centuries. AB - Coping with illness is a topic well established in social psychology, and in other social sciences. In this essay I focus upon coping with health. I restrict myself to health as an invidivual activity. Starting with a differentiation between natural and deliberate health, which was made in the times of the Enlightenment, I look into alternative health accounts represented in German autobiographies. PMID- 11623549 TI - [Matter and spirit: the unconscious in Carl Gustav Carus's psychology (1779 1868)]. AB - Carl Gustav Carus, one of the originators of a doctrine centered on the unconscious, is an interesting figure from current viewpoints. The doctrine he espoused was psychological, but in addition, the author sought foundations for his thinking in the biological knowledge of his time. The unconscious that Carus postulated was simultaneously biological, material and psychological in nature. Thus the history of psychism--the history of the soul--was related with the individual's and the species's biological history. From this perspective the unconscious was recognized as an indispensable element of rational thought. This theory, which recalls in many aspects that of C.G. Jung, made possible the medical study of psychic life and the revaluation of unconscious factors of psychism which were usually denigrated by modern anthropologists and moralists. PMID- 11623550 TI - [Scientific agriculture in the nineteenth century Murcian press as seen by local authors]. AB - This article studies the writings on agriculture published by local authors in the cultural and scientific press in the Region of Murcia during the second half of the nineteenth century. All magazines of the period were reviewed, and the most important information from ten of them, published between 1865 and 1898, was extracted. The articles in these magazines defended three main ideas: the use of chemical fertilizers, the recourse to other sciences (such as meteorology and electricity) within agriculture, and the need to renovate and improve traditional agricultural industries (silk and esparto). But the measures proposed by local scientists did not have the desired impact on the landowning class. PMID- 11623551 TI - [The neurological and embryological studies of Santiago Ramon y Cajal]. AB - The neurological and embryological work of Santiago Ramon y Cajal appeared in three stages: a) Between 1888 and 1893 observations on the development of neuron prolongations led to the observation of the growth cone and formulation of the neurotropic hypothesis. b) Between 1905 and 1908 the study of regenerative phenomena in nerves and nervours centers presented a large body of evidence consistent with the neurotropic hypothesis. c)Between 1910 and 1914 an experimental program was undertaken to test the neurotropic hypothesis; this program led to conclusions on the origin and chemical nature of the growth stimulating factor. These contributions initiated an important line of research that none of Ramon y Cajal's disciples could continue. In the nineteen fifties a group of researchers from three disciplines (biochemistry, embryology and neurohistology) discovered the existence of nerve growth factor (NGF), thus initiating a fertile new field of knowledge in cell biology. PMID- 11623552 TI - Six seconds per eyelid: the medical inspection of immigrants at Ellis Island 1892 1914. AB - Beginning in 1892, immigrants to the United States were subject to a medical inspection, created to restrict the entry of persons with a"loathsome or dangerous contagious" disease or mental defficiency. Ellis Island, which received over 10 million newcomers between 1900 and 1914, served as the largest ever medical screening facility. Far from reflecting a unified policy, the medical inspection offered a complicated compromise amidst a swirl of competing interests. Many industrialists blamed the waves of Southern and Eastern European immigrants for urban joblessness, filth, unrest, overcrowding, and disease. In an era of depression, labor groups opposed immigrant competitors for scarce jobs. Nativists believed immigrants could not overcome their defects because these were genetically transmitted. Germ theory proponents recognized communication of microorganisms as the problem, with controlling the spread of infections as the solution. Many Progressive reformers held that the scientific screening of immigrants offered a systematic solution for the disorder. Dozens of immigrant aid societies struggled to attenuate the effects of the inspection, and as depression subsided after 1900, employers, too, favored the influx of immigrants. This paper examines the social and political basis for the inspection, its realization at Ellis Island, and the reasons for its inability to debar large numbers of immigrants. PMID- 11623553 TI - [Internationalism and science. Social and scientific bases of the European information science movement]. AB - As part of a continuing line of research on scientific documentation we propose in this article a novel approach to the study of the European information science movement at the end of the nineteenth and beginning of the twentieth centuries. We suggest that this movement took place within the context of increasing internationalism of scientific endeavours, a process which was paralleled by the standardization of units, weight and measures for the different sciences. We investigate problems arising from scientific communication in connection with other aspects apparently unrelated to Information Science. Specifically, we refer to conflicts between nationalism and colonialism; concordance and discord between science policy and the corporate interests of nonscientific associations; higher educational policy; the professionalization of sciences; and the economic interests at stake as a consequence of the use of different information models. PMID- 11623554 TI - Veneral disease, public health and social control: the Scottish experience in a comparative perspective. AB - During the first half of the twentieth century, VD became in many countries a metaphor for the forces of physical and moral pollution that appeared to threaten social order and racial progress. By reference to some central aspects of the Scottish experience in a comparative perspective, this article seeks to identify the common denominator of anxieties and assumptions which fuelled public health initiatives towards VD and which defined the boundaries within which VD policy options were discussed. In particular, it will explore various dimensions of social control associated with the treatment and regulation of VD; the degree to which VD controls and procedures have targetted and stigmatised sexually active women, their use to regulate the sexual behaviour of the young, and the way in which discourses shaping medical practice and policy towards VD have enshrined both class and racial stereotyping. The article also examines the powerful moral agenda which shaped the categories and content of treatment and the focus of epidemiology and public health debate. Finally, the institutional and cultural factors shaping the distinctively compulsionist stance of Scottish public health administration towards VD will be explored as a means of identifying some of the possible comparators needed for broader comparative analysis of VD policy in the twentieth century. PMID- 11623555 TI - [The health problems of the virreinato de vueva Granada. Four unpublished documents dating from 1790-1800]. AB - This study is an attempt to investigate health care in the Virreinato de Nueva Granada (1739-1820). Although written reports and testimonies of persons who wielded power within the medical profession during this period, and of person at the highest levels of political power, have already been studied, information is still lacking on the opinions and views of persons who did not occupy high posts, and persons who were influenced by their authors' interests and sympathy (or antagonism) toward the rest of the profession. PMID- 11623556 TI - The fear of (one's own) history: on the relations between medical anthropology, medicine and history. AB - Even though for most of medical anthropologists, history of medicine is far from their professional interest, that is not the case in South European and specially in Latin American medical anthropology. For us, history of medicine is a seminal point of academic discussion in the last two decades particularly in those anthropologists who work on the processes of health/disease/care linked to medicalization. Among others interesting consequences, common areas of interest develop. This article aims to explore a main obstacle to the full conquest of interdisciplinarity, namely the persistence of sabaltern discourses and practices related to medical history and to social sciences among the medical professions, which at the same time becomes also an artifact that led social scientists to misunderstand the image of medical history in medical practice. PMID- 11623557 TI - [Thesis on the history of medicine and science read in Spanish universities, 1995 1997]. PMID- 11623558 TI - [Health and the mass media]. AB - Since the end of last century, due to the diffusion of certain--mostly contagious -diseases, the problem of communicating health issues to the public has emerged as crucial within the context of health care and prevention. The development of mass communication technologies, together with the transformation occured in the sphere of health attitudes and behaviours, have made this problem even more urgent. The plurality of messages and communication agents present the different media and more or less directly related to health has become so high as to discourage the adoption of simplified communication models--linear, unidirectional models--traditionally employed to understand such phenomenon. PMID- 11623559 TI - The origins of modern anesthesia throughout the American experience spanning the world wars. PMID- 11623560 TI - In memoriam: Donald P. Todd, M.D. PMID- 11623561 TI - Gwenifer C.M. Wilson, MD, MBBS, DA (Syd), FANZCA WM laureate of the history of anesthesia. PMID- 11623562 TI - Anesthesiology in California: the early years. AB - This article briefly reviews the early history of anesthesia in California. Much of the history of anesthesia in California has not been completely documented yet and is complex due to the large size of the state. What follows is the most current historical information, and some essential references for further reading. PMID- 11623563 TI - A place to visit in Jerusalem: the Chagall Windows in the Hadassah hospital. PMID- 11623564 TI - Occupational medicine in the Idria mercury mine in the 18th century. AB - Of all medical sciences in Slovenia, occupational medicine has the longest tradition. It is not a mere coincidence that it had developed already at the beginning of 18th century in Idria. The Mercury mine in Idria, is the second largest European mine of its kind, next to the Spanish Almaden, and has been owned by the Habsburg dynasty for four centuries. To attain higher production, the miners in Idria received medical and social care much earlier than anywhere else; chronic intoxication caused by mercury fumes greatly hindered their working ability. The first and, at the same time, one of the most prominent doctors in Idria, J.A. Scopoli (1723-1788) perfectly described the symptoms of chronic intoxication with mercury in his work De Hydrargyro Idriensi Tentamina Physico Chymico-Medica (Venice, 1761) and thus ranked himself among the early medical writers of occupational medicine, medical hygiene and toxicology. His predecessors were Ellenbog, Paracelsus, Mattioli and some others. The article describes the situation in the mine of Idria in the 17th and 18th century and focusses on Scopoli's mineralogical and medical discussion on mercury miners and mercurialism. PMID- 11623565 TI - In the steps of hospes. AB - This brief review traces the evolution of hospitals from their origins to the present. PMID- 11623566 TI - Saints, miracles and healings: eternal challenges. AB - Can miraculous healings be equalized with "spontaneous remissions" from modern medical terminology? Following the trace of (mostly) medieval miracle accounts, the present paper, though arguing against the use of the term "spontaneous", supports the idea of equalization, finding clear examples of failed or incomplete healings, relapses, and the cases of saints who themselves were passing through the process of illness. In conclusion of this interdisciplinary approach combining historical material with modern knowledge, it is advocated that a significant corpus of miraculous healings have been based on suggestive mechanisms. PMID- 11623567 TI - How do cathartic drugs act? A case study on Gregor Horst (1578-1636) and his attempt to defend Galenist theory. AB - This case study deals with the argument of the Galenist author Gregor Horst (1578 1636), Medical Professor at Giessen University, Germany, and later town phyusician in Ulm, in the discussion on how purgatives act. Horst tried to reconcile a number of different opinions within a Galenist framework. His vast erudition enabled him to compare several classical as well as contemporary opinions. He takes into account Galen (129-c.200/216), Erasistratos (c. 330-255 BC), Asclepiades (fl. 1st century BC), the Hippocratic Corpus and the Problemata Aristotelis from antiquity, Mesue and Mundinus (c. 1270-1326) from the Middle Ages, and Jean Fernel (c. 1497-1558), Girolamo Cardano (1501-c. 1576), Johannes Costaeus (d. 1603), Laurent Joubert (1529-1583), Francisco Valles (1524-1592), Tobias Dorncreilius (1571-1605) and Gavriele Falloppio (1523-1562) from contemporary authors. Horst also integrated some Paracelsian ideas from Joseph Duchesne alias Quercetanus (1549-1609). In his attempt to preserve fundamentals of Galenic thought, Horst created a complicated theory nearly breaking under its own weight. He shows a rising divergence within traditional views as well as the fragmentation of Renaissance Galenism which took place already before the discovery of the blood circulation. PMID- 11623568 TI - The medical statues of Paris. AB - Many statues of doctors have been erected in Paris. Sadly, many bronze monuments were deliberately destroyed during the Second World War, including memorials to Claude Bernard, Broca, Charcot, Pean, Raspail and Ricord, and to Berlioz who was a medical student in Paris. Only those of Bernard and Berlioz were replaced after the war. Bronzes of Bichat, Clemenceau, Pinel and the Barons Larrey (Dominique Jean and Hippolyte - father and son) survived the cull, as did the stone monuments commemorating Servetus, Vulpian, Tarnier and Marey. PMID- 11623569 TI - Resources for the history of medicine in Canada. PMID- 11623570 TI - State-of-the-art surgery, circa 1897-1905. PMID- 11623572 TI - The Max Planck Society stamp. PMID- 11623571 TI - Three Mexican murals of philatelic significance. PMID- 11623573 TI - American presidents as a medical theme on stamps. PMID- 11623574 TI - Antiques of the pharmacy in medical philately. PMID- 11623576 TI - Indian doctors - Dr. Ram Nath Chopra. PMID- 11623575 TI - The glycon snake. PMID- 11623578 TI - Professional and family responses to mental retardation in East Bengal and Bangladesh, 1770s-1990s. AB - Since the 1770s, formal knowledge about conditions later known as mental retardation (learning difficulities/disabilities) slowly accumulated with civil administrators, physicians, psychologists and teachers in East Bengal/Bangladesh. Factors in this growth of knowledge are reviewed. Most people with mental retardation and their families managed without professional advice. Some children with mental retardation were casually integrated in ordinary schools. Rooted in local cultures and concepts, the accumulated knowledge and experience of both families and professionals should be recognized, formulated and used in modern disability service planning. It risks being obscured by imported knowledge having greater prestige but less relevance. PMID- 11623577 TI - Munchausen, his attitudes to medicine. PMID- 11623579 TI - The history of herbs at the New York Academy of Medicine Library. PMID- 11623580 TI - The winds of change. PMID- 11623581 TI - 'It begins with the goose and ends with the goose': medical, legal, and lay understandings of imbecility in Ingram v Wyatt, 1824-1832. AB - A number of historians have recently suggested that we need to get out of the asylum if we are to fully understand attitudes to insanity in the nineteenth century. Arguing that accounts of the medicalization of madness have ignored the importance of non-medical attitudes to lunacy and idiocy, recent studies have stressed the need to explore family attitudes and responses in more detail. Unfortunately, efforts to escape the asylum have to some extent been hampered by a persistent reliance on institutional records. This institutional dependence is understandable: certificates of insanity, reception orders, case-books, and asylum registers, together with published documents, constitute the major record of historical constructions of the lunatic and idiotic mind. However, there may be more resourceful ways of exploring both medical and non-medical attitudes to idiocy. In this paper, I want to use the records from a contested will case, Ingram v Wyatt, to demonstrate that records from the ecclesiastical courts can provide access to a domain where the definitions and meanings of idiocy and imbecility were routinely considered by lawyers, lay witnesses, judges, and doctors. I shall argue that such cases constitute a fruitful site for excavating lay, professional legal, and medical attitudes to imbecility, for exploring the complex relationship between medical and non-medical understandings of capacity, and for situating those understandings within the context of professional developments in law and medicine and contemporary concerns about inheritance. PMID- 11623582 TI - 'Purgatory on earth': an account of breast cancer from nineteenth-century France. AB - The subject of this article is the terminal illness of Zelie Martin who died from breast cancer in 1877. She was a Catholic woman of Normandy, a professional lace maker, and the mother of five daughters. Her extensive correspondence, which records her fatal illness, is the main source for this study. Her accounts of the disease are compared with medical texts of the period. Religious responses to illness, and the suppport offered by family members are also described. PMID- 11623583 TI - Profession, skill, or domestic duty? Midwifery in Sheffield, 1881-1936. AB - Midwives today trace their professional identity back to the period following the midwifery regulation of 1902, when provisions were made for the training and registration of all midwives, and for the gradual elimination of the untrained practitioner. Some historians have argued that this represented a definite break and signalled the willingness of midwives to move towards a professional status. A comparison of midwifery in Sheffield pre- and post-regulation demonstrates no significant change in the practice and profiles of those in the occupation; all midwives remained primarily married or widowed part-time workers. Training for midwives was instituted early in Sheffield. Those trained had fairly high caseloads for the period, but their social and economic status was no different from non-trained midwives in the area. Regulation had a significant impact on the attitude of doctors towards midwives, who were increasingly viewed as part of a medical structure of care. Some midwives attempted to pursue collective action in order to improve their prospects, but they were in the minority. The limits to their professional development were demonstrated by their lack of control over supervision, their subordinate relationship to doctors, and their inability to work in unison. PMID- 11623584 TI - The medical officer of health, the social worker, and the problem family, 1943 to 1968: the case of family service units. AB - It has sometimes been assumed that the Report of the Seebohm Committee on the Local Authority and Allied Personal Social Services of 1968 and subsequent Local Authority (Social Services) Reorganization signalled a reduction in the influence of Medical Officers of Health in the care of poor and disorganized families and an increase in that of social workers. This article considers the role of Medical Officers of Health in the care of such families in the period after the Second World War, and their relationship with one of the key voluntary social work agencies in the field, Pacifist Service Units/Family Service Units. By examining the shift in responsibility from public health doctors to social workers and using the Bristol Family Service Unit as a case study, it argues that in many areas the Children and Young Persons Act of 1963 was used formally to transfer responsibility for such families to the Children's Departments and that the process was complete before the Seebohm Committee reported in 1968. It also suggests that those families in difficulty who remained the responsibility of the Public Health Department, and who were thought to have increased in number during the course of the 1960s, presented health visitors and public health doctors with a different range of problems, although they continued to be labelled problem families. PMID- 11623585 TI - Eugenics and birth control: contraceptive provision in North Wales, 1918-1939. AB - The close relationship between the provision of birth control advice and the ideology of eugenics deserves closer attention. This paper focuses on the enthusiasm for eugenic ideas amongst an influential section of the medical profession and their ability to initiate contraceptive provision. A study of North Wales suggests that clinic provision in the interwar period reflected the enthusiasm or hostility of the medical profession more closely than the needs or demands of the female population, and illustrates how, for some doctors, the issue of contraception was seen in the wider context of the nation's health. PMID- 11623586 TI - Chronic pulmonary disease in South Wales coal mines: an eye-witness account of the MRC surveys (1937-1942). AB - In the mid-1930s reports were accumulating from the British coalfields, particularly from the anthracite area of South Wales, that coal face workers suffered a disabling lung condition that was not recognized as the (compensatable) silicosis of rock workers. The Second World War was threatening and discontent was rife. Government, through the Medical Research Council, initiated a medical and environmental investigation of chronic pulmonary disease in South Wales coalminers to make a systematic survey. The medical surveys, 1936 1942, were undertaken by a member of MRC staff, Dr Philip D'Arcy Hart assisted by Dr Edward Aslett of the Welsh National Memorial Association. One colliery (Ammanford) was intensively investigated; fifteen others less so; coal trimmers at the docks were added. The main observations were to confirm and describe radiographically the frequency of serious lung lesions apparently due to coal dust, and distinguishable from classical silicosis. Among recommendations accepted by Government, the lung condition became recognized for compensations, and the generic term pneumoconiosis of Coal Workers' was substituted for silicosis. PMID- 11623587 TI - The conundrum of eighteenth-century English population growth. [Review of: Wrigley, EA; Davies, RS; Oeppen, JE; Schofield RS. English population history from family reconstitution 1580-1837. Cambridge University Press, 1997]. PMID- 11623588 TI - The failure of a scientific critique: David Heron, Karl Pearson and Mendelian eugenics. PMID- 11623589 TI - Evolution and the Eucharist: Bishop E. W. Barnes on science and religion in the 1920s and 1930s. PMID- 11623590 TI - The editor and serendipity. PMID- 11623591 TI - Pharmaceutical wholesale distribution in the United Kingdom, 1950-1990. PMID- 11623592 TI - Sugar in the Middle Ages. PMID- 11623593 TI - On pseudoscience and treponemal disease in the Western Pacific. PMID- 11623594 TI - Heaps of health, metaphysical fitness: Ayurveda and the ontology of good health in medical anthropology. AB - Because most scholars take it for granted that medicine is concerned with healing and problems of ill health, the way in which various medical systems define good health has not been adequately studied. Moreover, good health as such is usually regarded as a natural, normative state of being even by most medical anthropologists, who otherwise take a critical, relativist perspective on the subject of illness, pain, and disease. Using the case of Ayurvedic medicine, this article shows that there is a very different way of looking at the question of how health is embodied. This perspective is proactive and concerned with overall fitness rather than reactive and primarily concerned with either illness or disease. The argument presented here therefore seeks to go beyond the limiting- although extremely useful--orientation of remedial health care and suggest a radical challenge to some of the most basic ontological assumptions in the cross cultural comparative study of medical systems. PMID- 11623595 TI - Dr. Elihu H. Smith and "The Simplist" essay serial in the New Hampshire Journal; or, Farmer's Weekly Museum. PMID- 11623596 TI - Politics and science. PMID- 11623597 TI - Constraints on the origin and evolution of life. PMID- 11623598 TI - Epistemic dualism of mind and body. PMID- 11623599 TI - Death and resurrection in the middle ages: some modern implications. PMID- 11623600 TI - Thomas Samuel Kuhn (18 July 1922- 17 June 1996). PMID- 11623601 TI - Eliot Stellar (1 November 1919-12 October 1993). PMID- 11623602 TI - [Know the ways? On the occasion of Hildegard's of Bingen 900th birthday]. AB - Hildegard is regarded as one of the most important women of the Middle Ages. Her contemporaries from all over the world wrote letters to her searching for help and prayer. Universally working she wrote works about medicine, natural history, compositions of chants for the honour of God and his creation and more than three hundred letters to people all over the world including the popes and the emperor. Hildegard's work and the way she understood herself were strongly marked by vision and prophecy. Her works were of divine origin by vision and audition. Her aim was the religious interpretation of the whole universe and a Christian life in the sense of the bible. Heaven and earth, faith and natural science, medicine and religion, the human existence in all its facts and potentials, everything was a mirror of divine love to her. In her first work Scivias ("Know the Ways") she is considering on the history of creation and salvation, from the origin of the world and of man over Christ's salvation to the fulfillment at the end of times. In the centre is standing the human being as microcosm reflecting the whole world in all conditions and laws. Man is the main work of god, reflecting in his doing and thinking God's love. Man has to know the ways that means to live the life of love in all consequences including reproduction by creating a new human being for the praise of God. PMID- 11623603 TI - [Not Available]. AB - By studying the etiology and the causalities of the cholera breaking out in the German cities since the 1830s the young scientific discipline "Hygiene" tried to influence urban administrations to prevent the contamination of the soil with human excrements. Most of the Hygienists followed the theory developed by Max von Pettenkofer, the first German professor of Hygiene, that the soiling was the causing factor of most of the intestinal diseases. This theory based on the hypothesis of a prerequisite fermentation of a germ in the soil before being capable to produce disease in a susceptible individual. According to this - never irrefutably proved - theory the cities should be aware of the condition of soil (Bodenbeschaffenheit), whereas the pollution of the running water was not considered to be dangerous by reason of the supposed self-purification of running streams. PMID- 11623604 TI - The walls without and the walls within - leprosy and social control in South Africa. PMID- 11623605 TI - [Not Available]. PMID- 11623606 TI - On a wing and a prayer: the biomechanics of the Rev. Dr. Samuel Haughton (1821 1897). AB - In 1873, Samuel Haughton published Principles of Animal Mechanics. Based on research begun in 1862, it was a response to Darwin's The Origin of Species by Means of Natural Selection published three years earlier. In this article, the nature of Haughton's biomechanical researches is described by reviewing and re analysing some of his original work. He showed how muscles could be seen as designed to carry out the maximum amount of work with the least expenditure of energy. Haughton used the results to argue against Darwin's theory of natural selection, the "unproved hypothesis" as Haughton called it. Despite correspondence with Darwin, Haughton received no scientific rebuttal of his arguements. To this day, it would seem, there is a lack of concordance between the biomechanical view of organic life as "optimised" and the evolutionary view of life under continual transformation as organic forms descended "from a supposed common ancestor." PMID- 11623607 TI - Henry Vaughan: poet and doctor of physic. PMID- 11623608 TI - History and bioethics: the uses of Thomas Percival. PMID- 11623609 TI - Reading and teaching social medicine. [Review of: Henderson GE; King NMP; Strauss RP; Estroff SE; Churchill LR. The social medicine reader. Duke University Press, 1997]. PMID- 11623610 TI - Crippled manhood: infantile paralysis and the construction of masculinity. PMID- 11623611 TI - 'The organic mendacity of woman': Otto Weininger, hysteria, and the political ontology of the self. PMID- 11623612 TI - Life in the asylum: patients' letters from Morningside, 1873-1908. PMID- 11623613 TI - The Georgian idiot hospital at Bath. PMID- 11623614 TI - Thomas Laycock, psychiatry and neurology. PMID- 11623615 TI - Carl Wernicke and the concept of 'elementary symptom'. AB - Examination of contemporary medical conference papers reveal that the German clinician, Carl Wernicke, conducted a unique on-going inquiry into psychiatric nosology. Wernicke was searching for what he called the elementary symptoms of mental disorder, or, in other words, the single psychopathological feature, from which all others arose. From 1892 onwards, he postulated a variety of such elementary symptoms. Wernicke's theory makes sense in terms of such categories as anxiety-psychosis and hallucinosis. His work contrasts with that of Kraepelin and also with modern diagnostic criteria. Neither Wernicke nor his followers pursued the theory of elementary symptoms, but an examination of his work sheds light on modern ideas about diagnosis. PMID- 11623616 TI - 'On the pathology of convulsions,' by Sir J.R. Reynolds. (Classical Text No. 36) PMID- 11623617 TI - History of mental retardation: an essay review. AB - The history of mental retardation previously focused on residential institutions and the ideas of professionals. Given that the vast majority of people with mental retardation lived in their family homes or other locations in their communities, this emphasis has been misleading. Recent historical studies by James W. Trent Jr.; Philip M. Ferguson; Steven Noll; and the British scholars in David Wright and Anne Digby's collection, From Idiocy to Mental Deficiency, have opened up the field by describing the complicated relationships between families and the state, by outlining the development of lay concepts of mental disabilities, and by acknowledging the wide diversity of experiences of people with mental disabilities. PMID- 11623619 TI - George A. Miller, language, and the computer metaphor of mind. AB - This article asks why the analogy between humans and computers was understood by cognitive psychologists to mean that "minds exist and that it is our job as psychologists to study them". Earlier psychologists, such as Clark Hull, used analogies between humans and complex machines such as telephone switchboards to defend a rigorous behaviorism. How, then, did the computer metaphor of mind come to be seen as the root concept underlying a paradigm shift from behaviorism to cognitivism? To answer this question, this article examines the life and work of George A. Miller, one of the most prominent of a generation of psychologists who began their careers as "good behaviorists" but later came to embrace cognitivism. PMID- 11623618 TI - The altered rationale for the choice of a standard animal in experimental psychology: Henry H. Donaldson, Adolf Meyer, and "the" albino rat. AB - The mid 20th-century dominance of albino rats in nonhuman experimental psychology research often presumed that the animal embodied fundamental psychological processes that could generalize to a wide range of vertebrates. The author describes the conceptual basis for the original choice of white rats by the 2 individuals most responsible for establishing rats as a prominent animal model in the life sciences at the turn of the century: Henry H. Donaldson and Adolf Meyer. The author stresses the comparative rationale that justified their choice and argues that they sought generality through attention to diversity and species differences. Their approach contrasts sharply with the later view of the rat as a generic animal model that could represent similarities shared by all vertebrates. It is suggested that the change resulted from an emphasis on standardization produced by the growing industrialization of the life sciences in America. PMID- 11623620 TI - Graduate education and postdoctoral training opportunities in history of psychology at North American universities and colleges. PMID- 11623621 TI - Solomon Diamond (1906-1998). PMID- 11623622 TI - Social aspects of biological discussions in Bulgaria from the end of the thirties of the 20th century. AB - The paper discusses the standpoints of the Bulgarian scientist Metodi POPOF to the discussion on the racial identity of the Bulgarians at the eve of the Second World War. PMID- 11623623 TI - The halakhic chapter of ovarian transplantation. PMID- 11623624 TI - "If I don't get my vitamins...anything can happen": nutrition in twentieth century popular culture. PMID- 11623625 TI - Food of the gods as mortals' medicine: the uses of choclate and cacao products. PMID- 11623626 TI - Historical images of the drug market--LX. [Continued regularly]. PMID- 11623627 TI - Scurvy and the early Portuguese explorers. PMID- 11623628 TI - Milk sickness- a plague on the new west. PMID- 11623629 TI - 500 Years of Portuguese misericordias. PMID- 11623630 TI - William Harvey - better psychiatrist than cardiologist. PMID- 11623631 TI - Tommy Douglas. PMID- 11623632 TI - Medical philately - the Scots. PMID- 11623633 TI - Jose Trueta Raspall (1897-1977). PMID- 11623635 TI - William Petty: Oxford anatomist and physician. PMID- 11623634 TI - Dr. Edmund Trench (1608-1669): a Puritan physician in the age of Harvey. PMID- 11623636 TI - Joseph William Bazalgette (1819-1891): a major figure in the health improvements of Victorian London. PMID- 11623637 TI - Mary Ann Dacomb Scharlieb: a medical life from Madras to Harley Street. PMID- 11623638 TI - J Rutherford Ryley: pioneer of antisepsis in New Zealand. PMID- 11623639 TI - William Redfern (1775?-1833): mutineer to colonial surgeon in New South Wales. Part I: shock and recovery. PMID- 11623640 TI - John Snow (1813-1858) and Benjamin Ward Richardson (1828-1896): a notable friendship. PMID- 11623641 TI - Sir Frederic William Hewitt MVO MD. Part I: early life and work on nitrous oxide. PMID- 11623642 TI - Marx and medicine. Part I: before the publication of Das Kapital. PMID- 11623643 TI - C B Fry: thwarted genius? PMID- 11623644 TI - Bernard Mandeville and the therapy of "the clever politician". PMID- 11623645 TI - The statesman and the ophthalmologist: Gladstone and Magnus on the evolution of human colour vision, one small episode of the nineteenth-century Darwinian debate. AB - Among the numerous nineteenth-century sorties into particular aspects of the Darwinian debate are two 1877 publications. The first, Die Geschichtliche Entwickelung des Farbensinnes, was a treatise on the evolutionary development of human colour vision by Hugo Magnus, an obscure German ophthalmologist. The other, The Colour-Sense, was an article by William Ewart Gladstone, the great British statesman. Magnus, working from linguistic science and optical physiology, developed the theory that humankind had passed through successive stages of colour recognition, from none to full perception, brightest colours first. Gladstone supported the theory with data from his studies of Homeric colour words, placing Homer at a very early stage. Their theory was not accepted. It assumed colour vocabulary to be an index of colour recognition, and too little was known about the nature or age of early man. The present study intends to follow this particular episode as an excellent example of the scholarship, argumentation, and limited scientific knowledge of the time, as applied to human evolution. PMID- 11623646 TI - The lens production by Christiaan and Constantijn Huygens. AB - Ever since they began to take an interest in lens grinding, the brothers Christiaan and Constantijn Huygens searched for high-quality glass to turn in to lenses. Historical research in combination with optical measurements on preserved lenses has allowed the verification of the lenses ground by the brothers, and also provided information on who helped them with the necessary knowledge and material. PMID- 11623647 TI - The homoepathic management of cholera in the nineteenty century with special reference to the epidemic in London, 1854. AB - During the nineteenth century homoeopaths claimed better results than their conventional colleagues did for the treatment of epidemic cholera. Those of the London Homoeopathic Hospital in 1854 have been put forward, for 150 years, as evidence of the efficacy of homoeopathy. The evidence is examined in this paper. Failure to inflict exhausting allopathic treatments must have contributed considerably to the homoeopathic success. However it appears probable that the homoeopathic remedies themselves played an active part in the successful treatment of cholera cases. PMID- 11623648 TI - [The reception of homoeopathy among Polish physicians in the 19th century]. AB - The 19th century Polish academic community showed a consistently negative attitude towards the Hahnemannian doctrine. On the other hand, homoeopathy spread more and more widely in Polish society. Popular homoeopathic journals and advisory literature expressed scepticism towards science and materialism or adopted viewpoints close to spiritualism. Furthermore these publications aimed at linking homoeopathy with traditional religious folklore. Homoeopathic domestic medical literature gave the opportunity for medical self-help at a time when relatively few people had access to professional medical services - due to financial reasons in the cities and due to a lack of physicians in rural areas. Additionally homoepathy offered hope to those whose ailments could not be cured by the professional academic medicine. The reception of homoeopathy in Poland was nevertheless limited. The doctrine was commonly known nowhere near as popular as the medical self-help that derived from what is called traditional "folk medicine". Also homoeopathy never was a serious competitor to the therapeutic arsenal of late 19th century academic medicine. PMID- 11623649 TI - Homeopathy and the Russian orthodox clergy: Russian homeopathy in search of allies in the second part of the 19th and beginning of the 20th centuries. AB - During about 40 years of the struggle of Russian homeopaths to spread homeopathy in Russia failed. They had been convinced that all their efforts to introduce homeopathy into the state medical system similar to allopathy, through attracting physicians to homeopathy, proved unsuccessful. In the 1860s-70s, homeopaths had tried to attract laymen, and the clergymen at first, not only as supporters from "above" but also from "below". The Russian Orthodox church rendered help on all levels of its organization taking an active part in the spreading of homeopathy in the Russian Empire when the rural clergy treated peasants with homeopathic medicines and urban clergy participated in activities of the homeopathic societies. Thousands of Russian rural priests treated people with homeopathic drugs in the villages within the unsatisfactory system of Zemstvo medicine until the First World War. The difficult socio-economic situation in Russia in the studied period, as well as an insufficient number of homeopathic physicians prevented wide diffusion of homeopathy among Russian clergymen and further spreading this form of treatment in Russia. PMID- 11623650 TI - [The "Proletarized" national health-scheme doctor. Aspects of the social self image of physicians in the Weimar Republic]. AB - The expansion of the health insurance system during the Weimar Republic changed the professional practice of the physicians considerably, The article discusses the coherence between physicians' perception of this change and their concept of their own social role and position in the German society of the Weimar Republic. Many physicians felt "proletarized" not only because of their difficult economic situation or their problematic relations with the sick-funds. The feeling of "proletarization" was based also on their experiences in their daily occupational practice in the health insurance system. Their changed relations with patients from lower strata or the "mass practice" didn't correspond to the ideal conception of the socially well-respected "burgerlicher Hausarzt" and this charge was interpreted as a sign of the social decline (so it was claimed) of the physician. PMID- 11623651 TI - [Erwin H. Ackerknecht and the Berg/Rath Affair in 1964. On the coping of German medical historians with their history]. AB - In 1964, the Zurich medical historian Erwin H. Ackerknect announced his decision to resign from the German Society of Medical History, Natural Science and Technology (Deutsche Gesellschaft fur Geschichte der Medizin, Naturwissenschaft und Technik - DGGMNT) in a letter to 150 colleagues and prominent personalities in scientific, academic and political circles. Ackerknecht explained that he was resigning from the Society because the medical faculty of the University of Gottingen, supported by its professor of medical history, Gernot Rath - also chairman of the DGGMNT - had awarded the Venia legendi medical history chair to the x-ray specialist and medical historian Alexander Berg. Berg was ideologically compromised by his co-authorship of a book that embraced the ideals of National Socialism and in which he was mentioned as a Obersturmfuhrer of SS. Apart from describing the events surrounding Berg's promotion to the teaching position, this article presents Ackerknecht's perspective on the situation, the continuing influence of further Nazi era's leading historians of medicine the war - enabling Berg to assume his position - as well as the DGGMNT's controversial reactions to Ackerknecht's resignation and the consequences that the affair was to have for the Society. PMID- 11623652 TI - [Defense, attack, and street fighting. The role of medicine and military illustrated the example of the cholera epidemics in Prussia]. AB - This article intends to illustrate the introduction of military rhetoric into medical discourse during the cholera epidemic of 1831/32 in Europe. Even before the era of bacteriology, illness and epidemics were considered to be the military enemies of mankind. Beginning with the rise of the military in early modern times, the language of medical discourses oriented itself on the influential military institutions. Sickness appeared as a warring aggressor. Since the time of the plague at the very latest, military connotations were commonplace in Europe, and this tendency became stronger during the conflicts of the 19th century. In this vein, during the inner crises of Germany at the end of this century, cholera was, at least in the descriptive rhetoric, understood as an inner, destructive, and anarchic enemy. PMID- 11623653 TI - Stabilizing the boundary between US politics and science: the role of the Office of Technology Transfer as a boundary organization. AB - The sociological study of boundary-work and the political-ecomomic approach of principal-agent theory can be complementary ways of examining the relationship between society and science: boundary-work provides the empirical nuance to the principal-agent scheme, and principal-agent theory provides structure to the thick boundary description. This paper motivates this complementarity to examine domestic technology transfer in the USA from the intramural laboratories of the US National Institutes of Health (NIH). It casts US policy for technology transfer in the principal-agent framework, in which politicians attempt to manage the moral hazard of the productivity of research by providing specific incentives to the agents for engaging in measurable research-based innovation. Such incentives alter the previously negotiated boundary between politics and science. The paper identifies the crucial role of the NIH Office of Technology Transfer (OTT) as a boundary organization, which medicates the new boundary negotiations in its routine work, and stabilizes the boundary by performing successfully as an agent for both politicians and scientists. The paper hypothesizes that boundary organizations like OTT are general phenomena at the boundary between politics and science. PMID- 11623654 TI - Crimes of reason, crimes of passion: suicide and the adulterous woman in nineteenth-century France. AB - The anxieties that determined the nineteenth-century French obsession with female behavior found symbolic expression in the adulterous and suicidal woman. We see this clearly in novels where both adultery and suicide feature prominently, but the anxiety these themes provoked was not limited to works of fiction. A striking number of moral essays and medical studies were devoted to the subject of feminine nature during this period, and it is here especially that the dangerous tendencies of independent and sexually active women were revealed. By analyzing the literary representation of the suicidal and adulterous woman in the works of male and female writer alongside the theories of physicians, critics, and moral reformers, the author demonstrates how this image came to symbolize much more than the violation of ethical standards. In literature as in life, unconventional women needed to be severely punished lest their defiant attitudes inspire further acts of rebellion. PMID- 11623655 TI - The "rights" of husbands and the "duties" of wives: power and desire in the American bedroom, 1850-1910. AB - Historians of the nineteenth-century family have long argued for the dominance of a patriarchal model of marital relations in which demanding husbands subjected their passionless wives to a continual grind of emotional and sexual brutalization. This perspective has been challenged by revisionist historians who have argued that the compasionate marital ideal, characterized by considerate husbands and sexually satisfied wives, best reflected the experiences of middle class married men and women. Based on the sexual experiences described in the pamphlets, letters, and newspaper articles written by sexual radicals known as "Free Lovers," this article argues that the late nineteenth-century marriage bed still was a site of conflict. Opening the door into the Victorian bedroom, the Free Lovers provide a unique view of both marital models in operation and transition that sheds light on the dynamic of change in which married couples struggled, failed,and sometimes achieved the erotic relationships promised by the companionate ideal. PMID- 11623657 TI - Prostitutes in history: from parables of pornography to metaphors of modernity. PMID- 11623656 TI - Infanticide and infant abandonoment in the new South: Richmond, Virginia, 1865 1915. AB - The Civil War and Reconstruction and the South's postbellum industrialization produced economic dislocation on a tremendous scale. One product of that economic upheaval was an increasing problem of infanticides and infant abandonments. This case study of Richmond, Virginia, examines patterns of abandonment and neonaticide as documented in records of the city almshouse and the city coroner. It demonstrates that race shaped the options available to women with problem pregnancies in that African American women had access to fewer social welfare unstitutions such as maternity homes. As a result, unmarried black women kept their out-of-wedlock babies more often than did whites, but they also committed infanticide at higher rates than did whites. Moreover, racial trends in infanticides and infant abandonment suggest that Ricomond's white working class experienced economic advancements at the turn of the twentieth century, while the city's black working class continued to live in depression-like conditions throughout the period. PMID- 11623658 TI - New world, new stars: patriotic astrology and the invention of Indian and Creole bodies in Colonial Spanish America, 1600-1650. PMID- 11623659 TI - What moves when technologies migrate? "Software" and hardware in the transfer of biological electron microscopy to postwar Australia. PMID- 11623660 TI - Two institutions and two eras: reflections on the field of medical history: an interview: Owsei Temkin questioned by Gert Brieger. PMID- 11623661 TI - [Not Available]. PMID- 11623662 TI - Ideology and mental health care - two historical perspectives. AB - Two dominant caring ideologies have prevailed in mental health care over the past two centuries and are observable in modern nursing theory and practice. The first is grounded in philosophy and focuses on such issues as: "What is it to be human?"; "How should the good life be lived?" and "What conditions enable human beings to realise their potential?" The best example of this humanistic approach can be seen in the care that was provided at the York Retreat in the late eighteenth and early nineteenth centuries. The second ideology is the result of the rise of biological psychiatry during and after the Second World War. Psychiatric nurses serving in the forces worked alongside doctors as autonomous practitioners and brought their considerably extended expertise back to their civilian work. This paper examines the ethos of the York Retreat and the innovative work of nurses during the Second World War and shows how they have influenced mental health nursing today. PMID- 11623663 TI - Gladys Carter - an advocate of higher education for nurses. AB - Gladys Carter was once well-known as an author of midwifery and nursing texts and articles. She was appointed the first Boots Scholar in Nursing Research at the University of Edinburgh in 1952. The outcome of her work, the Carter Report (unpublished) lent weight to the reform of the Nurse Tutors' course offered at that time by the RCN Scottish Board and to the establishment of the Department of Nursing Studies at the University of Edinburgh. This paper discusses the contributions made by Miss Carter to the case for higher education for nurses. PMID- 11623664 TI - Community mental health nursing, 1954 to 1990: a review of policy, practice and service organisation. AB - From the middle of the last century to the middle of the 1950s, people experiencing mental health problems in the UK invariably faced admission to asylums and segregation from wider society. A steady increase in asylum admissions meant that, by 1955, there were 150,000 asylum beds. Reflecting this institutional mode of care and treatment, nurses caring for mentally ill people, until just over 40 years ago, worked exclusively in asylum settings. This paper traces the evolution of the community mental health nursing (CMHN) profession in the UK. Particular attention is paid to the following influences: The mental health policy context within which CMHN services were created and then expanded. The evolving collective professional identity of CMHNs. The changing relationships between CMHNs and other professional groups. PMID- 11623665 TI - A personal perspective of nursing history. AB - This paper was first presented at the Learning Nursing History Conference in July 1998. In it Maggie Furness describes her experiences of learning and teaching nursing history in Wales. PMID- 11623666 TI - A preliminary survey of midwifery training in Edinburgh, 1844 to 1870. AB - A brief review of the teaching of midwifery in Edinburgh from the creation of the first chair of midwifery in 1723 to the introduction of mandatory teaching of midwifery to medical students in 1833 is given. The evidence that women continued to be taught after this date is examined and the hypothesis that the latter led to the reduction or termination of midwifery training for women is shown to be untrue by examination of the casebooks for the Edinburgh Royal Maternity Hospital (founded in 1844) and associated documents. The nature of the training offered to female pupils prior to 1871, and the contemporary confusion of the terms midwife and nurse, are also examined. PMID- 11623667 TI - Reflections on the life of Monica Baly. AB - Following the death last November of Monica Baly, we publish tributes from friends and colleagues in her memory. We begin with an obituary written by Laurence Dopson. PMID- 11623668 TI - Historical studies in science and technology and the uses to which they can be put. PMID- 11623669 TI - "Ars sine arte:" Nicholas Lemery and the end of alchemy in eighteenth-century France. PMID- 11623670 TI - Environmental imperatives reconsidered: demographic crises in western North America during the medieval climatic anomaly. AB - Review of late Holocene paleoenvironmental and cultural sequences from four regions of western North America show striking correlations between drought and changes in subsistence, population, exchange, health, and interpersonal violence during the Medieval Climatic Anomaly (A.D. 800-1350). While ultimate causality is difficult to identify in the archaeological record, synchrony of the environmental and cultural changes and the negative character of many human responses--increased interpersonal violence, deterioration of long-distance exchange relationships, and regional abandonments--suggest widespread demographic crises caused by decreased environmental productivity. The medieval droughts occurred at a unique juncture in the demographic history of western North America when unusually large populations of both hunter-gathers and agriculturalists had evolved highly intensified economies that put them in unprecedented ecological jeopardy. Long-term patterns in the archaeological record are inconsistent with the predicted outcomes of simple adaptation or continuous economic intensification, suggesting that in this instance environmental dynamics played a major role in cultural transformations across a wide expanse of western North America among groups with diverse subsistence strategies. These events suggest that environment should not be overlooked as a potential cause of prehistoric culture change. PMID- 11623671 TI - Colchicum autumnale and the gout. Naked ladies and portly gentlemen. PMID- 11623672 TI - Ageing through the ages. PMID- 11623673 TI - Achievements in Russia of Sir James Wylie BT., MD. - A Scottish graduate. PMID- 11623674 TI - Special collections at the University of Medicine and Dentistry of New Jersey libraries. PMID- 11623675 TI - The legacy of New Jersey physician book collectors. AB - For 70 years New Jersey physicians generously gave books from their personal libraries to create a medical library in the state. Today, the old and rare medical books they collected are available to new generations of physicians and scholars in the history of medicine collection at UMDNJ Smith Library. PMID- 11623676 TI - A guide to resources in medical history in New Jersey: a project of the Medical History Society of New Jersey. PMID- 11623677 TI - Does the history of science have a future? PMID- 11623678 TI - Tropical climate and moral hygiene: the anatomy of a Victorian debate. PMID- 11623679 TI - The holey spine: a summary of the history of scientific investigation of the intervertebral foramina. AB - The intervertebral foramina (IVFs) are important to all individuals who treat disorders of the spine, but this region is of special historic significance to chiropractors. This is because some of the earliest descriptions of the mechanism of action of chiropratic were related to the IVFs. The history of investigation of the IVFs is very rich spanning time from the fifth century B.C. to the present. Several professions were based upon theories related to the IVFs or upon serious investigations of the IVFs, and the results of other investigations were reported out of proper context in order to criticize chiropractic and other professions. The history of investigation of the IVFs can be divided into three time periods: 1) very early descriptions of neural foramina and the IVFs; )2 discussions of IVFs by developing professions and the studies of the IVFs by Swanberg in the early twentieth century; and 3) studies of the IVFs in the middle and late twentieth century. This paper discusses the major activities of each of these time periods. PMID- 11623680 TI - Victor Coxon, member, B.J.'s Black Tie Club at Palmer, 1936-1941. AB - The 1930's era was a turbulent time for B.J. Palmer who was proposing radical changes in chiropractic methodologies, i.e., the Hole-in-one upper cervical approach, neurocalometer examinations and heavy reliance on x-ray for vertebral listings. Palmer needed and found an inner circle of loyal supporters at the Fountain Head who were named the "Black Tie Club," identified at important Palmer functions wearing the flowing black tie--the Windsor. One such Black Tie Club member was Victor Coxon--a 1930 Palmer School graduate who passed away recently. The present article explores Coxon's assistant directorship of the B.J. Palmer Chiropractic Clinic, some of his many writings, as well as correspondence Dr. Coxon had with the author. PMID- 11623681 TI - Michael A. Giammarino, D.C., D.A.C.B.R.: student, teacher, leader. AB - Born in Brooklyn in 1909, Michael A. Giammarino was one of the first chiropractic radiologists. After receiving his D.C. from Palmer in 1932, he worked in private practice in Brooklyn for six years. However, chiropractic was not licensed in New York so he moved to Coatesville, Pennsylvania, where he ran a successful private practice until his retirement in 1985. During that time, he became interested in radiology and attended many seminars and lectures on the subject, including one in 1946, taught by Waldo G. Poehner, D.C., the first postgraduate course in chiropractic roentgenology ever given. Poehner surprised him at the next convention of the National Chiropractic Association by nominating him for the position of vice-president of the Council on Roentgenology. Giammarino then became involved in the creation of the certification program in roentgenology, which evolved into today's Diplomate of the American Chiropractic Board of Radiology. Giammarino is a past-president of the Board as well as the Pennsylvania Licensed Chiropractors' Association. In addition to these activities, he taught many courses in radiology and undertook an extensive radiographic study of scoliosis in identical twins. He still lives in Coatesville and is very active in the community. PMID- 11623682 TI - D.D. Palmer: the origins of the Palmer School and the itinerant schoolman, 1897 1913. AB - For the last sixteen years of his life, Daniel David Palmer was involved in at least ten institutions in four states offering a course in chiropractic. In a five year period spanning the end of nineteenth and the start of the twentieth centuries, D.D. began the chiropractic educational experience with the Chiropractic School and Cure in Davenport's Ryan Building, suceeded by the Palmer School and Infirmary of Chiropractic (PSIC), followed by the Palmer School of Chiropractic. Further documentation is needed to place Palmer in the East during late 1900, where he may have engaged in the first of his preceptor schools. The Discoverer went to California in 1902 where he presided over the Chiropractic School and Infirmary first in Pasadena and then in Santa Barbara. Returning to Davenport, he joined his son B.J. at the school until he sold his interest in 1906 and moved to Oklahoma City. Between 1907 and 1908, he was part of the Palmer Gregory College and then his own Palmer College, moving to Portland, Oregon. This involved two institutions through 1911, when the senior Palmer settled in Los Angeles, conducted his own school and lectured at the Ratledge and Universal colleges until his death. PMID- 11623683 TI - C.D. Greenall, D.C. and the 1907 California Medical Practice Act. AB - The development of the legal status of the chiropractic profession often resulted from continual persecution by the medical authorities who held almost exclusive power to license health care providers. While the medical boards may seem to offer an "olive branch" in the legislative wars over licensure in the form of drugless practitioner licenses, naturopathic endorsements, or licenses under the "all other" category, their goal was to contain and eliminate all rival professions. A previous article dealt with the prosecution of C.D. Greenall, D.C., at the hands of the medical board. Since writing that article, I have had the opportunity to read The Chiropractor and to develop more fully an understanding of Dr. Greenall and his actions. Not all prosecutions of chiropractic doctors were instigated by the medical profession; some were insisted upon by other chiropractic doctors. Dr. Greenall and his legal counsel were just such a team. With a goal of having California's 1907 Medical Practice Act declared unconstituional, Dr. Greenall presented himself for prosecution. This article more fully details Dr. Greenall and his attempts to gain some form of recognition for the chiropractic profession. PMID- 11623684 TI - James F. McGinnis, D.C., N.D., C.P. (1873-1947): spinographer, educator, marketer and bloodless surgeon. AB - Perhaps best remembered for his contributions to B.J. Palmer's earliest developments in spinography, James F. McGinnis also pioneered in marketing methods while a straight chiropractic practitioner in Iowa. His advertising brought him to the attention of organized medicine, which sought his prosecution. Relocating to California in the early 1920s, he broadened his scope of practice and earned a naturopathic doctorate. In the 1930s he became one of the best known of several chiropractic bloodless surgeons and traveled around the nation to teach his methods. Although initially a passionate member of the Universal Chiropractors Association and receptive to Palmer's introduction of the neurocalometer, McGinnis eventually changed his political allegiance and became an active member of the National Chiropractic Association. He died in 1947 while on a teaching tour of Claifornia's San Joaquin Valley. PMID- 11623685 TI - "The man who made Peekskill famous": Dr. C.R. Johnston--first blind chiropractor. AB - Can a blind person be taught the art and science of chiropractic? If so, can a blind chiropractor be successful in practice? In 1918, Charles Robinson "C.R." Johnston, at the age of thirty-nine, was graduated from the Palmer School of Chiropractic--becoming not only the first blind D.C., but also one of the best known and most successful of his era. He practiced for twenty-five years in the small Hudson Valley community of Peekskill, New York, where his reputation as a "miracle healer" attracted hundreds of patients each week. The local press dubbed him "The Man Who Made Peekskill Famous." C.R. Johnston had come a long way from the Nevada mining camp where he was born. Accidentally blinded at age twenty seven, he achieved notable success as a merchant before seeming to defy logic in choosing to begin again in a controversial new profession. But his attainments in chiropractic became equally inspirational... and the stuff of legend. PMID- 11623686 TI - A 36" circumference tumor in the left quadriceps femoris muscle: a recollection. PMID- 11623687 TI - [Archival sources for the history of malaria in Italy and some open historiographical issues]. PMID- 11623688 TI - [An archival inventory about malaria]. AB - The Archivio Centrale dello Stato is publishing the Repertorio delle fonti per la storia della malaria in Italia, which collects all the archival sources held in the Archivio, concerning the history of malaria and antimalarial activities in Italy from the Unity to the eradication of the disease. The article proposes an overview of the institutional sources which has been located and points out the specific role played by the various Ministeries in dealing with the malaria problem in Italy. PMID- 11623689 TI - [The sanitary administration in Italy and malaria]. AB - The basis for an adequate management of the public health in Italy were layed only from 1888. The article presents the situation of the sanitary organization between XIX and XX centuries; the orgin and the evolution of specific laws concerning malaria. Some aspects of the fight against malaria performed by the Public administration are here described, on the basis of the sources in the Archivio centrale dello Stato; the first antimalaria compaigns; some important occasions of check, planned by the Italian Ministery of Internal Affairs to value the practical opportunity of specific choices. PMID- 11623690 TI - [The archives of the ministry for agriculture]. AB - The documents concern the following topics: the studies performed by the Italian Ministry of Agriculture, Industry and Commerce between 1870 and 1890 on the causes of unhealthiness of the lands around Rome and the methods to remove them, i.e. irrigation canals and agricultural transformations; the role played by the General Direction of the Land reclamation of the Ministry of Agriculture and Forests from 1929 in the realization of the interventions of hydraulic and antianopheles reclamation address to modify the environmental conditions, and in the realization of assistants services and antimalaria prophylaxis in the reclamation zones. PMID- 11623691 TI - [The institutions and the fight against malaria]. AB - The article deals with the history of three different Institutions fighting, through specific ways and competences against malaria in Italy: the Opera Nazionale per i Combattenti (1917-1978), primarily involved in the reclamation programs, the malariological Institute Ettore Marchiafava (1927-1967), with aims of study and research, and the Istituto interprovinciale antimalarico per le Venezie (1926-1967), a regional institution specialized in the systems of eradication. The ACS keeps all the documents the research is referring to. PMID- 11623692 TI - [Grassi's archives of the museum of comparative anatomy of Rome University "La Sapienza"]. AB - The documents, reprints, books, correspondence of Grassi, found in his room at the University of Rome when he died, have been kept in the Institute of Comparative Anatomy, directed by Grassi himself from 1896 until 1925. This fund keeps documents concerning the whole life of the scientist, with a special reference to the Roman period. Numerous are the documents concerning his malariological studies between 1898 and 1910. A first reconaissance has been made in 1980 and then, twice in 1994 and 1998, the fund has been reorganized and an inventory of it has been made. It is collected in 48 boxes containing archivistic documents, 11 boxes of reprints and other publications. The inventory of archival documents has been computerized. PMID- 11623693 TI - [The archival sources for malaria at the ASDMAE]. AB - The Archivio Storico Diplomatico of the Italian Ministry for Foreign Affairs holds a rich documentary fund concerning the role played by Italy in the field of international antimalaria campaigns either as a member of the League of Nations or through a direct partnership with other nations. The article offers an historical reconstruction of the Offices of the Italian Ministry for Foreign Affairs involved in international collaboration. Moreover, the archival positions and the features of the records will be described. PMID- 11623694 TI - [The archives of the section of history of medicine]. AB - The Section of History of Medicine of the Department of Experimental Medicine and Pathology of the Rome University "La Sapienza" keeps the Archives of Angelo Celli, Amico and Francesco Bignami, Giuseppe Sanarelli. The Archives, primarily composed by medical notes, note books, correspondence, have been reorganized and an inventory has been made and computerized. The documents of the scientists Celli and Bignami testify their contribution to the study of malaria and of the pathological anatomy of the infection; Sanarelli's notebooks allow to reconstruct his scientific career. During the inventory, various groups of documents belonging to Alessandro Solivetti (1834-1893), Francesco Todaro (1839-1912), Giorgio Roster (1843-1927), Giuklio Bizzozero (1846-1901), Angelo Maffucci (1847 1903), Ettore Marchiafava (1847-1935), Giovanni Battista Grassi (1854-1925), Giovanni Mingazzini (1859-1929), Giuseppe Bastianelli (1862-1959), Vittorio Ascoli (1863-1931), Raffaele Bastianelli (1863-1961), Guiseppe Ovio (1863-1957), Vittorio Puntoni (1887-1970), Pietro Di Mattei (1896) have been found. PMID- 11623696 TI - Documentation of the history of malaria in Italy at the Rockefeller Archive Center. AB - The Rockefeller Archive Center holds approximately 50,000 pages of archival documents pertaining to the history of anti-malaria programs in Italy in the 20th century. Reports on the status of public health in Italy occur in the archives dating from 1915, but there was no sustained Rockefeller commitment to anti malaria work in Italy until 1924. The article presents a brief description of the sources for the study of the history of malaria in Italy that are held at the Rockefeller Archive Center. PMID- 11623695 TI - [The Guido Casini Fund]. AB - The Parasitology Institute of the University of Rome "La Sapienza" keeps documents from the Societa per gli Studi della Malaria, from the Istituto Superiore di Malariologia Ettore Marchiafava and from the Ente Regionale per la Lotta Antianofelica in Sardegna (Erlaas). The papers arrived in the private Archive of Guido Casini, malariologist and secretary of the Istituto Marchiafava, who involved himself in many activities performed by those Bureaux and who recently gave the documentary sources as a donation to the Parasitology Institute. The intervention of reorganization and inventory of the Guido Casini Fund is in its final phase; it will allow to reconstruct the institutional events of these Bureaux and to point out their important sanitary, scientific and political contribution in Italy and abroad. PMID- 11623697 TI - [Golgi's documents about the history of malaria]. AB - Camillo Golgi played a key role in the studies of malaria infection. Among his outstanding contributions to the topic are the description of the intraerythrocytic cycle of the malaria parasite Plasmodium, responsible for the quartan and tertian fever, and the discovery of the temporal relationship between the recurrent attacks of fever and parasite's multiplication in human blood. Moreover, Golgi was also actively involved in the campaigns against malaria performed in the first ten years of this century by his pupil Adelchi Negri. Golgi's archive at the Museum for the History of the Pavia University keeps important materials on the role of this scientist in the history of malariology. Here we summarize and report some brief extracts of the documents (mainly letters from the nineteenth century biologists to Golgi) relevant to the history of human malaria. PMID- 11623698 TI - [The Sardinian archives for malaria history]. AB - The paper makes some references to the documentary funds for malaria history retained in state and private archives. The most important are seven: the State archives of Cagliari, Sassari, Nuoro, the Provincial administration archive of Sassari, the ERLAAS (Ente regionale per la lotta antianofelica in Sardegna) archive. The private archives are deposited in town libraries of Iglesias and Olzai. The documentation available allows to carry out a lot of research on various courses; a) activity of land reclamation on marshy zones between XIX and XXth century; b) issues of the anti-malarial legislation in the early twentieth century for peculiar social classes such as railwaymen and miners. They were the first to assay the quinine for preventive treatment; c) the anti-anopheles struggle during the Fasciste regime (it was carried out with oil and Paris green and with the predator fish of the genus Gambusia as well) d) organization of anti anopheles campaign of ERLASS after World War II. PMID- 11623700 TI - [The historical museum for teaching of University of Rome III and the archive of the Ente Scuole per i Contadini Dell'agro Romano]. AB - The Historical Didactic Museum, founded in 1986, testifies the history of the school institution in Italy. In the Archivio delle Scuole per i Contadini dell'Agro Romano is available the related documentation on the work done by physicians and teachers against malaria and illiteracy in the roman lands, well testifying the political, cultural and scientific context and the will, possibilities and strategies to confront the serious problems hindering the economical and social growth of the lands around Rome. PMID- 11623699 TI - [Archives, photographies, maps for malary in Latina Province]. AB - After an historical introduction about ancient institutional regime of present Littoria/Latina province (until 1870 organized in Naples kingdom and Papal States), this essay is going to a swift analysis of marshes who reigned all over the land from the periphery of Rome to Fondi, when transient sheperds and woodmen were the only human beings of marshy land. So teachers for that unlettered people came into these lands, and so physicians came to fight against malary, first symbiotic enemy of man. So drainages were tried from Roman's epoch to Medieval and Illuministic one. We'll see Popes, feudal ladies and at last drainage trusts, all working to improve human life before the birth of Latina province. New cities and towns were born just during these trials; after the experiences of Angelo Celli, Italian Red Cross and Istituto per il risanamento antimalarico della regione pontina, many laws looked to medical aid for workers in malaric zones (exactly specified in topographic maps). In 1934 the Comitato provinciale antimalarico was introduced all over italian territory with the R.D.n. 1265. PMID- 11623701 TI - [Malaria in Grosseto Maremma: a social disease]. AB - Several kind of sources testify that, since XIVth century, people living in Grosseto during the summer moved to healthy towns located in neighbouring hills. Starting from the XVIth century malaria became a true scourge for people living in Maremma (especially day labourers and soldiers), and local "signorie" planned some attempts to improve their condition. However, only after the unification of Italy, and the discovery of the role of anopheles in transmitting the etiological agent, the fight against malaria acquired a scientific basis. At the end of the last century, the epidemiology of malaria in the Maremma Grossetana was studied by outstanding scientists (Koch, Grassi and Gosio among others). The present essay explores the archival sources concerning the history of malaria in the Maremma Grossetana from the beginning of "estataura" to antimalarial campaigns carried out during the first three decades of the XXth Century. PMID- 11623702 TI - [Rome and malaria]. AB - This article offers an overview on the roman Archivio Storico Capitolino papers reconstructing the history of malaria in the city of Rome and in the countryside from 1870 to the 2nd post-war period. The researches must be based on the critical evaluation of the Deliberations of the Consiglio Comunale of Rome, reflecting the social history of life in the city. The chronological continuity of this archivistic series allows to follow the history of Malaria in Rome since the Unity of Italy. The papers of the VIII Bureau of Hygiene and Sanity offer interesting points of views for the period 1883-1940, useful for deeply investigating the attitude of Roman Administration towards the fight against malaria. The roman Library of the Archivio Capitolino keeps an important bibliography, collected by the Campidoglio since the past century. PMID- 11623703 TI - [Sources for the history of malaria in the historical archives of the Accademia Dei XL and the Accademia Dei Lincei]. AB - A research has been performed in the Historical Archives of the Accademia dei XL and the Accademia dei Lincei, to verify the presence of documentary sources concerning the activity of some malariologists members of the above mentioned institutions. During the search, the Authors found out an envelope sealed out by Giovan Battista Grassi in 1925. At the moment, it is not possible to specify what kind of material the envelope keeps, because of the necessity to wait the deliberation of the classes, and consequently the beginning of the Academic courses. PMID- 11623704 TI - [Malary in Basilicata]. AB - In this paper the geological, idrographical, climatical, and, above all, social and cultural conditions, favouring the atavic presence of malary in Basilicata (Lucania) -in the late 19th century the death-rate was three times the national average - are shortly surveyed. From these remarks we tried to outline the main steps of the struggle against malary in the first half of the 20th century, when land reclaimers, doctors, hospital attendants, hydraulic engineers, workmen, and farmers joined their efforts to eradicate the plague. PMID- 11623705 TI - [Notes on the sources for the study of malariatherapy in Italy]. AB - The article presents the results of a critical evaluation of the clinical histories of 1240 cases of progressive paresis recorded in the S. Maria della Pieta (1911-1950) and reconstructs the scientific discussion about the results of malariatherapy and its action mechanism. The bibliographical study led to a regional characterization of the therapy in the scientific orientation and techniques. The authors are now working out the data, hoping for a future debate on the topic. PMID- 11623706 TI - [Not Available]. PMID- 11623707 TI - Auenbrugger, Corvisart, and the perception of disease. PMID- 11623708 TI - New insights into the Far Eastern pattern of mortality. AB - Some of the highest levels of excess mortality of males found anywhere in the world were present in several Far Eastern populations during the 1960s and 1970s but have progressively disappeared since that time. This study uses cause-of death data to determine the diseases responsible for the existence and attenuation of these sex differences in Hong Kong, Singapore, and Taiwan. The results indicate that respiratory tuberculosis is the single most important underlying cause of the existence and attenuation of the pattern, that the role of liver diseases is not clear cut, and that other causes (such as cardiovascular diseases) are also important. A review of numerous risk factors yields no compelling reason why these populations experienced such large sex differences in mortality. However, it seems likely that public health and biomedical improvements (particularly those related to the reduction in mortality from tuberculosis) played a critical role in the attenuation of the Far Eastern mortality pattern. PMID- 11623709 TI - The activities of Professor Curt Krause in Bulgaria. AB - Prof. C. Krause spent six years in Bulgaria, from 1928 to 1934. He officially assumed his position on October 10, 1928, as he delivered his opening lecture titled About the past, present and future of the general pathology and pathological anatomy. He worked skillfully and with utmost devotion on the organization of the department of General Pathology and Pathological Anatomy at the Veterinary Faculty. The educational process normalized. Seven students completed their doctoral theses under his leadership and first research assistants were prepared. He lay the foundations of the pathoanatomical museum in his department. Prof. Krauseus contributions to the development of the pathological anatomy in Bulgaria both as a scientific discipline and as a veterinary practice are substantial. In 1939, Prof. Krause received the highest honour for his work in Bulgaria - he was awarded the title of doctor honoris causa of veterinary medicine of the Sofia University. PMID- 11623710 TI - On the Roman god Verminus. AB - An inscription from the II century BC, dedicated to the Roman god Verminus and considered to be due to the rising threat of human worm infections, is studied from linguistic and historical points of view. Having analyzed the historical sources we have reached the conclusion that the erection of the shrine was not related to the human helminthosis but to the epidemic infectuous disease which affected both animal and humans. PMID- 11623711 TI - "Ox in boots:" an expression in the Sumerian farmer's instruction elucidated by later evidence. PMID- 11623712 TI - Linda Warden BA ALA. PMID- 11623714 TI - Galling wasp sexual misbehavior in the human scientist. [Review of:Jones JH. Alfred C. Kinsey: A public/private life. W.W. Norton, 1997]. PMID- 11623713 TI - Orphanages: the strength and weakness of a macroscopic view. [Review of: Hacsi, T.A. Second home: orphan asylums and poor families in America. Harvard University Press, 1998]. PMID- 11623715 TI - Mental disorder after two wars: sauce for the goose, but none for the gander. [Review of: Dean ET. Shook over hell: post-traumatic stress, Vietnam, and the Civil War. Harvard University Press, 1997]. PMID- 11623716 TI - The enduring effects of cohort characteristics on age-specific homicide rates, 1960-1995. AB - In the past decade, young people in the United States have been two to three times more likely than in the two previous decades to commit homicides, while those 25 years and older have been less likely to commit homicides than were members of their age groups in the earlier time period. These changes in youth homicide rates are associated with two cohort characteristics that are theoretically linked to criminality: relative size of cohorts and the percentage of cohort member born to unwed mothers. These effects persist throughout the life span, are independent of age and historical period, and can explain fluctuations in homicide arrest rates before the recent upturn. PMID- 11623718 TI - Introverted, extroverted, and perverted controversy: Jung against Freud. AB - Like many controversies in science, the one between Freud and Jung is overloaded with ad hominem arguments despite the incompatibility of such arguments with the pretensions of both sides to attain scienfific ad rem validity. Unlike natural scientists, Freud and Jung regarded their own ad hominem arguments as relevant to general and impersonal truths. They practically legitimized such a use claiming to have a clinical basis for the rejection of the opponent's objections by a de validating analysis of the opponent's personality as a whole. The argument of this paper is that the de-validating strategy was neither an inevitable psychological outcome of the intricate interpersonal relationships in analytic situations nor the logical consequence of any clinical or scientific psycho analytical discovery. It followed from the epistemological invalid pretension to have a general theory of mind which could explain by mental analysis the existence of "unreasonable opinions," and the application of the same principles to the opinion that the theory itself is unreasonable. Such a pretension, apparently specific to mystical traditions in theology and metaphysics, was deeply rooted in the modern epistemological tradition. The paper examines the impact of the differenct branches of that tradition on Freud and Jung's respective ideologies, theories, and practice, including the ad hominem malpractice. PMID- 11623717 TI - Do disputes over priority tell us anything about science? AB - Conflicts between scientists over credit for their discoveries are conflicts, not merely in, but of science because discovery is not a historical event, but a retrospective social judgment. There is no objective moment of discovery; rather, discovery is established by means of a hermeneutics, a way of reading scientific articles. The priority conflict between Roger Guillemin and Andrew Schally over the discovery of the brain hormone, TRF, serves as an example. The work of Robert Merton, Thomas Kuhn, Augustine Brannigan, and Grygory Markus shows that scientists read scientific articles by means of the application of a set of pragmatic rules that subtend the normative requirements of what counts as a scientific discovery. In other words, there is a hermeneutics of science, but it is internal to that form of life. Recategorization of priority conflicts has an impact on our view of scientific controversy generally. The impact is the revision of the boundary lines of scientific controversy and the further specification of its fine-structure. PMID- 11623719 TI - What is a tachistoscope? Historical explorations of an instrument. AB - This essay addresses the historiographical question of how to study scientific instruments and the connections between them without rigidly determining the boundaries of the object under historical scrutiny beforehand. To do this, I will explore an episode in the early history of the tachistoscope--defined, among other things, as an instrument for the brief exposure of visual stimuli in experimental psychology. After looking at the tachistoscope described by physiologist Volkmann in 1859, I will turn to the gravity chronometer, constructed by Cattell at Wundt's Leipzig institute of psychology in the 1880s. Taking Wittgenstein's notion of family resemblances as a methodological suggestion to travel from one member to another to find out just how members relate to one another, I will investigate part of the family to which both the trachistoscope and the gravity chronometer turn out to belong. A detailed analysis of these instruments, using both historical sources and historical accounts of psychological instruments, may demonstrate that the instrument is not a standard package that, if well applied, will simply secure good results. Each package needs to be assembled again and again; the particular package that is assembled may differ on different occasions. Thus an alternative is developed to an understanding of instruments as univocally functioning material means. PMID- 11623720 TI - Old and cared for: place of residence for elderly women in eighteenth-century Toulouse. AB - Although they lacked the ideological and economic advantages of patriarchal authority, women in eighteenth-century France were no less likely than men to receive support in their old age from friends and family. Elderly women rarely lived on their own, and when they could not rely on their children for support, they found care in more distant kin and friends. This support was not derived from economic coercion but from a vague sense of moral duty. Informal networks of care sufficed for both the rich and the poor except in cases of extreme illness. PMID- 11623721 TI - Globalization and the trade in human body parts. AB - Since the early 1980s, the number and variety of organ transplantations has increased enormously worldwide. Accompanying this increase has been the emergence of a market for human body parts. This paper argues that, while the trade in human body parts is conditioned by technological advances, it must be understood in the broader context of globalization, specifically the extension and intensification of a capitalist mode of exchange. In this regard, it is argued that the trade in human body parts mirrors the "normal" system of unequal exchanges that mark other forms of trade between the developed and undeveloped regions of the world. PMID- 11623722 TI - Midwifery in Canada and Sweden: a cross-national comparison. PMID- 11623723 TI - Delivering midwifery in Ontario: how and why midwifery was integrated into the provincial health care system. PMID- 11623724 TI - Issues of integration and professionalization in the home birth movement in Australia. PMID- 11623725 TI - Labour dispute: Alberta midwives and nurses battle over birth attendance. PMID- 11623726 TI - A new profession to the white population in Canada: Ontario midwifery and the politics of race. PMID- 11623727 TI - Midwifery: an Australian perspective. PMID- 11623729 TI - Walking the diversity talk: curriculum within first year midwifery education. PMID- 11623728 TI - Nulliparous women's perception of the risk of pregnancy after age 35. PMID- 11623730 TI - Why did Quebec decide to experiment with the practise of midwifery rather than legalise the profession? PMID- 11623731 TI - Psychiatry without mind in the eighteenth century: the case of British iatro mathematicians. PMID- 11623732 TI - Sterne, Edward Baynard, and the history of cold bathing: medical Shandeism. PMID- 11623733 TI - "An Edinburgh surgeon of great eminence" in De Quincey's Confessions of an English opium-eater. PMID- 11623734 TI - Dickens's changing responses to hereditary insanity in household words and all the year round. PMID- 11623735 TI - Jung and the Kabbalah. AB - Jung's use of Kabbalistic symbols and ideas as well as his personal Kabbalistic vision are critically examined. It is argued that as great as Jung's acknowledged affinity is to the Kabbalah, his unacknowledged relationship was even greater. Jung has been accused of being a contemporary Gnostic; however, the interpretations Jung placed on Gnosticism and the texts Jung referred to on alchemy were profoundly Kabbalistic, so much so that one would be more justified in calling the Jung of the Mysterium Coniunctionis and other late works a Kabbalist in contemporary guise. Although Jung, at least during the 1930s, appears to have had powerful motives that limited his receptivity to Jewish ideas, his highly ambivalent and at times reproachable attitude toward Judaism should not prevent one from appreciating the affinities between Jungian psychology and Jewish mystical thought. PMID- 11623736 TI - The moral of her story: exploring the philosophical and religious commitments in Mary Whiton Calkins' self-psychology. AB - Over the course of 3 decades, from the turn of the century to the late 1920s, Mary Whiton Calkins articulated and defended a system of self-psychology that held that psychology as a field should be organized as the science of selves. Calkins' system was far from popular at the time, which leads one to question why she persisted in dedicating herself to the cause of defending it. Previous research has sought answers to this question through examination of Calkins' experience as a faculty member at Wellesley College. In this article it is additonally argued that Calkins was not prepared to abandon her system of self psychology because it was intricately connected to her ideas about ethics and morality. PMID- 11623737 TI - Otto Rank, the Rankian circle in Philadelphia, and the origins of Carl Rogers' person-centered psychotherapy. AB - Otto Rank's will therapy helped shape the ideas and techniques of relationship therapy developed by the Philadelphia social workers Jessie Taft, Virginia Robinson, and Frederick Allen in the 1930s. Rank's work and these ideas and techniques in turn strongly influenced the formulation of Carl Rogers' person centered psychotherapy. This article compares and contrasts will, relationship, and person-centered approaches to psychotherapy and discusses the social factors- primarily the professional conflicts between a male-dominated psychiatry and female social workers over the independent practice of psychotherapy--that were crucial in the dissemination of Rank's psychological thought and the early popularity of Rogers. PMID- 11623738 TI - History of a historian of psychology in the United States. AB - This article focuses on the author's activities in the United States relating to the history of psychology. It does not deal with his involvement in applied psychology in Europe (1937-1939), and it only touches on research on malnutrition and behavior, illumination and performance, and aging carried out in the Laboratory of Physiological Hygiene at the University of Minnesota (1941-1958). Activities bearing on the history of psychology dominated the years spent at Lehigh University (1959-1979) and the years of retirement (1979-present). The principal events include organizing the first scientific meeting of the American Psychological Association's Division 26, History of Psychology (1966); two summer institutes on the history of psychology (1968, 1971); the editing of a historically oriented volume on psychology in the USSR (1972) and of R.I. Watson's papers on the history of psychology (1977); organizing and editing a volume containing 6 monographs on the history of psychology in the United States (1984); and editing a volume concerned with international research during the years 1919-1981 on malnutrition and behavior. PMID- 11623739 TI - Marx and medicine. Part II: After the publication of Das Kapital. PMID- 11623740 TI - The myth of Mozart's poor health and weak constitution. PMID- 11623741 TI - The iconography of Girolamo Fracastoro (c. 1483-1553). Part I: woodcuts and engravings. PMID- 11623744 TI - William Redfern (1775?-1883): mutineer to colonial surgeon in New South Wales. Part II: promise and default. PMID- 11623742 TI - Sir Frederic William Hewitt MVO MD. Part II: the Anaesthetic Bill and professional and private life. PMID- 11623743 TI - Frederik Ruysch: master anatomist and depictor of the surreality of death. PMID- 11623745 TI - Erasmus Darwin FRS (1731-1802) and the foxglove controversy. PMID- 11623746 TI - Arthur Lynch: parliamentarian, physician and author. PMID- 11623747 TI - Dr. Itsuro Tashiro, compiler of a unique medical history of the Miyazaki region. PMID- 11623748 TI - A historical review on the recognition of well-being and diseases in Japanese literature: its multiplex construction. AB - In 1997 the Japanese government enacted a law concerning organ transplantation offered by brain-dead patients. However, there were no cases of transplantation carried out according to this law during this one year. This might be partly explained by the psychological background of the recognition of well-being, disease or death among Japanese citizens. This investigation was performed in an attempt to reveal the psychological background of matter among Japanese citizens as shown in Japanese literature from ancient to modern times. The result showed that a multiplex construction exists in the recognition of well-being, disease or death which is partly inherited by modern Japanese citizens. (1) Pre-Buddhist era: people believed that soul and spirit were immortal, and also believed in the miraculous power of language. (2) Old-Buddhist era: people believed in the power of an evil spirit or imprecation, and incantation and prayers were very common procedures to avoid such ill omens. (3) New-Buddhist era: people felt themselves drawn toward yearning for the world of Buddha, and believed in the future existence. (4) Confucianism and Buddhism era: people worshiped God and Buddha, and accepted any trouble as misfortune. (5) Modern science era: people recognize the value of rationality. PMID- 11623749 TI - Inoculation in Boston from 1721 to American Independence. AB - In 1721, a smallpox epidemic in Boston occurred and inoculation was introduced. It has been said that the inoculation in Boston was under the influence of England, but it has been shown this is not correct. It was clergyman Mather and surgeon Boylston who promoted inoculation, while doctor Douglass, a graduate from Edinburgh University, strongly opposed inoculation. The selectmen in Boston opened a town-meeting and discussed inoculation, and finally rejected the introduction of inoculation into Boston. The Boston citizens were also strongly opposed to inoculation and they even threw a lighted hand grenade into Mather's room. Since then, controversies over inoculation broke out every time a smallpox epidemic occurred. In 1775, George Washington became the commander of the war of Independence. He took a countermeasure to get rid of the smallpox epidemic in his army and he inoculated all army and recruit members. Meanwhile the English commander Howe, who did not pay attention to smallpox, had to decide to withdraw from Boston, since the smallpox epidemic broke out among the English army. In this paper I tried to clarify the controversies over inoculation in Boston, and the fact that smallpox epidemic and inoculation were related to the success of the immigration of the Puritans and also to the success of the independence of the New World from the British Empire. PMID- 11623750 TI - New information about Seishu Hanaoka's family tree according to the burial records of Jizoji Temple. AB - Since Shuzo Kure published his voluminous monograph entitled "Seishu Hanaoka and His Surgery" in 1923, the biography of Hanaoka has been widely studied and two monographs were published in 1964 and 1973 to describe in detail the life and activities of Hanaoka. In spite of these historical studies, for more than seventy years several important persons have been unclarified in the pedigree of the Hanaokas. Recently the author made a repeated survey of two volumes of the burial records of Jizoji temple of Naka town, Wakayama Prefecture. The temple had been the family temple of the Hanaokas during Seishu Hanaoka's lifetime. About one hundred and eight posthumous names, given names, and death dates of the Hanaokas were found in the records, which can be classified into several branches. The most important findings are: 1) the given and posthumous name and death date of Seishu's younger sister (Otane) was identified and another younger sister's posthumous name and death date were guessed with a strong probability; 2) Seishu's third son's death date was identified and the given and necromancy name and, death date of Seishu's third daughter were made clear. In addition, several important findings on Seishu's ancestors are presumed from this investigation of the burial records. These new findings are very useful to understand the background of Hanaoka's study on "Mafutsu-to" and his biography. PMID- 11623751 TI - A sermon against the dangerous and sinful practice of inoculation by the English minister Edmond Massey. PMID- 11623752 TI - David Harker: October 19, 1906-February 27, 1991. PMID- 11623753 TI - Yandell Henderson: April 23, 1873-February 18, 1944. PMID- 11623754 TI - Stephen W. Kuffler: August 24, 1913-October 11, 1980. PMID- 11623755 TI - Berta V. Scharrer: December 1, 1906-July 23, 1995. PMID- 11623756 TI - Victor Chandler Twitty: November 5, 1901-March 22, 1967. PMID- 11623757 TI - George Brownlee Craig, Jr. July 8, 1930-December 21, 1995. PMID- 11623758 TI - Hallowell Davis: August 31, 1896-August 22, 1992. PMID- 11623759 TI - Carl Barton Huffaker: September 30, 1914-October 10, 1995. PMID- 11623760 TI - Joseph Carl Robnett Licklider: March 11, 1915-June 26, 1990 PMID- 11623761 TI - Isadore Perlman: April 12, 1915-August 3, 1991. PMID- 11623762 TI - Francis Otto Schmitt: November 23, 1903-October 3, 1995. PMID- 11623763 TI - James Augustine Shannon: August 9, 1904-May 20, 1994. PMID- 11623764 TI - Maxwell Finland: March 15, 1902-October 25, 1987. PMID- 11623765 TI - Clinton Nathan Woolsey: November 30, 1904-January 14, 1993. PMID- 11623766 TI - The early regulation of figs in the United States. AB - When the Food and Drugs Act became law in 1906, the commercial fig industry in California had just become established. Domestic figs began to compete with imported figs, especially from Turkey and Greece. Fig culture, both in the Near East and the American West, was beset by many threats, especially insect pests. The Bureau of Chemistry in the U.S. Department of Agriculture (USDA), enforcer of the 1906 law, undertook to protect consumers from spoiled figs from overseas and in interstate commerce. Simultaneously the USDA helped both domestic and Turkish growers to counter infestation. Through the State Department, sanitary controls in Smyrna were enhanced. Scientific experts from Agriculture educated American growers and packers in protective techniques. A high point of both legal actions and educational endeavors came in the late 1920s. In the 1930s, the state of California assumed the role of guiding inspection and helping dispose of substandard figs. World War II brought retrogression in fig quality, requiring a new corrective campaign by the Food and Drug Administration, successor to the Bureau of Chemistry, to prevent spoiled figs from reaching the market. By the 1950s, the need for such legal actions was rare. PMID- 11623767 TI - On infanticide, the peculiar institution, and public memory. [Review of: Weisenburger, S. Modern medea: a family story of slavery and child-murder from the Old South. New York: Hill and Wang, 1998]. PMID- 11623768 TI - Cleaning up our act: germ consciousness in America. [Review of: Tomes, N. The gospel of germs: men, women, and the microbe in American life. Harvard University Press, 1998]. PMID- 11623769 TI - The 1941 sulfathiazole disaster and the birth of good manufacturing practices. PMID- 11623770 TI - Arrangement (and fitting) of drug stores--part 2. PMID- 11623771 TI - What did Bayer do before aspirin? PMID- 11623772 TI - Book review response. PMID- 11623773 TI - Vernacularization as an intellectual and social bridge. The Catalan translations of Teodorico's Chirurgia and of Arnau de Vilanova's Regimen Sanitatis. AB - This study analyzes the dissemination and readership of two medieval medical works in Catalan. Combining the use of diverse sources such as the manuscripts themselves, post-mortem inventories, and the prologues written by the translators, the study shows how the diffusion of these works exemplifies the two main audiences to which vernacular texts were addressed. These were, on the one hand, literate but not Latinate surgeons and other practitioners interested in the new medicine emanating from the emerging universities; and on the other, nobles and burghers interested in issues of health and disease and in natural philosophy in general. The framework for the study is the general process of consolidation of the new medical system which developed in late medieval Latin Europe. PMID- 11623774 TI - The English vernacular afterlife of Benvenutus Grassus, opthalmologist. AB - This paper traces the history in print of a treatise on ophthalmology by Benvenutus Grassus, De probatissima arte oculorum, originally written in Latin in the late thirteenth century and translated into English in the fifteenth century. It presents evidence of the appearance in print of the English translation as a section of Philip Barrough's The Method of Phisicke in 1583, a book that went through ten subsequent reprintings, the last appearing in 1652. Other evidence is presented on the influence of Benvenutus treatise in ophthalmological works published in the earlier half of the seventeenth century, and both greater and lesser traces are shown to exist. The last appearance of the treatise is in an auctioneer's catalogue of 1713, where apparently the book failed to find a buyer. PMID- 11623775 TI - Alchemy and the use of vernacular languages in the late middle ages. PMID- 11623776 TI - Early history of veterinary public health in the United States. PMID- 11623777 TI - Animal therapy over the ages: 1. acutherapy. PMID- 11623778 TI - A retrospective of veterinary medicine at Oklahoma State University. PMID- 11623779 TI - Why study veterinary history. PMID- 11623780 TI - The history of sexuality: from ancient polymorphous perversity to modern genital love. PMID- 11623781 TI - Defining ancient Greek sexuality. PMID- 11623782 TI - Stones, stars, mazes, and placentas. PMID- 11623783 TI - Album angels: parent-child relations as reflected in 19th-century photos, made after the death of a child. PMID- 11623785 TI - Psychological history in France: 1968-1997. PMID- 11623784 TI - The deal with the devil to "Save" psychoanalysis in Nazi Germany. PMID- 11623786 TI - Psychological history in Germany and its problems with obtaining approval from historical science: state of research - perspectives. PMID- 11623787 TI - Dutch historians and depth psychology. PMID- 11623788 TI - Unearthed ancient Chinese medical literatures currently preserved in Russia. AB - An outline probing a Russian exploration team exploiting the ancient literature remains existed in the vast northwestern region in China was made in this paper for the medical literatures already publicized which are collected at the Heicheng Department of Ayrmita Museum attached to the Petersburg Branch of Oriental Institute of Russian Academy of Sciences. The process of excavation and its collection preserved in the Museum is first dealt with, followed in order by the Museum filed numbers of medical literatures unearthed by the Russians in Dunhuang, Heicheng and Khotan and their book titles, authors, contents and care. PMID- 11623789 TI - [Preliminary exploration on TCM literature of Heishuicheng collected in Russia]. AB - The Heishuicheng literature collected in Russia was excavated by the Russian explorer Kotzlov at the remained site of Heishunicheng of Xixia in Inner Mongolia early this century, and carried back and preserved in Petersburg, Russia. This rare treasure was well and secretly hidden in clandestine room for a long period, not known to any other people. The detailed contents and characteristic and appearance of the valuable TCM literatures among them and its academic and research significance are explored here. PMID- 11623790 TI - Investigation on Qiong yao shen shu (Qiongyao's Magical Book). AB - Written in about the period of late Yuan to early Ming dynasties, Qiongyao's Magical Book is attributed to a Taoist who was also conversant with acupunture art. By investigation, it is found that there are, at least, three books carrying the same title of Qiongyao's Magical Book, including a 3 volume Qiongyao's Magical Book now lost; a 3 - volume Qiongyao's Magical Book of Discovery (also called The Acupuncture Classic of Qiongyao the Immortal printed in the Ming dynasty, which is entirely different from the previous one and is an apocrypha; and a 4 - volume Qiongyao's Magical Book printed in the Qing dynasty also called Qiongyao's Great Collections of Magical Books wiich is a mixture of authentic and apocryphal texts in which 2 medical books irrelevant to the original are attached to the end of volume 3, with supplements by later writers intermingled in other volumes. PMID- 11623791 TI - Study on the date of compilation of Wen bing tiao bian (Systemic Discourse on Warm Diseases). AB - It has long been recognized that Wu Jutong compiled Wen bing tiao bian in the year 1798. Through study on the printing time of the book, prefaces in the book written by Zhu Bin and Zheng Bao, and the contents of the book, it is claimed that the book was written in 1798, and by then his work was not yet finished. The first manuscript was completed in 1804, finalized and printed in 1813. The chapter of "Supplemented discourse on predominant qi of autumn dryness" was written in 1835, while Pili (thunderbolt) powder and its description were supplemented in 1836. In other words, the compilation of the whole work, from writing to finalized first manuscript, lasted for 15 years, and that for the completion of the whole book, 38 years. PMID- 11623792 TI - Introduction to historical facts of Qin Qin's struggle for right of TCM development. AB - The posthumous lengthy article titled "The Course of Establishment of National Association of TCM Physicians and Working Report" by Qin Qin reflected the difficult course of TCM professional fighting against the National Government. This includes the following aspects: the difficulties of TCM professionals encountered since the establishment of ROC, elimination of Weng and Liu's proposal, founding of TCM Institution (Guo yi guan) but excluded from the administrative system, failure of the intention to making use of political force, the disparity of positions between traditional and western medicine, the overlook of TCM education, the preliminary elevation of TCM position, the preparation of the National Association of TCM physicians and its formal establishment, inscription to the meeting, and working report, petition for establishing a TCM school, and strive for support from public opinion. PMID- 11623793 TI - Characteristics of development of modern western medical ethics. AB - The paper reviews the development of Western medical ethics during 17-19th centuries. The transformation of the theories of the medical ethics from ancient to modern took place in the period because of the changes of social construction and medical care. The modern philosophical and ethical theories provided a powerful backing for the medical ethics. What is medicine and what is a physician's proper role were again defined against the background. So the medical ethics had some new characters in the period, including the increase of government's duty for people's health care, resurrection of virtue, the establishing of professional ethical code, and the birth of the civil right for health care. PMID- 11623794 TI - A developmental history of thoracoscopic surgery. AB - Thoracoscopic surgery, an old yet new discipline, has a history of 88 years, undergoing 4 stages in its course of development, namely, development, flourishing, decline and rejuvenation. This author claims that its developmental history can be divided into 5 periods, viz. embryonic stage of traditional thoracoscopic surgery and its flourishing, stagnation period, and the development and mature period of modern thoracoscopic surgery. In China, this discipline starts rather late and lags behing the advanced level of the world as a whole. PMID- 11623795 TI - Inspiration and development of modern medical education in Henan Province. AB - The medical education in Henan is introduced during the period from Opium War to 1948, with emphasis laid on the developmental course of the highest academic institution, the Medical Department of Hanan Zhongshan University and several high advanced vocational nurse schools, all for western medicine, as well as officially - run Henan Medical School and several privately - run TCM schools, all for TCM, with their establishment and characteristics mentioned. It is also pointed out that this histroy can shed light on the current medical educational reform. PMID- 11623796 TI - Modern woman medical education in China after the introduction of western medicine. AB - In 1879, Nanhua (Southern China) Medical School, the earliest school for western medical professionals in China, first admitted women to study medicine in separate class. In 1885, Yamei King became the first woman conferred a medical doctor degree from the US. The first woman medical school, the Canton Woman Medical School, began to enroll students. In 1933, of the 3655 students in the 28 medical schools, 619 were female, representing 16.94% of the total. Among these schools, 2 were exclusively for females, 3 for males, the remaining 23 for both sexes. In 1934, special committee for nurse and midwife were set up in the medical education committee in Ministry of Education. Up to this year, there were 2 state - run, 10 province - run and 206 private - nurse's schools, and 21 schools for midwife training. PMID- 11623797 TI - A brief development history of clinical application of drugs containing henbane. AB - There is a long history in the application of drugs containing henbane with its application in ancient time and studies in modern time. For over 3 decades, it has been applied in over 100 kinds of disorders with satisfactory results. PMID- 11623798 TI - Nomenclature, functions and classification of surgical knives of Ming-Qing dynasties. AB - Based on the diagrams of knives recorded in laryngological literature of the Qing dynasty, together with the surgical lancets unearthed in Ming tomb of Jiangyin region, the nomenclature of all surgical knives and its functions are discussed and then classified. It is claimed that the configuration of the knives as a whole, either obligue or round, are the basis of its functions and classification. Thus, the knives are divided into 4 groups, vis. lancets, curved knives, obligue - edged knives and plain knives, involving over 30 kinds of surgical knives. PMID- 11623799 TI - A retrospect of research on Chinese medical history in the past five years. PMID- 11623800 TI - Study on Shamanistic healing art of Mongolian nationality. AB - Shamanism, the earliest religious belief of Mongolian nationality, has a remote origin. It was highly developed and mature as early as in the matriachal society. The primitive healing art contributed to the belief of ancient Shamanism by folk people was combined with ancient Mongolian medicine. Appraising from the development of history of Mongolian medicine as a whole, Shamanism did exert a positive influence rather than a negative one. PMID- 11623801 TI - Medical history and the science of medical history. PMID- 11623802 TI - Why sickness and death rates do not move parallel to one another over time. AB - Scholars sometimes claim that mortality and morbibity move papallel to one another over time. Using case studies from nineteenth-century England and Wales, this essay plots actual relationships in historical populations and explores why parallelism should not be expected. The implication of finding that mortality and morbidity chart independent courses is that they are either shaped by different factors or by the same factors operating in different ways. Hence morbidity should not be expected to be controlled by policies formulated to control mortality. PMID- 11623803 TI - Morbidity and mortality during the health transition: a comment on James C. Riley, "Why sickness and death rates do not move parallel to one another over time." PMID- 11623804 TI - Reply to Bernard Harris: morbidity and mortality during the health transition: a comment on James C. Riley. PMID- 11623805 TI - The orgins of vaccinia virus--an even shorter rejoinder. PMID- 11623806 TI - The origins of vaccinia virus - a brief comment. PMID- 11623807 TI - Body, image, text in early modern Europe. PMID- 11623808 TI - Graeco-Roman case histories and their influence on Medieval Islamic clinical accounts. AB - The medieval Islamic medical tradition was the direct heir of Classical and Hellenistic medicine thanks to an unprecedented movement of translation into Arabic, commentaries and systematizations of Greek scientific texts. In the process of assimilation, not only theoretical principles, but also literary models of presenting medical knowledge were adopted, amongst them the case history. Since the clinical account can be used as a tool for medical instruction as well as an instrument for professional self-promotion, this study seeks to investigate which purpose most motivated Islamic physicians, and to demonstrate the extent to which they were influenced by the stylistic patterns which served them as a model. This article comprises an analysis of the context, literary devices and purpose of case histories of the Epidemics, Rufus of Ephesos and Galen, and compares them with those by the tenth-century Islamic physician Abu Bakr Muhammad b. Zakariya al-Razi. Author of the largest number of case histories preserved within the medieval Islamic medical literature, al-Razi's clinical records constitute an instrument with which to study and expand medical knowledge as well as providing useful material for students' medical training. Although al Razi fused elements from the sources which served him as a model, he did not emulate Galen's use of the clinical history to assert himself in order to gain authority and prestige, but remained faithful to the Hippocratic essence. PMID- 11623809 TI - How to read Simon Forman's casebooks: medicine, astrology, and gender in Elizabethan London. AB - Simon Forman's astrological casebooks record thousands of medical consultations. Amidst the wealth of information in these documents, however, it is unclear to what extent Forman relied on the stars for diagnoses and therapies, or how the casebooks reflect the dymanic between Forman and his clients. This article attempts to answer these questions by reading the casebooks alongside Forman's guide to astrological physic. This approach reveals that astrology was paramount in Forman's evaluations and treatments of his patients. According to Forman, in order for him to effect a cure, he had to be trusted. It was particularly difficult to treat women because their health depended on the state of their wombs, and on their sexual activity, subjects about which women were notoriously duplicitous. The task of the astrologer was first to assess whether or not a woman was sexually active, and only then could he make a judgement about her disease. At the same time, in demonstrating an ability to discern whether or not she was being honest about her sexual activities, Forman won her confidence. By accounting for the role of astrology and the dynamics between the patient and the physician, this article provides the framework within which to read one of the most comprehensive records of medical practices in early modern England. PMID- 11623810 TI - The countrie continues sicklie': white mortality in Jamaica, 1655-1780. AB - The tropical regions of the New World in the early modern era offered European migrants great wealth but were also demographically deadly. This paper presents hard data on white mortality in seventeenth- and eighteenth-century Jamaica and shows that white susceptibility to disease, especially yellow fever, led to appalling white mortality. High white mortality, especially in urban areas in the first half of the eithteenth century, meant that Jamaica did not become a settler society full of native-born whites, as occurred in plantation British North America. The failure of white settlement and continuing high mortality accentuated whites'penchant for fast living, for fatalism, and contributed to slaveowners' callous disregard for the welfare of their slaves. White life chances were not helped by inappropriate medical attention. Although Jamaican doctors' explanations of high white mortality were occasionally correct, their adherence to humoral and miasmic theories of medicine led them to promote remedies that were at best ineffectual, at worst detrimental. Contemporaries, however, refused to accept the facts of white demographic decline, in part because to do so would have been to deny the possibility that Jamaica would become Anglicized rather than Africanized. PMID- 11623811 TI - Blood, coughs, and fever: tuberculosis and the working class of Buenos Aires, Argentina, 1885-1915. AB - This article, utilizing medical histories and municipal public health reports, focuses on tubercular men, women, and children of the working poor in Buenos Aires between 1885 and 1915. Crowded living conditions and an insanitary working environment increased the poor's susceptibility to tuberculosis. Both public health officials and physicians assumed that the living and working conditions and the immorality of the labouring class encouraged the spread of tuberculosis from their neighbourhoods to those of the elite. The Anti-Tuberculosis League and the efforts of doctors to bring about prevention and cures, which generally mirrored those of the United States and Europe, failed to decrease the death rate from tuberculosis in Buenos Aires between 1885 and 1915. Medical knowledge was limited, while public health officials had neither the time nor funding to change a system that was embedded in the working and living structures of the community. The tubercular poor chose to evade prevention policies and relied on the limited services of sanatoriums, clinics, and hospitals only as a last resort. PMID- 11623812 TI - "The real point is control": the reception of Barbara McClintock's controlling elements. AB - In the standard narrative of her life, Barbara McClintock discovered genetic transposition in the 1940s but no one believed her. She was ignored until molecular biologists of the 1970s "rediscovered" transposition and vindicated her heretical discovery. New archival documents, as well as interviews and close reading of published papers, belie this narrative. Transposition was accepted immediately by both maize and bacterial geneticists. Maize geneticists confirmed it repeatedly in the early 1950s and by the late 1950s it was considered a classic discovery. But for McClintock, movable elements were part of an elaborate system of genetic control that she hypothesized to explain development and differentiation. This theory was highly speculative and was not widely accepted, even by those who had discovered transposition independently. When Jacob and Monod presented their alternative model for gene regulation, the operon, her controller argument was discarded as incorrect. Transposition, however, was soon discovered in microorganisms and by the late 1970s was recognized as a phenomenon of biomedical importance. For McClintock, the award of the 1983 Nobel Prize to her for the discovery of movable genetic elements, long treated as a legitimation, may well have been bittersweet. This new look at McClintock's experiments and theory has implications for the intellectual history of biology, the social history of American genetics, and McClintock's role in the historiography of women in science. PMID- 11623813 TI - Essay review: the historiography of immunology is still in its infancy. PMID- 11623814 TI - Coleridge's "theory of life". AB - Coleridge has been seen by some not so much as a poet spoiled by philosophy, but as a philosopher who was also a poet. It could be argued that his major endeavor was an attempt to save the life sciences form the mechanistic interpretation which he saw as the outcome of Lockean "mechanico-corpuscularian" philosophy. This contribution describes that endeavour. It shows its connection to the social circumstances of the time. It discusses its relationship to the poetic sensibility of the "Lake poets" and to the German thought which Coleridge absorbed during and after his sojourn in Gottingen in 1798-99. It describes the nature of his "Theory of Life" as seen not only from the posthumous publication itself, but also from the numerous hints and struggles recorded in his voluminous notebooks, letters and lecture notes. It is concluded that, although never adequately assembled, it forms the only serious attempt to construct a profound alternative to the ultimately mechanistic biology of Charles Darwin and the psysiologists of the second half of the century. As such it strongly influenced the young Richard Owen and, as is well known, was eventually overwhelmed by the Darwin-Huxley synthesis of the 1860s. Nevertheless, insofar as Coleridge's concept of life ultimately derived from his ambition to find a way of healing the Cartesian divide, we may wonder whether the recent upsurge in consciousness studies may cause us to look again at his panentheistic ideas and, discarding the obsolete and fanciful metaphysics, recast them into a more acceptable form. PMID- 11623815 TI - Darwinism and the origin of life: the role of H.C. Bastian in the British spontaneous generation debates, 1868-1873. AB - Henry Charlton Bastian's support for spontaneous generation is shown to have developed from his commitment to the new evolutionary science of Darwin, Spencer, Huxley and Tyndall. Tracing Bastian's early career development shows that he was one of the most talented rising young stars among the Darwinians in the 1860s. His argument for a logically necessary link between evolution and spontaneous generation was widely believed among those sympathetic to Darwin's ideas. Spontaneous generation implied materialism to many, however, and it had associations in Britain with radical politics and amateur science. Huxley and the X Club were trying to create a public posture of Darwinism that kept it at arm's length from those negative associations. Thus, the conflict that developed when Huxley and the X Club opposed Bastian was at least as much about factional in fighting among the Darwinians as it was about the experiments under dispute. Huxley's strategy to defeat Bastian and define his position as "non-Darwinian" contributed significantly to the shaping of Huxley's famous address "Biogenesis and Abiogenesis." Rhetorically separating Darwinism from Bastian was thus responsible for Huxley's first clear public statement that a naturalistic origin of life was compatible with Darwin's ideas, but only in the earth's distant past. The final separation of the discourse on the meaning of Brownian movement and "active molecules" from any possible link with spontaneous generation also grew out of Huxley's strategy to defeat Bastian. Clashes between Bastian and the X Club are described at the BAAS, the Royal Society, and in the pages of Nature and other journals. PMID- 11623816 TI - J.C. Prichard and the concept of "moral insanity". Classic text no.37. PMID- 11623817 TI - Demystifying mentalities by G.E.R. Lloyd. [Review of: Lloyd, G.E.R. Demystifying mentalities. Cambridge University Press, 1990]. PMID- 11623818 TI - Morphine withdrawal, treatments 1900-30. AB - The treatments used between 1900 and 1930 for morphine withdrawal are discussed. The accounts are mainly taken from contemporary textbooks which contain fascinating descriptions of their authors' preferred methods and criticisms of regimes given by other therapists. Delirium, produced by atropine or similar substances, is advocated to cover withdrawal symptoms. The present paper draws parallels with current issues, e.g. withdrawal of opiate under cover of general anaesthesia, follow-up studies and cost-benefit analyses. The particular problems of addicted doctors in 1900-1930 are addressed as are the comparisons then made with non-medically qualified addicts. It is important we keep in mind past mistakes and over-valued ideas so as to reduce any similarly misplaced optimism in our current treatment options. PMID- 11623819 TI - The International Symposium on 'History of Psychiatry on the threshold of the twenty-first century. PMID- 11623820 TI - Post-traumatic neurosis in nineteenth-century Germany: a disease in political, juridical and professional context. PMID- 11623821 TI - Hypnosis, false memory and multiple personality: a trinity of affinity. AB - This paper presents a discussion of the relationship between hypnosis, false memory, and multiple personality. Since Morton Prince's classic case of multiple personality (Prince 1906), only two other cases rival Prince's original work (Thigpen and Cleckley 1957, Schreiber 1973) in popularity. This paper illustrates startling new material regarding the third most famous of multiple personality cases, that of Sybil. Tape recordings recently discovered document the fraudulent construction of multiple personality. The importance of the role of hypnosis is discussed in this presentation. The author of this paper knew the author of Sybil, Flora Schreiber, through many years before her death, and therefore is able to present first-hand information about the author and her work. PMID- 11623822 TI - Coping with quantity and quality: computer-based research on case records from the "Wittenauer Heilstatten" in Berlin (1919-1960). AB - Computer-aided research on hospital records has been used increasingly by historians in recent decades. We reviewed a representative sample of four thousand patient records from the "Wittenauer Heilstatten" (known as "Karl Bonhoeffer-Nervenklinik" since 1965) over the period 1919-1960. Special focus was placed on the daily lives of patients, and we attempted to trace continuity and discontinuity through three differeent political systems. This paper outlines our research methodology by describing the structure of data entries, the use of special computer software and problems encountered with historical sources. It outlines the medical and social information which was obtainable and concludes by discussing the use of additional historical sources, necessitated by the limitations of case records. PMID- 11623823 TI - Robert Boyle's approach to the ministrations of Valentine Greatrakes. PMID- 11623824 TI - How anaesthesiology came to Sweden. PMID- 11623825 TI - History of anesthesia: early use of nitrous oxide. PMID- 11623826 TI - Mortality during the first 25 years of general anesthesia in America: contemporary outcome studies. PMID- 11623827 TI - Thomas Drysdale Buchanan (1876-1940). PMID- 11623828 TI - "This is something which will go round the world". PMID- 11623829 TI - Charles Brenton Huggins (22 September 1901-12 January 1997). PMID- 11623830 TI - [Medical humanism at the Faculte de medecine de Paris: one hundred years of history (1795-1898)]. AB - During the nineteenth century, tumultuous relationships existed between the public authorities, the Paris Medical Faculty, its students and teachers, the medical and the popular press. These agitated debates concerned the value of teaching history in medical studies. This paper aims to follow the main steps of these debates through various texts: the new plan for the structure of Medicine in France (1790); the creation (1795), suppression (1822) and restoration (1870) of the Paris chair of the History of Medicine; Guerin's report (1830) concerning the a new reorganization of the Paris Medical Faculty; Dr. Dezeimeris's petitions (1837) addressed to the French Minister of State for Education. These debates remain topical and instructive. PMID- 11623831 TI - Claude Bernard and pancreatic function revisited after 150 years. AB - In 1848, Claude Bernard described the lipolytic function of the pancreas. His experimental procedure was original and as he always affirmed, easily replicable. In this study we repeated the original Bernardian experiments for emulsification and saponification of fats, following the original descriptions from his laboratory manuscripts. The results were astonishingly similar to those obtained by Bernard, confirming the validity of his experiments and conclusions, as well as emphasising again his original concepts on the importance of experimental repeatability in scientific medicine. Considering the surgical difficulties we encountered, we must conclude that Claude Bernard required great manual dexterity to obtain these results without the benefit of modern technology and anaesthesia. PMID- 11623832 TI - Historical declines in tuberculosis in England and Wales: improving social conditions or natural selection? AB - A reinvestigation of the relationship between the decline of tuberculosis and improvement in social conditions in England and Wales during Victorian times. DESIGN: A retrospective study using data published in the annual reports of the Registrar General from 1853 to 1910. The diseases studied, in addition to tuberculosis were, dysentery and cholera including their total and infant mortality. Social conditions were evaluated from earnings and population density per house. Tuberculosis mortality declined at an annual average rate of 1.71% (95%CI 0.77 to 2.63) whereas total mortality, infant mortality and mortality from cholera and dysentery and house population density showed no statistically significant decline over the same period. Real earnings increased by 1.05% (C10.29 to 1.81). Improving social conditions do not provide the total explanation for the decline in tuberculosis during Victorian times. Other factors, principally natural selection, probably played a role. Part of the current increase in tuberculosis may be caused by effective drug therapy eliminating natural selection. PMID- 11623833 TI - Getting a feel for percussion. AB - When Auenbrugger introduced percussion it was direct or immediate percussion of the chest. Corvisart was the first to recognise that percussion not merely gave a sound but also a sensation to the percussing fingers. When Piorry introduced mediate percussion the sensation was more readily appreciable. However, there were many astute clinicians who ignored the sensation and these included Stokes, Hope, Latham and Gerhard. To this day some popular handbooks of physical signs do not mention this valuable component of percussion. PMID- 11623834 TI - Joseph Daquin, Piedmontese Savoyard physician, a "not well-known chiarugi". AB - We present a critical review of La philosophie de la folie, second edition, published in 1804. Joseph Daquin's thoughts and clinical activity in the psychiatric field are described. Daquin's ideas about various forms of madness and the different therapeutic, moral, physical treatments, his anatomical studies, successes and failures are presented. Several clinical cases are described. The author's view of the moon's influence on madness is described. Finally it is shown how very important was the human person and the moral treatment of madness for Daquin, in contrast with the current opinion at the end of 1700. PMID- 11623835 TI - [The beginnings of physiology of the human brain, from antiquity to the Renaissance]. AB - For more than 3,000 years in Western civilizations, the knowledge of the human body gained very little ground at first, due to taboos. The body was regarded as sacred and Medicine only resorted to plants in order to heal. Hippocrates was not familiar with anatomy as the human body could not be dissected. He developed a theory of humors connected with the primary elements and opposing the dry and the moist. Even though he did not know the nervous system, he nonetheless pointed out that emotions stemmed from the brain and were caused ty particles (pneuma) emitted by the objects around us. Galien was one of the first to mention physiology but could only dissect animals to understand Man. He took up the theory of humors but did not reach any concrete results as he considered the brain as made up of faeces. Only in 1000 AD did Avicenne try to shape the cell theory with its three cells (the ventricles in today's parlance) in direct relation to the nerves, which he described but did not represent. Representation of the nerves was only be given in the mid-13th century by Khalifah in his ophtalmology treaty. Finally, during the Renaissance, when books started conveying both text and pictures, brain physiology emerged; Albert le Grand was its first expounder and his work was then taken up in a 1475 inculabulum in which 5 cells instead of 3 are described and represented. Leonardo da Vinci was the second one; at the end of the 15th century he dissected may corpses to understand human morphology. Unfortunately his work, which was conducted very rigorously from an anatomical point of view only surfaced at the end of the 19th century. He was the first to conduct the anatomical cross-dissection of the brain. Last came Magnus Hundt and Georg Reisch; in the early 16th century they still represented the three cells of Avicenne even though Reisch described more sophisticated connections between the organs of the senses. PMID- 11623836 TI - [Hippocrates and his legacy: a colloquium in Brussels, May 7 and 8, 1999]. PMID- 11623837 TI - Other centres of calculation, or, where the Royal Society didn't count: commerce, coffee-houses and natural philosophy in early modern London. PMID- 11623838 TI - Correspondence networks and the Royal Society, 1700-1750. PMID- 11623839 TI - The Royal Society and the emergence of science as an instrument of state policy. PMID- 11623840 TI - Medieval descriptions and doctrines of stroke: preliminary analysis of select sources. Part I: The struggle for terms and theories - late antiquity and early Middle Ages. AB - This first of a series of papers on the history of stroke presents an examination of a number of exemplary Greek and Latin sources, ranging from late antiquity to the dawn of the Middle Ages. We first establish a chronological order of various groups of texts and, whenever possible, ascertain the relationship of one group of writings to another. In the second century A.D., Galen had used the Hippocratic concept of humoral imbalance as a fundamental explanatory mechanism for the interpretation of clinical manifestations of apoplexy. Galen definitely rejected the Aristotelian precept of the primacy of the heart. According to his teaching, stroke resulted from the accumulation of a thick and dense humor in the ventricles of the brain blocking the passage of the animal spirit. Galen's Greek texts became axiomatic for compilers of the Byzantine period (Aetius of Amida, Alexander of Tralles, Paulus of Aegina). But his ideas contrasted starkly with the theories of the Methodical School which exerted - through the Latin writings of Caelius Aurelianus - a certain influence on authors of the Latin West (Cassius Felix, Theodorus Priscianus). References to stroke can also be found in many theological writings of the early Middle Ages. PMID- 11623841 TI - Medieval descriptions and doctrines of stroke: preliminary analysis of select sources. Part II: between Galenism and Aristotelism - Islamic theories of apoplexy (800-1200). AB - This second paper on medieval descriptions and doctrines of stroke reviews concepts outlined by famous Muslim physicians of the Middle Ages such as Rhazes, Haly Abbas, Avicenna, and Averroes. Contrary to a popular belief, Islamic neurological texts represent not only a bridge between ancient and western medieval medical knowledge, but also document remarkable advancements. Whereas statements on diagnosis and prognosis lack originality, the endeavors of physician-philosophers and medical authors led to substantial additions and important changes in theory. Such modifications include the integration of ventricular doctrine and particularly the attempt to unify Aristotelian and Galenic tenets which resulted in a complex discussion about the seats and causes of apoplexy. The fairly simple model handed down by Galenists of the Byzantine period was replaced by more detailed classifications, which proposed "cerebral" as well as "vascular" origins of the disease without suggesting a "cerebrovascular" etiology. Islamic therapeutic strategies included dietetic, pharmacological and surgical elements. The use of the cautery in "chronic apoplexy" was a special feature of Arabic surgery. PMID- 11623842 TI - Medieval descriptions and doctrines of stroke: preliminary analysis of select sources. Part III: multiplying speculation - the high and late Middle Ages (1000 1450). AB - By analyzing a body of texts compiled by various medical authors from the 11th to the 15th century, four basic developments can be noted: (1) From the beginning of the eleventh century the reception, translation and assimilation of Arabian and arabicized ancient texts became the ultimate goal of Western medicine (Constantine the African, Arnad of Villanova, et al.). Concepts of stroke were consequently guided by textual tradition, not by observation. (2) Scholastic speculations about different aspects of apoplexy, especially those concerning its origins, were numerous (Johannes Platearius, Batholomaeus Salernitanus, Pietro d'Abano, Giacomo da Forli). Although most medieval physicians used the ancient doctrine of the four humors as model and explanation, opinions differed in many ways. (3) Attempts developed to present a simple outline of the etiology, the prognosis, and the treatment of the disease (Gilbertus Anglicus, Bernard of Gordon, John of Gaddesden). (4) Although lacking in originality, many of these writers nevertheless achieved a certain uniformity in presenting main topics, thus setting the standard for later practitioners. PMID- 11623843 TI - The transition from animal spirits to animal electricity: a neuroscience paradigm shift. AB - The Animal Spirits Paradigm had been in place for over a thousand years as a general way of looking at the nervous system, and was completely ingrained into the fabric of scientific thinking. However, the community of researchers in the 17th and 18th centuries abandoned their long-held assumptions, and started anew with the novel assertion that the currency of nervous function was, instead of Animal Spirits, a uniquely amimal electricity. This conceptual rearrangement represented a scientific revolution in thinking, a change in absolute perspective that required the reinterpretation of old data within a completely novel framework. The manner in which this transition occurred followed the general form of scientific paradigm shifts as outlined by Thomas Kuhn (Kuhn, 1962) PMID- 11623844 TI - Successful cervical disc surgery by Professor Angelo Chiasserini Sr of Rome in 1937: a historical case report. AB - Although resection of cervical "chondromas" had been reported since the late twenties, the true nature of this condition was not recognized at that time. This paper reports a case of "inferior cervical radiculitis by herniation of nucleus pulposus" operated by Prof. Angelo Chiasserini Sr, one of the founders of Italian neurosurgery, in January 1937. To our knowledge this represents one of the first examples of correct etiopathogenetic interpretation of cervical disc disease. Surgery was followed by excellent recovery, a quite remarkable result in those times. The case history is reported in detail, and a short historical sketch of cervical disc disease is depicted. PMID- 11623845 TI - Confabulations: a conceptual history. AB - Confabulations are inaccurate or false narratives purporting to convey information about world or self. It is the received view that they are uttered by subjects intent on "covering up" for a putative memory deficit. The epidemiology of confabulations is unknown. Speculated causes include amnesia, embarrassment, "frontal lobe" damage, a subtype of "personality", a dream-like event, and a disturbance of the self. Historical analysis shows that "confabulation" was constructed at the turn of the century as part of a network of concepts (e.g. delusion, fixed idea, etc.) meant to capture narratives with dubious content. This paper deals with the history of the construction of the word and concept of confabulation and with earlier recognitions of the behaviours that serve as their referent and puts forward a model based on historical data. Two phenomena are included under "confabulation": "untrue" utterances by subjects with memory impairment and "fantastic" utterances marshalled with conviction by subjects suffering from psychoses and no memory deficit. Under different disguises, the "covering up" or "gap filling" hypothesis is still going strong. Although superficially plausible, it poses problems in regards to the issue of "awareness of purpose": if full awareness is presumed then the semantics of the concept of "purpose" is severely stretched and confabulations cannot be differentiated from delusions. PMID- 11623846 TI - In memory of Eugene Aserinsky (1921-1998). PMID- 11623847 TI - Zen and the art of death. PMID- 11623848 TI - The role and significance of Luo Zhiyuan's Shu yi hui bian in the history of plague in Lingnan (south of the five ridges). AB - Being the earliest monograph on plague in China, Luo Zhiyuan's Shu yi hui bian, not included in the National Catalogue of TCM Books, include the following contents: personal idea on the etiology of plague; Luo's friend Wu Xuanchang' unpublished Shu yu zhi fa on the treatment and manifestations of plague; Luo's specific recipe for plague based on medified Wang Qingren's Jie du huo xue decoction based on Wang Qingrens yi lin gai cuo; therapy for critical cases; many therapies applied on Lingnan, including experimental recipes, external therapy, preventive methods, and preventing recurrence methods; Luo's special administrating methods, including persisting day-and-night method, immediate persisting method, single-dose persisting method, and double-dose persisting method. He also gave several cured case records. His book, featuring unique idea with good effect, was repeatedly printed and extensively distributed, exerting influence, more or less, on the plague monographs of later ages, and occupying important position in the history of plague on Lingnan and the whole country as well. His idea of "that poisons and static blood" in pathogenesis and therapeutic principle of antitoxicity and activating blood is coincided with the results of present day clinical and laboratory studies. His administration of medicines is heuristic to the therapy of critical cases with Chinese medicaments and to the recognition of pathogenesis, etiology, and treatment of modern plague as well as other diseases of similar etiology and pathognesis and is worth of further study. PMID- 11623849 TI - Textual research on the original edition of Zhu Jie Shang Han Lun. AB - Many scholars believe that the original edition of Zhu Jie Shang Han Lun is the Song edition of Shang Han Lun proofread and corrected by Lin Yi. After comparing Shang Han Lun proofread and corrected by Lin Yi with that by Cheng's, it is found that there are many different words between them, which are difficult to be explained by that all these different words are caused by Cheng Wuji's negligence. Although some words in Zhu Jie Shang Han Lun are different from that in Shang Han Lun proofread and corrected by Lin Yi, part of these words are identical with that in Jin Gui Yu Han Jing, hence, the conclusion that these different words aren't caused by Cheng Wuji's arbitrary changes. There are many different editions of Shang Han Lun in the Song dynasty, for example, when comparing Shang Han Lun quoted by Guo Yong in Shang Han Bu Wang Lun with Shang Han Lun proofread and corrected by Lin Yi, it is found that the original editon used by Guo Yong is not the edition proofread and corrected by Lin Yi, but not all the scholars studying Shang Han Lun in the Song dynasty adopted Shang Han Lun proofread and corrected by Lin Yi, the original edition used by Cheng Wuji is not the edition proofread and corrected by Lin Yi. PMID- 11623850 TI - Exploration on the characteristics of classification in Huangdi nei jing tai su. AB - Taishu, a book compiled by Yang Shangshan by imperial order, and completed in the reign of Gaozong of the Tang dynasty is the earliest complete commentary of Neijing now extant as well as early monograph interpreting Neijing by classification. By analysing the text of Taishi, Lingshu, Suwen and Jiayijing, this paper summarizes the characteristics of Yang Shangshan's classified compilation of the classical text. First, the whole text was classifiedly compiled from whole chapters or large paragraphs, with the text from Jiujuan (9 volume) arranged before those from Suwen. Second, deletion of duplicated text. For the duplicated text, those from Juijuan were mostly adopted, with those from Suwen discarded. Third, there are overlapping texts of eight strange channels, indicating the compilors' preference of the theory of channels. Fourth, systematization of Neijing theoretical system by dividing the chapters on the basis of different classes. PMID- 11623851 TI - Personal opinion on the date of first printing of Jing yue quan shu (Jingyue's Complete Book). AB - Generally, the date of the first printing is based on the description, "Introduction to the Complete Book", in the postscript written by his grandson Lin Riwei, saying that "in the year of Gengchen (1) brought (my draft) to eastern Guangdong to tell the Fangbo master Lu... (who) donated his salary for the printing which lasted for several months". By Fangbo, it is another name for the position of Buzhengsi (Provincial administrative commissioner). Here, it refers to Lu Chao, by then the commissioner of Guangdong. In the Chronicle of Qing Officials, it is recorded that Lu Chao was in charge of Guangdong provincial commissioner in the year 37-40 of Kangxi reign (1688-1671). Together with other reference data, I draw the conclusion that Jingyue's Complete Book should be first printed in the year 1700. PMID- 11623852 TI - Indepth exploration on history of Qing doctors traveling to Japan. AB - During the one hundred years and more from the beginning of the 18th century to the beginning of the 19th century, about 16 Chinese doctors, at the invitation of Japanese, went to Japan successively by trade ships to practice medicine and teach Chinese medicine. They also conducted academic exchanges with Japanese doctors. Because both the Japanese authorities of that time and the emperor of Qing dynasty implemented the policy of closing the country, they could only do things in certain areas within limited time. By consulting a vast amount of data and following the footprints of some of the Chinese doctors in Japan, the author has got things into shape about the comings and goings of the doctors who went to Japan during the century and their activities, with the stressed point laid on the achievements of such influential doctors as Zhu Laizhang, Zhu Zizhang, Zhou Qilai, Zhao Songyang, Li Renshan, Hu Zhaoxin and so on. PMID- 11623854 TI - Problems and countermeasures in current research on the science of history. PMID- 11623853 TI - The historical materials of stomatological diseases in Zhu Su's Pu Ji Fang. AB - Pu Ji Fang, compiled by Zhu Su (Ming Dynasty), was the largest and most voluminous medical prescription book in ancient China. In the book, the author collected nearly all the achievements in the ancient times on stomatological medicine comprehensively and systematically. From it, we can see that doctors of traditional Chinese medicine at that time had very rich experiences on the knowledge of treatment and prevention of diseases of the oral cavity. It also reflects that the TCM stomatological medicine had reached a rather high standard. PMID- 11623855 TI - Historical studies of the systems of diagnosis and treatment of exopathogenic diseases. AB - The systems of diagnosis and treatment of exopathogenic diseases has a long history. The six channel pattern identification and the defense - qi- construction - blood and triple - jiao pattern identifications are the most famous but not complete. The exterior, interior, excess and heat pattern identification and the six channel qi transformation pattern identification, founded by Liu Hejian, Yang Lishan, Yu Shiyu and Yu Genchu et al. during the Jin and Qing dynasties, should be considered the other two important systems, which can be used as supplements to schools of Shanghan (cold damage) and Wenbing (warm disease). Moreover, it should be pointed out that treatment according to the pattern identification is not the only way to treat exopathogenic disease. Rather, treatment according to the disease, which chiefly are the experience of folk doctors recorded in formulary books during the Jin and Tang dynasties, supplied many effective formulas for various systems of the treatment according to the pattern identification in later ages. One of them lays emphasis on the technics of thinking, the other on the accumulation of personal experience. The combination of the two is the right way to promote the therapeutic effect of exopathogenic disease. PMID- 11623856 TI - The influence of military career on Zhang Jingyue's medical thinking. AB - Military career, the basis of Zhang Jingyue's idea of warm - nourishing thinking, exerted certain influence on the formation of decisive temperament and combination of military theory with medcal theory, which is of significance on the history of military medicine. PMID- 11623857 TI - The theory of "expelling pathogens regardless of hard stool", a significant contribution of Wu Youke. AB - Though there are famous theories of "assorted Qi", "membranous origin", the contribution of Wu Youke's Wen yi lun (On Warm Pestilence) of the theory of " expelling pathogens regardless of hard stool" (EPRHS) is even more important. The main points of this theory includes: it is essential to expel pathogens at an early stage, while for attacking therapy, expelling pathogens with rhubarb is essential. EPRHS elucidates the significance of expelling pathogens in attacking therapy theoretically, and elevates the efficacy clinically with profound influence in later ages. In the past 2 decades, the early application of rhubarb to elevate the therapeutic effect for the treatment of pneumonia, epidemic meningitis, and Bencephalitis even in the absence of hard constipated stool marks the significance of Wu's such theory. PMID- 11623858 TI - Progress and appraisal of midwife manipulaton in the Ming dynasty. AB - There was progress of midwife manipulation in the Ming dynasty as compared with that of the Shi Can Lun written by Yang Zijian of the Northern Song dynasty, as manifested by the extensive description seen in all medical books on gynecology and obstetrics, with its therapeutic effects popularly accepted by medical professionals. More importantly, the manipulations were promoted, including good preparatory works, trimming nails and lubricating the hands with oil before the operation. Further, the exact fetal position should be determined and all the indications for operation be clear, and the method of embryotomy and separation of placenta were also appeared. This is an attentive part of Chinese obstetrics in the Ming dynasty. Though there were still some shortcomings, all these new techniques were, under the conditions then, effective first - aid measures deserving attention. PMID- 11623859 TI - The history of cupping therapy. AB - As an important and integral part of non - drug folk therapy on TCM, there were also many other names for cupping therapy, such as "horning", "needlehorn", "sucking method", "fire - cupping", "boiling bamboo cylinder". By textual investigation, considerable clear recognition can be reached on the names, cupping instruments, cupping measure, indications and contradictions in different historical stages. Presently, cupping therapy is combined with other measures, such as drug therapy, acumoxibustions etc. In recent years, multi - functional vacuum cupping devices made of high - technical materials mark a great leap forward of the features of cupping devices and sucking measures. PMID- 11623860 TI - Ben cao tu jing (Illustrated Canon of Herbology) and the origin of modern identification of Chinese materia medica. AB - There is certain relation between the development of modern identification of Chinese materia medica and Ben cao tu jing. The purpose of Su Song's compilation of this book and the tasks of modern identification of Chinese materia medica, including the verification of genuineness, superiority of the drugs to ensure their qualities, are quite similar, and quite close in their contents. Suffice it to say that Ben cao tu jing made considerable contribution to modern identification of Chinese drugs, with a role of linking the past with the present. PMID- 11623861 TI - A brief history of antibiotic science. AB - As the greatest achievement in the history of microbiology, the story of antibiotic is an extremely inspired chapter in its history. Like the developmental process of other sciences, antibiotic reveals a history of first accumulating experience, followed by the stage of interpretation of the phenomena as other experimental study. Meantime, there is no end to the discovery of new antibiotics. Currently, the scope and province of antibiotic research is expanding both in its profundity and coverage. PMID- 11623862 TI - Influence of religious belief on Mongolian medicine. AB - Religious belief exerts certain influence on early development of Mongolian medicine. Up to early 20th century, some aspects of Mongolian medicine, including diagnostic methods and therapeutic remedies were all dyed with religion. Hence, the study of Mongolian medical history involves culture, philosophy and religious belief, especially culture in its broad sense, and micro - religion, such as the witchery culture of remote ancient time, totem in primitive religion and all kinds of worshipping and beliefs. PMID- 11623863 TI - Zhang Binglin and traditional Chinese medicine. AB - As an important thinker and scholar as well as a famous physician in modern Chinese history, Zhang Binglin extensively read medical books, ancient and modern, and absorbed modern western medical knowledge. He achieved great attainments in the studies on Shang han lun and in the confluence of Chinese and western medicine. His achievements include the "hypothesis of Shang han in a broad sense", "Conception of Six - channels - Six - Departments", questioning on spreading the shang han disease by channels, assessment of commentaries on shang han in successive ages, theory on "Triple - jiao - lymphatic system", "elimination of five - element theory" and discourse on damp - warmness diseases. As the "teacher of reform in modern TCM", Zhang's unique idea and achievements established his position in the history of modern Chinese medicine. PMID- 11623864 TI - Review essay: Plagues, healers, and patients in early modern Europe. PMID- 11623865 TI - Donne, geography, and the Hymn to God in my sicknesse. PMID- 11623866 TI - The gender specific role of male nurses in Dutch asylums: 1890-1910. AB - In the Netherlands, mental health nursing evolved within the context of the rise of scientific psychiatry, which emphasized organic origins of mental illness. Psychiatrists introduced new somatic treatments and designed a mental nurse training system which was aimed at creating a nursing staff skilled in somatic care. This created new opportunities for women, while at the same time restricting the role of men in nursing. The position of male nurses was marginalized, both in number and status. The introduction of mental nurse training in the Meerenberg asylum near Amsterdam illustrates the point. The career of male nurse PN Bras reflected the ambivalent experience of male nurses, and exemplified the strong reaction of male nurses against the gendered image of the womanly nurse. PMID- 11623867 TI - The development of nursing at the General Hospital, Birmingham, 1779-1919. AB - In 1996 the archives of many of the Birmingham hospitals were deposited in the Birmingham Reference Library. This has afforded nurse historians the opportunity to conduct research into the development of nursing in the city. This is to be welcomed as there is little published work regarding nursing in Birmingham. This paper examines the development of nursing from the Hospital's opening in 1779 until 1919. By the latter date, a modern system of nursing, consisting of a disciplined, salaried and well-trained staff, managed to a greater degree by nurses had emerged in the Hospital. PMID- 11623868 TI - Mouth care practices in nursing and research-based education: an historical analysis of instructional nursing texts 1870-1997. AB - In this paper we examine 68 nursing textbooks published between 1870 and 1997 to examine the historical background to contemporary mouth care practice(s) in nursing and the extent to which they are based on research evidence. The analysis shows that, although there has been some variation in the types of equipment and preparations recommended for use over the past 120 years, descriptions of the actual nursing practices themselves have not varied greatly; nor has the discourse varied noticeably. Since the 1970s, there is a progressive increase in references to research. However, the instructional style and discursive frames in which mouth care is discussed reflect an approach to body care that is relatively unchanged in over a century. Individual nursing practices appear as decontextualised and procedurally oriented. With the exception of assessment techniques, written accounts of mouth care practices do not reflect the influence of more recent conceptual or rhetorical standpoints in nursing. PMID- 11623869 TI - Restored to life, and power, and thought. AB - This paper describes the personal experiences of a nurse working on a hospital ward in England during the Second World War. PMID- 11623870 TI - Concerns regarding nursing leadership: 1948 to 1998. AB - This paper is based on some of the data and findings of a six-year research study into the roles, relationships and leadership styles of leaders of nursing. The study was carried out between April 1992 and June 1998, at a time when concerns were being expressed about a perceived lack of nursing leadership, and/or a decline in the effectiveness of nursing leaders. To examine possible causes for this situation it was decided that interviews with past nursing leaders would be carried out, with a view to obtaining from them the factors which had influenced them during their careers, especially when they reached leadership positions within the profession. As the people interviewed had retired from their leadership posts in nursing it was also considered of interest to explore with them their perceptions of the profession that they had helped to create and their influence on it. Arguments in this paper are supported by extracts from some of the interviews. PMID- 11623871 TI - Check list for hematology in philately. PMID- 11623872 TI - Three Mexican murals of philatelic significance. Part 2 PMID- 11623873 TI - Hippocrates and Galen. PMID- 11623874 TI - Three Mexican medical murals of philatelic significance. Part III. PMID- 11623875 TI - Phrenology - confrontation between Spurzheim and Gordon - 1816. AB - All the contemporary evidence suggests that Spurzheim was an extremely personable individual. Evidence from his correspondence suggests that his lectures and demonstrations were very popular and well attended, and geared specifically to the level of knowledge and understanding of his audience. He gave afternoon lectures that were popular with ladies and idle people, and more serious lectures in the evenings to professional and scientific gentlemen. He was less interested in the neuroanatomical basis of the science, as developed by Gall, being more interested in its general applicability in helping to improve the lot of the people. He gave his audiences what they wanted to hear. The scientific basis of the subject was plausible, and was not readily testable by the scientific methods available at the time. PMID- 11623876 TI - Styles of psychiatric practice, 1906-1925: clinical evaluation of the same patient by James Jackson Putnam, Adolph Meyer, August Hoch, Emil Kraepelin and Smith Ely Jelliffe. PMID- 11623877 TI - History of psychiatry in Australia, pre-1960. PMID- 11623878 TI - The moral government of idiots: moral treatment in the work of Seguin. AB - This paper considers the role which moral treatment played in the treatment of idiots in the nineteenth century and particularly in the work of Edouard Seguin. It uses this discourse to identify some of the key elements of the definition of what constituted the "moral", viz. teleology, discipline and humane treatment. By way of interpretation, moral treatment and the "physiological method" of treating idiocy are presented as being based more on utility in securing the ends of social and productive subjects than on humanitarian notions of care or treatment. In additon, the paper supports the view that moral teatment allowed physicians to claim effectiveness in a field in which success had otherwise eluded them. PMID- 11623879 TI - Affective disorders among Jews: a historical review and meta-analysis. AB - Descriptions of affective disorders among Jews date back to biblical times. For over a century the psychiatric literature has debated whether Jews are more vulnerable to affective disorders. To ascertain the validity of this finding we undertook a meta-analysis of data extracted from the literature published to date. Forty-three studies were identified that could be analysed statistically using Cohen's d and a Mantel-Haenszel summary odds ratio. An increased, but weak overall risk was found for males. Possible biases of the literature are discussed, including differential help-seeking patterns, lack of accounting for readmission rates, failure to control for confounding variables, and an anti Semetic orientation on the part of researchers. Reasons for why Jews have higher rates of affective disorders than non-Jews are explored. PMID- 11623880 TI - Cotard's "On hypochondriacal delusions in a severe form of anxious melancholia". PMID- 11623881 TI - Anorexia nervosa as viable behaviour: extreme self-deprivation in historical context. AB - When anorexia nervosa is considered from a critical historical perspective, several key features emerge. For one, striking similarities can be found between the sociocultural milieux of medieval fasting women and modern anorexics. Although the presentation of self-starvation has changed over the centuries, the syndrome can still be identified and shown to flourish during eras and in societies in which individuals (mainly women) lacked adequate attention, control, respect and/or economic power, and when a socially acceptable avenue for expression existed. In this context, the steady increase in the incidence of anorexia nervosa over the last fifty years is seen to parallel specific cultural and economic events that favoured thiness. PMID- 11623882 TI - Thomas Sydenham, John Ray, and some contemporaries on species. PMID- 11623883 TI - Apostles and Zionists: the influence of religion on demographic change in rural Zimbabwe. AB - Religion has acted as a brake on demographic transition in a number of historical and contemporary populations. In a study in two rural areas of Zimbabwe, we found substantial differences in recent demographic trends between Mission and Independent or "Spirit-type" churches. Birth rates are higher in some Spirit-type churches and, until recently, infant mortality was also higher. Recent increases in mortality were seen within Mission churches but not in Spirit-type churches. Missiological and ethnographic data indicate that differences in religious teaching on healthcare-seeking and sexual behaviour and differences in church regulation could explain this contrast in demographic patterns. More restrictive norms on alcohol consumption and extra-marital relationships in Spirit-type churches may limit the spread of HIV and thereby reduce its impact on mortality. These contrasting trends will influence the future religious and demographic profile of rural populations in Zimbabwe. PMID- 11623884 TI - The concept of the body from a historical viewpoint. PMID- 11623885 TI - Tea in Japan. PMID- 11623886 TI - History of Korean medicine. PMID- 11623887 TI - Venereal disease and public health administration in Newfoundland in the 1930s and 1940s. AB - In the 1930s, veneral disease was identified in Newfoundland as a serious public health problem. Through The Health and Public Welfare Act, 1931, the country had a comprehensive regulatory system for dealing with VD, but in practice it lacked the resources to enforce the legislation. H.M. Mosdell, the key official involved, favored the opening of a lock hospital. Wartime conditions, especially the arrival of thousands of members of the Canadian and American armed forces, magnified the VD problem facing Newfoundland but facilitated new control measures. In 1943 a lock hospital was actually opened but the introduction of pencillin soon led to its closure. PMID- 11623888 TI - [A conjoined birth: the emergence of kinesiotherapy in France and the establishment of physiotherapy in Quebec: trajectories in mirrors]. AB - In France, the development of manual care was considerably conditioned by its popular origin, whereas in Quebec such treatments were put into practice in a country where nothing of the kind had ever existed. Although France had left its mark there, it was from England that the first qualified practitioners--already called physiotherapists--came. In those two countries, World War I had been a period of organization and recognition which had brought out the practice as a complement of military surgery. In Quebec, the medical issues at stake, which were important at first, were progressively reduced because of private activity exploiting physiotherapists. The profession's protection system showed its efficiency by having doctors' lack of competence in physiotherapy acknowledged. Such a situation led on the free access to physiotherapy for patients. But the sharing of medical acts with other professions remained a serious handicap. In France, the medical issues at stake remain significant. Physicians have always kept physiotherapists and physiotherapy under control through medical prescription, physiotherapists being perceived as considerably less threatening towards the autonomy of the profession. On the other hand, the organization of officially recognized health professions prevents them from encroaching upon one another's professional acts. PMID- 11623889 TI - Assistant angels: Canadian voluntary aid detachment nurses in the Great War. AB - Canada's Voluntary Aid Detachment nurses of the Great War have yet to be recognized in Canadian nursing history. This article offers a synopsis of the evidence traced thus far in the search to recover their history, and presents some of the issues that history addresses. Comparisons to the much larger and well-documented British VADs of the era testify to similarities in social origin from among the more privileged Protestant, middle and upper classes from across Canada. Yet significant distinctions have been found in both the academic and employment profile of Canada's VADs. The research addresses conflicts that surrounded issues in the professionalization of nursing, the gendered dimensions of nursing as "women's work," both in peace and war, and tensions deriving from the juxtaposition of both volunteer and career nurses in the hospital environment. The postwar effects of VAD nursing are also addressed, both from the perspective of the women themselves and the emerging Canadian society witnessing the evolution of the "working girl" and the voting woman. While stil incomplete, this research promises to recover a dynamic community of Canadian women, contributing new insights into women's history, medical history, and Canada's history. PMID- 11623890 TI - Perspectives on patients' history: methodological considerations on the example of recent German-speaking literature. AB - Patient-history is a recently developed branch of medical-historical search, and its methodology has not yet been sufficiently developed. In particular, the specific character of patient-centered research still has not received sufficient attention. What kinds of questions can, and should, such research attempt to answer, and from which perspectives? This contribution to the discussion offers some help towards the development of ways of orienting such research towards achieving proximity to the patients' viewpoint. This aim is best achieved when the mental picture of patients is reconstructed and, in addition, the specific point of view of the patient is adopted. The article illustrates some possibilities and problems of this branch of research by citing the example of relevant recent German-language studies, especially in the field of the relationship of patients to approved doctors in the nineteenth century. PMID- 11623891 TI - [Drops of milk and thirst for power: the under side of the struggle against infant mortality in Montreal, 1910-1953]. AB - This study discusses the development of the network of baby clinics in francophone Montreal, beginning in the 1910s, which were to be the source of serious conflicts between various advocates, namely, groups of priests and physicians, members of the Saint-Jean-Baptiste National Federation, and municipal government. Child-saving, a fitting nationalist project to bring together elites in the same cause, instead degenerated into a power struggle. Conceived in different terms and after the various political ambitions of the parties became irreconciliable, the organization for the battle against infant mortality in Montreal proved to be a powerful reflection of the discords which separated those who were concerned about the future of the nation and those with ambitions for their personal advancement. PMID- 11623892 TI - The right to the best medical care: Dr. W.P. Warner and the Canadian Department of Veterans Affairs, 1945-55. AB - Dr. W.P. Warner was appointed as the first Director General of Treatment Services of the Canadian Department of Veterans Affairs, in March 1945. Prior to his appointment, Warner had been the Deputy Director General of Medical Services in the Royal Canadian Army Medical Corps (RCAMC). During his 10 years as Director General, Warner dramatically re-organized Treatment Services to ensure the right of every disabled veteran to "the best medical care." To meet his goal he drew on his experience in academic and military medicine and established new links between Canadian faculties of medicine and veterans medical services. Physicians, involved in diagnosis and treatment, were employed on a part-time basis and held university appointments. Postgraduate and undergraduate teaching programs for physicians and other health professions were established. Professional consultants and Medical Advisory Committees were developed to provide advice on all aspects of medical care. Finally, medical research and new clinical investigative units were established in Canadian veterans' hospitals. As a result of Warner's new policies, academic medicine was placed in the forefront of veterans medical services and developed the first national model for the integration of medical care, education, and research in Canada. Indeed, many current Canadian practices in medical care, education, and research can find some of their roots in the policies and programs of Treatment Services that began in 1945 under Warner's leadership. PMID- 11623893 TI - Eugenics, McGill, and the Catholic Church in Montreal and Quebec: 1890-1942. AB - Tracing the origins of eugenics in Canada and seeking to apply a national model, the article explores the juxtaposition between the movement's origin in Britain and its popularity in the Canadian academic milieu, and its condemnation in Quebecois intellectual circles. The first aspect of the movement is explored through the work of two McGill professors, Carrie Derrick and J.G. Adami. In contrast, there is both apathy and resistance from the Quebecois polity--and the influence of Catholicism in forming a resistant position to the eugenics movement -to consider. The impact of works by Blais, Forest, and others are examined in this respect. The conclusion argues for a bifurcated response to eugenic ideas in Quebec, divided along linguistic-cultural lines. PMID- 11623894 TI - [The long controversy over anti-tuberculosis vaccination in Canada: the Calmette Guerin bacillus (BCG), 1925-1975]. AB - The focus of this article is the history of Canada's reception of Bacillus Calmette-Guerin (BCG), an anti-tuberculosis vaccine which has almost constantly been plagued with controversy. The article examines this vaccine NRCC sponsored introduction in 1925, which led to the creation of the Associate Committee on Tuberculosis Research, a committee almost unique for its acrimonious debates. It also analyzes the interests at stakes in the ultimate rejection of the BCG by the federal Department of Agriculture veterinary services and, with the exception of Quebec and Newfoundland, by almost all public health authorities in Canada. Based on sources never taped before, this paper sheds a light on the multiple ramifications of a little known episode of the Canadian public health history. PMID- 11623895 TI - Current bibliography in the history of technology (1996-1997). PMID- 11623896 TI - Imagining vermin in early modern England. PMID- 11623897 TI - The besotted king and his Adonis: representations of Edward II and Gaveston in late nineteenth-century England. PMID- 11623898 TI - Freud in the "Tropics". PMID- 11623899 TI - The early years of pharmaceutical education in Bradford up to 1927. PMID- 11623900 TI - The big C: cancer cures or quackery? PMID- 11623901 TI - John Gerarde and his contemporaries. PMID- 11623902 TI - Martindale: the men and the books. PMID- 11623903 TI - The continental parallel: the Netherlands. PMID- 11623904 TI - Curatives and colours. PMID- 11623905 TI - The ancient doctrine of signatures or similitudes. PMID- 11623906 TI - Salus populi - the endeavours of Edward Dillon Mapother (1835-1908). AB - Edward Dillon Mapother had an impressive career as surgeon, dermatologist, author, professor and President of the Royal College of Surgeons in Ireland and first Medical Officer of health for Dublin in 1864. Considered an authority on eczema, gout and the curative powers of spa waters, Mapother returned to the full time practice of dermatology, moving to London in 1888. He died at his London home on the 3rd of March 1908. PMID- 11623907 TI - The incorporation of pre-modern scientific theories into Rabbinic literature: the case of innate heat. PMID- 11623908 TI - Sir Arthur Hurst (1879-1944): master of medicine. PMID- 11623909 TI - William Osler and the New York Times, 1897-1931. PMID- 11623910 TI - Wiliam Turner (c. 1508-1568): physician, botanist and theologian. PMID- 11623911 TI - Denis Browne and the specialization of paediatric surgery. PMID- 11623912 TI - Mabel's normalcy: Mabel Purefoy FitzGerald and the study of man at altitude. PMID- 11623913 TI - Joseph Bell (1837-1911): a clinician's literary legacy. PMID- 11623914 TI - Samuel Johnson's lung disease. PMID- 11623915 TI - The Napoleonic cancer gene? PMID- 11623916 TI - The iconography of Girolamo Fracastoro (c. 1483-1553). Part II: portraits and sculptural works. PMID- 11623917 TI - Collecting cookbooklets. PMID- 11623918 TI - No place like Holmes: the rare books and special collections department of the Francis A. Countway Library of Medicine. PMID- 11623919 TI - "A healthy heritage: collecting for the future of medical history;" symposium held at the Wellcome Library, February 25-26, 1999: one American's view of the proceedings. PMID- 11623920 TI - Herbart's mathematical psychology. AB - J.F. Herbart (1824/1890b) provided a mathematical theory about how mental ideas (Vorstellungen) in consciousness at Time 1 (T1) could compete, possibly driving 1 or more Vorstellungen below a threshold of consciousness. At T1 a Vorstellung A could also fuse with another, B. If at a later T2, A resurfaced into consciousness, it could help B to re-resurface into consciousness. This article describes the historical and mathematical background of Herbart's theory, outlines the mathematical theory itself with the aid of computer graphics, and argues that the theory can be applied to the modern problem of predicting recognition latencies in short-term memory (Sternberg's task; Sternberg, 1966) PMID- 11623921 TI - Wundt's laboratory at Leipzig in 1891. AB - This article describes Wundt's laboratory at Leipzig in 1891 as viewed by a Belgian psychologist, J.J. Van Biervliet (1859-1945). Although few French speaking psychologists worked in Wundt's laboratory, several of those who did reports wrote on how students were trained there. Van Biervliet decided to visit Wundt's laboratory at Leipzig in order to strengthen the foundation of his own laboratory at the University of Ghent and to become familiar with Wundt's experimental techniques. A translation of J.J. Van Biervliet's (1892) article "Experimental Psychology. Wundt's Institute at Leipzig" is presented here as one of the first and most complete articles in French describing the functioning of Wundt's laboratory. PMID- 11623922 TI - The founding of the psychological laboratory, University College London: "Dear Galton...yours truly, J Sully". AB - The events leading up to the founding of the Psychological Laboratory at University College London are examined in the light of correspondence from James Sully to Francis Galton. The correspondence reveals the dependence of Sully on Galton for detailed advice at every stage of the process, possible reasons for which are discussed. It also provides sufficient clues to enable identification of a hitherto anonymous donor. Although Galton may have inspired and advised on the initial setting up of the laboratory, his influence on its work did not become apparent until after his death. PMID- 11623923 TI - "A coarse and clumsy tool": Helen Thompson Wooley and the Cincinnati Vocation Bureau. AB - From 1911 to 1921, Helen Thompson Wooley served as director of the Vocation Bureau of the Cincinnati Public Schools. In this position she designed and supervised a massive longitudinal study comparing the development of adolescents who remained in school with those who left school to go to work. Although the original goals of this study were not accomplished, the achievements of the Vocation Bureau brought national recognition to the city and to Helen Wooley. The accomplishments of the bureau reflected Wooley's view of the role of experimental psychology in contributing to the scientific understanding of adolescents and to educational and social reforms. PMID- 11623924 TI - Enrichment of words by visual images: books, slides, and videos. AB - This article reviews additions to 3 ways of visually enriching verbal accounts of the history of psychology: illustrated books, slides, and videos. Although each approach has its limitations and its merits, taken together they constitute a significant addition to the printed word. As such, they broaden the toolkits of both the learners and the teachers of the history of psychology. Reference is also made to 3 earlier publications. PMID- 11623925 TI - Robert Campbell Davis (1925-1999) PMID- 11623926 TI - A note on the commemoration of the 150th anniversary of Phineas Gage's accident. PMID- 11623927 TI - Practitioners and saints: medical men in canonization processes in the thirteenth to fifteenth centuries. AB - This article shows that recourse to expert medical judgement for authenticating miracles has medieval roots which lead to the thirteenth century. It provides a survey of those cases in the printed versions of canonization processes from c. 1200 to c. 1500 where medical men actively appeared as witnesses. It shows how, from the second half of the thirteenth century, many canonization processes (overwhelmingly in southern Europe) included at least one medical man who witnessed or gave expert testimony as a supplier of medicine. The physicians who appeared as expert witnesses were expected to rule out the possibility that there was a natural explanation for the wonderous cure. To acquire medical confirmation that a certain cure was miraculous seemed highly desirable to those wishing to substantiate claims of sanctity. Physician witnesses were often called upon to evaluate cases of which they had personal knowledge because of the medical know how they possessed: however, medical science was not considered so universal that any physician could review the case (as is theoretically the case today in the medical council at the Vatican). Thus, to the therapeutic function of physicians and surgeons in southern Europe from the second half of the thirteenth century, a hitherto neglected duty should be added: whenever necessary, the community as well as the local ecclesiastical authorities expected the suppliers of medical services to contribute to the formal recognition of an apparent saint. PMID- 11623928 TI - Patient pathways: solving the problem of institutional mortality in London during the later nineteenth century. AB - This paper confronts a major problem in relation to the metropolitan and urban mortality declines in Britain during the later nineteenth century: the extent to which cause-specific death rates at district level were distorted by an official failure to redistribute deaths occurring in institutions back to "normal" place of residence. Describing and analysing the manner in which hospital and infirmary provision in the capital during this period determined the geographical incidence of mortality, the article develops methodologies that bring the researcher progressively closer to more accurate spatial facts of demographic and epidemiological experience. Devoting separate sections to general voluntary and fever hospitals as well as to institutions administered by the Metropolitan Asylums Board, the paper also engages with similar problems in relation to workhouses and Poor Law infirmaries. By way of conclusion, it shows that, far from generating demographically trivial results, the process of redistribution radically revises the epidemiological history of London in the crucial years between the 1860s and the mid-1880s and provides a dataset that will allow controlled interrogation of the metropolitan mortality decline during this period. PMID- 11623929 TI - Gender and aesthetic norms in popular hygienic culture in Germany from 1900 to 1914. AB - The paper concerns the construction of gender norms in popular hygienic literature at the turn of the century. It argues that the formulation of aesthetic gender norms for women's and men's bodies was a response to social developments which were perceived as a threat to the middle-class ideology of separate spheres for the sexes. Concerns about the blurring of gender distinctions were expressed in the aesthetic idiom of the educated middle class. Aesthetic norms for each sex were established and contrasted with the degenerate body forms of contemporaries. The spectre of masculinized women and feminized men was raised, reflecting a deep-seated uneasiness about changing gender roles and identities. The increasing assertiveness of women as expressed in feminist activism was interpreted by anti-feminist authors as a sign of degeneracy. For these authors any articulation of self-interest by women was suspect. Strong sexual desires of women which could serve as the basis for the independent articulation of female sexual interests were denied or declared as abnormal. Feminist critics argued that it was the lack of economic and social independence of women which was the reason for the declining health and beauty of the female sex. PMID- 11623930 TI - Food, hygiene, and the laboratory. A short history of food poisoning in Britain, circa 1850-1950. AB - Public health concern with food safety and food poisoning emerged in Britain in the 1880s following the first indication that acute gastric illness was caused by a specific organism. Although incidents were for many years only sparsely reported, the central medical department and its scientists were anxious to extend their knowledge of the incidence, specific causal organisms, and epidemiology of the illness. This paper argues for a widespread incidence of food poisoning in Britain in the nineteenth century and traces the social economic, and hygienic contexts within which it occurred. As deadlier infections retreated, food poisoning became an increasing concern of local and national health authorities, who sought both to raise public awareness of the condition as illness, and to regulate and improve food handling practices. Notification of cases was begun in 1939, and this, together with social changes during and after the Second World War, produced an escalating spiral of reported incidents which still continues. This trend, it is argued, is essentially an artefact, whose significance is reduced if considered in its broader historical context. PMID- 11623931 TI - Essay reviews. [Review of: Rabinow P. Making PCR: a story of biotechnology. University of Chicago Press, 1996; and Fujimura J. Crafting science: a sociohistory of the quest for the genetics of cancer. Harvard University Press, 1996]. PMID- 11623932 TI - Forty years on. PMID- 11623933 TI - Ninety years of Chagas disease: a success story at the periphery. AB - Periphral countries are at a disadvantage with respect to the construction of scientific knowledge, which is mostly carried out by a small number of traditional core loci countries. However, in a few cases, groups of scientists are able to break through exclusion barriers. Sometimes they tackle relevant issues, share values and procedures with core loci representatives, and take part in heated controversies: in short, they participate in the construction of legitimate science. These scientists form centers of excellence in scientifically marginal countries. In this paper, contextual conditions involving the emergence, establishment and decline of such enterprises are discussed, on the basis of examples drawn from the history of Chagas disease (Cd). In this history, we see a major discovery established, deconstructed and re-established. Quantitative analyses of publication on CD over 70 years show the relation between the choice of different types of journals and methodological approaches, and the legitimation strategies adopted by different groups of practitioners. It also shows the outcomes of such strategies in terms of production concentration, emergence of new authors and growth of institutional work. This story shows that it is important for the pioneers to establish a different intellectual culture in their local environment. Unless they do so, and gain its acceptance among their immediate colleagues, the enterprise cannot preserve its status as a centre of excellence. PMID- 11623934 TI - An agenda for STS: Porter on trust and quantification in science, politics and society. [Review of: Porter TM. Trust in numbers: the pursuit of objectivity in science and public life. Princeton University Press, 1995]. PMID- 11623935 TI - The measure of man: technologizing the Victorian body. PMID- 11623936 TI - How might we map the cultural fields of science? Politics and organisms in restoration France. PMID- 11623937 TI - Lazzaro Spallanzani (1729-1799). PMID- 11623938 TI - Special collections of the Central Library at the University of Veterinary Science in Budapest: collection of veterinary history (museum). PMID- 11623939 TI - [Not Available]. PMID- 11623941 TI - [Not Available]. PMID- 11623940 TI - [Not Available]. PMID- 11623942 TI - Pioneers in animal reproduction - V: Ed. Sorensen (1898-1972). PMID- 11623943 TI - The Veterinary Medicine Museum established in 1973 at the Royal Veterinary and Agricultural University in Copenhagen. PMID- 11623944 TI - [The establishment and closure of the Veterinary School in Karlsruhe]. AB - In 1784 in Karlsruhe a veterinary school was established. Its first Director was Ernst Jacob VIERORDT. At first the period of the study was determined two years. Connected with the chaos of wars of liberation the veterinary school was closed in 1814. 1823 teaching was started newly under the direction of TSCHEULIN. 1844 the period of the study was prolonged to three years. Because of lack of money, and because the two professors FUCHS and DITTWEILER could not manage the necessary specialization in the veterinary medicine without additonal teaching staff, 1860 the veterinary school was closed definitively. PMID- 11623945 TI - [Some letters addressed by Eric Vibourg to Jean-Baptiste Huzard of Paris]. PMID- 11623946 TI - Anton J. Carlson: witness for the prosecution. PMID- 11623947 TI - From rudbeckia to echinacea: the emergence of the purple cone flower in modern therapeutics. PMID- 11623948 TI - A short history of the pharmacognosy collection of the University of Berne (Switzerland). PMID- 11623949 TI - Stamps on Danish prescription covers. PMID- 11623950 TI - Treatment for the Caisson disease. PMID- 11623951 TI - Arrangement (and fitting) of drug stores--part 3. PMID- 11623952 TI - Koan Ogata's obtainment of Dutch scientific books. AB - Koan Ogata (1810-1863), a medical doctor in Osaka, is renowned for his contribution to the spread of vaccination and for his private school Teki-juku, a Rangaku school where education of Western learning was done by means of the Dutch language. In many letters collected in "Ogata Koan no Tegami" (1980-1996), he asked help for obtaining various Dutch scientific books to his former students, Shuhei Mitsukuri and Ryotei Takeya during several years around 1859: Mitsukuri was a staff member of the Foreign Affairs and intermittently Bansho Shirabesho (Institute for Western Learning) of the Tokugawa Shogunate in Edo, while Takeya was a medical doctor of the Fukuoka Clan. Moreover, Ogata wrote to Mitsukuri in 1858 that he had asked Yukichi Fukuzawa in Edo to buy a Dutch wordbook for him. On the other hand, Genki Kusaka, a student at the Teki-juku, noted in a letter to his parents in 1854 that Ogata had bought Dutch books from Tsuji, official Dutch interpreter of Nagasaki, when the Tsuji stopped by in Osaka on the way to Edo in the February of the year. This paper outlines the above letters to show how Koan Ogata tried to obtain Dutch books from Edo and Nagasaki; their titles and areas are discussed in view of the history of Western learning, and identification is made on the two books that have been left unclarified. PMID- 11623953 TI - Fertility policy in Ceausescu's Romania. AB - This study tests a model for the impact that Ceausescu's pro-natalist policies had on the Romanian fertility rate between 1967 and 1989. Using time-series analysis the authors' findings show that the Ceausescu regime continually struggled with the Romanian population to increase the national birthrate. As a result the regime's policies, there was a significant increase in overall fertility between 1967 and 1989, when the Ceausescu regime was overthrown. Reasons are offered as to why Romania pursued such policies and was able to make them work, while other Eastern and Central European regimes proved to be less able to sustain drives to increase national fertility. This article also presents a model of what has happened to the Romanian fertility rate since 1989, showing that there has been a significant decline in fertility in the post-Communist period. PMID- 11623954 TI - The demographic transition then and now: processes, perspectives, and analyses. AB - Fifty years have passed since the post-World War II development of demography as an academic field. During this time, one of the central focuses of research has been the study of demographic and fertility transitions. The authors review a selection of research developments and analytic issues that have appeared in the literature. After presenting, in roughly chronological order, the general development of this research work, they raise questions concerning theory and methodology. In doing so, they argue that some research directions have been overemphasized to the neglect of others. PMID- 11623955 TI - Stephane Tarnier and the origin of incubators for premature babies. PMID- 11623956 TI - Rontgen's rays and his Scottish disciples. PMID- 11623957 TI - Apochryphal Tobit and the truth: couching for cataracts in antiquity. PMID- 11623958 TI - Sir Robert Philip's contribution to the development of tuberculosis services. PMID- 11623960 TI - Mandrake. PMID- 11623959 TI - The Royal Victoria Hospital, Edinburgh 1894-1994, a brief history. PMID- 11623961 TI - Peter Lowe: founder of the faculty - man of mystery. PMID- 11623963 TI - Less than meets the eye: the strange career of Dorothea Dix. [Review of: Brown, T.J. Dorothea Dix: New England reformer. Harvard University Press, 1998]. PMID- 11623962 TI - The coming of rhubarb. PMID- 11623964 TI - History of Kyoto Pharmaceutical University. AB - The origin of Kyoto Pharmaceutical University dates back to the year 1884, when the German School of Kyoto was founded in Kamigyo Ward. Those who established this school were disciples of Rudolf Lehmann, who came to Japan in 1869 and was employed as a teacher of German and mathematics by Kyoto Prefecture in the following year. After he had taught in Ogakusha, or the European Learnings School, and other prefectural schools in Kyoto, he moved to Tokyo in 1882. Soon after the establishment of the German School of Kyoto, the Pharmaceutical Department was set up as an additional course. In 1890, this department was closed and a new school named the Pharmaceutical School of Kyoto was established. This school developed into Kyoto Pharmaceutical College in 1919 and then to Kyoto Parmaceutical University in 1949 after the Second World War. PMID- 11623965 TI - The historical study of an ethics for American pharmacists. AB - The Code of Ethics for pharmacists clarifies the standards of professional conduct. The code should be positively enforced in every country, and must play its role as the conduct standard for pharmacists at all times. American pharmacists did not suddenly become ethical in the 1980s. An appreciation of the importance of professional ethics has a long history starting when the Philadelphia College of Pharmacy adopted a Code of Ethics in 1848. Since the first legislation of the American Pharmacy Code of Ethics as far back as 1852, the code has been revised in 1922, 1952, 1969, 1981 and 1994. The term of between revisions has gotten shorter over the years, reflecting the change in the status and the proficiency of pharmacists in 146 years. Its historical meaning is quite significant. PMID- 11623966 TI - History of the Vessel Corkstopper for liquid medicines in Japan. AB - In this report it was found that in 1860, namely Gan-nen of Man-en in Japanese, cork caps were used for bottles of liver oil produced at fukuoka-han. On the other hand, it was previously proposed that the cork cap was first used for bottles of eye medicine, "Seikisui." This use occurred at least after 1867, namely the Third year of Keiou in Japanese. Therefore, it was clarified that the cork cap was used for liquid medicine in the form of a stopper for bottles of liver oil at least several years earlier than for "Seikisui." PMID- 11623967 TI - Dr. Nobuo Yamada's whole life, dead due to his radioactive studies at the Radium Institute (Part 2): in celebration of the 100-year anniversary of the discovering radium, 1898-1998. AB - On the occasion of the 100th anniversary of the discovery of radium by M. & Mme. Curie, commemorative lecture meetings were held in Japan in 1998 as follows. 1) The 42nd Symposium on Radiochemistry was held in Sendai on September 18. Dr. M. Sakanoue, Professor Emeritus Kanazawa University, presented a commemorative lecture entitled "Collaborative Research done by Irene Curie and Nobuo Yamada." He explained an outline of the studies on the measurement of long-range particles emitted by various radioactive substances such as polonium, radium and thorium. In addition to his lecture, I made a comment on the curriculum vitae of Dr. N. Yamada. 2) On October 24, another commemorative lecture meeting was held in Tokyo. At this meeting, Helene Langevin-Joliot, daughter of Irene Joliot-Curie presented a lecture on whole life of M. & Mme. Curie as a guest speaker. After meeting ended, I had the opportunity to talk with her personally. I have been investigating references describing the cause of death of Dr. Nobuo Yamada and found the following. The inadequacy of an apparatus for protection from radioactivity in the 1920s and reference to the death of Dr. Nobuo Yamada specifically were described in an article written by Dr. S. Iimori and in a nonograph written by Dr. M. Furukawa. The tragedy of scientists who suffered severe radiation syndrome during experiments at the Radium Institute was described in a biography of Marie Curie written by Susan Quinn. PMID- 11623968 TI - Herbological studies of Coptidis rhizoma (Part 2): on the old Japanese name of Coptis japonica makino. AB - The rhizome of Coptis plant of the family ranunculaceae has been used in traditional Chinese medicine as a crude drug (Huanglian in present Chinese). In Japan, the rhizome of Coptis japonica Makino (the botanical name of which is "Ohren" in modern Japanese) has been utilized as a crude drug since the Nara era. The Japanese name in those days was "Kakumakusa based on descriptions in old books written in the Heian era. It changed to "Kakumikusa" early in the Edo era, and then changed again to Kakumakusa later in the Edo era. Through this herbological study, it was conjectured as follows: The resemblance between Chinese characters (or MA) and (or MI) in cursive style caused mis-copying of the character. After the "Honzo-wamyo, written in the Heian era, was revised in the late Edo era, and on which the name was accurately written as Kakumakusa, the mistake was corrected. PMID- 11623969 TI - A distinct break between butane and pentane. AB - In organic chemistry, hydrocarbon compounds with one to four carbon atoms are given individual names such as methane, ethane, propane and butane, whereas those with five carbons or more are named by the serial Greco-Roman numerals like pentane pente, 5), hexane hex, 6 (and heptane hepta, 7). The author points out a distinct conceptual break between the numbers four and five. There have been arguments that primitive cultures had numerals only up to four, and a quantum mental leap was required to cross the boundary after four. Linguistic discussions are made to substantiate the break by scrutinizing the spellings of the numbers "five", "eight" and "nine" of the proto-Indo-European language. In ancient Roman times, 1 (children's ages were counted by winters up to four and by years from five on, 2 (the first four calender months had real names and after four they were called by serial numbers, (3) children up to the fourth were given individual names but from the fifth child on they were named by serial number words, and (4) the words of the number of times had a sharp break between four and five. In various Indo-European languages long ago, the numbers one through four were inflected adjectives, while the numbers beyond four were non inflectable. All the above observations indicate an existence of a conceptual break after the number four. The author concludes that the notion of such break latently survived in peoples' minds for a long time and came to light when naming of the hydrocarbons was attempted in the 19th century. PMID- 11623970 TI - History of faculty of pharmaceutical sciences, Nagoya City University for 115 years. PMID- 11623971 TI - For David Bloor...and beyond: a reply to David Bloor's Anti-Latour. PMID- 11623973 TI - Reply to Bruno Latour. PMID- 11623976 TI - Anti-Latour. PMID- 11623977 TI - The rise and fall of American posture. PMID- 11623979 TI - Geoffrey Sharman Dawes, C.B.E. 21 January 1918-6 May 1996. PMID- 11623983 TI - Andre Michel Lwoff 8 May 1902-30 September 1994. PMID- 11623981 TI - Roderic Alfred Gregory, C.B.A., 29 December 1913-5 September 1990. PMID- 11623986 TI - Robert Henry Stewart Thompson, C.B.E., 2 February 1912-16 January 1998. PMID- 11623988 TI - John Zachary Young, 18 March 1907-4 July 1997. PMID- 11623990 TI - Adolf Friedrich Johann Butenandt 24 March 1903-18 January 1995. PMID- 11623992 TI - Sir Barry Albert Cross, C.B.E. 17 March 1925-27 April 1994. PMID- 11623994 TI - Elizabeth Blackwell at Geneva Medical College: reflections on the 150th anniversary of women in medicine. PMID- 11623996 TI - EB and me, or, that girl there is doing an exhibit. PMID- 11623998 TI - Sir Henry Duncan Littlejohn - a dynamic figure in forensic medicine and public health in the nineteenth century. PMID- 11623999 TI - Saint John's wort (Hupericum Perforatum). A balm for hurt minds? PMID- 11624001 TI - The life and trials of T.R. Allinson ex-L.R.C.P.ED. 1858-1918. PMID- 11624003 TI - The noble crusade: Richmond P. Hobson and the struggle to limit the international narcotics trade, 1920-1925. PMID- 11624004 TI - The bones of Rolando Kuehn. PMID- 11624005 TI - Hysteria: a cross-cultural comparison of its origins and history. PMID- 11624006 TI - Mental disorder among the Incas in ancient Peru. AB - The work of the chroniclers served as a source of information about the occurrence of mental diseases among the Incas. From this source it appears that melancholy was by far the most important disease among mental disorders. The disease did not only affect the common Incas: melancholy was rather frequent among the family of the Inca emperor. Like other diseases, mental diseases were treated by the Incas with a mixture of magic and empirical medicinal products. The latter were mainly of botanical nature, but also some minerals were applied to treat depressive disorders. Some typical syndromes of contemporary folk medicine, such as susto and related ailments, were not mentioned by the chroniclers. PMID- 11624007 TI - The psychiatrists Oscar Wattenberg and Johannes Enge and the history of psychiatry in the Hanseatic city of Lubeck between 1900 and 1945. PMID- 11624009 TI - Prestwich Hospital in the twentieth century: a case study of slow and uneven progress in the development of psychiatric care. AB - In 1921 Montagu Lomax published his book The Experiences of An Asylum Doctor, in which he used his experiences as a locum at Prestwich Hospital to criticize standards of mental health care in Britain. Lomax's criticisms of Prestwich Hospital led to a Royal Commission and the 1930 Mental Treatment Act. However, many of the circumstances described by Lomax could still be observed at Prestwich in the 1960's and 1970's. The oral testimony of nurses who worked at Prestwich between 1922 and 1975 and documentary sources are considered in an attempt to explain how a hospital which had been the centre of debates about psychiatric reform in the nineteen-twenties failed to emerge as one of the country's more progressive psychiatric hospitals. PMID- 11624008 TI - Soviet psychiatrists under Stalinist duress: the design for a new Societ psychiatry and its demise. AB - A Scientific Session of the USSR Academy of Sciences and the USSR Academy of Medical Sciences met in 1950 in Moscow, to comply with the order of I.V. Stalin to institutionalize the theory of higher nervous activity of I.P. Pavlov. This Scientific Session decreed that annual scientific conferences should be held to consider problems related to Pavlovian physiology. In response to this call, a session on the Physiological Teachings of the Academician I. P. Pavolv on Psychiatry and Neuropathology was convened in Moscow in 1951. Certain influential Soviet psychiatrists - V.A. Giliarovski, M.O. Gurevich and A. S. Shmarian were condemned for adhering to anti-Marxist ideology and to psychiatric theories conceived by Western psychiatrists. The named psychiatrists acknowledged the correctness of the accusations, admitted their errors, and promised in the future to follow Pavlov's teachings on psychiatry. The session's Presidium urged the development of a New Soviet Psychiatry based upon experimental and clinical findings and consistent with the Pavlovian conceptualization of higher nervous activity, which considered pychiatric and neurotic syndromes in terms of the dynamic localization of the brain's functions. Long-range consequences of the 1951 session are considered. PMID- 11624010 TI - Pieterson's Haematoma auris. PMID- 11624011 TI - Lancelot Hogben, F.R.S. (1895-1975): a review of his autobiography. [Review of: Hogben, A; Hogben, A.: Lancelot Hogben - scientific humanist. Woodbridge, Suffolk: Merlin Press, 1998]. PMID- 11624012 TI - Irish links of the multinational chemist Joseph Black (1728-1799). AB - Joseph Black (1728-1799) is remembered for his discovery of carbon dioxide and his characterisation of latent heat and specific heat. He was a chemist by chance, a physicist by inclination, and a physician by necessity. His discovery of carbon dioxide was as important for biology as it was for chemistry, and his work on heat laid a sound foundation for the study of temperature regulation in man and animals. PMID- 11624014 TI - Recharging at the Fordyce: confronting the machine and nature in the modern bath. PMID- 11624013 TI - Removing roots: "North American Hiroshima maidens" and the X ray. PMID- 11624015 TI - The strange career of DDT: experts, federal capacity, and environmentalism in World War II. PMID- 11624016 TI - Between a rock and a hard place: a history of American sweatshops, 1820-present, at the National Museum of American History. PMID- 11624017 TI - Resistance to psychology in holocaust scholarship. PMID- 11624018 TI - Participation in mass atrocities: a social psychological perspective. PMID- 11624019 TI - A nice type of the English scientist" Tansley and Freud. PMID- 11624020 TI - The meaning of dream books. PMID- 11624021 TI - The shark behind the sofa: the psychoanalytic theory of dreams. PMID- 11624022 TI - The fertility impact of changes in the timing of childbearing in the developing world. AB - This study examines the role of tempo effects in the fertility declines of less developed countries. These effects temporarily inflate the total fertility of a population during periods when the age at childbearing declines and deflate it when childbearing is postponed. An analysis of data from the World Fertility Surveys and the Demographic and Health Surveys demonstrates that fertility trends observed in many less developed countries are likely to be distorted by changes in the timing of childbearing. In most countries women are delaying childbearing, which implies that observed fertility is lower than it would have been without tempo changes. This pattern is most clearly documented in Taiwan, where accurate birth statistics from a vital registration system make it possible to estimate the tempo components of fertility annually from 1978 to 1993. The small but unexpected rise in the total fertility of Colombia in the early 1990s is attributed to a decline in the negative tempo distortion that prevailed in the 1980s. Similar interruptions of ongoing fertility declines may occur in the future in other countries when existing negative tempo effects are removed. PMID- 11624023 TI - Childhood mortality and quality of care among abandoned children in nineteenth century Italy. AB - A great deal of scholarly attention has been devoted in recent years to the large scale abandonment of new born babies in the European past, with special emphasis given to the staggering rates of infant mortality among the foundlings. For the most part, scholars have agreed with the foundling home officials of the past in assigning much of the blame for this excess mortality to the women who took in the foundlings as wetnurses and subsequently as foster mothers. This article takes issue with this view, based on an examination of the children abandoned at the foundling home of Bologna, Italy in the nineteenth century. Four cohorts of foundlings are examined - those abandoned in 1809-30, 1829-30, 1849-50, and 1869 70 (N=3615) - as we trace the changing pattern of infant and early childhood mortality. Longitudinal methods are used in examining the life course of these foundlings and the determinants of their mortality. PMID- 11624024 TI - Recent European fertility patterns: fitting curves to 'distorted' distributions. AB - Recent patterns of fertility in Europe show marked differences between countries. Recent United Kingdom and Irish fertility curves show 'distortions' in terms of a 'bulge' in early age fertility, distinct from the smoother curves of other European countries. These patterns may not be adequately described by mathematical functions used by previous studies to model fertility curves. A mixture model with two component distributions may be more appropriate. The suitability of the simple and mixture Hadwiger functions is examined in relation to the fertility curves of a number of European countries. While the simple Hadwiger model fits recent period age-specific fertility distributions for some countries, others which display a 'bulge' in early age fertility distributions for some countries, others which display a 'bulg' in early age fertility require a mixture Hadwiger model. Some of the parameters of the Hadwiger models appear to be related to familiar demographic indices. The simple and mixture Hadwiger models appear useful in describing and comparing fertility patterns across European countries. PMID- 11624025 TI - Medical thought of Dosan Manase's early years. (1) The meaning of the work "Toryu". AB - Dosan Manase was a famous Japanese doctor in the Muromachi era and was in the vanguard of the Goseiha school of Sino-Japanese traditional medicine. In his "Shinmyakukudenshu" we found an interesting account to explain the meaning of the word "Toryu", which was often found in the medical books written in Dosan's early years. This word signifies "our school" in a general sense, but in this book Dosan used it with the additional meaning of his medical thought originating in Zhu dan xi who was a famous Chinese doctor in the Yuan age. In addition, he mentioned in the same book that Toryu was introduced from China into Japan by Dodo, succeeded by Sanki and propagated by himself. Moreover our extensive investigation of other medical literature showed that Dosan, in his early years, tried to develop a system of medical thought on the basis of that of Zhu dan xi. This is worthy of note because it differs considerably from the stance adopted in Dosan's later years : while he valued Zhu dan xi, he referred to many medical books by various authors, and tried not to favour any particular school. PMID- 11624026 TI - The development of scholarship in the Igakkan. (1) The founding of the Igakkan. AB - The Igakkan was an institute for medical education in Tokugawa Japan, which was founded by Taki Motoaka (1693-1766) in 1765 and became a bakufu institution in 1791. This paper looks at the latter process (for the purpose of this abstract, I will refer to this as bureaucratization) in the context of Tokugawa educational policy, particularly in comparison with Shoheiko, a school for training bureaucrats. Also, this paper examines sources written during the Kansei period (1789-1801), many of which have been neglected in the field. I show that the Kansei reforms significantly shaped medical thought in the late Tokugawa period. The paper is divided into three parts, and will be published in this and the two forthcoming issues. The titles of the three parts are as follows: Part 1. The Founding of the Igakkan Part 2. Government doctors during the Kansei Reform Period, As Seen in Yoshino zoshi Part 3. The Place of Evidential Scholarship in the late Tokugawa Period. In Part 1, I show that while the Shoheiko confirmed Shushigaku (sometimes referred to as Neo-Confucianism) as an orthodoxy, supporting the existing political structure, the scholars in the Igakkan were never confined by Sushigaku. PMID- 11624027 TI - On the prevalence of Asiatic cholera in Okinawa, 1879 and "Ryukyu-kiko" Written by Hironobu Tsuchiya. AB - The greatest prevalence of Asiatic cholera since the adoption of modern statistics was in 1879. Especially in Okinawa Prefecture, its morbidity rate was the largest in Japan in that year. Dr. Hironobu Tsuchiya, who was appointed as an official of the Department of Inner Affairs, wrote "Ryukyu-kiko" as a private memorandum. He wrote more about the situation of administrative confusion than he did about the condition of Asiatic cholera. This paper also mentions the brief sketch of Tsuchiya's life and the description of the manufacturing methods, effectiveness and use of chemical drugs which are contained in his "Sinyaku shoko". PMID- 11624028 TI - On the circumstances of the publication of the 1855 edition of "Roshia Gyuto Zensho" (Russian Vaccination Book). AB - There is a report that the 1850 edition of "Roshia Gyuto Zensho" (Russian Vaccination Book) translated by Sajuro Baba and edited by Sen-an Riko is not extant and that the 1855 edition of the book is the first edition. The author found an important document entitled "Shichu-Torishimari Zokuruishu - Shoseki-no bu" at the National Diet Library, which includes several official records describing the publication circumstances of "Roshia Gyuto-Zensho" issued in 1856. This document has scarcely been referred to by medical historians before. It reads as follows: "Ihachi Subaraya, the publisher, asked the magistrate of Edo to permit him to publish and sell two volumes of the translated vaccination book entitled "Roshia Gyuto Zensho" in 1856. The magistrate consulted the members of astronomy division of the Tokugawa Shogunate concerning its possible publication and gave finally a sanction to the publisher after careful consideration. There is a description in the records which shows that two volumes of the 1850 edition were submitted for check, indicating that the 1855 edition is the second and the 1850 edition is the first edition. Behind the situation regarding the granting of permission to the publisher by the Shougunate, there would have been the fact that Sajuro Baba, the translator of the book, was one of the founders of the division of astronomy of the Shogunate. PMID- 11624029 TI - "Igakusho Goyodome" (memorandum on Medical School of Edo) written by Royosai Tezuka. PMID- 11624030 TI - Yoshino Zoshi: research materials related to families of doctors. PMID- 11624031 TI - Research on the Ikeda documents: working group for the study of the Ikeda documents PMID- 11624032 TI - The historical materials about the medical system of the Edo Shogunate. PMID- 11624033 TI - In memory of Shoichi Yamagata. PMID- 11624035 TI - A brief history of the Gillet family: three generations of chiropractors in Belgium. PMID- 11624034 TI - Introduction and development of pathology. AB - If one defines pathology as gross and microscopic examination of abnormal tissue there was no comparable discipline in traditional medicine of Korea until the introduction of Western medicine in Korea. However, when one widens the scope of pathology to include pathogenesis and etiology, there were some pathology-related descriptions in Oriental medicine long before this period. The pathology based on Virchow's cellular pathology was introduced to Korea through two tracks independently in 1910s. One was academic pathology, through Japanese pathologists, namely Dr. Inamoto and Dr. Tokumitzu, and the other track was hospital pathology through Western missionaries who introduced the American system of laboratory medicine (clinical pathology). It was Japanese who dominated the introduction and development in Korea. The Koreans played a minor role in the development of pathology from the introduction period until 1945, when the Korea was liberated from Japan. Pathology teaching, research and hospital service had been consistently carried out through three medical schools, namely Severance Medical School and two government medical schools until 1945. After independence, the Korean Society of Pathologists was quickly organized and made a rapid promotion. The Korean war provided opportunities to experience and adopt the American pathology system in Korea. The hospital pathology system has been established, together with the pathology specialty system in Korea. Balanced promotion of research pathology and service pathology is expected in Korea. PMID- 11624036 TI - Three oldest chiropractic diplomas. PMID- 11624037 TI - Laid to uneasy rest: D.D. Palmer, 1913. AB - A study of the documentary records related to D.D. Palmer's death in Los Angeles in 1913 provided several surprises and a number of unanswered questions. How tall was D.D. Palmer? Why were the Founder's attending physicians persuaded to change their opinions about the primary cause of death? Was there a private autopsy, and what of the reported abscess in Palmer's side? What role did D.D.'s widow play in the patricide controversy? There is more to the documentary trail to explore. PMID- 11624038 TI - Ruth Rose Ashworth-Cleveland: a pioneer's journey as seen through personal letters. AB - Ruth Rose Ashworth-Cleveland accomplished a great deal during her eighty years of life. It is generally known that she was one of the founders of Cleveland Chiropractic College. However, she was also an accomplished public speaker and active in several chiropractic organizations for much of her adult life. Not much is known of her life after she left Cleveland Chiropractic College in the early 1940s. It is the author's hope in writing this to give the reader a greater awareness of her accomplishments, and of her as a person. PMID- 11624040 TI - From Africa to Africa. AB - Chiropractic, an American-born profession, has grown and developed internationally, especially within the last decade. In reality, however, this growth started long ago in other countries. This article explores the development of the profession in South Africa by examining the life of an American-trained, South African-born, chiropractor. During this time, the international chiropractic community was a small group with close ties to America. This was, in part, due to the fact that chiropractic education was only available in the United States and one was not considered "legitimate" unless he or she was American trained. The struggles of the profession are not unique to America; they have also occurred elsewhere. Chiropractic evolution in South Africa is examined as well as the development of registration (licensing) and tertiary education. PMID- 11624039 TI - Commonwealth laws of Massachusetts v. early chiropractic pioneers, 1911-1915. AB - The first few chiropractors in Massachusetts practiced as they desired, unmolested by the authorities. All this changed after Joe Shelby Riley, D.C., established his New England College of Chiropractic in Boston in 1911. Printed publicity got out as to the tuition costs, length of the course and what graduates could expect to earn in a short time, when the police stepped in. They arrested first J.O. Zimmerman, D.C., of Boston, followed by Dr. Riley, a school president, then Samuel Mendelson, D.C., in Lynn, all for illegal practices. From the judical decision in Commonwealth v Zimmerman, 1915 by the Supreme Judicial Court (State Supreme Court), the high court held that the practice of chiropractic to be the illegal practice of medicine without a license, according to the Commonwealth laws of 1902. Next came the Commonwealth v New England College of Chiropractic; this case was shortly followed on appeal from the Municipal Court in Boston, to the Suffolk County Superior Court, to the Supreme Judicial Court like Zimmerman. In this case against Dr. Riley and his school, the high court affirmed the school to be illegal because Dr. Riley had failed to receive authority from the Great General Court (the Legislature) to get a bill passed authorizing the school to have the right of granting degrees. According to the Boston Herald, all this legal action was the culmination of a campaign spearheaded by the Massachusetts Medical Society. PMID- 11624041 TI - Talk of the town in 1921: chiropractic and "talking sickness". AB - In 1921 Waukegan, Illinois, there was an eight-year-old girl who had what was called "talking sickness." She reportedly talked constantly for eight straight days and nights. After medical care failed to help, a local chiropractor was called to adjust the young girl, and she apparently experienced marked improvement thereafter. News of the seemingly spectacular recovery reached a fever pitch across the United States in the spring of 1921, in both lay and professional publications. The slightly different versions of this case, from slightly biased sources on each side of the fence (such as Fountain Head News on the one side and The Journal of the American Medical Association on the other), as well as coverage from newspaper reports are explored. PMID- 11624042 TI - C. Sterling Cooley, D.C., F.I.C.C.: politician, innate fundamentalist and Palmer historian. AB - From the day he graduated from the Palmer-Gregory Chiropractic College in 1908 until his death in 1965, C. Sterling Cooley considered himself a student of D.D. Palmer. Friend to three generations of the Palmers, he nonetheless found his own path through the stormy politics of his era. Appointed to the first Board of Chiropractic Examiners in Oklahoma in 1921, he served for many years as president and secretary and, later, as a member of the state's basic science board. Cooley helped establish the International Chiropractic Congress in 1928 and was elected the third president of the broad-scope National Chiropractic Association (NCA) in 1935. The first serious steps in the NCA's educational reform efforts took place during his term on the society's executive board (1936-41). Concerned that both the NCA and the International Chiropractor's Association were ignoring the principles of chiropractic as set forth by Old Dad Chiro, Cooley devoted his final two decades to studying, speaking and writing about the life and teachings of the founder. His career epitomizes that segment of the profession which held that authority in defining and practicing chiropractic must derive from the principles of the "Old Master." PMID- 11624044 TI - Women in medicine and the issue in late nineteenth-century Alabama. PMID- 11624045 TI - A pioneer Alabama doctor's ledger. PMID- 11624043 TI - Miner's hospitals come to the coal fields: acute care nursing 1900-1920. PMID- 11624046 TI - The chronology of Galen's early career. PMID- 11624047 TI - Estimates of infant mortality on the western frontier: the use of genealogical data. PMID- 11624048 TI - Classifying causes of death during the late nineteenth and early twentieth centuries: the case of German infant mortality. PMID- 11624049 TI - Mother love and infant death, 1750-1920. PMID- 11624050 TI - Tobacco among the Cherokees. PMID- 11624051 TI - "A hand to hold while dying": Dr. Charles A. Leale at Lincoln's side. PMID- 11624053 TI - The doctor who never refused a call: [Arthur James] Hood, M.D. PMID- 11624052 TI - The cultural model of the menstrual cycle. PMID- 11624054 TI - The silent charity: a history of the Cincinnati Maternity Society. PMID- 11624055 TI - An appreciation of Dr. Tadao Sato. PMID- 11624056 TI - Monica Baly, British nurse historian. PMID- 11624057 TI - Jane Renwick Smedburg Wilkes: North Carolina nurse pioneer. PMID- 11624058 TI - Hildegard E. Peplau 1909-1999: nursing scholar, educator and leader. PMID- 11624059 TI - A dentist on an oil painting. PMID- 11624060 TI - William C. Gorgas and the Gorgas Hospital. PMID- 11624061 TI - Let there be light. PMID- 11624062 TI - The 25th general assembly of the Japan Medical Congress. PMID- 11624064 TI - Collecting (medical) topicals. PMID- 11624065 TI - Carlos de la Torre y de la Huerta (medical doctor, pharmacist, malacologist) PMID- 11624063 TI - Portuguese physicians. PMID- 11624066 TI - Coughing blood: tuberculosis deaths and data on the Yakama Indian Reservation, 1911-64. AB - Tuberculosis was the foremost killer of First Nations populations during the late nineteenth and early twentieth centuries. According to data from Death Certificates collected by the Yakama County Health Department and preserved by the Office of Indian Affairs, tuberculosis among the 14 tribes of the Yakama Nation took the lives of 619 people between 1911-64. The model age group was those Yakama between 15-19, with people between 15-39 suffering 329 (53%) deaths. Changes in contact with bacteria, diet, housing, and seasonal rounds resulting from reservation life influenced high tubercular death rates among Yakama when compared to Whites and non-Whites in the US and the population of Washington. PMID- 11624067 TI - Perfect subjects: race, tuberculosis, and the Qu'Appelle BCG Vaccine Trial. AB - This article examines how Native children of the Qu'Appelle reserves in southern Saskatchewan became the subjects of a trial of the BCG vaccine for tuberculosis in 1933. Race and theories of racial evolution were referred to in the construction of the Native people as "primitives" and the reserves as disease menaces to the surrounding communities. Dr. R.G. Ferguson, medical superintendent of the nearby Qu'Appelle Sanatorium conducted the trial in order to prove that BCG could provide resistance to tuberculosis even among the "less evolved races." While BCG afforded some protection against tuberculosis, nearly one-fifth of the children in the trial died from diseases of poverty, gastroenteritis and pneumonia, as a result of the lethal living conditions on the reserves. PMID- 11624068 TI - The ethics of farming-out: ideology, the state, and the asylum in nineteenth century Quebec. AB - This article traces the development of the farming-out system of asylum provision which emerged in Quebec for the treatment and care of those who were considered to be insane. The kind of asylum provision that developed in Quebec was met with strong criticism by alienists elsewhere in Ontario, Britain and the United States who considered farming-out to be highly unethical. These criticisms were not lost on the state which tried to exercise increased control over the daily affairs of the asylum. But for much of the nineteenth century the state largely failed in these efforts. The community response to the rise of the farming-out system further complicated the role of the state in the management and control of insanity. I argue that the farming-out system is best considered as the product of complex relations between the state officials, alienists, and community members. This understanding of asylum development in Quebec has important implications for the study of the nineteenth-century state formation. PMID- 11624069 TI - Major medical explanations for high infant mortality in nineteenth-century Europe. AB - Statistics initially developed as a recognized field in the social sciences in the middle of the nineteenth century. The European medical profession first made use of mounting statistical evidence to dramatize infant mortality, one of the great social problems of the century. Those telling statistics amply demonstrated the general proportions of the problem as well as pinpointing the fact that a large percentage of the dying was neonatal in character. The medical profession also insisted that these infants were passing away from a series of ailments. Number one on their list was what they called debility, followed by respiratory disorders, gastro-intestinal problems, and convulsions. While nineteenth-century European medicine did not necessarily solve this social problem, it did evidently convince the larger society that these high tolls were morally unacceptable. PMID- 11624070 TI - [A provincial physician's interest in mineral waters and monsters in the 17th century]. AB - After 15 years of medical practice, a physician working in Gatinais (a region situated south of Orleans) decided, in 1649, to write books, which he did until he was 80 years old in 1692. One of these books, whose English title was, The Poor Man's Physician and Surgeon (published in London in 1704) had a great success. The first two (1649 and 1650) dealt with esoteric topics for the time. Analyzing these works presents the opportunity to understand how this "Doctor of the University of Montpellier" interpreted traditional anatomy and physiology, as well as his receptiveness to new therapeutic methods. PMID- 11624071 TI - Wood engraving and the illustration of American surgical texts during the nineteenth century. AB - Wood engraving as a medium of book illustration emerged at the end of the eighteenth century. In spite of its immediate technical and economic advantages to publishers of medical and surgical books, engraving on metal continued to dominate book illustration until the fourth decade of the nineteenth century. This study examines the two phenomena principally responsible for propelling wood engraving to the forefront of surgical book illustration, ie., the emergence of the mass-circulation illustrated periodical, and the use of wood engraving in the illustration of British surgical texts post-1840, the source of most surgical literature published in the United States until the 1860s. This study also examines the use of wood engraving in surgical book illustration after the universal acceptance of the medium by American publishers. PMID- 11624072 TI - William Fulton Gillespie, 1891-1949: transitional figure in western Canadian academic surgery. AB - The professional life of William Fulton Gillespie, third professor of surgery at the University of Alberta (1939-49) and tenth president of the Royal College of Physicians and Surgeons of Canada (1947-49), exemplifies a critical transitional period in Canadian postgraduate surgical training and in western Canadian academic surgery. This article explores the background, the training, the professional career, and the personal character of a surgical scholar and student of the humanities and arts, a man who was thrust into the professorship of surgery in a maturing western Canadian medical school following the financial restraints of the Great Depression and during the challenges faced as a result of the World War II. PMID- 11624073 TI - Genetics and "race" in the Merchant of Venice. PMID- 11624074 TI - "I'll cry myself sick": illness in Wuthering Heights. PMID- 11624075 TI - Troubled teen or troubled system?: TV interprets the Zion malpractice case. PMID- 11624076 TI - Dr Samuel Auguste Tissot. PMID- 11624077 TI - Dr John Fothergill and eighteenth-century medicine. PMID- 11624078 TI - The accomplishments of Sir James Cantlie. AB - Sir James Cantlie succeeded in his diverse endeavours. A pioneer in first aid medicine in Britain, he wrote several important manuals on the topic. The interlude in Hong Kong set the stage for his role in Chinese history with his involvement with Sun Yat-Sen, the father of modern China, and in the establishment of the present Faculty of Medicine at the University of Hong Kong. The contact with tropical diseases sustained a career that included the founding of the current Royal Society of Tropical Medicine and Hygiene, and the extant Transactions of the Royal Society of Tropical Medicine and Hygiene. As a surgeon, he argued for a new concept of hepatic lobulation based on the vascular supply, and became recognized as the father of the surgical anatomy of the liver. The scope of Cantlie's achievements is rivalled by few physicians, and his legacy remains with us to this day. PMID- 11624079 TI - Rudolf Virchow: pathologist, public health physician, liberal politician, anthropologist, and opponent of anti-Semitism. PMID- 11624080 TI - James Paget Henry: master physiologist. PMID- 11624081 TI - Figures in the historical dispute over renal function. Part I: from ancient times to the first microscopes. PMID- 11624082 TI - James Marion Sims and the rise of gynaecological surgery. PMID- 11624083 TI - Jonathan Hutchinson and John Hughlings Jackson: reflections on a friendship. PMID- 11624084 TI - The death of King George II, with a biographical note on Dr Frank Nicholls, physician to the King. PMID- 11624086 TI - Mortality of rural landless men before the black death: the Glastonbury head-tax lists. PMID- 11624085 TI - How the fatal illness of Frederick the Noble affected an Anglo-American friendship: unpublished letters from Dr Morell Mackenzie to Dr Robert Myles. PMID- 11624087 TI - Laboratory science and common sense. PMID- 11624089 TI - The portrayal of veterinary medicine in films. PMID- 11624088 TI - The remarkable history of treatment for milk fever. PMID- 11624091 TI - Some early American graduates of British veterinary schools. PMID- 11624090 TI - Animal therapy over the ages: 2. chiropractic and 3. homeopathy. PMID- 11624092 TI - Maister Peter Lowe (circa 1550-1610): founder of the Royal College of Physicians and Surgeons of Glasgow. PMID- 11624094 TI - The spreading of six comprehensive medical books of the Ming dynasty to Japan and their influence. AB - Plenty of medical books were spread to Japan from China in the Ming dynasty. The most influential ones include the six comprehensive books, viz, "Yi Shu Da Quan", "Yu Ji Wei Yi", "Yi Xue Zheng Chuan", "Yi Xue Men", "Wan Bing Hui Chun" and "Nan Bei Jing Yan Yi Fang Da Quan", all spread quite fast. To begin with, they promoted the reprinting of Chinese medical books in Japan in large amount since the 16th century, providing convenient textbooks for Japanese medical teaching. Finally, they help to develop the scholastic thought of "Dao San" in theory and practice. As a result, they also helped to rejuvenate Japanese medicine. PMID- 11624093 TI - The snowdrop (Galanthus nivalis): from Odysseus to Alzheimer. PMID- 11624095 TI - [Discassion on the date of appearance of the title Shen nong ben caojing (Shennong's Herbal Classic)]. AB - It is said, in general literatures, that the title of shen nong ben cao jing appeared in pre- Qin period. It can be negated, through studies on Han shu yi wen zhi (Biblie - graphies in Book of Han Dynasty), relics unearthed from Han tombs in Mawangdui, the history of nomencleture for ancient books, and the date of appearance of ancient canons, that the said - title first appeared in the pre - Qin period. The name of "ben cao" was first appeared in western Han dynasty. There were officials of necromaneer (fan shi) and ben cao in western Han dynasty. During Chengdi Emperor of Han, some seventy such officials were dismissed and returned to their homelands. Pingdi Emperor re-summoned these officials. Several scores of officials responded to the edict, among them, those responsible for ben cao complied a book on ben cao (herbology) and alleged it to be written by shennong so as to win confidence with the authority and to acquire the official title of ben cao dai zhao (Herbal Attendant) for themselves. It is, therefore, natural that the title of shen nong ben cao jing can only have appeared at the time of Herbal Attendant in Western Han dynasty. PMID- 11624096 TI - [Shi Ji Yao Yu, the earliest extant monograph on TCM nursery]. AB - Nursery of traditional Chinese medicine (NTCM) has a long history. However, due to the change and influence of the era, society, life style, and many other factors, NTCM did not become an independent discipline for a long period. Although there have been many articles about NTCM appearing in various historical books of traditional Chinese medicine, books specializing on NTCM were not available until later. The earliest ancient book, which is still currently available, describing NTCM in details is the "Shi Ji Yao Yu" written by Qian Xiang in the Qing Dynasty. The book explains the key issues of taking care of a patient's emotional well-being, life style, diet, illness, and drug administration which are of great practical significance now and for the future. PMID- 11624097 TI - [A review on TCM literatures of Ming - Qing periods]. AB - A systematic review is made on TCM literatures of Ming - Qing periods on the following aspects, including clinical literature, popularization, variorum, literature studies and features of outward appearance. The causes of the overall development of TCM literatures, and its promotion on TCM scholarship are also discussed. It is pointed out that the TCM literatures, being the main body of TCM literature as a whole, should become the main goal for modern studies. The books mentioned here are arranged in chronological order of its writing dates. PMID- 11624098 TI - [Study on Cao Xi's medical works]. AB - Cao Xi is a famous physician of the Wei - Jin Dynasties. His medical works had been lost since the Song Dynasty. But there are some fragments of its text retained in some extant medical literatures. Through analysing these lost remained texts, Cao Xi's medical works are systematically studied. Some errors about Cao Xi's medical works are thus corrected. PMID- 11624099 TI - [Judging the date of Neijing (Inner Canon) through study on semantic changes]. AB - In the pre - Qin literature, the characters "ti", "pi", "nian" refer to "tear", "beast skin" and "year" respectively and it became "nasal discharge", "man's skin" and "age" respectively in the Han dynasty, which never appeared in the pre Qin period. By studying the semantic changes in books of different times, the meanings of the above 3 characters, that frequently occurred in Neijing, are identical with those books of the Han dynasty. Hence, it can be concluded that Neijing can only be completed not early than the Han dynasty. PMID- 11624100 TI - [Review of external therapy for internal diseases in Ming yi lei an (Classified Medical Records of Famous Doctors)]. AB - External therapy was applied for internal diseases in 78 case records in Classified Medical Records of Famous Doctors, including 19 kinds of external therapies for 41 categories of internal disease involving 40 famous doctors. The external therapy embodied the principle of "treatment according to differential diagnosis of Zhen "of TMC", "regular treatment", "contrary treatment" and multiple routes of administration were given in accordance with the differentiation, demonstrating that ancient doctors paid high attention to external therapy for internal diseases. PMID- 11624101 TI - [Tan Yunxian, a woman physician of Ming dynasty, and her Nu yi za yan (Random talks of a woman physician)]. AB - Inherited from the heritage of her family, Tan Yunxian read of medical works day and night. After practicing, it was said that "she always get wonderful therapeutic effects in treating those females who refuse to see a male physician". As one of the few women physicians in history, she left down Nu yi za yan which altogether 31 case reports are included, dealing with habitual abortion, menstrual disorders, postpartum diseases, and abdominal lumps, with records on moxibustion therapy applied skillfully. From a clinical view point, though only a little number of case records are included, all the treatment are successful with rich experience worth while for reference to later ages. PMID- 11624102 TI - [Qiu Xi and vaccination]. AB - Qui-Xi was one of the earliest Chinese who learned cowpox vaccination in the early 19th century. He spent all his life on vaccination career, explained and supplemented the cowpox vaccination by TCM theory, and thus did great contribution to the prevention of smallpox in China. Guangdong, as an early trade window opening to abroad, provided an environment of social thought and economic support to him. PMID- 11624104 TI - [Discussions on acute pharyngo - laryngeal diseases treated with acupuncture by physicians of successive ages]. AB - Originated from Neijing, the acupuncture treatment for acute pharyngo-laryngeal diseases was applied by Zhang Zhongjing under the guidance of Neijing and many acupuncture treatments for the disorders were mentioned by Huangfu Mi in his first monograph on acupuncture- moxibustion. Sun Simiao of the Tang dynasty further developed this technique and different therapeutic styles were developed by the Four Schools of Jinyuan dynasties. It was further supplemented by Yang Jizhou and Xue Ji of the Ming dynasty, and the scope of acupuncture treatment was further expanded by Zheng Meijian with disciplinary features and therapeutic mechanism. All the above descriptions from successive ages further pushed forward the development in this field. PMID- 11624103 TI - [Distinguished medical students of Boji Hospital in Guangzhou (1855 - 1900)]. AB - Guangzhou Boji Hospital (The Canton Hospital) was the most famous western medical hospital established in 1835. John G. Kerr, an American doctor with the Presbyterian Mission, was the founder of the hosptial. He became the director of Boji Hospital in 1855 and worked there for 44 years. Chen Mengnan, Kang Guangren, Sun Yatsen (Zhongshan), Zheng Shiliang, Zhang Zhujun and Shi Jingran were medical students of Boji Hospital in this period. They had made important contributions to China during the rapid changing society of the late Qing dynasty. PMID- 11624105 TI - [Health education Chinese school in late 19th century and early 20th century]. AB - At the early stage of modern Chinese new - style schools, there appeared the embryonic form of health school. In the 1920s, the term health education had already been commonly applied, and health education in the school was developed gradually in large and medium - sized cities, with the establishment of health educational institutions successively. In 1931, a professional school for training teachers of health education was established in Central University, and the 20s and 30s saw the inspiring developing stage of health education in Chinese schools. PMID- 11624106 TI - [Dr. Tu Tsung-ming, a famous physician in Taiwan]. AB - Dr. Tu had achieved great successes in the field of snake venom research in the middle of twenty-century in Taiwan. He ushered a new epoch in venomology from the epidemiological studies of the snake-bite to the chemical analysis of the venoms, from the venom harmful disadvantages to the venom beneficial advantages, and from the pharmacological research to the field of toxicological and biochemical research. He established a method for urine examination to detect the morphine residue. This method was then developed as a routine examination for excitant for athletics in later ages. Dr. Tu was the first professor of pharmacology in Taiwan and also a famous educator and historian in medical science with rather high achievement. PMID- 11624108 TI - [An outline on the early pharmacetical development before Galen]. AB - The period before Galen (including his time) is known as ancient herbal period of pharmacy, which is an important component in the developing history of pharmacy. Some characteristics and rules about early pharmacy development are reflectd from the origin of pharmacy, Babylonian - Assyrian pharmacy, ancient Egyptian pharmacy, ancient Greek pharmacy and Rome pharmacy in different periods and areas. PMID- 11624107 TI - [Anatomy cadaver ceremonies in Taiwan]. AB - The practice of holding annual ceremonies in honor of cadaver donors in Taiwan's medical schools has a history of nearly a hundred years. It originated in Japan, where such ceremonies have been widely held in medical schools since the practice was founded by Toyo Yamawaki, who was the first medical scholar in Japan to engage in dissection of the human body and was the author of the first anatomy book to appear in Japan, the Zoshi. The practice of holding donor ceremonies was introduced into Taiwan after the Jaiwu Sino - Japanese war, when the island became a Japanese colony. The tradition was upheld in the Viceroy's Medical School, the Viceroy's College of Medicine, and Taihoku (Taipei) Imperial University College of Medicine, and continued since the restoration of Chinese power to the present. The practice of holding cadaver donor ceremonies in institutions of medical education is intended to express respect for the donor as well as to encourage the practice of cadaver donation to the benefit of medical education. PMID- 11624109 TI - [Look back on the tenth revision of the international classification of diseases (ICD - 10)]. AB - Following the 6th revision, the 10th revision of ICD is another revision of significance as a milestone. The major change is the replacement of pure numerical form of code structure by alphabet - numerical one. There is also progress in the classification thinking in ICD-10, marking the progress toward maturity of the thinking in disease classification. Descriptions are given to the general condition, revision of its contents, the conception of classified 'family' of disease classification, and the new renewal mechanism in the 10th revision. PMID- 11624110 TI - Complacent and conflicting scientific expertise in British and American drug regulation: clinical risk assessment of triazolam. AB - This paper presents a case study in the production and interpretation of regulatory science, focusing on the conflicting British and American clinical risk assessments of triazolam (Halcion) - the most controversial sleeping pill in the world. The regulation of triazolam is shown to be more permissive in the USA than in the UK. Six principal socio-political factors are put forward to explain this; differential regulatory trust; regulators' socio-technical data selections; medico-scientific disciplinary influences; organizational and professional interests; conflicts of interest of expert advisers; and the growth of the neo liberal regulatory state. The risk assessments of both the British and American regulatory agencies are shown to be complacent relative to technical standards which the agencies themselves later accepted. It is suggested that, when the interests of pharmaceutical manufacturers and patients diverge, regulatory assessments are crucially affected by whether regulators are predisposed to award the benefit of the scientific doubts to the manufacturers or patients, and by the balance of such predispositions both within and between regulatory institutions of scientific expertise. The triazolam case indicates that the amount of trust placed in the pharmaceutical industry by the British American regulatory systems may hamper detection of flaws in manufacturers' medical data in a timely manner and, as a consequence, compromise patients' interests. Some policy implications for drug regulation are sketched. PMID- 11624111 TI - Parliamentary cultures and human embryos: the Dutch and British debates compared. AB - Twenty years ago, the technology of in vitro fertilization created a new artefact: the human embryo outside the woman's body. In many countries, political debates developed around the artefact. One of the central questions in these debates is whether it is permissible to use human embryos in research and, if so, under what conditions. To date, no uniform answer to this question has been given by the governments and parliaments of the different nation states. This highlights the importance of national cultures and local dynamics in the process of crafting the space for human embryo research. In this paper I approach the issue of the national context by comparing the Dutch and British parliamentary debates on human embryos. Though some arguments used in both debates were similar, the outcomes were very different. In the UK, the Human Fertilisation and Embryology Act was passed in 1990. In the Netherlands, several bills on human embryos have been drafted, but each of them was withdrawn from the proceedings before reaching Parliament. To understand the processes which led to these different outcomes, I scrutinize the roles in the Netherlands of the political parties, of the scientists' lobby and of women speakers, and compare them with the findings of the UK debate. I also reflect upon the role played by gender in these two culturally different political contexts. PMID- 11624112 TI - 'A sort of destiny': the multi-jurisdictional response to sewage pollution in the Great Lakes, 1900-1930. AB - At the turn of the twentieth century, water pollution was the primary vector spreading waterborne disease and a public health issue. In the Great Lakes basin, unprecedentedly high mortality from typhoid fever prompted a conference of federal and provincial public health officials in 1910. Three related initiatives resulted: the provincial government amended the Public Health Act in 1912; federal legislators attempted to develop national pollution control legislation between 1912 and 1915; the International Joint Commission investigated cross boundary pollution in 1912 and recommended a convention to control it. Of the three initiatives, only the provincial Public Health Act amendments were carried to fruition. By 1915, the almost universal adoption of chlorine treatment for municipal water supplies effectively controlled waterborne disease and there was no longer a perceived need for further action. PMID- 11624113 TI - [The Institut de Belleville: expansion and decline of research on biological control in Canada, 1909-1972]. AB - Ever since the beginnings of economic entomology in Canada, research in biological control has drawn substantial support from the Federal Department of Agriculture. Enjoying a stable institutional environment with the establishment of the Dominion Parasite Laboratory in Belleville, Ontario, in 1929, biological control has also occupied an important position on the research agenda of the Department until the late sixties. Support from the scientific authorities was nevertheless fraught with important paradoxes. For example, research laboratories in biological control were built at a time when North American economic entomologists relied almost exclusively on synthetic chemical compounds like DDT. For some historians of science, the autonomy of Canadian entomologists explains the growth of this research program in the aftermath of World War II. However, the autonomy of the scientific community is a notion that is taken for granted in these historical explanations. In this article, I will demonstrate the institutional dynamic underlying the autonomy of Canadian entomologists in pursuing a research agenda suited to their interests. I will pay close attention to the role of certain actors -- foreign entomological services and the forest and pulp and paper industries - in the rise of a Canadian expertise in biological control. As well, I will show how their interventions forced a reorganization of research on the biological control of insect pests in agriculture and in forestry, and how this reorganization eventually entailed the dismantling of the Belleville laboratory in 1972. PMID- 11624115 TI - In search of medical history. PMID- 11624114 TI - "Spray, Spray, Spray!": insecticides and the making of applied entomology in Canada, 1871-1914. AB - As insecticides were adopted by Canadian farmers and fruit-growers after 1871, the resources conferred on economic entomology by the Dominion and Ontario governments grew. In 1886, with the establishment of the Experimental Farms system, James Fletcher, the Dominion entomologist and botanist, and his colleagues inherited the task of promoting insecticides to orchardists and others. In 1898-1900, in response to the arrival in Ontario of the San Jose scale, Canada and Ontario adopted laws mandating the use of insecticides, as sprays and fumigants, in orchards and at plant quarantine stations. To meet the resulting demand for trained technicians and scientifically-minded farmers, the institutions of applied entomology federally and at the Ontario Agricultural College were further developed. In 1910, after a decade of rapid diffusion of insecticides, Parliament adopted the Destructive Insects and Pest Act, thus creating a national system of horticultural hygiene. PMID- 11624116 TI - William Osler re-visited. PMID- 11624118 TI - War and medicine--the American Civil War. PMID- 11624117 TI - Adam's chromosomes. PMID- 11624119 TI - Musician's maladies--of what did they die? Maurice Ravel (1872-1937). PMID- 11624120 TI - 50 years ago: the birth of molecular medicine. PMID- 11624121 TI - The relocation of the Adler Museum of Medicine: an opportunity for transformation and integration. AB - This article discusses the proposed relocation of the Adler Museum of Medicine from the grounds of the South African Medical Research Institute in Braamfontein to the Faculty of Health Sciences in York Road, Parktown. It outlines the future role of the new Adler Museum and investigates principles governing museum design which are applied to the design proposals for the Museum. An analysis is made of the existing Faculty of Health Sciences building as a precursor to the formulation of a design concept which seeks to incorporate the Adler Museum into the existing Medical School building. Using a medical analogy, the condition of the present Medical School building (the quality of environment and amenity offered) is diagnosed in terms of architectural and spatial criteria. A curative design solution which includes application of architectural and urban design principles and relies on the relocation of the Adler Museum to the foyer of the existing Medical School is proposed. PMID- 11624122 TI - R.R., B.J. and the "Long Blue Shadows". PMID- 11624123 TI - Early educational tracts helped to build chiropractic. PMID- 11624124 TI - Dr. Adelbert C. Douglass: a great healer, a small town physician, one of the early chiropractors. An oral history. PMID- 11624125 TI - Joseph W. Howe, D.C., D.A.C.B.R. and the development of modern chiropractic radiology. AB - Born in Galeton, Pennsylvania, on 27 May 1930, Joseph W. Howe has been extremely influential raising the educational standards for radiology in chiropractic. After receiving his D.C. from Palmer in 1952, he worked in private practice in Pennsylvania until being drafted into the Army, where he worked as a radiologic technician. After returning to civilian life and his practice, he attended many seminars and lectures on the subject, including one in 1958, taught by Roland Kissinger, D.C. at the National College of Chiropractic (NCC), the first postgraduate course in chiropractic roentgenology ever administered by a college. Howe then took and passed the second exam given by the American Board of Chiropractic Roentgenologists and was awarded certificate number eight in 1959. He helped to form the American Chiropractic College of Radiology and became its first Radiological Health Consultant. In 1968, he joined the Associates Diagnostic and Research Center (ADRC) in Tallmadge, Ohio, where he was able to concentrate on research and establish an off-campus facility for radiology residents of NCC. During this time Howe also lent his expertise to the Houston Conference on Spinal Manipulation. However, financial difficulties with the Center led Howe to leave, and accept a full time position teaching at NCC. Howe ultimately found himself too involved with administrative duties and not enough with the radiology that he loved, so he moved his family across the country in order to accept the radiology department chair at Los Angeles College of Chiropractic (LACC) in 1978. There he was given freedom to build the department to his high standards, and it retains the strongest residency in the profession, with up to six residents at any one time and links to prestigious radiologists like Donald Resnick, M.D. and Steve Rothman, M.D. Officially, Howe retired in 1998, but he still occasionally teaches residents and the Westwood-based radiology practice that he donated to LACC continues, run by the radiology faculty. PMID- 11624126 TI - California's Radiation Protection Act: first in the nation, 1969. AB - This is a chronology of events, of bills introduced, those that died in committee or were vetoed by the Governor before enactment of California's Radiation Control Act, first in the nation and enacted in 1969. Seeing confidential documents from Committee and Governor's Office for the first time adds color to the article. This article also memorializes Senator Walter W. Stiern and Mr. Gordon H. Garland who carried the chiropractic torch to make our inclusion into this act a reality. PMID- 11624127 TI - Australian information on Victor Coxon. PMID- 11624128 TI - The Bakkum Chiropractic Clinic and Hospital. AB - The number of chiropractic facilities that offered in-patient care peaked in the period between World Wars I and II. Little information is available about the vast majority of these facilities. One of these was the Bakkum Chiropractic Clinic and Hospital in Waukon, Iowa. The proprietor was Roy C. Bakkum, D.C., who along with his wife, Jessie H. Bakkum, D.C., opened this thirty bed facility in 1936. The only therapeutic intervention that the majority of patients received at this facility was hole-in-one (HIO) adjustment. Unfortunately, mainly because of economic pressures, the facility closed in 1950. The Bakkum Chiropractic Clinic and Hosptial may have been fairly typical of the small chiropractic facilities that offered in-patient care. Most of them closed in the post-World War II period, mostly due to economic difficulties. Dr. Roy Bakkum not only had the vision of chiropractors as true primary care-givers, but tried to implement that vision to the best of his ability. He saw the chiropractic adjustment as the main therapeutic intervention that the vast majority of people should receive, even as in-patients. Radical allopathic or surgical intervention would have only been called upon as needed, rather than being the usual and customary primary care that is currently the norm. PMID- 11624129 TI - Thomas Henry Storey, D.O., D.C. 1843 to 1923. AB - Who was Thomas Henry Storey? Dedicated healer or charlatan? A danger to his patients or hero to the profession? He graduated from the Palmer School and Infirmary of Chiropractic in 1901. One of the largest chiropractic colleges, the Los Angeles College of Chiropractic, would be founded by one of his patients in 1910 and incorporated in 1911. He led the founder of chiropractic on his first expedition to Los Angeles. Thomas' seventy-nine year life span took him from Canada through the north central United States to the West Coast from Washington to California and south into Mexico. He was, at various times, a taxidermist, a farmer and, in later years, a rancher. He studied and practiced many types of healing and even operated a chiropractice school for a time. He invented the most ubiquitous of all chiropractic equipment, the bifid table. Whether he desired it or not, Thomas was often thrust into the spotlight, usually under less than admirable circumstances. Even in death, the remnants of his life remained a complicated morass that took sixteen years to resolve in the courts. It is hoped this article will shine some light on a colorful chiropractic pioneer who has been shrouded in a veil of mystery. PMID- 11624130 TI - Life University Bell Tower commemorates jailed pioneers. PMID- 11624131 TI - Marek Shimerda in My Antonia: a noteworthy medical etiology. PMID- 11624132 TI - Neuroanniversaries 1999. PMID- 11624133 TI - Origins of the Creutzfeldt and Jakob concept. AB - A review of the publications of Hans Creutzfeldt and Alfons Jakob pertaining to the concept which bears their name (CJD) reveals that they described a neuropathological syndrome and were opposed to its classification as a neurological disease. The evidence on which Creutzfeldt and Jakob based their view is reevaluated, and studies by other workers are cited in which a range of environmental and genetic factors generated the CJ syndrome, challenging the proposition that CJD is a disease with a single cause. PMID- 11624134 TI - Hysteria behind the scenes: Jane Avril at the Salpetriere. AB - Jane Avril (1868-1943), the famous dancer of the Moulin Rouge, immortalized by Toulouse-Lautrec, left behind published Memoires (1933). Trustworthy and written with verve, they include an account of her admission to Charcot's service at the Salpetriere in December 1882. There she was kept until June 1884, not so much because of illness but to protect her from her mother's abuse. Jane Avril provides unvarnished testimony of the daily life of the women with hysteria among whom she lived. She wrongly accuses them of simulation. But she accurately portrays the rivalry of the 'crazy girls' who vied to become the center of attention, and she sheds light on the factors that came together to make hysteria contagious (she herself escaped), the loading of symptomatology and the cultivation of the ailment. Charcot has been criticized on this score, since he showed his recognition of the underlying process when he pronounced isolation to be necessary to treatment. If Charcot accommodated hysteria, the ailment amply rewarded him with a fame that continues to this day to overshadow his achievement in neuropathology that he brilliantly forged using the "anatomo-clinical method." PMID- 11624135 TI - On the discovery of Clostridium botulinum. AB - A description is given of a food intoxication in 1895 at Ellezelles, a village in Belgium. As a result 3 persons died within a few days and others became seriously ill. A thorough investigation by E. van Ermengem led to the discovery of Clostridium botulinum and botulinum toxin. About 75 years later a subtype of the toxin proved to be highly effective in the treatment of dystonias and is now widely used. PMID- 11624137 TI - Production and reception of meaningful sound in Foville's 'encompassing convolution'. AB - In the history of neurology. Achille Louis Foville (1799-1879) is a name deserving to be remembered. In the course of time, his circonvolution d'enceinte of 1844 (surrounding the Sylvian fissure) became the 'convolution encompassing' every aspect of aphasiology, including amusia, ie., the localization in a coherent semicircle of semicircle of cerebral cortext serving the production and perception of language, song and instrumental music in health and disease. PMID- 11624136 TI - A perplexing document in the early history of Gilles de la Tourette Syndrome: Melotti's rendition of a "Lecture of Charcot" (including a complete translation from the Italian with commentary). AB - In 1885, Dr. Guilio Melotti published an Italian translation of a lecture on "Convulsive Tics with Coprolalia and Echolalia" given by Jean-Martin Charcot. Although this lecture often has been cited as an authoritative statement of Charcot's view, until now it has not been translated into English. The lecture presents a number of statements that appear nowhere else in Charcot's published corpus, including some that seem to contradict Charcot's other pronouncements on maladie des tics. Although the Melotti-Charcot lecture may portray Charcot's position accurately in many passages, the article most likely is a compilation from a variety of sources. PMID- 11624138 TI - Portrayal of lobotomy in the popular press: 1935-1960. AB - This study analyzed the content of popular press articles on lobotomy between the years 1935 and 1960. Both a qualitative and quantitative analysis provided evidence that the press initially used uncritical and sensational reporting styles, with the content of articles on lobotomy becoming increasingly negative through time. The initial positive bias occurred despite opposing views in the medical community, which provided a basis for more balanced coverage. These findings support the theory that biased reporting in popular press articles may have been a factor influencing the quick and widespread adoption of lobotomy as a psychiatric treatment. PMID- 11624139 TI - Jiri Prochaska: on the 250th anniversary of his birth. PMID- 11624140 TI - Just what is the inferior cerebellar peduncle? PMID- 11624141 TI - Proceedings of the Third Annual Meeting of the International Society for the History of the Neurosciences (ISHN), June 7-9, 1998, Annapolis, Maryland, USA. PMID- 11624142 TI - The British contribution to the neurosciences. PMID- 11624143 TI - Using multi-media to enhance history education: Glasgow, A Tale of Two Cities? and Tiree, Famine and Clearance 1840-1900. AB - Advances in information technology raise issues central to history education. Debates have focused on how pupils learn history by emphasising the development of critical thinking which in turn provides the basis of a theoretical framework for the use of IT in history. Martyn Wild identifies seven areas of teaching and learning enhanced through IT ranging from child-centered learning to pedagogy. James Schick argues that appropriate software brings out the absorbing, fascinating and enjoyable nature of history. This article discusses how multi media computer programs, Glasgow, A Tale of Two Cities? and Tiree, Famine and Clearance 1840-1900 enhance the delivery of history in Scottish Primary and Secondary Schools within the criteria established by Martyn Wild. These programs relate to recent curricular changes in Scotland and help satisfy current demands for more Scottish history within overall history syllabuses. Moreover, it will be argued that appropriate software motivates pupils and enhances the central role of the classroom teacher. PMID- 11624144 TI - [History of the discovery of Mexican hallucinogenic mushroooms] (Fr). PMID- 11624145 TI - Christianization of the soul: religious traditions in the care of people with learning disabilities in the Netherlands in the nineteenth century. AB - Educational and therapeutic optimism with respect to those with learning disabilities led to new developments in some countries around the mid-nineteenth century. In the Netherlands there was little specialist care and few special initiatives were taken before the end of the century. The dominant expert opinion was that these people required the standard care offered by the asylum. Two mid nineteenth-century initiatives, however, are worth analysing, since they signal the cautious start of special institutional education in the Netherlands: the Idiotenschool (School for Idiots) in The Hague and the class for idiots at the Meerenberg Asylum. However, the most important alternative to care in the asylum was offered by institutions with explicitly religious motives, which evolved from Catholic charity and Protestant philanthropy for many different types of socially weak and dependent groups. This article will examine the nineteenth-century religious roots of the care of people with learning disabilities in the Netherlands; it will also show how older educational ideas began to reappear in this context by the end of the century. PMID- 11624146 TI - State regulation and the hazards of milk, 1900-1939. AB - This examination of milk safety before the Second World War focuses on the manner in which government regulation was shaped by the agricultural lobby, acting through the Ministry of Agriculture. Dairy farmers used their market strength to resist the introduction of many regulations which were regarded as desirable and even essential from a public health perspective. These included compulsory pasteurization, favoured by the Ministry of Health and the BMA, but successfully resisted by farmers in the 1930s on commercial grounds and so not actually realized until 1949. This episode crystallized the three related conflicts of interest--between rural and urban areas, the needs of agriculture and public health, and the Ministries of Agriculture and Health--which restricted the expansion of state regulation, ensuring that milk still remained a potentially hazardous and occasionally lethal commodity in the late 1930s. PMID- 11624147 TI - The early days of the MRC Social Medicine Research Unit. AB - During the 1940s, in Britain, there was great activity in the field of social medicine. This was generated by an upsurge in interest in social issues and a desire to promote occupational health research. In 1948 the Medical Research Council established a Social Medicine Research Unit. The background to the creation of the Unit and its early work are discussed. By the early 1950s, the political atmosphere had changed and criticisms of the Unit's work during the debate about continued funding in 1952 are considered. Important work on the relationship between coronary heart disease and physical exercise, and the results of a study of infant mortality, were published in the mid-1950s. A brief account of the subsequent history of the Unit, until its closure in 1975, is given. PMID- 11624148 TI - Rhetoric and the social construction of sickness and healing. AB - An important element in recent science studies has been the analysis of the social rhetoric involved in the construction of disciplines and knowledge. An explicit use of rhetorical and semiotic frames of reference would illuminate many aspects of the history of medicine and could provide a unifying framework for the field. Medical theories were always intended for use and therefore had to be plausible in the eyes of patients. The interpretation of signs and the construction of explanations lie at the heart of diagnosis, therapy and prognosis. These are usually interactive processes and the efficacy of medical interventions therefore depends upon meaning, narrative and persuasion. Since mental processes are not rigidly separated from bodily functions, trust and expectation have physiological effects that are required for successful healing in all cultures at all times. The conduct of patients and practitioners always turns on the expectation of cure and the establishment of confidence. The efficacy of rhetoric was more readily recognized by practitioners in the past than it has been by social historians of medicine. Once mind-body dualism has been discarded, it can be seen that historians are not studying the context of healing but its very heart. PMID- 11624149 TI - Making sense of technologies in medicine. PMID- 11624150 TI - Is medical education asking too much of bioethics? PMID- 11624151 TI - Meanings, policies, and medicine: on the bioethical enterprise and history. PMID- 11624153 TI - 350th anniversary of Les Passions de I'Ame. AB - 1999 marks the three hundred and fifieth anniversary of the publication of Descrates' final work: Les Passions de l'Ame. This short paper commemorates that event and discusses the circumstances contributing to its origin and the questions which it still raises for neuropsychology three hundred and fifty years later. PMID- 11624154 TI - Transcranial brain injuries caused by metal rods and pipes over the past 150 years. AB - Penetrating through and through (transcranial) injuries of the head and brain by foreign bodies other than bullet or shrapnel are extremely unusual. Although the case of Phineas Gage (1848) has been the most widely publicized, and stimulated much interest in brain function, additional surviving cases of through and through brain penetration by bars, rods or pipes have been reported. The author reviews 12 published cases over the last 150 years and describes two additional cases. The management of these cases is described. This group of patients for the most part experienced a functional outcome despite neurologic deficits. PMID- 11624155 TI - Jules Soury, Le Systeme Nerveux Central (Paris, 1899). PMID- 11624156 TI - Walter Rudolf Hess (1881-1973) and his contribution to neuroscience. AB - The present account includes a brief life history of Walter Rudolf Hess (1881 1973) and a review of his major neurophysiological contributions. Hess belonged to the nearly extinct generation of great universalists among students of human physiology. He began his scientific work in hemodynamics and ophthalmology, then studied the functional organization and regulation of circulation and respiration and developed a number of highly sophisticated instruments which fostered his international reputation. By electrically stimulating the brain of the unanesthetized, freely moving animal he explored the functional organization and localization of the cat diencephalon in terms of autonomic, extrapyramidal motor functions, and instinctive behavior, e.g. hunger, thirst, fear, and rage. His thoughts on biological order led him to consider the problems of psychic forces. He was convinced of the close correlation of behavioral research and neurophysiology and believed that neuronal patterns determine the content of consciousness without providing clues concerning the transformation of such patterns into subjective experience. PMID- 11624157 TI - Historiography and historians of neuroscience: towards diversity in the ISHN. AB - This article introduces and critiques the historiographical tradition of the history of the neurosciences as it has been established in the International Society for the History of the Neurosciences (ISHN). The founding members of the ISHN were practitioner-historians, practitioners of the neurosciences with an interest in the great moments, ideas and controversies in the history of their field. The historiographical precedent set by these clinician-historians emphasized those aspects of history most interesting to them. Academic historians bring a different approach to the history of neurosciences, particularly an interest in studying the intellectual and cultural contexts of both the inherited and the forgotten ideas about the nervous system. Their approach to history has not been well presented in the ISHN, in part because the current historiographical tradition does not address their interests. This article highlights the methodological and epistemological differences between academic and practitioner-historians and discusses the difficulties that other historical societies have faced in trying to bring them together. The article then suggests ideas for symposia that might facilitate an interdisciplinary dialogue and a revised historiographical tradition that speaks to the needs of both academic and historians and practitioner historians. PMID- 11624158 TI - Margaret Kennard on sparing and recovery of function: a tribute on the 100th anniversary of her birth. AB - Margaret Kennard was an American pioneer in the experimental study of sparing and recovery of function. Her most famous experiments were performed on monkeys and apes at Yale University during the late 1930s and early 1940s. By describing the behavioral effects of brain damage on infantile, juvenile, and older primates, she drew new attention to just how important developmental status can be at the time of neural insult. Kennard also conducted experiments which showed that even adult primates can exhibit significant sparing and recovery of function, especially if brain lesions are made in stages rather than all at once. In many respects, Kennard helped launch the modern era of research on sparing and recovery of function by demonstrating that several factors in addition to lesion locus can affect post-injury performance and by recognizing that, if neural reorganization does occur, it probably takes place in spared parts of the damaged system. PMID- 11624159 TI - Juhn A. Wada and the sodium amytal test in the first (and last?) 50 years. AB - Fifty years ago Juhn A. Wada developed the intracarotid amobarbital procedure (IAP), a test in which first one and then the other cerebral hemisphere is temporarily anaesthetised through direct intracarotid application of sodium amytal. The IAP was devised initially as a method to allow unilateral electroconvulsive shock therapy for psychosis. The method subsequently proved its value for the lateralisation of language and, following adaption of the test protocol, for the assessment of memory functions. Thus the IAP became the standard test in the presurgical evaluation for resective surgical treatment of medically intractable epilepsy. This paper will briefly review the history of the IAP, the controversies concerning its current applications and its expected eventual replacement by less invasive and more easily repeatable methods, notably functional magnetic resonance imaging. PMID- 11624160 TI - Nixon as madman. PMID- 11624162 TI - Contributions of American mental philosophers to psychology in the United States. AB - Professors of mental philosophy who taught and wrote textbooks in colleges and universities in the United States before the Civil War contributed significantly to the development of the new psychology that replaced mental philosophy in the last quarter of the 19th century. Their contributions have been neglected in textbooks on the history of psychology, even those devoted to the history of psychology in the United States. These mental philosophers eased the transition to, and influenced the nature of, the new psychology in the United States by establishing a place in the curriculum for mental philosophy that the new psychology came to occupy; by identifying the topics for laboratory methods to address; by pursuing an empirical, inductive, scientific approach to the study of the mind; and by their tradition of functional analysis that came to characterize psychology in the United States. PMID- 11624161 TI - From "Anna O." to Bertha Pappenheim: transforming private pain into public action. AB - Bertha Pappenheim ("Anna O,") was treated for hysteria by Josef Breuer when she was a young adult. As a mature adult she became a leading social worker, writer, and feminist activist in the German Jewish community. This article examines her therapy with Breuer, her own struggle for recovery, and some links between her earlier and later life, in particular the lack of intimate relationships in her life and her work against the victimization of women. Throughout the article psychoanalytic interpretations, social history, and feminist analyses are integrated to provide a contextualized examination of Pappenheim's life. PMID- 11624163 TI - L'annee psychologique: history of the founding of a 100-year-old. AB - The authors present the history of the founding of the French journal L'Annee Psychologique. The names of Theodule Ribot (1839-1916), Henry Beaunis (1830 1921), and Alfred Binet (1857-1911) are closely associated with the journal. Ribot's election to the chair of Experimental and Comparative Psychology at the College de France in 1888 marked the official emancipation of psychology in France. Because there was no laboratory associated with the chair, Beaunis, a physiological psychologist from Nancy, proposed to Ribot the creation of the first French laboratory of experimental psychology (1889). Under Beaunis's direction, this laboratory was established at the Sorbonne in Paris but was in fact dependent on another educational institution, L'Ecole Pratique des Hautes Etudes. In 1893 the laboratory's research was first published in a yearly journal named Travaux du Laboratoire de Psychologie Physiologique (2 volumes: 1893-1894). Binet, who joined the laboratory in 1891, was not satisfied by the form of this publication. With Beaunis's agreement, he then created L'Annee Psychologique in 1894 to develop the reputation of the laboratory's research. The authors present the evolution and vicissitudes of the journal from 1895 to 1912, with a glance up to the present. PMID- 11624164 TI - Dispelling the "mystery" of computational cognitive science. AB - H. Crowther-Heyck (1999) argued that early advocates of computational cognitive science, especially George Miller, aimed to bring about a revival of traditional mentalism, including the issues of consciousness and free will. He therefore found it inexplicable, and even "ironic," that they selected the computer as their main research tool because computers seem no more conscious and no more free than, for instance, the telephone switchboard that was one of the behaviorists' key metaphors. I argue, by contrast, that this misunderstands the main thrust of cognitive science, which was not to bring back all of traditional mentalism, but was rather only to give a rigorous account of intentionality. Once this is recognized, Crowther-Heyck's "mystery" of cognitive science is dispelled because, as is well known, computers use symbolic representations, and thus were seen by the early cognitive scientists as being prime mechanical models of intentional processes. PMID- 11624165 TI - Mystery and meaning: a reply to Green (2000). AB - In "George A. Miller, Language, and the Computer Metaphor of Mind" (see Note 1), I sought to explain how and why Miller invested the computer metaphor of mind with such strongly revolutionary, antibehaviorist meanings. In reply, Christopher Green (see Note 2) has argued that the answer to this question has to do with the importance of mental representation was an important issue to cognitivists. In response, I argue that, though mental representation was an important issue to cognitivists, there were several other factors of equal or greater importance: specifically, the fascination of Miller and his cohort with language and communication, their frustration with the narrowness of the disciplinary vision of the behaviorists, and their involvement in a different experimental program than that of mainstream behaviorists. PMID- 11624166 TI - In pursuit of precision: the calibration of minds and machines in late nineteenth century psychology. AB - A prominent feature of late nineteenth-century psychology was its intense preoccupation with precision. Precision was at once an ideal and an argument: the quest for precision helped psychology to establish its status as a mature science, sharing a characteristic concern with the natural sciences. We will analyse how psychologists set out to produce precision in 'mental chronometry', the measurement of the duration of psychological processes. In his Leipzig laboratory, Wundt inaugurated an elaborate research programme on mental chronometry. We will look at the problem of calibration of experimental apparatus and will describe the intricate material, literary, and social technologies involved in the manufacture of precision. First, we shall discuss some of the technical problems involved in the measurement of ever shorter time-spans. Next, the Cattell-Berger experiments will help us to argue against the received view that all the precision went into the hardware, and practically none into the social organization of experimentation. Experimenters made deliberate efforts to bring themselves and their subjects under a regime of control and calibration similar to that which reigned over the experimental machinery. In Leipzig psychology, the particular blend of material and social technology resulted in a specific object of study: the generalized mind. We will then show that the distribution of precision in experimental psychology outside Leipzig demanded a concerted effort of instruments, texts, and people. It will appear that the forceful attempts to produce precision and uniformity had some rather paradoxical consequences. PMID- 11624167 TI - [Marcel Labbe's (1870-1937) conferences in Istanbul University Medical School]. AB - Marcel Labbe, a French physician, who was famous with his studies on nutrition and diabetes, visited Istanbul three times, in 1908, 1922 and 1930. During his second visit in 1922, he gave seven lectures at Istanbul University Medical School about diabetes mellitus, hyperglysemia of diabetics, acidosis, nefrotic diseases, liver insufficiency, endocrin diseases and anaphylactia. These lectures were translated and published in Turkish. During his third visit he lectured on paradiabetes and visited historical places and cities of Istanbul, and also visited Yalova thermal springs and Brusa. Labbe respected Turkish physicians with whom he had established close relations with in Paris, where he also met Ord. Prof. Dr. Suheyl Unver (1898-1986) who was a very famous professor and researcher in medical history. In return, he was respected by Turkish physicians, as well. Labbe's research was translated into Turkish and published in Turkish journals. PMID- 11624168 TI - [1846-1847 academic year report of the Imperial School of Medicine]. PMID- 11624169 TI - The drug "Hindiba". PMID- 11624170 TI - [Notes on the medicine of the anatolian seljuk period]. AB - In this study some remarkable medical practices during the period of Anatolian Seljuks are related. We see a widespread use of poisonous snakes as medicine. Ahi Evren Seyh Nasirud-din Mahmud, the leader of the Ahi organization which was a guild of artisans and traders of the period, explains in his book that he produced an antidote from poisonous snakes. Ahi Evren was the most famous doctor of the period. He complied a work on anatomy. He used to go to the mountains in the winter and utilized snake poison for preparing medicine. During the period of Anatolian Seljuk, in almost all the cities there were hospitals as health centers. At the time it was too difficult to bring patients from the village to the city; therefore the doctors of the health centers travelled from village to village, from town to town to treat the patient. The statesmen paid doctors for treating patients in certain regions. During this period, it was assumed that artificial fertilization could be made outside the womb. If the problem of access to the sources of this period is solved, there may be found interesting information on this subject. PMID- 11624171 TI - [Medical practitioners during the reign of the Sultan Alaaddin Keykubadi]. AB - Medical practitioners who were educated in the field of medicine or practiced medicine in Anatolia during the reign of Sultan Alaaddin Keykubad I from 1220 to 1237, are introduced in this study. The aim of this study is to contribute to bringing into light the medical history of the Seljukian period, a field not sufficiently studied today. Medical practitioners who served the Sultan Alaaddin Keykubad I were specially studied; and the following physicians were noted in the study: Sadr Faraid al-Din, Mohammed Cacermi, Badr al-Din Ibn Harir, lzz al-Din Ibn Hubel el-Mavsili, Takiy el-Din Res'ani, Safiy al-Din Devl Nasrani, Surgeon Vasil, Abu Salim al-Nasrani al-Yakubi al-Malati, Abu'l Farac al-Nasrani, Physician Hasnum, Physician Gabreil, Muvaffak al-Din Abd al-Latif b. Yusuf al Bagdadi, Physician Shermon, Physician Ahron, Abu Bakr. PMID- 11624172 TI - [The insane in Turkish oral tradition]. AB - In this research, information on oral folk tradition about the insane and insanity were collected. The proverbs and locations where folkloric information was collected is also studied. Amongst Turkish people it is believed that the insane are ingenuous, honest and that they do not have any ulterior motives; therefore, the fact that people tolerate their obsurdity, must be taken into consideration. PMID- 11624173 TI - [Cleaniness and hygiene from infancy to adolescence in Karabuk, Safranbolu, Eflani and Eskipazar]. AB - This paper on cleanliness and hygiene from infancy to adolescence is obtained from knowledge collected by means of an interview with women and men informed on the subject. This research is consisted of four main chapters: 1. Environmental and physical hygiene; 2. Baby and child care; 3. Beliefs regarding menstruation; it is commonly called regl - of French origin - in Turkish, which is called "colored" (renkli) days in this area, due to the similarity in the sound of the two words; 4. Beliefs and practices concerning circumcision. This essay deals in washing clothes with usual cleaning agents or using ash alone and ashed water without scrubbing. The practice of hair removal among women and girls is described. Swadding clothes, cradles, pots called havruz and subek for urination of babies in the district, are dealt with in detail. The customs and practices regarding menstruation are described and classified. Before the use of bikini underpants, pads and the menstruation cloth was one of the most important items of a girl's dowry. The techniques used in circumcision in this region were carefuly studied and the beliefs regarding circumcision were put down. This research was completed in fifty one weeks. Various objects obtained during the research have been handed over to the Medical History Museum of Cerrahpasa Medical School. PMID- 11624174 TI - [The punishment of a pharmacist in Istanbul in 1853]. AB - Yakop who ran a pharmacy in Istanbul was accused of malpractice in 1853. The pharmacist had prepared a bottle of cod liver oil for a patient and a bottle of croton oil for another one. He had neglected to label the bottles which were administered by mistake to the patients by his apprentice. The patient who drank a spoonful of croton oil was intoxicated immediately and died. As soon as the event was reported, the police asked the deceased person's family if they intended to sue the pharmacist. They did not. However, the police forces started an investigation and asked the School of Medicine whether the pharmacist was guilty. The School answered that the pharmacist had neglected to label the bottles and was found guilty of causing the death. The Supreme Court took up the matter and sentenced Mr. Yakop to six months imprisonment and decided to close his pharmacy. The decision was published in Takvim-i Vekayi, the official newspaper of the State. PMID- 11624175 TI - [Health policy of Refik Saydam and its reflections to the public health center: Hifzissihha Merkezi]. AB - Doctor Refik Saydam is an unforgettable name by virtue of his work in the field of health services, especially regarding those he performed in the early years of the Turkish Republic. In this paper, a brief overview of his life story is followed by a presentation of his activities and enterprises, particularly those related to health policies and health services. To emphasize the importance of his contributions and to show the course taken during his time, his performance is explained with respect to the conditions of his period. Following this phase, information is given about the Hifzissihha Merkezi with a historical approach. It is an institute baring the name of doctor Saydam, who founded it, which finds its origin on the basis of doctor Saydam's ideas about the vital importance of preventive medical services and public health. Finally, the whole subject is thoroughly discussed and evaluated. PMID- 11624176 TI - [A 15th century manuscript concerning hemorroid and its treatment]. AB - This study is about a 15th century Turkish text, a general survey of hemorroid. A copy of the text is available in the Diyarbakir Public Library. The 48 page treatise was composed upon the request of a statesman of the time. Hemorroid is described in terms of diagnosis, classification and treatment. This study contains important information on the methods of the treatment of hemorroids. A glossary is inserted at the end of the study in order to be used for deciphering the text, which is a rare example of old Turkish medical literature. PMID- 11624177 TI - [A brief history of the development of Turkish pharmacognosy]. AB - 1839-1909: The Foundation Period: The education of pharmacy through the apprenticeship system ended up as a "Pharmacology Branch" of the "Military Medical School" which was founded in 1839 in Istanbul during the Ottoman Empire. A "Civil Pharmacology Branch" was founded in 1867. The education of pharmacognosy, called "Matiere Medicale" and "Mufredat-i Tip" too, was started during this period. 1909 (1913)-1945: The Institutionalization Period; The education of pharmacognosy as it is understood today was included in the curriculum of the Pharmacology School in 1909, before the foundation of the Turkish Republic; however, the pharmacognosy education was eventually started in 1913. During this period, the School of Pharmacology was administratively a part of the Medical School: and later the School of Science; then it was reattached to the Medical School, yet it had its own separate building. 1945-1963: The Period of Development: This is the period when academic studies on pharmacognosy started and a "Pharmacognosy Institute" was established as a part of the Pharmacology School of the Medical School in 1945. Professor doctor Sarim Celebioglu, who had a Ph.D from Berlin University, was appointed as a director of this institute and directed it until 1962. Approximately for 40 years the education and research on pharmacognosy and pharmaceutical botany was handled only in the Istanbul University. 1962-1997: Reform and Improvement Period: Today there are eight pharmacology schools in Turkey; three in Ankara, one in Erzurum (1997), one in Eskisehir, two in Instanbul and one in Izmir. Pharmacognosy education is carried out in all of these schools. Additionally, there are three research centers which were founded by the pharmacognosy divisions of the Ankara, Anadolu and Istanbul Universities. PMID- 11624178 TI - [Medical manuscripts in the library of the Deontology Department of the Ankara University Medical School]. AB - At every academical platform on medical history and its instruction, lack of Turkish medical historiography is mainly emphasized. There are two main factors determining the situation: 1-There isn't any comprehensive Turkish medical history textbook. 2-There are difficulties in reaching the primary sources in this field. Everybody agrees with the importance of reaching medical manuscripts easily and reading and evaluating them in medical history. For this reason, it is important to know where we can find them. In this article, medical manuscripts which are available in the library of the Deontology Department of Ankara University Medical School are introduced. The manuscripts have been listed in alphabetical order of the authors' name. The bibliographic items, such as the size, writing style, and type of paper used, are mentioned. PMID- 11624179 TI - [Some medical documents written by Ahmed Cevdet Pasha]. AB - The assumption that civilization was originated in the East, was one of the most important points emphasized by the intelligentsia of the late Ottoman reign. This conviction was appreciated in the thought of Ahmed Cevdet Pasha (1823 - 1895), a famous figure of the period. Cevdet Pasha, who believed that the source of science and education was started in the East, claimed that Europe was acquainted with Islamic science during the Crusades. In this paper Cevdet Pasha's ideas related with small-pox, cholera, plague, poisons and microbes are mentioned. This study is based on Cevdet Pasha's documents related with these subjects; and the transcriptions of the texts are given. PMID- 11624180 TI - [Identifying the author of Gazi Ayintab (1926): a survey on medical geography in the southeastern province]. AB - The Ministry of Health of the young Turkish Republic launched a project to survey the physical and organizational infrastucture of health services inherited from the Ottoman Empire. The first monography was published in 1922 by Dr. Riza Nur, the Minister of Health himself on his native Sinop province. A total of 17 reports were compiled and published before 1928, the year of latinization of the Turkish alphabet. The authors of this collection titled The Medical and Social Geography of Turkey were contemporary local health authorities. In one of these monographs published in 1976 on Gazi Ayintab the author was not noted. Our research indicates that this author was Dr. Hamdi (Kasim) Ozkan. Gazi Ayintab is reviewed briefly. PMID- 11624181 TI - [Not Available]. PMID- 11624182 TI - [Not Available]. PMID- 11624183 TI - [Not Available]. PMID- 11624184 TI - Professor Unver and Istanbul. PMID- 11624185 TI - [Not Available]. PMID- 11624186 TI - [Not Available]. PMID- 11624187 TI - [Not Available]. PMID- 11624188 TI - [The influence of Mustafa Zeki Pasha on the progress of the Turkish veterinary medicine]. AB - Good results of the administration of Mustafa Zeki Pasha, as the General Minister of Military Schools and Field Marshal of the Imperial Arsenal of Ordanance and Artillery, on the progress of Turkish veterinary medicine is unforgettable. Above all, he accepted that veterinary art was very important for the country and tried to make it a respectable and attractive profession. He improved the education in the veterinary classes. He secured the rank of captain for the new graduates instead of lieutenancy. He sent the most capable students to France for veterinary medical education for the purpose of training new instructors. Veterinary bacteriology started in Turkey under the auspices of his administration. PMID- 11624189 TI - [Hernia surgeons of Scutari, Istanbul]. AB - The Ottoman capital was constituted of four judicial regions (mevleviyet, molla kursusu): Istanbul (within the citywalls), Galata (the Roumelian side of Bosphorous from Kasimpasha to Rumelifeneri), Eyup (western bank of the Golden Horn and Scutari. Since one judicial court did not suffice for this spacious area, each region was subdivided into districts (niyabets) called Mamure and Cedide where a large collection of records registered chronologically were reserved at the law court archives. I have studied 168 judicial records of Scutari. Among them, a document with the record number of 139, attracted my attention because of its interesting content. In view of this document of the 17th century, a physician could not be blamed or legally responsible for a risky operation if the patient had given his consent in advance. In this case, the patient was a man called Yanni from Agriboz Island. He was suffering from inguinal hernia. The healer was a woman called Saliha Sultan binti Kupeli, a Coptic, who practiced as a surgeon. Since some risk is inherent in medical operations, a contract was made between the patient and the surgeon, while the consent was given in case of any legal actions for damages. Therefore the surgeon was in need of a guarantee which was to be stated in the contract and confirmed by the judge (kadi). This article gives examples of this kind of case. PMID- 11624190 TI - [From Mithridates to Mesir]. AB - Mesir, an antidote, a theriaca, an Anatolian preparation of mithridaticum will be studied in this paper, based on two kinds of information related with the history of medicine and folklor: 1- The folkloric approach derived and flourished around Manisa and Merkez Efendi. The authentic character of mesir in view of medical and cultural history. Merkez Efendi who lived in Manisa (Anatolia) in the late 15th century was a man of religion initiating novices at Hafsa Sultan lodge, and upon Shaikh Sumbul Efendi's decease came to Istanbul, so as to take the lead of his religious order. It was believed that he invented a special paste called "mesir" in Manisa, which was a sort of antidote; and on this occasion he was appointed as the chief physician to the darussifa (hospital), then. The historical facts do not support this information, because the discovery of the mesir paste goes back to a thousand and a half years before Merkez Efendi's time, since it was mentioned by Hippocrates, Galen, ancient Greek and old Islamic (Avicenna's and others') works. On the other hand, this fact does not change the folkoric rites and beliefs originated in Manisa and about Merkez Efendi; as this city, together with its surroundings, was the center of the Kyberle (Phyrigia) myth which originates with the Attis spring banquets which symbolize the awakening of Nature on March 21st by the casting of various flowers, especially violets to the river Phyrigia, Sangarios (Sakarya River now). The casting of the mesir paste from the minarets of mosques in Manisa every spring is probably the continuation of the same belief in Anatolia, today. PMID- 11624191 TI - [European physician - travellers and the Ottoman Empire]. AB - The Ottoman Empire has always been a centre of attraction for the West all through its history. On the occasion of various reasons, Western travellers visited the Empire and published a great deal of journals, pamphlets, books and memoirs of their journeys in the country based on their impressions, observations, experiences and missions etc. Most of these books of travel were printed, though some of them sank into oblivion in manuscripts in the European archives and libraries. Unfortunately we do not have a specific library in Istanbul where these printed travel books are collected, except for those in private collections. In this paper, the three books of travel chosen from my personal library and written by an English, a French and a German-Swiss military physician are going to be reviewed successively. The book firstly studied, Memories of the Crimean War from January 1855 to June 1866, was written by Dr. D. A. Reid and printed in London in 1911. It narrates the impressions, and services of the physician in the Crimean war and gives information on the sick, the wounded, infirmaries and the diseases in the battle field and also on the military hospitals and medical care in Istanbul. The second book titled Impressions de Voyage de Paris a Sebastopol, was written by Dr. Felix Maynard, and published by Alexandra Dumes in Paris in 1855. It relates the impressions of the author during his visits to the various parts of the cities and people in Greece and Istanbul. The third book Erinnerungen eines Schweizerarztes aus dem griechisch-turkischen Krieg was written by Dr. Armin Muller who served in Athens during the Turkish-Greek war in 1897 and returned to Germany via Istanbul. The book published in Zurich in 1905 reflects the scenes of the battle viewed from the Greek front; and the writer's favorite impressions about the Turkish people and Istanbul in general. PMID- 11624192 TI - [Military pharmacology education outside the imperial school of medicine]. AB - In 1870, just after starting medical education in Turkish at the Imperial School of Medicine (Mekeb-i Tibbiye-i Sahani) favor in the pharmacology and surgery courses decreased; and even pharmacology graduates continued their education to be physicians. This change gave rise to the shortage of pharmacists and surgeons in the army, and consquently in 1873 the branch of surgery and in 1876 pharmacology were inaugurated at the Haydarpasa Military Hospital. Those who had studied at this Hospital for three years were given a diploma for pharmacy practice (ameliyat eczaciligi sehadetnamesi) and were appointed to the army and to military hospitals. The years of education was raised to four years in 1888, and it was reduced to three years again in 1891. According to Charles Bonkowski, the chemist of Sultan Abdulhamid II, the instruction of military pharmacology was independent from the School of Medicine; he suggested the foundation of a higher school of pharmacy in Istanbul on the standards of the Paris Higher School of Pharmacology (Ecole Superieur de Pharmacie de Paris) where he had studied and graduated in 1865. Unfortunately this advice was not realised; but a department of pharmacology was opened within the Military High School for Veterinarians (Baytar Rustiye-i Askeriyesi) in Eyup in order to educate the students properly. This institution, renamed as the Military High School for Veterinarians and Pharmacists (Baytar ve Eczact Mekteb-i Rustiye-i Askeriyesi), had sent its graduates to the Imperial School of Medicine for many years. Since this process had proved to be useful, the Pharmacology Branch at the Haydarpasa Military Hospital was closed in 1892. In 1895, another military school which was called Eczaci ve Timarci Sibyan Mektebi started instruction on the Naval Hospital. Graduates of this school were appointed to the naval offices for minor operations. PMID- 11624193 TI - [Suidas and Eustatius on the hippocratic epidemics VI 4.18]. AB - An Hippocratic aphorism from Epidemics VI 4.18 quoted in two byzantine scholarly works testify the wide influence of alexandrian commentaries on this difficult treatise in Byzantine cultivated society. PMID- 11624194 TI - Lesser known profiles of morbid anatomists in the XVII and XVIII centuries (and at the beginning of the XIX century). AB - The almost unkown Morbid Anatomy of Harvey, Cocchi, Lancisi, Baglivi, Bellini and Malpighi is presented. These Scientists, better known in other fields of Medicine, made important contributions to "Organ Pathology". Lorenzo Bellini, moreover, with his "inter-organic" pathology, ruled by nerve fluids and blood circulation, may be considered also a precursor of Bichat. PMID- 11624195 TI - [The price of the drugs in Rome: economy and pharmacy from 1700 till 1870]. AB - Since the Middle Ages pharmacists had played an important role as producers and retailers of drugs, many of them exotic and precious. Proof is the resignation of the church of San Lorenzo by Martin V to the guild of apothecaries. 100 years later, Pope Clemens VII introduced the principle of drug taxes. The first roman tax was published in 1558. Until Garibaldi overthrew the papal state in 1870, these principles had remained the same, only to be interrupted by the French occupation at the beginning of the 19th century. An analysis of the drug prices shows the general development of drug costs between 1700 and 1854, the prices and the drug trade in particular being especially dependent on strong political tendencies. The introduction of new drugs and the omission of old ones had a remarkable effect on the costs, a fact which is represented by a study about the development of the prices comparing different drug groups. A further comparison between the wages and the cost of living explains why mainly members of the higher social classes could afford to buy drugs in pharmacies. This economical study of taxes emphasizes the fact that drugs, in regard to their development in prices, can hardly be compared to other goods. PMID- 11624196 TI - [Medicine and religion in the work of Johann Nepomuk Ringseis]. AB - Johann Nepomuk Ringseis (1785-1880), professor of a medical clinic at the University of Munich, claimed in his System of Medicine (1841) that medicine should be founded like all sciences, in the traditional (catholic) doctrine of Revelation. He maintained the origin of disease from the orginal sin and the therapeutic efficacy of prayers and sacraments. The article shows, how he tried to give a scientific explanation of such effects and how his particular philosophical premises nevertheless made it possible for him not to abandon in practice the traditional methods of medical treatment. PMID- 11624197 TI - [Epidemics and the evolution of medicine in Iran during the XIX century]. AB - In a description of a historical case in 19th Century Persia, this article endeavours to show how changes in medical thought occurred. It argues that Medical Modernisation was apparent in the internal changes in traditional medicine. While cholera was frequently recorded, as an epidemic disease, over several centuries in the Persian Medical literature, why and how it became at this period, before contact with Western medicine, under close scrutiny by the traditional medicine. This new scrutiny is illustrated in the writings of Shirazi, a traditional court doctor, who endeavoured to describe cholera, diarrhoea and plague. In doing this, he introduced a significant change in the meanings of vaba and ta'un (generic terms attributed to any epidemic disease). Shirazi used them specifically to mean what we understood as cholera, for the former, and plague for the latter. The internal change in traditional medical thought, together with the awakening of socio-political consciousness regarding the spread of epidemics, were the main factors clearing the path to a natural integration of Western medicine in 19th century Iran. PMID- 11624198 TI - [Heterologous fecundation and the issue of paternity: a long lasting querelle]. AB - The almost total disinterest of legislators in the area of artificial fecundation has prompted the frequent involvement of magistrates thereby giving rise to innovations which depart from the previous tendencies of jurisprudence. The latest sentence of the Supreme Court on heterologous fecundation and the issue of paternity merits special attention because of its innovative principles. PMID- 11624199 TI - [Surgical Roman instruments in the Museum of History of Medicine of the University of Rome "La Sapienza"]. AB - The Museum of History of Medicine at the University of Rome "La Sapienza" keeps numerous roman surgical instruments, dating from the 1st century A.D. This article offers a short review of the critical literature existing on the topic, together with a temporary catalogue of the instruments. PMID- 11624200 TI - [Erotic temperance: fortune and development of an Epicurean suggestion in the imperial Roman age]. AB - The purpose of this writing is to follow the course of an idea, namely that of erotic temperance, which the Epicureans most proably derived as a corollary of their originary ethics. It was during the imperial Roman age that such an idea met a certain audience for different reasons, two of which at least cannot remain unnoticed. The first reason was the theoretical and clinic support given to this idea by such Epicurean oriented physicians as Rufus and Soranus, and by Areteus; the other one should have been the meeting of the notion of erotic temperance with such ethical principles as the moderation, the control of the passions, the impassibility of man towards life events, and a new vision the relationship between husband and wife, which entered into the pattern of the gentlemen's behaviour during the imperial age contributing to the starting of a new ethics. But, if erotic temperance represented on the one hand an ideal for the cultivated class of Roman imperial society, it was on the other perceived as a scrupulously observed realty by Germans, and as one of the principal reasons of their physical and mortal energy. Furthermore, the ideal of a severe erotic control of the early Christians offer precise evidence, will represent an important ground of agreement for theirs and contemporary pagan ethics. PMID- 11624201 TI - [Methodology of scientific transmission in the Middle Ages]. AB - The objective of this article is to analyze the mode of transmission of medical scientific knowledge in the Middle Ages. It is based on two unpublished manuscripts, a Tacuinum sanitatis and a Treatise on the Gout, which are start from different assumptions and motivations, but which share the will to disseminate certain useful knowledge to cure the disease. The first manuscript exhibits little rigour and seems to have been written in order to prove the supremacy of empirical science over theoretical science. The second one is methodologically more rigorous and integrative, since it tries to maintain a balance between theoretical and practical knowledge. The coexistence of both manuscripts certifies two different ways of practising medicine in the middle of the 15th century. PMID- 11624202 TI - [Giovanni Marinello, gallant physician of the late XVI century]. AB - The works of Giovanni Marinello on women's diseases and cosmetics offer two main benefits: on the one hand we get traditional medical notions about female physiology and pathology presented in a comprehensible way, through the use of vernacular and the unpretentious style, while on the other hand they give precious information on aspects of everyday life. Problems connected with health and illness, life appearance of the body or pain and the strategies to eliminate them occupy a big part of these practical treatise, in which we find not only prescriptions but also discoursive parts. Reflections about esthetical canons and ideals, about the relationship between nature and art or technology and the human duty to enter in competition with natural laws are some of the topics discussed. The analysis of Marinello's texts pousses on the content but also on the form to present them to a mostly feminine audience of readers. PMID- 11624203 TI - Renaissance mummies in Italy. AB - The paleopathological study of 40 Italian Renaissance mummies has allowed us to perform about 20 diagnoses, of which 5 concern infectious (smallpox, hepatitis, condyloma, syphilis and pneumonia), 4 metabolic (obesity, atherosclerosis, gallstones and uric acid nephrolithiasis), 2 articular (DISH and rheumatoid arthritis) and 2 neoplastic (skin apithelioma and colon adenocarcinoma) diseases. The mummy of an anonymous child, dated back to the 16th century (C14=1569 +/- 60), presented a diffuse vesiculo-pustular exanthema. Macroscopic aspects and regional distribution suggested smallpox, while EM reavealed many egg-shaped, virus-like particles (250 x 50 nm), with a central dense core. Following incubation with anti-smallpox virus antiserum and protein A-gold complex immunostaining, the particles resulted completely covered with protein A-gold. These results clearly show that this Neapolitan child died of a severe form of smallpox some four centuries ago. The mummy of Maria of Aragon, Marquise of Vasto (1503-1568), reavealed on the left arm an oval, cutaneous ulcer (15x10 nm) with linen dressing. Indirect immunofluorescence with anti-treponema pallidum antibody identified a large number of filaments with the morphological characteristics of fluorescent treponemes. EM evidenced typical spirochetes, with axial fibril. These findings clearly demonstrate a treponemal, probably venereal, infection. The mummy of Ferrante I of Aragon, King of Naples (1431-1494), revealed an adenocarcinoma extensively infiltrating the muscles of the small pelvis. A molecular study of the neoplastic tissue evidenced a typical mutation of the K ras gene codon 12:the normal sequence GGT (glycine) was altered into GAT (aspartic acid). At present this genetic change is the most frequent mutation of the K-ras gene in sporadic colorectal cancer. The alimentary "environment" of the Neapolitan court of the XV century, with its abundance of natural alimentary alkylating agents, well explains this acquired mutation. These and other diseases as, for example, a fatal puerperal complication, a thyroid goiter, a case of Wilson's cirrhosis, some cases of anthracosis and other peculiar traumatic conditions, such as a mortal stab-wound, can elucidate the pathocenosis of the wealthy classes of the Italian Renaissance. PMID- 11624204 TI - [The Galenic treatise on the Anatomical Procedures and its first Latin translation by Demetrius Chalcondylas]. AB - The Anatomical Procedures is Galen's most complete treatise on anatomy, which the Western culture came to know only in the Renaissance. Its first Latin translation was made by Demetrius Chalcondylas (1423-1511). He was a teacher of some translators of the ancient Greek physicians, and an owner of many Greek medical manuscripts. The translation by Chalcondylas was revised and published by Berengario da Carpi in 1529, and was reprinted only once, in 1531. Its philological analysis proves that it depends on a Greek manuscript, a copy of Par. gr. 1849, which is now lost. The humanist physician Nicolo Leoniceno knew the translation by Calchondylas before it was published, for he quoted it in his Apologia printed in 1522. Therefore, this translation circulated as a manuscript, which was so far ignored. PMID- 11624205 TI - From marine hospital to public health service. AB - The United States Pulic Health Service traces its origin back to an act for the relief of sick and disabled seamen signed into law on July 16, 1798. This paper discusses the evolution of the system of marine hospitals set up under this law into a federal public health agency that was eventually named the Pulic Health Service in 1912. PMID- 11624206 TI - Hans Spemann on vitalism in biology: translation of a portion of Spemann's autobiography. PMID- 11624207 TI - The development of Francis Galton's ideas on the mechanism of heredity. AB - Galton greeted Darwin's theory of pangenesis with enthusiasm, and tried to test the assumption that the heredity particles circulate in the blood by transfusion experiments on rabbits. The failure of these experiments led him to reject this assumption, and in the 1870s he developed an alternative theory of heredity, which incorporated those parts of Darwin's theory that did not involve the transportation of hereditary particles throughout the system. He supposed that the fertilized ovum contains a large number of hereditary elements, which he collectively called the "stirp," a few of which are patent, developing into particular cell types, while the rest remain latent; the latent elements can be transmitted to the next generation, while the patent elements, with rare exceptions, cannot since they have developed into cells. The problem with this theory is that it does not explain the similarity between parent and child unless there is a high correlation between latent and patent elements. Galton probably came to realize this problem during his subsequent statistical work on heredity, and he quietly dropped the idea that patent elements are not transmitted in Natural Inheritance (1889). Galton thought that brothers and sisters had identical stirps, and he attributed differences between them to variability in the choice of patent elements from the stirp, that is to say to developmental variability. He attributed the likeness of monozygotic twins to the similarity of their developmental environment. Galton's twin method was to track the life history changes of twins to see whether twins who were similar at birth diverged in dissimilar environments or whether twins who were dissimilar at birth converged in similar environments. It is quite different from the modern twin method of comparing the similarities between monozygotic and dizygotic twins, on the assumption that monozygotic twins are genetically identical whereas dizygotic twins are not. It has been argued that Galton foreshadowed Weismann's theory in the continuity of the germ-plasm, but this is only true in a weak sense. They both believed that the inheritance of acquired characters was either rare or impossible, but Galton did not forestall the essential part of Weismann's theory, that the germ-plasm of the zygote is doubled, with one part being reserved for the formation of the germ-cells. PMID- 11624208 TI - Naturalists, molecular biologists, and the challenges of molecular evolution. AB - Biologists and historians often present natural histoy and molecular biology as distinct, perhaps conflicting, fields in biological research. Such accounts, although supported by abundant evidence, overlook important areas of overlap between these areas. Focusing upon examples drawn particularly from systematics and molecular evolution, I argue that naturalists and molecular biologists often share questions, methods, and forms of explanation. Acknowledging these interdisciplinary efforts provides a more balanced account of the development of biology during the post-World War II era. PMID- 11624209 TI - Style and space: designing a medical school building for women in the 1870s. PMID- 11624210 TI - The enduring appeal of the Victorian family doctor. PMID- 11624211 TI - Nursing leadership in the US 1950s-1970s: a discourse analysis. AB - This paper proposes that the development of nursing leadership and the struggle for professionalisation from the time of the early nineteenth century to the late twentieth century may be conceived as a series of products of constituent discourses. However, particular attention is focused on the concept of leadership as it pertains to the nursing profession in the US between the 1950s-1970s. This time-frame is an important period in the discursive formation of the idea of leadership and professionalisation as the US literature on these subjects in the areas of sociology, psychology, education and business administration exercised a strong influence on the microsocial world of professional nursing practice in the US and, indeed elsewhere, for example, Australia and the UK. The sociological complexity of the concept of leadership ultimately meant that it came to be regarded as a dynamic process pervading the existence of all people; their interrelationships, their morale, their confidence and their capacity to achieve. These features are reflected through the perceptions, beliefs and experiences of the American nursing profession as its constituent discourse appeared during the 1950s-1970s. Thus the paper is a discourse analysis on leadership in nursing with particular attention given to the bureaucratic authority of the hospital, the drive for the creation of a profession and the idea of leadership itself. PMID- 11624212 TI - Nurses as observers and monitors: an Australian experience 1930-1950. AB - During the time of nursing reforms being advocated by Nightingale in the 1860s, the medical profession was also undergoing considerable change and reform. Scientific developments were beginning to make an impact on the world of medicine, and health reformists were campaigning for public health initiatives. As part of this health reformation, nurses took on the tasks of observation and monitoring of patients (formally delegated to trainee doctors) within the wards of the general hospitals. This was a significant alteration in responsibility for nurses, when compared with the almost exclusive domestic duties they were responsible for prior to these reforms. However, this monitoring role did not remain solely at the bedside, and over time, nurses engaged in a number of ward monitoring activities as well, such as counting cutlery and crockery. This paper explores this monitoring role of nurses and how it related to the activities of doctors and hospital administrators. The material contained in this paper is based on research conducted into the general nursing practices of trainee nurses at the Rockhampton Hospital during the 1930s and 1940s. This paper focuses on the years 1930-1950 because this era witnessed many changes with regards to both the medical and nursing professions. These changes included an increase in the influence of medical technology and the role of the hospital as the primary location for the treatment of ill-health. PMID- 11624213 TI - The novel and nursing history: a consideration of potential sources. AB - The use of novels in general as a historical source is discussed in this paper. The author shows that, while they must be used with extreme caution, a novel can provide insight for the historian. Literature concerning the role of novels for informing nursing history is reviewed in the paper. The novel Jean Becomes a Nurse by Yvonne Trewin is considered in detail. The novel's aim, stated in its Introduction, of encouraging readers to become nurses, is highlighted. Aspects of the book's content are analyzed including clinical detail, nursing as a vocation and the use of Nightingale motifs. The task-oriented approach to care depicted in the book is also mentioned. The novel is seen to provide insight into the perception and attitudes of nurses towards nursing in the 1950s in the UK. The paper ends by suggesting areas for future research. PMID- 11624214 TI - The impact of the beat generation and popular culture on the development of Martha Rogers's Theory of the Science of Unitary Beings. AB - In the 1940s and 1950s, Greenwich Village, and New York City in general, were places that were participating in great change. Beat Generation writers, pop artists and contemporary musicians were redefining their crafts. In the midst of all this lived Martha Rogers, who was redefining her craft, nursing. In this paper the author argues, in what could be defined as a beginning and informal hermeneutic analysis, that in order to fully understand the Science of Unitary Human Beings it is necessary to understand the social context in which the theoretical framework was developed. Implications arising from the insights that emerge from this brief exploration of the social context in which the Science of Unitary Human Beings developed, which concentrates on the writing of the Beat Generation, are discussed. PMID- 11624215 TI - The missing relative: the home help service in England and Wales 1918-1974 part I. AB - Although recent work in social policy has illustrated how the work of home helps means that they straddle the health-social services boundary, there has been relatively little work on the earlier history of this service. In this the first of two articles, the author attempts to remedy this neglect, and considers the development of the home help service in England and Wales between 1918 and 1974, examining the overall evolution of the service. In the second article (to be published in the next issue of the journal), three themes are discussed in greater detail: the issue of training, regional variations in provision, and what home helps actually did for their clients. Although the focus is on England and Wales as a whole, in the second part the author illustrates particular themes through a case study of the Midlands city of Leicester, a local authority in which the home help service was particularly highly developed. PMID- 11624216 TI - Confronting nursing's past: Hilde Steppe (1947-1999). PMID- 11624217 TI - Yakushi Buddha (Buddha of Healing) and its medicinal container in Japan. PMID- 11624218 TI - Alchemical symbols at the Museum of Pharmacy of the Jagiellonian University. PMID- 11624219 TI - "Pray let the medicines be good": the New England apothecary in the seventeenth and early eighteenth centuries. PMID- 11624220 TI - War and medicine--Norman Bethune (1890-1939). PMID- 11624222 TI - Vincent Van Gogh (1853 - 1890) and Dr Paul Gachet (1828 - 1909). PMID- 11624221 TI - The role of Dr Johan Arvedson (1862-1936) in the emergence and development of physiotherapy. PMID- 11624223 TI - Birth centenary--Max Theiler (1899-1972): South Africa's first Nobel Laureate. PMID- 11624224 TI - From the diaries of Dr. J. B. S. Greathead MB MC (Edin.) MRCS (Eng.)--the Gadd Assault and the Edinburgh Connection. PMID- 11624225 TI - The path to history. PMID- 11624226 TI - Richard Jasper Durling (1932-1999). PMID- 11624227 TI - Louise M. Darling (1911-1999). PMID- 11624229 TI - [The debut of Jennerian vaccination in the mining regions of Transylvania]. AB - The first attempts at vaccination by Jenner's method in Transylvania (Romania) were made in 1801; vaccination became compulsory in 1808. By researching the mining archives, details about the evolution of vaccination activities were found. The most important are: the initiative of the surgeon Peter Molnar from Sacaramb (June 1801), the first vaccinations performed by the chief medical officer of the mining area (November-December 1801), the consistent reporting of vaccination, payment of the vaccinator surgeons, vaccination promotion and means of providing vaccination material. PMID- 11624228 TI - The Rhazes manuscript at the Reynolds Library, University of Alabama at Birmingham. PMID- 11624230 TI - The position of nervous diseases between internal medicine and psychiatry in the XIXth century. AB - It is frequently said and believed that the history of clinical neurology of the 19th century has much in common with the history of psychiatry. Though neurology and psychiatry are neighboring clinical disciplines, the development of clinical neurology differs from that of psychiatry in 19th century Europe. The history of bedside neurology is that of gradual separation of nervous diseases from other internal diseases. Despite the efforts of the German psychiatrists, any influence of psychiatry on that process was very limited. PMID- 11624231 TI - [The replication and utilization of a new embalming instrument from an instrumentarium dating from the 30th dynasty of Egypt]. AB - Following our researches on the technique of the priest embalmer in Ancient Egypt, we have copied this instrument and used it on a cadaver, which appears to be as efficacious in maintaining the buccal cavity wide open. Thus prepared, the priest was able to carry out the purification rites. PMID- 11624232 TI - The extraordinary influences of two British physicians on medical education and practice in Texas at the turn of the 20th century. AB - In 1891, two British doctors emigrated to Galveston, Texas to become professors in a new medical school. During long and outstanding careers, William Keiller and James Edwin Thompson transferred the best of Old World traditions in anatomy and surgery. The University of Texas Medical Branch became an outstanding teaching institution because of their dedication to professional excellence. PMID- 11624233 TI - [The tribulations of the mysterious Dr. B...., precursors of the endoscopy]. AB - The author is an experienced student of the origins and development of endoscopy from its beginnings with the speculum. Among the various contributors in this field in the medical literature of the 19th century appear the mysterious doctors B.....I. These names were the result of alterations, modifications and misspellings of the same name. Such entries became so ingrained in the literature they were hardly contested. One of the essential tasks of the historian is to verify and criticize even primary sources (Marc Bloch). This is especially true of early documents, no matter how surprising and enthusiastic they may be. PMID- 11624234 TI - Puerto Cabello and the Bubonic Plague epidemic (1903-1908). AB - Epidemics have a social-economic character which affect certain historic periods. The Bubonic Plague, known as the Black Death, in the Middle Ages, caused the deaths of a quarter of Europe's population. The last plague epidemic originated in China, in the year 1893, and then spread to Europe at the end of the century. The French port of Marseille, in 1903, was the open door to the American Continent, the plague being detected in Panama in 1905 and officially recognised by Cipriano Castro's Government in 1908. The Venezuelan epidemic occurred during the Liberal Restoration Period. It was met by the Sanitary Authorities with a vision of 'medical positivism'. In our present research, we analyze the importance of Puerto Cabello, together with La Guaira and Cumana, the ports of arrival for the major quanity of European imports by steamships during 1903-1908. The sanitary strategy of medical health advisors and the nonfulfilment of proposed rules within the framework of the crisis of the Venezuelan Liberalism allowed the illness to enter and spread. PMID- 11624235 TI - [Advances in the education of medical history, spreading dialectical materialism]. PMID- 11624236 TI - [Development of the diagnosis and treatment of glaucoma in China]. AB - Diagnosis and treatment of glaucoma is one of the greatest achievements in the development ophthalmology. The process of achieving is also a very inspiring chapter in its history. As histories of other sciences, the development of diagnosis and treatment of glaucoma is achieved through the following process: After accumulation for many years, then it entered the stage of explaining the phenomenon with the development of other sciences. Finally, its situation is determined by experiment and being widely applied in clinical practice. Meanwhile, there is no end for the findings of new diagnostic and therapeutic methods. More achievements will surely be made for developments in relevant sciences and increasing needs in clinical practice. PMID- 11624237 TI - [Evolution of conception on apoplexoid (lei zhong feng) disorder]. AB - Viewing separately from the etiology and the disease itself, the ancient literature gave two definitions, totally different from each other, for apoplexoid disorders within the category of apoplexy, each experienced a process of starting, development and evolution stages. Both exerted an active promotion to the development of apoplexy. PMID- 11624238 TI - [A brief history of discovery of Helicobacter pylori]. AB - The theoretical background for the diagnosis and treatment of upper digestive ulcer, gastritis and stomach carcinema was challenged by H. pylori, a microbe seems only under the microscope. This paper makes a brief review on the brief history of discovery and recent conclusion on the microbe, and explores its challenge to the traditional conception. PMID- 11624240 TI - [Study on the bathing habit in Qin - Han Period]. AB - By investigating the bathing utensils and bathing style, the bathing habit in Qin - Han dynasties were discussed. It is claimed that bathing had been a daily habit in that period, being a sign of advanced civilization. Its implication on the significance is also analyzed. PMID- 11624239 TI - [Research on the plague epidemic in Guangzhou (Canton) in 1894]. AB - Early in the end of the 1870s, there were signs of local epidemic that occurred in the region of the end of Pearl River valley, most probably spread from the Beihai epidemic region through sea route. A severe epidemic of plague occurred in 1894 under the unusal dry and warm weather. However, the weather had nothing to do with the epidemic after the outbreak of the epidemic. Reports on the victims inside the city were focused in April to July, especially in May, first appeared in the regions inhabited by Muslin and Manchu centered in the whole area of western city and southern old city, where cases showed a tendency to distribute along the circular river around the city. The manifestations included swollen nodules, fever, chilliness, and coma. The death toll numbered to 0.1 million. TCM treatment includes cooling, dispersing, detoxification and blood activation, as well as acupuncture and rubbing with cold water, etc. PMID- 11624241 TI - [A historical review of the study of electrical activity of heart and origination of electrocardiography]. AB - This paper has an overall review of the historical process of electrocardiographic development and the origination of modern electrocardiography in retrospect and also has an analysis of the scientific background, the important events and the historical effect of outstanding figures throughout the development. The experience and laws contained in the historical development are briefly summerized in this paper. At the same time the authors point out that the establishment of modern electrocardiography and the related technical development are crystallization of the wisdom and the result of the hard work of many scientists including the figures who should have been awarded Nobel Prizes. PMID- 11624242 TI - [Buddhist influences on Sun Simiao's precious prescriptions for emergency]. AB - Living in a period when the Buddhism was quite flourishing, Sun had a close contact with the monk Dao Xuan, the founder of Nanshan Sect Buddhism. Sun's Quian jin fang adopted all schools including Buddhism, evidenced by the following 3 aspects: 1) Direct Buddhist influence, mainly on medical morality; 2) Indian medicine coming together with Buddhism, including the theory of "four - element theory", the conception of all matters are medicines, pills of all disorders, recipes, and keep - fit art. Buddhism acts as a carrier here; 3) the achievements of treatment for beriberi by monks. However, Buddhist influence was far inferior to Taoism as far as Sun's work is concerned. PMID- 11624243 TI - [Civilization of Song Dynasty and studies on the rearrangement of ancient literatures of TCM]. AB - The features and causes of flourishing of Song civilization were dealt with from the viewpoints of style of learning, art and literature etc., were explored based on contemporaneous political and economical factors. The achievements in the study and systematization are explained through the collection, collation, and research on TCM books. The relationship between the highly cultural prosperity and systematization of Song TCM books is also analyzed on the characteristics of Song civilization. Based on these backgrounds, the features of systemtization of Song TCM books and its influence on the development of medicine in the Song dynasty are also discussed. PMID- 11624244 TI - [Textual research on the chronicle of Wang Fengchun's life]. AB - Wang Fengchun was a noted doctor in Beijing, but there were a lot of discrepancies and errors about the chronicle of Wang's life in the literatures. This article was a textual research on the chronicle of Wang Fengchun's life, such as the date of birth, the time when migrated to Beijing, and the number of years practised medicine in Beijing, mostly based on the Bo Lu Yi An. PMID- 11624245 TI - [The main schools of TCM in Zhejiang]. AB - The history of the main academic TCM schools is described, beginning from Danxi school of Zhu Zhenheng of the Yuan dynasty to the 1980s. Established the theory of "exuberant yang and insufficient yin", Zhu set up the therapy of nourishing yin to decrease fire. In the late Ming dynasty, Zhao Xianke and Zhing Jingyue founded the warm - tonification school, Zhao's theory on vital gate exerted profound influence on the basic theory of later ages. At the turn of Ming - Qing dynasties, a Qiantang school was set up by Zhang Shuichen, Zhang Zhicong and Zhang Xijun, Zhang Zhi cong being the synthetizen. The Shao school of cold disease refers mainly to the physicians in the shaoxin region who studied the warm heat disorders (especially damp - warm diseases) which was mature at the turn of Qing dynasty and the Republican period, whose influence remained until the 1980s. PMID- 11624246 TI - [Clearing the doubts of all Wang Bing in the Tang dynasty]. AB - The problem is probed on the clues provided by Si ku ti yao zheng (Analysis on Summary of Books in Four Parts). It is claimed that the Wang bing (*) recommended by Wei Kang and that recommended by Yuwen Rong in Yu Jiaxi's work refer to the same person, both are identical to the time of the author of Su wen. Further, the time of the above 2 Wang Bing(s) and the Wang Bing recorded in lie nu zhuan (Biongraphies of chaste women) as the son of Wang Lin, are also overlapped with the time of the author of Su wen. It is possible that they are the same person. However, the details of the Wang Bing mentioned in Lang guan shi zhu ti ming (inscription for Lang guan Stone Pillar) is unknown. Again, it is unlikely that the Wang Bing (*) is the author of Su wen and can be only a farfetched analogy drawn after Su Fu's poet. PMID- 11624247 TI - [Facts of medical works written by Wang Ji]. AB - There is a lot of medical works written by the noted physician of Ming dynasty, Wang Ji. However, exactly how many works were written by him, remains obscure. By investigation, it is known that altogether he wrote 11 kinds of books in 70 volumes, among them, 2 kinds in 4 volumes were copied manuscripts. On the basis of this, the dates and editions of these manuscripts were made clear. This is of significance to the study of Wang's life story. PMID- 11624248 TI - [A chronicle of Song Daren's life]. PMID- 11624249 TI - [Kim Doo-jong: a life for the history of Korean medicine]. AB - Kim Doo-jong, the founder of the history of medicine in Korea, was born on 2nd March, 1896. After finishing his primary education in his home town, he went to Seoul to receive a higher education. He entered Keijo Medical College in 1918. However, at the end of his first year, he participated in the 3 . 1 movement which protested against Japanese harsh rule over Korea. On account of his participation in the movement, he was forced to leave the college which was run by the Japanese colonial government. Then he went to Japan to enter Kyoto Municipal Medical College, from which college he graduated in 1924. After the graduation, he went to Beijing to work in a hospital run by Japanese. Having felt uncomfortable about the situation in Beijing, he moved to Manchuria, where he opened his private clinic and saw patients for 7 years. As the life as a clinician did not satisfy him, he gave up his practice, and determined to devote himself to the study of history of medicine. He was 43 years old when he started studying history of medicine at the Dong Ah Institute, an affiliated research institute of Manchuria Medical College founded by Japanese. The institute had a large and magnificent collection of ancient texts of oriental medicine. He set on historical studies on the oriental medicine from the perspective of the Western medicine. His doctorial dissertation was about anatomy in oriental medicine. He intended to continue his study on organology, myology, etc., but the sudden end of the World War II made him return to Korea. This meant that he could not make access to the large collection of the institute, and his themes of the research had to be changed. On returning to Korea, he established the Department of the History of Medicine in Seoul National University, which was the only and the first one of its kind. He wrote History of Korean Medicine, which still remains one of the most important works on the history of Korean medicine. He was very energetic and active in his academic activities even during his late years. He passed away on 18th May 1988 at the age of 92. PMID- 11624250 TI - [Introduction of the modern western medicine in late Choson period (I)]. AB - Generally it has been thought that the modern western medicine was introduced into Korea by Japanese physicians and Western missionaries. But some recent studies have revealed that in the late Choson period, Koreans and Korean government played the essential roles in the introduction of it. This paper summarized and discussed the self-reliant activities of Koreans at the time, mainly in introducing the smallpox vaccination method and establishing Jejoong Won Hospital, the first modern hospital in Korea. PMID- 11624251 TI - [The fate of the old Jejoong Won following the establishment of the new Jejoong Won (Severance Hospital)]. AB - Dr. Allen, the first Protestant missionary in Korea, had an opportunity of saving the life of the queen's nephew shortly after his arrival in Korea in 1884. In gratitude the King established the Royal Korean Hospital (Jejoong Won), the first hospital in Korea, and appointed Dr. Allen in charge of the medical affairs of the hospital. After Dr. Allen's resignation from the mission, the work was successively carried on by Drs. JW Heron, RA Hardie, CC Vinton and OR Avison, the last of whom arrived in 1893. In 1894 the connection of the Hospital with the Korean Government was severed and the work taken over by the Northern Presbyterian Mission. Since then, it has been a distinctly mission institute. In 1900, while attending the Ecumenical Conference of Foreign Missions in Carnegie Hall, New York, Dr. Avison made the acquaintance of a philanthropist LH Severance, who made a gift of $10,000 for a new hospital. This building, the first modern hospital in Korea, was opened and dedicated in 1904. It was named the Severance Hospital. As the new hospital was built, the old hospital building was to be returned to the Korean Government according to the agreement made in 1894. On retaking the old hospital, the Korean Government paid $30,289.99 won for the renovation of the original building and new buildings established in the site during the period of Avison's entire charge of Jejoong Won. The old hospital building was used as an official residence for a diplomatic adviser Stevens, who was assassinated for his pro-Japan activities, and as a social club for Japanese officials. PMID- 11624252 TI - [A study on the movement for establishing a private isolation hospital under the rule of Japanese imperialism]. AB - Koreans had an ill feeling against the only public isolation hospital, and their ill feeling was a cause the movement for establishing a private isolation hospital. The bad seating capacity and the nearness to downtown of public isolation hospital, and some violence caused in the course of taking a patient to the public isolation hospital were concrete causes of the movement for establishing a private isolation hospital. The three purposes of the movement for establishing a private isolation hospital are as follows. First, for the purpose of removing the national ill feeling, Koreans had to establish the isolation hospital by themselves. Second, for the purpose of curing the patients, doctors needed to use Oriental medicine together. Third, for the purpose of doing away with the anxiety of infection, the isolation hospital had to be located in a distant place from downtown. The movement for establishing a private isolation hospital didn't succeed. It only ended up establishing a contagious ward in Severance hospital. Because whenever an isolation hospital was planned to be constructed somehere, the residents worrying about the infection opposed to the construction, and enough money didn't be gathered. Abve all, rich pro-Japanese men didn't contribute enough money. The middle and lower classes contributed almost all of the money. The movement for estabishing a private isolation hospital was the extension of anti-Japanese national feeling that sprung from the March 1st movement. In view of strenghtening Korean ability, the movement for establishing a private isolation hospital had a common cause with the Shilryokyangsong movement in the early 1920s. PMID- 11624253 TI - [Unification of Oriental and Western medicine with study on Oriental and Western medicine]. AB - In Korea the system of medical management has been bifurcated into two parts since the restoration of nation from Japanese after World War II. One is 'Western Medicine' and the other is 'Oriental Medicine' like Chinese but not like Japanese. The authors attempted to study on the unification of both medicines to prevent the confusion of medicare for people. The major part of medical care is accomplished by Western medicine among people in Korea and China. However, Oriental medicine is still present as well as college of Oriental medicine in small number. There have been long struggles between two parts of medicine because of each assertions for the theories. The ancient medicine has been likely to have its characteristics either in Western or Oriental medicine although in many countries were succeeded by Western medicine except a few Asian countries such as Korea and China. In Japan since the license of Oriental(herb) medicine was ceased about one hundred years ago, the Western medicine has been authorized by law until today and the herb is the secondary medicine as a kind of folk treatment as well as continuous and enormous study for scientification. In only China and Korea this herb medicine has been kept to use as a part of medicine by law though China has developed combined medicine to use both Western and Oriental medicine by one physician since previous prime minister Chou En-Lai around the year 1950 who made a recommendation to the two medical societies, Western and Oriental. This fact has a big sense to establish the unification of two medicines in near future in Korea as well as China. For this accomplishment of medical unification both parts of medicine require sincere and enormous efforts to study the theory and practice of herb medicine even from now on. This unification of two medicines will provide the best medicare in most convenient way to the people in the world creating new world medicine like the third medicine including alternative medicine. The acupuncture is changing to a new method in Western medicine especially applying into anesthesia and pain clinic in even USA and Western countries at this time. In conclusion the unification of the Western and Oriental medicine will provide the most reasonable and practical medicare including alternative medicine to people in the world. Because the Oriental medicine will be used at least separately to supplement the Western medicine by one physician. PMID- 11624254 TI - [A study on medical educational system in North Korea]. AB - Medical education in North Korea began with 2 medical colleges established during the 1930s and 1940s, and each Province came to have one medical college by the 1970s. It is presumed to exist 14 medical colleges in 1992. Apart from medical colleges, there are several kinds of medical schools. the number of medical practitioners has increased as the number of educational institutes for medicine increased. In 1996, there was 29.7 medical practitioners for 10,000 persons. They have several kinds of academic degrees in North Korea. They include: Wonsa, candidate Wonsa, doctor, vice-doctor, candidate doctor. In the university they have professor, associate professor, associate professor, lecturer, and research assistant. Academic degrees and positions are given not by the university nor research institute, but by the Government Board for Awarding Academic Degree and Position. Concerning research institutes, there is Chosen Institute for Medical Science that once was a medical research center under the Central Science Academy, and became an independent institute in 1963. Besides this institute, universities have their own research institutes, and there are also some other independent institutes. PMID- 11624255 TI - [On the traditional surgery of Choson period (II)]. AB - In this paper, authors discussed the classification of swelling (Chong), swelling treatment methods (Chi-Chong) in Choson period, traditional notions about the natural history, treatment principles, popular healing methods of swelling, and depicted specially designed acupuncture instruments applied to it. Among the six professional guide books at that time, A Secret Recipe of Swelling Treatment (16th century) introduced the invasive surgical method into the narrow disease category i.e. carbuncle and furuncle, cellulitis, erysipelae, and gravitation abscess. The writer named these diseases as 'fire, stone, water, hemp, silk carbuncle', following each specific characteristics. Another surgical book, Orientation to Swelling Treatment (16th century) extended the surgical method to 'non-external' but 'looks-like swelling' diseases, such as pleurisy, tympanitis, testicular swelling, sequestrum of osteomyelitis. It is natural that some researchers doubted whether the book was used in real practice. However, the content of the book is too detailed to be regarded as an imaginary product. From these books and other materials, we found that the traditional notion of swelling was closely related with the notions of 'knotted' or 'pent in'. So 'pent-up rancor' or grudge was thought to aggravate any kind of swelling, and was tabooed or contraindicated in swelling treatment. 'Knotting in mind' was regarded as one of the principal etiologies of 'swelling and abscess formation in the body'. 'Fire in mind' was also regarded as one of the causes of phlegm aggregation resulting in swelling. PMID- 11624256 TI - [History of the Korean medical journals (1945-1995) - principally on the basic science journals]. AB - The development of Korean medical journals is summarized as the following: 1) Until the early 1960s there were not basic medical journals except Journal of the Korean Society for Microbiology (first issued in the year of 1958), so researchers of basic medical science had difficulty in publishing their articles. 2) Many of the basic medical journals made their first appearance around the mid 1960s, but the progress was not striking until the mid-1980s. 3) From the mid 1980s most of the journals rapidly developed in the aspect of quality as well as quantity. The increase in the number of issues per year and articles per an issue, and the increment of the articles written in English are remarkably found. The increase in the number of researchers, appropriate education and training, improvement of the research facilities, the growth of research fund, and increment of the international academic exchange are thought to be the main factors of such development. Besides those factors, the devotion of the editors of the journals played the important role. PMID- 11624257 TI - Practicing between earth and heaven: women healers in seventeenth-century Bologna AB - In the highly stratified medical system of seventeenth-century Bologna, women healers occupied a low-rank position. Officially women could practice medicine only as midwives or as holders of permits for the sale of patent medicines. Women were a relatively marginal group even within unauthorized medical practice. Of the criminal proceedings against unlicensed healers only 12% were directed against women. In contrast, women were prominent in religious healing--as shown by the record of healing miracles attributed to female saints, and the importance of female convents as centers of supernatural healing. The different status of women in each case might be related to the different role of the body in lay and religious medical practices. While contact with the <> of the saints was absolutely central in religious healing, <> was considered a mark of inferiority in lay medical practice. PMID- 11624258 TI - At birth: the modern state, modern medicine, and the royal midwife Louise Bourgeois in seventeenth-century France. AB - In this article I explore the connections between state centralization, the professionalization of healing, and the end of the royal midwife Louise Bourgeois' (1563-1636) illustrious career in seventeenth-century France. Specifically, I analyze seventeenth-century narratives of two events which frame Louise Bourgeois' public career as a writer and royal midwife in order to demonstrate the way that the changing meanings of childbirth and the role of the midwife in the medical hierarchy were bound up in state formation and consolidation. The result for midwives was that, though they could still practice, they were ultimately considered marginal to the medical community. PMID- 11624259 TI - [Birth and death of a profession. Certified midwives in Mexico (Spanish)]. AB - This study examines the rise and development of professional midwifery in Mexico. The authors sustain that this profession was created in the 19th century by the medical profession as a means to eliminate traditional midwives and obtain access to pregnant women, women about to give birth, and women in the puerperal period. The relationship between physicians and midwives was never without its contradictions; however, conflicts increased after the establishment of gynecology as a specialty in Mexico. In the 20th century, physicians imposed increasingly stringent limitations on the activities of certified midwives and instead promoted training for traditional midwives, until professional midwifery was abandoned. PMID- 11624260 TI - [Women in health: practices and knowledges. Introduction]. PMID- 11624261 TI - "You worked on your own, making your own decisions and coping on your own": midwifery knowledge, practice and independence in the workplace in Britain, 1936 to the early 1950s. AB - Midwifery knowledge is a complex entity-comprising of training and experiential elements-not fixed but mutable, both informed and altered by practice. This study uses oral history accounts to explore how midwives viewed themselves and how they interacted with widwifery knowledge in an attempt to gain a greater understanding of their power and independence in the workplace and, as a result, of their professional status. Midwifery knowledge cannot simply be defined as the technical skills taught in training; it was also shaped by the environment in which practice took place and midwife's relationships with women and with doctors. PMID- 11624262 TI - Publish or perish: the scientific publications of women physicians in late Imperial Russia. AB - Women physicians in late 19th century Russia emerge just as the Russian professions begin attempting to achieve some degree of autonomy from bureaucratic interference. Women took advantage of this discourse to portray themselves as competent professionals dedicated to bettering the lives of Russian people. Quite often these attempts to justify their work in the profession also motivated them to publish their scientific findings so that they could be viewed as legitimate scholars and physicians. This article concentrates on six women physicians, Elizabeth Drentel'n, Aleksandra Ekkert, Maria Pokrovskaia, Evgeniia Serebrennikova, Anna Shabanova, and Maria Volkova. PMID- 11624263 TI - [Women's education according to the first women to receive doctorates in medicine from Spanish universities, 1882]. AB - This study looks at the topic of women's education as considered by the first two women to receive the degree of Doctor in Medicine from a Spanish university. Delores Aleu and Martina Castells decided to present as a doctoral thesis the development of an issue of particular relevance during the final decades of the 19th century. The importance given to public education and the difficulties young women encountered in participating under the same conditions as young men led these two women--who both held a bachelor's degree--to raise the issue and defend personal and social reasons that justified their full participation in different levels of education. PMID- 11624265 TI - From "uncertifiable" medical practice to Berlin Clinic of Women Doctors: the medical career of Franziska Tiburtius (M.D. Zurich, 1876). AB - Problems in gender expectations and relationships complicated increasing professionalization of medical arts at an important point of transformation toward the modern industrial European state. Subordination of women's work in these processes altered possible outcomes for German society in general and for female medical careers in particular. Franziska Tiburtius was one of twenty German women who graduated from the coeducational medical school in Zurich, Switzerland, in the nineteenth century. She was a founder of the Clinic of Women Doctors despite prohibitions against certifying women as physicians. Imperial Germany was the last Western nation to admit women to full medical practice in 1899. PMID- 11624266 TI - Sisterhood's ordeals: shared interests and divided loyalties in Finnish wartime nursing. AB - The aim of this article is to highlight early Finnish nursing in a special wartime context. Occupational development of nursing is envisioned by addressing at a more general level women's mutual relationships and the opportunities and obstacles of the process of occupational development. The article debates two main issues. Establishing occupational domains was a process of selecting suitable labour force and training women morally, as well. The hierarchical order of nursing is manifested especially in the questions of auxiliary labour and the so-called amateur scare. War was still a time of romanticism with visible military and religious models, but women also struggled for their right to have rights. PMID- 11624264 TI - In search of an "Authentic" women's medicine: the strange fates of Trota of Salerno and Hildegard of Bingen. AB - Despite centuries of debate about the medieval writers Trota and Hildegard, there still remain widely disparate views of them in both popular and scholarly discourses. Their alternate dismissal or romanticization is not due to a simple contest between antifeminist and feminist tendencies. Rather, issues of gender have intersected in varying ways with other agendas (intellectual, nationalist, etc.). Recent philological researches have helped not only to clarify why these earlier interpretations were created in the first place, but also to raise our understanding of these women and their work to a new, higher level. PMID- 11624268 TI - Constructing the pediatric nurse: eugenics and the gendering of infant hygiene in early twentieth century Berlin. AB - This article explores the connections between infant mortality, eugenic thinking, and the professional development of pediatricians and pediatric nurses in the early twentieth century. It argues that the goal of the physicians affiliated with Germany's National Hospital to Combat Infant Mortality was to create and disseminate a centrally-controlled message about infant hygiene, and to transform infant care into a medically-managed event. The deeply gendered ways in which both the hygienic program, and the medical division of labor were constructed, had the ambiguous result of expanding training opportunities for pediatric nurses, while at the same time, severely limiting their professional autonomy. PMID- 11624267 TI - "Able to do things which they have never dreamed": Shi Meiyu's vision of nursing in early twentieth century China. AB - This essay explores the writings of Shi Meiyu, a Chinese woman medical missionary, concerning the nursing school she ran in Jiujiang, China from 1896 to 1920. During this period, in both the writings of Western missionaries and Chinese reformers, images of sick Chinese women were frequently used to condemn many aspects of Chinese society. My essay looks at the ways that Shi Meiyu, in her discussions of the health of Chinese women, shifted the focus to a vision of Chinese women as skilled healers. I also explore Shi's search for the funding to adapt her nursing school to the increasing emphasis on <> medicine. PMID- 11624269 TI - [The Assistance maternelle de Montreal (1912-1961). An example of marginalization of philanthropic active women in the field of care for pregnants (French)]. AB - This article examines the story of the Assistance maternelle de Montreal, an organization founded in 1912 by a group of bourgeois catholic women to provide material assistance and free medical services to poor pregnant mothers of the city. I want to show that even if the timid intervention of the Quebec state allowed the AM to survive during the almost 50 years, the rise of the experts in the health field--a phenomenon to which the AM has largely contributed--and in the philanthropic sector led to the marginalization of the female volunteers within the very institution they had created. PMID- 11624270 TI - [Discourse on the social illness: leprosy in the Viceroyalty of Nueva Granada in the transition from the 17th to the 18th century (Spanish)]. AB - The significance of leprosy in the Viceroyalty of Nueva Granada in the transition from the 17th to the 18th century is analyzed. In addition, we analyze treatments recommended by physicians in the viceroyalty, which were closely related with the etiology and pathogenesis which all doctors attributed to Saint Lazarus's disease. The diversity of opinions led to different therapeutic measures, not only with regard to alleviating the patient's symptoms, but also with a view to preventing it to spread to the rest of the population. As a guiding theme we use the theories defended by the most representative physicians in the viceroyalty, and the views of patients themselves and the society they lived in. PMID- 11624271 TI - [Degeneration theory and clinical psychiatry in restoration Spain (Spanish)]. AB - Spanish historiography on degenerationism has focused on topics such as criminality, alcoholism, or its influence on naturalistic literature. From this perspective the lack of studies on how this theory affected psychiatrists in Spain is noteworthy. The aim of this paper is to analyze the relationship between clinical psychiatry and degenerationism. We stress three topics: morbid heredity and the nature of degeneration, physical and psychic stigmas, and the boundaries of degenerationism. To this end we examine different sources that include articles in the medical press, pamphlets and psychiatric treatises. PMID- 11624272 TI - The development and present state of history of medicine in Britain. AB - This is a personal account of scholarship in the history of medicine in Britain, from the 1960s onwards, drawn from recollections and knowledge of the literature. The institutional development of the subject is reviewed, emphasizing the contributions of the Wellcome Trust; the various modes of historical research and writing are surveyed and assessed. Modest suggestions are made for renewing the historiography of medical sciences and technologies--to contribute to the politics of knowledge and to wider histories. PMID- 11624273 TI - [Theses on the history of medicine and science presented in Spanish universities, 1998]. PMID- 11624274 TI - [Academic power versus feminine authority: the Paris Medical School against Jacoba Felicie (1322)]. AB - This article analyzes the trial that the Faculty of Medicine at Paris pursued against Jacoba Felicie in 1322. Drawing on her parents' narratives, it attempts to interpret Jacoba's medical practice and the particular nature of the relationship that she established with her parents. In order to identify and describe this relationship, we use a basic distinction between power and authority. PMID- 11624276 TI - "Be unto me as a precious ointment": Lady Grace Mildmay, sixteenth-century female practioner. AB - Lady Grace Mildmay's manuscripts represent an unusual presentation of three interrelated areas of family, devotion, and medicine. By examining her autobiography, meditations, and medical papers, I draw together literary analysis and discourses of female devotional and social practices with that of medical discourses to illustrate the ways in which women practitioners may have acquired and disseminated medical knowledge, and interacted with their patients, as well as how Lady Mildnay, and presumably other landed women practitioners, formed a textual community of women who administerd medical treatment to lay people in late sixteenth-century England. PMID- 11624275 TI - Women healers in the medical marketplace of 16th-century Lyon. AB - Although women's legal and marital status make them almost invisible in archival documents, what traces remain suggest that women participated in Lyon's medical marketplace in various ways and under various guises. At Lyon's municipally funded poor hospital, the Hotel-Dieu, widows and wives of surgeons, repentant prostitutes, birth attendants, and <> cared for the destitute and sick of Lyon, in the capacity of midwives, physicians, surgeons, and barbers. Though the records almost always identify women practitioners simply as <> or by their first and last name, many of them engaged in the identical tasks as male practitioners. Outside of the hospital, wives acted as barbers or surgeons alongside or in place of their husbands when widowed. In the final analysis, municipal authorities accepted the help of female healers on the basis of their traditional medical knowledge, joint work identity with their practitioner husbands, and proven skill. PMID- 11624277 TI - Der Entdecker des Atrioventrikularbundels Dr. Sunao Tawara--Nachbemerkungen. PMID- 11624278 TI - The development of scholarhip in the Igakkan (2): government doctors during the Kansei reform period, as seen in Yoshino zoshi. AB - Yoshino zoshi has never been used in previous studies of Japanese medical history. It gives detailed information on government doctors during the time when the Igakkan was bureaucratized. It is a collection of reports of rumors written by his advisors for Matsudaira Sadanobu, the instigator of the Kansei reforms. Thus Yoshino zoshi was directly related to the formation of the reform policies. Furthermore, it reveals background stories behind official promotions and demotions, and the feelings of the individuals concerned, which are not visible in official documents. The following topics are discussed: rumors during the early Kansei Reform period; the clinical achievement reports as they related to promotions and demotions during 1788; the reputations of doctors in the service of daimyos and those serving townspeople; orders given to government doctors in 1789; the gambling scandal of Seijukan; the fall of the Nakarai family; the expanding power of Taki Rankei; the founding of the Igakkan; and the Ninomaru Seiyakujo. PMID- 11624279 TI - Activities of medical treatment and culture carried out by modern Japan in China- a study on the Dojin association. AB - After the Qing-Japanese War and under the background following the guidelines of "Safeguarding the Qing Nation" and of "Japan Fever" in China, the Dojin Association was founded in 1902 by some people in the medical circle and by the cadres of the Toa Dobun Association. The original purpose of its activities was to popularize the modern medicine and medical therapy of Japan in neighboring countries in a bid to promote peace and amicability with them. Prior to the incident of Lu Gou Bridge, the activities in China were mainly involved in cultural and hospital operations; after the incident, they were changed to dispatching diagnostic and anti-epidemic teams until the said Association was dissolved in 1946. This paper will chiefly deal with the activities of the former period of the Dojin Association, especially with the evaluation of its following functions in regard to the expansion of Japan in the continent: First: the function of assisting Japan to invade China was increasing day by day; Second: Although the function to resist the medical and cultural activities conducted by American and European rivals was not so obvious, yet, it was effective to some extent; Third: The popularization of modern medicine and medical therapy of Japan obtained good results but also suffered some failure due to the above mentioned first point. In other words, in terms of time and extent, assisting Japan to invade China was the most characteristic function of the Dojin Association. PMID- 11624280 TI - The life of Dr. Masao Sumita (1878-1946), a founder of modern orthopaedic surgery in Kyushu. AB - The life of Dr. Masao Sumita, who was the first professor of the Department of Orthopaedic Surgery at Kyushu University in Fukuoka during 1912-1925, was one of the founders of modern orthopaedic surgery in Japan. His technique of operative procedures had gained a national reputation, and the successful results of his operations of arthroplasty in over 300 joints, along with his other enormous academic achievements were reported. However, he was accused of conducting private clinic activities outside the university hospital, which was considered illegal as a national public official. The free attitude to medical practice that he had experienced during his stay in European countries, where conducting private clinic work, even outside the national university was approved, led to this unjustifiable incident in Japan. He was subsequently purged from the university due to this accusation. In his family life he was survived by his wife and four children. His life story seemed to the author to be a drama with rise and fall. Consequently, the author would like to reveal Sumita's outstanding academic achievements and real personal image as an ingenious surgeon and scholar, in spite of the sorrowful aspect of his life. PMID- 11624281 TI - A bibliographical study on Shutei Nakagawa's "Mayaku-ko" (a collection of anesthetics and analgesics)--a comparism of four manuscripts. AB - The greatest achievement of Seishu Hanaoka, one of the greatest surgeons in the Edo period, was the innovation of an oral general anesthetic called "Mafutsu-San" and its clinical application, however, the detailed circumstances of the innovation remain unkown to us. Shutei Nakagawa, a close friend of Hanaoka, wrote a small pamphlet entitled "Mayaku-ko" in 1796. This brochure is very important for clarifying the process of Hanaoka's study on the general anesthetic. At present I have found four manuscripts of "Mayaku-ku" which are in the Fujikawa Library of Kyoto University, Soda's Library (Personal Library), the Kyo-u Library of Takeda Pharmaceutical Company, and Matsuki's Library (Author's Library). They are classified bibliographically into two groups. The one includes two manuscripts of the Fujikawa Library and Soda's Library, which describe twenty prescriptions. The other two are the manuscripts of Kyo-u and Matsuki's Libraries describing only fourteen recipes. Among them, the Fujikawa's manuscript is the best, because it has a postscript by Yakushi Mori who transcribed this manuscript from the orginal by Shutei Nakagawa. The Fujikawa manuscript has four illustrations of plants in the end of the manuscript which the other three manuscripts lack. As the original manuscript by Nakagawa was lost in a fire in 1867, it is possible to make an accurate reproduction of the original by bibliographical comparison of four extant manuscripts. PMID- 11624282 TI - Newspaper reporting of hazards in the UK and Sweden. AB - Public understanding of risks is likely to be informed by the media. We report a cross-national study looking at how newspapers in Sweden and the United Kingdom characterize a variety of risks, focusing on two months around the 10th anniversary of the Chernobyl accident. Approximately four times as many reports about risks were found in Sweden as in the U.K., possibly reflecting a Swedish safety culture. The Bovine Spongiform Encephalopathy (BSE) crisis dominated reporting in both countries, especially in the U.K. The proportion and pattern of reports on Chernobyl was similar across countries. However, in Sweden, there was an increase in reports about other nuclear hazards after the anniversary, suggesting that generalization of media concern may have occurred. Generally, BSE was discussed using a greater number of characterizations in the U.K., while Chernobyl was reported using more characterizations in Sweden. Reports about hazards tended to be alarmist rather than reassuring, and rarely used statistics to express degrees of risk. PMID- 11624283 TI - Arthur Ernest Mourant: 11 April 1904-29 August 1994. PMID- 11624284 TI - Alexander George Ogston: 30 January 1911-29 June 1996. PMID- 11624285 TI - Helio Gelli Pereira: 23 September 1918-16 August 1994. PMID- 11624286 TI - Norman Wingate Pirie: 1 July 1907-29 March 1997. PMID- 11624287 TI - Tadeus Reichstein: 20 July 1897-1 August 1996. PMID- 11624288 TI - Reproductive control in apartheid South Africa. AB - Since its inception in 1974, the South African family planning programme has been widely believed to be linked with white fears of growing black numbers. The programme has been repeatedly attacked by detractors as a programme of social and political control. Yet, in spite of the hostile environment, black women's use of services has steadily increased. Using historical and anthropological evidence, this paper delineates the links between the social and political context of racial domination and individual fertility behaviour. It is argued that the quantitative success of the family planning programme is rooted in social and economic shifts conditioning reproductive authority and fertility decision making. State policies of racial segregation and influx control, ethnic 'homeland' politics, and labour migration of men transformed opportunities and constraints for black women and men, and altered local and household expectations of childbearing. Women came to manage their own fertility as they increasingly found themselves in precarious social and economic circumstances. PMID- 11624289 TI - Interacting effects of nutrition and social class differentials on fertility and infant mortality in the pre-industrial population. AB - Inadequate nutrition of both the mother and her offspring at each stage of its development - before pregnancy, in the womb, in infancy and during early childhod - played an important role in the patterns of subfertility and infant mortality in a saturated, marginal, preindustrial community. It is suggested that the three social classes had different diets but all were deficient in some essential constituents. Differences in nursing practices in the social groups contributed to differential exogenous mortality and to malnourishment and maternal depletion in the subsistence and (paradoxically) in the elite classes, producing an interacting web of effects and generating a vicious circle from which they could not escape for 150 years. Although the population apparently preferred daughters, the persistent generation effect of low birthweight girls bearing low birthweight daughters probably contributed to the steady-state conditions in this compromised community. PMID- 11624290 TI - The animated pain of the body. PMID- 11624291 TI - The Museum for the History of the University of Pavia and the birth of histology. AB - A brief overview is provided on the development of histology as an independent discipline at the University of Pavia, through documents and preparations preserved in the Museum for the History of the University. Studies on the organization of tissues and cells started blooming in the mid-1850s, when morphological observations were supported by significant technical advancements in microscopy and tissue preparation. The role of Albert Koelliker, the great father of European Histology in the second half of the 19th century, is also discussed. Koelliker had several contacts with Camillo Golgi and promoted the diffusion of Golgi's discoveries. The authors also underline the innovative role of Camillo Golgi in the histological approach to research and in the foundation of modern histology. PMID- 11624292 TI - Microscopy in Camillo Golgi's times. AB - The research by Camillo Golgi in histology and pathology dates from 1865, the year in which he obtained his MD degree, to 1923, when his last scientific article was published. Beginning in the mid 1855s, microscope manufacturers in Europe started producing objectives based on the principle of immersion introduced in 1847 by Giovan Battista Amici. The immersion objectives greatly improved the resolution of microscopic observations at high magnifications. From 1860 to 1872, technological improvements in microscope optics and the practicality of their use provided a larger community of investigators effective tools needed to study the structure of the nervous system. This progress in microscopy was associated with the application of new histological techniques, mastered by the chromoargentic reaction introduced by Golgi in 1873. In 1872, further progress in microscopy stemmed from the application of notions of applied physics to the production of microscope optics. These developments in microscopy will be briefly reviewed here. PMID- 11624293 TI - Camillo Golgi's scientific biography. AB - Born in Corteno, a tiny village in the province of Brescia, Camillo Golgi studied at the University of Pavia where he graduated in medicine in 1865 under the guidance of the psychiatrist Cesare Lombroso who sparked his vocation to study the brain. Golgi then began to learn histological techniques under the direction of the pathologist Giulio Bizzozero. In 1872 he moved to Abbiategrasso as chief of a hospital for chronic diseases. In a rudimentary laboratory he developed the silver-bichromate staining technique, the 'black reaction', which was a breakthrough for nervous tissue structure research. While in Abbiategrasso Golgi demonstrated the branching of the axons, and observed striatal and cortical lesions in a case of chorea. He returned to Pavia as Professor of Histology and General Pathology, and made a series of important discoveries that still bear his name: the Golgi tendon organ, the Golgi-Mazzoni corpuscles, another Golgi method to stain nerve cells based on the use of potassium dichromate and mercuric chloride, the canaliculi of the parietal cells of the gastric glands (Muller Golgi tubules), the Golgi-Rezzonico myelin's annular apparatus (or Golgi Rezzonico horny funnels), the cycle of malarian parasites (Golgi cycle), the relationship between recurrent malarian fever bouts and the multiplication of the Plasmodium in the blood (Golgi law), the relationship between the vascular pole of the Malpighian glomerulus and the distal tubule, the Golgi's pericellular nets and finally, and most importantly, the cytoplasmic 'internal reticular apparatus' (Golgi apparatus). In 1906 Golgi was awarded the Nobel prize for Medicine or Physiology. He died in Pavia on 21 January 1921. PMID- 11624294 TI - The Golgi Stain: invention, diffusion and impact on neurosciences. AB - The black reaction, invented in 1873 by Camillo Golgi (1843-1926, was the first technique to reveal neurons in their entirety, i.e. with all their processes. This important development passed unnoticed at first and only received wide international attention after a long delay. The Golgi stain was widely employed for almost thirty years and was directly responsible for major advances in our knowledge of the microscopic anatomy of the nervous system, as well as in other fields of study. In the hands of other researchers, the black reaction provided vital evidence that helped to establish the neuron theory. The Golgi stain was almost forgotten in the period between the two World Wars, but the introduction of the electron microscope to neurocytological resarch revived its use around the middle of the twentieth century. Today, the black reaction is still used extensively not only in combination with electron microscopy, but also as an autonomous technique in studies on the evolution, ontogeny, and organization of the nervous system. PMID- 11624295 TI - Camillo Golgi: a clinical pathologist. AB - Camillo Golgi opened new avenues in histology and neurobiology as well as in clinical neurology and internal medicine. This is demonstrated by investigations Golgi performed during 1861-1876 on the etiology and pathology of mental diseases, on the neuropathology of Huntington's chorea (Golgi provided the first detailed description at the microscopic level of pathological changes in the basal ganglia and cerebral cortex of one case of chorea), on meningiomas and cerebral gliomas. In the period following these investigations, Golgi focused especially on infectious diseases. He pursued fundamental studies on malaria (which remain among the most important and original of his contributions) on rabies, as well as on smallpox and influenza. Thus, Camillo Golgi should be remembered for his discoveries of the black reaction and the Golgi apparatus, as well as for the modern impulse he was able to give to clinical neurology and internal medicine. PMID- 11624296 TI - Gustaf Retzius and Camillo Golgi. AB - Gustaf Retzius (1842-1919), the Swedish anatomist and anthropologist, and Camillo Golgi were contemporaries. They met on several occasions and came in closer contact when Golgi, together with Ramon y Cajal, was awarded the Nobel Prize in Physiology or Medicine in Stockholm in 1906. Retzius came from an illustrious family. His father was professor of anatomy at Karolinska Institutet and Gustaf himself made a fast career. At 35, he was appointed to a professorship in histology, especially created for him at Karolinska Institutet, and later he became professor of anatomy in the same institution. Retzius was exceedingly productive, and published more than 300 scientific papers, most of which dealt with the nervous system and sensory organs. The majority of these were included in his magnificent volumes Biologische Untersuchungen, Neue Folge (Biological Investigation, New Series), which appeared from 1890 to 1921, and in Das Gehororgan der Wirbelthiere ("The Acoustic Organ of Vertebrates", 1881 and 1884), which may be his internationally better know contribution. Much of his work, especially on invertebrates, was based on Ehrlich's methylene blue method, but he also used the Golgi method early on. Particularly his studies of the innervation of the sensory organs became of great importance for the support of the neuron doctrine. His standing internationally was reflected in his membership in many of the most prominent academies abroad, as well as in invitations to him to give a "Croonian Lecture" in 1908 and "The Huxley Lecture" in 1909. PMID- 11624297 TI - Camillo Golgi on the structure of the hippocampus. AB - Golgi's only paper on the pes Hippocampi major was published in 1883 and then reprinted and translated a number of times. In it he stated that the fascia dentata provided the best information available to date on how nerve fibers and nerve cells are related. Based on the revolutionary silver chromate method he had introduced a decade earlier, Golgi described two sources of axons from the fascia dentata: one consisted of direct axons from the granule cells, and the other coonsisted of indirect axons from a diffuse neural net or reticulum that was generated from collaterals of the direct axons. The same basic arrangement was described for Ammon's horn, but neither was illustrated, and it is important to bear in mind that this work was published before the "neuron doctrine" and "law of functional polarity" were elaborated in the 1890's. PMID- 11624298 TI - Colgi, Cajal and the Neuron Doctrine. AB - Camillo Golgi and Santiago Ramon y Cajal shared the Nobel Prize in 1906 for their work on the histology of the nerve cell, but both held diametrically opposed views about the Neuron Doctrine which emphasizes the structural, functional and developmental singularity of the nerve cell. Golgi's reticularist views remained entrenched and his work on the nervous system did not venture greatly into new territories after its original flowering, which had greater impact than is now commonly credited. Cajal, by contrast, by the time he was awarded the Nobel Prize, was already breaking new ground with a new staining technique in the field of peripheral nerve regeneration, seeing the reconstruction of a severed nerve by sprouting from the proximal stump as another manifestation of the Neuron Doctrine. Paradoxically, identical studies were going on simultaneously in Golgi's laboratory in the hands of Aldo Perroncito, but the findings did not seem to influence Golgi's thinking on the Neuron Doctrine. PMID- 11624299 TI - The perineuronal net: a weapon for a challenge. AB - Theories and data do not always fit and sometimes are sources of conflicts among scientists. This is the case of a morphological structure, the perineuronal net, which was denied on the basis of an ideological conflict between two giants of neurosciences: Camillo Golgi and Santiago Ramon y Cajal. The perineuronal net is a reticular structure enveloping many neurons. Orginally reported by Golgi in 1893 and 1898 and confirmed by several authors before the turn of the century, the perineuronal net was used by Golgi to support the reticular theory of the organization of the nervous system. Ramon y Cajal, the paladin of the neuronal theory who had also observed this anatomical structure, denied its existence suggesting that it was a fixation artifact. After Cajal's statements, only a few Italian scientists continued to work in this field, and after the 1930s the perineuronal net was forgotten. Only the recent advances in histochemical and immunocytochemical technology confirmed the existence of this structure opening new fields in functional neuroanatomy and neuropathology. PMID- 11624300 TI - Evolution of the concept of "extracellular matrix' in the brain. AB - The question as to whether an extracellular matrix exists between cells in the adult brain has been debated since the end of the last century. In the early years, zones containing neuropil and glial processes were mistakenly believed to represent this substance. But Golgi's discovery of the "perineuronal net" paved the way for future study of the true extracellular matrix. In the 1950s, application of histochemical techniques established the existence of interstitial material between nerve cells. Unfortunately the similarity between the pericellular distribution of this material and Golgi's "pericellular nets" was overlooked. The detection of an extracellular volume fraction in the central nervous system furnished further indirect proof for the existence of an extracellular matrix in the brain. However, the repeated failure of electron microscopy to reveal a substantial space between cell processes undermined the acceptance of the concept of "extracellular matrix" in the central nervous system. Nowadays this concept has, however, been firmly established. PMID- 11624301 TI - Some aspects of the history of the law of dynamic polarization of the neuron. From William James to Sherrington, from Cajal and van Gehuchten to Golgi. AB - William James was the first to suggest that propagation of impulses in the nervous system proceeds in one direction, from sensory to motor neurons, but not viceversa. His law of forward direction preceded the formulation of the law of dynamic polarization of van Gehuchten and Cajal, which assumed that nerve impulses are conducted cellulipetally along dendrites and cellulifugally along axons, based on different anatomo-functional properties of these neuronal components. Golgi did not accept the law of dynamic polarization because he believed that dendrites are involved in the nutrition of the neuron rather than in impulse propagation, and that impulses can travel in any direction in the axonal components of the diffuse nerve network. Sherrington in turn experimentally demonstrated that intraneuronic conduction is reversible, whereas, in accord with James's law, propagation of impulses along neuronal chains is irreversible, due to the valve-like action of synapses. The story of the law of dynamic polarization shows that neither Golgi nor Cajal paid much heed to Sherrington's findings and to neurophysiological studies in general, probably because they felt that histology alone could provide the key for understanding the general functioning of the nervous system. It is argued here that this attitude was detrimental to the progress of the neurosciences, because a multidisciplinary approach based on different techniques is inevitably called for in order to develop a plausible theory of the nervous system. PMID- 11624302 TI - The discovery of the Golgi apparatus. AB - The existence of the cell organelle which is now known as Golgi apparatus or Golgi complex, or simply as 'the Golgi", was first reported by Camillo Golgi in 1898, when he described in nerve cells an 'internal reticular apparatus' impregnated by a variant of his chromoargentic staining. It soon became clear that the newly-identified cytoplasmic structure occurred in a variety of cell types. However, the reality of the organelle was questioned for decades, until it was finally ascertained with electron microscopy. The Golgi apparatus was destined to become a protagonist of the research in cytology and cell biology pursued in the second half of the twentieth century. PMID- 11624303 TI - The legacy of Camillo Golgi for modern concepts of brain organization. AB - The experimental advance made by Camillo Golgi's 'black reaction' has been universally recognized as the start of the modern revolution in the study of the nervous system. By contrast, his concepts of nervous organization, particularly his support for the idea of a 'nervous reticulum', have been universally rejected. The premise of the present paper is that ideas of a biologist of this stature deserve re-examination. Golgi's arguments for considering the holistic function of the brain seem to come from his experience as a physician, and presage the views of the gestaltists and, more recently, the conceptual underpinnings of artificial neural networks. His interest in the possible nutritional roles of neuronal dendrites can be seen to anticipate current investigations, at the cellular level, of the metabolic basis of brain imaging. These and other currents in Golgi's thought deserve further study. PMID- 11624305 TI - Physicians on British stamps. PMID- 11624304 TI - From the vacuum to the vaccum tube. PMID- 11624306 TI - Errors in cancellations of medical interest. PMID- 11624307 TI - Foster and Sharpey's tour of Europe. AB - An account by Michael Foster of a tour of European physiological laboratories he made with William Sharpey in 1870. PMID- 11624308 TI - The Reverend Dr William Henry Dallinger, F.R.S. (1839-1909). AB - William Dallinger illustrates a social outsider concerned with the application of science to the physical, intellectual and spiritual health of his homeland, who forced his way into the scientific life of his nation. His path was encouraged by mentors such as William McKenny who steered him into the Methodist ministry, James Drysdale who helped him get established as a scientist and John Tyndall, Thomas Huxley and Charles Darwin who encouraged his scientific efforts and smoothed his way into his nation's highest scientific circles. The shadowy figures of John Wesley and John Ray played a role in affirming the validity of his scientific interests and concerns for science education. PMID- 11624309 TI - A history of the Liverpool School of Pharmacy. PMID- 11624310 TI - Mr Gulliver's letter book: a Belgravia pharmacy one hundred years ago. PMID- 11624311 TI - Trepanation or trephination? The orthography of paleopathology. PMID- 11624312 TI - Francis Crumpe - a pioneer of intravenous therapy. PMID- 11624313 TI - The idea of nature in Maimonides' philosophy of medicine: Jewish or Greek? PMID- 11624314 TI - The healing narratives of the Synoptic Gospels: a call to Monotheism, a call to wellness. PMID- 11624315 TI - The Gittin "Book of Remedies". PMID- 11624316 TI - Mai gargutani? an obscure medical term in Bava Kamma 85a. PMID- 11624317 TI - Obstetrics in Jewish sources. PMID- 11624318 TI - Origins of clinical neurology: M.H. Romberg and his 'Lehrbuch der Nervenkrankheiten des Menschen' (1840-1846). PMID- 11624319 TI - Conjoined twins in the Aggadah (a two-headed man). PMID- 11624320 TI - Heinrich Neumann von Hethars at the Evian Refugee Conference (1938). PMID- 11624321 TI - Hebrew translations from medical treatises of Montpellier. PMID- 11624322 TI - The "other" physicians: the Amorites of the Rabbis and the Magi of Pliny. PMID- 11624323 TI - Hidden difficulties in the Sages' terminology for women's bodies. PMID- 11624324 TI - "From Athens to Jerusalem:" medicine in Hellenized Jewish lore and in Early Christian literature". PMID- 11624325 TI - "Cleansing" the "Leper" in the Old and New Testaments. PMID- 11624326 TI - Some new medical manuscripts from St. Petersburg. PMID- 11624327 TI - The development of psychiatry and neurology in the nineteenth century. Translated from the German by M.Whitrow. PMID- 11624328 TI - Constance Pascal: pioneer of French psychiatry. Translated from the French by C.S.Breathnach. PMID- 11624329 TI - City and country in German psychiatry in the nineteenth and twentieth centuries - the example of Freiburg. AB - The situation (geography, topography) of asylums played an important role in German psychiatry during the last two centuries. In the first half of the nineteenth century asylums were built in the countryside. Although their establishment was partly driven by a bourgeois effort towards reform it was also still underpinned by the old autocratic ideas in respect to social ranking and by patriarchal medical concepts. Yet university psychiatry along the lines of Wilhelm Griesinger (1817-1868) was city-oriented. University psychiatry seemed to satisfy the needs of a modern industrialized state more effectively, but asylum psychiatry in Bismarckian and Wilhelmine times on the other hand corresponded strongly to the needs of the hierachical state. The history of the psychiatric hospital of the University of Freiburg illustrates how critical the dualism of country-oriented versus city-oriented psychiatry was for twentieth-century German psychiatry. PMID- 11624330 TI - An investigation into the precedents of modern drug treatment in psychiatry. AB - This paper examines some of the factors associated with the introduction of a range of new drug treatments into psychiatry in the 1950s and 1960s. The nature of psychiatry in the United Kingdom in preceding decades is examined and a continuous emphasis on biological explanations and treatments of mental disorder is revealed. Physical treatment procedures such as insulin coma therapy and shock treatment received most attention. Older drug treatments, although widely used, excited little interest during this time. The new drug treatments by contrast received much attention and began to be regarded as having specific effects on different mental disorders. It is suggested that a combination of long-standing professional concerns and commercial factors helped to account for the rapid acceptance and employment of the new drugs. In turn, these drugs helped to strenghten the hegemony of the medical approach to mental illness. PMID- 11624331 TI - 'Pitiless psychology': the role of prevention in British military psychiatry in the Second World War. PMID- 11624332 TI - 'Delire':Diderot and D'Alembert (Translated from french article) PMID- 11624336 TI - The ABCs of survival behind barbed wire: experience in the Far East, 1941-45. PMID- 11624337 TI - Deporting "Ah Sin" to save the white race: moral panic, racialization, and the extension of Canadian drug laws in the 1920s. AB - This article argues that a Vancouver anti-drug campaign was critical to the extension of Canada's drug laws in the early 1920s. The highly racialized drug panic resulted in extraordinarily severe drug legislation including six-month sentences for possession. This had particularly devastating effects on Chinese Canadians who were targeted by enforcement officials and faced the possibility of deportation. However, the drug panic also affected drug users of all backgrounds who for long afterwards faced lengthy sentences for possession as well as civil liberties violations such as extraordinary search legislation and restrictions on the right to an appeal. PMID- 11624338 TI - Masculinity, work and the fountain of youth: Irving Fisher and the life extension Institute, 1914-31. AB - In 1914, Progressive Era reformer Irving Fisher and the wealthy contractor Harold Ley founded the Life Extension Institute (LEI), a business venture organized to address the problems of American health. For approximately two decades, from 1914 until the death of its medical director in 1931, the Life Extension Institute widely promoted its health maintenance program of annual physical examinations and health literature. The advertised goal of the LEI was to extend life without old age, as well as improve masculinity and good business practices through adherence to health principles. The first two decades of activities of the Life Extension Institute offer a window for examining early twentieth-century ideas about the relationships between health, old age, and masculinity. The LEI literature constructed a picture of healthy, vigorous, and efficient American working men that helped to cement ideals of masculinity to ideals of health. PMID- 11624339 TI - From despair to hope: the nursing care of children with leukemia, 1940-1980. PMID- 11624340 TI - From medical astrology to medical astronomy: sol-lunar and planetary theories of disease in British medicine, c. 1700-1850. AB - After 1700, astrology lost the respect it once commanded in medical circles. But the belief that the heavens influenced bodily health persisted - even in learned medicine - until well into the nineteenth century. The continuing vitality of these ideas owed much to the new empirical and mechanical outlook of their proponents. Taking their cue from the work of Robert Boyle and Richard Mead, a number of British practitioners amassed statistical evidence which purported to prove the influence of the Moon upon fevers and other diseases. Such ideas flourished in the colonies and in the medical services of the armed forces, but their exponents were not marginal men. Some, like James Lind, were widely respected and drew support for their views from such influential figures as Erasmus Darwin. PMID- 11624341 TI - European traditional healers persecuted as witches and Kenyan traditional doctors. PMID- 11624342 TI - ["Ryouka" of the old-system high schools and the related people of the pharmaceutical field]. PMID- 11624344 TI - [Visit to historical places to pharmacy--Hirado city, Nagasaki prefecture]. PMID- 11624343 TI - [Visit to historical places related to pharmacy--the settlement of Kobe and its surroundings, where German pharmaceuticals were traded]. PMID- 11624345 TI - [Evolution of clinical pharmacy--toward the 21st century]. PMID- 11624346 TI - [Documents related to a medical prescription book in the Date Museum (Date City, Hokkaido)]. AB - This is a report of a prescription book which Munetomo Murayama, a medical doctor attached to the Date Watari Feudal Clan, inherited from his ancestors and handed on to his descendants. It is now preserved in the Date Museum in Date, Hokkaido, Japan, and the records there show that it was donated by a descendant of Dr. Murayama. The prescription book is unique in its detailed descriptions that are different from traditional medicine. It describes specific illnesses and the medications that were used in their treatment. The illnesses described are not serious ailments but illnesses commonly encountered in daily life and commonly available (over-the-counter) drugs recommended for the treatment of stomach ailments, diarrhea ; drugs for external use, also 'tochino' (a non-prescription drug commonly used for all kinds of illnesses in old times in Japan), drugs for tiredness, hemorrhoids, cough relief, aroma therapy, and others. Some of the drugs are also recognized today as being effective and having medicinal effects. They are thought to be agents with medicinal effects and the treatments reported by Dr. Murayama are separate and different from the Shimizu style in which they are applied. PMID- 11624347 TI - [The development of the Japanese pharmaceutical industry (part 7). Histories of medical advertisements from Taisho Era till Showa Era]. AB - Medical advertisements in newspapers have been used quite often as a means of sales promotion since the Meiji Era. Medical advertisements were quantitatively the leading advertisements in Japanese newspapers from the Taisho Era to early in the Showa Era. When World War II broke out, the quanity of advertisements in newspapers decreased markedly. After the war ended, the quantity of radio commercials for medicine increased quite rapidly. In the 1960s, however, pharmaceutical companies were criticized for over-promoting and improperly using medicines. PMID- 11624348 TI - [Historical study on the moth repellent, "Fujisawa Camphor" (1)]. AB - "Fujisawa Camphor" was introduced for sale as a moth repellent for home use in 1897. As a background that camphor was produced on a commercial basis, the following were studied: (1) Camphor was already used as a moth repellent by some people in the Endo Period. (2) With the Sino-Japanese War as a turning point, armaments were increased and they made military uniforms which were made of wool. It also made Western woolen clothes spread in general. (3) As people were in danger to catch infectious diseases in those days, they had a habit of avoiding bad odors and drifting fragrances like camphor were used in rooms to prevent the plague. (4) In those days, a technique for refining camphor was established, so white crystal-line camphor was produced on a commercial basis. PMID- 11624349 TI - [Memoirs on Chlorodyne and Shinyaku]. AB - Dr. J. Collins Browne, a British army surgeon in India, invented a secret remedy for cholera-infected patients in the fifth decade of the 19th century. After his resignation from the army, the formula was given to a pharmacist in London for the purpose of manufacture and marketing as a patented medicine named Chlorodyne. Chlorodyne was well-accepted as paregoric for several decades. The formula of Chlorodyne was adopted in the 3rd Revision of the British Pharmacopoeia (1885) as "Compound Tincture of Chloroform and Morphine." In 1906, the 3rd Revision of Japanese Pharmacopoeia listed "Compound Tincture and Morphine" according to the formula of the 4th Revision of British Pharmacopoeia (1898). References written in 1870 and 1873 recorded the importation of Chlorodyne to Japan. In 1871, Dr. Jyun Matsumoto, Chief Military Surgeon Major General advised the manufacturers of traditional medicines to produce patented medicines to spread in western countries. Preparations of formula seeming to resemble Chlorodyne was named "Shinyaku" and were marketed from 1872. The name Shinyaku represented a medicine of marvellous efficacy, because the word split, Shin and Yaku, means "divine or almighty" and "medicine," respectively. Although the orginal formula of Shinyaku was not preserved, modifications of the formula were made to meet legal restrictions over the change of time. Needless to say, Morphine hydrochloride, Diluted hydrocyanic acid and tincture of Indian hemp were replaced with other ingredients to assure safety and lately Chloroform deleted from the formula as well. Shinyaku enjoyed good sales for a long time owing to its efficacy of restorative and refrigerant. PMID- 11624350 TI - [Dispensing]. AB - A historical account is presented of the usage of the term "(tiaoji in Chinese or chozai in Japanese)" to denote the deed of dispensing a medicine. The author concludes that its usage should most probably be of Japanese origin though the word has been in use in China for a long time, however, for meanings unrelated to medicine. China may have imported this particular meaning from Japan in more recent times. PMID- 11624351 TI - The Genozo lion. PMID- 11624352 TI - Prescription books as historical sources. PMID- 11624353 TI - Lionel Lockyer (1600-72) & his Pillulae Radiis Solis Extractae. PMID- 11624354 TI - The Royal College of Physicians and Surgeons of Glasgow: a short history. PMID- 11624355 TI - Robert Louis Stevenson, Father Damien, and the lepers of Moloka'i. PMID- 11624356 TI - Robert the Bruce and leprosy. PMID- 11624357 TI - Biographies of eminent Scottish physicians: Professor Sir Ian Hill. PMID- 11624358 TI - Jan Strzembosz (1545-1606). His manuscript and collection of books. PMID- 11624359 TI - [Jean Rostand: the learned]. PMID- 11624360 TI - [The divergences and common points in the theory of vision in De aspectibus of Ibn-Haytham and Perspectiva by Witelo]. PMID- 11624361 TI - Spock on the examining table. [Review of: Grant, J. Raising baby by the book: the education of American mothers. Yale University Press, 1998; Maier, T. Dr. Spock: an American life. Harcourt Brace & Company, 1998]. PMID- 11624363 TI - Consuming smoke: cigarettes in American culture. [Review of: Tate, Cassandra. Cigarette Wars: the triumph of "The Little White Slaver." Oxford University Press, 1999]. PMID- 11624362 TI - Becoming Erikson. [Review of: Friedman LJ. Identity's architect: a biography of Erik H. Erikson. Scribner, 1999]. PMID- 11624364 TI - Paul Ehrlich and his Magic bullets--revisited. PMID- 11624365 TI - Stubbs, Steel, and Richard II as insane: the origin and evolution of an English historiographical myth. PMID- 11624366 TI - Salvador E. Luria (13 August 1912-6 February 1991). PMID- 11624367 TI - Locating rods and cones: microscopic investigations of the retina in mid nineteenth century Berlin and Wurzburg. AB - This paper is concerned with the diversity of microscopic research in nineteenth century life sciences. It examines how two researchers, Ernst Wilhelm Brucke and Heinrich Muller, investigated the structure and function of the retina. They did so in significantly different ways, thereby developing quite different accounts of this organ and its role in the process of vision. Both investigators were carrying out microscopic investigations, both were particularly concerned with interpreting their findings in terms of physiological function, and both employed the physical sciences in their microscopic research. Their approaches differed, however, with respect to the conceptual tools they applied to their findings. The cases indicate that the common tendency to associate microscopic research mainly with morphological studies of organic material is not appropriate. To understand nineteenth-century microscopy and its place in the sciences of life, close attention should be paid to the manner in which microscopic investigations were performed. It is only then that the flexibilty and versatility of microscopic research comes into view. PMID- 11624368 TI - The envisioning of cells. AB - Microscopical consideration played a crucial role in German physiology in the period of, grosso modo, 1780-1830. Specifically, a conception of material change was established, according to which all life is grounded in the process of the generation of microscopical forms out of an amorphous, primitive generative substance. Embryological development, tissue growth, and the generation of microorganisms were all considered to be the manifestation of this fundamental developmental process. In contrast to the common historiography, I try to understand Theodor Schwann's 1838 discovery of the cell theory in terms of the epistemological categories he applied to the prevailing conceptions of life and living matter. I argue that Schwann was able to discern cells not because of any superior microscopical methods, but rather as part of his wider investigative endeavor to explicate life processes according to specific causal agents. I argue that Schwann was able to demonstrate the existence of cells only when he considered animal tissues in terms of a causal relation between specific material agents and their effect, that is, the developmental history of tissue. PMID- 11624369 TI - Invisible enemies: bacteriology and the language of politics in imperial Germany. AB - The text analyzes the related semantics of bacteriology and politics in imperial Germany. The rapid success of bacteriology in the 1880s and 1890s was due not least to the fact that scientific concepts of bacteria as "the smallest but most dangerous enemies of mankind" (R. Koch) resonated with contemporary ideas about political enemies. Bacteriological hygiene was expected to provide answers to social and political problems. At the same time metaphors borrowed from bacteriological terminology were incorporated into the political language of the time. While the "high command of our doctors" (F.J. Cohn) fought diseases, some contemporaries were identified with members of the evil species of "bacillus communis odii." Both imperialistic politics and bacteriological science relied on images of inferior and invisible but potent enemies. Both were able to increase their prestige via a mutual interchange of their vocabularies. PMID- 11624370 TI - The medical philately of the Knights of St. Johns of Malta. PMID- 11624371 TI - Doctor John Rutty [1698-1775]: medicine and meteorology. PMID- 11624372 TI - Richard Woodhouse's Cause Book: the opium-eater, the magazine wars, and the London literary scene in 1821. PMID- 11624373 TI - [Not Available]. PMID- 11624375 TI - Religion and medicine: on the adaptation of Latin and vernacular medical texts to Hebrew readership. PMID- 11624374 TI - [Not Available]. PMID- 11624376 TI - [Not Available]. PMID- 11624377 TI - [Not Available]. PMID- 11624378 TI - [Not Available]. PMID- 11624379 TI - [Not Available]. PMID- 11624380 TI - [Not Available]. PMID- 11624381 TI - [Not Available]. PMID- 11624382 TI - [Not Available]. PMID- 11624383 TI - [Not Available]. PMID- 11624384 TI - [Not Available]. PMID- 11624385 TI - John Clarke (1760-1815): Licentiate in Midwifery of the Royal College of Physicians of London and Doctor of Medicine of the University of Frankfurt an der Older. PMID- 11624386 TI - [Not Available]. PMID- 11624387 TI - [Not Available]. PMID- 11624388 TI - [Not Available]. PMID- 11624389 TI - [Not Available]. PMID- 11624390 TI - [Not Available]. PMID- 11624391 TI - Herzog Christian der Jungere von Braunschweig-Wolfenbuttel (1599-1626). PMID- 11624392 TI - [Not Available]. PMID- 11624393 TI - [Not Available]. PMID- 11624394 TI - [Not Available]. PMID- 11624396 TI - The inferiority complex: the Koch-Gross theory. PMID- 11624395 TI - [Not Available]. PMID- 11624397 TI - [Not Available]. PMID- 11624398 TI - [Not Available]. PMID- 11624399 TI - [Not Available]. PMID- 11624400 TI - [Not Available]. PMID- 11624401 TI - [Not Available]. PMID- 11624402 TI - [Not Available]. PMID- 11624403 TI - [Not Available]. PMID- 11624404 TI - [Not Available]. PMID- 11624405 TI - [Not Available]. PMID- 11624406 TI - [Not Available]. PMID- 11624407 TI - [Not Available]. PMID- 11624408 TI - A history of conceptualization of diphtheria. PMID- 11624409 TI - [Ethnics of the body - a study on the ethical meanings of body in Spinoza and Yi Jae-Ma]. AB - Michel Foucault has brought some considerable changes in our way of seeing the human body. He argued that the body is not merely a natural object, but a medium of numerous social messages and even the most favorable habitat of power. According to him, the birth of social institutions, such as asylums, clinics, and jails, have been closely linked to the process of modernization and further that the very process through which the body becomes an object of social control has been an important part of our modernization. He proposed a new concept, viz., the social stigma carved on the body and provided us certain clues that makes us think newly of the boundary between nature and culture. Although his arguments opened a new perspective on our body, it did have a premise of so-called "the passivity of body" as its limitation. The body is not just a purely natural object, nor a purely social construction. It resides at both sides simultaneously and the disease, an incident happened within the body, reveals subtle relationship between these two. Those who see the body as an object of power as such or a medium of certain social messages tend to consider it only as an objective being, yet on the other side of this standpoint, the Cartesian dualism is hidden as a premise. Deleuze defined, in his book on Spinoza, the ethics of Spinoza as a practical study mainly dealing with the mode of existence. Provided that this definition is correct enough, we may term this practical study for the mode of existence of the body as the ethics of the body. Spinoza proposed a very unique view with regard to the body, which differs from that of the Cartesian Dualism. It is based on the entire system of his philosophy, viz., the system of the univocity of substance and the immanence of being which finally appears in the form of ethics. In the later half of this article, a very unique medicine whose starting point is none other than this kind of ethics, a practical study for the mode of existence, was dealt with. It is named Sasang(Four Symbol) medicine which was founded upon the long tradition of one of the most profound ethical teachings of mankind, Confuciaism. Sasang medicine of Yi Jae-ma is in a sense a continuation of the Neo-Confucianism tradition of Korea in the field of medicine. PMID- 11624410 TI - [The correlation of medicine and evolutionism - the evolutionism in Metchinikov's medical thought]. AB - The correlation of medicine and evolutionism was negligent in the history of science. This article analyzes the correlation of medicine and evolutionism in Metchinikov's medical thought. Metchinikov was concerned about the correlation of medicine and evolutionism. In the late nineteenth century when Metchinikov was engaged in his work, the evolutionism grew up with physico-chemical biology and ecology after The Origin of Species by Darwin. At that time, the evolutionism was pitted against the neo-darwinism and the neo-lamarckism. Metchinikov agreed with the neo-lamarckism because their biological methodology was non-discriminatory. The point of his problem was on the inflammation theory. Metchinikov accepted the theory of a struggle for existence by Darwin, but blamed the theory of a struggle in species. After all, he accepted the theory of a struggle in individual life by neo-lamarckism. PMID- 11624411 TI - [The life of Henry E. Sigerist - academic scholarship vs. social activism]. AB - The objective of this paper is to investigate chronologically the life of Sigerist as follows: (i) how Henry Sigerist (1891-1957) became interested in medical history, (ii) how he succeeded Karl Sudhoff (1853-1938) as professor of the history of medicine in the University of Leipzig, (iii) why he came to the Johns Hopkins in 1932, (iv) what he did for health care reform in the U.S. and Canada, (v) why he returned to his motherland in 1947, and (vi) how health professions have been globally influenced by his life. Based on the solid academic scholarship of medical history and sociology, Sigerest was energetically engaged in health care reform. What distinguished his social activism from other health care reformers is that wheras most health care reformers take the positivism-centered perspective to transform the existing health care system, Sigerist integrated historical vision with sociologically a pedagogic mission to pursue health care progress. PMID- 11624412 TI - [The early medical textbooks in Korea: medical textbooks published at Je Joong Won-Severance Hospital Medical School]. AB - Kwang Hye Won(Je Joong Won), the first western hospital in Korea, was founded in 1885. The first western Medical School in Korea was open in 1886 under the hospital management. Dr. O. R. Avison, who came to Korea in 1893, resumed the medical education there, which was interrupted for some time before his arrival in Korea. He inaugurated translating and publishing medical textbooks with the help of Kim Pil Soon who later became one of the first seven graduates in Severance Hospital Medical School. The first western medical textbook translated into Korean was Henry Gray's Anatomy. However, these twice-translated manuscripts were never to be published on account of being lost and burnt down. The existing early anatomy textbooks, the editions of 1906 and 1909, are not the translation of Gray's Anatomy, but that of Japanese anatomy textbook of Gonda. The remaining oldest medical textbook in Korean is Inorganic Materia Medica published in 1905. This book is unique among its kind that O. R. Avison is the only translator of the book and it contains the prefaces of O. R. Avison and Kim Pil Soon. The publication of medical textbook was animated by the participation of other medical students, such as Hong Suk Hoo and Hong Jong Eun. The list of medical textbooks published includes almost all the field of medicine. The medical textbooks in actual existence are as follows: Inorganic Materia Medica (1905), Inorganic Chemistry (1906), Anatomy I (1906), Physiology (1906), Diagnostics I (1906), Diagnostics II (1907), Obstetrics (1908), Organic Chemistry (1909), Anatomy (1909), and Surgery (1910). PMID- 11624413 TI - [Kim Pil Soon, a great doctor]. AB - Kim Pil Soon was born at Sorae Village of Hwang Hye Province, the birth place of the Protestantism in Korea. He was brought up under the strong influence of Christianity and received modern education at Pae Chae School according to the recommendation of Rev. Underwood. In 1899, Kim Pil Soon, who had been working at Je Joon Won as an assistant and interpreter of Dr. Sharrocks, was employed by Dr. Avison to help prepare medical textbooks and was asked to participate in the medical education. He acquired medical knowledge through his work of translating various medical texts, which enabled him to teach other medical students. He participated in the administration of the Hospital, taking charge of the provision of meals for in-patients as well as directing the construction of Severance Hospital buildings. His experience of treating soldiers wounded during the turmoil of the forced dismission of the Korean Army by the Japanese led him to reflect seriously on Korea's fate in peril. In addition, he became a member of Sinmin Society, a secret political association, to engage in the independence movement. In 1908, Kim Pil Soon graduated from Severance Hospital Medical School as one of the first seven graduates. On graduation, he was appointed as a professor and took the charge of school affairs in 1910. At first, he worked as an assistant physician of ward and surgery, then he took the responsibility of the outpatient clinic in 1911. But suddenly, in December 1911, he exiled to China to escape from the Japanese police who was in pursuit of him on account of his involvement in the so-called 105-Person Affair, a fabricated affair served as a pretext for the persecution of the independence movement. He continued the independence movement in the form of an ideal village movement and in the training of the Independence Army. In 1919, however, he was poisoned to death in a mysterious way. Kim Pil Soon dedicated himself to the independence movement that demanded personal sacrifice: giving up his prospective career as a doctor, professor, and hospital administrator. He no longer remained as an ordinary clinician who treats only diseased persons, but transformed himself to the Great Doctor, a time-old ideal type of doctor in the East Asian countries who treats and cures the diseased nation, by dedicating himself to the independence movement. PMID- 11624414 TI - Natural history and the Encyclopedie. AB - The general popularity of natural history in the eighteenth century is mirrored in the frequency and importance of the more than 4,500 articles on natural history in the Encyclopedie. The main contributors to natural history were Daubenton, Diderot, Jaucourt and d'Holbach, but some of the key animating principles derive from Buffon, who wrote nothing specifically for the Encyclopedie. Still, a number of articles reflect his thinking, especially his antipathy toward Linnaeus. There was in principle a natural tie between encyclopedism, with its emphasis on connected knowledge, and the task of natural historians who concentrated on the relationships among living forms. Both the encyclopedists and the natural historians aimed at a sweeping overview of knowledge, and we see that Diderot's discussions of the encyclopedia were apparently informed by his reading of natural history. Most of the articles on natural history drew from traditional sources, but there are differences in emphasis and choice of subject, depending upon the author. Diderot's 300 contributions are often practical, interesting, and depend upon accounts from other parts of the world. Jaucourt, who wrote more articles on natural history than anyone else, followed in his foodsteps. Daubenton's 900 articles reflected a more narrow, professional approach. His contributions concluded for the most part with Volume 8, and Jaucourt carried on almost single-handedly after that. While staking out traditional ground (description, taxonomy) and advancing newer theoretical views linked with Buffon, natural history in the Encyclopedie avoided almost completely the sentimentalism concerning nature that developed after Rousseau. PMID- 11624415 TI - Sex cells: gender and the language of bacterial genetics. AB - Between 1946 and 1960, a new phenomenon emerged in the field of bacteriology. "Bacterial sex," as it was called, revolutionized the study of genetics, largely by making available a whole new class of cheap, fast-growing, and easily manipulated organisms. But what was "bacterial sex?" How could single-celled organisms have "sex" or even be sexually differentiated? The technical language used in the scientific press - the public and inalienable face of 20th century science - to describe this apparently neuter organism was explicit" the cells "copulated," had "intimate contact," "conjugal unions," and engaged in "menage a trois" relationships. And yet, to describe bacteria as sexually reproducing organisms, the definition of sex itself had to change. Despite manifold contradictions and the availability of alternative language, the notion of sexually active (even promiscuous) single-celled organisms has persisted, even into contemporary textbooks on cell biology and genetics. In this paper I examine the ways in which bacteria were brought into the genetic fold, sexualized, and given gender; I also consider the issues underlying the durability of "bacterial sex." PMID- 11624417 TI - Essay review: recent introductory philosophy of biology texts. PMID- 11624416 TI - From bacteriology to biochemistry: Albert Jan Kluyver and Chester Werkman at Iowa State. AB - This essay explores connections between bacteriology and disciplinary evolution of biochemistry in this country during the 1930s. Many features of intermediary metabolism, a central component of biochemistry, originated as attempts to answer fundamental bacteriological questions. Thus, many bacteriologists altered their research programs to answer these questions. In doing so they changed their disciplinary focus from bacteriology to biochemistry. Chester Hamlin Werkman's (1893-1962) Iowa State career illustrates the research perspective that many bacteriologists adopted. As a junior faculty member in the Bacteriology Department in the late 1920s, Werkman faced a powerful professional dilemma: establishing a research identity that distinguished him from his colleagues with flourishing national and international reputations. His solution was to radically alter his research program from traditional bacteriology to a biochemistry program, which reflected the influence of the Dutch microbiologist/biochemist, Albert Jan Kluyver (1888-1956). Werkman was extremely successful in this career change. His laboratory made significant contributions to biochemistry, and Werkman achieved a notable degree of personal success. His career began in the shadow of his departmental bacteriological colleagues; within a decade he became the department's dominant research figure, as a biochemist. Werkman's personal success, however, had profound consequences for the disciplinary future of bacteriology at Iowa State. PMID- 11624418 TI - Diffusion theory in biology: a relic of mechanistic materialism. AB - Diffusion theory explains in physical terms how materials move through a medium, e.g. water or a biological fluid. There are strong and widely acknowledged grounds for doubting the applicability of this theory in biology, although it continues to be accepted almost uncritically and taught as a basis of both biology and medicine. Our principal aim is to explore how this situation arose and has been allowed to continue seemingly unchallenged for more than 150 years. The main shortcomings of diffusion theory will be briefly reviewed to show that the entrenchment of this theory in the corpus of biological knowledge needs to be explained, especially as there are equally valid historical grounds for presuming that bulk fluid movement powered by the energy of cell metabolism plays a prominent note in the transport of molecules in the living body. First, the theory's evolution, notably from its origins in connection with the mechanistic materialist philosophy of mid nineteenth century physiology, is discussed. Following this, the entrenchment of the theory in twentieth century biology is analyzed in relation to three situations: the mechanism of oxygen transport between air and mammalian tissues; the structure and function of cell membranes; and the nature of the intermediary metalbolism, with its implicit presumptions about the intracellular organization and the movement of molecules within it. In our final section, we consider several historically based alternatives to diffusion theory, all of which have their precursors in nineteenth and twentieth century philosophy of science. PMID- 11624419 TI - An unmanly vice: self-pollution, anxiety, and the body in the eighteenth century. AB - The campaign against masturbation offers one of the outstanding success stories in the history of medical popularization. This paper seeks to identify the reasons for this success, focusing on the campaign's early stages, from the late seventeenth century onwards. It first identifies a series of often quite explicit political, ideological, and economic motives such as religious notions of 'uncleaniness', bourgeois concerns about self-control, marriage, and population growth, and the financial interests of the London veneral trade. Drawing, in particular, on the 'confessions of self-declared victims of masturbation in eighteenth-century patient letters, it then shows that the physical and mental symptoms attributed to masturbation very successfully addressed some of the deepest anxieties in contemporary society, anxieties about virility, gender identity, and physical selfhood. Finally, applying Bourdieu's notion of 'habitus', the central role of a new, implicitly male, more solid, closed and self-contained dominant body image is underlined. Framing the interpretation and the very experience of the body among the proponents and the recipients of anti onanist discourse alike, it helped to make the dangers of masturbation an almost irrefutable, objective truth. PMID- 11624420 TI - Academic general practice in Manchester under the early National Health Service: a failed experiment in social medicine. AB - During the Second World War, medical academics hoped to reform medical practice and education in Great Britain, increasing doctors' sensitivity to the social and environmental causes of ill health and orientating them towards prevention. At the start of the National Health Service (NHS), central planning aimed to raise the status of isolated urban general practitioners (GPs) by grouping them in an experimental health centre. This offered a locus for social medicine, encouraging cooperation and research with local authority staff (nurses, midwives, and social workers). The Manchester case study confirms that health centre working could not be disseminated while conditions for teamwork were absent elsewhere. The failure of academic planning can be attributed to a top-down approach upon demoralized urban practice. While the participants did not form an autonomous group, economic incentives drove the growth of group practice elsewhere and made health centres superfluous to government. The College of General Practitioners developed in parallel, offering an alternative path towards an academic discipline. The case study also suggests a relationship between the emergence of groups and a psychological orientation in practice. A patient-centred model became important within teaching and gave identity to the displine, but it probably had little impact on everyday practice. PMID- 11624421 TI - The history of health and medicine in contemporary Britain: reflections on the role of audio-visual sources. AB - Recent policy discussions about extending the system of legal deposit to material published in formats other than print, for example film, video, and television, offer an opportunity to reflect on the role of audio-visual sources in the contemporary history of health and medicine. In the course of the twentieth century, audio-visual media have become the means of communicating ideas and information about health and medicine to a mass audience. However, health and medical historians rarely draw upon film, television, or video as historical source material. This paper encourages a greater role for these sources by outlining different ways of approaching audio-visual material as historical source, and introducing a selection of research tools and tips for accessing our audio-visual heritage. PMID- 11624422 TI - And the answer is ... 42. PMID- 11624423 TI - Review article. [Review of: Andrews, J; Briggs, A; Porter, R, etc. The History of Bethlem. Routledge, 1997]. PMID- 11624424 TI - 'To be insert in the Mercury': medical practitioners and the press in eighteenth century Edinburgh. AB - The eighteenth century was a period of development and change in Scottish society, its structures, and institutions. In Edinburgh the Royal College of Physicians, the Incorporation of Surgeons (Royal College from 1778), and the University attempted to improve medical and surgical training, and in the second half of the century the Scottish Enlightenment found its intellectual home in the capital. At the same time, the newspaper press was consolidating and Scots had access to a number of newspapers which appeared regularly, such as the Caledomian Mercury and Edinburgh Advistiser. The press became a major vehicle for the dissemination of information and opinion of all sorts, and examination of surviving newspapers had yielded a substantial amount of evidence on the use of the press by medical practitioners and their organizations. The medical contents of the newspapers demonstrate the progress of the institutions, the activities of individual practitioners, the changing nature of lay practice, and some of the tensions which existed in Edinburgh medicine and society in the hotbed of the Enlightenment period. PMID- 11624425 TI - 'They might as well brand us': working-class resistance to compulsory vaccination in Victorian England. AB - From its origins in resistance to the 1853 Compulsory Vaccination Act, the Victorian anti-vaccination movement successfully challenged the public health policies of an increasingly interventionist state. Anti-vaccinationists were not only middle-class reformers, but were also drawn from a politically active working class. These campaigners saw compulsory vaccination as an extreme example of class legislation, for its policy and administration implicitly targeted working-class infants and inflicted multiple penalties on a public who considered themselves 'conscientious objectors'. Anti-vaccinationism was quickly absorbed into English working-class culture. Indeed, it helped to reorganize working-class identities around the site of the vulnerable body thereby absorbing many people into a working class who interpreted the violation of their bodies as a form of political tyranny. Participation in this movement was, however, also an exclusive exercise for anti-vaccinators, as respectable working-class citizens distinguished themselves from members of the 'undeserving' classes. This paper explores the class nature of the Vaccination Acts, their relationship to the New Poor Law, and the political implications of their administration. It also imbeds anti-vaccinationism firmly within working-class culture, illustrating the campaign's relationship to popular protest and entertainment, and this legislation's impact upon working-class bodies. PMID- 11624426 TI - Profit is a dirty word: the development of the public baths and wash-houses in Britain 1847-1915. AB - Researh on sanitary reform in nineteenth-century Britain has focused mainly on the introduction of large-sanitary infrastructure, especially waterworks and sewage systems. Other sanitary measures such as the provision of public baths and wash-houses have been ignored, or discussed in the limited context of working class responses to middle-class sanitarianism. Yet by 1915 public baths and wash houses were to be found in nearly every British town and city. A detailed analysis of these 'enterprises' can provide a useful way of understanding the changing priorities of public health professionals and urban authorities as well as the changing attitudes of the working classes. Connections between personal cleanliness and disease evolved during the century, particularly after the formation of germ theory in the 1880s. This paper demonstrates how the introduction of public baths and wash-houses in Liverpool, Belfast, and Glasgow was initially a direct response to sanitary reform campaigns. It also shows that the explicit public health ideology of these developments was constantly compromised by implicit concerns about municipal finance and the potential profit that such enterprises could generate. This city-based analysis shows that this conflict hindered the full sanitary benefit which these schemes potentially offered. PMID- 11624427 TI - The Ceylon malaria epidemic of 1934-35: a case study in colonial medicine. AB - In 1934-35 Ceylon suffered a major malaria epidemic which affected one and a half million people out of a population of five and a half million. This paper will first examine the orgins and course of the epidemic but the main focus is on the measures the authorities adopted to deal with the disaster. In 1931 Ceylon had attained 'home rule' under the Donoughmore Constitution. The epidemic was a first and major test of the efficacy of the new government. Examining the responses of the imperial government, the colonial government and the colonial medical services to this medical emergency establishes that the epidemic was a turning point in the health services of Ceylon and thus Sri Lanka, that the legacy of colonial medicine is essentially mixed and that the complexity and contradictory nature of colonial medicine can only be understood by detailed contextual research. PMID- 11624428 TI - Mateu Orfila's Elemens de chimie medicale and the debate about the medical applications of chemistry in early nineteenth-century France. PMID- 11624429 TI - Rychard Bostok of Tandridge, Surrey (C. 1530-1605), M.P., Paracelsian propagandist and friend of John Dee. PMID- 11624430 TI - Pioneers in animal reproduction - VI. M.C. Chang (1908-1991). PMID- 11624431 TI - Arnold Theiler, founder of Onderstepoort. PMID- 11624432 TI - Rabies in Madeira Island in 1892 - historical notes. PMID- 11624434 TI - [Not Available]. PMID- 11624433 TI - [Not Available]. PMID- 11624435 TI - [Not Available]. PMID- 11624436 TI - [Not Available]. PMID- 11624437 TI - [The historic passage of the "marechal-expert" to the "hippiatre" to the veterinarian. The influences of infectious diseases]. PMID- 11624438 TI - The Boer War - a veterinary perspective. PMID- 11624439 TI - [Making order out of disorder: the epizootic of 1814]. PMID- 11624440 TI - [The contribution of Gilbert Breschet to the study of rabies and glanders]. PMID- 11624441 TI - [Some letters sent from Belgium to Professor Bernhard Bang in Copenhagen]. PMID- 11624442 TI - Professor Dr. Ljudevit Jurak (1881-1945). AB - Many physicians have given their lives performing their duties at work; many have fallen victims to laboratory accidents or have contracted the disease they were studying. Great numbers of them have also died in civil or military hospitals during the bombardment, or in the field. We shall keep in our memory not only them but also those who were killed in prisons only because they had not conformed to the regime they lived under. Some have been lucky enough to escape and live today some place far away from home. As scientists they have contributed greatly to their new home countries far from the inconvenient conditions they used to live in before. PMID- 11624443 TI - Robert von Ostertag (1864-1940). A veterinarian contemporary with R. Virchow and R. Koch. PMID- 11624444 TI - Epigenesis of the monstrous form and preformistic 'genetics' (Lemery - Winslow - Haller). AB - The present essay analyzes an eighteenth-century phase of the querelle des monstres and highlights two main points. 1) As the cases of Lemery and Winslow demonstrate, in the period when preformation was the dominant view, the dispute over the origin of monsters carried into the very field of preformation the contrast which had originally opposed it to the now defeated model of epigenesis, namely the alternative between mechanical genesis and pre-existence of the monstrous form itself. 2) One of the most important episodes in the shift of teratology from a primarily theological or metaphysical issue to a purely natural one was due to Albrecht von Haller. Haller shifted the dispute from anatomy to embryology, and it is on an embryological base and not on metaphysics that he built his own demonstration of the original nature of the monster. He was furthermore the only scientist of authority who dealt with teratology from an epigenetic standpoint. His numerous changes of view in the field of embryology did in fact never affect his early adherence to the thesis of original monstrosity. PMID- 11624445 TI - The vernacularization of science, medicine, and technology in late medieval Europe: broadening our perspectives. AB - The "vernacularization" of medieval texts dealing with scientific subjects was a more complicated process than earlier views would suggest. While popularizations were certainly important, some vernacular texts were written for specialists (especially in medicine). Certain texts describing practical knowledge had no Latin original to draw from or relied on models from Antiquity quite unrelated to contemporary practice. Their study is further complicated by the state of research, which in some cases is relatively good (e.g. treatises on hunting) but in others doesn't even allow for a preliminary overview (e.g. surgeries). Other complicating factors are distribution (the limited circulation, e.g., of 'encyclopedias" against the presence of the ps.-Aristotelian Secreta Secretorum in all languages) and the availabilty of inventories, Middle Dutch and Middle English texts being the best documented. The essay concludes on some speculations about the similarity between contemporary English and Medieval Latin as scientific languages, and possible future developments. PMID- 11624446 TI - Caught in the electronic revolution. Observations and analyses by some historians of science, medicine, technology, and philosophy. PMID- 11624448 TI - Psychoanalysis, dreams, history: an interview with Hanna Segal. PMID- 11624449 TI - Hogarth's mad King and his audiences. PMID- 11624450 TI - A. McGehee Harvey: 30 July 1911 - 8 May 1998. PMID- 11624451 TI - Konrad Z. Lorenz (7 November 1903-27 February 1989). PMID- 11624452 TI - Roger Wolcott Sperry (20 August 1913-17 April 1994). PMID- 11624453 TI - Effects of societal intergration, period, region, and culture of suicide on male age-specific suicide rates: 20 developed countries, 1955-1989. AB - Multiple indicators of societal integration and proxies for the culture of suicide form the model used to explain variation in male age-specific suicide rates from 1955 to 1989 in 20 developed countries. The hypothesis that certain determinants of suicide rates have changed over the period between 1955 and 1989 was rejected, as was the hypothesis that there are effects of period, net of measured predictors. The determinants of suicide rates do vary by age, with the culture of suicide playing an especially important role in the 35-64 age group. PMID- 11624454 TI - The contraceptive revolution in Israel: changing family planning practices among ethnoimmigrant groups. AB - This paper uses data from the 1974-1975 Israel Fertility Survey and the 1987-1988 Study of Fertility and Family Formation to examine trends in fertility control among ethnoimmigrant groups in Israel. From 1974 to 1988, Israel underwent extremely rapid economic growth and there occurred what might be considered a contraceptive revolution in the realm of family planning. Specifically, the nonuse of family planning and reliance on less effective techniques of fertility control (withdrawal and abortion) were largely replaced by more efficient modes (e.g., pill, IUD) of family size limitation. In addition, ethnic differences in patterns of fertility control diminished. Meanwhile, socioeconomic and cultural variables such as religiosity and income maintained their importance as determinants of variation of family planning practices among Israeli women. PMID- 11624455 TI - [Gito Teruoka (1889-1966) and medical history]. PMID- 11624456 TI - [The historical materials about the medical system of the Edo Shogunate (9)-2]. PMID- 11624457 TI - War and medicine--Baron Dominique Jean Larrey (1766-1842). PMID- 11624458 TI - Pursued by Genetics Part 2 (abridged). PMID- 11624459 TI - Selections from the diaries of Dr. J.B.S. Greathead MB MC (Edin.) MRCS (Eng.). PMID- 11624460 TI - [The history of Korean traditional medicine]. AB - Records of ethnic medicine in the Kokuryo, Baekjae and Shilla dynasties can be found in foreign literature, and evidence that a medicine unique to Korean was being developed in the Koryo dynasty can be found in Korean historical records. With the founding of Chosun, Hyang-yak medicine was established, and a medicine purely and uniquely Korean took root. The Chosun dynasty saw the development of a new form of medicine called Dong-Ui medicine, and an independent system emphasizing practicality was established as the new tradition of Korean medicine. Korean medicine continued in the Chosun dynasty without significant changes from the Koryo dynasty. However, tides of enlightenment brought Western medicine onto the shores of the Korean peninsula. Western medicine began to gain the recognition and trust of part of the royal court. Nonetheless, ordinary people still preferred Dong-Ui, Korean medicine, and they did not have a full understanding of Western medicine. As Chosun began to adopt enlightenment policies in the footsteps of Japan through the Kabo (1894) Revolution, Japan drove the Ching rulers out of the Korean peninsula and openly started interfering in Chosun's internal affairs. After repelling Russia, Japan's intervention in the Korean peninsula became even more aggressive, taking over Chosun's politics, diplomacy and military. Its encroachment on Chosun's sovereignty was at times even more cruel than during Japan's Meiji period. PMID- 11624461 TI - [People's way to fight the epidemic diseases in the early Choson period]. AB - Epidemic diseases in the early Choson period were big problems to the people and society. However, the weapons to the epidemic diseases were very limited at that time. There were few drugs and well-trained practitioners for people. Most people could only depend on religious means and simple folklore medicine including inhalation of specific flavor. People tried to overcome or prevent the epidemics by praying, sorcery, ornaments, runaway and isolation. In most cases, the epidemic diseases came with or broke out from the famine, severe labour (especially in civil engineering) imposed by the ruling class. The epidemics of that time are thought to be typhoid fever, epidemic typhus, or similar febrile diseases. PMID- 11624462 TI - [Medical education in Je Joon Won]. AB - Medical education in Je Joong Won was proposed and initiated by Dr. HN Allen. In his proposal of building a new hospital, submitted to the king in 1885, he expressed his wish to teach Western medicine to young Koreans at the hospital. The king welcomed his proposal and the plan was soon realized. Je Joon Won, the first modern hospital in Korea, opened on April 10th, 1885. The following year, on March 29th, Dr. Allen began medical school attached to the hospital. Many applicants were recruited by the government and 16 students were selected through the entrance examination. At first, they were taught English and finally 12 students out of them were selected after three months of teaching. The selected students were taught arithmetic, physics, chemistry, anatomy and physiology. The medical education at this period cannot be evaluated entirely successful since none of the 12 students was presumed to have worked as a practitioner. PMID- 11624463 TI - [An overview on reality of Dong-In Uywon(Hospital) and effects on culture of medicine]. AB - From a review on the reality of Dong-In Hospital which was a hospital founded by Dong-Aa Dong-In-Hywe Foundation which was a corporation of governmental patron around Ulsa(1905) protective treaty between Japan and Korea, and this hospital seemed to be dissoluted just before the annexation signing of Korea to Japan. The building with site of Dong-In Hospital in Taegu was sold to Kyung-Sang Pook-Do province and Jaa-Hye Hospital was constructed instead as a virtual conscience. So it is impossible to say this Jaa-Hye Hospital as the predecessor of Dong-In Hospital although Jaa-Hye Hospital which was belonging to Kyung-Sang Pook-Do province as Kyung-Sang Pook-Do Hospital had changed the name several times until being Taegu Medical School Hospital by using as Taegu Medical Institute College Hospital which was absorbed to U.S. military government after the restoration of independence from Japan. Since 1953 Kyungpook National University absorbed Taegu Medical School, it is possible to use Taegu Medical School Hospital as the predecessor of Kyungpook National University Hospital whereas it is impossible to use Jaa-Hye Hospital as the predecessor with nationality on the basis of the health and medical administrative system. PMID- 11624464 TI - [Japanese ethnology and Chosen people during Japanese annexation period]. PMID- 11624466 TI - [Periodic health examination in its historical perspectives]. AB - The origin of the periodic health examination can be traced to Horace Dobell, a British physician. The periodic health examination became popular in the early 20th century with many advocates such as the life insurance companies, private corporate industry, medical professionals, and the prepaid health care in North America. The contents and legitimacy of periodic health examination has changed markedly over time according to the objectives. There were various objectives of the periodic health examination according to the advocates: reduction of morbidity and mortality, scientific knowledge, economic savings, professional empowerment, the patient-physician relationship, satisfaction of patient demand, and efficient administration. Recent remarkable changes led by Canadian Task Force and U.S. Preventive Services Task Force were the emphasis of reduction of disease-specific morbidity and mortality, risk adjusted application, and the inclusion of counseling, immunization, and chemoprophylaxis. Health screening has become a promising medical practice in Korea. The main environment of the periodic health examination in Korea is fee-for-service system, the national medical insurance system, and Korean cultural background. However, the consensus of Korean government and society for controlling medical cost will limit the irrational prosperity of periodic health examination in near future. PMID- 11624465 TI - Great debate on environmental lead poisoning in the U.S.A.: a historical analysis. PMID- 11624467 TI - First known lenses originating in Egypt about 4600 years ago! AB - The first lenses (ca. Vth Dynasties of the Old Kingdom of Egypt. These lenses are found in The Louvre Museum in Paris and the Egyptian Museum in Cairo. They were components of extraordinary eye constructs in statues which had unique qualities. Namely, the "eyes" appear to follow the viewer as he/she rotates about these statues in any direction. This effect can be photographed and reproduced 2620 2400 B.C., 4620-4400 Before Present=B.P.) appeared mainly during the IVth and optically. This effect has been modeled here. The lenses were ground from high quality (!) rock crystal (a form of quartz, n approximately 1.46). Each had a convex and highly polished front "corneal" surface. Thus, in a sense, these were multifocal lenses. The iris aperture may or may not have been open to a substantial posterior "vitreous" cavity formed largely by curved copper plates which extended forward to create the lid structures of these eyes. Were these a form of schematic eyes? Could such fine quality and complex (sophisticated) lenses be the first lenses? Clearly, the observer was intended to look at these eyes and follow their apparent movements. The total structure of these eyes indicated an advanced understanding of ocular anatomy and a surprising knowledge of optics. There are many questions. PMID- 11624468 TI - Psychology in the human sciences in France, 1920-1940: Ignace Meyerson's historical psychology. AB - Between World War I and World War II, psychology adopted a direction open to human sciences; I. Meyerson was the main organizer of this choice. Leading the Societe de Psychologie and the Journal de Psychologie Normale et Pathologique, he tried to construct an individual and collective psychology that reflected not only the scientific preoccupations of his masters and friends but also their political choices: They had been the founders of the Human Rights League at the end of the 19th century. Behind Durkheim and Seignobos, with Mauss, Levy-Bruhl, and Blondel, Meyerson answered the new historians' call for a unified science of "mentalities," a historical psychology of collective representations. Meyerson offered to sociologists, anthropologists, linguists, and historians several forums to debate in which psychology was the unifying science. But at the end of the World War II, his psychology was marginalized, and a postivistic and behavioristic way was preferred. Meyerson's historical psychology disappeared from academic psychology, but historians have preserved its legacy. PMID- 11624469 TI - Francis Cecil Sumner: his views and influence on African American higher education. AB - During the mid-1920s, Francis Cecil Sumner, the first African American to earn a PhD in psychology, published 2 articles concerning strategies for the higher education of African American youths. These articles called for a system of segregated education emphasizing an "industrial" style advocated by Booker T. Washington, as well as suggesting a measure of character development. The justification cited by Sumner for such unequal education for African Americans was the cultural inferiority of that population. The present article argues that Sumner's views were couched in terms that fit the prevailing paradigm of the White establishment, with the purpose of generating political and economic support for any type of higher education for African Americans. Evidence drawn from Sumner's early education and his graduate school days at Clark University, as well as testimonials from colleagues and students, are provided in support of this hypothesis. PMID- 11624470 TI - Recontextualizing Kenneth B. Clark: an Afrocentric perspective on the paradoxical legacy of a model psychologist-activist. AB - Kenneth B. Clark, whose scientific and political legacy has been the subject of controversy over the years, presented as an important model of Afrocentric scientific praxis. Key characteristics of the Afrocentric scholar are outlined. Using Clark's academic and nonacademic writings as evidence, it is argued that Clark, though complex, exemplifies these characteristics. Clark's profound yet at times obscure vision of integration and his views on the role of empathy and respect in education are presented in detail. Clark's life and work are than reexamined and recast through the lens of W.E. Cross's (1971,1991) nigrescence model and the political-historical lens of the 2-phase Black social movement. It is concluded that academicians interested in promoting diversity, particularly within the social sciences, as well as psychologists looking for models of activist praxis, examine and learn from the life and work of Clark. PMID- 11624471 TI - Triarchic theories of intelligence: Aristotle and Sternberg. AB - Aristotle's triarchic theory of intelligence prefigures, but apparently does not serve directly as a source for, Sternberg's comparable contemporary theory. The indepently derived similarities in their gross structure lend weight to some triarchic view. Sternberg's analytical, practical, and creative intelligences closely resemble Aristotle's theoretical, practical, and productive excellences of intelligence. Each comparable component incorporates significantly related ideas. Disparities may be attributed to a variety of differences in the aims, methods, and resources of Aristotle's and Sternberg's inquiries. This is not the first time in the history of psychology that roughly parallel investigations have yielded comparable theories, but it is surely among the most temporally disjoined. PMID- 11624472 TI - Cross-disciplinary verification of theories: the case of the triarchic theory. AB - There are at least 4 good reasons to study the history of psychology. First, we can give credit to those who deserve it. Second, historical views can provide converging operations that help demonstrate the validity of our own views (or rather, operations that invalidate our views). Third, we learn that other natural and social sciences can inform our views. Fourth, we learn that philosophical and psychological analyses often converge. I show how historical views can inform current thinking about intelligence. PMID- 11624473 TI - Salvaging the self in a world without soul: William James's The Principles of psychology. AB - This article explores William James's transformation of the religious soul into the secular self in The Principles of Psychology. Although James's views on the self are familiar to many historians of psychology, the article places his treatment of the self within the broader social and cultural context of a secularizing, industrializing society. There were palpable tensions and anxieties that accompanied the cultural shift, and these are particularly transparent in James's Principles. James attempted the project of secularizing the soul in order to promote a natural science of the mind but with marked ambivalence for the project, because it left out some of the moral and metaphysical questions of great interest to him. PMID- 11624474 TI - [A study on the producing locations of medicines included in Shennong's Classic of Meteria Medica]. AB - By analysing the regional charactertics of distribution of producing locations of medicines included in Shennong's Classic of Meteria Medica, it is pointed out that, based on quantity of production, Yizhou of the 13 bu - administrative regions and Taishan Prefecture are the locations for massive production of medicines in the Han dynasty. Judging from distribution of locations, Luoyang, the Eastern Capital and Chang'an the Western Capital are the two centers, with the former more productive than the latter. It is suggested that the Hongnong Prefecture, the mid point between Luoyang and Chang'an, was an important crude drug trading center in the Eastern Han dynasty. The records of producing locations in Shennong's Classic of Meteria Medica reflects the importance it attaches to the genuine producing sites and demonstrates the changes of genecine locations of drug production since the Qin - Han periods. PMID- 11624475 TI - [Explanation for "Jin Shuo Yin Kai" in Ben cao gang mu shi yi (Supplements to compendium of materia medica)]. AB - The entry of "Jin Shuo Yin Kai" included in volume 7 of Ben Cao Gang Mu Shi Yi refers to Adiantum flabellulatum L. Fagopyrum cymesum Meisn, and polygenum penfoliatum L. respectively. PMID- 11624476 TI - [Inheritance of Qin - Han medicine by Shang Han Za Bing Lun and its development]. AB - Generally recognized to be completed at the end of the Eastern Han dynasty. Shang Han Za Bing Lun is clearly seen to inherit and develop the medicine of Qin - Han period in the aspects of preventive conception.differentiation of 6 - Channel diagnosis, decoction - prescription based on differential diagnosis and miscellaneous internal diseases. The conclusion is based on an overall and profound analysis on authentic writing materials, thus provides a useful enlightenment to contemporary study on TCM. PMID- 11624477 TI - [Effective case records of Luo Tianyi in the army as recorded in Wei Sheng Bao Jian (hygienic precious minor)]. AB - During his life in the army in 1252 - 1261, Luo Tianyi wrote down case records taken from his patients, including soldiers, military officials and their relatives. In addition to infectious diseases such as malaria, dysentery, vomiting and diarrhea and seasonal epidemics, he also treated psychosis, digestive disorders, cold damage, beriberi, coughing and cold in the legs and external diseases such as eye diseases, boils and carbuncles, hernia. The therapeutics he applied included recipes, pills, powders, pastes as well as acu - moxibustion. PMID- 11624478 TI - [Discussion on the contribution of Thousand golden prescriptions to the art of tuina]. AB - Thousand Golden Prescriptions, including Thousand Golden Prescriptions for Emergencies and Supplements to Thousand Golden Prescriptions is an important medical book containing the main medical achievements before the Tang dynasty. It attaches great attention to daily tuina for health-care, enriches its contents, and makes a description to the method of tuina for children, offering detailed materials for later ages with significant reference value, and makes an important contribution to the art of tuina. PMID- 11624479 TI - [A study on evolution of the term impotence and its classification and diagnosis]. AB - Called "bu qi" (unable to erect) in the pre-Qin period, it was called "yin wei" (yin flabbiness) during Qin-Han to Jin-yuan dynasties, and called "yang wei" (yang flabbiness) since the Ming dynasty, though a few books called it Yin flabbiness, but both Yang- and Yin- flabbiness didn't appear simultaneously in the same work. It was categorized under seven-injuries, kidney disorders, consumptive diseases, five non-masculine and sexual diseases before the Tang dynasty, and categorized under miscellaneous diseases since Jin dynasty. It was typed into bu ju (non erected), bu jian (non hardened) and bu jiu (non persistent). Some classified on the basis of etiology. It was pointed out that this disorder refers to inability to errect though the patient has a desire to erect, instead of unwilling to erect. The changes of the idea reflect the different levels of recognition in different historical periods. PMID- 11624480 TI - [Recognition of tumors in Tibetan medicine]. AB - In Gyud - bzhi written in the 8th century, there are materials on tumors. As the experience enriched, the recognition on tumors became mature and formed its unique theory, with effective treating principle, summary, which opened a new approach to the treatment of tumors. PMID- 11624481 TI - [Comparison between the developmental history of Chinese medicine and foreign medicine]. AB - Long-term coexistence, and side-by-side development and two medical system in one country, is the realistic and long-term situation in our country. In the development history of these two medical systems, there are close relation between traditional Chinese medicine(TCM) and the development of philosophical thinking, and between western medicine and the development of natural science. TCM pays attention to the development of clinical medicine, and don't have independent basic medicine which are subordinate to clinical medicine, such as anatomy, nor experimental medicine, such as animal experiments. TCM being the accumulation and summary of clinical experience. However, western medicine develops animal experiments and basic displines from early period, and develops clinical medicine with the aid of natural science. The refractory diseases always exist in human society, so TCM can display its abilities forever. PMID- 11624482 TI - [History of surgical treatment for emphysema]. AB - Great efforts have been paid to the effective surgical managements of diffused emphysema in the past century, which can be grossly divided into three stages, namely, the early exploration, lung transplantation and lung volume reduction surgery. Lung transplantation, developed in the 80's, and especially lung volume reduction surgery, which was developed in the 90's, was recognized as the most effective therapy for terminal stage of emphysema, which offers a new approach for the victims of emphysema. PMID- 11624483 TI - [Investigation on the evolution of the titles of zhen zhu (cinnabar) and zhen zhu (pearl) and its confusion, ancient and modern]. AB - There used to be confusion since ancient time on both zhen zhus. They are two different materials, different from their original materials, nomenclature and dates of their medicinal application. Based on ancient formularies, the two "zhen zhu" were confusedly used to a great extent. The causes of such confusion lie on their exactly identical Chinese pronunciation and the evolution of the Chinese writing characters; both also share some similar functions; and the confusion as recorded by herbological works of successive ages. There are also such confusion in modern books of pharmacy. Points for differentiation of both and conclusion are given here. PMID- 11624484 TI - [Production of medicinal fish-liver oil in the Fukuoka Clan at the end of the Edo period, and its utilization]. PMID- 11624485 TI - In search of the historical record. PMID- 11624486 TI - Pharmacists and immunization: increasing involvement over a century. PMID- 11624487 TI - Trouble in paradise: a brief review of therapeutic contention in America, 1790 1864. PMID- 11624488 TI - The story of electromagnetism in X ray. PMID- 11624489 TI - The doctor's own rose. PMID- 11624491 TI - Betancourt Davalos, Pedro E. PMID- 11624490 TI - Ian Clunies Ross: veterinary parasitologist, and more. PMID- 11624492 TI - Spinoza in Denmark and the fall of Struensee, 1770-1772. PMID- 11624493 TI - Contesting metaphors and the discourse of consciousness in William James. PMID- 11624494 TI - Women in mental health nursing: angels or custodians? AB - Like other 'Cinderella' services mental health nursing has received much less attention from historians than general nursing. However a study of its history can illuminate such issues as the division of labour, gender, images of nursing, professionalisation and unionisation. Drawing on primary historical sources, including hospital archives and contemporaneous reports and journals, the author considers the role of women in mental health nursing, from its origins to the onset of the NHS in 1948. The development of mental health nursing differed substantially from general nursing. It could be argued that the tensions between the two were never more apparent than in the debate surrounding the registration of nursing in the early twentieth century. Female mental health nurses fighting with police in the Radcliff Strike in 1922 portrays a much less famous image in nursing's history than Florence Nightingale with her lamp. The dichotomy between the custodial nature of the Victorian asylum system and the caring ethos espoused by the advocates of 'moral management' created many tensions. Images of nurses as angels, responding to a calling or vocation, sat uneasily with the large numbers of men working in the asylums and the growth of trade unionism in this period, particularly after the foundation of the National Asylum Workers Union in 1910. The periods of industrial unrest in the mental hospitals of the inter-war years saw women members playing an important role; this has important ramifications for mental health nursing today. PMID- 11624495 TI - Nurse education at the London Homeopathic Hospital 1903-1947: preparation for professional specialists or marginalised Cinderellas? AB - This paper provides a summarised account of research in progress on Nurses' Registers from the London Homoeopathic Hospital, 1903-1947. The particular question addressed in this paper relates to nurses role in homoeopathy at the hospital during the above period, as it emerges from the registers. Comparison with nursing at the hospital in the 1990s is provided by reference to a research report by Clara Harris, who conducted research on contemporary nurses' role at the hospital. The role of nurses is seen in the context of the uneasy relationship between homoeopathic and orthodox doctors. Research on the Nurses' Registers forms part of a larger project concerning the history of the London Homoeopathic Hospital from 1889 till 1947. The first phase of the research, conducted jointly by Bernard Leary (a homoeopathic doctor) and Anna Bosanquet (a social scientist) and author (1993-95), and funded by the Wellcome Trust, related to analysis of 300 volumes of clinical patient notes (approximately 60,000 individual records) from the period 1889-1923, which were found in the hospital basement by the domestic services manager in 1992. Phase 2 of this research project is being undertaken by the author without funding and was commenced in 1996. Nurses' Registers from the period 1903-1947 were analysed in detail, recording a wide range of information about student nurses at the hospital during this period. Data from the 1903-1947 registers will be compared with information collected by Clara Harris in a project funded by the old North East Thames Regional Health Authority in 1922. The role of nurses in the nineteenth century and at the present time will be seen in the context of medical homoeopathic practice, and the relevant research by Nicholls is referred to briefly. It is important to stress that the discussion relates to homoeopathic nursing, not to nurses who have left their nursing posts to become 'lay' homoeopaths (the title used by homoeopathic doctors for all non-medical homoeopathic practitioners). PMID- 11624497 TI - Ghost of the past: capturing history and the history of nursing. AB - Historians of nursing are presented with the formidable task of attempting to decipher the history of a group about whom the documents are scarce, and who have rarely, if ever, written about themselves. It can be rather like a lottery searching through archives for documentary evidence, the task is hardly more tractable when the archival material does not exist. It is hard enough to decipher the ideas of our predecessors, virtually impossible when these ideas were written by some other than to whom they refer. This, it could be argued, prevents historians of nursing from undertaking the sort of history expounded by the followers of the positivist tradition, including Geoffrey Elton. For Elton, the documents were everything, and that they above all else should be the point of focus, if they do not exist how can a history of nursing be attempted at all. In 1961 Edward Hallett Carr's, What is History? was published. Richard Evans 36 years later argues that the question is not so much 'What is history?', but 'Is it possible to do history at all?'. In this paper the aim is to identify the difficulties in doing historical research, and also ask a third question, 'What or whom is history for?' PMID- 11624496 TI - Narratives on prolonged baths from psychiatric care in Sweden during the first half of the twentieth century. AB - Prolonged baths were used within psychiatric care in Sweden during the first half of the twentieth century. Eight reports from nursing staff about experiences of prolonged baths were analysed. The aim is to gain a better understanding of what it could have meant for caregivers to give prolonged baths. The nursing staff described their work with the baths as an extremely tiresome and trying duty that was delegated to inexperienced personnel. They regarded the patients as impossible to communicate with verbally. Prolonged baths were said to have been used on 'the most severely disturbed', violent, or untidy patients. The nurses describe the patients' discomfort and protests, but also point out that the baths had the intended effect of calming down disturbed patients. Prolonged baths also functioned as a restraint. PMID- 11624498 TI - The early NHS and the crisis of public health nursing. AB - Establishment of the NHS in 1948 is rightly seen as a major turning point in health care in the United Kingdom. Notwithstanding conditions of severe austerity, the NHS succeeded remarkably well in its basic remit to make all essential medical care available to the entire population, free at point of delivery. The benefits of the new system extended across the entire front of its services. However, it is important to recognise that the reforms of 1948 were uniformly advantageous. It has for instance long been recognised that the NHS failed to bring about the expected transformation in standards of general medical practice. In this short paper the author argues that public health represented a further major sphere of underdevelopment. The fact that, with minor exceptions, public health is the least studied aspect of the early NHS is itself suggestive of its status as the Cinderella of the modern health services. The author also underlines the adverse implications of this inferior position for domiciliary midwifery, district nursing and health visiting. These constituted small but strategically important sectors of nursing, all of which fell under public health administration in the new health service. The author concentrates on the first phase of the NHS, the period between 1948 and 1974, now often regarded as its golden age. For the purposes of this discussion, most of the evidence relates to the formative phase of the new service, when many major policy questions relating to public health were first confronted. It is suggested that the early neglect of public health and its constituent nursing functions has left a legacy of problems that have still not entirely been resolved. For the purposes of this paper the term will be used to embrace the totality of health functions administered by departments of local government in the period from 1948 to 1974. Most of these services fell within the public health departments of local government, headed by the Medical Office of Health (MOH). However, some important functions involving the nurses were located in other departments. Especially important was the School Health Service, which was reformed in 1944, ahead of the NHS. This was a largely independent service under the administration of Local Education Authorities. Some of the problems of public health nursing related to this fragmentation of responsibility. PMID- 11624499 TI - Medical and nursing education in the nineteenth century: comparisons and comments. AB - In the mid-nineteenth century, apprenticeship in medicine, as described by the novelist Mrs Gaskell gradually gave way to a more scientific model. This transition was characterised by a greater theoretical emphasis in the medical curriculum with less clinical practice. Reform of medical schools was however 'patchy', and there was no harmonisation of curricula or examinations until the end of the century. Against this background, nursing was concomitantly struggling to emerge as a distinctive profession. Prototype schools of nursing were established in hospitals after 1860, in which teaching was conducted by Resident Medical Officers and the Matrons. Comparisons between the evolution of medical and nursing education are drawn with reference to admission criteria; curricular models; examinations and outcomes. Underpinning these issues, the questions of the quality of education for medical and nursing students, and the relationship of medical to nursing knowledge, are discussed. PMID- 11624502 TI - Early modern controversies about the one-sex model. AB - This essay traces the opposition of the Galenic notion of a homology between male and female genitalia (the "one-sex model") and identifies the French physician Andre Dulaurens as the first outspoken opponent. After Dulaurens, the German physician Johann Peter Lotichius makes the opposition to that model more clearly an argument that may be called "feminist." PMID- 11624501 TI - Anatomizing the past: physicians and history in Renaissance culture. AB - In many different ways Renaissance physicians concerned themselves with the reading and writing of history. This article examines the role of historical interests in learned medical culture and the participation of physicians in the broader historical culture of the period. PMID- 11624503 TI - The emergence of cognitive science in France. AB - A comparison between the development of cognitive science in France and the USA enables us to analyze some national differences linked to specific connections between the scientific, military, economic and political worlds. The influence of new practices and tools developed during World War II and the Cold War appears to be of crucial importance in understanding the development of this new field, as well as that of cybernetics, computer science, artificial intelligence and molecular biology. This paper can be considered as a study in how the differing contexts in France and the USA shaped the history of the construction of cognitive science in each of these two countries. In spite of various differences, some common aspects may be pointed out: in both cases, computer experts and psychologists using a computational modelling approach were those first engaged in the construction of cognitive science. If in France neuroscience oriented cognitive science research was stronger than in the USA, it seems that the artificial intelligence orientation is also of growing importance in France. PMID- 11624500 TI - The missing relative: the home help service in England and Wales 1918-1974 part 2. AB - Although recent work in social policy has illustrated how the work of home helps means that they straddle the health-social services boundary, there has been relatively little work on the earlier history of this service. In this the second of two articles, the author attempts to remedy this neglect, and considers the development of the home help service in England and Wales between 1918 and 1974, examining the overall evolution of this service. In the second article (to be published in the next issue of the journal), three themes are discussed in greater detail: the issue of training, regional variations in provision, and what home helps actually did for their clients. Although the focus is on England and Wales as a whole, in this second part the author illustrates particular themes through a case study of the Midlands city of Leicester, a local authority in which the home help service was particularly highly developed. Part one was published in the last issue of the International History of Nursing Journal (volume 5, number 1, Winter 1999 issue). PMID- 11624504 TI - Eli Sagan's psychoanalytic anthropology and its interfaces with psychohistory. PMID- 11624505 TI - Descartes the doctor: rationalism and its therapies. AB - During the Scientific Revolution one important gauge of the quality of reformed natural philosophical knowledge was its ability to produce a more effective medical practice. Indeed, it was sometimes thought that philosophers who pretended to possess new and more potent philosophical knowledge might display that possession in personal health and longevity. Rene Descartes repeatedly wrote that a better medical practice was a major aim of his philosophical enterprise. He said that he had made important strides towards achieving that aim, on that basis, he offered practical medical advice to others and advertised the expectation that, taking his own advice, he would live a very long time. This paper describes what Cartesian medicine looked like in practice and what that practice owed to the power of modernist Reason. PMID- 11624506 TI - At the source of western science: the organization of experimentalism at the Accademia del Cimento (1657-1667). AB - The Accademia del Cimento, founded by the Medici princes, Ferdinando II, Grand Duke of Tuscany, and his brother, Leopoldo, later Cardinal, had members and programmes of research very different from earlier academies in Italy. The Cimento foreshadowed later European academies and institutions specifically devoted to research and improvement of natural knowledge. It issued only one publication, the Saggi di naturali esperienze, and most of the observations and experimental results from its brief life remain unpublished. The Roman Accademia fisica-matematica, associated with Queen Christina of Sweden, continued to some extent its emphasis on experiment, while The Royal Society, with which it maintained links, placed even greater reliance on experiment and its validation through unvarnished publication. Comparisons between the Cimento and its contemporaries, The Royal Society and the French academy, illuminate the origin of scientific institutions in the early modern period. PMID- 11624507 TI - "Always affectionately William James" letters to a young lady. PMID- 11624508 TI - Measuring fertility within marriage between 1841 and 1891 using parish registers and the census enumerators' books. PMID- 11624509 TI - Jamie the Saxt's A Counterblaste to tobacco. AB - King James VI of Scotland (Jamie the Saxt) became James I of England in 1603. This led to what is now known as the United Kingdom: indeed the flag, the Union Jack, is named after him. He was probably the best educated king to sit on a European throne, although he often lacked sagacity. He authorised a new translation of the Bible, now known as the King James Bible. He is also remembered for his abhorrence of smoking tobacco, which he ably expressed in A Counterblaste to Tobacco in 1604. PMID- 11624510 TI - Peptic ulcer surgery - an obituary. PMID- 11624511 TI - Early Nigerian doctors, their Edinburgh connection and their contribution to medicine in West Africa. PMID- 11624512 TI - Proust, memory and the Engram. AB - The French novelist Marcel Proust (1871-1922) was born at Auteuil, Paris and was a semi-invalid all his life, cosseted by his mother until her death in 1905 when he was 34 years old. His hitherto 'social butterfly' existence was transformed. He withdrew himself from society and lived in a sound-proof flat giving himself entirely to introspection. Delving into the 'self' below the levels of superficial consciousness, he set himself to transforming into art the realities of experience as known to the inner emotional self. In his monumental 13 volume novel, A la recherche du temps perdu, it is evident how no detail ever escapes the amazingly observant eye of the artist, and how his experience is subjected to close scrutiny and a searching analysis. His characters are described in terms of their concealed emotional lives, evolving in a plane that has nothing to do with temporal dimensions. PMID- 11624513 TI - [Not Available]. AB - The investigation make historical analysis of the fundamental normative documents and publications of medical deontology. It study the rise and enrich of of the medico-deontological rules, which control the behavioral of the Bulgarian physicians during the last century. The authors put accent over the work of the famous Bulgarian legal medical man Professor Ivan Moskov (1894-1952) "Deontology- obligations and rights of the physician and short medical low" (1946). He offers a new division into periods. PMID- 11624514 TI - The pentration of the ideas of Pasteur into the Romanian medicine. PMID- 11624515 TI - [Bulgarian physicians in Western Europe in the Middle Ages]. PMID- 11624516 TI - Breast Cancer death of Empress Theodora, wife of Justinian of Byzantine, in the sixth century; introduction. PMID- 11624517 TI - Why clinical neurology did not appear in the 18th century. PMID- 11624518 TI - [Not Available]. PMID- 11624520 TI - [Not Available]. PMID- 11624521 TI - [Not Available]. AB - The authors investigation the life-work and health of the well-known Bulgarian writer of the Bulgarian national revival (1799-1871), with complex methods. During the summer in 1998 they made investigation and represervation of the heart of Peter Beron, which was preserved in the museum of town Kotel (Museum of the writers of the Bulgarian national revival). They made historical reconstruction of his teeth condition. The investigation was devoted to two hundredth anniversary of doctor Peter Beron. PMID- 11624519 TI - Managed care, economical and medical ethics. PMID- 11624522 TI - [Not Available]. PMID- 11624523 TI - [Not Available]. AB - The development of labour healthcare in Bulgaria is treated from the author in following directions: staff, material and technical security, organization of the activity of the health service of the factories and their interrelations with territorial health establishments etc. The solution of the labour healthcare "problems have to find place during the caring out of the structural reforms of the healthcare" system in Bulgaria. PMID- 11624524 TI - [Not Available]. PMID- 11624525 TI - [Not Available]. AB - The authors are investigated the life and all activity of the man of note since the time of Bulgarian National Renaissance. He graduate Medical Faculty in Bucurest and establish contacts with g.s. Rakovsky, Vasil Levsky and others Bulgarian revolutionary. After his back in Bulgaria he was physician in the town Stara Zagora and Sliven. N. Planinsky, bishop Seraphim, D-r Geogry Mirovich and other create the first society of the Red Cross. With co-operation of P.R. Slaveikov, publish the first Bulgarian newspaper in Sliven "Bulgarian flag". His public activity was illuminate as like as people "representative and functionary of the United". PMID- 11624526 TI - [Not Available]. AB - The authors made medical-historical review of the development of the Health resort in South-West Bulgaria, since the antiquity to our days. Special attention is detached of the investigate of Health resort during the second semi-centennial of the XX century. The authors investigations reflect over the fluoric mineral waters. This type waters are very important for tooth prophylaxis and osteoporosis. Important contribution is the proved stimulating effect of fluoric mineral waters. The type waters are very important for tooth prophylaxis and osteoporosis. Important contribution is the proved stimulating effect of fluoric mineral waters in the village Ognianovo. There the fluorine is 5.5 gram by the litre. PMID- 11624527 TI - [Euthanasia - a historical perspective]. PMID- 11624528 TI - [Not Available]. PMID- 11624529 TI - [Not Available]. AB - Parallel with military physicians in Bulgarian army working and the military orthodox clergy. It is very important factor for success activity soldier's conscious. The author consider, that religious spirit is necessary for soldier and commander. The Moscow's newspaper "Russian world" publish on 23 January, 1913 interview by D-r Socolevsky with military epidemiologist prof. Kraws were the professor said: "The chaplains much help me in the control over the cholera, especially near Chataldga 1912-1913. They saved Bulgaria army from the cholera, this terribly whip." The physicians Sikarsky, Goldmier,Stamatov and others write that the chaplains execute his duty as exemplary hospitals. Command of the military clergy during the period 1912-1918 is Velikoturnovo's bishop losiv (1870 1918). He become ill on the front. PMID- 11624530 TI - [Not Available]. PMID- 11624531 TI - A new approach towards the study of the History of Medicine. PMID- 11624533 TI - [Not Available]. AB - The teaching of Biology at the Medical Faculty in Sofia started in 1918 with Botany and Zoology. Already in the next year, it was radically changed by Metodii Popov: 1. Instead of Botany he introduced General Biology, and instead of Zoology - Parasitology (including a general review of the evolution of non-vertebrate animals) and Comparative Anatomy of the Vertebrates; 2. He adapted the teaching of Biology to the needs of the medical education. Those changes were possible thanks to the considerable medical background of M. Popov - it started in 1911 with suitable specialization and research activities, and continued with the establishment of Department of Biology and the Medical Faculty, and the involvement of medics, besides biologists, in its academic staff. During the past years there have been a lot of changes in the curriculum both in its schedule and contents. Some of them were as a result of the development of the biological science and the integration with the other disciples, but some were forced by the administration. Today the students have 90 hours of lectures and a practical course of 90 hours as well. They have at their disposal textbooks on "Biology", "Parasitology" and "Comparative Anatomy of the Vertebrates", as well as, a "Textbook for the practical Course on Biology". Their knowledge is evaluated during the practical course, at two colloquia, and at a practical and theoretical (oral) exam at the end of the first year of education. PMID- 11624532 TI - Out-of-auditorium activities in teaching of medicine. PMID- 11624534 TI - Veterinary education of Bulgarian prior to the establishment of the Veterinary Faculty in Bulgaria. PMID- 11624535 TI - National and international components in teaching on history of medicine. PMID- 11624537 TI - [Not Available]. PMID- 11624536 TI - [Not Available]. AB - The pharmacists are highly qualified specialists that possess knowledge in the field of biology, chemistry and special medical disciplines. This defines their potential for a realization in different scientific fields. The article points out the place and the role of pharmacists with higher education as leaders in the drug security policy of the country. Here are seen the different fields of realization of the pharmaceutical staff in the pharmacy system, chemical - pharmaceutical and food industry, laboratories for a drug analysis, scientific research institutes, medical control of the social security, and army. The main functions of the pharmacy are formulated as follows: drug delivery, pharmaceutical services and a function connected with health policy. PMID- 11624538 TI - Medical elements in Istria Frescos and Graffitos. PMID- 11624539 TI - [Not Available]. PMID- 11624540 TI - Medicine as science and art in Ancient Greece. PMID- 11624541 TI - [Not Available]. AB - In the paper is made effort to show of the achievement of the clinical sciences during the XX century. The criterion for selection of the medical results, are: the concept, discovery, invention, perfecting. The diagnostics of the disease during XX century is developing since the symptom to the syndrome and diagnosis. Science-technical progress determine the development of the resuscitalogy the cardiosurgery, creation of the pharmacotherapy decrease mortality from infectious diseases. The genetics of inherited disease was cleared during XX century. Arised new sciences like to the neurosurgery, the otoneurology and others. PMID- 11624542 TI - [Not Available]. PMID- 11624543 TI - [Not Available]. PMID- 11624544 TI - [Not Available]. AB - The first record on the hereditary concepts on the nature of heredity and its mechanism, dates back to the 5th, 6th century B.C. The most prominent representatives are philosophers and people of Medicine, their views reflecting the priority philosophical systems in ancient Hellas. During the Middle Ages pre formation theories have been the predominant ones with representatives of the two major trends: ovalists and antimaculists. The ancient Hypothetical concepts for the hereditary processes which go back to the Bulgarian Middle Ages are associated with the first Bulgarian Encyclopedia "Shestodnev" by Joan Ekzarh. The hypothetical concepts on the heredity reflect the theoretical concepts of their authors and find their indirect reflection in Bulgaria by way of the literature in translation which has been wide spread. During the period of the Revival there has been wide spread. During the period of the Revival there has been a strong influence on the concepts of P. Beron, D. Mutev and V. Beron exerted by the mechanical paradigm of the 18th Century. There have been spread widely also the descriptions of the hereditary phenomena in the Bulgarian literature of the Revival. PMID- 11624545 TI - Development and prospects of people's care in the social homes. AB - The article analyses one of the specialized activities of nurses - the care for mentally handicapped people in Holland and Bulgaria. The attention is focused on its deficiency in the social homes, substantiating the necessity of the nursing specialization which seems unfamiliar to us and at the same time already well established in Europe - the social nurse. The major aims of the Bulgarian-Dutch project in this direction have been defined; coordinator from Bulgarian side is the Medical College in Vratsa. PMID- 11624546 TI - [Not Available]. AB - The research study work is connected with certain for evaluation. Their knowledge is a precondition for a more qualitative and efficient work. The research study that took place gave us some notion to what extent the Bulgarian scientists in the field of medicine are aware of these criteria. What is the number of their scientific publications in Bulgarian and foreign magazines during the period 1991 96. The study gives an idea about how many of them have doctors